Nutraceuticals and natural product pharmaceuticals 9780128164501, 0128164506

Table of contents :
Content: 1. Introduction to nutraceuticals and pharmaceuticals 2. Nutrigenomics and antioxidants 3. How plant secondary metabolites impact human health 4. Nutraceuticals and metabolic syndrome 5. Pharmacokinetics and bioavailability of natural products 6. Epigenetics and personalized nutrition 7. Innovative sources 8. Production of natural products with pharmaceutical potential 9. Food matrices that improve the oral bioavailability of pharmaceuticals and nutraceuticals 10. From nutraceuticals to nanopharmaceuticals 11. Reorientation of nutraceuticals and pharmaceuticals applications in an open innovation model 12. Convergence between nutraceuticals and western medicine 13. Ethno-pharmaceutical formulations 14. Effects of nutritional supplements on human health

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Nutraceuticals and Natural Product Pharmaceuticals

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Nutraceuticals and Natural Product Pharmaceuticals

Edited by

Charis M. Galanakis Department of Research & Innovation, Galanakis Laboratories, Chania, Greece Food Waste Recovery Group, ISEKI Food Association, Vienna, Austria

Academic Press is an imprint of Elsevier 125 London Wall, London EC2Y 5AS, United Kingdom 525 B Street, Suite 1650, San Diego, CA 92101, United States 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom Copyright © 2019 Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress ISBN: 978-0-12-816450-1 For Information on all Academic Press publications visit our website at https://www.elsevier.com/books-and-journals

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Contents List of Contributors .............................................................................................................................. xi Preface ................................................................................................................................................. xv

CHAPTER 1 Introduction to Nutraceuticals and Pharmaceuticals ......................... 1 Kata Trifkovic´ and Maja Benkovic´ 1.1 A Brief History of Nutraceuticals and Pharmaceuticals ........................................... 2 1.2 Nutraceuticals ............................................................................................................. 3 1.2.1 The Definition .................................................................................................. 3 1.2.2 What Is Functional Food?................................................................................ 4 1.2.3 Why Nutraceuticals and Functional Foods?.................................................... 6 1.2.4 What Can Be Referred to as Nutraceuticals?.................................................. 7 1.2.5 Nutraceuticals in Disease Prevention .............................................................. 7 1.3 Pharmaceuticals........................................................................................................ 13 1.3.1 The Definition ................................................................................................ 13 1.3.2 Development .................................................................................................. 15 1.3.3 Chemical Composition and Classification .................................................... 19 1.3.4 Naturally-Based Pharmaceuticals .................................................................. 20 1.4 Legislation ................................................................................................................ 21 1.4.1 Legislation on Pharmaceuticals ..................................................................... 21 1.4.2 Legislation on Nutraceuticals ........................................................................ 21 1.5 The Differences and the Overlapping...................................................................... 23 1.6 The Future Perspectives ........................................................................................... 24 1.6.1 What Needs to Be Done? .............................................................................. 24 1.6.2 Novel Trends in Nutraceuticals Production .................................................. 24 References................................................................................................................. 25

CHAPTER 2 Nutrigenomics and Antioxidants ........................................................ 33 2.1 2.2 2.3 2.4

Bilyaminu Abubakar, Ooi Der Jiun, Maznah Ismail and Mustapha Umar Imam Introduction .............................................................................................................. 34 Nutrigenomics .......................................................................................................... 35 Antioxidants and Their Mode of Action ................................................................. 36 Nutrigenomic Basis of Antioxidant Vitamins ......................................................... 41 2.4.1 Vitamin A....................................................................................................... 41 2.4.2 Vitamin C....................................................................................................... 44

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2.4.3 Vitamin D....................................................................................................... 44 2.4.4 Vitamin E ....................................................................................................... 45 2.5 Nutrigenomic Basis of Antioxidant Mineral Elements ........................................... 46 2.5.1 Magnesium ..................................................................................................... 46 2.5.2 Molybdenum .................................................................................................. 46 2.5.3 Manganese...................................................................................................... 50 2.5.4 Selenium......................................................................................................... 50 2.5.5 Chromium....................................................................................................... 51 2.6 Nutrigenomic Basis of Antioxidant Phytochemicals .............................................. 51 2.6.1 Polyphenols .................................................................................................... 51 2.6.2 Flavonoids ...................................................................................................... 58 2.6.3 Sulforaphane................................................................................................... 60 2.7 Conclusions .............................................................................................................. 60 Acknowledgments .................................................................................................... 61 References................................................................................................................. 61

CHAPTER 3 Plant Secondary Metabolites With Hepatoprotective Efficacy................................................................................................ 71 Ashutosh Gupta and Abhay K. Pandey 3.1 Introduction .............................................................................................................. 71 3.2 Liver Diseases and Their Overview ........................................................................ 72 3.3 Physiological Role of Liver ..................................................................................... 73 3.3.1 Carbohydrate Metabolism.............................................................................. 73 3.3.2 Fat Metabolism .............................................................................................. 74 3.3.3 Protein Metabolism and Storage of Vitamins ............................................... 74 3.3.4 Neutralization of Toxic Substance ................................................................ 74 3.4 Mode of Hepatotoxicity ........................................................................................... 74 3.4.1 Reactive Metabolites Formation.................................................................... 74 3.4.2 Lipid Peroxidation and Redox Cycling ......................................................... 75 3.4.3 Effect of Chemical Agents on Major Cellular Systems................................ 75 3.4.4 Modification in Calcium Homeostasis .......................................................... 75 3.4.5 Drug-Induced Hepatotoxicity ........................................................................ 76 3.5 Phytochemicals......................................................................................................... 79 3.5.1 Current Status of Therapeutic Plants............................................................. 80 3.5.2 Hepatoprotective Properties of Phytochemicals and Their Mode of Action ........................................................................................................ 80 3.6 Conclusion ................................................................................................................ 91 Acknowledgment ...................................................................................................... 94 References................................................................................................................. 94 Further Reading ...................................................................................................... 104

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CHAPTER 4 Effects of Nutritional Supplements on Human Health..................... 105

4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8

´ Marı´a de la Luz Cadiz Gurrea, So´nia Soares, ´ ´ Francisco Javier Leyva Jimenez, A´lvaro Fernandez Ochoa, Diana Pinto, Cristina Delerue-Matos, Antonio Segura Carretero and Francisca Rodrigues Abbreviations.......................................................................................................... 105 Introduction ............................................................................................................ 106 Cardiovascular Diseases......................................................................................... 107 Cancer..................................................................................................................... 111 Metabolic Syndrome .............................................................................................. 113 Diabetes .................................................................................................................. 118 Neurodegenerative Diseases .................................................................................. 124 Overall Mortality.................................................................................................... 127 Conclusion .............................................................................................................. 129 Acknowledgments .................................................................................................. 130 References............................................................................................................... 130

CHAPTER 5 Optimizing Performance Under High-Altitude Stressful Conditions Using Herbal Extracts and Nutraceuticals .................... 141 5.1 5.2 5.3 5.4 5.5 5.6 5.7

5.8 5.9 5.10 5.11 5.12 5.13

5.14

Geetha Suryakumar, Richa Rathor, Akanksha Agrawal, Som Nath Singh and Bhuvnesh Kumar High Altitude, Hypobaric Hypoxia, and Oxidative Stress .................................... 142 High Altitude
Induced Maladies.......................................................................... 142 Imbalance in Redox Homeostasis Affects Skeletal Muscle.................................. 143 Skeletal Muscle Atrophy at High Altitude ............................................................ 144 Herbs for High Altitude Maladies: Literature Citation ......................................... 146 Multiple Stress Animal Model for Evaluation of Adaptogenic Activity.............. 147 Herbal Adaptogens/Performance Enhancers ......................................................... 148 5.7.1 Panax Ginseng.............................................................................................. 148 5.7.2 Ginkgo Biloba .............................................................................................. 149 5.7.3 Withania Somnifera ..................................................................................... 150 5.7.4 Ocimum Sanctum......................................................................................... 151 Composite Indian Herbal Preparation-I................................................................. 151 Composite Indian Herbal Preparation-II................................................................ 152 Sea Buckthorn as Adaptogen ................................................................................. 152 Curcumin ................................................................................................................ 154 Rhodiola Imbricata................................................................................................. 155 Ganoderma Lucidum.............................................................................................. 156 5.13.1 Emblica Officinalis .................................................................................... 157 5.13.2 Cordyceps Sinensis .................................................................................... 158 Conclusion .............................................................................................................. 159

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References............................................................................................................... 159 Further Reading ...................................................................................................... 166

CHAPTER 6 Nutraceuticals and Metabolic Syndrome ........................................ 167 Jacob A. Walker, Benjamin M. Dorsey and Marjorie A. Jones What Are Nutraceuticals and How Do They Differ From Supplements?............ 168 Metabolic Syndrome Defined ................................................................................ 168 Diagnostic Criteria ................................................................................................. 170 Obesity and Hyperlipidemia .................................................................................. 170 Lipoproteins, Cholesterol, and Atherosclerosis..................................................... 172 Hyperglycemia ....................................................................................................... 173 Hypertension (High Blood Pressure) ..................................................................... 173 C-Reactive Protein ................................................................................................. 173 Insulin-Like Growth Factor-1 ................................................................................ 174 Reactive Oxygen Species and General Ways to Detoxify Them ......................... 174 Therapy/Treatment After Diagnosis of Metabolic Syndrome............................... 177 6.11.1 Obesity and Hyperlipidemia Therapy/Treatment...................................... 177 6.11.2 Cholesterol Therapy/Treatment ................................................................. 177 6.11.3 Hyperglycemia and Diabetes Therapy/Treatment..................................... 178 6.11.4 C-Reactive Protein Therapy/Treatment..................................................... 178 6.11.5 Insulin-Like Growth Factor-1 Therapy/Treatment.................................... 178 6.11.6 Hypertension .............................................................................................. 179 6.12 Role(s) of Nutraceuticals ....................................................................................... 179 6.12.1 An Overview of Uses of Nutraceuticals in the Treatment of Metabolic Syndrome ............................................................................. 179 6.12.2 Traditional Chinese Medicine in the Treatment of Metabolic Syndrome ................................................................................................... 179 6.12.3 Various Nutraceuticals Sold to and Used by the Public With or Without Consultation With Their Physicians ....................................... 181 6.12.4 Excipients Used in Nutraceuticals............................................................. 183 6.13 Side Effects of Nutraceuticals................................................................................ 185 6.14 Final Thoughts on the Future of Nutraceuticals.................................................... 185 References............................................................................................................... 187 Further Reading ...................................................................................................... 195 6.1 6.2 6.3 6.4 6.5 6.6 6.7 6.8 6.9 6.10 6.11

CHAPTER 7 Food Matrices That Improve the Oral Bioavailability of Pharmaceuticals and Nutraceuticals............................................... 197 Sheila C. Oliveira-Alves, Ana Teresa Serra and Maria R. Bronze 7.1 Introduction ............................................................................................................ 197 7.2 The Concept of Bioaccessibility, Bioavailability, and Bioactivity....................... 199

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7.3 Factors That Limit the Oral Bioavailability of Lipophilic Bioactive Agents ...... 201 7.3.1 Bioaccessibility ............................................................................................ 203 7.3.2 Absorption .................................................................................................... 204 7.3.3 Transformation ............................................................................................. 208 7.4 Food Matrix Design That Improve the Oral Bioavailability of Lipophilic Compounds............................................................................................................. 209 7.4.1 Delivery Systems ......................................................................................... 209 7.4.2 Excipient Systems ........................................................................................ 220 7.5 Conclusion .............................................................................................................. 222 References............................................................................................................... 222 Further Reading ...................................................................................................... 231

CHAPTER 8 Innovative Sources ........................................................................... 235 8.1 8.2 8.3

8.4

˘ ˘ s, Sonia Socaci Lavinia Florina Calinoiu, Anca Farca¸ and Dan Cristian Vodnar Introduction ............................................................................................................ 235 Innovative Sources of Nutraceuticals .................................................................... 236 Factors that Influence the Biological Properties of Bioactive Compounds from Agro-Industrial By-Products ......................................................................... 243 8.3.1 Digestion Process ......................................................................................... 243 8.3.2 Food Processing ........................................................................................... 250 Conclusions ............................................................................................................ 251 Acknowledgment .................................................................................................... 252 References............................................................................................................... 252 Further Reading ...................................................................................................... 265

CHAPTER 9 Ethno-Pharmaceutical Formulations ................................................ 267 9.1 9.2 9.3 9.4

9.5 9.6 9.7

Hikoichiro Maegawa Introduction ............................................................................................................ 267 History .................................................................................................................... 268 Pharmacopoeia ....................................................................................................... 269 WHO Monographs on Selected Medicinal Plants................................................. 269 9.4.1 Volume 1...................................................................................................... 270 9.4.2 Volume 2...................................................................................................... 270 9.4.3 Volume 3...................................................................................................... 283 9.4.4 Volume 4...................................................................................................... 283 9.4.5 Commonly Used in the Newly Independent States .................................... 290 European Union Monograph.................................................................................. 290 Botanical Drugs in the United States .................................................................... 300 Herbal Medicinal Products in Japan ...................................................................... 301

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9.8 Discussion............................................................................................................... 302 9.8.1 Quality Control of Herbal Medicines.......................................................... 302 9.8.2 Efficacy and Safety of Herbal Medicines ................................................... 304 Acknowledgments .................................................................................................. 305 References............................................................................................................... 305

CHAPTER 10 Reorientation of Nutraceuticals and Pharmaceuticals Applications in an Open Innovation Model...................................... 313 10.1 10.2

10.3

10.4

10.5

Barbara Bigliardi Introduction ............................................................................................................ 313 Industry Convergence: A Literature Background ................................................. 314 10.2.1 The Patterns of Industry Convergence ...................................................... 315 10.2.2 Drivers, Challenges, and Consequences of Industry Convergence .......... 316 10.2.3 The Process of Industry Convergence....................................................... 317 The Role of Open Innovation in Industry Convergence ....................................... 318 10.3.1 Open Innovation and the Food Industry.................................................... 322 10.3.2 Open Innovation and the Pharmaceutical Industry ................................... 323 Evidence of Industry Convergence From the Food and Pharmaceuticals Industries ................................................................................................................ 324 10.4.1 The Case of Nutraceuticals........................................................................ 324 Conclusions ............................................................................................................ 328 References............................................................................................................... 330 Further Reading ...................................................................................................... 335

Index .................................................................................................................................................. 337

List of Contributors Bilyaminu Abubakar Deparment of Pharmacology and Toxicology, Usmanu Danfodiyo University, Sokoto, Nigeria; Centre for Advanced Medical Research and Training, Usmanu Danfodiyo University, Sokoto, Nigeria Akanksha Agrawal Defence Institute of Physiology and Allied Sciences, Delhi, India Maja Benkovic´ Faculty of Food Technology and Biotechnology, Department of Process Engineering, University of Zagreb, Zagreb, Croatia Barbara Bigliardi Department of Engineering and Architecture, University of Parma, Parma, Italy Maria R. Bronze iBET, Instituto de Biologia Experimental e Tecnolo´gica, Oeiras, Portugal; ITQB, Instituto de Tecnologia Quı´mica e Biolo´gica Anto´nio Xavier, Universidade Nova de Lisboa, Oeiras, Portugal; ´ iMed.ULisboa, Faculdade de Farmacia, Universidade de Lisboa, Av. das Forc¸as Armadas, Lisboa, Portugal ´ Marı´a de la Luz Cadiz Gurrea Department of Analytical Chemistry, University of Granada, Granada, Spain; Research and Development of Functional Food Centre (CIDAF), PTS Granada, Granada, Spain Antonio Segura Carretero Department of Analytical Chemistry, University of Granada, Granada, Spain; Research and Development of Functional Food Centre (CIDAF), PTS Granada, Granada, Spain ˘ Lavinia Florina Calinoiu Faculty of Food Science and Technology, University of Agricultural Sciences and Veterinary Medicine Cluj-Napoca, Cluj-Napoca, Romania; Institute of Life Sciences, University of Agricultural Sciences and Veterinary Medicine Cluj-Napoca, Cluj-Napoca, Romania Cristina Delerue-Matos ´ REQUIMTE/LAQV, Instituto Superior de Engenharia do Porto, Instituto Politecnico do Porto, Porto, Portugal Benjamin M. Dorsey Department of Chemistry, Illinois State University, Normal, IL, United States ˘ s Anca Farca¸ Faculty of Food Science and Technology, University of Agricultural Sciences and Veterinary Medicine Cluj-Napoca, Cluj-Napoca, Romania; Institute of Life Sciences, University of Agricultural Sciences and Veterinary Medicine Cluj-Napoca, Cluj-Napoca, Romania Ashutosh Gupta Department of Biochemistry, University of Allahabad, Allahabad, India

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List of Contributors

Mustapha Umar Imam Department of Medical Biochemistry, Usmanu Danfodiyo University, Sokoto, Nigeria; Centre for Advanced Medical Research and Training, Usmanu Danfodiyo University, Sokoto, Nigeria Maznah Ismail Laboratory of Molecular Biomedicine, Institute of Bioscience, Universiti Putra Malaysia, Serdang, Malaysia ´ Francisco Javier Leyva Jimenez Research and Development of Functional Food Centre (CIDAF), PTS Granada, Granada, Spain Ooi Der Jiun Laboratory of Molecular Biomedicine, Institute of Bioscience, Universiti Putra Malaysia, Serdang, Malaysia Marjorie A. Jones Department of Chemistry, Illinois State University, Normal, IL, United States Bhuvnesh Kumar Defence Institute of Physiology and Allied Sciences, Delhi, India Hikoichiro Maegawa Pharmaceutical Evaluation Division, Pharmaceutical Safety and Environmental Health Bureau, Ministry of Health, Labour and Welfare, Tokyo, Japan ´ A´lvaro Fernandez Ochoa Department of Analytical Chemistry, University of Granada, Granada, Spain; Research and Development of Functional Food Centre (CIDAF), PTS Granada, Granada, Spain Sheila C. Oliveira-Alves iBET, Instituto de Biologia Experimental e Tecnolo´gica, Oeiras, Portugal Abhay K. Pandey Department of Biochemistry, University of Allahabad, Allahabad, India Diana Pinto REQUIMTE/LAQV, Faculty of Sciences, University of Porto, Porto, Portugal Richa Rathor Defence Institute of Physiology and Allied Sciences, Delhi, India Francisca Rodrigues ´ REQUIMTE/LAQV, Instituto Superior de Engenharia do Porto, Instituto Politecnico do Porto, Porto, Portugal Ana Teresa Serra iBET, Instituto de Biologia Experimental e Tecnolo´gica, Oeiras, Portugal; ITQB, Instituto de Tecnologia Quı´mica e Biolo´gica Anto´nio Xavier, Universidade Nova de Lisboa, Oeiras, Portugal Som Nath Singh Defence Institute of Physiology and Allied Sciences, Delhi, India So´nia Soares REQUIMTE/LAQV, Faculty of Sciences, University of Porto, Porto, Portugal

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Sonia Socaci Faculty of Food Science and Technology, University of Agricultural Sciences and Veterinary Medicine Cluj-Napoca, Cluj-Napoca, Romania; Institute of Life Sciences, University of Agricultural Sciences and Veterinary Medicine Cluj-Napoca, Cluj-Napoca, Romania Geetha Suryakumar Defence Institute of Physiology and Allied Sciences, Delhi, India Kata Trifkovic´ Teagasc Food Research Center, Food Bioscience Department, Moorepark, Fermoy, Co., Cork, Ireland; Faculty of Technology and Metallurgy, Department of Chemical Engineering, University of Belgrade, Belgrade, Serbia Dan Cristian Vodnar Faculty of Food Science and Technology, University of Agricultural Sciences and Veterinary Medicine Cluj-Napoca, Cluj-Napoca, Romania; Institute of Life Sciences, University of Agricultural Sciences and Veterinary Medicine Cluj-Napoca, Cluj-Napoca, Romania Jacob A. Walker Department of Chemistry, Illinois State University, Normal, IL, United States

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Preface Chronic diseases are nowadays one of the main causes of death worldwide associated with factors like high consumption of processed foods and low consumption of plants. This fact has generated more health-conscious people that try to follow well-being lifestyle approaches such as the Mediterranean diet and increased exercise. Nevertheless, these approaches are in some cases too complex and even unrealistic for individuals and single patients in modern societies. As a consequence, many consumers have turned their interest in the active role of natural supplements and medicinal herbs (often referred to as nutraceuticals and natural product pharmaceuticals, respectively) to prevent lifestyle diseases. For instance, different studies suggest the use of dietary supplements to attenuate many of the pathophysiological processes involved in the development of these diseases. But what is the difference between nutraceuticals and pharmaceuticals? Pharmaceuticals include drugs for use as medications to be administered to patients for curing, vaccination or alleviation of a symptom. A nutraceutical is defined as any substance that is food or a part of food that provides medical or health benefits, for the prevention and treatment of diseases. Nutraceuticals include a broad range of categories such as dietary supplements, functional foods, and herbal products. The active compounds or phytochemicals in plants, especially fruits, have been associated with numerous health benefits and are used as ingredients in bioactive products. Nutraceuticals and pharmaceuticals are different categories of products, but they still exhibit high similarities and overlapping among their properties and functionalities. The confusion and the lack of a distinguished border between nutraceuticals and pharmaceuticals are mostly the result of the nonexistent comprehensive definition on what are considered as nutraceuticals. Over the last years, researchers have investigated these issues in details (natural sources, health effects, bioaccessibility, functions, etc.) whereas the developments of applications in functional food, nutraceutical and pharmaceutical industries have attracted great interest. However, modern food chemists and biochemists, pharmacologists, and nutritionists often deal with the development of new products that may have health effects for both prevention and treatment of diseases. To this line, a different and more integral kind of information is needed, particularly a new reference bridging the gap between nutraceuticals and natural product pharmaceuticals. Food Waste Recovery Group (www.foodwasterecovery.group of ISEKI Food Association) has organized different teaching and development actions in the field of food science and technology, including the basic theory entitled “The Universal Recovery Strategy,” a reference module, training activities (e-course, training workshops, and webinars), literature references, e-courses, an experts’ database, news channels (social media pages, videos, and blogs) for on time dissemination of knowledge and finally an open innovation network, aiming at bridging the gap between academia and the food industry. In addition, the group has published textbooks dealing with food waste recovery technologies, valorization of particular food processing by-products (derived from olive, grape, cereals, coffee, meat processing, etc.), sustainable food systems, innovations in the food industry and traditional foods, nutraceuticals, and non-thermal processing, as well as targeting functional compounds such as polyphenols, proteins, carotenois, and dietary fiber. Following these efforts, the current book aims to bring together the discovery of nutraceuticals and natural product pharmaceuticals. Indeed, it highlights the similarities of both products in terms of understanding

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how they can benefit human health. The ultimate goal of this book is to support the current industrial applications as well as those that are under development. This book consists of 10 Chapters. Chapter 1, Introduction to Nutraceuticals and Pharmaceuticals, offers an overview on the history and the definition of nutraceuticals and pharmaceuticals, regulatory background, development processes, differences, similarities, and future challenges involved in understanding and defining the borderline between nutraceuticals and pharmaceuticals, which is still, up to this day, indistinct. Although the situation is much clearer with pharmaceuticals, nutraceuticals still remain to be fully defined and legally recognized. In Chapter 2, Nutrigenomics and Antioxidants, the nutrigenomic interactions between primary and secondary antioxidants, as well as the human genome are reported with a view to highlighting the indirect mechanistic bases of the bioactivity of antioxidants. Nutrigenomic concepts have been employed to study the role of individual bioactive compounds in foods on health outcomes via their interactions with biomolecules in the body. Oxidative stress remains one of the most important contributors to the development and progression of chronic diseases, while antioxidants have been shown to ameliorate oxidative stress-induced processes. The direct scavenging effects of antioxidants on free radicals have long been established, and more recently nutrigenomic tools have provided insights into how individual antioxidants exert their effects via nutrigenomic alterations and epigenetic modifications. The use of plants, its secondary metabolites, and the consumption of fruits played a significant role in human health maintenance. Different scientific studies have proposed that plants with therapeutic properties can be attributed due to the presence of bioactive compounds. Chapter 3, Plant Secondary Metabolites With Hepatoprotective Efficacy, incorporates the findings based on research conducted into herbal extracts and bioactive compounds, which may offer new options to the restricted therapeutic possibilities that, occur at present in the management of hepatic abnormalities. Cross-sectional and prospective cohort studies have shown an association between a nutritional supplements diet and a lower prevalence and incidence of chronic diseases. However, the number of clinical studies is very limited and in some cases controversial. Chapter 4, Effects of Nutritional Supplements on Human Health, revises the role of a variety of dietary supplements in treating some of these chronic diseases through evaluation of the evidence-based effects of nutritional supplements on human health, from cohort studies to clinical trials and meta-analysis. On the other hand, the therapeutic activity of several plants has been implied to mitigate the high-altitude stress and related maladies. Chapter 5, Optimizing Performance Under High-Altitude Stressful Conditions Using Herbal Extracts and Nutraceuticals, reviews several known adaptogens that through scientific evidences have been shown to ameliorate stress-induced diseases and also boost physical endurance during stressful conditions. In Chapter 6, Nutraceuticals and Metabolic Syndrome, the use of nutraceuticals for metabolic syndrome therapies is explored. Metabolic syndrome is characterized by having three or more out of six variables (risk factors), ranging from high triglycerides, to elevated waist circumference and high blood pressure. It is also characterized by elevated serum cholesterol (cholesterolemia), and is considered as the consequence of a complex interaction of factors generally leading to increased insulin resistance and high blood glucose. As it can be understood, better knowledge of what nutraceuticals represent and more appropriate formulations leading to improved bioavailability, will likely increase the use of these agents for preventing or treating diseases. Bioavailability includes gastrointestinal digestion, absorption, metabolism, tissue distribution, and bioactivity. From a

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pharmacological point of view, bioavailability is the rate and extent to which the therapeutic moiety is absorbed and becomes available at the drug action site. From the nutritional point of view, bioavailability refers to the fraction of the nutrient that is stored or available in physiological functions. Bioaccessibility is defined as the quantity of a compound that is released from its matrix in the gastrointestinal tract, becoming available for absorption (e.g. enters the blood stream). Finally, bioactivity is the specific effect upon exposure to a substance, including tissue uptake and the consequent physiological response (e.g. antioxidant, anti-inflammatory, etc.). Many biologically active compounds present in foods (e.g. nutrients, vitamins, etc.) are highly lipophilic agents that normally have poor oral bioavailability due to limited bioaccessibility, low absorption, or chemical transformation within the gastrointestinal tract. Therefore, a variety of strategies have been developed to increase absorption of lipophilic compounds using delivery systems, such as microemulsions, nanoemulsions, emulsions, solid lipid nanoparticles, hydrogel beads, and liposomes. Chapter 7, Food Matrices That Improve the Oral Bioavailability of Pharmaceuticals and Nutraceuticals, discusses delivery and excipient systems of nutraceuticals and natural product pharmaceuticals, and provides examples demonstrating their potential efficacy for improving the bioavailability of lipophilic bioactives. Nowadays, consumers are more health-conscious and interested in the active role of natural supplements and medicinal herbs to prevent lifestyle diseases, which are treating the health of the society. Fruits and vegetables contain bioactive compounds that can be extracted and incorporated into dietary supplements. Subsequently, the development of new nutraceutical and pharmaceutical products based on natural active ingredients using agro-industrial wastes is an emerging trend. Chapter 8, Innovative Sources, highlights the innovative sources of natural active ingredients/bioactive compounds from food processing by-products to be used in the nutraceutical and pharmaceutical sectors, as well as factors influencing their biological activity. Traditional and complementary medicine is an important and often underestimated part of health care. The usage of these products for health promotion, self-health care, and disease prevention may actually reduce health-care cost, whereas it could play a significant role for the economic development of numerous countries. On the other hand, usage of poor quality, adulterated, or counterfeit products and exposure to misleading or unreliable information are some risks associated with traditional and complementary medicine products. Therefore, Chapter 9, Ethno-Pharmaceutical Formulations, describes monographs of ethno-pharmaceuticals prepared by knowledge base regulation, and discusses issues related to efficacy, safety, and quality of herbal medicines. Finally, Chapter 10, Reorientation of Nutraceuticals and Pharmaceuticals Applications in an Open Innovation Model, discusses the extent to which the food and pharmaceutical industries show tendencies to converge, and how open innovation may be adopted in order to help their convergence. In addition, it investigates the role of open innovation within this context and shows how industry convergence is fast becoming a dominant logic in the emerging nutraceuticals industry. Industry convergence is defined as “the process of blurring boundaries between two or more disparate industries by combining their scientific knowledge, technology, and markets.” This is a phenomenon that has received significant interest among researchers and practitioners over the past decades. Advances in biotechnology and genomics research have enabled a generic technology platform that has fueled a more “open” approach to innovation and learning. Conclusively, the book addresses food scientists, food chemists and food biochemists, nutritionists, pharmacists, and researchers working with food applications as well as those who are interested in the development of innovative products, nutraceuticals, natural products pharmaceuticals,

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and functional foods. It could also be used by university libraries and institutes all around the world as a textbook and/or ancillary reading in undergraduate and post-graduate level multidiscipline courses dealing with natural products and nutritional chemistry, food chemistry, food science, technology, and pharmacognosy, especially in post graduated programs. I would like to express my gratitude to all the authors for accepting my invitation to participate in this book project. Their collaboration, as well as their acceptance of the editorial guidelines and timeline is highly appreciated. I consider myself fortunate to have had the opportunity to collaborate with many experts from different countries, particularly colleagues from Japan, India, Ireland, Italy, Malaysia, Nigeria, Portugal, Romania, Serbia, Spain, and the United States. I would also like to thank Acquisition Editor Megan Ball, Book Manager Katerina Zaliva, and Elsevier’s production team for their assistance during editing and production. Last but not least, I have a message for all the readers. Those cooperative projects of hundreds of thousands of words may contain errors or gaps. Therefore, instructive comments and even criticism are always welcome. Therefore, please do not hesitate to contact me in order to discuss any issues of nutraceuticals and natural product pharmaceuticals. Charis M. Galanakis1,2 1

Food Waste Recovery Group, ISEKI Food Association, Vienna, Austria Research & Innovation Department, Galanakis Laboratories, Chania, Greece

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INTRODUCTION TO NUTRACEUTICALS AND PHARMACEUTICALS

Kata Trifkovic´ 1,2 and Maja Benkovic´ 3 1

Teagasc Food Research Center, Food Bioscience Department, Moorepark, Fermoy, Co., Cork, Ireland 2Faculty of Technology and Metallurgy, Department of Chemical Engineering, University of Belgrade, Belgrade, Serbia 3Faculty of Food Technology and Biotechnology, Department of Process Engineering, University of Zagreb, Zagreb, Croatia

CHAPTER OUTLINE 1.1 A Brief History of Nutraceuticals and Pharmaceuticals ........................................................................2 1.2 Nutraceuticals ..................................................................................................................................3 1.2.1 The Definition .............................................................................................................. 3 1.2.2 What Is Functional Food? .............................................................................................. 4 1.2.3 Why Nutraceuticals and Functional Foods? ..................................................................... 6 1.2.4 What Can Be Referred to as Nutraceuticals? ................................................................... 7 1.2.5 Nutraceuticals in Disease Prevention.............................................................................. 7 1.3 Pharmaceuticals ............................................................................................................................ 13 1.3.1 The Definition ............................................................................................................ 13 1.3.2 Development.............................................................................................................. 15 1.3.3 Chemical Composition and Classification...................................................................... 19 1.3.4 Naturally-Based Pharmaceuticals................................................................................. 20 1.4 Legislation..................................................................................................................................... 21 1.4.1 Legislation on Pharmaceuticals ................................................................................... 21 1.4.2 Legislation on Nutraceuticals ...................................................................................... 21 1.5 The Differences and the Overlapping ............................................................................................... 23 1.6 The Future Perspectives ................................................................................................................. 24 1.6.1 What Needs to Be Done?............................................................................................. 24 1.6.2 Novel Trends in Nutraceuticals Production.................................................................... 24 References ........................................................................................................................................... 25

In the vast variety of different medicines capable of curing or preventing diseases, the consumers are looking for something more, or better said, less. They are returning more and more to “as it once was,” with a paradigm “natural is better.” Indeed, data shows that the market for natural products and functional foods has an estimated value of 168 billion dollars and enabled the growth of the food industry by 8.6% in the last 10 years to 2012 (Vicentini et al., 2016). The benefits of Nutraceuticals and Natural Product Pharmaceuticals. DOI: https://doi.org/10.1016/B978-0-12-816450-1.00001-5 © 2019 Elsevier Inc. All rights reserved.

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CHAPTER 1 INTRODUCTION TO NUTRACEUTICALS

natural sources of bioactive ingredients are many: they can be found literally everywhere, they are inexpensive, and have beneficial health effects, or at least it is claimed (and not always proven) so. Natural sources include food, dietary supplements, medicinal plants, food-waste bioactives, etc. The idea behind the use of natural products is usually prevention of onset of different diseases. Ghosh and Smarta (2017) state that there has been a visible paradigm shift from cure to prevention, where the consumers turn more and more to healthy lifestyles, dietary supplements, or nutraceuticals in order to avoid or stall the onset of various diseases. The existence of those bioactive naturally occurring compounds opens a whole new market for the pharmaceutical industries which are investing more funds in dietary supplement development, but also new opportunities for the food industry to develop, market, and sell functional food products. However, the existence of a so-called “gray area” between pharmaceuticals and food is more and more pronounced (Santini and Novellino, 2018), usually for bioactives containing products that claim to have health benefits, but those benefits have not yet been scientifically proven or do not have sufficient data on their stability, efficacy, or toxicity. This chapter offers an overview on the history and the definition of nutraceuticals and pharmaceuticals, regulatory background, development processes, differences and similarities, and future challenges involved in understanding and defining the borderline between nutraceuticals and pharmaceuticals, which is still, up to this day, indistinct.

1.1 A BRIEF HISTORY OF NUTRACEUTICALS AND PHARMACEUTICALS When describing a brief history of pharmaceuticals, we actually have to start with nutraceuticals. Namely, the history of medicines dates to around 2000 BCE, and there is historical evidence that humans were prescribing medications as far as the Sumerian times. These “medications” were actually preparations made from medicinal plants. The use of medicinal plants for curing diseases also continues in the Greek times, around 400 BCE, from when Diocles of Carystus is known for treating diseases with herbal medicines. Medicinal plants were considered medicines up to the CE 1800s. After that, it is believed that the age of modern pharmacy begins. Namely, rational drug discovery begins with morphine isolation by the German apothecary assistant Friedrich Sertu¨rner in the mid-1800s. Following that, with the development of organic chemical synthesis, development of synthetic drugs was also possible, leading to a discovery of epinephrine, norepinephrine, amphetamines, barbiturates, etc. A revolution in antiinfective drugs development happened after the discovery of penicillin in 1928 by Alexander Fleming, which opened the door to new antibiotics development. The change in lifestyle led to development of new anticholestemic and antihypertensive drugs, as well as antidepressanst and oral contraceptives. Today’s pharmaceutical industry has a production value of 996.9 billion US dollars and a growth rate of 2.8% (data available for 2014) (International Federation of Pharmaceutical Manufacturers & Associations, 2017). As for nutraceuticals history, the term “nutraceuticals” was first developed in 1989 by Stephen DeFelice. Prior to that, there was research on the functional properties of food and the ability of certain foods to alleviate certain conditions connected to diseases or even prevent diseases, but the term “nutraceuticals” was not in use. From the early 1990s up to today, the

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rising demands of consumers for functional foods and nutritional supplements have grown rapidly, and it is estimated that the nutraceuticals market will be worth 578 billion US dollars by 2025 (Grand View Research, 2017).

1.2 NUTRACEUTICALS 1.2.1 THE DEFINITION As previously mentioned, the neologism “nutraceuticals” has been derived from words “nutrition” and “pharmaceuticals,” by the M.D. Stephen DeFelice, back in 1989 (DeFelice, 1989). DeFelice established the Foundation for Innovation in Medicine, in Cranford, NJ (Brower, 1998), and had proposed the Guidelines For The Nutraceutical Research & Education Act—NREA; he had also advised to initiate the Nutraceutical Commission, a regulatory body to approve nutraceuticals, and accompanying research grant program specifically designed for nutraceuticals clinical research (DeFelice, 2002). According to DeFelice, nutraceuticals comprise of foodstuffs, dietary supplements, and medical foods, with a distinctive health impact in either prevention and/or treatment of diseases (DeFelice, 1989). As highlighted, there is no need for strict discrimination of health and medical claims in relation to nutraceuticals; both are related to maintaining health and disease prevention, or, finally, treatment. In line with the philosophy of the father of medicine, Hippocrates, “let food be thy medicine and medicine be thy food,” nutraceuticals are seen as a way to maintain health and prevent diseases (Fig. 1.1). Nutraceuticals have also been referred to as “medicinally or nutritionally functional foods”; besides, they can appear under the label of medical foods, phytochemicals, designer or functional foods, herbal products, nutritional supplements, pharmaconutrients, dietary integrators, etc. (Aronson, 2017; Bull et al., 2010; Hardy, 2000). This abundance of terminology often leads to confusion, especially since there are no internationally assented definitions and designations of nutraceuticals. In general, all of these terms are used, usually arbitrary, to designate nutrients or nutrient-enriched foods that can be employed in prevention or treatment of diseases (Hardy, 2000). On the contrary, to some food-related terminology that is legally recognized and defined (Table 1.1), nutraceuticals still lack in official definition and appropriate regulation. There are a number of different definitions of nutraceuticals available in literature. For example, nutraceuticals have been defined as “functional foods that aid in the prevention and/or treatment of disease(s) and/or disorder(s) other than anemia” (Kalra, 2003). Anemia has been emphasized in definition since, according to the author, the majority of functional foods exhibit antianemic effect to some extent. This author, opposite to some others, discriminates functional foods from nutraceuticals, emphasizing that functional food for one user, can act as nutraceutical for another (Kalra, 2003). Dillard and German (2000) defined nutraceuticals as “any nontoxic food extract supplement that has scientifically proven health benefits for both disease treatment and prevention.” Zeisel (1999) proposed to define nutraceuticals as “diet supplements that deliver a concentrated form of a presumed bioactive agent from food, presented in a nonfood matrix, and used to enhance health in dosages that exceed those that could be obtained from normal foods.” Espin et al. (2007) defined nutraceuticals as “pharmaceutical forms (pills, powders, capsules, vials, etc.) containing food bioactive compounds as active principles.” On the contrary, Wildman (2001) outlined that

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FIGURE 1.1 Illustration of different approaches to maintaining health.

“nutraceuticals or functional foods are any food or food ingredients that may provide beneficial health effects beyond the traditional nutrients they contain.” As can be seen, the dosage forms of what is considered to be nutraceuticals also varies greatly, indicating once again the necessity for universal and legitimate definitions of nutraceuticals. The additional divergence in terminology/definitions can be noticed regarding the assimilation of functional food and nutraceuticals; some definitions claim that “nutraceuticals are functional food” with specific properties, but others distinguish these two terms.

1.2.2 WHAT IS FUNCTIONAL FOOD? The term “physiologically functional foods” originates from Japan in the 1980s, and was used to describe “any food or ingredient that has a positive impact on an individual’s health, physical performance, or state of mind, in addition to its nutritive value” (Goldberg, 1994). This definition implies three specific conditions that food must comply with in order to be considered as functional food: (1) it has to be a natural ingredient, not occurring in form of pill, capsule, or any other medical/pharmacological form; (2) it has to be a part of a normal daily diet; and (3) once consumed, it has to improve or regulate a specific metabolic process or mechanism, in that way preventing or

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Table 1.1 Legally Recognized Nutrition-Related Definitions and Terminology Term

Definition

Source

Food (or foodstuff)

Any substance or product, whether processed, partially processed or unprocessed, intended to be, or reasonably expected to be ingested by humans. Foodstuffs the purpose of which is to supplement the normal diet and which are concentrated sources of nutrients or other substances with a nutritional or physiological effect, alone or in combination, marketed in dose form, namely forms such as capsules, pastilles, tablets, pills and other similar forms, sachets of powder, ampoules of liquids, drop dispensing bottles, and other similar forms of liquids and powders designed to be taken in measured small unit quantities. • Foods with a new or intentionally modified primary molecular structure; • Foods consisting of, isolated from or produced from microorganisms, fungi or algae; • Food consisting of, isolated from or produced from material of mineral origin; • Foods consisting of, isolated from or produced from plants or their parts and is consisting of, isolated from or produced from a plant or a variety of the same species obtained by traditional or nontraditional propagating practices (more details in New Regulation); • Food consisting of, isolated from or produced from animals or their parts, except for animals obtained by traditional breeding practices (more details in New Regulation); • Food consisting of, isolated from or produced from cell culture or tissue culture derived from animals, plants, microorganisms, fungi or algae; • Foods and food ingredients to which has been applied a production process not currently used, where that process gives rise to significant changes in the composition or structure of the foods or food ingredients which affect their nutritional value, metabolism or level of undesirable substances; • Food consisting of engineered nanomaterials. Any substance or combination of substances presented as having properties for treating or preventing disease in human beings; or any substance or combination of substance which may be used in or administered to human beings either with a view to restoring, correcting or modifying physiological functions by exerting a pharmacological, immunological or metabolic action, or to making a medical diagnosis.

“General Food Law Regulation” Regulation (EC) No. 178/2002 “Food Supplements Directive” Directive 2002/46/EC

Food supplements

Novel foods

Medicinal products

“Novel Food Regulation” Regulation (EC) No. 258/97 “New Regulation” Regulation (EU) 2015/2283

“Medicinal Product Directive” Directive 2004/27/EC amending Directive 2001/83/EC

controlling a disease (Hardy, 2000). This broad definition encompasses a wide range of products, from the fortified foods from one side (like iodized salts for example) to the specific medical foods from the other side. In theory, these two extremes should fall under different regulations, where the

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medical foods (defined as in Table 1.1), should be marketed under firmer conditions and medical supervision. This, however, is not the case, since medical foods are available widely in pharmacies and health food stores (sometimes even supermarkets) (Mueller, 1999). Zeisel (1999) defined functional foods to be ostensibly similar to conventional foods, but they “deliver one or more active ingredients (that have physiological effects and perhaps enhance health) within the matrix of a food (e.g., a bread or breakfast cereal with added high-dose folic acid).” In addition, to be regarded as functional food, it has to be consumed as part of a regular diet. Espin et al. (2007) used a definition given by International Life Science Institute to describe functional foods: “foods that when consumed regularly exert a specific health-beneficial effect that goes beyond their nutritional properties and this effect has to be scientifically confirmed.” An alternative definition of functional food, claiming that “when food is being cooked or prepared using scientific intelligence with or without knowledge of how or why it is being used, the food is called functional food” (Kalra, 2003). Going over the number of available definitions of functional foods and taking into account different meanings these might have in different countries, in 2017 the Functional Food Center proposed a new definition of functional foods (Martirosyan and Miller, 2018): “Natural or processed foods that contain biologically active compounds which, in defined effect, and nontoxic amounts provide clinically proven and documented health benefits utilizing specific biomarker for the prevention, management, or treatment of chronic disease or its symptoms.” Having all aforementioned in mind, it is difficult to precisely distinguish the differences between nutraceuticals and functional foods. As they are overlapping on several levels (both are considered to improve heath, to bring additional value to a normal diet, to be mainly derived from nature, to name a few), and in absence of uniform definition, either legitimate or scientific one, it is not unusual that literature and consumers refer to those as either functional food or nutraceutical, but implying both.

1.2.3 WHY NUTRACEUTICALS AND FUNCTIONAL FOODS? Although the food industry is traditionally perceived as the industry branch with the lowest research activities (Bigliardi and Galati, 2013; Christensen et al., 1996; Garcia Martinez and Briz, 2000), in recent years consumer driven requirements for healthier foods that exceed basic nutritional needs are governing developments of novel foods, for example, nutraceuticals and functional foods. As the expectancy of life in modern days increases, and with the increasing costs related to healthcare, people tend to pay more attention to disease prevention and health protection, so they can enjoy improved quality of life in their advanced years (Kotilainen et al., 2006; Robertfroid, 2000). Therefore, research on functional foods and nutraceuticals are proving to be the most interesting areas of innovation in food industry (Annunziata and Vecchio, 2011; Siro et al., 2008). From the other side, in the competitive food market, companies that aim to distinguish themselves and gain vanguard status, are introducing the new nutritionally enriched products and/or products targeting certain groups of consumers in order to satisfy growing consumers’ demands (Bigliardi and Galati, 2013; Menrad, 2004).

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1.2.4 WHAT CAN BE REFERRED TO AS NUTRACEUTICALS? In line with absent regulation, it is difficult to classify what falls under a wide umbrella of nutraceuticals. Hence, it is possible to find different classifications of nutraceuticals, based on their natural sources, pharmacological activity, chemical nature, etc. (Chauhan et al., 2013). The majority of these classifications are suggested by scientists, and there is a great need for national and international regulatory bodies to step up and provide some classification(s) that can be widely recognized and accepted. In addition, diversity of what is considered a nutraceutical hinders the uniform classification. Based on the natural source they are coming from, nutraceuticals can be categorized as the products derived from mineral, plant, animal, or microbial sources (Chauhan et al., 2013). Some authors propose to categorize nutraceuticals based on the food source, into the following groups: dietary fibers, probiotics, prebiotics, polyunsaturated fatty acids, antioxidant vitamins, polyphenols, and spices (Chauhan et al., 2013; Kalia, 2005; Verma and Mishra, 2016). Regarding the food source, nutraceuticals can also be categorized as emerging from traditional or nontraditional foods. Traditional nutraceuticals would entail natural, whole foods, with a new insight on potential health benefits; basically, there is no change in the food itself, but in the consumers’ perception (e.g., lycopene from tomatoes, omega-3 fatty acids from salmon). On the other hand, nontraditional nutraceuticals appear on the market as a result of agricultural/food engineering and product development (e.g., β-carotene enriched rice, calcium-fortified orange juices, or cereals with added vitamins) (Tank Dharti et al., 2010). Another proposed classification of nutraceuticals is based on their proven efficiency status: (1) potential nutraceuticals and (2) established nutraceuticals, where a potential nutraceutical can gain the status of established only after its efficiency is proven trough the clinical study (Pandey et al., 2010). A wide range of nutraceutical/functional food products with claimed health benefits is already available on the market. Some of the examples are given in Table 1.2. In addition, a comprehensive database of phytochemicals that can serve not only to food professionals but also general public concerned in personal well-being, is one provided by United States Department of Agriculture Agricultural Research Service, called: “Dr. Duke’s Phytochemical and Ethnobotanical Databases.” It is possible to use this database to search for specific plant, specific chemical, specific activity, specific chemical with specific activity, or for ethnobotany searches (Dillard and German, 2000).

1.2.5 NUTRACEUTICALS IN DISEASE PREVENTION The global health problems of a modern society in developed countries are associated to unhealthy diet, irregular sleeping habits, and lack of daily physical exercises, all of those leading to development of “metabolic syndrome”—an increased risk of diabetes mellitus, cardiovascular morbidity, and mortality (Holub, 2006). There have been arguments that inclusion of nutraceuticals and functional food ingredients in a daily diet can fight those, and consequently decrease the costs related to healthcare (Santini et al., 2017). In addition to nutraceuticals, it is possible to find various health enhancing and promoting products on the market, such as dietary supplements and similar products (pro- and prebiotics, herbal products, etc.). Although the administering form of these products can

Table 1.2 Examples of Market-Available Nutraceuticals and Functional Foods (www.nutraceuticalsworld.com) Product

Dosage Form

Functional Ingredients/Benefits

Company

Fairlife smart snacks

Nutritious beverages

Fairlife, LLC

Sunflower Date Bar

Protein bar

BasicBites

Soft chews

Atkins Protein Wafer Crisps ProBites LLP Forever Beautiful

Snack bar

Cold ultra-filtered milk, lactose-free, gluten-free, with 50% more protein and 50% less sugar than regular milk, rich in calcium and prebiotics Rich in protein, omega-3 fatty acids, and fiber; tested for a wide variety of allergens including peanuts, soy, milk, and gluten Sugar-free, with prebiotics, clinically shown to help maintain enamel health High in protein and fiber, low in sugar

Chews Powder

Rowdy Bar

Energy bar

EPIC Performance

Protein bar

Protein & Probiotics Hot Oatmeal Eat Your Coffee Bar YQ by Yoplait

Ready-to-eat oatmeal

V8 1 Hydrate

Plant-based isotonic beverage Dairy-based nutritional bar

G¯oL Bars

Snack bar Yogurt

Collagen Wrap Beyond Sausage

Sandwich wrap “Meat form plant” sausage

Replenishing plantbased protein Plant Protein Milk

Beverage targeting female consumers Plant milk

BOOST Simply Complete BluePrint Kombucha Drinks

Nutritional drink Kombucha drink

CLIF Kid Zbar Fruit 1 Veggie

Snack for kids

Long-life probiotic Superfood mix, supports healthy skin and hair, contains organic chia, acai, maqui, acerola cherries, maca and blueberry powders Superfood yacon root, improves gut-health Cage-free egg whites, nuts, and dried fruit, rich in proteins, no added sugars Oats, red quinoa, chia seeds and probiotic cultures (1 billion CFUs, rich in fiber and proteins Dates, oats, nut butter, coffee, rich in fiber, energy booster Ultra-filtered milk, low in sugar (40% less than the leading Greek low fat yogurt), high in protein Naturally occurring electrolytes and glucose of the sweet potato, quickly replenishes fluids and nutrients Organic whole milk protein, provides more sustained delivery of amino acids for muscle repair Cauliflower, collagen, egg, chia flour Mixture of pea, fava bean and rice protein (with a unique texture of pork sausage), beet, wrapped in a 100% plant-based casing derived from algae Plant protein from pea, chia, cacao, and hemp, in coconut water and with virgin coconut oil Pea-protein (richer in protein than, e.g., almond milk), calcium (50% more than dairy milk) Filtered water, milk protein concentrate, cane sugar, blend of 25 vitamins and minerals Organic cold-pressed vegetable and fruit juices with the power of fermented tea, improving digestion and immunity 10
11 g of whole grains, calcium and fiber, in addition to variety of fruit purees and vegetable powders

ZEGO Snacks

Ortek Therapeutics Atkins Anlit, Ltd. Your Super

Rowdy Prebiotic Foods EPIC Provisions thinkThin

Eat Your Coffee Yoplait Campbell Soup Company Garden of Life

Cali’flour Foods Beyond Meat

Apre`s

Bolthouse Farms Nestl´e Health Science BluePrint, Hain Celestial Group’s Clif Bar & Company

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be quite similar (pills, capsules, tablets, liquid forms), the main difference is that nutraceutical’s clinical efficiency must be scientifically proven, while it is not obligatory for other mentioned products (Santini et al., 2017). Still, scientists are in discussion on the actual efficiency of nutraceuticals. When the clinical and epidemiological studies are employed to prove the effectiveness of nutraceuticals, it is usually disclosed that certain benefits can be related to the specific nutraceutical, but over a prolonged period (decade or more) of specific diet. The hypothesis behind this is that the desirable health-beneficial effect in the short-term approach is demonstrated at the modest level, that over a prolonged period leads to still modest, but highly desirable benefit to the human health (Espin et al., 2007). Numerous health benefits are related to functional foods and nutraceuticals, in particular specific compound(s) they contain. Some of them are listed in the following subsections.

1.2.5.1 Nutraceuticals and hypertension As hypertension is one of the most widely present cardiovascular diseases, numerous studies have been dedicated to exploring the potential of nutraceuticals in fighting it. It was shown that antioxidant-based nutraceuticals have the ability to lower blood pressure, at the same time being highly tolerable and safe to use (Santini et al., 2017). A review by Borghi and Cicero (2017) summarized the literature on the clinically detectable effect of nutraceuticals on lowering the blood pressure, highlighting the role of compounds such as potassium, magnesium, L-arginine, vitamin C, beet juice, cocoa flavonoids, melatonin (released in controlled manner), and garlic extract. Example: Garlic is rich in nutraceuticals based on S-allylcysteine and organosulfides (both containing bioactive sulfur) that exhibit promising results in hypertension treatment (Frankel et al., 2016; Mota, 2016). Another study showed that the effect of aged garlic extract on lowering blood pressure was similar to the effect of standard medications (Ried and Fakler, 2014). In addition, other constituents of garlic extract, such as organo-selenium compounds, steroid saponins and sapogenins (e.g., β-chlorogenin), vitamin B6 and B12, flavonoids, lectins and N-fructosyl-amino acids, may contribute to the cardioprotective effect (Charu et al., 2014).

1.2.5.2 Nutraceuticals and hypercholesterolemia One of the main diseases connected with metabolic syndrome is dyslipidemia, usually developed as a consequence of unhealthy lifestyle and diet. The traditional treatment involves statins, which are not always well tolerated by patients. In that respect, scientists are working on nutraceutical preventive approach to treat metabolic syndrome and related modern-life diseases (Afilalo et al., 2008). There are already nutraceuticals on the market that target metabolic syndrome diseases, among them hypercholesterolemia, such as omega-3 fatty acids, psyllium, soluble fibers, red yeast rice, berberine, apple phytocomplex, to name a few of the most studied (Santini et al., 2017). Example: Recently, a new source of n-3 fatty acids—krill oil has been proposed for treatment of hypercholesterolemia. Krill oil is extracted from small crustaceans of the Euphausiacea order. It has shown a beneficial effect on several metabolic syndromes related conditions by affecting the process of inflammation, glucose tolerance, and lowering lipids and triglycerides. Although the content of fatty acids in krill oil is similar to those of fish oil, two n-3 polyunsaturated fatty acids, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), are found to be phospholipidsbound in krill oil, as opposed to triglycerides-bound EPA and DHA in fish oil. This has an effect on the bioavailability of EPA and DHA, where the studies showed that phospholipids-bound fatty

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acids are absorbed at higher extent (Ko¨hler et al., 2015). In addition, when the effects of administering esterified n-3 fatty acids and krill oil were compared in a randomized clinical trial, results showed a similar effect on total cholesterol, HDL- and LDL-cholesterol, and triglycerides level (Cicero et al., 2016). Moreover, FDA has accepted the krill oil as generally recognized as safe, and the European Union has granted it novel food status (Santini et al., 2017).

1.2.5.3 Nutraceuticals and type 2 diabetes Type 2 diabetes (relative or absolute lack of insulin), and associated complications, still remain one of the main medical challenges. The adverse effects associated to available drugs are governing the research to discover new ways of disease prevention and treatment (Ros et al., 2015). In line with that, various phytochemicals have been tested for efficiency in diabetes treatment. The mechanism of action of these compounds is usually based on inhibition of glucose and amylose, affecting the glucose transporters and uptake, as well as inhibition of specific enzymes and hormones activities (Santini et al., 2017). The nutraceuticals such as amorfrutins, Morus alba (white mulberry), fatty acids, and phlorizin are exploited for their antidiabetic activity. Example: Holistic medicine has been utilizing M. alba L. leaves as a remedy for diabetes for centuries. Following that, Kar et al. (2015) have highlighted that the potential of M. alba L. extract can be related to inhibition of Cytochrome P450 group of enzymes; in addition, they have underlined no significant interaction of M. alba L. extract compounds with other drugs, emphasizing the safety of the extract. In a parallel study, the hypoglycaemic effects of M. alba L. leaves aqueous extract on diabetic rats was compared with the effect of Glibenclamide, a widely used hypoglycaemic drug (Madalageri et al., 2016); it was shown that utilization of 600 mg/kg of M. alba L. extract reduced the blood sugar level and the effect detected was comparable to the effect of Glibenclamide drug, proving that nutraceuticals with M. alba L. extract can be successfully used to control sugar level in blood.

1.2.5.4 Nutraceuticals and inflammation and oxidative stress The inflammation process in human organism, usually triggered by physical or chemical injury, provokes the reaction of the immune system (Weiss, 2008). In traditional pharmaceutical approach, treatment would entail the use of antiinflammatory agents, usually nonsteroidal antiinflammatory drugs, and antirheumatic agents; however, these drugs carry a risk of unwanted side effects (e.g., dose-dependency, or difficulties of utilization for primary prevention). In addition to that, the modern lifestyle and indulging in nonhealthy dietary habits lead to the increased consumption of foods high in sugar, salt, fat, especially saturated and transfats, as well as red meat (Galland, 2010). To prevent this, plant-based food and ingredients can be used. In the last few decades, the “big bang” on the healthy food market was set off by phytochemicals, in particular the research on their role as antioxidant, analgesic, antiinflammatory, antibacterial, antiparasitic, and antiviral, as well as antimutagenic agent (Dillard and German, 2000). Polyphenolic compounds constitute the largest group of plant secondary metabolites, and they encompass the variety of different classes, such as terpenoids, phenolic metabolites, and alkaloids and other nitrogen-containing plant constituents (Harborne, 1999). Example: The famous “French paradox,” where the low incidence of cardiovascular disease among French people despite the high consumption of saturated fats, has been correlated to the high consumption of red wine, rich in polyphenols, governed the research on health impact of grape

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polyphenols. It was shown that they can decrease chronic inflammation in two probable ways, either by reducing reactive oxygen species levels (e.g., acting as antioxidants) or modulating the pathways of inflammation (Santini et al., 2017). Sung et al. (2012) highlighted that grape flavonoids and proanthocyanidins impact the chronic inflammation by targeting multiple inflammation pathways, on contrary to the synthetic mono-targeted antiinflammatory drugs. The limiting factor in polyphenols utilization can be their low bioavailability and absorption; however, some studies showed that despite poor absorption (especially when administered orally), grape polyphenols can decrease the oxidative damage of DNA (Scalbert et al., 2002).

1.2.5.5 Nutraceuticals and allergy Western societies in a modern time are suffering from increased incidence for allergy development, especially in children. The reason for it, as usually highlighted, can be found in so-called “hygiene hypothesis,” the paradigm claiming that the surplus of “cleanliness” of our environments consequently leads to the decreased exposure to infectious stimuli necessary for the development of human immune system. Basically, as the immune system becomes hypersensitive to the typically harmless substances, the white blood cells, in particular mast cells and basophils, are produced at higher extent, provoking the inflammatory response of different intensity (Grammatikos, 2008). The traditional pharmaceutical approach to allergy treatment usually entails the antihistamine and corticosteroids drugs, which might have some side effects if used for prolonged periods of time. The nutraceutical approach might be helpful to overcome those problems. Namely, the allergy treatment has advanced to the active stimulation of the immune system so to encourage its advancement and development of higher tolerance. Example: Quercetin is a polyphenolic compound, belonging to group of flavonoids, which exhibits natural antihistaminic effect. Rich sources of quercetin are red wine, apples, grapefruit, onions, and black tea. Studies showed that quercetin can reduce the inflammation caused by hay fever, gout, bursitis, arthritis, and asthma (Rajasekaran et al., 2008). Principally, quercetin acts by blocking allergy-related substances and inhibiting secretion of mast cells, consequently decreasing the levels of certain proteins (such are tryptase, histidine decarboxylase, etc.) (Shaik et al., 2006). An animal study conducted on mice showed that quercetin (along with another flavonoid—isoquercitrin) can suppress eosinophilic inflammation process, in that way effectively attenuating the murine model of asthma (Rogerio et al., 2007). These findings suggest that quercetin can be used in the treatment of allergies, either as a primary therapy or in combination with conventional treatment methods.

1.2.5.6 Nutraceuticals and eye disorders Age-related macular degradation (AMD) is a retina disease that affects the sight of millions of aging individuals in modern days and eventually can lead to vision loss (Ambati and Fowler, 2012; Nagineni et al., 2014); it accounts for as high as 50% of all registered patients with blindness (Slakter and Stur, 2005). Since the etiology of AMD is still not fully disclosed (although some findings indicate that the cause can be found in aging, cardiovascular disease, heredity, smoking, exposure to UV light, malnutrion, etc.) (van Leeuwen et al., 2003), there is a lack of treatments for curing or preventing the development of disease (Yi et al., 2005). Hence, novel treatment and prevention approaches are very much needed.

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Nutraceuticals can have an important role in facing AMD. For example, it is known that carotenoids (such as β-carotene, lutein, and zeaxanthin) have a protective effect for eye health; they can act as shields against development of diseases related to exposure to UV light, cataract, or AMD (Tank Dharti et al., 2010). Lutein and zeaxanthin can be found in plants (brussel sprouts, cabbage, kale, broccoli, lettuce, green beans and peas, spinach) in the form of mono- and di-esters of fatty acids. Recently, it has been shown that marigold flower is a rich source of these carotenoids, up to 86% of weight can be attributed to zeaxanthin and lutein (Brookmeyer et al., 2007). Another carotenoid, astaxanthin (usually found in marine food, such as sea bream, trout, salmon, shrimp), is also a promising nutraceutical in maintaining eye health, in addition to other health-beneficial effects ascribed to astaxanthin (such as its role in protection against oxidative stress and support of the immune system) (Nasri et al., 2014). Example: Resveratrol is polyphenolic compound belonging to the group of stilbenes. It can be found in various plants and fruits, but grape skin is one of the richest sources. Resveratrol is ascribed with antiaging, antidiabetic, anticancer, and cardioprotective effects, in addition to modulation of cell proliferation, inflammation, and apoptosis (Brakenhielm et al., 2001; Harikumar and Aggarwal, 2008; Jian et al., 2012; Pervaiz and Holme, 2009). A recent study has focused on resveratrol role in alleviation of AMD (Nagineni et al., 2014). They have demonstrated that resveratrol can successfully suppress the inflammatory processes that lead to chloroidal neovascularization, the main characteristics of one of the AMD types (wet AMD). Hence, authors propose the consumption of resveratrol rich functional foods and nutritional supplements either on its own or as an addition to standard therapies for chloroidal neovascularization in AMD.

1.2.5.7 Nutraceuticals and obesity One of the global health problems nowadays is increased obesity, in both adults and children. There are estimations that more than 315 million of people are affected (Nasri et al., 2014), which puts great pressure on the health system. More importantly, the patients suffering from obesity are experiencing increased risks of hypertension, angina pectoris, heart failure, hyperlipidemia, thrombosis, osteoarthritis, cancer, respiratory disorders, and reduced fertility (Caterson and Gill, 2002). World Health Organization (WHO) had anticipated that the obesity-related diseases will account for more than two-thirds of global diseases by 2020 (Baboota et al., 2013). The approach to tackle obesity problems where the healthier diet with caloric restrictions is combined with physical exercising has shown only moderate results (Nasri et al., 2014). At the same time, available antiobesity drugs have shown some serious side effects, such as pulmonary hypertension, greater risks of heart attack and stroke, suicidality, and depression (Carter et al., 2012; Higgins et al., 2013; Kang and Park, 2012; Mark, 2009). In that respect, patients suffering from obesity are looking into alternative approaches that can include both pharmaceuticals and nutraceuticals with a potential to help in managing body weight. Nutraceuticals such as capsaicin and Psyllium fiber can be of help in weight loss (Rubin and Levin, 1994). Herbal-derived nutraceuticals, for instance caffeine, ephedrine, and ma huangguarana have a promising effect assisting in weight loss (Boozer et al., 2001). Similarly, green tea has been known for its ability to promote weight loss, possibly due to the increased energy expenditure. The polyphenolic compounds found in green tea, mainly epigallocatechin gallate, epigallocatechin, and epicatechin gallate, are responsible for the positive effects ascribed to green tea (Hursel et al., 2009; Lu et al., 2012).

1.3 PHARMACEUTICALS

13

Example: Since obesity is an inflammatory disease, help in treatment can be sought among antioxidant and antiinflammatory nutraceuticals. Among numerous nutraceuticals that exhibit those characteristics, curcumin has been the extensively researched one. Curcumin, also known as turmeric, has been used for centuries in India (some Ayurveda literature records mentioning curcumin date as far as 3000 BCE) for treatment of various health conditions, one of them being obesity. Scientists have identified more than a hundred different compounds in curcumin (Nakayama et al., 1993; Ohshiro et al., 1990; Ravindranath and Satyanarayana, 1980). The role of curcumin in obesity treatment is that it interacts with adipocytes, pancreatic and hepatic stellate cells, macrophages, as well as muscle cells; in these interactions curcumin suppresses proinflammatory metabolic reactions, as well as stimulates cell proliferation, leading to reversion of insulin resistance, hyperlipidemia, hyperglycemia, and similar health conditions related to obesity (Aggarwal, 2010).

1.3 PHARMACEUTICALS 1.3.1 THE DEFINITION In recent decades, with a continuously increasing occurrence of diseases such as diabetes, heart diseases, respiratory diseases, depression, or even vitamin and mineral deficiency, the focus of the health and the pharmaceutical industries is shifting from disease treatment toward disease prevention. Prevention includes consummation of different synthetic or natural compounds (e.g., vitamins, minerals, fibers, bioactive compounds such as polyphenols) for which there are sound scientific evidence and health claims that they improve or benefit the health of the consumers (Santini and Novellino, 2018). The pharmaceutical industry is mostly oriented toward synthetic products, which include drugs used to cure diseases, but also dietary supplements (e.g., vitamins and minerals). On the other hand, the food industry is oriented toward naturally occurring bioactive compounds. According to Ghosh and Smarta (2017), there are areas in which the border between “food” and “pharma” is not well defined, as the former often contains several bioactive compounds, including secondary plant molecules, fibers, fatty acids, probiotics, etc. This section will deal with the definition of pharmaceuticals, regulations, and conditions which need to be met to be considered as a pharmaceutical. There are several definitions of pharmaceutics in the literature. Roy (2011) defines pharmaceuticals as synthetic chemicals used as drugs. Periˇsa and Babi´c (2016) define pharmaceuticals as compounds that are used for treatment or prevention of disease in humans or animals and can also be used as growth promoters in veterinary medicine. According to Zrnˇcevi´c (2016), besides drugs that treat diseases, pharmaceuticals also include dietary supplements used in human and veterinary medicine. Goyal and Goyal (2018) state that pharmaceuticals are normally considered as chemicals that affect physiological functions, designed specifically for a medical use under a physician’s supervision and subject to Food and Drugs Administration (in the United States), the European Medicines Agency (in Europe), or other regulatory agencies (the rest of the world) approval. Different countries have different definitions of pharmaceutics (drugs, pharmaceutical, or medical drugs), but most of them refer to the basic use of such compounds to treat illness. Some of the definitions by countries are listed below.

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CHAPTER 1 INTRODUCTION TO NUTRACEUTICALS

The Australian Department of Health uses the term “therapeutic goods” which are defined as products for use in humans in connection with preventing, diagnosing, curing, or alleviating disease, ailment, defect, or injury; influencing, inhibiting, or modifying a physiological process or testing the susceptibility of persons to a disease or ailment. It is important to emphasize that the Australian regulations include ingredients or components of a therapeutic and devices which are used to modify or a replace a body part in this definition (Australian Government, 2018). The American Food and Drug Administration defines a drug as: 1. a substance recognized by an official pharmacopoeia or formulary; 2. a substance intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease; 3. a substance (other than food) intended to affect the structure or any function of the body; 4. a substance intended for use as a component of a medicine but not a device or a component, part or accessory of a device and; 5. biological products are included within this definition and are generally covered by the same laws and regulations, but differences exist regarding their manufacturing processes (chemical process versus biological process). A definition of a drug product is also given by the FDA: the finished dosage form that contains a drug substance, generally, but not necessarily in association with other active or inactive ingredients (FDA, 2018a). The European Union uses directives and regulations to define pharmaceuticals in all member countries. In the EU Directive 2001/83/EC definitions of a “medicinal product” and “active substance” are given. Medicinal product is defined as any substance or combination of substances presented as having properties for treating or preventing disease in human beings; or any substance or combination of substances that may be used in or administered to human beings either with a view to restoring, correcting, or modifying physiological functions by exerting a pharmacological, immunological, or metabolic action, or making a medical diagnosis. Active substance is defined as any substance or mixture of substances intended to be used in the manufacture of a medicinal product and that, when used in its production, becomes an active ingredient of that product intended to exert a pharmacological, immunological, or metabolic action with a view to restoring, correcting, or modifying physiological functions, or making a medical diagnosis. Japan uses the following definition: the term drugs refers to the following substances: 1. substances listed in the Japanese pharmacopeia; 2. substances (other than quasi-drugs and regenerative medicine products), that are intended for use in the diagnosis, treatment, or prevention of disease in humans or animals; and which are not equipment or instruments, including dental materials, medical supplies, sanitary materials, and programs; 3. substances (other than quasi-drugs, cosmetics or regenerative medicine products) that are intended to affect the structure or functions of the body of humans or animals, and which are not equipment or instruments (Japan Pharmaceutical Manufacturers Association, 2015). As mentioned previously, the definitions listed in this section refer only to a few selected countries. Although present, definitions in other countries, especially when looking at continents, are numerous. The aim of the regulatory frameworks, institution and officials today is shifted towards

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15

a harmonization of definitions. For example, the European Union is an example where the harmonization has already been implemented, but on many Asian, African, and South American countries the harmonization is still underway.

1.3.2 DEVELOPMENT In order for a compound to be considered a pharmaceutical, or an active substance, it must undergo numerous stages of development, testing, and clinical trials. Pharmaceutical development is envisioned to design a quality product and a manufacturing process that can consistently deliver the product with its intended performance (Singh et al., 2018). Development stages of pharmaceuticals (drugs) are shown in Fig. 1.2. The basic research process starts with collecting a comprehensive knowledge on the disease that needs to be cured up to the molecular level. After knowing all the mechanisms and metabolic pathways involved, the drug discovery process begins. Siddiqui et al. (2017) state that the process of drug development starts with the innovation of a drug molecule (active pharmaceutical ingredient) that has shown therapeutic value to battle, control, check or cure diseases. When the compound is discovered, it undergoes preclinical trials where it is passed through stages which include safety tests and a series of experiments to prove that it is absorbed in the bloodstream, distributed to proper site of action in the body, metabolized sufficiently, successfully excreted from the body and

FIGURE 1.2 Development stages of pharmaceuticals.

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CHAPTER 1 INTRODUCTION TO NUTRACEUTICALS

Table 1.3 Phases of Clinical Trials Phase of Clinical Trial

Number and Type of Subjects

Phase I

50
200 healthy subjects

Phase II

100
400 patients with the target disease 1000
5000 patients with the target disease

Phase III

Investigation Safety, efficacy, pharmacokinetics and pharmacodynamics in healthy individuals Safety and efficacy in a small group of patients Safety and efficacy in a large group of patients

its nontoxicity is demonstrated. These tests are done either using living cells or test animals, or insilico, using mathematical modeling tools. The next stage in the pharmaceutical development process is clinical trials. A candidate drug must go through extensive studies in humans to demonstrate that it is safe and effective. Clinical trials include three phases, each with a specific goal, and are usually expensive, time-consuming, and include a large number of medical personnel and testing subjects (PhRMA, 2015). Phases of clinical trials are shown in Table 1.3. As demonstrated in Table 1.3, the clinical trial phases differ by the number and the type of individuals. Firstly, a small group of healthy individuals are chosen as the test subjects and the first stage is to answer questions like: “Is the drug efficient and safe?; “How is the drug absorbed, metabolized, and removed from the body?”; and “Does the drug cause side effects?” In phase II the drug is introduced to a group of patients with a targeted disease to assess its safety and efficacy. Optimal dose is also determined in this phase. Phase III includes a larger group of patients, so statistically significant data about efficacy and safety required for the drug approval can be gathered. The drug approval is usually done by application forms which can reach up to 100,000 pages of data collected throughout the trials and this data is then reviewed by scientists, physicians, and statisticians, and the decision on whether to grant approval is made. After the approval is granted, postapproval research and monitoring begins; the drug is then monitored on thousands or even millions of patients with the targeted disease to assess the pharmacovigliance and to compare the newly developed medicine with similar medicines for the targeted disease. It is important to emphasize that all the above stages are mandatory for pharmaceutical development. Furthermore, the strict control of pharmaceuticals continues even after their approval and during their application. If a certain compound (synthetic or natural) is identified to have healing or beneficial properties, in order to be called a pharmaceutical, it must undergo all the testing and the approval stages. If not, it can only be advertised as a nutritional supplement, if the regulations therefore are also met. While the pharmaceuticals must follow specific legislation on efficacy, safety, production, and use in therapy to be authorized and marketed, these rules are not in general followed for food supplements and nutraceuticals (Santini and Novellino, 2018). Due to high costs and a timely process, a novel model of pharmaceutical development has been proposed, in a great way inspired by the discovery and extensive use of natural bioactive compounds. The reverse pharmacology path is a transdisciplinary endeavor designed to reduce three

1.3 PHARMACEUTICALS

17

FIGURE 1.3 Phases of reverse pharmacology path for pharmaceutical development.

major bottlenecks of pharmaceutical development: time, cost, and toxicity (Patwardhan et al., 2008). The main stages of reverse pharmacology are shown in Fig. 1.3. Generally speaking, the scope of reverse pharmacology is to understand the mechanisms of action at multiple levels of biology and to optimize safety, efficacy, and acceptability of the leads in natural products based on relevant science. In this approach the candidate travels a reverse path from “clinics to laboratory” rather than classical “laboratory to clinics.” This approach can shorten the “drug to market” time from the traditional 10 to 15 years to a much shorter 4
5 years (Patwardhan et al., 2008). According to Goyal and Goyal (2018), a more rational and economic search for new lead structures from nature must be a priority in drug development and it is therefore desirable that the knowledge of phytoconstituents, leads and hits identified with the reverse pharmacology approach can be extended for the development of new drug entities on the fast track through translational phytopharmacology. Some of the examples of drugs discovered from botanical sources using the reverse pharmacology approach include the alkaloids from Rauwolfia serpentine used for depression and Parkinson disease treatment, alkaloids from Tinospora cordifolia with immunomodalotory effects, and saponins from Asparagus racemosus which prevent steress induced increase in plasma cortisol levels. There is also an example of ongoing drug development from botanic sources (standardized extracts of Zingiber officinale, Boswellia serata, Phyllanthus embilica, and T. cordifolia) with exploratory studies on a small number of patients (Patwardhan et al., 2008).

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CHAPTER 1 INTRODUCTION TO NUTRACEUTICALS

Besides reverse pharmacology, other paths of pharmaceuticals development are emerging: holistic targeting, network pharmacology, genomic driven discovery, proteomics, chemical and bioinformatics, systems biology, etc. (Patwardhan and Chaguturu, 2017). Holistic drug targeting method is aimed toward a complex, holistic approach of finding novel drugs for complex diseases such as cancers, neurological disorders, metabolic syndromes, and infectious diseases. In today’s medicine, a combination of single-target drugs is prescribed to treat such complex diseases, which often involves taking a handful of pills for the patient. In the holistic approach, the drug discovery paradigm is shifted from single-target single-drug toward a multitarget drug discovery approach. Targeting several disease-contributing factors is a more holistic approach to drug management wherein the drug development strategies are guided by integrating all available information from diverse perspectives, such as disease etiology and systems biology (Roy and Chaguturu, 2017). The utilization of such holistic approaches is aimed toward helping in further tailoring personalized care in disease treatment, as well as disease management and prevention. Although beneficial for the patient, the holistic approach is time consuming and costly, since many factors and disciplines are involved in a multitarget drug discovery: systems biology, genetics, proteomics, chemical genetics, modeling and in-silico screening, biochemical screening, CRISPR, and many more. Network pharmacology has emerged over the past few decades with the rapid development of computational tools as a new approach in drug development. It uses computational power to understand drug actions and interactions with multiple targets (Hopkins, 2007; Chandran et al., 2017). According to Zhang et al. (2013) and Chandran et al. (2017), network pharmacology was first used as an important tool in understanding complex relationships between naturally based, botanical drugs, and the whole body. In the case of network pharmacology, traditional knowledge on certain botanical drug sources can play a vital role in defining the effects of drugs on the whole body, since it has a potential in discovering new therapeutic options, as well as improving existing ones. Furthermore, with the increasing awareness of the consumers on the benefits of the botanical drug sources, a new area of network pharmacology is rapidly developing: network ethnopharmacology. According to Fang et al. (2013), a comprehensive herbal medicine information system has been developed which integrates information of more than 200 anticancer herbal recipes with over 900 individual ingredients and 8500 small organic molecules isolated from herbal medicines. This database is extensively used in scientific research and new drug discovery. The genomics driven drug discovery process was described by Chaguturu (2017) using the ovarian cancer example. The author mentioned extensive data on integrated genomic analyses of the ovarian carcinoma which represents a starting point to apply systematic, genome-wide, systems biology approaches to identify novel therapeutic targets for ovarian cancer. Based on genomics data, a list of disease-relevant drug targets is selected, among which an ideal one is chosen for further development and screening using forward and reverse chemical genomic studies. Proteomics is a research area that deals with identification, quantification, function, activities, and modifications of proteins. In pharmaceutical development, it can be used in the following cases: identification of potential therapeutic targets, lead optimization, evaluation of drug toxicity and, more recently, in defining the mechanisms of action of botanic drugs. For example, resveratrol, as a botanic compound, has been used a preventive agent for various chronic conditions (cancer, cardiovascular atheroschlerosis, hypertension, and diabetes). With the use of proteomics, the

1.3 PHARMACEUTICALS

19

mechanism of action of resveratrol which targets the ovarian cancer cell lines has been discovered, unraveling the potential use of resveratrol as a pharmaceutical (Joshi and Patil, 2017). Informatics, as a universal discipline also aids the pharmaceutical development process greatly. Examples of relevant computational analyses in pharmaceutical development include clustering and feature selection methods to identify the genetic targets, numerical integration to quantitatively appreciate genetic interdependencies relative to the proposed targets, statistical validation techniques to assess the effect of active molecules on the targets, machine learning to rationalize structure-activity relationships, and Newtonian physics to understand the complex biochemical interactions between drugs and the target (Lushington and Chaguturu, 2017). In most cases, traditional medicines have been developed through real life experiences and direct observations in people with diseases, which represent extremely complex biological systems. The idea behind systems biology is using the computational tools for the “reduction” of the whole organism into less complex units: groups of tissues, cells and molecules, where only interactions between the target and the drug are monitored. The final goal of the systems biology is to provide predictive models of behavior of diverse molecular systems to identify such functional interactions (Patwardhan et al., 2008). Based on all of the above mentioned, systems biology is not only aimed to the understanding and development of pharmaceutical drugs, but also nutraceuticals and drugs derived from natural sources. All of those approaches have been successfully applied in both fields, nutra and pharma.

1.3.3 CHEMICAL COMPOSITION AND CLASSIFICATION When assessing the chemical and molecular structure of pharmaceutics, Zrnˇcevi´c (2016) states that there are over 4000 active pharmaceutical ingredients used in human medicine, with an average annual production of over 100,000 tons, which are usually 200
500 kDa organic molecules, lipophilic and moderately soluble in water. Schultheiss and Newman (2009) estimated that over half of the medicines on the market are administered as salts, mostly due to their improved solubility. Pharmaceuticals are classified into 14 main (first level) groups based on the ATC classification system (anatomical therapeutic chemical classification system) according to the organ or system on which they act and their therapeutic, pharmacological, and chemical properties: 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14.

Alimentary tract and metabolism; Blood and blood forming organs; Cardiovascular system; Dermatologicals; Genito-urinary system and sex hormones; Systemic hormonal preparations, excluding sex hormones and insulins; Antiinfectives for systemic use; Antineoplastic and immunomodulating agents; Musculo-skeletal system; Nervous system; Antiparasitic products, insecticides, and repellents; Respiratory system; Sensory organs; Various (WHO, 2017).

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CHAPTER 1 INTRODUCTION TO NUTRACEUTICALS

In this type of classification, the first level demonstrates the organ or system in which the pharmaceutical acts, while the lower levels (2
5) include the therapeutic subgroup, pharmacological subgroup, chemical subgroup, and the chemical substance. Some references also include a classification based on duration of release: immediate, delayed, prolonged, and controlled (Barich et al., 2016). Immediate release includes administration of a drug in a single dose being released to the target area immediately after application, which is useful for acute therapeutic treatment requiring a short period of action. Delayed release allows multiple doses to be incorporated into a single dosage form, alleviating the problem of frequent dosing. The prolonged release includes the release of the drug, for example, by slowing the dissolution rate of the drug. The controlled release implies constant release rate throughout the desired dosage period (Barich et al., 2016). Furthermore, a classification is present based on the methods of administration: oral, parenteral, transdermal, aerosol, and other. Oral administration is the most commonly used method, mostly due to the ease and the comfort of application. In this case the drug as swallowed through the moth, disintegrated in the stomach and bile and absorbed to the bloodstream in the small intestine. The disadvantages include low pH values in the stomach, as well as a certain period of time which needs to pass before the drug starts to work. Parenteral administration includes different injections and implants but is avoided due to its invasive nature. Transdermal delivery is gaining popularity nowadays due to its noninvasiveness and the possibility of prolonged release of substances via different skin patches. Aerosol administration is specific because small droplets of medicine are formed which are then sprayed into the sight of administration: nose, mouth, or skin. In order to ensure uniform delivery, a strict control of droplet particle size is acquired. Other methods of administration include suspensions, emulsions, ointments, and suppositories (Barich et al., 2016).

1.3.4 NATURALLY-BASED PHARMACEUTICALS The above stated data clearly shows the complexity, the timeliness, and the rules of the pharmaceuticals development. Now, if a nutraceutical positively impacts human health, it can be considered a pharmaceutical only if it passes all the stages of the process development. But the real question to be asked is: is it worth it? Major pharmaceutical companies emphasize that the research considering bioactive natural products is often time-consuming, highly complex, and ineffective. Also, a problem of patents arises, since it is not allowed to patent naturally occurring bioproducts and traditional medicinal herbs. Despite that, there are pharmaceuticals derived from herbals and natural sources present on the market, which have passed all of the development stages of pharmaceuticals. The “small molecule natural products” have been proven as a source of the most successful development of new drugs. The examples of nutraceuticals which became pharmaceuticals include the natural occurring yohimbine alkaloid reserpine, as an antihypertensive and tranquilizing agent and galanthamine isolated from Galanthus nivalis approved for treatment of Alzheimer’s disease. Furthermore, almost 74% of anticancer agents approved between 1981 and 2002 were natural products, natural product derived, or natural product inspired (Goyal and Goyal, 2018). Statins represent another example of naurally derived pharmaceuticals. They act as inhibitors of the HMG CoA reductase enzyme an

1.4 LEGISLATION

21

thus act as antihypercholesteremic agents with long-term cardiovascular benefits. Examples of statins include mevastatin and lovastatin isolated from Penicillium brevicompatin and Aspergillus terreus, as well as the Atorvastatin as one of the most commercially successful drugs (Goyal and Goyal, 2018).

1.4 LEGISLATION 1.4.1 LEGISLATION ON PHARMACEUTICALS From the pharmaceuticals point of view, drugs are not ordinary consumers products, and in most cases (not in all cases) consumers are not in a position to make decisions when to use drugs, which drugs to use, how to use them, and to weight potential benefits against risks as no medicine is completely safe (Ra¨go and Santoso, 2008). The regulations are, therefore, set to promote and protect public health. The WHO, the directing and coordinating technical agency for health within the United Nations, is responsible for shaping the principles of drug regulations. The WHO states the following functions of medicines regulations: • • • • • • •

Licensing of the manufacture, import, export, distribution, promotion, and advertising of medicines; Assessing the safety, efficacy and quality of medicines, and issuing marketing authorization for individual products; Inspecting and surveillance of manufacturers, importers, wholesalers, and dispensers of medicines; Controlling and monitoring the quality of medicines on the market; Controlling promotion and advertising of medicines; Monitoring safety of marketed medicines including collecting and analyzing adverse reaction reports; Providing independent information on medicines to professionals and the public (WHO, 2003).

For regulations in a specific country, national medicines regulatory agencies are responsible, whose work and regulatory systems are then under the supervision of the WHO. Active regulative provide rules for conducting clinical trials, authorization of medicines, but also regulate the required quality, safety, and efficacy of medicines. List of the regulatory framework for some continents and countries is shown in Table 1.4. It is important to emphasize that each country has the freedom to have its own regulatory framework for medicines, but in recent years, harmonization of frameworks is encouraged (NdomondoSigonda et al., 2017; Valverde, 2014). An example of such harmonization is the European Union: in the EU, a medicinal product for human use may be authorized either by the European Commission through the centralized procedure or by national competent authorities through a mutual recognition, decentralized or national procedure.

1.4.2 LEGISLATION ON NUTRACEUTICALS As mentioned before and despite the positive attitude and growing demand for nutraceuticals and functional foods, both from the researchers and consumers’ perspectives, regulation wise they still

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CHAPTER 1 INTRODUCTION TO NUTRACEUTICALS

Table 1.4 Regulatory Frameworks for the European Union, United States, Canada, Latin America, Asia, and Australia Country/ Continent European Union

United States Canada Latin America Africa

Asia Australia

Framework Status

References

The requirements and procedures for marketing authorization, as well as the rules for monitoring authorized products, are primarily laid down in Directive 2001/83/EC and in Regulation (EC) No 726/2004 Federal Food, Drug, and Cosmetic Act Food and Drugs Act, Food and Drug Regulations

EU Commision (2018)

National regulations, Pan American Health Organization, harmonization of the regulation underway National Medicines Regulation Authorities (by country), harmonization proposed by establishing the African Medicines Agency South-East Asia Regulatory Network, national agencies Australian Regulatory Guidelines for Prescription Medicines (ARGPM)

FDA (2018b) Government of Canada (2018a), Government of Canada (2018b) Valverde, 2014 Ndomondo-Sigonda et al., 2017

WHO (2018) TGA (2018)

remain in the gray area between food, food supplements, and pharmaceuticals, all of those being officially recognized in appropriate legislation. Although nutraceuticals are lyrically referred to as “beyond the diet, but before the drugs” (Santini and Novellino, 2014; El Sohaimy, 2012), there is still need for legitimate assessment of their safety and efficiency and subsequently development of official definitions, so to provide information on where exactly beyond diet and before drugs nutraceuticals fit. To exemplify, monitoring safety and efficiency of medicines, as well as scrutinizing marketing of pharmaceuticals, from one side, are under jurisdiction (in Europe) of European Medicines Agency; from the other side, providing scientific background to food safety assessment is the responsibility of European Food Safety Authority. European Commission has initiated a framework to assess safety of “novel foods,” and from January 2018 the new Regulation (EU) 2015/2283 on novel foods is in place, to repeal and replace Regulation (EC) No 258/97 and Regulation (EC) No 1852/2001. It defines categories of food that fall under the term of “novel foods.” The Food Supplements Directive 2002/46/EC states, “there is a wide range of nutrients and other ingredients that might be present in food supplements including, but not limited to, vitamins, minerals, amino acids, essential fatty acids, fibers, and various plants and herbal extracts.” However, nutrients are defined solely as vitamins and minerals (list of permitted ones is provided in the annex to Directive). Furthermore, herbal extracts as food ingredients are referenced in Food Fortification Regulation 1925/2006. None of these are mentioning the term nutraceuticals. Hence, it is of outmost importance to provide appropriate regulation for nutraceuticals. Prior to this, it is necessary to evaluate nutraceuticals in terms of their mechanism of action, efficiency, and safety, not only in in vitro but also in in vivo settings, so the reliable clinical data are obtained (Santini et al., 2018). Numerous research findings are highlighting the benefits of certain food

1.5 THE DIFFERENCES AND THE OVERLAPPING

23

component, for example, bioactive compound, focusing on the in vitro results; however, the safety perspectives as well as efficiency of these compounds needs to be ascertained in the clinical trials. In addition, issues of mechanisms of action, effective doses, and bioavailability, as well as possible interactions with other (food or pharmaceutical) products, need to be addressed (Santini et al., 2018). By collecting all of these data, a ground base for nutraceuticals’ legal assessment and definitions would be laid down for the relevant authorities, so the appropriate measures to classify and legally regulate nutraceuticals can be taken into action.

1.5 THE DIFFERENCES AND THE OVERLAPPING Based on everything mentioned before, it is difficult to precisely define the differences between nutraceuticals and pharmaceuticals, since there are numerous examples of their overlapping. The first major difference is that the pharmaceuticals are subject to strict regulations and are obligated to pass through the whole procedure of development, trials and approval. On the other hand, a nutraceutical can become a pharmaceutical if it proves to be adequate to pass the same procedures. In that case, it can be marketed as a pharmaceutical with sound scientific evidence on its functionality and health benefits. Regulatory aspects for nutraceuticals and pharmaceuticals are also closely related to the whole development and approval process. Goyal and Goyal (2018) claim that the major difference emerging between pharmaceuticals and nutraceuticals is with respect to varied regulatory status in different countries. Since different countries have different (if any) regulations on nutraceuticals, a problem appears due to either lack of definitions of nutraceuticals or presence of definitions which are not unified and comprehensible in stating what is considered a nutraceutical. Secondly, the source and the origin can be considered as a differentiator of nutraceuticals and pharmaceuticals. For example, most of the pharmaceuticals present at the market are obtained by chemical synthesis, often not finding their origin in biological products or foods. On the other hand, an overlapping is present in aforementioned cases where a pharmaceutical is of food origin and is considered a pharmaceutical since it was regulatory approved as such. A clear difference is visible when speaking about the moment in which nutraceuticals and pharmaceuticals are consumed, where for nutraceuticals “better to be safe than sorry” or the “beyond the diet, before the drugs” rule applies (they are mostly used in prevention) (Santini and Novellino, 2017), while pharmaceutical are consumed when there has already been a visible onset of disease and pharmaceuticals (drugs) are needed to cure it. However, vitamin C could be an example of overlapping in this case: scurvy is a disease caused by the lack of vitamin C in the diet, and it is cured only by vitamin C supplements which can be administered as both nutraceuticals and pharmaceuticals, as well as a part of a diet rich in vitamin C. This also implies that pharmaceuticals work on symptoms on the particular part or whole body, giving immediate effect or results at the cost of side effects, whereas, nutraceuticals are claimed to work on the root of the cause (Goyal and Goyal, 2018). It is also considered that pharmaceuticals act as soon as the drug is dissolved in the stomach and absorbed in the bloodstream through the colon. Nutrients, on the other hand, need a longer time period to be effective, as it is often said by the physicians and also present

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CHAPTER 1 INTRODUCTION TO NUTRACEUTICALS

on the labels of nutraceuticals that at least a period of 1
3 months of consummation is required to experience the benefits. And lastly, people’s perception can act as a distinguisher between nutraceuticals and pharmaceuticals. Namely, it is often considered that, in order to get a pharmaceutical, you need a doctor’s prescription, while nutraceuticals are available without a prescription.

1.6 THE FUTURE PERSPECTIVES 1.6.1 WHAT NEEDS TO BE DONE? As discussed, nutraceuticals can be defined as such if they provide medical or health benefits. What is appealing to the customers is their natural origin, which is one of the reasons why a growing demand for nutraceuticals exists. However, that growing demand shades the frontier existing between pharmaceuticals and nutraceuticals. Different country specific regulations, safety, and health claim substantiation are the main challenges nutraceuticals are experiencing. Additionally, the challenge is absence of a shaped supranational regulation for nutraceuticals, which would recognize their potential and possible role as therapeutic tools in some pathological conditions based on assessed safety, known mechanism of action, clinically proven efficacy in both reducing the risk of illness onset and enhancing overall well-being (Santini and Novellino, 2017). Furthermore, the regulatory framework of dietary supplements should be restructured so it can include nutraceuticals as a separate category, with a similar approach as the one with pharmaceuticals, but used on nutraceuticals. Until then, the thin line between pharmaceuticals and nutrient-based nutraceuticals will remain indistinct.

1.6.2 NOVEL TRENDS IN NUTRACEUTICALS PRODUCTION The constantly growing consumers’ affinities toward the naturally sourced products are already reflecting in contemporary research trends—the science community is focused on bringing as much functionality as possible from nature (exactly the area were nutraceuticals fit). However, the stateof-the art research endeavors are going even further; scientists are trying to source the nutraceuticals and other valuable components that can be used in functional foods or as food additives from what has been perceived as a food waste. Food waste is a vast term; it can comprise fruit and vegetable peels, seeds, stems, shells, brans, or the residues after extraction of juice, oil, sugar, or starch, as well as the residuals accumulated during processing in dairy and seafood industry (Kumar et al., 2017). A lot of examples can be found in literature—extraction of epicatechin, gallocatechin, catechins, anthocyanins, polyphenolic acids, and other polyphenolic compounds from apple peel and pomace (Wolfe and Liu, 2003), avocado peel and seeds (Deng et al., 2012), banana peel (Gonz´alez-Montelongo et al., 2010; Someya et al., 2002), grapes skin and seed (Maier et al., 2009; Negro et al., 2003); extraction of tocopherols, sterols and squalene from by-products of palm oil milling (Tan et al., 2007); extraction of β-carotene and carotenoids from carrot peel (Chantaro et al., 2008), tomato skin and pomace (Strati and Oreopoulou, 2011); extraction of chlorophyll from cucumber peel (Zeyada et al., 2008) or extraction of β-glucan and γ-oryzanol from barley and rice bran (Oliveira et al., 2012; Perretti et al., 2003; Sainvitu et al., 2012). Those are just a few

REFERENCES

25

examples, but the possibilities for extraction of bioactive compounds from food-waste sources are nearly limitless. In combination with emerging new technologies for the components extraction, purification, and isolation (Galanakis, 2015), it can be concluded that the by-products of food supply chain should not be identified as a food waste but rather as a rich mine of value-added nutraceuticals.

REFERENCES Afilalo, J., Duque, G., Steele, R., Jukema, J.W., de Craen, A.J., Eisenberg, M.J., 2008. Statins for secondary prevention in elderly patients. J. Am. Coll. Cardiol. 51, 37
45. Aggarwal, B.B., 2010. Targeting inflammation-induced obesity and metabolic diseases by curcumin and other nutraceuticals. Annu. Rev. Nutr. 30, 173
199. Ambati, J., Fowler, B.J., 2012. Mechanisms of agerelated macular degeneration. Neuron 75, 26
39. Annunziata, A., Vecchio, R., 2011. Functional foods development in the European market: a consumer perspective. J. Funct. Foods 3, 223
228. Aronson, J.K., 2017. Defining ‘nutraceuticals’: neither nutritious nor pharmaceutical. Br. J. Clin. Pharmacol. 83, 8
19. Australian Government, 2018. What are therapeutic goods? Available from: ,https://www.tga.gov.au/whatare-therapeutic-goods. (accessed 14.11.18.). Baboota, R.K., Bishnoi, M., Ambalam, P., Kondepudi, K.K., Sarma, S.M., Boparai, R.K., et al., 2013. Functional food ingredients for the management of obesity and associated co-morbidities
a review. J. Funct. Foods 5, 997
1012. Barich, D.H., Zell, M.T., Munson, E.J., 2016. Physicochemical properties, formulation, and drug delivery. In: Wang, B., Hu, L., Siahaan, T.J. (Eds.), Drug Delivery. John Wiley & Sons, Hoboken, pp. 35
48. Bigliardi, B., Galati, F., 2013. Innovation trends in the food industry: the case of functional foods. Trends Food Sci. Tence Technol. 31, 118
129. Boozer, C.N., Nasser, J.A., Heymsfield, S.B., Wang, V., Chen, G., Solomon, J.L., 2001. An herbal supplement containing Ma Huang-Guarana for weight loss: a randomized, double-blind trial. Int. J. Obes. Relat. Metab. Disord. 25, 316
324. Borghi, C., Cicero, F.G., 2017. Nutraceuticals with a clinically detectable blood pressure lowering effect: a review of available randomized clinical trials and their meta-analyses. Br. J. Clin. Pharmacol. 83, 163
171. Brakenhielm, E., Cao, R., Cao, Y., 2001. Suppression of angiogenesis, tumor growth, and wound healing by resveratrol, a natural compound in red wine and grapes. FASEB J. Express 15, 1798
1800. Brookmeyer, R., Johnson, E., Ziegler-Graham, K., Arrighi, H.M., 2007. Forecasting the global burden of Alzheimer’s disease. Alzheimers Dement. 3, 186
191. Brower, V., 1998. Nutraceuticals: poised for a healthy slice of the healthcare market? Nat. Biotechnol. 16, 728
731. Bull, E., Rapport, L., Lockwood, B., 2010. What is nutraceutical? Pharm. J. 265, 57
58. Carter, R., Mouralidarane, A., Ray, S., Soeda, J., Oben, J., 2012. Recent advancements in drug treatment of obesity. Clin. Med. 12, 456
460. Caterson, I.D., Gill, T.P., 2002. Obesity: epidemiology and possible prevention. Best. Pract. Res. Clin. Endocrinol. Metab. 16, 595
610. Chaguturu, R., 2017. Genomics-driven drug discovery process. In: Patwardhan, B., Chaguturu, R. (Eds.), Innovative Approaches in Drug Discovery. Academic Press, London, pp. 165
194.

26

CHAPTER 1 INTRODUCTION TO NUTRACEUTICALS

Chandran, U., Mehendale, N., Patil, S., Chaguturu, R., Patwardhan, B., 2017. Network pharmacology. In: Patwardhan, B., Chaguturu, R. (Eds.), Innovative Approaches in Drug Discovery. Academic Press, London, pp. 127
164. Chantaro, P., Devahastin, S., Chiewchan, N., 2008. Production of antioxidant high dietary fiber powder from carrot peels. LWT Food Sci. Technol. 41, 1987
1994. Charu, K., Yogita, S., Sonali, S., 2014. Nutraceutical potential of organosulfur compounds in fresh garlic and garlic preparations. Int. J. Pharm. Bio Sci. 5, 112
126. Chauhan, B., Kumar, G., Kalam, N., Ansari, S.H., 2013. Current concepts and prospects of herbal nutraceutical: a review. J. Adv. Pharm. Technol. Res. 4, 4
8. Christensen, J.L., Rama, R., Von Tunzelmann, N., 1996. Study on Innovation in the European Food Products and Beverages Industry. European Innovation Monitoring System, EIMS Publication, 35. European Commission, Directorate General XIII, Luxembourg. Cicero, A.F.G., Rosticci, M., Morbini, M., Cagnati, M., Grandi, E., Parini, A., et al., 2016. Lipid-lowering and anti-inflammatory effects of omega 3 ethyl esters and krill oil: a randomized, cross-over, clinical trial. Arch. Med. Sci. 12, 507
512. DeFelice, S.L., 1989. The nutraceutical revolution: fueling a powerful, new international market Harvard University Advanced Management Program in Biomedical Research and Development, Como, Italy. DeFelice, S.L., 2002. FIM Rationale and proposed guidelines for the nutraceutical research and education Act
NLEA. In: FIM’s 10th Nutraceutical Conference November 10
11, 2002. Deng, G.-F., Shen, C., Xu, X.-R., Kuang, R.-D., Guo, Y.-J., Zeng, L.-S., et al., 2012. Potential of fruit wastes as natural resources of bioactive compounds. Int. J. Mol. Sci. 13, 8308
8323. Dillard, C.J., German, B.J., 2000. Phytochemicals: nutraceuticals and human health. J. Sci. Food. Agric. 80, 1744
1756. Directive 2001/83/EC of the European Parliament and of the Council, Off J L 311, 0067
0128. Directive 2002/46/EC of the European Parliament and of the Council, Off J L 183, 0051
0057. Directive 2004/27/EC of the European Parliament and of the Council, Off J L 136, 0034
0057. El Sohaimy, S.A., 2012. Functional foods and nutraceuticals-modern approach to food science. World Appl. Sci. J. 20, 691
708. Espin, J.C., Garcia-Conesa, M.T., Tomas-Barberan, F.A., 2007. Nutraceuticals: facts and fiction. Phytochemistry 68, 2986
3008. EU Commision, 2018. Legal framework governing medicinal products for human use in the EU. Available from: ,https://ec.europa.eu/health/human-use/legal-framework_en. (accessed 26.07.18.). Fang, Z., Lu, B., Liu, M., Zhang, M., Yi, Z., Fen, C., et al., 2013. Evaluating the pharmacological mechanism of Chinese medicine Si-Wu-Tang through multi-level data integration. PLoS One 8 (11), e72334. FDA, 2018a. Available from: ,https://www.fda.gov/Drugs/InformationOnDrugs/ucm079436.htm. (accessed 14.11.18.). FDA, 2018b. Federal Food, Drug, and Cosmetic Act (FD&C Act). Available from: ,https://www.fda.gov/regulatoryinformation/lawsenforcedbyfda/federalfooddrugandcosmeticactfdcact/default.htm. (accessed 26.07.18.). Frankel, F., Priven, M., Richard, E., Schweinshault, C., Tongo, O., Webster, A., et al., 2016. Health functionality of organosulfides: a review. Int. J. Food Prop. 19, 537
548. Galanakis, C.M., 2015. Food Waste Recovery: Processing Technologies and Industrial Techniques. Academic Press, USA. Galland, L., 2010. Diet and inflammation. Nutr. Clin. Pract. 25, 634
640. Garcia Martinez, M., Briz, J., 2000. Innovation in the Spanish food & drink industry. Int. Food Agribus Manage. Rev. 3, 155
176.

REFERENCES

27

Ghosh, D., Smarta, R.B., 2017. Pharmaceuticals to Nutraceuticals: A Shift in Disease Prevention. CRC Press, Florida. Goldberg, I., 1994. Functional Foods, Designer Foods, Pharmafoods, Nutraceuticals. Chapman & Hall, London. Gonz´alez-Montelongo, R., Lobo, M.G., Gonz´alez, M., 2010. Antioxidant activity in banana peel extracts: testing extraction conditions and related bioactive compounds. Food. Chem. 119, 1030
1039. Government of Canada, 2018a. Food and Drugs Act. Available from: ,http://laws-lois.justice.gc.ca/eng/acts/ F-27/index.html. (accessed 26.07.18.). Government of Canada, 2018b. Food and Drug Regulations (C.R.C., c. 870). Available from: ,http://lawslois.justice.gc.ca/eng/regulations/C.R.C.,_c._870/index.html. (accessed 26.07.18.). Goyal, R.K., Goyal, N., 2018. From nutraceuticals to pharmaceuticals: old wine new bottle. Available from: ,http://www.indus.org/healthcare/Secientific%20Sessions/Dr.%20Ramesh%20K.%20Goyal%20-% 20From%20Nutraceuticals%20to%20Pharmaceuticals%20-%20Old%20Wine%20in%20New%20Bottle% 20for%20New%20Drug%20Discovery.pdf. (accessed 23.07.18.). Grammatikos, A.P., 2008. The genetic and environmental basis of atopic diseases. Ann. Med. 40, 482
495. Grand View Research, 2017. Nutraceuticals Market Size Worth $578.23 Billion By 2025. Available from: ,https://www.grandviewresearch.com/press-release/global-nutraceuticals-market. (accessed 31.10.18.). Harborne, J.B., 1999. Classes and functions of secondary products from plants. In: Walton, J.N., Brown, D.E. (Eds.), Chemicals from Plants Perspectives on Plant Secondary Products. Imperial College Press, London, pp. 1
25. Hardy, G., 2000. Nutraceuticals and functional foods: introduction and meaning. Nutrition 16, 688
697. Harikumar, K.B., Aggarwal, B.B., 2008. Resveratrol. A multitargeted agent for age-associated chronic diseases. Cell Cycle 7, 1020
1035. Higgins, G.A., Silenieks, L.B., Lau, W., de Lannoy, I.A., Lee, D.K., Izhakova, J., et al., 2013. Evaluation of chemically diverse 5-HT(2C) receptor agonists on behaviours motivated by food and nicotine and on side effect profiles. Psychopharmocology 226, 475
490. Holub, B.J., 2006. Potential for functional food ingredients to reduce health care costs. International Food and Health Innovation Conference, Malmo, Sweden, October 25-27. Hopkins, A.L., 2007. Network pharmacology. Nat. Biotechnol. 25, 1110
1111. Available from: https://www. nutraceuticalsworld.com/ (accessed on 13 October). Hursel, R., Viechtbauer, W., Westerterp-Plantenga, M.S., 2009. The effects of green tea on weight loss and weight maintenance: a meta-analysis. Int. J. Obes. 33, 956
961. International Federation of Pharmaceutical Manufacturers & Associations, 2017. The pharmaceutical industry and global health: facts and figures. Available from: ,https://www.ifpma.org/wp-content/uploads/2017/02/ IFPMA-Facts-And-Figures-2017.pdf. (accessed 26.07.18.). Japan Pharmaceutical Manufacturers Association, 2015. Pharmaceutical Administration and Regulations in Japan. Available from: ,http://www.jpma.or.jp/english/parj/pdf/2015.pdf. (accessed 14.11.18.). Jian, B., Yang, S., Chaudry, I.H., Raju, R., 2012. Resveratrol improves cardiac contractility following traumahemorrhage by modulating sirt1. Mol. Med. 18, 209
214. Joshi, K., Patil, D., 2017. Proteomics. In: Patwardhan, B., Chaguturu, R. (Eds.), Innovative Approaches in Drug Discovery. Academic Press, London, pp. 273
294. Kalia, A.N., 2005. Textbook of Industrial Pharmacognosy. CBS Publisher and Distributor, New Delhi, pp. 204
208. Kalra, E.K., 2003. Nutraceutical
definition and introduction. AAPS Pharm. Sci. 5, E25. 1
2. Kang, J.G., Park, C.Y., 2012. Anti-obesity drugs: a review about their effects and safety. Diabetes Metab. J. 36, 13
25.

28

CHAPTER 1 INTRODUCTION TO NUTRACEUTICALS

Kar, A., Mukherjee, P.K., Saha, S., Bahadur, S., Ahnuned, S.K.M., Pandit, S., 2015. Possible herb-drug interaction of Morus alba L. a potential anti-diabetic plant from Indian Traditional medicine. Ind. J. Tradit Med. 14, 626
631. Ko¨hler, A., Sarkkinen, E., Tapola, N., Niskanen, T., Bruheim, I., 2015. Bioavailability of fatty acids from krill oil, krill meal and fish oil in healthy subjects
a randomized, singledose, cross-over trial. Lipids. Health Dis. 14, 19. 1
10. Kotilainen, L., Rajalahti, R., Ragasa, C., Pehu, E., 2006. Health enhancing foods: opportunities for strengthening the sector in developing countries, Discussion Paper 30, World Bank, Washington, DC. Kumar, K., Yadav, A.N., Kumar, V., Vyas, P., Dhaliwal, H.S., 2017. Food waste: a potential bioresource for extraction of nutraceuticals and bioactive compounds. Bioresour. Bioprocess 4, 18. Lu, C., Zhu, W., Shen, C.L., Gao, W., 2012. Green tea polyphenols reduce body weight in rats by modulating obesity-related genes. PLoS One 7, e38332. Lushington, G.H., Chaguturu, R., 2017. Chemical informatics. In: Patwardhan, B., Chaguturu, R. (Eds.), Innovative Approaches in Drug Discovery. Academic Press, London, pp. 295
314. Madalageri, N.K., Nagaraj, L., Nidamarthi, S.B., 2016. Evaluation and comparative study of hypoglycaemic activity of Morus alba with oral hypoglycaemic drug (Glibenclamide) in alloxan induced diabetic rats. J. Evol. Med. Dent. Sci. 48, 3162
3165. Maier, T., Schieber, A., Kammerer, D.R., Carle, R., 2009. Residues of grape (Vitis vinifera L.) seed oil production as a valuable source of phenolic antioxidants. Food. Chem. 112, 551
559. Mark, A.L., 2009. Cardiovascular side effects of anti-obesity drugs: a yellow flag in the race to effective, safe pharmacotherapy for obesity. Circulation 120, 719
721. Martirosyan, D., Miller, E., 2018. Bioactive compounds: the key to functional foods. BCHD 8, 36
39. Menrad, K., 2004. Innovations in the food industry in Germany. Res. Policy 33, 845
878. Mota, A.H., 2016. A review of medicinal plants used in therapy of cardiovascular diseases. Int. J. Pharm. Phytochem. Res. 8, 572
591. Mueller, C., 1999. The regulatory status of medical foods and dietary supplements in the United States. Nutrition 15, 249
251. Nagineni, C.N., Raju, R., Nagineni, K.K., Kommineni, V.K., Cherukuri, A., Kutty, R.K., et al., 2014. Resveratrol suppresses expression of VEGF by human retinal pigment epithelial cells: potential nutraceutical for age-related macular degeneration. Aging Dis. 5, 88
100. Nakayama, R., Tamura, Y., Yamanaka, H., Kikuzaki, H., Nakatani, N., 1993. Curcuminoid pigments from Curcuma domestica. Phytochem 33, 501
502. Nasri, H., Baradaran, A., Shirzad, H., Rafieian-Kopaei, M., 2014. New concepts in nutraceuticals as alternative for pharmaceuticals. Int. J. Prev. Med. 5, 1487
1499. Ndomondo-Sigonda, M., Miot, J., Naidoo, S., Dodoo, A., Kaale, E., 2017. Medicines regulation in Africa: current state and opportunities. Pharm. Med. 31, 383
397. Negro, C., Tommasi, L., Miceli, A., 2003. Phenolic compounds and antioxidant activity from red grape marc extracts. Bioresour. Technol. 87, 41
44. Ohshiro, M., Kuroyanagi, M., Ueno, A., 1990. Structures of sesquiterpenes from Curcuma longa. Phytochem 29, 2201
2205. Oliveira, R., Oliveira, V., Aracava, K.K., da Costa Rodrigues, C.E., 2012. Effects of the extraction conditions on the yield and composition of rice bran oil extracted with ethanol—a response surface approach. Food Bioprod. Process. 90, 22
31. Pandey, M., Verma, R.K., Saraf, S.A., 2010. Nutraceuticals: new era of medicine and health. Asian J. Pharm. Clin. Res. 3, 11
15. Patwardhan, B., Chaguturu, R., 2017. Innovative Approaches in Drug Discovery. Academic Press, London.

REFERENCES

29

Patwardhan, B., Vaidya, A.,D.,B., Chorgade, M., Joshi, S.P., 2008. Reverse pharmacology and systems approaches for drug discovery and development. Curr. Bioact. Compd. 4, 201
212. Periˇsa, M., Babi´c, S., 2016. Farmaceutici u okoliˇsu. Kem Ind. 65, 471
482. Perretti, G., Miniati, E., Montanari, L., Fantozzi, P., 2003. Improving the value of rice by-products by SFE. J. Supercrit. Fluids 26, 63
71. Pervaiz, S., Holme, A.L., 2009. Resveratrol: its biologic targets and functional activity. Antioxid Redox Sig. 11, 2851
2893. PhRMA, 2015. Biopharmaceuticals Research and Development: The process behind new medicines. Available from: ,http://phrma-docs.phrma.org/sites/default/files/pdf/rd_brochure_022307.pdf. (accessed 20.07.18.). Ra¨go, L., Santoso B., 2008. Drug regulation: history, present and future. In: van Boxtel, C.J., Santoso, B., Edwards, I.R. (Eds.), Drug Benefits and Risks: International Textbook of Clinical Pharmacology, revised second ed. IOS Press and Uppsala Monitoring Centre, Uppsala, pp. 65
77. Rajasekaran, A., Sivagnanam, G., Xavier, R., 2008. Nutraceuticals as therapeutic agents: a review. Res. J. Pharm. Tech. 1, 328
340. Ravindranath, V., Satyanarayana, M.N., 1980. An unsymmetrical diarylheptanoid from Curcuma longa. Phytochem 19, 2031
2032. Regulation (EC) No. 178/2002 of the European Parliament and of the Council, Off J L 031, 0001
0024. Regulation (EU) 2015/2283 of the European Parliament and of the Council, Off J L 327/1, 1-12. Regulation (EC) No. 258/97 of the European Parliament and of the Council, Off J L 043, 0001
0006. Ried, K., Fakler, P., 2014. Potential of garlic (Allium sativum) in lowering high blood pressure: mechanisms of action and clinical relevance. Integr. Blood Press Control 7, 71
82. Robertfroid, M.B., 2000. A European consensus of scientific concepts of functional foods. Nutrition 16, 689
691. Rogerio, A.P., Kanashiro, A., Fontanari, C., da Silva, E.V.G., Lucisano-Valim, Y.M., Soares, E.G., et al., 2007. Anti-inflammatory activity of quercetin and isoquercitrin in experimental murine allergic asthma. Inflamm. Res. 56, 402
408. Ros, J.L., Francini, F., Schinella, G.R., 2015. Natural products for the treatment of type 2 diabetes mellitus. Planta Med. 81, 975
994. Roy, J., 2011. An Introduction to Pharmaceutical Sciences: Production, Chemistry, Techniques and Technology. Biohealthcare Publishing, New York. Roy, A., Chaguturu, R., 2017. Holistic drug targeting. In: Patwardhan, B., Chaguturu, R. (Eds.), Innovative Approaches in Drug Discovery. Academic Press, London, pp. 65
88. Rubin, S.A., Levin, E.R., 1994. Clinical review 53: the endocrinology of vasoactive peptides: synthesis to function. J. Clin. Endocrinol. Metab. 78, 6
10. Sainvitu, P., Nott, K., Richard, G., Blecker, C., J´eroˆme, C., Wathelet, J.-P., et al., 2012. Structure, properties and obtention routes of flaxseed lignan secoisolariciresinol: a review. Biotechnol. Agron. Soc. Environ. 16, 115. Santini, A., Novellino, E., 2014. Nutraceuticals: beyond the diet before the drugs. Curr. Bioact. Compd. 10, 1
12. Santini, A., Novellino, E., 2017. To nutraceuticals and back: rethinking a concept. Foods 6, 74. 1
3. Santini, A., Tenore, G.C., Novellino, E., 2017. Nutraceuticals: a paradigm of proactive medicine. Eur. J. Pharm. Sci. 96, 53
61. Santini, A., Novellino, E., 2018. Nutraceuticals
shedding light on the grey area between pharmaceuticals and food. Expert. Rev. Clin. Pharm. 11, 545
547. Santini, A., Cammarata, S.M., Capone, G., Ianaro, A., Tenore, G.C., Pani, L., et al., 2018. Nutraceuticals: opening the debate for a regulatory framework. Br. J. Clin. Pharmacol. 84, 659
672.

30

CHAPTER 1 INTRODUCTION TO NUTRACEUTICALS

Scalbert, A., Morand, C., Manach, C., R´em´esy, C., 2002. Absorption and metabolism of polyphenols in the gut and impact on health. Biomed. Pharmacother. 56, 276
282. Schultheiss, N., Newman, A., 2009. Pharmaceutical cocrystals and their physicochemical properties. Cryst. Growth Des. 9, 2950
2967. Shaik, Y.B., Castellani, M.L., Perrella, A., Conti, F., Salini, V., Tete, S., et al., 2006. Role of quercetin (a natural herbal compound) in allergy and inflammation. J. Biol. Regul. Homeost. Agents. 20, 47
52. Siddiqui, M.R., AlOthman, Z.A., Rahman, N., 2017. Analytical techniques in pharmaceutical analysis: a review. Arab. J. Chem. 10, S1409
S1421. Singh, H., Khurana, L.K., Singh, R., 2018. Pharmaceutical development. In: Vohora, D., Singh, G. (Eds.), Pharmaceutical Medicine and Translational Clinical Research. Academic Press, London, pp. 33
46. Siro, I., Kapolna, E., Kapolna, B., Lugasi, A., 2008. Functional food. Product development, marketing and consumer acceptance - a review. Appetite 51, 456
467. Slakter, J.S., Stur, M., 2005. Quality of life in patients with age-related macular degeneration: impact of the condition and benefits of treatment. Surv. Ophthalmol. 50, 263
273. Someya, S., Yoshiki, Y., Okubo, K., 2002. Antioxidant compounds from bananas (Musa cavendish). Food. Chem. 79, 351
354. Strati, I.F., Oreopoulou, V., 2011. Effect of extraction parameters on the carotenoid recovery from tomato waste. Int. J. Food Sci. Technol. 46, 23
29. Sung, B., Prasad, S., Gupta, S.C., Patchva, S., Aggarwal, B.B., 2012. Regulation of inflammation-mediated chronic diseases by botanicals. In: Shyur, L.F. (Ed.), Advances in Botanical Research: Recent Trends in Medicinal Plants Research, vol. 62. Academic Press, Oxford, UK, pp. 57
132. Tan, Y.A., Sambanthamurthi, R., Sundram, K., Wahid, M.B., 2007. Valorisation of palm by-products as functional components. Eur. J. Lipid Sci. Technol. 109, 380
393. Tank Dharti, S., Gandhi, S., Shah, M., 2010. Nutraceuticals-portmanteau of science and nature. Int. J. Pharm. Sci. Rev. Res. 5, 33
38. TGA, 2018. Australian Regulatory Guidelines for Prescription Medicines (ARGPM). Available from: ,https:// www.tga.gov.au/publication/australian-regulatory-guidelines-prescription-medicines-argpm. (accessed 26.07.18.). Valverde, J.L., 2014. Latin American pharmaceutical overview. Pharm. Pol. Law 16, 179
206. van Leeuwen, R., Klaver, C.C., Vingerling, J.R., Hofman, A., de Jong, P.T., 2003. Epidemiology of age-related maculopathy. Eur. J. Epidemiol. 18, 845
854. Verma, G., Mishra, M.K., 2016. A review on nutraceuticals: classification and its role in various diseases. IJPT 7, 152
160. Vicentini, A., Liberatore, L., Mastracola, D., 2016. Functional foods: trends and development of the global market. Ital. J. Food Sci. 28, 338
351. Weiss, U., 2008. Inflammation. Nature 454, 427. Available from: https://doi.org/10.1038/454427a. WHO, 2003. Effective medicines regulation: ensuring safety, efficacy and quality, no. 7. Available from: ,http://apps.who.int/iris/bitstream/handle/10665/68391/WHO_EDM_2003.2.pdf;jsessionid 5 01B5083D50BC932B529280FB03A092F6?sequence 5 1. (accessed 26.07.18.). WHO, 2017. ATC/DDD Index 2018. WHO Collaborating Centre for Drug Statistics Methodology. Available from: ,https://www.whocc.no/atc_ddd_index/. (accessed 23.07.18.). WHO, 2018. South East Asia Regulatory Network SEARN. Available from: http://www.searo.who.int/entity/ medicines/regulation/en/. (accessed 23.07.18.). Wildman, R.E.C., 2001. Nutraceuticals: a brief review of historical and teleological aspects. In: Wildman, R.E. C. (Ed.), Handbook of nutraceuticals and functional foods. CRC Press, Boca Raton, Fla, pp. 1
12. Wolfe, K.L., Liu, R.H., 2003. Apple peels as a value-added food ingredient. J. Agric. Food. Chem. 51, 1676
1683.

REFERENCES

31

Yi, C., Pan, X., Yan, H., Guo, M., Pierpaoli, W., 2005. Effects of melatonin in age-related macular degeneration. Ann. NY Acad. Sci. 1057, 384
392. Zeisel, S.H., 1999. Regulation of nutraceuticals. Science 285, 1853
1855. Zeyada, N.N., Zeitoum, M., Barbary, O., 2008. Utilization of some vegetables and fruit waste as natural antioxidants. Alex J. Food Sci. Technol. 5, 1
11. Zhang, B., Wang, X., Li, S., 2013. An integrative platform of TCM network pharmacology and its application on a herbal formula, Qing-Luo-Yin, Evid. Based Complement Alter. Med., 2013. ID 456747. Zrnˇcevi´c, S., 2016. Farmaceutici i metode obrade otpadne vode iz farmaceutske industrije. Hrvatske vode 96, 119
136.

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NUTRIGENOMICS AND ANTIOXIDANTS

2

Bilyaminu Abubakar1,4, , Ooi Der Jiun2, , Maznah Ismail2 and Mustapha Umar Imam3,4 1

Deparment of Pharmacology and Toxicology, Usmanu Danfodiyo University, Sokoto, Nigeria 2Laboratory of Molecular Biomedicine, Institute of Bioscience, Universiti Putra Malaysia, Serdang, Malaysia 3Department of Medical Biochemistry, Usmanu Danfodiyo University, Sokoto, Nigeria 4Centre for Advanced Medical Research and Training, Usmanu Danfodiyo University, Sokoto, Nigeria

CHAPTER OUTLINE 2.1 2.2 2.3 2.4

Introduction ................................................................................................................................... 34 Nutrigenomics ............................................................................................................................... 35 Antioxidants and Their Mode of Action ............................................................................................ 36 Nutrigenomic Basis of Antioxidant Vitamins ..................................................................................... 41 2.4.1 Vitamin A................................................................................................................... 41 2.4.2 Vitamin C................................................................................................................... 44 2.4.3 Vitamin D .................................................................................................................. 44 2.4.4 Vitamin E................................................................................................................... 45 2.5 Nutrigenomic Basis of Antioxidant Mineral Elements ........................................................................ 46 2.5.1 Magnesium ................................................................................................................ 46 2.5.2 Molybdenum .............................................................................................................. 46 2.5.3 Manganese ................................................................................................................ 50 2.5.4 Selenium ................................................................................................................... 50 2.5.5 Chromium.................................................................................................................. 51 2.6 Nutrigenomic Basis of Antioxidant Phytochemicals .......................................................................... 51 2.6.1 Polyphenols ............................................................................................................... 51 2.6.2 Flavonoids ................................................................................................................. 58 2.6.3 Sulforaphane ............................................................................................................. 60 2.7 Conclusions................................................................................................................................... 60 Acknowledgments ................................................................................................................................. 61 References ........................................................................................................................................... 61



These authors contributed equally.

Nutraceuticals and Natural Product Pharmaceuticals. DOI: https://doi.org/10.1016/B978-0-12-816450-1.00002-7 © 2019 Elsevier Inc. All rights reserved.

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2.1 INTRODUCTION Since the existence of early man, he has been associated with diet. So diet has been a basic foundation in the life of humans. It provides calories, enhances growth and development, and maintains the body’s cells. Diet has been acknowledged to provide beyond its traditional function of calorie provision since the classical Greek era. This is as enumerated in the tenet, “let food be thy medicine and medicine be thy food,” as advocated by Hippocrates. Since the 1970s, antioxidant and/or nutrigenomic composition of food has dominated the food industry space. In 2015 the market size of the functional food industry was worth over USD 129 billion (https://www.grandviewresearch. com/industry-analysis/functional-food-market/request). The growing reality that nutrigenomics visa`-vis antioxidants could augment human well-being and/or retard chronic disease progression has led to a global interest in functional food and related food substances. In recent times, the terms nutrigenomics and functional food have been closely associated with the functionality of the food nutrient beyond the traditional calorie provision and growth and development. The term functional food was coined in the 1980s in Japan (Hasler, 2002). Even though the term has no universal accepted definition, it has been defined by the International Life Science Institute as “foods that, by virtue of the presence of physiologically-active components, provide a health benefit beyond basic nutrition” (Hasler, 2002; Prates and Alfaia, 2002). Nutrigenomic food, which came up much later (2001), could be defined as any food substance that can interact and alter gene expressions vis-a`-vis their sequelae due to the presence of phytochemicals or zoochemicals as the case may be. Based on the above definitions, all nutrigenomic food substances could be termed as functional food and not the other way around. The term, functional food, is therefore more encompassing than nutrigenomic food. Bioactive principles are the common unifying agent among nutrigenomic food and functional foods. These phyto- and/or zoochemicals occur in various forms which include lipids, peptides, phenols, alkaloids, glycosides, and triterpinoids. They elicit the desired physiologic and/or therapeutic effect through inhibition and induction of gene expression, inhibition, and induction of enzyme activity, inhibition, and activation of receptor activities, direct bioactive-endogenous chemical interaction, and/or through antioxidant activities (Serrano et al., 2015). Antioxidant action is without doubt one of the most researched modes of action of nutrigenomic and/or functional foods. It involves gene expression regulation for nutrigenomic food subtances and electron donation and metal ion chelation for functional food. To improve research outcomes in unraveling the interaction between bioactive principles in diet and endogenous biomolecules, dissection of the underlying molecular mechanisms responsible for the observed physiologic/therapeutic responses are due to diet. In this respect, omics science has eased the part to research success in nutrition. Progresses made in next generation sequencing, magnetic resonance, and microarray technologies have facilitated massive metabolomics and proteomic profiling, gene expression, and determining global and in-depth examination of pathologic and physiologic expressions. Nutrigenomic, nutritranscriptomis, nutriproteomic, and nutrimetabolomic technologies have all been employed in studying functional food with nutrigenomic being the forerunner. While proteomics and metabolomics are premised upon electrophoresis, liquid chromatography (separation techniques), and mass spectometry, genomics and transcriptomics are premised upon microarray science and next generation sequencing (Kato, 2008; Rezzi et al., 2007; Rist et al.,

2.2 NUTRIGENOMICS

35

2006; Subbiah, 2006; Trujillo et al., 2006). Nutridynamics is the result of the interaction between nutrients (bioactives) and biomolecules. Put simply, nutrigenomics, nutritranscriptomics, nutriproteomics, and nutrimetabolomics are all nutridynamic studies (Trujillo et al., 2006). Nutrikinetics focus on what the body does to these bioactive principles on consumption or administration up until they are available for action with their target biomolecules. This includes gastro-intestinal digestion, bioaccessibility, absorption, metabolism, and tissue distribution of bioactive principles. This concept is very important as not all of the amount of consumed bioactives get to the target site of action (van Duynhoven et al., 2012). The high throughput of the omics sciences has made them the technology of choice in the study of nutrition science. This chapter focuses on functional food as antioxidants with nutrigenomic properties.

2.2 NUTRIGENOMICS The nature versus nurture discourse is usually the theme whenever the etiology of later-life human diseases is being discussed. Present day scientists have acknowledged that neither nature nor nurture can singly expound the biological processes that dictate the health of an individual. More often than not, a mutant gene or presence of an epigenetic signature usually indicates predisposition to a disease. Whether this genetic or epigenetic predisposition translates into a later-life disease, is a factor of the interaction between the environment and the genome. Numerous gene-based approaches to the study of disease (noncommunicable) and health are hinged on this narrative. Nutrigenomics is a sprout of one such endeavor. Being the progenitor of all other omic technologies, nutrigenomics is argued to be the most essential. It is the exploitation of the genomic set-up using nutrition and other lifestyle variables. There is no denying the fact that the genome is extremely important in setting limits to function, but the environment modulates the extent to which these genes express their genetic set-up. Nutrigenomic food substances with antioxidant mode of action (dietary antioxidant) have been in the forefront of nutrigenomic research. This is evident because oxidative stress is a mutual pathophysiological feature of almost all noncommunicable diseases (Pen˜a-Oyarzun et al., 2018). Reactive radicals and nonradicals of oxygen and nitrogen derivatives respectively are generated by all aerobic cells to maintain cellular chemical homeostatsis. The generation of these reactive oxygen and nitrogen species (RONS) is related to cellular metabolic processes like immune defense, signaling process, etc. Specific enzymes that generate RONS include lipoxygenase, angiotensin II, nicotinamide adenine dinucleotide phosphate oxidase (respiration), myeloperoxidase, etc. Oxidative stress occurs when there is a net positive production of RONS due to overproduction and/or impaired neutralization of these radicals. Failure to neutralize excess RONS leads oxidation of large biomolecules like DNA, lipids, and proteins. This may lead to mutation of such biomolecule and subsequent disease occurrence (Liguori et al., 2018). Antioxidant food components mostly produce their effects via interacting with free radicals (direct effect) or biomoleclues to alter gene expression (indirect effect). Alterations in gene expression could come as a result of a more direct effect on induction or inhibition of the transcription process or remotely via modifications of epigenetic events. Thus, whether through alteration of the transcription process or modification of epigenetic signatures, several antioxidant food components

36

CHAPTER 2 NUTRIGENOMICS AND ANTIOXIDANTS

(nutrigenomic food) could enhance or retard the expression of genes responsible for important endogenous antioxidant enzymes like catalase, superoxide dismuthase, and glutathione. This is even more evident when the exposure to these antioxidants is in utero (Thompson and Al-Hasan, 2012; Drever et al., 2012). Nuclear factor erythroid-2-related factor-2 (Nrf2 or NFE2L2) is a transcription factor that directs the adaptive response to cellular oxidative stress and harmful xenobiotics by upregulating the synthesis of antioxidant enzymes. For example, sulforaphane, a dietary isothiocyanate present in broccoli, cabbage, and watercress has been demonstrated to induce enhanced Nrf2-mediated expression of the cellular defense enzymes heme oxygenase-1, NAD(P)H:quinone oxidoreductase-1 (NQO1) (Houghton et al., 2016). Also anethole, an essential oil found in anise and fennel fruits, was demonstrated to prevent H2O2-induced collagen metabolism alterations and apoptosis in human skin fibroblasts (Galicka et al., 2014). This implies that these fruits could be useful in preventing oxidative stress-related ailments. Overall, the nutrigenomic food substances with antioxidant actions act through either, enhancing transcriptomic and proteomic expression of free-radical defense enzymes (indirect action) or, prevention of oxidation of large biomolecules by the bioactive substances in the food (direct action).

2.3 ANTIOXIDANTS AND THEIR MODE OF ACTION As the name implies, antioxidants are molecules that inhibit the oxidation of other molecules. More elaborately, an antioxidant is any molecular species that can significantly prevent or retard oxidation of a vulnerable substrate in low concentration either by chelation of redox metals or by quenching free radicals. Those that quench free radicals are usually termed reactive oxygen specie (ROS) scavengers. To grasp the mechanism of actions of dietary and naturally occurring endogenous antioxidants, it is pertinent to understand endogenous free-radical generation and reactions. In a bid to fulfill 1 their daily metabolic requirements, cells generate ROSs like singlet oxygen
( O2), lipid hydroperox:2 ide (LOOH), hydrogen peroxide (H2O2), superoxide anion radical O2 , hydroxyl radical (_OH), alkoxyl radical (RO_), and peroxyl radical (ROO_). 1. Activation of NADPH oxidase, preceded by oxygen uptake as shown in the equation below will result in the formation of superoxide anion radical. This is generated by a number of enzymes during catalytic function: ðoxidaseÞ

1 1 2O2 1 NADPH
! 2O2 2 1 NADP 1 H

The superoxide anion radical via superoxide dismutase (SOD) is then converted to H2O2: ðSODÞ

1 2O2 2 1 2H
! H2 O2 1 O2

2. In neutrophils, myeloperoxidase could catalyse the conversion of hydrogen peroxide to a potent oxidant called hypochlorous acid. This is called the myeloperoxidase-halide- H2O2 system. ðMPOÞ

C12 1 H2 O2 1 H1
! HOCI1H2 O

2.3 ANTIOXIDANTS AND THEIR MODE OF ACTION

37

3. During respiratory burst, via Fenton and Haber-Weiss reactions in the mitochondria during oxidative respiration, ROSs are generated. H2 O2 1 Fe21 -˙OH 1 OH2 1 Fe31 2

O˙2 1 H2 O2 -˙OH 1 OH2 1 O2

ðFenton0 s reactionÞ

ðHaber 2 Weiss reactionsÞ

4. Reactive nitrogen specie such as nitric oxide (NO_) are generated from arginine in the presence of NO synthase. L 2 Arg 1 O2 1 NADPH-NO˙ 1 citrulline

Although antioxidants exert their effect through a number of several basic mechanisms which include decreasing concentration of oxygen, chelating redox metals, preventing protein modification, preventing DNA damage, breaking free-radical chain reactions, scavenging species involved in peroxidation initiation, activating internal antioxidant enzymes, and quenching singlet oxygen (Lu¨ et al., 2010), there are two fundamental mechanisms of action that have been hypothesized for antioxidants in biological systems. These include: 1. The chain- breaking mechanism where an electron from the antioxidant is donated to the free radical (indirect action) (Nimse and Pal, 2015). 2. The quenching of chain initiating catalyst through removal of RONSs (direct action) (Nimse and Pal, 2015). Extensive studies have detailed how primary (SOD, catalase, glutathione peroxidase [GPx]) and secondary antioxidants (glutathione, coenzyme Q, carotenoids, flavonoids, vitamins, and minerals) (Fig. 2.1) exert their effects through direct mechanism of action (Weydert and Cullen, 2010), although some of these, as will be discussed later in this chapter have been shown to also exert indirect effects. Antioxidants through indirect antioxidant action could also modify epigenetic events. Epigenetic signatures (DNA methylation, histone modification, and chromatin remodeling) due to antioxidants have been widely reported in the literature. Moreira et al. demonstrated how retinol treatment in Wistar rat Sertoli cells induced histone modifications (Moreira et al., 2000). Also Chung and colleagues showed that vitamin C promotes DNA demethylation of the epigenome in embryonic stem cells (Chung et al., 2010). Other studies have shown that B vitamins including folate, B12, and B6 are essential enzymatic cofactors required for DNA methylation (Li et al., 2018b). Furthermore, antioxidants through phosphorylation, acetylation, and methylation of the DNA and histone octamer, alter gene expression. These alterations could lead to later-life consequences (positive or negative) in individuals exposed to these antioxidants (Thompson and Al-Hasan, 2012). Furthermore, nuclear factor-κB (NF-κB) (Fig. 2.2) and nuclear factor (erythroid-derived 2)like 2 (Nrf2) (Fig. 2.3) are the two important transcription factors that modulate cellular responses to inflammation and oxidative stress respectively. Phase II antioxidant proteins are responsible for mopping up ROSs, and Nrf2 mediates the transcription of these proteins. This leads to protection against the accumulation of toxic metabolites (Wardyn et al., 2015). Nuclear factor-κB (NF-κB) is a family of transcription factors whose chief action includes mediating immune responses to inflammation, bacterial and viral infections, cell proliferation, and

38

CHAPTER 2 NUTRIGENOMICS AND ANTIOXIDANTS

FIGURE 2.1 (A) Primary and secondary antioxidants. (B) Scheme showing how primary antioxidants neutralize reactive oxygen species to produce water (H2O) and oxygen, or produce substrates for intermediary glucose metabolism. GCS, glutamyl cysteine synthase; GS, glutamyl synthase; GSH, glutathione; GSSG, reduced glutathione; GR, glutathione reductase; GPx, glutathione peroxidase; H2O2, hydrogen peroxide; CAT, catalase; O22, oxygen free radical; SOD, superoxide dismutase; NADPH, reduced dihydronicotinamide-adenine dinucleotide phosphate; NADP 1 , dihydronicotinamide-adenine dinucleotide phosphate; G6PD, glucose-6-phosphate dehydrogenase. (A) Adapted from http://bionov.fr/en/sod-b/primary-antioxidants. (B) Adapted from Weydert, C.J., Cullen, J.J., 2010. Measurement of superoxide dismutase, catalase and glutathione peroxidase in cultured cells and tissue. Nat. Protoc. 5(1), 51.

protection against UV radiation (Li et al., 2008). Recent findings in the last decade have demonstrated possible interplay between these pathways (Fig. 2.4) (Bellezza et al., 2010). Accordingly, both pathways are regulated by redox sensitive transcription factors like hypoxia inducible factor-1α, nuclear factor (erythroid-derived 2)-like 2 (Nrf2), and activator protein-1. Also, escalation of cytokine production due to increased nitrosative and oxidative stress has been associated with lack of Nrf2 (Wardyn et al., 2015).

2.3 ANTIOXIDANTS AND THEIR MODE OF ACTION

39

FIGURE 2.2 NF-κB activation is believed to be regulated by IκBα, which when stimulated, is phosphorylated to release NFκB through the classical, atypical, or alternate pathways. Adapted from Bellezza, I., Mierla, A.L., Minelli, A., 2010. Nrf2 and NF-κB and their concerted modulation in cancer pathogenesis and progression. Cancer. 2(2), 483
497.

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CHAPTER 2 NUTRIGENOMICS AND ANTIOXIDANTS

FIGURE 2.3 Nrf2 activation is reported to be mediated by Keap-1, which when stimulated via oxidative stress releases Nrf2 for nuclear translocation. Occasionally, Keap1 disrupts ARE/Nrf2 interaction via nuclear-cytoplasmic shuttling. Adapted from Bellezza, I., Mierla, A.L., Minelli, A., 2010. Nrf2 and NF-κB and their concerted modulation in cancer pathogenesis and progression. Cancer. 2(2), 483
497.

2.4 NUTRIGENOMIC BASIS OF ANTIOXIDANT VITAMINS

41

FIGURE 2.4 Cross-talk between Nrf2 and NF-κB has been suggested to induce intracellular events that produce opposite effects. Green lines indicate pathway induction, while red lines indicate pathway inhibition, and black lines show concerted modulation. Adapted from Bellezza, I., Mierla, A.L., Minelli, A., 2010. Nrf2 and NF-κB and their concerted modulation in cancer pathogenesis and progression. Cancer. 2(2), 483
497.

2.4 NUTRIGENOMIC BASIS OF ANTIOXIDANT VITAMINS 2.4.1 VITAMIN A Vitamin A, an essential fat-soluble vitamin, is derived from the diet as preformed vitamin A (retinol and retinyl esters) or provitamin A (beta carotene). Dietary vitamin A is mainly transported as a component of chylomicrons to the liver. The liver acts as the major site for vitamin A metabolism, storage, and mobilization where retinyl esters are hydrolyzed to free retinol, bound to retinolbinding protein and delivered to the tissues. Metabolic conversion of retinol to all-transretinoic acid subsequently takes place in target cells. All-transretinoic acid translocates to the nucleus and induces gene transcription by activating retinoic acid receptors. Retinoic acid is an important mediator in regulating normal vision, immune system, cell growth, differentiation, and organogenesis (O’Byrne and Blaner, 2013; Li et al., 2014). All-trans retinol has previously been reported to act as an efficient lypoperoxyl radical scavenger and chain-breaking antioxidant via its H atom donating capacity. Interestingly, retinol may concomitantly function as a pro-oxidant in generating the highly reactive hydroxyl radicals (Dao et al., 2017). Being the hormonally active form of vitamin A, all-trans retinoic acid too appears to exhibit both antioxidant and pro-oxidant properties in biological systems. As shown in Table 2.1, all-trans retinoic acid may trigger or disrupt Keap1-Nrf2 activation, thereby affecting oxidative homeostasis

Table 2.1 Nutrigenomics Implications of Antioxidant Vitamins Nutrigenomics Implications Experimental Model Antioxidant Vitamin A

Description of Antioxidant-RNA/Protein Interaction

Regulated RNA/Protein Expressions

Mode of Treatment [Concentrations]

All-trans retinoic acid mediates NRF2 activation.

m NRF2, HO-1 k eNOS, PKCβ2, NCF1, NOX2 m NRF2, GPX1, TRXR1, RARα k KEAP1, NFκB-p65, iNOS, IKKβ, IκBα, IL-1 β k Akr1c1, Akr1c2, GSTM5, GCLC, NQO1, GSTA1/2

Pretreatment of all-trans retinoic acid (concentration-dependent) protects against oxidative stress by modulating NRF2 and NF-κB pathways. All-trans retinoic acid interferes with recruitment of NRF2 to the ARE.

Vitamin C

All-trans retinoic acid disrupts KEAP1-NRF2 activation. Ascorbic acid mediates NRF2 activation. Ascorbic acid induces activation of PI3K/ Nrf-2-dependent pathway. Ascorbic acid disrupts the activation of both NRF2 and NF-κB pathways.

Vitamin D

Ascorbic acid has no effect on the transcription factor Nrf2. 1,25-dihydroxyvitamin D3 mediates oxidative stress by regulating NRF2 and NFκB pathways via vitamin D receptor.

Maxacalcitol, an active vitamin D analog, activates the Nrf2-Keap1 antioxidant pathway.

k KEAP1, NRF2 m NRF2, NQO1, HO-1 m NRF2, HO-1 k HMGB1 m KEAP1, BACH1 k NFκB, TNFα, NRF2, p-NRF2, KAP1, p21, HO-1 m Col2a1, Agc1 k Colla1, Nrf2, Ap1, Mmp-3, NFκB, pNFκB 2 NQO1, HO-1, γGCS m NRF2, TRX 2 NF-κB k NOX4, pNF-κB m NRF2, HO-1 k TGF-β1, α-SMA, p-SMAD2, p-SMAD3 m NRF2, Sod2, Gpx, Nqo1, Hmox1 k pNF-κB-p65, Mcp1, Tgf-β, Vcam m Gclc, Nqo1, Hmox1, Sod2, Cat 2 Nrf2 m NRF2, VDR, Gclc, Gclm, Ho-1 k KEAP1, Tgf-β, p22, p47

Species

Tissue/Cell Line

References

Feeding trial [1 mg/kg body weight]

• Rat

• Kidney

Molina-Jijo´n et al. (2015)

Cell culture treatment [0
4 μg/mL]

• Bovine

• Mammary epithelial cells

Shi et al. (2018b)

Intraperitoneal injection [10 mg/kg body weight]; Cell culture treatment [1 μM] Cell culture treatment [10 μM] Feeding trial [100 mg/kg body weight; 4 weeks] Cell culture treatment [10
300 μM]

• Mouse • Human

• Small Intestine • MCF-7 cells

Wang et al. (2007)

• Human

• U251 glioma cells

• Rat

• Liver

• Mouse

• RAW 264.7 cells

Shi et al. (2017) Lawal et al. (2011) Kim et al. (2015)

Cell culture treatment [100 μM]

• Human

• Fibroblasts cells

Ge˛gotek et al. (2017)

Cell culture treatment [100
200 μM]

• Human

• C28/I2 chondrocyte cells

Chang et al. (2015)

Cell culture treatment [50 μmol/L] Cell culture treatment [25
50 nM]

• Human

• Keratinocyte cells

• Mouse

• 3T3-L1 adipocytes

Wagner et al. (2010) Manna et al. (2017)

Intraperitoneal injection [100 ng]

• Mouse

• Lung

Wang et al. (2016)

Cell culture treatment [0.1
100 nM]

• Human

Teixeira et al. (2017)

Feeding trial [5 μg/kg body weight; twice per week]

• Rat

• Human umbilical vein endothelial cell • Liver

Feeding trial [0.2 μg/kg body weight]

• Rat

• Kidney

Nakai et al. (2013)

Zhu et al. (2017b)

Vitamin E

Synthetic alpha tocopherol acetate (50% purity) exerts differential effects on antioxidant genes expression. Tocovid (α-tocotrienol 12.4%, β-tocotrienol 2.5%, γ-tocotrienol 19.2%, δ-tocotrienol 6.3% and α-tocopherol 11.3%) affords protective effects against oxidative stress. Surplus of dietary vitamin E does not affect NRF2 signaling.

γ-Tocotrienol inhibits nuclear translocation of NF-κB and upregulates Nrf2 activation.

γ-Tocotrienol induces NRF2 activation.

α-Tocopherol induces NRF2 activation.

m Sod, Il-1β 2 Il-6, Il-8, Tnf-α k Nrf2, Gpx2, Ho-1 m NRF2, MRP1 2 KEAP1

Feeding trial [200 mg/kg body weight]

• Rat

• Intestine

Sun et al. (2018)

Feeding trial [200 mg/kg body weight]

• Mouse

• Brain

Shang et al. (2018)

m Nqo1 2 NQO1, GPX, HO-1, Nrf2, Keap1, Cat, Gclm, Gpx1, Gst1a, Hmox1, Sod1, Sult1b1, Ugt1a6 m NRF2, Nox3 2 Muc5ac, Icam1, Tgfβ, Mmp9, iNos k NFκB, Muc5b, Tnfα, Mmp12, Nox1, Nox2, Nox4, p22Phox, p67Phox, m NRF2 (nuclear), Ho-1, Nqo1 2 NRF2 (cytosolic) k KEAP1 m NRF2, HO-1 k NFκB

Feeding trial [25
2500 mg/kg body weight]

• Rat

• Liver

Eder et al. (2017)

Feeding trial [30, 100 and 250 mg/kg body weight]

• Mouse

• Lung

Peh et al. (2015, 2017)

Cell culture treatment [10 nM]

• Human

• RT7 Oral keratinocyte cell line

Takano et al. (2015)

Intraperitoneal injection [100 mg/kg body weight]

• Mouse

• Lung

Duan et al. (2017)

Gene symbols are italicized and with the first letter in upper-case. Protein symbols are in capital letters and not italicized. m, upregulation; k, downregulation; 2, no change in expression.

44

CHAPTER 2 NUTRIGENOMICS AND ANTIOXIDANTS

(Molina-Jijo´n et al., 2015; Shi et al., 2017, 2018b; Wang et al., 2007). While the findings require further studies, it is suggested that the structure, interaction with the other compounds, concentration, and partial pressure of oxygen may contribute to the observed antioxidant and pro-oxidant properties (Young and Lowe, 2001).

2.4.2 VITAMIN C Vitamin C, also known as ascorbic acid or L-ascorbic acid, is a water soluble vitamin and an essential component of human diet. Unlike most animals, humans and primates are not able to synthesize ascorbic acid endogenously owing to mutations in gulonolactone oxidase, rendering the terminal enzyme involved in the ascorbic acid biosynthetic pathway nonfunctional. While approximately 70%
90% of the dietary vitamin C intake is ordinarily absorbed, the human body pool of ascorbic acid undergoes steady-state turnover via tightly-regulated intestinal absorption, renal tubule reabsorption, and ascorbic acid catabolism (Padayatty and Levine, 2016). Intestinal ascorbic acid absorption is inverse dose-dependent. The process, being regulated by active transporters, gives rise to higher ascorbic acid absorption with lower dietary intake. Meanwhile, the renal tubule reabsorption and ascorbic acid catabolic rate are directly related to the body pool size. Excess ascorbic acid in the body may be filtered at the renal glomeruli and excreted from the body via urine. In the body, ascorbic acid catabolism mainly involves oxidation to dehydroascorbic acid. Dehydroascorbic acid may subsequently be oxidized to L-xylose, threonic acid, and oxalic acid for urinary excretion, or reduced back to ascorbic acid via the action of glutathione or reduced nicotinamide-adenine-dinucleotide system (Chazot and Kopple, 2013; Litwack, 2017). Most of the ascorbic acid’s biological properties are associated to its redox functionalities. Ascorbic acid prevents the oxidation of loosely bound ferrous iron to its ferric form, thereby keeping the enzyme prolyl hydroxylase in an active state. The prolyl hydroxylase enzyme is involved in the hydroxylation of proline and lysine, which are important components of procollagen molecule, the precursor molecule to the protein collagen (Pullar et al., 2017). In addition, ascorbic acid demonstrates similar redox properties in catecholamine biosynthesis and microsomal cytochrome P450 enzyme activity (Aranibar et al., 2009; Figueroa-M´endez and Rivas-Arancibia, 2015). At a high concentration, however, ascorbic acid may also exhibit bimodal activity being a pro-oxidant (Chakraborthy et al., 2014). The present nutrigenomics analysis on Keap1-Nrf2 pathway revealed similar findings (Table 2.1). Ascorbic acid may either induce, has no effect, or disrupts the activation of Keap1-Nrf2 pathway (Lawal et al., 2011; Kim et al., 2015; Ge˛gotek et al., 2017; Chang et al., 2015; Wagner et al., 2010). While some of the discrepancies may be explicated by experimental design and methodology flaws, the roles of ascorbic acid in triggering and protecting against oxidative damage remain to be addressed in future studies (Carr and Frei, 1999).

2.4.3 VITAMIN D Being a group of fat-soluble secosteroids, vitamin D is unique as it can either be produced in the human body or be derived from th diet. Briefly, vitamin D exists in two forms. Vitamin D3 (cholecalciferol) is the form synthesized by the human skin from a cholesterol-like precursor (7-dehydrocholesterol) in response to sunlight exposure. On the other hand, the dietary form comprises of

2.4 NUTRIGENOMIC BASIS OF ANTIOXIDANT VITAMINS

45

both vitamin D3 and vitamin D2 (ergocalciferol). Vitamin D3 is obtained from animal sources while D2 is a molecule of plant origin, deriving from the UV-irradiated fungal and plant sterol ergosterol (Black et al., 2017). Vitamin D, either be produced in the skin or ingested from diet, is packaged into chylomicrons and transported into the blood circulation through the lymphatic system. In the liver, vitamin D undergoes hydroxylation to form 25(OH)D by mitochondrial and microsomal vitamin D-25-hydroxylases. Once 25(OH)D is formed, it is further metabolized in the kidney into the biologically active 1,25(OH)2D. The production of 1,25(OH)2D maintains normal levels of calcium and phosphorus in the serum, thereby helping in optimizing bone health and sustaining a wide range of metabolic and physiological processes (Nair and Maseeh, 2012; Ovesen et al., 2003). Other than maintaining normal calcium metabolism, the different forms of vitamin D also exhibit efficient antioxidant activity and reduce free-radical damage (Mokhtari et al., 2017; Ke et al., 2016). It is suggested that the various forms of vitamin D shared a close molecular relationship to that of cholesterol and ergosterol, hence forming a structural basis for the observed antioxidant properties (Wiseman, 1993). Nutrigenomic studies revealed that the biologically active 1,25 (OH)2D may cross the plasma membrane and interact with the specific vitamin D receptor. This ligand-receptor complex may subsequently enhance transcription of mRNAs which code for antioxidant response element via Nrf2 transcription factor activation (Manna et al., 2017; Wang et al., 2016; Teixeira et al., 2017; Zhu et al., 2017b).

2.4.4 VITAMIN E Vitamin E comprises a family of naturally occurring compound homologues. The tocopherol homologues (alpha-, beta-, gamma- and delta-forms) contain a 16-carbon phytyl side chain, whereas tocotrienols homologues (alpha-, beta-, gamma- and delta-forms) are unsaturated and have three double bonds in the carbon side chain. The synthetic 2R-stereoisomer forms of α-tocopherol, mainly differentiated by phytyl chain rotations in various directions that do not occur naturally, are also widely available (Me`ne-Saffran´e and DellaPenna, 2010). Being a fat-soluble vitamin, efficient intestinal absorption of vitamin E involves effective emulsification, proper solubilization within mixed bile salt micelles, followed by enterocytes uptake and secretion into blood circulation through the lymphatic system. While the absorption processes of all the tocopherol homologues are similar, the α-form predominates in blood and tissue. The other tocopherols are preferentially catabolized in the liver. Thus, although vitamin E represents the collective term for a group of structurally related compounds, the appropriate recommended dietary allowance is only based on the α-tocopherol form as it is conceived to be the most biologically active (Schmo¨lz et al., 2016). The antioxidant properties of vitamin E, being a peroxyl radical scavenger that terminates the lipid peroxidation chain reactions, are well described. In general, all the different isoforms of citamin E (except α-tocopherol) possess similar antioxidant functions with the rate constants for hydrogen atom, donating ability falls within one order of magnitude. Interestingly, α-tocopherol has always been demonstrating greater potency versus the other isoforms, across the different in vitro chemical testing systems (Traber and Atkinson, 2007). While the antioxidant efficacy of α-tocopherol and the other isoforms of vitamin E in biological membranes remain to be established, the differences in α-tocopherol potency in comparison to the other isoforms in vivo may be due to hepatic discrimination favoring α-tocopherol. In the present

46

CHAPTER 2 NUTRIGENOMICS AND ANTIOXIDANTS

review, both α-tocopherol and γ-tocotrienol induce NRF2 pathway activation (Peh et al., 2015, 2017; Takano et al., 2015; Duan et al., 2017). While synthetic alpha tocopherol acetate exerts differential effects on antioxidant genes expression (Sun et al., 2018) and a surplus of vitamin E does not affect NRF2 signaling (Eder et al., 2017), a mixture of different vitamin E isoforms demonstrated protective effects against oxidative stress (Shang et al., 2018).

2.5 NUTRIGENOMIC BASIS OF ANTIOXIDANT MINERAL ELEMENTS Minerals are inorganic substances necessitated for the normal functioning of the body. The major minerals (calcium, phosphorus, sodium, potassium, chloride, and magnesium) and trace minerals (iron, zinc, selenium, chromium, and molybdenum) are needed in small amounts for a variety of functions. While minerals are essential dietary constituents, they can promote free-radical formation by acting as pro-oxidants. Reactive transition metals such as iron and copper may propagate the formation of reactive radicals, thereby causing an imbalance between reactive radicals and antioxidant/scavenging defense systems. Thus, iron and calcium are usually kept bound to the transferrin or ceruloplasmin transport protein, rendering them less available to promote oxidative damage. Mineral elements, on the other hand, are also important components for the body antioxidant functions. Preventive antioxidants, including catalase (iron-containing) and GPx (selenium-containing), require the presence of minerals to suppress formation of free radicals by decomposing hydrogen peroxide. The nutrigenomic effects of various minerals in affecting the cross-talk between Nrf2 and NF-κB signaling are shown in Table 2.2.

2.5.1 MAGNESIUM Being an important enzyme cofactor, magnesium is needed for the modulation of diverse biochemical reactions including protein synthesis, bone metabolism, muscle and nerve functions, as well as blood pressure regulation. Magnesium deficiency has been shown to associate with oxidative stress development, particularly by inducing stress response, triggering systemic inflammatory response,s and increasing the amount of easily oxidized lipoproteins. The interrelationship and homeostasis between magnesium with calcium, potassium, and sodium have been shown to play a key role in the regulation process (Zheltova et al., 2016). While an excessive dose of magnesium may result in serious side effects, Han et al. reported that magnesium sulfate may be beneficial in intrahepatic cholestasis of pregnancy via NRF2 signaling activation (Han et al., 2018a). Appropriate dose and course of magnesium sulfate administration, however, need to be properly considered.

2.5.2 MOLYBDENUM Sulfite oxidase, xanthine oxidase, and aldehyde oxidase are some of the molybdenum cofactordependent enzymes. The enzymes are involved in sulfur amino acid, purine, and aldehyde metabolism. While molybdenum deficiency in humans is uncommon, it mainly relates to prolonged total parenteral nutrition and genetic defects interfering with the molybdoenzymes activation. Molybdenum application has been reported to enhance antioxidant defense in plants (Wu et al., 2017; Al-Issawi et al., 2016).

Table 2.2 Nutrigenomics Implications of Antioxidant Minerals Nutrigenomics Implications Experimental Model Description of Antioxidant-RNA/ Protein Interaction

Regulated RNA/Protein Expressions

Mode of Treatment [Concentrations]

Magnesium

Magnesium sulfate induces Nrf2 activation.

m NRF2, PRDX6 k IL-1β, TNF-α, IFN-γ

Manganese

Manganese (II) chloride induces Nrf2 activation.

m NRF2 (cytosolic & nuclear), HO-1

Intraperitoneal injection [270 mg/kg body weight] Cell culture treatment [300 μM]

Antioxidant

Selenium

• Rat

• Placenta

Han et al. (2018a)

• Rat

• PC12 Pheochromocytoma cell line

Li et al. (2011a,b), Zhang et al. (2017a) da Silva Santos et al. (2014) Bahar et al. (2017)

• Rat

• Primary cultures of astrocytes

m TNF-α, IL-1β, IL-6, COX2, iNOS, Nfκb, Ho-1, Nrf2

Intraperitoneal injection [15 mg/kg body weight] Intraperitoneal injection [25 mg/kg body weight; 4 or 8 doses] Feeding trial [3.65
27.86 mg/kg diet]

• Rat

• Brain

• Rat

• Brain

Santos et al. (2012)

• Grass carp

• Intestine and muscle

Jiang et al. (2015, 2016)

Cell culture treatment [30 μM]

• Human • Mouse

• Human gastric cancer cell lines • Xenografts

Gong and Li (2016)

Feeding trial [2.0 mg/kg diet]

• Chicken

• Spleen

Chen et al. (2017)

Cell culture treatment [1.0 μM]

• Chicken

• Primary cultures of hepatocytes

Zhang et al. (2017b)

Cell culture treatment [5 μM]

• Human

• Human esophageal squamous cell carcinoma cell line

Liu et al. (2015)

Low- and high-doses of manganese sulfate disrupt NRF2 signaling

Low- and high-dose m Il-8, Tnf-α, Nfκb 2 Keap1 k Nrf2, Il-10, Tgf-β, Iκb, Tor, Mn-Sod, Cat, Gpx, S6k1 m SBP1 k NRF2, β-CATENIN, CMYC, GSK-3β, CYCLIND1 m KEAP1, GPX1, TRXR1 k NRF2, HO-1 m Nrf2, Nqo1, Gst, Gclc, Gclm 2 Ho-1 m NRF2 k KEAP1

Methylseleninic acid activates Nrf2 signaling

References

Cell culture treatment [500 μM]

m Mn-SOD (low dose) 2 NRF2, Mn-SOD (high dose)

Sodium selenite induces Nrf2 signaling activation

Tissue/Cell Line

m NRF2

Dose dependent antioxidant/prooxidant activity of managnese (II) chloride.

Sodium selenite suppresses Nrf2 signaling activation

Species

(Continued)

Table 2.2 Nutrigenomics Implications of Antioxidant Minerals Continued Nutrigenomics Implications Experimental Model Antioxidant

Chromium

Description of Antioxidant-RNA/ Protein Interaction

Regulated RNA/Protein Expressions

Mode of Treatment [Concentrations]

Optimum selenium in the diet did not affect Nrf2 signaling.

m GPX1, TRXR1 2 HO-1, NQO1 k NRF2 m Nrf2, Sod1, Sod2, Tnf-α, Il8, Il-1β, Ifn-γ

Potassium dichromate induces NRF2 signaling activation.

Species

Tissue/Cell Line

References

Feeding trial [ , 0.01
0.18 mg/ kg diet]

• Mouse

• Liver

da Silva Santos et al. (2014)

• Zebrafish

• Gills

Yin et al. (2018)

• Rat

• Liver

Kalayarasan et al. (2008)

m NRF2 k NFκB

Treatment concentration [15 mg/L] Single subcutaneous injection [17 mg/kg body weight] Feeding trial [200 μg/kg diet]

• Chicken

• Muscle

Sahin et al. (2017)

m NRF2, IκB k NFκB, HNE

Feeding trial [8 μg/ day]

• Rat

• Brain • Kidney

m NRF2, HO-1, GLUT2 k NFκB/p65, HNE m NRF2, SOD2, GCLC, HO1, CAS-3

Feeding trial [8 μg/ day]

• Rat

• Liver

Sahin et al. (2012), Selcuk et al. (2012) Tuzcu et al. (2011)

Cell culture treatment [3.12550 μM] Cell culture treatment [1
5 μM]

• Human

• Human liver HepG2 cell line

Das et al. (2015)

• Human

• Human bronchial epithelial BEAS-2B cell line

Roy et al. (2016)

Cell culture treatment [2
100 μM]

• Mouse

• Hepatoma Hepa1c1c7 cell line

He et al. (2007)

Feeding trial [30 mg/kg diet]

• Rat

• Brain

Aguirre and Culotta (2012)

m NRF2

Chromium picolinate and chromium histidinate induces NRF2 signaling activation under heat stress. Chromium picolinate and chromium histidinate induces NRF2 signaling activation in diabetic rats. Chromium histidinate induces NRF2 signaling activation in obese rats. Hexavalent chromium [Cr(VI)] induces NRF2 signaling activation. Hexavalent chromium [Cr(VI)] induces NRF2 signaling activation.

Molybdenum

Hexavalent chromium [Cr(VI)] activates gene transcription as a cellular defense against Cr(VI)induced toxicity. Molybdenum dehydrate (high dose) promote toxicity via oxidativeinflammatory mechanisms.

m NRF2, COX-2, TNF-α, pIκBα, pNF-κBα/p65, NFκBα/p65 (nuclear) k IκBα m NRF2, HO-1, NQO1, MT1 2 CYP1A1 m Tnf-α 2 Nrf2

Zinc

Zinc sulfate induces Nrf2-mediated antioxidants effect. Zinc sulfate induces Nrf2-mediated antioxidants effect. Zinc hydroaspartate did not induce NRF2 activation.

Zinc sulfate

Zinc sulfate heptahydrate

Zinc carbonate

Zinc carbonate Zinc sulfate

Zinc sulfate Zinc sulfate

m NRF2, p-AKT, Zn/CuSOD, Mn-SOD, HO-1 2 GPX1 m NRF2 2 miR-122, miR-34a m MTs, GPR3, 2 NRF2, HO-1, BDNF m NRF2 (nuclear), HO-1 2 NRF2 (cytosolic) k Il-1β, Il-18, CASPASE-1, NLRP3 m NRF2, HO-1, BCL-2, PCNA, SOD1, MT, GPX5 2 COX-2 k NF-κBα, IL-6 m NRF2, SOD1, SOD2, NQO1, p-AKT, p-GSK-3β, FYN (cytosolic) k PAI-1, TNF-α, CTGF, TGF-β1, FYN (nuclear) m NRF2, Cat, Nqo1, Mt k CTGF, 3-NT, 4-HNE 2 NRF2, Mt-1a, Mt-1e, Mt2a m Nrf2, Nqo1 2 Keap1, Gclc m Nqo1, Gclc, 2 Keap1, Gclc

Cell culture treatment [25 μM]

• Human

• Human Chondrosarcoma SW1353 cell line

Huang et al. (2018)

Intraperitoneal injection [5 mg/kg body weight] Oral gavage [15 mg/ kg body weight]

• Rat

• Liver

Mard et al. (2017)

• Rat

• Brain

Omar and Tash (2017)

Cell culture treatment [25 μM]

• Human

• Human peritoneal mesothelial HMrSV5 cell line

Fan et al. (2017)

Feeding trial [10 & 30 mg/kg drinking water]

• Rat

• Testis

Maremanda et al. (2016)

Feeding trial [0.85
150 mg/kg diet]

• Mouse

• Kidney

Yang et al. (2017)

Feeding trial [10
90 mg/kg diet]

• Mouse

• Aorta

Chen et al. (2016)

Cell culture treatment [5
100 μM] Feeding trial [300 mg/kg diet]

• Bovine

• Aortic endothelial cells

Fujie et al. (2016)

• Mouse

• Liver

Wang et al. (2015)

Cell culture treatment [50 μM]

• Rat

• Renal tubular epithelial NRK-52E cell line

Gene symbols are italicized and with the first letter in upper-case. Protein symbols are in capital letters and not italicized. m, upregulation; k, downregulation; 2, no change in expression.

50

CHAPTER 2 NUTRIGENOMICS AND ANTIOXIDANTS

The causal effect of human molybdenum dietary intake and protection against oxidative damage, however, remains to be elucidated (EFSA Panel on Dietetic Products NaAN, 2010). In particular, it is of concern that Helaly et al. reported a high dose of molybdenum dehydrate (30 mg/kg/day) which may promote brain toxicity in rats via oxidative-inflammatory mechanisms. Both the hippocampal and frontal regions of the rat treated with molybdenum dehydrate showed upregulation in interleukin 6 protein expression and TNF-α gene expression while NRF2 signaling remains unaffected (Helaly et al., 2018).

2.5.3 MANGANESE Manganese is commonly found in food sources including nuts, legumes, seeds, tea, whole grains, and leafy green vegetables. Although the body could store up to 20 mg of manganese in several important organs such as kidneys, liver, pancreas, and bones, dietary intake serves as an important source for manganese. The antioxidant effect of manganese, particularly being the cofactor for SOD enzymes, is well studied. Additionally, manganese may contribute against oxidative damage via the formation of nonproteinaceous manganese-containing antioxidant complexes. The mineral has an advantage over iron as it owns higher reduction potential and hence, less prone to propagation of reactive hydroxyl radicals (Coassin et al., 1992; Aguirre and Culotta, 2012; Reddi and Culotta, 2011). Nutrigenomic studies revealed concentration-related effects of manganese (II) chloride on NRF2 activation in rats (Li et al., 2011a,b; Zhang et al., 2017a; da Silva Santos et al., 2014; Bahar et al., 2017; Santos et al., 2012). Peculiarly, both low- and high-doses of manganese sulfate, however, disrupt the NRF2-NF-κB signaling in grass carp (Jiang et al., 2015, 2016). While the present nutrigenomic analyses may be subject to the difference in chemical compositions and testing organisms, it would be necessary to assess the likely value of possible further research.

2.5.4 SELENIUM Selenium, one of the essential trace elements in human biological system, has been widely promoted as a dietary supplement for health benefit. Naturally found in water, soil, and some common food, both the organic and inorganic forms of selenium are readily being absorbed by the small intestine; in turn they render normal metabolic functions via regulating the synthesis of selenoproteins and selenoenzymes. The mineral serves as an important cofactor for numerous antioxidant enzymes, including GPx, thioredoxin reductase, and iodothyronine deiodinases (Tinggi, 2008; Baraboĭ and Shestakova, 1999). Though selenium is generally considered as an important component for antioxidant enzyme production and may play a key role in the treatment of hyperlipidaemia, hyperglycemia, and hyperphenylalaninemia, its potential toxicity due to overdosing is also of particular concern. Chemically, selenium rapidly induces formation of intramolecular disulfide bond with cysteine residues or thiol groups in substrates, ensuing indirect ROSs generation and oxidative damage. Selenium overdose may increase oxidizing cellular environment, trigger genome instability and DNA damage, lead to initiation of cell apoptosis, and can be lethal (Wang et al., 2017). Nutrigenomic studies of selenium treatment on antioxidant NRF2 protection revealed mixed responses. Both Gong et al. and Chen et al. reported that sodium selenite suppresses NRF2regulated antioxidant response (Gong and Li, 2016; Chen et al., 2017). NRF2 signaling was not

2.6 NUTRIGENOMIC BASIS OF ANTIOXIDANT PHYTOCHEMICALS

51

affected by optimum selenium in the diet as well (Dong et al., 2016). On the other hand, Zhang et al. reported NRF2-mediated protection on primary cultures of hepatocytes while Liu et al. demonstated that methylseleninic acid may trigger NRF2 pathway activation in human esophageal squamous carcinoma cells (Zhang et al., 2017b; Liu et al., 2015). Given the present experimental data, the issue on chemical forms of selenium and dosage intake shall be taken into serious consideration while promoting the use of selenium as a nutritional supplement or therapeutic agent.

2.5.5 CHROMIUM Chromium is naturally found in a wide variety of food sources including fruits, vegetables, and whole grain products. The mineral is essential for carbohydrate and lipid metabolism, as well as demonstrating a beneficial role in the regulation of insulin action. The bioavailability, however, is affected by the different forms of chromium. In brief, organic chromium such as chromium picolinate, chromium nicotinate, chromium methionine, and chromium yeast have greater bioavailability (in the range of 10%
25%) in comparison to inorganic chromium including chromium chloride and chromium oxide (in the range of 0.5%
2%) (Mertz, 1969; Haq et al., 2016) (Table 2.3). Despite the fact that different forms of chromium have diverse bioavailability, all of them demonstrated similar nutrigenomics findings. Treatment with either potassium dichromate, chromium picolinate, chromium histidinate, or hexavalent chromium [Cr(VI)] induces the activation of NRF2antioxidant signaling and attenuates NF-κB-inflammatory responses across different organisms, tissue, and cell types (Yin et al., 2018; Kalayarasan et al., 2008; Sahin et al., 2012, 2017; Selcuk et al., 2012; Tuzcu et al., 2011; Das et al., 2015; Roy et al., 2016; He et al., 2007). The nutrigenomics findings, along with the wide safety profile of chromium, may further justify its use as an efficacious therapeutic or dietary supplement agent.

2.6 NUTRIGENOMIC BASIS OF ANTIOXIDANT PHYTOCHEMICALS 2.6.1 POLYPHENOLS Being one of the most abundant antioxidants, polyphenols are widely found in dietary sources including fruits, vegetables, grains, spices, and herbs. Polyphenols are ordinarily classified based on aromatic ring(s) bearing one or more hydroxyl moieties. Among polyphenols, different structural variants exist. The secondary metabolites of plants may range from simple to highly polymerized molecules with complex structures which in turn, impart varying biological activities. The phenolic acids, further grouped into benzoic acid and cinnamic acid derivatives, are among the largest that account for about a third of the polyphenolic compounds (Santhakumar et al., 2018). Hydroxybenzoic acids include benzoic acid, protocatechuic acid, vanillic acid, and syringic acid. Benzoic acid-derived phenolic acids are structurally simple. The variations merely comprise of aromatic ring hydroxylations and methylations. Nevertheless, intramolecular hydrogen bonding, such as the structure and position of hydroxyl group to carboxylate group, is important for antioxidant activity. It was reported that hydroxybenzoic acids with hydroxyl group in ortho and para position are effective scavengers against superoxide radicals (Velika and Kron, 2012). Nutrigenomics studies on hydroxybenzoic acids derivatives revealed that the compounds may also act to

Table 2.3 Nutrigenomics Implications of Phytochemicals Nutrigenomics Implications Experimental Model Phytochemicals

Description of Antioxidant-RNA/ Protein Interaction

Regulated RNA/Protein Expressions

Mode of Treatment [Concentrations]

Species

Tissue/Cell Line

References

Phenolic acid—hydroxybenzoic acids Benzoic acid

2-Hydroxy-4-methoxy benzoic acid induces antioxidant enzyme activities

Protocatechuic acid

Protocatechuic acid ameliorates oxidative damage via NRF2 activation Protocatechuic acid increases expression of antioxidant enzymes and Nrf2

Vanillic acid

Vanillic acid attenuates oxidative stress via activation of NRF2

Syringic acid

Syringic acid enhances Nrf2 expression in cytosolic and nuclear fractions

m HO-1, IL-1β k TNF-α, IL-6, IL-10, MPO m SOD, GPX, HO-1, p-AMPK (Thr172), pNRF2

Oral gavage [200 mg/kg body weight]

• Rat

• Liver

Alshammari et al. (2017)

Cell culture treatment [10
100 μM]

• Human

Han et al. (2018b)

m CAT, SOD1, NRF2 k Il-6, Il-1β, Tnf-α, Cox-2, p-AKT, pERK1/2, pSTAT3, NF-κB m GSH, NRF2, HO-1, p-AKT (Ser473), GSK3β (Ser9) k BAX, CAS-3, PARP-1 m NRF2 (nuclear & cytosolic), GSH, GPX, CAT 2 iNOS k CYP2E1, ADH, GSSG, IL-6, TNF-α, COX-2, NF-κB p65

Intraperitoneal injection [30 & 60 mg/kg body weight]

• Mouse

• Human umbilical vein endothelial cells (HUVECs) • Colon

Intraperitoneal injection [30 mg/kg body weight]

• Mouse

• Brain

Amin et al. (2017)

Oral gavage [40 & 80 mg/kg body weight]

• Mouse

• Liver

Yan et al. (2016)

m NRF2 (nuclear & cytosolic), GSH, GPX, CAT 2 iNOS k CYP2E1, ADH, GSSG, IL-6, TNF-α, COX-2, NF-κB p65 m NRF2, HO-1, γ-GCLC 2 p-c-JUN k p-c-FOS m SOD, eNOS, Nrf2 k NO

Oral gavage [40 & 80 mg/kg body weight]

• Mouse

• Liver

Yan et al. (2016)

Cell culture treatment [20
100 μM]

• Human

• Human foreskin fibroblast-derived (Hs68) cells

Hseu et al. (2018)

Cell culture treatment [20 μmol/L]

• Human

• Human brain microvascular endothelial cells

Li et al. (2016)

Crespo et al. (2017)

Phenolic acid—hydroxycinnamic acids Cinnamic acid

Cinnamic acid enhances Nrf2 expression in cytosolic and nuclear fractions

Trans-cinnamic acid induction activation of Nrf2-mediated antioxidant genes Cinnamic acid upregulates antioxidant enzymes gene expression by NRF2 activation

Ferulic acid

Ferulic acid activates PI3K/Aktmediated Nrf2/HO-1 signaling pathway

m SOD, HO-1, NRF2, p-AKT

Cell culture treatment [5
20 μM]

• Rat

Ferulic acid modulates the colocalization of NF-κB and Nrf2 in nuclei of duodenal cells

m SOD, CAT, GSH, HO-1, NRF2 (nuclear), NF-κB (nuclear), k p-IKBα, COX-2, IL-6, IL-8, TNF-α, NRF2 (cytosolic) m p65 NF-κB (cytosolic) k p65 NF-κB (nuclear), p-IKK, TAK1, NRF2

Oral gavage [50 mg/kg body weight]

• Mouse

Cell culture treatment [100 μM]

• Mouse

m CAT, Mn-SOD, Zn-SOD, NRF2, KU70 k pATM, p53, Gadd45a m Ho-1, Gst, NRF2 k KEAP1

Oral gavage [50 mg/kg body weight]

• Mouse

Cell culture treatment [1
10 μg/mL]

• Rat

m Ho-1, NRF2, p-ERK

Cell culture treatment [0.001-0.1 μM]

• Human

m GSH, p-ERK, NRF2 (nuclear), Gclc, Gclm, Nqo, Ho-1 k NRF2 (cytosolic) m NRF2 (nuclear), NF-κB (cytosolic), HO-1, SOD, GPX, IκB-α 2 NRF2 (cytosolic) k IL-6, TNF-α, IL-1β, NF-κB (nuclear), pIκB-α m NRF2 (nuclear), pNRF2, HO-1, NQO1, p62, pERK1/2, PP2A-A, PP5, Gclc 2 NRF2 (cytosolic), KEAP1, MKP3, Gclm m NRF2, HO-1, NQO1, GCLC, GSH, SOD, CAT k NLRP3, Pro-CASPASE-1, CASPASE1, Pro-IL-1β, IL-1β, TNF-α, IL-6 m NRF2 (nuclear), HO-1, p-AKT k NRF2 (cytosolic), AKT

Cell culture treatment [0.2
5 μM]

• Human

Oral gavage [10 mg/kg body weight]

Ferulic acid regulates both NF-κB and NRF2 responses

Ferulic acid induces upregulation of NRF2 expression Ferulic acid regulates Keap1-Nrf2-ARE signaling pathway Ferulic acid induces NRF2 nuclear translocation and transcriptional activity

Chlorogenic acid

Chlorogenic acid induces the activation of Nrf2/HO-1

Chlorogenic acid activates Nrf2 antioxidative signaling pathway

Chlorogenic acid enhances Nrf2mediated antioxidant pathway

• Rat intestinal epithelial (IEC-6) cells • Intestinal epithelial cells

He et al. (2019)

• Murine macrophage-like RAW 264.7 cell line • Liver

Lampiasi and Montana (2018) Das et al. (2017b)

• Primary rat hepatocyte & cardiomyocyte • Human lymphoblastoid AHH-1 cell line • Human umbilical vein endothelial cells (HUVECs)

Song et al. (2016)

• Rat

• Kidney

Bao et al. (2018)

Cell culture treatment [10
50 μM]

• Human

• Human fetal hepatocyte L-02 cell line

Wei et al. (2017)

Oral gavage [60 mg/kg body weight]

• Rat

• Liver

Shi et al. (2018a)

Cell culture treatment [25
100 μM]

• Mouse

• Mouse osteoblastic MC3T3-E1 cell line

Han et al. (2017)

Das et al. (2017a)

Ma et al. (2011) Ma et al. (2010)

(Continued)

Table 2.3 Nutrigenomics Implications of Phytochemicals Continued Nutrigenomics Implications Experimental Model Phytochemicals

Description of Antioxidant-RNA/ Protein Interaction

Regulated RNA/Protein Expressions

Mode of Treatment [Concentrations]

Species

Tissue/Cell Line

References

m NRF2 k MMP9, p65 (nuclear), p65 (cytosolic), EGR1 (nuclear), EGR1 (cytosolic), SERPINE1, TF, Il-1β, Tnfα m NRF2, GSH, SOD, CAT, Ho-1, Gclc, Nqo1 k CYP2E1 m GSH, Nrf2, Prx1,2,3,5,6, Ephx2, Polr2k, 2 Prx4, Fmo5, Mt1, Mt2, Sod1, Sod2

Oral gavage [20 mg/kg body weight]

• Rat

• Liver

Zheng et al. (2016)

Oral gavage [60 mg/kg body weight]

• Rat

• Liver

Shi et al. (2016)

Cell culture treatment [10
40 mg/kg]

• Human

• Human fetal hepatocyte L-02 cell line

Pang et al. (2015)

Oral gavage [10
100 mg/kg body weight] Cell culture treatment [5
20 μmol/L]

• Mouse

• Liver

Singh et al. (2019)

• Human

Liu et al. (2019a)

m GSH, SOD, CAT, HO-1, NRF2, AP-1 2 NF-κB

Cell culture treatment [5 μM]

• Human

m NRF2 (cytosolic), 2 NF-κB p50 (cytosolic & nuclear), NF-κB p65 (nuclear) k NRF2 (nuclear), NF-κB p65 (cytosolic), SOD1, 5-LO m NRF2, CAT, GSH, GPX, SOD k KEAP1

Cell culture treatment [25 μM]

• Human

• SH-SY5Y Neuroblastoma cells • Human hepatocarcinoma HepG2 cell line Human acute promyelocytic leukemia NB4 cells

Feeding trial [0.03% diet]

• Rat

• Heart, Lung, Kidney

Li et al. (2018a)

Intraperitoneal injection [20 & 40 mg/kg body weight] Intraperitoneal injection [30 mg/kg body weight]

• Rat

• Cerebral cortex

Gao et al. (2018)

• Rat

• Lung

Wang et al. (2018b)

Oral gavage [10 mg/kg body weight]

• Mouse

• Heart

Wang et al. (2018a)

Flavonols Rutin (Quercetin3-O-rutinoside)

Rutin modulates Nrf2 expression in a dose-dependent manner

m Nrf2, GPX, GR, GST, GSH, SOD k iNOS

Quercetin

Quercetin exerts neuroprotection by mediating activation of Nrf2/ARE pathway Quercetin attenuates oxidative stress by activation of NRF2

m GLO-1, NRF2, p-NRF2, γ-GCS

Quercetin enhances the levels of proinflammatory NF-kB p65 in the nucleus but not NRF2 level

Resveratrol

Resveratrol protects against oxidative stress by activating the Keap1/Nrf2antioxidant defense system

m NRF2, GPX, SOD, CAT, HO-1 k TNFα, IL-β, IL-6, NF-κB p65 m NRF2, IL-10, SOD, p-AKT, HO-1 2 AKT k MIP-2, IL-18, CASPASE 3 m NRF2, HO-1, MT, SOD1, SOD2, NQO1 k 3-NT, 4-HNE

Lee et al. (2018) Rubio et al. (2018)

Kaempferol

Kaempferol modulates Nrf2 signaling pathway

m NRF2, GPX, CAT, SOD k GSK3β m NRF2, GSH, SOD, CAT, GPX, GCLC, UGT1A1 2 BCL-2 k HO-1, NITROTYROSINES, TNFα, IL-6, BAX20, CYP2E1

Intraperitoneal injection [21 mg/kg body weight]

• Rat

• Brain

Hussein et al. (2018)

Intraperitoneal injection [125 mg/kg body weight]

• Mouse

• Liver

Tsai et al. (2018)

m NRF2 (nuclear), GSH, SOD, HO-1, k NRF2 (cytosolic), KEAP1

Cell culture treatment [10
40 μM]

• Human

Zhu et al. (2017a)

m NRF2 (nuclear), HO-1, IκBα k NRF2 (cytosolic), KEAP1, IL-6, IL-1β, iNOS, COX-2, p-IκBα, P-NFκB (p65) m NRF2, k TNF-α, NF-κB, PCNA, CYP1A1 m NRF2, HO-1, GSH, SOD, CAT, PPAR-γ k NFκB, TNF-α, COX-2 m NRF2, HO-1, GSH, SOD, GPX, GST, PPAR-γ k NFκB, TNF-α, p-SMAD3 m NRF2 (nuclear), HO-1, p-AKT, pGSK3β 2 AKT, GSK3β, NF-κB p65 (total), IκBα k NF-κB p65 (nuclear), RAGE, p-IκBα m NRF2, SOD, CAT, GPX, GR, G6PD k KEAP1 m NRF2 (nuclear), HO-1, pERK1/2 2 NRF2 (cytosolic), pJNK1/2, pp38

Cell culture treatment [10
40 μM]

• Mouse

• Human retinal pigment epithelial (ARPE-19) cells • Mouse macrophage RAW 264.7 cell line

Oral gavage [50 mg/kg body weight]

• Mouse

• Lung

Bodduluru et al. (2015)

Oral gavage [100 mg/kg body weight]

• Rat

• Gastric mucosa

Elshazly et al. (2018)

Oral gavage [50
100 mg/kg body weight]

• Rat

• Liver

Mahmoud et al. (2017)

Oral gavage [20
80 mg/ kg body weight]

• Mouse

• Cerebral cortex

Hong and An (2018)

Oral gavage [100 mg/kg body weight]

• Rat

• Heart

Elavarasan et al. (2012)

Cell culture treatment [20
80 mg/kg]

• Human

• Human fetal hepatocyte L-02 cell line

Chen et al. (2010a,b)

Flavanones Hesperetin

Hesperidin

Hesperetin upregulates the Keap1-Nrf2/ HO-1 signal pathway

Hesperidin mediates activation of Nrf2/ ARE/HO-1 pathway

Ren et al. (2016)

(Continued)

Table 2.3 Nutrigenomics Implications of Phytochemicals Continued Nutrigenomics Implications Experimental Model Phytochemicals

Description of Antioxidant-RNA/ Protein Interaction

Regulated RNA/Protein Expressions

Mode of Treatment [Concentrations]

Species

Tissue/Cell Line

References

Flavones Luteolin

Luteolin mediates PI3K/AKT/Nrf2 signaling pathway

m NRF2, p-NRF2, pERK1/2 2 p-JNK m Nrf2, Trx1, Park2 2 TNF-α, Pink1 k IL-1β, Lrrk2 m NRF2 (nuclear), GSH, HO-1, NQO1, NF-κB (cytosolic), p-PI3K, p-AKT 2 PI3K k NF-κB (nuclear), TNF-α, AKT m NRF2 (nuclear), p-AKT, p-GSK3β, Ho-1, Nqo1 k FYN (nuclear) m NRF2 (total & nuclear), HO-1, NQO1, SOD, GSH, BCL-2, IκBα, NF-κB (cytosolic), p-AKT k NF-κB (nuclear), TNF-α, IL-6, IL-1β, p-IKKα 2 GPX, SOD, CAT k NRF2, NF-κB, CTnl, KIM-1

Cell culture treatment [1
100 nM]

• Human

• Human Hepatoma HepG2 Cells

Kitakaze et al. (2019)

Cell culture treatment [1
20 μM]

• Mouse

• Murine microglial BV2 cells

Elmazoglu et al. (2018)

Oral gavage [80 mg/kg body weight]

• Rat

• Heart

Baiyun et al. (2018)

Oral gavage [100 mg/kg body weight]

• Rat

• Heart

Yang et al. (2018)

Oral gavage [100 mg/kg body weight]

• Mouse

• Lung

Liu et al. (2018)

Oral gavage [100
200 mg/kg body weight]

• Rat

• Kidney, heart

Oyagbemi et al. (2018)

m NRF2, HO-1, SOD, GPX

Cell culture treatment [12.5
100 μmol]

• Rat

He et al. (2018)

m NRF2, Lc3, Caspase-9

Cell culture treatment [12.5 μM] Intraperitoneal injection [5 mg/kg body weight]

• Human

• Primary cultured cerebral cortical neurons • Colon cancer HCT-116 cell line • Bladder smooth muscle

Flavan-3-ols Epigallocatechin gallate (EGCG)

m NRF2 (total & nuclear), HO-1, NQO1, CAT, SOD, GPX, PCNA k CASPASE3

• Rat

Enkhbat et al. (2018) Gu et al. (2018)

m NrRF2 and γ‑GCS

Cell culture treatment

• Mouse

m NRF2 (nuclear), HO-1, NQO1

Cell culture treatment [10
50 μM]

• Human

m NRF2 (nuclear), HO-1, NQO1, GCLC, GCLM, p-AKT m NRF2 k NOX4

Cell culture treatment [10
30 μM] Cell culture treatment [1
10 μM]

• Human

m NRF2, HO-1, NQO1, GSH, SOD, CAT, k TNF-α, IL-6, IL-1β, NLRP3, IL-1β p17, ASC m NRF2 (nuclear), HO-1, p-AMPK 2 AMPK k NRF2 (cytosolic) m NRF2, AKR1C1, HO-1,

Intraperitoneal injection [65 mg/kg body weight]

• Rat

Cell culture treatment [1
100 μM] Cell culture treatment [1
100 μM]

• Mouse renal tubular epithelial cells • Human hepatoma HepG2 cells

Du et al. (2018)

• Human trabecular meshwork cells • Human Aortic Smooth Muscle Cells • Retinal tissue

Liu et al. (2019b) Zhang et al. (2019)

• Human

• Human pancreatic cancer cell

Chen et al. (2018)

• Human

• Human Keratinocyte HaCaT cell

Bauman et al. (2018)

Mi et al. (2018)

Isothiocyanates Sulforaphane

Sulforaphane attenuates oxidative stress through activation of Nrf2 signaling

Sulforaphane exerts protective effects on diabetic retinopathy

• Human

Gene symbols are italicized and with the first letter in upper-case. Protein symbols are in capital letters and not italicized. m, upregulation; k, downregulation; 2, no change in expression.

Li et al. (2019)

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ameliorate oxidative damage by inducing endogenous antioxidant system (Alshammari et al., 2017; Han et al., 2018; Crespo et al., 2017; Amin et al., 2017; Yan et al., 2016). Hydroxycinnamic acids have a general structure of C6-C3 derived directly from cinnamic acid. The compounds with a hydroxycinnamic structure include cinnamic acid, ferulic acid, and chlorogenic acid. It has been reported that physicochemical properties (such as dissociation constant, lipid solubility, and redox potential), as well as aromatic ring modifications (such as position of hydroxyl groups, electron withdrawing or donating moieties, and carboxylic function alteration) impart significant importance to the hydroxycinnamic acids derivatives antioxidant activity (Razzaghi-Asl et al., 2013). Nutrigenomic studies showed that cinnamic acid enhances NRF2 expression in both cytosolic and nuclear fractions, which in turn upregulate antioxidant enzymes gene expression (Yan et al., 2016; Hseu et al., 2018; Li et al., 2016). Being one of the hydroxycinnamic acids derivatives, the distinctive structural motifs (3-methoxy, 4-hydroxyl, and carboxylic groups) of ferulic acid denote its superior free-radical scavenging capability. In comparison to other phenolic acids, it is also more readily being absorbed by the body and remains in the blood for a longer period of time. Ferulic acid has also received a lot of attention for its wide range of therapeutic effects and physiological functions. Nevertheless, nutrigenomic studies revealed that ferulic acid treatment may affect both antioxidant and inflammation mechanisms. While ferulic acid may protect against oxidative stress via regulation of NRF2 responses (He et al., 2019; Lampiasi and Montana, 2018; Das et al., 2017b; Song et al., 2016; Ma et al., 2010, 2011), it has also been shown to modulate colocalization of NF-κB and NRF2 in the nuclei (Das et al., 2017a). Although the inflammatory responses were not up-regulated in the reported study, the mechanism of ferulic acid on both NF-κB and NRF2 responses may be worth further investigation. Chlorogenic acid represents an ester of caffeic and quinic acids. Its isomer composition is complex and varies. Similar to other dietary polyphenols, chlorogenic acid exhibits a wide range of biological and pharmacological functions. In particular, the health benefits as a result of chlorogenic acid, have protective effects against free radicals and prooxidants-induced oxidative damage. The nutrient-gene analysis showed that chlorogenic acid induces activation of NRF2 antioxidative signaling pathway (Bao et al., 2018; Wei et al., 2017; Shi et al., 2016, 2018a; Han et al., 2017; Zheng et al., 2016; Pang et al., 2015). Nevertheless, further investigation into its antioxidant and prooxidant mechanisms revealed pro-oxidant activity of chlorogenic acid when redox-active metals present in the system. Nonreducing metals including aluminum and zinc also enhance its prooxidative effect by rendering a spin-stabilizing effect on the phenoxyl radical. While chlorogenic acid-derived phenoxyl radicals are relatively short-lived and the effects tend to be minimal, coconsumption of chlorogenic acid and metals may not be favorable and remain to be elucidated (Liang and Kitts, 2015).

2.6.2 FLAVONOIDS Flavonoids, also belong to the polyphenols family, share a common structure of 15-carbon skeleton (two phenyl rings and a heterocyclic ring) with a wide-ranging structural diversity. Quercetin and rutin (quercetin-3-O-rutinoside) are among the two natural flavonoids with important antioxidant properties. While most nutrigenomic studies report the capability of the compounds in attenuating oxidative stress by NRF2 activation (Singh et al., 2019; Liu et al., 2019a; Lee et al., 2018), Rubio

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et al. demonstrates that quercetin exerts differential effects on NRF2 and NF-κB activities using NB4 leukemia cells. The study reports that quercetin reduces the pro-inflammatory NF-κB p65 in the cytosol, correspondingly enhances them in the nucleus. The compound further decreases nuclear NRF2 and increases cytosolic NRF2, thereby deranging antioxidant defense system (Rubio et al., 2018). Given the present experimental data, the nutrigenomic effects of quercetin on different cell types and proper dosage may be worth further investigation. Resveratrol (trans-3,5,40 -trihydroxystilbene) is a compound largely isolated from the skins of red grapes. Resveratrol has been studied extensively and nutrigenomic analysis has shown that it affords protection against oxidative stress by activating the Keap1/Nrf2-antioxidant defense system (Li et al., 2018a; Gao et al., 2018; Wang et al., 2018a,b). However, while it is important to note that resveratrol does have potential biological attributes, research has also demonstrated that the compound may exhibit pro-oxidant properties in the presence of transition metal, thus triggering oxidative breakage of cellular DNA (De La Lastra and Villegas, 2007). Further investigations into the complete gene signaling network and interaction points may provide important basis for the use of resveratrol. Kaempferol (3,40 ,5,7-tetrahydroxyflavone) is a type of flavonoid easily extracted from various plant materials, including broccoli, grapes, ginkgo biloba, tea, and tomatoes. The phytochemical has demonstrated antioxidant efficacy using an array of in vitro and in vivo studies. Nutrient-gene study depicts that kaempferol restores redox imbalance via its efficient radical scavenging capacity and modulation of NRF2 activation (Hussein et al., 2018; Tsai et al., 2018). Nevertheless, the compound could also potentially cause erythrocytes hemolysis in the absence of any ROSs (Vellosa et al., 2011). It is suggested that although kaempferol may impart scavenger action over free radicals and endogenous antioxidant protective effect, it could also be detrimental by acting over erythrocytes and some other cell types. Hesperetin (hesperitin-7-O-glucoside) belongs to the flavanone class of flavonoids. Hesperidin (hesperitin-7-O-rutinoside) is a naturally occurring flavanon-glycoside that is predominantly found in citrus fruits. Both hesperetin and hesperidin are potent antioxidants that possess direct radical scavenging and NRF2 cellular antioxidant defense augmentation capacity (Zhu et al., 2017a; Ren et al., 2016; Bodduluru et al., 2015; Hong and An, 2018; Elavarasan et al., 2012; Chen et al., 2010a,b). In addition, hesperidin may also trigger activation of PPAR-γ (Elshazly et al., 2018; Mahmoud et al., 2017). Being a nuclear receptor that regulates transcription of genes involving mainly fatty acid and energy metabolism, its activation could potentially lead to insulin sensitization, as well as improved fatty acids and glucose metabolism. However, PPAR-γ also acts as key regulator of adipogenesis and thus, the hesperidin may also trigger adipocyte differentiation (Siersbæk et al., 2010). Being one of the important flavone, luteolin (30 ,40 ,5,7-tetrahydroxy flavone) is commonly found in several plant species including fruits, vegetables, and medicinal herbs. Similar to most naturally present flavonoids compounds, luteolin possesses both antioxidant and pro-oxidant capacity (Lin et al., 2008). Nutrigenomic analysis shows that luteolin may mediate endogenous antioxidative function by modulating NRF2 signaling pathway (Kitakaze et al., 2019; Elmazoglu et al., 2018). Studies have demonstrated that the compound induces nuclear translocation of NRF2 and reduces its cytoplasmic level (Baiyun et al., 2018; Yang et al., 2018; Liu et al., 2018). On the other hand, the study by Oyagbemi et al. shows that luteolin reduces NRF2 expression and did not induce antixodant enzymes expression (Oyagbemi et al., 2018).

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Epigallocatechin gallate (EGCG), a flavan-3-ol, is one of the most abundant tea catechin and is being widely researched for its potential health benefits. Being the ester of epigallocatechin and gallic acid, EGCG antioxidant and pro-oxidant effects are largely dependent on its concentration and pH. Overall, EGCG has been shown to be one of the most potent NRF2 activators. The compound mediates antioxidant enzyme expression via activation NRF2-ARE signaling pathway (He et al., 2018; Enkhbat et al., 2018; Gu et al., 2018; Du et al., 2018; Mi et al., 2018). However, it is important to note that EGCG may also function as a pro-oxidant, independently from antioxidative mechanisms, under some cellular contexts. In particular, it is suggested that EGCG exerts concentration-specific responses (Kim et al., 2014). Thus, it might be helpful to identify the effective dosage of EGCG to improve physiological outcomes.

2.6.3 SULFORAPHANE Sulforaphane is a naturally occurring sulfur-containing compound found within the isothiocyanate group. The phytochemical compound is commonly found in cruciferous vegetables including broccoli, cabbages, cauliflowers, and Brussels sprouts. Sulforaphane has been widely studied for its chemopreventive activities in cells, animal models, and human subjects (de Figueiredo et al., 2015). It is proposed that sulforaphane exerts anticancer activity via epigenetic mechanisms and the NRF2 signaling pathway (Su et al., 2018). Accumulating evidences support that it mediates expression and activity of a battery of cytoprotective proteins via NRF2 activation (Liu et al., 2019b; Zhang et al., 2019; Li et al., 2019; Chen et al., 2018). Interestingly, it is reported that ROSs may further enhance activation of sulforaphane-regulated antioxidant response element, even with substantial suppression of NRF2 protein levels (Bauman et al., 2018). The results suggest that NRF2 protein levels and antioxidant response element-mediated gene expression may not be conflating. Essentially, epigenetic restoration of NRF2 may provide new research insights and different preventive approaches against oxidative stress-related diseases.

2.7 CONCLUSIONS In aggregate, this chapter documented nutrigenomic interactions between various antioxidants and the human genome as the bases for the antioxidant effects of these nutrients. This suggests that antioxidants in addition to their direct effects on biochemical processes, also produce changes in gene expression as their mode of action against oxidative stress-induced chronic diseases. The concept of food synergy has been used to describe how dietary components in foods may not produce effects that are the sum of those of the individual components present in the food, largely because some may be inhibited by the presence of others or they may even be bound to the food matrix, which prevents them from producing their effects. Thus, further studies are needed to evaluate the simultaneous effects of these antioxidants since multiples of these antioxidants in food may not always produce additive effects. Moreover, there is the need for more clinical trials to establish the clinical validity of the findings from studies on the nutrigenomic effects of antioxidants.

REFERENCES

61

ACKNOWLEDGMENTS The authors thank members of the College of Health Sciences, Usmanu Danfodiyo University and those of the Laboratory of Molecular Biomedicine, University Putra Malaysia for their contributions to this book chapter.

REFERENCES Aguirre, J.D., Culotta, V.C., 2012. Battles with iron: manganese in oxidative stress protection. J. Biol. Chem. 287 (17), 13541
13548. Al-Issawi, M., Rihan, H.Z., Al-Shmgani, H., Fuller, M.P., 2016. Molybdenum application enhances antioxidant enzyme activity and COR15a protein expression under cold stress in wheat. J. Plant Interact. 11 (1), 5
10. Alshammari, G.M., Balakrishnan, A., Chinnasamy, T., 2017. 2-Hydroxy-4-methoxy benzoic acid attenuates the carbon tetra chloride-induced hepatotoxicity and its lipid abnormalities in rats via anti-inflammatory and antioxidant mechanism. Inflamm. Res. 66 (9), 753
763. Amin, F.U., Shah, S.A., Kim, M.O., 2017. Vanillic acid attenuates Aβ 1-42-induced oxidative stress and cognitive impairment in mice. Sci. Rep. 7, 40753. Aranibar, N., Bhaskaran, V., Ott, K.H., Vassallo, J., Nelson, D., Lecureux, L., et al., 2009. Modulation of ascorbic acid metabolism by cytochrome P450 induction revealed by metabonomics and transcriptional profiling. Magn. Reson. Chem. 47 (S1), S12
S19. Bahar, E., Kim, J.-Y., Yoon, H., 2017. Quercetin attenuates manganese-induced neuroinflammation by alleviating oxidative stress through regulation of apoptosis, iNOS/NF-κB and HO-1/Nrf2 pathways. Int. J. Mol. Sci. 18 (9), 1989. Baiyun, R., Li, S., Liu, B., Lu, J., Lv, Y., Xu, J., et al., 2018. Luteolin-mediated PI3K/AKT/Nrf2 signaling pathway ameliorates inorganic mercury-induced cardiac injury. Ecotoxicol. Environ. Saf. 161, 655
661. Bao, L., Li, J., Zha, D., Zhang, L., Gao, P., Yao, T., et al., 2018. Chlorogenic acid prevents diabetic nephropathy by inhibiting oxidative stress and inflammation through modulation of the Nrf2/HO-1 and NF-ĸB pathways. Int. Immunopharmacol. 54, 245
253. Baraboĭ, V., Shestakova, E., 1999. Selenium: the biological role and antioxidant activity. Ukrains’ kyi biokhimichnyi zhurnal 76 (1), 23
32. 2004. Bauman, B.M., Jeong, C., Savage, M., Briker, A.L., Janigian, N.G., Nguyen, L.L., et al., 2018. Dr. Jekyll and Mr. Hyde: oxidizable phenol-generated reactive oxygen species enhance sulforaphane’s antioxidant response element activation, even as they suppress Nrf2 protein accumulation. Free Radical Biol. Med. 124, 532
540. Bellezza, I., Mierla, A.L., Minelli, A., 2010. Nrf2 and NF-κB and their concerted modulation in cancer pathogenesis and progression. Cancer 2 (2), 483
497. Black, L.J., Lucas, R.M., Sherriff, J.L., Bjo¨rn, L.O., Bornman, J.F., 2017. In pursuit of vitamin D in plants. Nutrients 9 (2), 136. Bodduluru, L.N., Kasala, E.R., Barua, C.C., Karnam, K.C., Dahiya, V., Ellutla, M., 2015. Antiproliferative and antioxidant potential of hesperetin against benzo (a) pyrene-induced lung carcinogenesis in Swiss albino mice. Chem. Biol. Interact. 242, 345
352. Carr, A., Frei, B., 1999. Does vitamin C act as a pro-oxidant under physiological conditions? FASEB. J. 13 (9), 1007
1024. Chakraborthy, A., Ramani, P., Sherlin, H.J., Premkumar, P., Natesan, A., 2014. Antioxidant and pro-oxidant activity of Vitamin C in oral environment. Indian. J. Dent. Res. 25 (4), 499. Chang, Z., Huo, L., Li, P., Wu, Y., Zhang, P., 2015. Ascorbic acid provides protection for human chondrocytes against oxidative stress. Mol. Med. Rep. 12 (5), 7086
7092.

62

CHAPTER 2 NUTRIGENOMICS AND ANTIOXIDANTS

Chazot, C., Kopple, J.D., 2013. Vitamin metabolism and requirements in renal disease and renal failure. Nutritional Management of Renal Disease. Elsevier, pp. 351
382. Chen, M., Gu, H., Ye, Y., Lin, B., Sun, L., Deng, W., et al., 2010a. Protective effects of hesperidin against oxidative stress of tert-butyl hydroperoxide in human hepatocytes. Food Chem. Toxicol. 48 (10), 2980
2987. Chen, M.-c, Ye, Y.-Y., Ji, G., Liu, J.-w, 2010b. Hesperidin upregulates heme oxygenase-1 to attenuate hydrogen peroxide-induced cell damage in hepatic L02 cells. J. Agric. Food. Chem. 58 (6), 3330
3335. Chen, J., Wang, S., Luo, M., Zhang, Z., Dai, X., Kong, M., et al., 2016. From the cover: zinc deficiency worsens and supplementation prevents high-fat diet induced vascular inflammation, oxidative stress, and pathological remodeling. Toxicol. Sci. 153 (1), 124
136. Chen, M., Li, X., Fan, R., Cao, C., Yao, H., Xu, S., 2017. Selenium antagonizes cadmium-induced apoptosis in chicken spleen but not involving Nrf2-regulated antioxidant response. Ecotoxicol. Environ. Saf. 145, 503
510. Chen, X., Jiang, Z., Zhou, C., Chen, K., Li, X., Wang, Z., et al., 2018. Activation of Nrf2 by sulforaphane inhibits high glucose-induced progression of pancreatic cancer via AMPK dependent signaling. Cell. Physiol. Biochem. 50 (3), 1201
1215. Chung, T., Brena, R.M., Kolle, G., Grimmond, S.M., Berman, B.P., Laird, P.W., et al., 2010. Vitamin C promotes widespread yet specific DNA demethylation of the epigenome in human embryonic stem cells. Stem Cell. 28, 1848
1855. Available from: https://doi.org/10.1002/stem.493. Coassin, M., Ursini, F., Bindoli, A., 1992. Antioxidant effect of manganese. Arch. Biochem. Biophys. 299 (2), 330
333. Crespo, I., San-Miguel, B., Mauriz, J.L., Ortiz de Urbina, J.J., Almar, M., Tun˜o´n, M.J., et al., 2017. Protective effect of protocatechuic acid on TNBS-induced colitis in mice is associated with modulation of the SphK/ S1P signaling pathway. Nutrients 9 (3), 288. Dao, D.Q., Ngo, T.C., Thong, N.M., Nam, P.C., 2017. Is Vitamin A an Antioxidant or a Pro-oxidant? J. Phys. Chem. B 121 (40), 9348
9357. Das, J., Sarkar, A., Sil, P.C., 2015. Hexavalent chromium induces apoptosis in human liver (HepG2) cells via redox imbalance. Toxicol. Rep. 2, 600
608. Das, U., Sengupta, A., Biswas, S., Adhikary, A., Dey Sharma, R., Chakraborty, A., et al., 2017a. Alteration of murine duodenal morphology and redox signalling events by reactive oxygen species generated after whole body γ-irradiation and its prevention by ferulic acid. Free. Radic. Res. 51 (11
12), 886
910. Das, U., Manna, K., Khan, A., Sinha, M., Biswas, S., Sengupta, A., et al., 2017b. Ferulic acid (FA) abrogates γ-radiation induced oxidative stress and DNA damage by up-regulating nuclear translocation of Nrf2 and activation of NHEJ pathway. Free. Radic. Res. 51 (1), 47
63. Dong, R., Wang, D., Wang, X., Zhang, K., Chen, P., Yang, C.S., et al., 2016. Epigallocatechin-3-gallate enhances key enzymatic activities of hepatic thioredoxin and glutathione systems in selenium-optimal mice but activates hepatic Nrf2 responses in selenium-deficient mice. Redox Biol. 10, 221
232. Drever, N., Yin, H., Kechichian, T., Costantine, M., Longo, M., Saade, G.R., et al., 2012. The expression of antioxidant enzymes in a mouse model of fetal alcohol syndrome. Am. J. Obstet. Gynecol. 206 (4), 358. e19-22. Du, X., Yu, J., Sun, X., Qu, S., Zhang, H., Hu, M., et al., 2018. Impact of epigallocatechin-3-gallate on expression of nuclear factor erythroid 2-related factor 2 and γ-glutamyl cysteine synthetase genes in oxidative stress-induced mouse renal tubular epithelial cells. Mol. Med. Rep. 17 (6), 7952
7958. Duan, L., Li, J., Ma, P., Yang, X., Xu, S., 2017. Vitamin E antagonizes ozone-induced asthma exacerbation in Balb/c mice through the Nrf2 pathway. Food Chem. Toxicol. 107, 47
56. van Duynhoven, J.P.M., van Velzen, E.J.J., Westerhuis, J.A., Foltz, M., Jacobs, D.M., Smilde, A.K., 2012. Nutrikinetics: concept, technologies, applications, perspectives. Trends Food Sci. Technol. 26, 4
13.

REFERENCES

63

Eder, K., Siebers, M., Most, E., Scheibe, S., Weissmann, N., Gessner, D.K., 2017. An excess dietary vitamin E concentration does not influence Nrf2 signaling in the liver of rats fed either soybean oil or salmon oil. Nutr. Metab. (Lond). 14 (1), 71. EFSA Panel on Dietetic Products NaAN, 2010. Scientific opinion on the substantiation of health claims related to molybdenum and contribution to normal amino acid metabolism (ID 313) and protection of DNA, proteins and lipids from oxidative damage (ID 341) pursuant to Article 13(1) of Regulation (EC) No 1924/ 2006. EFSA J. 8 (10), 1745. Available from: https://doi.org/10.2903/j.efsa.2010.1745. Elavarasan, J., Velusamy, P., Ganesan, T., Ramakrishnan, S.K., Rajasekaran, D., Periandavan, K., 2012. Hesperidin-mediated expression of Nrf2 and upregulation of antioxidant status in senescent rat heart. J. Pharm. Pharmacol. 64 (10), 1472
1482. Elmazoglu, Z., Yar Saglam, A.S., Sonmez, C., Karasu, C., 2018. Luteolin protects microglia against rotenoneinduced toxicity in a hormetic manner through targeting oxidative stress response, genes associated with Parkinson’s disease and inflammatory pathways. Drug Chem. Toxicol. 1
8. Elshazly, S.M., El Motteleb, D.M.A., Ibrahim, I.A.-H., 2018. Hesperidin protects against stress induced gastric ulcer through regulation of peroxisome proliferator activator receptor gamma in diabetic rats. Chem. Biol. Interact. Enkhbat, T., Nishi, M., Yoshikawa, K., Jun, H., Tokunaga, T., Takasu, C., et al., 2018. Epigallocatechin-3gallate enhances radiation sensitivity in colorectal cancer cells through nrf2 activation and autophagy. Anticancer Res. 38 (11), 6247
6252. Fan, Y., Zhang, X., Yang, L., Wang, J., Hu, Y., Bian, A., et al., 2017. Zinc inhibits high glucose-induced NLRP3 inflammasome activation in human peritoneal mesothelial cells. Mol. Med. Rep. 16 (4), 5195
5202. de Figueiredo, S.M., Binda, N.S., Nogueira-Machado, J.A., Vieira-Filho, S.A., Caligiorne, R.B., 2015. The antioxidant properties of organosulfur compounds (sulforaphane). Recent Patents Endocr. Metab. Immune Drug Discov. 9 (1), 24
39. Figueroa-M´endez, R., Rivas-Arancibia, S., 2015. Vitamin C in health and disease: its role in the metabolism of cells and redox state in the brain. Front. Physiol. 6, 397. Fujie, T., Segawa, Y., Uehara, A., Nakamura, T., Kimura, T., Yoshida, E., et al., 2016. Zinc diethyldithiocarbamate as an inducer of metallothionein in cultured vascular endothelial cells. J. Toxicol. Sci. 41 (2), 217
224. Galicka, A., Kre˛towski, R., Nazaruk, J., Cechowska-Pasko, M., 2014. Anethole prevents hydrogen peroxideinduced apoptosis and collagen metabolism alterations in human skin fibroblasts. Mol. Cell Biochem. 394 (1-2), 217
224. Gao, Y., Fu, R., Wang, J., Yang, X., Wen, L., Feng, J., 2018. Resveratrol mitigates the oxidative stress mediated by hypoxic-ischemic brain injury in neonatal rats via Nrf2/HO-1 pathway. Pharm. Biol. 56 (1), 440
449. Gong, J., Li, L., 2016. Sodium selenite inhibits proliferation of gastric cancer cells by inducing SBP1 expression. Tohoku J. Exp. Med. 239 (4), 279
285. Gu, M., Liu, C., Wan, X., Yang, T., Chen, Y., Zhou, J., et al., 2018. Epigallocatechin gallate attenuates bladder dysfunction via suppression of oxidative stress in a rat model of partial bladder outlet obstruction. Oxid. Med. Cell Longev. 2018. Ge˛gotek, A., Bielawska, K., Biernacki, M., Zare˛ba, I., Sura˙zy´nski, A., Skrzydlewska, E., 2017. Comparison of protective effect of ascorbic acid on redox and endocannabinoid systems interactions in in vitro cultured human skin fibroblasts exposed to UV radiation and hydrogen peroxide. Arch. Dermatol. Res. 309 (4), 285
303. Han, D., Chen, W., Gu, X., Shan, R., Zou, J., Liu, G., et al., 2017. Cytoprotective effect of chlorogenic acid against hydrogen peroxide-induced oxidative stress in MC3T3-E1 cells through PI3K/Akt-mediated Nrf2/ HO-1 signaling pathway. Oncotarget 8 (9), 14680.

64

CHAPTER 2 NUTRIGENOMICS AND ANTIOXIDANTS

Han, F., Xu, L., Huang, Y., Chen, T., Zhou, T., Yang, L., 2018a. Magnesium sulphate can alleviate oxidative stress and reduce inflammatory cytokines in rat placenta of intrahepatic cholestasis of pregnancy model. Arch. Gynecol. Obstet. 1
8. Han, L., Yang, Q., Ma, W., Li, J., Qu, L., Wang, M., 2018b. Protocatechuic acid ameliorated palmitic-acidinduced oxidative damage in endothelial cells through activating endogenous antioxidant enzymes via an Adenosine-monophosphate-activated-protein-kinase-dependent pathway. J. Agric. Food. Chem. 66 (40), 10400
10409. Hasler, C.M., 2002. Functional foods: benefits, concerns and challenges—a position paper from the American Council on Science and Health. J. Nutr. 132 (12), 3772
3781. Available from: https://doi.org/10.1093/jn/ 132.12.3772. Haq, Z., Jain, R., Khan, N., Dar, M., Ali, S., Gupta, M., et al., 2016. Recent advances in role of chromium and its antioxidant combinations in poultry nutrition: a review. Vet. World 9 (12), 1392. He, X., Lin, G.X., Chen, M.G., Zhang, J.X., Ma, Q., 2007. Protection against chromium (VI)
induced oxidative stress and apoptosis by Nrf2. Recruiting Nrf2 into the nucleus and disrupting the nuclear Nrf2/Keap1 association. Toxicol. Sci. 98 (1), 298
309. He, F., Zhang, Y., Chen, S., Ye, B., Chen, J., Li, C., 2018. Effect of EGCG on oxidative stress and Nrf2/HO-1 pathway in neurons exposed to oxygen-glucose deprivation/reperfusion. Zhong nan da xue xue bao Yi xue ban 5 J. Central South Univ. Med. Sci. 43 (10), 1041
1047. He, S., Guo, Y., Zhao, J., Xu, X., Song, J., Wang, N., et al., 2019. Ferulic acid protects against heat stressinduced intestinal epithelial barrier dysfunction in IEC-6 cells via the PI3K/Akt-mediated Nrf2/HO-1 signaling pathway. Int. J. Hyperthermia 35 (1), 112
121. Helaly, A., Mokhtar, N., Firgany, A.E.-D.L., Hazem, N.M., El Morsi, E., Ghorab, D., 2018. Molybdenum bupropion combined neurotoxicity in rats. Regul. Toxicol. Pharmacol. 98, 224
230. Hong, Y., An, Z., 2018. Hesperidin attenuates learning and memory deficits in APP/PS1 mice through activation of Akt/Nrf2 signaling and inhibition of RAGE/NF-κB signaling. Arch. Pharm. Res. 41 (6), 655
663. Houghton, C.A., Fassett, R.G., Coombes, J.S., 2016. Sulforaphane and other nutrigenomic Nrf2 activators: can the clinician’s expectation be matched by the reality? Oxid. Med. Cell Longev. 7857186. Hseu, Y.-C., Korivi, M., Lin, F.-Y., Li, M.-L., Lin, R.-W., Wu, J.-J., et al., 2018. Trans-cinnamic acid attenuates UVA-induced photoaging through inhibition of AP-1 activation and induction of Nrf2-mediated antioxidant genes in human skin fibroblasts. J. Dermatol. Sci. 90 (2), 123
134. ,https://www.grandviewresearch.com/industry-analysis/functional-food-market/request.. Huang, T.-C., Chang, W.-T., Hu, Y.-C., Hsieh, B.-S., Cheng, H.-L., Yen, J.-H., et al., 2018. Zinc protects articular chondrocytes through changes in Nrf2-mediated antioxidants, cytokines and matrix metalloproteinases. Nutrients 10 (4), 471. Hussein, R.M., Mohamed, W.R., Omar, H.A., 2018. A neuroprotective role of kaempferol against chlorpyrifos-induced oxidative stress and memory deficits in rats via GSK3β-Nrf2 signaling pathway. Pestic. Biochem. Physiol. 152, 29
37. Jiang, W.-D., Tang, R.-J., Liu, Y., Kuang, S.-Y., Jiang, J., Wu, P., et al., 2015. Manganese deficiency or excess caused the depression of intestinal immunity, induction of inflammation and dysfunction of the intestinal physical barrier, as regulated by NF-κB, TOR and Nrf2 signalling, in grass carp (Ctenopharyngodon idella). Fish. Shellfish. Immunol. 46 (2), 406
416. Jiang, W.-D., Wu, P., Tang, R.-J., Liu, Y., Kuang, S.-Y., Jiang, J., et al., 2016. Nutritive values, flavor amino acids, healthcare fatty acids and flesh quality improved by manganese referring to up-regulating the antioxidant capacity and signaling molecules TOR and Nrf2 in the muscle of fish. Food Res. Int. 89, 670
678. Kalayarasan, S., Sriram, N., Sureshkumar, A., Sudhandiran, G., 2008. Chromium (VI)-induced oxidative stress and apoptosis is reduced by garlic and its derivative S-allylcysteine through the activation of Nrf2 in the hepatocytes of Wistar rats. J. Appl. Toxicol. 28 (7), 908
919.

REFERENCES

65

Kato, H., 2008. Nutrigenomics: the cutting edge and Asian perspectives. Asia. Pac. J. Clin. Nutr. 17, 112
115. Ke, C.-Y., Yang, F.-L., Wu, W.-T., Chung, C.-H., Lee, R.-P., Yang, W.-T., et al., 2016. Vitamin D3 reduces tissue damage and oxidative stress caused by exhaustive exercise. Int. J. Med. Sci. 13 (2), 147. Kim, H.-S., Quon, M.J., Kim, J.-A., 2014. New insights into the mechanisms of polyphenols beyond antioxidant properties; lessons from the green tea polyphenol, epigallocatechin 3-gallate. Redox Biol. 2, 187
195. Kim, S.R., Ha, Y.M., Kim, Y.M., Park, E.J., Kim, J.W., Park, S.W., et al., 2015. Ascorbic acid reduces HMGB1 secretion in lipopolysaccharide-activated RAW 264.7 cells and improves survival rate in septic mice by activation of Nrf2/HO-1 signals. Biochem. Pharmacol. 95 (4), 279
289. Kitakaze, T., Makiyama, A., Samukawa, Y., Jiang, S., Yamashita, Y., Ashida, H., 2019. A physiological concentration of luteolin induces phase II drug-metabolizing enzymes through the ERK1/2 signaling pathway in HepG2 cells. Arch. Biochem. Biophys. Lampiasi, N., Montana, G., 2018. An in vitro inflammation model to study the Nrf2 and NF-κB crosstalk in presence of ferulic acid as modulator. Immunobiology 223 (4
5), 349
355. De La Lastra, C.A., Villegas, I., 2007. Resveratrol as an Antioxidant and Pro-Oxidant Agent: Mechanisms and Clinical Implications. Portland Press Limited. Lawal, A.O., Lawal, A.F., Ologundudu, A., Adeniran, O.Y., Omonkhua, A., Obi, F., 2011. Antioxidant effects of heated garlic juice on cadmium-induced liver damage in rats as compared to ascorbic acid. J. Toxicol. Sci. 36 (5), 549
557. Lee, Y.-J., Beak, S.-Y., Choi, I., Sung, J.-S., 2018. Quercetin and its metabolites protect hepatocytes against ethanol-induced oxidative stress by activation of Nrf2 and AP-1. Food. Sci. Biotechnol. 1
9. Li, W., Khor, T.O., Xu, C., Shen, G., Jeong, W.S., Yu, S., et al., 2008. Activation of Nrf2-antioxidant signaling attenuates NFkappaB-inflammatory response and elicits apoptosis. Biochem. Pharmacol. 76 (11), 1485
1489. Li, H., Wu, S., Shi, N., Lian, S., Lin, W., 2011a. Nrf2/HO-1 pathway activation by manganese is associated with reactive oxygen species and ubiquitin
proteasome pathway, not MAPKs signaling. J. Appl. Toxicol. 31 (7), 690
697. Li, H., Wu, S., Shi, N., Lin, W., You, J., Zhou, W., 2011b. NF-E2-related factor 2 activation in PC12 cells: its protective role in manganese-induced damage. Arch. Toxicol. 85 (8), 901
910. Li, Y., Wongsiriroj, N., Blaner, W.S., 2014. The multifaceted nature of retinoid transport and metabolism. Hepatobiliary Surg. Nutr. 3 (3), 126
139. Li, X.D., Gu, L.W., Ran, Q.S., Zhou, P., Zhan, X.L., Li, C.H., et al., 2016. Protective effects of three phenylallyl compounds from Guizhi decoction ox-LDL-induced oxidative stress injury of human brain microvascular endothelial cells. Zhongguo. Zhong. Yao. Za. Zhi. 41 (12), 2315
2320. Available from: https://doi.org/ 10.4268/cjcmm20161224. Li, X.N., Ma, L.Y., Ji, H., Qin, Y.H., Jin, S.S., Xu, L.X., 2018a. Resveratrol protects against oxidative stress by activating the Keap‑1/Nrf2 antioxidant defense system in obese‑asthmatic rats. Exp. Ther. Med. 16 (6), 4339
4348. Li, X., Wang, T., Zhao, M., Huang, T., Sun, D., Han, L., et al. DNA methylation variant, B-vitamins intake and longitudinal change in body mass index [published online ahead of print 17 May 2018b]. Int. J. Obes. Li, S., Yang, H., Chen, X., 2019. Protective effects of sulforaphane on diabetic retinopathy: activation of the Nrf2 pathway and inhibition of NLRP3 inflammasome formation. Exp. Anim. 18
0146. Liang, N., Kitts, D.D., 2015. Role of chlorogenic acids in controlling oxidative and inflammatory stress conditions. Nutrients 8 (1), 16. Liguori, I., Russo, G., Curcio, F., Bulli, G., Aran, L., Della-Morte, D., et al., 2018. Oxidative stress, aging, and diseases. Clin. Interv. Aging. 13, 757
772. Available from: https://doi.org/10.2147/CIA.S158513.

66

CHAPTER 2 NUTRIGENOMICS AND ANTIOXIDANTS

Lin, Y., Shi, R., Wang, X., 2008. Shen H-M. Luteolin, a flavonoid with potential for cancer prevention and therapy. Curr. Cancer Drug. Targets 8 (7), 634
646. Litwack, G., 2017. Vitamins and nutrition. In: Litwack, G. (Ed.), Human Biochemistry. Academic Press, Los Angeles, CA, pp. 645
680. Liu, M., Hu, C., Xu, Q., Chen, L., Ma, K., Xu, N., et al., 2015. Methylseleninicacid activates Keap1/Nrf2 pathway via up-regulating miR-200a in human esophageal squamous cell carcinoma cells. Biosci. Rep. BSR20150092. Liu, B., Yu, H., Baiyun, R., Lu, J., Li, S., Bing, Q., et al., 2018. Protective effects of dietary luteolin against mercuric chloride-induced lung injury in mice: involvement of AKT/Nrf2 and NF-κB pathways. Food Chem. Toxicol. 113, 296
302. Liu, Y.-W., Liu, X.-L., Kong, L., Zhang, M.-Y., Chen, Y.-J., Zhu, X., et al., 2019a. Neuroprotection of quercetin on central neurons against chronic high glucose through enhancement of Nrf2/ARE/glyoxalase-1 pathway mediated by phosphorylation regulation. Biomed. Pharmacother. 109, 2145
2154. Liu, Y., Liu, P., Wang, Q., Sun, F., Liu, F., 2019b. Sulforaphane attenuates H2O2-induced oxidant stress in human trabecular meshwork cells (HTMCs) via the phosphatidylinositol 3-kinase (PI3K)/serine/threonine kinase (Akt)-mediated factor-E2-related factor 2 (Nrf2) signaling activation. Med. Sci. Monitor. 25, 811
818. Lu¨, J., Lin, P.H., Yao, Q., Chen, C., 2010. Chemical and molecular mechanisms of antioxidants: experimental approaches and model systems. J. Cell Mod. Med. 14, 840
860. Ma, Z.-C., Hong, Q., Wang, Y.-G., Tan, H.-L., Xiao, C.-R., Liang, Q.-D., et al., 2010. Ferulic acid protects human umbilical vein endothelial cells from radiation induced oxidative stress by phosphatidylinositol 3kinase and extracellular signal-regulated kinase pathways. Biol. Pharm. Bull. 33 (1), 29
34. Ma, Z., Hong, Q., Wang, Y., Liang, Q., Tan, H., Xiao, C., et al., 2011. Ferulic acid induces heme oxygenase-1 via activation of ERK and Nrf2. Drug Discov. Therapeut. 5 (6), 299
305. Mahmoud, A.M., Mohammed, H.M., Khadrawy, S.M., Galaly, S.R., 2017. Hesperidin protects against chemically induced hepatocarcinogenesis via modulation of Nrf2/ARE/HO-1, PPARγ and TGF-β1/Smad3 signaling, and amelioration of oxidative stress and inflammation. Chem. Biol. Interact. 277, 146
158. Manna, P., Achari, A.E., Jain, S.K., 2017. Vitamin D supplementation inhibits oxidative stress and upregulate SIRT1/AMPK/GLUT4 cascade in high glucose-treated 3T3L1 adipocytes and in adipose tissue of high fat diet-fed diabetic mice. Arch. Biochem. Biophys. 615, 22
34. Mard, S.A., Akbari, G., Dianat, M., Mansouri, E., 2017. Protective effects of crocin and zinc sulfate on hepatic ischemia-reperfusion injury in rats: a comparative experimental model study. Biomed. Pharmacother. 96, 48
55. Maremanda, K.P., Khan, S., Jena, G., 2016. Role of zinc supplementation in testicular and epididymal damages in diabetic rat: involvement of Nrf2, SOD1, and GPX5. Biol. Trace Elem. Res. 173 (2), 452
464. Me`ne-Saffran´e, L., DellaPenna, D., 2010. Biosynthesis, regulation and functions of tocochromanols in plants. Plant. Physiol. Biochem. 48 (5), 301
309. Mertz, W., 1969. Chromium occurrence and function in biological systems. Physiol. Rev. 49 (2), 163
239. Mi, Y., Zhang, W., Tian, H., Li, R., Huang, S., Li, X., et al., 2018. EGCG evokes Nrf2 nuclear translocation and dampens PTP1B expression to ameliorate metabolic misalignment under insulin resistance condition. Food Function 9 (3), 1510
1523. Mokhtari, Z., Hekmatdoost, A., Nourian, M., 2017. Antioxidant efficacy of vitamin D. J. Parathyr. Dis. 5 (1), 11
16. Molina-Jijo´n, E., Rodrı´guez-Mun˜oz, R., del Carmen Namorado, M., Bautista-Garcı´a, P., Medina-Campos, O. N., Pedraza-Chaverri, J., et al., 2015. All-trans retinoic acid prevents oxidative stress-induced loss of renal tight junction proteins in type-1 diabetic model. J. Nutr. Biochem. 26 (5), 441
454.

REFERENCES

67

Moreira, J.C.F., Dal-Pizzol, F., Rocha, A.B., Klamt, F., Ribeiro, N.C., Ferreira, C.J.S., et al., 2000. Retinolinduced changes in the phosphorylation levels of histones and high mobility group proteins from Sertoli cells. Braz. J. Med. Biol. Res. 33 (3), 287
293. Available from: https://doi.org/10.1590/S0100879X2000000300005. Nair, R., Maseeh, A., 2012. Vitamin D: the “sunshine” vitamin. J. Pharmacol. Pharmacotherap. 3 (2), 118. Nakai, K., Fujii, H., Kono, K., Goto, S., Kitazawa, R., Kitazawa, S., et al., 2013. Vitamin D activates the Nrf2Keap1 antioxidant pathway and ameliorates nephropathy in diabetic rats. Am. J. Hypertens. 27 (4), 586
595. Nimse, S.B., Pal, D., 2015. Free radicals, natural antioxidants, and their reaction mechanisms. RSC Adv. 5, 27986
28006. O’Byrne, S.M., Blaner, W.S., 2013. Retinol and retinyl esters: biochemistry and physiology. J. Lipid Res. jlr. R037648. Omar, N.N., Tash, R.F., 2017. Fluoxetine coupled with zinc in a chronic mild stress model of depression: providing a reservoir for optimum zinc signaling and neuronal remodeling. Pharmacol. Biochem. Behav. 160, 30
38. Ovesen, L., Brot, C., Jakobsen, J., 2003. Food contents and biological activity of 25-hydroxyvitamin D: a vitamin D metabolite to be reckoned with? Ann. Nutr. Metab. 47 (3
4), 107
113. Oyagbemi, A.A., Omobowale, T.O., Ola-Davies, O.E., Asenuga, E.R., Ajibade, T.O., Adejumobi, O.A., et al., 2018. Luteolin-mediated Kim-1/NF-kB/Nrf2 signaling pathways protects sodium fluoride-induced hypertension and cardiovascular complications. Biofactors 44 (6), 518
531. Padayatty, S.J., Levine, M., 2016. Vitamin C: the known and the unknown and Goldilocks. Oral Dis. 22 (6), 463
493. Pang, C., Sheng, Y.-c, Jiang, P., Wei, H., Ji, L.-L., 2015. Chlorogenic acid prevents acetaminophen-induced liver injury: the involvement of CYP450 metabolic enzymes and some antioxidant signals. J. Zhejiang Univ. SCIENCE B. 16 (7), 602
610. Peh, H.Y., Ho, W.E., Cheng, C., Chan, T.K., Seow, A.C.G., Lim, A.Y., et al., 2015. Vitamin E isoform γ-tocotrienol downregulates house dust mite
induced asthma. J. Immunol. 1500362. Peh, H.Y., Tan, W.D., Chan, T.K., Pow, C.W., Foster, P.S., Wong, W.F., 2017. Vitamin E isoform γ-tocotrienol protects against emphysema in cigarette smoke-induced COPD. Free Radical Biol. Med. 110, 332
344. Pen˜a-Oyarzun, D., Bravo-Sagua, R., Diaz-Vega, A., Aleman, L., Chiong, M., Garcia, L., et al., 2018. Autophagy and oxidative stress in non-communicable diseases: a matter of the inflammatory state? Free Radic. Biol. Med. 124, 61
78. Prates, J., Alfaia, C., 2002. Functional foods from animal sources and their physiologically active components. Revue M´ed. V´et. 153 (3), 155
160. Pullar, J., Carr, A., Vissers, M., 2017. The roles of vitamin C in skin health. Nutrients 9 (8), 866. Razzaghi-Asl, N., Garrido, J., Khazraei, H., Borges, F., Firuzi, O., 2013. Antioxidant properties of hydroxycinnamic acids: a review of structure-activity relationships. Curr. Med. Chem. 20 (36), 4436
4450. Reddi, A.R., Culotta, V.C., 2011. Regulation of manganese antioxidants by nutrient sensing pathways in Saccharomyces cerevisiae. Genetics 111, 134007. genetics. Ren, H., Hao, J., Liu, T., Zhang, D., Lv, H., Song, E., et al., 2016. Hesperetin suppresses inflammatory responses in lipopolysaccharide-induced RAW 264.7 cells via the inhibition of NF-κB and activation of Nrf2/HO-1 pathways. Inflammation 39 (3), 964
973. Rezzi, S., Ramadan, Z., Fay, L.B., Kochhar, S., 2007. Nutritional metabonomics: applications and perspectives. J. Proteome. Res. 6, 513
525. Rist, M.J., Wenzel, U., Daniel, H., 2006. Nutrition and food science go genomic. Trends Biotechnol. 24, 1
7. Roy, R.V., Pratheeshkumar, P., Son, Y.-O., Wang, L., Hitron, J.A., Divya, S.P., et al., 2016. Different roles of ROS and Nrf2 in Cr (VI)-induced inflammatory responses in normal and Cr (VI)-transformed cells. Toxicol. Appl. Pharmacol. 307, 81
90.

68

CHAPTER 2 NUTRIGENOMICS AND ANTIOXIDANTS

Rubio, V., Garcı´a-P´erez, A.I., Herr´aez, A., Diez, J.C., 2018. Different roles of Nrf2 and NFKB in the antioxidant imbalance produced by esculetin or quercetin on NB4 leukemia cells. Chem. Biol. Interact. 294, 158
166. Sahin, K., Tuzcu, M., Orhan, C., Gencoglu, H., Ulas, M., Atalay, M., et al., 2012. The effects of chromium picolinate and chromium histidinate administration on NF-κB and Nrf2/HO-1 pathway in the brain of diabetic rats. Biol. Trace Elem. Res. 150 (1-3), 291
296. Sahin, N., Hayirli, A., Orhan, C., Tuzcu, M., Akdemir, F., Komorowski, J., et al., 2017. Effects of the supplemental chromium form on performance and oxidative stress in broilers exposed to heat stress. Poult. Sci. 96 (12), 4317
4324. Santhakumar, A.B., Battino, M., Alvarez-Suarez, J.M., 2018. Dietary polyphenols: structures, bioavailability and protective effects against atherosclerosis. Food Chem. Toxicol. 113, 49
65. Santos, D., Milatovic, D., Andrade, V., Batoreu, M.C., Aschner, M., Dos Santos, A.M., 2012. The inhibitory effect of manganese on acetylcholinesterase activity enhances oxidative stress and neuroinflammation in the rat brain. Toxicology 292 (2
3), 90
98. Schmo¨lz, L., Birringer, M., Lorkowski, S., Wallert, M., 2016. Complexity of vitamin E metabolism. World J. Biol. Chem. 7 (1), 14. Selcuk, M.Y., Aygen, B., Dogukan, A., Tuzcu, Z., Akdemir, F., Komorowski, J.R., et al., 2012. Chromium picolinate and chromium histidinate protects against renal dysfunction by modulation of NF-κB pathway in high-fat diet fed and Streptozotocin-induced diabetic rats. Nutr. Metab. (Lond). 9 (1), 30. Serrano, J.C., Jove, M., Gonzalo, H., Pamplona, R., Portero-Otin, M., 2015. Nutridynamics: mechanism(s) of action of bioactive compounds and their effects. Int. J. Food. Sci. Nutr. 66 (1), S22
S30. Shang, J., Yan, H., Jiao, Y., Ohta, Y., Liu, X., Li, X., et al., 2018. Therapeutic effects of pretreatment with tocovid on oxidative stress in postischemic mice brain. J. Stroke Cerebrovasc. Dis. 27 (8), 2166
2174. Shi, H., Shi, A., Dong, L., Lu, X., Wang, Y., Zhao, J., et al., 2016. Chlorogenic acid protects against liver fibrosis in vivo and in vitro through inhibition of oxidative stress. Clin. Nutr. 35 (6), 1366
1373. Shi, L., Li, H., Zhan, Y., 2017. All‑trans retinoic acid enhances temozolomide‑induced autophagy in human glioma cells U251 via targeting Keap1/Nrf2/ARE signaling pathway. Oncol. Lett. 14 (3), 2709
2714. Shi, A., Shi, H., Wang, Y., Liu, X., Cheng, Y., Li, H., et al., 2018a. Activation of Nrf2 pathway and inhibition of NLRP3 inflammasome activation contribute to the protective effect of chlorogenic acid on acute liver injury. Int. Immunopharmacol. 54, 125
130. Shi, H., Yan, S., Guo, Y., Zhang, B., Guo, X., Shi, B., 2018b. Vitamin A pretreatment protects NO-induced bovine mammary epithelial cells from oxidative stress by modulating Nrf2 and NF-κB signaling pathways. J. Anim. Sci. 96 (4), 1305
1316. Siersbæk, R., Nielsen, R., Mandrup, S., 2010. PPARγ in adipocyte differentiation and metabolism-Novel insights from genome-wide studies. FEBS Lett. 584 (15), 3242
3249. da Silva Santos, V., Bisen-Hersh, E., Yu, Y., Cabral, I.S.R., Nardini, V., Culbreth, M., et al., 2014. Anthocyanin-rich acai (Euterpe oleracea Mart.) extract attenuates manganese-induced oxidative stress in rat primary astrocyte cultures. J. Toxicol. Environ. Health, Part A. 77 (7), 390
404. Singh, S., Singh, D.K., Meena, A., Dubey, V., Masood, N., Luqman, S., 2019. Rutin protects t-butyl hydroperoxide-induced oxidative impairment via modulating the Nrf2 and iNOS activity. Phytomedicine 55, 92
104. Song, Y., Wen, L., Sun, J., Bai, W., Jiao, R., Hu, Y., et al., 2016. Cytoprotective mechanism of ferulic acid against high glucose-induced oxidative stress in cardiomyocytes and hepatocytes. Food Nutr. Res. 60 (1), 30323. Subbiah, M.T.R., 2006. Nutrigenetics and nutraceuticals: the next wave riding on personalized medicine. Translat. Res. 149, 55
61. Su, X., Jiang, X., Meng, L., Dong, X., Shen, Y., Xin, Y., 2018. Anticancer activity of sulforaphane: the epigenetic mechanisms and the Nrf2 signaling pathway. Oxid. Med. Cell Longev. 2018.

REFERENCES

69

Sun, Y., Zhang, J., Song, W., Shan, A., 2018. Vitamin E alleviates phoxim-induced toxic effects on intestinal oxidative stress, barrier function, and morphological changes in rats. Environ. Sci. Pollut. Res. 1
11. Takano, H., Momota, Y., Kani, K., Aota, K., Yamamura, Y., Yamanoi, T., et al., 2015. γ-tocotrienol prevents 5-FU-induced reactive oxygen species production in human oral keratinocytes through the stabilization of 5-FU-induced activation of Nrf2. Int. J. Oncol. 46 (4), 1453
1460. Teixeira, T.M., da Costa, D.C., Resende, A.C., Soulage, C.O., Bezerra, F.F., Daleprane, J.B., 2017. Activation of Nrf2-antioxidant signaling by 1, 25-dihydroxycholecalciferol prevents leptin-induced oxidative stress and inflammation in human endothelial cells
3. J. Nutr. 147 (4), 506
513. Thompson, L.P., Al-Hasan, Y., 2012. Impact of oxidative stress in fetal programming. J. Pregnancy. Article ID 582748. Available from: https://doi.org/10.1155/2012/582748. Tinggi, U., 2008. Selenium: its role as antioxidant in human health. Environ. Health Prev. Med. 13 (2), 102. Traber, M.G., Atkinson, J., 2007. Vitamin E, antioxidant and nothing more. Free Radical Biol. Med. 43 (1), 4
15. Trujillo, E., Davis, C., Milner, J., 2006. Nutrigenomics, proteomics, metabolomics and the practice of diets. J. Am. Diet. Assoc. 106, 403
414. Tsai, M.-S., Wang, Y.-H., Lai, Y.-Y., Tsou, H.-K., Liou, G.-G., Ko, J.-L., et al., 2018. Kaempferol protects against propacetamol-induced acute liver injury through CYP2E1 inactivation, UGT1A1 activation, and attenuation of oxidative stress, inflammation and apoptosis in mice. Toxicol. Lett. 290, 97
109. Tuzcu, M., Sahin, N., Orhan, C., Agca, C.A., Akdemir, F., Tuzcu, Z., et al., 2011. Impact of chromium histidinate on high fat diet induced obesity in rats. Nutr. Metab. (Lond). 8 (1), 28. Velika, B., Kron, I., 2012. Antioxidant properties of benzoic acid derivatives against superoxide radical. Free Radicals Antioxidants 2 (4), 62
67. Vellosa, J.C.R., Regasini, L.O., Khalil, N.M., Bolzani, Vd.S., Khalil, O.A., Manente, F.A., et al., 2011. Antioxidant and cytotoxic studies for kaempferol, quercetin and isoquercitrin. Ecl´etica quimica. 36 (2), 07
20. Wagner, A.E., Ernst, I., Iori, R., Desel, C., Rimbach, G., 2010. Sulforaphane but not ascorbigen, indole-3carbinole and ascorbic acid activates the transcription factor Nrf2 and induces phase-2 and antioxidant enzymes in human keratinocytes in culture. Exp. Dermatol. 19 (2), 137
144. Wang, X.J., Hayes, J.D., Henderson, C.J., Wolf, C.R., 2007. Identification of retinoic acid as an inhibitor of transcription factor Nrf2 through activation of retinoic acid receptor alpha. Proc. Natl. Acad. Sci. 104 (49), 19589
19594. Wang, F., Li, Y., Cao, Y., Li, C., 2015. Zinc might prevent heat-induced hepatic injury by activating the Nrf2antioxidant in mice. Biol. Trace Elem. Res. 165 (1), 86
95. Wang, Z., Zhang, H., Sun, X., Ren, L., 2016. The protective role of vitamin D3 in a murine model of asthma via the suppression of TGF-β/Smad signaling and activation of the Nrf2/HO-1 pathway. Mol. Med. Rep. 14 (3), 2389
2396. Wang, N., Tan, H.-Y., Li, S., Xu, Y., Guo, W., Feng, Y., 2017. Supplementation of micronutrient selenium in metabolic diseases: its role as an antioxidant. Oxid. Med. Cell Longev. 2017. Wang, G., Song, X., Zhao, L., Li, Z., Liu, B., 2018a. Resveratrol prevents diabetic cardiomyopathy by increasing Nrf2 expression and transcriptional activity. Biomed. Res. Int. 2018. Wang, Y., Wang, X., Zhang, L., Zhang, R., 2018b. Alleviation of acute lung injury in rats with sepsis by resveratrol via the phosphatidylinositol 3-kinase/nuclear factor-erythroid 2 related factor 2/heme oxygenase-1 (PI3K/Nrf2/HO-1) pathway. Med. Sci. Monitor Int. Med. J. Exp. Clin. Res. 24, 3604. Wardyn, J.D., Ponsford, A.H., Sanderson, C.M., 2015. Dissecting molecular cross-talk between Nrf2 and NFκB response pathways. Biochem. Soc. Trans. 43 (4), 621
626. Wei, M., Zheng, Z., Shi, L., Jin, Y., Ji, L., 2017. Natural polyphenol chlorogenic acid protects against acetaminophen-induced hepatotoxicity by activating ERK/Nrf2 antioxidative pathway. Toxicol. Sci. 162 (1), 99
112.

70

CHAPTER 2 NUTRIGENOMICS AND ANTIOXIDANTS

Weydert, C.J., Cullen, J.J., 2010. Measurement of superoxide dismutase, catalase and glutathione peroxidase in cultured cells and tissue. Nat. Protoc. 5 (1), 51. Wiseman, H., 1993. Vitamin D is a membrane antioxidant Ability to inhibit iron-dependent lipid peroxidation in liposomes compared to cholesterol, ergosterol and tamoxifen and relevance to anticancer action. FEBS Lett. 326 (1-3), 285
288. Wu, S., Hu, C., Tan, Q., Xu, S., Sun, X., 2017. Nitric oxide mediates molybdenum-induced antioxidant defense in wheat under drought stress. Front. Plant Sci. 8, 1085. Yan, S.-l, Wang, Z.-h, Yen, H.-f, Lee, Y.-j, Yin, M.-c, 2016. Reversal of ethanol-induced hepatotoxicity by cinnamic and syringic acids in mice. Food Chem. Toxicol. 98, 119
126. Yang, F., Li, B., Dong, X., Cui, W., Luo, P., 2017. The beneficial effects of zinc on diabetes-induced kidney damage in murine rodent model of type 1 diabetes mellitus. J. Trace Elem. Med. Biol. 42, 1
10. Yang, J.-T., Wang, J., Zhou, X.-R., Xiao, C., Lou, Y.-Y., Tang, L.-H., et al., 2018. Luteolin alleviates cardiac ischemia/reperfusion injury in the hypercholesterolemic rat via activating Akt/Nrf2 signaling. Naunyn Schmiedebergs Arch. Pharmacol. 391 (7), 719
728. Yin, J., Wang, A.-P., Li, W.-F., Shi, R., Jin, H.-T., Wei, J.-F., 2018. Time-response characteristic and potential biomarker identification of heavy metal induced toxicity in zebrafish. Fish. Shellfish. Immunol. 72, 309
317. Young, A.J., Lowe, G.M., 2001. Antioxidant and prooxidant properties of carotenoids. Arch. Biochem. Biophys. 385 (1), 20
27. Zhang, Z., Guo, Z., Zhan, Y., Li, H., Wu, S., 2017a. Role of histone acetylation in activation of nuclear factor erythroid 2-related factor 2/heme oxygenase 1 pathway by manganese chloride. Toxicol. Appl. Pharmacol. 336, 94
100. Zhang, C., Lin, J., Ge, J., Wang, L.-L., Li, N., Sun, X.-T., et al., 2017b. Selenium triggers Nrf2-mediated protection against cadmium-induced chicken hepatocyte autophagy and apoptosis. Toxicol. In Vitro 44, 349
356. Zhang, M., Xu, Y., Qiu, Z., Jiang, L., 2019. Sulforaphane attenuates angiotensin II-induced vascular smooth muscle cell migration via suppression of NOX4/ROS/Nrf2 signaling. Int. J. Biol. Sci. 15 (1), 148. Zheltova, A.A., Kharitonova, M.V., Iezhitsa, I.N., Spasov, A.A., 2016. Magnesium deficiency and oxidative stress: an update. Biomedicine 6 (4). Zheng, Z., Shi, L., Sheng, Y., Zhang, J., Lu, B., Ji, L., 2016. Chlorogenic acid suppresses monocrotalineinduced sinusoidal obstruction syndrome: the potential contribution of NFκB, Egr1, Nrf2, MAPKs and PI3K signals. Environ. Toxicol. Pharmacol. 46, 80
89. Zhu, C., Dong, Y., Liu, H., Ren, H., Cui, Z., 2017a. Hesperetin protects against H2O2-triggered oxidative damage via upregulation of the Keap1-Nrf2/HO-1 signal pathway in ARPE-19 cells. Biomed. Pharmacother. 88, 124
133. Zhu, C.-G., Liu, Y.-X., Wang, H., Wang, B.-P., Qu, H.-Q., Wang, B.-L., et al., 2017b. Active form of vitamin D ameliorates non-alcoholic fatty liver disease by alleviating oxidative stress in a high-fat diet rat model. Endocr. J. 64 (7), 663
673.

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3

Ashutosh Gupta and Abhay K. Pandey Department of Biochemistry, University of Allahabad, Allahabad, India

CHAPTER OUTLINE 3.1 Introduction ................................................................................................................................... 71 3.2 Liver Diseases and Their Overview .................................................................................................. 72 3.3 Physiological Role of Liver ............................................................................................................. 73 3.3.1 Carbohydrate Metabolism ............................................................................................ 73 3.3.2 Fat Metabolism .......................................................................................................... 74 3.3.3 Protein Metabolism and Storage of Vitamins ................................................................. 74 3.3.4 Neutralization of Toxic Substance ................................................................................ 74 3.4 Mode of Hepatotoxicity................................................................................................................... 74 3.4.1 Reactive Metabolites Formation ................................................................................... 74 3.4.2 Lipid Peroxidation and Redox Cycling........................................................................... 75 3.4.3 Effect of Chemical Agents on Major Cellular Systems .................................................... 75 3.4.4 Modification in Calcium Homeostasis........................................................................... 75 3.4.5 Drug-Induced Hepatotoxicity ....................................................................................... 76 3.5 Phytochemicals ............................................................................................................................. 79 3.5.1 Current Status of Therapeutic Plants ............................................................................ 80 3.5.2 Hepatoprotective Properties of Phytochemicals and Their Mode of Action........................ 80 3.6 Conclusion .................................................................................................................................... 91 Acknowledgment................................................................................................................................... 94 References ........................................................................................................................................... 94 Further Reading .................................................................................................................................. 104

3.1 INTRODUCTION The liver is the principal metabolic organ of the body that actively contributes in essential functions to regulate nearly all metabolic processes and homeostasis of the body. It is present in the upper right side of the abdomen with an average weight of 1.5 kg in a healthy person having a body weight of 75 kg. It performs more than 500 major functions including breakdown of food constituents to critical blood components, preservation of minerals and vitamins, production of essential Nutraceuticals and Natural Product Pharmaceuticals. DOI: https://doi.org/10.1016/B978-0-12-816450-1.00003-9 © 2019 Elsevier Inc. All rights reserved.

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plasma proteins and minerals, which are used in hormonal balance, metabolic processes, and detoxification of toxic compounds of the body (Ghany and Hoofnagle, 2005). Moreover, it is a major site for synthesizing blood-clotting factors which avert blood from clotting during circulation (Saleem et al., 2010). It also regulates the normal glucose level in fasting condition and promotes the glycogen metabolism (Michael et al., 2000). A wide range of studies suggested that the free radicals (reactive oxygen species (ROS)/RNS) exert oxidative stress which is a major cause of hepatic abnormalities like degeneration, necrosis apoptosis, swelling, etc. While in some other cases hepatic sicknesses are mostly triggered by chemicals and drugs when taken in very high quantities (Sharma et al., 2017), other causes of hepatic damage may include lipid peroxidation and covalent binding leading to consequent tissue injury. Free radicals such as peroxyl, superoxide, hydroxyl, and alkoxy radicals, etc. lead to damage of lipid membrane, protein, and nucleic acid (Singh et al., 2008; Pal et al., 2014). During hepatic injury the efficacy of natural antioxidant system is altered. Free radicals are produced by both from external factors (X-rays, UV radiation, pollutants) as well as internal factors (normal metabolic process in mitochondria). Intracellular concentration of free radicals is governed by both the generation by endogenous or exogenous factors and their elimination by various endogenous antioxidant system (enzymatic and nonenzymatic) (Haque et al., 2014). Even though there had been appreciable developments in conventional medical treatment in the past 20 years, drugs existing for the treatment of hepatic abnormalities were restricted in efficiency and could have provoked numerous adverse side effects. In response to these reasons that limit the use of conventional drugs, efforts were continuously being made to develop new sources of agents with hepatoprotective potential (Mamat et al., 2013). Therefore, the use of alternative medicines, predominantly herbal/plant-based treatments, has grown globally due to its therapeutic potential and less toxicity, to cure various diseases. The plant kingdom is a natural treasure of herbal medicinal agents. In recent years various therapeutic plants were evaluated to check their hepatoprotective potential in animal models. Traditional medicines and their formulations with favorable results against numerous pathological disorder have recently been considered as alternative therapies (Biswas et al., 2014). A number of natural compounds have been isolated and identified for their physicochemical and pharmacological activities.

3.2 LIVER DISEASES AND THEIR OVERVIEW Liver sickness is a dangerous disease that causes huge morbidity and mortality worldwide. It is a chief organ for degradation of drugs and chemicals, hence it protects living beings from toxic foreign materials. Xenobiotics, microorganisms, metabolic diseases, autoimmune diseases, inherited hepatic diseases, and hepatic malignancies are major causative agenst of hepatic abnormalities (Daniel, 2009). According to a study, about 1.3 million of the population of the world die due to viral hepatitis annually, over 350 million population are suffering chronically from hepatitis-B virus (HBV), and 170 million population are infected with hepatitis-C virus (HCV) (Lok et al., 2001; Daniel, 2009). The recent statistical analysis suggests that the global burden of hepatic complications has increased with time and has shown a huge impact on the overall population throughout the world. It is assumed that compensated cirrhosis and hepatic cancer will reach more than 80% in the year 2020. Besides the viral infections, increased ratio of alcohol consumption and obesity

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globally, it can be expected that the load of hepatic diseases associated with alcohol and nonalcoholic diseases will be increased twofold. Likewise, those persons having chronic hepatic diseases are more prone to develop severe infections like HIV infection and hepatic carcinoma (WHO, 2002).

3.3 PHYSIOLOGICAL ROLE OF LIVER The liver is the center of metabolic homeostasis (Fig. 3.1). Some of its major functions are described below.

3.3.1 CARBOHYDRATE METABOLISM The liver promotes the processing of food particles that are absorbed from the digestive tract after some time. It converts glucose into glycogen which is a storage form of carbohydrate. This glycogen can be reconverted into glucose if there is any demand of energy to operate cellular processes (Guyton and Hall, 2006).

FIGURE 3.1 Physiological roles of liver.

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3.3.2 FAT METABOLISM In the liver, fatty acids oxidation, as well as formation of lipoproteins, cholesterol, and phospholipids are conducted. Fatty acids are synthesized during lipid digestion and are used in the formation of cholesterol and other substances. The liver also play a major role in the conversion of certain amino acids into others (Guyton and Hall, 2006).

3.3.3 PROTEIN METABOLISM AND STORAGE OF VITAMINS The liver synthesizes blood-clotting protein and plasma proteins. If there are any irregularities in the liver, it can take more time in clot formation in comparison to the normal process. Albumin, another plasma protein formed by the hepatic cells, can bind with various water insoluble elements and promote osmotic pressure. The phagocytic cells of the liver produce acute-phase proteins in response to microbes. These proteins performed the inflammation process, tissue repair, and immune cells activation activities (Reichen, 1999). The liver also acts as a storage organ of certain micro and macromolecules. It stores vitamins including vitamins A, D, K, B12, fats, iron, and copper (Adi and Alturkmani, 2013; Sherwood, 1997). It also accumulates enough glucose in the form of glycogen to provide energy.

3.3.4 NEUTRALIZATION OF TOXIC SUBSTANCE The liver plays a critical task in eliminating body wastes, toxins, hormones, drugs, and other toxic xenobiotic compounds. These compounds are mixed with blood either by metabolic product formed within the body or in the form of drugs or other foreign complexities. Hepatic enzymes modify most of the toxins for their proper elimination through the urine. Breakdown of hemoglobin leads to the formation of bilirubin and is excreted in the form of bile through the liver (Adi and Alturkmani, 2013). Whereas, hepatic macrophages remove damaged red blood cells from the blood.

3.4 MODE OF HEPATOTOXICITY Xenobiotics or chemical agents induced toxicity on the liver may contain various mechanisms of cytolethality (Muriel and Rivera Espinoza, 2008; Sharma et al., 2019). Such mechanisms either have a direct impact on cellular organelles including nucleus, endoplasmic reticulum, microtubules, the cytoskeleton, and mitochondria or they have an indirect effect through the stimulation and prevention of signaling kinases, transcription factors, and gene-expression profiles. The resultant intracellular imbalance may lead to cell death caused by either cell necrosis or nuclear disassembly (apoptosis) or by swelling and cell lysis. Some of them are discussed in the subsequent sections.

3.4.1 REACTIVE METABOLITES FORMATION Many liver toxins such as viz. carbon tetrachloride (Boll et al., 2001), amodiaquine (Zhu et al., 2014), acetaminophen (Piver et al., 2001), isoniazid (Kumar et al., 2013), Metanil yellow (Sharma

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et al., 2018) are metabolically converted into reactive toxic metabolites and then bind covalently to the major cellular components thus inactivating major cellular functions (Muriel and Rivera Espinoza, 2008). Glutathione provides potential detoxification mechanism for most electrophilic reactive metabolites. Oxidative stress, alkylating agents, and excess substrates for conjugation can trigger the reduction of glutathione thus rendering cells to become more prone to the chemicals’ toxicity (Faghihzadeh et al., 2014). The reactive metabolites may also damage hepatic proteins, leading to an immune competent and immune-mediated injury.

3.4.2 LIPID PEROXIDATION AND REDOX CYCLING Lipid peroxidation is the most common factor associated with cell death due to the overproduction of free radicals which is caused by alteration in the intracellular pro-oxidant to antioxidant equilibrium in favor of pro-oxidants (Sharma et al., 2017). Lipid peroxy radicals increases cell membrane permeability, membrane proteins inactivation, decreases cell membrane fluidity, and loss of mitochondrial membranes polarity. Metal ions contribute in redox cycling while cycling of oxidized and reduced forms of a toxicant lead to the production of free radicals which suppress glutathione activity by oxidizing critical protein sulfydryl groups participated in enzymatic or cellular regulation or can induce lipid peroxidation. Intake of excessive ethanol triggers free-radical production, lipid peroxidation, and glutathione reduction (Saukkonen et al., 2006). Hydrocarbons linked with halogen, hydroperoxides, sodium vanadate, iodoacetamide, cadmium, acrylonitrile, and chloroacetamide are also suggested to exhibit hepatotoxicity because of lipid peroxidation.

3.4.3 EFFECT OF CHEMICAL AGENTS ON MAJOR CELLULAR SYSTEMS Toxic substance can directly attack certain major cellular components like plasma membrane, mitochondria, endoplasmic reticulum, nucleus, and lysosomes, and thus alter their properties. Hepatic toxins act as an uncoupling agent in mitochondrial electron transport process or directly as an inhibitor (Monshouwer et al., 1995). Covalent binding of intracellular proteins to drug reduces adenosine triphosphate (ATP) levels which in turn enhance actin protein disruption and integrity of cell membrane. Phalloidin, a toxin derived from mushroom increases plasma membrane permeability by binding with actin and thus damaging the cytoskeleton (Wieland and Faulstich, 1978). Toxins such as chenodeoxycholate, phenothiazines, chlorpromazine. and erythromycin show surfactant property in plasma membrane (Seeman, 1972).

3.4.4 MODIFICATION IN CALCIUM HOMEOSTASIS Calcium governs an inclusive range of essential physiological functions. Cytosolic-free calcium is present in a steadily lower concentration. The concentration of intracellular calcium ion is nearly 1027M whereas it is 1023M in the extracellular fluid. Hepatotoxicity induced by a chemical may be associated with calcium homeostasis modifications (Pounds and Rosen, 1988; Nicotera et al., 1990). Nonspecific increase in permeability of the plasma membrane, mitochondrial membrane, and SER membrane leads to calcium homeostasis alterations by upregulating intracellular calcium ion concentration. NADPH, a cofactor associated with calcium pump, may also disrupt calcium homeostasis when present in reduced concentration. Disturbance in calcium homeostasis leads to

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activation of several membrane destructive enzymes viz. proteases, ATPases, endonucleases, and phospholipases which act upon ATP synthesis, mitochondrial metabolism, and microfilament’s structures. Cadmium, acetaminophen, iron, quinines, and peroxides are some of them that show such a type of mechanism on liver injury.

3.4.5 DRUG-INDUCED HEPATOTOXICITY Drug-induced hepatic anomalies are the primary reason of acute liver failure worldwide (Deng et al., 2009; Kaplowitz, 2004; Lee, 2003). Nearly all drugs are considered as foreign materials to the body and thus are metabolized or eliminated by a wide range of biochemical transformations such as decline of fat solubility and change of biological properties (Fig. 3.2) (Tostmann et al., 2008). Adverse drug reactions can be classified into type-A or type-B reactions. Type-A reactions are dose-dependent and occur in a fairly steady time period. Individuals vulnerable to type-A reactions, usually result in direct toxicity of the native form drug or its metabolites (Pham et al., 1997), for example, acetaminophen-induced hepatotoxicity (Amar and Schiff, 2007) or phenytoin- induced hepatotoxicity (Shear and Spielberg, 1988). Type-B reactions are not directly associated with the pharmacological action of drug (Senior, 2008). It arises in a small population of individuals and persisst at doses that do not lead to toxicity. Additionally, they have not been reproducible in mammalian models (Kaplowitz, 2004), for example, troglitazone-induced hepatotoxicity (Deng et al., 2009) or isoniazid-induced hepatotoxicity (Kumar et al., 2013). Some of the drugs develop toxicity and possess potential adverse effects.

FIGURE 3.2 Metabolism of drug and its associated complications in liver.

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3.4.5.1 Antitubercular drugs Antitubercular drug-induced hepatic injury (ATDH) is a severe problem and a major cause of treatment disruption and alteration in routine treatment during tuberculosis (TB) management course (Khalili et al., 2009). ATDH leads to a high rate of morbidity and mortality wordwide. Elevations of serum transaminases are a common sign in the case of the antituberculosis treatment. However, hepatic damage can be dangerous when not identified at the initial stage or medication is interrupted during treatment. Drugs including isoniazid, paracetamol,l and pyrazinamide have been suggested to be highly toxic to the liver. The chance of antitubercular drug associated toxicity has been increased by various factors. Some of them are chronic viral infection, preexisting chronic liver disease, nutritional status, high intake of alcohol, older age, advanced stage of TB, contaminated food, overuse of hepatotoxic drugs, and inappropriate dose of drugs (Tostmann et al., 2008; Khalili et al., 2009). Detoxification of drugs and its metabolites are interrelated which depends on the potential of hepatic enzymes (Chang and Schaino, 2007). Most antitubercular drugs are lipid soluble and are transformed into aqueous compounds by phase I and II biotransformation enzymes in liver. Toxicity arises by isoniazid which is considered idiosyncratic, that is, reactive toxic metabolites rather than the native form of drug which are primarily responsible for toxicity. A rapid onset of toxicity was detected in the rabbit model after treatment with isoniazid at 3-hour intervals for 2 days (Sarich et al., 1996). Some animal models showed elevated serum transaminases levels for a maximum duration of 36 hours during hepatic necrosis. The mechanism of action of hepatotoxicity associated to rifampicin is not fully known and hence there is no proof for the presence of toxic metabolite of this drug (Westphal et al., 1994). Administration of rifampicin along with isoniazid increases the risk of developing hepatotoxicity (Steele et al., 1991). Rifampicin promotes isoniazid hydrolase which in turn increases hydrazine synthesis and thus leads to toxicity in combination. Another antitubercular drug pyrazinamide, inhibits the action of CYP450 isoenzymes (Maffei and Carini, 1980). But during the investigation of mammalian hepatic microsomes, it was found that it possesses a noninhibitory effect on the CYP450 isoenzymes (Nishimura et al., 2004).

3.4.5.2 Anticoagulants drug Oral anticoagulants drugs like phenprocoumon, ximelagatran, acenocoumarin, warfarin, heparin, and enoxaparin are frequently used for avoidance of clot formation in blood vessel and stroke (Arora and Goldhaber, 2006). Anticoagulant-induced hepatic abnormalities have been seen to be connected with asymptomatic increase of serum transaminases, clinically important hepatitis, and serious hepatic failure. Ximelagatran, warfarin, and dabigatran upregulates alkaline phosphatase (ALP); whereas, jaundice was identified with ximelagatran and warfarin (Arora and Goldhaber, 2006). Phenprocoumon-related hepatic injury associated with direct injury of hepatocytes by reactive metabolites resulted into amplified antigenicity and a consequent immune-allergic reaction. It also involves CYP450 enzymes that cause decline of ionic gradients, reduction of ATP levels, cell edema, and damage (Schimanski et al., 2004). Heparin is involved in direct toxicity, immunemediated hypersensitivity, and membrane modification reaction in liver (Carlson et al., 2001).

3.4.5.3 Anticonvulsants or antiepileptic drugs Anticonvulsant drugs may also be associated with hepatotoxicity. Clonazepam, primidone, chloral hydrate, sultiam, and diazepam are not causes of severe hepatic abnormalities. Sodium valproate is

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a prominent anticonvulsant with a lower rate of hepatotoxicity (Green, 1984). It is transformed into valproyl adenosine monophosphate and valproyl coenzyme A in the mitochondrial matrix. The valproate induction promotes the diminution of coenzyme A, thus affecting the intra-mitochondrial storage of this cofactor and impairs mitochondrial enzymes which are involved in ß-oxidation of fatty acids (Murray et al., 2008). Phenobarbital is hardly recognized to develop hepatic abnormalities with hepatocellular and cholestatic liver injury and also hypersensitivity reaction. Individuals who take phenytoin generally have threefold elevated levels of transaminase as compared to normal values (ULN). Intake of felbamate was expressively lowered due to its relation with aplastic anemia and sometimes hepatic injury (Deng et al., 2009).

3.4.5.4 Antihyperlipidemic drugs Ezetimibe that lowers the cholesterol by decreasing its absorption at the small intestinal brush border cell, sometimes leads to hepatic injury such as acute autoimmune hepatitis and chronic cholestatic hepatitis (Stolk et al., 2006). Fenofbrate activates an autoimmune hepatitis response specially when taken with statin medications (Alsheikh-Ali et al., 2004). Atorvastatin and lovastatinmediated hepatic abnormalities have been connected with a diversified action of liver damaged, normally occurring months after the beginning of the treatment (Bhardwaj and Chalasani, 2007). The mode of injury from antihyperlipidemic is classically hepatocellular or mixed in nature with unusual cases of pure cholestatic hepatitis (Chitturi and George, 2002; Parra and Reddy, 2003). Provastatin has been reported to develop acute intrahepatic cholestasis (Hartleb et al., 1999). Simvastatin-induced hepatic abnormalities are supposed to arise due to drug-to-drug interactions (Ricaurte et al., 2006).

3.4.5.5 Antiretroviral and antimalarial drugs Liver destructive action of antiretroviral drugs revealed that three different classes, including protease inhibitors, nucleoside reverse transcriptase inhibitors (NRTIs), and nonnucleoside reverse transcriptase inhibitors (NNRTIs) are mainly responsible for toxicity (Brind, 2007). They develop hepatic abnormalities by various mechanisms such as mitochondrial impairment by nucleoside equivalents like stavudine and didanosine, hypersensitivity reactions by nevirapine, efavirenz, or abacavir, direct hepatic harm by using maximum doses of ritonavir and immune reconstitution process, mainly in rigorously immunosuppressed individuals with primary chronic HBV. Nucleoside analogs (NRTIs), particularly zerit, videx, and retrovir are linked with hepatic steatosis and lactic acidosis (Piroth, 2005). Steatohepatitis promotes the advancement of hepatic fibrosis in a person with severe HCV infection. NNRTIs, especially viramune, are related to hepatic necrosis and hepatitis. It is assumed that for the liver, nevirapine is more toxic in comparison to efavirenz (Van Leth et al., 2004). The underlying prolonged HCV infection promotes the risk of elevation of hepatic enzyme. Inhibitors of protease have been concerned with periods of hepatotoxicity, with fosamprenavir/low-dose ritonavir, lopinavir/low-dose ritonavir, and nelfnavir being less toxic (Sulkowski et al., 2004), and tipranavir/ low-dose ritonavir being more hepatotoxic (Rockstroh et al., 2006). Indeed, a person suffering with chronic HCV is at risk of enzymatic alterations following exposure to most antiretroviral medications. Amodiaquine, an antimalarial drug can develop liver disorder in human beings by transforming into reactive metabolite, iminoquinone by hepatic peroxidases and microsomes (Shimizu et al., 2009). The reactive metabolites can permanently bind to proteins which develop toxicity by altering

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the cellular function. These types of individuals have been observed to have antidrug IgG antibodies (Clarke et al., 1991). Amodiaquine can induce immune response in a mammalian model similar to that in humans, but it is not enough to result in clinical toxicity (Clarke et al., 1990).

3.4.5.6 Chemotherapeutic drug, glucocorticoids, and anabolic androgenic steroids Chemotherapeutic medications use poisonous chemicals or drugs like antimetabolites, antitumor antibiotics, platinum, tyrosine kinase inhibitors, alkylating agents, biologic response transformers, and androgens to destroy carcinoma cells (King and Perry, 2001; Perry, 1992). During treatment process, if these toxins accumulate in the body faster than its degradation in the liver, hepatic abnormalities arises (Lim et al., 2010). Chemotherapeutic drugs alone or in association with other drugs may develop liver toxicity or hypersensitivity reactions (King and Perry, 2001). Glucocorticoids enhance storage of glycogen in hepatocytes. Administration of steroidal drugs is an unusual cause of inflamed liver in children, while prolonged use of steroids leads to developing steatosis in human beings (Iancu et al., 1986; Alpers et al., 1982). Anabolic androgenic steroids, generally referred to as nutritional supplements, cause severe hepatotoxicity (Saukkonen et al., 2006; Kafrouni et al., 2007).

3.4.5.7 Nonsteroidal antiinflammatory drugs Nonsteroidal antiinflammatory drugs (NSAID) like acetylsalicylic acid elevate hepatic enzymes and develop acute cytolytic, cholestatic, or mixed hepatitis conditions. Serum transaminases and ALP are specific liver markers that are used as an early warning sign for hepatic abnormalities. In critical cases, there may be supplementary signs and symptoms of anorexia, vomiting, nausea, abdominal pain, weakness, and jaundice along with increased prothrombin time and bilirubin level (Manov et al., 2006). In that case, NSAID both dose-dependent and idiosyncratic-based mechanism have been involved. Phenylbutazone and aspirin have been associated with intrinsic hepatotoxicity. Whereas, Ibuprofen, piroxicam, sulindac, diclofenac, indomethacin, and phenylbutazone are concerned with idiosyncratic reaction; the biochemical and clinical significance of diclofenac in living beings are concerned with both impairment of ATP production by mitochondria and reactive metabolites formation specifically N, 5-dihydroxydiclofenac, which leads to direct injury.

3.5 PHYTOCHEMICALS Plants are the major source of medications in folk medicinal systems, nutraceuticals, pharmaceutical intermediates, modern medicines, food supplements, and also act by adding chemical moieties in synthetic medicines (Dewick, 1996). Phytochemicals are categories under several classes such as flavonoids, phenol, carotenoids, alkaloids, tocopherols, terpenoids, polyphenols, saponins, phytosterols, and organosulfur compounds. Phytochemicals within planst generally provide protection against pests, pathogens, predators, and the external environment (Cowan, 1999). There are more than 7500 different polyphenolic compounds are identified in plant kingdom which are medicinally important. Grains, Cereals, fruits, legumes, nuts, vegetables and spices are rich in polyphenols (Opara and Rockway, 2006). A good knowledge of essential and nonessential compounds of plant origin and their actions for biological activities in the term of health and diseases are necessary for

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accepting nutrition as a tool for health management (Gupta et al., 2017). Natural compounds are widely present in diets and have potential to regulate various metabolic pathways, which protect living beings from various ailments. Broad spectrum in vitro, in vivo, and clinical studies suggested that the natural bioactive compounds effectively govern acute and chronic hepatic complications (Opara and Rockway, 2006).

3.5.1 CURRENT STATUS OF THERAPEUTIC PLANTS Use of herbal formulation throughout the world tended to decrease in the late 19th to early 20th centuries. The World Health Organization’s (WHO, 2001) report revealed that around 60% of the world’s population uses traditional medicine, while nearly 80% of the population of developing countries are completely based upon traditional system of medicine (Fransworth, 1994). Currently, a folk herbal medicinal system is used in China, India, Nepal, Bhutan and other developing countries (Pandey, 2007). Medicinal plants are actively used in modern drugs by providing active compounds upon which a new drug is synthesized. Newman and coworker (2003) reported that nearly 75% of antiinfectious drugs and 60% of anticancer drugs approved during 1981
2002, have been derived from natural resources, although 61% of all newly discovered chemical moieties recommended as a drugs during the same period were inspired by natural compounds (Gupta et al., 2005). Hence the search for new medicinal herbs for drug advancement and dietary ingredients have enhanced in the last few years. Botanists, microbiologists, biochemist and pharmacologists are currently discovering medicinal herbs for phytochemicals and active components that would be useful for management of various diseases (Mishra et al., 2013).

3.5.2 HEPATOPROTECTIVE PROPERTIES OF PHYTOCHEMICALS AND THEIR MODE OF ACTION Bioactive compounds are a natural source of antioxidants and antiinflammatory biomolecules, which are actively used in amelioration of hepatic injury. Generally they are profusely present in plants such as phenol, flavonoids, alkaloids, polyphenols, terpenoids, glycosides, and saponins. Several in vivo, in vitro, and ex-vivo studies have suggested that bioactive components possess immunomodulatory, antioxidant, antimicrobial, antimutagenic, hypoglycemic, hypolipidemic, antiinflammatory, gastroprotective, anticancer, and chemopreventive activities (Kumar and Pandey, 2013). Bioactive components suppress the antagonistic effects of drugs/chemicals and their metabolites. These compounds up-egulate intracellular signaling pathways and trigger Nrf2 molecule through initiation of the P1K3/AKt and extracellular-signal-regulated kinase (ERK), and thereby it operates various transcriptional factors but alternately it adversely regulates SP/NR1 signaling pathways. In general, bioactive compounds perform a critical role in neutralization of oxidative stress induced by drugs/chemicals and normalizes intracellular enzymes, protects cells from toxicity, and detoxifies various toxic compounds from the cell.

3.5.2.1 Glycyrrhizin Glycyrrhizin, an active constituent of Glycyrrhiza uralensis, is used as a folk medicine in hepatitis. Fujisawa et al. (2000) suggested that it possesses significant antiinflammatory properties in hepatic

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and other cellular organs. Glycyrrhizin regulates the cytolytic activity of complement system by stimulating both alternative and classical pathways. Additional studies demonstrated that glycyrrhizin reduces the lytic process where membrane attack complex is formed. In vivo analysis has shown that glycyrrhizin can prevent hepatic inflammation by increasing the secretion of interleukin-10 (IL-10) in concanavalin-A (Con A)-induced hepatitis in animal model. Advance studies on mechanism disclose that glycyrrhizin can alter the mouse dendritic cells properties with autoimmune hepatitis and enhance antiinflammatory cytokines’ production (Abe et al., 2003). A European clinical study revealed the medicinal properties of glycyrrhizin against viral hepatitis. Sixty-nine out of seventy-two individuals completed treatment, in the untreated group, there was no change observed in ALT level. Whereas, three and six-time glycyrrhizin-treated individuals recovered ALT enzyme toward normal level at the end of treatment. In the six-time treated group, 20% (3 of 15) of individuals attained normal ALT levels and the three-time treatment group, the result was about 10% (4 of 41). No significant side effects have been observed during the study (Van Rossum et al., 2001).

3.5.2.2 Resveratrol Resveratrol (3,5,40 -trans-trihydroxystilbene), a polyphenolic compound, has been isolated from grapes, red wine, peanuts, berries, and other natural sources. It possesses antioxidant, antiinflammatory, anticarcinogenic, and antifibrogenic properties (Mates et al., 2011; Chvez et al., 2008). During the process of metabolic breakdown it is converted into resveratrol sulfate and a small fraction of resveratrol glucuronide (Yu et al., 2002). When resveratrol was given in the form of aglycone or glucuronide, it promotes enterohepatic circulation (Marier et al., 2002). Williams et al. (2009) on their study reported that high-purity transresveratrol at several times of exposure and doses did not show any kind of toxicity. Furthermore, they did not find any adverse effect on 700 mg/day for 90 days as the higher dose and time of exposure. Cheng et al. (2012) revealed that resveratrol can trigger ERK signaling pathway, which in turn enhanced the activation and translocation of Nrf2 to the nucleus, thus upregulatesd HO-1 and glyoxalase expression. Another study also supported that resveratrol by promoting the translocation of Nrf2 to the nucleus, provided an alternative pathway for protection from oxidative stress (Bagul et al., 2012). Resveratrol lowers the acetylation of peroxisome proliferator-activated receptor gamma coactivator 1-a and upregulates its activity by promoting protein deacetylase sirtuin 1, thus improving mitochondrial function and protecting against metabolic abnormalities (Lagouge et al., 2006). In an experiment designed by Crowell et al. (2004) suggested that resveratrol at the highest dose (3000 mg/day for 4 weeks) leads to renal abnormalities with a decrease body weight, food intake, and other tissue-specific markers lesions.

3.5.2.3 Tragopogon porrifolius Tragopogon porrifolius (family Asteraceae) is well known for its edible shoot and root (Mroueh et al., 2011). The nutritive importance of this plant is related to vitamins, polyphenols, fructooligosaccharides, and monounsaturated and essential fatty acids, possesses probiotic activity on the intestinal microflora. Hentriacontane, hexadecanoic acid, hexahydrofarnesylacetone, and 4-vinyl guaiacol, are some of the most abundant bioactive compounds present in T. porrifolius (Konopinski, 2009; Formisano et al., 2010). It has shown hepatogenic/hepatoprotective property in various hepatic abnormalities induced by diverse toxic agents including drugs, chemicals, pollutants, and parasites, bacteria, or viral infections. These therapeutic attributes of plants are associated

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with the polyphenolic compounds. Antioxidant efficacy of methanolic extract of T. porrifolius aerial part against CC14-mediated hepatic injury in rodents showed enhanced activity of hepatic antioxidant enzymes in a dose-dependent manner. Nearly 250 mg/kg concentration of extract increases the activity of SOD, CAT, and GST. Constituently, in CC14-mediated hepatic injury, the plant extract restored the activity of AST, ALT, and LDH toward normal level (Govind, 2011). Whereas, T. porrifolius stem aqueous extract during inflammation, lipemia, gastric ulcer, oxidative stress, glycemia, and hepatotoxicity showed significant reduction in the levels of serum glucose, cholesterol, triglyceride, and hepatic enzymes. In addition, T. porrifolius also exhibited potent radical scavenging activity (Zeeni et al., 2014).

3.5.2.4 Silymarin Silymarin is a combination of flavonolignans extracted from Silybum marianum (milk thistle seeds). Major constituents of silymarin comprises silibinin, silidianin, silicristin and isosilibinin. Silibinin, an active compound of silymarin has been extensively used as hepatoprotective and anticancerous agent. Bonifaz et al. (2009) studied the antiviral efficacy of silymarin and suggested that it can suppress protein expression and reduce multiplication of HCV core mRNA. The antiviral activity of silymarin differs because of interferon which suppresses the JAK/STAT signaling pathway. It prevents the access and transmission of HCV by averting microsomal triglyceride transfer protein activity and decreases production of apolipoprotein B. Mayer and coworkers (2005) on their study reported therapeutic efficacy of silymarin against HBV and HCV. They suggested that in hepatitis patients silymarin can decrease serum transaminases levesl, although the serum viral content and histology have not been altered by silymarin. A clinical study on the immunomodulatory activity of silymarin against hepatitis-C patient revealed that it can prevent inflammation during in vivo and in vitro analysis. It also decreases the production and proliferation of T-cell by lowering proinflammatory cytokine with enhancing antiinflammatory IL-10 (Adeyemo et al., 2013). Silibinin also showed the inhibitory effect on HCV by suppressing clathrin-dependent trafficking. It promotes assembly of clathrin-coated pits and vesicles in hepatocytes and terminates the clathrin associated endocytic pathway by disturbing the absorption and trafficking of transferrin (Blaising et al., 2013).

3.5.2.5 Phyllanthus niruri Phyllanthus niruri is a subtropical plant, widely spread throughout the world. It is used as folk medicine against chronic hepatitis, intestinal infections, and kidney disease (Liu et al., 2014; Ibrahim et al., 2013). Quercetin rhamnoside, quercetin glucoside, gallic acid, and geranin are some major bioactive compounds identified in P. niruri which possess hepatoprotective, antibacterial, and antiviral properties (Amin et al., 2012). In the past few years, studies were designed to disclose the antiviral property and safety of P. niruri by chemical and biochemical experiments. Lam et al. (2006) reported that P. niruri ethanolic fraction could suppress HBsAg production with downregulating the expression of HBsAg mRNA which shows that its mechanism may be associated with the upregulation of annexin A7 protein.

3.5.2.6 Salvia miltiorrhiza Salvia miltiorrhiza is a folk Chinese medicine used for the management of cardiovascular and cerebrovascular disorder. Recent studies have proposed that it can upsurge blood circulation in

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hepatocytes to suppress the potential destruction by removing toxic compounds from the liver. The active compound of S. miltiorrhiza can also possess hepatoprotective efficacy against CCl4 associated hepatotoxicity. It shows hepatic protection due to down-regulation of NF-kB and p38 signaling pathways in hepatic Kupffer cells (Yue et al., 2014). Treatment of high iron comprising mice with S. miltiorrhiza will recover normal morphology of liver, reducing iron accumulation and downregulating the expression of collagens (type I and III), TGF-ß mRNA and triggering the expression of matrix metalloprotein-9 mRNA in the hepatocytes. Moreover, S. miltiorrhiza can also reduce malondialdehyde (MDA) content and increase SOD activity and glutathione (GSH) content while down-regulating tumor necrosis factor (TNF)-α, IL-1a, and caspase-3 expression (Zhang et al., 2013a,b).

3.5.2.7 Gallic acid Gallic acid, a trihydroxybenzoic acid is a major constituent of Punica granatum pericarp. Extensive studies have proven that it has strong antiobesity and antioxidant activities. Chao and cowerker (2014) revealed that it recovers the glucose and lipid metastasis associated anomalies in NAFLD mice. It shows hepatoprotective efficacy by regulating amino acids, choline, lipid, and glucose metabolism. Histological study of high fat diet-induced NAFLD rat indicated that the lipid droplets were remarkably reduced in gallic acidtreated group than control group. Cholesterol level and triacylglycerol were also found to be expressively lesser after gallic acid treatment. Moreover, gallic acid administration reduced oxidized glutathione (GSSG) content and amplified the antioxidative enzyme level. These observations suggested that gallic acid can suppress NAFLD associated oxidative stress, dyslipidaemia and hepatosteatosis in rats (Hsu and Yen, 2007).

3.5.2.8 Baicalin Baicalin (C21H18O11) is an active constituent of Scutellaria baicalensis and capable of protecting the liver from oxidative damage by promoting fatty acid binding protein expression and activity of intracellular enzymes (Ai et al., 2011). In vivo studies revealed that it contains antiinflammatory, antioxidant, and antiapoptotic properties, and supports its hepatoprotective efficacy during hepatic ischemia/reperfusion induced aberrations (Kim et al., 2010). Wan et al. observed that a diet having baicalin (0.25% and 1%) possesses hepatoprotective effects against excessive iron intake associated with hepatotoxicity in mouse during a 50 day treatment. The mechanism behind this may be an iron chelation and antioxidant property of baicalin (Zhao et al., 2005). Baicalein, (C15H10O5), another bioactive component extracted from S. baicalensis, also established agent against hepatic abnormalities. A recent study demonstrated that baicalein promotes hepatic cells regeneration by modifying IL-6 and TNF-a facilitated signaling pathways (Huang et al., 2012). Moreover, molecular mechanisms of apoptosis in hepatocytes were shown to have a protective effect on mitochondria, prevention of the cytochrome C oozing, decrease of Bax/Bcl-2 ratio, and reduction of transcription factor phosphorylation (NF-kB, JNK and ERK) (Wu et al., 2010).

3.5.2.9 Prangos ferulacea Prangos ferulacea is an Iranian herbal medicine commonly used in gastrointestinal abnormalities. In addition to Iran, other species of this genus are found in Caucasia, Central Asia, and East Europe to Turkey. It has been used in traditional medicine such as emollient, carminative,e and tonic for gastrointestinal complications, sedative, antibacterial, antiviral, antifungal, antihelminthic,

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antiinflamatory, and antiflatulent. Flavonoids, alkaloids, sesquiterpenes, saponins, coumarines, tannins, monoterpenes, and terpenoids are essential constituents identified in P. ferulacea. It was found that the oils isolated from fruits and leaves were rich in monoterpenes, mainly α- and β-pinene, while some of them showed antioxidant activity against oxidative damages. In a study, the antioxidant efficacy of P. ferulacea is described to be higher in comparison to α-tocopherol. Hydroalcoholic extract of P. ferulacea modified hepatic physiology and the activities of serum AST and ALT. In alloxan-induced diabetes in rats, the serum ALT and AST levels increased significantly (Massumi et al., 2007; Akhgar et al., 2011). Moreover, hepatic necrosis, vacuole formation in cytoplasm and lymphocytic inflammation was also observed. Treatment of diabetic rats by root extract exhibited remarkable decrease in enzymes. Hydroalcoholic extract of root has also shown alterations in aminotransferases activity and prevents the histopathological changes in the liver associated with alloxan-induced diabetes (Kafash Farkhad et al., 2012).

3.5.2.10 Dioscin Dioscin is a steroidal saponin found exclusively in Dioscorea opposita and has been medicinally accepted for their protective activity in fatty liver. Recent studies validated that it can slow down the process of lipid storage in the liver and hence reduced body weight, enhanced energy expenditure with more oxygen consumption, and decreased serum AST, ALT levels. Another study on mechanisms explored that dioscin combats oxidative damage, prevents inflammation, prevents triglyceride and cholesterol synthesis, reduces mitogen-activated protein kinase phosphorylation levels, triggers β-oxidation of fatty acid, and enhances autophagy to improve fatty liver conditions. These outcomes suggested that dioscin may be a suitable compound for obesity and NAFLD treatment (Liu et al., 2015). Various other studies also revealed its tremendous protective property against alcoholic fatty liver by countering alcohol-induced oxidative stress, inflammatory cytokine production, apoptosis, mitochondrial function, and in vivo hepatic steatosis (Xu et al., 2014).

3.5.2.11 Schisandra chinensis Recent therapeutic studies on Schisandra chinensis reported that it may control the body’s humoral balance, trigger immune responses, and possess anti-HBV properties (Yim et al., 2009). Xue et al. (2015a,b) isolated and studied seven new lignans and a schischinone, along with some known lignans from its fruit. They observed that two lignans showed remarkable anti-HBV property by preventing HBV DNA replication with less significant hepatotoxicity. Schisandrin B, a dibenzocyclooctadiene compound present in S. chinensis fruit possesses healing property against hepatitis. The antiinflammatory activity of Schisandrin B was studied by Checker et al. (2012) and disclosed that it stimulated translocation of nuclear factor erythroid-derived factor 2-related factor (Nrf2) and enhanced the transcription of HO-1. Schisandrin B also prevented the translocation of NF-kB in stimulated lymphocytes and down-regulated the expression of downstream inflammation related genes.

3.5.2.12 Periplocoside A Preplacoside A (PSA), a glycoside of Preplacoside sepium is exclusively used in rheumatoid arthritis as traditional medicine. It was found that pretreatment with PSA has remarkably improved the hepatic damage, secretion of interleukin-4, interferon-γ, and ALT levels were intensely reduced, which further repressed the hepatic necrosis and normalized the hepatic function in vivo. In vitro

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evaluation revealed that PSA decreased cytokines secretion, which is necessary for inflammatory response viz., IL-4, and IFN-γ produced by natural killer T-cells upon stimulation with anti-CD3 mAb or a-galactosylceramide. Moreover, no significant toxicity of PSA has been observed during in vitro and in vivo analysis. These findings supported that PSA may have a therapeutic potential for autoimmune-related hepatitis management in humans (Wan et al., 2008; Zhang et al., 2009).

3.5.2.13 Astragalus membranaceus Astragalus membranaceus stimulates hepatic metabolic processes, enhances lung activity and gastrointestinal tract, stimulates wound restoration, and provides relief from fatigue. Saponins and flavonoids including calycosin, formononetin, astragaloside, and calycosin-7-Obeta-D-glucoside are the main bioactive compounds present in A. membranaceus (Cai et al., 2015; Yu et al., 2014). Recent studies proposed that it could alter immunologic system, prevent virus development, and prevent cancer cell proliferation (Gao et al., 2014; Liu, 1991). Some researchers explored the beneficial properties of A. membranaceus in an individual with viral hepatitis. Furthermore, in vivo analysis suggested that it prevents DNA replication in duck HBV. A. membranaceus treatment also declines pathological alterations in duck HBV than the untreated group. Advance molecular studies have supported that active components of A. membranaceus suppress HBV activities which may be due to the presence of triterpenoid saponin (Wang et al., 2009).

3.5.2.14 Argimonia eupatoria Argimonia eupatoria is employed for the treatment of various disorders such as inflammation. Its aqueous extract enrich numerous phenolic compounds while ethyl acetate extract has shown to possess antioxidant potential with lower toxicity (Correia et al., 2007). A. eupatoria is rich in phenolic, coumarins, tannins, terpenoids, and flavonoidal compounds viz. coumaric acid, quercitrin, chlorogenic acid, gallic acid, and protocatechuic acid (Giao et al., 2009). The hepatoprotective activity of A. eupatoria was evaluated against diethylnitrosamine and CC14-mediated hepato-carcinogenesis, whereas, aqueous extract was tested against ethanol-induced hepatic injury. Oral administration of A. eupatoria extract at concentration 10, 30, 100, and 300 mg/kg against chronic consumption of ethanol pronouncedly normalized serum aminotransferase activities and pro-inflammatory cytokines. CYP450 activity and lipid peroxidation were elevated with reduced glutathione concentration during ethanol consumption. Plant extract also mitigated oxidative stress and toll-like receptorrelated inflammatory signaling (Yoon et al., 2012).

3.5.2.15 Panax notoginseng Panax notoginseng is a member of genus Panax. It has been found that P. notoginseng extracts reduced ethanol-induced lipid accumulation by suppressing the formation of MDA, glutathione (GSH) and ROS, downregulating IL-6 and TNF-α levels, along with promoting SOD activity in liver and prevent cytochrome P450 2E1 (CYP2E1) induction (Ding et al., 2015; Yang et al., 2009). In vivo analysis of P. notoginseng against NAFLD individuals revealed that saponins present in it can release oxidative stress and insulin resistance. Concentration of MDA, hydroxy radical (OH_), and pro-inflammatory cytokine (TNF-α) decreases after P. notoginseng administration. Whereas, total antioxidant capacity and SOD activity were improved with upgraded insulin resistance.

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3.5.2.16 Puerarin Puerarin is a form of isoflavones obtained from Pueraria lobata. It stimulates hepatic metabolic function and lowers serum ALT, AST, and total-bilirubin level with lesser ECM contents while increases the amount of albumin and total protein in hepatic fibrosis. In vivo study suggested that puerarin could prevent the CCl4-induced liver fibrosis. Its mechanisms may be related with the alteration of peroxisome proliferator-activated receptor (PPAR)-γ protein expression and PI3K/Akt signaling pathway (Guo et al., 2013). Puerarin associated TNF-α/NF-kB signaling may also promote antifibrosis efficacy in liver. Moreover, puerarin administration resulted in a decline expression of TNF-α and NF-kB, the inflammatory response in liver was regularized and metabolic activities were also enhanced (Li et al., 2013). Puerarin can also induce apoptosis in hepatic stellate cells, which perform a crucial role in hepatic fibrosis. Furthermore, the mechanism associated studies revealed that puerarin in hepatic stellate cells induced apoptosis by down-regulation of bcl-2 mRNA cells (Zhang et al., 2006).

3.5.2.17 Camptothecin Camptothecin is referred to as a toxic quinoline alkaloid, extensively used as a DNA topoisomerase-I suppressor in cancer treatment. It is typically isolated from Camptotheca acuminata stem or bark and worked as an anticancer agent in folk Chinese medicine. Li et al. (2011) observed that it can down-regulate SMMC-7721 cell progression by blocking S and G2/M stages of cell cycle and promote mitochondrial associated apoptosis pathway. It can also upregulate TRAILmediated apoptosis in HCC cells by suppressing free radicals formation and ERK/p38-dependent DR5. Additional investigation supported HCC cells pretreated with antioxidants or DR5 specific inhibitors of p38 and ERK can suppress camptothecin- TRAIL-related cell apoptosis by preventing DR5 expression (Jayasooriya et al., 2014). In vivo studies supported that the camptothecin in combination with N-trimethyl chitosan (CPT-TMC) may increase solubility and enhance potential for hepatic cancer treatment. In liver oncogenic BALB/c mice model, CPT-TMC remarkably reduces cancer progression and lymphatic metastasis along with extended survival time, while no significant side-effect have been observed. Thus, CPT-TMC combination is a nontoxic and effective medicinal compound for hepatic cancer therapy (Zhou et al., 2010).

3.5.2.18 Citrullus lanatus Citrullus lanatus fruits are edible as a febrifuge when ripe completely or almost putrid. Its fruit is diuretic and useful for the treatment of dropsy and kidney stones. Fruit peel is recommended in diabetes and alcoholic toxicity. C. lanatus aqueous extract is a good source of lycopene, glucose, vitamin C, fiber, and β-carotene. Watermelon juice suppresses SOD activity and LDL-cholesterol, while enhances CAT activity and HDL-cholesterol, which could reveal its antioxidant property (Georgina et al., 2011). The majority of cucurbitacin has shown cytoprotective activity against HepG2 cells. Cucurbitacin was suggested to have high efficacy as antifibrosis agent. Administration of CC14 once in a week for 28 days caused remarkable upsurge of hepatic serum markers viz. AST, ALT and total bilirubin, while there was a reduction in albumin as compared to the untreated group. Furthermore, CC14 along with ursodeoxycolic acid or watermelon juice appreciably diminished these alterations. After CC14 administration, the LPO level elevated in kidney, brain, and liver tissues. Meanwhile, ursodeoxycolic and acid watermelon juice treatment inhibited

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increment in LPO. Outcomes suggested that, watermelon juice protecedt liver from CC14-induced toxicity probably due to the antioxidant potential and prevention of production of lipid peroxide (Altas et al., 2011).

3.5.2.19 Curcumin Curcumin is a diphenylheptanoid extracted from turmeric. It is mainly used as food colorant and has also been recommended in various studies for its significant anticancer effects in in vitro and in vivo analysis. Notarbartolo et al. (2005) revealed that when curcumin is used alone or in combination with doxorubicin or cisplatin, it can suppress cancer cell propagation and promote apoptosis in the liver. Further studies suggested that curcumin altered activation of NF-kB and IAP gene expression. For curcumin-resistant hepatic carcinoma cells, a recent analysis has explored that Chk1-associated G2/M cell cycle block may be linked with curcumin resistance and Chk1 could be an effective site for future analysis in retreating resistance and promoting the clinical efficacy of curcumin (Wang et al., 2008).

3.5.2.20 Berberine Berberine is a quaternary ammonium salt obtained from plant of Berberis, such as Coptis chinensis, that has been proposed as a potent natural compound which prevents triglyceride accumulation (Fan et al., 2013). It can promote insulin resistance in NAFLD by upregulating the expression of insulin receptor substrate-2 and altering signaling pathway associated with insulin (Xing et al., 2011). In a study berberine-containing nanoparticles (BBR-SLNs) can release hepatosteatosis in by lowering lipogenesis and enhancing lipolysis in hepatocytes. Additional investigation of mechanisms suggested that these nanoparticles can lower the lipogenic genes expression such as stearoyl-CoA desaturase, sterol regulatory element-binding protein 1c and fatty acid synthase, and upregulate lipolytic gene expression including carnitine palmitoyltransferase-1 (Xue et al., 2015a,b).

3.5.2.21 Hesperidin Hesperidin (C28H34O15) is a glycosidic flavanone present enormously in citrus fruits. It is assumed that hesperidin play an important role in plant defense system. In vitro studies proposed that it act as a good antioxidant and maintain blood vessels’ integrity (Farombi et al., 2008). Hesperidin has strong healing property against DNA damage, suppressing the activity of micronuclei damaged by UV-irradiation (Hosseinimehr and Nemati, 2006). It can retrieve the liver against doxorubicininduced hepatotoxicity by boosting the activities of serum and tissue-specific enzymes. In addition, it has shown a remarkable rise in hepatic glutathione level, glutathione peroxidase, glutathione-Stransferase, and peroxidase activities, and has lowered the lipid peroxidation concentration. Pretreatment with rutin and hesperidin may cure the liver from doxorubicin-induced injury (Hozayen et al., 2014). Hesperidin also possesses anticancer activity against colon, esophagus, tongue, and urinary bladder carcinoma (Tanaka et al., 2000).

3.5.2.22 Bupleurum chinense Bupleurum chinense is commonly used herbs for management of exterior syndrome in ancient Chinese medicine. Its leaves have been supposed to be a less medicinally active part in Chinese medicine, but a recent investigation has recommended that the saikosaponins isolated from leaves

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possess appreciable antioxidant and hepatoprotective activities. An in vitro study revealed that saikosaponins possess radical scavenging efficacy against DPPH radicals and can reduce superoxide anion synthesis in hepatocytes (Liu et al., 2006). It is present in different isoforms and each form may have different biological property. Studies during the past few years on saikosaponin-C have been observed in which the HBV-infected hepatocytes when co-cultured with saikosaponin-C showed significant reduction in HBV antigen expression in growing medium (Chiang et al., 2003). Saikosaponin-B2 also possesses appreciable antiviral activity. In vitro analysis found that it can downregulate early entry of HCV by neutralizing virus particles, preventing its attachment and fusion, and hence inhibiting HCV infection in primary human hepatocytes (Lin et al., 2015).

3.5.2.23 Cynara scolymus Cynara scolymus traditionally used for the treatment of digestive disorders, moderate hyperlipidemia, and hepatic bilary diseases. Leaf extract was examined for the presence of luteolin, cynarin, caffeic acid, chlorogenic acid, and other polyphenol and flavonoid compounds, which possess antioxidant activities. C. scolymus leaf extract has been useful in hepatic complications (Gebhardt, 1997). It also positively controls the alterations in rat liver enzymes induced by CC14 along with histopathological impairment (Fallah Huseini et al., 2011). In artichoke extract pretreated rats transaminase activity remarkably declined while histopathological modifications were ameliorated (Mehmetc¸ik et al., 2008). C. scolymus also regulated hyperlipidemia, oxidative stress, and abnormal lipid profiles (Heidarian et al., 2011). In rabbit leaf extract neutralized CC14-induced hepatotoxicity with modification in triglycerides, leukocytes, blood sugar, cholesterol, and a number of erythrocytes (Paunescu et al., 2009). Furthermore, C. scolymus appreciably retained the hepatic redox condition as it is exhibited by a noteworthy rise in antioxidant enzyme activities and decline in glutathione accompanied by lipid peroxidation inhibition (LPOI), decreased nitric oxide, protein oxidation, TNF-α, and stabilized membrane permeability in paracetamol-mediated toxicity in rats (Ali et al., 2012).

3.5.2.24 Polygonum cuspidatum Polygonum cuspidatum has been used in folk medicinal system for chronic hepatitis, jaundice, cough, hyperlipidemia, and arthralgia treatment. It is a perennial plant widely grown a in moist environment and ubiquitously distributed worldwide (Zhang et al., 2013a,b). Anthraquinones, resveratrol, and polydatin are some known active compounds present in P. cuspidatum. The latest pharmacological evaluation has found that P. cuspidatum retain hepatoprotective and antiviral properties (Peng et al., 2013). In vitro analysis has also proved that a P. cuspidatum aqueous fraction (30 μg/mL) could decrease the hepatitis-B expression. Whereas, ethanol fraction (10 μg/mL) could suppress the replication of HBV DNA (Chang et al., 2005).

3.5.2.25 Gynostemma pentaphyllum Gynostemma pentaphyllum is a herbaceous climbing plant found in the eastern region of Asia. It is widely used in controlling cholesterol and avoiding obesity and fatty liver in various countries. Wang et al. (2013) observed that its extracts can promote lipid metabolism by downregulating trimethylamine N-oxide (TMAO) production and stimulating the excretion of phosphatidylcholine. G. pentaphyllum extract efficiently prevents cholesterol and triglycerides accumulation along with

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neutralizing free radicals in NAFLD model. An additional mechanism associated study suggested that G. pentaphyllum stimulates NO production which protects the liver from oxidative damage and modifies the molecular structure of mitochondrial phospholipid cardiolipin (Muller et al., 2012). A clinical trial revealed that intake of G. pentaphyllum for 6-months can remarkably decline serum AST, ALP, insulin along with a decrease in body mass index, and insulin resistance index. ALT had reduction of 80.2 to 63.2 and total cholesterol had fallen from 228.5 to 206.1 (Chou et al., 2006). These studies supported that G. pentaphyllum can be a suitable medicinal plant for NAFL patients. Recent analysis proposed that ombuine (C17H14O7), a flavonoid extracted from G. pentaphyllum significantly suppresses the intracellular triglyceride and cholesterol level in hepatocarcinoma and reduces lipogenic genes expression by stimulating PPARa and ß/d. Moreover, Ombuine also reduces cholesterol level by activating ATP binding cassette cholesterol transporter A1 and G1 protein expression (Malek et al., 2013).

3.5.2.26 Camellia sinensis Camellia sinensis leaves synthesized organic compounds that may protect plants from harmful pathogens, and these compounds are termed as polyphenolic compounds (Friedman, 2007), which include epigallocatechin, caffeine, tannins, catechin, and epicatechin (Wang and Goodman, 1999). C. sinensis possesses free-radical scavenging and antioxidant properties (Crespy and Williamson, 2014). The extract of C. sinensis and its main polyphenolic compound catechin have medicinal significance against prevention and therapeutics in several diseases (Ostrowska and Skrzydlewska, 2006). It exerts improvement in hepatic metabolic processes by preventing the neutralizing overproduction of ROS and boosting antioxidant defense system capacity. Thus C. sinensis extract has protective effects against ethanol toxicity (Lodhi et al., 2014).

3.5.2.27 Cucurbita pepo Cucurbita pepo (pumpkin) are assumed to be a treasure house of antioxidants, polyunsaturated fatty acids (PUFA) and fibers which are known to have hepatoprotective and antiatherogenic properties (Makni et al., 2008). In most countries of the world it is vigorously used in diabetes where it is used internally and superficially for treatment of worms and parasites. Pumpkin is also rich in oleic acid, linoleic acid, and tocopherols and has very high oxidative stability (Stevenson et al., 2007). Linoleic acid, a PUFA present in pumpkin seed oil, is known to increase membrane fluidity and allows for osmosis, intracellular, and extracellular gaseous exchange (Lovejoy, 2002). Pumpkin oil may play an important role in the protection against alcohol-induced hepatotoxicity and oxidative stress. Pretreatment with pumpkin oil may have hepatoprotective effects, which are varied and include oxidation, antilipid peroxidation enhanced detoxification, and protection against glutathione depletion (Abou Seif, 2014).

3.5.2.28 Zingiber officinale Zingiber officinale (Ginger) is extensively used throughout the world in foods as a spice. For centuries, it has been used as a natural medicine for the management of diabetes, catarrh, asthma, rheumatism, stroke, gingivitis, toothache, constipation, and nervous system diseases (Pandey, 2007). In bromobenzene-induced hepatotoxicity, different concentrations of ginger extract cause alteration in antioxidant enzymes, free radicals, biochemical parameters, and drug metabolizing enzymes

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(El-Sharaky et al., 2009). The antioxidant molecules prevent ROS production which are potent DNA damaging agent and associated with carcinogenesis (Patel et al., 2000). Ginger root aqueous extract may also causes hepatoprotective activity against aspartame, which causes hepatotoxicity and oxidative stress. Ginger root extract normalized functional hepatic markers (ALT, AST, ALP, γ-GT), serum total protein, albumin and total bilirubin levels, serum LDH activity, α-fetoprotein, and TNF, increased levels of antioxidant enzymes, and reduced levels of MDA (Hozayen and Seif, 2015).

3.5.2.29 Nigella sativa Nigella sativa contains more than 30 oil compounds. The volatile oil has been showed to possess thymoquinone and number of monoterpenes viz. α-pinene and p-cymene. CC14 enhanced the LPO and hepatic enzymes (serum or tissue), along with reduction in antioxidant enzyme levels. N. sativa administration facilitated decline in LPO and liver enzyme levels and promoted antioxidant enzyme activities (Kanter et al., 2005). The enzymes levels, oxidative stress index, total oxidative status, and myeloperoxidase were remarkably lower in N. sativa treated rodents. Whereas, total antioxidant capacity in hepatocytes was appreciably higher as compared to untreated rats (Yildiz et al., 2008). It is effective in management of rheumatism and associated inflammatory problems (Alemi et al., 2013). Furthermore, the antiinflammatory activity of aqueous extract was demonstrated by inhibition efficacy against carrageenan-induced paw edema (Al-Ghamdi, 2001). Thymoquinone pretreated mice significantly suppressed the increased serum enzyme levels along with reduction in MDA content. Thymoquinone expressively increased hepatic nonprotein sulfhydryl (
SH). N. sativa helps in prevention of enzymes present in the hepatic neoglucogenesis pathway (Houcher et al., 2007).

3.5.2.30 Naringenin Naringenin (5,7,40 -thihydroxyflavanone) is a flavanone compound found in citrus fruits and tomatoes. It possesses a vast range of pharmacological properties including hypolipidemic, antihypertensive, antiinflammatory, antioxidant, and antifibrotic functions (Patel et al., 2014). Mira et al. (2002) showed that it has a capacity of reducing the Fe31 and Cu21 but with less potential than quercetin. Chtourou et al. (2015) found that naringenin prevents the reduction of SOD, CAT, GPx, and GSH. Conversely, it also prevented lipid peroxidation, ALT and AST. Relevant results were obtained by Yen et al. (2009) using naringenin alone and in naringenin-loaded nanoparticle system. Both forms demonstrated antioxidant and hepatoprotective activities with caspases 3 and 8 activation. Goldwasser et al. (2011) in their study reported that naringenin activates PPARα and suppresses very low density lipoprotein production without causing lipid accumulation in hepatocytes, in HCV model. Similar results were showed by Cho et al. (2011), who have found that naringenin intake causes significant depletion in the amount of total triglycerides and cholesterol in plasma and the liver of rats. Pretreatment with naringenin-7-O-glucoside increased NQO1, ERK, and phosphorylation and translocation of Nrf2 to the nucleus in H9C2 cardiomyocytes and upregulated mRNA expression of GCLC and GCL modifier (Han et al., 2008). Similarly Esmaeili and Alilou (2014), showed that naringenin was capable of attenuating CCl4-induced hepatotoxicity by downregulating TNF-α, iNOS, and cyclooxigenase-2 by increasing Nfr2 and HO-1 expression.

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3.6 CONCLUSION Herbal plants and their formulations based on traditional therapeutic systems, which are used in the management of hepatic abnormalities, are not satisfactory due to their side effects on the kidneys or other cellular organs. Hence it is necessary to develop new hepatoprotective drugs. The current chapter encompasses a comprehensive update and detailed evaluation of extensively used herbal medicine and their formulations against chronic liver diseases (Table 3.1). These plants or bioactive compounds may offer new options to the restricted therapeutic possibilities that occur at present in the management of hepatic abnormalities and should be considered for future studies. These studies also showed that the hepatoprotective activity of herbs is due to the presence of glycosides, flavonoids, triterpenes, and phenolic compounds that are able to prevent oxidative damage, eliminating virus infection, suppressing fibrogenesis, and preventing tumor cell progression. In future studies, basic research along with clinical trials should be designed in such a way that it checks potential toxicity and side effects of herbal medicines. More medicinal herbs and bioactive compounds with no side effects and significant efficacy are expected to be recognized against handling chronic liver abnormalities in the future. Table 3.1 Mechanism of Action of Plants and Their Bioactive Compounds in Various Hepatic Abnormalities S. No.

Herbs/ Phytochemicals

Sources

Mode of Actions

References

1.

Astragalus membranaceus

Astragalus membranaceus

Wang et al. (2009)

2.

Baicalin

Scutellaria baicalensis

3.

Berberine

Coptis chinensis

4.

Bupleurum chinense

Bupleurum chinense

1. Prevent duck HBV DNA replication. 2. Kill serum HBeAg and HBV DNA in chronic viral hepatitis. 1. Suppress total cholesterol, triglycerides, LDL, ALT and AST level, and promote serum HDL by facilitating of CaMKKβ/AMPK/ACC pathway. 2. Lessening the ischemia/reperfusion damage in alcoholic fatty liver by lessening of myeloid differentiation factor-88 and TLR4 protein expressions and the nuclear translocation of NF-kB after reperfusion. 1. Falling TG accumulation in the FFA-associated hepatic steatosis. 2. Enhancing insulin resistance of NAFLD by triggering the expression of IRS-2. 3. Decreasing lipogenesis and stimulating lipolysis by averting the expression of SCD1, FAS, SREBP1c, and increasing the expression of CPT1. 1. Possess free radical scavenging potential and inhibiting the superoxide anion formation. 2. Lowering the expression of inflammatory cytokine.

Xi et al. (2015) Kim et al. (2012)

Fan et al. (2013) Xing et al. (2011)

Liu et al. (2006) Lin et al. (2012) (Continued)

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Table 3.1 Mechanism of Action of Plants and Their Bioactive Compounds in Various Hepatic Abnormalities Continued S. No.

Herbs/ Phytochemicals

Sources

Mode of Actions

References

5.

Camptothecin

Camptotheca acuminata

6,

Curcumin

7.

Dioscin

Curcuma longa Dioscorea opposita

Li et al. (2011) Jayasooriya et al. (2014) Zhou et al. (2010) Wang et al. (2008) Liu et al. (2015) Xu et al. (2014)

8.

Gallic acid

Punica granatum

9.

Glycyrrhizin

Glycyrrhiza uralensis

10.

Gynostemma pentaphyllum

Gynostemma pentaphyllum

11.

Panax notoginseng

Panax notoginseng

1. Suppress growth of SMMC-7721 cell by inhibiting cell cycle at the S and G2/M phases, and inducing intrinsic apoptotic pathway. 2. Encourage TRAIL-associated apoptosis in HCC cells by upregulating ROS and ERK/p38 dependent DR5. 1. Preventing cell proliferation and inducing apoptosis on hepatic carcinoma cells. 1. Neutralizing oxidative damage, preventing inflammation, cholesterol and triglyceride formations, lowering MAPK phosphorylation levels, promoting β-oxidation of fatty acid, and introducing autophagy to recover fatty liver situations. 2. Protective effect against alcoholic fatty liver by inhibiting alcohol-mediated oxidative damage, inflammatory cytokine production, mitochondrial function, apoptosis, and liver steatosis. 1. Improving reduced glucose and lipid homeostasis in high-fat diet
associated NAFLD mice. 2. Lowering GSSG content and oxidative stress and promote GSH peroxidase, glutathione, GSH S-transferase, and GSH reductase levels in hepatic tissue. 1. Suppress hepatitis C virus by reducing the activity of phospholipase A2. 2. Downregulating the cytolytic activity of complement system. 3. Trigger the secretion of IL-10 by dendritic cells. 4. Controlling HBV proliferation, decreasing serum ALT. 1. Stimulate lipid metabolism by reducing TMAO production and enhancing phosphatidylcholine. 2. Inhibiting cholesterol and triglycerides accumulation along with lowering oxidative stress by promoting NO production and affects the molecular composition of the mitochondrial phospholipid. 1. Attenuating the ethanol-mediated lipid accumulation in liver by inhibiting the production of MDA, GSH l and reactive ROS, reducing TNF-alpha and IL-6 levels, as well as enhancing the SOD activity in liver, and abrogated CYP2E1 induction.

Chao et al. (2014). Hsu et al. (2007)

Matsumoto et al. (2013) Abe et al. (2003) Matsuo et al. (2001)

Wang et al. (2013) Muller et al. (2012) Chou et al. (2006) Ding et al. (2015) Yang et al. (2009)

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Table 3.1 Mechanism of Action of Plants and Their Bioactive Compounds in Various Hepatic Abnormalities Continued S. No.

Herbs/ Phytochemicals

Sources

Mode of Actions

References

2. Relieve oxidative stress and insulin resistance in NAFLD rats. 12.

Periplocoside A

Periploca sepium

13.

Phyllanthus niruri

Phyllanthus niruri

14,

Polygonum cuspidatum Puerarin

Polygonum cuspidatum Pueraria lobata

16.

Salvia miltiorrhiza

Salvia miltiorrhiza

17.

Schisandra chinensis Silymarin

Schisandra chinensis Silybum marianum

Camellia sinensis

Camellia sinensis

15.

18.

19.

1. Ameliorating of ConeA-induced autoimmune hepatitis by lowering the secretions of (IL)-4, IFN-γ, and ALT. 1. Inhibiting HBsAg secretion and HBsAg mRNA expression by upregulation of annexin A7. 2. Removing serum HBsAg, HBeAg, and HBV DNA. 1. Downregulate HBeAg expression and the production of HBV DNA. 1. Attenuating the CCl4-induced toxicity in the hepatic cells of hepatic fibrosis rats, mediating antifibrosis effects through modulating the PPAR-gamma expression and inhibiting the PI3K/Akt signal pathway. 2. Mediating antifibrosis effects in hepatic fibrosis rats through downregulating the TNF-alpha and NF-kB expression. 3. Introducing apoptosis in hepatic stellate cells by downregulating bcl-2 mRNA. 1. Suppressing inflammation in the liver by inhibition of NFkB and p38 signaling. 2. Improve hepatic morphology, decreasing iron deposition as well as inhibiting the expression of type I and type III collagen, TGF-β mRNA, and increase expression of MMP-9 mRNA in the liver. 1. Anti-HBV activity by suppressing HBV DNA replication. 1. Downregulating the HCV core mRNA and protein expression blocking of HCV entry and transmission by inhibiting microsomal triglyceride transfer protein activity, apolipoprotein B secretion, and infectious virion production into culture supernatants. 2. Decreasing serum transaminases in chronic viral hepatitis but not affecting viral content in vivo. Inhibiting inflammatory by suppressing the proinflammatory cytokine and upregulating the IL-10. 1. It promote antioxidant activity and protect liver and various toxic compounds due to the presence of epigallocatechin, caffeine, tannins, catechin, and epicatechin as a bioactive compound.

Wan et al. (2008) Lam et al. (2006) Liu et al. (2001) Chang et al. (2005) Guo et al. (2013) Li et al. (2013) Zhang et al. (2006)

Yue et al. (2014) Zhang et al. (2013)

Xue et al. (2015) Bonifaz et al. (2009) Wagoner et al. (2010) Mayer et al. (2005). Strickland et al. (2005) Adeyemo et al. (2013)

Wang and Goodman (1999)

(Continued)

94

CHAPTER 3 PLANT SECONDARY METABOLITES

Table 3.1 Mechanism of Action of Plants and Their Bioactive Compounds in Various Hepatic Abnormalities Continued S. No.

Herbs/ Phytochemicals

Sources

Mode of Actions

References

20.

Cucurbita pepo

Cucurbita pepo

21.

Zingiber officinale

Zingiber officinale

22.

Naringenin

Citrus fruits

1. Linoleic acid, present in it increases membrane fluidity and allow osmosis. 2. Inhibit lipid peroxidation and promote detoxification of liver. 1. Root extract promotes serum ALT, AST, ALP, γ-GT level, and increase cellular antioxidant enzymes. 1. Upregulate the production of SOD, CAT, GPx, and GSH as well as prevent lipid peroxidation. 2. It downregulate TNF-α, iNOS, and cox-2 while promote Nrf2 and HO-1expression in CCl4induced oxidative stress.

Lovejoy (2002) Abou Seif (2014a) Hozayen and Abou Seif (2014) Chtourou et al. (2015) Motawi et al. (2014)

ACKNOWLEDGMENT A. Gupta acknowledges the financial support from University Grants Commission, New Delhi in the form of UGC-CRET fellowship. Both the authors acknowledge DST-FIST and UGC-SAP assisted Department of Biochemistry, University of Allahabad for providing infrastructure facility.

REFERENCES Abe, M., Akbar, F., Hasebe, A., Horiike, N., Onji, M., 2003. Glycyrrhizin enhances interleukin-10 production by liver dendritic cells in mice with hepatitis. J. Gastroenterol. 38 (10), 962
967. Adeyemo, O., Doi, H., Rajender Reddy, K., Kaplan, D.E., 2013. Impact of oral silymarin on virus- and nonvirus-specific t-cell responses in chronic hepatitis c infection. J. Viral. Hepat. 20 (7), 453
462. Adi, A.H., Alturkmani, H.J., 2013. Physiologically lucky: the role of medical physiology in modern medical education: an interview. Perspect. Med. Educ. 2 (2), 99
103. Ai, Z.L., Zhang, W.S., Yao, S.K., Xie, B.S., Gao, C., 2011. Effect of baicalin on liver fatty acid binding protein in oxidative stress model in vitro. Chin. J. Hepatol. 19 (12), 927
931. Akhgar, M.R., Pahlavanzadeh-Iran, S., Lotfi-Anari, P., Faghihi-Zarandi, A., 2011. Composition of essential oils of fruits and leaves of Prangos ferulacea (L.) Lindl. growing wild in Iran. Trends Mod. Chem. 1, 1
4. Alemi, M., Sabouni, F., Sanjarian, F., Haghbeen, K., Ansari, S., 2013. Anti-inflammatory effect of seeds and callus of Nigella sativa L. extracts on mix glial cells with regard to their thymoquinone content. AAPS Pharm. Sci. Tech. 14 (1), 160
167. Al-Ghamdi, M.S., 2001. The anti-inflammatory, analgesic and antipyretic activity of Nigella sativa. J. Ethnopharmacol. 76 (1), 45
48. Ali, Z.Y., Atia, H.A., Ibrahim, N.H., 2012. Possible hepatoprotective potential of Cynara scolymus, Cupressus sempervirens and Eugenia jambolana against paracetamol-induced liver injury: in-vitro and in-vivo evidence. Nat. Sci. 10 (1), 75
86.

REFERENCES

95

Alpers, D.H., Sabesin, S.M., Schiff, L., Schiff, E.R., 1982. Diseases of the Liver. JB Lippincott, Philadelphia, pp. 813
845. Alsheikh-Ali, A.A., Kuvin, J.T., Karas, R.H., 2004. Risk of adverse events with fibrates. Am. J. Cardiol. 94 (7), 935
938. Altas, S., Kizil, G., Kizil, M., Ketani, A., Haris, P.I., 2011. Protective effect of DiyarbakIr watermelon juice on carbon tetrachloride-induced toxicity in rats. Food. Chem. Toxicol. 49 (9), 2433
2438. Amar, P.J., Schiff, E.R., 2007. Acetaminophen safety and hepatotoxicity-where do we go from here? Expert. Opin. Drug. Saf. 6 (4), 341
355. Amin, Z.A., Abdulla, M.A., Ali, H.M., Alshawsh, M.A., Qadir, S.W., 2012. Assessment of in vitro antioxidant, antibacterial and immune activation potentials of aqueous and ethanol extracts of Phyllanthus niruri. J. Sci. Food. Agric. 92 (9), 1874
1877. Arora, N., Goldhaber, S.Z., 2006. Anticoagulants and transaminase elevation. Circulation 113 (15), 698
702. Bagul, P.K., Middela, H., Matapally, S., Padiya, R., Bastia, T., Madhusudana, K., et al., 2012. Attenuation of insulin resistance, metabolic syndrome and hepatic oxidative stress by resveratrol in fructose-fed rats. Pharmacol. Res. 66 (3), 260
268. Bhardwaj, S.S., Chalasani, N., 2007. Lipid lowering agents that cause drug induced hepatotoxicity. Clin. Liver. Dis. 11 (3), 597-vii. Biswas, A., D’Souza, U.J.A., Bhat, S., Damodar, D., 2014. The hepatoprotective effect of Hibiscus rosa sinensis flower extract on diet-induced hypercholesterolemia in male albino wistar rats. Int. J. Med. Pharm. Sci. 4 (6), 1
10. Blaising, J., Levy, P.L., Gondeau, C., Phelip, C., Varbanov, M., Teissier, E., et al., 2013. Silibinin inhibits hepatitis C virus entry into hepatocytes by hindering clathrin-dependent trafficking. Cell Microbiol. 15 (11), 1866
1882. Boll, M., Weber, L.W., Becker, E., Stampfl, A., 2001. Mechanism of carbon tetrachloride-induced hepatotoxicity. Hepatocellular damage by reactive carbon tetrachloride metabolites. Z. Naturforsch. C 56 (7-8), 649
659. Bonifaz, V., Shan, Y., Lambrecht, R.W., Donohue, S.E., Moschenross, D., Bonkovsky, H.L., 2009. Effects of silymarin on hepatitis c virus and haem oxygenase-1 gene expression in human hepatoma cells. Liv. Int. Off. J. Int. Assoc. Study Liv 29 (3), 366
373. Brind, A.M., 2007. Drugs that damage the liver. Medicine. 35 (1), 26
30. Cai, L., Cao, B., Lin, D., 2015. Effects of traditional Chinese medicine huangqi injection (radix astragali) on random skin flap survival in rats. J. Reconstr. Microsurg. 31 (8), 565
570. Carlson, M.K., Gleason, P.P., Sen, S., 2001. Elevation of hepatic transaminases after enoxaparin use: case report and review of unfractionated and low molecular weight heparin induced hepatotoxicity. Pharmacotherapy 21 (1), 108
113. Chang, C.Y., Schaino, T.D., 2007. Review article: drug hepatotoxicity. Aliment. Pharmacol. Ther. 25 (10), 1135
1151. Chang, J.S., Liu, H.W., Wang, K.C., Chen, M.C., Chiang, L.C., Hua, Y.C., et al., 2005. Ethanol extract of Polygonum cuspidatum inhibits hepatitis B virus in a stable HBV-producing cell line. Antiviral. Res. 66 (1), 29
34. Chao, J., Huo, T.I., Cheng, H.Y., Tsai, J.C., Liao, J.W., Lee, M.S., et al., 2014. Gallic acid ameliorated impaired glucose and lipid homeostasis in high fat diet-induced NAFLD mice. PLoS One 9 (2), e96969. Checker, R., Patwardhan, R.S., Sharma, D., Menon, J., Thoh, M., Bhilwade, H.N., et al., 2012. Schisandrin B exhibits anti-inflammatory activity through modulation of the redox-sensitive transcription factors Nrf2 and NFkB. Free Radic. Biol. Med. 53 (7), 1421
1430. Cheng, A.S., Cheng, Y.H., Chiou, C.H., Chang, T.L., 2012. Resveratrol upregulates Nrf2 expression to attenuate methylglyoxal-induced insulin resistance in Hep G2 cells. J. Agric. Food. Chem. 60 (36), 9180
9187.

96

CHAPTER 3 PLANT SECONDARY METABOLITES

Chiang, L.C., Ng, L.T., Liu, L.T., Shieh, D.E., Lin, C.C., 2003. Cytotoxicity and anti-hepatitis b virus activities of saikosaponins from bupleurum species. Planta Med. 69 (8), 705
709. Chitturi, S., George, J., 2002. Hepatotoxicity of commonly used drugs: nonsteroidal anti-inflammatory drugs, antihipertensives, antidiabetic agents, psycotropic drugs. Semin. Liver. Dis. 22 (2), 195
206. Cho, K.W., Kim, Y.O., Andrade, J.E., Burgess, J.R., Kim, Y.C., 2011. Dietary naringenin increases hepatic peroxisome proliferators activated receptor α protein expression and decreases plasma triglyceride and adiposity in rats. Eur. J. Nutr. 50 (2), 81
88. Chou, S.C., Chen, K.W., Hwang, J.S., Lu, W.T., Chu, Y.Y., Lin, J.D., et al., 2006. The add-on effects of Gynostemma pentaphyllum on nonalcoholic fatty liver disease. Altern. Ther. Health Med. 12 (3), 34
39. Chtourou, Y., Fetoui, H., Jemai, R., Ben Slima, A., Makni, M., Gdoura, R., 2015. Naringenin reduces cholesterolinduced hepatic inflammation in rats by modulating matrixmetalloproteinases2, 9 via inhibition of nuclear factor κB pathway. Eur. J. Pharmacol. 5 (746), 96
105. Chvez, E., Reyes-Gordillo, K., Segovia, J., Shibayama, M., Tsutsumi, V., Vergara, P., et al., 2008. Resveratrol prevents fibrosis, NF-kB activation and TGF-β increases induced by chronic CCl4 treatment in rats. J. Appl. Toxicol. 28 (1), 35
43. Clarke, J.B., Maggs, J.L., Kitteringham, N.R., Park, B.K., 1990. Immunogenicity of amodiaquine in the rat. Int. Arch. Allergy Appl. Immunol. 91 (4), 335
342. Clarke, J.B., Neftel, K., Kitteringham, N.R., Park, B.K., 1991. Detection of antidrug IgG antibodies in patients with adverse drug reactions to amodiaquine. Int. Allergy Appl. Immunol. 95 (4), 369
375. Correia, H.S., Batista, M.T., Dinis, T.C., 2007. The activity of an extract and fraction of Agrimonia eupatoria L. against reactive species. Biofactors 29 (2-3), 91
104. Cowan, M.M., 1999. Plant products as antimicrobial agents. Clin. Microb. Rev. 12 (4), 564
582. Crespy, V., Williamson, G., 2014. A review of the health effects of green tea catechins in vivo animal models. J. Nutr. 134 (12), 3431
3440. Crowell, J.A., Korytko, P.J., Morrissey, R.L., Booth, T.D., Levine, B.S., 2004. Resveratrol-associated renal toxicity. Toxicol. Sci. 82 (2), 614
619. Daniel, L., 2009. Global burden of hepatitis C. Liver. Int. 29 (1), 74
81. Deng, X., Luyendyk, J.P., Ganey, P.E., Roth, R.A., 2009. Inflammatory stress and idiosyncratic hepatotoxicity: hints from animal models. Pharmacol. Rev. 61 (3), 262
282. Dewick, P.M., 1996. Tumor Inhibition From Plants: Tease and Evans. Elsevier Health Sciences, Philadelphia, PA. Ding, R.B., Tian, K., Cao, Y.W., Bao, J.L., Wang, M., He, C., et al., 2015. Protective effect of Panax notoginseng saponins on acute ethanol-induced liver injury is associated with ameliorating hepatic lipid accumulation and reducing ethanol-mediated oxidative stress. J. Agric. Food. Chem. 63 (9), 2413
2422. El-Sharaky, A.S., Newairy, A.A., Kamel, M.A., Eweda, S.M., 2009. Protective effect of ginger extract against bromobenzene-induced hepatotoxicity in male rats. Food. Chem. Toxicol. 47 (7), 1584
1590. Esmaeili, M.A., Alilou, M., 2014. Naringenin attenuates CCl4 induced hepatic inflammation by the activation of an Nrf2 mediated pathway in rats. Clin. Exp. Pharmacol. Physiol. 41 (6), 416
422. Faghihzadeh, F., Adibi, P., Rafiei, R., Hekmatdoost, A., 2014. Resveratrol supplementation improves inflammatory biomarkers in patients with nonalcoholic fatty liver disease. Nutr. Res. 34 (10), 837
843. Fallah Huseini, H., Zareei Mahmoudabady, A., Ziai, S.A., Mehrazma, M., Alavian, S.M., Mehdizadeh, M., et al., 2011. The effects of Cynara scolymus L. leaf and Cichorium intybus L. root extracts on carbon tetrachloride induced liver toxicity in rats. J. Med. Plants 10 (37), 33
40. Fan, H., Chen, Y.Y., Bei, W.J., Wang, L.Y., Chen, B.T., Guo, J., 2013. In vitro screening for antihepatic steatosis active components within coptidis rhizoma alkaloids extract using liver cell extraction with hplc analysis and a free fatty acid-induced hepatic steatosis hepg2 cell assay. Evid. Based Complement Altern. Med. 2013, 459390.

REFERENCES

97

Farombi, E.O., Shrotriya, S., Na, H.K., Kim, S.H., Surh, Y.J., 2008. Curcumin attenuates dimethylnitrosamineinduced liver injury in rats through Nrf2-mediated induction of heme oxygenase-1. Food. Chem. Toxicol. 46 (4), 1279
1287. Formisano, C., Rigano, D., Senatore, F., Bruno, M., Rosselli, S., 2010. Volatile constituents of the aerial parts of white salsify (Tragopogon porrifolius L., Asteraceae). Nat. Prod. Res. 24 (7), 663
668. Fransworth, N.R., 1994. Ethnopharmacology and drug development. In: Chadwick, D.J., Marsh, J. (Eds.), Ethnobotany and the Search for New Drugs, CIBA Foundation Symposium, 185. John Wiley and Sons, Chichester, New York, pp. 42
51. Friedman, M., 2007. Overview of antibacterial, antitoxin, antiviral and antifungal activities of tea flavonoids and teas. Mol. Nutr. Food. Res. 51 (1), 116
134. Fujisawa, Y., Sakamoto, M., Matsushita, M., Fujita, T., Nishioka, K., 2000. Glycyrrhizin inhibits the lytic pathway of complement-possible mechanism of its anti-inflammatory effect on liver cells in viral hepatitis. Microbiol. Immunol. 44 (9), 799
804. Gao, J., Liu, Z.J., Chen, T., Zhao, D., 2014. Pharmaceutical properties of calycosin, the major bioactive isoflavonoid in the dry root extract of radix astragali. Pharm. Biol. 52 (9), 1217
1222. Gebhardt, R., 1997. Antioxidative and protective properties of extracts from leaves of the artichoke (Cynara scolymus L.) against hydroperoxide induced oxidative stress in cultured rat hepatocytes. Toxicol. Appl. Pharmacol. 144 (2), 279
286. Georgina, E.O., Kingsley, O., Esosa, U.S., Helen, N.K., Frank, A.O., Anthony, O.C., 2011. Comparative evaluation of antioxidant effects of watermelon and orange, and their effects on some serum lipid profile of Wister albino rats. Int. J. Nutr. Metab. 3 (8), 97
102. Ghany, M., Hoofnagle, J.H., 2005. Approach to the patient with liver disease. In: sixteenth ed. Kasper, D.L., Braunwald, E., Fauci, A.S., Hauser, S.L., Longo, D.L., Jameson, J.L. (Eds.), Harrison’s Principles of Internal Medicine, vol. 2. McGraw Hill, New York, pp. 1808
1813. Giao, M.S., Pereira, C.I., Fonseca, S.C., Pintado, M.E., Malcata, F.X., 2009. Effect of particle size upon the extent of extraction of antioxidant power from the plants Agrimonia eupatoria, Salvia sp. and Satureja montana. Food. Chem. 117 (3), 412
416. Goldwasser, J., Cohen, P.Y., Lin, W., Kitsberg, D., Balaguer, P., et al., 2011. Naringenin inhibits the assembly and long term production of infectious hepatitis C virus particles through a PPAR mediated mechanism. J. Hepatol. 55 (5), 963
971. Govind, P., 2011. Medicinal plants against liver diseases. Int. Res. J. Pharm. 2 (5), 115
121. Green, S.H., 1984. Sodium valproate and routine liver function tests. Arch. Dis. Child. 59 (9), 813
814. Guo, C., Xu, L., He, Q., Liang, T., Duan, X., Li, R., 2013. Anti-fibrotic effects of puerarin on CCl4-induced hepatic fibrosis in rats possibly through the regulation of PPAR-γ expression and inhibition of pi3k/akt pathway. Food. Chem. Toxicol. 56, 436
442. Gupta, R., Gabrielsen, B., Ferguson, F.M., 2005. Nature’s medicines: traditional knowledge and intellectual property management. Case studies from the National Institutes of Health (NIH), USA. Curr. Drug Discov. Technol. 2 (4), 203
219. Gupta, A., Kumar, R., Kumar, S., Pandey, A.K., 2017. Pharmacological aspects of Terminalia belerica. In: Mahdi, A.A., Abid, M., Ali-Khan, M.M., Ansari, M.I., Maheshwari, R.K. (Eds.), Molecular Biology and Pharmacognosy of Beneficial Plants. Lenin Media Private Limited, Delhi, India, pp. 52
64. Guyton, A., Hall, J., 2006. Text Book of Medical Physiology, eleventh ed Saunders, Philadelphia, PA, pp. 859
864. Han, X., Pan, J., Ren, D., Cheng, Y., Fan, P., Lou, H., 2008. Naringenin 7-O-glucoside protects against doxorubicininduced toxicity in H9c2 cardiomyocytes by induction of endogenous antioxidant enzymes. Food. Chem. Toxicol. 46, 3140
3146.

98

CHAPTER 3 PLANT SECONDARY METABOLITES

Haque, A., Tahmina, Afsana, S.K., Sarker, I.R., Hossain, M., Islam, S., 2014. Antioxidant and hepatoprotective effects of aqueous and ethanol extracts of Dendrophthoe falcate Linn leaves. Pharmacology online 2014, 90
101. Hartleb, M., Rymarczyk, G., Januszewski, K., 1999. Acute cholestatic hepatitis associated with provastatin. Am. J. Gastroenterol. 94 (5), 1388
1390. Heidarian, E., Jafari-Dehkordi, E., Seidkhani-Nahal, A., 2011. Lipid-lowering effect of artichoke on liver phosphatidate phosphohydrolase and plasma lipids in hyperlipidemic rats. J. Med. Plants Res. 5 (19), 4918
4924. Hosseinimehr, S.J., Nemati, A., 2006. Radioprotective effects of hesperidin against gamma irradiation in mouse bone marrow cells. Brit. J. Radiol. 79 (941), 415
418. Houcher, Z., Boudiaf, K., Benboubetra, M., Houcher, B., 2007. Effects of methanolic extract and commercial oil of Nigella sativa L. on blood glucose and antioxidant capacity in alloxan-induced diabetic rats. Pteridines 18 (1), 8
18. Hozayen, W.G., Seif, H.S.A., 2015. Chemopreventive effects of Zinger officinal extract against aspartame induced nephrotoxicity and oxidative stress in rat model. JIARM 3 (1), 261
273. Hozayen, W.G., Abou-Seif, H.S., Amin, S., 2014. Protective effects of rutin and/or hesperidin against doxorubicin-induced hepatotoxicity. Int. J. Clin. Nutr. 2 (1), 11
17. Hsu, C.L., Yen, G.C., 2007. Effect of gallic acid on high fat diet-induced dyslipidaemia, hepatosteatosis and oxidative stress in rats. Br. J. Nutr. 98 (4), 727
735. Huang, H.L., Wang, Y.J., Zhang, Q.Y., Liu, B., Wang, F.Y., Li, J.J., et al., 2012. Hepatoprotective effects of baicalein against CCL4-induced acute liver injury in mice. World J. Gastroenterol. 18 (45), 6605
6613. Iancu, T.C., Shiloh, H., Dembo, L., 1986. Hepatomegaly following short-term high dose steroid therapy. J. Pediatr. Gastroenterol. Nutr. 5 (1), 41
46. Ibrahim, D., Hong, L.S., Kuppan, N., 2013. Antimicrobial activity of crude methanolic extract from Phyllanthus niruri. Nat. Prod. Commun. 8 (4), 493
496. Jayasooriya, R.G., Choi, Y.H., Hyun, J.W., Kim, G.Y., 2014. Camptothecin sensitizes human hepatoma hep3b cells to trail-mediated apoptosis via ros-dependent death receptor 5 upregulation with the involvement of mapks. Environ. Toxicol. Pharmacol. 38 (3), 959
967. Kafash Farkhad, N., Farokhi, F., Tukmacki, A., Soltani Band, K., 2012. Hydroalcoholic extract of the root of Prangos ferulacea (L.) Lindl can improve serum glucose and lipids in alloxan-induced diabetic rats. Avicenna J. Phytomed. 2 (4), 179
187. Kafrouni, M.I., Anders, R.A., Verma, S., 2007. Hepatotoxicity associated with dietary supplements containing anabolic steroids. Clin. Gastroenterol. Hepatol. 5 (7), 809
812. Kanter, M., Coskun, O., Budancamanak, M., 2005. Hepatoprotective effects of Nigella sativa L and Urtica dioica L on lipid peroxidation, antioxidant enzyme systems and liver enzymes in carbon tetrachloridetreated rats. World J. Gastroenterol. 11 (42), 6684
6688. Kaplowitz, N., 2004. Drug-induced liver injury. Clin. Infect. Dis. 38 (2), 44
48. Khalili, H., Dashti-Khavidaki, S., Rasoolinejad, M., Rezaie, L., Etminana, M., 2009. Anti-tuberculosis drugs related hepatotoxicity: incidence, risk factors, pattern of changes in liver enzymes and outcome. Daru 17 (3), 163
167. Kim, S.J., Moon, Y.J., Lee, S.M., 2010. Protective effects of baicalin against ischemia/reperfusion injury in rat liver. J. Nat. Prod. 73 (12), 2003
2008. King, P.D., Perry, M.C., 2001. Hepatotoxicity of chemotherapy. Oncologist 6 (2), 162
176. Konopinski, M., 2009. Influence of intercrop plants and varied tillage on yields and nutritional value of salsify (Tragopogon porrifolius L.) roots. Acta Sci. Pol. Hortorum. Cultus 82, 27
36. Kumar, S., Pandey, A.K., 2013. Chemistry and biological activities of flavonoids: an overview. SciWorldJ 2013, 162750.

REFERENCES

99

Kumar, S., Gupta, A., Pandey, A.K., 2013. Calotropis procera root extract has the capability to combat free radical mediated damage. ISRN Pharmacol. 2013. Lagouge, M., Argmann, C., Gerhart-Hines, Z., Meziane, H., Lerin, C., Daussin, F., et al., 2006. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC1alpha. Cell 127 (6), 1109
1122. Lam, W.Y., Leung, K.T., Law, P.T., Lee, S.M., Chan, H.L., Fung, K.P., et al., 2006. Antiviral effect of Phyllanthus nanus ethanolic extract against hepatitis b virus (hbv) by expression microarray analysis. J. Cell. Biochem. 97 (4), 795
812. Lee, W.M., 2003. Drug-induced hepatotoxicity. N. Engl. J. Med. 349 (5), 474
485. Li, Q., Qiu, W., Zhu, Q., Zu, Y., Deng, X., Zhao, T., et al., 2011. Camptothecin-20(s)-o-[n-(3’alpha, 12’alphadihydroxy-24’-carbonyl-5’beta-cholan)]-lysine, a novel camptothecin analogue, induces apoptosis towards hepatocellular carcinoma smmc-7721 cells. Molecules 16 (9), 7803
7814. Li, R., Xu, L., Liang, T., Li, Y., Zhang, S., Duan, X., 2013. Puerarin mediates hepatoprotection against ccl4induced hepatic fibrosis rats through attenuation of inflammation response and amelioration of metabolic function. Food. Chem. Toxicol. 52, 69
75. Lim, A.Y., Segarra, I., Chakravarthi, S., Akram, S., Judson, J.P., 2010. Histopathology and biochemistry analysis of the interaction between sunitinib and paracetamol in mice. BMC Pharmacol. 10 (14), 1
17. Lin, L.T., Chung, C.Y., Hsu, W.C., Chang, S.P., Hung, T.C., Shields, J., et al., 2015. Saikosaponin b2 is a naturally occurring terpenoid that efficiently inhibits hepatitis c virus entry. J. Hepatol. 62 (3), 541
548. Liu, Z.Y., 1991. Progress in pharmacological research on radix astragali. Chin. J Mod. Dev. Tradit. Med. 11, 312
314. Liu, C.T., Chuang, P.T., Wu, C.Y., Weng, Y.M., Chen, W., Tseng, C.Y., 2006. Antioxidative and in vitro hepatoprotective activity of Bupleurum kaoi leaf infusion. Phytother. Res. 20 (11), 1003
1008. Liu, S., Wei, W., Li, Y., Lin, X., Shi, K., Cao, X., et al., 2014. In vitro and in vivo anti-hepatitis b virus activities of the lignan nirtetralin b isolated from Phyllanthus niruri L. J. Ethnopharmacol. 157 (2014), 62
68. Liu, M., Xu, L., Yin, L., Qi, Y., Xu, Y., Han, X., et al., 2015. Potent effects of dioscin against obesity in mice. Sci. Rep. 5, 7973. Lodhi, P., Tandan, N., Singh, N., Kumar, D., Kumar, M., 2014. Research article Camellia sinensis (L.) Kuntze extract ameliorates chronic ethanol-induced hepatotoxicity in albino rats. Evid. Based. Complement. Alternat. Med. 2014, 7 pages. Lok, A.S., Heathcote, E.J., Hoofnagle, J.H., 2001. Management of hepatitis B: 2000-summary of a workshop. Gastroenterology 120 (7), 1828
1853. Lovejoy, J.C., 2002. The influence of dietary fats in insulin resistance. Curr. Diab. Rep. 2 (5), 430
440. Maffei, F.R., Carini, M., 1980. The inhibitory effect of pyrazinamide on microsomal monooxygenase activities is related to the binding to reduced cytochrome P-450. Pharmacol. Res. Commun. 12 (6), 523
537. Makni, M., Fetoui, H., Gargouri, N.K., Garoui, M., Jaber, H., Makni, J., et al., 2008. Hypolipidemic and hepatoprotective effects of flax and pumpkin seed mixture rich in u-3 and u-6 fatty acids in hypercholesterolemic rats. Food. Chem. Toxicol. 46 (12), 3714
3720. Malek, M.A., Hoang, M.H., Jia, Y., Lee, J.H., Jun, H.J., Lee, D.H., et al., 2013. Ombuin-3-o-beta-d-glucopyranoside from Gynostemma pentaphyllum is a dual agonistic ligand of peroxisome proliferator-activated receptors α and δ/β. Biochem. Biophys. Res. Commun. 430 (4), 1322
1328. Mamat, S.S., Kamarolzaman, M.F.F., Yahya, F., Mahmood, N.D., Shahril, M.S., 2013. Methanol extract of Melastoma malabathricum leaves exerted antioxidant and liver protective activity in rats. BMC Complement. Altern. Med. 13, 326. Manov, I., Motanis, H., Frumin, I., Iancu, T.C., 2006. Hepatotoxicity of antiinflammatory and analgesic drugs: ultrastructural aspects. Acta Pharmacol. Sin. 27 (3), 259
272.

100

CHAPTER 3 PLANT SECONDARY METABOLITES

Marier, J.F., Vachon, P., Gritsas, A., Zhang, J., Moreau, J.P., Ducharme, M.P., 2002. Metabolism and disposition of resveratrol in rats: extent of absorption, glucuronidation, and enterohepatic recirculation evidenced by a linked-rat model. J. Pharmacol. Exp. Ther. 302 (1), 369
373. Massumi, M.A., Fazeli, M.R., Alavi, S.H.R., Ajani, Y., 2007. Chemical constituents and antibacterial activity of essential oil of Prangos ferulacea (L.) Lindl. fruits. Iran J. Pharm. Sci. 3 (3), 171
176. Mates, J.M., Segura, J.A., Alonso, F.J., Marquez, J., 2011. Anticancer antioxidant regulatory functions of phytochemicals. Curr. Med. Chem. 18 (15), 2315
2338. Mayer, K.E., Myers, R.P., Lee, S.S., 2005. Silymarin treatment of viral hepatitis: a systematic review. J. Viral. Hepat. 12 (6), 559
567. Mehmetc¸ik, G., Ozdemirler, G., Kocak-Toker, N., Cevikbas, U., Uysal, M., 2008. Effect of pretreatment with artichoke extract on carbon tetrachlorideinduced liver injury and oxidative stress. Exp. Toxicol. Pathol. 60 (6), 475
480. Michael, M.D., Kulkarni, R.N., Postic, C., 2000. Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction. Mol. Cell 6 (1), 87
97. Mira, L., Fernandez, M.T., Santos, M., Rocha, R., Florencio, M.H., Jennings, K.R., 2002. Interactions of flavonoids with iron and copper ions: mechanism for their antioxidant activity. Free. Radic. Res. 36 (11), 1199
1208. Mishra, A., Sharma, A.K., Kumar, S., Saxena, A.K., Pandey, A.K., 2013. Bauhinia variegata leaf extracts exhibit considerable antibacterial, antioxidant and anticancer activities. BioMed Res. Int. 2013, 915436. Monshouwer, M., Witkamp, R.F., Nijmeijer, S.M., Van-Leengoed, L.A., Verheijden, J.H., Van Miert, A.S., 1995. Infection (Actinobacillus pleuropneumoniae)-mediated suppression of oxidative hepatic drug metabolism and cytochrome P450 3A mRNA levels in pigs. Drug Metab. Dispos. 23 (1), 44
47. Mroueh, M., Daher, C., El-Sibai, M., Tenkerian, C., 2011. Antioxidant and hepatoprotective activity of Tragopogon porrifolius methanolic extract. Planta Med. Available from: https://doi.org/10.1055/s-00311282460. Muller, C., Gardemann, A., Keilhoff, G., Peter, D., Wiswedel, I., Schild, L., 2012. Prevention of free fatty acid-induced lipid accumulation, oxidative stress, and cell death in primary hepatocyte cultures by a Gynostemma pentaphyllum extract. Phytomed. Int. J. Phytother. Phytopharmacol. 19 (5), 395
401. Muriel, P., Rivera Espinoza, Y., 2008. Beneficial drugs for liver diseases. J. Appl. Toxicol. 28 (2), 93
103. Murray, K.F., Hadzic, N., Wirth, S., Bassett, M., Kelly, D., 2008. Drug-related hepatotoxicity and acute liver failure. J. Pediatr. Gastroenterol. Nutr. 47 (4), 395
405. Newman, D.J., Cragg, G.M., Snader, K.M., 2003. Natural products as sources of new drugs over the period 1981-2002. J. Nat. Prod. 66 (7), 1022
1032. Nicotera, P., Bellomo, G., Orrenius, S., 1990. The role of Ca21 in cell killing. Chem. Res. Toxicol. 3, 484
494. Nishimura, Y., Kurata, N., Sakurai, E., Yasuhara, H., 2004. Inhibitory effect of antituberculosis drugs on human cytochrome P450-mediated activities. J. Pharmacol. Sci. 96 (3), 293
300. Notarbartolo, M., Poma, P., Perri, D., Dusonchet, L., Cervello, M., D’Alessandro, N., 2005. Antitumor effects of curcumin, alone or in combination with cisplatin or doxorubicin, on human hepatic cancer cells. Analysis of their possible relationship to changes in nf-kb activation levels and in IAP gene expression. Cancer Lett. 224 (1), 53
65. Opara, E.C., Rockway, S.W., 2006. Antioxidants and micronutrients. Dis. Mon. 52 (4), 151
163. Ostrowska, J., Skrzydlewska, E., 2006. The comparison of effect of catechins and green tea extract on oxidative modifications of LDL in vitro. Adv. Med. Sci. 5, 298
303. Pal, S., Bhattacharjee, A., Mukherjee, S., Bhattacharya, K., Khowala, S., 2014. Antioxidant and hepatoprotective activity of ethanolic extract of Alocasia indica Tuber. Am. J. Phytomed. Clin. Therapeut. 2 (2), 191
208.

REFERENCES

101

Pandey, A.K., 2007. Anti-staphylococcal activity of a pan-tropical aggressive and obnoxious weed Parthenium histerophorus: an in vitro study. Natl. Acad. Sci. Lett. 30 (11/12), 383
386. Parra, J.L., Reddy, K.R., 2003. Hepatotoxicity of hypolipidemic drugs. Clin. Liver. Dis. 7 (2), 415
433. Patel, K., Krishna, K., Sokoloski, E., Ito, Y., 2000. Preparative separation of curcuminoids from crude curcumin and turmeric powder by pH-zone refining countercurrent chromatography. J. Liq. Chrom. Relat. Tech. 23 (14), 2209
2218. Patel, K., Singh, G.K., Patel, D.K., 2014. A review on pharmacological and analytical aspects of naringenin. Chin. J. Integr. Med. 24 (7), 551
560. Paunescu, A., Ponepal, C.M., Draghici, O., Marinescu, A.G., 2009. The CCl4 action upon physiological indices in Lepus timidus and the protective role of some substances. An. UO Fasc. Biol 16 (2), 104
107. Peng, W., Qin, R., Li, X., Zhou, H., 2013. Botany, phytochemistry, pharmacology, and potential application of Polygonum cuspidatum sieb.Et zucc.: a review. J. Ethnopharmacol. 148 (3), 729
745. Perry, M.C., 1992. Chemotherapeutic agents and hepatotoxicity. Semin. Oncol. 19 (5), 551
565. Pham, T.V., Lu, S., Kaplowitz, N., 1997. Acetaminophen hepatotoxicity. In: Taylor, M.B. (Ed.), Gastrointestinal Emergencies, second ed Williams and Wilkins, Baltimore, pp. 371
388. Piroth, L., 2005. Liver steatosis in HIV-infected patients. AIDS Rev. 7 (4), 197
209. Piver, B., Berthou, F., Dreano, Y., Lucas, D., 2001. Inhibition of CYP3A, CYP1A and CYP2E1 activities by resveratrol and other nonvolatile red wine components. Toxicol. Lett. 125 (1-3), 83
91. Pounds, J.G., Rosen, J.F., 1988. Cellular Ca21 homeostasis and Ca21 mediated cell processes as critical targets for toxicant action: conceptual and methodological pitfalls. Toxicol. Appl. Pharmacol. 94 (3), 331
341. Reichen, J., 1999. The role of the sinusoidal endothelium in liver function. News Physiol. Sci. 14, 117
121. Ricaurte, B., Guirguis, A., Taylor, H.C., Zabriskie, D., 2006. Simvastatin-amiodarone interaction resulting in rhabdomyolysis, azotemia, and possible hepatotoxicity. Ann. Pharmacother. 40 (4), 753
757. Rockstroh, J., Sulkowski, M., Neubacher, D., Mayers, D., Stern, J., 2006. 24-week effcacy of tipranavir boosted with ritonavir in hepatitis B or C coinfected patients. In: 45th Interscience Conference on Antimicrobial Agents and Chemotherapy. Saleem, T.S.M., Chetty, C.M., Ramkanth, S., Rajan, V.S.T., Kumar, K.M., Gautham, K., 2010. Hepatoprotective herbs-a review. Int. J. Res. Pharm. Sci. 1 (1), 1
5. Sarich, T.C., Youssef, M., Zhou, T., Adams, S.P., Wall, R.A., Wright, J.M., 1996. Role of hydrazine in the mechanism of isoniazid hepatotoxicity in rabbits. Arch. Toxicol. 70 (12), 835
840. Saukkonen, J.J., Cohn, D.L., Jasmer, R.M., Schenker, S., Jereb, J.A., Nolan, C.M., et al., 2006. An offcial ATS statement: hepatotoxicity of antituberculosis therapy. Am. J. Respir. Crit. Care. Med. 174 (8), 935
952. Schimanski, C.C., Burg, J., Mohler, M., Hohler, T., Kanzler, S., Otto, G., et al., 2004. Phenprocoumon-induced liver disease ranges from mild acute hepatitis to (sub-) acute liver failure. J. Hepatol. 41 (1), 67
74. Seeman, P., 1972. The membrane actions of anesthetics and tranquilizers. Pharmacol. Rev. 24 (4), 583
655. Seif, H.S.A., 2014. Ameliorative effect of pumpkin oil (Cucurbita pepo L.) against alcohol-induced hepatotoxicity and oxidative stress in albino rats. Beni-Suef. Univ. J. Basic Appl. Sci. 3 (3), 178
185. Senior, J.R., 2008. What is idiosyncratic hepatotoxicity? What is it not? Hepatology 47 (6), 1813
1815. Sharma, U.K., Sharma, A.K., Gupta, A., Kumar, R., Pandey, A., Pandey, A.K., 2017. Pharmacological activities of cinnamaldehyde and eugenol: antioxidant, cytotoxic and anti-leishmanial studies. Cell Mol. Biol. 63 (6), 73
78. Sharma, U.K., Kumar, R., Ganguly, R., Gupta, A., Sharma, A.K., Pandey, A.K., 2018. Cinnamaldehyde, an active component of cinnamon provides protection against food colour induced oxidative stress and hepatotoxicity in albino Wistar rats. Vegetos 31 (2), 123
129. Sharma, U.K., Kumar, R., Gupta, A., Ganguly, R., Singh, A.K., Ojha, A.K., Pandey, A.K., 2019. Ameliorating efficacy of eugenol against metanil yellow induced toxicity in albino Wistar rats. Food Chem. Toxicol. 126, 34
40.

102

CHAPTER 3 PLANT SECONDARY METABOLITES

Shear, N., Spielberg, S., 1988. Anticonvulsant hypersensitivity syndrome: in vitro assessment of risk. J. Clin. Invest. 82 (6), 1826
1832. Sherwood, L., 1997. Human Physiology: From Cells to Systems, third ed Wadsworth, Boston, MA, p. 880. Shimizu, S., Atsami, R., Itokawa, K., Iwasaki, M., Aoki, T., Ono, C., et al., 2009. Metabolism dependent hepatotoxicity of amodiaquine in glutathione-depleted mice. Arch. Toxicol. 83 (7), 701
707. Singh, N., Kamath, V., Narasimhamurthy, K., Rajini, P.S., 2008. Protective effects of potato peel extract against carbonatetrachloride-induced liver injury in rats. Environ. Toxicol. Pharmacol. 26 (2), 241
246. Steele, M.A., Burk, R.F., DesPrez, R.M., 1991. Toxic hepatitis with isoniazid and rifampin. A meta-analysis. Chest 99 (2), 465
471. Stevenson, D.G., Eller, F.J., Wang, L., Jane, J.L., Wang, T., Inglett, G.E., 2007. Oil and tocopherol content and composition of pumpkin seed oil in 12 cultivars. J. Agric. Food. Chem. 55 (10), 4005
4013. Stolk, M.F., Becx, M.C., Kuypers, K.C., Seldenrijk, C.A., 2006. Severe hepatic side effects of ezetimibe. Clin. Gastroenterol. Hepatol. 4 (7), 908
911. Sulkowski, M., Mehta, S., Chaisson, R., Thomas, D., Moore, R., 2004. Hepatotoxicity associated with protease inhibitor-based antiretroviral regimens with or without concurrent ritonavir. AIDS 18 (17), 2277
2284. Tanaka, T., Kohno, H., Tsukio, Y., Honjo, S., Tanino, M., Miyake, M., 2000. Citrus limonoids obacunone and limonin inhibit azoxymethane-induced colon carcinogenesis in rats. Biofactors 13 (1-4), 213
218. Tostmann, A., Boeree, M.J., Aarnoutse, R.E., de Lange, W.C.M., Van der ven, A.J., Dekhuijzen, R., 2008. Antituberculosis drug-induced hepatotoxicity: concise up-to-date review. J. Gastroenterol. Hepatol. 23 (2), 192
202. Van Leth, F., Phanuphak, P., Ruxtrungham, K., Baraldi, E., Miller, S., Gazzard, B., et al., 2004. Comparison of frst-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: a randomised open-label trial, the 2NN Study. Lancet 363 (9417), 1253
1263. Van Rossum, T.G., Vulto, A.G., Hop, W.C., Schalm, S.W., 2001. Glycyrrhizin-induced reduction of alt in European patients with chronic hepatitis C. Am. J. Gastroenterol. 96 (8), 2432
2437. Wan, J., Zhu, Y.N., Feng, J.Q., Chen, H.J., Zhang, R.J., Ni, J., et al., 2008. Periplocoside A, a pregnane glycoside from Periploca sepium bge, prevents concanavalin a-induced mice hepatitis through inhibiting nktderived inflammatory cytokine productions. Int. Immunopharmacol. 8 (9), 1248
1256. Wang, W., Goodman, M.T., 1999. Antioxidant property of dietary phenolic agents in a human LDL-oxidation ex vivo model: interaction of protein binding activity. Nutr. Res. 19 (2), 191
202. Wang, W.Z., Cheng, J., Luo, J., Zhuang, S.M., 2008. Abrogation of G2/M arrest sensitizes curcumin-resistant hepatoma cells to apoptosis. FEBS Lett. 582 (18), 2689
2695. Wang, S., Li, J., Huang, H., Gao, W., Zhuang, C., Li, B., et al., 2009. Anti-hepatitis B virus activities of astragaloside IV isolated from radix astragali. Biol. Pharm. Bull. 32 (1), 132
135. Wang, M., Wang, F., Wang, Y., Ma, X., Zhao, M., Zhao, C., 2013. Metabonomics study of the therapeutic mechanism of Gynostemma pentaphyllum and atorvastatin for hyperlipidemia in rats. PLoS One 8 (11), e78731. Westphal, J.F., Vetter, D., Brogard, J.M., 1994. Hepatic side-effects of antibiotics. J. Antimicrob. Chemother. 33 (3), 387
401. WHO, 2001. Legal Status of Traditional Medicines and Complementary/Alternative Medicine: A Worldwide Review, 2001. WHO Publishing. Wieland, T., Faulstich, H., 1978. Amatoxins, phallotoxins, phallolysin and antamanide: the biologically active components of poisonous Amanita mushrooms. CRC Crit. Rev. Biochem. 5 (3), 185
260. Williams, L.D., Burdock, G.A., Edwards, J.A., Beck, M., Bausch, J., 2009. Safety studies conducted on highpurity trans-resveratrol in experimental animals. Food. Chem. Toxicol. 47 (9), 2170
2182. World Health Organization, 2002. Diet, Physical Activity and Health. World Health Organization, Geneva. Wu, Y.L., Lian, L.H., Wan, Y., Nan, J.X., 2010. Baicalein inhibits nuclear factor-kB and apoptosis via c-flip and mapk in d-galn/lps induced acute liver failure in murine models. Chem. Biol. Interact. 188 (3), 526
534.

REFERENCES

103

Xing, L.J., Zhang, L., Liu, T., Hua, Y.Q., Zheng, P.Y., Ji, G., 2011. Berberine reducing insulin resistance by up-regulating IRS-2 mRNA expression in nonalcoholic fatty liver disease (NAFLD) rat liver. Eur. J. Pharmacol. 668 (3), 467
471. Xu, T., Zheng, L., Xu, L., Yin, L., Qi, Y., Xu, Y., et al., 2014. Protective effects of dioscin against alcoholinduced liver injury. Arch. Toxicol. 88 (3), 739
753. Xue, M., Zhang, L., Yang, M.X., Zhang, W., Li, X.M., Ou, Z.M., et al., 2015a. Berberine-loaded solid lipid nanoparticles are concentrated in the liver and ameliorate hepatosteatosis in db/db mice. Int. J. Nanomed. 10 (1), 5049
5057. Xue, Y., Li, X., Du, X., Li, X., Wang, W., Yang, J., et al., 2015b. Isolation and anti-hepatitis b virus activity of dibenzocyclooctadiene lignans from the fruits of Schisandra chinensis. Phytochemistry 116, 253
261. Yang, X., Liao, M., Yang, Z., Guo, J., Gao, Q., 2009. Effect of Panax notoginseng on genes expression of cyp and gst in liver tissues of rats. China J. Chin. Mater. Med. 34 (18), 2390
2393. Yen, F.L., Wu, T.H., Lin, L.T., Cham, T.M., Lin, C.C., 2009. Naringeninloaded nanoparticles improve the physicochemical properties and the hepatoprotective effects of naringenin in orallyadministered rats with CCl(4)induced acute liver failure. Pharm. Res. 26 (4), 893
902. Yildiz, F., Coban, S., Terzi, A., Ates, M., Aksoy, N., Cakir, H., et al., 2008. Nigella sativa relieves the deleterious effects of ischemia reperfusion injury on liver. World J. Gastroenterol. 14 (33), 5204
5209. Yim, S.Y., Lee, Y.J., Lee, Y.K., Jung, S.E., Kim, J.H., Kim, H.J., et al., 2009. Gomisin n isolated from Schisandra chinensis significantly induces anti-proliferative and pro-apoptotic effects in hepatic carcinoma. Mol. Med. Rep. 2 (5), 725
732. Yoon, S.J., Koh, E.J., Kim, C.S., Jee, O.P., Kwak, J.H., Jeong, W.J., et al., 2012. Agrimonia eupatoria protects against chronic ethanol-induced liver injury in rats. Food. Chem. Toxicol. 50 (7), 2335
2341. Yu, C., Shin, Y.G., Chow, A., Li, Y., Kosmeder, J.W., Lee, Y.S., et al., 2002. Human, rat, and mouse metabolism of resveratrol. Pharm. Res. 19 (12), 1907
1914. Yu, K.Z., Liu, J., Guo, B.L., Zhao, Z.Z., Hong, H., Chen, H.B., et al., 2014. Microscopic research on a multisource traditional chinese medicine, astragali radix. J. Nat. Med. 68 (2), 340
350. Yue, S., Hu, B., Wang, Z., Yue, Z., Wang, F., Zhao, Y., et al., 2014. Salvia miltiorrhiza compounds protect the liver from acute injury by regulation of p38 and nfkappab signaling in kupffer cells. Pharm. Biol. 52 (10), 1278
1285. Zeeni, N., Daher, C.F., Saab, L., Mroueh, M., 2014. Tragopogon porrifolius improves serum lipid profile and increases short-term satiety in rats. Appetite 72, 1
7. Zhang, S., Ji, G., Liu, J., 2006. Reversal of chemical-induced liver fibrosis in wistar rats by puerarin. J. Nutr. Biochem. 17 (7), 485
491. Zhang, J., Ni, J., Chen, Z.H., Li, X., Zhang, R.J., Tang, W., et al., 2009. Periplocoside A prevents experimental autoimmune encephalomyelitis by suppressing IL-17 production and inhibits differentiation of th17 cells. Acta Pharmacol. Sin. 30 (8), 1144
1152. Zhang, H., Li, C., Kwok, S.T., Zhang, Q.W., Chan, S.W., 2013a. A review of the pharmacological effects of the dried root of Polygonum cuspidatum (hu zhang) and its constituents. Evid. Based Complement. Altern. Med. 2013, 13 pages. Zhang, Y., Xie, Y., Gao, Y., Ma, J., Yuan, J., et al., 2013b. Multitargeted inhibition of hepatic fibrosis in chronic iron-overloaded mice by Salvia miltiorrhiza. J. Ethnopharmacol. 148 (2), 671
681. Zhao, Y., Li, H., Gao, Z., Xu, H., 2005. Effects of dietary baicalin supplementation on iron overload-induced mouse liver oxidative injury. Eur. J. Pharmacol. 509 (2-3), 195
200. Zhou, L., Li, X., Chen, X., Li, Z., Liu, X., Zhou, S., et al., 2010. In vivo antitumor and antimetastatic activities of camptothecin encapsulated with n-trimethyl chitosan in a preclinical mouse model of liver cancer. Cancer Lett. 297 (1), 56
64. Zhu, Q., Sun, Y., Zhu, J., Fang, T., Zhang, W., Li, J.X., 2014. Antinociceptive effects of sinomenine in a rat model of neuropathic pain. Sci. Rep. 1 (4), 7270.

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FURTHER READING Cottart, C.H., Nivet-Antoine, V., Laguillier-Morizot, C., Beaudeux, J.L., 2010. Resveratrol bioavailability and toxicity in humans. Mol. Nutr. Food. Res. 54 (1), 7
16. Emim, J.A., Oliveira, A.B., Lapa, A.J., 1994. Pharmacological evaluation of the anti-inflammatory activity of a citrus bioflavonoid, hesperidin, and the isoflavonoids, duartin and claussequinone, in rats and mice. J. Pharm. Pharmacol. 46 (2), 118
122. Zhang, L., Wang, G., Hou, W., Li, P., Dulin, A., Bonkovsky, H.L., 2010. Contemporary clinical research of traditional chinese medicines for chronic hepatitis B in china: an analytical review. Hepatology 51 (2), 690
698.

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4

2 ´ ´ Marı´a de la Luz Cadiz Gurrea1,2, So´nia Soares3, Francisco Javier Leyva Jimenez , 1,2 3 4 1,2 ´Alvaro Fernandez ´ Ochoa , Diana Pinto , Cristina Delerue-Matos , Antonio Segura Carretero and Francisca Rodrigues4 1

Department of Analytical Chemistry, University of Granada, Granada, Spain 2Research and Development of Functional Food Centre (CIDAF), PTS Granada, Granada, Spain 3REQUIMTE/LAQV, Faculty of Sciences, University of Porto, Porto, Portugal 4REQUIMTE/LAQV, Instituto Superior de Engenharia do Porto, Instituto ´ Politecnico do Porto, Porto, Portugal

CHAPTER OUTLINE Abbreviations...................................................................................................................................... 105 4.1 Introduction ................................................................................................................................. 106 4.2 Cardiovascular Diseases .............................................................................................................. 107 4.3 Cancer ........................................................................................................................................ 111 4.4 Metabolic Syndrome .................................................................................................................... 113 4.5 Diabetes ...................................................................................................................................... 118 4.6 Neurodegenerative Diseases......................................................................................................... 124 4.7 Overall Mortality .......................................................................................................................... 127 4.8 Conclusion .................................................................................................................................. 129 Acknowledgments ............................................................................................................................... 130 References ......................................................................................................................................... 130

ABBREVIATIONS AD AM APP BMI BP BW COX-2 CV CVD DBP

Alzheimer’s disease anthropometric measures amyloid precursor protein body mass index blood pressure body weight cyclooxygenase-2 cardiovascular cardiovascular disease diastolic blood pressure

Nutraceuticals and Natural Product Pharmaceuticals. DOI: https://doi.org/10.1016/B978-0-12-816450-1.00004-0 © 2019 Elsevier Inc. All rights reserved.

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DHA DPP-4 EGCG EVOOs EPA FBG GLUT-4 GTE HbA1c HDL HOMA-IR IL LDL MetS MN MUFA NF-κB nPCR PCOS PD PSA PUFAs RCTs SBP T2DM TC TG TSE WBG WC WMD WHO

docosahexaenoic acid dipeptidyl peptidase-IV epigallocatechin-3-gallate extra-virgin olive oils eicosapentaenoic acid fasting blood glucose glucose transporter-4 green tea extract hemoglobin A1c high-density lipoprotein homeostatic model assessment for insulin resistance interleukin low-density lipoprotein metabolic syndrome micronucleus monounsaturated fatty acid nuclear factor-kappa B normalized protein catabolic rate polycystic ovary syndrome Parkinson’s disease prostate-specific antigen polyunsaturated fatty acids randomized controlled trials systolic blood pressure type 2 diabetes total cholesterol triglycerides tomato seeds wild bitter gourd waist circumference weighted mean difference World Health Organization

4.1 INTRODUCTION In the last few decades, nutritional supplements consumption has increased in the Western world for all age groups, mainly due to the intensification concern related to wellness (del Balzo et al., 2014). Different food supplements are indicated for chronic diseases such as cardiovascular (CV), cancer, or diabetes. Nevertheless, the long-term potentially dangerous effects related to an indiscriminate consumption of them are still unknown and are becoming a matter of public-health concern (del Balzo et al., 2014). According to the European Commission and the US Food and Drug Administration, dietary supplements are defined as concentrated sources of nutrients or other substances with a nutritional or physiological effect that increase the overall dietary intake by supplementing the normal diet, being marketed in measured doses such as pills, tablets, capsules, or liquids (EC; FDA). The term “dietary supplement” encompasses a wide range of different substances, including vitamins, minerals, herbal and botanical substances, fish oils, glucosamine,

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creatine, and essential fatty acids. In 2014 del Balzo et al. stated that the consumption of dietary supplements is influenced by different factors such as gender, age, educational level, socioeconomic status, place of residence, or even ethnicity (del Balzo et al., 2014). Nutraceuticals are dietary supplements that contain a concentrated form of a presumed bioactive substance originally derived from a food, but now present in a nonfood matrix, and used to enhance health in dosages exceeding those obtainable from normal foods (Derosa and Maffioli, 2015; Angelo et al., 2017; Sahebkar et al., 2016). Recent studies estimated the dietary supplement intake in different countries and groups around the world (Shipkowski et al., 2018). Shipkowski et al. observed that the use of botanical dietary supplements, generally available as whole plants, plant parts, powdered plant material, or plant extracts, is widespread in the United States. According to Smith et al. (2017), over 20,000 dietary supplements in the botanical ingredient category are available in the United States marketplace, being estimated that approximately $7.5 billion was spent on botanical dietary supplements in 2016. Indeed, the Euromonitor International estimated that the annual expenditure on food supplements in the European Union by 2020 will be a h7.9 billion and is constantly growing. The top 10 European markets are Italy, Germany, Russia, the United Kingdom, France, Poland, Norway, Finland, Belgium, and Spain. In 2013 Bailey et al. examined the motivations for dietary supplement use and characterized the types of products used for the most commonly reported motivations, also examining the role of physicians and healthcare practitioners in guiding choices about dietary supplements (Bailey et al., 2013). The authors observed that the most common reasons for using supplements were to “improve” (45%) or “maintain” (33%) overall health. Normally, women used calcium products for “bone health” (36%), whereas men were more likely to report supplement use for “heart health or to lower cholesterol” (18%). Older adults ($60 years) were more likely than younger individuals to report motivations related to site-specific reasons like heart, bone and joint, and eye health. Only 23% of products were used based on recommendations of a healthcare provider. Multivitamin
mineral products were the most frequently reported type of supplement taken, followed by calcium and ω-3 or fish oil supplements. For consumers that never tried dietary supplements the question is always the same: Are the dietary supplements effective in preventing or even treating chronic diseases? The role of the nutritional supplements on human health divides the public opinion, being of great interest to find scientific evidences of their effects. The aim of this chapter is to provide an overview of the potential association between nutritional supplements diet and a lower prevalence and incidence of chronic diseases, such as cardiovascular disease (CVD), cancer, metabolic syndrome, diabetes, and neurodegenerative diseases as well as a reduced overall mortality. In this way, cross-sectional and prospective cohorts and other studies published in the last 10 years were critically analyzed and detailed.

4.2 CARDIOVASCULAR DISEASES CVD is the leading global cause of morbidity and mortality worldwide, being responsible for 46% of noncommunicable disease deaths (Kahleova et al., 2018; Chen et al., 2014a,b). A major risk factor to develop CVD is hyperlipidemia (Chen et al., 2014a,b). The risk of myocardial infarction may be reduced by healthy lifestyle choices by .80%, with nutrition playing a key role (Kahleova et al., 2018). In fact, this increase has been linked to lifestyle factors, such as the high consumption

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of fatty and processed foods, the low consumption of whole plant foods, and the lack of exercise (NCEP, 2002). In that way, nutrition may be the most important factor in preventing premature CVD death and disability, surpassing other habits such as no smoking and physical activity. The past two decades have witnessed a surge of interest in finding natural products with lipid-regulating activities (Chen et al., 2014a,b; Scicchitano et al., 2014; Cicero et al., 2012). Clinical trials incorporating dietary supplements have shown to be effective in preventing and even reversing CVD (Jeong et al., 2018). According to Chen et al. (2014a,b), hypolipidemic nutraceuticals and functional foods help to improve serum lipid profiles reducing total cholesterol (TC), triglyceride (TG), and low-density lipoprotein (LDL) cholesterol, while elevating high-density lipoprotein (HDL) cholesterol. Blood cholesterol levels are a well-documented risk factor for CVD (Vivekananthan et al., 2003). Particularly, oxidized low LDL plays a key role in the pathogenesis of atherosclerosis (Vivekananthan et al., 2003). A number of nutraceuticals have shown promising effects in terms of improving the lipid profile and modifying CV risk, such as plant sterols/stanols, berberine, red yeast rice (monacolin K), resveratrol, curcuminoids, flaxseed, garlic, anthocyanins, spirulina, green tea (polyphenols or extracts), fish oil, chitosan, glucomannan, or even β-glucans (Sahebkar et al., 2016; Chen et al., 2014a,b; Ursoniu et al., 2018). For example, in 2013, Dong et al. performed a meta-analysis to assess the safety of berberine (an isoquinoline derivative alkaloid isolated from several Chinese herbal medicines, such as Coptis chinensis) and its effects on blood lipid profiles (n 5 874 participants) (Dong et al., 2013). The results demonstrated that the administration of berberine produced a significant reduction in the TC, TG, and LDL cholesterol levels, with a remarkable increase in HDL and without serious adverse effects (Dong et al., 2013). On the other hand, in 2003, Vivekananthan et al. performed a meta-analysis to assess the effect of α-tocopherol (vitamin E), β-carotene, or both, in the reduction of CV events (Vivekananthan et al., 2003). Seven randomized trials of vitamin E treatment and, separately, eight β-carotene treatments, including 1000 or more patients were performed. The dose range for vitamin E was 50
800 IU, and for β-carotene was 15
50 mg. According to the authors, vitamin E did not provide benefit in mortality when compared with the control or significantly decrease the risk of CV death or cerebrovascular accident. In what concerns β-carotene, a small but significant increase in all-cause mortality and a slight increase in CV death was observed. The author’s results do not support the routine use of vitamin supplements containing β-carotene and vitamin A, β-carotene’s biologically active metabolite, recommending that clinical studies of β-carotene should be discontinued. More recently, Derosa et al. (2018) evaluated the efficacy and safety of a nutraceutical agent containing fermented red rice, phytosterols, and olive polyphenols in Caucasian patients with low CV risk, both at fasting and after an oral fat load. For this randomized controlled trial (RCT), 80 patients received as addition to diet and physical activity a nutraceutical combination containing fermented red rice, sterol esters and stanols, curcumin, and olive polyphenols or placebo (control group), once a day. At time 0 and after 3 months, the body mass index (BMI), the fasting plasma glucose, the lipid profile, the soluble intercellular adhesion molecule-1, the soluble vascular cell adhesion molecule-1, and the soluble endothelial-leukocyte adhesion molecule-1 were evaluated at fasting and after an oral fat load. A reduction of TC, TG, and LDL cholesterol, both compared to baseline and to placebo were observed. Also, a reduction of soluble intercellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, and sE-selectin in the group treated with the nutraceutical combination, both compared to baseline and to placebo, were noted. The parameters

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recorded during the oral fat load improved when compared to the oral fat load performed at baseline with the nutraceutical combination. Several studies were performed to evaluate the effect of red yeast rice in cholesterol lowering (Gerards et al., 2015; Johnston et al., 2017). Red yeast rice is a standardized food-based ingredient containing monacolin K (which is chemically identical to lovastatin) and considered a powerful natural cholesterol-lowering agent (Johnston et al., 2017). Statins are commonly used and accepted as the most effective treatment for the LDL cholesterol reduction. However, these compounds have been associated with adverse symptoms, such as elevated hepatic enzyme levels, gastrointestinal symptoms, and high creatine phosphokinase levels (Jeong et al., 2018; Gerards et al., 2015; Johnston et al., 2017). In a recent systematic review, Gerards et al. (2015) showed the effectiveness of red yeast rice in the LDL cholesterol reduction and its safety, reinforcing the use of this foodbased ingredient as an alternative to the statins. Since the main compound of red yeast rice, monacolin K, has been proven to be effective in LDL cholesterol reduction, additional combinations of this with others lipid-lowering natural compounds have also been evaluated (Gonnelli et al., 2015; Magno et al., 2018). In 2014 Gonnelli and coworkers investigated the efficacy and the safety of a nutraceutical combination mainly consisting of red yeast rice extract (in a quantity equivalent to 3 mg monacolins), berberine, and policosanols (MBP-NC) (Gonnelli et al., 2015). The single center, randomized, double-blind, placebo-controlled study was performed in 60 patients with lowmoderate risk hypercholesterolemia (Gonnelli et al., 2015). After a run-in period of 3 weeks on a stable hypolipidic diet, the patients were randomized to receive a pill of MBP-NC (n 5 30) or placebo (n 5 30) once a day after dinner, in addition to the hypolipidic diet. The efficacy and tolerability of the treatment were fully assessed after 4, 12, and 24 weeks. The results showed a significant reduction of total and LDL cholesterol after 4 weeks remaining stable after 12 and 24 weeks. Nevertheless, no significant changes in HDL cholesterol, fasting glucose, and TG serum levels were observed. Magno et al. (2018) tested the efficacy and safety of a dietary supplement already in the market (N) that contain monacolin K, and a novel association (A) containing monacolin K, L-arginine, coenzyme Q10 and ascorbic acid, in a controlled, randomized, open-label, cross-over clinical study. Both dietary supplements (A and N) contained 10 mg of monacolin K. The clinical trial enrolled 20 Caucasian outpatients aged 18
75 years with serum LDL cholesterol between 130 and 180 mg/dL (Magno et al., 2018). The authors evaluated the TC, the LDL cholesterol, the HDL cholesterol as well as the TG, among others parameters, measured at the start and at the end of a treatment period of 8 weeks, separated by a 4-week washout period. The results confirmed the LDL cholesterollowering properties of monacolin K, showing a reduction of weighted mean difference (WMD) of 36.4 mg/dL during N treatment and WMD of 40.1 mg/dL during A treatment. Moreover, at variance with a supplement already in the market (N), the novel association (A) of monacolin K with L-arginine, coenzyme Q10, and ascorbic acid produces a significant reduction of TG without significant effects on HDL. Recently, the effect of argan oil [argan tree (Argania spinosa L. Skeels)] on plasma lipids for the reduction of CVD risk was reviewed (Ursoniu et al., 2018). Besides its antioxidant powder, mainly due to its high content in bioactive compounds such as polyphenols, phytosterols, and tocopherols, the elevated amount of monounsaturated and polyunsaturated fatty acid (MUFA and PUFA, respectively) give this food-based ingredient interesting pharmacological properties

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(Ursoniu et al., 2018). In this systematic review and meta-analysis, five trials with administration of argan oil were selected. The administration occurred during a period of at least 2 weeks in 292 participants. The results showed a significant reduction of TC, LDL cholesterol, and TG when compared with the control treatment, and an increase of the HDL cholesterol. These results have shown the potentiality of argan oil in the reduction of the risk of CV outcomes as well as cardiometabolic risk. In the last few years, a relation between polyphenols and the reduction of CVD risk has been evaluated. These compounds are present in plants and natural foods, being known for their antioxidant properties. Therefore the daily consumption of these bioactive compounds could be related to the prevention and treatment of CVD. Curcumin, for example, is a natural polyphenolic compound mainly present in Curcuma longa L. (commonly known as turmeric) with diverse and attractive biological activities. The lipid-lowering properties of curcumin have been extensively studied by different authors but the conclusions are controversy (Sahebkar, 2014; Qin et al., 2017). In 2014 Sahebkar performed a systematic review and meta-analysis for clinical evidences of curcumin supplementation effects on blood lipids (Sahebkar, 2014). The authors selected five RCTs that comprise different arms treatment (n 5 133 patients with curcumin and 90 as control group) and investigated the effect of curcumin on TC, LDL cholesterol, HDL cholesterol, and TG (Sahebkar, 2014). The results showed insignificant reductions on TC, LDL cholesterol, HDL cholesterol, and TG. Posteriorly, other RCTs evaluated the effects of turmeric and curcumin on blood lipid levels (Rahmani et al., 2016; Rahimi et al., 2016; Amin et al., 2015) and a subsequent meta-analysis was performed by Qin et al. to assess the efficacy and safety of both in lowering lipid levels (Qin et al., 2017). The results of the analysis of seven eligible studies (n 5 649 patients) showed a significant reduction of LDL cholesterol and TG. In addition, the authors demonstrated a superior effectiveness of curcumin in lowering the TC levels in patients with metabolic syndrome and a greater effect of the turmeric extract on TC levels reduction, while HDL cholesterol levels were not improved (Qin et al., 2017). Quercetin (2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-chromen-4-one) is one of the major dietary flavonoids (Lamson and Brignall, 2000). In 2017 Sahebkar published a meta-analysis of RCTs in order to understand and quantify the effects of quercetin supplementation on plasma lipids (Sahebkar, 2017). The study comprises 442 subjects (221 in the quercetin and 221 in the control group) in a total of five RCTs which evaluated TC, LDL cholesterol, HDL cholesterol, and TG (Sahebkar, 2017). The results do not suggest any clinically relevant effect of quercetin supplementation on plasma lipids, showing a significant increase in TC, a decline in TG and any effects in LDL and HDL cholesterol concentrations. Moreover, the authors observed changes in plasma TG, but not other indices of lipid profile were significantly associated with quercetin dose and duration of supplementation. Another polyphenol of interest in the prevention and reduction of the risk of CVD is catechin, which is present in green tea. Green tea catechins are known to have cholesterol-lowering effects and mainly consist of (2)-epicatechin (EC), (2)-epigallocatechin (EGC), (2)-epigallocatechin-3-Ogallate (EGCG), and (2)-epicatechin-3-O-gallate (Imbe et al., 2016). They investigated the potential effect of “Benifuuki” (Camellia sinensis var. Benifuuki), a green tea high consumed in Japan that contains EGCG and (2)-epigallocatechin-3-O-(3-O-methyl)-gallate (EGCGv3Me) in abundance. The authors compared the results to those obtained with “Yabukita” (C. sinensis var. Yabukita)

4.3 CANCER

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which contains high levels of EGCG, and with barley infusion, which does not contain any catechin. The study enrolled 155 participants that were divided in three groups: “Benifuuki,” “Yabukita,” or barley infusion. The changes in TC and LDL cholesterol levels were evaluated after a period of 12 weeks of consumption. Taking into account that the green tea drinking habits of the subjects could influence the results, the groups were posteriously separated based on tea habit. The study showed a significant decrease in TC and LDL cholesterol levels in “Benifuuki” and “Yabukita” groups in the subjects without a tea habit, in comparison with the effect of barley infusion. Nevertheless, as stated by Sahebkar et al. (2016), a number of important questions remain to be addressed, including whether longer durations of therapy would result in a better response and the exact safety profile of nutraceuticals, especially at doses higher than those consumed in an average diet. In addition, data regarding the effects of nutraceutical supplementation on the incidence of CV outcomes are lacking, and it is not clear whether additional lipid lowering by nutraceuticals can modify the residual CV risk that remains after statin therapy.

4.3 CANCER The occurrence of cancer is increasing due to the growth and aging of the population, as well as the increasing prevalence of established risk factors, such as smoking, overweight (relating to abnormal and/or inappropriate food consumption), physical inactivity, and changing of reproductive patterns associated with urbanization and economic development (Torre et al., 2016). The World Health Organization (WHO) reports that more than 8 million people die from cancer each year, and this is estimated to be 13% of all deaths worldwide. Moreover, WHO highlights that there are about 100 types of cancer, each requiring unique diagnosis and treatment. Of these types of cancer, the five most common cancers in men (in order of frequency) are lung, stomach, liver, colorectal, and esophagus while in women the most common are breast, lung, stomach, colorectal, and cervical (Daglia, 2017). Dietary pattern, foods, and food components could be important in reducing the incidence of some types of cancer (Daglia, 2017). Dietary agents have gained considerable attention over the last decade as chemopreventive agents against some types of cancer (Daglia, 2017). Hanahan and Weinberg (2011) highlight that several food-related components can hinder the biological development of cancer. Among them, polyphenols are the most prevalent and inside this large group of compounds, curcumin is one of the most important, displaying marked anticancer effects (Feitelson et al., 2015; Tuorkey, 2014). Curcumin, or turmeric (bis-α, β-unsaturated β-diketone), is a polyphenol derived from the roots of the perennial C. longa plant that has the ability to inhibit different cell signaling pathways in cancer cells such as the nuclear factor-kappa B (NF-κB), activator protein 1, cyclooxygenase-2 (COX-2), matrix metalloproteinases, cyclin D1, epidermal growth factor receptor, Akt, β-catenin, and tumor necrosis factor (Kotecha et al., 2016; Pulido-Moran et al., 2016; Perrone et al., 2015). According to the authors, curcumin kills cancer cells resistant to pro-apoptotic stimuli, induces nonapoptotic-related cell death pathways in cancer cells, impairs the biology of cancer stem cells, and is bioselective (Lefranc et al., 2017). In 2008 Dhillon et al. performed a phase II trial in patients (n 5 25) with pancreatic cancer (Dhillon et al., 2008). In this study, patients received 8 g of curcumin by mouth daily until disease progression,

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with restaging every 2 months. The authors monitored the serum cytokine levels for interleukin (IL)-6, IL-8, IL-10, and IL-1 receptor antagonists and peripheral blood mononuclear cell expression of NF-κB and COX-2. Curcumin downregulated the expression of NF-κB, COX-2, and phosphorylated signal transducer and activator of transcription 3 in peripheral blood mononuclear cells from patients, presenting biological activity. Nevertheless, considerable interpatient variation in plasma curcumin levels was observed, and more clinical trials were necessary to conclude about the anticancer activity. According to Eskra et al. (2019) soy, rich in bioactive isoflavones, is a dietary component that has beneficial effects on prostate cancer patients. The isoflavones’ anticancer activity is due to the modulation of cell proliferation expression and apoptotic genes, as well as the inhibition of cell migration and metastasis and antioxidant activity (Eskra et al., 2019). In 2010 deVere et al. performed a double-blind, placebo-controlled, randomized trial in 53 men with prostate cancer (deVere White et al., 2010). The treatment group consumed a supplement containing 450 mg genistein, 300 mg daidzein, and other isoflavones daily over 6 months. The prostate-specific antigen (PSA) was measured in both groups at baseline, 3 and 6 months later. The authors concluded that the PSA concentrations did not change. Another example is lycopene, which the effect in prostate cancer development remains undetermined (Paur et al., 2017). Paur et al. tested the ability of lycopene-rich tomato intervention to reduce the levels of PSA in 79 prostate cancer patients randomized to a nutritional intervention with (1) tomato products containing 30 mg lycopene per day; (2) tomato products plus selenium, Ω-3 fatty acids, soy isoflavones, grape/pomegranate juice, and green/black tea (tomato-plus); or control diet for 3 weeks (Paur et al., 2017). The authors did not observe differences in PSA-values between the intervention and control groups. The effect may depend on both aggressiveness of the disease and the blood levels of lycopene, selenium, and Ω-3 fatty acids. Recently, Zhao and Wang (2018) evaluated the effect of ω-3 PUFA-supplemented parenteral nutrition on inflammatory and immune function in postoperative patients with gastrointestinal malignancy through a meta-analysis study. The authors included 16 randomized clinical trials that enrolled 1008 volunteers, 506 in the Ω-3 group, and 502 in the control group. This meta-analysis confirmed that early intervention with ω-3 fatty acid emulsion in gastrointestinal cancer could not only improve the postoperative indicators of immune function, reduce inflammatory reaction, and improve the postoperative curative effect but also improve the immune suppression induced by conventional parenteral nutrition or tumor. Therefore postoperative patients with gastrointestinal cancer should add ω-3 unsaturated fatty acids in their parenteral nutrition formula. In another study, Lohr et al. (2016) tested a novel, multicomponent crystalline form of the naturally occurring compound genistein, AXP107-11, with improved oral bioavailability to be used in combination with gemcitabine in treatment-naı¨ve patients (n 5 16) with inoperable pancreatic carcinoma. The volunteers have taken orally escalating doses (400
1600 mg daily) of AXP107-11 in combination with standard gemcitabine treatment (1000 mg/m2/week) for the first 7 of 8 weeks and thereafter for a maximum of 4 3 4-week treatment cycles. The authors concluded that the median overall survival time was 4.9 months. Seven patients (44%) survived longer than 6 months and 19% were alive at the 1-year follow-up. A favorable pharmacokinetics profile with high serum levels without signs of either hematological or nonhematological toxicity was observed. Nevertheless, further studies with AXP107-11 in pancreatic cancer patients are needed to conclude about the safety and toxicity of this new compound.

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In concern to breast cancer, Samavat et al. (2017) conducted a randomized, double-blinded, placebo-controlled phase II clinical trial to investigate whether supplementation with green tea extract (GTE) modifies mammographic density, as a potential mechanism, involving 1075 healthy postmenopausal women. Volunteers consumed four daily decaffeinated GTE capsules containing, 315 mg total catechins, including 843 mg EGCG for 12 months. The supplementation for 12 months did not significantly change the percent or absolute mammographic density in all women (Samavat et al., 2017). More recently, Going et al. (2018) in a pilot breast cancer trial evaluated the effect of vitamin D supplementation in serum 27-hydroxycholesterol, an endogenous selective estrogen receptor modulator that drives the growth of estrogen receptor-positive breast cancer. For the study, 29 breast cancer patients were supplemented with low dose (400 IU/day) or high dose (10,000 IU/day) of vitamin D in the interval between biopsy and surgery. The authors concluded that vitamin D can inhibit the estrogen receptor (Going et al., 2018).

4.4 METABOLIC SYNDROME Metabolic syndrome (MetS) is a complex disease, which includes the combination of several metabolic disorders such as obesity, type 2 diabetes (T2DM), hypertension, and dyslipidemia (lowered HDL, raised LDL and TG). MetS has been associated with oxidative stress, systemic inflammation, central adiposity, and an increased risk of developing other diseases such as CVDs, cancer, dementia, T2DM, nonalcoholic fatty liver disease, or infertility (Ahima, 2016). This disease is currently a serious health problem mainly due to an increase of obesity rates and sedentary lifestyles worldwide (Gungor, 2014). According to the International Diabetes Federation, a quarter of the adult population suffers from MetS (Kaur, 2014) and its prevalence is currently spreading at an alarming rate, being the main cause of mortality in modern societies. In the past, different criteria were employed to diagnostic this disease (Cameron et al., 2004). However, in 2009 the criteria were unified by the consensus of several organizations (Alberti et al., 2009). Thus MetS is currently diagnosed when at least three of the following criteria are present: (1) central obesity (large waist circumference (WC): women $ 88 cm; men $ 102 cm, although these numbers can vary depending on the country and population); (2) high blood pressure (BP) ($130/ $ 85 mm Hg or in treatment for hypertension); (3) reduced HDL cholesterol (women , 50 mg/dL, men , 40 mg/dL); (4) high TG level ($150 mg/dL or treated for this abnormality); and/or (5) elevated fasting glucose ($100 mg/dL or patient of T2DM) (Alberti et al., 2009). One important aspect to prevent and treat MetS is to change the lifestyle focusing on increasing the physical activity and adopting a healthier diet (Pitsavos et al., 2006). Regarding eating habits, it has been shown that the consumption of a Mediterranean diet, based on plant-derived products (such as vegetables, fruits, grains, nuts, olive oil) has preventive effects against MetS (Babio et al., 2009; Esposito et al., 2004; Richard et al., 2013). In this way, vegetable sources such as garlic (Hosseini and Hosseinzadeh, 2015), grapes (Akaberi and Hosseinzadeh, 2016), rosemary (Hassani et al., 2016), saffron (Razavi and Hosseinzadeh, 2017), cinnamon (Mollazadeh and Hosseinzadeh, 2016), hibiscus (Perez-Torres et al., 2013), green tea (Basu et al., 2013; Sae-tan et al., 2011), wild bitter (Tsai et al., 2012), or barberry (Firouzi et al., 2018) have shown preventive and curative

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properties against MetS. The benefits of this diet are highly related to the high concentration of bioactive compounds, mainly MUFA and PUFA as well as phenolic compounds (Amiot et al., 2016). In recent years, nutritional supplements are gaining popularity in order to prevent or help in the treatment of certain diseases, among them MetS. In 2017 a survey carried out in Korea that showed a low prevalence of MetS in dietary supplements consumers when compared to nonconsumers (Kim et al., 2017). These supplements usually contain antioxidants, minerals, and PUFA, which due to their bioactive properties are helpful to prevent MetS. Table 4.1 details the principal studies that evaluated the effects of dietary supplements on MetS. As it is possible to observe, the dietary supplements employed in most of the studies are based on an isolated bioactive compound, plant extracts, or a formulation that combines bioactive compounds from several natural sources. Regarding isolated bioactive compounds, researches have been carried out to study the effect in MetS of a dietary supplementation based on the following compounds: resveratrol (Korsholm et al., 2017; Mendez-del Villar et al., 2014), quercetin (Egert et al., 2010; Egert et al., 2009), hesperidin (Rizza et al., 2011), and berberine (Perez-Rubio et al., 2013). Regarding berberine hydrochloride supplementation, Perez-Rubio et al. (2013) reported a decrease in weight, BP, TG, as well as total insulin secretion. Resveratrol supplementation was also able to reduce the total insulin secretion as well as the BMI (Mendez-del Villar et al., 2014). Korsholm et al. (2017) performed a more advanced study to identify the metabolic pathways altered by resveratrol supplementation in MetS patients, evaluating different biological fluids (urine, plasma) and tissues (fat, muscle) by metabolic profiling analysis. According to the authors, sulfated androgen precursors, long-chain PUFA, and aromatic amino acid derivatives related to gut microbiota were altered in different samples after the supplementation. The beneficial properties are not usually associated with a specific compound from plantderived products. In contrast, the combination of several compounds can amplify the bioactive properties. For these reasons, some dietary supplements, which have been tested with MetS patients, are based on plant extracts. For instance, several studies have been carried out with supplements based on grapes (Barona et al., 2012; Sivaprakasapillai et al., 2009; Urquiaga et al., 2015), bitter gourd (Tsai et al., 2012), green tea (Basu et al., 2013; Bogdanski et al., 2012; MielgoAyuso et al., 2014), cinnamon (Gupta Jain et al., 2017; Ziegenfuss et al., 2006), garlic (Go´mezArbel´aez et al., 2013), Aronia melanocarpa (Broncel et al., 2010), or Aloe vera (Devaraj et al., 2013) extracts (Table 4.1). Green tea has been one of the most studied sources due to its antioxidant, antiproliferative, and antiinflammatory properties. Most of the supplements are mainly enriched on EGCG, the major green tea catechin derivative, as for example, commercial capsules (TEAVIGO, DSM) made up of 97% EGCG pure. The intervention study performed with these capsules in 100 MetS subjects showed a reduction in diastolic BP (Mielgo-Ayuso et al., 2014). Other studies have also been performed using capsules from GTEs with high content in EGCG (Basu et al., 2013; Bogdanski et al., 2012). Basu et al. used capsules purchased from Solaray, which contained 230 mg of EGCG, proving a decrease in body weight (BW), BMI, and BP in MetS patients (Basu et al., 2013). Bogdanski et al. (2012) utilized green tea capsules (from 379 mg of GTE, 208 mg were of EGCG), reporting benefits on BP, cholesterol levels, and insulin resistance. In general, the intervention studies carried out with supplements derived from plant extracts, presented positive effects in some MetS features. For example, food supplements derived from cinnamon extracts reduced the fasting blood glucose (FBG), the systolic blood pressure, and improved

Table 4.1 Summary of Some Studies Performed Using Bioactive Compounds From Natural Sources or Commercial Food Supplements in Metabolic Syndrome Supplement

Description of Source or Responsible Compounds

Resveratrol

Resveratrol

66 Men with MetS

75 mg twice daily or 500 mg twice daily for 4 months

Transresveratrol capsules (500 mg) Hesperidin

Trans-resveratrol

24 Subjects with MetS

3 3 500 mg for 90 days

Hesperidin (98% pure)

28 Subjects with MetS

500 mg/day for 3 weeks

Berberine

Berberine hydrochloride

24 Subjects with MetS

Gelatine capsules of Quercetin

Quercetin

93 Subjects with MetS

500 mg, 3 times per day for 3 months 150 mg/day for 6 weeks

Green tea supplement. Capsules purchased from Solaray Green tea capsules

Green tea (230 mg EGCG)

35 Subjects with obesity and MetS

2 capsules/day for 8 weeks

Green tea/379 mg of GTE (208 mg of EGCG)

56 Obese, hypertensive subjects

1 capsule/day for 3 months

Population

Dose/ Intervention

Parameters

Results

References

Global metabolic profiling in urine, plasma, fat and muscle samples AM, blood pressure, FBG, lipid profile, insulin Lipid profile, inflammation

Decrease in sulfated androgen precursors. Long-chain PUFAs (n3 and n-6) increase in adipose tissue

Korsholm et al. (2017)

Decrease in BW, BMI, fat mass, WC, and total insulin secretion Improves endothelial function. Decrease in circulating biomarkers of inflammation and TC. Increase in HDL Decrease in WC, SBP, TG, Total insulin secretion Decrease in SBP, HDL cholesterol

Mendez-del Villar et al. (2014)

Decrease in body weight and BMI, blood pressure

Basu et al. (2010)

Decrease in blood pressure, TC, TG, FBG, LDL Increase in HDL Insulin resistance

Bogdanski et al. (2012)

FBG, insulin levels, TG, HDL Blood pressure, AM, lipid profile, oxidative stress, inflammation AM, blood pressure, FBG, and lipid profile, oxidative stress AM, blood pressure, lipid profile, FBG, total antioxidant, insulin levels

Rizza et al. (2011)

Perez-Rubio et al. (2013) Egert et al. (2010), Egert et al. (2009)

(Continued)

Table 4.1 Summary of Some Studies Performed Using Bioactive Compounds From Natural Sources or Commercial Food Supplements in Metabolic Syndrome Continued Supplement TEAVIGO

TM

Description of Source or Responsible Compounds Green Tea extract (97% pure EGCG)

Population 100 Overweight men 38 Males subjects with at least one component of MetS

Dose/ Intervention 2 capsules/day for 8 weeks

Red wine grape pomace flour (WGPF)

Red wine grapes

Grape seed extract (Meganatural BP) Freeze-dried whole grape powder

Grape

27 Subjects with MetS

150 or 300 mg/day for 4 weeks

Grape

24 Men with MetS

46 g/day for 4 weeks

WBG capsules

Bitter gourd

42 Subjects with MetS

4.8 g/day for 3 months

Cinnulin PF

Cinnamon

500 mg/day for 12 weeks

Cinnamon capsules

Cinnamon

22 Subjects with prediabetes and MetS 116 Subjects with MetS

AGE (Kyolic)

Garlic

46 Subjects with MetS

20 g of WGPF/day for 16 weeks

3 g/day (6 capsules) for 16 weeks 1.2 g/day for 12 weeks

Parameters

Results

References

AM, lipid profile, FBG, blood pressure Clinical evaluation, AM, blood pressure, and biochemical blood analysis Blood pressure, lipid profile, and FBG

Decrease in DBP

Mielgo-Ayuso et al. (2014)

Improved blood pressure, glycemia, and postprandial insulin

Urquiaga et al. (2015)

Improved blood pressure

Sivaprakasapillai et al. (2009)

Decrease in weight, BMI. Increases antiinflammatory markers in the absence of dyslipidemia Decrease in the incidence of MetS

Barona et al. (2012)

Decrease in FBG, SBP. Improve body composition

Ziegenfuss et al. (2006)

Decrease in measures of glycemia, adiposity, abdominal obesity, lipids, blood pressure Increases plasma levels of adiponectin

Gupta Jain et al. (2017)

AM, lipid profile, inflammation, and oxidative stress Clinical evaluation, AM, and biochemical blood analysis FBG, SBP, AM

AM, blood pressure, metabolic parameters AM, blood pressure, biochemical determinations, endothelian function

Tsai et al. (2012)

Go´mez-Arbel´aez et al. (2013)

Aronia extract (Aronox, Agropharm, Poland) UP780 and AC952 (Aloe products)

A. melanocarpa, Anthocyanins

25 Subjects with MetS

300 mg/day for 2 months

AM, blood pressure, lipid profile

Decrease in SBP, DBP, LDL, TC, oxidative stress markers

Broncel et al. (2010)

A. vera inner leaf gel powder (500 mg with or without 2% aloesin)

2 capsules/day for 8 weeks

AM, FBG, insulin levels, lipid profile, oxidative stress

Decrease in LDL and TC (AC952); Reductions in FBG, insulin (UP780)

Devaraj et al. (2013)

Vitamin D supplement

Vitamin D

45 Subjects with MetS and impaired fasting glucose 80 Subjects with MetS

50,000 IU vitamin D for 16 weeks

Decrease in TG levels

Salekzamani et al. (2016)

Fish oil capsules (Opcao Fenix) and extra-virgin olive oil Kepar

Fish oil and extra-virgin olive oil. Fish oil capsules (180 mg EPA and 120 mg DHA from sardines); Virgin olive oil (6.4 g oleic acid) C. longa, silymarin, guggul lipids, chlorogenic acid, and inulin

102 Subjects with MetS

3 g/day (capsules) and 10 mL/day of extra virgin olive oil for 3 months 2 pills/day for 4 months

Effects on lipid metabolism and oxidative stress

Venturini et al. (2015)

Decrease in BW, BMI, WC, FBG, TC

Patti et al. (2015)

NRT

Cocoa polyphenols, Soy isoflavones, and myoinositol

60 Women with menopause and MetS

NRT/day for 6 months

Decrease in FBG, TG, visfatin. Resistin Increases in bone-ALP

Anna et al. (2014)

Curcuminbased dietary supplement Curcumin C3 complex with bioperine

800 mg of C. longa extract, 8 of piperine from P. nigrum extract Curcuminoids with piperine

44 Subjects with MetS

2 capsules/day for 1 month

FBG, insulin resistance, serum lipid profile, AM, blood pressure AM, blood pressure, lipid profile, inflammation, and oxidative stress AM, lipid profile, FBG, parameters, and oxidative stress FBG, lipid profile, Adiponectin, resistin, boneALP AM, body composition

Decrease in BMI, WC, BW

Di Pierro et al. (2015)

100 Subjects with MetS

1000 mg/day for 8 weeks

Decrease in LDL and TG. Increase HDL

Panahi et al. (2014)

78 Subjects with MetS

AM, blood pressure, lipid profile

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the body composition and lipid profiles (Perez-Rubio et al., 2013; Gupta Jain et al., 2017); whereas grapes extracts were able to improve BP, glycemia, postprandial insulin as well as weight reduction (Barona et al., 2012; Sivaprakasapillai et al., 2009; Urquiaga et al., 2015). Apart from phenolic compounds, other important families of compounds with bioactive properties against MetS are the Ω-3 PUFA (Poudyal et al., 2011). A dietary intervention study showed that the combination of extra olive oil with fish oil capsules [which contained 180 mg of eicosapentaenoic acid (EPA) and 120 mg of docosahexaenoic acid (DHA) from sardines] had benefits on lipid metabolism and oxidative stress in MetS patients (Venturini et al., 2015). Moreover, vitamins also have an important role in MetS, specifically a vitamin D insufficiency has been correlated to a higher risk of MetS (Bea et al., 2015). Eighty MetS patients showed a reduction in TG levels after vitamin D supplementation for 16 weeks (Salekzamani et al., 2016). In order to achieve a greater effectiveness against MetS, some food supplements have been formulated mixing ingredients from different vegetal sources. For example, a natural replacement therapy, which was made up with 30 mg of cocoa polyphenols, 80 mg of soy isoflavones and 2 g of myo-inositol, was offered to 60 postmenopausal women with MetS (Anna et al., 2014). A decrease of FBG and blood TG levels was reported by the authors. Another study was performed using a supplement called Kepar (Rikrea, Italy) in 78 patients with MetS (Patti et al., 2015). This natural supplement, which is available in the Italian market, contains 160 mg of C. longa, 24 mg of guggul lipids, 14 mg of chlorogenic acid, 102 mg of silymarin, and 2.5 mg of inulin. A significant reduction in BMI, WC, FBG, as well as TC was reported (Patti et al., 2015). Another food supplement that conducted excellent results in weight loss was formulated with 800 mg of C. longa extract (made up 95% of curcumin), complexed with sunflower phospholipids (20% phosphatidylserine), and blended with 8 mg of piperine from Piper nigrum extract (Di Pierro et al., 2015). The purpose of this formulation was to increase the bioavailability by complexing the mixture with phospholipids and reducing the urinary excretion by means of piperine. In a similar way, Panahi et al. (2014) explored the effect of a curcuminoids (Curcumin C3 complex) supplementation with piperine (Bioperine), demonstrating an improvement in the lipid profile of MetS patients. In conclusion, an increase of the physical activity and the adoption of a balanced diet, together with the consumption of dietary supplements may be a good strategy to prevent and treat MetS. Although these supplements improve some of the parameters that define MetS, most of them cannot manage to alleviate all the features or all the characteristics related to the MetS. In that way, it is important to highlight that most studies have been preliminary, employing small groups of patients and using test supplements that are not yet commercialized. Therefore further studies are needed to guarantee the beneficial properties of dietary supplements on MetS.

4.5 DIABETES Diabetes mellitus (DM) rises up as a growing threat to global health causing a significant increase in premature mortality, morbidity, and healthcare costs. This disease affected 422 million of people in 2014 and its prevalence increases more rapidly in middle and low-income countries rather than developed countries (Mathers and Loncar, 2006). Moreover, it was estimated that approximately 5 million deaths were caused only by type II diabetes, achieving the seventh leading cause of death

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in 2030 (Mathers and Loncar, 2006; Bilous and Donnelly, 2010; Leite et al., 2013). In this sense, diabetes is a group of metabolic disorders typified by hyperglycemia that results from a lack or an impaired secretion of insulin by pancreatic β-cells, a diminished cell’s sensitivity to insulin or both causes (Leite et al., 2013). The factors involved in the development of this disease are related to excess body fat, poor diet, physical inactivity, high BP, or genetic factors. All of them are also risk factors associated with metabolic syndrome. This long time hyperglycemia status can procure dysfunction and failure of eyes, kidneys, nerves, heart, and/or blood vessels (WHO, 2016). As it is well known, diabetes are classified in two great categories: (1) type I diabetes, characterized by an absolute deficiency of insulin secretion caused by an autoimmune response that triggers destruction of pancreatic β-cells mediated by T-cell (Ezuruike and Prieto, 2014) and (2) type II diabetes mellitus (T2DM), which curses with a combination of tissue resistance to insulin activity and/or an unbalanced compensation in insulin secretion response, markedly related with obesity and sedentary lifestyle (Report of the expert committee on the diagnosis and classification of diabetes mellitus, 2003; Zimmet et al., 2001). In spite of the fact that studies remark that hyperglycemia leading to T2DM can be controlled with diet and regular physical activity (Astrup and Finer, 2000; Scheen and Ernest, 2002), there are cases where these healthy arrangements are not enough to control this altered condition. For this reason, various synthetics drugs have been developed with different targets to control hyperglycemia, but none of them are able to definitively alleviate this disease. In this way, sulfonylureas and meglitinides take part in stimulation of insulin release from β-cells in the pancreas (Landgraf, 2000; Seino, 2012). Conversely, metformin as biguanide is currently used to decrease plasma glucose concentrations in T2DM by increasing the tissues’ insulin sensitivity (Clarke, 1977). In addition, some drugs can inhibit enzymatic action of α-glucosidase or dipeptidyl peptidase-IV (DPP-4). Finally, thiazolidinediones act by increasing and decreasing genes expression that promote the carbohydrates’ metabolism, specifically glucose, leading to more glucosedependent cells and thus, decreasing the circulating glucose (Inzucchi et al., 2012). In spite of being a good way to manage altered glycemia conditions and, consequently, to treat diabetes, these drugs can present different adverse effects such as headache, weight gain, increased appetite, or CVDs (Inzucchi et al., 2012; Nathan et al., 2009; Intensive, 1998). Moreover, some drugs can lead to renal damage and dysfunction (Inzucchi et al., 2012; Nathan et al., 2009) and neurological disorders (Hussein et al., 2004; Sarafidis et al., 2010). These facts have led to the development of a new class of therapeutic antidiabetic supplements with compounds retrieved from natural sources. Several authors have demonstrated that plants have a huge variety of bioactive compounds, which improve some physiological functions such as glucose manage, fat metabolism, or inflammatory processes, among others (Herranz-Lopez et al., 2015; Yang et al., 2013). Therefore many studies are focused on knowing the phytochemicals’ efficacy in antidiabetic food supplements or potential compounds that could be added in these food supplements to control the glucose metabolism and to reduce or handle the diabetes drawbacks. Table 4.2 summarizes the most recent studies performed using bioactive compounds retrieved from natural sources or commercial food supplements in diabetes treatment. Micronutrients are elements present in trace amounts of the human diet and are essential for organism functionality, being part of some enzymes, protein complexes, or hormones, and required in amounts lower than 100 mg/day (Higdon and Drake, 2012). Furthermore, micronutrients are involved in glucose homeostasis. However, the concentration of these elements in plasma could decrease in altered conditions. A specific example is diabetes where hypomagnesaemia is a

Table 4.2 Summary of Some Studies Performed Using Bioactive Compounds From Natural Sources or Commercial Food Supplements in Diabetes Responsible Compounds

Assay

Population

Dose/ Intervention

Parameters

Results

References

N.S.

Chromium picolinate

In vivo

SpragueDawley rats diabetes induced

100 μg/kg per day during 3 weeks

Blood glucose and insulin sensitivity

Uslu and At˙Ila Uslu (2018)

In vivo

Brazilian adults with T2DM

600 μg per day during 16 weeks

Chromium picolinate

In vivo

400 μg per day during 12 weeks

N.S

Magnesium

In vivo

Iranian T2DM patients Mexican T2DM patients

Fasting blood glucose (FBG), postprandial glucose, HbA1c FBG, HbA1c

Increased insulin sensitivity and decreased blood glucose Decreased fasting blood and postprandial glucose and HbA1c Decreased FBG, HbA1c

Commercial capsules of Chromium picolinate

Chromium picolinate

N.S

N.S

Magnesium pidolate

In vivo

Commercial capsules of α-lipoic acid

α-Lipoic acid

In vivo

α-Lipoic acid

In vivo

Overweight/ obese PCOS patients

α-Lipoic acid 1 EPA

In vivo

Spanish overweight/ obese women

Supplement

Source

Chromium picolinate

Magnesium

α-Lipoic acid

Commercial capsules of α-lipoic acid and EPA

Elderly diabetic patients Thai T2DM patients

2.5 g per day during 16 weeks

FBG, HbA1c, fastin insulin, HOMA-IR

5.5 g per day during 4 weeks

FBG

300, 600, 900, 1200 mg during 6 months 400 mg per day during 3 months

FBG and HbA1c

300 mg 1 α-lipoic acid

Body weight, HOMA-IR, insulin

1.3 g EPA during 10 weeks

Insulin, glucose, TG, BMI, and HOMA index

Decreased FBG, HbA1c, HOMA-IR Increased fasting blood insulin No significant differences Decreased FBG and HbA1c Decreased insulin, glucose, TG, BMI, and HOMA index Decreased body weight, HOMA-IR

Paiva et al. (2015)

Parsaeyan and Mozaffari
Khosravi (2012) Rodriguez-Moran and GuerreroRomero (2003)

Barbagallo et al. (2010) Porasuphatana et al. (2012) Genazzani et al. (2018)

Huerta et al. (2015)

Punarnava

White Mulberry

N.S.

Boerhaavia diffusa

Morus alba

Extracts of M. alba, Trigonella goenun graecum seed and P. quinquefolius

Not determined

In vitro

Inhibition of α-glucosidase, pancreatic lipase activity Body weight, FBG, Plasma insulin, HbA1c

Not determined

In vivo

Induced diabetes albino rats

200 mg/kg during 4 weeks

Not determined

In vivo

SpragueDawley rats

50,100 and 200 mg/kg during 4 weeks

Blood glucose reduction

1Deoxynojirimycin

In vivo

Healthy adults

3.6 g per day during 5 weeks

Insulin and postprandial blood glucose

N.S.

In vivo

1 g before a meal

Postprandial blood glucose

N.S.

In vitro

T2DM and healthy patients Human adipocytes

N.S.

In vivo

SpragueDawley rats insulin resistance

42, 84, and 169 mg/kg during 4 weeks

Blood glucose, insulin secretion, insulin resistance index

Inhibition of α-glucosidase, pancreatic lipase activity Reduction in FBG and HbA1c Increase of plasma insulin Dosedependent blood glucose reduction Decreased insulin secretion, and postprandial blood glucose Decreased postprandial blood glucose Inhibition of α-glucosidase. Improve insulin sensitivity and glucose uptake Decreased blood glucose

Oyebode et al. (2018)

Pari and Satheesh (2004)

Nalamolu et al. (2004)

Kimura et al. (2007)

Mudra et al. (2007)

Kan et al. (2017)

(Continued)

Table 4.2 Summary of Some Studies Performed Using Bioactive Compounds From Natural Sources or Commercial Food Supplements in Diabetes Continued Supplement

Source

Tribitor

Extract of white mulberry, white bean, and green coffee

PolyGlycopleX

N.S., Not specified.

Responsible Compounds

Assay

Population

N.S.

In vivo

Healthy adults

Extract of white mulberry, white bean, green coffee, inulin, and glucomannan

N.S.

In vivo

Healthy adults

N.S.

Glucomannan, sodium alginate, xanthan gum

In vivo

N.S.

Glucomannan, sodium alginate, xanthan gum

In vivo

Healthy people with normal weight or overweight Japanese adults with abdominal overweight

Dose/ Intervention

Parameters

Results

References

600 mg white mulberry and 120 mg of white bean extracts and 400 mg of green coffee dissolved in water before five different meals 600 mg white mulberry and 120 mg of white bean extracts, 400 mg of green coffee, 2000 mg inulin, and 3000 mg glucomannan dissolved in water before a meal 2.5 and 5 g per day in two doses during 3 weeks

Fasting and postprandial blood glucose and insulin levels

Decreased postprandial blood glucose and insulin levels

Adamska-Patruno et al. (2018)

Fasting and postprandial blood glucose and insulin levels

Decreased postprandial blood glucose and insulin levels

Adamska-Patruno et al. (2018)

Body weight, HOMA-IR, insulin, and blood glucose

Decreased HOMA-IR, insulin

Reimer et al. (2010)

15 g per day in three doses during 14 weeks

FBG

Decreased FBG

Reimer et al. (2013)

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common symptom (Swaminathan, 2003). To achieve a normal glycemic status in diabetic patients, some supplementations with micronutrients have been studied as a co-adjuvant in diabetic therapy (Barbagallo et al., 2010; Uslu and Uslu, 2018). In the case of magnesium supplementation, controversial results were reported since hypoglycemic effects cannot be ascribed. However, studies with chromium supplementation demonstrated an improved one glycemic homeostasis in subjects with blood glucose disturbances. This element enhances the insulin sensitivity, increasing insulin binding, insulin receptor number, and β-cells sensitivity (Anderson, 1997). A dose of 400 μg of chromium picolinate can decrease blood glucose as well as fasting and postprandial blood glucose (Uslu and Uslu, 2018; Paiva et al., 2015; Parsaeyan and Mozaffari
Khosravi, 2012). α-Lipoic acid (1,2-dithiolane-3-pentanoic acid) is a fatty acid that can be synthetized enzymatically in the mitochondrion from octanoic acid or found in different foods such as spinach, red meat, potatoes, or broccoli (Packer et al., 2001; Shay et al., 2009). In vivo model experiments have demonstrated that α-lipoic acid modulates and increases the glucose use based on the activation of adenoside monophosphate
activated protein kinase in skeletal muscles, which improves the glucose transporter-4 (GLUT-4) (Shen et al., 2007). The contribution of α-lipoic acid to diabetes treatment has been demonstrated in several trials as shown in Table 4.2. Moreover, in the other inquiry, the administration of α-lipoic acid and α-lipoic acid with eicosapentaenoic acid to treat overweight and obese women were compared. This combination provided a decrease in FBG, insulin levels, and homeostatic model assessment for insulin resistance (HOMA-IR) with significant differences with control group (Huerta et al., 2015). The beneficial properties are not usually associated with a single compound but rather to a group of chemicals or even to a complete plant extract. From this point of view, a large number of botanical extracts have been tested revealing a great capacity to manage hyperglycemia. For example, 1 g of white mulberry enriched in iminosugars before meals can decrease the postprandial glucose concentration by inhibition α-glucosidases (Kimura et al., 2007). In addition, Panax ginseng, also known as Asian or Korean red ginseng, produced an enhancement of glucose uptake by upregulation of glucose transporters as GLUT-4 (Lai et al., 2006). Indeed, a mix of these herbs was tried together with an extract of Lagerstroemia speciosa leaves in db/db mice, a noninsulindependent model. This mixture was revealed to be an alternative to antidiabetic treatment since it diminished the blood glucose and HbA1c and increased insulin sensitivity in experimental models by over expression of liver and adipose tissue peroxisome proliferator
activated receptors (Park et al., 2005). Once all safety and effectiveness assays have been performed and the mechanism of action has been known, commercial supplements are developed proving several doses and mixes are either bioactive compounds and/or plant extracts. In this scenario, multiple commercial mixes can be found with diverse ingredients. As shown in Table 4.2, PolyGlycopleX has been framed from compounds belonging to dietary fiber, concretely glucomannan, sodium alginate, or xanthan gum. The antithyperglycemic effect of this food supplement is based on the delay of gastric emptying provided by soluble dietary fiber (Raninen et al., 2011) succeeding a decreasing of postprandial, FBG, and HOMA-IR (Reimer et al., 2010, 2013). Tribitor is another food supplement that contains a mixture of three different plant extracts. This product comprises 1200 mg of white kidney bean extract (containing 4000 units of inhibition of amylase activity), 600 mg of whit mulberry leaf extract (enriched with 18 mg of 1-deoxynojirimycin), and 400 mg of green coffee bean extract (with 200 mg of chlorogenic acid). As revealed in

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Table 4.2, Tribitor is a suitable alternative to control postprandial hyperglycemia, decreasing glycemia after ingestion of high glycemic index/load meals (Adamska-Patruno et al., 2018). Taking into account the results of aforementioned studies, botanical sources are revealed to be an important alternative to develop food supplements, which are able to manage efficiently hyperglycemia caused by diabetes. Moreover, the antihyperglycemic properties of plants and their natural origin may alleviate side effects of synthetic drugs. For these reasons, plants provide a huge variety of bioactive compounds, which administered alone or in combination, can ameliorate diabetes metabolic disorders in order to decrease prevalence and mortality expected in the decades to come.

4.6 NEURODEGENERATIVE DISEASES Neurodegenerative diseases are estimated to surpass cancer as the second most common prevalent cause of death among elderly by the 2040s (Ansari et al., 2010). These diseases occur when nerve cells in the brain or peripheral nervous system lose function over time and ultimately die. Although treatments may help relieve some of the physical or mental symptoms associated with neurodegenerative diseases, there is currently no way to slow or stop the disease progression (Sciences, 2018). Examples of neurodegenerative diseases are Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease, amyotrophic lateral sclerosis, frontotemporal dementia, and the spinocerebellar ataxias. These diseases are diverse in their pathophysiology, with some causing memory and cognitive impairments and others affecting the person’s mobility, speech, or breathing (Gitler et al., 2017). Moreover, these age-dependent disorders are becoming increasingly prevalent, in part due to the increase of old population. The major problem is that these disorders are normally detected late which restricts the efficacy of the treatment options (Batista and Pereira, 2016). Inflammation and oxidative stress, among other hazardous elements, are key components of the chronic neurodegenerative pathology. Given the idea that the increase of oxidative and nitrosative stress may be the major contributors to several neurological diseases and brain aging, the ingestion of foods or dietary supplements enriched in phenolic compounds may have positive effects on brain health (Weber, 2015). Recent advances have identified novel targets for the treatment of neurological ailments through nutritional supplement approaches (Srivastava and Yadav, 2016). AD is the most common type of dementia, being currently incurable. Drug discovery for AD has been strongly focused on β-amyloid, as genetic evidence from the familial cases supported by the hypothesis that β-amyloid must be driving the disease process. Unfortunately, numerous clinical trials with active and passive amyloid vaccines as well as ɣ-secretase inhibitors have failed. Consequently, alternative therapeutic targets, such as neuroinflammation, have been suggested for the prevention and treatment of AD (Karunaweera et al., 2015). In this scenario, the pharmacology and therapeutic potential of nutritional supplements have been investigated. Regarding health benefits of Ω-3 supplementation, epidemiological and preclinical studies indicate that consumption of long-chain Ω-3 PUFAs may slow cognitive decline and prevent the progression of mental health disorders such as AD (Thomas et al., 2015). Thomas et al. (2015) reviewed the controlled studies conducted on patients with mild cognitive impairment (a precursor to early AD) and supplemented with Ω-3 fatty acids, suggesting a positive effect on cognitive performance following supplementation from 3 to 12 months. Moreover, among 918 cognitively

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normal participants included in the analyses, 171 took capsules daily for 3 years that contained n-3 PUFA, Ginkgo biloba leaf dry extracts, and lycopene. Higher adherence to supplementation intervention was associated with lower AD incidence in both unadjusted and adjusted models (Bun et al., 2015). On the other hand, circulating levels of uridine, selenium, vitamins B12, E and C, folate, DHA, and EPA have been shown to be lower in patients with AD than in healthy individuals. Rijpma et al. showed that these nutrients could be increased in patients with mild and mild-to-moderate AD by 24
48 weeks oral supplementation with Souvenaid (containing a specific nutrient combination) (Rijpma et al., 2015). An uptake was observed within 6 weeks and a plateau phase was reached for most nutrients during prolonged intake, increasing the availability of precursors and cofactors necessary for the formation of neuronal membranes and synapses in the brain. This explains the use of micronutrients oral supplementation to replenish nutritional deficits in patients with AD (Rijpma et al., 2015). Furthermore, a double-blind, multisite, phase II study was conducted with 106 individuals with AD (Medicine, 2018). Volunteers were randomized to a nutraceutical formulation (NF) containing folate, α-tocopherol, B12, S-adenosylmethionine, N-acetyl cysteine, acetyl-L-carnitine or placebo for 3 or 6 months, followed by an open-label extension where participants received NF for 6 additional months. Participants receiving NF improved within 3 months in cognitive performance (Remington et al., 2015). Abundant evidence implicates oxidative stress in AD pathogenesis. Thus antioxidant polyphenolic compounds have been considered as an alternative therapeutic strategy for AD (Choi et al., 2012). For example, green tea catechins are able to inhibit the formation, extension, and destabilization of Aβ fibrils (Bieschke et al., 2010). Indeed, EGCG protected cultured hippocampal cells and PC12 cells from Aβ-induced death, and reduced Aβ levels in the brain of a mouse model for AD (Feng et al., 2018). Catechins have also been shown to enhance the release of the nonamyloidogenic soluble form of amyloid precursor protein (APP) into the conditioned media of human SH-SY5Y neuroblastoma and of rat pheochromocytoma PC12 cells. The molecular mechanism whereby EGCG modulates APP processing involves the activation of α-disintegrin and metalloprotease 10 (ADAM10), which belong to a family of zinc metalloproteases, contributing to the α-secretase activity (Rossi et al., 2008). There are currently about five clinical trials listed in the NIH registry that investigate the effect of resveratrol on AD (Medicine, 2018). Interestingly, a phase II study with 119 individuals that presents mild-to-moderate AD found that resveratrol was safe and generally well tolerated at doses up to 1 g orally twice daily (Medicine, 2018). Minor side effects, such as gastrointestinal nausea and diarrhea, were reported (Pasinetti et al., 2015). In 2009 Thomas et al. reported a potential protective effect of a polyphenol through an enriched diet (curcumin and grape seed) in the reduction of DNA damage events in AD mice (Thomas et al., 2009). Telomere length was significantly reduced in buccal mucosa in AD mice relative to controls. A significant 10-fold decrease in buccal micronucleus (MN) frequency was found for AD mice fed with a diet containing curcumin or microencapsulated grape seed extract and a sevenfold decrease was observed for AD mice fed with nonencapsulated grape seed extract when compared to the control diet. Similarly, in polychromatic erythrocytes a significant reduction in MN frequency was found for the microencapsulated grape seed extract cohort. These results suggest a potential protective effect of polyphenols against genomic instability events in different somatic tissues of a transgenic mouse model for AD (Thomas et al., 2009). In the study by Pate et al. (2017), the ability of five polyphenols, namely flavone, apigenin (API), luteolin (LUT), kaempferol (KAE), and quercetin, to

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ameliorate Aβ oligomer-induced neuronal responses were evaluated. The results proved that these compounds exert antioxidant capabilities toward the reduction of Aβ1
42 oligomer-induced intracellular reactive oxygen species. In addition, LUT and quercetin attenuate the oligomer-induced caspase activation through antioxidant action. Accordingly, with the exception of KAE, all compounds predominately reduced cellular responses through antioxidant capabilities. However, KAE attenuated both oligomer-induced intracellular Reactive Oxygen Species (ROS) and caspase activation via synergism between antioxidant and antiaggregation mechanisms. These results identify the promise of these compounds as natural therapeutics for AD and demonstrate their potential for synergistic action (Pate et al., 2017). PD is the second most prevalent neurodegenerative disorder, usually suffered by people over the age of 60. This disease is characterized by the loss of dopamine-producing neurons in substantia nigra and the development of Lewy bodies followed by striatal dopamine depletion, resulting in postural instability, bradykinesia, rigidity, and tremors (Elumalai and Lakshmi, 2016). A number of epidemiological studies suggest that plant-derived foods or supplements might delay the initiation and progression of PD. For example, Hang et al. described several nutraceuticals that provided neuroprotection in experimental models and may serve as alternatives to synthetic drug compounds such as L-DOPA (Hang et al., 2016). Polyphenols are one possibility to PD treatments. FigueiredoGonz´alez et al. (2018) successfully demonstrates for the first time, that rich-phenolic extracts obtained from Galician extra-virgin olive oils (EVOOs) could act as multitarget ligands, directly inhibiting CNS-related enzymes. Although both EVOOs exhibited a weaker activity than the positive controls, they were able to inhibit simultaneously BuChE, 5-LOX, hMAO-A, and hMAO-B, in a dose-dependent manner. Only “Brava” oil showed a dual inhibition against both cholinesterase enzymes, which could imply the increased efficacy of the treatment of several disorders affecting CNS (Figueiredo-Gonz´alez et al., 2018). Since tomato seeds (TSE) are known to be a rich source of bioactives, efforts are directed toward their utilization as a source of antioxidants. Gokul and Muralidhara (2014) proposed that oral supplements of TSE significantly attenuate rotenone-induced oxidative impairments and damage to dopamine system in the striatum and limbic structures, important for motor and affective pathologies. In addition, Patil et al. (2014) endorsed API and LUT as the prospective molecules in treating PD. These compounds have neuroprotective role against 1-mehtyl-4-phenyl-1,2,3,6-tetrahydropyridine-inducedparkinsonian mouse model. The neuroprotective effect could be attributed to the strong antioxidant potential and inhibitory role on different key events involved in neuroinflammation. API and LUT increased brain-derived neurotrophic factor levels in the substantia nigra pars compacta, which demonstrated their neurotrophic potential (Patil et al., 2014). Spirulina has also been applied as a supplement in PD models. In this sense, Kumar et al. (2017) have demonstrated using DJ-1βΔ93 flies, a PD model of Drosophila, the therapeutic effect of spirulina and its active component C-phycocyanin (C-PC) in the improvement of life span and locomotor behavior. Furthermore, supplementation of spirulina and C-PC individually and independently reduced the cellular stress marked by deregulating the expression of heat shock protein 70 and JunN-terminal kinase signaling in DJ-1βΔ93 flies (Kumar et al., 2017). In 2015 Chattopadhyaya et al. (2015) assessed the protective effect of Spirulina fusiformis, alone and in combination with amantadine, in a 6-hydroxydopamine (6-OHDA) induced rat model. The authors observed that the pretreatment with spirulina showed antiparkinsonism effect on behavior and antioxidant parameters on 6-OHDA induced dopaminergic damaged rats. Spirulina also potentiates the antiparkinsonian effect of amantadine when administered in combination (Chattopadhyaya et al., 2015).

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The data reviewed by Barbosa et al. (2014) demonstrated that numerous compounds isolated from different species of macroalgae could be used as neuroprotective agents. Nevertheless, further researches are needed to explore their maximum therapeutic potential, to be employed as nutraceuticals in the treatment and/or prevention of neurodegenerative diseases (Barbosa et al., 2014). However, plant extracts such as Centella have been associated with a decrease of the age-related reduction in cognitive function mostly due to the plant’s bioactive constituents namely the asiaticoside, asiatic acid, madecassoside, and madecassic acid (Hashim, 2011).

4.7 OVERALL MORTALITY Some reviews and meta-analysis indicate that nutritional supplements can be effective in the reduction of the overall mortality. However, controversial outcomes highlight the importance to perform more studies about dietary supplements’ impacts on all-cause mortality, especially in older adults with serious diseases. Hospitalized older adults ($65 years) present a greater risk of malnutrition and an increased risk of mortality that lead to a negative impact on clinical and economic outcomes (Somanchi et al., 2011). The administration of dietary supplements in malnourished patients could reduce complications and mortality as well as improve nutritional status and increase BW (Elia et al., 2016; Milne et al., 2009). These supplements might present high caloric content and include specific components, such as vitamin D, amino acids, protein, and β-hydroxy-β-methylbutyrate (Cawood et al., 2012; Molfino et al., 2013). However, the efficacy on mortality of hospitalized older adults is still unclear. In a systematic review, high protein dietary supplements (providing $ 20% total calories from protein) considerably reduced the mortality rate (Milne et al., 2009), while another study did not showed consistent findings (Beck et al., 2013). Notably, Deutz et al. (2016) suggested that the use of high protein supplements in hospitalized older adults is related to a consistent reduction in mortality rate, showing at 90 days a mortality rate significantly lower in the intervention group (4.8%) relatively to the placebo (9.7%). Calcium supplements are also commonly used by elders to prevent osteoporosis (Xiao et al., 2013). Although calcium intake has well-described benefits on bone health, with the increasing demand for calcium supplements, it is of great interest to study its association with nonskeletal effects and mortality. In a meta-analysis performed by Asemi et al. (2015), supplemental calcium intake was associated with a reduced risk of all-cause mortality. However, there was not a significant association between calcium supplementation and mortality related to CVD and cancer (Asemi et al., 2015). In other studies, an inverse association between supplemental calcium intake and the risk of mortality from CVD (Langsetmo et al., 2013; Natoli et al., 2013; Palmer et al., 2011) and prostate cancer (Giovannucci et al., 2007; Schwartz and Skinner, 2012) was observed. An appropriate calcium intake is also one of the major recommendations for osteoporosis prevention in rheumatoid arthritis patients (Grossman et al., 2010). These patients present an increased risk of mortality, the most common cause of death being CVD (Sokka et al., 2008). Nevertheless, calcium supplementation has also been implicated as a risk factor for CVD (Rautiainen et al., 2013). In fact, calcium supplements were described as predictors of increased all-cause mortality and risk of death from CVD in rheumatoid arthritis patients (Provan et al., 2017). Protein supplements have been increasingly used in medical care. Actually, the prescription and use of protein supplements in dialysis patients with low serum albumin levels (#3.5 g/dL) has

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been associated with a substantial low mortality rate and improvements on nutritional status (Benner et al., 2018; Weiner et al., 2014). Likewise, Benner et al. (2018) and Weiner et al. (2014) reported a significant reduction of mortality rate in these patients with 69% and 29%, respectively, comparing to control group. The dietary supplements’ efficacy could be evaluated by nutritional markers such as the serum albumin concentration, the normalized protein catabolic rate (nPCR), and the postdialysis BW (Benner et al., 2018). Indeed, nPCR is useful to evaluate the dietary protein intake, since hemodialysis induces a catabolic state that leads to a decrease in protein synthesis (Ikizler, 2005). Thus low nPCR values are associated with high mortality and morbidity (Eriguchi et al., 2017). On the other hand, serum albumin is a nonspecific marker for protein-energy wasting. Low serum albumin level is described as a strong indicator of increased mortality risk (Iseki et al., 1993; Mehrotra et al., 2011). According to Benner et al. (2018), dietary supplement patients achieved lower serum albumin concentrations, while nPCR values and postdialysis BWs were higher than the control group. Thereafter, the administration of intradialytic supplements could contribute to a positive protein anabolic state, providing an advantage in all-cause mortality (Pupim et al., 2005; Veeneman et al., 2003). High protein dietary supplements are also widely used to improve clinical outcomes and mortality posthip fractures (Grigg et al., 2014). Some studies suggest a reduced risk of death in oral nutritional supplements users, reporting a significant lower mortality rate in the intervention group comparing with controls (Grigg et al., 2014; Eneroth et al., 2006; Sullivan et al., 1998). However, other studies described similar mortality rates between intervention and control groups (Myint et al., 2013; Espaulella et al., 2000). Contradictory results highlight the need to undertake further researches in order to analyze the effects of different types of high protein dietary supplements on postfracture mortality. Early enteral nutrition is a type of supplementation recommended to use in sarcopenia, a disease characterized by a loss of skeletal muscle mass and its functions, having been demonstrated that this supplementation is independently associated with low in-hospital mortality in sarcopenic patients (with a mortality rate significantly low ranging 9%) (Koga et al., 2018). A high mortality rate within children younger than 5 years was also observed in low-income countries which could be related to vitamin A deficiency (WHO, 2009). A study conducted in infants from Tanzania reached no significant effect of vitamin A supplements on overall mortality in children with 6 months of age. Similar results were obtained for mortality at 3 days, 28 days, and 12 months of age, concluding that neonatal vitamin A supplementation did not provide positive effects on children survival (Masanja et al., 2015). Other previous studies showed opposite results, ranging between no association (West et al., 1995) to potential benefits (Rahmathullah et al., 2003; Klemm et al., 2008) and possible harms (Malaba et al., 2005). Selenium is considered an essential trace element. However, single nucleotide polymorphisms in selenoproteins could be responsible for age-related disorders as CVD and cancer (Rayman, 2012). The relation between selenium intake and all-cause mortality was described as a U-shape, with minimal mortality at a concentration of B135 μg/L (Bleys et al., 2008). An inverse association between selenium status and mortality has been described in populations with low selenium intake (Lauretani et al., 2008; Sun et al., 2016). Besides, no study provides information about mortality in populations with high selenium intake. Similarly, cancer and CVD mortality seems to rise, but the impact was not statistically significant (Rayman et al., 2018). Therefore a long-term selenium supplementation with high doses could lead to harmful effects on health probably related to selenolates produced by selenoprotein depletion and metabolization. These compounds have the

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ability to promote redox-cycle, induce oxidative stress by generation of superoxide radicals and, accordingly, increase the risk of cancer and CVD (Spallholz et al., 2004). On the other hand, supranutritional selenium supplementation could also cause protein misfolding or unfolding (Zu et al., 2006). In conclusion, people with deficient selenium status could benefit from additional selenium intake, depending on their baseline level and dose. However, high-dose selenium supplements should be avoided by citizens from countries with an appropriate selenium intake. In addition, the growing consumers’ concern with health and well-being has supported a high demand for herbal/botanical supplements. Previous studies reported inconsistent findings on the effects of herbal supplements in life quality among colon/colorectal cancer patients since some authors reported a positive relation between herbal supplementation and life quality (Molassiotis et al., 2005; Chen et al., 2014a,b), while others found no association (Sewitch and Rajput, 2010; Can et al., 2009). Besides, Chen et al. (2018) observed no significant impact of herbal/botanical supplements in all-cause mortality. Generally, the outcomes of these studies do not provide sufficient convincing arguments for the dietary supplements’ administration with the purpose of reducing the risk of mortality. Nevertheless, there seems to be a direct association between malnutrition and morbidity. Patients with disease-related malnutrition have a reduced functional capacity and high physical and mental stress, as well as high risk of mortality. Thus malnourished patients do not only require more medical care and longer hospital stays, but also increase the costs affecting the economic aspect. For these reasons, it is worthwhile to evaluate the clinical and economic relevance of nutritional intervention through the cost-effectiveness ratio.

4.8 CONCLUSION Different diseases, such as cancer, diabetes, or metabolic syndrome, represent a public-health problem in modern countries, mostly due to lifestyle factors such as the high consumption of fatty and processed foods and the absence of exercise. In some cases, the genetic inheritance is also responsible for their development. In that way, in the last decade the intake of dietary supplements have increased in modern societies with the aim to reduce the risk of these chronic diseases of which the origins are complex. Different bioactive compounds, natural or synthetic, have been incorporated in dietary supplements, and clinical trials have been performed in order to evaluate the safety and efficacy of these products. The results are not consensual. For example, for neurodegenerative disorders, an extremely complex disease in what concerns to etiology and pathobiochemistry, the observations until date support the development of nutritional supplements that include micronutrients, phenolic compounds, plant extracts, or macroalgae. Nevertheless, for CVD additional data regarding the effects of nutraceutical supplementation on the incidence of CV outcomes are lacking, and it is not clear whether additional lipid lowering by nutraceuticals can modify the residual CV risk that remains after statin therapy. A number of important questions remain to be addressed, including whether longer durations of therapy would result in a better response and the exact safety profile of nutraceuticals, especially at doses higher than those consumed in an average diet. Further investigations are urgently needed to understand the security and efficacy of high-dose and longterm supplementation in these diseases. Finally, it should be highlighted that to promote health, current public-health messages only advocate supplements in specific circumstances, but not in optimally nourished populations.

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ACKNOWLEDGMENTS This work received financial support from project PTDC/ASP-AGR/29277/2017-Castanea sativa shells as a new source of active ingredients for Functional Food and Cosmetic applications: a sustainable approach, supported by national funds by FCT / MCTES and co-supported by Fundo Europeu deDesenvolvimento Regional (FEDER) throughout COMPETE 2020 - Programa Operacional Competitividade e Internacionalizac¸a˜o (POCI01-0145-FEDER-029277). Diana Pinto is thankful for the research grant from project POCI-01-0145-FEDER029277. The work was also supported by UID/QUI/50006/2019 with funding from FCT/MCTES through national funds. The author Francisco Jim´enez gratefully acknowledges the Spanish Ministry of Economy and ´ lvaro Fern´andez Competitiveness (MINECO) for the FPI grant given to develop this work. The author, A Ochoa received support from the Spanish Ministry of Education, Culture and Sports (FPU grant 14/03992). Marı´a de la Luz C´adiz Gurrea also thanks to the projects AGL2015-67995-C3-2-R and RTI2018-096724-BC22 (Spanish Ministry of Science, Innovation and Universities) and Andalusian Regional Government Council of Innovation and Science (P11-CTS-7625).

REFERENCES Adamska-Patruno, E., et al., 2018. A synergistic formulation of plant extracts decreases postprandial glucose and insulin peaks: results from two randomized, controlled, cross-over studies using real-world meals. Nutrients 10 (8). Ahima, R.S., 2016. Overview of metabolic syndrome. In: Ahima, R.S. (Ed.), Metabolic Syndrome: A Comprehensive Textbook. Springer International Publishing, Cham, pp. 3
12. Akaberi, M., Hosseinzadeh, H., 2016. Grapes (Vitis vinifera) as a potential candidate for the therapy of the metabolic syndrome. Phytother. Res. 30 (4), 540
556. Alberti, K.G., et al., 2009. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 120 (16), 1640
1645. Amin, F., et al., 2015. Clinical efficacy of the co-administration of turmeric and black seeds (Kalongi) in metabolic syndrome—a double blind randomized controlled trial—TAK-MetS trial. Compl. Ther. Med. 23 (2), 165
174. Amiot, M.J., Riva, C., Vinet, A., 2016. Effects of dietary polyphenols on metabolic syndrome features in humans: a systematic review. Obes. Rev. 17 (7), 573
586. Anderson, R.A., 1997. Nutritional factors influencing the glucose/insulin system: chromium. J. Am. Coll. Nutr. 16 (5), 404
410. Angelo, M.P., et al., 2017. Nutraceuticals as an important part of combination therapy in dyslipidaemia. Curr. Pharm. Design 23 (17), 2496
2503. Anna, R., et al., 2014. Effects of a new flavonoid and myo-inositol supplement on some biomarkers of cardiovascular risk in postmenopausal women: a randomized trial. Int. J. Endocrinol. 2014, 7. Ansari, J.A., Siraj, A., Inamdar, N.N., 2010. Pharmacotherapeutic approaches of Parkinsons disease. Int. J. Pharmacol. 6, 584
590. Asemi, Z., et al., 2015. Total, dietary, and supplemental calcium intake and mortality from all-causes, cardiovascular disease, and cancer: a meta-analysis of observational studies. Nutr. Metab. Cardiovasc. Dis. 25 (7), 623
634. Astrup, A., Finer, N., 2000. Redefining type 2 diabetes: ‘diabesity’ or ‘obesity dependent diabetes mellitus’? Obes. Rev. 1 (2), 57
59.

REFERENCES

131

Babio, N., Bullo, M., Salas-Salvado, J., 2009. Mediterranean diet and metabolic syndrome: the evidence. Public Health Nutr. 12 (9a), 1607
1617. Bailey, R.L., et al., 2013. Why us adults use dietary supplements. JAMA Int. Med. 173 (5), 355
361. del Balzo, V., et al., 2014. A cross-sectional survey on dietary supplements consumption among Italian teenagers. PLoS One 9 ((7), e100508. Barbagallo, M., et al., 2010. Oral magnesium supplementation improves vascular function in elderly diabetic patients. Magnes. Res. 23 (3), 131
137. Barbosa, M., Valentao, P., Andrade, P.B., 2014. Bioactive compounds from macroalgae in the new millennium: implications for neurodegenerative diseases. Mar. Drugs 12 (9), 4934
4972. Barona, J., et al., 2012. Grape consumption increases anti-inflammatory markers and upregulates peripheral nitric oxide synthase in the absence of dyslipidemias in men with metabolic syndrome. Nutrients 4 (12), 1945
1957. Basu, A., et al., 2010. Green tea supplementation affects body weight, lipids, and lipid peroxidation in obese subjects with metabolic syndrome. J. Am. Coll. Nutr. 29 (1), 31
40. Basu, A., et al., 2013. Green tea supplementation increases glutathione and plasma antioxidant capacity in adults with the metabolic syndrome. Nutr. Res. 33 (3), 180
187. Batista, P., Pereira, A., 2016. Quality of life in patients with neurodegenerative diseases. J. Neurol. Neurosci. 7 (1), 1
7. Bea, J.W., et al., 2015. Concentrations of the vitamin D metabolite 1,25(OH)2D and odds of metabolic syndrome and its components. Metabolism 64 (3), 447
459. Beck, A.M., Holst, M., Rasmussen, H.H., 2013. Oral nutritional support of older (65 years 1 ) medical and surgical patients after discharge from hospital: systematic review and meta-analysis of randomized controlled trials. Clin. Rehabil. 27 (1), 19
27. Benner, D., et al., 2018. Effects of oral nutritional supplements on mortality, missed dialysis treatments, and nutritional markers in hemodialysis patients. J. Renal Nutr. 28 (3), 191
196. Bieschke, J., et al., 2010. EGCG remodels mature alpha-synuclein and amyloid-beta fibrils and reduces cellular toxicity. Proc. Natl. Acad. Sci. U.S.A. 107 (17), 7710
7715. Hypoglycaemia. In: Bilous, R., Donnelly, R. (Eds.), Handbook of Diabetes. Wiley-Blackwell, Oxford, UK. Bleys, J., Navas-Acien, A., Guallar, E., 2008. Serum selenium levels and all-cause, cancer, and cardiovascular mortality among US adults. Arch. Intern. Med. 168 (4), 404
410. Bogdanski, P., et al., 2012. Green tea extract reduces blood pressure, inflammatory biomarkers, and oxidative stress and improves parameters associated with insulin resistance in obese, hypertensive patients. Nutr. Res. 32 (6), 421
427. Broncel, M., et al., 2010. Aronia melanocarpa extract reduces blood pressure, serum endothelin, lipid, and oxidative stress marker levels in patients with metabolic syndrome. Med. Sci. Monit. 16 ((1), Cr28-34. Bun, S., et al., 2015. A combination of supplements may reduce the risk of Alzheimer’s disease in elderly Japanese with normal cognition. J. Alzheimers Dis. 45 (1), 15
25. Cameron, A.J., Shaw, J.E., Zimmet, P.Z., 2004. The metabolic syndrome: prevalence in worldwide populations. Endocrinol. Metab. Clin. North Am. 33 (2), 351
375 (table of contents). Can, G., et al., 2009. Quality of life and complementary and alternative medicine use among cancer patients in Turkey. Eur. J. Oncol. Nurs. 13 (4), 287
294. Cawood, A.L., Elia, M., Stratton, R.J., 2012. Systematic review and meta-analysis of the effects of high protein oral nutritional supplements. Ageing Res. Rev. 11 (2), 278
296. Chattopadhyaya, I., et al., 2015. Neuroprotective effect of Spirulina fusiform and amantadine in the 6-OHDA induced Parkinsonism in rats. BMC Complement Altern. Med. 15, 296. Chen, G., et al., 2014a. Nutraceuticals and functional foods in the management of hyperlipidemia. Crit. Rev. Food Sci. Nutr. 54 (9), 1180
1201.

132

CHAPTER 4 EFFECTS OF NUTRITIONAL SUPPLEMENTS

Chen, M., et al., 2014b. FOLFOX 4 combined with herbal medicine for advanced colorectal cancer: a systematic review. Phytother. Res. 28 (7), 976
991. Chen, Q., et al., 2018. Association of herbal/botanic supplement use with quality of life, recurrence, and survival in newly diagnosed stage II colon cancer patients: a 2-y follow-up study. Nutrition 54, 1
6. Choi, D.Y., et al., 2012. Antioxidant properties of natural polyphenols and their therapeutic potentials for Alzheimer’s disease. Brain Res. Bull. 87 (2
3), 144
153. Cicero, A.F., Ferroni, A., Ertek, S., 2012. Tolerability and safety of commonly used dietary supplements and nutraceuticals with lipid-lowering effects. Exp. Opin. Drug. Saf. 11 (5), 753
766. Clarke, B.F., 1977. Biguanide treatment in diabetes mellitus: a short review. Scottish Med. J. 22 (2), 167
170. Daglia, M., 2017. The role of dietary pattern, foods, nutrients and nutraceuticals in supporting cancer prevention and treatment. Semin. Cancer Biol. 46, iv. Derosa, G., Maffioli, P., 2015. Nutraceuticals for the treatment of metabolic diseases: evidence from clinical practice. Exp. Rev. Endocrinol. Metab. 10 (3), 297
304. Derosa, G., et al., 2018. Effects on oral fat load of a nutraceutical combination of fermented red rice, sterol esters and stanols, curcumin, and olive polyphenols: a randomized, placebo controlled trial. Phytomedicine 42, 75
82. Deutz, N.E., et al., 2016. Readmission and mortality in malnourished, older, hospitalized adults treated with a specialized oral nutritional supplement: a randomized clinical trial. Clin. Nutr. 35 (1), 18
26. Devaraj, S., et al., 2013. Effects of Aloe vera supplementation in subjects with prediabetes/metabolic syndrome. Metab. Syndr. Relat. Disord. 11 (1), 35
40. Dhillon, N., et al., 2008. Phase II trial of curcumin in patients with advanced pancreatic cancer. Clin. Cancer Res. 14 (14), 4491
4499. deVere White, R.W., et al., 2010. Effects of a high dose, aglycone-rich soy extract on prostate-specific antigen and serum isoflavone concentrations in men with localized prostate cancer. Nutr. Cancer 62 (8), 1036
1043. Di Pierro, F., et al., 2015. Potential role of bioavailable curcumin in weight loss and omental adipose tissue decrease: preliminary data of a randomized, controlled trial in overweight people with metabolic syndrome. Preliminary study. Eur. Rev. Med. Pharmacol. Sci. 19 (21), 4195
4202. Dong, H., et al., 2013. The effects of berberine on blood lipids: a systemic review and meta-analysis of randomized controlled trials. Planta Med. 79 (6), 437
446. EC, European Commission. Food supplement Available from: ,http://ec.europa.eu/food/food/labellingnutrition/supplements/.. Egert, S., et al., 2009. Quercetin reduces systolic blood pressure and plasma oxidised low-density lipoprotein concentrations in overweight subjects with a high-cardiovascular disease risk phenotype: a double-blinded, placebo-controlled cross-over study. Br. J. Nutr. 102 (7), 1065
1074. Egert, S., et al., 2010. Serum lipid and blood pressure responses to quercetin vary in overweight patients by apolipoprotein E genotype. J. Nutr. 140 (2), 278
284. Elia, M., et al., 2016. A systematic review of the cost and cost effectiveness of using standard oral nutritional supplements in community and care home settings. Clin. Nutr. 35 (1), 125
137. Elumalai, P., Lakshmi, S., 2016. Role of quercetin benefits in neurodegeneration. Adv. Neurobiol. 12, 229
245. Eneroth, M., Olsson, U.B., Thorngren, K.G., 2006. Nutritional supplementation decreases hip fracture-related complications. Clin. Orthop. Relat. Res. 451, 212
217. Eriguchi, R., et al., 2017. Longitudinal associations among renal urea clearance-corrected normalized protein catabolic rate, serum albumin, and mortality in patients on hemodialysis. Clin. J. Am. Soc. Nephrol. 12 (7), 1109
1117.

REFERENCES

133

Eskra, J.N., Schlicht, M.J., Bosland, M.C., 2019. Lack of combination effects of soy isoflavones and taxane chemotherapy of castration-resistant prostate cancer. Prostate. 79 (2), 223
233. Espaulella, J., et al., 2000. Nutritional supplementation of elderly hip fracture patients. A randomized, doubleblind, placebo-controlled trial. Age Ageing 29 (5), 425
431. Esposito, K., et al., 2004. Effect of a Mediterranean-style diet on endothelial dysfunction and markers of vascular inflammation in the metabolic syndrome: a randomized trial. JAMA 292 (12), 1440
1446. Ezuruike, U.F., Prieto, J.M., 2014. The use of plants in the traditional management of diabetes in Nigeria: pharmacological and toxicological considerations. J. Ethnopharmacol. 155 (2), 857
924. FDA, U.S., U.S. Food and Drug Administration. Dietary supplement. Available from: ,http://www.fda.gov/ food/dietarysupplements/.. Feitelson, M.A., et al., 2015. Sustained proliferation in cancer: mechanisms and novel therapeutic targets. Semin. Cancer Biol. 35, S25
S54. Feng, S., et al., 2018. (2)-Epigallocatechin-3-gallate protects PC12 cells against corticosterone-induced neurotoxicity via the hedgehog signaling pathway. Exp. Ther. Med. 15 (5), 4284
4290. Figueiredo-Gonz´alez, M., et al., 2018. Nutraceutical potential of phenolics from ‘brava’ and ‘mansa’ extravirgin olive oils on the inhibition of enzymes associated to neurodegenerative disorders in comparison with those of ‘picual’ and ‘cornicabra’. Molecules (Basel, Switzerland) 23 (4), 722. Firouzi, S., et al., 2018. Barberry in the treatment of obesity and metabolic syndrome: possible mechanisms of action. Diab. Metab. Synd. Obesity Targets Therapy 11, 699
705. Genazzani, A.D., et al., 2018. Modulatory effects of alpha-lipoic acid (ALA) administration on insulin sensitivity in obese PCOS patients. J. Endocrinol. Invest. 41 (5), 583
590. Gerards, M.C., et al., 2015. Traditional Chinese lipid-lowering agent red yeast rice results in significant LDL reduction but safety is uncertain—a systematic review and meta-analysis. Atherosclerosis 240 (2), 415
423. Giovannucci, E., et al., 2007. Risk factors for prostate cancer incidence and progression in the health professionals follow-up study. Int. J. Cancer 121 (7), 1571
1578. Gitler, A.D., Dhillon, P., Shorter, J., 2017. Neurodegenerative disease: models, mechanisms, and a new hope. Dis. Models Mech. 10 (5), 499
502. Going, C.C., et al., 2018. Vitamin D supplementation decreases serum 27-hydroxycholesterol in a pilot breast cancer trial. Breast Cancer Res. Treat. 167 (3), 797
802. Mendez-del Villar, M., et al., 2014. Effect of resveratrol administration on metabolic syndrome, insulin sensitivity, and insulin secretion. Metab. Syndr. Relat. Disord. 12 (10), 497
501. Gokul, K., Muralidhara, 2014. Oral supplements of aqueous extract of tomato seeds alleviate motor abnormality, oxidative impairments and neurotoxicity induced by rotenone in mice: relevance to Parkinson’s disease. Neurochem. Res. 39 (7), 1382
1394. Go´mez-Arbel´aez, D., et al., 2013. Aged garlic extract improves adiponectin levels in subjects with metabolic syndrome: a double-blind, placebo-controlled, randomized, crossover study. Mediat. Inflam. 2013, 6. Gonnelli, S., et al., 2015. Efficacy and tolerability of a nutraceutical combination (red yeast rice, policosanols, and berberine) in patients with low-moderate risk hypercholesterolemia: a double-blind, placebo-controlled study. Curr. Therap. Res. 77, 1
6. Grigg, M., Arora, M., Diwan, A.D., 2014. Role of nutritional supplementation in elderly patients with hip fractures. J. Orthop. Transl. 2 (1), 26
34. Grossman, J.M., et al., 2010. American College of Rheumatology 2010 recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthr. Care Res. (Hoboken) 62 (11), 1515
1526. Gungor, N.K., 2014. Overweight and obesity in children and adolescents. J Clin. Res. Pediatr. Endocrinol. 6 (3), 129
143.

134

CHAPTER 4 EFFECTS OF NUTRITIONAL SUPPLEMENTS

Gupta Jain, S., et al., 2017. Effect of oral cinnamon intervention on metabolic profile and body composition of Asian Indians with metabolic syndrome: a randomized double -blind control trial. Lipids Health Dis. 16 (1), 1
11. Hanahan, D., Weinberg, R.A., 2011. Hallmarks of cancer: the next generation. Cell 144, 646
674. Hang, L., Basil, A.H., Lim, K.L., 2016. Nutraceuticals in Parkinson’s disease. Neuromol. Med. 18 (3), 306
321. Hashim, P., 2011. Centella asiatica in food and beverage applications and its potential antioxidant and neuroprotective effect. Int. Food Res. J. 18 (4), 1215
1222. Hassani, F.V., Shirani, K., Hosseinzadeh, H., 2016. Rosemary (Rosmarinus officinalis) as a potential therapeutic plant in metabolic syndrome: a review. Naunyn-Schmiedeberg’s Arch. Pharmacol. 389 (9), 931
949. Herranz-Lopez, M., et al., 2015. Lemon verbena (Lippia citriodora) polyphenols alleviate obesity-related disturbances in hypertrophic adipocytes through AMPK-dependent mechanisms. Phytomedicine 22 (6), 605
614. Higdon, J., Drake, V.J., 2012. An Evidence-Based Approach to Vitamins and Minerals: Health Benefits and Intake Recommendations. Thieme, New York. Hosseini, A., Hosseinzadeh, H., 2015. A review on the effects of Allium sativum (garlic) in metabolic syndrome. J. Endocrinol. Invest. 38 (11), 1147
1157. Huerta, A.E., et al., 2015. Effects of alpha-lipoic acid and eicosapentaenoic acid in overweight and obese women during weight loss. Obesity (Silver Spring) 23 (2), 313
321. Hussein, Z., et al., 2004. Effectiveness and side effects of thiazolidinediones for type 2 diabetes: real-life experience from a tertiary hospital. Med. J. Aust. 181 (10), 536
539. Ikizler, T.A., 2005. Effects of hemodialysis on protein metabolism. J. Ren. Nutr. 15 (1), 39
43. Imbe, H., et al., 2016. “Benifuuki” green tea, containing O-methylated EGCG, reduces serum low-density lipoprotein cholesterol and lectin-like oxidized low-density lipoprotein receptor-1 ligands containing apolipoprotein B: a double-blind, placebo-controlled randomized trial. J. Funct. Foods 25, 25
37. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet, 1998. 352(9131), p. 837
853. Inzucchi, S.E., et al., 2012. Management of hyperglycemia in type 2 diabetes: a patient-centered approach. Position Statement ADA EASD 35 (6), 1364
1379. Iseki, K., Kawazoe, N., Fukiyama, K., 1993. Serum albumin is a strong predictor of death in chronic dialysis patients. Kidney Int. 44 (1), 115
119. Jeong, S., et al., 2018. A randomized, double-blind, placebo-controlled trial investigating cholesterol-lowering effects and safety of yellow yeast rice in adults with mild to moderate hypercholesterolemia: a study protocol. Medicine 97 (30), e11634. Johnston, T.P., et al., 2017. Preventing cardiovascular heart disease: promising nutraceutical and nonnutraceutical treatments for cholesterol management. Pharmacol. Res. 120, 219
225. Kahleova, H., Levin, S., Barnard, N.D., 2018. Vegetarian dietary patterns and cardiovascular disease. Prog. Cardiovasc. Dis. 61 (1), 54
61. Kan, J., et al., 2017. A novel botanical formula prevents diabetes by improving insulin resistance. BMC Compl. Altern. Med. 17 (1), 352. Karunaweera, N., et al., 2015. Plant polyphenols as inhibitors of NF-κB induced cytokine production-a potential anti-inflammatory treatment for Alzheimer’s disease? Front. Mol. Neurosci. 8, 24. Kaur, J., 2014. A comprehensive review on metabolic syndrome. Cardiol. Res. Pract. 2014, 21. Kim, S., et al., 2017. Total antioxidant capacity from dietary supplement decreases the likelihood of having metabolic syndrome in Korean adults. Nutrients 9 (10).

REFERENCES

135

Kimura, T., et al., 2007. Food-grade mulberry powder enriched with 1-deoxynojirimycin suppresses the elevation of postprandial blood glucose in humans. J. Agric. Food Chem. 55 (14), 5869
5874. Klemm, R.D., et al., 2008. Newborn vitamin A supplementation reduced infant mortality in rural Bangladesh. Pediatrics 122 (1), e242
e250. Koga, Y., et al., 2018. Early enteral nutrition is associated with reduced in-hospital mortality from sepsis in patients with sarcopenia. J. Crit. Care 47, 153
158. Korsholm, A.S., et al., 2017. Comprehensive metabolomic analysis in blood, urine, fat, and muscle in men with metabolic syndrome: a randomized, placebo-controlled clinical trial on the effects of resveratrol after four months’ treatment. Int. J. Mol. Sci. 18 (3), 554. Kotecha, R., Takami, A., Espinoza, J.L., 2016. Dietary phytochemicals and cancer chemoprevention: a review of the clinical evidence. Oncotarget 7 (32), 52517
52529. Kumar, A., et al., 2017. Supplementation of Spirulina (Arthrospira platensis) improves lifespan and locomotor activity in paraquat-sensitive DJ-1beta(Delta93) flies, a Parkinson’s disease model in Drosophila melanogaster. J. Diet. Suppl. 14 (5), 573
588. Lai, D.M., et al., 2006. Mediation of beta-endorphin by ginsenoside Rh2 to lower plasma glucose in streptozotocin-induced diabetic rats. Planta Med. 72 (1), 9
13. Lamson, D.W., Brignall, M.S., 2000. Antioxidants and cancer, part 3: quercetin. Altern. Med. Rev. 5 (3), 196
208. Landgraf, R., 2000. Meglitinide analogues in the treatment of type 2 diabetes mellitus. Drugs Aging 17 (5), 411
425. Langsetmo, L., et al., 2013. Calcium and vitamin D intake and mortality: results from the Canadian Multicentre Osteoporosis Study (CaMos). J. Clin. Endocrinol. Metab. 98 (7), 3010
3018. Lauretani, F., et al., 2008. Low plasma selenium concentrations and mortality among older communitydwelling adults: the InCHIANTI Study. Aging Clin. Exp. Res. 20 (2), 153
158. Lefranc, F., Tabanca, N., Kiss, R., 2017. Assessing the anticancer effects associated with food products and/or nutraceuticals using in vitro and in vivo preclinical development-related pharmacological tests. Semin. Cancer Biol. 46, 14
32. Leite, R.S., et al., 2013. Oral health and type 2 diabetes. Am. J. Med. Sci. 345 (4), 271
273. Lohr, J.M., Karimi, M., Omazic, B., Kartalis, N., Verbeke, C.S., Berkenstam, A., et al., 2016. A phase I dose escalation trial of AXP107-11, a novel multi-component crystalline form of genistein, in combination with gemcitabine in chemotherapy-naive patients with unresectable pancreatic cancer. Pancreatol 16 (4), 640
645. Magno, S., et al., 2018. LDL-cholesterol lowering effect of a new dietary supplement: an open label, controlled, randomized, cross-over clinical trial in patients with mild-to-moderate hypercholesterolemia. Lipids Health Dis. 17 (1), 124. Malaba, L.C., et al., 2005. Effect of postpartum maternal or neonatal vitamin A supplementation on infant mortality among infants born to HIV-negative mothers in Zimbabwe. Am. J. Clin. Nutr. 81 (2), 454
460. Masanja, H., et al., 2015. Effect of neonatal vitamin A supplementation on mortality in infants in Tanzania (Neovita): a randomised, double-blind, placebo-controlled trial. Lancet 385 (9975), 1324
1332. Mathers, C.D., Loncar, D., 2006. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med. 3 (11), e442. Medicine, U.S.N.L.o. ClinicalTrials.gov. 2018. Available from: ,https://clinicaltrials.gov/ct2/results? cond 5 Alzheimer 1 Disease&term 5 resveratrol&cntry 5 &state 5 &city 5 &dist.. Mehrotra, R., et al., 2011. Serum albumin as a predictor of mortality in peritoneal dialysis: comparisons with hemodialysis. Am. J. Kidney Dis. 58 (3), 418
428. Mielgo-Ayuso, J., et al., 2014. Effects of dietary supplementation with epigallocatechin-3-gallate on weight loss, energy homeostasis, cardiometabolic risk factors and liver function in obese women: randomised, double-blind, placebo-controlled clinical trial. Br. J. Nutr. 111 (7), 1263
1271.

136

CHAPTER 4 EFFECTS OF NUTRITIONAL SUPPLEMENTS

Milne, A.C., et al., 2009. Protein and energy supplementation in elderly people at risk from malnutrition. Cochrane Database Syst. Rev. (2), p. Cd003288. Molassiotis, A., et al., 2005. Complementary and alternative medicine use in colorectal cancer patients in seven European countries. Compl. Ther. Med. 13 (4), 251
257. Molfino, A., et al., 2013. Beta-hydroxy-beta-methylbutyrate supplementation in health and disease: a systematic review of randomized trials. Amino Acids 45 (6), 1273
1292. Mollazadeh, H., Hosseinzadeh, H., 2016. Cinnamon effects on metabolic syndrome: a review based on its mechanisms. Iranian J. Basic Med. Sci. 19 (12), 1258
1270. Mudra, M., et al., 2007. Influence of mulberry leaf extract on the blood glucose and breath hydrogen response to ingestion of 75 g sucrose by type 2 diabetic and control subjects. Diabetes Care 30 (5), 1272
1274. Myint, M.W., et al., 2013. Clinical benefits of oral nutritional supplementation for elderly hip fracture patients: a single blind randomised controlled trial. Age Ageing 42 (1), 39
45. NCEP, Third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III) final report. Circulation, E. National Cholesterol Education Program (NCEP) Expert Panel on Detection, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III), Editor. 2002, pp. 3143
3421. Nalamolu, R.K., Boini, K.M., Nammi, S., 2004. Hypoglycemic effect of Boerhaavia diffusa leaf extract. Trop. J. Pharm. Res. 3 (1), 305
309. Nathan, D.M., et al., 2009. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes care 32 (1), 193
203. Natoli, J.L., et al., 2013. Is there an association between elevated or low serum levels of phosphorus, parathyroid hormone, and calcium and mortality in patients with end stage renal disease? A meta-analysis. BMC Nephrol. 14, 88. Oyebode, O.A., et al., 2018. Boerhaavia diffusa inhibits key enzymes linked to type 2 diabetes in vitro and in silico; and modulates abdominal glucose absorption and muscle glucose uptake ex vivo. Biomed. Pharmacother. 106, 1116
1125. Packer, L., Kraemer, K., Rimbach, G., 2001. Molecular aspects of lipoic acid in the prevention of diabetes complications. Nutrition 17 (10), 888
895. Paiva, A.N., et al., 2015. Beneficial effects of oral chromium picolinate supplementation on glycemic control in patients with type 2 diabetes: a randomized clinical study. J. Trace Elem. Med. Biol. 32, 66
72. Palmer, S.C., et al., 2011. Serum levels of phosphorus, parathyroid hormone, and calcium and risks of death and cardiovascular disease in individuals with chronic kidney disease: a systematic review and metaanalysis. JAMA 305 (11), 1119
1127. Panahi, Y., et al., 2014. Lipid-modifying effects of adjunctive therapy with curcuminoids-piperine combination in patients with metabolic syndrome: results of a randomized controlled trial. Compl. Ther. Med. 22 (5), 851
857. Pari, L., Amarnath Satheesh, M., 2004. Antidiabetic activity of Boerhaavia diffusa L.: effect on hepatic key enzymes in experimental diabetes. J. Ethnopharmacol. 91 (1), 109
113. Park, M.-Y., Lee, K.-S., Sung, M.-K., 2005. Effects of dietary mulberry, Korean red ginseng, and banaba on glucose homeostasis in relation to PPAR-α, PPAR-γ, and LPL mRNA expressions. Life Sci. 77 (26), 3344
3354. Parsaeyan, N., Mozaffari
Khosravi, H., 2012. Effect of chromium supplementation on blood glucose, hemoglobin A1c, lipid profile and lipid peroxidation in type 2 diabetic patients. Iran. J. Diabetes Obesity 4 (4), 178
184. Pasinetti, G.M., et al., 2015. Roles of resveratrol and other grape-derived polyphenols in Alzheimer’s disease prevention and treatment. Biochim. Biophys. Acta 1852 (6), 1202
1208.

REFERENCES

137

Pate, K.M., et al., 2017. Anthoxanthin polyphenols attenuate abeta oligomer-induced neuronal responses associated with Alzheimer’s disease. CNS Neurosci. Ther. 23 (2), 135
144. Patil, S.P., et al., 2014. Neuroprotective and neurotrophic effects of Apigenin and Luteolin in MPTP induced parkinsonism in mice. Neuropharmacology 86, 192
202. Patti, A.M., et al., 2015. Effect of a natural supplement containing Curcuma longa, guggul, and chlorogenic acid in patients with metabolic syndrome. Angiology 66 (9), 856
861. Paur, I., et al., 2017. Tomato-based randomized controlled trial in prostate cancer patients: effect on PSA. Clin. Nutr. 36 (3), 672
679. Perez-Rubio, K.G., et al., 2013. Effect of berberine administration on metabolic syndrome, insulin sensitivity, and insulin secretion. Metab. Syndr. Relat. Disord. 11 (5), 366
369. Perez-Torres, I., et al., 2013. Hibiscus sabdariffa Linnaeus (Malvaceae), curcumin and resveratrol as alternative medicinal agents against metabolic syndrome. Cardiovasc. Hematol. Agents Med. Chem. 11 (1), 25
37. Perrone, D., et al., 2015. Biological and therapeutic activities, and anticancer properties of curcumin. Exp. Ther. Med. 10 (5), 1615
1623. Pitsavos, C., et al., 2006. Diet, exercise and the metabolic syndrome. Rev. Diabet. Stud. 3 (3), 118
126. Porasuphatana, S., et al., 2012. Glycemic and oxidative status of patients with type 2 diabetes mellitus following oral administration of alpha-lipoic acid: a randomized double-blinded placebo-controlled study. Asia Pac. J. Clin. Nutr. 21 (1), 12
21. Poudyal, H., et al., 2011. Omega-3 fatty acids and metabolic syndrome: effects and emerging mechanisms of action. Prog. Lipid Res. 50 (4), 372
387. Provan, S.A., et al., 2017. Calcium supplementation and inflammation increase mortality in rheumatoid arthritis: a 15-year cohort study in 609 patients from the Oslo Rheumatoid Arthritis Register. Semin. Arthritis Rheum 46 (4), 411
417. Pulido-Moran, M., et al., 2016. Curcumin and health. Molecules 21 (3), 264. Pupim, L.B., et al., 2005. Recombinant human growth hormone improves muscle amino acid uptake and whole-body protein metabolism in chronic hemodialysis patients. Am. J. Clin. Nutr. 82 (6), 1235
1243. Qin, S., et al., 2017. Efficacy and safety of turmeric and curcumin in lowering blood lipid levels in patients with cardiovascular risk factors: a meta-analysis of randomized controlled trials. Nutr. J. 16 (1), 68. Rahimi, H.R., et al., 2016. The effect of nano-curcumin on HbA1c, fasting blood glucose, and lipid profile in diabetic subjects: a randomized clinical trial. Avicenna J. Phytomed. 6 (5), 567
577. Rahmani, S., et al., 2016. Treatment of non-alcoholic fatty liver disease with curcumin: a randomized placebocontrolled trial. Phytother. Res. 30 (9), 1540
1548. Rahmathullah, L., et al., 2003. Impact of supplementing newborn infants with vitamin A on early infant mortality: community based randomised trial in southern India. BMJ 327 (7409), 254. Raninen, K., et al., 2011. Dietary fiber type reflects physiological functionality: comparison of grain fiber, inulin, and polydextrose. Nutr. Rev. 69 (1), 9
21. Rautiainen, S., et al., 2013. The role of calcium in the prevention of cardiovascular disease—a review of observational studies and randomized clinical trials. Curr. Atheroscler Rep. 15 (11), 362. Rayman, M.P., 2012. Selenium and human health. Lancet 379 (9822), 1256
1268. Rayman, M.P., et al., 2018. Effect of long-term selenium supplementation on mortality: results from a multiple-dose, randomised controlled trial. Free Radic. Biol. Med. 127, 46
54. Razavi, B.M., Hosseinzadeh, H., 2017. Saffron: a promising natural medicine in the treatment of metabolic syndrome. J. Sci. Food Agric. 97 (6), 1679
1685. Reimer, R.A., et al., 2010. Increased plasma PYY levels following supplementation with the functional fiber PolyGlycopleX in healthy adults. Eur. J. Clin. Nutr. 64 (10), 1186
1191.

138

CHAPTER 4 EFFECTS OF NUTRITIONAL SUPPLEMENTS

Reimer, R.A., et al., 2013. Changes in visceral adiposity and serum cholesterol with a novel viscous polysaccharide in Japanese adults with abdominal obesity. Obesity (Silver Spring) 21 (9), E379
E387. Remington, R., et al., 2015. A phase II randomized clinical trial of a nutritional formulation for cognition and mood in Alzheimer’s disease. J. Alzheimers Dis. 45 (2), 395
405. Report of the expert committee on the diagnosis and classification of diabetes mellitus, 2003. Diabetes Care 26 (Suppl. 1), S5
S20. Richard, C., et al., 2013. Effect of the Mediterranean diet with and without weight loss on markers of inflammation in men with metabolic syndrome. Obesity (Silver Spring) 21 (1), 51
57. Rijpma, A., et al., 2015. Effects of Souvenaid on plasma micronutrient levels and fatty acid profiles in mild and mild-to-moderate Alzheimer’s disease. Alzheimers Res. Ther. 7 (1), 51. Rizza, S., et al., 2011. Citrus polyphenol hesperidin stimulates production of nitric oxide in endothelial cells while improving endothelial function and reducing inflammatory markers in patients with metabolic syndrome. J. Clin. Endocrinol. Metab. 96 (5), E782
E792. Rodriguez-Moran, M., Guerrero-Romero, F., 2003. Oral magnesium supplementation improves insulin sensitivity and metabolic control in type 2 diabetic subjects: a randomized double-blind controlled trial. Diabetes Care 26 (4), 1147
1152. Rossi, L., et al., 2008. Benefits from dietary polyphenols for brain aging and Alzheimer’s disease. Neurochem. Res. 33 (12), 2390
2400. Sae-tan, S., Grove, K.A., Lambert, J.D., 2011. Weight control and prevention of metabolic syndrome by green tea. Pharmacol. Res. 64 (2), 146
154. Sahebkar, A., 2014. A systematic review and meta-analysis of randomized controlled trials investigating the effects of curcumin on blood lipid levels. Clin. Nutr. 33 (3), 406
414. Sahebkar, A., 2017. Effects of quercetin supplementation on lipid profile: a systematic review and metaanalysis of randomized controlled trials. Crit. Rev. Food Sci. Nutr. 57 (4), 666
676. Sahebkar, A., et al., 2016. Lipid-modifying effects of nutraceuticals: an evidence-based approach. Nutrition 32 (11), 1179
1192. Salekzamani, S., et al., 2016. Effect of high-dose vitamin D supplementation on cardiometabolic risk factors in subjects with metabolic syndrome: a randomized controlled double-blind clinical trial. J. Endocrinol. Invest. 39 (11), 1303
1313. Samavat, H., et al., 2017. A randomized controlled trial of green tea extract supplementation and mammographic density in postmenopausal women at increased risk of breast cancer. Cancer Prev. Res. (Phila) 10 (12), 710
718. Sarafidis, P.A., et al., 2010. Effect of thiazolidinediones on albuminuria and proteinuria in diabetes: a metaanalysis. Am. J. Kidney Dis. 55 (5), 835
847. Scheen, A.J., Ernest, P., 2002. New antiobesity agents in type 2 diabetes: overview of clinical trials with sibutramine and orlistat. Diabetes Metab. 28 (6 Pt 1), 437
445. Schwartz, G.G., Skinner, H.G., 2012. A prospective study of total and ionized serum calcium and time to fatal prostate cancer. Cancer Epidemiol. Biomarkers Prev. 21 (10), 1768
1773. Scicchitano, P., et al., 2014. Nutraceuticals and dyslipidaemia: beyond the common therapeutics. J. Funct. Foods 6, 11
32. Sciences, N.I.o. E.H. Neurodegenerative Diseases, 2018. Available from: ,https://www.niehs.nih.gov/ research/supported/health/neurodegenerative/index.cfm.. Seino, S., 2012. Cell signalling in insulin secretion: the molecular targets of ATP, cAMP and sulfonylurea. Diabetologia 55 (8), 2096
2108. Sewitch, M.J., Rajput, Y., 2010. A literature review of complementary and alternative medicine use by colorectal cancer patients. Compl. Ther. Clin. Pract. 16 (1), 52
56.

REFERENCES

139

Shay, K.P., et al., 2009. Alpha-lipoic acid as a dietary supplement: molecular mechanisms and therapeutic potential. Biochim. Biophys. Acta 1790 (10), 1149
1160. Shen, Q.W., et al., 2007. Ca2 1 /calmodulin-dependent protein kinase kinase is involved in AMP-activated protein kinase activation by alpha-lipoic acid in C2C12 myotubes. Am. J. Physiol. Cell Physiol. 293 (4), C1395
C1403. Shipkowski, K.A., et al., 2018. Naturally complex: perspectives and challenges associated with Botanical Dietary Supplement Safety assessment. Food Chem. Toxicol. 118, 963
971. Sivaprakasapillai, B., et al., 2009. Effect of grape seed extract on blood pressure in subjects with the metabolic syndrome. Metabolism 58 (12), 1743
1746. Smith, T., et al., 2017. Herbal supplement sales in US increase 7.7% in 2016. HerbalGram 115, 56
65. Sokka, T., Abelson, B., Pincus, T., 2008. Mortality in rheumatoid arthritis: 2008 update. Clin Exp Rheumatol 26 (5 Suppl. 51), S35
S61. Somanchi, M., Tao, X., Mullin, G.E., 2011. The facilitated early enteral and dietary management effectiveness trial in hospitalized patients with malnutrition. JPEN J. Parenter Enteral Nutr. 35 (2), 209
216. Spallholz, J.E., Palace, V.P., Reid, T.W., 2004. Methioninase and selenomethionine but not Semethylselenocysteine generate methylselenol and superoxide in an in vitro chemiluminescent assay: implications for the nutritional carcinostatic activity of selenoamino acids. Biochem. Pharmacol. 67 (3), 547
554. Srivastava, P., Yadav, R.S., 2016. Efficacy of natural compounds in neurodegenerative disorders. Adv. Neurobiol. 12, 107
123. Sullivan, D.H., et al., 1998. Nightly enteral nutrition support of elderly hip fracture patients: a phase I trial. J. Am. Coll. Nutr. 17 (2), 155
161. Sun, J.W., et al., 2016. Dietary selenium intake and mortality in two population-based cohort studies of 133 957 Chinese men and women. Public Health Nutr. 19 (16), 2991
2998. Swaminathan, R., 2003. Magnesium metabolism and its disorders. Clin. Biochem. Rev. 24 (2), 47
66. Thomas, J., et al., 2015. Omega-3 fatty acids in early prevention of inflammatory neurodegenerative disease: a focus on Alzheimer’s disease. Biomed. Res. Int. 2015, 172801. Thomas, P., et al., 2009. Grape seed polyphenols and curcumin reduce genomic instability events in a transgenic mouse model for Alzheimer’s disease. Mutat. Res. 661 (1
2), 25
34. Torre, L.A., et al., 2016. Global cancer incidence and mortality rates and trends—an update. Cancer Epidemiol. Biomarkers Prevention 25 (1), 16
27. Tsai, C.-H., et al., 2012. Wild bitter gourd improves metabolic syndrome: a preliminary dietary supplementation trial. Nutr. J. 11, 4. Tuorkey, M.J., 2014. Curcumin a potent cancer preventive agent: mechanisms of cancer cell killing. Intervent. Med. Appl. Sci. 6 (4), 139
146. Urquiaga, I., et al., 2015. Wine grape pomace flour improves blood pressure, fasting glucose and protein damage in humans: a randomized controlled trial. Biol. Res. 48, 49. Ursoniu, S., et al., 2018. The impact of argan oil on plasma lipids in humans: systematic review and metaanalysis of randomized controlled trials. Phytother. Res. 32 (3), 377
383. Uslu, H., At˙Ila Uslu, G., 2018. Effects of chromium picolinate on oxidative stress and hyperglycemia in experimental type 2 diabetic rats. Asian J. Pharm. Clin. Res. 11 (10), 532. Veeneman, J.M., et al., 2003. Protein intake during hemodialysis maintains a positive whole body protein balance in chronic hemodialysis patients. Am. J. Physiol. Endocrinol. Metab. 284 (5), E954
E965. Venturini, D., et al., 2015. Effects of extra virgin olive oil and fish oil on lipid profile and oxidative stress in patients with metabolic syndrome. Nutrition 31 (6), 834
840. Vivekananthan, D.P., et al., 2003. Use of antioxidant vitamins for the prevention of cardiovascular disease: meta-analysis of randomised trials. Lancet 361 (9374), 2017
2023.

140

CHAPTER 4 EFFECTS OF NUTRITIONAL SUPPLEMENTS

WHO, 2016. Global Report on Diabetes. World Health Organization. WHO, 2009. Global prevalence of vitamin A deficiency in populations at risk 1995
2005. WHO Global Database on Vitamin A Deficiency. World Health Organization, Geneva. Weber, J.T., 2015. Methodologies and limitations in the analysis of potential neuroprotective compounds derived from natural products. New Horizons Transl. Med. 2 (3), 81
85. Weiner, D.E., et al., 2014. Oral intradialytic nutritional supplement use and mortality in hemodialysis patients. Am. J. Kidney Dis. 63 (2), 276
285. West Jr., K.P., et al., 1995. Mortality of infants , 6 mo of age supplemented with vitamin A: a randomized, double-masked trial in Nepal. Am. J. Clin. Nutr. 62 (1), 143
148. Xiao, Q., et al., 2013. Dietary and supplemental calcium intake and cardiovascular disease mortality: the National Institutes of Health-AARP diet and health study. JAMA Intern. Med. 173 (8), 639
646. Yang, Y.S., et al., 2013. Polyphenols of Hibiscus sabdariffa improved diabetic nephropathy via attenuating renal epithelial mesenchymal transition. J Agric. Food Chem. 61 (31), 7545
7551. Zhao, Y., Wang, C., 2018. Effect of omega-3 polyunsaturated fatty acid-supplemented parenteral nutrition on inflammatory and immune function in postoperative patients with gastrointestinal malignancy: a metaanalysis of randomized control trials in China. Medicine (Baltimore) 97 (16), e0472. Ziegenfuss, T.N., et al., 2006. Effects of a water-soluble cinnamon extract on body composition and features of the metabolic syndrome in pre-diabetic men and women. J. Int. Soc. Sports Nutr. 3 (2), 45
53. Zimmet, P., Alberti, K.G., Shaw, J., 2001. Global and societal implications of the diabetes epidemic. Nature 414 (6865), 782
787. Zu, K., et al., 2006. Enhanced selenium effect on growth arrest by BiP/GRP78 knockdown in p53-null human prostate cancer cells. Oncogene 25 (4), 546
554.

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OPTIMIZING PERFORMANCE UNDER HIGH-ALTITUDE STRESSFUL CONDITIONS USING HERBAL EXTRACTS AND NUTRACEUTICALS

5

Geetha Suryakumar, Richa Rathor, Akanksha Agrawal, Som Nath Singh and Bhuvnesh Kumar Defence Institute of Physiology and Allied Sciences, Delhi, India

CHAPTER OUTLINE 5.1 5.2 5.3 5.4 5.5 5.6 5.7

High Altitude, Hypobaric Hypoxia, and Oxidative Stress................................................................ 142 High Altitude
Induced Maladies................................................................................................. 142 Imbalance in Redox Homeostasis Affects Skeletal Muscle............................................................ 143 Skeletal Muscle Atrophy at High Altitude..................................................................................... 144 Herbs for High Altitude Maladies: Literature Citation .................................................................... 146 Multiple Stress Animal Model for Evaluation of Adaptogenic Activity............................................. 147 Herbal Adaptogens/Performance Enhancers ................................................................................. 148 5.7.1 Panax Ginseng ....................................................................................................... 148 5.7.2 Ginkgo Biloba ........................................................................................................ 149 5.7.3 Withania Somnifera ................................................................................................ 150 5.7.4 Ocimum Sanctum................................................................................................... 151 5.8 Composite Indian Herbal Preparation-I ........................................................................................ 151 5.9 Composite Indian Herbal Preparation-II ....................................................................................... 152 5.10 Sea Buckthorn as Adaptogen ...................................................................................................... 152 5.11 Curcumin................................................................................................................................... 154 5.12 Rhodiola Imbricata ..................................................................................................................... 155 5.13 Ganoderma Lucidum ................................................................................................................... 156 5.13.1 Emblica Officinalis ............................................................................................... 157 5.13.2 Cordyceps Sinensis............................................................................................... 158 5.14 Conclusion ................................................................................................................................ 159 References ......................................................................................................................................... 159 Further Reading .................................................................................................................................. 166

Nutraceuticals and Natural Product Pharmaceuticals. DOI: https://doi.org/10.1016/B978-0-12-816450-1.00005-2 © 2019 Elsevier Inc. All rights reserved.

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5.1 HIGH ALTITUDE, HYPOBARIC HYPOXIA, AND OXIDATIVE STRESS Exposure to high altitude is a major physiological stressor which affects the oxygen availability in our body. More than 140 million people reside at altitudes over 2500 m above sea level worldwide. Physiological stresses, imposed by hypoxia, cold, wind, and harmful ionizing radiations, contribute to a decrease in physical and mental performance at high altitude. The reduced pressure of atmospheric oxygen, known as hypobaric hypoxia (HH), has several consequences for the oxygen economy of the body and activates adaptive mechanisms for coping with the low oxygen tensions. With increasing altitude, an exponential decrease in oxygen partial pressure is observed and associated with parallel reduction in atmospheric oxygen density. For instance, at sea level, total air pressure is 760 mm Hg (or 101 kPa) while at the top of Mt. Everest (8848 m), it drops to 253 mm Hg (or 34 kPa). Further, oxygen constitutes approximately 21% of the total atmospheric pressure with 160 mm Hg at sea level which decreases to 53 mm Hg at Mt. Everest. This condition of reduced barometric pressure and reduced inspired fraction of oxygen is known as HH (Conkin and Wessel, 2008). India together with Nepal has the world’s highest mountains. The high-altitude environment has posed the same unique challenges to soldiers throughout history, from Alexander the Great’s Himalayan expedition in the 4th century BCE to the Indo-Pakistan Kargil Conflict in 1999. At high altitudes of the Eastern and Western Himalayas, rarefied atmosphere with low oxygen availability can affect both physical as well as mental performance of the soldier. An Indian soldier, who is genetically adapted and trained to work at temperatures ranging from 5 C to 35 C prevalent at sea level in most regions of the country, has to work in the high-altitude areas where besides subzero temperature and low oxygen levels, his/her body has to adapt to multiple environmental and psychological stresses. Thus performance maintenance at high altitude is a big challenge. Enhanced free radical generation leading to oxidative stress has been implicated in the pathophysiology of hypoxic exposure under high-altitude environment. Decreased oxygen pressure at high altitude leads to enhanced generation of reactive oxygen (ROS) and nitrogen species (RONS). The degree of altitude makes the difference in the severity of the oxidative damage. Severe responses to high altitude are usually initiated above 3000 m (Lewis et al., 2016). Numerous reactive species generating system are activated at high altitude such as mitochondrial electron transport chain (ETC), xanthine oxidase (XO), and nitric oxide (NO) synthase (NOS) (Radak et al., 1995). Indeed, prolonged imbalance between antioxidant activities and excessive ROS production trigger the oxidative damage in DNA, proteins, and lipids (Sinha et al., 2010; Mrakic-Sposta et al., 2014, 2015). Not only acute hypoxic exposure (Magalhaes et al., 2004) but also chronic hypoxia (Askew, 2002; Dosek et al., 2007) is reported to augment oxidative stress.

5.2 HIGH ALTITUDE
INDUCED MALADIES Exposure to low ambient oxygen at high altitude may lead to medical problems from the mild symptoms of acute mountain sickness (AMS) to the potentially fatal high-altitude pulmonary edema (HAPE) and high-altitude cerebral edema. The most common ailment of high altitude is AMS and the symptoms are headache, nausea, anorexia, insomnia, lassitude, vomiting, and dizziness (Roach et al., 2018). In addition, sleep disturbances, risk of cold injuries and frostbites also develop at high

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FIGURE 5.1 High-altitude maladies and its associated symptoms.

altitude due to extreme low temperature are more at high altitude. Although individually all these factors form potent psychophysiological stressors; when present together they evoke a formidable challenge to the human adaptability and survival under such environmental vagaries. Evidence shows a significant fall in work efficiency and physical performance under high-altitude conditions. Cardiopulmonary changes in cardiac output and blood pressure, a marked decrease in body mass, and loss of muscle function are a known response to the HH. The impairment in the physical performance capacity is further exacerbated by increased oxidative stress, polycythemia, and decreased lactate production. Further, the other health maladies associated with high altitude are sleep disturbances (Ray et al., 2011), hypophagia (Simler et al., 2006), oxidative stress (Arya et al., 2013), alternations of acetylcholine neurotransmitter (Muthuraju et al., 2011), compromised cognitive functions (Muthuraju and Pati, 2014), immune failure, decreased appetite, muscle loss, or atrophy, etc. (Askew, 1997; Hackett and Roach, 2004; Paralikar, 2012; Rathor and Suryakumar, 2016) (Fig. 5.1).

5.3 IMBALANCE IN REDOX HOMEOSTASIS AFFECTS SKELETAL MUSCLE One of the major factors affecting the physical performance at high altitude is due to disturbance in redox homeostasis of skeletal muscle. Production of free radicals like RONS is a necessary consequence of aerobic metabolism. Cellular redox milieu is maintained by RONS which is a natural physiological modulator; and controls a wide range of known and unknown physiological and pathophysiological processes. Similarly, anaerobic metabolism during physical exercise above a certain intensity or exercise at high altitude results in oxidative damage to different macromolecules and affects different organs (Radak et al., 2001; Sinha et al., 2009, 2010). ROS are free radicals/unpaired electrons widely produced in eukaryotic cells as a result of incomplete, one electron reduction of O2 in mitochondria. Superoxide radical (O22) is a primary member of ROS formed by the uncoupled transfer of electron from complex I and III in the ETC (Dro¨ge, 2002; Trachootham et al., 2008). Generation of mitochondrial ROS in skeletal muscles

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occurs under various conditions such as in the course of intense contractile activity and due to inflammatory response. Secondarily, XO is one of the major sources of ROS generation in anaerobic conditions (Radak et al., 1995). The empirical data from the previous studies suggest that both high-altitude exposure and intense exercise could result in oxidative damage and shift the redox state of cells. Past studies highlighted the proteome imbalance due to oxidative protein damage which resulted in increased carbonylation of muscular proteins at an altitude of 4000 m (Radak et al., 1997). They have strongly emphasized on the weakened antioxidant defense system in the cells on altitude exposure. Our own studies have reported the increased oxidant-induced protein damage on acute and chronic hypoxic exposure which results in disrupted skeletal muscle proteostasis (Agrawal et al., 2017, 2018). Increasing evidence indicates that dysregulation of Ca21 in skeletal muscles results in caspases and calpain activation and leads to degradation of myofibrillar proteins and muscle loss.

5.4 SKELETAL MUSCLE ATROPHY AT HIGH ALTITUDE D’Hulst and Deldicque (2017) stated that the severity of high altitude
associated muscle atrophy depends on the combined effect of duration and degree of hypoxia exposure. Both of the parameters are important for playing a role in muscle atrophy. Indeed, it is still unclear which parameter, altitude, or time spent at altitude is most decisive in muscle atrophy. Numerous studies depicted changes in metabolic processes especially in protein metabolism in skeletal muscle (Preedy et al., 1985; Vats et al., 1999). Four weeks’ HH exposures at 4300 m altitude lead to negative nitrogen and water balance (Consolazio et al., 1968). MacDougall et al. (1991) also reported reduced muscle cross-sectional area by approximately 25% at approximately 5500 m for 40 days’ HH exposure. Weight loss has been observed in sojourners at high altitude (Macdonald et al., 2009). Recent evidences also suggested the alteration in appetite control and consequent reduction of energy intake as a significant feature of weight loss (Kayser and Verges, 2013). It is also depicted clearly that more than 60% weight loss is fat-free mass which further leads to decline of muscle contractility and physical performance (Wing-Gaia, 2014). High altitude
mediated HH leads to loss of body mass and protein loss (Macdonald et al., 2009). Chronic hypoxia was previously known to alter skeletal muscle mass in humans (Rose et al., 1985) as well as animals (Favier et al., 2010; Hayot et al., 2011). Few reports suggested that cross-sectional area of thigh muscle decreased by 10% after sojourns went to the Himalayas. Morphological studies provided evidences of decrease muscle fiber size mainly due to loss of myofibrillar proteins (Hoppeler et al., 1990). One of the metabolic adaptive responses played by the cell is inflammation and oxidative stress which enhances under low oxygen availability conditions (Miyata et al., 2011; Eltzschig and Carmeliet, 2011). Consecutively, disruption of intracellular redox balance and inflammation aggregately led to skeletal muscle mobilization (van Hall, 2012). Basically, hypoxia perturbs the efficiency of mitochondrial ETC that leads to leaking of electrons to molecular oxygen and ultimately excessive ROS generation (Murray, 2009). On the other hand, interleukin 1 (IL-1), interleukin 6 (IL-6), and Creactive protein also upregulates during expeditions at high altitude (Hartmann, 2000). These two

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145

mechanisms are linked to skeletal muscle wasting via activating HIF-1α and NF-κB catabolic pathways and inhibiting anabolic mammalian target of rapamycin (mTOR) pathway (de Theije et al., 2011) (Fig. 5.2). Recently our research focus was to explore the mechanisms contributing to high altitude
associated muscle atrophy in which we reported that elevated protein turnover rate is the major factor for muscle loss due to HH exposure (Chaudhary et al., 2012a). In general, protein turnover rate is decisive by two factors: rate of protein synthesis and protein degradation. In the case of chronic HH, once a comparison was done in protein synthesis and degradation rate, it was noted that protein synthesis was 1.5-fold higher while protein degradation was 5.0-fold higher during chronic HH. Further, it was also observed that ubiquitin-proteosome pathway (Ub-proteosome) and calpain pathways were found to be increased during chronic HH which was considered as the main culprit of protein degradation (Chaudhary et al., 2012b) (Fig. 5.3). Our group has reported that oxidative protein modification affects the skeletal muscle homeostasis under acute HH. In addition, our study highlighted that ROS activates numerous signals and perturbed the protein environment of muscle cells with altered calcium ion homeostasis, which is a key factor for the activation of multiple downstream signaling participants in muscle proteolysis. Our recent study describes that skeletal muscle atrophy at high altitude is a multifaceted condition triggered by several cellular stress response pathway, and perturbed proteostasis is the consequence for the progression of muscular atrophy and a decline in physical performance (Agrawal et al., 2018).

FIGURE 5.2 Skeletal muscle wasting via activating HIF-1α and NF-κB catabolic pathways and inhibiting anabolic mammalian target of rapamycin (mTOR) pathway.

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FIGURE 5.3 Ubiquitin-proteosome pathway (Ub-proteosome) and calpain pathways: main culprit of muscle protein loss.

5.5 HERBS FOR HIGH ALTITUDE MALADIES: LITERATURE CITATION Plants/herbal products are very suitable for optimizing and enhancing physical endurance and performance under strenuous conditions. Ayurveda is the most developed and widely practiced in India since ancient times (1500
800 BCE). The term comes from the Sanskrit root Au (life) and Veda (knowledge). Thus Ayurveda is the science and art of living healthy long life, has proper nutrition and lifestyle at its core. Today this system of medicine is being practiced in countries like Nepal, Bhutan, Sri Lanka, Bangladesh, and Pakistan, while the traditional system of medicine in the other countries like Tibet, Mongolia, and Thailand appear to be derived from this only. This branch is gaining interest very fast due to fewer side effects, easy availability, and cost effectiveness. The World Health Organization (WHO) listed approximately 20,000 plant species as world yielding drugs in which over 2500 species which consist of medicinal activity is in credit of India. Plants have rich vitamins, minerals, and other bioactive components which synergistically showed medicinal activities. The use of nutrients and nutritional factors in improving endurance, skilled work performance, sports, and mental work has also been acknowledged very well. Russians gave another word, adaptogens, to nutrients and biologically active substances derived from plants that are useful in enhancing work performance under adverse stressful environments, in sports, among soldiers, miners, students, workers, and aged individuals. These substances affected the immune system and improved cardio respiratory system, overall physical stamina, and mental alertness. The use of plant extracts having medicinal properties seems to be more natural, less expensive, and involve therapies that are gentler and largely without side effects. In India, drugs of herbal origin have been used in traditional systems of medicines. Recently there has been an ever-increasing interest in the research on different plant species to evaluate their therapeutic applications all over the world. Environmental conditions that induce or

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favor photo oxidative stress are part of plant’s everyday life. Higher plants have a stationary lifestyle and the potential to adapt to physical, chemical, and biological factors to maintain homeostasis. It is critical for plants to readily recognize dangerous and harmful stress factors and to effect suitable responses to them. The accumulated knowledge suggests that plants express new genes and establish new metabolic activities depending on the type and strength of the stress factors (Lamb et al., 1989; Nover et al., 1989; Chandra and Low, 1995). Plants have acquired an essential system to reduce and scavenge active oxygen species, which are naturally generated during photosynthesis and respiration (Asada, 1996). Plants synthesize thousands of metabolites that are used for their growth, development, reproduction, and defense against attacks by many different kinds of organisms and are able to survive in often harsh and ever-changing environments. Natural products are a rich source of unique and biologically active compounds. Medicinal plants provide raw materials and traditional knowledge which are important to the development of herbal medicine. Medicinal plants are important for pharmacological research and drug development. They may be directly useful as therapeutics or serve as models for pharmacologically active compounds. Herbal medicines are prepared from any part of the plant such as leaves, roots, stem, or fruit. Primary metabolites of plants are different organic compounds such as carbohydrates, proteins, and nucleic acids. They are products of fundamental metabolic pathways of the plant which include glycolysis, the Krebs cycle, and the Calvin cycle. In addition, plants produce several secondary metabolites via secondary biochemical pathways in response to specific environmental stimuli, such as herbivore-induced damage, pathogen attacks, or nutrient deprivation. These secondary metabolites are the major phytoconstituents of the plant and are responsible for their ability to survive and overcome the stress imposed by their environment. The essential role of the secondary metabolites is well proved by the energy invested by the plant in their synthesis, and these phytoconstituents play an important role as antioxidants, free radical scavengers, UV light absorbers, and antiproliferative agents; these phytoconstituents also defend the plant against microorganisms and competitor plants and survive in severe environmental stress conditions. The secondary metabolites largely fall into three classes of compounds such as alkaloids, terpenoids and phenolics.

5.6 MULTIPLE STRESS ANIMAL MODEL FOR EVALUATION OF ADAPTOGENIC ACTIVITY Our laboratory have developed a passive cold
hypoxia
restraint (CHR) animal model, which is used to evaluate the performance enhancement efficacy of adaptogenic substances, and the parameter for measuring the performance studied was indicative of hypothalamic and metabolic functions of the organism (Ramachandran et al., 1990). Several herbs have been already tested for their adaptogenic potential using this system. This technique has been employed based on the hypothesis that plants growing under adverse climatic conditions of high altitude contain biomolecules which help them to sustain in such environment and supplementation of such plant products to the animals increase their performance during exposure to a stressful, cold, and hypoxic environment (Divekar et al., 1996). In this model, overnight fasted rats are exposed to a decompression chamber maintained at a cold temperature (5 C), a low atmospheric pressure of 428 mm Hg pressure equivalent to an

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altitude of 4572 m, and restraint stress simultaneously. Under such stressful conditions, a rectal probe is inserted 2 cm past the rectum and the rectal temperature (Trec) is monitored once per minute by using a 16-channel Iso-Thermex temperature recorder. The gradual fall in rectal temperature is recorded from 37 C to 23 C. Attainment of a colonic temperature of 23 C is taken as the termination point of the exposure, as any further fall in colonic temperature resulted in high incidence of mortality. After exposure, the animals are kept in a deconditioning chamber for recovering temperature from 23 C to 37 C at a normal atmospheric pressure and ambient temperature of 32 C. The rat continues to be restrained during recovery period. The time taken to attain Trec of 23 C and its recovery to Trec of 37 C is used as a measure of endurance. This CHR model has been exploited for evaluating the adaptogenic and antistress efficacy of many herbal formulations. This is based on the simple principle that any formulation that is capable to resist a change in its rectal temperature (a physiological marker) after being exposed to simulated high-altitude conditions developed by CHR model could be considered as adaptogens for cold, hypoxia, and restraint stress.

5.7 HERBAL ADAPTOGENS/PERFORMANCE ENHANCERS Adaptogens are an exclusive class of medicinal plants that are capable of maintaining homeostasis, restoring and protecting the body. As per definition “an adaptogen doesn’t have a specific action; it helps you respond to any influence or stressor, normalizing your physiological functions” (Fig. 5.4). DIPAS, our research institute extensively worked on adaptogens, herbal formulations which could enhance nonspecific resistance to stress and improve physical performance.

5.7.1 PANAX GINSENG Panax ginseng was used in traditional Chinese medicines and well known for its healing properties. The bioactive substances present in P. ginseng have properties to enhance physical endurance, stamina, and to cope better with muscular fatigue. This plant is widely used as an adaptogen throughout the world, and the active component of P. ginseng is ginsenosides. Past literature suggests its effect on the CNS (memory, learning, and behavior), cardiovascular system, and endocrine function. Growing evidences suggest the antioxidant, antiinflammatory, antidiabetic, anticancer, and protective effects of ginseng due to enhanced NO synthesis in endothelium of different organs. Further, the elevated levels of NO contribute to ginseng-associated vasodilatation and aphrodisiac action (reviewed by Rajabian et al., 2018). A study by Kumar et al. reported the adaptogenic activity of a herbo-vitamin-mineral preparation containing P. ginseng. Using the CHR animal model, the maximum effect (45%) of P. ginseng was observed in developing cold tolerance and recovery from acute hypothermia as compared to the control group. Further, the potent role of P. ginseng in glucose utilization during endurance and enhanced fat utilization in support of thermogenesis and recovery from acute hypothermia was also evaluated. In addition, studies have shown the protective activity of ginseng root saponins at a dose of 100 mg/kg, i.p., in decreasing rectal temperature of hypoxia-exposed rats (235 mm Hg) (Liu and Xiaob, 1992; Kumar et al., 1996).

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FIGURE 5.4 Supplementation of adaptogens improve mental and physical performance in stress conditions.

5.7.2 GINKGO BILOBA The leaves of Ginkgo biloba (GB) are well known as a natural source of flavonoids and polyphenolic compounds. GB extract is one of the most widely used medicinal plant and used as a therapeutic target in various neurodegenerative diseases such as Alzheimer’s (AD) (Ramassamy et al., 1992), memory loss, mild cognitive impairment (Zhang et al., 2016), cancer, and cardiovascular illnesses (Mahadevan and Park, 2008). Other studies show its beneficial effects in both obesity and type-2 diabetes (reviewed by Mohanta et al., 2014). The GB extract has been traditionally used as therapeutic agents for enhancing cognitive and physiological performance. Administration of GB extract enhanced the aerobic performance of healthy volunteers as expressed by increased VO2 max by augmenting their antioxidant enzymes and providing better neuroprotection through increased exercise-induced production of brainderived neurotrophic factor activity. GB extract contains flavonoids and terpenes which may increase muscle tissue blood flow by stimulating the release of endothelium-derived relaxing factor, thus improving muscle endurance by enhancing muscular energy production. Similarly, other studies have reported that GB extract improvises the exercise performance demonstrated by pain-free walking in patients with peripheral occlusive arterial disease (Peters et al., 1998). GB extract also has potent antioxidant potential, scavenges ROS, and increases the activities of antioxidant enzymes, such as superoxide dismutase (SOD), glutathione peroxidase, catalase (CAT), and hemeoxygenase-1 (reviewed by Ude et al., 2013).

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The memory enhancing, mood improving and antidepressant effects of GB extract have been well evaluated which paves the way of this extract in prevention of neurodegenerative diseases. Ischemia, impaired blood circulation, is a common underlying condition of cardiovascular and cerebral vascular diseases. Cardioprotective effects of GB extract are through antioxidant, antiplatelet activity, and increased blood flow through the release of NO and prostaglandins. The extract also improves coronary blood flow through antiplatelet activity and by improving contractile functions. GB extract exhibited a chemopreventive action at various levels with antioxidant, antiangiogenic properties, and also influenced gene expression of several key proteins involved in anticancer activity (reviewed by Mahadevan and Park, 2008).

5.7.3 WITHANIA SOMNIFERA Withania somnifera (WS), commonly known as Ashwagandha, Indian Ginseng, or Winter Cherry, belongs to the Solanaceae family. The plant is well known for its multipurpose effect on various systems of the human body such as the neurological, immune, endocrine, and reproductive system. This herb has numerous biological activities such as adaptogenic, antioxidant, anticancer, antidepressant, cardioprotective, immunomodulating, antibacterial, antifungal, antiinflammatory, and neuroprotective. The major phytoconstituents present in the plant are withanolides, sitoindosides, and several other alkaloids that have a potential medicinal and therapeutic efficacy. These phyoconstituents are known to act against oxidant-induced damage and have potent antistress activity. Several in vitro and in vivo studies demonstrated that WS extract has significant immunomodulatory activity and enhanced cognitive function related to memory and learning. Further, this extract has potent antiinflammatory activity in various disease models of nephritis and lupus by modulating proinflammatory cytokines such as IL-6 and TNF-α. The WS extract also inhibited NFkB and IL-8 in cellular models of cystic fibrosis. WS extract also modulated key signaling pathways of cancer such as p53 signaling, DNA damage, and apoptosis signaling which proved its potent anticancer activity. In vitro studies using human lymphoma U937 cells shows the anticancerous effect of WS extract by enhancing the production of ROS via regulating different signaling cascades which are critically involved in apoptosis. Similarly, other studies reported the use of WS extract in radiationinduced apoptosis in human renal cancer cells by excessive generation of ROS, dephosphorylation of AKT, and ER stress. Cardioprotective effect of WS extract was demonstrated in a rat model which showed that prophylactic treatment with the extract restored the myocardial oxidant/antioxidant balance and antiapoptotic effects. Various studies conducted in the past on WS extract explored the apoptogenic and antistress activity. In a human clinical study by using WS extract, reduced level of serum cortisol was observed. Similarly in a rat model of foot shock stress, the extract shows the protective efficacy against the oxidative free radicals and lipid peroxidation in rat frontal cortex and striatum. The most interesting aspect of WS extract was enhancing the physical performance indicated in the results of several research works in animal as well as human studies. In a study by Singh et al., administration of WS extract exhibited better physical performance and muscle endurance in an animal model of swimming which was observed with the increased duration of swimming (Singh et al., 1982). In addition, several studies reported that WS extract possesses the physical performance enhancing property and may be used to enhance stamina (Raj et al., 2018). Studies from our own institute evaluated the protective efficacy of WS extract on HH in animal models. The results

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indicate that WS extract attenuated HH-induced memory and hippocampal neurodegeneration by enhancing the levels of antioxidant such as GSH through activation of the glutathione biosynthesis pathway in hippocampal cells. The protective effect of WS extract on the hippocampal cells was mediated by the Nrf2 pathway and NO in a corticosterone-dependent manner (Baitharu et al., 2014).

5.7.4 OCIMUM SANCTUM Ocimum sanctum (OS) is also known as Holy Basil or Tulsi, and belongs to the family of Lamiaceae. This plant is well known for its medicinal and spiritual properties in Ayurveda which includes aiding cough, asthma, diarrhea, fever, dysentery, arthritis, eye diseases, indigestion, gastric ailments, etc. Major phytoconstituents of OS are eugenol, ursolic acid, rosmarinic acid, apigenin, myretenal, luteolin, β-sitosterol, and carnosic acid (Pattanayak et al., 2010). Several researchers have demonstrated the medicinal and therapeutic potential of OS extract in in vitro and in vivo models. The antioxidant activity of OS was evaluated by Subramanian et al. (2005) which showed free radical scavenging, antilipid peroxidation, and superoxide radical scavenging properties of the extract. Researchers investigated the reduced level of uric acid by the administration of OS extract, which is the most important causing factor of arthritis. Further the extract also exhibited significant antiinflammatory activity evaluated by the inhibition of cyclooxygenase-1 (COX-1) and COX-2 (Kelm et al., 2000). Emerging evidences reported the protective effect of OS extract against radiation-induced chromosomal damage in mice due to its free radical scavenging and metal-chelating properties (Uma Devi et al., 2000). In addition studies also have observed the radiation-induced protection of OS against bone marrow damage by using the plant extract. OS extracts show that antistress activity was evaluated by the reduced level of cortisol release and CHHR1 receptor activity using in vitro studies. Further, the antistress activity of the OS extract has been well demonstrated by the significantly lower levels of cortisone and creatine kinase in acute stress-induced rats as compared to the normal group (Gupta et al., 2007). Further literature also indicates that pretreatment with OS extract decreased the stomach ulcer index and plasma corticosterone in 4-hour restraint stress. Enhancing physical performance activity of OS extract was evaluated by several researchers in different animal models which showed enhanced aerobic metabolism, increased swimming duration and latency and attenuation of oxidative tissue damage leading to normalization of several physiological and biochemical parameters caused by physical stressors. Further, OS extract protected the animals from acute and chronic noise-induced stress in experimental animals by increasing neurotransmitter and ECG responses (Richard et al., 2016).

5.8 COMPOSITE INDIAN HERBAL PREPARATION-I Basically, composite Indian herbal preparation-I (CIHP-I) is a mixture of a number of herbs. The cumulative effect of these herbs enhanced the physical and mental performance. Studies using CIHP-1 against CHR stress found that a 3-week oral administration of CIHP-I at the dose of 15 mg/kg showed potent adaptogenic and antistress activity. The time taken to attain Trec of 23 C

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increased by 30% at the dose of 7.5 mg. Administration of CIHP-I to mice for 4 days at the dose of 50
150 mg/kg body weight increased survival time of swimming and also prevented stressinduced changes in the adrenals (Singh et al., 1978). Further the CIHP also increased the oxygen demand at high terrestrial altitude and also improved nutrition and cell-mediated immunity.

5.9 COMPOSITE INDIAN HERBAL PREPARATION-II Another form of composite Indian herbal preparation-II (CIHP-II) is a preparation of 39 plant components and 6 minerals (Graver et al., 1995). Administration of CIHP-II at a dose of 1 mg/kg body weight showed potent antistress activity as observed by a significant delay in the time for attaining Trec of 23 C and a quick recovery to 37 C. Large-scale human field trials of CIHP-II were also conducted for introduction into the armed forces operating under extreme climatic conditions. In this study, a double-blind placebo-controlled randomized field trial was carried out on age-matched and body weight
matched volunteers to ascertain efficacy of CIHP in curtailing altitude-induced maladies during acute induction to an altitude of 3500 m and following a prolonged residence at extreme altitude of 4800
6000 m. A significant decrease in AMS symptom score and an increase in arterial oxygen saturation (SaO2) were observed in CIHP-II-administered volunteers as compared to the placebo-treated group. Hence, CIHP-II administration was able to significantly curtail the altitude-induced deterioration of the physical and mental performance of the soldiers during prolonged residency at high and extreme altitude.

5.10 SEA BUCKTHORN AS ADAPTOGEN Our laboratory has extensively worked on a Himalayan medicinal plant, sea buckthorn (SBT) which has gained a lot of recognition in the recent years for its medicinal and nutritional value. SBT (Hippophae rhamnoides L.) (Elaeagnaceae) is a thorny nitrogen-fixing deciduous shrub, drought, cold resistant, and native to Europe and Asia. This plant has been used extensively in the traditional system of medicine for treatment of asthma, skin diseases, gastric ulcers, and lung disorders. All parts of this plant are considered to be a good source of a large number of bioactive substances such as vitamins, carotenoids, phytosterols, polyunsaturated fatty acids, and some essential amino acids with remarkable activity against common human diseases. SBT berries are rich sources of vitamin C, carotenoids, minerals, vitamin B, vitamin E, and vitamin K. Seeds contain high-quality oil which has many bioactive substances. The fruits have a distinctive sour taste and a unique aroma reminiscent of pineapple. The characteristic long and narrow leaves of the plant are rich in many bioactive components especially phenolic representatives such as flavonols, leucoanthocyanidins, (2)epicatechin, (1)gallocatechin, (2)epigallocatechin, and gallic acid (Suryakumar and Gupta, 2011; Upadhyay et al., 2009). The fresh leaves which are rich in total carotenoids, chlorophyll, proteins, amino acids (0.73% lysine, 0.13% methionine and cysteine), minerals (Ca, Mg, and K), folic acid, catechins, esterified sterols, triterpenols, and isoprenols (Guan et al., 2006) have also been reported. The flavonoids in various parts of the plant and unsaturated

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fatty acids in oils are known to improve the cardiovascular system (Zeb, 2006), prevent coronary heart disease, and relieve symptoms of diabetes mellitus (Eccleston et al., 2002). Initial research using in vitro models showed the protective effect of SBT leaf extract against chromium-induced oxidative stress. The results showed an excellent antioxidant activity of this extract even in the animal model. The antioxidant and immunomodulatory activity of SBT were evaluated in vitro using rat splenocytes and macrophages. The leaf extract of SBT exhibited potent antioxidant activity and inhibited the oxidant-induced free radical levels and enhanced the antioxidant levels. The immunomodulatory activity was also demonstrated in cell lines where the extract enhanced the levels of interleukins IL-2 and γ-IFN and specifically activated the cell-mediated immune response. In the glial cells, the SBT extract ameliorated the hypoxia-induced oxidative damage (Narayanan et al., 2005) and also protected the animals from chromium-induced oxidative damage in the animals. SBT administration also attenuated the nicotine-induced oxidative damage in rat. The fruit flavones of SBT were studied for its antioxidant activity and significantly attenuated the oxidant-induced apoptosis in cells by decreasing intracellular calcium levels and caspase activity. Further, seed oil of SBT also showed potent antioxidant activity in mice by enhancing the antioxidant enzymes and decreasing the lipid peroxidation. The antiinflammatory activity of SBT was also well documented in vitro and in adjuvantinduced arthritis (AIA) rat model (Ganju et al., 2005). In the cell line, the extract inhibited the NO levels induced by LPS and also showed immune boosting and antiaging effect (Mishra et al., 2011). Several researchers have documented the hepatoprotective activity of SBT. Administration of the extract significantly ameliorated the hepatic damage as evidenced by biochemical and histopathological observations in CCl4-induced liver injury. The anticancer activity was also demonstrated in several in vitro studies. Isorhamnetin, a flavonoid from SBT, was found to have cytotoxic effects against human hepatocellular carcinoma cells (Teng et al., 2006). The research suggested that isorhamnetin have proapoptotic effects by inducing downregulation of several oncogenes and upregulation apoptotic proteins. Further, the flavonoid also decreased protein synthesis by reducing the PI3K-Akt-mTOR pathway. Recently Kim et al. (2017) have observed that leaf extract of SBT inhibited the proliferation of rat C6 glioma cells by upregulation of proapoptotic proteins BCl-2 and Bax. Emerging evidences reported that SBT extracts induced the expressions of apoptotic-related genes in several carcinoma cell lines such as the human breast carcinoma cell line, Bcap-37, HepG2 human liver cancer cells, and lung cancer cells. Researchers suggested that the proapoptotic effects of SBT cells were induced by the downregulation of oncogenes and suppressed cell proliferation by inhibiting the PI3K-Akt-mTOR pathway (Zhang et al., 2005; Li et al., 2015). Further in vivo studies showed that SBT extracts inhibit skin papillomagnesis by decreasing the activity of phase II enzymes in mice (Padmavathi et al., 2005). A recent study by Wang et al. (2015) observed the antitumor activity in Lewis lung carcinoma (LLC) which was found to have enhanced the lymphocyte proliferation, augmented macrophage activities, and promoted natural killer cell activity in tumor-bearing mice. SBT extracts have high content of biologically active compounds and antioxidants which has potent radioprotective activity. Several research works have demonstrated the radioprotective efficacy of SBT extracts and reported the inhibition of DNA strand breaks and reduced expressions of caspases induced by radiation (Kumar et al., 2002). In addition, SBT extracts showed immunostimulatory properties which play an important role in its radioprotective efficacy (Prakash et al., 2005; Olas et al., 2018).

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The SBT extract also showed antistress and adaptogenic activity when tested in CHR animal model where resistance in fall of rectal temperature is taken as a marker for physical endurance. Oral administration of SBT extract (100 mg/kg BW) had significant antistress activity (Saggu and Kumar, 2007). SBT extracts ameliorated the oxidative damage in the liver and muscle during CHR exposure and poststress recovery. Further results suggested a shift of anaerobic metabolism to aerobic during multiple stress exposure and also during poststress recovery. Exposure to high altitude leads to illnesses such as high-altitude pulmonary and cerebral edema which occurs due to extravasation of fluid from intra to extravascular space particularly in the lungs and brain. Our studies have shown that SBT leaf extract and seed oil inhibited the hypoxia-induced transvascular leakage in the lungs and brain (Purushothaman et al., 2011). Administration of SBT also enhanced the hypoxic tolerance by increasing the hypoxic survival time and decreasing the plasma catecholamine levels. To explore the mechanism behind the protective effects of SBT, various signaling mechanisms were evaluated. Administration of SBT extract led to a marked increase in the expression of hypoxia-responsive proteins such as HIF-1α and HO-1. SBT also substantially exacerbated the production of NO, probably through the higher iNOS and eNOS expression. Interestingly, SBT attenuated the ER stress response as observed by the downregulation of ER stress markers CHOP and PERK. SBT induced antiinflammatory and antiapoptotic responses in the hypoxia-exposed animals also contributed to the enhanced hypoxic tolerance. Our study draws attention to the modulation of proteostasis signaling mechanisms by SBT which mediate its protective effects against hypoxic injury (Rathor et al., 2015; Jain et al., 2016).

5.11 CURCUMIN Curcumin is a diferuloylmethane derived from the Indian spice plant turmeric (Curcuma longa L) which has been shown to regulate several key signaling pathways. The uses of turmeric, for treatment of different inflammatory diseases, have been described in Ayurveda and in traditional Chinese medicine for thousands of years. The active component of turmeric is curcumin, which was identified almost two centuries ago. Modern science has revealed that curcumin mediates its effects by modulating several important molecular targets. Curcumin has potential antiinflammatory and antioxidant properties with several other therapeutic advantages. Earlier studies reported that it has properties to scavenge free radical species such as the superoxide anion radicals, hydroxyl radicals, and nitrogen dioxide radicals (Unnikrishnan and Rao, 1995; Sreejayan and Rao, 1997), and also inhibit lipid peroxidation in different animal models (Sreejayan and Rao, 1994). Curcumin ameliorated oxidant-induced damage in kidney cells (LLC-PK1) via inhibition of lipid peroxidation and cytolysis (Cohly et al., 1998). Curcumin shows anticancer effects by modulating key targets and signaling molecules such as transcription factors, growth regulators, adhesion molecules, apoptotic genes, and angiogenesis regulators (Aggarwal et al., 2003). Indians have a lower incidence of bowel cancer which has been attributed to the daily use of turmeric in Indian food (Mohandas and Desai, 1999). Further studies show the apoptotic activity of curcumin in a variety of cells such as prostate cancer cells (Dorai et al., 2001).

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Ancient use of curcumin in wound healing is well known. Indians use curcumin for local application as a remedy for several conditions such as skin diseases, insect bites, and chicken pox (Nadkarni, 1976). Efficacy of wound healing activity of curcumin has been demonstrated in several studies which show increased expressions of fibronectin and collagen and faster wound contraction (Sidhu et al., 1998; Mani et al., 2002). Curcumin has been shown to inhibit hypoxia-induced oxidative stress, vascular leakage in lungs, and also attenuated hypoxia-induced NFkB expression (Sagi et al., 2008). Curcumin administration also significantly decreased the water content and transvascular leakage in the brain of rats exposed to 24-hour HH. Curcumin prophylaxis significantly attenuated the upregulation of NF-κB and downregulated the levels of proinflammatory cytokine levels (Sarada et al., 2015). Surfactant system is mainly affected by ROS, proteases, and cytokines released by the inflammatory cells which take place in many pathological conditions such as HAPE, acute respiratory distress syndrome, and chronic obstructive pulmonary diseases. A recent study by Mathew et al. evaluated the prophylactic administration of curcumin in reducing the oxidative stress and enhancing the prosurvival signaling under hypoxia using both in vitro and in vivo studies. Their observations indicated that the enhanced expression of Phase II antioxidant enzymes via upregulation of Nrf2 and HIF-1α pathway maintains the pulmonary surfactant homeostasis (Mathew and Sarada, 2018) In our recent study we explored the efficacy of curcumin in amelioration of hypoxia-induced skeletal muscle atrophy. Our observations indicate that administration of Curcumin ameliorated the oxidative stress induced by chronic HH and resulted in a decline of protein degradation. It was also observed that inhibition of oxidative stress by curcumin resulted in increased expressions of Myf 5, Myo D, and myogenin as oxidative stress which has been shown to impair the myogenic regulatory factors under stressful conditions. Further curcumin enhanced the physical performance under HH which was observed by the time taken by rats to get fatigued while running on a treadmill (Chaudhary et al., 2019).

5.12 RHODIOLA IMBRICATA Rhodiola is another important high-altitude medicinal plant that is widely distributed throughout Europe and Asia. There are more than 200 known species of this plant and its roots are a rich source of various biologically active molecules such as phenyl propanoids (rosavins, rosin), phenyl ethanol derivatives (salidroside, tyrosol), organic acids, flavonoids, and tannins (Khanum et al., 2006). Roots of Rhodiola have been known for its medicinal use in traditional folk medicine of China, Tibet, and Mongolic to enhance physical endurance, to treat fatigue and gastrointestinal ailments. Systematic scientific studies were carried out on the root extracts of Rhodiola, which demonstrated to have cytoprotective and antioxidant activity. The extracts of Rhodiola also have antifatigue, anticancer, and neuroprotective bioactivities. Modulation of immune response by Rhodiola has been demonstrated in several studies. Extract of Rhodiola was evaluated for immunomodulatory activity in human peripheral blood mononuclear cells (hPBMCs) and mouse macrophage cell line RAW 264.7 which shows the stimulation of proinflammatory cytokines such as IL-6 and TNF-α and also enhanced the production of NO (Mishra

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et al., 2008). Moreover, Rhodiola extract inhibited the proliferation of human T-cell lymphoma cell line EL-4 and erythroleukemic cell line HL-60. The number of TNF-α spots was increased and there was an upregulation of TLR-4 mRNA expression in Rhodiola extract
treated hPBMCs. This study hence, concluded that Rhodiola has a potent immune stimulatory activity which might be useful in immunocompromised individuals (Mishra et al., 2012). The wound healing activity was evaluated by (Gupta et al., 2007) using rat excision wound model. Treatment with Rhodiola extract led to faster healing of wounds as indicated by the improved rate of wound contraction and decreased time taken for epithelialization. The treatment of Rhodiola extract also increased cellular proliferation and collagen synthesis and also increased the DNA, protein, hydroxyproline, and hexosamine content. Rhodiola was also enhanced in antioxidant levels in the granulation tissue. The results of this study suggested a significant wound healing activity in Rhodiola extract. The dose-dependent adaptogenic activity was carried out on the aqueous extract of Rhodiola imbricata using CHR animal model. The maximum effective dose of the extract was observed at 100 mg/kg BW with adaptogenic and antistress activity. The results also suggested potent antioxidant activity in the extract as it significantly ameliorated the oxidative stress induced by CHR and maintained cell membrane permeability in the blood, liver, and muscle of rats during CHR exposure and also postexposure recovery (Gupta et al., 2009).

5.13 GANODERMA LUCIDUM Ganoderma lucidum (GL), is an edible mushroom, commonly known as “lingzhi,” that has a long history of use for promoting health and longevity in China, Japan, and other Asian countries. This mushroom is a rich source of a wide range of bioactive substances such as terpenoids, steroids, phenols, nucleotides and their derivatives, glycoproteins, and polysaccharides. Mushroom proteins contain all the essential amino acids and are especially rich in lysine and leucine. It has been reported that polysaccharides, peptidoglycans, and triterpenes are three major physiologically active constituents in G. lucidum. G. lucidum has been evaluated for anticancer activity in several cell lines and was found to induce cell cycle arrest and apoptosis. Through the regulation of expression of different signals, tumor cells were arrested by G. lucidum at different points of cell cycle. In one study G. lucidum extract induced G0/G1 phase arrest in estrogen-dependent breast MCF-7 cells through the downregulation of estrogen-α receptor and serine/threonine-specific protein kinase Akt/nuclear factor κB (NF-κB) signaling (Jiang et al., 2006). In another study, extract of G. lucidum administration led to decrease in the levels of COX-2 enzyme and enhanced NO synthesis (Hong et al., 2004). Further GL extract suppressed phosphorylation of ERK1/2 and Akt signaling, which downregulated their downstream NF-κB and proto-oncoprotein (c-Jun and c-Fos) activities, resulting in apoptosis. Several components of G. lucidum such as polysaccharides and triterpenoids demonstrated to have a potent antioxidant activity in in vitro studies (Lee et al., 2001; Mau et al., 2002). Other studies have reported the antibacterial activity of G. lucidum extract in animal models and observed the marked increase in the survival rates ( . 80% compared to 33% in controls) (Ohno et al., 1998). In another study, the antimicrobial effect of G. lucidum was examined by using its water extract

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against 15 species of bacteria alone and in combination with 4 kinds of other antibiotics. G. lucidum showed its protective efficacy and found to be more effective than antibiotics against Escherichia coli, Micrococcus luteus, Staphylococcus aureus, Bacillus cereus, Proteus vulgaris, and Salmonella typhi, but less effective against other species tested in experimental study (Yoon et al., 1994). Further, it has been observed that alcoholic extract of G. lucidum maintains cellular redox status of cells under hypoxic stress and effectively restores cellular viability at a concentration of 600 μg/mL. Alcoholic extract of G. lucidum reduced oxidative stress levels as measured by measuring reactive oxygen species, lipid peroxidation, and reduced glutathione-to-oxidized glutathione ratio, HIF-1α and its regulatory genes. Later on, certain phytoconstituents of G. lucidum extracts such as nucleobases and flavonoids were identified using high-performance thin-layer chromatography. Results indicated the significant quantity of both the phytoconstituents. Recent study has been carried out on G. lucidum spore powder (GLSP) which is a potential engross candidate. Antiepileptic effect of GLSP has been reported in both in vivo and in vitro model (Wang et al., 2014). A study by Wang et al. reported that GLSP may be an effective candidate for treating patients with epilepsy and reduced the weekly seizure frequency (Wang et al., 2018). A recent study by our institute observed the antioxidant activity of G. lucidum by preparing phenolic rich fractions (PRFs) from aqueous extract and were assessed by total phenolic content, total flavonoid content, ferric-reducing antioxidant power, and 2,2-azino-bis(3-ethylbenzothiazoline)-6sulfonic acid assays. Quantification of flavonoids and nucleobases present in the fractions was carried out by HPTLC and found to be the richest source of phytoconstituents. Further the nucleobases like adenine, cytosine, and uracil contribute significantly toward antifungal and antibacterial activities. With this, antibacterial activity of the fractions was evaluated against E. coli, S. typhi, and S. aureus. It was observed that pathogenic activity of bacteria significantly inhibited by PRFs. In addition, the protective effect of the PRFs of G. lucidum in counteracting hypoxia was observed in HEK 293 cell lines (Misra et al., 2018).

5.13.1 EMBLICA OFFICINALIS Fruits of Emblica officinalis (ES) (family Euphorbiaceae) commonly known as “amla” or the Indian gooseberry. It has numerous biological activities such as antioxidant, antibacterial, antifungal, antidiabetic, and hepatoprotective properties (Dhir et al., 1991; Jeena et al., 1999; Bhattacharya et al., 1999), apoptogenic (Rege et al., 1999) and anticancerous activities (Jose et al., 2001). Khandelwal et al. (2002) reported its cytoprotective activity analyzed by acute cadmium toxicity. Administration of ES extract resulted in an enhanced cell survival, decreased free radical production, and higher antioxidant levels. Recent in vitro studies have also demonstrated that fruit extract of amla relieves the immunosuppressive effects of chromium in rat lymphocytes (Sairam et al., 2002). Ganju et al. demonstrated that amla and shankhpushpi have a significant antiinflammatory activity in AIA rat model. They observed a significant reduction in swelling and redness of inflamed areas in treated animals as compared to the control untreated group. The dosing regimen used in these experiments covered the clinically relevant stage of the immune response. There was no toxicity, anorexia, or weight loss observed in any of the treated animals. The individual effects of both amla and shankhpushpi have antiarthritic properties in AIA as they selectively inhibited T-cell

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activation, which was clearly indicated by decreased lymphocyte proliferation. Further the observations indicate that NO production in amla and shankhpushpi treated animals was significantly lower as compared to controls, indicating that one of the possible mechanisms for curtailing the progression of AIA in animals might have been a decreased cellular production of NO by inhibiting NOS activity and the ability to counteract NO induced oxidative damage, which eventually helps in remodeling of cells (Ganju et al., 2003).

5.13.2 CORDYCEPS SINENSIS Cordyceps sinensis (CS) is an Ascomycete fungus and well documented in the Tibetan traditional medicine. It is a rich source of various bioactive compounds. Cordycepin (-30 -deoxyadenosine) and cordycepic acid (D-mannitol) are the most active components of CS. It also includes various constituents such as vitamins—mainly E, K, B1, B2, B12—carbohydrates, proteins, sterols, nucleosides, and essential elements. CS has a potential therapeutic efficacy in healing and with the least side effects. Apoptotic effect of CS was reported by Chun-Yi Jen and team in Taiwan using MA-10 cells (mouse Leydig tumor cell). They observed the apoptotic features of cell line with decrease in cell cycle G1 phase and G2 phase after subjecting the cell to the cordycepin of different doses. Further they have illustrated the apoptotic signaling pathway and observed the upregulation in the expressions of caspase 7, 3, and 9. Similarly, other evidences also suggest its potent role in human colorectal cancer cells with cordycepin using SW480 and SW620 cells in vitro. They concluded that apoptosis was induced by cordycepin in SW480 and SW620 cells by inhibiting cell proliferation. Further study by Wu et al. (2014) also demonstrated the cordycepin activity in gallbladder cancer cells in vitro. CS has a role in the treatment of memory impairment in AD. This was observed in F11 neurohybrid cells by studying the role of M1 muscarinic acetylcholine receptor (M1 mAChR). The results by Ji et al. suggested the stimulatory effect of CS in ERK phosphorylation leading to its protective effect in AD (Ji et al., 2009). Similar results were also confirmed in vivo using amnesia mice model suggesting the attenuation of memory impairment by the use of CS extract. Antiaging effect of CS extract was demonstrated in the D-galactose-induced aged mice. Its antiaging effects were characterized by oxidative stress, sexual dysfunction, memory impairment, and age-related enzymes. CS administration attenuated the aging-induced oxidative stress by significant reduction in the level of lipid peroxidation level and monoamine oxidase, improved learning and memory, and sexual response. SOD, GSH-px, and CAT activity suggested an affirmative effect on antiaging enzymes. CS administration resulted in drastic improvement in fasting blood glucose, glucose-tolerance test, polydipsia, and related hypoglycemic activity have been demonstrated in various diabetic animal models. Further, the combinational effect of CS with Tripterygium wilfordii polyglycosidium was observed in diabetic nephropathy rat model. They observed the significant improvement in glomerular disorder, tubulointerstitial damage, and glomerular podocyte. Another bioactive component of CS is a plant chemical, isoflavones belonging to phytoestrogen, extracted using ethyl acetate. It is used against ovariectomized rat to see its effect on estrogen deficiency osteoporosis. Isoflavones extracted from CS treatment enhanced the levels of osteocalcin and decreased calcium in urine and plasma. Further it also reduced the level of inorganic phosphate in plasma and collagen type I and interferon.

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Emerging evidences from the past revealed that CS has immune stimulation and energy boosting potential. CS enhances the physical performance and endurance of athletes and sports man. University of California, Los Angeles (UCLA) (Chen et al., 2010); their evaluation consisted of the measurement of metabolic threshold based on the accumulation of lactate which indicates improved aerobic activity in the particular subject and the other parameter was ventilatory threshold, increased in this factor downregulates the accumulation of lactate and further facilitates buffering of accumulated lactic acid. In the experiment, after 12 weeks of treatment with CS, metabolic threshold and ventilator threshold were observed to be increased by 10.5% and 8.5% respectively, ultimately leading to decrease in muscle fatigue and improved strength and exercise load. The effect of C. sinensis in enhancing hypoxic tolerance was studied using A549 cell line as a model system. The results demonstrated the efficacy of the aqueous extract of CS in amelioration of hypoxia-induced oxidative damage and induction of several adaptive genes such as antioxidant gene HO-1 (heme-oxygenase-1), MT (metallothionein), and Nrf2 (nuclear factor erythroid-derived 2-like 2). The extract also enhanced the expression of HIF1 (hypoxia-inducible factor-1) and its regulated genes; erythropoietin, vascular endothelial growth factor, and glucose transporter-1 was observed. Further a decrease in NFκB levels expression of proinflammatory cytokines like TNF-α was also observed and these changes contributed to the increase in hypoxic tolerance of CS (Singh et al., 2013).

5.14 CONCLUSION This series of studies highlight the translation of traditional ethnopharmacological wisdom with a scientific rationale for the development of products for acclimatization to high altitude. Herbs have a wide range of therapeutic effects, and through systematic scientific investigations using various animal models and clinical trials, our research has translated this knowledge into products for enhancing performance under stressful conditions.

REFERENCES Aggarwal, B.B., Kumar, A., Bharti, A.C., 2003. Anticancer potential of curcumin: preclinical and clinical studies. Anticancer Res. 23 (1A), 363
398. Agrawal, A., Rathor, R., Kumar, R., Suryakumar, G., Ganju, L., 2018. Role of altered proteostasis network in chronic hypobaric hypoxia induced skeletal muscle atrophy. PLoS ONE 13 (9), e0204283. Agrawal, A., Rathor, R., Suryakumar, G., 2017. Oxidative protein modification alters proteostasis under acute hypobaric hypoxia in skeletal muscles: a comprehensive in vivo study. Cell Stress Chaperones. 22 (3), 429
443. Arya, A., Sethy, N.K., Singh, S.K., Das, M., Bhargava, K., 2013. Cerium oxide nanoparticles protect rodent lungs from hypobaric hypoxia-induced oxidative stress and inflammation. Int. J. Nanomedicine. 8, 4507
4520. Asada, K., 1996. Radical production and scavenging in chloroplasts. Photosyn. Environ. 5, 123
150. Askew, E.W., 1997. Nutrition and performance in hot, cold, and high altitude environments. In: Wolinsky, I. (Ed.), Nutrition in Exercise and Sport, third ed. CRC Press, Boca Raton, FL, pp. 597
619.

160

CHAPTER 5 OPTIMIZING PERFORMANCE UNDER HIGH-ALTITUDE

Askew, E.W., 2002. Work at high altitude and oxidative stress: antioxidant nutrients. Toxicology 180 (2), 107
119. Baitharu, I., Jain, V., Deep, S.N., Shroff, S., Sahu, J.K., Naik, P.K., et al., 2014. Withanolide A prevents neurodegeneration by modulating hippocampal glutathione biosynthesis during hypoxia. PLoS One 9 (10), e105311. Bhattacharya, A., Chatterjee, A., Ghosal, S., Bhattacharya, S.K., 1999. Antioxidant activity of active tannoid principles of Emblica officinalis (Amla). Ind. J. Exp. Biol. 37, 676
680. Chandra, S., Low, P.S., 1995. Role of phosphorylation in elicitation of the oxidative burst in cultured soybean cells. Proc. Natl. Acad. Sci. U.S.A. 92, 4120
4123. Chaudhary, P., Suryakumar, G., Prasad, R., Singh, S.M., Ali, S., 2012a. Effect of acute hypobaric hypoxia on skeletal muscle protein turnover. Al Ameen J. Med. Sci. 5, 355
361. Chaudhary, P., Geetha, S., Prasad, R., Singh, S.N., Ali, S., 2012b. Chronic hypobaric hypoxia mediated skeletal muscle atrophy: role of ubiquitin
proteasome pathway and calpains. Mol. Cell. Biochem. 364, 101
113. Chaudhary, P., Sharma, Y.K., Sharma, S., Singh, S.N., Suryakumar, G., 2019. High altitude mediated skeletal muscle atrophy: protective role of curcumin. Biochimie 156, 138
147. Chen, S., Li, Z., Krochmal, R., Abrazado, M., Kim, W., et al., 2010. Effect of Cs-4 (Cordyceps sinensis) on exercise performance in healthy older subjects: a double-blind, placebo-controlled trial. J. Altern. Complement. Med. 16, 585
590. Cohly, H.H., Taylor, A., Angel, M.F., Salahudeen, A.K., 1998. Effect of turmeric, turmerin and curcumin on H2O2-induced renal epithelial (LLC-PK1) cell injury. Free Radic. Biol. Med. 24 (1), 49
54. Conkin, J., Wessel III, J.H., 2008. Critique of the equivalent air altitude model. Aviat. Space Environ. Med. 79, 975
982. Consolazio, C.F., Matoush, L.O., Johnson, H.L., Daws, I.A., 1968. Protein and water balances of young adults during prolonged exposure to high altitude (4300 m). Am. J. Clin. Nutr. 21, 154
161. D’Hulst, G., Deldicque, L., 2017. Human skeletal muscle wasting in hypoxia: a matter of hypoxic dose? J. Appl. Physiol. 122, 406
408. de Theije, C., Costes, F., Langen, R.C., Pison, C., Gosker, H.R., 2011. Hypoxia and muscle maintenance regulation: implications for chronic respiratory disease. Curr. Opin. Clin. Nutr. Metab. Care. 14, 548
553. Dhir, H., Roy, A.K., Sharma, A., Talukdar, G., 1991. Modification of clastogenicity of lead and aluminium in mouse bone marrow cells by Phyllanthus emblica fruit extract. Mutat. Res. 24, 305
312. Divekar, H.M., Radhey, S., Gupta, A.K., et al., 1996. Screening of adaptogenic activity of some laddakhi plants. DIPAS (Ministry of Defence, India) Report No. 1/96: Ministry of Defence (Indian Govt), New Delhi. Dosek, A., Ohno, H., Acs, Z., Taylor, A.W., Radak, Z., 2007. High altitude and oxidative stress. Respir. Physiol. Neurobiol. 158, 128
131. Dorai, T., Cao, Y.C., Dorai, B., Buttyan, R., Katz, A.E., 2001. Therapeutic potential of curcumin in human prostate cancer. III. Curcumin inhibits proliferation, induces apoptosis, and inhibits angiogenesis of LNCaP prostate cancer cells in vivo. Prostate 47 (4), 293
303. Dro¨ge, W., 2002. Free radicals in the physiological control of cell function. Physiol. Rev. 82 (1), 47
95. Eccleston, C., Baoru, Y., Tahvonen, R., Kallio, H., Rimbach, G.H., Minihane, A.M., 2002. Effect of an antioxidant rich juice (seabuckthorn) on risk factors for coronary heart disease in humans. J. Nutr. Biochem. 13, 346
354. Eltzschig, H.K., Carmeliet, P., 2011. Hypoxia and inflammation. New Engl. J. Med. 364, 656
665. Favier, F.B., Costes, F., Defour, A., Bonnefoy, R., Lefai, E., Baug´e, S., et al., 2010. Downregulation of Akt/ mammalian target of rapamycin pathway in skeletal muscle is associated with increased REDD1 expression in response to chronic hypoxia. Am. J. Physiol. Regul. Integr. Comp. Physiol. 298 (6), R1659
R1666. Ganju, L., Karan, D., Chanda, S., Srivastava, K.K., Sawhney, R.C., Selvamurthy, W., 2003. Immunomodulatory effects of agents of plant origin. Biomed. Pharmacother. 57, 296
300.

REFERENCES

161

Ganju, L., Padwad, Y., Singh, R., Karan, D., Chanda, S., Chopra, M.K., et al., 2005. Anti-inflammatory activity of seabuckthorn (Hippophae rhamnoides) leaves. Int. Immunopharmacol. 5, 1675
1684. Graver, S.K., Divekar, I.M., Kumar, R., Pahw, M.I., Bharadwaj, S.K., Gupta, A.K., et al., 1995. Experimental evaluation of a Composite Indian Herbal Preparation-I (CIHP-I) as an adaptogen and its mechanism of action. Int. J. Pharmacogn. 33, 148
154. Guan, T.T.Y., Cenkowski, S., Hydamaka, A., 2006. Effect of drying on the nutraceutical quality of sea buckthorn (Hippophae rhamnoides L. ssp. sinensis) leaves. J. Food. Sci. 70 (9), E514
E518. Gupta, A., Kumar, R., Upadhyay, N.K., Pal, K., Kumar, R., Sawhney, R.C., 2007. Effect of Rhodiola imbricata on dermal wound healing. Planta Lett. 11. Gupta, V., Lahiri, S.S., Sultana, S., Kumar, R., 2009. Mechanism of action of Rhodiola imbricata Edgew during exposure to cold, hypoxia and restraint (C
H
R) stress induced hypothermia and post stress recovery in rats. Food Chem. Toxicol. 47 (6), 1239
1245. Hackett, P.H., Roach, R.C., 2004. High altitude cerebral edema. High. Alt. Med. Biol. 5, 136
146. Hartmann, G., 2000. High altitude increases circulating interleukin-6, interleukin-1 receptor antagonist and Creactive protein. Cytokine 12, 246
252. Hayot, M., Rodriguez, J., Vernus, B., Carnac, G., Jean, E., Allen, D., et al., 2011. Myostatin up-regulation is associated with the skeletal muscle response to hypoxic stimuli. Mol. Cell. Endocrinol. 332 (1
2), 38
47. Hong, K.J., Dunn, D.M., Shen, C.L., Pence, B.C., 2004. Effects of Ganoderma lucidum on apoptotic and antiinflammatory function in HT-29 human colonic carcinoma cells. Phytother. Res. 18, 768
770. Hoppeler, H., Kleinert, E., Schlegel, C., Claassen, H., Howald, H., Kayar, S.R., et al., 1990. Muscular exercise at high altitude. II. Morphological adaptation of skeletal muscle to chronic hypoxia. Int. J. Sports Med. 11, S3
S9. Jain, K., Suryakumar, G., Prasad, R., Ganju, L., Singh, S.B., 2016. Enhanced hypoxic tolerance by Seabuckthorn is due to upregulation of HIF-1α and attenuation of ER stress. J. Appl. Biomed. 14 (1), 17
83. Jeena, K.J., Joy, K.L., Kuttan, R., 1999. Effect of Emblica offıcinalis, Phyllanthus amarus and Picrorhiza kurroa on N-nitrosodiethylamine induced hepatocarcinogenesis. Cancer Lett. 136, 11
16. Ji, D.B., Ye, J., Li, C.L., Wang, Y.H., Zhao, J., et al., 2009. Antiaging effect of Cordyceps sinensis extract. Phytother. Res. 23, 116
122. Jiang, J., Slivova, V., Sliva, D., 2006. Ganoderma lucidum inhibits proliferation of human breast cancer cells by down-regulation of estrogen receptor and NF-kappaB signaling. Int. J. Oncol. 29, 695
703. Jose, J.K., Kuttan, G., Kutan, R., 2001. Antitumor activity of Emblica officinalis. J. Ethanopharmacol. 75, 65
69. Kayser, B., Verges, S., 2013. Hypoxia, energy balance and obesity: from pathophysiological mechanisms to new treatment strategies. Obes. Rev. 14, 579
592. Kelm, M.A., Nair, M.G., Strasburg, G.M., DeWitt, D.L., 2000. Antioxidant and cyclooxygenase inhibitory phenolic compounds from Ocimum sanctum Linn. Phytomedicine 7, 7
13. Khandelwal, S., Shukla, L.J., Shanker, R., 2002. Modulation of acute Cadmium toxicity by Emblica officinalis fruit in rat. Ind. J. Exp. Biol. 40, 564
570. Khanum, F., Bawa, A.S., Singh, B., 2006. Rhodiola rosea: a versatile adaptogen. Compreh. Rev. Food Sci. Food Saf. 4 (3), 55
62. Kim, S.J., Hwang, E., Yi, S.S., Song, K.D., Lee, H.K., Heo, T.H., et al., 2017. Sea buckthorn leaf extract inhibits glioma cell growth by reducing reactive oxygen species and promoting apoptosis. Appl. Biochem. Biotechnol. 182 (4), 1663
1674. Kumar, R., Grover, S.K., Divekar, H.M., Gupta, A.K., Shyam, R., Srivastava, K.K., 1996. Enhanced thermogenesis in rats by Panax ginseng, multivitamins and minerals. Int. J. Biometeorol. 39 (4), 187
191. Kumar, I.P., Namita, S., Goel, H.C., 2002. Modulation of chromatin organization by RH-3, a preparation of Hippophae rhamnoides, a possible role in radioprotection. Mol. Cell. Biochem. 238, 1
9.

162

CHAPTER 5 OPTIMIZING PERFORMANCE UNDER HIGH-ALTITUDE

Lamb, C.J., Lawton, M.A., Dron, M., Dixon, R.A., 1989. Signals and transduction mechanisms for activation of plant defenses against microbial attack, Cell., 56. pp. 215
224. Lee, J.M., Kwon, H., Jeong, H., et al., 2001. Inhibition of lipid peroxidation and oxidative DNA damage by Ganoderma lucidum. Phytother Res. 15, 245
249. Lewis, P., Sheehan, D., Soares, R., Coelho, A.V., O’Halloran, K.D., 2016. Redox remodelling is pivotal in murine diaphragm muscle adaptation to chronic sustained hypoxia. Am. J. Respir. Cell Mol. Biol. 55, 12
23. Li, Q., Ren, F., Yang, C., Zhou, L., Liu, Y., Xiao, J., et al., 2015. Anti-proliferation effects of isorhamnetin on lung cancer cells in vitro and in vivo. Asian Pac. J. Cancer Prev. 16, 3035
3042. Liu, C.X., Xiaob, P.G., 1992. Recent advances on ginseng research in China. J. Ethnopharmacol. 36 (1), 27
38. Macdonald, J.H., Oliver, S.J., Hillyer, K., Sanders, S., Smith, Z., Williams, C., et al., 2009. Body composition at high altitude: a randomized placebo-controlled trial of dietary carbohydrate supplementation. Am. J. Clin. Nutr. 90, 1193
1202. MacDougall, J.D., Green, H.J., Coates, G., Cymerman, A., Young, P., Houston, C.S., 1991. Operation Everest II: structural adaptations in skeletal muscle in response to extreme simulated altitude. Acta Physiol. Scand. 142, 421
427. Magalhaes, J., Ascensao, A., Viscor, G., Soares, J., Oliveira, J., Marques, F., et al., 2004. Oxidative stress in humans during and after 4 hours of hypoxia at a simulated altitude of 5500 m. Aviat. Space Environ. Med. 75, 16
22. Mahadevan, S., Park, Y., 2008. Multifaceted therapeutic benefits of Ginkgo biloba L.: chemistry, efficacy, safety, and uses. J. Food. Sci. 73 (1), R14
R19. Mani, H., Sidhu, G., Kumari, R., Gaddipati, J., Seth, P., Maheshwari, R., 2002. Curcumin differentially regulates TGF-beta1, its receptors and nitric oxide synthase during impaired woundhealing. Biofactors 16, 29. Mathew, T., Sarada, S.K.S., 2018. Intonation of Nrf2 and Hif1-α pathway by curcumin prophylaxis: a potential strategy to augment survival signaling under hypoxia. Respir. Physiol. Neurobiol. 258, 12
24. Mau, J.L., Lin, H.C., Chen, C.C., 2002. Antioxidant properties of several medicinal mushrooms. J. Agric. Food. Chem. 50, 6072
6077. Mishra, K.P., Padwad, Y.S., Jain, M., Karan, D., Ganju, L., Sawhney, R.C., 2008. Aqueous extract of Rhodiola imbricata rhizome stimulates proinflammatory mediators via phosphorylated IkappaB and transcription factor nuclear factor-kappaB. Immunopharmacol. Immunotoxicol. 28 (2), 201
212. Mishra, K.P., Mishra, R., Yadav, A.P., Jayashankar, B., Chanda, S., Ganju, L., 2011. A comparative analysis of immunomodulatory potential of seabuckthorn leaf extract in young and old mice. Biomed. Aging Pathol. 1 (1), 61
64. Mishra, K.P., Ganju, L., Singh, S.B., 2012. Anti-cellular and immunomodulatory potential of aqueous extract of Rhodiola imbricata rhizome. Immunopharmacol. Immunotoxicol. 34 (3), 513
518. Misra, J., Joshi, A., Rajput, R., Singh, K., Bansal, A., Misra, K., 2018. Phenolic rich fractions from mycelium and fruiting body of Ganoderma lucidum inhibit bacterial pathogens mediated by generation of reactive oxygen species and protein leakage and modulate hypoxic stress in HEK 293 cell line. Adv. Pharmacol. Sci. 2018, 6285615. Miyata, T., Takizawa, S., van Ypersele de Strihou, C., 2011. Hypoxia. 1. Intracellular sensors for oxygen and oxidative stress: novel therapeutic targets. Am. J. Physiol. Cell Physiol. 300, C226
C231. Mohandas, K.M., Desai, D.C., 1999. Epidemiology of digestive tract cancers in India. V. Large and small bowel. Indian J. Gastroenterol. 18 (3), 118
121. Mohanta, T.K., Tamboli, Y., Zubaidha, P.K., 2014. Phytochemical and medicinal importance of Ginkgo biloba L. Nat. Prod. Res. 28 (10), 746
752.

REFERENCES

163

Mrakic-Sposta, S., Gussoni, M., Montorsi, M., Porcelli, S., Vezzoli, A., 2014. A quantitative method to monitor reactive oxygen species production by electron paramagnetic resonance in physiological and pathological conditions. Oxid. Med. Cell. Longev. Article ID 306179, 10 pp. Mrakic-Sposta, S., Gussoni, M., Moretti, S., Pratali, L., Giardini, G., Tacchini, P., et al., 2015. Effects of mountain ultra-marathon running on ROS production and oxidative damage by micro-invasive analytic techniques. PLoS One 10 (11), e0141780. Murray, A.J., 2009. Metabolic adaptation of skeletal muscle to high altitude hypoxia: how new technologies could resolve the controversies. Genome Med. 1, 117. Muthuraju, S., Pati, S., 2014. Effect of hypobaric hypoxia on cognitive functions and potential therapeutic agents. Malays. J. Med. Sci. 21, 41
45. Muthuraju, S., Maiti, P., Pati, S., Solanki, P., Sharma, A.K., Singh, S.B., et al., 2011. Role of cholinergic markers on memory function of rats exposed to hypobaric hypoxia. Eur. J. Pharmacol. 672 (1
3), 96
105. Nadkarni, K.M., 1976. Curcuma longa. In: Nadkarni, K.M. (Ed.), Indian Materia Medica. Popular Prakashan Publishing Company, Bombay, pp. 414
416. Narayanan, S., Ruma, D., Gitika, B., Sharma, S.K., Pauline, T., Sai Ram, M., et al., 2005. Antioxidant activities of seabuckthorn (Hippophae rhamnoides) during hypoxia induced oxidative stress in glial cells. Mol. Cell. Biochem. 278, 9
14. Nover, L., Scharf, K.D., Neumann, D., 1989. Cytoplasmic heat shock granules are formed from precursor particles and are associated with a specific set of mRNAs. Mol. Cell. Biol. 9, 1298
1308. Ohno, N., Miura, N.N., Sugawara, N., Tokunaka, K., Kirigaya, N., Yadomae, T., 1998. Immunomodulation by hot water and ethanol extracts of Ganoderma lucidum. Pharm. Pharmacol. Lett. 4, 174
177. Olas, B., Skalski, B., Ulanowska, K., 2018. The anticancer activity of sea buckthorn [Elaeagnus rhamnoides (L.) A. Nelson]. Front. Pharmacol. 9, 232. Padmavathi, B., Upreti, M., Singh, V., Rao, A.R., Singh, R.P., Rath, P.C., 2005. Chemoprevention by Hippophae rhamnoides: effects on tumorigenesis, phase II and antioxidant enzymes, and IRF-1 transcription factor. Nutr. Cancer 51, 59
67. Paralikar, S.J., 2012. High altitude pulmonary edema-clinical features, pathophysiology, prevention and treatment. Ind. J. Occup. Environ. Med. 16, 59
62. Pattanayak, P., Behera, P., Das, D., Panda, S.K., 2010. Ocimum sanctum Linn. A reservoir plant for therapeutic applications: an overview. Pharmacogn. Rev. 4 (7), 95
105. Peters, H., Kieser, M., Ho¨lscher, U., 1998. Demonstration of the efficacy of Ginkgo biloba special extract EGb 761 on intermittent claudication—a placebo-controlled, double-blind multicenter trial. Vasa. 27 (2), 106
110. Prakash, H., Bala, M., Ali, A., Goel, H.C., 2005. Modification of gamma radiation induced response of peritoneal macrophages and splenocytes by Hippophae rhamnoides (RH-3) in mice. J. Pharm. Pharmacol. 57, 1065
1072. Preedy, V.R., Smith, D.M., Sugden, P.H., 1985. The effects of 6 hr hypoxia on protein synthesis in rat tissue in-vivo & in vitro. Biochem. J. 228, 179
185. Purushothaman, J., Suryakumar, G., Shukla, D., Jayamurthi, H., Kasiganesan, H., Kumar, R., et al., 2011. Modulation of hypoxia-induced pulmonary vascular leakage in rats by seabuckthorn (Hippophae rhamnoides L.). Article ID 574524, 13 pp. Radak, Z., Asano, K., Inoue, M., Kizaki, T., Oh-Ishi, S., Suzuki, K., et al., 1995. Superoxide dismutase derivative reduces oxidative damage in skeletal muscle of rats during exhaustive exercise. Journal of Applied Physiology 79129
79135. Radak, Z., Asano, K., Lee, K.C., Ohno, H., Nakamura, A., Nakamoto, H., et al., 1997. High altitude training increases reactive carbonyl derivatives but not lipid peroxidation in skeletal muscle of rats. Free Radical Biol. Med. 22, 1109
1114.

164

CHAPTER 5 OPTIMIZING PERFORMANCE UNDER HIGH-ALTITUDE

Radak, Z., Sasvari, M., Nyakas, C., Kaneko, T., Tahara, S., Ohno, H., et al., 2001. Single bout of exercise eliminates the immobilization-induced oxidative stress in rat brain. Neurochem. Int. 39, 33
38. Raj, J.P., D’Cruz, J.M., Toms, T., Muralidharan, P., Rao, M., 2018. Physical endurance enhancing capacity of Withania somnifera root powder post-water extraction in mice. Pharmacog. Res. 10 (3). Rajabian, A., Rameshrad, M., Hosseinzadeh, H., 2018. Therapeutic potential of Panax ginseng and its constituents, ginsenosides and gintonin, in neurological and neurodegenerative disorders: a patent review. Expert. Opin. Ther. Pat. 29 (1), 55
72. Ramachandran, U., Divekar, H.M., Grover, S.K., Srivastava, K., 1990. New experimental model for the evaluation of adaptogenic products. J. Ethanopharmacol. 29, 275
281. Ramassamy, C., Christen, Y., Clostre, F., Costentin, J., 1992. The Ginkgo biloba extract, EGb761, increases synaptosomal uptake of 5-hydroxytryptamine: in-vitro and ex-vivo studies. J. Pharm. Pharmacol. 44, 943. Rathor, R., Suryakumar, G., 2016. Muscle atrophy at high altitude. J. Clin. Mol. Endocrinol. 1, 18. Rathor, R., Sharma, P., Suryakumar, G., Ganju, L., 2015. A pharmacological investigation of Hippophae salicifolia (HS) and Hippophae rhamnoides turkestanica (HRT) against multiple stress (C-H-R): an experimental study using rat model. Cell Stress Chaperones. 20 (5), 821
831. Ray, K., Dutta, A., Panjwani, U., Thakur, L., Anand, J.P., Kumar, S., 2011. Hypobaric hypoxia modulates brain biogenic amines and disturbs sleep architecture. Neurochem. Int. 58 (1), 112
118. Rege, N.N., Thatte, U.M., Dahanukar, S.A., 1999. Adaptogenic properties of six rasayana herbs used in Ayurvedic medicine. Phytother. Res. 13, 275
291. Richard, E.J., Illuri, R., Bethapudi, B., Kumar, A.S., Bhaskar, A., Chandrasekaran, C.V., 2016. Anti-stress activity of Ocimum sanctum: possible effects on hypothalamic-pituitary-adrenal axis. Phytother. Res. 30 (5). Roach, R.C., Hackett, P.H., Oelz, O., Ba¨rtsch, P., Luks, A.M., MacInnis, M.J., et al., 2018. The 2018 Lake Louise acute mountain sickness score. High. Alt. Med. Biol. 19, 1
4. Rose, M.S., Houston, C.S., Fulco, C.S., Coates, G., Sutton, J.R., Cymerman, A., 1985. Operation Everest. II: nutrition and body composition. J. Appl. Physiol. 65 (6), 2545
2551. Saggu, S., Kumar, R., 2007. Possible mechanism of adaptogenic activity of seabuckthorn (Hippophae rhamnoides) during exposure to cold, hypoxia and restraint (C
H
R) stress induced hypothermia and post stress recovery in rats. Food Chem. Toxicol. 45 (12), 2426
2433. Sagi, S., Patir, H., Mishra, C., Pradhan, G., Mastoori, S.R., Ilavazhagan, G., 2008. Role of oxidative stress and NFkB in hypoxia-induced pulmonary edema. Exp. Biol. Med. 233, 1088. SaiRam, M., Neetu, D., Yogesh, B., Anju, B., Dipti, P., Pauline, T., et al., 2002. Cyto-protective and immunomodulatory properties of amla (Emblica officinalis) on lymphocytes: an in-vitro study. J. Ethanopharmacol. 81, 5
10. Sarada, S.K.S., Titto, M., Himadri, P., Saumya, S., Vijayalakshmi, V., 2015. Curcumin prophylaxis mitigates the incidence of hypobaric hypoxia-induced altered ion channels expression and impaired tight junction proteins integrity in rat brain. J. Neuroinflammation. 12, 113. Sidhu, G.S., Singh, A.K., Thaloor, D., Banaudha, K.K., Patnaik, G.K., Srimal, R.C., et al., 1998. Enhancement of wound healing by curcumin in animals. Wound Repair Regen. 6 (2), 167
177. Simler, N., Grosfeld, A., Peinnequin, A., Guerre-Millo, M., Bigard, A.X., 2006. Leptin receptor-deficient obese Zucker rats reduce their food intake in response to hypobaric hypoxia. Am. J. Physiol. Endocrinol. Metab. 290 (3), E591
E597. Singh, N., Nath, R., Lata, A., Singh, S.P., Kohli, R.P., Bhargava, K.P., 1982. Withania somnifera (Ashwagandha), a rejuvenating herbal drug which enhances survival during stress (an adaptogen). Int. J. Crude Drug Res. 20, 29
35. Singh, N., Nath, N., Misra, N., Kohli, R.P., 1978. An experimental evaluation of anti stress effects of Gariforti (an Ayurvedic drug). J. Crude Drug Res. 16, 125
136.

REFERENCES

165

Singh, M., Tulsawani, R., Koganti, P., Chauhan, A., Manickam, M., Misra, K., 2013. Cordyceps sinensis increases hypoxia tolerance by inducing heme oxygenase-1 and metallothionein via Nrf2 activation in human lung epithelial cells. Biomed. Res. Int. 2013, 569206. Sinha, S., Singh, S.N., Ray, U.S., 2009. Total antioxidant status at high altitude in lowlanders and native highlanders: role at uric acid. High altitude Med. Biol. 10, 269
274. Sinha, S., Dutta, A., Singh, S.N., Ray, U.S., 2010. Protein nitration lipid peroxidation and DNA damage at high altitude in acclimatized lowlanders and native highlanders: relation with oxygen consumption. Res. Physiol. Neurobiol. 171, 115
129. Sreejayan, Rao, M.N.A., 1994. Curcuminoids as potent inhibitors of lipid peroxidation. J. Pharm. Pharmacol. 46, 1013
1016. Sreejayan, Rao, M.N.A., 1997. Nitric oxide scavenging by curcuminoids. J. Pharm. Pharmacol. 49 (1), 105
107. Subramanian, M., Chintalwar, G.J., Chattopadhyay, S., 2005. Antioxidant and radioprotective properties of an Ocimum sanctum polysaccharide. Redox. Rep. 10, 257
264. Suryakumar, G., Gupta, A., 2011. Medicinal and therapeutic potential of Sea buckthorn (Hippophae rhamnoides L.). J. Ethnopharmacol. 138, 268
278. Teng, B., Lu, Y., Wang, Z., Tao, X., Wei, D., 2006. In vitro anti-tumor activity of isorhamnetin isolated from Hippophae rhamnoides L. against BEL-7402 cells. Pharm. Res. 54, 186
194. Trachootham, D., Lu, W., Ogasawara, M.A., Nilsa, R.D., Huang, P., 2008. Redox regulation of cell survival. Antioxid. Redox. Signal. 10 (8), 1343
1374. Ude, C., Schubert-Zsilavecz, M., Wurglics, M., 2013. Ginkgo biloba extracts: a review of the pharmacokinetics of the active ingredients. Clin. Pharmacokinet. 52, 727. Uma Devi, P., Ganasoundari, A., Vrinda, B., Srinivasan, K.K., Unnikrishnan, M.K., 2000. Radiation protection by the Ocimum flavonoids orientin and vicenin: mechanisms of action. Radiat. Res. 154, 455
460. Unnikrishnan, M.K., Rao, M.N.A., 1995. Curcumin inhibits nitrogen dioxide induced oxidation of hemoglobin. Mol. Cell. Biochem. 146, 35
37. Upadhyay, N.K., Kumar, R., Mandotra, S.K., Meena, R.N., Siddiqui, M.S., Sawhney, R.C., et al., 2009. Safety and healing efficacy of sea buckthorn (Hippophae rhamnoides L.) seed oil on burn wounds in rats. Food. Chem. Toxicol. 47 (6), 1146
1153. van Hall, G., 2012. Cytokines: muscle protein and amino acid metabolism. Curr. Opin. Clin. Nutr. Metab. Care. 15, 85
91. Vats, P., Mukherjee, A.K., Kumria, M.M., Singh, S.N., Patil, S.K., Rangnathan, S., et al., 1999. Changes in activity levels of glutamine synthetase, glutaminase and glycogen synthetase in rats subjected to hypoxic stress. Int. J. Biometeorol. 42, 205
209. Wang, S.Q., Li, X.J., Qiu, H.B., Jiang, Z.M., Simon, M., Ma, X.R., 2014. Anti-epileptic effect of Ganoderma lucidum polysaccharides by inhibition of intracellular calcium accumulation and stimulation of expression of CaMKII α in epileptic hippocampal neurons. PLoS One 9 (7), e102161. Wang, H., Gao, T., Du, Y., Yang, H., Wei, L., Bi, H., et al., 2015. Anticancer and immunostimulating activities of a novel homogalacturonan from Hippophae rhamnoides L. berry. Carbohydr. Polym. 131, 288
296. Wang, G.H., Li, X., Cao, W.H., Li, J., Wang, L.H., 2018. A retrospective study of Ganoderma lucidum spore powder for patients with epilepsy. Medicine (Baltimore) 97 (23), e10941. Wing-Gaia, S.L., 2014. Nutritional strategies for the preservation of fat free mass at high altitude. Nutrients 6, 665
681. Wu, W.D., Hu, Z.M., Shang, M.J., Zhao, D.J., Zhang, C.W., et al., 2014. Cordycepin down-regulates multiple drug resistant (MDR)/HIF-1alpha through regulating AMPK/mTORC1 signaling in GBC SD gallbladder cancer cells. Int. J. Mol. Sci. 15, 12778
12790. Yoon, S.Y., Eo, S.K., Kim, Y.S., Lee, C.K., Han, S.S., 1994. Antimicrobial activity of Ganoderma lucidum extract alone and in combination with some antibiotics. Arch. Pharm. Res. 17, 438
442.

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CHAPTER 5 OPTIMIZING PERFORMANCE UNDER HIGH-ALTITUDE

Zeb, A., 2006. Anticarcinogenic potential of lipids from hippophae—evidence from the recent literature. Asian Pac. J. Cancer Prev. 7, 32
34. Zhang, P., Mao, Y.C., Sun, B., Qian, M., Qu, W.J., 2005. Changes in apoptosis-related genes expression profile in human breast carcinoma cell line Bcap-37 induced by flavonoids from seed residues of Hippophae rhamnoides L. Ai Zheng 24, 454
460. Zhang, H.F., Huang, L.B., Zhong, Y.B., Zhou, Q.H., Wang, H.L., Zheng, Q.Q., et al., 2016. An overview of systematic reviews of Ginkgo biloba extracts for mild cognitive impairment and dementia. Front. Aging Neurosci. 8, 276.

FURTHER READING Akanksha, A., Rathor, R., Kumar, R., Suryakumar, G., Ganju, L., 2018. Role of altered proteostasis network in chronic hypobaric hypoxia induced skeletal muscle atrophy. PLoS One 13 (9), e0204283. Bharadwaj, H., Prasad, J., Pramanik, S.N., Kishnani, S., Zachariah, T., Chaudhary, K.L., et al., 2000. Effect of prolonged exposure to high altitude on skeletal muscles of Indian soldiers. Def. Sci. J. 50, 167
176. Brouns, F., 1992. Nutritional aspects of health and performance at lowland and altitude. Int. J. Sports Med. 13, S100
S106. Calbet, J.A., Robach, P., Lundby, C., 2009. The exercising heart at altitude. Cell. Mol. Life Sci. 66, 3601
3613. Edwards, L.M., Murray, A.J., Tyler, D.J., Kemp, G.J., Holloway, C.J., et al., 2010. The effect of high-altitude on human skeletal muscle energetics: P-MRS results from the Caudwell Xtreme Everest expedition. PLoS One 5, e10681. Mathieu-Costello, O., 2001. Muscle adaptation to altitude: tissue capillarity and capacity for aerobic metabolism. High. Alt. Med. Biol. 2, 413
425. Rongsen, A., 1992. Sea buckthorn a multipurpose plant for fragile mountains. ICIMOD occasional paper No. 20, Kathmandu, Nepal, pp. 6
7, 18
20. Schols, A.M., 2002. Pulmonary cachexia. Int. J. Cardiol. 85, 101
110. Suomela, J.P., Ahotupa, M., Yang, B., Vasankari, T., Kallio, H., 2006. Absorption of flavonols derived from sea buckthorn (Hippophae¨ rhamnoides L.) and their effect on emerging risk factors for cardiovascular disease in humans. J. Agric. Food. Chem. 54 (19), 7364
7369. Ting, H.C., Hsu, Y.W., Tsai, C.F., Lu, F.J., Chou, M.C., Chen, W.K., 2011. The in vitro and in vivo antioxidant properties of seabuckthorn (Hippophae rhamnoides L.) seed oil. Food. Chem. 125, 652
659. Weng, C.J., Chau, C.F., Yen, G.C., Liao, J.W., Chen, D.H., Chen, K.D., 2009. Inhibitory effects of Ganoderma lucidum on tumorigenesis and metastasis of human hepatoma cells in cells and animal models. J. Agric. Food. Chem. 57, 5049
5057.

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NUTRACEUTICALS AND METABOLIC SYNDROME

6

Jacob A. Walker, Benjamin M. Dorsey and Marjorie A. Jones Department of Chemistry, Illinois State University, Normal, IL, United States

CHAPTER OUTLINE 6.1 6.2 6.3 6.4 6.5 6.6 6.7 6.8 6.9 6.10 6.11

What Are Nutraceuticals and How Do They Differ From Supplements? ........................................... 168 Metabolic Syndrome Defined ...................................................................................................... 168 Diagnostic Criteria ..................................................................................................................... 170 Obesity and Hyperlipidemia ........................................................................................................ 170 Lipoproteins, Cholesterol, and Atherosclerosis............................................................................. 172 Hyperglycemia ........................................................................................................................... 173 Hypertension (High Blood Pressure) ............................................................................................ 173 C-Reactive Protein ..................................................................................................................... 173 Insulin-Like Growth Factor-1 ....................................................................................................... 174 Reactive Oxygen Species and General Ways to Detoxify Them ...................................................... 174 Therapy/Treatment After Diagnosis of Metabolic Syndrome ........................................................... 177 6.11.1 Obesity and Hyperlipidemia Therapy/Treatment ....................................................... 177 6.11.2 Cholesterol Therapy/Treatment............................................................................... 177 6.11.3 Hyperglycemia and Diabetes Therapy/Treatment...................................................... 178 6.11.4 C-Reactive Protein Therapy/Treatment .................................................................... 178 6.11.5 Insulin-Like Growth Factor-1 Therapy/Treatment...................................................... 178 6.11.6 Hypertension........................................................................................................ 179 6.12 Role(s) of Nutraceuticals............................................................................................................ 179 6.12.1 An Overview of Uses of Nutraceuticals in the Treatment of Metabolic Syndrome ........ 179 6.12.2 Traditional Chinese Medicine in the Treatment of Metabolic Syndrome...................... 179 6.12.3 Various Nutraceuticals Sold to and Used by the Public With or Without Consultation With Their Physicians ........................................................................ 181 6.12.4 Excipients Used in Nutraceuticals.......................................................................... 183 6.13 Side Effects of Nutraceuticals..................................................................................................... 185 6.14 Final Thoughts on the Future of Nutraceuticals ............................................................................ 185 References ......................................................................................................................................... 187 Further Reading .................................................................................................................................. 195



Corresponding author.

Nutraceuticals and Natural Product Pharmaceuticals. DOI: https://doi.org/10.1016/B978-0-12-816450-1.00006-4 © 2019 Elsevier Inc. All rights reserved.

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6.1 WHAT ARE NUTRACEUTICALS AND HOW DO THEY DIFFER FROM SUPPLEMENTS? The term nutraceuticals (the combination of two words
nutrient and pharmaceutical) is a moderately agreed upon term that was coined in 1989 by L. Stephen DeFelice (Radhika et al., 2011). This is a broad umbrella term used to describe products derived from food sources (both plant and animal) and has implications for extra health benefits (DeFelice, 1995). The area of nutraceuticals/ functional foods/dietary supplements has been reviewed by multiple authors (Cencic and Chingwaru, 2010; Radhika et al., 2011) in terms of what these are and how they differ from one another. In addition, the classification and regulation of these various terms is of interest as reviewed by Singh and Sinha (2012) and Santini et al. (2018).

6.2 METABOLIC SYNDROME DEFINED As early as 1923, concerns about patients with more than one identifiable factor, such as having high blood glucose, gout, and high blood pressure, led the medical community to begin to identify what we now call metabolic syndrome (Kylin, 1923). Metabolic syndrome was first named as “syndrome x” and had the central features of development of cardiovascular atherosclerotic diseases, insulin resistance, and diabetes mellitus type-2 (Reaven, 1988). However, this syndrome was soon expanded by several international organizations such as the World Health Organization, the European Group for the Study of Insulin Resistance, the American Association of Clinical Endocrinology, the American Heart Association, and others to incorporate a cluster of interconnected factors (Kassi et al., 2011). A brief history of definitions for metabolic syndrome was presented by Aguirre et al. (2016). Metabolic syndrome is unique because it is not a strictly defined disease with a well-defined pathology. Instead, metabolic syndrome is now recognized as a cluster of risk factors that, when coupled together, greatly increases the patients’ risk of heart disease, stroke, and diabetes (Metabolic Syndrome, 2018). These risk factors include high blood pressure, high blood sugar, excess body fat around the waist (visceral obesity), and hyperlipidemia due to high cholesterol and high triglycerides. Recently the high sensitivity C-reactive protein (hs-CRP) level has also been added to the criteria by some researchers (Ridker et al., 2004; Gowdaiah et al., 2016). In addition, other abnormalities such as sleep apnea, nonalcoholic liver disease, and chronic low-grade inflammation have been considered so that the syndrome is now clinically even more complex (Kassi et al., 2011; Armstrong, 2006). Aguirre et al. (2016) also argued that insulin-like growth factor-1 (IGF-1) deficiency, with its important roles in regulation of lipids and carbohydrate metabolism, should be considered as an additional risk factor. Each of these risk factors has its own clinical diagnosis and having one risk factor does not mean the patient has metabolic syndrome. Having three or more of these factors is generally accepted as “at severe risk” for developing cardiovascular disease (Kaur, 2014; Srikanthan et al., 2016). Srikanthan et al. (2016) recently reviewed the use of these previously mentioned biomarkers to diagnose and manage metabolic syndrome. An additional consideration is that metabolic syndrome appears to be a progressive syndrome that, if unrecognized and untreated, becomes increasingly fatal. Grundy (2006b) indicated that borderline risk factors progress to categorical risk factors. In addition, metabolic syndrome has been diagnosed

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169

in both children and adults (Kassi et al., 2011). Genetic factors are also being evaluated for roles in metabolic syndrome. Ziki and Mani (2017) have reviewed these contributions and estimate that the heritability for each of the potential contributors to metabolic syndrome exceeds 50%. However, only a few genes have so far been discovered that indicate an association of diverse traits with metabolic syndrome. For example, mutations in the genes for the hormone leptin and its receptor are associated with obesity and insulin resistance. Claussnitzer et al. (2015) reported that the FTO gene (fat mass and obesity-associated gene) mediates the obesity phenotype. In the United States, the estimated number of adults that meet the criteria for metabolic syndrome is more than one-third of the population (Moore et al., 2017). Although metabolic syndrome likely started in the Western world, it is now spreading globally with the Western lifestyle (Saklayen, 2018). The International Diabetes Federation estimates that about 25% of the world’s population have metabolic syndrome (Nolan et al., 2017). However, the estimates vary widely related to the country, the age group evaluated, as well as ethnicity and gender of the population studied. Nolan et al. (2017) estimated that 5%
7% of young adults worldwide and one-third of all adults have at least one risk factor for metabolic syndrome. Such estimates clearly lead to concern about the lifetime burden of this syndrome in terms of economic costs and quality of life. Current global estimates of costs of healthcare and loss of economic activity are in the trillions of dollars (Saklayen, 2018). Fig. 6.1 is a visual presentation of some of the various potential contributors to metabolic syndrome:

Viseral obesity

C-reactive protein

Hyperglycermia

Metabolic syndrome Insulin resistance and insulin-like growth factor-1

Hyperlipidemia

Hypertension

FIGURE 6.1 Potential contributors to metabolic syndrome.

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6.3 DIAGNOSTIC CRITERIA Having only a single risk factor does not mean the person will be diagnosed with metabolic syndrome; however, this factor can be an indicator for increased risk or possibility of acquiring more risk factors. Some of the diagnostic criteria include large waist circumference (greater than 40 in. males/ and 35 in. females), high serum cholesterol (greater than 190 mg/dL), high serum triglycerides (greater than 150 mg/dL), reduced high-density lipoprotein (HDL; less than 40 mg/dL for men and 50 mg/dL for women), high blood pressure (greater than 130/85 mmHg), and fasting high blood sugar greater than 100 mg/dL (Gan et al., 2006; Nordestgaard et al., 2016; Kassi et al., 2011). Levels of hs-CRP greater than 3 mg/L are also being used in the diagnosis of metabolic syndrome (Gowdaiah et al., 2016). In addition, Aguirre et al. (2016) have reviewed multiple studies, both in vivo and in vitro, indicating that insulin-like growth factor-1 (IGF-1) is a key hormone in the pathophysiology of metabolic syndrome and that its role has thus far been undervalued. Difficulty in diagnosis of metabolic syndrome is complicated by the set of criteria applied in the diagnosis and, as of yet, this is not agreed upon worldwide. The joint interim statement (consensus definition) for the criteria of metabolic syndrome in adults indicated that there should be no single obligatory component but rather all individual components of metabolic syndrome should be considered in risk analysis and thus treatments (Kassi et al., 2011).

6.4 OBESITY AND HYPERLIPIDEMIA Obesity is generally defined as abnormal or excessive body fat accumulation (World Health Organization 2018). This is generally evaluated using body mass index (BMI), which is a ratio of weight (in kilograms) to the square of height in meters thus units of BMI are kg/m2. Adults with BMI values greater than 30 kg/m2 are considered obese (Seidell, 2000). Factors that contribute to obesity are both genetic and lifestyle (Saklayen, 2018; World Health Organization, 2018; Nolan et al., 2017). It is estimated that in the United States that over two-thirds of US adults are either overweight or obese (Yang and Colditz, 2015) and worldwide, in 2016, 1.9 billion adults were considered overweight with over 650 million considered to be obese. The prevalence of obesity was reported to have nearly tripled from 1975 to 2016 (World Health Organization, 2018). The prevalence of overweight and obese adults is not uniformly distributed globally (James et al., 2001). One of the most visibly noticeable risk factors that indicates the development of metabolic syndrome is a large waistline (Metabolic Syndrome, 2014). Another term for this is abdominal (visceral) obesity, and this is characterized by excess deposition of adipose tissue around the stomach and waist regions of the body (Ginsberg and MacCallum, 2009). Excess fat in the midsection of the body is particularly unhealthy due to its increased risk for contributing to heart disease compared to fat deposition in other parts of the body. The deposition of fat in the body is directly related to triglyceride levels in the bloodstream and is correlated with a high lipid diet among other factors such as sedentary lifestyle, alcohol consumption, and eating habits. Since large waist circumference (related to increases in visceral fat) is characteristic of metabolic syndrome, a better understanding of the adipose tissues (composed mainly of adipocytes also called fat cells) is important. Other cell types are also found in adipose tissue such as stem cells,

6.4 OBESITY AND HYPERLIPIDEMIA

Resistin 2001 Lipocalin-2 2007

ADAMTS1 and Chemerin 1997

Isthmin-2 2014 Asprosin 2016 Slit2-2 2016

171

Lipocalin5 2018

Fat cells (adipocytes)

Leptin 1994 Adiponectin 1995

FIGURE 6.2 Some of the hormones produced by fat cells (adipose tissue) and year they were discovered.

preadipocytes, macrophages, neutrophils, lymphocytes, and endothelial cells (Esteve, 2014). Until 1994, fat cells were generally considered as only storage cells for lipids. However, Zhang et al. (1994) using massively obese mutant mice, reported that a protein (subsequently called leptin) was missing in these mice. The protein is now understood to be a product of the ob gene and is part of a signaling pathway from adipocytes that functions to regulate the size of the fat stores. The discovery of this leptin protein has led to the discovery of other adipocyte hormones (shown in Fig. 6.2) which have potent roles. Such roles include regulating of appetite (leptin), increasing insulin sensitivity and reducing inflammation (adiponectin), controlling fat stem cell differentiation (ADAMTS1), increasing inflammation (chemerin, lipocalin-2), affecting blood pressure (chemerin which is a vasoconstrictor), mediating insulin resistance (resistin, retinol-binding protein 4, and lipocalin-2), improving fat metabolism in the liver (isthmin-2), modulating glucose release from the liver (asprosin), increasing glucose metabolism (slit2-C), and increasing skeletal muscle metabolism (lipocalin-5). As reviewed by Madhusoodanan (2018), these hormones offer an explanation for the clinical observation that visceral fat is more likely than subcutaneous fat to be problematic in metabolic syndrome. These hormones thus offer targets for control of fat storage disorders and obesity-linked problems such as hypertension, heart disease, diabetes, and thus metabolic syndrome. The term hyperlipidemia is generally defined as high lipids (triglycerides and cholesterol) in the blood (WebMD, 2018). The term used to specifically describe high levels of triglycerides (especially from dietary fats) in the bloodstream is hypertriglyceridemia which is characterized by levels of 150 mg of triglycerides/dL of blood or higher (Fung and Frohlich, 2002; Nordestgaard et al., 2016). To determine whether triglycerides and cholesterol within the bloodstream are too high, a fasting lipid panel test is done, which is a blood test that is performed after an 8
12 hour fast (Mora et al., 2008). However, recently Nordestgaard et al. (2016), indicated that fasting is not routinely

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required in all lipid profile cases. When the test is performed, a blood sample is taken and the total lipid and lipoprotein content is evaluated. This gives an indication of how much of a risk the patient has for developing additional health problems such as acute pancreatitis. Hyperlipidemia is reported to be the cause of 7% of all cases of pancreatitis and is the most common cause that is not related to alcohol consumption and gallstones (Gan et al., 2006).

6.5 LIPOPROTEINS, CHOLESTEROL, AND ATHEROSCLEROSIS Atherosclerosis, also known as arteriosclerosis or hardening of the arteries, is a complex disease in which “plaque” accumulates on the inner walls of arteries leading to blockage. Atherosclerosis is considered in general to be a progressive inflammatory disease with both lifestyle and genetic contributions (Lusis, 2012). The accumulating “plaque” generally consists of lipids such as cholesterol and triglyceride as well as calcium. This leads to a reduced flow of blood to organs and thus tissue damage (NIH Atherosclerosis, 2018). Coronary heart disease is characterized by “plaque” blocking arteries to heart muscle leading to chest pain and heart attacks or rupture of arteries (NIH Atherosclerosis, 2018). Herrington et al. (2016) indicated that atherosclerosis is a leading cause of vascular disease worldwide yet in some countries, the mortality rates have decreased likely due to intervention strategies. Lipoproteins in the bloodstream were reported in 1967 as the primary carriers of triglycerides, phospholipids, cholesterol, and cholesterol esters and have been of high interest for more than 50 years due to the correlation with coronary heart disease and atherosclerosis (Fredrickson et al., 1967; Ference et al., 2017). Lipoprotein classes that are most commonly found in the blood are HDL, low density lipoprotein (LDL), very low density lipoprotein (VLDL), and following digestion of dietary lipid, the chylomicrons. The original work done to separate these classes of lipoproteins was based on their differential density so that centrifugation allowed a clear separation of these classes (Kritchevsky, 1986). The density of the lipoprotein is directly related to its size and the lipid/cholesterol content relative to the protein content (Kritchevsky, 1986). HDL is on average 55% protein by weight, LDL is 37% cholesteryl esters by weight, and VLDL is 50% triglycerides by weight. The reason for defining lipoproteins as a function of density is that the levels of each lipoprotein class are correlated with the risk of developing atherosclerosis since the different classes have different proportion of the different lipids (reviewed by Calandra et al., 2011). Atherosclerosis is a disease that is correlated with high levels of LDLs in the bloodstream and, if left untreated, can lead to a heart attack or stroke (Lusis, 2000). When LDL concentrations rise too high in the blood, the LDL particles can stick to the inside of arterial walls. When this happens, the endothelial cells of the artery create adhesion sites for immune cells to bind to the artery wall and generate what is known as a fatty streak with foam cells, which will produce a fibrous cap as smooth muscle cells cover it (Lusis, 2000). Over time though the fibrous cap can be worn away, or if damaged smooth muscle cells fail to be replaced, the plaque can burst. When this happens, tissue factors on the foam cells interact with clotting factors in the blood creating a clot known as a thrombus. The blood clot can then either constrict or completely block blood flow in the artery and cause a heart attack or stroke (Lusis, 2000).

6.8 C-REACTIVE PROTEIN

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6.6 HYPERGLYCEMIA Another risk factor for metabolic syndrome is hyperglycemia, which is characterized by high fasting glucose concentrations (Ginsberg and MacCallum, 2009). This puts a patient at risk for developing type-2 diabetes which involves the development of resistance to insulin in muscle and liver tissue (Kassi et al., 2011). The prevalence of diagnosed type-2 diabetes in the United States is about 10%, thus some 30 million adults according to the Centers for Disease Control and Prevention (2018). The World Health Organization reported (2017) that in 2014 worldwide an estimated 422 million adults had diabetes and this value had increased from about 108 million in 1980. The most common symptoms of early type-2 diabetes are frequent urination and a constant thirst; the patients may also feel hungry more often than they should. A person who might be at risk for developing type-2 diabetes would have blood glucose concentrations of 100
125 mg/dL (Abdul-Ghani and DeFronzo, 2009). There are two main causes for type-2 diabetes; first is buildup of insulin resistance in muscle and liver tissue, and the other is impaired β-cell function in the pancreas due to over-excretion of insulin. The most common early complications facing type-2 diabetics is the development of ulcers on extremities, primarily feet and legs. A primary reason is the decrease in blood circulation that can affect healing of ulcers and damage to the feet. When patients develop an infection in their lower extremities that is resistant to treatments, in many cases the limbs must be amputated (Deshpande et al., 2008).

6.7 HYPERTENSION (HIGH BLOOD PRESSURE) The cause of hypertension can be linked to many different factors such as a high salt diet, lifestyle, impaired kidney function, impaired arterial function, and genetic links (High Blood Pressure: Overview, 2015). If patients are found to have a systolic pressure greater than 140 mmHg and a diastolic pressure greater than 90 mmHg then they are diagnosed with high blood pressure. Having high blood pressure can have severely detrimental effects on the heart, kidneys, brain, and circulatory system. High blood pressure coupled with high cholesterol are the two most common predictors of for heart disease and can greatly increase the chances of a heart attack or stroke (Ginsberg and MacCallum, 2009). Recent studies have reported that patients with a metabolic syndrome diagnosis have a 2.5-fold higher risk of developing chronic kidney disease (Singh and Kari, 2013).

6.8 C-REACTIVE PROTEIN C-reactive Protein (CRP), made in the liver, is a highly conserved plasma protein that is composed of five identical subunits, each with a molecular weight of 23 kDa, that binds phosphocholine (especially of oxidized LDL) and calcium ions (reviewed by Black et al., 2004). This CRP can activate the classical complement pathway, bind to immunoglobulin receptors, and stimulate phagocytosis. CRP is considered by some as perhaps the best marker of inflammation (Nash, 2005). Since low-grade inflammation is a characteristic of metabolic syndrome, the role of CPR is thus an important consideration (Devaraj et al., 2009). Some important work by

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Ridker et al. (1998, 2000, 2003) indicated that CRP levels are elevated in patients diagnosed with metabolic syndrome. However, Timpson et al. (2005) did not find evidence that CRP is causal in the pathology of metabolic syndrome in British women. Methods to clinically measure CRP have resulted in more sensitive tests for which the results are reported as hs-CRP. These tests measure the same protein as earlier tests but at different sensitivity levels (Methodist Hospital Pathology Center, 2011). Recent studies of hs-CRP measurements in India (Gowdaiah et al., 2016) and China (Sun et al., 2015) have extended the use of these measurements to support the addition of CRP to risk factors for metabolic syndrome. In several studies, the Pritikin Eating Plan (Pritikin Longevity Center, accessed 2018) combined with regular exercise has been reported effective in lowering CRP. Such an antiinflammatory diet includes two to three servings of fish such as salmon or sardines per week or taking fish oil supplements. Also recommended is taking antiinflammatory herbs including ginger and turmeric and following one’s doctor’s recommendations for heart health. That also means quitting smoking, watching one’s diet (particularly avoiding foods that predominantly consist of flour, fat, and/or sugar), and getting regular exercise.

6.9 INSULIN-LIKE GROWTH FACTOR-1 Consistent data from both in vitro and in vivo studies indicated the association between lower than normal levels of IGF-1 (also called somatomedin C) and problems in various risk factors for metabolic syndrome (Aguirre et al., 2016). IGF-1, a 70 amino acid polypeptide, is mainly produced by the liver and released into the blood. It is also produced to some extent by all tissues in the body with approximately 75% from liver and the rest from other tissues. The levels of IGF declines with age and age-related degenerative processes. IGF-1 provides an inhibitory signal for growth hormone (GH) secretion in the hypothalamus. IGF-1 can bind to its own putative receptor (IGF-1R) or can also bind to the insulin receptor but with lower affinity. Thus IGF-1 has been implicated in many physiological activities involving cell proliferation, lipid metabolism, carbohydrate metabolism, and antiinflammatory activity, along with reducing intramitochondrial generation of free radical thus reducing reactive oxygen species (ROS; Aguirre et al., 2016). However, as of yet the role of IGF-1 is still not well understood in metabolic syndrome (Aguirre et al., 2016). The recognition of reduction in GH/IGF levels as a function of increasing age has led, in some cases, to prescribing of GH replacement therapy (Scarth, 2006). However, such usage may result in high levels of GH in relation to IGF-1 which have been reported to have pro-carcinogenic effects. Some long-term drug and nutraceutical safety trials appear to affect the activities of the GH/IGF axis and thus may have long-term implications that are detrimental (Scarth, 2006). The review by Scarth (2006) indicated that there is an important GH/IGF axis that modulates metabolism.

6.10 REACTIVE OXYGEN SPECIES AND GENERAL WAYS TO DETOXIFY THEM All aerobes (oxygen-utilizing organisms) must deal with the innate chemical reactivity of molecular oxygen (O2) due to its high electron affinity. The reactivity of molecular oxygen (itself a reactive

6.10 REACTIVE OXYGEN SPECIES AND GENERAL WAYS

e– + O 2

2 H2O + O2

Formation of superoxide anion radical(O2. – )

SOD

175

CAT

Formation of hydrogen peroxide

(H2O2)

GSSG +

Molecular damage

2 H2O Formation of hydroxy radical

2 GSH

(HO.)

HOO . and ROO .

Molecular damage

GPx

Fenton reactions

Molecular damage

FIGURE 6.3 Formation and detoxification of reactive oxygen species: potential roles of UV light, other ionizing radiation, molecular oxygen, metal ions, and various fates of some of the reactive oxygen species (note straight arrows indicate detoxification directions and curved arrows indicate potential routes leading to molecular damage).

di-radical) and subsequent products formed (many of which are also radicals) thus require a robust antioxidant protective system. Other factors such as smoking and alcohol use also contribute to this oxidative stress of organisms. A simplified overview of reactive species formation, propagation, and termination is shown in Fig. 6.3. A number of agents such as ionizing radiation and metal ions, especially Fe21 via the Fenton reactions, result in the molecular oxygen gaining an electron to become the superoxide anion radical (O2 2 ; reviewed by Hayyan et al., 2016). The red arrows indicate pathways that lead to molecular damage to membranes, proteins, and nucleic acids due to the reactivity of radicals especially with pi electrons of double bonds. This molecular damage then leads to cellular damage that, if not repaired in a timely fashion, leads to cell death (Hayyan et al., 2016). The green arrows indicate pathways that lead to termination of the radical cascade with subsequent formation of water and molecular oxygen and oxidized glutathione (GSSG). Three important enzymes classes are also indicated in Fig. 6.3. Superoxide dismutases (SODs; EC 1.15.1.1), catalases (CAT; EC 1.11.1.6), and glutathione peroxidases (GPxs; EC 1.11.1.9) are important enzymes that detoxify ROS thus protecting cells from oxidative damage. SOD catalyzes the conversion of superoxide anion radical to hydrogen peroxide which is important since the superoxide anion radical is one of the main ROS (McCord, and Fridovich, 1969). There are three major families of SODs defined by the type of metal ion used (Cu/Zn type, Fe or Mn type, and Ni type) in the catalytic activity as well as the three dimensional protein folding patterns (Borgstahl et al., 1996; Cao et al., 2008; Antonyuk et al., 2009). In general, these enzymes have been recognized as among

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the most catalytic efficient of any enzymes (B7 3 109 M21 s21) apparently functioning at the “diffusion controlled” limit. Defective SOD has been implicated as an important contributor to the pathology in familial amyotrophic lateral sclerosis as reported by Cao et al. (2008). Catalase also is catalytically very efficient and is important in protecting cells from the oxidative damage by ROS, especially hydrogen peroxide (Chelikani et al., 2004). These enzymes contain heme iron which is involved in the mechanism of decomposition of the hydrogen peroxide to water and molecular oxygen (Maehley and Chance, 1954; Aebi, 1984). Studies with catalase deficient mice have suggested that these animals are more sensitive to oxidant tissue damage and more likely to develop diabetes (Ho et al., 2004; Heit et al., 2017). A role of glutathione (a tripeptide involved in controlling the oxidative potential in cells; GSH) is also shown in Fig. 6.3 as a cosubstrate for GPx and this GSH compound is oxidized to the disulfide form (GSSG) as the hydroxyl radical is reduced to water. The GPx family is important to detoxify hydrogen peroxide and thus reduce the amount that is converted to the hydroxyl radical for which we have no enzyme detoxification system. In addition, the hydroxyl radical is highly reactive with proteins and lipids as well as nucleic acids (Sies, 1993; Reiter et al., 1995). There are seven well-established isozymes of GPx with different ones found in various tissues, both inside and outside of cells; four of these enzymes require selenium to be functional and at least one of these enzymes is a selenoprotein containing selenocysteine amino acid rather than the cysteine amino acid (Epp et al., 1983; Sedigni et al., 2014; Yang et al., 2014; Socha et al., 2014). Thus sufficient dietary selenium is an important consideration in detoxification of ROS by some pathways. H2 O 1 ionizing radiation such as UV light or radioactivity 1 O2 -O2 2

Also, the superoxide anion radical is produced during normal functioning of the electron transport chain at the NADH-ubiquinone oxidoreductase (complex I) level (Kussmaul and Hirst, 2006). Note the role of the Fenton reactions (shown below) in the production of ROS such as the hydroxyl radical and peroxy radical (R 5 hydrocarbon peroxy radical formed following abstraction of a H  from a biological molecule such as a lipid): Fenton reactions: Fe21 1 H2 O2 -Fe31 1 HO 1 OH2 Fe

31

1 H2 O2 -Fe

21



(6.1)

1

1 HOO 1 H

The roles of other ROS detoxification systems such as antioxidants are also important. Our diets can provide both fat-soluble vitamins (such as vitamin E and vitamin A) and a number of plant isoprene derivatives such as quinones, polyphenols, and flavonoids such as anthocyanins in addition to some of the water-soluble vitamins such as vitamin C. Diets thus have an obvious role to help regulate the levels of the fairly reactive and nonspecific ROS species that are made as a normal part of aerobic metabolism. Diets deficient in these antioxidants, which can react with free radicals thereby sparing lipids, proteins, and nucleic acids, thus can lead to more biological stress and inflammatory reactions. Nutraceuticals that provide antioxidant capability thus can provide important roles in ROS detoxification.

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6.11 THERAPY/TREATMENT AFTER DIAGNOSIS OF METABOLIC SYNDROME While still controversial, the definition and diagnosis of metabolic syndrome is becoming more accepted along with the concept that treatment of this syndrome as a single entity rather than as individual conditions is important (Grundy, 2006a). As such, there is developing some consensus that holistic therapeutic approaches are needed and not just a focus on one or two of the metabolic syndrome risk factors. Such approaches involve attention to diet, to exercise, to weight control, and prescription of pharmaceuticals especially the statin class of drugs to lower cholesterol and metformin to lower blood glucose. There is a growing recognition among the medical field and medical researchers that there are no quick fixes for metabolic syndrome as well as for individual risk factors.

6.11.1 OBESITY AND HYPERLIPIDEMIA THERAPY/TREATMENT For obesity, weight control with the goal of weight reduction is a high priority in managing this aspect of metabolic syndrome. Counseling for caloric restriction and increased exercise generally involves increased consumption of vegetables, whole grains, fruits, and fish while increased exercise generally involves walking, intermittent aerobic activity for 60 or 30 minutes of moderateintensity exercise most days of the week (Armstrong, 2006). Drug treatment for hyperlipidemia is usually done by the administration of statins to control serum cholesterol and triglycerides however, other lipid-lowering drugs, such as bile acid sequestrants (ezetimibe) can be used in patients who do not tolerate statins (Last et al., 2017).

6.11.2 CHOLESTEROL THERAPY/TREATMENT Though formation of plaques in arteries can be life threatening, the treatments to help lower LDL and raise HDL have become fairly effective (Wilt et al., 2004) with statins such as Lipitor being one of the bestselling prescription drugs of all time (Williams, 2017). Lipitor generated $1.76 billion US dollars in sales for Pfizer in 2016 alone (Williams, 2017). Usually the most common way to test whether a patient is at risk is a blood test which assesses total cholesterol, HDL, LDL, and triglyceride levels in the blood. The cholesterol concentrations that are deemed too high by the American Heart Association are LDL more than 160 mg/dL which is the threshold for high LDL with LDL less than 100 mg/dL being optimum (Fletcher, 2017). HDL is the opposite with higher concentrations being desirable; the concentration that is generally considered optimal is HDL more than 60 mg/dL (Fletcher, 2017). If HDL concentrations fall to less than 40 mg/dL with high levels of LDL, a person is generally considered at risk for developing atherosclerosis and has a risk factor for metabolic syndrome. The most common treatment is the administration of a class of drugs known as statins of which Lipitor is the most prescribed; these drugs have been shown to effectively lower LDL levels when coupled with a low cholesterol diet and regular exercise (McFarland et al., 2014). Statins are effective inhibitors of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA) which is the second enzyme in the cholesterol biosynthetic pathway and is

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the main point of regulation in the pathway (McFarland et al., 2014). This then decreases the ability to synthesize cholesterol in cells; reduction of endogenous cholesterol along with reduction of intake of dietary cholesterol should then be coupled to decrease serum cholesterol levels. Along with inhibiting the biological production of cholesterol, statins have been found to upregulate the LDL receptor of the surface of multiple cell types which helps with clearing excess LDL from the blood and decreases the chance of atherosclerotic plaque buildup (Kim et al., 2004a,b). However, a common issue when taking statins is the need for dietary restriction, primarily the removal of grapefruit and grapefruit juice from the diet. The consumption of grapefruit juice has been found to inhibit a class of enzymes in the liver called cytochrome p450, which are responsible for metabolizing most statins along with other drugs (Lee et al., 2016). It has even been shown that regular consumption of grapefruit juice can cause large increases in serum statin concentrations by up to 260% depending on the form or mixture of statin administered (Lee et al., 2016). Though the statins are generally regarded as safe, a common side effect is myopathy, specifically pain and weakness in the muscles and is thought to affect 0.5%
1% of patients on statins (Collins et al., 2016).

6.11.3 HYPERGLYCEMIA AND DIABETES THERAPY/TREATMENT For those diagnosed with type-2 diabetes the most common drug treatment is metformin which is used to reestablish insulin sensitivity by blocking glucose production via gluconeogenesis in the liver. The most common side effects of this drug are gastrointestinal irritation including cramps, nausea, diarrhea, vomiting, and increased flatulence (Bolen et al., 2014). The easiest way to reduce the effect of hyperglycemia and developing type-2 diabetes without a drug treatment is glycemic control (Kim et al., 2005a,b). Glycemic control is generally related to maintaining a diet low in both added sugars (simple sugars such as glucose and complex such as starch) and excessive saturated fat. A healthy diet, when coupled with regular exercise, has been shown to reduce fasting glucose levels and reestablish insulin sensitivity in muscle and liver tissue (Kim et al., 2005a,b). Though exercise is a very general term, most types, such as aerobic, interval, or resistance exercise training have been reported to be effective (Roberts et al., 2013).

6.11.4 C-REACTIVE PROTEIN THERAPY/TREATMENT Reduction in CRP levels have been noted in some patients on statin therapy as well as some patients on aspirin therapy (Stoppler, 2018).

6.11.5 INSULIN-LIKE GROWTH FACTOR-1 THERAPY/TREATMENT In some instances, replacement of recombinant IGF-1 has been prescribed especially for children with deficiencies (Ranke, 2015). There appears to be little pharmaceutical therapy for low levels of IGF-1 in adults.

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6.11.6 HYPERTENSION High blood pressure (hypertension) is a significant contributor to metabolic syndrome and is a significant health risk even in those without metabolic syndrome. Generally, if a patient has high blood pressure, a diuretic is given to try to remove excess water and salt from the bloodstream to reduce the overall pressure. If these are ineffective then angiotensin-converting enzyme inhibitors, alpha-blockers or beta-blockers can be prescribed. Sometimes medication is not needed and a low salt diet can help lower the osmolality of the blood to help reduce the blood pressure and, along with exercise, blood pressure can be controlled. There are currently multiple nutraceuticals that are consumed with the goal of treating high blood pressure. Borghi and Cicero (2017) reviewed studies, especially meta-analyses and randomized clinical trials, from 1990 to 2015, on dietary supplements and nutraceuticals claiming to show an effect on human blood pressure. Evidence for antihypertensive effects for vitamin C, cocoa flavonoids, beetroot juice, coenzyme Q10, and aged garlic extract seem to be dose related and have overall good tolerability.

6.12 ROLE(S) OF NUTRACEUTICALS 6.12.1 AN OVERVIEW OF USES OF NUTRACEUTICALS IN THE TREATMENT OF METABOLIC SYNDROME The reported commonalities among nutraceuticals appear to be their potential abilities to affect cell transporters (such as P-glycoprotein), modify cell receptors (such as G-protein coupled receptors and nuclear hormone receptors), enzyme activities (such as HMG-CoA reductase), cell behavior (such as cell division and apoptosis), modify gene expression, modify the immune system and thus immune responses, modify metabolism, and to function as antioxidants (reviewed by Nasri et al., 2014; Andrew and Izzo, 2017). Some nutraceuticals appear to have only one or two of these potential activities while others have an apparent broader range of activities.

6.12.2 TRADITIONAL CHINESE MEDICINE IN THE TREATMENT OF METABOLIC SYNDROME Yin et al. (2008) reviewed the history and current use of traditional Chinese medicine in the treatment of metabolic syndrome contending that such traditional medicines can be alternative as well as complementary medicines. They present 22 traditional Chinese herbs and their potential activities useful in the treatment of metabolic syndrome and some of the risk factors. In particular, they highlighted the therapeutic potential of three herbs, ginseng, rhizome coptidis (with berberine as the major active molecules), and bitter melon. These three herbs are implicated in the reduction of five of the six risk factors of metabolic syndrome. Ginseng (from the root of Panax ginseng) has been studied in animal models and in human trials for treatment of diabetes, obesity, and hyperlipidemia along with other aging-associated problems. Yin et al. (2008) indicated that ginseng contains many bioactive compounds with ginsenosides (saponins) having demonstrated bioactivities in

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the regulation of blood glucose and blood pressure. However, the authors did indicate that the molecular mechanism(s) of ginseng are largely unknown. Yin et al. (2008) also reviewed berberine, a plant alkaloid from roots and bark of rhizome coptidis, indicating that it is the active compound for antidiabetes and antiinfection effects. Berberine was reported to reduce blood glucose levels in diabetic patients with comparable activity to sulfoureas or metformin, when given to diabetic patients prior to major meals. In animal models of type-2 diabetes, berberine reduced body weight and increased insulin tolerance. In rats fed high-fat diets, berberine decreased serum triglycerides, reduced deposition in liver, and reduced liver steatosis. Berberine also was shown to activate AMP-kinase (AMPK) and to inhibit ATP synthesis in the mitochondria. In 3T3-L1 adipocytes, in vitro, berberine inhibited several genes involved in lipid metabolism such as fatty acid synthase, acetyl-CoA carboxylase, and lipoprotein lipase. In addition, berberine appears to increase the expression of LDL receptors in liver cells thus helping to reduce blood cholesterol levels. The third herb that Yin et al. (2008) considered important for use in treatment of metabolic syndrome is bitter melon which contains a “plant insulin” polypeptide with hypoglycemic effects that are exhibited after subcutaneous injection or oral administration in mice. Extracts of bitter melon fruit decreased hyperlipidemia and hyperglycemia in diabetic rats as long as the animals received the extracts. After withdrawal of the extract, the high levels of lipid and carbohydrate in the blood were again evident. The authors suggested that antioxidant function and protection of pancreatic β-cells by the extract was part of the mechanism. The bitter melon may also have inhibited glucose absorption by inhibition of jejunum brush border membrane. However, results from human clinical trials were less obviously effective especially when the trials were randomized, double-blind, and placebo-controlled. Yin et al. (2008) also mentioned tea, especially green tea, as another important treatment for metabolic syndrome and this has been expanded by Yang et al. (2017). In this review by Yang et al. (2017), the authors proposed that tea has two major mechanisms by which metabolic syndrome is modulated: (1) decreasing the absorption of lipids and proteins in the intestine thus reducing calorie intake; and (2) tea polyphenolics (such as catechins, epigallocatechin gallate, quercetin and some alkaloids such as caffeine and theobromine) that function to activate AMPK which would then decrease gluconeogenesis and fatty acid synthesis. Therefore there would be an increase in metabolism which would lead to weight loss. Thus control of body weight and reduction of severity of metabolic syndrome are coupled. In addition, tea catechins have antioxidant potential, and thus can help control formation and effects of ROS such as superoxide anion radical, singlet oxygen, hydrogen peroxide, and the hydroxyl radical. Both green and black teas have up to 30% of dry weight as phenolic compounds which can have an antioxidant ability thus have a substantial contribution to detoxification of ROS (Lin et al., 1998; Lobo et al., 2010). It is not surprising, therefore, that the use of matcha (green powder made from special green tea leaves grown in the shade for about 3 weeks before harvest, drying, and powdering) is currently enjoying popularity by health conscientious people (Groom, 2018). However, Yang et al. (2017) also reported that the fundamentals of green tea mechanisms are not yet well established. However, green tea components have been reported to be able to affect four of the six major risk factors for metabolic syndrome especially considering their impact on ROS that are associated with inflammation, DNA damage, lipid damage, and protein damage (Lobo et al., 2010).

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6.12.3 VARIOUS NUTRACEUTICALS SOLD TO AND USED BY THE PUBLIC WITH OR WITHOUT CONSULTATION WITH THEIR PHYSICIANS Nutraceuticals with reported effects on metabolic syndrome (reviewed by Cicero et al., 2013; Kaur et al., 2015; Affuso et al., 2012; Santini and Novellino, 2017; Nasri et al., 2014) and various risk factors include curcumin (turmeric), genistein, red yeast rice, fish oils, ginger, apple polyphenolics, cannabinoids (CBD), and garlic, in addition to the traditional Chinese herbs discussed in Section 6.11.1. In the following section, we present a summary of three of these nonprescription nutraceuticals (supplements, functional foods) currently being taken to help cope with metabolic syndrome and which risk factors that contribute to metabolic syndrome may be the target. In addition to tea, these three nutraceuticals may have the best evidence for their actual effectiveness (Sirtori et al., 2017). We are not making a rigid distinction between the terms nutraceuticals, supplements, functional foods, phytochemicals, or herbal extracts for this discussion.

6.12.3.1 Curcumin (turmeric; a diarylheptanoid) Kunnumakkara et al. (2017), reviewed curcumin use for multiple chronic diseases. They report over 100 different clinical trials with curcumin and their extensive reference section has over 250 citations. These show that this nutraceutical is safe, easily tolerated, and has some efficiency treating metabolic diseases (diabetes especially), cardiovascular diseases, skin diseases (psoriasis), inflammatory diseases, viral diseases, cancers, neurodegenerative diseases, and others such as alcohol intoxication and cholecystitis. Thus curcumin may be seen as affecting three of the six major risk factors for metabolic syndrome. For example, one clinical trial using of 500 mg/day in healthy humans, reported markedly lowered serum cholesterol and triglyceride levels (Pungcharoenkul and Thongnopnua, 2011) demonstrating safety and efficiency. Alwi et al. (2008) showed that in a trial with acute coronary syndrome patients, curcumin (at 15 mg per day, three times a day) effectively reduced the serum total cholesterol and LDL levels in patients. Chuengsamarn et al. (2012, 2014) reported that curcumin delayed the development of type-2 diabetes mellitus and reduced the metabolic profiles of high-risk populations. Na et al. (2014) reported that curcuminoids lowered blood glucose levels in overweight/obese type-2 diabetic patients. The major molecular targets of curcumin appear to involve effects on growth factors, enzymes especially kinases, inflammatory cytokines, transcription factors, apoptotic regulators, receptors, and adhesion molecules. One of the major points Kunnumakkara et al. (2017) made is that this compound is synergistic with other nutraceuticals such as resveratrol, catechins, quercetin, and genistein. Kunnumakkara et al. (2017) also emphasize that more clinical trials, in different populations, are needed, especially since curcumin has low water solubility and low bioavailability. To increase water solubility, liposomal preparations as well as oil preparations have been developed (Anand et al., 2007, 2008). In addition, synthesis of structural analogues of curcumin have been found to increase bioavailability and increase antioxidant activity (Sahu et al., 2016). As of yet, there have been few studies on the effects of nutraceuticals on the adipose cell hormones. Tang et al. (2009) reported that curcumin reduced the leptin receptor expression in hepatic stellate cells in vitro thus interrupting leptin signaling and reducing hyperlipidemia which is seen in obese patients with nonalcoholic steatohepatitis. Curcumin also reduced the levels of ROS

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in a dose dependent manner. Tang et al. (2009) also measured increases in cellular levels of glutathione (GSH). Contrary to the many studies reporting success with curcumin, Lowe (2017) in his blog, is quite skeptical about much of the research related to curcumin and bemoans the number of people willing to sell curcumin tablets for a variety of ailments. He cautions consumers and researchers to be more concerned about the stability, the water solubility, and the pharmacokinetics of curcumin and derivatives.

6.12.3.2 Genistein Genistein is one of the family of isoflavones isolated from soybean. Nagaraju et al. (2013) reviewed the pleiotropic effects of genistein in metabolic and inflammatory diseases. Szkudelska and Nogowski (2007) reported that dietary genistein led to alterations in insulin and leptin levels. Others have reported that Genistein has been associated with reducing adipocyte growth and reducing the progression of metabolic syndrome (Xia and Weng, 2010). Daily oral intake of soy isoflavones, containing genistein, resulted in a reduction of mean serum leptin in 86 obese postmenopausal women after 6 months (Llaneza et al., 2011). In insulin-deficient diabetic mice, genistein was shown to improve glycemic control and pancreatic β-cell function (Fu et al., 2012). In a study by Valsecchi et al. (2011) genistein was shown to reduce content of tumor necrosis factor-α and interleuklin-6 in the sciatic nerves of diabetic mice as well as modulate nitric oxide release from endothelial cells. In a clinical randomized, double-blind study of 42 overweight men and women, those given genistein exhibited a decrease in body weight, BMI, waist circumference, leptin, and an increased insulin sensitivity (Salas et al., 2017). Orgaard and Jensen (2008) reported that soy isoflavones helped reduce obesity. Structurally genistein is similar to estrogens and thus considered to be a phytoestrogen (Kuiper et al., 1998). Isoflavone can bind to estrogen receptors and thus have been used in postmenopausal women (North American Menopause Society, 2011; Kuiper et al., 1998). The transition from premenopause to postmenopause is characterized by many features of metabolic syndrome such as hypertriglyceridemia, elevated LDL levels, elevated blood pressure, and impaired glucose tolerance/diabetes (Janssen et al., 2008). Thus some studies have been reported on isoflavone testing in postmenopausal women with metabolic syndrome. Using a randomized, double-blind and placebo-controlled design, 120 women received 54 mg genistein daily for a year or received a placebo. After 1 year the genistein recipients had decreased fasting glucose and insulin levels as well as decreased total cholesterol, LCL, and triglycerides relative to the placebo group. The systolic and diastolic blood pressure was also reduced in genistein recipients (Squadrito et al., 2013). Cardiac function (assessed by strain-echocardiography measurements) in postmenopausal women with metabolic syndrome following genistein supplementation was reported by de Gregorio et al. (2017). They reported that there was a significant improvement of left atrial function relative to controls. In both animal studies and cancer cell lines, isoflavones haven been shown to reduce cancer cell growth and reduce tumorigenesis (reviewed by Kim et al., 2005a,b). They also demonstrated that genistein significantly decreased the IGF-1 stimulation of insulin-receptor-substrate-1 phosphorylation as well as protein kinase-B (Akt) phosphorylation. The authors’ speculation is that this is one of the mechanisms by which genistein inhibits cell proliferation. Thus genistein has been reported to be able to affect five of the six major risk factors for metabolic syndrome.

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6.12.3.3 Red yeast rice Red yeast rice is also known as “koji” in Japanese and refers to grain or bean grown with a mold culture. This is a traditional preparation dating back to about 300 BCE (Shurtleff and Aoyagi, 2012). The preparation of the red yeast rice requires water soaked rice (steamed, cooked, or used raw) that is then inoculated, under carefully controlled conditions, with Monascus purpureus mold spores. This is incubated until the rice grain turns bright red with a purple outside. This red yeast rice preparation is used in food and wines, since it adds color and flavor, as well as in Chinese medicine (Erdogrull and Azirak, 2004). Endo (2004) reviewed the origin of the statins from isolation of monacolins, such as monacolin K which is identical to lovastatin, from Monascus cultures (as well as lovastatin from Aspergillus cultures grown on rice). Red yeast rice products that contain monacolin K have thus been a concern (FDA Warning, 2007). Unfortunately different growth conditions lead to variability in the amount of the monacolin K found. In addition to the concern of monacolins when using red yeast rice, an additional concern is that some preparations contain the toxin citrinin (Gordon et al., 2012). Citrinin has been shown to accumulate in the kidneys and lead to renal failure along with liver and gastrointestinal tract damage (Krejci et al., 1996; Doughari, 2015). Since these statins, and subsequent pharmaceutical derivatives, were shown to affect LDLcholesterol levels, they have been used clinically. A meta-analysis of 91 randomized clinical trials (with 68,485 participants) indicated a 24%
49% reducing in LCL-cholesterol depending on the statin used (Edwards and Moore, 2003). In addition, statins are also prescribed for high triglyceride levels in the serum (Last et al., 2017). Xiong et al. (2017) reviewed the various effects of red yeast rice supplements in 21 randomized, controlled trials (with 4558 patients). In general, the red yeast rice supplements reduced total serum cholesterol, LDL-cholesterol, and CRP, thus affecting two of the six major risk factors for metabolic syndrome. However, there were no effects of diastolic blood pressure, triglyceride levels, or HDC-cholesterol when compared to placebo plus conventional therapy. They concluded that the majority of the trials had low methodological quality and suggested that more rigorously designed trials were warranted before red yeast rice should be recommended to hypertensive patients (Xiong et al., 2017). Younes et al. (2018) reported the work of the Panel on Food Additives and Nutrient Sources added to food that reviewed the question of the safety of monacolins in red yeast rice. The panel did indicate that the intake of monacolins from red yeast rice could reach a therapeutic dose in the range of lovastatin. However, the panel was also concerned that the levels could not be easily predicted and controlled in the various nutraceutical preparations and thus may be a safety concern.

6.12.4 EXCIPIENTS USED IN NUTRACEUTICALS The quality of nutraceuticals is a function of both the active ingredient/s and the excipients used in the formulation of the nutraceutical (Pifferi et al., 1999). It is estimated that the nutraceutical excipient market will be worth 4.3 billion USD by 2022 (https://www.marketsandmarkets.com). Excipients are utilized to aid in the manufacturing, administration, or absorption of the active ingredient in a nutraceutical (Vrani´c, 2004). It is typical for excipients to be used to prevent the degradation of the active ingredient in a nutraceutical as well as in a pharmaceutical. These methods of degradation include hydrolysis, oxidation, photolysis, polymerization, isomerization, and change in

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acid-base character. These mechanisms are largely influenced by pH, concentration, and temperature (Vrani´c, 2004). Excipients are further divided into various functional classifications. These classifications include binders, diluents, disintegrants, lubricants, wetting agents, solvents, fillers, emulsifiers, absorption enhancers, sustained release matrices, preservatives, sweeteners, and stabilizing, coloring or flavoring agents (Mills, 2007; Nahata, 2009). When taking an active compound, the compound itself, the dose, the route, the frequency of administration, and duration of the treatment are all considerations of treatment. Ideally, excipients are biologically inactive, nontoxic, and do not interact with the active ingredient in the formulation, but there is mounting evidence that this is not always the case. Thus while excipients play a valuable role as components of nutraceutical formulations, they are also problematic. Here, we define the common uses of excipients, commonly used excipients in those groups, along with some specific examples of known problems with some groups of excipients used in pharmaceutical drug and nutraceutical formulations. Excipients are commonly used in drug formulations for a variety of different reasons and are treated as pharmaceutically inactive substances although they may not be inactive for everyone (Mahan et al., 2011). A diluent is any substance that provides bulk and allows for accurate dosing of active ingredients. Common organic diluents include sugars such as lactose, glucose, sucrose, or sorbitol as well as vegetable oils such as soybean oils, corn oils, and safflower oils (Mahan et al., 2011). The presence of lactose is a likely problem for lactose intolerant people. Soybean oils may be problematic for persons taking thyroid replace therapy since soy is considered a goitrogen and contains phytoestrogens (Shomon, 2018). Common inorganic diluents include silicates, or salts of the following metals: calcium, magnesium, sodium, or potassium. Binders, compression aids, and granulating agents bind tablet ingredients together giving form and mechanical strength. Some commonly used agents include natural or synthetic polymers of sugars, alcohols, or cellulose derivatives. Disintegrants are substances that aid in dispersion of the tablet during digestion allowing release of the active ingredient. These compounds are typically moderately or highly water soluble, and include starch, cellulose and cellulose derivatives, alginates, and crospovidone (cross linked polyvinyl N-pyrrolidone, or PVP). Glidants are substances that improve the flow of powders during tablet manufacturing by reducing friction and adhesion between particles. Glidants include colloidal or anhydrous silicon and other silica compounds. Lubricants’ function is similar to glidants, but also may decrease the rate of disintegration and dissolution. Some common lubricants include stearic acid and its salts, with magnesium stearate being one of the most commonly used lubricant salts. Tablet coatings and films are substances that protect the active ingredients from the environment and moisture. Common tablet coatings include sucrose and natural or synthetic polymers. Polymers insoluble in acid such as cellulose acetate phthalate are used as enteric coatings to delay release of the active ingredient. In addition, recent interest in nanodeliver systems for encapsulation of nutraceuticals has been growing (Ishak et al., 2017). Coloring agents are used to improve acceptability to patients and help prevent counterfeiting (www.nps.org.au/australian-prescriber/articles/pharmaceutical-excipients-where-do-we-begin). Coloring agents are overwhelmingly synthetic dyes and natural colors. It is also common for pigments that are found naturally in foods to be used as coloring agents (Haywood and Glass, 2011). Although excipients are valuable tools for these various reasons, there has been longstanding positions in the literature that they are not necessarily biologically inactive. For example, rice starch is gluten-free whereas wheat starch is not. Thus consumers need to be informed when various excipients have been added so that they can make more informed choices.

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Everyone taking a modern drug formulation is at risk of experiencing side effects from both the active and the inactive ingredients in the formulation (Wang, 1993). There are commonly known problems with several of the excipients used in drug formulations. Additives, such as sulfites, benzoates, aspartame, saccharin, oleic acid, benzyl alcohol, lactose, soy lecithin, propylene glycol, and sorbitan trioleate have been reported to cause allergic reactions. (See: www.drugs.com/inactive/. This site also has an excellent alphabetical list of inactive ingredients. May 2, 2014). Sugar alcohols such as sorbitol or mannitol can cause diarrhea due to osmotic effects (Johnson et al., 1994). Blue dyes, such as Blue No. 1(bright blue) and Blue No. 2 (indigo carmine) are suspected as the cause of many allergic reactions (Swerlick and Campbell, 2013). A review looking at 38 excipient classes with 300 known side effects or contraindications was performed. This study showed that of the 8900 drugs investigated, 5567 of them contained one or more of the excipients in the 38 groups: 2483 contained one excipient, 1891 contained two excipients, and 1265 contained three or more of these excipients. Of the listed side effects, 410 were attributed to the route of administration and the threshold dose (Fusier et al., 2003). Furthermore, the use of potentially toxic excipients in susceptible groups (very low birth weight neonates, patients with contact dermatitis, patients with very large surface area burns, and patients with a history of asthma) to alter drug bioavailability may pose more risk than previously assumed (Golightly et al., 1988). Further concern for neonates has been expressed. An investigation looking at 48 hospitalized newborns showed that a majority of these newborns were prescribed drugs not approved for that population, and two-thirds of these were prescriptions used off label. These drugs contained 60 different excipients, more than half of which were potentially harmful (Fister et al., 2015). Excipient choice may also alter the pharmacokinetic profile of a drug in preclinical trials (Buggins et al., 2007). Thus while useful in drug formulations, excipients do pose risks that should be investigated and regulated with both the pharmaceutical drugs and nutraceutical preparations in which they are used, perhaps on a case-by-case dependent basis.

6.13 SIDE EFFECTS OF NUTRACEUTICALS More and more incidences of nutraceuticals’ side effects are being reported and appear to be a common problem of patient and physician communication. If and when asked, patients appeared reluctant or forgot to indicate use of nutraceuticals and supplements to their physician. There are some case reports of endometriosis in women consuming isoflavone supplements (Mahady et al., 2003) and there is a likelihood, not yet established, of increased risk of estrogen-sensitive cancers (Ronis et al., 2018). A specific case report in which a 70 year old woman was taking a dietary supplement of monacolin K (from red yeast rice that is similar to statin drugs; https://nccih.nih.gov/ health/redyeastrice), without informing her physician, and experienced rhabdomyolysis which was determined to be from the drug interactions of her prescribed pharmaceuticals (Russo et al., 2016).

6.14 FINAL THOUGHTS ON THE FUTURE OF NUTRACEUTICALS Since the number of cases of metabolic syndrome as well as the various risk factors are likely to continue to increase worldwide (this was coined the nutraceutical revolution by Santini and

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Novellino, 2017), with the concomitant increase in healthcare costs (Yin et al., 2008), the interest in nutraceuticals by the public is only likely to increase. This will then generate an increased interest in governmental regulation in the area of nutraceuticals. This is a consequence of the problem of commercially available products with nonuniformity in composition, purity, and labeling, thus safety cannot be absolutely guaranteed to the consumer (Santini and Novellino, 2017). With the lack of clarity in classifying items as nutraceuticals, supplements, functional foods, and so on, regulation and legislation actions are likely to be very problematic. Singh and Sinha (2012) reviewed the classification and regulatory acts of nutraceuticals and clearly laid out the various problems within countries and between countries for problems of identifying what is being regulated and the problems of obtaining high quality data to help with the regulatory issues. For the nutraceutical industries, the two major challenges are the credibility of labeling claims and uncertainty about the regulatory laws especially between countries (Singh and Sinha, 2012). Santini et al. (2018) reviewed the current regulatory state of nutraceuticals and laid a framework for debating such regulation. They recommend that nutraceuticals need to be distinguished from other food products such as supplements and then to identify targets, safety assessment, mechanism(s) of action, efficacy assessments especially substantiated by clinical studies, further evaluation of possible side effects, and of possible interactions with other products. They acknowledge that resolving these issues of definitions and regulation will be a substantial challenge especially in terms of funding. Dwyer et al. (2018) have also reviewed the regulatory challenges for dietary supplements and pointed out one regulatory problem especially for traditional medicines (Chinese medicines, Ayurvedic medicines, and other medicines embedded in various cultures). An important question is: should regulatory standards apply to traditional medicines used in the traditional manner? Regulatory agencies and legislation will need to address these issues both locally as well as globally. Although there has been an increase in actual usage over the past few years, especially with the ease of purchasing nutraceuticals at various websites and stores, the actual clinical effectiveness of nutraceuticals has been studied only to a limited degree especially by independent researchers. There are too few well-designed, double-blinded, controlled experiments with human and with animals. Although this is the case, there are some peer reviewed studies that support usage of nutraceuticals especially those for which few side effects have been reported. However, the fundamental mechanism(s) by which these nutraceuticals truly function remains to be firmly established. There are currently a few good animal models and good in vitro cell culture models established. Panchal and Brown (2011) did review the various rodent models for metabolic syndrome research, including genetic models of obesity and type-2 diabetes, genetically engineered diabetic mice, and chemically induced rodent models of diabetes (use of alloxan and streptozotocin) as well as diet-induced diabetes. They then correlated these models with various interventions (both pharmaceuticals as well as nutraceuticals) for reversal or prevention of metabolic syndrome; they reported variable success depending on the model and intervention. The interplay between nutraceuticals and gut microbiota is an important area that must be assessed, and this has been reviewed by Catinean et al. (2018). After evaluating evident (observational, in vitro, and in vivo clinical studies or animals experiments), these reviewers concluded that the composition of the microbiota affect the health status of patients, and that pharmaceuticals (especially antibiotics) and nutraceuticals can affect these microbes. Cencic and Chingwaru (2010) reported that the role(s) of gut microflora are important and that the use of cell culture can be very important in studying effects of nutraceuticals on both

REFERENCES

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the microflora and the host intestinal cells. Gradisnik et al. (2006) reported that a pig functional cell model of epithelial cells and macrophages (coculture) was promising. Because metabolic syndrome is a collection of risk factors, when nutraceuticals are used they are generally taken with the purpose of reducing the severity of the risk factors with perhaps little understanding of the net result of interactions of the various risk factors. Though the usage of the nutraceuticals is now more of a focus to be explored in the clinical and basic research settings, it is worth noting that some nutraceuticals have showed effectiveness. This information is communicated by word of mouth, by the internet, especially by companies selling nutraceuticals and health plans, and by popular newspapers and magazines, for treating risk factors associated with metabolic syndrome. Lastly, Aronson (2017) reviewed the status of nutraceuticals and developed the theme that nutraceuticals are not yet ready to be fully considered as either nutritious or pharmaceutical due to the lack of high quality clinical trials and clarity in definitions. He also referred to the 2014 lecture by Stephen L. DeFelice, who coined the term nutraceutical, in which Dr. DeFelice confessed that there is considerable uncertainty about what they are and if they actually work going so far in his lecture to indicate they are not proven (DeFelice, 2014). Thus there is much work yet to be done in this very interesting field. In conclusion, more studies of nutraceuticals and their potential roles in prevention of and/or treatment of metabolic syndrome are clearly important and will require the attention of various disciplines and groups (nutrition, biochemistry, healthcare providers, governmental agencies, and nutraceutical suppliers, among others) to gain a fundamental understanding. Since the problems involved in metabolic syndrome are not likely to be decreasing, such a coordinated approach will be critical.

REFERENCES Abdul-Ghani, M.A., De Fronzo, R.A., 2009. Plasma glucose concentration and prediction of future risk of type 2 diabetes. Diabetes Care 32 (Suppl. 2), S194
S198. Aebi, H., 1984. Catalase in vitro. Methods Enzymol. 105, 121
126. Affuso, F., Mercurio, V., Ruvolo, A., Pirozzi, C., Micillo, F., Carlomagno, G., et al., 2012. A nutraceutical combination improves insulin sensitivity in patients with metabolic syndrome. World J. Cardiol. 4 (3), 77
83. Aguirre, G.A., De Ita, J.R., de la Garza, R.G., Castilla-Cortazar, I., 2016. Insulin-like growth factor-1 deficiency and metabolic syndrome. J. Transl. Med. 14 (3), 1
23. Available from: https://doi.org/10.1186/ s12967-015-0762-z. Alwi, I., Santoso, R., Suyono, S., Sutrisna, B., Suyatna, F.D., Kresno, S.B., et al., 2008. The effect of curcumin and lipid level in patients with acute coronary syndrome. Acta Med. Indones. 40, 201
210. Anand, P., Kunnumakkara, A.B., Newman, R.A., Aggaarwal, B.B., 2007. Bioavailability of curcumin: problems and promises. Mol. Pharm. 4, 807
818. Anand, P., Sundaram, C., Jhurani, S., Kunnumakkara, A.B., 2008. Curcumin and cancer: an “old-age” disease with an “old-age” solution. Cancer Lett. 267, 133
164. Andrew, R., Izzo, A.A., 2017. Principles of pharmacological research of nutraceuticals. Br. J. Pharm. 174, 1177
1194. Antonyuk, S.V., Strange, R.W., Marklund, S.L., Hasnain, S.S., 2009. The structure of human extracellular copper-zinc superoxide dismutase at 1.7 A resolution: insights into heparin and collage binding. J. Mol. Biol. 388 (2), 310
326.

188

CHAPTER 6 NUTRACEUTICALS AND METABOLIC SYNDROME

Armstrong, C., 2006. AHA and NHLBI review diagnosis and management of the metabolic syndrome. Am. Fam. Phys. 74 (6), 1039
1047. Aronson, J.K., 2017. Defining ‘nutraceuticals’: neither nutritious nor pharmaceutical. Br. J. Clin. Pharmacol. 83, 8
19. Black, S., Kushner, I., Samols, D., 2004. C-reactive protein. J. Biol. Chem. 279 (47), 48487
48490. Bolen, S., Feldman, L., Vassy, J., Wilson, L., Yeh, H., 2014. Systematic review: comparative effectiveness and safety of oral medications for Type 2 diabetes mellitus. Ann. Int. Med. 147, 386
399. Available from: https://doi.org/10.7326/0003-4819-147-6-200709180-00178. Borghi, C., Cicero, A.F., 2017. Nutraceuticals with a clinically detectable blood pressure-lowering effect: a review of available randomized clinical trials and their meta-analyses. Br. J. Clin. Pharmacol. 83 (1), 163
171. Borgstahl, G.E., Parge, H.E., Hickey, M.J., Johnson, M.J., Boissinot, M., Hallewell, R.A., et al., 1996. Human mitochondrial manganese superoxide dismutase polymorphic variant Ile58Thr reduces activity by destabilizing the tetrametic interface. Biochemistry 35 (14), 4287
4297. Buggins, T.R., Dickenson, P.A., Taylor, G., 2007. The effects of pharmaceutical excipients on drug disposition. Adv. Drug Deliv. Rev. 59 (15), 1482
1503. Calandra, S., Tarugi, P., Speedy, H.E., Dean, A.F., Bertolini, S., Shoulders, C.C., 2011. Mechanisms and genetic determinants regulating sterol absorption, circulating LDL levels, and sterol elimination: implications for classification and disease risk. J. Lipid Res. 52, 1885
1926. Cao, X., Antonyuk, S.V., Seetharaman, Sv, Whitson, L.J., Taylor, A.B., Holloway, S.P., et al., 2008. Structures of the G85R variant of SOD1 in familial amyotrophic lateral sclerosis. J. Biol. Chem. 283 (23), 16169
16177. Catinean, A., Neag, M.A., Muntean, D.M., Bocsan, I.C., Buzoianu, A.D., 2018. An overview on the interplay between nutraceuticals and gut microbiota. Peer J. 6, e4465. Available from: https://doi.org/10.7717/ peerj.4465. Cencic, A., Chingwaru, W., 2010. The role of functional foods, nutraceuticals, and food supplements in intestinal health. Nutrients 2, 611
625. Available from: https://doi.org/10.3390/nu2060611. Centers for Disease Control and Prevention, 2018. Type-2 diabetes. ,https://www.cdc.gov/diabetes/basics/ type2.html. (accessed 30.10.18.). Chelikani, P., Fita, I., Loewen, P.C., 2004. Diversity of structures and properties among catalases. Cell. Mol. Life Sci. 61 (2), 192
208. Chuengsamarn, S., Rattanamongkolgul, S., Luechapudiporn, R., Phisalaphong, C., Jirwatnotai, S., 2012. Curcumin extract for prevention of Type-2 diabetes. Diabetes Care 35, 2121
2127. Chuengsamarn, S., Rattanamongkolgul, S., Phonrat, B., Tungtrongchitr, R., Jirawatnotai, S., 2014. Reduction of atherogenic risk in patients with Type-2 diabetes by curcuminoid extract: a randomized controlled trial. J. Nutr. Biochem. 25, 144
150. Cicero, A.F.G., Tartagni, E., Ertek, S., 2013. Nutraceuticals for metabolic syndrome management: from laboratory to benchside. Curr. Vasc. Pharmacol. 11, 1
7. Claussnitzer, M., Dankel, S.N., Kim, K.H., Quon, G., Meuleman, W., Haugen, C., et al., 2015. FTO obesity variant circuitry and adipocyte browning in humans. N. Engl. J. Med. 373 (10), 895
907. Collins, R., Reith, C., Emberson, J., Armitage, J., Baigent, C., Blackwell, L., et al., 2016. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet 388 (10059), 2532
2561. Available from: https://doi.org/10.1016/S0140-6736(16)31357-5. DeFelice, L.S., 1995. The nutraceutical revolution, its impact on food industry. Trends Food Sci Technol. 6, 59
61. DeFelice, L.S., 2014. Nutritional stymied: the nutraceutical solution Plenary Lecture September 9, 2014. XXV National Congress of the Italian Chemical Society-SCI-the University of Calabria. ,www.fimdefelice.org..

REFERENCES

189

De Gregorio, C., Marini, H., Alibrandi, A., DiBenedetto, A., Bitto, A., Adamo, E.B., et al., 2017. Genistein supplementation and cardiac function in postmenopausal women with metabolic syndrome: results from a pilot strain-echo study. Nutrients 9 (6), 584. Available from: https://doi.org/10.3390/nu9060584. Deshpande, A.D., Harris-Hayes, M., Schootman, M., 2008. Epidemiology of diabetes and diabetes-related complications. Phys. Ther. 88 (11), 1254
1264. Devaraj, S., Singh, U., Jialal, I., 2009. Human C-reactive protein and the metabolic syndrome. Curr. Opin. Lipidol. 20 (3), 182
189. Available from: https://doi.org/10.1097/MOL.Ob013e32832ac03e. Doughari, J.H., 2015. The occurrence, properties and significance of citrinin mycotoxin. J. Plant Pathol. Microbiol. 6, 11
17. Dwyer, J.T., Coates, P.M., Smith, M.J., 2018. Dietary supplements: regulatory challenges and research resources. Nutrients 10, 41. Available from: https://doi.org/10.3390/nu10010041. Edwards, J.E., Moore, R.A., 2003. Statins in hypercholesterolaemia: a dose-specific meta-analysis of lipid changes in randomized, double blind trials. BMC Fam. Pract. 4, 18. Available from: https://doi.org/ 10.1186/1471-2296-4-18. Endo, A., 2004. The origin of the statins. Atheroscler. Suppl. 5 (3), 125
130. Epp, O., Ladenstein, R., Wendel, A., 1983. The refined structure of the selenoenzyme glutathione peroxidase at 0.2 nm resolution. Eur. J. Biochem./FEBS 133 (1), 51
69. Erdogrull, O., Azirak, S., 2004. Review of the studies on the red yeast rice (Monascus purpureus). Turkish Electr. J. Biotech. 2, 37
49. Esteve, R.M., 2014. Adipose tissue: cell heterogeneity and functional diversity. Endocrinol. Nutr. 61 (2), 100
102. Available from: https://doi.org/10.1016/j.endonu.2013.03.011. FDA Warning about Red Yeast Rice, 2007. ,https://wayback.archive-it.org/7993/20170112170448/http:// www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm153116. htm.. Ference, B.A., Ginsberg, H.N., Graham, I., Ray, K.K., Packard, C.J., Bruckert, E., et al., 2017. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur. Heart J. 38 (32), 2459
2472. Fister, P., Urh, S., Karner, A., Kurzan, M., Paro-Panjan, D., 2015. The prevalence and pattern of pharmaceutical and excipient exposure in a neonatal unit in Slovenia. J. Matern. Fetal Neonatal Med. 28 (17), 2053
2061. Fletcher, J., 2017. What should my cholesterol level be at my age? MedicalNewsToday. ,https://www.medicalnewstoday.com/articles/315900.php. (accessed 25.10.18.). Fredrickson, D.S., Levy, R.I., Lees, R.S., 1967. Fat transport in lipoproteins
an integrated approach to mechanisms and disorders. N. Engl. J. Med. 276, 34
42, 94
103, 148
156, 215
225, 273
281 (five part review article). Fu, Z., Gilbert, E.R., Pfeiffer, L., et al., 2012. Genistein ameliorates hyperglycemia in a mouse model of nongenetic type 2 diabetes. Appl. Physiol. Nutr. Metab. 37, 480
488. Fung, M.A., Frohlich, J.J., 2002. Common problems in the management of hypertriglyceridemia. CMAJ 167 (11), 1261
1266. Fusier, I., Tollier, C., Husson, M.C., 2003. Medicines containing pharmaceutical excipients with known effects: a French Review. Pharm. World 25 (4), 152
155. Gan, S.I., Edwards, A.L., Symonds, C.J., Beck, P.D., 2006. Hypertriglyceridemia-induced pancreatitis: a casebased review. World J. Gastroenterol. 12 (44), 7197
7202. Ginsberg, H.N., MacCallum, P.R., 2009. The obesity, metabolic syndrome, and type 2 diabetes mellitus pandemic: Part I. Increased cardiovascular disease risk and the importance of atherogenic dyslipidemia in persons with the metabolic syndrome and type 2 diabetes mellitus. J. Cardiometab. Syndr. 4 (2), 113
119.

190

CHAPTER 6 NUTRACEUTICALS AND METABOLIC SYNDROME

Golightly, L.K., Smolinske, S.S., Bennett, M.L., Sutherland III, E.W., Rumack, B.H., 1988. Pharmaceutical excipients adverse effects associated with “Inactive” ingredients in drug products (Part I). Med. Toxicol. 3 (2), 128
165. Gordon, R.Y., Cooperman, T., Obermeyer, W., Becker, D.J., 2012. Marked variability of monacolin levels in commercial red yeast rice products: buyer beware!. Arch. Int. Med. 170 (19), 1722
1727. Gowdaiah, P.K., Manatha, R.R., Nirgude, D., Hosamani, P.B., 2016. High sensitivity C-reactive protein in metabolic syndrome. Int. J. Adv. Med. 3 (3), 607
610. Gradisnik, R., Filipic, B., de Vaureix, C., Lefevre, R., La Bonnardiere, C., Cencic, A., 2006. Establishment of a functional cell culture model of the pig small intestine. LINZ ALTEX 23. ALTEX Altern. Tierexp. 23, 94. Groom, J., 2018. The surprising health benefits of matcha. HeathPrep. ,https://healthprep.com/fitness-nutrition/ health-benefits-ofmatcha/?utm_source 5 google&utm_medium 5 search&utm_campaign 5 1469409739& utm_content 5 58095227678&utm_term 5 matcha%20tea%20drink&gclid 5 EAIaIQobChMI2ZnaxpjD3g IVC5BpCh0IUw4JEAMYASAAEgKjJvD_BwE.. Grundy, S.M., 2006a. Drug therapy of the metabolic syndrome: minimizing the emerging crisis in polypharmacy. Nat. Rev. Drug Discov. 5, 295
309. Grundy, S.M., 2006b. Metabolic syndrome: connecting and reconciling cardiovascular and diabetes worlds. J. Am. Coll. Cardiol. 47 (6), 1093
1100. Haywood, A., Glass, B.D., 2011. Pharmaceutical Excipients. Australian Prescriber. Hayyan, M., Hashim, M.A., AlNashef, I.M., 2016. Superoxide ion: generation and chemical implications. Chem. Rev. 16 (5), 3029
3085. Available from: https://doi.org/10.1021/acs.chemrev.5b00407. Heit, C., Marshall, S., Singh, S., Yu, X., Charkoftaki, G., Zhao, H., et al., 2017. Catalase deletion promotes prediabetic phenotype in mice. Free Radical Biol. Med. 103, 48
56. Herrington, W., Lacey, B., Sherliker, P., Armitage, J., Lewington, S., 2016. Epidemiology of artherosclerosis and the potential to reduce the global burden of atherotherombotic disease. Circ. Res . Available from: https://doi.org/10.1161/CIRCRESAHA.115.307611. High blood pressure: Overview, 2015. Retrieved November 30, 2016, from: ,https://www.ncbi.nlm.nih.gov/ pubmedhealth/PMH0072423/.. Ho, Y.S., Xiong, Y., Ma, W., Spector, A., Ho, D.S., 2004. Mice lacking catalase develop normally but show differential sensitivity to oxidant tissue injury. J. Biol. Chem. 279 (31), 32804
32812. https://www.marketsandmarkets.com/PressReleases/nutraceutical-excipient.asp (accessed October 2018). Ishak, K.A., Annuar, M.M.S., Ahmad, N., 2017. Nano-delivery systems for nutraceutical application (Chapter 9). Nanotechnology Applications in Food. Elsevier, pp. 179
202. James, P.T., Leach, R., Kalamara, E., Shayeghi, M., 2001. The worldwide obesity epidemic. Obes. Res. 9 (Suppl. 4), S228
S233. Janssen, I., Powell, L.H., Drawford, S., Lasley, B., Sutton-Tyrrell, K., 2008. Menopause and the metabolic syndrome: the study of women’s health across the nation. Arch. Intern. Med. 168, 1568
1575. Johnson, K.R., Govel, L.A., Andritz, M.H., 1994. Gastrointestinal effects of sorbitol as an additive in liquid medications. Am. J. Med. 97 (2), 185
191. Kassi, E., Pervanidou, P., Kaltsas, G., Chrousos, G., 2011. Metabolic syndrome: definitions and controversies. BMC Med. 9 (1), 48. Available from: https://doi.org/10.1186/1741-7015-9-48. Kaur, J., 2014. A comprehensive review on metabolic syndrome. Cardiol. Res. Pract. 2014. Available from: http://doi.org/10.1155/2014/943162. Kaur, G., Mukundan, S., Wani, V., Kumar, M.S., 2015. Nutraceuticals in the management and prevention of metabolic syndrome. Austin J. Pharmacol. Ther. 3 (1), 1
6. Kim, S., Kim, C.H., Vaziri, N.D., 2005a. Upregulation of hepatic LDL receptor-related protein in nephrotic syndrome: response to statin therapy. Am. J. Physiol. Endocrinol. Metab. 288, E813
E817. Available from: https://doi.org/10.1152/ajpendo.00266.2004.

REFERENCES

191

Kim, E.J., Shin, H.-K., Park, J.H.Y., 2005b. Genistein inhibits insulin-like growth factor-1 receptor signaling in HT-29 human colon cancer cells: a possible mechanism of the growth inhibitor effect of genistein. J. Med. Food 8 (4), 431
438. Krejci, M.E., Bretz, Ns, Koechel, D.A., 1996. Citrinin produces acute adverse changes in renal function and ultrastructure in pentobarbital-anesthetized dogs without comcomitant reductions in [potassium] plasma. Toxicology 106, 167
177. Kritchevsky, D., 1986. Atherosclerosis and nutrition. Nutr. Int. 2, 290
297. Kuiper, G.G., Lemmen, J.G., Carlsson, B., et al., 1998. Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor β. Endocrinology 139, 4252
4263. Kunnumakkara, A.B., Bordoloi, D., Padmavathi, G., Monisha, J., Roy, N.K., Prasad, S., et al., 2017. Curcumin, the golden nutraceutical: multitargeting for multiple chronic diseases. Br. J. Pharm. 174 (11), 1325
1348. Available from: https://doi.org/10.1111/bph.13621. Kussmaul, L., Hirst, J., 2006. The mechanism of superoxide production by NADH:ubiquinone oxidoreductase (complex I) from bovine heart mitochondria. PNAS 103 (20), 7607
7612. Kylin, E., 1923. Studien u¨ber das Hypertonie-Hyperglyka¨mie-Hyperurika¨mie Syndrom [German]. Z. Innere Med. 44, 105
112. Last, A.R., Ference, J.D., Menzel, E.R., 2017. Hyperlipidemia: drugs for cardiovascular risk reduction in adults. Am. Fam. Phys. 95 (2), 78
87. Lee, J.W., Morris, J.K., Wald, N.J., 2016. Grapefruit juice and statins. Am. J. Med. 129, 26
29. Lin, J.K., Lin, C.H., Ling, Y.C., Lin-Shian, S.Y., Juan, I.M., 1998. Survey of catechins, gallic acid and methylxanthines in green, oolong, puerch and black teas. J. Agric. Food Chem. 46, 3635
3642. Llaneza, P., Gonzalez, D., Fernandez-Inarreak, J., et al., 2011. Soy isoflavones, diet, and physical exercise modify serum cytokines in healthy obese postmenopausal women. Phytomedicine 18, 245
250. Lobo, V., Patil, A., Phatak, A., Chandra, N., 2010. Free radicals, antioxidants and functional foods: impact on human health. Pharmacogn. Rev. 4 (8), 118
126. Available from: https://doi.org/10.4103/09737847.70902. Lowe, D., 2017. Curcumin will waste your time. In the Pipeline. ,http://blogs.sciencemag.org/pipeline/ archives/2017/01/12/curcumin-will-waste-your-time.. Lusis, A.J., 2000. Atherosclerosis. Nature 407, 233
241. Lusis, A.J., 2012. Genetics of atherosclerosis. Trends Genet. 28 (6), 267
275. Madhusoodanan, J., 2018. The secret life of fat cells. ACS Cent. Sci. 4 (9), 1078
1080. Maehley, A.C., Chance, B., 1954. The assay of catalases and peroxidases. Methods Biochem. Anal. 1, 357
424. Mahady, G., Parrot, J., Lee, C., Yun, G., Dan, A., 2003. Botanical dietary supplement use in peri- and postmenopausal women. Menopause 10, 65
72. Mahan, L.K., Raymond, J.L., Escott-Stump, S., 2011. Krause’s Food and the Nutrition Care Process, thirteenth ed. Elsevier, Inc9781437722338. McCord, J.M., Fridovich, I., 1969. Superoxide dismutase. An enzymic function for erythrocuprein (hemocuprein). J. Biol. Chem. 244 (22), 6049
6055. McFarland, A.J., Anoopkumar-Dukie, S., Arora, D.S., Grant, G.D., McDermott, C.J., Perkins, A.V., et al., 2014. Molecular mechanisms underlying the effects of statins in the central nervous system. Int. J. Mol. Sci. 15 (1), 20607
20637. Available from: https://doi.org/10.3390/ijms151120607. Metabolic syndrome, 2014. Retrieved November 30, 2016, from: ,https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0062969/.. Metabolic syndrome - Symptoms and causes - Mayo Clinic. Retrieved October 31, 2018, from: ,https://www. mayoclinic.org/diseases-conditions/metabolic-syndrome/symptoms-causes/syc-20351916.. Methodist Hospital Pathology Center, Technical Bulletin, 2011. ,http://thepathologycenter.org/uploads/PDFs/ resources/CRP%20and%20hs%20CPR%20Measure%20the%20Same%20Thing.pdf..

192

CHAPTER 6 NUTRACEUTICALS AND METABOLIC SYNDROME

Mills, S., 2007. Pharmaceutical Excipients-An Overview Including Consideration for Pediatric Dosing. The World Health Organization, New York, NY, ,www.nps.org.au/australian-prescriber/articles/pharmaceutical-excipients-where-do-we-begin. (accessed 07.10.18.). Moore, J.X., Chaudhary, N., Akinyemiju, T., 2017. Metabolic syndrome prevalence by race/ethnicity and sex in the United States, National Health and Nutrition Examination Survey, 1988-2012. Prev. Chronic Dis. 14, 160287. Available from: https://doi.org/10.5888/pcd14.160287. Mora, S., Rifai, N., Buring, J.E., Ridker, P.M., 2008. Fasting compared with nonfasting lipids and apolipoproteins for predicting incident cardiovascular events. Circulation 118, 993
1001. Na, L.X., Yan, B.L., Jiang, S., Cui, H.L., Li, Y., Sun, C.H., 2014. Curcuminoids target decreasing serum adipocyte-fatty acid binding protein levels in the flucose-lowering effect in patients with Type-2 diabetes. Biomed. Environ. Sci. 27, 902
906. Nagaraju, G.P., Zafar, S.F., El Rayes, B.F., 2013. Pleiotropic effects of genistein in metabolic, inflammatory, and malignant diseases. Nutr. Rev. 1
11. Available from: https://doi.org/10.1111/nure.12044. Nahata, M.C., 2009. Safety of “inert” additives or excipients in pediatric medicines. Arch. Dis. Child. Fetal Neonatal Ed. 94, F392
F393. Nash, D.T., 2005. Relationship of C-reactive protein, metabolic syndrome and diabetes mellitus: potential role of statins. J. Natl. Med. Assoc. 97 (12), 1600
1607. Nasri, H., Baradaran, A., Shirzad, H., Rafieian-Kopaei, M., 2014. New concepts in nutraceuticals as alternative for pharmaceuticals. Int. J. Prevent. Med. 5 (12), 1487
1499. NIH Atherosclerosis, 2018. ,https://www.nhlbi.nih.gov/health-topics/atherosclerosis.. Nolan, P.B., Carrick-Ranson, G., Stinear, J.W., Reading, S.A., Dalleck, L.C., 2017. Prevalence of metabolic syndrome and metabolic syndrome components in young adults: a pooled analysis. Prevent. Med. Rep. 7, 211
215. Nordestgaard, B.G., Langsted, A., Mora, S., Kolovou, F., et al., 2016. Fasting is not routinely required for determination of a lipid profile: clinical and laboratory implications including gladding at desirable concentration cut-points-a joint consensus statement from the European Atherosclerosis Society and European Federation of Clinical Chemistry and Laboratory Medicine. Eur. Heart J. 37, 1944
1958. North American Menopause Society, 2011. The role of soy isoflavones in menopausal health: report of The North American menopauseSociety/Wulf H. Utian Translational Science Symposium in Chicago, IL, October 2010. Orgaard, A., Jensen, L., 2008. The effects of soy isoflavones on obesity. Exp. Biol. Med. (Maywood) 233, 1066
1080. Panchal, S.K., Brown, L., 2011. Rodent models for metabolic syndrome research. J. Biomed. Biotechnol. Available from: https://doi.org/10.1155/2011/351982Article ID 351982, 14 pages. Pifferi, G., Santoro, P., Pedrani, M., 1999. Quality and functionality of excipients. Farmaco 54 (1
2), 1
14. Pritiken Longevity Center, 2018. Pritikin diet & eating plan. ,https://www.pritikin.com/healthiest-diet/pritikin-eating-plan. (accessed 31.10.18.). Pungcharoenkul, K., Thongnopnua, P., 2011. Effect of different curcuminoid supplement dosages on total in vivo antioxidant capacity and cholesterol levels of healthy human subjects. Phytother. Res. 25, 1721
1726. Radhika, P.R., Singh, R.B.M., Sivakumar, T., 2011. Nutraceuticals: an area of tremendous scope. Int. J. Res. Ayurveda Pharm. 2 (2), 410
415. Ranke, M.B., 2015. Treatment with recombinant human insulin-like growth factor-1 in severe primary IGF deficiency and beyond. Horm. Res. Paediatr. 83, 358
360. Reaven, G.M., Banting Lecture, 1988. Role of insulin resistance in human disease. Diabetes 37, 1595
1607. Reiter, R.J., Melchiorri, D., Sewerynet, E., et al., 1995. A review of the evidence supporting melatonin’s role as an antioxidant. J. Pineal Res. 18 (1), 1
11.

REFERENCES

193

Ridker, P.M., Glynn, R.J., Hennekens, C.H., 1998. C-reactive protein adds to the predictive value of total and HDL cholesterol in determining risk of first myocardial infarction. Circulation 97, 2007
2011. Ridker, P.M., Hennekens, C.H., Buring, J.E., Rifai, N., 2000. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N. Engl. J. Med. 342, 836
843. Ridker, P.M., Buring, J.E., Cook, N.R., Rifai, N., 2003. C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events: an 8-year follow-up of 14719 initially healthy American women. Circulation 107, 391
3397. Ridker, P.M., Wilson, P.W.F., Grunday, S.M., 2004. Should C-reactive protein be added to metabolic syndrome and to assessment of global cardiovascular risk? Circulation 109, 2818
2825. Roberts, C.K., Hevener, A.L., Barnard, R.J., 2013. Metabolic syndrome and insulin resistance: underlying causes and modification by exercise training. Compr. Physiol. 3 (1), 1
58. Ronis, M.J.J., Pedersen, K.B., Watt, J., 2018. Adverse Effects of nutraceuticals and dietary supplements. Annu. Rev. Pharmacol. Toxicol. 58, 583
601. Russo, R., Gallelli, L., Cannataro, R., et al., 2016. When nutraceuticals reinforce drug side effects: a case report. Curr. Drug Safety 11 (999), 1-1. Sahu, P.K., Sahu, P.K., Sahu, P.L., Agarwal, D.D., 2016. Structure activity relationship, cytotoxicity and evaluation of antioxidant activity of curcumin derivatives. Bioorg. Med. Chem. Lett. 26, 1342
1347. Saklayen, M.G., 2018. The global epidemic of the metabolic syndrome. Curr. Hypertens. Rep. 20 (2), 12. Available from: https://doi.org/10.1007/s11906-018-0812-z. Salas, R.T.G., Guevara-Cruz, M., Villanueva-Luna, P., Guizar-Heredia, M., Villalobos, G.H.T., Ontivros, E.P., et al., 2017. Effect of the bioactive compounds genistein and resveratrol on insulin resistance in patients with metabolic syndrome. FASAB J. 31 (1), Suppl. 944.10. Santini, A., Novellino, E., 2017. Nutraceuticals in hypercholesterolaemia: an overview. Br. J. Pharm. 174, 1450
1463. Santini, A., Cammarata, S.M., Dapone, G., Ianaro, A., Tenore, G.C., Pani, L., et al., 2018. Nutraceuticals: opening the debate for a regulatory framework. Br. J. Clin. Pharmacol. 84, 659
672. Scarth, J., 2006. Modulation of the growth hormone-insulin-like growth factor (GH-IGF) axis by pharmaceutical, nutraceutical and environmental xenobiotics: an emerging role for xenobiotic-metabolizing enzymes and the transcription factors regulating their expression. A review. Xenobiotica 36 (2
3), 119
218. Sedigni, O., Makhlough, A., Shokrzadeh, M., Hoorshad, S., 2014. Association between plasma selenium and glutathione peroxidase levels and severity of diabetic nephropathy in patients with type two diabetes mellitus. Nephro-Urology Monthly 6 (5), 321355. Seidell, J.D., 2000. Obesity, insulin resistance, and diabetes-a worldwide epidemic. Br. J. Nutr. 83 (Suppl. 1), S5
S8. Shomon, M., 2018. Soy and the thyroid: a look at the controversies. Verywellhealth. ,https://www.verywellhealth.com/soy-and-the-thyroid-3231800. (accessed 25.10.18.). Shurtleff, W., Aoyagi, A., 2012. History of Koji - Grains and/or Beans Overgrown with a Mold Culture (300 BCE to 2012). Soyinfo Center, Lafayette, CA. Sies, H., 1993. Strategies of antioxidant defense. Eur. J. Biochem. 215 (2), 213
219. Singh, A.K., Kari, J.A., 2013. Metabolic syndrome and chronic kidney disease. Curr. Opin. Nephrol. Hypertens. 22 (2), 198
203. Available from: https://doi.org/10.1097/MNH.0b013e32835dda78. Singh, J., Sinha, S., 2012. Classification, regulatory acts and applications of nutraceuticals for health. Int. J. Pharm. Biol. Sci. 1, 177
187. Sirtori, C.R., Pavanello, C., Calagresi, L., Ruscica, M., 2017. Nutraceutical approaches to metabolic syndrome. Ann. Med. 49 (8), 678
697. Available from: https://doi.org/10.1080/07853890.2017.1366042.

194

CHAPTER 6 NUTRACEUTICALS AND METABOLIC SYNDROME

Socha, K., Kochanowicz, J., Karpinska, E., Soroczynska, J., Jakoniuk, M., Mariak, Z., et al., 2014. Dietary habits and selenium, glutathione peroxidase and total antioxidant status in the serum of patients with relapsing-remitting multiple sclerosis. Nutr. J. 13, 62. Squadrito, F., Marini, H., Bitto, A., Altavilla, D., Polito, F., Adamo, E.B., et al., 2013. Genistein in the metabolic syndrome: results of a randomized clinical trial. J. Clin. Endocrinol. Metab. 98 (8), 3366
3374. Srikanthan, K.F.A., Visweshwar, H., Shapiro, J.I., Sodhi, K., 2016. Systematic review of metabolic syndrome biomarkers: a panel for early detection, management, and risk stratification in the West Virginian population. Int. J. Med. Sci. 13 (1), 25
38. Available from: https://doi.org/10.7150/ijms.13800. Stoppler, M.C., 2018. C-reactive protein CRP test, ranges, symptoms, and treatment. MedicineNet. ,https:// www.medicinenet.com/c-reactive_protein_test_crp/article.htm#what_is_c-reactive_protein_crp.. Sun, M., Zhang, L., Chen, S., Liu, X., Shao, X., Zou, H., 2015. Association of C-reactive protein and metabolic disorder in a Chinese population. Int. J. Environ. Res. Public Health 12 (7), 8228
8242. Swerlick, R.A., Campbell, C.F., 2013. Medication dyes as a source of drug allergy. J. Drugs Dermatol. 12 (1), 99
102. Szkudelska, K., Nogowski, L., 2007. Genistein-a dietary compound inducing hormonal and metabolic changes. J. Steroid Biochem. Mol. Biol. 105, 37
45. Tang, Y., Zheng, S., Chen, A., 2009. Curcumin eliminates leptin’s effects on hepatic stellate cell activation via interrupting leptin signaling. Endocrinology 150 (7), 3011
3020. Timpson, N.J., Lawlor, D.A., Harbard, R.J., Gaunt, T.R., Day, I.N.M., Palmer, L.J., et al., 2005. C-reactive protein and its role in metabolic syndrome: mendelian randomization study. Lancet 366, 1954
1959. Valsecchi, A.E., Franchi, S., Panerai, A.E., et al., 2011. The soy isoflavone genistein reverses oxidative and inflammatory state, neuropathic pain, neurotropic and vascular deficient in diabetes mouse model. Eur. J. Pharmacol. 650, 694
702. Vrani´c, E., 2004. Basic principles of drug-excipient interactions. BJBMS 4 (2), 56
58. Wang, Y.L., 1993. Adverse effects of pharmaceutical excipients in drug therapy. Ann. Acad. Med. Singapore 22 (1), 99
102. WebMD, 2018. What is the definition of hyperlipidemia. ,https://www.webmd.com/heart-disease/heart-failure/qa/what-is-the-definition-of-hyperlipidemia.. Williams, S., 2017. The 19 best-selling prescription drugs of all times. The Motley Fool. ,https://www.fool. com/investing/2017/03/13/the-19-best-selling-prescription-drugs-of-all-time.aspx.. Wilt, T.J., Bloomfield, H.E., MacDonald, R., Nelson, D., Rutks, I., Ho, M., et al., 2004. Effectiveness of statin therapy in adults with coronary heart disease. Arch. Intern. Med. 164 (13), 1427
1436. World Health Organization: Global Report on Diabetes, 2017. ,www.who.int/diabetes/global-report/. (accessed 29.10.18.). World Health Organization: Obesity and Overweight, 2018. ,www.who.int/news-room/fact-sheets/detail/ obesity-and-overweight. (accessed 31.10.18.). Xia, X., Weng, J., 2010. Targeting metaolic syndrome: candidate natural agents. J. Diabetes 2, 243
249. Xiong, X., Wang, P., Li, W.X., Zhang, Y., Li, S., 2017. The effects of red yeast rice dietary supplement on blood pressure, lipids profile, and C-reactive protein in hypertension: a systematic review. Crit. Rev. Food Sci. Nutr. 57 (9), 1
6. Available from: https://doi.org/10.1080/10408398.2015.1018987. Yang, L., Colditz, G.A., 2015. Prevalence of overweight and obesity in the United States, 2007-2012. JAMA Intern. Med. 175 (8), 1412
1413. Yang, S., Jensen, M.K., Rimm, E.B., Willett, W., Wu, T., 2014. Erythrocyte superoxide dismutase, glutathione peroxidase, and catalase activities and risk of coronary heart disease in generally healthy women: a prospective study. Am. J. Epidemiol. 180 (9), 901
908.

FURTHER READING

195

Yang, C.S., Zhang, J., Zhang, L., Huang, J., Wang, Y., 2017. Mechanisms of body weight reduction and metabolic syndrome alleviation by tea. Mol. Nutr. Food Res. 60 (1), 160
174. Available from: https://doi.org/ 10.1002/mnfr.201500428. Yin, J., Zhang, H., Ye, J., 2008. Traditional Chinese medicine in treatment of metabolic syndrome. Endocr. Metab. Immune. Disord. Drug Targets 8 (2), 99
111. Younes, M., Aggett, P., Aguilar, F., Crebelli, R., Dusemund, B., et al., 2018. Scientific opinion of the safety on monacolins in red yeast rice. EFSA J. Available from: https://doi.org/10.2903/j.efsa.2018.5368published by John Wiley and Sons, Ltd on behalf of European Food Safety Authority. Zhang, Y., Proenca, R., Maffei, J., Barone, M., Leopold, L., Friedman, J.M., 1994. Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425
432. Ziki, M.D.A., Mani, A., 2017. Metabolic syndrome: genetic insights into disease pathogenesis. Curr. Opin. Lipidol. 27 (2), 162
171.

FURTHER READING Dietary supplement - Wikipedia ,https://en.wikipedia.org/wiki/Dietary_supplement. (accessed October 2018). WebMD, 2016. FAQs about dietary supplements. ,https://www.webmd.com/vitamins-and-supplements/supplement-faq..

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FOOD MATRICES THAT IMPROVE THE ORAL BIOAVAILABILITY OF PHARMACEUTICALS AND NUTRACEUTICALS

7

Sheila C. Oliveira-Alves1, Ana Teresa Serra1,2 and Maria R. Bronze1,2,3 1

iBET, Instituto de Biologia Experimental e Tecnolo´gica, Oeiras, Portugal 2ITQB, Instituto de Tecnologia Quı´mica e Biolo´gica Anto´nio Xavier, Universidade Nova de Lisboa, Oeiras, Portugal 3iMed.ULisboa, ´ Faculdade de Farmacia, Universidade de Lisboa, Av. das Forc¸as Armadas, Lisboa, Portugal

CHAPTER OUTLINE 7.1 Introduction ................................................................................................................................. 197 7.2 The Concept of Bioaccessibility, Bioavailability, and Bioactivity ..................................................... 199 7.3 Factors That Limit the Oral Bioavailability of Lipophilic Bioactive Agents ........................................ 201 7.3.1 Bioaccessibility ........................................................................................................ 203 7.3.2 Absorption ............................................................................................................... 204 7.3.3 Transformation ......................................................................................................... 208 7.4 Food Matrix Design That Improve the Oral Bioavailability of Lipophilic Compounds .......................... 209 7.4.1 Delivery Systems ...................................................................................................... 209 7.4.2 Excipient Systems .................................................................................................... 220 7.5 Conclusion .................................................................................................................................. 222 References ......................................................................................................................................... 222 Further Reading .................................................................................................................................. 231

7.1 INTRODUCTION The nutraceuticals are bioactive substances commonly found in foods, such as fruits, vegetables, edible seeds, nuts, and cereals, which are therefore often consumed in this form and provide health benefits. Nutraceuticals found in foods may not be essential for maintaining normal human functions, but may enhance human health and well-being by inhibiting certain diseases or improving human performance (McClements and Xiao, 2017). Many of these nutraceutical ingredients isolated from foods or nature state are used in medicinal and commercial industries for cosmetics, dietary supplements, fortified foods, and additives (Kuppusamy et al., 2014).

Nutraceuticals and Natural Product Pharmaceuticals. DOI: https://doi.org/10.1016/B978-0-12-816450-1.00007-6 © 2019 Elsevier Inc. All rights reserved.

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Numerous different classes of nutraceuticals are found in both natural and processed foods including flavonoids, terpenes, isothiocyanates, curcuminoids, phenolic acids, bioactive peptides, bioactive polysaccharides, vitamins, and lipophilic bioactives (Holst and Williamson, 2008; Chai et al., 2018). The lipophilic bioactives have gained attention as their regular consumption and body tissue levels have been associated with several health benefits, especially in reducing the risks of many diseases, such as diabetes (Miyashita et al., 2018; Itsiopoulos et al., 2018), cancer (Guam´anOrtiz et al., 2017; Eltweri et al., 2017), cardiovascular diseases (Colussi et al., 2017; Petyaev et al., 2018), and neurodegenerative diseases (Hooper et al., 2018; Cho et al., 2018). The main lipophilic bioactive agents include nutrients, such as oil-soluble vitamins (such as vitamins A, D, and E), polyunsaturated fatty acids (such as omega-3 family), carotenoids (such as astaxanthin, lutein, β-carotene, and lycopene,) and phytosterols (such as campesterol, β-sitosterol, and stigmasterol), or nutrients that are soluble in lipids such as coenzyme Q10, curcumin, and triterpenoids from olive oil. However, the potential health benefits of these lipophilic bioactives are often not fully realized because of their chemical instability, poor water solubility, and low oral bioavailability (BA) after ingestion (Fern´andez-Garcı´a et al., 2012; Rein et al., 2013; McClements et al., 2015a). Indeed, studies have shown that the lipophilic bioactives derived from plants or food sources need to be bioavailable in order to exert any beneficial effects (McClements et al., 2008; McClements and Xiao, 2014; Zhang and McClements, 2016). Therefore BA is a key step in ensuring bioefficacy of bioactive agents, and their bioefficacy may be improved through enhanced BA (Rein et al., 2013). The BA of bioactive compounds can be enhanced using two major strategies (Fig. 7.1). In the first strategy, the bioactive compounds are isolated from natural sources (such as plants, animal, microorganism or food), purified, and then converted into a nutraceutical ingredient, such

FIGURE 7.1 Schematic diagram of the difference between functional and excipient foods. Adapted from McClements, D.J., Xiao, H., 2014. Excipient foods: designing food matrices that improve the oral bioavailability of pharmaceuticals and nutraceuticals. Food Funct. 5, 1320
1333.

7.2 THE CONCEPT OF BIOACCESSIBILITY

199

as vitamin D, lycopene, β-carotene, α-linolenic acid (ALA), lutein, and others, which are then incorporated into a food matrix, such as food or beverage products (McClements and Xiao, 2014; McClements, 2017a). Alternatively, the functional food contains one or more nutraceutical ingredients that can be dispersed directly within a food matrix or a suitable delivery system, and this delivery system is then incorporated into a food matrix (McClements and Xiao, 2014; McClements et al., 2016; McClements, 2017a). The nutraceuticals isolated from a natural source are encapsulated within a delivery system that is specifically designed to enhance their bioavailability, an example of this approach would be a ω-3 fatty acid ingredient isolated from fish oil or oilseed that is encapsulated within an oil-in-water emulsion that could then be added within a food matrix, such as yogurts, sauces, margarines, or milk drinks (Ruiz Ruiz et al., 2015; Komaiko et al., 2016). Emulsion-based delivery systems are widely used in the food industry, due to their ease of fabrication from widely used food ingredients and processing operations. Thus delivery systems must be carefully designed to ensure that they are compatible with the food, so they can be incorporated in a safe, economic, effective, convenient, and effective form (McClements et al., 2016). In the second strategy, the bioactive compounds are kept in their natural source, and are coingested with specifically designed excipient foods (McClements and Xiao, 2014; McClements et al., 2016; McClements, 2017a). These namely excipient foods do not have any biological activity themselves, but they enhance the BA of the bioactive compounds in the foods when they are ingested together by increasing their bioaccessibility, thereby boosting their bioactivity and potential health benefits (McClements and Xiao, 2014; McClements et al., 2016). An example of this approach is an oil-in-water excipient emulsion consumed at the same with yellow peppers, which increases the carotenoid bioaccessibility from yellow peppers (Liu et al., 2015). In summary, oil-in-water emulsions can be used as delivery systems or as excipient systems, but for delivery systems, the bioactive agents are encapsulated within the oil phase of the emulsion, and for excipient systems a bioactive-free emulsion is consumed with a bioactive-rich food (Zhang and McClements, 2016). In this chapter, we focus on enhancing the BA of lipophilic bioactive agents found in foods (fruits and vegetables), but the same principles could also be applied to other supplements and pharmaceuticals. In the remainder of this review, the concept of BA, bioaccessibility, and bioactivity is initially considered, prior highlighting the main factors, limiting the BA of lipophilic bioactive components, and discussing the improve of oral BA of lipophilic compounds using a delivery system and excipient system in food products.

7.2 THE CONCEPT OF BIOACCESSIBILITY, BIOAVAILABILITY, AND BIOACTIVITY On oral consumption, the uptake of nutrients and phytochemicals into the body is not complete, and a certain percentage is not absorbed. To quantify the amount that is actually absorbed, distributed to the tissue, metabolized and eventually excreted, the term BA was introduced (Holst and Williamson, 2008). Oral BA has been defined as the fraction of an ingested component (or its metabolic products) that eventually ends up in the systemic circulation and is available for use in physiologic functions

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or to be stored in the body (Holst and Williamson, 2008; Cardoso et al., 2015; Arroyo-Maya and McClements, 2016). From the nutritional point of view, the overall BA of lipophilic bioactives can be defined as (Arroyo-Maya and McClements, 2016; McClements and Xiao, 2017): BA 5 FB 3 FA 3 FT

(7.1)

Here, bioaccessibility coefficient (FB) is defined as the fraction of lipophilic bioactives released from the food matrix in the gastrointestinal lumen and thereby made available for intestinal absorption; absorption coefficient (FA) is the fraction of bioaccessible lipophilic bioactives absorbed by the intestinal epithelium; and transformation coefficient (FT) is the fraction of lipophilic bioactives that reach the systemic circulation in a metabolically active form. After the lipophilic compounds reach the systemic circulation they are distributed between different tissues, where they may be stored, utilized, or excreted (Arroyo-Maya and McClements, 2016). Indeed, a lipophilic bioactive agent BA encompasses the release of the food matrix and concomitant availability for absorption, absorption itself, metabolism, tissue distribution, and bioactivity (Fern´andezGarcı´a et al., 2009; Cardoso et al., 2015). Thus the BA of lipophilic bioactives may be limited by three main factors: bioaccessibility, absorption, and transformation (McClements and Xiao, 2017). Bioaccessibility has been defined as the quantity or fraction of compound that is released from the food matrix within the human gastrointestinal tract (GIT) and is in the right form to be absorbed (Holst and Williamson, 2008). For lipophilic bioactive agents, bioaccessibility is defined as the fraction of lipophilic compound solubilized within the mixed micelle phase after lipid digestion and absorbed through epithelial tissue. Bioaccessibility encompasses all sequences of events that occur during the digestive process of food into the human body, which includes the release of lipophilic bioactives from the food matrix, solubilization in the gastrointestinal fluids, interactions with other components within the GIT, absorption through epithelial tissue, and presystemic intestinal and hepatic metabolism (Fern´andezGarcı´a et al., 2009; McClements, 2018c). Therefore bioaccessibility can be described as the sum of digestibility and absorption (Fern´andez-Garcı´a et al., 2012). The absorption of lipophilic bioactives can be influenced by solubility, interactions with other dietary ingredients, molecular transformations, different cellular transporters, metabolism and the interaction with the gut microbiota, resulting in changes in their BA (Rein et al., 2013; Alminger et al., 2014). In this context, BA involves the efficient digestion and assimilation of a nutrient or bioactive compound, which once absorbed, performs a positive function in the body. Indeed, the concept of BA includes bioaccessibility and bioactivity terms, as shown in Fig. 7.2 (Fern´andezGarcı´a et al., 2009; Cardoso et al., 2015). Bioactivity is a set of phenomena that occur after a nutrient or bioactive compound has reached systemic circulation, which includes transport to target tissue, absorption by the target tissue, phenomena linked to biomolecular interactions, metabolism in the target tissue, generation of a biomarker, and physiological effects (Fern´andez-Garcı´a et al., 2009; Cardoso et al., 2015). Bioactive compound is simply a substance that has biological activity and the ability to modulate one or more metabolic processes, which result in the promotion of health. Thus a lipophilic bioactive compound is defined as a component from food or dietary supplements that has a positive effect on the organism, in other words, causes a reaction or triggers a response in the living tissue (Guaadaoui et al., 2014). Indeed, the concept of BA includes availability for absorption, metabolism, tissue distribution, and bioactivity. Therefore the possible effectiveness of lipophilic bioactive agents in the human body is determined by their BA. In general, the most abundant lipophilic bioactives in our diet are

7.3 FACTORS THAT LIMIT THE ORAL BIOAVAILABILITY

201

FIGURE 7.2 The concept of bioavailability. ´ ´ ´ ´ Adapted from Fernandez-Garcı´a, E., Carvajal-Lerida, I., Perez-G alvez, A., 2009. In vitro bioaccessibility assessment as a prediction tool of nutritional efficiency. Nutr. Res. 29, 751
760.

not necessarily those able to result in the highest tissue concentrations or those revealing biological effects (Manach et al., 2005; Alminger et al., 2014). Therefore many researches have focused to study the main factors that limit the oral BA of lipophilic bioactive agents and to develop different types of delivery systems and excipient systems that can be used to improve their BA.

7.3 FACTORS THAT LIMIT THE ORAL BIOAVAILABILITY OF LIPOPHILIC BIOACTIVE AGENTS Lipophilic compounds are basic constituents of the human diet and take an active part in the acceptability, flavor, and perception of foods (Meynier and Genot, 2017). These compounds may be found in solid or liquid form, and may be surrounded by complex food matrices that impact their release, digestion, and absorption (McClements, 2018b). The lipophilic compounds in a food may not be initially accessible by the lipases and other enzymes originating from the stomach and small intestine, as they are trapped in an impermeable matrix, such as protein, sugars, and dietary fiber (McClements et al., 2008).

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The oral BA of lipophilic bioactive agents is relatively low due to their low bioaccessibility, poor solubility, susceptibility to degradation, and low absorption rate through the small intestinal epithelium (Salvia-Trujillo et al., 2016; Chai et al., 2018). Bioaccessibility of lipophilic compound is influenced by the composition of the digested food matrix, the synergisms, and antagonisms of the different components, but also by physicochemical properties, such as pH, temperature, and texture of the matrix (Fern´andez-Garcı´a et al., 2009; Rein et al., 2013). There are a number of factors that limit the oral bioavailability of lipophilic compounds found in foods. The classification of the bioavailability of lipophilic compounds can be been described using a nutraceutical bioavailability classification scheme (NuBACS), which has recently been discussed in detail elsewhere (McClements et al., 2015a, 2016). The coefficient parameters FB, FA, and FT represent the fractions of overall oral BA of the nutraceutical ingredient. The bioaccessibility coefficient (FB) is mainly influenced by the compounds’ liberation from the food matrix (L), poor solubility in the gastrointestinal fluids (S), and possible interactions that might promote insolubility (I). The absorption coefficient (FA) is affected by physicochemical and physiological factors, such as poor transport through the mucus layer (ML), membrane permeation (MP), the presence of efflux transporters (ET) in the epithelium cells, inhibition of active transporters (AT) and tight junctions (TJ). The transformation coefficient (FT) of lipophilic compounds is affected by changes in their activity due to chemical (CT) or biochemical (BT) transformation. The above-mentioned factors that limit the oral BA have been summarized in Fig. 7.3.

FIGURE 7.3 The major factors that may limit the oral bioavailability of lipophilic compounds. Adapted from McClements, D.J., Li, F., Xiao, H., 2015a. The nutraceutical bioavailability classification scheme: classifying nutraceuticals according to factors limiting their oral bioavailability. Annu. Rev. Food Sci. Technol. 6, 13.11
13.29.

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203

7.3.1 BIOACCESSIBILITY Bioaccessibility describes the fraction of a compound potentially available for further uptake and absorption. Due to the complexity of food compounds, many factors affect their transition during digestion, and also to the different mechanisms of absorption of water soluble and lipid soluble molecules, unraveling the BA of food constituents (Rein et al., 2013). Therefore the amount of any nutraceutical bioaccessible may differ greatly from its total concentration in the native food matrix. In vitro studies have reported that the bioaccessibility (micelle solubilization) and absorption (cell culture uptake) of lipophilic bioactive agents from fruits and vegetables are greatly increased in the presence of lipids (McClements and Xiao, 2014). In solid foods, mastication may facilitate the release of a significant fraction of bioactives (Salvia-Trujillo et al., 2016). For example, an increase in carotenoid bioaccessibility has been reported after mastication of mangoes (Low et al., 2015). However, this release is not always complete and there may still be a significant part of bioactive compounds trapped in the food matrix. In this context, the bioaccessibility may be affected by three main factors in the GIT: •

•

Liberation (L): The bioaccessibility of a lipophilic bioactive agent may be limited by its ability to be released from the food matrix. After ingestion, the lipophilic compounds should be released from the food matrix and delivered to the appropriate site-of-action within the human body. However, depending on the type of food, the lipophilic compounds may be rapidly released from the food matrix during digestion, or they can be fully or partially retained (SalviaTrujillo et al., 2016). Certain types of lipophilic compounds found in natural or processed food are trapped within specific structure, such as plant or animal cells and solid matrices (McClements and Xiao, 2017). Consequently, the lipophilic compounds have to be released from these structures before they can be absorbed. For example, carotenoid bioaccessibility is generally quite low in raw fruits and vegetables, since carotenoids need to be released from the cellular matrix. Carotenoids are located inside the plant cells within the chromoplast organelles, and the release of carotenoids from fruits/vegetables food matrix represents a crucial step (Palmero et al., 2016). For this reason, the natural foods have to be processed to facilitate the release of the nutraceutical ingredients. The method of food preparation and the chemical composition of the plant food may increase or reduce the carotenoid BA. Studies have demonstrated that the moderate cooking, mashing, and grating destroy plant tissue structure, thereby increasing surface area and interactions of hydrolytic enzymes and emulsifiers with food particles during the gastric and small intestinal phases of digestion, and consequently increasing the carotenoid BA (Horvitz et al., 2004; Failla and Chitchumroonchokchai, 2005; Cilla et al., 2018). In addition, studies reported that the strong resistance of almond cell walls limits the release of lipophilic compounds and their level of absorption increases with a higher degree of mastication (Ellis et al., 2004; Cassady et al., 2009; Michalski et al., 2013). Solubilization (S): The poor solubility of lipophilic compounds seriously hinders their dissolution in aqueous medium and absorption under gastrointestinal conditions in the human body and consequently limits their bioaccessibility (Chai et al., 2018). Moreover, low solubility in water and chemical instability of these compounds are the main causes of their low BA since they must pass through many barriers before being absorbed. The lipophilic compounds usually have to be incorporated into the hydrophobic inside the mixed micelles formed in the gastrointestinal fluids before they can be absorbed (McClements and Xiao, 2017). The mixed

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micelle phase is actually a complex colloidal dispersion consisting of micelles, vesicles, liquid crystals, and other structures that can solubilize lipophilic bioactives (McClements and Xiao, 2014; McClements et al., 2016). The ingestion of high amounts of lipids favors the production of digestion enzymes and bile salts, increasing the solubilization capacity of the mixed micelle phase (Salvia-Trujillo et al., 2016). For example, carotenoids must be emulsified in the lipid phase of chyme, and solubilized into mixed micelles in the lumen to be accessible for uptake by absorptive epithelial cells (Failla and Chitchumroonchokchai, 2005). Studies have shown that diets content in long fatty acid chains in triglyceride molecules improve the bioaccessibility and BA of carotenoids (Borel et al.,1998; Huo et al., 2007). The lipid digestion products, such as free fatty acids, monoglycerides, phospholipids, and fat-soluble vitamins are solubilized in mixed micelles with bile salts and other surfactant molecules, which are absorbed into the systematic bloodstream (Joyce et al., 2016). Therefore a key event in the absorption of digested lipids is their solubilization within mixed bile salt/phospholipid micelles and vesicles and their subsequent transport to the stomach intestinal walls (Porter et al., 2007; McClements et al., 2008). Interactions (I): The foods contain various types of different components, including proteins, polysaccharides, dietary fibers, minerals, and chelating agents that can physically interact with lipophilic compounds or interfere with micelle formation, and thereby increase or decrease their absorption (McClements et al., 2008; McClements and Xiao, 2017). Some lipophilic compounds may interact with polysaccharides, dietary fibers, or other components within the GIT and form insoluble complexes that are not absorbed. For example, long-chain fatty acids can form insoluble salts with calcium and magnesium in the small intestine that are not easily absorbed (McClements et al., 2008, 2016). Verrijssen et al. (2015) attributed the low BA of β-carotene, possibly due to interaction of pectin with the micelles, as it might change the surface properties and influence the micellar incorporation. Thereby, Riedl et al. (1999) demonstrated that citrus pectin reduced the BA of β-carotene by 42% and found that soluble fiber, like pectin, has a stronger effect than insoluble fiber. Yonekura and Nagao (2009) reported that soluble fibers inhibited carotenoid micellization mainly by increasing the medium viscosity. The fiber interferes with micelle formation by partitioning bile salts and fat in the gel phase of dietary fiber. Thus the fiber may entrap the lipids and bile salt molecules, thereby avoiding micelle formation with carotenoids, which may block the passive absorption in the small intestine (Palafox-Carlos et al., 2011).

7.3.2 ABSORPTION Once the lipophilic compounds have been released from food matrix and solubilized within the gastrointestinal fluids within mixed micelles (Fig. 7.4), they must be transported through the lumen, across ML, and epithelium cells lining the small intestine (Porter et al., 2007; McClements et al., 2016). There are two major types of epithelial cells that line the GIT in regions where the majority of absorption occurs, enterocytes and M-cells (Bohdanowicz and Grinstein, 2013; McClements and Xiao, 2014). Enterocytes are the most abundant type of cell lining the GIT, have microvilli on the lumen side, and absorb nutrients and nutraceutical ingredients via active transport or passive diffusion (McClements and Xiao, 2014; Chai et al., 2018). Conversely, M-cells are much less numerous than enterocytes, typically occupying less than 1% of the epithelium surface, but they are much

FIGURE 7.4 Schematic representation of the mechanisms involved in the absorption of lipophilic compounds in the gastrointestinal tract. Adapted from Salvia-Trujillo, L., Martı´n-Belloso, O., McClements, D.J., 2016. Excipient nanoemulsions for improving oral bioavailability of bioactives. Nanomaterials 6, 1
17.

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more efficient than enterocytes at absorbing particulate matter (McClements and Xiao, 2014). Mcells are mainly found in specialized regions on the epithelium surface referred to as “Peyer’s patches,” possess more mitochondria but fewer lysosomes than enterocytes and do not have a mucous glycocalyx covering their surface (Tyrer et al., 2006; Chai et al., 2018). M-cells are primarily responsible for absorbing ingested antigens, such as macromolecules, microorganisms, and certain types of particles, and participate in immune responses due to their special structure (McClements and Xiao, 2014; Chai et al., 2018). The absorption of particles that are small enough to travel through the ML and reach the surface of the epithelial cells typically occurs by an endocytosis mechanism (Bohdanowicz and Grinstein, 2013; McClements and Xiao, 2014). In this case, particles come into contact with the outer wall of the cell membrane, the membrane then wraps itself around the particle, and then part of the membrane buds-off to form a vesicle-like structure with a particle trapped inside that moves into the interior of the cell (McClements and Xiao, 2014). The uptake of certain types of bioactives is limited because their transport across one or more of these barriers is inhibited. Therefore intestinal cell uptake depends on the physical barriers that the lipophilic bioactives must overcome (Salvia-Trujillo et al., 2016). In addition, the rate and fraction of absorption can vary widely between individuals since the inter-individual variability in BA depends on several key factors including diet, genetic background, gut microbiota composition and activity (Rein et al., 2013). Thus the absorption of these compounds is affected by physicochemical and physiological factors: •

•

Mucus layer transporter (ML): Nutraceutical ingredients have limited diffusion across the intestinal mucus and have low permeability through the intestinal epithelium, greatly influencing their BA (Chai et al., 2018). The ML is a porous hydrogel layer that coats the enterocytes in the epithelium cells, which has the function of protecting the underlying epithelial cells from damage; metabolizing nutrients and other substances due to the presence of metabolic enzymes; and selective permeation control by acting as a semi-permeable membrane (Scaldaferri et al., 2012; Salvia-Trujillo et al., 2016; McClements and Xiao, 2017). The ability of the ML to act as a semi-permeable membrane is due to both size and interaction effects (McClements and Xiao, 2017). If the mixed micelles are larger than the pore size (  400 nm) or strongly interact with the ML, then transport through this layer might be significantly inhibited (Ensign et al., 2012; McClements et al., 2016). The transport of a bioactive substance through the ML may also be retarded if there are attractive interactions between the nutraceutical ingredient and mucus molecules, such as electrostatic or hydrophobic interactions (McClements et al., 2015a). The food matrices should be designed to ensure that any nutraceuticals released into the gastrointestinal fluids are sufficiently small and noninteracting with the ML (McClements and Xiao, 2017). Therefore bioactive lipids and their digestion products are normally small hydrophobic molecules that can easily diffuse through the pores in the ML, either as individual molecules or as part of mixed micelles. Consequently, ML transport is not usually a rate-limiting step (McClements et al., 2015a). Membrane permeation (MP): Bioactive lipids have relatively high epithelium cell membrane permeability, given that their hydrophobic character (log P . 1) allows them to be easily incorporated into the lipid bilayers of the cell membranes (Dahan et al., 2009; Dahan and Miller, 2012; McClements et al., 2015a). Many lipophilic bioactive agents can travel through the epithelial cell membrane via a passive transport mechanism because they are highly soluble

7.3 FACTORS THAT LIMIT THE ORAL BIOAVAILABILITY

•

•

207

within the nonpolar interior of the phospholipid bilayer of the cell membrane (McClements et al., 2015a; McClements and Xiao, 2017). Passive diffusion is an energy-independent pathway due to osmotic pressure and occurs through either paracellular or transcellular routes (Chai et al., 2018). Transcellular diffusion is a process by which small lipophilic molecules fuse to the cellular membrane and are then transferred to the membrane, while paracellular diffusion occurs when small hydrophilic molecules are transported through the junctions between intestinal epithelium cells (Burton et al., 1991; McClements and Xiao, 2014; Chai et al., 2018). Specifically, bilayer permeability is not usually a rate-limiting step for bioactive lipids (McClements et al., 2015a). Efflux transporter (ET): The BA of certain types of lipophilic bioactive agents is relatively low due to the presence of ET in the membranes of the intestinal epithelial cells (Constantinides and Wasan, 2007; Fasinu et al., 2011; McClements et al., 2016). The efflux mechanism can reduce the BA of nutraceutical ingredients by decreasing the total amount absorbed, as well as by increasing the extent of its metabolism within the GIT (McClements et al., 2016). Bioactive compounds can be pumped out from enterocytes by p-glycoprotein (P-gp) via, a “multidrug resistance” mechanism, leading to limited BA. Although the nutraceutical ingredients can pass through mucus barriers, they encounter efflux pump polyglycoproteins on the epithelial cell surface that pump them back into the lumen via a “multiple-drug resistance” mechanism (Chai et al., 2018). It has been reported that the low BA of polyphenols is primarily caused by this mechanism (Liu and Hut, 2007; Chai et al., 2018). Certain nutraceutical ingredients might block the ET, such as quercetin, resveratrol, and piperine which may act as efflux inhibitors for certain pharmaceutical agents (Choi et al., 2009; Jin and Han, 2010; Challa et al., 2013; SalviaTrujillo et al., 2016; McClements et al., 2016). For instance, both P-gp and multidrug resistant protein (MRP) have been shown to pump out a wide range of lipophilic bioactives from epithelial cells (McClements and Xiao, 2014). Incorporating efflux inhibitors in a food may increase the absorption, thus the bioactivity of a nutraceutical ingredient due to this mechanism. Therefore there is growing interest in the identification and characterization of efflux inhibitors suitable for utilization in functional foods (McClements and Xiao, 2017). Active transporter (AT): Bioactive agents may also be transported through epithelial cell membranes by passive or active transport mechanisms. In practice, the permeability of many nutraceutical ingredients depends on active transport mechanisms, such as specific transporter proteins embedded within the epithelium bilayer membrane (Fasinu et al., 2011; Dahan and Miller, 2012). Many bioactive components are known to have active transport mechanisms via the specific receptors located on enterocytes, including amino acids, monosaccharides, vitamins, and some phytochemicals, while fatty acids are absorbed through enterocytes via passive diffusion (Dudhatra et al., 2012; McClements and Xiao, 2017; Chai et al., 2018). However, when there are relatively low levels of fatty acids present in the lumen of the GIT, the active transport mechanism is dominant, and when there are relatively high levels the absorption is realized by passive transport across the lipid bilayers (Kindel et al., 2010; McClements et al., 2015a). The fraction of nutraceuticals absorbed by the epithelium cells may be relatively high when the nutraceuticals are present at low concentrations or in the GIT, due to these active transport mechanisms (McClements et al., 2015a; McClements and Xiao, 2017). Nanoparticles of nutraceutical ingredients can also be transported through active transport via energydependent mechanisms, which is more efficient than passive transport (Chen et al., 2011;

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Chai et al., 2018). AT have been reported to facilitate the movement of different types of nutraceuticals, through the membrane of epithelial cells (Dudhatra et al., 2012; McClements and Xiao, 2014). Tight junction transporter (TJ): Adjacent cells of the monolayer of epithelial cells are sealed together by the formation of TJ
complex protein systems. Many food components can affect the functioning of TJ modifying expression of tight junction protein components and affecting signaling pathways involved in tight junction regulation (Kosi´nska and Andlauer, 2013). TJ are important barriers of permeation between cells, especially for high-molecular-weight compounds (Ramesan and Sharma, 2009; Chai et al., 2018). The dimensions of the TJ are relatively small, thereby they only allow molecules with smaller dimensions to travel through, such as amino acids and sugars (Seki et al., 2008; Tsutsumi et al., 2008; McClements and Xiao, 2017). Therefore bioactive lipids would not be expected to travel across TJ easily, because they tend to associate with each other in aqueous environments and form colloidal particles that are too large to pass through the narrow pores separating epithelium cells (McClements et al., 2015a).

7.3.3 TRANSFORMATION The BA and bioactivity of nutraceutical ingredients are a result of their chemical structures and molecular conformation (McClements et al., 2016; McClements and Xiao, 2017). Some lipophilic compounds are susceptible to chemical and biochemical transformations within the GIT, which may alter their BA and bioactivity. The bioactivity of some nutraceutical ingredients may be increased when they undergo chemical transformation, in other words, the metabolites may be more bioactive than the parent nutraceuticals. Thus the bioactivity nutraceutical ingredients can be affected by chemical and biochemical transformations: •

•

Chemical transformation (CT): The chemical structures of some nutraceutical ingredients can be altered within food due to processing, cooking and storage, or within the GIT, when they pass through the mouth, stomach, small intestine, and colon as a result of specific chemical reactions, such as oxidation, hydrolysis, reduction, and isomerization (McClements and Xiao, 2017). For example, carotenoid bioaccessibility may also be increased by reducing their chemical degradation within foods or within the GIT by incorporating natural antioxidants (Liu et al., 2015). Studies assessing bioaccessibility of carotenoids and flavonoids in fruit juices reported that thermal pasteurization increased carotenoid bioaccessibility, while bioaccessibility of flavonoids remained the same in the fresh fruit juice (Aschoff et al., 2015; Buniowska et al., 2017). Moreover, carotenoids are present in different isomer forms in fruits and vegetables, and their cis-isomers are more bioavailable than trans-isomers because the long linear structure of trans-isomer are difficult to fit into mixed micelles (Ferruzzi et al., 2006). Vitamin E is highly unstable to oxidation and may therefore be lost during the processing and storage of food products due to its chemical degradation (Yang and McClements, 2013). Biochemical transformation (BT): Certain types of nutraceutical ingredients are susceptible to biochemical transformations, such as enzymatic reactions or substrate interactions, which can cause changes in their bioaccessibility, absorption, and bioactivity characteristics (Alminger et al., 2014; McClements and Xiao, 2017). For instance, fatty acids are released differently by

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209

digestive enzymes (lipases, phospholipases) depending on the type of molecules they are esterified on, and many studies have been performed to identify the impact of the carrier molecule on fatty acid BA (Ramı´rez et al., 2001; Michalski et al., 2013). Fatty acids esterified as phospholipids or triglycerides may show different availability since the phospholipids contain a phosphate group and a nitrogen base that may interact in several metabolic pathways (Ziesel and Blusztajn, 1994; Ramı´rez et al., 2001). Moreover, studies suggest that simultaneous dietary intake of resveratrol and curcumin might increase the conversion of ALA to eicosapentaenoic acid and docosahexaenoic acid (Wu et al., 2015; Torno et al., 2017; Granda and Pascual-Teresa, 2018).

7.4 FOOD MATRIX DESIGN THAT IMPROVE THE ORAL BIOAVAILABILITY OF LIPOPHILIC COMPOUNDS The designer foods are similar in appearance to normal foods and are consumed regularly as a part of diet. Currently, foods have been designed to improve their nutritional profiles by reducing the levels of macronutrients believed to have adverse health impacts (such as saturated fats, digestible carbohydrates, synthetic colors, and salt) or to enrich them with food components that are believed to bring beneficial health effects (such as vitamins, carotenoids, phytosterols, dietary fibers, omega3 fatty acids, or nutraceuticals ingredients). However, due to the organoleptic properties, physicochemical stability, or poor oral BA of some lipophilic compounds or nutraceuticals ingredients, many researchers are developing delivery systems and excipient foods to increase their oral BA and improve their nutraceutical biological activity.

7.4.1 DELIVERY SYSTEMS Delivery systems are specifically designed to contain compounds or nutraceutical ingredients to be encapsulated, delivered, and released with a specific concentration-time profile at a particular site of action (McClements, 2012b). Delivery systems can be planned to reduce the total calorie content of food, to mask off-flavors, to decrease the chemical degradation, to preserve functional properties, or to increase the BA of bioactive agents. However, it is important to approach delivery systems that can increase costs and production complexity; but may also not be stable during processing and storage within a food product, and the nutraceutical ingredients incorporated cannot be released within the GIT, or may be easily degraded by enzymes within the GIT (McClements, 2013; Zuidam and Velikov, 2018). The stability of bioactive compounds is a critical parameter for their successful incorporation into various delivery systems since they are sensitive to oxygen, light, heat, and water. For that reason, it is necessary to know the properties of delivery systems and to use adequate materials to predict the behavior and stability of bioactive agents incorporated within food matrix. The delivery system may differ in shape (such as spheres, rods) and/or in morphology (such as homogenous, core
shell), thus the ability to select the right size range for a delivery system is essential for assuring a good balance between stability and reactivity (Velikov and Pelan, 2008; Zuidam and Velikov, 2018). Delivery systems can be prepared from a variety of different materials

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FIGURE 7.5 Desirable characteristics of delivery systems for food applications. Adapted from McClements, D.J., 2012b. Requirements for food ingredient and nutraceutical delivery systems. In: Encapsulation Technologies and Delivery Systems for Food Ingredients and Nutraceuticals Woodhead Publishing Series in Food Science, Technology and Nutrition. Woodhead Publishing, Cambridge, pp. 3
18; Gonc¸alves, R.F.S., Martins, J.T., Duarte, C.M.M., Vicente, A.A., Pinheiro, A.C., 2018. Advances in nutraceutical delivery systems: from formulation design for bioavailability enhancement to efficacy and safety evaluation. Trends Food Sci. Technol. 78, 270
291.

(such as lipids, surfactants, proteins, carbohydrates, minerals, and water) using a range of different processing operations. During the development and selection of a delivery system, it is important to consider some desirable characteristics of edible delivery systems for utilization by food industries (McClements et al., 2008; McClements, 2012b; Gonc¸alves et al., 2018). The most relevant characteristics are described below (Fig. 7.5): •

•

Food grade: The delivery systems applied in food products must be composed of natural biomaterials or allowed food additives that have been granted GRAS (generally recognized as safe) status, and are produced through relatively mild manufacturing conditions (Augustin and Hemar, 2009; Benshitrit et al., 2012). Among the food-grade materials that can be used to produce carrier structures for the delivery of lipophilic bioactives are: polysaccharides (pectin, gum arabica, carrageenan, chitosan), polymers (poly(lactic-co-glycolic acid)), lipids (phospholipids, fatty acids), proteins (whey protein, soy proteins, casein), and surfactants (polysorbates, soy, or egg lecithin) (Aditya et al., 2017). The processing operations must also have regulatory approval in the country where the food will be marketed (McClements, 2012b; Gonc¸alves et al., 2018). Economic production: In the food industry, the grade materials and nutraceutical ingredients used to produce delivery systems must be economically manufactured, and fabrication method should be technically and economically feasible, reproducible, and robust (McClements, 2012b; Zhang and McClements, 2016). The benefits gained from encapsulating the nutraceutical ingredients within a delivery system (such as enhanced shelf life, improved solubility, preserved functionality, increased BA) should outweigh the additional costs associated with encapsulation (McClements, 2012b; Ting et al., 2014).

7.4 FOOD MATRIX DESIGN THAT IMPROVE THE ORAL BIOAVAILABILITY

•

•

•

•

•

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Compatibility: The selection of the appropriate food-grade material requires an understanding of the bioactive compound properties, as well as the nature of the food matrix, in which such compounds will be incorporated (McClements and Li, 2010; Simo˜es et al., 2017). The delivery system should be compatible with the food matrix and not affect the organoleptic properties of the food products (such as flavor, texture, taste, appearance, and texture). For example, the phospholipids are used in delivery systems because they are known to be more compatible with the human body and are considered more biodegradable (Asghar et al., 2018). Efficient retention: Ideally, a delivery system should have a high loading capacity and loading efficiency. The loading capacity (LC) is a measure of the mass of encapsulated material per unit mass of carrier material, while loading efficiency (LE) is a measure of the ability of the delivery system to retain the encapsulated material over time (McClements et al., 2009). Thus a delivery system should be capable of encapsulating a large amount of lipophilic bioactive or nutraceutical ingredient per unit mass of carrier material and should efficiently retain the encapsulated component until it reaches a specific site of action (McClements, 2012b). The loading capacity and loading efficiency are dependent on the bioactive compound properties and on the encapsulation material used, such as molecular weight, chemical nature, polarity, and volatility of the bioactive compound and its interactions with the food matrix (Augustin and Hemar, 2009; Gonc¸alves et al., 2018). Protection: The ability of the delivery systems to protect encapsulated bioactive compounds from chemical degradation depends on their dimensions, composition, and internal structure (McClements, 2017a,b). Delivery systems may have to be designed to protect nutraceutical compounds during processing, storage, and transport from adverse factors such as undesirable interactions with other food ingredients and chemical degradation reactions (McClements et al., 2008; McClements, 2012b). The rate of these chemical degradation reactions may be promoted by certain factors that need to be controlled during the processing operations, such as heat, light, oxygen, pH, or specific chemicals (McClements et al., 2009). Furthermore, these systems should also protect the nutraceutical compounds from the GIT environment (such as high activity of digestive enzymes and harsh acidic conditions in stomach) (Gonc¸alves et al., 2018). Controlled release: One of the main desirable characteristics of delivery systems is the controlled release ability, which consists in releasing the encapsulated nutraceutical compounds with specific concentration-time profile at a particular site of action (targeted release) or in response to a specific environmental stimulus (triggered release). The release process may have a number of different profiles (targeted release, triggered release, sustained release, and other) and physicochemical mechanisms, which have recently been discussed (McClements, 2012b; Gonc¸alves et al., 2018). For example, encapsulation of ALA and linoleic acid (LA) using spring dextrin improved their stability and achieved the target delivery to the small intestine (Xu et al., 2013). The release time and release rate of bioactive compounds can be controlled through incorporating layers of digestive protection material on vehicle surfaces and selecting resources with different digestive sustainability (Asghar et al., 2018). Bioavailability: Some nutraceuticals have good solubility, stability, and BA characteristics and can simply be directly incorporated into foods. On the other hand, the efficacy of many lipophilic compounds is limited due to their poor aqueous solubility characteristics, low chemical stability, and low BA (Yao et al., 2014; McClements et al., 2015a; McClements, 2017a). Therefore the delivery systems have been used as strategies to enhance the BA/

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bioactivity of bioactive components. Indeed, an edible delivery system should be capable of controlling the BA/bioactivity of the encapsulated compound at a particular site of action. The oral BA of lipophilic bioactive compounds has increased by encapsulating them within colloidal delivery systems, such as microemulsions, nanoemulsions, or solid lipid nanoparticles (SLN), biopolymer particles, and microgels. These colloidal delivery systems can be specifically designed to improve the oral BA/bioactivity of lipophilic bioactive agents by altering their bioaccessibility, absorption, or transformation (Yao et al., 2014). Examples of delivery systems that could be developed to increase the BA of lipophilic compounds are shown in Table 7.1. These colloidal delivery systems have their own advantages and disadvantages, and numerous factors must be considered when selecting an appropriate delivery system for a specific application. The most important types of colloidal delivery systems for lipophilic compounds are listed below: •

Microemulsions: Microemulsions are defined as a system of water, oil, and surfactants which is a single optically isotropic and thermodynamically stable liquid solution (Lawrence and Rees, 2012). These mixtures of oil (O), water (W), and surfactant (S) can form a variety of different systems depending on their composition and the environmental conditions (particularly temperature). A microemulsion contains particles with radii somewhere in the range of 2
50 nm and can be categorized as oil-in-water (O/W) or water-in-oil (W/O) types depending on the relative location of the polar and nonpolar domains in the system (McClements, 2011). In general, microemulsions consist of three types of microstructures, and are most likely to be formed depending on composition, which are oil-in-water, bicontinuous, and water-in-oil microemulsion (Lawrence and Rees, 2012). Oil-in-water microemulsions contain colloidal particles dispersed in water that consist of small clusters of surface active molecules (surfactants) that have their hydrophobic tails located toward the interior and their hydrophilic heads located toward the exterior (McClements and Xiao, 2017). The surfactant molecules in an oil-in-water microemulsion are organized so that their nonpolar tails associated with each other form a hydrophobic core, reducing the thermodynamically unfavorable contact area between nonpolar groups and water and minimizing the interfacial tension (McClements et al., 2011). Specifically, water-in-oil microemulsions contain colloidal particles dispersed in oil where the surfactants are organized so that their hydrophilic heads form the interior and their hydrophobic tails face toward the exterior (McClements and Xiao, 2017). When the volume fraction of water is low, and in system where the amount of water and oil are similar, a bicontinuous microemulsion may result. Therefore bicontinuous microemulsions occur when both oil and water exist as a continuous phase in the presence of a continuously fluctuating surfactantstabilized interface (Lawrence and Rees, 2012). For a microemulsion, the free energy of the colloidal dispersion (droplets in water) is lower than the free energy of the separate phases (oil and water), which means that a microemulsion is thermodynamically stable (McClements, 2012a), they form spontaneously, and remain stable indefinitely provided environmental conditions are not altered. If these conditions are changed (such as ingredient addition or temperature changes), then it may no longer be thermodynamically stable (Rao and McClements, 2012; Yao et al., 2014). They are prone to appear either transparent or only slightly turbid, have high solubilization capacity for lipophilic compounds, and are easy to prepare and scale up for commercial applications (Gonc¸alves et al., 2018). Oil-in-water microemulsion is the type of colloidal dispersion suitable for encapsulation and delivery of

Table 7.1 Potential Health Benefits and Limitations of Main Lipophilic Compounds Nutraceutical Type

Nutraceuticals

Food Sources

Limitations

Carotenoids

Astaxanthin

Microalgae (Haematococcus pluvialis); microorganism (Xanthophyllomyces dendrorhous), shrimp (Pandalus borealis, krill)

Lutein

Fruits, green vegetables, egg yolks, corn, marigold flowers

β-Carotene

Citrus fruits, green vegetables, carrot, yellow squash, paprika, pumpkin, sweet potato, tomato, broccoli

• Low water solubility • Poor oxidation stability • Poor bioavailability • Low water solubility • Poor oxidation stability • Poor bioavailability • Low water solubility • Poor oxidation stability • Poor bioavailability

Fucoxantin

Brown algaes (Laminaria japonica and Undaria pinnatifida)

Lycopene

Tomatoes and its products, watermelon, guava, grapefruit

• Low water solubility • Poor bioavailability • Low water solubility • Poor bioavailability

Potential Health Benefits

Delivery Systems

References

• Antioxidant • Antiinflammatory • Anticancer

• Nanoemulsions • Emulsions

• Antioxidant • Improve vision

• Emulsions • Solid lipid nanoparticles

• • • •

Antioxidant Antiaging Anticancer Preventing heart disease

• • • •

• • • • • • • •

Antioxidant Antiinflammatory Anticancer Antidiabetic Antioxidant Antiinflammatory Anticancer Preventing heart disease

• Nanoparticles • Nanoemulsions

• Anarjan and Tan (2013) • Odeberg et al. (2003), Zhou et al. (2018), Liu et al. (2016b) • Davidov-Pardo et al. (2016), Weigel et al. (2018) • Liu and Wu (2010) • Zhang et al. (2016b), Mun et al. (2015a,b) • Qian et al. (2012) • Peng et al. (2018) • Salvia-Trujillo et al. (2013), Boon et al. (2010), Chen et al. (2017) • Li et al. (2018a) • Salvia-Trujillo et al. (2015)

Hydrogel beads Nanoemulsions Microemulsions Emulsions

• Nanoemulsions • Microemulsions • Emulsions

• Ha et al. (2015), Li et al. (2018b) • Lopes et al. (2010), AmiriRigi and Abbasi (2016) • Salvia-Trujillo and McClements (2016), Meronia and Raikos (2018) (Continued)

Table 7.1 Potential Health Benefits and Limitations of Main Lipophilic Compounds Continued Nutraceutical Type

Nutraceuticals

Food Sources

Limitations

Potential Health Benefits

Delivery Systems

References

Polyphenols

Curcumin

Spice turmeric (Curcuma longa)

• Low water solubility • Poor bioavailability

• • • •

• • • •

Triterpenoids

Oleanolic acid

Olive (Olea europaea L.) oil, grape

• Low water solubility

• Antiinflammatory • Anticancer

• Nanoemulsions • Nanoparticles • Liposomes

Hydroxytyrosol

Olive (O. europaea L.) oil, leaves of the olive tree

• Low water solubility

• • • •

Antioxidant Antiinflammatory Anticancer Improve vision

• Emulsions • Microemulsion • Liposomes

D3

Beef liver, dairy products, egg yolk, fish

• Low water solubility • Poor oxidation stability

• Antiinflammatory • Control of biochemical pathways

• Nanoemulsions • Emulsions

E

Vegetable oils, nuts and almonds, seeds, wheat germs, peppers

• Low water solubility • Poor oxidation stability

• • • • •

• • • •

• Ahmed et al. (2012), Wang et al. (2008), Zou et al. (2016) • Li et al. (2005) • Kharat et al. (2018), AraizaCalahorra et al. (2018) • Kakkar et al. (2011) • Xi et al. (2009), Alvarado et al. (2015) • Chen et al. (2005) • Liu et al. (2017) • Flaiz et al. (2016) • Chatzidaki et al. (2016) • Bonechi et al. (2019) • Ozturk et al. (2015a) • Winuprasith et al. (2018), Golfomitsou et al. (2018) • Yang et al. (2017), Parthasarathi et al. (2018) • Wilhelm et al. (2018) • Mayer et al. (2013), Ozturk et al. (2015b), Ma et al. (2009)

Vitamin

Antioxidant Antiinflammatory Anticancer Anti-Alzheimer’s

Antioxidant Antiaging Anticancer Anti-Alzheimer’s Preventing heart disease

Nanoemulsions Liposomes Emulsions Solid lipid nanoparticles (SLP)

Emulsions Microemulsions Nanoemulsions Liposomes

PUFAs

ω-3 Fatty acids

Fish oil, oilseed, vegetable oil

• Low water solubility • Poor oxidation stability

• Antiinflammatory • Preventing heart disease

• Emulsions • Nanoemulsions • Hydrogel beads

Phytosterols

Campesterol, β-sitosterol and stigmasterol

Vegetable oils, nuts, almonds, seeds

• Preventing heart disease

• Liposomes

Coenzyme

Coenzyme Q10

Meat, seafood

• Low water solubility • Poor oxidation stability • Low water solubility • Poor oxidation stability

• Antioxidant • Preventing heart disease

• Emulsions • Nanoemulsions

• Walker et al. (2015), Salminen et al. (2013) • Komaiko et al. (2016) • Salcedo-Sandoval et al. (2015) • Alexander et al. (2012)

• Kommuru et al. (2001), Balakrishn et al. (2009) • Cho et al. (2014)

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lipophilic components within the beverage industry. However, microemulsions in food formulations have been limited by the toxicity of surfactants and cosurfactants used. Studies have been done in order to develop food-grad microemulsion free of cosurfactants, but the removal of these surfactants result in the decrease of solubility and instability of microemulsion (Augustin and Hemar, 2009). Nanoemulsions: Nanoemulsions may be of the oil-in-water (O/W) or water-in-oil (W/O) type depending on whether the oil is dispersed as droplets in water (McClements, 2012a). Oil-inwater nanoemulsions consist of small oil droplets dispersed in an aqueous medium, and are particularly suitable templates for the development of delivery systems because of their good water-dispersibility, high optical clarity, enhanced physical stability, and improved BA (McClements and Rao, 2011). In practice, water-in-oil nanoemulsions consist of emulsifiercoated water droplets dispersed in oil, and are therefore more suitable for encapsulating polar nutraceutical ingredients within the hydrophilic interior of the water droplets (McClements and Xiao, 2017). A nanoemulsion can be considered to be a conventional emulsion that contains very small droplets, which consist of particles with mean radii between 10 and 100 nm (McClements, 2011; Gleeson et al., 2016; Soukoulis and Bohn, 2018). However, other studies define that nanoemulsions consist of particles with radii (d , 200 nm) and emulsions with radii (d . 200 nm) to be particularly effective delivery systems for bioactive compounds (McClements and Rao, 2011; Rao and McClements, 2012a; McClements and Xiao, 2017). Nanoemulsions can be fabricated by low-energy (spontaneous formation due to high concentrations of surfactants) or high-energy methods (mechanical disruption of oil phase resulting in nanosized droplets). A nanoemulsion is usually prepared using the same components as a microemulsion, such as oil, water, surfactant and possibly a cosurfactant (McClements, 2012a). Conventionally, nanoformulations for lipophilic nutraceuticals are classified into three categories according to the types of wall materials, which are lipid and surfactant-based nanocarriers, polysaccharide-based nanocarriers, and protein-based nanocarriers (Oehlke et al., 2014; Pradhan et al., 2013; Shin et al., 2015). Nevertheless, the major distinction between a nanoemulsion and a microemulsion is therefore their thermodynamic stability since that the nanoemulsions are thermodynamically unstable, whereas microemulsions are thermodynamically stable (McClements, 2012a). Nanoemulsions have been described as excellent carriers for lipophilic bioactive compounds with enhanced properties compared to conventional emulsions (Salvia-Trujillo et al., 2016). There are advantages of using nanoemulsions rather than conventional emulsions as they can greatly increase the BA of lipophilic substances; they scatter light weakly and so can be incorporated into optically transparent products; they can also be used to modulate the product texture; and they have a high stability to particle aggregation and gravitational separation (McClements, 2011). Nanoemulsions have a higher digestion rate in the GIT compared to conventional emulsions, since they have more binding site available for digestive enzymes, such as lipase (SalviaTrujillo et al., 2013, 2016). A study demonstrated that the rate and extent of lipid digestion increased with decreasing mean droplet diameter (small (0.2 μm)  medium (0.4 μm) $ large (23 μm)), which was attributed to the increase in lipid surface area exposed to pancreatic lipase with decreasing droplet size (Salvia-Trujillo et al., 2013). The mechanisms leading to an enhanced BA of the bioactive compounds by application of nanocarriers are based on improvement solubility under gastrointestinal conditions, enhancement of residence time in

7.4 FOOD MATRIX DESIGN THAT IMPROVE THE ORAL BIOAVAILABILITY

•

217

GIT regions, the controlled release within the GIT or an improved transfer through the intestinal wall (Oehlke et al., 2014). Moreover, some risks may be associated with the oral ingestion of nanoemulsions, such as their ability to change the biological fate of bioactive components within the GIT and the potential toxicity of some of the components used in their preparation (McClements, 2011). Emulsions: Emulsions are defined according to the spatial distribution of the oil and water phases relative to each other. Conventionally, emulsions are classified as either oil-in-water (O/W) emulsions in which oil forms the dispersed phase (oil droplets) and water forms the continuous phase (such as milk and sauces), or water-in-oil (W/O) emulsions in which water forms the dispersed phase and oil forms the continuous phase (such as butter and margarines) (McClements, 2005; Chung and McClements, 2014). Structurally complex emulsions with enhanced functional properties also can be formed using advanced processing methods, such as oil-in-water-in-water (O/W1/W2) emulsions, water-in-oil-in-water (W1/O/W2) emulsions, and oil-in-water-in-oil (O1/W/O2) emulsions since these emulsions have been extensively explored to fortify the food products with various bioactives (Chung and McClements, 2014; Aditya et al., 2017). The emulsions contain droplets that are relatively large (r . 100 nm), and so they are optically opaque and susceptible to breakdown through gravitational separation and droplet aggregation mechanisms (McClements and Rao, 2011; Zhang and McClements, 2016). Generally, the emulsions can be made using two categories, based on the underlying principles involved in the droplet formation, which are defined as high energy (high shear mixers, high pressure homogenization, microfluidization, and sonication) or low-energy (phase inversion temperature and spontaneous emulsification) methods (McClements, 2012c). Therefore the emulsions are thermodynamically unstable, and consequently tend to breakdown over time due to a variety of physicochemical mechanisms, including gravitational separation, flocculation, coalescence, particle coalescence, Ostwald ripening, and phase separation (Chung and McClements, 2014; McClements and Jafari, 2018). These physicochemical mechanisms have recently been discussed in detail (McClements and Jafari, 2018). For these reason, the food industries developed emulsions that show a sufficient long kinetic stability. Kinetic stability is usually engineered into products by incorporating substances known as stabilizers, such as emulsifiers, texture modifiers, weighting agents, and ripening retarders (McClements and Li, 2010; McClements, 2018c). The formation, stability, and functional performance of emulsion-based delivery systems are highly dependent on the nature of emulsifiers used (McClements and Xiao, 2017). In fact, the control of emulsion stability is essential in the food industry due to the development of commercial products that maintain their desirable sensory and physicochemical properties throughout the products shelf life. There are several possible strategies available to retard emulsion instability by modulating the properties of the dispersed, continuous, and interfacial phases (Chung and McClements, 2014). Although, some emulsions are thermodynamically unstable, they have a number of potential advantages as delivery systems for nutraceutical ingredients and bioactive compounds. Oil-in-water emulsions are currently the most widely used emulsion-based delivery systems in many industrial applications (such as soups, dressings, dips, creams, beverage, and desserts) as their composition and structure can be easily manipulated. For example, luteinenriched emulsions can be used as delivery systems for natural colorants or nutraceuticals for application in commercial food and beverage products. A study showed that lutein could be encapsulated in emulsion-based delivery systems formulated from only natural ingredients, such

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as natural surfactants (quillija saponins) and natural antioxidants (ascorbic acid) because it exhibited good physical and chemical stability (Weigel et al., 2018). Solid lipid nanoparticles (SLN): SLNs consist of a suspension of crystalline lipid nanoparticles dispersed within an aqueous medium, with each nanoparticle being stabilized against aggregation by an emulsifier coating (Gao and McClements, 2016). SLNs can be fabricated in submicron size range from 50 to 500 nm using high-melting-point lipids (such as lipids solid at room temperature and also at body temperature) and stabilized by surfactants, which are biodegradable, biocompatible, and nontoxic (Aditya and Ko, 2015). SLNs are similar to oil-inwater emulsions and nanoemulsions, but the oil phase is crystallized (McClements and Xiao, 2017). In practice, SLNs are fabricated using a lipid phase with a narrow melting range, such as pure triacylglycerols (TAGs) or hydrocarbons, in order to produce a highly ordered crystalline structure, enabling the physical entrapment of lipophilic bioactive compounds (Soukoulis and Bohn, 2018). In general, SLNs are formed from high-melting-point lipids using a two-step process: first, a nanoemulsion is prepared at a temperature above the melting point of the lipid phase to ensure that it remains liquid throughout the homogenization process. Second, this nanoemulsion is cooled to a temperature below the melting point to promote crystallization of the lipid phase (Yao et al., 2014). Therefore SLNs can also be produced using low-energy methods by spontaneously forming a nanoemulsion at high temperatures and then cooling it to induce lipid crystallization (Gao and McClements, 2016). The crystallization of the lipid phase may retard molecular diffusion within the nanoparticle interior, thereby improving the retention and chemical stability of encapsulated bioactive ingredients (Weiss et al., 2008; Gao and McClements, 2016). The effect of fat crystallization on the digestion and release of emulsified lipids can have important implications for the application of solid lipid particles as delivery systems for lipophilic bioactive compounds, such as ω-3 fatty acids, conjugated linoleic acid (CLA), phytosterols, or carotenoids (McClements and Li, 2010). The lipid composition, surfactant type, and manufacturing of SLNs have been used to encapsulate lipophilic agents (Weiss et al., 2008; Aditya and Ko, 2015; Gao and McClements, 2016; Soukoulis and Bohn, 2018). There are various industrially feasible methods available to fabricate the SLNs, generally SLNs are fabricated using either top down (high pressure homogenization, microfluidization, and membrane contactor method) or bottom up (emulsification
solvent evaporation and emulsification
solvent diffusion) methods (Aditya and Ko, 2015). SLNs have been investigated for their ability to encapsulate and protect lipophilic bioactive compounds in foods, supplements, and pharmaceuticals. The lipophilic compounds may be protected from chemical or physical degradation in SLPs, but still be released when they pass through the digestive system, though at a somewhat slower rate than from a liquid droplet (McClements and Li, 2010). SLPs present some advantages, such as controlled and targeted release, high chemical stability, good biodegradability and biocompatibility, high loading capacity, and low cost (Gao and McClements, 2016; Gonc¸alves et al., 2018). A study demonstrated that the degradation of β-carotene encapsulated in NLCs was much reduced when compared to its encapsulation (Zhang et al., 2013). Hydrogel beads: Hydrogels beads (microgels) consist of spherical particles, usually in the range 1
1000 μm, which are prepared using a two-step process. In a first step, a solution containing a mixture of nutraceutical compounds and biopolymers is made to form one or more small particles. In a second step, the biopolymer molecules within the small particles are cross-linked

7.4 FOOD MATRIX DESIGN THAT IMPROVE THE ORAL BIOAVAILABILITY

•

219

with each other using an appropriate method leading to the formation of a hydrogel matrix within the beads (McClements, 2017a). Hydrogel beads can be formed using a variety of methods (such as complexation, antisolvent precipitation, homogenization, injection, shearing, and thermal processing) depending on the nature of the biopolymers and crosslinking agents used (Zhang et al., 2015; McClements and Xiao, 2017). The nature of the polymer used determines the physicochemical and functional properties of the hydrogel formed, such as its rheological, optical, stability, and release properties (Nakagawa et al., 2013; Komaiko and McClements, 2015). Typically, the main biopolymers used to fabrication food-grade microgels are food-grade proteins (such as whey protein, casein or gelatin) or polysaccharides (such as chitosan, agar, alginate, carrageenan, pectin, or starch). Each of the different methods available for production of hydrogel beads has certain advantages and limitations for particular applications, thus more details about these methods can be found in recent review articles (Zhang et al., 2015; McClements, 2017b). Microgel particles have gained considerable interest as a delivery system due to their potential to encapsulate, protect, and release nutraceuticals. However, one disadvantage of this delivery system is that changes in bead composition, structure, and charge can lead to changes in their ability to retain, protect, and release nutraceutical agents (McClements, 2017a). Microgels are important constituents of many foods, including yogurts, desserts, spreads, and some meat products, where they provide desirable appearance, texture, flavor, and stability characteristics (Komaiko and McClements, 2015). For example, hydrogel beads may also be used to modulate the gastrointestinal fate of carotenoids. Studies demonstrated that β-carotene-enriched lipid droplets had higher bioaccessibility when incorporated into starch-based hydrogels, which was attributed to the ability of the hydrogels to inhibit excessive droplet flocculation in the stomach and small intestine, thereby allowing the lipase to access the lipid droplet surfaces more easily (Mun et al., 2015a,b). Liposomes: Liposomes, sphere-shaped, are formed when phospholipids self-assemble into a lipid bilayer due to hydrophobic interactions with the fatty acid chain (Gleeson et al., 2016). In other words, liposomes have a hydrophilic interior that can be used to encapsulate polar nutraceutical ingredients and a hydrophobic region in the bilayer that can be used to encapsulate lipophilic compounds (McClements and Xiao, 2017). Liposomes have the same aqueous phase on both sides of the phospholipid bilayer, and their size can vary from 50 nm to 1 μm in diameter (Singh et al., 2012). These systems may contain one (unilamellar) or more (multilamellar) phospholipid bilayers depending on the preparation method and ingredients used (McClements, 2018a). Liposome may also contain lipid or lipid chains such as sphingolipids, cholesterol, long-chain fatty acids, and phosphatidylethanolamine (van Meer et al., 2008; Lee, 2017). This delivery system is suitable for polar and hydrophilic materials because its aqueous portions take the functional compounds to absorption and digestion sites through the GIT (Asghar et al., 2018). Different liposome structures may be formed, varying both in terms of overall liposome size and the number of concentric bilayers contained within each vesicle, but these differences can affect a number of liposome characteristics, including chemical stability and the rate of release of entrapped material (Singh et al., 2012). Due to the limited chemical and physical stability of liposomes and low encapsulation efficiency, the formation of large unilamellar vesicles is most appropriated for food ingredients, allowing for higher encapsulation efficiency, smaller capsule size, and higher cost effectiveness (Gouin, 2004; Soukoulis and Bohn, 2018). There is considerable interest in utilizing liposomes as delivery systems because

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they can be produced from natural components, such as phospholipids. The biostructural compatibility with biological membranes turns liposomes into versatile drug delivery systems with many pharmaceutical applications (Elsayed et al., 2007; Dima et al., 2015). The main applications of liposomes in the food industry have been the use of lipophilic compounds, such as vitamins (A and E) and phytosterols. For example, vitamin E was incorporated together with tea polyphenol and the results demonstrated increase of the encapsulation efficiencies (94.05%) of complex liposome delivery system (Ma et al., 2009).

7.4.2 EXCIPIENT SYSTEMS The nutraceutical compounds are present within natural or processed foods (such as raw or cooked fruits and vegetables), which are coingested with other food (excipient food). The concept of excipient foods has been introduced as an alternative, thereby the bioactive compounds might be left in their natural sources (fruits, vegetables, edible seeds, and cereals) and consumed along with a specific formulation able to improve their bioactivity (McClements and Xiao, 2014; Salvia-Trujillo et al., 2016). In general, an excipient food is specifically designed to increase the BA of nutraceutical compounds that are coingested with it (McClements et al., 2015b, 2016). The design of an excipient food also depends on the physicochemical properties of the nutraceuticals, as well as the major factors that normally inhibit its BA, such as low bioaccessibility, susceptibility to degradation, and poor absorption profile (McClements et al., 2015b). The excipient foods may contain one or more different types of excipient ingredients to enhance the BA of one or more different nutraceutical compounds present in food matrix. The excipient ingredient is a food-grade ingredient that has the ability to increase the BA and bioactivity of certain bioactive compounds (McClements et al., 2015b). In fact, when designing an excipient food, some factors must be considered: (1) the composition and structure of the food matrix must be specifically designed to increase the BA of bioactive compounds of interest; (2) the excipient food must have physicochemical and sensory properties that consumers find desirable so as to ensure good compliance (good sensorial attributes); (3) a food matrix (beverage or food product) selected must be easily incorporated and consumed into a routine daily diet; (4) the excipient food itself should not promote any adverse health effects if consumed regularly due to its composition, such as high in fat, cholesterol, sugar, or salt; (5) the excipient food should have a sufficiently long shelf-life and be easy to storage and to use (McClements and Xiao, 2014; McClements et al., 2015b). Excipient foods may be fluids, semi-solids, or solids that may be consumed by drinking (beverages) or eating (foods). The nature of the excipient food might depend on the type of nutraceutical-rich food that is being consumed. Salad dressings, sauces, yogurts, creams, soups, dips, ice-creams, butter, and margarine are some examples of potential excipient foods. An example, the bioaccessibility of carotenoids in a salad may be increased by consuming it with a specifically designed salad dressing (McClements and Xiao, 2014; Karakaya et al., 2015). This excipient dressing (excipient food) may contain various food components that increase the BA of the natural bioactive compounds (carotenoids) present in food matrix (salad), such as lipids that increase GIT solubility, antioxidants that inhibit chemical transformations, enzyme inhibitors that retard metabolism, or permeation enhancers that increase absorption.

7.4 FOOD MATRIX DESIGN THAT IMPROVE THE ORAL BIOAVAILABILITY

221

In summary, excipient foods and ingredients can increase the absorption of dietary carotenoids and other lipophilic compounds by facilitating one or more processes associated with the bioaccessibility and BA of fat-soluble microconstituents present in the diet, such as solubilization within lipid droplets, increased transit time within the gut, uptake from micelles by absorptive epithelial cells, and stimulation of the assembly and secretion of chylomicrons into lymph (Kopec and Failla, 2018). In particular, the emulsions and nanoemulsions are specifically useful templates for the design of excipient foods because BA-enhancing lipophilic, amphiphilic, and hydrophilic food ingredients can all be incorporated into a single system (Liu et al., 2016a). The details of excipient emulsions and excipient nanoemulsions are highlighted below: •

•

Excipient emulsions: Excipient emulsion can be defined as an emulsion (d . 100 nm) that consists of emulsifier-coated lipid droplets dispersed within an aqueous medium (McClements et al., 2016). Oil-in-water emulsions can also be used as excipient systems, therefore for excipient systems a bioactive-free emulsion is consumed with a bioactive-rich food. Indeed, oilwater emulsions are especially effective vehicles for developing excipient foods due to the wide flexibility in designing their compositions and structures (McClements et al., 2016). Typically, the composition, size, and interfacial properties of the lipid droplets are optimized based on the ability to extract and solubilize lipophilic nutraceuticals from food matrices and to protect their from chemical or biochemical degradation within the GIT (McClements and Xiao, 2017). Studies shown that excipient emulsions can be used to increase the BA of carotenoids in a range of produce, including mangoes (Liu et al., 2016a), carrots (Zhang et al., 2016a), yellow peppers (Liu et al., 2015), and tomatoes (Salvia-Trujillo and McClements, 2016). Excipient emulsions have increased the solubility and bioaccessibility of powdered curcumin (Zou et al., 2015). Excipient nanoemulsions: Excipient nanoemulsions have been described as an oil-in-water emulsion with a very small droplet size (d , 100 nm) dispersed in water (Zhang and McClements, 2016). Their small droplet dimensions confer them with unique properties, such as improved physical stability, high optical clarity, and enhanced BA (McClements, 2011; SalviaTrujillo et al., 2016). Furthermore, the small droplets are also rapidly digested in the small intestine to form mixed micelles that can solubilize hydrophobic nutraceuticals (Liu et al., 2016a). Nanoemulsions typically have a higher digestion rate in the GIT compared to conventional emulsions due to the fact that they have more binding sites available for digestive enzymes, such as lipase (Salvia-Trujillo et al., 2013, 2016). For instance, the lipid droplet in the excipient nanoemulsions increased curcumin bioaccessibility, which can be attributed to the ability of the lipid digestion products (free fatty acids and monoacylglycerols) to form mixed micelles that can solubilize this hydrophobic compounds in the intestinal fluids (Zou et al., 2016).

There are various potential benefits of developing excipient foods to increase the BA of bioactive compounds. The long-term consumption of low levels of nutraceutical compounds improves human performance, enhances well-being, or inhibits the onset of chronic diseases, such as diabetes, atherosclerosis, hypertension, and cancer (McClements and Xiao, 2014). Although excipient food technology could be used to create new food products specifically developed to enhance BA of bioactive compounds in natural products and to improve human performance, it is also important to evaluate the safety of these excipient products before their application and intake.

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In fact, there are some concerns that must be valued, so due to increase of the nutraceutical BA, the excipient food may also enhance the BA of any toxic agents present in a food product (McClements et al., 2016; Gonc¸alves et al., 2018). The concept of excipient foods is relatively new, and a considerable amount of research is still required in this area. Nevertheless, it is a promising approach for improving the BA characteristics of many anticancer nutraceuticals in food.

7.5 CONCLUSION Nutraceuticals offer the opportunity to prevent onset of lifestyle-associated chronic diseases due to their antioxidant, antiinflammatory, anticancer, anti-Alzheimer’s, and antiarteriosclerosis activities, among others. Therefore the food industry is increasingly focusing on the development of functional food and excipient food. Functional food can be specifically designed to modulate bioaccessibility, absorption, or transformation profile of nutraceuticals within GIT, improving their BA and consequently, their bioactivity using a suitable delivery system. Similarly, excipient food enhances the BA of bioactive compounds, such as lipophilic compounds, vitamins, and nutrients present in natural products. Many of the biologically active compounds present in foods are highly lipophilic agents that normally have low water solubility and poor oral BA. For this reason, a variety of strategies have been developed to increase absorption of lipophilic compounds using delivery systems (microemulsions, nanoemulsions, emulsions, SLNs, hydrogel beads, and liposomes), which present specific properties and materials. Also, excipient systems have been created as an alternative approach to improve intake of bioactives from natural sources, such as fruits, vegetable, cereals, and natural products. Up to date, these strategies have been mainly applied to carotenoids, phytosterols, ω-3 fatty acids, vitamins D and E, and triterpenoids. Future studies should focus on improving the physicochemical characteristics and functionality of the delivery systems, and excipient systems demonstrate their efficacy in practice and potential health effects.

REFERENCES Aditya, N.P., Ko, S., 2015. Solid lipid nanoparticles (SLNs): delivery vehicles for food bioactives. RSC Adv. 5, 30902
30911. Aditya, N.P., Espinosa, Y.G., Norton, I.T., 2017. Encapsulation systems for the delivery of hydrophilic nutraceuticals: food application. Biotechnol. Adv. 35, 450
457. Ahmed, K., Li, Y., McClements, D.J., Xiao, H., 2012. Nanoemulsion- and emulsion based delivery systems for curcumin: encapsulation and release properties. Food Chem. 132 (2), 799
807. Alexander, M., Lopez, A.A., Fang, Y., Corredig, M., 2012. Incorporation of phytosterols in soy phospholipids nanoliposomes: encapsulation efficiency and stability. Food Sci. Technol. 47 (2), 427
436. Alminger, M., Aura, A.-M., Bohn, T., Dufour, C., El, S.N., Gomes, A., et al., 2014. In vitro models for studying secondary plant metabolite digestion and bioaccessibility. Compr. Rev. Food Sci. Food Safety 13, 413
436. Alvarado, H.L., Abregoa, G., Souto, E.B., Garduno-Ramirez, M.L., Clares, B., Garcı´a, M.L., et al., 2015. Nanoemulsions for dermal controlled release of oleanolic and ursolic acids: in vitro, ex vivo and in vivo characterization. Colloids Surf. B: Biointerfaces 130 (1), 40
47.

REFERENCES

223

Amiri-Rigi, A., Abbasi, S., 2016. Microemulsion-based lycopene extraction: effect of surfactants, cosurfactants and pretreatments. Food Chem. 197, 1002
1007. Anarjan, N., Tan, C.P., 2013. Chemical stability of astaxanthin nanodispersions in orange juice and skimmed milk as model food systems. Food Chem. 139, 527
531. Araiza-Calahorra, A., Akhtar, M., Sarkar, A., 2018. Recent advances in emulsion-based delivery approaches for curcumin: from encapsulation to bioaccessibility. Trends Food Sci. Technol. 71, 155
169. Arroyo-Maya, I.J., McClements, D.J., 2016. Application of ITC in foods: a powerful tool for understanding the gastrointestinal fate of lipophilic compounds. Biochim. Biophys. Acta 1860, 1026
1035. Aschoff, J.K., Kaufmann, S., Kalkan, O., Neidhart, S., Carle, R., Schweiggert, R.M., 2015. In vitro bioaccessibility of carotenoids, flavonoids, and vitamin C from differently processed oranges and orange juices [Citrus sinensis (L.) osbeck]. J. Agric. Food Chem. 63 (2), 578
587. Asghar, A., Randhawa, M.A., Masood, M.M., Abdullah, M., Irshad, M.A., 2018. Chapter 10 - Nutraceutical formulation strategies to enhance the bioavailability and efficiency: an overview. Role of Materials Science in Food Bioengineering. Handbook of Food Bioengineering. Elsevier, pp. 329
352. Augustin, M.A., Hemar, Y., 2009. Nano- and micro-structured assemblies for encapsulation of food ingredients. Chem. Soc. Rev. 38, 902
912. Balakrishn, P., Lee, B.-J., Oh, D.H., Kim, J.O., Lee, Y.-I., Kim, D.-D., et al., 2009. Enhanced oral bioavailability of Coenzyme Q10 by self-emulsifying drug delivery systems. Int. J. Pharm. 374 (1
2), 66
72. Benshitrit, R.C., Levi, C.S., Tal, S.L., Shimoni, E., Lesmes, U., 2012. Development of oral food-grade delivery systems: current knowledge and future challenges. Food Funct. 3 (1), 10
21. Bohdanowicz, M., Grinstein, S., 2013. Role of phospholipids in endocytosis, phagocytosis, and macropinocytosis. Physiol. Rev. 93 (1), 69
106. Bonechi, C., Donati, A., Tamasi, G., Pardini, A., Rostom, H., Leone, G., et al., 2019. Chemical characterization of liposomes containing nutraceutical compounds: tyrosol, hydroxytyrosol and oleuropein. Biophys. Chem. 246, 25
34. Boon, C.S., McClements, D.J., Weiss, J., Decker, E.A., 2010. Factors influencing the chemical stability of carotenoids in foods. Crit. Rev. Food Sci. Nutr. 50, 515
532. Borel, P., Tyssandier, V., Mekki, N., Grolier, P., Rochette, Y., Alexandre-Gouabau, M.C., et al., 1998. Chylomicron β-carotene and retinyl palmitate responses are dramatically diminished when men ingest β-carotene with medium-chain rather than long-chain triglycerides. J. Nutr. 128, 1361
1367. Buniowska, M., Carbonell-Capella, J.M., Frigola, A., Esteve, M.J., 2017. Bioaccessibility of bioactive compounds after non-thermal processing of an exotic fruit juice blend sweetened with Stevia rebaudiana. Food Chem. 221, 1834
1842. Burton, P.S., Conradi, R.A., Hilgers, A.R., 1991. Mechanisms of peptide and protein absorption. Adv. Drug Deliv. Rev. 7, 365
385. Cardoso, C., Afonso, C., Lourenc¸o, H., Costa, S., Nunes, M.L., 2015. Bioaccessibility assessment methodologies and their consequences for the risk-benefit evaluation of food. Trends Food Sci. Technol. 41, 5
23. Cassady, B.A., Hollis, J.H., Fulford, A.D., Considine, R.V., Mattes, R.D., 2009. Mastication of almonds: effects of lipid bioaccessibility, appetite, and hormone response. Am. J. Clin. Nutr. 89 (3), 794
800. Chai, J., Jiang, P., Wang, P., Jiang, Y., Li, D., Bao, W., et al., 2018. The intelligent delivery systems for bioactive compounds in foods: physicochemical and physiological conditions, absorption mechanisms, obstacles and responsive strategies. Trends Food Sci. Technol. 78, 144
154. Challa, V.R., Babu, P.R., Challa, S.R., Johnson, B., Maheswari, C., 2013. Pharmacokinetic interaction study between quercetin and valsartan in rats and in vitro models. Drug Dev. Ind. Pharm. 39 (6), 865
872. Chatzidaki, M.D., Arik, N., Monteil, J., Papadimitriou, V., Leal-Calderon, F., Xenakis, A., 2016. Microemulsion vs emulsion as effective carrier of hydroxytyrosol. Colloids Surf. B: Biointerfaces 137 (1), 146
151.

224

CHAPTER 7 FOOD MATRICES THAT IMPROVE THE ORAL BIOAVAILABILITY

Chen, Y., Liu, J., Yang, X., Zhao, X., Xu, H., 2005. Oleanolic acid nanosuspensions: preparation, in-vitro characterization and enhanced hepatoprotective effect. J. Pharm. Pharmacol. 57, 259
264. Chen, M.C., Sonaje, K., Chen, K.J., Sung, H.W., 2011. A review of the prospects for polymeric nanoparticle platforms in oral insulin delivery. Biomaterials 32, 9826
9838. Chen, J., Li, F., Li, Z., McClements, D.J., Xiao, H., 2017. Encapsulation of carotenoids in emulsion-based delivery systems: enhancement of β-carotene water-dispersibility and chemical stability. Food Hydrocolloids 69, 49
55. Cho, H.T., Salvia-Trujillo, L., Kim, J., Parka, Y., Xiao, H., McClements, D.J., 2014. Droplet size and composition of nutraceutical nanoemulsions influences bioavailability of long chain fatty acids and Coenzyme Q10. Food Chem. 156, 117
122. Cho, K.S., Shin, M., Kim, S., Lee, S.B., 2018. Recent advances in studies on the therapeutic potential of dietary carotenoids in neurodegenerative diseases. Oxid. Med. Cell Longev. 2018, 1
13. Choi, J.S., Choi, B.C., Kang, K.W., 2009. Effect of resveratrol on the pharmacokinetics of oral and intravenous nicardipine in rats: possible role of P-glycoprotein inhibition by resveratrol. Pharmazie 64 (1), 49
52. Chung, C., McClements, D.J., 2014. Structure
function relationships in food emulsions: improving food quality and sensory perception. Food Struct. 1 (2), 106
126. Cilla, A., Bosch, L., Barber´a, R., Alegrı´a, A., 2018. Effect of processing on the bioaccessibility of bioactive compounds
a review focusing on carotenoids, minerals, ascorbic acid, tocopherols and polyphenols. J. Food Compos. Anal. 68, 3
15. Colussi, G., Catena, C., Novello, M., Bertin, N., Sechi, L.A., 2017. Impact of omega-3 polyunsaturated fatty acids on vascular function and blood pressure: relevance for cardiovascular outcomes. Nutr. Metab. Cardiovasc. Dis. 27, 191
200. Constantinides, P.P., Wasan, K.M., 2007. Lipid formulation strategies for enhancing intestinal transport and absorption of P-glycoprotein (P-gp) substrate drugs: in vitro/in vivo case studies. J. Pharm. Sci. 96 (2), 235
248. Dahan, A., Miller, J.M., 2012. The solubility-permeability interplay and its implications in formulation design and development for poorly soluble drugs. AAPS J. 14 (2), 244
251. Dahan, A., Miller, J.M., Amidon, G.L., 2009. Prediction of solubility and permeability class membership: provisional BCS classification of the world’s top oral drugs. AAPS J. 11 (4), 740
746. Davidov-Pardo, G., Gumus, C.E., McClements, D.J., 2016. Lutein-enriched emulsion-based delivery systems: influence of pH and temperature on physical and chemical stability. Food Chem. 196, 821
827. Dima, S., Dima, C., Iord˘achescu, G., 2015. Encapsulation of functional lipophilic food and drug biocomponents. Food Eng. Rev. 7, 417
438. Dudhatra, G.B., Mody, S.K., Awale, M.M., Patel, H.B., Modi, C.M., Kumar, A., et al., 2012. A Comprehensive review on pharmacotherapeutics of herbal bioenhancers. Sci. World J. 2012. Ellis, P.R., Kendall, C.W., Ren, Y., Parker, C., Pacy, J.F., Waldron, K.W., et al., 2004. Role of cell walls in the bioaccessibility of lipids in almond seeds. Am. J. Clin. Nutr. 80, 604
613. Elsayed, M.M.A., Abdallah, Y.O., Naggar, F.V., Khalafallah, M.N., 2007. Lipid vesicles for skin delivery of drugs: reviewing three decades of research. Int. J. Pharm. 332, 1
16. Eltweri, A.M., Thomas, A.L., Metcalfe, M., Calder, P.C., Dennison, A.R., Bowrey, D.J., 2017. Potential applications of fish oils rich in omega-3 polyunsaturated fatty acids in the management of gastrointestinal cancer. Clin. Nutr. 36, 65
78. Ensign, L.M., Cone, R., Hanes, J., 2012. Oral drug delivery with polymeric nanoparticles: the gastrointestinal mucus barriers. Adv. Drug Deliv. Rev. 64 (6), 557
570. Failla, M.L., Chitchumroonchokchai, C., 2005. In vitro models as tools for screening the relative bioavailabilities of provitamin A carotenoids in foods. HarvestPlus Tech. Mon. Series 3 (1
32).

REFERENCES

225

Fasinu, P., Pillay, V., Ndesendo, V.M.K., du Toit, L.C., Choonara, Y.E., 2011. Diverse approaches for the enhancement of oral drug bioavailability. Biopharm. Drug. Dispos. 32 (4), 185
209. Fern´andez-Garcı´a, E., Carvajal-L´erida, I., P´erez-G´alvez, A., 2009. In vitro bioaccessibility assessment as a prediction tool of nutritional efficiency. Nutr. Res. 29, 751
760. Fern´andez-Garcı´a, E., Carvajal-L´erida, I., Jar´en-Gal´an, M., Garrido-Fern´andez, J., P´erez-G´alvez, A., HorneroM´endez, D., 2012. Carotenoids bioavailability from foods: from plant pigments to efficient biological activities. Food Res. Int. 46, 438
450. Ferruzzi, M.G., Lumpkin, J.L., Schwartz, S.J., Failla, M., 2006. Digestive stability, micellarization, and uptake of -carotene isomers by CACO-2 human intestinal cells. Agric. Food Chem. 54, 2780
2785. Flaiz, L., Freire, M., Cofrades, S., Mateos, R., Weiss, J., Jim´enez-Colmenero, F., et al., 2016. Comparison of simple, double and gelled double emulsions as hydroxytyrosol and n-3 fatty acid delivery systems. Food Chem. 213, 49
57. Gao, S., McClements, D.J., 2016. Formation and stability of solid lipid nanoparticles fabricated using phase inversion temperature method. Colloids Surf. A: Physicochem. Eng. Aspects 499, 79
87. Gleeson, J.P., Ryan, S.M., Brayden, D.J., 2016. Oral delivery strategies for nutraceuticals: delivery vehicles and absorption enhancers. Trends Food Sci. Technol. 53, 90
101. Golfomitsou, I., Mitsou, E., Xenakis, A., Papadimitriou, V., 2018. Development of food grade O/W nanoemulsions as carriers of vitamin D for the fortification of emulsion based food matrices: a structural and activity study. J. Mol. Liquids 268, 734
742. Gonc¸alves, R.F.S., Martins, J.T., Duarte, C.M.M., Vicente, A.A., Pinheiro, A.C., 2018. Advances in nutraceutical delivery systems: from formulation design for bioavailability enhancement to efficacy and safety evaluation. Trends Food Sci. Technol. 78, 270
291. Gouin, S., 2004. Microencapsulation: industrial appraisal of existing technologies and trends. Trends Food Sci. Technol. 15, 330
347. Granda, H., Pascual-Teresa, S., 2018. Interaction of polyphenols with other food components as a means for their neurological health benefits. J. Agric. Food Chem. 66, 8224
8230. Guaadaoui, A., Benaicha, S., Elmajdoub, N., Bellaoui, M., Hamal, A., 2014. What is a bioactive compound? A combined definition for a preliminary consensus. Int. J. Nutr. Food Sci. 3 (3), 174
179. Guam´an-Ortiz, L.M., Orellana, M.I.R., Ratovitski, E.A., 2017. Natural compounds as modulators of nonapoptotic cell death in cancer cells. Curr. Genomics 18, 132
155. Ha, T.V.A., Kim, S., Choi, Y., Kwak, H.-S., Lee, S.J., Wen, J., et al., 2015. Antioxidant activity and bioaccessibility of size-different nanoemulsions for lycopene-enriched tomato extract. Food Chem. 178 (1), 115
121. Holst, B., Williamson, G., 2008. Nutrients and phytochemicals: from bioavailability to bioefficacy beyond antioxidants. Curr. Opin. Biotechnol. 19, 73
82. Hooper, C., De Souto Barreto, P., Pahor, M., Weiner, M., Vellas, B., 2018. The relationship of omega 3 polyunsaturated fatty acids in red blood cell membranes with cognitive function and brain structure: a review focussed on Alzheimer’s disease. J. Prevent. Alzheimer’s Dis. 5 (1), 78
84. Horvitz, M.A., Simon, P.W., Tanumihardjo, S.A., 2004. Lycopene and β-carotene are bioavailable from lycopene “red” carrots in humans. Eur. J. Clin. Nutr. 58, 803
811. Huo, A., Ferruzzi, M.G., Schwartz, S.J., Failla, M.L., 2007. Impact of fatty acyl composition and quantity of triglycerides on bioaccessibility of dietary carotenoids. J. Agric. Food Chem. 55 (22), 8950
8957. Itsiopoulos, C., Marx, W., Mayr, H.L., Tatucu-Babet, O.A., Dash, S.R., George, E.S., et al., 2018. The role of omega-3 polyunsaturated fatty acid supplementation in the management of type 2 diabetes mellitus: a narrative review. J. Nutr. Intermediary Metabolism 14, 1
10. Jin, M.J., Han, H.K., 2010. Effect of piperine, a major component of black pepper, on the intestinal absorption of fexofenadine and its implication on food
drug interaction. J. Food Sci. 75 (3), H93
H96.

226

CHAPTER 7 FOOD MATRICES THAT IMPROVE THE ORAL BIOAVAILABILITY

Joyce, P., Whitby, C.P., Prestidge, C.A., 2016. Nanostructuring biomaterials with specific activities towards digestive enzymes for controlled gastrointestinal absorption of lipophilic bioactive molecules. Adv. Colloid Interface Sci. 237, 52
75. Kakkar, V., Singh, S., Singla, D., Kaur, I.P., 2011. Exploring solid lipid nanoparticles to enhance the oral bioavailability of curcumin. Mol. Nutr. Food Res. 55 (3), 495
503. Karakaya, S., Nehir, El, S., Simsek, S., 2015. Functional salad dressing as an excipient food. Turkish J. Agric. Food Sci. Technol. 3 (11), 849
855. Kharat, M., Zhang, G., McClements, D.J., 2018. Stability of curcumin in oil-in-water emulsions: impact of emulsifier type and concentration on chemical degradation. Food Res. Int. 111, 178
186. Kindel, T., Lee, D.M., Tso, P., 2010. The mechanism of the formation and secretion of chylomicrons. Atheroscler. Suppl. 11 (1), 11
16. Komaiko, J., McClements, D.J., 2015. Food-grade nanoemulsion filled hydrogels formed by spontaneous emulsification and gelation: optical properties, rheology, and stability. Food Hydrocolloids 46, 67
75. Komaiko, J., Sastrosubroto, A., McClements, D.J., 2016. Encapsulation of ω-3 fatty acids in nanoemulsionbased delivery systems fabricated from natural emulsifiers: sunflower phospholipids. Food Chem. 203, 331
339. Kommuru, T.R., Gurley, B., Khan, M.A., Reddy, I.K., 2001. Self-emulsifying drug delivery systems (SEDDS) of coenzyme Q10: formulation development and bioavailability assessment. Int. J. Pharm. 212 (2), 233
246. Kopec, R.E., Failla, M.L., 2018. Recent advances in the bioaccessibility and bioavailability of carotenoids and effects of other dietary lipophiles. J. Food Compos. Anal. 68, 16
30. Kosi´nska, A., Andlauer, W., 2013. Modulation of tight junction integrity by food components. Food Res. Int. 54, 951
960. Kuppusamy, P., Yusoff, M.M., Maniam, G.P., Ichwan, S.J.A., Soundharrajanc, I., Govindan, N., 2014. Nutraceuticals as potential therapeutic agents for colon cancer: a review. Acta Pharm. Sin. B 4 (3), 173
181. Lawrence, M.J., Rees, G.D., 2012. Microemulsion-based media as novel drug delivery systems. Adv. Drug Deliv. Rev. 64, 175
193. Lee, S., 2017. Chapter 4 - Strategic design of delivery systems for nutraceuticals. Nanotechnology Applications in Food: Flavor, Stability, Nutrition and Safety 65
86. Li, L., Braiteh, F.S., Kurzrock, R., 2005. Liposome-encapsulated curcumin: in vitro and in vivo effects on proliferation, apoptosis, signaling, and angiogenesis. Cancer 104 (6), 1322
1331. Li, H., Xu, Y., Sun, X., Wang, S., Wang, J., Zhu, J., et al., 2018a. Stability, bioactivity, and bioaccessibility of fucoxanthin in zein-caseinate composite nanoparticles fabricated at neutral pH by antisolvent precipitation. Food Hydrocolloids 84, 379
388. Li, D., Li, L., Xiao, N., Li, M., Xie, X., 2018b. Physical properties of oil-in-water nanoemulsions stabilized by OSA-modified starch for the encapsulation of lycopene. Colloids Surf. A: Physicochem. Eng. Aspects 552, 59
66. Liu, Z., Hut, M., 2007. Natural polyphenol disposition via coupled metabolic pathways. Expert Opin. Drug Metab. Toxicol. 3, 389
406. Liu, C.-H., Wu, C.-T., 2010. Optimization of nanostructured lipid carriers for lutein delivery. Colloids Surf. A: Physicochem. Eng. Aspects 353 (2
3), 149
156. Liu, X., Bi, J., Xiao, H., McClements, D.J., 2015. Increasing carotenoid bioaccessibility from yellow peppers using excipient emulsions: impact of lipid type and thermal processing. J. Agric. Food Chem. 63 (38), 8534
8543. Liu, X., Bi, J., Xiao, H., McClements, D.J., 2016a. Enhancement of nutraceutical bioavailability using excipient nanoemulsions: role of lipid digestion products on bioaccessibility of carotenoids and phenolics from mangoes. J. Food Sci. 81 (3), 754
761.

REFERENCES

227

Liu, X., McClements, D.J., Cao, Y., Xiao, H., 2016b. Chemical and physical stability of astaxanthin-enriched emulsion-based delivery systems. Food Biophys. 11 (3), 302
310. Liu, Y., Luo, X., Xu, X., Gao, N., Liu, X., 2017. Preparation, characterization and in vivo pharmacokinetic study of PVP-modified oleanolic acid liposomes. Int. J. Pharm. 517, 1
7. Lopes, L.B., VanDeWall, H., Li, H.T., Venugopal, V., Li, H.K., Naydin, S., et al., 2010. Topical delivery of lycopene using microemulsions: enhanced skin penetration and tissue antioxidant activity. J. Pharm. Sci. 99 (3), 1346
1357. Low, D.Y., D’Arcy, B., Gidley, M.J., 2015. Mastication effects on carotenoid bioaccessibility from mango fruit tissue. Food Res. Int. 67, 238
246. Ma, Q.H., Kuang, Y.Z., Hao, X.Z., Gu, N., 2009. Preparation and characterization of tea polyphenols and vitamin E loaded nanoscale complex liposome. J. Nanosci. Nanotechnol. 9, 1379
1383. Manach, C., Williamson, G., Morand, C., Scalbert, A., R´em´esy, C., 2005. Bioavailability and bioefficacy of polyphenols in humans. I. Review of 97 bioavailability studies. Am. J. Clin. Nutr. 81, 230S
242S. Mayer, S., Weiss, J., McClements, D.J., 2013. Behavior of vitamin E acetate delivery systems under simulated gastrointestinal conditions: lipid digestion and bioaccessibility of low-energy nanoemulsions. J. Colloid Interface Sci. 404, 215
222. McClements, D.J., 2005. Food Emulsions: Principles, Practices, and Techniques. CRC Press, Boca Raton, FL, pp. 1
632. McClements, D.J., 2011. Edible nanoemulsions: fabrication, properties, and functional performance. Soft Matter 7, 2297
2316. McClements, D.J., 2012a. Nanoemulsions vs microemulsions: terminology, differences, and similarities. Soft Matter 8, 1719
1729. McClements, D.J., 2012b. Requirements for food ingredient and nutraceutical delivery systems. Encapsulation Technologies and Delivery Systems for Food Ingredients and Nutraceuticals Woodhead Publishing Series in Food Science, Technology and Nutrition. Woodhead Publishing, Cambridge, pp. 3
18. McClements, D.J., 2012c. Advances in fabrication of emulsions with enhanced functionality using structural design principles. Curr. Opin. Colloid Interface Sci. 17, 235
245. McClements, D.J., 2013. Utilizing food effects to overcome challenges in delivery of lipophilic bioactives: structural design of medical and functional foods. Expert Opin. Drug. Deliv. 10 (12), 1621
1632. McClements, D.J., 2017a. Recent progress in hydrogel delivery systems for improving nutraceutical bioavailability. Food Hydrocolloids 68, 238
245. McClements, D.J., 2017b. Designing biopolymer microgels to encapsulate, protect and deliver bioactive components: physicochemical aspects. Adv. Colloid Interface Sci. 240, 31
59. McClements, D.J., 2018a. Delivery by Design (DbD): a standardized approach to the development of efficacious nanoparticle- and microparticle-based delivery systems. Compr. Rev. Food Sci. Food Safety 17 (1), 200
2019. McClements, D.J., 2018b. The biophysics of digestion: lipids. Curr. Opin. Food Sci. 21, 1
6. McClements, D.J., 2018c. Enhanced delivery of lipophilic bioactives using emulsions: a review of major factors affecting vitamin, nutraceutical, and lipid bioaccessibility. Food Funct. 9, 22
41. McClements, D.J., Li, Y., 2010. Structured emulsion-based delivery systems: controlling the digestion and release of lipophilic food components. Adv. Colloid Interface Sci. 159, 213
228. McClements, D.J., Rao, J., 2011. Food-Grade nanoemulsions: formulation, fabrication, properties, performance, biological fate, and potential toxicity. Crit. Rev. Food Sci. Nutr. 51 (4), 285
330. McClements, D.J., Xiao, H., 2014. Excipient foods: designing food matrices that improve the oral bioavailability of pharmaceuticals and nutraceuticals. Food Funct. 5, 1320
1333. McClements, D.J., Xiao, H., 2017. Designing food structure and composition to enhance nutraceutical bioactivity to support cancer inhibition. Semin. Cancer Biol. 46, 215
226.

228

CHAPTER 7 FOOD MATRICES THAT IMPROVE THE ORAL BIOAVAILABILITY

McClements, D.J., Jafari, S.M., 2018. Improving emulsion formation, stability and performance using mixed emulsifiers: a review. Adv. Colloid Interface Sci. 251, 55
79. McClements, D.J., Decker, E.A., Park, Y., Weiss, J., 2008. Designing food structure to control stability, digestion, release and absorption of lipophilic food components. Food Biophys. 3, 219
228. McClements, D.J., Decker, E.A., Park, Y., Weiss, J., 2009. Structural design principles for delivery of bioactive components in nutraceuticals and functional foods. Crit. Rev. Food Sci. Nutr. 49, 577
606. McClements, D.J., Li, F., Xiao, H., 2015a. The nutraceutical bioavailability classification scheme: classifying nutraceuticals according to factors limiting their oral bioavailability. Annu. Rev. Food Sci. Technol. 6, 13.11
13.29. McClements, D.J., Zou, L., Zhang, R., Salvia-Trujillo, L., Kumosani, T., Xiao, H., 2015b. Enhancing nutraceutical performance using excipient foods: designing food structures and compositions to increase bioavailability. Compr. Rev. Food Sci. Food Safety 14 (6), 824
847. McClements, D.J., Saliva-Trujillo, L., Zhang, R., Zhang, Z., Zou, L., Yao, M., et al., 2016. Boosting the bioavailability of hydrophobic nutrients, vitamins, and nutraceuticals in natural products using excipient emulsions. Food Res. Int. 88, 140
152. Meronia, E., Raikos, V., 2018. Formulating orange oil-in-water beverage emulsions for effective delivery of bioactives: improvements in chemical stability, antioxidant activity and gastrointestinal fate of lycopene using carrier oils. Food Res. Int. 106, 439
445. Meynier, A., Genot, C., 2017. Molecular and structural organization of lipids in foods: their fate during digestion and impact in nutrition. OCL 24 (2), D202. Michalski, M.C., Genot, C., Gayet, C., Lopez, C., Fine, F., Joffre, F., et al., 2013. Multiscale structures of lipids in foods as parameters affecting fatty acid bioavailability and lipid metabolism. Prog. Lipid Res. 52, 354
373. Miyashita, K., Nishikawa, S., Hosokawa, M., 2018. Therapeutic effect of fucoxanthin on metabolic syndrome and type 2 diabetes. Nutritional and Therapeutic Interventions for Diabetes and Metabolic Syndrome, 2nd edition 343
355. Mun, S., Kim, Y.R., Shin, M., McClements, D.J., 2015a. Control of lipid digestion and nutraceutical bioaccessibility using starch-based filled hydrogels: influence of starch and surfactant type. Food Hydrocolloids 44, 380
389. Mun, S., Kim, Y.-R., McClements, D.J., 2015b. Control of b-carotene bioaccessibility using starch-based filled hydrogels. Food Chem. 173, 454
461. Nakagawa, K., Sowasod, N., Tanthapanichakoon, W., Charinpanitkul, T., 2013. Hydrogel based oil encapsulation for controlled release of curcumin by using a ternary system of chitosan, kappa-carrageenan, and carboxymethylcellulose sodium salt. Food Sci. Technol. 54 (2), 600
605. Odeberg, J.M., Lignell, A., Pettersson, A., Hoglund, P., 2003. Oral bioavailability of the antioxidant astaxanthin in humans is enhanced by incorporation of lipid based formulations. Eur. J. Pharm. Sci. 19, 299
304. Oehlke, K., Adamiuk, M., Behsnilian, D., Gra¨f, V., Mayer-Miebach, E., Walza, E., et al., 2014. Potential bioavailability enhancement of bioactive compounds using food-grade engineered nanomaterials: a review of the existing evidence. Food Funct. 5, 1341
1359. Ozturk, B., Argin, S., Ozilgen, M., McClements, D.J., 2015a. Nanoemulsion delivery systems for oil-soluble vitamins: influence of carrier oil type on lipid digestion and vitamin D3 bioaccessibility. Food Chem. 187, 499
506. Ozturk, B., Argin, S., Ozilgen, M., McClements, D.J., 2015b. Formation and stabilization of nanoemulsionbased vitamin E delivery systems using natural biopolymers: whey protein isolate and gum arabic. Food Chem. 188 (1). Palafox-Carlos, H., Ayala-Zavala, J.F., Gonz´alez-Aguilar, G.A., 2011. The role of dietary fiber in the bioaccessibility and bioavailability of fruit and vegetable antioxidants. J. Food Sci. 76 (1), R6
R15.

REFERENCES

229

Palmero, P., Panozzo, A., Colle, I., Chigwedere, C., Hendrickx, M., Loey, A.V., 2016. Role of structural barriers for carotenoid bioaccessibility upon high pressure homogenization. Food Chem. 199, 423
432. Parthasarathi, S., Muthukumar, S.P., Anandharamakrishnan, C., 2018. Influence of droplet size on stability, in vivo digestion, and oral bioavailability of vitamin E emulsions. Food Funct. 7 (5), 2294
2302. Peng, C., Svirskis, D., Lee, S.J., Oey, I., Kwak, H.-S., Chen, G., et al., 2018. Design of microemulsion system suitable for the oral delivery of poorly aqueous soluble beta-carotene. J. Pharm. Dev. Technol. 23 (7), 682
688. Petyaev, I.M., Dovgalevsky, P.Y., Klochkov, V.A., Chalyk, N.E., Pristensky, D.V., Chernyshova, M.P., et al., 2018. Effect of lycopene supplementation on cardiovascular parameters and markers of inflammation and oxidation in patients with coronary vascular disease. Food Sci. Nutr. 6, 1770
1777. Porter, C.J., Trevaskis, N.L., Charman, W.N., 2007. Lipids and lipid-based formulations: optimizing the oral delivery of lipophilic drugs. Nat. Rev. Drug. Discov. 6 (3), 231
248. Pradhan, M., Singh, D., Singh, M.R., 2013. Novel colloidal carriers for psoriasis: current issues, mechanistic insight and novel delivery approaches. J. Control Release 170, 380
395. Qian, C., Decker, E.A., Xiao, H., McClements, D.J., 2012. Nanoemulsion delivery systems: influence of carrier oil on β-carotene bioaccessibility. Food Chem. 135, 1440
1447. Ramesan, R.M., Sharma, C.P., 2009. Challenges and advances in nanoparticle-based oral insulin delivery. Expert Rev. Med. Devices. 6 (6), 665
676. Ramı´rez, M., Amate, L., Gilb, A., 2001. Absorption and distribution of dietary fatty acids from different sources. Early Hum. Dev. 65, S95
S101. Rao, J., McClements, D.J., 2012. Food-grade microemulsions and nanoemulsions: role of oil phase composition on formation and stability. Food Hydrocolloids 29, 326
334. Rein, M.J., Renouf, M., Cruz-Hernandez, C., Actis-Goretta, L., Thakkar, S.K., Pinto, M.S., 2013. Bioavailability of bioactive food compounds: a challenging journey to bioefficacy. Br. J. Clin. Pharmacol. 75 (3), 588
602. Riedl, J., Linseisen, J., Hoffmann, J., Wolfram, G., 1999. Some dietary fibers reduce the absorption of carotenoids in women. J. Nutr. 129, 2170
2176. Ruiz Ruiz, J.C., Ortiz Vazquez, E.D.L.L., Segura Campos, M.R., 2015. Encapsulation of vegetable oils as source of omega-3 fatty acids for enriched functional foods. Food Sci. Nutr. 57 (7), 1423
1434. Salcedo-Sandoval, L., Cofrades, S., Ruiz-Capillas, C., Matalanis, A., McClements, D.J., Decker, E.A., et al., 2015. Oxidative stability of n-3 fatty acids encapsulated in filled hydrogel particles and of pork meat systems containing them. Food Chem. 184 (1), 207
213. Salminen, H., Herrmann, K., Weiss, J., 2013. Oil-in-water emulsions as a delivery system for n-3 fatty acids in meat products. Meat Sci. 93 (3), 659
667. Salvia-Trujillo, L., McClements, D.J., 2016. Enhancement of lycopene bioaccessibility from tomato juice using excipient emulsions: influence of lipid droplet size. Food Chem. 210, 295
304. Salvia-Trujillo, L., Qian, C., Martı´n-Belloso, O., McClements, D.J., 2013. Influence of particle size on lipid digestion and β-carotene bioaccessibility in emulsions and nanoemulsions. Food Chem. 141, 1472
1480. Salvia-Trujillo, L., Sun, Q., Um, B.H., Park, Y., McClements, D.J., 2015. In vitro and in vivo study of fucoxanthin bioavailability from nanoemulsion-based delivery systems: impact of lipid carrier type. J. Funct. Foods 17, 293
304. Salvia-Trujillo, L., Martı´n-Belloso, O., McClements, D.J., 2016. Excipient nanoemulsions for improving oral bioavailability of bioactives. Nanomaterials 6, 1
17. Scaldaferri, F., Pizzoferrato, M., Gerardi, V., Lopetuso, L., Gasbarrini, A., 2012. The gut barrier new acquisitions and therapeutic approaches. J. Clin. Gastroenterol. 46 (9), S12
S17. Seki, T., Harada, S., Hosoya, O., Morimoto, K., Juni, K., 2008. Evaluation of the establishment of a tight junction in Caco-2 cell monolayers using a pore permeation model involving two different sizes. Biol. Pharm. Bull. 31 (1), 163
166.

230

CHAPTER 7 FOOD MATRICES THAT IMPROVE THE ORAL BIOAVAILABILITY

Shin, G.H., Kim, J.T., Park, H.J., 2015. Recent developments in nanoformulations of lipophilic functional foods. Trends Food Sci. Technol. 46, 144
157. Simo˜es, L.S., Madalena, D.A., Pinheiro, A.C., Teixeira, J.A., Vicente, A.A., Ramos, O.L., 2017. Micro- and nano bio-based delivery systems for food applications: in vitro behavior. Adv. Colloid Interface Sci. 243, 23
45. Singh, H., Thompson, A., Liu, W., Corredig, M., 2012. 11 - Liposomes as food ingredients and nutraceutical delivery systems. Encapsulation Technologies and Delivery Systems for Food Ingredients and Nutraceuticals. Woodhead Publishing Series in Food Science, Technology and Nutrition. Woodhead Publishing, Cambridge, pp. 287
318. Soukoulis, C., Bohn, T., 2018. A comprehensive overview on the micro- and nano-technological encapsulation advances for enhancing the chemical stability and bioavailability of carotenoids. Crit. Rev. Food Sci. Nutr. 58 (1), 1
36. Ting, Y., Jiang, Y., Ho, C.-T., Huang, Q., 2014. Common delivery systems for enhancing in vivo bioavailability and biological efficacy of nutraceuticals. J. Funct. Foods 7, 112
128. Torno, C., Staats, S., de Pascual-Teresa, S., Rimbach, G., Schulz, C., 2017. Fatty acid profile is modulated by dietary resveratrol in rainbow trout (Oncorhynchus mykiss). Mar. Drugs. 15 (8), 252. Tsutsumi, K., Li, S.K., Hymas, R.V., Teng, C.L., Tillman, L.G., Hardee, G.E., et al., 2008. Systematic studies on the paracellular permeation of model permeants and Oligonucleotides in the rat small intestine with chenodeoxycholate as enhancer. J. Pharm. Sci. 97 (1), 350
367. Tyrer, P., Foxwell, A.R., Cripps, A.W., Apicella, M.A., Kyd, J.M., 2006. Microbial pattern recognition receptors mediate M-cell uptake of a Gram-negative bacterium. Infect. Immun. 74 (1), 625
631. van Meer, G., Voelker, D.R., Feigenson, G.W., 2008. Membrane lipids: where they are and how they behave. Nat. Rev. Mol. Cell Biol. 9, 112
124. Velikov, K.P., Pelan, E., 2008. Colloidal delivery systems for micronutrients and nutraceuticals. Soft Matter 4, 1964
1980. Verrijssen, T.A.J., Verkempinck, S.H.E., Christiaens, S., Loey, A.M.V., Hendrickx, M.E., 2015. The effect of pectin on in vitro β-carotene bioaccessibility and lipid digestion in low fat emulsions. Food Hydrocolloids 49, 73
81. Walker, R., Decker, E.A., McClements, D.J., 2015. Development of food-grade nanoemulsions and emulsions for delivery of omega-3 fatty acids: opportunities and obstacles in the food industry. Food Funct. 6 (1), 42
55. Wang, X.Y., Jiang, Y., Wang, Y.W., Huang, M.T., Ho, C.T., Huang, Q.R., 2008. Enhancing anti-inflammation activity of curcumin through O/W nanoemulsions. Food Chem. 108 (2), 419
424. Weigel, F., Weiss, J., Decker, E.A., McClements, D.J., 2018. Lutein-enriched emulsion-based delivery systems: influence of emulsifiers and antioxidants on physical and chemical stability. Food Chem. 242, 395
403. Weiss, J., Decker, E.A., McClements, D.J., Kristbergsson, K., Helgason, T., Awad, T., 2008. Solid lipid nanoparticles as delivery systems for bioactive food components. Food Biophys. 3, 146
154. Wilhelm, E.A., Vogt, A.G., Reis, A.S., Pinz, M.P., Souza, J.F., Haas, S.E., et al., 2018. The efficacy of microemulsion-based delivery to improve vitamin E properties: evaluation of the antinociceptive, antioxidant, antidepressant- and anxiolytic-like activities in mice. J. Pharm. Pharmacol. 70, 1723
1732. Winuprasith, T., Khomein, P., Mitbumrung, W., Suphantharika, M., Nitithamyong, A., McClements, D.J., 2018. Encapsulation of vitamin D3 in pickering emulsions stabilized by nanofibrillated mangosteen cellulose: impact on in vitro digestion and bioaccessibility. Food Hydrocolloids 83, 153
164. Wu, A., Noble, E.E., Tyagi, E., Ying, Z., Zhuang, Y., Gomez-Pinilla, F., 2015. Curcumin boosts DHA in the brain: implications for the prevention of anxiety disorders. Biochim. Biophys. Acta, Mol. Basis Dis. 1852, 951
961.

FURTHER READING

231

Xi, J., Chang, Q., Chan, C.K., Meng, Z.Y., Wang, G.N., Sun, J.B., et al., 2009. Formulation development and bioavailability evaluation of a self-nanoemulsified drug delivery system of oleanolic acid. AAPS PharmSciTech 10 (1), 172
182. Xu, J., Zhao, W., Ning, Y., Bashari, M., Wu, F., Chen, H., et al., 2013. Improved stability and controlled release of ω3/ω6 polyunsaturated fatty acids by spring dextrin encapsulation. Carbohydr. Polym. 92 (2), 1633
1640. Yang, Y., McClements, D.J., 2013. Vitamin E bioaccessibility: influence of carrier oil type on digestion and release of emulsified a-tocopherol acetate. Food Chem. 141, 473
481. Yang, Y., Xiao, H., McClements, D.J., 2017. Impact of lipid phase on the bioavailability of vitamin E in emulsion-based delivery systems: relative importance of bioaccessibility, absorption, and transformation. J. Agric. Food Chem. 65, 3946
3955. Yao, M., Xiao, H., McClements, D.J., 2014. Delivery of lipophilic bioactives: assembly, disassembly, and reassembly of lipid nanoparticles. Annu. Rev. Food Sci. Technol. 5, 53
81. Yonekura, L., Nagao, A., 2009. Soluble fibers inhibit carotenoid micellization in vitro and uptake by Caco-2 cells. Biosci. Biotechnol. Biochem. 73 (1), 196
199. Zhang, R., McClements, D.J., 2016. Enhancing nutraceutical bioavailability by controlling the composition and structure of gastrointestinal contents: emulsion-based delivery and excipient systems. Food Struct. 10, 21
36. Zhang, L., Hayes, D.G., Chen, G., Zhong, Q., 2013. Transparent dispersions of milk-fat-based nanostructured lipid carriers for delivery of β-carotene. J. Agric. Food Chem. 61 (39), 9435
9443. Zhang, Z., Zhang, R., Chen, L., Tong, Q., McClements, D.J., 2015. Designing hydrogel particles for controlled or targeted release of lipophilic bioactive agents in the gastrointestinal tract. Eur. Polym J. 72, 698
716. Zhang, R.J., Zhang, Z.P., Zou, L.Q., Xiao, H., Zhang, G.D., Decker, E.A., et al., 2016a. Impact of lipid content on the ability of excipient emulsions to increase carotenoid bioaccessibility from natural sources (raw and cooked carrots). Food Biophys. 11 (1), 71
80. Zhang, Z., Zhang, R., McClements, D.J., 2016b. Encapsulation of b-carotene in alginate-based hydrogel beads: impact on physicochemical stability and bioaccessibility. Food Hydrocolloids 61, 1
10. Zhou, Q., Yang, L., Xu, J., Qiao, X., Li, Z., Wang, Y., et al., 2018. Evaluation of the physicochemical stability and digestibility of microencapsulated esterified astaxanthins using in vitro and in vivo models. Food Chem. 260, 73
81. Ziesel, S.H., Blusztajn, J.K., 1994. Choline and human nutrition. Annu. Rev. Nutr. 14, 269
296. Zou, L., Zheng, B., Liu, W., Liu, C., Xiao, H., McClements, D.J., 2015. Enhancing nutraceutical bioavailability using excipient emulsions: influence of lipid droplet size on solubility and bioaccessibility of powdered curcumin. J. Funct. Foods 15, 72
83. Zou, L., Zheng, B., Zhang, R., Zhang, Z., Liu, W., Liu, C., et al., 2016. Food matrix effects on nutraceutical bioavailability: impact of protein on curcumin bioaccessibility and transformation in nanoemulsion delivery systems and excipient nanoemulsions. Food Biophys. 11 (2), 142
153. Zuidam, N.J., Velikov, K.P., 2018. Choosing the right delivery systems for functional ingredients in foods: an industrial perspective. Curr. Opin. Food Sci. 21, 15
25.

FURTHER READING Anarjan, N., Tan, C.P., Nehdi, I.A., Ling, T.C., 2012. Colloidal astaxanthin: preparation, characterisation and bioavailability evaluation. Food Chem. 135, 1303
1309. Anuradha, C.V., 2018. Chapter 18 - Astaxanthin, a marine carotenoid against hepatic oxidative stress: a systematic review. Liver
Oxidat. Stress Dietary Antioxidants 2018, 211
228.

232

CHAPTER 7 FOOD MATRICES THAT IMPROVE THE ORAL BIOAVAILABILITY

Bourlieu, C., Bouhallab, S., Lopez, C., 2009. Biocatalyzed modifications of milk lipids: applications and potentialities. Trends Food Sci. Technol. 20, 458
469. Buggenhout, S.V., Alminger, M., Lemmens, L., Colle, I., Knockaert, G., Moelants, K., et al., 2010. In vitro approaches to estimate the effect of food processing on carotenoid bioavailability need thorough understanding of process induced microstructural changes. Trends Food Sci. Technol. 21, 607
618. Cervantes-Paz, B., Ornelas-Paz, J.J., Ruiz-Cruz, S., Rios-Velasco, C., Ibarra-Junquera, V., Yahia, E.M., et al., 2017. Effects of pectin on lipid digestion and possible implications for carotenoid bioavailability during pre-absorptive stages: a review. Food Res. Int. 99, 917
927. Comhaire, F.H., Garem, Y., Mahmoud, A., Eertmans, F., Schoonjans, F., 2005. Combined conventional/antioxidant “Astaxanthin” treatment for male infertility: a double blind, randomized trial. Asian J. Androl. 7 (3), 257
262. Harrison, E.H., 2012. Mechanisms involved in the intestinal absorption of dietary vitamin An and provitamin A carotenoids. Biochim. Biophys. Acta 1821, 70
77. Iwamoto, T., Hosoda, K., Hirano, R., Kurata, H., Matsumoto, A., Miki, W., et al., 2000. Inhibition of lowdensity lipoprotein oxidation by astaxanthin. J. Atheroscler. Thromb. 7, 216
222. Kajita, M., Tsukahara, H., Kato, M., 2009. The effects of a dietary supplement containing astaxanthin on the accommodation function of the eye in middle-aged and older people. Med. Consult. New Remedies 46 (3), 89
93. Lo´pez-Lluch, G., Pozo-Cruz, J., S´anchez-Cuesta, A., Bel´en Cort´es-Rodrı´guez, A.B., Pl´acido Navas, P., 2018. Bioavailability of coenzyme Q10 supplements depends on carrier lipids and solubilization. Nutrition 57, 133
140. Martı´nez-Delgado, A.A., Khandual, S., Villanueva
Rodrı´guez, S.J., 2017. Chemical stability of astaxanthin integrated into a food matrix: effects of food processing and methods for preservation. Food Chem. 225, 23
30. Mashhadi, N.S., Zakerkish, M., Mohammadiasl, J., Zarei, M., Mohammadshah, M., Haghighizadeh, M.H., 2018. Astaxanthin improves glucose metabolism and reduces blood pressure in patients with type 2 diabetes mellitus. Asia Pac. J. Clin. Nutr. 27 (2), 341
346. Masoudi, A., Dargahi, L., Abbaszadeh, F., Pourgholami, M.H., Asgari, A., Manoochehri, M., et al., 2017. Neuroprotective effects of astaxanthin in a rat model of spinal cord injury. Behav. Brain. Res. 329, 104
110. McClements, D.J., 2015. Enhancing nutraceutical bioavailability through food matrix design. Curr. Opin. Food Sci. 4, 1
6. Naguib, Y.M., 2000. Antioxidant activities of astaxanthin and related carotenoids. J. Agric. Food Chem. 48 (4), 1150
1154. Parker, R.S., Swanson, J.E., You, C.-S., Edwards, A.J., Huang, T., 1999. Bioavailability of carotenoids in human subjects. Proc. Nutr. Soc. 58, 155
162. Pegoraro, N.S., Barbieri, A.V., Camponogara, C., Mattiazzi, J., Brum, E.S., Marchiori, M.C.L., et al., 2017. Nanoencapsulation of coenzyme Q10 and vitamin E acetate protects against UVB radiation-induced skin injury in mice. Colloids Surf. B: Biointerfaces 150, 32
40. Rock, C.L., Lovalvo, J.L., Emenhiser, C., Ruffin, M.T., Flatt, S.W., Schwartz, S.J., 1998. Bioavailability of bcarotene is lower in raw than in processed carrots and spinach in women. J. Nutr. 128 (5), 913
916. Saura-Calixto, F., Serrano, J., Gon˜i, I., 2007. Intake and bioaccessibility of total polyphenols in a whole diet. Food Chem. 101, 492
501. Shu, G., Khalid, N., Chen, Z., Neves, M.A., Barrow, C.J., Nakajima, M., 2018. Formulation and characterization of astaxanthin-enriched nanoemulsions stabilized using ginseng saponins as natural emulsifiers. Food Chem. 255, 67
74.

FURTHER READING

233

Vakarelova, M., Zanoni, F., Lardo, P., Rossin, G., Mainente, F., Chignola, R., et al., 2017. Production of stable food-grade microencapsulated astaxanthin by vibrating nozzle technology. Food Chem. 221, 289
295. Yamashita, E., 2006. The effects of a dietary supplement containing astaxanthin on skin condition. Carot. Sci. 10, 91
95. Yamashita, E., 2015. Let astaxanthin be thy medicine. Pharm. Nutr. 3, 115
122. Yasui, Y., Hosokawa, M., Mikami, N., Miyashita, K., Tanaka, T., 2011. Dietary astaxanthin inhibits colitis and colitis-associated colon carcinogenesis in mice via modulation of the inflammatory cytokines. Chem. Biol. Interact. 193, 79
87. Yuan, J.-P., Juan Peng, J., Kai Yin, K., Wang, J.-H., 2011. Potential health-promoting effects of astaxanthin: a high-value carotenoid mostly from microalgae. Mol. Nutr. Food Res. 55, 150
165. Zhang, L., Wang, H., 2015. Multiple mechanisms of anti-cancer effects exerted by astaxanthin. Mar. Drugs. 13, 4310
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CHAPTER

INNOVATIVE SOURCES

8

1,2 ˘ ˘ s1,2, Sonia Socaci1,2 and Dan Cristian Vodnar1,2 Lavinia Florina Calinoiu , Anca Farca¸ 1

Faculty of Food Science and Technology, University of Agricultural Sciences and Veterinary Medicine Cluj-Napoca, Cluj-Napoca, Romania 2Institute of Life Sciences, University of Agricultural Sciences and Veterinary Medicine Cluj-Napoca, Cluj-Napoca, Romania

CHAPTER OUTLINE 8.1 Introduction ................................................................................................................................. 235 8.2 Innovative Sources of Nutraceuticals ............................................................................................ 236 8.3 Factors That Influence the Biological Properties of Bioactive Compounds From Agro-Industrial By-Products .................................................................................................. 243 8.3.1 Digestion Process ..................................................................................................... 243 8.3.2 Food Processing ....................................................................................................... 250 8.4 Conclusions................................................................................................................................. 251 Acknowledgment................................................................................................................................. 252 References ......................................................................................................................................... 252 Further Reading .................................................................................................................................. 265

8.1 INTRODUCTION Worldwide, the food industry generates millions of tons of plant-derived wastes which can be exploited as sources of high-value components: proteins, fibers, polysaccharides, phytochemicals, lipids, and fatty acids (Socaci et al., 2017). Approximately 38% of food by-products are produced during food processing (Ayala-Zavala et al., 2010), whereas their disposal creates serious environmental problems and intelligent waste management is crucial in the growth of food industries (Kumar et al., 2017). Nowadays, the agro-industrial wastes represented the main source of animal feeds, fertilizers, or biofuels (Fatih Demirbas et al., 2011). The active compounds or phytochemicals in plants have been associated with numerous health benefits and are used as ingredients in many nutraceutical and pharmaceutical products today (Cardona et al., 2013; Ozcan et al., 2014). Given the importance and wide biological activities of natural bioactive compounds in plant tissues, their bioactive properties, and their broad diversity of structures and functionalities, these compounds represent an impressive source of molecules with a

Nutraceuticals and Natural Product Pharmaceuticals. DOI: https://doi.org/10.1016/B978-0-12-816450-1.00008-8 © 2019 Elsevier Inc. All rights reserved.

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crucial role in the development of new products (Wu and Chappell, 2008). Some of those compounds can be found in nature at high concentration such as polyphenols but others can only be found at very low levels, so that massive harvesting is needed to obtain sufficient amounts, and their structural diversity and complexity make chemical synthesis unprofitable. The generally used methods for their extraction are the conventional liquid
liquid or solid
liquid extraction while the advanced methods include pressurized-liquid extraction, subcritical and supercritical extractions, and microwave- and ultrasound-assisted extractions. In addition, these extraction techniques have been improved with previous steps (enzyme-and instant controlled pressure drop-assisted extractions) that help to release the compounds from the matrix. These technologies could provide in the next few years an innovative approach to increase the production of specific compounds for use as nutraceuticals (Gil-Ch´avez et al., 2013). In the last 25 years about 60%
70% of newly approved drugs for cancer and infectious diseases were derived from natural bioactive compounds (Newman and Cragg, 2012). It is important to notice that more than two-thirds of the world population still rely on medicinal plants for their primary pharmaceutical care (Gil-Ch´avez et al., 2013). However, although these compounds have been tested empirically by the population, obtaining some beneficial effects for human health, more scientific evidence is needed in order to support their efficacy and to ensure their safety. Agro-industrial waste is one of the future sectors, which must be explored for their bioactive potential, whereas fruit and vegetable juice and pulp industries generate the highest amounts (Vodnar et al., 2017; Dulf et al., 2017). The wastes generated by this sector include peels/skins, pomace and seeds, stems, shells, bran, trimmings, and residues. The peels, seeds, shanks, leaves, wastewater, and unusable pulp constitute more than 40% of total plant food (Goni and HervertHernandez, 2011). They comprise high amounts of significant compounds, such as minerals, organic acids, dietary fibers, polyphenols, and carotenoids that could be revalorized in their own specific market (S´anchez-Zapata et al., 2009). Waste products deriving from fruit and vegetable processing industries could be much more valorized mainly for two important reasons: (1) due to their low price and their considerable existing amounts, and (2) due to their valuable bioactive potential (Vodnar et al., 2017). This chapter discusses the different sources of nutraceuticals and pharmaceuticals, giving a basis on underutilized sources such as food processing by-products, while also evaluating the influence of food digestion and food processing on bioactive compounds.

8.2 INNOVATIVE SOURCES OF NUTRACEUTICALS Several sources of active ingredients from plants are being used in manufacture of nutraceuticals. Innovative sources of active ingredients from plants that can be divided into primary and secondary metabolites (Wu and Chappell, 2008). The primary metabolites are sugars, amino acids, fatty acids, and nucleic acids, as well as the compounds considered ubiquitous to all plants for growth and development, like growth regulators and cell wall components, among others (Gil-Ch´avez et al., 2013). Natural biosynthesis of these metabolites depends on the physiology and developmental stage of the plant. There are at least fourteen classes of secondary metabolites (chemical compounds) from fruits and vegetables that exert biological activities and can potentially be used to promote human health. These include alkaloids, amines, cyanogenic glycosides, diterpenes,

8.2 INNOVATIVE SOURCES OF NUTRACEUTICALS

237

flavonoids, glucosinolates, monoterpenes, nonprotein amino acids, phenylpropanes, polyacetylenes, polyketides, sesquiterpenes, tetraterpenes, triterpenes, saponins, and steroids (Gil-Ch´avez et al., 2013). Examples of commercially useful plant secondary metabolites are carotenoids, terpenoids, alkaloids, phenylpropanoids, and more specific compounds such as corilagin, ellagic acid, vinblastine, vincristine, β- and α-farnesene, among others (Nobili et al., 2009; Yang et al., 2011). These compounds are commonly utilized for the production of pharmaceuticals (Shahidi, 2009) and more recently it has been proposed for their use as nutraceuticals to increase the functionality of natural compounds (Ayala-Zavala et al., 2010). Recently, several researches led to the identification of bioactive compounds useful for formulation of functional food or nutraceutical products from food by-products. The food processing industry waste comprises the biological by-products and wastes generated by processing of the harvested material, with the aim of more ready-to-eat food products. They include various types of solid wastes, such as fruit pomace, seeds generated via juice, sauce or jam production, spent grain powders produced during production of grain flours, or can also include different liquid wastes such as spent biomass rich water or spent food extracts (Routray and Orsat, 2017). On this perspective in the production of pomegranate juice, peel and pericarp, rich in cyanidin3,5-diglucoside, cyanidin-3-diglucoside and delphinidin-3,5-diglucoside could be used for production of anthocyanin-based nutraceuticals products (Gil et al., 2000). The bioactive potential of pomegranate seeds was underlined by Lucci et al. (2015) whose findings revealed that pomegranate “Dente di Cavallo” seed extract comprises high amounts of punicic acid, α-linoleic, and α-linolenic acids with significant antioxidant and antiproliferative activities, therefore representing an important health-related ingredient in formulations of products aimed to prevent cancer. The broccoli leaves and stalks, as well as the tomato peel are major by-product sources of glucosinolates, phenolic acids, flavonoids, lycopene tocopherols, sitosterols (Perretti et al., 2013; Domı´nguez-Perles et al., 2010). Peach and apricot by-product comprising peel and kernel are important sources of dietary fiber, phenols, carotenoids, and peptides (V´asquez-Villanueva et al., 2015; Study on Extraction of Carotenoids from Skin Residue of Apricot, 2013). There was an estimation that olive oil processing produces 25 kg of by-products per tree per year whereas leaves represent 5% of the weight of olives in oil extraction. At the same time, the olive oil processing produces 35 kg of solid waste (cake) and 100 L of liquid waste (oil mill wastewaters) per 100 kg of olives (Berbel et al., 2018). Olive mill wastewaters generated contain significant biophenols such as hydroxytyrosol and tyrosol (Olive Mill Waste | ScienceDirect). In particular, hydroxytyrosol is the most important antioxidant phenolic compound occurring in olive oil (Galanakis and Kotsiou, 2017), and numerous studies have focused on its health-related effects based on the antioxidant and antimicrobial activities (Veneziani et al., 2017), as well as its potential to inhibit the low-density lipoprotein oxidation (Polyphenols in olive related health claims, 2011). Oleuropein, and other bioactive secoiridoids could be recovered from olive leaves and olive-processing by-products up to 30%, w/w of the grapes processed by wine industry generated a solid waste (stems, skins, and seeds) whereas grape seed are rich in catechins and skins are rich in resveratrol, quercetin and its derivatives. Proanthocyanidins could be obtained from grape stems (Teixeira et al., 2014). Dietary fiber and phenolic acids are significant bioactive compounds resulted from cereal processing that can be extracted and incorporated in new products (Vitaglione et al., 2008; Gani et al., 2012; Laddomada et al., 2015; Elleuch et al., 2011). As shown in Table 8.1, an increasing number of scientific studies have been performed on natural bioactive compounds from by-products sources. They comprise a diverse range of structures

238

CHAPTER 8 INNOVATIVE SOURCES

Table 8.1 Innovative Sources of Active Ingredients From Food Processing By-Products By-Products Source

Bioactive Compounds

Applications

References

Penggan peel

Hesperidin

Ma et al. (2008)

Hawthorn seeds

Flavonoids

Litchi seeds

Polysaccharides

Peanut skins

Phenolic compounds

Grape seeds

Polyphenols, Proanthocyanidins

Grape skin from three varieties: Cabernet Sauvignon, ´ `re, and Cabermene Ribier Grape seed oil (byproduct) Citrus peels and pomace: Yen Ben and Meyer lemon, grapefruit, mandarin, and orange Rapeseed

Anthocyanins

Food, nutraceutical and pharmaceutical industry. Possess antioxidant, antiinflammatory and antiallergic activities. Health-promoting compounds negatively associated with coronary heart diseases. Food and biomedical applications. Posse’s antitumoral, antioxidant, and hypoglycemic properties. Pharmaceutical applications of health-promoting compounds including cancer prevention. Pharmaceutical, cosmetical and food industry. Anticarcinogenic, antiviral, anticancer, and may act against oxidation of lowdensity lipoproteins. Food additives providing health benefits.

Triacylglycerides

Antioxidants

Passos et al. (2010)

Total phenolics

Antioxidant and free radical scavenging activities. Implications in human health. Nutraceuticals.

Kim et al. (2009), Hayat et al. (2009), Li et al. (2006)

Phenolics, tocopherols, and phospholipids

Prevention and treatment of chronic diseases: heart and neurodegenerative diseases, aging, cancer, and rheumatoid arthritis. Effectiveness against colon cancer; Food industry; Nutraceuticals. Prevention of diseases including cancer, fatty liver, hypercalcicuria, kidney stones, and so on. Protective effect against cardiovascular, coronary heart diseases, and cancer.

SzydłowskaCzerniak et al. (2010a,b)

Apple pomace and peels

Polyphenols

Rice, rye and wheat bran

Phenolic acids, flavonols and anthocyanins

Tomato skins and seeds

Lycopene

Pan et al. (2012)

Chen et al. (2011)

Ballard et al. (2010)

Vodnar et al. (2017), Li et al. (2011), Yilmaz et al. (2011)

Mun˜oz et al. (2004)

Oszmia´nski et al. (2011), Calinoiu et al. (2017) Pourali et al. (2010), Anson et al. (2012), Andersson et al. (2014) Szabo et al. (2018)

8.2 INNOVATIVE SOURCES OF NUTRACEUTICALS

239

Table 8.1 Innovative Sources of Active Ingredients From Food Processing By-Products Continued By-Products Source

Bioactive Compounds

Applications

References

Roasted wheat germ

Phenolic compounds and tocopherols

Gelmez et al. (2009)

Coriander seeds

Antioxidant fractions

Mangosteen pericarp

Xanthones

Hibiscus cannabinus L. seed Wheat straw, germ, and bran

Edible oil

Eggplant peel

Anthocyanins

Mangifera pajang peels

Phenolics

Banana peels from two cultivars (Grande Naine and Gruesa) Parkia speciosa pod agro-waste Apricot pomace

Total phenols and anthocyanins

Pharmaceutical, food and cosmetic formulation. Biological control agents against insects. Diet supplements in nutraceuticals industries. Inhibition of lipid peroxidation, antioxidant activity, neuroprotective and inhibitor of HIV-1 protease. Functional foods and nutraceuticals. Lowering LDL and increasing HDL. Dietary supplements for cardiovascular health— Nutraceuticals. Antioxidant activity/natural food colorings. Antioxidant/ health benefits: treatment for stomach ache and diarrhea. Antioxidant/compounds with food and nutraceutical applications and health benefits. Antioxidant/nutraceutical agent for protection of human health. Nutraceutical, pharamaceutical and food industries. Food and nutraceutical industries. Food and nutraceutical industries.

Vodnar et al. (2017)

Red beet pomace/pulp Carrot pulp and peels

Chokeberry pomace Brewing industry waste Plum fruit by-products

Berry pomace

Policosanols

Total phenolic and flavonoids Phenolic compounds, flavonoids, lipids and antioxidant potential Betacyanins, anthocyanins Phenolic acids, anthocyanins, fatty acids, flavonoids Phenolic compounds and lipids Polyphenols, lipids and fatty acids, essential amino acids Total phenolic contents, flavonoids, antioxidant activity and lipid fractions Total phenolic contents, antioxidant activities, and lipid fractions

Nutraceutical, pharamaceutical, and food industries. Nutraceutical, pharamaceutical, and food industries.

Yepez et al. (2002) Zarena and Udaya Sankar (2009)

Chan and Ismail (2009) Dunford et al. (2010)

Todaro et al. (2009) Prasad et al. (2011)

Gonz´alezMontelongo et al. (2010) Gan and Latiff (2011) Dulf et al. (2017)

Vodnar et al. (2017), Arscott and Tanumihardjo (2010) Dulf et al. (2018) F˘arca¸s et al. (2017)

Food and nutraceutical industry

Dulf et al. (2016)

Food and nutraceutical industry

Dulf et al. (2015)

(Continued)

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CHAPTER 8 INNOVATIVE SOURCES

Table 8.1 Innovative Sources of Active Ingredients From Food Processing By-Products Continued By-Products Source

Bioactive Compounds

Applications

References

Coffea arabica leaves

Xanthone, echinoid and flavonoi Essential oil, oleoresin and dietary fiber content Polyphenols-condensed tannins: catechin, epicatechi, epigallocatechin, flavonolsquercetin, kaempherol, insoluble dietary fiber

Unique nutraceutical compounds Nutraceutical compoundsantimicrobial activities Nutraceutical

de Almeida et al. (2018) Arun et al. (2018)

Olive oil wastewater

Hydroxytyrosol, tyrosol

Health-beneficial effects; antioxidant and antimicrobial activities; Nutraceutical, pharamaceutical and functional food industries.

Oat mill waste

β-Glucan

Potato processing wastewater Guava juice industry by-products

Lipid biomass and linolenic acid via microbial fermentation Insoluble dietary fibers, phytosterols, saponins

Health-beneficial effects; functional ingredients; nutraceutical, food, and pharmaceutical industries. Nutraceuticals

Oat bran

Dietary fibers

Lemon by-product (peel, seed, fruit pulp)

Dietary fiber, iron, phenolic compounds (Hesperedin), carotenoids

Spent cumin seeds Nut leaves, skin, husks, bark, shells (almond, hazelnut, peanut, pecan, pistachios)

Nutraceuticals: decreased the rate of body weight gain; reduction of hepatic steosis. Reduce serum cholesterol due to its capacity to bind bile acid; constipation management; increased bioavailability of vitamin B12. Nutraceuticals

Ayala-Zavala et al. (2018), Pereira et al. (2007), Montella et al. (2013), Esfahlan et al. (2010), Chen et al. (2010), Prado et al. (2013), VazquezFlores et al. (2017), Tomaino et al. (2010), Francisco and Resurreccion (2008), Ma et al. (2014) Olive Mill Waste | ScienceDirect, Galanakis and Kotsiou (2017), Veneziani et al. (2017), D’Antuono et al. (2014), Galanakis (2011, 2012) Patsioura et al. (2011)

Muniraj et al. (2015)

Amaya-Cruz et al. (2015) Drzikova et al. (2005), Sturtzel et al. (2010)

Gorinstein et al. (2001), O’Shea et al. (2012)

8.2 INNOVATIVE SOURCES OF NUTRACEUTICALS

241

Table 8.1 Innovative Sources of Active Ingredients From Food Processing By-Products Continued By-Products Source

Bioactive Compounds

Applications

References

Onion by-product

Fiber content, quercetin, biosugar

Benı´tez et al. (2012), Choi et al. (2015)

Sugar beet pulp

Dietary fiber

Decrease in serum lipid and total cholesterol increment, generally caused by high fat diet. Improve lipid metabolism.

By-product from curcumin production Pomegranate by-product (seeds)

Turmeric oil

Olive leaves

Tocopherol, aliphatic alcohol (including policosanol), squalene, phytosterols, and triterpene contents, linolenic acid Secoiridoid oleuropein, secoiridoids, flavonoids, triterpenes

Antioxidant activities and antimutagenicity Nutraceuticals

Nutraceuticals

Leontowicz et al. (2001) Jayaprakasha et al. (2014) Caligiani et al. (2010), Verardo et al. (2014)

El and Karakaya (2009)

and functionalities providing a complex of molecules very significant for the production of nutraceuticals, pharmaceutical formulations, functional foods, and food additives. The tissues’ distribution of food phenolics is affected by genetic pathways, being specific to each crop and variety, therefore influencing the production of secondary metabolites (de Camargo et al., 2018). Plant food by-products are often more abundant sources of phenolics than their corresponding starting materials (Vodnar et al., 2017; C˘alinoiu and Vodnar, 2018; de Oliveira et al., 2017). Many of them are naturally occurring in high concentration, such as polyphenols. Certain polyphenols, such as hydroxycinnamates, coumarins, anthocyanins, ellagic acid, lignans, and ellagitannins approved as nutraceuticals are able to alter human cellular signaling and gene expression (Santini and Novellino, 2014; Lachance and Das, 2007; Espı´n et al., 2007). For a long time, agricultural by-products were perceived as nonvalue materials considering their removal from production, their nonefficient treatment processes. and their negative environmental impact. Nowadays, the growing population and their demands turned the swift toward sustainable food and agricultural sectors by valorization, the agro-industrial wastes as a source of nutraceuticals and functional food (Galanakis, 2013). Agro-industrial wastes are today considered as a low-cost source of significant bioactive compounds, available in large amounts, which can be easily exploited and recovered considering the existent technologies, allowing their reuse inside the food production line as functional additives or ingredients (Rahmanian et al., 2014). Wheat bran, generated by the flour milling industry, is usually considered a by-product. Instead, it is an important source of antioxidants, like phenolic acids, fibers, and minerals (Vitaglione et al., 2008) having a series of benefits on human health (Gani et al., 2012; C˘alinoiu and Vodnar, 2018; Brouns et al., 2012; Bondia-Pons et al., 2009). Phenolic acids, besides acting as antioxidants, also have antiinflammatory effects on the gastrointestinal (GI) system. Moreover, the whole-wheat grains present a more complex and beneficial nutritional profile than refined grains, due to the bran composition (Laddomada et al., 2015). Therefore, the utilization of wheat bran, due to its multiple

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benefits, has drawn important attention, and the ways to increase their bioactive content is of major interest (Laddomada et al., 2017). The genetic aspect of species and cultivars was explored as a possible way for increasing the content of phenolic acid in wheat. Based on the existing studies, it was concluded that genetic influence represents only a small factor as the environmental ones have a major influence on the final content of phenolic acids (Rawat et al., 2013; Shewry et al., 2012). Anyway, the use of an efficient breeding program for elite durum wheat was suggested as a possible solution for increasing the phenolic acid content in its germplasm (Laddomada et al., 2017). The olive oil wastewaters source of bioactive compounds, for a long time, was perceived as hazardous waste being a burden on the olive oil industry. The phytotoxicity is due to the high phenolic content (0.5
24 g/L), which represents as well the antioxidant content with potential healtheffect (D’Antuono et al., 2014). Olive oil wastewaters usually contains 98% of the total phenols in the olive fruit (Obied et al., 2005) and contain soluble dietary fibers, such as pectin characterized by gelling property with application as a fat replacement in meat products (Vierhuis et al., 2003; Galanakis et al., 2010b). Their recovery was investigated by Galanakis et al. (2010a), reporting the membrane technologies as very effective for their clarification and recovery. Moreover, hydroxytyrosol is one of the few nutraceuticals approved by the European Food Safety Authority for its healthy LDL cholesterol maintaining effect (Polyphenols in olive related health claims, 2011). The antioxidant activity of hydroxytyrosol was reported in the plasma and liver of rats (Visioli et al., 2001; Casalino et al., 2002), its cardio-protective benefits have been assessed on human cells (L´eger et al., 2000) and its cytoprotective potential against methylmercury (MeHg)-induced neurotoxicity on IMR-32 human neuroblastoma cells (Mohan et al., 2016). Therefore, the olive oil wastewaters are recognized as an important available and low-cost source with significant bioactive content that can be exploited as natural antioxidants for the food, nutraceutical, and pharmaceutical compounds with health related-benefits. Nut by-products are produced from crushed nuts processes and harvested process, including nut meal, skin, hull, and vine (root, stem, leaves, and flowers) (Zhao et al., 2012). For example, the peanut skins comprise valuable antioxidants, such as procyanidins, being a cheap source for use as functional ingredients in foods or nutraceuticals, positively impacting the human health and the environment (Yu et al., 2006). The potato processing industries generate huge amounts of starchy wastewater and peel waste causing significant negative environmental impact due to their disposal (Varzakas et al., 2016). The potato processing wastewater due to its high starchy content represents a potential source of nutraceutical compounds via microbial fermentation. Recently, Muniraj et al. (2015) investigated the bioconversion of potato processing wastewater into lipid-rich biomass and linolenic acid using two oleaginous fungi-Aspergillus flavus I16-3 and Mucor rouxii-with previous removal of nitrogen and phosphorus from wastewater. This study demonstrated the nutraceutical potential of potato processing wastewater via biotechnological production of microbial lipids and linolenic acid. Plant seeds generated by the food processing industries are significant by-products rich in hydrophilic and lipophilic antioxidants, as well as edible oils delivering beneficial health effects (Durante et al., 2017). Recently, nanotechnology has become one of the major fields of research for increasing the bioavailability of bioactive compounds in food, pharmaceutical, and nutraceutical areas (McClements et al., 2015; Salvia-Trujillo et al., 2015; Zhang et al., 2014). For colloidal delivery systems, nanoemulsions have many advantages, for instance it increases dissolution and solubility rate owing to its

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large surface area of small particle size. Nanoemulsion provides large surface area for intestine enzymatic reaction, improving diffusion across the mucus layer covering the intestinal epithelium and thus improving the bioavailability (Salvia-Trujillo et al., 2013). In addition, nanoemulsions were already demonstrated to improve physiochemical stability comparing to conventional emulsions (Cheong et al., 2016). The secondary metabolites from plant food by-products attracted much attention due to their action in the management of metabolic disorders such as diabetes and obesity, but also considering polyphenols’ antiinflammatory effects. For these reasons, their application in the area of functional foods and nutraceuticals has been recommended.

8.3 FACTORS THAT INFLUENCE THE BIOLOGICAL PROPERTIES OF BIOACTIVE COMPOUNDS FROM AGRO-INDUSTRIAL BY-PRODUCTS 8.3.1 DIGESTION PROCESS Food digestion is a multi-scale process, whereas the first step that occurs is the size reduction of food in the mouth and stomach, for an increased availability of trapped compounds with the aim of a latter absorption by the intestinal membrane (Kong and Singh, 2008). Therefore, digestion can be characterized by the following, namely disintegration and dissolution processes. The fastness breaking capacity of compounds in small molecules is called disintegration. The dissolving capacity of compounds into the intestinal juice for absorption is called dissolution. Both mentioned processes can suffer delays through the processing conditions used at the manufacturing/preparation stage (Kong and Singh, 2008). Due to ethical, expensive, and laborious constrains, the in vitro models are preferred instead of in vivo experiments when studying the effects of digestion on different bioactive compounds, the bioaccessibility of these compounds, and their degree of absorption. Usually, an in vitro model mimics the oral phase, the stomach, small intestinal digestion, and rarely the large intestine part. The existing models can vary in several aspects, such as digestion phases, pH, enzymes, time of digestion, bile acids, etc. There are two types of in vitro digestion models, namely static, where the quantities and concentrations of materials are preestablished, and dynamic, where a continuous digestion is simulated with the implied changes of conditions. The second type manages to identify much better with the in vivo models, even though it is more expensive and laborious (Alminger et al., 2014). There is a current trend in healthy foods and compounds bioavailability, which is becoming more and more popular (Norton et al., 2007). The main issue in the release and bioavailability is the interactions process that occurs (Parada and Aguilera, 2007). For instance, the flavonoids combined to β-glucosides are easily absorbed in the small intestine, being accessible for the enzymes metabolism. However, when the flavonoids are combined with rhamnose moiety, they become nonaccessible for absorption in the small intestine being necessary for the sugar moieties cleavage action of the intestinal microbiota (da Silva Pinto, 2013). Therefore, in order to have an increased and balanced release of bioactive compounds it is indicated to interfere in the structure, for instance at manufacturing stage. For this, it is necessary to elucidate and completely understand the interaction that takes place between food matrix and the active ingredients, as well as its behavior during

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human digestion process (Norton et al., 2007; Sanz and Luyten, 2006). The disintegration kinetics of compounds during the stomach digestive process is of a major importance for a proper evaluation of their bioavailability in the GI tract. The processing conditions could be adapted at the manufacturing stages in order to obtain an optimal and controlled release in the targeted locations of the GI tract. However, the bioavailability of poorly-soluble bioactive compounds could be improved by incorporating them into oil-in-water nanoemulsions (Assadpour and Jafari, 2018).

8.3.1.1 Gastric digestion In the Fig. 8.1 is an illustration of the main compartments of human stomach, namely fundus, body, antrum, and pylorus. The reservoir for undigested material is represented by the proximal part composed of fundus and body which are responsible for the emptying of liquids, whereas the grinder, mixer, and sieve of solid food are represented by the distal stomach (antrum) which, by propelling actions, acts as a pump for gastric emptying of solids (Arora et al., 2005). The glands found in the stomach are responsible for secreting the gastric juice composed of gastric acid, bile salts, and digestive enzymes where the food bolus dissolves by the gastric juices penetration. Peristaltic waves are responsible for homogenizing and pushing forward the contents until reaching the pylorus, which contracts to slow gastric emptying resulting in a continuing mixing of gastric contents. The final content, named chyme, is composed of aqueous solutions, fats, and solids which after passing through pylorus enters the duodenum. A deep knowledge on the gastric disintegration of compounds is hard to reach due to a lack of research studies on this topic considering its huge complexity that compresses decisional factors like gastric acid, mechanical forces, enzymatic reactions, etc. In addition, the stomach physiology

FIGURE 8.1 The stomach compartments. Data from Wikipedia Stomach | SEER Training. [cited 2018 Nov 27]. Available from: ,https://training.seer.cancer.gov/anatomy/ digestive/regions/stomach.html. (Stomach | SEER Training); Stomach, 2018. In: Wikipedia. [cited 2018 Nov 27]. Available from: ,https://en.wikipedia.org/w/index.php?title 5 Stomach&oldid 5 869964105. (Stomach, 2018).

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is less known. Therefore, all these aspects, adding the stomach wall movement, the rheological properties of gastric content, the flow state of gastric fluid, and mechanical forces intervening on foods and compounds must be better understood. In order to improve the process development and clinical studies for specific microstructures, a deep knowledge of food disintegration and the involved interactions during the gastric tract are necessary. In addition, there is a real need for studying the food gastric disintegration in order to design a proper evaluation of the involved interferences among food and drugs during digestion process. The disintegration process of a drug is strongly modified by the food components’ presence. For instance, according to Collins et al. (1996) and to Weitschies et al. (2005), the delayed drug absorption is the result of the food intake action on the prolonged stay of the pellet in the final compartment of the stomach (antrum). This fact is in agreement with Abrahamsson et al.’s (2004) findings that suggested as a possible explanation for delay, the consequence of a film formation around the tablet, which is directly dependent either on the tablet’s ingredients either on the composition of food present. However, Kenyon et al. (1998) reported an increased absorption of some tablets, like saquinavir, due to the presence of food and implicitly due to an elongated gastric emptying time, resulting in an improved bioavailability of this drug tablet. In addition, food can modify the pH of gastric juice. For example, usually an ingested meal enhances the growth of gastric pH up to 4.5 (normally ranging between 1.3 and 2.5), the increase being influenced by the buffering capacity of the food. According to Tyssandier et al. (2003), a diet rich in tomato, spinach, or carrot purees, like the western-type one, directly after its ingestion increases the pH up to 6.2, gradually dropping between 1.8 and 2.9 after 3 hours digestion. Rios et al. (2002) reported a similar example, after the intake of a cocoa drink (5.4-pH immediately after ingestion and its decrease by 1.9 after 3 hours digestion). Usually, when simulating the gastric digestion in a static model, most of the authors, reproduced a pH below 2.5, but there are also exceptions, like the experimental studies of Reboul et al. (2006) and Dhuique-Mayer et al. (2007), who considered the intermediate value of the pH (Kumar et al., 2017). Things are very different when there is a dynamic model involved, where the changes of pH are always taken into consideration (Blanquet-Diot et al., 2009). Therefore, in order to succeed to control the food supplements’ dissolution during the digestion process in the stomach, a deep knowledge on food decomposition is mandatory.

8.3.1.2 Stomach/gastric emptying The concept of stomach emptying has a major and defined role in human digestion. There is a matter of rapid or delayed emptying which can influence obesity, diabetes, or stomach disorder problems (Rayner et al., 2001; Cardoso-Ju´nior et al., 2007). However, dominating the gastric emptying is the key for an optimal digestion. According to Cardoso-Ju´nior et al. (2007), a rapid emptying sustains the overconsumption of calories while a delayed emptying encourages the obesity, diabetes, gastroesophageal ebb-tide, and aging (Vaisman et al., 2006). According to Rayner et al. (2001), the solution to dominate these diseases stands in a correct modulation rate of gastric emptying. However, in the literature, there are many examples of how the food composition and texture influence this modulation rate. For instance, the acid-unstable emulsions added to preprocessed foods conducted a fast gastric emptying, while the acid-stable emulsions induced a slow gastric emptying and implicitly a reduction in the ingested food (Marciani et al., 2007). Nevertheless, the future belongs to the creation of prestructured foods for a successful control of the compounds release rate and implicitly of the stomach emptying rate (Norton et al., 2007).

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8.3.1.3 Gastric juice and stomach movements According to Vertzoni et al. (2005), the resting volume of a stomach is below or equal to 25 mL, whereas the gastric juice starts being secreted once the food or compound is ingested and the stomach begins to expand. It is well known that the amount of gastric juice produced per day is around 2
3 L. The increase curve of gastric juice secretion starts from 1 mL/min in the fasted state and reaches 10
50 mL/min after food ingestion (Chm et al., 2004). Therefore, the food quantity, protein composition, and the dish structure/texture contribute to an accelerate secretion (Marciani et al., 2001). The ones responsible for gastric secretion are the pepsinogens, hydrochloric acid, water, and mucus. The hydrochloric acid has a major role due to its several functions, like contribution to the acid denaturation of digested food, pepsinogens activation, and destroying the majority of the bacteria present in the stomach. The pepsin enzyme is found in the stomach under its inactivated form, namely pepsinogen, which is activated by the gastric juice while the role of the mucus is to create a gelatinous layer on the top of the mucosal area. According to the literature, the content of gastric juice is defined by pepsin and mucin, in a quantity of 0.8
1 mg/mL, respectively 1.5 mg/mL (Vertzoni et al., 2005; Dean and Ma, 2007). The stomach pH differs upon the stomach state condition, subject’s health status, food composition, quantity, and pH, therefore stomach pH can increase from 1.3
2.5 range (fasted state, healthy subjects) to 4.5
5.8 range (fed state, healthy subjects). As mentioned above, also the food composition, pH, and quantity influence the stomach pH restoring. The food supplements’ digestion is influenced by the buffer capacity, tension from the surface, osmolarity, and bile salts. All these components have higher values in the fed state compared to fasted state. For example, the buffer capacity ranges from 5 to 30 mmol/L ΔpH21, the bile salts concentration ranges from 80 to 275 μM, the tension from the surface ranges from 28 to 51 mN/m, and the osmolarity from 191 to 200 mOsm/kg in gastric juice (Kalantzi et al., 2006). It was reported by Abrahamsson et al. (2004) that the gastric juice density is very similar to the one of water, even if it is a viscous fluid characterized by a viscosity ranging from 0.01 to 2 Pa∙s. In addition, Dikeman and Fahey (2006) called it a non-Newtonian fluid with pseudo plastic behavior. What is interesting is the effect resulted by high viscosity meal ingestion, namely a rapid decrease of the meal viscosity due to a fast-gastric dilution. It is very difficult to assess a proper estimation of the digest’s viscosity mainly because the gastric juice is a non-Newtonian fluid and, in consequence, its viscosity is correlated with the shear speed. Another consequence of this fact is that the final digest comprises also the particulates and semisolids affecting again the viscosity valuation, therefore the indicated solution is to make a density separation of the digest sample (Dikeman and Fahey, 2006). A much more suitable approach for a correct rheological determination of such fluid is the use of a mixer viscometer with an interrupted helical (Omura and Steffe, 2003). Another important aspect in the stomach digestion is the stomach motility, which differs in the fasted and fed states. Continuous movement characterizes the fed state, while a four-stage movement, each lasting for a certain period of time (Arora et al., 2005), composes the fasting state. According to the literature, the contractions can be regular tonic and peristaltic. The action called “terminal antral contraction” implies an increase of the contraction width as soon as the peristaltic movement hits the pylorus (Schulze, 2006), therefore the contraction of the pylorus is induced, and implicitly, the shrinking of the sphincter, creating a small pyloric opening. This effect determines the retropulsion of the chyme, namely its return in the stomach. The retropulsion

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process is desirable as it mingles and emulsifies the food together with the gastric juices, resulting in high grinding and friction with the stomach wall. Due to the recurrent propulsion, grinding and retropulsion processes, the soft and firmness exclusion is produced (Schwizer et al., 2006). The “sieving effect” implies a constant flux of the liquids and small particles from the stomach into the duodenum due to the antropyloric contractions. The large particles, which exceed the pyloric opening, are detained in the stomach, whereas the fasting movement mode is restored once the stomach emptied all the food (Dressman, 1986). In disintegration of solid food/compounds, the “terminal antral contraction” process is of major importance due to its intense mechanical action on the solids.

8.3.1.4 Intestinal digestion The release of active ingredients within the GI fluids must be absorbed by the intestine epithelial cells before it is bioavailable for the organism (McClements et al., 2015). The bioavailability fate of bioactive compounds also depends on their molecular structure before they are ready for absorption. This is due to the complex process of GI digestion, which may lead them to undergo some chemical transformation, such as hydrolysis, reduction, and oxidation, whereas some bioactive compounds may undergo degradation under different pH or undergo isomerization (cis-trans) before they become bioavailable (McClements et al., 2015). The intestine is responsible for a number of vital functions within the human organism, the most important being the digestion and absorption of compounds. The intestinal specific enzymes plays a major role in nutrients digestion, but still there is a lack of experimental studies exploring their impact. Therefore the intestinal phase of digestion is very difficult to be modeled (Picariello et al., 2016), whereas approximately 60%
75% of small intestinal cells turnover daily. The intestinal system is composed of small and large intestine. The small intestine is composed of three compartments, namely duodenum, ileum, and jejunum; and its major role is absorption of the food nutrients. The specific intestinal enzymes are the pancreatic ones, namely amylase, lipase, and trypsin whose major responsibility is to decompose the nutrients in order to be easily absorbed. Another specific substance within the small intestine (duodenum) is the bile acid which plays an important role in the formation of the micelles contributing to the lipid absorption. A considerable aspect is the fact that the entire absorption process takes place in the other two compartments, namely jejunum and ileum (Encyclopedia of Toxicology). The absorptive surface is composed of villi, which have microstructures called microvilli forming a brush border. Due to their movements and the small intestine motility, the compounds get in contact with this microstructure facilitating the absorption process. According to the literature, there are four different absorption ways, namely active transport, passive diffusion, facilitated diffusion, and endocytosis (Fedoruk and Hong, 2014). The endocytosis is a similar process with phagocytosis and all these different absorption/transport ways starting in the intestinal lumen are influencing the bioavailability of bioactive compounds. The passive diffusion and facilitated diffusion imply a diffusion to a varied concentration through the intestinal cells into the blood circulation while the active transport acts in contradistinction to the varied concentration creating either an enhanced amount of compounds in the blood circulation, or a reject of the compounds back to the intestinal lumen (Brand et al., 2006; Poster abstracts). In the hydrolyze process of carbohydrates (starch), the pancreatic enzyme
amylase has the first action by breaking them down into oligo- and di-saccharides. The microvilli enzymes fulfill the second action of hydrolyzing these structures. In the end, the monosaccharides, like glucose, being

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already very small molecules, are directly absorbed via the active transport mechanism. With respect to proteins, their hydrolysis process starts in the stomach where the enzymes pepsins have the first splitting action, but their total digestion finalizes in the small intestine (duodenum) under the action of trypsin. Due to trypsin action, oligo- and di-peptides, but also amino acids are resulting. The last category are directly absorbed by active transport way and the dipeptides are hydrolyzed by the microvilli enzymes, as in the case of carbohydrates, afterward being absorbed. The fat hydrolyze and absorption processes are a bit longer. Mainly, the fat contains long-chain triglycerides. Their breaking down process starts in the duodenum under the action of several enzymes, like lipase, colipase, and bile salts. Due to the bile salts action, water
fat insoluble compounds become accessible for the lipase. Colipase acts together and for the benefit of lipase, namely to hydrolyze the triglycerides into di- and mono-glycerides, and fatty acids. The mono forms are directly absorbed by diffusion mechanism. The fat metabolism is chain length dependent. More precisely, the long-chain fatty acids are esterified to triglycerides forming chylomicrons and very low-density lipoproteins, while the medium-chain fatty acids are not reesterified going directly into the venous linking to albumen (Fedoruk and Hong, 2014). In addition, the intestinal digestion includes the absorption of vitamins, minerals, water, and salts. When referring to Crohn’s disease, these bile salts are not absorbed due to an ileum disable cause and, therefore, the fat absorption is defectuos. Due to an active presence of endocrine cells into the small intestine, it is important to know that its secretory products have a strong influence on digestion (Encyclopedia of Toxicology). In the experimental study of Picariello et al. (2016), the use of brush border membrane (BBM) enzymes to simulate the intestinal digestion of dietary polypeptides was being explored as a future possible alternative to better reproduce the in vivo model. The concept of “brush border” or microvilli, because they are used concomitant to express the same aspect, compose the small intestinal surface. For assessing the in vitro intestinal digestion using BBM vesicles, they are isolated from the jejunum of rat, pig, and cow. However, according to previous experiments, the BBM vesicles from pig jejunum are more similar to the human ones, and have other important advantages, like higher stability and availability, but also have a strong physiological correlation due to a monocompartment stomach and omnivore alimentation of pigs (Mach et al., 2014). Considering all the latest studies on dietary peptides digestion, there is still a lack of information with respect to the real interactiontaking place between these peptides and the intestinal mucosa, as well as their impact on the human body. Indeed, there is a need for a better understanding of the different digestion processes among adults and children (M´enard et al., 2014) and the influence of food matrices and processing on the intestinal digestion (Bourlieu et al., 2015). It is strongly recommended that any in vitro digestion model that targets the bioaccessibility and bioavailability of food compounds, should involve the jejunal degradation process. Nevertheless, the way the intestinal digestion influences the bioaccessibility of phenolic compounds is directed by the following factors: intestinal enzymes and their action on the residual matrix, which can enhance the phenolic compounds; phenolic compounds’ degradation that can be accelerated by the oxygen and/or other transition-metal ions; absorption mechanisms (Marze, 2017).

8.3.1.5 In vitro digestion models The bioactive compounds’ digestion is characterized by a series of aspects and depends on its characteristics, on the content and structure of the food matrix, and on each person’s unique response to

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the digesting compound and meal while passing the GI tract (Fedoruk and Hong, 2014). The in vitro methods have many advantages when compared with in vivo ones, mainly due to a reduced labor and time, which implicitly decreases the costs. In addition, when using the in vitro techniques there is no need for ethical approval, delivering results with high accuracy and reproducibility. Screening the literature, an impressive number of in vitro digestion models was found, which applies for several domains, such as nutrition, toxicology, pharmacology, etc. Two categories of in vitro digestion models, namely static and dynamic (Kong and Singh, 2008) were defined. The static model, as the name already suggests it, does not reproduce the physical processes, like the peristaltic motility or the pH modification, which takes place in the human digestion. In addition, in general, this type of model, does not take into consideration the food structure and its chemical characteristics. For describing the model, it can be stated that this is a simple process composed of a simulated gastric digestion that implies a peptic hydrolysis at a pH of 1.5 for 1
2 hours with continuously agitation at 37 C (Hoebler et al., 2002). For a quantitative evaluation of the active ingredients and nutrients delivered, more precisely their bioavailability assessment, this is an indicated model and the literature presents several examples using the static digestion model. For example, the tyrosol in enriched custards (Sanz and Luyten, 2006); the carotenoids in carrot matrix (Hedr´en et al., 2002); the antioxidants in whole grain foods (Nagah and Seal, 2005); the isoflavonoids in soy bread (Walsh et al., 2003); the bioaccessibility of organic pollutants (Dean and Ma, 2007); and the viability of microencapsulated probiotics (Vodnar and Socaciu, 2014; Pop et al., 2016). The second model is the dynamic model which reproduces the physical movements, the pH changes, and the food influence, in a very similar way with the in vivo situation (Moreno, 2007). The latest studies describe a dynamic computer-controlled GI model named Tiny-TIM (TNO intestinal model) which has controlled temperature, pH, enzymes secretion, and peristaltic movements (Minekus, 2015). It is composed of two different parts simulating the stomach and the small intestine while all the physiological data, namely digestive juices and the pH can be mimicked with its precise composition. In order to describe the simulated digestion, in the gastric compartment 1 M hydrogen chloride, gastric electrolytes solution, lipase, and pepsin were added, while for the intestinal digestion 1 M sodium bicarbonate, small intestine electrolytes solution, pancreatic, bile, and trypsin were added. All the parameters are computer controlled and the peristaltic gates were connected to each sector (stomach and small intestine) via a flexible internal silicon tube through which the food is circulates between the sectors. In the study of Hemery et al. (2010) the Tiny TIM in vitro digestion model was used to simulate a wheat-based bread digestion. The protocol for this digestion consisted of a sample of 30 g (fresh product) thawed bread, where this sample was previously mixed with artificial saliva (5.5 mg aamylase, 10 mL citrate buffer (pH 5 6) and 50 mL gastric electrolytes solution) and with milli-Q water until reaching the 150 mL volume. After obtaining the mixture, the stomach digestion started by placing the sample in the corresponding compartment. The stomach emptying time was 70 minutes. The dialysis system composed of a semi-permeable hollow fiber membrane of cellulose diacetate connected to the small intestine compartment, had the role of simulating the absorption and collecting the digested nutrients. According to this study protocol, the digested products, among them which were also the phenolic acids, were periodically collected, frozen, and stored at 20 C until analysis. In the study of Souliman et al. (2006, 2007), it was demonstrated the high accuracy of TIM as an in vitro GI model. The key of success for TIM relays in its capacity to mimic the most precise

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in vivo pH, peristaltic movements, contraction force, and use of enzymes, being an extremely useful tool for predicting the in vivo drug tablets behavior. In the paper of Minekus (2015), TIM model (or Tiny TIM) was used for studying the bioaccessibility of nutrients, like proteins, carbohydrates, and lipids from a wide range of meals. Here, bioaccessibility was calculated based on the fraction of a compound, which was absorbed by the intestinal membrane. Further, for determining the bioavailability of these compounds, the use of in silico modeling, for interpreting the bioaccessibility profiles was necessary. In the case of protein digestion in TIM, the bioaccessibility was determined by calculating the quantity of protein nitrogen absorbed from the total protein nitrogen quantity of the meal. In the case of carbohydrates’ digestion, the Tiny TIM model was used, whereas the calculation of glycemic response is based on a homeostasis model assessment in silico modeling interpretation (Matthews et al., 1985) of the glucose and fructose released quantities. In the case of lipid digestion in TIM, due to the complex micelle formed (undigested fat and micelles), 50 nm filters are used for separation, whereas only the micelle compounds are accessible for intestinal uptake. Several authors have determined the bioaccessibility of different bioactive compounds using this model, such as Van Loo-Bouwman et al. (2014) for carotenoids; Ribnicky et al. (2014) for blueberry anthocyanin; and Minekus et al. (2005) for lipid digestion of partially hydrolyzed guar gum. In addition, another recent literature study developed the in vitro GI dynamic system as a new approach for simulating the stomach and small intestine digestion for milk protein. It is a computer-based system, controlling the pH, gastric, and intestinal secretions, as well as emptying rate, and was validated for infants (M´enard et al., 2014). Another literature example of two-stage dynamic in vitro GI model is the one described by Yang and McClements in 2013 (McClements, 2013), which, also, tries to simulate the conditions of the human stomach and intestine for assessing the bioaccessibility of β-carotene. Yi et al. (2014), described the same model but with some modification of the sample ratio: simulated gastric fluid: simulated intestinal fluid by 1:1.5:2.

8.3.2 FOOD PROCESSING According to the literature, there is a strong influence of food processing on bioactive compounds’ digestion. During manufacturing or cooking, the food matrix changes its physical and chemical attributes contributing to an increase/decrease release and uptake of compounds in the small intestine. By decreasing the food size, the gastric emptying is increased, therefore favoring the absorption (Pera et al., 2002). A significant example is the in vitro digestion study on carrots, where, according to Hedr´en et al. (2002), the homogenized carrots had a higher carotenoid release than carrots pieces (21% vs 3%). The heat treatment may considerably influence the protein, starch, fat, and vitamins’ digestion (Lee et al., 2016), but positively contributes to an increase bioavailability of carotenoid and lycopene in vegetables (Yeum and Russell, 2002). The rice digestion in rats was explored by Lee et al. (2016) (Lee et al., 2016) after subjecting it to different cooking methods (electric cooker, microwave oven, stone pot, autoclaving). It was concluded that there is a direct correlation between the increase in cooked rice starch hydrolysis and increase in gelatinization. The idea that food processing and dietary fat positively influence the bioaccessibility of carotenoid was sustained since 1999 by Garrett et al. (1999). Considering the heating process, like cooking, and its breaking impact on the plant tissue and on the carotenoid-protein structures, it can be stated that this type of treatment increased the bioaccessibility of these compounds. Actually,

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cooking increased both, the bioaccessibility and bioavailability of all -trans β-carotene, causing also carotenoid isomerization (Aherne et al., 2010). With respect to lycopene bioaccessibility, the processing methods have a huge influence. For example, in the study of Karakaya and Yılmaz (2007), a similar bioaccessibility between raw tomato lycopene (29%) and canned tomato lycopene (22%) was described, while the sun-dried tomato lycopene presented a higher bioaccessibility (58%). In the Colle et al. (2010) study, a negative influence of two different processing treatments, namely high-pressure homogenization (HPH) and HPH combined with heat processing (90 C for 30 minutes), on in vitro lycopene bioaccessibility was reported. The explanation of this negative impact lies in the formation of a fiber network by the HPH, which captures the lycopene being nonaccessible for further enzymes. It is interesting that this type of treatment had no negative influence on αand β-carotene bioaccessibility of carrots, and increased the lutein bioaccessibility of green beans (McInerney et al., 2007), suggesting that its effects is matrix or nutrient-structure dependent.

8.4 CONCLUSIONS Nowadays, people are more aware about the ingredients contained in the foods they consume, preferring those obtained from natural sources due to the often-imagined negative effects that some compounds obtained by chemical synthesis may provoke. Increased health awareness along with environmental consciousness has further augmented the scientific interest in this area. In fact, this new perspective turns the problem of food by-product management into an opportunity. It is clear that natural bioactive compounds are the future in the field pharmacological and nutraceuticals. Nevertheless, some topics must be investigated prior to successful applications in the food and pharmaceutical industries to replace the common “synthetic pharmaceuticals” by “natural nutraceuticals.” More research is needed in the near future to demonstrate the effectiveness with more in vivo studies in order to advance more rapidly the design of new nutraceuticals. Food digestion and food processing are major factors that influence the biological activities of plant active natural ingredients. The next generation of structured food for health is the key for a better understanding of GI digestion and for an increased bioavailability of bioactive compounds. The interactions taking place between the food matrix and the active ingredients are very important to be explored, as well. In order to find the proper solution for a controlled release of nutrients in the established areas of the GI tract, it is very important to pose significant knowledge of the food disintegration, stomach emptying, and (pre)treatments for an increased nutrients’ bioavailability (processing conditions at the manufacturing stage). Even though the reutilization of food by-products is a major topic and has drawn attention among researchers, the recovery performance should be maximized, therefore innovative technologies such as ultrasound assisted extraction, enzymatic assisted extraction, microwave extraction, etc. must be further investigated. Nevertheless, there is a strong need for assessing whether by modifying the production process (e.g., reduction of temperatures and processing pressures) without influencing food quality, it is possible to further preserve the bioactive molecules present in the waste to further increase the recovery of these compounds for application in nutraceutical industry.

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ACKNOWLEDGMENT This work was supported by three grants of Ministry of Research and Innovation, CNCS - UEFISCDI, project number PN-III-P1-1.1-TE-2016-0973, project number PN-III-P1-1.1-TE-2016-0661 and project number PNIII-P1-1.1-PD-2016-0869, within PNCDI III.

REFERENCES Abrahamsson, B., Albery, T., Eriksson, A., Gustafsson, I., Sjo¨berg, M., 2004. Food effects on tablet disintegration. Eur. J. Pharm. Sci. 22 (2), 165
172 [cited 2018 Oct 19]; Available from: ,http://www.sciencedirect. com/science/article/pii/S0928098704000648.. Aherne, S.A., Daly, T., Jiwan, M.A., O’Sullivan, L., O’Brien, N.M., 2010. Bioavailability of β-carotene isomers from raw and cooked carrots using an in vitro digestion model coupled with a human intestinal Caco2 cell model. Food Res. Int. 43 (5), 1449
1454 [cited 2018 Oct 22]; Available from: ,http://www.sciencedirect.com/science/article/pii/S0963996910001304.. Alminger, M., Aura, A.-M., Bohn, T., Dufour, C., El, S.N., Gomes, A., et al., 2014. In vitro models for studying secondary plant metabolite digestion and bioaccessibility. Compr. Rev. Food Sci. Food Saf. 13 (4), 413
436 [cited 2018 Aug 29]; Available from: ,https://onlinelibrary.wiley.com/doi/abs/10.1111/1541-4337.12081.. Amaya-Cruz, D.M., Rodrı´guez-Gonz´alez, S., P´erez-Ramı´rez, I.F., Loarca-Pin˜a, G., Amaya-Llano, S., Gallegos-Corona, M.A., et al., 2015. Juice by-products as a source of dietary fibre and antioxidants and their effect on hepatic steatosis. J. Funct. Foods 17, 93
102 [cited 2018 Nov 28]; Available from: ,http:// www.sciencedirect.com/science/article/pii/S1756464615002340.. ˚ man, P., Landberg, R., 2014. Recent findings on certain bioactive compoAndersson, A.A.M., Dimberg, L., A nents in whole grain wheat and rye. J. Cereal Sci. 59 (3), 294
311 [cited 2018 Sep 4]; Available from: ,http://www.sciencedirect.com/science/article/pii/S0733521014000150.. Anson, N.M., Hemery, Y.M., Bast, A., 2012. Haenen GRMM. Optimizing the bioactive potential of wheat bran by processing. Food Funct. 3 (4), 362 [cited 2018 Sep 12]; Available from: ,http://xlink.rsc.org/? DOI 5 c2fo10241b.. Arora, S., Ali, J., Ahuja, A., Khar, R.K., Baboota, S., 2005. Floating drug delivery systems: a review. AAPS PharmSciTech 6 (3), E372
E390. Available from: https://doi.org/10.1208/pt060347 [cited 2018 Oct 19]. Arscott, S.A., Tanumihardjo, S.A., 2010. Carrots of many colors provide basic nutrition and bioavailable phytochemicals acting as a functional food. Compr. Rev. Food Sci. Food Saf. 9 (2), 223
239 [cited 2018 Oct 18]; Available from: ,https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1541-4337.2009.00103.x.. Arun, K.B., Chandran, J., Venugopal, V.V., Madhavankutty, T.S., Nisha, P., 2018. Spent cumin seeds generated from ayurvedic industry as a source of bioactive compounds for nutraceutical/functional food applications. J. Food Process Preserv. 42 (1), e13392 [cited 2018 Oct 16]; Available from: ,https://onlinelibrary. wiley.com/doi/abs/10.1111/jfpp.13392.. Assadpour, E., Jafari, S.M., 2018. A systematic review on nanoencapsulation of food bioactive ingredients and nutraceuticals by various nanocarriers. Crit. Rev. Food Sci. Nutr. 1
47. Available from: https://doi.org/ 10.1080/10408398.2018.1484687 [cited 2018 Sep 25]. Ayala-Zavala, J.F., Rosas-Domı´nguez, C., Vega-Vega, V., Gonz´alez-Aguilar, G.A., 2010. Antioxidant enrichment and antimicrobial protection of fresh-cut fruits using their own byproducts: looking for integral exploitation. J. Food Sci. 75 (8), R175
R181 [cited 2018 Oct 17] Available from: ,https://onlinelibrary. wiley.com/doi/abs/10.1111/j.1750-3841.2010.01792.x.. Ayala-Zavala, J.F., Gonz´alez-Aguilar, G., Siddiqui, M.W., 2018. Plant Food By-Products. Taylor & Francis Group [cited 2018 Oct 19]. Available from: ,https://www.taylorfrancis.com/..

REFERENCES

253

Ballard, T.S., Mallikarjunan, P., Zhou, K., O’Keefe, S., 2010. Microwave-assisted extraction of phenolic antioxidant compounds from peanut skins. Food Chem. 120 (4), 1185
1192 [cited 2018 Oct 17]; Available from: ,http://www.sciencedirect.com/science/article/pii/S0308814609013739.. Benı´tez, V., Moll´a, E., Martı´n-Cabrejas, M.A., Aguilera, Y., Lo´pez-Andr´eu, F.J., Esteban, R.M., 2012. Onion (Allium cepa L.) by-products as source of dietary fiber: physicochemical properties and effect on serum lipid levels in high-fat fed rats. Eur. Food Res. Technol. 234 (4), 617
625. Available from: https://doi.org/ 10.1007/s00217-012-1674-2 [cited 2018 Nov 28]. Berbel, J., Posadillo, A., Berbel, J., Posadillo, A., 2018. Review and analysis of alternatives for the valorisation of agro-industrial olive oil by-products. Sustainability 10 (1), 237 [cited 2018 Oct 22]; Available from: ,https://www.mdpi.com/2071-1050/10/1/237.. Blanquet-Diot, S., Soufi, M., Rambeau, M., Rock, E., Alric, M., 2009. Digestive stability of xanthophylls exceeds that of carotenes as studied in a dynamic in vitro gastrointestinal system. J. Nutr. 139 (5), 876
883 [cited 2018 Oct 19]; Available from: ,https://academic.oup.com/jn/article/139/5/876/ 4670363.. Bondia-Pons, I., Aura, A.-M., Vuorela, S., Kolehmainen, M., Mykka¨nen, H., Poutanen, K., 2009. Rye phenolics in nutrition and health. J. Cereal Sci. 49 (3), 323
336 [cited 2018 Sep 18]; Available from: ,http:// www.sciencedirect.com/science/article/pii/S0733521009000149.. Bourlieu, C., M´enard, O., De La Chevasnerie, A., Sams, L., Rousseau, F., Madec, M.-N., et al., 2015. The structure of infant formulas impacts their lipolysis, proteolysis and disintegration during in vitro gastric digestion. Food Chem 182, 224
235 [cited 2018 Oct 22]; Available from: ,http://www.sciencedirect. com/science/article/pii/S0308814615003507.. Brand, W., Schutte, M.E., Williamson, G., van Zanden, J.J., Cnubben, N.H.P., Groten, J.P., et al., 2006. Flavonoid-mediated inhibition of intestinal ABC transporters may affect the oral bioavailability of drugs, food-borne toxic compounds and bioactive ingredients. Biomed. Pharmacother. 60 (9), 508
519 [cited 2018 Oct 22]; Available from: ,http://www.sciencedirect.com/science/article/pii/S0753332206002447.. Brouns, F., Hemery, Y., Price, R., Anson, N.M., 2012. Wheat aleurone: separation, composition, health aspects, and potential food use. Crit. Rev. Food Sci. Nutr. 52 (6), 553
568. Caligiani, A., Bonzanini, F., Palla, G., Cirlini, M., Bruni, R., 2010. Characterization of a potential nutraceutical ingredient: pomegranate (Punica granatum L.) seed oil unsaponifiable fractionPlant Foods Hum. Nutr. 65 (3), 277
283 [cited 2018 Nov 28] . Available from: https://doi.org/10.1007/s11130-010-0173-5. C˘alinoiu, L.F., Vodnar, D.C., 2018. Whole grains and phenolic acids: a review on bioactivity, functionality, health benefits and bioavailability. Nutrients 10 (11), 1615 [cited 2018 Nov 27]; Available from: ,https:// www.mdpi.com/2072-6643/10/11/1615.. Calinoiu, L.-F., Mitrea, L., Precup, G., Bindea, M., Rusu, B., Dulf, F.-V., et al., 2017. Characterization of grape and apple peel wastes’ bioactive compounds and their increased bioavailability after exposure to thermal process. Bull. Univ. Agric. Sci. Vet. Med. Cluj-Napoca-Food. Sci. Technol. 74 (2), 80
89. Cardona, F., Andr´es-Lacueva, C., Tulipani, S., Tinahones, F.J., Queipo-Ortun˜o, M.I., 2013. Benefits of polyphenols on gut microbiota and implications in human health. J. Nutr. Biochem. 24 (8), 1415
1422 [cited 2018 Aug 29]; Available from: ,http://linkinghub.elsevier.com/retrieve/pii/S0955286313000946.. Cardoso-Ju´nior, A., Gonzaga Vaz Coelho, L., Savassi-Rocha, P.R., Vignolo, M.C., Abrantes, M.M., Miranda de Almeida, A., et al., 2007. Gastric emptying of solids and semi-solids in morbidly obese and non-obese subjects: an assessment using the 13C-octanoic acid and 13C-acetic acid breath tests. Obes. Surg. 17 (2), 236
241. Available from: https://doi.org/10.1007/s11695-007-9031-4 [cited 2018 Oct 19]. Casalino, E., Calzaretti, G., Sblano, C., Landriscina, V., Felice Tecce, M., Landriscina, C., 2002. Antioxidant effect of hydroxytyrosol (DPE) and Mn2 1 in liver of cadmium-intoxicated rats. Comp. Biochem. Physiol. Part C Toxicol. Pharmacol. 133 (4), 625
632 [cited 2018 Nov 27]; Available from: ,http://www.sciencedirect.com/science/article/pii/S1532045602001801..

254

CHAPTER 8 INNOVATIVE SOURCES

Chan, K.W., Ismail, M., 2009. Supercritical carbon dioxide fluid extraction of Hibiscus cannabinus L. seed oil: a potential solvent-free and high antioxidative edible oil. Food Chem. 114 (3), 970
975 [cited 2018 Oct 18]; Available from: ,http://www.sciencedirect.com/science/article/pii/S0308814608012673.. Chen, P., Yanling, C., Shaobo, D., Xiangyang, L., Guangwei, H., Ruan, R., 2010. Utilization of almond residues. Int. J. Agric. Biol. Eng. 3 (4), 1
18 [cited 2018 Oct 19]; Available from: ,http://ijabe.org/index. php/ijabe/article/view/348.. Chen, Y., Luo, H., Gao, A., Zhu, M., 2011. Ultrasound-assisted extraction of polysaccharides from litchi (Litchi chinensis Sonn.) seed by response surface methodology and their structural characteristics. Innov. Food Sci. Emerg. Technol. 12 (3), 305
309 [cited 2018 Oct 17]; Available from: ,http://www.sciencedirect.com/science/article/pii/S1466856411000439.. Cheong, A.M., Tan, K.W., Tan, C.P., Nyam, K.L., 2016. Kenaf (Hibiscus cannabinus L.) seed oil-in-water Pickering nanoemulsions stabilised by mixture of sodium caseinate, Tween 20 and β-cyclodextrin. Food Hydrocoll. C (52), 934
941 [cited2018 Oct 18]; Available from: ,https://www.infona.pl//resource/bwmeta1.element.elsevier-66eb3c8e-502d-3f08-bdbd-72e0638028af.. Chm, V, van de kamp, E., Cjm, R., 2004. Development and applicability of an in vitro digestion model in assessing the bioaccessibility of contaminants from food. Ontwikkeling en toepasbaarheid van een digestiemodel om de bioaccessibility van contaminanten uit voeding te bepalen. [cited 2018 Oct 19]; Available from: ,https://rivm.openrepository.com/rivm/handle/10029/256399.. Choi, I.S., Cho, E.J., Moon, J.-H., Bae, H.-J., 2015. Onion skin waste as a valorization resource for the byproducts quercetin and biosugar. Food Chem. 188, 537
542 [cited 2018 Nov 28]; Available from: ,http://www.sciencedirect.com/science/article/pii/S0308814615007505.. Colle, I., Van Buggenhout, S., Van Loey, A., Hendrickx, M., 2010. High pressure homogenization followed by thermal processing of tomato pulp: influence on microstructure and lycopene in vitro bioaccessibility. Food Res. Int. 43 (8), 2193
2200 [cited 2018 Oct 22]; Available from: ,http://www.sciencedirect.com/ science/article/pii/S0963996910002590.. Collins, P.J., Horowitz, M., Maddox, A., Myers, J.C., Chatterton, B.E., 1996. Effects of increasing solid component size of a mixed solid/liquid meal on solid and liquid gastric emptying. Am. J. Physiol.-Gastrointest. Liver Physiol. 271 (4), G549
G554 [cited2018 Oct 19];Available from: ,https://www.physiology.org/doi/ abs/10.1152/ajpgi.1996.271.4.g549.. D’Antuono, I., Kontogianni, V.G., Kotsiou, K., Linsalata, V., Logrieco, A.F., Tasioula-Margari, M., et al., 2014. Polyphenolic characterization of olive mill wastewaters, coming from Italian and Greek olive cultivars, after membrane technology. Food Res. Int. 65, 301
310 [cited 2018 Nov 27]; Available from: ,https://linkinghub.elsevier.com/retrieve/pii/S0963996914006371.. da Silva Pinto, M., 2013. Tea: a new perspective on health benefits. Food Res. Int. 53 (2), 558
567 [cited 2018 Aug 29]; Available from: ,http://www.sciencedirect.com/science/article/pii/S0963996913000653.. de Almeida, R.F., Trevisan, M.T.S., Thomaziello, R.A., Breuer, A., Klika, K.D., Ulrich, C.M., et al., 2018. Nutraceutical compounds: echinoids, flavonoids, xanthones and caffeine identified and quantitated in the leaves of Coffea arabica trees from three regions of Brazil. Food Res. Int. [cited 2018 Oct 18]; Available from: ,https://linkinghub.elsevier.com/retrieve/pii/S0963996918307919.. Dean, J.R., Ma, R., 2007. Approaches to assess the oral bioaccessibility of persistent organic pollutants: a critical review. Chemosphere 68 (8), 1399
1407 [cited 2018 Oct 19]; Available from: ,http://www.sciencedirect.com/science/article/pii/S0045653507004079.. de Camargo, A.C., Schwember, A.R., Parada, R., Garcia, S., Maro´stica Ju´nior, M.R., Franchin, M., et al., 2018. Opinion on the hurdles and potential health benefits in value-added use of plant food processing byproducts as sources of phenolic compounds. Int. J. Mol. Sci. 19 (11), 3498 [cited 2018 Nov 27]; Available from: ,https://www.mdpi.com/1422-0067/19/11/3498..

REFERENCES

255

de Oliveira, W.P., Biasoto, A.C.T., Marques, V.F., Dos Santos, I.M., Magalha˜es, K., Correa, L.C., et al., 2017. Phenolics from winemaking by-products better decrease VLDL-cholesterol and triacylglycerol levels than those of red wine in wistar rats. J. Food Sci. 82 (10), 2432
2437. Dhuique-Mayer, C., Borel, P., Reboul, E., Caporiccio, B., Besancon, P., Amiot, M.-J., 2007. β-Cryptoxanthin from Citrus juices: assessment of bioaccessibility using an in vitro digestion/Caco-2 cell culture model. Br. J. Nutr. 97 (5), 883
890 [cited 2018 Oct 19]; Available from: ,https://www.cambridge.org/core/journals/ british-journal-of-nutrition/article/cryptoxanthin-from-citrus-juices-assessment-of-bioaccessibility-using-anin-vitro-digestioncaco2-cell-culture-model/3994814CCBA463DFDC74320F09E7459A.. Dikeman, C.L., Fahey Jr., G.C., 2006. Viscosity as related to dietary fiber: a reviewCrit. Rev. Food Sci. Nutr. 46 (8), 649
663 [cited 2018 Oct 22] . Available from: https://doi.org/10.1080/10408390500511862. Domı´nguez-Perles, R., Martı´nez-Ballesta, M.C., Carvajal, M., Garcı´a-Viguera, C., Moreno, D.A., 2010. Broccoliderived by-products—a promising source of bioactive ingredients. J. Food Sci. 75 (4), C383
C392. Dressman, J.B., 1986. Comparison of canine and human gastrointestinal physiology. Pharm. Res. 3 (3), 123
131. Available from: https://doi.org/10.1023/A:1016353705970 [cited 2018 Oct 22]. Drzikova, B., Dongowski, G., Gebhardt, E., Habel, A., 2005. The composition of dietary fibre-rich extrudates from oat affects bile acid binding and fermentation in vitro. Food Chem. 1
2 (90), 181
192 [cited 2018 Nov 28]; Available from: ,https://www.infona.pl//resource/bwmeta1.element.elsevier-23a26d5e-f8993d8a-bdb2-71d5b564c85e.. Dulf, F.V., Vodnar, D.C., Dulf, E.-H., To¸sa, M.I., 2015. Total phenolic contents, antioxidant activities, and lipid fractions from berry pomaces obtained by solid-state fermentation of two sambucus species with Aspergillus niger. J. Agric. Food Chem. 63 (13), 3489
3500. Available from: https://doi.org/10.1021/acs. jafc.5b00520 [cited 2018 Oct 18]. Dulf, F.V., Vodnar, D.C., Socaciu, C., 2016. Effects of solid-state fermentation with two filamentous fungi on the total phenolic contents, flavonoids, antioxidant activities and lipid fractions of plum fruit (Prunus domestica L.) by-products. Food Chem. 209, 27
36 [cited 2018 Oct 18]; Available from: ,http://www. sciencedirect.com/science/article/pii/S0308814616305337.. Dulf, F.V., Vodnar, D.C., Dulf, E.-H., Pintea, A., 2017. Phenolic compounds, flavonoids, lipids and antioxidant potential of apricot (Prunus armeniaca L.) pomace fermented by two filamentous fungal strains in solid state systemChem Cent. J. 11 (1), 92 [cited 2018 Oct 18] . Available from: https://doi.org/10.1186/s13065017-0323-z. Dulf, F.V., Vodnar, D.C., Dulf, E.-H., Diaconeasa, Z., Socaciu, C., 2018. Liberation and recovery of phenolic antioxidants and lipids in chokeberry (Aronia melanocarpa) pomace by solid-state bioprocessing using Aspergillus niger and Rhizopus oligosporus strains. LWT - Food Sci. Technol. 87, 241
249 [cited2018 Oct 18]; Available from: ,http://www.sciencedirect.com/science/article/pii/S0023643817306436.. Dunford, N.T., Irmak, S., Jonnala, R., 2010. Pressurised solvent extraction of policosanol from wheat straw, germ and bran. Food Chem. 119 (3), 1246
1249 [cited 2018 Oct 18]; Available from: ,http://www.sciencedirect.com/science/article/pii/S0308814609009297.. Durante, M., Montefusco, A., Marrese, P.P., Soccio, M., Pastore, D., Piro, G., et al., 2017. Seeds of pomegranate, tomato and grapes: an underestimated source of natural bioactive molecules and antioxidants from agri-food by-products. J. Food Compos. Anal. 63, 65
72 [cited 2018 Nov 27]; Available from: ,http:// www.sciencedirect.com/science/article/pii/S0889157517301801.. El, S.N., Karakaya, S., 2009. Olive tree (Olea europaea) leaves: potential beneficial effects on human health. Nutr Rev 67 (11), 632
638 [cited 2018 Nov 28]; Available from: ,https://academic.oup.com/nutritionreviews/article/67/11/632/1851027.. Elleuch, M., Bedigian, D., Roiseux, O., Besbes, S., Blecker, C., Attia, H., 2011. Dietary fibre and fibre-rich by-products of food processing: characterisation, technological functionality and commercial applications:

256

CHAPTER 8 INNOVATIVE SOURCES

a review. Food Chem 124 (2), 411
421 [cited 2018 Oct 22]; Available from: ,http://www.sciencedirect. com/science/article/pii/S0308814610007880.. Encyclopedia of Toxicology, second ed., 2005 [cited 2018 Oct 22]; Available from: ,https://www.elsevier. com/books/encyclopedia-of-toxicology/wexler/978-0-08-054800-5.. Esfahlan, A.J., Jamei, R., Esfahlan, R.J., 2010. The importance of almond (Prunus amygdalus L.) and its byproducts. Food Chem. 120 (2), 349
360 [cited 2018 Oct 19]; Available from: ,http://www.sciencedirect. com/science/article/pii/S0308814609011236.. Espı´n, J.C., Garcı´a-Conesa, M.T., Tom´as-Barber´an, F.A., 2007. Nutraceuticals: facts and fiction. Phytochemistry 68 (22), 2986
3008 [cited 2018 Oct 18]; Available from: ,http://www.sciencedirect.com/ science/article/pii/S0031942207005717.. F˘arca¸s, A.C., Socaci, S.A., Mudura, E., Dulf, F.V., Vodnar, D.C., Tofan˘a, M., et al., 2017. Exploitation of brewing industry wastes to produce functional ingredients. Brewing Technology.. InTech. Fatih Demirbas, M., Balat, M., Balat, H., 2011. Biowastes-to-biofuels. Energy Convers. Manag. 52 (4), 1815
1828 [cited 2018 Oct 22]; Available from: ,http://www.sciencedirect.com/science/article/pii/ S0196890410005157.. Fedoruk, M.J., Hong, S., 2014. Gastrointestinal system. Encyclopedia of Toxicology. Elsevier, pp. 702
705 [cited 2018 Aug 29]; Available from: ,http://linkinghub.elsevier.com/retrieve/pii/B9780123864543000269.. Francisco, M.L.D.L., Resurreccion, A.V.A., 2008. Functional components in peanuts. Crit. Rev. Food Sci. Nutr. 48 (8), 715
746. Available from: https://doi.org/10.1080/10408390701640718 [cited 2018 Oct 19]; Available from. Galanakis, C.M., 2011. Olive fruit dietary fiber: components, recovery and applications. Trends Food Sci. Technol. 22 (4), 175
184 [cited 2018 Nov 27]; Available from: ,http://www.sciencedirect.com/science/ article/pii/S0924224410002943.. Galanakis, C.M., 2012. Recovery of high added-value components from food wastes: conventional, emerging technologies and commercialized applications. Trends Food Sci. Technol. 26 (2), 68
87 [cited 2018 Nov 27]; Available from: ,http://www.sciencedirect.com/science/article/pii/S0924224412000532.. Galanakis, C.M., 2013. Emerging technologies for the production of nutraceuticals from agricultural by-products: a viewpoint of opportunities and challenges. Food Bioprod. Process. 91 (4), 575
579 [cited 2018 Nov 27]; Available from: ,http://www.sciencedirect.com/science/article/pii/S0960308513000059.. Galanakis, C.M., Kotsiou, K., 2017. Chapter 10 - Recovery of bioactive compounds from olive mill waste. In: Galanakis, C.M. (Ed.), Olive Mill Waste. Academic Press, pp. 205
229. [cited 2018 Nov 27]; Available from: ,http://www.sciencedirect.com/science/article/pii/B9780128053140000108.. Galanakis, C.M., Tornberg, E., Gekas, V., 2010a. Clarification of high-added value products from olive mill wastewater. J. Food Eng. 99 (2), 190
197 [cited 2018 Nov 27]; Available from: ,http://www.sciencedirect.com/science/article/pii/S0260877410000907.. Galanakis, C.M., Tornberg, E., Gekas, V., 2010b. A study of the recovery of the dietary fibres from olive mill wastewater and the gelling ability of the soluble fibre fraction. LWT - Food Sci. Technol. 43 (7), 1009
1017 [cited 2018 Nov 27]; Available from: ,http://portal.research.lu.se/portal/en/publications/astudy-of-the-recovery-of-the-dietary-fibres-from-olive-mill-wastewater-and-the-gelling-ability-of-the-soluble-fibre-fraction(e0e10678-d5f2-4a54-8e44-0816ed80b121).html.. Gan, C.-Y., Latiff, A.A., 2011. Optimisation of the solvent extraction of bioactive compounds from Parkia speciosa pod using response surface methodology. Food Chem. 124 (3), 1277
1283 [cited 2018 Oct 18]; Available from: ,http://www.sciencedirect.com/science/article/pii/S0308814610009271.. Gani, A., Sm, W., Fa, M., Hameed, G., 2012. Whole-grain cereal bioactive compounds and their health benefits: a review. J. Food Process. Technol. 3 (3), [cited 2018 Sep 7]; Available from: ,https://www. omicsonline.org/whole-grain-cereal-bioactive-compounds-and-their-health-benefits-a-review-2157-7110. 1000146.php?aid 5 4593..

REFERENCES

257

Garrett, D.A., Failla, M.L., Sarama, R.J., 1999. Development of an in vitro digestion method to assess carotenoid bioavailability from meals. J. Agric. Food Chem. 47 (10), 4301
4309. Available from: https://doi.org/ 10.1021/jf9903298 [cited 2018 Oct 22]. Gelmez, N., Kıncal, N.S., Yener, M.E., 2009. Optimization of supercritical carbon dioxide extraction of antioxidants from roasted wheat germ based on yield, total phenolic and tocopherol contents, and antioxidant activities of the extracts. J. Supercrit. Fluids 48 (3), 217
224 [cited 2018 Oct 18]; Available from: ,http://www.sciencedirect.com/science/article/pii/S0896844608003707.. Gil, M.I., Tom´as-Barber´an, F.A., Hess-Pierce, B., Holcroft, D.M., Kader, A.A., 2000. Antioxidant activity of pomegranate juice and its relationship with phenolic composition and processing. J. Agric. Food Chem. 48 (10), 4581
4589. Gil-Ch´avez, G.J., Villa, J.A., Ayala-Zavala, J.F., Heredia, J.B., Sepulveda, D., Yahia, E.M., et al., 2013. Technologies for extraction and production of bioactive compounds to be used as nutraceuticals and food ingredients: an overview. Compr. Rev. Food Sci. Food Saf. 12 (1), 5
23 [cited 2018 Oct 16]; Available from: ,https://onlinelibrary.wiley.com/doi/abs/10.1111/1541-4337.12005.. Goni, I., Hervert-Hernandez, D., 2011. By-products from plant foods are sources of dietary fibre and antioxidants. In: Rasooli, I. (Ed.), Phytochemicals - Bioactivities and Impact on Health. InTech [cited 2018 Oct 22]. Available from: ,http://www.intechopen.com/books/phytochemicals-bioactivities-and-impact-onhealth/by-products-from-plant-foods-are-sources-of-dietary-fibre-and-antioxidants.. Gonz´alez-Montelongo, R., Gloria Lobo, M., Gonz´alez, M., 2010. Antioxidant activity in banana peel extracts: testing extraction conditions and related bioactive compounds. Food Chem. 119 (3), 1030
1039 [cited 2018 Oct 18]; Available from: ,http://www.sciencedirect.com/science/article/pii/S0308814609009819.. ˆ ´zˇ , M., et al., 2001. Comparison of Gorinstein, S., Martı´n-Belloso, O., Park, Y.-S., Haruenkit, R., Lojek, A., Cı some biochemical characteristics of different citrus fruits. Food Chem. 74 (3), 309
315 [cited 2018 Nov 28]; Available from: ,http://www.sciencedirect.com/science/article/pii/S0308814601001571.. Hayat, K., Hussain, S., Abbas, S., Farooq, U., Ding, B., Xia, S., et al., 2009. Optimized microwave-assisted extraction of phenolic acids from citrus mandarin peels and evaluation of antioxidant activity in vitro. Sep. Purif. Technol. 70 (1), 63
70 [cited 2018 Oct 18]; Available from: ,http://www.sciencedirect.com/science/article/pii/S1383586609003657.. Hedr´en, E., Diaz, V., Svanberg, U., 2002. Estimation of carotenoid accessibility from carrots determined by an in vitro digestion method. Eur. J. Clin. Nutr. 56 (5), 425
430 [cited 2018 Oct 22]; Available from: ,https://www.nature.com/articles/1601329.. Hemery, Y.M., Anson, N.M., Havenaar, R., Haenen, G.R.M.M., Noort, M.W.J., Rouau, X., 2010. Dryfractionation of wheat bran increases the bioaccessibility of phenolic acids in breads made from processed bran fractions. Food Res. Int. 43 (5), 1429
1438 [cited 2018 Aug 29]; Available from: ,http://linkinghub. elsevier.com/retrieve/pii/S0963996910001146.. Hoebler, C., Lecannu, G., Belleville, C., Devaux, M.-F., Popineau, Y., Barry, J.-L., 2002. Development of an in vitro system simulating bucco-gastric digestion to assess the physical and chemical changes of food. Int. J. Food Sci. Nutr. 53 (5), 389
402. Available from: https://doi.org/10.1080/0963748021000044732 [cited 2018 Oct 22]. Jayaprakasha, G.K., Jena, B.S., Negi, P.S., Sakariah, K.K., 2014. Evaluation of antioxidant activities and antimutagenicity of turmeric oil: a byproduct from curcumin production. Z. Naturforschung C 57 (9
10), 828
835 [cited2018 Nov 28]; Available from: ,https://www.degruyter.com/view/j/znc.2002.57.issue-910/znc-2002-9-1013/znc-2002-9-1013.xml.. Kalantzi, L., Goumas, K., Kalioras, V., Abrahamsson, B., Dressman, J.B., Reppas, C., 2006. Characterization of the human upper gastrointestinal contents under conditions simulating bioavailability/bioequivalence studies. Pharm. Res. 23 (1), 165
176. Available from: https://doi.org/10.1007/s11095-005-8476-1 [cited 2018 Oct 22].

258

CHAPTER 8 INNOVATIVE SOURCES

Karakaya, S., Yılmaz, N., 2007. Lycopene content and antioxidant activity of fresh and processed tomatoes and in vitro bioavailability of lycopene. J. Sci. Food Agric. 87 (12), 2342
2347 [cited 2018 Oct 22]; Available from: ,https://onlinelibrary.wiley.com/doi/abs/10.1002/jsfa.2998.. Kenyon, C.J., Brown, F., McClelland, G.R., Wilding, I.R., 1998. The use of pharmacoscintigraphy to elucidate food effects observed with a novel protease inhibitor (saquinavir). Pharm. Res. 15 (3), 417
422. Available from: https://doi.org/10.1023/A:1011972230829 [cited 2018 Oct 19]. Kim, J.-W., Nagaoka, T., Ishida, Y., Hasegawa, T., Kitagawa, K., Lee, S.-C., 2009. Subcritical water extraction of nutraceutical compounds from citrus pomaces. Sep. Sci. Technol. 44 (11), 2598
2608. Available from: https://doi.org/10.1080/01496390903014375 [cited 2018 Oct 18]. Kong, F., Singh, R.P., 2008. Disintegration of solid foods in human stomach. J Food Sci 73 (5), R67
R80 [cited 2018 Aug 29]; Available from: ,http://doi.wiley.com/10.1111/j.1750-3841.2008.00766.x.. Kumar, K., Yadav, A.N., Kumar, V., Vyas, P., Dhaliwal, H.S., 2017. Food waste: a potential bioresource for extraction of nutraceuticals and bioactive compoundsBioresour. Bioprocess. 4 (1), 18 [cited 2018 Oct 22]. Available from: https://doi.org/10.1186/s40643-017-0148-6. Lachance P.A., Das Y.T. Chapter 1.11
Nutraceuticals. In: Taylor J.B. and Triggle D.J. (Ed.), Comprehensive Medicinal Chemistry II, Volume 1, 2007, Elsevier,449-461. Available from: https://www. sciencedirect.com/science/article/pii/B008045044X000146. Laddomada, B., Caretto, S., Mita, G., 2015. Wheat bran phenolic acids: bioavailability and stability in whole wheat-based foods. Molecules 20 (9), 15666
15685 [cited 2018 Aug 29]; Available from: ,http://www. mdpi.com/1420-3049/20/9/15666.. Laddomada, B., Durante, M., Mangini, G., D’Amico, L., Lenucci, M.S., Simeone, R., et al., 2017. Genetic variation for phenolic acids concentration and composition in a tetraploid wheat (Triticum turgidum L.) collection. Genet. Resour. Crop Evol. 64 (3), 587
597. Available from: https://doi.org/10.1007/s10722-0160386-z [cited 2018 Aug 29]. Lee, S.-J., Lee, S.Y., Chung, M.-S., Hur, S.J., 2016. Development of novel in vitro human digestion systems for screening the bioavailability and digestibility of foods. J. Funct. Foods 22, 113
121 [cited 2018 Aug 29]; Available from: ,http://linkinghub.elsevier.com/retrieve/pii/S1756464616000062.. L´eger, C.L., Kadiri-Hassani, N., Descomps, B., 2000. Decreased superoxide anion production in cultured human promonocyte cells (THP-1) due to polyphenol mixtures from olive oil processing wastewaters. J. Agric. Food Chem. 48 (10), 5061
5067. Available from: https://doi.org/10.1021/jf991349c [cited 2018 Nov 27]. Leontowicz, M., Gorinstein, S., Bartnikowska, E., Leontowicz, H., Kulasek, G., Trakhtenberg, S., 2001. Sugar beet pulp and apple pomace dietary fibers improve lipid metabolism in rats fed cholesterol. Food Chem 72 (1), 73
78 [cited 2018 Nov 28]; Available from: ,http://www.sciencedirect.com/science/article/pii/ S0308814600002077.. Li, B.B., Smith, B., Hossain, M.M., 2006. Extraction of phenolics from citrus peels: II. Enzyme-assisted extraction method. Sep. Purif. Technol. 48 (2), 189
196 [cited 2018 Oct 18]; Available from: ,http:// www.sciencedirect.com/science/article/pii/S1383586605002157.. Li, Y., Skouroumounis, G.K., Elsey, G.M., Taylor, D.K., 2011. Microwave-assistance provides very rapid and efficient extraction of grape seed polyphenols. Food Chem. 129 (2), 570
576 [cited 2018 Oct 17]; Available from: ,http://www.sciencedirect.com/science/article/pii/S0308814611006340.. Lucci, P., Pacetti, D., Loizzo, M.R., Frega, N.G., 2015. Punica granatum cv. Dente di Cavallo seed ethanolic extract: antioxidant and antiproliferative activities. Food Chem. 167, 475
483. Ma, Y., Ye, X., Hao, Y., Xu, G., Xu, G., Liu, D., 2008. Ultrasound-assisted extraction of hesperidin from Penggan (Citrus reticulata) peel. Ultrason. Sonochem. 15 (3), 227
232 [cited 2018 Oct 17]; Available from: ,http://www.sciencedirect.com/science/article/pii/S1350417707000636.. Ma, Y., Kerr, W.L., Swanson, R.B., Hargrove, J.L., Pegg, R.B., 2014. Peanut skins-fortified peanut butters: effect of processing on the phenolics content, fibre content and antioxidant activity. Food Chem. 145,

REFERENCES

259

883
891 [cited 2018 Oct 19]; Available from: ,http://www.sciencedirect.com/science/article/pii/ S0308814613012272.. Mach, N., Berri, M., Esquerr´e, D., Chevaleyre, C., Lemonnier, G., Billon, Y., et al., 2014. Extensive expression differences along porcine small intestine evidenced by transcriptome sequencing. PLoS One 9 (2), e88515 [cited 2018 Oct 22]; Available from: ,https://journals.plos.org/plosone/article?id 5 10.1371/journal.pone.0088515.. Marciani, L., Gowland, P.A., Fillery-Travis, A., Manoj, P., Wright, J., Smith, A., et al., 2001. Assessment of antral grinding of a model solid meal with echo-planar imaging. Am. J. Physiol.-Gastrointest. Liver Physiol. 280 (5), G844
G849 [cited 2018 Oct 19]; Available from: ,https://www.physiology.org/doi/abs/ 10.1152/ajpgi.2001.280.5.G844.. Marciani, L., Wickham, M., Singh, G., Bush, D., Pick, B., Cox, E., et al., 2007. Enhancement of intragastric acid stability of a fat emulsion meal delays gastric emptying and increases cholecystokinin release and gallbladder contraction. Am. J. Physiol.-Gastrointest. Liver Physiol. 292 (6), G1607
G1613 [cited 2018 Oct 19]; Available from: ,https://www.physiology.org/doi/abs/10.1152/ajpgi.00452.2006.. Marze, S., 2017. Bioavailability of nutrients and micronutrients: advances in modeling and in vitro approaches. Annu. Rev. Food Sci. Technol. 8, 35
55. Matthews, D.R., Hosker, J.P., Rudenski, A.S., Naylor, B.A., Treacher, D.F., Turner, R.C., 1985. Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28 (7), 412
419. Available from: https://doi.org/10.1007/BF00280883 [cited 2018 Oct 22]. McClements, D.J., 2013. Edible lipid nanoparticles: digestion, absorption, and potential toxicity. Prog. Lipid Res. 52 (4), 409
423 [cited 2018 Aug 29]; Available from: ,http://www.sciencedirect.com/science/article/pii/S0163782713000295.. McClements, D.J., Zou, L., Zhang, R., Salvia-Trujillo, L., Kumosani, T., Xiao, H., 2015. Enhancing nutraceutical performance using excipient foods: designing food structures and compositions to increase bioavailability. Compr. Rev. Food Sci. Food Saf. 14 (6), 824
847 [cited 2018 Aug 29]; Available from: ,https:// onlinelibrary.wiley.com/doi/abs/10.1111/1541-4337.12170.. McInerney, J.K., Seccafien, C.A., Stewart, C.M., Bird, A.R., 2007. Effects of high pressure processing on antioxidant activity, and total carotenoid content and availability, in vegetables. Innov Food Sci Emerg Technol 8 (4), 543
548 [cited 2018 Oct 22]; Available from: ,http://www.sciencedirect.com/science/article/pii/S1466856407000598.. M´enard, O., Cattenoz, T., Guillemin, H., Souchon, I., Deglaire, A., Dupont, D., et al., 2014. Validation of a new in vitro dynamic system to simulate infant digestion. Food Chem 145, 1039
1045 [cited 2018 Oct 22]; Available from: ,http://www.sciencedirect.com/science/article/pii/S0308814613012880.. Minekus, M., 2015. The TNO gastro-intestinal model (TIM). In: Verhoeckx, K., Cotter, P., Lo´pez-Expo´sito, I., Kleiveland, C., Lea, T., Mackie, A., et al.,The Impact of Food Bioactives on Health. Springer International Publishing, Cham, pp. 37
46. [cited 2018 Aug 29]; Available from: ,http://link.springer.com/10.1007/ 978-3-319-16104-4_5.. Minekus, M., Jelier, M., Xiao, J., Kondo, S., Iwatsuki, K., Kokubo, S., et al., 2005. Effect of partially hydrolyzed guar gum (PHGG) on the bioaccessibility of fat and cholesterol. Biosci. Biotechnol. Biochem. 69 (5), 932
938 [cited 2018 Oct 22]; Available from: ,https://www.jstage.jst.go.jp/article/bbb/69/5/ 69_5_932/_article/-char/ja/.. Mohan, V., Das, S., Rao, S.B.S., 2016. Hydroxytyrosol, a dietary phenolic compound forestalls the toxic effects of methylmercury-induced toxicity in IMR-32 human neuroblastoma cells. Environ Toxicol 31 (10), 1264
1275 [cited 2018 Nov 27]; Available from: ,https://onlinelibrary.wiley.com/doi/abs/10.1002/tox.22134.. Montella, R., Coı¨sson, J.D., Travaglia, F., Locatelli, M., Malfa, P., Martelli, A., et al., 2013. Bioactive compounds from hazelnut skin (Corylus avellana L.): effects on Lactobacillus plantarum P17630 and

260

CHAPTER 8 INNOVATIVE SOURCES

Lactobacillus crispatus P17631. J. Funct. Foods 5 (1), 306
315 [cited 2018 Oct 19]; Available from: ,http://www.sciencedirect.com/science/article/pii/S1756464612001673.. Moreno, F.J., 2007. Gastrointestinal digestion of food allergens: effect on their allergenicity. Biomed. Pharmacother. 61 (1), 50
60 [cited 2018 Oct 22]; Available from: ,http://www.sciencedirect.com/science/article/pii/S0753332206003374.. Muniraj, I.K., Xiao, L., Liu, H., Zhan, X., 2015. Utilisation of potato processing wastewater for microbial lipids and γ-linolenic acid production by oleaginous fungi. J. Sci. Food Agric. 95 (15), 3084
3090 [cited 2018 Nov 27]; Available from: ,https://onlinelibrary.wiley.com/doi/abs/10.1002/jsfa.7044.. Mun˜oz, O., Sepu´lveda, M., Schwartz, M., 2004. Effects of enzymatic treatment on anthocyanic pigments from grapes skin from chilean wine. Food Chem. 87 (4), 487
490 [cited 2018 Oct 17]; Available from: ,http://www.sciencedirect.com/science/article/pii/S0308814604000020.. Nagah, A.M., Seal, C.J., 2005. In vitro procedure to predict apparent antioxidant release from wholegrain foods measured using three different analytical methods. J. Sci. Food Agric. 85 (7), 1177
1185 [cited 2018 Sep 24]; Available from: ,https://onlinelibrary.wiley.com/doi/abs/10.1002/jsfa.2106.. Newman, D.J., Cragg, G.M., 2012. Natural products as sources of new drugs over the 30 years from 1981 to 2010. J. Nat. Prod. 75 (3), 311
335 [cited 2018 Oct 17]; Available from: ,https://doi.org/10.1021/np200906s.. Nobili, S., Lippi, D., Witort, E., Donnini, M., Bausi, L., Mini, E., et al., 2009. Natural compounds for cancer treatment and prevention. Pharmacol. Res. 59 (6), 365
378 [cited 2018 Oct 17]; Available from: ,http:// www.sciencedirect.com/science/article/pii/S1043661809000516.. Norton, I., Moore, S., Fryer, P., 2007. Understanding food structuring and breakdown: engineering approaches to obesity. Obes. Rev. 8 (s1), 83
88 [cited 2018 Oct 19]; Available from: ,https://onlinelibrary.wiley. com/doi/abs/10.1111/j.1467-789X.2007.00324.x.. Obied, H.K., Allen, M.S., Bedgood Danny, R., Prenzler, P.D., Robards, K., 2005. Investigation of Australian olive mill waste for recovery of biophenols. J. Agric. Food Chem. 53 (26), 9911
9920. Available from: https://doi.org/10.1021/jf0518352 [cited 2018 Nov 27]. Olive Mill Waste | ScienceDirect. [cited 2018 Nov 27]. Available from: ,https://www.sciencedirect.com/ book/9780128053140/olive-mill-waste.. Omura, A.P., Steffe, J.F., 2003. Mixer viscometry to characterize fluid foods with large particulates. J Food Process. Eng. 26 (5), 435
445 [cited 2018 Oct 22]; Available from: ,https://onlinelibrary.wiley.com/doi/ abs/10.1111/j.1745-4530.2003.tb00611.x.. Oszmia´nski, J., Wojdyło, A., Kolniak, J., 2011. Effect of pectinase treatment on extraction of antioxidant phenols from pomace, for the production of puree-enriched cloudy apple juices. Food Chem. 127 (2), 623
631 [cited 2018 Oct 17]; Available from: ,http://www.sciencedirect.com/science/article/pii/ S0308814611001439.. Ozcan, T., Akpinar-Bayizit, A., Yilmaz-Ersan, L., Delikanli, B., 2014. Phenolics in human health. Int. J. Chem. Eng. Appl. 5 (5), 393
396 [cited 2018 Oct 15]; Available from: ,http://www.ijcea.org/index.php? m 5 content&c 5 index&a 5 show&catid 5 58&id 5 752.. O’Shea, N., Arendt, E.K., Gallagher, E., 2012. Dietary fibre and phytochemical characteristics of fruit and vegetable by-products and their recent applications as novel ingredients in food products. Innov. Food Sci. Emerg. Technol. 16, 1
10 [cited 2018 Nov 28]; Available from: ,http://www.sciencedirect.com/science/ article/pii/S1466856412000884.. Pan, G., Yu, G., Zhu, C., Qiao, J., 2012. Optimization of ultrasound-assisted extraction (UAE) of flavonoids compounds (FC) from hawthorn seed (HS). Ultrason. Sonochem. 19 (3), 486
490 [cited 2018 Oct 17]; Available from: ,http://www.sciencedirect.com/science/article/pii/S1350417711002288.. Parada, J., Aguilera, J.M., 2007. Food microstructure affects the bioavailability of several nutrients. J Food Sci. 72 (2), R21
R32 [cited 2018 Aug 29]; Available from: ,https://onlinelibrary.wiley.com/doi/abs/ 10.1111/j.1750-3841.2007.00274.x..

REFERENCES

261

Passos, C.P., Silva, R.M., Da Silva, F.A., Coimbra, M.A., Silva, C.M., 2010. Supercritical fluid extraction of grape seed (Vitis vinifera L.) oil. Effect of the operating conditions upon oil composition and antioxidant capacity. Chem. Eng. J. 160 (2), 634
640 [cited 2018 Oct 18]; Available from: ,http://www.sciencedirect.com/science/article/pii/S1385894710003232.. Patsioura, A., Galanakis, C.M., Gekas, V., 2011. Ultrafiltration optimization for the recovery of β-glucan from oat mill waste. J. Membr. Sci. 373 (1), 53
63 [cited 2018 Nov 27]; Available from: ,http://www.sciencedirect.com/science/article/pii/S0376738811001529.. Pera, P., Bucca, C., Borro, P., Bernocco, C., De Lillo, A., Carossa, S., 2002. Influence of mastication on gastric emptying. J. Dent. Res. 81 (3), 179
181. Available from: https://doi.org/10.1177/0810179 [cited 2018 Oct 22]. Pereira, J.A., Oliveira, I., Sousa, A., Valenta˜o, P., Andrade, P.B., Ferreira, I.C.F.R., et al., 2007. Walnut (Juglans regia L.) leaves: phenolic compounds, antibacterial activity and antioxidant potential of different cultivars. Food Chem. Toxicol. 45 (11), 2287
2295 [cited 2018 Oct 19]; Available from: ,http://www. sciencedirect.com/science/article/pii/S0278691507001949.. Perretti, G., Troilo, A., Bravi, E., Marconi, O., Galgano, F., Fantozzi, P., 2013. Production of a lycopene-enriched fraction from tomato pomace using supercritical carbon dioxide. J. Supercrit. Fluids 82, 177
182 [cited 2018 Oct 22]; Available from: ,http://www.sciencedirect.com/science/article/pii/S0896844613002623.. Picariello, G., Ferranti, P., Addeo, F., 2016. Use of brush border membrane vesicles to simulate the human intestinal digestion. Food Res. Int. 88, 327
335 [cited 2018 Aug 29]; Available from: ,http://linkinghub. elsevier.com/retrieve/pii/S0963996915302416.. Polyphenols in olive related health claims. European Food Safety Authority, 2011. [cited 2018 Nov 27]. Available from: ,https://www.efsa.europa.eu/en/efsajournal/pub/2033.. Pop, O.L., Vodnar, D.C., Suharoschi, R., Mudura, E., Socaciu, C., 2016. L. plantarum ATCC 8014 entrapment with prebiotics and lucerne green juice and their behavior in simulated gastrointestinal conditions. J. Food Process. Eng. 39 (5), 433
441 [cited 2018 Oct 19]; Available from: ,https://onlinelibrary.wiley.com/doi/ abs/10.1111/jfpe.12234.. Poster abstracts: Drug Metabolism Reviews: Vol 44, Nosup1. [cited 2018 Oct 22]. Available from: ,https:// www.tandfonline.com/doi/abs/10.3109/03602532.2012.744573?journalCode 5 idmr20.. Pourali, O., Asghari, F.S., Yoshida, H., 2010. Production of phenolic compounds from rice bran biomass under subcritical water conditions. Chem. Eng. J. 160 (1), 259
266 [cited 2018 Oct 18]; Available from: ,http://www.sciencedirect.com/science/article/pii/S1385894710001981.. Prado, A.C.P., do, Manion, B.A., Seetharaman, K., Deschamps, F.C., Barrera Arellano, D., Block, J.M., 2013. Relationship between antioxidant properties and chemical composition of the oil and the shell of pecan nuts [Caryaillinoinensis (Wangenh) C. Koch]. Ind. Crops Prod. 45, 64
73 [cited 2018 Oct 19]; Available from: ,http://www.sciencedirect.com/science/article/pii/S0926669012006334.. Prasad, K.N., Hassan, F.A., Yang, B., Kong, K.W., Ramanan, R.N., Azlan, A., et al., 2011. Response surface optimisation for the extraction of phenolic compounds and antioxidant capacities of underutilised Mangifera pajang Kosterm. peels. Food Chem 128 (4), 1121
1127 [cited 2018 Oct 18]; Available from: ,http://www.sciencedirect.com/science/article/pii/S0308814611005061.. Rahmanian, N., Jafari, S.M., Galanakis, C.M., 2014. Recovery and removal of phenolic compounds from olive mill wastewater. J. Am. Oil Chem. Soc. 91 (1), 1
18. Available from: https://doi.org/10.1007/s11746-0132350-9 [cited 2018 Nov 27]. Rawat, N., Laddomada, B., Gill, B.S., 2013. Genomics of cereal-based functional foodsIn: Gupta, P.K., Varshney, R.K. (Eds.), Cereal Genomics II. Springer Netherlands, Dordrecht, pp. 247
274. [cited 2018 Sep 5] . Available from: https://doi.org/10.1007/978-94-007-6401-9_10. Rayner, C.K., Samsom, M., Jones, K.L., Horowitz, M., 2001. Relationships of upper gastrointestinal motor and sensory function with glycemic control. Diabetes Care 24 (2), 371
381 [cited 2018 Oct 19]; Available from: ,http://care.diabetesjournals.org/content/24/2/371..

262

CHAPTER 8 INNOVATIVE SOURCES

Reboul, E., Richelle, M., Perrot, E., Desmoulins-Malezet, C., Pirisi, V., Borel, P., 2006. Bioaccessibility of carotenoids and vitamin E from their main dietary sources. J. Agric. Food Chem. 54 (23), 8749
8755. Available from: https://doi.org/10.1021/jf061818s [cited 2018 Oct 19]. Ribnicky, D.M., Roopchand, D.E., Oren, A., Grace, M., Poulev, A., Lila, M.A., et al., 2014. Effects of a high fat meal matrix and protein complexation on the bioaccessibility of blueberry anthocyanins using the TNO gastrointestinal model (TIM-1). Food Chem. 142, 349
357 [cited 2018 Oct 22]; Available from: ,http:// www.sciencedirect.com/science/article/pii/S0308814613010029.. Rios, L.Y., Bennett, R.N., Lazarus, S.A., R´em´esy, C., Scalbert, A., Williamson, G., 2002. Cocoa procyanidins are stable during gastric transit in humans. Am. J. Clin. Nutr. 76 (5), 1106
1110 [cited 2018 Oct 19]; Available from: ,https://academic.oup.com/ajcn/article/76/5/1106/4689589.. Routray, W., Orsat, V., 2017. Chapter 8 - Plant by-products and food industry waste: a source of nutraceuticals and biopolymers. In: Grumezescu, A.M., Holban, A.M. (Eds.), Food Bioconversion. Academic Press, pp. 279
315. [cited 2018 Nov 28]. (Handbook of Food Bioengineering). Available from: ,http://www. sciencedirect.com/science/article/pii/B9780128114131000085.. Salvia-Trujillo, L., Qian, C., Martı´n-Belloso, O., McClements, D.J., 2013. Influence of particle size on lipid digestion and β-carotene bioaccessibility in emulsions and nanoemulsions. Food Chem. 141 (2), 1472
1480. Salvia-Trujillo, L., Sun, Q., Um, B.H., Park, Y., McClements, D.J., 2015. In vitro and in vivo study of fucoxanthin bioavailability from nanoemulsion-based delivery systems: impact of lipid carrier type. J. Funct. Foods (17), 293
304 [cited 2018 Oct 18]; Complete Available from: ,https://www.infona.pl//resource/ bwmeta1.element.elsevier-f6b845b5-b6a2-3326-9c8a-e58d8068cce9.. S´anchez-Zapata, E., Fuentes-Zaragoza, E., Fern´andez-Lo´pez, J., Sendra, E., Sayas, E., Navarro, C., et al., 2009. Preparation of dietary fiber powder from tiger nut (Cyperus esculentus) milk (“Horchata”) byproducts and its physicochemical properties. J. Agric. Food Chem. 57 (17), 7719
7725. Santini, A., Novellino, E. 2014. Nutraceuticals: beyond the diet before the drugs. [cited 2018 Oct 18]; Available from: ,https://www.ingentaconnect.com/content/ben/cbc/2014/00000010/00000001/art00001.. Sanz, T., Luyten, H., 2006. Effect of thickening agent in the in vitro mouth, stomach and intestine release of tyrosol from enriched custards. Food Hydrocoll. 20 (5), 703
711 [cited2018 Oct 19]; Available from: ,http://www.sciencedirect.com/science/article/pii/S0268005X05001487.. Schulze, K., 2006. Imaging and modelling of digestion in the stomach and the duodenum. Neurogastroenterol. Motil. 18 (3), 172
183 [cited 2018 Oct 22]; Available from: ,https://onlinelibrary.wiley.com/doi/full/ 10.1111/j.1365-2982.2006.00759.x.. Schwizer, W., Steingoetter, A., Fox, M., 2006. Magnetic resonance imaging for the assessment of gastrointestinal function. Scand. J. Gastroenterol. 41 (11), 1245
1260. Available from: https://doi.org/10.1080/ 00365520600827188 [cited 2018 Oct 22]. Shahidi, F., 2009. Nutraceuticals and functional foods: whole versus processed foods. Trends Food Sci. Technol. 20 (9), 376
387 [cited 2018 Oct 17]; Available from: ,http://www.sciencedirect.com/science/ article/pii/S092422440800229X.. Shewry, P.R., Charmet, G., Branlard, G., Lafiandra, D., Gergely, S., Salgo´, A., et al., 2012. Developing new types of wheat with enhanced health benefits. Trends Food Sci. Technol. 25 (2), 70
77 [cited 2018 Sep 13]; Available from: ,https://hungary.pure.elsevier.com/en/publications/developing-new-types-of-wheatwith-enhanced-health-benefits.. Socaci, S.A., F˘arca¸s, A.C., Vodnar, D.C., Tofan˘a, M., 2017. Food wastes as valuable sources of bioactive molecules. Superfood Funct. Food
Dev. Superfoods Their Roles Med. [cited 2018 Oct 18]; Available from: ,https://www.intechopen.com/books/superfood-and-functional-food-the-development-of-superfoodsand-their-roles-as-medicine/food-wastes-as-valuable-sources-of-bioactive-molecules.. Souliman, S., Blanquet, S., Beyssac, E., Cardot, J.-M., 2006. A level A in vitro/in vivo correlation in fasted and fed states using different methods: applied to solid immediate release oral dosage form. Eur. J. Pharm.

REFERENCES

263

Sci. 27 (1), 72
79 [cited 2018 Oct 22]; Available from: ,http://www.sciencedirect.com/science/article/ pii/S0928098705002526.. Souliman, S., Beyssac, E., Cardot, J.-M., Denis, S., Alric, M., 2007. Investigation of the biopharmaceutical behavior of theophylline hydrophilic matrix tablets using USP methods and an artificial digestive system. Drug Dev. Ind. Pharm. 33 (4), 475
483. Available from: https://doi.org/10.1080/03639040601128654 [cited 2018 Oct 22]. Stomach | SEER Training. [cited 2018 Nov 27]. Available from: ,https://training.seer.cancer.gov/anatomy/ digestive/regions/stomach.html.. Stomach, 2018. In: Wikipedia. [cited 2018 Nov 27]. Available from: ,https://en.wikipedia.org/w/index.php? title 5 Stomach&oldid 5 869964105.. Study on Extraction of Carotenoids from Skin Residue of Apricot. Modern Food Sci. Technol. 2013-03. [cited 2018 Oct 22]. Available from: ,http://en.cnki.com.cn/Article_en/CJFDTOTAL-GZSP201303034.htm.. Sturtzel, B., Dietrich, A., Wagner, K.-H., Gisinger, C., Elmadfa, I., 2010. The status of vitamins B6, B12, folate, and of homocysteine in geriatric home residents receiving laxatives or dietary fiber. J. Nutr. Health Aging 14 (3), 219
223. Available from: https://doi.org/10.1007/s12603-010-0053-6 [cited 2018 Nov 28]. Szabo, K., C˘atoi, A.-F., Vodnar, D.C., 2018. Bioactive compounds extracted from tomato processing byproducts as a source of valuable nutrients. Plant Foods Hum Nutr [cited 2018 Oct 1]; Available from: ,https://www.readcube.com/articles/10.1007/s11130-018-0691-0.. Szydłowska-Czerniak, A., Karlovits, G., Hellner, G., Szłyk, E., 2010a. Effect of enzymatic and hydrothermal treatments of rapeseeds on quality of the pressed rapeseed oils: part II. Oil yield and oxidative stability. Process Biochem 45 (2), 247
258 [cited 2018 Oct 18]; Available from: ,http://www.sciencedirect.com/ science/article/pii/S1359511309003031.. Szydłowska-Czerniak, A., Karlovits, G., Hellner, G., Dianoczki, C., Szłyk, E., 2010b. Effect of enzymatic and hydrothermal treatments of rapeseeds on quality of the pressed rapeseed oils: Part I: Antioxidant capacity and antioxidant content. Process Biochem. 45 (1), 7
17 [cited 2018 Oct 18]; Available from: ,http:// www.sciencedirect.com/science/article/pii/S1359511309002426.. Teixeira, A., Baenas, N., Dominguez-Perles, R., Barros, A., Rosa, E., Moreno, D.A., et al., 2014. Natural bioactive compounds from winery by-products as health promoters: a review. Int. J. Mol. Sci. 15 (9), 15638
15678. Todaro, A., Cimino, F., Rapisarda, P., Catalano, A.E., Barbagallo, R.N., Spagna, G., 2009. Recovery of anthocyanins from eggplant peel. Food Chem. 114 (2), 434
439 [cited 2018 Oct 18]; Available from: ,http:// www.sciencedirect.com/science/article/pii/S0308814608011564.. Tomaino, A., Martorana, M., Arcoraci, T., Monteleone, D., Giovinazzo, C., Saija, A., 2010. Antioxidant activity and phenolic profile of pistachio (Pistacia vera L., variety Bronte) seeds and skins. Biochimie 92 (9), 1115
1122 [cited 2018 Oct 19]; Available from: ,http://www.sciencedirect.com/science/article/pii/ S0300908410001380.. Tyssandier, V., Reboul, E., Dumas, J.-F., Bouteloup-Demange, C., Armand, M., Marcand, J., et al., 2003. Processing of vegetable-borne carotenoids in the human stomach and duodenum. Am. J. Physiol.Gastrointest. Liver Physiol. 284 (6), G913
G923 [cited 2018 Oct 19]; Available from: ,https://www. physiology.org/doi/abs/10.1152/ajpgi.00410.2002.. Vaisman, N., Reuven, Y., Uzi, M., Georgi, G., Boehm, G., 2006. Camel’s milk and gastric emptying. Clin. Nutr. 25 (4), 622
625 [cited 2018 Oct 19]; Available from: ,http://www.sciencedirect.com/science/article/pii/S0261561406000562.. Van Loo-Bouwman, C.A., Naber, T.H.J., Minekus, M., van Breemen, R.B., Hulshof, P.J.M., Schaafsma, G., 2014. Food matrix effects on bioaccessibility of β-carotene can be measured in an in vitro gastrointestinal model. J. Agric. Food Chem. 62 (4), 950
955. Available from: https://doi.org/10.1021/jf403312v [cited 2018 Oct 22].

264

CHAPTER 8 INNOVATIVE SOURCES

Varzakas, T., Zakynthinos, G., Verpoort, F., 2016. Plant food residues as a source of nutraceuticals and functional foods. Foods Basel Switz. 5 (4). V´asquez-Villanueva, R., Marina, M.L., Garcı´a, M.C., 2015. Revalorization of a peach (Prunus persica (L.) Batsch) byproduct: extraction and characterization of ACE-inhibitory peptides from peach stones. J. Funct. Foods 18, 137
146 [cited 2018 Oct 22]; Available from: ,http://www.sciencedirect.com/science/article/ pii/S1756464615003503.. Vazquez-Flores, A.A., Wong-Paz, J.E., Lerma-Herrera, M.A., Martinez-Gonzalez, A.I., Olivas-Aguirre, F.J., Aguilar, C.N., et al., 2017. Proanthocyanidins from the kernel and shell of pecan (Carya illinoinensis): average degree of polymerization and effects on carbohydrate, lipid, and peptide hydrolysis in a simulated human digestive system. J. Funct. Foods 28, 227
234 [cited 2018 Oct 19]; Available from: ,http://www. sciencedirect.com/science/article/pii/S1756464616303413.. Veneziani, G., Novelli, E., Esposto, S., Taticchi, A., Servili, M., 2017. Chapter 11 - Applications of recovered bioactive compounds in food products. In: Galanakis, C.M. (Ed.), Olive Mill Waste. Academic Press, pp. 231
253. [cited 2018 Nov 27]; Available from: ,http://www.sciencedirect.com/science/article/pii/ B978012805314000011X.. Verardo, V., Garcia-Salas, P., Baldi, E., Segura-Carretero, A., Fernandez-Gutierrez, A., Caboni, M.F., 2014. Pomegranate seeds as a source of nutraceutical oil naturally rich in bioactive lipids. Food Res. Int. 65, 445
452 [cited 2018 Nov 28]; Available from: ,http://www.sciencedirect.com/science/article/pii/ S0963996914002932.. Vertzoni, M., Dressman, J., Butler, J., Hempenstall, J., Reppas, C., 2005. Simulation of fasting gastric conditions and its importance for the in vivo dissolution of lipophilic compounds. Eur. J. Pharm. Biopharm. 60 (3), 413
417 [cited 2018 Oct 19]; Available from: ,http://www.sciencedirect.com/science/article/pii/ S0939641105001062.. Vierhuis, E., Korver, M., Schols, H.A., Voragen, A.G.J., 2003. Structural characteristics of pectic polysaccharides from olive fruit (Olea europaea cv moraiolo) in relation to processing for oil extraction. Carbohydr. Polym. 51 (2), 135
148 [cited 2018 Nov 27]; Available from: ,http://www.sciencedirect.com/science/ article/pii/S0144861702001583.. Visioli, F., Caruso, D., Plasmati, E., Patelli, R., Mulinacci, N., Romani, A., et al., 2001. Hydroxytyrosol, as a component of olive mill waste water, is dose-dependently absorbed and increases the antioxidant capacity of rat plasma. Free Radic. Res. 34 (3), 301
305. Vitaglione, P., Napolitano, A., Fogliano, V., 2008. Cereal dietary fibre: a natural functional ingredient to deliver phenolic compounds into the gut. Trends Food Sci. Technol. 19 (9), 451
463 [cited 2018 Aug 29]; Available from: ,http://linkinghub.elsevier.com/retrieve/pii/S0924224408000447.. Vodnar, D.C., Socaciu, C., 2014. Selenium enriched green tea increase stability of Lactobacillus casei and Lactobacillus plantarum in chitosan coated alginate microcapsules during exposure to simulated gastrointestinal and refrigerated conditions. LWT - Food Sci. Technol. 57 (1), 406
411. Vodnar, D.C., C˘alinoiu, L.F., Dulf, F.V., Stef˘ ¸ anescu, B.E., Cri¸san, G., Socaciu, C., 2017. Identification of the bioactive compounds and antioxidant, antimutagenic and antimicrobial activities of thermally processed agro-industrial waste. Food Chem. 231, 131
140. Walsh, K.R., Zhang, Y.C., Vodovotz, Y., Schwartz, S.J., Failla, M.L., 2003. Stability and bioaccessibility of isoflavones from soy bread during in vitro digestion. J. Agric. Food Chem. 51 (16), 4603
4609. Available from: https://doi.org/10.1021/jf0342627 [cited 2018 Oct 19]. Weitschies, W., Wedemeyer, R.-S., Kosch, O., Fach, K., Nagel, S., So¨derlind, E., et al., 2005. Impact of the intragastric location of extended release tablets on food interactions. J. Control. Release 108 (2), 375
385 [cited 2018 Oct 19]; Available from: ,http://www.sciencedirect.com/science/article/pii/S0168365905003986.. Wu, S., Chappell, J., 2008. Metabolic engineering of natural products in plants; tools of the trade and challenges for the future. Curr. Opin. Biotechnol. 19 (2), 145
152 [cited 2018 Oct 17]; Available from: ,http://www.sciencedirect.com/science/article/pii/S0958166908000190..

FURTHER READING

265

Yang, B., Jiang, Y., Shi, J., Chen, F., Ashraf, M., 2011. Extraction and pharmacological properties of bioactive compounds from longan (Dimocarpus longan Lour.) fruit—a review. Food Res. Int. 44 (7), 1837
1842 [cited 2018 Oct 17]; Available from: ,http://www.sciencedirect.com/science/article/pii/S0963996910003820.. Yepez, B., Espinosa, M., Lo´pez, S., Bolan˜os, G., 2002. Producing antioxidant fractions from herbaceous matrices by supercritical fluid extraction. Fluid Phase Equilibria 194
197, 879
884 [cited 2018 Oct 18]; Available from: ,http://www.sciencedirect.com/science/article/pii/S0378381201007075.. Yeum, K.-J., Russell, R.M., 2002. Carotenoid bioavailability and bioconversion. Annu. Rev. Nutr. 22 (1), 483
504. Available from: https://doi.org/10.1146/annurev.nutr.22.010402.102834 [cited 2018 Oct 22]. Yi, J., Li, Y., Zhong, F., Yokoyama, W., 2014. The physicochemical stability and in vitro bioaccessibility of beta-carotene in oil-in-water sodium caseinate emulsions. Food Hydrocoll. 35, 19
27 [cited 2018 Oct 22]; Available from: ,http://www.sciencedirect.com/science/article/pii/S0268005X13002270.. ¨ zvural, E.B., Vural, H., 2011. Extraction and identification of proanthocyanidins from grape Yilmaz, E.E., O seed (Vitis vinifera) using supercritical carbon dioxide. J. Supercrit. Fluids 55 (3), 924
928 [cited 2018 Oct 17]; Available from: ,http://www.sciencedirect.com/science/article/pii/S0896844610004092.. Yu, J., Ahmedna, M., Goktepe, I., Dai, J., 2006. Peanut skin procyanidins: composition and antioxidant activities as affected by processing. J. Food Compos. Anal. 19 (4), 364
371 [cited 2018 Nov 27]; Available from: ,http://www.sciencedirect.com/science/article/pii/S0889157505001080.. Zarena, A.S., Udaya Sankar, K., 2009. Supercritical carbon dioxide extraction of xanthones with antioxidant activity from Garcinia mangostana: characterization by HPLC/LC
ESI-MS. J. Supercrit. Fluids 49 (3), 330
337 [cited 2018 Oct 18]; Available from: ,http://www.sciencedirect.com/science/article/pii/ S0896844609000825.. Zhang, Y., Shang, Z., Gao, C., Du, M., Xu, S., Song, H., et al., 2014. Nanoemulsion for solubilization, stabilization, and in vitro release of pterostilbene for oral delivery. AAPS PharmSciTech 15 (4), 1000
1008. Zhao, X., Chen, J., Du, F., 2012. Potential use of peanut by-products in food processing: a review. J. Food Sci. Technol. 49 (5), 521
529 [cited 2018 Nov 27]; Available from: ,https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3550843/..

FURTHER READING Preparatory study on food waste across EU 27. European Environment Agency. [cited 2018 Oct 18]. Available from: ,https://www.eea.europa.eu/data-and-maps/data/external/preparatory-study-on-food-waste..

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CHAPTER

ETHNO-PHARMACEUTICAL FORMULATIONS

9 Hikoichiro Maegawa

Pharmaceutical Evaluation Division, Pharmaceutical Safety and Environmental Health Bureau, Ministry of Health, Labour and Welfare, Tokyo, Japan

CHAPTER OUTLINE 9.1 9.2 9.3 9.4

Introduction ................................................................................................................................. 267 History ........................................................................................................................................ 268 Pharmacopoeia ............................................................................................................................ 269 WHO Monographs on Selected Medicinal Plants ............................................................................ 269 9.4.1 Volume 1 ................................................................................................................. 270 9.4.2 Volume 2 ................................................................................................................. 270 9.4.3 Volume 3 ................................................................................................................. 283 9.4.4 Volume 4 ................................................................................................................. 283 9.4.5 Commonly Used in the Newly Independent States ....................................................... 290 9.5 European Union Monograph .......................................................................................................... 290 9.6 Botanical Drugs in the United States ............................................................................................. 300 9.7 Herbal Medicinal Products in Japan .............................................................................................. 301 9.8 Discussion................................................................................................................................... 302 9.8.1 Quality Control of Herbal Medicines ........................................................................... 302 9.8.2 Efficacy and Safety of Herbal Medicines..................................................................... 304 Acknowledgments ............................................................................................................................... 305 References ......................................................................................................................................... 305

9.1 INTRODUCTION Global life expectancy has increased continuously and substantially in the past 40 years (Wang et al., 2012). These public health benefits resulted in a huge increase in health spending. Total health expenditure grew from 4% of GDP to 15% in the United States over the past century (Jakovljevic and Getzen, 2016). The global disease burden has continued to shift away from communicable to noncommunicable diseases such as mental and behavioral disorders, musculoskeletal disorders, and diabetes (Murray et al., 2012). The development of a more innovative approach through rational integration of the best therapeutic choices from modern and traditional systems is Nutraceuticals and Natural Product Pharmaceuticals. DOI: https://doi.org/10.1016/B978-0-12-816450-1.00009-X © 2019 Elsevier Inc. All rights reserved.

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urged in India and China, as both countries have a high burden of psychiatric illness (Chaturvedi and Patwardhan, 2016; Thirthalli et al., 2016). Some forms of traditional medicine such as Ayurveda, traditional Chinese medicine and Unani medicine are popular nationally, as well as being used worldwide. The output of Chinese medical materials was estimated to amount to US $83.1 billion in 2012, an increase of more than 20% from the previous year. Traditional and complimentary medicine (T&CM) is used due to one of the primary sources of healthcare, cultural and historical influences, and complementary therapy. In the last decade, there has been an increase in self-healthcare as consumers choose to be more proactive about their own health (WHO, 2013a). Self-care is what people do for themselves to establish and maintain health, and prevent and deal with illness. This consists of hygiene (general and personal), nutrition (type and quality of food eaten), lifestyle (sporting activities, leisure, etc.), environmental factors (living conditions, social habits, etc.), socioeconomic factors (income level, cultural benefits, etc.), and selfmedication (WHO, 1998). As one element of self-care, self-medication is the selection and usage of medicines by individuals to treat self-recognized illnesses or symptoms (WHO, 1998). Responsible self-medication requires that medicines used are of proven safety, quality, and efficacy, and that medicines used are those indicated for conditions that are self-recognizable and for some chronic or recurrent conditions (following initial medical diagnosis) (WHO, 1998). T&CM is an important and often underestimated part of healthcare. T&CM is found in almost every country in the world and the demand for its services is increasing. Also usage of T&CM for health promotion, self-healthcare, and disease prevention may actually reduce healthcare costs, and T&CM plays a significant role in the economic development of a number of countries (WHO, 2013a). On the other hand, usage of poor quality, adulterated, or counterfeit products, and exposure to misleading or unreliable information are some risks associated with T&CM products. Therefore, the WHO promotes the safety, efficacy, and quality of T&CM through knowledge base regulation (WHO, 2013a). This chapter describes mainly monographs of ethno-pharmaceuticals prepared by knowledge base regulation, and discusses issues related to efficacy, safety, and quality of herbal medicines.

9.2 HISTORY “Pharmaceuticals” is thought to have been discovered through the illnesses experienced by human beings who find out treatment resources among animals, plants, and minerals in nature, and the information is passed down from generation to generation. Ancient medicines were thought to be discovered from trial and error, as it is said that a deity in Chinese religion, “Shennong” who appears in Shen Nong Ben Cao Jing (300 BC-200 AD), the ancient Chinese pharmacopeia, took plants himself to discover pharmaceuticals and was poisoned 70 times a day (Mikage and Kimura, 2013). The four great civilizations of the world arose along the Tigris and Euphrates rivers in the Middle East, in a region named Mesopotamia, along the Nile Valley in Egypt, along the Indus River in parts of what are now India and Pakistan, and along the Yellow River in China. Each of the four great civilizations had their own medicine. Medical laws were described in the code of

9.4 WHO MONOGRAPHS ON SELECTED MEDICINAL PLANTS

269

Hammurabi, which is a Babylonian code of law of ancient Mesopotamia. In Egypt, use of medicinal herbs such as aloe was described in The Ebers Papyrus (BC 1552) (Mikage and Kimura, 2013). Ayurveda is traditional Indian medicine and 1200
1500 plants have been incorporated into the official Ayurvedic pharmacopeia in more than 3000 years (Kumar et al., 2017). In China, The Shen Nong Ben Cao Jing was the first compendium of herbal medicine and it contained records of 365 plants, illustrating their characteristic features, therapeutic properties, and methods of usage. Roman medicine, followed by modern medicine was highly influenced by Greek medicine. The Greeks were influenced by Egyptian theories and practices. De Materia Medica, written by a Greek military physician in the Roman Army during the period of the Roman Emperor Nero, Pedaniou Dioscorides (1 century CE), is considered as the forerunner of modern pharmacopoeias. De Materia Medica includes more than 900 herbal drugs. In addition, it includes detailed information about those drugs, such as botanical descriptions, medical effects, methods of preparation and storage (Mikage and Kimura, 2013; Staub et al., 2016).

9.3 PHARMACOPOEIA The term “pharmacopoeia” is derived from ancient Greek, meaning “drug manufacturing.” Pharmacopeia is a legally binding, set of standards for pharmaceuticals used in a country or region, prepared by a national or regional authority. Quality standards consist of a series of appropriate tests to confirm the identity and purity of the product and ascertain the strength (or amount) of the active substance and its performance characteristics, if necessary. Reference substances, that is, highly characterized physical specimens, are used for testing to ensure qualities such as identity, strength, and purity of pharmaceuticals. Pharmacopoeia as a public tool maintains the quality of pharmaceuticals by collecting recommended procedures for analysis. As of 2013, there are 24 Pharmacopoeias prepared by WHO, the European Union, and several other countries (Croatia, Czech Republic, Finland, France, Germany, Portugal, Serbia, Spain, Sweden, Switzerland, United Kingdom (UK), Kazakhstan, Russia, Ukraine, China, India, Indonesia, Japan, Korea, the United States, Argentina, and Mexico) (WHO, 2013b).

9.4 WHO MONOGRAPHS ON SELECTED MEDICINAL PLANTS Selected plants were widely used and important in all WHO areas and it was thought that sufficient scientific information could be used to demonstrate safety and effectiveness. This content was obtained by a systematic review of scientific literature from 1975 to the end of 1995. The references reviewed are pharmacopoeias of Africa, the United Kingdom, China, the Netherlands, Europe, France, Germany, Hungary, India, Japan, as well as many other reference books. Draft monographs are widely distributed and more than 100 experts from over 40 countries commented. More countries and experts were involved each time a new volume was published. Each monograph consists of two parts. The first part consists of the pharmacopoeia summary for quality assurance: plant characteristics, distribution, identification test, purity test, chemical assays, and active or major chemical components. The second part consists of clinical applications,

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pharmacology, contraindications, warnings, precautions, potential side effects, and dosage regimens. Clinical applications have three categories: 1. Medical uses are supported by clinical data including controlled, randomized, double-blind studies, trials without controls, cohort studies, or well-documented observations of therapeutic applications. 2. Medical uses are supported by pharmacopoeia or well-documented literature. 3. Medical uses are supported by traditional uses described in informal pharmacopoeia and other literature. As of 2018, monographs have been issued in five volumes.

9.4.1 VOLUME 1 Volume 1 was published in 1999 and consists of 28 monographs (WHO, 1999a). In the monograph, those in the first category supported by clinical data are shown in Table 9.1. Seventeen of twenty-eight monographs have medical uses supported by clinical data. Pediatric doses are provided in the six plants (Aloe, Flos Chamomillae, Herba Echinaceae Purpureae, Semen Plantaginis, Folium Sennae, Rhizoma Zingiberis). Plants from all over the world are listed in Volume 1. Volume 1 states that Ginkgo biloba is used for dementia and cognitive impairment. However, the results from recent clinical trials for cognition showed that no differences have been found between G. biloba and placebo, and it is concluded that the evidence that G. biloba has predictable and clinically significant benefits for people with dementia or cognitive impairment is inconsistent and unreliable (Birks and Grimley Evans, 2009). Recently, it is globally believed that microbiomes are related to health. It has been found that chronic diseases such as obesity, diabetes, intestinal disease, and cancer are related to patterns of intestinal bacterial flora. Certain ingredients of herbal medicines influence the balance of bacterial species living in the gut. For example, extracts from G. biloba leaves have been shown to increase the amount of beneficial bacteria such as Lactobacillus and Bifidobacteria in the gut. A beneficial bacterial increase in the gut is associated with many health benefits in humans. In particular, it is known to modulate the immune system to reduce the risk of autoimmune diseases such as type 1 diabetes (Crow, 2011).

9.4.2 VOLUME 2 Volume 2 was published in 1999 and consists of 30 monographs (WHO, 1999b). In the monograph, those in the first category supported by clinical data are shown in Table 9.2. Nineteen of thirty monographs have medical uses supported by clinical data. In Volume 2, there were no plants provided for pediatric dosage. Plants from all over the world are listed in Volume 2 as well as Volume 1. Herba Hyperici listed in Volume 2, commonly known as St John’s wort, should be used with caution when taking prescription medications. St John’s wort has clinically significant interactions with prescribed medicines including warfarin, cyclosporin, theophylline resulting in a decrease in the concentrations or effects of the medicines through the induction of cytochrome P450

Table 9.1 Summary of WHO Monographs on Selected Medicinal Plants Vol. 1 Supported by Clinical Data Geographical Distribution

Dosage Forms/Posology

Uses Supported by Clinical Data

Bulbus Allii Cepae

Bulbus Allii Cepae (onion) is probably indigenous to western Asia, but it is commercially cultivated worldwide, especially in regions of moderate climate.

The principal use of Bulbus Allii Cepae today is to prevent age-dependent changes in the blood vessels, and loss of appetite.

Bulbus Allii Sativi

Bulbus Allii Sativi is probably indigenous to Asia, but it is commercially cultivated in most countries.

Aloe

Native to southern and eastern Africa, and subsequently introduced into northern Africa, the Arabian peninsula, China, Gibraltar, the Mediterranean countries, and the West Indies. It is commercially cultivated in Aruba, Bonaire, Haiti, India, South Africa, the United States, and Venezuela.

Fresh juice and 5% and 50% ethanol extracts have been used in clinical studies. A daily dosage is 50 g of fresh onion or 20 g of the dried drug; doses of preparations should be calculated accordingly. Fresh bulbs, dried powder, volatile oil, oil macerates, juice, aqueous or alcoholic extracts, aged garlic extracts (minced garlic that is incubated in aqueous alcohol (15%
20%) for 20 months, then concentrated), and odorless garlic products (garlic products in which the alliinase has been inactivated by cooking; or in which chlorophyll has been added as a deodorant; or aged garlic preparations that have low concentrations of water-soluble sulfur compounds). The juice is the most unstable dosage form. Alliin and allicin decompose rapidly, and those products must be used promptly. Dried Bulbus Allii Sativi products should be stored in well-closed containers, protected from light, moisture, and elevated temperature. Average daily dose is as follows: fresh garlic, 2
5 g; dried powder, 0.4
1.2 g; oil, 2
5 mg; extract, 300
1000 mg (as solid material). Other preparations should correspond to 4
12 mg of alliin or about 2
5 mg of allicin. Bulbus Allii Sativi should be taken with food to prevent gastrointestinal upset. Powdered, dried juice, and preparations thereof for oral use. The correct individual dose is the smallest amount required to produce a soft-formed stool. As a laxative for adults and children over 10 years old, 0.04
0.11 g (Curacao or Barbados Aloe) or 0.06
0.17 g (Cape Aloe) of the dried juice, corresponding to 10
30 mg hydroxyanthraquinones per day, or 0.1 g as a single dose in the evening.

As an adjuvant to dietetic management in the treatment of hyperlipidemia, and in the prevention of atherosclerotic (agedependent) vascular changes. The drug may be useful in the treatment of mild hypertension.

Short-term treatment of occasional constipation.

(Continued)

Table 9.1 Summary of WHO Monographs on Selected Medicinal Plants Vol. 1 Supported by Clinical Data Continued Herba Centellae

Flos Chamomillae

Geographical Distribution

Dosage Forms/Posology

Uses Supported by Clinical Data

The plant is indigenous to the warmer regions of both hemispheres, including Africa, Australia, Cambodia, Central America, China, Indonesia, the Lao People’s Democratic Republic, Madagascar, the Pacific Islands, South America, Thailand, the southern part of the United States, and Vietnam. It is especially abundant in the swampy areas of India, the Islamic Republic of Iran, Pakistan, and Sri Lanka up to an altitude of approximately 700 m. The plant is indigenous to northern Europe and grows wild in central European countries; it is especially abundant in eastern Europe. Also found in western Asia, the Mediterranean region of northern Africa, and the United States. It is cultivated in many countries.

Dried drug for infusion; galenic preparations for oral administration. Powder or extract (liquid or ointment) for topical application. Package in well-closed, light-resistant containers. Oral dose: 0.33
0.68 g or by oral infusion of a similar amount three times daily.

Treatment of wounds, burns, and ulcerous skin ailments, and prevention of keloid and hypertrophic scars. Extracts of the plant have been employed to treat second- and third-degree burns. Extracts have been used topically to accelerate healing, particularly in cases of chronic postsurgical and posttrauma wounds. Extracts have been administered orally to treat stress-induced stomach and duodenal ulcers.

Dried flower heads, liquid extract (1:1 in 45% alcohol), tinctures, and other galenicals. Store in well-closed containers, protected from light. Internal use Adult dose of flower head: Average daily dose 2
8 g, three times a day; of fluid extract of 1:1 in 45% ethanol: Dose 1
4 mL, three times a day. Child dose of flower head: 2 g, three times daily; fluid extract (ethanol 45%
60%): Single dose 0.6
2 mL. Should not be used by children under 3 years old. External use For compresses, rinses or gargles: 3%
10% (30
100 g/L) infusion or 1% fluid extract or 5% tincture. For baths: 5 g/L of water or 0.8 g/L of alcoholic extract. For semisolid preparations: hydroalcoholic extracts corresponding to 3%
10% (30
100 g/kg) of the drug. For vapor inhalation: 6 g of the drug or 0.8 g of alcoholic extract per liter of hot water.

Internal use Symptomatic treatment of digestive ailments such as dyspepsia, epigastric bloating, impaired digestion, and flatulence. Infusions of chamomile flowers have been used in the treatment of restlessness and in mild cases of insomnia due to nervous disorders. External use Inflammation and irritations of the skin and mucosa (skin cracks, bruises, frostbite, and insect bites), including irritations and infections of the mouth and gums, and hemorrhoids. Inhalation Symptomatic relief of irritations of the respiratory tract due to the common cold.

Rhizoma Curcumae Longae

Cambodia, China, India, Indonesia, Lao People’s Democratic Republic, Madagascar, Malaysia, the Philippines, and Vietnam. It is extensively cultivated in China, India, Indonesia, Thailand, and throughout the tropics, including tropical regions of Africa.

Radix Echinaceae

Echinacea species are native to the Atlantic drainage area of the United States and Canada, but not Mexico. Their distribution centers are in Arkansas, Kansas, Missouri, and Oklahoma in the United States. E. pallida was cultivated in Europe for a number of years and was mistaken for E. angustifolia.

Herba Echinaceae Purpureae

Echinacea purpurea is native to the Atlantic drainage area of the United States, Canada, but not Mexico. Its distribution centers are in Arkansas, Kansas, Missouri, and Oklahoma in the United States. Echinacea purpurea has been introduced as a cultivated medicinal plant in parts of north and eastern Africa and in Europe.

Herba Ephedrae

Ephedra species are found in Afghanistan, Central America, China, India, regions of the Mediterranean, Mongolia, and North America.

Powdered crude plant material, rhizomes, and corresponding preparations. Store in a dry environment protected from light. Air dry the crude drug every 2
3 months. Crude plant material, 3
9 g daily; powdered plant material, 1.5
3.0 g daily; oral infusion, 0.5
1 g three times per day; tincture (1:10) 0.5
1 mL three times per day. Powdered roots, and galenics and preparations thereof for internal use. E. angustifolia root Hot water (about 150 mL) is poured over about 0.5 teaspoon (about 1 g) of powdered plant material, allowed to steep for 10 min, passed through a strainer, and taken orally three times a day between meals. Liquid extract (1:5, 45% ethanol), 0.5
1 mL three times daily. Tincture (1:5, 45% ethanol), 2
5 mL three times daily. E. pallida root Daily dose, tincture (1:5 with 50% ethanol by volume) from original dry extract (50% ethanol), corresponding to 900 mg of root. Powdered aerial part, pressed juice, and galenic preparations thereof for internal and external use. Oral daily dosage of Herba Echinaceae Purpureae, 6
9 mL expressed juice for no longer than 8 successive weeks. External use of semisolid preparations containing at least 15% pressed juice for no longer than 8 successive weeks. Information on dosages for children is not available. Powdered plant material; extracts and other galenicals. Store in well-closed, light-resistant containers. Crude plant material: 1
6 g for decoction daily. Liquid extract (1:1 in 45% alcohol): 1
3 mL daily. Tincture (1:4 in 45% alcohol): 6
8 mL daily.

The principal use of Rhizoma Curcumae Longae is for the treatment of acid, flatulent, or atonic dyspepsia.

Preparations of Radix Echinaceae are administered orally in supportive therapy for colds and infections of the respiratory and urinary tract. Beneficial effects in the treatment of these infections are generally thought to be brought about by stimulation of the immune response.

Herba Echinaceae Purpureae is administered orally in supportive therapy for colds and infections of the respiratory and urinary tract. Beneficial effects in the treatment of these infections are generally thought to be brought about by stimulation of the immune response. External uses include promotion of wound healing and treatment of inflammatory skin conditions. Herba Ephedrae preparations are used in the treatment of nasal congestion due to hay fever, allergic rhinitis, acute coryza, common cold, and sinusitis. The drug is further used as a bronchodilator in the treatment of bronchial asthma. (Continued)

Table 9.1 Summary of WHO Monographs on Selected Medicinal Plants Vol. 1 Supported by Clinical Data Continued Geographical Distribution

Dosage Forms/Posology

Uses Supported by Clinical Data

Folium Ginkgo

Native to China, but grown as an ornamental shade tree in Australia, southeast Asia, Europe, Japan, and the United States. It is commercially cultivated in France and the United States.

Standardized extracts (dry extracts from dried leaves, extracted with acetone and water, drug: extract ratio 35
67:1) contain 22%
27% flavone glycosides and 5%
7% terpene lactones, of which approximately 2.8%
3.4% consists of ginkgolides A, B, and C and 2.6%
3.2% bilobalide. The level of ginkgolic acids is below 5 mg/kg. Coated tablets and solution for oral administration are prepared from standardized purified extracts. Dried extract (as described in dosage forms), 120
240 mg daily in 2 or 3 divided doses; 40 mg extract is equivalent to 1.4
2.7 g leaves. Fluid extract (1:1), 0.5 mL three times a day.

Radix Ginseng

Mountain regions of China (Manchuria), the Democratic People’s Republic of Korea, Japan, the Republic of Korea, and the Russian Federation (eastern Siberia). It is commercially produced mainly by cultivation.

Crude plant material, capsules, and tablets of powdered drugs, extracts, tonic drinks, wines, and lozenges. Store in a cool, dry place in wellsealed containers. Daily dose (taken in the morning): Dried root 0.5
2 g by decoction; doses of other preparations should be calculated accordingly.

Extracts as described. “Dosage forms” have been used for symptomatic treatment of mild-to-moderate cerebrovascular insufficiency (demential syndromes in primary degenerative dementia, vascular dementia, and mixed forms of both) with the following symptoms: Memory deficit, disturbance in concentration, depressive emotional condition, dizziness, tinnitus, and headache. Such extracts are also used to improve pain-free walking distance in people with peripheral arterial occlusive disease such as intermittent claudication, Raynaud disease, acrocyanosis, and postphlebitis syndrome, and to treat inner ear disorders such as tinnitus and vertigo of vascular and involutive origin. Extracts and doses other than those described in dosage forms and posology are used for similar but milder indications. Radix Ginseng is used as a prophylactic and restorative agent for enhancement of mental and physical capacities, in cases of weakness, exhaustion, tiredness, and loss of concentration, and during convalescence.

Semen Plantaginis

P. afra and P. indica, western Mediterranean countries; P. asiatica, Japan. P. ovata, Asia and the Mediterranean countries; the plant is cultivated extensively in India and Pakistan and adapts to western Europe and subtropical regions.

Radix Rauwolfiae

The plant is found growing wild in the sub-Himalayan tracts in India and is also found in Indonesia, Myanmar, and Thailand. Over collection of Radix Rauwolfiae in India has significantly diminished supply and since 1997 there has been an embargo on export of this drug from India. Reserpine is currently either extracted from the roots of Rauvolfia vomitoria of African origin or produced by total synthesis.

Rhizoma Rhei

Rheum officinale and R. palmatum are cultivated in China (Gansu, Sichuan, and Qinghai provinces), the Democratic People’s Republic of Korea, and the Republic of Korea. There are several commercial grades (rhizome with or without rootlets, peeled or unpeeled, in transverse or longitudinal cuts).

Seeds, powder, and granules. Store in wellclosed containers in a cool dry place, protected from light. The suggested average dose is 7.5 g dissolved in 240 mL of water or juice taken orally 1
3 times daily depending on the individual response. The recommended dose for children aged 6
12 years is one-half the adult dose. For children under 6 years, a physician should be consulted. An additional glass of liquid is recommended after ingestion of the drug and generally provides an optimal response. Continued use for 2 or 3 days is needed for maximum laxative benefit. Crude drug and powder. Package in well-closed containers and store at 15 C
25 C in a dry place, secure against insect attack. Powder, 200 mg daily in divided doses for 1
3 weeks; maintenance 50
300 mg daily. Doses of other preparations should be calculated accordingly. Doses of Radix Rauwolfiae should be based on the recommended dosage of rauwolfia alkaloids, which must be adjusted according to the patient’s requirements and tolerance in small increments at intervals of at least 10 days. Debilitated and geriatric patients may require lower dosages of rauwolfia alkaloids than do other adults. Rauwolfia alkaloids may be administered orally in a single daily dose or divided into two daily doses. Dried plant material and preparations standardized to contain 10
30 mg of hydroxyanthracene derivatives per dose. Package in well-closed, light-resistant containers. The individually correct dosage is the smallest dosage necessary to maintain a soft stool. The average dose is 0.5
1.5 g of dried plant material or in decoction; preparations standardized to contain 10
30 mg of hydroxyanthracene derivatives, usually taken at bedtime.

As a bulk-forming laxative used to restore and maintain regularity. Semen Plantaginis is indicated in the treatment of chronic constipation, temporary constipation due to illness or pregnancy, irritable bowel syndrome, constipation related to duodenal ulcer or diverticulitis. It is also used to soften the stools of those with hemorrhoids, or after anorectal surgery.

The principal use today is in the treatment of mild essential hypertension. Treatment is usually administered in combination with a diuretic agent to support the drug’s antihypertensive activity, and to prevent fluid retention, which may develop if Radix Rauwolfiae is given alone.

Short-term treatment of occasional constipation.

(Continued)

Table 9.1 Summary of WHO Monographs on Selected Medicinal Plants Vol. 1 Supported by Clinical Data Continued Geographical Distribution

Dosage Forms/Posology

Uses Supported by Clinical Data

Folium Sennae

The plant is indigenous to tropical Africa. It grows wild near the Nile river from Aswan to Kordofan, and in the Arabian peninsula, India and Somalia. It is cultivated in India, Pakistan, and the Sudan.

Short-term use in occasional constipation.

Radix Valerianae

Valeriana officinalis (sensu lato) is an extremely polymorphous complex of subspecies with natural populations dispersed throughout temperate and subpolar Eurasian zones. The species is common in damp woods, ditches, and along streams in Europe, and is cultivated as a medicinal plant, especially in Belgium, England, eastern Europe, France, Germany, the Netherlands, the Russian Federation, and the United States. The plant is probably native to southeast Asia and is cultivated in the tropical regions in both the eastern and western hemispheres. It is commercially grown in Africa, China, India, and Jamaica; India is the world’s largest producer.

Crude plant material, powder, oral infusion, and extracts (liquid or solid) standardized for content of sennosides A and B. Package in well-closed containers protected from light and moisture. The correct individual dose is the smallest required to produce a comfortable, soft-formed motion. Powder: 1
2 g of leaf daily at bedtime. Adults and children over 10 years: standardized daily dose equivalent to 10
30 mg sennosides (calculated as sennoside B) taken at night. Internal use as the expressed juice, tincture, extracts, and other galenical preparations. External use as a bath additive. Store in tightly closed containers, in a cool dry place, protected from light. Dried root and rhizome, 2
3 g drug per cup by oral infusion, 1
5 times per day, up to a total of 10 g and preparations correspondingly. Tincture (1:5, 70% ethanol), 0.5
1 teaspoon (1
3 mL), once to several times a day. External use, 100 g drug for a full bath.

Dried root powder, extract, tablets, and tincture. Powdered ginger should be stored in well-closed containers (not plastic) which prevent access of moisture. Store protected from light in a cool, dry place. For motion sickness in adults and children more than 6 years: 0.5 g, 2
4 times daily. Dyspepsia, 2
4 g daily, as powdered plant material or extracts.

The prophylaxis of nausea and vomiting associated with motion sickness, postoperative nausea, pernicious vomiting in pregnancy, and seasickness.

Rhizoma Zingiberis

As a mild sedative and sleep-promoting agent. The drug is often used as a milder alternative or a possible substitute for stronger synthetic sedatives, such as the benzodiazepines, in the treatment of states of nervous excitation and anxietyinduced sleep disturbances.

Table 9.2 Summary of WHO Monographs on Selected Medicinal Plants Vol. 2 Supported by Clinical Data Geographical Distribution

Dosage Forms/Posology

Uses Supported by Clinical Data

Herba Andrographidis

Widely found and cultivated in tropical and subtropical Asia, southeast Asia, and India.

Prophylaxis and symptomatic treatment of upper respiratory infections, such as the common cold and uncomplicated sinusitis, bronchitis and pharyngotonsillitis, lower urinary tract infections, and acute diarrhea.

Rhizoma Cimicifugae Racemosae

Indigenous to eastern North America.

Folium cum Flore Crataegi

Common to the temperate areas of the northern hemisphere, including eastern areas of North America, parts of South America, east Asia, and Europe.

Radix Eleutherococci

Indigenous to southeast Asia, northern China, the Democratic People’s Republic of Korea, Japan and the south-eastern part of the Russian Federation.

Crude drug, capsules, tablets and pills. Store in a well-closed container, protected from light and moisture. For pyrexia: A decoction from 3 g crude drug, twice daily. For the common cold: 1.5
3.0 g powdered crude drug three times daily, after meals and at bedtime. For diarrhea: A decoction from 3 to 9 g crude drug as a single dose as needed, or two tablets of 500 mg four times daily, after meals and at bedtime. Crude drug, and isopropyl alcohol or ethanol extracts. Store in a well-closed container, protected from light and moisture. Daily dosage: 40%
60% isopropyl alcohol or ethanol extracts of the crude drug, corresponding to 40 mg drug. Crude drug for infusion and hydroalcoholic extracts. Store in a well-closed container, protect from light and moisture. Daily dosage: 160
900 mg dried 45% ethanol or 70% methanol extract (drug: Extract ratio 4
7:1) standardized to contain 18.75% oligomeric procyanidins (calculated as epicatechin) or 2.2% flavonoids (calculated as hyperoside), respectively (26
29, 31
34, 84); 1.0
1.5 g comminuted crude drug as an infusion 3
4 times daily. Therapeutic effects may require 4
6 weeks of continuous therapy. Powdered crude drug or extracts in capsules, tablets, teas, syrups, fluid extracts. Store in a well-closed container, protected from light. Daily dosage: 2
3 g powdered crude drug or equivalent preparations.

Treatment of climacteric symptoms such as hot flushes, profuse sweating, sleeping disorders, and nervous irritability.

Treatment of chronic congestive heart failure stage II, as defined by the New York Heart Association.

As a prophylactic and restorative tonic for enhancement of mental and physical capacities in cases of weakness, exhaustion and tiredness, and during convalescence.

(Continued)

Table 9.2 Summary of WHO Monographs on Selected Medicinal Plants Vol. 2 Supported by Clinical Data Continued Geographical Distribution

Dosage Forms/Posology

Uses Supported by Clinical Data

Cortex Frangulae

Indigenous to Mediterranean countries and temperate regions of Africa, western Asia, and Europe.

Short-term treatment of occasional constipation. As a single dose, for total intestinal evacuation before X-rays and other diagnostic examinations when electrolyte solutions alone are insufficient for adequate evacuation or the use of electrolyte solutions is not possible.

Folium et Cortex Hamamelidis

Indigenous to the Atlantic coast of North America, found in damp woods ranging from Nova Scotia to Florida and as far west as Texas.

Finely cut and powdered crude drug, powder, dried extract, liquid and solid preparations. Store in a tightly closed, light-resistant container for a maximum of 3 years. The correct dosage for the treatment of occasional constipation is the smallest dosage necessary to maintain a soft stool. Daily dosage: 0.5
2.5 g crude drug taken directly or in a decoction; 0.5
2.5 mL 25% ethanol extract; all preparations standardized to contain 20
30 mg hydroxyanthracene derivatives calculated as glucofrangulin A; taken at bedtime, or in two divided doses, one in the morning and one at bedtime. Dried leaves and bark for decoctions; steam distillate, ointment, and suppositories. Fresh leaves and twigs are collected in the spring and early summer to make a steam distillate. Store in a wellclosed container, protected from light. External use: Steam distillate, undiluted or diluted 1:3 with water to make poultices; 20%
30% in semisolid preparations. Extracts: In semisolid and liquid preparations corresponding to 5%
10% of the crude drug. Crude drug: Decoctions from 5
10 g to 1 cup (250 mL) water for poultices and wound irrigation. Rectal suppositories: 1
3 times daily the quantity of a preparation corresponding to 0.1
1.0 g crude drug, use Hamamelidis water undiluted or diluted 1:3 with water. Other preparations: Several times daily, corresponding to 0.1
1.0 g drug in preparations, or witch hazel water undiluted or diluted with water.

Topically for minor skin lesions, bruises and sprains, local inflammation of the skin and mucous membranes, hemorrhoids, and varicose veins.

Semen Hippocastani

Indigenous to western Asia, is now widely cultivated in parks, gardens, and along city streets of many countries worldwide, including those in Europe, and the United States.

Herba Hyperici

Indigenous to northern Africa, South Africa, South America, Asia, Australia, Europe and New Zealand, and is naturalized in the United States of America. The plant material is harvested at flowering time.

Aetheroleum Melaleucae Alternifoliae

Indigenous to Australia, where it is grown commercially.

Folium Melissae

Indigenous to western Asia and the eastern Mediterranean region, and is cultivated in central, eastern and western Europe, and the United States.

Crude drug and extracts. Store away from light and humidity. Daily dosage: 250.0
312.5 mg twice daily of a standardized powdered extract of the crude drug (equivalent to 100 mg aescin) containing 16%
20% triterpene glycosides, calculated as aescin; topical gels containing 2% aescin. Dried crude drug for decoction, powdered drug or extracts in capsules, tablets, tinctures and drops. Topical preparations include the oil, infusions, compresses, gels, and ointments. Store in a well-closed container, protected from light. Daily dosage: 2
4 g crude drug. Internal use: Standardized tinctures or fluid extracts, or standardized hydroethanolic or dried hydromethanolic extracts, up to a daily dose of 900 mg extract (equivalent to 0.2
2.7 mg total hypericin). Essential oil. Store in a well-filled, airtight container, protected from heat and light. External application of the essential oil at concentrations of 5%
100%, depending on the skin disorder being treated.

Comminuted crude drug; powder, tea bags, dried and fluid extracts for infusions and other galenical preparations. Store in a tightly closed container, protected from light. Do not store in plastic containers. Daily dosage for oral administration (for gastrointestinal disorders and as a sedative for nervous disturbances of sleep). Infusion: 1.5
4.5 g crude drug per cup several times daily as needed; 45% alcohol extract (1:1): 2
4 mL three times daily; tincture (1:5 in 45% alcohol): 2
6 mL three times daily.

Internally, for treatment of symptoms of chronic venous insufficiency, including pain, feeling of heaviness in the legs, nocturnal calf-muscle spasms, itching, and edema. Externally, for the symptomatic treatment of chronic venous insufficiency, sprains, and bruises. Symptomatic treatment of mild and moderate depressive episodes (classified as F32.0 and F32.1, respectively), in the International Statistical Classification of Diseases and Related Health Problems, Tenth revision (ICD-10).

Topical application for symptomatic treatment of common skin disorders such as acne, tinea pedis, bromidrosis, furunculosis, and mycotic onychia (onychomycosis), and of vaginitis due to Trichomonas vaginalis or Candida albicans, cystitis and cervicitis. Externally, for symptomatic treatment of herpes labialis.

(Continued)

Table 9.2 Summary of WHO Monographs on Selected Medicinal Plants Vol. 2 Supported by Clinical Data Continued Geographical Distribution

Dosage Forms/Posology

Uses Supported by Clinical Data

Daily dosage for topical application (for herpes labialis). Cream containing 1% of a lyophilized aqueous extract applied 2
4 times daily from the appearance of prodromal signs to a few days after the healing of the lesions, for a maximum of 14 days. Aetheroleum Menthae Piperitae

Commercially cultivated in eastern and northern Europe and the United States, and is found in Africa.

Oleum Oenotherae Biennis

Indigenous to Europe and is naturalized in North America.

Essential oil, concentrated peppermint emulsion, peppermint spirit and other galenic preparations. Store in a well-closed container, protected from light. Internal use For digestive disorders, daily dosage: 0.2
0.4 mL essential oil three times daily in dilute preparations or suspensions. By inhalation: 3
4 drops essential oil in hot water. Lozenges: 2
10 mg essential oil per lozenge. For irritable bowel syndrome, daily dosage: 0.2
0.4 mL essential oil three times daily in enteric-coated capsules. External use 5%
20% essential oil in dilute, semisolid or oily preparations; 5%
10% essential oil in aqueous-ethanol; nasal ointments containing 1%
5% crude drug. Fixed oil, neat or in capsule form. Store in a well-filled, airtight glass container, protected from heat and light. Daily dosage: 320
480 mg fixed oil (calculated as g-linolenic acid) in divided doses for atopic eczema, and 240
320 mg in divided doses for mastalgia.

Internally for symptomatic treatment of irritable bowel syndrome, and digestive disorders such as flatulence and gastritis. Externally for treatment of myalgia and headache.

Internally for symptomatic treatment of atopic eczema, diabetic neuropathy, and mastalgia. Clinical evidence for its use in the treatment of rheumatoid arthritis is conflicting, as are the results of trials in women with premenstrual syndrome. Further well-designed clinical trials are needed to clarify these data. The results from clinical trials do not support the use of Oleum Oenotherae Biennis for the treatment of climacteric symptoms or psoriasis.

Rhizoma Piperis Methystici

Cortex Rhamni Purshianae

Indigenous to and cultivated in the islands of Oceania, from Hawaii to Papua New Guinea, with the notable exception of New Caledonia, New Zealand and most of the Solomon Islands. Found in mountain forests of equatorial Africa including Angola, Cameroon, Ethiopia, Ghana, Kenya, Madagascar, Malawi, Mozambique, Republic of Congo, South Africa, Uganda, United Republic of Tanzania, Zambia and Zimbabwe. Indigenous to south-western Canada and the Pacific north-west of the United States.

Fructus Serenoae Repentis

Indigenous to the south-east of the United States of America, from South Carolina to Florida.

Cortex Pruni Africanae

Comminuted crude drug and extracts for oral use. Store in a tightly closed container, away from light. Daily dosage: Crude drug and extracts equivalent to 60
210 mg kava pyrones. Lipophilic extract of the crude drug. Store in a cool, dry place. Daily dosage: 75
200 mg lipidosterolic extract of the crude drug, in divided doses. To minimize gastrointestinal disturbances, take with food or milk. Finely cut crude drug, powder, dried extracts, extract, fluid extract, other liquid and solid preparations. Store in a tightly sealed, light-resistant container. The correct dosage for the treatment of occasional constipation is the smallest dosage necessary to maintain a soft stool. Daily dosage: 0.3
1.0 g crude drug in a single dose; all preparations standardized to contain 20
30 mg of hydroxyanthracene derivatives calculated as cascaroside A; taken at bedtime, or in two divided doses, one in the morning and one at bedtime. Crude drug, lipidosterolic extracts (nhexane, 90% ethanol or fluid [carbon dioxide] supercritical extracts standardized to contain 70%
95% free fatty acids and corresponding ethyl esters), and preparations thereof. Store in a tightly closed container in a cool, dry place. Daily dosage: 1
2 g crude drug or 320 mg (as a single dose or 160 mg twice daily) of a lipidosterolic extract (n-hexane, 90% ethanol or supercritical fluid [carbon dioxide] extract standardized to contain between 70% and 95% free fatty acids and corresponding ethyl esters), or equivalent preparations.

Short-term symptomatic treatment of mild states of anxiety or insomnia, due to nervousness, stress, or tension.

Treatment of lower urinary tract symptoms of benign prostatic hyperplasia (BPH) Stages I and II, as defined by Alken (e.g., nocturia, polyuria, and urinary retention), in cases where diagnosis of prostate cancer is negative. Short-term treatment of occasional constipation.

Treatment of lower urinary tract symptoms (nocturia, polyuria, urinary retention) secondary to BPH Stages I and II, as defined by Alken, in cases where diagnosis of prostate cancer is negative.

(Continued)

Table 9.2 Summary of WHO Monographs on Selected Medicinal Plants Vol. 2 Supported by Clinical Data Continued Geographical Distribution

Dosage Forms/Posology

Uses Supported by Clinical Data

Fructus Silybi Mariae

Indigenous to North Africa, Asia Minor, southern Europe, and southern Russian Federation; naturalized in North and South America, Australia, China, and Central Europe.

Supportive treatment of acute or chronic hepatitis and cirrhosis induced by alcohol, drugs, or toxins.

Herba Tanaceti Parthenii

Indigenous to south-east Europe, as far east as the Caucasus, but commonly found throughout Europe and the United States.

Radix Urticae

Urtica dioica is indigenous to Africa and western Asia, but is now found in all temperate regions of the world in Africa, North and South America, Asia, Australia, and Europe. Owing to the difficulty in botanical differentiation between Urtica dioica and U. urens in the wild, they are often harvested together. Although both species have a similar distribution, U. urens has become less widely distributed due to the reduction of its habitat.

Usually standardized extracts for phytomedicine; crude drug for decoction. Store in a well-closed container, protected from light and humidity. Daily dosage: 12
15 g crude drug; 200
400 mg silymarin, calculated as silybin, in standardized preparations. A parenteral preparation, silybin hemisuccinate sodium salt, is available in Germany for treatment of poisoning due to ingestion of Amanita phalloides. The total dosage is 20 mg/kg body weight, given as four infusions over a 24-h period, with each dose administered over a 2-h period. Crude drug for decoction; powdered drug or extracts in capsules, tablets, tinctures and drops. Store in a well-closed container, protected from light and humidity. Daily dosage: Encapsulated crude drug equivalent to 0.2
0.6 mg parthenolide (as a chemical marker) for prevention of migraine. Crude drug for infusion; hydroalcoholic extracts. Store in a well-closed container, protected from light and humidity. Daily dosage: 4
6 g crude drug or equivalent preparations as an infusion; 600
1200 mg dried 20% methanol extract (5: 1); 1.5
7.5 mL 45% ethanol extract (1: 1); 5 mL 40% ethanol extract (1: 5).

Prevention of migraine. Although Herba Tanaceti Parthenii has been used for treatment of rheumatoid arthritis, a clinical study failed to prove any beneficial effects.

Symptomatic treatment of lower urinary tract disorders (nocturia, polyuria, urinary retention) resulting from BPH Stages I and II, as defined by Alken, in cases where diagnosis of prostate cancer is negative.

9.4 WHO MONOGRAPHS ON SELECTED MEDICINAL PLANTS

283

isoenzymes such as CYP3A4 and CYP1A2 (Henderson et al., 2002). It is likely that more than one chemical constituent in a botanical drug or the active constituents may not be identifiable, and standards in vivo bioavailability and pharmacokinetic studies that measure the blood or urine concentration of the active moieties or active metabolites may be difficult or impossible to perform (FDA, 2016). Drug interactions of herbal medicines should be examined and collecting drug interaction information in post marketing surveillance is important. Herbal medicines are believed to be safe because they are derived from natural sources, but all medicines carry a risk. Because a number of cases of hepatotoxicity connected to Rhizoma Cimicifugae Racemosae (commonly known as Black Cohosh, root) listed in Volume 2 was reported in the European Union, EMA evaluated the connection of herbal medicinal products containing Black Cohosh and hepatotoxicity. In conclusion, the connection of herbal medicinal products containing Black Cohosh and hepatotoxicity should be seen as a signal. In addition, EMA advise patients that if they develop signs and symptoms suggestive of liver injury (fatigue, loss of appetite, yellowing of the skin and eyes, or severe upper abdominal pain with nausea and vomiting or dark urine), they should stop taking herbal medicinal products containing Black Cohosh and consult their doctor immediately (EMEA, 2007). In 2002 the FDA cautioned that there are potential risks of severe liver injury associated with the use of supplements, containing kava (Rhizoma Piperis Methystici listed in Volume 2). Products containing kava have been associated with rare liver injuries in Western countries, and the FDA is investigating the relationship between the usage of kava containing supplements and liver injury and trying to determine a biological explanation and identify the different source of kava that causes liver injury in the United States and the European Union (Teschke and Schulze, 2010). Recognizing that there are risks in the use of herbal medicines, the latest regulatory information should be paid attention for safe use of herbal medicines.

9.4.3 VOLUME 3 Volume 3 was published in 2002 and consists of 31 monographs (WHO, 2002). In the monograph, those in the first category supported by clinical data are shown in Table 9.3. Nine of thirty-one monographs have medical uses supported by clinical data. In Volume 3, pediatric doses are provided in Radix Ipecacuanhae. Plants from all over the world are listed in Volume 3 as well as Volumes 1 and 2, and there are plants used in India containing Ayurvedic medicine, such as Gummi Gugguli, Folium Azadirachti, and Oleum Azadirachti. Various herbs are commonly used as an alternative medicine for dysmenorrhea, which is a painful gynecological complaint, but scientific assessment is necessary for their effectiveness. The effectiveness of Semen Trigonellae Foenugraeci (fenugreek) listed in Volume 3, and Rhizoma Zingiberis (ginger) listed in Volume 1, and Folium Guavae (guava) listed in Volume 4 for primary dysmenorrhea were evaluated regarding pain scores or rates of pain relief. There was very limited evidence of effectiveness for fenugreek and ginger, and there is no consistent evidence of effectiveness for guava (Pattanittum et al., 2016).

9.4.4 VOLUME 4 Volume 4 was published in 2009 and consists of 28 monographs (WHO, 2009). In the monograph, those in the first category supported by clinical data are shown in Table 9.4.

Table 9.3 Summary of WHO Monographs on Selected Medicinal Plants Vol. 3 Supported by Clinical Data Geographical Distribution

Dosage Forms/Posology

Uses Supported by Clinical Data

Fructus Ammi Majoris

Indigenous to Egypt, and widely distributed in Europe, the Mediterranean region and western Asia. Cultivated in India.

Treatment of skin disorders such as psoriasis and vitiligo (acquired leukoderma).

Folium Azadirachti

Indigenous to India, and widely distributed in South and Southeast Asia. Cultivated in Africa, the South Pacific Islands, South and Central America and Australia, and in southern Florida and California in the United States.

Oleum Azadirachti

Indigenous to India, and widely distributed in South and Southeast Asia. Cultivated in Africa, the South Pacific Islands, South and Central America and Australia, and in southern Florida and California in the United States. Indigenous to Bangladesh, India, and Pakistan.

Powdered dried fruits for oral use. Store in a tightly sealed container away from heat and light. Average daily dose: Fructus Ammi Majoris 0.02
0.04 g orally in divided doses (dosage schedule not specified); xanthotoxin 0.25
0.7 mg/kg bw. Clinical treatment requires management by a healthcare provider. Dried leaves for infusions and decoctions, and extracts and tinctures. Store leaves in a cool, dry place. Infusion (1:20): 15
30 mL. Tincture (1:5): 4
8 mL. External applications: 70% ethanol extract of the leaves diluted to 40%, apply twice daily. Oil. Store in a tightly sealed container away from heat and light. Dose: 1.0
5.0 mL of oil for intravaginal applications.

Gummi Gugguli

Powdered oleo-gum resin; petroleum ether or ethyl acetate extracts of the oleo-gum resin; other galenical preparations. Store in a tightly sealed container away from heat and light. Average daily dose: Oleo-gum resin 3
4.5 g in two or three divided doses; petroleum ether extracts of the oleo-gum resin 500 mg two or three times.

External applications for treatment of ringworm. However, data from controlled clinical trials are lacking.

As a contraceptive for intravaginal use, as a mosquito repellent, and for treatment of vaginal infections. However, further controlled clinical trials are needed before the oil can be recommended for general use. Treatment of hyperlipidemia and hypercholesterolemia. Clinical investigations to assess the use of extracts of the oleo-gum resin for the treatment of obesity were negative.

Radix Harpagophyti

Indigenous to the Kalahari desert and savannas of Angola, Botswana, Namibia, and South Africa, being found southwards from central Botswana.

Radix Ipecacuanhae

Indigenous to Brazil and Central America.

Aetheroleum Lavandulae

Indigenous to the northern Mediterranean region. Cultivated in southern Europe, and in Bulgaria, Russian Federation, the United States, and the former Yugoslavia.

Dried roots for decoctions and teas; powdered roots or extract in capsules, tablets, tinctures, and ointments. Store in a well-closed container, protected from light. Daily dose: For loss of appetite 1.5 g of the roots in a decoction, 3 mL of tincture (1:10, 25% ethanol); for painful arthrosis or tendonitis 1.5
3 g of the roots in a decoction, three times, 1
3 g of the roots or equivalent aqueous or hydroalcoholic extracts. Dried roots and rhizomes, liquid extracts, fluid extract, syrup, and tincture. Dried roots and rhizomes should be stored in a tightly sealed container, protected from light. As an emetic in cases of poisoning other than corrosive or petroleum-based products. Doses should be followed by ingestion of copious volumes of water. Doses may be repeated once, 20
30 min after the initial administration, if emesis has not occurred. Adults: Ipecac syrup, 15
30 mL (21
42 mg total alkaloids). Children: 6 months
1 year, 7
14 mg of total alkaloids (5
10 mL) of Ipecac Syrup; older children, 21 mg of total alkaloids represented in 15 mL Ipecac Syrup. Essential oil. Store in a well-closed container, in a cool, dry place, and protected from light. Essential oil by inhalation, 0.06
0.2 mL three times per day; internally, 1
4 drops (approximately 20
80.0 mg) on a sugar cube per day.

Treatment of pain associated with rheumatic conditions.

A syrup made from the roots is used as an emetic, to empty the stomach in cases of poison ingestion.

Inhalation therapy for symptomatic treatment of anxiety, restlessness, and to induce relaxation. Externally in balneotherapy for the treatment of circulation disorders.

(Continued)

Table 9.3 Summary of WHO Monographs on Selected Medicinal Plants Vol. 3 Supported by Clinical Data Continued Geographical Distribution

Dosage Forms/Posology

Uses Supported by Clinical Data

Testa Plantiginis

Indigenous to Asia and the Mediterranean countries. Cultivated extensively in India and Pakistan; adapts to western Europe and subtropical regions.

Dried seed coats available commercially as chewable tablets, granules, wafers, and powder. Store in a well-closed container, in a cool dry place, and protected from light. The section of Posology described “No information available”.

Semen Trigonellae Foenugraeci

Indigenous to the Mediterranean region, China, India, and Indonesia. Cultivated in these countries.

Dried seeds, extracts, fluid extracts, and tinctures. Store in a tightly sealed container away from heat and light. Average daily dose. Internal use, cut or crushed seed, 6 g, or equivalent of preparations; infusion, 0.5 g of cut seed macerated in 150 mL cold water for 3 h, several cups; fluid extract 1:1 (g/mL), 6 mL; tincture 1:5 (g/mL), 30 mL; native extract 3
4:1 (w/w), 1.5
2 g. External use: Bath additive, 50 g of powdered seed mixed with 250 mL water, added to a hot bath; poultice, semisolid paste prepared from 50 g of powdered seed per liter of hot water, apply locally.

A bulk-forming laxative used therapeutically for restoring and maintaining bowel regularity. Treatment of chronic constipation, temporary constipation due to illness or pregnancy, irritable bowel syndrome, and constipation related to duodenal ulcer or diverticulitis. Also indicated for stool softening in the case of hemorrhoids, or after anorectal surgery. As a dietary supplement in the management of hypercholesterolemia, to reduce the risk of coronary heart disease, and reduce the increase in blood sugar levels after eating. As an adjunct for the management of hypercholesterolemia, and hyperglycemia in cases of diabetes mellitus. Prevention and treatment of mountain sickness.

Table 9.4 Summary of WHO Monographs on Selected Medicinal Plants Vol. 4 Supported by Clinical Data Geographical Distribution

Dosage Forms/Posology

Uses Supported by Clinical Data

Fructus Agni Casti

Native to the Mediterranean region and Asia. Cultivated in warm temperate regions of the world, and obtained primarily from Mediterranean countries, especially Albania and Morocco.

Orally for the symptomatic treatment of gynecological disorders including corpus luteum insufficiency and hyperprolactinemia, premenstrual syndrome, menstrual irregularities, cyclic mastalgia, and also to treat hormonally induced acne.

Gummi Boswellii

Native to India.

Semen Cucurbitae

Native to North America and cultivated worldwide.

Crude drug, extracts, fluid extracts, tinctures, and infusions. The dried berries should be stored in airtight nonplastic containers and protected from light, heat, moisture, and insect infestation. Dry native extract: 8.3
12.5:1 (w/w), approximately 1.0% casticin: 1 tablet containing 2.6
4.2 mg native extract, swallowed whole with some liquid each morning. Dry native extract: 9.58
11.5:1 (w/w): 1 tablet containing 3.5
4.2 mg native extract each morning with some liquid. Dry native extract: 6.0
12.0:1 (w/w), approximately 0.6% casticin. For premenstrual syndrome: 1 tablet containing 20 mg native extract daily with water. Fluid extract: 1:1 (g/mL), 70% alcohol (V/V): 0.5
1.0 mL. Tincture: Ethanol 58% (100 g of aqueous alcoholic solution contains 9 g of 1:5 tincture): 40 drops, once daily with some liquid each morning. Tincture: Ethanol 53% (10 g of the solution contains 2 g crude drug mother tincture): 30 drops twice daily. Tablet: Containing 162 mg of crude drug mother tincture (1:10 with 62% ethanol), twice daily. Hydroalcoholic extracts (50%
70% V/V): Corresponding to 30
40 mg dried fruit. Crude drug, extracts. Crude drug: 1
3 g daily (frequency not specified). Extracts: 300
350 mg three times daily. Crude drug and extracts. Oral daily dose: 10 g of seed; equivalent preparations.

Orally for the management of arthritis, bronchial asthma, Crohn’s disease, and ulcerative colitis. For symptomatic treatment of difficulties with micturition associated with Stages I and II prostatic adenoma and irritable bladder. (Continued)

Table 9.4 Summary of WHO Monographs on Selected Medicinal Plants Vol. 4 Supported by Clinical Data Continued Geographical Distribution

Dosage Forms/Posology

Uses Supported by Clinical Data

Folium Cynarae

Native to the Mediterranean, northern Africa and southern Europe, and the Canary Islands; cultivated in subtropical regions.

Treatment of digestive complaints (e.g., dyspepsia, feeling of fullness, flatulence, nausea, stomach ache, and vomiting). Adjunct treatment of mild-to-moderate hypercholesterolemia.

Folium Guavae

Native to tropical America, but now pantropical.

Lichen Islandicus

Grows in northern, eastern and central Europe, Siberia, and North America.

Fructus Macrocarponii

Native to eastern North America.

Crude drug, extracts and other galenical preparations for internal use. Average oral daily dose: For hypercholesterolemia and dyspepsia, 1
2 g of a dried aqueous extract. Adult daily dose: 5
10 g of crude drug; or equivalent preparations. Crude drug, decoctions, extracts, and teas. As a mouthwash: 15 mL of aqueous extract three times daily for at least 1 min per session. For diarrhea: 500 mg of the powdered leaf three or four times daily. Crude drug, extracts, fluidextract, infusion, and tinctures. As a demulcent to treat inflammation and dryness of the pharyngeal mucosa: Comminuted herb for infusions and other galenical formulations for internal use. For loss of appetite: Comminuted herb, cold macerates for internal use. Average daily dosage: 4
6 g of herb in divided doses, or equivalent preparations. Infusion: 1.5 g of crude drug in 150 mL water. Fluid extract 1:1 (g/mL): 4
6 mL. Tincture 1:5 (g/mL): 20
30 mL. Crude drug, extracts, juice, tablets, capsules. Store in a well-closed container, in a refrigerator. For the prevention of UTIs in adults the recommended daily dose of cranberry juice is 30
300 mL of a 30% pure juice product; for the treatment of UTIs in adults the daily dosage range is 360
960 mL or equivalent. Capsules containing a concentrated cranberry extract: 1
6 capsules daily, equivalent to 3 fluid ounces (90 mL) cranberry juice or 400
450 mg cranberry solids.

Oral treatment of acute diarrhea, gingivitis, and rotaviral enteritis.

Used orally as a demulcent to treat inflammation and dryness of the pharyngeal mucosa.

Orally as adjunct therapy for the prevention and symptomatic treatment of urinary tract infections in adults. Two clinical trials have assessed the effect of the fruit juice in pediatric populations, but the results were negative. Results from clinical trials involving the use of cranberry for the treatment of children with neurogenic bladder were also negative and do not support the use of cranberry products in pediatric populations.

Fructus Myrtilli

Found in Europe and in the North American Rocky Mountains.

Cortex Salicis

Native to Europe and Asia, and naturalized in North America.

Radix Withaniae

Widespread from the Mediterranean coast to India in semiarid habitats.

Crude drug, extracts, tablets, and capsules. Internal: Daily dosage of crude drug 20
60 g. Extracts: 80
160 mg of extract standardized to 25% anthocyanosides (three times daily). The dose of anthocyanosides is 20
40 mg three times daily. External: 10% decoction; equivalent preparations. Crude drug, dried hydroalcoholic or aqueous extracts, tinctures, and fluid extracts. Adult oral daily dose: Extracts, tinctures, or fluid extracts equivalent to 120
240 mg of total salicin, or 6
12 g of powdered drug material as a decoction (corresponding to 120
240 mg of total salicin) in two divided doses. Crude drug, extracts and tinctures. Powdered crude drug: 3
6 g of the dried powdered root. Orally as an antistress agent: 250 mg twice daily.

Oral use for the symptomatic treatment of dysmenorrhea associated with premenstrual syndrome, circulatory disorders in patients with capillary leakage or peripheral vascular insufficiency and ophthalmic disorders. Used orally for the symptomatic treatment of fever and pain, and symptomatic treatment of mild rheumatic conditions.

As an antistress agent to improve reaction time.

290

CHAPTER 9 ETHNO-PHARMACEUTICAL FORMULATIONS

Ten of twenty-eight monographs have medical uses supported by clinical data. In Volume 4, there were no plants provided for pediatric dosage. Plants from all over the world are listed in Volume 4 as well as Volumes 1, 2, and 3. Gummi Boswellii, listed in Volume 4 consists of the dried gum resin of Boswellia serrata. Boswellia serrata is one of the ancient and most valued herbs in Ayurveda. Gum resin extracts of Boswellia serrata have been traditionally used in folk medicine for centuries to treat various chronic inflammatory diseases described in “uses supported by clinical data” (Table 9.4). The Indian government promotes the fact that Indian traditional medicine Ayurveda is based on science (Pulla, 2014). Scientific assessment of traditional medicine is important for effective and safe usage of traditional medicines. Cranberries, listed as Fructus Macrocarponii, in Volume 4 have been widely used for the prevention and treatment of urinary tract infections (UTIs) for decades. In 2002, a meta-analysis showed that cranberry products did not significantly reduce the occurrence of symptomatic UTI (RR 0.86, 95% CI 0.71
1.04) compared to placebo. Although several small studies have shown small benefits for women with recurrent UTIs, there were no statistically significant differences when the results of a much larger study were included. It is concluded at this time that cranberry juice cannot be recommended for the prevention of UTIs (Jepson et al., 2012).

9.4.5 COMMONLY USED IN THE NEWLY INDEPENDENT STATES Due to economic reasons, access to conventional medicines is limited in Newly Independent States (NIS) (Armenia, Azerbaijan, Belarus, Georgia, Kazakhstan, Kyrgyzstan, Republic of Moldova, Russian Federation, Tajikistan, Turkmenistan, Ukraine, Uzbekistan), monographs for NIS were issued in 2010 (WHO, 2010). This monograph consists of 30 monographs, which are selected monographs from Volumes 1, 2, 3, and 4, and newly added 13 monographs. In the newly added monographs, those in the first category supported by clinical data are shown in Table 9.5. Nine of thirteen monographs newly added in NIS have medical uses supported by clinical data. Among the plants newly added in NIS, there were no plants provided for pediatric dosage. Folium cum Flore Crataegi, Hawthorn Leaf and Flower listed in NIS is used for treatment of chronic congestive heart failure Stage II, as defined by the New York Heart Association. A metaanalysis of 10 clinical trials including 855 patients with chronic heart failure suggest that there was a significant benefit in symptom control and physiologic outcomes from use of hawthorn extract as an adjunctive treatment for patients with chronic heart failure (Pittler et al., 2008). It is necessary to review the latest information to use herbal medicines effectively and safely.

9.5 EUROPEAN UNION MONOGRAPH In the European Union, European Medicines Agency (EMA)’s The Committee on Herbal Medicinal Products (HMPC) is creating monographs of herbal medicines. In monographs, herbal medicines with scientific efficacy and safety clinical trial data and at least 10 years of experience in the European Union are classified as “well-established use.” At least one high-quality clinical trial is required for evaluating the efficacy of herbal medicines classified as “well-established use” (EMA). The herbal medicines classified in this category are shown in Table 9.6.

Table 9.5 Summary of WHO Monographs on Selected Medicinal Plants NIS (Newly Added Monographs) Supported by Clinical Data Herba Bidentis

Herba Chelidonii

Folium cum Flore Crataegi

Geographical Distribution

Dosage Forms/Posology

Uses Supported by Clinical Data

Indigenous to damp and temperate regions near fresh water sources throughout Asia, Africa, Australia, Europe, North America, and New Zealand. The plant is found in the damp regions of newly independent states, such as in Northern Siberia and the southern part of the far east region. Indigenous to all of Europe and to the temperate and subarctic regions of Asia, and northern Africa. Found widely in Caucasia and the European part of newly independent states, rare in Siberia and the Far East.

An herbal tea or a briquette of Herba Bidentis. Internal use. One tablespoon of the infusion (1:20) is administered 3
4 times a day. External use as a bath. One glass of an infusion of 10 g of cut herb together with 100 g of cooking salt or sea salt per bath. Crude drug, powdered drug for infusions, tablets containing 4 mg total alkaloids. Internal use. 1
2 tablets each containing 4 mg total alkaloids three times a day; 2
5 g herb, equivalent to 12
30 mg of total alkaloids calculated as chelidonine. External use as a bath. An infusion from two tablespoonfuls of the cut herb added to 500 mL of water per bath. Crude drug for infusion and hydroalcoholic extracts. Store in a well-closed container, protected from light and moisture. Daily dosage: 160
900 mg dried 45% ethanol or 70% methanol extract (drug: extract ratio 4
7:1) standardized to contain 18.75% oligomeric procyanidins (calculated as epicatechin) or 2.2% flavonoids (calculated as hyperoside), respectively; 1.0
1.5 g comminuted crude drug as an infusion 3
4 times daily. Therapeutic effects may require 4
6 weeks of continuous therapy.

Internally used for treatment of chronic dysentery, and acute and chronic enteritis. Oral administration and simultaneous external application have been used in patients with psoriasis.

Common to the temperate areas of the northern hemisphere, including eastern areas of North America, parts of South America, east Asia, and Europe.

Used for the symptomatic treatment of mild-to-moderate spasms of the upper gastrointestinal tract, minor gallbladder disorders, and dyspeptic complaints such as bloating and flatulence.

Treatment of chronic congestive heart failure Stage II, as defined by the New York Heart Association.

(Continued)

Table 9.5 Summary of WHO Monographs on Selected Medicinal Plants NIS (Newly Added Monographs) Supported by Clinical Data Continued Geographical Distribution

Dosage Forms/Posology

Uses Supported by Clinical Data

Herba Equiseti

Distributed throughout the temperate zone of the northern hemisphere. Indigenous to all of America, Europe and North Africa, as well as parts of Asia. Found widely throughout the newly independent states region, with the exception of deserts, paramos, and the northern regions.

An open clinical trial has indicated a possible diuretic effect.

Fructus Hippophae¨s recens

Indigenous to Europe and some northern regions of Asia, it is widely distributed throughout the temperate regions of Asian countries. In the newly independent states, it is grown in the Caucasus and the Ural Federal District, in southern Siberia, and also in Altai and the Sayan Mountains. It is domesticated in various parts of the world.

Herba Leonuri

Indigenous to central and eastern Europe and Scandinavia and Central Asia; also found in Caucasia and western Siberia. It was introduced to North America and has become established in the wild. It is also cultivated.

Cut herb for infusions, decoctions, and other equivalent galenical preparations. For internal use. Average daily dose 6 g of herb as a decoction or infusion (1:5) given in divided doses three times daily. Fluid ethanol extract: 1:1 (g/mL), half a teaspoon (2 mL) two times daily. Tincture: 1:5 (g/ mL), 10 mL three times daily. For external use. To prepare a decoction for use in making a cataplasm or compress: Add 10 g of herb to 1 L of boiling water for direct application to the skin. As a bath additive: add 2 g of herb to 1 L of hot water and steep for 1 h, then add it to water in the bath. Fresh fruits and derived infusion, tincture, oil, fresh juice, and syrup. For internal use. Infusion: 40
50 g of the fresh fruit per liter of water, 2
3 cups per day. Tincture (1:5): 30
50 drops 1
3 times per day. Dosage of oil of Hippophae¨ fruit for internal use: one teaspoon 2
3 times daily, 30
40 min before meals. For external use. 5
10 mL of oil per tampon, used for wetting of tampons. Comminuted herb for infusions and other galenical preparations for internal use. The average daily dosage is 2
4.5 g of dried herb or equivalent preparations. For internal use. Infusion (2
4.5 g of dried herb in 150 mL boiled water for 10
15 min), one tablespoonful three times daily between meals. Tincture (1:5 in 45% ethanol) 2
6 mL, three times daily. Fluid extract (1:1 in 25% ethanol) 2
6 mL, three times daily.

The fruits of Hippophae¨ rhamnoides are used in the treatment of cirrhosis of the liver.

Positive cardiovascular effects have been reported in open clinical trials.

Herba Polygoni avicularis

Widespread in the temperate zones throughout the world. A common weed.

Folium Salviae

Indigenous to the whole Mediterranean region. Cultivated worldwide.

Ground herb for infusions and other galenical preparations for internal use and for local application. Daily dose: 4
6 g of drug; or equivalent preparations. For internal use. Infusion: to 3 tablespoons (15 g) of the herb, add 200 mL of boiling water and allow to stand for 15 min; divide 75 mL of the infusion into three parts and drink three times daily, 20
40 min before meals. A cup of tea is prepared by placing 1.5 g of the chopped drug into cold water, heating to boiling, and straining after 10 min, 3
5 times a day. Cut herb for infusions, ethanol extracts, and distillates for gargles, rinses, and other topical applications, as well as for internal use. In addition, the fresh plants may be pressed to yield a juice. Internal. Daily dose: 4 g of drug or equivalent preparations. Infusion: ne tablespoon of an infusion (4 g of the leaf) in 200 mL of boiling water, three times daily. Tincture: 75 drops of a tincture (1:10 in 55% or 70% ethanol), three times daily. Fluid extract: 1
4 mL (1:1 in 45% ethanol), three times daily. Dry extract: 160 mg of dry aqueous extract corresponding to 880 mg of drug, three times daily. For gargles and rinses. Infusion: 3 g of herb or 2
3 drops of essential oil in 150 mL of water. Tincture: 1:10 in 70% ethanol. Extract: 5 g of ethanol extract in 1 glass water. External. Cataplasm or irrigation: 30 g of cut herb in 200 mL of boiling water for 20 min, applied to affected area.

Used for the supportive treatment of gingivitis.

The management of mild-to-moderate Alzheimer disease.

(Continued)

Table 9.5 Summary of WHO Monographs on Selected Medicinal Plants NIS (Newly Added Monographs) Supported by Clinical Data Continued Styli cum stigmatis Zeae maydis

Geographical Distribution

Dosage Forms/Posology

Uses Supported by Clinical Data

Indigenous to Central America, it is now cultivated worldwide as green fodder or as a cereal crop.

Dried styles and/or stigmas used for infusion and other galenical preparations for topical applications, as well as for internal use. For internal use. Daily dosage of dried styles and/or stigmas, 4
8 g or infusion (4
8 g in 200 mL of boiling water), one tablespoon three times daily. Tincture (1:5) in 25% ethanol, 5
15 mL three times daily. Liquid extract of stigmas (1:1) in 25% ethanol, 4
8 mL three times daily. For external use: Cataplasm or bath, 4
5 tablespoons of stigmas in 400 mL (two glasses) of boiling water for 20 min applied to affected area or added to the bath water.

The stigmas and styles of Zea mays are used for the supportive treatment of chronic nephritis.

Table 9.6 Summary of European Union Monograph Classified as “Well-Established Use”

Indication Agni casti fructus (EMA, 2010a,c) Aloe (EMA, 2016b,c)

For the treatment of premenstrual syndrome.

Capsici fructus (EMA, 2015a,c)

For the relief of muscle pain such as low back pain.

Cimicifugae racemosae rhizome (EMA, 2018a,b)

For the relief of menopausal complaints (such as hot flushes and profuse sweating).

Echinaceae purpureae herba (EMA, 2015f, 2014b)

For the short-term prevention and treatment of common cold.

Frangulae cortex (EMEA, 2006; EMEA, 2007f)

For short-term use in cases of occasional constipation.

Ginkgo folium (EMA, 2015b, 2014a)

For the improvement of (age associated) cognitive impairment and of quality of life in mild dementia.

For short-term use in cases of occasional constipation.

Herbal Substances and/or Preparations Referred in the Monograph Herbal preparation Dry extract (drug extract ratio [DERa] 6
12:1), extraction solvent: ethanol 60% m/m Herbal preparation Dry extract (DER 1-3:1), extraction solvent: water, standardized to contain 28.6%
36.6% hydroxyanthracene derivatives, calculated as aloin (photometric method). Herbal preparations • Soft extract (DER 4
7:1), standardized to 2.0%
2.78% total capsaicinoids, extraction solvent ethanol 80% V/V • Soft extract (DER 1.5
2.5:1), extraction solvent ethanol 96% V/V • Soft extract (DER 11
30:1), extraction solvent propan-2-ol Herbal preparations • Dry extract (DER 5
10:1), extraction solvent ethanol 58% V/V • Dry extract (DER 4.5
8.5:1), extraction solvent ethanol 60% V/V • Dry extract (DER 6
11:1), extraction solvent propan-2-ol 40% V/V Herbal preparations • Expressed juice (1.5
2.5:1) • Dried juice corresponding to the expressed juice above Herbal substance Dried, whole, or fragmented bark of the stems and branches, standardized Herbal preparation Standardized herbal preparations there of Herbal preparation Dry extract (DER 35
67:1), extraction solvent: Acetone 60% m/m3

Dosage Form and Method of Administration/Posology, See Indicated References Herbal preparation in solid dosage form for oral use./ Posology, see EMA (2010c) Standardized herbal preparations in liquid or solid dosage forms for oral use./Posology, see EMA (2016b) Herbal preparation in a medicated plaster or in semisolid dosage forms for cutaneous use./ Posology, see EMA (2015a)

Herbal preparation in solid dosage forms for oral use./ Posology, see EMA (2018a)

Herbal preparations in solid or liquid dosage forms for oral use./ Posology, see EMA (2015f) Solid or liquid dosage forms for oral use./Posology, see European Medicines Agency (2006)

Herbal preparations in solid or liquid dosage forms for oral use./ Posology, see EMA (2015b) (Continued)

Table 9.6 Summary of European Union Monograph Classified as “Well-Established Use” Continued

Indication Hederae helicis folium (EMA, 2017d,e)

Used as an expectorant in case of productive cough.

Hippocastani semen (EMEA, 2009a,d)

For treatment of chronic venous insufficiency.

Hyperici herba (EMEA, 2009b,c)

For the treatment of mild-to-moderate depressive episodes (according to ICD-10).

For the short-term treatment of symptoms in mild depressive disorders. Lini semen (EMA, 2015d,e)

For the treatment of habitual constipation or in conditions in which easy defecation with soft stool is desirable.

Herbal Substances and/or Preparations Referred in the Monograph Herbal preparations • Dry extract (DER 4
8:1), extraction solvent ethanol 24%
30% m/m • Dry extract (DER 6
7:1), extraction solvent ethanol 40% m/m • Dry extract (DER 3
6:1), extraction solvent ethanol 60% m/m • Liquid extract (DER 1:1), extraction solvent ethanol 70% V/V • Soft extract (DER 2.2
2.9:1), extraction solvent ethanol 50% V/V: propylene glycol (98:2) Herbal preparations • Dry extracts (40%
80% V/V ethanol) standardized to contain 16%
28% triterpene glycosides, calculated as aescin (photometric method) • Extract (standardized to a content of 50 mg triterpene glycosides calculated as aescin) Herbal preparations • Dry extract (DER 3
7:1), extraction solvent methanol (80% V/V) • Dry extract (DER 3
6:1), extraction solvent ethanol (80% V/V) Herbal preparation Dry extract (DER 2.5
8:1), extraction solvent ethanol (50%
68% V/V) Herbal substance As defined in the Ph. Eur. Monograph.

Dosage Form and Method of Administration/Posology, See Indicated References Herbal preparations in solid or liquid dosage forms for oral use./ Posology, see EMA (2017d)

Herbal preparations in modified or immediate release dosage forms for oral use./Posology, see EMEA (2009d)

Herbal preparation in solid dosage forms for oral use./ Posology, see EMEA (2009b)

Herbal preparation in solid dosage forms for oral use./ Posology, see EMEA (2009b) Herbal substance for oral use./ Posology, see EMA (2015d)

Menthae piperitae aetheroleum (EMEA, 2007b, 2008c)

For the symptomatic relief of minor spasms of the gastrointestinal tract, flatulence, and abdominal pain, especially in patients with irritable bowel syndrome. For the symptomatic relief of mild tension type headache.

Plantaginis ovatae semen (EMA, 2013a,f)

For the treatment of habitual constipation.

Plantaginis ovatae Seminis tegumentum (EMA, 2013b,c)

In conditions in which easy defecation with soft stools is desirable, for example, in cases of painful defecation after rectal or anal surgery, anal fissures or hemorrhoids. For the treatment of habitual constipation.

In conditions in which easy defecation with soft stool is desirable, for example, in cases of painful defecation after rectal or anal surgery, anal fissures and hemorrhoids.

Psyllii semen (EMA, 2013d,e)

In patients to whom an increased daily fiber intake may be advisable, for example, as an adjuvant in constipation predominant irritable bowel syndrome, as an adjuvant to diet in hypercholesterolemia. For the treatment of habitual constipation.

In conditions in which easy defecation with soft stool is desirable, for example, in cases of painful defecation after rectal or anal surgery, anal fissures or hemorrhoids.

Herbal preparation Essential oil obtained by steam distillation from the fresh aerial parts of the flowering plant. Herbal preparation Essential oil obtained by steam distillation from the fresh aerial parts of the flowering plant Herbal substance Dried ripe seeds Herbal preparation Powdered herbal substance Herbal substance Dried ripe seeds Herbal preparation Powdered herbal substance Herbal substance Episperm and collapsed adjacent layers removed from the seeds. Herbal preparation Powdered herbal substance Herbal substance Episperm and collapsed adjacent layers removed from the seeds. Herbal preparation Powdered herbal substance Herbal substance Episperm and collapsed adjacent layers removed from the seeds Herbal preparation Powdered herbal substance Herbal substance Ripe, whole, dry seeds Herbal preparation Powdered herbal substance Herbal substance Ripe, whole, dry seeds Herbal preparation Powdered herbal substance

Gastro-resistant capsules for oral use./Posology, see EMEA (2007b) Liquid or semisolid preparation for cutaneous use./Posology, see EMEA (2007b) Solid dosage forms such as granules or powders for oral use./ Posology, see EMA (2013f) In solid dosage forms such as granules or powders for oral use./ Posology, see EMA (2013f) Solid dosage forms such as granules or powders for oral use./ Posology, see EMA (2013b)

In solid dosage forms such as granules or powders for oral use./ Posology, see EMA (2013b)

Solid dosage forms such as granules or powders for oral use./ Posology, see EMA (2013b)

In solid dosage forms such as granules or powders for oral use./ Posology, see EMA (2013d) Solid dosage forms such as granules or powders for oral use./ Posology, see EMA (2013e) (Continued)

Table 9.6 Summary of European Union Monograph Classified as “Well-Established Use” Continued

Indication Rhamni purshianae cortex (EMEA, 2007d, 2008b) Rhei radix (EMEA, 2007e, 2008a)

For short-term use in cases of occasional constipation.

Ricini oleum (EMA, 2016d,e)

Laxative for short-term use in cases of occasional constipation.

Salicis cortex (EMA, 2017b,c)

For the short-term treatment of low back pain.

Sennae folium (EMEA, 2006b, 2007a)

For short-term use in cases of occasional constipation.

Sennae fructus (EMEA, 2006a, 2007c)

For short-term use in cases of occasional constipation.

Thymi herba and Primulae radix (EMA, 2016f,g)

Used as an expectorant in case of productive cough.

For short-term use in cases of occasional constipation.

Herbal Substances and/or Preparations Referred in the Monograph Herbal substance Dried, whole or fragmented bark, standardized Herbal preparation Standardized herbal preparations thereof Herbal substance Whole or cut, dried underground parts, standardized Herbal preparation Standardized herbal preparations thereof Herbal preparation Fatty oil obtained from seeds of Ricinus communis L. by cold expression Herbal preparation Dry extract (8
14:1) extraction solvent ethanol 70% V/V, 15% total salicin Herbal substance Dried leaflets, standardized Herbal preparation Standardized herbal preparations thereof Herbal substance Dried fruits, standardized Herbal preparation Standardized herbal preparations thereof Herbal preparations • Liquid extract from Thyme (DER 1:2
2.5), extraction solvent ammonia solution 10% m/m: glycerol 85% m/m: ethanol 90% V/V: water (1:20:70:109) and tincture from Primula root (ratio of herbal substance to extraction solvent 1:5), extraction solvent ethanol 50% V/V • Liquid extract from Thyme (DER 1:2
2.5), extraction solvent ammonia solution 10% m/m: glycerol 85% m/m: ethanol 90% V/V: water (1:20:70:109) and liquid extract from Primula root (DER 1:2
2.5), extraction solvent ethanol 70% m/m • Dry extract from Thyme (DER 6
10:1), extraction solvent ethanol 70% V/V and dry extract from Primula root (DER 6
7:1), extraction solvent ethanol 47.4% V/V

Dosage Form and Method of Administration/Posology, See Indicated References Solid or liquid dosage forms for oral use./Posology, see EMEA (2007d) Solid or liquid dosage forms for oral use./Posology, see EMEA (2007e)

Liquid or solid dosage forms for oral use./Posology, see EMA (2016d) Solid dosage form for oral use./ Posology, see EMA (2017b) Solid or liquid dosage forms for oral use./Posology, see EMEA (2006b) Solid or liquid dosage forms for oral use./Posology, see EMEA (2006a) Herbal preparations in liquid or solid dosage forms for oral use./ Posology, see EMA (2016f)

Valerianae radix (EMA, 2016a,h)

Relief of mild nervous tension.

Sleep disorders.

Valerianae radix and Lupuli flos (EMA, 2011a, 2010b)

For the relief of sleep disorders.

Vitis viniferae folium (EMA, 2017a,f)

For treatment of chronic venous insufficiency, which is characterized by swollen legs, varicose veins, a feeling of heaviness, pain, tiredness, itching, tension, and cramps in the calves. For the prevention of nausea and vomiting in motion sickness.

Zingiberis rhizome (EMA, 2012a,b) a

Herbal preparations Dry extract (DER 3
7.s4:1), extraction solvent: ethanol 40%
70% V/V Herbal preparations Dry extract (DER 3
7.s4:1), extraction solvent: ethanol 40%
70% V/V Herbal preparations used in fixed combinations of • Dry extracts of valerian root (DER 4
8:1, methanol 45%
51% m/m) and hop strobiles (DER 3
10:1, methanol 40%
51% m/m) • Dry extracts of valerian root (DER 4
7:1, ethanol 70% V/V) and hop strobiles (DER 4
8:1, methanol 40% V/V) Herbal preparation Dry extract (DER 4
6:1); extraction solvent water.

Herbal preparation Powdered herbal substance

Solid dosage forms for oral use./ Posology, see EMA (2016h) Solid dosage forms for oral use./ Posology, see EMA (2016h) Solid or liquid dosage forms for oral use./Posology, see EMA (2011a)

Herbal preparation in solid dosage forms for oral use./ Posology, see EMA (2017f)

Herbal preparations in solid dosage forms for oral use./ Posology, see EMA (2012b)

DER means the ratio between the quantity of herbal substance used in the manufacture of an herbal preparation and the quantity of the herbal preparation obtained. The number (given as the actual range) written before the colon is the relative quantity of the herbal substance; the number written after the colon is the relative quantity of the herbal preparation obtained.

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Ten of twenty-six plants classified as well-established use (Capsici fructus, Hederae helicis folium, Lini semen, Plantaginis ovatae seminis tegumentum, Psyllii semen, Ricini oleum, Sennae fructus, Thymi herba and Primulae radix, Valerianae radix and Lupuli flos, Vitis viniferae folium) are also listed from Tables 9.1 to Table 9.5 of the WHO Monographs on Selected Medicinal Plants supported by clinical data. In 2012, the Medicines and Healthcare Products Regulatory Agency (MHRA) warned echinacea herbal products should not be used by children under 12 years old. Children under 12 could have a low risk of developing allergic reactions such as rushes and this outweighed any perceived benefits (MHRA, 2012). The use of herbal medicines for children should be done with care. Dozens of women who had taken Chinese herbs as part of a weight loss program experienced resultant kidney failure in the 1990s. Aristolochic acid, a natural ingredient of many traditional Chinese medicines (TCMs) as antiinflammatory agents was identified as the causative agent. Health Canada advised consumers not to use products containing aristolochic acid. Recently, as China issued a new draft guideline to scrap clinical trial requirements for TCMs based on classical recipes, clinical evaluation of traditional Chinese herbal remedies is suggested to satisfy efficacy and safety concerns (Traditinal Chinese medicine needs proper scrutiny, 2017). To use herbal medicines effectively and safely, it is important to use them with reference to evidence from clinical trials as well as European Union monographs classified as “well-established use.”

9.6 BOTANICAL DRUGS IN THE UNITED STATES In the United States, Veregen and Fulyzaq are approved as medicines. A summary of these approval contents is shown in Table 9.7. Veregen was approved as a medicine in October 2006. Antioxidant properties of green tea catechins are known, but the clinical significance of this property is unknown. Regarding efficacy, the response rate defined as the proportion of patients with complete clinical (visual) clearance of all external genital and perianal warts (baseline and new) by week 16 was assessed by a placebocontrolled randomized double-blind clinical trial. The response rate is significantly higher in the Veregen treatment group (53.6%) than the placebo group (35.3%). Regarding safety, there were three serious adverse events (SAEs) (less than 1%) related to the drug occurring in woman and consisting of local reactions. Most side effects reported with Veregen were mild-to-moderate skin and application site reactions. Fulyzaq was approved as a medicine in December 2012. The red latex of Croton lechleri Mull. Arg., also called dragon’s blood, is an herbal medicine commonly used for the treatment of diarrhea and for wound healing in South America. Regarding efficacy, the proportion of patients with a clinical response, defined as less than or equal to two watery bowel movements per week during at least 2 of the 4 weeks of the placebo-controlled phase, was assessed by a placebo-controlled randomized double-blind clinical trial. A significantly larger proportion of patients in the Fulyzaq treatment group experienced clinical response (17.6%) compared with patients in the placebo group (8.0%). Regarding safety, SAEs were an infrequent 3% (19/696) in the Fulyzaq group, and 2% (6/ 274) in the placebo group. There are no safety concerns with Fulyzaq.

9.7 HERBAL MEDICINAL PRODUCTS IN JAPAN

301

Table 9.7 Summary of Approved Botanical Drugs in the United States Brand Name

Description

Dosage and Administration

Indications and Usage

Veregen (FDA, 2012a)

Veregen (sinecatechins) Ointment, 15% is a botanical drug product for topical use. The drug substance in Veregen is sinecatechins, which is a partially purified fraction of the water extract of green tea leaves from Camellia sinensis (L.) O Kuntze, and is a mixture of catechins and other green tea components.

Veregen is a topical ointment indicated for the treatment of external genital and perianal warts (Condylomata acuminata) in immunocompetent patients 18 years and older.

Fulyzaq (FDA, 2012b)

It contains 125 mg of crofelemer, a botanical drug substance that is 95% derived from the red latex of Croton lechleri Mull. Arg.

• Veregen is to be applied three times per day to all external genital and perianal warts. • Apply about an 0.5 cm strand of ointment to each wart using the finger(s), dabbing it on to ensure complete coverage and leaving a thin layer of the ointment on the warts. • Veregen is not for ophthalmic, oral, intravaginal, or intraanal use. One 125 mg delayed-release tablet taken orally twice a day, with or without food.

Fulyzaq is an antidiarrheal indicated for the symptomatic relief of noninfectious diarrhea in adult patients with HIV/ AIDS on antiretroviral therapy.

9.7 HERBAL MEDICINAL PRODUCTS IN JAPAN Traditional herbal medicines in Japan are classified into two categories, which are Kampo products and non-Kampo crude drug products. Kampo products include ethical Kampo formulations and OTC Kampo formulations. Ethical Kampo formulation is listed in the National Health Insurance (NHI) price list and obtained through a doctor’s prescription with NHI reimbursement (Maegawa et al., 2014). OTC Kampo formulations can be purchased and used for self-medication in primary health care settings. Also non-Kampo crude drug products have been well regulated, since nonKampo crude drug products are no less important than Kampo medicines. Regarding Western herbal medicinal products, “Application Guideline for Western Traditional Herbal Medicines as OTC Drugs” was published in 2007 (MHLW, 2007), and two European ethno-pharmaceuticals have been approved as OTC drugs (PMDA, 2010; PMDA, 2014). A summary of these approval contents is shown in the Table 9.8. Antistax was approved as an OTC drug in January 2011. Red vine leaf extract is categorized under “well-established use” in the EMA monograph as Vitis viniferae folium (Table 9.6). Grapevine leaves and extract have been traditionally used for the treatment of symptoms associated with venous insufficiency for more than 70 years in France (EMA, 2017a). Regarding efficacy, changing the limb volume using water displacement after 12 weeks administration was assessed by a placebo-controlled randomized double-blind multicenter clinical trial. The limb volume decreased significantly in the Antistax treatment group (
42.2 6 74.6 g) compared with the placebo group (133.7 6 96.1 g). Regarding safety, in the clinical trial for non-Japanese, the side effects observed

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CHAPTER 9 ETHNO-PHARMACEUTICAL FORMULATIONS

Table 9.8 Summary of Approved European Herbal Medicinal Products as Pharmaceuticals in Japan Brand Name Antistax

Prefemin

Dosage and Administration

Indications

Antistax, containing 360 mg of red vine leaf extract (2 capsules) as a daily dose. Two capsules once a day for persons over 20 years old. Prefemin containing 20 mg of chest berry extract (1 tablet) as a daily dose. One tablet once a day for persons over 18 years old

It is indicated for swelling of the lower legs, ankles and heavy, achy, tired legs associated with venous disorder caused by long periods of standing or sitting. It is indicated for mitigation of premenstrual syndrome (PMS): breast swelling, headache, irritation, and mood swings.

in this drug group were mild in 2 cases (2.3%, 2/87 cases). In the clinical trial for Japanese, side effects observed were mild in 12 cases (6.7%, 12/180 cases) and were recovering or recovered. Prefemin was approved as an OTC drug in April 2014. Chest berry 60% ethanol dry extract is categorized under “well-established use” in the EMA monograph as Agni casti fructus (Table 9.6). Regarding efficacy, the changes from the baseline to the end of administration of the visual analog scale (VAS) a total score of 6 symptoms (irritated feelings, dysthymia, anger, headache, breast pain, and abdominal distension) was assessed by a placebo-controlled randomized double-blind multicenter clinical trial. The total VAS score significantly decreased in the treatment group (2128.5) compared with the placebo group (278.1). Regarding safety, side effects were not observed in the clinical trials for non-Japanese. There was one moderate case of side effects (1.4%, 1/69 cases) in the Japanese clinical trial.

9.8 DISCUSSION 9.8.1 QUALITY CONTROL OF HERBAL MEDICINES In the European Union, to ensure the quality of crude drugs, botanical raw materials are processed in accordance with the guideline on good agricultural and collection practice (GACP) for starting materials of herbal origin (EMEA, 2006c). WHO also published the Guidelines on GACP for medicinal plants (WHO, 2003). In the US Food and Drug Administration (FDA) guidance, botanical raw materials are also processed in accordance with GACP (FDA, 2016). Also, botanical raw material from representative cultivation sites or farms is important for the manufacturing of the clinical drug substance for multiple batch Phase 3 studies. Starting materials of Veregen and Fulyzaq must be collected in specified sites (FDA, 2006; Lee, 2015). The first step in the quality assurance of natural products is the usage of raw materials from the right origin (and the right source). Therefore, it is clearly stated in JP17 Article 4 of the General Rules for Crude Drugs that the origin of crude drugs is to serve as the acceptance criteria (MHLW, 2016). DNA barcoding of global plant species has been a major focus in the fields of biodiversity and conservation. These DNA barcodes can also be used as reliable tools to facilitate the identification of botanical raw

9.8 DISCUSSION

303

material for the safe and effective use of herbs and quality control. Together with recent progress in molecular biology techniques and the accumulation of genetic information on plants, differentiating methods of crude drugs based on genotypes have been established. Unlike morphological and other methods that are based on phenotypic characteristics, the genotypic methods are not affected by environmental factors. Also, the methods have several advantages; specialized expertise and skill for classification are not needed, and objective results are easily obtained. “Purity Tests on Crude Drugs Using Genetic Information” has been listed as General Information since JP15 Edition Supplement I. In the EMA Guideline on quality of herbal medicinal products /traditional herbal medicinal products (EMA, 2011b), genetic classification is not mentioned on the identification of raw material origin. However, the FDA guidance encourages the development of a genetic taxonomic method (FDA, 2016). In the case of Veregen, genetic information was used as one of the identification criteria for botanical raw material origin (FDA, 2006). From the viewpoint of quality assurance, genetic information will be used more for identification of botanical raw material origin in the future. Because herbal preparations are multicomponent systems and whole herbal preparations are regarded as active ingredients, quality control for whole herbal preparations is required. Regarding quality control of herbal preparations, “WHO guidelines for assessing quality of herbal medicines with reference to contaminants and residues (WHO, 2007)” and “WHO guidelines for selecting marker substances of herbal origin for quality control of herbal medicines (WHO, 2017)” are compared with the “Guidelines on specifications of EMA: guidelines on specifications: test procedures and acceptance criteria for herbal substances, herbal preparations (EMA, 2011c),” the FDA guidance (FDA, 2016), and “Application Guidance for OTC non-Kampo Crude Drug Extract Products in Japan (MHLW, 2015)” (Table 9.9). The WHO guidelines specialize in contaminants, residues, and selecting marker compounds for quality control of herbal medicines. As the criteria to be set in quality control of herbal preparations in the WHO guidelines are especially related to efficacy and safety of herbal medicines directly, the criteria are all included in the EU guideline, the US guidance, and the Japanese guidance. Regarding managing the whole herbal preparations, mass balance, and biological assay in the United States, and extract content in Japan, are specific to the respective countries. In the review report of Veregen, biological assays were discussed as follows: bioassays can be used in combination with established chemistry, manufacturing, and control (CMC) specifications to compare the similarity of botanical raw materials when adding new cultivars, changing providers of previously used cultivars, or implementing other manufacturing changes. A more comprehensive approach, such as combining bioactivity equivalence and CMC specifications, will be preferable to only the CMC specifications. The most desirable bioassays would include those that are able to correlate the bioactivity of the drug substance with clinical effects (FDA, 2006). Also, in the review of Fulyzaq, the possibility of developing an in vitro pharmacological test as a bioassay for quality control was discussed. Finally, evaluation of the possibility of establishing a clinically relevant bioassay for qualifying future manufacturing changes is required in post-approval (FDA, 2012c). In the future, if there is any feasibility in vitro bioassays that can correlate biological activity of herbal extract with clinical effect, bioassay as standard and test methods of herbal extract may be one of the options for quality control to evaluate quality equivalence when changing the manufacturing method or to ensure quality consistency.

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Table 9.9 Comparison of Criteria for Quality Control of Herbal Preparations in WHO Guidelines With European Union Guideline, United States Guidance, and Japanese Guidance Japanese Guidance (MHLW, 2015)

WHO Guidelines (WHO, 2007, 2017)

EMA Guideline (EMA, 2011c)

FDA Guidance (FDA, 2016)

Properties

x(Microscopic features)

x(Appearance)

x(Appearance, smell, taste)

Identification test Moisture content Assay (content) Impurity test

x 3 x x(Chemical contaminantsa, biological contaminantsb, solventsc, agrochemical residuesd, residual solventsc) 3 3 3 3 3

x(Containing organoleptic characters) x x x x(Residual solvents, heavy metals, microbial limits, mycotoxins, pesticides)

x 3 x x(Residual pesticides, elemental impurities, residual solvents, radioisotope, microbial limits, adventitious toxins)

x 3 x x(Heavy metal, arsenic, residual pesticide)

3 3 3 3 3

x x x 3 3

x 3 3 x x

3

3

x

Loss on drying Biological assay Mass balancee Total ash Acid-insoluble ash Extract content

3

In principle, xmeans required criteria, or criteria to be set. 3 means unnecessary criteria or not mentioned. a Toxic metals and nonmetals, persistent organic pollutants, radionuclide, and biological toxins. b Bacteria, fungi, parasites, and insects. c Organic solvents. d Pesticides, fumigants, and antiviral agents. e Quantifying other class of compounds (e.g., lipid, protein) that contribute to the mass balance of the botanical substance.

9.8.2 EFFICACY AND SAFETY OF HERBAL MEDICINES The indications for the use of herbal medicine are required for appropriate clinical evidence. In the European Union, the EMA’s HMPC published monographs for herbal medicines. In the monograph, “well-established use” status is given to substances that have been in use in the European Union for at least 10 years and have had recognized efficacy in well-designed controlled clinical study and an acceptable level of safety (EMA, 2017g). In the United States, the FDA published the Botanical Drug Development Guidance for Industry (FDA, 2016). In this guidance, Phase 3 clinical studies of botanical drugs have the same purpose as Phase 3 clinical studies of nonbotanical drugs. Specific to botanical drugs, analyses of batch effects on clinical endpoints should be considered when the drug product batches exhibit variations, potentially affecting clinical outcomes. In the first United States approved botanical drug Veregen, two randomized, placebo-controlled, double-blind

REFERENCES

305

clinical trials demonstrated scientifically consistent efficacy, and safety with different batches (FDA, 2006). Making changes to manufacturing methods during clinical development could change the chemical profile of the drug substance in the resulting botanical drug product and may warrant bridging studies to justify reliance of previous clinical testing results (FDA, 2016). Therefore, it is necessary to demonstrate efficacy and safety in randomized controlled trials using application products or products having quality equivalence with application products to approve herbal products as medicines. Clinical trials of drugs already used as traditional medicines have been carried out and scientific evidence of efficacy and safety is rarely reconstructed. Although long-term use without any evidence of risk may indicate that a medicine is harmless, chronic toxicological risks may have occurred but may not have been recognized (WHO, 2000). In recent years, attempts to evaluate the safety and usage of traditional medicines using real world evidence such as patient registries/databases have been reported (Heitmann et al., 2013; Huang et al., 2015), and it is expected that the real world evidence will be used in the future.

ACKNOWLEDGMENTS I am grateful to Mr. Martin McCubbin, Mr. Masaharu Yamamoto, Mr. Katsuhito Terasawa, and Mr. Takahiko Inami for their help. I would also like to thank my family (Junko, Moe, and Fumika Maegawa) for their help. The view expressed in this chapter is that of the author and does not necessarily reflect the official views of Ministry of Health, Labour and Welfare (MHLW). Please note that in this chapter, some proper nouns such as the title of guidelines or committee names in English were the provisional translation from Japanese literature by the author.

REFERENCES Birks, J., Grimley Evans, J., 2009. Ginkgo biloba for cognitive impairment and dementia. Cochrane Database Syst. Rev. 1, CD003120. Chaturvedi, S., Patwardhan, B., 2016. Building bridges for integrative medicine. Lancet Psychiatry. 3, 705
706. Crow, J.M., 2011. Microbiome: that healthy gut feeling. Nature 480, S88
S89. Traditional Chinese medicine needs proper scrutiny, 2017. editorial, Nature. 551, 541. EMA, Herbal medicinal products. ,http://www.ema.europa.eu/ema/index.jsp?curl 5 pages/regulation/general/ general_content_000208.jsp&mid 5 WC0b01ac05800240cf.. EMA, November 25, 2010a Assessment report on Vitex agnus-castus L., fructus. EMA/HMPC/144003/2009. ,http://www.ema.europa.eu/docs/en_GB/document_library/Herbal_-_HMPC_assessment_report/2011/08/ WC500110098.pdf.. EMA, May 06, 2010b. Assessment report on Valeriana officinalis L., radix and Humulus lupulus L., flos. EMA/HMPC/215214/2008. ,http://www.ema.europa.eu/docs/en_GB/document_library/Herbal_-_HMPC_ assessment_report/2010/09/WC500096127.pdf.. EMA, November 25, 2010c. Community herbal monograph on Vitex agnus-castus L., Fructus. EMA/HMPC/ 144006/2009. ,http://www.ema.europa.eu/docs/en_GB/document_library/Herbal_-_Community_herbal_ monograph/2011/08/WC500110099.pdf..

306

CHAPTER 9 ETHNO-PHARMACEUTICAL FORMULATIONS

EMA, June 06, 2011a. Community herbal monograph on Valeriana officinalis L., radix and Humulus lupulus L., flos. EMA/HMPC/585558/2007 Corr.1. ,http://www.ema.europa.eu/docs/en_GB/document_library/ Herbal-Community_herbal_monograph/2010/09/WC500096128.pdf.. EMA, March 31, 2011b. Guideline on quality of herbal medicinal products1/traditional herbal medicinal products. EMA/CPMP/QWP/2819/00 Rev. 2, EMA/CVMP/814/00 Rev. 2, EMA/HMPC/201116/2005 Rev. 2. ,http:// www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2011/09/WC500113209.pdf.. EMA, March 31, 2011c. Guideline on specifications: test procedures and acceptance criteria for herbal substances, herbal preparations and herbal medicinal products/traditional herbal medicinal products. EMA/ CPMP/QWP/2820/00 Rev. 2, EMA/CVMP/815/00 Rev. 2, EMA/HMPC/162241/2005 Rev. 2. ,http:// www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2011/09/WC500113210.pdf.. EMA, March 27, 2012a. Assessment report on Zingiber officinale Roscoe, Rhizome. EMA/HMPC/577856/ 2010. ,http://www.ema.europa.eu/docs/en_GB/document_library/Herbal_-_Hmpc_assessment_report/ 2012/06/wc500128140.pdf.. EMA, March 27, 2012b. Community herbal monograph on Zingiber officinale Roscoe, rhizome. EMA/HMPC/ 749154/2010. ,http://www.ema.europa.eu/docs/en_GB/document_library/Herbal_-_Community_ herbal_monograph/2012/06/WC500128142.pdf.. EMA, May 14, 2013a. Assessment report on Plantago ovata Forskk., Semen. EMA/HMPC/304360/2012. ,http://www.ema.europa.eu/docs/en_GB/document_library/Herbal_-_HMPC_assessment_report/2013/07/ WC500146512.pdf.. EMA, May 14, 2013b. Community herbal monograph on Plantago ovata Forssk., Seminis Tegumentum. EMA/ HMPC/199774/2012. ,http://www.ema.europa.eu/docs/en_GB/document_library/Herbal_-_Community_ herbal_monograph/2013/07/WC500146508.pdf.. EMA, May 14, 2013c. Assessment report on Plantago ovata Forssk., Seminis Tegumentum. EMA/HMPC/ 199775/2012. ,http://www.ema.europa.eu/docs/en_GB/document_library/Herbal_-_HMPC_assessment_ report/2013/07/WC500146506.pdf.. EMA, May 14, 2013d. Community herbal monograph on Plantago afra L. et Plantago indica L., Semen. EMA/HMPC/599747/2012. ,http://www.ema.europa.eu/docs/en_GB/document_library/Herbal__Community_herbal_monograph/2013/07/WC500146770.pdf.. EMA, May 14, 2013e. Assessment report on Plantago afra L. et Plantago indica L., Semen. EMA/HMPC/ 599745/2012. ,http://www.ema.europa.eu/docs/en_GB/document_library/Herbal_-_HMPC_assessment_ report/2013/07/WC500146768.pdf.. EMA, May 14, 2013f. Community herbal monograph on Plantago ovata Forssk., Semen. EMA/HMPC/ 304390/2012. ,http://www.ema.europa.eu/docs/en_GB/document_library/Herbal_-_Community_herbal_ monograph/2013/07/WC500146514.pdf.. EMA, January 28, 2014a. Assessment report on Ginkgo biloba L., Folium. EMA/HMPC/321095/2012. ,http://www.ema.europa.eu/docs/en_GB/document_library/Herbal_-_HMPC_assessment_report/2015/04/ WC500185241.pdf.. EMA, November 24, 2014b. Assessment report on Echinacea purpurea (L.) Moench., Herba Recens. EMA/ HMPC/557979/2013. ,http://www.ema.europa.eu/docs/en_GB/document_library/Herbal_-_HMPC_ assessment_report/2015/04/WC500185435.pdf.. EMA, May 05, 2015a. European Union herbal monograph on Capsicum annuum L. Var. minimum (Miller) Heiser and small fruited varieties of Capsicum frutescens L., Fructus. EMA/HMPC/674139/2013. ,http:// www.ema.europa.eu/docs/en_GB/document_library/Herbal_-_Community_herbal_monograph/2015/06/ WC500188825.pdf.. EMA, January 28, 2015b. European Union herbal monograph on Ginkgo biloba L., Folium. EMA/HMPC/ 321097/2012. ,http://www.ema.europa.eu/docs/en_GB/document_library/Herbal_-_Community_herbal_ monograph/2015/04/WC500185243.pdf..

REFERENCES

307

EMA, May 05, 2015c. Assessment report on Capsicum annuum L. Var. Minimum (Miller) Heiser and small fruited varieties of Capsicum frutescens L., Fructus. EMA/HMPC/674138/2013. ,http://www.ema.europa. eu/docs/en_GB/document_library/Herbal_-_HMPC_assessment_report/2015/06/WC500188823.pdf.. EMA, March 10, 2015d. European Union herbal monograph on Linum usitatissimum L., Semen. EMA/HMPC/ 377675/2014. ,http://www.ema.europa.eu/docs/en_GB/document_library/Herbal_-_Community_ herbal_monograph/2015/07/WC500189486.pdf.. EMA, March 10, 2015e. Assessment report on Linum usitatissimum L., Semen. EMA/HMPC/377674/2014. ,http://www.ema.europa.eu/docs/en_GB/document_library/Herbal_-_HMPC_assessment_report/2015/07/ WC500189484.pdf.. EMA, November 24, 2015f. European Union herbal monograph on Echinacea purpurea (L.) Moench, Herba Recens.EMA/HMPC/48704/2014 Corr 1 ,http://www.ema.europa.eu/docs/en_GB/document_library/ Herbal_-_Community_herbal_monograph/2015/04/WC500185437.pdf.. EMA, February 02, 2016a. Assessment report on Valeriana officinalis L., radix and Valeriana officinalis L., Aetheroleum. EMA/HMPC/150846/2015. ,http://www.ema.europa.eu/docs/en_GB/document_library/ Herbal_-_HMPC_assessment_report/2016/04/WC500205373.pdf.. EMA, November 22, 2016b. European Union herbal monograph on Aloe barbadensis Mill. and on Aloe (various species, mainly Aloe ferox Mill. and Its Hybrids), Folii Succus Siccatus. EMA/HMPC/625788/2015. ,http:// www.ema.europa.eu/docs/en_GB/document_library/Herbal_-_Herbal_monograph/2017/04/WC500225529.pdf.. EMA, November 22, 2016c. Assessment report on Aloe barbadensis Mill. and on Aloe (various species, mainly Aloe ferox Mill. and Its Hybrids), Folii Succus Siccatus. EMA/HMPC/759585/2015. ,http://www.ema. europa.eu/docs/en_GB/document_library/Herbal_-_HMPC_assessment_report/2017/04/WC500225527.pdf.. EMA, February 02, 2016d. European Union herbal monograph on Ricinus communis L., Oleum. EMA/HMPC/ 572974/2014. ,http://www.ema.europa.eu/docs/en_GB/document_library/Herbal_-_Herbal_monograph/ 2016/03/WC500202573.pdf.. EMA, February 02, 2016e. Assessment report on Ricinus communis L., Oleum. EMA/HMPC/572973/2014. ,http://www.ema.europa.eu/docs/en_GB/document_library/Herbal_-_HMPC_assessment_report/2016/03/ WC500202571.pdf.. EMA, April 05, 2016f. European Union herbal monograph on Thymus vulgaris L. or Thymus zygis L., Herba and Primula veris L. or Primula elatior (L.) Hill, radix. EMA/HMPC/84990/2015 Corr.1. ,http://www. ema.europa.eu/docs/en_GB/document_library/Herbal_-_Herbal_monograph/2016/06/WC500208441.pdf.. EMA, April 05, 2016g. Assessment Report on Thymus vulgaris L. or Thymus zygis L., Herba and Primula veris L. or Primula elatior (L.) Hill, Radix. EMA/HMPC/85124/2015. ,http://www.ema.europa.eu/docs/ en_GB/document_library/Herbal_-_HMPC_assessment_report/2016/06/WC500208438.pdf.. EMA, February 02, 2016h. European Union herbal monograph on Valeriana officinalis L., Radix. EMA/ HMPC/150848/2015, Corr.1. ,http://www.ema.europa.eu/docs/en_GB/document_library/Herbal_-_ Herbal_monograph/2016/04/WC500205376.pdf.. EMA, May 30, 2017a. Assessment report on Vitis vinifera L., folium. EMA/HMPC/464682/2016. ,http://www. ema.europa.eu/docs/en_GB/document_library/Herbal_-_HMPC_assessment_report/2018/01/WC500240973.pdf.. EMA, January 31, 2017b. European Union herbal monograph on Salix [various species including S. purpurea L., S. daphnoides Vill., S. fragilis L.], cortex. EMA/HMPC/80630/2016. ,http://www.ema.europa.eu/docs/ en_GB/document_library/Herbal_-_Herbal_monograph/2017/07/WC500230920.pdf.. EMA, January 31, 2017c. Assessment report on Salix [various species including S. purpurea L., S. daphnoides Vill., S. fragilis L.], cortex. EMA/HMPC/80628/2016. ,http://www.ema.europa.eu/docs/en_GB/document_library/Herbal_-_HMPC_assessment_report/2017/07/WC500230918.pdf.. EMA, November 21, 2017d. European Union herbal monograph on Hedera helix L., folium. EMA/HMPC/ 325716/2017. ,http://www.ema.europa.eu/docs/en_GB/document_library/Herbal_-_Herbal_monograph/ 2018/08/WC500253895.pdf..

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EMA, November 21, 2017e. Assessment report on Hedera helix L., folium. EMA/HMPC/325715/2017. ,http://www.ema.europa.eu/docs/en_GB/document_library/Herbal_-_HMPC_assessment_report/2018/08/ WC500253896.pdf.. EMA, May 30, 2017f. European Union herbal monograph on Vitis vinifera L., folium. EMA/HMPC/464684/ 2016. ,http://www.ema.europa.eu/docs/en_GB/document_library/Herbal_-_Herbal_monograph/2018/01/ WC500240974.pdf.. EMA, September 19, 2017g. Guideline on the assessment of clinical safety and efficacy in the preparation of EU herbal monographs for well-established and traditional herbal medicinal products, EMA/HMPC/ 104613/2005 Rev. 1. ,http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/ 2017/11/WC500239383.pdf.. EMA, March 27, 2018a. European Union herbal monograph on Cimicifuga Racemosa (L.) Nutt., rhizome. EMA/HMPC/48745/2017. ,http://www.ema.europa.eu/docs/en_GB/document_library/Herbal__Herbal_monograph/2018/07/WC500251368.pdf.. EMA, March 27, 2018b. Assessment report on Cimicifuga Racemosa (L.) Nutt., rhizome. EMA/HMPC/48744/ 2017. ,http://www.ema.europa.eu/docs/en_GB/document_library/Herbal_-_HMPC_assessment_report/ 2018/07/WC500251366.pdf.. EMEA (European Medicines Agency, currently EMA), October 26, 2006a. Community herbal monograph on Cassia senna L., Fructus and Cassia Angustifolia Vahl, Fructus. Doc. Ref. EMEA/HMPC/51871/2006 Corr.1. ,http://www.ema.europa.eu/docs/en_GB/document_library/Herbal_-_Community_herbal_ monograph/2009/12/WC500018202.pdf.. EMEA, October 26, 2006b. Community herbal monograph on Cassia senna L. and Cassia Angustifolia Vahl, folium. Doc. Ref. EMEA/HMPC/51869/2006 Corrigendum1. ,http://www.ema.europa.eu/docs/en_GB/ document_library/Herbal_-_Community_herbal_monograph/2009/12/WC500018215.pdf.. EMEA, February 20, 2006c. Guideline on Good Agricultural and Collection Practice (GACP) for starting materials of herbal origin. ,http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/ 2009/09/WC500003362.pdf.. EMEA, April 27, 2007a. Assessment report on Cassia senna L. and Cassia Angustifolia Vahl, folium. Doc. Ref. EMEA/HMPC/51868/2006 Corr. ,http://www.ema.europa.eu/docs/en_GB/document_library/Herbal_-_ HMPC_assessment_report/2009/12/WC500018219.pdf.. EMEA, October 31, 2007b. Community herbal monograph on Mentha X Piperita L., Aetheroleum. Doc. Ref. EMEA/HMPC/349466/2006. ,http://www.ema.europa.eu/docs/en_GB/document_library/Herbal_-_ Community_herbal_monograph/2010/01/WC500059313.pdf.. EMEA, April 27, 2007c. Assessment report on Cassia senna L., Fructus and Cassia Angustifolia Vahl, Fructus. Doc. Ref. EMEA/HMPC/51870/2006. ,http://www.ema.europa.eu/docs/en_GB/document_ library/Herbal_-_HMPC_assessment_report/2009/12/WC500018206.pdf.. EMEA, September 07, 2007d. Community herbal monograph on Rhamnus Purshianus D.C., Cortex. Doc. Ref. EMEA/HMPC/513579/2006Corr. ,http://www.ema.europa.eu/docs/en_GB/document_library/Herbal_-_ Community_herbal_monograph/2009/12/WC500018424.pdf.. EMEA, October 31, 2007e. Community herbal monograph on Rheum palmatum L. and Rheum Officinale Baillon, Radix. Doc. Ref. EMEA/HMPC/189624/2007Corr. ,http://www.ema.europa.eu/docs/en_GB/ document_library/Herbal_-_Community_herbal_monograph/2009/12/WC500018401.pdf.. EMEA, July 05, 2007f. Assessment report on Rhamnus frangula L., Cortex. Doc. Ref. EMEA/HMPC/76306/ 2006. ,http://www.ema.europa.eu/docs/en_GB/document_library/Herbal_-_HMPC_assessment_report/ 2009/12/wc500018613.pdf.. EMEA, June 05, 2008a. Assessment report for Rhubarb (Rhei radix). Doc. Ref. EMEA/HMPC/189626/2007. ,http://www.ema.europa.eu/docs/en_GB/document_library/Herbal_-_HMPC_assessment_report/2009/12/ WC500018404.pdf..

REFERENCES

309

EMEA, June 05, 2008b. Assessment report Rhamnus Purshianus D.C.; Rhamni Purshianae cortex; Cascara and herbal preparation(s) thereof with well-established use and traditional use. Doc. Ref. EMEA/HMPC/ 513580/2006. ,http://www.ema.europa.eu/docs/en_GB/document_library/Herbal_-_HMPC_ assessment_report/2009/12/WC500018426.pdf.. EMEA, September 04, 2008c. Assessment report on Mentha X Piperita L., Aetheroleum. Doc. Ref. EMEA/ HMPC/349465/2006. ,http://www.ema.europa.eu/docs/en_GB/document_library/Herbal_-_HMPC_ assessment_report/2010/01/WC500059311.pdf.. EMEA, July 16, 2009a. Assessment report on Aesculus hippocastanum L., Semen. London. Doc. Ref. EMEA/ HMPC/225304/2008. ,http://www.ema.europa.eu/docs/en_GB/document_library/Herbal_-_HMPC_ assessment_report/2010/01/WC500059103.pdf.. EMEA, November 12, 2009b. Community herbal monograph on Hypericum perforatum L., Herba. Doc. Ref. EMA/HMPC/101304/2008. ,http://www.ema.europa.eu/docs/en_GB/document_library/Herbal_-_ Community_herbal_monograph/2010/01/WC500059145.pdf.. EMEA, November 12, 2009c. Assessment report on Hypericum perforatum L., Herba. Doc. Ref. EMA/HMPC/ 101303/2008. ,http://www.ema.europa.eu/docs/en_GB/document_library/Herbal_-_HMPC_ assessment_report/2010/01/wc500059144.pdf.. EMEA, July 16, 2009d. Community herbal monograph on Aesculus hippocastanum L., Semen. Doc. Ref. EMEA/HMPC/225319/2008. ,http://www.ema.europa.eu/docs/en_GB/document_library/Herbal_-_ Community_herbal_monograph/2010/01/WC500059105.pdf.. EMEA, May 8, 2007g. Assessment of case reports connected to herbal medicinal products containing Cimicifugae Racemosae Rhizoma (Black Cohosh, Root). 2007EMEA/HMPC/269258/2006 Rev. 1 http://www.ema.europa. eu/docs/en_GB/document_library/Herbal_-_HMPC_assessment_report/2010/02/WC500074167.pdf EMEA, 2006. Community herbal monograph on Rhamnus frangula L., CORTEX 26 October 2006. Doc. Ref. EMEA/HMPC/76307/2006 Corrigendum1. ,http://www.ema.europa.eu/docs/en_GB/document_library/ Herbal_-_Community_herbal_monograph/2009/12/WC500018614.pdf.. FDA, September 15, 2006. VergenTM 15% ointment botanical review. ,https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021902s000_botanicalr.pdf.. FDA, 2012a. Veregen (sinecatechins) ointment, 15%, for topical use highlights of prescribing information. ,https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021902s025lbl.pdf.. FDA, 2012b. FULYZAQ. (crofelemer) delayed-release tablets, for oral use highlights of prescribing information. ,https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202292Orig1s000Lbl.pdf.. FDA, August 08, 2012c. Crofelemer 125 mg tablet botanical review. ,https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202292Orig1s000BotanicalR.pdf.. FDA, December, 2016. Botanical drug development guidance for industry. pharmaceutical quality/CMC, Revision 1. ,https://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-gen/documents/document/ ucm458484.pdf.. Heitmann, K., Nordeng, H., Holst, L., 2013. Pregnancy outcome after use of cranberry in pregnancy - the Norwegian mother and child cohort study. BMC Complem. Alternat. Med. 13, 345. Henderson, L., Yue, Q.Y., Bergquist, C., Gerden, B., Arlett, P., 2002. St. John’s wort (Hypericum perforatum): drug interactions and clinical outcomes. Br. J. Clin. Pharmacol. 54, 349
356. Huang, M.C., Pai, F.T., Lin, C.C., Chang, C.M., Chang, H.H., Lee, Y.C., et al., 2015. Characteristics of traditional Chinese medicine use in patients with rheumatoid arthritis in Taiwan: a nationwide population-based study. J. Ethnopharmacol. 176, 9
16. Jakovljevic, M., Getzen, T.E., 2016. Growth of global health spending share in low and middle income countries. Front. Pharmacol. 7, 21. Jepson, R.G., Williams, G., Craig, J.C., 2012. Cranberries for preventing urinary tract infections. Cochrane Database Syst. Rev. 10, CD001321.

310

CHAPTER 9 ETHNO-PHARMACEUTICAL FORMULATIONS

Kumar, S., Dobos, G.J., Rampp, T., 2017. The significance of ayurvedic medicinal plants. J. Evid. Based Complement. Altern. Med. 22, 494
501. Lee, S.L., October 6, 2015. Botanical drug development and quality standards. FDA/PQRI Conference on Advancing Product Quality. ,http://pqri.org/wp-content/uploads/2015/10/01-PQRI-Lee-Botanicals-20151. pdf.. MHLW, March 22, 2007. Application guideline for western traditional herbal medicines as OTC drugs. Notification of yakusyokushinsahatsu No. 0322001, Japan. ,http://www.pmda.go.jp/files/000203243.pdf. (in Japanese). MHLW, December 25, 2015. The application guidance for OTC non-Kampo crude drug extract products. Notification of Yakuseishinsa No.1225-6. ,http://www.pmda.go.jp/files/000209984.pdf. (In Japanese). MHLW, April 1, 2016. The Japanese Pharmacopoeia Seventeenth Edition. ,http://www.pmda.go.jp/files/ 000217650.pdf.. MHRA, 2012. Press release: Echinacea herbal products should not be used in children under 12 years old. ,http://webarchive.nationalarchives.gov.uk/20141206003656/http://www.mhra.gov.uk/NewsCentre/ Pressreleases/CON180627.. Maegawa, H., Nakamura, T., Saito, K., 2014. Regulation of traditional herbal medicinal products in Japan. J. Ethnopharmacol. 158, 511
515. Mikage, M., Kimura, M., 2013. Traditional medicine and pharmacognosy. Augmented edition. Tokyo: Nankodo, pp. 44
45. In Japanese. Murray, C.J.L., Vos, T., Lozano, R., Naghavi, M., Flaxman, A.D., Michaud, C., et al., 2012. Disabilityadjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380, 2197
2223. PMDA (Pharmaceuticals and Medical Devices Agency), January 15, 2014. The review report of Prefemin, Japan. ,http://www.pmda.go.jp/otc/2014/O201400003/380077000_22600APX00214000_Q100_1.pdf. (in Japanese). Pattanittum, P., Kunyanone, N., Brown, J., Sangkomkamhang, U.S., Barnes, J., Seyfoddin, V., et al., 2016. Dietary supplements for dysmenorrhoea. Cochrane Database Syst. Rev. 3, CD002124. PMDA, November 8, 2010. The review report of Antistax, Japan. ,http://www.pmda.go.jp/otc/2011/ O201100003/53035300_22300APY00001000_Q100_1.pdf. (in Japanese). Pittler, M.H., Guo, R., Ernst, E., 2008. Hawthorn extract for treating chronic heart failure. Cochrane Database Syst. Rev. 1, CD005312. Pulla, P., 2014. Searching for science in India’s traditional medicine. Science 346, 410. Staub, P.O., Casu, L., Leonti, M., 2016. Back to the roots: a quantitative survey of herbal drugs in Dioscorides’ De Materia Medica (ex Matthioli, 1568). Phytomedicine. 23, 1043
1052. Teschke, R., Schulze, J., 2010. Risk of kava hepatotoxicity and the FDA consumer advisory. JAMA. 304, 2174
2175. Thirthalli, J., Zhou, L., Kumar, K., Gao, J., Vaid, H., Liu, H., et al., 2016. Traditional, complementary, and alternative medicine approaches to mental health care and psychological wellbeing in India and China. Lancet Psych. 3, 660
672. WHO, 2007. WHO guidelines for assessing quality of herbal medicines with reference to contaminants and residues. ,http://apps.who.int/medicinedocs/documents/s14878e/s14878e.pdf.. WHO, 1998. The role of the pharmacist in self-care and self-medication. ,http://apps.who.int/medicinedocs/ pdf/whozip32e/whozip32e.pdf.. WHO, 1999a. WHO monographs on selected medicinal plants, Vol. 1. ,http://apps.who.int/medicinedocs/pdf/ s2200e/s2200e.pdf.. WHO, 1999b. WHO monographs on selected medicinal plants, Vol. 2. ,http://apps.who.int/medicinedocs/pdf/ s4927e/s4927e.pdf..

REFERENCES

311

WHO, 2000. General guidelines for methodologies on research and evaluation of traditional medicine. ,http:// apps.who.int/medicinedocs/en/d/Jwhozip42e/.. WHO, 2002. WHO monographs on selected medicinal plants, Vol. 3. ,http://apps.who.int/medicinedocs/documents/s14213e/s14213e.pdf.. WHO, 2003. WHO Guidelines on Good Agricultural and Collection Practices (GACP) for medicinal plants. ,http://apps.who.int/medicinedocs/pdf/s4928e/s4928e.pdf.. WHO, 2009. WHO Monographs on Selected Medicinal Plants, Vol. 4. ,http://apps.who.int/medicinedocs/ documents/s16713e/s16713e.pdf.. WHO, 2010. WHO monographs on medicinal plants commonly used in the Newly Independent States. ,http://apps.who.int/medicinedocs/documents/s17534en/s17534en.pdf.. WHO, 2013a. Traditional medicine strategy: 2014-2023. http://apps.who.int/iris/bitstream/10665/92455/1/ 9789241506090_eng.pdf?ua 5 1 WHO, 2017. WHO guidelines for selecting marker substances of herbal origin for quality control of herbal medicines. WHO Technical Report Series, No. 1003, Annex 1. ,http://apps.who.int/medicinedocs/documents/s23240en/s23240en.pdf.. WHO, 2013b. Review Of World Pharmacopoeias, 2013. ,http://www.who.int/medicines/areas/quality_safety/ quality_assurance/resources/InternationalMeetingWorldPharmacopoeias_QAS13-512Rev1_25032013. pdf.. Wang, H., Dwyer-Lindgren, L., Lofgren, K.T., Rajaratnam, J.K., Marcus, J.R., et al., 2012. Age-specific and sex-specific mortality in 187 countries, 1970-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380, 2071
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CHAPTER

REORIENTATION OF NUTRACEUTICALS AND PHARMACEUTICALS APPLICATIONS IN AN OPEN INNOVATION MODEL

10 Barbara Bigliardi

Department of Engineering and Architecture, University of Parma, Parma, Italy

CHAPTER OUTLINE 10.1 Introduction ............................................................................................................................... 313 10.2 Industry Convergence: A Literature Background ........................................................................... 314 10.2.1 The Patterns of Industry Convergence..................................................................... 315 10.2.2 Drivers, Challenges, and Consequences of Industry Convergence .............................. 316 10.2.3 The Process of Industry Convergence ..................................................................... 317 10.3 The Role of Open Innovation in Industry Convergence................................................................... 318 10.3.1 Open Innovation and the Food Industry .................................................................. 322 10.3.2 Open Innovation and the Pharmaceutical Industry ................................................... 323 10.4 Evidence of Industry Convergence From the Food and Pharmaceuticals Industries ......................... 324 10.4.1 The Case of Nutraceuticals.................................................................................... 324 10.5 Conclusions............................................................................................................................... 328 References ......................................................................................................................................... 330 Further Reading .................................................................................................................................. 335

10.1 INTRODUCTION Industries differ based on their structures, products, actors, processes, technologies, inputs, competition, standards and regulations, and so on. These differences reflect the diverse innovation system that each industry, and consequently each company belonging to a specific industry, used to adopt (Pavitt, 1984). When convergence occurs, these differences blur. Indeed, industry convergence is defined as “the process of blurring boundaries between two or more disparate industries by combining their scientific knowledge, technology, and markets” (Kim et al., 2015, p. 1736).

Nutraceuticals and Natural Product Pharmaceuticals. DOI: https://doi.org/10.1016/B978-0-12-816450-1.00010-6 © 2019 Elsevier Inc. All rights reserved.

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Research on industry convergence has been analyzed more frequently in the literature focussing on computing, communication and consumer electronics (e.g., Stieglitz, 2002; Chon et al., 2003). However, other examples exist. For instance, Prahalad (1998) studied industry convergence between cosmetic and pharmaceutical industries, which lead to the so-called “cosmeceuticals.” Similarly, new industry segments are keep emerging at the boundaries between the food and the pharmaceutical industries (Bro¨ring et al., 2006): the “nutraceuticals and functional foods” (NFFs) sector. In general, when two (or more) industries converge, companies operating in each sector need knowledge and technologies that are not present within their expertise. Consequently, when industry convergence occurs, firms face challenges related to the acquisition of the required unfamiliar knowledge and technologies outside their boundaries. These challenges stress the need for a more open approach to innovation. Based on these premises, this chapter studies, on the one hand, the extent to which the food and pharmaceutical industries show tendencies to converge, and on the other hand, how open innovation may be adopted in order to help their convergence. Specifically, this chapter investigates the role of open innovation within this context. The remainder of this chapter is structured as follows: Section 10.2 proposes a literature background on industry convergence and specifically investigates the main issues that emerged from the review of the literature (namely, the patterns of industry convergence, its drivers and consequences, and the process of industry convergence). Then, in Section 10.3 the role of open innovation in industry convergence is described, and as a result of the literature review on industry convergence and on the role of open innovation, a theoretical framework of industry convergence is proposed. It includes drivers, challenges, types, consequences and facilitators of industry convergence. This framework should be adopted when investigating industry convergence applied within any industries. Finally, aiming at increasing the understanding of industry convergence, the framework will be applied to the food industry, as detailed in Section 10.4. This sector is currently converging with the pharmaceutical industry, and as a result nutraceuticals products are obtained. The same section also proposes an overview of the most popular examples of nutraceuticals products that resulted from this convergence. Finally, conclusions and future trends are highlighted in Section 10.5.

10.2 INDUSTRY CONVERGENCE: A LITERATURE BACKGROUND Today, due to the accelerated life cycle in technology and the consequent markets’ rapid technological saturation, companies, in addition accelerating their rate of technological innovation, are also forced to expand the scope of their products or services. To do that, they are more and more combining their product or service features with those of other markets. Such behavior leads to what is called in the literature as “industry convergence” (e.g., Benner and Ranganathan, 2013; Choi and Valikangas, 2001; Curran, 2013; Curran and Leker, 2011; Curran et al., 2010). Industry convergence has been defined as first by OECD as “the blurring of technical and regulatory boundaries between sectors of the economy” (OECD, 1992, p. 13), and then other authors agreed in defining it as “the process of blurring boundaries between two or more disparate industries by combining their scientific knowledge, technology, and markets” (e.g., Kim et al., 2015, p. 1736).

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Industry convergence may result in integration as well as the intersection between two previously separate industries. The analysis of the available literature on industry convergence highlights three main aspects of this phenomenon: (1) the patterns of industry convergence, (2) its drivers and consequences, and (3) the process of industry convergence. These aspects are explored in the following of the section, first in general terms, and then applied to the specific industries (food and pharma) investigated in the book.

10.2.1 THE PATTERNS OF INDUSTRY CONVERGENCE Two main patterns of industry convergence have been identified in the literature. Starting from two distinct industries, labeled as Industry A and Industry B (left side of Fig. 10.1), these industries converge and result in the emergence of the industry labeled as AB (the gray area in the same figure). This new industry may be a new industry segment (called “converged segment”), as well as an out-and-out new industry. In the case a converged segment emerges, it usually results from the overlapping of Industry A and Industry B, deriving from the sharing of technology, value chains, and markets between the original industries (Curran and Leker, 2011). The degree of industry convergence can vary among industries, meaning that the intensity of overlapping between Industry A and Industry B can be higher or lower depending on the industries investigated. In other words, the gray area depicted in Fig. 10.1 may be more or less large. For the sake of completeness, Hamel and Prahald (1994) also proposed a third convergence that may occur between two industries and result in that they called “unstructured arenas,” meaning that the boundaries of the new AB industry are indefinable and in constant flux. Industry convergence can also occur within the same industry (within-industry convergence) (Hacklin, 2007). Specifically, within-industry convergence occurs among subindustries within the same sector (i.e., Industry A and its subindustries A1 and A2), and results in the overlapping of A1

FIGURE 10.1 The patterns of industry convergence.

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and A2. An example of this type of convergence is that between the automobile and electronics subindustries within the manufacturing sector. Further, two main types of convergence can be identified: convergence in substitutes and convergence in complements (Greenstein and Khanna, 1997). Convergence in substitutes means that different and interchangeable products share their features providing the same function for the enduser. Greenstein and Khanna (1997) referred to this type of convergence with the formula “1 1 1 5 1.” Conversely, convergence in complements means that different and unrelated products bundle together becoming a new and integrated product and providing added to the end-user [“1 1 1 5 3” paraphrasing Greenstein and Khanna (1997)]. In a similar way, Pennings and Puranam (2001) proposed the distinction between demand-side and supply-side convergence. The latter type of convergence is observable when technologies across different industries on the input side are applied. Conversely, the former type of convergence is observable when there is an orientation towards satisfying several needs in one transaction. This classification has been then adapted by Stieglitz (2003), who considered the distinction between technology-side and product-side convergence. The result of both these classifications is a 2x2 matrix with four types of convergence. Thus it is possible to talk about, in general, convergence of technology (supply-side convergence) and convergence of the market (demand-side convergence) (Cho et al., 2015; Curran and Leker, 2011; Curran et al., 2010; Hacklin et al., 2009, 2010; Kim et al., 2014). Technology convergence usually occurs through the recombination of existing technologies into a new technology with new or improved functionality (Cho et al., 2015; Hacklin, 2007; Kodama, 1991; Pennings and Puranam, 2001). Thus the new technology replaces the previously established ones, resulting in the blurring of industrial boundaries, that is, industry convergence as previously defined. Different studies available in the literature stress that technology convergence is the main type of industry convergence (Cho et al., 2015; Curran and Leker, 2011; Fai and Von Tunzelmann, 2001; Hacklin et al., 2009; Pennings and Puranam, 2001). As far as market convergence is concerned, it occurs when companies, in order to overcome the reduced market return from their existing products, expand their market boundaries and, as a consequence, markets overlap (Andergassen et al., 2006; Choi and Valikangas, 2001; D’Aveni et al., 2010; Hacklin et al., 2013; Kim et al., 2014; Pennings and Puranam, 2001; Zhang and Li, 2010). A typical example of market convergence happens when market demand for a product has become saturated because the supply of products exceeds consumers’ needs (Kim and Lee, 2009; Kim and Kim, 2015). In order to overcome this market saturation, companies differentiate their products by integrating new features belonging to other industries, thus capturing new market demand. Usually, supply-side convergence does not go hand in hand with the demand-side one, as highlighted by Gambardella and Torrisi (1998) in their study observing the electronics industry.

10.2.2 DRIVERS, CHALLENGES, AND CONSEQUENCES OF INDUSTRY CONVERGENCE As far as drivers of industry convergence are concerned, they may be classified in external and internal drivers. As for the external ones, the literature recognizes technological changes and

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innovation as the main drivers. These drivers include the emergence of technology platforms such as the Internet, new process technologies or new standards (Bores et al., 2003; Lei, 2000; Nystro¨m and Hacklin, 2005; Wirtz, 2001). The literature usually proposes as second external driver deregulation. Deregulation is the result of a policymakers’ decision to lower entry barriers for new competitors with the final aim to make the competition grow (Lei, 2000, Bor´es et al., 2003). Typical examples of deregulations are telecom or financial deregulations (Nystro¨m and Hacklin, 2005; Curwen, 2006; Palmberg and Martikainen, 2006; Vong Srivastava and Finger, 2006). Internal drivers depend on the actions and behavior of a company. The literature proposes as main drivers the entrepreneurial managerial creativity (Yoffie, 1997), corporate diversification strategies (Stieglitz, 2003; Palmberg and Martikainen, 2006), and so on. The literature also presents studies describing the consequences of industry convergence. These include economic consequences, such as market enlargement and increased competition (Greenstein and Khanna, 1997; Bor´es et al., 2003), as well as value chain reconfiguration (Greenstein and Khanna, 1997; Wirtz, 2001). Consequences of industry convergence may also be negative because it can affect the strategic response of a company. Indeed, as industry convergence occurs, companies (especially the entrant and incumbent ones) may face uncertainties and risks. Specifically, the literature identifies two main challenges for innovation management in the context of convergence, the first of which is grounded on the resource-based view of the firm: the competences and knowledge gaps of companies, and the uncertainty about the competences and knowledge to develop (Bro¨ring, 2013). These challenges are more or less evident according to the distance that exists between the converging industries: specifically, the greater the distance, the more profound are these challenges.

10.2.3 THE PROCESS OF INDUSTRY CONVERGENCE Industry convergence is usually seen as a linear process: it starts with two (or more) industries that merge, thus generating several different outcomes. According to previous studies (e.g., Hacklin, 2008; Curran and Leker, 2011; von Delft, 2013), the process industry convergence can be divided into four main phases, namely: (1) initialization, (2) knowledge diffusion, (3) consolidation, and (4) maturation. These phases are depicted in Fig. 10.2: the upper part of the figure shows the linear process in terms of phases, while the lower part of the same figure shows what happens in each phase. In the initialization phase, R&D of two (or more) distinct industries (in the figure, A and B) are independent of each other. During the second phase (i.e., knowledge diffusion), knowledge (represented by the circles, and specifically gray-dots circles represents the knowledge from Industry A and the circles with gray lines represents the knowledge from Industry B) starts being diffused between the two industries, and the distance between the two knowledge areas decreases starting the consolidation phase (phase 3). Indeed, moving from the knowledge diffusion phase to the consolidation one, the circles get close. During the third stage, technology development and combination occur, thus leading to technology convergence and/or market convergence. Finally, sectors merge, completing the industrial convergence process (maturation phase). As a result, a new AB industry as well as a new AB converged segment may emerge, as previously depicted also in Fig. 10.1.

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FIGURE 10.2 The linear process of industry convergence.

10.3 THE ROLE OF OPEN INNOVATION IN INDUSTRY CONVERGENCE After industry convergence has occurred, companies operating in the markets that converged need knowledge and capabilities from other industries in order to apply the new products’ functions or features, to realign their resources, capabilities and competencies (Vong Srivastava and Finger, 2006), as well as to remain competitive (Bro¨ring and Leker, 2007). Thus to obtain the necessary knowledge and capabilities of other industries, companies use to establish interorganizational dynamics across industries, such as, among others, R&D partnerships, alliances, joint ventures, mergers and acquisitions, and licensing (Curran and Leker, 2011). In addition, because industry convergence, as previously stressed, may create uncertainty, companies use to collaborate with actors belonging to related industries also in order to limit the risks they may face (Bor´es et al., 2003; Lei, 2000; Hacklin et al., 2004). In 2003 Henry Chesbrough published his book describing the shift from the “closed innovation paradigm” (i.e., the inside-driven innovation), to the new (even if some researchers disagree with this affirmation) “open innovation paradigm” (i.e., a business model that uses both internal and external ideas to generate value) (Chesbrough, 2003). He defined open innovation (henceforth, OI) as follows: “Open Innovation is a paradigm that assumes that firms can and should use external ideas as well as internal ideas, and internal and external paths to market, as the firms look to advance their technology. Open Innovation combines internal and external ideas into architectures and systems whose requirements are defined by a business model” (Chesbrough, 2003). More recently, the same author proposed a different definition, that is: “Open innovation is the use of purposive inflows and outflows of knowledge to accelerate internal innovation, and expand the

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markets for external use of innovation, respectively. [This paradigm] assumes that firms can and should use external ideas as well as internal ideas, and internal and external paths to market, as they look to advance their technology” (Chesbrough, 2006). In other words, OI means the use of purposive inflows and outflows of knowledge with the twofold aim to accelerate internal innovation and to expand the markets for external use of that innovation. At a firm level, the adoption of the OI paradigm allows companies discovering new market, product, and services that would be hard to discover or develop by an organization alone (Almirall and Casadesus-Masanell, 2010). At the interorganizational network level, OI means pooling diverse and complementary resources so that a large group of industrial and research organizations is allowed to increase their innovative outputs and to answer to a wide variety of customers’ needs (e.g., Vanhaverbeke, 2006). OI networks comprise different actors: suppliers, customers, competitors, universities and research centers, etc. (Bigliardi and Galati, 2016). According to Chesbrough and Crowther (2006), for example, OI has two main dimensions: inbound and outbound. Gassmann and Enkel (2004) and Enkel et al. (2009) suggested the third dimension named “coupled process.” In addition to the identification of these three dimensions, the literature also identifies, within each dimension, a number of activities (practices) that are carried out by companies when adopting a specific dimension of OI. Concerning the inbound process, a company uses, in addition to inhouse R&D, external R&D provided by actors such as suppliers or consumers, enrich their own skills and knowledge by integrating external actors into the internal innovation process. For example, companies may directly involve consumers in their innovation process by developing or codeveloping products based on their specifications (Burcharth et al., 2014; Gassmann, 2006; Spithoven et al., 2013; van de Vrande et al., 2009). In a similar way, companies may systematically collaborate with external partners (such as universities, research centers, or other firms) to support their innovation process (Burcharth et al., 2014; Lee et al., 2010; van de Vrande et al., 2009; Wynarczyk et al., 2013) or to purchase R&D work from others (Chesbrough, 2006; Chesbrough and Crowther, 2006; Gassmann, 2006; Wynarczyk et al., 2013). Alternatively, enterprises may use to buy, sell or use external intellectual property (IP) such as patents (Burchart et al., 2014; Chesbrough, 2006; Gassmann, 2006; Lee et al., 2010; van de Vrande et al., 2009; Wynarczyk et al., 2013). Finally, due to the growing diffusion of the use of the internet, companies are recently adopting more and more to search for innovative ideas or technologies to be adopted in their innovation processes. Conversely, in the case of outbound OI activities, companies look for external organizations to commercialize their knowledge or technology, thus earning profits by bringing ideas, patents, and other forms of IP rights to the market. They can, for example, sell or license their patents or knowhow (Gassmann, 2006; Lee et al., 2010; Lichtenthaler and Ernst, 2007; van de Vrande et al., 2009; Wynarczyk et al., 2013), mainly to monetize their existing technologies. In addition, companies can make their own unused innovations available to others for free (Burcharth et al., 2014; Chesbrough, 2003; Lee et al., 2010; Wynarczyk et al., 2013) as well as actively participate in others’ innovation (Lee et al., 2010; van de Vrande et al., 2009; Wynarczyk et al., 2013). Finally, the coupled process implies that companies cooperate and cocreate with complementary partners by coupling the two previous types of activities. In coupled OI, companies cooperate with other organizations in strategic networks (Enkel et al., 2009; Gassmann and Enkel, 2004). The main practices included in each dimension are summarized in Table 10.1. It clearly emerges that collaboration is one of the key ingredients of the OI paradigm. Anyway, differences exist between OI and collaborative innovation. Indeed, as highlighted by West and

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Table 10.1 OI Dimensions and Main Practices Dimensions

Practices

Examples

Main References

Inbound

Consumer involvement

Product development based on consumers’ specifications

External networking

Systematic collaboration with external actors (such as universities or research centers and other firms) aimed at supporting the innovation process Buy, sell, or use external IP (such as patents)

Gassmann (2006), van de Vrande et al. (2009), Spithoven et al. (2013), Burcharth et al. (2014) Chesbrough (2006), Chesbrough and Crowther (2006), Gassmann (2006), van de Vrande et al. (2009), Lee et al. (2010), Wynarczyk et al. (2013), Burcharth et al. (2014)

Inward IP licensing

Internet exploration

Know how acquisition Outbound

Outward IP licensing

Systematic use of the internet with the final aim to search for innovative ideas or technologies Purchase of R&D results Sell of patents, licenses or know how

Knowledge exploitation Make available to others for free own unused innovations Knowledge provision Coupled

Alliances with complementary companies

Active participation in others’ innovation projects Combination of the outside-in process (to gain external knowledge) with the inside-out one (to bring ideas to market)

Chesbrough (2006), Gassmann (2006), van de Vrande et al. (2009), Lee et al. (2010), Wynarczyk et al. (2013), Burcharth et al. (2014) Burcharth et al. (2014)

Gassmann (2006), Wynarczyk et al. (2013), Burcharth et al. (2014) Gassmann (2006), Lichtenthaler and Ernst (2007), van de Vrande et al. (2009), Lee et al. (2010), Wynarczyk et al. (2013) Chesbrough (2003), Lee et al. (2010), Wynarczyk et al. (2013), Burcharth et al. (2014) van de Vrande et al. (2009), Lee et al. (2010), Wynarczyk et al. (2013) Gassmann and Enkel (2004), Enkel et al. (2009)

OI, Open innovation; IP, intellectual property.

Gallagher (2006), while the collaboration is characterized by occasional exploitation of external partnerships, OI implies to systematically explore a wide range of internal and external sources for innovation opportunities. Moreover, Lichtenthaler (2011) also stressed that two characteristics of OI exist which distinguish it from a simple collaboration for innovation, that is: first, OI requires the integration of inward and outward knowledge transfer, second internal and external innovationrelated activities are complementary of each other. The OI approach as previously described can thus be used as a means to cope with the challenges that companies may face when industry convergence occurs. Specifically, while the inbound process may be used to internalize external knowledge, the outbound one can be used to commercialize internal knowledge. Similarly, the coupled process involves an exchange between the two different parties involved in the innovation process. Among these, while at a first sight all the three

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processes may seem relevant for innovation in an industrial convergence context, the inbound process is the more relevant one. In particular, in order to overcome the uncertainties and risks that may derive from industry convergence, inbound activities are crucial because companies need competences and knowledge that are not available in their own industry. Thus companies seek help from R&D partnerships, strategic alliances, joint ventures and mergers and acquisitions (Bro¨ring et al., 2006; Chiesa and Toletti, 2004; Harianto and Pennings, 1994), licensing (Arora et al., 2001), networks with producers of complementary products (Cartwright, 2002), or industry consortia (Bor´es et al., 2003). Based on the concepts reported above, and taking into account the analysis of the literature on industry convergence and on OI, it is now possible to propose a theoretical framework that should be adopted when investigating industry convergence applied within any industries. This framework is depicted in Fig. 10.3 and includes the drivers, challenges, types and consequences

FIGURE 10.3 The theoretical framework.

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of industry convergence. In addition, it shows how OI can help the occurrence of industry convergence by acting as facilitator. Specifically, it shows the main drivers (both external and internal) that determine industry convergence, as well as the main consequences deriving from the same (Bor´es et al., 2003; Bro¨ring, 2013; Greenstein and Khanna, 1997; Wirtz, 2001), as emerged from the analysis of the literature. In order to overcome the challenges that companies have to face when industry convergence occurs (Bor´es et al., 2003; Bro¨ring, 2013; Curwen, 2006; Lei, 2000; Nystro¨m and Hacklin, 2005; Palmberg and Martikainen, 2006; Vong Srivastava and Finger, 2006; Wirtz, 2001), OI, in terms of inbound, outbound, and coupled process (Bro¨ring, 2013; Chesbrough, 2003; Chesbrough and Crowther, 2006; Enkel et al., 2009; Gassmann and Enkel, 2004), may act as facilitators. Industry convergence is considered in all its possible classification proposed by the literature, that is: convergence in substitutes or in complements (Greenstein and Khanna, 1997), demand-side and supply-side convergence (Cho et al., 2015; Curran and Leker, 2011; Curran et al., 2010; Hacklin et al., 2009, 2010; Kim et al., 2014; Pennings and Puranam, 2001; Stieglitz, 2003), and technology-side and product-side (Cho et al., 2015; Curran and Leker, 2011; Curran et al., 2010; Hacklin et al., 2009, 2010; Kim et al., 2014; Pennings and Puranam, 2001; Stieglitz, 2003). Aiming at increasing the understanding of industry convergence, the same framework will be applied in Section 10.4 to the food industry, that is currently converging with the pharmaceutical industry, and specifically to the case of nutraceutical products.

10.3.1 OPEN INNOVATION AND THE FOOD INDUSTRY The food industry has always been considered a traditional sector characterized by low-intensity research activities. Its focus has been mainly minimizing production costs thus devoting little attention to customer needs (Bigliardi and Galati, 2013a,b). The industry is now facing greater pressure from the ever-growing demand of consumers for variety, quality, and convenience. As highlighted by different authors (e.g., Bigliardi and Galati, 2013a,b; Galati et al., 2016; Omta and Folstar, 2005; Traill and Meulenberg, 2002), the industry has experienced a shift from a supply-driven approach to a demand-driven one. Consequently, innovation started playing a fundamental role in creating products that meet consumer needs: consumers, indeed, require a new type of products that necessarily require the adoption of innovative technological solutions and new business models. These rapidly changing and evolving consumers’ requirements, combined with other challenges that the industry is facing [such as shortened product life cycles, the competitive time-to-market race (Bellairs, 2010; Martinez et al., 2014) and the growing difficulty in meeting the heterogeneous requirements of numerous players (Beckeman et al., 2013; Saguy and Sirotinskaya, 2014)], lead to the necessity of a new paradigm for the development, acquisition and implementation of innovation. Indeed, as a matter of fact, many of the critical factors food companies need to develop successful innovation reside outside the boundaries of the firm, and as a consequence companies started recognizing the difficulties that they may face in dealing with innovation only internally. Just think about the recent advances in biotechnology, nanotechnology and preservation technology, that all represent unique opportunities for application in the food industry (Bigliardi and Galati, 2013a). The paradigm of OI addresses these challenges and opportunities (Bigliardi and Galati, 2013b; Costa and Jongen, 2006).

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Food companies are slowly integrating external players in their innovation processes. These actors may range from consumers to suppliers, research centers, universities and laboratories (Mikkelsen et al., 2006). The central role of consumers in reducing the costs of developing innovation and the time-to-market innovative products is evidenced by several authors (e.g., Bigliardi and Galati, 2013b; Bigliardi et al., 2016; Bonney et al., 2007; Thomke and von Hippel, 2002; van Rijiswijk and Frewer, 2008). Similarly, different studies highlighting the importance of supplier involvement in food product development (e.g., de Jong and Marsill, 2006; Huston and Sakkab, 2006; Vanhaverbeke and Cloodt, 2006; van der Valk and Wynstra, 2005). Other researchers stressed the importance of the link with academia (Bigliardi and Galati, 2016; Saguy, 2011; Samadi, 2014).

10.3.2 OPEN INNOVATION AND THE PHARMACEUTICAL INDUSTRY Conversely, the pharmaceutical industry, for its nature, considers innovation as one of the main driver (if not the main one) for its growth (European Commission Joint Research Centre, 2012; PhRMA, 2011). Similar to the food industry, also this sector has also experienced different challenges (e.g., increased complexity, new technologies, the availability of highly qualified experts outside the traditional pharmaceutical companies, the increased pressure on time and cost), referred, in particular, to the management of R&D activities. As a consequence, pharmaceutical companies have opened their R&D organizations to external innovation, thus leading to the development of OI (Schuhmacher et al., 2013). Numerous examples are provided by the extant literature: to cite only someone, GlaxoSmithKline (GSK) and its Center for Excellence for External Drug Discovery (http://www.out- sourcing-pharma.com/Preclinical-Research/GSKopensCentre-of-Excellence), Pfizer and its Centers for Therapeutic Innovation (http://www.pfizer.com/ research/rd_works/centers_for_therapeutic_innovation.jsp), Eli Lilly and the Fully Integrated Pharma Network, the Phenotypic Drug Discovery Initiative, the Target Drug Discovery Initiative and Chorus (http://www.choruspharma.com/about-us.html). OI offers a number of options to face the above-mentioned challenges. The early alliance is an example of how pharma companies use to collaborate with biotechnology companies in early R&D activities (Schuhmacher et al., 2013). Also, crowdsourcing offers a potential to gain access to external ideas: indeed, it provides contact to a global scientific community, as well as virtual R&D, where small groups of scientists discover and develop a new drug candidate with the help of external resources. Indeed, the main actors involved in the OI adoption by pharmaceutical companies usually refer to academia and biotech companies (Gassman et al., 2010; Sambandan and Hernandez Raja, 2015). As for academia, its collaboration interests the R&D process at earlier stages. In addition to lab-based R&D facilities, virtual research and project management units are also now adopted, with the main aim to collect and preserve the scientific expertise in the therapeutic areas of interest (Raja and Sambandan, 2015). As for the collaboration with biotech companies, the biotechnology company involved in the alliance provides innovation and offers nondifferentiating capabilities, ideas, know-how, and technologies, while the pharmaceutical company contributes to the discovering and development of an early drug candidate (Schuhmacher et al., 2013). A relationship between pharma and biotech companies are not limited to alliances, but also take place in the form of outsourcing, M&A, or licensing.

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10.4 EVIDENCE OF INDUSTRY CONVERGENCE FROM THE FOOD AND PHARMACEUTICALS INDUSTRIES Industry convergence has been investigated mainly in relation to specific sectors. For example, many examples exist in computers, communication and electronics industries, in the automotive industry, where electronics and software have been integrated more and more (e.g., Adamsson, 2007; Hacklin and Wallin, 2013), and in the construction industry, where intelligent building resulted by the convergence between material design and electronics (e.g., Hacklin et al., 2009). Aware of the importance of industry convergence, researchers have attempted to understand this phenomenon (e.g., Bro¨ring and Leker, 2007), and analyzed its application within other industry. For example, recent studies exist investigating the patterns of industry convergence between the food and pharmaceutical industries (e.g., Bro¨ring and Leker, 2007; Curran and Leker, 2011; Curran et al., 2010; Preschitschek et al., 2013; Weenen et al., 2013).

10.4.1 THE CASE OF NUTRACEUTICALS Nutraceuticals are the result of the boundary-blurring innovation that emerges at the intersection between the food and pharmaceutical industries and leads to the industry convergence between these two sectors (Eussen et al., 2011). Dr. Stephen DeFelice coined the term “nutraceutical” from “nutrition” and “pharmaceutical” in 1989 (DeFelice, 2002), referring to “any substance that is a food or part of a food and provides medical or health benefits, including the prevention and treatment of disease” (p. 59). They are the results of the convergence and the overlap of food and pharmaceutical industries that lead to the emergence of a new interindustry converged segment at the border between foods and drugs. Specifically, nutraceuticals represent a case of convergence in complements (Greenstein and Khanna, 1997), meaning that foods and drugs bundle together becoming the new and integrated product named nutraceutical. Such a product integrates different technologies and consumer trends, without leading to a phasing out of the original industries. Nutraceuticals may range from isolated nutrients or dietary supplements to genetically engineered designer foods or processed foods such as cereals, soups, and beverages. As for the distinction between demand-side and supply-side convergence proposed by different authors (e.g., Pennings and Puranam, 2001; Stieglitz, 2003), in the case of nutraceuticals converging trends are observed in both directions: convenience, nutritional needs, prevention for the demand-side, and nutritional science, genomics, nutrigenomics for the supply-side. This result contrasts the observation by Gambardella and Torrisi (1998). Specifically, Bro¨ring et al. (2006) showed the case of a company, originally active in the industry segment of speciality chemical ingredients, that decided to enter the fast-growing consumer market of supplements and started an R&D project aimed at the development of a hydrolyzed whey protein targeting high blood pressure. This project was focused on the development of a new consumer product based on parallel technology development and was carried out by means of a collaboration with a food company interested in entering the nutraceutical sector. On the one side, the food company lacked technological competence; on the other side, the pharmaceutical firm lacked the marketing experience. Thus to overcome these reciprocal lacks of market-related and technology-related competencies, they settled a joint venture and developed the hydrolyzed whey protein.

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As far as drivers are concerned, and specifically as for the external ones, new technologies and their rapid diffusion are the main external drivers for industry convergence between food and pharmaceutical industries (Bro¨ring, 2005; Bro¨ring and Cloutier, 2008). In particular, advances in the field of biotechnology and genomics played a significant role in driving industry convergence. For instance, the progress in biotechnology leads to the development of bioactive food and pharmaceutical ingredients. Similarly, knowledge from genomics, crop science, genetic engineering and modern medicine allowed the development of nutritional products for medical prevention (Zhang and Li, 2010). Also, regulation is presented as a driver for convergence between food and pharma (Bro¨ring, 2013). Specifically, the regulatory environment in which companies belonging to the industries involved in convergence, and in particular its legal definitions (e.g., what is a functional food or a nutraceutical) and regulations (e.g., health claims), determine what companies can or cannot produce. However, in the case of nutraceuticals, legal definitions are not always available, as well as regulations are in continuous and slow evolution. As a consequence, regulation can also be considered as a challenge in terms of investment that food companies have to realize in order to enter the nutraceutical sector, and of the clinical research, expertise is required. Different studies exist stressing, in addition to technologies, the importance also market trends as external drivers. Specifically, the main market trends highlighted by researchers are the ageing population, rising health care costs, demand for healthier food products, consumers’ proactive behavior and the willingness to pay for health benefit (e.g., Bro¨ring, 2010; Bro¨ring, 2013). As for the challenges, they mainly refer to the competence and knowledge gaps of companies belonging to the industries involved: specifically, both nutritional and pharmaceutical companies require technological and market competences (Bro¨ring, 2013). Indeed, while food companies have a high level of market competencies and may lack technological knowledge (i.e., clinical trials), contrarily the pharmaceutical ones are characterized by a high level of technological competencies but suffer in terms of the market ones (i.e., knowledge of consumers’ needs and requirements) (Bro¨ring, 2005, 2013; Rothaermel and Deeds, 2006). Thus the sectors are complementary to each other. In order to fill these gaps, OI can be adopted as facilitators. Specifically, in order to obtain a nutraceutical, food and pharma companies may establish an R&D or other forms of collaboration in order to acquire the required knowledge and competencies above mentioned. According to the available literature, the most appropriate OI activities are the inbound and the coupled ones (e.g., Bro¨ring, 2005, 2013). For example, in order to acquire the missing R&D and technological competences, food firms may benefit from R&D networks. Similarly, companies may benefit from crossindustry acquisitions or interindustry R&D collaborations. The first and more obvious consequence deriving from industry convergence between food and pharma is the enlargement of the market in terms of new products, both in terms of enrichment of foods with functional ingredients, as well as in terms of new and personalized products (Bro¨ring, 2010; Green and van der Ouderaa, 2003). As previously detailed, in this research industry convergence is considered as proceeding along an evolutionary trajectory consisting of four phases, as depicted in Fig. 10.2, namely: (1) initialization, (2) knowledge diffusion, (3) consolidation, and (4) maturation. In the case of nutraceuticals, the process may be slightly modified by adding, within the second stage (knowledge diffusion), and technological diffusion (Fig. 10.4). As previously stressed, in fact, competences in terms both of knowledge and technology are required by the companies involved in the development of a

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FIGURE 10.4 The linear process of industry convergence.

nutraceutical product. In the initialization phase, the R&D of food and pharmaceutical industries remains independent and the characteristics of each sector differ due to the different competence profiles of each industry, as previously described. Indeed, while in the food sector companies are characterized by a path-dependent development of B2C-marketing practices, in the pharmaceutical sector firms are characterized by technological path dependency. Thus while food companies pay attention to consumers’ insight, pharmaceutical companies pay more attention to the development of distinct technology programs. The development of nutraceuticals products requires both technological and consumer-marketing resources. As a consequence, in the knowledge and technology diffusion phase, both types of knowledge start being diffused between the food and the pharmaceutical industries, thus diminishing the distance in terms of competences (consolidation phase). Joint R&D collaborations are used to be established in these stages to close the competence gaps. Finally, as a result of this process, the nutraceuticals interindustry segment emerges. In addition, it is possible to also adapt the theoretical framework proposed in Fig. 10.3 to the case of nutraceuticals. The resulting framework is depicted in Fig. 10.5 and entails all the peculiarities highlighted in the previous lines. Specifically, the figure depicts the drivers and challenges, the classification of convergence and the main consequences of industry convergence specific of the case investigated. In a similar way, as far as OI is concerned, only the inbound and coupled process is proposed as facilitators, as stressed by the literature (Bro¨ring, 2005, 2013). The literature also provides a number of examples of nutraceuticals developed under an OI approach. For instance, in order to develop new radical innovations involving the development of new technology platforms, several companies established a systematic collaboration with companies belonging to different industries as well as Universities and research centers. This R&D

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Facilitators • Open innovation (Bröring, 2013; Chesbrough, 2003; Chesbrough and Cowhter, 2006; Enkel et al., 2009; Gassmann and Enkel, 2004) • Inbound OI activities (i.e., R&D networks, cross-industry acquisitions, interindustry R&D collaborations) (Bröring, 2005, 2013) • Coupled process (Bröring, 2005, 2013)

Drivers and challenges

• External drivers: • Technological changes and innovation (i.e., new technologies and their rapid diffusion, advances in the field of biotechnology and genomics) (Bröring, 2005; Bröring and Cloutier, 2008; Zhang et al., 2010) • Deregulation (i.e., regulatory environment, legal definitions, regulations) (Bröring, 2010, 2013) • Challenges: • Competences and knowledge gaps of companies (i.e., technological and market competences) (Bröring, 2005, 2013; Rothaermel and Deeds, 2006)

Industry convergence

• Convergence in complements (i.e., foods and drugs bundle together becoming the new and integrated product) (Greenstein and Khanna, 1997) • Demand-side and supplyside convergence (i.e., convenience, nutritional needs, prevention for the demand-side; nutritional science, genomics, nutrigenomics for the supply-side) (Bröringet al., 2006) • Technology-side and product-side convergence (i.e., technologies and similar technological platforms for the technology-side; diseases prevention, nutritive and preventive functions for the product-side) (Bröring, 2005, 2010; Bröring and Cloutier, 2008; Pennings and Puranam, 2001; Zhang et al., 2010)

Consequences

• Economic consequences • Market enlargement and increased competition (i.e., enrichment of foods with functional ingredients, new and personalized products) (Bröring, 2010; Green and van der Ouderaa, 2003)

FIGURE 10.5 The theoretical framework adapted to the case of nutraceuticals.

network resulted in NuGO (Nutrigenomics Organization), an association of Universities and research institutes focusing on the joint development of the research areas of molecular nutrition, personalized nutrition, nutrigenomics and nutritional systems biology. The main result obtained is the development and advancement of nutrigenomics platforms, and it was allowed by the reciprocal sharing of the competencies of each partner. Similarly, Royal DSM, a global science-based company active in health, nutrition and materials, realized that it did not have sufficient knowledge about their consumers market. In order to fill these competences gaps, it has established a systematic partnership with Team Sunweb and sports nutrition specialists, BORN. The collaboration has resulted in the creation of ISO PRO 1 , an energy beverage with optimal muscle recovery benefits that contains DSM’s Peptopro ingredient to aid faster protein absorption and support immediate muscle recovery, both during and after exercise. An example of the successful alliance in developing nutraceuticals is provided by Kraft Foods and Medisyn, a small niche, Minnesota-based

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Table 10.2 Examples of Nutraceutical Developed Under an OI Approach Example

Objective

OI Activities (OI Model)

Actors Involved

Green tea with a combination of polydextrose Nestle` Health Science SA

To gain synergies and mutual benefits

R&D collaboration (inbound)

Food (Tate&Lile) and Canadian hot drinks specialist

To close competencerelated gaps, gain synergies and strengthen the product/technology portfolio To close technologyrelated gaps To penetrate into FF growth

Acquisitions, M&A activities (inbound)

A food company (Nestle`) and pharmaceutical start-up (CM&D)

R&D networks (inbound)

NFFs and drinks

To attain health claims for FF and drinks

R&D collaborations (coupled)

NuGo

To develop a new technology platform To close competence and technology-related gaps

R&D networks (coupled)

Food companies and INAF— Institute of NFFs A food company (Kraft Foods) and a small niche pharmaceutical/ biotechnology company (Medisyn) Global food and drinks companies (Unilever, Coca Cola, PepsiCo) and drug manufacturers, pharmaceutical and biotechnology companies Universities, research institutes

NFFs NFFs

Peptopro

Alliance (coupled)

R&D collaborations (coupled)

A chemical (DSM) company, and consumer goods companies (Team SunWeb, BORN)

OI, Open innovation; NFFs, nutraceuticals and functional foods.

pharmaceutical/biotechnology company. The alliance allowed the former to penetrate offensively into functional foods (FFs) market, and to the second to apply its proprietary technology to its known chemicals and compounds for functional food products (Hardy, 2010). The examples previously described and others obtained by the literature are summarized in Table 10.2:

10.5 CONCLUSIONS The objective of this chapter was to investigate the role of OI when the convergence between food and pharma occurs. To do that, at first it studied the extent to which the food and pharmaceutical industries show tendencies to converge, and, as second, how open innovation may be adopted in order to help their convergence. Industry convergence is defined, according to the available literature (e.g., Kim et al., 2015, p. 1736), as “the process of blurring boundaries between two or more disparate industries by combining their scientific knowledge, technology, and markets.” When industry convergence occurs between food and pharmaceutical industries, NFFs result. These products add health benefits over and above the nutritional values of traditional food products (Frewer

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et al., 2003). The reasons that lead a consumer to buy such products are multiple, but the main one is their growing desire to use foods that may help in the prevention of chronic illnesses (e.g., cardiovascular disease, Alzheimer’s disease, etc.), as well as to optimize their health (e.g., by boosting their immune system) (Regmi and Gehlhar, 2005; Sadler, 2005). The development of this kind of product has been described in the literature as complex, expensive and risky (Kleef et al., 2002; Siro et al., 2008). To complicate things further, the area where food and health markets merge has generated a need for new knowledge and competencies for personnel and companies working in this context (Bro¨ring, 2005; Mark-Herbert, 2003). Among the factors that may facilitate filling these gaps, the literature proposes interindustry relationships, research-oriented collaborative networks and other types of collaboration. All these kinds of collaborations and relationships, if established in a systematic way, fall under the name of OI (Chesbrough, 2003). OI implies collaborative product development by pharmaceutical and food companies, with sharing of resources, knowledge and competencies. The development of nutraceuticals appears to be a long-term trend with the important market and technological potential. Competition in this field is becoming more and more intense, and companies have to face new consumer groups. To survive in such a context, companies have to develop their nutraceutical products by taking consumers’ needs into consideration. A recent report on food and drink industry trends in Europe (Food Drink Europe, 2014) identifies five general consumers’ expectations, namely: pleasure, health, physical, convenience, and ethics. Therefore, the involvement of the consumer is crucial in the innovation process. In addition, a crucial role is covered by academia. University has always been associated with the economic system to the teaching and researching role. Recently, its role has changed significantly in response to the changes that occurred in industries such as the food and pharmaceutical ones. Specifically, as stressed both in the food and pharmaceutical-related literature, the boundaries between academia and these two industries are becoming more permeable as industry convergence occurs. As far as the pharmaceutical industry is concerned, the most basic research (i.e., new therapies) occurs outside the walls of pharmaceutical laboratories and in particular within academia. Among the main contributions from academia, the knowledge about disease biology, big data techniques and human genetics can be cited. As pharmaceutical companies need academia, academia also needs pharmaceutical companies. Indeed, academic researchers turn to pharmaceutical companies to expand their discoveries beyond academia to patients. Consequently, due to this common interest, academic and pharmaceutical scientists should improve collaboration more and more, for instance by means of alliances or R&D networks. Similarly, as for the food industry, academia plays an emerging role that food companies use to collaborate with it to exploit knowledge and technology transfer (Perkmann and Walsh, 2007). Important food companies such as Nestl´e (Traitler et al., 2011), Procter & Gamble and Unilever (Dodgson et al., 2006), established a wide network of collaborations with a very large number of universities and research centers around the world. From the university side, the collaboration between the food industry and universities traditionally allow raising funding for their research from industry to generate outputs useful for academic publications (Etzkowitz et al., 2000). From the food companies side, collaboration with a university represents an alternative for these enterprises to access sources of skills, expertise, talents required, funds, and facilities for their innovation process. Thus also in the food context, mutual benefits can be identified.

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In addition to the benefits above mentioned, also some hindering factor has to be noticed. An example is provided by the collaboration established by the company CAG functional foods and a Swedish biotech business aimed at the introduction of a probiotic product in the US market. Even if the collaboration has allowed both firms to fill the respective gaps in terms of knowledge and competencies, it also suffered serious difficulties among the partners due to IP rights and brand ownership issues (Mark-Herbert, 2003). In particular, indeed, the commercialization of new nutraceuticals products may pose serious challenges of protecting IP rights in order to secure a higher premium. IP rights are assuming increasing importance for innovative firms (Gloet and Terziovski, 2004), also for those operating in the food industry (Bigliardi and Galati, 2013a). They are used to defend the company’s competitive position but also to create revenue from innovation (Allen, 2003), and as stressed by Candelin-Palmqvist et al. (2012), they represent critical factors for research partnerships and innovation projects. In particular, the adoption of the OI paradigm is shaking up the conventional understanding of IP protection, due to the risks entailed in the paradigm itself (Alexy and Reitzig, 2012). Thus, a policy aimed at maintaining and enhancing the brand image of the company in the new converged segment is required. In conclusion, in the actual context of demographic, economic, and social challenges for the food and pharmaceutical industries, the establishment of systematic collaboration, under an OI approach, with research institutes and academia on the one side, and consumers on the other side, may serve as a unique opportunity for the development of nutraceuticals.

REFERENCES Adamsson, N., 2007. Interdisciplinary Integration in Complex Product Development: Managerial Implications of Embedding Software in Manufactured Goods (Ph.D. dissertation). Royal Institute of Technology. Alexy, O., Reitzig, M., 2012. Managing the business risks of open innovation. McKinsey Quarterly 1 (1), 17
21. Allen, K.R., 2003. Bringing New Technology to Market. Pearson College Division. Almirall, E., Casadesus-Masanell, R., 2010. Open versus closed innovation: a model of discovery and divergence. Acad. Manage. Rev. 35 (1), 27
47. Andergassen, R., Nardini, F., Ricottilli, M., 2006. Innovation waves, self-organized criticality and technological convergence. J. Econ. Behav. Org 61 (4), 710
728. Arora, A., Fosfuri, A., Gambardella, A., 2001. Markets for technology and their implications for corporate strategy. Ind. Corp. Change 10 (2), 419
451. Beckeman, M., Bourlakis, M., Olsson, A., 2013. The role of manufacturers in food innovations in Sweden. Br. Food J. 115 (7), 953
974. Bellairs, J., 2010. Open innovation gaining momentum in the food industry. Cereal Foods World 55 (1), 4
6. Benner, M.J., Ranganathan, R., 2013. Divergent reactions to convergent strategies: investor beliefs and analyst reactions during technological change. Org. Sci. 24 (2), 378
394. Bigliardi, B., Galati, F., 2013a. Innovation trends in the food industry: the case of functional foods. Trends Food Sci. Technol. 31 (2), 118
129. Bigliardi, B., Galati, F., 2013b. Models of adoption of open innovation within the food industry. Trends Food Sci. Technol. 30 (1), 16
26. Bigliardi, B., Galati, F., 2016. Which factors hinder the adoption of open innovation in SMEs? Technol. Anal. Strategic Manage 28 (8), 869
885.

REFERENCES

331

Bonney, L., Clark, R., Collins, R., Fearne, A., 2007. From serendipity to sustainable competitive advantage: insights from Houston’s Farm and their journey of co-innovation. Supply Chain Manage.: Int. J. 12 (6), 395
399. Bor´es, C., Saurina, C., Torres, R., 2003. Technological convergence: a strategic perspective. Technovation 23 (1), 1
13. Bro¨ring, S., 2005. The Front End of Convergence in Converging Industries: The Case of Nutraceuticals and Functional Foods. Gabler-Verlag, Wiesbaden. Broring, S., 2010. Developing innovation strategies for convergence-Is’ open innovation’imperative? Int. J. Technol. Manag 49 (1/2/3), 272
294. Bro¨ring, S., 2013. The role of open innovation in the industry convergence between foods and pharmaceuticals. In: Martinez, Marian Garcia (Ed.), Open Innovation in the Food and Beverage Industry. Woodhead Publishing, Cambridge, pp. 39
62. Bro¨ring, S., Leker, J., 2007. Industry convergence and its implications for the front end of innovation: a problem of absorptive capacity. Creativity Innov. Manage. 16 (2), 165
175. Bro¨ring, S., Cloutier, L.M., 2008. Value-creation in new product development within converging value chains: an analysis in the functional foods and nutraceutical industry. Br. Food J. 110 (1), 76
97. Bro¨ring, S., Martin Cloutier, L., Leker, J., 2006. The front end of innovation in an era of industry convergence: evidence from nutraceuticals and functional foods. R&D Manage 36 (5), 487
498. Burcharth, A.L.D.A., Knudsen, M.P., Søndergaard, H.A., 2014. Neither invented nor shared here: the impact and management of attitudes for the adoption of open innovation practices. Technovation 34 (3), 149
16. Candelin-Palmqvist, H., Sandberg, B., Mylly, U.M., 2012. Intellectual property rights in innovation management research: a review. Technovation 32 (9-10), 502
512. Cartwright, P.A., 2002. Only converge: networks and connectivity in the information economy. Bus. Strategy Rev. 13 (2), 59
64. Chesbrough, H., 2003. Open Innovation: The New Imperative for Creating and Profiting From Technology. Harvard Business School Press, Boston, MA. Chesbrough, H., 2006. Open Business Models. Harvard Business School Press, Cambridge, MA. Chesbrough, H., Crowther, A.K., 2006. Beyond high tech: early adopters of open innovation in other industries. R&D Manage. 36 (3), 229
236. Chiesa, V., Toletti, G., 2004. Network of collaborations for innovation: the case of biotechnology. Technol. Anal. Strategic Manage. 16 (1), 73
96. Cho, Y., Kim, E., Kim, W., 2015. Strategy transformation under technological convergence: evidence from the printed electronics industry. Int. J. Technol. Manage. 67 (2/3), 4. Choi, D., Valikangas, L., 2001. Patterns of strategy innovation. Eur. Manage. J. 19 (4), 424
429. Chon, B.S., Choi, J.H., Barnett, G.A., Danowski, J.A., Joo, S.H., 2003. A structural analysis of media convergence: cross-industry mergers and acquisitions in the information industries. J. Media Econ. 16 (3), 141
157. Costa, A.I., Jongen, W.M.F., 2006. New insights into consumer-led food product development. Trends Food Sci. Technol. 17 (8), 457
465. Curran, C.S., 2013. The Anticipation of Converging Industries. A Concept Applied to Nutraceuticals and Functional Foods. Springer, London. Available from: https://doi.org/10.1007/978-1-4471-5170-8. Curran, C.S., Leker, J., 2011. Patent indicators for monitoring convergence
examples from NFF and ICT. Technol. Forecast. Soc. Change 78 (2), 256
273. Curran, C.S., Bro¨ring, S., Leker, J., 2010. Anticipating converging industries using publicly available data. Technol. Forecast. Soc. Change 77 (3), 385
395. Curwen, P., 2006. Fixed-mobile convergence. info 8 (3), 3
11. D’Aveni, R.A., Dagnino, G.B., Smith, K.G., 2010. The age of temporary advantage. Strategic Manage. J. 31 (13), 1371
1385.

332

CHAPTER 10 REORIENTATION OF NUTRACEUTICALS

De Jong, J.P., Marsili, O., 2006. The fruit flies of innovations: a taxonomy of innovative small firms. Res. Policy 35 (2), 213
229. DeFelice, S.L., 2002. FIM rationale and proposed guidelines for the nutraceutical research & education Act NREA, November 10, 2002. Foundation for Innovation in Medicine. Retrieved at: ,http://www.fimdefelice.org/archives/arc.researchact.html.. Dodgson, M., Gann, D., Salter, A., 2006. The role of technology in the shift towards open innovation: the case of Procter & Gamble. R&D Manage 36 (3), 333
346. Enkel, E., Gassmann, O., Chesbrough, H., 2009. Open R&D and open innovation: exploring the phenomenon. R&D Manage 39 (4), 311
316. Etzkowitz, H., Webster, A., Gebhardt, C., Terra, B.R.C., 2000. The future of the university and the university of the future: evolution of ivory tower to entrepreneurial paradigm. Res. Policy 29 (2), 313
330. European Commission Joint Research Centre, Directorate General Research, 2012. The 2012 EU Industrial R&D Investment Scoreboard. European Commission. Eussen, S.R., Verhagen, H., Klungel, O.H., Garssen, J., van Loveren, H., van Kranen, H.J., et al., 2011. Functional foods and dietary supplements: products at the interface between pharma and nutrition. Eur. J. Pharmacol. 668, S2
S9. Fai, F., Von Tunzelmann, N., 2001. Industry-specific competencies and converging technological systems: evidence from patents. Struct. Change Econ. Dyn. 12 (2), 141
170. Food Drink Europe, 2014. Data & Trends of the European Food and Drink Industry 2013-2014. Frewer, L., Scholderer, J., Lambert, N., 2003. Consumer acceptance of functional foods: issues for the future. Br. Food J. 105 (10), 714
730. Galati, F., Bigliardi, B., Petroni, A., 2016. Open innovation in food firms: implementation strategies, drivers and enabling factors. Int. J. Innov. Manage 20 (03), 1650042. Gambardella, A., Torrisi, S., 1998. Does technology convergence imply convergence in markets? Evidence from the electronics industry. Res. Policy 27, 445
463. Gassmann, O., 2006. Opening up the innovation process: towards an agenda. R&D Manage. 36 (3), 223
228. Gassmann, O., and Enkel, E. (2004). “Towards a theory of open innovation: three core process archetypes”, in: Proceedings of the R&D Management Conference, Lisbon, Portugal, July 6
9. Gassmann, O., Enkel, E., Chesbrough, H., 2010. The future of open innovation. R&D Manage. 40 (3), 213
221. Gloet, M., Terziovski, M., 2004. Exploring the relationship between knowledge management practices and innovation performance. J. Manuf. Technol. Manage. 15 (5), 402
409. Green, M.R., Van der Ouderaa, F., 2003. Nutrigenetics: where next for the foods industry? Pharmacogenet. J. 3, 191
193. Greenstein, S., Khanna, T., 1997. What does industry convergence mean. In: Yoffie, D.B. (Ed.), Competing in the Age of Digital Convergence. Harvard Business School Press, Boston, 2010226. Hacklin, F., 2007. Management of Convergence in Innovation: Strategies and Capabilities for Value Creation Beyond Blurring Industry Boundaries. Springer Science & Business Media. Hacklin, F., 2008. Management of Convergence in Innovation
Strategies and Capabilities for Value Creation beyond Blurring Industry Boundaries. Physica-Verlag, Heidelberg. Hacklin, F., 2010. Management of Convergence in Innovation: Strategies and Capabilities for Value Creation Beyond Blurring Industry Boundaries. Physica-Verlag HD, London, pp. 18
67. Hacklin, F., Klang, D., Baschera, P., 2013. Managing the convergence of industries: Archetypes for successful business models. Media and convergence management. Springer, Berlin, Heidelberg, pp. 25
36. Hacklin, F., Wallin, M.W., 2013. Convergence and interdisciplinarity in innovation management: a review, critique, and future directions. Service Ind. J 33, 774
788. Hacklin, F., Raurich, V., Marxt, C., 2004. How incremental innovation becomes disruptive: the case of technology convergence, in: Proceedings of the IEEE International Engineering Management Conference, Singapore, 2004.

REFERENCES

333

Hacklin, F., Marxt, C., Fahrni, F., 2009. Coevolutionary cycles of convergence: an extrapolation from the ICT industry. Technol. Forecast. Soc. Change 76, 723
736. Hardy, N., 2010. Future innovations in food and drinks to 2015. Business Insights, London, No. BI00014 - 024. Harianto, F., Pennings, J.M., 1994. Technological convergence and scope of organizational innovation. Res. Policy 23 (3), 293
304. Huston, L., Sakkab, N., 2006. Connect and develop. Harvard Bus. Rev. 84 (3), 58
66. Kim, W., Lee, J., 2009. Measuring the role of technology-push and demand-pull in the dynamic development of semiconductor industry: the case of the global DRAM market. J. Appl. Econ. 7, 83
108. Kim, W., Kim, M., 2015. Reference quality-based competitive market structure for innovation driven markets. Available at SSRN: ,http://ssrn.com/abstract 5 2519039.. Kim, E., Cho, Y., Kim, W., 2014. Dynamic patterns of technological convergence in printed electronics technologies: patent citation network. Scientometrics 98 (2), 975
998. Kim, N., Lee, H., Kim, W., Lee, H., Suh, J.H., 2015. Dynamic patterns of industry convergence: evidence from a large amount of unstructured data. Res. Policy 44 (9), 1734
1748. Kodama, F., 1991. Emerging Patterns of Innovation: Sources of Japan’s Technological Edge. Harvard Business School Press, Boston, MA. Lee, S., Park, G., Yoon, B., Park, J., 2010. Open Innovation in SMEs
An Intermediated Network Model. Res. Policy 39 (2), 290
300. Lei, D.T., 2000. Industry evolution and competence development: the imperatives of technology convergence. Int. J. Technol. Manage. 19, 699
738. Lichtenthaler, U., 2011. Open innovation: past research, current debates, and future directions. Acad. Manage. Perspect. 25 (1), 75
93. Lichtenthaler, U., Ernst, H., 2007. External technology commercialization in large firms: results of a quantitative benchmarking study. R&D Manage 37 (5), 383
397. Mark-Herbert, C., 2003. Development and marketing strategies for functional foods. AgBioForum 6 (1 e 2), 75
78. Mikkelsen, B.E., Kristensen, N.H., Nielsen, T., 2006. Innovation processes in large-scale public foodservice— case findings from the implementation of organic foods in a Danish County. J. Foodservice Bus. Res 8 (2), 87
105. Nystro¨m, A., and Hacklin, F. (2005), “Operator value creation through technological convergence: the case of VoIP”, in: International Telecommunications Society (ITS), 16th European Regional Conference, Porto, Portugal. OECD, 1992. Telecommunications and Broadcasting: Convergence or Collision? OECD Publishing, Paris. Omta, S.W.F., Folstar, P., 2005. Integration of innovation in the corporate strategy of agri-food companies. Innovation in agri-food systems. Product Quality and Consumer Acceptance 221
230. Palmberg, C., Martikainen, O., 2006. Diversification in response to ICT convergence
indigenous capabilities versus R&D alliances of the Finnish telecom industry. info 8 (4), 67
84. Pavitt, K., 1984. Sectoral patterns of technical change: towards a taxonomy and a theory. Res. Policy 13 (6), 343
373. Pennings, J.M., Puranam, P., 2001. Market convergence and firm strategy: new directions for theory and research. in: ECIS Conference, The Future of Innovation Studies, Eindhoven, The Netherlands (vol. 20, no. 23.09). Perkmann, M., Walsh, K., 2007. University
industry relationships and open innovation: towards a research agenda. Int. J. Manage. Rev. 9 (4), 259
280. Pharmaceutical Research and Manufacturers of America (PhRMA), 2011. Pharmaceutical Industry 2011 Profile. PhRMA. Prahalad, C.K., 1998. Managing discontinuities: the emerging challenges. Res. Technol. Manage. 41 (3), 14
22. Preschitschek, N., Niemann, H., Leker, J., Moehrle, G.M., 2013. Anticipating industry convergence: semantic analyses vs IPC co-classification analyses of patents. Foresight 15 (6), 446
464.

334

CHAPTER 10 REORIENTATION OF NUTRACEUTICALS

Regmi, A., Gehlhar, M.J., 2005. New Directions in Global Food Market. Economic Research Services. USDA. Rothaermel, F.T., Deeds, D.L., 2006. Alliance type, alliance experience and alliance management capability in high-technology ventures. J. Bus. Venturing 21 (4), 429
460. Sadler, J., 2005. Innovation in Functional Food and Drinks. Business Insights Ltd. Saguy, I.S., 2011. Paradigm shifts in academia and the food industry required to meet innovation challenges. Trends Food Sci. Technol. 22 (9), 467
475. Saguy, I.S., Sirotinskaya, V., 2014. Challenges in exploiting open innovation’s full potential in the food industry with a focus on small and medium enterprises (SMEs). Trends Food Sci. Technol. 38 (2), 136
148. Samadi, S., 2014. Open innovation business model in the food industry: exploring the link with academia and SMEs. J. Econ., Bus. Manage. 2 (3), 209
213. Sambandan, P., Hernandez Raja, B., 2015. Open innovation in pharmaceutical industry, a case study of Eli Lilly: how do big pharmas implement OI?
a critical analysis of the current OI practices through a case study. Retrieved at: ,http://www.diva-portal.org/smash/get/diva2:824465/FULLTEXT01.pdf.. Schuhmacher, A., Germann, P.G., Trill, H., Gassmann, O., 2013. Models for open innovation in the pharmaceutical industry. Drug Discov. Today 18 (23-24), 1133
1137. Siro, I., K´apolna, E., K´apolna, B., Lugasi, A., 2008. Functional food. Product development, marketing and consumer acceptance—A review. Appetite 51 (3), 456
467. Spithoven, A., Vanhaverbeke, W., Roijakkers, N., 2013. Open innovation practices in SMEs and large enterprises. Small Bus. Econ 41 (3), 537
562. Stieglitz, N., 2002. Industry dynamics and types of market convergence. In: DRUID Summit Conference on Industrial Dynamics of the New and Old Economy-Who is Embracing Whom. Copenhagen/Elsinore June 6
8, 2002, pp. 1
36. Stieglitz, N. (2003). “Digital dynamics and types of industry convergence: the evolution of the handheld computers market. In: Jens Frosley Christensen and Peter Maskell (Eds.), The Industrial Dynamics of the New Digital Economy, Cheltenham, UK, 2, 179-208. Thomke, S., Von Hippel, E., 2002. Customers as innovators: a new way to create value. Harvard Bus. Rev. 80 (4), 74
85. Traill, W.B., Meulenberg, M., 2002. Innovation in the food industry. Agribusiness: Int. J 18 (1), 1
21. Traitler, H., Watzke, H.J., Saguy, I.S., 2011. Reinventing R&D in an open innovation ecosystem. J. Food Sci 76 (2), R62
R68. van de Vrande, V., Jong, J.P.J.D., Vanhaverbeke, W., Rochemont, M.D., 2009. Open innovation in SMEs: trends, motives and management challenges. Technovation 29, 423
437. Van der Valk, W., Wynstra, F., 2005. Supplier involvement in new product development in the food industry. Ind. Market. Manage. 34 (7), 681
694. Van Kleef, E., Van Trijp, H.C.M., Luning, P., Jongen, W.M.F., 2002. Consumer-oriented functional food development: how well do functional disciplines reflect the ‘voice of the consumer’? Trends in Food Sci. Technol. 13 (3), 93
101. Van Rijswijk, W., Frewer, L.J., 2008. Consumer perceptions of food quality and safety and their relation to traceability. Br. Food J. 110 (10), 1034
1046. Vanhaverbeke, W., 2006. The interorganizational context of open innovation. In: Chesbrough, H., Vanharbeke, W., West, J. (Eds.), Open Innovation: Researching a New Paradigm. Oxford University Press, pp. 205
219. Vanhaverbeke, W., Cloodt, M., 2006. Open innovation in value networks. Open Innovation: Researching a New Paradigm. Oxford University Press, pp. 258
281. von Delft, S., 2013. Inter-industry innovations in terms of electric mobility: Should firms take a look outside their industry? J. Bus. Chem 10 (2), 67
87. Vong Srivastava, J., Finger, M., 2006. Fixed to Mobile Convergence (FMC): technological convergence and the restructuring of the European telecommunications industry. SPRU 40th Anniversary B12 Conference, Brighton, UK.

FURTHER READING

335

Weenen, T.C., Ramezanpour, B., Pronker, E.S., Commandeur, H., Claassen, E., 2013. Food-pharma convergence in medical nutrition n
best of both worlds? PLoS One 8 (12), e82609. West, J., Gallagher, S., 2006. Challenges of open innovation: the paradox of firm investment in open-source software. R&D Manage. 36 (3), 319
331. Wirtz, B.W., 2001. Reconfiguration of value chains in converging media and communications markets. Long Range Planning 34 (4), 489
506. Wynarczyk, P., Piperopoulos, P., McAdam, M., 2013. Open innovation in small and medium-sized enterprises: an overview. Int. Small Bus. J. 31 (3), 240
255. Yoffie, D.B., 1997. Competing in the age of digital convergence. Harvard Business School Press. Zhang, Y., Li, H., 2010. Innovation search of new ventures in a technology cluster: the role of ties with service intermediaries. Strategic Manage. J. 31 (1), 88
109.

FURTHER READING Garcia Martinez, M., Lazzarotti, V., Manzini, R., S´anchez Garcı´a, M., 2014. Open innovation strategies in the food and drink industry: determinants and impact on innovation performance. Int. J. Technol. Manage 66 (2-3), 212
242. Prahalad, C.K., Hamel, G., 1994. Strategy as a field of study: why search for a new paradigm? Strategic Manage. J. 15 (S2), 5
16. Preschitschek, N., Curran, C.S., Leker, J., 2011. The importance of access to resources in a setting of industry convergence: the case of agriculture and chemistry. Technology Management in the Energy Smart World (PICMET), 2011 Proceedings of PICMET’11. IEEE, pp. 1
9. Zhang, X., Yap, Y., Wei, D., Chen, G., Chen, F., 2008. Novel omics technologies in nutrition research. Biotechnol. Adv 26 (2), 169
176.

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Index Note: Page numbers followed by “f” and “t” refer to figures and tables, respectively.

A Absorption, 204
208, 205f coefficient, 200, 202 Acenocoumarin, 77 Acetaminophen, 74
75 Acetaminophen-induced hepatotoxicity, 76 Active oxygen species, 146
147 Active transporters (AT), 202, 207
208 Acute mountain sickness (AMS), 142
143 AD. See Alzheimer’s disease (AD) ADAM10. See α-disintegrin and metalloprotease 10 (ADAM10) Adaptogens, 148, 149f Adenosine triphosphate (ATP), 75 Adipose tissues, 170
171 Adjuvant-induced arthritis (AIA) rat model, 153 Aerobic cells, 35 Aerosol administration, 20 Aetheroleum Lavandulae, 284t Aetheroleum Melaleucae Alternifoliae, 277t Aetheroleum Menthae Piperitae, 277t Age-related macular degradation (AMD), 11 Agni casti fructus, 295t Agricultural by-products, 241 Agro-industrial wastes, 236, 241 AIA rat model. See Adjuvant-induced arthritis (AIA) rat model ALA. See α-linolenic acid (ALA) Aldehyde oxidase, 46
50 Alkaline phosphatase (ALP), 77 Alkoxyl radical (RO), 36
37 Alkylating agents, 74
75 Allergy, 11 Aloe, 270, 271t, 295t ALP. See Alkaline phosphatase (ALP) α-disintegrin and metalloprotease 10 (ADAM10), 125
126 α-glucosidase, 118
119 α-linolenic acid (ALA), 198
199 α-lipoic acid, 123 Alzheimer’s disease (AD), 124, 149 AMD. See Age-related macular degradation (AMD) American Food and Drug Administration, 14 Amla. See Emblica officinalis (ES) Amodiaquine, 74
75, 78
79 AMP-kinase (AMPK), 180 Amphetamines, 2 AMPK. See AMP-kinase (AMPK) AMS. See Acute mountain sickness (AMS)

Amyloid precursor protein (APP), 125
126 Anabolic androgenic steroids, 79 Ancient medicines, 268 Anticancer activity of SBT, 153 Anticoagulants anticoagulant-induced hepatic abnormalities, 77 drug, 77 Anticonvulsants, 77
78 Antiepileptic drugs, 77
78 Antihistamine, 11 Antihyperlipidemic drugs, 78 Antiinflammatory activity of SBT, 153 Antiinflammatory agents, 10 Antimalarial drug, 78
79 Antioxidants, 34, 176, 241
242 mineral elements, 46
51, 47t chromium, 51 magnesium, 46 manganese, 50 molybdenum, 46
50 selenium, 50
51 and mode of action, 36
40 phytochemicals, 52t flavonoids, 58
60 polyphenols, 51
58 sulforaphane, 60 vitamins, 42t vitamin A, 41
44 vitamin C, 44 vitamin D, 44
45 vitamin E, 45
46 Antiretroviral drug, 78
79 Antistax, 301
302, 302t Antitubercular drug-induced hepatic injury (ATDH), 77 Antitubercular drugs, 77 Apigenin (API), 125
126 APP. See Amyloid precursor protein (APP) Argania spinosa L. (Argan tree), 109
110 Argimonia eupatoria, 85 Aristolochic acid, 300 Aromatic ring hydroxylations, 51
58 Arterial oxygen saturation (SaO2), 152 Arteriosclerosis. See Atherosclerosis Ascorbic acid. See Vitamin C Ashwagandha. See Withania somnifera (WS) Asian or Korean red ginseng. See Panax ginseng Asparagus racemosus, 17 Aspergillus terreus, 20
21

337

338

Index

Aspirin, 79 Astaxanthin, 12 Asteraceae, 81
82 Astragalus membranaceus, 85 AT. See Active transporters (AT) ATDH. See Antitubercular drug-induced hepatic injury (ATDH) Atherosclerosis, 172 ATP. See Adenosine triphosphate (ATP) Autoimmune diseases, 270 Autoimmune hepatitis, 78, 80
81 AXP107-11, 112 Ayurveda, 146, 268
269

B BA. See Bioavailability (BA) Bacillus cereus, 156
157 Baicalein, (C15H10O5), 83 Baicalin (C21H18O11), 83 Barbiturates, 2 BBM. See Brush border membrane (BBM) Benifuuki, 110
111 Benzoic acid-derived phenolic acids, 51
58 Berberine, 87, 180 β-carotene, 24
25 Bifidobacteria, 270 Bile acid, 247 sequestrants, 177 Bioaccessibility, 199
201, 203
204 coefficient, 200, 202 Bioactive compounds, 80, 198
199, 237 factors influencing biological properties, 243
251 Bioactive lipids, 206
207 Bioactive principles, 34 Bioactivity, 199
201 Bioavailability (BA), 198
201, 201f, 243
244 food matrix design that improve oral BA of lipophilic compounds, 209
222 functional and excipient foods, 198f of lipophilic bioactives, 199
200 Biochemical transformation (BT), 202, 208
209 Biologically active compounds, 6 Biophenols, 237 Black Cohosh. See Rhizoma Cimicifugae Racemosae Blue dyes, 185 BMI. See Body mass index (BMI) Body mass index (BMI), 108
109, 170 Boswellia serrata, 17, 290 Botanical drugs in United States, 300, 301t “Brava” oil, 126 Bromobenzene-induced hepatotoxicity, 89
90 Brush border membrane (BBM), 248 BT. See Biochemical transformation (BT)

Bulbus Allii Cepae, 271t Bulbus Allii Sativi, 271t Bupleurum chinense, 87
88

C Calcium ion homeostasis, 145 modification in calcium homeostasis, 75
76 supplements, 127 Calvin cycle, 147 Camellia sinensis, 89 Camptotheca acuminata, 86 Camptothecin, 86 Camptothecin in combination with N-trimethyl chitosan (CPT-TMC), 86 Cancer, 111
113 Cannabinoids (CBD), 181 Capsici fructus, 295t Carbohydrate metabolism, 73 Cardioprotective effect of WS extract, 150 Cardiovascular diseases (CVD), 106
111 Carotenoids, 12, 24
25, 213t, 250
251 Catalase (CAT), 149, 174
176 Catechin, 110
111, 125
126 CBD. See Cannabinoids (CBD) Centella, 127 Chain-breaking mechanism, 37 Chemical agents, 74 on major cellular systems, 75 Chemical transformation (CT), 202, 208 Chemistry, manufacturing, and control (CMC) specifications, 303 Chemotherapeutic drug, 79 Chloral, 77
78 Chlorogenic acid, 58 chlorogenic acid-derived phenoxyl radicals, 58 Cholesterol, 45, 172 therapy/treatment, 177
178 Cholinesterase enzymes, 126 CHR animal model. See Cold
hypoxia
restraint (CHR) animal model Chromium (Cr), 51 picolinate, 119
123 Chronic cholestatic hepatitis, 78 Chronic hypoxia, 144
145 Chronic inflammation, 10
11 CIHP-I. See Composite Indian herbal preparation-I (CIHP-I) Cimicifugae racemosae rhizome, 295t Citrullus lanatus, 86
87 CLA. See Conjugated linoleic acid (CLA) Clonazepam, 77
78 Closed innovation paradigm, 318
319

Index

CMC specifications. See Chemistry, manufacturing, and control (CMC) specifications Code of Hammurabi, 268
269 Coenzyme, 213t Cold
hypoxia
restraint (CHR) animal model, 147 Collaboration, 319
320 Colloidal delivery systems, 242
243 Coloring agents, 184 Committee on Herbal Medicinal Products (HMPC), 290 Composite Indian herbal preparation-I (CIHP-I), 151
152 Composite Indian herbal preparation-II (CIHP-II), 152 Concanavalin-A (Con A), 80
81 Conjugated linoleic acid (CLA), 218 Controlled release ability, 211 “Converged segment”, 315 Convergence in complements, 316 of market, 316 in substitutes, 316 of technology, 316 Coptis chinensis, 87 Cordycepic acid, 158 Cordycepin, 158 Cordyceps sinensis (CS), 158
159 Coronary heart disease, 172 Cortex Frangulae, 277t Cortex Hamamelidis, 277t Cortex Pruni Africanae, 277t Cortex Rhamni Purshianae, 277t Cortex Salicis, 287t Corticosteroids drugs, 11 Cosmeceuticals, 313
314 Coupled process, 320
321 COX-1. See Cyclooxygenase-1 (COX-1) C-phycocyanin (C-PC), 126 CPT-TMC. See Camptothecin in combination with Ntrimethyl chitosan (CPT-TMC) Cr(VI). See Hexavalent chromium (Cr(VI)) Cranberries, 290 C-reactive Protein (CRP), 144
145, 173
174 therapy/treatment, 178 Crowdsourcing, 323 CRP. See C-reactive Protein (CRP) CS. See Cordyceps sinensis (CS) CT. See Chemical transformation (CT) Cucurbita pepo, 89 Cucurbitacin, 86
87 Curcuma longa L. (Turmeric), 110
112 Curcumin, 12, 87, 110
112, 154
155, 181
182 CVD. See Cardiovascular diseases (CVD) Cyclooxygenase-1 (COX-1), 151 Cyclooxygenase-2 (COX-2), 111
112

339

Cynara scolymus, 88 CYP2E1. See Cytochrome P450 2E1 (CYP2E1) CYP450 isoenzymes, 77 Cytochrome P450 2E1 (CYP2E1), 85 Cytochrome p450, 178 isoenzymes, 270
283 Cytokine production, 37
38

D De Materia Medica, 269 Dehydroascorbic acid, 44 Delivery systems, 209
220 Demand-side convergence, 316 Deregulation, 316
317 DHA. See Docosahexaenoic acid (DHA) Diabetes, 118
124 studies performed using bioactive compound, 120t Diabetes mellitus (DM), 118
119 Diabetes therapy/treatment, 178 Diazepam, 77
78 Diclofenac, 79 Diet, 34 Dietary fiber, 237 Dietary supplements, 3
4, 106
107, 114 Dietary vitamin A, 41 Digestion process, 243
250 gastric digestion, 244
245 gastric juice and stomach movements, 246
247 in vitro digestion models, 248
250 intestinal digestion, 247
248 stomach/gastric emptying, 245 2-(3,4-Dihydroxyphenyl)-3,5,7-trihydroxy-4H-chromen-4-one, 110 Diluent, 184 Dioscin, 84 Dioscorea opposita, 84 Dipeptidyl peptidase-IV (DPP-4), 118
119 Disease-contributing factors, targeting, 18 Disintegrants, 184 Disintegration process, 243 Dissolution process, 243 1,2-Dithiolane-3-pentanoic acid. See α-Lipoic acid DM. See Diabetes mellitus (DM) Docosahexaenoic acid (DHA), 9
10, 118 DPP-4. See Dipeptidyl peptidase-IV (DPP-4) Dragon’s blood, 300 Droplet formation, 217
218 Drug-induced hepatotoxicity, 76
79, 76f anticoagulants drug, 77 anticonvulsants or antiepileptic drugs, 77
78 antihyperlipidemic drugs, 78 antiretroviral and antimalarial drugs, 78
79

340

Index

Drug-induced hepatotoxicity (Continued) antitubercular drugs, 77 chemotherapeutic drug, glucocorticoids, and anabolic androgenic steroids, 79 NSAID, 79 Dynamic model, 249 in vitro GI model, 250

E Early enteral nutrition, 128 Ebers Papyrus, The, 268
269 EC. See (
)-Epicatechin (EC) Echinaceae purpureae herba, 295t Efflux transporters (ET), 202, 207 EGC. See (
)-Epigallocatechin (EGC) EGCG. See Epigallocatechin gallate (EGCG) Eicosapentaenoic acid (EPA), 9
10, 118 Electron transport chain (ETC), 142 Electrophilic reactive metabolites, 74
75 EMA. See European Medicines Agency (EMA) Emblica officinalis (ES), 157
158 Emulsions, 217
218 Endocytosis, 247 Endogenous antioxidant system, 71
72 Enoxaparin, 77 Enterocytes, 204
208 Enzyme prolyl hydroxylase, 44 Eosinophilic inflammation process, 11 EPA. See Eicosapentaenoic acid (EPA) (
)-Epicatechin (EC), 110
111 (
)-Epicatechin-3-O-gallate, 110
111 Epigallocatechin gallate (EGCG), 60, 110
111, 125
126 (
)-Epigallocatechin (EGC), 110
111 Epinephrine, 2 Ergosterol, 45 ERK. See Extracellular-signal-regulated kinase (ERK) Erythrocytes hemolysis, 59 ES. See Emblica officinalis (ES) Escherichia coli, 156
157 Essential fat-soluble vitamin, 41 Essential plasma proteins and minerals, 71
72 Essential trace elements, 50 ET. See Efflux transporters (ET) ETC. See Electron transport chain (ETC) Ethical Kampo formulation, 301 Ethno-pharmaceutical formulations, 268 botanical drugs in United States, 300 efficacy and safety of herbal medicines, 304
305 European Union monograph, 290
300 herbal medicinal products in Japan, 301
302 history, 268
269 pharmacopoeia, 269 quality control of herbal medicines, 302
303

WHO monographs on selected medicinal plants, 269
290 usage in Newly Independent States (NIS), 290, 291t for vol. 1, 270, 271t for vol. 2, 270
283, 277t for vol. 3, 283, 284t for vol. 4, 283
290, 287t Euphausiacea order, 9
10 European Medicines Agency (EMA), 290 European Union monograph, 290
300, 295t EVOOs. See Extra-virgin olive oils (EVOOs) Excess ascorbic acid, 44 Excipient emulsions, 221 Excipient nanoemulsions, 221 Excipient systems, 220
222 Excipients in nutraceuticals, 183
185 Extra-virgin olive oils (EVOOs), 126 Extracellular-signal-regulated kinase (ERK), 80 Extraction techniques, 235
236 Eye disorders, 11
12 Ezetimibe, 78, 177

F Fasting blood glucose (FBG), 114
118 Fat cells, 170
171, 171f Fat metabolism, 74 Fat-soluble secosteroids, 44
45 Fat-soluble vitamin, 45 Fatty acids, 235 oxidation, 74 Fatty streak with foam cells, 172 FBG. See Fasting blood glucose (FBG) FDA. See US Food and Drug Administration (FDA) Fenton reactions, 176 fenugreek. See Semen Trigonellae Foenugraeci (fenugreek) Ferulic acid, 58 Fibers, 235 Flavone, 125
126 Flavonoids, 11, 58
60, 243
244 Folium Azadirachti, 283, 284t Folium cum Flore Crataegi, 277t, 290, 291t Folium Cynarae, 287t Folium Guavae (Guava), 283, 287t Folium Melissae, 277t Folium Salviae, 291t Food, 5t by-products, 235 digestion, 243 functional, 1
2, 4
6, 34 processing, 250
251 supplements, 5t waste, 24
25

Index

Food industry industry convergence evidence from, 324
328 open innovation and, 322
323 Food matrix, 198
199 design that improve oral BA of lipophilic compounds, 209
222 delivery systems, 209
220 excipient systems, 220
222 Foodstuffs, 3, 5t Frangulae cortex, 295t Free radicals, 71
72 French paradox, 10
11 Fructus Agni Casti, 287t Fructus Ammi Majoris, 284t Fructus Hippophae¨s recens, 291t Fructus Macrocarponii, 287t Fructus Myrtilli, 287t Fructus Serenoae Repentis, 277t Fructus Silybi Mariae, 277t Fulyzaq, 300, 301t, 302
303 Functional foods, 1
2, 4
6, 34 industry, 34 physiologically, 4
6

G GACP. See Good agricultural and collection practice (GACP) Galanthus nivalis, 20
21 Gallic acid, 83 Ganoderma lucidum (GL) (Lingzhi), 156
159 CS, 158
159 ES, 157
158 Ganoderma lucidum spore powder (GLSP), 157 Garlic extract, 9 Gastric digestion, 244
245 Gastric juice and stomach movements, 246
247 Gastrointestinal system (GI system), 241
242 Gastrointestinal tract (GIT), 200 GB. See Ginkgo biloba (GB) Genistein, 112, 182 Genomics driven drug discovery process, 18 GH. See Growth hormone (GH) GI system. See Gastrointestinal system (GI system) Ginger. See Zingiber officinale (Ginger) Ginkgo biloba (GB), 149
150, 270 Ginkgo folium, 295t GIT. See Gastrointestinal tract (GIT) GL. See Ganoderma lucidum (GL) (Lingzhi) GlaxoSmithKline (GSK), 323 Glidants, 184 GLSP. See Ganoderma lucidum spore powder (GLSP) Glucocorticoids, 79 Glucose, 73 Glucose transporter-4 (GLUT-4), 123

341

Glutathione (GSH), 75, 82
83, 85, 176, 181
182 Glutathione peroxidase (GPx), 37, 174
176 Glycogen, 73 Glycyrrhiza uralensis, 80
81 Glycyrrhizin, 80
81 Good agricultural and collection practice (GACP), 302
303 GPx. See Glutathione peroxidase (GPx) Green tea, 114, 180 catechins, 125
126 Green tea extract (GTE), 113 Growth hormone (GH), 174 GSH. See Glutathione (GSH) GSK. See GlaxoSmithKline (GSK) GTE. See Green tea extract (GTE) Guava. See Folium Guavae (Guava) Gummi Boswellii, 287t, 290 Gummi Gugguli, 283, 284t Gynostemma pentaphyllum, 88
89

H HAPE. See High-altitude pulmonary edema (HAPE) Hardening of arteries. See Atherosclerosis Harmonization, 21 HBV. See Hepatitis-B virus (HBV) HCV. See Hepatitis-C virus (HCV) HDL. See High-density lipoprotein (HDL) Hederae helicis folium, 295t Heme-oxygenase-1 (HO-1), 159 Heparin, 77 Hepatic cells, 74 Hepatic enzymes, 74 Hepatic Kupffer cells, 82
83 Hepatic necrosis, 77 Hepatitis-B virus (HBV), 72
73 Hepatitis-C virus (HCV), 72
73 Hepatocytes, 50
51 Hepatoprotective properties of phytochemicals and mode of action, 80
90 A. eupatoria, 85 A. membranaceus, 85 B. chinense, 87
88 baicalin, 83 berberine, 87 C. lanatus, 86
87 C. pepo, 89 C. scolymus, 88 C. sinensis, 89 camptothecin, 86 curcumin, 87 dioscin, 84 G. pentaphyllum, 88
89 gallic acid, 83 glycyrrhizin, 80
81

342

Index

Hepatoprotective properties of phytochemicals and mode of action (Continued) hesperidin, 87 N. sativa, 90 naringenin, 90 P. cuspidatum, 88 P. ferulacea, 83
84 P. niruri, 82 P. notoginseng, 85 PSA, 84
85 puerarin, 86 resveratrol, 81 S. chinensis, 84 S. miltiorrhiza, 82
83 silymarin, 82 T. porrifolius, 81
82 Z. officinale, 89
90 Hepatotoxicity mode, 74
79 effect of chemical agents on major cellular systems, 75 drug-induced hepatotoxicity, 76
79 lipid peroxidation and redox cycling, 75 modification in calcium homeostasis, 75
76 reactive metabolites formation, 74
75 Herba Andrographidis, 277t Herba Bidentis, 291t Herba Centellae, 271t Herba Chelidonii, 291t Herba Equiseti, 291t Herba Hyperici, 270
283, 277t Herba Leonuri, 291t Herba Polygoni avicularis, 291t Herba Tanaceti Parthenii, 277t Herbal adaptogens/performance enhancers, 148
151 GB, 149
150 Ocimum sanctum, 151 Panax ginseng, 148 WS, 150
151 Herbal medicinal products in Japan, 301
302 Herbal medicines, 283 efficacy and safety of, 304
305 quality control of, 302
303 Herbal-derived nutraceuticals, 12 Herbs for high altitude maladies, 146
147 Hesperetin (hesperitin-7-O-glucoside), 59, 87 Hexavalent chromium (Cr(VI)), 51 HH. See Hypobaric hypoxia (HH) HIF1. See Hypoxia-inducible factor-1 (HIF1) High altitude, 142 herbs for high altitude maladies, 146
147 high altitude
induced maladies, 142
143, 143f imbalance in redox homeostasis of skeletal muscle, 143
144 skeletal muscle atrophy at, 144
145 High blood pressure. See Hypertension

High protein dietary supplements, 128 High sensitivity C-reactive protein (hs-CRP), 168
169 High-altitude pulmonary edema (HAPE), 142
143 High-density lipoprotein (HDL), 170 High-pressure homogenization (HPH), 250
251 Hippocastani semen, 295t Hippophae rhamnoides L., 152 HMG-CoA. See 3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA) HMPC. See Committee on Herbal Medicinal Products (HMPC) HO-1. See Heme-oxygenase-1 (HO-1) Holy Basil. See Ocimum sanctum Homeostasis, 71
72 hPBMCs. See Human peripheral blood mononuclear cells (hPBMCs) HPH. See High-pressure homogenization (HPH) hs-CRP. See High sensitivity C-reactive protein (hs-CRP) Human peripheral blood mononuclear cells (hPBMCs), 155
156 Hydrate, 77
78 Hydrogels beads, 218
219 Hydrogen peroxide (H2O2), 36
37 3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGCoA), 177
178 Hydroxybenzoic acids, 51
58 Hydroxycinnamic acids, 58 6-Hydroxydopamine (6-OHDA), 126 Hydroxyl radical (OH), 36
37 Hydroxytyrosol, 237, 242 Hygiene hypothesis, 11 Hypercholesterolemia, 9
10 Hyperglycemia, 173 therapy/treatment, 178 Hyperici herba, 295t Hyperlipidemia, 170
172 therapy/treatment, 177 Hypertension, 9, 173, 179 Hypertriglyceridemia, 171 Hypobaric hypoxia (HH), 142 Hypochlorous acid, 36 Hypomagnesaemia, 119
123 Hypoxia-inducible factor-1 (HIF1), 159

I Ibuprofen, 79 IGF-1. See Insulin-like growth factor-1 (IGF-1) IL. See Interleukin (IL) In vitro digestion models, 248
250 In vitro models, 153, 243 Inbound process, 319
321 Indian ginseng. See Withania somnifera (WS) Indian gooseberry. See Emblica officinalis (ES)

Index

Indomethacin, 79 Indus River, 268
269 Industry convergence, 313
317 drivers, challenges, and consequences of, 316
317 evidence from food and pharmaceuticals industries, 324
328 case of nutraceuticals, 324
328, 327f, 328t linear process, 318f, 326f open innovation role in, 318
323 patterns, 315
316, 315f Inflammation, 10
11 Informatics, 19 Innovative sources of active ingredients from food processing by-products, 238t factors influencing biological properties of bioactive compounds, 243
251 of nutraceuticals, 236
243 Inorganic diluents, 184 Insulin-like growth factor-1 (IGF-1), 168
170, 174 therapy/treatment, 178 Intellectual property (IP), 319 Interactions, 204 Interleukin (IL), 111
112 IL-1, 144
145 IL-6, 144
145 IL-10, 80
81 International Life Science Institute, 34 Intestinal ascorbic acid absorption, 44 Intestinal digestion, 247
248 IP. See Intellectual property (IP) Isoforms, 45 Isoniazid, 74
75 Isothiocyanate group, 60

K Kaempferol (KAE), 59, 125
126 Kampo products, 301 Keap1/Nrf2-antioxidant defense system, 59 Kepar, 118 Kinetic stability, 217
218 Koji. See Red yeast rice Krebs cycle, 147

L LA. See Linoleic acid (LA) Lactobacillus, 270 Lactose, 184 L-ascorbic acid. See Vitamin C LC. See Loading capacity (LC) LDL. See Low-density lipoprotein (LDL) LE. See Loading efficiency (LE)

343

Legislation on nutraceuticals, 21
23 on pharmaceuticals, 21, 22t Leptin, 170
171 Lewis lung carcinoma (LLC), 153 Liberation, 203 Lichen Islandicus, 287t Lingzhi. See Ganoderma lucidum (GL) (Lingzhi) Lini semen, 295t Linoleic acid (LA), 211 Lipid hydroperoxide (LOOH), 36
37 Lipid peroxidation inhibition (LPOI), 88 Lipid(s), 235 lipid-lowering drugs, 177 peroxidation, 75 Lipitor, 177
178 Lipophilic bioactive agents, 198 oral BA of, 201
209 Lipophilic bioactives, 198 Lipophilic compounds, 201 absorption, 205f factors limiting oral bioavailability of, 202f health benefits and limitations, 213t Lipoproteins, 172 Liposomes, 219
220 Liver, 71
72 diseases, 72
73 physiological role, 73
74 carbohydrate metabolism, 73 fat metabolism, 74 neutralization of toxic substance, 74 protein metabolism and storage of vitamins, 74 sickness, 72
73 LLC. See Lewis lung carcinoma (LLC) Loading capacity (LC), 211 Loading efficiency (LE), 211 Low-density lipoprotein (LDL), 107
108, 172 LPOI. See Lipid peroxidation inhibition (LPOI) Lupuli flos, 295t Luteolin (LUT), 59, 125
126 Lycopene, 112 Lysine, 44

M M1 muscarinic acetylcholine receptor (M1 mAChR), 158 Magnesium, 46 Malondialdehyde (MDA), 82
83 Mammalian target of rapamycin pathway (mTOR pathway), 144
145 Manganese, 50 Mannitol, 185 MBP
NC, 109 M-cells, 204
208

344

Index

MDA. See Malondialdehyde (MDA) Medical foods, 3
6, 5t Medical laws, 268
269 Medications, 2 Medicinal plants, 147 Medicinal products, 5t, 14 “Medicinally or nutritionally functional foods”, 3 Medicines, 1
2 Medicines and Healthcare Products Regulatory Agency (MHRA), 300 Membrane permeation (MP), 202, 206
207 Membrane technologies, 242 Menthae piperitae aetheroleum, 295t Metabolic disorder management, 243 Metabolic syndrome (MetS), 7
9, 113
118, 115t, 168
169 therapy/treatment after diagnosis, 177
179 C-reactive protein, 178 cholesterol, 177
178 hyperglycemia and diabetes, 178 hypertension, 179 insulin-like growth factor-1, 178 obesity and hyperlipidemia, 177 traditional Chinese medicine, 179
180 treatment, 179 Metabolomics, 34
35 Metallothionein (MT), 159 Metanil yellow, 74
75 Metformin, 118
119, 178 Methylmercury (MeHg), 242 MetS. See Metabolic syndrome (MetS) MHRA. See Medicines and Healthcare Products Regulatory Agency (MHRA) Microbial sources, 7 Micrococcus luteus, 156
157 Microemulsions, 212
216 Microgels, 218
219 Micronucleus (MN), 125
126 Micronutrients, 119
123 Microvilli concept, 247
248 Minerals, 6, 46, 71
72 antioxidant, 46
51, 47t Mitochondrial electron transport process, 75 ML. See Mucus layer (ML) MN. See Micronucleus (MN) Monacolin K, 109 Mortality, 127
129 Morus alba, 10 MP. See Membrane permeation (MP) MRP. See Multidrug resistant protein (MRP) MT. See Metallothionein (MT) mTOR pathway. See Mammalian target of rapamycin pathway (mTOR pathway) Mucus layer (ML), 202, 206 “Multidrug resistance” mechanism, 207

Multidrug resistant protein (MRP), 207 Multiple stress animal model for evaluation of adaptogenic activity, 147
148 Myeloperoxidase-halide-H2O2 system, 36

N NAD(P)H:quinone oxidoreductase-1 (NQO1), 36 Nanoemulsions, 216
217, 242
243 Nanotechnology, 242
243 Naringenin (5,7,4ʹ-thihydroxyflavanone), 90 National Health Insurance (NHI), 301 Natural antioxidant system, 71
72 Natural bioactive compounds, 235
241 Naturally-based pharmaceuticals, 20
21 Network ethnopharmacology, 18 Network pharmacology, 18 Neurodegenerative diseases, 124
127 Neutralization of toxic substance, 74 Newly Independent States (NIS), 290 commonly used medicinal plants in, 290, 291t NF-κB. See Nuclear factor-κB (NF-κB) NFE2L2. See Nuclear factor erythroid-2-related factor-2 (Nrf2) NFFs sector. See Nutraceuticals and functional foods sector (NFFs sector) NHI. See National Health Insurance (NHI) Nigella sativa, 90 Nile Valley in Egypt, 268
269 NIS. See Newly Independent States (NIS) Nitric oxide (NO), 37, 142 Nitric oxide synthase (NOS), 142 NNRTIs. See Nonnucleoside reverse transcriptase inhibitors (NNRTIs) Non-Kampo crude drug products, 301 Noncommunicable diseases, 267 Nonnucleoside reverse transcriptase inhibitors (NNRTIs), 78 Nonsteroidal antiinflammatory drugs (NSAID), 10, 79 Norepinephrine, 2 Normalized protein catabolic rate (nPCR), 127
128 NOS. See Nitric oxide synthase (NOS) Novel foods, 5t nPCR. See Normalized protein catabolic rate (nPCR) NQO1. See NAD(P)H:quinone oxidoreductase-1 (NQO1) NREA. See Nutraceutical Research & Education Act (NREA) Nrf2. See Nuclear factor erythroid-2-related factor-2 (Nrf2) NRTIs. See Nucleoside reverse transcriptase inhibitors (NRTIs) NSAID. See Nonsteroidal antiinflammatory drugs (NSAID) NuBACS. See Nutraceutical bioavailability classification scheme (NuBACS) Nuclear factor erythroid-2-related factor-2 (Nrf2), 36
38, 40f, 41f, 84, 159 Nuclear factor-κB (NF-κB), 37
38, 111
112, 156 activation, 39f

Index

Nucleoside reverse transcriptase inhibitors (NRTIs), 78 NuGO. See Nutrigenomics Organization (NuGO) Nut by-products, 242 Nutraceutical bioavailability classification scheme (NuBACS), 202 Nutraceutical Research & Education Act (NREA), 3 Nutraceuticals, 2
4, 7, 126, 168, 179
185, 197. See also Pharmaceuticals approaches to maintaining health, 4f CRP, 173
174 diagnostic criteria, 170 differences and the overlapping, 23
24 in disease prevention, 7
13 and allergy, 11 and eye disorders, 11
12 and hypercholesterolemia, 9
10 and hypertension, 9 and inflammation and oxidative stress, 10
11 and obesity, 12
13 and type 2 diabetes, 10 excipients in, 183
185 functional food, 4
6 future of, 185
187 hyperglycemia, 173 hypertension, 173 IGF-1, 174 industry convergence in, 324
328, 327f, 328t innovative sources of, 236
243 legislation on, 21
23 lipoproteins, cholesterol, and atherosclerosis, 172 market-available nutraceuticals and functional foods, 8t metabolic syndrome, 168
169 therapy/treatment after diagnosis, 177
179 traditional Chinese medicine, 179
180 treatment, 179 novel trends in nutraceuticals production, 24
25 obesity and hyperlipidemia, 170
172 public with or without consultation with physicians, 181
183 regulatory framework of dietary supplements, 24 ROS, 174
176 side effects, 185 Nutraceuticals and functional foods sector (NFFs sector), 313
314 Nutridynamics, 34
35 Nutrigenomics, 35
36 of antioxidant mineral elements, 46
51 phytochemicals, 51
60 vitamins, 41
46 composition, 34 effects, 46 technology, 34
35 Nutrigenomics Organization (NuGO), 326
328

345

Nutrikinetics, 34
35 Nutrimetabolomic technology, 34
35 Nutriproteomic technology, 34
35 Nutrition, 3, 107
108 Nutritional supplements, 79 bioactive compounds, 120t cancer, 111
113 CVD, 107
111 diabetes, 118
124, 120t effects on human health, 106
107 MetS, 113
118, 115t mortality, 127
129 neurodegenerative diseases, 124
127 Nutritranscriptomis technology, 34
35

O O1/W/O2 emulsions. See Oil-in-water-in-oil emulsions (O1/W/ O2 emulsions) Obesity, 12
13, 170
172 therapy/treatment, 177 Ocimum sanctum (OS), 151 6-OHDA. See 6-Hydroxydopamine (6-OHDA) OI. See Open innovation (OI) Oil-in-water emulsions, 199 Oil-in-water microemulsion (O/W microemulsion), 212
216 Oil-in-water-in-oil emulsions (O1/W/O2 emulsions), 217
218 Oil-in-water-in-water emulsions (O/W1/W2 emulsions), 217
218 Oleum Azadirachti, 283, 284t Oleum Oenotherae Biennis, 277t Oleuropein, 237 Olive mill wastewaters, 237 Olive oil wastewaters, 242 Ombuine (C17H14O7), 88
89 ω-3 PUFA-supplemented parenteral nutrition, 112 Open innovation (OI), 314, 318
319, 321f dimensions and main practices, 320t and food industry, 322
323 paradigm, 318
319 and pharmaceutical industry, 323 role in industry convergence, 318
323 Oral administration, 20 Oral BA, 199
200 food matrix design that improve oral BA of lipophilic compounds, 209
222 of lipophilic bioactive agents, 201
209 Organic chemical synthesis, 2 Organic diluents, 184 OS. See Ocimum sanctum (OS) OTC Kampo formulations, 301 Outbound process, 320
321 O/W microemulsion. See Oil-in-water microemulsion (O/W microemulsion)

346

Index

O/W1/W2 emulsions. See Oil-in-water-in-water emulsions (O/ W1/W2 emulsions) Oxidative stress, 10
11, 71
72, 74
75, 142

P Panax ginseng, 123, 148 Panax notoginseng, 85 Parkinson’s disease (PD), 124, 126 Passive diffusion, 206
207 Patterns of industry convergence, 315
316 PD. See Parkinson’s disease (PD) Penicillium brevicompatin, 20
21 Pepsinogen, 246 Peristaltic waves, 244 Peroxisome proliferator-activated receptor (PPAR), 86 Peroxyl radical (ROO radical), 36
37 Peyer’s patches, 204
208 P-glycoprotein (P-gp), 207 P-gp. See P-glycoprotein (P-gp) Phalloidin, 75 Pharmaceuticals, 2
3, 13
15, 268. See also Nutraceuticals chemical composition and classification, 19
20 development, 15
19, 15f differences and the overlapping, 23
24 industry convergence evidence from pharmaceuticals industries, 324
328 legislation on, 21 naturally-based pharmaceuticals, 20
21 open innovation and pharmaceutical industry, 323 phases of clinical trials, 16t Pharmacopoeia, 269 Phenolic acids, 51, 237, 241
242 Phenolic rich fractions (PRFs), 157 Phenprocoumon, 77 Phenylbutazone, 79 Phyllanthus P. embilica, 17 P. niruri, 82 Physiologically functional foods, 4
6 Phytochemicals, 79
90, 235
236 antioxidant, 51
60, 52t hepatoprotective properties of phytochemicals, 80
90 therapeutic plants, 80 Phytoconstituents, 147 Phytosterols, 213t Phytotoxicity, 242 Piroxicam, 79 Plant(s), 6, 79
80 food by-products, 237
241 kingdom, 72 plant-derived wastes, 235 plants/herbal products, 146 secondary metabolites, 236
237

liver diseases, 72
73 mode of hepatotoxicity, 74
79 physiological role of liver, 73
74 phytochemicals, 79
90 Plantaginis ovatae semen, 295t Plantaginis ovatae Seminis tegumentum, 295t PolyGlycopleX, 123 Polygonum cuspidatum, 88 Polyphenolic compounds, 10, 125
126 Polyphenols, 51
58, 126, 213t, 235
241 Polysaccharides, 235 Polyunsaturated fatty acids (PUFA), 89, 213t PPAR. See Peroxisome proliferator-activated receptor (PPAR) Prangos ferulacea, 83
84 Prefemin, 302, 302t Preplacoside A (PSA), 84
85 PRFs. See Phenolic rich fractions (PRFs) Primary metabolites of plants, 147 Primidone, 77
78 Primulae radix, 295t Proanthocyanidins, 237 Procyanidins, 242 Proline, 44 Prostate-specific antigen (PSA), 112 Protein(s), 235 degradation, 145 metabolism and storage of vitamins, 74 rate of protein synthesis, 145 supplements, 127
128 Proteomics, 18
19, 34
35 Proteus vulgaris, 156
157 PSA. See Preplacoside A (PSA); Prostate-specific antigen (PSA) Psyllii semen, 295t Psyllium fiber, 12 Puerarin, 86 PUFA. See Polyunsaturated fatty acids (PUFA)

Q Quality control of herbal medicines, 302
303 Quercetin, 11, 58
59, 110, 125
126

R Radix Eleutherococci, 277t Radix Harpagophyti, 284t Radix Ipecacuanhae, 284t Radix Withaniae, 287t Randomized controlled trial (RCT), 108
109 Rauwolfia serpentina, 17 RCT. See Randomized controlled trial (RCT) Reactive hydroxyl radicals, 41
44 Reactive metabolites formation, 74
75

Index

Reactive oxygen and nitrogen species (RONS), 35, 142
143 Reactive oxygen species (ROS), 36, 71
72, 142
144, 174 formation and detoxification, 175f and general ways to detoxification, 174
176 Rectal temperature (Trec), 147
148 Red yeast rice, 109, 183 Redox cycling, 75 homeostasis of skeletal muscle, imbalance in, 143
144 redox-active metals, 58 Resveratrol (trans-3,5,4ʹ-trihydroxystilbene), 12, 59, 81 supplementation, 114 Retinoic acid, 41 Retropulsion process, 246
247 Reverse pharmacology path, 16
17 Rhamni purshianae cortex, 295t Rhei radix, 295t Rhizoma Cimicifugae Racemosae, 277t, 283 Rhizoma Piperis Methystici, 277t Rhizoma Zingiberis (ginger), 283 Rhodiola imbricata, 155
156 Ricini oleum, 295t Roman medicine, 269 RONS. See Reactive oxygen and nitrogen species (RONS) ROS. See Reactive oxygen species (ROS) Rutin, 58
59

S SAEs. See Serious adverse events (SAEs) Salicis cortex, 295t Salmonella typhi, 156
157 Salvia miltiorrhiza, 82
83 SBT. See Sea buckthorn (SBT) Schisandra chinensis, 84 Scurvy, 23 Scutellaria baicalensis, 83 Sea buckthorn (SBT), 152
154 Secondary metabolites of plants, 147 Selenium, 50
51, 128
129 Self-care, 268 Self-medication, 268 Semen Cucurbitae, 287t Semen Hippocastani, 277t Semen Trigonellae Foenugraeci (fenugreek), 283, 284t Sennae folium, 295t Sennae fructus, 295t Serious adverse events (SAEs), 300 Serum albumin, 127
128 Shankhpushpi, 157
158 Shen Nong Ben Cao Jing, The, 268
269 Silybum marianum, 82 Silymarin, 82 Skeletal muscle atrophy at high altitude, 144
145

347

SLN. See Solid lipid nanoparticles (SLN) Small molecule natural products, 20
21 SOD. See Superoxide dismutase (SOD) Sodium valproate, 77
78 Solid lipid nanoparticles (SLN), 212, 218 Solid wastes, 237 Solubilization, 203
204 Somatomedin C. See Insulin-like growth factor-1 (IGF-1) Sorbitol, 185 Soy, 112 Soybean oils, 184 Spirulina, 126 Spirulina fusiformis, 126 St John’s wort, 270
283 Staphylococcus aureus, 156
157 Static model, 249 Statins, 109, 178 Steatohepatitis, 78 Stomach digestion, 246 Stomach/gastric emptying, 245 Styli cum stigmatis Zeae maydis, 291t Substantia nigra pars compacta, 126 Sugar alcohols, 185 Sulfhydryl group(
SH group), 90 Sulfite oxidase, 46
50 Sulforaphane, 60 Sulindac, 79 Sultiam, 77
78 Superoxide dismutase (SOD), 36, 149, 174
176 Superoxide radical (O22), 143
144 Supply-side convergence, 316

T T&CM. See Traditional and complimentary medicine (T&CM) T2DM. See Type II diabetes mellitus (T2DM) Tablet coatings and films, 184 TAGs. See Triacylglycerols (TAGs) TB. See Tuberculosis (TB) TC. See Total cholesterol (TC) TCMs. See Traditional Chinese medicines (TCMs) Technology convergence, 316 “Terminal antral contraction” process, 246
247 Testa Plantiginis, 284t 3,4ʹ,5,7-Tetrahydroxyflavone. See Kaempferol (KAE) TG. See Triglyceride (TG) Thiazolidinediones, 118
119 Thrombus, 172 Thymi herba, 295t Tight junctions (TJ), 202, 208 Tigris and Euphrates rivers in Middle East, 268
269 TIM. See TNO intestinal model (TIM) Tinospora cordifolia, 17

348

Index

Tiny-TIM model, 249 TJ. See Tight junctions (TJ) TMAO. See Trimethylamine N-oxide (TMAO) TNF. See Tumor necrosis factor (TNF) TNO intestinal model (TIM), 249 Tomato seeds (TSE), 126 Total cholesterol (TC), 107
108 Toxic substance, 74 Toxins, 75 Trace minerals, 46 Traditional and complimentary medicine (T&CM), 268 Traditional Chinese medicines (TCMs), 268, 300 in treatment of metabolic syndrome, 179
180 Traditional medicines, 72, 268 Tragopogon porrifolius, 81
82 Transcellular diffusion, 206
207 Transformation, 208
209 Transformation coefficient (FT), 200, 202 Triacylglycerols (TAGs), 218 Tribitor, 123
124 Triglyceride (TG), 107
108 Trihydroxybenzoic acid, 83 Trimethylamine N-oxide (TMAO), 88
89 Tripterygium wilfordii, 158 Triterpenoids, 213t TSE. See Tomato seeds (TSE) Tuberculosis (TB), 77 Tulsi. See Ocimum sanctum Tumor necrosis factor (TNF), 82
83 Turmeric. See Curcuma longa L. (Turmeric) Type I diabetes, 118
119 Type II diabetes mellitus (T2DM), 10, 113, 118
119, 173 Tyrosol, 237

U Unani medicine, 268 University of California, Los Angeles (UCLA), 159 Unstructured arenas, 315 Urinary tract infections (UTIs), 290 US Food and Drug Administration (FDA), 302
303

V Valerianae radix, 295t Valuable antioxidants, 242 Veregen, 300, 301t, 302
305 Very low density lipoprotein (VLDL), 172 Visual analog scale (VAS), 302 Vitamin(s), 71
72, 213t

antioxidant, 41
46, 42t protein metabolism and storage of, 74 vitamin A, 41
44 vitamin C, 44 vitamin E, 45
46 Vitis viniferae folium, 295t

W W1/O/W2 emulsions. See Water-in-oil-in-water emulsions (W1/O/W2 emulsions) Waist circumference (WC), 113 Warfarin, 77 Water-in-oil microemulsion (W/O microemulsion), 212
216 Water-in-oil-in-water emulsions (W1/O/W2 emulsions), 217
218 WC. See Waist circumference (WC) Weight loss, 144
145 Weighted mean difference (WMD), 109 Wheat bran, 241
242 WHO. See World Health Organization (WHO) Winter Cherry. See Withania somnifera (WS) Withania somnifera (WS), 150
151 WMD. See Weighted mean difference (WMD) W/O microemulsion. See Water-in-oil microemulsion (W/O microemulsion) World Health Organization (WHO), 12, 80, 111
112, 146 monographs on selected medicinal plants, 269
290 for vol. 1, 270, 271t for vol. 2, 270
283, 277t for vol. 3, 283, 284t for vol. 4, 283
290, 287t NIS, 291t WS. See Withania somnifera (WS)

X Xanthine oxidase (XO), 46
50, 142, 144 Xenobiotics, 74 Ximelagatran, 77

Y “Yabukita”, 110
111 Yellow River in China, 268
269

Z Zingiber officinale (Ginger), 17, 89
90 Zingiberis rhizome, 295t