Natural Products in Vector-Borne Disease Management 0323919421, 9780323919425

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Natural Products in Vector-Borne Disease Management

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Natural Products in Vector-Borne Disease Management

Edited by

Nagendra Singh Chauhan Drugs Testing Laboratory Avam Anusandhan Kendra, Raipur, Chhattisgarh, India

Durgesh Nandini Chauhan Columbia Institute of Pharmacy, Raipur, Chhattisgarh, India

Academic Press is an imprint of Elsevier 125 London Wall, London EC2Y 5AS, United Kingdom 525 B Street, Suite 1650, San Diego, CA 92101, United States 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom Copyright © 2023 Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. ISBN 978-0-323-91942-5 For information on all Academic Press publications visit our website at https://www.elsevier.com/books-and-journals

Publisher: Stacy Masucci Acquisitions Editor: Kattie Washington Editorial Project Manager: Howi M. De Ramos Production Project Manager: Sajana Devasi P K Cover Designer: Greg Harris Typeset by STRAIVE, India

Dedication To my father late Shri Sitaram Singh Chauhan, who stood beside me and gave me strength in each step of my life. My father is my hero and guide, and I follow the path that he has shown me. To Professor Tu Youyou, Nobel Prize laureate, who ­discovered artemisinin and dihydroartemisinin, used to treat malaria.

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Contents Contributors xvii Foreword xxiii Preface xxv

1.

Potentials of natural products in vector-borne diseases management: Current and future perspectives Devyani Rajput, Umesh Kumar Patil, Durgesh Nandini Chauhan, Kamal Shah, and Nagendra Singh Chauhan Introduction 1 Ancient 2 Modern 2 Vector-borne disease and its management 5 Malaria 5 Filariasis 5 Dengue 5 Zika virus 5 Chikungunya 5 Yellow fever virus 6 Miscellaneous 6 Natural products 7 Neem oil 7 Citronella oil 8 Lavender oil 8 Peppermint oil 8 Allium sativum 8 Citrullus colocynthis L. 9 Ocimum basilicum L. 9 Dysoxylum malabaricum 9 Khaya senegalensis 9 Ficus benghalensis 10 Lansium domesticum 10 Moschosma polystachyum 10 Ocimum sanctum 10 Magnolia salicifolia 10

vii

viii  Contents Triphyophyllum peltatum 11 Microcos paniculata 11 S. curtisii 11 Piper longum 11 Pisonia alba 12 Terminalia chebula 12 Mechanism of action of phytochemicals in target insect body 12 Epidemiology 13 WHO guidelines for vector-borne diseases 14 Future prospects 14 Current trends, opportunities, and knowledge gaps in vector-borne diseases management with botanical products 17 Conclusion 18 References 18

2.

Evidence-based review of medicinal plants for the management of onchocerciasis Yaw Duah Boakye, Theresa Appiah Agana, Esther Afua Oteng-Amankwah, Vivian Etsiapa Boamah, and Christian Agyare Introduction 27 Epidemiology 28 Life cycle of Onchocerca volvulus 28 Clinical manifestation and diagnosis of onchocerciasis 29 Current treatment and challenges 30 Models for assessing the antionchocerca activity of plant extracts and isolated compounds 30 Methods used for pinpointing herbal materials and natural products with antionchocerca from published literature 31 Plants used for treating onchocerciasis 31 Annonaceae 31 Apocynaceae 32 Araceae 34 Combretaceae 34 Cucurbitaceae 34 Cyperaceae 35 Euphorbiaceae 36 Fabaceae 37 Flacourtiaceae 39 Lamiaceae 39 Meliaceae 39 Piperaceae 40 Rubiaceae 41 Sapotaceae 42 Verbenaceae 42 Conclusion 42 References 45

Contents ix

3.

Plant-derived compounds as potential treatment for arboviruses Vivaldo Gomes da Costa and Marielena Vogel Saivish Introduction 51 Alphaviruses 52 CHIKV 53 MAYV 53 Flaviviruses 53 Dengue virus 54 Zika virus 54 West Nile virus 55 Japanese encephalitis virus 55 Plant-derived antivirals against arboviruses infections 55 References 58

4.

Natural products in the management of onchocerciasis Ivan Kahwa, Innocent Ayesiga, Sharon Nakalema, Racheal Alinaiswe, Rachel Mbabazi, and Shabnoor Iqbal Introduction 63 Conventional drugs for onchocerciasis and their resistance 65 Ivermectin 65 Moxidectin 65 Ivermectin-albendazole 65 Ivermectin-diethylcarbamazine-albendazole 66 Amocarzine 66 Secondary plant metabolites with antionchocerca activity 66 Pure natural products with antionchocerca activity 73 Safety and toxicity profiles of the natural products agents 74 Mode of action of natural plant products 75 Inhibit polymerization of structural protein 75 Disturb membrane fluidity 76 Conclusion 76 References 76

5.

Combating the vectors and management of vector-borne diseases with essential oil nanoemulsions Anindita Dey, Sumanta Dey, Sanghita Das, Madhumita Majumder, Papiya Nandy, and Ashesh Nandy Introduction What is vector? Types of vectors Types of vector-borne disease Prevention of vectors and management of vector-borne diseases Essential oils Chemical composition of EOs Applications of EOs

82 84 84 85 88 89 90 90

x  Contents Nanoemulsion Properties of NEms Components of NEms Methods for NEms preparation Essential oil nanoemulsion EONEms on vector-borne diseases Concluding remarks References

6.

91 91 94 94 96 96 104 105

Natural product for management of babesiosis Sora Yasri and Viroj Wiwanitkit Introduction 115 Clinical information on babesiosis 115 Role of natural products in management of babesiosis 117 Treatment 117 Prevention 121 Conclusion 121 Conflict of interest 121 References 121 Further reading 123

7.

Antimicrobial peptides, nanocarrier systems, and databases: Therapeutic platform against leishmaniasis Ameer Khusro, Chirom Aarti, and Muhammad Umar Khayam Sahibzada Introduction Global leishmaniasis surveillance: WHO report Currently available leishmaniasis drugs Antimicrobial peptides: An overview AMPs as antileishmanial agents Nanotechnology-based treatment of leishmaniasis Phytocompounds-based nanoformulation as antileishmanial agents Drugs-loaded nanocarrier systems as antileishmanial agents Databases toward developing new antileishmanial drugs Leish-ExP (Leishmania-Exclusive Protein) database LeishBase database Conclusions and future perspective References

8.

125 127 128 130 131 134 134 138 140 140 141 162 163

Marine organisms as natural drug leads in combating vector-borne diseases Fadia S. Youssef Introduction Shedding the light on leishmaniasis Seaweeds (macro-algae) with promising antileishmanial activity

171 172 174

Contents xi

Marine invertebrates with a promising antileishmanial activity 179 Phylum Porifera 179 Phylum Cnidaria 180 Phylum Chordata 181 Phylum Mollusca 182 Phylum Arthropoda 182 Phylum Echinodermata 182 Phylum Ectoprocta 183 Shedding the light on malaria 183 Marine organisms with promising antimalarial activity 185 Shedding the light on trypanosomiasis 188 Marine organisms with promising antitrypanosomal activity 189 References 192

9.

Plant and marine-derived antimalarial agents Marjan Talebi, Saeed Samarghandian, Tahereh Farkhondeh, and Mohsen Talebi Introduction 201 Experiments to assess antimalarial activities of various agents 203 Mechanisms of action (MOA) proposed for isolated antimalarial compounds from natural products 205 Overview of numerous plant and marine-derived antimalarial agents 206 Important plants and marine species with antiplasmodial activities 206 Alkaloids 207 Terpenes and terpenoids 208 Phenolic compounds 209 Other phytochemical compounds 211 Natural products with malaria transmission blocking activity 212 Concluding remarks 212 References 212

10. Natural products in the management of schistosomiasis Tanvir Yusuf Shaikh, Kiran D. Baviskar, Ashish Jain, Kamal Shah, Mohan Lal Kori, and Santram Lodhi Introduction 223 Schistosoma life cycle 225 Pathophysiology 226 Current treatment 228 Chemotherapy 228 Antischistosomal agents of synthetic origin 228 Formulation of vaccine 230 Natural products for management of schistosomiasis 231 Other miscellaneous compounds 246 Conclusion 246 References 247 Further reading 256

xii  Contents

11. An update on antileishmanial agents from natural resources Koushal Billowria, Rouchan Ali, Ram Kumar, and Pooja A. Chawla Introduction 257 Life cycle 258 Natural products in the management of Leishmaniasis 259 Conclusion 282 References 282

12. Plants with antidengue properties: A systematic review Parul Grover, Monika Bhardwaj, Lovekesh Mehta, Pooja A. Chawla, Viney Chawla, and Shubham Sharma Introduction 291 Epidemiology 292 Pathophysiology of dengue fever 293 Symptoms of dengue 293 Transmission of dengue 293 Treatment and management of dengue 295 Plant species used to treat dengue 296 Acacia catechu 296 Allium sativum 296 Andrographis paniculata 296 Anisuan 297 Azadirachta indica 297 Boerhavia diffusa 297 Carapichea ipecacuanha 297 Castanospermum australe 298 Curcuma longa 298 Echinacea 298 Glycyrrhiza glabra 298 Kaempferia parviflora 298 Mimosa scabrella 298 Momordica charantia 299 Myrtopsis corymbosa 299 Papaya leaves 299 Pippli 299 Uncaria tomentosa 300 Zostera marina 300 Conclusion 300 References 305

13. Natural products in Japanese encephalitis Prasanti Sharma, Neelima Sharma, Anoop Kumar, Nagendra Singh Chauhan, and Pooja A. Chawla Introduction Plant extracts in vector control

309 312

Contents xiii

Isolated phytochemicals in vector control Antiviral activity of plant-derived agents and their mechanism of action Conclusion References

319 319 323 327

14. Algae natural products for potential vector-borne disease management Joana Assunção, Helena M. Amaro, and A. Catarina Guedes Introduction 335 Vector-borne diseases characterization and context 336 Algae importance 344 Algae-derived agents against VBD 345 Polysaccharides 345 Pigments 348 Proteins (lectins and griffithsin) 353 Polyphenols 354 Other compounds—Secondary metabolites 354 Alga-based extracts and fractions 359 Alga-based vaccine strategies 363 Alga-based larvicidal strategy 368 Challenges and perspectives 370 References 371

15. Natural products in the management of trypanosomiasis Ritu Tomar, Rahul Tiwari, Rupa Gupta, Samir Bhargava, Dheeraj Bisht, Vijay Singh Rana, and Neeraj Kumar Sethiya Introduction About trypanosomiasis Epidemiology Current therapeutic approaches and associated challenges Natural products in the management of trypanosomiasis Plants against trypanosomiasis (in vitro studies) Marine sources Phytochemical against trypanosomiasis Plants against trypanosomiasis (in vivo studies) Patents Mode of actions Conclusion Conflict of interest Sources of funding Acknowledgment References Further reading

379 380 380 381 382 382 391 391 391 391 391 404 404 404 404 404 411

xiv  Contents

16. Concept of vector-borne diseases in Ayurveda: A review Manindra Mohan Shrivastava, Umesh K. Patil, Kamal Shah, Mayank Krishna Kulshrestha, Durgesh Nandini Chauhan, Awdhesh Prasad, and Nagendra Singh Chauhan Introduction 413 Agantuka roga 413 Janapadodhwamsa 414 Krimi 415 Conclusion 434 References 434

17. Medically important vector-borne disease control through seaweeds against the chikungunya Ramachandran Ishwarya and Baskaralingam Vaseeharan Vector-borne disease Mosquito-borne diseases Chikungunya Vector-borne disease control Vector control Natural products Seaweed Acknowledgments References

437 438 438 440 441 442 443 444 444

18. Nanobiomaterials as novel modules in the delivery of artemisinin and its derivatives for effective management of malaria Krishna Yadav, Deependra Singh, Manju Rawat Singh, Nagendra Singh Chauhan, Sunita Minz, and Madhulika Pradhan Introduction 447 ARTM derivatives 448 ARTM and derivatives: Pharmacokinetics 451 Delivery systems loaded with ARTM and its derivatives 451 Polymer-drug conjugates (poly-drug-con) 451 Micelles 453 Liposomes 453 Nanocapsules 454 Niosomes 455 Ethosomes 455 Solid lipid nanoparticle 455 Nanoparticles 456 Conclusions 458 Acknowledgments 461

Contents xv

Conflict of interest References

461 461

19. Scientific and ethnopharmacological evidence of Carica papaya for the effective management of vector-borne disease Neelesh Malviya, Rajiv Saxena, Ruchi Gupta, and Sapna Malviya Introduction 467 Ethnomedical considerations 470 Pharmacognostical character 470 Origin and distribution 471 Macroscopic character 471 Microscopic characters 477 Phytochemistry 477 Fruits 477 Seeds 481 Leaves 484 Juice 486 Roots 486 Medicinal use of Carica papaya Linn. in vector-borne diseases 487 Antidengue effects 487 Antimalarial activity 489 Chikungunya 490 Agent for vector control in Filariasis 491 Antiviral action against Zika virus (family: Flaviviridae) 491 Japanese encephalitis 491 Chagas disease (American trypanosomiasis) 492 Conclusion 492 References 492 Further reading 497

20. Nanoemulsion as a promising carrier of plant-derived repellents for mosquito-borne malaria control: Nanotechnology aspects António B. Mapossa and Alcides Sitoe Introduction Mosquito repellents for malaria prevention Plant-derived mosquito repellents Controlled release nanotechnology Nanoemulsion as carrier of essential oils (EOs) Preparation of nanoemulsions Characterization of nanoemulsions Stability of the nanoemulsion Application of nanoemulsion in malaria control Conclusions and recommendations

499 500 501 502 505 506 507 508 510 511

xvi  Contents Acknowledgments Conflicts of interest References

512 512 512

21. Insect repellent plants: A recent update S.K. Sukrutha, R. Ramachandra, and Santosh Anand Introduction Alkaloids Terpenoids Saponins Essential oils Conclusion Acknowledgment References

517 518 520 524 526 528 529 529

22. Natural products employed in the management of malaria Katta Santharam, Prabhakar Mishra, Kamal Shah, and Santosh Anand Introduction 533 First-generation natural products against malaria 534 Exploration of antiplasmodial drugs: Discovery of diverse pharmacophores 535 Macrocyclic alkaloids 535 β-Carboline alkaloids 538 Piperidine alkaloids and phenol derivatives 539 Pyrroles 540 Xanthones 541 Phloroglucinols 541 Quinones 542 Anthraquinones 542 Macrolides 543 Terpenes 544 Cyclodepsipeptides as antiplasmodial compounds 545 Natural compounds and their mosquitocidal potential 547 Conclusion 549 Acknowledgment 549 References 550 Index 557

Contributors Numbers in parenthesis indicate the pages on which the authors’ contributions begin.

Chirom Aarti (125), Research Department of Plant Biology and Biotechnology, Loyola College, Chennai, Tamil Nadu, India Theresa Appiah Agana (27), Department of Pharmaceutics, Faculty of Pharmacy and Pharmaceutical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana Christian Agyare  (27), Department of Pharmaceutics, Faculty of Pharmacy and Pharmaceutical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana Rouchan Ali (257), Department of Pharmaceutical Chemistry and Analysis, ISF College of Pharmacy, Moga, Punjab, India Racheal Alinaiswe  (63), Department of Pharmacy, Faculty of Medicine, Mbarara University of Science and Technology, Mbarara, Uganda Helena M. Amaro  (335), CIIMAR/CIMAR-LA—Interdisciplinary Centre of Marine and Environmental Research, University of Porto, Novo Edifício do Terminal de Cruzeiros de Leixões, Avenida General Norton de Matos, Matosinhos, Portugal Santosh Anand (517, 533), Department of Biotechnology, REVA University, Bengaluru, Karnataka, India Joana Assunção  (335), CIIMAR/CIMAR-LA—Interdisciplinary Centre of Marine and Environmental Research, University of Porto, Novo Edifício do Terminal de Cruzeiros de Leixões, Avenida General Norton de Matos, Matosinhos; LEPABE— Laboratory for Process Engineering, Environment, Biotechnology and Energy, University of Porto, Porto, Portugal Innocent Ayesiga  (63), Faculty of Medicine, Mbarara University of Science and Technology, Mbarara, Uganda Kiran D. Baviskar (223), Department of Pharmaceutics, Smt. Sharadchandrika Suresh Patil College of Pharmacy, Chopda, Maharashtra, India Monika Bhardwaj  (291), Natural Product Chemistry Division, Indian Institute of Integrative Medicine, Jammu, Jammu and Kashmir, India Samir Bhargava (379), Faculty of Pharmacy, DIT University, Dehradun, Uttarakhand, India Koushal Billowria (257), Department of Pharmaceutical Chemistry and Analysis, ISF College of Pharmacy, Moga, Punjab, India Dheeraj Bisht (379), Department of Pharmaceutical Sciences, Sir J.C. Bose Technical Campus, Bhimtal, Kumaun University, Nainital, Uttarakhand, India xvii

xviii  Contributors Yaw Duah Boakye  (27), Department of Pharmaceutics, Faculty of Pharmacy and Pharmaceutical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana Vivian Etsiapa Boamah (27), Department of Pharmaceutics, Faculty of Pharmacy and Pharmaceutical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana A. Catarina Guedes (335), CIIMAR/CIMAR-LA—Interdisciplinary Centre of Marine and Environmental Research, University of Porto, Novo Edifício do Terminal de Cruzeiros de Leixões, Avenida General Norton de Matos, Matosinhos, Portugal Durgesh Nandini Chauhan  (1, 413), Columbia Institute of Pharmacy, Raipur, Chhattisgarh, India Nagendra Singh Chauhan  (1, 309, 413, 447), Drugs Testing Laboratory Avam Anusandhan Kendra (State Government Lab of AYUSH), Government Ayurvedic College, Raipur, Chhattisgarh, India Pooja A. Chawla  (257, 291, 309), Department of Pharmaceutical Chemistry and Analysis, ISF College of Pharmacy, Moga, Punjab, India Viney Chawla  (291), Department of Pharmaceutics, University Institute of Pharmaceutical Sciences and Research, Baba Farid University of Health Sciences, Faridkot, Punjab, India Vivaldo Gomes da Costa (51), Department of Cellular Biology, University of Brasília, Brasília, District Federal, Brazil Sanghita Das (81), Department of Physics, Jadavpur University, Kolkata, West Bengal, India Anindita Dey (81), Department of Botany, Asutosh College; Centre for Interdisciplinary Research and Education, Kolkata, West Bengal, India Sumanta Dey (81), Centre for Interdisciplinary Research and Education, Kolkata, West Bengal, India Tahereh Farkhondeh  (201), Faculty of Pharmacy, Birjand University of Medical Sciences, Birjand, Iran Parul Grover  (291), KIET School of Pharmacy, KIET Group of Institutions, DelhiNCR, Ghaziabad, Uttar Pradesh, India Ruchi Gupta  (467), Smriti College of Pharmaceutical Education, Indore, Madhya Pradesh, India Rupa Gupta  (379), Amity Institute of Pharmacy, Amity University; Department of Pharmacy, Sushant University, Gurugram, Haryana, India Shabnoor Iqbal  (63), Department of Zoology, Government College University Faisalabad, Faisalabad, Pakistan Ramachandran Ishwarya (437), Mandapam Regional Centre, ICAR—Central Marine Fisheries Research Institute, Mandapam, Tamil Nadu, India Ashish Jain (223), Department of Pharmaceutical Sciences, Dr. Harisingh Gour Central University, Sagar, Madhya Pradesh, India

Contributors xix

Ivan Kahwa  (63), Pharm-Bio Technology and Traditional Medicine Centre of Excellence; Department of Pharmacy, Faculty of Medicine, Mbarara University of Science and Technology, Mbarara, Uganda Ameer Khusro  (125), Centre for Research and Development, Department of Biotechnology, Hindustan College of Arts & Science, Padur, OMR, Chennai, India Mohan Lal Kori  (223), Vedica College of B. Pharmacy, RKDF University, Bhopal, Madhya Pradesh, India Mayank Krishna Kulshrestha  (413), Department of Rasashastra Avum Bhaisajya Kalpana, Government Ayurveda College, Bilaspur, Chhattisgarh, India Anoop Kumar (309), Department of Pharmacology, Delhi Pharmaceutical Sciences and Research University (DPSRU), New Delhi, India Ram Kumar (257), Department of Pharmaceutical Chemistry and Analysis, ISF College of Pharmacy, Moga, Punjab, India Santram Lodhi  (223), Sri Sathya Sai Institute of Pharmaceutical Sciences, RKDF University, Bhopal, Madhya Pradesh, India Madhumita Majumder (81), Department of Botany, Raidighi College, Raidighi, West Bengal, India Neelesh Malviya (467), Smriti College of Pharmaceutical Education, Indore, Madhya Pradesh, India Sapna Malviya  (467), Modern Institute of Pharmaceutical Science, Indore, Madhya Pradesh, India António B. Mapossa (499), Department of Chemical Engineering, Institute of Applied Materials, University of Pretoria, Pretoria, South Africa Rachel Mbabazi  (63), Department of Pharmacy, Faculty of Medicine, Mbarara University of Science and Technology, Mbarara, Uganda Lovekesh Mehta  (291), Amity Institute of Pharmacy, Amity University, Noida, Uttar Pradesh, India Sunita Minz (447), Department of Pharmacy, Indira Gandhi National Tribal University, Amarkantak, Madhya Pradesh, India Prabhakar Mishra (533), Department of Biotechnology, REVA University, Bengaluru, Karnataka, India Sharon Nakalema  (63), Department of Pharmacy, Faculty of Medicine, Mbarara University of Science and Technology, Mbarara, Uganda Ashesh Nandy (81), Centre for Interdisciplinary Research and Education, Kolkata, West Bengal, India Papiya Nandy (81), Centre for Interdisciplinary Research and Education, Kolkata, West Bengal, India Esther Afua Oteng-Amankwah  (27), Department of Pharmaceutics, Faculty of Pharmacy and Pharmaceutical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana

xx  Contributors Umesh Kumar Patil (1, 413), Phytomedicine and Natural Product Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour Vishwavidyalaya (A Central University), Sagar, Madhya Pradesh, India Madhulika Pradhan  (447), Gracious College of Pharmacy, Abhanpur, Chhattisgarh, India Awdhesh Prasad  (413), Shri N.P.A., Govt. Ayurvedic College, Raipur, Chhattisgarh, India Devyani Rajput  (1), Phytomedicine and Natural Product Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour Vishwavidyalaya (A Central University), Sagar, Madhya Pradesh, India R. Ramachandra (517), Department of Biotechnology, REVA University, Bengaluru, Karnataka, India Vijay Singh Rana (379), Faculty of Pharmacy, DIT University, Dehradun, Uttarakhand, India Muhammad Umar Khayam Sahibzada (125), Department of Pharmacy, The Sahara College Narowal, Narowal, Punjab, Pakistan Marielena Vogel Saivish  (51), Virology Research Laboratory, Department of Dermatological, Infectious and Parasitic Diseases, Faculty of Medicine of São Jose do Rio Preto, São José do Rio Preto, Brazil Saeed Samarghandian (201), Noncommunicable Diseases Research Center, Neyshabur University of Medical Sciences, Neyshabur, Iran Katta Santharam (533), Department of Biotechnology, REVA University, Bengaluru, Karnataka, India Rajiv Saxena  (467), Smriti College of Pharmaceutical Education, Indore, Madhya Pradesh, India Neeraj Kumar Sethiya  (379), Faculty of Pharmacy, DIT University, Dehradun, Uttarakhand, India Kamal Shah (1, 223, 413, 533), Institute of Pharmaceutical Research, GLA University, Mathura, Uttar Pradesh, India Tanvir Yusuf Shaikh  (223), Department of Pharmaceutics, Smt. Sharadchandrika Suresh Patil College of Pharmacy, Chopda, Maharashtra, India Neelima Sharma (309), Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Jharkhand, India Prasanti Sharma (309), Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Jharkhand, India Shubham Sharma  (291), KIET School of Pharmacy, KIET Group of Institutions, Delhi-NCR, Ghaziabad, Uttar Pradesh, India Manindra Mohan Shrivastava  (413), Shri N.P.A., Govt. Ayurvedic College, Raipur, Chhattisgarh, India Deependra Singh  (447), University Institute of Pharmacy, Pt. Ravishankar Shukla University, Raipur, Chhattisgarh, India

Contributors xxi

Manju Rawat Singh (447), University Institute of Pharmacy, Pt. Ravishankar Shukla University, Raipur, Chhattisgarh, India Alcides Sitoe (499), Department of Chemistry, Eduardo Mondlane University, Maputo, Mozambique S.K. Sukrutha (517), Department of Microbiology, Jnanabharathi Campus, Bangalore University, Bengaluru, Karnataka, India Marjan Talebi  (201), Department of Pharmacognosy, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran Mohsen Talebi (201), Department of Chemistry and Biochemistry, University of Texas at Arlington, Arlington, TX, United States Rahul Tiwari  (379), Faculty of Pharmacy, DIT University, Dehradun, Uttarakhand, India Ritu Tomar (379), Faculty of Pharmacy, DIT University, Dehradun, Uttarakhand, India Baskaralingam Vaseeharan  (437), Biomaterials and Biotechnology in Animal Health Lab, Department of Animal Health and Management, Alagappa University, Karaikudi, Tamil Nadu, India Viroj Wiwanitkit  (115), Dr DY Patil University, Pune, India; Department of Eastern Medicine, Government College University Faisalabad, Faisalabad, Pakistan; Hainan Medical University, Haikou, China; Faculty of Medicine, University of Nis, Nis, Serbia; Joseph Ayobalola University, Ikeji-Arakeji, Nigeria; Suranaree Institute of Technology, Nakhorn Ratchasima, Thailand Krishna Yadav  (447), Raipur Institute of Pharmaceutical Education and Research, Sarona, Raipur; University Institute of Pharmacy, Pt. Ravishankar Shukla University, Raipur, Chhattisgarh, India Sora Yasri (115), KMT Center, Bangkok, Thailand Fadia S. Youssef  (171), Department of Pharmacognosy, Faculty of Pharmacy, AinShams University, Abbasia, Cairo, Egypt

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Foreword

This book titled Natural Products in Vector-Borne Disease Management is an informative compilation of the role of various plants and their active constituent in the treatment and their mechanisms of action in various vector-borne diseases, especially Malaria, Dengue, and Encephalitis. This book will be of value and interest to both postgraduate students and research students working in the area of natural products as well as allied sciences branches, e.g., microbiology, drug delivery, biotechnology, pharmacognosy, and toxicology. The book will benefit all scientific community, especially clinicians and pharmacists involved in all treatment of vector-borne diseases. I applaud the editors—Dr. N.S. Chauhan who has been my student for many years at the Department of Pharmaceutical Sciences, Dr. H.S. Gour University and Smt. Durgesh Nandini Chauhan—for their excellent compilation of chapters contributed by well-known scientists and academicians from different countries. All 22 chapters are different from each other in content, but share a single objective of role of natural product in various vector-borne diseases. The most noteworthy chapters include “Scientific and ethnopharmacological evidence of Carica papaya for the effective management of vector-borne disease,” “Concept of vector-borne diseases in Ayurveda: A review,” and “Nanobiomaterials as novel modules in the delivery of artemisinin and its derivatives for effective management of malaria.”

xxiii

xxiv  Foreword

This book is an attempt to bring together the views, expertise, and experiences of leaders in the research and development of natural products. The authors successfully navigate the chapter contents with updated literature. I believe this book will remain a valuable resource for years to come. a

V.K. Dixita,b Department of Pharmaceutical Sciences, Dr. Harisingh Gour University, Sagar, Madhya Pradesh, India b Faculty of Technology, Dr. Harisingh Gour University, Sagar, Madhya Pradesh, India

Preface This book, Natural Products in Vector Borne Disease Management, explores a wide range of topics related to the role of natural products from plants or marine sources used in various types of vector-borne diseases, in chapters written by leading industrial and academic experts in the field. Therefore, this book will offer guidance to current, new, and future researchers working in the field of phytopharmaceuticals, ethnopharmacology, ethnomedicine, alternative medicine, clinical medicine, and microbiology. This book covers the role of natural products in various vector-borne diseases like onchocerciasis, babesiosis, arboviruses, leishmaniosis, schistosomiasis, encephalitis trypanosomiasis, chikungunya, malaria, and dengue. The book has 22 chapters. Chapter 1 discusses natural products in vector-borne disease management. Chapters 2, 3, 4, 6, 10, 11, 12, 13, 15, and 22 explore the role of natural products for the management of onchocerciasis arboviruses, babesiosis, schistosomiasis, leishmanial, dengue, encephalitis, trypanosomiasis, and malaria vectors. Chapters 5, 7, 18, and 20 demonstrate the impact of drug delivery systems like nanobiomaterials and nanoemulsions in various vectorborne diseases like leishmaniasis and malaria. Chapters 8, 9, 14, and 17 extend an expert opinion on marine natural products in vector-borne disease management Chapter 16 discusses the importance of Ayurveda in vector-born disease management, Chapter  19 explores the role of Carica papaya in the effective management of vector-borne disease, and Chapter 21 discusses insect-repellent plants. This book is valuable for all professionals involved in the prevention, diagnosis, and treatment of vector-borne diseases using natural products. The book provides cutting-edge updated information and future perspectives on natural product bioactives as emerging sources of lead compounds for new drug discovery against vector borne diseases, which offer possible hope for the cure of these fatal diseases. This work could not have been completed in a timely manner without the cooperation of the contributors, and their expertise and time in the production of this volume. Individually, the authors are the leaders in their field, and collectively, they embody an international collection of knowledge and experience in the phytochemical and pharmacology of natural products, to whom we are very grateful.

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xxvi  Preface

We would like to express our sincere gratitude and thanks to helpful Elsevier/ Academic Press editorial team members including Howi M. De Ramos, Selvaraj Raviraj, P.K. Sajana Devasi, and Kattie Washington for their continued support, cooperation, and assistance. We deeply appreciate my long-term mentor Prof. V.K. Dixit, who taught me something new in every conversation. Finally, I would like to thank my daughters Harshita and Ishita, for their love, understanding, support, and encouragement while this book was being written. We hope that you enjoy reading our book. Nagendra Singh Chauhan Durgesh Nandini Chauhan

Chapter 1

Potentials of natural products in vector-borne diseases management: Current and future perspectives Devyani Rajputa, Umesh Kumar Patila, Durgesh Nandini Chauhanb, Kamal Shahc, and Nagendra Singh Chauhand a

Phytomedicine and Natural Product Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour Vishwavidyalaya (A Central University), Sagar, Madhya Pradesh, India, bColumbia Institute of Pharmacy, Raipur, Chhattisgarh, India, cInstitute of Pharmaceutical Research, GLA University, Mathura, Uttar Pradesh, India, dDrugs Testing Laboratory Avam Anusandhan Kendra (State Government Lab of AYUSH), Government Ayurvedic College, Raipur, Chhattisgarh, India

Introduction An infectious pathogen transmits from an infected human or animal host to an uninfected one by a vector, which is an organism. Arthropods are most frequently used as vectors. Dengue, malaria, Zika virus, yellow fever, chikungunya, onchocerciasis, schistosomiasis, lymphatic filariasis, leishmaniasis, Chagas disease, and Japanese encephalitis are among the most common vector-borne diseases in the world, according to the World Health Organization. Lyme disease, tickborne encephalitis, African trypanosomiasis, and West Nile fever are additional vector-borne illnesses that are significant in the region. The majority of vectorborne diseases are found in low- and middle-income nations that are tropical or subtropical in climate (Djalante, 2019; Wachsmuth et al., 2018). The World Health Organization (WHO) estimates that higher than 1 million people die every year as a result of vector-borne illnesses (VBDs), which make up more than 17% of all infectious diseases. A capable vector, such as a mosquito, midge, or fly, transmits vector-borne diseases from one person to another (Lemon & Institute of Medicine U.S. Forum on Microbial Threats, 2008). Numerous VBDs are categorized as neglected tropical diseases (NTDs), including onchocerciasis, leishmaniasis, human African trypanosomiasis (HAT), and arboviral illnesses including dengue and chikungunya. Prioritization and funding for NTD research have lagged until the last 5 to 10 years, and the burden Natural Products in Vector-Borne Disease Management. https://doi.org/10.1016/B978-0-323-91942-5.00015-X Copyright © 2023 Elsevier Inc. All rights reserved.

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of these diseases is little recognized. We still do not fully understand key facets of NTD biology, prevention, and epidemiology. While there are fewer deaths from vector-borne NTDs than from malaria globally, these diseases nonetheless generate high rates of morbidity and place a considerable cost on public health; for example, dengue infections grew by about 450% globally from 1990 to 2013 (Undp et al., n.d.-a; Wilson et al., 2020). A few zoonotic NTDs also provide a veterinary health risk. The main way for regulating many VBDs both historically and currently is vector control. Additionally, vector control is now the sole available strategy to safeguard populations against various infections, including West Nile disease, chikungunya, Zika, and dengue (for which a vaccine is licensed but not widely utilized due to safety concerns). By minimizing or preventing human interaction with the vector, vector control seeks to reduce the spread of infections. Targeting young vectors can be accomplished by using larvicides, predator species, chemical or biological larvicides, or by removing suitable aquatic habitats (e.g., habitat modification or manipulation). Adult vectors can be gotten rid of using methods like indoor residual spraying (IRS), space spraying, and others that kill adult vectors and/or minimize adult vector interactions (blood-feeding success) with human and/or animal reservoir hosts (e.g., topical repellents, house screening, insecticide-treated bed nets [ITNs], insecticide-treated dog collars). A number of cutting-edge vector control techniques are also being developed, such as genetically altering mosquitoes, infecting vectors with bacteria (like Wolbachia), and treating eaves tubes with insecticide (Takken and van den Berg, 2019; Undp et al., n.d.-b; Walther et al., 2016).

Ancient Ayurvedic system of medication looked into causes, indication, and remedial options for a numeral of diseases, such as transmissible diseases. It covers pathogenic with nonpathogenic organisms which are found in the human body. It also includes parasite, worm, and other microbe descriptions. Ayurveda researcher provided details on pathogenic organisms, including their types and nature, with their role in disease progression. Ayurveda describes on epidemics and infectious diseases which connects to the vector-borne diseases management. The Ayurvedic physician also discussed natural treatment options for vector-borne diseases, such as the use of plants and plant-based formulations. Ayurveda is the world’s oldest scientifically codified medical system. According to Ayurveda, there are three types of transmissible diseases: Agantukaroga, Janapadodhwamsa, and Krimi.

Modern Vector control strategies Insecticides, predators, pathogens, lure-and-kill trapping, environmental management, and other techniques are used to “suppress” the vector population,

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while “vector population replacement” involves genetically modifying the vector so that it either stops reproducing its nonviable generations, or it loses the capacity to reproduce or spread disease (de Rossiter Corrêa et al., 2004). Biochemical strategies ● India employs pesticides such as organochlorines (DDT), organophosphates (malathion), and particular classes of synthetic pyrethroids for indoor residual spraying (IRS), fogging, and aerial spraying (deltamethrin, cyfluthrin, alpha-cypermethrin, lambda-cyhalothrin, etc.) (Poopathi and Tyagi, 2006). ● The WHO has approved the treatment of water for larvae with temephos and Bti. Biological control agents ● Biological agents can be employed to target several mosquito life stages, including parasites, viruses, and predators. To reduce the number of mosquito larvae, viruses, fungi, bacteria, fish, predatory insects like dragonflies and copepods, and notonectids have all been used. ● Materials that have been insecticide-treated, such as long-lasting insecticide nets (LLIN). ● It consists of wall hangings, window curtains, insecticide-treated nets (ITNs), and long-lasting insecticide nets (LLINs), the need for which has risen recently (Sinh Nam et al., 2000). Repellents ● Repellents are created using chemical substances that have an unpleasant taste or smell to mosquitoes. ● Better repellent plants belong to different families, for example, Poaceae family—particularly Cymbopogon species—being the dominant one. Asteraceae, Fabaceae, and Lamiaceae species all exhibit encouraging outcomes. ● Indalone, N,N-diethyl-m-toluamide, and dimethylphthalate 2-ethyl-1, ­3-hexane diol (Rutgers 612) are examples of synthetic compounds that have been utilized as repellents (DEET) (Tisgratog et al., 2016). Insect traps ● The ovitrap, also known as an oviposition trap, was primarily created for the purpose of monitoring Aedes vectors. Later, it was modified to make it deadly to Aedes aegypti adults or larvae. ● Use of a propane-burning apparatus that produces CO2, heat, and water vapor attracts mosquitoes to the flame. A relatively modern way of eliminating mosquitoes without the use of harmful chemicals involves drawing them into a net or holder where they are gathered (Kline, 2007; Table 1).

TABLE 1  Synthetic drugs available for vector-borne diseases and their side effects. S. no.

Drug

Uses

Side effect

References

1.

Albendazole

Albendazole, an antihelminthic drug, can be used to treat a variety of parasitic worm infestations, including ascariasis, filariasis, or roundworm disease, giardiasis, trichuriasis, pinworm disease, neurocysticercosis, and hydatid disease

Stomach aches, headaches, vomiting, dizziness, and reversible hair loss

Horton (2000)

2.

Artemether and lumefantrine

Antimalarial medication called artemether and lumefantrine is prescribed for malaria

Headache, lightheadedness, weakness, soreness in the muscles or joints, exhaustion, trouble getting or keeping asleep, vomiting, and loss of appetite

Adaramoye et al. (2008)

3.

Atovaquone

Antibiotic atovaquone is used for treating malaria in conjunction with proguanil, toxoplasmosis, and Pneumocystis pneumonia (PCP)

Anxiety, nausea, diarrhea, headache, dizziness

Baggish and Hill (2002)

4.

Chloroquine

Lupus erythematosus, rheumatoid arthritis, and COVID-19 infection are all conditions treated with chloroquine

Upset stomach, headache, nausea, loss of appetite, stomach pain, rash, itching

Carvalho (2020)

5.

Hydroxychloroquine

Antimalarial medication hydroxychloroquine is used for lupus erythematosus, rheumatoid arthritis, and malaria

Nausea, dizziness, loss of appetite, diarrhea, rash, headache stomach pain, vomiting

Sharma (1998)

6.

Mefloquine

Antimalarial medication mefloquine is recommended for treating malaria

Vivid dreams, visual disturbances, anxiety, difficulty in sleeping, dizziness

Ritchie et al. (2013)

7.

Pentamidine

Pentamidine is an antibiotic that is used to treat yeast infections, leishmaniasis, and pneumonia

Chest pain or congestion, coughing, difficulty in swallowing, skin rash, wheezing, burning pain, dryness

Hellier et al. (2000)

8.

Quinine

Quinine is an antimalarial medication that is recommended for both malaria and leg cramps at night

Blurred vision, change in color vision, changes in behavior, confusion, diarrhea, hearing loss, ringing in the ears

Man-SonHing et al. (1998)

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Vector-borne disease and its management Malaria Approximately three billion people live in more than 80 countries where malaria is endemic and spread by anopheline mosquitoes. Sub-Saharan Africa is the area in the globe with the highest prevalence of malaria, accounting for more than 85% of cases and 90% of fatalities, the majority of which are children under the age of 5. Malaria continues to have a very detrimental influence on public health, with 228 million cases reported worldwide, of which 213 million (93%) were reported in Africa alone. Recent big outbreaks have wreaked havoc in many places (Tuteja, 2007).

Filariasis Wuchereria bancrofti and Brugia spp. are two mosquito-transmitted pathogens that can produce a variety of clinical manifestations (including lymphedema in more than 15 million people and hydrocele in 25 million males), and at least 36 million people still have these symptoms of chronic illness. But it is clear that reducing its vectors is necessary for eradicating lymphatic filariasis (Taylor et al., 2010).

Dengue The dengue virus, which has four different serotypes, is caused by the flaviviridae family. With 3.6 billion people living in areas at risk of transmission and hundreds of millions of dengue fever cases recorded each year, it is currently the most common arthropod-borne viral disease affecting humans and is responsible for continuing epidemics in many nations (Kularatne, 2015).

Zika virus Numerous nations in Latin America and the Pacific also have continuing outbreaks brought on by the flaviviridae. While Aedes albopictus is regarded as a secondary vector, Aedes aegypti is thought to be the main vector connected to ZIKV outbreaks. But this virus’s incidence and dissemination are also influenced by a number of additional species. It is currently regarded as one of the diseases that poses the greatest threat to public health (Musso and Gubler, 2016).

Chikungunya The togaviridae family is the cause of chikungunya fever (CHIKF), which is characterized by an antalgic stance gait and excruciating articular pain. Up to 90% of people with infection who progress to the chronic stage may do so (52%

6  Natural products in vector-borne disease management

in the American continent). Recently, a number of outbreaks have been reported in a number of nations (Vu et al., 2017).

Yellow fever virus Flaviviridae is a hemorrhagic, possibly fatal RNA virus that causes outbreaks in a number of nations, particularly in populations that have not received vaccinations. It emerges in cycles, with outbreaks spaced roughly 7–10 years apart. In the summer of 2016, 42 nations detected a danger of transmission, with 29 of them in Africa in 2017. In addition, 47 nations declared YFV endemic. Numerous outbreaks are still being documented, with the highest fatality rate of up to 33.6%. The safest, most affordable, and most efficient means to prevent YF is vaccination; “70 to 90 million doses are generated worldwide annually (Douam and Ploss, 2018).”

Miscellaneous In each year, the WHO reports 67,000 cases of Japanese encephalitis, of which 20 to 30% result in death and 30% to 50% of survivors develop severe neurological complications. It is still possible to find new strains that are genetically related to bacteria that were present in earlier epidemics. The main arbovirus responsible for epidemic encephalitis in the United States was the St. Louis encephalitis virus (Diaz et al., 2018). Numerous cases are being caused by its resurgence. Horses are the domesticated species that contract the West Nile virus most frequently, much like humans do. Neurological symptoms are the most frequently reported symptom in 80% of instances, and 90% of those 20% who do exhibit clinical signs pass away. However, recent outbreaks involving people have received attention. It is common to find different pathogenic blood-borne bacteria in mosquitoes (Petersen and Roehrig, 2001). It is not yet known if these bacteria can develop and eventually spread during blood meals or if their presence in mosquitoes can be related to their uncommon ingestion of blood meals or environmental acquisition. In adult mosquitoes, various pathogenic alpha-proteobacteria have been discovered (xeno-monitoring studies), including Ehrlichia spp., Anaplasma spp., Bartonella spp., Candidatus Neoehrlichia, and Rickettsia spp. More intriguingly, research has revealed that Anopheles mosquitoes may be capable of transmitting the rickettsiosis-causing agent Rickettsia felis, which causes fever rickettsiosis. The principal vector of the disease in Sweden and Finland is mosquitoes (Aedes), which are first known to carry Francisella tularensis. There are many complex factors that may explain the spread of these diseases; however, climate change and population growth continue to be the main ones. Inadequate vector-control efforts, limited access to high-quality healthcare, rapid and unplanned urbanization of tropical regions combined with unsanitary conditions, and a deterioration of public health infrastructures are just a few of the factors that may be involved (Gofton et al., 2015; Grech-Angelini et al., 2020; Hodžić et al., 2015; Table 2).

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TABLE 2  Types of vector-borne diseases and their causative agents. Vector

Species

Diseases

Mosquitoes

Culex quinquefasciatus

Lymphatic filariasis

Anopheles

Malaria, lymphatic filariasis (in Africa)

Culex species

Japanese encephalitis

Aedes albopictus

Chikungunya, dengue, west nile virus

Haemagogus

Yellow fever

Aedes aegypti

Dengue, yellow fever, chikungunya, zika virus

Flies

Sandflies

Leishmaniasis, sandfly fever (phlebotomus fever)

Flies

Flies (various species)

Human African trypanosomiasis, onchocerciasis (river blindness)

Ticks

Crimean-Congo hemorrhagic fever, tick-borne encephalitis, typhus, lyme disease, relapsing fever (borreliosis), rickettsial diseases (spotted fever and Q fever), tularaemia

Cyclops

Dracunculiasis (guinea worm disease)

Aquatic snails

Schistosomiasis (bilharziasis)

Bugs

Triatomine bugs

Chagas diseases (American trypanosomiasis)

Natural products The world of plants contains a vast, untapped reservoir of phytochemicals that could be widely utilized in mosquito control programs in place of industrial insecticides. It has been shown that certain plant-derived secondary components, such as isoflavonoids, steroids, alkaloids, terpenes, pterocarps, and lignans, have the capacity to kill mosquito larvae depending on their chemical make-up. They also reported the isolation of several bioactive toxic components from various plants and described how lethal each of these components was to various mosquito species (Shaalan et al., 2005).

Neem oil Azadirchata indica is indigenous to India and other Southeast Asian nations; the neem tree is an evergreen tropical tree. Neem is a member of the Meliaceae plant family (Islas et al., 2020). Azadirachtin, Nimbidol, Nimbin, Sodium ­nimbinate

8  Natural products in vector-borne disease management

Nimbidin, Gedunin, Salannin, and Quercetin are the active ingredients in the use of neem oil as an insecticide. The ability of neem to naturally repel mosquitoes is a crucial tool in the war against malaria. By altering their behavior and physiology, neem derivatives kill almost 500 pests, including ticks, mites, insects, and nematodes, around the world. Neem typically repels bugs and stunts their growth rather than immediately killing them. Neem treatments are ideal for pest control in rural areas since they are reasonably priced, safe for use on higher animals, and attract the most beneficial insects (Chauhan et al., 2018; Singh, 2019).

Citronella oil Cymbopogon winterianus Jowitt (Cardiopteridaceae) is a native of tropical Asia and India. It is a common herb in Asian cooking (Afzal et  al., 2018). Active ingredients include citronellal, geraniol, and citronellol are all abundant in Cymbopogon winterianus essential oil. Various ingredients in citronella include l-limonene, citronellyl acetate, ellemol, and other sesquiterpene alcohols. The best option is typically citronella oil because it is a safe, natural alternative to pharmaceutical insect repellents like DEET. They come in the form of solid goods like candles and cartridges that repel insects using citronella oil. In addition, citronella oil is applied as tablets or pellets around trees and plants as well as in outdoor living spaces (Dutta et al., 2016; Wany et al., 2013).

Lavender oil Lavender, True Lavender, Garden Lavender, Lavanda, and Lavandula are other names for Lavandula angustifolia (family Lamiaceae) (De et al., 2012). It is a perennial plant that is evergreen. Active components consist of pinene, linalyl acetate, geraniol, linalool, cineol, limonene, borneol, and tannins are some of the therapeutic substances found in it (Geetha and Roy, 2014).

Peppermint oil A perennial herb, Mentha piperita L (Labiatae), grows 30–90 cm tall. Square, branching stems that are either upright or rising and always have a quadrangular top (Ilyina et  al., 2017). Peppermint oil is watery in viscosity, transparent to pale yellow in color, and has a fresh, menthol-like aroma. Menthone is an active component. p-Menthane-3,8-diol is a significant breakdown product of menthol, the alcohol present in mint oils used as a peppermint flavoring. The EPA has authorized the use of p-menthane-3,8-diol as a mosquito repellant since 2000. The essential oil of Mentha piperita shows outstanding and potential anti-Aedes aegypti adult repellant properties (Regnault-Roger et al., 2012; Werrie et al., 2020).

Allium sativum Garlic is the common name for Allium sativum L. Oil bulbs have been proven to have larvicidal effect against Culex pipiens mosquito larva, while garlic extracts

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are used to kill Anopheles stephensi and Culex quinquefasciatus mosquito larva (Cheraghi Niroumand et al., 2016; Muturi et al., 2018).

Citrullus colocynthis L. Bitter cucumber, bitter apple, and desert ground are common names for Citrullus colocynthis L. Schrad. A medical herb called Citrullus colocynthis is utilized as a mosquito repellent that also kills mosquito eggs and larvae (Afzal et al., 2018). Leaf extracts from Citrullus colocynthis have larvicidal effects on Culex quinquefasciatus larvae in their early fourth instar. Extracts from the entire plant kill the early fourth instar larva of Anopheles stephensi, while extracts from the plant’s seeds also kill the third instar larvae of Culex quinquefasciatus and Anopheles stephensi (Pravin et al., 2013; Rahuman et al., 2008).

Ocimum basilicum L. Culex quinquefasciatus, Anopheles stephensi, and some female Culex pipiens mosquito species are repulsed by the essential oils of Ocimum basilicum, popularly known as great basil. Ocimum basilicum plant stem extracts have larvicidal effects on Culex quinquefasciatus larvae (Moore, 2006; Paulraj and Ignacimuthu, n.d.).

Dysoxylum malabaricum This plant, commonly known as white cedar, was investigated for larvicidal, pupicidal, adulticidal, and antiovipositional effects against Anopheles stephensi using methanolic preparations of the leaves (Senthil Nathan et al., 2006). Anopheles stephensi is 90% larvicidal, pupicidal, and adulticidal when the plant is extracted with 4% methanol. By preventing the adult mosquitoes’ reproductive cycle, it also reduces the population rate. Researchers used 3-, 24-, and ­25-trihydroxycycloartane and beddomeilactone with ethyl acetate-extracted Dysoxylum malabaricum to measure the larvicidal, pupicidal, and adulticidal activities against Anopheles stephensi. Three, twenty-four, and twenty-five trihydroxycycloartane and beddomeilactone, both of which limit Anopheles stephensi’s growth, had a 90% larval mortality rate at 10 ppm concentration (Masur et al., 2014).

Khaya senegalensis Khaya senegalensis is also known as Khaya wood and African Mahogany. The plant’s seeds are extracted using acetone, ethanol, hexane, and methanol, among other solvents (Shaalan et al., 2006). The effectiveness of these extracts against Culex annulirostris was investigated. At varied concentrations, various seed extracts were used, including acetone (12 mg/L), ethanol (5.1), hexane (5.08), and methanol (7.62). At a concentration of 100 mg/L with LC50, these extracts have a 100% death rate (Mukaila et al., 2021).

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Ficus benghalensis Banyan, also known as Ficus benghalensis, is toxic to Culex quinquefasciatus and Anopheles stephensi mosquito species (Govindarajan et al., 2011b). This plant has been shown to be larvicidal against various Culex and Anopheles mosquito larval stages. Chi-square test was used to obtain the 95% confidence limits for the data at LC50 and LC90 values. Early, second, third, and fourth instar larvae of Culex quinquefasciatus and Anopheles stephensi are resistant to the methanolic extracts of Ficus benghalensis, which are used as larvicides (Khaliq and Abdul Khaliq, 2017).

Lansium domesticum Lansium domesticum is also known as langsat. Aqueous solution is used to extract parts of this plant, and the resulting substance has larvicidal effects on Culex quinquefasciatus (Klungsupya et al., 2015).

Moschosma polystachyum The mosquito species Culex quinquefasciatus was used to assess the herb Moschosma polystachyum’s toxicity (Maheswaran and Ignacimuthu, 2013). At concentrations of 1.0 and 2.5 mg/cm2, the active ingredient octacosane provided protection for 85.2±1.7 min and 54.6±2.3 min, respectively. Octacosane’s overall percentage of protection was 96.2±0.9 at a concentration of 2.5 mg/cm2 and 86.4±1.3 at a concentration of 1.0 mg/cm2 (Govindarajan et al., 2011a).

Ocimum sanctum Utilizing mosquito bioassay-guided fractionation, the hexane extract of Ocimum sanctum was examined and produced components 1 and 2 (Kelm and Nair, 1998). NMR spectral data from the 1H and 13C bands were used to determine the structures of these substances. The substances eugenol (1) and (E)-6hydroxy-4,6-dimethyl-3-heptene-2-one (2) demonstrated mosquitocidal effect on fourth-instar Aedes aegyptii larvae at 200 and 6.25 g mL−1 in 24 h, respectively (Rahuman et al., 2008).

Magnolia salicifolia Six mosquitocidal chemicals were obtained from Magnolia salicifolia after bioassay-guided isolation and purification. When separated from the bark, geranial and neral caused 100 ppm in 24 h of 100% mortality in 4th instar Aedes aegypti (Kishore et al., 2014). At 20 ppm in 24 h, trans-anethole from the leaves showed 100% death in Aedes aegypti 4th instars. Methyl eugenol from the leaves and isomethyl eugenol isolated from leaves, fruits, and flowers, respectively, both demonstrated 100% death in 4th instar Aedes aegypti after 24 h at 60

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and 80 ppm. The sesquiterpene lactone costunolide, which was first discovered in the fruits of Magnolia salicifolia, caused Aedes aegypti of the fourth instar to die completely within 24 h (Tamaki et al., 2018; Tsuruga et al., 1984).

Triphyophyllum peltatum The root bark of Triphyophyllum peltatum yielded the novel naphthylisoquinoline alkaloid 5′-O-demethyldioncophylline A (Bringmann et  al., 1998). A bromination-benzylation process substantially aided in its ordinarily challenging separation from the primary alkaloid, dioncophylline A, which was the dominant component. The resulting derivative made it possible to conduct an anomalous X-ray diffraction crystal structure research, which verified the novel alkaloid’s entire absolute stereostructure. The validity of the structure was further strengthened by a partial synthesis from dioncopeltine A. It was demonstrated that the natural product has antimalarial effects on erythrocytic Plasmodium falciparum (Li et al., 2017).

Microcos paniculata An innovative alkaloid (N-methyl-6 beta-(deca-1′,3′,5′-trienyl)-3 ­beta-methoxy-2 beta-methylpiperidine) discovered in the stem bark of Microcos paniculata has demonstrated effective insecticidal activity against Aedes aegypti second instar larvae (Abdullah Aziz et al., 2013).

S. curtisii A new pentacyclic Stemona alkaloid with a pyrido[1,2-a]azepine A,B-ring system named stemocurtisinol and the well-known pyrrolo[1,2-a]azepine alkaloid oxyprotostemonine have been discovered from a root extract of Stemona curtisii. X-ray crystallography and spectral data interpretation were used to identify the structure and relative stereochemistry of stemocurtisinol. Its C-4 and C-19 positions are in the opposite configuration as oxystemokerrin, of which it is a diastereoisomer. On mosquito larvae, the various alkaloid components had a considerable larvicidal effect (IC(50) 4–39 ppm) (Anopheles minimus HO) (Mungkornasawakul et al., 2004; Online Research Online, 2005).

Piper longum After 24 h, it was discovered that a methanol extract of Piper longum fruit was effective at 10 microg/ml against Culex pipiens pallens mosquito larvae. This activity was discovered to be caused by the piperidine alkaloid pipernonaline, whose 24-h median lethal dose (LD50) was 0.21 mg/liter. The three organophosphorous insecticides malathion, chlorpyrifos-methyl, and pirimiphos-methyl, which were utilized for comparison in this investigation, had LD50 values that were not significantly greater than those of pipernonaline (Rahuman et al., 2008).

12  Natural products in vector-borne disease management

Pisonia alba Pisonia alba leaf extracts were examined for their ability to kill mosquitoes such as Aedes aegypti, Anopheles stephensi, and Culex quinquefasciatus (Baranitharan et al., 2019). The 24-h LC50 values of the Pisonia alba extracts were evaluated by Probit analysis after 25 early fourth instar larvae of Anopheles stephensi, Culex quinquefasciatus, and Aedes aegypti (Anopheles stephensi, Culex quinquefasciatus, and Aedes aegypti) were exposed to various concentrations (50–250,106) (Thakur et al., 2017).

Terminalia chebula Hexane, benzene, ethyl acetate, methanol, and chloroform extracts of Terminalia chebula were tested for their toxicity against these three key vector mosquitoes (Culex quinquefasciatus, Anopheles stephensi, Aedes aegypti) (Veni et al., 2017). Larval mortality was seen 24 h after exposure. The Terminalia chebula methanol extract had LC50 values of 87.13, 93.24, and 111.98 ppm against the larvae of Anopheles stephensi, Aedes aegypti, and Culex quinquefasciatus, respectively. All extracts demonstrated a modest larvicidal effect (Thanigaivel et al., 2017).

Mechanism of action of phytochemicals in target insect body Secondary metabolites that have evolved to defend plants from herbivores typically make up the poisonous active components in plant extracts. As the insects consume these secondary metabolites, they may be exposed to toxic substances that have relatively nonspecific effects on a range of molecular targets. Proteins (including receptors, enzymes, signaling molecules, structural proteins, and ion channels) are some of these targets, along with biomembranes, nucleic acids, and other cellular components (Wink, 2008). The main one of them is anomalies in the nervous system, which in turn has a variety of consequences on insect physiology at various receptor sites (such as in neurotransmitter synthesis, storage, release, binding, and re-uptake, receptor activation and function, enzymes involved in signal transduction pathway). The mechanism of action of plant secondary metabolites on insect body discovered numerous physiological disturbances, such as acetylecholinesterase inhibition (by essential oils), GABAgated chloride channel (by thymol), disruption of sodium and potassium ion exchange (by pyrethrin), and inhibition of cellular respiration (by rotenone) (Hussain et al., 2019). Aside from hormonal imbalance, mitotic poisoning (azadirachtin), disruption of the molecular events of morphogenesis, alteration of the cholinergic system’s behavior and memory (by essential oil), blockage of calcium channels (by ryanodine), inhibition of nerve cell membrane action (by sabadilla), blockage of octopamine receptors (by thymol), etc., this disruption also includes alteration of the hormones and their balance. Acetylcholinesterase

Natural products in vector-borne diseases management  Chapter | 1  13

(AChE) is a crucial enzyme that stops the transmission of nerve impulses through the synaptic pathway, and it has been observed that AChE is resistant to organophosphorus and carbamates. It is generally known that one of the primary resistance mechanisms in insect pests is a modification in the AChE gene (Nahak, 2015; Tehri and Singh, 2015).

Epidemiology Medical and veterinary entomologists provide major contributions to multidisciplinary programs that study, track, and manage parasites transmitted by vectors and are essential to comprehending the epidemiology of diseases transmitted by vectors. Medical entomology is essential to public health during times of large outbreaks, war, starvation, or natural calamities that devastate communities and increase exposure to vectors (Barker and Reisen, 2018). Because neither the invaders nor the indigenous population were immune to the new parasites they were exposed to, massive movements of populations (such as military personnel) into regions where vector-borne diseases are common have had devastating effects on both. An increase in the spread of parasites and their vectors into new geographic regions has been caused by recent changes in international travel health regulations, affordable and accessible rapid transportation, and the recent expansion of global trade, putting at risk populations of people and other animals that had not previously been exposed to them (Eder et al., 2018). Emerging infectious diseases are a group of pathogen outbreaks that have been spreading across the globe. Vector-borne parasites are responsible for a sizable portion of newly emerging infectious diseases, either as a result of anthropogenic (humaninduced) changes that have given vectors or parasites opportunities to expand their distribution in time or space or because the parasites have evolved into more virulent or drug-resistant forms (Chan et al., 1999). Epidemiology developed became a science through the examination of infectious disease epidemics. The natural history and spread of diseases among human and animal populations are the focus of the contemporary academic area of epidemiology (etymology: epi ¼ upon, demos ¼ people, logos ¼ study). Arthropod vectors, vertebrate hosts, and parasites are the basic causes of vectorborne illnesses (Keeling et al., 2011). Because an arthropod is necessary for the transfer of the parasite to uninfected hosts as well as interactions between the parasite and its vertebrate host, the spread of diseases by arthropods is particularly complicated. Environmental factors such as temperature and rainfall have an effect on these processes by affecting the rate of parasite maturation within the arthropod host as well as the abundance of arthropod and vertebrate hosts throughout time and space (O’Dwyer et al., 2020). To comprehend the epidemiology of arthropod-borne diseases, one must have a thorough grasp of the biology of parasites, vectors, and hosts as well as how they interact in varied ecosystems. The frequency of interaction between vertebrate hosts and vectors varies, ranging from infrequent (such as with

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­ osquitoes) to intimate and constant (e.g., sucking lice). The host frequently m provides the vector with a home and food in the form of blood or other tissues (Mills et  al., 2010). The vector, vertebrate host, and parasite are brought together in time and place by the vector’s blood feeding, which has the potential to transmit parasites from infected to vulnerable vertebrate hosts. A vector normally needs to eat two blood meals for the parasite to spread over the course of its lifetime—the first to become infected and the second to do so. Blood meals provide the arthropod with the nutrients it requires for metabolism, metamorphosis, and/or reproduction (Lefèvre and Thomas, 2008).

WHO guidelines for vector-borne diseases The global vector control response 2017–30, which was created over the course of an intense consultation process that began in June 2016, is anticipated to be approved by the seventieth World Health Assembly in May 2017. The response was developed in close collaboration with numerous experts and partners from all over the world under the overall direction of Pedro Alonso, Director of the Global Malaria Programme, Dirk Engels, Director of the Department of Control of Neglected Tropical Diseases, and John Reeder, Director of the Special Programme for Research and Training in Tropical Diseases (World Health Organization, 2018). Millions of individuals throughout the world are infected by viruses, parasites, and bacteria that are spread by mosquitoes, flies, bugs, and other vectors. Numerous illnesses are brought on by them, including those caused by the Zika virus, leishmaniases, Chagas disease, and malaria. To improve vector management globally, the World Health Organization (WHO) has created a new strategy. At the 2017 World Health Assembly, Member States applauded this integrated approach and endorsed a resolution in favor of the plan (WHO, 2022; Zinszer et al., 2020). Since 2014, there have been significant outbreaks of the diseases zika virus, yellow fever, dengue, malaria, and chikungunya due to social, demographic, and environmental reasons. If vector control is properly done, the majority of vectorborne diseases can be avoided. Strong political and financial commitment has significantly reduced the prevalence of Chagas disease, onchocerciasis, and malaria (Fritzell et al., 2016). Vector control has not yet been utilized to its fullest extent or had its greatest influence on other vector-borne diseases. This condition can be improved by realigning programs to maximize the delivery of interventions that are pertinent to the local context. This solution requires for improved sectoral and intersectoral cooperation, improved community involvement in vector management, reinforced monitoring systems, greater public health entomology (and malarialogy) expertise, and novel interventions with proven efficacy (Moise et al., 2021).

Future prospects Many infectious diseases are spread through the use of arthropod vectors. More than three billion individuals are currently exposed to vector-borne infections

Natural products in vector-borne diseases management  Chapter | 1  15

because they live in endemic regions. It is extremely difficult to forecast the prevalence of vector-borne diseases in the future due to significant changes in the biology of arthropod vectors. However, the ecology and distribution of arthropod vectors are significantly impacted by both urbanization and climate change. Such processes frequently cause a nonrandom process of biodiversity loss that homogenizes species biotically (Githeko et al., 2000). The data now available demonstrate a trend toward progressive rises in the prevalence and quantity of human-associated vectors that may thrive in urban environments, raising the possibility that these vectors will come into contact with human hosts. We anticipate a rise in the prevalence of vector-borne diseases as a result. We believe that resources ought to be made accessible and should be focused on integrated vector management plans that use tried-and-true vector control tools. In addition, adhering to environmental regulations and establishing fundamental sanitary infrastructure at the beginning of IVM’s development would significantly save expenditures. This might improve IVM’s ability to lessen social health determinants and social injustices brought on by exposure to vectors (Campbell-Lendrum et al., 2015; Martens et al., 1995). Climate change is one of the largest threats to human health in the 21st century. The climate directly influences health through climatic extremes, air quality, sea-level rise, and other effects on food production systems and water supplies. Infectious diseases are influenced by climate, and these diseases have had a major impact on the development of civilizations throughout history as well as the expansion of humankind into new lands (Schaffner et al., 2021). Our analysis focuses on significant regional shifts in the distribution of vectors and pathogens that have been noticed recently in temperate, peri-Arctic, Arctic, and tropical highland regions. These changes were predicted by experts around the world. If we do not mitigate and adapt to climate change, there will probably be more alterations in the future. A few of the significant factors that affect the spread and severity of human diseases include the movement of people, animals, and goods; current control measures; the availability of effective medications; the standard of public health services; human behavior; and political stability and conflicts. Due to the rise in medication and insecticide resistance, significant funding and research efforts must be maintained to continue the battle against current and new diseases, especially those that are vector-borne (Caminade et al., 2019; Schaffner et al., 2021). Compounds that are insecticidal, acaricidal, and repellant have a sizable and expanding industry worldwide. For instance, the global market for insect repellents was worth 3.2 billion US dollars in 2016 and is anticipated to grow to 5 billion by 2022. This market might be more lucrative for some companies than vaccinations, which would decrease support for and interest in ­ectoparasite ­control vaccines (Jain et  al., 2020). It is possibly one of the factors that prevented BM86-based vaccines from finding success on the market despite their efficacy. It has long been accepted that combining vaccination with other preventative therapies, such as insecticides, acaricides, and

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repellents, is the most effective way to manage ectoparasite vectors. Vaccines should be seen as an alternative and complementary intervention to insecticides and acaricides in order to effectively control ectoparasites. This will increase demand for vaccines while reducing the need for these chemicals (Medlock and Leach, 2015). When creating vaccinations to manage ectoparasite vectors, security and cost-effectiveness are crucial considerations. To address these issues, research should focus on effective formulations with cutting-edge adjuvants for oral vaccination delivery and nanoparticle-based vaccines (Parham et al., 2015). In general, vaccines for ectoparasite vector control in people and companion animals are thought to prevent infestations and the spread of infections. Based on the knowledge currently available, it might be possible to create vaccinations that stop the spread of bacteria and protozoan parasites, which take hours to days to spread when a vector feeds on blood. However, the majority of viruses spread quickly after a vector bite, making transmission prevention more challenging (Khan, 2015). In order to affect the life cycle of the vector and transmit illnesses, various biological processes rely on interaction with the ectoparasite; as a result, the immune response to vaccination (such as antibodies) cannot prevent vector attachment or feeding. One open question is how to combine vectorand pathogen-derived antigens to target both of them with a single vaccination (Merino et al., 2013). Two further innovative strategies have been proposed to control illnesses with alpha-Gal on their surface and tick vector infestations: developing vaccines based on alpha-Gal glycoproteins and glycolipids and targeting tick galactosyltransferases. However, these options still require validation (Otranto and Wall, 2008). Food-grade nanoparticles are one type of nanotechnology that can be used to overcome mosquito drug and insecticide resistance that has developed as a result of traditional treatment methods used to halt dengue and malaria outbreaks. When contrast to metallic nanoparticles, food-grade nanoparticles have no adverse effects (Estrada-Peña et  al., 2012). They respect both people and the environment. Transgenic (genetically altered) mosquitoes and a medication cocktail have been tested to address difficulties. These techniques provide difficulties because multidrugs are present in mosquito bodies and trans-genes are destroyed. Nanomedicines are predictable and may help with the treatment of dengue and malaria. The use of nanoparticles in a multidrug combination may have promising results. Special consideration should be given to biodegradable nanoparticles with various drug encapsulating, food-grade nanoparticles like curcumin, and metallic nanoparticles like ZnO in order to stop the evolution. Future advancements in food-based nanoparticles, which are safer than metallic pharmaceuticals, multidrugs, and biodrugs, may help Pakistan and other developing countries eradicate vector-borne diseases. More investigation is required to determine the larvicidal efficacy of food-based nanoparticles against the mosquito larvae that transmit malaria and dengue disease (Hromníková et al., 2022; Tsao, 2009).

Natural products in vector-borne diseases management  Chapter | 1  17

Current trends, opportunities, and knowledge gaps in vector-borne diseases management with botanical products The use of natural and synthetic repellents, available in many pharmaceutical forms, is rising rapidly as a result of the advent of vector-borne illnesses like Dengue, Zika, Chikungunya, Yellow Fever, and Malaria. The formulation choice will be influenced by the type of repellent active (natural or synthetic), pharmacological forms (spray, lotion, cream, gel), action time length (short or long), environment of exposure, and the user (adult, pregnant women, children, newborn) (Lee, 2018). Essential oils, DEET, IR3535 (ethyl butylacetylaminopropionate), icaridin (Picaridin), and DEET are the most widely used repellents. Each of these compounds has benefits and drawbacks. DEET is the industry standard since it is the most effective and oldest insect repellent on the market. Due of this, a variety of traditional formulations with DEET in spray and lotion form are readily accessible on the market. However, DEET is contraindicated in pregnant women and children up to 6 months old due to its toxicity. DEET has been a choice along with other popular items like IR3535 and icaridin (picaridin), which are made of less dangerous components. The best choice due to the lower levels of toxicity exhibited is IR3535, which may be given for children over 6 months of age and pregnant women. Children older than 6 months old and pregnant women may be taken IR3535 because it has the lowest level of toxicity of the three alternatives (Anoopkumar and Aneesh, 2022; Raveen et al., 2017). Icaridin has the advantage of having the longest-lasting effect among the aforementioned repellents and is as effective as DEET while being less harmful. Controlled release technologies have served as the foundation for the novel formulations (CRS). Among the CRSs for repellents are polymer micro/nanocapsules, micro/solid lipid nanoparticles, nanoemulsions/microemulsions, liposomes/niosomes, nanostructured hydrogels, and cyclodextrins. To extend the duration of the repellent activity and reduce penetration and, consequently, systemic toxicity, numerous formulations based on micro- and nanocapsules with DEET and essential oils exist. Unexplored in terms of research is the creation of new IR3535 and icaridin formulations. The current trend is to use natural repellent actives like essential oils, which have a short-lived repellent effect after being applied to the skin but are low toxic and environmentally benign. Natural repellents have been transported by CRSs to enhance long-lasting repellent efficacy, lessen skin permeability, and limit systemic effects (Messenger and Rowland, 2017; Tavares et al., 2018). Due to their effectiveness, affordability, and environmental friendliness, plant-based pesticides have recently attracted a lot of interest. Plants produce a variety of phytochemicals, which are defense compounds that can be employed to control insect outbreaks. Chemical ecology examines the role that particular chemicals (allele chemicals) play in how organisms interact with one another

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and their environments (Senthil-Nathan, 2015). These defense mechanisms, known as allelochemicals, affect a wide range of molecular targets, including as cellular proteins, enzymes, nervous system signal transduction (neurotransmitter synthesis, storage, and release, as well as receptor binding), as well as herbivore or microbe metabolic processes (Mpumi et al., 2016). Plants are protected against microbial parasites and arthropods by their secondary metabolites, such as carotenoids, terpenes, sterols, phenols, alkaloids, and flavanoids. For example, Chloroxylon swietenia is effective against Anopheles gambiae, Culex quinquefasciatus, Aedes aegypti, and Calocedrus decurrens (Makkar et al., 2007). Essential oils, terpenes, and other plant extract-based larvicides disrupt biochemical processes, particularly those related to neuroinhibition, neuroexcitation, endocrinological balance, neuromuscular fatigue, and respiratory capacity. This causes an inability to breathe, immobility, and paralysis, which ultimately results in death (Gupta and Gupta, 2022). However, it has been asserted that plant extracts, which are more complex in nature than synthetic insecticides and contain a variety of components, inhibit the development of resistance to botanical insecticides through the interaction of their physiological and behavioral effects (Haddi et al., 2020).

Conclusion In conclusion, awareness is growing about VBDs after many years in which they barely made an impact. In an era of climate change and globalization, it is critical to develop the necessary skills and bring together existing knowledge in research in close collaboration with public health, practitioners, policy, and the affected population to create tools and policies that can quickly identify, anticipate, evaluate, and mitigate risks. Knowing what has already been learned in more severely affected regions of the world is crucial for creating concepts and models that can be modified for temperate regions with changing climatic circumstances. Studies on how diseases are affected by extreme events, precipitation patterns, and seasonality are largely lacking. Additionally, disease and vector dissemination internationally is aided by globalization and international air travel. Nevertheless, keeping an eye on weather forecasts can assist identify early signs of outbreaks of vector-borne diseases and act as a risk reduction early warning system.

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Chapter 2

Evidence-based review of medicinal plants for the management of onchocerciasis Yaw Duah Boakye, Theresa Appiah Agana, Esther Afua Oteng-Amankwah, Vivian Etsiapa Boamah, and Christian Agyare Department of Pharmaceutics, Faculty of Pharmacy and Pharmaceutical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana

Introduction Onchocerciasis, commonly known as river blindness is transmitted by Onchocerca volvulus. It is among the 10 neglected tropical diseases and a major cause of blindness in the world (Nakajima, 1992). Onchocerciasis causes life-long problems and has unfavorable effects on the socioeconomic growth of the affected societies (Prost, 1986). Aside from onchocerciasis being a major cause of blindness, it is capable of causing long-term disfiguring skin changes, weight loss, musculoskeletal complaints, and perhaps epilepsy. The vector for this disease is Simulium damnosum-blackfly which lives near rivers, hence the common name “river blindness” (CDC, 2015). The adult worms of Onchocerca volvulus often cause no symptoms and at worst induce the development of noticeable nodules known as onchocercomas. These nodules are found in different regions of the body depending on the type of Onchocerca volvulus strain. For the African strain, the nodules are found mainly in the pelvic area, with few along the spine and chest. Nodules are found around the waist in the Central America strain (George et  al., 1985). Ivermectin is the drug usually prescribed for the treatment of onchocerciasis. However, it is only microfilaricidal, and is administered once within 6 to 12 months and continuously for quite a few years (Aziz, 1986). Doxycycline is used as an adjunct therapy in some affected areas. It reduces the activity of the worm by killing an associated bacteria called Wolbachia (Brunette, 2011). One area that is gaining acceptability worldwide is the development and evaluation of active phytoconstituents from plants in the management of chronic diseases. It is, therefore, necessary to look out for new drugs, preferably compounds isolated from medicinal plants to treat ­onchocerciasis. Ethnomedicines are now Natural Products in Vector-Borne Disease Management. https://doi.org/10.1016/B978-0-323-91942-5.00004-5 Copyright © 2023 Elsevier Inc. All rights reserved.

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playing a central role in the treatment of both infectious and noninfectious diseases (Ates and Erdogrul, 2003). Onchocerca volvulus is an arthropod-borne roundworm that causes river blindness. It belongs to the family Onchocercidae. It is found primarily in Sub-Saharan Africa and the only known definitive hosts are humans (Duke, 1993). Onchocerca volvulus can live in humans from 8 to 15 years, and microfilariae can live up to 2 years (Richard-Lenoble, 2006). It is a dioecious species, containing males and females, and they form nodules under the human skin. Male worms move around the subcutaneous tissues freely while the female worms are permanent in the fibrous nodules they create under the skin. Although the female worms may attract the male worms using unidentified pheromones, the release of their oocytes does not depend on the male worm (Schulz-Key and Soboslay, 1994). Onchocerca ochengi identified in cows is closely related to Onchocerca volvulus, a strain of medical importance. They both share certain similarities; a common vector, similar susceptibility of microfilariae to ivermectin, and both have adult worms located in intradermal/subcutaneous nodes (McCall et  al., 1992). The bovine parasites are comparatively common in Africa which is easy to obtain at a low cost, which makes it a good choice in antionchocerca studies (Samje et al., 2014).

Epidemiology Onchocerca volvulus infection is mainly existent in tropical climates, especially sub-Saharan Africa. A report from the World Health Organization (WHO) states that onchocerciasis is prevalent in 37 nations including Central, East and West Africa, the Arabian Peninsula, and parts of South and Central America (Otabil et al., 2019). The savanna part of the Volta river basin found in West Africa is reported as one of the most endemic onchocerciasis zones in the world. This area comprises parts of Benin, Ghana, Mali, Ivory Coast, Niger, Togo, and the whole of Upper Volta (WHO, 1976). Because the vector, Similium blackfly, breeding habitat is in water, onchocerciasis is more severe along the major rivers in the northern and central areas of the continent (WHO, 1976). A study by the Global Burden of Disease in 2017 showed that among at least 20.9 million people infected with onchocerciasis globally, 14.6 and 1.15 million had skin diseases and vision loss in 2017. The WHO has certified four countries: Columbia, Mexico, Ecuador, and Guatemala as onchocerciasis-free areas (CDC, 2015). Recent data analysis in Ghana showed that patients with glaucoma had a higher prevalence of onchocerciasis-skin snip test results was positive even after adjustment for confounding factors (OR = 3.50, CI = 95%, 1.10–11.18) (Egbert et al., 2005).

Life cycle of Onchocerca volvulus Onchocerciasis is transmitted through the bite of a Similium blackfly which has been infected by the worm, Onchocerca volvulus. Since it can take several years

The management of onchocerciasis  Chapter | 2  29

for larvae to develop within the body and grow, it can take several years for a person to first notice the symptoms of onchocerciasis after first being bitten by a blackfly (Somorin, 1983). People who are at greater risk of acquiring this disease live near or travel near the rivers of sub-Saharan Africa (CDC, 2015). The human is the only definitive host, whereas the intermediate host is a black fly. A female black fly suckles on the blood of an infected human host and ingests microfilariae. In the first larval stage, the microfilariae enter the muscles of the gut and thoracic region of the fly. The larvae then migrate to the mouth of the fly and moves into the saliva where they go through the maturation process for 7 days. The infected black fly at this stage feeds on another blood meal, whereas the mature larvae are passed into the human’s blood. The larvae now undergo two forms of molting in the subcutaneous tissues. They form nodules and begin to mature within a period of 6 to 12 months. In the subcutaneous tissue, the adult male worms begin to mate with the female worms to produce a large number of microfilariae in a day. The microfilariae migrate back to the skin. In this way, the black fly ingests a new set of microfilariae to restart the cycle. Visual loss as a complication of the disease results due to the larvae being dead inside the eye (CDC, 2015; Gaware et al., 2011).

Clinical manifestation and diagnosis of onchocerciasis Onchocerciasis either manifests in the form of dermal or ocular signs, skin involvement consists of pruritis, thickening of the skin, nodules on the skin, hyperpigmentation, and inflammation (Otabil et al., 2019). Ocular manifestation involves any tissue of the eye: conjunctiva, retina, and optic nerves (Okulicz, 2018). Even though mild infections are often difficult to control, individuals who live close to rivers or in localities where river blindness is endemic are most likely to be affected by this condition. The signs experienced during the infection can be grouped into three phases, and they include: 1. Erisipela de la Costa: This occurs in the first phase of infection where an intense swelling of the face and sometimes pruritis are experienced (James et al., 2006). 2. Mal Morando: The dermal layer of the skin is more susceptible to hyperpigmentation and inflammation in this stage, and hence, the affected area darkens as a result of increased production of melanin (Jillson, 1982). 3. Sowda: In this stage, the dermatological condition now becomes persistent and hyperactive during this stage. The skin becomes prone to secondary bacterial infections, resulting in swollen lymph nodes (Jillson, 1982). Diagnosis of onchocerciasis can be done in several ways: 1. Looking within bumps under the skin for adult worms (CDC, 2015). 2. Biopsy of the skin being placed in physiological solutions (e.g., normal saline) in search of the larva (CDC, 2015). This is known as the slit lamp exam.

30  Natural products in vector-borne disease management

3. Looking in an infected eye for larvae (CDC, 2015). 4. Nodules can be surgically removed from the skin of the patient and examined for adult worms (CDC, 2015).

Current treatment and challenges The only recommended drug for the treatment of onchocerciasis is ivermectin. It is only microfilaricidal, and it works by attaching to glutamate-gated Cl− ion pathways in muscle and nerve cells of invertebrates resulting in paralysis, and eventually the death of the parasite. It is administered once within 6 to 12 months and continuously for several years (Aziz, 1986). There have been several reports which indicate that there is diminishing effectiveness of ivermectin in affected patients, and there is the need to keep monitoring the safety and efficacy of it in endemic areas. Doxycycline is used as an adjunct therapy in some affected areas. It reduces the activity of the worm by killing an associated bacteria called Wolbachia (Brunette, 2011). Challenges associated with these two drugs are nonavailability in deprived communities, contraindications in pregnancy and children below 8 years, also resistance to the antibiotic doxycycline (Leggat, 2009). A study conducted by Osei-Tweneboana et  al. (2007) in Ghana states that there is an increased risk of ivermectin resistance in Onchocerca volvulus in some communities and it is manifested as a more rapid return to a high microfilariae load even after treatment. Since ivermectin is only microfilaricidal, there is a probability of getting re-infected with the microfilariae which will enable the parasite to continue to live, but with the use of a macrofilaricide, no multiplication of microfilariae will occur (Ngwewondo et al., 2018). This and many more challenges have made it imperative to look out for new drugs to treat onchocerciasis.

Models for assessing the antionchocerca activity of plant extracts and isolated compounds In vitro models target one or more life stages of the parasite and are used singly or in combination. The assays target inhibition of motility in the parasite and inhibition of microfilaria release (Rao et  al., 2000, 2009); others include the 3-[4,5-dimethylthiazol-2-yl]2,5-diphenyl tetrazolium bromide (MTT) reduction assay which entails a conversion of a tetrazolium salt to formazan. The most commonly used assays are MTT reduction and motility assays. In combined assays, a product is said to be effective when it results in total prevention of motility and/or greater than 50% inhibition in the MTT reduction (Comley et al., 1989). The recent analysis includes the evaluation of the IC50 (the concentration which accounts for 50% inhibition of parasite motility) and the CC50 (cytotoxic concentration which accounts for 50% of killed cells), and a­ ssessment

The management of onchocerciasis  Chapter | 2  31

using VERO Cell line C1008 (African green monkey kidney cells) (Huber and Koella, 1993; Page et al., 1993).

Methods used for pinpointing herbal materials and natural products with antionchocerca from published literature Electronic databases such as Google Scholar, Science Direct, and PubMed were used to search for medicinal plants which have been documented for treating onchocerciasis. PROTA and www.theplantlist.org were used to search for the geographical location and uses of some of the plants. Research on published articles with ethnopharmacological knowledge on onchocerciasis was used. Studies that report plants with antionchocerca activity but have no evidence were excluded. The botanical titles of plants and their parts, and type of solvent used to extract the plants and active compounds were extracted from various articles.

Plants used for treating onchocerciasis Due to the nonavailability of ivermectin in deprived communities where river blindness occurs as well as nonadherence or resistance issues from patients who are put on the adjunct therapy doxycycline, it has become a necessity to look out for new drugs that can help in treating the disease. The use of traditional medicine for both infectious and noninfectious diseases in recent times is gaining acceptability worldwide due to the presence of active constituents in the plants which can be further isolated and evaluated to a significant effect. Below are some medicinal plants which may be used in treating onchocerciasis.

Annonaceae Polyalthia suaveolens Engl. & Diels is a tree located in Angola, Cameroon, and Nigeria. It is known for its antitrypanosomal and antirheumatic activities (Ngantchou et al., 2010). Titanji et al. (1990) reported that a molecule, oliverine (A), purified from Polyalthia suaveolens was found to be active against Onchocerca volvulus with LC100 of 100 μg/mL. Another compound polycarpol (B) isolated from the bark of Polyalthia suaveolens was reported to be active in vitro against Onchocerca gutturosa with 42% viability reduction of the worms (Nyasse et al., 2006; Fig. 1). Annona senegalensis Persoon is a deciduous shrub that grows approximately between 2 and 6 m tall. It is commonly known as African custardapple (National Research Council, 2008). The specimen type was collected in Senegal, hence the name, senegalensis, but its native in West Tropical

32  Natural products in vector-borne disease management

Oliverine (A)

Polycarpol (B)

FIG. 1  Chemical structure of oliverine (A) and polycarpol (B) isolated from Polyalthia suaveolens.

Africa: Zimbabwe and Kenya. Annona senegalensis is known for its antidiarrheal, anticonvulsant, ­antimalarial, and antimicrobial properties (Mustapha, 2013). Phytochemicals present in this plant include alkaloids, terpenoids, and steroids (Ngwewondo et al., 2018). Ndjonka et al. (2011) found out ethanol extract obtained from leaves of this plant had activity against Onchocerca ochengi. A dose-dependent activity against the adult male and female worms of Onchocerca ochengi was seen with this extract; however, Ajaiyeoba et al. (2006) in previous studies state that the cytotoxic effect of methanol leaf extract of Annona senegalensis in vitro against A2730 ovarian cancer was low (IC50 = 28.8 μg/mL). Hence, before this plant can be considered safe and effective for use, pure compounds obtained from its extract need to be tested against the parasite individually. Pachypodanthium staudtii. Engl & Diels is a tree that is found in Central and West Africa. Traditionally, its usage is in the management of cancers, oedema, swellings, pain, pulmonary troubles, vermifuges, dyspnea, and coughs (Oliver-Bever, 1985). The antionchocerca activity of a compound, oliverine (A), isolated from Polyalthia suaveolens was found to be active against Onchocerca volvulus with LC100 of 100 μg/mL (Titanji et al., 1990).

Apocynaceae Rauvolfia vomitoria Afzel. is a shrub that varies widely in height, between 0.5 and 20 m tall, and found mainly in the Western part of Africa. Its common name is poison devil’s pepper (Burkill, 1994). In Africa, it is used traditionally in the management of skin infections and snake bites. The main phytoconstituents present in Rauvolfia vomitoria are alkaloids. Reserpiline happens to be the major component in its root and stem bark with reserpine and reserpinine being the second and third, respectively. Reserpine, a wellknown antihypertensive, has an indirect effect on the peripheral and central nerve terminals. It impairs the storage of biogenic amines resulting in the

The management of onchocerciasis  Chapter | 2  33

­ epletion of ­norepinephrine, serotonin, and dopamine. Depletion of norepid nephrine leads to a decrease in blood pressure (Schmelzer and Gurib-Fakim, 2007). In a study conducted by Attah et al. (2013), extracts of the Rauvolfia plant were evaluated in vitro to determine its antionchocerca effect. At the end of the study, Rauvolfia plant root extract immobilized Onchocerca volvulus microfilariae at different levels in vitro; hence this validates its potential use in the treatment of onchocerciasis. Voacanga africana (Scott-Elliot) Stapf. is an erect tree that is found mainly in West Africa. This plant is sometimes being grown for its ornamental purposes—it has sweet-scented flowers. The seeds of Voacanga have been found to contain voacangine, indole alkaloids, and other related substances. Diarrhea can be cured when a decoction of its leaves is taken by an enema as well as fatigue due to shortness of breath (Wickens and Burkill, 1986). Voacangine (C) and voacamine (D) purified from the stem bark of Voacanga africana have been reported to reduce the activity of both microfilariae and adult male worms of Onchocerca ochengi. The IC50 for voacangine were 5.49 and 9.07 μM for microfilariae and adult males, respectively, while for voacamine, the IC50 values were 2.49 and 3.45 μM for microfilariae and adult males, respectively (Smith et al., 2015; Fig. 2). Alstonia boonei De Wild, commonly known as “Nyame Dua” in Ghana (Busia, 2007) and cheese-wood in English, is a tree that is commonly found in tropical West Africa. The known therapeutic uses of its bark are its analgesic and antidiabetic effects (Hadi and Bremner, 2001). Phytoconstituents present in this plant are alkaloids, tannins, triterpenoids, and ursolic acid (Busia, 2007). A study reported by Ebigwai et al. (2012) indicates that both the leaves and stem bark ethanol extract of Alstonia boonei exhibit significant larvicidal activity against Similium yahense. However, the larvicidal properties of the phytoconstituents obtained in this plant need to be extensively studied by isolating the active ingredients that cause larval mortality and then use them in clinical trials to better assess its potential use as a substitute to ivermectin and other chemical larvicides.

Voacangine (C)

Voacamine (D)

FIG. 2  Chemical structure of voacangine (C) and voacamine (D) isolated from Voacanga africana.

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Araceae Anchomanes difformis (Blume.) Engl. is a perennial herbaceous plant with a bulky thorny stem that originates mainly in the forests of Sierra Leone to West Cameroon. This is known in Ghana as “Nyame kyin”-God’s umbrella. In Ghana, the sap from its stem is used to treat eyesores (Wickens and Burkill, 1986). The tubes/rhizomes of this plant are used to treat Buruli ulcers, rheumatism, and to manage diabetes and asthmatic attacks. A decoction is prepared from the sap and used (Yemoa et  al., 2008). Nkoh et  al. (2015) conducted a study to determine its antionchocerca activity on Onchocerca ochengi which is also closely related to Onchocerca volvulus. The extract of the rhizome of this plant displayed 100% significance in its use, confirming its use in the treatment of onchocerciasis.

Combretaceae Anogeissus leiocarpus (DC.) Guill. & Perr., also known as African birch, is a tall deciduous tree that is found mainly in the Savanna regions of tropical Africa (Arbab, 2014). An active constituent known as castalagin has been isolated from its stem bark (Shuaibu et al., 2008). Ethanol extract of Anogeissus leiocarpus leaves was assessed in vitro for its antionchocerca activity and was found that the extract affected Onchocerca ochengi microfilariae by 0.06 mg/mL and adult worm by 0.09 mg/mL (Ndjonka et al., 2012). The isolated phenolics acids, ellagic (E), gallic (F), and gentisic (G) acids, obtained from the crude ethanol extract of Anogeissus leiocarpus affected the survival of Onchocerca ochengi with an LC50 of 0.09, 2.10, and 0.68 mM for ellagic, gallic, and gentisic acids on adult worms, respectively. The compounds resulted in the death of microfilaria with an LC50 of 0.03, 1.59, and 0.26 mM for ellagic, gallic, and gentisic acids, respectively (Ndjonka et al., 2014; Fig. 3). Guiera senegalensis J.F. Gmel. is a shrub mostly found in the SudanoSahelian region (Africa) and grows up to about 3 m in height (Akuodor et al., 2013). It is used traditionally for the management of fever, ulcer, leprosy, increase lactation (Oliver-Bever, 1985), skin diseases, dysentery, and diarrhea (Iwu, 1993). The in vitro antionchocerca effect of ethanol leaves and stem bark extract of Guiera senegalensis showed activity against Onchocerca ochengi with LC50 of 12.5 and 17.5 μg/mL for stem bark and leaves extract, respectively (Ndjonka et al., 2017).

Cucurbitaceae Cucurbita pepo ovifera var ovifera commonly known as acorn squash is a sprawling vine with yellow fruit-bearing flowers and is native to North America. The leaves and fruits are usually used as food (Schultes, 1991). The plant has been used as an effective tapeworm remover for children. The fruit

The management of onchocerciasis  Chapter | 2  35

Ellagic acid (E)

Gallic acid (F)

Gentisic acid (G) FIG. 3  Isolated phenolic acids from Anogeissus leiocarpus: (E) ellagic acid; (F) gallic acid; and (G) gentisic acid.

pulp is used as a decoction to alleviate intestinal inflammation (Chevallier, 1997). The seeds are used as vermifuge and diuretic (Chevallier, 1997) and to treat hypertrophy of the prostate (Duke, 1993). The leaves of Cucurbita pepo are also applied externally to treat burns (Chopra et  al., 2002). The ethanol leaves and seeds extracts of Cucurbita pepo were reported to be active against Onchocerca ochengi adult worms with LC50 of 20 and 17 μg/mL, respectively (Kalmobé et al., 2017).

Cyperaceae Cyperus articulatus L. is a perennial herb that grows in damp and flooded areas along rivers (Taylor, 2005). Its common name is Piri-piri. It has a beneficial effect on the digestive system and is usually used to treat nausea, vomiting, and flatulence especially in South America (Taylor, 2005). Piripiri contains flavonoids, saponins, tannins, polyphenols, linoleic acid, and terpenes as its active constituents (Samje et al., 2014). In a study conducted by Samje et al. (2014), only the hexane extract of essential oil isolated from roots/rhizomes of this plant prevented the growth of Onchocerca ochengi. The oil destroyed both the adult worm of Onchocerca ochengi and microfilariae in a dose-dependent pattern with IC50 of 23.4 μg/mL and 31.25 μg/mL, respectively.

36  Natural products in vector-borne disease management

Euphorbiaceae Euphorbia hirta L. is a hairy plant that grows annually with many branches from the base to the top (Williamson, 2002). The stem sap of this plant is used in the treatment of eye styes and its leaf poultice is used on boils (Watson, 1958). Attah et al. (2013) evaluated the ethanol extract of Euphorbia hirta to determine its effect against Onchocerca volvulus microfilariae. At the end of the study, it was found out that at different levels in vitro, Euphorbia hirta immobilized microfilariae. The effects of the hexane, chloroform, and ethyl acetate fractions of Euphorbia hirta against Onchocerca ochengi was studied in vitro by Ndjonka et al. (2011). Results from the study showed that the ethyl acetate fraction was most active with an IC50 of 6.25 μg/mL against the worms. Margaritaria discoidea (Baill.), commonly called the egossa red pear, pheasant-berry, or bushveld peacock-berry, is native to the warmer, higher rainfall regions of Africa (Wickens and Burkill, 1986). Its barks are commonly used in the management of stomachaches, inflammations, and kidney complaints (Kerharo and Adam, 1974; Ewan, 1964). The activity of different fractions of the stem bark, leaves, and roots of Margaritaria discoidea extracted with methylene chloride and hexane was studied in vitro (Cho-Ngwa et al., 2010). Results from the study showed that both methylene chloride leaves and hexane root extracts prevented the movement of Onchocerca ochengi microfilariae at a concentration of 500 μg/mL. The hexane roots extracts showed the highest potency with an IC50 value of 31.25 μg/mL. Tragia benthamii Bak. is a climbing plant, or rarely an erect shrub with woody stems that can be about 1 to 4.5 m long, covered with stinging hairs. It can be found in countries such as Angola, Botswana, Cote D’Ivoire, Ethiopia, Mozambique, and Zimbabwe. It is used in the management of backaches, malaria gonorrhea, and stomachaches (Reddy et al., 2017). The hexane extracts of seeds and roots of Tragia benthamii were found to be active against Onchocerca ochengi microfilariae with IC50 of 31.25 μg/mL each. On adult Onchocerca ochengi worms, the methylene chloride leaves extract and hexane roots and seeds extract were reported to be active with IC50s of 31.12, 13.12, and 13.90 and μg/mL, respectively (Cho-Ngwa et al., 2016). Discoglypremna caloneura (Pax) Prain is a rainforest tree with a height of about 30 m. It is usually found in Central and West African countries. Its seeds are used in African traditional medicine as an emetic and purgative against diarrhea, dysentery, and edema. Its crushed leaves are used as a decoction in the management of bronchial problems. The bark decoction is used as an emetic agent and in the prevention of food poisoning in Congo (Burkill, 1994; Toukam et al., 2017). The antionchocerca effect of 3-O-acetyl aleuritolic acid (H) obtained from the bark of Discoglypremna caloneura was studied in vitro by Nyasse et al. (2006) on adults’ males of Onchocerca gutturosa. The isolated compound was found to inhibit worm viability by 39.8% (Fig. 4).

The management of onchocerciasis  Chapter | 2  37

3-O-acetyl aleuritolic acid (H) FIG. 4  Chemical structure of 3-O-acetyl aleuritolic acid isolated from Discoglypremna caloneura.

Fabaceae Cassia aubrevillei Pellegr. is a deciduous tree with a height between 8 and 10 m tall and found in West and Central Africa. It is commonly known as “Ganna Ganna” (Schmid and Neuwinger, 2001). This plant is now being threatened by deforestation because it is logged for timber. Cassia species are well known for their purgative and laxative properties. Kilian et al. (1990) reported that an aqueous extract from the bark of Cassia aubrevillei showed in vitro microfilaricidal activity. However, it had no significant changes on the adult worms. The isolated compound, chrysophanic acid (I), showed good microfilaricidal activity. Its alcohol extract produced the best results, killing microfilariae within 24 h at a concentration of 50 μg/mL (Kilian et al., 1990). This could validate the use of “Ganna Ganna” as an alternative in the treatment of onchocerciasis. Acacia nilotica (L.) Willd. ex delile is a tropical tree that grows to a height of about 15 to 18 m. It is usually found in tropical Africa and Asia and can survive in arid and moist areas (Seigler, 2003). Several parts of the tree such as the leaves, seeds, fruits, roots, stem bark, and gum are traditionally used in Africa for treating hemorrhage, colds, pneumonia, diarrhea, and bronchitis (Atif, 2012). Vildina et al. (2017) isolated five compounds, namely, catechin-3O-­gallate (J), epicatechin-3-O-gallate (K), gallocatechin (L), epigallocatechin (M), and epigallocatechin-3-O-gallate (N) from the hydroalcoholic fruit extract of Acacia nilotica. The compounds were found to be toxic to microfilariae (Mf), female, and male Onchocerca ochengi worms. The epigallocatechin 3-O-gallate showed the highest potency with LC50 of 1.3, 1.0, and 1.2 μg/mL, respectively, against the microfilariae, female, and male worms. The other compounds ­epicatechin-3-O-gallate, epigallocatechin, catechin-3-O-gallate, and gallocatechin showed antionchocerca activities with LC50 of 1.0, 2.1, and 2.1 μg/mL, 3.3, 3.3, and 2.1 μg/mL, 4.2, 4.5, and 7.6 μg/mL, 3.2, 5.5, and 4.2 μg/mL, respectively, against the microfilariae, female, and male worms (Fig. 5).

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Chrysophanic acid (I)

Catechin-3-O-gallate (J)

Gallocatechin (L )

epicatechin-3-O-gallate (K)

Epigallocatechin ( M)

Epigallocatechin-3-O-gallate (N)

FIG.  5  Isolated compounds with antionchocerca activities. (I) Chrysophanic acid from Cassia aubrevillei: (J) catechin-3-O-gallate, (K) epicatechin-3-O-gallate, (L) gallocatechin, (M) epigallocatechin, (N) epigallocatechin-3-O-gallate isolated from Acacia nilotica.

The management of onchocerciasis  Chapter | 2  39

Flacourtiaceae Homalium africanum (Hook f.) Benth. is a woody tropical plant. It can be found in Madagascar and Southeast Asia (Applequist 2013). It is used traditionally for the management of malaria, skin diseases, and as an aphrodisiac (Okokon et al., 2006; Ajibesin et al., 2008). Cho-Ngwa et al. (2010) studied the in vitro effects of different solvent extracts of Homalium africanum on microfilariae and adults of Onchocerca ochengi. The methylene chloride extract was reported to show the highest efficacy against microfilariae with IC50 values of 31.25 μg/mL and IC100 of 62.5 μg/mL.

Lamiaceae Ocimum gratissimum L. is also known as African bail. It is a perennial shrub native to Tropical Africa, India, and South-East Asia (Sulistiarini, 1999). This plant is mainly known for its culinary and ornamental uses (Orwa et al., 2009). Decoction of the leaves of Ocimum gratissimum is used to manage mental illness in the Savanna areas (Akinmoladun et al., 2007). The flowers of this plant are rich in essential oils; hence, it is often used in the preparation of infusions and teas (Rabelo et al., 2003). Some phytoconstituents extracted from this plant are ocimene, terpineol, eugenol, caryophyllene, and humulene (Usip et al., 2006). In an experiment conducted by Usip et al. (2006), volatile oil extracted from the leaves of Ocimum gratissimum was used as a topical repellent on some group of individuals who had been bitten by the Similium blackfly. At the end of the experiment, it was reported that topical application of 20% v/v of the volatile oil gave protection against the Similium blackfly for 3 h. This result is very promising in the future as it can help formulate a potent natural product in the control of onchocerciasis transmission by preventing the nuisance created by the Similium blackfly on the skin (Aisien et al., 2004).

Meliaceae Khaya senegalensis Desr. A. Juss, a deciduous plant frequently called African mahogany, is mostly located in the tropical parts of Africa. Its leaves are used in treating headaches, and the roots are used as a febrifuge (Bonhage-Freund, 2006). The bark extract of Khaya senegalensis is used for treating jaundice as well as dermatoses. This plant is known to contain certain phytoconstituents such as phenols, flavonoids, saponins, and sterol. The bioactive compound terpinol was purified from the ethanol extract of its bark (Liu et al., 2007; Zhang et al., 2009). A study done by Ndjonka et al. (2011) revealed that aqueous bark and ethanol leaves extracts of Khaya senegalensis exhibited activity against Onchocerca ochengi by affecting the survival and development of both the young and adult worms with LC50 of 0.55 and 0.13 mg/L for the ethanol leaves and aqueous bark extracts, respectively.

40  Natural products in vector-borne disease management

Trichilia emetica Vahl is an evergreen plant with a height of 25 m. It is usually found in South Africa, Zimbabwe, Mozambique, and other African countries (Hutchings et al., 1997). The bark of Trichilia emetica is used to prevent intestinal and stomach ailments, its root decoctions for the management of fever and as a purgative, and fruit or leaf poultices for the management of skin infections. Seed oil extracts are used to treat rheumatism and to dress cuts and wounds (Schmid and Neuwinger, 2001). The activity of Trichilia emetica against Onchocerca ochengi was evaluated and the report indicates that the ethanol roots and leaves extracts exhibited activity with an LC50 of 12.5 and 14 μg/mL, respectively (Ndjonka et al., 2017). Carapa procera DC., commonly called the African crabwood, is native to the Amazon rainforest, Vietnam, and the West African tropics. It differs from being a sprawling tree in a swampy forest to a tall tree in lowland rain forests and has a height of about 30 m tall. Carapa procera is traditionally used for the management of gastrointestinal worms, wound infections, fever, and malaria (Tchana et  al., 2014; Oliver-Bever, 1985). The oil obtained from its seeds is used in veterinary care (Dembélé et al., 2015). Carapolide A (O), a compound isolated from the methanol seed extracts of Carapa procera, showed microfilaricidal activity of 100 μg/mL against Onchocerca volvulus worms (Titanji et al., 1990; Fig. 6).

Piperaceae Piper umbellatum L., commonly known as a cow-foot leaf, is a perennial herb that is native to South America but has been widely naturalized throughout the tropics and the Indian Ocean Islands (Domis and Oyen, 2008). This plant is a common weed of cacao plantations in Ghana and oilpalm plantations in Cameroon. The leaves of Piper umbellatum are widely

Carapolide A (O) FIG. 6  Chemical structure of Carapolide A isolated from Carapa procera.

The management of onchocerciasis  Chapter | 2  41

known for treating jaundice, malaria, and menstrual disorders. In Brazil, it is mostly used in baths to subdue uterine complaints (Domis and Oyen, 2008). A study of the phytochemical constituents of Piper umbellatum showed that sterols and saponins were present in its methylene chloride leaves extract (Cho-Ngwa et al., 2016). Methylene chloride leaves e­ xtract showed in  vitro activity at 500 μg/mL against Onchocerca ochengi male worms and microfilariae with IC50 of 16.63 μg/mL and 32.13 μg/mL, ­respectively (Cho-Ngwa et al., 2016).

Rubiaceae Morinda lucida Benth. is an evergreen shrub also known as Brimstone tree in Nigeria and grows mostly in Senegal, Sudan, and southward to Angola. Its local name in “Twi” is Konkroma. Its bitter-tasting roots are used for flavoring foods and alcoholic beverages. A bark or leaf decoction of Morinda lucida is used to treat jaundice in Cote D’Ivoire. Morinda lucida contains anthraquinones and 18 anthraquinones have been noted in its bark and wood, in which some are lucidin, alizarin, and purpuroxanthin (Adesida and Adesogan, 1972). Tannins, flavonoids, and saponisides have also been obtained from Morinda lucida. Methanol leaves extract of Morinda lucida when screened showed the highest activity against both the microfilariae (IC100 of 125 μg/mL) and adult worm of Onchocerca ochengi (IC100 of 250 μg/mL) (Samje et al., 2014). Craterispermum laurinum (Poir.) Benth. is a tree with a height of about 7 m and native to Western Africa, mainly, Senegal and Congo (Jansen, 2005). Decoction of its roots or infusion of its roots is taken orally to treat fever, veneral diseases, and cough (Jansen, 2005). In a study conducted by Samje et  al. (2014), Craterispermum laurinum exhibited in  vitro activity against Onchocerca ochengi, which is closely related to the human form, Onchocerca volvulus. The methanol extract of the leaves was reported to be the most active. The extract showed activity against microfilariae with an IC100 of 250 μg/mL. A concoction is prepared (200 mL) and drunk thrice daily for about a month depending on the manifesting signs and symptoms (Samje et al., 2014). Nauclea latifolia Smith., also known as African peach, is a shrub that is native in West Tropical Africa, especially Ghana and Gabon (Mabberley, 2008). In northern Nigeria, its aqueous leaves extract is used to manage diabetes (Gidado et al., 2005) while the bark extract is known to be effective in treating wounds and coughs (Gidado et al., 2005). Nauclea latifolia is known to contain naucleamides, flavonoids, and caffeic acid (Boerjan et al., 2003). Glutathione-S-transferases in helminths are suitable sites for anthelminthic molecules since they can enable worms to evade the host immune response. Hydromethanol extracts from the stem bark of Nauclea latifolia had heat-stable inhibitory activities against recombinant Onchocerca

42  Natural products in vector-borne disease management

glutathione S-transferases in  vitro with an IC50 of 28 μg/mL. This could ­validate its potential use in the traditional treatment of onchocerciasis (Fakae et al., 2000).

Sapotaceae Vitellaria paradoxa C. F. Gaertn. is usually located in Ghana, Nigeria, Chad, Senegal, Sudan, and Niger. It is commonly called the shea butter tree and grows to about 14 m tall. Fat obtained from Vitellaria paradoxa plant is applied as an ointment for headaches, rheumatic pains, wounds and fever (Jiofack et al., 2009; Iwu, 1993). Ndjonka et  al. (2017) reported that the ethanol stem bark extract of Vitellaria paradoxa exhibited activity against Onchocerca ochengi in vitro with LC50 of 60 μg/mL.

Verbenaceae Lantana camara L. with common names wild sage and tick berry is a plant that is native to Mexico, The Caribbean, and Tropical South Africa. It is used to alleviate disorders of the skin and improve the health of the digestive system in some parts of the native countries. Decoction of its bark and fresh leaves is used to treat fever and toothache, respectively. This plant is known to contain alkaloids, flavonoids, saponins, and tannins (Mariyajancyrani, 2009). The main compounds isolated from the plant are valencene and Y-gurjunene (Ghisalberti, 2020). In a study conducted by Ngwewondo et al. (2018), all 12 extracts of Lantana camara tested in  vitro on Onchocerca ochengi showed a 100% activity at 500 μg/L against adult worms and microfilariae. The highest activity observed was with the hexane leaves extract of Lantana camara with IC50 of 35.1 and 3.8 μg/mL for the adult females and microfilariae, respectively A summary table of showing the medicinal plants that have been screened for anti-onchocerca activity, their respective families, the part(s) of the plant tested as well as the solvent(s) used for extraction (Table 1).

Conclusion This chapter lists down some medicinal plants that have been studied for their antionchocerca activities. The known secondary metabolites of these plants may be potential sources of novel antionchocerca compounds, but further evaluations need to be done to identify and confirm the active molecules. Further studies are needed to enlighten the dose-dependent effect of most of the extracts and their toxicity.

TABLE 1  Medicinal plants species with antionchocerca activity. Species

Family name

Parts used

Solvent for extraction

References

Annona senegalensis Pers.

Annonaceae

Leaves, stem bark

Ethanol

Ndjonka et al. (2011)

Polyalthia suaveolens Engl. & Diels

Annonaceae

Bark

Isolated compounds

Titanji et al. (1990) Nyasse et al. (2006)

Pachypodanthium staudtii Engl. & Diels

Annonaceae

Leaves, barks and roots

Isolated compound

Titanji et al. (1990)

Rauvolfia vomitoria Afzel.

Apocynaceae

Roots

Ethanol

Attah et al. (2013)

Voacanga africana Stapf.

Apocynaceae

Stem bark

Ethanol

Attah et al. (2013)

Alstonia boonei De Wild.

Apocynaceae

Stem

Aqueous and ethanol

Ebigwai et al. (2012)

Anchomanes difformis (Blume.) Engl.

Araceae

Roots, rhizome

Methanol

Nkoh et al. (2015)

Anogeissus leiocarpus (DC.) Guill. & Perr.

Combretaceae

Bark, Leaves

Ethanol

Ndjonka et al. (2012)

Guiera senegalensis J. F. Gmel.

Combretaceae

Leaves stem bark and roots

Ethanol

Ndjonka et al. (2017)

Cucurbita pepo ovifera var ovifera

Cucurbitaceae

Leaves and seeds

Ethanol

Kalmobé et al. (2017)

Cyperus articulatus L.

Cyperaceae

Roots/rhizome

Hexane

Samje et al. (2014)

Euphorbia hirta L.

Euphorbiaceae

Whole plant

Ethanol, hexane, chloroform and ethyl acetate fractions

Attah et al. (2013) Ndjonka et al. (2011)

Margaritaria discoidea (Baill.)

Euphorbiaceae

Leaves, stem barks and roots

hexane, methylene chloride, ethyl acetate and methanol

Cho-Ngwa et al. (2010)

Tragia benthamii Bak.

Euphorbiaceae

Roots and seeds and leaves

Hexane, methylene chloride and methanol

Cho-Ngwa et al. (2016) Continued

TABLE 1  Medicinal plants species with antionchocerca activity—cont’d Species

Family name

Parts used

Solvent for extraction

References

Discoglypremna caloneura (Pax) Prain

Euphorbiaceae

Bark

Isolated compounds

Nyasse et al. (2006)

Cassia aubrevillei Pellegr.

Fabaceae

Roots

Aqueous

Kilian et al. (1990)

Acacia nilotica (L.) Willd. ex Delile

Fabaceae

Fruit

Hydro-alcoholic

Vildina et al. (2017)

Homalium africanum (Hook f.) Benth.

Flacourtiaceae

Stem barks and roots

Hexane, methylene chloride, ethyl acetate and methanol

Cho-Ngwa et al. (2010)

Ocimum gratissimum L.

Lamiaceae

Leaves

Extract of oil

Usip et al. (2006)

Khaya senegalensis Desr. A. Juss.

Meliaceae

Bark

Ethanol

Attah et al. (2013)

Trichilia emetica Vahl

Meliaceae

Seeds

Methanol

Titanji et al. (1990)

Carapa procera DC.

Meliaceae

Seeds

Methanol

Titanji et al. (1990)

Piper umbellatum L.

Piperaceae

Leaves

Methylene chloride

Cho-Ngwa et al. (2016)

Morinda lucida Benth.

Rubiaceae

Leaves

Methanol

Samje et al. (2014)

Craterispermum laurinum (Poir.) Benth.

Rubiaceae

Leaves

Methanol

Samje et al., (2014)

Nauclea latifolia Sm.

Rubiaceae

Stem bark

Hydro-methanol

Fakae et al. (2000)

Vitellaria paradoxa C.F. Gaertn.

Sapotaceae

Stem barks, leaves and roots

Ethanol

Ndjonka et al. (2017)

Lantana camara L.

Verbenaceae

Bark, leaves

Ethanol and hexane

Ngwewondo et al. (2018)

The management of onchocerciasis  Chapter | 2  45

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46  Natural products in vector-borne disease management Chopra, R.N., Nayar, S.L., Chopra, I.C., Asolkar, L.V., Kakkar, K.K., Chakre, O.J., Varma, B.S., 2002. Glossary of Indian Medicinal Plants. Council of Scientific and Industrial Research, New Delhi. Comley, J.C., Townson, S., Rees, M.J., Dobinson, A., 1989. The further application of MTT-­ formazan colorimetry to studies on filarial worm viability. Trop. Med. Parasitol. 40, 311–316. Dembélé, U., Lykke, A.M., Koné, Y., Témé, B., Kouyaté, A.M., 2015. Use-value and importance of socio-cultural knowledge on Carapa procera trees in the Sudanian zone in Mali. J. Ethnobiol. Ethnomed. 11. Article number: 14. Domis, M., Oyen, L.P.A., 2008. In: Schmelzer, G.H., Gurib-Fakim, A. (Eds.), Piper umbellatum L. PROTA (Plant Resources of Tropical Africa)/Ressources végétales de l’Afrique tropicale, Wageningen, Netherlands. Duke, B.O.L., 1993. The population dynamics of Onchocerca volvulus in the human host. Trop. Med. Parasitol. 44 (2), 61–68. Ebigwai, J.K., Ilondu, E.M., Markson, A., Ekeleme, E., 2012. In vitro evaluation of the essential oil extract of six plant species and ivermectin on the microfilaria larva of Simulium yahense. Res. J. Med. Plant 6 (6), 461–465. Egbert, P.R., Jacobson, D.W., Fiadoyor, S., Dadzie, P., Ellingson, K.D., 2005. Onchocerciasis: a potential risk factor for glaucoma. Br. J. Ophthalmol. 89 (7), 796–798. Ewan, J., 1964. Woody Plants of Ghana, with Special Reference to Their Uses. Oxford University Press, F. R. Irvine. Fakae, B.B., Campbell, A.M., Barrett, J., Scott, I.M., Teesdale‐Spittle, P.H., Liebau, E., Brophy, P.M., 2000. Inhibition of glutathione S‐transferases (GSTs) from parasitic nematodes by extracts from traditional Nigerian medicinal plants. Phytother. Res. 14 (8), 630–634. Gaware, V.M., Dhamak, K.B., Kotade, K.B., Dolas, R.T., Somwanshi, S.B., Nikam, V.K., Khadse, A.N., 2011. Onchocerciasis: an overview. Pharmacology 1, 1012–1022. George, G.H., Palmieri, J.R., Connor., D. H., 1985. The onchocercal nodule: interrelationship of adult worms and blood vessels. Am. Soc. Trop. Med. Hyg. 34, 1144–1148. Ghisalberti, E.L., 2020. Lantana camara. In: Encyclopedia of Biological Invasions. vol. 71. University of California Press, pp. 428–430. Gidado, A., Ameh, D.A., Atawodi, S.E., 2005. Effect of Nauclea latifolia leaves aqueous extracts on blood glucose levels of normal and alloxan-induced diabetic rats. Afr. J. Biotechnol. 4 (1), 91–93. Hadi, S., Bremner, J.B., 2001. Initial studies on alkaloids from Lombok medicinal plants. Molecules 6 (2), 117–129. Huber, W., Koella, J.C., 1993. A comparison of three methods of estimating EC50 in studies of drug resistance of malaria parasites. Acta Trop. 55 (4), 257–261. Hutchings, A., Scott, A.H., Lewis, G., Cunningham, A.B., 1997. Zulu Medicinal Plants: An Inventory. University of Natal Press, Durban. Iwu, M.M., 1993. Handbook of African Medicinal Plants. CRC Press. James, W.D., Berger, T.G., Elston, D.M., Odom, R.B., 2006. Andrews’ Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 978-0-7216-2921-6. Jansen, P.C.M., 2005. In: Jansen, P.C.M., Cardon, D. (Eds.), Craterispermum laurinum (DC.) Benth. PROTA (Plant Resources of Tropical Africa)/Ressources végétales de l’Afrique Tropicale, Wageningen, Netherlands. Jillson, O.F., 1982. Andrews’ Diseases of the Skin, Clinical Dermatology. Saunders Elsevier. Jiofack, T., Fokunang, C., N, G., 2009. Ethnobotanical uses of some plants of two ethnoecological regions of Cameroon. Afr. J. Pharm. Pharmacol 3 (13), 664–684. Kalmobé, J., Ndjonka, D., Dikti, J., Liebau, E., 2017. Antifilarial activity of Cucurbita pepo ovifera var ovifera (Cucurbitaceae) on Onchocerca ochengi adult Worms. Br. J. Pharm. Res. 17 (2), 1–8.

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48  Natural products in vector-borne disease management Oliver-Bever, B., 1985. Medicinal Plants in Tropical West Africa. Cambridge University Press, Cambridge. Orwa, C., Mutua, A., Kindt, R., Jamnadass, R., Anthony, S., 2009. Eugenia Stipitata. Agroforestry Database: A Tree Reference and Selection Guide Version 4.0. World Agroforestry Centre, pp. 1–8. Osei-Tweneboana, M.Y., Eng, J.K.L., Boakye, D.A., Gyapong, J.O., Prichard, R.K., 2007. Prevalence and intensity of Onchocerca volvulus infection and efficacy of ivermectin in endemic communities in Ghana: a two-phase epidemiological study. Lancet 369, 2021–2029. Otabil, K.B., Gyasi, S.F., Awuah, E., Obeng-Ofori, D., Atta-Nyarko, R.J., Andoh, D., et al., 2019. Prevalence of onchocerciasis and associated clinical manifestations in selected hypoendemic communities in Ghana following long-term administration of ivermectin. BMC Infect. Dis. 19 (1), 1–7. Page, B., Page, M., Noel, C., 1993. A new fluorometric assay for cytotoxicity measurements in vitro. Int. J. Oncol. 3 (3), 473–476. Prost, A., 1986. The burden of blindness in adult males in the savanna villages of West Africa exposed to onchocerciasis. Trans. R. Soc. Trop. Med. Hyg. 80 (4), 525–527. Rabelo, M., Souza, E.P., Soares, P.M.G., Miranda, A.V., Matos, F.J.A., Criddle, D.N., 2003. Antinociceptive properties of the essential oil of Ocimum gratissimum L. (Labiatae) in mice. Braz. J. Med. Biol. Res. 36 (4), 521–524. Rao, U.R., Salinas, G., Mehta, K., Klei, T.R., 2000. Identification and localization of glutathione S-transferase as a potential target enzyme in Brugia species. Parasitol. Res. 86, 908–915. Rao, R.U., Huang, Y., Fischer, K., Fischer, P.U., Weil, G.J., 2009. Brugia malayi: effects of nitazoxanide and tizoxanide on adult worms and microfilariae of filarial nematodes. Exp. Parasitol. 121 (1), 38–45. Reddy, B.S., Rao, N.R., Vijeepallam, K., Pandy, V., 2017. Phytochemical, pharmacological and biological profiles of Tragia species (family: Euphorbiaceae). Afr. J. Tradit. Complement. Altern. Med. 14 (3), 105–112. Richard-Lenoble, D., 2006. Onchocerca volvulus. EMC - Biologie Médicale 1 (1), 1–8. Samje, M., Metuge, J., Mbah, J., Nguesson, B., Cho-Ngwa, F., 2014. In  vitro anti-Onchocerca ochengi activities of extracts and chromatographic fractions of Craterispermum laurinum and Morinda lucida. BMC Complement. Altern. Med. 14. Article number: 325. Schmelzer, G., Gurib-Fakim, A., 2007. Rauvolfia vomitoria Afzel. PROTA (Plant Resources of Tropical Africa, Wageningen, Netherlands. Schmid, R., Neuwinger, H.D., 2001. African traditional medicine: a dictionary of plant use and applications, with supplement: search system for diseases. Taxon 50 (1), 310. Schultes, R.E., 1991. Cornucopia: A Source Book of Edible Plants. Kampong Publications, ISBN: 0-9628087-0-9. Schulz-Key, H., Soboslay, P.T., 1994. Reproductive biology and population dynamics of Onchocerca volvulus in the vertebrate host. Parasite 1 (1), 53–55. Seigler, D.S., 2003. Phytochemistry of Acacia—Sensu lato. Biochem. Syst. Ecol. 31 (8), 845–873. Shuaibu, M.N., Pandey, K., Wuyep, P.A., Yanagi, T., Hirayama, K., Ichinose, A., Tanaka, T., Kouno, I., 2008. Castalagin from Anogeissus leiocarpus mediates the killing of Leishmania in vitro. Parasitol. Res. 103 (6), 1333–1338. Smith, B.B., James, A.M., Fidelis, C.N., Jonathan, A.M., Simon, M.N.E., 2015. Isolation and characterization of filaricidal compounds from the stem bark of Voacanga africana, a plant used in the traditional treatment of onchocerciasis in Cameroon. J. Med. Plant Res. 9 (14), 471–478. Somorin, A.O., 1983. Onchocerciasis. Int. J. Dermatol. 22, 182–188.

The management of onchocerciasis  Chapter | 2  49 Sulistiarini, D., 1999. Ocimum gratissimum L. In: Oyen, L.P.A., Dung, N.X. (Eds.), Plant Resources of South-East Asia No 19: Essential-Oil Plants. Bogor, Indonesia, PROSEA Foundation. Taylor, L., 2005. The Healing Power of Rainforest Herbs: A Guide to Understanding and Using Herbal Medicinals. Square One Publishers, p. 519. Tchana, M.E.S., Fankam, A.G., Mbaveng, A.T., Nkwengoua, E.T., Seukep, J.A., Tchouani, F.K., Nyassé, B., Kuete, V., 2014. Activities of selected medicinal plants against multi-drug resistant gram-negative bacteria in Cameroon. Afr. Health Sci. 14 (1), 167–172. Titanji, V.P.K., Evehe, M.S., Ayafor, J.F., Kimbu, S.F., 1990. Novel Onchocerca volvulus filaricides from Carapa procera, polyalthia suaveolens and Pachypodanthium staudtii. Acta Leiden. 59 (1–2), 377–382. Toukam, P.D., Yamthe, L.R.T., Tchinda, A.T., Boyom, F.F., Mbafor, J.T., 2017. Antiplasmodial, anti-inflammatory and DPPH scavenging activities of extracts of the stem barks of Discoglypremna caloneura (Pax) Prain. World J. Pharm. Sci. 5 (6), 235–239. Usip, L., Opara, K.N., Ibanga, E.S., Atting, I.A., 2006. Longitudinal evaluation of repellent activity of Ocimum gratissimum (Labiatae) volatile oil against Simulium damnosum. Mem. Inst. Oswaldo Cruz 101 (2), 201–205. Vildina, J.D., Kalmobe, J., Djafsia, B., Schmidt, T.J., Liebau, E., Ndjonka, D., 2017. Anti-­ Onchocerca and anti-Caenorhabditis activity of a hydro-alcoholic extract from the fruits of Acacia nilotica and some proanthocyanidin derivatives. Molecules 22 (5). 3390 22050748. Watson, H.E., 1958. The wealth of India. Nature 181 (4615), 1026–1027. WHO, 1976. Epidemiology of onchocerciasis. Report of a WHO expert committee. World Health Organ. Tech. Rep. Ser. 597, 1–94. Wickens, G.E., Burkill, H.M., 1986. The useful plants of west tropical Africa. Kew Bull. 41 (2), 471. Williamson, E.M., 2002. Major Herbs of Ayurveda. Churchill Livingstone, China. Yemoa, A.L., Gbenou, J.D., Johnson, R.C., Djego, J.G., Zinsou, C., Moudachirou, M., QuetinLeclercq, J., Bigot, A., Portaels, F., 2008. Identification and phytochemical study of plants used in the traditional treatment of Buruli ulcer in Benin. Ethnopharmacol. 42, 48–55. Zhang, H., Tan, J., VanDerveer, D., Wang, X., Wargovich, M.J., Chen, F., 2009. Khayanolides from African mahogany Khaya senegalensis (Meliaceae): a revision. Phytochemistry 70 (2), 294–299.

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Chapter 3

Plant-derived compounds as potential treatment for arboviruses Vivaldo Gomes da Costaa and Marielena Vogel Saivishb a

Department of Cellular Biology, University of Brasília, Brasília, District Federal, Brazil, Virology Research Laboratory, Department of Dermatological, Infectious and Parasitic Diseases, Faculty of Medicine of São Jose do Rio Preto, São José do Rio Preto, Brazil b

Introduction Infectious diseases have been a major concern for human health for thousands of years, and they have been well known in ancient civilizations (Egyptian, Greek, Roman, and Mesopotamian). The etiological agent of certain infectious diseases can be caused by a wide variety of microorganisms (bacteria, fungi, protozoa, and viruses) (Kausar et al., 2021; Huremović, 2019; Balloux and van Dorp, 2017). The structure of viruses is relatively simple because it consists of a protein coat, nucleic acid, viral enzymes, and, sometimes, a lipid envelope. Another striking feature of viruses is their nature as obligate intracellular pathogens, thus requiring the use of the host cell’s biochemical machinery for replication (Balloux and van Dorp, 2017; Champe and Fisher, 2007). Because of the simplicity of viruses in terms of their chemical constitution, when compared to other microorganisms, and because of their obligatory intracellular parasitism, they create extreme difficulties in the development of drugs with selective toxicity (Huremović, 2019; Champe and Fisher, 2007). Moreover, because of the viral replication cycle, antiviral drugs can affect the function of the hosts’ pathways, resulting in a high risk of side effects (Bule et al., 2019). Therefore, the main concern regarding the development of antiviral drugs is that they act on a specific target, increasing the selectivity and reducing the toxic effects (Dal Pozzo and Thiry, 2014). The first antiviral drug approved was idoxuridine, in 1963, and later 118 drugs were approved against nine infectious diseases in humans (human immunodeficiency virus, hepatitis B virus, hepatitis C virus, human herpesvirus, human cytomegalovirus, influenza virus, respiratory syncytial virus, human papillomavirus, and varicella-zoster virus infections) (De Clercq and Li, 2016). Natural Products in Vector-Borne Disease Management. https://doi.org/10.1016/B978-0-323-91942-5.00008-2 Copyright © 2023 Elsevier Inc. All rights reserved.

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Approved drugs show how difficult it is to get approval of drugs for marketing, as there are more than 220 viruses causing infection in humans and only 5% of viral species have clinical antiviral treatments (Tompa et al., 2021; Woolhouse et al., 2012). This complexity involves the fact that drug development can be divided into several phases: preclinical phase (drug testing in nonhuman), which consists of cell culture (in vitro) and animals (in vivo) testing laboratories. The preclinical phase usually takes 3 to 4 years to complete; if successful, this phase is followed by an approval from the regulatory agencies such as the Food and Drug Administration (FDA), United States, as an investigational new drug. The next steps are clinical phases 1, 2, and 3 with drug testing in people. In clinical phase 1, safety tests are carried out for a small group of healthy volunteers; the objective is to determine the lowest effective dose of the new treatment and highest tolerated dose. Regarding phase 2, safety testing takes place in a small group of patients with the disease to analyze whether the drug is effective and also defines their therapeutic regimen. For drugs that reach phase 3 with the dosage and therapeutic regimen generally defined, there is an increase in the number of patients tested and the effectiveness of the new drug is evaluated compared to other existing treatments, if any; more robust information on potential adverse effects and contraindications is also obtained. Finally, the manufacturer then files a new drug application with the FDA for approval, but the regulatory agencies are still in postapproval surveillance (phase 4) (Lipsky and Sharp, 2001). In this chapter, we will discuss the use of plant-derived antiviral agents as a potential source of drug development for the treatment of arbovirus (arthropod-­ borne viruses) infections. Arboviruses comprise an ecological and diverse group of viruses that are mostly transmitted by mosquitoes, phlebotomine sandflies, and ticks, including viruses of wide geographical spread causing human diseases, such as dengue, yellow fever, West Nile, Japanese encephalitis, Zika, and chikungunya (Jones et al., 2020). Plants products and their derivatives provide a huge source of new antiviral drugs that may have the potential to treat viral diseases. Plant-derived products have been a source of therapeutic potential for millennia and are still to this day (Atanasov et al., 2015; Mishra et al., 2013).

Alphaviruses Alphaviruses, belonging to the Togaviridae family, are transmitted to humans by arthropods, causing severe illnesses, including chronic arthritis and fatal encephalitis (Fox and Diamond, 2016; Rivas et al., 1997). Viral particles are enveloped and has an icosahedral capsid that coats and protects the genetic material of positive-sense, single-stranded RNA with the following species that can cause acute or chronic musculoskeletal and joint-associated syndromes: Chikungunya virus (CHIKV), Ross River virus, Mayaro virus (MAYV), Semliki Forest virus, Sindbis virus, and O’nyong-nyong virus (Silva and Dermody, 2017). The

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following pathogens are associated with the central nervous system: Eastern equine encephalitis virus, Western equine encephalitis virus, and Venezuelan equine encephalitis virus. In summary, alphaviruses are of great concern to human public health because they are considered emerging and re-emerging in different regions of the world (Olivia et al., 2015). Therefore, it is necessary to promote research aimed at contributing to the understanding, prevention, and treatment of viral diseases. In this sense, the next sections include information regarding the alphavirus species and the antiviral treatments that have been studied.

CHIKV CHIKV, grouped within the Alphavirus genus of the Togaviridae family, is the etiological agent of chikungunya fever, which is an arboviral illness characterized by a sudden onset of fever associated with muscle and joint pain. CHIKV was first isolated from humans and mosquitoes in the 1950s during a viral outbreak in Tanzania by a doctor at Lulindi and Newala Hospital. CHIKV has since (re-)emerged and spread to several other geographical areas with infection reported in different countries from tropical and subtropical continents. Regarding viral transmission, both urban and sylvatic CHIKV transmission cycles have been described with Aedes aegypti and Aedes albopictus known as the main vectors in the urban cycle, with horizontal and vertical transmission observed between vectors and humans (Silva et al., 2018).

MAYV MAYV belongs to the Togaviridae family and the Alphavirus genus. The disease caused by MAYV is called Mayaro fever, which results in nonspecific symptoms similar to that of chikungunya fever such as an acute fever (˃38°C) lasting 4 to 5 days, headache, eye pain, skin rash, myalgia, and arthralgia, which can last from 3 to 6 months, or it can progress to a chronic disease exhibiting symptoms similar to that of arthritis. Regarding MAYV transmission, the main vector belongs to the species Haemagogus janthinomys. Normally, humans are unintentionally infected by MAYV when entering a natural environment in Central or South America, thus becoming susceptible to coming in contact with the virus vector (Auguste et al., 2015; Vasconcelos, 1998).

Flaviviruses Flaviviruses, belonging to the Flaviviridae family, are transmitted to humans by hematophagous mosquito vectors and/or ticks, predominantly causing flulike symptoms; however, they can also cause severe hemorrhagic syndromes disease, neurologic manifestations, and congenital anomalies (Slon Campos et al., 2018; Chan et al., 2016). The viral particle size is approximately 50 nm,

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enveloped with positive single-stranded RNA. The viral genome (∼11 kb) encodes a polyprotein and after its processing, three structural proteins (membrane, envelope, and capsid proteins) and seven nonstructural proteins (NS1, NS2A/2B, NS3, NS4A/4B, and NS5) are generated. The following flavivirus species cause disease dynamics: dengue virus (DENV), ZIKV, West Nile virus (WNV), and Japanese encephalitis virus (JEV). In summary, the threat of flavivirus emergence and re-emergence highlights the need for a detailed fundamental understanding of these viruses to apply countermeasures that can reduce their impact on public health (Pierson and Diamond, 2020).

Dengue virus Dengue virus (DENV) belongs to the Flavivirus genus, Flaviviridae family, and has genetic material consisting of positive sense, single-stranded RNA. The virion has a spherical morphology of 40–60 nm in diameter, but the capsid is icosahedral, and the lipid envelope contains an envelope and membrane proteins. The DENV group contains four genetically and antigenically related viruses that are known as serotypes 1–4. Every year, there are approximately 390 million cases of dengue. About 70% of the cases come from Asian countries, mainly India, which registers 34% of the global burden of the disease. India is followed by Africa (16%) and America (14%). For the America, Brazil and Mexico alone register more than 50% of dengue cases on the continent (Wilson and Chen, 2014). Regarding the clinical picture of dengue, DENV infection, in most cases, is asymptomatic, but it can result in serious clinical conditions such as severe dengue with hemorrhagic fever or shock syndrome dengue fever (Guzman et al., 2016).

Zika virus Zika virus (ZIKV) is a neurotropic arbovirus whose main transmission vector is Aedes aegypti. ZIKV has other modes of transmission including vertical transmission from an infected mother to the fetus through the placenta (Chan et al., 2016). ZIKV was first isolated from the blood of a rhesus monkey in 1947 in the Zika Forest, Uganda. Later, the virus spread sporadically to the Asian and American continents. Although ZIKV infection is predominantly asymptomatic, it has symptoms such as fever, headache, retro-orbital pain, chills, malaise, sore throat, and pruritic maculopapular rash. In addition, regarding complications of ZIKV infections, there is a positive association between cases of Guillain-Barré syndrome and cases of ZIKV. In Brazil, a possible association between intrauterine infection by ZIKV and microcephaly was initially proposed in 2015. This was based on the detection of a sudden increase in the incidence of microcephaly, after confirmation of the circulation of this virus in the country (Agumadu and Ramphul, 2018; Chan et al., 2016).

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West Nile virus West Nile virus (WNV) is a mosquito-borne flavivirus containing enveloped virus particle, single-stranded RNA genome with positive polarity. The virus is an emerging neurotropic human pathogen that causes West Nile fever and encephalitis. WNV is mainly transmitted by mosquitoes of the Culex genus, which can be mentioned: C. quinquefasciatus, C. stigmatosoma, C. thriambus, C. pipiens, and C. nigripalpus. WNV is considered to be maintained in nature in an enzootic mosquito-bird-mosquito transmission cycle (Colpitts et al., 2012). It is endemic to many parts of the world. It was first isolated from a febrile patient in Uganda in 1937, and later, it was detected in the United States, Europe, the Middle East, and Africa (Suthar et al., 2013).

Japanese encephalitis virus Japanese encephalitis virus (JEV) is an emerging arbovirus, which is an important cause of encephalitis in humans in the South East Asia region (Filgueira and Lannes, 2019; Simon-Loriere et al., 2017). Concerning the viral transmission cycle, Culex and Aedes mosquitos transfer JEV between birds and other species. Since the viral load is low in human JEV infection, then humans are considered dead-end hosts with approximately 1% succumbing to encephalitis. Therefore, it is observed that most cases of JEV infection are asymptomatic, but for severe cases, the fatality rate is high as it can be higher than 25% (Pearce et al., 2018).

Plant-derived antivirals against arboviruses infections The (re)emergence of arboviral diseases caused by ZIKV, DENV, WNV, JEV, CHIKV, and MAYV has raised international concerns and continues to have an impact on socioeconomic systems. Mosquito-borne viral diseases are transmitted by culicine mosquitoes, mainly those in the Aedes and Culex genera. DENV remains one of the most important arboviruses, and annually millions of infections are caused by the DENV, resulting in thousands of deaths. WNV emerged in North America in 1999 and a total of 51,702 cases and 2376 deaths were reported. Recent estimates indicate that the number of WNV infections is 3.5 million in the United States (Ronca et al., 2021). The recent introduction of CHIKV and ZIKV in the Americas has caused outbreaks and has impacted public health and the economy. It is worth mentioning that during the emergence of the ZIKV infection, it was estimated that at least 3000 cases of newborn microcephaly with more than a million people were infected in Brazil (Dong and Dimopoulos, 2021; Sikka et al., 2016; Stanaway et al., 2016). In summary, arboviruses are a significant cause of virus-associated morbi-mortality in humans worldwide, and the lack of vaccines (except for JEV) or antiviral drugs against arboviruses reinforces the importance of continued studies aimed at antiviral research or arboviral disease prevention (Hegde and Gore, 2017). In this context,

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plant-derived drugs seem to be a good option to reach the desired antiviral effect against a specific arboviral infection. Several plant-derived compounds have been tested in vitro for their antiviral potential against arbovirus infections. Thus, the plant extracts and natural compounds derived from plants showed positive results in inhibiting a specific viral agent. In the next paragraphs, let us briefly discuss some of these plant extracts and natural compounds (Fig. 1). Aphloia theiformis, a small shrub native to East Africa and the island of Madagascar, is an edible and medicinal endemic plant from the Reunion and Indian Ocean Islands, which exerts health benefits such as antioxidant and antiinflammatory effects because it is highly concentrated in polyphenols fraction, alkaloids molecules, triterpenoid, and steroidal glycosides. The authors assessed whether solvent-free extracts of the aforementioned plants prevent ZIKV and DENV infections in vitro. The concentration of plant extracts needed to inhibit 50% of the ZIKV infectivity was 100 μg/mL. The data showed that Aphloia theiformis is a prominent therapeutic target in combating infections caused by ZIKV and DENV (Clain et al., 2018). The other extracts evaluated for their applicability as antiviral agents were four culinary and medicinal mushrooms cultivated in Malaysia: Lignosus rhinocerotis, Pleurotus giganteus, Hericium erinaceus, and Schizophyllum commune. Extracts from these mushrooms were used to test their effect in inhibiting DENV-2 replication in cell culture in the laboratory. The concentration of plant extract needed to inhibit 50% of viral infectivity ranged from 226 to 637 μg/mL. The data revealed that mushroom aqueous extracts interfere with DENV-2 infection, which involves the steps of virion attachment and the step of entry in the cytoplasm of host cell (Ellan et al., 2019). Among the plant extracts mentioned in Fig. 1, silymarin is a complex extracted from Silybum marianum (milk thistle). Silybum marianum is a species of flowering plant belonging to the Asteraceae family, originating from southern Europe to Asia and currently found throughout the world. Regarding silymarin complex, it consists of a flavonoid (taxifolin) and flavonoglignans (silibinins, isosilibinins, silydianin, silychristin, and isosilychristin). For the silymarin complex, antiviral activity against CHIKV and hepatitis C virus has been shown. Recent studies have shown in vitro antiviral activity against MAYV. The beneficial effects of the silymarin complex are possibly associated with a protective effect on cellular oxidative stress induced by MAYV infection (Camini et al., 2018). Natural compounds extracted from plants contain a large number of molecules that exhibit inhibitory effects on viral infections. In this context, quercetin (3,3′,4′5,7-pentahydroxyflavone) has been shown to have in vitro inhibitory effects against mosquito-borne flavivirus (DENV) and alphavirus (MAYV). For DENV infection, the half maximal inhibitory concentration of quercetin was 35.7 μg/mL when it was used after virus adsorption into the cells (Zandi et al., 2011). A low concentration of quercetin was also observed to inhibit 90% of the viral infectivity of MAYV; in this case, only 25 μg/mL of the molecule was needed (dos Santos et al., 2014).

Potential treatment for arboviruses  Chapter | 3  57

FIG.  1  Plant extracts and natural compounds derived with antiviral potential against flavivirus and alphavirus infections. The source of the compound and possible mechanisms of action in vitro are shown (Clain et al., 2019; Moghaddam et al., 2014; Balasubramanian et al., 2019; Mounce et al., 2017; Chen et al., 2013; Vázquez-Calvo et al., 2017; Carneiro et al., 2016; Fang et al., 2015; Gaudry et al., 2018; Zhang et al., 2012; Frabasile et al., 2017; Lee et al. 2019a,b; Malakar et al., 2018; Lani et al., 2015, 2016; Weber et al., 2015; Kaur et al., 2013).

Curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione), a flavonoid from the flavonol subgroup, is a natural compound derived from turmeric (Curcuma longa). The turmeric (Indian Saffron) is a yellow pigment used spice and coloring agent in food. Turmeric is a type of herb belonging to the ginger family, which is widely grown in southern and southwestern Asia. The antiviral activity of curcumin has been observed to inhibit HIV replication. In relation to arboviral infection, curcumin exerted inhibitory activity in vitro for DENV and CHIKV infections (Chen et al., 2013). Baicalein (5,6,7-trihydroxyflavone) is another flavonoid among the flavone subgroup that exhibits antiviral activities against herpes viruses, influenza virus,

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and human cytomegalovirus (Xu et al., 2010; Evers et al., 2005; Lyu et al., 2005). The in vitro antiviral effect of baicalein was also observed against CHIKV and JEV. The half-maximal concentration of baicalein was 84.18 μg/mL, indicating that it is a good antiviral molecule; however, the mechanism conferring the antiviral properties of baicalein anti-JEV is unknown (Johari et al., 2012). Resveratrol (3,5,4′-trihydroxy-trans-stilbene), a stilbenoid derived mainly from grapes and peanuts, has been shown to exert inhibitory effects against ZIKV. From the experiments, it was suggested that resveratrol inhibited viral binding at the host cell and had a direct effect on viral particles, probably due to virucidal activity. In summary, in the postinfection treatment, with 80 μM of RES, a > 90% reduction in viral titer and ZIKV mRNA copy number was observed (Mohd et al., 2019). For many centuries, several plant-derived compounds represent a valuable resource for active compounds that exhibit antiviral activities. This review provides a long list of molecules resulting from plants that have shown antiviral activities against several arboviruses in vitro. However, the data mainly reflect in in vitro antiviral trials, thus showing the importance of future studies analyzing the molecules in in vivo trials and their effects in randomized, double-blind, placebo-controlled clinical trials with humans.

References Agumadu, V.C., Ramphul, K., 2018. Zika virus: a review of literature. Cureus 10, e3025. https://doi. org/10.7759/cureus.3025. Atanasov, A.G., Waltenberger, B., Pferschy-Wenzig, E.M., Linder, T., Wawrosch, C., Uhrin, P., 2015. Discovery and resupply of pharmacologically active plant-derived natural products: a review. Biotechnol. Adv. 33, 1582–1614. Auguste, A.J., Liria, J., Forrester, N.L., Giambalvo, D., Moncada, M., Long, K.C., et al., 2015. Evolutionary and ecological characterization of Mayaro virus strains isolated during an outbreak, Venezuela, 2010. Emerg. Infect. Dis. 21, 1742–1750. Balasubramanian, A., Pilankatta, R., Teramoto, T., Sajith, A.M., Nwulia, E., Kulkarni, A., Padmanabhan, R., et al., 2019. Inhibition of dengue virus by curcuminoids. Antivir. Res. 162, 71–78. Balloux, F., van Dorp, L., 2017. Q&A: what are pathogens, and what have they done to and for us? BMC Biol. 15, 1–6. Bule, M., Khan, F., Niaz, K., 2019. Antivirals: past, present and future. In: Malik, Y., Singh, R., Yadav, M. (Eds.), Recent Advances in Animal Virology. vol. 6. Springer, Singapore, pp. 425–446. Camini, F.C., da Silva, T.F., da Silva Caetano, C.C., Almeida, L.T., Ferraz, A.C., Alves Vitoreti, V.M., et al., 2018. Antiviral activity of silymarin against Mayaro virus and protective effect in virus-induced oxidative stress. Antivir. Res. 158, 8–12. Carneiro, B.M., Batista, M.N., Braga, A.C.S., Nogueira, M.L., Rahal, P., 2016. The green tea molecule EGCG inhibits Zika virus entry. Virology 496, 215–218. Champe, H.R.A.P.C., Fisher, B.D., 2007. Lippincott’s Illustrated Reviews: Microbiology. Lippincott Williams & Wilkins, Philadelphia. Chan, J.F., Choi, G.K., Yip, C.C., Cheng, V.C., Yuen, K.Y., 2016. Zika fever and congenital Zika syndrome: an unexpected emerging arboviral disease. J. Inf. Secur. 72, 507–524. Chen, T.-Y., Chen, D.-Y., Wen, H.-W., Ou, J.-L., Chiou, S.-S., Chen, J.-M., et al., 2013. Inhibition of enveloped viruses infectivity by curcumin. PLoS One 8 (5), e62482.

Potential treatment for arboviruses  Chapter | 3  59 Clain, E., Sinigaglia, L., Koishi, A.C., Gorgette, O., Gadea, G., Viranaicken, W., et al., 2018. Extract from Aphloia theiformis, an edible indigenous plant from Reunion Island, impairs Zika virus attachment to the host cell surface. Sci. Rep. 8, 10856. Clain, E., Haddad, J.G., Koishi, A.C., Sinigaglia, L., Rachidi, W., Desprès, P., et  al., 2019. The polyphenol-­rich extract from Psiloxylon mauritianum, an endemic medicinal plant from Reunion Island, inhibits the early stages of dengue and Zika virus infection. Int. J. Mol. Sci. 20, 1860. Colpitts, T.M., Conway, M.J., Montgomery, R.R., Fikrig, E., 2012. West Nile virus: biology, transmission, and human infection. Clin. Microbiol. Rev. 25, 635–648. Dal Pozzo, F., Thiry, E., 2014. Antiviral chemotherapy in veterinary medicine: current applications and perspectives. Rev. Sci. Tech. 33, 25812204. De Clercq, E., Li, G., 2016. Approved antiviral drugs over the past 50 years. Clin. Microbiol. Rev. 29, 695–747. Dong, S., Dimopoulos, G., 2021. Antiviral compounds for blocking arboviral transmission in mosquitoes. Viruses 13, 108. dos Santos, A.E., Kuster, R.M., Yamamoto, K.A., Salles, T.S., Campos, R., Meneses, M.D.F., et al., 2014. Quercetin and quercetin 3-O-glycosides from Bauhinia longifolia (Bong.) Steud. show anti-Mayaro virus activity. Parasit. Vectors 7, 130. Ellan, K., Thayan, R., Raman, J., Hidari, K.I.P.J., Ismail, N., Sabaratnam, V., 2019. Anti-viral activity of culinary and medicinal mushroom extracts against dengue virus serotype 2: an in-vitro study. BMC Complement. Altern. Med. 19, 260. Evers, D.L., Chao, C.F., Wang, X., Zhang, Z., Huong, S.M., Huang, E.S., 2005. Human cytomegalovirus-­inhibitory flavonoids: studies on antiviral activity and mechanism of action. Antivir. Res. 68, 124–134. Fang, C.-Y., Chen, S.-J., Wu, H.-N., Ping, Y.-H., Lin, C.-Y., Shiuan, D., et al., 2015. Honokiol, a lignan biphenol derived from the Magnolia tree, inhibits dengue virus type 2 infection. Viruses 7, 4894–4910. Filgueira, L., Lannes, N., 2019. Review of emerging Japanese encephalitis virus: new aspects and concepts about entry into the brain and inter-cellular spreading. Pathogens. 8, 111. Fox, J.M., Diamond, M.S., 2016. Immune-mediated protection and pathogenesis of chikungunya virus. J. Immunol. 197, 4210–4218. Frabasile, S., Koishi, A.C., Kuczera, D., Silveira, G.F., Verri, W.A., Duarte Dos Santos, C.N., Bordignon, J., et al., 2017. The citrus flavanone naringenin impairs dengue virus replication in human cells. Sci. Rep. 7, 41864. Gaudry, A., Bos, S., Viranaicken, W., Roche, M., Krejbich-Trotot, P., Gadea, G., et al., 2018. The flavonoid isoquercitrin precludes initiation of Zika virus infection in human cells. Int. J. Mol. Sci. 19, 1093. Guzman, M., Gubler, D., Izquierdo, A., Martinez, M., Halstead, S.B., 2016. Dengue infection. Nat Rev Dis Primers. 2, 16055. Hegde, N.R., Gore, M.M., 2017. Japanese encephalitis vaccines: immunogenicity, protective efficacy, effectiveness, and impact on the burden of disease. Hum. Vaccin. Immunother. 13, 1–18. Huremović, D., 2019. Brief history of pandemics (pandemics throughout history). In: Psychiatry of Pandemics, pp. 7–35. Johari, J., Kianmehr, A., Mustafa, M.R., Abubakar, S., Zandi, K., 2012. Antiviral activity of baicalein and quercetin against the Japanese encephalitis virus. Int. J. Mol. Sci. 13, 16785–16795. Jones, R., Kulkarni, M.A., Davidson, T.M.V., RADAM-LAC Research Team, Talbot, B., 2020. Arbovirus vectors of epidemiological concern in the Americas: a scoping review of entomological studies on Zika, dengue and chikungunya virus vectors. PLoS One 15, e0220753. Kaur, P., Thiruchelvan, M., Lee, R.C.H., Chen, H., Chen, K.C., Ng, M.L., et al., 2013. Inhibition of chikungunya virus replication by harringtonine, a novel antiviral that suppresses viral protein expression. Antimicrob. Agents Chemother. 57, 155–167.

60  Natural products in vector-borne disease management Kausar, S., Khan, F.S., Rehman, M.I.M.U., Akram, M., Riaz, M., Rasool, G., et  al., 2021. A review: mechanism of action of antiviral drugs. Int. J. Immunopathol. Pharmacol. 35. 20587384211002621. Lani, R., Hassandarvish, P., Chiam, C.W., Moghaddam, E., Chu, J.J.H., Rausalu, K., et al., 2015. Antiviral activity of silymarin against chikungunya virus. Sci. Rep. 5, 11421. Lani, R., Hassandarvish, P., Shu, M.-H., Phoon, W.H., Chu, J.J.H., Higgs, S., et al., 2016. Antiviral activity of selected flavonoids against chikungunya virus. Antivir. Res. 133, 50–61. Lee, J.L., Loe, M.W.C., Lee, R.C.H., Chu, J.J.H., 2019a. Antiviral activity of pinocembrin against Zika virus replication. Antivir. Res. 167, 13–24. Lee, J.K., Chui, J.L.M., Lee, R.C.H., Kong, H.Y., Chin, W.-X., Chu, J.J.H., 2019b. Antiviral activity of ST081006 against the dengue virus. Antivir. Res. 171, 104589. Lipsky, M.S., Sharp, K., 2001. From idea to market: the drug approval process. J. Am. Board Fam. Pract. 14, 362–367. Lyu, S.Y., Rhim, J.Y., Park, W.B., 2005. Antiherpetic activities of flavonoids against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) in vitro. Arch. Pharm. Res. 28, 1293–1301. Malakar, S., Sreelatha, L., Dechtawewat, T., Noisakran, S., Yenchitsomanus, P.-T., Chu, J.J.H., et al., 2018. Drug repurposing of quinine as antiviral against dengue virus infection. Virus Res. 255, 171–178. Mishra, K.P., Sharma, N., Diwaker, D., Ganju, L., Singh, S.B., 2013. Plant derived antivirals: a potential source of drug development. J. Virol. Antivir. Res. 2, 2. Moghaddam, E., Teoh, B.-T., Sam, S.-S., Lani, R., Hassandarvish, P., Chik, Z., et al., 2014. Baicalin, a metabolite of baicalein with antiviral activity against dengue virus. Sci. Rep. 4, 5452. Mohd, A., Zainal, N., Tan, K.K., AbuBakar, S., 2019. Resveratrol affects Zika virus replication in vitro. Sci. Rep. 9, 14336. Mounce, B.C., Cesaro, T., Carrau, L., Vallet, T., Vignuzzi, M., 2017. Curcumin inhibits Zika and chikungunya virus infection by inhibiting cell binding. Antivir. Res. 142, 148–157. Olivia, L.W., Obanda, V., Bucht, G., Mosomtai, G., Otieno, V., Ahlm, C., et al., 2015. Global emergence of alphaviruses that cause arthritis in humans. Infect. Ecol. Epidemiol. 5, 1. Pearce, J.C., Learoyd, T.P., Langendorf, B.J., Logan, J.G., 2018. Japanese encephalitis: the vectors, ecology and potential for expansion. J. Travel. Med., S16–S26. Pierson, T.C., Diamond, M.S., 2020. The continued threat of emerging flaviviruses. Nat. Microbiol. 5, 796–812. Rivas, F., Diaz, L.A., Cardenas, V.M., Daza, E., Bruzon, L., Alcala, A., et al., 1997. Epidemic Venezuelan equine encephalitis in La Guajira, Colombia, 1995. J. Infect. Dis. 175, 828–832. Ronca, S.E., Ruff, J.C., Murray, K.O., 2021. A 20-year historical review of West Nile virus since its initial emergence in North America: has West Nile virus become a neglected tropical disease? PLoS Negl. Trop. Dis. 15, e0009190. Sikka, V., Chattu, V.K., Popli, R.K., Galwankar, S.C., Kelkar, D., Sawicki, S.G., et al., 2016. The emergence of zika virus as a global health security threat: a review and a consensus statement of the INDUSEM Joint Working Group (JWG). J. Global Infect. Dis. 8, 3–15. Silva, L.A., Dermody, T.S., 2017. Chikungunya virus: epidemiology, replication, disease mechanisms, and prospective intervention strategies. J. Clin. Invest. 127, 737–749. Silva, J.V.J.J., Ludwig-Begall, L.F., Oliveira-Filho, E.F., Oliveira, R.A.S., Durães-Carvalho, R., Lopes, T.R.R., et al., 2018. A scoping review of chikungunya virus infection: epidemiology, clinical characteristics, viral co-circulation complications, and control. Acta Trop. 188, 213–224. Simon-Loriere, E., Faye, O., Prot, M., Casademont, I., Fall, G., Fernandez-Garcia, M.D., et  al., 2017. Autochthonous Japanese encephalitis with yellow fever coinfection in Africa. N. Engl. J. Med. 376, 1483–1485.

Potential treatment for arboviruses  Chapter | 3  61 Slon Campos, J.L., Mongkolsapaya, J., Screaton, G.R., 2018. The immune response against flaviviruses. Nat. Immunol. 19, 1189–1198. Stanaway, J.D., Shepard, D.S., Undurraga, E.A., Halasa, Y.A., Coffeng, L.E., Brady, O.J., et  al., 2016. The global burden of dengue: an analysis from the Global Burden of Disease Study 2013. Lancet Infect. Dis. 16, 712–723. Suthar, M., Diamond, M., Gale Jr., M., 2013. West Nile virus infection and immunity. Nat. Rev. Microbiol. 11, 115–128. Tompa, D.R., Immanuel, A., Srikanth, S., Kadhirvel, S., 2021. Trends and strategies to combat viral infections: a review on FDA approved antiviral drugs. Int. J. Biol. Macromol. 172, 524–541. Vasconcelos, P.F.C., 1998. Arboviruses pathogenic for man in Brazil. In: Travassos da Rosa, A.P.A., Vasconcelos, P.F.C., Travassos da Rosa, J.F.S. (Eds.), An Overview of Arbovirology in Brazil and Neighbouring Countries. Instituto Evandro Chagas, Belém, pp. 72–99. Vázquez-Calvo, Á., Jiménez de Oya, N., Martín-Acebes, M.A., Garcia-Moruno, E., Saiz, J.-C., 2017. Antiviral properties of the natural polyphenols delphinidin and epigallocatechin gallate against the flaviviruses West Nile virus, Zika virus, and dengue virus. Front. Microbiol. 8, 1314. Weber, C., Sliva, K., Von Rhein, C., Kümmerer, B.M., Schnierle, B.S., 2015. The green tea catechin, epigallocatechin gallate inhibits chikungunya virus infection. Antivir. Res. 113, 1–3. Wilson, M.E., Chen, L.H., 2014. Dengue: update on epidemiology. Curr. Infect. Dis. Rep. 17, 457. Woolhouse, M., Scott, F., Hudson, Z., Howey, R., Chase-Topping, M., 2012. Human viruses: discovery and emergence. Philos. Trans. R. Soc. Lond. Ser. B Biol. Sci. 367, 2864–2871. Xu, G., Dou, J., Zhang, L., Guo, Q., Zhou, C., 2010. Inhibitory effects of baicalein on the influenza virus in vivo is determined by baicalein in the serum. Biol. Pharm. Bull. 33, 238–243. Zandi, K., Teoh, B.T., Sam, S.S., Wong, P.F., Mustafa, M.R., AbuBakar, S., 2011. Antiviral activity of four types of bioflavonoid against dengue virus type-2. Virol. J. 8, 560. Zhang, T., Wu, Z., Du, J., Hu, Y., Liu, L., Yang, F., et al., 2012. Anti-Japanese-encephalitis-viral effects of kaempferol and daidzin and their RNA-binding characteristics. PLoS One 7, e30259.

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Chapter 4

Natural products in the management of onchocerciasis Ivan Kahwaa,b, Innocent Ayesigac, Sharon Nakalemab, Racheal Alinaisweb, Rachel Mbabazib, and Shabnoor Iqbald a

Pharm-Bio Technology and Traditional Medicine Centre of Excellence, Mbarara University of Science and Technology, Mbarara, Uganda, bDepartment of Pharmacy, Faculty of Medicine, Mbarara University of Science and Technology, Mbarara, Uganda, cFaculty of Medicine, Mbarara University of Science and Technology, Mbarara, Uganda, dDepartment of Zoology, Government College University Faisalabad, Faisalabad, Pakistan

Introduction Onchocerciasis commonly known as river blindness is a tropical disease characterized by cutaneous and ocular manifestations among humans. Cutaneous manifestations of the disease may be classified into acute and chronic papular onchodermatitis, onchocercal atrophy, and depigmentation (Okonkwo et  al., 2020). The symptomatic manifestations include subcutaneous granulomas which contain a collection of microfilariae worms (Schwartz et al., 2020). The microfilariae worms in the nodules often present with tenderness and itchy skin resulting in hyperpigmentation (Small, 2021). Furthermore, nodular manifestations progress forming pustular vesicles. Ocular manifestations involve symptoms of both the anterior and posterior eye segments. These symptoms often arise from the microfilariae infestations in the different chambers. Also, the death of the microfilariae in the eye segments results in an inflammatory process (Komlan et al., 2018). Inflammatory cytokine expression results in optic structure destabilization. The inflammatory markers normally produced are IL-13 and IL-4. The microorganism also produces antigenic molecules such as Ov39, Ov150, and Ov16 antigens which trigger an immunological response, especially in the posterior chamber. The outcome is a cross-reaction with indwelling antibodies which also affects the integrity of the ocular structures. The major presentations of the disease are secondary glaucoma, keratitis, and uveitis. These without adequate management can result in complete blindness (Myers et al., 2021). The disease is caused by a parasitic worm, Onchocerca volvulus, belonging to the phylum Nematoda. Furthermore, the parasitic worm belongs to the genus Onchocerca in the family Filaridae. The infective parasitic worms (microNatural Products in Vector-Borne Disease Management. https://doi.org/10.1016/B978-0-323-91942-5.00012-4 Copyright © 2023 Elsevier Inc. All rights reserved.

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filariae) are transported by female blackflies belonging to the genus Simulium (Brattig et  al., 2020). These undergo differentiation and multiplication in the vector over two or more weeks. The larvae are transmitted to the host organism through multiple bites from the black fly. In the host, the microfilariae undergo further development for over 6 to 12 months. During this stage, the organism can be isolated in several connective tissues and body specimen like blood and stool (Otabil et al., 2019). Globally, over 37 million people are believed to be infected with the disease, with approximately 99% of these cases in Africa by 2019. 99% of the African cases were distributed across 31 countries by 2017. Over 300,000 infected people are estimated to be completely blind (CDC, 2017). Approximately, 1.15 and 20.9 million people had total blindness and skin infection, respectively, by CDC (2017). It is estimated that the disease affects females more than males because of the exposure rates with more than 90% risk of contracting the disease. The risk is amplified among individuals who live along river banks and in the tropical climate belt. The distribution of the disease is dependent on the presence of black flies. These are located along fast-flowing rivers and river banks (Hill et al., 2019). However, rapid multiplication of flies and worms is favored by the tropical climate. The tropical climate belt is mostly in Africa, Latin America, and Southeast Asia (Izwan-Anas et al., 2021). Across Africa, Sudan and Uganda were declared by the WHO to have received mass drug administration (Fig. 1).

FIG. 1  Onchocerca volvulus life cycle in the human and vector host. Note the difference among parasite timescales in humans (years for mature worms; months for microfilariae) and vector parasites (days). This will influence population dynamics modeling and the effect of control efforts. Abbreviations: L5 are juvenile adults; L, larvae; Mf, microfilariae; L1-L4, different stages of larval development; W, adult worms.

The management of onchocerciasis  Chapter | 4  65

Conventional drugs for onchocerciasis and their resistance Ivermectin Ivermectin is a powerful antiparasitic drug and the first commercially marketed medicine for human use in macrocyclic lactones. It is generated by the soil microorganism Streptomyces avermitilis and operates via the opening of GABA (Glutamate Gated and Gamma Amino Butyric acid), which leads to enhanced chloride conductivity and paralysis of motors and ions in parasites (Sharun et al., 2020). It paralyzes and destroys microfilariums, which relieves extreme skin itching and stops the progression to blindness. Macrofilariae also suppress the production of new microfilariae for several months after therapy to reduce transmission (WHO). Martin Walker et al. revealed that four or more consecutive ivermectin therapies largely destroy the microfilariae and perpetually sterilize the female Onchocerca volvulus. Consecutive treatments are therefore important for the elimination of onchocercose (Walker et al., 2017). Ivermectin (IVM) is a safe and effective medicine for the treatment of onchocerca and diminishes the person’s ability to transfer the Onchocerca volvulus infection when personalized (Taylor et al., 1990). The immature microfilaria but not the adult worms die after one dosage. The incidence of onchoceral blindness is reduced by up to 80%. Ivermectin has undesirable symptoms such as skin rashes, headaches, fever, and pains in the muscles, articulations, and lymph glands (Ritter et al., 2019). Ivermectin resistance in humans is not documented. Studies in Ghana, however, have revealed “suboptimal reactions” (SORs) to ivermectin and are defined phenotypically by faster (bad response) than expected (good reaction rates) rates of skin repopulations with Onchocerca volvulus microfilariae (Awadzi et al., 2004).

Moxidectin Moxidectin is a noncyanogenic macrocyclic lactone produced by fermentation of the Streptomyces cyanogniseus sp. bacteria. It binds to the glutamate-gated chloride canals of the parasite, increasing channel permeability with chloride ion inflow, which results in excretory pore failure, flaccid paralysis, and the host’s reaction to the parasite. Another approach is to change immunomodulative protein and molecule secretion, therefore limiting the capacity of the parasite to avoid host immunological reactions. Moxidectin was well tolerated in phase 1 clinical studies between 3 and 36 mg. The therapeutic dosage advised is 8 mg (Milton et al., 2020).

Ivermectin-albendazole Albendazole (ALB) combines ivermectin with albendazole and is aimed at having a better treatment outcome for patients presenting with onchocerciasis. In

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a study conducted by Awadzi et al. (1995), using 150 μg/kg of ivermectin plus 400 mg of albendazole as a single dose for managing onchocerciasis, it was found that there was no important effect of the combination of IVM plus ALB on the skin and ocular parasites compared to IVM alone. In 2020, another study was conducted using the same combination but with a higher dose (200 μg/kg of IVM and 800 mg single dose of ALB). Unfortunately, this higher dose still failed to show better results compared to using ivermectin alone for sterilizing, killing adult worms, or achieving sustained microfilarial clearance (Batsa Debrah et al., 2020). Therefore, the combination of ivermectin with albendazole does not offer any significant advantage over use of ivermectin alone.

Ivermectin-diethylcarbamazine-albendazole The combination of ivermectin plus diethylcarbamazine and albendazole achieved sustained microfilariae clearance for 3 years in 96% of the individuals with moderate-to-heavy filarial infections in Papua New Guinea compared with standard therapy of diethylcarbamazine plus albendazole administered once a year over the same period of time. Although the frequency of adverse effects was higher in triple drug regimen compared to the double regimen (i.e., 27% vs 5%) (Thomsen et al., 2016).

Amocarzine Amocarzine also known as CGP 6140, is an N-methylpiperazine adduct of amoscanate. It affects the motility of filarial worms in vitro, with the primary site of action being the mitochondrion. Amocarzine results in swelling of the mitochondrion and inhibition of respiration and other related metabolic functions (Ko et al., 1992). In a study carried out by Zak et al. (1991), it was found that the mean microfilarial skin density was reduced by 45% on day 4 and 95% on day 8, and therefore, concluded that amocarzine had marked microfilaricidal effects on the skin of patients with onchocerciasis as evidenced histologically. Amocarzine of 3 mg/kg was given twice daily after dinner to 100 men who did not have vector control and the study was conducted in Ghana. The findings showed that amocarzine did not influence male or intrauterine embryos and that it was a less powerful microfilaricide and did not suppress skin microfilaria. This study tested ivermectin with amocarzine and found that it was equal to ivermectin with amocarzine alone. It determined, therefore, that amocarzine had no part in Africa’s therapy of onchocercose. Amocarzine resulted in Mazzotti reactions such as itching, rash, peripheral sense, and swelling (Awadzi et al., 1997).

Secondary plant metabolites with antionchocerca activity See Table 1.

TABLE 1  Essential oil, alkaloids, triterpenoids, and phenolic compounds with antionchocerca properties. Natural compounds

Plant

Family

Plant part

Extraction method

References

Camphenol, 6

Cyperus articulatus

Cyperaceae

Roots

Maceration

Metuge et al. (2014)

l-Beta-pinene

C. articulatus

Cyperaceae

Roots

Maceration

Metuge et al. (2014)

cis-Verbenol

C. articulates

Cyperaceae

Roots

Maceration

Metuge et al. (2014)

cis-Sabinol

C. articulates

Cyperaceae

Roots

Maceration

Metuge et al. (2014)

(−)-Myrtenol

C. articulates

Cyperaceae

Roots

Maceration

Metuge et al. (2014)

Umbellulone

C. articulates

Cyperaceae

Roots

Maceration

Metuge et al. (2014)

cis-Verbenone

C. articulates

Cyperaceae

Roots

Maceration

Metuge et al. (2014)

(2E,3Z)-2-Ethylidene-6-methyl-3,5heptadienal

C. articulates

Cyperaceae

Roots

Maceration

Metuge et al. (2014)

Bicyclo[4.4.0]dec-2-ene-4-01, 2-methyl9-(prop-1-en-3-01-2-yl)-

C. articulates

Cyperaceae

Roots

Maceration

Metuge et al. (2014)

Sesquiterpenes

C. articulates

Cyperaceae

Roots

Maceration

Metuge et al. (2014)

Isolongifolene, 9,10-dehydro-

C. articulates

Cyperaceae

Roots

Maceration

Metuge et al. (2014)

Copaene

C. articulates

Cyperaceae

Roots

Maceration

Metuge et al. (2014)

α-Cubebene

C. articulates

Cyperaceae

Roots

Maceration

Metuge et al. (2014)

Cadina-1 (10),6,8-triene

C. articulates

Cyperaceae

Roots

Maceration

Metuge et al. (2014)

4,4,11,11-Tetramethyl-7tetracyclo[6.2.1.0(3.8)0(3.9)]undecanol

C. articulates

Cyperaceae

Roots

Maceration

Metuge et al. (2014)

Monoterpene

Continued

TABLE 1  Essential oil, alkaloids, triterpenoids, and phenolic compounds with antionchocerca properties—cont’d Natural compounds

Plant

Family

Plant part

Extraction method

References

Naphthalene

C. articulates

Cyperaceae

Roots

Maceration

Metuge et al. (2014)

(−)-Calamenene

C. articulates

Cyperaceae

Roots

Maceration

Metuge et al. (2014)

(+)-Epi-bicyclosesquiphellandrene

C. articulates

Cyperaceae

Roots

Maceration

Metuge et al. (2014)

(4-Nitrophenyl) 2,3,4-trifluorobenzoate

C. articulates

Cyperaceae

Roots

Maceration

Metuge et al. (2014)

7-Tetracyclo[6.2.1.0(3.8)0(3.9)] undecanol, 4,4,11,11-tetramethyl-

C. articulates

Cyperaceae

Roots

Maceration

Metuge et al. (2014)

Occidentalol

C. articulates

Cyperaceae

Roots

Maceration

Metuge et al. (2014)

Cycloisolongifolene, 8,9-dehydro

C. articulates

Cyperaceae

Roots

Maceration

Metuge et al. (2014)

Caryophyllene oxide

C. articulates

Cyperaceae

Roots

Maceration

Metuge et al. (2014)

Longipinocarvone

C. articulates

Cyperaceae

Roots

Maceration

Metuge et al. (2014)

α-Copaen-11-ol

C. articulates

Cyperaceae

Roots

Maceration

Metuge et al. (2014)

cis-Z-α-Bisabolene epoxide

C. articulates

Cyperaceae

Roots

Maceration

Metuge et al. (2014)

Longiverbenone

C. articulates

Cyperaceae

Roots

Maceration

Metuge et al. (2014)

2,2,7,7-Tetramethyltricyclo[6.2.1.0(1,6)] undec-4-en-3-one

C. articulates

Cyperaceae

Roots

Maceration

Metuge et al. (2014)

(3-Hydroxy-4,8a-dimethyl-6-prop-1en-2-yl-2,3,5,6,7,8-hexahydro-1Hnaphthalen-2-yl) acetate

C. articulates

Cyperaceae

Roots

Maceration

Metuge et al. (2014)

Acetic acid, 3-hyd roxy-6-isopropenyl-4, 8a-dimethyl-1,2,3,5,6,7,8, 8aoctahydronaphthalen-2-yl ester

C. articulates

Cyperaceae

Roots

Maceration

Metuge et al. (2014)

Perhydrocyclopropa[e]azulene-4,5,6triol, 1,1,4,6-tetramethyl

C. articulates

Cyperaceae

Roots

Maceration

Metuge et al. (2014)

1-H-Cycloprop[e]azulen-7-01, decahydro-1,1,7-trimethyl-4-methylene-, [1ar-(1 aà,4aà,7a,7aa,7bà)]

C. articulates

Cyperaceae

Roots

Maceration

Metuge et al. (2014)

(−)-Spathulenol

C. articulates

Cyperaceae

Roots

Maceration

Metuge et al. (2014)

Corymbolone

C. articulates

Cyperaceae

Roots

Maceration

Metuge et al. (2014)

Spiro[4.5]decan-7-one, 1,8-dimethyl8,9-epoxy-4-isopropyl

C. articulates

Cyperaceae

Roots

Maceration

Metuge et al. (2014)

9H-Cycioisolongifolene, 8-oxo

C. articulates

Cyperaceae

Roots

Maceration

Metuge et al. (2014)

8α-Hexahydro-4

C. articulates

Cyperaceae

Roots

Maceration

Metuge et al. (2014)

E-15-Heptadecenal

C. articulates

Cyperaceae

Roots

Maceration

Metuge et al. (2014)

6-Isopropenyl-4,8a-dimethyl1,2,3,5,6,7,8,8aoctahydronaphthalene-2, 3-diol

C. articulates

Cyperaceae

Roots

Maceration

Metuge et al. (2014)

2(1H)-Naphthalenone, 4a,5,6, 7, 8,8a-hexahydro-6-[1-(hydroxymethyl) ethenyl]-4,8adimethyl-, [4ar(4aà,6à,8aà)]

C. articulates

Cyperaceae

Roots

Maceration

Metuge et al. (2014)

Juniper camphor

C. articulates

Cyperaceae

Roots

Maceration

Metuge et al. (2014)

C. articulates

Cyperaceae

Roots

Maceration

Metuge et al. (2014)

Polyterpenes Tetracosamethyl-cyclododecasiloxane

Continued

TABLE 1  Essential oil, alkaloids, triterpenoids, and phenolic compounds with antionchocerca properties—cont’d Natural compounds

Plant

Family

Plant part

Extraction method

References

Cyclodecasiloxane, eicosamethyl

Cyperus articulatus

Cyperaceae

Roots

Maceration

Metuge et al. (2014)

α-Pinene

Polyalthia suaveolens

Annonaceae

Bark of stem

Hydrodistillation

Nyegue et al. (2008)

β-Pinene

P. suaveolens

Annonaceae

Bark of stem

Hydrodistillation

Nyegue et al. (2008)

p-Cymene

P. suaveolens

Annonaceae

Bark of stem

Hydrodistillation

Nyegue et al. (2008)

δ-Elemene

Enantia chlorantha/P. suaveolens

Annonaceae

Bark of stem

Hydrodistillation

Nyegue et al. (2008)

α-Copaene

E. chlorantha/P. suaveolens

Annonaceae

Bark of stem

Hydrodistillation

Nyegue et al. (2008)

β-Elemene

E. chlorantha/P. suaveolens

Annonaceae

Bark of stem

Hydrodistillation

Nyegue et al. (2008)

α-Cubebene

P. suaveolens

Bark of stem

Hydrodistillation

Nyegue et al. (2008)

α-Gurjunene

E. chlorantha/P. suaveolens

Annonaceae

Bark of stem

Hydrodistillation

Nyegue et al. (2008)

β-Copaene

P. suaveolens

Annonaceae

Bark of stem

Hydrodistillation

Nyegue et al. (2008)

α-Humulene

E. chlorantha/P. suaveolens

Annonaceae

Bark of stem

Hydrodistillation

Nyegue et al. (2008)

γ-Muurolene

E. chlorantha

Annonaceae

Bark of stem

Hydrodistillation

Nyegue et al. (2008)

γ-Amorphene

P. suaveolens

Annonaceae

Bark of stem

Hydrodistillation

Nyegue et al. (2008)

α-Muurolene

E. chlorantha/P. suaveolens

Annonaceae

Bark of stem

Hydrodistillation

Nyegue et al. (2008)

Cubebol

P. suaveolens

Bark of stem

Hydrodistillation

Nyegue et al. (2008)

Triterpenes

Limonene

β-Caryophyllene

Germacrene D

γ-Cadinene Calacorene

E. chlorantha

Annonaceae

Bark of stem

Hydrodistillation

Nyegue et al. (2008)

Germacrene B

P. suaveolens

Annonaceae

Bark of stem

Hydrodistillation

Nyegue et al. (2008)

1,5-Epoxysalvial-4(14)-ene 1585 12.3 Spathuleno

E. chlorantha

Annonaceae

Bark of stem

Hydrodistillation

Nyegue et al. (2008)

Caryophyllene oxide Salvial-4(14)-ene1-one

E. chlorantha/P. suaveolens

Annonaceae

Bark of stem

Hydrodistillation

Nyegue et al. (2008)

P. suaveolens

Annonaceae

Bark of stem

Hydrodistillation

Nyegue et al. (2008)

E. chlorantha

Annonaceae

Bark of stem

Hydrodistillation

Nyegue et al. (2008)

Cadalene

E. chlorantha

Annonaceae

Bark of stem

Hydrodistillation

Nyegue et al. (2008)

Voacangine

Voacanga africana

Apocynaceae

Bark of stem

Column chromatography

Babiaka et al. (2020)

Voacristine

V. africana

Apocynaceae

Bark of stem

Column chromatography

Babiaka et al. (2020)

Coronaridine

V. africana

Apocynaceae

Bark of stem

Column chromatography

Babiaka et al. (2020)

Tabernanthine

V. africana

Apocynaceae

Bark of stem

Column chromatography

Babiaka et al. (2020)

Iboxygaine

V. africana

Apocynaceae

Bark of stem

Column chromatography

Babiaka et al. (2020)

Humulene epoxide II 1-Epi-cubenol Epi-α-Cadinol α-Cadinol Alkaloids

Continued

TABLE 1  Essential oil, alkaloids, triterpenoids, and phenolic compounds with antionchocerca properties—cont’d Natural compounds

Plant

Family

Plant part

Extraction method

References

Voacamine

V. africana

Apocynaceae

Bark of stem

Column chromatography

Babiaka et al. (2020)

Voacorine

V. africana

Apocynaceae

Bark of stem

Column chromatography

Babiaka et al. (2020)

Conoduramine

V. africana

Apocynaceae

Bark of stem

Column chromatography

Babiaka et al. (2020)

Catechin

Epigallocatechin gallate

–

–

Methanolic extract

Muñoz-Cazares et al. (2017)

Catechin-gallate

E. gallate

–

–

Muñoz-Cazares et al. (2017)

Epicatechin gallate

E. gallate

–

–

Muñoz-Cazares et al. (2017)

Curcumin

Curcuma longa

Zingiberaceae

Roots

Methanolic extract

Muñoz-Cazares et al. (2017)

Demethoxycurcumin

C. longa

Zingiberaceae

Roots

Methanolic extract

Muñoz-Cazares et al. (2017)

Bisdemethoxycurcumin

C. longa

Zingiberaceae

Roots

Methanolic extract

Muñoz-Cazares et al. (2017)

Phenolic derivatives

The management of onchocerciasis  Chapter | 4  73

Pure natural products with antionchocerca activity Gallic acid is a phenolic acid compound contained in a majority of plants such as Terminalia chebula, Terminalia bellerica, Phyllanthus emblica (Vazirian et  al., 2011; Borde et  al., 2011), Camellia sinensis, Arctostaphylos uva-ursi, Corylus avellana, Oenothera biennis, Vitis vinifera (Karamac et  al., 2006), Anogeissus leiocarpus (Ndjonka et al., 2014), Acacia Arabica, Acacia catechu, Eugenia jambolana, Terminalia chebula, Terminalia belerica, Punica granatum, Bacopa monnieri (Borde et  al., 2011; Vazirian et  al., 2011), Alchemilla vulgaris, Allium ursinum, Acorus calamus, Solidago virgaurea (Condrat et al., 2010), Allium cepa (Pucciarini et al., 2019), and in Chickpea flour‐based active films (Kocakulak et  al., 2019). In an in  vitro study conducted against adults and microfilariae of the bovine filarial nematode Onchocerca ochengi, it was observed that gallic acid isolated from the ethanolic extracts of Anogeissus leiocarpus showed antionchocerca activity at LC50 of 9.98 mM (Ndjonka et  al., 2014). Gentisic acid is a diphenolic acid compound widely distributed in plants such as Gentiana lutea, Vitis vinifera, Citrus limon, Citrus aurantium, Citrus sinensis, Pterocarpus santalinus, Helianthus tuberosus, Hibiscus rosa-sinensis, Olea europaea, Sesamum indicum (Harris et al., 2007), Persea americana, Flacourtia indica, Actinidia deliciosa, Malus domestica, Momordica charantia, Rubus fruticosus, Catharanthus roseus (Juurlink et  al., 2014) and mushrooms such as Polyporus tumulosus and Penicillium patulum (Budavari, 1989). Gentisic acid isolated from ethanol extracts of A. leiocarpus significantly affected the survival of Onchocerca ochengi microfilariae and Onchocerca ochengi adults at LC50 = 7.81 mM (Ndjonka et al., 2014). Ellagic acid is a polyphenolic acid compound derived from gallic acid whose high content levels are found in fruits such as Rubus chamaemorus L., Rubus fruticosus, Fragaria × ananassa, Punica granatum, Diospyros kaki L. f, seeds such as Carya illinoinensis and Juglans regia L., grapes such as Vitis vinifera contain ellagic acid. Other sources of ellagic acid include species of genus Prunus such as Prunus persica L. and Prunus domestica L. (Ríos et al., 2018). Ellagic acid isolated from ethanol extracts of A. leiocarpus strongly affected the survival of Onchocerca ochengi microfilariae and Onchocerca ochengi adults with a high value of LC50 = 0.03 mM (Ndjonka et al., 2014). Polycarpol is a triterpene commonly found in aerial parts of some of the plants in the family Annonaceae; these include Bocageopsis pleiosperma, Onychopetalum amazonicum, Unonopsis duckei, Unonopsis stipitata, Unonopsis rufescens, Unonopsis floribunda (Silva et al., 2015), Polyalthia suaveolens (Nyasse et al., 2006), and Polyalthia oliveri (Kouam et al., 2014). In an in  vitro study by Nyasse et  al. (2006), polycarpol isolated from the bark of Polyalthia suaveolens exhibited a mortality reduction of 28.6% on male Onchocerca gutturosa worms.

74  Natural products in vector-borne disease management

Polyveoline is a sesquiterpene alkaloid found in Greenwayodendron oliveri and Polyalthia suaveolens (Nyasse et al., 2006; Kemgni et al., 2021; Ngantchou et al., 2010). In an in vitro study by Nyasse et al. (2006), polyveoline isolated from the bark of Polyalthia suaveolens showed a mortality reduction of 14.3% on male Onchocerca gutturosa worms. 3-O-acetyl aleuritolic acid is a pentacyclic triterpenoid found in Garcia parviflora, Aleurites moluccana, Discoglypremna caloneura, and Alchornea cordifolia (Reyes et  al., 2010; Alimboyoguen et  al., 2014; Nyasse et  al., 2006; Siwe-Noundou et  al., 2019). 3-O-acetyl aleuritolic acid showed a significant inhibitory on the vitality of adult male worms of Onchocerca gutturosa with a mortality reduction of 57.1% (Nyasse et al., 2006). Oliverine is an isoquinoline alkaloid present in both Polyalthia suaveolens or Pachypodanthium staudtii (Akendengue et al., 2005). An in vitro study by Titanji et al. (1990) on Onchocerca volvulus showed that oliverine isolated from Pachypodanthium staudtii showed a significant activity at a concentration of 100 μg/mL after 24 h of incubation. Chrysophanic acid is an anthraquinone compound isolated from Rheum officinale and Polygpnum cuspidatum (Choi, 2016). In an in vitro study carried out by Kilian et al. (1990) on microfilaria, chrysophanic acid present in an alcohol extract of the bark of Cassia aubrevillei showed a significant microfilaricidal activity at a concentration 50 μg/mL in 24 h. Mustakone is a sesquiterpenoid isolated from two species of Cyperaceae family, that is, Cyperus rotundus and Cyperus articulatus. Mustakone present in the hexane rich extract of Cyperus articulatus was found to kill microfilariae and adult male and female worms of Onchocerca ochengi at IC50 of 17.41 and 21.89 lg/mL, respectively (Metuge et al., 2014). Linoleic acid is a polyunsaturated omega-6 fatty acid abundant in nuts, fats, and oils; in a study by Metuge et al. (2014), linoleic acid present in the hexane rich extract of Cyperus articulatus was found to kill microfilariae and adult male and female worms of Onchocerca ochengi at IC50 of 31.03 and 44.16 lg/ mL, respectively.

Safety and toxicity profiles of the natural products agents According to Cho-Ngwa et al. (2010), cytotoxic studies on Matricaria discoidea and Hydrodictyon africanum pure leaf extracts revealed selective index values of 0.5 and 2.63, respectively, with no toxicity observed on mammalian cells. However, crude extracts produced selective indices, greater than 1, indicating a higher chance of toxicity. Therefore, extract purification is vital in increasing the efficacy against the mf strains. The microfilariae response was observed at 125 μg/mL at IC100 for the methanoic extracts of both M. discoidea and H. africanum (Cho-Ngwa et al., 2010). Crude extracts of essential oil from Cyperus articulatus have not shown toxicity at a dose of 2000 mg/kg administered to the mice. Oil filaricidal activity

The management of onchocerciasis  Chapter | 4  75

was at 31.25 and 23.4 μg/mL for both adult female and male worms, rendering the oil safe (Metuge et al., 2014). Cho-Ngwa et al. (2016) also studied the activity of Tragia benthami and Piper umbellatum against Onchocerca ochengi strains that revealed safety results. The study results also showed a low selective index of the extracts at IC50. Therefore, there is oil isolation ease from the crude extracts, which increases the filaricidal effects. Pure extracts of the oil did not show significant results regarding mammalian cell toxicity (Cho-Ngwa et al., 2016).

Mode of action of natural plant products DNA-damaging compounds are often cytotoxic and antiparasitary. Typical damage to DNA occurs when alkylating DNA chemicals make covalent connections with the bases of DNA. If DNA repair enzymes do not fix these alkylations, DNA damage results in point mutations, frame-shift mutations, and deletions. If these mutations occur in coding genes of vital proteins, they may help to kill parasites. Aristologenic acid, pyrrolizidine alkaloids, secondary metabolites, ptaquiloside, and furanoquinolin alkaloids are common compounds which are found in medicinal plants and inhibit DNA damage. These molecules are usually hydrophobic, aromatic, flat, and intercalate nuclear pairs. These chemicals stabilize the double helix of DNA and inhibit the replication process. Typical mutations produced by natural products are frame-shift mutations and deletions that lead to cell death (Wink, 2007). In the protoberberin and benzophenanthridine alkaloids, typical DNA intercalatory chemicals are abundant, such as berberine and sanguinary (Wink and Schimmer, 2010; Schmeller et al., 1997). Many plants which generate such alkaloids are famous for their antiparasitics, antibiotics, and antivirals activities, including alkaloids along with quinolines, alkaloids with beta carboline, anthraquinones, alkaloids with furanoquin, emetins, and furanocoumarins (Wink, 2007; Wink and Schimmer, 2010). Some intercalary chemicals are required to the replication of the enzyme DNA like topoisomerase I or II. Cells cannot divide if DNA topoisomerases are stopped. The indole alkaloid from Camptotheca acuminata, Ervatamia heyneana, and Mostuea brunonis would be a typical inhibitor of the topoisomerase (Wink, 2007; Wink and Schimmer, 2010; Efferth et al., 2007). Alkylating and intercalating cells or topoisomerase inhibitors frequently undergo programmed apoptosis (Wink, 2007). Cell death can even occur in single cell protozoa (Rosenkranz and Wink, 2008).

Inhibit polymerization of structural protein The cytoskeleton of the cell contains microtubules and actin filament, which are the main proteins for the eukaryotic cell architecture. The proper arrangement of mitotic spindle necessary for cell division is crucial. A number of natural products are known to have affinity for microtubules. Some of them inhibit

76  Natural products in vector-borne disease management

polymerization of tubulin into microtubules, such as colchicine, sanguinarine, and podophyllotoxin. Some of these natural compounds are now employed in ­cancer chemotherapy. They often have antiparasitic characteristics (Wink, 2007; Efferth et al., 2007; Stanton et al., 2011).

Disturb membrane fluidity The cell membrane is a phospholipid bilayer that surrounds all live cells. The cell membrane prevents cellular metabolites from escape and also limits the irrelevant input of polar or poisonous foreign chemicals. Natural products have detergent properties as a larger class of wide-distributed triterpenes and steroid saponins are present in more than 30% of higher plants and interfere with the fluidity or permeability of the biomembrane (Wink, 2008; Wink and Van Wyk, 2008). The lipophilic secondary metabolites such as phenyl propanoids or terpenoids in multiple plants’ essential oils may disrupt the fluidity and function of the membrane (Wink, 2008). There are therefore a certain number of antibacterial and antiparasitary pro for several of the lipophilic mono- and sesquiterpenes, phenyl propanoids, and isothiocyanates (Wink and Van Wyk, 2008).

Conclusion The rationale and contribution of natural products compounds in the management of onchocerciasis is clearly stated and cannot be ignored. This chapter has summarized most of the in vitro and in vivo studies on natural compounds such as crude extracts of plants, essential oils, and also isolated pure compounds. Few studies have been conducted on the cytotoxic effects of natural products, which is very vital in the process of discovering novel drugs from natural sources. Therefore, the safety and toxicity profiles of most of these plant extracts should be evaluated.

References Akendengue, B., Lemamy, G.J., Bourobou, H.B., Laurens, A., 2005. Bioactive natural compounds from medico-magic plants of Bantu area. In: Studies in Natural Products Chemistry. Elsevier. Alimboyoguen, A.B., Kathlia, A.D., Shen, C., Li, W., Ragasa, C., 2014. Chemical constituents of the bark of Aleurites moluccana L. Willd. J. Chem. Pharm. Res. 6, 1318–1320. Awadzi, K., Addy, E.T., Opoku, N.O., Plenge-Bönig, A., Büttner, D.W., 1995. The chemotherapy of onchocerciasis XX: ivermectin in combination with albendazole. Trop. Med. Parasitol. 46 (4), 213–220. Awadzi, K., Opoku, N.O., Attah, S.K., Addy, E.T., Duke, B.O.L., Nyame, P.K., Kshirsagar, N.A., 1997. The safety and efficacy of amocarzine in African onchocerciasis and the influence of ivermectin on the clinical and parasitological response to treatment. Ann. Trop. Med. Parasitol. 91 (3), 281–296. Awadzi, K., Boakye, D.A., Edwards, G., Opoku, N.O., Attah, S.K., Osei-Atweneboana, M.Y., Lazdins-Helds, J.K., Ardrey, A.E., Addy, E.T., Quartey, B.T., Ahmed, K., 2004. An investigation of

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The management of onchocerciasis  Chapter | 4  79 Pucciarini, L., Ianni, F., Petesse, V., Pellati, F., Brighenti, V., Volpi, C., Gargaro, M., Natalini, B., Clementi, C., Sardella, R., 2019. Onion (Allium cepa L.) skin: a rich resource of biomolecules for the sustainable production of colored biofunctional textiles. Molecules 24 (3), 634. Reyes, B.M., Ramírez-Apan, M.T., Toscano, R.A., Delgado, G., 2010. Triterpenes from Garcia parviflora. Cytotoxic evaluation of natural and semisynthetic friedelanes. J. Nat. Prod. 73 (11), 1839–1845. Ríos, J.L., Giner, R.M., Marín, M., Recio, M.C., 2018. A pharmacological update of ellagic acid. Planta Med. 84 (15), 1068–1093. Ritter, J., Flower, R.J., Henderson, G., Loke, Y.K., Macewan, D.J., Rang, H.P., 2019. Rang and Dale’s Pharmacology. Elsevier. Rosenkranz, V., Wink, M., 2008. Alkaloids induce programmed cell death in bloodstream forms of trypanosomes (Trypanosoma b. brucei). Molecules 13, 2462–2473. Schmeller, T., Latz-Brüning, B., Wink, M., 1997. Biochemical activities of berberine, palmatine and sanguinarine mediating chemical defence against microorganisms and herbivores. Phytochemistry 44, 257–266. Schwartz, R.A., Al‐Qubati, Y., Zieleniewski, Ł., Shah, R., Kapila, R., 2020. Onchocerciasis (river blindness): larva‐induced eczema (onchodermatitis) from an important oculocutaneous tropical disease spilling over into North America and Europe. Int. J. Dermatol. 59 (9), 1065–1070. Sharun, K., Dhama, K., Patel, S.K., Pathak, M., Tiwari, R., Singh, B.R., Sah, R., Bonilla-Aldana, D.K., Rodriguez-Morales, A.J., Leblebicioglu, H., 2020. Ivermectin, a new candidate therapeutic against SARS-CoV-2/COVID-19. Ann. Clin. Microbiol. Antimicrob. 19 (1), 23. Silva, F., Lima, B.R.D., Soares, E.R., Almeida, R.A.D., Silva Filho, F.A.D., Corrêa, W.R., Salvador, M.J., De Souza, A.Q., Koolen, H.H., De Souza, A.D., Pinheiro, M.L., 2015. Polycarpol in Unonopsis, Bocageopsis and Onychopetalum Amazonian species: chemosystematical implications and antimicrobial evaluation. Rev. Bras 25, 11–15. Siwe-Noundou, X., Musyoka, T.M., Moses, V., Ndinteh, D.T., Mnkandhla, D., Hoppe, H., Bishop, Ö.T., Krause, R.W., 2019. Anti-HIV-1 integrase potency of methylgallate from Alchornea cordifolia using in vitro and in silico approaches. Sci. Rep. 9 (1), 1–9. Small, K.W., 2021. Onchocerciasis. In: Uveitis. Springer, Cham, pp. 245–247. Stanton, R.A., Gernert, K.M., Nettles, J.H., Aneja, R., 2011. Drugs that target dynamic microtubules: a new molecular perspective. Med. Res. Rev. 31, 443–481. Taylor, H.R., Pacque, M., Munoz, B., Greene, B.M., 1990. Impact of mass treatment of onchocerciasis with ivermectin on the transmission of infection. Science 250 (4977), 116–118. Thomsen, E.K., Sanuku, N., Baea, M., Satofan, S., Maki, E., Lombore, B., Schmidt, M.S., Siba, P.M., Weil, G.J., Kazura, J.W., Fleckenstein, L.L., 2016. Efficacy, safety, and pharmacokinetics of coadministered diethylcarbamazine, albendazole, and ivermectin for treatment of bancroftian filariasis. Clin. Infect. Dis. 62 (3), 334–341. Titanji, V.P., Evehe, M.S., Ayafor, J.F., Kimbu, S.F., 1990. Novel Onchocerca volvulus filaricides from Carapa procera, Polyalthia suaveolens and Pachypodanthium staudtii. Acta Leiden. 59 (1–2), 377–382. Vazirian, M., Khanavi, M., Amanzadeh, Y., Hajimehdipoor, H., 2011. Quantification of gallic acid in fruits of three medicinal plants. Iran. J. Pharm. Res. 10 (2), 233. Walker, M., Pion, S.D., Fang, H., Gardon, J., Kamgno, J., Basáñez, M.G., Boussinesq, M., 2017. Macrofilaricidal efficacy of repeated doses of ivermectin for the treatment of river blindness. Clin. Infect. Dis. 65 (12), 2026–2034.

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Chapter 5

Combating the vectors and management of vector-borne diseases with essential oil nanoemulsions Anindita Deya,b, Sumanta Deyb, Sanghita Dasc, Madhumita Majumderd, Papiya Nandyb, and Ashesh Nandyb a

Department of Botany, Asutosh College, Kolkata, West Bengal, India, bCentre for Interdisciplinary Research and Education, Kolkata, West Bengal, India, cDepartment of Physics, Jadavpur University, Kolkata, West Bengal, India, dDepartment of Botany, Raidighi College, Raidighi, West Bengal, India

Abbreviations AChE CHIKV DDT DENV EONEms EOs GABA IVM JEV LC50 O/W O/W/O ONNV PIC PIT RFV SDM TBE W/O

acetylcholinesterase Chikungunya virus dichlorodiphenyltrichloroethane Dengue virus essential oil nanoemulsion essential oils gamma-aminobutyric acid integrated vector management Japanese encephalitis virus lethal concentration 50 oil in water oil-in-water-in-oil emulsion O’nyong’nyong virus phase inversion composition phase inversion temperature Rift Valley fever virus solvent diffusion method tick-borne encephalitis water in oil

Natural Products in Vector-Borne Disease Management. https://doi.org/10.1016/B978-0-323-91942-5.00006-9 Copyright © 2023 Elsevier Inc. All rights reserved.

81

82  Natural products in vector-borne disease management W/O/W WHO WNV YFV ZIKV

water-in-oil-in-water emulsion World Health Organization West Nile virus yellow fever virus Zika virus

Introduction Vector-borne diseases are sickness caused by the vectors. A vector is a vehicle that transmits an infectious agent for different diseases from an infected animal to a human or another animal. Vectors are frequently arthropods like mosquitoes, ticks, fleas, and others. The spread of the vectors is influenced by a complex set of demographics, environmental, and social factors. Such diseases exist across the world but profoundly influence in the tropical and subtropical areas and disproportionately affect the poorest population (Fig. 1). Vector-borne diseases account for more than 17% of the infectious diseases on the planet. It causes an excess of 700,000 deaths annually. Since 2014, major outbreaks of Dengue, malaria, Chikungunya, Yellow fever, and Zika cause a significant fraction of the global infectious disease burden. Malaria, a life-threatening protozoan disease, is at risk for 40% of the world’s population. It results in more than 400,000 deaths every year (Al-Awadhi et al., 2021). Similarly, Dengue claims 40,000 death annually, while Zika, a newly introduced one affecting the babies while in utero (Paixão et al., 2018). For diseases like Zika, Dengue, West Nile fever, there are no perpetual cures. The only way to stave off such diseases is managing the vectors in a green and cost-effective way. Since there are many effective controls for vector management against multiple diseases, they can be integrated together to battle at once (Golding et al., 2015). Hence, World Health Organization (WHO) proposed the term “integrated vector management” (IVM) as the process for planning and executing strategy for vector control (World Health Organization, 2015). Preventive measures so far have been proposed against varieties of vectors, among which the popular ones are habitat and environmental control, limiting exposure to vectors, mechanical control, chemical, and biological controls. Although chemical control is considered as the most prime element in controlling the vector-borne disease management, it produces different kinds of pollution issues, which brings concern over environmental safety. Synthetic chemicals, although effective for vector control, have strong effects on the living world and cause biological toxicity, affecting our ecosystem (Aktar et  al., 2009). Essential oils (EOs) extracted from aromatic plants are ecologically sound to control the vectors and also applicable against pathogens with minimum ill-effects on animals and public health (Echeverría and Duarte Galhardo de Albuquerque, 2019). Traditionally, the fragrance of EOs was in use as insect repellents; however, recent studies reveal the most promising inhibitory effect on larval growth (Lee, 2018).

FIG. 1  Risk for Vector Borne Diseases at world scenario. The map is drawn using data from the website: https://www.who.int/heli/risks/vectors/vector/en/.

84  Natural products in vector-borne disease management

In later stages, issues related to solubility and stability lead to novel inclusion of nanoformulation of tiny-sized droplets known as nanoemulsions (NEms). NEms have many implementations in diverse fields like agriculture, food safety, cosmetics, and pharmaceutical industries (Chime et  al., 2014). NEm is a colloidal dispersion system prepared easily with simple composition and having higher thermodynamic stability with low cost of production, prepared by two different immiscible phases along with an emulsifying surfactant (Jaiswal et al., 2015). These possibilities provide a substantial advantage of using NEms as acceptable carriers of active EOs in the field of biological and pharmacological uses. This chapter describes some studies accomplished with the way to combat vectors with its main focus on essential oil nanoemulsions (EONEms) application in vector control and handling of different vector-borne diseases in an inexpensive and environment-friendly approach leading to sustainable development.

What is vector? Any organism (vertebrate or invertebrate) that is capable of functioning as a carrier of an infectious agent between organisms of a different species is called vector (Kuno and Chang, 2005; World Health Organization, 2016). In epidemiology, a slightly more flexible interpretation would be that any host transmitting a pathogen of importance to humans to or between one or more hosts is considered to be a vector. Basically, a vector is another host in a multihost parasite’s life cycle (Wilson et al., 2017). A vector does not cause infectious disease itself but transmits infection by conveying pathogens from one host to another (KwaZulu-Natal Department of Health, 2020).

Types of vectors There are two types of vectors that convey infectious organisms to a host: mechanical and biological. Microbes do not multiply within mechanical vectors: mechanical vectors only physically transport microbes from host to host (Otake et al., 2003). Some flies carry pathogens responsible for different intestinal infections, but these infectious microbes do not need flies to develop or to complete their life cycle. In contrast, some infectious agents must undergo development or propagate within a biological vector before the biological vector can transmit the microbes (KwaZulu-Natal Department of Health, 2020; Otake et al., 2003). Generally, these infectious pathogens travel inside insect’s hemolymph, and a specific vector is obligatory for completing their life cycle. Vector-borne diseases of different types are transmitted by hematophagous arthropods, including mosquitoes, ticks, sand flies, and triatomine bugs (Dantas-Torres and Otranto, 2016). Most vector-borne diseases exist in complex zoonotic cycles involving a variety of birds, rodents, and other vertebrate hosts (Gubler et al., 2001).

Combating the vectors and management  Chapter | 5  85

Types of vector-borne disease Globally, every year more than 1 billion people are infected and almost 1 million people die from vector-borne diseases, including malaria, Dengue, schistosomiasis, leishmaniasis, Chagas disease, Yellow fever, lymphatic filariasis, and onchocerciasis (World Health Organization, 2014). Most of these vector-borne diseases are transmitted by principal vectors, which include different species of mosquitoes, flies, bugs, ticks, and others, which are summarized in Table 1 (World Health Organization, 2014).

TABLE 1  Types of vector-borne diseases. Causative agent

Pathogen

Vector

Malaria

Protozoan parasite

Plasmodium sp.

Anopheles mosquito

Bite

Leishmaniasis

Protozoan parasite

Leishmania donovani

Phlebotomine sandfly

Bite

Sleeping sickness (African trypanosomiasis)

Protozoan parasite

Trypanosoma brucei

Tsetse fly

Bite

Chagas disease (American trypanosomiasis)

Protozoan parasite

Trypanosoma cruzi

Triatomine bug

Bite

Schistosomiasis

Trematode parasite

Schistosoma sp.

Aquatic snail

Skin penetration

Lymphatic filariasis

Nematode parasite

Wuchereria bancrofti

Culex, Aedes, Anopheles mosquitoes

Bite

Onchocerciasis (River blindness)

Nematode parasite

Onchocerca volvulus

Blackfly

Bite

Chikungunya

Virus

CHIKV

Aedes mosquito

Bite

Dengue

Virus

DENV

Aedes mosquito

Bite

Zika

Virus

ZIKV

Aedes mosquito

Bite

Yellow fever

Virus

YFV

Aedes mosquito

Bite

Rift Valley fever

Virus

RVFV

Aedes mosquito

Bite

Japanese encephalitis

Virus

JEV

Culex mosquito

Bite

West Nile fever

Virus

WNV

Culex mosquito

Bite

Disease

Method of transmission

Continued

86  Natural products in vector-borne disease management

TABLE 1  Types of vector-borne diseases—cont’d Causative agent

Pathogen

Vector

Method of transmission

Tick-borne encephalitis

Virus

TBEV

Tick

Bite

Crimean Congo hemorrhagic fever

Virus

Nairovirus

Tick

Bite

Lyme disease (Borreliosis)

Bacteria

Borrelia burgdorferi

Tick

Bite

Rickettsial fever

Bacteria

Rickettsia sp.

Tick

Bite

Tularemia

Bacteria

Francisella tularensis

Tick

Bite

Plague

Bacteria

Yersinia pestis

Oriental rat flea

Bite

Cholera

Bacteria

Vibrio cholerae

Fly

Mechanical transmission

Dysentery

Bacteria

Shigella dysenteriae

Fly

Mechanical transmission

Disease

Mosquito-borne diseases Mosquitos transmit a variety of diseases including protozoa, roundworms, and virus, including some arboviruses to humans (Foster and Walker, 2019). These arboviruses have epidemiological and clinical significance, which include Dengue virus (DENV), Japanese encephalitis virus (JEV), Chikungunya virus (CHIKV), Yellow fever virus (YFV), Rift Valley fever virus (RFV), West Nile virus (WNV), O’nyong’nyong virus (ONNV), and Zika virus (ZIKV) (Baxter et al., 2017). A variety of Aedes species carry Dengue virus, Chikungunya virus, Yellow fever virus, West Nile virus, Zika virus, and lymphatic filariasis (elephantiasis) pathogens (Cuervo-Parra et  al., 2016). Sabethes and Haemagogus species of mosquitos transmit Yellow fever virus. Mosquitos of Anopheles species carry malaria parasite, West Nile virus, and pathogen of lymphatic filariasis (De Rodaniche et al., 1956). Different species of Culex mosquito transmit pathogens of lymphatic filariasis (elephantiasis) and West Nile virus (Sejvar, 2016). Fly-borne diseases Flies transmit diseases either by contaminating food with feces or by biting. Flies transmit a large number of pathogenic microorganisms, which include

Combating the vectors and management  Chapter | 5  87

­ umerous bacteria, virus as well as parasites (Greenberg, 1965). Tsetse flies n are responsible for African trypanosomiasis or sleeping sickness (caused by two subspecies of protozoa, Trypanosoma brucei) (Farikou et  al., 2010). Pathogenic protozoa are responsible for visceral and cutaneous leishmaniasis, and pappataci fever virus are carried by Phlebotomine sandflies (Maroli et al., 2013). Black fly of Simulium species carries Onchocera volvulus, nematode responsible for onchocerciasis (river blindness) (Brattig et al., 2020). Deer fly transmits a filarial nematode (loa loa) that causes loa loa filariasis (Okonkwo et al., 2018).

Tick-borne diseases Tick-borne diseases are clinically very diverse in nature, and symptoms are generally nonspecific in most of the cases (Smith, 2005). Different species of ticks carry pathogens of tick typhus, tick-borne encephalitis (flavivirus), Lyme borreliosis (Borrelia burgdorferi), African tick bite fever (Rickettsia africae), ­relapsing fever (Borrelia spp.), Mediterranean spotted fever (Rickettsia conorii), Crimean Congo hemorrhagic fever (Naiovirus), Rocky Mountain spotted fever (Rickettsia rickettsia), tularemia (Francisella tularensis), etc. (DantasTorres et al., 2013). Flea-borne diseases Adult fleas are obligate hematophagous ectoparasites and mainly vessel feeders. They damage blood vessels and transmit pathogens (Bitam et  al., 2010). Various cat fleas (Ctenocephalides felis), rodent fleas (Nosopsyllus fasciatus), and human fleas (Phulex irritans) transmit numerous pathogenic microorganisms. Oriental rat fleas carry plague pathogen (Yersinia pestis) and infect humans (Baxter et al., 2017; Bitam et al., 2010). Other vector-borne diseases Triatomine bugs transmit protozoan parasite of American trypanosomiasis or Chagas disease (Trypanosoma cruzi). Chronic Chagas disease can lead to life-threatening heart and digestive disorders (World Health Organization, 2021). Rodents are reservoirs and hosts for several zoonotic diseases and transmit pathogen of leptospirosis, murine typhus, scrub typhus, leptospirosis, hantavirus hemorrhagic fever, and many other infectious bacteria, virus, worms, and protozoan parasites (Rabiee et al., 2018; Morand et al., 2015). Freshwater snails carry one type of trematode flatworms responsible for schistosomiasis (also known as bilharzia), a vector-borne disease. Snails release larval forms of that flatworm into water, which subsequently penetrate the human skin (TDR, For Research on Diseases of Poverty, UNICEF, UNDP, World Bank, WHO, 2009).

88  Natural products in vector-borne disease management

Prevention of vectors and management of vector-borne diseases Vector-borne diseases are prevalent in tropical and subtropical regions and account for more than 17% of all infectious diseases (World Health Organization, 2020). Worldwide, vector-borne diseases are one of the most dangerous health threats, and the emergence of this disease is driven by population growth, globalization, economic burden, and poor public health infrastructure in affected countries. Factors like urbanization, insecticide resistance, seasonal weather variation, interannual and interdecadal climate variability, increased human migration, and human settlement patterns directly affect the epidemiology of these diseases (Sutherst, 2004; Gubler, 1998). Influence of climate variability on vector-borne diseases is relatively easy to detect unlike the effect of climate change because of the slow rate of change. Adaptation to climate change and variability partially depend on the health infrastructure of the area (Sutherst, 2004). Besides these factors, variable precipitation patterns also exhibit a direct impact on the biology of vectors and parasites by increasing the number of breeding sites of vectors like mosquitos, snails. Favorable breeding and resting reservoirs and suitable climatic conditions lead to increased vector population, which results in disease outbreaks (Sutherst, 2004). Public health policy should include mass vaccination, regular surveillance in waste and sewage management systems in disease-prone areas, and proper usage of insect repellents, etc. (Osanloo et al., 2017). Nonbiodegradable plastics, unused empty containers, automobile tires, cellophane, and coconut shells, which are usually discarded in the environment, act as rodent harborages as well as excellent breeding sites of mosquitoes as they accumulate rainwater (World Health Organization, 2014). Water storage reservoirs, unplanned irrigation, and animal farming practices can enhance the breeding of mosquitoes and snails (Wilson et al., 2020). A proper vector management plan has to be adapted to overcome these malpractices. Moreover, multivariate analysis and appropriate clinical execution are needed to prevent disease transmission and cure. Implementation of integrated vector management (IVM) system includes understanding of vector and disease transmission, identification of local determinants of disease, optimization of resources for effective vector control, and obviously a comprehensive assessment and implementation of strategies (Beier et al., 2008). In larval source management, potential breeding sites of vectors are eliminated by appropriate larvicide spraying (Ministry of Health and Family Welfare, Government of India, National Strategic Plan, Malaria Elimination in India, 2017). Proper usage of larvicide compounds can prevent the completion of the life cycle of insects from the larval stage to the mature stage. Indoor, as well as outdoor residual insecticides, spraying is one of the effective methods for vector population control in large-scale reduction of vector breeding sites. Indoor spraying is effective for almost 3–6 months, depending on the insecticide used and the type of surface on which it is sprayed. Aerial spraying of insecticides has been

Combating the vectors and management  Chapter | 5  89

proven to be very helpful to control mosquitoes, sandflies, and blackflies breeding and reduce transmission during epidemics (World Health Organization, 2014). Selection of insecticides is very important as it may induce a toxic effect on human and environment. DDT (dichlorodiphenyltrichloroethane) was introduced as an insecticide for a vector management program to control malaria, typhus, and Dengue during the 1940s. But the use of DDT was also restricted because mosquitoes had developed resistance to the widely used chemical. Many malaria-endemic countries have replaced DDT with alternative insecticides. But several countries experience severe malaria outbreaks as mosquito species found to be resistant to conventional synthetic insecticides (World Health Organization, 2014). Unrestrained and repeated use of a single class of insecticides results in insecticide resistance of vectors and accumulation of nonbiodegradable toxic compounds. To overcome these problems, an integrated approach for effective vector management is required in endemic countries (Sharma et al., 2020; Hazra, 2017). According to a report published by World Health Organization (WHO), more than 20,000 deaths occurred every year due to the lethal effects of synthetic insecticides (Chhipa, 2017). WHO recommends assessing the scenario of insecticide resistance locally and implements comprehensive insecticide resistance management strategies effectively (World Health Organization, 2014). An alternative integrated vector control program by using natural biodegradable EO-based insecticides has considered promising alternatives (Sugumar et al., 2014; Ghosh et al., 2013). EOs contain complex secondary metabolites of plants including volatile phytochemicals (terpenes and their oxygenated compounds) (Ouattara et al., 1997). A variety of nanoformulations like nanoemulsions have been employed as a very efficient alternative to conventional chemical insecticides (McClements, 2012; Ostertag et al., 2012). Furthermore, several studies also discussed the excellent stability and larvicidal efficacy of environment-friendly oil nanoemulsion against insect larvae (Sundararajan et al., 2018).

Essential oils EOs, also known as volatile oil or ethereal oil, are complex molecular substances having specific therapeutical and energetic effects. EOs are present in 17,500 plant species belonging to orders of angiosperms like Asterales, Laurales, Magnoliales, Zingiberales, etc. (Figueiredo et  al., 2008). They are present in the specialized cells or glands of certain aromatic plant families (about 50 families) and are responsible for plant immunity. The secretory plant structures like glandular trichomes (members of Lamiaceae), secretory cavities (members of Myrtaceae and Rutaceae), and resin ducts (members of Asteraceae and Apiaceae) are responsible for the synthesis and accumulation of EOs in plants (Figueiredo et al., 2008). Sometimes land and sea animals, insects, mushrooms,

90  Natural products in vector-borne disease management

and microorganisms are also biosynthesizing similar volatile compounds apart from superior plants (Berger, 2007). The aromatic plants vary in odor and flavor, which are represented by the amount and characteristics of constituents present in EOs. Apart from aromatic compounds, indigenous pigments contribute to varying colors of EO and their use as ingredients in different fields. They play a role as defense substances in plants aimed at natural enemies but also attract insects to their host for pollination (Harrewijn et al., 2001). EOs are extracted through distillation (via steam and/or water) or mechanical methods like cold pressing. The aromatic compounds thus obtained are then combined with a carrier oil and are made ready for use. Modern technologies are now being improvised over conventional methods to improve their efficacy.

Chemical composition of EOs EOs are a complex combination of plant volatile compounds and are essentially composed of terpenoids and phenolic groups. Terpenes constitute monoterpene and sesquiterpenes, and the aromatic compounds include aldehyde, alcohol, phenol, methoxy derivative, and so on (Hedden et al., 2002). The main reservoir of these aromatic compounds is in the dedicated cell types present in almost every parts of the plant, from the flower or leaves to the roots based on the plant types (Bakkali et al., 2008; Mohamed et al., 2010). The composition of the EOs varies among different plant taxonomic groups and also within the species itself (Fokou et al., 2020). These variations are associated with many factors like abiotic and biotic, postharvest treatment, extraction method, and preservation techniques.

Applications of EOs EOs have been used medicinally long back. In later stages, EOs become popular in medicinal industries because of their activities as antiviral, antibacterial, antiparasitic, antispasmodic, antiinflammatory, and antioxidant (Abu-Shanab et al., 2005; Mimica-Dukić et al., 2003). They have a huge role in aromatherapy, cancer therapy, pharmaceuticals, and natural therapies as alternative medicines (Kelen and Tepe, 2008). Several types of EOs like thyme oil, oregano oil, and tea tree oil also have antibiotic properties. EOs act as hepatoprotective negotiators in the human body by preventing unsaturated fatty acids and the formation of reactive oxygen species that together cause the damage of tissues by changing metabolic activities (Lee et al., 2012; Celiktas et al., 2007; Tepe et al., 2007). They are also very popular in the cosmetic industries due to their loveable odor, in the food and beverage industries for their antioxidant and antimicrobials (Dorman and Deans, 2000; Rios and Recio, 2005). The efficiency of EOs is well accepted by the scientific world as EOs are free from contraindications and adverse effects that finally lead them to

Combating the vectors and management  Chapter | 5  91

i­ ntroduce green technology (Dorman and Deans, 2000). At the biological level, the EOs have important effects as repellents, insecticides, and growth reducers in a wide variety of insects. To control the pre- and postharvest phytophagous insects, EOs are very effectively used as insect repellents with vectors of diseases and for the control of domestic and/or garden insects (Celiktas et al., 2007). The compounds present within the insect’s specific EO mainly show neurotoxic effects, involving several modes of actions, in particular, through the inhibition of acetylcholinesterase (AChE), functionality disruption of gammaaminobutyric acid (GABA) receptors, and an agonist of octopaminergic system (Murry, 2009). EOs extracted from some plant species and their major uses are listed in Table 2.

Nanoemulsion NEm is a thermodynamically stable biphasic dispersion of two immiscible liquids with one and more stabilizers that contain small droplets, ranging from 20 to 200 nm (Sharma et al., 2010). Among the two immiscible phases, one must be aquatic and the other is oily in nature. Depending on the component proportions, NEm was of four categories (Duffus et al., 2016; Schröder et al., 2017; Schroder et al., 2018). (A) Water in oil (W/O): Here, water droplets are dispersed in oil and the emulsion is effective for delivering water-loving or hydrophilic substances. (B) Oil in water (O/W): Oil droplets are dispersed in the aqueous phase and responsible for delivering fat-loving or hydrophobic substances. (C) Bi-continuous: Here, oil and water form microdomains and remain interspersed within the system. (D) Multiemulsion or mixed system: Depending on application purposes, it is again of two types. (i) Oil-in-water-in-oil emulsion (O/W/O): When water droplets containing oil get disperse in the oil phase, it forms this kind of multiemulsion. (ii) Water-in-oil-in-water emulsion (W/O/W): Here, larger oil droplets containing water get dispersed in the hydrophilic phase. Later, a surfactant or co-surfactant is used to separate the two phases and thereby reduce the interfacial tension that brings the stability of the NEm. Adjusting the surfactant types and their ratios in the mixture stability of NEms can be changed (Sharma et al., 2010).

Properties of NEms NEms have many advantages over macroemulsions because of their properties. NEm is thermodynamically metastable but kinetically very stable, and this stability is not hampered by physical statuses like temperature, pressure, or any kind of chemical disturbance like change in pH, etc. (Bai Aswathanarayan et al., 2018). Optically, NEms are transparent or a little bit translucent as the

TABLE 2  Some popular types of EOs, along with their source and their major uses (Murry, 2009; Irshad et al., 2018; Aziz et al., 2010; Irshad et al., 2011, 2012a,b). Name of EO

Name of the plant

Parts used

Major uses

References

Lemon oil

Citrus limon

Fruits

Used in pharmaceutical and cosmetics industry

Murry (2009)

Grapefruit oil

Citrus x paradisi

Fruits

Used in aromatherapy

Murry (2009)

Tea tree oil

Melaleuca alternifolia

Leaves

Antibacterial, antifungal, antiinflammatory, and other medicinal uses

Murry (2009)

Timur oil

Zanthoxylum alatum

Root, stem, leaves

Used as antifungal, antibacterial, and an antioxidant

Irshad et al. (2018)

Sandalwood oil

Santalum album

Wood

Used primarily as a fragrance

Murry (2009)

Rose oil

Rosa centifoia

Flowers

Used as fragrance, sedatives, astringent, and in other medicinal uses

Murry (2009)

Ginger oil

Zingiber officinale

Rhizome

Used as expectorants, antispasmodic, carminative, and other medicinal purposes

Murry (2009)

Thyme oil

Thymus serpyllum

Whole plant

Used as insecticide, antibacterial, and antifungal agent

Aziz et al. (2010)

Lavender oil

Lavendula officinalis

Flowers

Mosquito repellent

Murry (2009)

Vetiver oil

Vetiveria zizaniodes

Roots

Used as antidepressant, stress reliever, fixative in perfumery, and in aromatherapy

Murry (2009)

Eucalyptus oil

Eucalyptus globules

Leaves and stem

Used as antispasmodic, antiviral, antiseptic, and as natural repellent

Murry (2009)

Chora oil

Angelica glauca

Root

Used in medicinal purposes

Irshad et al. (2011)

Citronella oil

Cymbopogon nardus

Leaves

Mosquito repellent

Murry (2009)

Jasmine oil

Jasminum officinale

Flowers

Used as fragrance

Murry (2009)

Geraniol oil

Geranium sp.

Flowers

Used in herbal medicine, aromatherapy, perfumery

Murry (2009)

Neem oil

Azadirachta indica

Fruits and seeds

Antibacterial, antiinflammatory, anticancerous, and as mosquito repellent

Murry (2009)

Greek catnip oil

Nepeta parnassica

Flowers

Mosquito repellent

Murry (2009)

Rosewood oil

Aniba rosaeodora

Wood

Used for skin care

Murry (2009)

Camphor oil

Cinnamomum camphora

Wood and leaves

Used in cosmetics and household cleaners

Murry (2009)

Black pepper oil

Piper nigrum

Fruits

Used as pain reliever

Murry (2009)

Candolle oil

Skimmea laureola

Leaves

Used in medicinal purposes

Irshad et al. (2012a)

Cinnamon oil

Cinnamomum verum

Bark and leaves

Used as uterine stimulant, antifungal, antibiotic, and flavoring substance

Murry (2009)

Clove oil

Syzygium aromaticum

Flower buds

Used in perfumes and medicines

Murry (2009)

Thyme oil

Thymus vulgaris

Leaves and flowers

Used as preservatives and in cosmetics

Murry (2009)

Spurflowers oil

Plectranthus rugosus

Leaves

Used as antifungal, antibacterial, and other pharmaceutical purposes

Irshad et al. (2012b)

94  Natural products in vector-borne disease management

particle size is ranging from 20 to 500 nm thereby scattering lightly having 10%–20% polydispersibility (Anton and Vandamme, 2011). The droplet size of NEm is very essential regarding the determination of stability, optical property, rheological property, and release nature in the medium. Due to the miniature particle size, droplet aggregation-like flocculation is very rare for NEms (Tadros et al., 2004).

Components of NEms NEm is composed of an emulsifier and immiscible liquids of two phases: the oil phase and the aquatic phase (Wooster et al., 2008). The oil phase is composed of various forms of lipids like diacylglycerols, monoacylglycerols, triacylglycerols, and free fatty acids. Based on their functional and nutritional viewpoints, the long-chain triacylglycerols are more accepted for NEm preparation among all others (Witthayapanyanon et al., 2006). Additionally, they are easily available and cheap in cost. Besides these, any other lipophilic components like waxes, oil-soluble vitamins, lipid substitutes, etc. may form the oleaginous part of NEm (Tadros et al., 2004; McClements and Rao, 2011). The aquatic phase is made up of amphiphilic surface-active molecules that can make polar solvent and cosolvent. Water is generally used as a polar solvent, whereas carbohydrates, proteins, alcohols, etc. are used as cosolvent (Saxena et al., 2017). The formation of NEm, its stability, and different properties are gleaned from the various characteristic features of aquatic and oil phases. These include the density, viscosity, refractivity, interfacial tension, and phase nature of the oil phase as well as the polarity, ionic strength, rheology, and phase behavior of the aquatic phase (Tadros et al., 2004; Saxena et al., 2017). Sometimes, flocculation, gravitational separation, coalescence, a sudden increase in mean droplet size, i.e., Ostwald ripening, may break the two separate phases of NEms but it can be prevented by introducing a stabilizing agent (Kabalnov, 2001). The stabilizer can form solid particulate NEm or layered NEm or often may act as a ripening agent, texture modifier, or emulsifier. Emulsifiers are cationic, anionic, nonionic, or zwitterionic surface-active molecules that help to form small, stable NEms by reducing the interfacial tension (Kabalnov, 2001). Different proteins, polysaccharides, colloidal lipid particles, flavonoids, etc. are used as common emulsifiers (Schroder et al., 2018).

Methods for NEms preparation NEms can be prepared by using a high-energy method or low-energy method or by some novel methods. Smaller droplets are produced in the high-energy methods where mechanical devices are used to disrupt the oil molecules and force them to interact with aquatic molecules (Schramm, 2006; Tadros et al., 2004). Preparation of NEms again can be categorized into three ways (Fig. 2). In the high-pressure valve homogenization technique, miniature droplets are

Combating the vectors and management  Chapter | 5  95

FIG. 2  Diagrammatic representation of NEm preparation techniques.

formed after disrupting the dispersed phase, and finally, the emulsifiers stabilize the droplets (Lee and Clements, 2010) In microfluidization technique, a special type of microchannel having a diameter of 50–300 μm is used to prepare the NEm (Mao et al., 2010; Bae et al., 2009). In the ultrasonic method, high sound waves create mechanical vibration and disrupt the coarse droplets to form tiny emulsions. Higher energy is required when sonication time is increased because higher number of droplets is dispersed during this time and droplet size also decreased (Jafari et al., 2007). In the low-energy method, the chemical potential is used as an input energy source to produce NEm. In this technique temperature, the composition of the NEm and interfacial properties play a vital role. This technique can be categorized into three phases: inversion temperature (PIT) method, phase inversion composition (PIC) method, and solvent diffusion method (SDM) (Anton and Vandamme, 2011). In PIT method, NEm is formed at a fixed constituent of the components in varying temperature, whereas in the case of PIC, hydrophilicity and lipophilicity of the emulsifier vary with the changes of component constituents at a fixed temperature (Maestro et al., 2008; Lee and Clements, 2010). SDM can be classified into spontaneous and membrane emulsification methods. In the spontaneous emulsification method, water, oil, and emulsifier are mixed together

96  Natural products in vector-borne disease management

and lightly stirred at a particular temperature (Anton et al., 2008; Bouchemal et al., 2004). Membrane emulsification is another novel technique where a microporous membrane is used, and within it, two different immiscible liquids are injected under pressure to generate the desired NEms (Nakashima et al., 2000). Thereby, in high-energy method, mechanical devices play the major role, and in low-energy method, properties of lipophilic phase and the physicochemical nature of surfactants play a critical role in the formation of NEm. Recently, novel techniques have been developed to prepare NEms over conventional techniques as the smart ways are cost-effective and easy to generate a wide range of NEms of varying materials. A bottom-up approach is popular where w/o NEm is formed by condensing water vapor in oil-surfactant solution (Guha et al., 2017). This method is much easier, fast, and cost-effective.

Essential oil nanoemulsion The above-mentioned NEm preparation techniques are used for the preparation of nanoformulated EOs (EONEms), which increase its bioactivity and protect the active constituents of EOs by preventing premature volatility.

EONEms on vector-borne diseases EOs derived from different plant parts like bark, flower, stem, rhizome from aromatic plant species are well known many years ago as their volatile chemical compounds are imposed on various pharmaceutical applications (Schramm, 2006; Tadros et  al., 2004). For a long time, EO is used to control insects, pests, and other etiological components, and very recently, they are more popular in vector-borne disease management because of their low cost and low risk ­environment-friendly nature (Urzúa et  al., 2011; Espinoza et  al., 2018). However, the hydrophobic nature of EO makes them difficult in many applications as we all know that maximum solubility creates more efficiency. EONEms resolves the problem to some extent. The major active components of some common EONEms having their mode of action against vectors are summarized in Table 3. Scientists have successfully applied EONEms against various insects, mosquito larvae, acari-like ticks, and mites (Ramar et al., 2017; Nuchuchua et al., 2009) to control all the blarney involvement in our ecosystem, which are briefly discussed below (Fig. 3).

Role as insecticide EONEms prepared from Ocimum sanctrum have a strong effect on adult species of Aedes aegypti and Culex fatigans (Ramar et al., 2017). Pimpinella anisum of Apiaceae family contains higher percentage (∼81%) of EO anethole that can morphologically as well as histologically damage the adult species of Tribolium castenium and its F1 progeny too which cause a huge damage of stored products (Hashem et  al., 2018). Camphor leaves EONEms (EONEm)

TABLE 3  A list of some EONEms with their major active constituents and mode of action. No.

Names of EO NEms

Major active constituents (%)

Applicants

Mode of action

References

1

Ocimum sanctrum EONEms

Methyl eugenol (67.80), E-caryophyllene (17.10)

A. aegypti, C. quinquefasciatus

EONEms exhibited 98% and 100% knockdown effect, respectively, against A. aegypti and C. quinquefasciatus at 50 mg/L

Ramar et al. (2017)

2

Pimpinella anisum EONEms

trans-anethole (88.49), γhimachalene (3.13), cis-isoeugenol (1.99), and linalool (1.79)

Tribolium castenium

EONEms having 199 nm of droplet size showed LC50 of 9.3% against pest’s progeny

Hashem et al. (2018)

3

Cinnamomum camphora (Camphor leaves) EO NEms

d-Camphor

T. castenium and Lesioderma serricorne

Fumigant and toxic effect on adult pests with LC50 at 8.5 mg/L lair

Guo et al. (2016)

4

Cymbopogon nardus EONEms

Geraniol (35.7), trans-citral (22.7), cis-citral (14.2), geranyl acetate (9.7), citronellal (5.8)

A. aegypti

Repellent effect for near about 282 min with 150–200 nm droplet size of EONEms

Nuchuchua et al. (2009)

5

Ocimum americanum EONEms

Camphor (38.6), limonene (10.60)

A. aegypti

Enhanced mosquito protection time up to 4.7 h

Nuchuchua et al. (2009)

6

Vetiveria zizanioide EONEms

β-Vetispirene (1.6–4.5), khusimol (3.4–13.7), vetiselinenol (1.3– 7.8), and α-vetivone (2.5–6.3)

A. aegypti

EONEms having a droplet size of 150–200 nm showed a repellent effect

Nuchuchua et al. (2009)

7

Lavandula officinalis EONEms

Inalool (34.1), 1,8-cineole (18.5), borneol (14.5), camphor (10.2)

Trichomonas vaginalis

EO and EONEms both showed an inhibitory effect of ∼82% against the macrophage at 100 μg/mL

Ziaei Hezarjaribi et al. (2017)

8

Zataria multiflora EONEms

Thymol (46.61), carvacrol (17.26), p-cymene (11.51), γterpinene (4.01)

Hydatid cysts

100% Lethality of EONEms was noticed at 8 mg/mL after 7 min of exposure on hydrated cysts

Kowsari et al. (2021)

(51.3)

Continued

TABLE 3  A list of some EONEms with their major active constituents and mode of action—cont’d No.

Names of EO NEms

Major active constituents (%)

Applicants

Mode of action

References 2

9

Achillea fragrantissima

β-Sesquiphellandrene (28.6) and α-thujone (33.8)

Tyrophagus putrescentia

LC50 values were 8.4 and 14.1 μL/cm having 78.5–104.6 nm droplet size

Al-Assiuty et al. (2019)

10

Achillea santolina

Eucalyptol (25.20)

Tyrophagus putrescentia

Act as fumigant with an LC50 value 21.8 μL/cm2 having 78.5–104.6 nm droplet size

Al-Assiuty et al. (2019)

11

Rosemary (Salvia rosmarinus) EONEms

α-Pinene (27.31), β-phellandrene (43.76), and criptone (5.88)

Tetranychus urticae

Acaricidal activity on both adult and immature T. urticae with LC50 723.71 μg mL−1

Al-Assiuty et al. (2019)

12

Eucalyptus tree (Eucalyptus globulus) EONEms

1,8-Cineol (49.07–83.59) and α-pinene (1.27–26.35)

C. quinquefasciatus

100% Larvicidal role of EONEm having 9.4 nm droplet size at 250 μg/ mL in 4-h exposure

Sugumar et al. (2014)

13

Ocimum basilicum EONEms

Linalool (10.00), methyl chavicol (60.30), methyl cinnamate (6.30)

A. aegypti

EONEms with 65-nm droplet size showed around 94% mortality of third-instar larvae after 24 h exposure

Sundararajan et al. (2018)

14

Vitex negundo EONEms

Caryophyllene (21.58), epiglobulol (47.13)

A. aegypti

81% and 79% mortality rate of second- and third-instar larvae, respectively, after exposed in EONEm

Balasubramani et al. (2017)

15

Artemisia dracunculus

Sabinene (42.38), isoelemicin (12.91)

Anopheles stephensi

EONEms with ∼15 nm particle size enhanced the larvicidal effect from 83.4% to 92.71% at 18 μg/mL

Osanloo et al. (2017)

Artemisia dracunculus

Sabinene (42.38), isoelemicin (12.91)

Anopheles stephensi

Chitosan-based EONEms having 168 nm particle size enhanced the larvicidal effect of EO from 2 to 4 days, whereas from 4 to 9 days with 222-nm-sized droplets

Osanloo et al. (2017)

16

Pterodon emerginatus

Safrole (70.64), camphor (7.97), and bicyclogermacrene (3.73)

C. quinquefasciatus

NEms having 125 nm show 100% larvicidal effect at 250 μg/mL

Oliveira et al. (2017), Turell (2012)

17

Azadirachta indica

Hexadecanoic acid (34.0), oleic acid (15.7)

C. quinquefasciatus

31-nm-sized EONEm induced LC50 at 11.75 μg/mL to the larvae only

Anjali et al. (2012)

18

Lipia alba

Geranial (50.94) and neral (33.32)

C. quinquefasciatus

NEms of 117 nm showed LC50 at 31.02 μg/mL against the larvae

Ferreira et al. (2019)

19

Citrus sinensis EONEms

Monoterpenes hydrocarbons (C10H16), including limonene (77.49%), myrcene (6.27%), and c-terpinene (3.34%)

C. pipiens

EONEms of ∼78 nm particle size decreased the LC50 of the EO from 86.3 to 27.4 μg/mL

Azmy et al. (2019)

20

Anacardium occidentale

β-Phellandrene + limonene (17.5), methyl chavicol (11.4), germacrene B (8), trans-αbergamotene (7.9)

A. aegypti

Applying EONEms of 52 nm against larvae LC50 of the EO reduced from 18.1 to 1.4 μg/mL

Kala et al. (2019)

21

Croton linearis

Guaiol (7.93), eudesma-4(15),7dien-1β-ol (4.94), and guaia3,10(14)-dien-11-ol (4.52)

A. aegypti

Larvicidal effect of 163-nm-sized EONEms decreased LC50 of the EO from 64.24 to 17.86 μg/mL

Amado et al. (2020)

22

Siparuna guianensis

Atractylone (18.65), trans-βelemenone (11.78), germacrene D (7.61), γ-elemene (7.04), and curzerene (7.1)

A. aegypti

EONEms having 176-nm droplet size decreased LC50 of the EO from 86.52 to 24.75 μg/mL against larval growth

Ferreira et al. (2020)

23

Ricinus communis

Thujone (31.71), 1,8-cineole (30.98), pinene (16.88), camphor (12.98), and camphene (7.48)

A. culicifacies

EONEms with 114 nm droplet size reduced the LC50 of the EO from 52.3 to 3.4 μg/mL

Sogan et al. (2018)

24

Ficus glomarata

Eugenol (27.0%), itaconic anhydride (15.4%), 3-methylcyclopenetane-1,2-dione (10.8%)

A. aegypti and C. quinquefasciatus

The 104-nm-sized EONEms decreased the LC50 of the EO from 60 to 20 μg/mL and from 48 to 22 against A. aegypti and C. quinquefasciatus, respectively

Nazeer et al. (2019)

Continued

TABLE 3  A list of some EONEms with their major active constituents and mode of action—cont’d No.

Names of EO NEms

Major active constituents (%)

25

Mentha piperata

Menthol (46.32), menthofuran (13.18), menthyl acetate (12.10), menthone (7.42), and 1.8-cineole (6.06)

26

Aeollanthus sauveolens EONEms

27

Ocimum sanctrum EONEms

Applicants

Mode of action

References

C. pipiens

35-nm droplet size of EONEms reduced the LC50 of the EO from 88.90 to 31.24 μg/mL when applied on larvae

Jesser et al. (2020)

Linalool (49.3) and (E)-βfarnesene (34.9)

A. aegypti

LC50 of the EO reduced remarkably when applied EONEms on mosquito larvae

Lima Santos et al. (2019)

Methyl eugenol (67.80), E-caryophyllene (17.10)

C. quinquefasciatus and A. aegypti

LC50 of adult mosquitoes reduced after 24 h of exposure to EONEms

Ramar et al. (2017)

Combating the vectors and management  Chapter | 5  101

FIG.  3  The application of nanoformulated EOs extracted from some plants against different vectors.

are highly toxic against T. castenium and Lesioderma serricorne, the common cigarette beetle causing huge economic loss by destroying dry-stored food products (Guo et al., 2016).

Role as repellent Repellent activity of EONEm was cited by many researchers. Long prevention time (∼3 h) by applying citronella oil nanoformulation against A. aegypti adults was recorded by Sakulku et al. (2009). Another study revealed that a proportion having 10: 5: 5 of citronella, basil, and vetiver oil extracted from Cymbopogon nardus, Ocimum americanum, and Vetiveria zizanioide, respectively, show a synergic effect to protect A. aegypti almost for 4.7 h (Nuchuchua et al., 2009). Another EONEms from Myristica fragrans (nutmeg oil) have a well-established insect-repellent activity, which was reported by Mohd Narawi against A. aegypti in 2020 (Mohd Narawi et al., 2020). Role as antiparasite Recent studies revealed that EONEm has a positive effect to combat etiological diseases by preventing disease-causing parasites. EONEm of Lavandula officinalis can prevent trichomoniasis, a sexually transmitted common disease caused by the flagellated parasite Trichomonas vaginalis (Ziaei Hezarjaribi et al., 2017). Shokri et al. and Bouyahya et al., later on, worked on varieties of Lavandula species and their formulated EONEm strongly oppose different species of Leishmania, a causal parasite of sickle sickness disease (Bouyahya et al., 2017; Shokri et al., 2017). EONEms formulated from Schinus mole can control trypanosome parasites with 80%–100% efficiency (Ghosh et al., 2013). The catastrophic activity of Zataria multiflora extracted from EONEms against hydatid cysts was observed by Elissondo et al. in 2013 (Baldissera et al., 2013;

102  Natural products in vector-borne disease management

Kowsari et al., 2021), and other researchers later recorded the scolicidal activity of the same nanopreparation (Moazeni et al., 2014; Yones et al., 2011).

Role against acari Acaricidal activity of EONEms prepared from Ocimum basilicum, Achillea fragrantissima, and Achillea santolina was noticed against Tyrophagus putrescentia, a stored food mite that causes heavy economic loss (Mahmoudvand et al., 2017). Rosemary EONEms have a similar effect on Tetranychus urticae, the two-spotted spider mice, way out a green pest management technique (AlAssiuty et  al., 2019). Santosh et  al. established that cinnamon oil NEms can control the Rhipicephalus microplus, common ticks on dairy cows (Dos Santos et al., 2017). This nanoformulation effectively impedes oviposition and diminishes the larvicidal growth of the ticks. Role against mosquitoes Larvicidal effect Among all other applications, EONEms have a vast role on mosquito-borne disease management, and this is generally happened by their inhibitory effect on mosquitoes’ larvae. Mosquito is a common vector in almost all countries in the world, which causes around 15–20 different kinds of diseases that takes over 1 million lives per year (Dos Santos et al., 2017; Minnesota Department of Health, 2018). EONEms derived from the Eucalyptus tree can restraint the larval growth of C. quinquefasciatus, was reported by Sugumar et al. (2014). They also proved that the EONEms showed a larvicidal effect after only 4 h of exposure, while the nonnano-EO showed it after 24 h of exposure. The Yellow fever mosquito, Aedes aegypti, is one of the major Dengue-transmitting vectors whose thirdinstar larvae can be destroyed by spraying Ocimum basilicum EONEms with ∼88% inhibitory efficiency (Sundararajan et  al., 2018). However, the inhibition efficacy reached 100% when the EONEm was diluted ten times than the previous concentration by Ghosh et  al. (2013). Later, it was also proved by Duarte et al that the fourth-instar larval stage of A. aegypti was diffident having 90% mortality rate with Rosemarinus officinalis EONEms (Duarte et  al., 2015). The major constituent of EONEms extracted from Baccharis reticulata is d-limonene, which potentially inhibits the larval growth of A. aegypti too by diminishing the acetylcholine esterase activity in larvae (Botas et  al., 2017). Also, a group of researchers from India revealed that EONEms collected from Vitex negundo plant can also inhibit the second- and third-instar larval stage of the same mosquito genus with near about 70% mortality rate (Balasubramani et al., 2017). The major causal vector of malaria in Iran, Anopheles stephensi, can be prevented by spraying EONEms formulated from Artemisia dracunculus, which was reported by Osanloo et al. (2017). The active component of the NEms is p-allylanisole, which acts as mosquito larvae inhibitor with i­ nsignificant

Combating the vectors and management  Chapter | 5  103

e­ cological risk (Osanloo et al., 2017). The larvicidal effect of nonnano-EO of A. dracunculus exhibited a larvicidal effect for 2 h, which increased to 4 h after nanoformulation having 168 nm droplet size with 1.6% EO. Another study by the same authors also showed that the inhibitory time increased from 4 to 9 days when the droplet size of the chitosan-based EONEms was 222 nm containing 6% EO. Oliveira et al in 2017 also experimented with Pterodon emerginatus and the oleoresin-based EONEms separated from this plant proved an effective tool to control C. quinquefasciatus, causal vector of avian malaria and many other diseases in tropical and subtropical regions (Oliveira et al., 2017; Turell, 2012). It was also reported that while EO of Azadirachta indica had no effect on mosquito larvae, the EONEms prepared from the same plant have a larvicidal effect on C. quinquefasciatus (Anjali et al., 2012). Ferreira et al. (2019) later also reported the similar effect of Lipia alba EONEms against A. aegypti and C. quinquefasciatus. Water-staying Culex pipiens larval growth can be checked by the safe use of EONEms isolated from Citrus sinensis in comparison with bulk emulsion (Azmy et al., 2019). EO of C. sinensis also exhibits a larvicidal effect; however, the lethal concentration 50 (LC50) of the EO decreased from 86.3 to 27.4 μg/mL after giving exposure to C. pipiens with nanoformulated EO of C. sinensis. Kala et al. in 2019 experimentally proved that nanoformulation of Anacardium occidentale released EO that can successfully destroy the larvae of A. culicifacies, and in the very next year, Amado et al. reported that Croton linearis EONEms show a larvicidal effect against A. aegypti (Kala et al., 2019; Amado et al., 2020). Nanopreparation of EO isolated from Siparuna guianensis also showed that the efficiency of larvicidal effect of EO enhanced much more against A. aegypti whenever they were formulated to EONEms (Ferreira et al., 2020). Ricinus communis EONEms having a particle size of ∼114 nm impede the growth of A. aegypti larvae with high efficiency within 24 h of treatment and also showed toxicity against third-instar larvae of A. culicifacies (Sogan et al., 2018). Ricinine and castor oil are the major component of R. communis that also have an insecticidal effect against A. caspius, C. pipiens, A. maculipennis, and Culiseta longiareolata (Aouinty et al., 2006). Emulsified nanocrystals (∼104 nm particle size) of EO extracted from Ficus glomarata and neem oil successfully executed repellent as well as a larvicidal effect against C. quinquefasciatus (Nazeer et al., 2019). Larvicidal role of nanoformulated EO of Mentha piperata has reported against C. pipiens (Jesser et al., 2020). EONEms from Aeollanthus sauveolens also have an inhibitory effect on the larval growth of A. aegypti. The active constituents of these NEms are linalool and (E)-b-farnesene that can hinder the third-instar larvae of A. aegypti (Lima Santos et al., 2019). Adulticidal effect There have many evidences of the larvicidal activity of EONEms prepared from a wide range of plant species. However, scanty research has been done so far

104  Natural products in vector-borne disease management

against the adulticide effect of these EONEms. Ramar et al. (2017) reported that fabrication of nanoformulated EO collected from Ocimum sanctrum in the filter paper showed knocking down and killing effect against C. quinquefasciatus and A. aegypti adult. Up to 50% lethality for adult mosquitoes was noticed after 24 h of exposure to the EONEms, and any side effect of residual spraying was not detected. This indicates a promising, environmentally benign nano-insecticidal role of EONEms that can potentially manage mosquito-borne diseases through combating adult mosquitoes.

Concluding remarks The involvement of green technology against vector-borne disease management definitely initiates a significant impact in our environment that will be helpful to develop a sustainable growth on which our health and economy d­ epend. There are many advantages of EONEms over EOs that attract the former in many industrial applications. The most important fact that was solved by the formation of EONEms was the solubility issue. Nonsolubility or low solubility of EOs prevents their use against insect larvae. However, the problem was deciphered after the invention of nanoformulated EOs, which is almost soluble in water and other hydrophilic preparations. In EONEms, surfactants are used in minute quantity, and therefore, they are less toxic to the biosystems. The gravitational force in nanodroplets is minimum that makes them more stable in our environment against various destabilizing phenomena. EONEms are kinetically and thermodynamically stable, and henceforth, aggregation, coalescence, and flocculation cannot occur automatically to lose their stability. The nanorange droplet size enhances the active surface area against vectors in both lipophilic and hydrophilic environments. EONEms can be delivered parenterally to the vectors over EOs as nanodroplets can be cleared slowly than nonnano and therefore have a longer residence time in the vector’s body. Another advantage of being tiny in size is their permeability through the cells of vectors. EONEms can be administered on vectors in various ways like in liquid form, as a sprayer, and as fumes whatever is needed. It secures the chemical constituents of respective EOs from oxidation and hydrolysis as they remain in oil droplet. However, some limitations still have to be resolved. The stability of EONEms can be disturbed by changing the pH and the temperature, and sometimes instability comes through Oswald ripening effect. The surfactant or co-surfactant used in NEm preparation creates a little or negligible toxicity that may often be harmful when used in foodstuffs, medicines, or cosmetics. The preparation process of EONEms is quite costly that may create a financial issue in lowincoming countries. To resolve this issue, cost-effective techniques like lowenergy and novel preparations techniques can be used. Therefore, surfactant selection during the preparation is crucial so that it becomes nontoxic and the

Combating the vectors and management  Chapter | 5  105

interfacial tension remains very low at the oil-water interface, which is the most prime requirement of NEm preparation. A great surge in research and development of nanoscience has shown that the formation of EONEms can be used in human endeavors with an enormous potency. The long-range applications of EOs have been more furnished with EONEms that not only spread the green route technology but also meet the enormous human need in satisfaction. Management of vectors by means of chemical control is no doubt playing a commanding role throughout the world. However, the global pollution issues encourage scientists to find out natural vector prevention techniques with nontoxic, biodegradable plant compounds that may not create hazardous residuals to be released in our ecosystem. In this circumstance, involvement of EONEms to prevent the transmission of infectious agents opens a new era in a technology-dependent world. However, awareness must be raised among the population about the use of EONEms over the traditional EOs against vectors to reach our destiny easily with enormous efficiency and accuracy.

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112  Natural products in vector-borne disease management Sogan, N., Kapoor, N., Kala, S., Patanjali, P., Nagpal, B., Kumar, V., Valecha, N., 2018. Larvicidal activity of castor oil Nanoemulsion against malaria vector Anopheles culicifacies. Int. J. Mosquito Res. 5, 01–06. Sugumar, S., Clarke, S.K., Nirmala, M.J., Tyagi, B.K., Mukherjee, A., Chandrasekaran, N., 2014. Nanoemulsion of eucalyptus oil and its larvicidal activity against Culex quinquefasciatus. Bull. Entomol. Res. 104 (3), 393–402. https://doi.org/10.1017/S0007485313000710. Sundararajan, B., Moola, A.K., Vivek, K., Kumari, B., 2018. Formulation of nanoemulsion from leaves essential oil of Ocimum basilicum L. and its antibacterial, antioxidant and larvicidal activities (Culex quinquefasciatus). Microb. Pathog. 125, 475–485. https://doi.org/10.1016/j. micpath.2018.10.017. Sutherst, R.W., 2004. Global change and human vulnerability to vector-borne diseases. Clin. Microbiol. Rev. 17 (1), 136–173. https://doi.org/10.1128/CMR.17.1.136-173.2004. Tadros, T., Izquierdo, P., Esquena, J., Solans, C., 2004. Formation and stability of nano-emulsions. Adv. Colloid Interf. Sci. 108–109, 303–318. https://doi.org/10.1016/j.cis.2003.10.023. Tepe, B., Daferera, D., Tepe, A.S., Polissiou, M., Sokmen, A., 2007. Antioxidant activity of the essential oil and various extracts of Nepeta flavida hub-Mor. from Turkey. Food Chem. 103 (4), 1358–1364. Turell, M.J., 2012. Members of the Culex pipiens complex as vectors of viruses. J. Am. Mosq. Control Assoc. 28 (4 Suppl), 123–126. https://doi.org/10.2987/8756-971X-28.4.123. Urzúa, A., di Cosmo, D., Echeverría, J., Santander, R., Palacios, S.M., Rossi, Y., 2011. Insecticidal effect of Schinus latifolius essential oil on the housefly, Musca domestica L. Bol. Latinoam. Caribe Plantas Med. Aromát. 10, 470–475. Wilson, A.J., Morgan, E.R., Booth, M., Norman, R., Perkins, S.E., Hauffe, H.C., Mideo, N., Antonovics, J., McCallum, H., Fenton, A., 2017. What is a vector? Philos. Trans. R. Soc. Lond. Ser. B Biol. Sci. 372 (1719), 20160085. https://doi.org/10.1098/rstb.2016.0085. Wilson, A.L., Courtenay, O., Kelly-Hope, L.A., Scott, T.W., Takken, W., Torr, S.J., Lindsay, S.W., 2020. The importance of vector control for the control and elimination of vector-borne diseases. PLoS Negl. Trop. Dis. 14 (1), e0007831. https://doi.org/10.1371/journal.pntd.0007831. Witthayapanyanon, A., Acosta, E.J., Harwell, J.H., Abatini, D.A., 2006. Formulation of ultralow interfacial tension systems using extended surfactants. J. Surfactant Deterg. 9, 331–339. https:// doi.org/10.1007/s11743-006-5011-2. Wooster, T.J., Golding, M., Sanguansri, P., 2008. Impact of oil type on nanoemulsion formation and Ostwald ripening stability. Langmuir 24 (22), 12758–12765. https://doi.org/10.1021/la801685v. Yones, D.A., Taher, G.A., Ibraheim, Z.Z., 2011. In vitro effects of some herbs used in Egyptian traditional medicine on viability of protoscolices of hydatid cysts. Korean J. Parasitol. 49 (3), 255–263. https://doi.org/10.3347/kjp.2011.49.3.255. Ziaei Hezarjaribi, H., Nadeali, N., Saeedi, M., Soosaraei, M., Jorjani, O.N., Momeni, Z., Fakhar, M., 2017. The effect of lavender essential oil and nanoemulsion on Trichomonas vaginalis in vitro. Feyz 21, 326–334.

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Chapter 6

Natural product for management of babesiosis Sora Yasria and Viroj Wiwanitkitb,c,d,e,f,g a

KMT Center, Bangkok, Thailand, bDr DY Patil University, Pune, India, cDepartment of Eastern Medicine, Government College University Faisalabad, Faisalabad, Pakistan, dHainan Medical University, Haikou, China, eFaculty of Medicine, University of Nis, Nis, Serbia, fJoseph Ayobalola University, Ikeji-Arakeji, Nigeria, gSuranaree Institute of Technology, Nakhorn Ratchasima, Thailand

Introduction A “natural product” is defined as any product derived from naturally existing material. The medical application of natural products is interesting. At present, natural products offer hope for management of many health disorders, as such natural products may contain useful chemical ingredients that can be helpful for management of clinical problems. Regarding vector-borne disease, it is still an important public health problem worldwide. The management of vector-borne disease by natural products is an interesting subject. Such natural products might have an active composition that is useful for prevention and treatment of vector-borne disease. In this short chapter, the authors summarize and discuss the use of natural products for management of babesiosis, an important but neglected tropical vector-borne disease.

Clinical information on babesiosis Babesiosis, or piroplasmosis, is a parasitic disease caused by infection with a eukaryotic parasite in the order Piroplasmida, typically, a Babesia. This disease is a malarial-like infection (Solano-Gallego et al., 2016; Krause, 2019; Vannier et  al., 2015; Beugnet and Moreau, 2015; Sanchez et  al., 2016). It is considered to be an important but neglected blood infection. Human babesiosis is an arthropod-borne disease. It is transmitted via tick bite. The disease is observed in some tropical areas such as in South America, Northeastern and Midwestern United States, and some parts of Europe (Gorenflot et al., 1998). Several ticks can transmit the human strain of babesiosis (Fig. 1). Therefore, it might be co-endemic with other tick-borne illnesses such as Lyme disease (Wormser et  al., 2006). The infection starts with being bitten by an infected Natural Products in Vector-Borne Disease Management. https://doi.org/10.1016/B978-0-323-91942-5.00005-7 Copyright © 2023 Elsevier Inc. All rights reserved.

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FIG. 1  Transmission of babesiosis.

tick, or can result from getting a blood transfusion from an infected donor of blood products (Solano-Gallego et al., 2016; Krause, 2019; Vannier et al., 2015; Beugnet and Moreau, 2015; Sanchez et  al., 2016). Additionally, uncommon modes of transmission such as vertical transmission are possible, which might cause congenital babesiosis (Fox et  al., 2006). Although it is uncommon, as babesiosis is sometimes transmitted via blood transfusion, screening for this parasite is a basic requirement in transfusion medicine (Lindholm et al., 2011). For animals, babesiosis is also considered as an important infectious disease. It can affect many kinds of animals, including domestic animals and cattle, and babesiosis epizootics can sometimes occur. Texas cattle fever, or redwater, is a well-known example of disease caused by babesiosis (Panti-May and Rodríguez-Vivas, 2020; Baneth, 2018). As earlier mentioned, babesiosis is classified as a blood infection, as red blood cells are the main affected cell. Intraerythrocytic parasites are a common hematological finding, with which the patient usually develops acute febrile illness (Solano-Gallego et al., 2016; Krause, 2019; Vannier et al., 2015; Beugnet and Moreau, 2015; Sanchez et al., 2016). There might be a history of contact with ticks or visiting an endemic area within 2 months (Solano-Gallego et al., 2016; Krause, 2019; Vannier et al., 2015; Beugnet and Moreau, 2015; Sanchez et  al., 2016). In some cases, infection might be severe and the patient might develop severe hemolytic anemia. Similar to malaria, the most serious outcome in severe babesosis infection might be death. The existence of parasites in red blood cells is similar to malaria, and consequently, differential diagnosis by an experienced clinical microscopist is necessary for correct identification. Recognition of the disease can help in early diagnosis of babesiosis. The treatment of babesiosis is based on standard medical management for vectorborne blood infections, in which symptomatic treatment is necessary. Specific antiparasitic drugs are recommended for getting rid of the pathogen. The drug of choice for treatment of babesiosis is a combination of atovaquone and azithromycin (Solano-Gallego et al., 2016; Krause, 2019; Vannier et al., 2015; Beugnet and Moreau, 2015; Sanchez et al., 2016). The therapy course is 1 week; however, this might be extended to at least 6 weeks in people with relapsing

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­babesiosis (Solano-Gallego et  al., 2016; Krause, 2019; Vannier et  al., 2015; Beugnet and Moreau, 2015; Sanchez et al., 2016). In severe cases, a combination of clindamycin and quinine should be used. Exchange transfusion is recommended in cases with very high parasitemia (Radcliffe et al., 2019). Regarding disease prevention, since the disease is a vector-borne disease, vector control is an effective method of prevention. Avoidance of contact with vectors is recommended. It is also advised that there be no travel to outbreak areas of babesiosis, since there is still no specific human vaccine or effective chemoprophylaxis (Radcliffe et al., 2019).

Role of natural products in management of babesiosis Treatment Some natural products are proposed for effective treatment of babesiosis, According to traditional and folk medicine, there are many herbs that might be useful for management of babesiosis. Examples of those herbs are as follows. 1. Boophone disticha Boophone disticha is a bulbous plant widely used in the folk medicine of South Africa. This plant is a member of the family Amaryllidaceae. Classically, Boophone disticha is used for treatment of equine babesiosis (Nair and Van Staden, 2014). However, toxicity of the plant extract is high and this plant is currently not used for any type of treatment (Nair and Van Staden, 2014). 2. Achillea millefolium Achillea millefolium can give essential oil. A recent study showed that essential oil derived from Achillea millefolium was active against Babesia parasites, with an IC50 value equal to 51.0 μg/mL (Batiha et al., 2020a). 3. Eugenia caryophyllus Eugenia caryophyllus can give essential oil. A recent study showed that essential oil derived from Eugenia caryophyllus was active against Babesia parasites, with an IC50 value equal to 60.3 μg/mL (Batiha et al., 2020a). 4. Citrus grandis Citrus grandis can give essential oil. A recent study showed that essential oil derived from Citrus grandis was active against Babesia parasites, with an IC50 value equal to 61.3 μg/mL (Batiha et al., 2020a). 5. Syzygium aromaticum L. Syzygium aromaticum L. is a spice that has traditionally been used for food preservation. It contains glycosides, saponins, tannins, alkaloids, flavonoids, steroids, and terpenes, and has various pharmacological activities (Subeki et al., 2004), among which, efficacy against Babesia parasites is reported (Subeki et al., 2004). 6. Arcangelisia flava Arcangelisia flava is a tropical plant. A recent animal model study showed that this plant extract had inhibitory effect against Babesia gibso without toxicity (Batiha et al., 2020b).

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7. Curcuma zedoaria Curcuma zedoaria is a tropical plant. A recent animal model study showed that this plant extract had inhibitory effect against Babesia gibso without toxicity (Batiha et al., 2020b). 8. Garcinia benthamiana Garcinia benthamiana is a tropical plant. A recent animal model study showed that this plant extract had inhibitory effect against Babesia gibso without toxicity (Batiha et al., 2020b). 9. Lansium domesticum Lansium domesticum is a tropical plant. A recent animal model study showed that this plant extract had inhibitory effect against Babesia gibso without toxicity (Batiha et al., 2020b). 10. Peronema canescens Peronema canescens is a tropical plant. A recent animal model study showed that this plant extract had inhibitory effect against Babesia gibso without toxicity (Batiha et al., 2020b). 11. Berberis vulgaris Extract of this plant displays antibabaseia activity (Batiha et  al., 2020b). In an in vitro study, the methanolic extract of Berberis vulgaris prohibited Babesia microti multiplication at 150 mg/kg by 66.7% (Batiha et al., 2020b). 12. Acetonic Rhus coriaria Extract of this plant displays antibabaseia activity (Batiha et al., 2020b). In an in vitro study, the methanolic extract of Acetonic Rhus coriaria prohibited Babesia microti multiplication at 150 mg/kg by 70% (Batiha et al., 2020b). 13. Cinnamomum verum In an in vitro study, extract of Cinnamomum verum was effective against Babesia microti in mice at 150 mg/kg (Batiha et al., 2020c). 14. Viola tricolor In a recent study, extract of Viola tricolor was shown to prohibit Babesia microti multiplication in mice by 35.1% (Batiha et al., 2020d). 15. Achillea millefolium In a recent study, extracts of this plant were antagonistic to Babesia canis at a 2 mg/mL concentration (Guz et al., 2019; Murnigsih et al., 2005). 16. Saxifraga spinulosa Flavonoid-based 3′-O-β-d-glucopyranosides (1–8) and galloyl glucosides (9, 11, 12) isolated from this plant are proven to have inhibitory effect against several Babesia species (Badral et al., 2017). 17. Elephantorrhiza elephantina Extract of Elephantorrhiza elephantina rhizome has an inhibitory effect against Babesia parasites at a concentration of 100 microg/m (Naidoo et al., 2005). 18. Peganum harmala L. Antibabesial effect of total alkaloid of Peganum harmala L. is reported in experimentally infected cattle (Fan et al., 1997; Hu et al., 1997). This is one

Natural product for management of babesiosis  Chapter | 6  119

of the few plants that has been scientifically studied for clinical effectiveness in a big animal in vivo trial (Fan et al., 1997; Hu et al., 1997). 19. Baeckea frutenscens Antibabesial effect of Baeckea frutenscens extract is reported (Murnigsih et al., 2005). 20. Brucea javanica Antibabesial effect of Brucea javanica extract is reported (Murnigsih et al., 2005). 21. Curcuma xanthorrhiza Antibabesial effect of Curcuma xanthorrhiza extract is reported (Murnigsih et al., 2005). 22. Strychnos lucida Antibabesial effect of Strychnos lucida extract is reported (Murnigsih et al., 2005). 23. Swietenia macrophylla Antibabesial effect of Swietenia macrophylla extract is reported (Murnigsih et al., 2005). 24. Cryptolepis sanguinolenta Extract of Cryptolepis sanguinolenta demonstrates antiparasitic activity against Babesia duncani (Zhang et al., 2021). 25. Scutellaria baicalensis Extract of Scutellaria baicalensis demonstrates antiparasitic activity against Babesia duncani (Zhang et al., 2021). 26. Polygonum cuspidatum Extract of Polygonum cuspidatum demonstrates antiparasitic activity against Babesia duncani (Zhang et al., 2021). 27. Alchornea cordifolia Extract of Alchornea cordifolia demonstrates antiparasitic activity against Babesia duncani (Zhang et al., 2021). 28. Baeckea frutenscens Extract of Baeckea frutenscens demonstrates antiparasitic activity against Babesia gibsoni (Murnigsih et al., 2005). 29. Brucea javanica Extract of Brucea javanica demonstrates antiparasitic activity against Babesia gibsoni (Murnigsih et al., 2005; Nakao et al., 2009; Subeki et al., 2007; Yamada et al., 2009). Bruceine A is the active ingredient that plays a role against parasites. In a recent trial in dogs, the Brucea javanica-derived bruceine A was effective in treatment (Nakao et al., 2009). 30. Curcuma xanthorrhiza Extract of Curcuma xanthorrhiza demonstrates antiparasitic activity against Babesia gibsoni (Murnigsih et al., 2005). 31. Strychnos lucida Extract of Strychnos lucida demonstrates antiparasitic activity against Babesia gibsoni (Murnigsih et al., 2005).

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32. Swietenia macrophylla Extract of Swietenia macrophylla demonstrates antiparasitic activity against Babesia gibsoni (Murnigsih et al., 2005). 33. Laurus nobilis In a recent study, extract of Laurus nobilis was shown to prohibit Babesia microti multiplication in mice by 56.1% (Batiha et al., 2020d). 34. Artemisia annua Artemisia annua is a well-known herb in Chinese traditional medicine. Artemisinin is the main product derived from this plant and has already been developed into a new drug for management of malaria, artemesin. For babesiosis, an experiment in rat model infected with Babesia microti showed that Artemisia annua, artesunate, and artemisinin were not effective in reducing or eliminating parasitemia (Lfawal et al., 2021). However, another report showed a contrasting result that Artemisia annua extract had strong antiparasitic activity (Zhang et  al., 2021). Further studies on this well-known Chinese herb are of interest. There are many herbal plants that have been studied for efficacy for treatment of babesiosis. However, most of these studies are in vitro studies. Curcuma species, for example, are widely reported for efficacy against Babesia species (Haddad et al., 2011), but few studies are in vivo studies. For herbs with supporting evidence for their antibabesial activity from in vivo studies, most are based on small animal or mice models. One herbal plant that is well established for its effectiveness in big animal models is Peganum harmala L. (Fan et al., 1997; Hu et al., 1997). Another plant with good clinical evidence in naturally infected animals (dog) is Brucea javanica (Nakao et al., 2009). Studies on real animal hosts provide interesting data for further research and development in searching for new therapies for human beings (Table 1). With new biotechnologies, natural products can be purified and isolated and applied for clinical usage. New trends in using natural product in management of babesiosis include the use of nanotechnology, with which direct active ingredients might be modified and used. For example, ellagic acid microspheres

TABLE 1  Herbal plants that might be good targets for further new antibabesial drug development. Plant

Details

Brucea javanica

Supporting evidence from big animal experimental studies

Peganum harmala L.

Supporting evidence from natural domestic dog cases

Curcuma species

Several reports from in vitro pharmacological studies

Artemisia annua

Confirmation for efficacy in malarial blood parasite, controversial evidence for Babesia species

Natural product for management of babesiosis  Chapter | 6  121

developed by nanomodification of plant-derived ellagic acid have been studied and proven effective in inhibiting Babesia species (Beshbishy et al., 2019).

Prevention Using natural products for babesiosis prevention is an interesting topic. Since babesiosis is a tick-borne disease, any natural product that can prevent tick infestation is useful for prevention of babesiosis (Wilson, 2002). Plant-based repellents are comparative to chemical repellants in tick control (Diaz, 2016); nevertheless, it is well accepted that plant-based extract causes a lower environmental and food contamination, lower toxicity to animals and humans, and slower development of resistance (Borges et al., 2011).

Conclusion Few natural products have been proposed and studied for effective management of babesiosis. Since babesiosis is a neglected tropical infection, limited funding and research interest are given to it. At present, there are few studies on natural products for management of babesiosis. Nevertheless, as the available reports usually give evidence that natural products might be useful for management of babesiosis, conclusively, natural products might be an effective tool for treatment and prevention of babesiosis. Further research and development on the exact clinical usefulness of natural products on babesiosis should be promoted.

Conflict of interest None.

References Badral, D., Odonbayar, B., Murata, T., Munkhjargal, T., Tuvshintulga, B., Igarashi, I., Suganuma, K., Inoue, N., Brantner, A.H., Odontuya, G., Sasaki, K., Batkhuu, J., 2017. Flavonoid and galloyl glycosides isolated from Saxifraga spinulosa and their antioxidative and inhibitory activities against species that cause piroplasmosis. J. Nat. Prod. 80 (9), 2416–2423. Baneth, G., 2018. Antiprotozoal treatment of canine babesiosis. Vet. Parasitol. 254, 58–63. Batiha, G.E., Alkazmi, L.M., Wasef, L.G., Beshbishy, A.M., Nadwa, E.H., Rashwan, E.K., 2020a. Syzygium aromaticum L. (Myrtaceae): traditional uses, bioactive chemical constituents, pharmacological and toxicological activities. Biomolecules 10 (2), 202. Batiha, G.E., Magdy Beshbishy, A., Adeyemi, O.S., Nadwa, E.H., Rashwan, E.K.M., Alkazmi, L.M., Elkelish, A.A., Igarashi, I., 2020b. Phytochemical screening and antiprotozoal effects of the methanolic Berberis vulgaris and acetonic Rhus coriaria extracts. Molecules 25 (3), 550. Batiha, G.E., Beshbishy, A.M., Guswanto, A., Nugraha, A., Munkhjargal, T., Abdel-Daim, M.M., Mosqueda, J., Igarashi, I., 2020c. Phytochemical characterization and chemotherapeutic potential of Cinnamomum verum extracts on the multiplication of protozoan parasites in vitro and in vivo. Molecules 25 (4), 996.

122  Natural products in vector-borne disease management Batiha, G.E., Beshbishy, A.M., Alkazmi, L., Adeyemi, O.S., Nadwa, E., Rashwan, E., El-Mleeh, A., Igarashi, I., 2020d. Gas chromatography-mass spectrometry analysis, phytochemical screening and antiprotozoal effects of the methanolic Viola tricolor and acetonic Laurus nobilis extracts. BMC Complement Med. Ther. 20 (1), 87. Beshbishy, A.M., Batiha, G.S., Yokoyama, N., Igarashi, I., 2019. Ellagic acid microspheres restrict the growth of Babesia and Theileria in  vitro and Babesia microti in  vivo. Parasit. Vectors 12 (1), 269. Beugnet, F., Moreau, Y., 2015. Babesiosis. Rev. Sci. Tech. 34 (2), 627–639. Borges, L.M., Sousa, L.A., Barbosa, C.S., 2011. Perspectives for the use of plant extracts to control the cattle tick Rhipicephalus (Boophilus) microplus. Rev. Bras. Parasitol. Vet. 20 (2), 89–96. Diaz, J.H., 2016. Chemical and plant-based insect repellents: efficacy, safety, and toxicity. Wilderness Environ. Med. 27 (1), 153–163. Fan, B., Liang, J., Men, J., Gao, F., Li, G., Zhao, S., Hu, T., Dang, P., Zhang, L., 1997. Effect of total alkaloid of Peganum harmala L. in the treatment of experimental haemosporidian infections in cattle. Trop. Anim. Health Prod. 29 (4 Suppl), 77S–83S. Fox, L.M., Wingerter, S., Ahmed, A., Arnold, A., Chou, J., Rhein, L., Levy, O., 2006. Neonatal babesiosis: case report and review of the literature. Pediatr. Infect. Dis. J. 25 (2), 169–173. Gorenflot, A., Moubri, K., Precigout, E., Carcy, B., Schetters, T.P., 1998. Human babesiosis. Ann. Trop. Med. Parasitol. 92 (4), 489–501. Guz, L., Adaszek, Ł., Wawrzykowski, J., Ziętek, J., Winiarczyk, S., 2019. In vitro antioxidant and antibabesial activities of the extracts of Achillea millefolium. Pol. J. Vet. Sci. 22 (2), 369–376. Haddad, M., Sauvain, M., Deharo, E., 2011. Curcuma as a parasiticidal agent: a review. Planta Med. 77 (6), 672–678. Hu, T., Fan, B., Liang, J., Zhao, S., Dang, P., Gao, F., Dong, M., 1997. Observations on the treatment of natural haemosporidia infections by total alkaloid of Peganum harmala L. in cattle. Trop. Anim. Health Prod. 29 (4 Suppl), 72S–76S. Krause, P.J., 2019. Human babesiosis. Int. J. Parasitol. 49 (2), 165–174. Lfawal, M.A., Gray, O., Dickson-Burke, C., Weathers, P.J., Rich, S.M., 2021. Artemisia annua and artemisinins are ineffective against human Babesia microti and six Candida sp. ELonghua. Chin. Med. 4, 12. Lindholm, P.F., Annen, K., Ramsey, G., 2011. Approaches to minimize infection risk in blood banking and transfusion practice. Infect. Disord. Drug Targets 11 (1), 45–56. Murnigsih, T., Subeki, M.H., Takahashi, K., Yamasaki, M., Yamato, O., Maede, Y., Katakura, K., Suzuki, M., Kobayashi, S., Chairul, Y.T., 2005. Evaluation of the inhibitory activities of the extracts of Indonesian traditional medicinal plants against Plasmodium falciparum and Babesia gibsoni. J. Vet. Med. Sci. 67 (8), 829–831. Naidoo, V., Zweygarth, E., Eloff, J.N., Swan, G.E., 2005. Identification of anti-babesial activity for four ethnoveterinary plants in vitro. Vet. Parasitol. 130 (1–2), 9–13. Nair, J.J., Van Staden, J., 2014. Boophone disticha (L.f.) Herb. (Amaryllidaceae). Traditional usage, phytochemistry and pharmacology of the South African medicinal plant. J. Ethnopharmacol. 151 (1), 12–26. Nakao, R., Mizukami, C., Kawamura, Y., Subeki, B.S., Yamasaki, M., Maede, Y., Matsuura, H., Nabeta, K., Nonaka, N., Oku, Y., Katakura, K., 2009. Evaluation of efficacy of bruceine A, a natural quassinoid compound extracted from a medicinal plant, Brucea javanica, for canine babesiosis. J. Vet. Med. Sci. 71 (1), 33–41. Panti-May, J.A., Rodríguez-Vivas, R.I., 2020. Canine babesiosis: a literature review of prevalence, distribution, and diagnosis in Latin America and the Caribbean. Vet. Parasitol. Reg. Stud. Rep. 21, 100417.

Natural product for management of babesiosis  Chapter | 6  123 Radcliffe, C., Krause, P.J., Grant, M., 2019. Repeat exchange transfusion for treatment of severe babesiosis. Transfus. Apher. Sci. 58 (5), 638–640. Sanchez, E., Vannier, E., Wormser, G.P., Hu, L.T., 2016. Diagnosis, treatment, and prevention of lyme disease, human granulocytic anaplasmosis, and babesiosis: a review. JAMA 315 (16), 1767–1777. Solano-Gallego, L., Sainz, Á., Roura, X., Estrada-Peña, A., Miró, G., 2016. A review of canine babesiosis: the European perspective. Parasit. Vectors 9 (1), 336. Subeki, M.H., Yamasaki, M., Yamato, O., Maede, Y., Katakura, K., Suzuki, M., Trimurningsih, C., Yoshihara, T., 2004. Effects of Central Kalimantan plant extracts on intraerythrocytic Babesia gibsoni in culture. J. Vet. Med. Sci. 66 (7), 871–874. Subeki, M.H., Takahashi, K., Nabeta, K., Yamasaki, M., Maede, Y., Katakura, K., 2007. Screening of Indonesian medicinal plant extracts for antibabesial activity and isolation of new quassinoids from Brucea javanica. J. Nat. Prod. 70 (10), 1654–1657. Vannier, E.G., Diuk-Wasser, M.A., Ben Mamoun, C., Krause, P.J., 2015. Babesiosis. Infect. Dis. Clin. N. Am. 29 (2), 357–370. Wilson, M.E., 2002. Prevention of tick-borne diseases. Med. Clin. North Am. 86 (2), 219–238. Wormser, G.P., Dattwyler, R.J., Shapiro, E.D., Halperin, J.J., Steere, A.C., Klempner, M.S., Krause, P.J., Bakken, J.S., Strle, F., Stanek, G., Bockenstedt, L., Fish, D., Dumler, J.S., Nadelman, R.B., 2006. The clinical assessment, treatment, and prevention of lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the infectious diseases society of America. Clin. Infect. Dis. 43 (9), 1089–1134. Yamada, K., Subeki, N.K., Yamasaki, M., Katakura, K., Matsuura, H., 2009. Share Isolation of antibabesial compounds from Brucea javanica, Curcuma xanthorrhiza, and Excoecaria cochinchinensis. Biosci. Biotechnol. Biochem. 73 (3), 776–780. Zhang, Y., Alvarez-Manzo, H., Leone, J., Schweig, S., Zhang, Y., 2021. Botanical medicines Cryptolepis sanguinolenta, Artemisia annua, Scutellaria baicalensis, Polygonum cuspidatum, and Alchornea cordifolia demonstrate inhibitory activity against Babesia duncani. Front. Cell. Infect. Microbiol. 11, 624745.

Further reading Gadaga, L.L., Tagwireyi, D., Dzangare, J., Nhachi, C.F., 2011. Acute oral toxicity and neurobehavioural toxicological effects of hydroethanolic extract of Boophone disticha in rats. Hum. Exp. Toxicol. 30 (8), 972–980.

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Chapter 7

Antimicrobial peptides, nanocarrier systems, and databases: Therapeutic platform against leishmaniasis Ameer Khusroa, Chirom Aartib, and Muhammad Umar Khayam Sahibzadac a

Centre for Research and Development, Department of Biotechnology, Hindustan College of Arts & Science, Padur, OMR, Chennai, India, bResearch Department of Plant Biology and Biotechnology, Loyola College, Chennai, Tamil Nadu, India, cDepartment of Pharmacy, The Sahara College Narowal, Narowal, Punjab, Pakistan

Introduction Neglected tropical diseases have been a colossal concern for the humankind since centuries. These diseases cause billions of mortalities globally, particularly in developing countries (Lewies et al., 2015). Despite the dreadful impact of these illnesses on a considerable populace of the world, they are still considered “neglected” due to lack of research funding from government agencies and minimal interest of pharma companies to develop effectual drugs (Feasey et al., 2010). Though all kinds of neglected tropical diseases do not lead to death, the morbidities and rapid dip in the economy of the countries are irrefutable. Thus, treatment and preventive strategies against these diseases become challenging for the society. In order to combat its dreadful impact, the international community took significant action in the late 2000s and established “Global Network for Neglected Tropical Disease Control” to monitor disparate issues related to neglected tropical diseases (Feasey et al., 2010). However, suffering due to different categories of neglected tropical diseases still continues today. Neglected tropical diseases are caused by disparate organisms, viz., bacteria, protozoa, parasites, and viruses. Vector-borne protozoan diseases are considered epidemic in different Mediterranean countries (Savoia, 2015). Leishmaniasis is the deadliest neglected vector-borne tropical diseases of South-East Asia, West Asia, America, East Africa, and North Africa which is generally caused by more than 30 Leishmania spp. (protozoan parasites) (Rama et al., 2015). This parasitic infection is transmitted to human through the bite of Natural Products in Vector-Borne Disease Management. https://doi.org/10.1016/B978-0-323-91942-5.00017-3 Copyright © 2023 Elsevier Inc. All rights reserved.

125

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approximately 90 female sandfly species. “Promastigotes” and “amastigotes” are two parasitic forms. Promastigotes (with flagella) and amastigotes (without flagellum) parasites are found in insect vector and humans, respectively. The infection initiates when the infected female sandfly bites and promastigotes are injected into the human skin during blood sucking process. Promastigotes penetrate different phagocytic cells and get transformed in the amastigotes (tissue stage). The multiplication of amastigotes occurs in the host cells by cell division mechanism, followed by bursting of cells and infection to other phagocytic cells. Amastigotes are transferred back into the sandflies when they bite again the infected human and get transformed into promastigotes in vector’s gut. Promastigotes are again injected into other healthy human through the bite of sandfly and causes infection, thereby repeating the life cycle of the parasite (Fig. 1) (Reithinger et al., 2007). Cutaneous leishmaniasis (CL), mucocutaneous leishmaniasis (MCL), and visceral leishmaniasis (VL) are three prime types of leishmaniasis. The CL is the common form of this infection (infecting 600,000 to 1 million people per year) which is further divided into localized CL and diffused CL. This form of infection shows skin lesions (mainly ulcer) on the body, leaving life-long scars. Approximately 95% of CL cases are found in the Americas, the Mediterranean basin, the Middle East, and Central Asia. In 2019, about 87% of new CL infection occurred in Afghanistan, Algeria, Brazil, Colombia, Iran, Iraq, Libya, Pakistan, the Syrian Arab Republic, and Tunisia. The MCL causes the damage to the mucosal membrane of the mouth, nose, and throat. This form of infection commonly occurs in Bolivia, Brazil, Ethiopia, and Peru. The VL is also called

FIG. 1  Life cycle of Leishmania sp.

AMPs, nanocarrier systems, and databases for leishmaniasis  Chapter | 7  127

as “kala-azar” and affects approximately 90,000 people worldwide annually. It is often deadly if left untreated. The irregular onset of fever, weight loss, splenomegaly, hepatomegaly, and reduced count of red blood corpuscles are the common symptoms of VL. The infection occurs mostly in Bangladesh, Brazil, East Africa, India, Kenya, Nepal, and Sudan with high mortality rate (Rama et al., 2015). There are several risk factors associated with the endemicity of leishmaniasis, including malnutrition, weak immunity, population shifting, poor housing, climate change, urbanization, and deforestation. Currently, molecular techniques (polymerase chain reaction) and serological tests (immunofluorescence antibody assay, enzyme-linked immunosorbent assay, western blot, rapid antigen test, and agglutination test) are some of the most common techniques used for diagnosing leishmaniasis infection (Savoia, 2015).

Global leishmaniasis surveillance: WHO report According to World Health Organization (WHO), leishmaniasis has been reported in 97 countries, of which 4 were included in 2017–18. In fact, a total of 200 countries reported the cases in 2018 but only 97 (49%) countries were considered endemic for leishmaniasis. Of 200, 88 (44%) countries were categorized endemic for CL, 3 (2%) countries had prior confirmed CL cases, 78 (39%) countries were classified endemic for VL, and 6 (3%) countries had earlier reported VL cases. On the other hand, 69 (35%) countries were reported endemic for both CL and VL. In the WHO Eastern Mediterranean Region (EMR), 82% (18/22) of countries were reported endemic for CL, 58% (21/36) of countries in the Region of the Americas (AMR), 47% (25/53) of countries in the European Region (EUR), 40% (19/47) of countries in the African Region (AFR), and 36% (4/11) of countries in the South-East Asia Region (SEAR). For VL, the proportions were 82% (18/22) for EMR, 55% (6/11) for SEAR, 51% (27/53) for EUR, 33% (12/36) in AMR, and 30% (14/47) for AFR. In the Western Pacific Region (WPR), the proportions of endemic countries were lower than that of other territories, with only 1 country (3%, 1/31), China, endemic for both VL and CL. Of the endemic countries, 25 countries were reported with maximum cases of leishmaniasis since 2014. Rest of the countries were included into low burden. In 2018, 253,435 new CL cases and 17,223 new VL cases were reported to WHO. In 2018, the VL cases were dispersed more equally among WHO regions than that of CL, with 27% of VL cases reported by AFR and by SEAR and 21% by EMR and by AMR; EUR and WPR reported only 2% and 1% of worldwide cases, respectively. Three eco-epidemiological hotspots for VL are East Africa (Ethiopia, Kenya, Somalia, South Sudan, Sudan, and Uganda) with 45% of the total cases worldwide, the Indian subcontinent (Bangladesh, India, and Nepal) with 28%, and Brazil with 20%. Brazil, Ethiopia, India, South Sudan, and Sudan (each) reported >1000 of VL cases. Including Bangladesh, China, Kenya, Nepal, and Somalia, these 10 countries reported >90% of VL cases

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globally. In 2018, 13 of 14 VL high-burden countries were reported based on the age and gender. Generally, 53% of VL cases were in people aged ≥15 years, 29% in aged 5–14 years, and 17% in aged 500

­ onkey bread. The height of the tree is grown up to 5–10 m tall. This m tree has the male and female flowers on the separate tree. Piliostigma thonningii can grow in the wooded grassland and wooded land, and the inner bark of the tree is used to make the rope (Bosset et  al., 1997). In Africa, it is used for the medicinal purposes against leishmania, for determining the in vitro activity of Piliostigma thonningii, in which the Leishmanial donovani culture is prepared in the presence of RPMI solution and having the fetal bovine serum with the pH of 5.5 and incubated in the medium for 37°C in the presence of CO2. After the incubation process, the extracted oil of the leaves of Piliostigma thonningii was added in the medium, and the analysis of the parasitic cell can be determined by Alamar blue fluorometric growth analysis. IC50 of the Leishmanial donovani was obtained to be 7.82 μM (Jain et al., 2012; Tarawneh et al., 2018). (22) Chilocarpus costatus: It is the genus of Chilocarpus, belonging to the family of Apocynaceae. It is mainly growing in India, Southeast Asia, and New Guinea. The nine extracted compounds of the plant Chilocarpus costatus have the antileishmanial activity. The IC50 inhibitory level of Leishmania donovani is 50 μg/mL (Zotz et al., 2021). (23) Asteraceae plants: It is the flowering plant, which consists of over 3200 known species of the flowers belonging to the family Asteraceae. It mainly grows in the hot or in the cold desert and is also available in each region of Antarctica. It is used as various herbal medicines and garden plants. For determining the inhibition of leishmanial activity of the Asteraceae plant, Leishmania donovani was cultured in the medium of 96-well microplate, and its oil (Fig. 12) is extracted with the DMSO solution, added to the medium, and incubated it at 26°C for 72 h, and determination were made under the microplate luminometer. IC50 values were calculated using a dose-response inhibition graph. and it will be 45 μg/mL (da Silva Filho et al., 2004). (24) Diospyros gracilescens: It is a genus from family of Ebenaceae (Roskov et  al., 2013). Diospyros has the inhibitory activity against Leishmania donovani. Extract of Diospyros gracilescens consisting of

Antileishmanial agents from natural resources  Chapter | 11  273

FIG. 12  Chemical structure of Asteraceae.

FIG. 13  Chemical structures of lupeol, betulin, sterols, and betulinic acid.

lupeol, betulin, sterols, and betulinic acid (Fig. 13) inhibits the activity of Leishmania donovani. The parasitic cells of leishmania were grown in the 96-well microplates by using the DMSO solution without providing any supplement to the cell culture, and the extract of Diospyros gracilescens was added into the plate and the solution was incubated for 72 h at 28°C. After the incubation, the inhibitory growth concentration of the cells was determined and calculated by the dose-response curve (IC50 = 5.84 μg/mL) (Siqueira-Neto et al., 2010). The various plant sources and their chemical constituents with IC50 values are mentioned in Table 3. (B) Marine source compounds against Leishmania In recent years, there has been an increase in interest in marine creatures as a possible origin of potentially new biological essential compounds. Hundreds of novel chemical entities have been discovered among the 28,000 chemicals of marine origin. Recent developments in natural resource drug research have

TABLE 3  Antileishmanial compounds obtained from the plant source having the in vitro and in vivo antileishmanial activity. Parasitic activity inhibition

IC50

References

Plant name/family

Part used

Libidibia ferrea/Fabaceae

Bark, leaf, stem, and seed

L. amazonensis

15.4 μg/mL

Henrique (2015b)

Piper nigrum/Piperaceae

Root and dried barriers

L. donovani

31.6 μg/mL 37.83 μg/mL

Ashokkumar et al. (2021)

Tridax procumbens/Asteraceae

Creeping stem

L. mexicana

30 μg/mL

Gutiérrez-Rebolledo et al. (2017)

Azadirachta indica/Meliaceae

Bark, leaf, and seed

L. donovani

17.66 μg/mL 24.66 μg/mL

Chouhan et al. (2015)

Cryptocarya aschersoniana/Clavicipitaceae

Leaf

L. amazonensis

4.46 μg/mL

Andrade et al. (2018)

E. peplus/Euphorbiaceae

Aerial part

L. donovani

1.01 μg/mL

Amin et al. (2017)

Zingiber zerumbet/Zingiberaceae

Fresh rhizomes

L. donovani

5 μg/mL

Mukherjee et al. (2016)

Aloe vera (L.)/Liliaceae

Leaves

L. tropica

6.25 mg/mL

Ulger et al. (2021)

Bixa orellana/Bixaceae

Seeds

L. amazonensis

22 μg/mL

García et al. (2011)

Plumbgin/Plumbaginaceae

Plumbgin free radicals

L. donovani and L. m. amazonensis

81% inhibition

Sumsakul et al. (2014)

Tetradenia riparia/Lamiaceae

Leaves, shrub

L. amazonensis

15.47 ± 4.6 ng/ mL

Cardoso et al. (2015)

Guazuma ulmifolia/Malvaceae

Leaves

L. braziliensis and L. infantum

1.0 μg/mL

Junior et al. (2016)

Morinda citrifolia/Rubiaceae

Fruit juice

L. amazonensis

275.3 μg/mL

Almeida-Souza et al. (2018)

Arrabidaea chica/Bignoniaceae

Leaves

L. amazonensis

50% inhibition

Silva-Silva et al. (2021)

Khaya anthotheca

Leaves, seeds, stem and root

Leishmania donovani

>30 μg/mL

Obbo et al. (2019)

Curcuma/Zingiberaceae

Gallium curcumin

Leishmania major

38%

Tahmasebi et al. (2013)

Piliostigma thoningii/Fabaceae

Leaves

Leishmania donovani

7.82 μM

Afolayan et al. (2018)

Chilocarpus costatus/Apocynaceae

Dry plant powder

Leishmania donovani

50 μg/mL

Azman et al. (2018)

Asteraceae plant/Asteraceae

Powder

Leishmania donovani

45 μg/mL

da Silva et al. (2009)

Diospyros gracilescens

Root, trunk, stem and bark

Leishmania donovani

5.84 μg/mL

Njanpa et al. (2021)

Allium cepa/Allium

Aqueous onion extract

Leishmania donovani

0.36 μg/mL

Saleheen et al. (2004)

Schinus terebinthifolius/Anacardiaceae

Leaves

L. infantum

15 and 58 μg/mL

Morais et al. (2014)

C. ambrosioides/Amaranthaceae

Aerial part

L. amazonensis

50%

Monzote et al. (2014b)

Valeriana jatamansi/Valerianaceae

Rhizome’s herb

L. donovani and L. major

3–7 μg/mL

Ghosh et al. (2011)

276  Natural products in vector-borne disease management

revealed a strong interest in organisms of aquatic eukaryotic or the algae for investigating the novel chemical entity, owing to their vast variety of bioactivities, including antileishmanial potential (Tchokouaha Yamthe et al., 2017). Various origin of marine natural products (MNPs) are sponges, green, brown and red algae, bacteria, phytoplankton, bryozoans, tunicates, and soft corals. The marine natural products have been classified into terpenoids, alkaloids, steroids, peptides, lactones, and fatty acid derivatives (Nweze et al., 2021). Natural compounds that are derived from algae of the sea source are recognized for their broad spectrum and potent bioactivities, which include antituberculosis, antihelminthic, antimicrobial, antioxidative, antiviral, anticoagulant, antimycobacterial, antipyretic, antiinflammatory, antidiabetic, anticoagulant, analgesic, insecticidal, anticancer, and antiprotozoan activities (Lauritano et  al., 2016; Bajpai, 2016). The antiparasitic marine natural substances were first discovered in the late 1980s, which increased the interest of several research groups worldwide, and marine secondary metabolites are now being investigated as drug leads for the treatment of neglected diseases like Chagas disease, malaria, and leishmaniasis (Tempone et al., 2011). (1) Dysidea avara Dysidea avara is a rosy to dark maroon or violet-colored, encrusting, highly conulated dictyoceratid sponge, found in sciaphilic microhabitats in the rocky sublittoral Mediterranean at depths of 80 meters. According to Imperatore et al., the quinone sesquiterpene avarone (Fig. 14) and its reduced form avarol (Fig. 14) are isolated from the sponge Dysidea avara. In the in vitro studies, both compounds have shown activity against the sepsis of Leishmania infantum and Leishmania tropica. The IC50 value of Leishmania infantum amastigote is 7.64 and 3.19 μmol/L and that of promastigotes is 28.1 and 7.42 μmol/L, and that of Leishmania tropica promastigotes is 20.28 and 7.08 μmol/L (Imperatore et al., 2020). (2) Paenibacillus polymyxa Paenibacillus polymyxa, commonly known as Bacillus polymyxa, is a Gram-positive, nitrogen-fixing bacterium, which is found in marine sediments, soil, plant tissues, and hot springs (Mahajan and Balachandran, 2017). According to Osei et al., an alkaloid paenidigyamycin A (Fig. 15) has been isolated from Ghanaian Paenibacillus species, which is derived from the soils of mangrove rhizosphere of the Pterocarpus santalinoides

FIG. 14  Chemical structures of avarone and avarol.

Antileishmanial agents from natural resources  Chapter | 11  277

FIG. 15  Chemical structure of paenidigyamycin A.

tree, which grows in the marshlands of Digya National Park, Ghana. When paenidigyamycin A tested against Leishmaniasis major (IC50 0.75), paenidigyamycin A was equally efficacious to amphotericin B, an antifungal drug that is used for antileishmaniasis (IC50 0.31 μM). Paenidigyamycin A was 22 times less effective against Leishmania donovani (IC50 7.02 M) than amphotericin B (IC50 0.32 M), confirming paenidigyamycin A’s specific efficacy against Leishmaniasis major (Osei et al., 2019). According to Neris et al., the whole extract of endophytic Paenibacillus polymyxa RNC-D was utilized to assess the leishmanicidal, cytokines production, and nitric oxide using RAW 264.7 macrophages, and the in vitro study indicates that the extract of Paenibacillus polymyxa RNC-D inhibits the activity of Leishmania amazonensis, with the EC50 values being 0.624 and 0.547 mg/mL (Neris et al., 2020). (3) Streptomyces sanyensis: Streptomyces sanyensis is a bacterium from the Streptomyces genus that was found in mangrove soil in Hainan, Sanya, and China. Indolocarbazoles are produced by Streptomyces sanyensis (Sui et al., 2011; Li et  al., 2013). According to Cartuche et  al., indolocarbazole staurosporine (Fig.  16) was isolated from cultures of Streptomyces sanyensis. Indolocarbazole staurosporine showed a potent activity against Leishmania amazonensis, and the IC50 will be 0.06–10.65 μmol/L and for promastigotes of Leishmania donovani, IC50 will be 0.50– > 40 μmol/L) (Cartuche et al., 2020).

FIG. 16  Chemical structure of staurosporine.

278  Natural products in vector-borne disease management

(4) Streptomyces sp. BVK2: Streptomyces sp. BVK2, a marine actinobacterial isolated from Kanyakumari (India) salt pan soil, produced substantial protease inhibitors and had antileishmanial activity. According to Sreedharan et al., in vitro tests indicated that BVK2 extract has potential efficacy against intracellular amastigotes forms of Leishmania donovani. The isolates BVK2 inhibit 87% of parasite, which is a promising finding that might lead to the development of antileishmanial medicines and the manufacturing of protease inhibitors. In an in vitro FACS (fluorescenceactivated cell sorting) test, 100 μg/mL extract of BVK2 was efficacious against amastigotes in infected J774A.1 macrophages. After double doses, the isolate BVK2 demonstrated a substantial antiparasitic activity, with an IC50 value of 27.1 g/mL (Sreedharan and Rao, 2017). (5) Bifurcaria bifurcata: Bifurcaria, a genus of brown algae seaweeds, is found on European shores and rocky North American, as well as in tidepools in the Atlantic Ocean. According to Smyrniotopoulos et  al., bifurcatriol (Fig. 17) was tested in vitro for antiprotozoal activity against Plasmodium falciparum, Leishmania donovani, Trypanosoma brucei rhodesiense, and Trypanosoma cruzi, to determine its overall cytotoxicity. With an IC50 value of 0.65 g/mL, bifurcatriol exhibited exceptional efficacy against the drug resistant strain K1 of malaria parasite, Plasmodium falciparum. The overall cytotoxic level against L6 cells was 56.6 g/mL. Other protozoan species showed only moderate activity, with IC50 values of 18.8 μg/mL (Leishmania donovani), 11.8 μg/mL (Trypanosoma brucei rhodesiense), and 47.8 μg/mL (Trypanosoma cruzi) (Smyrniotopoulos et al., 2017). According to Ainane et al., the antileishmanial activity of Bifurcaria bifurcata was determined, and their extraction was done by using the Soxhlet extractor. In the in  vitro study, the extracted products from the seaweed Bifurcaria bifurcata showed a remarkable activity against Leishmania infantum with the IC50 values being 46.83 and 63.83 μg/mL (Ainane et al., 2015). (6) Cystoseira baccata: Cystoseira baccata, brown seaweed from Fucaceae family, is found in the Baltic Sea, North East Atlantic and Mediterranean Seas. Baccata is a species name that means “berry-like” and alludes to the tiny air bladders (Roberts, 1967). The antileishmanial meroditerpenoids, (3R)- and (3S)-tetraprenyltoluquinol and (3R)- and (3S)tetraprenyltoluquinone, were isolated from the Cystoseira baccata. According to Bruno-de-Sousa et al., the inhibitory ability of the separated compounds was assessed using the MTT test against promastigotes after a bioactivity-guided fractionation of the Cystoseira baccata extract,

FIG. 17  Chemical structure of bifurcatriol.

Antileishmanial agents from natural resources  Chapter | 11  279

FIG. 18  Chemical structure of spiralyde A.

and the compounds ­ tetraprenyltoluquinol and tetraprenyltoluquinone inhibit the development of the Leishmaniasis infantum promastigotes (IC50 = 44.9 ± 4.3 and 94.4 ± 10.1 μM, respectively) (de Sousa et al., 2017). (7) Dictyota spiralis: Dictyota spiralis, a brown alga species, is found in the Mediterranean Sea and eastern Atlantic Ocean. Dictyota spiralis’s thallus is yellowish-brown in color, with a greenish iridescent tip on occasion. It grows in cluster of flattened, membranous, ribbon-like fronds with few branches that can reach 15 cm (6 in) in length and 4 mm (0.2 in) in width (Guiry, 2015; Lamare and Verlaque, 2021). According to Chiboub et  al., spiralyde A (Fig. 18), a novel dolabellane aldehyde, and five other known related diterpenes were isolated from the extracted component of brown algae of Dictyota spiralis using bioassay-guided fractionation. In the bioassayguided study, the compounds Spiralyde A and 3,4-epoxy-7,18-dolabelladiene showed the most inhibitory action against Leishmania amazonensis and Trypanosoma cruzi. Spiralyde A showed the best IC50 value of antiprotozoal activity against Leishmania amazonensis and Trypanosoma cruzi. 3,4-Epoxy7,18-dolabelladiene has also shown moderate efficacy against both parasites (IC50 = 15.47 ± 0.26 and 36.81 ± 5.20 μmol/L) (Chiboub et al., 2019). (8) Laurencia viridis: Laurencia, a genus of red algae, is found in tropical and temperate shores in littoral to sublittoral environments at depths of up to 65 m (213 ft) (Guiry and Guiry, 2016). According to Díaz-Marrero et al., in an in vitro study, 16 oxasqualenoid metabolites were either isolated from the natural source Laurencia viridis (red alga), or derived from lead compound dehydrothyrsiferol (DT) by semisynthetic procedures and were tested against Leishmania donovani, Leishmania amazonensis, and Trypanosoma cruzi. Eight substances including four natural substances (Fig. 19) possess potent activities against Leishmaniasis amazonensis and Leishmaniasis donovani with the IC50 range of 5.40–46.45 μmol/L (DiazMarrero et al., 2019). (9) Stypopodium zonale: Stypopodium zonale is a species from the family Dictyotaceae, is a golden brown or olive-colored alga, which is growing about 16 in. (40 cm) in length. The Stypopodium zonale is observed in the shallow waters in the Caribbean Sea, as well as in other tropical and ­subtropical oceans throughout the world (Colin, 1988). According to Soares et al., the major compound, meroditerpenoid atomaric acid (Fig. 20), was

280  Natural products in vector-borne disease management

FIG. 19  Chemical structures of natural oxasqualenoid metabolites compounds active against L. amazonensis and L. donovani.

FIG. 20  Chemical structure of atomaric acid and its methyl ester derivative.

isolated from the lipophilic extract of Stypopodium zonale, and its imitative compound called as methyl ester (Fig. 20) was obtained by the methylation process and tested against Leishmania amazonensis. And it was found that the meroditerpenoid atomaric acid and its methyl ester derivative inhibit the intracellular amastigotes of Leishmania amazonensis with IC50 values of 20.2 μM (9 μg/mL) and 22.9 μM (10 μg/mL) (Soares et al., 2016). (10) Paecilomyces sp. 7A22: The harzialactone A (HA) (Fig. 21), a previously identified substance derived from fungi of marine habitats, was obtained after fractionation of extracts from the culture broth of Paecilomyces species, fungus derived from the sea source. Harzialactone showed considerable action against promastigotes forms with an IC50 of 5.25 mg/mL as well as moderate action against intracellular amastigotes with an IC50 of 18.18 mg/mL in antileishmanial tests against Leishmania amazonensis (Braun et al., 2021). The various marine sources, their bioactive compounds, and class with IC50 values are mentioned in Table 4.

FIG. 21  Chemical structure of harzialactone A.

TABLE 4  Antileishmanial drugs derived from the marine environment. Source

Bioactive compound

Class

IC50

References

Avarone and avarol are sesquiterpenes

Quinone

Leishmaniasis infantum amastigote (7.64 and 3.19 μmol/L) and promastigotes (28.1 and 7.42 μmol/L), and Leishmaniasis tropica parasites (20.28 and 7.08 μmol/L)

Imperatore et al. (2020)

Paenibacillus polymyxa

Paenidigyamycin A

Alkaloid

Leishmaniasis major (0.75 μmol/L) and Leishmaniasis donovani (7.02 μmol/L)

Osei et al. (2019)

Streptomyces sanyensis

Indolocarbazole staurosporine

Alkaloid

Leishmaniasis amazonensis intra- and extracellular parasites (0.06–10.65 μmol/L), Leishmaniasis donovani (0.50–>40 μmol/L)

Cartuche et al. (2020)

Streptomyces sp. BVK2

Crude extract

unknown

100 μg/mL against amastigotes in infected J774A.1 macrophages

Sreedharan and Rao (2017)

Bifurcaria bifurcata (brown alga)

Bifurcatriol

Terpene

L. donovani amastigotes (18.8 μg/mL)

Smyrniotopoulos et al. (2017)

Cystoseira baccata

Tetraprenyltoluquinol and tetraprenyltoluquinone

Terpene

Leishmaniasis infantum intra and extracellular parasites (44.9 ± 4.3 and 94.4 ± 10.1 μmol/L)

de Sousa et al. (2017)

Dictyota spiralis

Spiralyde A

Terpene

L. amazonensis promastigotes (15.47 ± 0.26 and 36.81 ± 5.20 μmol/L)

Chiboub et al. (2019)

Laurencia viridis (red algae)

Oxasqualenoid metabolites

Terpene

Leishmaniasis amazonensis and Leishmaniasis donovani (5.40–46.45 μmol/L)

Diaz-Marrero et al. (2019)

Stypopodium zonale

The methyl ester derivative of atomaric acid

Terpene

Leishmaniasis amazonensis intracellular amastigotes (20.2 and 22.9 μmol/L)

Soares et al. (2016)

Harzialactone A

Lactone

Leishmania amazonensis (5.25 μg/mL) and intracellular parasites (18.18 μg/mL)

Braun et al. (2021)

Marine sponges Dysidea avara

Microbes from the sea

Marine algae

Marine fungi Paecilomyces sp. 7A22

282  Natural products in vector-borne disease management

Conclusion In this study, we have compiled the various studies of the antileishmanial compounds, which are obtained from the plant as well as the marine sources. The inhibitory concentration of the plant-prepared extract and marine compounds are given in the table, which gives the inhibitory determination of the leishmaniasis and its species of Leishmania amazonensis, Leishmania donovani, Leishmania braziliensis, Leishmania infantum, and Leishmaniasis major. In this study, natural products are highlighted as a possible source of novel and selective agents that contribute significantly to primary healthcare and are likely to be potential chemical replacements for the treatment of protozoan disorders, particularly leishmaniasis.

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288  Natural products in vector-borne disease management Perry, L.M., Metzger, J., 1980. Medicinal Plants of East and Southeast Asia: Attributed Properties and Uses. MIT Press. Prance, G., Nesbitt, M., 2012. The Cultural History of Plants. Routledge. Roberts, M., 1967. Studies on marine algae of the British Isles. 4. Cystoseira baccata (Gmelin) Silva. Br. Phycol. Bull. 3 (2), 367–378. Roskov, Y., Kunze, T., Paglinawan, L., Orrell, T., Nicolson, D., Culham, A., et al., 2013. Species 2000 & ITIS Catalogue of Life, 2013 Annual Checklist. Rottini, M.M., Amaral, A.C.F., Ferreira, J.L.P., Oliveira, E.S.C., de Andrade Silva, J.R., Taniwaki, N.N., et al., 2019. Endlicheria bracteolata (Meisn.) essential oil as a weapon against Leishmania amazonensis: in vitro assay. Molecules 24 (14), 2525. Saleheen, D., Ali, S.A., Ashfaq, K., Siddiqui, A.A., Agha, A., Yasinzai, M.M., 2002. Latent activity of curcumin against leishmaniasis in vitro. Biol. Pharm. Bull. 25 (3), 386–389. Saleheen, D., Ali, S.A., Yasinzai, M.M., 2004. Antileishmanial activity of aqueous onion extract in vitro. Fitoterapia 75 (1), 9–13. Sandur, S.K., Ichikawa, H., Sethi, G., Ahn, K.S., Aggarwal, B.B., 2006. Plumbagin (5-hydroxy2-methyl-1, 4-naphthoquinone) suppresses NF-κB activation and NF-κB-regulated gene products through modulation of p65 and IκBα kinase activation, leading to potentiation of apoptosis induced by cytokine and chemotherapeutic agents. J. Biol. Chem. 281 (25), 17023–17033. Shilpi, J.A., Taufiq-Ur-Rahman, M., Uddin, S.J., Alam, M.S., Sadhu, S.K., Seidel, V., 2006. Preliminary pharmacological screening of Bixa orellana L. leaves. J. Ethnopharmacol. 108 (2), 264–271. Siller, G., Gebauer, K., Welburn, P., Katsamas, J., Ogbourne, S.M., 2009. PEP005 (ingenol mebutate) gel, a novel agent for the treatment of actinic keratosis: results of a randomized, double‐ blind, vehicle‐controlled, multicentre, phase IIa study. Australas. J. Dermatol. 50 (1), 16–22. Silva-Silva, J.V., Moragas-Tellis, C.J., Chagas, M.S., Souza, P.V.R., Moreira, D.L., de Souza, C.S., et al., 2021. Carajurin: a anthocyanidin from Arrabidaea chica as a potential biological marker of antileishmanial activity. Biomed. Pharmacother. 141, 111910. Siqueira-Neto, J.L., Song, O.-R., Oh, H., Sohn, J.-H., Yang, G., Nam, J., et al., 2010. Antileishmanial high-throughput drug screening reveals drug candidates with new scaffolds. PLoS Negl. Trop. Dis. 4 (5), e675. Sirirugsa, P., Larsen, K., Maknoi, C., 2007. The genus Curcuma L.(Zingiberaceae): distribution and classification with reference to species diversity in Thailand. Gard. Bull. Singapore 59 (1–2), 203–220. Sladowski, D., Steer, S.J., Clothier, R.H., Balls, M., 1993. An improved MIT assay. J. Immunol. Methods 157 (1–2), 203–207. Smyrniotopoulos, V., Merten, C., Kaiser, M., Tasdemir, D., 2017. Bifurcatriol, a new antiprotozoal acyclic diterpene from the brown alga Bifurcaria bifurcata. Mar. Drugs 15 (8), 245. Soares, D.C., Szlachta, M.M., Teixeira, V.L., Soares, A.R., Saraiva, E.M., 2016. The brown alga Stypopodium zonale (Dictyotaceae): a potential source of anti-Leishmania drugs. Mar. Drugs 14 (9), 163. Soliman, A.M., Teoh, S.L., Ghafar, N.A., Das, S., 2019. Molecular concept of diabetic wound healing: effective role of herbal remedies. Mini-Rev. Med. Chem. 19 (5), 381–394. Sreedharan, V., Rao, K.B., 2017. Efficacy of protease inhibitor from marine Streptomyces sp. VITBVK2 against Leishmania donovani—an in vitro study. Exp. Parasitol. 174, 45–51. Steverdind, D., 2017. The history of Leishmaniasis. Parasit. Vectors 10, 82. Sui, J.L., Xu, X.X., Qu, Z., Wang, H.L., Lin, H.P., Xie, Q.Y., Ruan, J.S., Hong, K., 2011. Streptomyces sanyensis sp. nov., isolated from mangrove sediment. Int. J. Syst. Evol. Microbiol. 61 (7), 1632–1637.

Antileishmanial agents from natural resources  Chapter | 11  289 Sumsakul, W., Plengsuriyakarn, T., Chaijaroenkul, W., Viyanant, V., Karbwang, J., Na-Bangchang, K., 2014. Antimalarial activity of plumbagin in vitro and in animal models. BMC Complement. Altern. Med. 14 (1), 1–6. Suominen, J., 1973. Atlas florae Europaeae, preparation and relationship to Flora Europaea. Sociedade Broteriana, 29. Tahmasebi, R., Barazesh, A., Fouladvand, M., 2013. Evaluation of in vitro antileishmanial activity of curcumin and its derivatives “gallium curcumin, indium curcumin and diacethyle curcumin”. Eur. Rev. Med. Pharmacol. Sci. 17 (24), 3306–3308. Tarawneh, A.H., Al-Momani, L., León, F., Jain, S.K., Gadetskaya, A.V., Abu-Orabi, S.T., et  al., 2018. Evaluation of triazole and isoxazole derivatives as potential anti-infective agents. Med. Chem. Res. 27 (4), 1269–1275. Tariq, H., Zia, M., Muhammad, S.A., Khan, S.A., Fatima, N., Mannan, A., et al., 2019. Antioxidant, antimicrobial, cytotoxic, and protein kinase inhibition potential in Aloe vera L. Biomed. Res. Int. 2019. Tchokouaha Yamthe, L.R., Appiah-Opong, R., Tsouh Fokou, P.V., Tsabang, N., Fekam Boyom, F., Nyarko, A.K., Wilson, M.D., 2017. Marine algae as source of novel antileishmanial drugs: a review. Mar. Drugs 15 (11), 323. Teles, A.M., Rosa, T.D.S., Mouchrek, A.N., Abreu-Silva, A.L., Calabrese, K.S., Almeida-Souza, F., 2019. Cinnamomum zeylanicum, Origanum vulgare, and Curcuma longa essential oils: chemical composition, antimicrobial and antileishmanial activity. Evid. Based Complement. Alternat. Med. 2019. Tempone, A.G., de Oliveira, C.M., Berlinck, R.G., 2011. Current approaches to discover marine antileishmanial natural products. Planta Med. 77 (06), 572–585. Tiuman, T.S., Ueda-Nakamura, T., DgAc, G.C., Dias Filho, B.P., Morgado-Díaz, J.A., de Souza, W., et al., 2005. Antileishmanial activity of parthenolide, a sesquiterpene lactone isolated from Tanacetum parthenium. Antimicrob. Agents Chemother. 49 (1), 176–182. Torres-Santos, E., Lopes, D., Oliveira, R.R., Carauta, J., Falcao, C.B., Kaplan, M., et  al., 2004. Antileishmanial activity of isolated triterpenoids from Pourouma guianensis. Phytomedicine 11 (2–3), 114–120. Trotter, E., Peters, W., Robinson, B., 1980. The experimental chemotherapy of leishmaniasis, VI: the development of rodent models for cutaneous infection with L. major and L. mexicana amazonensis. Ann. Trop. Med. Parasitol. 74 (3), 299–319. Ulger, M., Ulger, S.T., Gultekin, E.O., Yabalak, E., Gulbudak, H., Delialioglu, N., et  al., 2021. In vitro Antileishmanial effect of the plant extracts from Aloe vera (L.) Burm. f. and Hypericum perforatum L. Leaves. Kafkas Univ. Vet. Fak. Derg. 27 (3), 363–370. Vallejo, M., Benavides, G., 1994. Características botánicas, usos y distribución de los principales árboles y arbustos con potencial forrajero de América Central. CATIE, Turrialba (Costa Rica). Programa de Agricultura Sostenible. Vega, C., Rolón, M., Martínez-Fernández, A., Escario, J., Gómez-Barrio, A., 2005. A new pharmacological screening assay with Trypanosoma cruzi epimastigotes expressing β-galactosidase. Parasitol. Res. 95 (4), 296–298. Vespucci, I.L., 2021. Filmes biodegradáveis: elaboração e validação em maracujá silvestre produzido para utilização na agricultura familiar. UFG. WHO, 2022. Leishmaniasis. Available from: https://www.who.int/newsroom/fact-sheets/detail/ leishmaniasis. Wood, J., 1920. The Nuttall Encyclopaedia. World Health Organization, 2000. General Guidelines for Methodologies on Research and Evaluation of Traditional Medicine. World Health Organization.

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Chapter 12

Plants with antidengue properties: A systematic review Parul Grovera, Monika Bhardwajb, Lovekesh Mehtac, Pooja A. Chawlad, Viney Chawlae, and Shubham Sharmaa a

KIET School of Pharmacy, KIET Group of Institutions, Delhi-NCR, Ghaziabad, Uttar Pradesh, India, bNatural Product Chemistry Division, Indian Institute of Integrative Medicine, Jammu, Jammu and Kashmir, India, cAmity Institute of Pharmacy, Amity University, Noida, Uttar Pradesh, India, dDepartment of Pharmaceutical Chemistry and Analysis, ISF College of Pharmacy, Moga, Punjab, India, eDepartment of Pharmaceutics, University Institute of Pharmaceutical Sciences and Research, Baba Farid University of Health Sciences, Faridkot, Punjab, India

Introduction DENV (Dengue virus) is a single-stranded positive-sense RNA virus that belongs to the Flaviviridae family, genus Flavivirus. Bite of infected female Aedes aegypti and Aedes albopictus mosquito results in the spread of dengue virus. The genome of DENV is approximately 11 kb in length (Halstead, 2008; Talarico et al., 2007). DENV-1, DENV-2, DENV-3, and DENV-4 are the four different serotypes that have been identified worldwide, but now the DENV-5 serotype has been identified as well (Mustafa et al., 2015). The most lethal of all serotypes is DENV-2, but in few studies, it is reported that major infection with DENV-1 or DENV-3 has a more hazardous disease than infection with DENV-2 or DENV-4 (Guzman and Istúriz, 2010; Goel et al., 2004; Tang et al., 2012; Chawla et al., 2014). DENV disease is also of three different types, viz., mild dengue fever (MDF), shock syndrome dengue (DSS), and hemorrhagic dengue fever (DHF). Of all the reported cases, 95% cases were reported as normal DF, while 5% of the cases were reported for severe DHF and DSS (FerreiraDe-Lima and Lima-Camara, 2018; Jain et al., 2008). It generally continues for 2–7 days and then is followed by extreme muscle and joint pain. Dengue fever (DF) is a mosquito-borne disease that spreads in damp and rainy conditions. The water that collects in coolers, ponds, playgrounds, and other open areas provides ideal breeding conditions for Aedes aegypti mosquitos. Due to its extreme body pain and muscle soreness, DF is also known as “break-bone” fever. The disease has spread to over 125 countries, infecting between 50 and 270 million people on a regular basis and causing a large number of deaths (Ferreira, 2012). Karnataka, Delhi, Kerala, Tamil Nadu, Haryana, Natural Products in Vector-Borne Disease Management. https://doi.org/10.1016/B978-0-323-91942-5.00022-7 Copyright © 2023 Elsevier Inc. All rights reserved.

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Maharashtra, Rajasthan, West Bengal, and Gujarat are the most impacted states in India. Dengue fever is accompanied with an antibody-dependent enhancement (ADE), which is a major concern. When a person is infected with one dengue serotype, the secondary infection of DENVs with other heterologous strains has a devastating effect and can result in DHF/DSS. Due to the ADE, there are currently no effective approved vaccinations against DENV (Chang et al., 2011; Kato et al., 2010). According to the World Health Organization (WHO), about 100 million cases of fever caused by dengue and dengue hemorrhagic fever (500,000 cases) are reported each year, with approximately 18,000 deaths. India has a rich traditional medicine system that boasts a number of plants used in the treatment and management of various diseases. A large number of these plants are described for their use against transmittable diseases, including contamination caused by virus infection. Medicinal plants contain lead components with better ability to act as virocides and larvicides against the DNV (dengue virus) and mosquito repellents against the dengue vector mosquitoes. Additionally, with progress in contemporary technology, medicinal plants usage is growing at a consistent pace. The growing prospects of medicinal plants in the treatment of dengue can be gauged from the quantum of published contents related to their use. This chapter aims to review the epidemiology, transmission, symptoms, and current status of dengue. A major highlight of this compilation will be medicinal plants and their active phytoconstituents that are active against dengue.

Epidemiology One of the dengue model estimates shows 390 million infections of DENV per year, of which 96 million established clinically. Another study on the happening of dengue evaluated that 3.9 billion people are at risk of infection with dengue viruses (Kyle and Harris, 2008). Though the risk of dengue exists in 129 countries, Asia accounts for around 70% of the actual burden (Qi et al., 2008; Snr et al., 2011). As per the latest data of the World Health Organization (WHO), dengue has affected several countries in the year 2020. The increased cases were found in Brazil, Bangladesh, Ecuador, Maldives, Cook Islands, Mauritania, Sri Lanka, Singapore, Thailand, Mayotte, Nepal, Timor-Leste, and Yemen including India (Amarasinghe et al., 2011) The effect of dengue continued in the year 2020 having a maximum effect on Kenya, Brazil, Colombia, Cook Islands, Per, Paraguay, and Reunion Island (Ben-Shabat et al., 2020). During this period, the COVID-19 pandemic health care and management systems are hard pressed worldwide. As the number of cases of dengue fever and other arboviral diseases rises in various countries, the WHO has emphasized the significance of maintaining efforts to detect, prevent, and treat vectorborne diseases such as dengue and other arboviral diseases during this crucial

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period, exposing urban populations at the highest risk for both diseases (Phadke et al., 2021). The combined effects of the COVID-19 and DF epidemics have the potential to be devastating to the communities at risk (Malibari et al., 2020).

Pathophysiology of dengue fever The proposed pathophysiology for dengue virus infection is: After the infected mosquito bites, the virus moves into the host organism along the skin. Cellular, humoral, and innate host immune responses are involved in the development of the illness, and the more severe clinical symptoms occur after the fast removal of the virus from the host organism (Goel et al., 2004). Therefore, the viral load does not associate with the most prominent clinical demonstration during the course of infection. Excessive plasma and protein loss happens due to variations in permeability of endothelial microvascular and thermoregulatory mechanisms. The theories that are proposed recommend that the activation of endothelial cell initiated by T-cells, monocytes, the complement system, and several inflammatory molecules arbitrates leakage of plasma. Because decreased platelet count (thrombocytopenia) is a typical clinical sign of dengue fever, it could be linked to megakaryocytopoiesis, as evidenced by infection of human hematopoietic cells and cell progenitor proliferation. This may result in damage of platelet, depletion, or dysfunction, or give rise to substantial hemorrhages.

Symptoms of dengue A high-grade fever is the first symptom of DF. The body temperature ranges between 39 and 40°C. Symptoms normally emerge four to 6 days after infection and can continue up to 10 days (Deeba et al., 2016). The symptoms of DF are shown in Fig. 1. Clinically, secondary symptoms are quite severe in people with thrombocytopenia, bleeding in DHF patients, and blood plasma leakage in DSS patients; in certain cases, the patient goes unconscious (Cecilia, 2014). Dengue infection can range from mild to life-threatening depending on the serotype (Ono et al., 2003). The majority of dengue fever infections are selflimiting, but a small number of cases can be serious, resulting in DHF and DSS (Gubler, 2006).

Transmission of dengue Dengue virus (DNV) transmission is through a human-to-mosquito-to-human cycle. Generally, it will take up approximately 4  days to spread the viremia in the body due to which the level of DNV is very much high in the blood of human. This will happen due to bite of infected Aedes aegypti mosquito. Once viremia spreads to the whole body, it generally stays there for approximately 5–12 days. Initially, there are no symptoms of viremia but as the time progresses after the bite of infected mosquito, there are symptoms of DNV in the body of

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Dizziness Adynamia

Rapid Pulse

Rash Insomnia

Heat Fever

Dengue Fever Symptoms Redness of Eyes

Redness of the Throat Vomiting

Anorexia

Pain in Bones

FIG. 1  Symptoms of dengue.

human being and these symptoms will last for more than a week. If any mosquito bites the person who is infected with DNV, it will become dengue vector after sucking the blood of that person. Then infection of that virus spread in the body of mosquito through blood of human within approximately 8–12 days. After this, infected mosquito can further transmit the infection to the other human while feeding (Abd Kadir et al., 2013). Once the mosquito is infected with DNV, then virus will remain in the body of mosquito for life long. In their entire life span, infected mosquitoes are able to infect the healthy human beings by biting them. Generally, the life of a mosquito is approximately 3–4 weeks. The main energy source for both female and male mosquitoes are plant nectars, fruit juices, and other plant sugars but to produce eggs, female mosquitoes require blood, so they bite humans. The female mosquito takes quite a lot of meals of blood prior to laying a batch of eggs, and during its lifetime, it can lay multiple

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Extrinsic Incubation Virus infects the midgut and eventually travels to the salivary glands (usually 8-10 days)

Mosquito Infection Mosquito takes a blood meal from a person with acute dengue

Midgut Proboscis

Salivary glands

Intrinsic Incubation The onset of symptoms usually takes 4-7 days

Human Infection One mosquito can infect several Humans

FIG. 2  Transmission of dengue.

batches of eggs. The virus chiefly stays in the salivary gland of female mosquito that infects human body by transmitting its saliva to blood of human while taking up the blood from human body. This will prevent the host’s blood from clotting and ease feeding. Rarely, dengue can be transmitted during blood transfusions or organ transplantations of infected donors. It is also found in study that an infected pregnant mother can pass on the virus infection to her fetus (Kumar Sarangi and Padhi, 2017). Fig. 2 shows the transmission of dengue.

Treatment and management of dengue Dengue fever has no specific treatment; doctors mainly provide symptomatic and supportive care. Ibuprofen, aspirin, and naproxen should be avoided when treating DF, and an appropriate dose of paracetamol is usually recommended (Abd Kadir et al., 2013). When patients are dehydrated, fluid replacements are particularly beneficial. Infected people should be admitted to the hospital when their symptoms worsen (Deen et al., 2006; Ahmad et al., 2011). Patients have been known to consume natural home treatments on the advice of Ayurvedic practitioners in order to enhance blood platelet counts (Sarala and Paknikar, 2014). Therefore, our focus is on the medicinal-based plants used for the treatment and management of dengue, which might be more efficient, safe, and less lethal than synthetic drugs.

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Plant species used to treat dengue Medicinal plants have always been an important element of traditional remedies and treatment sources for a variety of disorders in India and around the world (Piraino and Brandt, 1999). The bioactive compounds found in medicinal plants are a rich supply of medications, some of which have a strong antiviral activity (Balick and Cox, 1996). The use of extracts and derivatives of medicinal plants, according to the World Health Organization and Ayurveda, is beneficial in the fight against dengue fever (Herrmann Jr and Kucera, 1967). Ayurvedic medications derived from medicinal plants, according to the WHO, are generally safer, nontoxic, less harmful, and less expensive than synthetic treatments. Researchers have now turned their attention to nature, attempting to identify chemicals that could be employed as antiviral medicines against dengue fever. In particular, investigations have demonstrated that extracts from various portions of medicinal plants excel synthetic equivalents in terms of antiviral activity. Several natural compounds are reported to have antidengue properties. This chapter will highlight the plants and their active constituents used for the treatment of dengue. Some of the important plant species are discussed below:

Acacia catechu Acacia catechu belonging to family Fabaceae is a plant native to India and Southeast Asia. The peptides taken out from the plant caused a decrease in intracellular envelope proteins among all DENV serotypes subsequently in a dose-dependent manner. Among the four isolated peptides, three were found to be significantly active. Also, the crude extract of the peptide was reported to diminish virus production by 100-fold approximately with no reported toxic effect (Panya et al., 2019).

Allium sativum Allium sativum, commonly known as garlic belonging to the family Amaryllidaceae, is traditionally reported to have several therapeutic activities like anticarcinogenic, antihyperlipidemic, reducing platelet aggregation, antibacterial, and antioxidant. It originated from Central Asian countries. The active constituents reported to reduce inflammatory cytokines in DENV-2 infection are organo‑sulfur compounds available in garlic, namely, diallyl sulfide (DAS), diallyl disulfide (DADS), and alliin (Kusyati and Nyoman, 2017).

Andrographis paniculata Andrographis paniculata, commonly known as kalmegh, belongs to the family Acanthaceae. It is an erect herb that is very bitter in taste. This plant has been successfully used as traditional plant-based medicine for centuries. Chemically,

Plants with antidengue properties  Chapter | 12  297

it has major constituents, like diterpenoids, lactones, flavonoid glycosides, diterpene glycosides, and flavonoids. It is reported that methanolic extract of the plant is active against dengue fever particularly toward DENV-1 serotype (AliSeyed and Vijayaraghavan, 2020; Jayakumar et al., 2013).

Anisuan Pimpinella anisum having the common name Anisuan belongs to the family Apiaceae. The essential oil extracted from the plant has several constituents like cis-anethole, methylchavicol, p-anisaldehyde, linalool, α-terpineol, and trans-anethole that are reported to be extremely lethal to Aedes aegypti larvae (Prajapati et al., 2005).

Azadirachta indica Azadirachta indica, commonly known as Neem, belongs to the Meliaceae family. It is reported that aqueous extract of the plant has inhibitory potential toward replication of DENV-2 both in vitro and in vivo. The antiviral property of the aqueous extract was evaluated in C (6/36) (cloned cells of larvae of Aedes albopictus) cells employing virus inhibition assay. Another study reported the inhibitory potential of isolated compound azadirachtin against DENV-2. The leaves of the plant are reported to help in the propagation of platelets, blood cells, and WBCs that are among the main and most lethal targets for the virus infection (Dwivedi et al., 2016).

Boerhavia diffusa Boerhavia diffusa, commonly known as Punarnava, belongs to the Nyctaginaceae family. The various parts of plants and roots are being used traditionally for the treatment of hepatic, gastrointestinal, and gynecological illnesses. The ayurvedic mixture of the plant was given in combination with Tinospora cordifolia along with cow’s milk to dengue patients 2 or 3 times daily, and a considerable increase of platelet count of patients was seen with the reduction in body temperatures (Tang et al., 2012).

Carapichea ipecacuanha Carapichea ipecacuanha, commonly known as Ipecac, belongs to the family Rubiaceae. On account of hemorrhagic dengue, a homeopathic doctor can make use of home remedies as Ipecac root or Ipecacuanha. The dried roots of the plant help to stop bleeding. To avoid dengue becoming a pandemic disease, Ipecacuanha could be taken every day during dengue season. Statutory remedies could be assumed at the start of peak season and repeated once every 4 weeks during peak season (Qi et al., 2008).

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Castanospermum australe Castanospermum australe, commonly known as Moreton Bay Chestnut, belongs to the family Fabaceae. It is reported that the isolated compound, castanospermine, a natural alkaloid from the plant, has antiviral activity. Castanospermine may interrupt the folding of some viral proteins by inhibiting the elimination of the terminal glucose residue on N-linked glycans in the DNV (Sajeesh and Parimelazhagan, 2014).

Curcuma longa Curcuma longa, commonly known as curcumin, belongs to the family Zingiberaceae. The herbaceous, rhizomatous, perpetual plant of the ginger family is commonly utilized as a home-grown cure. The active constituent turmerone of Curcuma longa is reported to give mosquitocidal action against Aedes aegypti (Ichsyani et al., 2017).

Echinacea Echinacea commonly known as coneflowers belongs to the family Asteraceae. It is a genus of herbaceous flowering plants. The plants belonging to this genus have real antiviral properties as they motivate cells to yield additional proteins and interferon, made and discharged by lymphocytes in response to the attach by bacteria and viruses. Echinacea certainly increases interferon and consequently motivates the immune system as a whole (Tang et al., 2012).

Glycyrrhiza glabra Glycyrrhiza glabra, commonly known as licorice, belongs to the family Leguminosae. The plant is found in Europe, Asia, and the Middle East. The plant is traditionally reported to have antiviral, antioxidant, antibacterial, antiinflammatory, and antihyperglycemic activities. Prenylated stilbenoids and flavonoids from the plant have an established excellent property of docking to DENV protease (Zadeh et al., 2013).

Kaempferia parviflora Kaempferia parviflora, commonly known as Black Ginger, belongs to the family Zingiberaceae. Borneol and flavonoids are the main active chemical constituents of the plant. It is reported that the plant makes ineffective the serotype of dengue virus, DENV2. The plant extract is also used efficiently as a mosquito repellent (Kanjanapothi et al., 2004).

Mimosa scabrella Mimosa scabrella, commonly known as Hoehne, relates to the family Fabaceae. It is a fast-growing, 15–20 m high and up to 50 cm diameter tree native to

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the subtropical plateaus, cool, subtropical plateaus of southeastern Brazil. Galactomannans are the active compound from the seeds of this plant and have shown an excellent action against YFV and DENV-1 in vitro and in vivo (Ono et al., 2003).

Momordica charantia Momordica charantia, commonly known as bitter melon, is a part of the family Cucurbitaceae. It is a subtropical and tropical vine found throughout Africa, Asia, and the Caribbean. An antiviral experiment based on cytopathic effects revealed that the plant’s methanolic extract had an inhibitory effect on DENV-1 (Han et al., 2005).

Myrtopsis corymbosa It belongs to the family Rutaceae. The most active constituents of the plant were obtained from the source of bark. The active constituents were myrsellin, ramosin, and myrsellinol. The main active extract of bark is very much strong and able to carry out approximately 87% of DENV protease inhibition. The alkaloidal compounds myrsellinol, haplopin, γ fagarin, and skimmianine were found to be only slightly active against the DENV-NS5 (Coulerie et al., 2013).

Papaya leaves Papaya leaves are well known for the treatment of infection of dengue virus. They are well accepted worldwide for the prevention of various DNV infections. Most active constituents of Carica papaya (leaves of papaya) are l-tocopherol and papain. Along with glucosinolates (flavonoid and ascorbic acid), these active constituents were found to have cyanogenic action. They prevent tumor growth and also exert immune modulator effect by inhibiting the action of free radicals, which are correlated with the minimized production of peroxides of fat content, which in turn enhance the formation of RBC counts. The papaya leaf juice will also enhance the blood platelets level by diminishing the infection present in the body of human (Abd Elgadir et al., 2014; Özkan et al., 2011; Imaga et al., 2010; Bamisaye et al., 2013).

Pippli Piper longum, often known as papal or pippli, belongs to the Piperaceae family. Most active constituents present in Piper longum is piperine. In one research survey, Piper sarmentosum and Piper longum, which are obtained from the extraction of pippli, have more prominent actions against Aedes aegypti. Among these extracts of Piper longum, Piper ribesoides are less effective when compared to other species, and Piper longum is most effective as compared to Piper sarmentosum and Piper ribesoides (Mili et al., 2019).

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Uncaria tomentosa Uncaria tomentosa is commonly known as cat’s claw and belongs to Rubiaceae family. They are majorly found in the central and South America jungles. Uncaria tomentosa has been used in the treatment of various conditions like urinary tract infection (UTI), gastric ulcers, arthritis, viral infection, and various types of inflammation in the body. They are known to have a strong anti-DNV effect by lowering infected cell rates and cytokine activities, reducing the production of IFN-α, IL-10, and TNF-α. After treatment with Uncaria tomentosa, IL-10 levels in human monocytes contaminated with viral infection (DENV-2) fell from 572 ± 219 to 244 ± 60 pg mL−1 (Reis et al., 2008).

Zostera marina The common name of this flowering vascular medicinal-based plant is known as eelgrass. This plant belongs to Zosteraceae family and is majorly available in North America, Europe, and East Asia. Zostera marina is known to have many pharmacological activities such as antioxidant, antimicrobial, antitumor, antibacterial as well as antiviral actions. The most active constituents of the plant are zosteric acid (ZA) and p-sulfoxy-cinnamic acid. They were found to inhibit the action of all types of dengue virus, including DENV-1, DENV-2, DENV-3, and DENV-4, and blocked the entry of life cycle of virus in human body. The anti-DENV effect of zosteric acid (ZA) is more prominent with IC50 values of 2.3 μM (Rees et al., 2008). The plants active against dengue along with active phytoconstituents and their structure are tabulated in Table 1.

Conclusion Dengue is a very serious viral disease occurring worldwide. Till date, no proper treatment is available against the disease. But some plants are reported to be active against the disease and help in reducing the associated symptoms. A thorough review was conducted, and various medicinal plants active against the disease along with their reported phytoconstituents active against DENV are compiled in the chapter. But many plants are still left unexplored. It is necessary to extract and identify some components from medicinal plants that are useful in the treatment of DENV. This chapter also gives sufficient details of current status of dengue, transmission, symptoms, and pathophysiology. This review will help in providing platform for more potential compounds in future investigations.

TABLE 1  Plants and their phytoconstituents active against dengue virus. Plant

Family

Active constituent

Acacia catechu

Fabaceae

Catechin

Structure

References Panya et al. (2019)

OH HO HO

O

OH

HO

Allium sativum

Andrographis paniculata

Amaryllidaceae

Acanthaceae

Allicin

O S

Kusyati and Nyoman (2017)

S

Andrographolide

Ali-Seyed and Vijayaraghavan (2020) and Jayakumar et al. (2013)

OH H

O

OH

OH O

Anisuan

Apiaceae

Alpha-terpeneol, linalool

OH

Prajapati et al. (2005)

HO Continued

TABLE 1  Plants and their phytoconstituents active against dengue virus—cont’d Plant

Family

Active constituent

Boerhavia diffusa

Nyctaginaceae

Beta-sitosterol

Structure

References Tang et al. (2012)

H H

H

HO

Carapichea ipecacuanha

Rubiaceae

Emetin Cephalein

O

O H NH

Castanospermum austral

Fabaceae

Castanospermine

HO HO

Curcuma longa

Zingiberaceae

Turmerone

Echinacea

Asteraceae

Caffeic acid

Qi et al. (2008)

O

O

N

OH H OH N

Ichsyani et al. (2017)

O

Tang et al. (2012)

O HO HO

Sajeesh and Parimelazhagan (2014)

OH

Glycyrrhiza glabra

Leguminosae

Licorice, Liquorice

O

O

OH

HO

O OH

O OH HO

H O

O

H

O

Zingiberaceae Elaeagnaceae

Pinostrobin

OH

Fabaceae

Kanjanapothi et al. (2004)

O

O

Mimosa scabrella

Zadeh et al. (2013)

H

O

HO

Kaempferia parviflora

OH

OH

O

Galactomannan

Ono et al. (2003)

OH HO

OH O

HO

OH

O

OH O

OH

O

O

HO

OH

HO OH

Momordica charantia

Cucurbitaceae

kappa-Carrageenan

-

O O S O O

HO

Han et al. (2005)

OH OH

O O

H

-

O O S O O

OH

O

O

H

OH

O HO O O H

O

O

H OH OH

Continued

TABLE 1  Plants and their phytoconstituents active against dengue virus—cont’d Plant

Family

Active constituent

Myrtopsis corymbosa

Rutaceae

Myrsellinol

Structure

References Coulerie et al. (2013) OH

O

O

O OH

Pippli

Piperaceae

Piperine

Mili et al. (2019)

O O

N

O

Uncariatomentosa

Fabaceae

Quinic acid

Reis et al. (2008)

O OH

HO

OH

HO OH Zostera marina

Zosteraceae

P-Sulfoxycinnamic acid, zosteric acid

Rees et al. (2008)

O O S O O

HO

OH

Plants with antidengue properties  Chapter | 12  305

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Plants with antidengue properties  Chapter | 12  307 tive peptides demonstrating anti‐dengue virus activity isolated from the Asian medicinal plant Acacia Catechu. Chem. Biol. Drug Des. 93 (2), 100–109. Phadke, R., Mohan, A., Çavdaroğlu, S., Dapke, K., dos Santos Costa, A.C., Riaz, M.M., Hashim, H.T., Essar, M.Y., Ahmad, S., 2021. Dengue amidst COVID‐19 in India: the mystery of plummeting cases. J. Med. Virol. 93 (7), 4120. Piraino, F., Brandt, C.R., 1999. Isolation and partial characterization of an antiviral, RC-183, from the edible mushroom Rozites caperata. Antivir. Res. 43 (2), 67–78. Prajapati, V., Tripathi, A.K., Aggarwal, K.K., Khanuja, S.P.S., 2005. Insecticidal, repellent and oviposition-deterrent activity of selected essential oils against Anopheles stephensi, Aedes aegypti and Culex quinquefasciatus. Bioresour. Technol. 96 (16), 1749–1757. Qi, R.F., Zhang, L., Chi, C.W., 2008. Biological characteristics of dengue virus and potential targets for drug design. Acta Biochim. Biophys. Sin. 40 (2), 91–101. Rees, C.R., Costin, J.M., Fink, R.C., McMichael, M., Fontaine, K.A., Isern, S., Michael, S.F., 2008. In vitro inhibition of dengue virus entry by p-sulfoxy-cinnamic acid and structurally related combinatorial chemistries. Antivir. Res. 80 (2), 135–142. Reis, S.R.I., Valente, L.M., Sampaio, A.L., Siani, A.C., Gandini, M., Azeredo, E.L., D'Avila, L.A., Mazzei, J.L., Maria das Graças, M.H. and Kubelka, C.F., 2008. Immunomodulating and antiviral activities of Uncaria tomentosa on human monocytes infected with Dengue Virus-2. Int. Immunopharmacol. 8 (3), 468–476. Sajeesh, T., Parimelazhagan, T., 2014. Analgesic, anti-inflammatory, and GC-MS studies on Castanospermum australe A. Cunn. & C. Fraser ex Hook. Sci. World J. 2014, 587807. Sarala, N., Paknikar, S.S., 2014. Papaya extract to treat dengue: a novel therapeutic option? Ann. Med. Health Sci. Res. 4 (3), 320–324. Snr, S., Norma-Rashid, Y., Sofian-Azirun, M.J.W.A.S.E.T., 2011. Mosquitoes larval breeding habitat in urban and suburban areas, Peninsular Malaysia. World Acad. Sci. Eng. Technol. 58 (58), 569–573. Talarico, L.B., Duarte, M.E., Zibetti, R.G., Noseda, M.D., Damonte, E.B., 2007. An algal-derived DL-galactan hybrid is an efficient preventing agent for in vitro dengue virus infection. Planta Med. 73 (14), 1464–1468. Tang, L.I., Ling, A.P., Koh, R.Y., Chye, S.M., Voon, K.G., 2012. Screening of anti-dengue activity in methanolic extracts of medicinal plants. BMC Complement. Altern. Med. 12 (1), 1–10. Zadeh, J.B., Kor, Z.M., Goftar, M.K., 2013. Licorice (Glycyrrhiza glabra Linn) as a valuable medicinal plant. Int. J. Adv. Biol. Biomed. Res. 1 (10), 1281–1288.

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Chapter 13

Natural products in Japanese encephalitis Prasanti Sharmaa, Neelima Sharmaa, Anoop Kumarb, Nagendra Singh Chauhanc, and Pooja A. Chawlad a

Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Jharkhand, India, bDepartment of Pharmacology, Delhi Pharmaceutical Sciences and Research University (DPSRU), New Delhi, India, cDrugs Testing Laboratory Avam Anusandhan Kendra (State Government Lab of AYUSH), Government Ayurvedic College, Raipur, Chhattisgarh, India, d Department of Pharmaceutical Chemistry and Analysis, ISF College of Pharmacy, Moga, Punjab, India

Introduction Japanese encephalitis (JE), first described in 1871 in Japan (Endy and Nisalak, 2002), is one of the most prominent causes of viral encephalitis in the Asian continent (WHO, 2019). It is caused by the Japanese Encephalitis Virus (JEV), genus Flavivirus, belonging to the family Flaviviridae. The virus consists of a single-stranded, positive-sense RNA that is 11 kb in length, surrounded by a protein capsid and lipid bilayer (Turtle and Solomon, 2018; Luca et al., 2012). This family includes other viruses that cause infections like West Nile fever, dengue, and yellow fever in humans (Daep et al., 2014). Pigs, birds, horses, and humans are the identified hosts of JEV while mosquitoes of the genus Culex are the vectors. Onward transmission of the virus does not occur from humans (known as dead-end host) due to insufficient viremia (Endy and Nisalak, 2002). The pathogenic pathway of the virus within its host has been depicted in Fig. 1. The virus enters the host through the bite of the mosquito. It then replicates in the keratinocytes, monocytes, and dendritic cells from where it moves to the lymph nodes for further replication. When the virus is present in the blood (viremia), it activates the mast cells which releases mast-cell-specific protease chymase. This enzyme then promotes viral penetration into the brain by facilitating virusmediated breakdown of the blood-brain-brain and tight junctions (Hsieh et al., 2019). Once inside the CNS, JEV induces inflammation and neurological deficits (Misra and Kalita, 2010). The principal mosquito vector is Culex tritaeniorhynchus, although other Culex species may also transmit the disease (Rosen, 1986). A higher risk of infection has been associated with locations in close proximity to irrigated agricultural fields or water bodies that facilitate breeding of JE Natural Products in Vector-Borne Disease Management. https://doi.org/10.1016/B978-0-323-91942-5.00016-1 Copyright © 2023 Elsevier Inc. All rights reserved.

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310  Natural products in vector-borne disease management

FIG. 1  Pathogenic pathway of the Japanese encephalitis virus. The virus enters the host’s body through the mosquito bite. Once inside, it replicates in the keratinocytes, local lymph nodes, dendritic cells, monocytes, and T-cells. The multiplied virus then enters the bloodstream (viremia) through which it enters the CNS. This penetration is facilitated by the mast cells which upon activation by JEV releases the mast cell-specific protease chymase. Chymase enhances JEV-induced breakdown of BBB and cleavage of tight junctions resulting in increased permeability of the virus into the brain. Once inside, it leads to inflammation (encephalitis) and various neurological sequela (Hsieh et al., 2019).

Natural products in Japanese encephalitis  Chapter | 13  311

vectors (WHO, 2019; Keiser et al., 2005) as well as those where the number of animal hosts is higher (Endy and Nisalak, 2002). In the recent years, instances of JE have grown with around 67,900 annual global cases. Even though a majority of the infected cases are asymptomatic, JE is greatly feared because it results in approximately 20,000 deaths per year with the infection being fatal for 30% of the people developing clinical symptoms (WHO, 2019; Campbell et al., 2011). The clinical symptoms related to JEV infection include headache, fever, tremors, GI disturbance, vomiting, seizures, paralysis, disorientation and coma with 20%–30% of the survivors suffering from severe neurological consequences (WHO, 2019; Behan and Bakheit, 1991; Solomon et  al., 1998). A higher mortality rate has been reported among children infected with JEV and even for those who do survive; mental retardation, epilepsy, behavioral defects and parkinsonism have been commonly observed (Chaudhuri, 2002). There is no specific treatment for JE; pharmacotherapy is only used for symptomatic management, where study results on human subjects have shown that even with routinely used drugs, no significant benefit could be seen (Hoke et al., 1992; Solomon et  al., 2003). Despite a number of molecules showing potent antiJEV activity in animal models, their clinical trials have not revealed promising results, besides several are yet to be tested (Gould et al., 2008; Ishikawa and Konishi, 2015). Vaccination is the most effective long-term preventive measure against JE. There are four main types of vaccines against Japanese encephalitis: (1) Inactivated mouse brain-derived (2) Inactivated cell culture-derived (3) Live-attenuated cell culture-derived (4) Live-attenuated recombinant chimeric vaccine (Yun and Lee, 2014) However, among these, only the inactivated mouse-brain-derived vaccine is internationally licensed (Tsai, 2000) while the others have limited distribution and availability (World Health Organization, 2015). Therefore, not only are the vaccines scarcely available, they are expensive, require multiple doses, and have been associated with severe hypersensitivity and neurological adverse events (Plesner, 2003; Ginsburg et  al., 2017), which results in limited use of these vaccines in many endemic countries like India, Nepal, Cambodia, Bangladesh, Myanmar, and many more (Monath, 2002). The newer second-generation vaccines such as vectored subviral particles, JEV-pulsed dendritic cells, and repliconbased vaccines are still in the preclinical stage and their market availability in the near future is unlikely (Tsai, 2000; Barzon and Palù, 2018). Therefore, along with the implementation of mass immunization programs, development of potential antiviral drugs for the treatment of JE along with adequate vector control measures to mitigate viral transmission is a priority. Nature is a repository from where molecules have been extracted and refined for use against various diseases. Numerous studies have investigated the efficacy of natural compounds against JEV (Guo et al., 2019; Zhang et al., 2014; Goh et  al., 2020). Outstanding mosquitocidal and repellant properties have

312  Natural products in vector-borne disease management

been reported for a number of plant extracts and isolated compounds against the primary JE vector Culex tritaeniorhynchus (Benelli et al., 2018; Rajeswary et al., 2018; Govindarajan et al., 2016a,b; Govindarajan and Benelli, 2016a,b). In addition, metal nanoparticles synthesized using botanical extracts have shown high efficacy as insecticides (Kumar et al., 2020; Benelli, 2016; Aarthi et al., 2018; Amerasan et al., 2016; Veerakumar et al., 2014). The current vector control programs rely heavily on the use of synthetic products which not only affects nontarget organisms and defiles the environment but might also result in resistant mosquito strains (Lee et al., 2001; Hemingway and Ranson, 2000). In this regard, plant-derived products have emerged as environmentally safer alternatives (Elumalai et  al., 2012; Dhanasekaran et  al., 2013; Bagavan et  al., 2009; Benelli, 2015). Catnip oil, citronella oil, and oil of lemon eucalyptus are among the EPA-recommended natural repellants (EPA, n.d.). Plant extracts and their constituents from diverse species have been explored for their insecticidal potency against a number of vectors that spread diseases such as dengue, malaria, and filariasis among others (Das et  al., 2007; Pohlit et  al., 2011; Karmegam et al., 1997; Pavela, 2015; Kishore et al., 2014; Mathivanan et al., 2010). Current knowledge on the effectiveness of several natural products against Japanese encephalitis and their future potential uses has been discussed in the following sections.

Plant extracts in vector control For decades, plants have been extensively used as repellants (Pavela and Benelli, 2016) and for the control of arthropod vectors against a plethora of diseases (Pavela et al., 2019). The number of researches focused on identifying potential botanical substances against the JE vector has been steadily rising. Most studies have focused on investigating the larvicidal, ovicidal, and repellant effects of plant extracts and essential oils on Culex tritaeniorhynchus, the most important carrier of JEV. A total of 42 plant species were compared for their larvicidal efficacy (Table 1). LC50 and LC90 (concentration of the test substance used to kill 50% and 90% of the organism, respectively) are important parameters for determining the biological efficacy of the product being evaluated. It may be expressed in ppm or μg/ml. Of the 42 plant species, more than 50% showed LC50 values less than 100. Elumalai et al. (2012) examined the larvicidal potential of acetone, chloroform, and methanolic leaf extracts of Gymnema sylvestre R.Br. and reported strong lethal effects against the larva of Culex tritaeniorhynchus with LC50 values of 34.756, 31.351, 28.577 μg/mL, respectively, for each fraction. Similarly, for four plant species, Citrus sinensis L. (methanolic peel extract), Ocimum canum Sims (methanolic leaf extract), Ocimum sanctum Linn (ethyl acetate leaf extract), and Rhinocanthus nasutus Kurz (ethyl acetate leaf extract), the LC50 and LC90 values against the fourth instar larvae of Culex tritaeniorhynchus were as follows: 38.15 and 184.67 ppm, 72.40 and 268.93 ppm, 109.12 and 646.62 ppm, 39.32 and 176.39 ppm, respectively (Bagavan et  al., 2009).

TABLE 1  List of plants showing efficacy against the JE vector Culex tritaeniorhynchus. Sl. no.

Plant species

Family

Plant part used

Tested product

Activity

LC50/LD50

LC90/LD90

References

1

Boswellia ovalifoliolata

Burseraceae

Leaves

E. Oil

Larvicidal

97.95 μg/mL

182.73 μg/mL

Benelli et al. (2018)

2

Zingiber cernum

Zingiberaceae

Rhizome

E. Oil

Larvicidal

60.20 μg/mL

114.22 μg/mL

Rajeswary et al. (2018)

3

Origanum scabrum

Lamiaceae

Leaves

E. Oil

Larvicidal

78.87 μg/mL

144.99 μg/mL

Adulticidal

158.87 μg/mL

298.31 μg/mL

Govindarajan et al. (2016d)

4

Plectranthus barbatus

Lamiaceae

Leaves

E. Oil

Larvicidal

94.34 μg/mL

179.55 μg/mL

5

Cymbopogan citrates

Poaceae

Leaves

E. Oil

Larvicidal

136.58 ppm

243.18 ppm

6

Cinnamomum zeylanicum

Lauraceae

Bark

E. Oil

Larvicidal

124.70 ppm

225.36 ppm

7

Rosmarinus officinalis

Lamiaceae

Shoot

E. Oil

Larvicidal

115.38 ppm

211.53 ppm

8

Zingiber officinale

Zingiberaceae

Rhizome

E. Oil

Larvicidal

98.83 ppm

186.55 ppm

9

Coleus aromaticus

Lamiaceae

Leaves

E. Oil

Larvicidal

72.70 μg/mL

137.53 μg/mL

Govindarajan et al. (2013b)

10

Ocimum basilicum

Lamiaceae

Leaves

E. Oil

Larvicidal

14.01 ppm

23.44 ppm

Govindarajan et al. (2013a)

11

Syzygium zeylanicum

Myrtaceae

Leaves

E. Oil

Larvicidal

97.96 μg/mL

181.62 μg/mL

Govindarajan and Benelli (2016a)

Govindarajan et al. (2016a) Govindarajan (2011a)

Continued

TABLE 1  List of plants showing efficacy against the JE vector Culex tritaeniorhynchus—cont’d Sl. no.

Plant species

Family

Plant part used

Tested product

Activity

LC50/LD50

LC90/LD90

References

12

Heracleum sprengelianum

Apiaceae

Leaves

E. Oil

Larvicidal

40.9 μg/mL

76.6 μg/mL

Govindarajan (2016b)

13

Artemisia absinthium

Asteraceae

Leaves

E. Oil

Larvicidal

62.16 μg/mL

113.46 μg/mL

Govindarajan and Benelli (2016b)

14

Origanum vulgare

Lamiaceae

Leaves

E. Oil

Larvicidal

84.93 μg/mL

150.88 μg/mL

Govindarajan et al. (2016b)

15

Gymnema sylvestre

Asclepiadaceae

Leaves

Acetone extract

34.75 μg/mL

–

Larvicidal

16

Celosia argenta

Amaranthaceae

Leaves

Elumalai et al. (2012)

Chloroform extract

31.35 μg/mL

Methanolic extract

28.57 μg/mL

Ethanolic extract

Larvicidal

173.73 ppm

–

17

Anthocephalus cadamba

Rubiaceae

Leaves

Ethanolic extract

Larvicidal

157.68 ppm

–

18

Gnetum ula

Gnetaeceae

Leaves

Ethanolic extract

Larvicidal

160.97 ppm

–

19

Solena amplexicaulis

Cucurbitaceae

Leaves

Ethanolic extract

Larvicidal

109.37 ppm

–

20

Spermacoce hispida

Rubiaceae

Leaves

Ethanolic extract

Larvicidal

99.32 ppm

–

Dhanasekaran et al. (2013)

21

Citrus sinensis

Rutaceae

Peel

Methanolic extract

Larvicidal

38.15 ppm

184.67 ppm Bagavan et al. (2009)

22

Ocimum canum

Labiatae

Leaves

Methanolic extract

Larvicidal

72.40 ppm

268.93 ppm

23

Ocimum sanctum

Labiatae

Leaves

Ethyl acetate

Larvicidal

109.12 ppm

646.62 ppm

24

Rhinocanthus nasutus

Acanthaceae

Leaves

Ethyl acetate

39.32 ppm

176.39 ppm

Bagavan et al. (2009)

71.79 ppm

361.83 ppm

Kamaraj et al. (2009)

Flower

Methanol

Larvicidal

25

Habenaria plantaginea

Orchidaceae

Leaves

Aqueous extract

Larvicidal

149.43 μg/mL

279.70 μg/mL

Aarthi et al. (2018)

26

Aegle marmelos

Rutaceae

Leaves

Ethyl acetate extract

Larvicidal

99.03 ppm

479.23 ppm

Elango et al. (2009)

Acetone extract

Adulticidal

139.05 ppm

426.19 ppm

Elango et al. (2012)

Hexane extract

Larvicidal

88.50 ppm

416.39 ppm

Elango et al. (2009)

Ethyl acetate extract

Adulticidal

205.06 ppm

813.59 ppm

Elango et al. (2012)

Methanolic extrat

Larvicidal

105.19 ppm

507.86 ppm

Elango et al. (2009)

Methanolic extract

Adulticidal

222.10 ppm

794.42 ppm

Elango et al. (2012)

27

28

Andrographis paniculata

Cocculus hirsutus

Acanthaceae

Menispermaceae

Leaves

Leaves

Continued

TABLE 1  List of plants showing efficacy against the JE vector Culex tritaeniorhynchus—cont’d Sl. no.

Plant species

Family

Plant part used

Tested product

29

Eclipta prostrata

Compositae

Leaves

Activity

LC50/LD50

LC90/LD90

References

Ethyl acetate extract

Larvicidal

119.89 ppm

564.85 ppm

Elango et al. (2009)

Methanolic extract

Adulticidal

166.73 ppm

579.43 ppm

Elango et al. (2012)

30

Andrographis lineata

Acanthaceae

Leaves

Hexane extract

Adulticidal

251.24 ppm

837.09 ppm

Elango et al. (2012)

31

Tagetes erecta

Compositae

Leaves

Methanolic extract

Adulticidal

232.74 ppm

807.41 ppm

Elango et al. (2012)

31

Cassia auriculate

Cesalpinaceae

Leaves

Petroleum ether extract

69.83 ppm

335.26 ppm

Flower

Methanolic extract

Larvicidal

Kamaraj et al. (2009) 51.29 ppm

245.63 ppm

32

Leucas aspera

Labiatae

Flower

Methanolic extract

Larvicidal

81.24 ppm

300.45 ppm

33

Solanum torvum

Solanaceae

Leaves

Methanolic extract

Larvicidal

44.42 ppm

185.09 ppm

34

Vitex negundo

Verbenaceae

Seeds

Methanolic extract

Leaves

Hexane extract Petroleum ether

Kamaraj et al. (2009)

Kamaraj et al. (2009) 84.47 ppm

351.41 ppm

65.35 ppm

302.42 ppm

Kamaraj et al. (2009)

2.48 μg/mL

5.18 μg/mL

Karunamoorthi et al. (2008)

Larvicidal

35

Ipomaea cairica

Convolvulaceae

Whole plant

E. Oil

Larvicidal

36

Ficus benghalensis

Moraceae

Leaves

Methanolic extract

Larvicidal

14.8 ppm

78.3 ppm

85.84 ppm

159.76 ppm

Thomas et al. (2004) Govindarajan (2011b)

Benzene extract

93.25 ppm

170.10 ppm

Acetone extract

106.07 ppm

184.60 ppm

37

Hymenodictyon orixense

Rubiaceae

Leaves

Aqueous extract

Larvicidal

123.55 μg/mL

233.68 μg/mL

Govindarajan (2016a)

38

Anisomeles indica

Lamiaceae

Leaves

Aqueous extract

Larvicidal

131.27 μg/mL

250.19 μg/mL

Govindarajan et al. (2016c)

39

Annona squamosa

Annonaceae

Bark

Methanolic extract

Larvicidal

104.94 μg/mL

443.79 μg/mL Kamaraj et al. (2011)

40

Chrysanthemum indicum

Compositae

Leaves

Ethyl acetate extract

Larvicidal

42.29 μg/mL

172.34 μg/mL

41

Tridax procumbens

Asteraceae

Leaves

Ethyl acetate extract

Larvicidal

69.16 μg/mL

287.21 μg/mL

42

Artemisia annua

Asteraceae

Leaves

Methanolic extract

Larvicidal

52.8 ppm

874.6 ppm

Ethanolic extract

12.4 ppm

64.4 ppm

Chloroform extract

0.9 ppm

8.7 ppm

Acetone extract

61.6 ppm

828.4 ppm

Sharma et al. (2012)

318  Natural products in vector-borne disease management

Elango et al. studied the larvicidal (Elango et al., 2009), ovicidal, repellant, oviposition deterrent (Elango et al., 2010), and adulticidal properties (Elango et al., 2012) of six plant species Aegle marmelos, Andrographis lineata, Andrographis paniculate, Cocculus hirsutus, Eclipta prostrata, and Tagetes erecta, thereby suggesting that the obtained methanolic extracts could be used as potential eco-friendly insecticides. Considering the essential oils, one obtained from the rhizome of Zingiber cernuum was toxic to the third instar larvae of the JE vector with LC50 of 60.20 μg/mL and LC90 value 114.22 μg/mL. There was also a significant decrease (P 90%) inhibition of JEV by impeding viral RNA synthesis and viral Na+/ K+-ATPase enzyme activity. In-vivo study results showed valuable effect of ouabain against JEV-infected mice where mortality was reduced by nearly 60% (Guo et  al., 2019). Oxidative stress as a result of JEV infection is known to cause neuronal apoptosis and initiate inflammation (Zhang et al., 2014). Such outcomes were seen to be lowered with the use of antioxidants such as arctigenin, curcumin, and rosmarinic acid in mouse models. Arctigenin, a naturally occurring plant lignan, conferred neuroprotection in mouse brain through downregulation of caspase-3 (pro-apoptotic factor), suppression of microglia and proinflammatory mediators, reduced viral load, and inhibited free radical generation (Swarup et al., 2008). Curcumin, a phenolic antioxidant, is another compound that revealed promising antiviral effects by disintegration of viral envelope (Chen et al., 2013), dysregulating the ubiquitin-proteasome system in the infected cells, increasing neuronal cell viability, restoring cellular membrane integrity, and alleviating oxidative stress (Dutta et al., 2009). Rosmarinic acid has also been suggested as a therapeutic agent in reducing disease severity induced by JEV infection as it was seen to ameliorate viral transcription and inflammation within the CNS (Swarup et al., 2007). Flavonoids baicalein and quercetin exhibited in vitro antiviral activity against JEV. Baicalein showed higher intracellular inhibition (IC50 = 14.28 μg/mL) as well as extracellular virucidal effect (IC50 = 3.44 μg/mL) compared to quercetin (IC50 = 212 μg/mL). Baicalein also prevented viral adsorption into the Vero cells (Johari et  al., 2012). The effects of these flavonoids have been previously explored against the Sendai virus, human immunodeficiency virus, and hepatitis C virus where the inhibition of viral enzymes such as hemagglutinin-neuraminidase (Dou et al., 2011), integrase (Ahn et al., 2001), reverse transcriptase (Kitamura et al., 1998), and NS3 protease (Bachmetov et al., 2012) was responsible for their antiviral activity. Luteolin presented extracellular toxicity to JEV (Fan et  al., 2016) while flavonol kaempferol and isoflavonoid daidzin inhibited JEV by binding to viral mRNA and inhibiting protein synthesis and replication (Care et al., 2020). The virucidal potency of kaempferol was found to be higher than that of diadzin (Zhang et al., 2012). Chang et al. reported virucidal effects of Isatis indigotica extracts and two isolated compounds indigo and indirubin in  vitro. The proposed mechanism of action is a dose-dependent inhibition of viral replication and attachment, prior to or during viral exposure (Chang et al., 2012), whereas both pre- and postviral infection were curbed with the use of essential oil extracted from the seeds of ajwain (Trachyspermum ammi) at a concentration of 1 mg/mL (Roy et  al., 2015). Among the seven nonstructural (NS) proteins in

Natural products in Japanese encephalitis  Chapter | 13  323

JEV (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5), NS1 plays a vital role in replication; therefore, it may be beneficial to study the direct effects of these phytochemicals in inhibiting these NS proteins, thereby providing a deeper insight into their mechanism of action (Banerjee and Tripathi, 2019). In addition, aqueous extracts of the Chinese herbal medicine Astragali Radix were also evaluated for its antiviral potency wherein it demonstrated some protective effect in JEV-infected mice (Kajimura et  al., 1996a,b). In-silico studies have aimed at identifying compounds that target proteins such as chymase, viral helicase, and protease whose inhibition could possibly play a vital role in reducing infection (Kant et  al., 2021; Navyashree et  al., 2021). Upregulating the expression of IFN-stimulated gene 15 in human cell lines has resulted in potent inhibition of JE viral replication in-vitro (Hsiao et al., 2010); thus, phytochemicals capable of acting via this pathway could be a useful tool against JE. Table 3 lists the phytochemicals possessing antiviral activity along with their mechanism of action and target proteins. The mechanism of viral pathogenesis inside the infected host cell has been depicted in Fig. 2 along with the site of action of botanical antiviral agents. On the whole, these research findings illustrate that plant-derived compounds could hold great potential as preventative and therapeutic agents against Japanese encephalitis. However, the number of literatures is extremely limited which highlights the need for further research in this domain.

Conclusion Unfortunately, no specific treatment or antiviral agents have been identified for Japanese encephalitis. Therapy is mainly aimed at reducing disease severity and management of symptoms. Mass human and animal immunization programs, modernization of agricultural practices, and improved standard of living have helped curb the rate of infection in many urbanized countries; however, in several developing countries, factors such as vaccine unavailability and expense, variations in the dominant genotype of JEV (Schuh et al., 2014), lack of awareness, and monitoring are still important issues that need to be addressed (Erlanger et al., 2009). Therefore, until expanded immunization programs are not implemented throughout all the endemic regions, development of safe and efficacious alternatives to chemical insecticides for vector control as well as potent antiviral drugs against JEV is the need of the hour. Plants offer an extraordinarily diverse source of phytochemicals that could be developed into potential therapeutic agents against JE with good tolerability and least side effects. Vector control is also another area where plentiful plant-derived agents have demonstrated great potency. Efforts have been made to screen natural products library to identify different bioactive molecules against JEV. But regrettably, ongoing research in this area is extremely limited. Thus, it is of major importance that more emphasis be laid on seeking new phytochemicals against JE and simultaneously determining their inhibitory mechanisms against the virus and its vector. Combination therapies using natural compounds and synthetic antivirals for reducing disease severity

TABLE 3  List of compounds showing antiviral activity against JEV. Sl. no.

Compound

1

Ouabain

2

Digoxin

Structure

Class

Mechanism of action

Intracellular targets

References

Cardiac glycosides

– Inhibition of viral replication

– ATPase α 3 and ATPase α 2 isoforms

Guo et al. (2019)

3

4

Arctigenin

Curcumin

Phenylpropanoid dibenzyl­ butyrolactone lignan

– Suppression of microglial activation – Downregulation of proinflammatory cytokines – Antioxidant – Improved cell survival

– MAP kinases (phospho-p38, phospho-ERK ½, phospho-c-Jun) – Caspase-3 – Phosphotidylinositol-3 kinase (PI3K/Akt pathway)

Phenol

– Decreased production of viral particles – Antioxidant – Maintaining cell membrane integrity – Disruption of viral membrane proteins – Reduced cellular apoptosis

– Ubiquitin protease system (chymotrypsin and PGPH-like proteasome) – HSP-70 and SOD-1 – Phospho-p38MAPK, phosphor-ERK1/2, phosphor-JNK – pNFκβ

– Reduced viral proteins – Suppression of inflammation and microglial activation

– JEV-specific proteins (17 and 84 kDa) – Inflammatory cytokines

Swarup et al. (2007)

– Inhibition of viral RNA synthesis and cellular attachment

–

Chang et al. (2012)

5

Rosmarinic acid

Polyphenol

6

Indirubin

Heterocyclic indole

7

Indigo

Swarup et al. (2008)

Chen et al. (2013), Dutta et al. (2009)

Organic dye

Continued

TABLE 3  List of compounds showing antiviral activity against JEV—cont’d Sl. no.

Compound

8

Baicalein

9

Ajwain oil

10

Daidzin

Structure

–

Class

Mechanism of action

Flavonoid

– Inhibits viral adsorption – Potent extracellular antiviral activity

Essential oil

Intracellular targets

References

–

Johari et al. (2012)

– Virucidal effect

–

Roy et al. (2015)

– Viral inactivation by binding to viral mRNA and inhibition of viral protein synthesis

– Viral mRNA (fsRNA)

Care et al. (2020), Zhang et al. (2012)

– Extracellular virucidal effect – Inhibition of viral replication

– JEV E protein

Fan et al. (2016)

Isoflavone

11

Kaempferol

Polyhydric flavonol

12

Luteolin

Flavone

Natural products in Japanese encephalitis  Chapter | 13  327

Baicalein Indigo

Mature virion Viral RNA Viral protein

Viral aachment

Viral entry

Plasma Membrane

Endosome

Cytoplasm Endocytosis

Ouabain Indigo Luteolin

Arcgenin Indigo Luteolin Rosmarinic acid

Release of viral genome

Replicaon

Translaon

Assembly

Curcumin Maturaon

Release

Nucleus Kaempferol Rosmarinic acid

Arcgenin Curcumin Rosmarinic acid

Inflammatory response

Inflammatory and apoptoc response

FIG. 2  Entry, replication, maturation, and release of JEV from within the infected host cell and the target sites for botanical antiviral agents. JEV enters the host cell by adsorption thorough the plasma membrane (inhibited by baicalein and indigo) and forms endosomes within the cell. It releases viral RNA into the cytoplasm where multiplication and translation occur. Replication of viral genome is inhibited by ouabain, indigo, and luteolin by targeting different proteins while kaempferol attaches to the viral mRNA thereby attenuating translation. Rosmarinic acid prevents expression of viral proteins that is required for the formation of viral envelope. Curcumin dysregulates the ubiquitinprotease system that plays a vital role in the regulation of viral replication, assembly, and maturation. Other antiviral agents suppress the intracellular and extracellular inflammatory responses and promote cell survival.

is also an area that can be looked into. Interestingly, studies are also being directed toward the development of metal nanoparticles using plant extracts that have shown promising results toward the mitigation of mosquito vectors (Kumar et al., 2020). Furthermore, Appaiahgari et al. (2009) have studied the expression of viral proteins in transgenic plants that could pave way for the development of novel plant derived vaccines (Chen et al., 2017). Overall, extensive research in this direction is crucial for the development of natural insecticides and antiviral agents for effective control of vector-borne diseases.

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Natural products in Japanese encephalitis  Chapter | 13  333 Pavela, R., Maggi, F., Iannarelli, R., Benelli, G., 2019. Plant extracts for developing mosquito larvicides: from laboratory to the field, with insights on the modes of action. Acta Trop. 193, 236–271. https://doi.org/10.1016/j.actatropica.2019.01.019. Plesner, A.-M., 2003. Allergic reactions to Japanese encephalitis vaccine. Immunol. Allergy Clin. 23 (4), 665–697. Pohlit, A., Rezende, A., Lopes Baldin, E., Lopes, N., de Andrade, N.V., 2011. Plant extracts, isolated phytochemicals, and plant-derived agents which are lethal to arthropod vectors of human tropical diseases – a review. Planta Med. 77, 618–630. https://doi.org/ 10.1055/s-0030-1270949. Rajeswary, M., Govindarajan, M., Alharbi, N.S., Kadaikunnan, S., Khaled, J.M., Benelli, G., 2018. Zingiber cernuum (Zingiberaceae) essential oil as effective larvicide and oviposition deterrent on six mosquito vectors, with little non-target toxicity on four aquatic mosquito predators. Environ. Sci. Pollut. Res. 25, 10307–10316. https://doi.org/10.1007/s11356-017-9093-3. Rawani, A., Ray, A.S., Ghosh, A., Sakar, M., Chandra, G., 2017. Larvicidal activity of phytosteroid compounds from leaf extract of Solanum nigrum against Culex vishnui group and Anopheles subpictus. BMC Res. Notes 10 (1), 1–8. Rosen, L., 1986. The natural history of Japanese encephalitis virus. Annu. Rev. Microbiol. 40 (1), 395–414. Roy, S., Chaurvedi, P., Chowdhary, A., 2015. Evaluation of antiviral activity of essential oil of Trachyspermum Ammi against Japanese encephalitis virus. Pharmacogn. Res. 7 (3), 263. Schuh, A.J., Ward, M.J., Leigh Brown, A.J., Barrett, A.D.T., 2014. Dynamics of the emergence and establishment of a newly dominant genotype of Japanese encephalitis virus throughout Asia. J. Virol. 88, 4522–4532. https://doi.org/10.1128/JVI.02686-13. Sharma, G., Kumar, K., Sharma, A., Agrawal, V., 2012. Bioassay of Artemisia annua leaf extracts and artemisinin against larvae of Culex quinquefasciatus and Culex tritaeniorhynchus. J. Am. Mosq. Control Assoc. 28, 317–319. https://doi.org/10.2987/12-6275R.1. Singha, S., Adhikari, U., Ghosh, A., Chandra, G., 2012. Mosquito larvicidal potentiality of Holoptelea integrifolia leaf extract against Japanese encephalitis vector, Culex vishnui Group. J. Mosquito Res. 2 (4). Solomon, T., Kneen, R., Dung, N.M., Khanh, V.C., Thuy, T.T.N., Ha, D.Q., et  al., 1998. ­Poliomyelitis-like illness due to Japanese encephalitis virus. Lancet 351, 1094–1097. https:// doi.org/10.1016/S0140-6736(97)07509-0. Solomon, T., Dung, N.M., Wills, B., Kneen, R., Gainsborough, M., Diet, T.V., et al., 2003. Interferon alfa-2a in Japanese encephalitis: a randomised double-blind placebo-controlled trial. Lancet 361, 821–826. https://doi.org/10.1016/S0140-6736(03)12709-2. Suresh, U., Murugan, K., Benelli, G., Nicoletti, M., Barnard, D.R., Panneerselvam, C., Kumar, P.M., Subramaniam, J., Dinesh, D., Chandramohan, B., 2015. Tackling the growing threat of dengue: Phyllanthus niruri-mediated synthesis of silver nanoparticles and their mosquitocidal properties against the dengue vector Aedes aegypti (Diptera: Culicidae). Parasitol. Res. 114 (4), 1551–1562. Swarup, V., Ghosh, J., Ghosh, S., Saxena, A., Basu, A., 2007. Antiviral and anti-inflammatory effects of rosmarinic acid in an experimental murine model of Japanese encephalitis. Antimicrob. Agents Chemother. 51 (9), 3367–3370. Swarup, V., Ghosh, J., Mishra, M.K., Basu, A., 2008. Novel strategy for treatment of Japanese encephalitis using arctigenin, a plant lignan. J. Antimicrob. Chemother. 61, 679–688. https://doi. org/10.1093/jac/dkm503. Thomas, T.G., Rao, S., Lal, S., 2004. Mosquito larvicidal properties of essential oil of an indigenous plant, Ipomoea cairica Linn. Jpn. J. Infect. Dis. 57 (4), 176–177.

334  Natural products in vector-borne disease management Tsai, T.F., 2000. New initiatives for the control of Japanese encephalitis by vaccination: minutes of a WHO/CVI meeting, Bangkok, Thailand, 13±15 October 1998. Vaccine 18, 1–25. Turtle, L., Solomon, T., 2018. Japanese encephalitis—the prospects for new treatments. Nat. Rev. Neurol. 14, 298–313. https://doi.org/10.1038/nrneurol.2018.30. Veerakumar, K., Govindarajan, M., Hoti, S.L., 2014. Evaluation of plant-mediated synthesized silver nanoparticles against vector mosquitoes. Parasitol. Res. 113 (12), 4567–4577. Vincent, S., Kovendan, K., Chandramohan, B., Kamalakannan, S., Kumar, P.M., Vasugi, C., et al., 2017. Swift fabrication of silver nanoparticles using Bougainvillea glabra: potential against the Japanese encephalitis vector, Culex tritaeniorhynchus Giles (Diptera: Culicidae). J. Clust. Sci. 28, 37–58. https://doi.org/10.1007/s10876-016-1038-3. Wang, S., Liu, Y., Guo, J., Wang, P., Zhang, L., Xiao, G., et al., 2017. Screening of FDA-approved drugs for inhibitors of Japanese encephalitis virus infection. J. Virol. 91, 14. WHO, 2019. Japanese Encephalitis. https://www.who.int/news-room/fact-sheets/detail/japaneseencephalitis. World Health Organization, 2015. Wkly Epidemiol. Rec. 90, 69–88. Ye, J., Jiang, R., Cui, M., Zhu, B., Sun, L., Wang, Y., Zohaib, A., Dong, Q., Ruan, X., Song, Y., He, W., 2014. Etanercept reduces neuroinflammation and lethality in mouse model of Japanese encephalitis. J. Infect. Dis. 210 (6), 875–889. Yun, S.-I., Lee, Y.-M., 2014. Japanese encephalitis: the virus and vaccines. Hum. Vaccines Immunother. 10, 263–279. https://doi.org/10.4161/hv.26902. Zhang, T., Wu, Z., Du, J., Hu, Y., Liu, L., Yang, F., et al., 2012. Anti-Japanese-encephalitis-viral effects of kaempferol and daidzin and their RNA-binding characteristics. PLoS One 7, e30259. https://doi.org/10.1371/journal.pone.0030259. Zhang, Y., Wang, Z., Chen, H., Chen, Z., Tian, Y., 2014. Antioxidants: potential antiviral agents for Japanese encephalitis virus infection. Int. J. Infect. Dis. 24, e30–e36.

Chapter 14

Algae natural products for potential vector-borne disease management Joana Assunçãoa,b, Helena M. Amaroa, and A. Catarina Guedesa a

CIIMAR/CIMAR-LA—Interdisciplinary Centre of Marine and Environmental Research, University of Porto, Novo Edifício do Terminal de Cruzeiros de Leixões, Avenida General Norton de Matos, Matosinhos, Portugal, bLEPABE—Laboratory for Process Engineering, Environment, Biotechnology and Energy, University of Porto, Porto, Portugal

Introduction Vector-borne diseases (VBDs) are infectious diseases that are transmitted to humans by the so-called vectors that include parasites, bacteria, or viruses. Those are responsible by diseases like malaria, dengue, human leishmaniasis, human African trypanosomiasis (sleeping sickness), human American trypanosomiasis (Chagas disease), Zika virus fever, yellow fever, Japanese encephalitis, lymphatic filariasis among others, with minor expression but with large outbreaks in the affected areas, that affect millions of people every year with more than 700,000 deaths (WHO, 2020a). According to the World Health Organization (WHO), VBDs are among the most important global public health problems that are particularly found in subtropical and tropical regions, where typically most vulnerable people do not have access to sanitary conditions. VBDs constitute a burden for the affected countries, in particular by those with a poor economical context and fragile or practically nonexisting public healthcare systems. Unfortunately, the investment to prevent, mitigate, and develop the treatment of VBD is largely neglected by the public institutions, pharmaceutical entities, and public health programs across the globe, and the attention given in media to this problem is quite scarce, in particular by the so-called First World countries. Yet, due to emergence of climatic change, vector-borne diseases are in a potential risk of spreading for other noncommon affected areas including the First World countries; thus, the attention regarding those infectious diseases and the focus to search for new treatments and alternative therapies are widely increasing. Natural Products in Vector-Borne Disease Management. https://doi.org/10.1016/B978-0-323-91942-5.00007-0 Copyright © 2023 Elsevier Inc. All rights reserved.

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Most of such diseases are known as neglected tropical diseases (NTDs), because they did not receive as much as the attention as other diseases considering the treatment (Torres et al., 2014), with a few exceptions to malaria. The treatment for such diseases may exist (i.e., malaria, leishmaniasis, chikungunya), but can be extremely expensive in the affected countries and in other occasions nor even exist (i.e., Japanese encephalitis, dengue fever), only complement therapies to minimize symptoms. Part of the problem also lies in the lack of commitment by the multibillion dollar pharmaceutical entities into developing new drugs owing to the high difficult in financial return as any potential new medicine can be rejected at any point of the process and may take 10–15 years before reaching patients (Freile-Pelegrín and Tasdemir, 2019). Another problem associated with some NTDs (i.e., malaria, leishmaniasis) is increasing resistance to existing drugs. Also, some treatments can be quite harsh to the human body such as chemodrugs that use highly aggressive chemicals, e.g., benznidazole for the treatment of Chagas disease. Therefore, the development of new drugs and therapies urges, in particular, from natural-based solutions. Recent trends in drug screening indicate that research for new molecules from natural and sustainable sources, in particular from marine ones, has been gaining attention in the latest years for pharmaceutical and medical purposes (Blunt et al., 2011; De Jesus Raposo et al., 2013, 2015; Joseph, 2016). Particular attention goes to algal source compounds—including macro-, microalgae, and cyanobacteria—that are an exceptional source of novel bioactive natural compounds with a wide chemical diversity features (i.e., terpenes, alkaloids, polyketides, porphyrins, peptides, sterols) as a result of their developed defense mechanisms by different metabolic pathways to adapt to the most competitive environments (Markou et al., 2014). Several of their producing compounds include secondary metabolites (i.e., terpenes, polyketides, peptides, halogenated compounds, etc.), but also other primary metabolites including pigments, proteins, or polysaccharides. Several of such compounds were reported to possess important bioactive capacities including antitumor, antioxidant, immunomodulatory, antimicrobial, antiviral, or antifungal; those potential capacities can have important applications, both for pharmaceutical and medical purposes, but also in cosmeceutical, nutraceutical, and food industries to beneficiate the human health and their nutrition (De Jesus Raposo et  al., 2015; Pagels et  al., 2019; Levasseur et  al., 2020). Besides, with the potential of important biological capacities, i.e., antiinfective, antiviral, antiparasitic, antiprotozoal, algal compounds or extracts are promising to be explored as new drug candidates or be suitable as scaffold for new therapies and treatments of VBD.

Vector-borne diseases characterization and context VBDs are infectious diseases—i.e., malaria, dengue, yellow fever, Chagas disease, human African trypanosomiasis (HAT), leishmaniasis, Japanese encephalitis, chikungunya, lymphatic filariasis—caused by a group of viral, bacterial,

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or parasite pathogens in human populations, and are typically transmitted by the bite of infected vectors. Well-known vectors include blood-sucking mosquitoes that can contaminate/infect the host with disease-producing infections agents (i.e., virus) that have acquired from a previous blood meal from an infected animal/human (WHO, 2014a) as is the case of dengue or Zika virus fever. Besides mosquitoes, other types of vectors include fleas, ticks, flies, sandflies, or some freshwater aquatic snails (Table 1). These diseases prevail in tropical and subtropical conditions, yet parasitic diseases can appear in other regions of the globe affected by natural disasters (i.e., hurricanes), as it was the case of post-Hurricane Katrina (Louisiana, United States). Also where populations suffer from living poverty, with troubled political regions such as Syria, Sudan, South Sudan, and Afghanistan, and have been more prone to outbreaks of cutaneous and visceral leishmaniasis, causing the health system to collapse (FreilePelegrín and Tasdemir, 2019). A considerable number of diseases are recognized by WHO as VBD as shown in Table 1. The next paragraphs will list and summarize the most impactful VBD in human populations with the respective causative agents, and their major current treatment. Malaria: Across all known VBDs, the one causing most impact in human lives is malaria, in which more than 400,000 people dying every year, having significant impact on more vulnerable people such as elderly people, children, or immunocompromised people (WHO, 2020b). Malaria is transmitted to humans by Anopheles female mosquitoes’ bites that carry single-celled parasites of Plasmodium group. Plasmodium falciparum is by far one of the most lethal and responsible for the most human deaths (see the complete parasite full cycle Fig. 1), including symptoms of fever, vomiting, and headache that can last to 10–15 days after a bite. Several treatments can be prescribed for malaria including artemisinin-­ combined therapies—that work against the malaria parasite in different ways— or chloroquine; but unfortunately, the cases of drug resistance are still increasing (Balikagala et al., 2021). This is why malaria is one of the VBDs, that exceptionally receive more research funding for new treatments (Freile-Pelegrín and Tasdemir, 2019). Dengue, yellow fever, Zika, and chikungunya: Other VBDs like dengue, yellow fever, and Zika are spread by mosquitoes of the genera Aedes carrying a pathogenic RNA virus (genus Flavivirus); still chikungunya carries another family of virus belonging to Togaviridae family. Such diseases tend to erupt in large occurrences and paralyze health systems. Dengue, for instance, has been increasing its incidence about 30-fold, in the last 50 years. Due to severe dengue, every year around a million patients require hospitalization, which cause enormous economic and social disruption (WHO, 2014b). Most of such mosquito-borne viral infections cause typical manifestations like biphasic fever, headache, or severe cases like hemorrhagic disease, flaccid paralysis, and jaundice (Gould and Solomon, 2008). Most of them described that VBDs do not

TABLE 1  List of the most relevant VBD with respective vectors, causative agents, and potential treatments. Important observations

Current treatment

Treatment limitations/ observations

Refs.

VBD

Vector

Disease causative agent

Malaria

Anopheles (female mosquito)

Plasmodium falciparum Plasmodium vivax Plasmodium ovale Plasmodium malariae (protozoan vertebrates)

Anopheles bite has contaminated saliva that leads parasites through the blood stream and deposits in the liver and then to blood

Antimalaric drugs Chloroquine, primaquine Artemisinin-based combined therapy

Drug resistance

WHO (2020b)

Dengue Zika Chikungunya

Aedes Aegypti Aedes albopictus Aedes polynesiensis Aedes scutellaris (female mosquitoes)

RNA virus genera Flavivirus Dengue (DEN-1, DEN2, DEN-3, DEN-4 and DEN-5) Zika: Zika virus Chikungunya: Chikungunya virus (fam. Togaviridae)

The virus enters by the infected saliva of the Aedes vectors and enters to the blood stream inducing a viral infection—lymphotropic phenomenon (atypical inflammatory responses)

Specific antiviral drug not available Dengue: live attenuated vaccine (Dengvaxia)

High cost (vaccine)

Hotez et al. (2016), Wiwanitkit (2010), and Pujol et al. (2012)

Schistosomiasis (Bilharzia) (intestinal or urogenital)

Biomphalaria alexandrina (freshwater snail)

Schistosoma mansoni (intestinal) Schistosoma japonicum (intestinal) Schistosoma mekongi (intestinal) Schistosoma guineensis and related S. intercalatum (intestinal) Schistosoma haematobium (urogenital) (fluke worms)

Transmitted through the skin in contact with infected water; the larvae develop into adult schistosomes Cause immune reaction and damage to organs and blood vessels

Antihelminthic drug Praziquantel

High cost

WHO (2014a)

Japanese encephalitis

Culex sp. Culex tritaeniorhynchus

Japanese encephalitis virus (JEV) (flavivirus)

Mosquito bite

Vaccine prevention (Ixiaro) No antiviral treatment only to relieve the symptoms

Lymphatic filariasis (elephantiasis)

Culex quinquefasciatus Aedes sp. Anopheles sp.

Wuchereria bancrofti Brugia malayi Brugia timori (parasitic roundworms)

Mosquito bite

Diethylcarbamazine citrate Diethylcarbamazine Albendazole Ivermectin

Leishmaniasis

Phlebotomus argentipes (female phlebotomine sandflies) Lutzomyia (female sandflies)

Leishmania sp. Leishmania donovani (visceral) Leishmania infantum (visceral) Leishmania chagasi (visceral) Leishmania mexica (cutaneous) Leishmania tropica (cutaneous) Leishmania major (cutaneous) (protozoan parasites)

Sand flea bites Leishmaniasis (visceral) Mucocutaneous Cutaneous

Pentavalent antimonies: sodium stibogluconate, meglumine antimoniate Polyene antibiotic: amphotericin B, liposomal amphotericin B (LaMB) (for visceral leishmaniosis) Miltefosine (all types of leishmaniasis)

Vaccine (high cost)

WHO (2014a)

Freile-Pelegrín and Tasdemir (2019) and WHO (2014a) Low efficacy, long-course treatment regimen, high toxicity, adverse side effects, induction of parasite resistance, and high cost

Torres et al. (2014), Tchokouaha Yamthe et al. (2017), Herwaldt, 1999, Maltezou (2010), and Bern et al. (2006)

Continued

TABLE 1  List of the most relevant VBD with respective vectors, causative agents, and potential treatments—cont’d Important observations

Current treatment

Treatment limitations/ observations

VBD

Vector

Disease causative agent

Refs.

Chagas disease

Triatoma bugs Panstrongylus and Rhodnius genus (Triatomine insects or “kissing bugs”)

Trypanosoma cruzi (protozoan parasite)

Trypanosoma cruzi is found in “kissing bugs” feces. The person is infected orally through mucous membranes or breaks in the skin

Antiparasitic Benznidazole Nifurtimox

Side effects (Benznidazole), high toxicity and increased risk of cancer (Nifurtimox) Less effective for chronic cases High cost requires

Torres et al. (2014) and WHO (2014a)

Human African trypanosomiasis or HAT (sleeping sickness)

Glossina genus (tsetse fly)

Trypanosoma brucei gambiense Trypanosoma brucei rhodesiense (protozoan parasites)

Tsetse fly bite

Pentamidine (T. b. gambiense stage I) Suramin (T. b. rhodesiense stage I) Melarsoprol (T. b. rhodesiense stage II) Eflornithine (T. b. rhodesiense stage II) Nifurtimox-eflornithine combination (T. b. gambiense stage II) Fexinidazole (T. b. gambiense, both stages)

Toxicity and side effects In general, the treatment has elevated costs and limited availability (e.g., pentamidine only in United States)

Torres et al. (2014)

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FIG. 1  Complete full life cycle and maturation of parasite Plasmodium falciparum.

possess specific drug treatment, only to alleviate symptoms except for dengue. Dengue has now an innovative live attenuated vaccine (Dengvaxia), and a nucleoside dengue fever inhibitor is at clinical trials (phase I) (Hotez et al., 2016). Leishmaniasis: Leishmaniasis is a protozoan parasitic disease (genus Leishmania sp.) which is transmitted by the female Phlebotomus or the Lutzomyia sandflies (Tchokouaha Yamthe et al., 2017). Leishmaniasis is classified based on symptomatology as visceral, muco-cutaneous, and diffused cutaneous (Torres et al., 2014; Herwaldt, 1999); being the former, the most aggressive form of the disease is characterized by irregular bouts of fever, weight loss, anemia, and alterations in the spleen and liver. The cutaneous causes skin ulcers and can result in disfigurement similar to the effects of leprosy, and mucosal leishmaniasis can partially or totally destroy the mucous membranes of the nose, mouth, and throat cavities, and surrounding tissues (Tchokouaha Yamthe et  al., 2017). The Leishmania life cycle is dimorphic and heteroxene (needs more than one host), with an extracellular fusiform and flagellated promastigote stage in the sandfly’s midgut and a morphologically different intracellular amastigote stage in a mammalian host’s macrophages. To mention that, various models have been used in drug susceptibility assays

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based on two stages of the Leishmania parasite: (i) promastigotes model (the intracellular form in the sandfly gut) and (ii) amastigotes, the ones that reside inside the host cells, and thus, the forms that provoke the disease and therefore have physiological relevance. Yet, there are reports, in which, instead of intracellular amastigotes (more labor-intensive), axenic amastigotes are used (Tchokouaha Yamthe et al., 2017). Chagas disease: Chagas disease, or human American trypanosomiasis, is a parasitic disease caused by the protozoan Trypanosoma cruzi which is spread by the feces of triatomine insects, commonly known as kissing bugs (Triatoma, Panstrongylus, and Rhodnius genus) that tend to colonize places with low sanitary conditions (i.e., houses). Besides the contact with the vector (with their ­feces), Chagas disease can also be transmitted through ingestion of contaminated food, blood transfusions, organ donations, and congenital transmission (WHO, 2014a). Chagas disease involves an acute phase followed by a chronic phase that can be classified into undetermined, cardiac, or digestive types, each with different clinical symptoms (Torres et al., 2014). Human African Trypanosmiasis (HAT): HAT or sleeping sickness, the protozoan Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense that are transmitted by the bite of the genus Glossina, popularly known as tsetse flies. Usually, they have acquired their infection from other human being or animals harboring human pathogenic parasites (Freile-Pelegrín and Tasdemir, 2019). This VBD is characterized by two stages: (i) nonspecific symptoms such as fever, headache, generalized weakness, joint failure, and weight loss; (ii) parasites penetrate into central nervous system and proliferate in the blood-brain barrier, causing encephalic reaction, that can lead to death (Torres et al., 2014; Freile-Pelegrín and Tasdemir, 2019). Schistosomiasis (Bilharzia): Schistosomiasis is a chronic parasitic in infection caused by small worms, in particular Schistosoma genus. The main transmitters are infected freshwater snails Biomphalaria alexandrina. This VBD particularly affects the gastrointestinal and urogenital tracks. The trematodes infection is transmitted when Schistosoma larval forms are released from the snails to the water and the infested enters in contact with human skin. Such disease is treated with antihelminthic drugs. Japanese encephalitis: Japanese encephalitis is transmitted to humans through the infected Culex sp. mosquitoes through the Japanese encephalitis virus (JEV). This disease is characterized by the inflammation of the brain. For now, there is no viral treatment available, yet such disease can be prevented by the vaccine immunization (WHO, 2020a). Lymphatic filariasis (elephantiasis): It is a parasitic infection caused by nematode worms (Wuchereria bancrofti, Brugia malayi, Brugia timori) transmitted by the mosquitoes of the genii Culex, Aedes sp., and Anopheles sp. This VBD affects the lymphatic systems and disrupts the immune system (WHO, 2014a), resulting in chronic lymphedema (tissue swelling) and enlargement of the body parts (elephantiasis).

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A lot of efforts have been placed in the prevention of the transmission by controlling the vector populations, including physical (i.e., mosquito nets), chemical (i.e., insecticidal, larvicide), and in some cases biological (i.e., with bacteria Bacillus thuringiensis, for dengue control); such measures are applied in articulation with nonprofitable health organizations, and despite they provide an excellent opportunity to manage VBD, they are still insufficient and underused due to deficient investment and resources, infrastructures associated to the climatic, social, and economic context in which some countries are inserted. According to WHO (2014a), VBD affects more than 1 billion of people all over the world, being estimated with 17% of global burden of all infectious diseases (Caminade et al., 2016) and with more than half of the world’s population currently estimated to be at risk; thus, treatment and therapies are urgent. However, VBD affects the least-developed countries in the poorest segment of society and associated to a fragile healthcare system; in most of the cases, the transmission is potentiated by the climate (tropical and subtropical) (warm temperatures favor the thriving of the vectors), lack of basic sanitization in houses, and proximity to water- and filth-contaminated environments. More ecological changes can also potentiate such transmission; for instance, in endemic malariaoccurring regions, changing agriculture practices, expanding irrigation dams, deforestation, mining, urbanization, etc., causes deep environmental changes that affect Anopheles population (the mosquito vector of malaria), which boosts their breeding and the transmission of malaria (WHO, 2014b). In addition, the fragile economic context associated makes the populations quite vulnerable to get VBD. Unfortunately, the treatment of such diseases in the affected areas is quite difficult to assure, and deficiently accomplished by world human health organizations and other nonprofit organizations. Treatments for VBD are scarce in the market and not immediately available in the situations that are needed most; in the cases where such therapies are available, they are usually quite expensive and real burden to the patient families or the public health system. In other cases, in VBD, such as dengue or chikungunya, there are not neither effective treatment nor vaccine; or even when treatments are available, there are problems of drug resistance (i.e., malaria) (Marques et al., 2016) or collateral effects, which can be quite toxic or ineffective, leading the patients to dolorous therapies and eventually death. For example, leishmaniasis is used as first-line drug for treatment called pentavalent antimonial, which is a quite toxic compound, and for most of the patients, it is an ineffective treatment, which obviously leads to therapeutic failure (Fouladvand et al., 2011). There is an urgent need to screen new drug and potential new products to develop more efficient and effective treatment to VBD management. Bearing in mind that in the preexisting treatment, most of them are quite toxic and not so much effective, drug screening from natural sources is urgent. Indeed, the last years, the research on drug discovery has more focus on natural-based solutions, in particular from sustainable sources such as the marine environment. In this context, the marine algal-based products arise as promising candidates

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toward the development of new pharmacological therapies to prevent or treat VBD. Such compounds have called the attention by their remarkable biological capacities including antitumor, antiinflammatory, antimalaria, antiviral, or antiparasitic, among others (Rosales-Mendoza et al., 2020). Such compounds present a promising opportunity toward the development of new pharmacological products that is expected to overcome the side effects of the preexisting treatments and the drug resistance.

Algae importance Algae have been arising in the recent years as excellent sources of new bioactive-­ based natural compounds with interest to fight and prevent certain diseases (Torres et al., 2014). Algae and their extracts can be rich in proteins, peptides, fibers, pigments, vitamins, minerals, polyketides, polysaccharides, polyunsaturated fatty acids (PUFAs), steroids, antioxidants, and other secondary metabolites which hold potential biological capacities, including antitumor, antiinflammatory, antiviral, antiprotozoal, antibacterial, antioxidant, and immunomodulatory (Levasseur et  al., 2020; Rosales-Mendoza et  al., 2020; Tan and Hou, 2014). They hold value to be applied in a wide broad of industrial sectors such as food, nutraceutical, pharmacological, cosmeceutical, or feed (Brennan and Owende, 2010; Lau et al., 2015; Pagels et al., 2019; Rizwan et al., 2018). In fact, their commercial exploitation is increasing, and their economic reputation is expanding in the worldwide markets (Levasseur et al., 2020)—owing to the high content in functional and nutritional compounds that have been applied to functional foods and aquaculture (Levasseur et al., 2020). Algae comprise a large and diverse group, in terms of morphology and physiology of aquatic and photosynthetic organisms, where included are macroalgae (seaweed), microalgae, and cyanobacteria (the latter not truly algae, but prokaryotic organisms with photosynthetic capacity, known as blue-green alga; for a matter of convenience and possessing the same biotechnological value, they will be addressed in this chapter as algae). Typically, algae can be generally divided into the following: (i) red algae (phylum Rhodophyta); (ii) brown algae (phylum Heterokontophyta, class Phaeophyta); (iii) green algae (phylum Chlorophyta); and (iv) cyanobacteria (phylum Cyanophyta) (De Jesus Raposo et al., 2015). They usually grow photoautotrophically by converting chemical energy from sunlight and inorganic carbon sources to produce oxygen, biomass, and a wide range of organic compounds, including unique metabolites with economical interest (Tan, 2007; Singh et al., 2011; Vijayakumar and Menakha, 2015; Urtubia et al., 2016). But, they can also grow heterotrophically depending on the carbon source. Their ability to grow fast and biofixate high amounts of CO2, by simply consuming basic nutrients (i.e., light, water, carbon), has increased the attention to grow them in controlled cultivation conditions (i.e., raceways,

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photobioreactors)—in the case of microalgae and cyanobacteria (Assunção and Malcata, 2020)—or collect them directly in situ for farming, in the case of macroalgae/seaweed (Torres et al., 2014). Their ubiquitous distribution, diversity, and their incredible adaptation to the environment allowed them to evolve different strategies, which covered their metabolite chemical diversity—with a wide range of functional groups and biological features. Their exceptional richness includes a series of secondary metabolites (i.e., alkaloids, terpenes, polyketides, porphyrins, macrolides, cyclic polyethers, among others) (Torres et al., 2014; Assunção et al., 2017), which can indeed be relevant to be explored by pharmaceutical industry, potentially used as drug leads and thus discovery of new agents or new complement therapies against VBD. Interestingly, this area of research is increasing, and several studies with algae-based compounds or their extracts and fractionated compounds have outlined important biological effects with potential to be applied against VBD, in particular case with described antiprotozoal, antiviral, antihelminthic, or antiparasitic effects (Torres et al., 2014; Rosales-Mendoza et al., 2020; Orhan et al., 2006). The next subsubsections will entail in more detail the most studied alga-derived agents against VDP and their respective potential.

Algae-derived agents against VBD Polysaccharides Algal polysaccharides (PSs) are active biocompounds with a great structural variety—from algae family—but, in general, are composed of heteropolysaccharides (De Jesus Raposo et al., 2013). Algal PSs are crucial components of the algal cell walls, in particular in seaweeds and in some microalgae and cyanobacteria. Such complex polymers are described as having relevant rheological properties, thus useful as a thickening or gelling agent within food and cosmetic fields (De Jesus Raposo et  al., 2013; Levasseur et  al., 2020); also they were shown to be potentially useful as biosurfactants for oil and water bioremediation (Cruz et al., 2020; Singh et al., 2019). In addition, some of the most bioactive types of algal PS are sulfated polysaccharides (SPs), and they can be important in the biomedical field, namely by their antiviral, antiprotozoan, antimalarial, but also antiinflammatory, antitumor, antiimmunomodulatory, and anticholesterol properties (Freile-Pelegrín and Tasdemir, 2019; De Jesus Raposo et  al., 2013, 2015; Cruz et al., 2020). SPs of interest can be grouped according to algae division; for instance, fucoidans are produced by brown algae (Phaeophyceae), such as Sargassum sp., Undaria sp., Laminaria sp., Fucus sp., and Ectocarpus sp.; agars + carrageenans (sulfated galactans) and porphyrins are produced by red algae (Rhodophyta) such as Porphyridium sp., Chondrus sp., Eucheuma sp.; Gigartina sp., Porphyra sp., and Hypnea sp.; and ulvans are produced by the green seaweed Ulva sp. (De Jesus Raposo et al., 2013; Rosales-Mendoza et al., 2020). Under certain conditions, some species are able to secrete these useful compounds into the culture

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medium, which can be easily extracted, the so-called extra- or exocellular polysaccharides (EPSs) (De Jesus Raposo et al., 2013). Fucoidans: Fucoidans represent a group of SPs derived from the extracellular matrix of marine brown algae—and possessing some biological capacities similar to those of heparin. They are able to mediate several biological effects in mammalian cells—in particular antiinflammatory and anticoagulation. Besides, they possess interesting potential as antiviral agents against several infectious diseases such as cytomegalovirus, herpes virus, or human immunodeficiency virus SARS-CoV-2 (Hidari et al., 2008; Salih et al., 2021; Kwon et al., 2020). Remarkably, they have shown biological effect against dengue virus, in particular in one of the serotypes (DEN-2) (Hidari et  al., 2008; Talarico et  al., 2005). For instance, Hidari et  al. (2008) have shown that the sulfated group and glucoronic acid present in the extracted fucoidan of marine brown algae Cladosiphon okamuranus were responsible for the antiviral action against the serotype DEN-2. A mechanism of action indicated a direct interaction of the glycoprotein (EPG) present in the virus envelope. Fucoidans have also proven to have important immunomodulatory properties to combat the effects of the treatment resistance of visceral leishmaniasis and lead also to parasite suppression (Sharma et  al., 2014; Kar et  al., 2011). Fucoidans from Fucus vesiculosus were able to induce pro-inflammatory cytokine synthesis in tandem with the induction of nitric oxidase gene transcription, via mediated PKC in the mitogen-activated protein kinase (MAKP)/NF-κB pathway (as this is one of the main pathways inhibited by the parasite), which results on parasite Leishmania donovani suppression (Sharma et al., 2014). In addition, Kar et al. (2011) also demonstrated that the fucoidan-curative effect in visceral leishmaniasis is related with the T-cell differentiation from Th2 to Th1 mode and increased induction of macrophage superoxide and nitric oxide (NO) generation. In addition to the full restorative effect in mice liver and spleen, when administrated over 15 days postinfection, fucoidans also protected against reinfection. Fucoidans were also reported as having antimalarial capacity by protecting the cells of the host and neutralize the activity of the protozoan Plasmodium falciparum. For instance, Chen et al. (2009) reported that Undaria pinnatifida fucoidans were able to inhibit the invasion of Plasmodium merozoites into red blood cells (RBCs) both in vitro and in vivo. In particular, Balb/c mice (albino, immunodeficient laboratory-bred strain) treated with fucoidans over 4 days have reduced parasitemia over the treatment, hypothesizing the inhibition of the adhesion and interaction between merozoites and RBC by the direct binding of the function group containing the sulfate to the host cells, and thus preventing the parasite invasion. Carrageenans and Agarans (sulfated galactans—SG): Carregeenans and agarans are mainly present in extracellular matrix of red algae (Rhodophyta) and were demonstrated to inhibit both in vitro and in vivo infection of flaviviruses such as dengue virus (Talarico et al., 2005; Talarico and Damonte, 2007;

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Tisher et  al., 2006; Pujol et  al., 2002). Carregeenans are SPs that can be divided into different groups depending on its biochemical structure: iota, kapp, lambda, mu, nu, and theta forms, which occur as mixtures depending on the specie (Rosales-Mendoza et  al., 2020). The iota, kappa, and lambda forms are the most studied because of their antiviral properties. For instance, Tisher et  al. (2006) demonstrated that the iota/kappa/nu-hybrid carrageenans from Meristiella gelidium presented important antiviral capacity against the dengue virus. Talarico and Damonte (2007) also demonstrated that iota and lambda carregeenans prevent the viral multiplication of dengue virus DEN-2 and -3; it was proved to inhibit the viral attachment, but also to prevent viral internalization. Years earlier, Pujol et al. (2002) also showed that hybrid DL-galactan (carrageenan with minor quantities of agarans) extracted from the red seaweed Gymnogongrus torulosus, besides does not present toxic effects, has important inhibitory effects against herpes simplex virus and dengue virus, suggesting the same mechanism of action described above. SGs are also promising candidates to explore regarding considering their antimalarial effects. Marques et al. (2016) explored SGs from red alga Botryocladia occidentalis, and relevant inhibition of Plasmodium falciparum growth was observed under low anticoagulant concentrations (presence of heparin); the interaction of sulfated groups present in SGs with the coating of the parasite seems to be the main mechanism to inhibit RBC invasion. Besides, tests showed that SGs were able to improve the survival of mice infected with Plasmodium yoelii; besides reducing parasitemia to undetectable levels, immune response was enhanced and with the presence of antigens against the parasite. Thus, SGs have demonstrated to be important mediators in the retarded invasion of Plasmodium, but also in the promotion of immune response which indeed could be an interesting potential therapeutic approach to explore. Ulvan: Ulvans are also important described SPs found in green seaweed, in particular in the order Ulvales (Rosales-Mendoza et al., 2020). Their antiviral properties are known; Chiu et  al. (2012) found that extracts of Ulva lactuca contribute to the blockage of virus adsorption of the Japanese encephalitis virus (JEV)—one of the main causers of human encephalitis. In addition, an immune modulatory response was observed by reducing the pro-inflammatory cytokine action in mouse cells brains, and JEV symptoms seemed to be delayed in pretreated mice with Ulva SPs extracts. General SPs and EPS: General studies conducted with different algae and their extracts present SPs and EPS with important biological features, namely antiviral potential (Fabregas et al., 1999), to be explored in the VBD management. For instance, the green alga Caulerpa racemosa stood out with important antiviral action against DEN-2 virus. Porphyridium cruentum, EPS-rich extracts, were demonstrated to promote antiviral capacity against the African swine fever virus—a VBD that can have as main vectors pigs, but also ticks (Fabregas et al., 1999). Interestingly, the antiviral activity of EPS, in particular of SPs of Porphyridium sp., is not yet totally understood; yet it is known that

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offers a good protection against viruses without toxicity to the host cells (De Jesus Raposo et al., 2013; Chiu et al., 2012). Several mechanisms are proposed such as the inhibition of the binding/penetration of viral particles in the host cells (Hayashi et  al., 1996), but also the inhibition of internalization into the host cells, suppression of DNA replication, and/or protein synthesis (RosalesMendoza et al., 2020; Pujol et al., 2012; Ahmadi et al., 2015). Table 2 presents the main studies of algal-derived PS against VBD.

Pigments Across the major groups of algal compounds are pigments, that can be grouped into several classes including chlorophylls, carotenoids, and phycobiliproteins (PBPs). Pigment composition and quantity varies depending on the species; however, some groups present particular types of pigment classes (e.g., PBPs are only found in cyanobacteria and red algae). At physiological level, pigments display an important role as photoreceptors in algal cells by processing light by absorption and transfer the electrons to the reaction centers (i.e., phycobilisome, photosystems I and II) to carry out efficiently the process of photosynthesis (Markou and Nerantzis, 2013). Besides this active role in light harvesting, pigments such as carotenoids also display a role of algal cells photoprotection by preventing damage on photosystems and dissipation of reactive oxidative species (Fernandes et al., 2018). Algal-extracted rich pigments were reported to hold high biotechnological value. Because of their bright color, they can be used as natural colorant by the food and textile industries, besides have a wide span of benefits and therapeutical value with regard to biological systems and quite appealing to nutraceutical, cosmetic, and pharmaceutical industries (Levasseur et  al., 2020; Saini et  al., 2018). Most of these molecules—particularly carotenoids (i.e., fucoxanthin, β-carotene, lutein, zeaxanthin, astaxanthin, etc.) and phycobiliproteins (PBPs) (phycocyanin, allophycocyanin, and phycoerythrin)—exhibit antioxidant, antitumor, anticholesterol, antiinflammatory, immunomodulatory, antibacterial, and antiviral properties, besides to protect against cardiovascular, neurodegenerative, and metabolic diseases (Pagels et al., 2019; Levasseur et al., 2020; Mandal et al., 2020). Furthermore, phycocyanin and fucoxanthin seemed to have promising potential regarding their biological action against VBD as shown in Table 3 (Pankaj et al., 2010; Abd El-Ghany et al., 2018; Afolayan et al., 2008). PBPs are colored, nontoxic, and biodegradable water-soluble pigment-­ protein complexes, found to have relevant antimalarial properties (Pankaj et al., 2010). In the study of Pankaj et al. (2010), the PBP cyanobacterial phycocyanin (C-PC) isolated from Nostoc muscorum presented antimalarial action in vitro against chloroquine-sensitive and -resistant Plasmodium falciparum strains, even with low C-PC concentrations of 3.0 μg mL−1. The suggested mechanism of action was related with the interference in hemozoin polymerization by the

TABLE 2  Polysaccharides potential against VBD, with respective alga sources, biological capacity, and mechanism of action. Active compound

Alga source

Biological capacity

Mode of action

Model/observations

Refs.

Fucoidan

Cladosiphon okamuranus

Antiviral (DEN-2)

Affection of protein viral envelope receptors

Baby hamster kidney (BHK-21) cell line

Hidari et al. (2008)

Fucoidan

Fucus vesiculosus

Immunomodulatory (visceral leishmaniasis)

Binding to PKC in infected macrophage via mediated PKC in the MAKP/NF-κB pathway

RAW 264.7 murine macrophage cell line/reduction of pro-inflammatory response of cytokines/induction of NO production

Sharma et al. (2014)

Fucoidan

Undaria pinnatifida

Antileishmanial

Not defined

Leishmania tropica promastigotes cultures

Phull et al. (2017)

Fucoidan

Undaria pinnatifida

Antimalarial/antiplasmodial

Direct binding of the sulfate group of fucoidan RBC (host cell protection)

Plasmodium falciparum cultures and Balb/c mice Inhibition of adhesion of merozoites and RBC/delay the death by anemia

Chen et al. (2009)

Carrageenan G3d dl-galactan hybrid C2S-3

Gymnogongrus Griffithsia Cryptonemia crenulata

Antiviral (DEN-2)

Inhibition of viral multiplication

Vero cells cultures

Talarico et al. (2005)

Carrageenan (dl-galactan hybrid)

Gymnogongrus torulosus

Antiviral (DEN-2)

Interference in the binding of the surface envelope glycoprotein with the cell receptor

Vero cells cultures

Pujol et al. (2002)

Lambda/iotacarrageenan

Eucheuma spinosum Chondrus crispus

Antiviral (DEN-2 and DEN-3)

Interference with virus adsorption

Vero cells cultures

Talarico and Damonte (2007)

Polysaccharides

Continued

TABLE 2  Polysaccharides potential against VBD, with respective alga sources, biological capacity, and mechanism of action—cont’d Active compound

Alga source

Biological capacity

Mode of action

Model/observations

Refs.

Lambdacarrageenan

Chondrus crispus

Antiviral (DEN-2 and DEN-3)

Inhibition of viral entry

Human myelomonocytic cell line U937 and human myelogenous erythroleukemic K562 cells/99% inhibition in virus production from cells infected with immune complexes

Piccini et al. (2020)

Iota/kappa/ nu-hybrid carrageenan

Meristiella gelidium

Antiviral (DEN-2 and DEN-3)

Not defined

Vero cell cultures

Tisher et al. (2006)

Sulfated galactans

Botryocladia occidentalis

Antimalarial/antiplasmodial

Direct binding of sulfate groups to RBC (host cell protection)

Plasmodium yoelii cultures and Balb/C female mice

Marques et al. (2016)

Ulvan

Ulva lactuca (Chlorophyta)

Antiviral (Japanese encephalitis virus, JEV)

Inhibition of viral mRNA and proteins synthesis/reduction of pro-inflammatory cytokines—in the brains of JEV-infected mice

Vero cells and glia cells of JEV-infected C3H/HeN mice (the survival rate significantly increased)

Chiu et al. (2012)

EPS/SPs

Caulerpa racemosa (Chlorophyta)

Antiviral (DEN-2 serotype)

Blockade in virus adsorption and replication

Vero cells culture

Pujol et al. (2012)

EPS/SPs

Grateloupia indica (Rhodophyta)

Antiviral (DEN-2 serotype)

Blockade in virus adsorption and replication

Vero cells culture

Pujol et al. (2012)

EPS/SPs

Porphyridium cruentum (microalga, Rhodophyta)

Antiviral (African swine fever virus)

Inhibition of virus replication

Vero cells culture (derived from the kidney of an African green monkey)

Fabregas et al. (1999)

TABLE 3  Pigments, proteins, and polyphenols potential against VBD, with respective alga sources, biological activity, and mechanism of action. Active compound

Alga source

Biological activity

Mode of action

Model/observations

Refs.

C-phycocyanin

Anabaena oryzae SOS13 Nostoc muscorum SOS14 Spirulina platensis SOS13 (Cyanophyta)

Antischistosomal/ antimolluscicidal

Not defined

Biomphalaria alexandrina cultures

Abd El-Ghany et al. (2018)

C-phycocyanin

Nostoc muscorum (Cyanophyta)

Antiviral/ antiplasmodial

Interference in hemozoin formation—binding of C-PC to ferriprotoporphyrin-IX

Plasmodium falciparum cultures (chloroquinesensitive and chloroquineresistant lines)

Pankaj et al. (2010)

Fucoxanthin

Sargassum heterophyllum (Phaeophyta)

Antiviral/ antiplasmodial

Possible related with its antioxidant properties

P. falciparum cultures (chloroquine-sensitive strain D10)

Afolayan et al. (2008)

Lectin (Cyanovirin-N)

Scytonema varium (Cyanophyta)

Antiviral (dengue and Zika virus)

Binding to the glycosylated protein E of virus /inhibition of viral attachment and membrane fusion to host membrane cells

Protein bioinformatics tools (viral molecular dynamics)

Siqueira et al. (2017) and Routhu et al. (2019)

Lectin (Griffithsin)

Griffithsia sp. (Rhodophyta)

Antiviral (JEV)

Binding to the glycoproteins of virus, alteration in viral conformation /inhibition of viral attachment and membrane fusion to host membrane cells

BHK-21 cells BALB/c mice/reduction virus titers in mouse brain on Day 4 post-infection

Ishag et al. (2013)

Pigment

Proteins

Continued

TABLE 3  Pigments, proteins, and polyphenols potential against VBD, with respective alga sources, biological activity, and mechanism of action—cont’d Active compound

Alga source

Biological activity

Mode of action

Model/observations

Refs.

β-tocopheryl hydroquinone δ-tocopheryl hydroquinone

Amphiroa crassa (Rhodophyta)

Antiviral/ antiplasmodial

Not defined

Not defined

Stout et al. (2010)

Ellagic acid Velutin

Padina boryana, Acanthophora spicifera

Antitrypanosomal/ antileishmanial

Not defined

Trypanosoma cruzi and Leishmania donovani amastigotes cultures

Hassan et al. (2021)

Polyphenols

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binding of C-PC to ferriprotoporphyrin-IX present in the digestion vacuole created by the Plasmodium falciparum in RBC. Interestingly, C-PC extracted from different cyanobacteria [Anabaena oryzae SOS13, Nostoc muscorum SOS14, and Spirulina platensis SOS13] was also studied as a new approach to control schistosomiasis by controlling the vector snail Biomphalaria alexandrina. All cyanobacteria presented molluscicidal activity, but Anabaena oryzae SOS13 stood out with the highest LC50 and LC90 (38.492 and 49.976 μg mL−1, respectively) with no signs of cytotoxicity against non-target organisms (Tilapia fish) (Abd El-Ghany et al., 2018). Fucoxanthin carotenoid is also well-known pigment by their important antioxidant, antiinflammatory, and antimalarial properties (D’Orazio et al., 2012). Fucoxanthin derived from organic extract of brown seaweed Sargassum heterophyllum was shown to exhibit promising antiplasmodial action. In this study, Afolayan et al. (2008) could demonstrate the highest antiplasmodial capacity of fucoxanthin when compared with other isolated compounds, namely sargaquinoic acid, sargahydroquinoic acid, and sargaquinal. The authors point out that the possible mechanism of action might be related with its antioxidant properties.

Proteins (lectins and griffithsin) Lectins: One important group of proteins isolated from alga, with important antiviral properties, are lectins. These are proteins widely distributed across prokaryotic and eukaryotic species, and in the case of algae/cyanobacteria have been proposed to be developed for antiviral treatment, in particular for glycosylated enveloped virus (Praseptiangga, 2015). Lectins possess monomeric structures with low molecular weight, have the particularity of reversibly binding, inhibit glycoproteins, and do not requiring metal ions for their biological activities (Rosales-Mendoza et al., 2020; Praseptiangga, 2015). Among the most relevant described, lectins are cyanovirin-C (CVN), isolated from the cyanobacterium Scytonema varium and with demonstrated potential against influenza virus, HIV, Ebola (Praseptiangga, 2015; Bokesch et  al., 2003), and possibly dengue and Zika virus. Siqueira et  al. (2017) have proven by bioinformatics tools that CVN can be a potential inhibitor of dengue’s viral action, because it interacts with the viral glycoprotein E, an important point of contact between the virus and host cells that mediates the viral attachment and entry by membrane fusion, as it happens with HIV and Ebola virus. Zika virus also uses glycosylation of its envelope and the protein E to interact with the host (Routhu et al., 2019), and can also be a possible target of CVN molecule (Table 3). Furthermore, lectins isolated from the red alga Griffithsia sp.—griffithsin (GRFT)—also demonstrated both in vitro and in vivo relevant antiviral action against Japanese encephalitis virus (JEV) infection with minimum host toxicity (Ishag et al., 2013; Lee, 2019). In the study of Ishag et al. (2013), in vitro data showed a significant inhibition of virus infection in BHK-21 cells at nanomolar concentrations (105 ng mL−1) with the interaction between GRFT and JEV

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virions. Balb/c mice treated with GRFT did not show in vivo toxicity; besides, 4 days postinfection and after GRFT treatment, a significant reduction of viral titers was observed in mouse brains (Table 3).

Polyphenols Polyphenols are secondary metabolites that include polyphenolic molecules including phenolic acids, flavonoids, isoflavonoids, stilbenes, lignans, or phenolic polymers (Galasso et al., 2019). The content and composition are quite variable from algae to algae. Such compounds present several bioactivities of interest including radical scavenging, antiinflammatory, antiallergic, antitumor, antiaging, antimicrobial, and antiviral (Levasseur et al., 2020; Galasso et al., 2019). Few studies have focused on polyphenols against the bioactivity against VBD (Stout et al., 2010; Hassan et al., 2021) as observed in Table 3. Two polyphenols β-tocopheryl hydroquinone and δ-tocopheryl hydroquinone isolated from the red alga Amphiroa crassa showed low plasmodial activity, but the authors demonstrate that by oxidizing the compound δ-tocopheryl hydroquinone obtaining a δ-tocopherylquinone, the antiplasmodial activity was increased more than 20-fold to an IC50 of 10 μM, suggesting the quinone essential for bioactivity tocopherol-related compounds (Stout et al., 2010). Other polyphenols found were ellagic acid and velutina, and the first isolated from the dichloromethane extract of Padina boryana and the second isolated from the ethanol extract of Acanthophora spicifera were screened for their antitrypanosomal and antileishmanial bioactivities. Both compounds were proven to be in highest content in the extracts of those algae with the highest antiprotozoal activity against Trypanosoma cruzi and Leishmani donovani (Hassan et al., 2021).

Other compounds—Secondary metabolites Cyanobacteria Several other compounds with VBD activity—including a series of secondary metabolites such as polyketides, toxins, lipopeptides, depsipeptides, peptides, macrolides, alkaloids, terpenes, among others—were mainly isolated from marine cyanobacteria (Khalifa et al., 2021). This is due to efficient cyanobacterial evolution strategies with competent chemical defenses specialized in a wide range of metabolite production. Several studies point out such diversity relate with a wide range of biological capacities including antibacterial, antifungal, immunosuppressive, anticancer, and antiinflammatory, but also antiplasmodial/ antimalarial, antileishmanial, antiviral, or antiprotozoal (see Table 4). Curiously, most of the isolated cyanobacterial compounds regarding the different classes of secondary metabolites above described were mainly outlined for antiplasmodial/antimalarial effects, and a quite few for their antileishmaniasis action. Hierridin C, a polyketide isolated from Cyanobium sp. (Leão et al., 2019), the

TABLE 4  Cyanobacterium secondary metabolites with biological capacity potential against VBD and their main mechanism of action. Active compound

Class of compounds

Alga source

Hierridin C

Polyketide

Cyanobium sp.

Kakeromamide B

Pentapeptide

Ulongamide A

Biological activity

Mode of action

Model/observations

Refs.

Antimalarial/ antiprotozoal

Not defined

Plasmodium falciparum cultures

Leão et al. (2019)

Moorea producens

Antimalarial/ antiprotozoal

Binding to actin-like proteins of P. falciparum, preventing parasite invasion of host cells

P. falciparum and P. berghei cultures/moderate activity against Plasmodium berghei liver stage

SweeneyJones et al. (2020)

Cyclic depsipeptide

Moorea producens

Antimalarial/ antiprotozoal

Not defined

P. falciparum and P. berghei cultures/moderate activity against P. berghei liver stage

SweeneyJones et al. (2020)

Lyngbyabellin A

Cyclic depsipeptide

Moorea producens

Antimalarial/ antiprotozoal

Binding to microfilaments of P. falciparum, preventing parasite invasion of host cells (nonspecific mechanism)

P. falciparum and P. berghei cultures/moderate activity against P. berghei liver stage/ high activity against P. falciparum intraerythrocytic stage

SweeneyJones et al. (2020) and Fathoni et al. (2020)

18E-lyngbyaloside C

Macrolides

Moorea producens

Antimalarial/ antiprotozoal

Not defined

P. falciparum and P. berghei cultures/moderate activity against P. berghei liver stage

SweeneyJones et al. (2020)

Lyngbyaloside

Macrolides

Moorea producens

Antimalarial/ antiprotozoal

Not defined

P. falciparum and P. berghei cultures/moderate activity against P. berghei liver stage

SweeneyJones et al. (2020) Continued

TABLE 4  Cyanobacterium secondary metabolites with biological capacity potential against VBD and their main mechanism of action—cont’d Class of compounds

Alga source

Biological activity

Lyngbyabellin G

Cyclic depsipeptide

Moorea producens

Carbamin A

Linear lipopeptide

Dragomabin

Active compound

Mode of action

Model/observations

Refs.

Antimalarial/ antiprotozoal

Binding to microfilaments of P. falciparum, preventing parasite invasion of host cells (nonspecific mechanism)

P. falciparum cultures/high activity against P. falciparum (intraerythrocytic stage)

Fathoni et al. (2020)

Lyngbya majuscula

Antimalarial/ antiprotozoal

Not defined

P. falciparum chloroquine-resistant strain (Indochina W2)

McPhail et al. (2007)

Linear lipopeptide

Lyngbya majuscula

Antimalarial/ antiprotozoal

Not defined

P. falciparum chloroquine-resistant strain (Indochina W2)

McPhail et al. (2007)

Dragonamide A

Linear lipopeptide

Lyngbya majuscula

Antimalarial/ antiprotozoal

Not defined

P. falciparum chloroquine-resistant strain (Indochina W2)

McPhail et al. (2007)

Dolastin 10

Peptide

Dolabella auricularia

Antimalarial/ antiprotozoal

Arrest of nuclear division and apparent disassembly of mitotic microtubular structures of the parasite

P. falciparum FCH5·C2 cultures/ high parasite inhibition

Fennell et al. (2003)

Dolastin 15

Peptide

Symploca sp.

Antimalarial/ antiprotozoal

Not defined

P. falciparum FCH5·C2 cultures/ high parasite inhibition

Fennell et al. (2003)

Gallinamide A

Depsipeptide

Schizothrix sp.

Antimalarial/ antiprotozoal

Not defined

P. falciparum chloroquine-resistant strain (Indochina W2)

Linington et al. (2010)

Ikoamine

Lipopeptide

Okeania sp.

Antimalarial/ antiprotozoal

Not defined

P. falciparum 3D7 line

Iwasaki et al. (2020)

Mabuniamide

Lipopetpide

Okeania sp.

Antimalarial/ antiprotozoal

Not defined

P. falciparum 3D7 line

Ozaki et al. (2019)

Companeramide

Cyclic depsipeptides

Leptolyngbya sp.

Antimalarial/ antiprotozoal

Not defined

P. falciparum strains D6, Dd2, and 7G8

Vining et al. (2015)

Venturamide A

Hexapeptide

Oscillatoria sp.

Antimalarial/ antiprotozoal

Not defined

P. falciparum chloroquine-resistant strain (Indochina W2)

Linington et al. (2007)

Hoshinoamides A and B

Lipopeptides

Caldora penicillata

Antimalarial/ antiprotozoal

Not defined

P. falciparum cultures/inhibition of parasites at intraerythrocytic stage

Iwasaki et al. (2018)

Lagunamide A and B

Cyclic depsipeptides

Lyngbya majuscula

Antimalarial/ antiprotozoal

Not defined

P. falciparum cultures

Tripathi et al. (2010)

Bastimolide A

Polyhydroxy macrolide

Okeania hirsuta

Antimalarial/ antiprotozoal

Not defined

P. falciparum strains TM90-C2A, TM90-C2B W2, TM91-C235

Shao et al. (2015)

Calothrixin A-B

Quinone

Calothrix sp.

Antimalarial/ antiprotozoal

Not defined

P. falciparum strain FAF6

Rickards et al. (1999)

Almiramide A-C

Linear peptides

Lyngbya majuscula

Antileishmanial

Not defined

Leishmania donovani cultures

Sanchez et al. (2010)

Dragonamide A and E

Linear lipopeptide

Lyngbya majuscula

Antileishmanial

Not defined

Axenic amastigotes of L. donovani

Balunas et al. (2010)

Hermabide B

Linear lipopeptide

Lyngbya majuscula

Antileishmanial

Not defined

Axenic amastigotes L. donovani cultures

Balunas et al. (2010)

Viridamides A and B

Lipopeptides

Oscillatoria nigro-viridis

Antileishmanial/ antitrypanosomal

Not defined

Leishmania mexicana and Trypanosoma cruzi cultures

Simmons et al. (2008)

Iheyamide A

Linear peptides

Dapis sp.

Antitrypanosomal

Not defined

T. brucei rhodesiense strains IL150118 T. brucei brucei strain 221

Kurisawa et al. (2020)

Aplysiatoxin-related compounds

Polyketide

Trichodesmium erythraeum

Antiviral/ antichikungunya

Possible interference in the viral replication machinery after infection

BHK21 (baby hamster kidney) cells

Gupta et al. (2014)

358  Natural products in vector-borne disease management

cyclic peptides kakeromamide B and ulongamide A, lyngbyabellin A and G, the macrolides 18E-lyngbyaloside C, and lyngbyaloside isolated from Moorea producens (Sweeney-Jones et al., 2020) were recently reported as having relevant Plasmodium falciparum disruption activities. The kakeromamide B was hypothesized to bind with actin-like protein of Plasmodium falciparum and restrict parasite invasion in host cells (Sweeney-Jones et al., 2020). Other types of compounds such as linear lipopeptides, such as carbamin A, dragomabin, and dragonamides A, isolated from a Lyngbya majuscule also presented relevant antimalarial activities (i.e., IC50 = 4.3, 6.0 and 7.7 μM, respectively) (McPhail et al., 2007). Other isolated compounds from cyanobacteria presenting promising antiplasmodial activity against different types and stages of malaria include dolastin 10, dolastin 15 (Fennell et  al., 2003), gallinamide A (Linington et  al., 2010) or venturamide A (Linington et  al., 2007), ikoamide (Iwasaki et  al., 2020), companeramide (Vining et al., 2015), lagunamides A-B (Tripathi et al., 2010), mabuniamide (Ozaki et al., 2019), bastimolide A (Shao et al., 2015), and calothrixin A-B (Rickards et al., 1999). In addition, several other compounds were identified as promising drug leads to leishmaniasis and include dragonamide A and E and hermabide B isolated from Lyngbya species (Balunas et  al., 2010) and viridamide A (Simmons et  al., 2008). Almiramids A-C were also identified as lipopeptides revealing potent antiparasitic action against several genus of leishmania (Sanchez et al., 2010). In other study, Gupta et  al. (2014) isolated a novel class of aplysiatoxinrelated compounds (debromoaplysiatoxin and 3-methoxydebromoaplysiatoxin) from Trichodesmium erythraeum, in which strong antiviral activities were detected against the chikungunya virus (i.e., IC50 = 1.3 and 2.7 μM, respectively), with minimal concentration toxicity against host cells (baby hamster kidney cells). Regarding antitrypanosomal activities, iheyamides A isolated from Dapis sp. presented moderate action against Trypanosoma brucei rhodesiense and Trypanosoma brucei brucei (IC50 = 1.5 μM).

Macroalgae Several secondary metabolites and compounds isolated from marine macroalgae such as halogenated compounds (i.e., monoterpenes) (Afolayan et al., 2009; Teixeira et al., 2019), triterpenes, diterpenes (Teixeira et al., 2019; Lin et al., 2010; Gallé et al., 2013; Soares et al., 2016; de Sousa et al., 2017), polyphenols, acetogenins, among others, were also described with potential as drug leads against VBD (Torres et al., 2014). Indeed, halogenated compounds, terpenoids, and acetogenins from genera Bifurcaria, Laurencia, Dictyota, and Canistrocarpus were described as possessing important antiplasmodial, leishmanial, and/or trypanocidal action (Torres et  al., 2014; Gallé et  al., 2013; de Sousa et  al., 2017). For instance, Gallé et  al. (2013) showed that a French

Algae for vector-borne disease management  Chapter | 14  359

brown alga Bifurcaria bifurcata ethyl acetate extracts denote strong trypanosomal activity (IC50 = 0.53 μg mL−1). Eleganolone was identified in such extract in higher quantities, despite these authors have shown a mild action against Trypanosoma brucei rhodesiense trypomastigotes, while it has high selectivity against Plasmodium falciparum parasites in erythrocytic stages. It is suggested that trypanocidal activity of the extract may be due to synergistic effect of other minor compounds (i.e., oxygenated diterpenoids) separated during the extract fractionation (Gallé et al., 2013). Elatol, a sesquiterpene isolated from a Brazilian strain of a red seaweed Laurencia dendroidea, was reported to exhibit a dose-dependent effect against the epimastigote, trypomastigote, and amastigote forms of Trypanosoma cruzi, without any signs of cytotoxicity against mammalian cells or hemolytic effects in RBC. Besides, it was observed better activity against trypomastigote (IC50 = 1.38 μM) and intracellular amastigote forms (IC50 = 1.01 μM) (the main forms present in the host cells) than the reference drug benznidazole (IC50 = 7.8 μM) (Veiga-Santos et al., 2010; Desoti et al., 2012). This compound proved to have antileishmanial activity against L. amazonensis, with very low level of cytotoxicity (Da Silva Machado et al., 2011). Other compound isolated from Laurencia dendroidea is the sesquiterpene of interest is obtusol with activity against L. amazonensis (IC50 = 6.2 μM—promastigotes; IC50 = 3.1 μM— amastigotes). Soares et  al. (2016) also showed the antileishmanial activity (intracellular amastigotes) of diterpene dolabelladienetriol isolated from the Dictyota pfaffii brown alga in tandem with antiviral activity against HIV-1 virus. The authors demonstrate that dolabelladienetriol is able to hold L. amazonensis action by modulating host macrophage activity by inhibiting NO, TGF-β, and TNF-α production. Besides, the authors proved HIV-1 virus exacerbate the parasitic load in the host macrophage infection; thus, such compound seems promising as antiviral drug either in isolated cases or in cases associated with HIV-1 (Torres et al., 2014; Soares et al., 2012). Other examples show that bromophycolides and diterpene macrolides, in Callophycus serratus extracts, have relevant activity against the Plasmodium falciparum (Lin et  al., 2010; Lane et al., 2009). Table 5 depicts the relevant isolated compounds from macroalgae against VBD.

Alga-based extracts and fractions The random exploitation of extracts obtained from several species of marine algae is important for future research regarding the isolation of main bioactive compound and their use as potential drug, and thus, medical application regarding VBD. Several studies have also claimed the relevance of crude algabased extracts and purified fractions regarding their potential against VBD, namely their antiviral and antiprotozoal activity both in vitro and in vivo. For instance, Orhan et al. (2006) evaluated the antiprotozoal activity and the inhibition of FabI, a key enzyme of Plasmodium falciparum fatty acid ­biosynthesis

TABLE 5  Macroalgae secondary metabolites with potential against VBD and their main mechanism of action. Class of compounds

Alga source

Bromophycolide S

Diterpenebenzoate macrolide

Callophycus serratus (Rhodophyta)

Halogenated compounds

(Mono) terpenes

Eleganolone

Active compound

Biological activity

Mode of action

Model/observations

Refs.

Antimalarial/ antiplasmodial

Not defined

Plasmodium falciparum cultures/moderate activity parasite

Lin et al. (2010)

Plocamium cornutum (Rhodophyta)

Antimalarial/ antiplasmodial

Not defined

P. falciparum D10 strain (asexual erythrocyte stage)

Afolayan et al. (2009)

Diterpene

Bifurcaria bifurcate (Phaeophyta)

Antimalarial/ antiplasmodial/ antitrypanosomal

Not defined

P. falciparum chloroquineand pyrimethamineresistant K1 strain Trypanosoma brucei rhodesiense trypomastigotes cultures/ selective against P. falciparum and mild trypanosomal activity

Gallé et al. (2013)

Elatol

Sesquiterpene

Laurencia dendroidea (Rhodophyta)

Antitrypanosomal

Possible interference in parasite mitochondrial function (membrane and DNA disintegration, formation of mitochondrial reactive oxygen species (ROS))

Trypanosoma cruzi trypomastigotes cultures

Veiga-Santos et al. (2010) and Desoti et al. (2012)

Atomaric acid

Meroditerpene

Stypopodium zonale (Phaeophyta)

Antitrypanosomal

Possible action in redox metabolism; modulation of NO production and elicitation of ROS in infected host macrophage

T. cruzi amastigotes and trypomastigotes/vero cells/ high trypanosomicidal effects/high cytotoxicity against Vero cells

Teixeira et al. (2019)

5-chloro-1-(E)chlorovinyl-2,4dibromo-1,5dimethylcyclohexane

Halogenated diterpenes

Plocamium brasiliense

Antitrypanosomal

Possible action in redox metabolism; modulation of NO production and elicitation of ROS in infected host macrophage

T. cruzi amastigotes and trypomastigotes/vero cells/ moderate trypanosomicidal effects/low cytotoxicity against Vero cells

Teixeira et al. (2019)

Obtusol

Sesquiterpene

Laurencia dendroidea (Rhodophyta)

Antileishmanial

Not defined

Leishmania amazonensis promastigotes and amastigotes

Da Silva Machado et al. (2011)

Atomaric acid

Meroditerpene

Stypopodium zonale (Phaeophyta)

Antileishmanial

Possible action in redox metabolism; modulation of NO production and elicitation of ROS in infected host macrophage

Promastigotes L. amazonensis promastigotes and intracellular amastigotes

Soares et al. (2016)

(3R)- and (3S)tetraprenyltoluquinol 47

Meroditerpene

Cystoseira baccata (Phaeophyta)

Antileishmanial

Induction of cytoplasmatic vacuolization and interference in mitochondrial function (membrane disruption)

Leishmania infantum promastigotes and intracellular amastigotes

de Sousa et al. (2017)

4-Acetoxydolastane

Diterpene

Canistrocarpus cervicornis (Phaeophyta)

Antileishmanial

Induction of cytoplasmatic vacuolization and interference in mitochondrial function

L. amazonensis promastigote, axenic amastigote, and intracellular amastigotes

Dos Santos et al. (2011)

Dolabelladienetriol

Diterpene

Dictyota pfaffii

Antileishmanial

Modulation of host macrophage activity by inhibiting NO, TGF-b, and TNF-a production (mediators in killing parasites)

L. amazonensis intracellular amastigotes, promastigotes

Soares et al. (2012)

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of ­several marine algae extracts including Dictyota dichotoma, Halopteris scoparia, Posidonia oceanica, Scinaia furcellata, Sargassum natans, and Ulva lactuca. All extracts possessed antileishmanial activity, except for Halopteris scoparia. Ulva lactuca and Posidonia oceanica had the greatest leishmanicidal activity (IC50 = 5.9 and 8.0 μg mL−1, respectively). Antitrypanosomal activity was also demonstrated for all extracts, being Sargassum natans the most active one (IC50 = 7.4 μg mL−1). Concerning antimalarial effects, extracts of Ulva lactuca demonstrated to have efficient inhibition of enzyme FabI with no signs of mammalian cytotoxic effects. In a more recent work, Setyowati et al. (2019) showed that Spirulina platensis and Skeletonema costatum extracts have potential to disrupt the activity of PfMQO—Plasmodium falciparum enzyme malate quinone oxireductase—an enzyme that plays a role in the electron transport process in Plasmodium falciparum mitochondria. Wulandari et al. (2018) evaluate the antimalarial activity of Spirulina formulas, namely the crude extracts, a commercial available capsule, and an alkaloid fraction. All tested formulas possess activity against Plasmodium falciparum with the capsule obtaining the highest activity (IC50 = 2.16 μg mL−1). The authors hypothesize that antimalarial capacity of Spirulina capsules and crude extract is a result of synergistic effect of several active compounds including alkaloids, steroids, and saponin. Besides, they theorize that such extracts can act as chloroquine drug that disrupts the formation of hemozoin crystals—a by-product of the digestion of hemoglobin present in RBC by Plasmodium—that avoid toxicity of free heme derived from the erythrocyte digestion and increase the pH of the digestive vacuole. Several seaweed extracts showed to be potentially relevant against leishmaniasis (Tchokouaha Yamthe et  al., 2017; Fouladvand et  al., 2011; FreilePelegrin et al., 2008). Freile-Pelegrin et al. (2008) studied different aqueous and organic extracts of 27 species of marine algae from the Mexico Gulf, including red, brown, and green algae for their in  vitro capacity to inhibit Leishmania mexicana promastigote forms. Laurencia microcladia (Rhodophyta), Dictyota caribaea, Turbinaria turbinata, and Lobophora variegata (Phaeophyta) presented the most promising results with values of LC50 ranging from 10.9 to 49.9 g mL−1, with little signs of cytotoxicity against brine shrimp. In a similar study, Fouladvand et  al. (2011), with cold and hot water extracts of four seaweeds from Persian Gulf, have shown antileishmanial potential. Caulerpa sertularioides (Chlorophyta), Gracilaria corticata, Gracilaria salicornia (Rhodophyta), and Sargassum oligocystum (Phaeophyta) were the chosen species, and the best IC50 presented were for the red alga Gracilaria corticata for both hot and cold aqueous extracts (IC50 = 38 and 65 μg mL−1, respectively). In another work, Lakshmi et al. (2014) showed that Chondrococcus hornemanni red alga crude ethanol extract presented 88% inhibition against Leishmania donovani cultures. The fractionation with the same extract into hexane, chloroform, and n-­butanol soluble and insoluble fractions showed that n-butanol soluble fraction was the most effective (>78%) against promastigotes and intracellular amastigotes (75.8%) in vitro. In addition, crude ethanol extract has

Algae for vector-borne disease management  Chapter | 14  363

shown ­considerably good efficacy (75.38%) at the dose level of 250 mg kg−1 over 5 days. Other study by de Felício et  al. (2010), dichloromethane and n-­ hexane fractions (from MeOH:H2O (9:1) extracts) of red alga Bostrychia tenella (J. Agardh), presented antitrypanosomal and leishmanial potential. In the work of Spavieri et al. (2008), growth inhibitory activity against three parasitic protozoa (Trypanosoma brucei rhodesiense, Trypanosoma cruzi, and Leishmania donovani) of crude extracts (isopropyl alcohol) of four different green marine alga (Cladophora rupestris, Codium fragile ssp. tomentosoides, Ulva intestinalis, and Ulva lactuca) were also evaluated. All extracts were active against Trypanosoma brucei rhodesiense, with Cladophora rupestris being the most potent one (IC50 = 3.7 μg ml−1). Moderate trypanocidal effect of Cladophora rupestris and Ulva lactuca against Trypanosoma cruzi (IC50 = 80.8 and 34.9 μg mL−1, respectively) was observed. All four extracts showed antileishmanial activity, with no signs of cytotoxicity toward skeletal muscle myoblasts L6 cells, indicating specific antiprotozoal activity. In addition, the antifilarial activity of red alga Botryocladia leptopoda was described against human lymphatic filarial parasite Brugia malayi in rodents; but in spite of their low efficacy against worm adults in mice (after 5 days treatment with 100 and 200 mg kg−1), substantial proportions (71.05% and 68.6%, respectively) of adult female worms were found to be sterilized at these dose levels (Lakshmi et al., 2004). In another study, the potential of blue-green alga Aphanizomenon flos aquae was demonstrated against mice infected with Schistosoma mansoni, and their immunomodulatory and antioxidant effects were crucial to significantly inhibit liver damage (which usually accompanies schistosomiasis disease). Results point out to a reduction in worm burden in the liver and intestine (Mohamed et al., 2014). Microalgae ethanolic and methanolic extracts including Chlamydomonas reinhardtii, Scenedesmus obliquus, and Tetraselmis suecica also proved their potential with antitrypanosomal activity against Trypanosoma cruzi. In addition, Chlamydomonas reinhardtii ethanolic extracts were also to enhance the activity of the conventional antichagasic drug nifurtimox (Veas et al., 2020). Table 6 presents the main studies with algal extracts and fraction presenting antiviral and antiprotozoal effects.

Alga-based vaccine strategies Apart from the potential of alga-derived compounds, alga-based vaccines represent an interesting therapy approach for immune response development when dealing with VBD invasive pathogens which can lead to chronic infection. Algal species, in particular microalgae, can be explored as host systems for the production of recombinant pharmaceuticals, in particular the production of heterologous proteins or antigens that could be used for vaccine production. This notion has emerged because algae are genetically tractable, can provide

TABLE 6  Algal extracts and fractions with potential against VBD and their main mechanism of action. Active compound

Alga source

Biological activity

Mode of action

Model/observations

Refs.

Alga extract (ethanol)

Dictyota dichotoma Halopteris scoparia Posidonia oceanica Scinaia furcellata Sargassum natans Ulva lactuca

Antitrypanosomal Antileishmanial Antimalarial

Not defined

Trypanosoma brucei rhodesiense, Trypanosoma cruzei Leishmania donovani Plasmodium falciparum cultures

Orhan et al. (2006)

Alga extract (isopropyl alcohol)

Cladophora rupestris Codium fragile ssp. Tomentosoides Ulva intestinalis Ulva lactuca

Antitrypanosomal Antileishmanial

Not defined

T. brucei rhodesiense T. cruzei trypomastigotes cultures L. donovani axenic amastigotes cultures

Spavieri et al. (2008)

Alga extract (ethyl acetate)

Mastocarpus stellatus

Antimalarial/ antiplasmodial

Interference with nonselective metabolic pathways

P. falciparum cultures

VonthronSénécheau et al. (2011)

Alga extract (ethanol)

Spirulina platensis (Cyanophyta) Skeletonema costatum (Diatom)

Antimalarial/ antiplasmodial

Not defined

In vitro assay/inhibition of PfMQO mitochondrial enzyme

Setyowati et al. (2019)

Alga extract/capsule powder (ethanol)/alkaloid fraction (dichloromethane: chloroform:hexane)

Spirulina platensis (Cyanophyta)

Antimalarial/ antiplasmodial

Interference in hemozoin formation/increase pH in digestive vacuole

Plasmodium cultures

Wulandari et al. (2018)

Alga extract (dimethyl sulfoxide)

Laurencia microcladia (Rhodophyta) Dictyota caribaea Turbinaria turbinata Lobophora variegata (Phaeophyta)

Antileishmanial

Not defined

Leishmania mexicana promastigotes cultures

Freile-Pelegrin et al. (2008)

Algae extracts/type

Alga extract (hot and cold water)

Caulerpa sertularioides (Chlorophyta) Gracilaria corticata Gracilaria salicornia (Rhodophyta) Sargassum oligocystum (Phaeophyta)

Antileishmanial

Not defined

Leishmania sp. promastigotes cultures

Fouladvand et al. (2011)

Alga extract (hexane and dichloromethane)

Asparagopsis taxiformis Asparagopsis armata (Rhodophyta)

Antileishmanial

Not defined

L. donovani promastigotes cultures

Genovese et al. (2009)

Alga extract (ethanol crude extract + n-butanol soluble extract)

Chondrococcus hornemanni (Rhodophyta)

Antileishmanial

Not defined

L. donovani promastigotes cultures/J774A.1 macrophages/hamsters

Lakshmi et al. (2014)

Alga extract (n-hexane purified fraction)

Bostrychia tenella (Rhodophyta)

Antitrypanosomal/ antileishmanial

Not defined

T. cruzi trypomastigotes cultures L. amazonensis promastigote cultures

de Felício et al. (2010)

Alga extract (ethanolic and hydroethanolic)

Bryothamnion triquetrum Ceramium nitens Halimeda opuntia

Antileishmanial

Not defined

L. amazonensis promastigotes cultures

Parra et al. (2012)

Alga extract (n-hexane purified fraction)

Botryocladia leptopoda (Rhodophyta)

Antifilarial

Not defined

Brugia malayi maintained in rodents/adult female worms were found to be sterilized

Lakshmi et al. (2004)

Alga tablet powder

Aphanizomenon flos aquae (Cyanophyta)

Antischistosomal/ immunomodulatory

Not defined

Schistosoma mansoni infected mice/inhibition of liver damage

Mohamed et al. (2014)

Alga extract (crude ethanolic and methanolic extracts)

Chlamydomonas reinhardtii Scenedesmus obliquus Tetraselmis suecica (microalgae, Chlorophyta)

Antitrypanosomal

Not defined

T. cruzi trypomastigotes cultures

Veas et al. (2020)

Continued

TABLE 6  Algal extracts and fractions with potential against VBD and their main mechanism of action—cont’d Active compound

Alga source

Biological activity

Mode of action

Model/observations

Refs.

Alga extract (ethylacetate fraction)

Sargassum swartzii (Phaeophyta) Chondria dasyphylla (Rhodophyta)

Antimalarial/ larvicidal effect

Not defined

Anopheles stephensi larvae

Khanavi et al. (2011)

Alga extract (methanol crude extract)

Lobophora variegata (Phaeophyta)

Antidengue/larvicidal effect

Not defined

Aedes aegypti larvae

Manilal et al. (2011)

Alga extract (purified ethanolic fraction)

Champia parvula C. agardh (Rhodophyta)

Antidengue/larvicidal effect

Interference in carboxylesterase (α and β), GST, and CYP450 enzyme level in both III and IV instar larvae

Aedes aegypti larvae

Yogarajalakshmi et al. (2020)

Alga extract (chloroform crude extract:purified hexadecanoic acid fraction)

Chlorella vulgaris (microalgae, Chlorophyta)

Antidengue/larvicidal effect

Possible binding to intracellular macromolecules and inhibition of normal physiological functions

Aedes aegypti larvae/ hyperplasia of gut epithelial cells in larvae, broken membranes, and cytoplasmic masses

Sigamani et al. (2020)

Genetically transformed alga (RNAi)

Chlamydomonas reinhardtii Chlorella sp. (microalgae, Chlorophyta)

Antidengue/larvicidal effect

Inhibition of 3-hydroxykynureninand transaminase by algabased RNAi

Aedes aegypti larvae and adults/larvae integumentary systems and gut disruption (Chlamydomonas)/high rates of survival rates in adulthood (100%) (Chlamydomonas) Mortality rates up to 43% in larvae (Chlorella)

Fei et al. (2021)

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new low-cost production systems, with fast production under controlled conditions, and can provide a safety system—as many several species do not produce dangerous toxins or pathogens to human health (except some cyanobacteria) (Rosales-Mendoza et al., 2020; Gregory et al., 2012). So, focusing on VBD, several antigens and other biopharmaceuticals have been expressed in algal systems in particular in Chlamydomonas reinhardtii for Plasmodium falciparum (Gregory et  al., 2012; Dauvillée et  al., 2010), and Schizochytrium sp. (a photosynthetic heterokont protist) for Zika virus (Márquez-Escobar et al., 2018) toward vaccine development. A study performed by Dauvillée et al. (2010) has described genetically engineered starch granules containing plasmodial vaccine candidate antigens produced by the green microalga Chlamydomonas reinhardtii. They achieved fused granule-bound starch synthase (GBSS), the major protein associated to the starch matrix in all starchaccumulating plants and algae with C-terminal domains from the Plasmodium berghei Apical Major Antigen AMA1, or Major surface Protein MSP1. Mice were vaccinated both intraperitoneally and orally with the engineered starch particles (both co-delivered with help of an adjuvant or immune enhancer) and both strategies succeeded when compared to a lethal inoculum of Plasmodium berghei, by significantly reducing the load of parasite in rodent erythrocytes and prolonging their life span, besides having a complete infection recovery for the intraperitoneal delivery. The authors also demonstrated the correlation of the inhibition of the most virulent plasmodial species—the asexual development of Plasmodium falciparum in erythrocytes with the above findings. In another approach, Gregory et al. (2012) (Bokesch et al., 2003) showed the algal chloroplasts of Chlamydomonas reinhardtii were able to produce Plasmodium falciparum surface protein 25 (Pfs25) and 28 (Pfs28), both malaria transmission-blocking vaccine candidates. The transmission-blocking vaccines (TBVs) envisage combination of drug-based therapies which are based in the prevention of the spread of disease within the vector (i.e., malaria) (Jones et al., 2013). TBV can be developed against surface protein antigens expressed during parasite reproduction in mosquito; thus, when mosquito ingests blood from a vaccinated individual/mosquito infected with Plasmodium parasite, the antibodies generated over vaccination are expressed and prevent the development of later stages of the disease. Thus, when proteins Pfs25 and Pfs28 are recognized by antibodies, they are able to disrupt the sexual development of parasites in the mosquito midgut, thus preventing the transmission to humans. Such proteins are extremely difficult to reproduce in traditional recombinant systems (i.e., Escherichia coli), because their domains are structurally complex (i.e., repeated domains) and do not have glycosylated domains, as in eukaryotic expression systems (i.e., Saccharomyces cerevisiae). This study was the first recombinant system to successfully produce unmodified and aglycosylated Pfs25 or Pfs28 proteins, which were demonstrated to elicit antibodies in mice and able to recognize the native proteins of Plasmodium falciparum sexual stage lysates. Besides, Pfs25 was able to reduce oocysts in mosquito midguts,

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thus preventing the potential transmission of malaria to the human host; this is possible related with the expression of Pfs25 in the earlier targeted parasitic form (Gregory et al., 2012). Another effort focused in the Pfs48/45 candidates, which can also act as malaria transmission-blocking antibodies. By using Chlamydomonas reinhardtii chloroplast, the authors established the expression of one important domain, the C-terminal region of Pfs48/45, which exhibits the antigenic behavior. In another study, Jones et  al. (2013) could produce a new vaccine candidate against ZIKA virus called ZK using the green microalga Schizochytrium sp. This algae-made ZK protein was constructed as chimeric protein based on a β-subunit of Escherichia coli enterotoxin along with 3 epitopes from Zika virus envelope glycoprotein; the results showed a significant elicitation of humoral responses, namely system (IgG) and mucosal (IgA) immunity responses in Balb/c mice upon oral administration; subcutaneous immunization was not so relevant as in the oral vaccination. More, with the arising of new genetic editing technologies such as CRISPRCas 9 (clustered regularly interspaced short palindromic repeats (CRISPR)associated proteins) system could be an interesting alternative for gene modification and development of recombinant vaccines. This technology is also particularly pertinent because the production of secondary metabolites could be based on the modification of metabolic pathways to direct the metabolic flow to a specific product of interest (Rosales-Mendoza et al., 2020).

Alga-based larvicidal strategy Another common approach to managing VBD is the chemical control of the vectors, in particular when mosquitoes. Chemical methods, in particular the use of insecticides or larvicides, have been part of vector program control (i.e., Aedes aegypti). Yet, the use of such chemical substances can lead to vector resistance, besides they have enormous environmental impacts because they are toxic to fish and other nontarget organisms. Algae have been emerged as a potential interesting solution, as their extracts exhibit important larvicidal effects without the environmental impact and toxicity when compared to chemical substances. Several studies have demonstrated that alga extracts have relevant larvacidal effects toward the vectors of transmission of VBD (Khanavi et al., 2011; Manilal et al., 2011; Yogarajalakshmi et al., 2020; Sigamani et  al., 2020). For instance, macroalgae Sargassum swartzii (Phaeophyta) and Chondria dasyphylla (Rhodophyta) ethanolic extracts denoted a mortality rate of 96 and 95%, respectively, against Anopheles stephensi larvae (one of the vectors of malaria) (Khanavi et al., 2011). Similarly, Manilal et al. (2011) also investigated the comparative larvacidal effect between seven marine algae in 2nd larvae stages of Aedes aegypti (vector of dengue, malaria). Their effectiveness of larvae mortality was ranked from the strongest to the weakest as follows: Lobophora variegate (Phaeophyceae), Spatoglossum asperum

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(Phaeophyceae), Stoechospermum marginatum (Phaeophyceae), Sargassum wightii (Phaeophyceae), Acrosiphonia orientalis (Chlorophyta), Centroceras clavulatum (Rhodophyta), and Padina tetrastromatica (Phaeophyceae). In a more recent study, Yogarajalakshmi et  al. (2020) proved the larvicidal action of red marine algae Champia parvula (C. agardh) against the dengue mosquito vector Aedes aegypti. They demonstrated lethal dose of 100 ppm displayed relevant mortality across the 2nd and 3rd instars larva stages, with 98% and 97% mortality rates, respectively. In addition, they could observe dengue larva physiological alterations in their chief detoxifying enzymes (in sublethal doses was demonstrated significant reduction in the rate of α and β carboxylesterase and elevated activity of GST and CYP450 digestive enzymes in dose-dependent manner), which are important biomarkers of resistance. Such enzyme alterations can lead to the impairment of growth and metabolism imbalance on mosquito vector. Sigamani et al. (2020) also demonstrated the larvicidal potential of microalga Chlorella sp. extracts against dengue vector. The study revealed that chloroform extracts possessed effective larvicidal effect against 3rd instar Aedes aegypti larvae, with more than 90% of mortality rates by an exposure time of 24 h (IC50 = 159.20 ppm). More, the purification of Chlorella chloroform extracts helped to enhance the larvicidal effect, and shown they are particularly rich in hexadecanoic acid or palmitic acid (fatty acid). Other secondary metabolites were found such as β-sitosterol acetate or propionic acid, that single or combined were suggested to have synergistic upon larvacidal effect upon Aedes aegypti. In a distinct strategy, larvicidal effect was obtained not by extracts or pure extract fractions, but by a genetic-guided approach, namely the expression of ribonucleic acid interference (RNAi) to block the expression of specific enzymes fundamental in mosquito catabolism. This strategy is based on the use of RNAi to mediate the degradation of specific messenger RNA, and thus, preventing viral propagation in mosquitoes. Fei et al. (2021) expressed dsRNA in Chlamydomonas reinhardtii and Chlorella sp. targeting 3­ -hydroxykynurenine transaminase (3-HKT), an enzyme that catalyzes the transamination of ­3-hydroxykynurenine (3-HK) to xanthurenic acid (XA) in the tryptophan catabolism pathway. The 3-HK is a highly reactive intermediate, which will oxidize under normal physiological conditions and produce reactive oxygen species (ROS) that may kill the insects. The transgenic algae were used to feed Aedes aegypti mosquito larvae and adults, and the results showed that RNAi expressed in Chlamydomonas caused severe damages to the integumentary system and midguts with a mortality rates of 60%–100% in small-scale tests (groups of 10 larvae), and the survival rate was 0% in the large-scale testes (group of 300 individuals). For Chlorella sp., the mortality rates for larvae ranged from 6.7% to 43% to that fed with wild-type Chlorella. Such findings suggest a technology microalgae RNAi-based as a way to control mosquito populations which could be integrated in vector control programs (Fei et al., 2021).

370  Natural products in vector-borne disease management

Challenges and perspectives Alga are clearly important biotechnological platforms to be explored to combat VBD. Algal extracts and their derivative compounds such as polysaccharides, pigments, proteins, and polyphenols, besides their newly discovered secondary metabolites, have been shown to have important antitrypanosomal, antiprotozoal, and antimalarial properties and thus may have an important role in the development of new drug leads to fight VBD and improve therapies with toxic substances and fill treatment gaps in VBD. Algae possess a wide physiological diversity and distribution, because they are mainly photosynthetic which seems to be an interesting, sustainable, and relatively low-cost source to explore metabolites above described. Although the discovery of new compounds is a relatively new research field, most of those deserve a more intrinsic evaluation to generate solutions in a straightforward manner. On the one hand, it is important to screen the algal species with more potential to the production of certain metabolites against VBD; but it is important that such biological systems can be optimized and upscaled properly within a multidisciplinary approach (i.e., biology, physiology, engineering, etc.). Thus, strain selection, choice of the most adequate (photo)bioreactor, cultivation conditions, biomass downstream processing, and metabolite purification have to be addressed. Only following this path, the production of natural products from algae, in particular toward new VBD therapies, will be cost-effective. This can also contribute toward a more efficient synthesis and resolve the existing problems of chemical isolation, because several of the metabolites reported as being VBD agents—in particular the secondary metabolites—are produced in really low yields. This may hamper not only deeper fundamental studies on algal metabolite bioactivities, and in a more advanced stages may compromise preclinical or clinical trials. Low yields also can be a problem regarding the production of vaccines and antigens for VBD that will use (micro)alga as platform and delivery systems. Thus, the use of genetic tools and genetic engineering will be a probable solution to overcome such issue. This approach may help to increase target compounds quantities by improving their biochemical and metabolic pathways. As is the case of antigen production, the introduction of multigenic traits or complete biochemical pathways can be introduced by development of transformation and expression strategies that will guarantee the genetic stability, protein targeting to specific organelles, or even high secretion (Rosales-Mendoza et  al., 2020). Established expression techniques for target biopharmaceutical production include expression in the algal chloroplast or nucleus, which till now was optimized for microalga species such as the microalga Chlamydomonas (Rosales-Mendoza, 2013) and Schizochytrium. One of the main challenges is the low-protein yields, which many groups of research are trying to overcome by developing optimized expression strategy approaches. In this regard, those improvements include the generation of mutant high-performance strains with

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improved gene transgene expression at nuclear level, besides the amplification of signal peptides to allow efficient secretion of recombinant proteins. Several other strategies are promising such as the inclusion of inducible expression systems (i.e., chloroplast) to separate the growth phase and the expression phase, in order to maximize the target biopharmaceutical production, or even the inclusion of viral plasmids that lead to the generation of replicons and enhance the production of proteins. Several new genetic approaches like the use of new edition techniques of DNA as CRISPR-Cas 9 are also promising techniques in these regards (Rosales-Mendoza et al., 2020).

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Algae for vector-borne disease management  Chapter | 14  377 Spavieri, J., Kaiser, M., Casey, R., Hingley-Wilson, S., Lalvani, A., Blunden, G., Tasdemir, D., 2008. Antiprotozoal, antimycobacterial and cytotoxic potential of some British green algae. Phyther. Res. 22 (4), 544–549. Stout, E.P., Prudhomme, J., Le Roch, K., Fairchild, C.R., Franzblau, S.G., Aalbersberg, W., Hay, M.E., Kubanek, J., 2010. Unusual antimalarial meroditerpenes from tropical red macroalgae. Bioorg. Med. Chem. Lett. 20 (19), 5662–5665. Sweeney-Jones, A.M., Gagaring, K., Antonova-Koch, J., Zhou, H., Mojib, N., Soapi, K., Skolnick, J., McNamara, C.W., Zhou, H., Kubanek, J., 2020. Antimalarial peptide and polyketide natural products from the Fijian marine cyanobacterium Moorea producens. Mar. Drugs 18 (3), 167. Talarico, L.B., Damonte, E.B., 2007. Interference in dengue virus adsorption and uncoating by carrageenans. Virology 363 (2), 473–485. Talarico, L.B., Pujol, C.A., Zibetti, R.G.M., Faría, P.C.S., Noseda, M.D., Duarte, M.E.R., et  al., 2005. The antiviral activity of sulfated polysaccharides against dengue virus is dependent on virus serotype and host cell. Antivir. Res. 66 (2–3), 103–110. Tan, L.T., 2007. Bioactive natural products from marine cyanobacteria for drug discovery. Phytochemistry 68 (7), 954–979. Tan, C.P., Hou, Y.H., 2014. First evidence for the anti-inflammatory activity of fucoxanthin in highfat-diet-induced obesity in mice and the antioxidant functions in PC12 cells. Inflammation 37 (2), 443–450. Tchokouaha Yamthe, L.R., Appiah-Opong, R., Tsouh Fokou, P.V., Tsabang, N., Fekam Boyom, F., Nyarko, A.K., et al., 2017. Marine algae as source of novel antileishmanial drugs: a review. Mar. Drugs 15 (11), 1–28. Teixeira, V.L., Lima, J.C.R., Lechuga, G.C., Ramos, C.J.B., MCDS, P., Calvet, C.M., Bourguignon, S.C., 2019. Natural products from marine red and brown algae against Trypanosoma cruzi. Rev. Bras. Farm. 29 (6), 735–738. Tisher, P.C., Talarico, L.B., Noseda, M.D., Silvia, S.M., Damonte, E.B., Duarte, M.E.R., 2006. Chemical structure and antiviral activity of carrageenans from Meristiella gelidium against herpes simplex and dengue virus. Carbohydr. Polym. 63 (4), 459–465. Torres, F.A.E., Passalacqua, T.G., Velásquez, A.M.A., de Souza, R.A., Colepicolo, P., Graminha, M.A.S., 2014. New drugs with antiprotozoal activity from marine algae: a review. Rev. Bras. Farm. 24 (3), 265–276. Tripathi, A., Puddick, J., Prinsep, M.R., Rottmann, M., Tan, L.T., 2010. Lagunamides A and B: cytotoxic and antimalarial cyclodepsipeptides from the marine cyanobacterium Lyngbya majuscula. J. Nat. Prod. 73 (11), 1810–1814. Urtubia, H.O., Betanzo, L.B., Vasquéz, V., 2016. Microalgae and cyanobacteria as green molecular factories: tools and perspectives. In: Algae—Organisms for Imminent Biotechnology. IntechOpen, pp. 1–28. Veas, R., Rojas-pirela, M., Castillo, C., Olea-azar, C., Moncada, M., Ulloa, P., Rojas, V., Kemmerling, U., 2020. Microalgae extracts: potential anti-Trypanosoma cruzi agents? Biomed. Pharmacother. 127, 110178. Veiga-Santos, P., Pelizzaro-Rocha, K.J., Santos, A.O., Ueda-Nakamura, T., Filho, B.P.D., Silva, S.O., Sudatti, D.B., Bianco, E.M., Pereira, R.C., Nakamura, C.V., 2010. In vitro anti-trypanosomal activity of elatol isolated from red seaweed Laurencia dendroidea. Parasitology 137 (11), 1661–1670. Vijayakumar, S., Menakha, M., 2015. Pharmaceutical applications of cyanobacteria—a review. J. Acute Med. 5 (1), 15–23. Vining, O.B., Medina, R.A., Mitchell, E.A., Videau, P., Li, D., Serrill, J.D., Kelly, J.X., Gerwick, W.H., Proteau, P.J., Ishmael, J.E., McPhail, K.L., 2015. Depsipeptide companeramides from a panamanian marine cyanobacterium associated with the coibamide producer. J. Nat. Prod. 78 (3), 413–420.

378  Natural products in vector-borne disease management Vonthron-Sénécheau, C., Kaiser, M., Devambez, I., Vastel, A., Mussio, I., Rusig, A.M., 2011. Antiprotozoal activities of organic extracts from French marine seaweeds. Mar. Drugs 9 (6), 922–933. WHO, 2014a. WHO Factsheet Vector-Borne Diseases. Factsheet Number 387. [cited July 2020]:10. Available from: http://www.who.int/kobe_centre/mediacentre/vbdfactsheet.pdf. WHO, 2014b. A Global Brief on Vector-Borne Diseases (Report). World Health Organization. WHO, 2020a. Vector-Borne Diseases. [Internet] [cited Aug 2021]. Available from: https://www. who.int/news-room/fact-sheets/detail/vector-borne-diseases. WHO, 2020b. World Malaria Report 2020: 20  Years of Global Progress and Challenges. World Health Organization, Geneva. Wiwanitkit, V., 2010. Dengue fever: diagnosis and treatment. Expert Rev. Anti-Infect. Ther. 8 (7), 841–845. Wulandari, D.A., Sidhartha, E., Setyaningsih, I., Marbun, J.M., Syafruddin, D., Asih, P.B.S., 2018. Evaluation of antiplasmodial properties of a cyanobacterium, Spirulina platensis and its mechanism of action. Nat. Prod. Res. 32 (17), 2067–2070. Yogarajalakshmi, P., Venugopal Poonguzhali, T., Ganesan, R., Karthi, S., Senthil-Nathan, S., Krutmuang, P., Radhakrishnan, N., Mohammad, F., Kim, T.J., Vasantha-Srinivasan, P., 2020. Toxicological screening of marine red algae Champia parvula (C. Agardh) against the dengue mosquito vector Aedes aegypti (Linn.) and its non-toxicity against three beneficial aquatic predators. Aquat. Toxicol. 222, 105474.

Chapter 15

Natural products in the management of trypanosomiasis Ritu Tomara, Rahul Tiwaria, Rupa Guptab,c, Samir Bhargavaa, Dheeraj Bishtd, Vijay Singh Ranaa, and Neeraj Kumar Sethiyaa a

Faculty of Pharmacy, DIT University, Dehradun, Uttarakhand, India, bAmity Institute of Pharmacy, Amity University, Gurugram, Haryana, India, cDepartment of Pharmacy, Sushant University, Gurugram, Haryana, India, dDepartment of Pharmaceutical Sciences, Sir J.C. Bose Technical Campus, Bhimtal, Kumaun University, Nainital, Uttarakhand, India

Introduction In current period, a continuous surge of vector borne diseases (VBDs) exerts a massive load of morbidity and mortality worldwide. As per World Health Organization (WHO) records, VBDs accounts for more than 17% of all infectious diseases (WHO, 2020). Majority of VBDs include dengue, malaria, chikungunya, Japanese encephalitis, Zika virus, West Nile, and yellow fever and has been addressed by researchers; even continuous efforts are in progress to prevent and manage these diseases. However, few VBDs including trypanosomiasis are also continuously knocking and alarming for humans and animals health since its inception. Trypanosomiasis is usually referred to as sleeping sickness in Africa subcontinent and Chagas disease in South America. These are re-emergent infections, still not gaining the researcher’s attention, probably due to its regional impact. Different subspecies have been identified as cause of infection in different geographical locations, viz. Trypanosoma brucei rhodesiense (East African variants) and Trypanosoma brucei gambiense (West African variants), respectively (Jannin and Simarro, 2008; Franco et al., 2014; Sudarshi and Brown, 2015). Apart from the human trypanosomiasis, animal trypanosomiasis is reported in wild as well as in domestic animals (Giordani et  al., 2016). Particularly an alarming condition arises due to involvement of most of the domestic and wild animals as a reservoir of human pathogen parasites, especially T. b. rhodesiense (Hamill et al., 2013; Mehlitz and Molyneux, 2019). Thus, it is worthy to note that trypanosomiasis is now stirring toward extensive spread. Numerous efforts have been made to develop the therapeutic agent to manage these diseases. However, current clinical strategies to manage trypanosomiasis remain unsatisfactory, as new cases are in headway. This may be due to the poor understanding about the disease progression and limited data Natural Products in Vector-Borne Disease Management. https://doi.org/10.1016/B978-0-323-91942-5.00014-8 Copyright © 2023 Elsevier Inc. All rights reserved.

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on the clinical management. In fact, available therapy is also associated with serious adverse effects. In this challenging scenario, naturally occurring herbal interventions epitomize a valid and inspiring alternative to manage the condition. Therefore, the purpose of this chapter is to analyze the causative agents, pathogenesis, and to reconnoiter the potential herbal intervention that may open a new vista in the prevention and management of trypanosomiasis.

About trypanosomiasis African trypanosomiasis or sleeping sickness is mainly transmitted by tsetse flies (Glossina), which are Diptera of the family Glossinidae and generally infect humans, wild animals, and domestic stocks (Wamwiri and Changasi, 2016). Four major factors have been identified that may influence the potential of infection to transmit, viz. degree of parasitemia, duration of infection, number, and distribution in each infected individual with intensity of contact with the vectors. Some studies quoted that there might be chances of additional routes of transmission other than vector, viz. mechanical, vertical, accidental, blood transfusion, and sexual mode of transmission (Herwaldt, 2001; Franco et  al., 2014). The major causative agent is hemoflagellates protozoans from Trypanosoma genus. Multiple species of Trypanosoma have been identified, but mainly two subspecies, namely T. b. gambiense and T. b. rhodesiense, are infectious and responsible for sleeping sickness to humans. However, third subspecies of the group, T. b. brucei, is nonpathogenic for humans as it is generally lysed by a haptoglobin-like molecule present. However, it was found to be pathogenic to domestic and wild animals (Smith et al., 1995). Further, infection leads to CNS involvement and if untreated may even cause death (Shah et al., 2011). Eventually all three subspecies are utilized for experimental models of laboratory due to identical morphology. Interestingly, mice infection models of research have provided new insights and seem to be a valuable and versatile tool to understand both human and animal trypanosomiasis-associated pathology and immunology (Antoine-Moussiaux et al., 2008). Further, microscopic differentiation among these species is not that much effective unless specific molecular markers are known. Recently, serum resistance-associated (SRA) gene, a molecular marker, is currently being used to differentiate between the species.

Epidemiology Geographically, sleeping sickness or African trypanosomiasis is majorly limited to the African subcontinent (T. b. gambiense mainly reported in West, Central, and some part of East Africa, whereas T. b. rhodesiense mainly reported in East and Southern Africa). However, the prevalence has been extended to nonendemic countries suggested by reports on the basis of number of sleeping sickness cases reported and seen after 2000 due to extensive visit of many travelers across the boundaries (Neuberger et  al., 2014). It must be emphasized that

Management of trypanosomiasis  Chapter | 15  381

­ uman African trypanosomiasis continues to play a serious latent risk to travelh ers of European and US origin in East African regions, where T. b. rhodesiense is dominantly present as a wildlife reservoir. Further, there is no any difference in distribution of infection among men, women, and children. Surprisingly, immunocompromised patients especially suffering from HIV infection have little pathological impact by T. b. gambiense counter-attack (Louis et al., 1991; Pepin et al., 1992; Meda et al., 1995). Clinically, there are two major stages of transmission as follows: ●

●

Hemo-lymphatic stage (parasites dwell in the lymphatic system and bloodstream; shorter in case of rhodesiense, when compared with gambiense) revealed by intermittent fever, pruritus, headache, dermatologic problems, lymphadenopathies, asthenia, weakness, anemia, cardiac disorders, musculoskeletal pains, endocrine disturbances, and hepatosplenomegaly. Meningo-encephalitic stage (parasite crosses the BBB and invades the CNS accompanied by progressive neurological damage faster in rhodesiense compared to gambiense) revealed by neuropsychiatric signs with symptoms, disturbances of sleep, involuntary movements, slurred speech, optic neuritis, myelopathy, myositis, and cerebellar ataxia (Kennedy and Rodgers, 2019).

However, most of the signs and symptoms of both of these stages are overlapping and rendering the differentiation in each one. Additionally, rhodesiense is acute in nature that usually progresses to death within 6 months when compared with gambiense which is more chronic in nature with an average duration of death of almost 3 years (Odiit et al., 1997; Checchi et al., 2008). Interestingly, infected travelers from nonendemic countries have atypical symptoms such as gastro-intestinal including jaundice and diarrhea in association with an acute febrile illness. Rarely, sleep disturbances may also be observed (Urech et al., 2011). Other species such as Trypanosoma rotatorium (Hysek and Zizka, 1976), Trypanosoma theileri (Villa et al., 2008), Trypanosoma cruzi (QuijanoHernandez et  al., 2008), Trypanosoma evansi and Trypanosoma equiperdum (Brun et al., 1998), and Trypanosoma vivax (Shaw and Lainson, 1972) severally affect many animals and are reported in various parts of the world.

Current therapeutic approaches and associated challenges Therapeutic management for early stage of disease caused by both the variants is more effective and less toxic than that for late-stage onsets. Some of the available drugs include suramin (Wang, 1995; Barrett et al., 2007; Babokhov et al., 2013), pentamidine (Steverding, 2010; Hafiz and Kyriakopoulos, 2021), melarsoprol (Docampo and Moreno, 2003; Fairlamb and Horn, 2018), eflornithine (Pepin and Milord, 1994), nifurtimox (Priotto et al., 2009), eflornithine combined with nifurtimox (Kennedy, 2013), and fexinidazole (Mesu et  al., 2018; Fairlamb, 2019; Lindner et  al., 2020). However, expected therapeutic

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outcomes from currently available drugs for management of trypanosomiasis are not promising as most of the drugs are highly toxic, need parenteral administration and possibilities of producing drug resistance. Therefore, an alternative approach to use validated traditional medicinal plants and phytochemicals to achieve desired therapeutic outcome is better serving option. Therefore, herein several medicinal plants and phytochemicals are presented on the basis of outcome performed through several in vitro and in vivo studies.

Natural products in the management of trypanosomiasis Plants against trypanosomiasis (in vitro studies) Several plants have been studied in past to investigate the antitrypanosomiasis effect through series of in vitro studies (Table 1). The outcome of various plants according to classification as per their families is depicted herewith:

Aloaceae An in  vitro trypanocidal activity of Aloe gilbertii leaves exudates containing aloin, aloe-emodin, and rhein were observed (MIC: 0.4 mg/mL) on parasites obtained from infected mice with Trypanosoma congolense (Tewabe et al., 2014). Annonaceae One of the studies was carried out on essential oils obtained from leaves of Xylopia frutescens and Xylopia laevigata through hydrodistillation methods containing 24.8% of (E)-caryophyllene, 20.8% of bicyclogermacrene, 17.0% of germacrene D, 7.9% of β-elemene, and 6.8% of (E)-β-ocimene reported to possess trypanocidal activity against the T. cruzi (Y strain), with IC50 values lower than 30 and 15 μg/mL, respectively. Additionally, essential oil was also able to reduce the percentage of total T. cruzi-infected macrophages and the intracellular number of amastigotes at concentrations that were noncytotoxic to macrophages as an evidence from in vitro studies (da Silva et al., 2013). In a very similar study, essential oils obtained from the Annona pickelii and Annona salzmannii (Annonaceae) leaves through hydrodistillation methods were found to inhibit T. cruzi epimastigote with an IC50 lower than 100 μg/mL. The essential oil was further evaluated chemically and was found to have bicyclogermacrene (38%), (E)-caryophyllene (27.80%), α-copaene (6.9%), and α-humulene (4%) in A. pickelii, while δ-cadinene (22.6%), (E)-caryophyllene (21.4%), α-copaene (13.3%), bicyclogermacrene (11.3%), and germacrene D (6.9%) in A. salzmannii (Costa et al., 2013). Apocynaceae For the first time, antitrypanosomal activity was investigated in the leaves of Dyera costulata with IC50 values of 0.58 ± 0.01 μg/mL (selectivity index, SI > 169) against T. brucei brucei strain BS221 in a study conducted in past (Norhayati et al., 2013).

TABLE 1  Plants against trypanosomiasis (in vitro studies). Family

Plant name

Extract/derived compound

Causative species

LC50/IC50/EC50/MIC

References

Aloaceae

Aloe gilbertii

Exudates of leaves (Aloin, aloe-emodin, and rhein)

T. congolense

0.4 mg/mL

Tewabe et al. (2014)

Annonaceae

Xylopia frutescens and laevigata

Essential oils from leaves (caryophyllene, bicyclogermacrene, germacrene D, betaelemene, and beta-ocimene)

T. cruzi

15 and 30 μg/mL

da Silva et al. (2013)

Annonaceae

Annona pickelii and salzmannii

Essential oils of dried leaves (bicyclogermacrene, caryophyllene, α-copaene, and α-humulene from A. pickelii, while δ-cadinene, caryophyllene, α-copaene, bicyclogermacrene, and germacrene D)

T. cruzi

27.2 ± 1.4 and 89.7 ± 2.4 μg/mL

Costa et al. (2013)

Apocynaceae

Dyera costulata

Methanol extract of leaves

T. brucei brucei

0.58 ± 0.01 μg/mL (selectivity index >169)

Norhayati et al. (2013)

Asteraceae

Ageratum conyzoides

Hydroalcohol extract of aerial parts

T. cruzi

104.7 ± 3.78 μg/mL

Teixeira et al. (2014)

Asteraceae

Lychnophora salicifolia

Hexane, ethanol, and ethyl acetate extract (leaves and inflorescences) containing quercetin-7,3′,4′-trimethyl ether and the sesquiterpenoid lychnopholic acid

T. cruzi

32 ± 12.1%, 78 ± 2.7% and 91 ± 2.0%, respectively

Jordão et al. (2004)

Asteraceae

Artemisia annua

Dichloromethane extracts (artemisinin)

T. brucei

1.8–14.4 μg/mL

Naß and Efferth (2018) Continued

TABLE 1  Plants against trypanosomiasis (in vitro studies)—cont’d Family

Plant name

Extract/derived compound

Causative species

LC50/IC50/EC50/MIC

References

Asteraceae

Lychnophora pohli

Dichloromethane, methanol, and hydroalcohol extract (leaves and inflorescences)

T. cruzi

100 ± 0%, 83.47 ± 2.08% and 44.76 ± 3.21%, respectively

Grael et al. (2005)

Asteraceae

Ambrosia tenuifolia and scabra

Psilostachyin and psilostachyin C

T. cruzi

7.28 ± 0.20 and 4.74 ± 0.05 μM, respectively

Sülsen et al. (2016)

Bignoniaceae

Handroanthus impetiginosus

Hydroalcohol extract of aerial parts

T. cruzi

206.7 ± 21.73 μg/mL

Teixeira et al. (2014)

Boraginaceae

Bourreria pulchra

Pulchrol

T. cruzi

18.5 ± 9.6 μM

Terrazas et al. (2020)

Canellaceae

Cinnamodendron dinisii

Essential oils of leaves (monoterpene and sesquiterpenes hydrocarbons)

T. cruzi

282.93 μg/mL

Andrade et al. (2015)

Didymellaceae

Ascochyta viciae

Micronized crystalline powder (ascofuranone)

T. brucei brucei

250 μM

Minagawa et al. (1996)

Fabaceae

Pericopsis laxiflora

Methylene chloride extract of leaves

T. brucei rhodesiense

11.8 ± 0.8 μg/mL

Hoet et al. (2004a)

T. brucei brucei

39.2 ± 1.6 μg/mL

T. brucei rhodesiense

25.8 ± 4.5 μg/mL

T. brucei brucei

20 ± 11.3 μg/mL

Fabaceae

Cassia sieberiana

Methylene chloride extract of leaves

Hoet et al. (2004a)

Fabaceae

Myrocarpus frondosus

Essential oils of bark

T. cruzi

60.87 μg/mL

Azeredo et al. (2014)

Gramineae

Cymbopogon nardus

Methanol extract of whole plants

T. brucei brucei

0.31 ± 0.03 μg/mL (selectivity index >323)

Norhayati et al. (2013)

Hymenocardiaceae

Hymenocardia acida

Methylene chloride extract of leaves

T. brucei rhodesiense

9.1 ± 4.9 μg/mL

T. brucei brucei

5.0 ± 1.4 μg/mL

Hoet et al. (2004a)

Hymenocardiaceae

Hymenocardia acida

Extract of leaves

T. brucei brucei

2.5 mg/mL

Abubakar et al. (2019)

Lamiaceae

Ocimum gratissimum

Ethyl acetate extract of Ocimum gratissimum (lamiaceae) leaves

T. brucei brucei

2.08 ± 0.01 μg/mL

Nwodo et al. (2015a)

Lamiaceae

Turkish Origanum onites

Essential oil extracted from aerial parts (carvacrol, linalool, p-cymene, γterpinene, and thymol)

T. brucei rhodesiense

0.18 μg/mL

Tasdemir et al. (2019)

Lamiaceae

Vitex simplicifolia leaves

Ethyl acetate fraction containing methylated flavonoid constituents

T. brucei rhodesiense

4.7–12.3 μg/mL

Nwodo et al. (2015b)

Lauraceae

Cinnamomum verum

Essential oils of bark

T. cruzi

24.13 μg/mL

Azeredo et al. (2014)

Lauraceae

Litsea cubeba

Essential oil of fruits

T. brucei brucei

2.67 ± 1.12 nL/mL

Le et al. (2019)

Leguminosae

Entada abyssinica

Dichloromethane extract from root barks (kolavenol and kolavic acid)

T. brucei rhodesiense

2.5 mg/mL (8.6 μM)

Freiburghaus et al. (1998)

T. brucei

1.7 mM

Nyasse et al. (2004)

T. brucei rhodesiense

16.4 ± 8.8 μg/mL

Hoet et al. (2004a)

T. brucei brucei

1.5 ± 0.9 μg/mL

T. brucei rhodesiense

14.9 ± 10.7 μg/mL

T. brucei brucei

8.6 ± 5.9 μg/mL

T. congolense

9.1 × 10–4 μg/μL

Loganiaceae

Meliaceae

Meliaceae

Strychnos spinosa

Trichilia emética

Khaya senegalensis

Methylene chloride extract of leaves

Methylene chloride extract of leaves

Methanol extract of fresh stem barks

Hoet et al. (2004a)

Tauheed et al. (2020) Continued

TABLE 1  Plants against trypanosomiasis (in vitro studies)—cont’d Family

Plant name

Extract/derived compound

Causative species

LC50/IC50/EC50/MIC

References

Menispermaceae

Tricilasia patens

Methanol extract of leaves

T. brucei brucei

31.25 μM

Del Rayo Camacho et al. (2002)

Myrtaceae

Eugenia uniflora

Essential oils of bark

T. cruzi

70 μg/mL

Azeredo et al. (2014)

Rubiaceae

Gardenia erubescens

Ethanol extract of leaves

T. brucei brucei

20 mg/mL

Abu et al. (2009)

Rubiaceae

Mitracarpus scaber

Ethanol extract containing azaanthraquinone

T. congolense

250 μM

Nok (2002)

Rutaceae

Ruta graveolens

Hydroalcohol extract of aerial parts

T. cruzi

207.7 ± 18.6 μg/mL

Teixeira et al. (2014)

Siparunaceae

Siparuna guianensis

Essential oils of leaves (monoterpene and sesquiterpenes hydrocarbons)

T. cruzi

209.30 μg/mL

Andrade et al. (2015)

Verbenaceae

Lippia sidoides

Essential oil of leaves

T. cruzi

28.9 μg/mL

de Melo et al. (2020)

Verbenaceae

Lippia origanoides

Essential oil of leaves

T. cruzi

26.2 μg/mL

de Melo et al. (2020)

Verbenaceae

Vitex simplicifolia

Methanol extract of leaves

T. b. rhodesiense

4.7–13.8 μg/mL

Nwodo et al. (2015b)

Verbenaceae

Lantana camara

Essential oils of leaves

T. cruzi

201.94 μg/mL

Barros et al. (2016)

Zingiberaceae

Zingiber officinale

Essential oils extracted from rhizomes

T. brucei brucei

3.10 ± 0.08 nL/mL

Le et al. (2019)

Zingiberaceae

Curcuma longa

Essential oils extracted from rhizomes

T. brucei brucei

3.17 ± 0.72 nL/mL

Le et al. (2019)

Zingiberaceae

Curcuma zedoaria

Essential oils extracted from rhizomes

T. brucei brucei

2.51 ± 1.08 nL/mL

Le et al. (2019)

Management of trypanosomiasis  Chapter | 15  387

Asteraceae An in vitro study investigated the effect of Ageratum conyzoides extract on T. cruzi infection. The study revealed significant toxicity of extracts to both promastigotes and trypomastigotes. Further, extracts also cause significant decrease in the cell invasion rate, and significant reduction of intracellular amastigotes multiplication of both trypomastigotes and promastigotes was also observed (Teixeira et al., 2014). In another study, the ethyl acetate extract of Lychnophora salicifolia leaves and inflorescences exhibit significant trypanocidal activity against trypomastigote forms of T. cruzi. Effect of the study was further suggested due to the presence of quercetin-7,3′,4′-trimethyl ether and the sesquiterpenoid lychnopholic acid (Jordão et al., 2004). Interestingly, not only Artemisia annua, but also one of its isolates artemisinin revealed inhibition of T. brucei trypanosomes. It was further reported that genus Artemisia, artemisinin, and its derivatives possess antitrypanosomal activity as an evidence from several other studies (Naß and Efferth, 2018). Further, dichloromethane and methanol extracts of Lychnophora pohlii leaves and inflorescences were found to exhibit trypanocidal activity as an evidence from an in vitro conducted against trypomastigote forms of T. cruzi. Additionally, the bioassay-guided fractionation of the dichloromethane extracts yield lychnopholide, centratherin, goyazensolide, and 15-desoxygoyazensolide, whereas methanol extract resulted to yield caffeic acid, luteolin, and vicenin-2 (Grael et al., 2005). In another study, two sesquiterpene lactones isolated from Ambrosia species, namely psilostachyin and psilostachyin C, have been demonstrated to have trypanocidal activity. It was further demonstrated that psilostachyin has five times more effect on reactive oxygen species generation when compared with psilostachyin C against T. cruzi after 4 h. Additionally, both sesquiterpenes lactones caused death of parasites by apoptosis. Similarly, combination of both compounds leads to have an additional trypanocidal effect. Mechanistically, antiparasitic effect by involving interaction with hemin is caused by psilostachyin; on the other hand, psilostachyin C interfered with sterol synthesis (Sülsen et al., 2016). Bignoniaceae An in vitro study investigated the effect of Handroanthus impetiginosa extract on T. cruzi infection. The study revealed significant toxicity of extracts to both promastigotes and trypomastigotes, respectively. Further, extracts also cause significant decrease in the cell invasion rate, and significant reduction in intracellular amastigotes multiplication of both trypomastigotes and promastigotes was also observed (Teixeira et al., 2014). Boraginaceae In a very recent study, pulchrol (benzochromene) isolated from the Bourreria pulchra roots exhibits potent antiparasitic activity toward T. cruzi (Terrazas et al., 2020).

388  Natural products in vector-borne disease management

Canellaceae Trypanocidal activity (IC50: 282.93 μg/mL) of the essential oils fractions obtained from Cinnamodendron dinisii Schwacke (Canellaceae) was tested against T. cruzi (Andrade et al., 2015). Didymellaceae In an earlier study, a prenylphenol antibiotic (ascofuranone) isolated from fungus, Ascochyta viciae, was potentially found to inhibit glucose-dependent cell respiration and glycerol-3-phosphate-dependent mitochondrial O2 consumption in a bloodstream forms of Trypanosoma brucei brucei of a long slender (Minagawa et al., 1996). Fabaceae The in vitro study pertaining to antitrypanosomal activity of methylene chloride extracts of Pericopsis laxiflora and Cassia sieberiana leaves and twigs against two strains of trypanosomes (T. b. brucei and T. b. rhodesiense) was observed. Activity was further co-related due to the presence of flavonoids and quinones (Hoet et al., 2004a). In another study, essential oils (EOs) obtained from Myrocarpus frondosus (IC50/24 h: 60.87 μg/mL) have been found to exhibit inhibitory activity against T. cruzi epimastigotes (Azeredo et al., 2014). Gramineae For the first time, antitrypanosomal activity of Cymbopogon nardus plant with IC50 values of 0.31 ± 0.03 μg mL−1 (SI > 323) was reported (Norhayati et al., 2013). Hymenocardiaceae A study pertaining methylene chloride extracts of Pericopsis laxiflora and Cassia sieberiana leaves and twigs was tested for in  vitro antitrypanosomal activity against two strains of trypanosomes (T. b. brucei and T. b. rhodesiense). Activity was further co-related due to the presence of flavonoids and quinones (Hoet et  al., 2004a). In a recent study, Hymenocardia acida extracts exhibit antitrypanosomal activity against T. b. brucei with minimum inhibitory concentration of 2.5 mg/mL (Abubakar et al., 2019). Lamiaceae The ethyl acetate extract of Ocimum gratissimum leaves exhibits antitrypanosomal activity (IC50: 2.08 ± 0.01 μg/mL; SI: 29) from an evidence of an in vitro study (Nwodo et  al., 2015a). Similarly, extracts and fractions obtained from Vitex simplicifolia leaves using methanol, and successive solvent extraction with hexane, dichloromethane, ethyl acetate, and butanol were observed for trypanocidal activity. Result of study demonstrated that isolated compound obtained from ethyl acetate fraction exhibited promising trypanocidal activity with IC50 values ranging from 4.7 to 12.3 μg/mL (Nwodo et al., 2015b). Further, a

Management of trypanosomiasis  Chapter | 15  389

recent in vitro study demonstrates trypanocidal activity of Turkish Origanum onites oil and its major components against T. b. rhodesiense (IC50: 180 ng/mL) and T. cruzi. This study further revealed presence of carvacrol (70.6%), linalool (9.7%), p-cymene (7%), γ-terpinene (2.1%), and thymol (1.8%) as major constituents of oil (Tasdemir et al., 2019).

Lauraceae Essential oils (EOs) obtained from Cinnamomum verum (IC50/24 h: 24.13 μg/ mL) have been found to exhibit inhibitory activity against T. cruzi epimastigotes (Azeredo et al., 2014). Similarly, antitrypanosomal activity (IC50: 2.67 ± 1.12 nL/ mL; SI > 10) of four essential oils obtained from Litsea cubeba was recorded in a recent study (Le et al., 2019). Leguminosae Bioassay-guided fractionation from Entada abyssinica root bark dichloromethane extract exhibits trypanocidal activity [IC50: 2.5 μg/mL (8.6 μM)] against T. b. rhodesiense (Freiburghaus et al., 1998). In subsequent study, a new kolavic acid derivative isolated from the Entada abyssinica (traditional plants of West and East Africa against sleeping sickness) stem bark exhibits strong and selective inhibitory activity (IC50: 0.012 mM) against GAPDH enzyme of T. brucei (Nyasse et al., 2004). Loganiaceae Earlier study depicted an antitrypanosomal activity of methylene chloride extracts of Strychnos spinosa leaves and twigs against two strains of trypanosomes (T. b. brucei and T. b. rhodesiense) (Hoet et al., 2004a). Meliaceae Antitrypanosomal activity (through an in  vitro study) of methylene chloride extracts of Trichilia emética leaves and twigs against two strains of trypanosomes (T. b. brucei and T. b. rhodesiense) were observed (Hoet et al., 2004a). Formulation containing Khaya senegalensis exhibits antitrypanosomal activity against T. congolense with an IC50 of 9.1 × 10−4 μg/μL (Tauheed et al., 2020). Menispermaceae In a study, Triclisia patens demonstrated antitrypanosomal activity (IC50: 31.25 μg/mL) against T. b. brucei bloodstream trypomastigote forms (Del Rayo Camacho et al., 2002). Myrtaceae In a study, essential oils (EOs) obtained from Eugenia uniflora (IC50/24 h: 70 μg/mL) have been found to exhibit inhibitory activity against T. cruzi epimastigotes (Azeredo et al., 2014).

390  Natural products in vector-borne disease management

Rubiaceae A study demonstrated to evaluate an in vitro antitrypanosomal activity from aqueous and ethanol extracts Anthocleista vogelii, Cussonia arborea, Blighia unijugata, Gardenia erubescens, Lophira lanceolata, Hymenocardia acida, Uapaca togoensis, and Stereospermum kunthianum (Nigerian plants). The results of current study demonstrated that Hymenocardia acida extracts were found to be active (IC50: 2.5 mg/mL) against T. b. brucei. Further, researcher demonstrated the first-time report on antitrypanosomal activity of Gardenia erubescens (IC50: 20 mg/mL) and Lophira lanceolata (IC50: 20 mg/mL) (Abu et al., 2009). In the past, one of the studies demonstrated that ethanol extract obtained from Mitracarpus scaber was found to exhibits trypanocidal activity against T. congolense as an evidence from both in  vitro and in  vivo studies (Nok, 2002). Rutaceae An in  vitro study investigated the effect of Ruta graveolens extract on T. cruzi infection. The study revealed significant toxicity in promastigotes and trypomastigotes by extracts. Further, extracts also cause significant decrease in the cell invasion rate, and significant reduction in the intracellular amastigotes multiplication of both trypomastigotes and promastigotes (Teixeira et al., 2014). Siparunaceae Trypanocidal activity of the essential oils obtained from Siparuna guianensis Aublet (Siparunaceae) was demonstrated against T. cruzi epimastigotes using the tetrazolium salt (MTT) colorimetric assay (Andrade et al., 2015). Verbenaceae Trypanocidal activity of the essential oils obtained from Lippia sidoides and Lippia origanoides against T. cruzi was reported. It was found that Lippia sidoides and Lippia origanoides cause significant reduction in T. cruzi-infected macrophages percentage and total number of intracellular parasites. It was further shown that both the oils are consistent with loss of viability and cause death of cell as an evidence from ultrastructural analysis (de Melo et al., 2020). In another study, different extracts and isolated compound from Vitex simplicifolia were evaluated for trypanocidal activities. It was demonstrated first time that isolated flavonoid compound from Vitex simplicifolia exhibited significant trypanocidal activities (Nwodo et al., 2015b). In another study, essential oil extracted from hydro-distillation from Lantana camara leaves was tested against T. cruzi. The results of study demonstrated that L. camara essential oil inhibited T. cruzi with IC50 of 201.94 μg/mL. Further, composition of L. camara essential oil analyzed by GC/MS revealed large amounts of (E)-caryophyllene (23.75%),

Management of trypanosomiasis  Chapter | 15  391

bicyclogermacrene (15.80%), germacrene D (11.73%), terpinolene (6.1%), and sabinene (5.92%) (Barros et al., 2016).

Zingiberaceae In a study, essential oil from 37 Vietnamese plants was tested against on T. b. brucei inhibition through an in vitro study. The result of study presented antitrypanosomal effect for the first time for 4 EOs, extracted from Curcuma longa (IC50: 3.17 ± 0.72), Curcuma zedoaria (IC50: 2.51 ± 1.08), Zingiber officinale (IC50: 3.10 ± 0.08), and Litsea cubeba (IC50: 2.67 ± 1.12 nL/mL). Additionally, it was also demonstrated that out of these five major compounds obtained from Curcuma longa essential oils and curlone was found to be most promising antitrypanosomal molecule (IC50: 1.38 ± 0.45 μg/mL; SI: 31.7 and 18.2) (Le et al., 2019).

Marine sources A study collected 29 species of marine algae and investigated for antitrypanosomal effects. Out of which, the organic extracts from Dictyota caribea Horning & Schnetter, Turbinaria turbinata Linnaeus, Lobophora variegata (J.V. Lamouroux) Womersley, and Laurencia microcladia Kützing showed best activity (León-Deniz et al., 2009).

Phytochemical against trypanosomiasis Several phytochemicals studied in past to investigate the antitrypanosomiasis effect through series of in vitro experiments were reported in Table 2. Further, chemical structure of each compound exhibiting antitrypanosomiasis effect is mentioned in Fig. 1.

Plants against trypanosomiasis (in vivo studies) Several plants studied in past to investigate the antitrypanosomiasis effect through series of in vivo studies are reported in Table 3.

Patents Several molecules and processes have been recently filed with intellectual property right applications and have been mentioned in Table 4.

Mode of actions Fig. 2 depicts different modes of action of various plants extracts and phytochemicals for pertaining antitrypanosomiasis effect.

TABLE 2  Phyto-constituents against trypanosomiasis (in vitro studies). Categories

Phytoconstituents/derived compounds

Causative species

LC50/IC50

References

Alkaloid

Quinidine (1)

T. brucei brucei

0.8 μM

Hoet et al. (2004b)

Cinchonin (2)

T. brucei brucei

1.2 μM

Hoet et al. (2004b)

Quinine (3)

T. brucei brucei

4.9 μM

Hoet et al. (2004b)

Cinchonidine (4)

T. brucei brucei

7.1 μM

Hoet et al. (2004b)

Berberine (5)

T. brucei brucei

0.5 μM

Hoet et al. (2004b)

Sanguinarine (6)

T. brucei brucei

1.9 μM

Hoet et al. (2004b)

Berbamine (7)

T. brucei brucei

2.6 μM

Hoet et al. (2004b)

Ancistroealaines A (8)

T. brucei rhodesiense

8 μM

Hoet et al. (2004b)

Ancistroealaines B (9)

T. brucei rhodesiense

5 μM

Hoet et al. (2004b)

Ancistrogriffithine A (10)

T. brucei rhodesiense

1.2 μM

Hoet et al. (2004b)

Oxoaporphines (11)

T. brucei brucei

IC100: 20 μM

Hoet et al. (2004b)

Pancracine (12)

T. brucei rhodesiense

2.4 μM

Hoet et al. (2004b)

Nangustine (13)

T. brucei rhodesiense

33.4 μM

Hoet et al. (2004b)

Haemanthidine (14)

T. brucei rhodesiense

3.5 μM

Hoet et al. (2004b)

Oxomaritidine (15)

T. brucei rhodesiense

9.8 μM

Hoet et al. (2004b)

Galanthine (16)

T. brucei rhodesiense

9.8 μM

Hoet et al. (2004b)

Aactinodaphne (17)

T. brucei brucei

3.2 μM

Hoet et al. (2004c)

Cassythine (18)

T. brucei brucei

6.0 μM

Hoet et al. (2004c)

Dicentrine (19)

T. brucei brucei

14.6 μM

Hoet et al. (2004c)

Suramin (20)

T. brucei brucei

0.06 μM

Hoet et al. (2004c)

Alkaloid

Alkamide

Diminazene aceturate

T. brucei brucei

0.02 μM

Hoet et al. (2004c)

Cocsoline (21)

T. brucei brucei

12.3 μM

Del Rayo Camacho et al. (2002)

Phaeanthine (22)

T. brucei brucei

2.4 μM

Del Rayo Camacho et al. (2002)

Thalisopidine (23)

T. brucei brucei

1.14 μM

Del Rayo Camacho et al. (2002)

Fangchinoline (24)

T. brucei brucei

0.39 μM

Del Rayo Camacho et al. (2002)

Dioncophyllines A and B (25)

T. brucei brucei and T. brucei rhodesiense

2–3 μM

Bringmann et al. (2003)

17-DMAG (26)

T. cruzi

0.27 μmol L−1

Martinez-Peinado et al. (2021)

Lepadins D (27)

T. cruzi and T. brucei rhodesiense

125.2 and 18.8 μM

Wright et al. (2002)

Lepadins E (28)

T. cruzi and T. brucei rhodesiense

5.2 and 0.9 μM

Wright et al. (2002)

Lepadins F (29)

T. cruzi and T. brucei rhodesiense

6.17 and 0.54 μM

Wright et al. (2002)

Fascaplysin (30)

T. brucei rhodesiense

630 nM

Kirsch et al. (2000)

2-Bromoascididemin (31)

T. brucei rhodesiense

0.7 μM

Copp et al. (2003)

Hybrids of cinchona alkaloids

T. cruzi

0.30–16.53 μg/mL

Musikant et al. (2019)

T. brucei

0.48–5.39 μM

Leverriera et al. (2015)

Azaanthraquinone (32)

T. congolense

250 μM

Nok (2002)

Glycerol + Azaanthraquinone

T. congolense

25 μM

Nok (2002)

Waltheriones G (33), Waltheriones H (34), and Waltheriones K (35)

T. cruzi

0.02–0.04 μM

Cretton et al. (2014)

Lissoclinotoxin E (36)

T. brucei brucei and T. cruzi

5 μM

Zulfiqar et al. (2017)

Alkamide dodeca-2E,4E-dienoic acid 4-hydroxy-2-phenyl-ethylamide

T. b. rhodesiense and T. cruzi

2.26 ± 0.18 and 1.88 μg/ mL

Zulfiqar et al. (2017)

Almiramide C (37)

T. brucei brucei

3 μM

Sanchez et al. (2013) Continued

TABLE 2  Phyto-constituents against trypanosomiasis (in vitro studies)—cont’d Categories

Phytoconstituents/derived compounds

Causative species

LC50/IC50

References

Antibiotic

Ascofuranone (38)

T. brucei

250 μM

Minagawa et al. (1996)

Ascofuranone+4 mM glycerol

T. brucei

0.03 μM

Minagawa et al. (1996)

Broussochalcone A (39)

T. brucei

2.17 ± 0.50 μM

Sun et al. (2016)

7-(4″-Hydroxy-3″-methoxyphenyl)-1 phenylhept-4-en-3-one (40)

T. brucei

2.48 ± 0.02 μM

Sun et al. (2016)

1′S-1′-Acetoxychavicol acetate (41)

T. brucei

4.70 ± 1.53 μM

Sun et al. (2016)

Kushenol F (42)

T. brucei

1.37 ± 0.01 μM

Sun et al. (2016)

Morusin (43)

T. brucei

3.40 ± 0.15 μM

Sun et al. (2016)

nn6,8-Diprenylorobol (44)

T. brucei

0.52 ± 0.01 μM

Sun et al. (2016)

Genistin (45)

T. brucei

3.31 ± 0.75 μM

Sun et al. (2016)

Flavonoids from Vitex simplicifolia leaves

T. b. rhodesiense

4.7–23.7 μg/mL

Nwodo et al. (2015b)

Glycoside

Theviridoside (46)

T. brucei brucei S427

17.80 ± 0.32 μM

Mahmoud et al. (2020)

Lactones

Psilostachyin C (47)

T. cruzi

4.74 μM

Sülsen et al. (2016)

Eupatoriopicrin (48)

T. cruzi

7.2 ± 0.3 μg/mL

Elso et al. (2020)

Estafietin (49)

T. cruzi

28.9 ± 4.1 μg/mL

Elso et al. (2020)

Eupahakonenin B (50)

T. cruzi

11.9 ± 4.5 μg/mL

Elso et al. (2020)

Minimolide (51)

T. cruzi

7.7 ± 0.4 μg/mL

Elso et al. (2020)

(+)-Syringaresinol (52)

T. cruzi

7.55 μM

Costa et al. (2018)

Goyazensolide (53)

T. cruzi

15.79 μg/mL

Grael et al. (2005)

Manassantin B (54)

T. brucei

3.54 ± 0.49 μM

Sun et al. (2016)

Flavonoid

Lignans

Phenolic

Steroid

Terpenoid

Curcumin (55) and genistein (56)

T. brucei rhodesiense

199.71 μM

Ettari et al. (2019)

Vanillin (57) and its acetyl derivative

T. cruzi

5.5 and 5.6 μM

Morais et al. (2020)

Ursolic acid (58)

T. cruzi

0.4 mg/mL

Leite et al. (2006)

Oleanolic acid (59)

T. cruzi

1.6 mg/mL

Leite et al. (2006)

Nerolidol (60)

T. brucei brucei (strain 427)

7.6 μM

Hoet et al. (2006)

Linalool (61)

T. brucei brucei (Strain 427)

16.3 μM

Hoet et al. (2006)

Saringosterol (62)

T. brucei brucei

7.8 μM

Hoet et al. (2007)

24-Hydroperoxy-24-vinylcholesterol (63)

T. brucei brucei

3.2 μM

Hoet et al. (2007) −1

Oligomycin (64)

T. cruzi

0.52 μmol L

Martinez-Peinado et al. (2021)

Curlone (65)

T. brucei brucei

1.38 ± 0.52 μg/mL

Le et al. (2019)

Carvacrol (66)

T. brucei rhodesiense

0.15 ± 0.04 μg/mL

Tasdemir et al. (2019)

Thymol (67)

T. brucei rhodesiense

0.11 ± 0.01 μg/mL

Tasdemir et al. (2019)

α-Pinene (68)

T. brucei rhodesiense

0.42 ± 0.24 μg/mL

Tasdemir et al. (2019)

α-Terpineol (69)

T. brucei rhodesiense

0.56 ± 0.4 μg/mL

Tasdemir et al. (2019)

Terpinen-4-ol (70)

T. brucei rhodesiense

0.66 ± 0.4 μg/mL

Tasdemir et al. (2019)

Thymoquinone (71)

T. brucei rhodesiense

0.11 ± 0.02 μg/mL

Tasdemir et al. (2019)

Komaroviquinone (72)

T. cruzi

0.25 μM

Suto et al. (2015)

Eugenol (73)

T. cruzi

383.3 μM

de Souza et al. (2020)

16-α-Hydroxy-cleroda-3,13 (14)-Z-dien15,16-olide (HDK-20) (74)

T. brucei

0.4 μg/mL

Ebiloma et al. (2018)

Essential oils

T. brucei

2.7–10.7 μg/mL

Kamte et al. (2018)

FIG. 1  Chemical structure of phyto-constituents effective against trypanosomiasis.

FIG. 1, CONT’D

FIG. 1, CONT’D

TABLE 3  Plants against trypanosomiasis (in vivo studies). Plant name

Extract/derived compounds

Animal model (with causative organism)

Dose

Effect

References

Gardenia sokotensis

80% Ethanol extract of root

Rabbits (T. b. brucei)

60 mg/kg/bw

Significant reduction in the level of parasitemia was observed following the 7-day treatment

Jodi et al. (2011)

Annona senegalensis

Crude and partially purified aqueous extract of whole plants

Mice (T. b. brucei)

200 mg/kg/bw

Completely cleared the parasites from circulation within 3 days

Ogbadoyi et al. (2007)

Momordica charantia

Methanol extract of leaves

Rat (T. b. brucei)

100–1000 mg/kg/ bw

Suppresses parasitemia

Mazadu et al. (2019)

Artemisia abyssinica

Methanol and dichloromethane extract

Mice (T. congolense)

400 mg/kg

Interference with the redox balance of the parasites acting either on the respiratory chain or on the cellular defenses against oxidative stress

Feyera et al. (2014)

Parthenium hysterophorus

50% Ethanol extract of flowers

Mice (T. evansi)

100 and 300 mg/kg

Suppression of parasitemia

Talakal et al. (1995a)

Xanthium strumarium

50% Ethanol extract of leaves

Mice (T. evansi)

100 and 300 mg/kg

Suppression of parasitemia

Talakal et al. (1995b)

Syzygium aromaticum

1,2,3-Triazole obtained from eugenol and dihydroeugenol

Mice (T. cruzi)

100 mg/kg

The di-hydroeugenol derivative 10 reduced more than 50% of the parasitemia

de Souza et al. (2020)

Echinops kebericho

Hydromethanol extract of root

Mice (T. congolense)

200 and 400 mg/kg

Suppression of parasite load

Abdeta et al. (2020) Continued

TABLE 3  Plants against trypanosomiasis (in vivo studies)—cont’d Plant name

Extract/derived compounds

Animal model (with causative organism)

Dose

Effect

References

Argentinian asteraceae

Eupatoriopicrin containing organic extract

Balb/c mice (T. cruzi)

1 mg/kg

Suppression of parasite load

Elso et al. (2020)

Azadirachta indica

Methanol extract of leaves

Rats (T. b. brucei)

125 mg/kg bw

Cleared the parasites fastest and prevented relapse infection with T. b. brucei

Omoja et al. (2011)

Anogeissus leiocarpus + Khaya senegalensis

Methanol stem bark extract

Rats (T. congolense)

500 mg/kg

Reduced complete cessation of parasite motility

Tauheed et al. (2020)

Coconut, olive, high oleic and linoleic safflower oil

Vegetable oils

C57BL/6J Mice (T. congolense)

0.2 mL

Suppression of parasite load

Kume et al. (2020)

Helietta apiculata

Chloroform stem barks extract

BALB/c mice (T. cruzi)

5, 10 and 50 mg/kg

Suppression of parasitemia

Ferreira et al. (2019)

Achyrocline satureioides

Essential oil (free and nanoencapsulated forms)

Rats (T. evansi)

1.5 mL/kg

Reduced creatinine levels

Do-Carmo et al. (2015)

Stevia maimarensis

Organic extracts

Balb/c mice (T. cruzi)

1 mg/kg/day

Suppression of parasitemia

Elso et al. (2020)

Melaleuca alternifolia

Oil and nanocapsules of oil

Mice (T. evansi)

0.3, 0.6 and 0.9 mL/kg

Extend animal longevity

Baldissera et al. (2014)

Dovyalis abyssinica

Dichloromethane and methanol extract of fresh leaves

Mice (T. congolense)

200 and 250 mg/kg

Suppression of parasitemia level

Tadesse et al. (2015)

Indigofera oblongifolia

Methanol extract of leaves

Mice (T. evansi)

100 mg/kg

The extract protected against hepatic damage caused by trypanosomiasis

Dkhil et al. (2020)

Artemisia abyssinica

Methanol and dichloromethane extract

Mice (T. congolense)

100, 200 and 400 mg/kg

Reduced parasitemia

Feyera et al. (2014)

Pterocarpus santalinoides

Hydroethanol leaves extract

Rat (T. brucei)

0.0625 mg/mL

Reduced trypanosomiasis

Obi et al. (2019)

Aloe gilbertii

Exudate containing rhein, aloin, and aloe-emodin

Mice (T. congolense)

200 and 400 mg/kg

Reduced the level of parasitemia

Tewabe et al. (2014)

Morus nigra

Tincture

Mice (T. cruzi)

25 μL

Reduced Chagas disease progression

Montenote et al. (2017)

Syzygium aromaticum

Essential oil of Syzygium aromaticum

Mice (T. cruzi)

100 mg/kg

37.5% inhibition

Junior et al. (2018)

402  Natural products in vector-borne disease management

TABLE 4  Patents filled with reference to natural product or herbal formulation for management of trypanosomiasis. Patent number

Patent title

PCT/JP2005/017927

Antitrypanosomiasis agent

WO2017/025416

Compounds, pharmaceutical composition, and combination containing said compounds and their use to prevent or treat Chagas disease, African human trypanosomiasis, African animal trypanosomiasis, and leishmaniosis

PCT/GB20 16/050406

Thiazole derivatives for the treatment of animal trypanosomiasis

CN201710615059.5A

Compound capable of killing Trypanosoma brucei and application thereof in treatment of trypanosomiasis

CN2010800509473A

Antitrypanosomiasis vaccines and diagnostics

JP2010163039A

Antitrypanosoma and trypanosomiasis

CN201510413561.9A

It is a kind of can it is sun-proof and can prevention of malaria, trypanosomiasis, and snail fever composition

CN201780012184.5A

For treating the composition and method of South American trypanosomiasis

JP2004200142A

Preventive/remedy for trypanosomiasis

PCT/EP2006/067149

African trypanosomiasis therapy with a nanobodyconjugated human

EP01903554A

Tubulin-based vaccine against trypanosomiasis

4511/CHENP/2012

Antitrypanosomiasis vaccines and diagnostic

LU101117A

Method for producing a composition comprising a 3-Op-coumaroyal ester of tormentic acid from a plant cell culture, application thereof as antiparasitics agent for the treatment of trypanosomiasis

2547/DELNP/2007

Antitrypanosomiasis agent

JP2008531517A

Pharmaceutical compositions containing nitrovinylfuran derivatives for the treatment of leishmaniasis and trypanosomiasis

US12/829,804

Bisbenzamidines and bisbenzamidoximes for the treatment of human African trypanosomiasis

APAP/P/1990/000180A

Pharmaceutical composition for the treatment of protozoal diseases particularly of trypanosomiasis, comprising d-carnitine or an acyl derivative of dcarnitine

Management of trypanosomiasis  Chapter | 15  403

TABLE 4  Patents filled with reference to natural product or herbal formulation for management of trypanosomiasis—cont’d Patent number

Patent title

US06/039,706

Compositions and methods for the treatment of chronic trypanosomiasis infections

GB08115815A

Compositions for the treatment of chronic trypanosomiasis infections

EP79301233A

Compositions for the treatment of chronic trypanosomiasis infections

PCT/ES2012/070550

Pharmaceutical composition comprising isometamidium chloride in solution for the treatment of trypanosomiasis in animals

US05/714,156

Method for the control of trypanosomiasis

CN2004800339458A

Novel phenol derivative, and antitrypanosomiasis medicine with the phenol derivative as effective ingredient

US13/859,717

Saponins and chromans derivatives mixture compositions against leishmaniasis, trypanosomiasis americana, malaria, trypanosomiasis africana, and Fasciola hepatica

US15/600,183

Compounds and compositions for the treatment of parasitic diseases

FIG. 2  Possible mechanism of action of natural products against trypanosomiasis.

404  Natural products in vector-borne disease management

Conclusion The neglected tropical diseases (NTDs) including human African trypanosomiasis (sleeping sickness) affect people worldwide and affecting millions of lives and require serious attention of healthcare professional toward development of effective medication. Recently, coronavirus disease 2019 (COVID-19) outbreak again creates a serious concern worldwide. The current chemotherapy has limited option and has their own limitation of absorption, toxicities, short duration of action, and the emergence of trypanosomal resistance. Research on considerable number of natural products with diverse molecular structures has revealed antiparasitic potency in the laboratory through series of in vitro and in vivo studies is included in the present chapter. Several plants, their extracts, and phytochemicals as an evidence from current chapter demonstrated a lead molecule for future drug development. Further, more focused research is required to confirm the mechanism of action and their drug development process. Additionally, more precise clinical research is required.

Conflict of interest The authors declare that there are no conflict of interest.

Sources of funding None.

Acknowledgment The authors are thankful to Faculty of Pharmacy, DIT University, Dehradun, India, for constant encouragement.

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Management of trypanosomiasis  Chapter | 15  411 Talakal, T.S., Dwivedi, S.K., Sharma, S.R., 1995a. In vitro and in vivo therapeutic activity of Parthenium hysterophorus against Trypanosoma evansi. Indian J. Exp. Biol. 33 (11), 894–896. Talakal, T.S., Dwivedi, S.K., Sharma, S.R., 1995b. In  vitro and in  vivo antitrypanosomal activity of Xanthium strumarium leaves. J. Ethnopharmacol. 49 (3), 141–145. https://doi. org/10.1016/0378-8741(95)01313-x. Tasdemir, D., Kaiser, M., Demirci, B., Demirci, F., Baser, K.H.C., 2019. Antiprotozoal activity of Turkish Origanum onites essential oil and its components. Molecules 24 (23), 4421. https://doi. org/10.3390/molecules24234421. Tauheed, A.M., Mamman, M., Ahmed, A., Suleiman, M.M., Balogun, E.O., 2020. In vitro and in vivo antitrypanosomal efficacy of combination therapy of Anogeissus leiocarpus, Khaya senegalensis and potash. J. Ethnopharmacol. 258, 112805. https://doi.org/10.1016/j.jep.2020.112805. Teixeira, T.L., Teixeira, S.C., da Silva, C.V., de Souza, M.A., 2014. Potential therapeutic use of herbal extracts in trypanosomiasis. Pathog. Glob. Health. 108 (1), 30–36. https://doi.org/10.11 79/2047773213Y.0000000120. Terrazas, P., Salamanca, E., Dávila, M., Manner, S., Giménez, A., Sterner, A.O., 2020. SAR: s for the antiparasitic plant metabolite Pulchrol. 1. The benzyl alcohol functionality. Molecules 25 (13), 3058. https://doi.org/10.3390/molecules25133058. Tewabe, Y., Bisrat, D., Terefe, G., Asres, K., 2014. Antitrypanosomal activity of aloin and its derivatives against trypanosoma congolense field isolate. BMC Vet. Res. 10, 61. https://doi. org/10.1186/1746-6148-10-61. Urech, K., Neumayr, A., Blum, J., 2011. Sleeping sickness in travelers—do they really sleep? PLoS Negl. Trop. Dis. 5 (11), e1358. https://doi.org/10.1371/journal.pntd.0001358. Villa, A., Gutierrez, C., Gracia, E., Moreno, B., Chacón, G., Sanz, P.V., Büscher, P., Touratier, L., 2008. Presence of Trypanosoma theileri in Spanish cattle. Ann. NY Acad. Sci. 1149, 352–354. https://doi.org/10.1196/annals.1428.016. Wamwiri, F.N., Changasi, R.E., 2016. Tsetse flies (Glossina) as vectors of human African trypanosomiasis: a review. Biomed. Res. Int. 2016, 6201350. https://doi.org/10.1155/2016/6201350. Wang, C.C., 1995. Molecular mechanisms and therapeutic approaches to the treatment of African trypanosomiasis. Annu. Rev. Pharmacol. Toxicol. 1995 (35), 93–127. https://doi.org/10.1146/ annurev.pa.35.040195.000521. WHO, 2020. https://www.who.int/news-room/fact-sheets/detail/vector-borne-diseases. (Accessed 30 June 2021). Wright, A.D., Goclik, E., König, G.M., Kaminsky, R., 2002. Lepadins D-F: antiplasmodial and antitrypanosomal decahydroquinoline derivatives from the tropical marine tunicate Didemnum sp. J. Med. Chem. 45 (14), 3067–3072. https://doi.org/10.1021/jm0110892. Zulfiqar, B., Jones, A.J., Sykes, M.L., Shelper, T.B., Davis, R.A., Avery, V.M., 2017. Screening a natural product-based library against kinetoplastid parasites. Molecules 22 (10), 1715. https:// doi.org/10.3390/molecules22101715.

Further reading Amazigo, U.V., Leak, S.G.A., Zoure, H.G.M., Okoronkwo, C., Diop-Ly, M., Isiyaku, S., Crump, A., Okeibunor, J.C., Boatin, B., 2021. Community-directed distributors—the “foot soldiers” in the fight to control and eliminate neglected tropical diseases. PLoS Negl. Trop. Dis. 15 (3), e0009088. https://doi.org/10.1371/journal.pntd.0009088. Hannaert, V., 2011. Sleeping sickness pathogen (Trypanosoma brucei) and natural products: therapeutic targets and screening systems. Planta Med. 77 (6), 586–597. https://doi.org/10. 1055/s-0030-1250411.

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Chapter 16

Concept of vector-borne diseases in Ayurveda: A review Manindra Mohan Shrivastavaa, Umesh Kumar Patilb, Kamal Shahc, Mayank Krishna Kulshresthad, Durgesh Nandini Chauhane, Awdhesh Prasada, and Nagendra Singh Chauhanf a

Shri N.P.A., Govt. Ayurvedic College, Raipur, Chhattisgarh, India, bPhytomedicine and Natural Product Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour Vishwavidyalaya (A Central University), Sagar, Madhya Pradesh, India, cInstitute of Pharmaceutical Research, GLA University, Mathura, Uttar Pradesh, India, dDepartment of Rasashastra Avum Bhaisajya Kalpana, Government Ayurveda College, Bilaspur, Chhattisgarh, India, eColumbia Institute of Pharmacy, Raipur, Chhattisgarh, India, fDrugs Testing Laboratory Avam Anusandhan Kendra (State Government Lab of AYUSH), Government Ayurvedic College, Raipur, Chhattisgarh, India

Introduction Ayurveda looks into causes, indications, and remedial options for numerous diseases, such as transmissible diseases. It covers pathogenic and nonpathogenic organisms, which are found in the human body. It also includes parasites, worms, and other microbe descriptions. Ayurveda researchers provided details on pathogenic organisms, including their types and nature, with their role in disease progression. Later on, Ayurveda concentrated on epidemics and infectious diseases. Ayurvedic physicians also discussed natural treatment options for vector-borne diseases, such as the use of plants and plant-based formulations. Ayurveda is the world’s oldest scientifically codified medical system. According to Ayurveda, there are three types of transmissible diseases: Agantukaroga, Janapadodhwamsa, and Krimi.

Agantuka roga Agantuka roga are the result of external factors, some of which are Bhoota, Visha, Vayu Agni, Kshata (injuries), Bhagna, Kama, Krodha, and Bhaya. According to Ayurveda, Bhoota are microorganisms that cause disruption in humans. The names Samsargaja (Sharma, 2001a), Upasargaja (Sharma, 2001b), and Sankramika roga (Sharma, 2001b) are used in Ayurveda to designate communicable and transmittable diseases. Acharya Susruta placed disease transmission like Upasargaja and Samsargaja within Daiva Bala Pravritta Vyadhi Natural Products in Vector-Borne Disease Management. https://doi.org/10.1016/B978-0-323-91942-5.00013-6 Copyright © 2023 Elsevier Inc. All rights reserved.

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(curses of humiliated divine beings) while classifying ailments (Sharma, 2001c). Vagbhatta is mentioned under Agantuja Rog (exogenous disease) (Gupta, 2003) that are occurred by Bhoot (microscopic creatures), Vayu (polluted air), and other factors.

Modes of transmission of diseases Regarding Kushta Roga, Acharya Sushruta and Vagbhatta discussed disease transmission modes (skin disorder) (Sharma, 2001d). By touching the patients’ body frequently, eating, breathing their expired air, sitting together, sleeping, wearing dress, garland, and ungentlemanly diseases such as Jwara (fever), Kushta (leprosy and some skin diseases), Netrabhishyanda (conjunctivitis), Sosha (consumption-pulmonary TB), and Aupasargika Rogas (infectious diseases) spread from person to person. The following are some examples of how this concept can be explained (Table 1). Janapadodhwamsa Environmental disasters such as pandemic and epidemic diseases are explained in this section. Charak Acharya has detailed causes, manifestations, prevention, and management of transmissible diseases, as well as factors like polluted air, water, land, and unusual weather that can devastate a group health (epidemics) (Tripathi, 2000a,b).

TABLE 1  Mode of transmission. Direct

Indirect

Direct/indirect

Gatra samsparsat – Touching the skin (body) – Direct skin-to-skin, and mucosa-to-mucosa contact

Vastropayoga – Sharing of clothes – Fomite-borne

Saha bhojanat – Taking a meal together – Food and beverages (ingestion)

Niswasat – Contact with exhaled air – Droplet infection (airborne) (inhalation)

Malyopayoga – Sharing of garlands – Fomite-borne

Saha shayyat – Sleeping together – Direct contact

Anulepana – Sharing of cosmetics – Fomite-borne

Saha asanat – Sitting together – Direct contact

Concept of vector-borne diseases in Ayurveda: A review  Chapter | 16  415

Krimi Another instance where transmissible diseases are mentioned is in the context of parasite infestation (Krimi). Ayurveda describes a variety of endoparasites and ectoparasites—both large and small—that lives in different parts of the body and cause disease. Masurika (chickenpox), Romantika (measles) (Shrikanthamurthy, 2018a), Upadamsa (Shrikanthamurthy, 2018b) (gonorrhea), and Phiranga (Misra, 2003) are among Aupasargika Rogas mentioned (Syphilis).

What are vectors? Vectors that spread infectious diseases from person to person are living organisms. Many carriers suck disease-causing microbes during a blood meal from an infected host (human or animal) and subsequently inject them into a new host during their next blood meal. The most common disease carriers are mosquitoes. Others include fleas, flies, ticks, sandflies, bugs, and some species of freshwater snails (Bargale and Shashirekha, 2016a). Table  2 shows the most common vector-borne diseases in India, according to the National Vector Borne Disease Control Programme (Bargale and Shashirekha, 2016b). 1. Malaria (Vishama Jvara) (CCRAS, 2014a,b) a. Malaria is the most common disease spread by mosquitoes. b. Malaria is a word that literally means “bad air.” It is an infection caused by a protozoal parasite. c. Infection with Plasmodium parasites causes malaria, and infected female Anopheles mosquitoes transmit it to humans. d. An estimated 300–500 million clinical cases of malaria and 1.1–2.7 million deaths each year are caused by Plasmodium falciparum. e. In 2003, India reported 1.65 million cases of malaria, with 0.7 million cases of P. falciparum malaria. f. This disease threatens the lives of 40% of the world’s population. g. In India, 80% of the population lives in malaria-free areas. In India, the malaria burden is concentrated in the 20% of the population who live in malaria-endemic areas, accounting for 80% of the total. h. Mosquitoes breed in polluted bodies of water, brackish water, wells, cisterns, fountains, overhead tanks, among other places.

TABLE 2  Most common vector-borne diseases in India. Disease

Vector

Malaria, dengue, chikungunya, filaria, Japanese encephalitis

Mosquito

Kala azar

Sandfly

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Symptoms i. Fever (high grade) ii. Body pain iii. Chills and rigors iv. Headache v. Nonspecific symptoms Severe malaria—consequences i. Jaundice ii. Liver failure iii. Bleeding problems iv. Multiorgan failure v. Seizure vi. Kidney failure vii. “Death” also a possible outcome (Gupta, 2019) Intervention/approaches (Vaidya, 1997) Charak and Sushruta have called this fever as Agantu fever because of vata Prakopa in the body. In Ayurveda, it is said that Santant Vishama fever rises twice a day. Anyedushka fever rises once a day. Tratiyaka fever rises on the third day. Chaturthak Visham fever rises after 2  days. Sant Vishma Jwara remains constant for 7, 10, and 12 days. Because there are special ups and downs in it, it is called Visham Santat fever (Su.U.36/53-65). The following medicines are beneficial for all Visham fevers: (1) Guduchayadi Kwath: Guduchi, Musta, Chiraita, Triphala, Daru Haldi, Prativisha, Katuki, Karanjaboj, Saptaparna, Parpat, Dhamasa, Kantakari, Cinchona, and two Tola with equal quantities of Kwath with Pippali powder should be given twice a day. (2) Mix 4 Ratti of red alum with a little sugar candy should be given thrice a day. (3) Godanti Bhasma should be given thrice a day with sugar candy in the flow of 4 Ratti. (4) Somla is being used in Ayurveda for malaria from time immemorial, for example, Harital is prepared by placing 1 Tola of red Fitkari in the middle of the powder of 5 Tola, with Gajaput and Bhasma in a size of 1 ratti once a day with Tulsi Swaras. Visham fever can be pacified by giving it three or four times. It has been found to be lethal for Somal schizonts and gametocytes. (5) Guduchi 4 in. long, Pippali 3 nos., Ajwain 4 Masha, and Badam 7 Haritaki 1 day and night for recurring mild fever. After soaking, filtering, and mixing a little salt should be given once in the morning for 15 days. (6) Nimbadi Churna (B.P.), Arishtadichurna (Yoga Chintamani): 10 Neem Leaves, Trikatu, Triphala, Trilavan, Dviksar Each1 Tola, Ajwaen 5 Tola should be given 3–4 Masha, 2–3 times/day. (7) Mahasudarshan Churna, Tribhuvan kirti, and Parijat vati are Ayurvedic medicines that have been proven to treat malaria (Ghate et al., 2012). (8) The interventions/approaches mentioned here are based on earlier CCRAS research (CCRAS, 1981, 2002a,b).

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TABLE 3  The formula of Ayush 64. 1.

Alstonia scholaris

Saptaparna

Bark aqueous extract

100 mg

2.

Picrorhiza kurroa

Katuki

Root aqueous extract

100 mg

3.

Swertia chirata

Kiratatikta

Whole plant aqueous extract

100 mg

4.

Caesalpinia crista

Kuberaksha

Seed powder

200 mg

Ayush 64 tablet: Ayush 64 contains 4 ingredients (Table 3). ● ● ●

Give 2 g honey 3 times per day for one week for adults. Give 1 g of honey 3 times per day 5–7 days for children aged 5 to 12 years. Give 500 mg of honey 3 times per day for 5–7 days for infants (younger than 5 years).

2. Dengue a. In Ayurvedic terms, dengue is classified as Abhishangaja Jvara, with Pittaja as the predominant pathological ground. b. Rakraja and Sannipataja Jwara are represented by complications. c. The dengue virus causes dengue fever. d. Dengue fever is pronounced “dengee.” e. From time to time, it manifests itself as an epidemic. f. The disease is also known as “break-bone fever” (Haddi Tod Bukhar). g. In tropical and subtropical countries, this is a common disease. h. The causative agent is a virus. i. The main vector is mosquito Aedes aegypti, also known as tiger mosquito. j. Transmission is made easier by the environment. k. Environmental considerations: • The disease season is from July to December. • Biting occurs primarily during the daytime. • Ideal temperature should be between 20°C and 28°C. • Humidity is at an all-time high. • In fresh water pools, the tiger mosquito breeds. Vulnerability to dengue • Vulnerability to dengue affects persons of all ages and genders. • Those who have previously been infected are also vulnerable. • If reinfected with dengue, the patients are more likely to develop a severe form of the disease. Symptoms 1. Fever 2. Pain behind the eyes 3. Headache 4. Joint pain

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5. Muscle pain 6. Skin rash In a small percentage of cases, the disease progresses to life-threatening dengue hemorrhagic fever, which causes low blood platelet levels, plasma leakage, and bleeding, or dengue shock syndrome, which causes dangerously low blood pressure (Bargale and Shashirekha, 2016c). Dengue hemorrhagic fever 1. A decrease in the platelet count (a blood component) causes bleeding 2. Gum bleeding 3. Bleeding into joints 4. Bleeding beneath the skin that discolors it 5. Petechial hemorrhages are a common complication 6. Black stools or even frank blood Ayurvedic view (Kumar Dilip, 2004) Dengue is a disease transmitted by mosquitoes. Ayurveda has identified that certain severe ailments can be developed due the bite of insects including mosquitoes. There are five different types of mosquitoes mentioned in Susrutha samhitha. It is quite difficult to have a direct correlation of dengue. Fever with any disease mentioned in Ayurvedic classics. But certain symptoms present in dengue fever have close similarity with different stages of the following diseases. 1. Amavatha (madhav nidan) Prodromal stages of the dengue fever are almost the same as those of Amavata, where the symptoms like generalized muscle pain, joint pain, anorexia, and fever are exhibited. 2. Sannipatha jwara Vatapitha Sannipatha jwara mentioned in Charaka Samhita (C.Chi.3/63) and Ashtanga Hridaya (A.H.Ni.2/32&34) can be correlated with the first stage of dengue fever. The first stage of the classical dengue fever is presented with generalized joint pain, bone pain, headache, red eyes, anorexia, vomiting, and fever. Hemorrhagic manifestations mentioned in Sannipatha Jwara can be correlated with the second stage of the dengue fever. Here, Sannipatha Jwara treatment can be adopted. 3. Vishama jwara (C.Chi.3/28-35) Vishama jwara mentioned in Charaka Samhita may be correlated with dengue fever because here the nature of fever occurring is the same as that of dengue fever, that is, saddleback fever (C.Chi.3/32). In Dathugata Jwara, symptoms occur according to the deterioration of Datus; myalgia in Rasadusti, rashes, bleeding in Rakthadushti, anorexia malaise in Mamsadusti, etc. 4. Aganthuka jwara (A.H.Ni.2/41) Dengue fever can be correlated with Abhishanga Jwara (C.Chi. 3/68), which is one among the four types of Aganthuka Jwara. In Susrutha Samhitha,

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­ osquito bite is considered to be a poison. In the Samprapthi Ghataka of m Aganthuka Jwara (A.H.Ni3/3), Vatha Kopa, followed by, Raktha Dushti occurs. This is similar to the Samprapthi of Aganthuka Jwara and Visha. In Visha Samprapti, Raktha Dhathu is first vitiated, followed by Kapha, Pitha, and Vata. In the first stage of this fever, Kapha predominant symptoms like anorexia, nausea, vomiting, and generalized muscle pain are seen. In the second stage, which is a Pitta predominant condition in which high fever and hemorrhage are seen? Last, due to the Vata aggravation, collapse, shock, and coma occur. Considering the aforementioned factors, it may be appropriate to incorporate the treatment for Gara, with a special emphasis on fever. Here, the significance of Langhana is less. 5. Rakthapitta: (A.H.Ni.3/3) As the hemorrhagic manifestations are predominant in dengue hemorrhagic fever, it can be correlated with Ubhayasritha Rakthapitta, where bleeding occurs through the mouth, nose, and skin (A.H.Ni.3/8). Dosha and Dathu predominance Dosha First stage: Kapha and Kaphavatha Second stage: Vatapitta and Pitta Third stage: Vata Dathu (1) Rasa: Anorexia, nausea, and vomiting (2) Raktha: bleeding and rashes (3) Mamsa: myalgia (4) Asthi: bone pain (5) Majja: joint pain Sadhyasadhyatha First stage (DF): Sadhya Second stage (DHF): Krichrasadhya Third stage (DSS): Asadhya Treatment principle First stage: Jwarahara Second stage: Jwarahara Vishahara Rakthapithahara Third stage: Ojovardhana (which improves immunity) Treatment 1. The symptoms of the prodromal stage of classical dengue fever are similar to those of Amavatha. Hence, treatment should be focused on alleviating Ama. Following medicines can be used at this stage: i. Decoctions of Musthadi Gana (S.Y.), Nagara(S.Y.), Parpadakamritha(S.Y.), and Kirathathiktha (S.Y.)

420  Natural products in vector-borne disease management

ii. Amritharishta (S.Y.), Parpadakadyarishta (S.Y.), and Sudarsanasava (S.Y.) iii. Sudarsana Choorna (S.Y.) and Shaddharana Choorna (S.Chi.2/2) iv. Vettumaran Gutika (S.Y.) and Agnikumara Rasa (S.Y.) 2. When the disease develops as a Sannipatha Jwara, the aforementioned treatment may be continued along with the following combination. i. Patoladi Kwatha (A.H.Chi) ii. Aragwadhadi Kwatha (A.H.Su.15/22-24) iii. Panchathikthakam Kwatha (S.Y.) iv. Guluchyadi Kwatha (A.H.Su.15/21) v. Chinnodbhavadi Kwatha (S.Y.) vi. Pachanamritha Kwatha (Chi. Manjari41-42) 3. In the second stage of the disease, patients show the symptoms of Vishamajwara. In this stage, we can use the following Kwatha and Gutika. i. Patolakaturohinyadi Kwatha (A.H.Su.15/21) ii. Drakshadi Kwatha (A.H. Chi.1/56-58) iii. Vilwadi Gutika (A.H.U.36/86) iv. Mrithasanjeevani Gutika (S.Y.) v. Dasangam Gutika (A.H.U.37/29) 4. External applications like dhara with milk, Lepana with Lakshadi Taila can be used along with the internal medication (Yogamritham). 5. In the hemorrhagic stage of the disease, management is very difficult. Following medicine may be tried at this stage. Blood transfusion is also required. i. Swarasa of vasa mixed with sugar and honey (A.H. Chi.2/28) ii. Hingula Bhasma mixed with Vasa Swarasa (Chi. Manjari) iii. Chadrakalarasa (Chi. Manjari) iv. Sahasravedhi Bhasma (Chi. Manjari) 6. In the final condition of this stage, ghritha preparations may be used: i. Thikthakam Ghrita (A.H. Chi.19/3-8) ii. Vrusha Ghritha (A.H. Chi.2/43-45) 7. In the third stage Ojovardhana drugs like Rasayana can be used. i. Pippalirasayana (A.H.U.39/120-124) Preventive aspects There are no preventive medicines but only preventive measures. ●

Mosquito eradication 1. Doopana using Aaranya Thulasi, Aparajitha, Pata, Nirgundi, Sarshapam, and Medhika. 2. Decoctions made up of Nimba Taila, Arishtaka Choorna, and Tamalapatra. 3. Application of coconut oil on the body. Dengue management: (according to CCRAS)

1. The following general instructions could be given to the patients (Table 4): ● Avoid chilled foods and beverages, as well as strenuous exercise and stressful situations. ● Get enough rest and sleep.

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TABLE 4  Dengue management for general instructions. 1.

2 g of Shunthi (dry ginger) powder twice per day

With infusion made with 100 mL (1/2 glass) boiling water and 5 g (one teaspoonful) of Guduchi (Giloy) powder One teaspoon of honey can be added to the infusion

Note: Children (aged 6 to 12 years) onefourth of the dose

2.

Mix 10–15 Tulsi leaves and 10–15 g of coriander powder in a liter of water that has been boiled for 10 min

Cooled to room temperature

Consumed at 3- to 4-h intervals throughout the day

Eat light, nutritive, warm, and easily digestible foods. Take care of your personal and environmental hygiene. ● Have a glass of cold milk with a sugar candy. 2. Other instructions for prevention: ● Make use of a mosquito net ● Use mosquito repellent ● Keep the patient under a mosquito mesh ● Do not leave open water and pooled clean water ● Nets and screens for doors and windows ● Keep your body covered by wearing long-sleeved shirts, pants, shoes, and socks 3. Drug ● ●

Any of the following formulations can be added to the aforementioned routine treatment: For fever ● ● ● ●

●

● ●

Sudarshanaghana Vati Amritottara Kwath Tulsi Svarasa In the beginning, Kwath made of Musta, Kiratatikta, Dhamasa, and Parpat may be recommended. Add Yashtimadhu, Rakta Chandana, and Vasa as well as sugar candy (Mishri) in case of a hemorrhagic condition. Godanti Bhasma Shamshamani Vati For dehydration

●

Green coconut water

422  Natural products in vector-borne disease management ● ● ●

Dhanyakadi Hima Dhaniya, Vasa, Parpat, Amla, Draksha Shadanga Paneeya Water of cardamom and clove Any of these fluids can be given in appropriate amounts at intervals of 3–4 h. Note:

●

The dosage and duration of treatment can be prescribed by the doctor based on the condition of the patient (CCRAS, 2016).

4. Chikungunya Chikungunya is a virus spread by the tiger mosquito (Aedes aegypti). In 2006, 14 lakh people in India were infected with Chikungunya. Symptoms 1. Body ache 2. Pain in small joints 3. Chills 4. Fever 5. Headache 6. Rashes on the skin (Bargale and Shashirekha, 2016d) Chikungunya: ayurveda point of view (CCRAS, 2009) ●

●

●

●

There is no mention of Chikungunya in Ayurveda. This is comparable to the condition in which jwar is linked to arthritis. We can find references in the Ayurveda literature where fever is linked to arthralgia/arthritis. Vata Kapha Jvara and Vata Pitta Jvara have symptoms that are similar to Chikungunya fever. Bhava Prakasha’s description of Sandhigata Sannipata Jvara is similar to chikungunya fever. Joint pains with swelling, sleeplessness, cough, and fever are all symptoms of Sandhigata Sannipata Jvara. According to Bhela Samhita, Sharada jvara is a seasonal fever that usually occurs before the rainy season and is caused by viral fevers (Sutra Sthana, 13).

Management of chikungunya in Ayurveda Chikungunya is a contagious disease that does not cause death. Chikungunya treatment modalities can be divided into two categories: Symptom modifiers (Table 5) and general health promoters (Table 6). Along with this, ways to clean the environment for vector control have also been told (Table  7). According to the symptoms (Table 8) and for general health (Table 9), single drug is described in chickungunia by the CCRAS. Antimicrobial agents has been used as vector control measures. Fumigation has been described in which the medicines of Ayurveda work effectively (Table 10). Single drugs in chikungunya fever

Concept of vector-borne diseases in Ayurveda: A review  Chapter | 16  423

TABLE 5  Symptom modifiers. 1.

Antitussive

Kasa hara

2.

Antipyretics

Jvara hara

3.

Antidyspneic

Swasa hara

4.

Analgesics

Vedanaa hara

5.

Antidiarrheal

Atisara hara

6.

Skin diseases

Kushtghna

7.

Antiinflammatory

Sotha hara

8.

Antipruritic

Kandughna

TABLE 6  General health-promoting agents. 1.

Immunomodulator

Rasayana

2.

Tonic

Balya

TABLE 7  Vector control measures/agents for environmental cleanliness. 1.

Antimicrobial agents

Bhuthaghna and Rakshoghna

2.

Fumigation

Dhoopana

Fever, arthritis, arthralgia, and other chikungunya symptoms are treated with Ayurvedic polyherbal/herbo-mineral/metallic formulations (Table  11). In Bhaishajya Ratnavali, there is a description of Jwara Har Dhuma Churna, which can be very beneficial in chikungunya, which is mentioned by CCRAS (Table 12). 5. Filariasis (Shlipada) India is home to the world’s largest endemic filariasis population. India now accounts for roughly 40% of world’s filariasis burden and 50% of those at risk for infection. It is a vector-borne disease (Table 13), with a periodical episode of fever, followed by lymphadenitis (Table 14). Ancient Indians called filariasis shlipada. According to the definition, shlipada means “an increase in the size of the foot.” The word “Shlipadam” comes from the phrase “shilavat padam shlipadam,” which literally means “stone-hard limb or foot.” (Bargale

424  Natural products in vector-borne disease management

TABLE 8  Symptom modifiers.  1.

Emblica officinalis Geartn.

Amalaki

 2.

Rubia cordifolia Linn.

Manjishta

 3.

Terminalia bellirica Roxb.

Vibhitaki

 4.

Cyperus rotundus Linn.

Musta

 5.

Terminalia chebula Retz.

Haritaki

 6.

Picrorhiza kurroa Royle ex. Benth

Katuki

 7.

Azadirachta indica A.Juss

Nimba

 8.

Pluchea lanceolata Oliver & Hiern

Rasna

 9.

Ocimum sanctum Linn.

Tulasi

10.

Commiphora wightii (Arn.) Bhandari

Guggulu

11.

Cissampelos pareira Linn.

Patha

12.

Curcuma longa Linn.

Haridra

13.

Andrographis paniculata Linn.

Bhunimbar

14.

Boswellia serrata Roxb.

Sallaki

15.

Zingiber officinale Rosc

Sunti

16.

Vitex negundo Linn.

Nirgundi

17.

Tinospora cordifolia Willd. Miers

Guduchi

TABLE 9  General health promoters. 1.

Glycyrrhiza glabra Linn.

Yastimadhu

2.

Withnia somnifera Dunal

Aswagandha

3.

Emblica officinalis Gaertn.

Amalaki

4.

Tinospora cordifolia Willd. Miers

Guduchi

and Shashirekha, 2016e) Ayurveda medicines are very effective in Shlipada by CCRAS (Table 15). 6. Japanese encephalitis (JE) Japanese encephalitis is a mosquito-borne encephalitis infecting mainly animals and incidentally humans. Only about 1 in 250 JE infections result in

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TABLE 10  Vector control measures. 1.

Shorea robusta Linn.

Sala

2.

Ocimum sanctum Linn.

Tulasi

3.

Desmodium gangeticum DC

Salaparni

4.

Azadirachta indica A. Juss

Nimba

5.

Commiphora wightii (Arn.) Bhandari

Guggulu

6.

Clitorea terneta Linn.

Aparajita

7.

Nardostachys jatamansi DC

Jatamansi

8.

Acorus calamus Linn.

Vacha

symptomatic illness (Table 16). It is an inflammation of the brain tissue due to infection, which is most often caused by viruses that enter the blood stream and then the cerebral spinal fluid, leading to the destruction of neural cells and inflammation of brain parenchyma (Bargale and Shashirekha, 2016f). In this disease, the result of Ayurveda medicine (Table 17) based on symptoms has been observed, but its description is not found directly in the Ayurveda literature. 7. Kala Azar Kala azar is a vector-borne disease (Table 18). There is no direct reference to kala azar in the Ayurveda literature. Its treatment in Ayurveda is also done keeping in mind the symptoms (Table 19). Kala azar ayurvedic treatment (Byadgi, 2011): a. Treatment of the spleen: plihaghna and plihodara management. b. Antihelminth/parasitic: Krimighna drugs. c. Antipyretics: Jvaraghna drugs. From time to time, clinical studies have been done in Ayurveda on vectorborne diseases, which have yielded remarkable results, using which these diseases can be prevented, which are shown in Table 20. Prevention from the vector-borne diseases (Bargale and Shashirekha, 2016g). 1. Reducing the source where the mosquito can breed i. Get rid of old containers, tins, tires, among other things. ii. Clean the tray beneath the refrigerator. iii. Keep water from becoming stagnant in and around your home. iv. Unclog any clogged drains. v. Fill the ditches with water. vi. At least once every seven days, completely empty and refill room air coolers and flower vases.

426  Natural products in vector-borne disease management

TABLE 11  Ayurvedic polyherbal/herbo-mineral/metallic formulations for chikungunya.  1.

Jirna ivara

Arogyavardhani Gutika

Visarpadi Chikitsa Adhyaya 20 verse106–108 Rasaratna Samuccahaya

 2.

Jwara

Ananda bhirava Rasa

Jvaradhikara, Adhyayo 2 verse 103 Rasendra Sara Samgraha

 3.

Jwara

Sudarshan Curna

Jvaradhikara verse 308–312 Bhaishajya Ratnavali

 4.

Sandhi shotha

Yogaraj Guggulu

Amavatadhikara verse 90–93 Bhaishajya Rotnavali

 5.

Sandhi shotha

Maha Yogaraj Guggulu

Madhyama Khanda Adhaya 7, verse56–60 Sarangadhara Samhita

 6.

Jwara

Sadanga kvatha Curna

Chikitsa Sthana 1 verse 15 Astangahridaya

 7.

Sandhi shool

Maharasnadi Kvatha Curna

Madhyama Khanda Adhyaya 2, verse 89–91 Sarangadhara Samhita

 8.

Parva shopha

Rasna erandadi Kvatha Curna

Kashaya Prakarana; verse 428, Sahasrayoga

 9.

Vata roga, Amavata

Rasnadi Kvatha Curna

Kashaya Prakarana verse 396, Sahasrayoga

10

Jwara

Panchatikta Kvatha Curna

Jvara Chikitsa; verse 132 Cakradatta

11.

Jwara

Patoladi Kvatha Curna

Sutrasthana, 15 verse 15 Astangahridaya

12.

Kapha Jwara

Nimbadi Kvatha Curna

Jvara Chikitsa; verse 101 Cakradatta

13.

Jwara, Sannipata Jwara

Darunagaradi Kvatha Curna

Kashaya Prakarana; verse 34, Sahasrayoga

14.

Parsva shoola, Jwara

Dasamula Kvatha Curna

Kasarogadhikara; verse 13, Bhaisajya Ratnavali

15.

Sannipata Jwara

Chinnodbhavadi Kvatha Curna

Kashaya Prakarana; verse 38 Sahasrayoga

16.

Vata roga

Gandharvahastadi Kvatha Curna

Kashaya Prakarana verse 394, Sahasrayoga

17.

Jeerna Jwara, Sannipata Jwara

Amritattaro Kvatha Curna

Kashaya Prakarana, verse 30 Sahasrayoga

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TABLE 12  Bhaishajya Ratnavali describes Jvara hara Dhuma churnas. 1.

Aparajitha Dhooma Curna

Devadaru, Nimba, Sarja, Vacha, Arka, Agaru, Gandha trina, and Guggulu are mixed and burned together

Jwaradhikara, verse 255, Bhaishajya Ratnavali

2.

Astanga Dhuma

Vacha, Sarsapa, Kushta, Yava, Nimba Patra, Haritaki, Guggulu, and Ghrita are all blended and burned together

Jwaradhikara, verse 254, Bhaishajya Ratnavali

TABLE 13  General description of filariasis. 1.

Microfilaria: 3 nematode parasites: Brugia malayi, Wuchereria bancrofti, and Brugia timori. The most common in India is Wuchereria bancrofti (98%)

Cause

2.

Culex mosquito

Vector

3.

Coastal areas due to hot and humid conditions

Prevalent area

TABLE 14  Clinical features of filariasis. 1. Asymptomatic

3. Fever

5. Limb swelling

2. Pain

4. Disfigurement of limbs

6. Allergic reactions may occur in some patients

vii. Keep the water tanks and containers tightly covered to prevent mosquitoes from getting inside and breeding. 2. Killing the mosquito and larvae i. Spraying the entire interior of the house. ii. When spray workers come to spray your house, do not turn them away. iii. Spraying behind photo frames, curtains, calendars, housecorners, and stores. iv. Incorporating mosquito larva-eating small fish (Gambusia, Lebister) into bodies of water. v. Pouring oil over water sources. vi. Using insecticidal sprays at least once a week in all areas of the house. vii. Spraying DDT, malathion, pyrethrum, and other pesticides. 3. Personal protection i. Wear clothing that covers as much of your body as possible. ii. Use mosquito repellents. iii. Use mosquito nets that have been treated with insecticides.

TABLE 15  Intervention according to CCRAS research in Shlipada (CCRAS, 2014a,b). 1.

Acute Shlipada swelling with fever

Ayush 64 tablet with water

For 2 weeks, 1 g three times a day

Saptaparna Ghana Vati with water

For 2 weeks, 1 g thrice a day

Nityananda Rasa with water after meal

For 2 weeks, 1 g twice a day

2.

Pittaja Shlipada with fever (early stage)

Sudarshana Ghana Vati with water

700 mg three times a day

3.

Chronic Kaphaja Shlipada with excessive swelling

Sudarshana Churna with warm water after meal

For 30 days, 3 g thrice/day For 2 weeks, Punarnavadyarishta after meal with water, 20 mL twice/day

Sudarshana Ghana Vati after meal

For 2 weeks, 500 mg thrice/day For 2 weeks, Punarnavadyarishta after meal with water, 20 mL twice/day

Kanchanara Guggulu and Gokshuradi Guggulu along with lukewarm water after food

For 4 weeks, 500 mg each thrice daily

Shlipadari Rasa along with Punarnava, Triphala and Pippali churna 5 g with water after food

For 30 days, 250 mg twice daily

Ayush 55 with water after meal Ingredients of Ayush 55 1. Purified sulfur 1 part 2. Purified mercury 1 part 3. Abhraka Bhasma 1 part 4. Lauha Bhasma 1 part 5. Shilajitu 3 part 6. Chitrakmool 4 parts (Plumbago zeylanica) 7. Guggulu (Commiphora wightii) 5 parts 8. Triphala 6 parts (each 2 parts) 9. Katuki 22 parts (Picrorrhiza kurroa) prepared in Nimba Swarasa (Azadirachta indica)

1 g twice day. Punarnavadyarishta 20 mL with water twice/day after meal

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TABLE 16  General description of JE. 1.

Agent

Group B arbovirus (Flavivirus)

2.

Vector

Culex mosquitoes

3.

Symptoms

Headache, fever, weakness, rapid progress to high-grade fever, seizure, neck pain, inability to speak, paralysis, and vomiting

4.

Danger signs

Paralysis, seizure, poor respiration, and unconsciousness

5.

Mostly present

Southern India, northeastern states, Haryana, Uttar Pradesh

6.

In ayurveda

Resembles Vatapittaj Jwara

TABLE 17  Ayurvedic medicines for JE (Singh, 2019). 1.

Shadanga Paniya

Replace water intake with Shadanga Paniya

After every 8 to 12 h, reprepare it

2.

Guluchyadi Kashayam Ingredients: 5 each equal part 1. Tinospora cordifolia—Giloy 2. Prunus cerasoides— Padmaka 3. Azadirachta indica— Neem 4. Pterocarpus santalinus— Lal Chandan 5. Coriandrum sativum— Dhania

In a saucepan, combine 48 g of this mixture with 768 mL water. Simmer it on a low heat setting. Simmer until only 1/8 of the liquid is left, or 96 mL. The decoction should then be filtered

For children, 1.5 mL/kg of body weight + 1/8th part Misri (crystal sugar) For adults, 96 mL + 12 g of Misri (crystal sugar)

3.

Kumar Kalyan Ras

With milk

65 mg twice a day for children

4.

Ratnagiri Ras

If used incorrectly, it could be a very dangerous medicine. As a result, only use this medication if you are certain that the encephalitis was caused by an infection. Second, after the first and second doses, this medicine causes a rise in fever. This is something you must also consider. After the third dose, it begins to reduce fever

3 mg per kg body weight

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TABLE 18  General description of kala azar (Rai, 2015). 1.

Cause

Protozoan parasite Leishmania donovani

2.

Vector

Sandfly of the genus Phlebotomus argentipes in India

3.

Synonyms

Kala azar, black fever, sandfly disease, dumdum fever, and espundia

4.

Affected areas in India

Jharkhand, West Bengal, Bihar, pockets of Uttar Pradesh

5.

Affected body organs

Liver, spleen, and bone

6.

Clinical features

i. Fullness of the abdomen due to an increase in size of the liver and spleen ii. Intermittent fever iii. A decrease in hemoglobin iv. Gray discoloration of the skin with loss of hair v. Weakness

7.

Synonym

Visceral leishmaniasis

8.

Alarming note

In developing countries, if the disease is not treated, the mortality rate can reach 100% in as little as 2 years

9.

In ayurveda

No mention of kala azar, but Satata Visham Jwara, Raktaja Krimi, and Plihodara are similar to the condition

TABLE 19  Natural treatment for kala azar (Chauhan, 2020). 1.

Tinospora cordifolia Giloy stem

Antibiotic, antibacterial, antiinflammatory, antispasmodic, and antipyretic properties reduce weakness, indigestion, fever, and many urinary tract infections

Decoction with neem peel, basil leaves

2.

Azadirachta indica—Neem leaves, twigs, bark, seeds, roots, fruits, or flowers

Antibacterial, anticarcinogenic, antiinflammatory, antioxidant, antimalarial, antimicrobial antiseptic, and antiviral properties

Powder

3.

Rubia cordifolia Linn Manjishta

Antiinflammatory, antibacterial, and antimicrobial, antispasmodic, and antioxidant properties

Decoction

4.

Spirulina

Antiinflammatory and antiviral properties

TABLE 20  Clinical studies of Ayurvedic medicine for vector-borne diseases. S. no.

Name of medicine

Clinical findings

References

1.

Ayush 64

Ayush 64 clinical trials have largely all been carried out on P. vivax malaria patients. By day 28, only 48.9% of patients had no parasites, compared with 100% of those receiving chloroquine treatment, due to significant recrudescence

Valecha et al. (2000)

2.

Ayush 64

Several uncontrolled field trials found that 82%–86% of patients were cleared of P. vivax parasites by days 7–9. Two studies suggested that symptomatic improvement was good. These showed that parasite clearance was achieved by day 6 in 72%–95% of patients

CCRAS (1987) Sharma et al. (1981)

3.

Ayush 64

Ayush 64 was administered to 29 cases; 21 of those cases responded favorably to the treatment, while the other eight were deemed unsuccessful. So far, nearly 95% of cases in the control group and 90.5% of cases in the Ayush 64 group have become parasite-free on the fourth day. The trial drug Ayush 64 was found to have good antimalarial properties in this study, with positive results in 72.41% of patients compared with 100% in the control group, and it was concluded that this drug had these properties

Chari et al. (1985)

4.

Neem, Kalmegh, and Harsingar

Neem, Kalmegh, and Harsingar are examples of traditional medicines that have been reportedly used but infrequently to treat malaria. In a clinical study in Mumbai on 120 malaria patients, 77% of them showed complete parasite eradication within 7 days of treatment with the leaf paste, and it was also determined to be safe. Along with the other NGOs in Orissa, Sambandh & FRLHT (www.iaim.edu.in), we also found it to be effective in our work in Balangir in 2011, primarily as a preventative measure

Ghate et al. (2012)

5.

Nyctanthes arbortristis Linn. (Parijat)

Ayurvedic plant Nyctanthes arbor-tristis Linn. (Parijat) is currently being used in clinical settings and has previously demonstrated ant malarial activity, with parasite clearance occurring in 76.6% of 120 patients

Godse et al. (2016)

6.

Azadirachta indica

A clinical trial of A. indica was successfully completed by 30 patients with uncomplicated Plasmodium falciparum malaria. A Juss was conducted in the tribal Tamalu and Orong villages of the Andaman and Nicobar Islands’ Car-Nicobar district, where malaria is endemic. A. Juss, a decoction of A. indica bark, was administered three times daily for 4 days in a row. The mean fever and parasite clearance times indicated a cure rate of 100%. The rate of recrudescence and reinfection was 1%. Within 21 days, a palpable spleen on day 0 stopped being palpable

Mehra (2006)

Continued

TABLE 20  Clinical studies of Ayurvedic medicine for vector-borne diseases—Cont’d S. no.

Name of medicine

Clinical findings

References

7.

Parijata Patraghanavati

In 28 cases of Plasmodium vivax malaria, this open-label study showed a highly positive response with a 90.32% cure rate. The 29th day did not see any relapse in any of these 28 cases. The remaining 03 cases had relapsed, with 1 case having a positive smear on day 15 and 2 cases having a positive smear on day 22

Bharathi et al. (2013)

8.

Indukanthaghrita

A prophylactic trial to assess the effectiveness of Kerala state’s widely used medicated ghee, Indukanthaghrita Study involved 67 patients in total, of whom 35 (74.46%) showed a good response, 11 (23.40%) a fair response, and 1 (02.12%) case showed no response. Nine patients were dropped from the study due to irregular drug intake

Bharathi et al. (2010)

9.

Latakaranja (Caesalpinia bonducella)

The antimalarial properties of cassane and norcassane type diterpenes from Caesalpinia crista, as well as their relationship between structure and activity, have been reported by Kalauni et al.

Kalauni et al. (2006)

10.

Latakaranja (Caesalpinia bonducella)

The antimalarial activity of cassane and norcassane type diterpene from the Indonesian C. crista plant against the development of Plasmodium falciparum has been reported by Linn et al.

Linn et al. (2005)

11.

Saptaparna (Alstonia scholaris R.Br.)

The antimalarial properties of this medication were reported by Gandhi and Vinayak

Gandhi and Vinayak (1990)

12.

Parijata (Nyctanthes arbor-tristis Linn.)

Pharmacological testing on Parijata reveals that it has antimalarial, antipyretic, and antimicrobial properties

CCRAS (2002a,b)

13.

Parijata (Nyctanthes arbor-tristis Linn.)

Around 120 patients were tested clinically for the safety and antimalarial efficacy of this plant’s fresh paste, and 92 (76.6%) of them showed complete relief

Karnik et al. (2008)

14.

Parijata (Nyctanthes arbor-tristis Linn.)

The antimalarial activity of Parijata has also been reported by Aminuddin et al.

Aminuddin and Subhash Khan (1993)

15.

Parijata (Nyctanthes arbor-tristis Linn.)

The antimalarial activity of Parijata has also been reported by Badam L. Rao et al.

Badam et al. (1988)

16.

Ayush 64 with Sphatika Bhasma and Guduchi Ghana Satwa

Ayush 64, Sphatika bhasma, and Guduchi satva were administered to 1194 patients in study I. 429 (8.96%) of the 896 finished cases experienced complete remission of malaria symptoms and clearance of parasitemia from blood

Saptaparna twak Ghanavati

Saptaparna tvak ghanavati completed study II. 194 (48.15%) of the 403 cases that were successfully resolved had parasitemia in the blood cleared up. Additionally, 127 people (31.51%) experienced full recovery from malaria symptoms. and a significant reduction in blood parasite load

Parijata Patra Ghanavati

Parijata patra ghanavati was administered to 430 cases in study III, 310 of which had successfully completed the course of treatment. Out of 310, 157 (50.64%) had relief from malaria symptoms and parasite removal from the blood. And 62 (20.00%) of them experienced relief from all of the symptoms of malaria as well as a significant reduction in the blood parasite load NOTE: Upon overall review, a high proportion of results were found in studies II (82.48%) and I (82.48%) (79.66%) Sphatika Bhasma and Guduchi Ghana Satwa are featured in (1) Ayush 64, (2) Saptaparna twak Ghanavati, and (3) Parijata Patra Ghanavati, respectively. Since all three trial drugs had successfully treated malaria, all formulations had therapeutic effects that ranged from 70% to 80%

Prameeladevi and Srinivas (2014)

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iv. Use mosquito repellents in the form of sprays, creams, coils, mats, and liquids. 4. Prophylactic measures of Ayurveda i. Sthana parityaga (change of residence—quarantine). ii. Dhoopana (fumigation). iii. Homa-japa (auspicious rituals). iv. Sadvritta palana (good conducts/ethics). v. Niyama (following rules and regulations). vi. Dana (charity). vii. Ritucharya (seasonal regimen). viii. Dinacharya (daily regimen). ix. Trayopastambha palana proper observance of Ahara (food), Nidra (sleep), and Brahmacharya (celibacy/safe sexual practices). x. Oshadha prayoga (medicaments). xi. Panchakrma therapy (purification). xii. Rasayana sevana (rejuvenation therapy) are some of the specific measures that have been mentioned as being beneficial in this situation. Prevention of Agantuja roga (exogenous diseases) (Tripathi, 2000b). Visha (poison) and Bhoota (evil spirit or germs or microorganisms) cause Agantuja or exogenous diseases, which can be avoided by Iindriyopasamaha (sense organ restraint), Vijnanam (knowledge of place, time, and one’s own capability), Smritihi (good memory), Prajnaparadha (intellectual error), and Desakala Atma and Sadvrittasyanuvartanam (good conduct).

Conclusion Because ancient scholars were familiar with Sankramak Roga (communicable diseases caused by microbial invasion), we can conclude that ancient Acharya were well versed in Sankramak Roga. In Samhitas, a detailed account has been given. Behavioral change is a critical component in lowering the burden of vector-borne diseases. Ayush collaborates with other organizations to provide education and raise public awareness about mosquitoes, ticks, bugs, flies, and other vectors so that people can protect themselves and their communities.

References Aminuddin, G.R.D., Subhash Khan, S.A., 1993. Treatment of Malaria through herbal drugs from Orissa. India Fitoterapia LXIV, 64, 545–548. Badam, L., Deolankar, R.P., Rojatkar, S.R., Nagsampgi, B.A., Wagh, U.V., 1988. Invitro antimalarial activity of medicinal plants of India. Indian J. Med. Res. 87, 379–383. Bargale, S.S., Shashirekha, H.K., 2016a. Epidemiology. In: Text Book of Sasthvritta. Chaukhambha Publication, New Delhi, p. 574 (Chapter 16). Bargale, S.S., Shashirekha, H.K., 2016b. National health programmes. In: Text Book of Sasthvritta. Chaukhambha Publication, New Delhi, p. 810 (Chapter 27).

Concept of vector-borne diseases in Ayurveda: A review  Chapter | 16  435 Bargale, S.S., Shashirekha, H.K., 2016c. Epidemiology. In: Text Book of Sasthvritta. Chaukhambha Publication, New Delhi, p. 634 (Chapter 16). Bargale, S.S., Shashirekha, H.K., 2016d. Epidemiology. In: Text Book of Sasthvritta. Chaukhambha Publication, New Delhi, p. 638 (Chapter 16). Bargale, S.S., Shashirekha, H.K., 2016e. Epidemiology. In: Text Book of Sasthvritta. Chaukhambha Publication, New Delhi, p. 641 (Chapter 16). Bargale, S.S., Shashirekha, H.K., 2016f. Text Book of Sasthvritta. Epidemiology. Chaukhambha Publication, New Delhi. (Chapter 16). 66, 814. Bargale, S.S., Shashirekha, H.K., 2016g. National health programmes. In: Text Book of Sasthvritta. Chaukhambha Publication, New Delhi, p. 816 (Chapter 27). Bharathi, K.B., Srinivasan, K., Revathi, R., Acharya, M.V., 2010. Clinical trial of I.G. formula as a prophylactic medicine in Vishama Jwara vis-à-vis malaria. J. Res. Ayurveda Siddha 31 (4), 13–22. Bharathi, K.A., Kanchana, S., Revathi, R., Lavekar, G.S., 2013. Clinical evaluation of efficacy of Parijata Patraghanavati in Vishamajvara Vis-à-Vis Malaria WSR to Srotodushti. J. Res. Ayurveda Siddha 34 (1–4), 61–72. Byadgi, P.S., 2011. Natural products and their antileishmanial activity—a critical review. Int. Res. J. Phamacol. 2 (4), 46–49. CCRAS, 1981. A clinical trial of Ayush—64 (a coded anti malarial medicine) in case of malaria. J. Res. Ayurveda Siddha 2 (1), 2309–2326. CCRAS, 1987. Ayush-64: A New Ayurvedic Anti-Malarial Compound. Central Council for Research in Ayurveda and Siddha, Ministry of Health and Family Welfare, Government of India, New Delhi, p. 128. CCRAS, 2002a. Research: An Overview. CCRAS, pp. 35–36. CCRAS, 2002b. Database on Medicinal Plants Used in Ayurveda. vol. 4 Dept. of Ayush, M/o Health and Family Welfare, Govt. of India, pp. 470–483. CCRAS, 2009. Management of Chikungunya Through Ayurveda and Siddha. CCRAS, Delhi, pp. 27–30. CCRAS, 2014a. Evidence based ayurvedic practice based on CCRAS R&D contributions, CCRAS2014, New Delhi., p. 39. CCRAS, 2014b. Evidence based ayurvedic practice based on CCRAS R&D contributions, CCRAS2014, New Delhi, 18, 19. CCRAS, 2016. Guidelines for Ayurvedic Practitioners for Clinical Management of Dengue. http:// www.ccras.nic.in/sites/default/files/CLINICAL_MANAGEMENT_OF_DENGUE.pdf. Chari, M.V., Venkataraghavan, S., Seshadri, C., Ramakrishna Shetty, B., Gowri, N., 1985. A double blind clinical trial with Ayush-64 an ayurvedic drug in Plasmodium vivax malaria. J. Res. Ayurveda Siddha 6 (1, 3 & 4), 105–116. Chauhan, V., 2020. Natural Treatment for Kala-Azar/Leishmaniasis (Black Fever). https://www. planetayurveda.net/natural-treatment-for-kala-azar-leishmaniasis-black-fever/. Gandhi, M., Vinayak, V.K., 1990. Preliminary evaluation of extracts of Alstonia scholaris bark for in vivo antimalarial activity in mice. J. Ethnopharmacol. 29 (1), 51–57. Ghate, U., et  al., 2012. PA01.56. Malaria cure by Herbal/Ayurvedic Medicine in Central Indian tribal belt. Anc. Sci. Life 32 (Suppl. 1), S106. Godse, C.S., Tathed, P.S., Talwalkar, S.S., Vaidya, R.A., Amonkar, A.J., Vaidya, A.B., Vaidya, A.D.B., 2016. Antiparasitic and disease-modifying activity of Nyctanthes arbor-tristis Linn. in malaria: an exploratory clinical study. J. Ayurveda Integr. Med. 7 (4), 238–248. Gupta, A.K., 2003. Sutrasthana (Chapter 4 verse 31). In: Ashtanga Hridayam of Vagbhata, twelfth ed. Choukhambha Sanskrit Samsthan, Varanasi, p. 38.

436  Natural products in vector-borne disease management Gupta, N., 2019. Epidemiology of communicable disease. In: Text Book of Swasthvritta. Chaukhambha Prakashak, Varanasi, p. 345. Kalauni, S.K., Awale, S., Tezuka, Y., Banskota, A.H., Linn, T.Z., Asih, P.B., Syafruddin, D., Kadota, S., 2006. Antimalarial activity of Cassane and Norcassane type Diterpenes from Caesalpinia crista and their structure activity relationship. Biol. Pharm. Bull. 29 (5), 1050–1052. Karnik, S.R., Tathed, P.S., Antarkar, D.S., Gidse, C.S., Vaisya, R.A., Vaidya, A.D.B., 2008. Antimalarial activity and clinical safety of traditionally used Nyctanthes arbor-tristis Linn. Indian J. Tradit. Knowl. 7 (2), 330–334. Kumar Dilip, K.V., 2004. Ayurvedic Perspective of Communicable Disease. Vaidyaratnam P.S. Varier Ayurveda College, Kottakkal, pp. 141–144. Linn, T.Z., Awale, S., Tezuka, Y., Banskota, A.H., Kalauni, S.K., Attamimi, F., Jun-Ya, U., Asih, P.B.S., Syafruddin, D., Tanaka, K., Kadota, S., 2005. Cassane-and Norcassane type Diterpenes from C. crista of Indonesia and their antimalarial activity against the growth of Plasmodium falciparum. J. Pharm. 68, 706–710. Mehra, R., 2006. Effect of Azadirachta indica A. Juss. on Falciparum Malaria cases in Car-Nicobar. AYU 27 (2), 26–29. Misra, B.S., 2003. Bhavaprakash of Sribhava Misra, Part II. Choukhambha Sanskrit Samsthan, Varanasi, pp. 560–561. Prameeladevi, K., Srinivas, P., 2014. A contemplative study on the clinical evaluation and efficacy of selective herbo-mineral formulations in vishama jwara (Malaria). Ayurpharm. Int. J. Ayur. Alli. Sci. 3 (8), 222–229. Rai, V.K., 2015. Sachitra Swasthvritta Vijyan. Chaukhambha Publication, New Delhi, p. 269. Sharma, A.R., 2001a. Sutrasthana. In: Sushruta Samhita, of Maharshi Susruta, first ed. vol. 1. Chaukhambha Surbharati Prakashan, Varanasi, p. 203 (Chapter 24 verse 7). Sharma, A.R., 2001b. Nidana sthana (Chapter 5 verse 33–34). In: Sushruta Samhita, of Maharshi Susruta, first ed. vol. 1. Chaukhambha Orientalia, Varanasi, p. 500. Sharma, A.R., 2001c. Sutrasthana (Chapter 24 verse 7). In: Sushruta Samhita, of Maharshi Susruta, first ed. vol. 1. Chaukhambha Orientalia, Varanasi, p. 203. Sharma, A.R., 2001d. Nidana sthana (Chapter 5 verse 33–34). In: Sushruta Samhita, of Maharshi Susruta, first ed. vol. 1. Chaukhambha Orientalia, Varanasi, p. 502. Sharma, K.D., Kapoor, M.L., Vaidya, S.P., Sharma, L., 1981. A clinical trial of “Ayush-64” (a coded antimalarial medicine) in cases of malaria. J. Res. Ayurveda Siddha II, 309–326. Shrikanthamurthy, K.R., 2018a. Madhava Nidana (English Translation). Chaukhamha Orientalia, Varanasi, p. 173 (Chapter 53). Shrikanthamurthy, K.R., 2018b. Madhava Nidana (English Translation). Chaukhamha Orientalia, Varanasi, p. 153 (Chapter 47). Singh, J., 2019. Ayurvedic Treatment of Encephalitis (Chamki Fever). https://www.ayurtimes.com/ ayurvedic-treatment-of-encephalitis. Tripathi, B., 2000a. Vimanasthana (Chapter 3 verse 3). In: Charaka Samhita of Agnivesa, Charaka Chandrika Hindi Commentary. Chaukhambha Surbharati Prakashan, Varanasi, p. 676. Tripathi, B., 2000b. Sutrasthana (Chapter 7 verse 53–54). In: Charaka Samhita of Agnivesa, Charaka Chandrika Hindi Commentary. Chaukhambha Surbharati Prakashan, Varanasi. 185, 186. Vaidya, D.D., 1997. Aadhunika Chikitsa Shastra. Motilal Banarsidaas Publishers, Delhi, p. 565. Valecha, N., Devi, C., Joshi, H., Shahi, V., Sharma, V., Lal, S., 2000. Comparative efficacy of ­Ayush-64 vs. chloroquine in vivax malaria. Curr. Sci. 781, 120–1122.

Chapter 17

Medically important vector-borne disease control through seaweeds against the chikungunya Ramachandran Ishwaryaa and Baskaralingam Vaseeharanb a

Mandapam Regional Centre, ICAR—Central Marine Fisheries Research Institute, Mandapam, Tamil Nadu, India, bBiomaterials and Biotechnology in Animal Health Lab, Department of Animal Health and Management, Alagappa University, Karaikudi, Tamil Nadu, India

Vector-borne disease Vector-borne diseases (VBDs) are infections caused by pathogens transmitted by arthropods such as mosquitoes, blackflies, sand flies, and bedbugs as well as dengue, chikungunya, human African trypanosomiasis (HAT), leishmaniasis, and malaria. Transmission dynamics depicts the variety of factors that influence how efficiently transmissions occur through time and space in a precise people. Fundamental reproductive numbers, host immunity, journey, and human activities are among these elements. Vectorial capability refers to a mosquito population's ability to transmit a pathogen to a new susceptible population (Anderson et al., 1991). Numerous VBDs, such as arboviral illnesses, are classed as neglected tropical diseases (NTDs) (WHO, 2017). The trouble of NTDs is weakly understood, and these diseases have endured from short of attention and asset until the last 5–10 years. The biology, epidemiology, and prevention of NTDs are all still poorly known. Despite the fact that the universal number of loss from vector-borne NTDs is fewer than that of malaria, they persist to produce elevated stage of morbidity and stand for a considerable public strength trouble as of 1990–2013. They impact just about 80% of the global people, excessively harming the poorest populations in the tropics and subtropics, and imposing a significant cost of sickness and mortality on the poorest of the poor around the world (Cohen et al., 2016). Most of these VBDs are co-endemic, and more than half of the global total is predicted to live in areas with two or more VBDs. They make a significant contribution to the worldwide trouble of disease, accounting for 17% of the estimated worldwide trouble of all infectious diseases Natural Products in Vector-Borne Disease Management. https://doi.org/10.1016/B978-0-323-91942-5.00018-5 Copyright © 2023 Elsevier Inc. All rights reserved.

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438  Natural products in vector-borne disease management

(Tyagi, 2016). Many VBDs can be controlled via vector control, which has been used in the past and is still used today. Furthermore, vector control is now the sole technique obtainable to care for peoples against diseases like dengue (for which a vaccine has been approved except it is not broadly utilized because of protection alarm), chikungunya, Zika, and West Nile disease. It has been conscientious for decreasing the chart of numerous VBDs to a greater extent than medications or vaccinations. The majority common process of controlling these diseases is vector control, which has a long and well-documented history. Fundamental information of VBD transmission covers population vulnerability, vectorial capability, and infectious agent interactions, as well as considerate of VBD transmission and perseverance, which is required for efficient avoidance and control interruptions. Identifying critical elements of VBD introduction, maintenance, and dissemination, in addition to ecological and climate factors, the urbanization process, socioeconomic circumstances, population dynamics, and mobility, is also important.

Mosquito-borne diseases Arthropod-borne disease transmission is one of the most serious risks to human and animal health in the world. Insects and diseases have been linked for generations, but it was not until the 19th century that hematophagous arthropods were added to the mix. Vector-borne diseases were conscientious for more human deaths than all further causes united until the early 20th century. Huge sections of the tropics, particularly in Africa, were unable to grow due to these diseases (Gubler, 1998). These can be dangerous vectors of many deadly arthropod-borne diseases, such as malaria, yellow fever, dengue fever, and chikungunya, which are transmitted to humans or animals via an arthropod bite (Benelli, 2015). The pathogen carried to humans by mosquitos, triatomine bugs, blackflies, ticks, mites, snails, and fleas could be parasites, protozoa, bacteria, or a virus (WHO, 2017). Despite significant progress in excess of the previous 50 years, the World Health Organization approximates that over 3 billion clinical signs of mosquitoborne diseases come about every year. Attacking mosquito vectors to destroy disease transmission has been a main control mechanism against major ­mosquito-borne diseases such as malaria, yellow fever, dengue fever, chikungunya fever, and Zika virus infection. Mosquito-borne diseases are propagated by a variety of factors, including seasonality, immediacy to breeding grounds, vector density, biting rates, and the quantity of infecting mosquitoes.

Chikungunya Chikungunya fever (CHIKV) is a mosquito-borne disease that spreads throughout tropical areas and is transmitted to humans by infected Aedes mosquitos (mostly Aedes aegypti and A. albopictus). It has emerged as a disease outbreak

Medically important vector-borne disease control  Chapter | 17  439

threat over the past two decades and created a universal threat in numerous countries in 2015. The word “chikungunya” comes from a Makonde expression that means “that which bends up,” referring to the curled position of infected individuals. Chikungunya communicate a disease to more than 1 million citizens each year, causing weakening joint agony (Weaver and Forrester, 2015). Human CHIKV infection is described by severe and unexpected combined ache and fever, which is frequently accompanied by extreme asthenia, arthralgia, myalgia, headache, and itchiness. Although this mosquito-borne disease is selflimited, with severe signs resolving in 1–2 weeks and no elevated death, it can show the way to rigorous, persistent, and debilitating arthritis, putting a strain on healthcare method. Polyarthralgia, on the other hand, is regular in 30%–40% of infected persons, can last for years, and the combined ache can be excruciating, limiting even the most basic daily activities (Schwartz and Albert, 2010). These clinic symbols are similar to those of dengue and Zika. Misdiagnoses are common, and while the majority of symptoms may go away, joint aches can last for months or even years, resulting in persistent pain and incapacity. A large proportion of infected people are symptomatic, with only about 15% of infected people having no symptoms. For CHIKV infections, there are presently no registered vaccines or particular therapies. It was initially purified from the blood of a flushed individual in Tanzania in 1952 through a febrile disease epidemic in Makonde, and it is a positive sense single-stranded RNA virus that is roughly 12 kb in length. It is a mosquito-transmitted pathogen of the genus alphavirus family Togaviridae (Morrison, 2014). It is divided into three genotypes: Asian, West African, and East Central South African, which are called for their personal geographical distributions. The viral particle is an icosahedral capsid with a lipid bilayer covering it. It is spherical in shape, around 70 nm in diameter, and sensitive to temperatures above 58°C. It has two open reading frames (ORFs), one on the 50th position and the other on the 30th position, with the ORF on the 50th position creating four nonstructural proteins (nsP 1–4) and the ORF on the 30th position producing structural proteins, which are made up of a capsid protein, 80 trimer-shaped spikes formed by E1 and E2 glycoproteins, and two small cleavage products (E3 and 6K) (Nunes et al., 2015). The CHIKV virus is spread in two cycles: urban and sylvatic. In areas with human epidemics, the urban cycle refers to transmission from human to mosquito to human, whereas sylvatic transmission, which involves natural primates and arboreal mosquitoes in Africa, refers to transmission from animal to mosquito to human. CHIKV's urban cycle has been blamed for a number of large CHIKV outbreaks in nations across the globe. CHIKV is predominantly continued in an urban cycle in more densely populated places, in which people serve as the primary hosts and mosquitos of the species Aedes serve as vectors. Although the virus has been isolated from other mosquitoes, it is mostly transmitted by A. aegypti and A. albopictus. The main vector of CHIKV transmission has traditionally been A. aegypti, but A. albopictus has played a key role in recent epidemics in Réunion, Europe, and Gabon, despite the fact that A. aegypti remains the s­ ignificant ­viral

440  Natural products in vector-borne disease management

vector, as evidenced by the Caribbean epidemic in 2013, and can survive in tropical and arid environments but not in cool temperatures (Crosby et  al., 2016). The change in A. albopictus has been attributed to a dearth of suitable A. aegypti vectors, with a mutation in the E1 envelope protein permitting A. albopictus to act as a viable vector. The A226V mutation in the E1 envelope protein improved CHIKV fitness and transmission to vertebrate species in A. albopictus (Tsetsarkin et al., 2007). Mosquitoes of the genus A. albopictus are exceedingly tenacious and have well-defined populations in temperate areas. There is a major fear that these vectors will spread into new places as a result of climate change. In summary, CHIKV has resurfaced as a severe hazard to universal community strength in the recent decade. When compared to other alphaviruses, CHIKV is unique in that it causes signs in a superior percentage of infected people, with 10%–70% of people living in a pretentious region appropriate infected and 50%–97% of those infected acquiring a medical manifestation. After a 4–7-day incubation period, symptoms usually occur. The condition is particularly brutal to newborns and the elderly, and it is linked to encephalitis in neonates. In comparison to individuals under 45 years of age, the death rate for those 65 and older is five times greater. The sickness is divided into two stages: a severe phase that lasts about a week and a severe stage, often recognized as the constant period that lasts months to years. One of the difficulties in accurately measuring the CHIKV problem is the large number of asymptomatic and moderate individuals who may not search for medicinal awareness. Unfortunately, there are no specific therapies or vaccinations available for CHIKV infection at this time. Several antiviral agents, monoclonal antibodies, and immunomodulatory medicines in the early stages of development could be utilized to prevent or cure CHIKV infection. As a result, CHIKV's recurrence and the massive scope of CHIKV-related outbreaks have highlighted a slew of dangerous research needs. Expanded mosquito control efforts, implementation of methods for identifying CHIKV in given blood, organs, and tissues for transplantation, and enlarged fundamental and translational study to improve our understanding of CHIKV biology, pathophysiology, handling, and avoidance are among these. Averting revelation to the virus during individual caring measures and using well-organized vector management tactics to restrict viral transmission are the greatest ways to alleviate the public strength risk from CHIKV.

Vector-borne disease control VBDs constitute the majority of serious concerns confronting universal public strength in the 21st century, accounting for further than 17% of the projected worldwide trouble of infectious diseases, causing more than 1 billion illnesses and over 1 million losses per year. Despite decades of control efforts, VBDs continue to be a major public health issue throughout the world's tropical and subtropical regions (WHO, 2017). At this time, many countries' urban health

Medically important vector-borne disease control  Chapter | 17  441

establishments are being surprised by an increase in vector-borne diseases, owing to increased concentrations of vectors and other pests, which are posing an ever-greater threat to their vector and pest management programs. Dengue, malaria, filariasis, Chagas disease, chikungunya, plague, and typhus are the most common urban arthropod vectors, with the urban environment favoring the establishment of trouble mosquitos, cockroaches, mice, and trouble bird species, which contribute to and intensify the issues. Mosquitoes and ticks are responsible for the bulk of VBD transmissions, and mosquito-transmitted diseases are now found in over 125 countries throughout the world, predominantly in tropical and subtropical areas, causing severe hazards to part of the global people (World Health Organization, 2016). Mosquito-borne diseases have a significant economic impact worldwide and result in millions of deaths each year. They infect roughly 700 million individuals worldwide each year, including 40 million in India alone (Ghosh et al., 2012). They are more widespread in developing and resource-poor countries, and they impose a huge morbidity and death burden. Synthetic insecticides, insect growth inhibitors, and microbiological control agents are the mainstays of recent control strategies. Synthetic chemicals, on the other hand, lead to a slew of negative consequences, including high operating costs, physiological resistance, pollution, resistance development, and hazardous impacts on nontarget creatures and human health (Herdiana et al., 2018). Currently, there is an insufficient weapon available to combat the most common illnesses and parasites transmitted by mosquitos. While chemical-based vector control programs have been in place for decades, their efficiency was quickly eroded due to the ability of growth of struggle among most vector species of these illnesses. Synthetic chemical pesticides have been shown to be successful, but their indiscriminate use against vector borne illness management has resulted in various ecological difficulties due to residue accumulation, development of resistance in target vectors, and their chronic impacts over the previous 5 decades (Wilson et al., 2020).

Vector control Because most arbovirus diseases lack a vaccine or therapy, the best answer is frequently to accept vector control methods, halting the illness communication cycle (Lees et al., 2015). The major purpose of this control is to decrease illness occurrence and death, through both civilized and socioeconomic goals in mind (Lacey, 2007). The airborne insecticides used to kill adult mosquitos have been found to be ineffective; thus the greatest strategy is to assault the larvae and their breeding sites (Beula et al., 2011). Physical, genetic, chemical, and biological vector control are all viable options (Neves et  al., 2011). Physical control refers to actions that do not comprise the use of chemicals to destroy mosquitos, such as the elimination of potential propagation place. The reduction or destruction of potential mosquito propagation place is the significant tread in mosquito population control because it eliminates the basis of mosquitos

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(Floore, 2006). The discharge of sterile mosquitos or hereditarily engineered mosquitos (Heringer et al., 2016), often known as SIT—sterile insect technique, is one of the interferences used to decrease adult populations. Another method, known as release of insects with dominant lethality (RIDL), involves releasing male insects with a dominant-lethal gene. This method moreover decreases mosquito flight and increases death through period, or creates mosquitos that are more resistant to viruses (Oliva et al., 2014). Because of their nonharmful properties, biopesticides produced from nature, such as certain plants or seaweeds, have recently gained popularity in biological control. As a result, there is an increasing requirement to substitute new involvement and research into upcoming-generation vector control approaches, such as attractants, pneumatic/ tracheal explosions in larval populations, biocides combined with nanoparticles, hereditarily adapted vectors, paratransgenics, and so on. Traditional repellent plant knowledge gained via ethnobotanical research is a precious source for the expansion of novel natural products (Achee et al., 2019). Consumers have recently become more interested in commercial repellent treatments including plant-based ingredients, which are typically marketed as “secure” in assessment to incorrigible artificial repellents, despite the fact that this is not always the case. There is a need to conduct more thorough evaluations of repellent chemicals and enlarge unique products that suggest both elevated repellency and customer protection. Such imaginative expertise have to moreover fit into the idea of included vector control management, which now has far superior connotation than ever before through including all available skills for effective vector control.

Natural products Because of their nonharmful properties, biopesticides produced from nature, such as some plants or microbes, have become more popular recently. Pathogens, such as fungi, parasites, like nematodes, or bacteria, are frequently used in biological management (Braga and Valle, 2007; Klaassen, 2013). They are generally unique to the objective, decreasing the troubles of reaching nontarget species, such as ordinary household animals and plants, in addition to being harmless to people. Plants provide a wide supply of chemicals that can be exploited to create effective antimosquito remedies. In comparison to artificial repellents, the use of plant-based insecticides against mosquitoes has become a significant method for the prevention of several mosquito-transmitted diseases. Insecticidal plantderived compounds have been utilized to control numerous types of vectors in recent years. Traditional medicines are used to keep people healthy by preventing various ailments. They are based on knowledge, experience, and practice (Tyagi and Shahi, 2002). Plant extracts have a variety of bioactive phytochemicals, making them a viable alternative for mosquito control. The majority of plants include molecules that protect them from phytophagous pests (Pichersky and Gershenzon, 2002). The explosive components generated by herbivory are

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currently best known for their ability to repel mosquitoes and other biting insects. Insects sense odors, and explosive odors bind to odorant receptor (OR) proteins on the ciliated dendrites of particular odor receptor neurons (ORNs), which are commonly found on the antennae and maxillary palps. Plants generate explosive “green leaf volatiles” when their leaves are ruined to prevent herbivores (Tyagi, 2016). Many plant volatiles, on the other hand, are likely to be restraining or repellant to insects due to their high vapor toxicity. There are numerous cases in India where plants have been oppressed, in whole or in part, for thousands of years; the majority notably through execution aching plants in dwellings or through flaming in flames following producing a formulation with animal excrement. Since plants are professed as a safe and believed technique of mosquito bite avoidance, there is currently a general understanding of employing these plant-based “natural” smelling repellents all over the world. Numerous scientific researches have shown that plant extracts or plant-derived products can be utilized to manage mosquito populations as an alternative option. Traditional medicinal plants can be used to prevent the spread of a range of vector-borne diseases. As a result, traditional medicines are appealing because they are generally proven to be biodegradable, natural, and safer than synthetic pharmaceuticals. Thus, in vector control, the hunt for natural pesticides is critical.

Seaweed Seaweeds were thought to have medical value in Asian societies as early as 3000 BC. They have been used for a variety of purposes, including feeding, medicine, fertilizer, a basis of therapeutic drugs, as a unprocessed substance in the industrialized manufacture of agar, alginate, and carrageenan (Manilal et al., 2009). They have several secondary metabolites, such as polyhalogenated monoterpenes, saturated fatty acids, and alkaloids; have been shown to have larvicidal activities against mosquitos (Poonguzhali and Nisha, 2012); these chemicals can also be utilized in conjunction with further pesticides (Bianco et al., 2013). In contrast, a lot of investigations at rest required an understanding of numerous aspects of their property and providence, such as degradation and environmental persistence rates, influence on nontarget organisms, and the potential for fighting development in target populations. However, according to Yu et al. (2014), seaweed extracts and isolated chemicals have considerable inhibitory effects on the cholinergic system, which could be the answer to the mechanistic difficulty. Toxic effects of seaweed and their compounds include morphological changes (e.g., deflections of abdominal papillae, deflection of larvae, and prepupa that have attempted to rise from the larval exoskeleton), changes in swimming actions, unusual growth and development, reduced life period, and reproduction rates difficulties. Finally, it is worth noting that the biological activities of specific seaweeds as well as their chemical composition are influenced by species, physiological parameters, pollution, season, and other environmental factors (Pérez et al., 2016).

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There are currently no antiviral medicines available for these mosquitoborne viral infections. The viral replicative cycle begins with virus attachment to the surface of the host cell, as it does for all enveloped RNA-composed viruses; thus, preventing virus binding is a precious antiviral technique since it permits for the construction of a first barrier to infection suppression. Because of their ability to affect cell surface characteristics, sulfated polysaccharides from seaweeds have been studied for their antiviral effects in order to prevent virus attachment. Rodrigues et al., (2017) reported a polysulfated fraction from the green alga Caulerpa cupressoides obtained in Northeastern Brazil termed ulvan (containing 11% sulfate and 6% uronic acids) that exhibited effective in vitro activity against DENV-1. Despite the fact that conservative tactics and techniques are beneficial in specific habitats and circumstances, vectors often remain unaffected, owing to their ability to rapidly enlarge struggle to the insecticides in use. As a result, it is critical to look for alternative products that work through other deadly processes on the vector. Because there is no one-size-fitsall solution to the problem of vector control or vector-borne illness control, such new systems should creatively connect with the IVM. It is important to note that applying seaweed extracts in the field may not always control pests, despite any encouraging results gained in the greenhouse or laboratory. Formulations made from these products have the potential to decrease major substance losses while also potentially improving control competency. In contrast, few researches have been conducted on the effects of seaweed extracts on arthropods or agricultural pests, especially in tropical areas. Given the huge number of seaweed species found in this part of the world, there is much to be discovered in terms of new active molecules against economically important phytophagous insects and mites.

Acknowledgments RI gratefully acknowledges the Science and Engineering Research Board, India, New Delhi, India, for the financial assistance Rendered [Ref: PDF/2020/001027].

References Achee, N.L., Grieco, J.P., Vatandoost, H., Seixas, G., Pinto, J., Ching, L., Martins, A.J., Juntarajumnong, W., Corbel, V., Gouagna, C., David, J.P., Logan, J.G., Orsborne, J., Marois, E., Devine, G.J., Vontas, J., 2019. Alternative strategies for mosquito-borne arbovirus control. PLOS Negl. Trop. Dis. 13, e0006822. Anderson, A.L., Apperson, C.S., Knake, R.I., 1991. Effectiveness of mist-blower applications of malathion and permethrin to foliage as barrier sprays for salt marsh mosquitoes. J. Am. Mosq. Contol Assoc. 7, 116–117. Benelli, G., 2015. Research in mosquito control: current challenges for a brighter future. Parasitol. Res. 114, 2801–2805. Beula, J.M., Ravikumar, S., Ali, M.S., 2011. Mosquito larvicidal efficacy of seaweed extracts against dengue vector of Aedes aegypti. Asian Pac. J. Trop. Biomed. 1, S143–S146.

Medically important vector-borne disease control  Chapter | 17  445 Bianco, E.M., Pires, L., Santos, G.K.N., Dutra, K.A., Reis, T.N.V., Vasconcelos, E., Cocentino, A.L.M., Navarro, D.M., 2013. Larvicidal activity of seaweeds from northeastern Brazil and of a halogenated sesquiterpene against the dengue mosquito (Aedes aegypti). Ind. Crop. Prod. 43, 270–275. Braga, I.A., Valle, D., 2007. Aedes aegypti: inseticidas, mecanismos de ação e resistência. Epidemiol. Serv. Saúde 16, 179–293. Cohen, J.P., Silva, L., Cohen, A., Awatin, J., Sturgeon, R., 2016. Progress report on neglected tropical disease drug donation programs. Clin. Ther. 38, 1193–1204. Crosby, L., Perreau, C., Madeux, B., Cossic, J., Armand, C., Herrmann-Storke, C., 2016. Severe manifestations of Chikungunya virus in critically ill patients during the 2013–2014 Caribbean outbreak. Int. J. Infect. Dis. 48, 78–80. Floore, T.G., 2006. Mosquito larval control practices: past and present. J. Am. Mosq. Control Assoc. 22, 527–533. Ghosh, A., Chowdhury, N., Chandra, G., 2012. Plant extracts as potential larvicides. Indian J. Med. Res. 135, 581–598. Gubler, D.J., 1998. Resurgent vector-borne diseases as a global health problem. Emerg. Infect. Dis. 4, 442–450. Herdiana, H., Sari, J.F.K., Whittaker, M., 2018. Intersectoral collaboration for the prevention and control of vector borne diseases to support the implementation of a global strategy: a systematic review. PLOS One 13, 1–21. Heringer, L., Johnson, B.J., Fikrig, K., Oliveira, B.A., Silva, R.D., Townsend, M., Ritchie, S.A., 2016. Evaluation of alternative killing agents for Aedes aegypti (Diptera: Culicidae) in the gravid Aedes trap (GAT). J. Med. Entomol. 53, 873–879. Klaassen, C.D., 2013. Toxic agents. In: Cassarett & Doull's Toxicology: The Basic Science of Poisons. Mc Graw-Hill Education, pp. 938–959. Lacey, L.A., 2007. Bacillus thuringiensis serovariety israelensis and Bacillus sphaericus for mosquito control. J. Am. Mosq. Control Assoc. 23, 133–163. Lees, R.S., Gilles, J., Hendrichs, J., Vreysen, M., Bourtzis, K., 2015. Back to the future: the sterile insect technique against mosquito disease vectors. Curr. Opin. Insect. Sci. 10, 156–162. Manilal, A., Sujith, S., Kiran, G.S., Selvin, J., Shakir, C., Gandhimathi, R., Panikkar, M.V., 2009. Biopotentials of seaweeds collected from southwest coast of India. J. Mar. Sci. Technol. 17, 67–73. Morrison, T.E., 2014. Reemergence of chikungunya virus. J. Virol. 88, 11644–11647. Neves, D.P., de Melo, A.L., Linardi, P.M., Vitor, R.W., 2011. Artrópodes. In: Parasitologia Humana. SciELO, pp. 347–401. Nunes, M.R.T., Faria, N.R., Vasconcelos, J.M., Golding, N., Kraemer, M.U.G., Oliveira, L.F., 2015. Emergence and potential for spread of chikungunya virus in Brazil. BMC Med. 213, 102. Oliva, C.F., Damiens, D., Benedict, M.Q., 2014. Male reproductive biology of Aedes mosquitoes. Acta Trop. 132, S12–S19. Pérez, M.J., Falqué, E., Domínguez, H., 2016. Antimicrobial action of compounds from marine seaweed. Mar. Drugs 14, 1–38. Pichersky, E., Gershenzon, J., 2002. The formation and function of plant volatiles: perfumes for pollinator attraction and defense. Curr. Opin. Plant Biol. 5, 237–243. Poonguzhali, T., Nisha, L.J.L., 2012. Larvicidal activity of two seaweeds, Ulva fasciata and Grateloupia lithophila against mosquito vector, Culex quinquefasciatus. Int. J. Curr. Sci. 4, 163–168. Rodrigues, J.A., Eloy, Y.R., Vanderlei, E.D., Cavalcante, J.F., Romanos, M.T., Benevides, N.M., 2017. An anti-dengue and anti-herpetic polysulfated fraction isolated from the coenocytic green seaweed Caulerpa cupressoides inhibits thrombin generation in vitro. Acta Sci. Biol. Sci. 16, 149–159.

446  Natural products in vector-borne disease management Schwartz, O., Albert, M.L., 2010. Biology and pathogenesis of chikungunya virus. Nat. Rev. Microbiol. 2010 (8), 491–500. Tsetsarkin, K.A., Vanlandingham, D.L., McGee, C.E., Higgs, S., 2007. A single mutation in chikungunya virus affects vector specificity and epidemic potential. PLoS Pathog. 3, 20. Tyagi, B.K., 2016. Advances in vector mosquito control technologies, with particular reference to herbal products. Herbal Insecticides, Repellents and Biomedicines: Effectiveness and Commercialization. Springer, New Delhi, India, pp. 1–19. Tyagi, B.K., Shahi, A.K., 2002. Genus cymbopogon (Poaceae) – a potent group of mosquito repellent bearing characteristics. Parasitology 91. Weaver, S.C., Forrester, N.L., 2015. Chikungunya: evolutionary history and recent epidemic spread. Antivir. Res. 120, 32–39. WHO, 2017. Global Vector Control Response 2017–2030. WHO, Geneva. Wilson, L., Courtenay, O., Kelly-Hope, L.A., Scott, T.W., Takken, W., Torr, S.J., Lindsay, S.W., 2020. The importance of vector control for the control and elimination of vector-borne diseases. PLOS Negl. Trop. Dis. 14, e0007831. World Health Organization, 2016. Zika Virus, Fact Sheet. World Health Organization. Yu, K.X., Jantan, I., Ahmad, R., Wong, C.L., 2014. The major bioactive components of seaweeds and their mosquitocidal potential. Parasitol. Res. 113, 3121–3141.

Chapter 18

Nanobiomaterials as novel modules in the delivery of artemisinin and its derivatives for effective management of malaria Krishna Yadava,b, Deependra Singhb, Manju Rawat Singhb, Nagendra Singh Chauhanc, Sunita Minzd, and Madhulika Pradhane a

Raipur Institute of Pharmaceutical Education and Research, Sarona, Raipur, Chhattisgarh, India, bUniversity Institute of Pharmacy, Pt. Ravishankar Shukla University, Raipur, Chhattisgarh, India, cDrugs Testing Laboratory Avam Anusandhan Kendra (State Government Lab of AYUSH), Government Ayurvedic College, Raipur, Chhattisgarh, India, dDepartment of Pharmacy, Indira Gandhi National Tribal University, Amarkantak, Madhya Pradesh, India, eGracious College of Pharmacy, Abhanpur, Chhattisgarh, India

Introduction The renowned herbal plant Artemisia annual is being utilized to get artemisinin (ARTM) which has the most potent medicinal assets. The medication has a sesquiterpene lactone structure with a focal peroxide bridge that distinguishes it from the different medications available. A number of its derivatives are semisynthetic, for example, artemether, artesunate, arteether artenimol, and artelinic acid (Efferth, 2017; Fontinha et al., 2020; Mishra et al., 2021). ARTM and its analogs have different recuperative services. They are utilized to treat joint agony, liver issues, seizures, loss of hunger, and menstrual problems. They likewise have remedial effects against malignant growth and possess anti-inflammatory properties. It is similarly used to treat sleep deprivation and stomach-related issues and to assist with irritating skin issues and wounds. They are equally significant as antibacterial agents. They advance the development of healthy cells as well as prevent, annihilate, and control viral infections (Aderibigbe, 2017; Jung et al., 2004; Krishna et al., 2008). They are powerful against malaria and other protozoan infections. The utilization of ARTM in the treatment of malaria is exceptionally well yet not in trend due to its cost contrasted with other antimalarials (Anti-M) drugs and has low solvency and bioavailability, short half-life, toxic behavior, and possession of drug resistance (Aderibigbe, 2017; Talapko et  al., 2019). Because of the pharmacological limitations mentioned Natural Products in Vector-Borne Disease Management. https://doi.org/10.1016/B978-0-323-91942-5.00003-3 Copyright © 2023 Elsevier Inc. All rights reserved.

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above, numerous scientists are creating subsidiaries with worked on helpful impacts, while others have consolidated ARTM with derivatives to make conveyance strategies that give more viable treatment (Aderibigbe, 2017; Al-Qurainy and Khan, 2010). In the current part of the chapter, we have explored the most recent advances in the incorporation of ARTM and its derivatives as anti-M and their delivery aspects as a potential tool for overcoming the limitation of these drugs while exploring its better health benefits for mankind.

ARTM derivatives As of now, there are several accessible derivatives of ARTM, for example, artesunate, artemether, arteether, artelinic acid, and artenimol (Fig.  1). However, only a few derivatives/hybrid composites holding ARTM have been associated with great pharmacological action in vivo and in vitro when contrasted with free ARTM. In this way, Wang and co-researchers (Wang et al., 2014) synthesized the derivative artesunate-indoloquinoline-hybrid-6 that was having an active anti-M effect (Fig. 2). The ARTM derivatives were created and studied by various scientists for investigating and enhancing the effectiveness of the parent compounds. In this path, He and co-scientists (He et  al., 2015) produced artesunate alpha-­ aminophosphonate analog-8 with the great antimicrobial measure that was

FIG. 1  Illustration showing the artemisinin derivatives (semisynthetic): (1) arteether, (2) artemether, (3) artesunate, (4) artelinic acid, and (5) dihydroartemisinin.

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FIG.  2  Illustration showing artesunate analogs: (A) artesunate-indoloquinoline hybrid 6, (B) artesunate-­podophyllotoxin analog 7, (C) artesunate α-aminophosphonate analog 8, and (D) artesunate-­safranol analog 9.

FIG. 3  Illustration showing artemisinin derivatives and hybrids: (A) primaquine artemisinin hybrid 10, (B) artemisinin derivatives 11, (C) artemisinin derivatives 12, and (D) artemisinin quinine hybrid 13.

furthermore improved when fused with roxithromycin which is an effective antibiotic (Fig. 2). Further, Griesbeck and co-scientists (Griesbeck et al., 2014) synthesized artesunate-safranol analog-9 by DCC coupling response of artesunic acid and safranol, trailed by photo‑oxygenation (Fig. 2). Despite that, no in vivo assessment was performed on the hybrid composite. Further, Capela and co-scientists (Capela et al., 2011) synthesized primaquine-ARTM analog-10 with powerful anti-M action counter to drug-resistant Plasmodium falciparum (Fig.  3A). In another study, Li and co-scientists (Li et  al., 2003) synthesized ARTM subsidiaries containing the Mannich base assembly and

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artesunate with superb ­anti-M action and great durability. Similarly, Chand and ­ co-scientists (Chand and Bhattacharya, 2016) synthesized beta-ether ­subsidiaries of ­dihydro-ARTM in splendid yield and great diastereo-selectivity. Further, Opsenica and co-scientists (Opsenica and Solaja, 2012) identified the design of ARTM subordinates 11 and 12 with upgraded anti-M action (Figs. 3B and 6C). Likewise, Walsh (Walsh et al., 2007) synthesized ARTM-quinine hybrids 13 with great anti-M action (Fig. 3D). In vitro assessment of the composite on the FcB1 and 3D7 variant of Plasmodium falciparum demonstrated that the powerful action of the synthesized composite was greater than that of the free ARTM medication. Similarly, Joubert and co-scientists (Joubert et  al., 2014) synthesized ARTM-acridine hybrid efficacious against cervical malignancy and malaria in vitro. Pandey and co-scientists (Pandey et al., 2016) synthesized a pyrrolidine-acridine-ARTM fusion with anti-M action appropriate for treatment in a blend. Moreover, Guo and co-scientists (Guo et al., 2012) synthesized artemisone and artemiside subsidiaries from dihydro-ARTM for the management of extreme murine malaria in vivo. Similarly, Wei and co-scientists (Wei et al., 2015) synthesized ­artemisone subsidiaries from dihydro-ARTM with antitumor action. Further, Soomro and co-scientists (Soomro et al., 2011) produced ARTM subsidiaries efficacious for the therapy of malignancy and other diseases. In a similar manner, Xu and co-scientists (Xu et al., 2016) synthesized dihydro-ARTM-cinnamic acid hybrid 14 that was effective against picked malignancy cell lines (Fig. 4).

FIG.  4  Illustration showing artemisinin derivatives and hybrids: dihydroartemisinin-cinnamic acid hybrid 14.

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ARTM and derivatives: Pharmacokinetics ARTM subsidiaries might be directed orally, intramuscularly, intravenously, or rectally. They have been found to incite neurotoxicity, which varies relying on the measures and strategy for the connection (Aderibigbe, 2017; Morris et al., 2011). The critical bioactive metabolite in the anti-M action of ARTM and its intermediates is dihydro-ARTM, and the alliance is perceived to be connected to the presence of the endoperoxide interface (Saifi et al., 2013). Free radicles of ARTM are additionally believed to frame a covalent linkage with heme or parasite proteins, restricting the hemozoin blend (Saifi et al., 2013; Yang et al., 1994). ARTM has a 1/2-life of 2 to 5 h, while artemether and artesunate have 1/2-life of 2 to 4 h and under 60 min, independently (Aderibigbe, 2017). ARTM digestion is intervened by the elements CYP2B6 and CYP3A4. CYP2A6 changes over artesunate to dihydro-ARTM, a working metabolite responsible for its anti-M action. Artemether is similarly quickly utilized by CYP3A4 and CYP3A5 to dihydro-ARTM. CYP3A4 changes over arteether to dihydroARTM. Glucuronidation changes over the particular metabolite dihydro-ARTM to different metabolites. Dihydro-ARTM is discharged as minuscule glucuronides in the bile (Aderibigbe, 2017). The occurrence of the endoperoxide atom is also accountable for ARTM and its replacement anticancer activity (Das, 2015; Olliaro et al., 2001). Their cytotoxic activities are generously diminished without the endoperoxide part. Iron and heme handling is fundamental in ARTM’s anticancer activity since it develops its cytotoxicity. It has been recommended that iron-association of ARTM harvests alkylating carbon-concentrated reformist and aficionado oxygen species, which prompt DNA hurt, drawn-out apoptosis, further developed catch, and diminished angiogenesis (Das, 2015). The antiviral activity has been found for ARTM intermediates, for example, artesunate. It hampers the in vitro expansion of human cytomegalovirus (HCMV) and herpes contaminations, the two of which cause genuine sicknesses in people. It was imagined that it works by obstructing basic administrative apparatuses in HCMV-ruined cells, along these lines meddling with having cell type and metabolic required for HCMV multiplication (Aderibigbe, 2017; Das, 2015).

Delivery systems loaded with ARTM and its derivatives Polymer-drug conjugates (poly-drug-con) Poly-drug-con are therapeutics constituted from biodegradable polymeric support, a targeting moiety, a drug molecule integrated into the polymer through a covalent linking, and a bioresponsive linker (Fig. 5; Ekladious et al., 2019). Majority of the anti-M drugs faces the issue of toxicity, resistance against malaria-­causing microorganism, limited bioavailability, poor aqueous solubility, and low biodegradability (Tse et al., 2019). To address these aforementioned issues, combination approach involving the use of two or more anti-M is currently preferred. In addition to this solubility, issue of poorly soluble ­antimicrobial

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FIG. 5  Illustration showing the conjugation between drug and polymers.

drugs is enhanced by forming drug-polymer conjugates. In this context, Wang et  al. combined dihydroartemisinin (dihydro-ARTM) with hydroxypropyl-­ cyclodextrin to fabricate an oral formulation. The incorporation of the drug into the modified cyclodextran resulted in increased dihydro-ARTM solubility and stability. It is essential to note, however, that cyclodextrin toxicity may occur at large doses. Auxiliary chemicals are used to counteract toxicity. Wang et al. utilized several auxiliary chemicals, which resulted in decreased cyclodextrin absorption and increased biological activity of the formulation (Wang et  al., 2013). Dal et al. integrated dihydro-ARTM onto polyethylene glycol (PEG) carriers to address their solubility issues and enhance the bioavailability of the drug. The conjugates were water-soluble and significantly improved the half-time of blood circulation in vivo. Delayed in vitro release of the integrated therapeutic molecule from the conjugates was observed, suggesting that the type of drug linker affects drug release processes (Dai et al., 2014). In another work, Xiao et al. developed C-10-phenoxy ARTM-chitosan conjugate through covalent linking to chitosan, which resulted in increased solubility of ARTM as compared to free ARTM medication (Xiao et al., 2013). Similarly, Yaméogo et al. also conjugated ARTM to cyclodextrin and prepared cyclodextrin nanostructures that were PEGylated with amphiphiles. The developed nanosuspension reduced the development of Plasmodium falciparum in vitro. Further, the conjugation of ARTM with cyclodextrin influenced the prolonged release of ARTM from the formulation (Yaméogo et al., 2012). Further, poly(organophosphazenes) cargoes of primaquine and dihydro-ARTM were developed by Kumar et al. The formulation examined for anti-M efficacy on Plasmodium berghei-infected mice revealed enhanced anti-M activity by combination therapy. The integration of ARTM derivatives onto polymers improved the aqueous solubility, greater stability, increased bioavailability by extending the medicine’s circulatory half-life, and was advantageous for combination therapy. The conjugated drug and its derivatives were released from conjugates in a pH-dependent manner, ­resulting in drug release at

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the appropriate spot. Conclusively, ARTM and its derivatives’ medicinal efficacy may be improved using polymer-drug conjugates (Kumar et al., 2015).

Micelles Micelles are polymeric cargoes employed for the transportation of a wide variety of bioactive chemicals. They are constituted of amphiphilic block copolymers that form an aquaphobic core to encapsulate lipophilic medications (Fig. 6A). Their form improves the prolonged bloodstream circulation and aids in sustained drug release mechanisms (Rashidzadeh et al., 2021). In this regard, Ismail et al. developed artesunate-heparin conjugate (ART-HEP) enriched nanocapsules for intracellular transport of ART for the treatment of malaria. Such modification led to significantly higher drug loading efficiency of ART than conventional ART-loaded nanoparticles. The developed nanocapsule-facilitated intracellular transportation of ART to the parasitic food vacuole and displayed an effective anti-M effect. Further, ART-HEP-based nanocapsules were reported to be safe and stable as observed by hemolytic activity. Notably, ART-HEPNCPs also displayed a higher inhibitory effect against Plasmodium falciparum than free ART in vitro. This expected slightly lower inhibitory effect of polymeric prodrug could be ascribed to the gradual release of ART from the polymer chain over time (Ismail et al., 2019). Bhadra et al. fabricated artemether-loaded methoxy polyethylene glycol micellar system for anti-M therapy. They reported that the developed formulation released the drug over a period of 48 h and exhibited improved stability of the formulation; while the system was risky due to the dense, hyperbranched micellar structures and the sluggish rate of disintegration. According to this, the micelle design is critical, as poorly designed micelle structures may influence their toxicity (Bhadra et al., 2005).

Liposomes Liposomes include amphiphilic molecules with an aqueous core and a lipid bilayer that separates the inner aqueous core from the exterior (Fig.  6B; Tagami et  al., 2015; Yadav et  al., 2020b, 2021a). By improving drug

FIG.  6  Illustration showing the structure of (A) micelles, (B) liposomes, and (C) Polymeric nanocapsules.

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a­ bsorption, lengthening biological half-life, and minimizing drug toxicity, they help encapsulated medicines work better. They can be broken down naturally and are biocompatible with living organisms. They communicate with cells using adsorption, endocytosis, membrane fusion, and lipid exchange. In terms of malaria prevention and treatment, liposomes have shown considerable efficacy as a nanocarrier for prophylactic and vaccine distribution. Due to harsh drug side effects and the development of resistance to current drug regimens, effective therapy for malaria is now quite restricted (Memvanga and Nkanga, 2021). Considering the herbal antimalarial drugs, liposomes that contain ARTM or derivatives are demonstrated to be more effective than free ART or derivatives. In this context, Isacchi et  al. fabricated ART-loaded polyethylene glycolbased liposomes. The blood-circulation time of the liposomal formulation was shown to be longer than that of the free medication when tested in vivo. They also reported a fivefold enhancement in the half-life of the liposomal formulation thereby suggesting the formulation to be a viable therapy for the cure of parasitic diseases. The prolonged blood circulation was a major impact on ARTM encapsulation to liposomes (Isacchi et al., 2011). In recent research, Duan et al. developed liposomes of artelinic acid-choline derivative (AD) to avoid the emergence of drug resistance by the synergistic effect of ARTMs and choline derivative. The efficacy of AD-liposomes examined by Peter’s 4-day suppression test on Plasmodium yoelii species revealed that the suppression percentage of AD-liposomes was significantly higher than that of dihydro-ART liposomes (P ≤ 0.05) and other control groups (P ≤ 0.05) (Duan et al., 2020).

Nanocapsules Nanocapsules are a kind of nanoparticle that consists of a core and a protective shell that contains bioactive substances (Fig.  6C). They offer many benefits, including extended drug release, increased bioavailability of therapeutic molecules, and decreased drug toxicity (Gomes et  al., 2018). Because of the benefits listed above, they have been utilized to encapsulate ARTM, its derivatives, and other herbal anti-M drugs. Chen et al. used a controlled drug release method to encapsulate ARTM in nanocapsules made of chitosan, gelatin, and alginate. ARTM-encapsulated nanocapsules demonstrated a protracted release mechanism. ARTM’s hydrophilic property was improved by encapsulating it in nanocapsules (Chen et al., 2009). In this context, Velasques et  al. developed quinine- and curcumin-loaded polymeric nanocapsules (NC-QC) and examine their anti-M efficacy on Plasmodium falciparum. The developed coencapsulated NCs displayed a significant decrease in the growth of test microorganisms as compared to free QN/ CR. Also, coencapsulation of QN and CR minimizes the side effects associated with continuous exposure to free drugs (Velasques et al., 2018).

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Niosomes Niosomes, like liposomes, are nonionic surfactant vesicles. They are more stable than liposomes and have a few features that make them superior to liposomes. They may be employed to integrate hydrophilic and lipophilic medicines, respectively, into the aqueous layer and the vesicular membrane (Mirzaei-Parsa et al., 2020). In this context, Thakkar & Brijesh packaged curcumin (CC) and primaquine (PRI) within niosomes and compared their respective monotherapy options for the treatment of malaria. They reported that upon treatment of developed PRI-CC noisome formulation to the Plasmodium berghei-infected mice exhibited cent percent antimalarial activity. They conclusively revealed that the developed formulation provided increased protection and survival rate, thus it could be a hopeful line in the treatment of malaria (Thakkar and Brijesh, 2018).

Ethosomes Ethosomes are soft lipid vesicles. Phospholipids, alcohol, and water make up their structure. They are used to administer drugs transdermal and dermally. They are simple to make, nontoxic, and patient-friendly (Yang et  al., 2017). Their usage, however, is restricted due to their low yield and very few ethosomebased herbal formulations have been employed for the treatment of malaria. In this regard, Shen et al. created anti-M artesunate-loaded ethosomes. The formulation substantially increased the accumulated penetration of artesunate over 8 h after delivery compared to the free medication. The mixture substantially eliminated Plasmodium parasites while preventing infection recurrence. Skin penetrating ability of ethosomes carrying ARTM derivatives indicates their ability to interact with the skin’s microstructure. However, bypassing the epidermal barrier for improved transdermal medication absorption is difficult. In the future, additional studies are needed to assess the long-term stability of ethosomal systems (Shen et al., 2015).

Solid lipid nanoparticle Solid lipid nanoparticles (SLNs) are typically made up of active drug molecules, solid lipids, surfactants, and/or cosurfactants. They have promising characteristics such as nanosize, a surface containing a free functional group to which ligands can be attached, and safe homing for both water and oil-loving molecules. Biocompatibility, physical stability, and degradability are SLN’s major attributes. SLN also protects integrated excipients from deterioration (Pradhan et  al., 2016, 2018). Nanostructured lipid carriers (NLC) are a new type of enhanced lipid nanoparticle built from a blend of solid and liquid lipids that remain solid when heated to body temperature. With these, SLN-related difficulties such as drug expulsion during polymorphic transition storage and relatively high water content of the dispersions would be alleviated, among other

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things (Pradhan et al., 2015, 2017). They are another important nanocarrier for the delivery of anti-M therapeutics. In this context, Nayak et  al. developed curcuminoids-loaded SLNs by a nanoemulsion technique and conducted pharmacodynamic activity using Plasmodium berghei-infected mice model and reported that curcuminoidsloaded SLNs exhibited two times enhancement in anti-M activity in Plasmodium berghei-infected mice model (Nayak et al., 2010). In this sequence, Aditya et al. fabricated artemether-loaded lipid nanoparticles and reported that the developed formulations did not show any liver and nephrotoxicity in  vivo. In addition, adult Swiss Albino mice treated with the developed formulation exhibited better therapeutic efficacy and less hemotoxicity than plain drug solution and marketed formulation (Nayak et al., 2010).

Nanoparticles Lipid-based nanoparticles Lipid-based nanoparticles (LBNs) may be divided into two types: solid LBNs and nanostructured LBNs. The size of solid LBNs falls between 50 and 1000 nm when encapsulating bioactive substances (Pradhan et al., 2021; Puri et al., 2009; Yadav et al., 2021b). They are biodegradable, biocompatible, and cost-effective to produce (Pradhan et al., 2021; Puri et al., 2009; Yadav et al., 2021c). They had a core element, and the emergence of a surfactant coating increased their stability. They are, although, constrained by particle accumulation, which is what causes drug burst release (Puri et  al., 2009). They have extraordinary crystal lattices that allow them to transport bioactive combinations in the molecular arrangement. In nanostructured LBNs with amorphous properties, the medicine burst effect is abridged (Puri et al., 2009). They have particle sizes ranging from 100 to 500 nm and might be utilized to transport bioactive combinations (Yadav et al., 2020a). Oral administration of LBNs containing ARTM and derivatives brought about worked on therapeutic advantages. Zhang and co-investigators (Zhang et al., 2013) made ARTM dimer piperazine subordinates that were loaded into lipid-based nanoparticles (NPs). The formulation restrained cell development more viably than the free drug (Zhang et al., 2013). The release of ARTM was pH-sensitive, which is connected with the existing pH-sensitive part called piperazine. The pace of ARTM discharge diminished as the pH of the environmental elements expanded. Dwivedi and co-investigators made areether-captured solid lipid NPs (SLNs) for the management of cerebral malaria (Dwivedi et al., 2014). Areether delivered gradually, and in  vivo testing uncovered that the medication-­loaded lipid expanded the medication’s oral bioavailability (Dwivedi et al., 2014). At the point when given orally, the formulations demonstrated support and were compelling. By consolidating areether onto SLNs, the drug was safeguarded from the acidic pH of the stomach, expanding bioavailability and therapeutic viability. Intravenously, LBNs containing ARTM derivatives were

Nanobiomaterials for artemisinin and its derivatives  Chapter | 18  457

given. Zhang and co-investigators explored the pharmacokinetics and tissue circulation of a dihydroxy-ARTM-encapsulated nanostructured lipid transporter following intravenous conveyance (Zhang et al., 2010). With a prolonged drug discharge phenomenon, the invention showed lower systemic toxicity (Zhang et al., 2010). Aditya and co-investigators distributed an investigation in which artemether was encapsulated onto lipid NPs, and after parenteral administration, their pharmacological adequacy was checked (Aditya et  al., 2010). The formulation was nonlethal and appropriate for delivery through the parenteral route. In vivo testing showed that the preparation was biocompatible and accommodating for the management of malaria (Aditya et al., 2010). There are many advantages of utilizing lipid-based NPs. Their utilization, be that as it may, is limited because of their gelation proclivity and deprived medication incorporation capacity.

Polymer-based NPs and inorganic-based NPs Polymer-based NPs NPs made of polymer(s) have been using in vivo to treat leishmaniasis, malaria, and other conditions (Mhlwatika and Aderibigbe, 2018; Yadav et al., 2021d). On that track, Need and colleagues developed polylactic-co-glycolic acid (PLGA) NPs containing ARTM for antileishmanial activity (Want et al., 2015). In vivo examination on a BALB/c mouse with leishmaniasis revealed that ARTM significantly reduced parasite problems in the spleen and liver compared to free ARTM (Want et al., 2015). The ARTM-encapsulated NPs revive CD80 particle expression, restoring adequate effector T-cell response. Gupta and colleagues synthesized ARTM HCl NPs from poly(ε-caprolactone) using a solvent evaporation method (Kumar et al., 2014). ARTM in vitro release from NPs was sustained for 24 h (Kumar et al., 2014). Nguyen and colleagues used an oil/water emulsion evaporation technique to encapsulate artesunate onto PLGA NPs in the anticancer effects of polymeric NPs encapsulated with ARTM derivatives (Nguyen et al., 2015). The cytotoxicity tests of the drug-encapsulated NPs on the cancer cell lines SCC-7, A549, and MCF-7 revealed that the NPs had a noteworthy impact on the disease cell lines. The details were consistent and appealing as an anticancer treatment (Nguyen et al., 2015). Several studies have demonstrated the physicochemical attributes of NPs encapsulated with ARTM and its derivatives, confirming that they are a promising therapeutic agent (Anand et al., 2012; Kakran et al., 2010). Further, Chadha and colleagues improved the anti-M activity of artesunate by complexing it with cyclodextrin and encapsulating it in chitosan/lecithin NPs. The NPs’ medicine release behavior was pH-controlled, and in vivo testing on Plasmodium berghei-infected mice via oral administration of the preparation revealed that consolidating artesunate onto the NP improved its therapeutic adequacy (Chadha et al., 2012). Further, Sun and colleagues used anticancer workouts to incorporate dihydro-ARTM onto gelatin and hyaluronan NPs (Sun et al., 2014). In vitro studies on A549 malignant growth cell lines revealed that drug-encapsulated NPs inhibited cell

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development more than free medicines. The anticancer action of the formulation was caused by drug accretion with NPs in an electric field milieu (Sun et al., 2014). Subsequently, Ibrahim and colleagues discovered anti-M activity in ARTM-encapsulated egg white NPs (Ibrahim et al., 2015). In vivo tests on humanized mice infected with Plasmodium falciparum by intravenous injection shown that NPs encapsulated with medication reduced parasitemia by 96% at a dose of 10 mg/kg/day (Ibrahim et  al., 2015). For combination treatment, Mama and colleagues (Ma et al., 2015) created PLGA-NPs encapsulated with dihydro-ARTM and doxorubicin. The efficacy of polymeric-NPs as leishmanial agents in vivo (Want et al., 2015), anticancer drugs (Nguyen et al., 2015; Sun et al., 2014), and anti-M agents (Chadha et al., 2012; Ibrahim et al., 2015) suggests that they are impending systems for the treatment of cancer-causing and protozoal infections. In any case, the size of the NPs may promote molecular aggregation, making storage and handling challenges. Inorganic-based NPs They are generally metal-based NPs produced to impart the additive benefits of the source metals. Wang and colleagues (Wang et al., 2011) investigated the impact of magnetic Fe3O4 NPs on artesunate for anticancer activity. In  vitro tests of K562 cell lines indicated that NPs combined with artesunate co-polymer inhibited cell proliferation and increased the rate of apoptosis more than the free drug (Wang et al., 2011). Anticancer ARTM was loaded onto iron NPs by Chen and colleagues (Chen et al., 2014). When tested on HeLa cell lines in vitro, the preparation diminished cell development. The extension of ARTM derivatives to inorganic-based NPs reduced negative effects while increasing natural action. Despite this, there are only a few investigation reports, indicating that more research is needed. Apart from the above discussed formulations, Table 1 presents an overview of ARTM and its derivative enriched nanoformulations for the treatment of malaria.

Conclusions ARTM and its derivatives have antibacterial, antiviral, antitumor, anticancer, and anti-inflammatory properties. They may also be used to treat other protozoan diseases. Because of their deprived bioavailability, lack of aqueous dissolvability, and short half-life, these medicinal compounds have been utilized to advance delivery methods that may upgrade their therapeutic effects. These compounds were developed and used with noteworthy methods to create formulations epitomized by ARTM and its subordinates, ensuing in formulations with better bioavailability, safety, pharmacokinetic properties, and lesser side effects than ARTM and its subordinates. ARTM and its subordinates’ therapeutic adequacy are affected by the delivery methods used to transport them. Because the therapeutic delivery of active components affects the destiny of the

TABLE 1  An overview of ARTM and its derivative enriched nanoformulations for the treatment of malaria. Type of nanocarriers Polymeric nanoparticles

Lipid nanoparticles

Artemisinin and its derivative

Polymer/lipid used

Remark

References

ARTM

PLGA

Enhanced encapsulation of medicament and controlled drug release

Alven and Aderibigbe (2020)

ARTM

Cyclodextrin

Significant enhancement of pharmacokinetic parameters of drug

Tse et al. (2019)

ARTM

Cyclodextrin

Controlled rate of drug release and significant inhibition of parasite growth

Yaméogo et al. (2012)

Artesunate

PLGA

Improved antimalarial activity in vivo with controlled release of artesunate

Oyeyemi et al. (2018)

Artesunate and ARTM

Chitosan/lecithin

Less mean percent parasitemia in vivo

Chadha et al. (2012)

Artemether

Phospholipon, theobroma oil, and beeswax

High parasitemia clearance with few side effects

Attama et al. (2016)

DihydroARTM

Steric acid

Good parasite chemo-suppression in vivo

Omwoyo et al. (2016)

Arteether

Phosphatidylcholine and labrasol

Augmented survival rate and a significantly delayed recurrence

Memvanga et al. (2013)

Artemether

Soybean oil (liquid lipid) and glyceryl trimyristate

Hemolytic toxicity was reduced, and the antiplasmodial activity was good when tested in animals

Aditya et al. (2010)

Artesunate

Glyceryl monostearate

Enhanced medication intestinal permeability and prolonged drug release

Masiiwa and Gadaga (2018) Continued

TABLE 1  An overview of ARTM and its derivative enriched nanoformulations for the treatment of malaria—cont’d Type of nanocarriers

Artemisinin and its derivative

Polymer/lipid used

Remark

References

Artemether

Human serum albumin

When compared to the free medication, the nanoparticles had dramatically improved solubility

Boateng-Marfo et al. (2018)

Artemether

Soybean oil, sodium oleate, glycerol, and egg lecithin, poloxamer

Decrease in the parasitemia levels after 3 days, and with parasitemia inhibition rate of 90%

Ma et al. (2014)

Artesunate

Glycerophosphorylcholine

The lengthened medication half-life in the body. This treatment significantly increased the parasite killing ability of the free medication in P. berghei-infected animals

Ismail et al. (2018)

Artesunate

Human serum albumin

At a dose of 10 mg/kg/day, parasitemia was inhibited by 96% and a lengthy median life expectancy without recurrence was reported

Ibrahim et al. (2015)

ARTM

PEG

ARTM’s half-life was extended by more than five times, and its blood circulation time was also improved

Isacchi et al. (2011)

Arteether

Phosphatidylcholine

Significant enhancement in cure rate with no recurrence

Aditya et al. (2012)

Artemether

Soybean oil

Significant antimalarial action in terms of parasitemia progression and parasitemia survival time

Parashar et al. (2016)

Arteether

Groundnut oil, Tween 80

A 100% cure for more than 45 days

Memvanga and Préat (2012)

Artemether and lumfantrine

Soybean oil and oleic acid

Comparatively high Cmax of artemether and lumefantrine from the nanoparticle was reported as compared to the pure drug solution

Yang et al. (2018)

Arteether

Tween 80, PEG 400

Improved drug bioavailability

Dwivedi et al. (2015)

Nanobiomaterials for artemisinin and its derivatives  Chapter | 18  461

drug within the carrier and at the targeted milieu, the materials used to create the nanocarriers influence drug release, survival, and degree of toxicity, as well as the activity of ARTM and subordinates. The design and materials of nanocarriers have a substantial influence on their toxicity, biodegradation frequency, and drug distribution level. There have been few conveyance systems of ARTM and its derivatives that have been studied for antibacterial efficacy, including ethosomes, micelles, nanocapsules, niosomes, and carbon nanotubes, among others, implying the need for more study on these systems. The majority of the systems were assessed in vitro and in vivo, and the findings were encouraging, indicating that there is a genuine necessity for further research on these systems to reach clinical preliminary stages since the development of medication opposition remains an overall problem.

Acknowledgments The authors do want to express their thankfulness to all of the institutions with which they are affiliated for providing the necessary resources required for the structure of this review.

Conflict of interest None.

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464  Natural products in vector-borne disease management Mirzaei-Parsa, M.J., Najafabadi, M.R.H., Haeri, A., Zahmatkeshan, M., Ebrahimi, S.A., PazokiToroudi, H., Adel, M., 2020. Preparation, characterization, and evaluation of the anticancer activity of artemether-loaded nano-niosomes against breast cancer. Breast Cancer 27, 243–251. Mishra, M., Mishra, V.K., Kashaw, V., Kashaw, S.K., 2021. Molecular approaches for malaria therapy. In: Plasmodium Species and Drug Resistance. IntechOpen. https://doi.org/10.5772/ intechopen.98396. Morris, C.A., Duparc, S., Borghini-Fuhrer, I., Jung, D., Shin, C.-S., Fleckenstein, L., 2011. Review of the clinical pharmacokinetics of artesunate and its active metabolite dihydroartemisinin following intravenous, intramuscular, oral or rectal administration. Malar. J. 10, 263. Nayak, A.P., Tiyaboonchai, W., Patankar, S., Madhusudhan, B., Souto, E.B., 2010. Curcuminoidsloaded lipid nanoparticles: novel approach towards malaria treatment. Colloids Surf. B. Biointerfaces 81, 263–273. Nguyen, H.T., Tran, T.H., Kim, J.O., Yong, C.S., Nguyen, C.N., 2015. Enhancing the in vitro anticancer efficacy of artesunate by loading into poly-D,L-lactide-co-glycolide (PLGA) nanoparticles. Arch. Pharm. Res. 38, 716–724. Olliaro, P.L., Haynes, R.K., Meunier, B., Yuthavong, Y., 2001. Possible modes of action of the artemisinin-type compounds. Trends Parasitol. 17, 122–126. Omwoyo, W.N., Melariri, P., Gathirwa, J.W., Oloo, F., Mahanga, G.M., Kalombo, L., Ogutu, B., Swai, H., 2016. Development, characterization and antimalarial efficacy of dihydroartemisinin loaded solid lipid nanoparticles. Nanomedicine 12, 801–809. Opsenica, D., Solaja, B., 2012. Artemisinins and synthetic peroxides as highly efficient antimalarials. Maced. J. Chem. Chem. Eng. 31, 137–182. Oyeyemi, O., Morenkeji, O., Afolayan, F., Dauda, K., Busari, Z., Meena, J., Panda, A., 2018. Curcumin-­artesunate based polymeric nanoparticle; antiplasmodial and toxicological evaluation in murine model. Front. Pharmacol. 9, 562. Pandey, S.K., Biswas, S., Gunjan, S., Chauhan, B.S., Singh, S.K., Srivastava, K., Singh, S., Batra, S., Tripathi, R., 2016. Pyrrolidine-acridine hybrid in artemisinin-based combination: a pharmacodynamic study. Parasitology 143, 1421–1432. Parashar, D., Aditya, N.P., Murthy, R.S.R., 2016. Development of artemether and lumefantrine coloaded nanostructured lipid carriers: physicochemical characterization and in vivo antimalarial activity. Drug Deliv. 23, 123–129. Pradhan, M., Alexander, A., Singh, M.R., Singh, D., Saraf, S., Saraf, S., Yadav, K., Ajazuddin, 2021. Statistically optimized calcipotriol fused nanostructured lipid carriers for effectual topical treatment of psoriasis. J. Drug Deliv. Sci. Technol. 61, 102168. Pradhan, M., Singh, D., Murthy, S.N., Singh, M.R., 2015. Design, characterization and skin permeating potential of Fluocinolone acetonide loaded nanostructured lipid carriers for topical treatment of psoriasis. Steroids 101, 56–63. Pradhan, M., Singh, D., Singh, M.R., 2016. Influence of selected variables on fabrication of Triamcinolone acetonide loaded solid lipid nanoparticles for topical treatment of dermal disorders. Artif. Cells Nanomed. Biotechnol. 44, 392–400. Pradhan, M., Singh, D., Singh, M.R., 2017. Fabrication, optimization and characterization of triamcinolone acetonide loaded nanostructured lipid carriers for topical treatment of psoriasis: application of Box Behnken design, in vitro and ex vivo studies. J. Drug Deliv. Sci. Technol. 41, 325–333. Pradhan, M., Alexander, A., Singh, M.R., Singh, D., Saraf, S., Saraf, S., Ajazuddin, 2018. Understanding the prospective of nano-formulations towards the treatment of psoriasis. Biomed. Pharmacother. 107, 447–463. https://doi.org/10.1016/j.biopha.2018.07.156.

Nanobiomaterials for artemisinin and its derivatives  Chapter | 18  465 Pradhan, M., Yadav, K., Singh, D., Singh, M.R., 2021. Topical delivery of fluocinolone acetonide integrated NLCs and salicylic acid enriched gel: a potential and synergistic approach in the management of psoriasis. J. Drug Deliv. Sci. Technol. 61, 102282. Puri, A., Loomis, K., Smith, B., Lee, J.H., Yavlovich, A., Heldman, E., Blumenthal, R., 2009. Lipidbased nanoparticles as pharmaceutical drug carriers: from concepts to clinic. Crit. Rev. Ther. Drug Carrier Syst. 26 (6), 523–580. https://doi.org/10.1615/critrevtherdrugcarriersyst.v26. i6.10. Rashidzadeh, H., Tabatabaei Rezaei, S.J., Adyani, S.M., Abazari, M., Rahamooz Haghighi, S., Abdollahi, H., Ramazani, A., 2021. Recent advances in targeting malaria with nanotechnologybased drug carriers. Pharm. Dev. Technol. 26, 807–823. Saifi, M., Beg, T., Harrath, H., Altayalan, F., Al-Quraishy, S., 2013. Antimalarial drugs: mode of action and status of resistance. Afr. J. Pharm. Pharmacol. 7, 148–156. Shen, S., Liu, S.-Z., Zhang, Y.-S., Du, M.-B., Liang, A.-H., Song, L.-H., Ye, Z.-G., 2015. Compound antimalarial ethosomal cataplasm: preparation, evaluation, and mechanism of penetration enhancement. Int. J. Nanomedicine 10, 4239–4253. Soomro, S., Langenberg, T., Mahringer, A., Konkimalla, V.B., Horwedel, C., Holenya, P., Brand, A., Cetin, C., Fricker, G., Dewerchin, M., Carmeliet, P., Conway, E.M., Jansen, H., Efferth, T., 2011. Design of novel artemisinin-like derivatives with cytotoxic and anti-angiogenic properties. J. Cell. Mol. Med. 15, 1122–1135. Sun, Q., Teong, B., Chen, I.-F., Chang, S.J., Gao, J., Kuo, S.-M., 2014. Enhanced apoptotic effects of dihydroartemisinin-aggregated gelatin and hyaluronan nanoparticles on human lung cancer cells. J Biomed Mater Res B Appl Biomater 102, 455–462. Tagami, T., Yanai, H., Terada, Y., Ozeki, T., 2015. Evaluation of phosphatidylserine-specific peptide-­conjugated liposomes using a model system of malaria-infected erythrocytes. Biol. Pharm. Bull. 38, 1649–1651. Talapko, J., Škrlec, I., Alebić, T., Jukić, M., Včev, A., 2019. Malaria: the past and the present. Microorganisms 7 (6), 179. https://doi.org/10.3390/microorganisms7060179. Thakkar, M., Brijesh, S., 2018. Physicochemical investigation and in vivo activity of anti-malarial drugs co-loaded in tween 80 niosomes. J. Liposome Res. 28, 315–321. Tse, E.G., Korsik, M., Todd, M.H., 2019. The past, present and future of anti-malarial medicines. Malar. J. 18, 93. https://doi.org/10.1186/s12936-019-2724-z. Velasques, K., Maciel, T.R., de Castro Dal Forno, A.H., Teixeira, F.E.G., da Fonseca, A.L., de Varotti, F.P., Fajardo, A.R., de Ávila, D.S., Haas, S.E., 2018. Co-nanoencapsulation of antimalarial drugs increases their in vitro efficacy against Plasmodium falciparum and decreases their toxicity to Caenorhabditis elegans. Eur. J. Pharm. Sci. 118, 1–12. Walsh, J.J., Coughlan, D., Heneghan, N., Gaynor, C., Bell, A., 2007. A novel artemisinin-quinine hybrid with potent antimalarial activity. Bioorg. Med. Chem. Lett. 17, 3599–3602. Wang, Y., Han, Y., Yang, Y., Yang, J., Guo, X., Zhang, J., Pan, L., Xia, G., Chen, B., 2011. Effect of interaction of magnetic nanoparticles of Fe₃O₄ and artesunate on apoptosis of K562 cells. Int. J. Nanomedicine 6, 1185–1192. Wang, D., Li, H., Gu, J., Guo, T., Yang, S., Guo, Z., Zhang, X., Zhu, W., Zhang, J., 2013. Ternary system of dihydroartemisinin with hydroxypropyl-β-cyclodextrin and lecithin: simultaneous enhancement of drug solubility and stability in aqueous solutions. J. Pharm. Biomed. Anal. 83, 141–148. Wang, N., Wicht, K.J., Shaban, E., Ngoc, T.A., Wang, M.-Q., Hayashi, I., Hossain, M.I., Takemasa, Y., Kaiser, M., El Tantawy El Sayed, I., Egan, T.J., Inokuchi, T., 2014. Synthesis and evaluation of artesunate–indoloquinoline hybrids as antimalarial drug candidates. Med. Chem. Commun. 5, 927–931.

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Chapter 19

Scientific and ethnopharmacological evidence of Carica papaya for the effective management of vector-borne disease Neelesh Malviyaa, Rajiv Saxenaa, Ruchi Guptaa, and Sapna Malviyab a

Smriti College of Pharmaceutical Education, Indore, Madhya Pradesh, India, bModern Institute of Pharmaceutical Science, Indore, Madhya Pradesh, India

Introduction As indicated by the World Health Organization, vector-borne illnesses represent over 17% of every infectious sickness and cause more than 1 million passing yearly. Vector-borne sicknesses are communicated from one individual to another through a capable vector, and as per the National Vector-borne Disease Control Program, different vector-borne diseases are prevailing in India including mosquitoes, Dengue, Japanese encephalitis, Chikungunya, and so on. As per vector definition they might be any arthropod or creature which conveys and sends infectious microbes and parasites straightforwardly or in a roundabout way from a tainted animal to a human or from a contaminated individual to another and makes sicknesses to the people (Kalluri et al., 2007). A genuine general medical issue has arisen lately in the nations of the SouthEast Asia Region, including India because of vector-borne diseases (Patel et al., 2011). Mosquitoes and many other blood-feeding arthropods are explored as vectors of many dreadful diseases caused by parasitic, viruses, and bacteria. Malaria fever along with dengue together causes more than 300 million cases and kills more than 1,000,000 individuals consistently. Vector-borne infections have been annihilated before yet have been either disposed of or decreased cases are observed in the last century. Nonetheless, over the most recent couple of years, we have seen a huge expansion in the recurrence of VBD cases and episodes, and the danger of resurgence currently looks always plausible. The absence of antibodies and other viable ­anticipation Natural Products in Vector-Borne Disease Management. https://doi.org/10.1016/B978-0-323-91942-5.00010-0 Copyright © 2023 Elsevier Inc. All rights reserved.

467

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for many of the VBDs and the intricacy of the illness life cycles require profoundly coordinated methodologies that focus on the sickness transmission framework instead of just the microorganisms (Christophides and Crisanti, 2013). It has been observed especially in tropical and subtropical areas that dengue is referred to as an infection of destitution as it is most firmly connected with helpless populaces (Rigau-Pérez et al., 1998). The principal significant pandemic of Japanese encephalitis (JE) was depicted in 1924 in Japan, in which around 6000 cases were accounted for. Right now, in India, JE is the chief reason for immunization-preventable encephalitis. JE is presently endemic in a few states in India like Bihar, Uttar Pradesh, Assam, Andhra Pradesh, Madhya Pradesh, Tamil Nadu, Kerala, West Bengal, and Union domains of Goa and Pondicherry (Tiwari et  al., 2012; Table 1). The effective management and treatment of all the vector-borne diseases are having objectives of control and decrease of sickness occurrence and also ideally, transmission process. End requires lessening transmission to levels that are not exactly self-supporting and have a numerical approach of disease transmission by the reduction in the reproduction number of pathogen and vector. The administration of suitable vaccines with high adequacy for the greater part of the vector-borne diseases can also play an important role in the control process of VBD. The principle objective of general mediations for these contaminations has been found successful with lessen human openness through vector control (Griffin, 2015).

TABLE 1  Important vector-borne diseases and its global impact (Nicoletti, 2020). Disease

Pathogen

Vector

Impact

Malaria

Plasmodium species

Anopheles species

600 million at risk (3–8 million deaths)

Dengue, chikungunya fever, urban yellow fever

Chikungunya virus

Aedes aegypti

3.5 million people at risk in 128 countries

Lymphatic filariasis

Arboviruses

Culex quinquefasciatus

1 million people at risk in 71 countries

Zika

Chikungunya virus

Aedes aegypti

About 80% people at risk

West Nile virus

Flavivirus species

Culex pipiens and others

Difficult to determine as many cases are asymptomatic

Scientific and ethnopharmacological evidence  Chapter | 19  469

Traditional medicines are used to treat and manage VBD for many years. Considering the example of malaria, the two main groups of medicine such as artemisinin and quinine derivatives which are used in modern antimalarial drugs are having plant sources. With the issues of expanding levels of medication resistance and troubles in the poor population of having the option to bear and access viable antimalarial drugs, conventional and traditional herbal remedies could be a significant and practical source of treatment. Carica papaya Linn. is also known as papaya, pawpaw, papaw, papita, papaia, arand-kharpuja and papaybaum which comes under Caricaceae family. It has different parts like fruit, seed, leaves, latex, and bark which have rich nutritional and medicinal value (Vij and Prashar, 2015). It is the factory of nutritive active compounds and is found throughout the year (Priyadarshi and Bhuwal, 2018). It has four genera in the whole world but its Carica Linn. (genus) mainly has four species in India that have unique medicinal values (Vij and Prashar, 2015). In different systems of medicine specifically in Ayurveda, it is a health improver and disease protective which affects the whole body (Oh et al., 2005). It is also used as a definite dietary and therapeutic agent to delay aging and it revitalizes and rejuvenates the whole functional dynamics of the body organs. It has been used in “Rasayana chikitsa” (Govindarajan et al., 2005). Fruits of Carica papaya Linn. are mainly found in tropical and subtropical regions. According to FAO (the Food and Agriculture Organization of the United Nations) (FAO, 2019), more than 6.8 million tons of fruits are produced worldwide each year. The United States, especially Brazil, produces 47% of fruit juices, which is produced year-round, as an important source of nutrients at low cost with good market access (Lidiani et al., 2019). Different parts of Carica papaya Linn. like leaves, seeds, fruits, and stems contain different active phytoconstituents such as alkaloids, flavonoids, saponins, tannins, cardiac glycosides, anthraquinones, cardenolides, Vitamins C, E, and different types of enzymes which have many types of pharmacological activities (Roshan et al., 2014). Carica papaya Linn. is also used for cosmetic benefits for human. Its white pulp when rubbed on the face reduces the pimples as well as wrinkles. It is also used as a bleaching agent, astringent, hand wash, and detergent bar. Experts advised that it can be used to eradicate dead (rough) skin cells and to replace them with new healthy cells. So it is also used as a brightening agent for the skin (Aravind et al., 2013). Leaf juice of Carica papaya Linn. is used for enhancing the platelet counts in a patient who is suffering from dengue fever. According to the literature review experts have revealed that different parts of Carica papaya Linn. have most prominent medicinal properties like antioxidant, antiviral, wound healing activity, antibacterial, antipyretic, antifertility activity, Hypoglycaemic, hepatoprotective activity, insecticidal, antimolluscal, antimalarial, diuretic activity, antidengue effects, antiulcer activity, antisickling activity, immunomodulatory activity, antitumor, antimicrobial and antiinflammatory activity (Priyadarshi and Bhuwal, 2018; Vij and Prashar, 2015).

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Ethnomedical considerations Different parts of the Carica papaya Linn. have different active phytoconstituents like vitamins, carbohydrates, terpenoids, flavonoids, alkaloids, carotenoids, glycosides, and numerous enzymes which have different ethnomedicinal potential usages. So, these potential usages are beneficial in different scientific studies (Saini et al., 2016; Saeed et al., 2014). Fresh leaves extraction (decoction) of Carica papaya Linn. is used for the treatment of high blood pressure, malaria, dengue, jaundice, overweight, tumor, asthma, indigestion, abortion, gonorrhea, arteriosclerosis, bacterial and viral diseases. Brown and yellow leaf extraction (decoction) is used as antianemia agents and body purifiers. Dried leaves extract is used as a tonic and blood purifier (Varisha et al., 2013; Osato et al., 1993; Krishna et al., 2008; Ayoola and Adeyeye, 2010; Nwofia et  al., 2012; Boshra and Tajul, 2013; Malathi and Vasugi, 2015; Ansari, 2016; Vij and Prashar, 2015). Dried flower extract (decoction) of Carica papaya Linn. is utilized in the treatment of jaundice, emmenagogue, febrifuge, and pectoral properties (Krishna et al., 2008). The unripe fruit of Carica papaya Linn. is used as antiulcer agent and can treat impotency. It has shown laxative effects and can avoid heart stroke (Krishna et  al., 2008; Ayoola and Adeyeye, 2010; Boshra and Tajul, 2013; Vij and Prashar, 2015; Kartikar and Basu, 1998; Vidya, 2005). Crude latex decoction is used to treat cough (whooping cough), burn pain, hemorrhoids, and diarrhea (Begum, 2014; Krishna et al., 2008; Boshra and Tajul, 2013). Stem bark extract (decoction) of Carica papaya Linn. is used for treating sexually transmitted diseases, and jaundice and has shown antifungal and antihemolytic activities (Krishna et  al., 2008; Vij and Prashar, 2015; Kartikar and Basu, 1998; Vidya, 2005). The root extract of Carica papaya Linn. is used in the treatment of syphilis, cough, respiratory diseases (bronchitis), analgesic and urinary bladder problems (Aruljothi et  al., 2014; Krishna et al., 2008; Boshra and Tajul, 2013; Vij and Prashar, 2015; Rashed et al., 2013). Seed powder of Carica papaya Linn. is used to cure piles, typhoid, intestinal worms, and sickle cell diseases and also protect kidneys from toxins (Aruljothi et  al., 2014; Begum, 2014; Nwofia et  al., 2012; Malathi and Vasugi, 2015; Vij and Prashar, 2015; Vidya, 2005). The seed extract of Carica papaya Linn. is used to demonstrate anthelmintic bactericidal antiamoebic activities. Seed juice of Carica papaya Linn. is used to treat bleeding (piles) (Krishna et al., 2008). The seed oil of Carica papaya Linn. is a good source of oil (25.6%) which is useful as biofuel for industrial and medicinal purposes (Hayatie et al., 2015).

Pharmacognostical character Carica papaya Linn. has 23 scientific species and among them, two are placed under angiosperms. Carica papaya Linn. is a flowering and perennial plant

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that comes under Caricaceae family. In India, common name of Carica papaya Linn. is Boppayi pandu (Telugu), Papita (Hindi and Punjabi), Pappali (Tamil), Park (Kannada), Amrut band (Oriya), Papaya (Gujarati), Omakai (Malayalam), Pepe (Bengal), Papai (Marathi), and Erankari (Rajasthan). In foreign countries, synonyms of Carica papaya Linn. plant are Pawpaw (Australia), Mamão (Brazil), Fruta bomb (Cuba), Papaya (France), Tree Watermelon (Holland), Papaya (Colombia, India, and United Kingdom) (Milind and Gurditta, 2011). The taxonomical classification of Carica papaya Linn. can be done as follows (Kaur et al., 2019; Yogiraj et al., 2014): Kingdom: Plantae Sub Kingdom: Tracheobionta Division: Magnoliophyta Class: Magnoliopsida Subclass: Dilleniidae Super division: Spermatophyta Phylum: Steptophyta Order: Brassicales Family: Caricaceae Genus: Carica Species: papaya L. Botanical name: Carica papaya

Origin and distribution Carica papaya Linn. originated from the lowlands east of Center America, from Mexico to Panama (Office of the Gene Technology Regulator, 2008). Some expert says that it originated in South America and some suggest it originated in Central America (Australia Office of the Gene Technology Regulator, 2003). Cultivation of Carica papaya Linn. is done mainly in tropical and subtropical countries. Which includes 57 countries like India, Mexico, Brazil, Indonesia, and Nigeria but among these India is the biggest producer of the Carica papaya Linn. (Office of the Gene Technology Regulator, 2008). In India, Carica papaya Linn. is mainly grown in Punjab, Andhra Pradesh, Bihar, Bengal, Maharashtra, Haryana, and Uttar Pradesh (Dinesh et al., 2015) (Figs. 1–9).

Macroscopic character Carica papaya Linn. is a small Dicotyledonous, diploid and polygamous species. It is a single-stemmed, perennial with sparingly branching and a rapidly growing tree. It is a hermaphrodite plant. Its height is 15–30 ft and its leaves are arranged spirally and are located at the top. The conspicuous scars of leaves and fruits are seen in the lower trunk (Agarwal et al., 2016; Sharma et al., 2013; Priyadarshi and Bhuwal, 2018).

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FIG. 1  Leaves of Carica papaya Linn.

FIG. 2  Latex of unripe fruit of Carica papaya Linn.

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FIG. 3  Ripe fruit of Carica papaya Linn.

FIG. 4  Seeds of Carica papaya Linn.

FIG. 5  Male flower of Carica papaya Linn.

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FIG. 6  Female flower of Carica papaya Linn.

FIG. 7  Bark of Carica papaya Linn.

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FIG. 8  Root of Carica papaya Linn.

FIG. 9  Tree of the Carica papaya Linn.

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Description of the morphology of various parts of the Carica papaya Linn.:

Roots Its root (Fig. 8) is whitish cream in color. Its youngest roots are differentiated by the endodermis, epidermis, and cortex. It is dense and nonaxis in nature (Jiménez et al., 2014). Stem Carica papaya Linn. is a single-stemmed tree and the top of the tree contains huge palmate leaves. Its stem has hollow cylindrical soft trunk. Its width is 30 cm at the base and about 5 cm at the top or crown (Begum, 2014; Jiménez et al., 2014; Dinesh et al., 2015). Leaves Leaves of Carica papaya Linn. are large, palmate (having 5–9 pinnate lobes) and has varied width of 40–60 cm. Its leaves have a width of 50–70 cm (20–28 in) and are hence large. It is arranged in spiral and groups in the upper part of the fully matured plant. It has a hollow stalk (30–105 cm) that grows almost horizontally and leaf blades are dorsoventrally situated (Milind and Gurditta, 2011) (Fig. 1). Flower Flower of the Carica papaya Linn. is bisexual. The female flower of the Carical papaya Linn. is pear-shaped in closed condition. The male flower of the Carica papaya Linn. has a small flower with long stalks even as the bisexual flowers are tubular. The bisexual plants are better, and so they are more preferred over male or female plants (Yogiraj et al., 2014). The flowers are actinomorphic, bracteolate, and do not move in the collection, and is arranged next to one central axis. The androecium is epipetalous (carrying leaves or corolla) made of 10 stamens twice. Internal anthers (turn inside) are situated on both sides. The calyx has five small lobes and is compact (gamosepalous) and the corolla with five leaves is gamopetalous which is elongated and yellow in color. The androecium is absent in female flower and it contains an ovary. Female flowers (Pistillate) are below the stem and bracteolate. The ovary is higher and has an unknown number of seeds (Kaur et al., 2019). Fruits Fruits of Carrica papaya Linn. are oval to spherical and it looks like berries. It has a fruit cavity so it resembles melon fruits. Its growth and weight depend upon the conditions of cultivation and temperature. Its fruits mature in 5–9 months. It weighs from 0.5 to 20 Ibs and are green (unripe) until ripe. In maturity, it is yellow or red orange in color (Dinesh et al., 2015; Milind and Gurditta, 2011). Its fruits are borne auxiliary on the stem, single and sometimes it may be in cluster.

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Seeds Carica papaya Linn. is cultivated from seeds. Its seeds (Fig. 4) are blackish in color, embryo (straight) and endosperm (fleshy), and cotyledons are oblong and plane (Jiménez et al., 2014). Its seeds are found in fruits cavity of Carica papaya Linn. Its seeds are black in color and coated with mucilaginous Substances. Its seeds are edible having a spicy taste. It shows antibacterial properties and also protects the kidney from failure (Barroso et al., 2016; Yogiraj et al., 2014). Microscopic characters The leaf of Carica papaya Linn. has a single layer of palisade parenchyma and epidermis cells but the leaf has a palisade parenchyma and epidermis and squishy and consist of 4–5 cells layers of mesophyll. Leaves have reflective grains and calcium oxalate crystals. The leaves contain stomata underneath with anisocytosis stomata (without subsidiary cells). Microscopy of the leaf showed epidermis, collenchymas, parenchyma, sclerenchyma, xylem, and phloem. Pith is absent in leaf of Carica papaya Linn. (Jiménez et al., 2014; Dinesh et al., 2015). A bulky cuticle, laticifers, epicarp parenchyma, mesocarp endocarp, and calcium oxalate crystal are shown by the unripped fruit of Carica papaya Linn. (Varisha et al., 2013).

Phytochemistry Different parts of the Carica papaya Linn. plant such as seeds, fruits, bark, leaves, stem, fruit juice, and latex contain different types of active phytoconstituents which have medicinal importance. It is also used in various purposes in the field of phytochemistry. Different parts of Carica papaya contain different active constituents which are shown below:

Fruits Fruits contain different active phytoconstituents such as carotenoids (βcarotene, cryptoxanthin, violaxanthin, and zeaxanthin), monoterpenoids (4-terpineol, linalool, and linalool oxide), carbohydrates (glucose, sucrose, and fructose) (Kaur et al., 2019). Some active phytoconstituents are isolated and characterized from Carica papaya Linn. like crude protein (13.63%), fat (1.29%), fibers (1.88%), moisture content (10.65%), carbohydrates (sugar 15.15%), minerals (Ca, P and Fe), l-ascorbic acid, vitamin B1(thiamine), vitamin B2 (riboflavin), vitamin B3 (niacin), carotene, amino acid, citric and malic acids (unripe fruits) (Vij and Prashar, 2015) volatile oil: Benzyl-β-d-glucoside (Fig. 10), Caricapinoside (Fig. 11), trans-Linalool oxide (Fig. 12), cis-Linalool oxide (Fig. 13), Butanoic acid (butyric acid) (Fig. 14), Benzyl isothiocyanate (Fig. 15), β-Cryptoxanthin (Fig. 16) and β-Carotene (Fig. 17) (Yogiraj et al., 2014; Krishna et al., 2008).

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FIG. 10  Benzyl-β-d-glucoside.

FIG 11  Caricapinoside.

FIG. 12  trans-Linalool oxide.

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FIG. 13  cis-Linalool oxide.

FIG. 14  Butanoic acid (butyric acid).

FIG. 15  Benzyl isothiocyanate.

Fruits of Carica papaya Linn. contain a lot of active phytoconstituents which have hypoglycaemic, abortifacient, diuretic, antiinflammatory, antiviral, antifungal, antibacterial, antiprotozoan, anthelmintic, antihypertensive, wound healing, antitumor, hypolipidimic, and antifertility activity (Anitha et al., 2018). The ripe fruits of Carica papaya Linn. are used in healing ulcers. Unripened fruit of Carica papaya Linn. is used for the treatment of malaria, h­ ypertension,

FIG. 16  Cryptoxanthin.

FIG. 17  β-Carotene.

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diabetes mellitus, jaundice, and intestinal helminthiasis (Maisarah et al., 2014). It is used for the prevention of stroke, controlling the blood cholesterol level, and also have anticancer activity (Arliana and Tunjung, 2015). It is used for preparation juice, jam, salads, jellies, and so on. Carica papaya Linn. also increases the absorption of iron in the human body. Carica papaya Linn. fruits contain alkaloid like carpaine which has depressing action in the heart (Adiaha, 2017).

Seeds Seeds of Carica papaya Linn. contain glucosinolates, benzyl isothiocyanate, benzylthiourea (Fig.  18), caricin, oil, myrosin enzyme, linoleic acid (Fig.  19), oleic acid (Fig.  20), fatty acid, crude protein and fiber, sinigrin, carpaine (Fig. 21), benzyl glucosinolate (Fig. 22), glucotropacolin, hentriacontane (Fig. 23), β-sitosterol and 1,2,3,4-Tetrahydropyridin-3-yl-octanoate (Fig. 24). It is used as an abortifacient, carminative, emmenagogue, vermifuge, and thirst quencher. It is used in psoriasis, bleeding of piles, treating the enlargement of the spleen and liver, ringworm disease and as an antioxidant (Maisarah et al., 2014; Kartikar and Basu, 1998; Oloyede, 2005). It is also used in hypertension, diabetes mellitus and hypercholesterolemia (Anitha et  al., 2018). Seeds are also used for treating sickle cell disease and poisoning disorders (Maciunas and Onofrio, 1986). Seeds of Carica papaya Linn. are a good source of oil (25.6%) which is used for different purposes like medicinal, biofuel, and industrial ones (Ikeyi et al., 2013). Seeds juice of Carica papaya Linn. has different medicinal activities like antimicrobial, antiinflammatory, contraceptive, antifertility, anthelmintic, contraceptive, and analgesic activity (Begum, 2014).

FIG. 18  Benzylthiourea.

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FIG. 19  Linoleic acid.

FIG. 20  Oleic acid.

FIG 21  Carpaine.

FIG. 22  Benzyl glucosinolate.

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FIG. 23  Hentriacontane.

FIG. 24  1,2,3,4-Tetrahydropyridin-3-yl-octanoate.

Leaves Leaves and heartwood of Carica papaya Linn. contain alkaloids such as carpinine, carpaine (Fig. 21), pseudocarpine, choline, and carposide. It also contains vitamins (Thiamine (vitamin B1), riboflavin (vitamin-B2), niacin (vitamin-B3), α-tocopherol (vitamin E) and ascorbic acid (vitamin C)), minerals (Ca, K, Mg, Fe, Co and Zn), sterols (β-sitosterol), anthraquinone (Fig. 25), phenolic compound (ferulic acid (Fig. 26), caffeic acid (Fig. 27), p-coumaric acid (Fig. 28), n-hexadecanoic acid (palmitic acid) (Fig. 29), cyanogenic compounds (benylglucosinolate), and flavonoids (kaempferol and myricetin) (Kaur et al., 2019; Elgadir et al., 2014; Yogiraj et al., 2014; Krishna et al., 2008; Zunjar et al., 2015; Burdick, 1971; Imaga et al., 2009). Leaves extract of Carica papaya Linn. is used to treat colic fever, beriberi, asthma, jaundice, malaria, dengue, and antiviral and immunomodulatory activity (Bergonio and Perez, 2016; Kavimandan and Saraf, 2016). It also has antiinflammatory, hypoglycaemic, antifertility, abortifacient, hepatoprotective, wound healing, antihypertensive, antitumor, antioxidant, anticancer, antiseptic, antispasmodic, antibacterial activities and is used for treating burns (Yogiraj et al., 2014; Agarwal et al., 2016; Ghori, 2013; Nugroho et al., 2017). It is also

FIG. 25  Anthraquinone.

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FIG. 26  Ferulic acid.

FIG. 27  Caffeic acid.

FIG. 28  p-Coumaric acid.

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FIG. 29  n-Hexadecanoic acid (palmitic acid).

used as blood purifier and to cure the gastrointestinal problem, dengue fever by increasing the number of platelets, WBC, and neutrophilis and in the management of sickle cell anemia (Nugroho et al., 2017; Joseph et al., 2015; Imaga and Adepoju, 2010).

Juice Juice of Carica papaya Linn. contains different active medicinal components like n-Butyric acid (Fig. 30), n-octanoic acid (Fig. 31), linoleic acid (Fig. 32), n-hexanoic acid (Fig. 33), myristic acid (Fig. 34), palmitic acid (Fig. 35), stearic acid (Fig. 36), and oleic acid (Fig. 37).

Roots Roots of Carica papaya Linn. contain Alkaloids such as carposide and enzymes like myrosin, xilitol, and so on. It is used for renal and urinary problems (Romasi et al., 2011). It also has abortifacient, diuretic and antifungal activities. It is also used to treat piles, bronchitis, cough, gastroenteritis, urethritis, otitis, typhoid fever, and wound infection (Romasi et al., 2011; Barroso et al., 2016; Canini et al., 2007; Vuong et al., 2015).

FIG. 30  n-Butyric acid.

FIG. 31  n-Octanoic acid.

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FIG. 32  Linoleic acid.

FIG. 33  n-hexanoic acid.

Medicinal use of Carica papaya Linn. in vector-borne diseases Antidengue effects Dengue comes under vector-borne viral disease (female mosquito-borne disease). It is mainly caused by the dengue virus (DENV, which belongs to Flaviviridae family). It is transmitted by Aedesaegypti mosquito bites (Ahmad et al., 2011). The symptoms of dengue appear (within 4–7 days) after exposure to the dengue virus in the form of high body temperature, red rashes, headache, nausea, vomiting, and muscular pain (Yunita et al., 2012). Thrombocytopenia is the main hallmark for diagnosis of dengue (Subenthiran et al., 2013). So the patients receive only supportive treatment for controlling the dengue fever by

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FIG. 34  Myristic acid.

FIG. 35  Palmitic acid.

FIG. 36  Stearic acid.

FIG. 37  Oleic acid.

maintaining the blood components, fluid prevention, and enhancing the platelets count. Currently, major research works have explored that leaves extract of Carica papaya Linn. has shown a potential role in curing dengue by treating thrombocytopenia which is caused by the dengue virus. Leaves extracts of Carica papaya Linn. are used to enhance the platelet count which reduces the complications of dengue infection (Dharmarathna et al., 2013). Leaves extract

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of Carica papaya Linn. has membrane stabilizing properties that protect blood cells from destruction due to stress. So, such properties can decrease platelet lysis in dengue patients (Ranasinghe et al., 2012). In the mice (DENV infected, AG129), the synthesis of cytokines (inflammatory) (CCL12/MCP-5, CCL8/ MCP-2, CCL6/MRP-1, IL1R1, PF4/CXCL4, and NAMPT/PBEF1) is significantly reduced by freeze-dried leaves juice of Carica papaya Linn. (Norahmad et al., 2019). Reduction in the expression of DENV NSI envelope protein and regulation of the expression of IFN-α in THP-1 cells is shown by the leaves extract of Carica papaya Linn. (Sharma et  al., 2019). So these studies have shown that leaves extract of Carica papaya Linn. is useful for preventing and treating dengue disease. Different mechanisms of action (Fig.  38) have been recommended to describe the significance of leave extract of Carica papaya Linn. to improve platelet counts. Flavonoids containing leaves extract of Carica papaya Linn. decrease protease action involved in the viral activity (Charan et al., 2016). Membrane stabilizing activity is shown by Carica papaya Linn. (Leaf extract) which may help in the reversal of platelet (peripheral) destruction by dengue virus (DENV) (Ranasinghe et  al., 2012). Leaf extract of Carica papaya Linn. has antioxidant and free radical scavenging properties which is used to prevent hemolysis and bleeding (Pandita et al., 2019). Reduction in the proliferation of platelets is induced by the dengue virus (by inhibiting megakaryocytopoiesis or inhibiting differentiation of stem cells into megakaryocyte precursor cells) (da Costa Barros and de-Oliveira-Pinto, 2018). An increase in the appearance of ALOX 12 gene is shown by the leaves extract of Carica papaya Linn. (Fig.  39). After that megakaryocyte production is increased and then it gets converted into platelets as well as the platelets through the 12-HETE mediated pathway are produced (McRedmond et al., 2004; Sundarmurthy et al., 2017).

Antimalarial activity Malaria also comes under vector-borne diseases which are caused by the genus plasmodium and include a lot of destructive symptoms (Laura et  al., 2011). The leaf extract of Carica papaya Linn. has shown antimalarial activity due to the presence of alkaloid content like quinine which works as an antimalarial

FIG.  38  Different mechanisms of action of leaves of Carica papaya Linn. in inhibiting thrombocytopenia.

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FIG. 39  Mechanism of the formation of platelets by Carica papaya Linn. extract.

agent (Robinson, 1985). Leaves extract of Carica papaya Linn. contains three types of alkaloids that exhibit high antiplasmodial activity (Raj and Patel, 1978; Banerjee and Banerjee, 1986; Pal and Srivastava, 1976). These compounds were analyzed in  vitro against four parasites (T. brucei rhodesiense, Trypanosome cruzi, L. donovani, and P. falciparum) and in the Plasmodium berghei mouse model. This study suggests that leaf extract contains different alkaloids but out of these carpine is the most active phytoconstituents which is selected by the in vitro method (Tasqiah, 2014). Petroleum ether extract of fruits of the rind of raw Carica papaya Linn. has shown significantly antimalarial activity (Bhat and Surolia, 2001).

Chikungunya The chikungunya vector is dangerous to human health as it is a contagious agent. Leaf methanolic extract of Carica papaya Linn. when combined with spinosad (an antiseptic) is found to be beneficial in larvicidal activity and it also

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acts against the chikungunya virus. It has a high mortality rate for caterpillar and pupa (Kalimuthu et al., 2011).

Agent for vector control in Filariasis Filariasis (Lymphatic) is a vector-borne parasitic infection which is caused by the parasitic nematode like Wuchereria bancrofti (Bancroftian filariasis), Brugia malayi, and Brugia timori. Several mosquito species transmit the parasites (Taylor et al., 2010; WHO, 2012). For Aedes aegypti larvicidal and pupicidal action, the leaf extract (methanolic) of Carica papaya Linn. has shown better bio-efficacy. It has shown inhibitory action against both larvae and pupae after 24 h of exposure. It has shown more mortality against the larvae and pupae (Kovendan et al., 2012). Dengue and filariasis transmitting vectors like Aedes aegypti as well as Culex quinquefasciatus are inhibited by Carica papaya Linn. (latex). Different solvents like chloroform, methanol, and aqueous subjected to larvicidal activity in dose-dependent methods were used to collect Latex and for fractionation. IC50 value studies showed that chloroform extract has prominent activity in instar larvae of Aedes aegypti as well as Culex quinquefasciatus followed by methanol and aqueous extract (Chandrasekaran et al., 2018).

Antiviral action against Zika virus (family: Flaviviridae) Zika virus (ZIKV, family: Flaviviridae) is an emerging and re-emerging RNA virus. It is associated with severe birth defects and emotional (neurological) disturbances in adults. The fruit pulp of Carica papaya Linn. is enriched with polyphenols which exhibits antiviral action and oppose the activity of the Zika virus in human cell (without loss of cell viability). Fermented pulp of Carica papaya Linn. has shown antiviral activity against Zika virus in different bacterial strains (Juliano et al., 2020).

Japanese encephalitis The mosquito Aedes aegypti is a transmitting agent of chikungunya, filariasis, dengue (dengue virus), malaria, Japanese-encephalitis, and yellow fever which are mainly found in tropical and subtropical regions (Sá et al., 2009; Kovendan et  al., 2011). Seeds of Carica papaya Linn. has potential larvicidal activity against Aedes aegypti (Diptera: Culicidae) and the characterization of the tegument enzyme responsible for the toxic activity. Aedes aegypti is a transmitting agent which is responsible for yellow and dengue fever. This work aimed to identify the component of Carica papaya Linn. seed which is toxic to Aedes aegypti and the identification of tegupain, the enzyme that generates it. The mixture of 1 tegument extract (17 µg/mL) and 1 cotyledon extract (27 µg/mL) of Carica papaya Linn. caused a hundred percent mortality in a bioassay. Its activity was enhanced by 2 mM, Dithiothreitol (at 37°C, pH 5.0). The Ethylene

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diamine tetraacetic acid did not alter the activity of the enzyme. Tegupain with cystatin (Kiapp2.43 nM), E64 (3.64 nM, 83% inhibition), and propeptide N-terminal sequence is inhibited which suggests that toxic activity is induced by the cysteine proteinase (novel enzyme) which gets activated after hydrolysis of acotyledon of Carica papaya Linn. seeds (Natalia et al., 2013).

Chagas disease (American trypanosomiasis) It is caused by Trypanosome cruzi (hemoflagellate protozoa). American trypanosomiasis is found in Mexico, Central America, and South America where 8 million people (approximate) are infected (Centers for Disease Control Prevention CDC, 2013). The chloroform seed extract of Carica papaya Linn. showed antiprotozoal activity against the subacute and chronic stage of Trypanosoma cruzi (hemoflagellate protozoa) infection. During the chronic stage of infection of Trypanosoma cruzi, a dose of 50 and 75 mg/kg (mixture of components like oleic, palmitic, and stearic acids) is evaluated in mice. It is recommended to carry out more studies to find out whether high doses of chloroformic extract or its administration in combination with other antichagasic drugs allow a better response over the intracellular phase of Trypanosoma cruzi in infected animal models and to determine whether the chloroform extract of Carica papaya Linn. can be used as an alternative to treatment during infection (indeterminate and chronic stage) (Matilde et al., 2014).

Conclusion Albeit customary medication is broadly used to treat VBD and is frequently more accessible and reasonable than Western medication, it isn’t without limits. First and foremost, there are not much clinical information on natural resources to treat VBD. Besides, there is no agreement, even among customary healers, on which plants, arrangements, and doses are the best. At last, the concentration of phytochemicals involved in the treatment of plant varieties changes significantly, contingent upon a few elements. But all these factors can be overcome by exhaustive research.

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Further reading Singh, S.P., Kumar, S., Mathan, S.V., Tomar, M.S., Singh, R.K., Verma, P.K., Kumar, A., Kumar, S., Singh, R.P., Acharya, A., 2020. Therapeutic application of Carica papaya leaf extract in the management of human diseases. DARU J. Pharm. Sci. 28, 735–744. World Health Organization, 2016. Vector-Borne Diseases. [Internet]. [cited 2017 Aug 17]. Available from http://www.who.int/en/news-room/factsheets/detail/vector-borne-diseases.

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Chapter 20

Nanoemulsion as a promising carrier of plant-derived repellents for mosquito-borne malaria control: Nanotechnology aspects António B. Mapossaa and Alcides Sitoeb a

Department of Chemical Engineering, Institute of Applied Materials, University of Pretoria, Pretoria, South Africa, bDepartment of Chemistry, Eduardo Mondlane University, Maputo, Mozambique

Introduction Malaria remains the most fatal mosquito-borne disease in areas where it is endemic. According to the WHO, in 2021, 241 million cases of malaria were reported, which caused 627,000 fatalities globally (WHO, 2020). These numbers were high compared with 227 million cases and 558,000 deaths registered in 2019. The most susceptible group affected by malaria is children under the age of 5 years (Winstanley, 2001; Benelli, 2016; Murugan and Sathishkumar, 2016; Tiwary et al., 2007; WHO, 2020). The WHO recommends indoor residual spraying (IRS) of insecticides in addition to the use of long-lasting insecticidetreated bed nets (LLINs) as the most practical approaches utilized in endemic areas for malaria control. However, these methods are only effective in indoor environments. Therefore, the development of new alternatives and cheap as well as biocompatible methods for malaria prevention in outdoor environments is required. For example, synthetic repellents have been explored in several studies where these are incorporated in polymer matrices to decrease their volatility and extend their activity against mosquito bites (Yener et al., 2022; Mapossa et al., 2019, 2020a, b, 2021b; Sitoe et al., 2020). Nowadays, plant-based repellent products are receiving increased interest among users, as these are mostly seen as “safe” compared to synthetic repellents, although this is sometimes a misunderstanding (Maia and Moore, 2011).

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Plant-based repellents are volatile organic compound mixtures composed mainly of hydrocarbons (terpenes) and compounds containing oxygen (Nerio et al., 2010; Toloza et al., 2008). Citronella oil was the plant-derived repellent most used before the introduction of synthetic repellents. Principally, it was used as a standard against other repellents being tested (Islam et  al., 2017a; Bissinger and Roe, 2010). The research on repellents obtained from plants is increasing daily due to the consumer demand for long-lasting mosquito bite protection. The search is for a safe, pleasant, and environmental-friendly product (Maia and Moore, 2011; Tavares et al., 2018). The principal issue is to reduce their volatility, consequently prolonging their performance or efficacy against mosquito bites. Nowadays, various research groups continue to work on the development of formulations-based repellents derived from plants, which aim to solve the issue of volatility associated with their length of protection. As an example, the performance of limonene capsules-treated textiles was assessed against Culex pipiens mosquitoes (Türkoğlu et al., 2020). The results demonstrated that, although the effectiveness of developed products decreased with washes, it still proved to be effective even after 20 washes. Nanoemulsion has attracted significant attention from researchers in medical application due to several reasons such as optical clarity, ease of preparation, stability, and high surface area (Lovelyn and Attama, 2011). This chapter provides an overview focused on repellents derived from plants based on nanoemulsions systems for malaria control. Furthermore, the preparation of nanoemulsions, characterization methods, and the stability of nanoemulsion are explored. Additionally, several studies that demonstrate the efficacy of essentials oils based on nanoemulsion systems against mosquitoes are presented and discussed. Finally, conclusions are drawn, and recommendations for the use of these nanoemulsions are presented.

Mosquito repellents for malaria prevention Insect repellents are volatile substances applied on person's skin, clothing, or other surfaces to discourage mosquitoes from landing or climbing on that surface (Diaz, 2016). To discourage contact of the mosquito with human skin, it is thought that most insect repellents produce a vapor barrier as their action (Nogueira Barradas et al., 2016; Nerio et al., 2010). Diverse chemical formulations of repellents exist on the market like lotions, powders, sprays, creams, oils, aerosols, and repellent impregnated in clothes. The applicability and suitability of a repellent is determined by the following factors: the active ingredient, odor, humidity, formulations, boiling point, vapor pressure, temperature, wind, solubility and release control mechanism, and device. For example, repellents with low boiling points provide a barrier only for a short period, becoming less effective, since they rapidly vaporize, while those with high boiling points tend to produce insufficient vapor to produce barriers, since they slowly vaporize, resulting in low repellence (Brown and Hebert, 1997).

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Different studies have highlighted and proved that the use of repellents play an important role for protection of people against mosquito bites (Islam et al., 2017b; Diaz, 2016; Auysawasdi et al., 2016; Alpern et al., 2016). In addition, studies about the use of devices/formulations as carriers of repellents to repel mosquitoes have increased more recently, showing very promising results of efficacy and repellence time against mosquitoes (Alpern et al., 2016; Mapossa et al., 2019). According to Diaz (2016) and Katz et al. (2008), an ideal insect repellent should have the following characteristics: (1) good efficacy against different kinds of insects; (2) pleasing odor; (3) neutral when impregnated in clothes; (4) without side effects on skin; (5) cost-effective; (6) chemically stable; (7) universally accessible for use; (8) nontoxic; and (9) inert to plastics that are normally used. Mosquito repellents are grouped into synthetic and plant-derived forms. Synthetic repellents include diethyltoluamide (DEET), icaridin, ethyl anthranilate, IR3535, and dimethyl phthalate. DEET is a mosquito repellent known as the gold standard amid the other various repellent available in the market (Yener et al., 2021). For example, several studies demonstrated that when DEET was entrapped in matrices, it was slowly released from the matrices and was effective against mosquito bites (Yener et al., 2021; Sungkapreecha et al., 2019, 2017; Mapossa et al., 2019). Additionally, studies have reported that icaridin, IR3535, and ethyl anthranilate are safe and nontoxic and have demonstrated good performance against mosquitoes (Mapossa et al., 2020b). Although these repellents have high activity against insects, many consumers still fear their use because they understand that the synthetic repellents are not “safe” compared with plant-based repellents. Plant-derived repellents include lemon eucalyptus oil, citronella oil, Lippia javanica, neem (Azadirachta indica), etc.

Plant-derived mosquito repellents Due to the perception that essential oils (EOs) from plants appear safer compared to synthetic ones and often are easier to acquire by people who live in rural areas, currently, their use as mosquito repellents has high consumer acceptance (Tisgratog et al., 2016). Various EOs have demonstrated good repellence activity in insect control. For example, the monoterpenes, such as limonene, citronellal, camphor, eugenol, terpinolene, and thymol, are commonly reported in the literature as repellents with good performance for mosquito control (Gillij et al., 2008; Jantan and Zaki, 1998; Nerio et al., 2010; Yang et al., 2004). Among sesquiterpenes, ß-caryophyllene is most often mentioned as a robust

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active ­ingredient against Aedes aegypti (Gillij et al., 2008; Nerio et al., 2010). The repellence activity of several essential oils seems to be associated with the presence of one or more volatile constituent substances (monoterpenes and sesquiterpenes) (Gonçalves et al., 2012; Trongtokit et al., 2005b). According to Odalo et  al. (2005), Tawatsin et  al. (2001), Trigg (1996), and Yoon et al. (2015), some repellents from plants are also effective against Anopheles mosquitoes. For example, Trongtokit et  al. (2005a) demonstrated that 40% citronella oil can provide protection for about 7–8 h. Therefore, nanoemulsion is one of the most used devices to reduce or regulate the evaporation of essential oils and increase or improve the repellence activity over time (Tavares et  al., 2018). Table  1 summarizes studies obtained in the literature about the repellence activity of EOs as repellents conducted in different countries. The results in Table 1 demonstrate that the many studies done by researchers have reported evidence of repellant activities of plant extracts or essential oils against malaria vectors worldwide. Thus, it is possible that in the near future, studies based on matrices applied to carrier repellents will guarantee affordable protection of people against mosquitoes in endemic regions (Maia and Moore, 2011).

Controlled release nanotechnology The technology of controlled release is used to control, adjust, or regulate the release of a substrate (active ingredient). The concentration of the formulation is ideally maintained as optimal or within optimal limits over time (Céspedes et al., 2007; Akelah, 1996; Kenawy et al., 1992; Mapossa et al., 2021a). The technology has the following advantages: (i) prolonged action of the active ingredient by supplying uninterruptedly necessary quantities of substrate to accomplish its action over extended time intervals; (ii) the reduction of ecological contamination; and (iii) being cost-effective by abolishing the period and reducing the cost of recurrent applications (Kenawy et al., 1992; Mapossa et al., 2021a). The undesirable occurrences of active ingredient loss caused by evaporation and degradation are reduced. In additional, the toxic odor may be masked (also making it chemically nontoxic) by combining the toxic reagent with polymer (Kenawy et al., 1992; Akelah, 1996; Dubey et al., 2011; Mapossa et al., 2021a). To choose a good formulation to release enough of the active ingredient and achieve the required effect with the lowest biological and environmental adverse risks, certain features are required: (i) the desired release rate; (ii) environmental conditions; (iii) nature of the carrier (e.g., the thermal behavior of the polymer, compatibility of the substrate, the cross-linking degree of the polymer);

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TABLE 1  Summary of studies of the efficacy of plant-based repellents conducted in different countries. Plant-based repellent compound

Efficacy of product (%)

Study type

Citronellol, limonene; geraniol (the concentration varied between 30% and 50% of EOs)

• Results showed that protection of 96% against mosquitos was achieved in 4 h. • Protection against Anopheles arabiensis was achieved in 6 h (90% of effectiveness). • 100% protection against Anopheles gambiae and Anopheles funestus for 6–7 h

• The field work occurred in Bolivia • This study was done in the laboratory • The field work was conducted in Tanzania

1,8-cineole and citronellal

• The result demonstrated 72% effectiveness against mosquitos for 2 h.

• The field study took place in Guinea Bissau

Eugenol, carvacrol, thymol cinnamaldehyde (100% concentration of EOs was used)

• 100% of efficacy against Aedes aegypti was achieved in 4 h and 100% of protection against Anopheles albimanus was reached in 3 h. • Repellence activity of 100% against Aedes aegypti, Anopheles Dirus, and Culex quinquefasciatus was achieved in 2, 3 and 4 h, respectively.

• The study was conducted in the laboratory • The study was conducted in the laboratory

Citronellal (the concentrations applied were of 40% and 100% of oil)

• Results demonstrated 100% performance of OEs over 7–8 h against Anopheles Stephensi. • 100% protection against Aedes aegypti and Culex quinquefasciatus was achieved in 2 h.

• The work was done in the laboratory • The study was done in the laboratory

Geraniol (10% and 100% of essential oil was applied)

• Results showed 100% protection against Anopheles culicifacies and 96% protection against Culex quinquefasciatus in 12 h.

• The study was done in the laboratory

(Continued)

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TABLE 1  Summary of studies of the efficacy of plant-based repellents conducted in different countries—cont’d Plant-based repellent compound

Efficacy of product (%)

Study type

Neem (azadirachtin saponins) (the concentration used varied from 1% to 2% of EOs applied)

• 94% protection against Anopheles spp was achieved in 4 h.

• The field work was done in India

Carvacrol, thymol, p-cymene, linalool, geraniol (all these oils were applied topically, however the concentration used was not revealed)

• 97% efficacy against Culex pipiens was reached in 2 h. • 94% protection against Culex pipiens was achieved in 2 h. • The protection against Culex pipiens was 92% for 1 h and 100% protection against Aedes aegypti was achieved in 4 h.

• The field study occurred in Bolivia • The study was done in the laboratory • The study was done in the laboratory

Myrcene, limonene, and cineol (5% of oil was applied)

• 100% of protection was achieved in 4 h against mosquitoes

• The field work was conducted in Egypt

Kaffir lime, limau, purut (100% of EOs combined with 5% of vanillin was applied)

• Over a period of 2–8 h, it was possible to achieve 100% protection against Anopheles stephensi, Aedes Aegypti, Culex quinquefasciatus, and Anopheles dirus. Therefore, the product retained efficacy throughout time investigated.

• The study was done in the laboratory

Turmeric, curcuma, Indian saffron (100% EOs was applied)

• The results demonstrated 100% protection against Aedes aegypti, Culex quinquefasciatus, and Anopheles dirus was achieved in 5 and 8 h, respectively.

• The study was done in the laboratory

Reproduced with permission from Maia, M.F., Moore, S.J., 2011. Plant-based insect repellents: a review of their efficacy, development and testing. Malar. J., 10, 1–15.

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(iv) stability during processing; (v) characteristics of the final product design; (vi) the desired protection time; (vii) the mechanism of application; and (viii) cost and formulation (Akelah, 1996; Mapossa et al., 2021a). One of the systems of controlled release technology that provides all these characteristics is known as nanoemulsion. This system will be described in the next section.

Nanoemulsion as carrier of essential oils (EOs) Repellents derived from plants, known as essential oils (EOs), have been extensively investigated due to their potential application as a natural ingredient in malaria control. However, their low boiling point, high vapor pressure (associated with high evaporation rate), and low solubility affect their performance in terms of the duration of protection. These are some of the factors that limit their use as a natural repellent to substitute synthetic repellents and insecticides (Da Silva et al., 2022). With the progress of nanotechnology, the development of nanoemulsions systems based on essential oils has become a promising alternative to resolve these limitations, because these formulations can slowly release the repellents and consequently, can extend the time of protection. Nanoemulsions are kinetically stable systems that can be grouped into three types: (i) the water phase is distributed within a continuous oil phase (W/O); (ii) the oil phase is dispersed within a continuous water phase (O/W), and (iii) bi-continuous, where micro domains of phases of oil and water are interdispersed (Mapossa et al., 2021a; Rai et al., 2018; Sood et al., 2014; Anjali et al., 2012; Nam et al., 2010). Fig.  1 shows the typical structure of a nanoemulsion system, where this demonstrates a simple three-component microemulsion (oil and water surfactant) (Harwansh et al., 2019). Additionally, the diameter of droplet varies from 30 nm to 200 nm, and the nanoscale droplet diameter decreases the effects of droplet aggregation, flocculation, and gravitation, consequently, significantly improving the stability of the emulsion (Fu et al., 2022). Nanoemulsions have advantages over other formulations-based on repellents (Feng et al., 2020). These advantages include: (i) good physical and chemical stability; (ii) better capacity of permeation and improved bioavailability due to the high surface area and small droplet size, which improve the transfer of molecules through biological membranes; (iii) high water solubility;

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FIG. 1  Three-component microemulsion demonstrates a hypothetical pseudo-ternary phase diagram (oil and water surfactant). (Republished with permission from Harwansh, R.K., Deshmukh, R., Rahman, M.A., 2019. Nanoemulsion: promising nanocarrier system for delivery of herbal bioactives. J. Drug Deliv. Sci. Technol., 51, 224–233, Elsevier.)

(iv) controlled release of active ingredients from encapsulation and solubilization; and (v) the nanomeulsions requires a lower amount of emulsifiers (de Oca-Ávalos et al., 2017; Feng et al., 2020; Li et al., 2016).

Preparation of nanoemulsions High- and low-energy are the principal methods used to prepare nanoemulsions. The high-energy method comprises high-pressure homogenization, ultrasonic emulsification specifically, microfluidics, and membrane emulsification. In this method efficient mechanical tools are used to producing disruptive forces that separate the oil and water phases and obtain droplets of oils (Silva et al., 2012). High-energy methods provide good control of size distribution and structure of the nanoemulsions, nevertheless, during the process of production of nanoemulsions, some compounds (chemicals) can suffer rapid degradation (Silva et al., 2012). Low-energy methods comprise phase inversion temperature (PIT), emulsion inversion point, and spontaneous emulsification in nonequilibrium (Koroleva and Yurtov, 2012). These methods rely on the spontaneous formation of droplets of oil in mixed systems such as oil/water/emulsifier when environmental conditions are changed (Silva et al., 2012). These methods are more preferred

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FIG.  2  Summary of the methods of preparation of nanoemulsions: (A) high energy and (B) low energy. (Republished with permission from Gupta, A., Eral, H.B., Hatton, T.A., Doyle, P.S., 2016. Nanoemulsions: formation, properties and applications. Soft Matter, 12, 2826–2841, RSC Publishing.)

by manufacturers due to the low cost of their equipment. (Jasmina et al., 2017). Additionally, these methods necessitate low energy for preparation of nanomeulsions (Silva et al., 2012). In general, the low-energy methods are not much accepted for production of food-grade nanoemulsions due to the high level of surfactants used, which negatively influences food formulation in taste and safety (Kumar et  al., 2019). Fig.  2 shows low-energy and high-energy techniques used for nanoemulsions preparation.

Characterization of nanoemulsions The limitations on the characterization of nanoemulsions systems are related to the prior sample dilution, which may result in molecular reorganizations or phase transitions (Bruxel et al., 2012). Therefore, for a better understanding of the structures formed of nanoemulsions, complementary methods are required. Zeta potential is a technique applicable to evaluating the properties of nanoemulsions such as surface charge and physical stability. In general, the value of zeta potential is ±30 mV for a stable suspension (Borthakur et  al., 2016). Borthakur et al. (2016) and Araújo et al. (2011) reported that the surfactants,

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concentration of electrolyte, the particle size and its morphology, pH of the solution, and state of hydration are major factors that influence zeta potential values. In addition, the stability of nanoemulsions is directly related to high values of zeta potential, which is explained by the presence of extremely charged particle droplet accumulation being inhibited. Dynamic Light Scattering (DLS) is a method that can be described as the photon correlation spectroscopy method. DLS offers a quick and suitable assessment of the profile and distribution of nanoemulsion size. Microscopy can be used to obtain the morphology of nanoemulsion (Klang et al., 2012) as, with microscopy techniques, the information of the size of droplet, shape, and the aggregation state of the nanoemulsions is obtained easily (Jin et al., 2016). The morphology of nanoemulsion-based essential oil was analyzed using transmission electron microscopy (TEM) (Nam et al., 2010). The results of TEM morphology of nanoemulsion demonstrated that these were influenced by the type of oil. Additionally, it was proved that the obtained droplet size was of a few micrometers (Nam et al., 2010). Kumar and Mandal (2018) reported in their studies that the morphology of the nanoemulsion formulations observed by TEM clearly showed the difference of droplet sizes (Fig. 3). Furthermore, from the micrographs it was possible to observe that high concentrations of surfactant affected the reduction of droplet size. Sundararajan et al. (2018) evaluated the morphology of nanoemulsion by scanning electron microscopy (SEM). Their results demonstrated that the essential oils entrapped in nanoemulsions presented a consistent distribution and a spherical form (Fig. 4). They also found that the external surface of each unit is approximately consistent and smooth, demonstrating that the polysorbate systems are continuous film covering EO droplets.

Stability of the nanoemulsion Nanoemulsion is suitable for final application because of several advantages that include high optical clarity, improved bioavailability of encapsulated substances, small droplet size, droplet aggregation, and good physical stability (de Oca-Ávalos et al., 2017). The stability of nanoemulsion is directly affected by the droplet size, thus, the selected preparation method for each formulation should optimize droplet size distribution. Dubey et al. (2011) reported that the nanoemulsions with homogenous structures comprise small droplets of >200 nanometres and they have a monomodal composition. The homogenous system demonstrates that the droplets in all system are well distributed or a regular distribution of droplets exists. In addition, de Oca-Ávalos et  al. (2017) described that, for the same formulations, the stability of nanoemulsion is always considered superior compared to conventional emulsions. The results demonstrated that the nanoemulsion structures presented high thermal, chemical, or physical stability and these continued unaffected over 6 months (de Oca-Ávalos et  al., 2017). The existence of long-term stability of nanoemulsion is one of

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FIG.  3  Micrographs of nanoemulsions with various concentrations of surfactants at (A) 0.5, (B) 1.0, (C) 1.5, and (D) 2.0 wt%, analyzed by TEM. (Republished with permission from Kumar, N., Mandal, A., 2018. Surfactant stabilized oil-in-water nanoemulsion: stability, interfacial tension, and rheology study for enhanced oil recovery application. Energy Fuel, 32, 6452–6466, ACS publications.)

FIG. 4  SEM micrographs of nanoemulsions (both images captured at 10 μm). (Republished with permission from Sundararajan, B., Moola, A.K., Vivek, K., Kumari, B.R., 2018. Formulation of nanoemulsion from leaves essential oil of Ocimum basilicum L. and its antibacterial, antioxidant and larvicidal activities (Culex quinquefasciatus). Microb. Pathog., 125, 475–485, Elsevier.)

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the requisites for engineering and nanotechnology. Furthermore, Lucia et  al. (2020) demonstrated that nanoemulsion-based eugenol oil remained stable for 28  months without any changes observed in structure. Besides the long-term stability observed, the nanoemulsion-based product proved to be more effective against Aedes aegypti mosquito larvae. For physical stability of nanoemulsions, one of the principal difficulties is related to the preventing of Ostwald ripening. This phenomenon is defined as the growth of bigger droplets at the expense of the smaller droplets due to the molecular diffusion of oil between droplets via continuous phase, where this is induced through the higher local oil solubility around smaller droplets than larger droplets (Donsì and Ferrari, 2016). Studies report that oils containing large chains of triglycerides, which display an insignificant solubility in aqueous phase, have a lower chance of Ostwald ripening compared to oils that contain components with high solubility in water (Donsì and Ferrari, 2016; Rao and McClements, 2012). Donsì et al. (2014) and Chang et al. (2015) also described that, if the used oils are prone to Ostwald ripening and it is, therefore, unavoidable, the Ostwald ripening rate can be diminished by changing the segmentation of essential oils between the droplets of lipid and the aqueous phase. Therefore, these can be mixed with medium- or long-chain triglycerides oils, obtaining an entropy of the mixing effect that counteracts the imbalance of droplet size effect. Zahi et al. (2014) improved the physically stability of an organogel-based nanoemulsion when this was incorporated with water-soluble limonene oil. Furthermore, the organogel structure obtained reduced the polarity of essential oil; consequently, Ostwald ripening did not occur. Guerra-Rosas et al. (2016) reported that if there is a weak combination of the EOs with the macromolecule, the destabilization process by Ostwald ripening becomes substantial.

Application of nanoemulsion in malaria control Recently, several studies reporting the preparation and application of ­nanoemulsions-based repellents against infectious diseases (i.e., malaria) transmitted by mosquitoes have increased and attracted interest by researchers due to their intrinsic physicochemical properties like optical transparency, low viscosity, and very small droplet sizes (20–200 nm) (Echeverría and Albuquerque, 2019). Furthermore, the potential use of these systems can be due to the lack of side effects such as those caused by classic formulations (lotions and solutions) available on the market (Tavares et al., 2018). The work done by Sugumar et al. (2014) demonstrated the high performance of nanomeulsion-based eucalyptus oil against Culex quinquefasciatus mosquitos. The authors described that the high activity of nanomeulsions was associated with the droplet size of the prepared nanoemulsions. Additionally, Nuchuchua et al. (2009) evaluated the effect of droplet size in the efficacy of nanoemulsion-based oils. Their results demonstrated that small droplet size significantly impacted the performance of nanomeulsion-based essential oils. Anjali et al. (2012) conducted a specific

Nanoemulsion as a promising carrier of plant  Chapter | 20  511

FIG. 5  Release rate of citronella oil affected by droplet size. (Republished with permission from Agrawal, N., Maddikeri, G.L., Pandit, A.B., 2017. Sustained release formulations of citronella oil nanoemulsion using cavitational techniques. Ultrason. Sonochem., 36, 367–374, Elsevier.)

study showing nanoemulsion-based neem oil formulations with medium and large droplets size presented lower performance than nanomeulsions with small droplet size against Culex quinquefasciatus mosquitos. Sakulku et  al. (2009) confirmed that the release rate of citronellal-based nanoemulsions was directly associated with the period of protection of nanoemulsions when tested against Aedes aegypti (Fig.  5). Agrawal et  al. (2017) reported the relationship of the release rate of citronella oil and droplet sizes of nanoemulsions (65 nm and 72 nm) carried out at 35°C. The results showed that the release rate was lower for a sample with large droplets compared to small droplets (Fig. 5). The same behavior was observed by other authors (Nuchuchua et al., 2009; Sakulku et al., 2009). Finally, a study done by (Sundararajan et al., 2018) demonstrated that the nanoemulsion-based EO of Ocimum basilicum L. was effective against Culex quinquefasciatus mosquito larva. For example, a significant mortality of mosquito larva was achieved in 24 h of exposure to nanoemulsion-based EOs. The findings demonstrated that nanoemulsions are formulations extensively used in combination with EOs to increase the physicochemical stability of the EOs and extend their repellence activity.

Conclusions and recommendations Most of the essential oils extracted from plants volatilize quickly. To increase their repellence activity, they must be freshly applied. Therefore, compared with synthetic repellents, especially those containing DEET in most of the topical formulations, the essential oils give a shorter time of protection. Although natural repellents have limited application in formulations due to high evaporation rates, the natural repellents can possibly reduce mosquito bites when used correctly and consistently. Furthermore, the growth of insecticide resistance and development of safe methods to control mosquito-borne malaria has induced

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research into plant-derived repellents. Thus, the development of nanoemulsions seems to be a promising way to improve plant oils formulations with the aim of increasing their duration of protection. The results of several studies suggest that the development of nanoemulsions with high surface area is a vital innovation for scientists as it can be used in biocompatible drug delivery, i.e., repellents for mosquito vector control. For example, Sundararajan et al. (2018) developed environmental and safe nanoemulsion systems as promising carriers for repellents and they demonstrated a good effectiveness against mosquito larvae. As a recommendation, various studies including entomological and epidemiological testing of the nanoemulsion-based repellents (essentials oils) and their toxicity must be carried out before their implementation on the market to be used by the public. These studies will guarantee the commercialization of nanoemulsionbased repellents that are safe or with minimum side effects for communities.

Acknowledgments The authors thank the Institute of Applied Materials, Department of Chemical Engineering, University of Pretoria, South Africa and the Department of Chemistry, Eduardo Mondlane University, Mozambique for their technical support during this research.

Conflicts of interest The authors declare no conflicts of interest.

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514  Natural products in vector-borne disease management Jin, W., Xu, W., Liang, H., Li, Y., Liu, S., Li, B., 2016. Nanoemulsions for food: properties, production, characterization, and applications. In: Emulsions. Elsevier. Katz, T.M., Miller, J.H., Hebert, A.A., 2008. Insect repellents: historical perspectives and new developments. J. Am. Acad. Dermatol. 58, 865–871. Kenawy, E., Sherrington, D., Akelah, A., 1992. Controlled release of agrochemical molecules chemically bound to polymers. Eur. Polym. J. 28, 841–862. Klang, V., Matsko, N.B., Valenta, C., Hofer, F., 2012. Electron microscopy of nanoemulsions: an essential tool for characterisation and stability assessment. Micron 43, 85–103. Koroleva, M.Y., Yurtov, E.V., 2012. Nanoemulsions: the properties, methods of preparation and promising applications. Russian Chem. Rev. 81, 21. Kumar, N., Mandal, A., 2018. Surfactant stabilized oil-in-water nanoemulsion: stability, interfacial tension, and rheology study for enhanced oil recovery application. Energy Fuel 32, 6452–6466. Kumar, M., Bishnoi, R.S., Shukla, A.K., Jain, C.P., 2019. Techniques for formulation of nanoemulsion drug delivery system: a review. Prevent. Nutr. Food Sci. 24, 225. Li, J., Fan, T., Xu, Y., Wu, X., 2016. Ionic liquids as modulators of physicochemical properties and nanostructures of sodium dodecyl sulfate in aqueous solutions and potential application in pesticide microemulsions. Phys. Chem. Chem. Phys. 18, 29797–29807. Lovelyn, C., Attama, A.A., 2011. Current state of nanoemulsions in drug delivery. J. Biomater. Nanobiotechnol. 2, 626. Lucia, A., Toloza, A.C., Fanucce, M., Fernandez-Pena, L., Ortega, F., Rubio, R.G., Coviella, C., Guzman, E., 2020. Nanoemulsions based on thymol-eugenol mixtures: Characterization, stability and larvicidal activity against Aedes aegypti. Bull. Insectol. 73, 153–160. Maia, M.F., Moore, S.J., 2011. Plant-based insect repellents: a review of their efficacy, development and testing. Malar. J. 10, 1–15. Mapossa, A.B., Sibanda, M.M., Sitoe, A., Focke, W.W., Braack, L., Ndonyane, C., Mouatcho, J., Smart, J., Muaimbo, H., Androsch, R., 2019. Microporous polyolefin strands as controlledrelease devices for mosquito repellents. Chem. Eng. J. 360, 435–444. Mapossa, A.B., Focke, W.W., Sitoe, A. & Androsch, R. Mosquito repellent microporous polyolefin strands. AIP Conference Proceedings, 2020a. AIP Publishing LLC, 020062. Mapossa, A.B., Sitoe, A., Focke, W.W., Izadi, H., Du Toit, E.L., Androsch, R., Sungkapreecha, C., Van Der Merwe, E.M., 2020b. Mosquito repellent thermal stability, permeability and air volatility. Pest Manag. Sci. 76, 1112–1120. Mapossa, A.B., Focke, W.W., Tewo, R.K., Androsch, R., Kruger, T., 2021a. Mosquito‐repellent controlled‐release formulations for fighting infectious diseases. Malar. J. 20, 1–33. Mapossa, A.B., López-Beceiro, J., Díaz-Díaz, A.M., Artiaga, R., Moyo, D.S., Mphateng, T.N., Focke, W.W., 2021b. Properties of mosquito repellent-plasticized poly (lactic acid) strands. Molecules 26, 5890. Murugan, S.B., Sathishkumar, R., 2016. Chikungunya infection: a potential re-emerging global threat. Asian Pac. J. Trop. Med. 9, 933–937. Nam, Y.S., Kim, J.-W., Shim, J., Han, S.H., Kim, H.K., 2010. Nanosized emulsions stabilized by semisolid polymer interphase. Langmuir 26, 13038–13043. Nerio, L.S., Olivero-Verbel, J., Stashenko, E., 2010. Repellent activity of essential oils: a review. Bioresour. Technol. 101, 372–378. Nogueira Barradas, T., Perdiz Senna, J., Ricci Junior, E., Regina Elias Mansur, C., 2016. Polymerbased drug delivery systems applied to insects repellents devices: a review. Curr. Drug Deliv. 13, 221–235.

Nanoemulsion as a promising carrier of plant  Chapter | 20  515 Nuchuchua, O., Sakulku, U., Uawongyart, N., Puttipipatkhachorn, S., Soottitantawat, A., Ruktanonchai, U., 2009. In vitro characterization and mosquito (Aedes aegypti) repellent activity of essential-oils-loaded nanoemulsions. AAPS PharmSciTech 10, 1234. Odalo, J.O., Omolo, M.O., Malebo, H., Angira, J., Njeru, P.M., Ndiege, I.O., Hassanali, A., 2005. Repellency of essential oils of some plants from the Kenyan coast against Anopheles gambiae. Acta Trop. 95, 210–218. Rai, V.K., Mishra, N., Yadav, K.S., Yadav, N.P., 2018. Nanoemulsion as pharmaceutical carrier for dermal and transdermal drug delivery: formulation development, stability issues, basic considerations and applications. J. Control. Release 270, 203–225. Rao, J., McClements, D.J., 2012. Impact of lemon oil composition on formation and stability of model food and beverage emulsions. Food Chem. 134, 749–757. Sakulku, U., Nuchuchua, O., Uawongyart, N., Puttipipatkhachorn, S., Soottitantawat, A., Ruktanonchai, U., 2009. Characterization and mosquito repellent activity of citronella oil nanoemulsion. Int. J. Pharm. 372, 105–111. Silva, H.D., Cerqueira, M.Â., Vicente, A.A., 2012. Nanoemulsions for food applications: development and characterization. Food Bioproc. Tech. 5, 854–867. Sitoe, A., Mapossa, A.B., Focke, W.W., Muiambo, H., Androsch, R., Wesley‐Smith, J., 2020. Development, characterization and modeling of mosquito repellent release from microporous devices. SPE Polym. 1, 90–100. Sood, S., Jain, K., Gowthamarajan, K., 2014. Optimization of curcumin nanoemulsion for intranasal delivery using design of experiment and its toxicity assessment. Colloids Surf. B Biointerfaces 113, 330–337. Sugumar, S., Clarke, S., Nirmala, M., Tyagi, B., Mukherjee, A., Chandrasekaran, N., 2014. Nanoemulsion of eucalyptus oil and its larvicidal activity against Culex quinquefasciatus. Bull. Entomol. Res. 104, 393–402. Sundararajan, B., Moola, A.K., Vivek, K., Kumari, B.R., 2018. Formulation of nanoemulsion from leaves essential oil of Ocimum basilicum L. and its antibacterial, antioxidant and larvicidal activities (Culex quinquefasciatus). Microb. Pathog. 125, 475–485. Sungkapreecha, C., Iqbal, N., Gohn, A.M., Focke, W.W., Androsch, R., 2017. Phase behavior of the polymer/drug system PLA/DEET. Polymer 126, 116–125. Sungkapreecha, C., Iqbal, N., Focke, W.W., Androsch, R., 2019. Crystallization of poly (l‐lactic acid) in solution with the mosquito‐repellent N,N‐diethyl‐3‐methylbenzamide. Polym. Crystall. 2, e10029. Tavares, M., Da Silva, M.R.M., de Siqueira, L.B.D.O., Rodrigues, R.A.S., Bodjolle-D'almeida, L., Dos Santos, E.P., Ricci-Júnior, E., 2018. Trends in insect repellent formulations: a review. Int. J. Pharm. 539, 190–209. Tawatsin, A., Wratten, S.D., Scott, R.R., Thavara, U., Techadamrongsin, Y., 2001. Repellency of volatile oils from plants against three mosquito vectors. J. Vector Ecol. 26, 76–82. Tisgratog, R., Sanguanpong, U., Grieco, J.P., Ngoen-Kluan, R., Chareonviriyaphap, T., 2016. Plants traditionally used as mosquito repellents and the implication for their use in vector control. Acta Trop. 157, 136–144. Tiwary, M., Naik, S., Tewary, D.K., Mittal, P., Yadav, S., 2007. Chemical composition and larvicidal activities of the essential oil of Zanthoxylum armatum DC (Rutaceae) against three mosquito vectors. J. Vector Borne Dis. 44, 198–204. Toloza, A.C., Lucia, A., Zerba, E., Masuh, H., Picollo, M.I., 2008. Interspecific hybridization of Eucalyptus as a potential tool to improve the bioactivity of essential oils against permethrinresistant head lice from Argentina. Bioresour. Technol. 99, 7341–7347.

516  Natural products in vector-borne disease management Trigg, J., 1996. Evaluation of a eucalyptus-based repellent against Anopheles spp. in Tanzania. J. Am. Mosquito Contr. Assoc.-Mosquito News 12, 243–246. Trongtokit, Y., Curtis, C.F., Rongsriyam, Y., 2005a. Efficacy of repellent products against caged and free flying Anopheles stephensi mosquitoes. Southeast Asian J. Trop. Med. Public Health 36, 1423. Trongtokit, Y., Rongsriyam, Y., Komalamisra, N., Apiwathnasorn, C., 2005b. Comparative repellency of 38 essential oils against mosquito bites. Phytotherapy Res.: Int. J. Devoted Pharmacol. Toxicol. Eval. Nat. Product Deriv. 19, 303–309. Türkoğlu, G.C., Sarıışık, A.M., Erkan, G., Yıkılmaz, M.S., Kontart, O., 2020. Micro-and nanoencapsulation of limonene and permethrin for mosquito repellent finishing of cotton textiles. Iranian Polym. J. 29, 321–329. WHO 2020. World malaria report 2019. Reference Source: https://www.who.int/malaria/publications/world-malaria-report-2019/en. Winstanley, P., 2001. Modern chemotherapeutic options for malaria. Lancet Infect. Dis. 1, 242–250. Yang, Y.-C., Lee, E.-H., Lee, H.-S., Lee, D.-K., Ahn, Y.-J., 2004. Repellency of aromatic medicinal plant extracts and a steam distillate to Aedes aegypti. J. Am. Mosq. Control Assoc. 20, 146–149. Yener, H.E., Hillrichs, G., Androsch, R., 2021. Phase behavior of solvent-rich compositions of the polymer/drug system poly (butylene succinate) and N,N-diethyl-3-methylbenzamide (DEET). Colloid Polym. Sci. 299, 873–881. Yener, H.E., Erdmann, R., Jariyavidyanont, K., Mapossa, A.B., Focke, W.W., Hillrichs, G., Androsch, R., 2022. Slow-DEET-release mosquito-repellent system based on poly (butylene succinate). ACS Omega 7, 8377–8384. Yoon, J.K., Kim, K.-C., Cho, Y., Gwon, Y.-D., Cho, H.S., Heo, Y., Park, K., Lee, Y.-W., Kim, M., Oh, Y.-K., 2015. Comparison of repellency effect of mosquito repellents for DEET, citronella, and fennel oil. J. Parasitol. Res., 1–6. https://doi.org/10.1155/2015/361021. Zahi, M.R., Wan, P., Liang, H., Yuan, Q., 2014. Formation and stability of d-limonene organogel-based nanoemulsion prepared by a high-pressure homogenizer. J. Agric. Food ­ Chem. 62, 12563–12569.

Chapter 21

Insect repellent plants: A recent update S.K. Sukruthaa, R. Ramachandrab, and Santosh Anandb a

Department of Microbiology, Jnanabharathi Campus, Bangalore University, Bengaluru, Karnataka, India, bDepartment of Biotechnology, REVA University, Bengaluru, Karnataka, India

Introduction Insects are wonderful organisms on earth playing a pivotal role as both useful and harmful creatures to human beings, cattle, and plants. They help in maintaining the ecological balance of the ecosystem. The nature has provided resources to every organism to survive on earth with special characters to attract or repel the organism. Insect infestation has a direct influence on food and stored grains as their impairment has led to 30% loss in the staple and 90% in the agriculture production (Singh et al., 2018). Different types of insects such as chewing, sap-sucking, and borings have been reported to cause damages in various plants (Noman et al., 2020). Use of chemical insecticides reduced the insect pests worldwide (Qasim and Hussian, 2015; Hafeez et al., 2019). However, they are nonbiodegradable, are highly toxic, and cause damage to nontarget organisms (Hussain et al., 2015; Qasim et al., 2018). Irrational use of these chemicals paved a way for the emergence of resistance insect pests and accumulation of toxic residues in the food chain causing various health hazards. The glitches of chemical-based insecticides increased the interest of researchers globally toward the practice of plant-based insecticides. Over the years, plants have developed explicit defensive approaches in response to insect attacks such as secondary metabolites, volatile organic compounds (VOCs), and essential oils (EOs). These compounds are well documented for their protective functions by means of induction and regulation of various defense signaling cascades. Primarily, insect attack initiates a series of reactions resulting in the production and accumulation of innumerous secondary metabolites such as terpenoids, alkaloids, flavonoids, saponins, and tannins (Jamwal et al., 2018). Plant VOCs are synthesized upon insect attack and induce hormonal defense signaling cascades. Secondary metabolites help the plants to identify the insect attacks and respond in a timely pattern. Growing body of evidence suggests that insects possess limited ability in terms of resistance and adaptation to secondary Natural Products in Vector-Borne Disease Management. https://doi.org/10.1016/B978-0-323-91942-5.00011-2 Copyright © 2023 Elsevier Inc. All rights reserved.

517

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metabolites. These metabolites synthesized by plant machineries exhibit toxicity toward insects and stimulate antixenosis mechanisms in plants. According to the Painter, “Theory of host plant resistance” resistance of plants against insects is defined as “the summation of the heritable features that impacts the ultimate extent of damage orchestrated by the insect pest (Painter, 1951).”

Alkaloids Alkaloids are nitrogen-containing secondary metabolites produced by microorganisms namely fungi, bacteria, plants, insects, and animals with complex and diverse structures (Lu et al., 2012; Chauhan et al., 2020; Behl et al., 2021). Conventionally, plant-based alkaloids are associated with traditional medicines since ancient times as sedatives, antitussives, purgatives, and treatments for a wide array of ailments. These compounds are widely distributed in nature and accounts for 25% in the plants. They are documented as natural insecticidal agents against wide array of insects infecting diverse plants (Table 1). Solanum alkaloids inhibited Tribolium castaneum larval growth in the artificial diets supplemented with 1 μmol g−1 glycoalkaloids, solamargine, solasonine, and tomatine, whereas significant inhibition was seen in diet with tomatine at 1 μmol g−1 concentration (Weissenberg et al., 1998). A comparative study was performed to ascertain the effectiveness of α-solanine, a glycoalkaloids (GAs), synthesized by dried fresh potato leaf extract on the lepidopteran, Galleria mellonella. Results showed that modulation of protein carbonyl, malondialdehyde concentrations, and activity of glutathione S-transferase enzyme in the fat body and midgut of the larvae was significant in α-solanine than EPL (Adamski et al., 2014). Treatment with different concentrations of Solanum nigrum extract and solasonine resulted in sublethal effect on Galleria mellonella larva namely the damage of fat body cells such as lysis of lipid droplets, reduced electron density in the cytoplasm, increase in intracellular space in the cytoplasm and the midgut such as strong vacuolization, and reduced electron cytoplasm density (Spochacz et al., 2021). Effect of Lycopersicon esculentum and Solanum tuberosum leaf extracts containing α-tomatine, α-chaconine, α-solanine, and glycoalkaloids on the reproduction and development of wild-type Drosophila melanogaster was investigated by Ventrella et al. (2016). Parental generation was treated with five different leaf extract concentrations and glycoalkaloids. The effect of exposure was observed on the later, nonexposed generation. In the first generation that has been exposed, decrease in the count of organisms reaching the imaginal and pupal stages was observed with each extract. Individual applications of extracts and glycoalkaloids resulted in faster development in parents insect. Notably, the effect was diminished in case of glycoalkaloids compared to extracts exposure. Conversely, enhancement in the rate of development was evident in the nonexposed generation. Further, treatment with extracts and glycoalkaloids displayed abnormality in body mass and malformations

TABLE 1  Insecticidal activities of selected alkaloids. Name of the plant/ compound/extract

Target insect

Mechanism of action

References

Synthetic camptothecin and hydroxyl-camptothecin

IOZCAS-Spex-II cells derived from Spodoptera exigua Hubner

Increase in oxidative stress, lipid peroxidation, DNA damage, and protein carbonylation

Ren et al. (2019)

Camptothecin (CPT) from Camptotheca acuminata Decne

Spodoptera frugiperda larvae

Inhibited larval growth compared to control, treatment with 1.0 μg/g CPT resulted in disorganized microvilli, reduced mitochondria, and endoplasmic reticulum content in midgut cells of larvae compared to control, treatment with 5 μg/g CPT resulted in chromatin condensation, decreased and deformed microvilli

Shu et al. (2021)

CPT from C. acuminata

S. frugiperda larvae

Treatment with 1 and 5 μg/g CPT resulted in modulation of detoxification pathways, immune response, hormone, fatty acids, and chitin biosynthesis in fat bodies was observed

Shu et al. (2021)

CPT from C. acuminata Compound A (2-nitroaminoimidazoline to CPT) Compound B (1-chloro-2-isocyanatoethane to HCPT)

Spodoptera exigua

Compound A was effective on third instar larvae in contact toxicity test and displayed cytotoxicity against IOZCASSpex-II cells from S. exigua Cytotoxicity, contact toxicity, and Topo I inhibitory action was markedly increased in Compound B

Yang et al. (2019)

CPT from C. acuminata

IOZCAS-Spex-II cells extracted from S. exigua Hubner

Treatment with CPT and HCPT resulted in mitochondrial damage such as disruption of cristae and membrane, apoptosis Significant increase in cytosolic Ca2+ and reduced mitochondrial membrane potential

Ren et al. (2017)

Piper nigrum containing piperine

Rhynchophorus ferrugineus Olivier

LD50 (219.88 mg/L) against R. ferrugineus Olivier 62% reduction in conversion of ingested to digested food Upregulation of detoxification genes (cytochrome P450, glutathione S-transferase, and esterase)

Hussain et al. (2017)

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like smaller black abdominal zone, deformed abdomens, and wings. Effect of sublethal potato and tomato leaf extract concentrations on Spodoptera exigua suggested that cells in the midgut were not modulated remarkably. However, fat body cells displayed increased endoplasmic reticulum edema and nuclear envelope, fusion of fat droplets, and mitochondria vacuolization in groups treated with potato than tomato extracts. Moreover, compared to tomato, potato leaf extracts exhibited high developmental alterations in Spodoptera exigua such as significant reduction in morphological malformations and hatching success (Adamski et al., 2016). A comparative analysis on the effects of senescent leaf Melia azedarach and Amaranthus viridis extract on Spodoptera exigua second instar larvae survival was studied. After 24 h, both the extracts showed markedly high insecticidal activity with LC50 value of 9.793 mg/mL and 50.5702 mg/mL. Further, extract of Melia azedarach significantly inhibited the activities of detoxification enzymes such as carboxylesterase and glutathione-S-transferase. Conversely, Amaranthus viridis extract inhibited glutathione-S-transferase only (Rachokarn et al., 2008). Seven 20(S)-t-butoxy carbonyl-amino acid derivatives of camptothecin (CPT), a quinolone alkaloid, isolated from Camptotheca acuminata were chemically synthesized and investigated for insecticidal, topoisomerase I (Topo I) inhibitory, cytotoxicity activities against Spodoptera exigua Hubner cell line. Markedly increase in contact and cytotoxicity was evident with the 20-position t-Boc amino acids introduction on CPT. However, inhibitory consequence on relaxation process of Spodoptera exigua Topo I was reduced. Furthermore, significant increase in contact and cytotoxicity activities was seen with the compounds 1d and 1g than CPT and hydroxyl-camptothecin (Wang et al., 2017).

Terpenoids Several studies have substantiated that terpenoids also exhibit a remarkable insecticidal activity (Table 2). Effect of dietary intake of fresh purple leaves of lettuce (Lactuca sativa) on Spodoptera eridania and Ceraeochrysa claveri with azadirachtin solution of 6 mg, and treatment of 18 mg a.i/L for egg clusters of Diatraea saccharalis for 7 days was studied. Profound decrease in the body mass, survival rate in Spodoptera eridania, and cytotoxicity in the perivisceral fat bodies’ parietal regions in both the species were observed. Further, ultrastructural cell damage such as swollen mitochondria and dilated cisternae of the rough endoplasmic reticulum of trophocytes was evident in both the species (Scudeler et  al., 2019). In another study, treatment with 35.2 μg/cm2 of phytol [(2E)-3,7,11,15-tetramethyl-2-hexadecen-1-ol], isolated from the plant leaves of matured Capsicum annuum, led to complete ovipositional deterrent activity against the females of Liriomyza trifolii from egg laying on the leaves of the host plants (Kashiwagi et al., 2005). Volatile (E)-nerolidol triggered the early defense response such as WRKY and mitogen-activated protein kinase activation, stimulation of abscisic acid, and jasmonic acid signaling mechanisms

TABLE 2  Insecticidal activities of selected terpenoids. Name of the plant/compound/ extract

Target insect

Mechanism of action

References

Munroniamide and ceramides from Munronia henryi

Pieris brassicae L.

Moderate to significant antifeeding activity

Qi et al. (2003)

Methanolicseed extract of Withania somnifera

Glyphodes pyloalis

Increased larval duration, reduced Fecundity, antifeedant activity Reduction in phenoloxidase enzyme activity, ovarial malfunction

Afraze et al. (2020)

Salannin from Azadirachta indica

Reticulitermes speratus

AFD, PC95 = 203.3 μg/disc

Ishida et al. (2014)

Artemisia annua crude leaf extracts

Glyphodes pyloalis

LC50 and LC20 values on fourth instar larvae was 0.33 and 0.22 g leaf equivalent/mL Fecundity of adults after larval treatment was 105.6 ± 16.84 eggs/female, whereas, the control was 392.74 ± 22.52 eggs/female Significantly affected glutathione S-transferase, α-amylase, protease, lipase, and esterase activity

Khosravi et al. (2011)

Aphanamixoid A from Aphanamixis polystachya

Helicoverpa armigera

Antifeedant activity, EC50 = 0.015 μmol/cm2

Cai et al. (2012)

Two triterpenoids, cabraleadiol and ocotillone, four limonoids, 3-betadeacetylfissinolide, 7-deacetoxy-7oxogedunin, methyl angolensate, and beta-photogedunin extracted from Arillus of Carapa guianensis and seeds and fruits of Cabralea canjerana

Spodoptera frugiperda

Beta-photogedunin and 7-deacetoxy-7-oxogedunin reduced pupal weight Larval stage was prolonged by 3-beta-deacetylfissinolide, cabraleadiol, and 7-deacetoxy-7-oxogedunin

Sarria et al. (2011)

Continued

TABLE 2  Insecticidal activities of selected terpenoids—cont’d Name of the plant/compound/ extract

Target insect

Mechanism of action

References

Gedunin, extracted from neem seed kernel oil

Nilaparvata lugens Plutella xylostella

Concentrations of 0.25, 0.5, and 1 mg/mL concentration resulted in 0%, 20%, and 40% mortality in Nilaparvata lugens Concentrations of 0.25, 0.5, and 1 mg/mL concentration resulted in moderate activity against P. xylostella, with 10%, 40%, and 60% mortality in Plutella xylostella No insecticidal activity against Myzus persicae and S. litura

Park et al. (2014)

Swietenolide from Cedrela odorata

S. littoralis

Antifeedant activity at 1000 μg/mL

Kipassa et al. (2008)

7-Deacetyl-17β-hydroxyazadiradion from Azadirachta indica

Heliothis virescens

High insect growth inhibitory activity (EC50 = 240 μg/mL)

Lee et al. (1988)

Azadirachtin from neem

D. melanogaster

Effective topically at two consecutive doses LD25 (0.28 μg) and LD50 (0.67 μg) on the early third instar larvae Reduced intake of food in the adults of both the sexes Digestive enzymes such as chitinase, α-amylase, and protease activities were decreased, and lipase activities were increased in the midgut of flies

Kilani-Morakchi et al. (2017)

Insect repellent plants: A recent update  Chapter | 21  523

in tea plants (Chen et  al., 2020). In a similar study, mechanical damage and wounding of tea green leafhopper, Empoasca (Matsumurasca) onukii Matsuda. E. (M.) onukii, to the leaves of Camellia sinensis induced the synthesis of volatile monoterpenes derived from linalool (Mei et  al., 2017). In another study, β-1,3-glucan laminarin, a plant elicitor, conferred protection to Camellia sinensis against Empoasca (Matsumurasca) onukii Matsuda by triggering salicylic and abscisic acid signaling pathways, mitogen-activated protein kinases, and WRKY. Further, increase in defensive enzymes such as callose, polyphenol oxidase, chitinase, phenylalanine ammonia lyase, and flavonol synthase was observed (Xin et al., 2019). High levels of volatile organic compounds (VOCs) namely(E)-4,8-­dimethyl1,3,7-nonatriene and (E)-β-caryophyllene, emitted by Psidium guajava L plants, induced the expression of defense-related early signaling pathways such as protease inhibitor, jasmonate, terpenoid, flavonoid, and phenylpropanoid, biosynthesis in Citrus sinensis L. Osbeck. This led to reduced developmental performance and behavioral preference in Diaphorina citri. Overall, these results suggest that intercropping of Citrus sinensis with Psidium guajava ­reduced the incidence of Diaphorina citri and huanglongbing disease in Citrus sinensis (Ling et al., 2022). In a similar study, Alquezar et al. (2019) for the first time reported that transgenic Arabidopsis plants conferred protection to Citrus sinensis trees against insect vector Diaphorina citri (responsible for carrying the pathogenic bacteria, Candidatus liberibacter) by emitting high levels of (E)-βcaryophyllene, a VOCs. This resulted in reduction of identification and settling of insect vector Diaphorina citri on citrus trees by 44% and 27% after 24 and 48 h, respectively. Exposure of 10 and 20 mgL−1 of azadirachtin, respectively, for 3–7 and 5 days induced the death of Drosophila melanogaster. Upon topical application to the adult fruit flies or larvae, sublethal toxicity (LD50 = 630 mg/L and LD50 = 670 mgL−1) was observed. In addition, molecular studies showed that azadirachtin modulated the regulation of hormones, posttranscriptional enzymes, proteins associated with transcription, translation, and cytoskeleton development. Furthermore, alleviated chitin and increase in chitinase levels were also noted (Zhang et al., 2018). In a similar study by Bezzar-Bendjazia et al. (2017), azadirachtin treatment to Drosophila melanogaster larvae markedly reduced the activity of various enzymes such as chitinase, α-amylase, and protease in the intestine and promoted lipase activity. Further, it also affected larval evasion, food intake, and digestion in Drosophila melanogaster. In another study, topical application of azadirachtin ranging from 0.1 to 2 μg to Drosophila melanogaster early third instar larvae led to cumulative mortality of immature stage. Further, at LD25 (0.28 μg) and LD50 (0.67 μg) concentration, it enhanced the period of pupal and larval development, significantly lowered fecundity of flies, and modulated adult oviposition preference and adult endurance of both the sex when compared to the controls (BezzarBendjazia et al., 2016).

524  Natural products in vector-borne disease management

Saponins Dolma et al. (2021) studied the insecticidal properties of tea saponin on diamondback moth larvae, Plutella xylostella (L.), and an aphid, Aphis craccivora Koch. Results suggested that, in residual toxicity assay, compared to control, treatment with saponin for 96 h was more found to be more efficacious in Aphis craccivora second instar larvae (LC50 = 540.79 mg/L) and Plutella xylostella (LC50 = 2106.32 mg/L). Under repellent activity test, 3000 and 4000 mgL−1 of saponin displayed higher repellence (49%) to third instar larvae of Aphis craccivora and Plutella xylostella. In another study, saponin extracted from Quilla jasaponaria Molina exhibited feeding deterrent activity (0.97) and toxicity (LC50 = 0.55 mg/mL) against pea aphid, Acyrthosiphon pisum (De Geyter et al., 2012). Triterpenoid saponins such as huzhangoside D, tomentoside A, clematograveolenoside A, and clematoside S were isolated from the roots and rhizomes of Clematis graveolens. After treatment with Aphis craccivora for 72 h, tomentoside A was found to be the most potent against Aphis craccivora (LC50 of 1.2 and 0.5 mg/mL), followed by clematoside S (LC50 = 2.3 and 1.9 mg/mL) and clematograveolenoside A (LC50 = 3.2 and 2.6 mg/mL), respectively. However, after 24 h of treatment with termite (Coptotermis homii), clematograveolenoside A was found to be highly toxic (LC50 of 0.1 mg/L) followed by the compounds clematoside S, huzhangoside D, and tomentoside A (LC50 = 0.1, 0.2 and 0.2 mg/ mL respectively) (Rattan et al., 2015). Cai et al. (2017) reported that ecotypes of Medicago truncatula inoculated with the Ensifer medicae (Sinorhizobium medica) WSM419 rhizobium exerted antifeedants property against Spodoptera exigua. Spiroconazole A, a steroidal saponin from Dracaena arborea demonstrated insecticidal activity at 25 ppm (Nya et al., 2016). Three divergent host plants such as radish (Raphanus sativus L. var. radiculus Persi), rape (Brassica campestris L.), and cabbage (Brassica oleracea L. var. capitata) were fed to diamondback moth, Plutella xylostella. Compared to control, larvae supplemented with cabbage exhibited higher antioxidant enzymes, namely catalase (CAT), peroxidase (POD), superoxide dismutase (SOD), and the malondialdehyde (MDA) levels, whereas on rape, compared to control, treatment with tea saponin after 24 h led to reduced CAT and SOD activities and to higher POD activities. After 12 h, increase in MDA levels was observed in larvae fortified with rape but reduced in larvae fed on radish. Overall, these results suggest that Plutella xylostella larvae were found to be more sensitive to rape, compared to radish and cabbage, respectively (Lin et  al., 2018). In another study, total saponins isolated employing 70% ethanol from Camellia oleifera seeds resulted in high and stomach toxicity (LC50 = 22.395 mg/L) and contact toxicity (LC50 = 8.459 mg/L) in Ectropis obliqua. This could be due to damage of epidermal waxy layer, resulting in severe dehydration. This led to the reduced intestinal villi and disruption of the intestinal wall cavities, thus leading to larval senescence (Cui et al., 2019; Table 3).

Insect repellent plants: A recent update  Chapter | 21  525

TABLE 3  Insecticidal activities of selected saponins. Name of the plant/ compound/ extract

Target insect

Mechanism of action

References

Tea

Diamondback moth

DBM larvae with LC20 and LC50 dosages of tea saponins resulted in poor growth rates, slower adult emergence percentages, reduced feed intake, pupal weights, frass production, percentage pupation, and diminished fecundity Extended time for digestion and the pupal and larval periods Increase in the concentration of juvenile and molting hormone

Cai et al. (2016)

Panax ginseng Panax quinquefolius L.

Pieris rapae

2% Ginsenosides showed antifeedant activity (86% and 89%) 1% Ginsenosides showed oviposition-deterring activity (78%)

Zhang et al. (2017)

Panax ginseng

4th-instar Mythimna separata larvae

Treatment with 5, 10, and 20 gL−1 of total ginsenoside for 8 h resulted in nonselective antifeeding rate (47.36%, 64.40%, and 88.67%) and selective antifeeding rate (34.19%, 44.29%, and 62.49%)

Tan et al. (2015)

Panax ginseng Total ginsenoside contains protopanaxdiol (PPD) and protopanaxtriol (PPT)

Ostrinia furnacalis

Maximum ovicidal activity was achieved at 100 mg/mL PDS in 0- (80.58 ± 0.95%), 1- (71.48 ± 5.70%), and 2-day-old eggs (64.31 ± 3.20%) Maximum antifeedant activity in third instar larvae was observed at 100 mg/mL PDS for 48 h (80.9 ± 4.36% in choice and 88.39 ± 3.43% in no-choice) than total ginsenosides and PTS

Liu et al. (2019)

Continued

526  Natural products in vector-borne disease management

TABLE 3  Insecticidal activities of selected saponins—cont’d Name of the plant/ compound/ extract

Target insect

Mechanism of action

References

Tea

Ebrechtella tricuspidata and Evarcha albaria

Treatment with tea saponins resulted in toxicity of third instar Ectropis oblique larvae (LC50 - 164.32 mg/mL) 30% TS treatment for 48 h resulted in 16.67% and 20% mortality of E. albaria and E. tricuspidata

Zeng et al. (2019)

Dried alfalfa

Ostrinia nubilalis

Intake of 0.5%, 1.6%, and 10% saponin within 9 days resulted in 53%, 60%, and 100% mortality

Nozzorrillo et al. (1997)

Essential oils Effectiveness of various essential oil (EO) concentration obtained from the three Apiaceae plants’ (Foeniculum vulgare, Anethum graveolens, and Pimpinella anisum) seeds upon molting, mortality, behavior, and gypsy moth larvae (GML, an important pest of hardwood forests) nutritional physiology was studied and compared with NeemAzal-T/S (neem), a commercially available insecticide. The chief constituents in the EOs were found to be trans-anethole in Pimpinella anisum, α-phellandrene, limonene, and carvone in Anethum graveolens and fenchone and trans-anethole in Foeniculum vulgare seeds. Results suggested that, at 1% EOs concentration, Pimpinella anisum and Foeniculum vulgare were comparatively superior antifeedants than Anethum graveolens and all the three EOs exhibited enhanced toxicity to the larvae compared to neem. Compared to all EOs, neem delayed second to third larval molting. However, 0.5% of Pimpinella anisum and Foeniculum vulgare EOs reduced relative consumption rate at fourth instar compared to neem and Anethum graveolens at 1% concentration displayed highest mortality. Treatments with the three EOs were highly efficacious in the reduction of growth rate, consumption, and metabolic parameters compared to control. Overall, these results indicated the EOs obtained from various Apiaceae plants could serve as a promising candidate for control of gypsy moth (Kostic et al., 2021; Spinozzi et al., 2021). In another study, an ecofriendly EOs comprising fenchone (25.5%) and trans-anethole (67.9%) from Foeniculum vulgare exhibited targeted insecticidal activity (LC90 = 2.4 and LC50 = 0.6 mL L−1) against Myzus persicae, an

Insect repellent plants: A recent update  Chapter | 21  527

polyphagous pest and a natural predator of Harmonia axyridis and showed no negative effect on the soil microflora, earthworms, and other nontarget predator (Pavela, 2018). Li et al. (2018) reported that treatment with essential oils extracted from Ajania nitida resulted in fumigant and contact toxicity against Tribolium castaneum and Lasioderma serricorne. In addition, treatment with Ajania nematoloba oil and Tribolium castaneum resulted in LD50 = 102.29 μg/ adult and LC50 = 69.45 mg/L air, and only contact toxicity for Lasioderma serricorne (LD50 = 53.43 μg/adult), respectively. Overall, these results suggest that, compared to Ajania nematoloba oil, Ajania nitida showed strong repellent and insecticidal activities against Lasioderma serricorne and Tribolium castaneum adults. Insecticidal properties of oregano essential oil were studied against Tenebrio molitor, an yellow mealworm beetle, pest of bran, grains, flour, and pasta worldwide. Treatment with OEO resulted in reduced survival rates of larvae (65%–54%), pupae (38%–44%), adults (30%–23%), and insect (6%–2%) with LD25, LD50, LD75, and LD90 compared to 100% survival rates in control, respectively. Further, treated Tenebrio molitor also displayed reduced respiration rate, altered behavior responses, toxicity, and low survival rates at different developmental stages (Plata-Rueda et al., 2021). In another study, the efficacy of citrus peel EOs in the form of emulsions and polyethylene glycol inclusion nanoparticles (EO-NPs) was ascertained against the tomato invasive pest Tuta absoluta. Results indicated that maximum mortality was observed in contact on larvae and eggs by EO emulsions and by larval ingestion in EO-NPs. Maximum toxicity to egg, larvae, and phytotoxicity was observed in EOs as emulsions than EO-NPs (Campolo et al., 2017). Evaluation of 14 EOs from 12 selected Lamiaceae plants was investigated for larvicidal and repellent properties against Aedes albopictus. The results indicated that maximum larvicidal activity was observed in EOs from Origanum vulgare, Origanum dictamnus, Origanum majorana, Ocimum basilicum, and Thymus vulgaris, and their key components were terpenes namely p-cymene, carvacrol, thymol, and γ-terpinene, whereas terpenoids such as thymol, carvacrol, piperitenone epoxide, and piperitenone, obtained from EOs of Melissa officinalis, Origanum dictamus, Mentha spicata, Satureja thymbra, and Origanum majorana, were found to be the most prominent repellents against Aedes albopictus adults (Giatropoulos et al., 2018). In another study, Bedini et al. (2020) investigated the effect of essential oils (EOs) from Rosmarinus officinalis L., Salvia officinalis L., and Allium sativum L. on the toxicity, oviposition deterrence, and the repellence in the blowfly Calliphora vomitoria. Results showed that 2.5 μL cm−2 of EOs exerted repellent activity and deterred the oviposition of females for 24 h. In addition, it also exhibited toxicity property by fumigation (LD50 from 1.76 to 31.52 μL insect−1) and topical application (LD50 from 0.44 to 1.97 μL insect−1) on adults Calliphora vomitoria. Furthermore, 40% of Calliphoridae was reduced in EO-charged mist-treated population in the meatprocessing room (Bedini et al., 2020). A study on effectiveness of eight EOs obtained from Trachyspermum ammi, Pimpinella anisum, Hazomalania ­voyronii,

528  Natural products in vector-borne disease management

Mentha longifolia, Origanum syriacum, Dysphania ambrosioides, Carlina acaulis, and Cannabis sativa was explored for insecticidal activity against two stored-product insect species Prostephanus truncates and Trogoderma granarium. Treatment with EOs of Carlina acaulis at 500 and 1000 ppm concentration resulted in >97% and 91.1% mortality within 3 days in Prostephanus truncates and Trogoderma granarium adults under stored maize and wheat sample, respectively, whereas 100% mortality was achieved in Trogoderma granarium adults with 1000 ppm EOs of Dysphania ambrosioides within 2 days of wheat postexposure. The Mentha longifolia EOs at 500 and 1000 ppm concentration exerted 97.8 and 100% mortality in Trogoderma granarium larvae after 3 and 2 days of contact, respectively. Furthermore, exposure of larvae to treated wheat for 7 days with EOs of Pimpinella anisum and Dysphania ambrosioides at a concentration of 1000 ppm resulted in 95.6% and 90% mortality (Kavallieratos et al., 2020). An ecofriendly 6% (w/w) Hazomalania voyronii essential oil-based nanoemulsion (HvNE) was evaluated for insecticidal activity against stored-product pests such as Tribolium confusum, Tribolium castaneum, and Tenebrio molitor. Treatment for 7 days at 500 and 1000 ppm resulted in the mortality rate of 13.0%, 18.7%, and 10.3% in Tribolium confusum and Tribolium castaneum adults and Tenebrio molitor larvae. However, at 1000 ppm, 92.1%, 97.4%, and 100% mortality rate was observed in 7 days postexposure, respectively. Overall, these results suggest that HvNE could be considered as ecofriendly and promising nano-insecticidal candidate for the management of storedproduct pests (Kavallieratos et  al., 2021). Water-distilled essential oil obtained from Clinopodium chinense (Labiatae) aerial parts containing bornyl acetate and piperitone exhibited fumigant toxicity at LC50 values of 351.69 and 311.12 lg/L against booklice, Liposcelis bostrychophila. Fumigant toxicity was found to be LC50 values of 351.69 and 311.12 lg/L in bornyl acetate and piperitone, respectively. The EO also exhibited contact toxicity against Liposcelis bostrychophila with an LC50 value of 215.25 lg/cm2. Furthermore, acute toxicity with LC50 values of 321.42, 275.00, and 139.74 lg/cm2 was observed in EOs containing bornyl acetate, caryophyllene, and piperitone, respectively (Li et al., 2015).

Conclusion Globally, research on the insecticidal activity of plethora of plants has received considerable attention. Investigations on increase in the use of natural, ecofriendly insecticides over the past decades have led to significant control of insects, thus opening a new avenue for sustainable pest management in contrast to many negative effects of synthetic insecticides. Their activities on insects must be systemically evaluated as well as their effects on nontarget organisms and the environment should be studied.

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Acknowledgment The authors acknowledge Department of Biotechnology, School of Applied Sciences, REVA University, for the facilities provided.

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Insect repellent plants: A recent update  Chapter | 21  531 Li, H.Y., Liu, X.C., Chen, X.B., Liu, Q.Z., Liu, Z.L., 2015. Chemical composition and insecticidal activities of the essential oil of Clinopodium chinense (Benth.) Kuntze aerial parts against Liposcelis bostrychophila Badonnel. J. Food Prot. 78, 1870–1874. Li, Y., Yan, S.S., Wang, J.J., Li, L.Y., Zhang, J., Wang, K., et al., 2018. Insecticidal activities and chemical composition of the essential oils of Ajania nitida and Ajania nematoloba from China. J. Oleo Sci. 67, 1571–1577. Lin, S., Chen, Y., Bai, Y., Cai, H., Wei, H., Tian, H., et al., 2018. Effect of tea saponin-treated host plants on activities of antioxidant enzymes in larvae of the diamondback moth Plutella xylostella (Lepidoptera: Plutellidae). Environ. Entomol. 47, 749–754. Ling, S., Rizvi, S.A.H., Xiong, T., Liu, J., Gu, Y., Wang, S., et al., 2022. Volatile signals from guava plants prime defense signaling and increase jasmonate-dependent herbivore resistance in neighboring citrus plants. Front. Plant Sci. 13, 833562. Liu, S., Wang, X., Xu, Y., Zhang, R., Xiao, S., Wang, Y., et al., 2019. Antifeedant and ovicidal activities of ginsenosides against Asian corn borer, Ostrinia furnacalis (Guenee). PLoS One 14, e0211905. Lu, J.-J., Bao, J.-L., Chen, X.-P., Huang, M., Wang, Y.-T., 2012. Alkaloids isolated from natural herbs as the anticancer agents. Evid. Based Complement. Alternat. Med. 2012, 485042. Mei, X., Liu, X., Zhou, Y., Wang, X., Zeng, L., Fu, X., et  al., 2017. Formation and emission of linalool in tea (Camellia sinensis) leaves infested by tea green leafhopper (Empoasca (Matsumurasca) onukii Matsuda). Food Chem. 237, 356–363. Noman, A., Aqeel, M., Qasim, M., Haider, I., Lou, Y., 2020. Plant-insect-microbe interaction: a love triangle between enemies in ecosystem. Sci. Total Environ. 699, 134181. Nozzorrillo, C., Arnason, J.T., Campos, F., 1997. Alfalfa leaf saponins and insect resistance. J. Chem. Ecol. 23, 995–1002. Nya, P.C., Moretti, R., Nicoletti, M., Calvitti, M., Tomassini, L., 2016. Larvicidal activity of steroidal saponins from Dracaena arborea on Aedes albopictus. Curr. Pharm. Biotechnol. 17, 1036–1042. Painter, R.H., 1951. Insect resistance in crop plants. Soil Sci. 72, 481. Park, E.S., Bae, I.K., Jeon, H.J., Lee, S.E., 2014. Limonoid derivatives and its pesticidal activities. Entomol. Res. 44, 158–162. Pavela, R., 2018. Essential oils from Foeniculum vulgare Miller as a safe environmental insecticide against the aphid Myzus persicae Sulzer. Environ. Sci. Pollut. Res. Int. 25, 10904–10910. Plata-Rueda, A., Zanuncio, J.C., Serrao, J.E., Martínez, L.C., 2021. Origanum vulgare essential oil against Tenebrio molitor (Coleoptera: Tenebrionidae): composition, insecticidal activity, and behavioral response. Plan. Theory 10, 2513. Qasim, M., Hussian, D., 2015. Efficacy of insecticides against Citrus psylla (Diaphorinacitri Kuwayama) in field and laboratory conditions. Cercet. Agron. Mold. 48, 91–97. Qasim, M., Husain, D., Islam, S.U., Ali, H., Islam, W., 2018. Effectiveness of Trichogramma chilonis Ishii against spiny bollworm in Okra and susceptibility to insecticides. J. Entomol. Res. Stud. 6, 1576–1581. Qi, S.H., Wu, D.G., Chen, L., Ma, Y.B., Luo, X.D., 2003. Insect antifeedants from Munronia henryi: structure of munroniamide. J. Agric. Food Chem. 51, 6949–6952. Rachokarn, S., Piyasaengthong, N., Bullangpoti, V., 2008. Impact of botanical extracts derived from leaf extracts Melia azedarach L. (Meliaceae) and Amaranthusviridis L. (Amaranthaceae) on populations of Spodoptera exigua (Hübner) (Lepidoptera: Noctuidae) and detoxification enzyme activities. Commun. Agric. Appl. Biol. Sci. 73, 451–457. Rattan, R., Reddy, S.G., Dolma, S.K., Fozdar, B.I., Gautam, V., Sharma, R., et al., 2015. Triterpenoid Saponins from Clematis graveolens and evaluation of their insecticidal activities. Nat. Prod. Commun. 10, 1525–1528.

532  Natural products in vector-borne disease management Ren, X., Zhang, L., Zhang, Y., Mao, L., Jiang, H., 2017. Mitochondria response to camptothecin and hydroxycamptothecine-induced apoptosis in Spodoptera exigua cells. Pestic. Biochem. Physiol. 140, 97–104. Ren, X., Zhang, L., Zhang, Y., Mao, L., Jiang, H., 2019. Oxidative stress induced by camptothecin and hydroxyl-camptothecin in IOZCAS-Spex-II cells of Spodoptera exigua Hübner. Comp. Biochem. Physiol. C Toxicol. Pharmacol. 216, 52–59. Sarria, A.L., Soares, M.S., Matos, A.P., Fernandes, J.B., Vieira, P.C., da Silva, M.F., 2011. Effect of triterpenoids and limonoids isolated from Cabraleacanjerana and Carapaguianensis (Meliaceae) against Spodoptera frugiperda (J. E. Smith). Z. Naturforsch. C. J. Biosci. 66, 245–250. Scudeler, E.L., Garcia, A.S.G., Padovani, C.R., Dos Santos, D.C., 2019. Pest and natural enemy: how the fat bodies of both the southern armyworm Spodoptera eridania and the predator Ceraeochrysa claveri react to azadirachtin exposure. Protoplasma 256, 839–856. Shu, B., Zou, Y., Yu, H., Zhang, W., Li, X., Cao, L., Lin, J., 2021. Growth inhibition of Spodoptera frugiperda larvae by camptothecin correlates with alteration of the structures and gene expression profiles of the midgut. BMC Genomics 22, 391. Singh, S.M., Siddhnath, B.R., Aziz, A., Pradhan, S., Chhaba, B., Kaur, N., 2018. Insect infestation in dried fishes. J. Entomol. Zool. Stud. 2, 2720–2725. Spinozzi, E., Maggi, F., Bonacucina, G., Pavela, R., Boukouvala, M.C., Kavallieratos, N.G., et al., 2021. Apiaceae essential oils and their constituents as insecticides against mosquitoes—a review. Ind. Crop Prod. 171, 113892. Spochacz, M., Chowanski, S., Szymczak-Cendlak, M., Marciniak, P., Lelario, F., Salvia, R., et al., 2021. Solanumnigrum extract and Solasonine affected hemolymph metabolites and ultrastructure of the fat body and the midgut in Galleria mellonella. Toxins (Basel) 13, 617. Tan, S.Q., Ma, L., Xu, Y.H., Lei, F.J., Zhang, A.H., Zhang, L.X., 2015. Anti-feeding activity of total ginsenoside from Panax ginseng to 4th-instar Mythimnaseparata larvae. Zhongguo Zhong Yao Za Zhi 40, 2787–2791. Ventrella, E., Adamski, Z., Chudzinska, E., Miądowicz-Kobielska, M., Marciniak, P., Buyukguzel, E., et al., 2016. Solanum tuberosum and Lycopersicon esculentum leaf extracts and single metabolites affect development and reproduction of Drosophila melanogaster. PLoS One 11, e0155958. Wang, L., Li, Z., Zhang, L., Zhang, Y., Mao, L., Jiang, H., 2017. Synthesis, insecticidal activity and inhibition on topoisomerase I of 20(S)-t-Boc-amino acid derivatives of camptothecin. Pestic. Biochem. Physiol. 139, 46–52. Weissenberg, M., Levy, A., Svoboda, J.A., Ishaaya, I., 1998. The effect of some Solanum steroidal alkaloids and glycoalkaloids on larvae of the red flour beetle, Tribolium castaneum, and the tobacco hornworm, Manduca sexta. Phytochemistry 47, 203–209. Xin, Z., Cai, X., Chen, S., Luo, Z., Bian, L., Li, Z., et al., 2019. A disease resistance elicitor laminarin enhances tea defense against a piercing herbivore Empoasca (Matsumurasca) onukii Matsuda. Sci. Rep. 9, 814. Yang, F., Wang, L., Zhang, L., Zhang, Y., Mao, L., Jiang, H., 2019. Synthesis and biological activities of two camptothecin derivatives against Spodoptera exigua. Sci. Rep. 9, 18067. Zeng, C., Wu, L., Zhao, Y., Yun, Y., Peng, Y., 2019. Tea saponin reduces the damage of Ectropis obliqua to tea crops, and exerts reduced effects on the spiders Ebrechtella tricuspidata and Evarcha albaria compared to chemical insecticides. PeerJ 6, e4534. Zhang, A., Liu, Z., Lei, F., Fu, J., Zhang, X., Ma, W., et  al., 2017. Antifeedant and ovipositiondeterring activity of total ginsenosides against Pieris rapae. Saudi J. Biol. Sci. 24, 1751–1753. Zhang, J., Sun, T., Sun, Z., Li, H., Qi, X., Zhong, G., et al., 2018. Azadirachtin acting as a hazardous compound to induce multiple detrimental effects in Drosophila melanogaster. J. Hazard. Mater. 359, 338–347.

Chapter 22

Natural products employed in the management of malaria Katta Santharama, Prabhakar Mishraa, Kamal Shahb, and Santosh Ananda a

Department of Biotechnology, REVA University, Bengaluru, Karnataka, India, bInstitute of Pharmaceutical Research, GLA University, Mathura, Uttar Pradesh, India

Introduction Malaria, a deadly disease accountable for innumerous deaths every year, is caused by the apicomplexan parasite Plasmodium falciparum. It is a noteworthy public health challenge majorly in the developing countries located in the tropical and subtropical regions. The effectiveness of treatment of this disease is losing its efficacy every year. Several clinical candidates presently in use are becoming obsolete owing to their gradual decrement in terms of treatment efficiency, development of drug resistance, intrinsic toxicity, and/or lack of adherence to treatment. In the past, chloroquine, dichlorodiphenyltrichloroethane, artemisinin-based combination therapy (ACT) (Fig. 1), and extensive usage of insecticide-treated bed nets have initially shown challenging effects toward the decline of malaria. However, prolonged use of these antimalarial moieties revealed the development of resistance against them (Lu et al., 2017; Tajuddeen and Van Heerden, 2019). Increased level of resistance in the malarial vectors has been attributed to the target site modifications and augmented metabolism (Kgoroebutswe et al., 2020; Martin et al., 2021). Major classes of drugs employed in public health to which these vectors have developed tolerance include organophosphates, carbamates, DDT, and pyrethroids. Furthermore, the emergence of multiple resistances and cross-resistances poses a serious concern in achieving the targets for the control of malaria (Kouamo et al., 2021; Egwu et al., 2022). Based on the above facts, devising highly effective and sustainable malaria control measures at an operational level necessitates regular monitoring and surveillance campaigns to evaluate the type and level of resistance.

Natural Products in Vector-Borne Disease Management. https://doi.org/10.1016/B978-0-323-91942-5.00009-4 Copyright © 2023 Elsevier Inc. All rights reserved.

533

534  Natural products in vector-borne disease management

FIG.  1  Structures of antimalarial drugs (chloroquine, dichlorodiphenyltrichloroethane, and artemisinin).

First-generation natural products against malaria Traditional knowledge of natural products has been a very rich source for the development of antimalarial drugs (Saggar et al., 2022). One of the earlier natural products that has been widely exploited in the treatment of malaria is quinine, which is extracted from the bark of Cinchona officinalis. It served as an indispensable antimalarial drug intervention almost for 4 centuries ever since its efficacy was first reported. Moreover, its routine practice is challenged by its composite dosing schedule, poor tolerability, poor compliance, and the accessibility of significantly efficient antimalarial drugs. Quinine has been successfully utilized in the designing of the synthetic drug chloroquine that has served as a lead molecule in treating Plasmodium-infected patients for many decades (Achan et al., 2011; de Sena et al., 2019). Existing drug-tolerant forms of Plasmodium species have necessitated the search for new drug molecules against Plasmodium species. Many research groups across the world are working to identify antimalarial drugs in natural products. Natural products have an upper edge over synthetic compounds owing to their diverse stereocenters, heteroatom presence, and adaptive conformations (Tajuddeen and Van Heerden, 2019). Discovery of artemisinin as an effective

The management of malaria  Chapter | 22  535

antiplasmodial drug from the leaves of Artemisia annua brought a significant revolution in the field of malaria treatment. Therefore, ACT is currently widely used to treat malarial patients. Extensive research works in the last two decades to identify antimalarial compounds led to the discovery of several diverse antiplasmodial chemotypes. Interestingly, many of the chemotype sources are reported from nonvegetalbased ones. Still, medicinal plants are undoubtedly the most broadly explored avenues for drugs against malaria due to their relative ease of access. The efficacy of a screening molecule is expressed as inhibition constant IC50, which means the concentration of a molecule that has been found to inhibit 50% of the replication of Plasmodium parasites. Industry standard value for IC50 generally accepted is ≤10 μM. Advances achieved in in  vitro screening techniques to identify compounds with antiplasmodial activity, aided by the availability of various strains, have given impetus to the identification of lead molecules that can lead to a potential drug molecule. Strains that have already been exploited for in  vitro screening include ­chloroquine-sensitive strains (MRC-pf-20, D6, HB3, 3D7, D10, NF54, F32, and T M4/8.2), chloroquine-resistant strains (FcB1, MRC-pf-303, PfINDO, Dd2, and FcM29), and multidrug-resistant strains (W2mef, NHP1337, K1, W2, TM93-C1088, FCR3, TM90-C2A, TM90-C2B, K1CB1, and TM91-C235). Subsequently, several novel assays have been developed by research groups across the world to evaluate the in vitro antimalarial activities of the screened entities. The most widely used techniques include hypoxanthine-incorporation assay, ELISA method that quantifies Plasmodium falciparum histidine-rich protein 2 and lactate dehydrogenase protein, and DNA-based fluorometric assay employing PicoGreen, along with microscopy (Noedl et  al., 2003; Co et al., 2009; Tajuddeen and Van Heerden, 2019). Each of these methods has its own pros and cons as well as specificity and sensitivity. Depending upon the chemical backbone of the natural product, antiplasmodial compounds can be categorized into 4 classes: macrocyclic alkaloids, diterpenes, macrolides, and cyclodepsipeptides (Althagbi et al., 2020). Macrocyclic alkaloids are a diverse group of molecules which can be further subdivided into several subclasses such as quinolines, quinones, piperidines, and beta-carbolines, based on their chemical backbone.

Exploration of antiplasmodial drugs: Discovery of diverse pharmacophores Macrocyclic alkaloids Quinolines Quinolines are heterocyclic chemical compounds having a benzene ring fused to the pyridine ring (Table 1). Chloroquine, mefloquine, and quinine that have been widely used for malarial treatment have a quinoline backbone. Napthylquinoline

TABLE 1  Different subclasses of macrocyclic alkaloids. Chemical name

Subclasses

Organisms

References

Shuangancistrotectorines A

Quinoline

Ancistrocladus tectorius

Xu et al. (2010a,b)

Jozimine A2

Ancistrocladus sp.

Bringmann et al. (2013)

Mbandakamine A Mbandakamine B

Ancistrocladus sp.

Bringmann et al. (2013)

Jozibrevines A, B, C

Ancistrocladus abbreviatus

Fayez et al. (2019)

Jozilebomines A, B

Ancistrocladus ileboensis

Li et al. (2017)

Ealapasamine A-C

Ancistrocladus ealaensis

Tshitenge et al. (2017)

Aspidosperma parvifolium

Girardot et al. (2012)

Flinderole A

Flindersia acuminata

Tchinda et al. (2012)

Dimethylisoborreverine

Flindersia amboinensis

Tchinda et al. (2014)

Hyrtiosulawesine

Aristolochia cordigera

Huang et al. (2017)

Marinacarboline A

Marinactinospora thermotolerans

Liew et al. (2014)

Senna spectabilis

Pivatto et al. (2014)

Ingamine A

Petrosid Ng5 Sp5

Ilias et al. (2012)

Netamine K

Biemna laboutei

Gros et al. (2014)

Haliclonacyclamine A

Heliclona sp.

Mani et al. (2011)

Jacaranda glabra

Gachet et al. (2010)

Robustasides D and G

Grevillea sp.

Ovenden et al. (2011)

Puberulic acid

Penicillium sp. FKI-4410

Iwatsuki et al. (2011)

Uleine

Cassine and spectaline

Jacaglabrosides A-D

Beta-carboline

Piperidine

Phenol derivatives

Hypericum lanceolatum

Zofou et al. (2011a,b)

Garcinia sp.

Guizzunti et al. (2012)

Mallotus oppositifolius

Harinantenaina et al. (2013) Dai et al. (2018)

Renella elliptica

Osman et al. (2010)

Urdamycin Urdmycinone E and G

Streptomyces sp. BCC45596

Supong et al. (2012)

Plumbagin

Markhamia tomentosa

Thiengsusuk et al. (2013)

Thiazoquinone

Plumbagio sp.

Longeon et al. (2010)

Polyketide3-ketoadociaquinone A

Xestospongia testudinaria

Supong et al. (2017)

Clindamycin

Streptomyces sp. BCC71188

Ferreira et al. (2017)

Epoxycytochalasin H

Diaperthermiriciae

5-Hydroxy-3-methoxyxanthone

Xanthones

Caged Garcinia xanthones (CGXs) Mallotojaponins B and C

Phloroglucinol

Anthraquinone 1,2, dimethoxy-6-methyl9,10-anthraquinone

Quinones

2 Formyl-3-hydroxy-9,10 anthraquinone 3 hydroxy-2-methyl-9.10 anthraquinone

Senna spectabilis

Pivatto et al. (2014)

Haliclonacyclamine A

Heliclona sp.

Mani et al. (2011)

Ingamine A

Petrosid Ng5sp5

Ilias et al. (2012)

Netamin B

Biemna laboutei

Gros et al. (2014)

Cassine, spectaline

Piperidines

538  Natural products in vector-borne disease management

classes of molecules are formed from naphthalene and isoquinoline moieties, joined through C-C or C-N axes. Naphthylisoquinoline-derived compounds are found in Central African and Southeast Asia Ancistrocladaceae family members and West African endemic plants of the Dioncophyllaceae family. Xu et al. (2010a,b) isolated five dimeric naphthylisoquinoline alkaloids shuangancistrotectorines A, B, C, D, and E from the twigs of Ancistrocladus tectorius plant found in China. Among these compounds, shuangancistrotectorines A, B, and D revealed significantly good antiplasmodial action with IC50 values of 0.05, 0.08, and 0.09 μM respectively against the F1 strain. Bringmann et al. (2013) isolated a novel naphthylisoquinoline alkaloid Jozimine A2 from the Ancistrocladus species of Congo. Jozimine A2 exhibits antiplasmodial activity at nanomolar concentrations, but it shows a cytotoxic effect on various cell lines. Extraction studies on Ancistrocladus species from Congo led to the identification of Mbandakamines A and B. These alkaloids have an unsymmetrical central biaryl axis. Mbandakamine A and Mbandakamine B exhibit antiplasmodial properties with IC50 values of 0.13 and 0.148 μM and have lower toxicity (Bringmann et al., 2013). A study of bioactive compounds from Ancistrocladus abbreviatus, a shrub in West Africa, led to the discovery of three novel classes of naphthylisoquinolines—jozibrevines A, B, and C. Among these three compounds, jozibrevine A exhibits antiplasmodial activity in the submicromolar range with an IC50 of 0.012 μM and it is found to be noncytotoxic on different cell lines (Fayez et al., 2019). Li et al. (2017) isolated two dimeric naphthylisoquinolines—jozilebomines A and B—from the roots of Congolese plant Ancistrocladus ileboensis. In these compounds, naphthylisoquinoline monomers are connected via an unprecedented 3′,6″ coupling in the binaphthalene core and are constitutionally unsymmetric. Both exhibited good-to-moderate antiplasmodial actions, with IC50 values of 0.043 and 0.102 μM, demonstrating only weak cytotoxic effects in rat skeletal myoblast cells. These compounds have also been reported to have properties to treat pancreatic cancer. Tshitenge et al. (2017) isolated ealapasamines A-C from Ancistrocladus ealaensis J. Léonard plant leaves. All these three ealapasamines display high antiplasmodial activity in the low nanomolar range. IC50 values of ealapasamines A, B, and C against NF54 and K1 strains are 418 and 452 nM, 210 and 138 nM, and 34 and 6.3 nM, respectively.

β-Carboline alkaloids β-Carboline alkaloids belong to a large group of chemical compounds containing indole groups (Table  1). Uleine, an indole alkaloid isolated from the barks of Aspidosperma parvifolium and Aspidosperma olivaceum, has been reported to be more effective on the W2 strain than the 3D strains. In addition to this, it exhibits low toxicity in Vero and HepG2A16 cell lines (Girardot et al., 2012). Further, its mechanism of action has also been documented. This accumulates in the parasite digestive vacuole, followed by protonation, thereby

The management of malaria  Chapter | 22  539

inhibiting heme polymerization (de Oliveira et  al., 2010). An ethnic tribe of DR Congo-Nkundo used Greenwayodendron suaveolens plant parts to treat malaria. Muganza et al. (2016) isolated and investigated the active ingredients responsible for the antiprotozoal activity from the plant root bark. They found that the N-acetyl-polyveoline and sesquiterpenyl indole alkaloid molecules have selective toxicity in the Plasmodium falciparum K1 strain with an IC50 value of 2.8 μM accompanied by cytotoxicity. Two indole-based compounds flinderole A and isoborreverine extracted from the Australian tree Flindersia acuminata (Rutaceae) bark and dimethylisoborreverine and flinderoles B and C from Flindersia amboinensis plant in Papua New Guinea exhibited antimalarial activity in drug-sensitive and -resistant forms (Tchinda et al., 2012, 2014). The mechanism of action of indole alkaloids is attributed to the reduced formation of hemozoin and changes in digestive vacuole formation. A bioactive compound, hyrtiosulawesine isolated from the climbing shrub Aristolochia cordigera, inhibited the Plasmodium falciparum FcB1 strain in vitro viability without exhibiting any kind of toxic effect on HepG2 cells (Huang et al., 2017). In addition, the bioactive compound, marinacarboline A extracted from actinomycetes Marinactinosporathermotolerans, inhabiting in South China Sea, was 18 folds more effective against the Dd2 multidrug-resistant strain than the 3D7 chloroquine-sensitive strain, and it was also found to be noncytotoxic to tumor cell lines at IC50 > 50 μM (Liew et al., 2014).

Piperidine alkaloids and phenol derivatives Piperidine alkaloid derivatives include nitrogen-containing heterocyclic compounds widely seen in plants of the Piperaceae family (Table 1). In Indonesian Maluku and Papua Islands, Carica papaya leaf decoction is administered for curing malaria and has been found to exhibit antiplasmodial activity in in  vitro conditions. Investigation of active ingredients in the alkaloid fraction leads to piperidine alkaloids. However, these purified alkaloids did not exhibit any activity in in vivo conditions, which leads to the conclusion that other compounds in the extract may be potentiating the antimalarial activity of the active ingredient (Julianti et  al., 2014). Studies on Senna spectabilis leaf active compounds—cassine and spectaline—revealed protective activity against Plasmodium falciparum in in  vitro conditions (Pivatto et  al., 2014). However, the semisynthetic version of the same exhibited less activity compared to the natural ones. Ilias et al. (2012) isolated ingamine A and dihydroingenamine, two related alkaloids from Petrosid Ng5 Sp5 (a marine sponge), and investigated the antiplasmodial properties of these moieties. Ingamine and dihydroingenamine D demonstrated significant antiplasmodial actions against chloroquine-resistant (W2) and chloroquine-sensitive (D6) strains of Plasmodium falciparum with IC50 values of 78 and 90 and 57 and 72 ng/mL respectively, while hydroxyingamine revealed less effectiveness (IC50 values of 200 and 140 ng/mL, respectively).

540  Natural products in vector-borne disease management

An interesting study carried out by Mani et  al. (2011) for antiplasmodial compounds using a high-throughput screening from the Solomon Islands marine sponges documented that the ethanolic extract from Haliclona sp. exhibited antiplasmodial activity. In addition, the isolated active ingredient haliclonacyclamine A was found to be more effective against chloroquine-resistant and -sensitive strains. Gros et al. (2014) reported an antiplasmodial activity in the extract of Biemnalaboutei, a sponge from Salary Bay in Madagascar with an IC50 of 3.2 μg/mL, and also found that the active ingredient was alkaloid netamine K. However, this compound exhibited cytotoxic activity. Zofou et  al. (2011a,b) investigated the leaf and stem bark extracts of Dacryodes edulis, a traditionally used West African medicinal plant, for antiplasmodial action and found its effectiveness for 3D7 and Dd2 parasites. Findings documented IC50 values of 6.45 and 8.62 μg/mL, respectively. Further, they found methyl gallate as the active constituent in the stem bark extract against schizonts and trophozoites. Gallic acid derivatives that exhibit antiplasmodial activity were isolated from Limonium leptophyllum and Diospyros sanza-minika (Tajuddeen and Van Heerden, 2019). Studies on Jacaranda glabra, a South American folkloric medicinal plant using its leaf extract, revealed its antiplasmodial efficacy against the K1 strain. Subsequently, phenylethanoid glycosides, jacaglabrosides A-D were isolated, and all were found to exhibit antiplasmodial action (Gachet et  al., 2010). Similar reports on Grevillea sp. leaf and twig extract revealed antiplasmodial activity, and the active ingredient has been found to be phenylpropanoid glycosides robustasides D and G containing hemiquinone. Both of these compounds exhibited activity against chloroquine-resistant Plasmodium falciparum when compared to chloroquine-sensitive strains and multidrug-resistant strains (Ovenden et al., 2011). Interestingly, Penicillium sp. FKI-4410 culture broth compounds, puberulic acid and viticolin B, demonstrated activity against Plasmodium sp. Puberulic acid showed potent efficacy against parasites FCR3 and K1 and was not at all cytotoxic against MCR-5 cells relative to viticolin B. Further, it exhibited activity similar to that of chloroquine and artesunate in Plasmodium bergheiinfected mice. Structural activity relationship of these molecules indicates that a methoxy group at C-2 and a hydroxy group at C-7 are vital for their activity whereas a carboxylic acid moiety at position C-4 improvises selectivity (Iwatsuki et al., 2011).

Pyrroles In an interesting study on Axinella and Agelas genera sponges, antiplasmodial activity has been documented by the bromopyrrole alkaloids extracted from them against the K1 strain (Scala et al., 2010). They reported that the type II fatty acid synthase (FAS-II) enzyme in Plasmodium might be the target for the bromopyrrole alkaloids. Findings on Australian marine sponge Zyzzya sp.

The management of malaria  Chapter | 22  541

e­ xtract revealed that compounds bispyrroloiminoquinone alkaloid and sitsikammamine C exhibit antiplasmodial activity in nanomolar concentration against the Dd2 and 3D7 strains of Plasmodium falciparum. Further, this compound has been found to be effective against schizonts and trophozoites (Davis et al., 2012).

Xanthones Xanthones are a group of compounds which have tricyclic xanthene and single oxo substitution at the 9th position (Table 1). Upegui et al. (2015) isolated xanthones from the plant husk of Garcinia mangostana and found that it inhibits Plasmodium falciparum FCR3, but interestingly, its effectiveness against the 3D7 strain was low. The compound was found to be noncytotoxic to U-937 cells (LC50 = 130.6 μM); however, it caused red blood cell hemolysis at 69.7 μM. Hypericum lanceolatum is a versatile plant with a medicinal value that has long been used by the inhabitants of the southwest province of Cameroon for the treatment of fever. In an attempt to rationalize its ethnomedicinal importance, the ethyl acetate fraction of stem bark was analyzed. Results demonstrated remarkable antiplasmodial activity against the parasite W2mef. A bioassayguided extract purification revealed 5-hydroxy-3-methoxyxanthone as the major active constituent. Although 5-hydroxy-3-methoxyxanthone exhibited good inhibitory action against Plasmodium falciparum SHF4 field isolate but failed to show its inhibition against the W2mef strain, it was found to be noncytotoxic in LLC-MK2 cells at the highest tested concentration of 100 μg/mL (Zofou et al., 2011a,b). Zakiah et al. (2021) synthesized five hydroxyxanthone derivatives and screened for antiplasmodial activity using the heme-polymerizing inhibition assay and in vitro assay. They found that among the 5 compounds, 1,6,8 trihydroxyxanthone exhibits the best antiplasmodial activity on the FCR-3 and 3D7 strains with an IC50 count of 6.10 ± 2.01 μM and 6.76 ± 2.38 μM, respectively. Garcinia species synthesize a distinctive class of metabolites named caged Garcinia xanthones (CGXs) that possess tricyclic rings. These compounds have the tendency to migrate to the cell mitochondria and cause mitochondrial damage (Guizzunti et al., 2012). Gambogic acid, a representative of CGX, causes fragmentation of mitochondria and morphological alterations in the parasites, but the electron transport chain of the mitochondria remains unaffected. This indicates an alternative mode of action from other available antimalarial drugs like atovaquone that target the mitochondria of the parasites. The cytotoxicity of gambogic acid against HEK293 cells was found to be in the μM range, making them selectively toxic against the parasites at active concentrations.

Phloroglucinols Mallotojaponins B and C, two novel dimeric phloroglucinols, have been extracted from the ethanolic leaf and inflorescence extracts of Mallotus ­oppositifolius

542  Natural products in vector-borne disease management

(Euphorbiaceae) (Table 1). Both of these compounds have demonstrated a significant potential against the HB3 and Dd2 strains and are cytotoxic against A2780 cancerous cells. Prenylation is necessary for the antiplasmodial actions of these moieties (Harinantenaina et  al., 2013; Dai et  al., 2018). Marti et  al. (2010) investigated the Symphonia globulifera root bark extract for the presence of antimalarial compounds and isolated a class of bioactive compounds named symphonones—a derivative of isogarcinol. These compounds showed effectiveness against the Plasmodium falciparum chloroquine-resistant strain FcB1 but exhibited a cytotoxic effect against MRC-5 cells.

Quinones Quinones are cyclohexadienones in which the carbonyl groups are located either at 1,2 or 1,4 positions and divided into several subclasses based on the backbone namely benzoquinones, anthraquinones, naphthaquinones, and thiazoquinones (Table 1).

Anthraquinones In an interesting screening study for antiplasmodial compounds, Dai et al. (2014) found the dichloromethane extract of Kniphofia ensifolia to be active against Dd2 parasites (IC50 = 6 μg/mL). Further, they isolated a class of anthraquinones having significant antiplasmodial activity. They also demonstrated that these compounds orchestrate moderate toxicity to the cancerous A2780 cells. Aloeemodin also an anthraquinone isolated from the same plant deliberated less effectiveness for Dd2 parasites (IC50 = 58 μM) and did not reveal antiproliferative action against A2780 cells. The same study documented that 3,4-di-O-methyl caffeoyl ester, a derivative of aloe-emodin, exhibited antiplasmodial activity and is noncytotoxic. Crude extracts of Streptomyces sp. BCC45596, a marine fungus isolated from Thailand, have been reported to have antiplasmodial activity with an IC50 of 1.45–3.56 μg/mL. Bioactive ingredients isolated responsible for the activity have been reported to be C-glycosylated benzanthraquinones, urdamycin E, and urdmycinone E and G. These compounds also showed activity at submicromolar concentration against the K1 strain, but have antiproliferative activity against cancerous KB and MCF-7 cells (Supong et al., 2012). Osman et al. (2010) found that Rennellia elliptica root extract exhibits inhibitory activity against Plasmodium falciparum. They documented three potent anthraquinones namely 3-hydroxy-2-methyl-9,10-anthraquinone, 2-formyl-3-hydroxy-9,10anthraquinone, and 1,2-dimethoxy-6-methyl-9,10-anthraquinone possessing strong antiplasmodial activity. Leaf extract of Pentas longiflora has long been traditionally employed by Kenyan tribes to treat malaria. Wanyoike et al. (2004) found that the root extracts have comparatively better antiplasmodial activity when compared to the

The management of malaria  Chapter | 22  543

leaf extracts. Bioactive compound search on this extract revealed two compounds, pyranonaphthoquinones pentalongin and psychorubrin, with activity against D6 and W2 strains, but both of these phytocompounds were found to be cytotoxic. In a similar line, bioactive compounds furanonaphthoquinones and plumbagin of Markhamia tomentosa and Plumbago species respectively showed antiplasmodial activity but were found to be cytotoxic (Tantangmo et al., 2010; Thiengsusuk et al., 2013). Longeon et  al. (2010) demonstrated that a marine sponge Xestospongia testudinaria from the Solomon Islands synthesized a halenaquinone-type polyketide3-ketoadociaquinone A, which selectively inhibits FcB1 and 3D7 strains. In an interesting study, Supong et al. (2017) reported that Streptomyces sp. BCC71188 crude extract inhibited Plasmodium falciparum (IC50 = 0.19 μg/mL). Two ingredients—clindamycin, a polyketide, and 17-­demethoxyreblastatin— extracted from this extract exhibited antiplasmodial activity in the K1 strain. Further, they have also shown that the quinone moiety in this compound is responsible for the cytotoxicity, and replacing it with the phenol group makes it more selective against the parasite. Findings on Axinyssadjiferi, a marine sponge, revealed that it produces three types of axidjiferosides A-C, a glycosphingolipid class of molecules. The consortium of these compounds specifically exhibits antiplasmodial activity against the FcB1 strain but does not have any activity against other protozoan parasites namely Leishmania donovani and Trypanosoma brucei (Farokhi et  al., 2013). Ferreira et  al. (2017) have found that Diaporthemiriciae, an endophytic fungus, synthesizes epoxycytochalasin H with potent antiplasmodial activity for D6 and W2 parasite strains. Further, these bioactive compounds did not exhibit any cytotoxic effect against Vero cells suggesting that the toxicity is selective to Plasmodium.

Macrolides Table 2 represents a few potential macrolides exhibiting antiplasmodial activity. On a screening study to identify antiplasmodial compounds in Callophycus serratus, a red alga found in Fijian sea led to 4 new bromophycolides, R-U, TABLE 2  Macrolide class of compounds. Chemical name

Source

References

Bromophycolides R-U

Callophycus serratus

Lin et al. (2010)

Kabiramide J

Pachatrissa nux

Sirirak et al. (2011)

Bastimolide A, B

Okeana hirsute

Shao et al. (2018)

Strasseriolides A-D

Strasseria geniculata

Annang et al. (2020)

Paecilomycin E, F

Paecilomyces sp. SCO925

Xu et al. (2010a,b)

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which have diterpene-benzoate moieties. These bromophycolides exhibit activity against Plasmodium falciparum in submicromolar concentration and modest toxicity in cell lines (Lin et al., 2010). In a similar line, the search for antimalarial compounds in the sponge Pachastrissanux leads to the identification of Kabiramide J and K that exhibits antimalarial activity and minor cytotoxicity (Sirirak et al., 2011). Shao et al. (2015) isolated bastimolide A, a macrolide molecule from Okeania hirsuta, a marine cyanobacterium, and found it to exhibit antiplasmodial activity, but it exhibits cytotoxic effect on Vero cells. A new analog of bastimolide A, 24-membered macrolide-bastimolide B, discovered that has a tertiary-butyl group and a long aliphatic chain exhibits better antiplasmodial activity against chloroquine-sensitive HB3 strain (Shao et al., 2018). In a large-scale screen for antimalarial compounds in fungi, a novel family of macrolides, strasseriolides A-D, has been identified from the cultures of Strasseriageniculata CF-247251S fungus obtained from plant tissues. IC50 values of strasseriolides A, B, C, and D were found to be 9.810, 0.013, 0.123, and 0.128 μM respectively, and these compounds did not exhibit any significant cytotoxicity against HepG2 cell lines (Annang et al., 2020). Recently, in vivo studies revealed that among the four strasseriolides, strasseriolide D is found to be very promising. StrasseriolideD-treated mice have been found to have 70% less parasitemia relative to the control, and toxicity studies revealed that this compound does not exhibit any cytotoxicity as well as cardiotoxicity in mice models. Therefore, it can be a promising drug and go for advanced testing and formulation against malaria. Paecilomyces sp. SC0924, a filamentous fungus, produces β-resorcylic acid lactones with a 14-member ring which includes paecilomycins A, E, and F and aigialomycin B and F. All these compounds show activity against Plasmodium sp. Among these compounds, paecilomycin E and aigialomycin F exhibited activity at submicromolar concentrations against 3D7 parasites but not that effective against Dd2 strain (Xu et al., 2010a,b). In addition to this, they did not have any cytotoxic effect on Vero cells. Inspired by the marine diversity and its repertoire of diverse molecules, Xu et al. (2022) isolated a resorcyclic acid lactone compound, zeaenol, from a marine fungus Cochliobolus lunatus. This group took an innovative approach and created many 67 derivatives of this compound by chemical processes such as esterification, acylation, chlorination, and acetalization. Screening of these semisynthetic compounds led to the discovery of 5 compounds with antimalarial activity. In addition to this, these 5 compounds do not have a cytotoxic effect on cell lines as well as the zebra fish embryos.

Terpenes Terpenes are a divergent group of molecules composed of isoprene C5 structural units widely distributed in nature (Table 3). Terpenes include diterpenes (C20), triterpenes (C30), monoterpenes (C10), tetra (C40), sesquiterpenes (C15), and polyterpenes. Artemisinin and its derivatives are one of the most ­successful drugs

The management of malaria  Chapter | 22  545

TABLE 3  Terpene class of molecules. Chemical name

Source

References

Kalihinol A, kalihinene and 6-hydroxykalihinene

Acanthella sp.

Manivel et al. (2020)

Bromophycolide A

Callophycus serratus

Stout et al. (2011)

Artemisinin

Artemisia annua

Tu (2016) and Miller and Su (2011)

widely used for treating malaria. Artemisinin is a sesquiterpene lactone isolated from the shrub Artemisia annua, a traditional medicinal plant from China (Miller and Su, 2011; Tu, 2016). Isolation of diterpene formamide compounds from marine sponge Cymbastelahooperi led to the discovery of two diterpene formamide compounds having antiplasmodial activity with an IC50 value of 0.5 and 14.8 μg/mL (Wright and Lang-Unnasch, 2009). White et al. (2015) isolated five sesquiterpenes from nudibranch Phyllidia ocellata of Mudjimba Island and found that three of these sesquiterpenes exhibited antiplasmodial activity with IC50 values ranging from 0.26 to 0.3 μM. Studies on Callophycus serratus, a red macroalga from Fiji, led to the discovery of a brominated diterpene compound, bromophycolide A, which exhibits antiplasmodial activity with an IC50 value of 377 ± 92 nM against Dd2 strain (Stout et  al., 2011). This molecule exhibits strong activity in the erythrocytic cycle of the parasites. Okinawan sponge Acanthella sp. tricyclic isocyanoditerpenoids—­ kalihinol A, kalihinene, and 6-hydroxykalihinene—exhibit antiplasmodial activity with IC50 values of 1.2, 10, and 80 nM, respectively (Sun et al., 2009; Manivel et al., 2020).

Cyclodepsipeptides as antiplasmodial compounds Few potent cyclodepsipeptides which revealed antimalarial activity have been enlisted in Table 4. Two novel cyclodepsipeptides, lagunamides A and B, purified from the cyanobacterium Lyngbya majuscula have been reported to exhibit antiplasmodial properties with IC50 values of 0.19 and 0.91 μM, respectively. However, they show a cytotoxic effect on leukemia cell lines in nanomolar concentrations (Tripathi et al., 2010). A cyclodepsipeptide, mollemycin A isolated from a Streptomyces sp. CMBM0244, exhibited potent antiplasmodial activity against 3D7 and Dd2 strains, but it shows mild cytotoxicity in human fibroblast cells (Raju et al., 2014). Actinoramide A is a new antiplasmodial peptide composed of 4 amino acids discovered in Streptomyces bangulaensis, isolated from the Papua New Guinea Sea. It exhibits activity against Dd2, HB3, cp250, and GB4 strains and no toxicity (Cheng et al., 2015). Screening study on peptides of Streptomyces sp. RK85-270 isolated from Indonesia led to the identification of octaminomycins A and B, that exhibit

546  Natural products in vector-borne disease management

TABLE 4  Cyclodepsipeptide class of molecules. Chemical name

Organism

References

Lagunamide A Lagunamide B

Lyngbya majuscula

Tripathi et al. (2010)

Actinoramide A

Streptomyces bangulaensis

Cheng et al. (2015)

Octaminomycin A Octaminomycin B

Streptomyces sp. RK85-270

Jang et al. (2017)

Fusaripeptide A

Endophytic fungi

Ibrahim et al. (2018)

Carmaphycin B

Symploca sp.

LaMonte et al. (2017)

Apicidin F

Fusarium fujikuroi

Von Bargen et al. (2013)

LZ1

Snake cathelicidin peptide derivative

Fang et al. (2019)

Hirsutellide A

Hirsutella kobayasii BCC 1660

Vongvanich et al. (2002) and Sahile et al. (2020)

a­ ntiplasmodial activity on K1, Dd2, and 3D7 strains and they are not found to be cytotoxic (Jang et al., 2017). A novel peptide known as fusaripeptide A, isolated from an endophytic fungus associated with Mentha longifolia, has been discovered to exhibit antiplasmodial activity against the D6 strain. However, the limitation of this peptide is that it shows a cytotoxic effect in PC12 and L5178 cancer cell cultures (Ibrahim et al., 2018). Screening for antiplasmodial compounds in Symploca sp., a cyanobacterium, led to the discovery of carmaphycin B, a tripeptide of sequence l-Val-l-Met sulfone-l-Leu, which exhibits good activity at nM concentration but exhibits toxicity on HepG2 cells. To address this toxicity, a research group modified the peptide sequence to d-Vall-Nle-l-Leu, which enhanced its activity and also did not exhibit any toxicity on HepG2 cells. This peptide has been tested together with artemisinin and found to be very effective in killing Plasmodium by targeting its proteasome (LaMonte et al., 2017). Apicidins are known inhibitors of histone deacetylase enzyme. Apicidin F, isolated from Fusarium fujikuroi that causes bakanae disease in rice in Japan, exhibits antiplasmodial activity with an IC50 value of 0.67 μM. Apicidin F is composed of l-phenylalanine, d-pipecolic acid, l-tryptophan, and l-2-­ aminooctanedioic acid (Von Bargen et al., 2013). LZ1, an antimicrobial peptide, the derivative of snake cathelicidin has been reported to exhibit antiplasmodial activity. In vitro studies have shown that this peptide exhibits strong suppression against Plasmodium falciparum (IC50 value of 3.045 μM), whereas in vivo studies revealed its activity against the P. berghei strain (Fang et  al., 2019). A cyclic hexadepsipeptide compound Hirsutellide A, isolated from an insect

The management of malaria  Chapter | 22  547

pathogen fungus Hirsutella kobayasii BCC 1660 and a synthetic version of this compound, has been found to be effective as an antiplasmodial compound (Vongvanich et al., 2002; Sahile et al., 2020). Further, it did not reveal any cytotoxicity in the Vero cell line.

Natural compounds and their mosquitocidal potential Mosquito vector control strategies are the majorly employed approaches to diminish the number of malaria cases. Relatively, the above measures include conventional strategies to combat the problem of vector-borne issues through longlasting insecticidal nets, indoor residual spraying, and larvicidal application. Among all these strategies to control the population of mosquitoes, the strategy which includes the hindrance of larval breeding locations plays a chief role in the control of dreadful diseases like malaria, particularly in those specialized sites, wherein the vectors have breeding tendencies. As per WHO, larvicidal application in those breeding niches situated in urban areas protecting humans is one of the best strategies toward the population of mosquito vectors. Larvicide control measures portray an efficacious tool for vector control, restricting the spread of malaria and other dreadful mosquito-borne diseases. As per Akbarzadeh et al. (2020), fruit extracts of Citrullus colocynthis exhibited an excellent control strategy against Anopheles stephensi Liston. The extracts of Citrullus colocynthis were exploited for repellent and larvicidal actions against Anopheles stephensi. The lethal concentration value of Citrullus colocynthis was found to be 180 mg/L. The physiological examination through histopathology demonstrated the efficacy of extracts on the gut epithelial cell layer. Vacuolization of midgut columnar and foregut cuboidal cells demonstrated the larvicidal efficacy of this extract. This experiment suggested that the natural extract of Citrullus colocynthis exhibited a remarkable larvicidal property which can become an effective strategy to control malaria vector mosquitoes. In another study by Vatandoost et  al. (2018), the extract of Bunium persicum and its essential oil exhibited a significant larvicidal effect against Anopheles stephensi and there can be a great strategy to develop a bio-benign insecticide to combat malaria mosquito vector breeding. The mosquitocidal activity of aqueous and ether extracts of Leucas aspera against Anopheles stephensi was analyzed. The plant extracts were studied toward the identification of the bioactive components. This plant depicted a significant and potent larvicidal efficacy. Crude isolate or extracted bioactive plant components could be applied in stagnant water bodies and other breeding sites toward controlling the dreadful Anopheles mosquito population (Elumalai et al., 2017). The study conducted by Louis et al. (2020) showed that the extract of Persea americana has excellent larvicidal activity in the order Anopheles stephensi. A study by Okbatinsae and Haile (2017) demonstrated the larvicidal efficacy of extracts from the leaves of seven different plants, i.e., Ricinus ­communis,

548  Natural products in vector-borne disease management

Azadirachta indica, Jatropha curcas, Datura stramonium, Lantana camara, Tagetes minuta, and Eucalyptus globulus as natural larvicidal agents against Anopheles gambiae third instar larvae. Essential oils (EOs) have numerous biological actions such as larvicidal efficacy which have been recommended as new alternatives in comparison to conventional and chemical-based larvicides. Various components of EOs acquire volatile properties, by the virtue of which they retain their activity of mosquito control. Components of dill EO were studied by GC-MS analysis. The larvicidal activity of dill seed oil was formulated and evaluated against Anopheles stephensi according to WHO guidelines (Osanloo et al., 2018). A nanoemulsion containing tarragon essential oil was successfully optimized and evaluated with respect to its larvicidal efficacy. The preparation substantially improved its larvicidal effect as a nanoemulsion preparation establishing it as a very potent and efficacious agent against mosquito vectors. The thyme oil nanoemulsion and its chitosan encapsulation were observed to be constant and efficient for Anopheles stephensi 3rd instar larvae; the geometrical dimension through the TEM analysis was found to be unique flower shaped. Furthermore, chitosan-encapsulated nanoemulsion revealed controlled release of phytochemicals and exhibited a potential larvicide at lower concentrations. The insecticidal property of EOs is reliant on their chemical configuration and synergistic interactions among various molecules. Findings documented that EO activity is the consequence of their inherent biologically active constituents. Generally, EO displaying competence for larvae and adult mosquitoes is due to the availability of phytochemicals like flavonoids, terpenoids, terpenes, alkaloids, etc. The larvicidal actions of the EO can be attributed to its constituting compounds (Ali et al., 2015). Another example was limonene, carvone, and cis-carveol from Mentha spicata displayed efficacious larvicidal activity against Anopheles stephensi. Also, β-elemene and α-humulene being two main components of EOs of Syzygium zeylanicum were effective against Anopheles subpictus (Govindarajan et al., 2016). Ar-turmerone, the foremost component of Curcuma longa essential oils, presented higher and lower competencies against larvae of Anopheles quadrimaculatus (Deletre et al., 2016). According to Bossou et al. (2013), Cymbopogon schoenanthus, Cymbopogon citratus, Chenopodium ambrosioides, Eucalyptus citriodora, and Eucalyptus tereticornis are potent plant sources which tend to have applicative potentials and can be used as substitutive compounds to pyrethroids toward controlling measures of Anopheles mosquito vector control (Norris et al., 2015). The ingredients of nine medicinally important EOs including orange, peppermint, clove, dill, tarragon, Zingiber, eucalyptus, lemon, and myrtle were identified and tested for their repellent behavior against the main malaria vector, Anopheles stephensi. The highest efficiency was demonstrated via clove and eucalyptus EOs (Moemenbellah-Fard et al., 2021). As per the findings of Wangrawa et al. (2021), the Lantana camara L., Hyptis spicigera Lam, Ocimum canum, and

The management of malaria  Chapter | 22  549

Hyptis suaveolens Poit. extracts revealed blood-feeding inhibition, ­oviposition deterrence, larvicidal activities, and excitorepellences against strains of ­ Anopheles gambiae s. s. and Anopheles coluzzii. EOs extracted from four plant species like hairy basil (Ocimum americanum), citronella (Cymbopogon nardus), sweet basil (Ocimum basilicum), and vetiver (Vetiveria zizanioides) were examined for their repellent and irritant activities against Anopheles minimus, using an excitorepellent test system. Pure EOs were analyzed for their efficacy against malarial vectors keeping DEET as a positive control. The oils from hairy basil, vetiver, and citronella depicted their potency as mosquito repellent products against Anopheles minimus (Nararak et al., 2016). According to the prevailing research studies, various forms of natural molecules like solidlipid nanoparticles, liposomes, and EO nanoemulsion have been tested for their efficacy as ovicidal, larvicidal, and adulticidal agents and repellents against dreadful mosquito strains causing malaria. Another research study which demonstrates the efficacy of natural compounds toward hindrance in the Anopheles mosquito population is about two foremost constituents extracted from plant species named Origanum vulgare. The phytoconstituents namely terpinen-4-ol and carvacrol seemed to be potential larvicides against Anopheles stephensi and Anopheles subpictus, depicting the lethal concentrations at 43.27 and 47.73 mg/L, respectively (Govindarajan and Benelli, 2016). Henceforth, this becomes very evident that the use of natural compounds toward mosquito vector control becomes a bio-benign and efficacious strategy. The older and conventional form of mosquito control through the application of chemical and hazardous insecticides and larvicides needs to have a replacement with herbal and natural strategies making a green approach to mosquito control, resulting in the control of dreadful mosquito-borne diseases like malaria (Table 5).

Conclusion The sources of potent candidate molecules can be natural products, synthetic compounds, or repurposing drugs. Currently used medications to combat various diseases including malaria are naturally occurring molecules synthesized by microorganisms, plants, and algae. The amalgamation of new advanced techniques including genetic manipulation of pathogens, robotics, bioinformatics, and bioimaging has attributed to several high-performance screening platforms for the lookout for novel antiparasitic drugs. Future studies are warranted to establish the potential of individual candidate molecules from plant origin to combat malaria.

Acknowledgment The authors acknowledge the Department of Biotechnology, School of Applied Sciences, for the necessary facilities.

550  Natural products in vector-borne disease management

TABLE 5  List of plant species and their potency against Anopheles vector. Plant species

Mosquito vector

References

Cinnamomum zeylanicum

Anopheles stephensi

Bassole et al. (2003)

Ocimum canum

Anopheles gambiae s.s

Wangrawa et al. (2018)

Curcuma longa

Anopheles gambiae s.s

Deletre et al. (2016)

Juniperus macropoda

Anopheles gambiae s.s

Zhu and Tian (2013)

Ocimum basilicum

Anopheles gambiae s.s

Ntonga et al. (2014)

Pimpinella anisum

Anopheles stephensi

Mdoe et al. (2014)

Feronia limonia

Anopheles stephensi

Senthilkumar et al. (2013)

Lippia multiflora

Anopheles gambiae s.s

Kulkarni et al. (2013)

Ocimum canum

Anopheles gambiae s.s

Ntonga et al. (2014)

Bunium persicum

Anopheles stephensi

Sanei-Dehkordi et al. (2016)

Syzygium zeylanicum

Anopheles stephensi

Dharmagadda et al. (2005)

Blumea densiflora

Anopheles stephensi

Liu et al. (2013)

Curcuma zedoaria

Anopheles stephensi

Pandey et al. (2009)

Origanum vulgare

Anopheles funestus

Tiwary et al. (2007)

Mentha spicata

Anopheles stephensi

Govindarajan et al. (2016)

Nigella sativa

Anopheles stephensi

Govindarajan et al. (2016)

Foeniculum vulgare

Anopheles quadrimaculatus

Deletre et al. (2016)

Artemisia gilvescens

Anopheles quadrimaculatus

Zhu and Tian (2013)

Citrus paradisi

Anopheles arabiensis

Ntonga et al. (2014)

Ruta chalepensis

Anopheles arabiensis

Mdoe et al. (2014)

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Index Note: Page numbers followed by f indicate figures and t indicate tables.

A

Acacia Arabica, 73 Acacia auriculiformis, 312–318 Acacia catechu, 73, 296 Acetonic Rhus coriaria, 118 Achillea millefolium, 117–118 Acorn squash, 34–35 Acorus calamus, 73 Acrosiphonia orientalis (Chlorophyta), 368–369 Actinidia deliciosa, 73 ACTs. See Artemisinin-based combination therapies (ACTs) Acyranthes aspera, 312–318 Acyrthosiphon pisum, 524 Adulticidal effect, 103–104 Aedes aegypti, 53, 420 Aedes albopictus, 53 Aegle marmelos, 312–318 African bail, 39 African birch, 34 African crabwood, 40 African custard-apple, 31–32 African Mahogany, 9, 39 African peach, 41–42 African trypanosomiasis, 1 Agantu fever, 416 Agantuja roga, 434 Ajania nematoloba oil, 526–527 Albendazole (ALB), 65–66 Alchemilla vulgaris, 73 Alchornea cordifolia, 119 Aleurites moluccana, 74 Algae natural products antigens and biopharmaceuticals, 367 aquatic and photosynthetic organisms, 344 based extraction and fractions, 359–363 antimalarial capacity of Spirulina capsules, 359–362 Aphanizomenon flos aquae, 363 Chondrococcus hornemanni, 362–363 growth inhibitory activity, 363 microalgae ethanolic and methanolic, 363

Plasmodium falciparum fatty acid, 359–362 red alga Botryocladia leptopoda, 363 seaweed, 362–363 based larvicidal strategy, 368–369 dengue larva physiological alterations, 368–369 hexadecanoic acid, 369 larvicidal effect, 369 larvicidal effects, 368–369 based vaccine strategies, 363–368 therapy approach, 363 clustered regularly interspaced short palindromic repeats (CRISPR), 368 derived agents against vector bone disease, 345–359 ellagic acid and velutina, 354 extraction, 344 fight and prevention diseases, 344 and fractions, 364–366t granule-bound starch synthase (GBSS), 367 pigments, 348–353 biological systems, 348 composition and quantity, 348 extracted rich, 348 fucoxanthin carotenoid, 353 Lectins possess monomeric structures, 353 Nostoc muscorum, 348–353 phycocyanin and fucoxanthin, 348 physiological level, 348 proteins, 353–354 proteins and polyphenols, 351–352t polyphenolic molecules, 354 polysaccharides, 345–348 biological features, 347–348 brown, 345–346 Carrageenans and Agarans, 346–347 fucoidans, 346 Plasmodium falciparum, 346 potential against vector bone disease, 349–350t ulvan, 347

557

558  Index Algae natural products (Continued) recombinant system, 367 secondary metabolites, 354–359 antiplasmodial activity, 358 aplysiatoxin-related compounds, 358 cyanobacteria, 354–358 cyanobacterium, 355–357t kakeromamide B, 354–358 Lyngbya species, 358 macroalgae, 358–359, 360–361t sesquiterpene, 359 species, 363–367 sunlight and inorganic carbon sources, 344–345 Algae natural products for vector-borne diseases (VBDs) Anopheles population, 343 biological capacities, 336 characterization and context, 336–344 agents and potential treatments, 338–340t Bacillus thuringiensis, 343 blood-sucking mosquitoes, 336–337 chagas disease, 342 Human African Trypanosmiasis (HAT), 342 Japanese encephalitis, 342 Leishmaniasis, 341–342 Lymphatic filariasis, 342 mosquito-borne viral infections, 337–341 Plasmodium falciparum, 337, 341f schistosomiasis (Bilharzia), 342 tropical and subtropical conditions, 336–337 climatic change, 335 efficient and effective treatment to, 343–344 infectious diseases, 335 problem associated with, 336 treatment and therapies, 343 treatment of, 335 World Health Organization (WHO), 335 Alkaloids extraction and glycoalkaloids, 518–520 insecticidal activities of, 519t instar larvae survival, 520 Lycopersicon esculentum, 518–520 secondary metabolites, 518 Solanum tuberosum, 518–520 traditional medicines, 518 Tribolium castaneum, 518 Allelochemicals, 17–18 Allium cepa, 73, 262 Allium sativum, 296 Allium ursinum, 73

Alphaviruses Chikungunya virus, 53 Mayaro virus, 53 Alphavirus genus, 53 Alstonia boonei De Wild. See Nyame Dua Amastigote Curcuma against the promastigotes, 272t intracellular, 262–263 promastigote and, 258–259 reticulo-endothelial system, 258–259 Zingiber zerumbet, 267 Amastigotes, 125–126 Amocarzine, 66 Andrographis lineata, 312–318 Andrographis paniculata, 296–297 Andrographis paniculate, 312–318 Anethum graveolens, 526 Animal trypanosomiasis, 379–380 Annatto dye, 262–263 Annonaceae, 31–32, 382 Annona senegalensis, 31–32 Anogeissus leiocarpus isolated phenolic acids from, 35f Anopheles female mosquitoes, 337 Anopheles stephensi, 9 Anthraquinones, 542–543 Antidengue effects, 487–489 Antiinflammatory, 343–344 Antileishmanial activity Arrabidaea chica, 269–270 of Bifurcaria bifurcata, 278 Cryptocarya aschersoniana, 259 plant sources, 259, 274–275t study on, 267–268 of Valeriana jatamansi, 264–265 of Valeriana wallichii, 265 vitro study of, 269–270 Antileishmanial drugs, 281t databases towards, 140–162 LeishBase database, 141–162 identifying and prioritizing potent targets, 141–162 MODELLER, 141 proteins of, 143–161t three-dimensional structure, 141 Leish-ExP (Leishmania-Exclusive Protein) database, 140–141 genus-specific proteins, 140–141 Leishmania genus-specific proteins, 142f species-specific proteins, 140 Antimalarial activities, 489–490 aforesaid techniques, 204–205 experiments to assess, 203–205

Index 559 multiomics (metabolomics) approaches, 204–205 Peters method, 204–205 in vitro antiplasmodial assays, 203–204 Antimalarial therapeutics niosomes, 455 utilization of, 447–448 Antimicrobial peptides action of, 130f amphipathic characteristic of, 130 antileishmanial activities of, 133, 135–136t agents, 131–134, 162 assays and morphological analysis, 131 bombinins H2 and H4, 133 defensin, 134 dermaseptin family-related, 132 Drosophila cecropin A, 133 effect of, 131f Hyalophora cecropin A, 133 leishmanicidal activity of Histatin 5 (Hst5), 134 magainin analogue, 133 recombinant HNP-1 (rHNP-1), 131–132 spinigerin property, 132 of Temp-SHd peptide, 132 biosynthesis of, 130 broad spectrum activities, 127, 130–131 dermaseptin family-related, 132 limitations, 162 microbes growth, 130 nanostructured lipid carriers (NLCs), 139 overview of, 130–131 prokaryotes and eukaryotes, 130 therapeutic, 131 Antionchocerca activity Anogeissus leiocarpus, 34 of isolated compounds, 30–31 medicinal plants species with, 43–44t on Onchocerca ochengi, 34 of plant extracts, 30–31 pure natural products with, 73–74 chrysophanic acid, 74 ellagic acid, 73 gallic acid, 73 gentisic acid, 73 linoleic acid, 74 3-O-acetyl aleuritolic acid, 74 oliverine, 74 Onchocerca ochengi, 73 polycarpol, 73 polyveoline, 73–74 secondary plant metabolites with, 66

Antiplasmodial 3-alkylpyridine marine alkaloid, 208 and antifarnesyltransferase activity, 211–212 asiatic acid, 209 blood schizonticidal and, 208 Combretum racemosum, 209 curcumin, 210 Entandrophragma congoense, 209 plant family Amaryllidaceae, 208 plants and marine species with antiplasmodial activities, 206–207 Pseudelephantopus spiralis, 209 vitro assays, 203–204 vivo assays, 204–205 Antischistosomal agents antigen, 228–229 broad-spectrum efficacy, 228–229 metrifonate, 229 oxamniquine, 229–230 praziquantel (PZQ), 228–229 of synthetic origin, 228–230 Antitrypanosomiasis phytochemical against trypanosomiasis, 391 plants extraction and phytochemicals, 391 study, 382 against trypanosomiasis, 391 Antitrypanosomiasis effect, 391 Antitumor, 343–344 Antiviral drugs against arboviruses infections, 55–58 baicalein effect, 57–58 against chikungunya virus and hepatitis C virus, 56 clinical treatments, 51–52 culinary and medicinal mushrooms, 56 of curcumin, 57 development of, 51 first, 51–52 against flavivirus and alphavirus infections, 57f plant-derived, 52, 55–56 research, 55–56 Antixenosis mechanism, 517–518 Anyedushka fever, 416 Apocynaceae, 32–33, 382 Arabidopsis plants, 523 Araceae, 34 Arboviral illnesses, 1–2, 437–438 Arboviruses infection Aphloia theiformis, 56 baicalein, 57–58 curcumin, 57

560  Index Arboviruses infection (Continued) dengue virus, 55–56 ecological and diverse group, 52 flavivirus and alphavirus infections, 57f Hericium erinaceus, 56 Lignosus rhinocerotis, 56 mosquito-borne viral diseases, 55–56 natural compounds, 56 plant-derived antivirals against, 55–58 Pleurotus giganteus, 56 resveratrol, 58 Schizophyllum commune, 56 silymarin, 56 socioeconomic systems, 55–56 treatment of, 52 virus-associated morbi-mortality, 55–56 Arcangelisia flava, 117 Arctigenin, 322–323 Arctostaphylos uva-ursi, 73 Aristologenic acid, 75 Aroeirapimenteira, 260–261 Aroeira-vermelha, 260–261 Arrabidaea chica, 269–270 Artemether, 245 and artesunate, 244–245 therapeutic efficacy of, 244–245 Artemisia absinthium, 319 Artemisia annua, 245 Artemisinin arteether, 448f artelinic acid, 448f artemether, 448f artesunate, 448f artesunate analogs, 449f -based combination therapies, 203 delivery systems, 451–458 dihydroartemisinin, 448f dihydroartemisinin-cinnamic acid hybrid 14, 450f drug-resistant Plasmodium falciparum, 448–450 and hybrids, 449f pharmacokinetics, 451 artemether, 451 bioactive metabolite, 451 endoperoxide atom, 451 human cytomegalovirus (HCMV), 451 pyrrolidine-acridine-artemisinin fusion, 448–450 research, 448–450 Artesunate, 245 Arthropod-borne disease transmission, 438 Arthropod vectors, 14–15

Ascophyllum nodosum, 174 Asteraceae plants, 272 Aupasargika Rogas, 414 Ayurvedic physician, 2 Ayurvedic system Agantukaroga, 2 Janapadodhwamsa, 2 Krimi, 2 Azadirachta indica, 7–8, 260, 297

B

Babesiosis for animals, 116 blood transfusion infection, 115–116 clinical information on, 115–117 diagnosing, 116–117 hemolytic anemia, 116 malarial-like infection, 115 natural products management of, 117–121 parasitic disease, 115 prevention of, 117, 121 texas, 116 therapy course for, 116–117 transmission of, 116f treatment of, 116–117, 120 Bacillus polymyxa, 276–277 Bacopa monnieri, 73 Baeckea frutenscens, 119 Baicalein, 322–323 Banyan. See Ficus benghalensis β-Carboline alkaloids, 538–539 Berberis vulgaris, 118 Bhoota, 434 Bifurcaria bifurcata, 174, 278 Bignoniaceae, 387 Bilharzia. See Schistosomiasis Bioactive substances, 454, 456 Bitter melon. See Momordica charantia Bixa orellana, 262–263 Black Ginger. See Kaempferia parviflora Black pepper. See Piper nigrum Blue-green alga, 344 Bocageopsis pleiosperma, 73 Boerhavia diffusa, 297 Boophone disticha, 117 Boraginaceae, 387 Break-bone fever, 291–292, 417 Brimstone tree, 41 Brucea javanica, 119 Bulb onion, 262 Bushveld peacock-berry, 36

Index 561

C

Camellia sinensis, 73, 520–523 Camptotheca acuminata, 75, 520 Candidatus Neoehrlichia, 6 Canellaceae, 388 Cannabis sativa, 527–528 Carapa procera, 40f Carapichea ipecacuanha, 297 Carica papaya management of vector-borne disease anthraquinone, 484f bark of, 474f brown and yellow leaf extraction, 470 caffeic acid, 485f chloroform seed extraction of, 492 cosmetic benefits, 469 cultivation of, 471 dried flower extraction of, 470 ethnomedical, 470 female flower of, 474f fermented pulp of, 491 ferulic acid, 485f flower of, 476 fruit pulp of, 491 fruits of, 469, 479–481 global impact, 468t juice, 486 Latex of unripe fruit of, 472f leaf, 472f, 476–477, 484–486, 489f extraction of, 484–486, 489 and heartwood of, 484 juice of, 469 linoleic acid, 487f macroscopic character, 471–477 flower, 476 fruits, 476 leaves, 476 roots, 476 seeds, 477 stem, 476 male flower of, 473f management and treatment of, 468 medicinal use of, 487–492 antidengue effects, 487–489 antimalarial activity, 489–490 microscopic characters, 477 morphology of parts, 476 myristic acid, 488f n-butyric acid, 486f n-hexadecanoic acid, 486f n-hexanoic acid, 487f n-octanoic acid, 486f oleic acid, 488f

origin and distribution, 471 palmitic acid, 488f parts of, 470, 477 p-Coumaric acid, 485f pharmacognostical character, 470–477 origin and distribution, 471 phytochemistry, 477–486 β-Carotene, 480f benzyl glucosinolate, 483f benzyl isothiocyanate, 479f benzylthiourea, 481f butanoic acid, 479f caricapinoside, 478f carpaine, 483f cis-Linalool oxide, 479f cryptoxanthin, 480f fruits, 477–481 hentriacontane, 484f linoleic acid, 482f oleic acid, 482f seeds, 481 1,2,3,4-Tetrahydropyridin-3-yl-octanoate, 484f trans-Linalool oxide, 478f platelets by, 490f ripe fruit of, 473f, 479–481 roots of, 475f, 486 seeds of, 473f, 481, 491–492 single-stemmed tree, 476 stearic acid, 488f taxonomical classification of, 471 traditional medicines, 469 tree of, 475f tropical and subtropical areas, 467–468 unripe fruit of, 470, 479–481 Carlina acaulis, 527–528 Carvacryl acetate, 241 Cassia aubrevillei, 37 Castanospermum australe, 298 Catharanthus roseus, 73 Cat’s claw. See Uncaria tomentosa Centroceras clavulatum (Rhodophyta), 368–369 Ceraeochrysa claveri, 520–523 Cercaria, 225 Chagas disease, 1, 342, 492 Charak, 416 Chaturthak Visham fever, 416 Chemical ecology, 17–18 Chemotherapy treatment praziquantel, 228 schistosomiasis infection, 228 Chenopodium ambrosioides, 261

562  Index Chikungunya fever (CHIKF), 1, 5–6, 438–440, 490–491 arthropods, 1 neglected tropical diseases (NTDs), 1–2 togaviridae family, 5–6 vector-borne illnesses, 17 vector control, 1–2 Chilocarpus costatus, 272 Chlamydomonas reinhardtii, 367–369 Chondria dasyphylla (Rhodophyta), 368–369 Chorda filum, 174 Chronic papular onchodermatitis, 63 Cinchona officinalis, 534 Cinnamomum verum, 118 Cinnamomum zeylanicum, 271 Citrullus colocynthis, 9 Citrus aurantium, 73 Citrus grandis, 117 Citrus limon, 73 Citrus sinensis, 73 Cocculus hirsutus, 312–318 Coleus aromatics, 319 Colpomenia peregrine, 174 Combretaceae, 34 Coneflowers. See Echinacea Controlled release nanotechnology advantages, 502–505 biological and environmental adverse risks, 502 evaporation and degradation, 502 nanoemulsion, 505 Conventional drugs, 65–66 Corylus avellana, 73 Cow-foot leaf, 40–41 Cryptocarya aschersoniana, 259 Cryptolepis sanguinolenta, 119 Cucurbitaceae, 34–35 Cucurbita pepo ovifera var ovifera. See Acorn squash Culex annulirostris, 9 Culex quinquefasciatus, 9–10 Culex tritaeniorhynchus, 309–312 essential oils against, 319 Habenaria plantaginea, 318–319 JE vector, 313–317t larva of, 312–318 larvicidal potency against, 320–321t mosquito vector, 309–311 plant extraction and essential oils, 312–318 Curcuma longa. See Curcumin Curcuma xanthorrhiza, 119 Curcuma zedoaria, 118 Curcumin, 271, 298, 322–323

Curcuma longa rhizomes, 237–238 schistosomicidal activity, 237–238 treatment, 237–238 vitro study, 237–238 Cutaneous leishmaniasis (CL), 126–127 Cyclodepsipeptides, 545–547 as antiplasmodial compounds, 545–547 apicidins, 546–547 class of molecules, 546t Cymbopogon winterianus, 8 Cyperaceae, 35 Cyperus articulatus, 74 Cyperus rotundus, 74 Cystoseira baccata, 174, 278–279 Cystoseira tamariscifolia, 174

D

DDT. See Dichloro-diphenyl-trichloroethane Delivery systems, artemisinin liposomes, 453–454 blood-circulation, 454 ethosomes, 455 inorganic-based nanoparticles, 458 lipid-based nanoparticles, 456–457 malaria prevention and treatment, 453–454 nanocapsules, 454 nanoformulations for the treatment of malaria, 459–460t niosomes, 455 polymer-based nanoparticles, 457–458 solid lipid nanoparticle, 455–456 micelles, 453 artesunate-heparin conjugate (ART-HEP), 453 micelles, liposomes and polymeric nanocapsules, 453f polymer-drug conjugates, 451–453 biodegradable polymeric support, 451–453 drug and polymers, 452f medication, 451–453 soluble antimicrobial drugs, 451–453 Dendritic cells, 309–311 Dengue fever (DF), 5 Aedes aegypti mosquito, 293–295 anisuan, 297 Azadirachta indica, 297 Boerhavia diffusa, 297 Carapichea ipecacuanha, 297 Castanospermum australe, 298 Curcuma longa, 298

Index 563 antibody-dependent enhancement (ADE), 292 antiviral medicines against, 296 arboviral diseases, 292–293 arboviral illnesses, 1–2 ayurvedic medications, 296 cases of, 292–293 clinical sign of, 293 COVID-19 and DF epidemics, 292–293 echinacea, 298 Glycyrrhiza glabra, 298 Kaempferia parviflora, 298 Mimosa scabrella, 298–299 Momordica charantia, 299 Myrtopsis corymbosa, 299 epidemiology, 292–293 female mosquito, 293–295 genome of, 291 hemorrhagic fever, 292 infections of, 292–293 management of, 295 medicinal plants, 292 growing of, 292 mosquito-borne disease, 291–292 papaya leaves, 299 pathophysiology of fever, 293 pippli Uncaria tomentosa, 300 Zostera marina, 300 plant species, 296–300 Acacia catechu, 296 Allium sativum, 296 Andrographis paniculata, 296–297 plasma and protein, 293 risk of, 292 single-stranded positive-sense RNA virus, 291 symptoms of, 293, 294f traditional medicine system, 292 transmission of, 293–295 treatment of, 16, 292, 295 vector-borne diseases, 1–2 vector-borne illnesses, 17 virus infection, 293 World Health Organization (WHO), 292 Zostera marina, 300 Dengue virus, 54 Depigmentation, 63 Desakala Atma, 434 Diarylheptanoid, 237–238 Dichloro-diphenyl-trichloroethane, 203 Dictyota caribaea, 174–175 Dictyota dichotoma, 174

Dictyota spiralis, 279 Didymellaceae, 388 Dihydroartemisinin, 245 Dinitrohinokinin, 246 Diospyros gracilescens, 272–273 Discoglypremna caloneura, 37f, 74 Disease management, 82 Disturb membrane fluidity, 76 Doxycycline, 27–28 Drosophila melanogaster, 518–520 Drug delivery, 447–448, 455 Drug resistance, 533 Dryopteris species, 235 Dysphania ambrosioides, 527–528

E

East African mahogany, 270 Echinacea, 298 Eclipta prostrata, 312–318 Ectoparasite vector control, 16 Eelgrass, 300 Eflornithine, 381–382 Egossa red pear, 36 Elephantorrhiza elephantina, 118 EONEms on vector-borne diseases active constituents and mode of action, 97–100t Adulticidal effect, 103–104 antiparasite, 101–102 insecticide, 96–101 Larvicidal effect, 102–103 plants against vector, 101f repellent, 101 role against acari, 102 role against mosquitoes, 102–104 EPSs. See Exocellular polysaccharides (EPSs) Eremanthus elaeagnus, 240–241 Ervatamia heyneana, 75 Essential oils (EOs), 89–91, 505, 526–528 applications of, 90–91 act as hepatoprotective negotiators, 90 efficiency of, 90–91 in medicinal industry, 90 pre- and postharvest phytophagous insects control, 90–91 source and uses of, 92–93t aromatic plants, 90 chemical composition of, 90 chief constituents in, 526 distillation methods, 90 effectiveness of, 527–528 evaporation of, 502

564  Index Essential oils (EOs) (Continued) larvicidal activity in, 527–528 nanoemulsion, 96, 505–507 secretory plant structures, 89–90 study in, 526–527 therapeutical and energetic effects, 89–90 treatment, 526–527 Ethosomes, 455 Eugenia caryophyllus, 117 Eugenia jambolana, 73 Euphorbiaceae, 36 Euphorbia peplus, 269 Exocellular polysaccharides (EPSs), 345–346

F

Fabaceae, 37, 388 Ficus benghalensis, 10 Filariasis, 5, 491 Flacourtiaceae, 39 Flacourtia indica, 73 Flaviviruses, 53–55 dengue virus, 54 hematophagous mosquito vectors, 53–54 Japanese encephalitis virus (JEV), 55 polipoprotein, 53–54 threat of, 53–54 West Nile virus (WNV), 55 Zika virus, 54 Flavonoids management of schistosomiasis, 239t, 240f phytochemicals, 238 Styrax species, 238 Flea-borne diseases, 87 Fly-borne diseases, 86–87 Foeniculum vulgare, 526–527 Food-grade nanoparticles, 16 Francisella tularensis, 6 Fucoxanthin carotenoid, 353 Fucus ceranoides, 174 Fucus serratus, 174 Fucus spiralis, 174 Fucus vesiculosus, 174 Furanoquinolin alkaloids, 75 Fusaripeptide A, 545–546

G

Gamma-aminobutyric acid (GABA), 90–91 Ganna, 37 Garcia parviflora, 74 Garcinia benthamiana, 118 Gentiana lutea, 73 Glycyrrhiza glabra, 298

Google Scholar, 31 Gramineae, 388 Great basil, 9 Greenwayodendron oliveri, 73–74 Guazuma ulmifolia, 268

H

Haemagogus janthinomys, 53 Halidrys siliquosa, 174 Harmonia axyridis, 526–527 Hazomalania voyronii, 527–528 Helianthus tuberosus, 73 Heracleum sprengelianum, 319 Herbal formulation for management of trypanosomiasis, 402–403t Hibiscus rosa-sinensis, 73 Himanthalia elongate, 174 Hoehne. See Mimosa scabrella Holoptelea integrifolia, 312–318 Homalium africanum, 39 Human African Trypanosmiasis (HAT), 1–2, 335, 342 Human American trypanosomiasis, 335 Human babesiosis, 115 Human health BM86-based vaccines, 15–16 climate change, 15 infectious diseases, 15 Human leishmaniasis, 335 Human trypanosomiasis, 379–380 Hymenocardiaceae, 388 Hymenodictyon orixense, 318–319

I

Icaridin, 17 Idoxuridine, 51–52 Iindriyopasamaha, 434 Indian Valerian, 264–265 Indoor residual spraying (IRS), 202 Infectious diseases approved drugs, 51–52 dosage and therapeutic regimen, 51–52 drug development, 51 Food and Drug Administration (FDA), 51–52 in human, 51–52 idoxuridine drug, 51–52 toxic effects, 51 virus structure, 51 Inflammatory cytokine, 63 Inorganic-based nanoparticles, 458 Insecticide-treated nets (ITNs), 202

Index 565 Insects chemical-based insecticides, 517–518 ecological balance of ecosystem, 517 resistance and adaptation to secondary metabolites, 517–518 types of, 517 Intraerythrocytic parasites, 116 Ipecac. See Carapichea ipecacuanha IRS. See Indoor residual spraying (IRS) Isolated antimalarial compounds alkylation, 205 cytokine storm, 205 DNA intercalation, 205 fatty acid biosynthesis (FAS II), 206 heme polymerization, 205 hemozoin’s biocrystallization, 205 histone deacetylases, 205 ionic homeostasis and signaling pathways, 205 malaria transmission blocking, 205 mitotic spindles, 205 myoinositol and R-glutamine influx, 205 from natural products, 205–206 organelle apicoplast, 205 parasite’s electron transport chain, 205 proteolytic processing, 205 reactive oxygen species (ROS), 205 ITN. See Insecticide-treated nets (ITNs) Ivermectin-albendazole, 65–66 Ivermectin-diethylcarbamazine-albendazole, 66 Ivermectin drug, 27–28, 30, 65

J

Japanese encephalitis (JE), 1, 6, 335, 342, 491–492 clinical symptoms, 311 dengue and yellow fever, 309–311 entry, replication, maturation, and release of, 327f identify potential inhibitors, 319 inflammation and neurological deficits, 309–311 mouse-brain-derived vaccine, 311 natural compounds against, 311–312 natural products against, 311–312 pathogenic pathway of, 310f pharmacotherapy, 311 plant-derived products, 311–312 plant extraction, 311–312 preventative and therapeutic, 322–323 replicon-based vaccines, 311 vaccination, 311 viral encephalitis, 309–311

Japanese encephalitis virus (JEV), 55 Jesuit’s tea, 261 Juice, 486 Jwara (fever), 414

K

Kaempferia parviflora, 298 Kala-azar, 126–127, 257–258 Kalmegh. See Andrographis paniculata Keratinocytes, 309–311 Khaya anthotheca. See East African mahogany Khaya senegalensis. See Khaya wood Khaya wood, 9 Kushta (leprosy), 414

L

Lamiaceae, 39, 388–389 Laminaria digitata, 174 Lansium domesticum (Langsat), 10, 118 Larvicidal effect, 102–103, 369 Lasioderma serricorne, 526–527 Lauraceae, 389 Laurencia microcladia, 174–175 Laurencia viridis, 279 Lavandula angustifolia, 8 Leathesia difformis, 174 Leguminosae, 389 Leishmamia genus specific proteins, 140 Leishmania amazonensis, 262–263 Leishmaniasis Allium cepa, 262f amazonensis and Leishmania guyanensis, 259 antileishmanial activity, 175 ascaridole chemical structure, 261f Asteraceae, 273f atomaric acid and its methyl ester, 280f bifurcatriol, 278f Bixa orellana, 264 braziliensis and infantum, 268 cases, 127–128 Chlorophyta marine macro-algae, 176–178 co-infection with HIV, 127–128 diagnosing, 127 disease transmission, 172–173 donovani infections, 257–258, 270, 272, 272t drugs, 128–130 AmBisome, 128–129 amphotericin B and miltefosine, 129f antileishmanial, 128, 128f Leishmaniasis (Continued)

566  Index availability of, 129 miltefosine, 129 drugs-loaded nanocarrier systems as antileishmanial agents, 138–140 antileishmanial activity, 138 carbohydrate-functionalized PLGA, 138–139 ligand-incorporated liposomes, 138 liposomes-encapsulated drugs, 138 metallic and metal oxide nanoparticles, 139 nanostructured lipid carriers (NLCs), 139 nanotubes, 140 plylactide-co-glycolide (PLGA), 138–139 polymeric nanoparticles, 138–139 silver nanoparticles (AgNPs), 139 slid lipid-based nanoparticles (SLNs), 139 essential oil act, 267–268 female parasitic worm, 257–258 harzialactone A, 280f human immunodeficiency virus (HIV), 127–128 inhibitory potential versus visceral, 176 ishwarane, 263f life cycle of, 258–259, 258f lupeol, betulin, sterols, and betulinic acid, 273f marine environment, 281t monoterpenes, diterpenes, and sesquiterpenes, 267f nanotechnology-based treatment of, 134–140 andrographolide, 137 bacopasaponin-C, 137 β-arboline alkaloids, 137 nanoformulation-based delivery systems, 134 phytocompounds-based nanoformulation as antileishmanial agents, 134–137 piperine, 137 quercetin, 134–137 saponins, 137 natural oxasqualenoid metabolites compounds, 280f natural products in, 259–280 Azadirachta indica, 260 biological activity and chemical composition, 259 Cryptocarya aschersoniana, 259 Leishmania parasites, 261–262 Leishmania tropica promastigotes, 261–262

Libidibia ferrea against the Leishmaniasis major, 259 medicinal purposes, 259 plants against Leishmaniasis, 259 paenidigyamycin A, 277f Phylum Porifera, 179–180 reduction of, 129–130 risk factors, 127 shedding the light on, 172–173 sources of, 257–258 spiralyde A, 279f staurosporine, 277f study of, 171 Tetradenia riparia, 265–266 therapeutic approaches versus, 172–173 treatment of, 128–129, 140 types of, 126–127, 172–173 Valeriana jatamansi, 266t vector-borne protozoan diseases, 125–126 visceral, 172–173 in vitro and in vivo antileishmanial activity, 274–275t World Health Organization report, 127–128 Libidibia ferrea, 259 Licorice. See Glycyrrhiza glabra Limonene epoxide, 241 Lipid-based nanoparticles, 456–457 Lipid envelope, 51 Liposomes, 453–454 Liriomyza trifolii, 520–523 Lobophora variegate, 174–175 Loganiaceae, 389 Lycopersicon esculentum, 518–520 Lyme disease, 1 Lymphatic filariasis, 1, 5, 342

M

Macrocyclic alkaloids, 535–538 actinoramide A, 545 Ancistrocladus tectorius plant, 538 anthraquinones, 542–543 antiplasmodial activity, 543–544 Aspidosperma olivaceum, 538–539 Aspidosperma parvifolium, 538–539 chloroquine-resistant and -sensitive strains, 540 cyclodepsipeptides as antiplasmodial compounds, 545–547, 546t cytotoxic effect on Vero cells, 544 Dacryodes edulis, 540 Garcinia species, 541 Greenwayodendron suaveolens, 538–539 HB3 and Dd2 strains, 541–542

Index 567 histone deacetylase enzyme, 546–547 Hypericum lanceolatum, 541 hyrtiosulawesine, 539 macrolides, 543–544, 543t Mbandakamine A and Mbandakamine B, 538 natural compounds, 547–549 phloroglucinols, 541–542 piperidine alkaloids and phenol derivatives, 539–540 plant husk of Garcinia mangostana, 541 purified alkaloids, 539 pyrroles, 540–541 quinolines, 535–538 quinones, 542 South American folkloric medicinal plant, 540 subclasses of macrocyclic alkaloids, 536–537t terpenes, 544–545, 545t xanthones, 541 Macrolides, 543–544 Magnolia salicifolia, 10–11 Malaria Anopheles mosquito vector, 202, 212 antimalarial drugs, 534f artemether and lumefantrine, 202 bioactive metabolites, 188f Caledonian sponge, 187 causal vector of, 102–103 chemotherapeutic agents, 203 first-generation natural products against, 534–535 genetic malfunction, 203 immune-potentiating strategy, 202 indoor residual spraying (IRS), 202 infection, 183–184, 202 insecticide-treated nets (ITNs), 202 life-threatening protozoan disease, 82 malarial vectors, 533 marine organisms antimalarial activity, 185–187 microbial-derived natural products, 212 mosquitos of Anopheles species, 86 nanomedicines, 16 parasites, 201–202 Plasmodium falciparum, 533 red blood cell (RBC), 202 shedding the light on, 183–185 synthetic agents, 202 transmission blocking activity, 212 treatment for, 533 utilization of insecticides, 183–184 vector-borne diseases, 1, 5–6, 82, 201

vector management program, 88–89 vector of avian, 102–103 visceral leishmaniasis, 172–173 war against, 7–8 World Health Organization (WHO) report, 201 Malaria (Vishama Jvara), 415–416 consequences, 416 intervention/approaches, 416 symptoms, 416 Malaria, delivery of artemisinin cervical malignancy and, 448–450 drugs, 453–454 nanoformulations for the treatment of, 459–460t prevention, 453–454 resistance against, 451–453 treatment, 447–448, 453, 455 Malus domestica, 73 Management of vector-borne diseases climate change effect, 88 health threats, 88 indoor spraying, 88–89 insecticides selection, 88–89 integrated vector management (IVM) system, 88–89 prevention of vectors and, 88–89 public health policy, 88 in tropical and subtropical regions, 88 vector control program, 89 World Health Organization (WHO) report, 88–89 Marine algae collection and examining, 171–172 eukaryotic photosynthetic organisms, 171–172 marine invertebrates, 172 phytochemical against trypanosomiasis, 391 phyto-constituents against trypanosomiasis, 392–395t phyto-constituents effects, 396f plants against trypanosomiasis, 391, 399–401t Marine-derived antimalarial agents alkaloids, 207–208 3-alkylpyridine marine alkaloid, 208 Cinchona species, 207 lycorane alkaloid compounds, 208 malaria patent and research articles, 206 marine organisms and endophytic fungi, 206 phenolic compounds, 209–211 Alpinia galanga, 211–212 ANKA-infected mice, 209–210

568  Index Marine-derived antimalarial agents (Continued) antimalarial efficacy, 210 cryptolepine, 211 curcumin-loaded eudragit-nutriosomes, 210 curcuminoid compound, 210 eucomic acid, 211 methyl gallate, 211 Moorea producens, 211–212 thiaplidiaquinones A and B, 211–212 plant and, 206–212 plants and marine species, 206–207 Buxus sempervirens, 207 Dichroea febrifuga, 207 licorice phytosomes, 206–207 medicinal plants with antimalarial activity, 207 terpenes and terpenoids, 208–209 African traditional medicine, 209 Artemisia genus, 208 artemisinin, 208 artimisone-self-microemulsifying drug delivery system, 208 Entandrophragma congoense, 209 Ghana’s folklore medicine, 208 lanostane triterpenes, 209 Spongia lamella, 209 traditional Chinese medicine (TCM), 208 ursane-type pentacyclic triterpenoids, 209 Zhumeria majdae, 209 Marine invertebrates Carijoa riisei, 180–181 Carijoa riisei octocoral, 180–181 Dragmaxia anomala hexane, 179–180 Haliclona species butanol fraction, 179–180 Heterogorgia uatumani, 180–181 Ircina campana methanol, 180 Macrorhynchia philippina, 180–181 Phylum Arthropoda, 182 Phylum Chordata, 181 Phylum Cnidaria, 180–181 Phylum Echinodermata, 182–183 Phylum Ectoprocta, 183 Phylum Mollusca, 182 Phylum Porifera, 179–180 steroidal compound, 180–181 subphylum Tunicata, 181 tunicate-derived molecules, 181 Marine organisms with antimalarial activity, 185–187 antimalarial activity versus chloroquineresistant, 187

with antitrypanosomal activity, 189–191 Agelas species, 189–191 12-deoxyascididemnin, 189–191 Paenibacillus polymyxa, 189–191 Plakortis angulospiculatus, 189–191 Spongia species and Ircinia species, 189–191 Axinella cannabina, 185 bioactive metabolites with promising antimalarial activity, 188f with promising antitrypanosomal activity, 192f cyanobacterium Moorea producens, 187 Haliclona sponge, 185–186 Hyrtios sponge, 187 manzamines, 185–186 natural products, 171 Plakortis halichondroides, 186 Plasmodium falciparum strain, 185–186 reservoir of bioactive natural agents, 171 Schizothrix species, 187 vector-borne diseases, 172f Marine sources, 280 Mayaro fever, 53 Medicago truncatula, 524 Medicinal plant as antileishmanial compounds, 162 with antionchocerca activity, 43–44t DNV (dengue virus) and mosquito repellents, 292 extraction, 139 growing of, 292 onchocerciasis treatment, 27–28, 31 traditional and phytochemicals, 381–382 treatment sources, 296 Medicinal plant for management of Onchocerciasis blindness, cause of, 27–28 clinical manifestation Erisipela de la Costa, 29 Mal Morando, 29 Sowda, 29 diagnosing of, 29 doxycycline, 30 ivermectin effectiveness of, 30 resistance in, 30 treatment of, 27–28 Onchocerca volvulus, 27–28 plants for treatment, 31–42 Annonaceae, 31–32 Annona senegalensis Persoon, 31–32 antionchocerca activities, 38f

Index 569 Apocynaceae, 32–33 Araceae, 34 Carapa procera, 40f Combretaceae, 34 Cucurbitaceae, 34–35 Cyperaceae, 35 Euphorbiaceae, 36 Fabaceae, 37 Flacourtiaceae, 39 isolated phenolic acids, 35f Lamiaceae, 39 medicinal plants species, 43–44t Meliaceae, 39–40 3-O-acetyl aleuritolic acid, 37f oliverine and polycarpol, chemical structure of, 32f Onchocerca gutturosa, 31 Piperaceae, 40–41 Rubiaceae, 41–42 Sapotaceae, 42 Verbenaceae, 42 voacangine and voacamine, chemical structure of, 33f treatment of, 30 Melarsoprol, 381–382 Meliaceae, 39–40, 389 Menispermaceae, 389 Mentha longifolia, 527–528 Mentha piperita L, 8 Mentha villosa oil, 241 Methyl ester, 279–280 Metrifonate, 229 Mexican tea, 261 Micelles, 453 Microfilariae worms, 63 Microscopic characters, 477 Millettia thonningii, 238 Mimosa scabrella, 298–299 Miscellaneous compounds, 246 Modern vector control biochemical strategies, 3 biological control agents, 3 insect traps, 3 repellents, 3 Momordica charantia, 73, 299 Monocytes, 309–311 Moreton Bay Chestnut. See Castanospermum australe Morinda citrifolia, 268–269 Morinda lucida, 41 Mosquito-borne diseases, 86, 438 Mostuea brunonis, 75 Moxidectin, 65

Mucocutaneous leishmaniasis (MCL), 126–127 Myrtaceae, 389 Myrtopsis corymbosa, 299

N

Nanocapsules, 454 Nanoemulsion of plant derived repellents advantages, 505 as carrier of essential oils (EOs), 505–507 characterization of, 507–508 Dynamic Light Scattering (DLS), 508 microscopy, 508 TEM morphology, 508 Zeta potential, 507–508 development of, 505 formulations-based on repellents, 505 hypothetical pseudoternary, 506f kinetically stable systems, 505 low-energy and high-energy techniques, 506–507 low-energy methods, 506–507 in malaria control, 510–511 nanoemulsion-based neem oil formulations, 510–511 medical application, 500 micrographs of, 509f microscopy, 508 preparation, 506–507, 507f high- and low-energy are the principal methods, 506 low-energy methods, 506–507, 507f stability of, 508–510 homogenous system, 508–510 organogel-based, 510 physical, 510 structure of, 505 technology, 505 typical structure of, 505 Zeta potential, 507–508 Nanoemulsions (NEms) advantages over, 91–94 category bi-continuous, 91 multiemulsion or mixed system, 91 oil in water (O/W), 91 water in oil (W/O), 91 components of, 94 emulsifier and immiscible liquids, 94 functional and nutritional viewpoints, 94 droplet size of, 91–94 environment-friendly oil, 89

570  Index Nanoemulsions (NEms) (Continued) EONEms on vector-borne diseases, 96–104 active constituents and mode of action, 97–100t adulticidal effect, 103–104 antiparasite role, 101–102 components of, 96 green technology, 104 insecticide role, 96–101 larvicidal effect, 102–103 repellent role, 101 research and development of nanoscience, 105 role against acari, 102 role against mosquitoes, 102–104 stability of, 104–105 essential oil, 96 formation of, 94 high-energy method or low-energy method, 94–95 high-pressure valve homogenization technique, 94–95 mechanical devices, 95–96 methods and preparation, 94–96 microfluidization technique, 94–95 nanoformulated extraction, 101f preparation techniques, 95f properties of, 91–94 ultrasonic method, 94–95 Nanomaterials as artemisinin delivery anticancer activity, 451 delivery systems loaded with, 451–458 derivatives and hybrids, 448–450, 448–450f free medication, 451–453 free radicles of, 451 hydrophilic property, 454 integration of, 451–453 liposomes, 453–454 pyrrolidine-acridine fusion, 448–450 synergistic effect of, 454 treatment of malaria, 459–460t utilization of, 447–448 Nanotubes, 140 Natural compounds Anopheles vector, 550t chitosan encapsulation, 547–548 fruit extraction, 547 larvicidal application, 547 and mosquitocidal potential, 547–549 physiological examination, 547 plant extraction, 547 plant leaf, 547–548 plant sources, 548–549

prevailing research study, 548–549 vector-borne issues, 547 Natural plant products, 75 Natural products antimalarial compounds from, 206–212 blocking activity, 212 drug discovery, 257–258 Hydrodictyon africanum, 74 malaria therapy, 202 with malaria transmission blocking activity, 212 management of Leishmaniasis, 259–280 marine, 273–276 from marine organisms, 171 Matricaria discoidea, 74 microbial-derived, 212 oil filaricidal activity, 74–75 Onchocerca ochengi, 74–75 plant-derived, 212 safety and toxicity profiles, 74–75 terrestrial plants, utilization of, 171 traditional medicine, 206 in vector-borne diseases adult, 1–2 Ayurveda, 2 cutting-edge, 1–2 deaths from, 1–2 food-based nanoparticles, 16 global response, 14 improvement of, 14 knowledge gaps in, 17–18 in low- and middle-income nations, 1 and management, 5–6 neglected tropical diseases (NTDs), 1–2 parasites, 13 prevalence of, 14–15 social health, 14–15 social injustices, 14–15 synthetic drugs for, 4t types and causative agents, 7t vector control, 14 World Health Organization guidelines for, 14 young, 1–2 in vector-borne diseases management Allium sativum, 8–9 citronella oil, 8 Citrullus colocynthis, 9 Dysoxylum malabaricum, 9 Ficus benghalensis, 10 Khaya senegalensis, 9 Lansium domesticum, 10 lavender oil, 8

Index 571 Magnolia salicifolia, 10–11 Microcos paniculata, 11 Moschosma polystachyum, 10 neem oil, 7–8 Ocimum basilicum, 9 Ocimum sanctum, 10 peppermint oil, 8 Piper longum, 11 Pisonia alba, 12 plant-derived secondary components, 7 Terminalia chebula, 12 Triphyophyllum peltatum, 11 Natural products in management of babesiosis Acetonic Rhus coriaria, 118 Achillea millefolium, 117 Alchornea cordifolia, 119 antibabesial drug development, 120t Arcangelisia flava, 117 Artemisia annua, 120 Babesia canis, 118 Babesia microti, 118 Babesia species, 118 Baeckea frutenscens, 119 Boophone disticha, 117 Brucea javanica, 119–120 Cinnamomum verum, 118 Citrus grandis, 117 Cryptolepis sanguinolenta, 119 Curcuma xanthorrhiza, 119 Curcuma zedoaria, 118 Elephantorrhiza elephantina, 118 Eugenia caryophyllus, 117 Garcinia benthamiana, 118 Lansium domesticum, 118 Laurus nobilis, 120 Peronema canescens, 118 Polygonum cuspidatum, 119 Scutellaria baicalensis, 119 Strychnos lucida, 119 Swietenia macrophylla, 119–120 use of nanotechnology, 120–121 Viola tricolor, 118 of Onchocerciasis black flies, 64 conventional drugs and resistance, 65–66 amocarzine, 66 ivermectin, 65 ivermectin-albendazole, 65–66 ivermectin-diethylcarbamazinealbendazole, 66 moxidectin, 65

Streptomyces avermitilis, 65 genus Simulium, 63–64 inflammatory process, 63 microfilariae worms, 63 parasitic worm, 63–64 total blindness and skin infection, 64 Nauclea latifolia Smith. See African peach Neem. See Azadirachta indica Neglected tropical diseases (NTDs), 1–2, 201, 336 amastigotes, 125–126 bilharzias, 224 causes, 125–126 Global Network for, 125 infections of parasitic agents, 223 parasitic neglected disease, 224 promastigotes, 125–126 research, 125 schistosomiasis, 223–224 treatment and preventive strategies, 125 Trematoda genus Schistosoma, 224 World Health Organization (WHO) record, 223 Nerolidol, 246 Netrabhishyanda (conjunctivitis), 414 Nifurtimox, 381–382 Niosomes, 455 NTDs. See also Neglected tropical diseases (NTDs) Nucleic acid, 51 Nyame Dua, 33 Nyame kyin-God’s umbrella, 34

O

Obligate intracellular pathogens, 51 Obophora variegate (Phaeophyceae), 368–369 Ocimum basilicum, 9 Ocimum canum Sims, 312–318 Ocimum sanctum, 10 Odor receptor neurons (ORNs), 442–443 Oenothera biennis, 73 Olea europaea, 73 Olyalthia suaveolens, 73–74 Onchocerca gutturosa, 74 Onchocercal atrophy, 63 Onchocerca ochengi, 28, 31–32, 34, 73 Onchocerca volvulus, 27–28, 63–64 arthropod-borne roundworm, 28 Euphorbia hirta, 36 female black fly, 29 human and vector host, 64f immature microfilaria, 65

572  Index Onchocerca volvulus (Continued) infection, 28, 65 life cycle of, 28–29 male and female worms, 28 Onchocerca ochengi, 34 onchocerca, treatment of, 65 Onchocercidae family, 28 Pachypodanthium staudtii, 74 Polyalthia suaveolens, 31 Rauvolfia plant root, 32–33 Similium blackfly, 28 Onchocerciasis, 1–2 Onchocercomas, 27–28 Onychopetalum amazonicum, 73 Origanum syriacum, 527–528 Origanum vulgare, 271, 319 ORNs. See Odor receptor neurons (ORNs) Oviposition trap, 3 Ovitrap. See Oviposition trap Oxamniquine, 229–230

P

Pachypodanthium staudtii, 74 Padina tetrastromatica (Phaeophyceae), 368–369 Paenibacillus polymyxa. See Bacillus polymyxa Papal. See Piper longum Papaya. See Carica papaya Parasite’s larval. See Cercaria Pathophysiology body’s defensive system, 227 chronic and prolonged disease, 226–227 immune pathological reactions, 227 liver ascites and esophageal varices, 227–228 proteolytic enzymes, 226–227 pulmonary schistosomiasis, 226–227 schistosome eggs, 227 symptoms of chronic schistosomiasis, 226–227 ultrasound, 227–228 urogenital schistosomiasis, 227 Pelvetia canaliculatam, 174 Penicillium patulum, 73 Pentamidine, 381–382 Pentavalent antimonial, 343 Peppercorn, 260 Peronema canescens, 118 Persea americana, 73 Pheasant-berry, 36 Phenol derivatives, 539–540

Phenolic compounds with antionchocerca properties oil, alkaloids and triterpenoids, 67–72t Phenolics acids, 34 Phloroglucinols, 541–542 Phyllanthus emblica, 73 Phylum Arthropoda, 182 Phylum Chordata, 181 Phylum Cnidaria, 180–181 Phylum Echinodermata, 182–183 Phylum Ectoprocta, 183 Phylum Mollusca, 182 Phylum Porifera, 179–180 Phytochemicals antitrypanosomiasis effect, 391 traditional medicinal plants and, 381–382 Phytochemistry, 477–486 Piliostigma thonningii, 271–272 Pimpinella anisum, 297, 526–528 Piperaceae, 40–41 Piperazine, 456–457 Piperidine alkaloids, 539–540 Piper longum, 11, 299 Piper nigrum, 260 Pippli, 299 Plant and marine-derived antimalarial agents, 206–212 Plant-derived agents antiviral activity of and action, 319–323 antiviral properties of phytochemicals, 319 baicalein, 322–323 immunofluorescence (IFA)-based, 322–323 luteolin, 322–323 ubiquitin-proteasome system, 322–323 Plant-derived mosquito repellents, 501–502 Plant-derived repellents for mosquito-borne malaria advantages, 505 age group, 499 Anopheles mosquitoes, 502 applicability and suitability of, 500 bites protection, 501 chemical formulations of, 500 efficacy of, 503–504t fatal mosquito-borne disease, 499 mosquito repellents, 501–502, 503–504t prevention, 500–502 protection, 501 repellents based-plants, 500 research on, 500 synthetic and plant-derived forms, 501 volatile organic compound mixtures, 500

Index 573 Plant sources chemical constituents, 273 against Leishmaniasis, 259 Plasmodium berghei, 367 Plasmodium falciparum, 337, 367 artelinic acid-choline derivative (AD), 454 curcuminoids-loaded SLNs, 456 development of, 451–453 drug-resistant, 448–450 FcB1 and 3D7 variant of, 448–450 micelles, 453 niosomes, 455 vivo testing on, 457–458 Plumbagin, 264 Polyalthia suaveolens, 73–74 oliverine, 32f polycarpol, 32f Polygonum cuspidatum, 119 Polygpnum cuspidatum, 74 Polymer-based nanoparticles, 457–458 Polymer-drug conjugates, 451–453 Polymerization of structural protein, 75–76 tubulin into microtubules, 75–76 Polyporus tumulosus, 73 Prajnaparadha, 434 Praziquantel oxamniquine, 229–230 schistosomiasis treatment, 228 strains of schistosomiasis, 229 Praziquantel (PZQ), 228–229 Promastigote Cryptocarya aschersoniana, 259 Curcuma against, 272t Leishmania amazonensis, 262–263 Leishmania tropica, 261–262 Promastigotes, 125–126 Prostephanus truncates, 527–528 Protein coat, 51 Ptaquiloside, 75 Pterocarpus santalinus, 73 PubMed, 31 Punarnava. See Boerhavia diffusa Punica granatum, 73 Pylaiella littoralis, 174 Pyrroles, 540–541 Pyrrolizidine alkaloids, 75

Q

Quinolines, 535–538 Quinones, 542

R

Rauvolfia vomitoria, 32–33 Repurposing drugs, 549 Rheum officinale, 74 Rickettsia felis, 6 River blindness, 63. See also Onchocerciasis Rosmarinic acid, 322–323 Rotundifolone, 241 Rubiaceae, 41–42, 390 Rubus fruticosus, 73 Rutaceae, 390

S

Saccorhiza polyschides, 174 Sadvrittasyanuvartanam, 434 Sandfly fever, 7t Santant Vishama fever, 416 Saponins, 524 Sapotaceae, 42 Sargassum heterophyllum, 353 Sargassum muticum, 174 Sargassum swartzii (Phaeophyta), 368–369 Sargassum wightii (Phaeophyceae), 368–369 Saxifraga spinulosa, 118 Schinus terebinthifolia, 260–261 Schistosoma guineensis, 225 Schistosoma haematobium, 225 Schistosoma intercalatum, 225 Schistosoma japonicum, 225 Schistosoma life cycle, 226f Schistosoma mansoni, 225 Schistosoma mekongi, 225 Schistosomiasis, 1, 87 alkaloids, 232–235 alkamides, 232–235 Allium sativum, 232 Artemether, 244–245 artemisinin derivatives, 241–246 bilharzias, 224 Biomphalaria snail species, 224 cephalopodium and liver, 232–234 chemotherapy treatment for, 228, 230 Chenopodium ambrosoides, 232 chimpanzees study, 238–240 Chinese herbal medications, 232–234 Citrus reticulate, 232 cor pulmonale, 227–228 Curcubita pepo, 232 Curcumin treatment, 237–238 diarylheptanoids, 237–238 endemic diseases, 223

574  Index Schistosomiasis (Continued) epiisopiloturine, 234–235 Eriosema griseum leaves, 231–232 essential oils, 235–236 flavonoids, 238, 239t, 240f fraction and isolated isoflavones, 238–240, 239t genus Schistosoma, 224 haematobium, 224 infection in humans, 224 intercalatum, 224 lignans and neolignans, 236–237, 237f medicinal plants, 231–232 Mentha crispa, 232 miscellaneous compounds, 247f mortality rate, 223–224 natural active principle, 231 natural product-derived pharmaceuticals, 231 natural products for management of, 231–246, 233t Olea europaea, 232 parasitic disease, 223–224 parasitic neglected disease, 224 pathological manifestation of, 226–227 primary schistosomiasis agent, 224 public health issue, 223–224 pulmonary, 226–227 rotundifolone, 241 saponins, 238–240 Schistosoma haematobium, 225 Schistosoma mansoni, 225 Schistosoma mekongi, 224 spread in human, 224 steroidal alkaloids, 232–234 terpenes, 241 terpenoids, 240–241, 242–243t, 244f therapy of, 231 Trematoda genus Schistosoma, 224 urinary, 226–227 urogenital, 227 vaginal, 226–227 Vernonia amygdalina, 240–241 Schistosomiasis (Bilharzia), 342 Science Direct, 31 Scutellaria baicalensis, 119 Scytosiphon lomentaria, 174 Seaweeds, 443–444 Asparagopsis, 176 brown algae, 174–175 Chlorophyta marine macro-algae, 176–178 cytotoxic effects versus mammalian skeletal myoblasts, 174

ethanol extraction, 175 ethyl acetate extraction, 176–178 fucosterol, 178–179 Laurencia dendroidea, 178–179 meroditerpenoids, 176–178 notable antileishmanial activity, 174–175 organic and alcohol extraction, 174 promastigotes and intracellular amastigotes, 176–178 with promising antileishmanial activity, 174–179 rhodophyta, 175 Secondary plant metabolites, 66 Seeds, 481 Senegalensis, 31–32 Sesamum indicum, 73 Shea butter tree, 42 Signaling, 517–518 Similium yahense, 33 Siparunaceae, 390 Smritihi, 434 Snail fever, 224 Solanum tuberosum, 518–520 Solidago virgaurea, 73 Solid lipid nanoparticle, 455–456 Sosha (consumption-pulmonary TB), 414 Spatoglossum asperum (Phaeophyceae), 368–369 Spodoptera eridania, 520–523 Stoechospermum marginatum (Phaeophyceae), 368–369 Streptomyces sanyensis, 277 Strychnos lucida, 119 Stypocaulon scoparium, 174 Stypopodium zonale, 279–280 Suramin, 381–382 Sushruta, 416 Swietenia macrophylla, 119 Syzygium zeylanicum, 319

T

Tagetes erecta, 312–318 Tenebrio molitor, 528 Terminalia bellerica, 73 Terminalia chebula, 12, 73 Terpenes, 544–545 Terpenoids, 520–523 Tetradenia riparia, 265–266 Therapeutic management drugs, 381–382 natural products of trypanosomiasis, 382–391

Index 575 aloaceae, 382 annonaceae, 382 apocynaceae, 382 asteraceae, 387 bignoniaceae, 387 boraginaceae, 387 canellaceae, 388 didymellaceae, 388 fabaceae, 388 gramineae, 388 hymenocardiaceae, 388 lamiaceae, 388–389 lauraceae, 389 leguminosae, 389 loganiaceae, 389 meliaceae, 389 menispermaceae, 389 myrtaceae, 389 plants against, 382–391, 383–386t rubiaceae, 390 rutaceae, 390 siparunaceae, 390 verbenaceae, 390–391 zingiberaceae, 391 Tick-borne diseases, 87 Tick-borne encephalitis, 1 Tiger mosquito. See Aedes aegypti Toxicity adult fruit flies, 523 Anethum graveolens, 526 fumigation, 527–528 plant machineries exhibit, 517–518 saponins, 524 TPM. See Traditional Persian medicine (TPM) Trachyspermum ammi, 527–528 Traditional Persian medicine, 203 Tratiyaka fever, 416 Tribolium castaneum, 518, 526–528 Tribolium confusum, 528 Trichilia emetica Vahl, 40 Tridax procumbens, 260 Triphyophyllum peltatum, 11 Trogoderma granarium, 527–528 Trypanosoma brucei gambiense, 379–380 Trypanosoma brucei rhodesiense, 379–380 Trypanosoma cruzi, 381 Trypanosoma equiperdum, 381 Trypanosoma evansi, 381 Trypanosoma rotatorium, 381 Trypanosoma theileri, 381 Trypanosoma vivax, 381 Trypanosomiasis, 171, 379–380 African, 380–381

hemoflagellates protozoans, 380 hemo-lymphatic stage, 381 jaundice and diarrhea, 381 meningo-encephalitic stage, 381 sleeping sickness, 380–381 Tsetse flies, 342 Turbinaria turbinate, 174–175

U

Uncaria tomentosa, 300 Unonopsis duckei, 73 Unonopsis floribunda, 73 Unonopsis rufescens, 73 Unonopsis stipitata, 73 Urogenital schistosomiasis, 227

V

Vaccination antischistosomal reactions, 230 artemisinin derivatives, 231 carbohydrate antigens, 230–231 corticosteroids, 230–231 first generation, 230 schistosomiasis disease, 230 Valeriana jatamansi, 264–265 Valeriana wallichii. See Valeriana jatamansi Vector bone diseases in Ayurveda Agantukaroga transmission, 413–414 transmission mode, 414t, 415–434 Janapadodhwamsa, 413–414 Krimi, 415–434 research, 413 transmissible diseases, 413 Vector-borne disease (VBD), 379–380, 437–438 of avian malaria, 102–103 biology of, 88 chikungunya fever (CHIKV) human infection, 438–440 mosquito-borne disease, 438–440 sickness, 438–440 vector of transmission, 438–440 virus, 438–440 control through seaweeds arthropods transmission, 437–438 chikungunya fever (CHIKV), 438–440 defined, 84–89 dengue-transmission, 102–103 with essential oil nanoemulsions annual death, 82 climate variability on, 88 EONEms on, 96–104

576  Index Vector-borne disease (VBD) (Continued) freshwater snails, 87 green technology against, 104 inexpensive and environment-friendly approach, 84 infection, 85 prevention and management of, 88–89 tropical and subtropical areas, 82 types of, 85–86t zoonotic cycles, 84 essential oils (EOs), 82–84 information of, 437–438 integrated vector management (IVM) system, 88–89 management against multiple diseases, 82 mosquito-borne diseases, 438 clinical signs of, 438 deadly arthropod-borne diseases, 438 risk in human and health, 438 mosquitoes and ticks, 440–441 natural products, 442–443 prevention of, 82, 88–89, 115 seaweed, 443–444 Caulerpa cupressoides, 444 property and providence, 443 RNA-composed viruses, 444 secondary metabolites, 443 vector-borne illness control, 444 spread of, 82 transmission dynamics, 437–438 tropical and subtropical regions, 440–441 types, 84, 85–86t Chronic Chagas disease, 87 flea-borne diseases, 87 fly-borne diseases, 86–87 mosquito-borne diseases, 86 principal vectors transmission, 85 tick-borne diseases, 87 Vector-borne diseases in ayurveda Ayurvedic medicine for, 431–433t clinical study, 425, 431–433t in India, 415t mosquito and larvae, 427 National Vector Borne Disease Control Programme, 415 natural treatment options for, 413 personal protection, 427 prevention from, 425 prophylactic measures, 434 Vector-borne illnesses (VBDs), 1, 17 Vector-borne infections, 14–15 Vector-borne protozoan diseases, 125–126 Vector control, 441–442 Culex tritaeniorhynchus, 312–318

Habenaria plantaginea, 318–319 isolated phytochemicals in, 319 Culex tritaeniorhynchus, 319 and essential oils, 319 larvicidal potency against Culex tritaeniorhynchus, 320–321t JE vector Culex tritaeniorhynchus, 313–317t plant extraction, 312–319 potential botanical substances, 312–318 toxic effects, 318–319 Vectors, 1 Ayush 64, 417t CCRAS research in Shlipada, 428t chikungunya, 422 in Ayurveda, 422 ayurveda point of view, 422 health-promoting agents, 423t symptom modification, 423t control measures, 423t, 425t dengue, 416–417 Aganthuka jwara, 418 Amavatha, 418 ayurvedic view, 418 blood transfusion, 420 for dehydration, 421 Dosha and Dathu predominance, 419 for fever, 421 ghritha preparations, 420 hemorrhagic fever, 418 Kwatha and Gutika, 420 Lakshadi Taila, 420 management for general instructions, 421t mosquito eradication, 420 Ojovardhana drugs, 420 patient instruction, 420–421 prodromal stage of classical, 419–420 Rakthapitta, 419 Sannipatha Jwara, 418, 420 symptoms, 417 treatment principle, 419 Vishama jwara, 418 vulnerability to, 417 flariasis (Shlipada), 423 ayurvedic polyherbal for chikungunya, 426t Bhaishajya Ratnavali, 427t general description of filariasis, 427t health promotion, 424t Japanese encephalitis (JE), 424 Ayurvedic medicines for, 429t general description of, 429t kala azar, 425 description of, 430t natural treatment for, 430t

Index 577 malaria, 415–416 mosquitoes, 415 symptom modification, 424t Verbenaceae, 42, 390–391 Veterinary entomology of arthropod-borne diseases, 13–14 medical and, 13 is essential to public health, 13 vector-borne parasites, 13 vertebrate hosts, frequency intercation of, 13–14 Vijnanam, 434 Viola tricolor, 118 Viral enzymes, 51 Visceral leishmaniasis (VL), 126–127 Visha, 434 Visham Santat fever, 416 Vitis vinifera, 73 Voacanga africana (Scott-Elliot) Stapf. voacamine, 33f voacangine, 33f Volatile, 520–523 Volatile oil. See Essential oils

W

West Nile, 1 Wolbachia, 27–28, 30 World Health Organization (WHO), 1, 14, 379–380 Wuchereria bancrofti, 5

X

Xanthones, 541

Y

Yellow fever virus, 6

Z

Zika virus, 1, 5, 14, 491 antiviral action against, 491 emerging and re-emerging RNA virus, 491 Zingiberaceae, 391 Zingiber cernuum, 312–318 Zingiber zerumbet, 267 Zostera marina, 300

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