Nutraceuticals: Sources, Processing Methods, Properties, and Applications 044319193X, 9780443191930

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Nutraceuticals

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Nutraceuticals Sources, Processing Methods, Properties, and Applications Edited by

Inamuddin Department of Applied Chemistry, Zakir Husain College of Engineering and Technology; Faculty of Engineering and Technology, Aligarh Muslim University, Aligarh, India

Tariq Altalhi Department of Chemistry, College of Science, Taif University, Taif, Saudi Arabia

Jorddy Neves Cruz Department of Pharmaceutical Sciences, Federal University of Para, Bele´m, Brazil

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 978-0-443-19193-0 For information on all Academic Press publications visit our website at https://www.elsevier.com/books-and-journals

Publisher: Nikki P. Levy Acquisitions Editor: Megan R. Ball Editorial Project Manager: Emerald Li Production Project Manager: Kumar Anbazhagan Cover Designer: Greg Harris Typeset by STRAIVE, India

Contents Contributors ........................................................................................................... xiii

CHAPTER 1

Nanotechnology based delivery of nutraceuticals .... 1 Shailendra Gurav, Sameer Nadaf, Goutam Kumar Jena, and Nilambari Gurav 1 Introduction of nanotechnology .....................................................1 2 Nutraceuticals.................................................................................2 2.1 Significance (health benefits/medical applications) .............. 2 3 Challenges of nutraceuticals/problems associated with nutraceuticals..................................................................................3 4 Bioavailability enhancement of nanoparticles...............................3 5 Nanoscale systems for delivery of nutraceuticals .........................3 5.1 Organic nanoparticles ............................................................. 4 5.2 Inorganic nanoparticles......................................................... 12 6 Physicochemical properties and characterization of nanoparticles.................................................................................22 7 Combination of nutraceuticals along with chemotherapeutic drugs using nanocarriers.................................22 8 Conclusion and future scope........................................................23 References.................................................................................... 24 Further reading ............................................................................ 34

CHAPTER 2

Applications of nutraceuticals for disease prevention and treatment ..................................... 35 Maheswata Moharana, Subrat Kumar Pattanayak, and Fahmida Khan 1 Introduction ..................................................................................35 2 Types of nutraceuticals ................................................................36 2.1 Chemical constituent-based nutraceuticals .......................... 37 2.2 Traditional nutraceuticals ..................................................... 39 2.3 Nonconventional nutraceuticals ........................................... 40 3 Application of nutraceuticals in therapeutics ..............................41 3.1 Nutraceuticals as anticancer agents...................................... 41 3.2 Antiviral nutraceuticals ........................................................ 42 3.3 Nutraceuticals for gastrointestinal disorders........................ 42 3.4 Antiinflammatory activity .................................................... 43

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3.5 Antidiabetic nutraceuticals ................................................... 43 3.6 Nutraceuticals for thyroid disease........................................ 44 4 Conclusion....................................................................................45 References.................................................................................... 45

CHAPTER 3

Use of vitamins and minerals as dietary supplements for better health and cancer prevention........................................................... 53 Saniya Arfin and Dhruv Kumar 1 Introduction ..................................................................................53 2 Vitamin A.....................................................................................54 2.1 Vitamin A metabolism ......................................................... 56 2.2 Anticancer role ..................................................................... 56 2.3 Mechanism of anticancer action .......................................... 57 3 Vitamin C .....................................................................................59 3.1 Bioavailability....................................................................... 59 3.2 Anticarcinogenic actions of vitamin C ................................ 60 3.3 Current studies and trials...................................................... 61 4 Vitamin D.....................................................................................61 4.1 CYP27B1 ............................................................................ 62 4.2 CYP24A1............................................................................ 63 4.3 VDR .................................................................................... 63 4.4 Anticancer effects of calcitriol ........................................... 64 4.5 Calcitriol-mediated transcriptional regulation ............................................................................ 64 4.6 Antiproliferative action ...................................................... 64 4.7 Apoptosis ............................................................................ 65 4.8 Autophagic induction ......................................................... 65 4.9 Angiogenesis....................................................................... 66 4.10 Immune modulation............................................................ 66 4.11 Inflammation....................................................................... 66 4.12 Altered cell metabolism ..................................................... 67 4.13 MicroRNA .......................................................................... 67 5 Vitamin E .....................................................................................67 5.1 Anticancer mechanisms........................................................ 68 5.2 Inflammation......................................................................... 68 5.3 Immune modulation.............................................................. 69 5.4 Antiproliferative action ........................................................ 69 5.5 Epigenetic modulation.......................................................... 69 5.6 Cancer stem cell targeting.................................................... 70

Contents

5.7 γTE, an adjuvant in radiation therapy.................................. 70 5.8 Clinical trials using tocopherols and tocotrienols for cancer prevention............................................................ 70 6 Minerals........................................................................................73 6.1 Selenium ............................................................................... 73 6.2 Zinc ....................................................................................... 75 7 Conclusion/future perspectives ....................................................77 References.................................................................................... 78

CHAPTER 4

Nutraceuticals and cosmeceuticals: An overview ........................................................ 99 Suriyaprabha Rangaraj, Vasuki Sasikanth, Subramanian Ammashi, and Thirumalaisamy Rathinavel 1 Introduction ..................................................................................99 2 Nutrition representing their therapeutic activities .....................100 2.1 Based on the chemical nature ............................................ 101 2.2 Based on the functional role .............................................. 106 3 Sources of nutricosmeceuticals..................................................112 3.1 Plant resources .................................................................... 112 3.2 Microbial resources ............................................................ 113 3.3 Marine sources.................................................................... 114 4 Applications of nutricosmeceuticals ..........................................115 4.1 Hair care ............................................................................. 115 4.2 Skin care ............................................................................. 115 4.3 Nail care.............................................................................. 117 5 Hurdles in nutricosmetics ..........................................................117 6 Cutting-edge technologies in nutricosmetic applications.................................................................................117 7 Consumer safety regulations......................................................118 8 Conclusion..................................................................................119 References.................................................................................. 119

CHAPTER 5

Review of methods for encapsulation of nutraceutical compounds ................................... 127 Debanjan Saha, Ankita Khataniar, Ajit Kumar Singh, and Anupam Nath Jha 1 Introduction ................................................................................127 2 Nutraceuticals in food biotechnology........................................129 2.1 Definition and types ........................................................... 129

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CHAPTER 6

2.2 Classification ...................................................................... 130 2.3 Nutraceuticals as therapeutics ............................................ 132 Materials used for encapsulation ...............................................134 3.1 What are the important criteria for the selection of the material?.............................................................................. 134 3.2 Substances used for encapsulating ..................................... 135 Microencapsulation of nutraceuticals ........................................137 4.1 Microencapsulation techniques .......................................... 137 4.2 Need for microencapsulation.............................................. 138 Techniques used in encapsulation .............................................138 5.1 Spray drying........................................................................ 139 5.2 Spray chilling...................................................................... 139 5.3 Fluidized bed coating ......................................................... 140 5.4 Coacervation ....................................................................... 140 5.5 Interfacial polymerization .................................................. 141 5.6 In situ polymerization......................................................... 141 5.7 Emulsification..................................................................... 142 5.8 Solvent evaporation ............................................................ 142 5.9 Extrusion ............................................................................. 143 Delivery of nutraceuticals ..........................................................143 6.1 Delivery systems of nutraceuticals..................................... 143 6.2 Advantages and disadvantages of delivery of nutraceuticals ...................................................................... 145 Probiotics encapsulation and nutraceuticals in food matrices ......................................................................................146 7.1 Probiotics as a vital tool toward human health ................. 146 7.2 Techniques and materials employed to encapsulate probiotic cells ..................................................................... 147 7.3 Encapsulated probiotics with food products ...................... 147 7.4 Effects of probiotics and nutraceuticals on therapeutics ......................................................................... 150 Conclusion..................................................................................150 Acknowledgment ....................................................................... 151 References.................................................................................. 151

Dietary medicine with nutraceutical importance .. 157 Toluwase Hezekiah Fatoki, Jesufemi Samuel Enibukun, and Ibukun Oladejo Ogunyemi 1 Introduction ................................................................................157 2 Nutraceuticals and dietary therapy ............................................158 3 Dietary constituents and bioactive compounds .........................159

Contents

4 Selected dietary source from plants and medicinal importance ..................................................................................160 5 Conclusion..................................................................................170 References.................................................................................. 171

CHAPTER 7

Overview on nutraceuticals and biotechnology .... 175 N. Rajak, A. Tiwari, P. Kumar, and N. Garg 1 Introduction ................................................................................175 2 Essential dietary supplements ....................................................176 3 Herbal nutraceuticals and their properties.................................177 3.1 Alkaloids ............................................................................. 177 3.2 Anthraquinones ................................................................... 178 3.3 Flavonoids........................................................................... 180 3.4 Saponins.............................................................................. 180 3.5 Essential oils ....................................................................... 180 3.6 Tannins................................................................................ 181 4 Role of biotechnology in the production of nutraceutical products ......................................................................................181 4.1 The increased amount of phytosterols (plant sterols) for reduced cholesterol ....................................................... 181 4.2 Production of increased levels of provitamin-A carotenoids through biotechnological advancements ........ 182 4.3 Antioxidants........................................................................ 183 4.4 Production of higher levels of essential fatty acids........... 183 4.5 Role of low-linolenic soybean ........................................... 183 4.6 Role of high-lysine maize in nutrition ............................... 185 4.7 Probiotics ............................................................................ 185 5 Conclusion..................................................................................185 Acknowledgments ..................................................................... 186 Conflict of interest..................................................................... 186 References.................................................................................. 186

CHAPTER 8

Advances in the development of a 3D-printed nutraceutical delivery platform ........................... 193 Srushti Tambe, Divya Jain, Purnima Amin, Suraj N. Mali, and Jorddy N. Cruz 1 Background ................................................................................193 2 Introduction to 3D printing ........................................................195 3 Materials used in 3D printing ....................................................197 3.1 Polymeric fibers.................................................................. 197 3.2 Powder materials ................................................................ 198 3.3 Bioinks ................................................................................ 198

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4 3D printing of nutraceuticals .....................................................204 4.1 Fused deposition modeling (FDM) 3D printing ................ 204 4.2 Stereolithography................................................................ 206 4.3 Selective laser sintering (SLS) 3D printing ....................... 208 4.4 Semisolid extrusion ............................................................ 210 4.5 Direct ink writing 3D printing process .............................. 212 4.6 4D printing process............................................................. 212 5 Challenges in the fabrication of 3D printed formulations ........214 6 Future perspectives.....................................................................215 7 Conclusion..................................................................................215 References.................................................................................. 216

CHAPTER 9

Nutraceuticals in agriculture .............................. 223 Pankaj Kumar Jaiswal, Roohi Kesharwani, Dilip K. Patel, Pankaj Verma, and Vikas Kumar 1 Introduction ................................................................................223 2 Sources of nutraceuticals ...........................................................224 References.................................................................................. 238

CHAPTER 10 Nutraceutical and therapeutic importance of clots and their metabolites ............................. 241 Nawal Abd El-Baky, Amro Abd Al Fattah Amara, and Elrashdy Mustafa Redwan 1 Introduction ................................................................................241 2 Nutraceuticals and functional foods that affect blood circulation and clotting ..............................................................243 2.1 Microbial fibrinolytic enzymes from food sources ......... 243 2.2 Mushroom fibrinolytic/thrombolytic enzymes................. 248 2.3 Minerals (calcium)............................................................ 248 2.4 Water-soluble tomato concentrate (WSTC)..................... 250 2.5 Phytochemicals ................................................................. 250 2.6 Omega fatty acids............................................................. 251 2.7 Vitamin K ......................................................................... 252 2.8 Heart-friendly herbs.......................................................... 252 2.9 Probiotics .......................................................................... 256 2.10 Prebiotics .......................................................................... 256 2.11 Gut microbe-generated metabolites from dietary nutrients ............................................................................ 256 3 Future prospects .........................................................................257 4 Conclusion..................................................................................258 References.................................................................................. 259

Contents

CHAPTER 11 Nutraceuticals to prevent and manage cardiovascular diseases .................................... 269 Sarah Elizabeth Prakash, Vaishnavi Chikkamagalur Manjunatha, Praveen Nagella, and Vasantha Veerappa Lakshmaiah 1 Introduction ................................................................................269 2 Nutraceuticals.............................................................................270 3 Classification of nutraceuticals..................................................270 3.1 Polyphenols......................................................................... 270 4 Dietary fibers .............................................................................273 5 Polyunsaturated fatty acids ........................................................274 6 Prebiotics and probiotics ...........................................................274 7 Spices .........................................................................................275 8 Extraction of nutraceuticals .......................................................276 9 Bioavailability of nutraceuticals................................................278 10 Engineered nanoparticles (ENs) ................................................279 11 Biopolymer-based nanoparticles................................................281 12 Cardiovascular diseases (CVD) .................................................282 13 Life style ....................................................................................283 13.1 Diabetes ............................................................................ 283 13.2 Hypertension ..................................................................... 284 13.3 Atherosclerosis.................................................................. 285 14 Conclusion..................................................................................285 References.................................................................................. 286 Index ......................................................................................................................293

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Contributors Amro Abd Al Fattah Amara Protein Research Department, GEBRI, City of Scientific Research and Technological Applications (SRTA-City), New Borg El-Arab City, Egypt Purnima Amin Department of Pharmaceutical Science and Technology, Institute of Chemical Technology, Mumbai, India Subramanian Ammashi PG and Research Department of Biochemistry, Rajah Serfoji Government College, Thanjavur, Tamil Nadu, India Saniya Arfin Department of Biotechnology, School of Health Sciences and Technology (SoHST), UPES University, Dehradun, Uttarakhand, India Jorddy N. Cruz Department of Pharmacy, Federal University of Para´, Para´, Brazil Nawal Abd El-Baky Protein Research Department, GEBRI, City of Scientific Research and Technological Applications (SRTA-City), New Borg El-Arab City, Egypt Jesufemi Samuel Enibukun Department of Medicine, College of Health Sciences, University of Ilorin, Ilorin, Kwara State, Nigeria Toluwase Hezekiah Fatoki Department of Biochemistry, Federal University Oye-Ekiti, Oye, Ekiti State, Nigeria N. Garg Department of Medicinal Chemistry, Faculty of Ayurveda, Institute of Medical Science, Banaras Hindu University, Varanasi, Uttar Pradesh, India Nilambari Gurav Department of Pharmacognosy, PES Rajaram and Tarabai Bandekar College of Pharmacy, Ponda, Goa, India Shailendra Gurav Department of Pharmacognosy, Goa College of Pharmacy, Goa University, Panaji, Goa, India Divya Jain Department of Pharmaceutical Science and Technology, Institute of Chemical Technology, Mumbai, India

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Pankaj Kumar Jaiswal Department of Pharmacy, IEC College of Engineering and Technology, Greater Noida, Uttar Pradesh, India Goutam Kumar Jena Department of Pharmaceutics, Roland Institute of Pharmaceutical Sciences, Berhampur, Odisha, India Anupam Nath Jha Department of Molecular Biology and Biotechnology, Tezpur University, Tezpur, India Roohi Kesharwani Department of Pharmacy, Chandra Shekhar Singh College of Pharmacy, Kaushambi, Uttar Pradesh, India Fahmida Khan Department of Chemistry, National Institute of Technology, Raipur, Chhattisgarh, India Ankita Khataniar Centre for Biotechnology and Bioinformatics, Dibrugarh University, Dibrugarh, India Dhruv Kumar Department of Biotechnology, School of Health Sciences and Technology (SoHST), UPES University, Dehradun, Uttarakhand, India P. Kumar Department of Medicinal Chemistry, Faculty of Ayurveda, Institute of Medical Science, Banaras Hindu University, Varanasi, Uttar Pradesh, India Vikas Kumar Department of Pharmaceutical Sciences, SHUATS, Naini, Prayagraj, Uttar Pradesh, India Suraj N. Mali Department of Pharmaceutical Sciences & Technology, Birla Institute of Technology, Ranchi, India Vaishnavi Chikkamagalur Manjunatha Department of Life Sciences, CHRIST (Deemed to be University), Bengaluru, Karnataka, India Maheswata Moharana Department of Chemistry, National Institute of Technology, Raipur, Chhattisgarh, India Sameer Nadaf Department of Pharmaceutics, Sant Gajanan Maharaj College of Pharmacy, Mahagaon, Maharashtra, India

Contributors

Praveen Nagella Department of Life Sciences, CHRIST (Deemed to be University), Bengaluru, Karnataka, India Ibukun Oladejo Ogunyemi Department of Nutrition and Biomedicine, Technical University of Munich, Munich, Germany Dilip K. Patel Department of Pharmacy, Government Polytechnic Jaunpur, Jagdishpur, Uttar Pradesh, India Subrat Kumar Pattanayak Department of Chemistry, National Institute of Technology, Raipur, Chhattisgarh, India Sarah Elizabeth Prakash Department of Life Sciences, CHRIST (Deemed to be University), Bengaluru, Karnataka, India N. Rajak Department of Medicinal Chemistry, Faculty of Ayurveda, Institute of Medical Science, Banaras Hindu University, Varanasi, Uttar Pradesh, India Suriyaprabha Rangaraj Department of Biotechnology, Sona College of Arts and Science, Salem, Tamil Nadu, India Thirumalaisamy Rathinavel Department of Biotechnology, Sona College of Arts and Science, Salem, Tamil Nadu, India Elrashdy Mustafa Redwan Protein Research Department, GEBRI, City of Scientific Research and Technological Applications (SRTA-City), New Borg El-Arab City, Egypt; Biological Sciences Department, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia Debanjan Saha Department of Molecular Biology and Biotechnology, Tezpur University, Tezpur, India Vasuki Sasikanth Department of Biotechnology, Sona College of Arts and Science, Salem, Tamil Nadu, India Ajit Kumar Singh Department of Molecular Biology and Biotechnology, Tezpur University, Tezpur, India Srushti Tambe Department of Pharmaceutical Science and Technology, Institute of Chemical Technology, Mumbai, India

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A. Tiwari Department of Medicinal Chemistry, Faculty of Ayurveda, Institute of Medical Science, Banaras Hindu University, Varanasi, Uttar Pradesh, India Vasantha Veerappa Lakshmaiah Department of Life Sciences, CHRIST (Deemed to be University), Bengaluru, Karnataka, India Pankaj Verma Department of Pharmacy, Government Polytechnic Jaunpur, Jagdishpur, Uttar Pradesh, India

CHAPTER

Nanotechnology based delivery of nutraceuticals

1

Shailendra Gurava, Sameer Nadafb, Goutam Kumar Jenac, and Nilambari Guravd a

Department of Pharmacognosy, Goa College of Pharmacy, Goa University, Panaji, Goa, India, b Department of Pharmaceutics, Sant Gajanan Maharaj College of Pharmacy, Mahagaon, Maharashtra, India, cDepartment of Pharmaceutics, Roland Institute of Pharmaceutical Sciences, Berhampur, Odisha, India, dDepartment of Pharmacognosy, PES Rajaram and Tarabai Bandekar College of Pharmacy, Ponda, Goa, India

1. Introduction of nanotechnology Nanotechnology is nothing but “technology on the nanoscale”. It investigates and controls the atomic/molecular structures of 1–100 nm in size [1]. Nanomaterials possess unique physicochemical features and can be used as adaptable scaffolds for biomolecule functionalization [2]. A reduction in the dimensions of materials can create small changes, and when the size decreases below 100 nm, drastic alterations in its properties can occur. Nanomaterials have unique features that can be used for commercial purposes that benefit the society [3]. Hydrophobic drug delivery systems are being developed using nanoparticles because of their unique physicochemical and biological features. As encapsulated bioactive compounds can be quickly digested, permeate the mucus barrier, or directly enter cells, their bioavailability is often increased when the particle size is lowered [4,5]. In recent years, medical and pharmacological applications of engineered nanoparticles have proven effective, particularly for diagnostic and therapeutic purposes [6]. In addition, botanical scientists are increasingly interested in nanotechnology, particularly in applying nanomaterials (NMs) as carriers of agrochemicals or plant biomolecules [7]. Nanotechnology has the potential to extend the use of innovative methods to create new products, replace existing production equipment, formulate novel materials for better performance, resulting in lower material and energy consumption, and also manage the environment [8].

Nutraceuticals. https://doi.org/10.1016/B978-0-443-19193-0.00006-X Copyright # 2023 Elsevier Inc. All rights reserved.

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CHAPTER 1 Nanotechnology based delivery of nutraceuticals

2. Nutraceuticals For the body to function normally, it relies heavily on the nutrients provided by food. Thus, they aid in preventing and treating numerous disorders. Research into the health-enhancing effects of some plant elements that could be used as nutraceuticals has been considerable. The term “Nutraceutical” was coined in the early 1980s by “Stephen DeFelice”, who founded, “Foundation for Innovation in Medicine” (FIM) in Cranford, New Jersey, and serves as its chairman [9]. “A food or component of a food that offers medical or health advantages, including the prevention and/or treatment of disease,” is how nutraceuticals are defined. Based on the chemical composition, mechanism of action, and natural source, they can be divided into three groups. For a long time, nutraceuticals have been viewed as an alternative medication. Supplements like this are becoming increasingly popular because of studies and evidence that these components in food are effective when appropriately digested [10]. Various formulations are produced to allow targeted delivery of nutraceuticals and sustained release from the nano-formulation, with improved bioavailability and therapeutic efficacy.

2.1 Significance (health benefits/medical applications) Heart disease, cancer, hypertension, and diabetes are the key disorders with which nutraceuticals have been linked for prevention and/or treatment. Osteoporosis, arthritis, and neural tube abnormalities are some of the other diseases related to nutraceuticals. Health benefits can be attributed to the wide variety of nutrients found in natural food sources. Lutein, zeaxanthin, beta carotene, and lycopene have numerous health benefits. For example, lutein and zeaxanthin protect the eyes from cataracts and macular degeneration, whereas beta carotene and lycopene help protect the skin from UV radiation. Lutein and lycopene have improved cardiovascular health, and lycopene has also reduced the risk of developing prostate cancer. High cholesterol, high blood pressure, and diabetes can be prevented by regularly consuming these and other beneficial nutrients. Products such as Hypericum perforatum, Gingko biloba, Saw palmedo extract, and ginseng are some of the most popular nutraceuticals currently available [10,11]. Nutraceuticals such as antioxidants, alpha-lipoic acid, and phosphatidylserine have proven effective in Alzheimer’s disease treatments [12,13]. Polyphenols from grapes and wine have been studied recently and showed changes in cellular metabolism and caused a reduction in vascular diseases. Several foods are rich in flavonoids, and their biological activities show action against free radicals, platelet aggregation, and antiinflammatory action. Increased colon cancer risk is associated with excessive meat and fat consumption. In contrast, dietary fiber has been linked to changes in the gut environment that protect against colorectal illnesses [14]. In addition, food sources rich in vitamin E may offer protection against Parkinson’s disease (PD). A decrease in PD symptoms was associated with a higher intake of creatine. In fruits and vegetables, carotenoid

5 Nanoscale systems for delivery of nutraceuticals

terpenes are highly pigmented and contribute to their coloration. Carotenoids and xanthophylls are the two types of chemicals that make up these pigments. Gamma-carotene, lycopene, and lutein are all carotenes that protect against cancers of the digestive system and uterus [15].

3. Challenges of nutraceuticals/problems associated with nutraceuticals Nutraceuticals occur in functional foods that defy food and drug regulation [16]. For nutraceutical industries, regulatory ambiguity and labeling claims are apparent risks [17]. Various challenges related to the development of nutraceuticals are often overlooked due to the absence of regulatory control. These obstacles include establishing the source of raw materials, chemical purity, existence of additional active compounds, lack of quality and scientific evidence, deceptive advertising, heavy metal contamination, supplements, and drug interactions [18]. There is inadequate data about recommended intake and effectiveness, even though, currently, nutraceuticals have become an essential topic in nutrition. Nutraceuticals cannot profess to be substituted for actual food but only a dietary supplement.

4. Bioavailability enhancement of nanoparticles Understanding the biological mechanisms that synchronize absorption and bioavailability (the rate and extent at which a drug reaches systemic circulation) is critical to creating effective nanoparticle delivery systems for nutrients, nutraceuticals, and related active substances [19,20]. They can be taken orally to reach the tissues and organs where they can have a positive impact on health. Nutraceuticals that are consumed have many obstacles that prohibit them from circulating in an active form in the body [21]. Nutraceutical bioavailability and bioefficacy have been increased with nanoparticle delivery methods. Encapsulated bioactive nutrients and nonnutrient can be made more resistant to environmental changes by using nanotechnology, and their release can be controlled. When used as carriers for nutrients, nanoparticles can help maintain health and prevent or perhaps treat disease [22].

5. Nanoscale systems for delivery of nutraceuticals Nanotechnology is an interdisciplinary field concerned with nanoscale particles ranging from 1 to 100 nm in size. When it comes to medicine, it is commonly used in drug delivery and tissue engineering. Nutraceutical solubility, bioavailability, chemical stability, texture, and taste have all improved due to their use in recent years in producing and distributing these supplements.

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Encapsulation of lipophilic minerals, vitamins, and nutraceuticals in nanoscale systems has become increasingly popular [23]. Therefore, nutraceuticals could benefit from the use of nanoscale delivery systems. For example, protecting the nutraceutical during processing or digestion, enhancing its stability, masking undesired smells or tastes, obtaining regulated release, and improving the solubility of nutraceuticals by enhancing their bioavailability [24]. Furthermore, much work needs to be carried out with nano-nutraceuticals derived from biotechnologically created, genetically modified, and tissue-cultured goods and techniques and means to demonstrate the efficacy of these and other similar products. Nevertheless, nano-sized nutraceutical items are widely accessible commercially [25]. Nutraceuticals, especially lipo-soluble vitamins, have been encapsulated in various delivery vehicles, i.e., nanoformulations. Based on enhanced absorption, amended stability, and reduced degradation in the digestive tract, numerous studies have highly recommended lipid-based nanoformulations. Over the next few years, nano-formulated delivery technologies for critical nutraceuticals are expected to continue to advance. Thus, a wide range of unique food products is likely to be employed with significant benefits [26].

5.1 Organic nanoparticles Organic nanoparticles consist of either natural or synthetic molecules ranging from 1 to 100 nm, employed in materials and life sciences [27]. A wide range of organic nanoparticles is obtained from nature [28]. A few examples of natural organic nanoparticles are milk emulsions, lipid bodies, protein aggregates etc. The most prominent feature of organic nanoparticles is that they provide the most accessible route of encapsulation of materials [29]. Therefore, the natural organic nanoparticles composed of biodegradable polymers can be employed in the biomedical field. Generally, organic nanoparticles are fabricated either by using “top-down” or “bottom-up” techniques [30]. In the case of the top-down approach, mechanical milling is the most commonly employed to produce organic nanoparticles. However, the most recently used techniques for fabricating organic nanoparticles are microfluidics and lithography, whereas, in the bottom-up approach, precipitation and condensation are the most commonly used methods.

5.1.1 Liposomes Liposomes are spherical concentric vesicles composed of phospholipid bilayers enclosing an aqueous core with particle sizes ranging from nanometer to micrometer [31]. These are particular types of drug carriers that can entrap all drugs [32]. Liposomes encapsulate water-soluble and water-insoluble medicines in their hydrophobic and aqueous cores [33]. Unilamellar vesicles (ULVs) and multilamellar vesicles (MLVs) are two types of liposomes distinguished by their size and number of bilayers (MLV). ULVs are categorized into large unilamellar vesicles (LUV) and small unilamellar vesicles (SUV).

5 Nanoscale systems for delivery of nutraceuticals

Preparation methods The liposomal preparation method involves four significant steps (Fig. 1.1),

Preparative techniques with a drug loading of liposomes The drug loading of liposomes is performed by using mainly two approaches. 1. Passive drug loading 2. Active drug loading Passive drug loading may be further classified into four types. 1. Mechanical dispersion method 2. Solvent dispersion method 3. Detergent removal method The most common method of preparation of liposomes is the thin-film evaporation method (Fig. 1.2).

Advantages and disadvantages Advantages of liposomes. • Improve therapeutic efficacy of the drug • Enhance the drug stability • Nontoxic, biodegradable, and biocompatible • Suitable for active targeting • Reduce toxicity by the encapsulation technique • The site avoidance effect has a lower chance of liposomes accumulating in soft tissues

Disadvantages of liposomes • • • • •

Poorly water-soluble Less elimination half-life Phospholipids prone to oxidation and hydrolysis reactions High cost of products Issues with stability

Examples See Table 1.1. Drying down lipids from organic solvent

Dispersing the lipid in aqueous media

Purifying the resultant liposome

FIG. 1.1 Flowchart depicting the method of preparation of liposomes.

Analyzing the final product

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FIG. 1.2 Schematic representation of the thin-film evaporation method for liposome preparation.

Table 1.1 Examples of nutraceuticals delivered using liposomes. Sr no.

Nutraceutical

Source

Type

Method

Key findings

Reference

Allicin, Ajoene, and Thiosulfinates D-limonene

Allium sativum

Phosphatidylcholineoleic acid liposomes

Thin-film hydration

[34]

Elettaria cardamomum

Nanoliposomes

A. sativum

Liposomes

Induce cell death; with glutathione depletion

[36]

4

Allicin and petivericin, thiosulfinats Allicin

Thin-layer hydration method coupled with homogenization and sonication Thin-film hydration technique

Improved microbiological stability of baked food products Enhanced antioxidant activity and preservative activities in food

A. sativum

Liposomes

Curcumin

Curcuma longa

Liposomes

6

Curcumin

C. longa

Liposomes

Thin film hydration

7

Curcumin

C. longa

Liposomes

Thin film hydration

8

Cinnamon oil

Cinnamomum zeylanicum

Liposomes

Thin-film hydration

9

Cinnamon oil

C. zeylanicum

Liposomes

Thin-film hydration

10

Thyme essential oil

Thymus vulgaris

Liposomes

Thin-film hydration

Enhanced antimicrobial effect Improved quality of dental care; alternatively used as regenerative endodontics practice Improved bioavailability, stability, and anticancer activity Enhanced anticancer activity for the treatment of skin cancer Inhibit bacterial multiplication and used in the field of food preservation Improved the active time and the stability of cinnamon oil in the elimination of MRSA biofilms Enhanced antimicrobial activity

[37]

5

Thin-film hydration technique Rotary evaporatorbased thin lipid film method

1

2

3

[35]

[38]

[39]

[40]

[41]

[42]

[34,43]

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CHAPTER 1 Nanotechnology based delivery of nutraceuticals

5.1.2 Solid lipid nanoparticles and nanostructured lipid carriers (SLNs and NLCs) Poorly soluble drugs require lipid-based formulations to improve solubility, dissolution, and oral bioavailability [44]. Among lipid-based formulations, SLNs and NLCs are on the front line of research. The SLN was first developed by three research groups, i.e., M€ uller et al. [44], Gasco et al. [44], and Westesen [45]. It possesses unique characteristics of nano-sized, high drug loading of lipophilic drugs, and biocompatibility due to being composed of physiological lipids. SLNs are made of 0.1%–30% w/w lipids distributed in an aqueous phase with 0.5%–5% w/w stabilizing surfactants [44]. The average diameter of SLNs lies between 40 and 1000 nm. The unique characteristics of SLNs are physical stability, protection from degradation of the entrapped drug, controlled release, and less cytotoxicity. In addition to these, SLNs can be produced without using an organic solvent with easy scaled up by employing a high homogenizer. The significant challenges associated with SLNs are low drug loading and expulsion of a drug during storage due to ß-modification. The second generation lipid-based formulation known as nanostructured lipid carriers (SLNs) was developed to meet the challenges of SLNs [20].

Method of preparation See Fig. 1.3. Method of preparation of NLC. See Fig. 1.4. Advantages of SLNs and NLCs. • Improved skin penetration and permeation • Biocompatibility as well as biodegradability of components of NLCs and SLNs make them more popular and acceptable • Accrual and film formation helps skin hydration • Simple as well as economic scale-up technique of production • Augmented drug solubility and more prolonged skin deposition (act as drug reservoir) • Avoid first-pass effect and its related adverse effects • Exhibit better stability at suitable storage conditions Disadvantages of SLNs and NLCs. • Wastage of large quantity of drugs • The release of drugs is not better-controlled • Not suitable for transdermal application (Table 1.2)

Polymeric micelles (PMs) PMs are nanovesicular structures that comprise amphiphilic (a polar head and nonpolar tail) copolymers ranging from 10 to 100 nm [55]. PMs are self-assembling amphiphilic polymers with distinguished attributes such as outstanding biocompatibility, improved blood circulation, diminished toxicity, and improved solubilization of water-insoluble drugs [56]. The amphiphilic molecules change physiological characteristics with a change in concentration. Their orientation and aggregation

5 Nanoscale systems for delivery of nutraceuticals

FIG. 1.3 Flowchart showing steps involved during preparation of SLNs.

FIG. 1.4 Flowchart showing steps involved during preparation of NLCs.

9

Table 1.2 Examples of nutraceuticals delivered using SLNs and NLCs. Sr no.

Nutraceutical

Source

Type

Method

Key findings

References

1

Curcumin

Curcuma longa

SLNs

Cold dilution of the microemulsion

[46]

2

Zataria multiflora

SLNs

High-pressure homogenizer method

3

Zataria multiflora essential oil Curcumin

C. longa

SLNs

4

Curcumin

C. longa

SLNS

5

Curcumin, polyphenol

C. longa

SLNs

Ethanolic precipitation technique followed by homogenization Emulsification and low-temperature solidification method Solvent injection technique

6

Curcumin

C. longa

NLCs

Simple, solvent-free green approach It prolonged circulation time as compared to the aqueous solution Enhanced anticancer activity of ZMSLN compared to that of the pure drug obtained on tested cell lines Exhibit radiosensitizing effect Enhanced anticancer potential as compared to pure curcumin Enhanced permeability as compared to solution Improved oral bioavailability Enhanced encapsulation efficiency Prevent photodegradation and hydrolysis Sustained release Significant cell growth suppression

7

Curcumin

C. longa

NLCs

8

Curcumin

C. longa

NLCs

Microemulsion followed by ultrasonication

9

Curcumin

C. longa

NLCs

Hot emulsification followed by probe sonication

Preemulsification followed by highpressure homogenization Hot high-pressure homogenization

Enhanced antitumor effect Curcumin concentration increased through nasal administration 41% curcumin released within 2 h in simulated gastric medium (SGM) Enhancement of stability in SGM Enhanced efficacy of curcumin Improved targetability Topical application for skin infection

[47]

[48]

[49]

[50]

[51]

[50,52]

[53]

[54]

5 Nanoscale systems for delivery of nutraceuticals

in the solution can change the physiological attributes and form “micelles.” The formation of micelles mainly depends on the size of the nonpolar tail of the amphiphilic molecule. Apart from this factor, other factors that affect micelle formation are the solvent system, the concentration of amphiphilic polymers, and temperature. The appearance of micelles starts only when the concentration of amphiphilic molecules crosses a minimum concentration, known as critical micellar concentration. At low concentrations, amphiphilic molecules exist as a separate entity in a medium and appear as subcolloidal particles. The PMs possess special physicochemical and morphological attributes in water to generate polymers of suitable applications. Suitable block copolymers are achieved by controlled synthesis by changing the ratio of block polymers, polymer molecular weight, chemical constitution, and coupling with biomolecules [57]. Due to their colloidal dimension, the PMs are suitable for sterilization by simple filtration. No special aseptic processing is required for them, which makes them costeffective. As the core of micelles is hydrophobic, the solubilization of hydrophobic moieties occurs due to hydrophobic-hydrophobic interactions. The solubility problem is associated with most drugs. Hence, PMs can be used to overcome the solubility issues of most water-insoluble drugs. The suitable incorporation of the drug can explain the enhancement of solubility of polymeric micelles into the block polymer micelles.

Method of preparation of micelles See Fig. 1.5.

Advantages and disadvantages Advantages. • Improved solubility of poorly water-soluble drugs • Improved rate of dissolution • Protecting drugs from the external environment • Provide stability to drug candidates • Enhance oral bioavailability • Polymeric micelles can be sterilized using a simple filtration method without aseptic processing due to their colloidal dimension Disadvantages. • High cost of preparation • Issues with drug loading • On administration of intravenous injections of micelles, the micellar solution gets extremely diluted, which results in deformation or disassembly and hence leakage and burst release of the drug occurs (Table 1.3)

11

12

CHAPTER 1 Nanotechnology based delivery of nutraceuticals

FIG. 1.5 Flowchart of the preparation method of polymeric micelles.

5.2 Inorganic nanoparticles Depending on particle size, inorganic nanoparticles have various physical and chemical characteristics. Nanoparticles made of metals, such as metal oxides and metal salts, are nontoxic and biocompatible, and they are significantly more stable than organic nanoparticles [68–70].

5.2.1 Metallic nanoparticles A metallic nanoparticle is a nano-sized (10–100 nm) metal and exhibits distinctive characteristics, namely, surface plasmon resonance and optical properties [71]. Metallic nanoparticles are composed of an inorganic metal or metal oxide core encased in an organic or inorganic shell material or metal oxide [72]. The most widely studied metal nanoparticles are silver nanoparticles (AgNPs) and gold nanoparticles (AuNPs).

Preparation methods Physical method. Plasma method Various plasma processes, such as arc discharge and glow discharge, can create metal and oxide nanoparticles [72]. In brief, metallic material in a pestle is heated in an evacuated chamber by outer high-voltage radio frequency (RF) heating coils. Following the entry of helium, high-temperature

Table 1.3 Examples of nutraceuticals delivered using polymeric micelles. Sr no.

Nutraceuticals

Source

Type

Method

Key findings

References

1

Curcumin

Curcuma longa

Polymeric micelles

Enhancement of antibacterial activity

[58]

2

Curcumin

C. longa

Curcumin

C. longa

4 5

Allicin and Whey protein Curcumin

Allium sativum C. longa

6

Curcumin

C. longa

Polymeric micelles

Nanoprecipitation method

7

Curcumin

C. longa

Polymeric micelles

Solvent casting method

8

Quercetin

Polymeric micelles

Thin-film hydration method

9

Oleanolic acid

10

Curcumin

Plants, fruits and vegetables Olea europaea C. longa

Polymeric micelles Polymeric micelles

Ultrasonic cleaner and centrifugation. Solvent evaporation technique

Improved solubility and bioavailability Enhance curcumin loading and delivery Antibacterial effect improved Suppressed development of colon cancer Improved stability of curcumin Improved pharmacokinetic parameters of curcumin Enhanced CNS targeting with improved therapy Improved cytotoxic potential for breast cancer Improved solubility of poorly soluble materials Autoxidation is the primary degradation pathway of curcumin

[59]

3

Polymeric micelles Polymeric micelles Polymeric micelles Polymeric micelles

Synthesis of block polymers followed by solvent evaporation by vigorous stirring Continuous processing Solvent evaporation method Ultrasonic pretreatment Single-step solid dispersion method

[60] [61] [62]

[63]

[64]

[65]

[66] [67]

14

CHAPTER 1 Nanotechnology based delivery of nutraceuticals

plasma is produced. Metal vapors are generated and move toward a cold collector rod, where nanoparticles are collected. Finally, the collected nanoparticles are passivated with oxygen. [73]. Physical vapor deposition (PVD) Herein, the solid metallic material is converted to vapors under vacuum. Then, vapors are allowed to redeposit on the target site. This is one of the feasible approaches to depositing diverse materials into thin films and nanostructures [74]. Microwave irradiation This technique irradiates the material with microwave radiation to produce nanoparticles [75]. Pulsed laser method AgNPs are mostly synthesized using this method. A revolving disc is used to mix the AgNO3 solution and a reducing agent. The disc is laserirradiated to generate hot spots on its surface. AgNPs are produced at hot spots due to the reaction of AgNO3 and the reducing agent. Nanoparticles can be separated by centrifugation [76]. Sonochemical reduction Sonochemistry is the field where the corresponding metal ion reduction is facilitated by its exposure to powerful ultrasound radiation (20 kHz–10 MHz) [77]. With a smaller diameter and uniform distribution, ultrasound radiation can synthesize nanoparticles without external reducing agents or capping agents [78]. Gamma radiation Gamma radiation produces solvated electrons by water radiolysis. Electrons are disseminated evenly in the medium to reduce the oxidation state of solvated metal ions [79]. Chemical methods. Polyol method This method is an approach for preparing distinct metallic nanoparticles of appropriate size, shape, and composition and is considered to be suitable for large-scale production. Herein, the metal precursor suspended in the high boiling polyol is reduced [80]. Different polyols having low to high molecular weights can be used. Ethylene glycol is generally used as a solvent while synthesizing metal oxide nanoparticles [76,81]. Microemulsion method Microemulsion-assisted fabrication of nanomaterials is a more robust strategy than other conventional synthesis methods. In brief, the technique commonly involves combining the two microemulsion systems containing metal salt and a reducing agent [82]. Biological methods. These approaches employ the manufacture of nontoxic metallic nanoparticles using plants, algae, fungi, bacteria, and viruses [83]. Furthermore, metal and metal oxide nanoparticles can be reduced and capped by enzymes and chemicals found in biological systems [84].

Advantages [71,85,86] Range of surface modification strategies. In general, administered nanoparticles bind to different receptors nonselectively and can cause unwanted or undesirable effects. Surface functionalization is a promising approach for circumventing the limitations of nonselective treatment modes and increasing the physicochemical

5 Nanoscale systems for delivery of nutraceuticals

properties of nanomaterials. The metallic and metal oxide nanoparticles have been functionalized on their surfaces in order to improve their targeting capabilities. Biocompatibility. Metals used in nanosystems must be biocompatible and not cause adverse effects on the host. The surface charge of nanomaterials or other parameters can influence the behavior of nanoparticles administered within the body. The entrapment of the metallic core by biomolecules improves biocompatibility. High stability. Metallic nanoparticles are highly stable and prevent pH-based drug degradation. The stability of metal or metal oxide nanomaterials is correlated with their size. Strong plasma absorption. Strong surface plasma resonance is the characteristic of metal nanoparticles. This phenomenon occurs when light strikes metallic nanoparticles. Here, the electrons on the metal surface are excited by photons. This parameter is useful in sensing devices. Biological system imaging. Metallic nanoparticles are well-known for scattering incident light and providing label-free sensing. This is also useful for studying and comprehending the interactions between nanoparticles and cells.

Disadvantages [71] Difficulty in scaling up the synthesis process. Interest in the synthesis of metal nanomaterials has drastically increased owing to their distinct properties. However, several process variables, such as temperature, pH of the system, and particle size, influence nanoparticle synthesis. Cytotoxicity. Reactive oxygen species (ROS) are produced in the body after the administration of metal nanoparticles. The cell membrane and DNA can be damaged by these ROS, which can lead to oxidative stress [87]. The electron transport chain is also dysregulated. Metallic nanoparticles have also been linked to charge-based toxicity. These nanoparticles cause inflammatory responses in the lungs as well [88]. Detailed toxic effects of metal nanoparticles are shown in Fig. 1.6.

Examples In the recent decade, the delivery of nutraceuticals through nanoparticles has received the great attention of several researchers. The findings of some research groups are summarized below (Table 1.4).

5.2.2 Quantum dots Quantum dots with sizes ranging from 2 to 10 nm emit fluorescence on excitation with a light source [103,104]. They have been widely used in biological and biomedical applications [38]. Reportedly, quantum dots have ample applications in the pharmaceutical sector, diagnosis, immunolabeling, and cell labeling tools [105].

15

16

CHAPTER 1 Nanotechnology based delivery of nutraceuticals

Activating tissue invasion and metastasis Phagocytosis

Cancer cells

Healty cells

Cancer progression

Metal NPs DNA damage Membrane damage Genome instability Mutation Loss of tumor suppressor genes

Oxidative stress increased ROS Production

ER stress ROS

NPs and metal ions interaction with cellular components: proteins, enzymes, DNA, cellular structures

ROS Metal ions release ROS

ROS

Phagosome

mitochondrium dysregulation and damage

Inflammation Genotoxicity Organelle dysfunction Energetics deregulation

Promotion (proliferation)

Affected cell

Apoptosis, Ferroptosis (cell toxicity)

Cell death

FIG. 1.6 Oxidative stress, inflammation, and genotoxicity from phagocytosed metallic NPs lead to cell death and cancer promotion. Adapted from S. Medici, M. Peana, A. Pelucelli, M.A. Zoroddu, An updated overview on metal nanoparticles toxicity, Semin. Cancer Biol. 76 (2021) 17–26. https://doi.org/10.1016/j.semcancer.2021.06. 020, with permission from Elsevier.

Preparation methods Formation of nano-sized semiconductor particles. In this technique, semiconductor precursors are swiftly injected into hot organic solvents containing molecules that direct quantum dot precipitation [106]. Epitaxial growth-lithography. Lithography technology produces quantum dots by combining high-resolution electron beam lithography and subsequent etching. However, quantum dots prepared with this technique suffer from numerous limitations [106,107]. Preparation of quantum dots through epitaxial mode follows the Stranski-Krastanov way of growth on the wetting layer with the formation of coherent islands without etching [106].

Advantages Quantum dots possess distinct optical and electronic properties, i.e., size-tunable emission, intense brightness, resistance to photobleaching, etc. Quantum dots with diverse compositions and dimensions can be prepared. They possess superior

Table 1.4 Examples of nutraceuticals delivered using metal or metal oxide nanoparticles. Sr. no.

Nutraceuticals

Source

Type

Method

Key findings

References

Crotalaria tetragona Capsicum annuum extract

AgNPs

Sunlight mediated

AgNPs

Photo-mediation

3

Yogurt

AuNPs

Photo-activated synthesis

4

Apigenin

Punica granatum L. Seed oil Flavonoid

AuNPs

–

5

Curcumin

AuNPs

6

Nonthermal process Hydrothermal approach A wet chemical process/surface modification process Chemical reduction method

Enhanced antibiofilm effect against foodborne pathogens Augmented bacteriostatic and bactericidal effect against Staphylococcus aureus Functional yogurt showed in vitro antioxidant and anticancer activities Improved anticancer effect against human cervical cancer Improved antibacterial activity against different strains High biocidal activity against bacteria and fungi Enhanced antioxidant and antibacterial activity against methicillin-resistant S. aureus

[89]

2

Afzelin and quercetrin Capsaicinoids

1

Catechin

Curcuma pseudomontana –

ZnO nanoparticles

7

Gallic acid

Antioxidant

ZnO nanoparticles

8

Plumbagin

Colloidal AgNPs

9

Folic acid

Roots of Plumbago indica –

10

Resveratrol

–

11

Plumbagin

P. indica

12

Catechin

Flavonoid

13

Gallic acid

Antioxidant

14

Tea polyphenol

Polyphenol

Iron oxide nanoparticles Gold nanoparticles AgNPs Magnetic iron oxide nanoparticles Iron oxide Nanoparticles

Magnetite nanoparticles

Coupling chemistry approach Green nanotechnology Oxido-reduction method The free radical grafting process Oxidationprecipitation of ferrous hydroxide method –

Improved the antiproliferative, antimitotic, and apoptotic activities Enhanced targetability in prostate cancer Enhanced activity against human breast cancer cells Enhanced sensitivity and selectivity toward cancer cells Induction of apoptosis in 98% of pancreatic tumor cells

[90]

[91]

[92] [93] [94] [95]

[96]

[97] [98] [99] [100]

Enhanced antioxidant and antimicrobial effects

[101]

Enhanced biocompatibility of nanoparticles

[102]

18

CHAPTER 1 Nanotechnology based delivery of nutraceuticals

photochemical stability than organic dyes or fluorescent proteins. Furthermore, the associated bright photoluminescence property enhances the sensitivity of in vivo imaging [108].

Disadvantages The use of quantum dots in imaging is associated with poor optical signal diffusion depth. The use of quantum dots also causes intrinsic toxicity. This toxicity could be assigned to the degradation of quantum dots, releasing free cadmium, and generating reactive oxygen species [109]. Instability and augmentation in hydrodynamic diameter following contact with serum proteins is also the limiting factor for quantum dot use [108].

Examples Quantum dot applications for nutraceutical delivery are shown below (Table 1.5),

5.2.3 Nanocomposite Composites are solid substances that are either engineered or produced by natural processes when two or additional diverse components with distinct physical or chemical characteristics are mixed to achieve a newer material that offers better properties than the original one [116,117]. Nanocomposites are multi-phase composites comprising one phase that has a nanoscale range (1–100 nm) like nanoparticles, nanotubes, etc. [118]. Properties of nanocomposites mainly rely on the dispersed matrix and phase materials [119]. The nanocomposites are further categorized as polymeric and nonpolymeric nanocomposites. Nonpolymeric nanocomposites are also termed inorganic nanocomposites and are classified as follows [120]: (1) Metal-based, (2) Ceramic-based, and (3) Ceramic-ceramic-based nanocomposites

Preparation methods Polymer nanocomposites are generally prepared using different methods and are categorized under four significant classes, i.e., (1) melt intercalation, (2) exfoliation adsorption, (3) in situ polymerization intercalation, and (4) template synthesis. Melt intercalation (melt blending). This technique is the most standard approach to preparing polymeric nanocomposites. Herein, the polymer and filler are mixed in the molten state at high temperatures under shear stress (extrusion or injection molding) to achieve uniform distribution. It involves no solvent use, thus making

Table 1.5 Examples of nutraceuticals delivered using quantum dots. Sr. no.

Nutraceutical

Type

Assay/model

Key findings

Reference

1

Quercetin

Cdse/ZnS quantum dots

Nitric oxide (NO) and assay

[110]

2

Quercetin

Cadmium telluride quantum dots

Superoxide anion scavenging assays

3

Rutin

Disc diffusion method

4

5

Aqueous extract of Merremia emarginata leaves Quercetin

Cadmium telluride quantum dots –

Flavonoid detection potential increased Enhanced cartilage regeneration was noted Enhanced antimicrobial effect Enhanced the antimicrobial activity

Curcumin

Methylthiazolyldiphenyltetrazolium bromide assay MTT assay

Enhanced proliferation of cancer cells Improved cytotoxicity against MCF-7 cells

[114]

6

Cadmium telluride quantum dots Glucosamine-conjugated graphene quantum dots

Lipid peroxidation activity, disc diffusion method, etc.

[111]

[112] [113]

[115]

20

CHAPTER 1 Nanotechnology based delivery of nutraceuticals

it a more convenient and economical process. The temperature should be controlled to avoid damage to the filler used [121–123]. Exfoliation adsorption (solvent casting). Exfoliation adsorption is a solution blending method. In this method, the solvent system that can solubilize the polymer or prepolymer and swells the nanofiller is selected. First, the nanofiller is allowed to swell and then mixed with the polymeric solution. The polymeric chain intercalates and displaces the solvent. The intercalated structure without the solvent remains intact, which results in nanocomposites [121–124]. In situ polymerization. In this method, nanofillers are allowed to swell within a monomer or its solution to polymerize between intercalated layers and generate nanocomposites. Polymerization can be facilitated by heat, radiation, or catalyst [121,124,125]. Template synthesis. This process entails creating the inorganic filler within an aqueous solution or polymeric gel and filler blocks. In this case, the polymer functions as a nucleating agent and promotes inorganic filler crystal formation. The polymer intercalates between the layers at this point, resulting in nanocomposites. [121,123].

Advantages Nanocomposites are lighter than traditional composites. In addition, they have better barrier properties than the pure polymer. The mechanical, thermal, and biodegradability properties of nanocomposites can be improved by using polymeric components [126].

Disadvantages Nanocomposites have a few drawbacks. They have a problem with long-term storage stability. Nanocomposites are also linked to a lack of structural integrity. Nanocomposites may corrode. Cytotoxicity is a significant concern for nanocomposites, just as it is for conventional nanoparticles [127].

Examples See Table 1.6.

Table 1.6 Examples of nutraceuticals delivered using nanocomposites. Sr. no.

Nutraceutical

Nanocomposite type

Key findings

References

1

Curcumin

Nanocomposites showed high antioxidant activity

[128]

2

Curcumin Curcumin

4

Quercetin

5

7

Lactobacillus rhamnosus GG Kluyveromyces lactis (probiotic microorganisms) Apigenin

Improved anticancer effect against MCF-7 and A549 cells Nanocomposites restored nerve damage and maintained neuronal morphology Improved anticancer activity against MCF-7 cells with high biocompatibility (3T3-L1 cells) Enhanced intestinal delivery of probiotics

[129]

3

Caseinate-laponite nanocomposites Graphene oxide nanocomposites Fe3O4 carbon dot nanocomposite Zinc oxide nanocomposite

8

Quercetin

9 10

Curcumin Resveratrol

11

Resveratrol

12

Citrus pectin

6

Bentonite/alginate nanocomposite Gelatin-graphene oxide nanocomposite Magnetic Fe2O3/ Fe3O4 nanocomposites Graphene oxide/iron oxide/Au nanocomposite Fe3O4 nanocomposites Nanocomposites Nanocomposites in situ gelling films Pectin-MgO nanocomposite

[129] [130] [131]

Higher mechanical stability and integrity in simulated conditions Enhanced magnetic targeting and active hyaluronic acid-targeting in lung cancer Favorable magnetization achieved

[132]

Improved antibacterial efficiency was observed Enhanced antiproliferation activity against ovarian cells The improved anticolorectal cancer effect

[135] [136]

Potent antibacterial activity and higher antioxidant activity than pectin

[137]

[133] [134]

[136]

22

CHAPTER 1 Nanotechnology based delivery of nutraceuticals

6. Physicochemical properties and characterization of nanoparticles Nanoparticle physicochemical properties can be explored with appropriate characterization techniques. So far, various characterization techniques have been reported (Table 1.7).

7. Combination of nutraceuticals along with chemotherapeutic drugs using nanocarriers Nutraceuticals have been employed as treatments for various ailments in the past. The advantages to one’s health are considerable. As a result, most research groups are interested in examining the possibilities. However, there are several drawbacks to using nutraceuticals, such as stability and solubility. Other naturally derived or synthetic compounds are delivered alongside nutraceuticals to produce a synergistic impact. A few instances of this type of research are provided in Table 1.8. Table 1.7 Characterization techniques for nanoparticles. Parameters

Characterization techniques

References

Particle size and size distribution

Photon correlation spectroscopy (PCS) Transmission electron microscopy (TEM) Atomic force microscopy (AFM) Zetasizer Wide-angle X-ray diffraction (WAXD), smallangle X-ray scattering (SAXS), scanning electron microscopy (SEM), and transmission electron microscopy (TEM) X-ray powder diffraction Differential scanning calorimetry Thermogravimetric analysis Differential scanning calorimetry

[138]

Zeta potential Structural and morphological characterization Solid-state characterization Thermal behavior

[139] [126,137]

[80] [137]

Table 1.8 Example of nutraceuticals co-delivered with chemotherapeutic drugs through nanoparticles. Sr. no.

Nutraceutical and drug combination

Type of nanoparticles

1

Curcuminerlotinib conjugate

Nanoassembly

2

Curcumin and paclitaxel

Albumin nanoparticles

Key findings

References

Extension in the median survival time of the tumor-bearing mice Improved performance in pancreatic cancer (MIA Paca-2 cells)

[139]

[140]

8 Conclusion and future scope

Table 1.8 Example of nutraceuticals co-delivered with chemotherapeutic drugs through nanoparticles—cont’d Nutraceutical and drug combination

Type of nanoparticles

3

Curcumin and doxorubicin

Polymeric nanoparticles

4

Curcumin and doxorubicin

Albumin nanoparticles

5

Quercetin and doxorubicin

Phytosomes

6

Quercetin and alantolactone

Nano-micelles

7

Quercetin and doxorubicin

8

Resveratrol and doxorubicin

Mesoporous silica nanoparticles PLGA nanoparticles

9

Resveratrol and paclitaxel Resveratrol and docetaxel

Polymeric nanoparticles Polymeric micelles

Quercetin and tamoxifen

PLGA nanoparticles

Sr. no.

10

11

Key findings

References

Synergistic cytotoxic and apoptotic effects on invasive B cell lymphoma Inhibition of adaptive treatment tolerance of cancer cells Increased apoptosis of MCF-7 breast cancer cells Synergistic immunogenic cell death was noted Enhanced activity against gastric carcinoma Significant inhibition of the DOX-resistant tumor growth Improved antiglioma activity Enhanced in vitro cytotoxicity against MCF-7 cells 3-fold increase in oral bioavailability was noted

[141]

[142]

[143]

[144]

[145]

[146]

[147] [148]

[149]

8. Conclusion and future scope Researchers have been paying close attention to the concept of a nutraceuticalloaded nanoparticulate systems in recent years due to their numerous benefits. The nanoparticulate systems have shown tremendous potential in augmenting the therapeutic potential of nutraceuticals and contributing to societal health improvement. Nutraceuticals can be entrapped within nanosystems to advance their aqueous stability, lumenal stability, and bioavailability. This increases the time that nutraceuticals circulate within the body. Further administration of nutraceuticals in combination with various synthetic substances appears to be beneficial. Various nutraceutical-based nanoformulations will undoubtedly hit the market in the future years.

23

24

CHAPTER 1 Nanotechnology based delivery of nutraceuticals

References [1] L. Zhang, F.X. Gu, J.M. Chan, A.Z. Wang, R.S. Langer, O.C. Farokhzad, Nanoparticles in medicine: therapeutic applications and developments, Clin. Pharmacol. Therapeut. 83 (5) (2008) 761–769. [2] I. Sanzari, A. Leone, A. Ambrosone, Nanotechnology in plant science: to make a long story short, Front. Bioeng. Biotechnol. 7 (2019) 120. [3] B. Bhushan, Introduction to nanotechnology, in: Springer Handbook of Nanotechnology, Springer, Berlin, Heidelberg, 2017, pp. 1–19. [4] A. Erfanian, H. Mirhosseini, B. Rasti, M. Hair-Bejo, S.B. Mustafa, M.Y.A. Manap, Absorption and bioavailability of nano-size reduced calcium citrate fortified milk powder in ovariectomized and ovariectomized-osteoporosis rats, J. Agric. Food Chem. 63 (24) (2015) 5795–5804. [5] M. Sessa, M.L. Balestrieri, G. Ferrari, L. Servillo, D. Castaldo, N. D’Onofrio, et al., Bioavailability of encapsulated resveratrol into nanoemulsion-based delivery systems, Food Chem. 147 (2014) 42–50. [6] B.Z. Tang, Y. Wang, P. Podsiadlo, N.A. Kotov, Biomedical applications of layer-bylayer assembly: from biomimetics to tissue engineering, Adv. Mater. 2136 (2006) 3203–3224, https://doi.org/10.1002/adma.200600113. [7] M.N. Khan, M. Mobin, Z.K. Abbas, K.A. AlMutairi, Z.H. Siddiqui, Role of nanomaterials in plants under challenging environments, Plant Physiol. Biochem. 110 (2017) 194–209, https://doi.org/10.1016/j.plaphy.2016.05.038. [8] M. Nasrollahzadeh, S.M. Sajadi, M. Sajjadi, Z. Issaabadi, An Introduction to Green Nanotechnology, 2019, pp. 1–27, https://doi.org/10.1016/b978-0-12-813586-0.00001-8. [9] J.K. Sahni, Exploring delivery of nutraceuticals using nanotechnology, Int. J. Pharmaceut. Investig. 2 (2) (2012) 53. [10] D. Bhowmik, H. Gopinath, B.P. Kumar, S. Duraivel, K.S. Kumar, Nutraceutical-a bright scope and opportunity of Indian healthcare market, Pharm. Innov. 1 (11, Part A) (2013) 29. [11] A. Santini, S.M. Cammarata, G. Capone, A. Ianaro, G.C. Tenore, L. Pani, E. Novellino, Nutraceuticals: opening the debate for a regulatory framework, Br. J. Clin. Pharmacol. 84 (4) (2018) 659–672. [12] E.T. Klatte, D.W. Scharre, H.N. Nagaraja, R.A. Davis, D.Q. Beversdorf, Combination therapy of donepezil and vitamin E in Alzheimer disease, Alzheimer Dis. Assoc. Disord. 17 (2) (2003) 113–116. [13] K. Hager, A. Marahrens, M. Kenklies, P. Riederer, G. M€ unch, Alpha-lipoic acid as a new treatment option for Azheimer type dementia, Arch. Gerontol. Geriatr. 32 (3) (2001) 275–282. [14] C.J. Dillard, J.B. German, Phytochemicals: nutraceuticals and human health, J. Sci. Food Agric. 80 (12) (2000) 1744–1756. [15] S. Franceschi, E. Bidoli, C.L. Vecchia, R. Talamini, B. D’Avanzo, E. Negri, Tomatoes and risk of digestive-tract cancers, Int. J. Cancer 59 (2) (1994) 181–184. [16] N.S. Kwak, D.J. Jukes, Functional foods. Part 1: the development of a regulatory concept, Food Control 12 (2) (2001) 99–107, https://doi.org/10.1016/S0956-7135(00) 00028-1. [17] R.K. Keservani, R.K. Kesharwani, A.K. Sharma, S.P. Gautam, S.K. Verma, Nutraceutical formulations and challenges, in: Developing New Functional Food and Nutraceutical Products, Academic Press, 2017, pp. 161–177, https://doi.org/10.1016/B9780-12-802780-6.00009-2.

References

[18] S.A. Rafat, M.H. Moghadasian, Nutraceuticals and nutrition supplements: challenges and opportunities, Nutrients 12 (6) (2020) 1593, https://doi.org/10.3390/nu12061593. [19] S.W. Page, J.E. Maddison, Principles of clinical pharmacology, in: Small Animal Clinical Pharmacology, 2, 2008, pp. 1–26, https://doi.org/10.1016/B978-070202858-8.50003-8. [20] E. Acosta, Bioavailability of nanoparticles in nutrient and nutraceutical delivery, Curr. Opin. Colloid Interface Sci. 14 (1) (2009) 3–15, https://doi.org/10.1016/j. cocis.2008.01.002. [21] M. Yao, D.J. McClements, H. Xiao, Improving oral bioavailability of nutraceuticals by engineered nanoparticle-based delivery systems, Curr. Opin. Food Sci. 2 (2015) 14–19, https://doi.org/10.1016/j.cofs.2014.12.005. [22] S. Punia, K.S. Sandhu, M. Kaur, A.K. Siroha, Nanotechnology: A successful approach to improve nutraceutical bioavailability, in: Nanobiotechnology in Bioformulations, Springer, Cham, 2019, pp. 119–133, https://doi.org/10.1007/978-3-030-17061-5_5. [23] D.J. McClements, E.A. Decker, Y. Park, J. Weiss, Structural design principles for delivery of bioactive components in nutraceuticals and functional foods, Crit. Rev. Food Sci. Nutr. 49 (6) (2009) 577–606, https://doi.org/10.1080/10408390902841529. [24] J. Chen, L. Hu, Nanoscale delivery system for nutraceuticals: preparation, application, characterization, safety, and future trends, Food Eng. Rev. 12 (1) (2020) 14–31, https:// doi.org/10.1007/s12393-019-09208-w. [25] A. Ali, U. Ahmad, J. Akhtar, M.M. Khan, Engineered nano scale formulation strategies to augment efficiency of nutraceuticals, J. Funct. Foods 62 (2019), 103554, https://doi. org/10.1016/j.jff.2019.103554. [26] L. Katata-Seru, B. Ramalapa, L. Tshweu, Nanoformulated delivery systems of essential nutraceuticals and their applications, in: Nanoemulsions-Properties, Fabrications and Applications, IntechOpen, 2019. [27] S. Mitragotri, P. Stayton, Organic nanoparticles for drug delivery and imaging, MRS Bull. 39 (3) (2014) 219–223. [28] M.J.R. Virlan, D. Miricescu, R. Radulescu, C.M. Sabliov, A. Totan, B. Calenic, et al., Organic nanomaterials and their applications in the treatment of oral diseases, Molecules 21 (2) (2016) 1–23. [29] F. Fang, M. Li, J. Zhang, C.S. Lee, Different strategies for organic nanoparticle preparation in biomedicine, ACS Mater. Lett. 2 (5) (2020) 531–549. [30] R.K. Shatrohan Lal, Synthesis of organic nanoparticles and their applications in drug delivery and food nanotechnology: a review, J. Nanomater. Mol. Nanotechnol. 03 (04) (2014). [31] S.J. Nadaf, S.G. Killedar, Novel liposome derived nanoparticulate drug delivery system: fabrication and prospects, Creat. J. Pharm. Res. 1 (3) (2015) 117–128. [32] A. Jain, P. Hurkat, S.K. Jain, Development of liposomes using formulation by design: basics to recent advances, Chem. Phys. Lipids [Internet] 224 (February) (2019) 104764, https://doi.org/10.1016/j.chemphyslip.2019.03.017. [33] C. Li, Y. Deng, A novel method for the preparation of liposomes: freeze drying of monophase solutions, J. Pharm. Sci. 93 (6) (2004) 1403–1414. [34] C.M.B. Pinilla, R.C.S. Thys, A. Brandelli, Antifungal properties of phosphatidylcholine-oleic acid liposomes encapsulating garlic against environmental fungal in wheat bread, Int. J. Food Microbiol. [Internet] 293 (January) (2019) 72–78,https://doi.org/10.1016/j.ijfoodmicro.2019.01.006. [35] F. Keivani Nahr, B. Ghanbarzadeh, H. Hamishehkar, H.S. Kafil, M. Hoseini, B.E. Moghadam, Investigation of physicochemical properties of essential oil loaded nanoliposome for enrichment purposes, Lwt 105 (February) (2019) 282–289.

25

26

CHAPTER 1 Nanotechnology based delivery of nutraceuticals

[36] B. Li, F. Zheng, J.P.R. Chauvin, D.A. Pratt, The medicinal thiosulfinates from garlic and Petiveria are not radical-trapping antioxidants in liposomes and cells, but lipophilic analogs are, Chem. Sci. 6 (11) (2015) 6165–6178. [37] C.M.B. Pinilla, P.M. Reque, A. Brandelli, Effect of oleic acid, cholesterol, and octadecylamine on membrane stability of freeze-dried liposomes encapsulating natural antimicrobials, Food Bioprocess Technol. 13 (4) (2020) 599–610. [38] B. Sinjari, J. Pizzicannella, M. D’Aurora, R. Zappacosta, V. Gatta, A. Fontana, et al., Curcumin/liposome nanotechnology as delivery platform for anti-inflammatory activities via NFkB/ERK/pERK pathway in human dental pulp treated with 2-HydroxyEthyl MethAcrylate (HEMA), Front. Physiol. 10 (June) (2019) 1–11. [39] M. Mahmud, A. Piwoni, N. Filiczak, M. Janicka, J. Gubernator, Long-circulating curcumin-loaded liposome formulations with high incorporation efficiency, stability and anticancer activity towards pancreatic adenocarcinoma cell lines in vitro, PLoS One 11 (12) (2016) 1–23. [40] V. De Leo, F. Milano, E. Mancini, R. Comparelli, L. Giotta, A. Nacci, et al., Encapsulation of curcumin-loaded liposomes for colonic drug delivery in a pHresponsive polymer cluster using a pH-driven and organic solvent-free process, Molecules 23 (4) (2018) 1–15. [41] H. Cui, W. Li, L.L. Changzhu Li, Intelligent release of cinnamon oil from engineered proteoliposome via stimulation of Bacillus cereus protease, Food Control 67 (2016) 68–74. [42] H. Cui, W. Li, C. Li, S. Vittayapadung, L. Lin, Liposome containing cinnamon oil with antibacterial activity against methicillin-resistant Staphylococcus aureus biofilm, Biofouling 32 (2) (2016) 215–225. [43] M. Al-Moghazy, H.S. El-sayed, H.H. Salama, A.A. Nada, Edible packaging coating of encapsulated thyme essential oil in liposomal chitosan emulsions to improve the shelf life of Karish cheese, Food Biosci. [Internet] 43 (April) (2021), 101230, https://doi.org/ 10.1016/j.fbio.2021.101230. [44] S. Weber, A. Zimmer, J. Pardeike, Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) for pulmonary application: a review of the state of the art, Eur. J. Pharm. Biopharm. [Internet] 86 (1) (2014) 7–22, https://doi.org/10.1016/j. ejpb.2013.08.013. [45] K. Westesen, B. Siekmann, Biodegradable colloidal drug carrier systems based on solid lipids, in: Microencapsulation, Marcel Dekker, New York, 1996, pp. 213–258. [46] M. Bhalekar, P. Upadhaya, A. Madgulkar, Formulation and characterization of solid lipid nanoparticles for an anti-retroviral drug darunavir, Appl. Nanosci. 7 (1–2) (2017) 47–57. [47] D. Chirio, E. Peira, C. Dianzani, E. Muntoni, C.L. Gigliotti, B. Ferrara, et al., Development of solid lipid nanoparticles by cold dilution of microemulsions: curcumin loading, preliminary in vitro studies, and biodistribution, Nano 9 (2) (2019). [48] A. Valizadeh, A.A. Khaleghi, G. Roozitalab, M. Osanloo, High anticancer efficacy of solid lipid nanoparticles containing Zataria multiflora essential oil against breast cancer and melanoma cell lines, BMC Pharmacol. Toxicol. 22 (1) (2021) 1–7. [49] Lakhani P., Patil A., Taskar P., Ashour E., Majumdar S., Curcumin-loaded nanostructured lipid carriers for ocular drug delivery: design optimization and characterization. J. Drug. Deliv. Sci. Technol. [Internet] 2018; 47: 159–66. Available from: doi:https:// doi.org/10.1016/j.jddst.2018.07.010.

References

[50] H. Ji, J. Tang, M. Li, J. Ren, N. Zheng, L. Wu, Curcumin-loaded solid lipid nanoparticles with Brij78 and TPGS improved in vivo oral bioavailability and in situ intestinal absorption of curcumin, Drug Deliv. 23 (2) (2016) 459–470. [51] D. Chirio, M. Gallarate, M. Trotta, M.E. Carlotti, E.C. Gaudino, G. Cravotto, Influence of α- and γ- cyclodextrin lipophilic derivatives on curcumin-loaded SLN, J. Incl. Phenom. Macrocycl. Chem. 65 (3) (2009) 391–402. [52] L. Minafra, N. Porcino, V. Bravata`, D. Gaglio, M. Bonanomi, E. Amore, et al., Radiosensitizing effect of curcumin-loaded lipid nanoparticles in breast cancer cells, Sci. Rep. 9 (1) (2019) 1–16. [53] S.V.K. Rompicharla, H. Bhatt, A. Shah, N. Komanduri, D. Vijayasarathy, B. Ghosh, et al., Formulation optimization, characterization, and evaluation of in vitro cytotoxic potential of curcumin loaded solid lipid nanoparticles for improved anticancer activity, Chem. Phys. Lipids [Internet] 208 (2017) 10–18, https://doi.org/10.1016/j.chemphyslip.2017.08.009. [54] E. Sadati Behbahani, M. Ghaedi, M. Abbaspour, K. Rostamizadeh, K. Dashtian, Curcumin loaded nanostructured lipid carriers: in vitro digestion and release studies, Polyhedron [Internet] 164 (2019) 113–122, https://doi.org/10.1016/j.poly.2019.02.002. [55] V.K. Rapalli, V. Kaul, T. Waghule, S. Gorantla, S. Sharma, A. Roy, et al., Curcumin loaded nanostructured lipid carriers for enhanced skin retained topical delivery: optimization, scale-up, in-vitro characterization and assessment of ex-vivo skin deposition, Eur. J. Pharm. Sci. [Internet] 152 (2020) 105438, https://doi.org/10.1016/j. ejps.2020.105438. [56] D.H. Shin, Y.T. Tam, G.S. Kwon, Polymeric micelle nanocarriers in cancer research, Front. Chem. Sci. Eng. 10 (3) (2016) 348–359. [57] V.K. Mourya, N. Inamdar, R.B. Nawale, S.S. Kulthe, Polymeric micelles: general considerations and their applications, Indian J. Pharm. Educ. Res. 45 (2) (2011) 128–138. [58] A. Sosnik, R.M. Menaker, Polymeric micelles in mucosal drug delivery: challenges towards clinical translation, Biotechnol. Adv. [Internet] 33 (6) (2015) 1380–1392,https://doi.org/10.1016/j.biotechadv.2015.01.003. [59] F. Huang, Y. Gao, Y. Zhang, T. Cheng, H. Ou, L. Yang, et al., Silver-decorated polymeric micelles combined with curcumin for enhanced antibacterial activity, ACS Appl. Mater. Interfaces 9 (20) (2017) 16880–16889. [60] A. Gupta, A.P. Costa, X. Xu, S.L. Lee, C.N. Cruz, Q. Bao, et al., Formulation and characterization of curcumin loaded polymeric micelles produced via continuous processing, Int. J. Pharm. [Internet] 583 (January) (2020) 119340, https://doi.org/10.1016/j. ijpharm.2020.119340. [61] R. Yang, S. Zhang, D. Kong, X. Gao, Y. Zhao, Z. Wang, Biodegradable polymercurcumin conjugate micelles enhance the loading and delivery of low-potency curcumin, Pharm. Res. 29 (12) (2012) 3512–3525. [62] X. Yang, Z. Li, N. Wang, L. Li, L. Song, T. He, et al., Curcumin-encapsulated polymeric micelles suppress the development of colon cancer in vitro and in vivo, Sci. Rep. 5 (May) (2015) 1–15. [63] M. Bagheri, M.H. Fens, T.G. Kleijn, R.B. Capomaccio, D. Mehn, P.M. Krawczyk, et al., In vitro and in vivo studies on HPMA-based polymeric micelles loaded with curcumin, Mol. Pharm. 18 (3) (2021) 1247–1263. [64] P. Keshari, Y. Sonar, H. Mahajan, Curcumin loaded TPGS micelles for nose to brain drug delivery: in vitro and in vivo studies, Mater. Technol. [Internet] 34 (7) (2019) 423–432, https://doi.org/10.1080/10667857.2019.1575535.

27

28

CHAPTER 1 Nanotechnology based delivery of nutraceuticals

[65] A. Patra, S. Satpathy, A.K. Shenoy, J.A. Bush, M. Kazi, M.D. Hussain, Formulation and evaluation of mixed polymeric micelles of quercetin for treatment of breast, ovarian, and multidrug resistant cancers, Int. J. Nanomedicine 13 (2018) 2869–2881. [66] J.Y. An, H.S. Yang, N.R. Park, T.-s. Koo, B. Shin, E.H. Lee, et al., Development of polymeric micelles of oleanolic acid and evaluation of their clinical efficacy, Nanoscale Res. Lett. 15 (1) (2020). [67] O. Naksuriya, M.J. Vansteenbergen, J.S. Torano, S. Okonogi, W.E. Hennink, A kinetic degradation study of curcumin in its free form and loaded in polymeric micelles, AAPS J. 18 (3) (2016) 777–787. [68] J. Zhang, L. Chen, W.H. Tse, R. Bi, L. Chen, Inorganic nanoparticles, engineering for biomedical applications, IEEE Nanotechnol. Mag. 8 (2014) 21–28. [69] W. Paul, C.P. Sharma, Inorganic nanoparticles for targeted drug delivery, in: P. Chandra (Ed.), Biointegration of Medical Implant Materials, second ed., Woodhead Publishing, 2020, pp. 333–373, https://doi.org/10.1016/B978-0-08-102680-9.00013-5. ˆ nanotechnology, in: [70] A.I. Lo´pez-Lorente, M. Valca´rcel, Analytical nanoscience and A M. Valca´rcel, A.I. Lo´pez-Lorente (Eds.), Comprehensive Analytical Chemistry, Elsevier, 2014, pp. 3–35, https://doi.org/10.1016/B978-0-444-63285-2.00001-8. [71] K.K. Harish, V. Nagasamy, B. Himangshu, K. Anuttam, Metallic nanoparticle: a review, Biomed. J. Sci. Tech. Res. 4 (2) (2018) 3765–3775, https://doi.org/10.26717/ BJSTR.2018.04.001011. [72] G. Saito, T. Akiyama, Nanomaterial synthesis using plasma generation in liquid, J. Nanomater. (2015) 1–21, https://doi.org/10.1155/2015/123696. [73] B.K. Kafle, Introduction to nanomaterials and application of UV^a€ visible spectroscopy for their characterization, in: Chemical Analysis and Material Characterization by Spectrophotometry, 2020, pp. 147–198, https://doi.org/10.1016/B978-0-12814866-2.00006-3. [74] Y.K. Yap, Physical vapor deposition, in: B. Bhushan (Ed.), Encyclopedia of Nanotechnology, Springer, Dordrecht, 2012. [75] C. Vollmer, E. Redel, K. Abu-Shandi, R. Thomann, H. Manyar, C. Hardacre, et al., Microwave irradiation for the facile synthesis of transition-metal nanoparticles (NPs) in ionic liquids (ILs) from metal-carbonyl precursors and Ru-, Rh-, and Ir-NP/IL dispersions as biphasic liquid-liquid hydrogenation nanocatalysts for cyclohexene, Chemistry 16 (12) (2010) 3849–3858, https://doi.org/10.1002/chem.200903214. [76] T. Cele, Preparation of nanoparticles, in: S.M. Avramescu, K. Akhtar, I. Fierascu, S.B. Khan, F. Ali, A.M. Asiri (Eds.), Engineered Nanomaterials - Health and Safety [Internet], IntechOpen, London, 2020, https://doi.org/10.5772/intechopen.90771. Available from: https://www.intechopen.com/chapters/71103. [77] K. Okitsu, R. Nishimura, Sonochemical reduction method for controlled synthesis of metal nanoparticles in aqueous solutions, in: Proceedings of 20th International Congress on Acoustics, ICA 2010, Sydney, Australia, 2010, pp. 23–27. [78] C.U. Okoli, K.A. Kuttiyiel, J. Cole, J. McCutchen, H. Tawfik, R.R. Adzic, et al., Solvent effect in sonochemical synthesis of metal-alloy nanoparticles for use as electrocatalysts, Ultrason. Sonochem. 41 (2018) 427–434, https://doi.org/10.1016/j. ultsonch.2017.09.049. [79] G.G. Flores-Rojas, F. Lo´pez-Saucedo, E. Bucio, Gamma-irradiation applied in the synthesis of metallic and organic nanoparticles: a short review, Radiat. Phys. Chem. 169 (2020), 107962, https://doi.org/10.1016/j.radphyschem.2018.08.011.

References

[80] K. Eid, H. Wang, L. Wang, Nanoarchitectonic metals, in: K. Ariga, M. Aono (Eds.), Micro and Nano Technologies, Supra-Materials Nanoarchitectonics, William Andrew Publishing, 2017, pp. 135–171, https://doi.org/10.1016/B978-0-323-37829-1.00006-7. [81] Y.G. Sun, Y.D. Yin, B.T. Mayers, T. Herricks, Y.N. Xia, Uniform silver nanowires synthesis by reducing AgNO3 with ethylene glycol in the presence of seeds and poly(vinyl pyrrolidone), Chem. Mater. 14 (2002) 4736–4745. [82] C. Manjunatha, R. Hari Krishna, S. Ashoka, Green synthesis of inorganic nanoparticles using microemulsion methods, in: B.R. Inamuddin, I. Ahamed, A.M. Asiri (Eds.), Green Sustainable Process for Chemical and Environmental Engineering and Science, Elsevier, 2021, pp. 41–67, https://doi.org/10.1016/B978-0-12-821887-7.00002-1. [83] K.N. Thakkar, S.S. Mhatre, R.Y. Parikh, Biological synthesis of metallic nanoparticles, Nanomed.: Nanotechnol. Biol. Med. 6 (2) (2010) 257–262, https://doi.org/10.1016/j. nano.2009.07.002. [84] A.A. Muna, M.A. Kareem, Encapsulation of metal and metal oxide nanoparticles by nutraceuticals: implications for biological activities, Curr. Nutraceutical. 2 (2) (2021) 156–165, https://doi.org/10.2174/2665978601666201207212204. [85] T.K. Sau, A. Biswas, P. Ray, Metal nanoparticles in nanomedicine: advantages and scope, in: S. Thota, C.C. Debbie (Eds.), Metal Nanoparticles: Synthesis and Applications in Pharmaceutical Sciences, Wiley-VCH Verlag GmbH & Co. KGaA, 2018, pp. 121–168, https://doi.org/10.1002/9783527807093.ch6. [86] C. Li, K.L. Shuford, Q.H. Park, W. Cai, Y. Li, E.J. Lee, et al., High-yield synthesis of single-crystalline gold nano-octahedra, Angew. Chem. Int. Ed. Eng. 46 (18) (2007) 3264–3268, https://doi.org/10.1002/anie.200604167. [87] V. Chandrakala, V. Aruna, G. Angajala, Review on metal nanoparticles as nanocarriers: current challenges and perspectives in drug delivery systems, Emergent. Mater (2022) 1–23, https://doi.org/10.1007/s42247-021-00335-x. [88] S. Medici, M. Peana, A. Pelucelli, M.A. Zoroddu, An updated overview on metal nanoparticles toxicity, Semin. Cancer Biol. 76 (2021) 17–26, https://doi.org/10.1016/j. semcancer.2021.06.020. [89] R. Lotha, N.S. Sundaramoorthy, B.R. Shamprasad, S. Nagarajan, A. Sivasubramanian, Plant nutraceuticals (Quercetrin and Afzelin) capped silver nanoparticles exert potent antibiofilm effect against food borne pathogen salmonella enterica serovar Typhi and curtail planktonic growth in zebrafish infection model, Microb. Pathog. 120 (2018) 109–118, https://doi.org/10.1016/j.micpath.2018.04.044. [90] R. Lotha, B.R. Shamprasad, N.S. Sundaramoorthy, R. Ganapathy, S. Nagarajan, A. Sivasubramanian, Zero valent silver nanoparticles capped with capsaicinoids containing Capsicum annuum extract, exert potent anti-biofilm effect on food borne pathogen Staphylococcus aureus and curtail planktonic growth on a zebrafish infection model, Microb. Pathog. 124 (2018) 291–300, https://doi.org/10.1016/j.micpath.2018.08.053. [91] D. Esther Lydia, A. Khusro, P. Immanuel, G.A. Esmail, N.A. Al-Dhabi, M.V. Arasu, Photo-activated synthesis and characterization of gold nanoparticles from Punica granatum L. seed oil: An assessment on antioxidant and anticancer properties for functional yoghurt nutraceuticals, J. Photochem. Photobiol. B 206 (2020), 111868, https://doi.org/ 10.1016/j.jphotobiol.2020.111868. [92] I. Rajendran, H. Dhandapani, R. Anantanarayanan, R. Rajaram, Apigenin mediated gold nanoparticle synthesis and their anticancer effect on human epidermoid carcinoma (A431) cells, RSC Adv. 5 (63) (2015) 51055–51066.

29

30

CHAPTER 1 Nanotechnology based delivery of nutraceuticals

[93] N. Muniyappan, M. Pandeeswaran, A. Amalraj, Green synthesis of gold nanoparticles using Curcuma pseudomontana isolated curcumin: its characterization, antimicrobial, antioxidant and anti-inflammatory activities, Environ. Chem. Ecotoxicol. 3 (2021) 117–124, https://doi.org/10.1016/j.enceco.2021.01.002. [94] B. Zhao, S. Deng, J. Li, C. Sun, Y. Fu, Z. Liu, Green synthesis, characterization and antibacterial study on the catechin-functionalized ZnO nanoclusters, Mater. Res. Express 8 (2021), 025006, https://doi.org/10.1088/2053-1591/abe255. [95] J. Lee, K.H. Choi, J. Min, H.J. Kim, J.P. Jee, B.J. Park, Functionalized ZnO nanoparticles with gallic acid for antioxidant and antibacterial activity against methicillin-resistant S. aureus, Nanomaterials (Basel) 7 (11) (2017) 365, https://doi.org/10.3390/nano7110365. [96] P. Appadurai, K. Rathinasamy, Plumbagin-silver nanoparticle formulations enhance the cellular uptake of plumbagin and its antiproliferative activities, IET Nanobiotechnol. 9 (5) (2015) 264–272, https://doi.org/10.1049/iet-nbt.2015.0008. [97] D. Bonvin, J.A.M. Bastiaansen, M. Stuber, H. Hofmann, E.M. Mionic, Folic acid on iron oxide nanoparticles: platform with high potential for simultaneous targeting, MRI detection and hyperthermia treatment of lymph node metastases of prostate cancer, Dalton Trans. 46 (37) (2017) 12692–12704, https://doi.org/10.1039/c7dt02139a. [98] S.Y. Park, S.Y. Chae, J.O. Park, K.J. Lee, G. Park, Gold-conjugated resveratrol nanoparticles attenuate the invasion and MMP-9 and COX-2 expression in breast cancer cells, Oncol. Rep. 35 (6) (2016) 3248–3256, https://doi.org/10.3892/or.2016.4716. [99] N. Duraipandy, R. Lakra, S. Kunnavakkam Vinjimur, D. Samanta, K. Purna Sai, M.S. Kiran, Caging of plumbagin on silver nanoparticles imparts selectivity and sensitivity to plumbagin for targeted cancer cell apoptosis, Metallomics 6 (11) (2014) 2025–2033, https://doi.org/10.1039/c4mt00165f. [100] O. Vittorio, V. Voliani, P. Faraci, B. Karmakar, F. Iemma, S. Hampel, et al., Magnetic catechin-dextran conjugate as targeted therapeutic for pancreatic tumour cells, J. Drug Target. 22 (5) (2014) 408–415, https://doi.org/10.3109/1061186X.2013.878941. [101] S.T. Shah, W.A. Yehya, O. Saad, K. Simarani, Z. Chowdhury, A. Alhadi, et al., Surface functionalization of iron oxide nanoparticles with gallic acid as potential antioxidant and antimicrobial agents, Nanomaterials (Basel) 7 (10) (2017) 306, https://doi.org/ 10.3390/nano7100306. [102] L. Sarma, J.P. Borah, A. Srinivasan, S. Sharma, Synthesis and characterization of tea polyphenol–coated magnetite nanoparticles for hyperthermia application, J. Supercond. Nov. Magn. 33 (2020) 1637–1644, https://doi.org/10.1007/s10948-019-05189-3. [103] S. Devi, M. Kumar, A. Tiwari, V. Tiwari, D. Kaushik, R. Verma, et al., Quantum dots: an emerging approach for cancer therapy, Front Mater. 8 (2022) 1–18, https://doi.org/ 10.3389/fmats.2021.798440. [104] H. Zhang, D. Yee, C. Wang, Quantum dots for cancer diagnosis and therapy: biological and clinical perspectives, Nanomedicine (London) 3 (1) (2008) 83–91, https://doi.org/ 10.2217/17435889.3.1.83. [105] A. Gour, S. Ramteke, N.K. Jain, Pharmaceutical applications of quantum dots, AAPS PharmSciTech 22 (7) (2021) 233, https://doi.org/10.1208/s12249-021-02103-w. [106] J. Drbohlavova, V. Adam, R. Kizek, J. Hubalek, Quantum dots - characterization, preparation and usage in biological systems, Int. J. Mol. Sci. 10 (2) (2009) 656–673, https:// doi.org/10.3390/ijms10020656. [107] M. Henini, Properties and applications of quantum dot heterostructures grown by molecular beam epitaxy, Nanoscale Res. Lett. 1 (2006) 32–45.

References

[108] H. Su, Z. Wang, G. Liu, Near-infrared fluorescence imaging probes for cancer diagnosis and treatment, in: X. Chen, S. Wong (Eds.), Cancer Theranostics, Academic Press, 2014, pp. 55–67, https://doi.org/10.1016/B978-0-12-407722-5.00005-0. [109] K.M. Tsoi, Q. Dai, B.A. Alman, W.C.W. Chan, Are quantum dots toxic? Exploring the discrepancy between cell culture and animal studies, Acc. Chem. Res. 46 (3) (2013) 662–671, https://doi.org/10.1021/ar300040z. [110] W.P. Hu, G.D. Cao, W. Dong, H.B. Shen, X.H. Liu, L.S. Li, Interaction of quercetin with aqueous CdSe/ZnS quantum dots and the possible fluorescence probes for flavonoids, Anal. Methods 6 (5) (2014) 1442–1447, https://doi.org/10.1039/ C3AY41745J. [111] R. Jeyadevi, T. Sivasudha, A. Rameshkumar, D.A. Ananth, G.S. Aseervatham, K. Kumaresan, et al., Enhancement of anti arthritic effect of quercetin using thioglycolic acid-capped cadmium telluride quantum dots as nanocarrier in adjuvant induced arthritic Wistar rats, Colloids Surf. B: Biointerfaces 112 (2013) 255–263, https://doi. org/10.1016/j.colsurfb.2013.07.065. [112] D.A. Ananth, A. Rameshkumar, R. Jeyadevi, S. Jagadeeswari, N. Nagarajan, R. Renganathan, et al., Antibacterial potential of rutin conjugated with thioglycolic acid capped cadmium telluride quantum dots (TGA-CdTe QDs), Spectrochim. Acta A Mol. Biomol. Spectrosc. 138 (2015) 684–692, https://doi.org/10.1016/j.saa.2014.11.082. [113] A. Rameshkumar, T. Sivasudha, R. Jeyadevi, B. Sangeetha, D.A. Ananth, G.S. Aseervatham, et al., In vitro antioxidant and antimicrobial activities of Merremia emarginata using thio glycolic acid-capped cadmium telluride quantum dots, Colloids Surf. B: Biointerfaces 101 (2013) 74–82, https://doi.org/10.1016/j.colsurfb.2012.05.034. [114] C.H. Wu, L. Shi, C.Y. Wu, D. Guo, M. Selke, X.M. Wang, Enhanced in vitro anticancer activity of quercetin mediated by functionalized CdTe QDs, Sci. China Chem. 57 (2014) 1579–1588, https://doi.org/10.1007/s11426-014-5165-0. [115] N. Ghanbari, Z. Salehi, A.A. Khodadadi, M.A. Shokrgozar, A.A. Saboury, Glucosamine-conjugated graphene quantum dots as versatile and pH-sensitive nanocarriers for enhanced delivery of curcumin targeting to breast cancer, Mater. Sci. Eng. C Mater. Biol. 121 (2021), 111809, https://doi.org/10.1016/j.msec.2020.111809. [116] W.H. Shin, H.M. Jeong, B.G. Kim, J.K. Kang, J.W. Choi, Nitrogen-doped multiwall carbon nanotubes for lithium storage with extremely high capacity, Nano Lett. 12 (2012) 2283–2288. [117] X. Liu, M. Antonietti, Molten salt activation for synthesis of porous carbon nanostructures and carbon sheets, Carbon 69 (2014) 460–466. [118] M. Sen, Nanocomposite materials, in: M. Sen (Ed.), Nanotechnology and the Environment [Internet], IntechOpen, London, 2020, https://doi.org/10.5772/intechopen.93047. Available from: https://www.intechopen.com/chapters/72636. [119] J. Wang, S. Kaskel, KOH activation of carbon-based materials for energy storage, J. Mater. Chem. 22 (2012) 23710–23725. [120] N. Khandoker, S.C. Hawkins, R. Ibrahim, C.P. Huynh, F. Deng, Tensile strength of spinnable multiwall carbon nanotubes, Procedia Eng. 10 (2011) 2572–2578. [121] J. Fawaz, V. Mittal, Synthesis of polymer nanocomposites: review of various techniques, in: V. Mittal (Ed.), Synthesis Techniques for Polymer Nanocomposites, Wiley-VCH Verlag GmbH & Co. KGaA, 2015, pp. 1–30. [122] S. Pavlidou, C.D. Papaspyrides, A review on polymer-layered silicate nanocomposites, Prog. Polym. Sci. 33 (2008) 1119–1198.

31

32

CHAPTER 1 Nanotechnology based delivery of nutraceuticals

[123] U. Gizem, Methods for preparation of nanocomposites in environmental remediation, in: M.H. Chaudhery, A.K. Mishra (Eds.), New Polymer Nanocomposites for Environmental Remediation, Elsevier, 2018, pp. 1–28, https://doi.org/10.1016/B978-0-12811033-1.00001-9. [124] M. Amin, Methods for preparation of nano-composites for outdoor insulation applications, Rev. Adv. Matter 34 (2013) 173–184. [125] S.S. Ray, M. Okamoto, Polymer/layered silicate nanocomposites: a review from preparation to processing, Prog. Polym. Sci. 25 (2003) 1539–1641. [126] de Oliveira A.D., Beatrice C.A.G., Polymer nanocomposites with different types of nanofiller. In (Ed.), Nanocomposites - Recent Evolutions. IntechOpen. https://doi. org/10.5772/intechopen.81329. [127] W. Liu, T.J. Webster, Toxicity and biocompatibility properties of nanocomposites for musculoskeletal tissue regeneration, in: H. Liu (Ed.), Nanocomposites for Musculoskeletal Tissue Regeneration, Woodhead Publishing, 2016, pp. 95–122, https://doi.org/10.1016/B978-1-78242-452-9.00004-2. [128] B. Qu, J. Xue, Y. Luo, Self-assembled caseinate-laponite® nanocomposites for curcumin delivery, Food Chem. 363 (2021), 130338, https://doi.org/10.1016/ j.foodchem.2021.130338. [129] X. Shi, Y. Wang, H. Sun, Y. Chen, X. Zhang, J. Xu, et al., Heparin-reduced graphene oxide nanocomposites for curcumin delivery: in vitro, in vivo and molecular dynamics simulation study, Biomater. Sci. 7 (3) (2019) 1011–1027, https://doi.org/10.1039/ c8bm00907d. [130] P. Sathishkumar, Z. Li, R. Govindan, R. Jayakumar, C. Wang, F.L. Gu, Zinc oxide-quercetin nanocomposite as a smart nano-drug delivery system: molecular-level interaction studies, Appl. Surf. Sci. 536 (2021), 147741, https://doi.org/10.1016/j. apsusc.2020.147741. [131] J. Kim, S.P. Hlaing, J. Lee, A. Saparbayeva, S. Kim, D.S. Hwang, et al., Exfoliated bentonite/alginate nanocomposite hydrogel enhances intestinal delivery of probiotics by resistance to gastric pH and on-demand disintegration, Carbohydr. Polym. 15 (272) (2021), 118462, https://doi.org/10.1016/j.carbpol.2021.118462. [132] J.L. Patarroyo, E. Fonseca, J. Cifuentes, F. Salcedo, J.C. Cruz, L.H. Reyes, Gelatin-graphene oxide nanocomposite hydrogels for kluyveromyces lactis encapsulation: potential applications in probiotics and bioreactor packings, Biomol. Ther. 11 (7) (2021) 922, https://doi.org/10.3390/biom11070922. [133] R. Liu, G. Rong, Y. Liu, W. Huang, D. He, R. Lu, Delivery of apigenin-loaded magnetic Fe2O3/Fe3O4@mSiO2 nanocomposites to A549 cells and their antitumor mechanism, Mater. Sci. Eng. C Mater. Biol. Appl. 120 (2021), 111719, https://doi.org/10.1016/j. msec.2020.111719. [134] A.S. Saqezi, M. Kermanian, A. Ramazani, S. Sadighian, Synthesis of graphene oxide/ iron oxide/Au nanocomposite for quercetin delivery, J. Inorg. Organomet. Polym. 32 (2022) 1541–1550, https://doi.org/10.1007/s10904-022-02259-3. [135] Z. Sadeghi-Ghadi, N. Behjou, P. Ebrahimnejad, M. Mahkam, H.R. Goli, M. Lam, et al., Improving antibacterial efficiency of curcumin in magnetic polymeric nanocomposites, J. Pharm. Innov. (2022) 1–16, https://doi.org/10.1007/s12247-022-09619-z. [136] S. Nam, S.Y. Lee, W.S. Kang, H.J. Cho, Development of resveratrol-loaded herbal extract-based nanocomposites and their application to the therapy of ovarian cancer, Nanomaterials (Basel) 8 (6) (2018) 384, https://doi.org/10.3390/nano8060384.

References

[137] R. Supreetha, S. Bindya, P. Deepika, H.M. Vinusha, B.P. Hema, Characterization and biological activities of synthesized citrus pectin-MgO nanocomposite, Results Chem. 3 (2021), 100156, https://doi.org/10.1016/j.rechem.2021.100156. [138] S. Saoji, N. Rarokar, P. Dhore, S. Dube, N. Gurav, S. Gurav, N. Raut, Phospholipid based colloidal nanocarriers for enhanced solubility and therapeutic efficacy of withanolides, J. Drug Deliv. Sci. Technol. 1 (70) (2022) 103251, https://doi.org/10.1016/ j.jddst.2022.103251. [139] K. Rodrigues, S. Nadaf, R. Rarokar, N. Gurav, P. Jagtap, P. Mali, et al., QBD approach for the development of hesperetin loaded colloidal nanosponges for sustained delivery: in-vitro, ex-vivo, and in-vivo assessment, OpenNano 1 (7) (2022) 100045, https://doi. org/10.1016/j.onano.2022.100045. e2001128. [140] K.A. Gawde, S. Sau, K. Tatiparti, S.K. Kashaw, M. Mehrmohammadi, A.S. Azmi, et al., Paclitaxel and di-fluorinated curcumin loaded in albumin nanoparticles for targeted synergistic combination therapy of ovarian and cervical cancers, Colloids Surf. B: Biointerfaces 167 (2018) 8–19, https://doi.org/10.1016/j.colsurfb.2018.03.046. [141] W. Guo, Y. Song, W. Song, Y. Liu, Z. Liu, D. Zhang, Z. Tang, O. Bai, Co-delivery of doxorubicin and curcumin with polypeptide nanocarrier for synergistic lymphoma therapy, Sci. Rep. 10 (1) (2020) 7832, https://doi.org/10.1038/s41598-020-64828-1. [142] S.M. Motevalli, A.S. Eltahan, L. Liu, A. Magrini, N. Rosato, W. Guo, et al., Co-encapsulation of curcumin and doxorubicin in albumin nanoparticles blocks the adaptive treatment tolerance of cancer cells, Biophys. Rep. 5 (2019) 19–30, https:// doi.org/10.1007/s41048-018-0079-6. [143] A. Minaei, M. Sabzichi, F. Ramezani, H. Hamishehkar, N. Samadi, Co-delivery with nano-quercetin enhances doxorubicin-mediated cytotoxicity against MCF-7 cells, Mol. Biol. Rep. 43 (2) (2016) 99–105, https://doi.org/10.1007/s11033-016-3942-x. [144] J. Zhang, L. Shen, X. Li, W. Song, Y. Liu, L. Huang, Nanoformulated co-delivery of quercetin and alantolactone promotes an antitumor response through synergistic immunogenic cell death for microsatellite-stable colorectal cancer, ACS Nano 13 (11) (2019) 12511–12524, https://doi.org/10.1021/acsnano.9b02875. [145] J. Fang, S. Zhang, X. Xue, X. Zhu, S. Song, B. Wang, et al., Quercetin and doxorubicin co-delivery using mesoporous silica nanoparticles enhance the efficacy of gastric carcinoma chemotherapy, Int. J. Nanomedicine 13 (2018) 5113–5126, https://doi.org/ 10.2147/IJN.S170862. [146] Y. Zhao, M.L. Huan, M. Liu, Y. Cheng, Y. Sun, H. Cui, et al., Doxorubicin and resveratrol co-delivery nanoparticle to overcome doxorubicin resistance, Sci. Rep. 6 (2016) 35267, https://doi.org/10.1038/srep35267. [147] T. Hussain, S. Paranthaman, S.M.D. Rizvi, A. Moin, D.V. Gowda, G.M. Subaiea, Fabrication and characterization of paclitaxel and resveratrol loaded soluplus polymeric nanoparticles for improved BBB penetration for glioma management, Polymers (Basel) 13 (19) (2021) 3210, https://doi.org/10.3390/polym13193210. [148] X. Guo, Z. Zhao, D. Chen, M. Qiao, F. Wan, D. Cun, et al., Co-delivery of resveratrol and docetaxel via polymeric micelles to improve the treatment of drug-resistant tumors, Asian J. Pharm. Sci. 14 (1) (2019) 78–85, https://doi.org/10.1016/j.ajps.2018.03.002. [149] A.K. Jain, K. Thanki, S. Jain, Co-encapsulation of tamoxifen and quercetin in polymeric nanoparticles: implications on oral bioavailability, antitumor efficacy, and druginduced toxicity, Mol. Pharm. 10 (9) (2013) 3459–3474, https://doi.org/10.1021/ mp400311j.

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Further reading K. Rodrigues, S. Gurav, A. Joshi, M. Krishna, A. Bhandarkar, Porous polymeric carrier system for modified drug release of boswellic acid, Chem. Sci. J. 11 (2) (2020) 1–12, https://doi. org/10.37421/csj.2020.11.210. S. Dessai, M. Ayyanar, S. Amalraj, P. Khanal, S. Vijayakumar, N. Gurav, et al., Bioflavonoid mediated synthesis of TiO2 nanoparticles: characterization and their biomedical applications, Mater. Lett. 311 (2022) 131639, https://doi.org/10.1016/j.matlet.2021.131639. C. Dias, M. Ayyanar, S. Amalraj, P. Khanal, V. Subramaniyan, S. Das, et al., Biogenic synthesis of zinc oxide nanoparticles using mushroom fungus Cordyceps militaris: characterization and mechanistic insights of therapeutic investigation, J. Drug Deliv. Sci. Technol. 73 (2022) 103444, https://doi.org/10.1016/j.jddst.2022.103444. S. Gurav, P. Usapkar, N. Gurav, N. Nadaf, M. Ayyanar, R. Verekar, et al., Preparation, characterization, and evaluation (in-vitro, ex-vivo, and in-vivo) of naturosomal nanocarriers for enhanced delivery and therapeutic efficacy of hesperetin, PLOS One (2022), https:// doi.org/10.1371/journal.pone.0274916. In press. M. Nilavukkarasi, V. Subramaniyan, M. Kalaskar, N. Gurav, S. Gurav, P. Praseetha, Capparis zeylanica L. conjugated TiO2 nanoparticles as bio-enhancers for antimicrobial and chronic wound repair, Biochem. Biophys. Res. Commun. 623 (2022) 127–132, https://doi.org/ 10.1016/j.bbrc.2022.07.064.

CHAPTER

Applications of nutraceuticals for disease prevention and treatment

2

Maheswata Moharana, Subrat Kumar Pattanayak, and Fahmida Khan Department of Chemistry, National Institute of Technology, Raipur, Chhattisgarh, India

1. Introduction Rapid industrialization and technological progress have resulted in enhanced living quality in terms of income and spending as part of economic growth. However, the eating habits of people have been highly hampered by this changing lifestyle. The consumption of junk food has skyrocketed, resulting in several diseases called “lifestyle diseases” that are associated with nutritional deficits [1]. Traditional herbal extracts and food have been perceived as important parts of a holistic approach for achieving total well-being and health since ancient times, particularly in the ancient Ayurveda system of India as well as Roman, Chinese, and Greek medicines [2]. Nutraceuticals have a major role in preventing such lifestyle diseases by achieving health benefits. The term “nutraceuticals” was first introduced by Stephen De Felice to describe a food product or its functional components that have medicinal as well as nutritional values. These are dietary supplements or functional food ingredients derived from natural products (plant sources) [3]. Nutraceuticals include fatty acids, antioxidants, and bioactive derivatives obtained from dietary sources. These are also familiar for their active role in the prevention and treatment of different diseases. Probiotics are recommended because they play an important role in preventing and controlling gastroenterological diseases [4]. Dietary supplements have been used to reduce hypertension. The effects of various nutraceutical products on blood pressure have been evaluated with particularly high nutrient minerals, amino acids, whole proteins, peptides, vitamins, lipid, and probiotics. However, other nutraceuticals such as green tea, flaxseed, and resveratrol have health benefits while chocolate flavanols have shown minimal risk of cardiovascular disease [3]. The usage of pharmaceutical products as medications in recent years has increased adverse effects and raised awareness of antimicrobial resistance. With the benefits of ease accessibility and cost effectiveness, nutraceuticals are becoming more and more popular as therapeutic and preventative alternatives. Research shows that nutraceutical products also help our immune systems work better [5–8]. Nutraceutical products have expanded roles in enhancing the response to infection, increasing Nutraceuticals. https://doi.org/10.1016/B978-0-443-19193-0.00005-8 Copyright # 2023 Elsevier Inc. All rights reserved.

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Nutrition Required for health & daily life

Pharmaceuticals Important for disease treatment

Nutraceuticals Preventive approach for diseases

FIG. 2.1 Concept of nutraceuticals.

immunomodulatory activity, and helping to reduce the effects of autoimmune diseases and hypersensitivity [9–11]. Immunological factors such as poor diets, lack of exercise, negative emotions, and environmental pollution affect human health, both for younger and older generations. The reversal of these variables is possible by the long-term use of nutraceuticals and products related to them. Nutraceuticals are available as single substances or in combination form such as powders, pills, and capsules [12,13]. Nutraceuticals are available in a variety of products from the food industry, the pharmaceutical industry, herbal and dietary supplement sectors, and the newly merged pharmaceuticals with agri-business or nutrition conglomerates [14]. The nutraceutical industries have three main segments: functional food, herbal products, and dietetic supplements. Of these, the fast-growing segments are nutritional supplements and herbal/natural products. Several factors such as rising healthcare costs, awareness of healthy nutrition, and rising demands for nutraceuticals are mainly responsible for the growth of nutraceutical industries [15]. The products are used to treat hypertension, excessive weight, high cholesterol, diabetes, arthritis, macular degeneration, cataracts, symptoms of menopause, loss of memory, digestive upset, and constipation; they are also helpful in reducing heart disease and the risk of cancer [14]. The following characteristics distinguish nutraceuticals from dietary supplements: they must not only improve diet but also support the prevention and treatment of disease, and they must be consumed as ordinary foods or as the primary component of a food or diet [16]. The advances of functional food concepts and nutraceuticals owe much to the benefits of dietary supplements beyond basic nutrition. Fortified dietary foods and citrus fruits are some examples of nutraceuticals [7] (Fig. 2.1).

2. Types of nutraceuticals Nutraceuticals are nonspecific biological therapeutics that have been used in promoting health, preventing disease, managing symptoms of a variety of diseases, and inhibiting disease-related processes. These mainly consist of chemical constituent-based nutraceuticals, traditional nutraceuticals, and nonconventional nutraceuticals.

2 Types of nutraceuticals

2.1 Chemical constituent-based nutraceuticals Some common types of nutraceuticals are based on chemical constituents, both traditional and nonconventional. These are categorized as nutrients, dietary supplements, and herbals.

2.1.1 Nutrients Nutrients are naturally occurring substances in our diets that meet nutritional standards, and they include vitamins, fatty acids, polysaccharides, and minerals. [17]. All the nutrients our bodies require can be found from natural foods such as vegetables, fruits, meat, and dairy products. Therefore, these nutrients are utilized to treat and control a variety of ailments, including diabetes, depression, high cholesterol, osteoporosis, osteoarthritis, and sleep disorders [18]. Antioxidants, minerals, and vitamins are all included in nutrition, and they can help with a number of health problems. Parkinson’s disease can be helped by including vitamin E in our diet. Alzheimer’s can be treated by increasing the antioxidant intake in our diet. Low-density lipoprotein oxidation can be reduced by taking vitamins, including C and E as well as beta carotenes [19]. In general, antioxidants are useful in preventing many cancer-related diseases and cerebrovascular diseases [20]. Table 2.1 shows the health benefits of different types of vitamins as nutrients.

2.1.2 Herbals Herbal products are generally obtained from a variety of plant sources. They have been used as medicines since ancient times in every part of the planet. The notion that herbs will provide some benefit over established allopathic treatments leads people to use herbal products as medicine [34]. Nutraceuticals play an important role in promoting health and preventing chronic disease through the use of herbal products. Herbal foods such as garlic, cabbage, licorice root, soybeans, and umbelliferous vegetables are often utilized in the treatment of cancer [14,35]. Citrus fruits are rich in folic acid, vitamin C, and soluble fibers that are thought to protect against cancer. Garlic powder has been shown to help in moderate hypertension [14,36]. Some common herbals used as therapeutic medicines are listed in Table 2.2.

2.1.3 Dietary supplement Dietary supplements are substances produced by combining certain necessary ingredients in our diet. These are consumed along with daily foods that include proteins, vitamins, minerals, and plant extracts [47]. The addition of supplements in our diet is to take care of a wide range of diseases. For example, glucosamine is used to treat osteoarthritis, black cohos is used to treat menopause, and ginkgo biloba is used to treat dementia [48]. High fat as well as low protein and carbohydrate ketogenic diets have been shown to enhance seizure management. The areas of nutraceuticals where calcium fortification is especially strong are cereals and grains. Kellogg’s, with its calcium-fortified All-Bran Plus and Nutrigrain bars, is a market leader. It was reported that minimally processed grains can help avoid diabetes as well as gastrointestinal disorders [49,50]. Dietary supplements come in a variety of doses and forms. Table 2.3 lists some well-known supplements as well as their major health advantages.

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CHAPTER 2 Applications of nutraceuticals for disease prevention and treatment Table 2.1 Nutrient and their health benefits. Nutrients

Health benefits

Reference

Vitamin A

Antioxidants are needed to maintain healthy vision and mucous membranes as well as treat skin disorders Aids in the alteration of food into energy, which is important for functioning of brain Helps the body to produce energy and stimulate chemical processes as well as maintain eyes, skin, and nervous system Regulation of optimal brain function Maintenance of central nervous system Helpful in healing wounds and alleviating the symptoms of the common cold Helps the body absorbs and use calcium and also regulates calcium and phosphate absorption Promotes healthy skin and eyes as well as strengthens the immune system against infection and sickness Helps in the formation of several proteins required for blood clotting and bone formation Helps build and maintain strong bones Helps in growth and development as well as production of hemoglobin Helps to regulate the production of thyroid hormones Forms fatty acids and glucose. Regulates metabolism levels, protects heart, promotes brain functions, and boosts the immune system

[21]

Vitamin B1 Vitamin B2

Vitamin B3 Vitamin B12 Vitamin C Vitamin D Vitamin E Vitamin K Calcium Iron Iodine Biotin

[22] [23]

[24] [25] [26] [27] [28] [29] [30] [31] [32] [33]

Table 2.2 Herbal products and their medicinal benefits for health. Herbal products

Health benefits

Reference

Phyllanthus Emblica (Amla)

Beneficial in diabetes and osteoarthritis while also having chondroprotective potential. Also, a diuretic with antiaging potential Improves digestive health, moisturizing and cooling properties; helps with wound healing and antiinflammatory activities Helps with digestion and insomnia while also having antiinflammatory, antimicrobial, and wound-healing properties Supports the body’s protective mechanisms against oxidative damage while also having antibacterial, antifungal, antithrombotic, hypotensive, and antihyperlipidemic properties Reduces stress and anxiety; improves appetite, has antibacterial and antiviral properties

[37]

Aloe Vera

Chamomile (Matricariarecutita) Garlic (Allium sativum)

Melissa (Melissa officinalis)

[38]

[39]

[40]

[41]

2 Types of nutraceuticals

Table 2.2 Herbal products and their medicinal benefits for health—cont’d Herbal products

Health benefits

Reference

Ginger (Zingiber officinale Rosc.)

Helpful in chronic diseases such as high blood pressure, heart and lung disease; prevents microbial food spoilage and oxidative stress Beneficial in treating coughs, wounds, infections, fevers, and inflammation Helpful in joint/muscular pain, headaches, rheumatoid arthritis, osteoarthritis, gout, and spine ailments Antioxidant, antiinflammatory, antimicrobial effects. Boosts weight loss, treats hepatitis C

[42]

Relieves cough, sore throat, ulcers, skin inflammation, stomach problems

[46]

Plantago seeds Willow bark (Salix alba) Licorice (Glycyrrhiza glabra) Slippery elm (Ulmus rubra)

[43] [44]

[45]

Table 2.3 Dietary supplements and their therapeutic properties. Dietary supplements

Health benefits

Reference

Ketogenic diets Minimally refined grains

Improve insulin sensitivity and appetite Calcium-fortified cereals and grains diminish the risk of diabetes and gastrointestinal cancer Enhance estrogen level, prevent breast cancer Antioxidant content can help prevent lung, prostate, breast, and other types of cancers. Vitamin D in mushrooms may prevent some kinds of cancer; also beneficial for type 2 diabetes. Potassium and vitamin C may contribute to cardiovascular health while choline content helps in muscle movement, learning, and memory Helpful in joint pain

[51] [52]

Build muscle, boost weight and fat loss, lower cholesterol, antihypertension properties, improves constipation and obesity

[56]

Phytoestrogens Edible mushrooms

Glucosamine sulphate and chondroitin sulphate Peptides/ hydrolysates

[53] [54]

[55]

2.2 Traditional nutraceuticals Natural dietary supplements and nutraceuticals, which are traditional remedies, have found a place in modern medicine. Omega-3 fatty acids in salmon, lycopene in tomatoes, and saponins in soy are examples of natural compounds in foods that provide benefits beyond basic nourishment [57]. They all contain xenobiotics, which are

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CHAPTER 2 Applications of nutraceuticals for disease prevention and treatment compounds that are foreign to humans [58]. Carotenoids are a class of traditional nutraceuticals that comprises natural pigments and substances found in plants, vegetables, and algae. The human diet contains a variety of carotenoid derivatives such as lutein, lycopene, zeaxanthin, crocetin, α-carotene, β-carotenoids, β-cryptoxanthin, and astaxanthin [59,60]. Functional foods not only give nutrition but also offer health advantages and disease prevention. These foods are high antiinflammatory compounds that help in avoiding diseases such as type 2 diabetes. Fermented milk products, soybeans, and citrus are all examples of functional foods [57,61]. A collagen hydrolysate is a kind of traditional nutraceutical possessing numerous health benefits [62,63]. Traditional nutraceuticals from plant sources include phytochemicals, which are beneficial concentrated or purified compounds with active components for biochemical and metabolic activities in humans. Examples of common phytochemicals are lutein, phytosterol, lycopene, etc. Phytochemicals also regulate the chemical balance in the brain, providing neuroprotective effects. Furthermore, consuming a lot of phytochemical-rich vegetables and fruits can help prevent neurological diseases [64,65]. Probiotics are helpful microbes found in foods, particularly in milk products. They enhance health by giving immunological and digestive benefits [66,67]. Furthermore, these live microbes can also help to restore intestinal bacteria equilibrium. Lactobacillus is an example of the most frequent probiotic found in the human stomach [68]. Prebiotics are nondigestible nutrients that help microorganisms develop and influence gut microbiota. A small chain of fatty acids is the degradation product of prebiotics that enter the bloodstream, impacting the gastrointestinal tract [69].

2.3 Nonconventional nutraceuticals Artificially produced foods are known as nontraditional nutraceuticals. Depending on the method of processing, nonconventional nutraceuticals are classified into fortified or recombinant nutraceuticals. An example of a nonconventional nutraceutical is rice supplemented with carotene [70,71]. Nutraceuticals that have been fortified with extra nutrients and/or substances are known as fortified nutraceuticals. Fortified nutraceuticals include foods that have additional micronutrients or vitamins such as calcium-fortified orange juice or milk with cholecalciferol used in vitamin D deficiency. Respiratory infections are treated with probiotic-fortified milk [57]. Recombinant nutraceuticals are produced by the techniques of genetic recombination as well as biotechnology. These foods and crops are generally engineered to produce products that contain recombinant chemicals and proteins to make us healthier. This type of nutraceutical includes iron rice, maize, golden mustard, golden rice, gold kiwi fruit, and multivitamin corn. The recombinant gene content in kiwifruit increases the levels of ascorbic acid, carotenoids, and lutein in our body while also boosting immune function [72,73].

3 Application of nutraceuticals in therapeutics

3. Application of nutraceuticals in therapeutics Nutraceuticals are claimed to offer therapeutic effects or protect against a variety of diseases. Fig. 2.2 shows a pictorial representation of nutraceuticals in the control of various diseases. Some of the major applications of nutraceuticals towad different diseases discussed in this chapter: (a) (b) (c) (d) (e) (f)

Anticancer agent, Antiviral properties, Treating gastrointestinal disorders, Antiinflammatory activity, Antidiabetic agents, Treating thyroid disease.

3.1 Nutraceuticals as anticancer agents A report from the World Health Organization shows that cancer is among the world’s five most incurable diseases, causing tens of thousands of deaths each year. In recent years, various pharmacological therapies have been used to treat cancer. Most of them have side effects such as diarrhea, nausea, vomiting, anemia, a reduced immune system, and hair loss. From this perceptive, various phytochemicals with anticancer effects have been investigated for cancer treatment based on molecular targeted therapies. Phytochemicals such as polysaccharides that are present in algae are high in nutrients, offering a broad range of biological benefits against cancer as well as immunomodulatory capabilities. The anticancer properties of algal polysaccharides include mortality, cell cycle arrest, gut flora, antiangiogenesis, and immunological

FIG. 2.2 Application of nutraceuticals for the management of different diseases.

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CHAPTER 2 Applications of nutraceuticals for disease prevention and treatment activities [74]. Dietary berries have lately been researched for their role in cancer prevention. Berries include a large number of plant pigments. [75,76]. Epigallocatechin 3-gallate, a phytochemical found in green tea, protects cells from harm and has anticancer potential. Daidzein and genistein, two isoflavones present in soy products, have been proven to inhibit protein tyrosine kinase [77,78]. Recent studies have shown that resveratrol has anticancer effects [79,80]. For ages, medicinal and edible mushrooms have been utilized as nutraceuticals to improve and treat a variety of ailments. Several mushroom species have also been used as immunostimulators and anticancer drugs, including schizophyllalum. Mushroom polysaccharides, the major bioactive compound found in mushrooms, are immunoceuticals that slow down the production of cancer cells by activating the host immune system. Ganoderma lucidum is an important medicinal mushroom that has long been used to treat hypertension and hepatitis [81]. In vivo and in vitro studies have shown that onions have high quantities of quercetin, which prevents colon cancer proliferation [82]. The lentinan compound β-1.3-glucan is naturally found in the edible mushroom lentinus edodes; it has been used as an anticancer drug for to treat colon cancer. Broccoli extract, pepper, soya, cloves, ginger, apples, fenugreek seeds, and red wine contain a high amount of selenium dietary fiber, which is essential in a 50% reduction of the risk of colon cancer [83,84]. Luteolin, a flavonoid occurring in green pepper, perilla, and other culinary plants, is used to treat colon cancer [85]. Vitamins also play a very crucial role in the prevention and treatment of cancer. Vitamin B complex can lower the risks of colon, rectal, and breast cancer. It was also found that vitamin D can play an important role in treating extraskeletal disorders and cancer [86].

3.2 Antiviral nutraceuticals Upon increasing age, due to thymus atrophy, the human body begins to create fewer T cells, making an individual vulnerable to deadly infections [87]. As a result, dietary supplements can play an important role in supporting the immune system and maximizing cell functions (especially those cells involved in the body’s immune system). Nutraceuticals aid in the functionalization of food and the promotion of diet as daily nourishment for good health. Resveratrol is a polyphenolic stilbene molecule found in fermented grapes. Its antiviral properties have been investigated in the context of a number of viruses, including influenza and hepatitis C [88,89]. Quercetin is a bioflavonoid nutraceutical that can be found in a wide range of food products such as vegetables. It has a wide spectrum of properties, including signal pathway modulation [90–92]. Pomegranate juice also showed greater antiviral activity against influenza strains and herpes viruses [93].

3.3 Nutraceuticals for gastrointestinal disorders The ability to treat gastric discomfort with various types of foods has long been recognized, as have the dietary impacts on gastrointestinal ailments. Ingredients

3 Application of nutraceuticals in therapeutics

from foodstuffs are thought to be useful; some have been identified, investigated, and sold as supplements [94]. Gastrointestinal disorders can be structural or functional. Functional gastrointestinal disorders are the more common form, but both types can impact the quality of life and psychological well-being, and can even be fatal. Many nutraceuticals have been introduced to the market to treat gastrointestinal disorders [95,96]. Phytochemicals of plants or nutraceuticals are bioactive in nature, providing many health benefits. Phytoestrogens, phenolic compounds, and secondary metabolites of phytochemicals possess antiinflammatory properties for intestines. Flavonoids impact and modulate the permeability of the intestinal barrier. Aloe vera is a traditional remedy for gastrointestinal disorders, including diarrhea and particularly inflammatory diseases [97]. For years, ginger (Zingiber offcinale rhizome) has been used to treat gastrointestinal disorders such as dyspepsia. It also protects against gastrointestinal irritations and diseases such as ulcers, nausea, stomach soreness, spasms, and gastrointestinal cancer [98,99].

3.4 Antiinflammatory activity One of the most well-known qualities of nutraceuticals is their antiinflammatory capabilities. Rheumatoid arthritis is a chronic inflammatory disease characterized by elevated oxidative stress and inflammatory biomarkers. The serious side effects of medications used to treat these disease necessitate the development of new, safer treatments [100]. Other nutraceuticals investigated were carrots, licorice, cumin, and fish oil; these have potential antiinflammatory impacts [100]. Cinnamaldehyde is a bioactive compound that can be found in high quantities in cinnamon oil. It is most commonly encountered as a trans-isomer. It is a very well-known phytonutrient showing antiinflammatory properties [101]. Garlic is very well known for its nutraceutical benefits. Allicin has been shown to have antiinflammatory, antiviral, and antioxidant properties [102]. Vitamin D also stimulates suppressive regulatory T cells and promotes antiinflammatory cytokines by Th2 cells, thereby suppressing Th1 cells and shifting proinflammatory cells to an antiinflammatory phenotype [103]. Black pepper contains a significant amount of piperine, which has antiinflammatory properties and can be used to prevent COVID-19 induced hyperinflammation [104].

3.5 Antidiabetic nutraceuticals Diabetes is a serious health issue causing morbidity and mortality around the world. The current estimate is that approximately 400 million people are affected [105]. Hyperglycemia (high blood sugar) is a symptom of diabetes mellitus, a metabolic disorder [106]. Despite the development and clinical use of antidiabetic drugs, 387 million people still suffer from diabetes [107]. To prevent this, many patients supplement conventional medication with complementary and alternative therapies. Nutraceuticals are thought to be safer pharmaceuticals because of their low cost and availability. Ayurvedic herb supplements and a variety of vitamins and

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CHAPTER 2 Applications of nutraceuticals for disease prevention and treatment micronutrients play imperative roles in the treatment of diabetes. Micronutrients such as alpha lipoic acid, carnitine, inositol, and calcium have been shown to be beneficial for diabetes [108]. By offering protection against oxidative stress, dietary antioxidants have also been shown to prevent or delay diabetes complications such as renal failure and brain damage [109]. Vitamin C is a chain-breaking antioxidant that helps to reduce diabetes-induced sorbitol accumulation and lipid peroxides. Parathyroid hormone (PTH) levels in vitamin D-deficient obese people are higher, which can reduce insulin sensitivity by causing a disproportionate rise in Ca2+ [110]. People with diabetes may be deficient in chromium, a trace element. Supplementing with chromium may enhance insulin sensitivity and glucose tolerance in persons with type 2 diabetes [111]. Aloe vera extract contains lectins and polysaccharides, which have been demonstrated to have antidiabetic activities [112]. Corosolic acid, originating from the leaves of the banaba plant, has antidiabetic effects. Gluco Trim, a product containing 1% corosolic acid, was shown to reduce blood glucose levels [113]. Omega-3 fatty acid supplements also have beneficial effects against diabetes. They lower triglycerides and very low density lipoprotein cholesterol as well as blood pressure [114]. Dietary fibers also have a major role in diabetes. In diabetic and even healthy people, soluble dietary fiber is linked to reducing postprandial glucose levels and enhancing insulin sensitivity [115].

3.6 Nutraceuticals for thyroid disease Thyroid gland activity is generally controlled by a thyroid-stimulating hormone, which improves thyroidal iodine absorption and is generated by the pituitary gland. In the presence of sufficient iodine ingestion, thyroid-stimulating hormone levels remain elevated, resulting in goiter. Even though iodine is still the most critical vitamin for thyroid gland function, melatonin and resveratrol both play vital roles in clinical thyroidology [116]. Over the last few years, the demand for nutraceuticals has been increasing due to their efficient preventive and therapeutic properties for a variety of pathological disorders, including thyroid disease. The polyphenolic compounds in human diets such as flavonoids and bioflavonoids are generally found in many plants. Flavonoids have been demonstrated to impede the function of thyroperoxidase, increasing the thyroid-stimulating hormones and the formation of goiter [117]. Lower vitamin D levels lead to an increased risk of disease such as thyroiditis. As a result, vitamin D supplements may help patients suffering from thyroid diseases [118]. People with autoimmune thyroid diseases may benefit from their antiinflammatory and immune-boosting properties [119]. Weight loss is a serious issue in thyroid dysfunction. As a result, people are using conjugated linolenic acid to help them achieve weight loss [120]. The thyroid hormone metabolism requires the mineral selenium. Sources of selenium in our daily intake include seafood, cattle, chicken, and eggs. Additionally, it is also available as a supplement. According to a study, selenium supplementation may lower thyroid enzyme levels in people with autoimmune hypothyroidism [121]. The mineral zinc in animal proteins, nuts, and whole grains also helps to produce thyroid hormones in our body [122].

References

4. Conclusion Nutraceuticals are a unique and exciting research topic in the development of innovative health products with enormous potential for health advantages such as efficacy, cost-effectiveness, and, most importantly, safety. Researchers around the world have found that adequate nutrition and dietary supplements are the only alternative to prevent and alleviate our lifestyle diseases. Nutraceuticals often have advantages over synthetic drugs. Their. novel pharmacological activity has attracted attention due to the possibility of clinical use, thereby improving disease prevention and treatment. Nutraceuticals that have been scientifically and medically authorized can surely improve health and prevent diseases, with some of them demonstrating efficacy comparable to traditional treatments. Furthermore, current and high-throughput technologies can help us better understand the underlying mechanism of actions and push this cutting-edge field of research to new heights for the benefit of humans, both monetarily and in terms of health outcomes.

References [1] S. Tank Dharti, S. Gandhi, M. Shah, Nutraceuticals-portmanteau of science and nature, Int. J. Pharm. Sci. Rev. Res. 5 (3) (2010) 33–38. [2] M. AlAli, M. Alqubaisy, M.N. Aljaafari, A.O. AlAli, L. Baqais, A. Molouki, et al., Nutraceuticals: Transformation of conventional foods into health promoters/disease preventers and safety considerations, Molecules 26 (9) (2021) 2540. [3] R.K. Srivastava, Need of nutraceuticals/functional food products for health benefits to world-wide people, J. Biotechnol. Biomed. Sci. 1 (4) (2018) 1. [4] G. Caramia, S. Silvi, Probiotics: from the ancient wisdom to the actual therapeutical and nutraceutical perspective, in: Probiotic bacteria and enteric infections, Springer, Dordrecht, 2011, pp. 3–37. [5] H.Y. Park, K.W. Lee, H.D. Choi, Rice bran constituents: Immunomodulatory and therapeutic activities, Food Funct. 8 (3) (2017) 935–943. [6] L. Das, E. Bhaumik, U. Raychaudhuri, R. Chakraborty, Role of nutraceuticals in human health, J. Food Sci. Technol. 49 (2) (2012) 173–183. [7] A. Cencic, W. Chingwaru, The role of functional foods, nutraceuticals, and food supplements in intestinal health, Nutrients 2 (6) (2010) 611–625. [8] R. Jayawardena, P. Sooriyaarachchi, M. Chourdakis, C. Jeewandara, P. Ranasinghe, Enhancing immunity in viral infections, with special emphasis on COVID-19: A review, Diabetes Metab. Syndr. Clin. Res. Rev. 14 (4) (2020) 367–382. [9] S. Babu, S. Jayaraman, An update on β-sitosterol: A potential herbal nutraceutical for diabetic management, Biomed. Pharmacother. 131 (2020), 110702. [10] F. Pivari, A. Mingione, C. Brasacchio, L. Soldati, Curcumin and type 2 diabetes mellitus: prevention and treatment, Nutrients 11 (8) (2019) 1837. [11] E.M. Williamson, X. Liu, A.A. Izzo, Trends in use, pharmacology, and clinical applications of emerging herbal nutraceuticals, Br. J. Pharmacol. 177 (6) (2020) 1227–1240. [12] D.M. Parikh, 16 Granulation of Plant Products and Nutraceuticals, Handbook of Pharmaceutical Granulation Technology, 2016, p. 349.

45

46

CHAPTER 2 Applications of nutraceuticals for disease prevention and treatment [13] M.O. Nafiu, A.A. Hamid, H.F. Muritala, S.B. Adeyemi, Preparation, standardization, and quality control of medicinal plants in Africa, in: Medicinal Spices and Vegetables from Africa, 2017, pp. 171–204. [14] S.L. Prabu, T.N.K. Suriyaprakash, C.D. Kumar, S.S. Kumar, Nutraceuticals and their medicinal importance, Int. J. Health Allied Sci. 1 (2) (2012) 47. [15] A. Perez-Sa´nchez, E. Barrajo´n-Catala´n, M. Herranz-Lo´pez, V. Micol, Nutraceuticals for skin care: A comprehensive review of human clinical studies, Nutrients 10 (4) (2018) 403. [16] E.K. Kalra, Nutraceutical-definition and introduction, AAPS Pharm. Sci. 5 (3) (2003) 27–28. [17] H. Dureja, D. Kaushik, V. Kumar, Developments in nutraceuticals, Indian J. Pharm. 35 (6) (2003) 363–372. [18] U. Ghani, M. Naeem, H. Rafeeq, U. Imtiaz, A. Amjad, S. Ullah, et al., A novel approach towards nutraceuticals and biomedical applications, Sch. Int. J. Biochem. 2 (2019) 245–252. [19] A.P. Sapkale, M.S. Thorat, P.R. Vir, M.C. Singh, Nutraceuticals-global status and applications: A review, Int. J. Pharm. Chem. Sci. 1 (3) (2012) 1166–1181. [20] S. Mobarhan, Micronutrient supplementation trials and the reduction of cancer and cerebrovascular incidence and mortality, Nutr. Rev. 52 (3) (1994) 102–105. [21] E.M. Dauqan, A. Abdullah, Medicinal and functional values of thyme (Thymus vulgaris L.) herb, J. Appl. Biol. Biotechnol. 5 (2) (2017) 2. [22] K. Mikkelsen, V. Apostolopoulos, Vitamin B1, B2, B3, B5, and B6 and the immune system, in: Nutrition and Immunity, Springer, Cham, 2019, pp. 115–125. [23] K. Thakur, S.K. Tomar, A.K. Singh, S. Mandal, S. Arora, Riboflavin and health: a review of recent human research, Crit. Rev. Food Sci. Nutr. 57 (17) (2017) 3650–3660. [24] V. Gasperi, M. Sibilano, I. Savini, M.V. Catani, Niacin in the central nervous system: an update of biological aspects and clinical applications, Int. J. Mol. Sci. 20 (4) (2019) 974. [25] L. Mahmood, The metabolic processes of folic acid and Vitamin B12 deficiency, J. Health Res. Rev. 1 (1) (2014) 5. [26] P. Pravina, D. Sayaji, M. Avinash, Calcium and its role in human body, Int. J. Res. Pharmaceut. Biomed. Sci. 4 (2) (2013) 659–668. [27] G.K. Schwalfenberg, A review of the critical role of vitamin D in the functioning of the immune system and the clinical implications of vitamin D deficiency, Mol. Nutr. Food Res. 55 (1) (2011) 96–108. [28] J.M. Graat, E.G. Schouten, F.J. Kok, Effect of daily vitamin E and multivitamin-mineral supplementation on acute respiratory tract infections in elderly persons: a randomized controlled trial, JAMA 288 (6) (2002) 715–721. [29] C. Vermeer, L.J. Schurgers, A comprehensive review of vitamin K and vitamin K antagonists, Hematol. Oncol. Clin. North Am. 14 (2) (2000) 339–353. [30] R.P. Heaney, The importance of calcium intake for lifelong skeletal health, Calcif. Tissue Int. 70 (2) (2002) 70. [31] N.S. Scrimshaw, Iron deficiency, Sci. Am. 265 (4) (1991) 46–53. [32] R.F. Hurrell, Bioavailability of iodine, Eur. J. Clin. Nutr. 51 (1) (1997) S9. [33] Sarojnalini, C., & Hei, A. (2019). Fish as an important functional food for quality life. U: Functional foods, (Lagouri, V., ured.), IntechOpen, London, 77-97. [34] M.J. Wargovich, C. Woods, D.M. Hollis, M.E. Zander, Herbals, cancer prevention and health, J. Nutr. 131 (11) (2001) 3034S–3036S.

References

[35] W.J. Craig, Phytochemicals: guardians of our health, J. Am. Diet. Assoc. 97 (10) (1997) S199–S204. [36] I.A. Sobenin, I.V. Andrianova, I.V. Fomchenkov, T.V. Gorchakova, A.N. Orekhov, Time-released garlic powder tablets lower systolic and diastolic blood pressure in men with mild and moderate arterial hypertension, Hypertens. Res. 32 (6) (2009) 433-437. [37] M. Gul, Z.W. Liu, R. Rabail, F. Faheem, N. Walayat, A. Nawaz, et al., Functional and Nutraceutical Significance of Amla (Phyllanthus emblica L.): a review, Antioxidants 11 (5) (2022) 816. [38] B.K. Vogler, E. Ernst, Aloe vera: a systematic review of its clinical effectiveness, Br. J. Gen. Pract. 49 (447) (1999) 823–828. [39] V. Gupta, P. Mittal, P. Bansal, S.L. Khokra, D. Kaushik, Pharmacological potential of Matricaria recutita—a review, Int. J. Pharm. Sci. Drug Res. 2 (1) (2010) 12–16. [40] N. Benkeblia, Antimicrobial activity of essential oil extracts of various onions (Allium cepa) and garlic (Allium sativum), LWT-Food Sci. Technol. 37 (2) (2004) 263–268. [41] A.C. De Sousa, C.R. Gattass, D.S. Alviano, C.S. Alviano, A.F. Blank, P.B. Alves, Melissa officinalis L. essential oil: antitumoral and antioxidant activities, J. Pharm. Pharmacol. 56 (5) (2004) 677–681. [42] H. Jiang, Z. Xie, H.J. Koo, S.P. McLaughlin, B.N. Timmermann, D.R. Gang, Metabolic profiling and phylogenetic analysis of medicinal Zingiber species: Tools for authentication of ginger (Zingiber officinale Rosc.), Phytochemistry 67 (15) (2006) 1673–1685. [43] F. Fernandez-Banares, J. Hinojosa, J.L. Sanchez-Lombrana, E. Navarro, J.F. MartınezSalmero´n, A. Garcıa-Puges, et al., Randomized clinical trial of Plantago ovata seeds (dietary fiber) as compared with mesalamine in maintaining remission in ulcerative colitis, Am. J. Gastroenterol. 94 (2) (1999) 427–433. [44] N. Harbourne, E. Marete, J.C. Jacquier, D. O’Riordan, Effect of drying methods on the phenolic constituents of meadowsweet (Filipendula ulmaria) and willow (Salix alba), LWT-Food Sci. Technol. 42 (9) (2009) 1468–1473. [45] R. Kaur, H. Kaur, A.S. Dhindsa, Glycyrrhiza glabra: a phytopharmacological review, Int. J. Pharm. Sci. Res. 4 (7) (2013) 2470. [46] L. Braun, Slippery Elm, J. Compl. Med.: CM 5 (1) (2006), https://doi.org/10.3316/ informit.090443849700468. [47] D. Dolkar, P. Bakshi, V.K. Wali, V. Sharma, R.A. Shah, Fruits as nutraceuticals, Eco. Env. Cons. 23 (2017) S113–S118. [48] S. Gupta, D. Chauhan, K. Mehla, P. Sood, A. Nair, An overview of nutraceuticals: current scenario, J. Basic Clin. Pharm. 1 (2) (2010) 55. [49] J. Salmeron, J.E. Manson, M.J. Stampfer, G.A. Colditz, A.L. Wing, W.C. Willett, Dietary fiber, glycemic load, and risk of non—insulin-dependent diabetes mellitus in women, JAMA 277 (6) (1997) 472–477. [50] J. Slavin, D. Jacobs, L. Marquart, Whole-grain consumption and chronic disease: protective mechanisms, Nutr. Cancer 27 (1) (1997) 14–21. [51] T.D. Swink, E.P. Vining, J.M. Freeman, The ketogenic diet: 1997, Adv. Pediatr. 44 (1997) 297–329. [52] N. Agrawal, A. Goyal, A. Jain, Nutraceuticals: Supplements For Building A Healthy World, Bull. Env. Pharmacol. Life Sci. 9 (2020) 01–08. [53] A.V. Sirotkin, A.H. Harrath, Phytoestrogens and their effects, Eur. J. Pharmacol. 741 (2014) 230–236.

47

48

CHAPTER 2 Applications of nutraceuticals for disease prevention and treatment [54] S.T. Chang, W.A. Hayes (Eds.), The biology and cultivation of edible mushrooms, Academic Press, 2013. [55] G.S. Kelly, The role of glucosamine sulfate and chondroitin sulfates in the treatment of degenerative joint disease, Alt. Med. Rev.: J. Clin. Therap. 3 (1) (1998) 27–39. [56] B. Herna´ndez-Ledesma, M.J. Garcı´a-Nebot, S. Ferna´ndez-Tome, L. Amigo, I. Recio, Dairy protein hydrolysates: Peptides for health benefits, Int. Dairy J. 38 (2) (2014) 82–100. [57] J. Singh, S. Sinha, Classification, regulatory acts and applications of nutraceuticals for health, Int. J. Pharma Bio Sci. 2 (1) (2012) 177–187. [58] S. Barnes, J. Prasain, Current progress in the use of traditional medicines and nutraceuticals, Curr. Opin. Plant Biol. 8 (3) (2005) 324–328. [59] K. Starska-Kowarska, Dietary carotenoids in head and neck cancer—molecular and clinical implications, Nutrients 14 (3) (2022) 531. [60] C.I. Cazzonelli, Carotenoids in nature: insights from plants and beyond, Funct. Plant Biol. 38 (11) (2011) 833–847. [61] A. Alkhatib, C. Tsang, A. Tiss, T. Bahorun, H. Arefanian, R. Barake, et al., Functional foods and lifestyle approaches for diabetes prevention and management, Nutrients 9 (12) (2017) 1310. [62] M.C. Go´mez-Guillen, B. Gimenez, M.A. Lo´pez-Caballero, M.P. Montero, Functional and bioactive properties of collagen and gelatin from alternative sources: a review, Food Hydrocoll. 25 (8) (2011) 1813–1827. [63] H. Song, B. Li, Beneficial effects of collagen hydrolysate: a review on recent developments, Biomed. J. Sci. Tech. Res 1 (2017) 458–461. [64] G.P. Kumar, F. Khanum, Neuroprotective potential of phytochemicals, Pharmacogn. Rev. 6 (2012) 81–90. [65] V. Lobo, A. Patil, A. Phatak, N. Chandra, Free radicals, antioxidants and functional foods: Impact on human health, Pharmacog. Rev. 4 (8) (2010) 118]. [66] Sa´nchez, B., Delgado, S., Blanco-Mı´guez, A., Lourenc¸o, A., Gueimonde, M., & Margolles, A. (2017). Probiotics, gut microbiota, and their influence on host health and disease. Mol. Nutr. Food Res., 61(1), 1600240. [67] C. Ceapa, H. Wopereis, L. Rezaı¨ki, M. Kleerebezem, J. Knol, R. Oozeer, Influence of fermented milk products, prebiotics and probiotics on microbiota composition and health, Best Pract. Res. Clin. Gastroenterol. 27 (1) (2013) 139-155]. [68] V.D.V. Valeriano, M.P. Balolong, D.K. Kang, Probiotic roles of Lactobacillus sp. in swine: insights from gut microbiota, J. Appl. Microbiol. 122 (3) (2017) 554–567. [69] D. Davani-Davari, M. Negahdaripour, I. Karimzadeh, M. Seifan, M. Mohkam, S.J. Masoumi, et al., Prebiotics: definition, types, sources, mechanisms, and clinical applications, Foods 8 (3) (2019) 92. [70] M. Roadjanakamolson, W. Suntornsuk, Production of $\beta $-carotene-enriched rice bran using solid-state fermentation of rhodotorulaglutinis, J. Microbiol. Biotechnol. 20 (3) (2010) 525–531. [71] V. Shekhar, A.K. Jha, J.S. Dangi, Nutraceuticals: A re-emerging health aid, in: Proceedings of the International Conference on Food, Biological and Medical Sciences (FBMS2014), Bangkok, Thailand, 2014, January, pp. 28–29. [72] A.N.M. Alamgir, Therapeutic Use of Medicinal Plants and Their Extracts: Volume 1, Springer International Publishing AG, 2017.

References

[73] W. Stonehouse, C.S. Gammon, K.L. Beck, C.A. Conlon, P.R. von Hurst, R. Kruger, Kiwifruit: our daily prescription for health, Can. J. Physiol. Pharmacol. 91 (6) (2013) 442–447. [74] Y. Ouyang, Y. Qiu, Y. Liu, R. Zhu, Y. Chen, H.R. El-Seedi, et al., Cancer-fighting potentials of algal polysaccharides as nutraceuticals, Food Res. Int. 147 (2021), 110522. [75] N. Ullah, M. Ahmad, H. Aslam, M.A. Tahir, M. Aftab, N. Bibi, S. Ahmad, Green tea phytocompounds as anticancer: a review, Asian Pacific J. Trop. Dis. 6 (4) (2016) 330–336. [76] F.S. Moreno, R. Heidor, I.P. Pogribny, Nutritional epigenetics and the prevention of hepatocellular carcinoma with bioactive food constituents, Nutr. Cancer 68 (5) (2016) 719–733. [77] M. Russo, G.L. Russo, M. Daglia, P.D. Kasi, S. Ravi, S.F. Nabavi, S.M. Nabavi, Understanding genistein in cancer: The “good” and the “bad” effects: a review, Food Chem. 196 (2016) 589–600. [78] M.A.R. Mazumder, P. Hongsprabhas, Genistein as antioxidant and antibrowning agents in in vivo and in vitro: a review, Biomed. Pharmacother. 82 (2016) 379–392. [79] F. Lefranc, N. Tabanca, R. Kiss, Assessing the anticancer effects associated with food products and/or nutraceuticals using in vitro and in vivo preclinical developmentrelated pharmacological tests, in: Seminars in Cancer Biology, 46, Academic Press, 2017, pp. 14–32. [80] J.A. Marcum, Nutrigenetics/nutrigenomics, personalized nutrition, and precision healthcare, Curr. Nutr. Rep. 9 (4) (2020) 338–345. [81] X. Zhou, J. Lin, Y. Yin, J. Zhao, X. Sun, K. Tang, Ganodermataceae: natural products and their related pharmacological functions, Am. J. Chin. Med. 35 (04) (2007) 559–574. [82] J.D. Potter, Colorectal cancer: molecules and populations, J. Natl. Cancer Inst. 91 (11) (1999) 916–932. [83] J.W. Finley, C.D. Davis, Y. Feng, Selenium from high selenium broccoli protects rats from colon cancer, J. Nutr. 130 (9) (2000) 2384–2389. [84] E.C. Miller, C.W. Hadley, S.J. Schwartz, J.W. Erdman, T.W.M. Boileau, S.K. Clinton, Lycopene, tomato products, and prostate cancer prevention. Have we established causality? Pure Appl. Chem. 74 (8) (2002) 1435–1441. [85] X. Montane, O. Kowalczyk, B. Reig-Vano, A. Bajek, K. Roszkowski, R. Tomczyk, et al., Current perspectives of the applications of polyphenols and flavonoids in cancer therapy, Molecules 25 (15) (2020) 3342. [86] S.M. Jeon, E. Shin, Exploring vitamin D metabolism and function in cancer, Exp. Mol. Med. 50 (4) (2018) 1–14. [87] N. Salam, S. Rane, R. Das, M. Faulkner, R. Gund, U. Kandpal, et al., T cell ageing: effects of age on development, survival & function, Indian J. Med. Res. 138 (5) (2013) 595. [88] Y. Abba, H. Hassim, H. Hamzah, M.M. Noordin, Antiviral activity of resveratrol against human and animal viruses, Adv. Virol. 2015 (2015). [89] G. Annunziata, M. Maisto, C. Schisano, R. Ciampaglia, V. Narciso, G.C. Tenore, E. Novellino, Resveratrol as a novel anti-herpes simplex virus nutraceutical agent: an overview, Viruses 10 (9) (2018) 473. [90] A.V.A. David, R. Arulmoli, S. Parasuraman, Overviews of biological importance of quercetin: a bioactive flavonoid, Pharmacog. Rev. 10 (20) (2016) 84.

49

50

CHAPTER 2 Applications of nutraceuticals for disease prevention and treatment [91] P. Lakhanpal, D.K. Rai, Quercetin: a versatile flavonoid, Internet J. Med. Update 2 (2) (2007) 22–37. [92] P.K. Agrawal, C. Agrawal, G. Blunden, Quercetin: antiviral significance and possible COVID-19 integrative considerations, Nat. Prod. Commun. 15 (12) (2020). 1934578X20976293. [93] D.M. Houston, J.J. Bugert, S.P. Denyer, C.M. Heard, Potentiated virucidal activity of pomegranate rind extract (PRE) and punicalagin against Herpes simplex virus (HSV) when co-administered with zinc (II) ions, and antiviral activity of PRE against HSV and aciclovir-resistant HSV, PLoS One 12 (6) (2017), e0179291. [94] X. Gao, J. Liu, L. Li, W. Liu, M. Sun, A brief review of nutraceutical ingredients in gastrointestinal disorders: Evidence and suggestions, Int. J. Mol. Sci. 21 (5) (2020) 1822. [95] M.A. Schonberg, E.S. Breslau, M.B. Hamel, K.M. Bellizzi, E.P. McCarthy, Colon cancer screening in US adults aged 65 and older according to life expectancy and age, J. Am. Geriatr. Soc. 63 (4) (2015) 750–756. [96] R. Penner, R.N. Fedorak, K.L. Madsen, Probiotics and nutraceuticals: non-medicinal treatments of gastrointestinal diseases, Curr. Opin. Pharmacol. 5 (6) (2005) 596–603. [97] I.E. Cock, The genus Aloe: Phytochemistry and therapeutic uses including treatments for gastrointestinal conditions and chronic inflammation, in: Novel Natural Products: Therapeutic Effects in Pain, Arthritis and Gastro-Intestinal Diseases, 2015, pp. 179–235. [98] H.P. Hoensch, R. Oertel, The value of flavonoids for the human nutrition: short review and perspectives, Clin. Nutrition Exp. 3 (2015) 8–14. [99] M. Romano, P. Vitaglione, S. Sellitto, G. D’Argenio, Nutraceuticals for protection and healing of gastrointestinal mucosa, Curr. Med. Chem. 19 (1) (2012) 109–117. [100] S.Y. Al-Okbi, Nutraceuticals of anti-inflammatory activity as complementary therapy for rheumatoid arthritis, Toxicol. Ind. Health 30 (8) (2014) 738–749. [101] P.V. Rao, Cinnamon: a multifaceted medicinal plant, Evid. Based Comp. Altern. Med. (2014) 1–12, https://doi.org/10.1155/2014/642942. [102] A. Lang, M. Lahav, E. Sakhnini, I. Barshack, H.H. Fidder, B. Avidan, Y. Chowers, Allicin inhibits spontaneous and TNF-α induced secretion of proinflammatory cytokines and chemokines from intestinal epithelial cells, Clin. Nutr. 23 (5) (2004) 1199–1208. [103] W. Dankers, N. Davelaar, J.P. Van Hamburg, J. Van De Peppel, E.M. Colin, E. Lubberts, Human memory Th17 cell populations change into anti-inflammatory cells with regulatory capacity upon exposure to active vitamin D, Front. Immunol. 1504 (2019) 1–10, https://doi.org/10.3389/fimmu.2019.01504. [104] A.S. Naidu, P. Pressman, R.A. Clemens, Coronavirus and nutrition: what is the evidence for dietary supplements usage for COVID-19 control and management? Nutr. Today 56 (1) (2021) 19–25. [105] A. Alkhatib, C. Tsang, J. Tuomilehto, Olive oil nutraceuticals in the prevention and management of diabetes: From molecules to lifestyle, Int. J. Mol. Sci. 19 (7) (2018) 2024. [106] A. Baldi, N. Choudhary, S. Kumar, Nutraceuticals as therapeutic agents for holistic treatment of diabetes, Int. J. Green Pharm. (Medknow Publications & Media Pvt. Ltd.) 7 (4) (2013) 278–287. [107] R.C. Gupta, R.B. Doss, R.C. Garg, R. Lall, A. Srivastava, A. Sinha, Nutraceuticals for diabetes and glucose balance, in: Nutraceuticals, Academic Press, 2021, pp. 83–100.

References

[108] R. Sharma, H. Amin, P.K. Prajapati, Plant kingdom nutraceuticals for diabetes, J. Ayurv. Herbal Med. 2 (6) (2016) 224–228. [109] V. Calabrese, M. Scuto, A.T. Salinaro, G. Dionisio, S. Modafferi, M.L. Ontario, et al., Hydrogen sulfide and carnosine: modulation of oxidative stress and inflammation in kidney and brain axis, Antioxidants 9 (12) (2020) 1303. [110] L.G. Danescu, S. Levy, J. Levy, Vitamin D and diabetes mellitus, Endocrine 35 (1) (2009) 11–17. [111] F.C. Lau, M. Bagchi, C.K. Sen, D. Bagchi, Nutrigenomic basis of beneficial effects of chromium (III) on obesity and diabetes, Mol. Cell. Biochem. 317 (1) (2008) 1–10. [112] S.N. Babu, A. Noor, Bioactive constituents of the genus Aloe and their potential therapeutic and pharmacological applications: a review, J. Appl. Pharm. Sci. 10 (11) (2020) 133–145. [113] K. Eshun, Q. He, Aloe vera: a valuable ingredient for the food, pharmaceutical and cosmetic industries—a review, Crit. Rev. Food Sci. Nutr. 44 (2) (2004) 91–96. [114] R.N. Thota, S.H. Acharya, M.L. Garg, Curcumin and/or omega-3 polyunsaturated fatty acids supplementation reduces insulin resistance and blood lipids in individuals with high risk of type 2 diabetes: a randomised controlled trial, Lipids Health Dis. 18 (1) (2019) 1–11. [115] A. Papathanasopoulos, M. Camilleri, Dietary fiber supplements: effects in obesity and metabolic syndrome and relationship to gastrointestinal functions, Gastroenterology 138 (1) (2010) 65–72. [116] S. Benvenga, U. Feldt-Rasmussen, D. Bonofiglio, E. Asamoah, Nutraceutical supplements in the thyroid setting: health benefits beyond basic nutrition, Nutrients 11 (9) (2019) 2214. [117] J.P. Spencer, Flavonoids: modulators of brain function? Br. J. Nutr. 99 (E-S1) (2008) ES60-ES77. [118] D. Kim, The role of vitamin D in thyroid diseases, Int. J. Mol. Sci. 18 (9) (2017) 1949. [119] J.E. Manson, S.S. Bassuk, I.M. Lee, N.R. Cook, M.A. Albert, D. Gordon, et al., The VITamin D and OmegA-3 TriaL (VITAL): rationale and design of a large randomized controlled trial of vitamin D and marine omega-3 fatty acid supplements for the primary prevention of cancer and cardiovascular disease, Contemp. Clin. Trials 33 (1) (2012) 159–171. [120] K.S. Ibrahim, E.M. El-Sayed, Dietary conjugated linoleic acid and medium-chain triglycerides for obesity management, J. Biosci. 46 (1) (2021) 1–14. [121] L.R. Santos, C. Neves, M. Melo, P. Soares, Selenium and selenoproteins in immune mediated thyroid disorders, Diagnostics 8 (4) (2018) 70. [122] A. Sanna, D. Firinu, P. Zavattari, P. Valera, Zinc status and autoimmunity: a systematic review and meta-analysis, Nutrients 10 (1) (2018) 68.

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CHAPTER

Use of vitamins and minerals as dietary supplements for better health and cancer prevention

3

Saniya Arfin and Dhruv Kumar Department of Biotechnology, School of Health Sciences and Technology (SoHST), UPES University, Dehradun, Uttarakhand, India

1. Introduction Several experimental studies suggest a strong connection between oxidative damage, aging, and cancer. According to epidemiological observations, decreased cancer incidence as well as longer life expectancy are observed when dietary consumption of fruits and vegetables is high, which may be attributed to their high natural antioxidant content. A significant number of experimental studies and human trials are in progress for understanding their effects. Various vitamins and minerals have been used as antioxidants in cancer patients to decrease the chemotherapy- and radiotherapy-caused oxidative damage, reducing dose-limiting toxicities of therapies and to improve outcome. Nutritional supplements have been perceived to have anticancer and antitoxic properties among cancer patients. Along with their notable beneficial effects, they have shown certain negative results on random cancer prevention trials. However, nutritional supplements may yield benefits to subsets of cancer patients when tailored according to the individual patient’s background genetics, diet, tumor histology, and previous treatment. Vitamin A, vitamin C, and E and some minerals like zinc, copper, and selenium, which are found in the food, act as antioxidants that work by neutralizing the free radicals produced in the body preventing damage. Some contradictory studies state that both tumor and normal cells are protected by antioxidants against chemotherapy-/radiation therapy-induced oxidative damage, while some studies demonstrate that they only protect normal cells without affecting the deleterious effects of radiation therapy on the cancer cells [1]. Although in head and neck cancer, patients’ antioxidants reduce radiotherapy-induced toxicity, they increase overall recurrence rates as well as higher mortality among smokers during radiotherapy treatment [2]. Smoking has been marked to have a similar impact as antioxidants Nutraceuticals. https://doi.org/10.1016/B978-0-443-19193-0.00003-4 Copyright # 2023 Elsevier Inc. All rights reserved.

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CHAPTER 3 Vitamins and minerals for better health

in decreasing oxygen-dependent radiation toxicity by increasing blood carboxyhemoglobin and tissue hypoxia [3]. Chemotherapy results in oxidative organ damage owing to cisplatin-induced toxicities caused by the formation of free radicals [4]. The antioxidant concentrations in the plasma decrease significantly during cisplatin chemotherapy for cancer. Among nonsmokers and drinkers, antioxidant supplements decreased the recurrence of colon adenomas; however, these supplements doubled the risk among participants consuming larger alcoholic amounts per day and smokers. In this chapter, we are going to focus on the vitamins, minerals, and the antioxidants that have been clinically proven toxic to cancers. Table 3.1 lists all the vitamins and minerals studied in various cancer prevention studies and their targets.

2. Vitamin A A group of lipophilic isoprenoids that are structurally as well as functionally similar consisting of polar linear hydrophilic chains and a cyclic group constitute vitamin A. Among these, the biologically active forms are retinol, retinal, and retinoic acid [16]. The human body cannot synthesize vitamin A and is mostly obtained from the liver [17]. Retinol, retinal, RA, and retinyl esters constitute the preformed vitamin A obtained from animal food sources, whereas the plant vitamin A forms include the provitamin A carotenoids such as α- and β-carotene as well as β-cryptoxanthin that generate vitamin A [18]. Retinal, the covalently bound cofactor of rhodopsin, is important for visual phototransduction. Cell differentiation as well as cell growth, immune function, embryogenesis, and reproduction, are all regulated by vitamin A [19]. Apart from these functions, vitamin A shields against inflammation and oxidative stress induced damage by exhibiting antioxidant properties. Recently, scientists suggested that vitamin A and the eukaryotic host cells and symbiotic microbes regulated each other [20,21]. There are four different generations of retinoids on the basis of structural differences: (i) the first includes all-trans retinoic acid (ATRA), retinol, retinaldehyde, tretinoin, and isotretinoin; (ii) acitretin and etretinate constitute the second generation; (iii) tazarotene, adapalene, and bexarotene are the thirdgeneration retinoids; and (iv) seletinoid G is fourth generation [22]. Retinoids have been extensively used as medicine specially in basal cell carcinoma treatment and skin health care such as inflammatory and keratinization skin diseases. Studies have also reported their effective use in acute promyelocytic leukemia and neuroblastoma treatment [23]. Various chemo-preventive studies have been performed focusing on identifying the role of vitamin A in chemoprevention and treatment of several cancers [24]. High dietary vitamin A has been associated to decrease in bladder cancer incidence [25,26].

Table 3.1 List of different vitamins and minerals in various cancer types. Supplement type

Cancer type studied

Molecular mechanism targeted

Reference

Vitamin A

Breast, glioma, lung, and colorectal cancer

[5,6]

Vitamin C

Pancreas, prostate, myeloma, breast, and lung

Vitamin D

Colorectal cancer, breast, prostate, or pancreatic cancer

Vitamin E

Breast cancer, colorectal cancer, ovarian cancer, and lung cancer

Selenium

Prostate, breast, lung, oropharyngeal, colorectal, bladder, skin, leukemias, uterine, and ovarian cancers Hepatic, gastric tumors, and colorectal cancer

Inhibition of transcription factor AP-1,EGF mediated cell growth, regulates apoptotic mediators Bax and Bcl-2, MMP inhibition, expression level and polymorphism of RARs, RXRs, and PPARβ/δ, Akt, Erk, JNK, and p38 DNA-methyl transferase inhibition, antioxidant, Expression level and polymorphism of GLUT, GST, MnSOD, SVCT, Hp, activation of apoptosis and autophagy Expression level and polymorphism of VDR target genes like cyclin C, p21WAF1/CIP TP53, p27, CYP24 gene Polymorphism of APOA5, CYP4F2, reduces unwanted side effect of cytotoxicity by targeting oxidative stress and inflammatory markers Antioxidant, restores epigenetic altered events; genomic stability, targets GPxsang, TrxRs Increases pro-inflammatory cytokines IL-1β, IL-6, and TNFα, inhibits, NF-κB, antioxidant, apoptotic induction

[14,15]

Zinc

[7,8]

[9,10]

[11,12]

[13]

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CHAPTER 3 Vitamins and minerals for better health

2.1 Vitamin A metabolism Humans derive retinoids from β-carotene that gets metabolized to retinal and retinol that binds retinol-binding protein 4 (RBP4) for transportation. Retinoids enter circulation via the lymphatic system after being packaged in the chylomicrons to get stored in the liver [27]. The cellular uptake of retinol is mediated via retinoic acid 6 (STRA6), that stimulates the transmembrane-spanning receptor expressed by the target cells [28,29]. The lipoprotein-specific receptors take up retinyl esters and β-carotene from the chylomicrons [30]. Within the cell, retinoids bind to CRBP or cellular retinol binding protein, CRABP, cellular retinoic acid binding protein and to the FABP5, fatty acid-binding protein for effective metabolization [31]. A series of oxidative steps activate the biological inactive retinol and the retinyl esters by converting them to retinaldehyde by the action of retinol dehydrogenases (RDHs) or alcohol dehydrogenases (ADHs). β-Carotene oxygenase (BCO) generates retinaldehyde from β-carotene, which is oxidized into an active metabolite RA, by the action of retinal dehydrogenases (RALDHs) [27]. Lecithin retinol acyltransferase (LRAT) generates retinyl esters from retinol [29]. RA either binds CRABP moving to the nucleus for receptor binding at RARs, RXRs, and PPAR, resulting in transcription of their downstream genes, or gets oxidized by the enzyme cytochrome P450 to inactive compounds [32,33]. RA binds the nuclear receptors in dimers, aiding binding to the RARE response elements in the target gene regulatory regions exerting varied biological effects [34].

2.2 Anticancer role The high receptor binding affinity and selectivity, pro-apoptotic, antiproliferative, and antioxidant effects by gene expression modulation are favorable characteristics of vitamin A and retinoids owing to which their cancer prevention potential has been extensively explored [35]. Higher incidence of spontaneous carcinogen-induced tumors has been correlated to vitamin A deficiency. Increased bladder cancer risk has been observed in low vitamin A intake patients [36]. A recent study reported that every 1 μmol/L increase in circulating concentrations of α- and β-carotene resulted in 76% and 27% reduction in bladder cancer risk, respectively [26]. Also, carotenoid level measurements before breast cancer are inversely associated to breast cancer risk. Various studies established that an inverse relationship exists between concentrations of retinol and carotenoids and risk of developing breast tumor [37]. Furthermore, about 70% reduction in invasive breast cancer risks and breast cancer nodal metastasis is reported when the serum and plasma α- and β-carotene levels are high [36,38]. Another study supported high levels of plasma carotenoids and the subsequently lowered benign breast disease risks [39,40]. Low plasma retinol levels have been observed to show lower overall survival in breast cancer patients [41,42]. Experimental evidence suggests that this inverse relation of lycopene, α- and β-carotene, and lutein to breast cancer risk is regardless of hormone receptor status [43,44]. Studies to identify beneficial

2 Vitamin A

vitamin A impact on breast cancer risks due to lifestyle factors like increased oxidative stress during smoking and alcohol intake have also been performed, showing higher total carotenoid plasma levels to be correlated with a reduced risk of developing breast cancer among smokers [45]. Researchers suggest carotenoids inhibit smoke-stimulated IGF signaling, thereby counteracting smoke-generated ROS which initiates tumors [46]. A study reported all-trans-retinoic acid treatment for 3 weeks resulted in RARβ induction in breast cancer patients showing growth arrest [47].

2.3 Mechanism of anticancer action The binding of retinoic acid to the RARs and RXRs mediates its diverse functions by modulating gene expression [48]. Scientists have reported an association between RAR and RXR expression levels and retinoid-mediated carcinogenesis. Investigations on premalignant and malignant tissues showed RARβ and RXRβ from among the three isotypes (α, β, and γ) to be inactivated in the cancer tissues along with low retinoid levels [49]. Breast cancer solid tumors were observed to show low RARβ2 mRNA expression levels with increased RARβ2 gene promoter methylation [50]. The expression of this gene induces retinoid-dependent and -independent pathways and is responsible for apoptosis induction as well as growth arrest. The binding of RARα with retinoids leads to upregulation of the RARβ gene, which inhibits breast cancer metastasis by activating cell differentiation and death of genes [27]. Increased RARβ2 levels have been correlated with tumor-suppressive effects [51]. Scientists have suggested that downregulation of matrix metalloproteinases (MMPs) by retinoids might possibly the mechanism behind inhibition of tumor growth and invasion by degradation of the extracellular matrix [52]. Altered invasive breast cancer morphology was observed using synthetic retinoid 4-HPR that enhanced E-cadherin expression, inducing β-catenin translocation to the cytoplasm from the nucleus, resulting in decreased cell infiltration [53]. Since unliganded RARα interact with ERα to stimulate estrogen-dependent cell proliferation in ER-positive tumors [54], when the retinoid binds to RARα, it results in antiestrogenic activity. In ER-negative tumors, which show significantly higher RARβ mRNA expression, it results in ATRA-dependent growth-inhibition [55] (Fig. 3.1). Tumor cell proliferation inhibition is observed in both ER-positive and -negative breast cancer patients; however, they follow different mechanisms. In ER-positive tumors, retinoids arrest the cell cycle resulting in senescence, by inhibiting cyclin D and reducing telomerase levels and suppress ER-negative tumors by stimulating p53 and p21 expression [7]. Various studies have shown carotenoids induce breast tumor apoptosis by inhibiting RAS-ERK signaling and downregulating the PI3K pathway [56]. Carotenoids have been reported to enhance apoptosis of breast cancer cells by acting synergistically to anticancer drugs like doxorubicin [57]. Carotenoids generate antitumorigenic effects by stimulating the ARE transcription system, increasing gap junction communication as well as ROS scavenging along with inhibiting IGFdriven cell proliferation [58]. Another mechanism of tumor toxicity asserted by

57

FIG. 3.1 The role of vitamin E, vitamin D, vitamin A, and vitamin C in inducing cancer cell death in the given order. Regulation of apoptosis by proapoptotic vitamin E isomers by induction of the caspase-mediated pathway of apoptosis as well as the caspase-independent pathway by inhibiting NF-κB and Akt.1,25(OH)2D3 induces apoptosis by interfering with TNF-α, EGF, β-catenin, and prostaglandins as well as activates the intrinsic apoptotic pathway. Its repression of NFκB-mediated gene transcription leads to immunosuppression. Retinol entering the blood stream is converted to retinal and then to retinoic acid (RA), which binds the RARα in the nucleus by the cellular retinoic acid-binding protein-2 (CRABP2). RA binds to receptors at the gene promoters: retinoic acid receptor-α (RARα) and retinoid X receptors (RXRs) at retinoic acid response elements (RAREs), leading to downstream target gene expression, such as RARβ, which induces cell differentiation and inhibits tumor growth. Vitamin C inhibits tumor progression by exerting a prooxidant effect and regulates the PPARγ signaling pathway.

3 Vitamin C

carotenoids includes enhancing lymphocytes and natural killer cells, thereby stimulating the immune system [59]. Astaxanthin has also been observed to block the PI3K/Akt/mTOR pathway, that results in inhibiting MYC protein translation [60]. Lycopene has also been reported to work in a similar way by attenuating Akt and mTOR phosphorylation, thereby enhancing proapoptotic Bax and p53 gene expressions, resulting in apoptosis [61]. Studies have suggested β-carotene inhibits Akt and ERK1/2 signaling by regulating oxidative stress-related gene expression. β-carotene resulted in cancer cell death by activating caspases and pro-death proteins such as Bax and Bak as well as p53expression and by suppressing pro-survival proteins like Bcl-2 and Bcl-xl in breast cancer studies [62]. Another breast cancer study demonstrated fucoxanthin inhibited malignant tumors by suppressing PI3K/Akt signaling as well as NF-κB levels [63]. ATRA decreases Bcl2 and increases Bax as well as caspase activity, leading to breast cancer cell death [64]. Studies on lung cancer have shown β-cryptoxanthin supplementation resulted in NF-κB and AP-1 expression inhibition and restoring the RARβ, SIRT1, and NAChRs/PI3K/Akt pathways, suppressing lung cancer development. β-Cryptoxanthin treatment supresses colon cancer by regulating p73 RNA splicing and increasing G6Pase and PEPCK and active acetylated-p53, thereby inhibiting HIF-1α and LDHA, in hepatic gastric and bladder tumors [65].

3. Vitamin C Vitamin C is a water-soluble antioxidant commonly used for common cold prevention. It is used as cofactor for hydrolases in collagen and catecholamine synthesis and has also been reported to exert gene expression regulation. Owing to its pro-oxidant properties, the use of vitamin C has been explored in cancer prevention and treatment. Vitamin C exists as three forms: the reduced form or ascorbic acid (AA) and dehydroascorbic acid (DHA), the oxidized state, and as ascorbyl radical in the intermediate state. The water-soluble AA acts as a nonenzymatic antioxidant and makes up most of the plasmatic vitamin C, whereas minimal amounts of DHA and ascorbyl radical exist in the body. Vitamin C plasma levels and body reserve lower than 17 μM and 350 mg, respectively, leads to a deficiency disease called scurvy [66]. Hypovitaminosis has been reported in diabetes mellitus as well as cancer patients [67]. Myeloid cancer patients undergoing azacitidine chemotherapy suffer from vitamin C hypovitaminosis ( γTE > other tocotrienols in # tumor development. δTE # NF-κB and targeted genes in tumors; the combination # (50%) pancreatic tumor more strongly than δTE (40%) Tocotrienols # tumor growth and " p21, p27, and caspase 3/ 9; # Akt phosphorylation; δTE was stronger against hypoxic tumor cells than nomoxic cells

[173]

[199]

[151]

[200]

[203]

[204]

[205]

6 Minerals

intake on cancer risks have been reported. Over the past decade, γT-, δT-, and γTrich mixed tocopherols (γTmTs) have been tested for their anticancer efficacy in various preclinical trials. Also, tocotrienol-rich fractions (TRFs) have been implemented in various animal studies to investigate tocotrienols for chemoprevention. However, based on the epidemiologic data, limited conclusions can be drawn taking the confounding factors in diets into consideration.

6. Minerals 6.1 Selenium Selenium is a critical microelement that exists in organic forms as selenocysteine, SLM or seleno-L-methionine, and MSC or Se-methylselenocysteine and inorganic   forms as selenates (SeO4 2 , HSeO4 , H2SeO4), selenades (H2Se, HSe ), and selenites 2  (SeO3 , HSeO3 , H2SeO3) [206]. Selenomethionine is the predominant form of selenium ingested by humans. A number of food items such as seafood, meat, grains, vegetables, dairy products, and nuts are sources of dietary selenium [207]. This nutritional element after ingestion gets incorporated directly into proteins as selenocysteine to form selenoproteins which have a wide variety of functions and tissue distribution [208]. Selenoproteins on metabolization generate various small molecular weight seleno-compounds capable of affecting DNA repair and epigenetics [209]. The accepted allowance of selenium in an adult’s diet is about 55 μg/day [210].

6.1.1 Selenium metabolism Selenium within the body is metabolized by several different pathways. SLM is converted to selenocystathionine by cystathionine β-synthase, which is then acted on by cystathionine γ-lyase to give selenocysteine, which further generates hydrogen selenide [211]. Selenocysteine β-lyase converts MSC directly to methylselenol. Selenites form H2Se on thioredoxin reductase action or selenodiglutathione by glutathione disulfide action, which is then converted to glutathioselenol to produce H2Se.This H2Se gets methylated to methylselenol before getting incorporated into selenoproteins during biosynthesis or is converted to seleno-phosphate [212]. Hydrogen selenide conversion to methylselenol occurs at high selenide concentrations and is rate-limiting. Methylselenol is methylated to dimethylselenol or trimethylselenol, the former being exhaled out, while the latter is excreted through urine [213]. Though the FDA has approved of only SLM for clinical use, MSC can be explored for therapeutic use owing to the ease of metabolic activation [214].

6.1.2 Anticancer role Immune modulation Selenium has been studied to improve the immune system by promoting immune cell differentiation and enhancing B cell activation and proliferation [215]. Low levels of selenium supplements have shown to augment immune responses in trials, and selenium deficiency has been reported to be associated to greater susceptible to infection

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[216]. Another study showed selenium supplementation enhanced T cell receptor signaling and IL-2 and INF-γ production, resulting in Th1 phenotype T cell differentiation. On the contrary, selenium deficiencies have been associated with Th2 phenotype T cell differentiation with reduced activation states, resulting in decreased T cell receptor signaling [215]. Another study reported increase in CD4 + T helper cells as well as reversal of tumor-induced suppression of CD8+ T cell on administration of selenized yeast supplements to EMT6 breast-tumor-bearing mice [217]. However, studies have confirmed excessive selenium intake results in substantial reduction in serum as well as thymus levels of IFN-γ and IL-2 cytokines, implying compromised immunity and escalated oxidative damage [218]. The individual’s initial selenium levels, the selenium dose and type, and the schedule determine the effectiveness of immune modulation.

Anticancer role Se exerts anticancer effects via several mechanisms, including enhancing immune response, inducing phase II conjugating enzymes that detoxify carcinogens; reducing DNA damage, oxidative stress, inflammation; incorporating into selenoproteins; altering DNA methylation status of tumor suppressor genes; inhibiting cell cycle and angiogenesis; and inducing apoptosis and kinase modulation [219].

Cancer therapeutics Selenium’s impact on cancer is complicated and maybe chemo-preventive, anticancer, or cancer-promoting. Since high selenium doses have been reported to promote cancer, researchers are now focusing on their usage in cancer therapeutics rather than prevention. SLM or MSC in high doses in combination with certain chemotherapeutic agents stabilized tumor vasculature along with selective enhanced drug delivery to tumor tissue [220]. Collectively, studies on several xenograft models led to the following conclusions: (1) limited therapeutic efficacy of selenium when administered alone; (2) high dose and sequence-dependent therapeutic efficacy of selenium in combination with anticancer drugs; (3) selenium-induced dose-dependent and time-dependent stabilization of tumor vasculature; and (4) provides normal tissue protection against drug toxicity and hence can be employed to mitigate tumor drug resistance [221]. A clinical trial using clear-renal-cell carcinoma (ccRCC) patients investigated the impact of combination of selenium with anticancer drugs showed increased axitinib efficacy against tumors [222]. Various studies support the observation that selenium downregulates the expression of angiogenesis-related genes such as HIFs and VEGF [223]. The downregulation of the regulators of angiogenesis, metastasis, DNA repair, and multidrug resistance-associated genes such as miRNA-210/155, HIF-1α and 2α by SLM or MSC has been shown to result in multidrug sensitization of several tumor cell types [224].

6 Minerals

DNA repair Selenium improves the effectiveness of chemotherapeutic agents by repairing DNA damage and protecting normal cells from the toxic effects. A study reported selenium led to increased expression of XPC, XPE, and Gadd45a, which are p53-dependent DNA repair proteins, thereby protecting mouse embryonic fibroblasts from DNA damage. The same protection was not attributed to tumor cells which lack p53 [225].

Nrf2 as a selenium target Selenium suppresses the Nrf2/Prx1 pathway, leading to reduced drug detoxification and increased cytotoxicity of anticancer drugs on tumor cells while reversing the effects toward normal tissues by maintaining redox homeostasis [224]. A study demonstrated that the cardiotoxic effects of doxorubicin were attenuated on selenium supplement administration by Nrf2 pathway activation, thereby reducing oxidative stress and inflammation [226]. Another study showed niacin and selenium together attenuated sepsis-induced lung injury by decreasing ROS and upregulating Nrf2 signaling [227]. Lower lung cancer incidence has been attributed to low serum selenium levels. However, increased cancer rates are observed in patients with higher serum selenium levels. Selenium has also been observed to reduce gastric cancer occurrence [228].

6.2 Zinc Zinc is an important mineral performing essential functions that are catalytic, structural, and regulatory in nature within the human body [14]. Zinc ions are associated with many metalloenzymes and are components of transcription factors, zinc fingers, and various structural and regulatory proteins [229]. 8 mg/day is the recommended dietary allowance (RDA) for adult women and 11 mg/day for men; however, it may change according to age [230]. High dietary intake of zinc exceeding 40 mg/day for prolonged periods of time may cause nausea and copper deficiency; however, it is not commonly known [14]. The richest sources of zinc content is red meat and sea food, such as oysters, while fish provides small amounts of zinc [231]. Several studies identify the role of zinc in cancer patients. Owing to the multitude of zinc functions, it has been playing an important role in protecting the body against the initiation and promotion of tumors [232].

6.2.1 Zinc absorption Adjustments made to absorption and excretion of zinc obtained from food by the gastrointestinal tract maintain zinc homeostasis [233]. The cellular uptake and distribution of zinc is ensured by several membrane-associated proteins that bring about intestinal removal and binding of zinc to cytosolic zinc chaperones which deliver zinc ions to various zinc-requiring proteins as well as subcellular compartments. The dietary zinc concentration, the individual’s physiological state, and presence of dietary promoters/inhibitors determine the amount of zinc absorbed [234].

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Other food constituents also influence the zinc bioavailability such as corn, cereals, rice, and legumes which form insoluble complexes with zinc ions, inhibiting zinc absorption [235]. Also, the number of proteins in the diet directly correlates to zinc bioavailability; however, a few proteins inhibit zinc absorption such as casein in milk and soy protein, [236]. Certain amino acids like histidine, methionine, citrate, and EDTA are reported to be zinc absorption promoters. Trace elements such as iron and cadmium present in foods also affect zinc bioavailability in the gastrointestinal tract by reducing zinc absorption when it is added to the diet, while calcium and cadmium studies show conflicting results [237]. In the gastrointestinal tract, the expression of Zip proteins regulates the zinc absorption contributing to maintain zinc homeostasis. Cysteine-rich intestinal protein (CRIP) has also been associated to zinc transport into the blood [238].

6.2.2 Anticancer role Immune modulation Zinc plays an essential role in the cellular and humoral immune response as the body’s defense against cancer [239]. Studies demonstrated that zinc deficiency results in ROS generation, impaired granulocyte recruitment, chemotaxis, as well as phagocytosis [240]. A decrease in granulocytes and NK cell number and the phagocytic capacity of macrophages have been observed with reduction in serum zinc levels. Zinc deficiency increases pro-inflammatory cytokines IL-1β, IL-6, and TNF-α and disturbs the balance between Th1 and Th2, increasing Th2 lymphocytes [241]. Zinc supplement administration increases IFN-γ, which induces Th1, thereby eliminating this imbalance, exerting immunoregulation and anticancer effects [242]. Also, Th1 cells target TNF-β in tumors, thereby inhibiting their proliferation [243]. Zn suppresses STAT3 activation, an important step in Th17 development [244]. Excess zinc inhibits lymphocyte function and IFN-γ production, bringing about immunosuppression [245]. Numerous studies have demonstrated zinc deficiency, which hampers the immune system anticancer activity by reducing the adhesion of monocytes to the endothelium, granulocyte chemotaxis, macrophage phagocytosis, reduced T cell and macrophage-secreted cytokine and NK cell activity, T-cell differentiation, and interleukin and antibody production.

Zn inhibits NF-κB Zinc modulates NF-κB by suppressing cyclic nucleotide phosphodiesterase (PDE), which inhibits the MAPK signaling pathway [246]. In human monocytes, zinc suppresses TNF-α production by inhibiting the LPS-induced activation of IκB inhibitor kinase-β (IKKb) and NF-κB [247]. Similarly, zinc inhibits PMA (phorbol 12-myristate 13-acetate)-mediated protein kinase C (PKC) translocation to the membrane by binding zinc finger-like motifs on PKC, which leads to NF-κB activity inhibition indirectly [248]. A transcriptional target of NF-κB, zinc transporter ZIP8 (SLC39A8) increases cytosolic zinc content, which induces the inhibition of NF-κB. Zinc-chelating compounds inhibit the breast cancer cell migration by targeting membrane transporter

7 Conclusion/future perspectives

ZIP10 [249]. On the contrary, cancer cell growth and invasiveness increases when ZIP7 expression increases, resulting in the breast cancer cell resistance to cancer treatment [250]. ZIP6, has also been associated with longer survival of patients and better prognosis in breast cancer patients. Zinc induces protein A-20 expression, which binds several proteins and deactivates them, preventing NF-κB pathway activation in a TNF-α-dependent manner. A20 deubiquitinates receptor interacting protein 1 (RIP1) in TNFR signaling, preventing its interaction with NF-κB. Another study reports a decrease in IL-1 and TNF gene expression on zinc supplementation downregulating inflammatory cytokines due to NF-κB inactivation by mRNA and DNA-specific binding for A20 [251]. Furthermore, zinc inhibits NF-κB activation by increasing PPAR-α expression that induces transcription of fatty acid β-oxidation enzymes [252]. Upregulated PPAR-α downregulates inflammatory cytokines and adhesion molecules.

Zinc as an antioxidant Zinc reduces oxidative stress and contributes to tumor inhibition as it exerts antioxidant activity by being a component of superoxide dismutase and inhibiting lipid peroxidation [253]. It prevents copper and iron from generating free radicals by displacing them from the membrane-binding sites [254]. The breakdown of protein chelates by zinc increases the concentration of free zinc regulating oxidative stress response, generating chemo-preventive action.

Apoptosis and autophagy Zinc influences removal of mutated or damaged cells that can trigger cancer initiation, thereby playing a role in apoptosis regulation [255]. Zinc blocks apoptosis and protects cells from death by inactivating caspase-3 [256]. Both decrease and increase in intracellular zinc concentrations toward toxic levels are capable of triggering apoptotic cascade [257]. Zn triggers the apoptotic process by blocking caspase-6 while activating caspase-3 and -8 [258]. In vitro addition of zinc has shown to prevent TNF-alpha-induced apoptosis in tumors [259]. Zinc increases the Bcl-2 to Bax ratio, thereby increasing cell resistance to apoptosis [260].

7. Conclusion/future perspectives The results of clinical trials have encouraged the research to develop platforms, such as synthetic retinoids as well as retinoid and chemotherapeutic agent combinations etc. that have already been tested for various tumor management. Though several preclinical studies demonstrate vitamins and mineral potential in cancer prevention and cancer treatment, there still is inadequate understanding of the molecular mechanisms of action. Also, the application of these vitamins and minerals in cancer prevention still need to be successful translated into the clinical setting. A more targeted approach may yield better benefits in patient subsets. More research needs to be performed to establish whether it could be possible to reduce possible cancer incidences

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by living a healthy lifestyle, keeping a weight check, a switch to low saturated fat and refined carbohydrate, high fiber diet, and reduced alcohol consumption along with vitamin and mineral supplements. Supplements could be advised to individualized patients considering their diet and genetics and tumor history to yield desired benefits in subsets of patients.

References [1] B.D. Lawenda, K.M. Kelly, E.J. Ladas, S.M. Sagar, A. Vickers, J.B. Blumberg, Should supplemental antioxidant administration be avoided during chemotherapy and radiation therapy, JNCI J. Natl. Cancer Inst. 100 (11) (2008) 773–783. Available from: https://aca demic.oup.com/jnci/article/100/11/773/895704. [2] F. Meyer, I. Bairati, A. Fortin, M. G
elinas, A. Nabid, F. Brochet, et al., Interaction between antioxidant vitamin supplementation and cigarette smoking during radiation therapy in relation to long-term effects on recurrence and mortality: a randomized trial among head and neck cancer patients, Int. J. Cancer 122 (7) (2008) 1679–1683, https:// doi.org/10.1002/ijc.23200. [3] M. Harvie, Nutritional supplements and cancer: potential benefits and proven harms, Am. Soc. Clin. Oncol. Educ. B 34 (2014) e478–e486. [4] N.I. Weijl, T.J. Elsendoorn, E.G.W.M. Lentjes, G.D. Hopman, A. Wipkink-Bakker, A.H. Zwinderman, et al., Supplementation with antioxidant micronutrients and chemotherapyinduced toxicity in cancer patients treated with cisplatin-based chemotherapy: a randomised, double-blind, placebo-controlled study, Eur. J. Cancer 40 (11) (2004) 1713–1723. [5] F. Lin, S.K. Kolluri, G.Q. Chen, X.K. Zhang, Regulation of retinoic acid-induced inhibition of AP-1 activity by orphan receptor chicken ovalbumin upstream promotertranscription factor, J. Biol. Chem. 277 (24) (2002) 21414–21422. Available from: https://pubmed.ncbi.nlm.nih.gov/11934895/. [6] L. Tratnjek, J. Jeruc, R. Romih, D. Zupancic, Vitamin A and retinoids in bladder cancer chemoprevention and treatment: a narrative review of current evidence, challenges and future prospects, Int. J. Mol. Sci. 22 (7) (2021). Available from: /pmc/articles/PMC8036787/. [7] A.C. Mamede, S.D. Tavares, A.M. Abrantes, J. Trindade, J.M. Maia, M.F. Botelho, The role of vitamins in cancer: a review, Nutr. Cancer 63 (4) (2011) 479–494. Available from: https://pubmed.ncbi.nlm.nih.gov/21541902/. [8] A.I. Irimie, C. Braicu, S. Pasca, L. Magdo, D. Gulei, R. Cojocneanu, et al., Role of key micronutrients from nutrigenetic and nutrigenomic perspectives in cancer prevention, Medicina (B Aires) 55 (6) (2019) 283. Available from: /pmc/articles/PMC6630934/. [9] P. Kuppusamy, M.M. Yusoff, G.P. Maniam, S.J.A. Ichwan, I. Soundharrajan, N. Govindan, Nutraceuticals as potential therapeutic agents for colon cancer: a review, Acta Pharm. Sin. B 4 (3) (2014) 173–181. Available from: https://pubmed.ncbi.nlm.nih. gov/26579381/. [10] T.M. Layne, S.J. Weinstein, B.I. Graubard, X. Ma, S.T. Mayne, D. Albanes, Serum 25hydroxyvitamin D, vitamin D binding protein, and prostate cancer risk in black men, Cancer 123 (14) (2017) 2698–2704. Available from: https://pubmed.ncbi.nlm.nih.gov/ 28369777/.

References

[11] P. Lance, D.S. Alberts, P.A. Thompson, L. Fales, F. Wang, J.S. Jose, et al., Colorectal adenomas in participants of the SELECT randomized trial of selenium and vitamin E for prostate cancer prevention, Cancer Prev. Res. (Phila.) 10 (1) (2017) 45–54. Available from: https://pubmed.ncbi.nlm.nih.gov/27777235/. [12] D. Tsavachidou, T.J. McDonnell, S. Wen, X. Wang, F. Vakar-Lopez, L.L. Pisters, et al., Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer, J. Natl. Cancer Inst. 101 (5) (2009) 306–320. Available from: https://pubmed. ncbi.nlm.nih.gov/19244175/. [13] S. Kurokawa, M.J. Berry, Selenium. Role of the essential metalloid in health, Met. Ions Life Sci. 13 (2013) 499–534. Available from: https://pubmed.ncbi.nlm.nih.gov/ 24470102/. [14] G. Faa, V.M. Nurchi, A. Ravarino, D. Fanni, S. Nemolato, C. Gerosa, et al., Zinc in gastrointestinal and liver disease, Coord. Chem. Rev. 252 (1011) (2008) 1257–1269. [15] D. Skrajnowska, B. Bobrowska-Korczak, Role of zinc in immune system and anti-cancer defense mechanisms, Nutrients 11 (10) (2019). Available from: /pmc/articles/ PMC6835436/. [16] Z. Huang, Y. Liu, G. Qi, D. Brand, S.G. Zheng, Role of vitamin A in the immune system, J. Clin. Med. 7 (9) (2018). Available from: https://pubmed.ncbi.nlm.nih.gov/30200565/. [17] N. Bushue, W. YJY, Retinoid pathway and cancer therapeutics, Adv. Drug Deliv. Rev. 62 (13) (2010) 1285–1298. Available from: https://pubmed.ncbi.nlm.nih.gov/20654663/. [18] G. Maiani, M.J.P. Casto´n, G. Catasta, E. Toti, I.G. Cambrodo´n, A. Bysted, et al., Carotenoids: actual knowledge on food sources, intakes, stability and bioavailability and their protective role in humans, Mol. Nutr. Food Res. 53 (S2) (2009) S194–S218, https://doi. org/10.1002/mnfr.200800053. [19] M. Clagett-Dame, D. Knutson, Vitamin A in reproduction and development, Nutrients 3 (4) (2011) 385–428. Available from: https://pubmed.ncbi.nlm.nih.gov/22254103/. [20] M.T. Cantorna, L. Snyder, J. Arora, Vitamin A and vitamin D regulate the microbial complexity, barrier function, and the mucosal immune responses to ensure intestinal homeostasis, Crit. Rev. Biochem. Mol. Biol. 54 (2) (2019) 184–192, https://doi.org/ 10.1080/10409238.2019.1611734. [21] N. Iyer, S. Vaishnava, Vitamin A at the interface of host–commensal–pathogen interactions, PLoS Pathog. 15 (6) (2019), e1007750. Available from: https://journals.plos.org/ plospathogens/article?id¼10.1371/journal.ppat.1007750. [22] A. Dattola, M. Silvestri, L. Bennardo, M. Passante, E. Scali, C. Patruno, et al., Role of vitamins in skin health: a systematic review, Curr. Nutr. Rep. 9 (3) (2020) 226–235. Available from: https://link.springer.com/article/10.1007/s13668-020-00322-4. [23] V. Dobrotkova, P. Chlapek, P. Mazanek, J. Sterba, R. Veselska, Traffic lights for retinoids in oncology: molecular markers of retinoid resistance and sensitivity and their use in the management of cancer differentiation therapy, BMC Cancer 18 (1) (2018). Available from: https://pubmed.ncbi.nlm.nih.gov/30384831/. [24] R. Ferreira, J. Napoli, T. Enver, L. Bernardino, L. Ferreira, Advances and challenges in retinoid delivery systems in regenerative and therapeutic medicine, Nat. Commun. 11 (1) (2020) 1–14. Available from: https://www.nature.com/articles/s41467-020-18042-2. [25] S. Wu, Y. Liu, J.E. Michalek, R.A. Mesa, D.L. Parma, R. Rodriguez, et al., Carotenoid intake and circulating carotenoids are inversely associated with the risk of bladder cancer: a dose-response meta-analysis, Adv. Nutr. 11 (3) (2020) 630–643. Available from: https://pubmed.ncbi.nlm.nih.gov/31800007/.

79

80

CHAPTER 3 Vitamins and minerals for better health

[26] J. Tang, R.J. Wang, H. Zhong, B. Yu, Y. Chen, Vitamin A and risk of bladder cancer: a meta-analysis of epidemiological studies, World J. Surg. Oncol. 12 (1) (2014) 1–9. Available from: https://link.springer.com/articles/10.1186/1477-7819-12-130. [27] P. Chlapek, V. Slavikova, P. Mazanek, J. Sterba, R. Veselska, Why differentiation therapy sometimes fails: molecular mechanisms of resistance to retinoids, Int. J. Mol. Sci. 19 (1) (2018). Available from: https://pubmed.ncbi.nlm.nih.gov/29301374/. [28] W.S. Blaner, STRA6, a cell-surface receptor for retinol-binding protein: the plot thickens, Cell Metab. 5 (3) (2007) 164–166. [29] R. Kawaguchi, J. Yu, J. Honda, J. Hu, J. Whitelegge, P. Ping, et al., A membrane receptor for retinol binding protein mediates cellular uptake of vitamin A, Science (80-) 315 (5813) (2007) 820–825, https://doi.org/10.1126/science.1136244. [30] P. Henning, H.H. Conaway, U.H. Lerner, Retinoid receptors in bone and their role in bone remodeling, Front. Endocrinol. (Lausanne) 6 (MAR) (2015). Available from: https://pubmed.ncbi.nlm.nih.gov/25814978/. [31] J.L. Napoli, Cellular retinoid binding-proteins, CRBP, CRABP, FABP5: effects on retinoid metabolism, function and related diseases, Pharmacol. Ther. 173 (2017) 19–33. Available from: https://pubmed.ncbi.nlm.nih.gov/28132904/. [32] X. Par
es, J. Farr
es, N. Kedishvili, G. Duester, Medium- and short-chain dehydrogenase/ reductase gene and protein families: medium-chain and short-chain dehydrogenases/ reductases in retinoid metabolism, Cell. Mol. Life Sci. 65 (24) (2008) 3936–3949. Available from: https://pubmed.ncbi.nlm.nih.gov/19011747/. [33] R.J.M. Hurst, K.J. Else, Retinoic acid signalling in gastrointestinal parasite infections: lessons from mouse models, Parasite Immunol. 34 (7) (2012) 351–359. Available from: https://pubmed.ncbi.nlm.nih.gov/22443219/. [34] M. Zasada, E. Budzisz, Retinoids: active molecules influencing skin structure formation in cosmetic and dermatological treatments, Postep Dermatol. Alergol. 36 (4) (2019) 392–397. Available from: https://pubmed.ncbi.nlm.nih.gov/31616211/. [35] I.P. Uray, E. Dmitrovsky, P.H. Brown, Retinoids and rexinoids in cancer prevention: from laboratory to clinic, Semin. Oncol. 43 (1) (2016). Available from: https:// pubmed.ncbi.nlm.nih.gov/26970124/. [36] A.H. Eliassen, X. Liao, B. Rosner, R.M. Tamimi, S.S. Tworoger, S.E. Hankinson, Plasma carotenoids and risk of breast cancer over 20 y of follow-up, Am. J. Clin. Nutr. 101 (6) (2015) 1197–1205. Available from: https://pubmed.ncbi.nlm.nih.gov/25877493/. [37] J.A. Kim, J.H. Jang, S.Y. Lee, An updated comprehensive review on vitamin a and carotenoids in breast cancer: mechanisms, genetics, assessment, current evidence, and future clinical implications, Nutrients 13 (9) (2021). Available from: /pmc/articles/ PMC8465379/. [38] C. Peng, C. Gao, D. Lu, B.A. Rosner, O. Zeleznik, S.E. Hankinson, et al., Circulating carotenoids and breast cancer among high-risk individual, Am. J. Clin. Nutr. 113 (3) (2021) 525–533. Available from: https://pubmed.ncbi.nlm.nih.gov/33236056/. [39] K. Cohen, Y. Liu, J. Luo, C.M. Appleton, G.A. Colditz, Plasma carotenoids and the risk of premalignant breast disease in women aged 50 and younger: a nested case-control study, Breast Cancer Res. Treat. 162 (3) (2017) 571–580. Available from: https:// pubmed.ncbi.nlm.nih.gov/28190250/. [40] C. Pouchieu, P. Galan, V. Ducros, P. Latino-Martel, S. Hercberg, M. Touvier, Plasma carotenoids and retinol and overall and breast cancer risk: a nested case-control study, Nutr. Cancer 66 (6) (2014) 980–988. Available from: https://pubmed.ncbi.nlm.nih. gov/25072980/.

References

[41] F. Formelli, E. Meneghini, E. Cavadini, T. Camerini, M.G. Di Mauro, G. De Palo, et al., Plasma retinol and prognosis of postmenopausal breast cancer patients, Cancer Epidemiol. Biomark. Prev. 18 (1) (2009) 42–48. Available from: https://pubmed.ncbi.nlm.nih.gov/ 19124479/. [42] R. Sato, et al., Prospective study of carotenoids, tocopherols, and retinoid concentrations and the risk of breast cancer, 11 (5) (2022) 451–457. Available from: https://pubmed. ncbi.nlm.nih.gov/12010859/. [43] R.M. Tamimi, S.E. Hankinson, H. Campos, D. Spiegelman, S. Zhang, G.A. Colditz, et al., Plasma carotenoids, retinol, and tocopherols and risk of breast cancer, Am. J. Epidemiol. 161 (2) (2005) 153–160. [44] B. Yan, M.S. Lu, L. Wang, X.F. Mo, W.P. Luo, Y.F. Du, et al., Specific serum carotenoids are inversely associated with breast cancer risk among Chinese women: a case–control study, Br. J. Nutr. 115 (1) (2016) 129–137. Available from: https:// www.cambridge.org/core/journals/british-journal-of-nutrition/article/specific-serumcarotenoids-are-inversely-associated-with-breast-cancer-risk-among-chinese-womena-casecontrol-study/40ADFD5947DD9550642A22750BE462E0. [45] Y. Wang, S.M. Gapstur, M.M. Gaudet, J.D. Furtado, H. Campos, M.L. Mccullough, Plasma carotenoids and breast cancer risk in the cancer prevention study II nutrition cohort, Cancer Causes Control 26 (9) (2015) 1233–1244. Available from: https://link. springer.com/article/10.1007/s10552-015-0614-4. [46] P. Palozza, R. Simone, A. Catalano, M. Russo, V. Bohm, Lycopene modulation of molecular targets affected by smoking exposure, Curr. Cancer Drug Targets 12 (6) (2012) 640–657. Available from: https://pubmed.ncbi.nlm.nih.gov/22463591/. [47] S. Toma, P. Raffo, G. Nicolo, G. Canavese, E. Margallo, C. Vecchio, et al., Biological activity of all-trans-retinoic acid with and without tamoxifen and alpha-interferon 2a in breast cancer patients, Int. J. Oncol. 17 (5) (2000) 991–1000. Available from: https:// pubmed.ncbi.nlm.nih.gov/11029503/. [48] J. Bastien, C. Rochette-Egly, Nuclear retinoid receptors and the transcription of retinoidtarget genes, Gene 328 (1–2) (2004) 1–16. [49] X.C. Xu, Tumor-suppressive activity of retinoic acid receptor-beta in cancer, Cancer Lett. 253 (1) (2007) 14–24. Available from: https://pubmed.ncbi.nlm.nih.gov/17188427/. [50] C.M. Lewis, L.R. Cler, D.-W. Bu, S. Z€ohbauer-M€ uller, S. Milchgrub, E.Z. Naftalis, et al., Promoter hypermethylation in benign breast epithelium in relation to predicted breast cancer risk, Clin. Cancer Res. 11 (1) (2005) 166–172. Available from: https:// aacrjournals.org/clincancerres/article/11/1/166/185482/Promoter-Hypermethylation-inBenign-Breast. [51] S.J. Freemantle, M.J. Spinella, E. Dmitrovsky, Retinoids in cancer therapy and chemoprevention: promise meets resistance, Oncogene 22 (47) (2003) 7305–7315. Available from: https://www.nature.com/articles/1206936. [52] P.J. Bostr€om, et al., Expression of collagenase-3 (matrix metalloproteinase-13) in transitional-cell carcinoma of the urinary bladder, Int. J. Cancer 88 (3) (2000) 417– 423. Available from: https://pubmed.ncbi.nlm.nih.gov/11054671/. [53] E. Wang, J. Li, G. Yang, S. Zhong, T. Liu, Impact of 4HPR on the expression of E-Cad in human bladder transitional epithelial cancer cells T24, J. Huazhong Univ. Sci. Technol. Med. Sci. 32 (2) (2012) 237–241. Available from: https://pubmed.ncbi.nlm.nih.gov/ 22528227/. [54] M.D. Salazar, M. Ratnam, M. Patki, I. Kisovic, R. Trumbly, M. Iman, et al., During hormone depletion or tamoxifen treatment of breast cancer cells the estrogen receptor

81

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[55]

[56]

[57]

[58] [59]

[60]

[61]

[62]

[63]

[64]

[65]

[66] [67]

[68]

apoprotein supports cell cycling through the retinoic acid receptor α1 apoprotein, Breast Cancer Res. 13 (1) (2011). Available from: https://pubmed.ncbi.nlm.nih.gov/21299862/. E. Garattini, M. Bolis, S.K. Garattini, M. Fratelli, F. Centritto, G. Paroni, et al., Retinoids and breast cancer: from basic studies to the clinic and back again, Cancer Treat. Rev. 40 (6) (2014) 739–749. H.A. Park, S.R. Brown, Y. Kim, Cellular mechanisms of circulating tumor cells during breast cancer metastasis, Int. J. Mol. Sci. 21 (14) (2020) 1–19. Available from: https:// pubmed.ncbi.nlm.nih.gov/32708855/. K. Vijay, P.R.R. Sowmya, B.P. Arathi, S. Shilpa, H.J. Shwetha, M. Raju, et al., Low-dose doxorubicin with carotenoids selectively alters redox status and upregulates oxidative stress-mediated apoptosis in breast cancer cells, Food Chem. Toxicol. 118 (2018) 675–690. C.O. Perera, G.M. Yen, Functional properties of carotenoids in human health, Int. J. Food Prop. 10 (2) (2007) 201–230, https://doi.org/10.1080/10942910601045271. F. Recchia, Interleukin-2 and 13-cis retinoic acid in the treatment of minimal residual disease: a phase II study, Int. J. Oncol. 20 (6) (2002) 1275–1282. Available from: https://pubmed.ncbi.nlm.nih.gov/12012010/. M.S. Kim, Y.T. Ahn, C.W. Lee, H. Kim, W.G. An, Astaxanthin modulates apoptotic molecules to induce death of SKBR3 breast cancer cells, Mar. Drugs 18 (5) (2020) 266. Available from: https://www.mdpi.com/1660-3397/18/5/266/htm. S.J. Peng, J. Li, Y. Zhou, M. Tuo, X.X. Qin, Q. Yu, et al., In vitro effects and mechanisms of lycopene in MCF-7 human breast cancer cells, Genet. Mol. Res. 16 (2) (2017). Available from: https://pubmed.ncbi.nlm.nih.gov/28407181/. G. Sowmya Shree, K. Yogendra Prasad, H.S. Arpitha, U.R. Deepika, K. Nawneet Kumar, P. Mondal, et al., β-Carotene at physiologically attainable concentration induces apoptosis and down-regulates cell survival and antioxidant markers in human breast cancer (MCF-7) cells, Mol. Cell. Biochem. 436 (1–2) (2017) 1–12. Available from: https:// pubmed.ncbi.nlm.nih.gov/28550445/. J. Wang, Y. Ma, J. Yang, L. Jin, Z. Gao, L. Xue, et al., Fucoxanthin inhibits tumourrelated lymphangiogenesis and growth of breast cancer, J. Cell. Mol. Med. 23 (3) (2019) 2219–2229. Available from: https://pubmed.ncbi.nlm.nih.gov/30648805/. M. Sabzichi, J. Mohammadian, M. Ghorbani, S. Saghaei, H. Chavoshi, F. Ramezani, et al., Fabrication of all-trans-retinoic acid-loaded biocompatible precirol: a strategy for escaping dose-dependent side effects of doxorubicin, Colloids Surf. B Biointerfaces 159 (2017) 620–628. Available from: https://pubmed.ncbi.nlm.nih.gov/28865358/. J.Y. Lim, X.-D. Wang, Mechanistic understanding of β-cryptoxanthin and lycopene in cancer prevention in animal models, Biochim. Biophys. Acta Mol. Cell Biol. Lipids 1865 (11) (2020) 158652. Available from: /pmc/articles/PMC7415495/. F. Vald
es, Vitamina C, Actas Dermosifiliogr. 97 (9) (2006) 557–568. A. Mosdøl, B. Erens, E.J. Brunner, Estimated prevalence and predictors of vitamin C deficiency within UK’s low-income population, J. Public Health (Bangkok) 30 (4) (2008) 456–460. Available from: https://academic.oup.com/jpubhealth/article/30/ 4/456/1512595. L. Gillberg, A.D. Ørskov, A. Nasif, H. Ohtani, Z. Madaj, J.W. Hansen, et al., Oral vitamin C supplementation to patients with myeloid cancer on azacitidine treatment: normalization of plasma vitamin C induces epigenetic changes, Clin. Epigenetics 11 (1) (2019) 1–11. Available from: https://clinicalepigeneticsjournal.biomedcentral.com/ articles/10.1186/s13148-019-0739-5.

References

[69] M. Lindblad, P. Tveden-Nyborg, J. Lykkesfeldt, Regulation of vitamin C homeostasis during deficiency, Nutrients 5 (8) (2013) 2860–2879. Available from: https://pubmed. ncbi.nlm.nih.gov/23892714/. [70] A.J. Michels, T.M. Hagen, B. Frei, Human genetic variation influences vitamin C homeostasis by altering vitamin C transport and antioxidant enzyme function, Annu. Rev. Nutr. 33 (2013) 45–70. Available from: https://pubmed.ncbi.nlm.nih.gov/ 23642198/. [71] B. Frei, L. England, B.N. Ames, Ascorbate is an outstanding antioxidant in human blood plasma, Proc. Natl. Acad. Sci. U. S. A. 86 (16) (1989) 6377–6381. Available from: https://pubmed.ncbi.nlm.nih.gov/2762330/. [72] M. Villagran, J. Ferreira, M. Martorell, L. Mardones, The role of vitamin C in cancer prevention and therapy: a literature review, Antioxidants 10 (12) (2021) (Available from: /pmc/articles/PMC8750500/). [73] A. Meister, Glutathione-ascorbic acid antioxidant system in animals, J. Biol. Chem. 269 (13) (1994) 9397–9400. Available from: https://pubmed.ncbi.nlm.nih.gov/ 8144521/. [74] V. Camarena, G. Wang, The epigenetic role of vitamin C in health and disease, Cell. Mol. Life Sci. 73 (8) (2016) 1645–1658. Available from: https://pubmed.ncbi.nlm.nih.gov/ 26846695/. [75] A.A. Chen, C.J. Marsit, B.C. Christensen, E.A. Houseman, M.D. Mcclean, J.F. Smith, et al., Genetic variation in the vitamin C transporter, SLC23A2, modifies the risk of HPV16-associated head and neck cancer, Carcinogenesis 30 (6) (2009) 977–981. Available from: https://pubmed.ncbi.nlm.nih.gov/19346260/. [76] M.R. Cho, J.H. Han, H.J. Lee, Y.K. Park, M.H. Kang, Purple grape juice supplementation in smokers and antioxidant status according to different types of GST polymorphisms, J. Clin. Biochem. Nutr. 56 (1) (2015) 49–56. Available from: https://pubmed.ncbi.nlm. nih.gov/25678751/. [77] M. Levine, S.J. Padayatty, M.G. Espey, Vitamin C: a concentration-function approach yields pharmacology and therapeutic discoveries, Adv. Nutr. 2 (2) (2011) 78–88. Available from: https://pubmed.ncbi.nlm.nih.gov/22332036/. [78] M.C.M. Vissers, A.B. Das, Potential mechanisms of action for vitamin C in cancer: reviewing the evidence, Front. Physiol. 9 (JUL) (2018) 809. [79] H.R. Harris, N. Orsini, A. Wolk, Vitamin C and survival among women with breast cancer: a meta-analysis, Eur. J. Cancer 50 (7) (2014) 1223–1231. [80] H. Lv, C. Wang, T. Fang, T. Li, G. Lv, Q. Han, et al., Vitamin C preferentially kills cancer stem cells in hepatocellular carcinoma via SVCT-2, NPJ Precis. Oncol. 2 (1) (2018). Available from: https://pubmed.ncbi.nlm.nih.gov/29872720/. [81] J.D. Schoenfeld, Z.A. Sibenaller, K.A. Mapuskar, B.A. Wagner, K.L. Cramer-Morales, M. Furqan, et al., O 2 and H2O2-mediated disruption of Fe metabolism causes the differential susceptibility of NSCLC and GBM cancer cells to pharmacological ascorbate, Cancer Cell 31 (4) (2017) 487–500.e8. Available from: https://pubmed.ncbi.nlm.nih. gov/28366679/. [82] M.J. Gonzalez, et al., Schedule dependence in cancer therapy: intravenous vitamin C and the systemic saturation hypothesis, J. Orthomol. Med. 27 (1) (2012) 9–12. Available from: https://pubmed.ncbi.nlm.nih.gov/24860238/. [83] J. Du, S.M. Martin, M. Levine, B.A. Wagner, G.R. Buettner, S.H. Wang, et al., Mechanisms of ascorbate-induced cytotoxicity in pancreatic cancer, Clin. Cancer Res. 16 (2) (2010) 509–520. Available from: https://pubmed.ncbi.nlm.nih.gov/20068072/.

83

84

CHAPTER 3 Vitamins and minerals for better health

[84] M. Fiorillo, F. To´th, F. Sotgia, M.P. Lisanti, Doxycycline, azithromycin and vitamin C (DAV): a potent combination therapy for targeting mitochondria and eradicating cancer stem cells (CSCs), Aging (Albany NY) 11 (8) (2019) 2202–2216. Available from: https:// pubmed.ncbi.nlm.nih.gov/31002656/. [85] J. Mandl, A. Szarka, G. Ba´nhegyi, Vitamin C: update on physiology and pharmacology, Br. J. Pharmacol. 157 (7) (2009) 1097–1110. Available from: https://pubmed.ncbi.nlm. nih.gov/19508394/. [86] M. Liu, H. Ohtani, W. Zhou, A.D. Ørskov, J. Charlet, Y.W. Zhang, et al., Vitamin C increases viral mimicry induced by 5-aza-20 -deoxycytidine, Proc. Natl. Acad. Sci. U. S. A. 113 (37) (2016) 10238–10244. Available from: https://pubmed.ncbi.nlm.nih. gov/27573823/. [87] D.A. Monti, E. Mitchell, A.J. Bazzan, S. Littman, G. Zabrecky, C.J. Yeo, et al., Phase I evaluation of intravenous ascorbic acid in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer, PLoS ONE 7 (1) (2012). Available from: https://pubmed.ncbi.nlm.nih.gov/22272248/. [88] C. Mun˜oz-Montesino, F.J. Roa, E. Pen˜a, M. Gonza´lez, K. Sotomayor, E. Inostroza, et al., Mitochondrial ascorbic acid transport is mediated by a low-affinity form of the sodium-coupled ascorbic acid transporter-2, Free Radic. Biol. Med. 70 (2014) 241–254. Available from: https://pubmed.ncbi.nlm.nih.gov/24594434/. [89] J. Luo, L. Shen, D. Zheng, Association between vitamin C intake and lung cancer: a doseresponse meta-analysis, Sci. Rep. 4 (2014). Available from: https://pubmed.ncbi.nlm. nih.gov/25145261/. [90] H. Fulan, J. Changxing, W. Yi Baina, Z. Wencui, L. Chunqing, W. Fan, et al., Retinol, vitamins A, C, and E and breast cancer risk: a meta-analysis and meta-regression, Cancer Causes Control 22 (10) (2011) 1383–1396. Available from: https://link.springer.com/arti cle/10.1007/s10552-011-9811-y. [91] N. Shenoy, E. Creagan, T. Witzig, M. Levine, Ascorbic acid in cancer treatment: let the phoenix fly, Cancer Cell. Cell Press 34 (2018) 700–706, https://doi.org/10.1016/j. ccell.2018.07.014. [92] K.K. Deeb, D.L. Trump, C.S. Johnson, Vitamin D signalling pathways in cancer: potential for anticancer therapeutics, Nat. Rev. Cancer 7 (9) (2007) 684–700. Available from: https://www.nature.com/articles/nrc2196. [93] D.R. Fraser, E. Kodicek, Unique biosynthesis by kidney of a biological active vitamin D metabolite, Nature 228 (5273) (1970) 764–766. Available from: https://pubmed.ncbi. nlm.nih.gov/4319631/. [94] J.W. Pike, M.B. Meyer, Regulation of mouse Cyp24a1 expression via promoterproximal and downstream-distal enhancers highlights new concepts of 1,25dihydroxyvitamin D3 action, Arch. Biochem. Biophys. 523 (1) (2012) 2 (Available from: /pmc/articles/PMC3314719/). [95] C. Carlberg, I. Bendik, A. Wyss, E. Meier, L.J. Sturzenbecker, J.F. Grippo, et al., Two nuclear signalling pathways for vitamin D, Nature 361 (6413) (1993) 657–660. Available from: https://www.nature.com/articles/361657a0. [96] R. Dou, K. Ng, E.L. Giovannucci, J.E. Manson, Z.R. Qian, S. Ogino, Vitamin D and colorectal cancer: molecular, epidemiological, and clinical evidence, Br. J. Nutr. 115 (9) (2016) 1643 (Available from: /pmc/articles/PMC4890569/). [97] M.R. Haussler, G.K. Whitfield, I. Kaneko, C.A. Haussler, D. Hsieh, J.C. Hsieh, et al., Molecular mechanisms of vitamin D action, Calcif. Tissue Int. 92 (2) (2013) 77–98. Available from: https://pubmed.ncbi.nlm.nih.gov/22782502/.

References

[98] M.R. Haussler, P.W. Jurutka, M. Mizwicki, A.W. Norman, Vitamin D receptor (VDR)-mediated actions of 1α,25(OH)2vitamin D3: genomic and non-genomic mechanisms, Best Pract. Res. Clin. Endocrinol. Metab. 25 (4) (2011) 543–559. [99] A.W. Norman, M.T. Mizwicki, D.P.G. Norman, Steroid-hormone rapid actions, membrane receptors and a conformational ensemble model, Nat. Rev. Drug Discov. 3 (1) (2004) 27–41. Available from: https://www.nature.com/articles/nrd1283. [100] L. Teleni, J. Baker, B. Koczwara, M.G. Kimlin, E. Walpole, K. Tsai, et al., Clinical outcomes of vitamin D deficiency and supplementation in cancer patients, Nutr. Rev. 71 (9) (2013) 611–621. Available from: https://academic.oup.com/nutritionreviews/arti cle/71/9/611/1854578. [101] P.J. Goodwin, M. Ennis, K.I. Pritchard, J. Koo, N. Hood, Prognostic effects of 25-hydroxyvitamin D levels in early breast cancer, J. Clin. Oncol. 27 (23) (2009) 3757–3763. [102] G. Bises, E. Ka´llay, T. Weiland, F. Wrba, E. Wenzl, E. Bonner, et al., 25-Hydroxyvitamin D3-1α-hydroxylase expression in normal and malignant human colon, J. Histochem. Cytochem. 52 (7) (2004) 985–989, https://doi.org/10.1369/jhc.4B6271.2004. [103] B.W. Ogunkolade, B.J. Boucher, P.D. Fairclough, G.A. Hitman, S. Dorudi, P.J. Jenkins, et al., Expression of 25-hydroxyvitamin D-1-alpha-hydroxylase mRNA in individuals with colorectal cancer, Lancet (London, England). 359 (9320) (2002) 1831–1832. Available from: https://pubmed.ncbi.nlm.nih.gov/12044381/. [104] P.R. Holt, et al., Colonic epithelial cell proliferation decreases with increasing levels of serum 25-hydroxy vitamin D1, Cancer Epidemiol. Biomarkers Prev. 11 (1) (2002) 113–119. Available from: https://aacrjournals.org/cebp/article/11/1/113/164395/ Colonic-Epithelial-Cell-Proliferation-Decreases. [105] H.C. Horva´th, P. Lakatos, J.P. Ko´sa, K. Ba´csi, K. Borka, G. Bises, et al., The candidate oncogene CYP24A1: a potential biomarker for colorectal tumorigenesis, J. Histochem. Cytochem. 58 (3) (2010) 277–285. Available from: https://pubmed.ncbi.nlm.nih.gov/ 19901270/. [106] M.G. Anderson, M. Nakane, X. Ruan, P.E. Kroeger, J.R. Wu-Wong, Expression of VDR and CYP24A1 mRNA in human tumors, Cancer Chemother. Pharmacol. 57 (2) (2006) 234–240. Available from: https://pubmed.ncbi.nlm.nih.gov/16180015/. [107] J.P. Ko´sa, P. Horva´th, J. W€olfing, D. Kova´cs, B. Balla, P. Ma´tyus, et al., CYP24A1 inhibition facilitates the anti-tumor effect of vitamin D3 on colorectal cancer cells, World J. Gastroenterol. 19 (17) (2013) 2621–2628. Available from: https://pubmed. ncbi.nlm.nih.gov/23674869/. [108] Y. Wang, J. Zhu, H.F. DeLuca, Where is the vitamin D receptor? Arch. Biochem. Biophys. 523 (1) (2012) 123–133. [109] H.S. Cross, P. Bareis, H. Hofer, M.G. Bischof, E. Bajna, S. Kriwanek, et al., 25hydroxyvitamin D3-1α-hydroxylase and vitamin D receptor gene expression in human colonic mucosa is elevated during early cancerogenesis, Steroids 66 (3–5) (2001) 287–292. [110] H.G. Pa´lmer, M.J. Larriba, J.M. Garcı´a, P. Ordo´n˜ez-Mora´n, C. Pen˜a, S. Peiro´, et al., The transcription factor SNAIL represses vitamin D receptor expression and responsiveness in human colon cancer, Nat. Med. 10 (9) (2004) 917–919. Available from: https:// pubmed.ncbi.nlm.nih.gov/15322538/. [111] M.B. Meyer, P.D. Goetsch, J.W. Pike, VDR/RXR and TCF4/β-catenin cistromes in colonic cells of colorectal tumor origin: impact on c-FOS and c-MYC gene expression, Mol. Endocrinol. 26 (1) (2012) 37–51. Available from: https://pubmed.ncbi.nlm.nih. gov/22108803/.

85

86

CHAPTER 3 Vitamins and minerals for better health

[112] F. Goeman, F. De Nicola, P.D.O. De Meo, M. Pallocca, B. Elmi, T. Castrignano`, et al., VDR primary targets by genome-wide transcriptional profiling, J. Steroid Biochem. Mol. Biol. 143 (2014) 348–356. Available from: https://pubmed.ncbi.nlm.nih.gov/ 24726990/. [113] M.R. Haussler, G.K. Whitfield, C.A. Haussler, J.C. Hsieh, P.D. Thompson, S.H. Selznick, et al., The nuclear vitamin D receptor: biological and molecular regulatory properties revealed, J. Bone Miner. Res. 13 (3) (1998) 325–349. Available from: https://pubmed.ncbi.nlm.nih.gov/9525333/. [114] S.S. Jensen, M.W. Madsen, J. Lukas, L. Binderup, J. Bartek, Inhibitory effects of 1alpha,25-dihydroxyvitamin D(3) on the G(1)-S phase-controlling machinery, Mol. Endocrinol. 15 (8) (2001) 1370–1380. Available from: https://pubmed.ncbi.nlm.nih. gov/11463860/. [115] A.C. Sintov, L. Berkovich, S. Ben-Shabat, Inhibition of cancer growth and induction of apoptosis by BGP-13 and BGP-15, new calcipotriene-derived vitamin D3 analogs, in-vitro and in-vivo studies, Investig. New Drugs 31 (2) (2012) 247–255. Available from: https://link.springer.com/article/10.1007/s10637-012-9839-1. [116] A. Chen, B.H. Davis, M.D. Sitrin, T.A. Brasitus, M. Bissonnette, Transforming growth factor-β1 signaling contributes to Caco-2 cell growth inhibition induced by 1,25(OH) 2D3, Am. J. Physiol. Gastrointest. Liver Physiol. (283) (2002) G864–G874, https://doi. org/10.1152/ajpgi.00524.2001. [117] Y.S. Oh, E.J. Kim, B.S. Schaffer, Y.H. Kang, L. Binderup, R.G. MacDonald, et al., Synthetic low-calcaemic vitamin D3 analogues inhibit secretion of insulin-like growth factor II and stimulate production of insulin-like growth factor-binding protein-6 in conjunction with growth suppression of HT-29 colon cancer cells, Mol. Cell. Endocrinol. 183 (1–2) (2001) 141–149. [118] F. Jiang, P. Li, A.J. Fornace, S.V. Nicosia, W. Bai, G2/M arrest by 1,25dihydroxyvitamin D3 in ovarian cancer cells mediated through the induction of GADD45 via an exonic enhancer, J. Biol. Chem. 278 (48) (2003) 48030–48040. [119] Q.M. Wang, J.B. Jones, G.P. Studzinski, Cyclin-dependent kinase inhibitor p27 as a mediator of the G1-S phase block induced by 1,25-dihydroxyvitamin D3 in HL60 cells, Cancer Res. 56 (2) (1996) 264–267. Available from: https://pubmed.ncbi.nlm.nih.gov/ 8542578/. [120] H.G. Pa´lmer, et al., Genetic signatures of differentiation induced by 1alpha,25dihydroxyvitamin D3 in human colon cancer cells, Cancer Res. 63 (22) (2003) 7799–7806. Available from: https://pubmed.ncbi.nlm.nih.gov/14633706/. [121] P. Li, C. Li, X. Zhao, X. Zhang, S.V. Nicosia, W. Bai, p27(Kip1) stabilization and G(1) arrest by 1,25-dihydroxyvitamin D(3) in ovarian cancer cells mediated through downregulation of cyclin E/cyclin-dependent kinase 2 and Skp1-Cullin-F-box protein/Skp2 ubiquitin ligase, J. Biol. Chem. 279 (24) (2004) 25260–25267. Available from: https:// pubmed.ncbi.nlm.nih.gov/15075339/. [122] Z. Hmama, D. Nandan, L. Sly, K.L. Knutson, P. Herrera-Velit, N.E. Reiner, 1alpha,25dihydroxyvitamin D(3)-induced myeloid cell differentiation is regulated by a vitamin D receptor-phosphatidylinositol 3-kinase signaling complex, J. Exp. Med. 190 (11) (1999) 1583–1594. Available from: https://pubmed.ncbi.nlm.nih.gov/10587349/. [123] G. Penna, L. Adorini, 1 Alpha,25-dihydroxyvitamin D3 inhibits differentiation, maturation, activation, and survival of dendritic cells leading to impaired alloreactive T cell activation, J. Immunol. 164 (5) (2000) 2405–2411. Available from: https://pubmed. ncbi.nlm.nih.gov/10679076/.

References

[124] A. Chen, B.H. Davis, M. Bissonnette, B. Scaglione-Sewell, T.A. Brasitus, 1,25Dihydroxyvitamin D(3) stimulates activator protein-1-dependent Caco-2 cell differentiation, J. Biol. Chem. 274 (50) (1999) 35505–35513. Available from: https://pubmed. ncbi.nlm.nih.gov/10585423/. [125] H.G. Pa´lmer, J.M. Gonza´lez-Sancho, J. Espada, M.T. Berciano, I. Puig, J. Baulida, et al., Vitamin D(3) promotes the differentiation of colon carcinoma cells by the induction of E-cadherin and the inhibition of beta-catenin signaling, J. Cell Biol. 154 (2) (2001) 369–387. Available from: https://pubmed.ncbi.nlm.nih. gov/11470825/. [126] T. Ylikomi, I. Laaksi, Y.R. Lou, P. Martikainen, S. Miettinen, P. Pennanen, et al., Antiproliferative action of vitamin D, Vitam. Horm. 64 (2002) 357–406. Available from: https://pubmed.ncbi.nlm.nih.gov/11898396/. [127] F. Jiang, J. Bao, P. Li, S.V. Nicosia, W. Bai, Induction of ovarian cancer cell apoptosis by 1,25-dihydroxyvitamin D3 through the down-regulation of telomerase, J. Biol. Chem. 279 (51) (2004) 53213–53221. Available from: https://pubmed.ncbi.nlm.nih. gov/15485861/. [128] M. Høyer-Hansen, L. Bastholm, P. Szyniarowski, M. Campanella, G. Szabadkai, T. Farkas, et al., Control of macroautophagy by calcium, calmodulin-dependent kinase kinase-beta, and Bcl-2, Mol. Cell 25 (2) (2007) 193–205. Available from: https:// pubmed.ncbi.nlm.nih.gov/17244528/. [129] L. Tavera-Mendoza, T.T. Wang, B. Lallemant, R. Zhang, Y. Nagai, V. Bourdeau, et al., Convergence of vitamin D and retinoic acid signalling at a common hormone response element, EMBO Rep. 7 (2) (2006) 180–185. Available from: https://pubmed.ncbi.nlm. nih.gov/16322758/. [130] L.E. Tavera-Mendoza, T. Westerling, E. Libby, A. Marusyk, L. Cato, R. Cassani, et al., Vitamin D receptor regulates autophagy in the normal mammary gland and in luminal breast cancer cells, Proc. Natl. Acad. Sci. U. S. A. 114 (11) (2017) E2186–E2194. Available from: https://pubmed.ncbi.nlm.nih.gov/28242709/. [131] G. DeMasters, X. Di, I. Newsham, R. Shiu, D.A. Gewirtz, Potentiation of radiation sensitivity in breast tumor cells by the vitamin D3 analogue, EB 1089, through promotion of autophagy and interference with proliferative recovery, Mol. Cancer Ther. 5 (11) (2006) 2786–2797. Available from: https://pubmed.ncbi.nlm.nih.gov/ 17121925/. [132] K. Sharma, R.W. Goehe, X. Di, M.A. Hicks, S.V. Torti, F.M. Torti, et al., A novel cytostatic form of autophagy in sensitization of non-small cell lung cancer cells to radiation by vitamin D and the vitamin D analog, EB 1089, Autophagy 10 (12) (2014) 2346–2361. Available from: https://pubmed.ncbi.nlm.nih.gov/25629933/. [133] I. Chung, M.K. Wong, G. Flynn, W.D. Yu, C.S. Johnson, D.L. Trump, Differential antiproliferative effects of calcitriol on tumor-derived and matrigel-derived endothelial cells, Cancer Res. 66 (17) (2006) 8565–8573. Available from: https://pubmed.ncbi. nlm.nih.gov/16951169/. [134] A. Cardu´s, E. Parisi, C. Gallego, M. Aldea, E. Ferna´ndez, J.M. Valdivielso, 1,25Dihydroxyvitamin D3 stimulates vascular smooth muscle cell proliferation through a VEGF-mediated pathway, Kidney Int. 69 (8) (2006) 1377–1384. Available from: https://pubmed.ncbi.nlm.nih.gov/16557229/. [135] B.Y. Bao, J. Yao, Y.F. Lee, 1alpha, 25-dihydroxyvitamin D3 suppresses interleukin-8mediated prostate cancer cell angiogenesis, Carcinogenesis 27 (9) (2006) 1883–1893. Available from: https://pubmed.ncbi.nlm.nih.gov/16624828/.

87

88

CHAPTER 3 Vitamins and minerals for better health

[136] M. Ben-Shoshan, S. Amir, D.T. Dang, L.H. Dang, Y. Weisman, N.J. Mabjeesh, 1α,25dihydroxyvitamin D3 (calcitriol) inhibits hypoxia-inducible factor-1/vascular endothelial growth factor pathway in human cancer cells, Mol. Cancer Ther. 6 (4) (2007) 1433–1439. Available from: https://aacrjournals.org/mct/article/6/4/1433/235258/125-dihydroxyvitamin-D3-Calcitriol-inhibits. [137] N. Penda´s-Franco, J.M. Garcı´a, C. Pen˜a, N. Valle, H.G. Pa´lmer, M. Hein€aniemi, et al., DICKKOPF-4 is induced by TCF/β-catenin and upregulated in human colon cancer, promotes tumour cell invasion and angiogenesis and is repressed by 1α,25dihydroxyvitamin D3, Oncogene 27 (32) (2008) 4467–4477. Available from: https:// www.nature.com/articles/onc200888. [138] A.S. Van Harten-Gerritsen, M.G.J. Balvers, R.F. Witkamp, E. Kampman, F.J.B. Van Duijnhoven, Vitamin D, inflammation, and colorectal cancer progression: A review of mechanistic studies and future directions for epidemiological studies, Cancer Epidemiol. Biomark. Prev. 24 (12) (2015) 1820–1828. Available from: https:// pubmed.ncbi.nlm.nih.gov/26396142/. [139] A.F. Gombart, N. Borregaard, H.P. Koeffler, Human cathelicidin antimicrobial peptide (CAMP) gene is a direct target of the vitamin D receptor and is strongly up-regulated in myeloid cells by 1,25-dihydroxyvitamin D3, FASEB J. 19 (9) (2005) 1067–1077. Available from: https://pubmed.ncbi.nlm.nih.gov/15985530/. [140] J. Sun, R. Mustafi, S. Cerda, A. Chumsangsri, Y.R. Xia, Y.C. Li, et al., Lithocholic acid down-regulation of NF-κB activity through vitamin D receptor in colonic cancer cells, J. Steroid Biochem. Mol. Biol. 111 (1–2) (2008) 37–40. [141] M. Veldhoen, V. Brucklacher-Waldert, Dietary influences on intestinal immunity, Nat. Rev. Immunol. 2012 (12) (2012). Available from: https://www.nature.com/articles/ nri3299. [142] C.H. Johnson, C.M. Dejea, D. Edler, L.T. Hoang, A.F. Santidrian, B.H. Felding, et al., Metabolism links bacterial biofilms and colon carcinogenesis, Cell Metab. 21 (6) (2015) 891–897. Available from: https://pubmed.ncbi.nlm.nih.gov/25959674/. [143] V. Lagishetty, A.V. Misharin, N.Q. Liu, T.S. Lisse, R.F. Chun, Y. Ouyang, et al., Vitamin D deficiency in mice impairs colonic antibacterial activity and predisposes to colitis, Endocrinology 151 (6) (2010) 2423–2432. Available from: https://pubmed. ncbi.nlm.nih.gov/20392825/. [144] X.P. Yu, T. Bellido, S.C. Manolagas, Down-regulation of NF-kappa B protein levels in activated human lymphocytes by 1,25-dihydroxyvitamin D3, Proc. Natl. Acad. Sci. U. S. A. 92 (24) (1995) 10990 (Available from: /pmc/articles/PMC40556/? report¼abstract). [145] Y. Han, Y. Zhang, T. Jia, Y. Sun, Molecular mechanism underlying the tumorpromoting functions of carcinoma-associated fibroblasts, Tumour Biol. 36 (3) (2015) 1385–1394. Available from: https://pubmed.ncbi.nlm.nih.gov/25680413/. [146] A.J. Levine, A.M. Puzio-Kuter, The control of the metabolic switch in cancers by oncogenes and tumor suppressor genes, Science (80-) 330 (6009) (2010) 1340–1344, https:// doi.org/10.1126/science.1193494. [147] M.A. Abu el Maaty, S. W€olfl, Vitamin D as a novel regulator of tumor metabolism: insights on potential mechanisms and implications for anti-cancer therapy, Int. J. Mol. Sci. 18 (10) (2017). Available from: /pmc/articles/PMC5666865/. [148] K. Adekola, S.T. Rosen, M. Shanmugam, Glucose transporters in cancer metabolism, Curr. Opin. Oncol. 24 (6) (2012) 650–654. Available from: https://pubmed.ncbi.nlm. nih.gov/22913968/.

References

[149] S. Alvarez-Dı´az, N. Valle, G. Ferrer-Mayorga, L. Lombardı´a, M. Herrera, O. Domı´nguez, et al., MicroRNA-22 is induced by vitamin D and contributes to its antiproliferative, antimigratory and gene regulatory effects in colon cancer cells, Hum. Mol. Genet. 21 (10) (2012) 2157–2165. Available from: https://academic.oup.com/ hmg/article/21/10/2157/2900589. [150] S.K.R. Padi, Q. Zhang, Y.M. Rustum, C. Morrison, B. Guo, MicroRNA-627 mediates the epigenetic mechanisms of vitamin D to suppress proliferation of human colorectal cancer cells and growth of xenograft tumors in mice, Gastroenterology 145 (2) (2013) 437–446. Available from: https://pubmed.ncbi.nlm.nih.gov/23619147/. [151] Q. Jiang, Natural forms of vitamin E as effective agents for cancer prevention and therapy, Adv. Nutr. 8 (6) (2017) 850. Available from: /pmc/articles/PMC5683003/. [152] R. Brigelius-Floh
e, M.G. Traber, Vitamin E: function and metabolism, FASEB J. 13 (10) (1999) 1145–1155. Available from: https://pubmed.ncbi.nlm.nih.gov/10385606/. [153] M.T. Ling, S.U. Luk, F. Al-Ejeh, K.K. Khanna, Tocotrienol as a potential anticancer agent, Carcinogenesis 33 (2) (2012) 233–239. Available from: https://academic.oup. com/carcin/article/33/2/233/2463536. [154] S.I. Grivennikov, F.R. Greten, M. Karin, Immunity, inflammation, and cancer, Cell 140 (6) (2010) 883–899. Available from: https://pubmed.ncbi.nlm.nih.gov/20303878/. [155] M. Tsujii, S. Kawano, S. Tsuji, H. Sawaoka, M. Hori, R.N. DuBois, Cyclooxygenase regulates angiogenesis induced by colon cancer cells, Cell 93 (5) (1998) 705–716. Available from: https://pubmed.ncbi.nlm.nih.gov/9630216/. [156] T.J. Sontag, R.S. Parker, Cytochrome P450 omega-hydroxylase pathway of tocopherol catabolism. Novel mechanism of regulation of vitamin E status, J. Biol. Chem. 277 (28) (2002) 25290–25296. Available from: https://pubmed.ncbi.nlm.nih.gov/ 11997390/. [157] Y. Jang, N.Y. Park, A.L. Rostgaard-Hansen, J. Huang, Q. Jiang, Vitamin E metabolite 130 -carboxychromanols inhibit pro-inflammatory enzymes, induce apoptosis and autophagy in human cancer cells by modulating sphingolipids and suppress colon tumor development in mice, Free Radic. Biol. Med. 95 (2016) 190–199. [158] Q. Jiang, X. Yin, M.A. Lil, M.L. Danielson, H. Freiser, J. Huang, Long-chain carboxychromanols, metabolites of vitamin E, are potent inhibitors of cyclooxygenases, Proc. Natl. Acad. Sci. U. S. A. 105 (51) (2008) 20464–20469. Available from: www.pnas.org/ cgi/content/full/. [159] Z. Jiang, X. Yin, Q. Jiang, Natural forms of vitamin E and 130 -carboxychromanol, a long-chain vitamin E metabolite, inhibit leukotriene generation from stimulated neutrophils by blocking calcium influx and suppressing 5-lipoxygenase activity, respectively, J. Immunol. 186 (2) (2011) 1173–1179. Available from: https://pubmed.ncbi.nlm.nih. gov/21169551/. [160] B. Sun, M. Karin, The therapeutic value of targeting inflammation in gastrointestinal cancers, Trends Pharmacol. Sci. 35 (7) (2014) 349–357. Available from: https:// pubmed.ncbi.nlm.nih.gov/24881011/. [161] Q. Jiang, Natural forms of vitamin E: metabolism, antioxidant, and anti-inflammatory activities and their role in disease prevention and therapy, Free Radic. Biol. Med. 72 (2014) 76–90. Available from: https://pubmed.ncbi.nlm.nih.gov/24704972/. [162] A.B. Kunnumakkara, B. Sung, J. Ravindran, P. Diagaradjane, A. Deorukhkar, S. Dey, et al., {Gamma}-tocotrienol inhibits pancreatic tumors and sensitizes them to gemcitabine treatment by modulating the inflammatory microenvironment, Cancer Res. 70 (21) (2010) 8695–8705. Available from: https://pubmed.ncbi.nlm.nih.gov/20864511/.

89

90

CHAPTER 3 Vitamins and minerals for better health

[163] Y. Wang, Q. Jiang, γ-Tocotrienol inhibits lipopolysaccharide-induced interlukin-6 and granulocyte colony-stimulating factor by suppressing C/EBPβ and NF-κB in macrophages, J. Nutr. Biochem. 24 (6) (2013) 1146–1152. Available from: https://pubmed. ncbi.nlm.nih.gov/23246159/. [164] A.A. Qureshi, J.C. Reis, C.J. Papasian, D.C. Morrison, N. Qureshi, Tocotrienols inhibit lipopolysaccharide-induced pro-inflammatory cytokines in macrophages of female mice, Lipids Health Dis. 9 (2010). Available from: https://pubmed.ncbi.nlm.nih.gov/ 21162750/. [165] S.A. Kwang, G. Sethi, K. Krishnan, B.B. Aggarwal, Gamma-tocotrienol inhibits nuclear factor-kappaB signaling pathway through inhibition of receptor-interacting protein and TAK1 leading to suppression of antiapoptotic gene products and potentiation of apoptosis, J. Biol. Chem. 282 (1) (2007) 809–820. Available from: https://pubmed.ncbi. nlm.nih.gov/17114179/. [166] A. Xiong, W. Yu, Y. Liu, B.G. Sanders, K. Kline, Elimination of ALDH+ breast tumor initiating cells by docosahexanoic acid and/or gamma tocotrienol through SHP-1 inhibition of Stat3 signaling, Mol. Carcinog. 55 (5) (2016) 420–430. Available from: https://pubmed.ncbi.nlm.nih.gov/25648304/. [167] Y. Wang, N.-Y. Park, Y. Jang, A. Ma, Q. Jiang, Vitamin E γ-tocotrienol inhibits cytokine-stimulated NF-κB activation by induction of anti-inflammatory A20 via stress adaptive response due to modulation of sphingolipids, J. Immunol. 195 (1) (2015). Available from: https://pubmed.ncbi.nlm.nih.gov/26002975/. [168] Z. Ren, M. Pae, M.C. Dao, D. Smith, S.N. Meydani, D. Wu, Dietary supplementation with tocotrienols enhances immune function in C57BL/6 mice, J. Nutr. 140 (7) (2010) 1335–1341. Available from: https://pubmed.ncbi.nlm.nih.gov/20484546/. [169] A.K. Radhakrishnan, D. Mahalingam, K.R. Selvaduray, K. Nesaretnam, Supplementation with natural forms of vitamin E augments antigen-specific TH1-type immune response to tetanus toxoid, Biomed. Res. Int. 2013 (2013). Available from: https:// pubmed.ncbi.nlm.nih.gov/23936847/. [170] D. Mahalingam, A.K. Radhakrishnan, Z. Amom, N. Ibrahim, K. Nesaretnam, Effects of supplementation with tocotrienol-rich fraction on immune response to tetanus toxoid immunization in normal healthy volunteers, Eur. J. Clin. Nutr. 65 (1) (2010) 63–69. Available from: https://www.nature.com/articles/ejcn2010184. [171] Q. Jiang, X. Rao, C.Y. Kim, H. Freiser, Q. Zhang, Z. Jiang, et al., Gamma-tocotrienol induces apoptosis and autophagy in prostate cancer cells by increasing intracellular dihydrosphingosine and dihydroceramide, Int. J. Cancer 130 (3) (2012) 685–693. Available from: https://pubmed.ncbi.nlm.nih.gov/21400505/. [172] S.J. Shah, P.W. Sylvester, γ-Tocotrienol inhibits neoplastic mammary epithelial cell proliferation by decreasing Akt and nuclear factor κB activity, Exp. Biol. Med. (Maywood) 230 (4) (2016) 235–241, https://doi.org/10.1177/153537020523000402. [173] Y. Hiura, H. Tachibana, R. Arakawa, N. Aoyama, M. Okabe, M. Sakai, et al., Specific accumulation of γ- and δ-tocotrienols in tumor and their antitumor effect in vivo, J. Nutr. Biochem. 20 (8) (2009) 607–613. [174] A. Gopalan, W. Yu, Q. Jiang, Y. Jang, B.G. Sanders, K. Kline, Involvement of de novo ceramide synthesis in gamma-tocopherol and gamma-tocotrienol-induced apoptosis in human breast cancer cells, Mol. Nutr. Food Res. 56 (12) (2012) 1803–1811. Available from: https://pubmed.ncbi.nlm.nih.gov/23065795/.

References

[175] S.K. Park, B.G. Sanders, K. Kline, Tocotrienols induce apoptosis in breast cancer cell lines via an endoplasmic reticulum stress-dependent increase in extrinsic death receptor signaling, Breast Cancer Res. Treat. 124 (2) (2010) 361–375. Available from: https:// pubmed.ncbi.nlm.nih.gov/20157774/. [176] S.E. Campbell, W.L. Stone, S. Lee, S. Whaley, H. Yang, M. Qui, et al., Comparative effects of RRR-alpha- and RRR-gamma-tocopherol on proliferation and apoptosis in human colon cancer cell lines, BMC Cancer 6 (2006). Available from: https:// pubmed.ncbi.nlm.nih.gov/16417629/. [177] K. Husain, R.A. Francois, S.Z. Hutchinson, A.M. Neuger, R. Lush, D. Coppola, et al., Vitamin E delta-tocotrienol levels in tumor and pancreatic tissue of mice after oral administration, Pharmacology 83 (3) (2009) 157–163. Available from: https:// pubmed.ncbi.nlm.nih.gov/19142032/. [178] K. Sakamoto, S. Maeda, Y. Hikiba, H. Nakagawa, Y. Hayakawa, W. Shibata, et al., Constitutive NF-κB activation in colorectal carcinoma plays a key role in angiogenesis, promoting tumor growth, Clin. Cancer Res. 15 (7) (2009) 2248–2258. Available from: https://aacrjournals.org/clincancerres/article/15/7/2248/74639/Constitutive-NF-B-Acti vation-in-Colorectal. [179] Y. Jang, X. Rao, Q. Jiang, Gamma-tocotrienol profoundly alters sphingolipids in cancer cells by inhibition of dihydroceramide desaturase and possibly activation of sphingolipid hydrolysis during prolonged treatment, J. Nutr. Biochem. 46 (2017) 49–56. [180] X. Ji, Z. Wang, A. Geamanu, A. Goja, F.H. Sarkar, S.V. Gupta, Delta-tocotrienol suppresses Notch-1 pathway by upregulating miR-34a in nonsmall cell lung cancer cells, Int. J. Cancer 131 (11) (2012) 2668–2677. Available from: https://pubmed.ncbi.nlm. nih.gov/22438124/. [181] X.H. Li, C.T. Ha, D. Fu, M.R. Landauer, S.P. Ghosh, M. Xiao, Delta-tocotrienol suppresses radiation-induced microRNA-30 and protects mice and human CD34+ cells from radiation injury, PLoS ONE 10 (3) (2015). Available from: https://pubmed. ncbi.nlm.nih.gov/25815474/. [182] Y. Huang, et al., A γ-tocopherol-rich mixture of tocopherols maintains Nrf2 expression in prostate tumors of TRAMP mice via epigenetic inhibition of CpG methylation, J. Nutr. 142 (5) (2012). Available from: https://pubmed.ncbi.nlm.nih.gov/22457388/. [183] Y. Huang, R. Wu, Z.Y. Su, Y. Guo, X. Zheng, C.S. Yang, et al., A naturally occurring mixture of tocotrienols inhibits the growth of human prostate tumor, associated with epigenetic modifications of cyclin-dependent kinase inhibitors p21 and p27, J. Nutr. Biochem. 40 (2017) 155–163. Available from: https://pubmed.ncbi.nlm.nih.gov/27889685/. [184] F. Pajonk, E. Vlashi, W.H. McBride, Radiation resistance of cancer stem cells: the 4 R’s of radiobiology revisited, Stem Cells 28 (4) (2010) 639–648. Available from: https:// pubmed.ncbi.nlm.nih.gov/20135685/. [185] S.U. Luk, W.N. Yap, Y.T. Chiu, D.T.W. Lee, S. Ma, T.K.W. Lee, et al., Gammatocotrienol as an effective agent in targeting prostate cancer stem cell-like population, Int. J. Cancer 128 (9) (2011) 2182–2191. Available from: https://pubmed.ncbi.nlm.nih. gov/20617516/. [186] K. Husain, B.A. Centeno, D. Coppola, J. Trevino, S.M. Sebti, M.P. Malafa, δ-Tocotrienol, a natural form of vitamin E, inhibits pancreatic cancer stem-like cells and prevents pancreatic cancer metastasis, Oncotarget 8 (19) (2017) 31554–31567. Available from: https://pubmed.ncbi.nlm.nih.gov/28404939/.

91

92

CHAPTER 3 Vitamins and minerals for better health

[187] A. Gopalan, W. Yu, B.G. Sanders, K. Kline, Eliminating drug resistant breast cancer stem-like cells with combination of simvastatin and gamma-tocotrienol, Cancer Lett. 328 (2) (2013) 285–296. Available from: https://pubmed.ncbi.nlm.nih.gov/23063651/. [188] K.S. Kumar, M. Raghavan, K. Hieber, C. Ege, S. Mog, N. Parra, et al., Preferential radiation sensitization of prostate cancer in nude mice by nutraceutical antioxidant γ-tocotrienol, Life Sci. 78 (18) (2006) 2099–2104. [189] S. Kulkarni, S.P. Ghosh, M. Satyamitra, S. Mog, K. Hieber, L. Romanyukha, et al., Gamma-tocotrienol protects hematopoietic stem and progenitor cells in mice after Total-body irradiation, Radiat. Res. 173 (6) (2010) 738–747. Available from: https://meridian.allenpress.com/radiation-research/article/173/6/738/43044/GammaTocotrienol-Protects-Hematopoietic-Stem-and. [190] S.P. Ghosh, S. Kulkarni, K. Hieber, R. Toles, L. Romanyukha, T.C. Kao, et al., Gammatocotrienol, a tocol antioxidant as a potent radioprotector, Int. J. Radiat. Biol. 85 (7) (2009) 598–606, https://doi.org/10.1080/09553000902985128. [191] X.H. Li, D. Fu, N.H. Latif, C.P. Mullaney, P.H. Ney, S.R. Mog, et al., δ-Tocotrienol protects mouse and human hematopoietic progenitors from γ-irradiation through extracellular signal-regulated kinase/mammalian target of rapamycin signaling, Haematologica 95 (12) (2010) 1996 (Available from: /pmc/articles/PMC2995556/). [192] J. Ju, S.C. Picinich, Z. Yang, Y. Zhao, N. Suh, A.N. Kong, et al., Cancer-preventive activities of tocopherols and tocotrienols, Carcinogenesis 31 (4) (2010) 533–542. Available from: https://academic.oup.com/carcin/article/31/4/533/2476925. [193] K. Husain, B. Centeno, D. Chen, et al., Prolonged survival and delayed progression of pancreatic intraepithelial neoplasia in LSL-KrasG12D/+;Pdx-1-Cre mice by vitamin E δ-tocotrienol, Carcinogenesis 34 (4) (2013) 858–863. Available from: https://academic. oup.com/carcin/article-abstract/34/4/858/2463259. [194] K. Husain, B.A. Centeno, D.T. Chen, S.R. Hingorani, S.M. Sebti, M.P. Malafa, Vitamin E δ-tocotrienol prolongs survival in the LSL-Kras G12D/+;LSLTrp53R172H/+;Pdx-1-Cre (KPC) transgenic mouse model of pancreatic cancer, Cancer Prev. Res. 6 (10) (2013) 1074–1083. Available from: https://aacrjournals.org/ cancerpreventionresearch/article/6/10/1074/50097/Vitamin-E-Tocotrienol-Prolongs-Sur vival-in-the-LSL. [195] M. Montagnani Marelli, M. Marzagalli, R.M. Moretti, G. Beretta, L. Casati, R. Comitato, et al., Vitamin E δ-tocotrienol triggers endoplasmic reticulum stressmediated apoptosis in human melanoma cells, Sci. Rep. 6 (2016). Available from: https://pubmed.ncbi.nlm.nih.gov/27461002/. [196] G.M. Springett, K. Husain, A. Neuger, B. Centeno, D.T. Chen, T.Z. Hutchinson, et al., A phase I safety, pharmacokinetic, and pharmacodynamic presurgical trial of vitamin E δ-tocotrienol in patients with pancreatic ductal neoplasia, EBioMedicine 2 (12) (2015) 1987–1995. [197] A.B. Kunnumakkara, B. Sung, J. Ravindran, P. Diagaradjane, A. Deorukhkar, S. Dey, et al., γ-Tocotrienol inhibits pancreatic tumors and sensitizes them to gemcitabine treatment by modulating the inflammatory microenvironment, Cancer Res. 70 (21) (2010) 8695–8705. Available from: https://aacrjournals.org/cancerres/article/70/21/8695/ 559844/Tocotrienol-Inhibits-Pancreatic-Tumors-and. [198] W.N. Yap, N. Zaiden, S.Y. Luk, D.T.W. Lee, M.T. Ling, Y.C. Wong, et al., In vivo evidence of gamma-tocotrienol as a chemosensitizer in the treatment of hormonerefractory prostate cancer, Pharmacology 85 (4) (2010) 248–258. Available from: https://pubmed.ncbi.nlm.nih.gov/20375535/.

References

[199] K.A. Manu, M.K. Shanmugam, L. Ramachandran, F. Li, C.W. Fong, A.P. Kumar, et al., First evidence that γ-tocotrienol inhibits the growth of human gastric cancer and chemosensitizes it to capecitabine in a xenograft mouse model through the modulation of NF-κB pathway, Clin. Cancer Res. 18 (8) (2012) 2220–2229. Available from: https:// pubmed.ncbi.nlm.nih.gov/22351692/. [200] ClinicalTrials.gov, Side Effects to FOLFOXIRI + Tocotrienol/Placebo as First Line Treatment of Metastatic Colorectal Cancer, ClinicalTrials.gov, 2016. Available from: https://clinicaltrials.gov/ct2/show/NCT02705300. [201] ClinicalTrials.gov, Tocotrienol as a Nutritional Supplement in Patients With Advanced Lung Cancer, ClinicalTrials.gov, 2015. Available from: https://clinicaltrials.gov/ct2/ show/NCT02644252. [202] ClinicalTrials.gov, Tocotrienol as a Nutritional Supplement in Patients With Advanced Ovarian Cancer, ClinicalTrials.gov, 2015. Available from: https://clinicaltrials.gov/ct2/ show/NCT02399592. [203] E. Pierpaoli, V. Viola, A. Barucca, F. Orlando, F. Galli, M. Provinciali, Effect of annatto-tocotrienols supplementation on the development of mammary tumors in HER-2/neu transgenic mice, Carcinogenesis 34 (6) (2013) 1352–1360. Available from: https://pubmed.ncbi.nlm.nih.gov/23430951/. [204] K. Husain, R.A. Francois, T. Yamauchi, M. Perez, S.M. Sebti, M.P. Malafa, Vitamin E δ-tocotrienol augments the antitumor activity of gemcitabine and suppresses constitutive NF-κB activation in pancreatic cancer, Mol. Cancer Ther. 10 (12) (2011) 2363–2372. Available from: https://pubmed.ncbi.nlm.nih.gov/ 21971120/. [205] A. Shibata, K. Nakagawa, T. Tsuduki, T. Miyazawa, δ-Tocotrienol treatment is more effective against hypoxic tumor cells than normoxic cells: potential implications for cancer therapy, J. Nutr. Biochem. 26 (8) (2015) 832–840. Available from: https:// pubmed.ncbi.nlm.nih.gov/25979648/. [206] Mahima, A.K. Verma, A. Kumar, A. Rahal, V. Kumar, D. Roy, Inorganic versus organic selenium supplementation: a review, Pak. J. Biol. Sci. PJBS 15 (9) (2012) 418–425. Available from: https://pubmed.ncbi.nlm.nih.gov/24163951/. [207] J.W. Finley, Bioavailability of selenium from foods, Nutr. Rev. 64 (3) (2006) 146–151. Available from: https://pubmed.ncbi.nlm.nih.gov/16572602/. [208] M.A. Reeves, P.R. Hoffmann, The human selenoproteome: recent insights into functions and regulation, Cell. Mol. Life Sci. 66 (15) (2009) 2457–2478. Available from: https://link.springer.com/article/10.1007/s00018-009-0032-4. [209] S. Bera, V. De Rosa, W. Rachidi, A.M. Diamond, Does a role for selenium in DNA damage repair explain apparent controversies in its use in chemoprevention? Mutagenesis 28 (2) (2013) 127–134. Available from: https://pubmed.ncbi.nlm.nih. gov/23204505/. [210] Statement By Norman I. Krinsky: Dietary Reference Intakes For Vitamin C, Vitamin E, Selenium, and Carotenoids. n.d. Available from: https://www8.nationalacademies.org/ onpinews/newsitem.aspx?RecordID¼s9810. [211] S.A. Mattmiller, B.A. Carlson, L.M. Sordillo, Regulation of inflammation by selenium and selenoproteins: impact on eicosanoid biosynthesis, J. Nutr. Sci. 2 (2013) 1–13. Available from: https://pubmed.ncbi.nlm.nih.gov/25191577/. [212] H.E. Ganther, Selenium metabolism, selenoproteins and mechanisms of cancer prevention: complexities with thioredoxin reductase, Carcinogenesis 20 (9) (1999) 1657–1666. Available from: https://pubmed.ncbi.nlm.nih.gov/10469608/.

93

94

CHAPTER 3 Vitamins and minerals for better health

[213] C. Thiry, A. Ruttens, L. De Temmerman, Y.J. Schneider, L. Pussemier, Current knowledge in species-related bioavailability of selenium in food, Food Chem. 130 (4) (2012) 767–784. [214] R. Garje, J.J. An, K. Sanchez, A. Greco, J. Stolwijk, E. Devor, et al., Current landscape and the potential role of hypoxia-inducible factors and selenium in clear cell renal cell carcinoma treatment, Int. J. Mol. Sci. 19 (12) (2018). Available from: https://pubmed. ncbi.nlm.nih.gov/30513765/. [215] F.K.W. Hoffmann, A.C. Hashimoto, L.A. Shafer, S. Dow, M.J. Berry, P.R. Hoffmann, Dietary selenium modulates activation and differentiation of CD4+ T cells in mice through a mechanism involving cellular free thiols, J. Nutr. 140 (6) (2010) 1155–1161. Available from: https://pubmed.ncbi.nlm.nih.gov/20375261/. [216] Q. Zhai, S. Cen, P. Li, F. Tian, J. Zhao, H. Zhang, et al., Effects of dietary selenium supplementation on intestinal barrier and immune responses associated with its modulation of gut microbiota, Environ. Sci. Technol. Lett. 5 (12) (2018) 724–730, https://doi. org/10.1021/acs.estlett.8b00563. [217] C.H. Guo, S. Hsia, D.Y. Hsiung, P.C. Chen, Supplementation with selenium yeast on the prooxidant-antioxidant activities and anti-tumor effects in breast tumor xenograftbearing mice, J. Nutr. Biochem. 26 (12) (2015) 1568–1579. Available from: https:// pubmed.ncbi.nlm.nih.gov/26344777/. [218] Y. Wang, L. Jiang, Y. Li, X. Luo, J. He, Effect of different selenium supplementation levels on oxidative stress, cytokines, and immunotoxicity in chicken thymus, Biol. Trace Elem. Res. 172 (2) (2016) 488–495. Available from: https://link.springer.com/ article/10.1007/s12011-015-0598-7. [219] (11) (PDF) Selenium and Tropical Diseases, Available from: https://www.researchgate. net/publication/235745925_Selenium_and_Tropical_Diseases. [220] R.G. Azrak, S. Cao, F.A. Durrani, K. Toth, A. Bhattacharya, Y.M. Rustum, Augmented therapeutic efficacy of irinotecan is associated with enhanced drug accumulation, Cancer Lett. 311 (2) (2011) 219–229. Available from: https://pubmed.ncbi.nlm.nih.gov/ 21872389/. [221] A.O. Rataan, S.M. Geary, Y. Zakharia, Y.M. Rustum, A.K. Salem, Potential role of selenium in the treatment of cancer and viral infections, Int. J. Mol. Sci. 23 (4) (2022). Available from: /pmc/articles/PMC8879146/. [222] Y. Zakharia, R. Garje, J.A. Brown, K.G. Nepple, L. Dahmoush, K. Gibson-Corley, et al., Phase1 clinical trial of high doses of Seleno-L-methionine (SLM), in sequential combination with axitinib in previously treated and relapsed clear cell renal cell carcinoma (ccRCC) patients, J. Clin. Oncol. 36 (6_suppl) (2018) 630, https://doi.org/ 10.1200/JCO.2018.36.6_suppl.630. [223] X. Zhang, C. He, R. Yan, Y. Chen, P. Zhao, M. Li, et al., HIF-1 dependent reversal of cisplatin resistance via anti-oxidative nano selenium for effective cancer therapy, Chem. Eng. J. 380 (2020), 122540. [224] Y. Zakharia, A. Bhattacharya, Y.M. Rustum, Selenium targets resistance biomarkers enhancing efficacy while reducing toxicity of anti-cancer drugs: preclinical and clinical development, Oncotarget 9 (12) (2018) 10765–10783. Available from: https://pubmed. ncbi.nlm.nih.gov/29535842/. [225] J.L. Fischer, E.M. Mihelc, K.E. Pollok, M.L. Smith, Chemotherapeutic selectivity conferred by selenium: a role for p53-dependent DNA repair, Mol. Cancer Ther. 6 (1) (2007) 355–361. Available from: https://pubmed.ncbi.nlm.nih.gov/17237294/.

References

[226] H.B. Yang, Z.Y. Lu, W. Yuan, W.D. Li, S. Mao, Selenium attenuates doxorubicininduced cardiotoxicity through Nrf2-NLRP3 pathway, Biol. Trace Elem. Res. (2021) 1–9. Available from: https://link.springer.com/article/10.1007/s12011-021-02891-z. [227] W.Y. Kwon, G.J. Suh, K.S. Kim, Y.S. Jung, S.H. Kim, J.S. Kim, et al., Niacin and selenium attenuate sepsis-induced lung injury by up-regulating nuclear factor erythroid 2related factor 2 signaling, Crit. Care Med. 44 (6) (2016) e370–e382. [228] G. Bjelakovic, D. Nikolova, L.L. Gluud, R.G. Simonetti, C. Gluud, Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases, Cochrane Database Syst. Rev. 2012 (3) (2012), https://doi.org/10.1002/ 14651858.CD007176.pub2. [229] S.S. Krishna, I. Majumdar, N.V. Grishin, Structural classification of zinc fingers: survey and summary, Nucleic Acids Res. 31 (2) (2003) 532–550. Available from: https://pubmed.ncbi.nlm.nih.gov/12527760/. [230] W. Maret, H.H. Sandstead, Zinc requirements and the risks and benefits of zinc supplementation, J. Trace Elem. Med. Biol. 20 (1) (2006) 3–18. [231] K. Yokoi, N.G. Egger, V.M.S. Ramanujam, N.W. Alcock, H.H. Dayal, J.G. Penland, et al., Association between plasma zinc concentration and zinc kinetic parameters in premenopausal women, Am. J. Physiol. Endocrinol. Metab. 285 (5) (2003) E1010–E1020. [232] D.K. Dhawan, V.D. Chadha, Zinc: a promising agent in dietary chemoprevention of cancer, Indian J. Med. Res. 132 (6) (2010) 676–682. Available from: https:// pubmed.ncbi.nlm.nih.gov/21245614/. [233] J.C. King, D.M. Shames, L.R. Woodhouse, Zinc homeostasis in humans, J. Nutr. 130 (5S Suppl) (2000). Available from: https://pubmed.ncbi.nlm.nih.gov/10801944/. [234] N.F. Krebs, Overview of zinc absorption and excretion in the human gastrointestinal tract, J. Nutr. 130 (5) (2000) 1374S–1377S. Available from: https://academic.oup. com/jn/article/130/5/1374S/4686378. [235] B. L€ onnerdal, Dietary factors influencing zinc absorption, J. Nutr. 130 (5S Suppl) (2000). Available from: https://pubmed.ncbi.nlm.nih.gov/10801947/. [236] B. Lonnerdal, A. Cederblad, L. Davidsson, B. Sandstrom, The effect of individual components of soy formula and cows’ milk formula on zinc bioavailability, Am. J. Clin. Nutr. 40 (5) (1984) 1064–1070. [237] B. Sandstrom, L. Davidsson, A. Cederblad, B. Lonnerdal, Oral iron, dietary ligands and zinc absorption, J. Nutr. 115 (3) (1985) 411–414. [238] J.M. Hempe, R.J. Cousins, Cysteine-rich intestinal protein and intestinal metallothionein: An inverse relationship as a conceptual model for zinc absorption in rats, J. Nutr. 122 (1) (1992) 89–95. [239] D. Sangthawan, T. Phungrassami, W. Sinkitjarurnchai, Effects of zinc sulfate supplementation on cell-mediated immune response in head and neck cancer patients treated with radiation therapy, Nutr. Cancer 67 (3) (2015) 449–456, https://doi.org/10.1080/ 01635581.2015.1004735. [240] R. Hasan, L. Rink, H. Haase, Chelation of free Zn2+ impairs chemotaxis, phagocytosis, oxidative burst, degranulation, and cytokine production by neutrophil granulocytes, Biol. Trace Elem. Res. 171 (1) (2015) 79–88. Available from: https://link.springer. com/article/10.1007/s12011-015-0515-0. [241] I. Wessels, H. Haase, G. Engelhardt, L. Rink, P. Uciechowski, Zinc deficiency induces production of the proinflammatory cytokines IL-1β and TNFα in promyeloid cells via epigenetic and redox-dependent mechanisms, J. Nutr. Biochem. 24 (1) (2013) 289–297. Available from: https://pubmed.ncbi.nlm.nih.gov/22902331/.

95

96

CHAPTER 3 Vitamins and minerals for better health

[242] K. Schroder, P.J. Hertzog, T. Ravasi, D.A. Hume, Interferon-gamma: an overview of signals, mechanisms and functions, J. Leukoc. Biol. 75 (2) (2004) 163–189. Available from: https://pubmed.ncbi.nlm.nih.gov/14525967/. [243] B.-C. Sheu, R.-H. Lin, H.-C. Lien, H.-N. Ho, S.-M. Hsu, S.-C. Huang, Predominant Th2/Tc2 polarity of tumor-infiltrating lymphocytes in human cervical cancer, J. Immunol. 167 (5) (2001) 2972–2978. Available from: https://pubmed.ncbi.nlm. nih.gov/11509647/. [244] C. Kitabayashi, T. Fukada, M. Kanamoto, W. Ohashi, S. Hojyo, T. Atsumi, et al., Zinc suppresses Th17 development via inhibition of STAT3 activation, Int. Immunol. 22 (5) (2010) 375–386. Available from: https://pubmed.ncbi.nlm.nih.gov/20215335/. [245] J.R. Arthur, R.C. McKenzie, G.J. Beckett, Selenium in the immune system, J. Nutr. 133 (5) (2003) 1457S–1459S. Available from: https://academic.oup.com/jn/article/133/5/ 1457S/4558526. [246] R. Roskoski, RAF protein-serine/threonine kinases: structure and regulation, Biochem. Biophys. Res. Commun. 399 (3) (2010) 313–317. Available from: https://pubmed.ncbi. nlm.nih.gov/20674547/. [247] M. Jarosz, M. Olbert, G. Wyszogrodzka, K. Młyniec, T. Librowski, Antioxidant and anti-inflammatory effects of zinc. Zinc-dependent NF-κB signaling, Inflammopharmacology 25 (1) (2017) 11–24. Available from: https://pubmed.ncbi.nlm.nih.gov/ 28083748/. [248] A. Brieger, L. Rink, H. Haase, Differential regulation of TLR-dependent MyD88 and TRIF signaling pathways by free zinc ions, J. Immunol. 191 (4) (2013) 1808–1817. Available from: https://pubmed.ncbi.nlm.nih.gov/23863901/. [249] N. Kagara, N. Tanaka, S. Noguchi, T. Hirano, Zinc and its transporter ZIP10 are involved in invasive behavior of breast cancer cells, Cancer Sci. 98 (5) (2007) 692–697. Available from: https://pubmed.ncbi.nlm.nih.gov/17359283/. [250] V. Lopez, S.L. Kelleher, Zip6-attenuation promotes epithelial-to-mesenchymal transition in ductal breast tumor (T47D) cells, Exp. Cell Res. 316 (3) (2010) 366–375. Available from: https://pubmed.ncbi.nlm.nih.gov/19852955/. [251] A.S. Prasad, B. Bao, F.W.J. Beck, O. Kucuk, F.H. Sarkar, Antioxidant effect of zinc in humans, Free Radic. Biol. Med. 37 (8) (2004) 1182–1190. Available from: https:// pubmed.ncbi.nlm.nih.gov/15451058/. [252] T. Lemberger, B. Desvergne, W. Wahli, Peroxisome proliferator-activated receptors: a nuclear receptor signaling pathway in lipid physiology, Annu. Rev. Cell Dev. Biol. 12 (1996) 335–363. Available from: https://pubmed.ncbi.nlm.nih.gov/8970730/. [253] I.N. Zelko, T.J. Mariani, R.J. Folz, Superoxide dismutase multigene family: a comparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and EC-SOD (SOD3) gene structures, evolution, and expression, Free Radic. Biol. Med. 33 (3) (2002) 337–349. [254] J. Pla´tenı´k, P. Stopka, M. Vejrazka, S. Stı´pek, Quinolinic acid — iron(II) complexes: slow autoxidation, but enhanced hydroxyl radical production in the Fenton reaction, Free Radic. Res. 34 (5) (2009) 445–459, https://doi.org/10.1080/10715760100300391. [255] E. John, T.C. Laskow, W.J. Buchser, B.R. Pitt, P.H. Basse, L.H. Butterfield, et al., Zinc in innate and adaptive tumor immunity, J. Transl. Med. 8 (2010). Available from: https://pubmed.ncbi.nlm.nih.gov/21087493/. [256] D.K. Perry, M.J. Smyth, H.R. Stennicke, G.S. Salvesen, P. Duriez, G.G. Poirier, et al., Zinc is a potent inhibitor of the apoptotic protease, caspase-3: A novel target for zinc in the inhibition of apoptosis, J. Biol. Chem. 272 (30) (1997) 18530–18533.

References

[257] P. Feng, T.L. Li, Z.X. Guan, R.B. Franklin, L.C. Costello, Direct effect of zinc on mitochondrial apoptogenesis in prostate cells, Prostate 52 (4) (2002) 311–318. [258] J.Y. Duffy, C.M. Miller, G.L. Rutschilling, G.M. Ridder, M.S. Clegg, C.L. Keen, et al., A decrease in intracellular zinc level precedes the detection of early indicators of apoptosis in HL-60 cells, Apoptosis 6 (3) (2001) 161–172. [259] M. Seve, F. Chimienti, A. Favier, R^ole du zinc intracellulaire dans la mort cellulaire programm
ee, Pathol Biol. 50 (3) (2002) 212–221. [260] Y. Fukamachi, Y. Karasaki, T. Sugiura, H. Itoh, T. Abe, K. Yamamura, et al., Zinc suppresses apoptosis of U937 cells induced by hydrogen peroxide through an increase of the Bcl-2/Bax ratio, Biochem. Biophys. Res. Commun. 246 (2) (1998) 364–369.

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Nutraceuticals and cosmeceuticals: An overview

4

Suriyaprabha Rangaraja, Vasuki Sasikantha, Subramanian Ammashib, and Thirumalaisamy Rathinavela a

Department of Biotechnology, Sona College of Arts and Science, Salem, Tamil Nadu, India, b PG and Research Department of Biochemistry, Rajah Serfoji Government College, Thanjavur, Tamil Nadu, India

1. Introduction Preventing disease and improving health are ultimately achieved through nutrition, which means a food or its part. Nutrition also affords many health benefits [1]. Numerous pharmacists, nutritionists, and physicians have been working together for the last two decades to extend new nutritional applications according to the requirements of the human populace. Nutrition plays a vital role in preventing or handling major lifestyle-oriented diseases such as cardiovascular disease, cancer, hypertension, diabetes, etc. Hence, manipulation of appropriate foodstuffs to keep up better health grasps worldwide acceptance to avoid such diseases. Stephen DeFelice [2] first defined a nutraceutical as “any compound that serves as a food or part of a food that provides medical/health benefits, including defense (against) and treatment of disease” [3]. Nutraceuticals can broadly be classified based on the following features [1]: (1) (2) (3) (4)

Food origin. Action mechanism. Chemical nature. Higher content in particular food items.

By considering the features of nutraceuticals, the food industries in many countries design different food compositions and contents amenable to the end user’s demand. Nutraceuticals formulated from the natural food products of India are currently of high demand among developed countries due to their potential therapeutic value [4]. Nutraceuticals. https://doi.org/10.1016/B978-0-443-19193-0.00004-6 Copyright # 2023 Elsevier Inc. All rights reserved.

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Plant-based foods in day-to-day life might be categorized as therapeutic agents, and they can also possess important ingredients for the production of drugs [5,6]. Exotic therapeutic activities of nutritive foods are [7,8]: (a) Antioxidant properties exerted from polyphenol compounds, tocopherols, carotenoids, resorcinol, etc. (b) Antiinflammatory properties of specific compounds in turmeric, citrus fruits, tomatoes, etc. (c) Anticancer activity exerted by genistein, limonene, etc. (d) Antibacterial activity. The nutritive value as well as therapeutic content in food makes more them specific for manipulation such as lycopene in the tomato, curcumin in turmeric, and quercetin in citrus fruit. Apart from therapeutic value, nutrition also directly or indirectly helps with the rejuvenation of our body tissues, which aids in the beauty of the skin. The problems and side effects rise from the use of chemical or synthetic pharmaceuticals, which makes people prefer food-based therapeutics to improve health and maintain beauty. Even though pharmaceuticals for cosmetic applications are endorsed by the US Food and Drug Administration (FDA), they are some allergic responses among few people using them on a regular basis. Skin aging is influenced by many factors such as temperature, sunlight, chemical vulnerability, and pollution. Hence, the importance of the cosmetic products that prevent such issues and also nutritive is currently anticipated by the people. Albert Kligman [9] first coined the term “cosmeceutical” at the National Scientific Meeting of the Society of Cosmetic Chemists (NSMSCC) in 1984, as “The products that are applied topically (that are) capable of modifying the status of skin and are not considered to perform drug or other cosmetic-like actions.” Cosmeceuticals are products comprised of active ingredients/combined formulations of biological origin with the characteristics of cosmetics and pharmaceuticals that contribute to the health and beauty of the skin [10,11]. In contrast to cosmeceuticals, cosmetics are used to cleanse and improve the appearance without any restorative value [5,6]. Combining cosmeceuticals and nutraceuticals leads to the novel term “nutricosmetics” [12], which is one of the blurry areas that consumers, food experts, and even cosmetics experts are unaware of [13]. This is represented in the block diagram (Fig. 4.1). The latest perception on Nutricosmetics are that they also known as “pills of beauty,” “beauty from inside,” and even “cosmetics administered orally” [14]. By reviewing the literature, we have compiled a comprehensive collection of the sources, formulations, and functional roles of nutricosmetics and their implications as well as regulations.

2. Nutrition representing their therapeutic activities Generally, the chemical nature of nutrition is in the form of carbohydrates, phenolic compounds, proteins, isoprenoids, lipids, and minerals, which are antioxidants, pro-/prebiotics, and dietary fibers. They signify appropriate therapeutic behavior

2 Nutrition representing their therapeutic activities

FIG. 4.1 Relationship between nutraceuticals and cosmeceuticals.

such as antimicrobial, antitumor, and antiinflammatory activities [4,15]. In fact, the antioxidant properties of nutrients of plant origin confer nutricosmeceutical behavior such as preventing skin damage, so can be used for formulating applicable creams [16–18]. Foods (vegetables, fruits, and oils) that are rich in vitamins and β-carotene have good antioxidant value by preventing or scavenging oxygen free radicals [4,15]. Similarly, the accomplishment of wrinkle free skin due to the antioxidant-mediated scavenging effect on free radicals also renders an antiaging effect. Nutraceuticals might be vitamins or minerals that are required in trace amounts, or they can be alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), magnesium, calcium, and phytochemicals that are required in larger quantities. Fiber in dietary intake, spices, herbal products, bioactive compounds, functional foods, dietary supplements, etc., are also served as nutraceutical properties. Examples of other nutraceuticals include natural foods, antioxidants, fortified dairy products, citrus fruits, milk, and cereals. Thus, innovations in nutricosmetics are being made on therapeutic traditional products and the mode of delivery suitable to industrial needs.

2.1 Based on the chemical nature Nutraceuticals are periodically developing along with the development of other new consumer products. With reference to function, nutraceuticals are classified into two types: potential nutraceuticals and established nutraceuticals. Potential nutraceuticals are substances that show a significant health or medical benefit to an individual. Potential nutraceuticals become established if they have enough clinical data that could explain the benefit of that particular compound. Based on the chemical nature and sources, nutraceuticals are classified as given in Fig. 4.2.

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FIG. 4.2 Classification of nutraceuticals.

2.1.1 Lipids Lipids play a crucial role by supplementing nutrition as well as normal biological functions. The functional lipids are categorized into various categories such as alpha-linolenic acid, eicosapentaenoic acid omega fatty acids, and fat-dissolvable vitamins. Structural lipids and lipid emulsions are used as delivery agents. Functional lipids are used as secondary coating compounds on microcapsules. They are also applied to boost biologically active centers to enrich antimoisturizing properties [16]. Microemulsions can be prepared spontaneously using the bioactive components of lipids laden with nutraceuticals; this is applied in drug delivery. A commercially available oral lipid supplement called SemsoSqualane is enriched with squalane, an aliphatic hydrocarbon. It results in minimal face wrinkles, reduced reactivity to ultraviolet (UV) rays on skin, increased gene expression encoding type-I collagen production, and reduced UV-induced DNA damage and cell necrosis. These effects correspond to the antioxidant activity of functional lipids. Several other studies show that fish oils could ameliorate eczemic lesions [17]. Psoriasis patients receiving the bioactive components of fish oil supplements show an average reduction of the psoriatic lesion that is related with the elevated Eicosapentaenoic Acid and Docosahexaenoic Acid (EPA-DHA) ratio in sera, lipids of the epiderma and neutrophils. These results suggest that a surge in leukotriene B5 in fish oil will be responsible for a reduction in inflammation through nutraceutical supplementation. Lipid-associated nutraceuticals such as sterol esters, isoflavones, etc., are accumulated as byproducts while processing oils and fats. There has been a negative ideology about oils and fats that relates directly to obesity and its associated diseases. Omega-3 fatty acids such as eicosapentaenoic acid, docosahexaenoic acids, and

2 Nutrition representing their therapeutic activities

polyunsaturated fatty acids (PUFA) are familiar for their beneficial health effects on cardiovascular diseases, neurodegenerative disorders, and other deteriorating disorders [18]. The primary sources of this fatty acid are oils derived from fish, seal blubber oil, oil from evening primrose and blackcurrant, etc. The frequently used coconut oil is a triglyceride source that acts as a better antiinflammatory compound; it is also used to treat malabsorption in children [19,20]. Oils such as sunflower oil, rapeseed oil, soybean oil, etc., are primary sources of phospholipids. These oils are widely used as recipients in nutraceutical and pharmaceutical formulations. Phosphatidyl choline and phosphatidyl serine are fundamental products for normal cell membrane function and a few of their derivatives are used in cancer treatment as well [21]. Fats and oils also have another important group of nutraceuticals. Especially, stanols and phytosterols show potent antioxidant properties and a versatile agent to reduce the serum cholesterol level [22]. Isoflavanones, other major nutraceutical present in soybean oil, show several health benefits against cardiovascular ailments, age-related disorders, hormoneinduced cancer, osteoporosis, etc. Scientists suggest that PUFA is a potent nutraceutical agent that combats cardiovascular disease as well as degenerative diseases of neurons such as Parkinson’s, dementia, and metabolic syndrome [23].

2.1.2 Proteins Every dietary supplement and functional food formulation includes proteins, peptides, and amino acids, as they exhibit distinct health properties. Protein deficiency is a major public health issue, particularly in developing countries [24]. A broad range of proteins and their derivatives promote muscle growth, reduce the deleterious effects of oxidative stress, mitigate cardiovascular issues, manage phenylketonuria (PKU), and defend the skin against harmful UV radiation [25]. The 10 essential amino acids combat acute inflammation, carcinogens, aging, reactive oxygen species (ROS), and neuron degeneration that occurs in cells. They also reduce the risk posed by the stress generated by the ROS and age-related deregulation in cells. In our post-COVID world, people long for natural food-based medications and immune boosters that could improve the general welfare of every human being. After COVID, everyone around the world gathered knowledge about altering their daily food habits. One of the major ingredients in everyone’s daily diet is the egg. Egg whites are comprised of important functional proteins such as ovalbumin (54%), ovomucin (3.5%), ovomucoid (11%), ovotransferrin (12%), and lysozyme (3.5%). This has maximum potential for industrial applications if the white and yolk are separated using proper techniques. Iron ions can easily get attached to ovotransferrin at a neutral pH, and they are released at an acidic pH (