Handbook of Food Bioactive Ingredients : Properties and Applications [1 ed.] 9783031281082, 9783031281099

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Seid Mahdi Jafari Ali Rashidinejad Jesus Simal-Gandara Editors

Handbook of Food Bioactive Ingredients Properties and Applications

Handbook of Food Bioactive Ingredients

Seid Mahdi Jafari • Ali Rashidinejad • Jesus Simal-Gandara Editors

Handbook of Food Bioactive Ingredients Properties and Applications

With 301 Figures and 131 Tables

Editors Seid Mahdi Jafari Faculty of Food Science and Technology Gorgan University of Agricultural Sciences and Natural Resources Gorgan, Iran

Ali Rashidinejad Riddet Institute Massey University Palmerston North, New Zealand

Jesus Simal-Gandara Nutrition and Food Science Group University of Vigo Vigo, Spain

ISBN 978-3-031-28108-2 ISBN 978-3-031-28109-9 (eBook) https://doi.org/10.1007/978-3-031-28109-9 © Springer Nature Switzerland AG 2023 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG. The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland Paper in this product is recyclable.

Preface

In recent years, the field of food science and nutrition has witnessed a remarkable growth in understanding the importance of bioactive ingredients in promoting human health and well-being. Bioactive compounds found in various foods have been extensively studied for their potential health benefits and therapeutic properties. These compounds possess a wide range of biological activities, such as antioxidant, anti-inflammatory, antimicrobial, anticancer, and cardiovascular-protective effects. The significance of bioactive ingredients in preventive medicine and the development of functional foods has sparked great interest among researchers, food technologists, nutritionists, and health professionals. The Handbook of Food Bioactive Ingredients: Properties and Applications aims to provide a comprehensive and up-to-date resource that encompasses the diverse aspects of bioactive ingredients in food. This handbook serves as a valuable tool for scientists, professionals, and students seeking an in-depth understanding of the properties and applications of various bioactive compounds. It presents a compilation of the latest research and knowledge in the field, including insights into their chemical composition, extraction techniques, bioavailability, and mechanisms of action. This comprehensive handbook is divided into several sections to cover the major classes of bioactive ingredients found in food. Each section provides a detailed exploration of the properties, sources, bioactivity, and potential applications of the specific bioactive compounds. The handbook covers a wide range of bioactive ingredients, including polyphenols, flavonoids, carotenoids, fatty acids, fiber, peptides, prebiotics, vitamins, and minerals, among others. Additionally, it delves into the latest advances in the identification and characterization of novel bioactive compounds from both traditional and unconventional sources. In order to ensure the relevance and currency of the information presented, this handbook incorporates corresponding references and citations from recent years. The cited research represents the most recent advancements in the field, offering readers an up-to-date perspective on the properties and applications of food bioactive ingredients. These references encompass a wide range of scientific publications, including peer-reviewed articles, books, and conference proceedings, authored by esteemed researchers and experts in the field.

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Preface

We think that this handbook will serve as a valuable resource for professionals and researchers working in the fields of food science, nutrition, pharmaceuticals, and preventive medicine. It offers a comprehensive overview of the properties and applications of bioactive ingredients, bridging the gap between scientific research and practical applications in the development of functional foods and dietary interventions. By harnessing the potential of bioactive ingredients, we can pave the way for a healthier and more sustainable future. Finally, we extend our sincere gratitude to all the contributors who have dedicated their expertise and time to enrich this handbook with their valuable insights. We hope that this comprehensive collection will inspire further research and innovation in the field of food bioactive ingredients and contribute to the advancement of human health and well-being. Gorgan, Iran Palmerston North, New Zealand Vigo, Spain September 2023

Seid Mahdi Jafari Ali Rashidinejad Jesus Simal-Gandara Editors

Contents

Volume 1 1

An Overview of Different Food Bioactive Ingredients . . . . . . . . . . Maria Garcia-Marti, Seid Mahdi Jafari, Ali Rashidinejad, Jianbo Xiao, and Jesus Simal-Gandara

Part I

1

Phenolic Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

27

2

Hydroxybenzoic Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Deyan Gong and Zhengbao Zha

29

3

Hydroxycinnamic Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nicoleta-Gabriela Hădărugă and Daniel-Ioan Hădărugă

59

4

Flavones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Daniel-Ioan Hădărugă and Nicoleta-Gabriela Hădărugă

111

5

Flavonols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Daniel-Ioan Hădărugă and Nicoleta-Gabriela Hădărugă

159

6

Flavanones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Daniel-Ioan Hădărugă and Nicoleta-Gabriela Hădărugă

223

7

Flavanols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Alexander Kanon, Andrew Carroll, and Dominic Lomiwes

277

8

Isoflavones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ludmila Křížová, Kateřina Dadáková, and Veronika Farková

313

9

Anthocyanins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Duc Toan Do, Niamh Harbourne, and Ashling Ellis

341

10

Chalcones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ramona Suharoschi, Oana Lelia Pop, Călina Ciont, Carmen Ioana Muresan, and Simona Codruţa Hegheş

365

vii

viii

Contents

11

Ellagitannins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Noha Ahmed Nasef, Doug Rosendale, and Starin McKeen

407

12

Gallotannins Hua-Feng He

..........................................

427

13

Procyanidins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mehmet Resat Atilgan and Oguz Bayraktar

443

14

Stilbenes and Its Derivatives and Glycosides . . . . . . . . . . . . . . . . . Nicoleta-Gabriela Hădărugă and Daniel-Ioan Hădărugă

487

15

Lignans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reza Karimi and Ali Rashidinejad

545

Part II

Carotenoids and Sterols . . . . . . . . . . . . . . . . . . . . . . . . . . . .

571

16

Lycopene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Itaciara Larroza Nunes, Jane Mara Block, Alejandro Cifuentes, Renan Danielski, and Flávia Barbosa Schappo

573

17

Beta-Carotene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mahdi Ebadi, Maryam Mohammadi, Akram Pezeshki, and Seid Mahdi Jafari

603

18

Lutein . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Tanya Luva Swer, Macdonald Ropmay, P. Mariadon Shanlang Pathaw, Ribhahun Khonglah, Chinglen Leishangthem, and Charis K. Ripnar

629

19

Zeaxanthin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Chi-Ching Lee and Mehmet Demirci

653

20

Astaxanthin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Chi-Ching Lee

687

21

Fucoxanthin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Abd Almonem Doolaanea, Mulham Alfatama, Hamzeh Alkhatib, and Saeid Mezail Mawazi

729

22

Bixin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ayesheh Enayati, Elham Assadpour, and Seid Mahdi Jafari

757

23

Crocins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Zohreh Karami, Seid Mahdi Jafari, and Kiattisak Duangmal

791

24

Dietary Phytosterols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sukanya Chakraborty, Ritika Parashar, Niraj Kumar Jha, Abhimanyu Kumar Jha, and Saurabh Kumar Jha

819

Contents

ix

Volume 2 Part III

Bioactive Peptides

................................

837

25

Marine Bioactive Peptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Priscilla Vásquez, Raúl E. Cian, and Silvina R. Drago

839

26

Non-marine Animal Bioactive Peptides . . . . . . . . . . . . . . . . . . . . . V. Chamorro, A. Pazos, J. Báez, A. M. Fernández-Fernández, and A. Medrano

869

27

Plant Bioactive Peptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . María Cristina Añón, Alejandra Quiroga, Adriana Scilingo, and Valeria Tironi

907

28

Microbial Bioactive Peptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Raúl E. Cian and Silvina R. Drago

941

Part IV

Essential Fatty Acids and Minerals . . . . . . . . . . . . . . . . . . .

965

29

Omega-3 Polyunsaturated Fatty Acids . . . . . . . . . . . . . . . . . . . . . . Niloufar Keivani and Seyed Fakhreddin Hosseini

967

30

Plant Oils Rich in Essential Fatty Acids . . . . . . . . . . . . . . . . . . . . . Saeid Jafari, Mahdi Ebrahimi, Kitipong Assatarakul, and Seid Mahdi Jafari

997

31

Trace Minerals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1021 Fahimeh Haghighatdoost, Noushin Mohammadifard, and Nizal Sarrafzadegan

Part V

Vitamins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1063

32

Vitamin A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1065 Fatima Molavi, Vahideh Sarabi-Aghdam, Saeed Mirarab Razi, and Ali Rashidinejad

33

Vitamin D . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1091 Chinnappan A. Kalpana, Nongmaithem Babita Devi, Somali Ghosh, and Ali Rashidinejad

34

Vitamin E . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1125 Maryam Esfandiari, Hadiseh Bagheri, Vahid Mirarab-Razi, Saeed Mirarab Razi, and Ali Rashidinejad

35

Vitamin K . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1149 Siva Raseetha, F. M. N. Azmi Aida, and Farhana Roslan

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Contents

36

Vitamin C . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1187 Saeed Mirarab Razi, Mehdi Mohammadian, and Ali Rashidinejad

37

B Vitamins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1209 Trias Mahmudiono and Chika Dewi Haliman

Part VI

Prebiotics and Dietary Fibers

.......................

1241

38

Xylooligosaccharides (XOS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1243 A. Cruz-Guerrero, L. Gómez-Ruiz, and F. Guzmán-Rodríguez

39

Fructooligosaccharides (FOS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1271 S. Alatorre-Santamaría, A. Cruz-Guerrero, and F. Guzmán-Rodríguez

40

Inulin Fiber . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1301 Angela Daniela Carboni, María Victoria Salinas, and María Cecilia Puppo

41

Galacto-oligosaccharides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1331 Carlos Vera, Cecilia Guerrero, and Andrés Illanes

42

Resistant Starch . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1357 Carlos Gabriel Arp, María Jimena Correa, and Cristina Ferrero

43

Human Milk Oligosaccharides (HMOS) . . . . . . . . . . . . . . . . . . . . . 1383 F. Guzmán-Rodríguez, S. Alatorre-Santamaría, and A. Cruz-Guerrero

44

Lactulose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1413 Cecilia Guerrero, Carlos Vera, and Andrés Illanes

45

Pectin Oligosaccharides (POS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1449 Cintia Mazzucotelli and María Gabriela Goñi

Part VII

Bioactive Live Organisms . . . . . . . . . . . . . . . . . . . . . . . . . .

1471

46

Probiotic Lactic Acid Bacteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1473 Fereshteh Ansari, Ali Bahadori, Shohre Alian Samakkhah, Haniyeh Rasouli Pirouzian, and Hadi Pourjafar

47

Non-LAB Bacterial Probiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1505 Morteza Khomeiri, Sima Taheri, and Ahmad Nasrollahzadeh

48

Probiotic Yeasts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1533 Sara Shahryari and Alireza Sadeghi

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1555

About the Editors

Seid Mahdi Jafari received his PhD in Food Process Engineering from the University of Queensland (Australia), in 2006. Now, he is a full-time Professor in GUASNR (Iran). He has published >550 papers in International Journals (h-index ¼ 90 in Scopus) and 100 book chapters/36 books with Elsevier, Springer, and Taylor & Francis. Selected achievements: (1) one of the top national researchers by the Iranian Ministry of Science, Research, and Technology (2017); (2) one of the world’s highly cited researchers by Clarivate Analytics (Web of Science), in 2018, 2019, and 2020; (3) a top reviewer in the field of agricultural and biological sciences by Publons (2018 and 2019). Personal Website: www.smjafari.com Ali Rashidinejad is an accomplished scholar and expert in the field of Food Science, with a special focus on phytochemicals and bioactive compounds. He obtained his PhD in Food Science from the prestigious University of Otago in New Zealand, solidifying his foundation of knowledge and expertise. He is currently a senior scientist and an academic member of Riddet Institute, Massey University (Palmerston North, New Zealand). On the field of bioactive ingredients, Dr. Rashidinejad has published numerous impactful papers in top-ranked international food science and nutrition journals, as well as co-authoring books and book chapters on various topics related to his field, further solidifying his authority in the subject matter. He is the primary investigator and first inventor of “FlavoPlus,” a new a groundbreaking method for xi

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About the Editors

delivery of hydrophobic flavonoids in functional foods. His research and contributions have not only expanded scientific knowledge but also hold promise for practical applications that can positively impact the food industry and public health. Jesus Simal-Gandara is Full Professor of Nutrition and Food Science at the Faculty of Food Science and Technology, University of Vigo (Spain). He got 1st Spanish Award of Completion of Pharmacy and PhD Prize at the Faculty of Pharmacy, University of Santiago de Compostela (Spain). He was Associate Professor in 1991 at the University of Vigo, and Full Professor since 1999. He is Corresponding Member of the Royal Academy of Medicine and Surgery of Galicia (1991), Member of the Scientific Committee of the Spanish Agency for Consumption, Food Safety and Nutrition (2013–2016), Research Medal of the Royal Galician Academy of Sciences 2020 Antonio Casares Rodriguez (Chemistry and Geology), President of the International Association of Dietary Nutrition and Safety (2020), Full Member of the Royal Academy of Pharmacy of Galicia (2021), 2023–2027 expert roster of the Joint (FAO/WHO) Expert Committee on Food Additives, and Associate Editor in Food Science and Nutrition (Wiley). He leads a research group of excellence, and was leading CIA3 – Environmental, Agricultural and Food Research Center (2008–2018). He was the Head of the Department of Analytical Chemistry and Food Science (2013–2018), and Vice-Chancellor for Internationalization at the University of Vigo (2018). He was nominated by Clarivate Analytics as Highly Cited Research (2018, 2020, and 2022). He performed research stays at the Universite de Paris-Sud (France), University of Delaware (USA), Fraunhofer-Institut fur Lebensmitteltechnologie und Verpackung (Germany), Central Science Laboratory (UK), TNOVoeding (the Netherlands), Packaging Industries Research Association (UK), and The Swedish Institute for Food and Biotechnology (Sweden). He has 26,810 citations in 500 papers ¼ 54 per paper; h-index ¼ 80 (http:// scholar.google.es/citations?user¼rmeHFXIAAAAJ& hl¼es&oi¼ao).

Contributors

Noha Ahmed Nasef Riddet Institute, Massey University, Palmerston North, New Zealand School of Food and Advanced Technology, Massey University, Palmerston North, New Zealand F. M. N. Azmi Aida Faculty of Applied Sciences, Universiti Teknologi MARA, Shah Alam, Malaysia S. Alatorre-Santamaría CBS, UAM Iztapalapa, Mexico City, Mexico Mulham Alfatama Faculty of Pharmacy, Universiti Sultan Zainal Abidin, Besut Campus, Besut, Terengganu, Malaysia Hamzeh Alkhatib Department of Pharmaceutical Technology, Faculty of Pharmacy, University College MAIWP International (UCMI), Batu Caves, Kuala Lumpur, Malaysia María Cristina Añón Laboratorio de Investigación, Desarrollo e innovación en Proteínas Alimentarias (LIDiPA), Centro de Investigación y Desarrollo en Criotecnología de Alimentos (CIDCA). CONICET, CICPBA, UNLP, La Plata, Argentina Fereshteh Ansari Razi Vaccine and Serum Research Institute, Agricultural Research, Education and Extension Organization (AREEO), Tehran, Iran Research Center for Evidence-Based Medicine, Health Management and Safety Promotion Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran Iranian EBM Centre: A Joanna Briggs Institute Affiliated Group, Tabriz, Iran Carlos Gabriel Arp Centro de Investigación y Desarrollo en Criotecnología de Alimentos (CIDCA), Universidad Nacional de La Plata-Facultad de Ciencias Exactas, Comisión de Investigaciones Científicas de la Provincia de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, La Plata, Argentina Elham Assadpour Food Industry Research Co., Gorgan, Iran Food and Bio-Nanotech International Research Center (Fabiano), Gorgan University of Agricultural Sciences and Natural Resources, Gorgan, Iran xiii

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Contributors

Kitipong Assatarakul Department of Food Technology, Faculty of Science, Chulalongkorn University, Bangkok, Thailand Nongmaithem Babita Devi Department of Food Science and Nutrition, Avinashilingam Institute for Home Science and Higher Education for Women, Coimbatore, India J. Báez Departamento de Ciencia y Tecnología de Alimentos, Facultad de Química, Universidad de la República, Montevideo, Uruguay Hadiseh Bagheri Islamic Azad University, Sari, Iran Ali Bahadori Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran Department of Medical Microbiology, Sarab Faculty of Medical Sciences, Sarab, Iran Oguz Bayraktar Faculty of Engineering, Department of Bioengineering, Ege University, Bornova, Izmir, Turkey Jane Mara Block Graduate Program in Food Science, Department of Food Science and Technology, Federal University of Santa Catarina, Florianópolis, Brazil Angela Daniela Carboni Centro de investigación en Desarrollo y Criotecnología de Alimentos – CIDCA (CIC-PBA, CONICET y Universidad Nacional de La Plata), La Plata, Argentina Andrew Carroll Immune Health and Physical Performance, Nutrition and Health, The New Zealand Institute for Plant and Food Research Limited, Palmerston North, New Zealand Sukanya Chakraborty Department of Biotechnology, School of Engineering and Technology (SET), Sharda University, Greater Noida, Uttar Pradesh, India V. Chamorro Instituto Tecnología de Alimentos, CIA, Instituto Nacional de Tecnología Agropecuaria (INTA), Buenos Aires, Argentina Instituto de Ciencia y Tecnología de Sistemas Alimentarios Sustentables (UEDD INTA CONICET), Buenos Aires, Argentina Raúl E. Cian Institute of Food Technology, CONICET, FIQ – UNL, Santa Fe, Argentina Alejandro Cifuentes Foodomics Lab, CIAL, National Research Council of Spain (CSIC), Madrid, Spain Călina Ciont Department of Food Science, Molecular Nutrition and Proteomics Lab, CDS3, Life Science Institute, University of Agricultural Science and Veterinary Medicine of Cluj-Napoca, Cluj-Napoca, Romania María Jimena Correa Centro de Investigación y Desarrollo en Criotecnología de Alimentos (CIDCA), Universidad Nacional de La Plata-Facultad de Ciencias

Contributors

xv

Exactas, Comisión de Investigaciones Científicas de la Provincia de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, La Plata, Argentina A. Cruz-Guerrero Departamento de Biotecnología, Universidad Autónoma Metropolitana-Iztapalapa, Mexico City, Mexico Kateřina Dadáková Department of Biochemistry, Faculty of Science, Masaryk University, Brno, Czech Republic Renan Danielski Department of Biochemistry, Memorial University of Newfoundland, St. John’s, NL, Canada Mehmet Demirci Faculty of Health Sciences, Department of Nutrition and Dietetics, Istanbul Sabahattin Zaim University, Istanbul, Turkey Duc Toan Do Riddet Institute, Massey University, Palmerston North, New Zealand Abd Almonem Doolaanea Department of Pharmaceutical Technology, Kulliyyah of Pharmacy, International Islamic University Malaysia, Kuantan, Pahang, Malaysia IKOP Sdn Bhd., Kulliyyah of Pharmacy, International Islamic University Malaysia, Kuantan, Pahang, Malaysia Silvina R. Drago Institute of Food Technology, CONICET, FIQ – UNL, Santa Fe, Argentina Kiattisak Duangmal Department of Food Technology, Faculty of Science, Chulalongkorn University, Bangkok, Thailand Emerging Processes for Food Functionality Design Research Unit, Chulalongkorn University, Bangkok, Thailand Mahdi Ebadi Department of Food Science and Technology, Faculty of Agriculture, University of Tabriz, Tabriz, Iran Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran Department of Food Research and Development, Zar Research and Industrial Development Group, Alborz, Iran Mahdi Ebrahimi Department of Veterinary Preclinical Sciences, Faculty of Veterinary Medicine, University Putra Malaysia, Serdang, Selangor, Malaysia Ashling Ellis AgResearch, Palmerston North, New Zealand Ayesheh Enayati Ischemic Disorders Research Center, Golestan University of Medical Sciences, Gorgan, Iran Maryam Esfandiari Institute of Higher Education Tajan, Qaemshahr, Iran Veronika Farková Department of Biochemistry, Faculty of Science, Masaryk University, Brno, Czech Republic

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Contributors

A. M. Fernández-Fernández Departamento de Ciencia y Tecnología de Alimentos, Facultad de Química, Universidad de la República, Montevideo, Uruguay Cristina Ferrero Centro de Investigación y Desarrollo en Criotecnología de Alimentos (CIDCA), Universidad Nacional de La Plata-Facultad de Ciencias Exactas, Comisión de Investigaciones Científicas de la Provincia de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, La Plata, Argentina Maria Garcia-Marti Nutrition and Bromatology Group, Analytical Chemistry and Food Science Department, Faculty of Science, Universidade de Vigo, Ourense, Spain Somali Ghosh Department of Food Science and Nutrition, Avinashilingam Institute for Home Science and Higher Education for Women, Coimbatore, India L. Gómez-Ruiz Departamento de Biotecnología, Metropolitana-Iztapalapa, Mexico City, Mexico

Universidad

Autónoma

Deyan Gong School of Food and Biological Engineering, Hefei University of Technology, Hefei, China María Gabriela Goñi Grupo de Investigación en Ingeniería en Alimentos (GIIAINCITAA), Departamento de Ingeniería Química y de Alimentos, Facultad de Ingeniería, Universidad Nacional de Mar del Plata, Buenos Aires, Argentina Consejo Nacional de Investigaciones Científico y Técnicas (CONICET), Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina Cecilia Guerrero School of Biochemical Engineering, Pontificia Universidad Católica de Valparaíso (PUCV), Valparaíso, Chile F. Guzmán-Rodríguez Departamento de Biotecnología, Universidad Autónoma Metropolitana-Iztapalapa, Mexico City, Mexico Daniel-Ioan Hădărugă Department of Applied Chemistry, Organic and Natural Compounds Engineering, Polytechnic University of Timişoara, Timişoara, Romania Nicoleta-Gabriela Hădărugă Department of Food Science, Banat’s University of Agricultural Sciences and Veterinary Medicine “King Michael I of Romania”, Timişoara, Romania Department of Food Science, University of Life Sciences “King Mihai I”, Timişoara, Romania Research Institute for Biosecurity and Bioengineering, Timişoara, Romania Fahimeh Haghighatdoost Isfahan Cardiovascular Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran Chika Dewi Haliman Departement of Nutrition, Faculty of Public Health, Universitas Airlangga, Surabaya, Indonesia

Contributors

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Niamh Harbourne Institute of Food and Health, School of Agriculture and Food Science, University College Dublin, Dublin, Ireland Hua-Feng He College of Pharmacy, Jining Medical University, Rizhao, People’s Republic of China Simona Codruţa Hegheş Department of Drug Analysis, “Iuliu Hat‚ieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania Seyed Fakhreddin Hosseini Department of Seafood Processing, Faculty of Marine Sciences, Noor, Iran Andrés Illanes School of Biochemical Engineering, Pontificia Universidad Católica de Valparaíso (PUCV), Valparaíso, Chile Saeid Jafari Department of Food Technology, Faculty of Science, Chulalongkorn University, Bangkok, Thailand Seid Mahdi Jafari Faculty of Food Science and Technology, Gorgan University of Agricultural Sciences and Natural Resources, Gorgan, Iran Abhimanyu Kumar Jha Department of Biotechnology, School of Engineering and Technology (SET), Sharda University, Greater Noida, Uttar Pradesh, India Niraj Kumar Jha Department of Biotechnology, School of Engineering and Technology (SET), Sharda University, Greater Noida, Uttar Pradesh, India Saurabh Kumar Jha Department of Biotechnology, School of Engineering and Technology (SET), Sharda University, Greater Noida, Uttar Pradesh, India Department of Biotechnology Engineering and Food Technology, Chandigarh University, Mohali, India Department of Biotechnology, School of Applied and Life Sciences (SALS), Uttaranchal University, Dehradun, India Chinnappan A. Kalpana Department of Food Science and Nutrition, Avinashilingam Institute for Home Science and Higher Education for Women, Coimbatore, India Alexander Kanon Immune Health and Physical Performance, Nutrition and Health, The New Zealand Institute for Plant and Food Research Limited, Palmerston North, New Zealand Zohreh Karami Department of Food Technology, Faculty of Science, Chulalongkorn University, Bangkok, Thailand Reza Karimi Department of Food Science and Technology, Faculty of Agricultural Sciences, University of Guilan, Rasht, Iran Niloufar Keivani Department of Pharmacy, University of Naples Federico II, Naples, Italy

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Morteza Khomeiri Department of Food Science and Technology, Gorgan University of Agricultural Sciences and Natural Resources, Gorgan, Iran Ribhahun Khonglah Directorate of Food Processing, Government of Meghalaya, Shillong, India Ludmila Křížová Department of Animal Breeding, Animal Nutrition and Biochemistry, Faculty of Veterinary Hygiene and Ecology, University of Veterinary Sciences, Brno, Czech Republic Chi-Ching Lee Faculty of Engineering and Natural Sciences, Department of Food Engineering, Istanbul Sabahattin Zaim University, Istanbul, Turkey Chinglen Leishangthem National Institute of Technology, Rourkela, India Dominic Lomiwes Immune Health and Physical Performance, Nutrition and Health, The New Zealand Institute for Plant and Food Research Limited, Palmerston North, New Zealand Trias Mahmudiono Departement of Nutrition, Faculty of Public Health, Universitas Airlangga, Surabaya, Indonesia Saeid Mezail Mawazi Department of Pharmaceutics, School of Pharmacy, Management and Science University, Shah Alam, Selangor, Malaysia Cintia Mazzucotelli Grupo de Investigación en Ingeniería en Alimentos (GIIAINCITAA), Departamento de Ingeniería Química y de Alimentos, Facultad de Ingeniería, Universidad Nacional de Mar del Plata, Buenos Aires, Argentina Starin McKeen Anagenix, Auckland, New Zealand A. Medrano Departamento de Ciencia y Tecnología de Alimentos, Facultad de Química, Universidad de la República, Montevideo, Uruguay Saeed Mirarab Razi Department of Food Science and Technology, Ferdowsi University of Mashhad, Mashhad, Iran Vahid Mirarab-Razi Islamic Azad University, Ayatollah Amoli Branch, Amol, Iran Maryam Mohammadi Department of Food Science and Engineering, Faculty of Agriculture, University of Kurdistan, Sanandaj, Iran Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran Mehdi Mohammadian Department of Food Science and Engineering, University College of Agriculture and Natural Resources, University of Tehran, Karaj, Iran Noushin Mohammadifard Isfahan Cardiovascular Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran Fatima Molavi Department of pharmaceutics, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran

Contributors

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Carmen Ioana Muresan Department of Food Science, Molecular Nutrition and Proteomics Lab, CDS3, Life Science Institute, University of Agricultural Science and Veterinary Medicine of Cluj-Napoca, Cluj-Napoca, Romania Ahmad Nasrollahzadeh Nobonyad Nasr Food Industry Specialists Company, Tehran, Iran Itaciara Larroza Nunes Graduate Program in Food Science, Department of Food Science and Technology, Federal University of Santa Catarina, Florianópolis, Brazil Ritika Parashar Department of Biotechnology, School of Engineering and Technology (SET), Sharda University, Greater Noida, Uttar Pradesh, India P. Mariadon Shanlang Pathaw Department of Science and Technology, North East Centre for Technology Application and Reach, Government of India, Shillong, India A. Pazos Instituto Tecnología de Alimentos, CIA, Instituto Nacional de Tecnología Agropecuaria (INTA), Buenos Aires, Argentina Instituto de Ciencia y Tecnología de Sistemas Alimentarios Sustentables (UEDD INTA CONICET), Buenos Aires, Argentina Facultad de Agronomía y Ciencias Agroalimentarias, Universidad de Morón, Buenos Aires, Argentina Akram Pezeshki Department of Food Science and Technology, Faculty of Agriculture, University of Tabriz, Tabriz, Iran Haniyeh Rasouli Pirouzian Department of Food Science and Technology, Faculty of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran Oana Lelia Pop Department of Food Science, Molecular Nutrition and Proteomics Lab, CDS3, Life Science Institute, University of Agricultural Science and Veterinary Medicine of Cluj-Napoca, Cluj-Napoca, Romania Hadi Pourjafar Dietary Supplements and Probiotic Research Center, Alborz University of Medical Sciences, Karaj, Iran María Cecilia Puppo Centro de investigación en Desarrollo y Criotecnología de Alimentos – CIDCA (CIC-PBA, CONICET y Universidad Nacional de La Plata), La Plata, Argentina Alejandra Quiroga Laboratorio de Investigación, Desarrollo e innovación en Proteínas Alimentarias (LIDiPA), Centro de Investigación y Desarrollo en Criotecnología de Alimentos (CIDCA). CONICET, CICPBA, UNLP, La Plata, Argentina Siva Raseetha Faculty of Applied Sciences, Universiti Teknologi MARA, Shah Alam, Malaysia Ali Rashidinejad Riddet Institute, Massey University, Palmerston North, New Zealand

xx

Contributors

Mehmet Resat Atilgan EBILTEM Science and Technology Application and Research Center, Ege University, Bornova, Izmir, Turkey Charis K. Ripnar Directorate of Food Processing, Government of Meghalaya, Shillong, India Macdonald Ropmay Directorate of Food Processing, Government of Meghalaya, Shillong, India Doug Rosendale Anagenix, Auckland, New Zealand Farhana Roslan Faculty of Applied Sciences, Universiti Teknologi MARA, Shah Alam, Malaysia Alireza Sadeghi Department of Food Science and Technology, Gorgan University of Agricultural Sciences and Natural Resources, Gorgan, Iran María Victoria Salinas Centro de investigación en Desarrollo y Criotecnología de Alimentos – CIDCA (CIC-PBA, CONICET y Universidad Nacional de La Plata), La Plata, Argentina Shohre Alian Samakkhah Department of Food Hygiene and Quality Control, Faculty of Veterinary of Medicine, Amol University of Special Modern Technology, Amol, Iran Vahideh Sarabi-Aghdam Bioprocessing and Biodetection Lab (BBL), Department of Food Science and Technology, Faculty of Agricultural Engineering and Technology, University of Tehran, Karaj, Iran Nizal Sarrafzadegan Isfahan Cardiovascular Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran Flávia Barbosa Schappo Graduate Program in Food Science, Department of Food Science and Technology, Federal University of Santa Catarina, Florianópolis, Brazil Adriana Scilingo Laboratorio de Investigación, Desarrollo e innovación en Proteínas Alimentarias (LIDiPA), Centro de Investigación y Desarrollo en Criotecnología de Alimentos (CIDCA). CONICET, CICPBA, UNLP, La Plata, Argentina Sara Shahryari Department of Food Science and Technology, Gorgan University of Agricultural Sciences and Natural Resources, Gorgan, Iran Jesus Simal-Gandara Nutrition and Bromatology Group, Analytical Chemistry and Food Science Department, Faculty of Science, Universidade de Vigo, Ourense, Spain Ramona Suharoschi Department of Food Science, Molecular Nutrition and Proteomics Lab, CDS3, Life Science Institute, University of Agricultural Science and Veterinary Medicine of Cluj-Napoca, Cluj-Napoca, Romania

Contributors

xxi

Tanya Luva Swer National Institute of Food Technology Entrepreneurship and Management (NIFTEM), Haryana, India Sima Taheri Department of Food Science and Technology, Gorgan University of Agricultural Sciences and Natural Resources, Gorgan, Iran Valeria Tironi Laboratorio de Investigación, Desarrollo e innovación en Proteínas Alimentarias (LIDiPA), Centro de Investigación y Desarrollo en Criotecnología de Alimentos (CIDCA). CONICET, CICPBA, UNLP, La Plata, Argentina Priscilla Vásquez Department of Food, Faculty of Pharmaceutical and Food Sciences, University of Antioquia, Medellin, Colombia Carlos Vera Department of Biology, Faculty of Chemistry and Biology, Universidad de Santiago de Chile (USACH), Santiago, Chile Jianbo Xiao Nutrition and Bromatology Group, Analytical Chemistry and Food Science Department, Faculty of Science, Universidade de Vigo, Ourense, Spain Zhengbao Zha School of Food and Biological Engineering, Hefei University of Technology, Hefei, China

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An Overview of Different Food Bioactive Ingredients Maria Garcia-Marti, Seid Mahdi Jafari, Ali Rashidinejad, Jianbo Xiao, and Jesus Simal-Gandara

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nutrition and Chronic Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Bioactive Ingredients and Functional Foods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Natural Sources of Bioactive Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Phenolic Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Carotenoids and Phytosterols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Bioactive Peptides (BPs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Marine Bioactive Peptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nonmarine Animal Bioactive Peptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Plant Bioactive Peptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Microbial Bioactive Peptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Essential Fatty Acids (EFAs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Live Organisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Essential Oils (EOs) and Oleoresins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Vitamins and Minerals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Other Bioactive Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abstract

The concept of bioactive compounds (bioactives) and their relationship with human diet is not a new idea; however, the desire to exploit their potential M. Garcia-Marti · J. Xiao · J. Simal-Gandara (*) Nutrition and Bromatology Group, Analytical Chemistry and Food Science Department, Faculty of Science, Universidade de Vigo, Ourense, Spain e-mail: [email protected] S. M. Jafari Faculty of Food Science and Technology, Gorgan University of Agricultural Sciences and Natural Resources, Gorgan, Iran A. Rashidinejad Riddet Institute, Massey University, Palmerston North, New Zealand © Springer Nature Switzerland AG 2023 S. M. Jafari et al. (eds.), Handbook of Food Bioactive Ingredients, https://doi.org/10.1007/978-3-031-28109-9_1

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leads to an understanding of the scientific basis of their mode of action. A bioactive compound is a chemical molecule that exerts a beneficial effect on some functions of the human body, e.g., improving health, and well-being, and reducing the risk of diseases. Over the last decades, there has been a resurgence of interest in ingredients obtained from natural sources, especially due to the public awareness of safe and healthy food products. Bioactives may be extracted from plant or animal sources, as well as from different environments such as the marine environment or microorganisms. Once isolated, these compounds can be used for nutritional, pharmaceutical, or cosmetic purposes by being added to other products. Throughout this chapter, the bioactives that can be used as ingredients for the manufacture of functional foods will be described. Thus, compounds such as phenolic compounds, carotenoids, bioactive peptides, fatty acids, essential oils, and vitamins, as well as living organisms will be discussed. In the next chapters, a more detailed description of various aspects related to these bioactives will be provided. In addition to their nutritional value, it is recognized that food can be health-promoting, so scientists and health and nutrition professionals are focused on translating scientific evidence into practical application in the consumer’s daily diet. Keywords

Functional foods · Bioactive compounds · Health · Nutrition · Health-promoting properties

Introduction Food is for human sustenance and nourishment, and it is necessary for growth and good condition. The traditional nutrition research has been focused on providing nutrients to nourish the population and prevent specific nutrient deficiencies. However, people are increasingly looking for foods with added nutritional benefits that play an important role in their body functions. Modern nutrition research is a new trend that targets health promotion, disease prevention, performance improvement, and risk assessment (Kussmann et al. 2007). Previous research has demonstrated the correlation between diet and physiology and the great possibilities of food to maintain or improve human health. The search for natural bioactive compounds (bioactives) is a salient subject in many laboratories and industries, due to potential characteristics for the treatment and prevention of human disorders that are interacting with biomolecules such as proteins or DNA; thus, these bioactives can be utilized as a therapeutic agent. Considering this fact and the properties of new food and new ways to human nourish, researchers aim for the extraction and characterization of new natural ingredients/compounds with long-term physiological effects and biological activity that can be added to functional foods. Although some

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of these are considered non-essential for life, they contribute to the maintenance of human body functions. Under these considerations and definitions, food bioactives can be incorporated into functional foods so that they contribute to consumers’ wellbeing via the most convenient way (i.e., food) (da Silva et al. 2016). Bioactives with beneficial effects on well-being are majority derived from the plant kingdom and to a lesser extent, from animals or marine sources like algae or live organisms including probiotics and yeasts. The consumption of fruits and vegetables is typically related to healthy lifestyle dietary habits because it has been suggested that diets rich in these phytochemicals promote good health (Dreosti 1996). Many of these beneficial effects come from different biomolecules such a phenolic compounds, vitamins, and minerals. On the other hand, lipophilic bioactives such as essential fatty acids, oils, and oleoresins derived from both plants and animal sources may also exert beneficial effects on health. These products have a special marketable interest, because of the growing concerns for healthy food and wellness that can be used as functional ingredients or nutraceuticals. Nonetheless, there are still some limitations related to the extraction, bioactivity, or large-scale production in substances extracted from natural sources. On the one hand, the selection of the best extraction method should be considered significant aspects such as cost, environmental impact, and required technical and chemical skills including solvent type, sample size, pH, temperature, or pressure. On the other hand, the evaluation of bioaccessibility and bioavailability for the understanding of the relationship between food and nutrition such as the effect of food matrix, transporters, molecular structures, and metabolizing enzymes is necessary. Bioactives need to tolerate food processing and be isolated from the interaction of food matrix, in order to be accessible in the gastrointestinal tract (GIT), undergo metabolism, and reach the target tissue of action. Bioavailability is a key index to elucidate the effects of dietary bioactives because it allows the identification of the action mechanisms about the benefits and provides more insight into the health effects of these molecules (Rein et al. 2013). Besides phytochemicals, live organisms such as probiotics or yeasts have also been widely used to promote health by reinforcing the natural flora; however, their effectiveness in improving health status depends on different factors such as their ability to deliver viable functional bacteria and withstanding the effects of GIT. For a proper release in the human body, the utilization of such bioactives requires proper corresponding food formulations and production techniques to maintain the active molecular form until the consumption. Throughout this book, various bioactives will be discussed in detail. These include a wide assortment of structures and functionalities with health benefits that provide an outstanding opportunity to improve public health through conventional products such as nutraceuticals or non-conventional products including functional food and food additives, which represent a formidable challenge to develop novel products with physiological benefits. The knowledge of the properties and applications of these bioactives leads to understanding their role and interactions, metabolism, or mechanism of action in the human body in order to promote health and reduce the risk of diseases.

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Nutrition and Chronic Diseases Diet is one of the modifiable habits that contributes to good health and prevents non-communicable diseases and improves the immune system to protect our body against harmful factors or pathogenic microorganisms. Non-communicable diseases are those diseases that are not transmissible from one person to another and include autoimmune diseases, cancer, most heart diseases, and chronic diseases such as diabetes or respiratory malfunctions, among others. According to the World Health Organization (WHO), non-communicable diseases kill 41 million people each year, equivalent to 71% of all deaths globally related to habits and lifestyle, especially diet, carried out throughout life. Malnutrition and unhealthy diets are a world health crisis with devastating consequences, especially in low- and middle-income countries and vulnerable and disadvantaged groups. These nutritional disorders are caused by an imbalanced intake of nutrients resulting in essential compound deficits for the proper functioning of the organism (Branca et al. 2019). Considering the so-called Laws of Correct Nutrition, an ideal and balanced meal with the proper amount of nutrients should focus on quality, quantity, harmony, and adequacy providing the energy required and necessary nutrients for maintaining vital functions in the human body (Chávez-Bosquez and Pozos-Parra 2016). From this point of view, it has been demonstrated that an unhealthy diet, malnutrition, and non-communicable diseases are closely linked. In contrast, eating a balanced diet based on healthy foods with a considerable supply of nutrients contributes to the promotion of health and prevents the risk of chronic diseases.

Bioactive Ingredients and Functional Foods As it was said before, there is a growing concern about healthy lifestyles and food habits. These changes in eating habits were aimed at reducing caloric intake and balance of complementary diet; however, this behavior has led to the prevention of serious diseases related to bad nutrition habits such as obesity, diabetes, and cardiovascular diseases. Due to that, there is a special attention to different stages of the food supply chain (from researchers to the experts in the food industry and regulatory authorities) for the development of the products that perform both functions; i.e., nourish and improve our health. In view of this, the food industry is currently focused on the development of the products that meet this demand, and functional foods have a great potential in providing adequate nutrition (Prakash et al. 2017). The functional food concept was born in Japan in the early 1990s with the definition of “Food for Specified Health Uses” (FOSHU) as a regulatory system for functional foods. After the introduction of this term, many products with proved health benefits were developed and launched on the market. Most of these claims were related to improving GIT, triglycerides content, high blood pressure, LDL cholesterol, and high blood glucose. After that, in 2015, the Dietary Supplement Health and Education Act system from the USA established a novel functional regulatory system called “Foods with Function Claims,” with more flexible health

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claims involving fatigue, eyes, memory, stress, sleep, joints, blood flow, body temperature, muscles, and body mass index, compared to FOSHU. As a result, the market for functional foods has never stopped growing, focusing on deep research studies about the identification of functional food ingredients as potent sources of fiber, protein, energy, minerals, vitamins, and antioxidants (Iwatani and Yamamoto 2019). Currently, the interplay between scientists and policymakers must be active to elucidate evidence that must be collected to demonstrate a link between biocompounds to a disease or health improvement. Once the results evaluated, the quality of the evidence must be assessed by the policy makers before presenting the results to agencies involved in food development and marketing as manufacturers or consumers (Weaver 2014). A bioactive compound is any molecule present in foods (from either plants or animals) that cause an effect on the organism that consumes it. Alike, a bioactive ingredient is defined as an ingredient that when it is inserted into food causes a positive effect on health. The difference between both definitions resides in that a bioactive compound is found in foods as a simple substance that has biological activity (Angiolillo et al. 2015). Nonetheless, a bioactive ingredient is a bioactive compound isolated from its natural source and added to a different functional food matrix preserving their characteristics even after extraction. The main bioactives include prebiotics, probiotics, amino acids, peptides, proteins, omega-3 fatty acids, structured lipids, phytochemicals, minerals, vitamins, fibers, carbohydrates, carotenoids, and phenolic compounds. Some bioactives such as chitosan, polyunsaturated fatty acids, and astaxanthin can be extracted from algae or industrial wastes from marine animals. These natural sources have great potential as functional food ingredients because of the physiological effects of improving human health (Suleria et al. 2015).

Natural Sources of Bioactive Compounds Are fundamental foods rich in phytochemicals, the primary natural source of dietetic fiber, minerals, vitamins, and bioactives, associated with improved quality of life? In the plant kingdom, bioactives are products of the secondary metabolism with a complex chemical composition produced in response to abiotic and biotic stress to perform different physiological reactions in cells and tissues. These response mechanisms are an excellent source of value-added bioactives commonly used in pharmaceutical industries, cosmetics, or dietary supplements, among others.

Phenolic Compounds Phenolic compounds are phytochemicals synthesized by the secondary metabolism of plants and play a fundamental role in the defense of plant species against stress conditions and other functions such as reproduction. However, these secondary metabolites have a restricted distribution in the plant kingdom because not all

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secondary metabolites are found in all plant groups. They are synthesized in small quantities and not in a generalized form. Moreover, their production is often being restricted to a certain plant genus, a family, or even some species (Jain et al. 2019). The content of these compounds in plants and fruits varies depending on genotype, species, environmental conditions, degree of maturity, soil composition, geographical location, and storage conditions (Haminiuk et al. 2012). As a clear overview, phenolic compounds produce different results in plant tissues of plants. Phenolic compounds play a fundamental role in hormonal signaling pathways such as auxin release and suppression, as well as in other signaling processes such as plant growth or fruit ripening. These compounds are responsible for leaf or fruit coloration, and they are protective agents against ionizing radiation. On the other hand, they also mediate processes against the attack of biotic agents, allowing the deterrence of herbivores or protecting the plant from infections caused by pathogens (Mannino and Micheli 2020). An average of 8000 phenolic compounds have been identified in plant kingdom. Phenolic compounds arise through two routes known as the shikimic acid route and the acetate malonate route, also known as the polyketide route. These compounds occur in conjugated forms linked to one or more sugar residues attached to hydroxyl groups or directly linked to a sugar (polysaccharide or monosaccharide) with an aromatic carbon. Polyphenols can be associated with other compounds including lipids or phenol conjugates (Kondratyuk and Pezzuto 2004). It is known that polyphenols play a key role in plant growth, regulation, and structure. Both natural phenols and larger polyphenols are extremely important in the ecology of most plants. Depending on their basic core, several aromatic rings, and the structural elements that interconnect these rings with each other, polyphenols can be cataloged in different groups: i.e., phenolic acids, flavonoids, stilbenes, and lignans (Fig. 1). Phenolic acids are one of the main groups of phenolic compounds found in different parts of plants such as seeds, leaves, or the skin of fruits. They are mostly bound with amides, esters, or glycosides. Phenolic compounds have carboxylic acid in their molecular structure and are further divided into two groups: hydroxybenzoic acid and hydroxycinnamic acid. It is important to highlight that the presence of more than one hydroxyl group and a greater separation of the carbonyl group to the aromatic ring increases the antioxidant capacity of these compounds. Phenolic acids consist of two groups including hydroxybenzoic acids and hydroxycinnamic acids. Hydroxybenzoic acids derive from benzoic acid and are found in a soluble state bound to sugars or organic acids, but they are also bound to the lignin of the cell wall. Within this group of phenolic acids, the main common compounds are p-hydroxybenzoic, protocatechuic, vanillic, and syringic. On the other hand, hydroxycinnamic acids are derived from cinnamic acid, and the most common compounds are ferulic, caffeic, p-coumaric, and synaptic acids (Kumar and Goel 2019). Flavonoids are widely distributed in the plant kingdom, as they are present in diverse parts of the plant such as the flowers and fruit, as well as in the leaves, stems, and roots. Structurally, they are composed of three carbon rings, but there is a wide diversity of these phytochemicals depending on how they are linked to each other the

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Fig. 1 Basic structure of phenolic compounds including phenolic acids, flavonoids, stilbenes, and lignans

doubles C-bonds or hydroxyl groups positions. Flavones such as apigenin or lutein can be found in legumes such as soybeans. Flavanones such as naringenin or hesperetin are present in different citrus fruits including oranges or lemons. On the other hand, flavonols are widely distributed in fruits such as onions, tomatoes, berries, and apples. Anthocyanins also belong to the group of flavonoids and are the molecules responsible for the different tonalities of fruits and flower plants. Red fruits such as strawberries and red grapes have a high concentration of these compounds (Tungmunnithum et al. 2018). Stilbenes’ structural skeleton consists of two carbon rings linked by an ethylene bridge, and they can exist in trans (E) and cis (Z) forms. Although more than a thousand natural stilbenes have been described, resveratrol is the best-known phenolic compound of this group. Stilbenes are distributed in a small group of plants such as Polygonaceae, Cyperaceae, Pinaceae, and Vitaceae. Grapes, and consequently red wine, are the major source of these compounds; however, stilbenes are also found in fruits including bananas, peaches, pineapples, or apples. They are also present in other foods such as nuts and dark chocolate (Benbouguerra et al. 2021). Although the basic structure of lignans consists of two carbon rings, they exhibit great structural diversity, which gives these compounds potent biological activities. Lignans have been described in beverages such as green and black tea (Uchiyama et al. 2011). The dietary source and effects of these compounds are described in Table 1.

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Table 1 Dietary source of phenolic compounds, flavonoids, stilbenes, and lignans and their healthpromoting properties (del Carmen Villegas-Aguilar et al. 2022) Chemical group Phenolic acid Flavonoids Stilbenes Lignans

Dietary source Lemon, grape, mulberry, coffee, cinnamon, nuts Honey, soybeans, orange, lemon, tomatoes Grapes, wine, banana, peaches, pineapple, nuts, dark chocolate Seeds, cereals, green and black tea

Effects Antioxidant, diabetes, and cardiovascular diseases Antihistaminic, anti-inflammatory, antioxidant Antioxidant, protect against oxidation stress Involved in the absorption of cholesterol

The growing interest in phenolic compounds and their increasing use in industrial products raise the need to know their properties and applications to optimize largescale extraction techniques and production. Many studies focus their interest on these compounds, owing to their wide distribution, as well as their ability to capture reactive oxygen and nitrogen species associated with diseases. It has been demonstrated that the natural extracts rich in phenolic compounds can be used as an ingredient for new added-value commercial products in the pharmaceutical, food, cosmetic, and even textile industries (Quideau et al. 2011). One of the most important characteristics of these compounds is their antioxidant property, which is important for fighting diseases caused by oxidative stress (Vuolo et al. 2019). In vitro studies have described the antioxidant capacity of phenolic compounds in different plant matrix extracts. In that sense, a food product with a high antioxidant capacity, thanks to its high concentration of these compounds, is kiwifruit (Liu et al. 2019). Other examples of fruits rich in phenolic compounds with high potential as antioxidants are mangoes and blueberries (and other berries), as well as several others (Gu et al. 2019). Antioxidant capacity and oxidative stress are closely related to inflammatory processes, which can lead to chronic diseases when this effect is maintained over time. Some studies have shown that phenolic compounds present in foods such as grapes, pomegranate, olive oil, red raspberries, or medicinal plants reduce inflammatory processes and effects related to the development of several chronic diseases such as diabetes, cancer, or Alzheimer’s (Taticchi et al. 2019), (Fan et al. 2020), (Tungmunnithum et al. 2018). In addition to their antioxidant capacity and anti-inflammatory properties, phenolic compounds have antiallergic, anti-thrombotic, antimicrobial, anti-neoplastic, and anticancer properties too (Biluca et al. 2020), which justify the significant number of publications that can be found in the scientific literature related to these compounds.

Carotenoids and Phytosterols Carotenoids are natural lipophilic pigments responsible for colors from yellow to red that are synthesized by plants, algae, and photosynthetic bacteria. From a chemical point of view, carotenoids are tetra-terpenes consisting of multiple isoprene units

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configuring a linear chain with conjugated double bonds. The polyene chain of the molecule, known as the chromophore, is responsible for the ability of carotenoids to absorb light in the visible region and, consequently, for their high coloring capacity. This structure can be modified by a cyclohexane ring at each end, extending or shorting the main chain or another chemical reaction such as isomerization, hydrogenation, or dehydrogenation. There are two types of carotenoids depending on the atoms in their structure: carotenes, which do not contain oxygen in their structure, and xanthophylls, which contain oxygenated functional groups in their structure. In xanthophylls, the most common oxygen functions are hydroxy (OH) and epoxy groups (5,6- or 5,8-epoxides) (Mercadante et al. 2017). Carotenoids must be consumed as a dietary source as they are not synthetized by humans. In the plant kingdom, carotenoids act in processes related to light harvesting during photosynthesis and protect plants against photooxidation. In addition, carotenoids are also precursors of signaling processes against stressors molecules. On the other hand, based on structural considerations, some of them can act as provitamin A and be converted into the visual pigment retinal in animals. Of the nearly fifty carotenoids available in the human diet that can be absorbed and metabolized, only six represent more than 95% of the total carotenoids in the blood usually studied in the context of diet and human health. Of these compounds, β-carotene, α-carotene, and β-cryptoxanthin have provitamin A activity. On the contrary, lycopene, lutein, and zeaxanthin are not pro-vitamin A. β-carotene has been described as responsible for diverse tonalities in plants, which gives them their characteristic color. It is responsible for the orange coloration of foods such as carrots, sweet potatoes, or pumpkin, as well as dark green vegetables such as broccoli or spinach (De Carvalho et al. 2018). Although β-carotene is the precursor of vitamin A, this vitamin can also be found in the matrix of foods of animal origin including milk derivatives and eggs, so it can also be incorporated directly as a natural source into the human diet. Several studies have demonstrated that vitamin A is essential for the proper tissue development in both stages of growth and repair. On the other hand, vitamin A plays a fundamental role in the correct functioning of vision and the immune system (Dowling 2020), (Huang et al. 2018). Lycopene is the main carotenoid found in red fruits and vegetables including tomatoes or watermelon. This carotenoid is not related to the vitamin A synthesis process, but when it is incorporated into the human diet, it can reduce the risk of chronic diseases, because of its antioxidant capacity (Imran et al. 2020). Even though lycopene intake in the diet is recommended due to its beneficial effects on the organism, it is not considered an essential nutrient and its intake varies in different areas of the world. Nevertheless, the consumption of lycopene-rich foods is closely related to a positive impact on human health and well-being. Lycopene acts, among other functions, as a protector of different molecules and tissues against the effects of oxidative damage, as well as stimulating cell growth and mediating immune and inflammatory responses. Lycopene and other carotenoids, however, can also be harmful depending on their concentration and the cellular environment by acting as pro-oxidants (Caseiro et al. 2020).

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Additionally, xanthophylls, lutein, and zeaxanthin are reported as antiinflammatory properties and have a fundamental role in the visual system protecting eyes against macular degeneration and age-related blindness. These compounds accumulate in the eyes and brain and are responsible for yellow spots of the macula lutea. On the other hand, these compounds have positive effects in diverse clinical conditions and are present in yellow and orange vegetables such as corn, orange peppers, kiwifruit, or grapes. Nowadays, there is an increasing interest in lutein and zeaxanthin due to their applications in the food, pharmaceutical, and nutraceutical industries as they can improve human health and reduce the risk of cancer or cardiovascular diseases (Buscemi et al. 2018). As previously mentioned, the main characteristic of carotenoids is their high antioxidant activity, which protects humans from different chronic diseases (Bohn 2019). Carotenoids arouse interest for researchers as they have a great potential for commercial applications in both the food and pharmaceutical industries. As these compounds are not synthesized by animals, they are considered a fundamental element of the diet. So many studies have focused on the synthesis pathways of these compounds in plants to elucidate the mechanisms involved in their synthesis in order to enhance their accumulation (Zhu et al. 2007). However, there is not enough information on the endogenous regulation of the genes involved in these metabolic pathways, which makes the study of this subject a challenge to overcome. Phytosterols are sterol molecules of vegetal origin and have a close structural resemblance to cholesterol, which is a sterol exclusively of animal origin. Phytosterols are an essential component of plant cell membranes, and their chemical structure consists of a sterol ring, which is common to all the sterols, and a side chain, which differentiates them from each other. There are more than 100 types of plant sterols but the most important are sitosterol, campesterol, and stigmasterol. On the other hand, stanol is a saturated sterol obtained by hydrogenation of the double bonds of the plant sterol molecule (Fernandes and Cabral 2007). It has been described that sterols included in the human diet have hypocholesterolemic effects since they are crucial allies to decrease the risk of cardiovascular diseases. Metabolic actions related to the hypocholesterolemic effect of phytosterols and phytostanols have been reviewed by several research works. In the intestinal lumen, phytosterols compete against dietary cholesterol absorption and endogenous cholesterol excreted in the bile. This causes a reduction in cholesterol absorption and, consequently, a decrease in serum cholesterol that leads to a compensatory increase in cholesterol synthesis by the liver and other tissues. Only a portion of phytosterols is absorbed by the intestine. This difference in the absorption rate relative to that of cholesterol is due in part to a selective process of sterol uptake and esterification of sterols in the intestinal mucosa (Jones et al. 1997). Other actions of phytosterol have been postulated to explain the hypocholesterolemic effect without convincing results; however, it has been proved that the combined action of sterols and stanols reduces total cholesterol and LDL cholesterol in plasma, with no effects in HDL cholesterol levels (Moruisi et al. 2006). Therefore, sterols and stanols represent a great natural potential for being included as an ingredient in functional foods. Currently, there are a lot of marketable

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Lycopene

E-carotene

D-carotene

OH

E-cryptoxanthin OH

OH

Zeaxanthin OH

OH

Lutein

Fig. 2 Structure of carotenoids

phytosterols-added products such as milk, juices, or yogurt that have been claimed to attest to their capacity to promote quality of life in the general population (Jones and Jew 2007). The structure of carotenoids is shown in Fig. 2 (Marhuenda-Munoz et al. 2019).

Bioactive Peptides (BPs) Proteins represent one of the main components of food, both from a functional and nutritional point of view. On one hand, they determine the physical and organoleptic properties of many foods. Thus, the consistency and texture of meat, cheese, or bread depend on the nature of the proteins that constitute them, and they can play a very important role, in influencing functional characteristics, such as the absorption of water or oil or the formation of emulsions, gels, and foams. On the other hand, proteins also constitute an important nutritional contribution representing a source of

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energy, nitrogen, and essential amino acids. In recent years, the study of food proteins as beneficial components, not only from a functional or nutritional point of view, has been receiving a great deal of attention. In this sense, the presence of different BPs in different foods has been deeply investigated (Chai et al. 2020). BPs are sequences of small-size amino acids. Each BP may be composed of about 2–15 amino acids. The function of these biomolecules depends on the amino acid composition and sequence, but their small size and low molecular weight facilitate the absorption of these molecules during the digestive process in order to exert their biological effects (Sánchez and Vázquez 2017). Within the protein, they are in an inactive form but can be activated when they are released during the digestive process in the organism. In some cases, proteins can also be activated for previous processes during the manufacturing of products, for example, hydrolyzed milk proteins during the cheese aging process (Daliri et al. 2017). Also, food proteins may be artificially digested using enzymatic hydrolysis reactors to release the BPs. The nutritional characteristics of proteins are not only limited to the nitrogen and energy contribution, as well as the essential amino acid content, but also the activity of BPs that can be released during food processing or GIT digestion. BPs have been found mainly in milk proteins and milk derivatives such as cheeses or yogurts. But their existence has also been observed in other animal proteins, fish, and vegetables such as soybeans, rice, chickpeas, and fungi. Several studies have demonstrated that these BPs have beneficial effects on the organism. They improve intestinal issues related to digestion and absorption of nutrients and minerals, stimulate an immune response, and reduce the risk of different diseases including cardiovascular and degenerative diseases. Moreover, their antithrombotics, antimicrobial, and hypercholesterolemic properties have been described (Udenigwe and Aluko 2012).

Marine Bioactive Peptides In recent years, there has been a growing interest in studying marine organisms, as they have proven to be a natural source of bioactives due to their potential nutritional and pharmacological purposes. The marine environment leads to the production of beneficial molecules for the organisms such as polyunsaturated fatty acids, vitamins, polysaccharides, and enzymes, as well as BPs (Cheung et al. 2015). Sponges are well-known health-promoting marine organisms distributed widely in the ocean. Some of the beneficial biopeptides that have been described related to them are cytosine arabinoside and geodiamolide (with anticancer properties) and jaspamide (with apoptotic effects in leukemia cells and E discodermin). Mollusks have been usually used in the pharmacology industry. Conotoxins have been widely studied due to their content in ziconotide, dolastins, keenamides, and kahalalides. These compounds may have different effects including analgesic and anticancer effects in some tumor cell lines. Ascidians are less known than other marine compounds, but they have beneficial effects related to antiviral, immunosuppressive, and antitumor activities thanks to compounds such as didemnins and tamandarins.

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Lastly, macroscopic marine algae, commonly known as seaweed, are another group of species capable of enhancing health due to biopeptides including lectins and phycobiliproteins (Jo et al. 2017).

Nonmarine Animal Bioactive Peptides As mentioned above, the interest in BPs and their health benefits have led to the development of food products based on the biological effects that these molecules produced in an organism. BPs from animal sources play an important role, owing to their antimicrobial, antithrombotic, and antioxidant properties. In addition, they reduce the risk of diseases related to blood pressure and cholesterol and may improve the absorption and bioavailability of other nutrients during the digestive process (Bhat et al. 2015). Proteins derived from animal sources are very significant components of the human diet since they are an essential source of amino acids and BPs. Their physiological effects include both direct actions in the organism as well as the basis of other hydrolyzed BPs during the intestinal tract. These hydrolyzed enzymes come from different sources including hydrolysis by digestive enzymes, enzymes available in food materials, or enzymes from microorganisms involved in food processing. Dairy proteins from animals such as cows, goats, and sheep is a very heterogeneous molecule group. Peptides may be activated both in the digestive process and in industrial food processing, including milk secretion or storage. These protein genetic polymorphisms affect both the milk composition and dairy by-products, since this behavior is associated with both the expression and the peptide sequence of the molecules, which consequently affect human nutrition (Albenzio and Santillo 2011). Despite being a source of beneficial peptides, many of these proteins have harmful effects on health because their consumption has been linked to milk allergic reactions. One of the main proteins responsible for allergic effects is casein, which has also been related to other diseases (Ballabio et al. 2011). On the other hand, products derived from milk (e.g., cheese) go through a maturation process where they accumulate BPs due to the action of both endogenous and microorganism enzymes responsible for some of those processes. The total content of peptides varies according to the maturation process and the raw material used, as well as the type of product being manufactured (López-Expósito et al. 2012). Although the largest sources of BPs of animal origin are mainly bovine milk and dairy products, there are also other important sources such as bovine blood, gelatine, meat, eggs, and fish. BPs of animal origin are mostly found in muscle, although they are also found in bones, collagen, and blood. The consumption of meat has been traditionally associated with diseases such as obesity and hypertension. However, these BPs perform specific physiological functions that make them suitable for their inclusion in functional foods, giving added value to both meat itself and meat by-products generated by the meat industry (Xing et al. 2019). Environmental conditions and agronomic practices significantly affect the content of these peptides in different animal models. Meat processing and the metabolic processes of the

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tissues involved can also affect the production of these biopeptides. This suggests that their concentrations can be increased by crossing and optimization of the production systems (Przybylski et al. 2016). Nonetheless, this message should not be confused with the overconsumption of highly processed meat products and those containing detrimental additives. Eggs are a very valuable food from a nutritional point of view: they are nutrientdense and provide energy and high amount of good-quality proteins. On the other hand, eggs also contain both unsaturated and saturated fatty acids, essential vitamins, and minerals. Some of the physiologically active compounds with positive effects on health are proteins including avidin, ovostatin, ovalbumin, ovotransferrin, ovomucin, lysozyme, and cystatin, mainly present in egg white. Other molecules such as carotenoids, aromatic amino acids, phosvitin, and phospholipids are components in egg yolk. These compounds have antioxidant activity, as well as anti-inflammatory, antimicrobial, and antiviral properties, which demonstrates the importance of understanding their role as a functional food in the prevention of chronic degenerative diseases (Nimalaratne and Wu 2015).

Plant Bioactive Peptides The use of plant-derived BPs for their inclusion in other foods has been a great source of interest in recent years. It has been demonstrated that these peptides may improve the properties of processed food products in the food industry such as meat, dairy products, flour-based products, and sauces. These biopeptides develop different functions depending on their nature and the food matrix to which they are added; e.g., these proteins can emulsify oil and increase its solubility in water. They are also used to enhance the aroma of foods and to form gels in the matrix of some foods (Oreopoulou and Tzia 2007). On the other hand, these peptides from plant origin also have beneficial properties for health, so they can be added to foods giving them added value as functional foods and nutraceutical products. They are being used as an alternative to animal proteins in diets where certain foods are restricted (Xu et al. 2019). One of the highlights of the use of BPs from plant origin for their inclusion in other foods is that these compounds can be obtained from plant residues from the food industry. The most used by-products from protein sources are wastes generated during the industrial processing of these foods, e.g., peel, seeds, and pomace of fruits (Gençdağ et al. 2021). On the other hand, proteins can also be obtained from horticultural plant by-products such as leaves, stems, or inedible parts of some plants (Sadh et al. 2018). The main sources of vegetal protein are high-protein plants such as cereals and legumes, although oilseeds are also a great source of protein. Soybean is the most widely used source of vegetable protein, as it possesses a high concentration of these compounds. Residues from the oil industry are also a great source of protein. While the highest concentration of BPs is found in oil by-products, major production crops such as cereals are beginning to gain popularity as a source of protein. In this regard, proteins extracted from cereals such as oats, wheat, and rice

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are being used because they are produced in large quantities and their residues can be widely utilized. As for fruits, potato, coconut, and orange peel are used for the extraction of BPs, as well as the pulp of other fruits such as tomatoes and apples (Görgüç et al. 2020).

Microbial Bioactive Peptides Due to the health problems attributed to chemical food additives of synthetic origin and the benefits of additives from natural sources, the food industry has been focusing on the supply and demand for the food products that do not contain chemical preservatives, are free of pathogenic microorganisms, and have a long shelf life. In this case, bacteriocins are an attractive option as part of the solution to these problems which are peptides with antimicrobial activity, secreted by many bacteria to inhibit the growth of other competing microorganisms. This compound has been considered safe for human consumption, due to the feasibility to be degraded during the digestive process (Silva et al. 2018). There is a great diversity of bacteriocins reported in most bacterial species, and even within the same species, different types of bacteriocins may be produced. The most studied bacteriocins are those produced by lactic acid bacteria. The production of bacteriocins depends on the growth and physiological activity of the producing strain, as well as the biomass obtained is correlated with the amount of bacteriocin produced. Bacteriocins participate in the fermentation and preservation of food, improving its hygienic quality by inhibiting the competitive flora, which includes pathogenic microorganisms, such as Listeria monocytogenes, Staphylococcus aureus, Bacillus cereus, Clostridium botulinum, and Salmonella.

Essential Fatty Acids (EFAs) EFAs are polyunsaturated fatty acids that cannot be synthesized in the human body, so their incorporation through the diet is essential for the proper functioning of the organism. Although the consumption of low-quality fatty acids is closely related to different diseases, their consumption does not decrease. However, it has been observed that the population is increasingly interested in maintaining a healthy lifestyle, which leads to the consumption of higher-quality polyunsaturated fatty acids (Sheppard and Cheatham 2018). Fatty acids are involved in the structure of cell membranes and gene expression and serve as a substrate for other metabolic pathways such as prostaglandin and eicosanoid synthesis. In addition to the intake of these fatty acids, their proportions must also be considered, as the concentration of fatty acids present in the structure of cell membranes can affect both their fluidity and the permeability of cells and proteins involved in cell signaling. On the other hand, several research works have demonstrated that these molecules are related to the reduction of risk diseases including cancer, cardiovascular disorders, or diseases related to the optimal development of tissues and organs (Djuricic and Calder 2021).

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Polyunsaturated fatty acids have been classified into two families: omega-3 (ω-3) and omega-6 (ω-6). The differences between these two compounds lie in the position of the double bonds in their structure, present in positions 3 and 6 of the carbon chain, respectively. One of the most important characteristics of these compounds is that the chain ω is never modified, which makes them more energetically stable. The precursors of these two compounds are EFAs, which are not synthesized endogenously and can only be acquired through food. These acids include alpha-linolenic acid (ALA), a precursor of omega-3 acid, and linoleic acid (LA), a precursor of omega-6 (D’Angelo et al. 2020). Within the family of omega-3 acids, the most important for the human diet are eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Although they come from the same family, their functions in the body differ. EPA is related to cell signaling processes and blood flow in the brain and is essential for the correct development of this organ. Moreover, that compound is a prostaglandin precursor. DHA has structural functions and is also important for visual functions in the first years of life. These compounds have been described in foods such as flaxseed, pumpkin seeds, and walnuts, as well as in fish such as salmon and tuna. However, recent studies suggest that their consumption has declined in recent years, and nowadays the population does not consume the proper amount of these fatty acids necessary for good health (Gogus and Smith 2010). Gamma-linolenic acid (GLA) and arachidonic acid (AA) belong to the family of omega-6 fatty acids. Similar to EPA, these acids participate in the synthesis of prostaglandins, and GLA, as with DHA, also has a structural function within cell membranes. These compounds have been described in plant oils such as sunflower and corn, although they have also been described in smaller amounts in soybean, sesame, and nuts such as almonds and peanuts (Kaur et al. 2014). As mentioned above, the consumption of these essential nutrients in the population is below the recommended amounts. To this end, different solutions have been developed in order to reduce this gap and improve the health and nutritional status of the population. One of the strategies that have been carried out is to increase the direct intake of these substances through products rich in fatty acids such as fish and nuts. However, this solution turns out to be not enough. Thus, the enrichment of some foods with fatty acids from fish oil origin or the improvement of raw materials by feeding animals producing human food (e.g., meat and fish), and using molecular techniques to increase the amount of these compounds in oilseed crops, have been suggested as the alternative approaches (Saini and Keum 2018).

Live Organisms As mentioned before, functional foods are those that have beneficial effects on health beyond the basic nutrition. According to this definition, functional foods may contain living organisms in their composition providing both nutrients and enough microorganisms in their food matrix to cause an effect on the body. The functions of these microorganisms are usually related to the balance of the intestinal flora and

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other related effects such as the growth of pathogens and the proper functioning of the immune system. In recent years, the study of microorganisms that inhabit the human body has taken a great interest because it has been demonstrated that an appropriate interaction between these microorganisms and their host is beneficial for health, while the imbalance in these microorganisms can increase the risk of some diseases. Some studies have even suggested that microorganisms maintain a dialogue with each other and with the environment, which makes them behave collectively. This communication is carried out through signaling molecules, which are specific for other microorganisms or for the host organism, which allows them to have health-promoting effects on GIT and on the nervous system (Oleskin and Shenderov 2019). The term microbiota refers to the microorganisms, mainly bacteria, that inhabit a specific part of the human body. In addition to bacteria, other microorganisms including viruses, archaea, unicellular organisms, and fungi are also found in a smaller proportion than bacteria in microbiota. Within the human body, the GIT has the highest microbial biomass. The behavior of microorganisms and the genes that encode them, known as the microbiome, is a dynamic system and can be modified by both extrinsic and intrinsic factors (Nguyen et al. 2018). Diet, some medical treatments, and lifestyle can change the composition and functions of these microorganisms, and, on the other hand, they can also be modified due to alterations in the immune system or genetic factors. These behavioral changes in the GIT microbiota have special interest since it has been shown that the alterations in these microorganisms directly affect health status. That is one of the reasons why microbiota has been considered a new biomarker of health status and has been linked to the maintenance of the nervous, muscular, and skeletal systems, as well as the urinary, digestive, and immune systems. Thus, the imbalance in the population of microorganisms in the intestine can trigger the development of diseases. On the contrary, a healthy and properly functioning intestinal microbiota has beneficial effects on the body, mainly related to digestive processes and the absorption of nutrients (Yadav et al. 2018). Currently, probiotic microorganisms are those that when administered in appropriate doses give a positive effect on the health of the host. However, this definition has not always been the case. When the gut microbiota and its relationship to health status became an interesting topic of study, probiotics were defined as substances that promote intestinal balance. However, later studies determined that probiotics not only affected gut balance, but also influenced the health status of the individual. Moreover, these substances must be live microorganisms with beneficial effects to be considered probiotics (Hill et al. 2014). Nowadays, probiotics are commercially marketed both in a pure state as capsules and added to some food products. Considering the consequences that the administration of these microorganisms can give to human health, the WHO together with the FAO (Food Agriculture Organization) of the United Nations Organization determined some points to consider that probiotics are safe for the individual. These guidelines include the study of their toxicity and virulent properties in microorganisms and cannot affect antibiotic resistance. Their metabolic activities,

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hemolytic activity, and whether they may have side effects or epidemiological effects are also determined (Rodrigues et al. 2020). In this sense, bacteria belonging to the genera Lactobacillus and Bifidobacterium have been recognized as safe, as they naturally occur both in food and in the human microbiota. Furthermore, these species have not been found to trigger problems or adverse health effects. Numerous studies have determined that Lactobacillus have a positive effect on health, since they have therapeutic effects on the individual. Microorganisms of this genus are found in the intestinal microbiota, and their consumption through food is related to digestive processes such as the bioavailability of nutrients, which causes beneficial physiological and nutritional effects. On the other hand, it has also been described that these bacteria improve the balance of the microbiota and protect against pathogens by improving the functions of the epithelial barrier and producing antimicrobial compounds (Zhang et al. 2018). Lactobacilli are considered extremely safe for health, since hardly any adverse side effects have been reported. Nonetheless, depending on the species of bacteria applied, their functions and health effects may be different since the effects on the body are exclusive to each strain, so an exhaustive study is required to determine its safety in human health. Lactobacillus species have been traditionally used for the preparation of fermented dairy foods, since they cause changes in milk and other foods that are beneficial to health. However, these bacteria are also found in other foods of animal origin, such as meat and fish, and of plant origin such as fruits, vegetables, cereals, and legumes (Pradhan et al. 2020). Bifidobacteria are also found in the human GIT and are involved in different functions of the digestive system as well as in the development of the infant immune system. These bacteria can generate vitamins and bioactives beneficial to health. Bifidobacteria also synthesize lactic acid, which is involved in the GIT problems related to metabolic acidosis. Moreover, bifidobacteria species possess antimicrobial and antiviral activities and can alleviate inflammatory effects produced in the intestine (Sharma et al. 2021). As mentioned above, the predominant microorganisms in GIT are bacteria; however, the presence of fungi suggests that these microorganisms also have beneficial effects in humans. One of the characterized enhancement yeasts present in the gut is Saccharomyces boulardii, also known as Saccharomyces cerevisiae var. boulardii or Saccharomyces cerevisiae. Numerous studies have determined that this yeast has therapeutic effects in humans, since it can improve disorders related to the digestive system. The presence of this yeast in the intestinal tract has its origin in the consumption of foods such as bread or drinks such as beer, in addition to other fermented foods. Currently, the strains of this yeast can be found on the market as a probiotic supplement for pharmaceutical purposes, since it has been shown that it does not present health risks and its use is completely safe.

Essential Oils (EOs) and Oleoresins EOs are natural fragrant compounds from aromatic plants that humans have used for therapeutic purposes since ancient times. These oils have been traditionally used for medical, antimicrobial, and cosmetic applications, and yet, the growing interest from

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the pharmaceutical, agricultural, and food industries makes them very interesting compounds to study (Sánchez-González et al. 2011). These oils are found in different parts of plants such as flowers, roots, fruits, and seeds, as well as in resins and on the surface of different plant tissues. Their properties vary significantly depending on their composition and the organ in which they are found (Masotti et al. 2003). In the vegetal kingdom, EOs play a crucial role in protecting plants against microorganisms and herbivores’ attacks and attracting some pollinators. The presence of different properties in aromatic oils is given by their chemical composition, mainly volatile compounds, and secondary metabolites such as terpenes, terpenoids, phenolic compounds, and aliphatic components are found. The proportion of these substances can vary both due to intrinsic factors of the plant, such as the plant variety, the state of maturation, or the organ that secretes the substances, as well as due to extrinsic factors such as culture practices or its extraction process. For humans, its consumption can increase the stimulation of enzymes that participate in digestive processes, increasing intestinal motility. These compounds also have anti-inflammatory properties and favor the stimulation of the immune system (Angioni et al. 2006). EOs involve a complex mixture of substances and molecules in different concentrations with highly variable characteristics. The major components of these oils are usually low molecular weight volatile compounds, where one or two of the components stand out above the rest of the substances (Pichersky et al. 2006). These mainly present molecules are responsible for biological characteristics in EOs. These molecules are classified into two different groups according to their biological origin: terpenes and aromatic compounds. Aromatic compounds, also known as aliphatic compounds, give the aroma to certain parts of plants such as fruits or flowers. Terpenes, on the other hand, are the ones that act mainly as food preservatives (Boncan et al. 2020). Terpenes are one of the main groups of chemical compounds present in EOs. Both structure and function of terpenes may be different from each other. The structural formation of terpenes consists of units based on five carbons, known as isoprene. Monoterpenes have 10 carbons in their structure; in contrast, sesquiterpenes are made up of 15 carbons. Both monoterpenes and sesquiterpenes are the main types of terpenes. On the other hand, aliphatic compounds are hydrocarbons with a linear structure present in some citrus as well as green leaves. In contrast, the aromatic compound has a benzene ring, and they are responsible for the pleasant odor in plants (Naveed et al. 2013). Aromatic oils are attributed to antioxidant and antimicrobial properties of these plants, so they have been commonly used in the food industry as natural preservatives to protect the properties of food (Mathavi et al. 2013). EOs, therefore, are presented as an alternative to the use of chemical substances, due to their interference with the growth of pathogens and their antimicrobial activity. An example is EOs from citrus fruits, which inhibit bacterial growth. Other EOs with similar functions are cinnamon oil, oregano oil, and thyme oil, although there is not enough information about the method of action of these extracts against pathogens (Bhavaniramya et al. 2019).

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Similar to EOs, oleoresins can also replace chemical additives in some foods and have antimicrobial and antioxidant properties. In addition, their consumption has anti-inflammatory and anti-carcinogenic effects on the human body. Oleoresins can also be obtained from different parts and provide different characteristics in food including aroma and flavor, pigments, or pungency (Sowbhagya 2019). The difference between oleoresins and EOs lies in the fact that oleoresins are more concentrated extracts that have in their composition, in addition to volatile compounds, and non-volatile compounds, which makes them more complex substances. As they do not contain non-volatile compounds in their composition, oleoresins have higher thermal stability than EOs. However, if extraction or storage method is not done properly, they can degrade and decrease their shelf life. Although many marketable products contain oleoresins in their composition, it is difficult to find scientific research that covers the different applications of oleoresins in food products as well as their quality and food safety standards. Their application as coloring agents is exemplified by spices such as paprika, peppers, and turmeric, while others such as ginger or mustard are commonly used to give foods pungency functions. Other substances such as cinnamon and cloves are also used for antimicrobial purposes in the food industry (Procopio et al. 2022).

Vitamins and Minerals Over the last few years, it has been described that food components including vitamins and minerals are essential for the development of the human body. Dietary intake is the main fount for these compounds, so appropriate vitamin and mineral intakes promote good health and decrease the risk of diseases. Although the life expectancy of the population has increased in recent years due to healthier lifestyles, the risk of chronic diseases has also increased. This increase in chronic diseases may be caused by inappropriate intake of substances that are essential for the body, resulting in functional and metabolic effects associated with a lack of nutrients or inadequate intake (Verkaik-Kloosterman et al. 2012). Vitamins and minerals are food components involved in the body’s immune response to pathogens by mediating immune-stimulating functions, so the lack of these nutrients can lead to poorer health and increase the risk of infectious diseases (Mitra et al. 2022). Vitamins are organic compounds indispensable for the proper development, growth, and regulation of cell function in the human body. Mineral elements are essential too; in contrast, they are inorganic substances. These substances have been often utilized as dietary supplements due to consumers’ interest; however, it has been described that both deficiency and excess intake can be harmful consequences to health. The essential vitamins and minerals are liposoluble vitamins A, D, E, and K; hydrosoluble vitamins B1, B2, B3, B4, B6, B8, B9, B12, and C; and minerals Ca, P, K, Na, Cl, Mg, Fe, Zn, I, Cr, Cu, F, Mo, Mn, and Se. Vitamins are organic molecules essential for the human body. Although they are essential for the production of energy, they are not necessary for high amount quantities. Only a small portion of consumed vitamins is required for metabolism.

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Vitamins have different functions in the human body. On the one hand, they participate as a substrate in metabolic pathways as well as mediators between cells, while they have antioxidant properties as well. Similar to vitamins, minerals are required too for proper metabolism function as well as the development and growth of body structure. Moreover, they are essential for maintaining the electrolyte balance in cells. As vitamins, minerals have been selected into two different groups: macro minerals and trace minerals. While macro elements are present in milligrams per kilogram, traces only are present in minor quantities (micrograms/kilograms). The presence of that compounds in organisms is not equal because each tissue has a different requirement. The concentration of vitamins and minerals in food may decrease due to different processes including blanching, milling, fermentation, and extrusion, as well as time, temperature, or storage conditions (Reddy and Love 1999).

Other Bioactive Compounds The definition of “prebiotic” has not been always the same over the years. Since the first time it was described, this term has been reviewed. The first definition of prebiotics was “Non-digestible food ingredient that beneficially affects the host by selectively stimulating the growth and/or activity of one or a limited number of bacteria in the colon, and thus improves host health” (Gibson and Roberfroid 1995). Afterward, the definition of prebiotic has been revised in order to define this concept exhaustively. Thus, the last definition that is currently used to define the term prebiotic was uploaded in 2017 as “a substrate that is selectively utilized by host microorganisms conferring a health benefit” (Gibson et al. 2017). Related to that concept, it is necessarily revised using three different criteria to include a substance as a prebiotic: (i) be able to withstand intestinal tract and digestion processes; (ii) be able to be metabolized and utilized by the microbial community that colonizes the human body including other areas besides intestinal microbiota such a urogenital tract, skin, or upper GIT; and (iii) be able to produce changes in growth or activity of microbiota related with health improvement (Sanders et al. 2019). The growing interest in finding target compounds has been lately under the spotlight of scientists to search for potential prebiotic substances. The most known accepted prebiotic compounds are carbohydrate-based compounds, phenolic compounds, polyunsaturated fatty acids, and carotenoids. It has been demonstrated that these molecules cause changes in the gut of the host’s microbiome by promoting good health and wellness. The metabolites resulting from the metabolism of these substances may cause changes in the epigenome of the microbiota for the benefit of the host. On the other hand, substances including chlorophylls, phytosterols, vitamins, and peptides have been described as a positive modulator of the microbiota (Arruda et al. 2022). Prebiotics may be found in fruits, vegetables, and animal-origin products as well as being chemically produced to be included in a food matrix. These prebiotic compounds can play different roles in their beneficial effects such as improving

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the quality of food or giving them more desirable visual and organoleptic properties for the consumer. Oligosaccharides have been described as polymers with no more than 20 monosaccharide units linked through glycosidic bonds. The most abundant oligosaccharides are disaccharides, with two monosaccharide units. These molecules cannot be digested or absorbed in the upper intestinal tract, so they have to be fermented by intestinal microbiota. Oligosaccharides have not received as much attention over the years, but recent studies have described some functional beneficial effects similar to dietary fiber in human health, especially in the intestinal tract. Oligosaccharides are not only used to add sweetness to food, they can be utilized in industrial processes as a potential component in functional foods (Roberfroid and Slavin 2000). They may be isolated from a variety of biomass sources by enzymatic hydrolysis or being chemically synthetized; however, there is a special interest in being extracted from natural founts. Although there are marketable products with oligosaccharides as a prebiotic compound (including inulin, fructooligosaccharides, and galactooligosaccharides), more information about their positive effects on health is required (Rastall 2010). Lastly, the concern about knowing the relationship between dietary fibers and their positive effects on the GIT has been increased due to the growing amount of proof in human nutrition. Although dietary fiber is not a well-defined chemical profile, it has been described that those substances such as cellulose, hemicellulose, lignin, and pectic substances can provide functional characteristics when added to food products. Consuming an adequate amount of soluble and insoluble fiber may reduce the risks of cardiovascular disease, diabetes obesity, and cancer. Due to that, dietary fibers are prepared as a supplement or nutritional ingredient in healthy foods and nutraceutical products (Dhingra et al. 2012). Human diets based on fiber including cereals, nuts, fruits, and vegetables have a beneficial effect on health, because their consumption has been linked to a decrease in the risk of chronic diseases (Brownlee 2011).

Conclusion As it is described throughout this work, food has a direct impact on both quality of life and human health. Bioactive compounds that can be easily used as ingredients in pharmaceutical industries, cosmetics, or dietary supplements come mainly from plants, such as phenolic compounds, carotenoids, vitamins and minerals, and some fatty acids. However, proteins from the animal kingdom or the marine environment, as well as microorganisms such as probiotics or yeasts, are also of special interest. Eating a balanced diet based on healthy foods with a considerable supply of nutrients contributes to the promotion of health and prevents the risk of chronic diseases. Thus, studying the mechanisms by which different bioactives produce a positive effect on the human body is fundamental for the development of useful functional foods aimed at the prevention and improvement of diseases.

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Part I Phenolic Compounds

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Hydroxybenzoic Acids Deyan Gong and Zhengbao Zha

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Salicylic Acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . P-Hydroxybenzoic Acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Protocatechuic Acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gentisic Acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3,5-Dihydroxybenzoic Acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pyrocatechuic Acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Vanillic Acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Syringic Acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gallic Acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ellagic Acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abstract

Nature generously offers a variety of sources like beverage crops, fruits, and vegetables rich in hydroxybenzoic acids compounds with excellent biochemical and antioxidant capabilities. As a group of bioeffective compounds, hydroxybenzoic acids are a prominent kind of phenolic acids. Hydroxybenzoic acids are the major aromatic secondary metabolites that impart food with typical organoleptic characteristics and link to many health benefits. Due to enormous dietary health benefits of hydroxybenzoic acids such as anti-inflammatory, antioxidant, anti-allergenic, immunoregulatory, antimicrobial, antiatherogenic, antithrombotic, antidiabetic, anticancer processes, and cardioprotective capabilities, they are attracting an ever-growing awareness in food technology, and extensive technical like medical, cosmetic, and pharmaceutical industries. It is anticipated that the advancement of hydroxybenzoic acids in functional foods may result in D. Gong · Z. Zha (*) School of Food and Biological Engineering, Hefei University of Technology, Hefei, China e-mail: [email protected] © Springer Nature Switzerland AG 2023 S. M. Jafari et al. (eds.), Handbook of Food Bioactive Ingredients, https://doi.org/10.1007/978-3-031-28109-9_2

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reversing some common illnesses such as inflammation, nervous system upsets, cerebrovascular or cardiovascular illnesses, and diabetes. This chapter presents an overview of various aspects related to hydroxybenzoic acids (including salicylic acid, p-hydroxybenzoic acid, protocatechuic acid, gentisic acid, 3,5-dihydroxybenzoic acid, pyrocatechuic acid, vanillic acid, syringic acid, gallic acid, and ellagic acid) and the importance of these hydroxybenzoic acids is emphasized, followed by details on chemistry, structure, functionality, safety and toxicity, oral delivery, and their applications in functional foods. Keywords

Hydroxybenzoic acids · Phenolic acids · Oral delivery · Functional foods · Bioavailability · Health properties

Introduction Hydroxybenzoic acids (HBAs) are aromatic carboxylic acids that contain a typical C6
C1 carbon skeleton structure. HBAs structure alterations (Fig. 1) include methoxylations and hydroxylations of the aromatic ring of 10 obvious Fig. 1 Chemical structures of obvious hydroxybenzoic acids: 1. salicylic acid; 2. p-hydroxybenzoic acid; 3. protocatechuic acid; 4. gentisic acid; 5. 3,5-dihydroxybenzoic acid; 6. pyrocatechuic acid; 7. vanillic acid; 8. syringic acid; 9. gallic acid; 10. ellagic acid

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natural-appearing HBAs (i.e., 1. salicylic acid; 2. p-hydroxybenzoic acid; 3. protocatechuic acid; 4. gentisic acid; 5. 3,5-dihydroxybenzoic acid; 6. pyrocatechuic acid; 7. vanillic acid; 8. syringic acid; 9. gallic acid; 10. ellagic acid), which are discussed in this chapter. HBAs are the major group of bioeffective compounds among phenolic chemicals sourcing in a variety of plants like spices, vegetables, fruits, and grains. They are the major aromatic secondary metabolites that impart food with typical organoleptic characteristics, and link to many health benefits (Robbins 2003). Reactive oxygen species (ROS) appear in peroxidation, which is reduced by antioxidants in the cells of the human body. The oxidative damage, lipid peroxidation to proteins, and DNA can cause lasting upsets like neurodegeneration, heart diseases, and cancers. Natural antioxidants compounds are applied to fight against ROS and avoid lasting upsets. Phenolic chemicals can reduce lipid peroxidation due to their redox capabilities (Ahameethunisa and Hopper 2010). Constructing new antioxidants is upsurging throughout the past years. As an influential class of natural functional components, HBAs have effective water and lipid solubility can reduce oxidative worsening. Natural bioeffective food components HBAs have been utilized as practical additives for foods color maintenance and impeding microbial expansion to extend the quality guarantee period of foods (Rashmi and Negi 2020). Studies of HBAs have centered on the free radical scavenging activity (Kiokias et al. 2020). HBAs are powerful antioxidants and can protect healthy cells by inhibiting apoptosis. Pharmacological medicament containing HBAs show distinct therapeutic effects as antimicrobial, anticancer, antioxidants, chondroprotective effect, antidiabetic activity, carbonic anhydrase suppressors, cathepsin D suppressor, anti-ulcerogenic, etc. HBAs have become the essential core for enhancement and designing of novel functional foods or pharmacological medicament. This chapter is an overview about the progress of food chemistry and function impacts containing HBAs, followed by details on chemistry and structure, safety and oral delivery, functionality, and functional food applications. The overall and detailed list of HBAs investigation will provide competent evidence to support the multifaceted bioactivity of each of the identified HBAs. This chapter will contribute to the further research for full use of health benefits of HBAs, and do promoting effects on humans’ health and technical advancements like cosmetic, medical industries, and functional food technology worldwide.

Salicylic Acid Chemistry and Structure Analgesics salicin and its metabolite salicylic acid (SA, 2-hydroxybenzoic acid) with the molecular formula C7H6O3 and 138.12 g/mol molecular weight (Fig. 1) are the first pharmacologically agents obtained from willow bark extracts in the nineteenth century. After that SA was acetylated to get nonsteroidal medicine aspirin (ASA,

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2-[acetyloxyl] benzoic acid) with more gastrointestinal (GI) friendly (Juurlink et al. 2014).

Safety and Oral Delivery ASA side effects have been analyzed. ASA can lessen the series of the threat of cardiovascular disease. But in diabetic patients who do not have cardiovascular upsets, ASA might also trigger GI upset and elevated bleeding rates. GI complications and adverse effects of ASA range from gastritis to GI bleeding. Patients with ASA adverse effects have various signs. Slight toxicity signs might be dizziness, tinnitus, vomiting, lethargy, and nausea (Blanca-Lopez et al. 2017). More serious signs include high anion gap metabolic acidosis, tachypnea leading to respiratory alkalosis, hyperthermia, seizures, hypoglycemia, hypokalemia, cerebral edema, and coma. ASA administration includes intravenous, oral, and rectal ways. After oral administration, liquid ASA agents will be absorbed much more quickly than tablets. Hydrolysis of ASA yields SA. With a narrow therapeutic window, SA offers proper anti-inflammatory influence (Christiansen et al. 2021). Absorption of ASA is pH sensitive, which is greater in the small intestine than stomach in the range of pH 3.5 to 6.5. At pH 6.5, there is almost no ASA stomach absorption. Metabolism of salicylate happens through two routes with salicyl phenolic glucuronide and salicylic acid metabolic product production. SA is eliminated in the kidney, and medications like antacids will boost renal elimination with the pH increase of urinary. ASA therapeutic doses are range from 150 to 300 mcg/mL, dosage >300 mcg/mL is poisonous. Blood concentrations of ASA therapeutic doses can vary from 3 to 10 mg/dL, and acute-poisonous effect concentrations range from 70 to 140 mg/dL. Functionality and Functional Food Applications In vivo, high salicylate doses for antihyperglycaemic can stimulate uncoupling, activate AMPK, and adjust transcription factor complex nuclear factor kappa B (NFκB) directly. Emergent clinical data indicate that medium salicylate doses have more substantial effects on the concentration of hepatic glucose than peripheral insulin. Lately, SA agents have been reported to adjust endoplasmic reticulum (ER) stress in adipocytes and fibroblasts. SA and ASA treatment for cancer has been proved. One study showed sodium salicylate can hinder the activity of urokinase in MDA MB-231 breast cancer cells (Madunić et al. 2017). SA was also reported to cause colon carcinoma cells apoptosis in vitro (Zitta et al. 2012), enhance hydrogen peroxide release and caspase-3/7 activity, and diminish pro-survival kinases erk1/2 phosphorylation in colon cancer cells (Zitta et al. 2012). SA and ASA are fitting with other clinical use agents to deal with various illnesses. One study in cervical cancer cells showed that cisplatin and SA had the same treatment targets. The collaborative interaction of cisplatin and SA realized 14-fold cisplatin dose decrease for efficient cancer treatment. Cisplatin and SA combination therapy in HeLa cells inhibited UHRF1, repressed metastatic genes expression, and increased apoptosis rate. ASA and SA have been recorded to present cancer treatment effects in melanoma implanted murine model (Ausina et al. 2020), and the

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efficacy was also confirmed in 2D- and 3D-cultured B16F10 melanoma cells. In both in vitro and in vivo melanoma models, ASA and SA initiated Akt/mTOR/AMPKdependent activation of nitric oxide synthase 3, which enhances ROS and nitric oxide production to stimulate ER stress response, to the increase of C/EBP homologous protein as one of the pro-apoptotic transcription factors. SA and ASA are promising functional food components and are accessible over the counter. The typical guidelines of ASA use are as follows: cardiovascular risk reduction, ankylosing spondylitis, angina pectoris prophylaxis, ischemic stroke prophylaxis, fever, colorectal cancer (CRC), revascularization procedures prophylaxis, osteoarthritis, myocardial infarction, systemic lupus erythematosus, rheumatoid arthritis. ASA can work as cyclooxygenase-1 (COX-1) enzymatic suppressor and cyclooxygenase-2 (COX-2) activity modifier. ASA binding to COX-2 is irreversible, which is different from other nonsteroidal anti-inflammatory medicines (NSAID) like ibuprofen/naproxen with reversible binding activity. ASA also blocks thromboxane A2 on platelets irreversibly to prevent aggregation of platelet (Zimmermann and Curtis 2018). Due to the mechanism of COX blocking, arachidonic acids are ferried into the lipoxygenase route. The modification of COX-2 is attributed to the production of anti-inflammatory lipoxins, which are called ASA-activated resolvins or lipoxins. Oral administration of 160 to 325 mg ASA will achieve about 90% COX inhibition efficacy, and the efficacy can last for almost 7 to 10 days. Inhibition of prostacyclin is attained with higher ASA doses.

P-Hydroxybenzoic Acid Chemistry and Structure p-Hydroxybenzoic acid (pHBA) with the molecular formula C7H6O3 and 138.12 g/mol molecular weight (Fig. 1) is one of the benzamide analogs, which is not only known as a natural food ingredient but also one of the gut flora metabolites from various dietetic phenols. Like SA, pHBA is metabolized by the gut microflora in a route via sulfate conjugation and decarboxylation reaction. As a plant allelochemical, pHBA can restrain the glycolysis processes of metabolic enzymes and the oxidative pentose phosphate mechanism directly to inhibit seed germination and root growth. pHBA also can powerfully reduce ion uptake, photosynthesis, and water transpiration, and lead to proteins and DNA damage in plant cells (Chen et al. 2015). As an obvious allelopathic chemical, pHBA is a kind of autotoxin from cucumber root exudates. Administration of pHBA can repress cucumber root growth through the reduction of meristem cell activity and length. The deficiency of root growth is triggered by ROS accumulation reduction and some ROS-scavengingassociated genes expression increase in root tips. pHBA is the most plentiful HBAs ingredient in the field soil samples. pHBA administration can enhance both the freezing tolerance of the spring wheat and drought tolerance of the winter wheat. In carrot, pHBA was also exhibited covalent binding to the newly synthesized cell wall polysaccharides, which will increase the impermeability and reinforcement of cell

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wall and result in enhanced endurance against freezing stress or pathogen illness (Horváth et al. 2007).

Safety and Oral Delivery Esters of pHBA were legalized as antimicrobial food additives, and JECFA checked their safety in 1973. The chronic and acute poisonous effect results of pHBA and esters with methyl, ethyl, propyl, or butyl group in dogs and mice are presented. All these chemicals have a low level of acute toxicity. The common side effect is acute myocardial depression with hypotension, which usually is transient and not cumulative. No proof of serum toxicity or tissues histological damage was observed in treated animals. pHBA esters are almost non-sensitizing and nonirritating to all skin of normal individuals. Various in vivo and in vitro tests have primarily shown that pHBA esters have no genotoxicity. The structure and function of pHBA esters have no carcinogenic potential. In the test of rodents, pHBA has a slight effect on estrogenic activity. The tests of methyl and ethyl pHBA esters also show that with a ~ 1000 mg/kg dosage per day, they have no adverse effect on sex hormone secretion or reproductive function of male individuals (Lemini et al. 1997). pHBA esters show very good bioavailability with oral delivery. Based on the animal tests results, parabens are absorbed well, and there is a very low concentration of paraben in blood. The main metabolites of parabens are free pHBA, glycine conjugate of pHBA, and lower quantities of sulfate and glucuronide conjugates. The phenolic group in pHBA and its metabolites have been proved to be intact in tablets, tissues, biological fluids of agents after parabens, and pHBA oral delivery test in humans. No matter the administration route, recoveries of parabens from the animals’ urine vary from 40% to 95% (Jones et al. 1956). Functionality and Functional Food Applications Due to its low cost, high bioactivity, and good availability, pHBA is regarded as a good candidate for application as efficient cyanobactericide/algaecide (Jiang et al. 2019). A study showed pHBA-modified Fe3O4 nanoparticles (MFN) can greatly inhibit bloom-forming Microcystis aeruginosa. A medium dosage of MFN (182 mg/L) can increase the pHBA algal repression and decrease the IC50 value of pHBA by half, which was corresponding to the sufficient •OH production by MFN. More obviously, MFN addition brought a more efficient physiological effect than pHBA treatment only. The cellular integrity of cyanobacterium M. aeruginosa was damaged seriously, and total protein content declined fast to deactivate M. aeruginosa through extracellular polysaccharide and microcystin release reduction (Zuo et al. 2021). As the brain-targeting group, pHBA conjugated with anti-programmed deathligand 1 (αPDL1) antibody to transport αPDL1 into brain for orthotopic glioblastoma treatment test. On the base of dopamine receptor-managed transcytosis, pHBA systems have efficaciously realized crossing blood-brain barrier (BBB) of antibody delivery. Modification of αPDL1 with pHBA did not weaken the PD-L1 protein binding activity and blocked the immune checkpoints efficacy of αPDL1. Brain-

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Fig. 2 Schematic diagram exhibiting modification of αPDL1 with pHBA delivery system for efficient immune checkpoints blocking in glioblastoma model (Guo et al. 2020). (Reprinted with permission from Guo et al. 2020. Copyright 2020, Elsevier B.V)

targeting functionalization supported αPDL1 to cross BBB and contributed to enhancing αPDL1 distribution in glioma. Therefore, pHBA-αPDL1 conjugation inhibited tumor growth more efficiently and extended the survival time compared to the unmodified αPDL1 treated glioblastoma models (Guo et al. 2020) (Fig. 2). pHBA and methyl paraben (MP) is renowned for a variety of biological functions, involving antidiabetic, anticancer, antibacterial, antiviral, anti-inflammatory, and anti-aging processes. Since they are widely utilized in pharmaceutical industries, food, and cosmetics, the need for sustainable raw materials for HBAs production is arousing great interest. Among a variety of parabens, MP is the most utilized preservative in pharmaceutical industries and cosmetics (Kim et al. 2020).

Protocatechuic Acid Chemistry and Structure Protocatechuic acid (PCA, 3,4-dihydroxybenzoic acid) with the molecular formula C7H6O4 and 154.12 g/mol molecular weight (Fig. 1), a gray crystalline solid which discolors in the air quickly. PCA is a broadly sourced natural HBAs, discovered in ordinary cereals, fruits, vegetables, teas, some plant drinks, and Chinese herbs. PCA can dissolve in ether and ethanol and is marginally soluble in water (Ryu et al. 2019). Additional, PCA is amphoteric and irreconcilable with strong bases and acids. PCA is dehydroxylated and methylated to obtain derivatives like 3-HBA and vanillic acid, respectively, in the base of its 3,4-hydroxylation group. Safety and Oral Delivery The acute-poisonous effect test in rats confirmed that LD50 was 500 mg/kg of PCA for oral dosage. The poisonous effect will exhaust the glutathione (GSH) in kidneys and liver; however, no mortality was recorded in animals. A series of experiments

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proved that low concentration (< 20 μg/mL) of PCA has no cytotoxicity. PCA also did not demonstrate carcinogenicity and genotoxicity (Di Nunzio et al. 2017). Pharmacokinetics of PCA about metabolism in animal tests were fast after being administrated by gavage, and two-phase metabolism was examined after rapid absorption. After 50 mg/kg PCA was orally administrated, 0.5 ~ 5 μg/mL of PCA remained steady in human blood for 24 h. Intestinal PCA might be absorbed by passive diffusion, after that PCA is dispersed into the liver, brain, heart, lungs, and kidneys. The PCA absorption constant and cumulative absorption rate rise with its dosage increase, without the phenomenon of high concentration saturation. PCA was chiefly absorbed at duodenum in normal. Additional, renal function decline by pyelonephritis will reduce the PCA elimination rate obviously and increase its uptake. Therefore, pathological state will change PCA pharmacokinetic performance. Most of PCA elimination was egested in feces and urine of mice or human. Additional, sulfate or glucuronide PCA conjugates together with 4-methylprotocatechuic acid have been discovered in feces and urine of mice or human, demonstrating that PCA experienced conjugation or partial methylation reaction in metabolism (Huang et al. 2019; Zhang et al. 2019a).

Functionality and Functional Food Applications PCA shows broad pharmacological efficacy and can serve as neuroprotective, antiinflammatory, antioxidant, antidiabetic, antibacterial, Alzheimer’s disease (AD), antiapoptotic, atherosclerosis, diabetes, or antitumor medicament. Unusually, it might perform dual-directional characters among various pharmacological modulation processes. For instance, PCA can play a role for antioxidants as same as oxidants, this might trigger both cell proliferation and apoptosis. The process variances depend on PCA dosage. The dosage performs a crucial role in the test of PCA pharmacological safety or efficacy (Song et al. 2020). PCA is an efficient antioxidant with a potency 10 times bigger than α-tocopherol. PCA performs an antioxidant activity character by following: 1. Inflammatory markers concentration reduction, e.g., proinflammatory cytokines (TNFα), lipid peroxidation, ROS, and MDA 2. Endogenous antioxidant enzymes increase processes, e.g., GST, SOD, CAT, GSH, GPx, and GR 3. Signaling mechanisms regulation, e.g., Keap1-Nrf2, mitogen-activated protein kinase (MAPK), NFκB 4. Oxidative damage decrease, e.g., ARE, and PI3K-Akt Metabolic syndrome (MS) is a series of metabolic upset about carbohydrates, fats, and proteins. MS is identified with the concomitant existence of several metabolic dysfunctions like hyperglycemia, hypertension, obesity, insulinemia, hyperuricemia, dyslipidemia, or fatty liver disease. PCA can prevent MS by reduction of insulin resistance, serum glucose level, and body mass index, and recovering hormone concentration (Ibitoye and Ajiboye 2018).

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PCA suppresses inflammation triggered by a variety of factors. For instance, PCA decreases inflammatory mediators’ generation of BV2 keratinocytes and microglia caused by inflammatory cytokines as same as lipopolysaccharide (LPS) generated by THP-1 macrophages and monocytes. PCA plays its anti-inflammatory efficacy by two key mechanisms. Firstly, it decreases the generation of inflammatory mediators like IL-6. Secondly, it decreases the expression concentration of inflammatory proteins and genes via STAT3, MAPKs, and NFκB mechanisms. The findings indicate novel possibilities or directions for the treatment of inflammatory diseases involving osteoarthritis, skin inflammation, cardiovascular diseases, or colitis. PCA plays neuroprotective efficacy via its functions via antioxidant, antiapoptotic agent, or anti-inflammatory agent. It might be beneficial for the treatment of neurodegenerative diseases like AD or Parkinson’s disease (PD), chemical medicament (D-galactose), hypoxia-caused nerve damage, or trauma. Thereby, it might be beneficial as a functional food to advance reproduction of neurons, enhance memory as well as learning abilities of mice, and improve cognitive dysfunction (Ju et al. 2015). PCA performs broad-spectrum antibacterial capability to bacteria like Helicobacter pylori, Acinetobacter barramundi, Pseudomonas ceruminous, or Bacillus cereus. PCA similarly suppresses the food spoilage bacteria growth, therefore decreasing food contamination. PCA plays antibacterial efficacy via enhancing oxidative stress or healing bacterial illness via urease suppression or antioxidant capability. Further, it has no injurious efficacy with probiotic bacteria, and its antibacterial activity toward pathogenic bacteria is biocompatible. Moreover, the combination of antibiotics along with PCA increases the antibacterial effect of antibiotics, decreases antibiotic dose, and improves therapeutic capability of agents that cannot be utilized owning to resistance. It is able to suppress some obvious viral medicament involving hepatitis virus, influenza virus, avian influenza virus, or HIV. Study exhibits that the PCA antiviral pathway is chiefly associated with apoptosis advancement (Ou et al. 2018). Anticancer activity of PCA exhibits repressive efficacy with colon, liver, breast, ovarian, or lung cancer. The pathway of advancement of apoptosis is similar to concomitant reduction with tumor growth or cell proliferation. It is a black raspberry metabolite, which suppressed DNA production or mutation. It similarly suppressed esophageal cancer in mice caused by N-nitrosomethylbenzylamine (Peiffer et al. 2016). The primary pathway involved cytokine (e.g., IL-1β, IL-10, or IL-12) expression or innate immune cells recruitment in tumor tissue. The antiangiogenic capability of it might be beneficial toward the treating of solid malignancies. Osteoporosis is a bone illness that induces a decline in microstructural quality as well as bone density, which is usually associated with fragile fractures. PCA lessens osteoporosis in vivo as well as in vitro via a variety of pathways. PCA increases osteoblasts mineralization, differentiation, or proliferation via the regulation of transcription factors signaling mechanisms, cytokines, as well as OPG/receptor activator of nuclear factor kappa B ligand (RANKL), which are primary to osteoporosis pathogenesis (Fig. 3). PCA might similarly suppress the mature osteoclasts’ bone resorption or macrophage osteoclasts differentiation caused by RANKL in a

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Fig. 3 The pathway of PCA against osteoporosis (Song et al. 2020). (Reprinted with permission from Song et al. 2020. Copyright 2020, Elsevier B.V)

dosage-dependent way, then cause the mature osteoclasts apoptosis (Park et al. 2016). It also caused obvious repair of LPS-caused bone loss in rats. PCA might offer nicer therapeutic or protective efficacy for osteoporosis patients than unnatural product. PCA exhibits organ protection activity. PCA prevents hepatotoxicity or nephrotoxicity via its antihypertensive, antioxidant processes, as well as regulation of enzyme activity. PCA might become an alternative treatment method for nephrotoxicity as well as hepatotoxicity. It had preventive as well as dosage-dependent efficacy with hypothalamic/pituitary/testicular axis of adolescent-to-mature mice since it eliminates reproductive deficiency, improves redox balance and endocrine function, enhances the generation of sperm as well as testosterone, then improves functional characteristics of sperm. Thereby, it increases reproductive function, then generates antiretinal photooxidative efficacy involving preventing the function as well as structure of rabbit’s photoreceptor cells from light-caused injury (Wang et al. 2016). This activity might be due to the reduction of photo-oxidation-caused oxidative stress of retinal cells. PCA do influence toward central analgesia across the BBB, but its exact function pathway remains unknown. The central antinociceptive efficacy might be achieved via spinal cholinergic modulation, particularly via noradrenergic or opioidergic modulation. More obviously, a primary pathway might relate to analgesia modulation caused at the spinal cord (Dikmen et al. 2019). The analgesic efficacy of 300 mg/kg PCA was the same as 5 mg/kg cannabinoid receptor agonist WIN552122 and 300 mg/kg dipyrone. PCA may play anti-aging efficacy via its antioxidant liveness in several pieces of research with O2•, ONOO, or H2O2 scavenging. It is an effective component

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toward antiwrinkle cosmetics due to its potential to cause human dermal fibroblasts differentiation as well as type I collagen synthesis via skin explants (Shin et al. 2020). PCA similarly performs antidepressant and antiallergic, and owns a wide range of pharmacological processes. PCA is utilized in healthcare or skin care products to strengthen health status, slow skin aging along with prolonging life span.

Gentisic Acid Chemistry and Structure Gentisic acid (GA, 2,5-dihydroxybenzoic acid [2,5-DHBA]) with the molecular formula C7H6O4 and 154.12 g/mol molecular weight (Fig. 1) is a diphenolic chemical or a benzoic acid derivative with pKa ¼ 2.95 (Abedi et al. 2020). It is a natural product from the genus Gentiana or an ASA metabolite. Safety and Oral Delivery Mutagenicity or cytotoxicity tests of GA with Hepatoma Tissue Culture (HTC) cells were identified and suggested no antiproliferative or cytotoxicity processes with 0.08–8 μg/mL GA. GA exhibited no clastogenic or mutagenic efficacy, no obvious micronuclei induction was examined. Nevertheless, ≧8 μg/mL GA was mutagenic. GA mutagenic potential with mammalian cells was examined, and it was nonmutagenic at levels of 10–1000 μg/mL. With 500 mg/kg GA gavage in Mice, after approximately 15 min, abundant genistate was discovered in blood, the highest level appeared after 1 h GA absorption and after that decreased fast. The GA egestion in urine is high, then less than 1% of the medicine is egested via bowel. Results of histopathological assessment exhibited an obvious enhancement in glucose, alkaline phosphatase (ALP), protein egestion, alanine aminotransferase (ALT), N-acetyl-3glucosaminidase, aspartate aminotransferase (AST), or urine volume levels after 72 h. The proximal tubular reproduction is exhibited in the renal cortex. Therefore, GA is indicated as a nephrotoxic metabolite with EC50 ¼ 342.41 mg/kg acutepoisonous effect, more toxic than SA (McMahon et al. 1991). High levels GA is one of aldose reductase suppressors, levels that are not probably gainable through the meal. Cytochrome P-2E1 (CYP2E1) and CYP3A4 are relevant to GA metabolism. The metabolism of GA is inconsistent, several are egested unchanged, or several as conjugates at position 5 (sulfate or glucuronide) (McMahon et al. 1991). Functionality and Functional Food Applications As one of the DiO-labeled somatostatin analogs, GA along with ascorbic acid is utilized toward radio-labeled somatostatin-analogs vial to maintain high radio compound purity to enhance the transport or storage time. In desorption/ionization spectrophotometry, GA is widely utilized toward matrix-assisted laser desorption/ ionization (MALDI) with nice resolution as well as high sensitivity (Hill et al. 1991). GA has been exhibited to play a character as a free radical scavenger or antioxidant with different types of chemical or physical stimulus. It has two hydroxyl

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groups at para position, thereby being a more effective antioxidant than monohydroxy HBAs. Additionally, it is one of the nuclear factor erythroid 2-associated activators, the primary translocation factor that manages phase II antioxidant enzymes expression, this is the most probably related pathway. Oxidized low-density lipoprotein (LDL) has numerous potentially atherogenic efficacy. The repressive efficacy of GA toward LDL oxidation might be recognized for antiatherogenic efficacy. GA antioxidant capabilities are chiefly attributed to its chelating liveness, radical scavenging liveness, or redox potential. GA (100 μM) obviously improved these injuries to mitochondria membrane of liver, and it also obviously suppressed hemolysis with 75 Gray gamma radiation of human erythrocytes (Joshi et al. 2012). GA like ASA suppresses prostaglandin production, probably through suppressing COX liveness. It indicates that GA-rich foods might decline heart attacks possibility because of the clot production. GA similarly suppresses LDL oxidation and suppresses phospholipid hydroperoxides production, and thereby, declines the atherogenesis possibility. The GA efficacy is often attributed to the scavenge liveness for free radicals or other oxidants, and nevertheless, GA as one of the Nrf2 activators is the most probably related pathway (Tomás-Barberán and Clifford 2000). Various GA researches have been fulfilled and exhibited in Fig. 4. Its various efficacies are mainly attributed to its antioxidant capabilities. In one study, the repressive efficacy toward skin tumor in rats was identified with 2 or 4 μg/0.2 mL acetone solution of GA for 3 days, and GA obviously improved antioxidant enzymes concentration, then suppressed the tumor advancement (Sharma et al. 2004). In D. melanogaster larvae trans-heterozygous study indicated that via DNA-injury protection, replicate, or repair by mitomycin C (MMC), GA inhibited genotoxicity. The CDK suppressors might be beneficial toward cancer protection or treating. In the anomalous angiogenesis study (Dachineni et al. 2017), neutralization of fibroblast growth factors (FGFs) is of great medicinal interest. GA (36 μM) has exhibited halfmaximum repressive liveness to FGF via strong anions binding at the surface groove of FGF. This may define a novel class of FGF suppressors. GA (2, 4, 8, or 16 μg/mL) suppressed the C6 glioma DNA synthesis. Similarly, GA antitumor liveness in vivo was scored with solid tumors of Ehrlich breast ascites carcinoma in rats. Gavage of 0.4 mg GA per day for 3 weeks decreased 33% Ehrlich ascites tumor-bearing rats mortality (Altinoz et al. 2018). GA exhibited an efficient preventive efficacy toward hepatotoxicity as well as genotoxicity caused by cyclophosphamide in rats. Fourteen days oral administration of 50 or 100 mg/kg GA obviously decreased micronuclei, malondialdehyde production, as well as fragmentation of DNA, enhanced GSH concentration, or improved antioxidant enzyme processes. After treating with cyclophosphamide enzymes of blood toxicity marker involving lactate dehydrogenase (LDH), ALT, as well as AST were enhanced, but GA pretreated groups decreased. It has the potential for progress or design of chemo-medicinal medicament that decreases the adverse effects with cyclophosphamide; it may suppress hOAT3, one of the organic anion transporters for egestion of several endogenous agents involving antiviral, anticancer, or antibiotics

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Fig. 4 Schematic description of GA pharmacological efficacy (Abedi et al. 2020). (Reprinted with permission from Abedi et al. 2020. Copyright 2019, John Wiley and Sons)

agent. GA may reverse OAT-mediated nephrotoxicity agents (Wang and Sweet 2012). The useful GA efficacy toward the rat model of cardiac hypertrophy or fibrosis was examined, and it altered cardiac hypertrophy and improved posterior wall thickness as well as ventricular septum. GA downregulates ERK1/2 signaling or expression of Sp1/GATA4, then exhibited antifibrotic or antihypertrophic efficacy. It similarly protects the progress of heart failure. Twenty-one days of oral administration of 10 or 100 mg/kg GA per day suppressed cardiac dysfunction and declined cardiac fibrosis as well as hypertrophy in heart failure model with dose-dependently. It similarly decreased lung size or remodeling of pulmonary vascular, triggering a reduction in lactic acidosis (Sun et al. 2019). The neuroprotective activity of GA toward PD was scored, and oral administration pretreating with 225 or 450 mg/kg GA triggered an important reduction toward haloperidol caused cataleptic behavior duration. It exhibited dosage dependently neuroprotective liveness toward different PD models in vivo.

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GA can suppress the accumulation of melanin, the methyl ester suppressed melanin synthesis in melanosomes of murine melanocytes cell assay by decreasing the synthesis or liveness of tyrosinase without any cytotoxicity. GA was identified as one of skin lightening agents candidate (Hosoi et al. 1985). GA may also play a character as one of the muscle relaxants. One study suggested that GA caused the relaxation of the guinea pig isolated trachea with EC50 ¼ 18 or 20 μM (Cunha et al. 2001). Due to some useful efficacy along with no side effects toward daily consumption of diet, GA has the potential to do duty for one of the food supplements.

3,5-Dihydroxybenzoic Acid Chemistry and Structure 3,5-dihydroxybenzoic acid (3,5-DHBA) with the molecular formula C7H6O4 and 154.12 g/mol molecular weight (Fig. 1) is one of the pro-neurogenic chemicals discovered in flesh of apple. Bioeffective factors discovered in apples directly influence hippocampal neurogenesis on the adult rat. 3,5-DHBA are poly-HBAs discovered in numerous natural products, like fruits, berries, or coffee (Ichwan et al. 2021). Safety and Oral Delivery 3,5-HBA are natural products belonging to the class of compounds generally recognized as safe. Since such substances may usually be orally administered in animals or humans at very high doses without obvious side effects (Liu et al. 2012). Functionality and Functional Food Applications Numerous bioeffective compounds are structurally associated with 3,5-DHBA, and several of them can bind to HCA2 receptor, while 3,5-DHBA can specifically and weakly bind to HCAR1. HCAR1 is one of Gi-coupled receptors, which can suppress adenylate cyclase to decrease cyclic adenosine monophosphate (cAMP) production after activation. 3,5-DHBA exhibits higher efficacy than lactate to decline cAMP concentration in SK-N-MC cell lines or hippocampal slices. Moreover, 3,5-DHBA also can arouse p90RSK, MEK1/2, or ERK1/2 phosphorylation in muscle myotubes (Ohno et al. 2018). 3,5-DHBA can influence synaptic signaling, energy metabolism, or ion homeostasis in hippocampal neurons. 3,5-DHBA can not only enhance neurogenesis or proliferation of NPC but also enhance the newborn cells’ maturation rate by the most efficient dosage with 62.5 mg/kg. It is proneurogenic, which obviously enhanced neurogenesis or the proliferation of neural precursor cells, not only via activating precursor cell proliferation but also by neuronal differentiation, promoting cell-cycle exit, or cellular survival. Among 2,3-DHBA, PCA, or 3,5-DHBA, 3,5-DHBA has the greatest efficacy (Ichwan et al. 2021). 3,5-DHBA is one of the HCA1 (EC50 ¼ 150 μM) and HCA2 (EC50 ¼ 172 μM) specific receptors agonist. Activation of HCA1 and HCA2 suppresses lipolysis in adipocytes, and altering diet to 3,5-DHBA might contribute to dyslipidemia management (Fig. 5).

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Fig. 5 Apple peel and flesh contain pro-neurogenic chemicals 3,5-DHBA (Ichwan et al. 2021). (Reprinted with permission from Ichwan et al. 2021. Copyright 2021, Elsevier B.V)

Pyrocatechuic Acid Chemistry and Structure Pyrocatechuic acid (2,3-dihydroxybenzoic acid, 2,3-DHBA) with the molecular formula C7H6O4 and molecular weight 154.12 g/mol (Fig. 1) is one of the aspirin metabolites. It normally exists in the blood even though there is no ASA intake, suggesting one of the food sources of either 2,3-DHBA or precursor compounds. 2,3-DHBA exists in some therapeutic herbs, involving Boreava orientalis or Madagascar rosy periwinkle, as same as in some fruits like cranberries, Satoko plum, or avocados. The major food source of 2,3-DHBA is the popular Aspergillus-fermented soy products in Japan, which may have more than 2 mmol/L 2,3-DHBA (Juurlink et al. 2014). Safety and Oral Delivery Cytotoxicity assays in HCT-116 cells exhibited that the IC50 for 2,3-DHBA was ~1.8 mM (Dachineni et al. 2017). Approximately 50% ASA is left in the GI lumen uningested after oral administration. The microflora that existed in the GI lumen might produce 2,3-DHBA and 2,5-DHBA from SA/aspirin, which is competent to induce cell proliferation suppression, then ASA can exert locally toward colorectal tumor (Sankaranarayanan et al. 2020). Functionality and Functional Food Applications ASA or SA metabolite 2,3-DHBA is produced via catalyzation of CYP450 in the CRC protection reactions in vivo. 2,3-DHBA can suppress cyclin-dependent kinase

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1 (CDK1) liveness in vitro (Dachineni et al. 2017). Dysregulated cell cycle is known to be one of the cancer hallmarks, and 500 μM 2,3-DHBA can suppress liveness of CDK-1 enzyme, whereas liveness suppression toward CDK2 or CDK4 should be with higher 2,3-DHBA levels more than 750 μM. 2,3-DHBA suppressed liveness of CDK6 enzyme beginning at 250 μM. 2,3-DHBA might promote the ASA chemopreventive capabilities via CDKs suppression (Sankaranarayanan et al. 2020). 2,3-DHBA declines NFκB activation caused by hydrogen peroxide, which performs a significant character toward inflammation. The function pathway for 2,3-DHBA efficacy might be hydrogen peroxide scavenging or possible antioxidant response activation. SA, pHBA, 3-HBA, acetylsalicylic acid, p-HBA methyl or propyl esters, 2,3-DHBA, 2,4-DHBA, 2,5-DHBA, 2,6-DHBA, 3,5-DHBA, PCA, and GA have tested by UV/VIS spectroscopy method, the best activity to scavenge peroxynitrite are observed to be GA, 2,4-DHBA, ad 3,5-DHBA (Hubková et al. 2014).

Vanillic Acid Chemistry and Structure Vanillic acid (VA) with the molecular formula C8H8O4 and 168.15 g/mol molecular weight (Fig. 1) is an oxidized form of vanillin. It is a pHBA substituted by a methoxy group at position 3. VA is the major chemical of extracts of the vanilla bean or pod, has a solid, melting point of 211.5  C, and solubility of 1.5 mg/mL at 14  C. VA is the intermediate chemical after bioconversion of ferulic acid to vanillin. VA is similarly generated when caffeic acid gets metabolized. It has a pleasant as well as creamy odor thereby commonly used as one of the flavoring agents in foods, cosmetics, or agents. VA is obtained from some cereals like whole grains, herbs, fruits, green tea, juices, beers, wines, as well as Chinese medicine for decades (Salau et al. 2020). Safety and Oral Delivery VA (1000 mg/kg, b.w.) is safe in a study of subacute poisonous efficacy, exhibited no side effect toward the process of erythropoiesis, leukopoiesis, or toward internal organs via gross necropsy, biochemical or hematological assessments, as well as histopathological researches. The blood sodium decline is not recognized as a side effect. It is reported as one of the metabolic products from PCA, 4-hydroxy-3methoxyphenylglycol, or 4-hydroxy-3-methoxymandelic acid, which is stable in urine with alkaline pH. The LD50 value of VA is reported to be 5020 mg/kg i.p. with mice or 2691 mg/kg i.p. with big rats (Mirza and Panchal 2020). Functionality and Functional Food Applications VA may be utilized as a promising, accessible, and new component of functional food or as one of the dietary supplements. VA was examined to have antidiabetic ability and is cardioprotective. Additionally, VA ameliorates glomerulonephritis. VA was reported to suppress snake venom 50 -nucleotides or carbonic anhydrase isozyme

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III. VA manages the expression of the transgene in mammalian cells or rats. VA exhibited a preventive efficacy with liver toxicity or ulcerative colitis. Moreover, it performs as an antifilarial agent or respiratory stimulant (Mirza and Panchal 2020). Although VA is utilized as one of the commonly utilized Chinese medicine herbs: Dong Quai (Angelica sinensis). Dong Quai has been utilized for thousands of years toward the treatment of menstrual disease, cerebrovascular illnesses, cardiovascular illnesses, or cognitive impairments. Recently, a useful efficacy against depression has been noted in preclinical researches. While researchers have reported that VA has neuroprotective efficacy in addition to analgesic, antioxidant, anti-inflammatory benefits toward nuclear factor-kappa B activation, proinflammatory cytokine generation, oxidative stress, or acetylcholinesterase. Additionally, the neuroprotective efficacy of VA has been indicated to be mediated via Akt or ERK signaling activation. Co-treating of VA along with levodopa-carbidopa (100 mg/kg þ 25 mg/kg, p.o.) leads to an obvious reduction in muscle rigidity or catalepsy as well as an obvious enhancement in body weight, rearing behavior, locomotion as well as muscle activity, exhibiting highest anti-Parkinson’s efficacy at 50 mg/kg dosage. Eosinophilic lesions were discovered to be very less in the VA co-treated group. It obviously prevented the brain from neuronal injury because of oxidative stress, then attenuated the motor deficiency (Sharma et al. 2021). VA has the potential to attenuate Aβ1–42 caused oxidative stress as well as cognitive impairment, thereby contributing to treating AD. VA is discovered in abundance in Black sesame pigment which is utilized as one of the dietary supplements for the protection of AD. VA is known to selectively and specifically suppress 50 -nucleotidase activity. VA has character toward neurological upsets. It attenuates β-amyloid in oxidative stress-triggered AD model. In Fig. 6, VA exhibited antidepressant efficacy via a decreasing behavioral despair in the forced swim test (FST). The immunochemical

Fig. 6 Schematic diagram exhibiting VA antidepressant efficacy with AMPARAkt  mTOR signaling transduction (Chuang et al. 2020). (Reprinted with permission from Chuang et al. 2020. Copyright 2020, American Chemical Society)

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results suggested that the VA antidepressant efficacy depends on the AMPARAkt  mTOR signaling transduction mechanism (Chuang et al. 2020). VA might attenuate reactive hyperemia along with strengthening BBB disruption following bilateral occlusion of the common carotid arteries or reperfusion, and then might increase neurological levels of anxiety-like behaviors in this model of cerebral hypoperfusion. These results indicate that VA might be a promising pretreating agent in cerebral hypoperfusion or an accessible neuroprotective agent toward deleterious neurodegenerative illnesses. Two weeks of 100 mg/kg VA pretreating before 30 min bilateral common carotid artery occlusion led to decreased infarct size in mice. Lower dosage with 10 mg/kg VA attenuated oxidative stress in isolated rat hearts exposed to cardiac ischemic damage (Morin et al. 2021). VA is utilized to cure the bone or joint illness Sambucus williamsii Hance in China for thousands of years. VA was examined to have substantial stimulation toward proliferation, ALP functions which simultaneously transformed the mRNA expression of genes that are relevant with osteoblast functions or osteoclastogenesis in UMR 106 cells (Xiao et al. 2014). High-fat diet (HFD) rats model triggered with VA exhibited indicatively attenuated body weight. The CCAAT/enhancer-binding protein α (C/EBPα) get declined, whereas the concentration of AMPKα increased in the white adipose tissue. VA has the potential to activate the AMPKα to play a character as a thermogenesis chemical toward treatment of obesity. Treating diabetic mice with gavage of VA at a dosage of 50 mg kg/body weight for 8 weeks resulted in an obvious decline in fasting blood glucose, insulin, or serum pressure concentration in comparison with the diabetic control group. VA provides a regulatory efficacy toward obesity-associated diabetic hypertension management via activation of tissue antioxidants (Jung et al. 2018). VA has the potential to prevent benzo pyrene-triggered lung cancer. VA has been utilized at a dosage of 200 mg/kg as well as benzo pyrene. It was examined that when VA is given to the rats as well as illness-inducing agent, an obvious recovery from the illness was there; orally administrated with 25 or 50 mg/kg body weight VA dosage for 4 weeks, VA was reported to have the anti-asthmatic ability (Bai et al. 2019).

Syringic Acid Chemistry and Structure Syringic acid (SRA, 4-hydroxy-3,5-dimethoxybenzoic acid) with the molecular formula C9H10O5 and molecular weight 198.17 g/mol (Fig. 1) is known as phytochemical, one of the bioeffective or poorly soluble HBAs, facilitates oxidation, polymerization, or condensation reactions, has important capabilities toward different areas such as therapeutic chemistry and pulp industries. SRA exists in numerous edible plants like grapes, olives, dates, cinnamon, pumpkin, red wine, honey, acai palm, or sesame. SRA comes from polyphenols or also known as flavonoids. SRA

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occurs more rarely compared to the corresponding sinapic acid. Free HBAs may result from hydrolysis of flavonoids like anthocyanins or hydroxy benzylglucosinolates with alkali or nonspecific enzymes (Sun et al. 2021).

Safety and Oral Delivery The lipophilicity of SRA coupled with the rapid egestion in vivo results in low bioavailability along with poor medicinal efficacy. SRA-loaded liposome (SRA-TPGS-Ls) was synthesized to increase SRA oral bioavailability. SRATPGS-Ls are synthesized through the method of thin-film dispersion, and SRATPGS-Ls are regular spherical nanoparticles with 96.48% EE. Pharmacokinetic tests exhibited a prolonged MRT and t1/2, and SRA bioavailability of oral administration was enhanced about 2.8 times. Biodistribution exhibited that SRA-TPGSLs maintained high liver medicine levels and slow metabolism in the kidney. In hepatotoxicity test triggered by CCl4, levels of CAT, GSH, hepatic T-AOC, SOD, or GSH-Px were significantly increased, whereas biological markers of blood AKP, ALT, or AST decreased after treating rats with SRA-TPGS-Ls. Histopathological tests identified that SRA-TPGS-Ls might significantly strengthen hepatic tissue status (Sun et al. 2021). After oral administration, the self-micro emulsifying medicine delivery system (SMEDDS) was diluted with GI fluids, then formed nanosized particles, which contributed to the medicine absorption due to larger interfacial surface area. Besides, the lipid in the SMEDDS might increase lymphatic transport and avoid the first-pass metabolism, therefore SRA bioavailability increased. In comparison with the SRA suspension, nanosized (16.38 nm) SRA-SMEDDS exhibited obvious prolonged Tmax, t1/2, or MRT after oral administration. Similarly, SRA-SMEDDS showed a slow in vivo metabolism, enhanced bioavailability (2.1-fold), and then increased liver accumulation (Sun et al. 2021). Functionality and Functional Food Applications SRA metal complexes have nicer biological adhibitions than SRA. Metal complexes antioxidant or antimicrobial processes were studied with molecular docking. Syringic complex with Fe3+ is discovered to have nicer antioxidant ability than the complex with Fe2+ along with SRA, while Fe2+ complex has nicer anti-bacterial ability than the Fe3+ complex (Kumar et al. 2021). SRA is known to own various capabilities like anti-hypertensive, antiangiogenic, anti-endotoxic, anti-hyperglycemic, antithrombotic ability, or chemopreventive toward skin cancer (Liu et al. 2019). In clinical practice, SRA has been utilized for the synthesis of dental cement or employed toward the treatment of bronchitis, along with hepatoprotective or neuroprotective processes in preclinical studies. More obviously, SRA owns positive efficacy with hyperlipidemia or NAFLD. SRA might decrease lipogenic genes, then increase fatty acid oxidation genes in HFD-triggered obese rats (John and Arockiasamy 2020).

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The SRA cytotoxic toward human hepatoma (HepG2) cell line was scored. SRA treatment triggered obvious cytotoxicity along with ROS liberation in HepG2 cells. Dye staining exhibited membrane distortion or blebbing toward SRA-treated cells. Apoptotic markers like expressions of caspases 3 or 9, cytochrome c, Bax, Apaf-1, or p53 gene were increased, suggesting the apoptosis induction probability toward HepG2 cells. The treatment triggered an obvious Bcl-2 gene expression decrease. SRA is cytotoxic with human HepG2 cell line, and this might be one of the promising agents toward anticancer treatment (Gheena and Ezhilarasan 2019). Isoproterenol (ISO) triggered myocardial injury was averted via SRA pre-cotreating. In Fig. 7, SRA was given orally to mice for 3 weeks at three levels (12.5, 25, or 50 mg/kg), the decline was discovered in the blood of marker enzymes (AST, ALT, LDH, CKMB) concentration, phospholipid peroxidation, proinflammatory cytokines (TNFα, IL 6), or protein carbonyl (PC). Moreover, GSH content along with antioxidant enzymes processes in the heart was raised. Enhancement in erythrocyte, as well as infarct size morphology, was examined. The SRA cardioprotective potential in the ISO rats model triggered by myocardial infarction (MI) might be attributed to endogenous antioxidant or anti-phospholipid peroxidative increase efficacy (Shahzad et al. 2019).

Fig. 7 Schematic diagram exhibiting prevention offered by syringic acid toward ISO triggered MI (Shahzad et al. 2019). (Reprinted with permission from Shahzad et al. 2019. Copyright 2019, Elsevier B.V.)

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Gallic Acid Chemistry and Structure As presented in Fig. 1, gallic acid (GA), known as 3,4,5-trihydroxy benzoic acid with the molecular formula C7H6O5 and 170.12 g/mol molecular weight, along with –OH groups at positions 3, 4, and 5. GA is a light yellow solid chemical with 235  C–240  C decomposition temperature to produce carbon monoxide or carbon dioxide. At 20  C, pKa and log P of GA are 4.40 and 0.70, respectively. GA can dissolve in ether, water, glycerol, or alcohol, and cannot dissolve in chloroform, ether petroleum, or benzene. It is one of the naturally appearing secondary metabolites discovered in a variety of plants, vegetables, nuts, fruits, or herbal medicines (Yang et al. 2020). Researches of GA structure have exhibited that it may play a character as an antioxidant because of the existence of –OH groups. Para-substituted -OH group was discovered to be highly active for radical scavenging, –OH influence antioxidant activity via intramolecular hydrogen bonding. The plenty of natural GA availability and its significant bioeffect contribute to its applications toward novel pharmacophores designing (Bai et al. 2021). Safety and Oral Delivery GA (200 μM) had no cytotoxic efficacy with HepG2 cells, but faintly cytotoxic to RAW 264.7 or B16F10 cells at levels greater than 200 μM. 210 mg/kg dosage of GA had no side effects with rats. The acute-poisonous effect of GA toward albino rats exhibited that the GA LD50 value is higher than 2000 mg/kg. Results suggested that it is efficient and safe at lower levels, and the GA in vivo toxicity is relatively low (Bai et al. 2021). After GA oral administration, the ingestion and metabolism are fast, and 70% of GA is absorbed after that about 16.67% intake was egested in unchanged form. Its key metabolite in human urine or blood is 4-O-Methygallic acid. Figure 8 exhibits that GA in vivo was chiefly distributed in the kidney, the lung contained the second maximum content, the level in the heart or liver was faintly lower than lung, and spleen had the lowest GA (Yang et al. 2020). To increase the GA efficiency and bioavailability by oral delivery, different amphipathic GA alkyl esters or phospholipid systems have been reported to enhance intestinal ingestion and exhibit nicer efficacy than GA. For instance, LF-GA-LIP as GA–lipid liposomes with lactoferrin decoration increased bioavailability via ingestion increase, blood function duration lengthening, and metabolism rate reduction. This might be exploited as one of the favorable delivery systems since it performed a slow-release efficacy in oral delivery, which is attributed to the amphipathic feature of lipid systems (Zhang et al. 2019b). Functionality and Functional Food Applications Ch-ZnO@gal nanoparticles have been synthesized by zinc oxide loaded with chitosan and GA, aiming for application as environment-friendly food packaging material. The incorporation of ZnO@gal into chitosan films significantly increased

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Fig. 8 The ingestion, metabolism, biodistribution of GA. H, M, or L mean high, middle, or low GA distribution, respectively (Yang et al. 2020). (Reprinted with permission from Yang et al. 2020. Copyright 2020, under the terms of the Creative Commons Attribution License (CC BY). Correspondence: Yulong Yin, [email protected]; Baichuan Deng, [email protected])

the desired mechanical capability of the chitosan films, showing an obvious antibacterial potential or strong antioxidant behavior (Yadav et al. 2021). Gallic acid has broad-spectrum medicinal capabilities in vitro involving antifungal, antiviral, or antibacterial processes. It can efficiently inhibit biofilm production of Escherichia coli, Shigella flexneri, and Staphylococcus aureus, or bacteria metabolism via modulation toward the expression of OpgH protein, pgaABCD gene, mdoH gene, or ica operon (Kang et al. 2018). Almost all mucosal lesions or Gastric cancer (GC) are associated with H. pylori. Via inhibiting H. pylori, offering antioxidant prevention, and blocking the function of H+, K+-ATPase, GA, and cinnamic acid from ginger extract might prevent the gastric mucosal lesions. Moreover, GA not only has efficient antibacterial ability but also against Eumycetes. GA also has high medicinal efficacy with gastric mucosal cell injury triggered by NSAID via oxidative stress reduction or mitochondrial apoptosis activation suppressing. Inflammatory bowel disease (IBD) like ulcerative colitis or Crohn’s disease relates to the abnormal host reaction to gut microbiota (GM). One of the pilot studies toward IBD patients discovered gallotannins along with GA intake from mango pulp remarkably enhanced the plenty of probiotics, which was accompanied via enhanced fecal

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butyric acid generation. The further nuclear magnetic resonance analysis for metabolites identification proved GA triggered metabolism enhancement of bile acid or carbohydrate and reduction of amino acid (Yang et al. 2020). GA can cause cancer cell apoptosis selectively without toxicity to human healthy cells. GA can decline the viability of colon cancer cells via cell proliferation inhibiting, signaling mechanisms modulating with OCT-1, AP-1, NFκB, or STAT-1. Moreover, GA can be antimetastatic and suppress gastric adenocarcinoma cancer metastasis, and the efficacy might work via transcriptional factor NFκB or Ras/PI3K/ AKT signaling repression (Yang et al. 2020). The anti-inflammatory pathways of GA chiefly involved NFκB or MAPK signaling mechanisms. Therefore, it weakens the inflammatory response via decreasing inflammatory chemokines, cytokines, adhesion compound release, or cell infiltration (Bai et al. 2021). Mice were administrated with 15 mg/kg manganese only or 30 mg/kg x-3-FA along with 20 mg/kg GA continuously for 2 weeks. GA or x-3FA co-treating inhibited manganese-mediated enhancements in the hepatorenal toxicity biomarkers, and biochemical data toward hepatorenal prevention were proved. GA or x-3-FA ameliorated manganese-triggered hepatorenal toxicity via decreasing the oxidative/inflammatory stress, and maintained tissue integrity in mice. Thereby, food supplements with GA or fish oil, which is rich in x-3FA, may do duty for nutriceutical presently available as prescriptive/non-prescriptive food supplements. GA can accelerate differentiation of T cells, and enhance Treg numbers to play anti-inflammatory efficacy, which has the feasibility to cure illnesses triggered via excessive immune cells activation. It might decline the tissue aggravated reaction via decreasing LPS. Figure 9 exhibits GA showed a preventive efficacy toward cellular

Fig. 9 The possible GA function pathway with the remission of immune-associated illnesses. The red box means animals with immune-associated upsets, the green box suggests the attenuation efficacy of GA with immune-associated upsets (Yang et al. 2020). (Reprinted with permission from Yang et al. 2020. Copyright 2020, under the terms of the Creative Commons Attribution License (CC BY). Correspondence: Yulong Yin, [email protected]; Baichuan Deng, [email protected])

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damage triggered by ROS in lymphocytes via immunomodulatory (binding with receptors like IL-4, IL-6, or INFα-2), cytoprotective capabilities, or antioxidant, offered efficient protection. Moreover, it suppressed nitric oxide or ROS generation, lymphocyte proliferation triggered by phagocytes, or proinflammatory cytokine release in blood cells (Yang et al. 2020). The synergistic efficacy of GA and asparaginase increased the antiproliferative efficacy on lymphoblastic cells. GA might increase immunomodulatory ability via increasing phagocytic capability, lysosomal volume, nitrite release, or intracellular calcium concentration in macrophages, downregulating the MAPK-linked phagocytic signaling mechanism in rat murine macrophages (Reyes et al. 2018).

Ellagic Acid Chemistry and Structure Ellagic acid (EA), one of the dimeric derivatives of GA, arises from acidic hydrolysis of ellagitannins with the molecular formula C14H6O8 and 302.19 g/mol molecular weight (Fig. 1), occurs as an odorless yellow powder, incompatible with hypoglycemic medicament. It is a planar compound that contains four –OH along with two lactone groups that show amphiphilic character. This dietary polyphenol is discovered in a wide variety of fruits. Raspberries, cranberries, strawberries, and grapes, as same as pomegranate seeds, are known for instance for their high content of EA. Sparing water solubility (9.7 μg/mL, 37  C) of EA enhances with pH, as same as the antioxidant function. In basic solutions, phenolic chemicals lack stability. With ionic form, these compounds undergo extensive transformations or are converted to quinones after oxidation. A stability test exhibited that EA content declines in a few weeks because of hydrolysis, suggesting that it should not be reserved in the enhydrous medium. EA has relatively high electron density with electron-donating groups, bestowing it to partake in π–π or hydrogen bonding interactions. It is fully or partially ionized, suggesting that all phenolic groups can deprotonate, two acidity pKa values were detected as 5.42 or 6.76 (Evtyugin et al. 2020). Safety and Oral Delivery Many factors may affect the bioavailability of EA, such as low aqueous solubility, limited intestinal ingestion, hydrolysis in vivo, EA precursor, catabolism by GM, and generation of urolithins (UROs). UROs are easily ingested, will disseminate in blood, then reach tissues or cells. Whereas, even by a higher EA-enriched products intake, in place of increasing EA level that of UROs will be enhanced, EA level cannot exceed 100 nM in blood. The individual variability in the responses to variable types and concentrations of UROs might cause side effects like cardiovascular upsets. Moreover, high level of UROs might induce apoptosis or DNA injury, leading to the progress of OS-associated pathologies like cancer. Therefore,

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commercialization of EA-enriched products should be subject to more careful modulation or management. An unmanaged large generation or distribution of EA-enriched foods, dietary supplements, reflects an outstanding problem, which might have heavy passive repercussions toward human health rather than active (Alfei et al. 2020). A variety of EA delivery methods have been exploited to increase EA bioavailability, such as for were. Studies mitigate EA’s bioavailability limitations or in the progress of. To increase the bioavailability and maximize its ability, efforts have been made to exploit a delivery system with a chitosan polymer in collagen, composite films, nanocapsules, or chitosan-based scaffolds to bolster EA adhibitions in nutraceuticals or functional foods (Shaik and Kowshik 2019).

Functionality and Functional Food Applications EA and ET’s scientific relevance is linked to materials like chelating medicament, electrochemical materials, copolymers, or ion-exchange resins. Because of its distinct structural and chemical characters, EA is proved to be applied as prospective bioengineered materials. Moreover, the synthesis of some potential EA-based polymer precursors provides novel options for polymer adhibitions. For example, through the EA assembling via hydrogen bonding or π-π interaction, EA is exploited as conductivity or fluorescence-based probes. Its conductivity selectively changes in the existence of nitrobenzene, suggesting the potential for the explosive compounds sensing. Another interesting EA adhibition is for pigmentation toward enhancing wine’s color (Zhang et al. 2018). It might be developed to protect against degenerative illnesses or chronic such as nervous system upsets, diabetes, or cardiovascular illnesses. It has been indicated that EA owns immunomodulatory efficacy in vivo via injuring T-cell function or inhibiting humoral immunity. The EA multifaceted bioeffect pathways depend chiefly on its anti-aging liveness or antioxidant power toward detrimental ROS. EA owns antiangiogenic, antithrombotic, antiatherogenic, as same as the capability to protect fever, ulcerative colitis, pain, obesity, hyperlipidemia, anti-inflammatory, antimutagenic, anti-aging, or antifibrosis capabilities (Baradaran Rahimi et al. 2020). EA applies its anticancer influences via its proapoptotic processes, antiproliferative, or function in subcellular signaling mechanisms. In breast cancer, two receptor mechanisms are proved: tyrosine kinase or estrogen receptors, particularly the epidermal growth factor receptors. EA not just interfaces or adjusts the impacts of these mechanisms, but also initiates the cell death via influencing kinase signaling in vitro or in vivo. The EA and pemetrexed combinational treatment toward breast cancer study shows EA can be recognized as one of the efficient chemo protectives as well as medicinal agents. Similarly, EA has a great activity to sensitize resistant tumor cells to medicinal medicament, via the suppression of P-glycoprotein efflux pumps, therefore increasing the efficiency of the dual medicine combination, then minimizing the appearance of multi-medicine resistance. EA enhanced the deacetylase ability of SIRT6 by up to 50-folds. It exhibited moderate suppression of SIRT1–3. Galloflavin and EA exhibited antiproliferative efficacy

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with human colon adenocarcinoma cells (Caco2). The chemicals increased SIRT6 expression while primary proteins in glycolysis were decreased. Galloflavin declined glucose transporter 1 (GLUT1) expression, EA influenced the expression of protein dehydrogenase kinase 1 (PDK1). Both Galloflavin and EA were able to form hydrogen bonds with Asp188 or Gly6 in SIRT6. EA enhanced SIRT6 ability, declined the PDK1 levels, and decreased glucose uptake or lactate generation. Taken together, Galloflavin and EA targeting SIRT6 liveness offer one of the novel insights toward the progress of anticancer treatment method (Rahnasto-Rilla et al. 2020). Animal researches have exhibited its preventive efficacy toward hepatotoxicity triggered by carbon tetrachloride, paracetamol, or cisplatin. Valproic acid is one of the commonly utilized medicines for epilepsy. The research examined the hepatoprotective efficacy of EA toward valproic acid-triggered hepatotoxicity in mice. EA (60 mg/kg/day, p.o.) was treated for one week, followed by a concomitant injection of valproic acid (250 mg/kg/day, i.p.) for another 14 consecutive days. Histopathological examination confirmed that treating with EA markedly attenuated valproic acid-triggered hepatic damage in mice (Evtyugin et al. 2020). EA regulates the inflammatory process via decreasing the inflammatory cytochemokines involving IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-12, IL-13, IL-17, IL-18, NFκB, TNFα, or as same as promoting the anti-inflammatory receptors or biomarker like IL-10, PPAR-α, PPAR-γ, or Nrf2. Moreover, EA might offer anticancer ability through increasing the apoptotic protein-associated mechanisms involving cyt-c, p53, GSK-3β, caspase 3, caspase 8, caspase 9, Bax, Nrf2, PARP cleavage, or Bax/Bcl-2 ratio, which cause cytotoxicity, S as well as G1-phases cell cycle inhibition. There are numerous research which exhibited that EA can play anticancer efficacy via reducing the cell proliferation level, such as COX-2, JAK2, PI3K, mTOR, NFκB, Bcl-2, MAPK, or MMP signaling mechanisms (Evtyugin et al. 2020).

Conclusion This chapter discusses the comprehensive list of HBAs, which have healthpromoting effects in humans worldwide. A few HBAs are well-known as bioeffective dietary components, but their multifaceted bioactivity depends chiefly on their redox potential and radical scavenging ability with minimal chelating activity. HBAs promote the overall health benefits primarily by virtue of their antioxidant, anti-inflammatory, antimicrobial, antimutagenic, hypoglycemic, or antiplatelet aggregating processes, as same as by the protection of stroke, cancer, or cardiovascular diseases. Nevertheless, their physiological efficacy toward the human body is still a subject of detailed investigation. Thereby, to make the full use of the health benefits of HBAs, awareness regarding the same will increase the overall well-being of the consumer. The findings overall provide competent evidence to support that each of the identified HBAs, via their dietary supplementation, might play health protective efficacy toward a wide range of pathogenic conditions.

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Hydroxycinnamic Acids Nicoleta-Gabriela Ha˘da˘ruga˘ and Daniel-Ioan Ha˘da˘ruga˘

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62 Chemistry and Functionality of Hydroxycinnamic Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63 Biosynthetic Pathways of Hydroxycinnamic Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70 Occurrence, Separation, Analysis, and Applications as Food Ingredients of Specific Hydroxycinnamic Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 Cinnamic Acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76 p-Coumaric Acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76 Caffeic Acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82 Ferulic and Sinapic Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82 Chlorogenic Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90 Rosmarinic, Chicoric, p-Coutaric, Caftaric, Fertaric Acids, and Other Minor Hydroxycinnamic Acid Derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99 Conclusion and Future Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104

Abstract

The “Hydroxycinnamic Acids” chapter focuses on the occurrence, separation, properties, food, and other applications of the main antioxidant compounds from this chemical class. An up-to-date review on the cinnamic acid as the reference compound, as well as on p-coumaric, caffeic, ferulic, sinapic, chlorogenic, and rosmarinic acids was presented. The recent identified hydroxycinnamic acid

N.-G. Hădărugă (*) Department of Food Science, Banat’s University of Agricultural Sciences and Veterinary Medicine “King Michael I of Romania”, Timişoara, Romania e-mail: [email protected] D.-I. Hădărugă Department of Applied Chemistry, Organic and Natural Compounds Engineering, Polytechnic University of Timişoara, Timişoara, Romania e-mail: [email protected] © Springer Nature Switzerland AG 2023 S. M. Jafari et al. (eds.), Handbook of Food Bioactive Ingredients, https://doi.org/10.1007/978-3-031-28109-9_3

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derivatives were also highlighted. A comprehensive biosynthetic approach for the above-mentioned hydroxycinnamic acids was discussed. An important part of this chapter was dedicated to the food applications of these antioxidants and the corresponding extracts as well as their interactions with other ingredients from food matrices. Cinnamic acid has no antioxidant activity, but it was investigated, together with cinnamaldehyde, as antimicrobial and preservative in food nanoemulsions and products. Many food applications were found for simple hydroxycinnamic acids and their derivatives. p-Coumaric, caffeic, ferulic, and sinapic acids were discussed in relation with their interactions with food biomacromolecules (proteins and oligo- and polysaccharides), antioxidant properties against degradation of some vegetable and food constituents such as anthocyanins, and even covalent binding to food biopolymers for novel ingredients and functional foods. Biotechnological aspects related to enhancing the hydroxycinnamic acid production and optimized extraction techniques were also investigated. These aspects were considered for hydroxycinnamic acid esters, such as mono- and di-p-coumaroyl/caffeoyl/feruloyl/sinapoylquinic acids, and the corresponding mixed esters, known as chlorogenic acids, rosmarinic, chicoric, or aldaric acids. Chlorogenic and rosmarinic acids are valuable natural antioxidants with many food applications even through the natural sources such as green coffee beans and rosemary, or concentrated formulations. Generally, chlorogenic and rosmarinic acids-based extracts, obtained by optimized production and extraction from various sources, are used. Finally, a comprehensive conclusion and future perspectives point out the main directions on hydroxycinnamic acids research and applications are presented. Keywords

Hydroxycinnamic acid derivatives · Natural food antioxidants · p-Coumaric acid · Caffeic acid · Ferulic acid · Sinapic acid · Chlorogenic acids · Rosmarinic acid Abbreviations 1

H/13C-NMR 4CL ABTS
+ AFM BHA BSA C3’H CD CE CG-CTA CoA COA-H

1

H/13C-nuclear magnetic resonance 4-coumarate:CoA ligase 2,20 -azino-bis(3-ethylbenzothiazoline-6-sulfonic acid radical cation Atomic force microscopy tertbutylated hydroxyanisole Bovine serum albumin p-coumaroyl shikimate 30 -hydroxlase Circular dichroism Capillary electrophoresis 2-(S-cysteinylglycyl)-trans-caftaric acid Coenzyme A Coumaric acid hexose derivatives

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COMT CPC CQA DLS DPPH
DSC DW FA-H FAME Far-UV CD FQA FRAP FT FT-IR FW GC-FID/MS GT-CA GT-CTA HCGQT HCT HPLC-DAD/FLD/MS/RI/ UV-Vis HPLC-MS/MS/MSn/ MRM-MS HPTLC HQT HS HS-SPME IUPAC LC  LC LC MIC NADP+/NADPH NIR ORAC PBAT

61

Caffeoyl-CoA O-methyl transferase Centrifugal partition chromatography Caffeoylquinic acid Dynamic light scattering 2,2-diphenyl-1-pycrylhydrazyl radical Differential scanning calorimetry Dry weight Ferulic acid hexose derivatives Fatty acid methyl ester Far-ultraviolet circular dichroism spectroscopy Feruloylquinic acid Ferric reducing antioxidant power Fourier transform Fourier transform infrared spectroscopy Fresh weight Gas chromatography coupled with flame ionization detector/mass spectrometry detector 2-(S-Glutathionyl)-trans-caffeic acid 5-(S-Glutathionyl)-trans-caftaric acid Hydroxycinnamoyl D-glucose:quinate hydroxycinnamoyl transferase Hydroxycinnamoyl-CoA:shikimate hydroxycinnamoyl transferase High pressure liquid chromatography coupled with diode array detector/fluorescence detector/mass spectrometry detector/refractive index detector/ ultraviolet-visible spectrophotometric detector Liquid chromatography coupled with tandem mass spectrometry (MS/MS or MSn)/multiple reaction monitoring-mass spectrometry detector High performance thin layer chromatography Hydroxycinnamoyl-CoA:quinate hydroxycinnamoyl transferase Headspace Headspace-solid-phase microextraction International Union of Pure and Applied Chemistry Two-dimensional liquid chromatography Liquid chromatography Minimum inhibitory concentration Nicotinamide adenine dinucleotide phosphate/ reduced form Near infrared spectroscopy Oxygen radical absorbance capacity Poly(butylene-adipate-co-terephthalate)

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PLA SARS-CoV-2 SEM SIFT-MS SPE SPLET SPME TAL TE TEAC TEM TG TLC UDP-GT UHPLC(UPLC)-MS/ MS/UV-Vis UV-Vis XRD

Poly(lactide) Severe acute respiratory syndrome coronavirus 2 Scanning electron microscopy Selected ion flowtube mass spectrometry Solid-phase extraction Sequential proton loss electron transfer Solid-phase microextraction Tyrosine ammonia lyase Trolox equivalent Trolox equivalent antioxidant capacity Transmission electronic microscopy Thermogravimetry Thin layer chromatography Uridine diphosphate glucosyltransferase Ultrahigh pressure liquid chromatography coupled with tandem mass spectrometry detector/ultraviolet-visible spectrophotometry detector Ultraviolet-visible spectrophotometry X-ray diffractometry

Introduction Cinnamic acid derivatives are generated through shikimic acid pathway. They belong to phenylpropanoid class. The starting materials in biosynthesis are phenyl-based amino acids, named L-Phe and L-Tyr. The core structure, cinnamic acid, is progressively hydroxylated and further methylated at the phenyl moiety level to various hydroxycinnamic acid derivatives, providing both hydroxy- and/or methoxycontaining compounds as final biologically active compounds. The main biological activity of hydroxycinnamic acids is the antioxidant activity due to the presence of phenolic hydroxyl groups. Further, anti-inflammatory, analgesic, antipyretic, antiviral, and anticancer activities or decreasing toxic effects of antitumor drugs were observed (Kumar and Pruthi 2014; Nagasaka et al. 2007). Some hydroxycinnamic acids displayed hepatoprotective, cardioprotective, neuroprotective, antidiabetic, and antilipidemic effects (Kumar and Pruthi 2014). The most known hydroxycinnamic acids are p-coumaric and caffeic acids bearing free hydroxyl groups, ferulic and sinapic (or sinapinic) acids with both hydroxyl and methoxy groups. Other compounds belong to the cinnamic acid esters. It is the case of chlorogenic and rosmarinic acids, which are caffeic acid esters with quinic and 3,4-dihydroxyphenyl-lactic acids, respectively (Jiang and Peterson 2010). In foods, hydroxycinnamic acids have multiple roles such as antioxidants and flavor generating aromas. Ferulic or caffeic acids can be thermally degraded to vanillin and guaiacol as flavoring compounds or to N-phenylpropenoyl-L-amino acid derivatives as astringent ingredient in roasted cocoa (Jiang and Peterson

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2010). However, there are many studies regarding the enhancing of the quality and stability of various food products by hydroxycinnamic acid derivatives (Budryn et al. 2016; İlyasoğlu et al. 2019; Jin et al. 2020; Marchev et al. 2021; Sharma et al. 2020). The chapter focuses on the main hydroxycinnamic acids as food bioactive ingredients. First, the structural and biosynthetic aspects are presented. The main hydroxycinnamic acids including p-coumaric, caffeic, ferulic, sinapic, chlorogenic, and rosmarinic acids are emphasized from the properties, occurrence, biological activities, and food application point of views. Moreover, other uncommon or minor hydroxycinnamic acids are discussed. Finally, the conclusion and perspectives regarding the food applications of hydroxycinnamic acids are presented.

Chemistry and Functionality of Hydroxycinnamic Acids Hydroxycinnamic acids have cinnamic acid as core structure. Naturally occurring cinnamic acid can be found on both geometric diastereoisomers, cis and trans (or Z and E, Fig. 1), the latter being more abundant due to its stability. More than 99% of cinnamic acid mixture is in trans form. However, trans-cinnamic acid can be converted in cis-cinnamic acid by photoisomerization (Letsididi et al. 2018). The systematic name (according to IUPAC – International Union of Pure and Applied Chemistry) of cis/trans-cinnamic acid is (2Z/E)-3-phenylpropen-2-enoic acid. Due to the conjugation of double bond with the phenyl moiety, the structure is planar. Cinnamic acid has a carboxyl group that provides an acidic property, with a pKa of 4.44 (https://pubchem.ncbi.nlm.nih.gov/). The presence of substituents on the phenyl moiety changes acidic properties. It is the case of acidic hydrogens from the phenol hydroxyl groups. Moreover, these substituents can change the acidity of the structure by electronic influence (Aguilar-Hernández et al. 2017). Cinnamic acid derivatives belong to esters and/or to phenol classes. Cinnamic acid esters contain mono/disaccharide or naturally occurring hydroxylated organic acids such as β-D-glucose or quinic acid, respectively (Crupi et al. 2018; FerreiraLima et al. 2018; Savona et al. 2017). On the other hand, the most valuable cinnamic acid derivatives are the phenol hydroxyl compounds, named hydroxycinnamic acids. They have one to three hydroxyl groups on the phenyl moiety, which can be methylated to methoxy groups. Only free hydroxyl groups provide antioxidant activity to hydroxycinnamic acids (Kiliç and Yeşiloğlu 2013; Mateos et al. 2018; Maurya and Devasagayam 2010). Fig. 1 Interconversion of trans- and cis-cinnamic acid forms

COOH

UV light t oC

trans-cinnamic acid

COOH cis-cinnamic acid

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Among free hydroxycinnamic acid derivatives, p-coumaric and caffeic acids are the most known (Aguilar-Hernández et al. 2017; Meinhart et al. 2019a). They have one or two hydroxyl groups in 3- or 3, 4 positions of the phenyl moiety, respectively (Fig. 2). Other isomers such as o- and m-coumaric acids exist. The acidity of these hydroxycinnamic acids is close to the core structure (pKa1 4.30–4.34) (AguilarHernández et al. 2017). However, they are less acidic than benzoic acid (pKa 4.20; https://pubchem.ncbi.nlm.nih.gov). These data are in good agreement with the theoretical charge density on the oxygen atom of the carboxyl group (0.324 to 0.325 for hydroxycinnamic acids and only 0.319 for benzoic acid), determined using semi-empirical methods (Austin Model 1, HyperChem, HyperCube; unpublished results from our laboratory). Due to the phenol hydroxyl groups, they provide important antioxidant activity. Both hydroxyl groups can be converted into oxy radicals in the presence of other free radicals such as peroxy radical from lipoprotein peroxidation or DPPH
radical (2,2-diphenyl-1-pycrylhydrazyl) for in vitro antioxidant activity determination (Fig. 3). First, one hydroxyl group from the caffeic acid is split by a radical homolytic reaction with DPPH
to form an oxy radical. Further, a dioxy diradical can be formed in the same manner. The final oxidation product is an ortho-benzoquinone derivative. However, the mechanism of antioxidant action of caffeic acid and its ester derivatives implies various pathways such as double hydrogen atom transfer, duplicated single electron transfer followed by proton transfer, double sequential proton loss electron transfer (SPLET), sequential double proton loss Fig. 2 Structures of the main free hydroxycinnamic acids

COOH

R3

R3=H; R4=OH: p-coumaric acid R3=OH; R4=OH: caffeic acid

R4

O 2N

O 2N

H

.

N

NO 2

N N

N O 2N

O 2N

HO

DPPH. = 517 nm

COOH

NO 2

HO

DPPH-H < 450 nm

max

COOH

max

.O

HO

Oxi radical

Caffeic acid .O

COOH

.O

O

COOH

O

Dioxi diradical

o-Benzoquinone derivative

Fig. 3 Possible mechanism of radical scavenging of caffeic acid by DPPH
(2,2-diphenyl-1pycrylhydrazyl) radical

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double electron transfer, or sequential proton loss hydrogen atom transfer (Yang et al. 2021). The presence of a substituent in the proximity of phenol hydroxyl group can influence the overall antioxidant activity and especially the redox reaction rate. Thus, caffeic acid has approximately the same antioxidant activity (determined by DPPH
method) with propyl gallate or tertbutylated hydroxyanisole (BHA). Antioxidant activity values of 92.4, 94.0, and 86.5% after 15 min of evaluation were obtained for caffeic acid, propyl gallate, and BHA solutions (1 mM), respectively (Ivanovici et al. 2018). On the contrary, the mean reaction rate of DPPH
with these antioxidant compounds significantly differs. Caffeic acid and propyl gallate have this rate of 1.9–2.5 μM/s for the first ½ min reaction time, while BHA of only 1.2 μM/s. On the other hand, the reaction rate is much higher for BHA at the final reaction time range of 3–15 min. This behavior can be easily explained by the presence of the bulky substituent tertbutyl at the proximate position of the hydroxyl group in BHA. In this case, the reaction is slower but has significant value even at later time (prolonged activity) (Ivanovici et al. 2018). Caffeic acid and propyl gallate have two or three hydroxyl groups, which are not bulky, the reaction with DPPH
is faster at the beginning, and the antioxidant is consumed more rapidly. An intermediate behavior can be observed for ferulic and sinapic acids, which have methoxy groups in the proximity of phenol hydroxyls. Ferulic and sinapic acids have both free hydroxyl and methoxy groups on the cinnamic acid structure (Fig. 4). The systematic names are (2E)-3-(4-hydroxy-3methoxyphenyl)prop-2-enoic acid and (2E)-3-(4-hydroxy-3,5-dimethoxyphenyl) prop-2-enoic acid. No significant differences between pKa1 values of caffeic, ferulic, and sinapic acids exist (4.25–4.30) (Aguilar-Hernández et al. 2017). On the other hand, hydroxyl group from the para position of phenyl is partially hindered by one or two methoxy groups. Ferulic acid has antioxidant potential, expressed as total antioxidant performance (TAP), similar to ()-epigallocatechin gallate and ascorbic acid. However, the antioxidant activity of ferulic acid, determined by various methods, is slightly lower than that of caffeic acid (Maurya and Devasagayam 2010). The antioxidant activity of sinapic acid is favorable influenced by the presence of the second methoxy group. Consequently, the total antioxidant activity of sinapic acid, determined by ferric ion reducing antioxidant power (FRAP) method, was four times higher than that of ferulic acid. On the contrary, the DPPH
inhibition concentration 50% (IC50) of ferulic acid was higher, demonstrating the prolonged effect of two methoxy groups in sinapic acid in comparison with COOH R3=OMe; R4=OH; R5=H: ferulic acid R3=R5=OMe; R4=OH: sinapic (sinapinic) acid

R3

R4 R5

Fig. 4 Structures of the main methoxylated hydroxycinnamic acids

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66

ferulic acid (Yang et al. 2021). This is revealed by the accessibility to the hydroxyl reaction center of ferulic and sinapic acids, as shown in Fig. 5 for 3D isosurface of the electrostatic potential (calculated by semi-empirical Austin Model 1 program, HyperChem, HyperCube; unpublished results from our laboratory). Hydroxycinnamic acids can be decarboxylated to the corresponding vinylphenols under thermal or enzymatic degradation (Fig. 6). They are responsible for food flavor such as cured meat products or some red wines (Terpinc et al. 2011). p-Coumaric, caffeic, ferulic, or sinapic acids provide 4-vinylphenol, 4-vinylcatechol, 4-vinylguaiacol, or 4-vinylsyringol having both flavoring and antioxidant potential. The antioxidant activity of vinylphenols is weaker than that of the corresponding hydroxycinnamic acids (Terpinc et al. 2011). Many hydroxycinnamic acids are found in nature as esters with naturally occurring organic acids bearing hydroxyl groups or saccharides. The most important are chlorogenic acids, which are caffeic acid esters with ()-quinic acid (Fig. 7). They exist both as cis and trans isomers. Position isomers such as 3-, 4-, and 5-Ocaffeoylquinic acids were also identified, among other di- and tricaffeoylquinic acids. Similar esters with quinic acid were identified for p-coumaric, ferulic, and

Fig. 5 Accessibility to the hydroxyl reaction center of ferulic (left) and sinapic acid (right), revealed by the arrow on the 3D isosurface of the electrostatic potential. The calculus was made using the semi-empirical Austin Model 1 program, HyperChem, HyperCube. The violet color indicates the electronegative surface (unpublished results from our laboratory)

COOH

R'

thermal/enzymatic -CO2

HO R" Hydroxycinnamic acids

3

R'

4 2 1

HO

6

5

R" 4-Vinylphenols

Fig. 6 Transformation of hydroxycinnamic acids to 4-vinylphenols: 4-vinylphenol from p-coumaric acid (R0 ¼ R00 ¼ H), 4-vinylcatechol from caffeic acid (R0 ¼ OH, R00 ¼ H), 4-vinylguaiacol from ferulic acid (R0 ¼ MeO; R00 ¼ H), and 4-vinylsyringol from sinapic acid (R0 ¼ R00 ¼ MeO)

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Hydroxycinnamic Acids

67

Hydroxycinnamic acid moiety

(-)-Quinic acid moiety R1 O

COOH

R3

R5 O

O O R4

O

HO

p-Coumaric acid moiety (A) O HO

HO

Caffeic acid moiety (B) O O H3C HO

Ferulic acid moiety (C) O O H3C HO O H3C

Sinapic acid moiety (D) Miscellaneous (examples)

R1=A, R3-R5=H: 1-O-p-Coumaroylquinic acid R1,R4,R5=H, R3=A: 3-O-p-Coumaroylquinic acid R1,R3,R5=H, R4=A: 4-O-p-Coumaroylquinic acid R1,R3,R4=H, R5=A: 5-O-p-Coumaroylquinic acid R1,R5=H, R3,R4=A: 3,4-di-O-p-Coumaroylquinic acid R1,R4=H, R3,R5=A: 3,5-di-O-p-Coumaroylquinic acid R1,R3=H, R4,R5=A: 4,5-di-O-p-Coumaroylquinic acid R1=B, R3-R5=H: 1-O-Caffeoylquinic acid R1,R4,R5=H, R3=B: 3-O-Caffeoylquinic acid R1,R3,R5=H, R4=B: 4-O-Caffeoylquinic acid R1,R3,R4=H, R5=B: 5-O-Caffeoylquinic acid R1,R5=H, R3,R4=B: 3,4-di-O-Caffeoylquinic acid R1,R4=H, R3,R5=B: 3,5-di-O-Caffeoylquinic acid R1,R3=H, R4,R5=B: 4,5-di-O-Caffeoylquinic acid R1=H, R3,R4,R5=B: 3,4,5-tri-O-Caffeoylquinic acid R1=C, R3-R5=H: 1-O-Feruloylquinic acid R1,R4,R5=H, R3=C: 3-O-Feruloylquinic acid R1,R3,R5=H, R4=C: 4-O-Feruloylquinic acid R1,R3,R4=H, R5=C: 5-O-Feruloylquinic acid R1,R5=H, R3,R4=C: 3,4-di-O-Feruloylquinic acid R1,R4=H, R3,R5=C: 3,5-di-O-Feruloylquinic acid R1,R3=H, R4,R5=C: 4,5-di-O-Feruloylquinic acid R1=B, R3-R5=H: 1-O-Sinapoylquinic acid R1,R4,R5=H, R3=B: 3-O-Sinapoylquinic acid R1,R3,R5=H, R4=B: 4-O-Sinapoylquinic acid R1,R3,R4=H, R5=B: 5-O-Sinapoylquinic acid R1,R5=H, R3,R4=B: 3,4-di-O-Sinapoylquinic acid R1,R4=H, R3,R5=B: 3,5-di-O-Sinapoylquinic acid R1,R3=H, R4,R5=B: 4,5-di-O-Sinapoylquinic acid R1,R4=H, R3=D, R5=B: 3-O-Sinapoyl-5-O-caffeoylquinic acid R1,R4=H, R3=D, R5=C: 3-O-Sinapoyl-5-O-feruloylquinic acid R1,R5=H, R3=diMe-B, R4=B: 3-Dimethoxycinnamoyl-4-caffeoylquinic acid

Fig. 7 The most important structures of chlorogenic acids and their homologue esters with quinic acid

sinapic acids cases (Kulapichitr et al. 2022). These hydroxycinnamic acids can form esters with quinic acid at all four disposable hydroxyl groups. Thus, derivatives with ester group in 1-, 1,3-, 1,4-, 1,5-, 3,4-, 3,5-, and 4,5- were identified (Fig. 7) (Jeon et al. 2019; Meinhart et al. 2018). Diesters with different hydroxycinnamoyl acid moieties were determined. However, more than 300 chlorogenic acid derivatives as

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68

major and minor components were identified in various vegetable sources. Their antioxidant activities are similar in the same group. Thus, caffeic acid and 5-caffeoylquinic acid have similar antioxidant activity at lower concentrations, as was determined by means of the oxidation behavior of triacylglycerols of sunflower oil (Marinova et al. 2009). This is obvious due to the similarity of the reaction center in the same hydroxycinnamic acid derivatives. Shikimic acid is also found in cinnamoyl-based esters (Döring and Petersen 2014). It is derived from dehydroquinic acid from the shikimate pathway (see section “Biosynthetic Pathways of Hydroxycinnamic Acids”). As a consequence, hydroxycinnamic acid esters with shikimic acid, such as trimethoxycinnamoylshikimic acid from yerba mate (Ilex paraguariensis A.St.-Hil.) drink, can also be found (Mateos et al. 2018). Rosmarinic acid is the caffeoyl ester with 3,4-dihydroxyphenyllactic acid. It is more hydrophobic than caffeic acid (logP of 1.70 and 1.42, respectively), but has similar antioxidant activity. It was observed that the antioxidant activity of extracts from some medicinal plants well correlated with the rosmarinic acid concentration. A study regarding the oxidation behavior of rosmarinic acid in the presence of DPPH
revealed that the induction period is much higher and the oxidation rate is lower than caffeic or chlorogenic acids (Guitard et al. 2016). However, the presence of four phenol hydroxyl groups on the rosmarinic acid structure allows scavenging four radicals (Fig. 8). This means that the rosmarinic acid:radical compound molar ratio is 1:4, which resembles with the cases of gallic acid and myricetin (Guitard et al. 2016). Hydroxycinnamic acids also occur as esters with aldaric acids, especially tartaric acid (Fig. 9). p-Coumaric, caffeic, and ferulic acids provide coutaric, caftaric, and fertaric acids by esterification with L(+)-tartaric acid (Ferreira-Lima et al. 2018). They can be found in various wine products. The corresponding diester of caffeic

OH O

COOH

HO O HO

OH

+

4 R.

Rosmarinic acid O O

COOH

O O

O +

O

Fig. 8 Mechanism of radical scavenging by rosmarinic acid

4 R-H

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Hydroxycinnamic Acids

69

O

COOH

O

COOH

Coutaric acid (R⬘=p-coumaroyl, R⬙=H) Caftaric acid (R⬘=caffeoyl, R⬙=H) Fertaric acid (R⬘=feruloyl, R⬙=H) Chicoric acid (R⬘=R⬙=caffeoyl)

R' R"

Fig. 9 Structures of hydroxycinnamic acid esters with aldaric acids; examples for coutaric, caftaric, fertaric, and chicoric acids

21

11 19

H

1 2

O O

H3C

9

10 3

O

H3C

4

5

H CH3

24

18 17

23

13

H

25

16

14

8

O

22

CH3 20

12

COOH6' CH3 27

15

H3C

26

O H3C

7 8

1

8'

3 4

7 6

2

HO

7' 5

6

5'

1'

CH3 OH

4' 3'

2'

CH O

COOH

O

HO

H3C

Oryzanol A (cycloartenyl ferulate)

8,8’-Disinapic acid

Fig. 10 Examples of hydroxycinnamic acid derivatives from phytosterol ester and hydroxycinnamic acid dimer classes

acid provides chicoric acid that can be found in chicory (Cichorium intybus L.) and dadelion (Taraxacum officinale F.H. Wigg.) (Lee et al. 2021). Esters of hydroxycinnamic acids with saccharides can provide compounds or components with various properties such as antioxidants for hydroxycinnamic acid glucopyranoside or bioinhibitors against plant cell degradation for ferulic acid crosslinked to polysaccharides (Anson et al. 2009; Du and Yu 2010). This linkage can reduce the bioavailability and antioxidant capacity of ferulic acid. Widely found in vegetable sources are glycosylated hydroxycinnamic acids at the phenol hydroxyl groups. Glycosides of hydroxycinnamic acids can be found in wines. It is the case of various p-coumaric, caffeic, and ferulic hexose derivatives or 2-(S-cysteinylglycyl)trans-caftaric acid (Crupi et al. 2018; Ferreira-Lima et al. 2018; Nemes and Orsat 2012). Moreover, ferulic acid esters with cycloartenol (oryzanol A, Fig. 10) or campestrol with lipophilic properties can be found in rice bran oil (Nagasaka et al. 2007). They provide antioxidant properties and other biological effects due to both biologically active moieties. Hydroxycinnamic acid-based alkaloids such as sinapine (sinapic acid ester with choline) from Brassicaceae botanical family including rapeseed and mustard can be found (Achinivu et al. 2021; Niu et al. 2013). Hydroxycinnamic acid dimers are also important in vegetable and cereals as antioxidants (Kumar and Pruthi 2014; Yang et al. 2021). Homogenous dimers having 8,30 -, 8-O-40 -, 8,50 -, and 8,80 -bonds (Fig. 10) were reported for all important hydroxycinnamic acids and p-coumaric, caffeic, ferulic, and sinapic acids (Grúz et al. 2015; Yang et al. 2021).

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N.-G. Ha˘da˘ruga˘ and D.-I. Ha˘da˘ruga˘

Biosynthetic Pathways of Hydroxycinnamic Acids Cinnamic acid and hydroxycinnamic acids are mainly biosynthesized through shikimate pathway, which is generally responsible for aromatic amino acids and phenylpropanoids biosynthesis (Ververidis et al. 2007). It must be mentioned that acids that are involved in biosynthesis react as anionic intermediates. The primarily key intermediate is phosphoenolpyruvate, which can be biosynthesized from α-Dglucose by glycolytic pathway or pentose phosphate cycle involving photosynthesis. In the first case, D-glucose 6-phosphate is successively converted to D-glyceraldehyde 3-phosphate, 3-phosphoglyceric acid, and phosphoenolpyruvate. The latest provide the shikimic acid that is further transformed in aromatic amino acids, namely, L-phenylalanine, L-tyrosine, and L-tryptophan. In the second case, the D-erytrose 4-phosphate is converted directly into shikimic acid (Hernández-Chávez et al. 2019; Ververidis et al. 2007). Detailed biosynthesis of shikimic acid involves the aldol type condensation of phosphoenolpyruvate and D-erytrose 4-phosphate to 3-deoxy-D-arabino-heptulosonic acid 7-phosphate, 3-dehydroquinic acid, 3-dehydroshikimic acid and finally to shikimic acid (Fig. 11). The next biosynthetic steps involve the second phosphoenolpyruvate molecule, providing chorismic acid. It is rearranged to propenic acid and further convert to aromatic phenyl-based amino acids, named L-phenylalanine and L-tyrosine (Fig. 12) (Hernández-Chávez et al. 2019; Ververidis et al. 2007). They can be obtained even through phenylpyruvic and 4-hydroxyphenylpyruvic acids or by means of L-arogenic acid as intermediate. These biosynthetic pathways are mostly present in plants. On the contrary, in some plants such as species from Graminae family, L-tyrosine is obtained by hydroxylation of L-phenylalanine (Ververidis et al. 2007). The main hydroxycinnamic acids are biosynthesized from L-phenylalanine or L-tyrosine by means of specific enzymes, namely, phenylalanine ammonia lyase and tyrosine ammonia lyase. p-Coumaric acid results even from L-phenylalanine, which is converted to cinnamic acid and further oxidized to p-coumaric acid, or directly from L-tyrosine (Fig. 13). Successive oxidation and methylation of some hydroxyl groups provide caffeic, ferulic, and sinapic acids (Ververidis et al. 2007). In a survey related to Escherichia coli, Rhodopseudomonas palustris, or Pseudomonas aeruginosa strains metabolic engineering for the biotechnological production of caffeic acid, four strains were evaluated (Hernández-Chávez et al. 2019). They used p-coumaric acid, L-tyrosine, glucose and glycerol, as well as lignocellulosic feedstock as substrates. The enzyme 4HPA3H from P. aeruginosa PAO1, expressed in E. coli, allows the highest caffeic acid production of a titer of 10.2 g/L with p-coumaric acid as substrate. When L-tyrosine was used as substrate, the best result was obtained for enzymes tyrosine ammonia lyase (TAL) from R. glutinis expressed in E. coli, with a caffeic acid titer of 0.28 g/L (Hernández-Chávez et al. 2019). If glucose and glycerol or cellulose from kraft pulp were used, the caffeic acid titer was in the range of 0.05–0.77 g/L (Hernández-Chávez et al. 2019). Chlorogenic acids are biosynthesized through three pathways. The most common is the ()-quinate pathway (Fig. 14). Thus, activated p-coumaroyl coenzyme A (CoA), which results from p-coumaric acid by means of 4-coumarate:CoA ligase

3

Hydroxycinnamic Acids

71 HO

O

O

HO

P

OH

HO

HO

O

OH

O P

O

HO

OH O CHO

HO

HO

OH

OH D-Glucose 6-phosphate

OH D-Glucose

HO

D-Glyceraldehyde 3-phosphate

O P

HO

OH

OH

HO

O

COOH

O P O

HO

COOH D-Glyceric acid 3-phosphate

COOH

CH2

O

3-Phosphoenolpyruvate + HO

HO

O P

HO

O P

HO

O HO

CHO

O HO

OH

OH 3-Deoxy-D-arabinoheptulosonic acid 7-phosphate

OH D-Erythrose 4-phosphate COOH

COOH -H2O HO

COOH

NADPH O

OH

OH 3-Dehydroshikimic acid O

OH

OH 3-Dehydroquinic acid

HO

HO

OH OH Shikimic acid

COOH

NADPH HO

OH

OH (-)-Quinic acid

Fig. 11 Biosynthetic pathways involved for obtaining of shikimic and ()-quinic acids

(4CL), is converted into p-coumaroyl quinate by means of hydroxycinnamoyl-CoA: shikimate hydroxycinnamoyl transferase (HCT). The last step is the hydroxylation at C30 position by p-coumaroyl shikimate 30 -hydroxlase (C30 H). The shikimate pathway (Fig. 15) involves the reaction of shikimic acid with activated p-coumaroyl coenzyme A (Hernández-Chávez et al. 2019; Ververidis et al. 2007). This is mediated by the hydroxycinnamoyl-CoA:quinate hydroxycinnamoyl transferase (HQT). The intermediate p-coumaroyl shikimate is converted to caffeoyl shikimate by the same C3’H. The cinnamoyl glucoside pathway (Fig. 16) involves the conversion of caffeic acid to caffeoyl glucose using uridine diphosphate glucosyltransferase (UDP-GT) followed by coupling with ()-quinic acid by means of hydroxycinnamoyl D-glucose:quinate hydroxycinnamoyl transferase (HCGQT). Another way is the conversion of caffeic acid into ferulic acid by caffeoyl-CoA O-methyl transferase (COMT), followed by activation to feruloylglucose and then to the chlorogenic acid derivative, feruloyl ()-quinate (Hernández-Chávez et al. 2019).

N.-G. Ha˘da˘ruga˘ and D.-I. Ha˘da˘ruga˘

72

COOH

COOH

COOH HO

HO

O

+

P HO

HO

OH

O

HO

OH

OH Shikimic acid 3-phosphate

OH Shikimic acid

CH2

O

CH2

P O

COOH -2H3PO4

Phosphoenolpyruvate

-H2O, -CO2

Phenylpyruvic acid COOH

COOH HOOC

COOH

COOH

COOH Pyridoxal phosphate O

NADP+

O OH Chorismic acid

NH2 L-Phenylalanine +

DP NA

HOOC O

NH2 Pyridoxal phosphate NA DP +

OH Prephenic acid

OH L-Arogenic acid

NADP+ -CO2

HO

COOH

COOH Pyridoxal phosphate O HO 4-Hydroxyphenylpyruvic acid

NH2 L-Tyrosine

Fig. 12 Biosynthesis of the phenyl-based amino acids involved in obtaining of hydroxycinnamic acids COOH

O2 NADPH

NH2

COOH Phenylalanine ammonia lyase

L-Phenylalanine

COOH

COOH NH2

HO

Tyrosine ammonia lyase HO

O

COOH

HO

O

S-Adenosyl methionine HO

Ferulic acid

Caffeic acid

COOH

H3C O2 NADPH HO

COOH S-Adenosyl methionine

p-Coumaric acid

L-Tyrosine

H3C

HO O2 NADPH

O

COOH

H3C HO

OH

O

Sinapic acid

H3C

Fig. 13 Biosynthetic pathways of the main hydroxycinnamic acids, p-coumaric, caffeic, ferulic, and sinapic acids, starting from L-phenylalanine or L-tyrosine

Rosmarinic acid biosynthesis involves the same starting compound, namely, (Fig. 17). However, the reactive intermediate p-coumaroyl-CoA can be obtained even from L-tyrosine or L-phenylalanine (Fig. 13). The dimeric type structural architecture of rosmarinic acid results from (R)-4-hydroxyphenyllactic acid and

L-tyrosine

3

Hydroxycinnamic Acids HO

73

O

COOH

HO

CoAS

COOH O

HCL/HQL

+ HO

OH

OH

HO

O OH

OH

OH

p-Coumaroyl-CoA

(-)-Quinic acid

HO

p-Coumaroyl quinate

COOH O

C3'H

OH HO

O OH OH Caffeoyl quinate (Chlorogenic acid)

Fig. 14 Biosynthesis of chlorogenic acids by shikimate pathway

O

COOH

COOH

CoAS

HCL/HQL

O

+ HO

OH

OH

HO

O OH

OH

OH

p-Coumaroyl-CoA

Shikimic acid

p-Coumaroyl shikimate

COOH O

O

C3'H

OH HO

HCL/HQL

O

OH CoAS

OH

OH

OH Caffeoyl-CoA

Caffeoyl shikimate HO

COOH + HCL/HQL

O

HO

COOH

OH HO

O OH OH

HO

Caffeoyl quinate (Chlorogenic acid)

OH OH (-)-Quinic acid

Fig. 15 Biosynthesis of chlorogenic acids by ()-quinate pathway

4-coumaroyl-CoA by means of hydroxycinnamoyl-CoA:hydroxyphenyllactate hydroxycinnamoyl transferase or rosmarinic acid synthase. The corresponding hydrolases convert this intermediate, 4-coumaroyl-40 -hydroxyphenyllactic acid, to two 3- or 30 -hydroxylated derivatives, caffeoyl-40 -hydroxyphenyllactic acid or 4-coumaroyl30 ,40 -dihydroxyphenyllactic acid, respectively (Fig. 17). These biosynthetic pathways

N.-G. Ha˘da˘ruga˘ and D.-I. Ha˘da˘ruga˘

74 O

O OH

O

HO

Caffeoyl-CoA 3-O-methyltransferase

HO

CH3

OH

OH

Caffeic acid

HO

UDP-glucosyltransferase

HO

UDP-glucosyltransferase

HO

O

O

Ferulic acid

HO

O

O OH

O

HO

O O

HO

OH

CH3

OH

OH

OH

Caffeoyl-glucose

Feruloyl-glucose

+ HO

HO

+ COOH

HO

OH

HO

OH (-)-Quinic acid HO

OH OH

Hydroxycinnamoylglucose quinate transferase

COOH

COOH

HO

COOH

O

(-)-Quinic acid Hydroxycinnamoylglucose quinate transferase O

OH HO

O OH OH Caffeoyl quinate (Chlorogenic acid)

O HO

O

CH3

OH OH Feruloyl quinate (Chlorogenic acid)

Fig. 16 Biosynthesis of chlorogenic acids by cinnamoyl glucoside pathway

involve hydroxycinnamoyl:hydroxyphenyllactate 3- or 30 -hydrolases. Finally, the vice versa hydroxylation using the same hydrolases provides rosmarinic acid (Petersen 2013). There were approaches for rosmarinic acid biosynthesis optimization using Salvia species (Savona et al. 2017). Salvia officinalis L. and S. dolomitica Codd were the best models for cell and tissue cultures for rosmarinic acid production. The key target enzyme for optimization of rosmarinic acid production was S. officinalis hydroxyphenylpyruvate reductase that convert 4-hydroxyphenylpyruvic acid into 4-hydroxyphenyllactic acid (Fig. 17). Biosynthesis regulation of rosmarinic acid can be performed by plant targeting, selection of high-growth and high-producing cell lines, obtaining cell lines with improved rosmarinic acid biosynthetic capacity, optimization, and scaling-up the bioprocess of rosmarinic acid production (Marchev et al. 2021). Plant in vitro biotechnologies based on calli and suspension cells of Ocimum basilicum L., Salvia officinalis L., Lavandula angustifolia “Vera” DC., Salvia miltiorrhiza Bunge, Agastache rugosa (Fisch. & C.A. Mey.) Kuntze, Melissa officinalis L., shoot cultures from Dracocephalum forrestii L., or hairy roots mainly from Salvia miltiorrhiza and Dracocephalum kotschyi Boiss have been proposed (Marchev et al. 2021; Petersen 2013).

3

Hydroxycinnamic Acids

75

Phenylalanine ammonia lyase

NH2

HO

O

Hydroxyphenyl pyruvate dioxygenase

OH

4-Hydroxyphenyllactic acid

4-Hydroxyphenylpyruvic acid

O + OH Hydroxycinnamoyl-CoA: hydroxyphenyllactate transferase HO Hydroxycinnamoyl: 4-Coumaroyl-CoA hydroxyphenyllactate 3'-hydrolase

COOH

O O HO

SCoA

OH

OH

COOH

O

COOH

O

H

HO

HO

L-Tyrosine

Hydroxycinnamoyl: hydroxyphenyllactate 3-hydrolase

COOH

COOH

COOH

HO

O

O

OH

HO

HO Caffeoyl-4'-hydroxyphenyllactic acid Hydroxycinnamoyl: hydroxyphenyllactate 3'-hydrolase

COOH

O HO O HO

4-Coumaroyl-3',4'-dihydroxyphenyllactic acid OH Hydroxycinnamoyl: hydroxyphenyllactate 3-hydrolase OH

Rosmarinic acid

Fig. 17 Biosynthetic pathways of rosmarinic acid

Occurrence, Separation, Analysis, and Applications as Food Ingredients of Specific Hydroxycinnamic Acids Cinnamic acid and its hydroxylated derivatives with the generic name of hydroxycinnamic acids have important influences from both food and pharmaceutical point of views. Hydroxycinnamic acids are widely found in plants, fruits, seeds and kernels, spices, cereals, and food products such as wines and teas (Döring and Petersen 2014; Grúz et al. 2015; Kiferle et al. 2011; Meinhart et al. 2017; TorresContreras et al. 2014; Zaro et al. 2015). They are especially valuable due to their antioxidant activity, which provide many biological activities (Kulapichitr et al. 2022; Liang and Were 2018; Tsai et al. 2012; Yang et al. 2021). However, a wide range of biological activities of hydroycinnamic acids were determined. Generally, hydroxycinnamic acids have implications in the regulation of lipid and glucose metabolisms, as well as anti-inflammatory activities. The biological activities include antidiabetic, antiobesity, cardio-vascular, hepatoprotective, and neuroprotective effects, as well as antitumor and analgesic activities (Ertas and Yener 2020). The occurrence, separation, and analysis of cinnamic acid and its derivatives, hydroxycinnamic acids, are systematically presented below. The discussion is mainly related with the food applications of these cinnamic derivatives or interactions with food ingredients and other related products.

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Cinnamic Acid Cinnamic acid is the only compound among this class that has not antioxidant activity due to the lack of phenol hydroxyl groups. However, it has many food applications and interactions with food ingredients (Table 1). Cinnamic acid interacts with gluten proteins and affects the dough properties. It was observed a dough breakdown, but especially for hydroxylated cinnamic acid derivatives (see below) (Krekora et al. 2020). Cinnamic acid, as the metabolite of cinnamaldehyde, interacts with human serum albumin, which is influenced by other food additives such as tertbutylhydroquinone, propyl gallate, Acid red 14, or carthamin yellow (Sun et al. 2018). The binding mechanism, as determined by multispectroscopic methods and molecular modeling, revealed a static quenching with a higher binding constant for cinnamaldehyde. This parameter is differently influenced by the abovementioned food additives, mostly for Acid red 14 and tert-butylhydroquinone. It was mentioned the potential health risks at combined use of food additives. The best biomaterial contained 40% cinnamaldehyde, having both bactericidal effects against Escherichia coli O157:H7 and Staphylococcus aureus PTCC 1337. On the other hand, zein nanofibers did not affect the color, texture, and sensory characteristics of sausages. Recent applications of cinnamic acid were as antimicrobials in food nanoemulsions and other food products (Letsididi et al. 2018). Both cinnamic acid and some of its derivatives (cinnamaldehyde, cinnamyl alcohol, methyl or allyl esters) revealed antimicrobial effects against Staphylococcus aureus, Salmonella typhimurium, Pseudomonas aeruginosa or Escherichia coli NCTC, Escherichia hirae, Staphylococcus aureus, respectively. trans-Cinnamic acid was used for inhibiting the biofilm formation by S. aureus, S. typhimurium, and P. aeruginosa at concentrations of 0.1, 0.2, and 0.39 mg/mL, respectively. Cinnamic acid-based nanoemulsions were applied for the reduction of aerobic mesophilic and psychrophilic bacteria in fresh cut lettuce by 65% and 61% (Letsididi et al. 2018). There are many studies reporting the separation/analysis of cinnamic acid in various food raw ingredients or processed food products (Pérez-Jiménez et al. 2010). They are summarized in a very useful way in the Phenol-Explorer database (available at http://phenol-explorer.eu, accessed on November 2021). The highest content of cinnamic acid was determined in cinnamon and green olive (20.1 and 14.33 mg/100 g FW, respectively). However, higher contents of cinnamic acid can be determined in food ingredients after hydrolysis such as in the case of green olive (21.0 mg/100 g FW) (see Table 1).

p-Coumaric Acid p-Coumaric acid is the first representative of hydroxycinnamic acid class, having one phenol hydroxyl group that confers antioxidant activity. Recent studies regarding the food application of p-coumaric acid are presented in Table 2. It interact with

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Table 1 Occurrence, separation, and analysis of cinnamic acid and some derivatives related to food applications or interactions with food ingredients and other related products Food application/food ingredients interaction Effect of cinnamic acid on the structure of gluten proteins in dough

Occurrence/source/ contenta Cinnamic acid in dough (0.05–0.2%)

Interaction with human serum albumin and other food additives

Cinnamic acid and cinnamaldehyde:human serum albumin (HSA) with a molar ratio of 1:10 and 1:20 trans-Cinnamic acid nanoemulsions with antimicrobial effects, MIC, of 0.78, 1.56, and 3.13 mg/mL against Staphylococcus aureus, Salmonella typhimurium, and Pseudomonas aeruginosa. Contents of 0.1, 0.2, and 0.39 mg/mL inhibited >50% the biofilm formation by the above-mentioned strains, respectively Cinnamic acid content of cinnamic acid esterified porous potato starch of 0.09–0.42%

Antimicrobial and antibiofilm effects on food nanoemulsions. Application to preservation of fresh-cut lettuce

Cinnamic acid for obtaining starch esters as biodegradable antioxidant materials for the food industry Cinnamic acid contents in fresh fruits, fruit juices, vegetable oils, spices, and nonalcoholic beverages

a

Fruits (American cranberry, Lingonberry, red currant, red raspberry, strawberry, 0.10–4.12 mg/100 g FW), fruit juices (orange juice, 0.02 mg/100 mL), olives (0.77–14.33 mg/100 g) vegetable oils (olive oil, 0.02 mg/100 mL), spices (cinnamon, 20.1 mg/100 g), coffee beverages (0.005 mg/100 mL); higher values in hydrolyzed food products

Separation and/or analysis FT-Raman spectroscopy, consistency (farinograph) 1 H-NMR, fluorescence spectroscopy, UV-Vis

Reference Krekora et al. (2020)

Sun et al. (2018)

Nanoemulsion parameters (mean particle size, polydispersity index)

Letsididi et al. (2018)

1 H- and 13C-NMR, FT-IR, SEM, DPPH
antioxidant activity for porous starch esters HPLC-UV-Vis/DAD/ MS, UV-Vis, GC-FID/MS (derivatized), 1H/13CNMR

Li et al. (2021)

PérezJiménez et al. (2010); http://phenolexplorer.eu

Cinnamic acid contents, expressed as mg/100 g fresh weight, FW (unless otherwise specified)

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78

Table 2 Occurrence, separation, and analysis of p-coumaric acid and derivatives related to food applications or interactions with food ingredients and other related products Food application/food ingredients interaction Effect of p-coumaric acid on the structure of gluten proteins in dough

Occurrence/source/ contenta p-Coumaric acid in dough (0.05–0.2%)

Nanoencapsulation of p-coumaric acid and its hexadecyl ester by amylose inclusion complex Copigmentation of malvidin 3-O-glucoside with p-coumaric acid

Loading capacity of 6.8% for hexadecyl pcoumarate

p-Coumaric acid for obtaining starch esters as biodegradable antioxidant materials for the food industry Enzymatic acylation of anthocyanins from blueberry with p-coumaric acid for improved color stability and antioxidant activity p-Coumaric acid in Mexican maize varieties after extraction by ultrafiltration p-Coumaric acid for the development of agroindustrial by-product valorization with applications in biotechnology p-Coumaric acid in barley grain for high phenolic content barley cultivars p-Coumaric acid content in seeds and hull of barley varieties

Separation and/or analysis FT-Raman spectroscopy, consistency (farinograph) DSC, XRD, FT-IR, HPLC-UV-Vis

Reference Krekora et al. (2020)

Wang et al. (2019a)

Pigment (oenin)/ copigment ( p-coumaric acid) molar ratios of 1:1, 1:10, 1:30, and 1:60. The pigment/copigment concentrations were 0.1 mM p-Coumaric acid content of the esterified porous potato starch of 0.11–0.42%

pH meter, UV-Vis

Malaj et al. (2013)

1 H- and 13C-NMR, FT-IR, SEM, DPPH
antioxidant activity for porous starch esters

Li et al. (2021)

Esterification of 30 mmol p-coumaric acid with 4.5 g native blueberry anthocyanins using immobilized Novozyme 435 at 60  C Concentrations of 24.56–76.21 mg/L in permeates

Total anthocyanin content (UV-Vis), DPPH
, FT-IR, XRD, 1 H-NMR

Liu et al. (2020)

Ultrafiltration, UHPLC-MS

DíazMontes et al. (2020)

Solid-state fermentation, HPLCUV-Vis

Carboué et al. (2020)

NIR, HPLC-UV-Vis

Han et al. (2017)

HPLC-DAD

Du and Yu (2010)

Solid-state fermentation of Aspergillus tubingensis, with optimum parameter values of 25  C for temperature and moisture content of 66% p-Coumaric acid content of 887.7–2573.7 μg/g (dry basis) p-Coumaric acid content in whole barley seed of 131–346 μg/g (dry basis)

(continued)

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Table 2 (continued) Food application/food ingredients interaction p-Coumaric acid in brewer’s spent grain

p-Coumaric acid in seagrasses with food applications p-Coumaric acid separation from agricultural residues by “sugaring out” method Antioxidant activity of p-coumaric acid as ingredient for pharmacological and food industry

p-Coumaric acid glucoside in flaxseeds Dicoumaric acids in plants and foods

p-Coumaric acid contents in alcoholic and nonalcoholic beverages, cereals and cereal products, fruits and fruit products, oils, seasonings, seeds and vegetables

Occurrence/source/ contenta p-Coumaric acid content of liquors obtained from brewer’s spent grain in the range of 67.1–138.8 mg/L p-Coumaric acid content in Halodule pinifolia and Cymodocea serrulata of 0.32 and 1.90 mg/g Maximum p-coumaric acid content for sugarcane bagasse alkaline hydrolysis of 2.0 g/L Inhibition of lipid peroxidation of 71.2% at a concentration of 45 μg/ mL, DPPH
radical scavenging activity of 55.6% (30 μg/mL), ferrous chelating capacity of 78.3% (45 μg/mL), hydrogen peroxide, superoxide, and ABTS
+ scavenging activity of 53.2, 45.1, and 98.4% (45, 20, and 10–20 μg/ mL, respectively) Recovery yield of 96.1%

In vitro oxidation of p-coumaric acid to p-coumaric dimers (8-30 -dicoumaric acid) in parsley at 0.15 μg/g DW and a coumaric acid/ coumaric dimer ratio of 133.0 Beer including regular product or alcohol free and dark products (0.04–0.12 mg/100 mL), wines (white, rosé, red, sparkling wine, 0.04–0.55 mg/100 mL), cereals (wheat, maize, oat, rice, rye, 0.02–0.33 mg/100 g FW),

Separation and/or analysis Alkaline hydrolysis, HPLC-UV-Vis

Reference Mussatto et al. (2007)

HPTLC

Kannan et al. (2013)

“Sugaring out” – new phase separation method, HPLC-UVVis DPPH
, lipid peroxidation assay, chelating activity on ferrous ions, FRAP, hydrogen peroxide scavenging activity, superoxide scavenging activity, ABTS
+ scavenging activity

Dhamole et al. (2016)

Microwave-assisted extraction, SPE, HPLC-UV-Vis UPLC-MS/MS

Nemes and Orsat (2012)

HPLC-UV-Vis/DAD/ MS/fluorimetry, GC-MS, UHPLC-MS/ MS, UV-Vis, 1H/13CNMR, CE, micellar LC, LC  LC

PérezJiménez et al. (2010); http:// phenolexplorer.eu

Kiliç and Yeşiloğlu (2013)

Grúz et al. (2015)

(continued)

N.-G. Ha˘da˘ruga˘ and D.-I. Ha˘da˘ruga˘

80 Table 2 (continued) Food application/food ingredients interaction

Occurrence/source/ contenta

Separation and/or analysis

Reference

dried fruits (plum, 1.11 and date, 5.77 mg/100 g), fruit berries (cranberry, bilberry, lingonberry, raspberry, redcurrant, strawberry, up to 4.30 mg/100 g), apples and pears (0.18–0.27 mg/100 g), fruit juices (grape, apple, pear, 0.02–0.93 mg/100 mL), kiwi and pomegranate juices (97%). The resin capacity utilization of 92% for a productivity of 7.0 g/L/ h (optimized parameters) Sinapic acid productivity of 10 mg/g mustard bran (43 mg total phenolics/g mustard bran)

In vitro oxidation of sinapic acid to sinapic dimers (8-80 -disinapic acid) in wheat sprouts and cabbage at 2.30/1.94 μg/g DW and a sinapic acid/sinapic dimer ratio of 2.1/9.9, respectively Sinapic acid and sinapine recovery from canola flour of 0.34–0.40 and 10.65–12.09 mg/g DW

Separation and/or analysis Particle analysis, rheological analysis, consumer acceptance

Reference Comunian et al. (2017)

1 H- and 13C-NMR, FT-IR, SEM, DPPH
antioxidant activity for porous starch esters

Li et al. (2021)

Catalyzed esterification, HPLCMS, ORAC, DPPH, FRAP, peroxide value, HS-SPME-GC-MS, DLS

da Silveira et al. (2020)

Semi-continuous adsorption on Amberlite FPX66, UHPLC-UV-Vis

MorenoGonzález et al. (2021)

Optimized chemoenzymatic hydrolysis, GC-MS (derivatized for fatty acids), FolinCiocalteu method, HPLC-DAD, HPLCRI UHPLC-MS/MS

Achinivu et al. (2021)

HPLC-UV-Vis, FolinCiocalteu method, UV-Vis

Cai and Arntfield (2001); Niu et al. (2013)

Grúz et al. (2015)

(continued)

N.-G. Ha˘da˘ruga˘ and D.-I. Ha˘da˘ruga˘

90 Table 5 (continued) Food application/food ingredients interaction Sinapic acid derivatives in processed rapeseed oil

Sinapic acid contents in alcoholic beverages, cereals, seeds, oils, and vegetables

Occurrence/source/contenta Sinapic acid and vinylsyringol recovery of 2.3 and 62.9 mg/100 g in crude rapeseed oil, 1.3 and 29.7 mg/100 g in postexpelled crude oil, 0.4 and 4.8 mg/100 g in superdegummed oil, respectively Beer (0.0073–0.07 mg/100 mL), walnut liquor (0.08 mg/100 mL), wines (0.05–0.07 mg/mL), cereals and cereal flour (0.01–0.21 mg/100 g FW), seeds (nuts, beans, soy, 0.04–0.28), rape seed or soy oils (0.0009–0.83), olive (10.82–44.0), cauliflower (4.28); higher values in hydrolyzed food products

Separation and/or analysis Peroxide value, FolinCiocalteu method, HPLC-UV-Vis

HPLC-UV-Vis/DAD/ MS/ HPLC-MS/MS, UV-Vis

Reference Koski et al. (2003)

PérezJiménez et al. (2010); http:// phenolexplorer.eu

Sinapic acid contents, expressed as mg/100 g fresh weight, FW (unless otherwise specified); DW – dry weight

a

cereal flours (up to 72.2 mg/100 g of hard wheat flour) or dark chocolate (24 mg/100 g), according to http://phenol-explorer.eu/contents/polyphenol/459#chro matography. Hydrolysis of vegetable and food samples consistently increases the ferulic acid contents up to 123.5 and 170.6 mg/100 g for common wheat germ and maize flours, respectively (Pérez-Jiménez et al. 2010). Sinapic acid and its derivatives such as sinapine or vinylsyringol were quantified in canola flour and rapeseed oil up to 12.1 mg sinapine/g canola flour (DW) and 62.9 mg vinylsyringol/100 g rapeseed oil (Cai and Arntfield 2001; Koski et al. 2003; Niu et al. 2013). High sinapic acid content was also obtained in raw and hydrolyzed olives (10.8–44.0 and 27.0–45.0 mg/100 g DW, respectively), as well as hydrolyzed samples of common wheat germs, cranberry, and whole grain rye flour (10.6–28.3 mg/100 g) (according to http://phenol-explorer. eu/contents/polyphenol/464#chromatography and (Pérez-Jiménez et al. 2010)).

Chlorogenic Acids Chlorogenic acids especially consist of mono- and dihydroxycinnamic acids esterified with ()-quinic acid at 3, 4, and/or 5 positions. However, trihydroxycinnamic acid esters, as well as derivatization at 1 position of the quinic acid exist.

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Consequently, chlorogenic acids will have the same number of phenol hydroxyls such as the original hydroxycinnamic acids. They have important antioxidant properties, even as chlorogenic acids or after hydrolysis, which provide free hydroxycinnamic acids discussed above. The conjugation or complexation of chlorogenic acids with proteins or polysaccharides can occur due to the presence of many H-bond forming groups both from hydroxycinnamic and quinic acid moieties (hydroxyl and carboxyl groups), as well as hydrophobic moiety consisting of cinnamic acid part. The interaction of chlorogenic acids with whey, egg white, gluten proteins (Krekora et al. 2020; Sun et al. 2020; Zhang et al. 2021), and cyclodextrins (Budryn et al. 2015; Górnas et al. 2009) was studied (Table 6). Highest binding affinity was obtained for both α- and β-lactoglobulin in comparison with bovine serum albumin. It was proved that the variation of the surface charge involves the electrostatic interaction between chlorogenic acids and proteins, especially H-bonding for lactoglobulins (Zhang et al. 2021). Egg white proteins were conjugated with chlorogenic acids for obtaining antioxidant emulsifiers as dual functionality food ingredients (Sun et al. 2020). The chlorogenic acid content was 7.13% and conjugation through L-cysteine, L-tyrosine, and L-tryptophan residues improved the emulsification properties by decreasing the surface hydrophobicity. Such aspects were also observed on the interaction with gluten proteins in dough (Krekora et al. 2020). Such interactions were also studied through previous nanoencapsulation of chlorogenic acids from green coffee in β-cyclodextrin. The chlorogenic acid contents in proteins from soy, whey, and egg white were 9.44–12.2, 11.8–13.1, and 12.1–14.4 g/100 g, respectively (Budryn et al. 2015). The presence of β-cyclodextrin reduces these interactions due to the formation of a 1:1 complex, but with a higher stability (Górnas et al. 2009). β-Cyclodextrin was also used for the purification of chlorogenic acids from green coffee beans extracts for applying to food products such as cookies, bread, mushroom, and meat stuffing (Budryn et al. 2016). Protein hydrolysates were added with changes on the bioaccessibility of chlorogenic acids. Another very recent application of chlorogenic acids was as inhibitor of heterocyclic amines in charcoal roasted lamb meats through to a competitive reaction between chlorogenic acids and precursors of heterocyclic amines. Recent studies were focused on the production, extraction, and recovery of chlorogenic acids from various sources (Table 6) such as sunflower by-products (Náthia-Neves and Alonso 2021), yerba mate (Butiuk et al. 2021), potato peels or tubers (Torres-Contreras et al. 2014), Eryngium planum L. and Glechoma hederacea by in vitro cultures (Döring and Petersen 2014; Kikowska et al. 2012) or from green coffee beans (Suárez-Quiroz et al. 2014; Upadhyay et al. 2012). Optimized processes allow to obtain chlorogenic acids with yields of 840 mg/100 g from sunflower cake, 1051 mg/L from yerba mate (Ilex paraguariensis St. Hil.), up to 62% content in the microwave-assisted extract from green coffee beans, or a production of 2.0% in suspension culture of Glechoma hederacea L., known as ground ivy (Butiuk et al. 2021; Döring and Petersen 2014; Náthia-Neves and Alonso 2021; Upadhyay et al. 2012). Chlorogenic acids were studied as stabilizing agents for oil-in-water emulsions or antioxidants in ready-to-eat fruits (Chen et al. 2018).

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Table 6 Occurrence, separation, and analysis of chlorogenic acids related to food applications or interactions with food ingredients and other related products Food application/food ingredients interaction Interaction of chlorogenic acid and whey proteins

Conjugation of chlorogenic acid with egg white proteins

Effect of chlorogenic acid on the structure of gluten proteins in dough Interaction of green coffee bean-based chlorogenic acid/β-cyclodextrin complex with whey, egg white and soy protein isolates Chlorogenic acid/β-cyclodextrin complex in coffee brew

Nanoencapsulated chlorogenic acids and green coffee extracts as aroma enhancers of food products

Recovery of chlorogenic acid from sunflower by-products

Occurrence/source/contenta Chlorogenic acid content in the corresponding β-lactoglobulin, α-lactoglobulin, and bovine serum albumin complexes of 2–64 μM Chlorogenic acid content of 7.13% in the egg white protein complex

Chlorogenic acid in dough (0.05–0.2%)

Chlorogenic acid content in soy, whey and egg white protein complexes of 9.44–12.2, 11.8–13.1, and 12.1–14.4 g/100 g, respectively Chlorogenic acid from coffee brew was complexed with β-cyclodextrin in solutions (22  C, 60 min) at initial concentrations of 1 mM and 10 mM, respectively Purification of chlorogenic acid from green coffee extracts by CPC (increased content by 50%) and β-cyclodextrin complexation with a content of 19 g/100 g complex Chlorogenic acid recovery yield of 55–136 mg/g extract and 3.2–15 mg/g sunflower by-product, by conventional extraction, 37–118 mg/g extract and 0.96–9.7 mg/g sunflower extract, according to the type of solvent (water or ethanol-water mixture), respectively

Separation and/or analysis Fluorescence spectroscopy, UV-Vis, DLS, Far-UV CD, TEM, molecular modeling

Reference Zhang et al. (2021)

Folin-Ciocalteu method, DPPH
and FRAP assays, HPLC-MS/MS, fluorescence analysis FT-Raman spectroscopy, consistency (farinograph) LC-MS/MS, ITC, molecular modeling

Budryn et al. (2015)

UV-Vis, fluorescence spectroscopy

Górnas et al. (2009)

CPC, UHPLC-DAD/ MS/MS, DSC, DPPH
assay

Budryn et al. (2016)

Microwave-assisted extraction, HPLCUV-Vis, FolinCiocalteu method, SEM, FT-IR

NáthiaNeves and Alonso (2021)

Sun et al. (2020)

Krekora et al. (2020)

(continued)

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Table 6 (continued) Food application/food ingredients interaction Chlorogenic acid extraction from yerba mate Extraction of chlorogenic acids from green coffee beans for use in functional foods Isolation of chlorogenic acids from green coffee for possible use as natural antioxidants in food or nonfood products Production of chlorogenic acid isomers in potato tubers

Production of chlorogenic acids in in vitro cultures of Eryngium planum L.

Production of chlorogenic acids in Glechoma hederacea

Oxidized chlorogenic acid as stabilizing agent of oil-in-water emulsions

Chlorogenic acids in Thai Arabica green coffee beans after drying

Occurrence/source/contenta Chlorogenic acid content of 1.051 g/L yerba mate extract for the optimized extraction parameters Yields as chlorogenic acid and chlorogenic acid content in extracts of 4.7–8.4% and 30.52–61.87%, respectively Total chlorogenic acid contents of 4.67–5.87 g/ 100 g DW

Various chlorogenic acids and derivatives contents in whole and wounded potato tubers during storage: 50.76–479.9, 26.46–252.8, 34.97–126.04, and 23.32–36.31 mg/kg for chlorogenic, neochlorogenic, cryptochlorogenic, and 3,5-dicaffeoylquinic acids, respectively Chlorogenic acid content of 0.19–1.1 mg/100 g DW in Eryngium planum L. plants, 0.12–0.63 mg/100 g in organ in vitro cultures, and 0.25–2.54 mg/100 g in callus cultures Chlorogenic acid content up to 1.3, 1.6, and 2.0% in Glechoma hederacea stems, flowers, and leaves, respectively Oxidized chlorogenic acid content of 0.1–1.5% (relative to porcine plasma protein hydrolysate) in stabilized rapeseed oil-in-water emulsions Variation of the total chlorogenic acids, as well as mono- and dichlorogenic acids during drying by

Separation and/or analysis HPLC-UV-Vis

Reference Butiuk et al. (2021)

Microwave-assisted extraction, UV-Vis, Folin-Ciocalteu methods, DPPH
assay Various extraction methods, TLC, HPLC-UV-Vis, 1 13 H/ C-NMR

Upadhyay et al. (2012)

HPLC-DAD/MSn

TorresContreras et al. (2014)

HPLC-DAD

Kikowska et al. (2012)

HPLC-UV-Vis

Döring and Petersen (2014)

Particle analysis, peroxide value, conjugated dienes, thiobarbituric acidreactive substances, protein oxidation Color measurements, ultrasonic-assisted extraction, UHPLCDAD/MS/MS,

Chen et al. (2018)

SuárezQuiroz et al. (2014)

Kulapichitr et al. (2022)

(continued)

N.-G. Ha˘da˘ruga˘ and D.-I. Ha˘da˘ruga˘

94 Table 6 (continued) Food application/food ingredients interaction

Chlorogenic acids in herbal teas in Anatolia

Chlorogenic acids in Brazilian roasted coffee

Chlorogenic acid in fermented broth and fruits

Chlorogenic acids in 64 Brazilian fruits

Chlorogenic acids in vegetables

Chlorogenic acids in coffee-related products

Occurrence/source/contenta various methods of 4008.0–4453.5, 3601.5–4024.5, and 336.0–443.5 mg/100 g DW, respectively Melissa officinalis, Sideritis libanotica subsp. Linearis, and Stachys thirkei of 333.63, 5849.68, and 35372.8 μg/g extract, respectively Various chlorogenic acid contents of 0.38–4.21, 0.87–8.26, or 0.84–9.12 mg/g roasted coffee (bio, organic, and conventional farming) for 3-, 4-, and 5-CQA Chlorogenic acid purity of 73.1–74.9% by using Colletotrichum acutatum S216 or Sphingomonas yabuuchiae N21 strains, and a content of 0.048–0.101% in mango pulp and peel 3-, 4-, and 5-Caffeoylquinic acids (CQA) were quantified up to 199.14 (abiu fruit, quince, and cherry), 80.25 (strawberry), and 522.33 mg/kg (tangerine, jackfruit, nectarine, quince, bilberry, and mulberry), respectively Highest 3-CQA contents of 47.9–136.3 mg/kg FW (collard greens), 4-CQA, 24.6–38.2 (asparagus), 5-CQA, 38.5–128.0 (purple lettuce), 3,4-CQA, 91.4–155.6 (celery), 3,5-CQA, 331.6–362.3 (bay leaf), 4,5-CQA, 44.2–62.9 (rosemary) Chlorogenic acid contents in instant coffee/ decaffeinated coffee/ instant coffee mix of 54.5/94.9/124.2 mg/L for

Separation and/or analysis

Reference

Folin-Ciocalteu, DPPH
, and FRAP assays

LC-MS/MS

Ertas and Yener (2020)

HPLC-MS

Badmos et al. (2020)

UV-Vis, HPLC-UVVis, FT-IR

Wang et al. (2019b)

HPLC-DAD

Meinhart et al. (2019a)

HPLC-DAD

Meinhart et al. (2019b)

HPLC-DAD

Jeon et al. (2019)

(continued)

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Table 6 (continued) Food application/food ingredients interaction

Chlorogenic acids in green Robusta and Arabica coffee beans

Chlorogenic acids isomers in 89 herbal infusions Chlorogenic acid effect in sunflower butter cookies

Chlorogenic acids in sweet cherry

Chlorogenic acid isomers in 100 Brazilian plants

Chlorogenic acid in processed and cooked eggplants

Occurrence/source/contenta 3-CQA, 63.5/109.7/134.0 for 4-CQA, 86.8/155.3/197.6 for 5-CQA. Lower concentrations for 3,4-, 3,5-, 4,5-diCQA ( urolithin D > urolithin B). The difference in potency between urolithin A and urolithin B suggests that the presence of a hydroxyl group at position 8 of urolithin A is important for its biological activity (Ceci et al. 2020). However, due to the intensive phase II metabolism, a novel formulation may be needed to increase plasma urolithin concentration and enhance their biological activity, particularly urolithin A which has clinical significance.

Ellagic Acid Delivery Systems Micro- and nano delivery systems are technologies that show promise at enhancing drug bioavailability (Ceci et al. 2020). EA micro- and nanoparticulate systems include microspheres, nanoparticles pH-dependent microassemblies, nano-sized metalla-cages, and nanogels (Ceci et al. 2020). Biopolymers have been used in the field of food and drug delivery systems for preparation of micro- and nano-carriers. These systems can be taken up by the gastrointestinal tract through transcytosis and prevent degradation and first-pass metabolism of encapsulated drugs. In relation to EA, chitosan and poly(d,l-lacticco-glycolic acid) (PLGA) are the most common delivery systems used (Ceci et al. 2020). Liposomes consisting of a spherical bilayer are currently being used in the food and agriculture industry for both oil and water-soluble compounds. Liposomes can be produced from natural phospholipids. Studies with hydrogenated soy

420

N. Ahmed Nasef et al.

phosphatidylcholine have demonstrated that complexation with phospholipid improves the bioavailability and enhances the bioactivity of EA in rats, leading to enhanced hepatoprotective activity (Ceci et al. 2020). Further modifications to the liposomal systems such as a biopolymer coating of soybean lecithin liposomes were shown to improve stability of the encapsulation system and sustained release of EA (Ceci et al. 2020). EA-phospholipid complexes based on the self-nanoemulsifying drug delivery system (SNEDDS) showed improved EA lipophilicity and higher oral bioavailability (Avachat and Patel 2015). More recently, a food-grade EA self-nanoemulsifying system (EA-SNEDS) was evaluated for potential applications in dietary supplements and functional foods (Wang et al. 2017). Studies in rats indicated that EA oral bioavailability was significantly enhanced compared to pomegranate extracts (Wang et al. 2017).

Ellagitannin Supplements and Functional Food Ingredient The most common sources for many of the ET-enriched supplements and food ingredients come from pomegranate. Most of the ET supplements on the market are sourced from pomegranate (Madrigal-Carballo et al. 2009). These supplements vary in part of the pomegranate used but can consist of extracts from the peel/mesocarp, seed (arils), and whole fruit and can sometimes include the plant leaves. A study in 2009 evaluated the authenticity and antioxidant capacity of 19 pomegranate supplements on the market (Madrigal-Carballo et al. 2009). The study found that only seven of the tested products contained a similar ET composition to pomegranate fruit. On the other hand, the majority of the supplements tested contained significantly higher amounts of EA compared to pomegranate fruit suggesting that these products are not stable and may indicate degradation during processing. Furthermore, the antioxidant capacity (using synthetic oxidant capacity methods) of the products containing ET was high. In contrast, the products containing mostly EA had significant variation in antioxidant capacity which was attributed to their low water solubility (MadrigalCarballo et al. 2009). A well-studied example of pomegranate supplement used for human consumption is POM Wonderful LLC which is obtained by aqueous extraction of the whole pomegranate fruit residue after juicing followed by solid phase extraction of the liquid concentrate and drying to produce a polyphenol-rich powder (Seeram et al. 2008). As mentioned in an earlier section of this chapter, it is now acknowledged that the nonedible part of pomegranate fruits contains high amounts of ETs and these by-products are being considered by the nutraceutical and food ingredients industry. Pomegranate peel and peel extract have been shown to have multiple health benefits. In nutraceutical products, pomegranate peel is mainly provided as a dry extract; however, the stability of these products varies. Further studies are needed to enhance stability of these products using micro- and nano-encapsulation systems.

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Pomegranate peel has been considered as a food ingredient with functional properties. The by-product of pomegranate juicing (pomegranate bagasse) has been shown to have good free radical scavenging properties when incorporated into beef sausages (El-Gharably and Ashoush 2011). Another study showed that incorporation of pomegranate peel and bagasse powders and extracts into chicken meat patties protected the patties against oxidative rancidity (Sharma and Yadav 2020). Another study incorporated pomegranate bagasse into bread and found that it significantly improved the antioxidant potential of the bread (Bhol et al. 2016).

Quality Control and Stability Testing During Ellagitannin Product Development ETs are highly susceptible to pH but the products of hydrolysis that form are otherwise stable in heat and over time (Sójka et al. 2019). ETs degrade rapidly in neutral and mildly basic conditions and rapidly hydrolyze to intermediate products in acidic conditions (Sójka et al. 2019). As such, in food and ingredient contexts, characterizing and quantifying intermediate products of hydrolysis, such as ellagic acid and gallic acid, which are also more bioavailable, may be more relevant. Additionally, the selection of an intermediate moiety can indicate the total phenolic content in a single value that is comprised of multiple ET structures that are co-abundant in a single plant product. Ideally, high-resolution characterization of the ETs is carried out during the product development phase, which informs the selection of intermediate product or moiety that can serve as a proxy indicator of the ETs present in a product during routine batch testing. Methods have been validated for the characterization and quantification of ETs in pomegranate products, berries, wines, cognacs, and some medicinal plants. Ultra-high-performance liquid chromatography coupled to diad array detection and electrospray ionization tandem mass spectrometry (UHPLC-DAD-ESI-MS/MS) is the current standard for highresolution characterization and quantification of specific compounds, and standards for isomers are available. Ellagic acid and gallic acid are the common moieties that are readily and reliably quantified by spectrophotometric methods that have been validated and accepted by international associations such as the Association of Official Agricultural Chemists (AOAC).

Conclusion ETs and their metabolites are phytochemicals found in many natural foods with several potential health benefits reported in vitro, in vivo, and from human feeding trials with ET-rich foods. In this book chapter we provide insights into the digestion, bioavailability, and application of ETs based on the latest and most relevant literature. Better understanding of these promising compounds will help inform the nutraceutical and functional food industry to produce more effective products with benefits for the local and global community.

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Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Chemical Characterization of GTs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Degradation and Synthesis of GTs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Distribution and Distinction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Physiological Activities of GTs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Antioxidant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anti-inflammatory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sensory Reinforcement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Antidiabetic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Antibacterial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Application of GTs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Food Processing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Food Package . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Plant Protection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Phylaxiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Safety and Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abstract

Gallotannins, characterized with the glycosidic core and galloyl unit, seemed as vital components of hydrolyzable tannins. Research over the past century draw aside the curtains of gallotannins to reveal the rich vistas which lay beyond. Since the first disclosure in 1900s, gallotannins had attracted amounts of attention. Initially applied in tanned leather, but with the discovery of their antioxidant effect and additional reaction mechanisms, application of gallotannins in food, medicine, feed, cosmetics, and other fields is increasing. Gallotannins contribute H.-F. He (*) College of Pharmacy, Jining Medical University, Rizhao, People’s Republic of China e-mail: [email protected] © Springer Nature Switzerland AG 2023 S. M. Jafari et al. (eds.), Handbook of Food Bioactive Ingredients, https://doi.org/10.1007/978-3-031-28109-9_12

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significantly to taste, flavor, color, stability, etc., while they could be used in food package. Contributing towards reducing the risk of chronic disease, gallotannins were recognized as important factors in long-term health increasingly. Pioneer studies verified that gallotannins could serve as a potentially valuable source of bioactive compounds. Inheriting previous research achievements, chemical structure of gallotannins was illustrated; degradation and synthetic routes to gallotannins were summarized. On this basis, distribution in the nature also including the distinction of gallotannins was discussed. More than that, activities involved in antioxidant, anti-inflammatory, enzyme inhibition, protein binding, and so on, as well as applications in the field of food industry, biopharmaceutical science, agricultural production, etc., were combed. Keywords

Gallotannins · Structural characteristic · Resource distribution · Physiological activities · Industrial application

Introduction Phytochemicals, especially plant-derived polyphenolic compounds, have been proven to possess a wide range of pharmacological properties and are recognized as naturally occurring antioxidants. Meantime, there is general consensus that diet rich in fruit, vegetables, and nuts is beneficial to health. To trace these phenomena to their sources, phytochemicals contained in these products play an essential role in the health benefits. Among the multitudinous food ingredients, tannins occupy an important place. Originally coined by Seguin to describe the substances present in vegetable extracts, tannin was introduced to convert animal skin to leather initially (Seguin 1976). In the nature, tannins have been found in a variety of food grains, fruits, wines, forages, and tea. Roughly divided into hydrolyzable and condensed tannins, tannins were reported with multiple health benefits. Containing a large number of hydroxyl or other functional groups, tannins are capable of forming cross-linkages with proteins and other macromolecules. Also, tannins could aggregate with alkaloids, gelatin, and proteins to form precipitation. Known as hydrolyzable tannins (HTs), gallotannins (GTs) and ellagitannins (ETs) are the most widely occurring tannins. Thereinto, GTs are one of the most often underlined components. Chemically, GTs are divided into the category of hydrolyzable tannins (HTs) and seemed as the simplest HTs in general (Haslam et al. 1961). Comparatively, GTs were more likely to interact with lipid membranes for its more hydrophobicity (Virtanen and Karonen 2020). Characterized with the glycosidic core and galloyl unit, GTs are present in nearly all plants in the nature. For the nutraceutical and prophylactic potential, GTs have been of scientific interest. Lots of fruitful pioneer research had been documented. Since antiquity, herbal containing gallo- or ellagitannins had been used to improve vascular health and many other diseases. GTs are associated with reduced risk of chronic diseases connected with the elevated

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inflammatory state particularly cardiovascular diseases (CVD), type-2 diabetes, inflammatory bowel diseases (IBD), and other gastrointestinal tract pathological conditions (Arapitsas 2012). Results of clinical, interventional, and animal in vivo studies clearly indicate the anti-inflammatory potential of GT-containing products. Despite study for centuries, there are still many confused conclusion and unresolved contradictions waiting to be figured out. For instance, structural definition as well as scientific classification is still ambiguous. Thus, due to the tanglesome definition as well as the multifarious functional activities, it is necessary to comb the superficial cognition about GTs.

Chemical Characterization of GTs Before discussing the biogenetic routes to hydrolyzable plant tannins, it appears helpful to insert a few comments on the structural principles and conventional definitions used in this field. First of all, it should be legible with regard to the chemical structure of GTs. Named as tannic acids inchoately, GTs were commercially available as a standardized extract. GTs are characterized by having a high degree of polymerization with an elevated number of galloyl moieties. From a structural point of view, GTs are polygalloyl esters of glucose, that is, they consist of a central polyol, most often glucose, which is surrounded by several GA units. Upon hydrolysis by acids, bases, or certain enzymes, GTs yield glucose and gallic acid. Apart from glucose, the galloyl unit derivatives are bounded to diverse polyol-, catechin-, or triterpenoid cores (Mena et al. 2015). For example, glucitol corecontaining GTs were identified from red maple (Acer rubrum) (Li et al. 2020). Unnatural GTs, taking 2-C-(hydroxymethyl)-branched aldoses as the central polyol, were designed and synthesized (Hricovíniová et al. 2021). Employing 1,5-anhydroalditol and inositol as the cyclic polyol cores, Machida and co-workers designed and obtained 14 unnatural gallotannin derivatives (Han et al. 2014). According to Niemetz (Niemeta and Gross 2005), GTs could further be subdivided into “simple” and “complex” galloylglucoses. Being the simplest member of GTs, 1-O-galloyl-β-D-glucopyranose (compound 1, Fig. 1) had been identified more than a century ago as a natural product. According to the number of galloyl groups, there are MoGG, one galloyl group; DiGG, two galloyl groups; TriGG, three galloyl groups; and TeGG, four galloyl groups. Full substitution of galloyl to glucose would 'simple' galloylglucoses 'complex' galloylglucoses OR

OH O HO HO

R=galloyl moiety OH

OH OC O

compound 1

OH OH

OR O

RO RO Galloylation

R=galloyl moiety RO RO

OH OR OC O

compound 2, PGG

Fig. 1 The structural illustration of gallotannins

OH OH

R=Galloyl / meta-digalloyl moiety O

Galloylation

O O

OR OC O

compound 3

C OH

OH

OH OH OH

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lead to 1,2,3,4,6-penta-O-galloyl-β-D-glucopyranose (PGG, compound 2, Fig. 1) (Torres-Leon et al. 2017), which seemed as the prototypical “complex” galloylglucoses (Li et al. 2021). Sequentially, GA units can be attached through depside bonds to form “complex” galloylglucoses with high MW. A typical representative of these “complex” galloylglucoses, the hexagalloylglucose, 2-Odigalloyl-1,3,4,6-tetra-O-galloyl-β-D-glucopyranose (compound 3), is depicted in Fig. 1. It must be emphasized, however, that gallic acid now combines with phenolic hydroxyls whose chemical properties are significantly different from those of the aliphatic OH-groups of glucose. The depside bonds between galloyl units are considerably less stable than the core ester linkages (Virtanen and Karonen 2020). Due to the presence of an esteric link between two galloyl moieties (depsidic link), GTs are also considered to be depsidic metabolites.

Degradation and Synthesis of GTs GTs could be easily degraded by bacteria, fungi, and yeasts. Catalyzed by different enzymes produced by microbes, hydrolysis and oxidation occur in the degradation of GTs. These enzymes refer to tannase, polyphenol oxidase, decarboxylase, gallic acid decarboxylase, pyrogallol 1,2-dioxygenase, pyrogallol phloroglucinol isomerase, phloroglucinol reductase, dihydrophloroglucinol hydrolase, phenol oxidase, etc. As known, the degradation of GTs consists of the following procedure sequentially: tannase participates into the first cleaving depside bonds (depsidase activity), followed by hydrolysis of the ester bond and the formation of gallic acid. Then, gallic acid is decarboxylated by gallic acid decarboxylase to form pyrogallol, which is converted to pyruvic acid, cis-aconitic acid, and 3-hydroxy-5-oxo-hexanoate, and finally enters the Krebs cycle (Karas et al. 2017). A study of ruminants revealed hydrolysis of ester and depside linkages of gallotannins by intestinal enzymes, and colonic microbiota yields the core polyol (glucose) and gallic acid. The resultant aglycone (gallic acid) is metabolized to pyrogallol and phloroglucinol and, ultimately, to acetate and butyrate. Eubacterium oxidoreducans and Coprococcus sp., which are present in the rumen and the distal portion of the monogastric intestine, are involved in this reaction. In the light of present situation, biodegradation of GTs is in an incipient stage, and further studies have to be carried out to exploit the potential of various GTs for large-scale applications in food, fodder, medicine, and tannery effluent treatment. When it turns to the synthesis of GTs, biosynthesis was to be discussed first. Enzyme studies conducted by Grundhofer indicated β-glucogallin was required as principal acyl donor for biosynthesis of GTs. Immunohistochemical studies with antibodies raised against pentagalloylglucose and the galloyltransferase catalyzing the formation of this ester revealed that leaf mesophyll cell walls were a typical site of origin and deposition of hydrolyzable tannins (Grundhofer et al. 2001). Gallic acid was derived from an early intermediate of the shikimate pathway, most likely 5-dehydroshikimate (Werner et al. 1997). Esterification of gallic acid

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and glucose to yield β-glucogallin (1-O-galloyl-β-D-glucose, 2) was catalyzed by enzyme extracts from oak leaves with UDP-glucose serving as activated substrate (Gross 1983a). These enzyme preparations were found to catalyze also the transformation of in situ formed β-glucogallin to di- and trigalloylglucoses without any further cofactors, indicating that β-glucogallin exerted a dual role, functioning not only as acyl acceptor but also as efficient acyl donor (Gross 1983b). Substitution of glucose hydroxyls was not randomly distributed in these conversions but displayed an unexpected extreme specificity, thus constituting the metabolic sequence βglucogallin ! 1,6-digalloylglucose ! 1,2,6-trigalloylglucose ! 1,2,3,6tetragalloylglucose ! 1,2,3,4,6-pentagalloylglucose. In association with the biosynthetic pathway, β-glucogallin is presumed to be the first intermediate and a key metabolite in the synthesis of GTs. This first biosynthetic pathway is completed by the formation of PGG (generally considered to be a simple galloylglucose ester). Supplementary experiments determined that the pathway to pentagalloylglucose was identical in both plant groups. The transition from “simple” galloylglucoses to “complex” gallotannins is marked by the addition of further galloyl residues to PGG to yield their characteristic meta-depside groups (Arapitsas 2012). During the second step, further galloylation reactions at the PGG core by which highmolecular metabolites are formed can contain up to 10 galloyl residues, with the formation of hexa-, hepta-, octa-, and so on galloylglucose derivatives (Buzzini et al. 2008). On the other hand, dependence on natural materials in short supply and difficulties in the isolation and purification have limited the research work and the practical utilization of GTs; chemical synthesis of GTs was documented unremittingly. Sylla and co-workers reported the first total chemical syntheses of two GTs, namely, hexagalloylglucose and decagalloylglucose, in both anomeric forms (Sylla et al. 2015). Commercial 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose was selected as the starting material to introduce the first galloyl moiety at the O3 position of the glucose unit. Successive galloylation reaction under mild nonacidic Steglich-type conditions gave the corresponding 3-O-galloylated D-glucofuranose. Final hydrogenolysis of the fully protected hexagalloyl-D-glucopyranoses under classical palladium-mediated conditions in THF at room temperature for 24 hours would give the hexagalloyl-β-glucopyranoses, PGG (Sylla et al. 2015). Employing benzylprotected gallic acid chloride as the substrate, reaction conditions that lead to high anomeric selectivity for the synthesis of GT were investigated. Accordingly, solvent for the reaction was of critical importance in order to achieve very high α:β selectivity, and the highest selectivity were found when acetonitrile was used as a solvent. Meanwhile, dichloromethane (CH2Cl2) was proven to accelerate the rate of mutarotation relative to the rate of condensation to the ester (Binkley et al. 2009). Starting from slight modification of methyl gallate, coupling with galloylation sequentially, alkyl GTs were synthesized to study the protective effects of synthetic polyphenols that are structurally related with natural compounds (Hricoviniova et al. 2020).

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Distribution and Distinction Various galloyl-glucopyranoses occur naturally in lots of plants. Representatively, occurrence of GTs was found in the tannins of Chinese galls (Rhus semialata) and Turkish galls (Gallae turcica). Also, GTs are present at sufficient levels to allow direct isolation from different plants such as Paeonia suffruticosa, Paeonia lactiflora (Li et al. 2021), Schinus terebinthifolius, and the leaves of Sicillian sumac (Rhus coriaria L.) and the common smoke tree (Cotinus coggygria Scop.) (Mena et al. 2015). The rapid development of instruments as well as the innovation in analytical methods facilitate the discovery of new novel GTs. Meanwhile, improved detection accuracy guaranteed the detection of GTs in a wider range of plant species. Based on the flow injection analysis-electrospray ionization-ion trap tandem mass spectrometry (FIA-ESI-IT-MS-MS) and matrix-assisted laser desorption/ionization-time-offlight mass spectrometry (MALDI-TOF-MS), a rapid and reliable analytical approach was proposed to investigate the full range of HTs present in the extracts of Astronium species and evidenced the existence of GTs in Astronium genus firstly (da Silva et al. 2011). According to Boulekbache-Makhlouf, 18 GTs were present in fruit of Eucalyptus globulus growing in Algeria (Boulekbache-Makhlouf et al. 2010). By means of high-performance liquid chromatography-electrospray ionization mass spectrometry (HPLC-ESI-MS) method, assisted by diode array detection, 14 GTs could be isolated from birch (Betula pubescens) leaves (Salminen et al. 1999). With the occurrence of absorption maxima between 275 and 280 nm on UV spectra, LCMS molecular ion and fragment ion peaks, combining with NMR survey to the proton and carbon signals, five GTs were identified from Sapria himalayana f. albovinosa in Myanmar (Iwashina et al. 2020). Among 42 edible beans, red sword bean (Canavalia gladiata) was found to have the highest content of GTs (Gan et al. 2018). And research result revealed that monogalloyl to hexagalloyl hexosides comprised the GTs film. With regard to the refined structure, the various sources of GTs yield products with differing chemical structures. The concentration of GTs is a highly plastic trait; it varies with plant genotype, tissue developmental stage, and environmental conditions. Several inconsistent theories have developed regarding the chemical composition of GTs distributed in different plants. Elucidating specific structures is much preferred to the general assays. Chelation with metal ions and the formation of complexes, a stable five-membered ring chelate between catechol and metal ion, guaranteed the detection of GTs by UV-Vis spectroscopy. Recent advances in describing GT structural variation in an ecological context has been made using HPLC-MS. The availability of simple colorimetric assays for the measurement of tannins and other phenolics has undoubtedly facilitated many ecological studies of tannins. Thus, the assay is dependent on the availability of the appropriate standard. The use of an inappropriate standard, for example, the commonly used quebracho tannin, can lead to large errors in quantification. The lack of commercially available ecologically relevant tannins continues to be a stumbling block for performing controlled studies on specific tannins. However, a growing number of researchers

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had prepared crude tannin extracts for use as tannin standards, and additional steps at tannin purification are feasible using a Sephadex LH-20 column (Barbehenn and Constabel 2011). Free gallic acids are also present in varying amounts, depending on the degree of hydrolysis. Oriental sumac tannins are polygalloyl glucose derivatives with a ratio of glucose to gallic acid of 1 to 9 or 10. Turkish gall nuts yield a tannin with a ratio of 1 glucose to 5 or 6 gallic acids (Beaseley et al. 1977). Characterized by MALDI-TOF-MS, relying on the alteration of cationization reagents, Cs+, K+, and Na+, different spectrum of Chinese GTs was given (Xiang et al. 2007). Certainly, extraction can make a big difference in analysis of GTs. Despite the lack of commercially available standards, pioneer papers dealing with extraction optimization, identification, and quantification of GTs were documented constantly. Although varying greatly but are fairly consistent across cultivars, GTs in various by-products (barks, kernels, peels, and old and young leaves) in a range of Brazilian mango cultivars were identified and quantitated (Barreto et al. 2008). Extraction of mango kernel fat with hexane did not affect the profile and contents of GTs. In contrast, significant changes were observed when methanol was used for the extraction of defatted mango kernels. Methanolysis of GTs to PGG took place. Simultaneous extraction and methanolytic conversion of GTs from mango seeds yield methyl gallate and PGG. Only methanol extraction but not hexane extraction led to the degradation of higher GTs, which is an important facet with respect to the utilization of by-products originating from mango fruit processing (Engels et al. 2012). In respect to extract process, high-speed countercurrent chromatography was applied to the separation of GTs from mango kernels. The kernels were defatted and subsequently extracted with aqueous acetone (80% (v/v)). The crude extract was purified by being partitioned against ethyl acetate. A hexane/ethyl acetate/methanol/ water solvent system (0.5:5:1:5 (v/v/v/v)) was used in the head-to-tail mode to elute tannins according to their degree of galloylation (tetra-O-galloylglucose to deca-Ogalloylglucose) (Engels et al. 2010).

Physiological Activities of GTs Various advantages, e.g., scavenge free radicals, antidiabetic, antimutagenic, and antimicrobial precipitate proteins and inhibit multifarious enzymes, were shown by these GTs. There is one consensus to be emphasized that GT structural details are important for many of their biological effects. The high molecular complexity and amount of hydroxyl groups (-OH) in GT are responsible not only for a plethora of methods for extraction and purification but also for the several pro- and antiphysiological effects of them such as enzyme inhibitions, protein excretion stimulation, AOXc, and antiproliferative effects. The GT-protein and GT-phospholipid interactions were the result of cooperative effects of hydrogen bonding and hydrophobic association, and hydrogen bonding was the predominant effect in the interactions between GTs and sugars (He et al. 2006). All these endowed the good prospects of GTs for use in the pharmaceutical industry.

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Antioxidant It is important to note that health benefits mentioned above all associated with the antioxidant capacity of GTs. These properties depend largely on the number of galloyl groups and their position (Hatano et al. 1990). A higher number of galloyl groups is linked with improved interactions with proteins and increased ability to scavenge 1,1-diphenyl-2-picryl-hydrazyl (DPPH) radicals. (Karas et al. 2017) According to the research, antioxidative activity of GTs increased proportionally to the number of galloyl moieties (Machida et al. 2021). The antioxidative capacities of GTs on lipid peroxidation were determined as PGG > TeGG>TGG > DiGG>GA (Olivas-Aguirre et al. 2015). The importance of the placement of the galloyl groups on the glucose core was indicated by a study of the inhibitory effects of 1,2,6-, 1,3,6and 3,4,6-TriGG on lipid peroxidation in mitochondria and microsomes of the liver where the greatest antioxidative effect was exhibited by 1,3,6-TriGG and the least effect by 3,4,6-TriGG (Kimura et al. 1984). More recently, it was shown that 1,2,3,6TeGG had a strong effect on the affinity of GTs to galloyltransferase, whereas 1,3,4,6-TeGG was inactive (Niemetz and Gross 1998). It is proven that galloyl groups of GTs are hydrophobic sites and that these groups can interact with aliphatic side chains of amino acids through hydrophobic association (Beaseley et al. 1977). Diversely, evaluation of antioxidant, antimicrobial, and antibiofilm activity indicated that the inhibitory effect was dependent on the type of sugar (Hricovíniová et al. 2021).

Anti-inflammatory In treatment with ulcerative colitis, a primary component of inflammatory bowel disease (IBD), GTs also exhibited significant advantages (Xiao et al. 2013). Protective effect on DSS-induced colitis was witnessed by treatment with corilagin, a gallotannin present in many medical plants. Acting on the NF-κB pathway, corilagin could mitigate colon inflammatory responses and apoptosis of intestinal epithelial cells. By a self-assembly technique, Turkish gall GTs (TGTs)-FeIII microcapsules were prepared. The microcapsules were more likely to accumulate on the inflammatory surface from ex vivo and in vivo adhesion experiments and effectively alleviate ulcerative colitis (UC) symptoms (Zhang et al. 2019a). New perspective on understanding anti-inflammatory effects attributed to HT containing products, especially their postulated effectiveness in IBD and cardiovascular diseases (CD), was given (Kiss and Piwowarski 2018). PGG inhibited the expression and activity of nitric oxide synthase (iNOS) and suppressed the production of nitric oxide (NO), as well as that of proinflammatory cytokines (interleukins and TNF-a); decreased the aggregation of thrombocytes and expression of the adhesive molecules VCAM-1, ICAM-1, and MCP-1 in human endothelial cells; or induced the relaxation of contracted aortic rings (Karas et al. 2017). As documented, GTs could dosedependently decrease gene expression and production of iNOS. As the result, lipopolysaccharide (LPS)-induced NO production was significantly reduced in macrophages. In other words, GTs isolated from Euphorbia species (Euphorbiaceae)

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showed inhibitory effect on the LPS-induced inflammatory reaction (Kim et al. 2009).

Sensory Reinforcement Being the predominant substance contributed to orosensory sensation of food, GTs were employed to investigate the aversive behavior on astringency of foods by naïve mice (Ramirez et al. 2011). Ingestion of serial dilutions of GTs by inbred mice was assessed by a one-bottle preference test. Drink intake was far predominant at night (circadian rhythm). GTs’ concentration dependently inhibited daily drink consumption. Sometimes we feel an astringent taste when we drink tea. Combination of tannin and oral salivary protein was responsible to the sensual experience.

Antidiabetic Due to numerous hydroxyl groups located on GTs skeleton, gallotannin-enzyme interactions occur at the pancreatic lipase (PL)-colipase complex interface, according to molecular docking. IC50 22.4 and 64.6 μM, respectively, implied GTs to be effective inhibitors, with strong affinity toward the enzyme substrate complex (uncompetitive inhibition), which endowed GTs to be used to treat dyslipidemias and obesity (Moreno-Cordova et al. 2020). Moreover, PGG stimulated glucose transport in adipocytes and suppressed adipocyte differentiation, thus exhibiting a potential beneficial activity toward diabetes and metabolic syndrome (Karas et al. 2017). Potential association between colon-derived SCFA production and metabolic improvement due to GCG-enriched red maple leaf extract administration highlights the utilization of red maple GTs as a dietary ingredient for preventing obesity and related metabolic diseases (Li et al. 2020). The aggregation propensity of GTs equipped them with the potential to be used as antidiabetic drugs. As a PARG inhibitor, treatment with GT resulted in protection up to a certain level of glomerular damage, suggesting compensatory glomerular hypertrophy. GTs of Aleppo oak origin are nonspecific promiscuous α-amylase inhibitors, which exert their effect through their aggregates (Szabo et al. 2021). Being an inhibitor of ɑ-glucosidase, GTs were reported to possess antidiabetic properties (Machida et al. 2021). They also showed protection in PARP cleavage which is a hallmark for apoptotic cell death signifying the protective role of GT in cell death signaling. The result portends GTs to be used as an alternative approach to ameliorate the development of streptozotocin-induced diabetic nephropathy (Chandak et al. 2009).

Antibacterial GTs were proven to be potent inhibitors and disruptors of a series of bacteria (Hricovíniová et al. 2021). As documented, outer membrane confers bacteria

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resistance to microbicide (Engels et al. 2011). Benefiting from the strong affinity for iron, GTs showed inhibitory activities against the growth of bacteria. In response to shin-whitening effect, GTs isolated from Chinese galls showed inhibitory activity against tyrosinase and inhibited the biosynthesis of melanin, which related to hyperpigmentation (Chen et al. 2009). In a study on the antitumor mechanism, cytotoxicity against Hep G2 and Chang hepatocellular carcinoma cells was exhibited by GTs (Han et al. 2014). Inhibiting cell adhesion and suppressing cell repair motility, GTs would induce apoptosis of hepatocellular carcinoma cells.

Application of GTs Food Processing GTs as a mediator was introduced to acid-swollen collagen (ASC) films for its reinforcement. Hypothetically, laccase (Lac) in LMS oxidizes GT to reactive quinone, which can attack ASC more easily compared to the direct catalyzation of Lac, resulting in an efficient cross-linking and related performance of ASC. The GT-containing LMS provides the potential to greenly modify collagenous materials extensively used in food industry, especially meat processing (Duan et al. 2020). High selectivity on the regulation of the growth of bacteria was shown by penta-, hexa-, and heptagalloylglucose; especially, the growth of several pathogenic bacteria is inhibited, whereas the growth of nonpathogenic lactic acid bacteria is not affected. This predicted the application of GTs as bio-preservatives in foods (Engels et al. 2009). GT was bound by pectin and fabricated insoluble gallotannin-pectin complexes; the maximum combination GT to pectin mass ratios were 0.28 and 0.47 for hydrochloric acid-extracted pectin (HEP) and chelating agent-extracted pectin (ChEP), respectively. ChEP was a better additive in beverage containing GTs, while HEP had better emulsifying stability (Zhang et al. 2019b). GTs improved collagen synthesis, reduced metalloproteinase-1 (MMP-1) expression in a dosedependent manner, and downregulated MMP-1 levels through the ERK/JNK signaling pathway in UVB-irradiated human cells. GTs also increased glutathione but did not increase transforming growth factor beta 1, which induces fibrosis (Ryeom et al. 2018).

Food Package In order to extend shelf-life and reduce the risk from foodborne bacteria, many efforts had been tried on packing films/coasting. For the sake of the food packaging legislation of many regions and given the inactivation or evaporation of the antimicrobial agents under the harsh conditions (traditionally, were high temperature, pressure, and shear forces), allyl isothiocyanate or nanosilver films were

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circumscribed for use in food packing. Furthermore, the negative impact on organoleptic qualities of food was also an important reason. Thus, universally approved and commercialized antimicrobial food packaging film was desired. For the proven antibacterial properties and food contact permit, GTs were introduced into food packaging films (Widsten et al. 2017). Thermal process would trigger the release of free gallic acid from GTs. And the high concentration of gallic acid would lead to the increase of antioxidant ability (Gonzalez et al. 2010). Especially, this character guaranteed GTs the inhibitory effect on lipid oxidation and convinced the use in food package.

Plant Protection Nevertheless, in the field of plant-insect interactions, GTs are still often referred to as anti-digestive protein-binding agents. The inherent affinity of these polyphenols for proteins renders it plausible that (1) they contribute to the chemical defense of plants against pathogenic microbes and herbivores via protein binding and enzyme inactivation and (2) they may also play an important role in limiting the infectivity of viral pathogens against insect herbivores. In particular, oak GTs reduce the infectivity of naturally occurring nuclear polyhedrosis viruses in gypsy moth caterpillars (Haslam 1989). GTs extracted from Sedum takesimense showed potent antibacterial activity against Ralstonia solanacearum in vitro and in vivo. The broad-spectrum activity against various plant-pathogenic bacteria displayed by GTs made the use as natural bactericides for the control of tomato bacterial wilt possible, and the strongest in vitro antibacterial activities of these GTs were against R. solanacearum (Vu et al. 2013). As documented, 1,2,6-tri-O-galloyl-b-D-glucopyranose isolated from Terminalia chebula fruit exhibited efflux pump inhibitory activity which may be one of the possible mechanisms of its antibacterial action against multidrugresistant uropathogenic E. coli (Bag and Chattopadhyay 2014). Besides, it was revealed by Tuominen and co-workers that contents of polyphenol, GTs, e.g., differed significantly between ontogenetic phases. According to this, the role of polyphenols in plant-herbivore interactions could be evaluated, or the best collection times of G. sylvaticum for compound isolation purposes could be planned (Tuominen and Salminen 2017).

Phylaxiology According to documents, calcium-activated Cl1 channel (CaCC) plays an important role in cell physiology. Being modulators, GTs strongly inhibited TMEM16A with IC50 of 10.0, which showed potential utility for treatment of hypertension, diarrhea, and cystic fibrosis. To some extent, GTs could seem as the molecular basis of red wine and green tea for their benefits in prevention of cardiovascular disease and antisecretory action (Namkung et al. 2010).

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Safety and Toxicity Despite the diverse physiological activities as well as the extensive application, especially in food industry, double-edged sword of GTs should not be neglected. Experimental data revealed that synthetic GTs, methyl 2,3,4,6-tetra-O-galloyl-α-Dglucoside (G4Glc), methyl 2,3,4,6-tetra-O-galloyl-α-D-mannoside (G4Man), and methyl 2,3,4-tri-O-galloyl-α-L-rhamnoside (G3Rham), possess significant radical scavenging/antioxidant activities and manifest very low genotoxic effect on human PBMCs. Moreover, tested compounds considerably reduce the level of DNA damage induced by hydrogen peroxide or Fe2+. The results imply that new synthetic GTs can be considered as nontoxic agents for subsequent design of new antioxidants with potential biomedical applications (Gross 1983b). Binding with protein would reduce the bioavailability of both proteins and polyphenols. Previous studies have suggested that flexible proline-rich proteins have high binding affinity for vegetable tannins and that the interaction between PGG and proline-rich peptides mainly involved hydrophobic stacking of the planar phenolic ring against the pyrrolidine ring of the proline. The ability of precipitation of protein by GTs has been related to the molecular weight (degree of esterification) and structural flexibility of tannins (Zhang et al. 2021). The ability of GTs to bind with proteins in the guts of mammals can have beneficial effects, depending on GT concentration and nutrient levels (Barbehenn and Constabel 2011).

Conclusion Standing on the foundation of pioneer work, perception of GTs was refreshed. Precise chemical structure about GTs was illustrated to define the structural characteristics accurately. In the wake of hydrolysis and oxidation, degradation takes place to yield bioavailable fragments. The mechanism was summarized cumulatively. Sequentially, synthetic routes to GTs were proposed from aspects of biosynthesis and chemical synthesis, respectively. In addition, the advantages of GTs in performing antioxidant, anti-inflammatory, enzyme inhibitions, protein-binding, etc. were combed systematically. Despite the amount of excellent research and sufficient attention being paid, accompanied with massive literature reports, insight into GTs is still at the very beginning stage. Concerted efforts are still needed to achieve more extensive and in-depth utilization of GTs. Orally administered GT-containing products due to the limited bioavailability of GTs can influence immune response at the level of the gastrointestinal tract as well as express modulating effects on the gut microbiota composition. More accurate delivery on affected areas and more efficient absorption and utilization are still in front of the urgent need to solve the problem. At the level of action mechanism, structure-function relationship indicated that naturally occurring GTs, in fact, do not represent the optimal protein recognition agents among polyphenolated templates (Feldman et al. 1999). For this reason, modification of the structure of GTs with the help of chemical synthesis was desired.

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Cross-References ▶ Ellagitannins ▶ Flavones

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Procyanidins

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Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Procyanidins: A General Overview of Structure, Sources, and Health Benefits . . . . . . . . . . . . . . . General Structure of Procyanidins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Main Derivatives and Structures of Procyanidins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Sources of Procyanidins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Beneficial Properties of Procyanidins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Bioavailability of Procyanidins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Bioavailability Studies of Procyanidins by Different Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Digestion Stability of Procyanidins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Extraction and Encapsulation Methods of Procyanidins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Extraction of Procyanidins from Different Sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Solid-Liquid Extraction of Procyanidins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ultrasound-Assisted Extraction of Procyanidins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Encapsulation of Procyanidins by Various Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Significance of the Encapsulation for the Appropriate Use of Procyanidins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Encapsulation of Procyanidins by Spray Drying . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Encapsulation of Procyanidins by Nanoemulsion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Combined Methods for the Encapsulation of Procyanidins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Liposomal Structure of Procyanidins for the Encapsulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Other Methods for the Encapsulation of Procyanidins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Food Applications of Procyanidins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Applications of Procyanidins in Various Food Matrices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Commercial Procyanidin-Rich Bioactive Extracts in Food Matrices . . . . . . . . . . . . . . . . . . . . . . Procyanidins as a Fortification Agent in Food Matrices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Safety and Regulations of Procyanidins from Different Sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Safety and Regulations of Procyanidin Derivatives from Cranberry Extract . . . . . . . . . . . . . .

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M. Resat Atilgan (*) EBILTEM Science and Technology Application and Research Center, Ege University, Bornova, Izmir, Turkey O. Bayraktar Faculty of Engineering, Department of Bioengineering, Ege University, Bornova, Izmir, Turkey © Springer Nature Switzerland AG 2023 S. M. Jafari et al. (eds.), Handbook of Food Bioactive Ingredients, https://doi.org/10.1007/978-3-031-28109-9_13

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Safety and Regulations of Procyanidin Derivatives from Grape Extract . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abstract

Due to their high antioxidant properties, phenolic substances are known as protective phytochemicals with health-promoting properties against some diseases and disorders caused by oxidative stress in the human body. These compounds are isolated from various plant sources by miscellaneous methods. Phenolics, which have the greatest diversity among the naturally derived compounds, have been studied to integrate their antioxidant properties into the human body through different food and biochemical applications for decades. Procyanidins are a class of polyphenols formed by the condensation of tannins and are the building blocks of the proanthocyanidin molecule. Procyanidins have been applied to scientific research concerning their therapeutic effects in the presence of high antioxidant properties. The application of procyanidins, extracted from the pulp and skin of many dark-colored berry fruits, especially red grapes, cocoa, and their seeds, in food, biochemistry, cosmetics, and textile fields, has been also researched in recent years. The main goal of this chapter is to review the structural properties, subgroups, classification, major sources, and bioaccessibility of the procyanidins phytochemicals. The second goal is to investigate the purification procedures of the procyanidin molecule from different sources by appropriate extraction methods following the encapsulation of the purified form with different methods. Various food and packaging applications of procyanidins in free or encapsulated form are also discussed by several research studies in the chapter. Moreover, the chapter includes the information on the sufficiency of the use of procyanidins in the varied food matrix and how it is supported by the safety and regulation documents. Keywords

Procyanidins · Bioavailability · Extraction · Encapsulation · Food applications

Introduction Along with the rise of the global population, the efficient use of resources has become difficult and limited. As an inevitable consequence of this, an increase has been happening in the rate of excessive consumption of existing resources. This situation has begun to have a serious and irreversible result for human anatomy and metabolism. In addition to the dramatic growth rate of the world population, depleted resources and deteriorating environmental conditions cause cellular and molecular destruction in the human body causing the shortening of its average lifespan (Khan et al. 2021). The components shown to cause this situation, which is formed by the combination of more than one factor, are free radicals, defined as

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aggressive metabolic by-products formed during the conversion of nutrients into energy by oxidation ins the human body. Under nominal conditions, these radicals are transformed and delivered to tissues by the vascular system in the human body. However, the balance of radical concentration is disturbed because of external and internal factors, and a large number of free radicals are formed. These free radicals, which can be transmitted without binding in the vascular system, cause oxidative damage in the molecular structure of the cells, named oxidative stress (Kumar and Pandey 2015). These radical molecules, known as reactive oxygen species/metabolites, damage cell components such as lipids, proteins, and DNA during oxidative stress sections. The main reasons, related to the formation of free radicals, can be listed as follows: unbalanced and unhealthy diet caused by food containing trans-lipids, excessive use of smoking, alcohol and drug, intense electromagnetic radiation, excessive UV light exposure, chronic inflammation, mineral overloading, extra physical activity more than necessary, fatigue, air, water, and environmental pollution, aging and excessive use of drugs/stimulants. As a result, these radicals are responsible for pathological disorders like atherosclerosis (hardening of the arteries), coronary heart/vascular diseases, cancer, cerebrovascular diseases, neurodegenerative diseases (such as Parkinson, Alzheimer, etc.), diabetes, eye diseases (such as macular degeneration or cataract related by the aging), acute renal and liver failure, lung diseases, emphysemic disorders, bronchitis, infertility/ovarian polycystic syndromes in female, decrease in sperm mobility and quality due to deterioration in sperm DNA structure in male, and degenerative disorders due to aging (Lagouge and Larsson 2013). The most effective procedure to prevent the formation of oxidative radicals is to eliminate the sources of oxidative stress, listed previously. To avoid the damage resulting from oxidant substances produced for these reasons, it is fundamental to consume bioactive components, called antioxidants, for the aim of neutralization and removal of the free radical oxidants in the body (Kumar et al. 2013; Ramana et al. 2018). Antioxidants can be classified as bio-beneficial substances having different chemical structures. These compounds are used to prevent the changes that may occur in the conditions where oxygen can affect easily oxidized substances even at very small concentrations, or prevent or delay the oxidative reactions promoted by oxygen and peroxide. They have the function of prohibiting the series of spontaneous reactions between the nutrient components and the consumed oxygen. Antioxidants neutralize the free radicals that arise as a result of these reactions and protect the human cells from these damages. It is essential that free radicals and antioxidants remain in balance in the body and thus neutralize free radicals in the bloodstream and intracellular structures (López-Jaén et al. 2013). The main antioxidant groups that prevent free radical formation can be listed as follows: water-soluble (vitamin C) and lipid-soluble (vitamins A and E) vitamins, intracellular type antioxidant compounds (glutathione), carotenoids (e.g., β-carotene, lycopene, and lutein), essential oils (e.g., lemon, rosehip or and rosemary oils), plant-based phenolics, which has main types as flavonoids (e.g., flavonols, isoflavones, or anthocyanidins), phenolic acid forms (e.g., p-hydroxybenzoic, caffeic, or p-coumaric types), third types as tannins (e.g., gallotannins-GTs,

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ellagitannins-ETs, proanthocyanidins-Pas, or condensed tannins-CTs), as well as stilbenes and lignan forms (Atta et al. 2017). Antioxidant substances, as previously stated, can play a role as an active ingredient in free radical-based disorders. Nonetheless, the application of antioxidant compounds as single or as a group (according to the functionality) with antimicrobial (for extending shelf life) or antidiabetic properties in different food and biological supplement products for supplementation is known as the most popular research subject for functional food product development (Leyva-Porras et al. 2021; Vitaglione et al. 2013). Procyanidins, as a derivative of proanthocyanidins, is an effective antioxidant compound, which is formed as a result of the condensation of a flavonoid class antioxidant substance-tannin (Rauf et al. 2019; Smeriglio et al. 2016). Resulting from the polymerization of 4 or more catechin and epicatechin molecules, this oligomeric compound is found in many plants and fruits (grape and its seeds, apple, aronia, black currant, black tea, cranberry, and cinnamon) in nature (USDA Database 2015). Consumption of plants with their vegetables and fruits containing the dimers of procyanidins with high antioxidant properties in the diet is essential to minimize the risk of many diseases and disorders (from heart diseases to diabetes, from cancer types to aging effects, from eye and skin disorders to hair loss) occurring in the cellular dimension in the human body (Lee 2017). As well as direct consumption by consuming plants, the applications of procyanidins have been investigated in the production of nutritional supplements and structurally compatible functional foods as the other natural compounds with antioxidant properties for decades (Masumoto et al. 2016). The interdisciplinary studies of medical and subdivisions of biosciences (like bioengineering, biochemistry, biology, food sciences, and nutrition) have been investigating the treatment methods of oxidative stress-induced diseases for recent years (Ramana et al. 2018). In addition, efforts of the researchers are underway to minimize the risk of developing stress-related diseases and to lead a healthy life based on a healthy diet (Man et al. 2020). In particular, case studies on focusing phenolic antioxidant compounds having high purity such as procyanidins, classified as a proanthocyanidins derivative tannin, and their use in different food and food supplement matrices in the industry have been widespread in the scientific world (Rodriguez-Mateos et al. 2014; Severo et al. 2021). This chapter aims to reveal the subtypes, sources, production, and bioavailability of procyanidins, which are a member of the flavonoid class, derived by the condensation reaction of the tannin groups. This chapter also includes a summary of literature examples for the application of procyanidins in different food matrices.

Procyanidins: A General Overview of Structure, Sources, and Health Benefits Among the natural antioxidant materials, phenolics can be classified as the most important plant-based compounds, within the research of its structural and functional varieties in addition to high antioxidant, antimicrobial, anticarcinogenic/antitumoral,

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antidiabetic, and similar benefits for the human body (Kumar et al. 2014). The polyphenols, which is one of the greatest subdivision of phytochemical groups of phenolics, consist of flavonoids (Panche et al. 2016). This group, which makes up about 60% of polyphenols with many subgroups and thousands of varieties, including quercetin, catechins, and anthocyanins, is found as the color pigment of the plant (Shabbir et al. 2021; Singh et al. 2016).

General Structure of Procyanidins Anthocyanins are water-soluble pigments that can be synthesized by the phenylpropanoid pathway and can appear red, purple, blue, or black depending on the pH level of the plant (Mattioli et al. 2020). A type of condensed tannin – procyanidin – is a member of the flavonoid class, derived as the oligomers of epicatechin monomers with the attachment of C6-C3-C6 diphenyl propane skeleton (Rauf et al. 2019). As a result of the bonds, formed by proanthocyanidins through hydroxylation mechanisms, the most common forms of derivatives are catechin and gallocatechin groups, which are known as the basis of procyanidins, propelargonidins, and prodelphinidins structures (Smeriglio et al. 2016). Based on the flavan-3-of monomers placed in A and B types, proanthocyanidins are classified as more than 15 subunits related to the hydroxylation (Ky et al. 2016). The most abundant subunits, found in food sources, are procyanidins, as well as propelargonidins and prodelphinidins, based on the degree of polymerization and substitution of monomers (Ky et al. 2016). Figures 1 and 2 represent the main structure of proanthocyanidin and the definition of R groups, which differs from the subunits (Fu et al. 2014). The most common of this derivative is procyanidins, which is found in natural food products such as flavan 3-ol epicatechin groups (Fu et al. 2014). The common derivatives of proanthocyanidins, including procyanidins, and substitutional groups are shown in Table 1 (USDA Database 2015). Procyanidins are classified according to their degree of polymerization and monomer numbers in polymer groups. Oligomers can be named as the procyanidins Fig. 1 Most abundant sub-units of the procyanidin (epicatechin; R1 ¼ OH & R2 ¼ H), prodelphinidin (epigalocatechin; R1 ¼ OH & R2 ¼ OH), and propelargonidin (epiafzelechin; R1 ¼ H & R2 ¼ H) monomers

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Fig. 2 Structures of procyanidin oligomers. (a) C6–C3–C6 phenolic rings of flavonoids, (b) (+)catechin (within R1 ¼ H & R2 ¼ OH) and()-epicatechin (within R1 ¼ OH & R2 ¼ H) monomers (with permission of Yang et al. 2021) Table 1 The most abundant “flavan-3-ols” derivatives and substituted groups of proanthocyanidins in food materials (USDA Database 2015) Proanthocyanidin derivatives Procyanidin Prodelphinidin Propelaronidin

Monomer structure of “flavan-3ols” Catechin Epicatechin Gallocatechin Epigallocatechin Afzelechin Epiafzelechin

Substitution pattern R1 R2 R3 OH H H OH H OH OH OH H OH OH OH H H H H H OH

R4 OH H OH H OH H

having a low degree of polymerization, whereas polymers were called for the procyanidins having higher ones. (Luo et al. 2020). A low degree of polymerization (dimers) has A and B types of structures by differing the configuration and monomer positions (Rue et al. 2018).

Main Derivatives and Structures of Procyanidins Procyanidins can be synthesized from proanthocyanidins, which are defined as the flavan-3-ol oligomers, in two ways: The first is by the bonds between fourth and seventh carbons or second and seventh carbon or second and fifth carbon atoms attached to singlet oxygen, in both situations, named as A-Type Procyanidins (Fig. 3a). Nonetheless, in the second mechanism, the linkage of either each monomer can be provided in the same structure or bonds between fourth and eighth or fourth and sixth carbon atoms, classified as B-Type Procyanidins (Fig. 3b and c). Figure 3 also represents the possibilities of B types (from B1 to B4 in Fig. 3b and from B5 to B8 in Fig. 3c) based on the orientation of OH and H groups. Besides the dimer formation, a rare structure of procyanidins appears as trimer form (Fig. 3d), named as

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Fig. 3 Procyanidin oligomers with respect to A, B, and C type formations: (a) Procyanidin dimer form of A-type with C4 ! C8 and C2–O–C7 linked, (b) Procyanidin dimer form of A-type with C4 ! C8 linked, (c) Procyanidin dimer form of A-type with C4 ! C6 linked, and (d) rare form of procyanidin in trimer C-type (with permission of Yang et al. 2021)

C1-type procyanidins by the combination of three epicatechin monomers between C4β and C8 carbons (Oracz et al. 2015; Wong et al. 2016). At a low level of pH, polyphenolic compounds are protected in stable form. Nevertheless, re-arrangement of procyanidins is observed between terminal C atoms at a pH level of 2 or lower. In this mechanism, nearly 25–28 polymeric chains of procyanidins and their oligomers can be appeared by arranging carbon bonds of catechin groups (Rue et al. 2018). On the other hand, the most abundant form of

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oligomeric degree for procyanidins is noticed up to 10–12 chains (Pasini et al. 2019). In case of well protecting from external factors (such as temperature, humidity, pH balance, and pressure), pure derived procyanidins from the nature, which are used without processing, preserve their functional properties. Like other phenolics. However, the forms obtained synthetically by processing for different purposes can be degraded by oxidation much faster (Orejola et al. 2017).

The Sources of Procyanidins The sources of procyanidins and proanthocyanidins vary in foods from red and black pigmented fruits within their grains to vegetables and nuts (Yang et al. 2020). As mentioned before, procyanidins are known as secondary metabolites, present in plant sources. Commonly procyanidins are found in several procyanidin-rich fruits such as grape, berry fruits (blueberry, bilberry, cranberry, strawberry), apple and apple peel, tropical fruits (such as mango and kiwi), apricot, cherry, and their seeds, as well as stems, secretions (such as pine bark), leaves, flowers, and roots (Yang et al. 2020). Other sources of procyanidins are nuts (walnut, hazelnut, peanut, almond, or pistachio), cereals, and cultivated crops (e.g., soybean, rice, cocoa, barley, and sorghum). In processed liquid food products, an amount of procyanidins can be found, such as fruit juices, beer, and wine, produced from procyanidin-rich plants. According to the dimer formation of procyanidins, different types of dimers are presented in various sources. For example spices such as cinnamon or cranberry and peanut contains much more A-type procyanidins. On the other hand, high amounts of B-type procyanidins are common in grapes and its seeds or apple, cocoa, and blueberry (USDA Database 2015). Table 2 summarizes the sources of procyanidins and their amounts per unit mass of source. It was noticed that the main sources of procyanidins are a red grape and its seeds (usually released to red wine) at high concentrations, as well as berry fruits, red apples, cocoa, and red radish (USDA Database 2015).

Beneficial Properties of Procyanidins Procyanidins act both as a natural antioxidant behavior (such as a color stabilizer or anti-rancidity for the unsaturated fat oxidation) with the promotion of proanthocyanidin or as a free radical scavenger to prevent long-term illnesses by its protective structure for the human body (Hellenbrand et al. 2015). By specific and complex neutralization mechanisms on undesired oxidative stress products (mainly free radicals), procyanidins show beneficial effects, acting as cellular antioxidation by scavenging free radicals, anticancer, antidiabetic, antiinflammatory, antiobesity, anti-infectious, and antiviral and prevention of mental and neurologic degenerative illnesses, such as Alzheimer as well as healing of the wounds (Gentile et al. 2012; Martin et al. 2013; Li et al. 2016a, b; Rowley et al. 2017; Yamashita et al. 2012; Zhang et al. 2016). According to the research, it might be generalized that different

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Table 2 Main natural sources and compositions of procyanidin based on the number of monomers (USDA Database 2015) Source of procyanidin Ground cinnamon Curry powder Apple (fuji) Apple (gala) Apple (golden delicious) Apple (granny skin) Apple (red delicious) Apricot Avocado Bilberry Blackberry Blueberry Sweet cherry Chokeberry Cranberry Crowberry Blackcurrant Red currant Elderberry Gooseberry Red grape Red grape seed Red grape skin Hops Lingonberry Yellow nectarine Peach Plum Raspberry Rose hip Rowanberry Strawberry Broad bean Almond Hazelnut Pecan Pistachio nut Walnut Red wine Malted chocolate drink Adzuki bean

Composition based on structural diversity (mg/100 g of source) Dimers Trimers 4–6’ers 7–10’ers Polymer 256.29 1252.20 2608.63 1458.32 2508.78 9.50 22.88 41.78 0.00 0.00 9.92 6.09 19.09 13.81 14.22 9.55 6.24 21.28 18.73 30.68 7.36 4.73 21.77 18.75 26.46 12.90 8.59 30.78 25.92 38.77 12.64 11.75 32.77 23.11 36.75 9.37 12.41 4.90 2.20 0.80 1.18 1.12 3.35 0.52 0.00 6.23 8.90 14.80 7.33 53.25 4.45 2.11 7.27 4.24 1.51 6.44 4.91 20.52 14.32 136.04 3.45 2.71 6.65 1.82 0.00 7.82 6.75 23.02 26.50 1265.98 17.71 16.35 56.84 46.21 217.64 35.90 21.20 32.50 23.10 57.70 2.91 2.19 7.75 7.21 135.08 2.11 0.77 5.54 3.95 32.60 10.62 5.63 10.80 0.00 0.00 1.72 1.45 4.76 4.74 68.88 2.37 1.08 5.39 4.98 36.41 360.88 44.07 664.00 400.30 1100.10 35.31 7.32 0.00 0.00 0.00 84.10 51.53 0.00 0.00 0.00 56.20 51.62 79.72 33.93 103.58 4.08 1.78 5.67 3.30 7.53 9.86 4.29 16.51 10.07 21.07 33.24 20.65 52.24 30.26 60.52 11.78 5.05 8.99 1.13 0.00 24.20 9.20 77.70 12.90 404.00 2.80 2.65 5.75 3.15 281.00 5.21 5.66 23.32 16.86 54.18 91.81 21.73 0.00 0.00 0.00 9.26 7.63 27.42 28.16 80.26 12.51 13.56 67.72 74.60 322.44 42.13 26.03 101.43 84.23 223.01 13.26 10.51 42.24 37.93 122.46 5.65 7.19 22.05 5.41 20.02 12.30 2.43 2.51 3.77 8.60 20.60 8.77 12.10 0.77 0.00 19.40 18.10 80.00 75.70 252.90 (continued)

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Table 2 (continued) Source of procyanidin Red kidney bean Pinto bean Cowpea Lentil Peanut Baking chocolate Cocoa bean Dry powder cocoa Barley flour Buckwheat grits Black rice Red rice Sorghum bran Sorghum grain

Composition based on structural diversity (mg/100 g of source) Dimers Trimers 4–6’ers 7–10’ers Polymer 26.40 29.10 117.70 105.30 263.40 19.22 16.18 125.90 135.62 459.63 18.92 21.58 47.90 9.81 32.66 1.20 0.11 0.03 0.00 0.00 33.20 48.80 48.10 0.00 0.00 162.84 123.63 358.40 240.22 562.75 831.29 785.70 2690.78 2224.21 1568.49 277.13 195.73 419.05 925.18 2435.11 15.77 22.02 5.30 0.00 0.00 33.90 14.20 26.50 7.60 0.00 2.50 5.20 15.90 6.92 0.00 3.37 3.22 22.89 20.14 37.41 95.56 123.72 650.32 784.19 2927.64 36.06 46.21 228.13 293.78 1346.28

stereotypes of procyanidins from varied sources can show the therapeutic effects on specified health problems.

Bioavailability of Procyanidins The studies about the metabolism and digestion of proanthocyanidins, as the basis of bioavailability in the human gastrointestinal tract, have been carried out by procyanidins, mainly due to the great abundance in many natural sources, summarized in Table 2 in the previous sections. As in most of the phytochemicals, the bioavailability studies of procyanidins were researched on the functional properties of antioxidant and prevention of disorders, caused by oxidative stress (Appeldoorn et al. 2009; Kumar and Pandey 2013). Research about the metabolism of procyanidins and their derivatives has been focused on the digestion of flavan-3-ol monomers (Ottaviani et al. 2012). It might be summarized that the formation of phase II metabolites, such as conjugated compounds of sulfated, methylated, or glucuronidated forms in the intestine and as well as in the liver after absorption into blood plasma during the post digestion of epicatechins (Zhang et al. 2016).

Bioavailability Studies of Procyanidins by Different Models Due to the cardioprotective and antimicrobial properties, primarily the bioavailability of Type-A, procyanidins have been investigated in the literature. Appeldoorn et al. (2009) applied the dimers of procyanidins by in vitro fermentation, extracted from grape seeds,

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in a high purification rate with the human gastrointestinal environment including microbiota. This procedure was observed to isolate and determine the main human metabolic molecules of epicatechins and catechins. As a result of the metabolism, hydroxylated phenyl carboxylic acids were formed such as phenolic acids 3-(3-hydroxyphenyl) propionic acid (3-HPP), 3-(3,4-dihydroxy phenyl) propionic acid (3,4-diHPP), 2-(3-hydroxyphenyl) acetic acid (3-HPA), 2-(4-hydroxyphenyl) acetic acid (4- HPA), 2-(3,4-dihydroxy phenyl) acetic acid (3,4-diHPA), 3-(phenyl) propionic acid (PPA), and benzoic acid (BA). The digestive fermentation process was realized without microbiota and with microbiota by four adults having a normal diet without any gastrointestinal disorder. As a result of the study, the stability of the dimer form of procyanidins could not be kept constant after 8 h of incubation without human microbiota was not completely stable over 8 h of incubation in the absence of microbiota. Nonetheless, it was also observed that the quantity of dimer structure of procyanidins was lower after 4 h of microbiota than that of the initial level. Decrease of dimer formation also increased phenolic acids, in the form of ethyl acetate soluble metabolites at 1.2 μmol (3,4-diHPA, 3-HPA, 3-HPP, and 4-HPA), formed by 5 μmol of procyanidins as B-type dimers. After 6 h of fermentation by microbiota, a minimum 12 mol % conversion of metabolites was provided by approximately the degradation of 1 mol of dimer resulting in 2 mol of metabolites (Appeldoorn et al. 2009). It was reviewed that dimer and trimer forms of procyanidins were digested at higher rates than monomeric forms (Kumar and Pandey 2013). The metabolism of procyanidins completes by the absorption from the intestinal system to blood plasma and urine by methylation and glucuronidation components. Serra et al. (2010) simulated the stability of procyanidins during the metabolism and bioavailability in the gastrointestinal system by in vitro and in vivo models. Moreover, this study also observed the digestion and bioavailability properties and stability of procyanidins, extracted from grape seed, in the presence of a carbohydrate-rich food matrix. The digestion model was developed as a discontinuous type, including the triple section started in the mouth and continued in the stomach, as gastric digestion, and finalized in the small intestine, as duodenal digestion. This simulation was carried out by procyanidins, obtained from the extraction of 300 mg of grape seed as a single form and 600 mg of the carbohydrate matrix, enriched by 300 mg of grape seed extract to evaluate the stability of procyanidins in food implementation. According to the results, it was defined that oligomers, mostly dimer and trimer formations of the procyanidins, were stable as the chyme form than that of pellet fraction in gastrointestinal simulation. It was also determined that oligomeric concentration in the fraction of procyanidins after digestion was higher than that of monomers. Trimer form was identified as the most common form in gastric fractions. It was also noticed that the digestion rate of procyanidins was higher in the presence of carbohydrate-rich products than that of a single form of extract of in vitro digestion test. It was seen that mostly epicatechins and catechins are abundant by the digestion test of extract, implied in carbohydraterich food (Serra et al. 2010).

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Digestion Stability of Procyanidins Moreover, Ottaviani et al. (2012) examined the digestion stability of procyanidins in the cocoa-based model drink. The simulated drink contained procyanidins with a degree of polymerization from 2 to 10. Then, 12 of the volunteers consumed 4 g of water per kg of body weight for controlling the hydration level of the blood plasma for each. Each volunteer consumed cocoa-based drinks at the same time. For the plasma separation to determine the digestion of procyanidins, blood samples were collected just before the consumption in addition to 1, 2, and 4 h after consumption of the drink. On the other hand, urine samples were collected after 24 h of consumption. As a result of the plasma and urine tests, it was summarized that B5-type procyanidins were not found as a result of the plasma test. Besides, B2-type procyanidins were found in all plasma samples of the volunteers. Besides the procyanidin, it was also commended that the most abundant procyanidins, found in blood plasma and urine samples, consist of microbial-extracted phenolic acids and phenylvalerolactone (Ottaviani et al. 2012). Stoupi et al. (2010a) maintained the total radioactivity of 14C labeled B-type procyanidins in urine and feces after oral consumption and digestion by male rats at the end of 4 days. It was observed that the bioavailability of B-type procyanidins was estimated at over 80% by the measured values of total urinary (labeled by 14C). After 6 h of oral consumption, it was measured that B-type procyanidins achieved the maximum level. It was also identified that eightfold larger values were measured after oral dosing instead of intravenous intake. In addition, B2-type procyanidins were released in the range of 63% from the excretion system at the end of 4 days. This study concluded that direct use of procyanidins and their derivatives without any encapsulating form to protect the main structure by the oral way caused the degradation in gastrointestinal complex preventing absorption into the small intestine (Stoupi et al. 2010a). Moreover, Stoupi et al. (2010b) also examined the catabolic difference of()epicatechins and the dimer form, named Type-B procyanidins under the circumstances of in vitro fecal microbiota. The catabolic products were defined by biomarkers. Approximately 5 mM of stock solutions were formed by()-epicatechins and Type-B procyanidins, separately under sonication for 2 h. Fecal microbiota, isolated from a healthy 30-years-old individual, was cultivated overnight with 0.1% of bacteriological peptone, prepared under anaerobic conditions at 37  C for 2 days. As a result of in vitro catabolism by incubation of microbiota in()-epicatechins and Type-B procyanidins for nearly 11 h, it was determined that 89–95% of recovery rate was achieved in addition to 84–88% of 3-(30 -hydroxy phenyl) propionic acid, 85–90% of 3-(30 ,40 -dihydroxy phenyl) propionic acid, 75–81% of 30 ,40 ,50 -trihydroxy benzoic acid, and 80–84% of 30 -hydroxy phenyl acetic acid. It was also reported that B2-type procyanidins in 10% of the portion were reduced by the separation of C4-C8 interflavan bonds by the catabolism of microbiota (Stoupi et al. 2010b). Engemann et al. (2012) catabolized two different procyanidins Type-A molecules, which had a more complex structure than that of type-B, by pig cecum model. Two types of Type-A procyanidins, classified as A2-type procyanidins and B1-type

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cinnamtannins, were extracted from lychee pericarp by acetone/water mixture, followed by ethyl acetate and Sephadex LH20 column absorption assisted by ethanol elution. Finally, greater than 97% of the purity level for A2-type procyanidins and 96% for B1-type cinnamtannins were obtained. For the digestion study, pig fecal inocula, determined as intestinal microbiota of the pig, was isolated in anaerobic conditions. After the inoculation of active and inactive microbiota to diluted stock solutions of A2-type procyanidins and B1-type cinnamtannins, cultivation was carried out for up to 8 h at 37  C under shaking. As a result of the isolation by recovery catabolites, it was defined that the degradation of 80% of A2-type procyanidins and 40% of B1-type cinnamtannins was observed after 8 h. It was also noticed that the degradation of dimer forms was faster than that of trimer forms. After the catabolism of A2-type procyanidins, the main catabolites phloroglucinol, 3,4,-dihydroxyphenylbenzoic acid (3,4-DHBA), 4,-hydroxyphenylbenzoic acid (4-HBA), 4,-hydroxyphenylbenzoic acid (4-HBA), 3-(3,4-dihydroxyphenyl)propionic acid (3-(3,4-DH)PA), 3-(4-hydroxyphenyl)propionic acid (3-(4-H)PA), 3-(3-hydroxyphenyl)propionic acid (3-(3-H)PA), and 3,4-dihydoxyphenylacetic acid (3,4-DHAA) were formed. Nonetheless, 4-hydoxyphenylacetic acid (4-HAA) and 3-hydoxyphenylacetic acid (3-HAA) were found by the catabolism of B1-type cinnamtannins, in addition to the catabolic products of A2-type procyanidins. It was measured that the quantities of (3-(4-H)PA), (3-(3-H)PA), (3,4-DHAA), and (4-HAA) were greater than the other catabolites. Mainly (3-(4-H)PA) catabolite was formed in the highest level for all microbiota experiments by the degradation of approximately 50% of the total A2-type procyanidins. On the other hand, B1-type cinnamtannins produced mainly (3,4-DHAA) catabolite in the highest amount after 8 h of microbiota incubation having higher bioavailability (Engemann et al. 2012).

Extraction and Encapsulation Methods of Procyanidins Extraction of Procyanidins from Different Sources Phenolic compounds play a fundamental role as the largest phytochemical group due to the diversity of their natural derivatives and functionalities in the science and research environment (Gibis and Weiss 2016; Wu et al. 2011). Phenolics consist of at least one hydrocarbon chain and more than one hydroxyl group through the structure (Tsao 2010). Due to this diversity of the molecular properties, there are both soluble (phenols, flavonoids, low and medium molecular weight tannins, etc.) and insoluble (protein-bound phenolic acids, high molecular weight tannins, etc.) phenolic components in plants. Nonetheless, it is not possible to obtain phenolic compounds with standard methods due to physical and chemical characteristics such as solubility, chemical structures, polarity differences, polymerization degrees, integration with complex structures such as protein and carbohydrates. Not only for phenolics but in the case of the whole phytochemicals also, several purification methods are required such as extraction, which is the most traditional and effective method of isolation,

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identification, and preparation for use (Carmelo-Luna et al. 2021; Toro-Uribe et al. 2018). In this process, the phytochemical is firstly separated from certain parts of the plant by different solvents that do not interact with other components chemically. Then, it is obtained in solid or liquid form with the physical and chemical distinctive properties of the solvents (such as change of state temperature, pH balance, vapor pressure, and water activity).

Solid-Liquid Extraction of Procyanidins Among the well-known extraction methods for phenolic compounds such as procyanidins, one of the most frequently used is solid-liquid extraction in the literature. This method is preferred for the solid phytochemicals, to be separated from the plants by dissolving chemicals in alcohol (ethanol, methanol) or ketone group (acetone), depending on their solubility and structure. Finally, solvents are removed by their volatility or polarity properties (Carmelo-Luna et al. 2021; Luo et al. 2020). Recent studies that frequently use solid-liquid extraction in the extraction phase of procyanidins and their derivatives for use for different purposes are present. Lavelli and Sri Harsha (2019) extracted polyphenols from grape skins, including the derivatives of procyanidins to encapsulate by alginate hydrogel. Grape skins were collected from purchased grape pomace and microbial inactivation was applied by freezing in order to prevent spoilage or fermentation of the carbohydrate-rich skin complex. Then, skins were dried in the oven at 60  C to reduce the humidity smaller than 5%. Dried samples were milled to obtain particles smaller than 2 mm. Ethanolization was carried out for the extraction period by 60% of ethanol in continuous stirring at 60  C for 2 h, detailed briefly in Spigno et al. (2015). Finally, the extract was obtained by centrifugation for 10 min. It was observed that the main derivatives of procyanidins, purified by total phenolic mixture were epicatechins, catechins, as well as B1 and B2 types of oligomeric procyanidins (Lavelli and Sri Harsha 2019). Gibis and Weiss (2016) extracted the polyphenolic compounds from spray-dried grape seed in a fraction of polyphenols with 30% of procyanidins. In this procedure, an acetate buffer at a pH of 3.8 was obtained by the mixture of acetic acid sodium acetate to better improve the stability and isolation of procyanidins. A 0.1 w/w% GSE solution was prepared to apply chitosan-coated liposomes in the next steps (Gibis and Weiss 2016). Zou et al. (2012) studied to extract procyanidins from cranberry fruit. According to the polymerization degree of procyanidins in cranberry, extraction solution was prepared by acidified methanol (by 0.5% of acetic acid) and procyanidins were released into this solution for 48 h at room temperature. In order to remove solute materials, the mixture was filtered under vacuum pressure by a rotary evaporator. In some cases, other biomolecules such as macromolecules or other natural biocomponents were removed by absorptive methods, using porous columns to obtain the highest purity of target phytochemical. Zou et al. (2012) poured the extraction mixture into resin (Amberlite FPX 66) columns by elution of 1% of acetic

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acid and methanol after evaporation to remove sugar by absorption for the aim of improving the powder yield of the procyanidins. The next column step (Sephadex LH-20) was applied by elution of the extraction mixture. The elution was done with elution by the order of 30% methanol, 60% methanol, and 80% methanol. By this procedure, other phytochemicals such as anthocyanidins and flavons were removed from the mixture. Finally, pure methanol was used to obtain a 60% yield of procyanidins following drying (Zou et al. 2012). Nevertheless, Wu et al. (2011) used sorghum grains [Sorghum bicolor (Linn.) Moench] as the source of procyanidins for extraction and measurement of biological activity. Sorghum grains were dried and cleaned to obtain powder form after milling. The extraction occurred by 70% ethanol with the solid-liquid ratio of 1:10 at 70  C, for 1 h. Rotary evaporation was used to remove solvents following the filtering. To increase the concentration of procyanidins after separation from the other phenolic compounds by absorption, the AB-8 resin column was integrated and elution of oligomeric procyanidins was obtained by washing 30% ethanol. In this study, the procyanidin-rich extract was sprayed to suspend final ethanol and to acquire powder form. A high yield of procyanidin-rich extract was then used to repair oxidative damage in mice by increasing the activities of superoxide dismutase and glutathione peroxidase. Besides, it was defined that inhibition of tumor growth and metastasis formation was seen by suppression of vascular endothelial growth factor in the presence of high purity of procyanidin-rich extract (Wu et al. 2011).

Ultrasound-Assisted Extraction of Procyanidins Some instruments are used to assist the extraction process due to their cost-effective properties serving a higher yield of the target component. An example of these is the type of instrument-ultrasonication, which does not require complex installation and use and allows structures that can create intramolecular spaces between molecules in large- and small-scale extraction processes by sound waves. By these molecular spaces, created by compression and expansion cycles, the separation process of phytochemicals from the extraction mixture is applied effectively. In addition, the solvent can solve more target phytochemicals and be easily separated from other natural components. Qin and Zhang (2012) extracted the perennial herb “Rhizome” from Rhodiola rose plant by ultrasonic-assisted solvent extraction. In this study, the herb plant was collected and dried in an oven (at 60  C) to increase solid material. Then, dried, ground, and meshed powder solid was mixed with various concentrations of ethanol-water solution from 20% to 70% to identify the highest yield of procyanidins. Ultrasonication was used at 50  C for 30 min to obtain better mixing and dissolving procyanidins into the solvent. It was defined that the best extraction yield results were seen as 11.26% at 1:40 (g/ml) of solid/liquid ratio after the extraction by 60% ethanol solution, assisted 30 min of ultrasonication at 50  C (Qin and Zhang 2012). On the other hand, Vukoja et al. (2021) studied to yield raspberry polyphenols including procyanidins by ultrasound-assisted extraction also. Nonetheless, the

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raspberry phenolics were extracted using the encapsulation process to increase the purity and yield of phytochemicals, as well as improve the stability and bioavailability through the gastrointestinal tract. Different concentration of plant cell wall polysaccharide-cellulose (2.5%, 5%, 7.5%, and 10% by weight) was used as encapsulating material. After mixing cellulose and raspberry juice, obtained in previous steps, and stirring at room temperature for nearly 1 h, centrifugation was applied to remove the supernatant. Under vacuum conditions (0.220 mbar) precipitates were freeze-dried (at 55  C). Then cellulose encapsulated raspberry precipitate was mixed with acidified (0.01% of HCl) methanol under ultrasonication for 15 min. Centrifugation and mixing by acidified methanol steps were replied four times to increase the purity of procyanidins. It was identified that the antioxidant properties of encapsulated procyanidins were preserved even after 12 months of storage at freezing conditions (Vukoja et al. 2021). Toro-Uribe et al. (2018) isolated cocoa polyphenols and procyanidins by ultrasound-assisted extraction following the liposomal encapsulation to prevent lipid oxidation. Unfermented fresh cocoa pods were selected for the separation of polyphenols in high yield. The cocoa beans were used after removing the mucilage layer. To extract the unreacted polyphenols in a high percent of yield, polyphenol oxidase was inactivated by 91% of ascorbic acid/ L-cysteine at high temperature (96  C) for 6–7 min and remained in an ice bath for 30 min. The beans were washed three times. After drying the chopped beans, milled at 20  C. Powdered bean samples were mixed with a 50% ethanol solution (0.008% by weight) at pH was adjusted as 6. Ultrasonication was done for 30 min before incubation at 70  C for 45 min. The mixture was then centrifuged, filtered, and evaporated under a vacuum to separate ethanol. Finally, powdered phytochemical was freeze-dried at 80  C to keep the stabilization (Toro-Uribe et al. 2018).

Encapsulation of Procyanidins by Various Methods The Significance of the Encapsulation for the Appropriate Use of Procyanidins Natural bioactive components are frequently used in industrial aspects of food, biochemistry, pharmacology, cosmetics, and textiles in addition to their beneficial properties such as antioxidant, antimicrobial, anticarcinogenic, antiobesity, and cardiovascular effects (López-Jaén et al. 2013). The common feature of almost all natural bioactive components is that they can easily bind to free radicals, formed as a result of oxidative stress due to their unstable and reactive structure (Lagouge and Larsson 2013). This feature provides easily degradable components due to environmental variables such as temperature, relative humidity, oxidation, ambient pH, enzyme and protein concentration, light properties, and solvents (Labuschagne 2018). As with the phenolic components of the procyanidins, high reactive phytochemicals are needed to cover by barrier structures following their intended use and

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biochemical properties to allow long-term storage and application, protected from external effects (Labuschagne 2018). This process, called encapsulation, is applied to preserve the structural properties, stability, and solubility of the bioactive component (Berendsen et al. 2015a, b; Gibis et al. 2012). The encapsulation process can also be applied to mask undesirable aromatic and color properties (Gondal et al. 2017). The coating material is selected according to the structural properties and biocompatibility of the bioactive component and applied to the extracted phytochemical in different proportions (Lavelli and Sri Harsha 2019; Tie et al. 2021). This application is carried out by different methods such as emulsification, fluidized bed coating, spray drying, liposome, and coacervation, according to the application of the encapsulated material.

Encapsulation of Procyanidins by Spray Drying The most common encapsulation process of polyphenolic compounds, including procyanidins, are the spray-drying technique (Díaz-Bandera et al. 2015; Santos et al. 2019). The objective of preferring a spray dryer in the microencapsulation process is simply to remove water content at high temperatures and in a short time. In this procedure, the coated phytochemical mixture was transferred through a nozzle and introduced by the hot gas flow. The atomized particles are in powder and mainly spherical form. Production of small and uniform spherical particles depends on the diameter of the outer nozzle, type, and temperature of aeration gas, and formulation of the sprayed mixture (Constanza et al. 2012; Diaz-Bandera et al. 2015; Wyspiańska et al. 2017). Like other polyphenolic compounds, several studies are present for the micro or nanoencapsulation of procyanidins by a spray dryer. Constanza et al. (2012) purified procyanidins from blanched peanut skins. The extraction steps were milling steps to get powder form, extraction by 70% of ethanol by stirring, vacuum filtering to separate and remove insoluble materials, removing ethanol from the soluble extract by vacuum evaporation (5–10 psi at 40  C), and storage at 4  C. The spray drying step was processed into two cases: half of the extracted material was coated by maltodextrin as the carrier agent (1:4 w/w) and the other half is uncoated. Two samples were spray dried at the inlet temperature of 160  C and outlet temperature of 90  C. Resulted powder forms were stored at 4  C. After the experimental procedure, it was defined that >four-fold increase was seen in total phenolics with maltodextrin and > 27-fold increase without maltodextrin. The phenolic degradation rate of 45.1% indicated that each carrier material might not be compatible based on the stability for each polyphenolic compound and their derivatives by spray drying encapsulation (Constanza et al. 2012). Similar study was done by Wyspiańska et al. (2017). The isolation and purification of procyanidins were realized from Bark of hawthorn fruit (Crataegus monogyna Jacq.). Acidified methanol (80%) by HCl (1%) was used for the extraction. Ultrasonic-assisted extraction was applied before centrifugation and drying. The next step was the addition of carrier materials (inulin and maltodextrin), in two different proportions (1:1 and 1:3 w/w) for each separately. After homogenization of

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four solutions at different concentrations, spray drying was operated by the inlet temperature of 150  C. Final powder materials were stored at different temperatures (20, 20, and  80  C) for 12 months. It was identified that a high amount of carrier agent resulted in higher dry matter of microcapsules (procyanidins: inulin 1:3, 95.4%). On the other hand, it was defined that the highest anti-inflammatory effect was observed as 21.1% by the microcapsules coated with maltodextrin in a ratio of 1:3 (Wyspiańska et al. 2017).

Encapsulation of Procyanidins by Nanoemulsion On the other hand, Cerda-Opazo et al. (2021) studied the identification of oil-inwater (O/W) nanoemulsion form of procyanidins, extracted from avocado peels by the safe method and materials. Nanoemulsion was preferred to maintain the high stability of extracted polyphenolic compounds. The extraction method of this study was well-described in Wong et al. (2016). The frozen avocado was washed with hot water at 90  C for 5 min and filtered to prepare homogenization and water extraction at 65  C for 1 h. The extraction mixture was acidified by formic acid at a pH was 2.5. Then elution of the sample was obtained by column with acidified water, followed by distilled water to separate carbohydrates and water-soluble components. Ethanolization of the mixture resulted in the pure extraction of procyanidins and the samples were lyophilized at 80  C. For the preparation of nanoemulsion at room temperature, a phosphatidylcholine-enriched fraction of soybean lecithin was used in addition to ethanol, stabilizers, sodium chloride salt to maintain ionic strength, and hydrochloric acid to adjust the pH of the final solution. The main reason for adding salt and acid was to simulate the nanoemulsion solution environment in the gastrointestinal tract. Finally, nanoemulsion was lyophilized to protect oxygen and light. As a result of the experimental procedure, the encapsulation efficiency of nanoemulsion including procyanidins was measured as 97%. Moreover, a lower particle size of the nanoemulsion with procyanidin-rich extract was seen (163 nm) than that of nanoemulsion without procyanidins (180 nm). The number of the procyanidinsnanoemulsion particles per unit volume (in ml) was 50% higher (4.7  1012) than that of blank nanoemulsion (3.2  1012). Nonetheless, viability tests were done using non-cancerous human cells (HEK293) and cancer cells (melanoma B16F10). It was reported that the nanoemulsion containing procyanidin-rich extract showed cytotoxicity on melanoma B16F10 cancer cells. Nanoemulsion in the presence of procyanidins also exhibited a protective effect on HEK293 human cells as the basis of anticarcinogenic property (Cerda-Opazo et al. 2021).

Combined Methods for the Encapsulation of Procyanidins Various carrier and coating materials are used for the encapsulation of procyanidins concerning the chemical formation, solubility, and stability rate at high temperatures. In another study, Berendsen et al. (2015a, b) experimented to increase stability and

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bioavailability of the purchased grape seed extract by both membrane emulsification (Berendsen et al. 2015a) and spray drying (Berendsen et al. 2015b). In both studies, procyanidins were emulsified by whey protein as single (1.0% wt. at pH ¼ 3.8) and with different polysaccharide stabilizers (0.5% wt.) such as carboxymethyl cellulose (0.25% wt. at pH ¼ 3.8), gum arabic (0.50% wt. at pH ¼ 4.8), and chitosan (0.05% wt. at pH ¼ 5.4). Water-in-oil emulsions were prepared by mixing the water phase (inner) and oil phase with the help of a rotary homogenizer. Then, 1:4 proportion of inner and outer phase emulsion was done in two steps by stirring and membrane. Finally, maltodextrin was mixed to the outer phase for better stability of wall material (1:3 w/w). In the second study, the emulsion was spray dried at an inlet temperature of 170  C and outlet temperature range of 80–90  C. These studies showed that a 16% of reduction in the encapsulation was observed by droplet membrane emulsion without spray dryer step (Berendsen 2015a). On the other hand, a better encapsulation rate and highest fraction of procyanidins were obtained (7.7–9.9 μm in size) in rehydrated whey protein and carboxyl methylcellulose microcapsules (Berendsen 2015b). Lavelli and Sri Harsha (2019) also encapsulated the extracted total phenolics from grape skins, including oligomeric procyanidins. The extraction procedure of grape skin phenolics was explained in detail in the previous section. This part of the study aimed to encapsulate the procyanidin-rich phenolics by microbeads method using sodium alginate hydrogels. The extracted mixture was introduced by 1.5% of sodium alginate/water solution as encapsulation material. The handling of microbeads was observed by a vibrating nozzle encapsulator, having a nozzle diameter of 300 μm under 0.5 bar of pressure and 1000 Hz of vibration frequency. Moreover, an electrical field was applied to the encapsulated particles to maintain the hardness of the outer shell. To remove moisture into microbeads in high stability, calcium chloride was used. As a result, the total encapsulation efficiency of the whole phenolic extract was found as 68%. Nonetheless, it was defined that the percent recovery of procyanidins and their derivatives after releasing microbeads were 49% and 47% for epicatechins and catechins, in addition to 74% and 34% for B1 and B2 type procyanidins, respectively. This study concluded that the stability of procyanidins in encapsulated microbeads might be increased in the presence of Ca2+ ions by the formation of a covalent bond between procyanidins and alginate shell (Lavelli and Sri Harsha 2019).

Liposomal Structure of Procyanidins for the Encapsulation On the other hand, the encapsulation process is also made by liposomal structure. Liposomes are used to entrap the high reactive phytochemical in a vesicle containing the cell wall membrane components including mainly lipoproteins. By this procedure, the bioavailability and delivery stability of bioactive components in the human gastrointestinal system can be improved in the presence of a strong bilayer structure. This bilayer form does not degrade in gastrointestinal fluid before delivering the target system in the presence of an appropriate stabilizer and small size (Toro-Uribe

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et al. 2018). Luo et al. (2020) extracted the oligomeric procyanidins from lychee pericarp and coated them with nanoliposomes. Lychee pericarps were crushed and mixed with 75% ethanol for 2 h. Then centrifuged and concentrated mixture was absorbed into AB-8 resin to remove protein and carbohydrate macromolecules. The eluted and concentrated mixture was washed with ethyl acetate. The mixture was dried under vacuum freezing to increase the yield of procyanidins and their derivatives. Liposomes were prepared by the thin-film dispersion method for better stability and size orientation of spheres. Egg yolk lecithin and cholesterol were mixed with anhydrous ethanol. After removing ethanol by vacuum rotary evaporation (50  C), phosphate-buffered saline and Tween 80 were added to the mixture followed by procyanidin. The mixture was pressurized by a homogenizer at 30 MPa three times to form a liposomal structure. It was defined that encapsulation efficiency was maximized at 90.92% by the load rate of procyanidins at 2%. This situation also resulted in a decrease in the loss of antioxidant activity of procyanidins during storage (Luo et al. 2020).

Other Methods for the Encapsulation of Procyanidins In some cases, capsulation of functional components gives place to micro or nanoemulsion methods due to the compatibility of common processes in the food industry such as high-pressure applications, fluidization, or ultrasonication (Pool et al. 2013).

Microfluidizer Method In the literature, some studies focus on nanoemulsions of phytochemicals for different purposes, encapsulated by rare methods like microfluidizer method. Chen et al. (2020) applied nanoencapsulated procyanidins using whey protein and β-carotene complex. Procyanidins were extracted from the lotus seedpod using a 70% ethanol mixture. Then weak polarity macroporous resin column was applied to separate lotus seedpod procyanidins. Finally, the mixture was evaporated to remove solvent completely and to obtain procyanidin powder form. In this study, whey protein nanoemulsion was prepared to identify the protective effect of nanoencapsulated procyanidins against environmental degradative effects both physically and chemically. Whey protein hydration was provided by mixing whey protein isolates (WPI) to buffer solution at 6.5 of pH under continuous stirring and storing at low temperature. β-carotene, known as the hydrophobic color pigment in various plants, was used as a stabilizer of nanoemulsion. Final concentration of WPI, polyphenolic mixture containing procyanidins and β-carotene was 1%, 0.01–0.1%, and 0.01% (w/w). A high shear rate was applied to integrate the whole components in addition to blending oil (10%). Finally, a microfluidizer was used to decrease the spherical formation of emulsified polyphenol mixture on the nano scale. It was noticed that particle size reduced in the range of 140–160 nm at a pH level of 6.5. Moreover, antioxidant property of lotus seedpod procyanidins in nanoemulsion form remained high level (63.7  1.6%) even on the seventh day of storage. It was also

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defined that stability of nanoemulsion was kept constant at both lower and higher pH level of 6.5 with the effect of β-carotene (Chen et al. 2020).

Coacervate Method To preserve the encapsulated high reactive phytochemicals from physical and chemical degradation such as oxidation, mainly due to environmental conditions (e.g., pH, temperature, pressure, relative humidity), some separation methods are applied to maintain different liquid phases. For this aim, the coacervate technique is used to obtain liquid-liquid phase separation in the homogeneous solution containing fully charged molecules. The resulting phases are colloidal polymer mixture and supernatant part in the same medium (Gharanjig et al. 2020). In the simple coacervate technique, the separation of phases occurs by the division of homogeneous polymer solution into a polymer-rich mixture, called coacervate, mixed with alcoholic aqueous solution and water concentrated poor polymer mixture, named as coacervation medium, in an equilibrium form. In the case of encapsulation needed for a mixture of two or more charged bioactive components, a complex coacervation process is essential for the association of oppositely charged molecules in the same solution as non-mixing phases of aqueous form in equilibrium (Marcillo-Parra et al. 2021). This process has been used in the microencapsulation of bioactive components for the food industry to maintain better implementation of charged molecules in higher yields and purity (Yang et al. 2020). For example, Tie et al. (2020) studied the bioactive and cross-linking properties of procyanidins after the microencapsulation process. Procyanidins were extracted from grape seeds by ethanol (60%) extraction in the presence of ultrasonic-assisted vacuum evaporation (45  C), and absorption by macroporous resin column for elution to remove watersoluble polysaccharides and color pigments. The final mixture was lyophilized and stored for the encapsulation process. Coacervation on the procyanidin-loaded complex was obtained by the mixture of gelatin (GE) and sodium alginate (SA). Different concentration of procyanidins (3.75, 5.00, and 6.25 mg/mL) were used within single concentrations of GE (10 mg/mL at pH ¼ 5.56) and SA (2.5 mg/mL). The final pH of the solution was adjusted to 4.2 by 10% of acetic acid. In order to improve the stability of the coacervation technique, the cross-linking procedure was used by Ca2+ ions due to its inexpensive and non-toxic structure. Three different concentration of Ca2+ ions (0.24, 0.48, and 0.72 mg/mL) were mixed by the coacervation mixture. It was identified that the spherical size improved to 150 nm in the presence of cross-linked Ca2+ ions. On the other hand, microencapsulation efficiency and yield were obtained as 81.19  1.47 and 87.86  2.67%, respectively (Tie et al. 2020). Several literature studies for the extraction of procyanidins from different sources and applied encapsulation processes in the last decade are summarized in Table 3. As a result of the studies, it might be summarized that procyanidins, supplied from different sources, are provided with different methods depending on the structural (polymerization) state of the source and the concentration of other macromolecules that the source includes. In addition, it is understood that the right material and method for encapsulation of procyanidins also differ according to the

Zou et al. (2012)

Article Wu et al. (2011)

Cranberry

Source of procyanidin Sorghum Bran

Acetic acid and methanol in vacuum filtering by rotary evaporator + column to remove sugar and to elute procyanidin

Extraction method 70% ethanolization extraction (@ 70  C and 1 h) þ filtering & rotary evaporation + column absorption + spray drying

Procyanidin + zein (from 1:8 to 1:2 w/w)

Emulsification & coating mixture N/A

Centrifugation and lyophilization

Encapsulation method N/A

Results The oxidative damage repair of procyanidin-rich extract (PARE) in mice by increasing the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) Inhibition of tumor growth and metastasis formation by suppression of vascular endothelial growth factor (VEGF) Particles: 391 (1:8 w/w) & 447 (1:2 w/w) nm Higher polymerized oligomers with higher loading ratio Loading ratio (% 86) @ procyanidin-zein mass ratio (1:2) Decrease of cytotoxicity in human promyelocytic leukemia by procyanidin-zein nanoparticles

Table 3 Summary of the literature for extraction and encapsulation methods of procyanidin from different sources in the period of 2011–2021

464 M. Resat Atilgan and O. Bayraktar

Grape and grape seeds

Blanched peanut skins

Rhizome of Rhodiola rosea herb

Grape seed extract

Gibis et al. (2012)

Constanza et al. (2012)

Qin and Zhang (2012)

Berendsen et al. (2015a)

Procyanidin + whey Droplets by membrane protein (WPI), emulsification Procyanidin + WPI þ carboxylmethyl cellulose (CMC), Procyanidin+ WPI þ Gum Arabic (GA), Procyanidin+ WPI þ Chitosan (Chi)

N/A

N/A Ethanolization (60%), drying at 60  C, grinding to powder form, ultrasonic wave-assisted extraction

N/A

Spray dryer (Tinlet ¼ 160  C Toutlet ¼ 90  C)

Dispersed liposomes by Dissolved liposome and high pressure homogenizer coating material @ mild by chitosan & pectin with ultrasound lecithin.

Ethanol (70% v/v) in water Procyanidin + by stirring and maltodextrin (1:4 w/w) lyophilization and soluble procyanidin extract without maltodextrin

Filtering with acetate buffer (acetic acid +anhydrous sodium acetate)

Procyanidins (continued)

Liposomal spheres: 50–120 nm No significant particle size change after 9 day of storage, Optimum pH ¼ 3.8 for storage 4-fold increase with and 27-fold increase without maltodextrin in total phenolics by spray dryer High phenolic degradation with maltodextrin High amount of procyanidins of 1st  6nd polymerization in the peanut skin extracts and spray-dried powders Best extraction rate results: 11,26% @ 1:40 (g/ml) of solid/liquid ratio, 60% ethanol, 30 min of extraction time, and 50  C of extraction temperature Low droplet size (8.2, 9.0, 9.7, and 11.8 μm) for emulsions stabilized with WPI-CMC, WPI-Chi, WPI, and WPI-GA Reduction of 16% in the encapsulation of polyphenols during premix membrane emulsification

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Bark of hawthorn fruit (Crataegus monogyna Jacq.)

Grape seed

Gibis and Weiss (2016)

Source of procyanidin

Wyspiańska, et al. (2017)

Article Berendsen et al. (2015b)

Table 3 (continued) Emulsification & coating mixture

Filtering with acetate buffer (acetic acid +anhydrous sodium acetate)

Encapsulation method Spray dried (Tinlet ¼ 170  C Toutlet ¼ 80–90  C) double emulsion with maltodextrin as wall material Spray dryer (Tinlet ¼ 150  C)

Primary liposomes (1.1% Drying (@ room T) w/w soy lecithin) using high-pressure homogenization (22,500 psi) and secondary liposomed coated by chitosan

Acetone wash of hawthor Procyanidin + barks + ultrasonication +2 maltodextrin and procyanidin and inulin times separation + centrifugation + vacuum evaporation (@ 38  C) þ vacuum drying (39–40  C)

Extraction method

Increasing the amount of carrier resulted in higher dry matter of microcapsules, (Procyanidin:Inulin 1:3, 95.4%) Highest anti-inflammatory effect: microcapsules with maltodextrin in a ratio of 1:3, 21.1% High entrapment efficiency for uncoated (88.2) and coated (99.5) liposomes Low in vitro release of bioactive material from liposomes coated by chitosan Controlled release in waterbased food systems to improve storage and process stability of liposomes

Results Highest procyanidin content: Rehydrated WPI þ CMC microcapsules with lowest particle size (7.7–9.9 μm)

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Cocoa

Grape pomace and grape skin

Lotus seedpod

Toro-Uribe et al. (2018)

Lavelli and Sri Harsha (2019)

Chen et al. (2020)

70% ethanol mixture + weak polarity macroporus resin column + evaporation

Ethanolic extraction + vacuum + freeze drying (@ -20  C and 72 h)

Ethanolic solution by ultrasonication, centrifugation, vacuum evaporation and lyophilization (@ -80  C)

High-pressure microfluidizer (3-times @ 12,000 psi)

Microbeads by a vibrating nozzle method (300 μm noozle @ 0.5 bar P, 1 kHz of vibration frequency & hardening, 1400 V of electrostatic field

475 mL of 1.5% alginate hydrogel +25 mL of the GS extract

Whey protein + lotus seedpod procyanidin (LSPC) nanoemulsion complex by β-carotene

Liposomal encapsulation

Soybean lecithin (5%, w/w) liposome delivery system

(continued)

Inhibition of the liposome oxidation by catechins and procyanidins from cocoa extract Potential use for the production of meat Higher antioxidant activity at pH ¼ 5.0 (particle size ¼ 77.45  8.67 nm) than that of pH ¼ 3.0 (particle size ¼ 56.56  12.29 nm) % 68 of encapsulation efficiency due to phenolic loss from the droplet to the hardening solution prior to gelation Particle size: 250–500 μm Release of grape skin phenolics from the alginate microbeads at pH ¼ 7.4 Mean particle diameters of the nanoemulsions: 0.14–0.16 μm, at pH 6.5 0.01% LSPC has strong antioxidant effects, with a β-carotene retention of 63.7  1.6% at seventh day storage Physically stable nanoemulsions at pH values

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Grape seeds

Lychee pericarp

Luo et al. (2020)

Source of procyanidin

Tie et al. (2021)

Article

Table 3 (continued)

75% ethanolization extraction + centrifugation + static absorption AB-8 resin column + ethyl acetate extraction and vacuum freeze dryer

60% ethanol mixture + ultrasonication + vacuum evaporation (@ 45  C) þ macroporous resin column + lyophilization

Extraction method

Nanoliposomes by egg yolk lecithin (mixture of cholesterol at 1:1 to 1:15 by w/w), cholesterol at 1: 10 to 1:50 by w/w, and by Tween 80 stabilizer (5–25 g/L of mixture)

Procyanidins-loaded complex coacervates by gelatin (GE) and sodium alginate (SA)

Emulsification & coating mixture

Film dispersion method assisted by vacuum evaporation (@ 50  C) and high-pressure homogenizer (@ 30 MPa by 3-times)

Pulsed ultrasonication + cross-linking by Ca2+ ions + centrifugation + lyophilization

Encapsulation method

above or below the isoelectric point of the whey proteins such as pH > 6.5 Microencapsulation efficiency and yield: 81.19  1.47 and 87.86  2.67% Improving with the presence of Ca2+ ions, spherical shape with a size of about 150 nm The decrease of mitochondrial membrane potential in PC-12 cells induced by H2O2, inhibited by PC coacervates The lowest particle size (83 nm) at OPC-lecithin ratio of 1:30 The highest encapsulation efficiency (90.92%) at OPC load rate (2%), less antioxidant activity loss of OPC during storage Increase of the ferric ion reducing antioxidant power (FRAP) Oxygen radical absorbance capacity (ORAC) and cellular antioxidant activity (CAA) as a result of the encapsulation by a phospholipid bilayer of OPC-liposomes

Results

468 M. Resat Atilgan and O. Bayraktar

Avocado peel

Purchased

Raspberry

Cerda-Opazo et al. (2021)

Tie et al. (2021)

Vukoja et al. (2021)

Acidified methanol of freeze drying @ mild ultrasonication

N/A

Phenolics + cellulose solution (2.5% to 10% w/w)

Inner phase: 1 wt % carboxymethyl cellulose sodium (CMC-Na) Middle phase: sodium alginate and EDTA-Ca-Na2 solution, Outer phase: palm oil, Tween 80, and acetic acid stabilized by chitosan

The freeze-dried powder Procyanidinof procyanidin-rich extract nanoemulsion: by ethanolization Phosphatidylcholine enriched soya bean lecithin + NaCl (for ionic strength) þ HCl (for pH adjust)

Freeze drying

Internalexternal gelation method to prepare coreshell microparticles by microfluidic chip

Lyophilization by cryoprotectant trehalose (5 and 10% w/v) @ 20  C

(continued)

Spheroidal particles of ≈160 nm, low polydispersity (PDI  0.1) High encapsulation efficiency of procyanidins (≈97%), safe ingredient in non-cancerous human cells (HEK293) Preferential cytotoxicity in cancer cells (melanoma B16F10) Nontoxic delivery system of microparticles Inhibitory effect on the decrease of mitochondrial membrane potential in Caco-2 cells caused by H2O2 and acrylamide. Higher stability of PCs embedded in microparticles than that of free PCs pH stimulus-responsive release of PCs from microparticles under neutral pH Increase in antioxidant activity after 12 months of storage α-amylase inhibition and antioxidant activity: highest in 2.5% solution

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Bi et al. (2021)

Article CarmeloLuna et al. (2021)

Purchased

Source of procyanidin Sorghum bran (Procyanidin (PCs) and procyanidin B1 (PB1)

Table 3 (continued)

N/A

Extraction method Solvent extraction (acetone/water/ acetic acid, 7:2.95:0.05 mL) by centrifugation, vacuum evaporation (@ 35  C), column load and rotary evaporation

Water-soluble chitosan copolymer + procyanidin to imply into chitosangraft-polyvinyl alcohol film

Emulsification & coating mixture acidic Gelatin-A and basic Gelatin-B nanoparticles with procyanidin mixture

Drying (@ 40  C)

Encapsulation method Centrifugation of gelatin +procyanidin mixture and lyophilization

Results Size of the nanoparticles in the range of 322–353 nm (PCs þ Gel A), 321.5 nm (PB1 þ Gel A) 320.9 nm (PCs þ Gel B) and 338.2 nm (PB1 þ Gel A) Higher encapsulation efficiency of PCs þ Gel A (77.9%) than that of PCs þ Gel B (27.0%), No release of procyanidin from gel nanoparticles during artificial digestion test Desirable PC encapsulation efficiency of over 95% Long-term release sustainability Stable mechanical and barrier properties with desirable antibacterial activity and biofilm inhibition against foodborne pathogenic microbes and spoilage bacteria Desirable results about the antimicrobial protection of salmon muscle samples

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structure of procyanidins and application area of the encapsulated material. In addition, it might be understood that the appropriate material and method for the encapsulation of procyanidins also differs according to the monomeric or oligomeric form of procyanidins and their derivatives within application area of the encapsulated material.

Food Applications of Procyanidins Nutritive foods and supplements are indispensable parts of the human diet, fortunately, the beneficial and functional natural and additional compounds in their content. In addition to being in the natural composition of plant foods, bioactive components extracted from these foods are included in different food processes in the most compatible way with their structures and enable functional food production. The main purpose for the consumption of these foods containing functional components for certain age groups is to ensure the continuity of metabolic reactions necessary for the basic building blocks of cells (Lorenzo and Eugenio 2011). Nevertheless, the second aim is to minimize the formation of radicals originating from oxidative stress by transferring the bioactive substances in the consumed foods to the cardiovascular system with high efficiency through digestion and absorbing on a cellular basis (Bakuradze et al. 2019). As mentioned previously, the amount of procyanidins and their derivatives in plant food products, as in natural phenolic compounds compatible with food products, is summarized in Table 1. Consumption of these foods and supplements resulting from processing technologies, as well as the direct consumption, helps to see more of the other functional benefits required for the human body, especially the antioxidant feature, and to minimize the risk of oxidative stress-based disorders. In the previous chapter, the handling procedures of procyanidins and their derivatives, which are extracted by different methods according to the structural status of the source and the amount and types of other bioactive components, were explained in pure or encapsulated form, according to the purpose of use and biodelivery feature. In this section, different food and packaging applications of procyanidins isolated by different methods, as single or the group with other phenolics obtained from its source, are explained.

Applications of Procyanidins in Various Food Matrices Several studies about the applications of procyanidins in food matrix or active packaging have been noticed since the extraction of procyanidins and purification was discovered for the aim of the use as enrichment in nutritive (Marchiani et al. 2016; Portman et al. 2020). The most abundant source of extracted and enriched procyanidins in food matrices or packaging materials are cocoa derivatives (nibs, hulls, and liquor) and grape, in addition to its seeds, due to the ease of availability and high total phenolic content, mainly flavonols and procyanidins (Di Mattia et al.

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2014; Marchiani et al. 2016; Stahl et al. 2009). Stahl et al. (2009) identified the total amount of phenolics, mainly procyanidins, by the direct use of cocoa and chocolate derivatives in various cocoa-containing recipes. These recipes were included in the bakery group (as cookies and cake), beverage group (as hot chocolate made by milk), and confectionary group (as chocolate frosting). After the preparation of the whole recipes, the amount of total antioxidant activity (by oxygen radical absorbance capacity method), total polyphenols (by colorimetric assay), and the flavanol monomers ([]-epicatechins and [+]-catechins) and oligomeric procyanidins (by reversed-phase high-performance liquid chromatography-HPLC) was measured. It was obtained that higher antioxidant activity of flavanol monomers and procyanidins in the frosting (86–109%) and hot drink (92–156%) was detected. Moreover, loss of antioxidant activity was seen due to the effect of the leavening agent (baking soda) in cake (as 4–27%). On the other hand, no loss of antioxidant activity or content of procyanidins was detected with the effect of the heating and baking process. Despite the protection of procyanidins, it might be said that the effect of dissolved leavening agents and other fundamental ingredients (such as preservatives, stabilizers, and emulsifiers) is to be investigated in the future (Stahl et al. 2009).

Commercial Procyanidin-Rich Bioactive Extracts in Food Matrices In some cases, commercialized bioactive extracts are preferred for the enrichment of the food matrix to minimize the risks of yield and purity loss during the extraction period (Frontela et al. 2011). One of these ready-to-use extracts is known as Pycnogenol ®, defined as the standardized extract, obtained from French maritime pine bark (Pinus pinaster Ait.) and commercially traded (Mármol et al. 2019). The main composition of Pycnogenol ® is the water-soluble polyphenols, including different polymerized chains of procyanidins and their derivatives as catechins and epicatechins. Frontela et al. (2011) enriched pineapple and red fruit juice, made from the proportioned mixture of red grape, raspberry, cherry, blackberry, and blackcurrant juices, by Pycnogenol ®. The stability test and comparison of the commercial and enriched juice samples were identified. Nonetheless, gastrointestinal digestion and bioavailability of enriched samples were measured by in vitro experiments. It was defined that enriched juices showed detectable catechins and epicatechins in addition to chlorogenic and ferulic acids as a result of possible hydrolysis of complex molecules by digestion test. Nevertheless, the pasteurization of enriched juice samples by thermal processing (at 90  C for 30 s) resulted in structural changes of the monomer and polymer portions of the polyphenols. Instead of the other phenolics, it was observed that the releasing of procyanidins and flavan groups were seen in digestion tests, proving that the nutritional enrichment of the commercial ready-to-use extracts, such as Pycnogenol ® might be used as the potential ingredient for different functional food matrices taking into account the process parameters, like temperature, pH, and chemical structure of the other components (Frontela et al. 2011).

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Procyanidins, extracted from the grapes, are common due to the high amount of catechins and epicatechins content even in skins and seeds. In addition to pharmacological and cosmetic applications, grape-derived extract of procyanidins can also be used in food applications (Mannozzi et al. 2018; Marchiani et al. 2016). Mannonzi et al. (2018) extracted oligomeric procyanidins from grape seed and applied them as the preservative material on fresh blueberry for 14 days of storage at 4  C. In order to increase the functionality of protection, edible chitosan was used as coating material with enrichment. During storage, microbiological and physicochemical quality aspects were examined. It was compared by the control samples (with non-enriched chitosan-coated and uncoated samples) that procyanidinenriched chitosan-coated samples maintained lower luminosity and higher blue hue color of blueberries. Besides, higher antiradical activity was detected than that of non-enriched coated and uncoated samples. As the basis of the inhibition of yeast and mold, it was defined that procyanidin-enriched and chitosan-based coated samples presented better results (Mannonzi et al. 2018).

Procyanidins as a Fortification Agent in Food Matrices Procyanidins are also used in food fortification to prevent oxidative stress disorders due to various factors in the human body, especially its antioxidant properties. In addition, there have been studies about implying procyanidins on functional edible films in order to prevent microbial degradation by increasing antimicrobial properties for foods (Bi et al. 2021; Bouhanna et al. 2021; Kim et al. 2016; Severo et al. 2021). Ramziia et al. (2018) added purchased procyanidins to fish gelatin-chitosan edible films by four different concentrations (0.25, 0.50, 0.75, and 1.00 mg/mL). Film stability and functionality (antimicrobial and radical scavenging activities) were also examined. According to the results, it was determined that increasing the amount of procyanidins (1.00 mg/mL) in edible film improved radical scavenging activity up to 95.63%. Despite the decrease in tensile strength (27.17%), the elongation rate increase was seen (33.42%). The covering property of the chitosan edible film, enriched with procyanidins, onto various fresh food products (such as fish, meat, and cheese) might be maintained (Ramziiya et al. 2017). On the other hand, Bouhanna et al. (2021) enriched a gelatin-based film-forming solution with procyanidin-rich fruit extract. Procyanidin-rich polyphenol extract was obtained from Arbutus unedo L. (Strawberry tree). Moreover, glycerol was used as a plasticizer for the film to improve mechanical properties like elongation and tensile strength. Bouhanna et al. (2021) also applied antimicrobial film to sardine fillets both with and without procyanidins incorporated. The measurement of total phenolics in the film showed that the most abundant flavonoid was B2-type procyanidins. It was observed that the water vapor permeability of the enriched gelatin film decreased. By the effect of procyanidins, the antibacterial effect of the procyanidin-incorporated film was higher against S. aureus, L. monocytogenes, and P. aeruginosa, in sardine fillets than that of the non-incorporated film (Bouhanna et al. 2021).

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Procyanidins, extracted from different sources, might be used for the application of film formation. Severo et al. (2021) prepared a biodegradable chitosan-based film complex of Procyanidin-A with polyethylene glycol and glycerol, used as plasticizers. Polyphenols, mainly A-type procyanidins and epicatechins, were yielded from cranberry extract. As a result of the tests, it was noticed that polyphenol enrichment improved food preservation properties, such as water and O2 permeability, as well as light transmission. Moreover, the anti-radical activity of procyanidins incorporated biodegradable film was measured as higher than that of non-incorporated film. The antimicrobial property of the film was proved by a 5-log reduction of E. coli and S. aureus (Severo et al. 2021). These results indicated that procyanidins and their monomeric or oligomeric derivatives might be an excellent alternative bioactive molecule for the enrichment of edible or biodegradable food packaging materials. The enrichment of procyanidins might be single or a group of phenolics by the same or different sources for better functional properties. The various studies about the implementation of procyanidins on food or packaging materials in 2009–2021 were summarized in Table 4.

Safety and Regulations of Procyanidins from Different Sources As stated in previous sections, the presence of procyanidins and their derivatives has been studied extensively due to high antioxidant and reactive properties in varied food and food supplement matrices for recent years. The main purpose of these studies is to optimize the compatibility of procyanidins and their derivatives in food matrices, preferred as functional additives due to their easy accessibility and low-cost production, without loss of biochemical and functional properties. As a result of the data obtained from these studies, the regulation studies on the food compatibility of procyanidins and the consumption characteristics of these functional foods by individuals have been carried out by official institutions and organizations such as the European Food Safety and Authority (EFSA). Several studies, based on the post-consumption health effects and side effect/toxicological studies for procyanidins obtained from different sources, were published.

Safety and Regulations of Procyanidin Derivatives from Cranberry Extract Cranberry extract powder is generally obtained as catechin and epicatectin oligomers by the most abundant ethanol extraction method from cranberry juice concentrate, following the elimination of dissolved sugar and organic acid by absorption and elution of extract to purify phenolic compounds. Then, phenolics including procyanidins are encapsulated by different methods, such as spray dryer by maltodextrin carrier. According to Brunswick Laboratories – 4-dimethylaminocinnamaldehyde

Pycnogenol ®

Cocoa nibs

Vitaglione et al. (2013)

Source of procyanidin Cocoa and chocolate derivatives

Frontela et al. (2011)

Literature Stahl et al. (2009)

Free polyphenol extract and encapsulated form by high-amylose maize starch nanocomplexes

Direct use of Pycnogenol ® extract

Addition of procyanidin Direct use of cocoa

To define stability of Pycnogenol ® stability by comparing the phenolic contents of commercial and Pycnogenol ®-enriched juices and in vitro gastrointestinal digestion To evaluate human bioavailability of cocoa flavanols and phenolic acids by consumption of nut creams To evaluate the difference in cocoa-nut cream enriched with free polyphenol extract or encapsulated form

Aim of the study Measurement of the antioxidant activity, total polyphenols, the flavanol monomers ([]epicatechin and [+]catechin) and oligomeric procyanidins in cocoacontaining recipes

Confectionary: Polyphenol-enriched cocoa-nut cream

Beverage: Enriched pineapple and red fruit juice (containing red grape, raspberry, cherry, blackberry, blackcurrant)

Food application(s) Cocoa-containing recipes: Bakery: Cookies & cake Beverage: Hot Chocolate Confectionary: Chocolate frosting

Procyanidins (continued)

Negligible epicatechin and procyanidin in urine by consumption of encapsulated form Lowest excretion of encapsulated form after 24 h of consumption Bitterness perception with the free extract Granularity in encapsulated extract samples

Result Antioxidant activity of flavanol monomers and procyanidins in the frosting: 86–109% Antioxidant activity in hot drink: 92–156% Loss of antioxidant activity by leavening agent (baking soda) in cake (4–27%) No loss of antioxidant activity or content of procyanidin by heating and baking. Increase in detectable chlorogenic and ferulic acids after digestion test of enriched juices, possible hydrolysis of complex molecules Higher detectable phenolic contents in enriched juice after digestion test.

Table 4 Summary of the literature for food applications of direct or encapsulated procyanidin extract in the period of 2009–2021

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Cocoa liquor

Grape pomace and skin

Purchased

Marchiani et al. (2016)

Ramziia et al. (2018)

Source of procyanidin Blueberry

Di Mattia et al. (2014)

Literature RodriguezMateos et al. (2014)

Table 4 (continued)

Direct use in 4 different conc. (0.25, 0.50, 0.75, and 1.00 mg/mL)

Purchased and direct use

Direct use by the liquor

Addition of procyanidin Direct use of extract

Aim of the study To determine the effects of proving, cooking, and baking on the anthocyanin, procyanidin, quercetin, in a blueberry-enriched baked product To determine the effect of long and short-term conching (STC & LTC) processes on the content of procyanidin and functional properties in chocolate production To identify the phenolic compounds, antioxidant activity, lactic acid bacteria, and consumer preferences of enriched yogurt To apply procyanidin to fish gelatin–chitosan edible films To examine the effects of procyanidin on the functional properties of the films and solutions Packaging: Fish gelatin–chitosan edible films incorporated with procyanidin

Dairy: Yoghurt enrichment by grape skin flours obtained from grape pomace

Confectionary: Dark chocolate

Food application(s) Bakery: Blueberryenriched baked product (Bun)

Scavenging activity (95.63% at 1.00 mg/mL of procyanidin Reducing tensile strength (27.17%), and increasing elongation at break (33.42%) Alternative as active packaging material for food applications (fish, meat, or cheese)

Procyanidin B1 detection in the yogurt with Pinot noir flour after 3 weeks of storage

A slight increase of the total procyanidin content by STC Procyanidin profile: Monomers by short term and polymers (up to tenth degree) by LTC Higher antiradical activity by LTC

Result Increase in dimer and trimer levels by 36% and 28% in all the process Dimers after cooking of the filling (18%), second proving (10%), and cooking (9%)

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Grape seeds

Cocoa hulls

Lentil (Lens culinaris M.)

Arbutus unedo L. (Strawberry tree) fruit extract

Mannozzi et al. (2018)

Papillo et al. (2019)

Portman et al. (2020)

Bouhanna et al. (2021)

Gelatin-based filmforming solutions + prociyanidn-rich fruit extract + glycerol

Direct use after extrusion of lentil

Microencapsulation coated by maltodextrin and/or gum arabic within spray drying and direct use

By chitosan-based coating mixture

To determine the functionality of edible chitosan coating, enriched with procyanidins on fresh blueberry quality maintenance and microbial growth, during storage To microencapsulate phenolics extracted from cocoa hulls by spraydrying, To apply capsulated phenolics as new heatstable ingredients for bakery products To develop a model extrusion technology for the use of flour derived from frost-damaged lentil To investigate the potential change of phenolic compounds at high T and P To obtain the gelatinbased film incorporated with A. unedo fruit extract, To investigate the Packaging: Gelatinbased film incorporated with procyanidin

Lentil-wheat composited flour

Bakery: Model biscuit

Storage: Protection of fresh blueberry at 4  C for 14 days

Procyanidins (continued)

Most abundant flavonoid: Procyanidin B2, Decrease of gelatin water vapor permeability, Great antibacterial effect against

Low luminosity & high blue hue color of blueberry, coated by chitosan + procyanidin High antiradical activity by chitosan coated samples, Higher yeast and mold growth inhibition by chitosan-based coated samples compared to the uncoated samples Constant polyphenolic profile of the powders, by extracted epicatechin, procyanidins B1, B2 and gallic acid Stability of capsules by maltodextrin - gum Arabic - best at 80:20 (w/w) Degradation of epicatechin and procyanidin B2 due to the sensitivity to heat treatments Increase in nutrient bioavailability but decrease the measurable phenolic compounds in food products by extrusion Decrease in the concentration of procyanidin due to extrusion process at high T and P

13 477

Cocoa extract

Cranberry extract

Severo et al. (2021)

Source of procyanidin

Bussy et al. (2020)

Literature

Table 4 (continued)

Chitosan-based film complex of ProcyanidinA with polyethylene glycol and glycerol

Direct use of cocoa flavonols including procyanidin

Addition of procyanidin

To determine the biodegradable chitosanbased film formation enriched by cranberry polyphenols for the applications of food packaging

antimicrobial effect against foodborne pathogens in sardine fillets during cool storage. To prepare an appropriate method to investigate flavanols and procyanidins in food and dietary supplements

Aim of the study

Cocoa-derived products: Cocoa extracts and powders, dark chocolate, ready-todrink powder mixtures and supplements Packaging: Chitosanbased film incorporated with cranberry polyphenols (including epicatechin and procyanidin typeA)

Food application(s)

Food preservation properties (light transmission, water, and O2 permeability) of chitosan-based film, Increase of anti-radical activity Antibiofilm property: Prevention of E. coli and S. aureus by 5-log reduction

Determination of procyanidin from degree of polymerization from 1 to 7 Effective use of model method to determine flavonols in cocoa-derived products

S. aureus, L. monocytogenes, and P. aeruginosa, into sardine fillets

Result

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(BL-DMAC) method (Palikova et al. 2010), the percentage of proanthocyanidins including monomeric, dimeric, and oligomeric procyanidins was 15–18%, based on the standard, specified for A2-type procyanidins (Turck et al. 2017). Final product was stored under dry conditions in double polyethylene bags. It has resulted in stability of proanthocyanidins including procyanidins kept constant after 30 months at room temperature (Turck et al. 2017). Cranberry extract powder was used in beverages including isotonic, low calorie, and normal fruit-flavored drinks, as well as iced tea drinks within 150 mg of cranberry extract/250 ml of portion. Extract powder was also applied on vitamin-enhanced waters (within 150 mg of cranberry extract/330 ml of portion), and dairy products such as yogurts (within 150 mg of cranberry extract/125 g of portion) and yogurt-based beverages including 150 mg of cranberry extract/200 ml of portion (Turck et al. 2017). Nonetheless, the stability of procyanidins was not affected even after 22 weeks of storage in water-type beverages at 25  C. This test was also repeated for the temperature of 32  C and no significant change occurred in the stability of proanthocyanidins including procyanidins after 12 weeks. After the degradation and digestion of cranberry extract powder, implied with several novel food materials, the toxicokinetic properties of proanthocyanidins and their derivatives (procyanidins in different polymeric degree) were evaluated. Nevertheless, it was also noted that low level of absorption was detected for the derivatives of dimeric and that dimer forms of procyanidins were degraded to monomers in acidic environment of in vitro digestion model. In vitro studies suggest that PAC polymers could be degraded into monomers under the acidic conditions of the stomach. Further studies are needed to identify the absorption of larger procyanidins in high level of polymerization through large intestine (Turck et al. 2017). Another study demonstrated the effect of cranberry proanthocyanidins and their derivatives, mixed by cranberry-based juice and cranberry capsules. The clinical human experiments were carried out with 54–140 adults consuming 36–72 mg of cranberry extract per day up to 12 weeks. No negative effect was seen on consumers without any undesired toxicological value on blood biochemistry. Although it requires more available clinical and biochemical studies, consumption of procyanidin derivatives into different food matrices does not pose a health risk, provided that they are consumed in certain portions by adults (Turck et al. 2017). One study reported the health effects after the consumption of cranberry juice including 3.6 mg of proanthocyanidin-rich (as well as its procyanidin derivatives) phenolic content per 200 g of portion or 36 mg of capsules (as food supplement) per day. After clinical studies, it was defined that a significant effect was observed on the undesired bacterial population in lower urinary tract of adult consumers. The inhibition of uropathogenic biofilm of E.coli was seen on the wall of urinary tract after the consumption of cranberry extract capsules after a period of time. Moreover, no toxicological or harmful effects were found in the blood analyzes of individuals after the use of procyanidin derivatives alone or as a food supplement (Agostoni et al. 2011a).

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Safety and Regulations of Procyanidin Derivatives from Grape Extract The alternative sources of procyanidins and their derivatives are also investigated, based on the appropriate use both directly or mixed with a compatible food matrix. Grape and grape seeds are the most abundant sources of procyanidins. One panel study, published by EFSA, determined the health and toxicologic effects of dimeric, trimeric, and oligomeric procyanidins extracted from grape (Vitis vinifera L.) seeds. The investigation of health effect of procyanidin was limited by ocular adaptation disorder in the presence of low luminant (dark) environment. Basically, 50 of 100 individuals consumed 4 tablets per day, within the dose of 50 mg of procyanidin derivatives per tablet for 5 weeks. Moreover, other half of 100 individuals did not consume any procyanidin-based food supplement. Because the test completion rate could not be maintained at the desired level and poor results were reported, no clear evidence was presented regarding the improvement of low vision in the dark in individuals, consumed procyanidin at the specified dose. Nonetheless, no harmful or toxic effect was determined for procyanidin enriched food supplement tablets after hematological tests of consumers after 5 weeks of experiment (Agostoni et al. 2011b). Since the food integration studies of procyanidins have been very recent, individual studies, based on their regulation and post-consumption health effects, are also limited. Provided that the biochemical structure, functional properties, and high reactivity of procyanidins are preserved, regulation and legislation studies in different food codex will increase in addition to the contribution of the novel studies for full compatibility of the molecule within structural integrity for different food matrices.

Conclusion This chapter summarized the biochemical structure and classification of the procyanidins molecule, primarily. Then, various methods of obtaining procyanidins and their derivatives by extraction from various sources due to factors such as other bioactive compounds contained in the source, solubility of procyanidin derivatives, solvent chemicals, and purpose of use were examined. Bioaccessibility and bioavailability studies of procyanidins and their derivatives have also been carried out as simulated in vivo and in vitro methods by fecal microbiota isolated from human individuals or different organisms. According to these studies, it is examined that the classification and properties of the metabolites, produced from the simple and complex structure of procyanidins and their derivatives, purified from different sources, is as a result of catabolism activities. The pathways and conditions, of which metabolites are formed as a result of the catabolism of procyanidins in the real

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or simulated human gastrointestinal tract, have been also examining for recent years. As a result of the participation of these metabolites on a cellular basis, additional studies are needed on whether they have antioxidant properties and how effective they are against other oxidative stress-induced disorders. Although not as much as anthocyanidin, studies on the direct or encapsulated application of procyanidin and its derivatives to food products have become more frequent in recent years. The mainstay of these studies is the impregnation of procyanidins into the food matrix by maintaining its functional properties under storage conditions without deteriorating the molecular structure. Thus, it is aimed to increase the bioavailability of food products enriched with procyanidins. On the other hand, the literature, in which procyanidins and their derivatives are used individually or as a group with other phenolics, is present in order to increase antimicrobial and radical scavenging activity properties in biodegradable food packages as well as in food products. As a result of these studies, it might be concluded that procyanidins can transfer its functional properties to the food or packaging product to which it is applied, provided that optimum processing conditions. Nonetheless, the biocompatibility of procyanidin with alternative process conditions or encapsulation materials should be examined by further studies. Particularly, the biochemical compatibility of procyanidins to different foods will be optimized more efficiently by increasing further studies based on regulation, safety, and health trials of procyanidins and its derivatives in food applications. By the support of the toxicological and hematological investigation, the benefits and bioavailability of procyanidinbased food and supplementals will be well defined based on the appropriate intake rates for individuals.

Cross-References ▶ Anthocyanins ▶ Beta-carotene ▶ Ellagitannins ▶ Flavones ▶ Gallotannins ▶ Hydroxybenzoic Acids ▶ Inulin Fiber ▶ Isoflavones ▶ Lignans ▶ Lycopene ▶ Stilbenes and Its Derivatives and Glycosides ▶ Vitamin A ▶ Vitamin C ▶ Vitamin E

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Stilbenes and Its Derivatives and Glycosides

14

Nicoleta-Gabriela Ha˘da˘ruga˘ and Daniel-Ioan Ha˘da˘ruga˘

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Chemistry and Functionality of Stilbenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biosynthetic Pathways and Metabolism of Stilbenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Chemical Stability, Encapsulation, and Incorporation of Stilbenes in Food Products . . . . . . . . . Occurrence, Separation, Analysis, and Applications of Specific Stilbenes as Food Ingredients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Stilbene Aglycones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Stilbene Glycosides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion and Future Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

490 496 510 517 534 534 537 538 539 539

Abstract

Stilbenes are naturally occurring compounds with valuable properties such as antioxidant, anticancer, anti-diabetic, and anti-hypercholesterolemia activities. The core structure of stilbenes is 1,10 -(ethene-1,2-diyl)dibenzene, which exists in both trans and cis forms. However, stilbene derivatives such as arylbenzofurans, bibenzyls, as well as stilbene oligomers also occur. Both aglycones and glycosylated forms can be found in plants, fruits, and vegetables. The most studied stilbene aglycone is resveratrol. It can be especially found in grapes

N.-G. Hădărugă (*) Department of Food Science, University of Life Sciences “King Mihai I”, Timişoara, Romania Research Institute for Biosecurity and Bioengineering, Timişoara, Romania e-mail: [email protected] D.-I. Hădărugă Department of Applied Chemistry, Organic and Natural Compounds Engineering, Polytechnic University of Timişoara, Timişoara, Romania e-mail: [email protected] © Springer Nature Switzerland AG 2023 S. M. Jafari et al. (eds.), Handbook of Food Bioactive Ingredients, https://doi.org/10.1007/978-3-031-28109-9_14

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(Vitis vinifera L.) in trans form, but forest berries and peanuts also contain resveratrol. Many resveratrol glycosides are found in Vitis species or wines (piceid/polydatin, 3,5-O-di-, 3,40 -O-di- or 3,5,40 -O-triglucosides of cis- and trans-resveratrol in cell cultures of Vitis species as well as cis-resveratrol 2-Cglucoside in white wine). Vitis species also contain rhapontigenin, piceatannol, pterostilbene from the stilbene aglycone class, viniferins and vitisins from stilbene oligomer class, astringin (piceatannol 3-O-glucoside), and viniferin and vitisin glycosides from stilbene glycoside class. Other stilbenes found in foodrelated sources are gnetol, gnetifolin, and gnetofuran in Gnetum species, prenylated or geranylated stilbenes such as chiricanines from Lonchocarpus chiricanus or Arachis hypogaea, phyllodulcin (natural sweetener), hydrangenol and thunberginol O-glucosides from some Hydrangea species, or mulberrosides (oxyresveratrol glycosides) from Morus alba. The presence of phenolic hydroxyl groups on the stilbene skeleton provides important antioxidant activity and further biological activities. Stilbene glycosides are less hydrophobic and more water soluble than the corresponding aglycones. Various interconversion methods using enzymatic synthesis exist. This chapter reviews the recent findings on the occurrence, chemistry, functionality, biosynthesis, and metabolism of stilbenes, stilbene derivatives, and their glycosides. Special attention has been given to the chemical stability, encapsulation, interaction, and incorporation of these natural compounds into food matrices, as well as to novel separation and production methods for these valuable food antioxidants. Keywords

Stilbenes · Stilbene glycosides · Stilbenoids · Natural food antioxidants · Vitis polyphenols · Resveratrol · Piceatannol · Piceid or polydatin Abbreviations 1

H/13C-NMR 4CL α-CD ABTS+ ACC ACS AFM ATR-FT-IR β-CD BHT BmCGTase

1

H/13C-nuclear magnetic resonance 4-coumarate:coenzyme A ligase α-cyclodextrin 2,20 -azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radical cation acetyl-coenzyme A carboxylase acetate assimilating enzyme atomic force microscopy attenuated total reflectance-Fourier transform infrared spectroscopy β-cyclodextrin tertbutylhydroxytoluene (2,6-di-tertbutyl-4-methylphenol) cyclomaltodextrin glucanotransferase from Bacillus macerans

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Stilbenes and Its Derivatives and Glycosides

C4H CD CGTase CoA CPC CUPRAC CYP450 DLS DMN DMPD+• DPPH• DSC DW ESI-MS FDA FRAP FT-IR FW γ-CD GC-MS GRAS HAT HOMO HP-β-CD HPLC-DAD/ESIMS/MS/MS2/UV-Vis

HP-TLC HRMS HSA HS-SBSE LUMO MAE MatB/C NADP+/NADPH NLC ORAC

489

cinnamate 4-hydroxylase circular dichroism cyclomaltodextrin glucanotransferase coenzyme A centrifugal partition chromatography cupric reducing antioxidant capacity cytochrome P450 dynamic light scattering dissolving microneedle N,N-dimethyl-p-phenylenediamine radical cation 2,2-diphenyl-1-picrylhydrazyl radical differential scanning calorimetry dry weight electrospray ionization-mass spectrometry Food and Drug Administration of the United States of America ferric reducing antioxidant power Fourier transform infrared spectroscopy fresh weight γ-cyclodextrin gas chromatography coupled with mass spectrometry detector generally recognized as safe hydrogen atom transfer highest occupied molecular orbital 2-hydroxypropyl-β-cyclodextrin high-pressure liquid chromatography coupled with diode array detector/electrospray ionization detector/ mass spectrometry detector/tandem mass spectrometry detector/ultraviolet-visible spectrophotometric detector high-performance thin-layer chromatography high-resolution mass spectrometry human serum albumin headspace stir bar sorptive extraction lowest unoccupied molecular orbital microwave-assisted extraction malonate assimilation pathway genes nicotinamide adenine dinucleotide phosphate/reduced form nanostructured lipid carrier oxygen radical absorbance capacity

490

PAL PcR3GAT PEG PT PTGS-1 QSAR QSPR ROMT ROS SDS-PAGE SEM SET SET-PT SLN SPLET STS SULT TAL TBARS TEAC TEM TG TLC TPTZ UAE UDP UGT UHPLC-DADESI-MS/FD/ QTOF-MS/MS2/n

UV-Vis VvSTS1 XRD

N.-G. Ha˘da˘ruga˘ and D.-I. Ha˘da˘ruga˘

phenylalanine ammonia lyase resveratrol 3-glycosyltransferase from Polygonum cuspidatum poly(ethylene glycol) prenyl transferase prostaglandin-endoperoxide synthase 1 (or COX-1) quantitative structure-activity relationship quantitative structure-property relationship resveratrol O-methyltransferase reactive oxygen species sodium dodecyl sulfate-polyacrylamide gel electrophoresis scanning electron microscopy single-electron transfer single-electron transfer followed by proton transfer solid lipid nanoparticle sequential proton loss electron transfer stilbene synthase sulfotransferase tyrosine ammonia lyase thiobarbituric acid reactive substances trolox equivalent antioxidant capacity transmission electron microscopy thermogravimetry thin-layer chromatography tripyridyltriazine ultrasound-assisted extraction uridine diphosphate uridine 50 -diphosphoglucuronyltransferase ultrahigh-pressure liquid chromatography coupled with photodiode array detector/electrospray ionization-mass spectrometry detector/fluorescence detector/quadrupole time of flight-mass spectrometry/tandem mass spectrometry detector ultraviolet-visible spectrophotometry Vitis vinifera L. synthetic stilbene synthase gene X-ray diffractometry

Introduction Stilbenoids are widely distributed in nature, but only in specific botanical families such as Asteraceae, Combretaceae, Cyperaceae, Dipterocarpaceae, Gnetaceae, Leguminosae, Liliaceae, Moraceae, Orchidaceae, Polygonaceae, Stemonaceae,

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and Vitaceae (Shen et al. 2013; Cho et al. 2019). They have the core of stilbene (1,10 -(ethene-1,2-diyl)dibenzene or bibenzylidene), namely the simple stilbene aglycones (having hydroxyl and methoxy groups on the A and B benzene rings; Figs. 1 and 2), prenyl or geranyl stilbene aglycones (Fig. 3), arylbenzofurans (Fig. 4), and other stilbene-based derivatives (having acyl, benzyl, carboxyl groups or terpenoid moieties; Fig. 5). Bibenzyls are stilbene homologues having the reduced form of stilbene and similar groups on the benzene rings (Figs. 6 and 7) (Xiao et al. 2008; Shen et al. 2013; Chou et al. 2018). Glycosylated stilbenoids are mainly found in vivo (both natural sources and during metabolization) and are hydrolyzed to the corresponding aglycones during extraction and processing of the natural sources (Chiva-Blanch et al. 2011; Wang et al. 2019). However, stilbene aglycones are

R3' R2' R2 R3 3 4

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2

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1' 6

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B

6'

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5'

4'

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R5 trans-Stilbene skeleton

R3'

3'

R5'

cis-Stilbene skeleton

Fig. 1 The schematic presentation of stilbene chemical structure

R3' R4'

R2' R3 R6' R4 R5

Slbene aglycones (simple) Resveratrol Isorhapongenin Rhapongenin Piceatannol Oxyresveratrol Gnetol Pteroslbene Phoyunbene A Phoyunbene B Phoyunbene C Phoyunbene D Halophilol A Gnetucleistol B Thunalbene Verussuslbene

cis/trans

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R4

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trans trans trans trans trans trans trans trans trans trans trans trans cis trans trans

OH OH OH OH OH OH OMe OMe OMe OMe OMe OMe OMe OMe OH

H H H H H H H H H H H OMe OH H H

OH OH OH OH OH OH OMe OH OH OH OH OH OMe OH OH

H H H H OH H H OMe OMe OMe OMe OMe OH H OH

H OMe OH OH H H H OH OMe OH OMe OH H OH OMe

OH OH OMe OH OH H OH OMe OH H H H H H OH

H H H H H H H H H H H H OH H H

Fig. 2 The main simple stilbene aglycone structures

N.-G. Ha˘da˘ruga˘ and D.-I. Ha˘da˘ruga˘

492

R3' R4' R2 R3 R5' R4

R6 R5

Slbene aglycones (prenyl- and geranylderivaves) Chiricanine A Chiricanine B

cis/ trans

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R5

R6

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OH OH

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Chiricanine C Chiricanine D

trans trans

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trans

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H

H

H

Mappain

trans

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H 2-OH-3Prn… 3-OH-2Prn… H

OH

OH

Grn

Fig. 3 Examples of prenyl- and geranyl-derivatives of stilbene aglycones (Prn prenyl, O. . .2/3OH-3/2-Prn 2/3-hydroxy-3/2-prenyl moiety between Rx and Ry positions, Grn geranyl)

HO OH R3

R2'

R2

O

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OH

O

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H3C

H3C

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H3C

Slbene aglycones (arylbenzofuran based) Gnefolin P Gnetofuran B Gnetofuran C Stemofuran A Stemofuran B Stemofuran D Stemofuran E Stemofuran G Artoindonesianin O 3-Prenyl-moracin M

R2

R3

R4

R5

R2’

H H H H H Me Me Me H H

OMe OMe OH OH OMe OH OH OH OMe OH

H H H H H H Me Me Prn H

OH OH OH OH OH OMe OMe OMe OH OH

OH OMe OMe H OH OH OH OH H H

Macrourin A R3’ R4’

R5’

H OH OH H H H H Me H OH

H H H H H H H H H Prn

H H H H H H H H OH H

Fig. 4 Examples of arylbenzofuran-based stilbene aglycones (Prn prenyl)

produced by enzymatic hydrolysis using cell and microbial cultures, as well as purified or immobilized enzymes (Medina-Bolivar et al. 2007; Basholli-Salihu et al. 2016; Wang et al. 2019; Zhou et al. 2022). Finally, stilbene oligomers can also be found in natural sources or aged wines (Ivanova-Petropulos et al. 2015; Romboli et al. 2015). Even though both trans and cis geometric isomers of stilbenes occur, transstilbenoids are more abundant, but they can be converted into the cis form under

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Stilbenes and Its Derivatives and Glycosides

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H3C

R3'

CH3 O

R4' R2 R3

O

H3C

R5

Other simple slbene aglycones 2-isoButanoyl-5-O-methyl-resveratrol 2-isoButanoyl-resveratrol Gnetupendin A Gnetupendin B Persilben

R2 iPrCO iPrCO p-HOBn 3,4-diHOBn COOH

R3 OH OH OH OH OMe

R5 OMe OH OH OH OMe

CH3

trans-5-(Terpinen-4-yloxy)-3methoxyslbene R3’ R4’ H OH H OH OMe OH OMe OH H H

Fig. 5 Examples of the other simple stilbene aglycones (Bn benzyl, iPr isopropyl)

R3' R2'

R4'

R2 R3

R4 R5

Simple bibenzyls

R2

R3

R4

R5

R2’

R3’

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Dendrobin A Dendrobin B Slbostemin A Slbostemin B Slbostemin C Slbostemin D BulbophyIIin Bulbophyllidin Densiflorol A Amoenylin Isoamoenylin

H H H H H H OH OH H H H

OMe OMe OH OH OH OH OMe OMe OMe OMe OMe

OH OH H Me Me Me

OH OMe OH OH OH OH

H H OMe H Me OMe H H H H H

OMe OMe H H H H OH OH

H H H H H H H H

OCH2O H H OH OMe

OMe OH OMe OMe

OCH2O H OH

OMe H

Fig. 6 Examples of the naturally occurring simple bibenzyls

ultraviolet (UV) irradiation by photoisomerization (Fig. 1) (Medina-Bolivar et al. 2007; Jensen et al. 2010; Delmas et al. 2011; Gomes-Silva et al. 2013; Zupančič et al. 2015; Eungsuwan et al. 2021). The trans form is more stable than the cis form, especially during redox reactions. The oxidation of stilbenes is favored by the presence of phenolic hydroxyl groups and this reaction is the basis of the antioxidant activity (Brisdelli et al. 2009; Delmas et al. 2011). The antioxidant mechanism involves the formation of oxyl radicals, which are then transformed into semiquinone radicals and further into neutral compounds such as stilbene dimers (Shang et al. 2009). Evaluation of the antioxidant activity of stilbenes can be performed by various classical methods, which can be differentiated according to the antioxidant mechanisms. The hydrogen atom transfer (HAT) mechanism appears for oxygen radical absorbance capacity (ORAC) or β-carotene bleaching assays, while the single-electron transfer (SET) mechanism is the basis of Folin-Ciocâlteu

N.-G. Ha˘da˘ruga˘ and D.-I. Ha˘da˘ruga˘

494 H3C

CH3

OH

OH

O O

O HO R3'

H

H3C OH

CH3

R3

Glepidon D

Typhaphthalide OH

R4 R5

O

COOH

R6

CH3

HO OH O

O OH

OH

Other bibenzyls (prenyl-, hydroxybenzyl-derivaves, etc.) Isoarundinin I Isoarundinin II Bulbocodin C Bulbocodin D Shanciguol Bulbucol

R3 OMe OH OMe OH OH OMe

Tragopogonic acid R4 H H p-HOBn p-HOBn H H

R5 OH OMe OH OMe OH OH

O

(S)-Phyllodulcin R6 H H H H p-HOBn H

R3’ OH OH OH OH OH OMe

Fig. 7 Examples of other bibenzyls, including prenyl- and hydroxybenzyl-derivatives (Bn benzyl)

reagent, ferric ion reducing antioxidant power (FRAP), 2,2-diphenyl-1picrylhydrazyl radical scavenging (DPPH•), 2,20 -azino-bis(3-ethylbenzothiazoline6-sulfonic acid) radical scavenging (ABTS+•), N,N-dimethyl-p-phenylenediamine radical scavenging (DMPD+•), or cupric reducing antioxidant capacity (CUPRAC) assays (Gülçin 2010; Rodríguez-Bonilla et al. 2017; Gülçin 2020). According to some studies (Gülçin 2012; Rodríguez-Bonilla et al. 2017; Gülçin 2020), both HAT and SET mechanisms are involved in the evaluation of antioxidant activity by methods such as superoxide anion radical (O2•), hydroxyl radical (HO•), hydrogen peroxide (H2O2), and even ABTS+• assays. Biosynthesis of stilbenes in plants and fruits starts from L-Phe and L-Tyr amino acids by a combined shikimate and acetate pathways (Dubrovina and Kiselev 2017; Duarte et al. 2020). Resveratrol and its glucoside piceid (or polydatin) or dimers are widely found in nature, especially in Vitis species, but also in mulberry (Morus species), peppervine stem and root (Ampelopsis species), some Dracaena species, peanuts (Arachis hypogaea L.), aerial parts of Amur maackia (Maackia amurensis Rupr.) or Ammopiptanthus mongolicus (Maxim.) Cheng f., root and stem of Japanese knotweed (Reynoutria japonica Houtt.), Paeonia  suffruticosa Andrews fruit pods, or tomato pomace (Anastasiadi et al. 2012; Fernández-Marín et al. 2013; Tian and Liu 2020; Benbouguerra et al. 2021; Li et al. 2021b; Abbasi-Parizad et al. 2022). Resveratrol naturally occurs in specific alcoholic beverages (wine and beer), but is also used in functional foods and food supplements (Chiva-Blanch et al. 2011; Guamán-Balcázar et al. 2016; Wei et al. 2020; Benbouguerra et al. 2021; Berenji et al. 2021). Viniferins and vitisins are oligomers of stilbenes that were also found in Vitis species (grapes, stems, shoots, or canes) and wines, together with resveratrol, piceatannol, and stilbene glycosides (e.g., piceid and astringin) (Chen and Wang

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Stilbenes and Its Derivatives and Glycosides

495

2009; Anastasiadi et al. 2012; Fernández-Marín et al. 2013; Gorena et al. 2014; Romboli et al. 2015; Benbouguerra et al. 2021; Gutiérrez-Escobar et al. 2021). On the other hand, piceatannol was identified in passion fruit seed or bagasse (Passiflora edulis Sims) (Viganó et al. 2016; Silva et al. 2021). Other simple stilbenes are oxyresveratrol from heartwood of Artocarpus lakoocha, gnetol from Gnetum hainanense or Gnetum africanum, pterostilbene from almonds, various Vaccinium berries (including blueberries), grape leaves and wines, phoyunbenes from Pholidota yunnanensis Rolfe (an orchid), halophilol A from Iris halophila (a herbal medicine), or gnetucleistol B from Gnetum cleistostachyum (a herb) (Xiao et al. 2008; Gabaston et al. 2020). Prenyl- and geranyl-stilbenes such as chiricanines were found in Arachis hypogaea (peanuts) or Lonchocarpus chiricanus, while mappain was identified in Macaranga mappa, which is used for the preservation of food (Xiao et al. 2008; de-Bruijn et al. 2018). Gnetifolins and gnetofurans are representatives for arylbenzofuran-based stilbenes and were found in Gnetum species, while stemofurans were identified in Stemona collinsae that is used in traditional medicine. Bibenzyl homologues were also found in Stemona species such as stilbostemins, while bulbophyllin and densiflorol A from the same stilbenoid class were found in ochids Bulbophyllum protractum and Dendrobium densiflorum, respectively (Xiao et al. 2008). Other bibenzyl, bis(bibenzyl) or phenanthroid derivatives are widely found in various orchids and ornamental species (e.g., Arundina bambusifolia and Pleione bulbocodiodes), or in liverworts (e.g., marchantins, plagiochins, and isoplagiochins) (Xiao et al. 2008; Shen et al. 2013). The resveratrol glycosides piceid gallate and p-coumarate were found in Pleuropterus ciliinervis Nakai, while mulberroside E was identified in cell cultures of Vitis vinifera and Morus alba (Xiao et al. 2008; Inyai et al. 2021). Other mulberrosides (A, D, and F) are oxyresveratrol glycosides and have also been found in Morus alba (Inyai et al. 2021). Astringin is a piceatannol glycoside and was identified in Vitis vinifera and some Picea species such as P. sitchensis or P. abies (Norway spruce), while isorhapontin, a isorhapontigenin glycoside, was found in P. abies, P. sitchensis, P. glauca (white spruce) or Gnetum africanum (Gabaston et al. 2020; Jylhä et al. 2021). Other stilbene glycosides are gnetifolin K (isorhapontigenin aglycone) in G. parvifolium, G. gnemon and G. africanum, rhaponticin (rhapontigenin aglycone) in Rhubarb rhizomes, tyrolobibenzyl C and thunberginol 8- or 40 -O-glucosides from bibenzyl class in Scorzonera humilis L. and Hydrangea maerophylla var. thunbergii (a food beverage made from fermented leaves), gnetifolin glycosides, gnemonosides, mirabilosides, and foeniculosides from oligostilbene class in Gnetum species, Welwitschia mirabilis, Foeniculum vulgare Miller (fennel), respectively (Xiao et al. 2008; Shen et al. 2013; Gabaston et al. 2020). Stilbenes are produced and extracted for food applications using optimized processes such as biosynthesis by metabolic-engineered cultures or ultrasoundassisted extraction (Wang et al. 2015; Shrestha et al. 2018; Park et al. 2021; Guo et al. 2022). The incorporation of stilbenes in food matrices is enhanced by encapsulation in various materials such as lipids/phospholipids for entrapment of resveratrol or piceid, cyclodextrins for resveratrol, oxyresveratrol, or piceid (Zhang et al.

496

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2016; Cheng et al. 2017; He et al. 2019; Matencio et al. 2020; Berenji et al. 2021). Moreover, resveratrol or pterostilbene was used for obtaining biofilms with applications in food packaging or food-grade nanoemulsions (Busolo and Lagaron 2015; Sun et al. 2015; Acevedo-Fani et al. 2017; Matos et al. 2018; Li et al. 2021a).

Chemistry and Functionality of Stilbenes Stilbenes (or stilbenoids) are the generic names for natural compounds that contain stilbene core. Stilbene structure has two benzene rings (A and B) connected by a 1,2ethylene moiety, which can be expressed as C6-C2-C6 scaffold (Fig. 1). A wide range of natural stilbenes exist; for example, monomers, dimers, trimers, tetramers, as well as more complex oligomers (Khawand et al. 2018; Benbouguerra et al. 2021). They occur as both aglycones and glycosides, through the phenolic hydroxyl groups (Oglycosides) or rarely as C-glycosides. The presence of phenolic hydroxyl groups confers antioxidant activity to these compounds, while the presence of other groups such as methoxy, prenyl, geranyl, galloyl, p-coumaroyl, carboxyl, substituted benzyl can modulate this antioxidant activity by modifying the susceptibility to oxidation and water solubility/bioavailability (Xiao et al. 2008; Brisdelli et al. 2009; Delmas et al. 2011; Shen et al. 2013; Zupančič et al. 2015). The classification of stilbenes takes into consideration both the core structure and the type of substituents. Thus, classes based on stilbene skeleton are simple stilbene aglycones containing hydroxyl or/and methoxy groups (Fig. 2), stilbene aglycones also containing terpene substituents (prenyl, hydroxyprenyl, or geranyl, Fig. 3), stilbene derivative aglycones having arylbenzofuran structure (Fig. 4), stilbene derivative aglycones based on bibenzyl skeleton (Figs. 6 and 7), as well as their glycoside derivatives (Figs. 8, 9, 10 and 11) (Xiao et al. 2008; Shen et al. 2013). By far, resveratrol (3,5,40 -trihydroxystilbene), which is mainly found in Vitis species, is the most known and studied polyphenol from the simple stilbene class. It contains three phenolic hydroxyl groups that provide important antioxidant activity. Resveratrol can act both as a chemopreventive and as a therapeutic agent (e.g., anticancerigene/antimutagenic, anti-inflammatory, antimicrobial, anti-aging, antiobesity, anti-diabetic, hepatoprotective, cardioprotective, and neuroprotective) (Brisdelli et al. 2009; Delmas et al. 2011; Waffo-Téguo et al. 2013). Homologs that only contain hydroxyl groups are piceatannol (3,5,30 ,40 -tetrahydroxystilbene) from Norway spruce, oxyresveratrol (3,5,30 ,40 -tetrahydroxystilbene) from monkey fruit, or gnetol (3,5-dihydroxystilbene) from African jointfir. However, the majority of simple stilbenes contain both phenolic hydroxyl and methoxy groups (e.g., rhapontigenin, isorhapontigenin, pterostilbene, or phoyunbenes) (Dvorakova and Landa 2017). Some simple stilbenes contain hemiterpenoid or monoterpenoid moieties in various positions, especially 2, 4, 6, or 50 . Chiricanines A and C from peanuts have prenyl moieties on the C4 or C2 and C4 positions, respectively. Chiricanines B and D have a cyclic 2/3-hydroxylated prenyl moiety to the corresponding chromane derivatives, while chiricanine E has a benzofuran moiety resulting in the cyclization of the 3-hydroxyprenyl substituent from the C6 position. On the other hand, mappain

14

Stilbenes and Its Derivatives and Glycosides

497 O

OH

O OH

O

HO

O

HO

HO

OH OH

HO

OH OH

OH

OH

Piceid/Polydan ((E)-resveratrol 3-O-β-D-glucopyranoside)

Resveratroloside ((E)-resveratrol 4’-O-β-D-glucopyranoside)

OH O

OH

O

O

HO

O

HO HO

HO

O OH

O

O OH

OH

OH O

HO

HO

OH

OH

Piceid 2”-O-gallate ((E)-resveratrol 2”-O-galloyl-β-Dglucopyranoside)

Piceid 2”-O-p-coumarate ((E)-resveratrol 2”-O-p-coumaroylβ-D-glucopyranoside) OH

OH

OH HO

O

O

HO

O HO HO

OH

HO OH

O

O OH

OH HO

OH

OH OH

(Z)-3,5,4'-Trihydroxyslbene 2-C-β-D-glucopyranoside O

(E)-Resveratrol 3,5-di-O-β-D-glucopyranoside OH

O

HO

O

O

OH

HO

HO HO

OH

OH

OH OH

O

HO

O

OH

O

O

OH

OH HO

OH

OH OH

(Z)-Resveratrol 3,5-di-O-β-D-glucopyranoside

(Z)-Resveratrol 3,4’-di-O-β-D-glucopyranoside

OH O

O

OH O

OH

HO

HO

+

Na O

-

O O

S

O

O

OH HO

OH

O

O HO

OH

O

OH

O OH

HO

OH

OH

OH OH

(Z)-Resveratrol 3,5,4’-tri-O-β-D-glucopyranoside

Piceid/Polydan 6”-sulfate, sodium salt ((E)-resveratrol 3-Oβ-D-glucopyranoside 6”-sulfate, sodium salt)

Fig. 8 Representative structures for resveratrol glycoside class

from Macaranga mappa has both hemi- and monoterpene moieties on C4 (prenyl) and C50 (geranyl) positions, respectively (Xiao et al. 2008; de-Bruijn et al. 2018). The cyclization of a 60 -hydroxylated stilbene at the C1 position of the ethenediyl moiety of stilbene provides the arylbenzofuran class of stilbenoids. Many structures from this class were found in some Gnetum and Stemona species and have hydroxyl and methoxy groups in the C3 and C5 positions of the phenyl group, as well as C2 and C3 positions on the benzofuran moiety (positions are originally related to stilbene core; for example, gnetifolin P, gnetofurans B, and C, or stemofurans A

N.-G. Ha˘da˘ruga˘ and D.-I. Ha˘da˘ruga˘

498 O

O

OH

OH O

OH

O HO

HO

OH

HO

O

OH

OH OH

OH

O O

OH

OH

O

OH

HO HO

OH

OH

OH

Mulberroside A ((E)-oxyresveratrol 3,4’-di-O-β-Dglucopyranoside)

OH

Mulberroside D ((Z)-oxyresveratrol 3,4’-di-O-β-Dglucopyranoside) OH

HO OH O HO O

O HO

OH

O

O HO

OH

OH

Muberroside F (moracin M 6,3’-di-O-β-D-glucopyranoside)

Fig. 9 Representative structures for oxyresveratrol glycoside class

OH

OH O

O

OH

O OH

HO

O

O

O OH

HO

HO

OH

OH OH

HO

OH

OH

OH OH

OH

(E)-Piceatannol 3,4’-di-O-β-D-glucopyranoside

Astringin ((E)-piceatannol 3-O-β-D-glucopyranoside) OH

OH O

O

O O

HO

O

O

O O

HO HO

OH

CH3

OH

OH OH

HO

OH

CH3

OH OH

Isorhaponn ((E)-isorhapongenin 3-O-β-Dglucopyranoside) O

OH

Gnefolin K ((E)-isorhapongenin 3,4’-di-O-β-Dglucopyranoside)

O CH3

OH

OH

CH3

OH

HO

HO O

O OH

HO

O O

HO HO

OH

OH OH

O

OH

OH

Rhaponcin ((E)-rhapongenin 3-O-β-D-glucopyranoside)

3,5-Dihydroxyslbene 3-O-neohesperidoside or 4'-norresveratrol 3-O-[α-L-rhamnopyranosyl-(1Æ2)-β-Dglucopyranoside]

Fig. 10 Representative structures for piceatannol, isorhapontigenin, rhapontigenin, and 40 -nor-resveratrol glycoside classes

and B, Fig. 4). However, some arylbenzofuran derivatives have methyl or prenyl groups such as stemofurans D, E, and F, respectively artoindonesianin O and 3-prenyl-moracin M from some Artocarpus species. On the other hand, simple

14

Stilbenes and Its Derivatives and Glycosides OH

O

H3C

499

HO

O

OH

O

H3C O

HO

O

HO

OH

OH

O

OH

OH

O

O

OH OH

OH

OH

OH

Tyrolobibenzyl C OH

OH

Tyrolobibenzyl E

OH

O CH3

HO O

CH3

O

O HO

CH3

O

O O

O

O

HO

O HO

O

O CH3 OH

OH OH

HO HO

OH

Dendromoniliside E

(3R)-Thunberginol H 8-O-β-D-glucopyranoside O CH3

O O

O

O

HO HO

OH OH

Scorzocrecoside I

Fig. 11 Examples of glycosylated structures of bibenzyls

stilbene aglycones having isobutanoyl, hydroxybenzyl, or carboxy groups at the C2 position of stilbene core were identified in Ekebergia benguelensis (isobutanoyl derivatives), Gnetum pendulum (hydroxybenzyl derivatives) or Polygonum persicaria L. (Jesusplant, carboxy derivatives). Moreover, 5-O-terpinen-4-yl derivative was identified in Alpinia katsumadai (Fig. 5) (Xiao et al. 2008; Gabaston et al. 2020). The saturated homologs at the linkage group (bibenzyl class) are provided by a similar biosynthesis pathway that involves the reduction of the p-coumaroyl-CoA intermediate using NADPH. They were found in many plants from Orchidaceae and Stemonaceae families. It is the case of dendrobins from noble dendrobium, stilbostemins from Stemona species, bulbophyllin and bulbophyllidin, densiflorol A, amoenylin and isoamoenylin from orchids Bulbophyllum protractum, Dendrobium densiflorum or Dendrobium amoenum, respectively (Xiao et al. 2008). They have hydroxyl and methoxy groups at various positions of the bibenzyl core, but compounds having methyl groups (e.g., stilbostemins B, C, and D) or methylenedioxi moiety (e.g., bulbophyllin and densiflorol A) also occur (Fig. 6). Other bibenzyl derivatives have p-hydroxybenzyl moieties on one or two positions

500

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of the A and B rings (e.g., isoarundinins from bamboo orchid, or bulbocodins, shanciguol, and bulbucol from the orchid Pleione bulbocodiodes) (Xiao et al. 2008). Glepidotin D have prenyl groups on the bibenzyl core and was found in Glycyrrhiza lepidota, while some bibenzyls have carboxy groups such as tragopogonic acid from the vegetable oyster or Jerusalem star (an ornamental flower and edible root) (Xiao et al. 2008; Zhao and Song 2017). Cyclization of a pre-existing carboxyl group from the C2 position at the C1 or C2 positions of ethylenediyl moiety provide lactone derivatives (Fig. 7) found in the medicinal plant Uganda (Typha eapensis, typhaphthalide) or some Hydrangea species (French hydrangea or tea of heaven, (S)-phyllodulcin) (Shen et al. 2013; Zhao and Song 2017). Piceid (or polydatin) is the 3-O-glucoside of resveratrol and accompanying the aglycone in grapes. It is also found in Japanese knotweed (Polygonum cuspidatum) and some Picea and Reynoutria species (Ivanova-Petropulos et al. 2015; Wang et al. 2019; Zhou et al. 2022). It is widespread in nature and was found at 10–15 times higher contents than resveratrol in P. cupsidatum (Wang et al. 2019). The water solubility of piceid is higher than resveratrol and the bioavailability varies in the same way (water solubility of piceid is 0.357 mg/mL, in comparison with