The role of functional food security in global health 9780128131480, 0128131489

Table of contents :
Content: Section 1: World Population and Food Availability 1. Estimates for World Population and Global Food Availability for Global Health 2. Estimates of Functional Foods Availability in Ten Highly Populated Countries 3. The Singh's Concept of Functional Foods and Functional Farming (4F) for World Health 4. Economic Burden of Noncommunicable Diseases and Economic Cost of Functional Foods for Prevention Section 2: Evolutionary Diet, Western Diet and NCDS 5. Evolutionary Diet and Evolution of Man 6. Globalization of Diets and Risk of Noncommunicable Dieseases 7. A Review on the Nutritional Challenges of School Children from the Perspective of Developing Countries 8. Functional Food Security for Prevention of Obesity and Metabolic Syndrome 9. Functional Food Security for Prevention of Diabetes Mellitus 10. Functional Food Security for Prevention of Cardiovascular Diseases 11. Effects of Western Style Foods on Risk of Non-Communicable Diseases 12. Role of Food and Nutrition in Cancer 13. Low Protein Rice: Medical Rice for Chronic Kidney Disease Section 3: Fatty Acids in the Diet and NCDS 14. High Omega-6/Omega-3 Fatty Acid Ratio Diets and Risk of Non-Communicable Diseases: Is the Tissue the Main Tissue? 15. Fatty Acids in Human Diet and Their Impact on Cognitive and Emotional Functioning Section 4: Western Type Foods 16. Fats and Oils for Health Promotion and Disease Prevention 17. Dietary Sugar Intake and Risk of Noncommunicable Diseases 18. Modern Eggs, Not Wild Type Eggs, Predispose Risk of Cardiovascular Disease, Diabetes and Cancer? Section 5: Functional Foods in the Diet 19. Cocoa Consumption and Prevention of Cardiometabolic Diseases and Other Chronic Diseases 20. Can Nuts Consumption Modulate Cardiovascular Diseases? Report of a Case and Review of Literature 21. Guava Enriched Functional Foods: Therapeutic Potentials and Technological Challenges 22. Health Effects and Safety of Soy and Isoflavones 23. Quark Cheese: Characteristics, Preparation and Recent Advances as a Functional Food 24. Nutraceuticals Section 6: Bee Products 25. Trigona Propolis and Its Potency for Health and Healing Process 26. The Role of Bee Products in the Prevention and Treatment of Cardiometabolic Disorders: Clinico-pharmacological and Dietary Study 27. Millets as Functional Food, a Gift from Asia to Western World Section 7: Spices as New Functional Foods 28. Fenugreek (Trigonella foenum-graecum L.): Distribution, Genetic Diversity and Potential to Serve as an Industrial Crop for the Global Pharmaceutical, Nutraceutical and Functional Food Industries 29. Functional and Therapeutic Applications of Some Important Spices Section 8: Nutrition, NCDS and Brain Dysfunction 30. Altered Circadian Energy Metabolism and Chronobiological Risk Factors of Chronic Diseases 31. Diet and Cancer: A Dysfunction of the Brain 32. Antioxidant Diets and Functional Foods Promote Healthy Aging and Longevity Through Diverse Mechanisms of Action 33. Beneficial Uses of Cinnamon in Health and Diseases: An Interdisciplinary Approach Section 9: Probiotics and Microbiome 34. Safety of Probiotics in Health and Disease 35. Developments on the Applications and the Suitability of Functional Fermented Sour Sobya as a Viable Source of Novel Probiotics in the Managements of Gastrointestinal Disorders and Blood Lipid Profiles 36. Bioactive Olive Oil Polyphenols in the Promotion of Health 37. Functional Food Security for Osteoporosis, Carcinogenesis, Atherosclerosis and Brain Degeneration 38. Modernization of Policy for Food Manufacturing and Farming May Be Necessary for Global Health 39. Epigenetic Modulation of Nutritional Factors in Plants, Animals and Humans: A New Approach for Developing Functional Foods 40. Effects of Diet and Nutrients on Epigenetic and Genetic Expressions

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The Role of Functional Food Security in Global Health

The Role of Functional Food Security in Global Health

Edited by

Ram B. Singh Ronald Ross Watson Toru Takahashi

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 r 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: 978-0-12-813148-0 For Information on all Academic Press publications visit our website at https://www.elsevier.com/books-and-journals

Publisher: Andre Gerhard Wolff Acquisition Editor: Megan Ball Editorial Project Manager: Jaclyn Truesdell Production Project Manager: Nilesh Kumar Shah Cover Designer: Matthew Limbert Typeset by MPS Limited, Chennai, India

List of Contributors Maria Abramova Faculty of Medicine, People’s Friendship University of Russia, Moscow, Russia; Division of Chronobiology and Chronomedicine, People’s Friendship University of Russia, Moscow, Russia Saikat K. Basu Department of Biological Sciences, University of Lethbridge, Lethbridge, AB, Canada Shigeru Beppu Forica Foods Co. Ltd, Niigata, Japan Maria Alexandra Sardinha Bernardo Centro de Investigac¸a˜o Interdisciplinar Egas Moniz, Instituto Superior de Cieˆncias da Sau´de Egas Moniz, Monte de Caparica, Caparica, Portugal Kshitij Bhardwaj Division of Chronomedicine, KG Medical University, Lucknow, Uttar Pradesh, India Harpal S. Buttar Department of Pathology and Laboratory Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada William Cetzal-Ix ´ Campeche, Mexico ´ Instituto Tecnolo´gico de China, Tanya Charkrabarti Indian Science Congress, Kolkata, West Bengal, India Anil K. Chauhan Centre of Food Science and Technology, Institute of Agricultural Sciences & Institute of Technology, Banaras Hindu University Varanasi, Varanasi, Uttar Pradesh, India; Indian Science Congress, Kolkata, West Bengal, India Hilton Chaves Hospital das Clı´nicas, Federal University of Pernambuco, Recife, Brazil Sergey Chibisov Faculty of Medicine, People’s Friendship University of Russia, Moscow, Russia; Department of General Pathology and Pathological Physiology RUDN University, Moscow, Russia Germaine Cornelissen Halberg Chronobiology Center, University of Minnesota, Minneapolis, MN, United States; East Slovak Institute of Cardiovascular Sciences, Kosice, Slovakia Eric Banan-Mwine Daliri Department of Food Science and Biotechnology, Kangwon National University, Chuncheon, South Korea J. Febin Prabhu Dass School of Bio Sciences & Technology, Vellore Institute of Technology University, Vellore, Tamil Nadu, India

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Amit Krishna De Indian Science Congress Association, Kolkata, West Bengal, India Minakshi De Surendranath College, Kolkata, West Benagal, India Galal Nagib Elkilany Department of Genetics, Junagarh University, Junagarh, Gujarat, India Keio Endo Tokyo Medical and Dental University, Tokyo, Japan Jan Fedacko Faculty of Medicine, PJ Safaric University, Kosice, Slovakia Al Mukhlas Fikri Department of Community Nutrition, Faculty of Human Ecology, Bogor Agricultural University, Bogor, Indonesia Narayan Ghorai Department of Zoology, WB State University, Kolkata, West Bengal, India Aditya K. Gupta Department of Medicine, Rajshree Medical College, Bareilly, Uttar Pradesh, India Anna Gvozdjakova Pharmacobiochemical Laboratory of 3rd Internal Clinic Faculty of Medicine, Comenius University in Bratislava, Bratislava, Slovakia Ghazi Halabi Halabi Cardiac Center, Aley, Lebanon Ester Halmy Obesity Research Center, Budapest, Hungary Svetoslav Handjiev Medical University of Sofia, Sofia, Bulgaria; Bulgrian Association of the Study of Obesity and Related Diseases (BASORD), BASORD, Bulgaria Teodora Handjieva-Darlenska Medical University of Sofia, BASORD, Bulgaria Kyle D. Hilsabeck McCord Research, Coralville, IA, United States Rie Horiuchi Mukogawa Women’s University, Nishinomiya, Japan Krasimira Hristova Department of Noninvasive Functional Diagnostic and Imaging, University National Heart Hospital, Sofia, Bulgaria Laila Hussein Department of Nutrition,National Research Center, Cairo, Egypt

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Adrian Isaza Everglades University, Tampa, FL, United States Arunporn Itharat Department of Applied Thai Traditional Medicine, Faculty of Medicine, Thammasat University Center of Excellence in Applied Thai Traditional Medicine Research (CEATMR), Thammasat University, Thailand Poonam Jaglan Center of Nutrition Research, Panipat, Haryana, India Peter Jarcuska ˇ arik, ´ Department of Gastroenterology, University of P.J. Saf Faculty of Medicine and University ˇ Hospital L. Pasteur, Kosice Lekh R. Juneja The Rohto Pharmaceutical Co. Ltd, Osaka, Japan; Department of Research and Development, Rohto Co Limited, Osaka, Japan; Department of Health Promotion Sciences, Health Sciences Center, Osaka, Japan; Global Head of International Business, R&D, Rohto Pharmaceutical Co., Ltd, Osaka, Japan Nurbani Kalsum Department of Agricultural Technology, State Polytechnic of Lampung, Lampung, Indonesia Tom C. Karagiannis Monash University, Epigenomic Medicine, Central Clinical School, The Alfred Centre, Prahran, VIC, Australia Kumar Kartikey Halberg Hospital and Research Institute, Moradabad, Uttar Pradesh, India Shairy Khan Center of Nutrition Research, Pune, Maharashtra, India; Department of Food Sciences, SNDT University, Pune, Uttar Pradesh, India Jarmila Kucharska´ Pharmacobiochemical Laboratory of 3rd Internal Clinic Faculty of Medicine, Comenius University in Bratislava, Bratislava, Slovakia Pramod Kumar Dean Academics Medical Sciences, TM University, Moradabad, Uttar Pradesh, India Aneliya Kuzeva Bulgrian Association of the Study of Obesity and Related Diseases (BASORD), BASORD, Bulgaria Byong H. Lee Department of Food Science and Biotechnology, Kangwon National University, Chuncheon, South Korea; Department of Microbiology/Immunology, McGill University, Montreal, QC, Canada Mahani Mahani Department of Food Industrial Technology, Faculty of Agroindustrial Technology, Padjajaran University, West Java, Indonesia

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Anuj Maheshwari BBDCODS, BBD University, Lucknow, Uttar Pradesh, India; Division of Chronomedicine, KG Medical University, Lucknow, Uttar Pradesh, India Kamlesh K. Maurya Centre of Food Science and Technology, Institute of Agricultural Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India D. Elizabeth McCord McCord Research, Coralville, IA, United States Maria Fernanda de Mesquita Centro de Investigac¸a˜o Interdisciplinar Egas Moniz, Instituto Superior de Cieˆncias da Sau´de Egas Moniz, Monte de Caparica, Caparica, Portugal Richa Mishra Department of Home Science, AryaMahila PG College, Banaras Hindu University, Varanasi, Uttar Pradesh, India Andrzej Frycz Modrzewski Krakow University, Krakow, Poland Viliam Mojto Pharmacobiochemical Laboratory of 3rd Internal Clinic Faculty of Medicine, Comenius University in Bratislava, Bratislava, Slovakia ´ Maria Mojtova´ St. Elizabeth University of Health and Social Work, Bratislava, Slovakia Masanori Nakajou Forica Foods Co. Ltd, Niigata, Japan Deog H. Oh Department of Food Science and Biotechnology, Kangwon National University, Chuncheon, South Korea Ekasit Onsaard Department of Foods, Ubon Ratchathani University, Ubon Ratchathani, Thailand Daniel Pella Faculty of Medicine, PJ Safaric University, Kosice, Slovakia Dominic Pella Department of Cardiology, East Slovak Institute of Cardiovascular Diseases, Kosice, Slovakia Dominik Pella East Slovak Institute of Medical Sciences, Kosice, Slovakia; Faculty of Medicine, PJ Safaric University, Kosice, Slovakia; East Slovak Institute of Cardiovascular Sciences, Kosice, Slovakia Wiriya Phomkong Ubon Ratchathani University, Ubon Ratchathani, Thailand Shantanav S. Rao Halberg Hospital and Research Institute, Moradabad, Uttar Pradesh, India

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Nancy B. Ray McCord Research, Coralville, IA, United States Banshi Saboo DiaCare and Hormone Institute, Ahmedabad, Gujarat, India Deepak Sah Shah Nursing Home, Moradabad, Uttar Pradesh, India Ratnabali Sengupta Department of Zoology, WB State University, Kolkata, West Bengal, India Jagdish P. Sharma JM Maternity Hospital, Seohara, Bijnore, Uttar Pradesh, India Anand R. Shewale University of Arkansas for Medical Sciences, Little Rock, AR, United States Maria Leonor Tavares da Silva Centro de Investigac¸a˜o Interdisciplinar Egas Moniz, Instituto Superior de Cieˆncias da Sau´de Egas Moniz, Monte de Caparica, Caparica, Portugal Amrat K. Singh Neuron Hospital, Kanth Road, Moradabad, Uttar Pradesh, India Garima Singh Halberg Hospital and Research Institute, Moradabad, Uttar Pradesh, India Jaipaul Singh School of Forensic and Applied Sciences, University of Central Lancashire, Preston, United Kingdom Meenakshi Singh Sr. Principal Scientist, Research, Project Planning and Business Development Directorate CSIR, New Delhi, India; Division of Food Standard, CSIR, New Delhi, India Mukta Singh Department of Home Science, Mahila Maha Vidyalaya, Banaras Hindu University, Varanasi, Uttar Pradesh, India Ram B. Singh Halberg Hospital and Research Institute, Moradabad, Uttar Pradesh, India; The Tsim Tsoum Institute, Krakow, Andrzej Frycz Modrzewski Krakow University, Krakow, Poland; East Slovak Institute of Cardiovascular Sciences, Kosice, Slovakia; Formerly, Food and Agriculture Organization, Bankok, Thailand Rana G. Singh Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India Reema Singh Halberg Hospital and Research Institute, Moradabad, Uttar Pradesh, India Vaishali Singh Halberg Hospital and Research Institute, Moradabad, India

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Shantanu Singhal Amrita Institute of Medical Sciences, Kochi, Kerala, India Manushi Srivastav Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India Ratan Srivastav Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India Ahmad Sulaeman Department of Community Nutrition, Faculty of Human Ecology, Bogor Agricultural University, Bogor, Indonesia Toru Takahashi Graduate School of Health Sciences, Fukuoka Women’s University, Fukuoka, Japan; Department of Human Environmental Medicine, Graduate School of Sciences, Fukuoka University, Fukuoka, Japan; Graduate School of Human Environment Science, Fukuoka University, Fukuoka, Japan; East Slovak Institute of Cardiovascular Sciences, Kosice, Slovakia Norihiro Takei Forica Foods Co. Ltd, Niigata, Japan ´ G. Telessy ´ Istvan ´ ´ Department of Pharmaceutics, University of Pecs, Pecs, Hungary Rukam S. Tomar Department of Biotechnology, Junagadh Agricultural University, Junagadh, Gujarat, India; Department of Plant Breeding and Genetic Engineering, Junagarh Agricultural University, Junagarh, Gujarat, India; Department of Genetics, Junagarh Agricultural University, Junagarh, Gujarat, India Abhishek D. Tripathi Centre of Food Science and Technology, Institute of Agricultural Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India Mari Uehara Tokyo University of Agriculture, Tokyo, Japan Ratna Upadhyay OmniActive Health Technologies New Technology Centre, Thane, Maharashtra, India ˇ a´ Oˇlga Vancov Pharmacobiochemical Laboratory of 3rd Internal Clinic Faculty of Medicine, Comenius University in Bratislava, Bratislava, Slovakia Viola Vargova Faculty of Medicine, PJ Safaric University, Kosice, Slovakia Narsingh Verma KG Medical University, Lucknow, Uttar Pradesh, India; Department of Medicine, BBDCODS, BBD University, Lucknow, Uttar Pradesh, India Shaw Watanabe President, Life Science Promoting Association, Tokyo, Japan

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Ronald R. Watson College of Public Health, School of Medicine, Tucson, AZ, United States Sanit Wichansawakun Division of Clinical Nutrition, Department of Internal Medicine, Thammasat University, Bangkok, Thailand Agnieszka Wilczynska The Tsim Tsoum Institute, Krakow, Andrzej Frycz Modrzewski Krakow University, Krakow, Poland; Krakow University, Krakow, Poland Douglas W. Wilson Centre for Ageing and Dementia Research, Swansea University, Swansea, United Kingdom; School of Medicine, Pharmacy and Health, Durham University, Durham, United Kingdom Poonam Yadav Centre of Food Science and Technology, Institute of Agricultural Sciences & Institute of Technology, Banaras Hindu University Varanasi, Varanasi, Uttar Pradesh, India Peiman Zandi Institute of Environment and Sustainable Development in Agriculture, Chinese Academy of Agricultural Sciences, Beijing, P.R. China

About the Editors Ram B. Singh, MBBS, MD (Int. Medi-Cardiol), DTNH, Certified Nutrition Specialist (USA), is president of the Tsim Tsoum Insitutute in Krakow, Poland. He is an honorary fellow of the Halberg Chronobiology Centre, a member of the Russian Academy of Medical Sciences, a fellow of the International Academy of Cardiovascular Sciences, and former president and founder of the Indian Society of Hypertension, International College of Cardiology, and International College of Nutrition. He is the editor of the World Heart Journal and former professor of medicine at Subharti Medical College. He has contributed over 550 research papers to peer reviewed journals and has received 14 International awards including the Dr. Zumkley Memorial award. Ronald Ross Watson, PhD, graduated from Brigham Young University in Provo, Utah, with a degree in chemistry in 1966. He earned his Ph.D. in biochemistry from Michigan State University in 1971. His postdoctoral schooling in nutrition and microbiology was completed at the Harvard School of Public Health. In 1982 Dr. Watson joined the faculty at the University of Arizona Health Sciences Center in the Department of Family and Community Medicine of the School of Medicine. He is currently professor of health promotion sciences in the Mel and Enid Zuckerman Arizona College of Public Health. For 30 years he was funded by NIH and Foundations to study dietary supplements in health promotion. Dr. Watson has edited more than 130 books on nutrition, dietary supplements and over-the-counter agents, and drugs of abuse, as scientific reference books. He has published 510 research and review articles. Toru Takahashi, PhD, conducts his research on the elucidation of the absorption mechanism of nutrients in the gastrointestinal tract, the elucidation of the absorption mechanism of water in the digestion tube, research on the functionality of nonwater-soluble dietary fiber, the elucidation of the mechanism of action in relaxation of blood glucose in water-soluble dietary fiber, research on the distribution of intestinal bacteria, and studies on nitrogen metabolism and the colon function of herbivores. Dr. Takahashi has additional related expertise in physiology, nutrition, fluid dynamics, statistics, and data mining.

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Foreword www.dmfrontiers.com In terms of leading economic terms and field implementation, so far, food security, as per the original official definition (1990 FAO/WHO Expert Panel https://www.nap.edu/read/11578/chapter/ 4#26), essentially means secured access to safe foods. Food security, as per such a simplistic market meaning, however, has become itself a common cause for the emergence of obesity and other degenerative diseases in a large subset of the population that is under transition from poverty to affluence and more. Restricted access to nutritious foods appears a far more promising food security endgame scenario to attempt to establish in human populations. In lay terms, better education and scarcity of nutritious foods than ignorance and abundance of foods per se. It is therefore no surprise that this volume extends on the concept of functional food security, recognizing the need for the ever more complex human to access a multi-functional or design diet and regimen. The editors propose a revised definition, which reads as follows: Food security should be considered present, when all people, at all times, have physical and economic access to sufficient, safe, and nutritious food, to meet their dietary needs and food preferences, in order to lead a holistically healthy, active, and productive life, physically, socially, mentally, and spiritually, with the aim of supporting human development. Functional/design food specifically addresses variations in genotypes and phenotypes which must be taken care of at metabolic and biochemical levels for sustaining food security at large, globally.

The collaboration of five UN agencies, with WHO and UNICEF joining IFAD and WFP as partners under FAO’s lead, reaffirms that “a peaceful, stable, and enabling political, social, and economic environment is the essential foundation for enabling states to give adequate priority to food security and the eradication of poverty (read of mal-education/nutrition, being under-/overnutrition). Democracy, promotion, and protection of all human rights and fundamental freedoms, including the right to development and the full and equal participation of men and women, are needed in order to achieve sustainable food security for all (http://www.fao.org/3/a-ax736e.pdf).” Back in 1990, a group of WHO Experts in health promotion/ill-health prevention produced a most interestingly original volume (Diet, Nutrition & The Prevention of Chronic Diseases) dedicated to new strategies for containing / eradicating the epidemic on non-communicable diseases. They essentially developed guidelines for increased consumption of fruits, vegetables and legumes. Some 15 years later, those WHO guidelines were reiterated in a 2003 Report of a Joint WHO/FAO Expert Consultation. Another 15 years passed for the present landmark volume “Functional Food Security in Global Health” to appear with the very same outspoken message, yet enlightened and expanded, based on research on diet, development, and diseases, conducted at various expert departments of universities and research centers, worldwide. The title of this volume meets all the descriptive criteria of nutritious foods, which is a key component of the definition of functional food security. In terms of market realities and sustainable economic growth though, nutritious foods translate into blank foods 1 food supplements 1 health care. It is therefore no surprise to see obesity and nonchronic degenerative diseases—the “new

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normal”—gaining ground among and across all human subpopulations worldwide, from poor to wealthy. Only the healthy elderly appear to have been able to adjust the equation to their own lifelong needs and benefits. The editors of this volume should be praised for their courage in keeping on promoting nutritious foods, an anti-macro-economic concept. Such a human concept may still have a chance though, as evidenced by the recent return and expansion of micro-economic models under the green/blue economy new trends. Restricted access to functional foods, i.e., functional food security, will eventually happen globally under the continuous support of WHO/FAO Expert Panels who have genuinely fought against mainstream money-first priorities for more than 30 years, to establish and promote human holistic health standards (Five UN agencies, with WHO and UNICEF joining IFAD and WFP as partners under FAO’s lead, encourage and support initiatives of World Food Forums/Summits on Security & International Congresses on Nutrition & Health / Non-Chronic Diseases from the International College of Nutrition (ICN), the International College of Cardiology (ICC), and the TsimTsoum Institute (TTI), all presided by Ram B Singh, the initiator and leading editor of this volume.) I cannot conclude this foreword without thanking them for their courage and determination. Fabien De Meester Managing Director, DMF Ltd Co

CONSULTED REFERENCES [1] WHO. Diet, nutrition, and prevention of chronic diseases. Report of a WHO Study Group. Geneva: WHO; 1990. [2] WHO Experts Committee. Globalization, diets and non-communicable diseases. Geneva: WHO; 2003. [3] FAO, 1996.Rome Declaration on World Food Security and World Food Summit Plan of Action. World Food Summit, Rome, November 13-17, 1996. [4] FAO, 2002. The State of Food Insecurity in the world. Rome, 2001. [5] Sen A. Poverty and Famines. Oxford: clarendon Press; 1981. [6] ICN2 Second International Congress on Nutrition. http://www.fao.org/about/meetings/icn2/en/accessed Nov 2017. [7] Feeding the world sustainably, editorial. The Lancet 2014;384(9956):1721. Available from: https://doi. org/10.1016/S0140-6736(14)62054-7, 15 November 2014. [8] Joint FAO/WHO Food Standards Programme Codex Committee on Food Labelling, 44th Session Asuncio´n, Paraguay, 16 20 October 2017. http://www.fao.org/fao-who-codexalimentarius/sh-proxy/ en/?lnk 5 1&url 5 https%253A%252F%252.Fworkspace.fao.org%252Fsites%252Fcodex%252FMeetings% 252FCX-714-44%252, accessed Nov 6, 2017. [9] FAO of the UNO. Guidelines on assessing biodiverse foods in dietary intake surveys, 2017 http://www. fao.org/documents/card/en/c/5d2034ff-a949-482a-801c-44b7b675f1dd/. [10] UNO Sustainable Development Goals.17 Goals to Transform Our world 2017. http://www.un.org/sustainabledevelopment/accessed Nov 2017.

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[11] Puska P, Tuomilehto J, Nissinen A, Vartiainen E, editors. The North Karelia Project. 20 year results and experiences. Helsinki: University Press; 1995. [12] Pietinen P, Vartiainen E, Seppa¨nen R, Aro A, Puska P. Changes in diet in Finland from 1972 to 1992: impact on coronary heart disease risk. Preventive Med 1996;25:243 50.

Preface This volume “Functional Food Security in Global Health” is inspired by the Seven Country study published in 1980, the Lyon Heart Study published in 1994, and an earlier book entitled “Wild Type Foods in Health Promotion and Disease Prevention,” edited by Fabien De Meester, and Ronald Watson, published in 2008. One important purpose of the volumes appears to be to awaken the WORLD, in particular the WHO and FAO who have made all efforts to control undernutrition and hunger by enhancing Food Security. It is surprising that in none of the WHO-FAO websites until 2017, is it clear that how much total food and Functional Food was available in the world in previous years and how much total food would be required in future to achieve the UNO targets of 2025 Sustainable Development Goals. Tripathi and coworkers, in this volume on “Functional Foods Security in Global Health” make an effort to provide estimates for world population and global food availability and in the second part Tomar et al. give the estimates of food production and food consumption in the 10 most populous countries to help the WHO and WHF in the planning of prevention of CVDs by 25% by 2025. In the third part of this section Takahashi from Japan and colleagues highlight Singh’s views on Functional Food Security and Functional Farming to increase the worldwide availability of functional foods. The second chapter is a dedicated effort by Shatanav S Rao who did a web search to estimate the economic burden of NCDs and economic cost of functional foods for prevention. In the third chapter, Lekh R Juneja from Japan and other experts provide an overview of the evolution of man and the evolutionary diets emphasizing the role of Paleolithic diet in the prevention of NCDs. In the second part of this chapter, Jan Fedacko from Slovak Republic and his colleagues review the role of Western diets in the development of NCDs. In the third part, R. Sengupta under the leadership of Saikat K. Basu reviews the nutritional challenges among school children in developing countries. In the fourth chapter Ram B. Singh reviews how food and nutrients play their role in damaging or protecting the cells and cause their impact on NCDs. The fifth chapter is about Functional Food Security for prevention of NCDs by Mukta Singh and colleagues (obesity and metabolic syndrome), by Anuj Maheshwari and colleagues (diabetes mellitus), by Shantanu Agarwal (CVDs), by Adrian Isaza and colleagues from United States (hypertension), by Promod Kumar (Cancer), and by Shaw Watanabe from Japan (chronic kidney disease, health promotion). In the sixth chapter, Ram B Singh and colleagues review the role of the omega6/omega-3 fatty acid ratio of the diet in the pathogenesis and prevention of NCDs. In the second part Agnieszka Wilczynska reviews the role of omega-3 fatty acids in neuropsychiatric dysfunction. In the next chapter on Western-type foods, Banshi Saboo et al, enumerate various adverse effects of trans fat, saturated fat, and omega-6 fat and suggest the blending of fats and oils to provide functional food type oil. In the second part Viliam Mojto from Slovak Republic and other colleagues review the adverse effects of sugar on NCDs. In the third part of this chapter, Dominik Pella from Slovak Republic and other colleagues, describe the adverse effects of eggs from hens fed industry manufactured feed. The next chapter includes article on functional foods commonly available in various countries. The first article by Reema Singh et al. is on cocoa consumption for prevention of CMDs and other chronic diseases. The next review by Viola Vargova from Slovak Republic and others, on nut

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consumption in the prevention of NCDs presents most interesting information for the audience. Dietary fiber in health and chronic diseases is the next part by Fedacko from Slovak Republic and other experts from various countries. The next topic on guava enriched functional foods, therapeutic potentials, and technological challenges is reviewed by Ratna Upadhyay and colleagues. In the next part of this chapter, Poonam Yadav presented a review on quark cheese as functional food, its characteristics, and recent advances. Finally, the subject of nutraceuticals is reviewed by T´elessy Istv´an from Hungary. Bee products have been discussed in a separate chapter by Ahmad Sulaeman and colleagues from Indonesia and another part of this chapter is presented by Teodora HandjievaDarlenska from Bulgaria. In the next chapter, Ram B. Singh and colleagues give important information about antioxidant and protein rich millets which could be a new functional food for worldwide use. Spices as new functional foods is the next chapter in which one article on fenugreek is presented by Saikat K. Basu from Canada along with other colleagues and a second article by Amid De gives detailed information on function and mechanism of action of all other spices. How nutrition influences brain function leading to NCDs is being discussed by Germaine Cornelissen by reviewing altered circadian metabolism and chronobiological risk factors of chronic diseases, and in the next article Ram B. Singh et al. review diet and cancer: a dysfunction of the brain. The next chapter on antioxidant, longevity and healthy aging is written by Sanit Wichansawakun from Thailand along with Anil K. Chauhan from India. A beneficial use of cinnamon in health and diseases is the topic reviewed by Maria Leonor from Portugal and other colleagues including Jaipaul Singh from the United Kingdom. Eric Banan-Mwine Daliri et al., from Korea and other colleagues from Canada present an interesting review on probiotics in health and diseases. The subject is complimented by Laila Hussain, President of the International College of Nutrition. The next chapter by Nancy B Ray and colleagues from the United States and Australia highlight bioactive beneficial effects of olive oil for health promotion. Functional food security for osteoporosis, atherosclerosis, carcinogenesis, and brain degeneration is the next chapter by Kumar Kartikey, Garima Singh, and Amrat K. Singh from India, which presents the interesting relationship of these diseases via oxidative stress and inflammation. The next chapter by Ram B. Singh, J.P. Sharma, Toru Takahashi, and Lekh Juneja from Japan with views from Rukam S. Tomar, Mukta Singh, Dr. Ester Halmy, and Ekasit Onsaard emphasizes the role of modernization of policy for food manufacturing and farming by using new technology for producing the currently expensive functional foods: nuts, olive oil, etc., at affordable cost, worldwide. In the next chapter, Rui Horuichi and Toru Takahashi from Japan along with Saikat K. Basu from Canada, present a review on a new hypothesis by Ram B. Singh on epigenetic modulation of nutritional factors in plants and animals to be used as a new approach for food production. Finally in the last chapter, Singh and colleagues present a review of genetic and epigenetic expressions in relation to food consumption. However, national responses from governments are crucially important and international collaboration and global perspectives are badly needed to popularize this concept to provide improved worldwide health. This publication on “Functional Food Security in Global Health” is a collection of papers written by experts in the fields of nutrition, food, epidemiology, internal medicine, pharmacy, biochemistry, food chemistry, economics, and marketing. It is expected that this volume would make a valuable contribution to the discussion on nutrition transition, globalization, and how to achieve

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functional food security for worldwide health promotion and prevention of noncommunicable diseases. The views expressed in the various articles are those of the authors. Hence, we are grateful to the authors for their effort. Ram B. Singh India

Toru Takahashi Japan

Ronald R. Watson United States

Editorial: Why Functional Food Security, Not Just Food Security

ANCIENT HISTORY Food has been considered important in the pathogenesis and prevention of noncommunicable diseases (NCDs) from the ancient times. Food as a source of healing was known to ancient physicians: Hippocrates (Greece, 600 BCE), Confucius (China, 512 BCE), Charaka and Sushruta (India, 600 BCE) [1]. Charaka tasted the urine of the patients and found sugar to diagnose “Madhumeh” (diabetes mellitus); Sushruta was a surgeon, who observed fat deposits in the channels carrying blood to the heart and named it “Madrog” in patients dying due to heart attacks. Hippocrates proposed that “let food be our medicine,” whereas Confucius, the Chinese philosopher taught his students, “The higher the quality of foods, the better, and never rely upon the delicacy of cooking.” Plus a dietary guideline by Confucius, based on experience, observation, and thinking was given as; “cereals, the basic, fruits the subsidiary, meat the beneficial and vegetable the supplementary.” According to WHO (1990), the concept of eating a diet rich in animal food, and a preference for meat and greasy food was well shaped in China [2]. However, possibly the meat was considered to be rich in healthy nutrients (omega-3 fatty acids and flavonoids) and from running animals (healthy fatty acid composition); and the total fat intake remained within desirable limits and was not excessive as in the Western countries [3 6]. In the 7th century BC, the adverse effects of salt were known to a Chinese physician, who proposed that “increased consumption of salt may cause hardening of the pulse.” Long before these statements by ancient physicians, diet was implicated for health and disease in the ancient scripture Srimad Bhagwadgita (3000 BCE). The first two lines in each of the four verses are in Sanskrit followed by its English translation [1]. Aayuh satvabalarogyam, sukhpreetiviverchanah, Rasyah snigdhah sthirah hradyah aharah satvikpriyah [1]. The sattvic foods are full of juice, good in taste and increase longevity, wisdom, power, health, happiness, peace and love. Yktaharviharasya, yuktachetasya karmasu Yktaswapnavbodhasya, yogo bhavati duhkhaha [1]. Yoga is protective against grief to those who have disciplined diet and lifestyle and controlled behavior; sleep and awakening. Katvamlalavanatyusnteekshanaruksha vidahinah Ahar rjassyestah, dukhahshokmaypradah [1]. The foods that are bitter, acid, fried, hot, pungent and dry, give rise to grief, mental stress and diseases. Yatyaman gatarasam, pootiparyushitachya yat, Uchhistamapi chamedhyam, bhojanam tamspriyam [1]

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Foods that are cold, prickled, putrefied and preserved are lured to criminals and give rise to criminal tendency and behavior.

EVOLUTIONARY DIET AND MEDITERRANEAN-STYLE DIETS It is important to focus on the diet and lifestyle of Homo sapiens and our predecessors, namely Homo erectus and Homo habilis who were primarily vegetarians. The Paleolithic diet of Homo sapians has been considered healthy by most experts; because it has a similarity with Mediterranean-style diets consumed by Cretans in Greece [3 6]. Hunting developed gradually when man moved away from other primates and become skilled in tool making; in developing social groups, mankind started organized hunting in bands and started living in large families [4 6]. New fossil records from the Jebel Irhoud archeological site in Morocco has pushed back the origins of our species by 100,000 years. The findings also revealed the possible menu of our ancient diet for our oldest-known Homo sapiens ancestors 300,000 years ago [7]. The newly discovered diet included plenty of gazelle meat and other game animals; with occasional wildebeest, zebra meat, and perhaps seasonal ostrich eggs. After the development of agriculture, about 10,000 years ago; food was easily available and stored. Thus, for about 99% of the time, humankind has been evolving from primate precursors to agriculturist, leading towards a hunter-gathering lifestyle [1 4]. Apparently, our bodies have evolved to be well adapted for doing what hunter-gatherers did and eating what they ate and also “when” they were eating [4,5]. But the major changes in the diet have occurred after 1910 with rapid wave of urbanization and industrialization that had significant impacts on health and diseases.

WORLD HEALTH ORGANIZATION AND FOOD AND AGRICULTURE ORGANIZATION AGENDA We greatly appreciate the honorable WHO experts for developing guidelines for increased consumption of fruits, vegetables, and legumes in 1990 [2]; and later guidelines to provide Functional Foods by Mark Wahlqvist and Niayana Wattanapenpaiboon for the prevention of NCDs in 2003 [10]. Despite the lack of attention by FAO of the UNO to encourage greater production of Functional Foods from 1990 to date, the WHO continued its efforts to have increased availability of Functional Foods at affordable cost by its active participation in the International Congress on Nutrition 1992 (World declaration on nutrition, 1992) organized by FAO (http://www.fao.org/docrep/v7700t/v7700t02.htm) as well as in the 2nd International Congress on Nutrition 2014, where WHO was a co-planner [11]. In the 1st International Conference on Nutrition (ICN), representatives from 159 countries and the European Community, 15 United Nations organizations, and 144 Non-Governmental Organizations participated. The 2nd International Conference on Nutrition (ICN2) was a high-level intergovernmental meeting that focused global attention on addressing malnutrition including overnutrition and related NCDs. Over 2200 participants attended the meeting, including representatives from more than 170 governments, 150 representatives from civil society, and nearly 100 from the

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business community [11]. Our group from the International College of Nutrition (India, Canada), International College of Cardiology (Slovakia), as well as The Tsim Tsoum Institute (Krakow, Poland) have been aggressively bringing up their view points, by planning conferences, and publications to attract the attention of FAO to encourage the world to produce Functional Foods to gain Functional Food Security rather than Food Security. Food Security without emphasis on Functional Foods is the major cause of the epidemic of cardiometabolic diseases (CMDs) and other chronic diseases—this is the important message the editors are giving in this volume: Functional Food Security in Global Health. Some experts believe that ICN2 created a crucial opportunity to make nutrition a central part of the post-2015 Sustainable Development agenda [12]. This joint effort aims to ensure that the goals and targets set are adequate to address the many challenges of global undernutrition as well as overnutrition related NCDs; and work towards building an international framework for accountability. The Global Nutrition Report, includes the Rome Declaration, a Framework for Action reaffirming the commitments made at the first International Conference on Nutrition in 1992, the World Food Summits in 1996 and 2002; and the World Summit on Food Security in 2009, as well as in relevant international targets and action plans, including the WHO 2025 Global Nutrition Targets and the WHO Global Action Plan for the Prevention and Control of NCDs 2013 20 [11,12]. The purpose is to instill a sense of urgency to achieve these goals which appears to be difficult unless substantial attention is given to produce functional foods in the world to achieve Functional Food Security at an affordable cost in both developed as well as developing and underdeveloped countries. The Rome Declaration includes commitments to eradicate hunger and all forms of malnutrition, to increase investments in effective interventions, and to develop coherent policies to enhance sustainable food systems. A delegation of civil society organizations described the recommendations as “weak and nonbinding,” and suggested that governments have not set the bar any higher than the first ICN meeting in 1992. Others have pointed to the inadequate attention given to the issue of sustainable diets and food systems. We share the same views, which are clear by review of the Rome Declaration statement: “all forms malnutrition” without mentioning overnutrition and NCDs. Such description decreases the gravity of this slow moving disaster of obesity and related diseases [11,12]. It is noteworthy that both WHO and FAO who have joined hands to educate the world about the utility and necessity of functional foods for prevention of NCDs—this is clear from the 2017 websites of these agencies [13,14]. The emphasis on the need for functional food production, labeling of nutrient contents, and the need for food biodiversity in the diet are interesting. However, there is overemphasis on undernutrition which is more political due to poor distribution and lack of implementation of government policies, despite adequate availability of food in the world. We agree that optimal nutrition is fundamental to human health and total health: social, physical, mental, and spiritual health and well-being [12]. However, we are not surprised from the estimates from the UN-FAO, that about 805 million people which is more than a tenth of the global population, remain chronically undernourished. Despite all the efforts from UN-FAO, only slow progress has been made in the reduction of undernutrition, the world now also faces growing epidemics of overweight, obesity, and diet-related NCDs [11]. It should be noted that the decline in undernutrition and the emergence of the epidemic of NCDs are natural transitions occurring during poverty to affluence which cannot be prevented by an emphasis on Food Security, unless the governments and

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other stakeholders are provided with appropriate health education related to foods, and make such policies to educate the worldwide food industry and populations. The fact is well known to WHO and FAO experts and reflected by the broad scope of the Global Nutrition Report, the authors noting that the coexistence of different forms of malnutrition is the “new normal” [11,13,14]. However, this is the not “new normal,” and it has been ignored due to overemphasis on undernutrition and hunger which are expected to disappear on their own with enhanced economic development in developing and underdeveloped nations. People with increased income will thereby have the economic ability to buy and consume quality food. The Global Nutrition Report concludes that progress towards World Health Assembly 2025 targets for maternal and child nutrition is too slow; although many countries have made substantial advances on some indicators, which appears to be wrong [13,14]. Since people have not been educated about Functional Food Security, all such children would end up with increased susceptibility to NCDs at young adulthood by increased consumption of fast foods. Improvements in nutritional status of mother and children can contribute substantially to Sustainable Development Goals (UNO) related to poverty, health, education, gender, and employment; but, it would be possible only by Functional Food Security, not just Food Security [15]. In both the WHO and FAO websites [13,14], it is not clear how much Total Food and Functional Food was available in the world in previous years and how much total food would be required in future to achieve the UNO targets of 2025 Sustainable Development Goals [15].

LANDMARK STUDIES; WHY FUNCTIONAL FOOD SECURITY? The Seven Country Study was the first major study which reported that dietary fat is a risk factor for cardiovascular diseases (CVDs), coronary artery disease (CAD), and stroke [8]. However, it is not the quantity but the quality of fat which may be responsible for CVDs and other chronic diseases. Further analysis of data revealed that flavonoids and omega-3 fatty acid contents of foods can explain the cause of variation in the risk of CAD and cancers in the seven countries: lower risk in Japan and Mediterranean countries; and greater risk in northern European countries and the United States where diets are rich in fast foods with the majority of the population having Food Security [8,9]. The North Karelia Project with 20-year results and experiences showed that heart disease mortality has declined in Finland by 55% among men and 68% among women between 1972 and 1992 [16,17]. The total fat content of the Finnish diet changed from 38% of energy to 34%, saturated fat from 21% to 16%, and polyunsaturated fat from 3% to 5% and the intake of cholesterol decreased by 16%. A shift from boiled to filtered coffee could have further decreased serum cholesterol by 0.3 mmol/L (11 mg/dL). Thus, these changes together could explain the total change in serum cholesterol, which has been on average 1.0 mmol/L (38 mg/dL). Fruit and vegetable consumption increased two- to threefold during this time period. It is clear that dietary changes seem to explain the decrease in serum cholesterol reduction in inflammation which has contributed to the dramatic decline in coronary heart disease mortality in Finland. There are six randomized, controlled trials with adequate sample size that have been published showing beneficial effects of diet on risk of CVDs [18 23]. These landmark clinical trials

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published after the Seven Country Study and the North Karelia Project, provided a proof that intervention with diet can cause significant decline in CVDs. Effects of changes in fat, fish, and fiber intakes on death and myocardial infarction in the Diet and Re-infarction Trial (DART) and the effect of Mediterranean-style diets in the Lyon Heart study revealed that mortality can be reduced by dietary interventions, without a decrease in serum cholesterol [18,20]. The Indian Experiment and the Indo-Mediterranean Diet Heart study reported that that diets rich in vegetables, fruits, nuts, and whole grain legumes in conjunction with mustard oil (rape seed) can cause significant decline in CVDs in patients post coronary artery disease [19,21]. The beneficial effects of these diets may be due to the decline in inflammation and increased content of omega-3 fatty acids and flavonoids in the diet [22]. The PREDIMED study is a large primary prevention trial, in which Mediterraneanstyle diets with nuts or olive oil were used to demonstrate, that both the diets caused significant decline in CVDs compared to the control group [23]. Further cohort studies in a large number of subjects showed that Mediterranean-style diets can cause significant decline in mortality and increase the survival [24 26]. The consumption of these diets may be associated with greater intake of antioxidant polyphenolics and flavonoids and omega-2 fatty acids, fiber, and vitamins which are known to decrease oxidative stress and inflammation and may have antiplatelet effects [22,27,28].

FUNCTIONAL FOOD SECURITY Functional Food Security may be defined as a state of food availability in a country when functional foods are available at affordable cost to all the segments of the society. Food is regarded as “functional” if when consumed as part of a usual diet it provides benefits to one or more target functions in body, beyond basic inherent nutrition. The first functional food products were launched in Japan where a food category called FOSHU (Foods for Specific Health Use) was established in 1991 to reduce the increasing healthcare costs. Antioxidant and redox systems require certain amounts of vitamins as well as nonvitamin components like polyphenols. Antioxidant and redox functions are important for all cells and tissues; however beneficial effects have not been proven except when consumed as a component of fresh fruit and vegetables. Gastrointestinal functions include the balancing of colonic microflora and control of nutrient bioavailability, food transit time, immune activity, endocrine activity, mucosal motility, and epithelial cell proliferation. The food components present in the functional foods may influence moods and behavior as well as cognitive and physical performances. There is regulation of metabolism of macronutrients—carbohydrates, amino acids, and fatty acids—and the related hormonal regulation, e.g., insulin/glucagon balance. Consuming Functional Dairy Products with targeted therapeutic benefits to inhibit TAMO can be a tasteful way to healthy life, free from CVDs and cancers. Functional Food Security appears to be adequate to address all the challenges of global malnutrition, including undernutrition and micronutrient deficiencies, as well as overweight, obesity, and diet-related NCDs [18 28]. More specific targets covering all of these issues are needed to galvanize funders, countries, and others to address these fundamental challenges. The sustainable

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development agenda should include the right to adequate nutrition which should be fully integrated; for example, sustainability has to be well enough defined to make such integration meaningful worldwide. Ram B. Singh Halberg Hospital and research Institute, Moradabad, Uttar Pradesh, India

Toru Takahashi Graduate School of Human Environmental Sciences, Fukuoka Women’s University, Fukuoka, Japan

REFERENCES [1] Singh RB, Reddy KK, Fedacko J, De Meester F, Wilczynska A, Wilson DW. Ancient Concepts of Nutrition and the Diet in Hunter-gatherers. Open Nutr J 2011;4:130 5. [2] WHO. Diet, nutrition, and prevention of chronic diseases. Report of a WHO Study Group. Geneva: WHO; 1990. [3] De Meester F. Wild-type land based foods in health promotion and disease prevention: the LDL-CC: HDL-CC model. In: Meester Fabien De, Watson RR, editors. Wild type foods in health promotion and disease prevention. NJ: Humana Press; 2008. p. 3 20. [4] Lee RB. What hunters do for a living: a comparative study. In: Lee RB, Devore I, editors. Man the Hunter. Chicago: Aldine; 1968. p. 41 3. [5] Eaton SB, Konner M. Paleolithic nutrition. A consideration of its nature and current implications. N Engl J Med. 1985;312(5):283 9. [6] Eaton SB, Konner M, Shostak M. Stone agers in the fast lane: chronic degenerative diseases in evolutionary perspective. Amer J Med 1988;84:739 49. [7] Hublin JJ, Ben-Ncer A, Bailey SE, Freidline SR, Neubauer S, Skinner MM, et al. New fossils from Jebel Irhoud, Morocco and the pan-African origin of Homo sapiens. Nature 2017;546:289 92. Available from: https://doi.org/10.1038/nature22336. [8] Keys A, Aravanis C, Blackburn H, Buzina R, Djordjevi´c BS, Dontas AS, et al. Seven countries. A multivariate analysis of death and coronary heart disease. Cambridge, MA: Harvard University Press; 1980. p. 381. [9] Hertog MGL, Kromhout D, Aravanis C, Blackburn H, Buzina R, Fidanza F, et al. Flavonoid intake and long-term risk of coronary heart disease and cancer in the Seven Countries Study. Arch Intern Med 1995;155:381 6. [10] WHO. Experts Committee, Globalization, diets and non-communicable diseases. Geneva: WHO; 2003. [11] ICN2 Second International Congress on Nutrition. http://www.fao.org/about/meetings/icn2/en/accessed Nov 2017. [12] Feeding the world sustainably, editorial. The Lancet 2014; Volume 384, Issue 9956, Page 1721, 15 November 2014; doi:10.1016/S0140-6736(14)62054-7. [13] Joint FAO/WHO Food Standards Programme Codex Committee on Food Labelling, 44th Session Asuncio´n, Paraguay, 16 20 October 2017. http://www.fao.org/fao-who-codexalimentarius/sh-proxy/en/ ?lnk 5 1&url 5 https%253A%252F%252Fworkspace.fao.org%252 Fsites%252Fcodex %252FMeetings% 252FCX-714-44%252, accessed Nov 6, 2017.

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[14] FAO of the UNO. Guidelines on assessing biodiverse foods in dietary intake surveys.2017 http://www. fao.org/documents/card/en/c/5d2034ff-a949-482a-801c-44b7b675f1dd/. [15] UNO Sustainable Development Goals.17 Goals to Transform Our world 2017. http://www.un.org/sustainabledevelopment/accessed Nov 2017. [16] Puska P, Tuomilehto J, Nissinen A, Vartiainen E, editors. The North Karelia Project. 20 year results and experiences. Helsinki: University Press; 1995. [17] Pietinen P, Vartiainen E, Seppa¨nen R, Aro A, Puska P. Changes in diet in Finland from 1972 to 1992: impact on coronary heart disease risk. Preventive Med 1996;25:243 50. [18] Burr ML, Fehily AM, Gilbert JF. Effects of changes in fat, fish and fiberfiber intakes on death and myocardial infarction: diet and re-infarction Trial(DART). Lancet 1989;757 61 ii. [19] Singh RB, Rastogi SS, Verma R, Laxmi B, Singh R, Ghosh S, et al. Randomized, controlled trial of cardio protective diet in patients with acute myocardial infarction: results of one year follow up. BMJ 1992;304:1015 19. [20] de Lorgeril M, Renaud S, Mamelle N, Salen P, Martin JL, Monjaud I, et al. Mediterranean alphalinolenic acid-rich diet in secondary prevention of coronary heart disease. Lancet 1994;343 (8911):1454 9. Erratum in: Lancet 1995,345 (8951):738. [21] Singh RB, Dubnov G, Niaz MA, Ghosh S, Singh R, Rastogi SS, et al. Effect of an Indo-Mediterranean diet on progression of coronary disease in high risk patients:a randomized single blind trial. Lancet 2002;360:1455 61. [22] Esposito K, Marfella R, Ciotola M, DiPalo C, Giugliano G, D’Armiento M, et al. Effect of a Mediterranean-style diet on endothelial dysfunction and markers of vascular inflammation in the metabolic syndrome: a randomized trial. JAMA 2004;292:1440 6. [23] Estruch R, Ros E, Salas-Salvado´ J, Covas MI, Corella D, Aro´s F, et al. PREDIMED Study Investigators. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med 2013;368 (14):1279 90. [24] Trichopoulou A, Costacou T, Bamia C, Trichopoulos D. Adherence to a Mediterranean diet and survival in a Greek population. N Engl J Med 2003;348:2599 608. [25] Sotos-Prieto M, Bhupathiraju SN, Mattei J, fung TT, Li Y, Pan A, et al. Association of changes in diet quality with total and cause-specific mortality. N Engl J Med 2017;377:143 53. Available from: https:// doi.org/10.1056/NEJMoa1613502. [26] Micha R, Pen˜alvo JL, Cudhea F, Imamura F, Rehm CD, Mozaffarian D. Association between dietary factors and mortality from heart disease, stroke, and type 2 diabetes in the United States. JAMA. 2017;317(9):912 24. Available from: https://doi.org/10.1001/jama.2017.0947. [27] Singh RB, Rastogi SS, Verma R, Bolaki L, Singh R, Ghosh S. An Indian experiment with nutritional modulation in acute myocardial infarction. Am J Cardiol 1992;69:879 85. [28] Simopoulos AP. An increase in the omega-6/omega-3 fatty acid ratio increases the risk for obesity. Nutrients 2016;8(3):128. Available from: https://doi.org/10.3390/nu8030128.

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ESTIMATES FOR WORLD POPULATION AND GLOBAL FOOD AVAILABILITY FOR GLOBAL HEALTH

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Abhishek D. Tripathi1, Richa Mishra2, Kamlesh K. Maurya1, Ram B. Singh3 and Douglas W. Wilson4 1

Centre of Food Science and Technology, Institute of Agricultural Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India 2Department of Home Science, AryaMahila PG College, Banaras Hindu University, Varanasi, Uttar Pradesh, India 3Halberg Hospital and Research Institute, Moradabad, Uttar Pradesh, India 4Centre for Ageing and Dementia Research, Swansea University, Swansea, United Kingdom

1.1 INTRODUCTION There is a continuous growth in the world population as well as food consumption, resulting in greater necessity and utility of food security for the world [1 3]. The world has been facing an epidemic of undernutrition along with population explosion, resulting in a need for increased food availability [1 4]. The concept behind food security is to increase the food availability, so that the imbalance between the demand and supply of food is covered [1]. In view of this fact, the World Food Summit in 1996, defined food security as follows “Food security exists when all people, at all times, have physical and economic access to sufficient, safe and nutritious food that meets their dietary needs and food preferences for an active and healthy life” [1,3]. A continuous growth in the population as well as malnutrition and related diseases would require that the global demand for food will increase for at least the next five decades [3 8]. The competition for land, water, and energy would continue to grow, apart from the overexploitation of fisheries, sea foods, and foods available from the forest [9]. Therefore, increased the requirement of foods will affect our ability to produce food as well as the urgent requirement to reduce the impact of the food system on the environment. Furthermore, there is a threat to food production due the effects of global changes in weather and climate. However, recent advancements in food technology, plant breeding, and genetic engineering would be able to produce more food and would ensure that it is used more efficiently and equitably, under a multifaceted and linked global strategy, to ensure sustainable and equitable food security for the world population [9 11]. This review emphasizes the new dimensions of functional food security which may be important in global health and longevity.

The Role of Functional Food Security In Global Health. DOI: https://doi.org/10.1016/B978-0-12-813148-0.00001-3 © 2019 Elsevier Inc. All rights reserved.

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1.2 FOOD AND AGRICULTURAL TRANSITION The evolution of farming occurred by domestication of plants about 10,000 years ago, between the Tigris and Euphrates rivers in Mesopotamia. This region includes the modern countries of Iran, Iraq, Turkey, and Syria, where people collected and planted the seeds of wild plants. The ancient people in these regions were able to judge from their experience how much water the plants need to grow [3 5]. They planted in areas with the right amount of sun and later on, after a few weeks or months when the plants blossomed, people harvested the food crops. Wheat, barley, lentils, and a variety of peas were the first domesticated plants in Mesopotamia. In other parts of the world, including eastern Asia, parts of Africa, and parts of North and South America, people also domesticated plants during the early period of civilization, including rice in Asia and potatoes and maize in South America. In the 20th century, the modern affluent society of the Western world began large-scale use of fertilizers and biotechnology for rapid growth of crops for greater yield of foods. Refining and processing of foods, storing and distributing them became widespread in the continuous search for a better economic model [5 8]. Industrialization and urbanization leading to economic development and affluence were associated with greater availability of foods to populations in middle- and highincome countries. Fig. 1.1 shows UNO estimates of emergence of obesity from 2014 to 2030 due to urbanization in big cities with populations of more than 10 million. However, foods available to the modern urban world are high in energy and fat but poor in nutrient density, resulting in obesity and metabolic syndrome. Diets in urban areas are characterized with a decrease in the consumption of omega-3 fatty acids, vitamins, antioxidants, and amino acids and a significant increase in the intakes of carbohydrates (mainly refined), fat (saturated, trans fat, and linoleic acid), and salt compared generally to those living in the Paleolithic period.

1.3 FOOD SECURITY AND FUNCTIONAL FOOD SECURITY Food security essentially is the combination of four important factors: food availability, food access, food utilization, and vulnerability [1,2]. The major challenge is to provide the world’s growing population with a sustainable, secure supply of safe, nutritious, and affordable high quality food using the least land, with lower input, and in the context of global climate change, other environmental changes and declining resources [1 3]. Recently the presence or absence of hunger has been the primary measurement to assess the food security as it applies to an individual’s wellbeing, which does not appear to be correct [1 3]. In the first decade of the 21st century it was thought that the world would overcome the divide between people who are free from hunger and those who are not [1 3]. Globally, hunger and poverty claim 25,000 lives every day. A decline in food availability may be associated with malnutrition with micronutrient deficiencies, leading to undernutrition and related diseases [6 8]. Low birthweight and childhood underweight are the leading risk factors that are responsible for death of 2 million children per year. The majority of the people with hunger are in the developing countries. Southern Asia faces the greatest hunger burden and hunger is the leading cause of undernutrition-related global burden of diseases. Nutrition in transition from poverty to affluence indicates that there is increased availability of

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FIGURE 1.1 Dietary patterns with urbanization in cities on future prevalence of obesity in big cities.

Western foods, particularly in urban areas, resulting in food security for most populations of the world [1 4,7,8] (Fig. 1.1). However, as per IHME News, USA, Oct 2015, “The biggest cause of early death in the world is not smoking or alcohol—it’s what you eat” (Staufenberg J, Oct 2015). This observation is supported by intensive research because both undernutrition due to food scarcity and overnutrition due to food security are associated with a significant increase in metabolic syndrome, which is a risk factor of death due to cardiovascular diseases (CVDs), diabetes, and cancer [6 8]. The world’s population suffering from undernourishment is around 12.5%, reduced from almost half of the world’s population in 1947 as per records of FAO, which may be due to better food security. However, 868 million people remain hungry, an estimated 2 billion people suffer from one or more micronutrient deficiencies and an estimated 1.4 billion people are overweight, of whom 500 million are obese, which predisposes to CVDs and other chronic diseases. It is clear that despite adequate food security, proper distribution of food and access to food by lower social classes is limited due to poverty [1 3,9]. Originally, the term “food security” was used to describe whether a country had access to enough food to meet dietary energy requirements [1,9]. National food security was used by some

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countries, which means that the country produces enough foods as per the requirements of the population. The use of the term food security at the national and global level tends to focus on the supply side of the food equation. The question raised is, “Is there enough food available?” where food is usually interpreted to mean dietary energy. But availability does not assure access, and enough calories do not assure a healthy and nutritious diet, hence distribution of the available food is critical. If food security is to be a measure of household or individual welfare, it has to address access. This was widely recognized by scholars and practitioners in the mid-1970s, and food security was defined as access by all people to enough food to lead a healthy and productive life. This definition was subsequently amplified by FAO to include the nutritional value and food preferences. Thus the definition agreed upon at the World Food Summit in 1996 is that food security exists when all people, at all times, have physical and economic access to sufficient safe and nutritious food to meet their dietary needs and food preferences for a healthy and active life [1,9]. However, food security has been provided but not by means of nutritious foods, resulting in obesity and its related diseases [4 8]. The food security has been the priority of most of the governments and health agencies, without much consideration for functional foods. It was unexpected that providing Western type foods, would enhance life expectancy for 60 years or more [1,6,9]. Thus, economic development has caused an increased intake of an unhealthy diet as well as physical inactivity, tobacco use, and alcohol consumption, which may be responsible for emergence of cardiometabolic diseases and other chronic diseases [4 9]. Dietary patterns high in complex carbohydrates and fiber give way to more varied diets with a lower proportion of fats, saturated fats, and sugars with high nutrient density [4,5]. Globally, calories obtained from meat, sugar, oils and fats have been increasing during recent decades, and those from fiber-rich foods such as wholegrains, pulses, and roots have been declining [9]. The consumption of processed and ready-prepared convenience foods is rapidly increasing in lower- and upper-middle-income countries [1 3]. Therefore, increased food availability without consideration of functional foods supply, appears to be the major cause of epidemics of obesity and other noncommunicable diseases (NCDs) [9 11]. Recently, the Global Burden of Diseases study has demonstrated that there is a marked reduction in death rates due to undernutrition and related diseases with an emergence of morbidity and mortality due to CVDs and other chronic diseases [7].

1.4 TOTAL WORLD POPULATION AND TOTAL FOOD AVAILABILITY The world population is currently growing at a rate of around 1.13% per year and the current average population change is estimated at around 80 million per year. The United Nations estimated that the world’s population will increase from 7.4 billion in 2016 to 8.1 billion in 2025, with most growth in developing countries and more than half in Africa [12]. By 2050, the world population will reach 9.6 billion, 34% higher than today and the majority of the increase will be in developing countries (Fig. 1.2). Urbanization will continue at an accelerated pace with multiple increases in incomes, and about 70% of the world’s population will be urban, compared to 49% today. In order to feed this larger, more urban, and richer population, food production (net of food used for biofuels) must increase by 70%. With the global population expected to be above 9 billion and given

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FIGURE 1.2 Population growth from 2015 to 2025 and 2050. Modified from Division of the Department of Economic and Social Affairs of the United Nations Secretariat (2007).

the demands for high protein and micronutrient-rich diets by populations with increasing incomes, governments around the world would be hard pressed to meet the demand. Between 1970 and 1990, global aggregate farm yield rose by an average of 2% each year, largely due to the green revolution and greater availability of manufactured ready-prepared foods as well as due to focused investments in research and technology [11]. Since 1990, aggregate farm yield growth has stagnated and even reversed in some areas for a variety of reasons (Fig. 1.2). Annual cereal production will need to rise to about 3 billion tons from 2.1 billion today and annual meat production will need to rise by over 200 million tons to reach 470 million tons. Table 1.3 shows the estimates of cereal production, utilization, and stocks [3]. The required increase in food production can be achieved if the necessary investment is undertaken and policies conducive to agricultural production are put in place. But increasing production is not sufficient to achieve food security. It must be complemented by policies to enhance access by fighting poverty, especially in rural areas, as well as effective safety net programs. Total average annual net investment in developing country agriculture required to deliver the necessary production increases would amount to US$83 billion. The required annual gross investment of US$209 billion, includes the cost of renewing depreciating investments, with the result of a separate study that estimated that developing countries on average invested US$142 billion (US$ of 2009) annually in agriculture over the past decade. The required increase is thus about 50%. These figures are totals for public

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CHAPTER 1 GLOBAL FOOD AVAILABILITY FOR GLOBAL HEALTH

and private investment, including investments by farmers, which will require a major reallocation in developing country budgets as well as in donor programs. It will also require policies that support farmers in developing countries and encourage them and other private participants in agriculture to increase their investment. Fig. 1.4, shows the increase in relative global production of crops and animals since 1991 to maintain food security [1]. Many countries will continue depending on international trade to ensure their food security. It is estimated that by 2050 developing countries’ net imports of cereals will more than double from 135 million metric tons in 2008/09 to 300 million in 2050. There is a need to move towards a global trading system that is fair and competitive, and that contributes to a dependable market for food. There is also a need to provide support and greater market access to developing country farmers so that they can compete on a more equal footing. Countries also need to consider joint measures to be better prepared for future shocks to the global system, through coordinated action in case of food crises, reform of trade rules, and joint finance to assist people affected by a new price spike or localized disasters.

1.5 FOOD PRODUCTION AND CLIMATE CHANGE Climate change and increased biofuel production represent major risks for long-term food security. The past half-century has seen marked growth in food production, allowing for a dramatic decrease in the proportion of the world’s people that are hungry, despite a two-fold increase in the total world population [13 16]. Nevertheless, more than one in seven people today still do not have access to sufficient protein and energy from their diet, and even more suffer from some form of micronutrient malnourishment [16]. The world is now facing a new set of intersecting challenges [17]. The global population will continue to grow, yet it is likely to plateau at some 9 billion people by roughly the middle of this century. A major correlate of this deceleration in population growth is increased wealth with higher purchasing power resulting in higher consumption and a greater demand for processed food, meat, dairy, and fish, all of which add pressure to the food supply system. Although countries in the southern hemisphere are not the main originators of climate change, they may suffer the greatest share of damage in the form of declining yields and greater frequency of extreme weather events. Studies estimate that the aggregate negative impact of climate change on African agricultural output up to 2080 2100 could be between 15% and 30%. Agriculture will have to adapt to climate change, but it can also help mitigate the effects of climate change, and useful synergies exist between adaptation and mitigation [18 20]. Biofuel production based on agricultural commodities increased more than three-fold from 2000 to 2008. In 2007 08 total usage of coarse grains for the production of ethanol reached 110 million tons, about 10% of global production. Increased use of food crops for biofuel production could have serious implications for food security. At the same time, food manufacturers are experiencing greater competition for land, water, and energy, and the regulations to curb the negative effects of food production on the environment which is becoming increasingly clear [18,19]. Despite these issues, the threat of the effects of substantial climate change and concerns about how mitigation and adaptation measures may affect the

1.5 FOOD PRODUCTION AND CLIMATE CHANGE

9

food system are challenging [20]. Recently, a Lancet Commission concluded that the response to climate change could be “the greatest global health opportunity of the 21st century” [20]. The purpose is to track the health impacts of climate hazards such as health resilience and adaptation, health co-benefits of climate change mitigation, economics and finance, and political and broader engagement [20]. It is extremely difficult to assess precisely the current status of global food security from such a broad concept, although the big picture is clear. About 2 billion of the global population of over 7 billion are food insecure because they fall short of one or several of the FAO’s dimensions of food security. Enormous geographic differences in the prevalence of hunger exist within this global estimate, in high-income countries to middle- and lower-income countries [1 3,13 19]. The projection shows that feeding a world population of 9.6 billion people in 2050 would require raising overall food production by some 70% between 2005/07 and 2050 [13 17]. Production in the developing countries would need to almost double. The demand of food is expected to continue to grow as a result both of population growth and rising income. Demand for cereal is projected to reach some 3 billion tonnes by 2050 (Fig. 1.3). The FAO has estimated that annual cereal production will have to grow by almost a billion tons (2.1 million tons) and meat production by over 200 million tons to reach a total of 470 million tons in 2050, 72% of which will be consumed in the developing countries, up from the 58% of today (Figs. 1.4 and 1.5).

FIGURE 1.3 Estimates of cereal production, utilization, and stocks. Modified from FAO 2016.

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CHAPTER 1 GLOBAL FOOD AVAILABILITY FOR GLOBAL HEALTH

Changes in the relative global production of crops and animals since 1961. Godfray et al, Science 2010 FAOSTAT, http://faostat.fao.org/default.aspx (2009). (A) 3.5

Relative production

3.0 2.5

Main grains (wheat, barley, maize, rice, oats) Coarse grains (millet, sorghum) Root crops (cassava, potato)

2.0 1.5 Millets are rich in flavonoids, should be increased

1.0 0.5 1960

(B) 5.0 4.5 Relative numbers

No increase in Legumes

4.0

1970

1980

1990

2000

2010

2000

2010

Chickens Pigs Cattle and buffalo Sheep and goats

3.5 3.0 2.5 2.0 1.5 1.0 0.5 1960

1970

1980

1990

FIGURE 1.4 Changes in relative global production of crops and animals since 1991. Modified from Godfray H.C.J., Beddington J.R., Crute I.R., Haddad L., Lawrence D., Muir J.F., et al. Food Security: the challenge of feeding 9 billion people. Science 2010; 327: 812-818.

1.6 TOTAL FUNCTIONAL FOODS AVAILABLE FOR CONSUMPTION The exact definition of functional foods is not yet decided and the exact quantities of functional foods available in the world are not known. However, according to the International College of Nutrition and most other agencies, functional foods are defined as those foods which contain certain nutrients or bioactive compounds that can address some physiological mechanism of our body providing a benefit [2,5]. Fruits, vegetables, legumes, nuts, spices, olive oil, mustard oil, canola oil, and flax seed oil are common functional foods which have been used for the management of obesity, metabolic syndrome, type 2 diabetes, and CVDs [2,5 8]. These foods are rich in essential and nonessential amino acids, omega-3 fatty acids, monounsaturated fatty acids, antioxidants, vitamins, and minerals which are known to be protective against CVDs and other chronic diseases [2,5] (Table 1.1). The micronutrient content of the foods can be altered by organic farming, altering soil

1.7 FOOD AND AGRICULTURE ORGANIZATION AGENDA

11

FIGURE 1.5 Estimates of global progress in food consumption pattern, 1964 2030 (FAO 2002).

in general farming, plant breeding, and genetic engineering. The food industry has a particular role in developing functional foods by incorporating protective micronutrients in the food matrix [5]. There is a considerable focus on the development of value-added functional food products to combat various diseases like CVDs, diabetes, cancer, anemia, and other chronic diseases [5 8]. Overwhelming evidence from epidemiological, in vivo, in vitro, trial data indicate that a plantbased diet can reduce the risk of chronic diseases, particularly CVDs, diabetes, and cancer. Epidemiological studies and intervention trials showed that cancer risk in people consuming diets high in fruits and vegetables was only one-half of that in those consuming lower amounts of these foods [4 8].

1.7 FOOD AND AGRICULTURE ORGANIZATION AGENDA The exact quantity of total foods and functional foods available in the world are not known. The latest outlook of the FAO for global cereal supply and demand in 2017/18 remains favorable and global stocks remain around their record-high opening levels [3,5] (Figs. 1.3 and 1.4). The forecasts for world cereal production by FAO are in 2017 at 2,594 million tons, 5 million tons lower than the May forecast and down 14.1 million tons (0.5%) year-on-year [3]. There are expectations of a 2.2% decline in global wheat output as well as lower barley and sorghum production. These declines would be covered by greater global maize output, driven primarily by strong rebounds in South America and Southern Africa, and a 0.7% increase in world rice production [3,5]. FAO also forecasts increased World cereal utilization in 2017/18 which is projected at a record level of 2 584 million tons, up 13 million tons (0.5%) from 2016/17, Fig. 1.3, [3]. This forecast stands 11 million

12

CHAPTER 1 GLOBAL FOOD AVAILABILITY FOR GLOBAL HEALTH

Table 1.1 Bioactive Components From Fruits Products and Their Potential Benefits S. N.

Source of Functional Food

Component

Potential Benefit

1

Pink pumpkin

Lycopene

2

Fruit skin

Insoluble fiber

3 4

Apples, citrus fruit Berries, cherries and red grapes

12 13

Tea, cocoa, chocolate Red wine, peanuts, cinnamon

5

Citrus fruit

6

Apples, pears citrus

Soluble fiber Anthocyanins cyaniding, delphinidin, malvidin Catechins, epicatechins Procyanidins and proanthocyanidi-ns Flavanones-hesperetin and naringenin Caffeic acid and ferulic acid Isoflavones-daidzein and genistein

Anticarcinogenic activity against prostate cancer Maintains the gastrointestinal tract reducing colon cancer Reduces the risk of cardiovascular disease Cellular antioxidant, and healthy brain function

Soybeans and soy-based foods

8

9

Guava, sweet red/green pepper, kiwi, citrus fruit, strawberries Citrus fruits, peels; lemon and other citrus fruit

Vitamin C

Limonoids

Good for heart Maintains urinary tract Cellular antioxidant defense Cellular antioxidant and maintenance of eye and heart Bone and immune health and healthy brain function, in women support menopausal health Neutralizes free radicals which may damage cells and support immune system Protection of lung tissue

tons below May expectations, reflecting lower estimates for wheat and maize, particularly for China [3,6]. The total wheat utilization is projected to decline by 0.4% from 2016/17, whereas the total use of coarse grains and rice are expected to grow by 0.8% and 1.2%, respectively [3]. The forecast of 7.3 million tons cereals (mainly wheat and maize inventories), for 2018, by FAO are much higher compared to 2017, because rice growth remains steady [3] (Fig. 1.4). Moreover some of the cereals and other crops would also be used as livestock feed which may increase the estimated demand. Since there may be weaker demand for wheat, maize, and sorghum, the world trade for cereals may decline by 5 million tons in 2017/18 due to decreased production of coarse grains [3]. It is a mistake that the coarse grain, such as millets, may also decline, which appears to be due to lack of knowledge of the farmers and consumers as well as concerned government departments, about their beneficial effects on health, Figs. 1.4 and 1.5 [2,4,5]. The FAO agenda for pulses and legumes appears too good because these foods are considered functional foods which can replace wheat and corn and provide functional food security. The 68th UN General Assembly of the FAO/UNO declared 2016 the International Year of Pulses (IYP) (A/ RES/68/231). It is important that sustainable development of health adopted by the global community in the 2030 agenda is not possible without adequate production of pulses and legumes [10,11].

1.8 DEVELOPMENT OF FUNCTIONAL FOOD BY FOOD MANUFACTURING

13

There is a unique opportunity, due to the International Year of Pulses 2016, to bring to the fore the challenges faced by the sector and to galvanize stakeholders to ensure the successful role of pulses in food and nutrition security, poverty alleviation, and sustainability. The main pulses are lentils, red beans, green beans, kidney beans, grams, peas, etc. They are rich in proteins and carbohydrates but also provide fatty acids, potassium, magnesium, minerals, and antioxidant flavonoids. The main purpose of the IYP 2016 is to highlight public awareness and the nutritional benefits of pulses and legumes, as part of sustainable food production aimed towards food security and nutrition which would be a new step towards functional food security. This effort would encourage connections throughout the food chain that would better utilize pulse-based proteins, further global production of pulses, better utilize crop rotations, and address the challenges in the trade of pulses and legumes. A substantial growth in the production of pulses is important for food diversity, environmental biodiversity, as well as having beneficial effects on climate change and health and provides sustainable future human development [6 8]. The IYP 2016 would also help in valuation and utilization of pulses throughout the food system, their benefits for soil fertility and climate change, and for combating malnutrition so that there is little emergence of obesity and metabolic syndrome. Pulses are a vital source of plant-based proteins and amino acids for people around the globe and should be eaten as part of a healthy diet for health promotion and prevention of obesity, as well as chronic diseases such as diabetes, CVDs, and cancer; they are also an important source of plant-based protein for animals. There is a need to increase connections throughout the food chain to further global production of pulses and legumes by promotion of research and increased utilization of crop rotations and address the challenges in the trade of pulses with the help of food technology. The term “pulses” is used solely for dry grain, which excludes crops harvested green for food, and classified as vegetable crops, as well as those crops used mainly for oil extraction. Pulse crops such as lentils, beans, peas, and chickpeas are a critical part of the general food basket. Pulses are leguminous plants that have nitrogen-fixing properties that can contribute to increasing soil fertility and have a positive impact on the environment [10,11]. The total of food wastage in developing and developed countries is given in Fig. 1.6. There is a need to develop new affordable technology to reduce food wastage which is important in increasing food production.

1.8 DEVELOPMENT OF FUNCTIONAL FOOD BY FOOD MANUFACTURING In the healthy food and beverage market, the key driver of most functional food innovation, from plant-based products to the introduction of full-fat functional dairy, is the rise of green juices, blueberries, raisins, walnuts, almonds, cocoa, tea, seaweed snacking, and several more healthy propositions. This attractive and most-powerful trend appears to be due to consumers’ choice for foods and ingredients from natural sources. The value of these foods has been demonstrated in the cohort studies and intervention trials [21 26]. Since supplementation of these foods brings a natural and intrinsic health benefit, companies can convey a compelling message about their benefits. It is clear that if people draw their own conclusions about the benefits of a naturally functional ingredient or product, then a health claim is not necessary [25]. Most of the foods and nutrients given above are blended by the food manufacturers into other foods to provide healthy recipes which may be good

14

CHAPTER 1 GLOBAL FOOD AVAILABILITY FOR GLOBAL HEALTH

Makeup of total food waste in developed and developing countries. H. Charles J. Godfray et al. Science 2010;327:812-818

Developing countries

USA

UK

0% On-farm Retail

50%

100%

Transport and processing Food Service

Home and municipal

FIGURE 1.6 Total of food wastage in developing and developed countries. Modified from Godfray H.C.J., Beddington J.R., Crute I.R., Haddad L., Lawrence D., Muir J.F., et al. Food Security: the challenge of feeding 9 billion people. Science 2010; 327: 812-818.

for health promotion. Calcium and vitamin D have been added by the dairy industry for fortification of dairy products to prevent bone and joint diseases in infants and children as well as among adults and elderly populations. Cocoa has become an important ingredient of all modern foods because of its flavor and flavanol content which activates NO release and insulin sensitivity [25]. There are a few other examples of products fortified with vitamins and minerals which include calcium-fortified confectionery and fruit drinks, and calcium-enriched milk with folic acid. Folic acid is considered as a vital nutrient in early pregnancy, protecting against spina bifida. Similarly the importance of calcium has been observed in combating and counteracting osteoporosis. The prevalence of osteoporosis is significantly lethal among the increasing population of elderly people in developed countries, and improving calcium intake has been seen as particularly significant in this sector of the functional foods market. However, increased intake of calcium salts has been found to cause more calcium in the arteries which can predispose to atherosclerosis. There is a significant increase in the number of people suffering from CVDs in the last two decades which appears to be due to increased prevalence of environmental risk factors and decline in nutrients in the diet, that are known to modulate blood cholesterol. This category includes omega-3 fatty acids and plant sterols. Examples of products in this area include a margarine containing plant sterol fatty acid esters designed to reduce cholesterol absorption, and omega-3-enriched eggs produced by chickens fed a micro-algal feed ingredient. Dietary fiber comprises the nondigestible structural carbohydrates of plant cell walls and associated lignans. Consumption of fiber has been

1.9 THE FUNCTIONAL FOODS MARKET

15

linked to a reduced risk of certain types of cancer, e.g., consumption of wheat bran has been linked to a reduced risk of colon cancer. High-fiber products include wholewheat pasta with three times the fiber of regular pasta. A probiotic can be defined as a live microbial food supplement which beneficially affects the host by improving its intestinal microbial balance. Probiotics are thought to have a range of potential health benefits, including cholesterol-lowering, cancer chemopreventative, and immuneenhancing effects. Probiotics are viewed currently as the world’s biggest functional food products. This sector of the functional foods market has been stimulated in recent years by the development of prebiotics, short-chain oligosaccharides which enhance the growth of beneficial bacteria already in the gut, and synbiotics which combine pro- and prebiotic characteristics. The field of gut health is now an area of intense research in functional food science. Cancer and other mutations can occur as a result of oxidative damage to DNA caused by free radicals generated as a damaging sideeffect of aerobic metabolism. Plant and animal cells defend themselves against these effects by deploying so-called antioxidant compounds to trap or quench free radicals and hence arrest their damaging reactions. Antioxidants thus play a role in the body’s defense against CVDs, certain (epithelial) cancers, visual impairments, arthritis, and asthma. Antioxidants include vitamin E, carotene, vitamin C, and certain phytochemicals. Functional products incorporating antioxidant supplements include sports bars containing vitamins C and E as well as a blend of several carotenoids (alphaand gamma-carotene and lycopene). Plant foods are rich in micronutrients, but they also contain an immense variety of biologically active, nonnutritive secondary metabolites providing color, flavor, and natural toxicity to pests and sometimes humans. These “phytochemicals” have been linked to reducing the risk of chronic diseases such as cancer, osteoporosis, and heart disease. They include glucosinolates and phenolic compounds like flavonoids which are very effective antioxidants. Examples of products including phytochemicals are children’s confectionery containing concentrates of vegetables such as broccoli, Brussels sprouts, cabbage, and carrots. More recently, herbs and botanicals such as ginkgo, ginseng, and guarana have been linked to improved physical and mental performance (Table 1.1). These may lead to a new generation of “performance” functional foods including these and other components such as creatine, caffeine, and tryptophan. Products in this area include beverages, chewing gum, and sports bars. One product that combines a range of functional claims is a fruit juice designed for the sports market containing carnitine, an amino acid to assist the body in producing energy and in lowering cholesterol, calcium to improve skeletal strength, and chromium picolinate to help build lean muscle mass.

1.9 THE FUNCTIONAL FOODS MARKET The commercialization of functional food was first observed in Japan in the early 1980s. Market values of the functional foods vary enormously and depend on the category of functional food. Japan has been proven as a major player in the functional food market as it has 5% of functional food sales whose value are US$3-4 billion as reported previously [27]. However this proportion is decreasing as the European and US markets expand. In this context, Yakult Honsha (founded in 1955) played a significant role by developing products based on the probiotic lactic acid bacteria

16

CHAPTER 1 GLOBAL FOOD AVAILABILITY FOR GLOBAL HEALTH

Lactobacillus casei Shirota which are sold as a fermented milk drink in 65 mL bottles. The US market was worth about US$8 billion in 1997 with growth at around 5% per annum. Latest estimates indicate that the revenue is generated by the functional food market worldwide in 2017 and provides a forecast for 2022. The functional food market generated a global revenue of approximately US$ 299.32 billion by the end of 2017 and was projected to reach US$ 441.56 billion by 2022 (https://www.statista.com/statistics/252803/global-functional-food-sales/). Due to the differing definitions there are specific difficulties in analyzing the development of the functional food market, resulting in strongly varying estimations concerning the market volume of such products. Based on a definition of functional food by which ingredients with an additional health value have been added to foods (and this is announced to the consumers), the global market of functional food is estimated to at least US$33 billion [28]. The most important and dynamic market represents the United States with an estimated market share of more than 50%. In the United States, the market is differentiated into functional food with specific health claims achieving a turnover of around US$0.5 billion and functional food without claims with an annual turnover of at least US$15 billion [29]. The findings indicate that extreme of global development including human development may initiate life expectancy above 80 years such as in Japan. The increased number of old people in high income countries, may cause decline in global development, particularly in global production of functional foods and other global amenities [30]. There are numerous factor which are promoting the growth of the functional food market. Current research is finding the linkage between diet and its effect on the prevention of chronic disease in elderly people in many developed countries. This is of enormous concern for this age group, as the elderly are more susceptible towards these chronic disease. Nowadays consumers are more health conscious and are looking for healthy and nutritious diet. Food technologies and industries are working to develop novel functional food and also adopting modification in the regulatory framework governing this sector.

1.10 SOME IMPORTANT NATURAL FUNCTIONAL FOODS There are certain foods which are quite rich in protective nutrients and poor in energy, which can be used in daily recipes to increase their consumption (Tables 1.1 1.4). These foods can also be incorporated into other food matrixes with moderate nutrient densities to make a healthy meal.

1.10.1 OATS Oats has been recognized as a healthful and nutritious cereal containing a high concentration of soluble fiber and dense nutrients. Irrespective of nutritionally rich cereal, it has physiological benefits like a positive effect on reducing hyperglycemia, hyperinsulinemia, hypercholesterolemia, and several other benefits. Oats products are a widely studied dietary source of the cholesterol-lowering soluble fiber β-glucan. There is now significant scientific agreement that consumption of this particular plant food can reduce total and low density lipoprotein (LDL) cholesterol, thereby reducing the risk of coronary heart disease (CHD).

1.10 SOME IMPORTANT NATURAL FUNCTIONAL FOODS

17

Table 1.2 Bioactive Components From Vegetable Food and Their Potential Benefits S. N.

Source of Functional Food

Component

Potential Benefit

1

Carrots, spinach and tomatoes

β-carotene

2

Kale, collards and broccoli

3 4 5

Watermelon, red/ pink pumpkin Pea, bean Cauliflower, broccoli sprouts, horseradish Garlic, onions, leeks, and scallions

Lutein and zeaxanthin Lycopene Soluble fiber Sulforaphane

Bolsters cellular antioxidant and defense, neutralize free radicals Maintains the eye health

6

7

Sweet potato

8

Cabbage, turnips, and member of mustard family Brussels sprout, kale turnips, Bok choy, and kohlrabi

9

10

Potato, peanuts, spinach

Diallylsufhide and allyl methyl trisulfide Pantothenic acid Thiols Glucosinolates

Lipoic acid and ubiquinone (coenzyme Q)

Anticarcinogenic activity against prostate cancer Reduces the risk of cardiovascular disease Enhances detoxification of undesirable compound and anticarcinogenic Enhances detoxification of undesirable compounds and also support heart, immune and digestive health Helps regulate metabolism and hormones synthesis Antimutagenic and anticarcinogenic properties and immune and cardiovascular properties Regulates white blood cell and cytokines and block enzyme that promote tumor growth (breast, liver, lungs stomach, and esophagus Liver detoxification activity

Table 1.3 Bioactive Components From Oil Seed and Cereal Food and Their Potential Benefits S. N.

Source of Functional Food

Component

Potential Benefit

1 2

Corn Wheat bran, corn bran

Lutein and zeaxanthin Insoluble fiber

3 4 5

Oat bran, oatmeal, flour Psyllium seed husk Cereal grain, brown rice

Beta glucan Soluble fiber Whole grains

6

Monounsaturated fatty acid

7

Tree nuts, olive oil, canola oil Walnuts oil, flaxseed oil

Maintains eye health Maintains the gastrointestinal tract reducing the colon cancer Effective against coronary heart disease Reduces the risk of cardiovascular disease Reduces the risk of cardiovascular disease, maintains blood glucose level Reduces the risk of cardiovascular disease,

8

Corn, soy, wheat

9

Flax seed, rye, seeds, and nuts lentils Sunflower seeds, almonds, hazelnuts

10

Polyunsaturated fatty acid and omega fatty acid Free stanols/sterols Lignans Vitamin E

Maintains heart and eye health and mental function Reduces cholesterol and prevent carcinogensis Supports maintenance of heart and immune health Neutralizes free radical which may damage cells and support immune system

18

CHAPTER 1 GLOBAL FOOD AVAILABILITY FOR GLOBAL HEALTH

Table 1.4 Bioactive Components From Dairy Food and Their Potential Benefits S. N.

Source of Functional Food

Component

Potential Benefit

1 2 3

Yogurt Curd Cheese, butter, margarine

Calcium Biotin Niacin

Reduces the risk of osteoporosis/microbiom Helps regulate metabolism and gut microbiom Supports cell growth and help regulate metabolism

1.10.2 SOY Soy flour and more highly purified soy proteins contain a number of constituents that can be used in combating a variety of diseases. Soy isoflavones may prevent diseases associated with postmenopausal women such as osteoporosis and CHD. Soy flour has a potential as an anticarcinogen. Soy was in the spotlight during the 1990s. Not only is soy a high quality protein, as assessed by the FDA’s “Protein Digestibility Corrected Amino Acid Score” method, it is now thought to play preventive and therapeutic roles in CVD, cancer, osteoporosis, and the alleviation of menopausal symptoms. The cholesterollowering effect of soy is the most well-documented physiological effect. A 1995 meta-analysis of 38 separate studies (involving 743 subjects) found that the consumption of soy protein resulted in significant reductions in total cholesterol (9.3%), LDL cholesterol (12.9%), and triglycerides (10.5%), with a small but insignificant increase (2.4%) in high density lipoprotein cholesterol [31].

1.10.3 FLAXSEED Flaxseed has emerged as a potential functional food, being a good source of alpha-linolenic acid, lignans, high quality protein, soluble fiber, and phenolic compounds. Among the major seed oils, flaxseed oil contains the most (57%) of the omega-3 fatty acid, alpha-linolenic acid. Recent research, however, has focused more specifically on fiber-associated compounds known as lignans. The two primary mammalian lignans, enterodiol and its oxidation product, enterolactone, are formed in the intestinal tract by bacterial action on plant lignan precursors [27]. A large number of clinical studies have recognized the tremendous potential of n-3 polyunsaturated fatty acids (PUFAs) against inflammatory mediators like prostaglandins E2, leukotriene B4, TNF-α, interleukin, and cytokines. These clinical studies revealed that n-3 PUFAs are helpful in the prevention of CHDs, atherosclerosis, rheumatoid arthritis, and asthma. Daily intake of 3 g EPA and DHA for more than 12 weeks was found to be effective in reducing the inflammation of rheumatoid arthritis. In rodents, flaxseed has been shown to decrease tumors of the colon and mammary gland [32] as well as of the lung [33]. Phipps et al. [34] demonstrated that the ingestion of 10 g of flaxseed per day elicited several hormonal changes associated with reduced breast cancer risk. Adlercreutz et al. [35] found that the urinary lignan excretion was significantly lower in postmenopausal breast cancer patients compared to controls eating a normal mixed or a lactovegetarian diet.

1.10.4 TOMATOES Tomatoes have gained significant attention within the last few years because of the high content of lycopene, which is the primary carotenoid found in this fruit, and which serves as an anticancerous

1.10 SOME IMPORTANT NATURAL FUNCTIONAL FOODS

19

compound [36]. Interestingly, lycopene is the most abundant carotenoid in the prostate gland [37]. Other cancers whose risks have been inversely associated with serum or tissue levels of lycopene include breast, digestive tract, cervix, bladder, skin, and possibly lung [38]. Research carried out on the importance of lycopene function deduced that increasing the level of the carotenoid reduced the risk of microbial infection.

1.10.5 GARLIC Garlic (Allium sativum) is likely the herb most widely quoted in the literature for medicinal properties [39]. The purported health benefits of garlic are numerous, including cancer chemopreventive, antibiotic, antihypertensive, and cholesterol-lowering properties [40]. Several epidemiologic studies also imply that the garlic may be predominantly effective in reducing risk in human cancer [41]. Garlic has also been advocated for the prevention of CVD—possibly the antihypertensive properties of garlic make it suitable for prevention of CVD. Previous findings suggest that due to insufficient evidence, it is not proper to recommend it for decreasing blood pressure but as a functional food vegetable for prevention of CVDs [42]. Bioactive components of garlic have been shown to inhibit tumorigenesis in various experimental models [43]. A few epidemiologic studies suggest that garlic may be effective in minimizing human cancer [41]. However, it is to be expected that garlic, as with other plants, will vary in composition depending on location, soil, climate, and a host of other factors.

1.10.6 BROCCOLI AND OTHER CRUCIFEROUS VEGETABLES An epidemiological study has associated the frequent consumption of cruciferous vegetables with decreased cancer risk. Verhoeven et al. [43] attributed the anticarcinogenic properties of cruciferous vegetables to their relatively high content of glucosinolates. Glucosinolates are a group of glycosides stored within cell vacuoles of all cruciferous vegetables. Myrosinase, an enzyme found in plant cells, catalyzes these compounds to a variety of hydrolysis products, including isothiocyanates and indoles. Indole-3 carbinol (I3C) is currently under investigation for its cancer chemopreventive properties, particularly of the mammary gland. In humans, I3C administered at 500 mg daily (equivalent to 350 500 g cabbage/day) for 1 week significantly increased the extent of estradiol 2-hydroxylation in women [44], suggesting that this compound may be a novel approach for reducing the risk of breast cancer.

1.10.7 CITRUS FRUITS Several epidemiological studies have shown that citrus fruits are protective against a variety of human cancers. Although oranges, lemons, limes, and grapefruits are a principal source of such important nutrients as vitamin C, folate, and fiber, Elegbede et al. [45] have suggested that another component is responsible for the anticancer activity.

1.10.8 CRANBERRY Cranberry juice has been recognized as efficacious in the treatment of urinary tract infections since 1914, when Blatherwick [46] reported that this benzoic acid-rich fruit caused acidification of the

20

CHAPTER 1 GLOBAL FOOD AVAILABILITY FOR GLOBAL HEALTH

urine. Previous investigations have focused on the ability of cranberry juice to inhibit the adherence of Escherichia coli to uroepitheial cells [47]. This phenomenon has been attributed to two compounds: fructose and a nondialyzable polymeric compound. A study carried out on 153 elderly women consuming 300 mL cranberry beverage daily showed a significant decrease by approximately 58% incidence of bacteriuria with pyuria compared to the control group after 6 months. The finding of this study clearly deduced the benefits of cranberry juice on the urinary tract [48].

1.10.9 TEA A great deal of attention has been directed to the polyphenolic constituents of tea, particularly green tea [49]. Polyphenols comprise up to 30% of the total dry weight of fresh tea leaves. Catechins are the predominant and most significant of all tea polyphenols [50]. The four major green tea catechins are epigallocatechin-3-gallate, epigallocatechin, epicatechin-3-gallate, and epicatechin. Approximately two-thirds of the studies found no relationship between tea consumption and cancer risk, while 20 found a positive relationship and only 14 studies found that tea consumption reduced cancer risk [51]. There are a few findings which suggest that tea consumption may reduce the risk of CVD. Hertog and coworkers [52] reported that tea consumption was the major source of flavonoids in a population of elderly people in the Netherlands. The intake of five flavonoids (quercetin, kaempferol, myricetin, apigenin, and luteolin), the majority derived from tea consumption, reduced death of people suffering with CHD.

1.10.10 WINE AND GRAPES It has been observed that wine, particularly red wine, can minimize the risk of CVD. The first evidence of wine intake effect on CVD was first noticed in 1979 when cohort studies showed a negative correlation between wine intake and death from ischemic heart disease in both genders. Red wine is also a significant source of trans-resveratrol, a phytoalexin found in grape skins [53]. Resveratrol has also been shown to have estrogenic properties [54] which may explain in part the cardiovascular benefits of wine drinking, and it has been shown to inhibit carcinogenesis in vivo [55].

1.10.11 FISH Omega-3 (n-3) fatty acids are an essential class of PUFAs derived primarily from fish oil. This has encouraged the examination of the role of n-3 fatty acids in different diseases—such as cancer and CVD—and in neonated growth. The cardioprotective effect of fish consumption has been observed in some prospective investigations [56], but not in others [57].

1.10.12 DAIRY PRODUCTS Most of the dairy products are functional foods, especially after feeding of healthy feedstock to animals to increase the omega-3 fatty acids, beta carotene, and flavonoids. They are one of the best sources of calcium, an essential nutrient which can prevent osteoporosis and possibly colon cancer. In addition to calcium, however, recent research has focused specifically on other components in dairy products, particularly fermented dairy products known as probiotics. Probiotics are defined as

REFERENCES

21

“live microbial feed supplements which beneficially affect the host animal by improving its intestinal microbial balance” [58]. More evidence supports the role of probiotics in cancer risk reduction, particularly colon cancer [59]. This observation may be due to the fact that lactic acid cultures can alter the activity of fecal enzymes (e.g., b-glucuronidase, azoreductase, nitro-reductase) that are thought to play a role in the development of colon cancer. Recently, probiotics have been suggested as a treatment for the prevention of NAFLD due to new research in this area [63–66]. Omega-3 fatty acid supplementation may have beneficial effects in regulating hepatic lipid metabolism, adipose tissue function, platelet function, arrhythmias, and inflammation [63]. Further studies indicate that supplementation with probiotics, prebiotics, and synbiotics has shown promising results against various enteric pathogens due to their unique ability to compete with pathogenic microbiota for adhesion sites [64–66]. These strategies may alienate pathogens or can modulate, stimulate, and regulate the immune responses in the host by initiating the activation of specific genes in and outside the host intestinal tract. There may be increase in lifespan and improvement in gut microbiota leading to decrease in fatty acid deposition in the hepatocytes [65,66].

1.10.13 BEEF An anticarcinogenic fatty acid known as conjugated linoleic acid (CLA) was first isolated from grilled beef in 1987 [60]. Since then, CLA has been shown to be effective in suppressing forestomach tumors in mice, aberrant colonic crypt foci in rats, and mammary carcinogenesis in rats [61]. In the mammary tumor model, CLA is an effective anticarcinogen in the range of 0.1% 1% in the diet. In a large cohort study, among 536,969 subjects, aged 50 71 years, follow-up after 16 years revealed enhanced prevalence of mortality and death due to CVD, diabetes, stroke, cancer, Alzheimer’s disease, liver and kidney disease which may arise due to processed and unprocessed red meat and poultry products [62]. The adverse effects were accounted for, in part, by heme iron and nitrate/nitrite from processed meat. However, CVD risk was reduced by substituting red meat with chicken, fish, or seafood. In brief, food security has been associated with a decrease in undernutrition, and with an increase in obesity and metabolic syndrome, which are risk factors of CVDs and other chronic diseases. Since functional foods have been demonstrated to provide protection from NCDs, it is possible that increased availability of functional foods at an affordable cost may lead to a greater consumption of these foods, resulting in health promotion and disease prevention.

REFERENCES [1] Godfray HCJ, Beddington JR, Crute IR, Haddad L, Lawrence D, Muir JF, et al. Food Security: the challenge of feeding 9 billion people. Science 2010;327:812 18. [2] Singh RB, Shastun S, Chibisov S, Itharat A, De Meester F, Wilson DW, et al. Functional food security and the heart. J Cardiol Therapy 2016;3(6):1 8. Available from: http://www.ghrnet.org/index.php/jct/article/view/1858. [3] Food and Agriculture Organization, United Nations of Organization 2016 2017. www.fao.org/worldfoodsituation/csdb/en/, Accessed August 2017.

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[4] Singh RB, Visen P, Sharma D, Sharma S, Mondal R, Sharma JP, et al. Study of functional foods consumption patterns among decedents dying due to various causes of death. Open Nutra J 2015;8:16 28. [5] Tomar RS, Tomar RS, Singh RB, Pal R, Tripathi A, Singh RB. You are, what you eat, which depends on available food and agriculture? World Heart J 2013;5:133 42. [6] Popkin BM, Horton S, Kim S, Ajay Mahal MS, Shuigao J. Trends in diet, nutritional status, and dietrelated non-communicable diseases in China and India: the economic costs of the nutrition transition. Nutr Rev 2001;59:379 90. [7] GBD. 2013 Mortality and Causes of Death Collaborators. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990 2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 2015;385:117 71. Available from: https://doi.org/ 10.1016/S0140-6736(14)61682-2. [8] Singh RB, De Meester F, Pella D, Basu TK, Watson RR. Globalization of dietary wild foods protect against cardiovascular disease and all cause mortalities? A Scientific Statement from the International College of Cardiology, Columbus Paradigm Institute and the International College of Nutrition. Open Nutra J 2009;2:42 5. [9] FAO http://www.fao.org/pulses-2016/about/en/accessed August 2017. [10] Velazquez E, Silva LR, Peix A. Legumes: a healthy and ecological source of flavonoids. Current Nutr Food Sci 2010;6:109 44. [11] World Health Organization. e-Library of Evidence for Nutrition Actions (eLENA) http://www.who.int/ elena/global-targets/en/ accessed July 2017. [12] United Nation,s Department of Economics and social Affairs. World population projected to reach 9.7 billion by 2050 http://www.un.org/en/development /desa/news/population/2015-report.html accessed 2017. [13] World Bank, World Development Report 2008: Agriculture for Development (World Bank, Washington, DC, 2008. [14] Food and Agriculture Organization. Declaration on world food security. World Food Summit. Rome: FAO; 1996. [15] Food and Agriculture Organization STAT, http://faostat.fao.org/default.aspx 2009, accessed 2017. [16] How To Feed The World In 2050, Expert Meeting 2009, State of Food Insecurity in the World, FAO, Headquarters, Rome, 2009. www.fao.org/docrep/012/ak542e/ak542e00.htm, accessed Sept 2017. [17] Evans A. The Feeding of the Nine Billion : Global Food Security. London: Chatham House; 2009. [18] Tilman D, Fargione J, Wolff B, D’Antonio C, Dobson A, Howarth R, et al. Forecasting agriculturally driven global environmental change. Science 2001;292:281 8. Available from: https://doi.org/10.1126/ science.1057544. [19] Parryetal ML. Intergovernmental panel on climate change. Contribution of Working Group II to the Fourth Assessment Report of the Intergovernmental Panel on Climate Change. Cambridge: Cambridge Univ. Press; 2007. [20] Watts N, Adger WN, Karlsson SA, Bai Y, et al. The Lancet Countdown: tracking progress on health and climate change. Lancet 2017;389:1151 64. [21] De Meester F, Takahashi T, Singh RB, Toda E, Hristova K, Fedacko J, et al. Nutrition in transition from Homo erectus to Homo modesties. World Heart J 2013;5:33 46. [22] Hristova K, Shiue I, Pella D, Singh RB, Chaves H, Basu TK, et al. Sofia declaration on transition of prevention strategies for cardiovascular diseases and diabetes mellitus in developing countries: a statement from the International College of Cardiology and the International College of Nutrition. Nutrition 2014. Available from: https://doi.org/10.1016/j.nut.2013.12.013. [23] FAO, UNO. The State ofFood and Agriculture: Sustainable Food Systems for Food Security and Nutrition http://www.fao.org/docrep/meeting/028/mg413e01.pdf accessed 2017. [24] Singh RB, Takahashi T, Shastun S, Elkilany G, Hristova K, Shehab A, et al. The concept of functional foods and functional farming (4 F) in the prevention of cardiovascular diseases: a review of goals from 18th world congress of clinical nutrition. J Cardiol Therapy 2015;2(4):341 4.

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[25] Hristova K, Nakaoka T, Otsuka K, Fedacko J, Singh R, Singh RB, et al. Perspectives on chocolate consumption and risk of cardiovascular diseases and cognitive function. Open Nutr J 2012;5:207 12. [26] Singh RB, Takahashi T, Nakaoka T, OtsukaK, Toda E, Shin HH, et al. Nutrition in transition from Homo sapiens to Homo economicus. Open Nutra J 2013;6:6 17. [27] Setchell KDR, Lawson AM, Borriello SP, Harkness R, Gordon H, Morgan DML, et al. Lignan formation in man—microbial involvement and possible roles in relation to cancer. Lancet 1981;4 7 ii. [28] Hilliam M. Functional food How big is the market? World Food Ingred 2000;12:50 2. [29] Hufnagel W. AktuellesMarktvolumen. Lebensmittelzeitung 2000;52(26):44. [30] Bongaarts J. Development: slow down population growth. Nature 2016;530:409 12. [31] Anderson JW, Johnstone BM, Cook-Newell ME. Meta-analysis of the effects of soy protein intake on serum lipids. New Engl J Med 1995;333:276 82. [32] Phipps WR, Martini MC, Lampe JW, Slavin JL, Kurzer MS. Effect of flax seed ingestion on the menstrual cycle. J Clin Endocrin Metab 1993;77:1215 19. [33] Thompson LU. Flaxseed, lignans, and cancer. In: Cunnane S, Thompson LU, editors. Flaxseed in human nutrition. Champaign, IL: AOCS Press; 1995. p. 219 36. [34] Yan L, Yee JA, Li D, McGuire MH, Thompson LU. Dietary flaxseed supplementation and experimental metastasis of melanoma cells in mice. Cancer Lett 1998;124:181 6. [35] Adlercreutz H, Fotsis T, Heikkinen R, Dwyer JT, Woods M, Goldin BR, et al. Excretion of the lignansenterolactone and enterodiol and of equol in omnivorous and vegetarian postmenopausal women and in women with breast cancer. Lancet 1982;1295 9 ii. [36] Gerster H. The potential role of lycopene for human health. J Am Coll Nutr 1997;16:109 26. [37] Clinton SK. Lycopene: chemistry, biology, and implications for human health and disease. Nutr Rev 1998;56:35 51. [38] Clinton SK, Emenhiser C, Schwartz SJ, Bostwick DG, Williams AW, Moore BJ, et al. Cis-trans lycopene isomers, carotenoids, and retinol in the human prostate. Cancer Epidemiol Biomarkers Prev 1996;5:823 33. [39] Nagourney RA. Garlic: medicinal food or nutritious medicine? J Med Food 1998;1:13 28. [40] Srivastava KC, Bordia A, Verma SK. Garlic (Allium sativum) for disease prevention. S Afr J Sci 1995;91:68 77. [41] Dorant E, van den Brandt PA, Goldbohm RA, Hermus RJJ, Sturmans F. Garlic and its significance for the prevention of cancer in humans: a critical review. Br J Cancer 1993;67:424 9. [42] Silagy CA, Neil HAW. A meta-analysis of the effect of garlic on blood pressure. J Hyper 1994;12:463 8. [43] Verhoeven DTH, Verhagen H, Goldbohm RA, van den Brandt PA, van Poppel G. A review of mechanisms underlying anticarcinogenicity by brassica vegetables. Chem Bio Interactions 1997;103:79 129. [44] Michnovicz JJ, Bradlow H. Altered estrogen metabolism and excretion in humans following consumption of indolecarbinol. Nutr Cancer 1991;16:59 66. [45] Elegbede JA, Maltzman TH, Elson CE, Gould M. Effects of anticarcinogenicmonoterpenes on phase II hepatic metabolizing enzymes. Carcinogenesis 1993;14:1221 3. [46] Blatherwick NR. The specific role of foods in relation to the composition of the urine. Arch Int Med 1914;14:409 50. [47] Schmidt DR, Sobota AE. An examination of the anti-adherence activity of cranberry juice on urinary and nonurinary bacterial isolates. Microbios 1988;55:173181. [48] Avorn J, Monane M, Gurwitz JH, Glynn RJ, Choodnovskiy I, Lipsitz LA. Reduction of bacteriuria and pyuria after ingestion of cranberry juice- A Reply. J Am Med Assoc 1994;272:589 90. [49] Harbowy ME, Balentine DA. Tea chemistry. Crit Rev Plant Sci 1997;16:415 80. [50] Graham HN. Green tea composition, consumption and polyphenol chemistry. Prev Med 1992;21:334350. [51] Yang CS, Wang ZY. Tea and cancer. J Natl Cancer Inst 1993;85:1038 49.

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[52] Hertog MGL, Feskens EJM, Hollman PCH, Katan MB, Krumhout D. Dietary antioxidant flavonoids and risk of coronary heart disease: the Zutphen Elderly Study. Lancet 1993;342:1007 11. [53] Creasy LL, Coffee M. Phytoalexin production of grape berries. J Am Soc Hort Sci 1998;113:230 4. [54] Gehm BD, McAndrews JM, Chien P-Y, Jameson JL. Resveratrol, a polyphenolic compound found in grapes and wine, is an agonist for the estrogen receptor. Proc Natl Acad Sci 1997;94:14138 43. [55] Jang M, Cai J, Udeani G, Slowing KV, Thomas CF, Beecher CWW, et al. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science 1997;275:218 20. [56] Krumhout D, Bosschieter EB, de LezenneCoulander C. The inverse relation between fish consumption and 20-year mortality from coronary heart disease. New Eng J Med 1988;5(312):1205 9. [57] Ascherio A, Rimm EB, Stampfer MJ, Giovannucci EL, Willett WC. Dietary intake of marine n-3 fatty acids, fish intake, and the risk of coronary disease among men. New Eng J Med 1995;332:977 82. [58] Fuller R. History and development of probiotics. In: Fuller R, editor. Probiotics. N.Y: Chapman & Hall; 1994. p. 1 8. [59] Mittal BK, Garg SK. Anticarcinogenic, hypocholesterolemic, and antagonistic activities of Lactobacillus acidophilus. Crit Rev Micro 1995;21:175 214. [60] Ha YL, Grimm NK, Pariza MW. Anticarcinogens from fried ground beef: health-altered derivatives of linoleic acid. Carcinogenesis 1987;8:1881 7. [61] Ip C, Chin SF, Scimeca JA, Pariza MW. Mammary cancer prevention by conjugated dienoic derivative of linoleic acid. Cancer Res 1991;51(22):6118 24. [62] Etemadi A, Sinha R, Ward MH, Graubard BI, Inoue-Choi M, Dawsey SM, et al. Mortality from different causes associated with meat, heme iron, nitrates, and nitrites in the NIH-AARP Diet and Health Study: population based cohort study. BMJ 2017;357. Available from: https://doi.org/10.1136/bmj.j1957 (Published09 May 2017)Cite this as: BMJ 2017;357:j1957. [63] Kobyliak N, Falalyeyeva T, Bodnar P, Beregova T. Probiotics supplemented with omega-3 fatty acids are more effective for hepatic steatosis reduction in an animal model of obesity. Probiotics Antimicrob Proteins 2017;9(2):123 30. Available from: https://doi.org/10.1007/s12602-016-9230-1. [64] Sharma K, Pooranachithra M, Balamurugan K, Goel G. Multivariate analysis of increase in life span of caenorhabditis elegans through intestinal colonization by indigenous probiotic strains. Probiotics Antimicrob Proteins 2018. Available from: https://doi.org/10.1007/s12602-018-9420-0. [65] Zhang Y, Tang K, Deng Y, Chen R, Liang S, Xie H, et al. Effects of shenling baizhu powder herbal formula on intestinal microbiota in high-fat diet-induced NAFLD rats. Biomed Pharmacother. 2018;102:1025 36. Available from: https://doi.org/10.1016/j.biopha.2018.03.158. [66] Kerry RG, Patra JK, Gouda S, Park Y, Shin HS, Das G. Benefaction of probiotics for human health: a review. J Food Drug Anal 2018. Available from: https://doi.org/10.1016/j.jfda.2018.01.002.

FURTHER READING Kohlmeier et al., 1997Kohlmeier L, Kark JD, Gomez-Gracia E, Martin BC, Steck SE, Kardinaal AFM, et al. Lycopene and myocardial infarction risk in the EURAMIC study. Am J Epidemiol 1997;146:618 26. Reuter et al., 1996Reuter HD, Koch HP, Lawson LD. Therapeutic effects and applications of garlic and its preparations. In: Koch HP, Lawson LD, editors. Garlic. The Science and Therapeutic Application of Allium sativum L. and Related Species. 2nd Ed Baltimore: Williams & Wilkins; 1996.

CHAPTER

ESTIMATES OF FUNCTIONAL FOODS AVAILABILITY IN THE 10 MOST HIGHLY POPULOUS COUNTRIES

2

Ram B. Singh1, Rukam S. Tomar2, Anil K. Chauhan3, Poonam Yadav3 and Shairy Khan4 1

Halberg Hospital and Research Institute, Moradabad, Uttar Pradesh, India 2Department of Biotechnology, Junagadh Agricultural University, Junagadh, Gujarat, India 3Centre of Food Science and Technology, Institute of Agricultural Sciences & Institute of Technology, Banaras Hindu University Varanasi, Uttar Pradesh, India 4Center of Nutrition Research, Pune, Maharashtra, India

2.1 INTRODUCTION A new agreement between Institute of Health Metrics and Evaluation (IHME) and the UNO’s Food and Agriculture Organization (FAO) has been made to exchange data, knowledge, and expertise to review the role of nutrition in the emergence of obesity and related noncommunicable diseases (NCDs) [1,2]. There is a need to find out through the world’s collective understanding about the role of nutrition in reducing high body weight [2]. The United Nations “Decade of Action on Nutrition” is an initiative covering 2016 25 to eradicate hunger, end malnutrition in all its forms (undernutrition, micronutrient deficiencies, overweight, or obesity), and reduce the burden of dietrelated NCDs in all age groups [1]. The study, involving 195 countries and territories from 1980 through 2015, aimed to create a healthier, more sustainable food system, indicating that functional food security for global health could be a right approach for health promotion and diseases prevention [2]. IHME has reported causes of mortality in the 10 most highly populous countries: China, India, United States, Indonesia, Brazil, Pakistan, Nigeria, Bangladesh, Russia and Japan [3]. The findings revealed that vegetable, fruit, fish, whole grain, omega-3 fatty acid, fiber, nuts, and seeds were inversely associated, whereas high trans fat, processed meat, and sweetened beverages were positively associated with mortality [3] (Fig. 2.1). The role of functional foods in NCDs has also been emphasized by the International College of Nutrition as well as by FAO and WHO [4 7]. Apart from these foods, other functional foods, spices, millets, probiotics can also decrease risk of NCDs. The consensus is that increased consumption of functional food can prevent obesity, as well as NCDs and prolong longevity, hence every effort should be made to increase the availability of functional foods at affordable cost. It seems that the FAO should take the lead to encourage the production of functional foods by individual countries. In the European Union (EU), all the information regarding functional food estimates and data on association of food intakes with risk of NCDs is also available [7 9]. This article aims to assess the The Role of Functional Food Security In Global Health. DOI: https://doi.org/10.1016/B978-0-12-813148-0.00002-5 © 2019 Elsevier Inc. All rights reserved.

25

26

CHAPTER 2 ESTIMATES OF FUNCTIONAL FOODS AVAILABILITY

Both sexes, Age-standardized, 2013, Deaths per 100,000 n Ba p Ja

1

1

1

1

1

1

12

4

3

7

4

6

2

Low fruit

3

4

7

3

5

4

5

2

5

4

Smoking

4

5

9

2

7

6

13

6

4

5

Ambient particulate matter

5

7

16

10

13

9

6

7

14

10

High body-mass index

6

11

2

7

2

2

2

14

2

7

Low whole grains

7

13

11

5

10

15

12

8

7

9

High fasting plasma glucose

8

8

4

11

8

10

11

10

9

11

Household air pollution

9

6

8

20

8

3

3

an

a si

1

6

es h

us R

ad gl

n ta is

1

2

ria

il

e ig N

az Br

1

2

es ia

on

k Pa

d In S U

1

High sodium

d In ia

na hi C

High blood pressure

Lead

10

18

19

18

19

17

17

13

21

19

Low physical activity

11

9

5

9

6

13

8

9

11

6

High total cholesterol

12

3

3

6

3

5

9

12

3

3

Low omega-3

13

12

12

22

14

14

14

16

17

21

Low fiber

14

15

15

15

16

18

19

18

16

14

Low nuts and seeds

15

16

10

13

12

16

16

17

12

12

Alcohol use

16

20

20

19

21

22

15

21

8

16

Low vegetables

17

10

8

4

9

7

10

5

10

8

Low glomerular filtration

18

14

14

14

11

12

4

11

15

13

Low PUFA

19

17

18

16

18

19

18

19

18

15

Secondhand smoke

20

22

22

17

22

21

22

22

19

18

High trans fat

21

19

17

21

15

11

20

15

20

17

High processed meat

22

21

13

20

17

20

21

20

13

20

High sweetened beverages

23

23

21

23

23

23

23

23

22

22

FIGURE 2.1 Functional food intake and risk of mortality in the 10 most highly populous countries. Modified from GBD study, reference 1, Lancet 2015.

quantitative production and consumption of functional foods in the 10 most highly populous countries to indicate the status of the world functional food situation.

2.2 THE AGENDA OF GLOBAL BURDEN OF DISEASES STUDY IHME is committed to producing more in-depth studies on the implications of obesity and overweight, with a new partnership with the United Nations, because none of the health agencies in the world can alone prevent NCDs [2]. Recent data from Global Burden of Disease study (GBD) include a systematic, scientific effort to quantify the magnitude of health loss from all major diseases, injuries, and risk factors by age, sex, and population. It is comprised of more than 2300 collaborators in 133 countries, the GBD study examines 300-plus diseases and injuries. Increased body weight was observed among 2.2 billion children and adults or in 30% of all the subjects, worldwide in 2015 [2]. This includes nearly 108 million children and more than 600 million adults with body mass index (BMI) exceeding 30 kg/m2. The prevalence of obesity among children has been lower than among adults, however, the rate of increase in childhood obesity in many countries was greater than that of adults. Of the 4.0 million deaths attributed to excess body weight in 2015,

2.4 ESTIMATES OF FAO FOR FUNCTIONAL FOODS PRODUCTION

27

nearly 40% occurred among people whose BMI was lower than the threshold considered “obese.” The highest prevalence of obesity among children and young adults was recorded in the United States at nearly 13%; Egypt topped the list for adult obesity at about 35%. Lowest rates were in Bangladesh and Vietnam, respectively, at 1%. China with 15.3 million and India with 14.4 million had the highest numbers of obese children. The United States with 79.4 million and China with 57.3 million had the highest numbers of obese adults in 2015.

2.3 WORLD HEALTH ORGANIZATION AGENDA (WHO) The WHO has accepted the targets lead down by World Heart Federation to achieve the overarching 25% by the year 2025 target. They selected eight targets for treatment of six key risk factors, as well as two health systems targets in the prevention and control of NCDs, particularly cardiovascular diseases (CVDs) [10,11]. However, International College of Nutrition and International College of Cardiology have modified this approach by giving greater emphasis on prevention of primary risk factors: dietary patterns, physical activity, mental stress, apart from tobacco and alcoholism [12,13]. It seems that this basic approach, can successfully tackle the eight targets, six directly aligning with risk factors of heart attack, heart failure, and stroke. These risk factors: tobacco use, sodium intake, physical inactivity, as well as biological risk factors: raised blood pressure, diabetes, and obesity, and one target for management of subjects at high risk of CVD, were laid down by WHO. The global cost of NCDs is nearly US$863 billion with 36 million deaths due to NCDs. Premature NCD deaths cannot be reduced by 25% unless primary, behavioral risk factors are duly taken up by WHO member states, professional organizations, public health experts, policy makers, healthcare providers, and key stakeholders [10 13]. Among 702,308 adult victims dying due to cardiometabolic deaths in 2012 in the United States, dietary factors were estimated to be associated with a substantial proportion of deaths from heart disease, stroke, and type 2 diabetes [14]. These results should help identify priorities, guide public health planning, and inform strategies to provide functional food security for health promotion as suggested by the International College of Nutrition [12,15].

2.4 ESTIMATES OF FAO FOR FUNCTIONAL FOODS PRODUCTION The exact quantity of functional food production and consumption have not been assessed by the FAO and WHO, although Western dietary patterns have been demonstrated to be causative and functional foods patterns to be protective against NCDs [10 13]. Table 2.1 shows the food consumption pattern in the 10 most highly populous countries as well as in countries of EU. The consumption of fruits, vegetables, and nuts appears to be adequate ( . 400 g/day) in China, India, United States, Brazil, Russia, Japan, and European countries. However, in Indonesia, Pakistan, Bangladesh, and Nigeria, the intake is lower which needs improvement. Further details of functional food production are given in Chapter 1, Estimates for World Population and Global Food Availability for Global Health. FAO has estimated that in the first half of this century, global demand for food, feed, and fiber is expected to grow by 70% [16]. There would be growing pressure on already scarce agricultural resources due to new and traditional demand for agricultural produce. With rapid urbanization,

Table 2.1 Food Consumption per Day/Person in Grams in 10 High Populous Countries and European Union Dairy Products Country

Fruits

Vegetables

Milk

Cheese

China India USA Indonesia Brazil Pakistan Nigeria Bangladesh Russia Japan EuropeanUnion Total Total /year

537.00 199.00 613.00 184.00 515.00 86.66 163.00 64.65 620.00 140.00 274.00 3396.31 1,239,653.15

900.00 194.00 358.00 100.00 130.00 87.00 191.00 58.00 288.00 291.00 325.00 2922.00 1,066,530

78.33 136.90 316.66 15.55 377.00 286.11 15.00 51.66 344.44 129.44 211.11 1962.20 716,203

0.55 42.77 0.28 1.11 0.28 0.02 7.50 46.11 98.61 35,992.65

Fish, Sea Foods

Poultry

Veg. Oil

Spices, Herbs

Tea

Coffee 178.4

Wheat

Rice

40.00 40.00 20.00 51.00 12.00 1.00 38.00 8.00 43.00 134.00 5.00 392.00 143,080

35.00 5.00 142.00 19.50 112.00 12.22 5.00 3.88 64.16 53.05 60.27 512.08 186,880

22.50 24.44 85.00 28.05 48.61 33.33 32.22 17.22 36.38 43.33 55.83 426.91 155,822

10.38 8.22 2.53 2.97 0.33 4.38 3.66 8.50 0.66 3.44 2.08 47.15 17,209

2.55 1.77 1.42 1.02 5.52 1.83 0.33 1.11 3.58 1.50 1.61 22.24 8117

167.30 222.00 52.32 144.10 341.64 54.79 56.71 268.76 113.50 300.27 13.33 52.38 18,980

178.40 167.30 222.00 52.32 144.10 341.64 54.79 56.71 268.76 113.50 300.27 1899.79 693,135

216.90 196.00 20.52 364.38 93.69 33.42 82.46 473.97 13.42 118.63 14.24 1613.39 588,745

Olive and rape seed oil are known to decrease cardiometabolic diseases and all-cause mortality (modified from Singh et al 2016, reference 1).

Modified from; freshplaza.com, hellibrary.com, cofeebi.com, google.com, accessed, July 2017.

Cashew Nut 0.64 0.54 4.93 1.64 3.15 10.90 3978

2.5 ESTIMATES OF FUNCTIONAL FOODS

29

agriculture will be forced to compete for land and water and it may also be required to serve on other major fronts: adapting to and contributing to the mitigation of climate change, helping preserve natural habitats, and maintaining biodiversity. The farmers will need new technologies to produce more from less land, with fewer hands. This perspective for 2050 gives an opportunity for investments from public and private stakeholders to ensure adequate potential for agricultural production. This approach may create infrastructure for markets, information and communication, as well as sustainable use of natural resources, and research for future advancements. The FAO agenda for functional food production, such as for pulses and legumes, appears to be good because these foods are considered functional foods which can replace wheat and corn and provide functional food security [16 19]. The 68th UN General Assembly of the FAO/UNO declared 2016 the International Year of Pulses (IYP) (A/ RES/68/231) to support food security which is in fact for functional food security [17]. The sustainable development of health adopted by the global community in the 2030 agenda is not possible without adequate production of pulses and legumes as well as vegetables, nuts, and fruits [17,18]. Since, the International Year of Pulses 2016 brings to the forefront the challenges faced by the sector, there is a need to emphasize the production of vegetables and nuts which are more potential functional foods. Such efforts may galvanize stakeholders to ensure the successful role of pulses and other functional foods in food and nutrition security, poverty alleviation, and sustainability. The main pulses are lentils, red beans, green beans, kidney beans, grams, peas, etc. Pulses are rich in magnesium, potassium, calcium, and other minerals as well as in antioxidant flavonoids and essential and nonessential amino acids, apart from high carbohydrates [17,18].

2.5 ESTIMATES OF FUNCTIONAL FOODS WITH REFERENCE TO NUTRIENTS There will be slow growth for the total demand for food and feed, close to the expected demand for food and feed which would require a significant growth in food production of 70% by 2050. This would require an additional quantity of nearly 200 million tons of meat and 1 billion tonnes of cereals [19,20]. It is important at this stage of planning to include more legumes and millets in the estimates for cereals and white meat in place of red meat. The most commonly available functional foods are vegetables, fruits, nuts, whole grains (legumes and millets), white meats (chicken, eggs, fish, and other sea foods), curd/yogurt, canola oil/rape seed oil/olive oil, spices, and cocoa/tea/coffee. Red and white meat and eggs from animals after feeding flax seeds (ω-3 fatty acids) and tea leaves (flavonoids) are also made functional by the food industry. Table 2.2, reveals the Singh’s and Saboo’s functional food portfolio for health promotion and disease prevention (vegetarians may replace with pulses, soya bean, cottage cheese, and yogurt) [5,15]. These foods are particularly rich in antioxidant vitamins, essential and nonessential amino acids, flavonoids and carotenoids, minerals and other vitamins, as well as and omega-3 fatty acids which have been demonstrated to be protective against NCDs and for health promotion [5,12,14,15]. Table 2.3 shows the data on food production (kilo tonnes) in the 10 most highly populous countries as well as in the EU which has more reliable information [21]. Total fruits (650,684), vegetables (1,113,768), milk (759,754), cheese (20,256), total sea foods (721,930), spices and herbs

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CHAPTER 2 ESTIMATES OF FUNCTIONAL FOODS AVAILABILITY

Table 2.2 Singh’s and Saboo’s Functional Food Portfolio for Health Promotion and Disease Prevention (for vegetarian, replace with soya bean, pulses, cottage cheese, and yogurt) Functional Foods

Amount (g/day)

Foods

Nutrient/Mechanism

Fruits Vegetables Nuts

200 300 200 300 30 50

Apple, grapes, guava, berries Green leaves, gourds Walnuts, almond, peanuts

Whole grains

400 500

Fish, sea foods

50 100g

Poultry Curd/yogurt Spices

50 100 100 200 10 20

Miscellaneous Fats and oils

5 10g 30 100

Gram, beans, peas, millets, soybean, pulses, porridge Salmon, any oily fish, e.g., mackerel Egg quail & hen, chicken, duck Prebiotic, probiotics Turmeric, fenugreek, cumin, coriander Cocoa, tea, coffee Olive, mustard/canola

Flavonoids, vitamin C Flavonoids, carotenoids Amino acids, ω-3 in walnut, low glycemic index, MUFA Flavonoids, amino acids, complex carbohydrates ω-3, amino acids, selenium, CoQ10 Amino acids Immunity, gut microbiome Flavonoids, minerals Flavanols Flavonoids, ω-3, MUFA

(2169.383), tea (5034.9), coffee (9209.0), and cashew nut (4354.112) appear to be adequate for the year 2017 but would need greater production for increased consumption by the year 2025 and 2050 [1,4,16,17,19]. Although poultry (106,014), wheat (713,183), and rice (745,710) are not purely functional foods, they are the main foods consumed all over the world, which need to be made functional by the food industry. The data on production of total vegetable oils are not yet known in these highly populous countries. Table 2.4 indicates the production of peanuts, walnuts, almonds, and pulses in kilo tonnes in the 10 most highly populous countries, as well as in the EU. The total kilo tonnes of peanuts (40,475), almonds (2741.386), walnuts (3425.834), and pulses (72,936) in the 10 most highly populous countries and in the EU appear to be adequate in the present year, but with an increase in consumption, due to health professional advice, a greater production would be required in these countries as well as by other countries.

2.6 EUROPEAN UNION AGENDA Fruit and vegetable production in Europe is increasing (Table 2.5). Fruits and vegetables are being supported by Common Market Organization (CMO) in the EU. EU countries are not well acquainted with spices and millets which are important functional foods from India (Tables 2.1 2.3). The main goals of the policy are: 1. 2. 3. 4.

development of sector, to be more competitive and market-oriented; reduce instability in producers’ income related to crisis; increase in consumption of fruit and vegetables throughout EU; and increase in use of techniques related to eco-compatible cultivation and production.

Table 2.3 Food Production in Kilo Tonnes the 10 Most Highly Populous Countries and in the European Union Dairy Products Country

Fruits

Vegetables

Milk

China India United States Indonesia Brazil Pakistan Nigeria Bangladesh Russia Japan EuropeanUnion Total

148,945 75,491 26,499 17,881 38,441 6026 11,055 3607 2920 3035 54,936 650,684

570,523 114,344 36,144 10,465 11,055 5071 12,809 4123 15,680 11,413 64,421 1,113,768

42,749 132,431 90,865 1365 32,454 37,861 566 3519 1750 7630 15,5533 759,754

Cheese 278 1.50 5009 44.6

8.76 1.00 609 124 9058 20,256

Total Sea Foods

Poultry

65,201 10,078 5465 10,828 1275 600 1027 3684 4608 4164 615,000 721,930

18,039 2309 19,944 1768 12,101 839 155 216 3285 1443 13,092 106,014

Veg. Oil

Spices, Herbs

Tea

Coffee

Wheat

Rice

99.402 1504

1804.6 1135

92.0 314 3.270 691.163 3037.0

121,727 93,510 57,967

205,015 159,200 8613 71,280 11,759 9800 4700 51,500 935 10,758 2787 745,710

5.726 74.737 6.366 155

495,170

2169.383

143.4 1.496

3.00 60.0 0.09 85.9 0.136 5034.9

9209.0

5718 24,231 80 52,091 812 143,333 713,183

Cashew Nut 0.750 725 116.915 80.630 900

4354.112

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CHAPTER 2 ESTIMATES OF FUNCTIONAL FOODS AVAILABILITY

Table 2.4 Production of Nuts and Pulses in Kilo Tonnes Country

Peanuts

Bangladesh Brazil China India Indonesia Japan Nigeria Pakistan Russia European Union United States Total

51.9 334 16,800 4695 1251 17.3 3071 71.4

Almonds

Walnuts

44.178 1.400

5.817 1.700 40.000

21.649

8.40 3058 40,475

1545.500 2741.386

Pulses 240 2804 4528 16,704 286 87.2 2560 603 2220 3246 2358 72,936

11.500 2.250 177.663 425.820 3425.834

Table 2.5 Fruit and Vegetable Production in Europe Tomatoes EU-28 Belgium Bulgaria Czech Republic Denmark Germany Estonia Ireland Greece Spain France Croatia Italy Cyprus Latvia Lithuania Luxembourg Hungary Malta Netherlands Austria Poland Portugal

17 562.2 253.1 121.7 5.6 10.6 80.9 0.9 4.4 995.1 4 832.7 787.9 36.3 6 410.3 16.1 6.1 7.7 0.1 200.4 12.0 890.0 55.7 789.6 1 407.0

Carrots 5 087.3 245.4 7.9 23.5 89.2 526.9 18.1 40.2 32.5 410.9 560.0 10.9 533.0 2.3 8.8 38.0 1.0 78.2 1.3 563.4 66.8 677.7 97.5

Onions 6 109.4 108.3 8.9 27.2 53.4 553.3 0.2 4.6 211.0 1 247.6 368.7 29.4 378.3 7.0 5.7 22.2 0.1 60.3 8.1 1 504.1 168.1 548.4 59.4

Apples 12 698.1 284.2 58.4 155.4 35.7 973.5 1.6 18.8 278.5 598.2 1 967.1 96.2 2 441.6 4.9 7.8 65.0 2.4 511.5 0.0 335.9 287.6 3 168.8 325.0

Peaches 2 540.0 0.0 34.4 1.6 0.0 0.0 0.0 0.0 626.6 720.9 114.7 3.7 921.2 2.3 0.0 0.0 0.0 37.4 0.7 0.0 2.9 9.9 35.6

Oranges 5 961.2 0.0 0.0 0.0 0.0 0.0 0.0 0.0 909.7 3 098.3 3.7 0.2 1 668.7 32.8 : 0.0 0.0 0.0 1.2 0.0 0.0 0.0 246.6

2.6 EUROPEAN UNION AGENDA

33

Table 2.5 Fruit and Vegetable Production in Europe Continued Tomatoes Romania Slovenia Slovakia Finland Sweden United Kingdom Iceland Switzerland Montenegro FYR of Macedonia Albania Turkey Bosnia and Herzegovina

464.8 5.7 19.5 36.5 14.8 97.2 0.1 45.7 2.7 173.4 256.5 12 615.0 41.2

Carrots 122.1 3.4 10.1 72.0 115.6 731.0 0.6 71.6 0.0 4.3 6.9 535.0 17.1

Onions 218.2 7.2 16.9 20.2 64.6 408.1 0.0 41.2 1.0 59.5 90.5 2 021.0 37.7

Apples

Peaches

459.1 83.9 46.3 6.0 25.4 459.6 0.0 141.7 2.8 136.9 91.8 2 570.0 91.5

20.5 5.6 2.1 0.0 0.0 0.0 0.0 0.0 0.0 12.0 : 561.0 9.2

Oranges 0.0 0.0 : 0.0 0.0 0.0 0.0 0.0 0.0 : 8.4 1 817.0 0.0

Modified from European Union webpage; http://ec.europa.eu/eurostat/statistics-explained/index.php/agriculturalcropes#vegetables.

In EU the agricultural price statistics are based on agreements between EUROSTAT and the Member States, voluntarily. In EU, absolute prices and calculated corresponding average prices for each country are being collected, as well as calculated price indices and periodically updated weights are also being carried out. Price indices are reported quarterly as well as annually while absolute prices are reported only annually by Eurostat. Eurostat is also responsible for converting all the agricultural prices which are in national currency into EURO either using fixed exchange rates or financial market exchange rates, in order to allow comparisons among the different countries of EU. Fig. 2.2 shows the funds allotment to food science in EU, indicating that preparation of animal feeds gets highest amount of money followed by prepared meals and dishes. In 2015, fruit price index increased by 7.1% to that of 2014 and by 3.8% to that of a period from 2010 to 2014. The median price of dessert apples was about h44.15 per 100 kg. It is noteworthy that in EU agriculture, the vegetable sector is a key sector weighting 13.6% of total EU agricultural output. In 2015, Netherlands (17.8%), Spain (16.7%) and Italy (16.5%) were the most important producers in terms of economic value, accounting for over 50% of vegetable output [21]. This year also saw the growth in production of most important vegetables; tomatoes, carrots, and onion. From the approximate 17.6 million tonnes of tomato production, the share from Italy and Spain (11.2 million tonnes) accounted to two-thirds of total produce. An estimated 6.1 million tonnes of onions and 5.1 million tonnes of carrots were also produced in EU (Table 2.5). The two countries, Poland and the United Kingdom together accounted for over a quarter (14.4% and 13.3% respectively) of total carrot production of EU-28 output in 2015. The Netherlands and Spain were the main Member States of EU’s producing together 45.0% of EU-28 total onion production for the year 2015. However, the production of carrots in these two EU countries remained relatively stable, at around 0.7 0.8 million tonnes, during the 2000 15 period. In comparison to 2014, the price index of fresh

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CHAPTER 2 ESTIMATES OF FUNCTIONAL FOODS AVAILABILITY

3%

3%

12%

4%

29%

4% 4%

12%

6% 6%

12%

5%

Drinks

Meat products

Dairy products

Chocolate and confectionery

Processed fruit and vegetables

Oils and fats

Fish and sea food products

Bakery and farinaceous products

Prepared meals and dishes

Prepared animal feeds

Grain mill and starch products

Other food products

FIGURE 2.2 Funds allotment to food science in European Union. Modified from, www.preparedfoods.com.

vegetables increased by 6.8%, and by 2.1% if compared to previous 5 years on the average basis. However, the tomatoes median price was h60.74 per 100 kg. The fruit sector also contributes 6.7% of EU agricultural output and is another key element in EU agriculture along with vegetable. In 2015, approximately 60% of fruit output came from Spain (33.4%), Italy (18.7%), and France (11.4%), who were the most important producers in terms of economic value. In terms of the volume harvested products, apples (12.7 million tons), oranges (6 million tons) and peaches (2.5 million tons) were the most important fruits in EU. The EU fruit sector offers a large number of different products. The cultivation of apples is common in all the EU countries of which Poland (25%), Italy (19.2%), and France (15.5%) are the largest producer of it. In EU, the cultivation of oranges is restricted by climatic conditions; the vast majority of oranges (80%) are produced in Spain (52%) and Italy (28%) [21].

2.6.1 GRAPES AND WINE PRODUCTION EU is the home of wine production while in terms of vine production, EU is the world’s leading producer and accounts for almost half of the global area under vine cultivation and approximately 65% of production by volume. In 2015, among the grapes producing countries, Italy (29.4%), France (26.3%), and Spain (23.6%) were the largest producer of grapes for wine use, making up 79.3% of total production. While, Germany (5.1%), Portugal (3.9%), Romania (3.2%), Greece (2.3%), Hungary (2%), and Austria (1.3%) were the other wine and grape producing countries with significant contribution from Bulgaria, Croatia, and Slovenia. The production of grapes for wine use in 2015, increased by around 3.5% compared to 2014, and it stood 3.4% above 5-year average levels. However the price of wine decreased by 2.2% compared to 2014 in 2015 but increased by 5.9% compared to the period of 2010 14. The median price of grape for wine production was h50.15 per 100 kg.

2.6 EUROPEAN UNION AGENDA

35

2.6.2 OLIVES AND OLIVE OIL PRODUCTION With almost three-quarters of global production, the EU is the largest producer of olive oil and olive fruit in the world (Fig. 2.3). Mediterranean region accounts for the cultivation of 95% of the olive trees in the world and hence most of the production of olive comes from Southern Europe, North Africa, and the Near East. Among the different countries of the EU, olives mainly come from Spain (65.6%), Italy (18.3%), Greece (8.6%), and Portugal (6.8%). The price index for olive oil was 36.1% in 2015, however if we consider the rate of change over the period 2010 14 the increase was 45.9%. The median price of extra virgin olive oil was h509.10 per 100 L. Agricultural products form a major part of the cultural identity of the EU’s people and its regions. The food habits and the broad array of food and drinks products, which are consumed or made available to humans and animals reveals the natural environments, climates, and farming practices across the EU. Indeed, agricultural product data also provide supply-side information, as regards price developments which are of particular interest to agricultural commodity traders and policy analysts [21]. Production of Olives for Olive Oil in Europe 2015. http://ec.europa.eu/eurostat/statistics-explained/index.php/Agricultural_production_-_crops#Vegetables Portugal 6.8%

Others 0.7%

Greece 8.6%

EU-28 total 10.4 million tonnes

Italy(') 18.3%

Spain 65.6%

(') Italy: 2014 data.

FIGURE 2.3 Olive fruit production in Europe in 2015. Modified from, www.ec.europe.eu 2015.

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CHAPTER 2 ESTIMATES OF FUNCTIONAL FOODS AVAILABILITY

2.6.3 FINAL ESTIMATES OF FOOD PRODUCTION IN INDIA 2016 17 India has not yet expertized in food processing and food preservation by maintaining the functional food status of the foods. The total horticulture production of India is estimated to be around 286 million tonnes during 2015 16 which is 2% higher than the previous year [22]. The horticulture production of the country during 2016 17 is estimated to be around 287 million tonnes which is marginally higher as compared to 2015 16. Production of fruits is estimated to be 90 million tonnes which is 1% higher than the previous years 2016 17. Production of vegetables is estimated to be around 169 million tonnes which is about 1.5% higher than the previous year. Production of spices is estimated to be around 7 million tonnes which is 14% higher than the previous year. Production of onion is estimated to be around 209 lakh tonnes which is 11% higher than the previous year. Production of potato is estimated to be around 434 lakh tonnes which is 10% lower than the previous year. Production of tomato is estimated to be around 187 lakh tonnes which is about 15% higher than the previous year. Production of fruits is estimated to be 92 million tonnes which is about 2% higher than the previous year. Production of vegetables is estimated to be around 168.6 million tonnes which is marginally lower by 0.3% than the previous year. The production of spices is estimated to be around 7 million tonnes which is almost same as previous year. Production of onion is estimated to be around 197 lakh tonnes which is 6% lower than the previous year, which was a bumper production year. Production of tomato is estimated to be around 189 lakh tonnes which is about 1% higher than the previous year. Production of potato is estimated to be around 439 lakh tonnes which is 1% higher than the previous year.

2.7 FOOD PROCESSING AND ROLE OF FOOD INDUSTRY IN FUNCTIONAL FOOD PROCESSING There is increased attention on potential health effects of food processing for health promotion and disease prevention [23 26]. It is important to undergo some processing for almost all the foods to be consumed. The food processing could be in the form of cooking, smoking, drying, salting, fermenting, preserving, heating, milling, and refining. After processing, the foods become more palatable with improvement in nutrient bioavailability, variety, shelf life, and convenience with a reduced risk of food-borne pathogens [27,28]. Potential harmful effects of food processing are: loss of nutrients; vitamins, minerals, omega-3 fatty acids, fiber, phenolics, and other bioactive agents [26 28]. There may be rapidity of digestion of starch and sugar and increased doses and introduction of unhealthy factors such as trans fat, advanced glycation end products, peroxidized nutrients, sodium, and other preservatives, heterocyclic amines, and other compounds [26 28]. There is a myth that frying foods is generally associated with a higher risk of CVD which is not supported by the available evidence [29]. In a meta-analysis of 23 studies, virgin olive oil significantly reduces the risk of CVDs, based on the results of a large randomized trial that included as part of the intervention the recommendation to use high amounts of virgin olive oil, also for frying foods [29]. Increased consumption of fried foods is probably related to a higher risk of weight gain, though the type of oil may perhaps modify this association [25,28,29]. There is evidence that some more natural foods such as eggs, butter, and unprocessed red meats are not linked to improved cardiometabolic outcomes. However, other packaged or processed

2.7 FOOD PROCESSING AND ROLE OF FOOD INDUSTRY

37

foods such as, nut and fruit-rich snacks, phenolic- and omega 3-rich vegetable oils and margarines are known to improve cardiometabolic health [23 29]. Similarly, several healthful foods, e.g., fruits, nuts, seafood, are minimally processed whereas several classes of processed foods are harmful such as cereals, refined grains, preserved meats, and other high-sodium foods, foods cooked by using hydrogenated oils [23 29]. These views sometimes create an impression to always select “natural” and always avoid processed or ultraprocessed foods which is wrong. It seems that many minimally processed foods are healthful, and many more highly processed foods are not, which can serve as a useful general rule, although, it is not absolute. It is possible that it is both the type of food and its processing are relevant. Focusing only on natural versus processed, the health professional, consumer, policy maker, and food producer should identify foods that are healthful and least processed. Foods rich in refined grains and starch, and with added sugars and harmful additives such as sodium, saturated fat, and trans fat should be avoided [23 30]. Since the global food production is moving toward more processed foods, there is a need for further research to define and disseminate methods for optimal processing, rather than an impractical focus on inhibition of food processing [28,29]. The consumption of dietary supplements, often at high or pharmacological doses, is common by the public, although there is no convincing evidence for beneficial effects. Observational studies and controlled trials do not support the use of many vitamins as potential therapies to prevent CVD or other conditions but most trials have negated the role of vitamins, minerals, and antioxidants in the prevention of NCDs. There is some evidence for the beneficial effects of fish oil, cocoa, tea, yogurt, curd, and coffee to provide benefits to health which can be used for prevention of diseases, despite processing and preserving [30 32]. There is strong evidence suggesting a higher risk of developing NCDs when fried foods are consumed more frequently (i.e., four or more times per week) [33]. However, a lack of detailed information on the type of oils used for frying foods, stratification of the different types of fried food, frying procedure (deep and pan frying), temperature and duration of frying, how often oils were reused and a lack of consideration of overall dietary patterns need further studies. Future research should also develop tools to better define fried food consumption at home versus away from home and to assess their effects on chronic diseases [33]. Food processing may be defined as a set of techno-economic activities carried out for conservation and handling of agricultural produce and to make it usable as food, feed, fiber, fuel, or industrial raw material. Food-processing industry includes different operations from the stage of harvest till the material reaches the end users in the desired form, packaging, quantity, quality, and price. Today development of the food processing (“Sunrise sector”) has been a priority for the majority of governments in developing countries. Investments in processing sectors are known to have significant multiplier effects due to backward and forward linkages in the productive chains. Natural functional foods are available in most countries but they are expensive: fish, nuts, vegetables, fruits, olive oil, spices, and herbs.

2.7.1 FOOD-PROCESSING: THE SUNRISE SECTOR Today India is attaining a good position as a global player for marketing and supply of processed food, feed, and a wide range of other plant and animal products. Processing of agro-produce is regarded as a “Sunrise Sector.” India being the world’s prominent grower of agro-food items aims to become the potential food provider of world.

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CHAPTER 2 ESTIMATES OF FUNCTIONAL FOODS AVAILABILITY

2.7.2 MILK PROCESSING India has vast a livestock population consisting of 38.5millon milch cattle and 38.1 million milch buffaloes constituting 13.9% and 64.4% of the world’s total milch animals, respectively. The Indian dairy industry has been growing at a 4% annually, almost three times that of the average growth rate of the dairy industry globally. Only 35% of the total milk produced goes into milk processing, while the rest of the milk is either consumed at farm level or sold as fresh, nonpasteurized milk through unorganized channels. Only 13% of the milk produced goes into organized dairy industry. Milk may be used to develop curd, butter milk, and yogurt which are probiotics Acidophilus present in probiotics has antimicrobial effects against Staphylococcus aureus, Salmonella, Escherichia coli, and Candida albicans. Lactobacillus brevis, abbreviated L. brevis, is a lactic acid producing probiotic that is helpful in synthesizing vitamins D and K. Lactobacillus rhamnosus is the common microbe present in probiotics.

2.7.3 PROCESSING OF CEREALS, PULSES AND OIL SEEDS Processing of grains includes milling of wheat, rice, and pulses. In the case of pulses, recovery percentage remains low with traditional processing methods. Yield of split pulses varies between 65% and 70% in traditional mills, which can be improved to 82% 85% with the adoption of modern techniques. In the country wheat is processed for flour, refined wheat flour, semolina, and grits. About 10.5 million tonnes of wheat is converted into wheat products by around 820 large flourmills in the country. Apart from the 820 large flourmills, oilseed processing is another major segment, an activity largely concentrated in the cottage industry.

2.7.4 FRUIT AND VEGETABLE PROCESSING Thus, the fruit and vegetable processing industry in India is highly decentralized. Traditionally prominent processed items included fruit pulps and juices: fruit based ready-to-serve beverages, canned fruits and vegetables, jams, squashes, pickles, chutneys, and dehydrated vegetables. With the changing face of processing in the country, products like frozen pulps and vegetables, frozen dried fruits and vegetables, fruit juice concentrates, and vegetable curries in restorable pouches, are also getting popularity in the industrial segment.

2.7.5 TECHNOLOGICAL CHOICES FOR VALUE ADDITION THROUGH TRADITIONAL PRODUCTS • • • • •

Shelling and decortications Cleaning grading and sorting Milling; rice milling, pulse milling, flour milling Value addition in fruits and vegetable by partial processing. Food packaging

2.7 FOOD PROCESSING AND ROLE OF FOOD INDUSTRY

39

It is important to legislate food composition to reduce calories, salt, saturated fat, sugar, and limit portion sizes. Elimination of industrially produced trans fats is an important step to prevent the availability of unhealthy foods. Legislate to restrict marketing foods high in fat, sugar, and salt to children. Tax foods rich in sugar and saturated fat, and alcoholic drinks. Make water and healthy food available in schools and workplaces. Regulate location and density of fast food outlets. But the most critical need is the development of human resources for the industry. Boosting literacy at village level, addressing concerns about the roles of women and child labor, and enhancing the practical skills, business knowledge, and “produce care” capabilities of farmers, workers, and consumers are critical aspects of agricultural modernization. It will also help to deliver a new future for those who may be marginalized within the farming and trading sector as the industry evolves. Fig. 2.4 shows the total vegetable oil production in developing and developed countries which indicate that most countries need to change the type of oil from soyabean, cotton seed, and palm oil to rape seed oil, which is being done in Canada [34]. In brief, estimates of functional food production appear to be adequate in the 10 most highly populous countries, but they need proper distribution by having better affordability to improve consumption. Several processed foods are healthful with minimal processing, but highly processed foods are not, a useful generalization. Food type and its processing, both may be relevant. Focusing only on natural versus processed is no good for health nor for industry. The food producer, consumer, health professional, and policy maker should emphasize foods that are both innately

USA Philipines Nigeria Malaysia Indonesia India soybean oil Ukraine

cottonseed oil

Russia

groundnut oil

EU-28

sunflower oil rapeseed oil

China

sesame oil Canada

maize oil

Brazil

palm oil palmkernel oil

Argentina 0

5000

10000

15000

20000

25000

30000

35000

coconut oil

FIGURE 2.4 Vegetable oil production in developing and developed countries. Modified from http://fediol.post-site.com/web/world%20production%20data/1011306087/list1187970075/f1.html.

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CHAPTER 2 ESTIMATES OF FUNCTIONAL FOODS AVAILABILITY

healthful and less processed. Reject foods rich in refined grains, starch, and added sugars and harmful additives such as sodium, saturated fat and trans fat. For all sectors, food safety, quality improvement, postharvest loss reduction, and supply chain management are strategic priorities for improving system efficiency and reducing the costs. If the reported high loss levels of agricultural sector (e.g., nearing 40% for fresh produce) could be reduced, in the 10 most highly populous countries, it could easily feed the entire world population and expand trade. Attention is needed to improve technology and logistics, enhance the comparative keeping quality of different vegetable types and varieties, and establish good agricultural practices. There is a need to prevent food wastage in most countries of the world.

REFERENCES [1] Food and Agriculture Organization, United Nations of Organization 2016-2017. www.fao.org/worldfoodsituation/csdb/en/, http://www.fao.org/3/a-i7343e.pdf. Accessed August 2017. [2] The GBD 2015 Obesity Collaborators. Health effects of overweight and obesity in 195 countries over 25 years. N Engl J Med 2017;377:13 27. Available from: https://doi.org/10.1056/NEJMoa1614362. [3] GBD 2013 Mortality and Causes of Death Collaborators. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990 2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;(385):117 71. [4] Godfray HCJ, Beddington JR, Crute IR, Haddad L, Lawrence D, Muir JF, et al. Food Security: the challenge of feeding 9 billion people. Science 2010;327:812 18. [5] Singh RB, Shastun S, Chibisov S, Itharat A, De Meester F, Wilson DW, et al. Functional food security and the heart. Journal of Cardiology and Therapy 2016;3(6):1 8. Available from: http: //www.ghrnet. org/index.php/jct/article/view/1858. [6] Singh RB, De Meester F, Pella D, Basu TK, Watson RR. Globalization of dietary wild foods protect against cardiovascular disease and all cause mortalities? A Scientific Statement from the International College of Cardiology, Columbus Paradigm Institute and the International College of Nutrition. Open Nutra J 2009;2:42 5. [7] FAO http://www.fao.org/pulses-2016/about/en/ accessed August 20170. [8] Velazquez E, Silva LR, Peix A. Legumes: a healthy and ecological source of flavonoids. Curr Nutr Food Sci 2010;6:109 44. [9] World Health Organization. e-Library of Evidence for Nutrition Actions (eLENA) http://www.who.int/ elena/global-targets/en/ accessed July 2017. [10] World Health Organization. Draft comprehensive global monitoring framework and targets for the prevention and control of non-communicable diseases. http://apps.who.int/gb/ebwha/pdffiles/WHA66/ A66_8-en.pdf?ua 5 1. Accessed May 15, 2015. [11] Sacco RL, Roth GA, Reddy KS, Arnett DK, Bonita R, Gaziano TA, et al. The heart of 25 by 25: achieving the goal of reducing global and regional premature deaths from cardiovascular diseases and stroke: a modeling study from the American Heart Association and World Heart Federation. Circulation 2016;133. Available from: https://doi.org/10.1161/CIR.0000000000000395 Published online before print May9, 2016.

REFERENCES

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[12] Hristova K, Pella D, Singh RB, Dimitrov BD, Chaves H, Juneja L, et al. Sofia declaration for prevention of cardiovascular diseases and type 2 diabetes mellitus: a scientific statement of the international college of cardiology and international college of nutrition; ICC-ICN Expert Group. World Heart J 2014;6:89 106 (Novapublishers, NY). [13] Chaves H, Pella D, Singh RB, Saboo B, Hristova K, Elkilany GEN, et al. The challenges of prevention of cardiovascular diseases. A scientific statement of the International College of Cardiology. World Heart J 2016;8:282 8. [14] Micha R, Penalyo JL, Cidhea F, Imamura F, Rehm CD, Mozaffarian D. Association between dietary factors and mortality from heart disease, stroke, and type 2 diabetes in the United States. JAMA. 2017;317 (9):912 24. Available from: https://doi.org/10.1001/jama.2017.0947. [15] Singh RB, De Meester F, Wilczynska A, Takahashi T, Juneja L, Watson RR. Can a changed food industry prevent cardiovascular and other chronic diseases. World Heart J 2013;5:1 8. [16] FAO, How to feed the world in 2050. Expert Meeting Proceedings 2009, State of Food Insecurity in the World, FAO, Headquarters, Rome, 2009. ftp://ftp.fao.org/docrep/fao/012/ak542e/ak542e00.pdf, accessed 2017. [17] FAO http://www.fao.org/pulses-2016/about/en/ accessed August 2017. [18] Velazquez E, Silva LR, Peix A. Legumes: a healthy and ecological source of flavonoids. Current Nutr Food Sci 2010;6:109 44. [19] FAO of United Nations. Food Out Look, Biannual Report on Food Outlook, 2017. http://www.fao.org/3/ a-i7343e.pdf, accessed 2017. [20] World Bank, World Development Report 2008: Agriculture for Development (World Bank, Washington, DC, 2008. [21] European Union. Fruit and Vegetable Regime. https://ec.europa.eu/agriculture/fruit-and-vegetables_en accessed 2017. [22] Ministry of Agriculture, Government of India. 3rd Advance Estimates of Production of Major Crops for 2016-17 Release http://pib.nic.in/newsite/PrintRelease.aspx?relid 5 161670, accessed sept 2017. [23] Mozaffarian D. Dietary and policy priorities for cardiovascular disease, diabetes, and obesity A Comprehensive Review. Circulation 2016;133:187 225. Available from: https://doi.org/10.1161/ CIRCULATIONAHA.115.018585. [24] Guzman-Castillo M, Ahmed R, Hawkins N, Scholes S, Wilkinson E, Lucy J, et al. The contribution of primary prevention medication and dietary change in coronary mortality reduction in England between 2000 and 2007: a modelling study. BMJ open 2015;5:e006070 2015;5:e006070. [25] Hoffman R, Gerber M. Food processing and the Mediterranean diet. Nutrients. 2015;7:7925 64. Available from: https://doi.org/10.3390/nu7095371. [26] Louzada ML, Baraldi LG, Steele EM, Martins AP, Canella DS, Moubarac JC, et al. Consumption of ultra-processed foods and obesity in Brazilian adolescents and adults. Prev Med 2015;81:9 15. Available from: https://doi.org/10.1016/j.ypmed.2015.07.018. [27] Dobarganes C, Marquez-Ruiz G. Possible adverse effects of frying with vegetable oils. Br J Nutr 2015;113(suppl 2):S49 57. Available from: https://doi.org/10.1017/S0007114514002347. [28] Monteiro CA, Moubarac JC, Cannon G, Ng SW, Popkin B. Ultraprocessed products are becoming dominant in the global food system. Obes Rev 2013;14(Suppl 2):21 8. Available from: https://doi.org/ 10.1111/obr.12107. [29] Sayon-Orea C, Carlos S, Martı´nez-Gonzalez MA. Does cooking with vegetable oils increase the risk of chronic diseases?: a systematic review. Br J Nutr 2015;113(Suppl 2):S36 48. [30] Singh RB, Takahashi T, Elkilany GN, Hristova K, Saboo B, maheshwari A, et al. The human microbiome and the heart. World Heart J 2016;8:371 8.

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[31] Chauhan AK, Singh RB, Ozimek L, Basu TK. Saturated fatty acid and sugar; how much is too much for health? A scientific statement of the International College of Nutrition. Viewpoint, World Heart J 2016;8:71 8. [32] Smith Jr SC, Collins A, Ferrari R, Holmes Jr DR, Logstrup S, McGhie DV, et al. Our time: a call to save preventable death from cardiovascular disease (heart disease and stroke). Circulation 2012;126:2769 75. Available from: https://doi.org/10.1161/CIR.0b013e318267e99f. [33] Gadiraju TV, Patel Y, Gaziano JM, Djouss´e L. Fried food consumption and cardiovascular Health: a review of current evidence. Nutrients 2015;7(10):8424 30 Epub 2015 Oct 6. [34] Fediol. http://fediol.postsite.com/web/world%20production%20data/ 1011306087/list 1187970075/f1. html, accessed in Sept 2017.

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THE SINGH’S CONCEPT OF FUNCTIONAL FOODS AND FUNCTIONAL FARMING (4 F) FOR WORLD HEALTH

3

Toru Takahashi1, Ram B. Singh2, Sergey Chibisov3, Rukam S. Tomar4, Tanya Charkrabarti5, Anil K. Chauhan5,6, Ekasit Onsaard7, Wiriya Phomkong8, Hilton Chaves9, Mukta Singh10, Ratan Srivastav11, Manushi Srivastav11, Rana G. Singh11 and Poonam Jaglan12 1

Graduate School of Health Sciences, Fukuoka Women’s University, Fukuoka, Japan 2Halberg Hospital and Research Institute, Moradabad, Uttar Pradesh, India 3Faculty of Medicine, People’s Friendship University of Russia, Moscow, Russia 4Agricultural University, Junagarh, India 5Indian Science Congress, Kolkata, West Bengal, India 6Center of Food Science and Technology, Institute of Agricultural Sciences & Institute of Technology, Banaras Hindu University Varanasi, Varanasi, Uttar Pradesh, India 7Department of Foods, Ubon Ratchathani University, Ubon Ratchathani, Thailand 8Ubon Ratchathani University, Ubon Ratchathani, Thailand 9 Hospital das Clı´nicas, Federal University of Pernambuco, Recife, Brazil 10Department of Home Science, Mahila Maha Vidyalaya, Banaras Hindu University, Varanasi, Uttar Pradesh, India 11Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India 12Center of Nutrition Research, Panipat, Haryana, India

3.1 INTRODUCTION Increased food availability has been associated with food security and a decline in deaths due to undernutrition but there is an emergence of noncommunicable diseases (NCDs) [1 3]. Recently, Singh et al. have proposed the concept of Functional Food and Functional Farming, to provide functional food security for promotion of health as well as prevention of NCDs [1]. Ministers and other participants from all across the globe gathered in Rome, Italy for the 2nd International Conference on Nutrition which was organized by WHO and FAO from 19th to 21st November, 2014. Another conference, the 21st World Congress on Clinical Nutrition which was held at Budapest, Hungary from 6th to 8th October, 2017 saw the participation of various food and agricultural scientists and epidemiologists from numerous countries [2]. The main objective of these efforts were to make nutrition an integral and crucial part of the post-2015 sustainable human and agricultural development agenda to provide slowly absorbed functional foods (FF) and functional farming (FF) which are rich in protective nutrients (4 F). This review aims to emphasize and ensure that the goals and aims which are set are satisfactory to address the challenges of worldwide malnutrition including undernutrition as well as overnutrition and related diseases.

The Role of Functional Food Security In Global Health. DOI: https://doi.org/10.1016/B978-0-12-813148-0.00003-7 © 2019 Elsevier Inc. All rights reserved.

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3.2 MODERN TRENDS IN DIETS AND DEVELOPMENT The epidemic of obesity and related NCDs develops along with economic development resulting in increased intake of saturated fat, refined starchy foods containing an excess of salt and sugar made by the food industry, in conjunction with physical inactivity [3 5,7]. The looming global pandemic of obesity started in the 1970s which saw a shift towards an increased dependence on processed food products, outdoor eating, and more usage of edible oils and sugar-sweetened beverages [7]. There was a substantial increase in sedentary time due to television viewing, indoor games, and reduced physical activities. In the developing countries, these changes began in the early 1990s, which became clearly recognized with the emergence of various diseases such as diabetes, hypertension, and obesity. It was seen that in most of the countries from sub-Saharan Africa to South Asia there was a rapid increase in obesity status with the simultaneous shifts in activities and diets [3 5]. However, in spite of the major health challenges faced, only a select few countries are serious in addressing the problems faced due to changes in diet and lifestyle [6,7]. Table 3.1 shows the actual causes of diet and lifestyle changes which should be closely studied by the policy makers to formulate new policies (Tables 3.2 and 3.3). It seems that at a macro level, urbanization and environmental transitions, which include changes in work patterns from heavy labor work to more sedentary occupations, increases in mechanization and computer-related activities, and also improved transportation, are a cause of the epidemic of NCDs [3 7]. Economic development has also been associated with the radical changes in food processing, production, distribution, and also the increase in the accessibility of unhealthy foods, which was also pointed out in the High Level Meeting of UNO [6,7]. With the increase in the number of fast food restaurants it has become easier for people to buy fast food. It has contributed hugely to the unhealthy diets as most of these food products contain high calories, large portion sizes, extremely refined carbohydrates, sugary beverages, high amount of fats, and great quantities of processed meat. Another cause is the increase in the number of large chain supermarkets who have displaced the local food and farm shops which provided fresh produce directly procured from farmers. The supermarkets have made food like high energy drinks, snacks, sugary beverages, and high processed foods easily available to the consumers at an affordable price [3 7]. In this aspect, Asia appears to be the leader, established by the data from Food and Agriculture Organization of the United Nation [8 10]. The rapid epidemiological transitions in rapidly Table 3.1 Effects of Industry on Quality Of Foods, Physical Activity and Human Physiological Demands Physiological demands Feeling to reduce exertion Preference for fatty foods Hunger, thirst, and satiety Preferences for sweetened Preference for feeling carefree

Quality of technology Assisting technologies like automobiles Oil seed revolution and inexpensive removal of oil Beverages revolution with poor nutrient calorie. Inexpensive caloric sweeteners via food processing Alcoholic beverages, television, cinema

Modified from Popkin B.M. The World is fat—the fads, trends, policies, and products that are fattening the human race. New York: Avery-Penguin Group; 2008.

3.2 MODERN TRENDS IN DIETS AND DEVELOPMENT

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Table 3.2 Functional Food Package for Prevention of Metabolic Syndrome (for vegetarian, replace with soya bean, cottage cheese and yogurt) Functional Foods

Amount (g/day)

Foods

Nutrient/Mechanism

Fruits Vegetables Nuts

200 300 200 300 30 50

Apple, grapes, guava, berries Green leaves, gourds Walnuts, almond, peanuts

Whole grains

400 500

Fish, sea foods Poultry Curd/yogurt Spices

50 100

Gram, beans, peas, millets, soybean, pulses, porridge Salmon, any oily fish, e g mackerel

Flavonoids, vitamin C, Flavonoids, carotenoids Amino acids, ω-3 in walnut, low glycemic index, MUFA Flavonoids, amino acids, complex carbohydrates ω-3, amino acids, selenium, CoQ10

50 100 100 200 10 20

Miscellaneous Fats and oils

5 10 30 100

Egg-quail & hen, chicken, duck Prebiotic, probiotics Turmeric, fenugreek, cumin, coriander Cocoa, tea, coffee Olive, mustard/canola

Amino acids, Immunity, gut microbiome Flavonoids, minerals Flavanols Flavonoids, ω-3, MUFA

Olive and rape seed oil are known to decrease cardiometabolic diseases and all-cause mortality. Modified from Singh R.B., Takahashi T., Shastun S., Elkilany G., Hristova K., Shehab A., et al. The concept of functional foods and functional farming (4 F) in the prevention of cardiovascular diseases: a review of goals from 18th world congress of clinical nutrition. J Cardiol Therapy 2015;2(4):341-344.

Table 3.3 Blend of Fats and Oils With Possible Beneficial Effects on Health Oils, /100 g Olive oil (50%) Rape seed/canola oil (20%) Rice bran oil (10%) Sesame oil (10%) Flax seed oil (10%) Blended oil 5 total 100.13 g

Saturated Fat 7.00 1.4

ω-6 Fat 7.50 4.11

ω-3 Fat 0.75 2.00

MUFA

Protective Nutrient

36.00 13.00

Flavonoids, MUFA ω-3, MUFA

2.5 1.5 1.10 13.50

3.4 4.00 0.66 19.67

0.21 0.1 5.5 8.56

3.80 4.00 1.60 58.4

Oryzenol Phytosterol ω-3, 54% ω-6/ω-3 ratio 5 2.29, resveratrol, oryzenol, phytosterol

Olive oil and rape seed oil are known to decrease cardiovascular diseases, diabetes, and all-cause mortality. No such evidence for other oils. MUFA, monounsaturated fatty acids. Modified from Singh R.B., Takahashi T., Shastun S., Elkilany G., Hristova K., Shehab A., et al. The concept of functional foods and functional farming (4 F) in the prevention of cardiovascular diseases: a review of goals from 18th world congress of clinical nutrition. J Cardiol Therapy 2015;2(4):341-344.

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CHAPTER 3 THE SINGH’S CONCEPT OF FUNCTIONAL FOODS

developing countries have also led to an increase in the production of beef, dairy products, eggs and poultry that fed ready-prepared feedstock [3 7]. There is also an increase in the processing of whole grains. Refined grains like polished rice and polished wheat flour have a reduced nutritional quality, which includes a reduction in the fiber content, micronutrients, and also phytochemicals. These modern strategies in food production and food storage need complete alteration by a new food policy for providing functional foods, as far as possible in their natural form [3,4,8 14]. Some experts have suggested changing the feed of the animals by adding flax seed cake and greens to get healthy meat, milk, and eggs which are rich in omega-3 fatty acids, flavonoids, minerals, and vitamins [11 15]. Mustard seed cake is commonly used as feed by the farmers in many parts of India to increase omega-3 fatty acids of the animal food. The Indo-Mediterranean foods which contains whole grains, fruits, vegetables, legumes, nuts, olive oil, mustard oil/canola oil have been found to be protective against NCDs [13,14]. Obesity is one of the biggest risk factors of NCDs: cardiovascular diseases, hypertension, coronary artery disease, strokes, heart failure, and other types of chronic diseases, such as type 2 diabetes mellitus, cancer, chronic respiratory diseases, bone and joint diseases, and neurodegenerative diseases [5 7]. There is a prospect to develop an international agreement on how to prevent undernutrition, so that there is no increase in human vulnerability to NCDs [7 9]. The Sofia declaration also proposed to policy makers and the general public, particularly mothers, to create an awareness about functional foods and a rich Mediterranean-like diet to prevent obesity in children [8,9]. The cardioprotective diets should be promoted to patients and their family members, particularly concentrating on pregnant mothers, infants, children, and also the elderly in order to popularize these interventions, particularly in middle- and lower-income developing countries where there is a rapid increase in CVDs and other chronic diseases [7 13]. Diabetes mellitus, asthma obesity, CVDs, autoimmune diseases, cancer, rheumatoid arthritis, and depression are associated with an increase in the production of thromboxane A2 (TXA2), leucotrienes, prostacyclin, tumor necrosis factoralpha, interleukins-1 and -6, and C-reactive proteins [8,12]. An increase in the intake of energy rich food containing high amounts of trans fat, saturated fats, omega-6 fat, and refined carbohydrates with a combination of reduced physical activity are known to boost all these biomarkers which have adverse proinflammatory effects resulting in NCDs [8 15]. All these energy-rich foods have poor nutritional quality which results in a decrease in the intake of vitamins, minerals, omega-3 fatty acids, flavonoids, essential amino acids, etc. [5 7]. It has been established by various studies that in the Paleolithic diet of Homo sapiens the protein intake was 2.5-fold greater (33 vs. 13%) as compared to the Western diet consumed by “Homo economicus” populations [8 14]. The diet of Homo sapiens had a higher intake of essential and nonessential amino acids, minerals, flavonoids, and omega-3 fatty acids while the Western diet of Homo economicus has an excess of energy-rich carbohydrates, trans fats, and saturated fats [12]. There has been a very definitive change in the food and nutrient intake towards high energy foods during the last 100 160 years [12 14].

3.3 DIET AND MORTALITY Due to the rapid changes in the lifestyle and food patterns there has been an increase in the instances of death and disability due to obesity and NCDs, specifically in the middle- and high-

3.4 GLOBALIZATION AND DIETARY PATTERNS

47

income counties [15 17]. Due to poor public health and lack of health education millions of deaths occur almost every year. CVDs have become a great challenge for the healthcare experts and governments of the countries as it appears to be a primary cause for poverty and also related to social, human, and overall economic development [6,16]. The Global Burden of Disease Study conducted from 1990 2013 has also established the greater burden of CVDs and chronic diseases in the overall development of the countries [16]. The study described that in 10 highly populated countries, the intake of fruits, vegetables, functional foods, fish, etc. was inversely proportional to mortality [16] (Fig. 3.1). In the United States a study conducted in the years 2000 to 2011 revealed that the death of premature infants was majorly due to undernutrition and infections with enterocolitis are major causes of death [17]. The children who survived were more prone to development of CVDs and type 2 diabetes in later years because of poor nutrition during fetal life and infancy. The relationship between food and Western diseases from an evolutionary point of view indicates that a sustainable human development may be challenging due to the conventional mechanisms followed during food scarcity [18] (Fig. 3.2)

3.4 GLOBALIZATION AND DIETARY PATTERNS Nutritional transition from traditional diets rich in staple foods and whole grains to unhealthy patterns, with added sugar and added fat, animal foods, refined carbohydrates, in most countries, are often linked with globalization and the making of a Western worst model of health [3,4,15a]. The nutrition transition occurs in parallel with economic, educational, demographic, and epidemiological alterations at population level and at country level. It has been seen that globalization has caused in an alleviation in infectious diseases and most of the experts of various fields have found this phenomenon to be inevitable [18 20]. Globalization has given transnational companies a powerful means to encourage consumption of unhealthy foods and drinks that replace healthier traditional food choices, and which gives rise to various diseases. Some countries like South Korea have had innovative interventions for promoting increased intake of functional foods [19]. The changes in policies of South Korea began during the 1980s, when NCDs became a big concern in the country, they started to promote the consumption of healthy foods, as unhealthy food patterns were found to be the main cause of the various diseases. This trend shows the efforts to solve health problems by changing the dietary patterns by health professionals and the government. The traditional Korean diet consists of low-fat food and a high quantity of vegetables. The Korean government has done a lot of advertising to teach and create an awareness among the public that the traditional Korean diet is a lot healthier than the Western eating habits which may predispose to obesity and metabolic syndrome. Hence most of the experts are also working towards the resumption of the traditional diet using approaches and techniques that are acceptable to the general public of Korea, e.g., publication of traditional recipes with small modifications [3,4,19,20]. This approach is also advertised in other Asian countries but with little success, due to the aggressive advertising by multinational companies. The North Karelia Project carried out in Eastern Finland showed good results with favorable changes in diet under the management of health professionals [20 22]. The proportions of

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FIGURE 3.1 Functional food intakes are inversely associated with risk of mortality in 10 high populous countries. Modified from Naghavi M., Wang H., Lozano R., Davis A. et al. Global, regional, and national age-sex specific all-cause and causespecific mortality for 240 causes of death, 1990 2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;385:117-171. doi: http://dx.doi.org/10.1016/S0140-6736(14)61682-2.

3.5 FUNCTIONAL FOODS AND FUNCTIONAL FARMING (4 F)

49

FIGURE 3.2 Dietary transition from poverty to food security leading to noncommunicable diseases followed by functional food security leading to health promotion.

saturated fats, salt, and sugar were decreased while the quantity of unsaturated fats and vegetable consumption increased, indicating a choice for functional foods [20 22]. However, it may be due to the efforts of mass media and the involvement of the community along with modifications in legislation that were considered to be the main tools that influenced the dietary habits of the Finnish population. A study conducted by Pietinen et al. showed that from the years 1972 to 1992 there was a major decrease in total serum cholesterol (1 mmol/L on average) that took place due to the changes in the diet of people from Western foods towards the healthier food consisting of large amounts of vegetables, poultry, functional food products, etc. [22].

3.5 FUNCTIONAL FOODS AND FUNCTIONAL FARMING (4 F) In Ayurveda, chyavanprash, which is an extract of herbs with honey, was the first functional food available in India, approximately 5000 years ago from now. Stargoose berry (amla) which is rich in vitamin C and flavonoids is the main ingredient of this functional extract of multiple foods. Other contents are asparagus, blue Egyptian water lily cardamom, ashwagandha (Winter cherry), chebulic myrobalan, Chinese cinnamon, clove, Indian rose chestnut, cinnamon bark, country mallow, bamboo manna, and Indian clarified butter. Thus the connection between food and health is not new. Though, the concept of functional food did not gain widespread recognition until after the 1980s, with the launch of the Japanese soft drink which contained dietary fiber known as “Fiber Mini” in the year 1988 [3,4]. After the introduction of functional food by the food industry of Japan, this innovative trend was promoted aggressively in Europe and also the United States during the whole of 1990s. Most food companies and policy makers struggle to make health claims for functional foods, and the

All-cause mortality

Cause-specific mortality

Vital registration, sample registration Cause of death database

Complete birth histories

Noise reduction

Cause mapping

Redistribution

Verbal autopsy data

Under-5 mortality estimation Household recall from censuses and surveys

Vital registration (ICD 9, BTL, ICD10) Noise reduction

MI ratio

Cause mapping

Redistribution

Summary birth histories

Cancer registries

Maternal surveillance

Household surveys Vital registration, sample registration

Negative binomial/fixed proportion

CODEm

Household recall from censuses and surveys

DisMod Other (ie, burial or mortuary and census)

Adult mortality estimation Maternal census CoDCorrect algorithm

Sibling history

Police data

HIV-free life table

Age pattern of excess mortality from HIV

Life table with HIV and excess mortality caused by war and disaster shocks

National registries

Case fatality rate

YLLs

Natural history models

Non-shock life tables

Intervention coverage

Consistency adjustment from EPP-Spectrum for CoDCorrect

Non-shock age-specific mortality

Prevalence

Cause-specific mortality Age-specific and sex-specific death numbers

Key Source data Process Results Database

SOURCE - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4340604/figure/F1/.

3.5 FUNCTIONAL FOODS AND FUNCTIONAL FARMING (4 F)

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definitions are extensively debated. Presently there is no legal definition for functional food, but it is generally defined as “a functional food will have at least one or more of its biological effects on our physiology and metabolism providing some benefits because of certain nutrients present in the food” [1]. There are many traditional products in most of the countries which have been advised by the physicians and consumed as functional foods, such as apples, soy, tomatoes, oats, porridge, monaka (big raisins with seeds), almonds, walnuts, germinating grains, honey, chaywanprash in India, konjac flour in China, and green tea in Japan that are promoted with stress on their health-promoting characteristics. Thus in Asia, the major attention has been on natural products including plant extracts, as functional foods, whereas in the United States, the emphasis has been on dietary fiber, vitamins, etc. [3,4]. According to the WHO expert group “functional foods are foods positioned in the market place for particular and identified physiological and health reasons” [3,4]. They may be traditional foods with newly defined function or may be called novel foods. Functional foods mostly include food items consumed as snacks along with meals, or drinks. It should be clear that most of the genetically modified foods which may be high in energy and low in the density of nutrients may have larger adverse effects on obesity, although these foods have been protective among subjects with undernutrition [23]. According to the International College of Nutrition Expert Group, Functional Foods (FF) may be defined as foods which contain certain nutrients that can affect some physiological functions in our body, thereby giving benefits [1,11]. Functional foods are beneficial for physical and mental performance as well as psychosocial behavior, which are the characteristics of overall health [3 6,11]. They may be rich in omega-3 fatty acids, polyphenolics, minerals, vitamins, and also essential and nonessential amino acids and low in energy [11]. The production of functional foods and functional farming (4 F) worldwide has increased the consumption of functional foods and their benefits on total health, cardiometabolic health, as well as global health [5 10]. There is also evidence that olive oil, mustard oil, and canola oil can decrease cardiovascular events and mortality, hence these oils should also be considered functional foods. The beneficial effects may be due to high content of omega-3 fatty acids in canola and mustard oil, and olive oil is rich in monounsaturated fatty acids and antioxidant polyphenolics. Extensive usage of fertilizers and biotechnological techniques for the rapid growth and higher yield of crops, different processing techniques in food, and food’s storage and distribution has contributed largely to the ongoing search for a superior economic model in the various countries [3 10]. The challenges faced by the food industries are to create and develop new functional foods, such as slowly absorbed biscuits, bread, candies, cakes, sirups, etc., which should also be rich in nutrients as well as low in energy [1,11]. A similar type of strategy is needed from functional farming to grow food which should be slowly absorbed, thus having a low glycemic index, although functional farming alone without the help of other techniques cannot serve this demand. Another strategy is to develop genetically modified food which will counteract undernutrition and be rich in nutrients and have a slow absorption rate [1,7 11,15,24 26]. The present approach of concentrating on staple foods for genetic modification needs modification by using this technology on expensive foods like walnuts, almonds, raisins, grapes, and apples which are not currently affordable [8,9].

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3.6 ADVERSE EFFECTS OF FOOD SECURITY World Health Organization has established that food security by means of increased food availability of Western foods can prevent morbidity and mortality due to undernutrition and reduced infections [3,4,10]. However, better food security without consideration for functional foods has been found to cause an epidemic of NCDs which has been lately considered in the High Level Meeting of the United Nations of Organization and International College of Nutrition [3,4,6 9,24 26]. Therefore, both the FAO as well as the UNO have developed a joint statement on The State of Food and Agriculture 2016: Sustainable Food Systems for Food Security and Nutrition [10]. However, this important agenda of FAO/UNO and ICN is not duly followed worldwide by the food manufacturers or by agriculture scientists involved with plant breeding and genetic engineering in all countries, despite the scientific proof from cohort studies and intervention trials [24 37]. These studies have demonstrated that control groups receiving a Western-type diet is inferior to intervention dietary patterns which are mainly functional foods. The prevalence of an unhealthy lifestyle among individuals with CVDs in most countries revealed that they were not aware of the benefits of adopting a healthier diet and a healthier lifestyle [24]. A prospective cohort study involving 153,996 adults, between the ages of 35 and 70 years, from around 628 urban and rural communities in three high-income countries, three lower-middleincome countries, seven upper-middle-income countries, and four low-income countries (LIC) is excellent [16]. Among 7,519 individuals who have reported coronary disease (past event: median, 5.0 [interquartile range {IQR}, 2.0 10.0] years ago) or strokes (past event: median, 4.0 [IQR, 2.0 8.0] years ago), 18.5% (95% CI, 17.6%-19.4%) continued to smoke; only 35.1% (95% CI, 29.6% 41.0%) undertook high levels of work- or leisure-related physical activity, and 39.0% (95% CI, 30.0% 48.7%) had healthy diets. Overall, 52.5% (95% CI, 50.7% 54.3%) quit smoking (by income country classification: 74.9% [95% CI, 71.1% 78.6%] in HIC; 56.5% [95% CI, 53.4% 58.6%] in UMIC; 42.6% [95% CI, 39.6% 45.6%] in LMIC; and 38.1% [95% CI, 33.1% 43.2%] in LIC). Levels of physical activity increased with increasing country income but this trend was not statistically significant. The lowest prevalence of eating healthy diets was in LIC (25.8%; 95% CI, 13.0% 44.8%) compared with LMIC (43.2%; 95% CI, 30.0% 57.4%), UMIC (45.1%, 95% CI, 30.9% 60.1%), and HIC (43.4%, 95% CI, 21.0% 68.7%). About 14.3% (95% CI, 11.7% 17.3%) did not undertake any of the three healthy lifestyle behaviors and 4.3% (95% CI, 3.1% 5.8%) undertook all three. It is clear from various studies that the prevalence of healthy lifestyles and diets is low among patients with CVDs, especially in countries which have a very varied income level; it was even lower in the poorer countries, which indicated that changing policies and health education is extremely important [24]. However, the cultural and traditional health behaviors of these low income population is generally protective against CVDs, although the threat of the growing influence of the Western world is rapidly increasing because of the lack of policies by the government protecting the health behavior of such countries [7,15a]. A Greek epic potential heart study discovered the structure of health effects of Mediterranean diets presenting the beneficial effects of fruits, whole grains, nuts, vegetables, fish, and olive oil [27]. A study of 600 subjects having high cardiovascular risk in India showed that eating an

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Indo-Mediterranean type of diet had beneficial health effects and greatly reduced all the risk factors [28]. Randomized, controlled intervention trials with Indo-Mediterranean-style foods, such as the Lyon diet heart study [31], Indian Experiment of Infarct Survival [29,30], and the IndoMediterranean diet heart study [32], discovered that ingestion of Mediterranean-style diets caused significant declines in CVDs in the intervention group as compared to the control group. In 404 patients having the Paleolithic diet with acute coronary syndromes, the effect of low omega-3 and omega-6 fatty acid ratio revealed that after a period of 2 years a significant decline occurred in all the causes related to cardiovascular and mortality events as compared to the group of low fat diet [33]. A PREDIMED study with subjects between the ages of 55 and 80 years having high risk of cardiovascular diseases showed that after a period of 4.8 years a significant decline occurs in the intervention group who received a Mediterranean-style diet as compared to the group who received a low-fat diet [34]. Thus this approach may be considered as a roadmap for the future generations for a healthier lifestyle. Another research also demonstrated the role of functional foods in healthier lifestyle. This study comprised of 38 healthy volunteers for a period of 2 weeks. It included a daily share of black and red cabbage (300g) [37]. Results of the study showed that the plasma lutein, β-carotene levels, and total antioxidant capacity were considerably increased. The conclusions also showed that Brassica supplementation positively influenced the serum lipid profile with a substantial decrease in total cholesterol level, LDL-cholesterol, and oxidized LDL [37]. There is evidence a big source of α-linolenic acid and phytoestrogens is flax seeds [38,39]. The main phytoestrogens contained in flax seeds are lignans whose metabolites—enterodiol and enterolactone—are known to influence estrogen function in females. In experimental studies in chickens, it was seen that flax seed improved the n-3 long-chain polyunsaturated fatty acids of eggs (3.25 v. 0.92 mg/g egg), mainly DHA, although its oxidative status presented some increase. The findings revealed that 10% dietary flax seed improved the lignans and n-3 polyunsaturated fatty acid content of hen eggs without adversely affecting the productive performance hens or the yolk cholesterol concentration [39]. There is a need to explore further particulars of the different dietary phytoestrogens and their metabolites (estrogen, equol, enterodiol, and enterolactone). The feeding experiment to produce Sim’s egg was introduced by Dr Sim in the 1990s. These results strengthen the hypothesis that the consequences of functional food intervention could be modified by baseline surroundings of the subjects which would be beneficial to attain sustainable human development goals [40]. However, we are failing due to a lack of interest by governments as well as UNO, led by high-income countries who are more interested in preserving the jobs created by the health care of NCDs [41]. The findings of PURE study can not be accepted as it needs further analysis of data on intake of dietary fatty acid and complex carbohydrtates before making a conclusion that total and saturated fat intake are safe and carbohydrates have adverse effects on mortality [42]. In brief, it is clear that there is strong evidence in favor of Functional Food and Functional Farming (4 F) to produce more functional foods and to provide these foods at affordable cost. These foods are part of the Mediterranean-style diets that are rich in minerals, fiber, vitamins, polyphenolics, omega-3 fatty acids, as well as essential and nonessential amino acids and monounsaturated fatty acids that are protective against NCDs.

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ACKNOWLEDGMENTS The authors would like to thank the International College of Nutrition for providing logistic support to write this article.

REFERENCES [1] Singh RB, Takahashi T, Shastun S, Elkilany G, Hristova K, Shehab A, et al. The concept of functional foods and functional farming (4 F) in the prevention of cardiovascular diseases: a review of goals from 18th world congress of clinical nutrition. J Cardiol Therapy 2015;2(4):341 4. [2] Singh RB, Beegom R, Mehta AS, Niaz MA, De AK, Mitra RK, et al. Social class, coronary risk factors and undernutrition, a double burden of diseases, in women during transition, in five Indian cities. Int J Cardiol. 1999;69(2):139 47. [3] World Health Organization. Gobalization, Diets and Non-communicable Diseases. Geneva: WHO; 2002. [4] Wahlqvist ML, Wattanapenpaiboon N. Can functional foods, make a difference to disease prevention and control? World Health Organization, Gobalization, Diets and Non-communicable Diseases. Geneva: WHO; 2002. [5] Popkin BM, Adair LS, Ng SW. NOW AND THEN: The Global Nutrition Transition: The pandemic of obesity in developing Countries. Nutr Rev. 2012;70:3 21. Available from: https://doi.org/10.1111/ j.1753-4887.2011.00456.x. [6] Beaglehole R, Bonita R, Alleyne G, Horton R, Li L, Lincoln P, et al. High-Level Meeting on noncommunicable diseases: addressing four questions. Lancet 2011;378:449 55. [7] Popkin BM. The World is fat—the fads, trends, policies, and products that are fattening the human race. New York: Avery-Penguin Group; 2008. [8] ICC-ICN Expert Group. Sofia declaration for prevention of cardiovascular diseases and type 2 diabetes mellitus: a scientific statement of the International College of Cardiology and International College of Nutrition. World Heart J 2014;6:89 107. [9] Hristova K, Shiue I, Pella D, Singh RB, Chaves H, Basu TK, et al. Sofia declaration on transition of prevention strategies for cardiovascular diseases and diabetes mellitus in developing countries: a statement from the International College of Cardiology and the International College of Nutrition. Nutrition 2014. Available from: https://doi.org/10.1016/j.nut.2013.12.013. [10] FAO. UNO. The State of Food and Agriculture 2016: Sustainable Food Systems for Food Security and Nutrition http://www.fao.org/docrep/meeting/028/mg413e01.pdf. [11] Singh RB, De Meester F, Wilczynska A, Takahashi T, Juneja L, Watson RR. Can a changed food industry prevent cardiovascular and other chronic diseases. World Heart J 2013;5:1 8. [12] Singh RB, Takahashi T, Nakaoka T, Otsuka K, Toda E, Shin HH, et al. Nutrition in transition from Homo sapiens to Homo economicus. The Open Nutra J 2013;6:6 17. [13] Singh RB, Saboo B, Mahashwari A, bharadwaj K, Verma NS, et al. Effects of Indo-Mediterranean style diet and low fat diet on incidence of diabetes in acute coronary syndromes. World Heart J 2017;9:25 37. [14] De Meester F. Wild-type land based foods in health promotion and disease prevention: the LDL-CC: HDL-CC model. In: De Meester Fabien, Watson RR, editors. Wild Type Foods in Health Promotion and Disease Prevention. NJ: Humana Press; 2008. p. 3 20. [15] Mendenhall E, Kohrt BA, Norris SA, Ndetei D, Prabhakaran D. Non-communicable disease syndemics: poverty, depression, and diabetes among low-income populations. Lancet (London, England) 2017;389 (10072):951 63.

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[15a] Takahashi T, Singh RB, Otsuka K, Watson RR, Wilson DW, De Meester F. The ‘West’ has made the worst model of health and pushing the world to the slow moving disaster on total health. World Heart J 2014;6:157 62. [16] Naghavi M, Wang H, Lozano R, Davis A, et al. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990 2013: a systematic analysis for the Global Burden of Disease Study 2013. The Lancet 2015;385:117 71. Available from: https://doi.org/10.1016/ S0140-6736(14)61682-2. [17] Patel RM, Kandefer S, Walsh MC, Bell EF, et al. Causes and timing of death in extremely premature infants from 2000 through 2011. N Engl J Med 2015;372:331 40. Available from: https://doi.org/ 10.1056/NEJMoa1403489. [18] Lindeberg S. Food and Western Disease: Health and Nutrition from an Evolutionary Perspective. Chichester, UK: Wiley-Blackwell; 2010. [19] Lee MN, Popkin BM, Kim S. The unique aspects of the nutrition transition in South Korea: theretention of healthful elements in their traditional diet. Public Health Nutrition 2002;5:197 203. [20] Puska P, Tuomilehto J, Nissinen A, Vartiainen E, editors. The North Karelia Project. 20 year results and experiences. Helsinki: University Press; 1995. [21] Pietinen P, Lahti-Koski M, Vartiainen E, Puska P. Nutrition and cardiovascular disease in Finland since the early 1970s: a success story. Journal of Nutrition, Health & Ageing 2001;5:150 9. [22] Pietinen P, Vartiainen E, Seppa¨nen R, Aro A, Puska P. Changes in diet in Finland from 1972 to 1992: impact on coronary heart disease risk. Preventive Medicine 1996;25:243 50. [23] Mishra S, Singh RB. Physiological and biochemical significance of genetically modified foods, An overview. The Open Nutra J 2013;6:18 26. [24] The PURE Investigators. Prevalence of a healthy lifestyle among individuals with cardiovascular disease in high-, middle- and low-income countries: The Prospective Urban Rural Epidemiology (PURE) Study. JAMA. 2013;309(15):1613 21. [25] De Meester F. Progress in lipid nutrition. In: Simopoulos AP, De Meester F, editors. A Balanced Omega-6/Omega-3 Fatty acid Ratio. Cholesterol and Coronary Heart Disease. World Rev Nutr Diet, 100. Basel: Karger; 2009. p. 110 21. [26] Chauhan AK, Singh RB, Ozimek L, Basu TK. Saturated fatty acid and sugar; how much is too much for health? A scientific statement of the international college of nutrition. View point, World Heart J 2016;8:71 8. [27] Trichopoulou A, Bamia C, Trichopoulos D. Anatomy of health effects of Mediterranean diets. Greek epic prospective heart study. BMJ 2009;338. Available from: https://doi.org/10.1136/bmj.b2337 Cite this as: BMJ 2009;338:b2337. [28] Singh RB, Rastogi SS, Niaz MA, Ghosh S, Singh R. Effects of fat modified and fruits vegetable enriched diets on blood lipids in the Indian diet heart study. Am J Cardiol 1992;69:869 74. [29] Singh RB, Rastogi SS, VermaR, Bolaki L, Singh R, Ghosh S. An Indian experiment with nutritional modulation in acute myocardial infarction. Am J Cardiol 1992;69:879 85. [30] Singh RB, Rastogi SS, Verma R, Laxmi B, Singh R, Ghosh S, et al. Randomized, controlled trial of cardioprotective diet in patients with acute myocardial infarction: results of one year follow up. BMJ 1992;304:1015 19. [31] De Lorgeril M, Renaud S, Mamelle N, et al. Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coronary heart disease. The Lancet 1994; vol. 343(no. 8911):1454 9. [32] Singh RB, Dubnov G, Niaz MA, Ghosh S, Singh R, Rastogi SS, et al. Effect of an Indo-Mediterranean diet on progression of coronary disease in high risk patients: a randomized single blind trial. Lancet 2002;360:1455 61.

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[33] Singh RB, Fedacko J, Vargova V, Pella D, Niaz MA, Ghosh S. Effect of Low W-6/W-3 Fatty Acid Ratio Paleolithic Style Diet in Patients with Acute Coronary Syndromes: A Randomized, Single Blind, Controlled Trial. World Heart J 2012;4:71 84. [34] PREDIMED Study Investigators. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med 2013. Available from: https://doi.org/10.1056/NEJMoa1200303. [35] Antman EM, Jessup M. Clinical Practice Guidelines for chronic cardiovascular disorders: A roadmap for the future. JAMA. 2014;311(12):1195 6. Available from: https://doi.org/10.1001/jama.2014.1742. [36] Darlenska TH, Handjiev S. Antioxidant vitamins and the heart. World Heart J 2014;6:179 84. [37] Bacchetti T, Tullii D, Masciangelo S, Gesuita R, et al. Effect of black and red cabbage on plasma carotenoid levels, lipid profile and oxidized low density lipoprotein. Journal of Functional Foods 2014;8:128 37. [38] Imran M, Anjum FM, Nadeem M, Ahmad N, Khan MK, Mushtaq Z, et al. Production of Bio-omega-3 eggs through the supplementation of extruded flaxseed meal in hen diet. Lipids in Health and Disease 2015;14:126 http://doi.org/10.1186/s12944-015-0127-x. [39] Mattioli S, Ruggeri S, Sebastiani B, Brecchia G, Dal Bosco A, CartoniMancinelli A, et al. Performance and egg quality of laying hens fed flaxseed: highlights on n-3 fatty acids, cholesterol, lignans and isoflavones. Animal 2017;11(4):705 12. Epub 2016 Nov 7. [40] Editorial. Feeding the world sustainably. The Lancet, 2014; 384:1721, November 2014; https://doi.org/ 10.1016/S0140-6736(14)62054-7 Cite or Link Using DOI. [41] Horton R. NCDs, why are we failing? Lancet 2017;390:346. [42] Reynolds AN. Associations of fats and carbohydrates with cardiovascular diseases mortality-PURE and simple. Lancet 2018;391:1676.

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ECONOMIC BURDEN OF NONCOMMUNICABLE DISEASES AND ECONOMIC COST OF FUNCTIONAL FOODS FOR PREVENTION

4

Shantanav S. Rao1, Ram B. Singh1, Toru Takahashi2, Lekh R. Juneja3,4, Jan Fedacko5 and Anand R. Shewale6 1

Halberg Hospital and Research Institute, Moradabad, Uttar Pradesh, India 2Graduate School of Health Sciences, Fukuoka Women’s University, Fukuoka, Japan 3The Rohto Pharmaceutical Co. Ltd, Osaka, Japan 4Department of Health Promotion Sciences, Health Sciences Center, Osaka, Japan 5Faculty of Medicine, PJ Safaric University, Kosice, Slovakia 6University of Arkansas for Medical Sciences, Little Rock, AR, United States

4.1 INTRODUCTION There is a rapid nutritional transition from poverty to economic development resulting in a decline in undernutrition and infections with an increased consumption of higher total and saturated fat, omega-6, and trans fat and lower intake of complex carbohydrate in most of the developing countries [1 5]. While in China the intake of edible oils and foods from animal origin are increasing, in India, there is a high intake of foods with dairy products, eggs, and meat and added sugar, particularly in the urban populations [5]. These dietary changes are associated with greater prevalence of obesity, hypertension, and stroke more in China than India which has more of metabolic syndrome and diabetes [2 5]. The costs of undernutrition in China were similar to cost of the diet-related noncommunicable diseases (NCDs) in 1995, but it is expected that there will be a rapid increase in the cost and prevalence of diet related NCDs by 2025. On the other hand, the cost of undernutrition would continue to decrease in India, even though the undernutrition cost did surpass overnutrition, diet-related NCDs costs in 1995 [1]. In view of the rapid increase in NCDs in India and their costs, it seems that similar economic costs of undernutrition and overnutrition would continue up to 2025. This review examines the estimates of the global economic burden of NCDs in the light of association of income causing a transition in diets and related diseases.

The Role of Functional Food Security In Global Health. DOI: https://doi.org/10.1016/B978-0-12-813148-0.00004-9 © 2019 Elsevier Inc. All rights reserved.

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4.2 DIET, DEVELOPMENT, AND DISEASE It is well known that increase in income is associated with diet and lifestyle changes resulting in NCDs [2 5], In a cross-sectional survey, among 3257 women, aged 25 64 years, the association between socioeconomic status (SES), food intake, and coronary risk factors was studied in the Five City Study, each one from five different regions of India [5]. The five cities were; Moradabad (n 5 902), Trivandrum (n 5 760), Calcutta (n 5 410), Nagpur (n 5 405), and Bombay (n 5 780). After pooling the data from all the regions, all the subjects were categorized into five social classes: class 1 (n 5 985), class 2 (n 5 790), class 3 (n 5 774), class 4 (n 5 602), and class 5 (n 5 206). Social classes 1 3 had a greater intake of proatherogenic foods; total visible fat, milk and milk products, meat and eggs, as well as sugar and confectionery, compared to lower social classes 4 and 5. There was an inverse relation between social class and consumption of rice, fruits, vegetables, wheat, and legume/total visible fat ratio. Mean body mass index (BMI), obesity, overweight, central obesity, and sedentary lifestyle were also significantly more common among subjects from higher social classes. Spearman’s rank correlation showed that body weight, BMI, wheat, rice, millets, total visible fat, milk and milk products, meat, eggs, sugar, and jaggery intakes were significantly correlated with social class. Social class 5 subjects had a lower intake of all foods and a lower BMI, suggestive of a higher rate of undernutrition among them. The pro-atherogenic foods and other coronary risk factors were more common among subjects with higher SES compared to lower social classes, which indicates that the urban populations of India have a double burden of diseases [1 4]. Since there was 2.5 3.0-fold increase in gross domestic product (GDP) in China as well as in India during the last two decades, it poses the possibility, that the cost of NCDs would be much higher among higher social classes 1 3, in these two countries [1]. Figs. 4.1 and 4.2 show food consumption patterns in lower middle-income countries (LMIC) and high-income countries (HIC), indicating the old relation and new relation, respectively, as given by the Food and Agriculture Organization (FAO). The diet in HIC in the 1970s was characterized with high fat including high fat and sugar and animal foods, whereas in low-income countries, it had more complex carbohydrates with unseparated edible oils and vegetable proteins with low animal fats, separated fat, and low sugar mostly grain-based diet (Fig. 4.1). With the increase in GDP by the 1990s, there was a graded increase in vegetable oils, animal foods, and sugar in low-income countries. However, in HIC, diets comprised of increased refined foods along with high animal foods and sugar (Fig. 4.2). Fig. 4.3 shows the dietary pattern transition from poverty to economic development causing an increase in meat and oils consumption and reduction in grains, which increases the cost of foods in developing countries (FAO, modified from USDA Dietary guidelines 2015, https:// health.gov/dietaryguidelines/2015). With the increase in meat, vegetable oil, and sugar. which are expensive, there was a decrease in the consumption of grains which are inexpensive, in most developing countries during the transition from poverty to economic development (Fig. 4.3).

4.3 IDENTIFY IMPACTS OF NONCOMMUNICABLE DISEASES The presence of NCDs can have direct as well as indirect adverse impacts on family, society, and country [11]. In previous studies, three important methods were implemented by the economists to

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FIGURE 4.1 Food consumption pattern in lower-middle-income countries (LMIC) and high-income countries (HIC). Modified from Popkin B.M., Horton S., Kim S., Mahal A., Shuigao J. Trends in Diet, Nutritional status, and diet-related noncommunicable diseases in China and India: The Economic Costs of the Nutrition Transition. Nutr Reviews 2001; 59: 379 390; Singh R.B., Beegom R., Verma S.P., Haque M., Singh R., Mehta A.S., et al. Association of dietary factors and other coronary risk factors with social class in women in five Indian cities. Asia Pacific J Clin Nutr, 2000; 9: 298 302.

calculate the economic burden of health problems [1,6,7]. The cost-of-illness approach which is a commonly used method that sets out to capture the economic impact of the disease [6]. It views the cost of NCDs as the sum of several categories of direct and indirect costs including personal medical care costs for diagnosis, procedures, drugs, and inpatient and outpatient care and nonmedical costs, such as the costs of transportation for treatment and care [5 7]. Apart from these, education, information, research and communication; and losses of income, as well as suffering, as additional costs are also part of this method. The economic growth approach with a value of lost output can assess these problems by finding out the possible effects according to GDP and possible exchange of total income by assessing the influence of NCDs on reduction in labor, money, and other factors in one or several nations at a production stage. The results related to macroeconomics of these diseases may be enhanced by the EPIC model of WHO, by connecting the existing disease to growth in economy. This is possible by modeling labor and capital, as depending negatively on NCDs. The

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FIGURE 4.2 Food consumption pattern with increase in gross domestic product in high- and low-middle-income countries. Modified from Popkin B.M., Horton S., Kim S., Mahal A., Shuigao J. Trends in Diet, Nutritional status, and diet-related noncommunicable diseases in China and India: The Economic Costs of the Nutrition Transition. Nutr Reviews 2001; 59: 379 390; Godfray H.C.J., Beddington J.R., Crute I.R., Haddad L., Lawrence D., Muir J.F., et al. Food Security: The challenge of feeding 9 billion people. Science 2010; 327: 812 818 and 812 818, DOI: 10.1126/science.1185383.

willingness of a population to spend money for the decreasing disability risk or death related to these diseases indicates the value of statistical life approach. This approach may be too much more than the influence of NCDs on total income. It is possible that it places an economic value on health deterioration [7].

4.4 ECONOMIC BURDEN OF NONCOMMUNICABLE DISEASES It has been established that NCDs are a clear threat to human health, as well as to economic development due to morbidity and mortality in adult age. NCDs are currently the world’s main killer comprising of 63% of total deaths in the world which includes 80% of deaths that occur in lowand middle-income countries [6]. More than half of the subjects who die of NCDs are in the prime of their productive years. Therefore, the disability imposed and the lives lost due to NCDs are also endangering industry competitiveness across borders. NCDs will cost more than US$30 trillion during the next two decades, representing 48% of global GDP in 2010, and pushing millions of people

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FIGURE 4.3 Dietary pattern transition from poverty to economic development showing increase in meat and oils and reduction in grains. Modified from USDA Dietary guidelines 2015, Popkin B.M., Horton S., Kim S., Mahal A., Shuigao J. Trends in Diet, Nutritional status, and diet-related non-communicable diseases in China and India: The Economic Costs of the Nutrition Transition. Nutr Reviews 2001; 59: 379 390; Godfray H.C.J., Beddington J.R., Crute I.R., Haddad L., Lawrence D., Muir J.F., et al. Food Security: The challenge of feeding 9 billion people. Science 2010; 327: 812 818 and 812 818, DOI: 10.1126/science.1185383.

below the poverty line. An additional US$16.1 trillion would be required to treat mental diseases over this time span, with dramatic impact on productivity and quality of life. However, millions of deaths can be averted and economic losses reduced by billions of dollars if added focus is put on prevention which mostly depends on a diet rich in functional foods and lifestyle modifications [6 13]. World Health Organization (WHO) and International College of Nutrition reports indicate that any measures taken at population level for decreasing the intake of western diet and sedentary behavior and preventing the tobacco intake and alcoholism, are estimated to cost US$2 billion per year for all developing and newly industrialized countries, which in fact translates to less than US $0.40 per person [11]. It is noteworthy that both the total number and importance of NCDs are increasing because health may depend on economic growth and may improve with health education and human development. Economic development can enhance universal trends of aging of the population worldwide with an increase in unhealthy lifestyle in association with rapid unplanned urbanization. HIC are the leaders in providing the most relevant evidence on the economic burden related to NCDs [6].

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The Chicago Council on Global Affairs reported the economic cost of global malnutrition including both undernutrition and overnutrition and obesity (Fig. 4.4). In the United States, obesity increases direct health care costs between US$475 and 3,225 per person per year. In the United Kingdom, obesity will cost d648 million per year in healthcare costs by 2020. The cost of treating overweight and obese is equal to 4% 9% of GDP in most countries. Obesity lowered China’s GNP by 3.58% in 2000 as mentioned in the Global Nutrition Report 2014. The global decline in productivity due to morbidity and mortality by 2030 due to NCDs is expected to be US$35 trillion (Fig. 4.3, www.chicagocouncil.org).

FIGURE 4.4 Economic cost of overnutrition and related diseases. Modified from “the Chicagocouncil.org/globalag, Popkin B.M., Horton S., Kim S., Mahal A., Shuigao J. Trends in Diet, Nutritional status, and diet-related non-communicable diseases in China and India: The Economic Costs of the Nutrition Transition. Nutr Reviews 2001; 59: 379 390; Godfray H.C.J., Beddington J.R., Crute I.R., Haddad L., Lawrence D., Muir J.F., et al. Food Security: The challenge of feeding 9 billion people. Science 2010; 327: 812 818 and 812 818, DOI: 10.1126/science.1185383; Bloom ´ D.E., Cafiero E.T., Jane-Llopis E., Abrahams-Gessel S., Bloom L.R., Fathima S., et al. The Global Economic Burden of Noncommunicable Diseases. Geneva: World Economic Forum. Geneva 2011.

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4.5 NONCOMMUNICABLE DISEASES IN LOW-INCOME COUNTRIES It has been estimated that in 2010 alone, the economic loss due to NCDs amounted to US$500 billion in LMICs, accounting for 4% of GDP in these countries [1,5,6]. According to the WHO prediction, the largest proportional rise in NCD deaths globally will occur in sub-Saharan Africa (SSA) by 2030 [6]. Considering the paucity of adequate social protection structures in most lowincome countries, the increasing economic burden due to NCDs is likely to become hazardous which may aggravate poverty among local communities, who already struggle to meet basic daily needs [6]. Since communicable diseases and undernutrition continue to occur in the low-income countries, researchers in these countries have paid limited attention to the economic burden imposed by NCDs [6]. In low-income countries, the few studies on costs associated with NCDs used facility-based convenience samples from patients diagnosed with a specific NCD or relied on various secondary data sources or on projections derived from assumptions of data and models first used in other settings [1,6,7]. In these settings, evidence from population-based studies specifically aimed at exploring the overall economic burden imposed by NCDs, especially by a broad range of NCDs is still sparse. Existing studies on catastrophic spending and impoverishment in low-income countries used NCDs as one of the explanatory variables influencing the odds of catastrophic spending and impoverishment [14,15]. The economic impact of NCDs specifically on affected households exists from other settings in LMIC [16 19]. However, given remarkable disparities in overall social and political settings, the available evidence cannot provide direct policy guidance for governments in low-income countries. From cross-sectional surveys, it is clear that traditional whole-grain-based diets including legumes and millets are consumed in rural areas and if they continued to be consumed along with green leafy vegetables will reduce the risk of NCDs and its consequences due to the adverse effects of economic development [14 19]. Evidence from previous studies on diet and coronary risk factors in relation to central obesity and insulin levels in rural and urban populations of north India indicate that the burden of the NCDs is two- to three-fold greater in the urban population compared to rural subjects [20]. Such differences in the NCD burden also exist in developing, compared to developed countries which may be determinant of economic burden and economic cost of NCDs. Fig. 4.5 shows estimates of rapid growth of income in developing and developed countries which may explain the role of economic status on food consumption by the communities and in the development of NCDs [21].

4.6 REDUCTION OF ECONOMIC COST OF NONCOMMUNICABLE DISEASES There are tremendous demands on social welfare and health systems due to NCDs, which may be associated with a decline in work output, prolonged disability, and diminished resources within families in the countries causing a decline in GDP [7,8]. The economic burden of NCDs should be combatted by governments by a change in policy, as well as by the private sector including health professionals and civil society by health education of the society. The problems associated with NCDs are being recognized by the Global business leaders. The World Economic Forum has been conducting a global survey since 2009, and recognized NCDs as one of the leading threats to

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FIGURE 4.5 Estimates of rapid growth of income in developing and developed countries. Modified from Mensbrugghe D.V.D., Osorio-Rodarte I., Burns A. and Baffes J. Macroeconomic environment, commodity markets: a longer term outlook, http://www.fao.org/3/a-ak967e.pdf, 2009. The five major NCDs, cardiovascular disease, chronic respiratory disease, cancer, diabetes, and mental illness, could contribute a cumulative output loss of US$ 47 trillion in the next 20 years from 2011, representing a loss of 75% of global GDP in 2010 (US$ 63 trillion) [22–24]. The investment required in population-based and individual level best buys to reduce and prevent NCDs is estimated to be around US$ 11.2 billion per year, or on a per-capita basis, in the much lower range of US$ 0.40–US$ 3 in upper middle-income countries [22,23]. In investment of just US$ 1–3 dollars per person per year, countries can dramatically reduce illness as well as death from NCDs. Margaret Chan, Director General WHO (2015), The defeat of NCDs via The 2011 Political Declaration on the Prevention and Control of NCDs, led by WHO under the leadership of the Assistant Director-General, could be a turning point in the history of global health [24]. However, it would be difficult unless Ten Commandments provided by Lord Buddha (The Eightfold Path) are given due consideration. Despite severe resistance by governments and health-harming industries, majority of the nations accepted that chronic diseases were a critical force influencing human development.

growth in the economy. There is a need to educate people, for the adoption of healthier lifestyles in particular by consumers, as well as by employees for the prevention of NCDs [7]. A common understanding of the action with a global vision are needed by all sectors and stakeholders may be a top priority, while the United Nations General Assembly is convening a High-Level Meeting about preventing NCDs [11]. NCDs need to be addressed by a strong multistakeholder approach with adequate response for a meaningful change because they are a major and increasing contributor to morbidity and mortality in developed and developing countries. The burden of the NCDs is preventable through modification of diet and lifestyle behaviors and increased attention to other

4.7 PREVENTION OF FOOD WASTAGE

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health strategies [11]. A recent focus on merging of health economics and functional food costs aims to assess the impact of diet on health promotion and disease prevention [7,11]. Efforts are made to evaluate the impact of changing dietary choices with increased functional food availability while incorporating the immediate impacts and downstream consequences [8 13]. It is possible that nutrition economics in relation to functional foods availability at an affordable cost would allow for the generation of policy-relevant evidence, and as such the discipline would be a crucial partner in achieving better population nutritional status and improvements in public health promotion [7,11]. There is a need to encourage the farmers by giving subsidies to grow pulses, millets, vegetables, nuts, and fruits which are rich in micronutrients, and the food industry should be advised to avoid using too much saturated fat, salt, and sugar [11 13].

4.7 PREVENTION OF FOOD WASTAGE TO REDUCE COST OF FOOD PRODUCTION In developing countries like India and China, the majority of the food waste occurs on farms and during transport and processing, whereas in developed countries like United States and United Kingdom, the majority of food waste occurs at home and municipal (Fig. 4.6). If the wastage of food is reduced, it may decrease the total cost of food production, making it affordable.

FIGURE 4.6 Food wastage in various countries at farm, during transport, and home and municipal. Modified from Godfray H.C.J., Beddington J.R., Crute I.R., Haddad L., Lawrence D., Muir J.F., et al. Food Security: The challenge of feeding 9 billion people. Science 2010; 327: 812 818 and 812 818, DOI: 10.1126/science.1185383.

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In both the developed and developing countries 30% 40% of food is lost to waste, though the causes of this loss can vary from one country to another country [5,6]. In developing countries, losses are mainly due to lack of knowledge or funds to invest in storage technology in the farm and also due to the absence of food-chain infrastructure, although data are scarce. In India, it is estimated that 35% 40% of fresh produce is lost because neither wholesale nor retail outlets have cold storage. In Southeast Asia, as much as one-third of the harvest is rice grain which may be lost after harvest to pests and spoilage. In developing countries, it has been observed that the farmer often has to sell immediately after harvesting to raise cash for his multiple needs (RBS). In HIC, due to a variety of reasons, the losses of foods before it goes to retailers, are much lower. However, there is growth in some losses arising from the retail, home stages, and food services as well as from the food chain. Therefore, food is relatively inexpensive, at least for the consumers in HIC which reduce the incentives to avoid waste [5,6]. Most restaurants in North America offer super-size portions and “buy one get one free” offers encourage waste of foods in many communities. Lack of literacy and litigation on food safety have led to a situation where safety margins often mean that food fit for consumption is thrown away [5,6]. Many developed countries throw away unwanted food, instead of it being used as animal feed or compost because of legislation to control diseases. In developing countries, public and private investment in transport infrastructure would reduce the opportunities for spoilage, whereas better-functioning markets and the availability of capital would increase the efficiency of the food chain. Education and extension services and market and finance mechanisms are required to protect farmers from having to sell at peak supply, by having the best technology and best practices, leading to gluts and wastage. A continuing research in postharvest storage technologies for improved technology, with the involvement of small-scale traders, millers, and producers for small-scale food storage in poorer contexts is a prime candidate for the introduction of state incentives for private innovation. The volume of waste produced by consumers in developed countries may be reduced by these steps, which is very challenging in a developed country, as it is closely linked to individual behavior and cultural attitudes of the people toward food [5,6]. In brief, global economic burden due to NCDs appears to be mainly due to CVDs and cancer which have become a serious burden for the world and business leaders that are aware of the problems posed by NCDs (Fig. 4.7). The disability imposed and the lives lost due to NCDs, are also endangering industry competitiveness across borders. NCDs will cost more than US$30 trillion during the next two decades, representing 48% of global GDP in 2010, and pushing millions of people below the poverty line. An additional US$16.1 trillion would be required to treat behavioral disorders over this time span, with dramatic impacts on productivity and quality of life [5 7]. There is a need to educate people and governments to produce more functional foods to make it affordable. Health professionals should give greater emphasis to developing strategies, how to facilitate the adoption of healthier functional food rich diet and lifestyles by consumers, as well as by employees for the prevention of NCDs.

4.7.1 CONFLICT OF INTEREST STATEMENT Anand Shewale is currently an employee at Allergan and previously held a summer internship at GlaxoSmithKline. This chapter was written while Dr. Shewale was a graduate student at the University of Arkansas for Medical Sciences and neither employer had any role in this work. No other conflict of interest has been declared by the authors.

REFERENCES

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Cardio vascular disease Cancer Other Chronic Disease Diabetes Chronic respiratory Disease Other Conditions

FIGURE 4.7 The global economic burden of Noncommunicable diseases. ´ Modified from Bloom D.E., Cafiero E.T., Jane-Llopis E., Abrahams-Gessel S., Bloom L.R., Fathima S., et al. The Global Economic Burden of Noncommunicable Diseases. Geneva: World Economic Forum. Geneva 2011.

REFERENCES [1] Popkin BM, Horton S, Kim S, Mahal A, Shuigao J. Trends in Diet, Nutritional status, and diet-related non-communicable diseases in China and India: The Economic Costs of the Nutrition Transition. Nutr Rev 2001;59:379 90. [2] Singh RB, Beegom R, Mehta AS, Niaz MA, De AK, Mitra RK, et al. Social class, coronary risk factors and undernutrition, a double burden of diseases, in women during transition, in five Indian cities. Int J Cardiol 1999;69(2):139 47. [3] Singh RB, Sharma JP, Rastogi V, Raghuvanshi RS, Moshiri M, Verma SP, et al. Prevalence of coronary artery disease and coronary risk factors in rural and urban populations of north India. Eur Heart J 1997;18 (11):1728 35. [4] Singh RB, Beegom R, Verma SP, Haque M, Singh R, Mehta AS, et al. Association of dietary factors and other coronary risk factors with social class in women in five Indian cities. Asia Pacific J Clin Nutr 2000;9:298 302. [5] Godfray HCJ, Beddington JR, Crute IR, Haddad L, Lawrence D, Muir JF, et al. Food Security: The challenge of feeding 9 billion people. Science 2010;327:812 18. Available from: https://doi.org/10.1126/science.1185383 812 818 and. [6] Bloom DE, Cafiero ET, Jan´e-Llopis E, Abrahams-Gessel S, Bloom LR, Fathima S, et al. Geneva The Global Economic Burden of Noncommunicable Diseases. Geneva: World Economic Forum; 2011.

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[7] Wijnkoop L, Jones PJ, Uauy R, Segal L, Milner J. Nutrition economics food as an ally of public health. Br J Nutr. 2013;109(5):777 84. [8] Singh RB, Chaudhury J, de Meester F, Wilczynska A, Dharwadker S, Wilson D. Association of high w-6/w-3 ratio Paleolithic diets and risk of cardiovascular diseases and other chronic diseases: Is the tissue the main issue. World Heart J 2012;4:189 220. [9] Wang DD, Li Y, Chiuve SE, Stampher MJ, Manson JE, Rimm EB, et al. Association of specific dietary fats with total and cause-specific mortality. JAMA Intern Med 2016;176(8):1134 45. Available from: https://doi.org/10.1001/jamainternmed.2016.2417. [10] Shehab A, Elkilany G, Singh RB, Hristova K, Chaves H, Cornelissen G, et al. Coronary risk factors in Southwest Asia. World Heart J, 7. New York, USA: Nova Publishers; 2015. p. 21 3. [11] Hristova K, Pella D, Singh RB, Dimitrov BD, Chaves H, Juneja L, et al. Sofia declaration for prevention of cardiovascular diseases and type 2 diabetes mellitus: a scientific statement of the international college of cardiology and international college of nutrition; ICC-ICN Expert Group. World Heart J 2014;6:89 106. [12] Esposito K, Marfella R, Ciotola M, Di Palo C, Giugliano F, Giugliano G, et al. Effect of a Mediterranean-style diet on endothelial dysfunction and markers of vascular inflammation in the metabolic syndrome: a randomized trial. JAMA 2004;292(12):1440 6. [13] Chauhan AK, Singh RB, Ozimek L, Basu TK. Saturated fatty acid and sugar; how much is too much for health? A scientific statement of the international college of nutrition. View point. World Heart J 2016;8:71 8. [14] Wang Q, Brenner S, Kalmus O, Banda HT, De Allegri M. The economic burden of chronic noncommunicable diseases in rural Malawi: an observational study. BMC Health Serv Res 2016;16(1):457. Available from: https://doi.org/10.1186/s12913-016-1716-8 Published online 2016. [15] Xu K, James C, Carrin G, Muchiri S. An Empirical Model of Access to Health Care, Health Care Expenditure and Impoverishment in Kenya. Learning from past Reforms and Lessons for the Future [Internet]. Geneva: World Health Organization; 2006. [16] Le C., Zhankun S., Jun D., Keying Z. The economic burden of hypertension in rural South-West China. Trop. Med. Int: Health; 2012. [17] Mukherjee K, Koul V. Economic burden of coronary heart disease on households in Jammu, India. Health Agenda 2014;2:29 36. [18] Bhojani U, Bs T, Devadasan R, Munegowda CM, Devadasan N, Kolsteren P. Out-of-pocket healthcare payments on chronic conditions impoverish urban poor in Bangalore, India. BMC Public Health 2012;12:990. Available from: https://doi.org/10.1186/1471-2458-12-990. [19] Wang Q, Brenner S, Leppert G, Banda TH, Kalmus O, De Allegri M. The economic burden of chronic non-communicable diseases in rural Malawi: an observational study. Health Policy Plan 2015;30 (2):242 52 Epub 2014. [20] Singh RB, Ghosh S, Niaz AM, Gupta S, Bishnoi I, Sharma JP, et al. Epidemiologic study of diet and coronary risk factors in relation to central obesity and insulin levels in rural and urban populations of north India. Int J Cardiol 1995;47(3):245 55. [21] Mensbrugghe D.V.D., Osorio-Rodarte I., Burns A. and Baffes J. Macroeconomic environment, commodity markets: a longer term outlook, 2009. http://www.fao.org/3/a-ak967e.pdf. [22] The financial burden of NCDs. 2018; https://ncdalliance.org/why-ncds/the-financial-burden-of-ncds [accessed 01.05.18]. [23] Economic Costs of Non-Communicable Diseases. The European Commission’s Science and Knowledge Service, 2018. https://ec.europa.eu/jrc/en/health-knowledge-gateway/societal-impacts/costs [accessed 01.05.18]. [24] Horton R, Sargent J. 2018 must be the year for action against NCDs. Lancet. 2018, Available from: https://doi.org/10.1016/S0140-6736(18)30674-3.

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EVOLUTIONARY DIET AND EVOLUTION OF MAN

5

Lekh R. Juneja1, Agnieszka Wilczynska2, Ram B. Singh2, Toru Takahashi3, Dominik Pella4, Sergey Chibisov5, Maria Abramova5, Krasimira Hristova6, Jan Fedacko7, Daniel Pella7 and Douglas W. Wilson8 1

The Rohto Pharmaceutical Co. Ltd, Osaka, Japan 2The Tsim Tsoum Institute, Krakow, Andrzej Frycz Modrzewski Krakow University, Krakow, Poland 3Graduate School of Human Environment Science, Fukuoka Women’s University, Fukuoka, Japan 4East Slovak Institute of Medical Sciences, Kosice, Slovakia 5Faculty of Medicine, People’s Friendship University of Russia, Moscow, Russia 6Department of Noninvasive Functional Diagnostic and Imaging, University National Heart Hospital, Sofia, Bulgaria 7Faculty of Medicine, PJ Safaric University, Kosice, Slovakia 8School of Medicine, Pharmacy and Health, Durham University, Durham, United Kingdom

5.1 INTRODUCTION The human race has evolved from its primate precursors and from organized hunter-gatherers who were more skillful workers [1]. It seems that after the origin of man in Africa, nutrients played an important role in the evolution of man by the interaction of genes and epigenes with nutrients [2,3]. About 10,000 years ago, man began cultivation as an adaptation leading to a marked development in agricultural technology and food storage. It is likely that the social functions of most of the farming groups were limited to food collection, food production, and food storage as well as playing, singing, and dancing. These activities were beneficial for them, socially and physiologically [4 7]. Paleontological records indicate that Homo erectus and Homo habilis populations were consuming basically vegetarian foods [1 3]. The hunting groups developed gradually with the consciousness of space and time as man moved away from other primate species and learned tool making [1]. The naturally available foods during the Paleolithic period are included in the Paleolithic diet rich in wild foods: vegetables, green leaves, fruits, nuts, seeds, honey, eggs, and fish. The meat was from running animals which has protective fatty acids [6 10]. The preagricultural humans were also similar to hunter-gatherers who continue to collect such foods which form modern man’s genetic nutritional requirement. However, before huntergathering, early man also had good health due to enormous physical activity and natural food diversity with limited or no mental stress, alcoholism, and tobacco intake which are considered important risk factors of cardiovascular diseases (CVDs) and other chronic diseases. After 1910, increase in industrialization and urbanization led to refining and processing of foods, storing for commercialization for a better economic development [10 14]. The flavonoids and omega-3

The Role of Functional Food Security In Global Health. DOI: https://doi.org/10.1016/B978-0-12-813148-0.00005-0 © 2019 Elsevier Inc. All rights reserved.

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fatty acids in the Japanese and the Mediterranean traditional diets appear to share a common standard ratio (omega-6/3 B 1/1) with the Paleolithic diet. However, diet and lifestyle in Japan showed marked changes from the 1950s to the 1980s as people became more affluent, without an increase in most CVDs [1]. This modern pattern of food availability, changes in lifestyle, and in political system, led by profit, translates into new opportunities and threats, as well as unprecedented challenges, for mankind in the whole of the Western world [14,15]. This review aims to find out the evidence of the evolution of diets and dietary transition in the light of human evolution.

5.2 EVOLUTION OF MAN It has been proposed that the origin of modern humans could be in the whole of Africa within the past 300,000 350,000 years. Humans may have evolved from their common ancestor, Homo erectus, which means “upright man” [4]. This extinct species of human lived between 1.9 million and 135,000 years ago. Homo sapiens, means “wise man” and our species is the only surviving species of the genus Homo sapiens but there is debate about wherefrom we came. The human evolution is explained by the “out of Africa” model or the “multiregional” model but the first one, is a widely accepted model [4]. It proposes that Homo sapiens evolved in Africa before migrating across the world. Recent findings of new fossils from Jebel Irhoud, from Morocco as well as the pan-African origin of Homo sapiens also support that human evolution took place over multiple preferred sites across the whole of Africa over a long period of time [4]. It is proposed that the preference for sites could be an adaptation for functional food nutrition to enhance the capability of its genome and epigenome [5]. It has been proposed that the evolutionary history of humans is written into their genome [5]. The human genome looks the way it does, because all the genetic changes that have affected our ancestors may have caused these shapes. The intermingling of the various populations may have led to the single Homo sapiens species we see today. However, current genomic evidence also supports a single “out of Africa” migration of modern humans, rather than the multiregional model. Further studies of the extinct hominids Neanderthals and Denisovans indicate that there was some 1% 3% mixing of genomes with humans in Europe and Asia. This interbreeding between two previously separated populations is called “admixture” and results in a mixing of genes and epigenes susceptible to environment in general, nutrients in particular, between the populations [5]. It is possible that species-specific traits may be explained by differences in gene regulation rather than differences at the protein level [5]. Evolutionary studies have done sequence comparisons as well as integrative analyses in which gene regulation is key to understanding species evolution. DNA methylation is an important epigenetic modification involved in the regulation of numerous biological processes but the evolution of the human methylome and the processes driving such changes are not well known [5]. There is close interplay between Cytosine-phosphate-Guanine (CpG) methylation and the underlying genome sequence, as well as its impact on evolution. Since some of the nutrients such as omega-3 fatty acids, choline, pyridoxine, folic acid, and vitamin B12 have been found to influence the epigenome, it is possible that functional food consumption may have a role in human evolution.

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5.3 PRIMARY RISK FACTORS AND GENETIC VARIATIONS The primary risk factors are diet, sedentary behavior, tobacco intake, alcoholism, and mental stress, which are commonly called health behaviors. The impact of dietary changes from the evolutionary diet on our total health are clear from several epidemiological studies, indicating a positive association of wealth with Western dietary pattern [1 3,6 10]. It has been observed that people living in the United States die sooner, and it is difficult to achieve the average life expectancy of 78 years. Americans also have higher rates of disease or injury compared to subjects living in 16 other rich countries [16]. There is globalization of wealth from high-income countries to middle- and lowerincome countries without much improvement in health behaviors. This situation is commonly seen in most states of America, although the health budget of the United States is much higher than any other country [16]. Evolutionary adaptations can also occur due to dietary changes, although sleep, sun exposure, physical activity, and dietary requirements may be genetically determined, These lifestyle factors can influence the epigenome as a mechanism of adaptation [17]. After the Neolithic Revolution (first agricultural revolution; c. 12000 BC) and particularly after the industrial revolution, profound changes in food intake and behavior have occurred. These changes are too recent on an evolutionary timescale for the full adaptation of the human genome [2,3,7,18 20]. During the Paleolithic period (from about 2.5 million years ago to 11,000 years ago), some of the genes which make up the human genome were selected, although some alleles have been targets of selection right from the Agricultural Revolution [3,8,21]. In fact, human beings living in Asia, Europe, Oceania, and the Americas share a common ancestor of African Homo sapiens, although they may have genetic diversity [22 24]. These alleles after agricultural progress were induced by changes in pathogens, fatal diseases, and harsh environments without any impact of sleep, exercise, and diet [24 27]. However, the epigenome appears to be susceptible to environmental alterations causing disease phenotypes. There are very few primitive hunter-gatherers in the world today, but in India, with its approximately 1.30 billion population, there are farmers, hunter-gatherers, and the rapidly growing towns with increasing numbers of poor urban slum dwellers, alongside a big affluent society [1,5]. Population studies indicate that the levels of risk factors, such as sedentary behavior, dietary patterns, alcohol consumption, salt intake, tobacco consumption, and chronic anxiety disorders, are important features of different population groups [1,8,17 20]. Epidemiological studies by verbal autopsy questionnaires reveal that the risk factors related to behavior and social determinants of health may be dependent on several attributes of socioeconomic status [1,8,17 24].

5.4 NUTRITIONAL TRANSITION FROM HOMO ERECTUS TO HOMO MODESTIS There have been tremendous changes in our environment which is now very different from that for which our genetic constitution was selected [1 3]. The consumption of food and nutrients among humans during various periods of evolution are given in the Tables 5.1 5.5. There is marked decline in the consumption of omega-3 fatty acids, antioxidants, vitamins and minerals, and proteins and significant increase in the intakes of carbohydrates, (mainly refined), fat (saturated, trans fat, linoleic acid), and salt compared to the Paleolithic period [1,4 10]. The major dietary changes

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Table 5.1 Nutrient Intake Among Various Social Groups Food and Nutrient

Hunter-Gatherer Society

Western Society

Asian Societies

Energy density Protein Animal Vegetable Carbohydrate Fiber Fat Animal Vegetable Total ω-3 Ratio ω-6: ω-3 Vitamins and minerals

Low High High Very low Low moderate (slowly absorbed) Low (,15 g) Low Low Very low High (2.3 g/day) Low 2.4 High

High Low moderate Low moderate Low moderate Moderate rapidly absorbed

Low Low Low Low High Slow High Low Low High 0.5 0.85 g 25 50 Moderate

High ( . 30 g) High High Low (0.2 g/day) High 15-20 Low

Modified from Eaton SB, Konner M. Paleolithic nutrition. A consideration of its nature and current implications. N Engl J Med. 1985;312(5):283 289; Eaton SB, Konner M, Shostak M. Stone agers in the fast lane: chronic degenerative diseases in evolutionary perspective. Amer J Med 1988. 84:739-749 and Singh RB, De Meester F, Wilczynska A. The Tsim Tsoum approaches for prevention of cardiovascular diseases. Cardiology Research and PracticeVolume, 2010, Article ID, 824938, 18 pages, doi:10.4061/2010/824938 De Meester F, Takahashi T, Singh RB, Toda E, Hristova K, Fedacko J, et al. Nutrition in transition from Homo erectus to Homo modesties. World Heart J 2013;5:33-46 De Meester F. Wild-type land based foods in health promotion and disease prevention: the LDL-CC:HDL-CC model. In: Wild TypeFoods in Health Promotion and Disease Prevention, Ed. Fabien DeMeester, RR Watson, Humana Press, NJ 2008, 3-20.

that have occurred after 1910 are greater consumption of trans fat, saturated fat, and omega-6 fat and meat from animals that are fed on grains and live at farm houses. The meat from these animals is rich in saturated fat and poor in antioxidant polyphenolics compared to the meat from running animals which is healthier [10]. In addition, the consumption of refined carbohydrates has increased with decreased consumption of essential and nonessential amino acids, complex carbohydrates, vitamins, polyphenolics and flavonoids, minerals, and omega-3 fatty acids. Changes in food intakes in conjunction with physical inactivity, pollution, tobacco, and alcohol consumption and increased psychosocial stress, particularly after 1910, may have damaged the epigenome, predisposing to emergence of phenotypes of chronic diseases [3]. Industrialization and urbanization have been associated with a greater intake of pro-atherogenic foods during the transition from rural areas to urban areas and from poverty (lower social classes 3 5) to affluence (higher social classes 1 2) [28 36]. Such alterations can cause differences in the food consumption patterns among various populations such as hunter-gatherers, and Western and Asian populations who have undergone economic development during further transition (Tables 5.1 and 5.3) [1 3]. In Western countries, the diets consumed by lower social classes have similarity with diets consumed among higher social classes in developing countries. Such dietary transitions may be associated with marked decline in the intake of flavonoids, omega-3 fatty acids, amino acids, and vitamins and significant increases in the intakes of salt, refined carbohydrates, trans fat, saturated fat, and omega-6 fat, and salt compared to food intakes in the Paleolithic period (Tables 5.1 5.5). In the Paleolithic diet, the

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Table 5.2 Estimated Fatty Acid Consumption in the Late Paleolithic Period Social Group Sources Plants Linoleic acid Alpha-linoleic acid Animal Linoleic acids Alpha-linolenic acid Total Linoleic acid Alpha linolenic acid Animal Arachidonic acid (ω-6) (AA) Long chain ω-3 fatty acids Eicosapentaenoic acid (ω-3) (EPA) Docosatetraenoic acid (ω-6) (DTA) Docosapentaenoic acid (ω-3)(DPA) Docosahexaenoic acid (ω-3)(DHA) Total long chain ω-3 fatty acids Ratios of ω-6/ω-3 Linoleic acid/alpha linolenic acid 1 AA 1 DTA/EPA 1 DPA 1 DHA Total ω-6/ω-3

Fatty Acids (g/day) en 35.65/day 4.28 11.40 4.56 1.21 8.84 12.60 1.81 0.39 0.12 0.42 0.27 1.20 0.70 1.79 0.77

Modified from Eaton SB, Konner M. Paleolithic nutrition. A consideration of its nature and current implications. N Engl J Med. 1985;312(5):283 289; Eaton SB, Konner M, Shostak M. Stone agers in the fast lane: chronic degenerative diseases in evolutionary perspective. Amer J Med 1988. 84:739-749 and De Meester F, Takahashi T, Singh RB, Toda E, Hristova K, Fedacko J, et al. Nutrition in transition from Homo erectus to Homo modesties. World Heart J 2013;5:33-46; Singh RB, De Meester F, Wilczynska A. The Tsim Tsoum approaches for prevention of cardiovascular diseases. Cardiology Research and PracticeVolume, 2010, Article ID, 824938, 18 pages, doi:10.4061/2010/824938.

consumption of protein was 2.5-fold greater (33% vs 13%) compared to the diet consumed by the modern populations (Table 5.3, Fig. 5.1). Approximately, 17% of plant species provide 90% of the world’s food supply today, causing a marked reduction in food diversity resulting in a greater intake of grains rather than vegetables, roots, and fruits. Refined grains are the most recent additions to food consumption patterns and vegetable oils, which are also refined, are high in omega-6 fatty acids and trans fats and low in omega-3 fatty acids and amino acids. These dietary changes represent a dramatic departure from those foods and nutrients to which we are adapted [1 3]. The account of wheat, rice, and corn has markedly increased to three-quarters of the world’s grain production, on which the world food supply is dependent. Several experts have estimated that diets in the late Paleolithic period were providing greater amounts of micronutrients such as magnesium, calcium, potassium, and ascorbic acid and a lower intake of sodium compared to the current diets of the developed and developing countries [1 3]. The richest source of micronutrients are green leafy vegetables that are commonly consumed in the Mediterranean region [7 10]. Today,

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Table 5.3 Nutrient Composition in the Late Paleolithic Society and Current Recommendations Nutrient per Day

Late Paleolithic Society

Current Recommendation

Total dietary energy% Protein Carbohydrate Fat Alcohol P/S ratio Cholesterol, mg Fiber, g Sodium, mg Calcium, mg Ascorbic acid, mg

33 46 21 20 1.41 520 100 150 690 1500 2000 440

12 58 30 Mmoderate alcohol 1.00 300 30 60 1100 3300 800 1600 60

Modified from Eaton SB, Konner M. Paleolithic nutrition. A consideration of its nature and current implications. N Engl J Med. 1985;312(5):283 289; Eaton SB, Konner M, Shostak M. Stone agers in the fast lane: chronic degenerative diseases in evolutionary perspective. Amer J Med 1988. 84:739-749 their references, De Meester F, Takahashi T, Singh RB, Toda E, Hristova K, Fedacko J, et al. Nutrition in transition from Homo erectus to Homo modesties. World Heart J 2013;5:33-46; Eaton SB, Konner M. Paleolithic nutrition. A consideration of its nature and current implications. N Engl J Med. 1985;312 (5):283 289, and De Meester F, Takahashi T, Singh RB, Toda E, Hristova K, Fedacko J, et al. Nutrition in transition from Homo erectus to Homo modesties. World Heart J 2013;5:33-46; Singh RB, De Meester F, Wilczynska A. The Tsim Tsoum approaches for prevention of cardiovascular diseases. Cardiology Research and PracticeVolume, 2010, Article ID, 824938, 18 pages, doi:10.4061/2010/824938

Table 5.4 Ethnic Differences in Fatty Acid Levels in Thrombocytes Phospholipids and Percentage of All Deaths From Cardiovascular Disease

Arachidonic acid (20:4 ω6) Eicosapentaenoic acid (20:5 ω-3) Ratio of ω-6/ω-3 Mortality from cardiovascular disease

Europe and United States (%)

Japanese Society (%)

Greenland Eskimos (%)

26 0.5 50 45

21 1.6 12 12

8.3 8.0 1 7

Modified from De Meester F, Takahashi T, Singh RB, Toda E, Hristova K, Fedacko J, et al. Nutrition in transition from Homo erectus to Homo modesties. World Heart J 2013;5:33-46; Singh RB, De Meester F, Wilczynska A. The Tsim Tsoum approaches for prevention of cardiovascular diseases. Cardiology Research and PracticeVolume, 2010, Article ID, 824938, 18 pages, doi:10.4061/2010/824938.

Paleolithic diets are consumed in the modified form of Mediterranean diet, Indo-Mediterranean diet, Japanese diet, and DASH diet which have been demonstrated to have protective effects, in the randomized, controlled trials [1 3,6 12]. These dietary patterns, if adopted by modern men, may lead to decline in chronic disease and increase in longevity, either directly or by epigenetic inheritance or by natural selection [1]. Apart from direct effects of environmental factors, epigenetic

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Table 5.5 Fatty Acids Ratio in the Diets of Various Societies Subjects

ω-6/ω-3

Paleolithic Greece prior to 1960 Japan India, rural India urban United Kingdom Northern Europe United States Eastern Europe Indian hunter-gatherers

0.79 1.00 2.00 4.00 5 6.1 38 50 15.00 15.00 16.74 20 25 1.00 2.00

Estimated Current, 7 10 Early, 1 2 Prior to 1960, 3 4 Prior to 1960, 5 10 Prior to 1960, 10.00 Prior to 1960, 10.00 Prior to 1950, 7 8 Estimated Estimated

Modified from De Meester F, Takahashi T, Singh RB, Toda E, Hristova K, Fedacko J, et al. Nutrition in transition from Homo erectus to Homo modesties. World Heart J 2013;5:33-46; Singh RB, De Meester F, Wilczynska A. The Tsim Tsoum approaches for prevention of cardiovascular diseases. Cardiology Research and PracticeVolume, 2010, Article ID, 824938, 18 pages, doi:10.4061/2010/824938; De Meester F. Wild-type land based foods in health promotion and disease prevention: the LDL-CC: HDL-CC model. In: Wild TypeFoods in Health Promotion and Disease Prevention, Ed. Fabien DeMeester, RR Watson, Humana Press, NJ 2008, 3-20.

damage can occur due to adverse effects of an unhealthy diet which may increase the susceptibility of the populations to NCDs [25 28,37].

5.5 NUTRITION IN TRANSITION AND DIET LINKED NONCOMMUNICABLE DISEASES Among wealthy populations in high income countries, 72% of deaths occur due to noncommunicable diseases (NCDs) with declines in morbidity and mortality due to CVDs [8,15 20]. There is a change in food quality with rise in income, characterized by an energy-rich Western-type diet and lifestyle with increased use of automobiles resulting in a lack of physical activity and an increase in psychosocial stress, tobacco consumption, and alcoholism [8,15 20,28 35]. The increase in primary risk factors is associated with a graded increase in obesity and metabolic syndrome, more in affluent classes 1 3 compared to the poor social classes (Fig. 5.2). General education and health education, occupation, household income, housing and availability of automobiles, television, car, and other luxury items are the main attributes of social classes [28 35]. The consumer items and housing are important determinant of lifestyle; physical activity, occupational stress and social health, in high income countries [28 35]. These characteristics are also important determinants of dietary patterns, as well as social behavior, related to health and diseases, and excess of any harmful factor can independently increase morbidity and mortality [28 35]. Therefore, these are important pathways for development of CVDs and other metabolic diseases of Homo economicus wealthy populations with an underlying lack of general and health education. Nutrition education

FIGURE 5.1 Nutrient intake among Paleolithic societies; from Homo sapiens to Homo economicus. with graded increase in inflammatory index and risk of NCDs. Modified from De Meester F, Takahashi T, Singh RB, Toda E, Hristova K, Fedacko J, et al. Nutrition in transition from Homo erectus to Homo modesties. World Heart J 2013;5:33-46; De Meester F. Wild-type land based foods in health promotion and disease prevention: the LDL-CC:HDL-CC model. In: Wild TypeFoods in Health Promotion and Disease Prevention, Ed. Fabien DeMeester, RR Watson, Humana Press, NJ 2008, 3-20.

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FIGURE 5.2 Effects of diet and lifestyle on body composition from Homo sapiens to Homo erectus and modern man, Homo economicus, in indicating body mind index. Modified from De Meester F, Takahashi T, Singh RB, Toda E, Hristova K, Fedacko J, et al. Nutrition in transition from Homo erectus to Homo modesties. World Heart J 2013;5:33-46; De Meester F. Wild-type land based foods in health promotion and disease prevention: the LDL-CC:HDL-CC model. In: Wild TypeFoods in Health Promotion and Disease Prevention, Ed. Fabien DeMeester, RR Watson, Humana Press, NJ 2008, 3-20.

for health promotion appears to be most important attribute, because knowledge and attitude about healthy foods and physical activity can cause significant decline in cardiometabolic diseases and improve physical, social, mental, and spiritual health leading to the emergence of Homo modestis populations (Fig. 5.2). In lower- and upper-middle-income countries, like India, China, Indonesia, and Brazil, increased affluence and a rise in income allow a greater availability of ready prepared foods. These populations have been observed to have higher risk of NCDs; which is an indicator of the transition from poverty to affluence [28 34]. However, this trend would revert after further development causing a decline in poverty and better health education resulting in a decline in primary risk factors and deaths due to NCDs among these populations [16,17,38 40].

5.6 GLOBALIZATION OF WEALTH WITHOUT HEALTH US health spending was US$2.7 trillion in 2011, which is US$8700 for every person in the country, and represents 17.9% of the economy. This is far greater than any other economically advanced country. Unfortunately, spending on health care bears little relation to good health. “Wealth but not health in US” and globalization of wealth reported that the United States has a greater budget for health care per person than other developed countries (Australia, Canada, France, Italy, most of the Nordic countries, Spain, and the United Kingdom). However, life expectancy is shorter at birth for American men and American women fare little better [16,17]. Americans fare the least in certain areas of health, infant mortality and low birth weight, injuries and homicides, teenage pregnancies and sexually transmitted infections, HIV/AIDS prevalence, drug-related deaths, obesity and diabetes, heart disease, chronic lung disease, and disability. Those with health insurance with education up to college level and with higher incomes and healthy behaviors have also suffer this

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disadvantage. Interestingly, Americans who reach 75 years old live longer compared to other countries, and they have lower deaths from stroke and cancer. Americans also have better future health benefits due to the low smoking rate and high household income. It is not absolutely clear why Americans are at a health disadvantage compared with those in other countries. Problems with health insurance may not allow access to health care for many Americans and they may also have poor primary health care. Unhealthy behaviors abound in the United States, such as drug abuse, overeating, not wearing motorcycle helmets, drinking and driving, and using firearms—all causes of poor health. Disparity in socioeconomic status and standard of education in the United States also add to income inequality [16,17]. A recent study among randomly selected death records of 2222 (1385 men and 837 women) decedents, aged 25 4 years at time of death were studied. Poverty was considered if the total family income was ,US$300 per month. Lack of knowledge on health education about the role of exercise, prudent diet, and adverse effects of tobacco use and alcoholism was studied by the validated questionnaires [31]. The findings showed that sedentary behavior, excess salt intake, and other typical Western dietary habits were significantly more common among decedents belonging to higher social classes 1 3, compared to those within lower social classes 4 and 5. Lack of knowledge regarding health education was significantly more common among decedents in lower social classes, who died more often due to communicable diseases. The study also revealed that deaths associated with diabetes mellitus and due to circulatory diseases were significantly more common among higher social classes 1 3, compared to lower social classes 4 and 5. However, deaths due to malignant diseases and chronic lung diseases were not associated with social class (except the social class of women with breast cancer), but total proportion of deaths due to NCDs, including these causes, were significantly greater among higher social classes 1 3, compared to lower social classes 4 and 5. The findings indicate that sedentary behavior, typical Western diet, and excessive salt intake, in conjunction with underlying lack of health education, may be the predisposing factors for deaths among decedents of higher social classes 1 3. Among lower social classes 4 and 5, general lack of health education may have caused more deaths due to communicable diseases, as well as injury and accidents. Malignant diseases and chronic lung diseases were common among all social classes. It is clear that knowledge about health education on diet and lifestyle appears to be most important attribute which should be assessed to determine social class of the subjects and among all Homo economicus populations. The INTERHEART study [40] among 11,119 patients with a first myocardial infarction and 13,648 age matched (up to 5 years older or younger) control subjects also showed that a prudent diet rich in fruits, vegetables, whole grains, as well as poultry may be protective against myocardial infarction, whereas an oriental diet could be neutral and a Western diet has adverse effects. In high income countries, lower social classes 3 and 4 have poor health behavior and greater risk factors of CVD and cancer mortality, as well as all-cause mortality than higher social classes [16,17,35,36,38 40]. The higher social classes (1 and 2) appear to have greater access to health education, spare time to increase physical activity, and additional resources to maintain prudent diets than lower social classes in the developed countries [38]. This situation is in contrast to lower social class 3 5, in developing countries, who are living with a scarcity of foods and irregular employment. Physically demanding occupations are common in developing countries, but do not exist in developed countries, where they have only social classes 1 4 [8,18 20,28 36,38 40]. It seems that in developing societies, urban populations have a double burden of diseases, related to

5.6 GLOBALIZATION OF WEALTH WITHOUT HEALTH

81

overeating as well as malnutrition because occupational physical activity decreases along with change in social class [28 33]. Popkin has also agreed with the above global nutrition dynamics in which the world is shifting rapidly toward a diet linked to NCDs [41] Adverse effects of Tamasic foods characteristics of the Western diet were also proposed by Indian ancient physicians, Charak and Sushruta in 600 BCE, as well as by Confucius in China (500 BCE), and by the Greek physician Hippocrates (500 BCE) who proposed let “food be our medicine” [42,43]. Around 5000 years ago, Indians were aware of the harmful effects of dietary ingredients which are evident from ancient scripture of the Bhagwata Gita (3100 BC). More recently, the US Preventive Service Task Force has also demonstrated that a functional food-rich diet and physical activity behavioral interventions for adults not at high risk for CVD can cause consistent modest benefits across a variety of important intermediate health outcomes across 6 12 months [44]. These benefits are mainly in blood pressure, low-density lipoprotein and total cholesterol levels, and adiposity, with evidence of a dose-response effect, with higher-intensity interventions conferring greater improvements. There is a need to develop further evidence on longer-term intermediate and health outcomes or on harmful effects of these interventions. De Meester has proposed “Body Mind Index 5 BMI” to address total health because physical, social, mental, and spiritual health may depend on body composition [45]. It is remarkable that animals including man in the wild do not suffer overweight. Even modern husbandry animals don’t. In contrast, companion pets may and societal man does. The human part—the mind—appears responsible for the disease (Fig. 5.3). It is important to analyze facts as primary and secondary risk factors. Food is here secondary. It contributes, yet does not cause the problem. Just as cholesterol contributes, but does not cause heart disease (www.columbus-concept.com). Once understood and accepted, such a basic principle allows one to take the right decision. This is an important explanation of why in the United States, there is wealth, but only limited health [16]. The Tsim Tsoum Concept is an extension of the Columbus Concept which includes Mind-Brain-Body interactions and highlights the role of mind in the pathogenesis of obesity and related NCDs [45]. Recently it From Memes (i) to Genes (i*) MEMES EXCHANGE ADDRESSING Short-term Memory

(i) Environment (i)

BODY Response

PC PE

(i*)

Long-term Memory

(in) PS

GENES Expression

FIGURE 5.3 Interaction of environmental factors with mind and body function and genes. Modified from De Meester F. Obesity is a communicable mind disease. Approaches to Ageing Control, J Spanish Soc Antiageing Medicine Longevity 2014; 18:7-10.

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has been proposed that our bodies exist to achieve maximal reproductive and genetic fitness, rather than be maximally healthy or live long, which means that caloric expenditure and time need conservation, without consideration of health goals [46]. The success of reproduction can diminish health outcomes as observed in rural Ethiopia. Reduction in the energy burden on women carrying large loads of water was expected to improve women’s nutritional status and hence their children’s health. However, the reduction in work stress improved women’s fertility, but increased malnutrition among their offspring. This can also occur due to insufficient time as well as micronutrients for a fertilized egg to adapt, which can have positive effects on the epigenome. In brief, food consumption patterns and health behavior have changed significantly in various populations, during the transition from Homo sapiens to Homo economicus and we need to have better health behaviors to develop into Homo modestis population—a sustainable development goal. The nutritional transition has been quite rapid during the last 100 160 years, causing increased intake of saturated fatty acids, trans fat, refined carbohydrates, and linoleic acid and decreases in omega-3 fatty acids and flavonoids, from grain-fed cattle, tamed at farm houses, rather than meat from running animals, resulting in the marked increase in morbidity and mortality due to NCDs. The population characteristics, such as dietary intakes, in conjunction with sedentary behavior, appear to be the fundamental causes of poor social, mental, and spiritual health characterized by hyperlipidemia, hyperglycemia, oxidative stress, and inflammation which are important mechanisms in the pathogenesis and prevention of diet-related chronic diseases [39 41,47,48]. It is possible that through education and indoctrination, a cultural change among families can generate them to take heed of advice on intervention with functional foods. It may give each generation healthier outcomes, a reduced health burden to individual and state, and even a world unification on this issue—what the world should do to turn into Homo modesties populations—the objective of sustainable development goals.

ACKNOWLEDGMENTS The International College of Nutrition and International College of Cardiology are thanked for supporting this study.

REFERENCES [1] De Meester F, Takahashi T, Singh RB, Toda E, Hristova K, Fedacko J, et al. Nutrition in transition from Homo erectus to Homo modesties. World Heart J 2013;5:33 46. [2] Eaton SB, Konner M. Paleolithic nutrition. A consideration of its nature and current implications. N Engl J Med 1985;312(5):283 9. [3] Eaton SB, Konner M, Shostak M. Stone agers in the fast lane: chronic degenerative diseases in evolutionary perspective. Amer J Med 1988;84:739 49. [4] Hublin JJ, Ben-Ncer A, Bailey SE, Freidline SR, Neubauer S, Skinner MM, et al. New fossils from Jebel Irhoud, Morocco and the pan-African origin of Homo sapiens. Nature 2017;546:289 92. Available from: https://doi.org/10.1038/nature22336.

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[5] Hernando-Herraez I, Garcia-Perez R, Sharp AJ, Marques-Bonet T. DNA Methylation: insights into human evolution. PLoS Genet 2015;11(12):e1005661. Available from: https://doi.org/10.1371/journal. pgen.1005661. [6] Singh RB, De Meester F, Wilczynska A. The Tsim Tsoum approaches for prevention of cardiovascular diseases. Cardiol Res Pract Volume 2010. Available from: https://doi.org/10.4061/2010/824938 Article ID, 824938, 18 pages. [7] Eaton SB, Eaton III SB, Sinclair AJ, Cordain I, Mann NJ. Dietary intake of long chain polyunsaturated fatty acids during the Paleolithic period. In: Simopoulos AP Ed. The return of w-3 fattyacids in the food supply. Land based Animal Food Products and their Health Effects. World Rev Nutr Diet 1998;83:12 23. [8] Carrera-Bastos P, Fintess-Villaba M, O’Keefe JH, Lindeberg S, Cordain L. The Western diet and lifestyle and diseases of civilization. Res Rep Clin Cardiol 2011;2:15 35. [9] Singh RB, Moshiri M, De Meester F, Juneja L, Muthusamy V, Manoharan S. The evolution of low w-6/w3 ratio dietary pattern and risk of cardiovascular diseases and diabetes. J Altern Med Res 2011;3:45 57. [10] De Meester F. Wild-type land based foods in health promotion and disease prevention: the LDL-CC: HDL-CC model. In: Fabien DeMeester RR, Watson, editors. Wild typefoods in health promotion and disease prevention. NJ: Humana Press; 2008. p. 3 20. [11] Esposito K, Glugliano D. Diet and inflammation: a link to metabolic and cardiovascular diseases. Eur Heart J 2006;27:15 20. [12] Katcher HI, Legro RS, Kunselman AR, et al. The effects of whole grain- enriched hypocaloric diet on cardiovascular disease risk factors in men and women with metabolic syndrome. Am J Clin Nutr 2008;87:79 90. [13] Fung TT, Malik V, Rexroad KM, Manson JE, Willett WC, Hu FB. Sweetened beverage consumption and risk of coronary heart in women. Amer J Clin Nutr 2009;89:1037 42. [14] De Meester F. Progress in lipid nutrition: the Columbus concept addressing chronic diseases. World Rev Nutr Diet 2009;100:110 21. [15] Marmot M, Allen J, Bell R, Bloomer E, Goldblatt P. Consortium for the European Review of Social determinants of Health and the Health Divide. WHO European review of social determinants of health and the health divide. Lancet 2012;380:1011 29. [16] Editorial. Wealth but not health in USA. Lancet 2013;381:177. Available from: https://doi.org/10.1016/ S0140-6736(13)60069-0. [17] Luca F, Perry GF, Di Rienzo A. Evolutionary adaptations to dietary changes. Ann Rev Nutr 2010;30:91 314. [18] Pettee KK, Ainsworth BE. The Building Healthy Lifestyles Conference: modifying lifestyles to enhance physical activity, diet, and reduce cardiovascular disease. Am J Lifestyle Med 2009;3(1 Suppl):6s 10s. [19] Frassetto LA, Schloetter M, Mietus-Synder M, et al. Metabolic and physiologic improvements from consuming a paleolithic, hunter gatherer type diet. Eur J Clin Nutr. 2009;63(8):947 55. [20] Singh RB, Reddy KK, Fedacko J, De Meester F, Wilczynska A, Wilson DW. Ancient concepts in nutrition and diets in hunter-gatherers. The Open Nutra J 2011;4:130 5. [21] Pritchard JK. How we are evolving. Sci Am. 2010;303(4):40 7. [22] White TD, Asfaw B, DeGusta D, et al. Pleistocene Homo sapiens from Middle Awash, Ethiopia. Nature. 2003;423(6941):742 7. [23] McDougall I, Brown FH, Fleagle JG. Stratigraphic placement and age of modern humans from Kibish, Ethiopia. Nature. 2005;433:733 6. [24] Manica A, Amos W, Balloux F, Hanihara T. The effect of ancient population bottlenecks on human phenotypic variation. Nature. 2007;448(7151):346 8. [25] Wang ET, Kodama G, Baldi P, Moyzis RK. Global landscape of recent inferred Darwinian selection for Homo sapiens. Proc Natl Acad Sci U S A. 2006;103(1):135 40.

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[26] Voight BF, Kudaravalli S, Wen X, Pritchard JK. A map of recent positive selection in the human genome. PLoS Biol 2006;4(3):e72. [27] Pollard KS, Salama SR, Lambert N, et al. An RNA gene expressed during cortical development evolved rapidly in humans. Nature 2006;443(7108):167 72. [28] Singh RB, Singh V, Kulshrestha SK, Singh S, Gupta P, Kumar R, et al. Social class and all cause mortality in an urban population of north India. Acta Cardiol 2005;60:611 17. [29] Singh RB, Fedacko J, Vargova V, Kumar A, Mohan A, Pella D, et al. Singh’s verbal autopsy questionnaire for assessment of causes of death, social autopsy, tobacco autopsy, and dietary autopsy based on medical records and interview. Acta Cardiol 2011;66:471 81. [30] Singh RB, Ghosh S, Niaz MA, Rastogi V. Validation of physical activity and socioeconomic questionnaire in relation to food intakes for the five city study and a proposed classification for Indians. J Assoc Phys India 1997;45:603 7. [31] Singh RB, Anjum B, Takahashi T, Martirosyan D, Pella D, De Meester F, et al. Poverty is the absolute cause of deaths due to noncommunicable diseases. World Heart J 2012;V4(2-3). [32] Singh RB, Beegom R, Mehta AS, Niaz MA, De AK, Mitra RK, et al. Social class, coronary risk factors and undernutrition, a double burden of diseases, in women during transition, in five Indian cities. Int J Cardiol 1999;69:139 47. [33] Singh RB, Sharma JP, Rasogi V, Niaz MA, Ghosh S, Beegom R, et al. Social class and coronary disease in a rural population of north India. Eur Heart J 1997;18:588 95. [34] Pednekar MS, Gupta R, Gupta PC. Illiteracy, low educational status and cardiovascular mortality in India. BMC Public Health. 2011;11:567. [35] Teo K, Chow CK, Vaz M, Rangarajan S, Yusuf S. The Prospective Urban Rural Epidemiology (PURE) study: examining the impact of societal influences on chronic noncommunicable diseases in low, middle, and high-income countries. Am Heart J. 2009;158:1 7. [36] Gillum RF. The epidemiological evolution in pattern of cardiovascular diseases in blacks. N Engl J Med 1996;335:1597 9. [37] Luca F, Perry GH, Di Rienzo A. Evolutionary adaptations to dietary changes. Annu Rev Nutr 2010;30:291 314. [38] Kesteloot H. Social class, all cause and cardiovascular mortality. Acta Cardiol 2004;59:117. [39] WHO. Mortality and Burden of Disease Estimates for WHO Member States in 2008. Geneva: World Health Organization; 2010. [40] Rosengren A, Hawken S, Ounpuu S, Sliwa K, Zubaid M, Almahmeed WA, et al. Association of psychosocial risk factors with risk of acute myocardial infarction in 11119 cases, 13648 controls from 52 countries (the INTERHEART Study): case control study. Lancet 2004;364:937 52. [41] Popkin BM. Global nutrition dynamics; the world is shifting rapidly toward a diet linked with noncommunicable diseases. Am J Clin Nutr 2006;83:289 98. [42] C. Samhita (Charka, 600 BC). Varanasi, Delhi: Chaukhambha Orientalia, 1981, translated by Sharma PV. Harvard Oriental Series. Motilal Banarsidass, Delhi, 1984. [43] S. Samhita (Sushruta, 600 BC), vol. 1 3, Varanasi: Sanskrit Series Office, 1999, translated by Bhisagratna Chaukhambha, Varanasi, 1984. [44] Patnode CD, Evans CV, Senger CA, Redmond N, Lin JS. Behavioral counseling to promote a healthful diet and physical activity for cardiovascular disease prevention in adults without known cardiovascular disease risk factors updated evidence report and systematic review for the US preventive services task force. JAMA. 2017;318(2):175 93. Available from: https://doi.org/10.1001/jama.2017.3303. [45] De Meester F. Obesity is a communicable mind disease. Approaches to Ageing Control, J Spanish Soc Antiageing Medicine Longevity 2014;18:7 10. [46] Wells JCK, Nesse RM, Sear R, Johnstone RA, Stearns SC. Evolutionary public health: introducing the concept. Lancet 2017;390:500 9.

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[47] Simopoulos AP. Evolutionary aspects of the dietary omega-6/omega-3 fatty acid ratio: medical implications. In: Simopoulos AP, De Meester F, editors. A Balanced Omega-6/Omega-3 Fatty acid Ratio. Cholesterol and Coronary Heart Disease. World Rev Nutr Diet, 100. Basel: Karger; 2009. p. 1 21. [48] Singh RB, DeMeester F, Mechirova V, Pella D, Otsuka K. Fatty acids in the causation and therapy of metabolic syndrome. In Wild type foods in health promotion and disease prevention, editors Fabien DeMeester and RR Watson. NJ: Humana Press; 2008. p. 263 84.

FURTHER READING Cornelissen G. When you eat matters: 60 years of Franz Halberg’s nutrition chronomics. The Open Nutra J 2012;5(Suppl):16 44. Hristova K, Nakaoka T, Otsuka K, Fedacko J, Singh R, Singh RB, et al. Perspectives on chocolate consumption and risk of cardiovascular diseases and cognitive function. The Open Nutraceuticals Journal 2012;5:207 12. Lindeberg S. Food and western disease: health and nutrition from an evolutionary perspective. Chichester, UK: Wiley-Blackwell; 2010. Pool LR, Burgard SA, Needham BL, Elliott MR, Langa KM, Mendes de Leon CF. Association of a negative wealth shock with all-cause mortality in middle-aged and older adults in the United States. JAMA 2018;319(13):1341 50. Available from: https://doi.org/10.1001/jama.2018.2055. Singh RB, De Meester F, Wilczynska A, Wilson DW, Hungin APS. The liver-pancreas and brain connection in the pathogenesis of obesity and diabetes mellitus. World Heart J 2010;2:319 26. Singh RB, Dubnov G, Niaz MA, Ghosh S, Singh R, Rastogi SS, et al. Effect of an Indo-Mediterranean diet on progression of coronary disease in high risk patients: a randomized single blind trialtrial. Lancet 2002;360:1455 61. Singh RB, Fedacko J, Vargova V, Pella D, Niaz MA, Ghosh S. Effect of low W-6/W-3 fatty acid ratio paleolithic style diet in patients with acute coronary syndromes: a randomized, single blind, controlled trial,. World Heart J 2012;4:71 84. Singh RB, Singh AK, Sharma JP, Singh RK, Kumar A, Singh G, et al. Nutrition in chronocardiology: we are indebted Professor Franz Halberg. The Open Nutr. J 2012;5(supple):45 65. Toda E, Toru T, Singh RB, Alam SE, et al. Can low w-6/w-3 ratio Paleolithic style diet stop cardiovascular diseases? Tissue is the Issue. Amer. Med. J. 2012;3:183 93. Wang PY, Caspi L, Lam CK, Chari M, Li X, Light PE, et al. Upper intestinal lipids trigger a gut-brain-liver axis to regulate glucose production. Nature 2008;452:1012 16.

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GLOBALIZATION OF DIETS AND RISK OF NONCOMMUNICABLE DISEASES

6

Jan Fedacko1, Toru Takahashi2, Ram B. Singh3, Dominik Pella4, Sergey Chibisov5, Krasimira Hristova6, Daniel Pella1, Galal Nagib Elkilany7, Rukam S. Tomar8 and Lekh R. Juneja9 1

Faculty of Medicine, PJ Safaric University, Kosice, Slovakia 2Graduate School of Human Environment Science, Fukuoka Women’s University, Fukuoka, Japan 3Halberg Hospital and Research Institute, Moradabad, Uttar Pradesh, India 4East Slovak Institute of Medical Sciences, Kosice, Slovakia 5Faculty of Medicine, People’s Friendship University of Russia, Moscow, Russia 6Department of Noninvasive Functional Diagnostic and Imaging, University National Heart Hospital, Sofia, Bulgaria 7Department of Genetics, Junagarh University, Junagarh, Gujarat, India 8Department of Biotechnology, Junagadh Agricultural University, Junagadh, Gujarat, India 9 The Rohto Pharmaceutical Co. Ltd, Osaka, Japan

6.1 INTRODUCTION The preagricultural humans’ diet consisted of naturally available wild foods: fruits, vegetables, green leaves, seeds, honey, eggs, fish, and meat from running animals, which shaped modern man’s genetic nutritional requirement [1 3]. Man laid down their spears and started farming around 10,000 years back, the adaptation towards farming in turn led to advancement in agriculture, unprecedented technical development, industry, and commerce. After 1910, in the 20th century, stress was added due to industrialization and urbanization, which led to refining of foods, storing, processing of foods, and distributing them in the continuous search of a better economic model [1 4]. Very few primitive hunter-gatherers are left today in the world. Farmers are the main community of India’s approximately 1.28 billion population, but the rapidly growing towns have boosted the number of poor urban slum dwellers as well as big affluent society [1,5]. Population studies indicate that physical inactivity, Western dietary patterns, alcoholism, tobacco use, and mental stress are important risk factors for the emergence of noncommunicable diseases (NCDs) [1 9]. Underlying these primary risk factors, the epidemic of NCDs has been attributed to urbanization and environmental transitions, including work pattern, changes from heavy labor to sedentary occupations, increased computerization and mechanization, and improved transportation due to automobiles resulting in obesity [10 14]. Obesity is also a risk factor of NCDs, including cardiovascular diseases (CVDs), type 2 diabetes, bone and joint diseases, cancer and neuropsychiatric diseases. Table 6.1 shows the global dietary transition in various stages of human development. There have been drastic changes in food production, and food processing, as well as in distribution systems, to increase the accessibility of unhealthy foods, due to economic development.

The Role of Functional Food Security In Global Health. DOI: https://doi.org/10.1016/B978-0-12-813148-0.00006-2 © 2019 Elsevier Inc. All rights reserved.

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Table 6.1 Dietary Transition and Emergence of Noncommunicable Diseases Pattern 3: Receding Food Scarcity & Poverty

Pattern 4: More Food, Less Exercise- Homo economicus

Pattern 5: Healthy Behavior-Homo modestis

Cereals predominant, diet less varied

Fewer starchy staples; more fruit, vegetables, animal protein; low variety

More fat (animal products, trans fat, ω-6 fat), sugar, processed foods; less fiber, less ω-3 fat and flavonoids

Higher-quality fats, reduced refined carbohydrates, more whole grains, fruit, vegetables rich in ω-3 and flavonoids

Robust, lean population; few nutritional deficiencies

Children and women suffer most from low fat intake, nutritionaldeficiency disease emerge, stature declines

MCHa nutrition problems, many deficiencies disappear, weaning diseases emerge, stature grows

Reduction in body fat and obesity, and NCDs, improvement in health (Epigenetic modulation and trans-generational inheritancenatural selection)

Economy

Huntergatherers

Agriculture, animal husbandry, homemaking begin; shift to monocultures

Household

Primitive, onset of fire Subsistence, primitive stone tools

Labor-intensive, primitive technology begins (clay cooking vessels)

Second agricultural revolution (crop rotation, fertilizer), Industrial Revolution, women join labor force Primitive water systems, clay stoves, cooking technology advances

Obesity, problems for elderly (Osteoporosis, fractures etc.), type 2 diabetes, hypertension, stroke, heart attack, brain degeneration, Psychological disorders, and cancer Fewer jobs with heavy physical activity, service sector and mechanization, household technology revolution

Homo sapiens Diet Given in Tables 1 5 Nutrition profile

Diet Nutritional status

Income and assets

Pattern 1: Huntergatherers

Pattern 2: Food ScarcityPoverty

Plants, lowfat wild animals, diet diversity by collecting foods.

Subsistence, few tools

Increases in income disparity and agricultural tools industrialization

Household technology mechanizes and proliferates

Rapid growth in income and income disparities, technology proliferation

Service sector mechanization and industrial rovo tization dominate, increase in leisure exercise offsets sedentary jobs Significant reduction in food preparation costs as a result of technologic change Decrease in income growth, increase in home and leisure technologies

6.1 INTRODUCTION

89

Table 6.1 Dietary Transition and Emergence of Noncommunicable Diseases Continued Homo sapiens Diet Given in Tables 1 5

Pattern 1: Huntergatherers

Pattern 2: Food ScarcityPoverty

Professional skill/ Education Demographic profile Mortality

Hunting

Stock breeding, cultivation

Low fertility, high mortality, low life expectancy

Age of Malthus; high natural fertility, short life expectancy, high infant and maternal mortality

Age structure

Young population

Young, very few elderly

Housing

Rural, low density

Rural, a few small, crowded cities

Food processing

Nonexistent

Food storage begins Nonexistent

Pattern 3: Receding Food Scarcity & Poverty

Pattern 4: More Food, Less Exercise- Homo economicus

Pattern 5: Healthy Behavior-Homo modestis

Industry, intensive agriculture Mortality declines slowly, then rapidly; fertility static, then declines; small, cumulative population growth, which later explodes Chiefly young, shift to older population begins

Processed unhealthy foods increased Life expectancy hits unique levels (ages 60 70), huge decline and fluctuations in fertility (e.g., postwar baby boom)

Functional foods availability increases Life expectancy extends to ages 70 and 90 y, disability-free period increases

Rapid decline in fertility, rapid increase in proportion of elderly person Dispersal of urban population decrease in rural green space

Increases in the proportion of elderly . 75 y of age

Numerous foodtransforming technologies

Technologies create functional foods and food constituent substitutes (i.e., macronutrient substitutes), GM foods

Chiefly rural, move to cities increases, international migration begins, megacities develop Storage processes (drying, salting) begin, canning and processing technologies emerge, with food refining and milling

Lower-density cities rejuvenate, increase in urbanization of rural areas encircling cities

a MCH, maternal and child health. Modified from Popkin 2006, and from De Meester F., Takahashi T., Singh R.B., Toda E., Hristova K., Fedacko J., et al. Nutrition in transition from Homo erectus to Homo modesties. World Heart J 2013;5:33 46; Popkin B.M. Global nutrition dynamics; the world is shifting rapidly toward a diet linked with non-communicable diseases. Am J Clin Nutr 2006:83:289-298.

Establishment of fast food restaurants have shown exponential global expansion in the last few decades, resulting in the increased availability of ready prepared and fast foods at an affordable cost in economically developed countries, resulting in increased morbidity and mortality due to NCDs [13 19].

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Interestingly, a recent study has demonstrated that increased consumption of functional foods improved, while consumption of Western-type foods worsened, the risk of NCDs across the world, with heterogeneity across regions and countries [19]. These global data on functional food and Western-type food consumption provide the best estimates of global nutrition dynamics across the world and enlighten policies and priorities for reducing the health and economic burdens of Western-type diets and NCDs [19]. The Japanese and the Mediterranean traditional diets share a common standard (omega-6/3 B 1/1) and are considered as prudent diets. The diets appear to be a combination of a high intake of food which is rich in functional food, although the Japanese lifestyle and diet went under transition from poverty in the 1950s to affluence by the year 1980s, without an increase in CVDs and other chronic diseases [4]. This review examines the available evidence on globalization of diets with the risk of NCDs.

6.2 THE FAILURE OF GLOBAL HEALTH COMMUNITY TO PREVENT NCDs The health community is not able to initiate strategies to counteract the market and health systems. The majority of the food systems have contributed to unhealthy diets with high calorie content, large portion sizes, and large amounts of processed meat, highly refined carbohydrates, sugary beverages, and unhealthy fats. This modern pattern of food availability, changes in lifestyle and in political system, led by profit, translates into new unprecedented threats, opportunities, and challenges for humankind in the form of increased morbidity and mortality due to NCDs [15 17]. The impact of these changes on our total health are clear from a review showing that Americans are least likely to reach the age of 50 years and are prone to higher rates of disease or injury as compared to the citizens of 16 other economically wealthy countries [18]. Here it appears that the globalization of wealth has been done without much improvement in health behavior because the health budget of the Western countries do not have a target for health education and there is hardly any government policy to provide functional foods at affordable cost, despite much higher health budgets than any other country [18]. Despite sufficient evidence that primary risk factors—Western-type foods, sedentary behavior, tobacco, alcoholism, and psychosocial stress—are actual risk factors of NCDs, the world health community is failing to respond effectively to the rising burden of NCDs [20,21]. It has also been proposed that sleep, sun exposure, physical activity, and dietary needs of humans are being determined genetically, hence changing these habits may be difficult although rapid urbanization has been associated with an alteration in many of these behaviors [1 3]. The answer for failure to prevent NCDs, has been summed up by Horton, (Editor, Lancet) in one word: fear; the fear of a species-threatening pandemic [21]. Prevention and treatment of NCDs is a concern for the ministry of health, ministry of food and nutrition, ministry of agriculture, ministry of commerce, and ministry of urban development. These ministries and concerned industries and agencies give employment to millions of people in every country of the world. One of the most concerned examples is the ministry of health, which includes the pharmaceutical industry, medical colleges, nursing colleges, pharmacy colleges, and other related industries that generate employment to several million, doctors, nurses, pharmacists, and paramedical staff. The drug industry gives employment to people working in the pharmaceutical industry as well as marketing and clinical trials of drugs which

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Table 6.2 Current Situation of Global Noncommunicable Diseases in 2015 Low-income countries; men 0.4 million, women 0.4 million, total 0.9 million, 6% Lower middle-income countries; men 3.6 million, women 2.6 million, total 6.1 million, 41% Upper middle-income countries; men 3.5 million, women 2.4 million, total 5.8 million, 39% High-income countries; men 1.4 million, women 0.8 million, total 2.2 million, 15% Total 8.9 million; men 6.2 million, women 15.0 million, 100% Modified from WHO, Noncommunicable Diseases Progress Monitor 2015. Geneva 2015. http://www.who.int/nmh/publications/ ncd-progress-monitor-2015/en/, accessed 2017.

exceeds billions of dollars. These financials gains and employments given to people do not allow political elites to concentrate on developing policies of prevention. These concerns are important for the economic prosperity of developed as well as developing countries, causing anxiety for a recalibration of priorities among global health leaders. An advocacy strategy based on four diseases and four risk factors seems increasingly out of touch with the realities in poor countries. Many political leaders believe that NCDs are just too big and too complex a challenge and need a different universal approach. In Geneva, WHO’s new Director-General, Tedros Adhanom Ghebreyesus, in his first speech named four urgent issues: health emergencies; universal health coverage; women’s, children’s, and adolescents’ health; and climate change. It seems that a pervasive fear in his mind has displaced all other health concerns discussed a few years ago in the High Level Meeting (HLM) of UNO [9]. Unfortunately, his speech did not include NCDs as a priority, although responsible for 71% of deaths worldwide. His speech in the meeting of the G20 leaders, underlined the importance of “pandemics, health emergencies, and weak health systems” and was silent again on the 39.8 million deaths annually from NCDs, as mentioned by Horton [21]. In the World Health Assembly, 2017, the Director General of WHO, called NCDs “a perfect storm” but storms come and disappear which is not possible in the case of NCDs. In the UNO’s HLM in 2011, a Political Declaration on the Prevention and Control of NCDs urged presidents and prime ministers, to take NCDs seriously, as a cause of premature mortality [9]. There is universal agreement that NCDs cause significant decline in economic as well as human development hence sustainable development goals cannot be achieved unless these diseases are controlled. Therefore, the investment in the prevention and treatment of NCDs can provide economic growth of the concerned community and country. The individual health security as well as global health security, which means universal health coverage, can also be achieved by prevention of NCDs [9,21]. The current situation of NCDs is given below. WHO estimates that in 2015, 15.0 million people between the ages of 30 and 69 died from NCDs, as shown below [22] Table 6.2.

6.3 THE WORLD NUTRITIONAL DYNAMICS AND RISK OF DISEASES Previous studies have clearly observed that there is food and nutrition dynamics, as well as social class dynamics in which an increase in socioeconomic status is associated with an increased intake

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of Western diet and sedentary behavior, resulting in a decrease in undernutrition and increase in NCDs [1 8,12 14,27 30]. A further increase in social class in association with health education is associated with increased intake of functional foods and an increase in spare time physical activity, resulting in a decline in NCDs [8 11,23 26]. Thus, NCDs come in a wave, first they occur to affluent populations with high income and those who are becoming rich during the economic growth of the developing countries, such as India, China, Indonesia. Then there is a decline in NCDs in affluent and educated populations after learning the methods of prevention. Population health education, that occurs with further economic growth, is associated with the globalization of prudent diets and physical activity, resulting in a decline in NCDs [8 11,23 26] Fig. 6.1. The main attributes of social classes are: general education and health education; occupation; household income; housing; and availability of automobiles, television, and other luxury items [11 14,27 30]. In high-income countries, housing and consumer durables are the main factors which determine the lifestyle: occupational stress, physical activity, and social health [11 14]. These attributes also determine the pattern of food consumption, as well as social behavior, which in turn may be societal determinants of health and diseases, and if any of these substance is misused may lead to morbidity and mortality [11 14,27 30]. Therefore, the pathways or the basic reason for development of NCDs are excess eating of Western-type foods, sedentary behavior, stress, tobacco use, and alcoholism among individuals and wealthy populations with an underlying lack of general and health education. Nutrition health education appears to be the most important

FIGURE 6.1 Pathway for globalization of Western- and Mediterranean-style diets and risk of noncommunicable diseases. Modified from De Meester F., Takahashi T., Singh R.B., Toda E., Hristova K., Fedacko J., et al. Nutrition in transition from Homo erectus to Homo modesties. World Heart J 2013;5:33 46; Hristova K., Pella D., Singh R.B., Dimitrov B.D., Chaves H., Juneja L., et al. Sofia declaration for prevention of cardiovascular diseases and type 2 diabetes mellitus: a scientific statement of the international college of cardiology and international college of nutrition; ICC-ICN Expert Group. World Heart J 2014;6:89 106.

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attribute, because knowledge and attitude about healthy foods and physical activity can substantially reduce NCDs and improve physical, social, mental, and spiritual health leading to health promotion.

6.3.1 GLOBALIZATION OF WESTERN-TYPE DIETS AND HEALTH In developing countries, like India, China, Indonesia, Brazil, Pakistan, Philippines, Thailand, Bangladesh, etc., with the increase in the income of higher social classes of these countries and greater availability of ready-prepared foods, it has been observed that the risk towards NCDs has increased including CVDs, coronary artery disease (CAD), stroke, hypertension, and type 2 diabetes mellitus [2 4]. Figs. 6.2 and 6.3 show the fat intake transition among Chinese populations in seven provinces indicating increased fat intake among subjects with higher income from 1989 to 1993, showing a dietary transition with economic growth [20]. However, some experts have proposed that both poverty as well as wealth may be the major cause of deaths and disability due to NCDs, but it does not seems to be absolutely true [9]. In the last 100 years due to industrialization and urbanization, major dietary changes have occurred, causing increased intake of total and saturated fatty acids Relationship among the proportion of the population consuming a low-fat diet(% energy from fat below 10Kcal), income, and urban residence, China Health and Nutrition Survey. 1989, 1993 50% 1989 40%

39.2%

% Consuming 30% fat

60%

66.6%

1989 1993 51.0%

50% 40%

36.4%

30% 22.8% 20%

19.1%

19.1%

10% 0%

Low

Middle Household income tertile

High

FIGURE 6.3 Proportion of subjects consuming .30% fat became significantly higher among all social classes in 1993 than in 1989 in China. Modified from Mendenhall E., Kohrt B.A., Norris S.A., Ndetei D., Prabhakaran D. Non-communicable disease syndemics: poverty, depression, and diabetes among low-income populations Lancet. 2017;389:951 963.

(SFA), trans fatty acids and linoleic acid, and meat from grain-fed domesticated cattle, rather than meat from running animals [1 3,12 14,27 30]. In general, the intake of refined carbohydrates has increased many times while the intake of complex carbohydrates, minerals, vitamins, essential amino acids, omega-3 fatty acids, and antioxidants has decreased. Particularly after 1910, these changes in diet in conjunction with mental strain, sedentary behavior, tobacco consumption, alcoholism, and pollution may have caused damage to our genes, leading to the rapid appearance of phenotypes of CVDs and other chronic diseases [1 3,12 14]. In wealthy countries, there has been a tremendous reduction in deaths due to communicable diseases but there has been an emergence of morbidity and mortality due to CVDs, which are now declining [11 14]. The increase in income has brought changes in food quality which are rich in energy—Western-type diet—and changes in lifestyle, characterized with use of automobiles, increase in occupational stress, alcoholism, tobacco consumption, and lack of physical activity have increased the changes of CVDs [11 14,27 30]. The food system transition has been associated with a marked increase in large chain supermarkets, which have displaced, fresh local food and farm shops resulting in a decreased availability of affordable fruits and vegetables directly sold by the farmers and increased the availability of highly processed foods, high-energy snacks, and sugary beverages [11 14]. Apart from changes in human dietary patterns, most parts of the world undergoing epidemiological transition have experienced a livestock revolution, characterized with increased production of beef, pork, dairy products, eggs,

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and poultry which is drastic in Asian countries [10 14,27 30]. The food and nutrition transition is also characterized with increased refinement of grain products. The whole grains are milled and processed to produce refined grains such as polished white rice and refined wheat flour which reduces the nutritional content of grains, including their fiber, micronutrients, and phytochemicals. Increased intake of these foods has been associated with increased risk of cardiometabolic diseases and other chronic diseases [7 14]. Industrialization and urbanization have also been associated with a greater consumption of pro-atherogenic foods during transition from lower social classes 4 5 (poverty) to higher social classes 1 3 [27 30]. The differences in diet and lifestyle can cause differences in the food and nutrient intake among rural and urban populations as well as among Asian and Western populations during the changeover from poverty to affluence [11 14,27 30]. A Western-type diet consumed by lower social classes in the developed countries and higher social classes in developing countries may be associated with marked reductions in the consumption of omega-3 fatty acids, vitamins, antioxidants, and amino acids and significant increases in the intake of carbohydrates (mainly refined), fat (saturated, trans fat, and linoleic acid), and salt compared to the Paleolithic period. The Nurses’ Health Study, included 88,520 women, aged 34 59 years, without previously diagnosed CAD, stroke, or diabetes in 1980, who were followed from 1980 to 2004. [30]. After 24 years of follow-up, we ascertained 3105 incident cases of CAD (nonfatal myocardial infarction and fatal CAD). After standard and dietary risk factors were adjusted for, the RRs (and 95% CIs) of CAD according to categories of cumulative average of SSB consumption (,1/mo, 1 4/mo, 2 6/wk, 1/d, and . or 5 2 servings/d) were 1.0, 0.96 (0.87, 1.06), 1.04 (0.95, 1.14), 1.23 (1.06, 1.43), and 1.35 (1.07, 1.69) (P for trend , 0.001). Regular consumption of sugar-sweetened beverages is associated with a higher risk of CAD in women. Artificially sweetened beverages were not associated with CAD [30]. Recently, a Diet and Health Study including general population from six states and two metropolitan areas in the United States and 16-year follow-up data involved 536,969 subjects, aged 50 71 years at baseline [15]. All-cause mortality (hazard ratio for highest versus lowest fifth 1.26, 95% confidence interval 1.23 to 1.29) and death due to nine different causes associated with red meat intake showed increased risk. All-cause and cause-specific mortality were also associated with increased intake of processed and unprocessed meats [15]. Heme iron and processed meat nitrate/nitrite were independently associated with increased risk of all-cause and cause-specific mortality. The highest fifth of white meat (poultry and fish) intake was associated with a 25% reduction in risk of all-cause mortality compared with the lowest intake level. Almost all causes of death showed an inverse association with white meat intake. It is possible that increased risks of all-cause mortality and death due to nine different causes associated with both processed and unprocessed red meat, accounted for, in part, by heme iron and nitrate/nitrite from processed meat. They also showed reduced risks associated with substituting white meat, particularly unprocessed white meat [15].

6.3.2 GLOBALIZATION OF PRUDENT DIETS AND PROTECTION FROM NCDs Functional foods, such as green leafy vegetables, are very rich sources of antioxidants, omega-3 fatty acids, vitamins (such as vitamins A, C, and K and folate), minerals (such as iron, magnesium, and calcium), and carotenoids appear to be high in the Mediterranean region [7 10]. The protective effects of prudent diets: Mediterranean type diets, Indo-Mediterranean diet, Japanese diet, and

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DASH diet, have been documented in several previous studies [1 3,22 26]. The World Health Organization and its experts clearly mentioned that eating 400 g/day of fruits, vegetables, and legumes can protect against NCDs [4,5]. Other experts from Asia and Europe also observed that increased supplementation of functional foods can decrease the risk of NCDs [23 26]. South Korea has had innovative interventions for promoting increased intake of functional foods to prevent NCDs [23]. The trend of pursuing healthy foods already began in the mid-1980s when NCDs became a major health concern in South Korea. This trend reflects efforts to solve health problems by improving dietary patterns by the health professionals and governments. The traditional Korean diet is low in fat and high in vegetables and the government has put a lot of effort into advertising and teaching the public that the traditional Korean diet is healthy and that adoption of Western eating habits may predispose to obesity and metabolic syndrome [23]. Most of the experts in Korea and Japan are working on the revival of the traditional diet using an approach that is acceptable to the contemporary citizens, e.g., publishing traditional recipes with slight modifications [23]. This approach is also advertised in other Asian countries but only to little success, due to aggressive advertising by multinational companies [1 3]. The North Karelia Project that was carried out in Eastern Finland was able to produce favorable changes in diet under the supervision of health professionals [24 26]. The proportions of saturated fats, salt, and sugar were decreased while the proportion of unsaturated fats and vegetable consumption increased, indicating a choice for functional foods [24 26]. However, it may be due to mass media and community involvement together with changes in legislation which were the main tools in this intervention that influenced the dietary habits of the whole Finnish population. Pietinen et al. estimated that between 1972 and 1992 a major decrease in total serum cholesterol (1 mmol/L on average) took place because of changes in the diet from Western foods to functional foods, vegetable, poultry, and sea foods [26]. In 2012, 702,308 cardiometabolic deaths occurred in US adults, including 506,100 from heart disease (371,266 CAD, 35,019 hypertensive heart disease, and 99,815 other CVDs); 128,294 from stroke (16,125 ischemic, 32,591 hemorrhagic, and 79,578 other); and 67,914 from type 2 diabetes [31]. High sodium (66,508 deaths in 2012; 9.5% of all cardiometabolic deaths) was associated with largest number of cardiometabolic deaths, low nuts/seeds (59,374; 8.5%), high processed meats (57,766; 8.2%), low seafood omega-3 fats (54,626; 7.8%), low vegetables (53,410; 7.6%), low fruits (52,547; 7.5%), and high SSBs (51,694; 7.4%). Between 2002 and 2012, population-adjusted US cardiometabolic deaths per year decreased by 26.5%. The greatest decline was associated with insufficient polyunsaturated fats (220.8% relative change; 95% UI, 218.5% to 222.8%), nuts/ seeds (218.0%; 95% UI, 214.6% to 221.0%), and excess SSBs (214.5%; 95% UI, 212.0% to 216.9%). The greatest increase was associated with unprocessed red meats (114.4%; 95% UI, 9.1% 19.5%). It is possible that dietary factors were estimated to be associated with a substantial proportion of deaths from heart disease, stroke, and type 2 diabetes [31]. Increased intake of nuts, fruits, vegetables, sea food, omega 3 fatty acids, and lower intake of salt without processed meat may be protective against these deaths. In an Indian study, death records of 2222 (1385 men and 837 women) decedents, aged between 25 and 64 years, were studied [32]. The findings showed that sedentary behavior, excess salt intake, and other typical Western dietary habits were significantly more common among decedents belonging to higher social classes 1 3, compared to those within lower social classes 4 and 5 (Fig. 6.4). Lack of knowledge regarding health education was significantly more common among decedents in lower social classes, who died more often due to communicable diseases. The study also revealed that deaths associated with diabetes mellitus and due to

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g/day 400 300 200 100 0

e, s il d s s, , ric ber eo cur nut ble eat lets h d tu nd oliv eta pea / a n g W mil a d g e k r n v es Mil ots sta udi its, and Ro Mu ncl Fru legum ts i u N and

g/day

Male Female

200 150 100 50 0

ds

foo

ter, f but Re d e i fa t rif Cla trans and d ine

ter, but W

ich -6 r

oils M

an eat

ggs de

t Sal

FIGURE 6.4 Food consumption pattern among subjects dying due to various causes of deaths. Modified from Singh R.B., Visen P., Sharma D., Sharma S., Mondol R., Sharma J.P., et al., Study of functional foods consumption patterns among decedents dying due to various causes of death. Open Nutra J 2015;8:16 28.

circulatory diseases were significantly more common among higher social classes 1 3, compared to lower social classes 4 and 5. However, deaths due to malignant diseases and chronic lung diseases were not associated with social class (except the social class of women with breast cancer), but total proportion of deaths due to NCDs including these causes were significantly greater among higher social classes 1 3, compared to lower social classes 4 and 5. The findings indicate that sedentary behavior, typical Western diet, and excessive salt intake, in conjunction with underlying lack of health education, may be the predisposing factors for deaths among decedents of higher social classes 1 3. Functional food intake was inversely associated with risk of deaths due to NCDs [32]. Clinical evidence on the role of Mediterranean style diets as functional food is very strong because, such diets are known to reduce all-cause mortality. The EPIC-NL Study is a cohort of 40,011 subjects with a follow-up of 10 15 years [33]. The Mediterranean diet included daily intakes of vegetables, fruits, legumes and nuts, grains, fish, fatty acids, meat, dairy, and alcohol (wine and beer). Among 34,708 participants free of CVD at baseline, 4881 CVD events occurred, and 487 persons died from CVD. Increased intake of Mediterranean diet by two-units (range 0 9) was inversely associated with fatal CVD (HR: 0.78; 95% CI: 0.69 0.88), total CVD (HR: 0.95

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(0.91 0.98)), myocardial infarction, stroke and pulmonary embolism [33]. It is clear that a better adherence to a Mediterranean-style diet was more strongly associated with fatal CVD than with total CVD. The associations were strongest for incident myocardial infarction, stroke, and pulmonary embolism. Effects of fruit and vegetable intake on incidence of CAD was examined in a metaanalysis among 278,459 subjects with 9143 CAD events during a median follow-up of 11 years [34]. Among subjects consuming more than five servings/day of fruit and vegetables, the pooled RR of CAD was significantly greater when compared with the subjects consuming less than three servings/day, (P 5 .0001 vs .06). This meta-analysis reported that increased consumption of fruit and vegetables, from less than three to more than five servings/day is related to a 17% reduction, whereas increased intake to three to five servings/day is associated with a smaller and borderline significant reduction in CAD risk [34]. These results provide strong evidence supporting that five or more servings per day of fruit and vegetables can provide substantial protection from CVDs. A large cohort study, involving 72,113 female nurses who were free of CAD, stroke, diabetes, and cancer, examined the association of dietary pattern with risk of NCDs [35]. During a follow-up of 18 years, 6011 deaths occurred (3319 (52%) as a result of cancer; 1154 (19%) resulting from CVDs; and 1718 (29%) resulting from other causes. There was a 17% lower risk of total mortality among those who were most adherent to the prudent diet (highest versus lowest quintile of adherence), a 28% lower risk of CVD mortality, and 30% lower mortality from non-CVD, noncancer causes. Cancer was not associated with the inverse prudent dietary pattern. A comparison of the highest and lowest quintiles of adherence showed that consumption of the Western diet was associated with increased total mortality (21%), CVD mortality (22%), cancer mortality (16%), and mortality from non-CVD, noncancer causes (31%). Hence, except for cancer, risk relationships for the prudent and Western dietary patterns appear to be the inverse of each other: mortality thus was increased as adherence to the prudent diet decreased and adherence to the Western diet increased [35]. The INTERHEART Study examined the relationship between dietary patterns and risk of acute coronary syndrome (ACS) in a standardized case-control study, involving participants from 52 countries. [36]. Using the principle-component analysis technique, the authors identified three major dietary patterns: Oriental (high intake of tofu and soy and other sauces); Western (high in fried foods, salty snacks, eggs, and meat); and prudent (high in fruit and vegetables). Consistent with previous studies in single within-population cohort studies, the authors found an inverse association between the prudent pattern score and risk of ACS and a significant positive association between the Western pattern score and increased risk of ACS. The Oriental pattern was not significantly associated with risk. The investigators constructed a dietary risk score based on seven food items on the food-frequency questionnaire (meat, salty snacks, fried foods, fruits, green leafy vegetables, cooked vegetables, and other raw vegetables) and found that a higher score (indicating a poor diet) was strongly associated with ACS risk: Those in the highest quartile of the score had nearly twofold increased risk, even after adjustment for established coronary risk factors. In sensitivity analyses, the investigators found a consistent association for the composite diet score between men and women and across different regions of the world (North America, Western Europe, Australia, Central Europe, Middle East, Africa, South Asia, Southeast Asia, China, and South America). On the basis of an arbitrary cut point of the score (top three quartiles versus the bottom quartile), the investigators estimated that 30% of MI could be explained by unhealthy diets worldwide [36]. Although Western-style changes in food patterns are widely believed to adversely

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influence risk of chronic diseases, few epidemiological studies have directly linked dietary patterns and mortality from coronary heart disease. The INTERHEART study is the first large study to quantify eating patterns in all geographic regions of the world. It provides evidence that despite different food habits in various populations, reproducible patterns can be found in diverse regions of the world. These findings are important because there has been a concern that dietary patterns derived through a data-driven approach such as principle-component analysis may be highly unstable and nonreproducible because of very different eating habits in different populations. The PREDIMED study, prospectively examined 1868 participants free of metabolic syndrome at baseline, in which 930 incident cases of metabolic syndrome were documented during a median follow-up of 3.24 years [37]. Increased consumption of .5 servings/wk of sugar sweetened beverages was compared with consumption of ,1 serving/wk, while all subjects were consuming Mediterranean style diets. The consumption of .5 servings/wk of all of the types of beverages analyzed was associated with an increased risk of metabolic syndrome and some of its components [37]. However, for sugar-sweetened beverages and bottled fruit juices these associations must be interpreted with caution because of the low frequency of consumption in this population. The occasional intake of sugar-sweetened beverages and an artificially sweetened beverage (1 5 servings/ wk) was not associated with the high risk of metabolic syndrome in middle-aged and elderly individuals at high risk of CVD. It is clear that despite Mediterranean diets, excess consumption of sugar-sweetened products may have adverse effects. Total and cause-specific mortality among 47,994 women in the Nurses’ Health Study and 25,745 men in the Health Professionals Follow-up Study from 1998 through 2010 were examined in relation to changes in diet quality over the preceding 12 years (1986 98) [17]. Dietary intakes were assessed with the use of the Alternate Healthy Eating Index 2010 score, the Alternate Mediterranean Diet score, and the Dietary Approaches to Stop Hypertension (DASH) diet score. The greatest improvement in diet quality (13% to 33% improvement), as compared with those who had a relatively stable diet quality (0% to 3% improvement), in the 12-year period were the following: 0.91 (95% CI%, 0.85 to 0.97) according to changes in the Alternate Healthy Eating Index score, 0.84 (95 CI%, 0.78 to 0.91) according to changes in the Alternate Mediterranean Diet score, and 0.89 (95% CI, 0.84 to 0.95) according to changes in the DASH score [17]. An improved quality of diet was significantly associated with a reduction in total mortality of 8% to 17% with the use of the three diet indexes and a 7% to 15% reduction in the risk of death from CVDs with the use of the Alternate Healthy Eating Index and Alternate Mediterranean Diet. The risk of death from any cause was significantly lower—by 14% (95% CI, 8 to 19) when assessed with the Alternate Healthy Eating Index score, 11% (95% CI, 5 to 18) when assessed with the Alternate Mediterranean Diet score, and 9% (95% CI, 2 to 15) when assessed with the DASH score—than the risk among participants with consistently low diet scores over time [17]. During the follow-up of 12 years, it was clear that improvement in diet quality was consistently associated with a decreased risk of death. The Global Burden of Diseases Study examined global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, from 1990 to 2013 [16]. Vegetable, fruit, fish, omega-3 fatty acids, fibre, nuts and seeds, and whole grain intakes were inversely associated with mortality. Increased intake of salt, processed meat, trans fat, high alcohol intake were positively associated with mortality in 10 high populous countries [16]. A recent study has demonstrated that nutritional management of blood glucose levels is a strategic target in the prevention and management of type 2 diabetes mellitus [10]. The population

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and the people should be health educated to implement such an approach, because it is essential to understand the effect of food on glycemic regulation for prevention of hyperglycemia. The results from human dietary interventions exploring the impact of dietary components and food consumption patterns, on blood glucose levels are important for prevention of adverse effects of glycemia. Major macronutrients—carbohydrate, protein and fat—micronutrient vitamins and minerals, nonnutrient phytochemicals, and additional foods including low-calorie sweeteners, vinegar, and alcohol can influence blood glucose levels [10]. These dietary components from functional foods have significant and clinically relevant effects on blood glucose modulation. Reduction in excess body weight, increased physical activity along with a functional food dietary regime to regulate blood glucose levels will not only be advantages in the management of diabetes, but will benefit the health of the population and limit the increasing worldwide incidence of diabetes and its cardiovascular complications [10]. Recently, dietary-patterning analysis has been increasingly used as an alternative method to traditional single-nutrient analysis because it can assess cumulative effects of the package of nutrients in the diet [31 37]. Habitual food consumption patterns are typically quantified by statistical methods such as factor or cluster analysis or diet-quality indexes based on prevailing dietary recommendations or healthy traditional diets, e.g., the Mediterranean style diet, and Indo-Mediterranean diet. Principle-component analysis is commonly used to define dietary patterns using food consumption information to identify common underlying dimensions (factors or patterns) of food intake. The method aggregates of specific food items based on the grading, to which these food items are correlated with each other. A summary score for each pattern is then derived and can be used to examine relationships between various eating patterns and outcomes of interest such as CAD and other chronic diseases. Previous validation studies found that two major patterns (the prudent and Western patterns) identified through principle-component analysis of food consumption data assessed by food frequency questionnaires were reproducible over time and correlated reasonably well with the patterns identified from diet records. In the countries with high income, lower social classes (3 and 4) have poor health behavior and have greater risk factors towards cancer and CVD mortality, as well as have higher chance of all-cause mortality than upper social classes [15 17,27 30]. In the developed countries, the higher social classes 1 and 2 to have greater access to health education, devote more time for physical activity, and have additional resources to maintain prudent diets in comparison to that of lower social classes. However, the in the developing countries the situation is just opposite for lower social class 3 5, who live with scarcity of foods and irregular employment [28 30]. Physically demanding occupations are more common in developing countries, but they hardly exist in developed countries, where they have only social classes 1 4 [18 21,31 38]. In the developing societies, it seems that the urban populations have a double burden of diseases, related to overeating as well as malnutrition because the occupational physical activity has decreased along with change in social class [27 30]. The above global nutritional dynamics has been accepted by the experts who have also agreed that the world is shifting rapidly toward a diet linked with NCDs [3] (Table 6.1, Fig. 6.1). In view of the technological advancements, humans have to live in a nutritional environment which completely differs from that for which our genetic constitution was selected, hence randomized, controlled trials are necessary to provide proof that Mediterranean-style diets are effective in the prevention of NCDs [19 30].

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6.4 RANDOMIZED, CONTROLLED TRIALS WITH MEDITERRANEAN-STYLE DIETS In a previous randomized, controlled trial, the experimental group received a significantly greater amount of fruits, vegetables and whole grains, nuts and mustard oil and a lower amount of refined bread, biscuits and sugar, and butter and clarified butter compared to control diet group at 1 and 2 years of follow-up [39,40] (Tables 6.3 6.5). Paleolithic-style diet and prudent diet had significant total adherence score in both the groups. Omega-6/Omega-3 fatty acid ratio was brought down to a significantly lower content in the Paleolithic style diet group A (n 5 204), compared to control group diet B (n 5 202) at entry to the study (3.5 6 0.76 vs 24.0 6 2.4 KJ/day, P , .001) as compared to that of the entry level, which was much higher (32.5 6 3.3). Even after 1 year of followup, the fatty acid ratio remained significantly much lower in the experimental group compared to the control group (4.4 6 0.56 vs 22.3 6 2.1 KJ/day, P , .001). After the follow-up of 2 years, the total mortality in the Paleolithic-style diet group was 14.7% as compared to the control group which had mortality of 25.2% (Table 6.5). The association of omega-6/omega-3 ratio of fatty acids with the mortality showed a gradient in both the groups independently, as well as among total number of deaths. The lower omega-6/omega-3 ratio of fatty acids (between 1 and 10) was significantly

Table 6.3 Effect of ω-3 Fatty Acid Rich Paleolithic Style Diet in Patients With Acute Myocardial Infarction Foods and nutrients Fruits and vegetables (g. day-1) Potato, radish, Legumes and pulses (g. Day-1) Almonds and walnuts (g. Day-1) Fish (g. Day-1) Chicken (g. Day-1) Mustard or soybean oil Butter or clarified butter (g. Day-1) Skim milk (mL day-1) Wheat chapatti Bread, biscuits (g. Day-1) Rice and wheat cereals (g. Day-1) Honey or raisins (g. Day-1) Sugar (g. Day-1) Total Adherence score (%) Total foods,

Paleolithic-Style Diet Group (n 5 204)

Standard Diet Group (n 5 202)

4 7 days 508.4(28.66) 60.5(6.8) 80.5(6.6)  82.4(5.7)  52.5(6.5) 

4 7 days 254.4(17.2) 72.0(12.5) 52.5(4.6)

After 1 years 220.5(19.6) 155.6(32.5) 45.6(5.6)

20.2(3.1) 76.2(6.5) 10.5(2.3) 10.5(2.6) 150.2(8.0) 50.6(6.6) 230.6(20.1) 30.2(3.1)

10.5(3.5) 66.5(10.5) 6.8(2.8) 12.6(3.5) 165.5(16.1) 55.6(7.8) 212.2(18.1) 35.6(4.8)

25.5(5.4) 123.0(30.0) 983.4(213)

30.5(7.6) 71.0(30.0) 862(204)

18.4(3.9) 2.5(0.6)  161.2(12.0) 5.5(1.6)  10.6(2.2) 25.6(2.4) 2.6(0.8) 16.4(3.7) 65.2(17.2) 1027(232)



After 1 years 575(91.4)  115(12.7)  95.0(8.9)  75.5(5.2)  22.4(4.1)  10.2(3.2) 31.5(5.5)  3.3(0.71) 152(14.5) 30.6(5.5) 25.5(6.2)  30.6(5.5) 5.5(1.2) 12.6(3.4) 63.9(14.8) 1184.6(254)

P values for mean (standard deviation) were obtained by comparison of intervention and control groups after 1 week, and after 1 year.  P , .05,  P , .01, Singh et al. [45] their Ref. [40].

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CHAPTER 6 GLOBALIZATION OF DIETS AND RISK

Table 6.4 Fatty Acid Consumption in the Paleolithic Style Diet Group and Standard Diet Group Fatty acid KJ/day Saturated Monounsaturated Polyunsaturated Omega-6 Omega-3 Omega-6/Omega-3 ratio Main dietary oil

Before Entry

At Entry

All patients (n 5 406) 10.0 (0.39) 9.3(0.38) 6.7 (0.30) 6.5(0.29) 0.2(0.07) 32.5(3.3)

Paleolithic (n 5 204) 7.0(0.22) 9.5(0.37) 8.1(0.44) 6.3(0.28) 1.8(0.13) 3.5(0.76)

Standard (n 5 202) 10.0(0.38) 7.6(0.26) 6.5(0.39) 6.3(0.29) 0.2(0.082) 31.5(2.4)

Paleolithic (n 5 204) 7.2(0.24) 8.0(0.35) 8.6(0.39) 7.0(0.36) 1.6(0.12) 4.4(0.56)

Standard (n 5 202) 10.8(0.36) 10.2(0.32) 7.0(0.26) 6.2(0.24) 0. 3(0.083) 20.6(2.1)

Peanut

Mustard

Sunflower

Mustard

Sunflower

Values are mean 6 Standard deviation



After 1 Year

P , .01, Singh et al 2012 [45], their Ref. [40].

Table 6.5 Numbers and Rate Ratios for End Points in the Paleolithic Style Diet Group and Standard Diet Group After 2 Years of Follow Up Events Total Cardiac mortality Fatal myocardial infarction Sudden cardiac death Total cardiovascular mortality Total mortality 

Paleolithic-Style Diet (n 5 204)

Control Diet (n 5 202)

Adjusted Rate Ratio (95% Confidence Interval)

27(13.2)

45(22.3)

0.59(0.52 0.67)

18(8.8)

27(13.3)

0.66(0.61—0.73)

9(4.4) 30(14.7)

18(8.9) 50(24.7)

0.50(o.38 0.73) 0.50(0.42 0.59)

30(14.7)

51(25.2)

0.59(0.51 0.67)



Values are number (%), P , .001, P , .01, Singh et al., 2012, [45] Total deaths; adjustment made for base line age, gender, body mass index, cholesterol and blood pressure.

and positively related to lower mortality rate, whereas an increase in omega-6/omega-3 fatty acid ratio above 10 was directly related to greater mortality (Fig. 6.5, Tables 6.3 6.5). The role of a low omega-6/omega-3 ratio Paleolithic-type of diet by increasing omega-3 and by decreasing omega-6 fatty acid in the Paleolithic-style diet can cause significant decline in cardiovascular and all-cause mortality (Fig. 6.5). Since ACSs and sudden cardiac death are more common in the morning in association with large meals, it would be pertinent to take breakfast comprising of 500 Kcal of functional foods in the morning to get maximum benefit of functional nutrients and to boost up the metabolism in the morning. As advised by Halberg et al., there will be no increase in the body weight by consuming 500 Kcal in the morning as compared to the same amount of energy in the

6.4 RANDOMIZED, CONTROLLED TRIALS

103

FIGURE 6.5 Effect of low omega-6/omega-3 fatty acid ratio diet on mortality (Ref. [35], Singh et al.).

evening [42,43]. Brain, liver, and heart connections are highly influenced by diet which may lead to NCDs [51,52]. However, diet rich in omega-3 and flavonoids such as that are found in IndoMediterranean diet which are also high in other nitric oxide activating foods may be protective against CVDs as well as other NCDs [39 44]. Mediterranean-style diets have been found to reduce cardiovascular events and all-cause mortality significantly in almost all the clinical trials conducted [44 52]. These studies indicate that the approach to functional food security by the WHO and FAO may be useful in the prevention of NCDs [53 55]. Recently, associations of fats and carbohydrate intake with CVDs and mortality in 18 countries from five continents (PURE) were reported in a prospective cohort study, indicating that total and saturated fat intake were safer compared to carbohydrates [57]. There are serious issues with the use of dietary data from the PURE study assessed by food frequency questionnaires by different sets of dietitians in different countries. It is established that complex carbohydrates such as those from pulses, whole grains, vegetables and fruits can decrease cardiometabolic diseases and mortality whereas refined carbohydrates are detrimental to health [31,58 60]. Providing only carbohydrate intake as a percentage of total energy is inadequate; measures of the quality of carbohydrates must also be considered. Fiber content, starch digestibility, and the amount of added sugar all provide important information when relating carbohydrate intake to disease or mortality incidence. The Food Frequency Questionnaires used in the PURE study ranged from 95 to 250 questions, which should be of sufficient detail to comment on multiple markers of carbohydrate quality or type (refined vs whole grains) as well as fatty acid quality. Without measuring quality of carbohydrates and fatty acids, it undermines the results from the PURE study. It seems the refrees assessing this paper and the concerned editor were not very serious in assessing the risk due to types of carbohydrates and fatty acids. It is established that omega-3 fatty acids, monounsaturated fatty acids esteric acids are protective against mortality whereas increased intake of saturated fat and omega-6 fat, particularly, when these fatty acids are oxidized, have detrimental effects on health [31,58 60]. In brief, during the transition phase from poverty to economic development, food consumption patterns and health behavior have changed significantly in various populations.

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However, in the last 100 160 years, the nutritional transition causing increased intake of SFA, trans fat, refined carbohydrates, and linoleic acid, has been quite rapid as compared to earlier. During this period there has been a decrease in the intake of omega-3 fatty acids and flavonoids, and an increase in meat from domesticated grain-fed cattle, rather than meat from running animals, which is resulting in a marked increase in morbidity and mortality due to CVDs. In the last century, the population characteristics have rapidly changed with dietary intakes, which, in conjunction with sedentary behavior, appears to be the main causes of poor mental, social, and spiritual health, as well as of hyperglycemia, hyperlipidemia, oxidative stress, and inflammation, which are very important mechanisms in the pathogenesis and prevention of diet-related CVDs [40 45,53 56]. It seems that through education and indoctrination, and a cultural change by taking heed of dietary advice, an intervention/prevention of NCDs could be achieved leading to healthier outcomes for each generation, a reduced health burden to individual and state, and even a world unification on this issue.

ACKNOWLEDGMENTS The International College of Nutrition and International College of Cardiology are thanked for supporting this study.

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[45] de Lorgeril M, Renaud S, Mamelle N, Salen P, Martin JL, Monjaud I, et al. Mediterranean alphalinolenic acid-rich diet in secondary prevention of coronary heart disease. Lancet 1994;343 (8911):1454 9. Erratum in: Lancet 1995,345 (8951):738. [46] De Lorgeril M, Salen P, Martin JL, Monjaud I, Delaye J, Mamelle N. Mediterranean diet, traditional risk factors and the rate of cardiovascular complications after myocardial infarction Final report of the Lyon Diet Heart Study. Circulation 1999;99:779 85. [47] Sofi F, Abbate R, Gensini GF, Casini A. Accruing evidence about benefits of adherence to Mediterranean diet on health: an updated systematic review with meta-analysis. Am J Clin Nutr 2010;92 (5):1189 96. [48] Salas-Salvado´ J, Fern´andez-Ballart J, Ros E, Martı´nez-Gonz´alez MA, Fito´ M, Estruch R, et al. PREDIMED Study Investigators. Effect of a Mediterranean diet supplemented with nuts on metabolic syndrome status: one-year results of the PREDIMED randomized trial. Arch Intern Med. 2008;168 (22):2449 58. Available from: https://doi.org/10.1001/archinte.168.22.2449. [49] Salas-Salvado´ J, Bullo´ M, Babio N, et al. For the PREDIMED Study Investigators. Reduction in the incidence of type 2 diabetes with the Mediterranean diet. Diabetes Care 2011;34:14 19. [50] Esposito K, Maiorino MI, Ciotola M, DiPalo C, Scognamiglio P, Gicchino M, et al. 11: effects of a Mediterranean-style diet on the need for anti-hyperglycemic drug therapy in patients with newly diagnosed type 2 diabetes: a randomized trial. Ann Intern Med 2009;151:306 14. [51] Singh RB, Niaz MA, Sharma JP, Kumar R, Rastogi V, Moshiri M. Randomized, double-blind, placebocontrolled trial of fish oil and mustard oil in patients with suspected acute myocardial infarction: the Indian experiment of infarct survival—4. Cardiovasc Drugs Ther. 1997;11 485 449. [52] Esposito K, Marfella R, Ciotola M, Di Palo C, Giugliano F, Giugliano G, et al. Effect of a Mediterranean-style diet on endothelial dysfunction and markers of vascular inflammation in the metabolic syndrome: a randomized trial. JAMA 2004;292(12):1440 6. [53] FAO UNO. The State of Food and Agriculture: Sustainable Food Systems for Food Security and Nutrition http://www.fao.org/ docrep/ meeting/ 028/mg413e01.pdf, accessed 2017. [54] Singh RB, Takahashi T, Shastun S, Elkilany G, Hristova K, Shehab A, et al. The Concept of Functional Foods and Functional Farming (4 F) in the Prevention of Cardiovascular Diseases: a review of goals from 18th World Congress of Clinical Nutrition. J Cardiol Therapy 2015;2(4):341 4. [55] Mishra S, Singh RB. Physiological and biochemical significance of genetically modified foods, an overview. Open Nutra J 2013;6:18 26. [56] Hristova K, Nakaoka T, Otsuka K, Fedacko J, Singh R, Singh RB, et al. Perspectives on chocolate consumption and risk of cardiovascular diseases and cognitive function. Open Nutraceut J 2012;5:207 12. [57] Dehghan M, Mente A, Zhang X, et al. Associations of fats and carbohydrate intake with cardiovascular disease and mortality in 18 countries from five continents (PURE): a prospective cohort study. Lancet. 2017;390:2050 62. [58] Reynolds AN. Associations of fats and carbohydrates with cardiovascular disease and mortality—PURE and simple? Lancet 2018;391:1676. [59] Singh RB, Shastun S, Chibisov S, Itharat A, De Meester F, Wilson DW, et al. Functional food security and the heart. J Cardiol Ther 2016;3(6):1 8. Available from: http://www.ghrnet.org/index.php/jct/ article/view/1858. [60] Fedacko J, Singh RB, Niaz MA, Bhardwaj K, Verma N, Gupta AK, et al. Association of coronary protective factors among patients with acute coronary syndromes. J Cardiol Ther 2016;4(5):671 7. Available from: http://www.ghrnet.org/index.php/jct/article/view/2027.

CHAPTER

A REVIEW ON THE NUTRITIONAL CHALLENGES OF SCHOOL CHILDREN FROM THE PERSPECTIVE DEVELOPING COUNTRIES

7

Ratnabali Sengupta1, Narayan Ghorai1, Saikat K. Basu2, Peiman Zandi3 and William Cetzal-Ix4 1

Department of Zoology, WB State University, Kolkata, West Bengal, India 2Department of Biological Sciences, University of Lethbridge, Lethbridge AB, Canada 3Institute of Environment and Sustainable Development in ´ Agriculture, Chinese Academy of Agricultural Sciences, Beijing, P.R. China 4Instituto Tecnolo´gico de China, ´ Campeche, Mexico

LIST OF ABBREVIATIONS BMI BMIZ BP CHDs CI CVDs DBP FAO GHI HAZ HC IFPRI ISAK MAP NFHS NNMB PCI SBP SD SE class SES WAZ

basal metabolic rate z score for BMI for age blood pressure coronary heart diseases conicity index cardiovascular diseases diastolic blood pressure Food and Agricultural Organization global hunger index z score for height for age hip circumference International Food Policy Research Institute International Society for the Advancement of Kinanthropometry mean arterial pressure National Family Health Survey National Nutrition Monitoring Bureau per capita income systolic blood pressure standard deviation socioeconomic class socioeconomic status z score for weight for age

The Role of Functional Food Security In Global Health. DOI: https://doi.org/10.1016/B978-0-12-813148-0.00007-4 © 2019 Elsevier Inc. All rights reserved.

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WB WC WHO WHR WHtR

West Bengal Waist circumference World Health Organization Waist
hip ratio Waist
height ratio

7.1 INTRODUCTION The nutritional status of the present generation is very important to assess their standard of living. A healthy diet is essential for human welfare and is well accepted in growth and development literature. The following chapter reviews the focus on the international nutritional goals, nutritional epidemiology, nutritional status, and its effect on growing age children and adolescents.

7.2 THE MILLENNIUM DEVELOPMENT GOALS In the Millennium summit of UN 2000, eight international development goals for the year 2015 were adopted—known as millennium development goals (MDGs). The partners for that venture were 189 United Nations member states and 22 international organizations, who were approached to mitigate those eight goals by 2015. The vital issues of the MDGs included eradication of extreme poverty and hunger, gender inequality by promoting women empowerment, reduction of child mortality, improvement of maternal health, and prevention of diseases like malaria and AIDS. They also aimed to ensure environmental sustainability to develop a global partnership.

7.3 THE GLOBAL HUNGER INDEX The global hunger index (GHI) is a statistical tool used to analyze and describe the hunger situation of a country or state, updated every year. This Index was developed by the International Food Policy Research Institute (IFPRI) [1]. In 2000, IFPRI ranked India 83 out of 115 countries with a GHI of 36.2. During September 2010, a UN conference had reviewed the progress of MDGs where IFPRI ranked India 63rd with a GHI of 21.3 [1]. The conference adopted a global plan to achieve the eight goals by 2015. New targets were women and children’s health, and to fight against poverty, hunger, and disease. As of 2013, progress towards the said goals was irregular. Some countries accomplished several goals, while others were totally off the track. Overall, GHI levels are down by 29% as compared to 2000. There is a remarkable improvement in child stunting as compared with past years, but the proportion of undernourished people only declined marginally from 17% to current 15% (Table 7.1).

7.5 NUTRITIONAL EPIDEMIOLOGY, AIM, CLASSIFICATION, AND METHODS

111

Table 7.1 Present Nutritional Status of India and Its Neighboring Countries Rank

Name of the Country

GHI

% of Malnutrition

29 72 75 84 90 97 107

China Nepal Myanmar Sri Lanka Bangladesh India Pakistan

7.7 21.9 22 25.5 27.1 28.5 33.4

8.8 7.8 14.2 22 16.4 15.2 22

Overall, GHI levels are down by 29% as compared to 2000. There is a remarkable improvement in child stunting as compared with past years, but the proportion of undernourished people only declined marginally from 17% to current 15% (Table 2.1) [1].

7.4 SOUTH ASIAN ENIGMA South Asia contributed the maximum number of hungry people in the world, just behind Caribbean and Sub-Saharan Africa respectively. Africa. Social inequality and low nutritional status of women were the main causes of child undernutrition in the south Asia region. China improved its ranking by 27.69% from 1999 to 2012 while India, over the same period, showed improvement of only 34%. In comparison to that, Brazil exhibited a better score over 5 years (2012
16). Countries that made substantial improvements are Venezuela, Mexico, Cuba, Ghana, Thailand, and Vietnam. There is a sluggish rate of improvement of undernutrition in most of the south Asian countries, popularly known as South Asian Enigma [2,3]. Studies provided the rate of undernutrition (67% on average) among rural boys across nine states of India [4]. Surprisingly, its neighboring country Bangladesh showed a much lower rate of undernutrition (44%) and rate of stunted rural children, from 61.4% (1997) to 41.4% (2011), which reflect a reduction of undernutrition [3]. The potential causes of that improvement may be parental education, birth order, birth interval, vaccination, better sanitation, and stoppage of open defecation [2]. The rate of undernutrition in Nepali refugees is 34% [5]. This rate is as low as 23% in rural African adolescents as reported by Phinney [6] and as high as in two Kenyan reports—61% [6] and 57% [5], respectively. Kenyan refugees exhibited a higher rate of undernutrition (75%) as reported by an International Rescue committee 1997 [7]. The main causes for African undernutrition are poverty, food insecurity, illiteracy, ignorance, poor sanitation, big family sizes, and government policy and corruption. Also, the face of malnutrition is female. Inspite of the target of reducing of hunger by 50% according to the MDG, among the world’s 800 million people, over 204 million are from sub-Saharan Africa [8].

7.5 NUTRITIONAL EPIDEMIOLOGY, AIM, CLASSIFICATION, AND METHODS 7.5.1 OVERVIEW Health research and policy formulation begins with a study among any population to get a panoramic view of their nutritional situation [9,10]. To enquire scientifically, the study methods are

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Table 7.2 Classification of Epidemiological Studies [39] 1. Observational designs

2. Experimental studies

a. Case reports and case series b. Ecologic studies c. Cross-sectional studies d. Cohort studies e. Case control studies Controlled and uncontrolled trials

broadly categorized into qualitative and quantitative; where qualitative methods provides an understanding and quantitative ones give reproducible and measurable evidences [11]. Here, nutritional tools focus on the health status of the population. All the studies between nutrition and health are collectively known as nutritional epidemiology [12] (Table 7.2).

7.5.2 AIM As stated by Rothman et al. [13], the principle aim of epidemiology is to identify the cause of a disease and the relevant risk factors, establishing the cause
effect relationship between the risk factors and health events. The stronger the association between the cause and the effect, the higher the probability of a causal relation between the exposure and the outcome existing.

7.5.3 CROSS SECTIONAL STUDIES Those studies collect information about specific health events and their outcomes in an individual or population [13] permitting the testing of a hypothesis. The surveys are done by National health departments, e.g., National Family and Health Survey (NFHS) and National Nutrition Monitoring Bureau (NNMB) in India [14,15].

7.5.3.1 Steps of Cross-Sectional Studies • • • • • •

Defining a target population Conducting literature reviews on subject(s) Determining the study objectives and methodology Sampling of the study population Developing the study tools for collection of data Analysis of data and interpretation of results.

7.5.4 NUTRITIONAL EPIDEMIOLOGIES: METHODS TO MEASURE The selections of appropriate nutritional assessment methods are the following: 1. Anthropometric Assessment
measurement of physical dimensions of the body Many anthropometric measurements are now being used to a varying extent in nutritional surveys. Jelliffe and Jelliffe [16] and Mahgoub [17] discussed the so-called age-independent

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measurements. They concluded that such measurements are not strictly independent of age; they “do not need knowledge of exact age to the month or week, but do require approximate age categorization.” From this point of view of classification it is evident that there can be no age-independent measure of retardation, because retardation actually refers to the relation between a given value and age. Secondly, no single measurement can give an age-independent evaluation of malnutrition, in the sense in which the term is defined above, because all bodily measurements alter with age. However, probably valid age-independent measures can be acquired by ratios of two measurements other than age; weight for height is the most evident instance [18]. An index which may be of practical use, particularly in emergency situations, is the ratio of mid-upper-arm circumference (MUAC) to height [19]. Essentially this gives the same information as weight for height, since a thin person tends to have a thin arm, but it is less sensitive and accurate. But this is age limited; gives information up to age 10 [20]. BMI is the best indicator of a subject’s nutritional status to date. Along with BMI, WC is a good indicator of fatness and health risk for children [21]. Waist
hip ratio (WHR), Waist
height ratio (WHtR) [22], and Conicity index (CI) [23] are also good predictors to assess chance of obesity in young ages, which is highly associated to adult obesity. The blood pressure (BP) is also a good indicator of cardiovascular diseases (CVDs) and hypertension [24]. Those methods are used to assess from moderate to severe [25] and acute to chronic malnutrition. These are also inexpensive and reproducible. The major indices are: height, weight, waist circumference (WC), and hip circumference (HC). Those indicators can be combined and interpreted for indices like BMI, height for age, weight for age, height for weight, WHR, WHtR, and CI [14,25]. Anthropometry is mainly significant during adolescence because it permits the supervising and assessment of the hormone-intervened changes in growth and maturation during this period [26,27]. 2. Biochemical assessment: provides nutritional status that reflects the long-term effect of growth and body composition. 3. Clinical assessment: includes clinical signs of deficiency. 4. Dietary assessment: provides information about foods obtained, nutrient intake calculated.

7.6 CLASSIFICATION OF NUTRITIONAL STATUS The relationship between nutrition and child health is a controversial issue and matter of extensive research. Malnutrition results in death in roughly 55% of 1- to 4-year-olds [28] per year. Anthropometric indicators of malnutrition are predictive of subsequent illness, diseases or death in communities of several countries in Africa and Asia [29]. Nutrition is largely determined by the environment, not the genetic factors in ones growth and development [20]. Malnutrition is often confused with undernutrition [30]. But actually it encompasses from undernutrition to overnutrition [31]. Undernourishment has been quite common in rural West Bengal (WB), India even 5 years ago [1,32], where subjects did not get enough high quality food rich in different necessary nutrients essential for normal growth and development [33]. This is often related to poverty, as malnutrition is closely related to poor availability or access to proper food [30,34].

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Muscular growth is seriously hampered during the active growth period of maturation in the young. Overnutrition is common in people belonging to higher socioeconomic strata according to Prasads classification of socioeconomic status (SES) (modified) [35].

7.6.1 UNDERNUTRITION Latest study demonstrated that globally 52 million subjects younger than 5 years of age die every year with most of these subjects live in developing countries and that 70% of them are from the continent of Asia [28]. More than 50% of these deaths are attributed to diarrhea, acute respiratory illness, malaria, measles, or cardiovascular diseases and other untreated conditions that are either preventable or treatable with inexpensive interventions [36]. Although malnutrition is widespread in developing countries, it is rarely considered among the leading causes of death [36]. Prevalence of undernutrition is double in rural areas than urban in 1999 [37] and higher in girls than boys, reducing the national progress from a socioeconomic perspective [38]. A strong correlation exists between infectious diseases like pneumonia, diarrhea, etc. with nutrition [36,39]. In Asia and Africa, 65% and 53% people are reported to be affected by pneumonia and diarroea, respectively [40], but no key nutritional intervention has been developed to resist those diseases especially in low- and middle-income countries. The major causes of undernutrition are poverty and poor hygiene, which make children more infection-prone and thus prone to malnutrition [41]. The factors aggravating the pathogens and transmission are higher ambient air, temperature, humidity, etc. [42]. All degrees of stunting, wasting, and underweight are related to anthropometric measures of undernutrition and hazards of death from infectious diseases except malaria [43]. Diarrhea could be reduced by 6%
26% and is associated with about 6% of measles deaths [44] but has not been successfully eradicated in ill-nourished subjects. Although the shortage of food is universal, children, adolescents, and old people are most affected. Malnutrition at early ages hampers proper growth along with height, weight, and muscularity [29]. For proper growth in childhood, children need sufficient calories for the maintenance of body metabolism with necessary proportions of carbohydrate, fat, protein, vitamins, minerals, and water [38]. The condition has often been referred to as undernutrition when there were not enough calories, protein, or micronutrients in the natural diet of the subjects studied [45]. Although the Indian economy is growing fast and it is one of the fastest growing countries in terms of population (more than 1.2 billion people); around 2 million deaths are reported every year in India due to malnutrition [28]. This has also been reported to be correlated to poor height increase among the subjects [29]. Undernutrition and infectious disease interact in a complex way, and manifest as either chronic undernutrition (stunting) or extreme thinness (wasting) [46]. Global reports estimate there are more than 195 million stunted and about 129 million underweight people, especially in Asia and sub-Saharan Africa [29].

7.6.1.1 Protein Energy Malnutrition The term Kwashiorkor and Marasmus are the two main diseases of protein energy malnutrition (PEM). In Kwashiorkor, the principal cause is incorrect diet with infectious diseases [47]. Food with less protein and high cellulose causes PEM in children and adolescents. Sometimes Kwashiorkar is aggravated by severe anemia and diarrhea.

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Nutritional marasmus is a consequence of extremely low nutrient intake, including protein, known as protein calorie malnutrition (PCM) in 1970; then it was expressed as protein energy malnutrition (PEM) [48]. Marasmus is another kind of PEM, that may be caused from lack of breastfeeding and lack of hygiene with a higher mortality rate [49]. It is a disease of low socioeconomic and educational level.

7.6.1.2 Moderate Acute Malnutrition In low-income and middle-income countries, acute malnutrition could result in morbidity and mortality [43]. Implementations of clinical guidelines has yielded excellent results in the last few decades. Moderate acute malnutrition (MAM) (weight for height z score # 2 SD and $ 3 SD) has also been lagging behind. MAM is more prevalent than SAM. These are prevalent in childhood and may continue into adolescence if not treated [40,50].

7.6.1.3 Severe Acute Malnutrition Children with severe acute malnutrition (SAM) exhibit a faster rate of protein synthesis. Malnutrition is the main cause for many deaths and when untreated, causes reduced mental and cognitive development [48]. It is a common factor in the development of many diseases. Nutritional immunodeficiency appears to be responsible for an increase of Tuberculosis [51].

7.6.2 OVERNUTRITION In contrast to malnourishment, overnourishment is common in people belonging to higher socioeconomic strata [35]. Overnutrition is a cumulative effect of diet and less physical activity. It is four times more prevalent in urban than rural areas, especially among the affluent [37]. Obesity is a worldwide problem today. Childhood obesity is a precursor of adulthood obesity which is rapidly increasing in both developing and developed countries, termed as “globesity” which refers to the universal health burden of obesity [52]. Patterns of overweight and obesity differ by age and gender, rural or urban residence, and socioeconomic pattern (SEP), and vary between and within countries [53]. A number of studies undertook to assess the prevalence of students overweight and obesity. Unfortunately, most of those dealt with height and weight only to investigate regional adiposity [54]. So, there was a strong need to deal with regional or central obesity (CO) by anthropometric indices other than considering height and weight only. Computed Tomography (CT) scanning and Magnetic Resonance Imaging (MRI) can directly measure intra-abdominal fat, but are very costly. Anthropometry has been proved as the most reliable measure to link fat distribution to health and its consequences [55].

7.6.3 DUAL BURDEN OF MALNUTRITION (UNDERNUTRITION AND OVERNUTRITION) Overnutrition, being a common problem for the affluent, is four times more prevalent in urban than rural areas [37]. In Columbia the dual burden of undernutrition and obesity affect children, adolescents, and adults. Along with that, anemia exists along with undernutrition in the same household (triple burden of malnutrition). Childhood stunting and overweight both existed in the Guatemalan indigenous population rather than nonindigenous [56]. A study on Malawian children reveals that

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they suffer from undernutrition due to less intake of micronutrient-rich foods and antioxidant-rich foods such as fish eggs, tomatoes, and citrus fruits [57].

7.6.4 PURPOSE AND THEORIES OF CLASSIFICATION The purpose of a classification is to be useful, and different classifications may be needed under different situations [58]. PCM is a qualitative measurement, able to distinguish patterns of severe malnutrition in subjects, whereas a quantitative classification is needed in community studies of prevalence and severity [11]. Secondly, a classification is of less value if it is not widely accepted, since its major use is to compare between results obtained by different people in different situations. Thirdly, a classification should be simple. Among several available classifications, the one by the Indian Academy of Pediatrics (IAP) is suitable for Indians but does not consider height as weight is very easy to measure accurately [59]. Age-independent classification (based on circumferences and not requiring age), SD classification [20] (based on international statistical cut
offs of height, weight (age restricted up to 10 years for weight)), and BMI are ideal to assess the nutritional status accurately. Anthropometric indicators are used as proxy indicators or indirect measures of malnutrition in population studies. Those have no real account nutrient intake or biochemical examination and are used for simplicity and their noninvasive approach. Additionally, these are sensitive to even minor changes of nutritional status of any population [60].

7.7 ANTHROPOMETRIC INDICATORS 7.7.1 WEIGHT FOR AGE The well-known Gomez classification of 1956 for first, second, and third degree malnutrition was supported on weight-for-age according to the Boston standards. Beaton and Bengoa [61] analyzed survey data received from different countries and used the Gomez classification; but comprised third degree malnutrition in all cases with edema regardless of body weight. The major difficulty in classification based on weight-for-age is that, in many communities the ages of subjects are not known. The major disadvantage of these classifications is not to consider the height of the subject (s). At present, WHO classification is adapted for considering weight-for-age (WAZ) [20] as a nutritional indicator.

7.7.2 HEIGHT FOR AGE The Eighth report of the FAO and WHO Expert Committee on Nutrition highlighted the importance of measurements of height or length. A recent standard indicator used is “height-for-age” [20]. Low height-for-age is generally referred to as “stunting.” It has been earlier pointed out that heightfor-age gives a picture of the past nutritional history. A reduction in the rate of linear growth could be referred to as retardation and stunting. Nutritional stunting is associated with impaired fat oxidation, resulting in obesity. Assessment of skeletal maturation assessment is probably the best indicator of age or maturity, because its development spans the entire period of growth [62,63].

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Undernutrition includes being remarkably short for ones age (stunting), being underweight for age, and being thin (thinness) for age. Subjects could be divided into: (1) normal; (2) malnourished but not retarded (acute malnutrition); (3) malnourished and retarded (acute and chronic malnutrition); and (4) retarded but not malnourished (including nutritional dwarfs and also people recovered from malnutrition). In studies performed at Midnapur district of WB, stunting and underweight were recorded to be as high as 23% and 27.9%, respectively [64].

7.7.3 WEIGHT FOR HEIGHT UNICEF in 2009 demarcated India as one of the Asian developing countries having millions of stunted children. Weight is an indicator of acute deficiencies. The standard indicator used here is “weight-for-age” (5
10 years of age only) and “weight-for-height” (up to 5 years of age). Stunting became a sign of a chronic restriction of linear growth [65]. Wasting (low weight-for-height) reflects acute weight loss of children with acute malnutrition [65]. Stunting (low height-for-age) is a better predictor of undernutrition than underweight (low weight-for-age). Underweight is a measure of both stunting and wasting [66]. Weight for age has the limitation of having the accuracy of the age (up to 5 years). Weight for height overcame the limitation and was expressed using Zscores [20]. India has a higher level of chronic than acute malnutrition (the possible predictors are child’s age maternal education, birth order, no of siblings, and standard of living). Diets of the rural population are insufficient, lacking nutrients. About 60% of the preschool children are underweight (, median -2SD weight for age of National Centre for Health Statistics (NCHS) and 62% are stunted (long duration malnutrition). About 15% of the children of 1
5 years of age suffer from shortduration malnutrition (wasting) [67]. A Keralian investigation by Rajaram et al. [68] revealed the higher prevalence of underweight and wasting and a lower prevalence of stunting in Kerala. In West Bengal, the overall rates of stunting and underweight were reported as 27.8% and 28.3%, respectively [23]. But Dambhare et al. [69] conducted a study at Wardha and revealed that 34.5% were stunted and 51.7% of children were underweight. Another study conducted at Wardha by Deshmukh et al. [70] showed that 53.8% of the adolescents were undernourished. A study from Puducherry by Joice [71], also revealed the significant malnutrition among both sexes. Thekdi et al. [72] carried out a study at Gujarat that demonstrated undernutrition among school children. Another study from Assam by Medhi et al. [73] reported rates of stunting in girls (50.4%) and boys (49.5%), respectively. A Puducherry study by Ananthakrishnan et al. [74] revealed that 57.6% had undernutrition. A study performed in Bangladesh by Rahman and Karim [75] revealed that 46.6% and 42.4% of children were stunted and underweight, respectively. Ghosh et al. [76] conducted a study in Nepal for undernutrition, where the rates of stunting and underweight were 44.5% and 49.5%, respectively. Some studies also revealed lower tendency of malnutrition. A study conducted at west Medinipur by Bose and Bisai [77] exhibited that the overall prevalence of undernutrition was 35.3%. Also, a Goa study by Banerjee et al. [78] demonstrated the prevalence of underweight as 33.3% where 40% young students were found undernourished in Darjeeling [79]. In the abovementioned studies the stunting and underweight were more prevalent in boys (51.91% and 61.45%) than girls (40.48% and 47.62%). Also it seemed to be significantly higher in early adolescent (54.21% and 58.88%) than late (40.48% and 47.62%).

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7.7.4 BMI FOR AGE BMI is considered to be more nutritionally than genetically related [80,81] among all other anthropometric indices. Thus in a diversely populated country like India, it is more suitable to apply BMI as an indicator of the nutritional status of the population [82,83]. Classification of BMI in children is complex as the subjects are in a growing phase, the rate of body physique and composition changes frequently in them [84]. BMI (weight in kg/height in sqm) significantly tracks those features from childhood to adolescence. BMI, strongly associated with sex and puberty, can be used for assessing thinness, overweight, and obesity in childhood and adolescence, as per BMI cut-offs of WHO from 0 to 19 years [20]. BMI increases gradually throughout adolescence [85]. A greater BMI may combine with a greater percentage of body fat and central fat distribution [21]. Children with an earlier increase in BMI are more likely to have increased BMIs in adulthood [86,87]. Mean BMI for girls has been found to be slightly higher than boys. The mean height of the rural boys of the present study was found to be lower; but the BMI was higher than urban boys of Kolkata previously reported by de Onis et al. [88] and Pandey et al. [89]. WB rural adolescent boys are significantly taller and heavier than girls from 14 years of age. As reported by Wang et al. [90], BMI is inadequate while describing the relationship between obesity and related diseases. Anthropometric indicators are typically based on age, height, weight, and BMI (derived from height and weight). The standard indicator used here is “BMI-for-age” (for 8
16 years) [20]. BMI is the best measure of overall obesity of children and young children [86,91]. The importance of BMI has been recognized for estimating cardiovascular disease (CVD) risk factors, by their positive association with hypertension [51,92]. Adolescent boys increase development of lean body mass and muscle differentiation, whereas girls face an increase of body fat of about 21% [93]. Chowdhury et al. [94] determined that height, weight, and BMI have an accumulated effect on sexual maturation. As stated by Bosch [95], taller and heavier girls show a better nutritional status and mature earlier than shorter and lighter girls. A study among Bengali adolescents revealed a moderate rate of undernutrition regardless of sex (36.49%) which was lower than those reported in other developing countries including India and irrespective of sex, the rate of undernutrition increased with the advancement of age [96]. Stunting in young children affects their cognitive development, academic performance, and economic productivity in adulthood [97]. Greater accumulation of body fat in the abdominal region might be the main determinant of obesity-related diseases like CHDs, type II diabetes, and hypertension [98,99]. The prevalence of overweight in affluent people was higher in India than other south Asian countries and a steady increase of overweight was seen from 6 to 9 years, and in the year 6 to 7 there was a trend of maximum gain of all linear measurements along with BMI [100]. Classification of CO was based on WC . 72 cm [101]. Girls are generally taller and heavier than boys in the age group of 8
16 years [102]. Bharati et al. [103] conducted a study on determinants of nutritional status of preschool children in India. It was found that the nutritional status of preschool children regressed with different sociodemographic parameters when age had been eliminated. Gender differences were found there; scores of weight-for-age and height-for-age showed a gloomy view in almost all Indian states. The mostly affected states are Uttar Pradesh, Bihar, Orissa, and Madhya Pradesh. A Brazilian study by Niehues et al. [104] showed a higher prevalence of overweight in the south (25.7%) and north (28.8%) Brazil and obesity in the southeast (15.4%) and south (10.4%) Brazil.

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In a study on prevalence of overweight and obesity in children and adolescents from 2 years to 19 years old in Brazil, as proposed by Ferrar and Golley [105], risk issues for adolescent overweight (comprising obesity) were lower levels of physical movements, higher levels of sedentary activities, low fruit and vegetable intake, and low socioeconomic position (SEP). Previous studies revealed a consistent increasing trend in CO is evident from 12 to 15 years of age. It had been observed among children in Baharian community [106,107] and Jamaica [108]. A study performed in the Netherlands demonstrated that there was no association between puberty and BMI [109,110]. A study from Israel found a similar pattern of obesity among boys and girls [80,111]. In a study conducted by Lamb et al. [112] on US students, BMI had indirectly measured body fat percentage and lipid concentration.

7.7.5 WAIST
HIP RATIO Waist
hip ratio (WHR) is the ratio of WC and HC. Waist always shows a negative correlation with age as hip growth is higher than waist [65]. WC only reflects abdominal fat and is not so much influenced by height. Moreover, WC correlates with measures of risk for CHDs [99,113]. WC has been proposed to replace WHR which is an easily measurable and interpretable indicator of abdominal obesity, being highly correlated with visceral fat. Several cross-sectional studies comparing WC, BMI, and WHR have shown that WC was the best indicator [114]. A study by Kuriyan et al. [115] suggested that WC increases with age for both girls and boys. The end of the curve continued to increase in boys and tended to plateau at 14 years in girls. WC correlates better with visceral adipose tissue and is a better predictor of cardiovascular disease than are BMI and waist-tohip ratio [116,117]. Significant sex difference in CO were found among young Punjabi students in Chandigarh, North India [118]. The higher prevalence of HC among girls may be related to the adolescent growth spurt and the effects of hormonal surge which occurs earlier in girls [119]. Similar studies were performed at Hoorn, Netherlands, where large hip and thigh circumferences weare found to be associated with a lower risk of type 2 diabetes among girls in comparison to boys, independently of BMI, age, and WC, whereas a larger WC is associated with a higher risk [120]. Current WC and WHR cut-offs had been identified from studies of majorly European populations. Cut-offs were identified among Aboriginal, Asian, African (Sub-Saharan), African-American, Hispanic, Middle Eastern, Pacific Islander, and South American populations. Asians should have a lower WC cut-off than Europeans [121].

7.7.6 WAIST
HEIGHT RATIO Waist
hip ratio (WHtR) is the ratio of waist (cm) and height (cm); a good indicator of overweight and obesity [22]. It is also an indicator of body shape and indicates the chance of chronic diseases during adulthood [122]. Rates of diabetes were higher for people from North American countries (13.5 new cases per 1000 person per year) [123] and lowest for the people from Asian countries (5.2 new cases per 1000 person/year) [124]. WHtR and CI are significantly associated with more chronic kidney diseases (CKDs) and CVDs than BMI [125]. Increasing BMI and WC were associated with only a minority of kidney diseases but WHR, WHtR, and CI were associated with each other. WHtR has been shown to be a useful predictor of multiple CHDs risk factors [126]. In a

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study correlating specified anthropometric variables, including WHtR, WC, BMI, and WHR with intra-abdominal fat (measured by computed tomography scanning), WHtR showed the highest correlation [127].

7.7.7 CONICITY INDEX Conicity index (CI) is the indicator of CO in combination with WHR. A central fat deposition has health complications in both children and adults in the future, e.g., high BP, CVDs, CKDs, etc. Anthropometry can correctly assess the truncal adiposity which continues from childhood to adulthood. According to the study of Taylor et al. [128], WC performs as an index of central adiposity in both children and adolescents of both sexes of any age group. Earlier studies suggested that WHR was poorly correlated to CO but now WC is the mostly anthropometric indicator of regional fat distribution. CO was reported to be related with various chronic health problems like high BP resulting CVDs [129,130]. The CI was associated to atherogenic risk but it could account for total obesity without the help of HC [131]. It is calculated with the formula: CI 5 Waist (cm) /0.109 3 Square Root of (Weight kg/ht in m). Conicity is an index of body fat distribution which expresses an individual’s WC relative to the circumference of a cylinder generated with that persons weight and height assuming a constant for body density [131]. The more central a person is in fat distribution, the higher the value of C [132]. In a study of by Mueller et al. [132] on cardiovascular reactivity and dimensions of anger and hostility in 60 African and Hispanic-American adolescents, anthropometry and sexual maturation strongly influence the anger and cardiovascular risk. C relates not only to body shape but also to body fat. Conicity may be an useful indicator of body fat distribution in studies of adolescents [132,133]. Excess visceral fat as evaluated by computed tomography (CT) was a predictor of cardiovascular illness in CKD patients [130]. In a study at western New York by Stranges et al. [134], evidence of association of fatty liver and central obesity were found in the young generation.

7.8 PHYSIOMETRIC INDICATORS 7.8.1 BLOOD PRESSURE A good indicator of CVDs, CHDs, diabetes, hypertension while combined with CO [24], the WC is strongly associated with the risk of hypertension, principally by the ambulatory blood pressure (BP) monitoring, when compared with casual BP measurement [135]. Ambulatory blood pressure monitoring (ABPM) had established roles in management of adult hypertension [136]. BP also provided quick information on metabolic risk possibilities [137]. Mean values of all the measurements: height, weight, mid-upper arm circumference, SBP, DBP, and pulse rate were observed to be higher in boys while compared to girls. There was a significant positive correlation between BMI and fat percentage with SBP and DBP [116]. Mean blood pressure (MAP) is calculated as follows [138]: MAP ðmm Hg:Þ 5 DBP 1 1=3 ðSBP 2 DBPÞ

(7.1)

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7.8.2 RELATIONSHIP OF BLOOD PRESSURE WITH WAIST CIRCUMFERENCE A study performed by Mohammadifard et al. [139] revealed that there would be a close relation between waist circumference (WC) and cardiovascular diseases (CVDs). WC had previously been related to BP and thus cardiovascular risk factors. WC was correlated similarly to BMI and WHR with most of the cardiovascular risk factors. Seidell et al. [140] concluded WC was the single most practical anthropometric measurement for use in health practices and promotion programmes related to high BP. WC was closely related to intra-abdominal fat mass and its changes reflect the changes in CVDs, CHDs, and hypertension. Large waist circumference was expected to be firmly associated with CVDs, diabetes mellitus, colon cancer in males, and breast cancer in females during adulthood. The previous studies suggested that WC is a very good predictor of overall health risks [141].

7.8.3 RELATION OF BLOOD PRESSURE WITH BODY MASS INDEX Linear correlations between SBP and DBP for all anthropometric measurements among males were found to be significant in the adult Brazilian men and BP increased with higher BMI and WC [142,143]. Significant (0.05 level of significance) positive correlation of BMI with SBP and DBP was suggested by many researchers [144,145]. BP among adolescents increased dramatically from 2000 to 2010 (19.29% to 22.26% and 14.69% to 16% in boys and girls, respectively). There was a significant (0.05 level of significance) positive correlation between BMI and body fat (%) with SBP and DBP [116] and central obesity was associated with high BP, independently of BMI. In Shandong (China), the occurrence of overweight (comprising obesity) was increased from 22.26% (boys) and 12.23% (girls) in 2000 to 33.81% (boys) and 19.48% (girls) in 2010 [146]. Elevated BP is a consequence of obesity [147]. In addition to that, India also exhibited an increasing trend of hypertension [148]. Rapsomaniki et al. [149] suggested that blood pressure was strongly associated with BMI and all cardiovascular diseases across all ages and that SBP and DBP were accordant. In a Korean study performed by Jones et al. [150], a strong correlation between BMI and BP was established for thin and obese children and adolescents. A number of studies had been performed in western countries but fewer in non-Western countries [151]. A study conducted on Seychelles children [152] revealed that both SBP and DBP were strongly associated with BMI, independently of sex, age, and height. Overweight and obesity could account for approximately one-fifth of all children with elevated BP. The Seychelles study also revealed that among 13.0% and 18.8% of obese boys and girls, respectively, the prevalence of high BP was 9.1% in boys and 10.1% in girls [153]. Both SBP and DBP were strongly associated with BMI in boys and in girls. Overweight (and obesity) could account for 18% of cases of elevated BP in boys and 26% in girls. Many studies have shown that BP is associated with BMI in children [153].

7.8.4 VARIATION OF BLOOD PRESSURE WITH AGE Many studies have found the relationship between BP and age (both SBP and DBP) to be significant among boys and girls [154,155]. In general, BP rises as people get older. Gender differences in BP are noticeable during puberty and continue through adulthood. A strong relationship between

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various anthropometric indicators and BP were found in Indian studies [156,157]. Other investigations by Gupta and Kapoor [156] and Shanthirani et al. [158] supported a strong relationship between BMI and BP across developed and developing countries [159,160]. Obesity tends to be associated with increased risk of diseases and morbidity [161]. BMI is broadly recognized as one of the best nutritional indicators in adults [91,162]. The importance of BMI has been recognized for estimating CVD risk factors, particularly due to their positive association with hypertension [92]. There is an independent association between general and abdominal obesity reflected by high BMI and WHR and the carotid artery wall thickens gradually indicting CVDs including a tendency towards stroke. Increased sedentary lifestyle like television watching or use of cellphone in children and adolescents had helped to aggravate increased intake of sodium [136,163].

7.9 PUBERTY AND MENARCHE 7.9.1 IMPACT OF NUTRITION ON PUBERTY AND MENARCHE Nutrition is the most important factor that affects pubertal growth and development including the sexual maturity through physical and physiological changes [164]. For several decades, adolescence was believed to start at 10 and persisted up to 19 years of age [20]. The development of secondary sexual characteristics and menarche were seen as milestones for determining sexual maturation in adolescent girls which seemed to be earlier (proceeded from 10 to 8 years) at a varying rate worldwide as a consequence of precocious puberty. Nutrition has an importance referring to age of onset of menstratuation; known as menarche. Adolescents gain 50% of adult weight and more than 20% of their adult height during this period [165,166]. Menarche is attained earlier by well-nourished adolescents [167,168]. A nominal amount of body fat is basically required for the menarche. Anthropometry provides the single most universally applicable technique for assessing the composition and monitoring changes in growth during menarche. Height, weight, BMI, WC, HC, WHR, WHtR, and CI are measured to evaluate the body shape changes in pre- and postmenarche girls [169,170]. The beginning of the secretion of large amounts of various hormones earlier in girls by the pituitary gland impacts adolescent physical and mental maturation [171]. Some evidences suggest that obesity can accelerate the onset of puberty in girls and may delay the onset of puberty in boys. Consumption of a balanced healthy diet in childhood and adolescence is required. Excessive eating of many processed, high-fat foods, may be one of the causes of precocious puberty [172].

7.9.2 EFFECT OF MENARCHE ON HEIGHT, WEIGHT, AND BMI; RELATION WITH OBESITY Menarche is attained earlier by well-nourished adolescents [167]. The adolescents look clumsy at the first phase of their development as the growth pattern is uneven including the lengthening of the calves and forearm followed by the hips, chest, and shoulder [173]. Presently, menarche is preceded in girls about 8
9 years [174], boys attains height surge after 13 while a typical girl attains

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95% of her adult height at about 1 year before menarche and the rest after attaining adolescence [175]. After the main growth spurt starts, it continues for 2
4 years at a much slower rate in boys whereas girls growth outperforms [20]. The beginning of the increase in growth velocity is about age 11 in boys and 9 in girls; but varies widely from individual to individual [20]. The peak height velocity in this study occurs at about 14 and 16 years which is similar to US students [176]. Long bones epiphysial closure is a remarkable end point of adolescent growth. If the epiphysial closure is earlier as a consequence of malnutrition, the full potential height fails to be achieved [177]. On average, smaller parents are having smaller children than children of taller parents; bone age is fairly accurate with chronologic age, those children usually show an appropriate rate of growth during early years of life and childhood days and accomplish sexual maturation and pubertal growth spurt at the usual ages [172]. The growth rate in menarche is associated with both the age and the height during the year prior to the menarche [178,179]. Postmenarche girls were having a high BMI with significantly higher height and weight than the premenarche counterparts [180]. Growth rate changes before and after menarche supported that the relationship between height and age is statistically significant (0.05 and 0.01 level of significance), demarcating their entrance into adolescence. The magnitude of the growth slope changes before and after menarche is almost 0.3 cm per year [181]. In some previous studies menarche age was positively associated with height and negatively associated with weight and BMI [182]. The various factors affecting the age at menarche directly and indirectly are geographic, socioeconomic, and environmental factors [183,184].

7.9.3 EFFECT OF MENARCHE ON WAIST CIRCUMFERENCE, WAIST
HIP RATIO, AND WAIST
HEIGHT RATIO The WC is signified to be a major indicator during the premenarche and postmenarche period, associated with sexual development. Girls with higher WC face early menarche and have excess body fat. It is important to control the occurrence of CO by observing the change of WC during puberty for girls’ health [185]. Many past worldwide and Indian studies [26,129,169,186] investigated central obesity by measuring WHR and CI in prepubertal and pubertal girls. Pubertal girls exhibited almost the same CO compared to prepubertal girls [169,187].

7.9.4 AGE AT MENARCHE Despite differences in genetic and social factors of different populations, the age of menarche appears almost the same in all developed countries, except African countries where girls experience late menarche. This data supports the hypothesis that obesity and menarche are not so correlated [188]. Previous studies suggested that race and ethnicity might be related to pubertal maturation in US girls [117]. In addition, socioeconomic and nutritional factors [189] work on sexual maturation [190]. Sexual maturation is also related to childhood obesity [190,191]. According to a study by Chumlea et al. [155] only 10% of US girls menstruate at 11 years old. Ethnicity specific data found that in the majority (80%) of non-Hispanic black girls menstrual age ranges between 10.5 and 13.6 years and in white US children between 10.5 and 11 years,

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respectively. Hence ethnicity might be a determinant of early menarche (in blacks) and late menarche (in whites) [155]. In a study at Jharkhand, India, the mean age of the studied population was 10.01 years, while the mean ages were 9.27 years and 13.70 years for pre- and postmenarche in Santal girls, respectively, where the mean age of menarche became 11.47 years [192]. Surveys done on US students revealed that the median age of menarche is found to be 12.4 years, in non-Hispanic black children it is 12.06 years, in Mexican Americans is an average of 12.25 years and in non-Hispanic Americans it is 12.55 years [155]. Previous studies [191] reported menarche data from a very large independent sample of white (n 5 15,439), black (n 5 1638) where median age of menarche is suggested as 12.88 and 12.16 years in white and blacks, respectively. Similar results suggested in German studies [193], (where a grouping of “early menarche” (#144 months/ 12 years) and “late menarche” ( . 144 months) had been done. Indian studies had reported mean ages of menarche and the different factors affecting it by ethnicity [28,194,195]. In earlier studies, different researchers also considered the menarche age of eastern Indian tribals [192,196,197]. While considering the birth order, first born reported a lower mean age at menarche (12.34 years) than the later born as 12.6 years [198]. The BMI rises during the prepubertal period constantly, resulting in an increase of body fat which might act as a signal for puberty-inducing signals originating from the central hypothalamic neurons [199]. There was no significant relation found between social background and menarche. Freedman et al. [102] explained the interrelationships between childhood levels of BMI and obesity as to be associated with an early puberty. Relatively fat children tended to undergo menarche earlier than thinner children [200]. Improvement in energy intake is associated with earlier onset of menarche [201,202]. Body fat plays a vital role to initiate puberty [181,203].

7.9.5 DETERMINANTS OF PUBERTAL DEVELOPMENT Family size also plays an important role in determining pubertal development. Findings showed that a large family and lower family income aggravates chances of precocious puberty [204]. Exposure to some endocrine disrupting agents (EDs) like polybrominated agents and lead can induce earlier onset of puberty [205].

7.10 SOCIODEMOGRAPHIC FACTORS SES is one of the most widely used aspects in the arena of social sciences. Various ways by which SES is estimated are family income, parents (especially of mothers) education, parent occupation, family size, number of siblings, and the order of birth in the family. SES is often associated with nutritional status of subjects which is related to their physical, physiological, and cognitive impacts prior birth to adulthood [206].

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7.10.1 CLASSIFICATION OF SOCIOECONOMIC STATUS To understand the SES of the community it is necessary to correlate its impact on health. Socioeconomic stratification is the key parameter to a community’s affordability, purchasing capacity, level of education, occupation, and income [35]. Different scales have been recommended by various experts. Prasads classification [35] based on the per capita monthly income (PCI) has been extensively used in India. It is calculated as: Per capita monthly income 5 Total monthly income of the family/Total members of family. Only the income is taken into consideration as a variable and it is simple to calculate. This can be applied to assess the SES in both rural and urban areas. It depends on several factors ; all India consumer price index (AICPI), Correction Factor (CF), costof-living index (COLI), which pertains to the existing Wholesale Price Index (WPI) in India. Based upon the total computation, five socioeconomic classes have been derived (Table 7.3). Chaudhury [207] analyzed the problem of insufficient ICDS and other findings for health by the government of SAARC countries to the poorer states with little nutritional support for women, children, and adolescents. Klasen [208] observed the occurrence of low income and child mortality was highest in Africa, but childhood undernutrition was highest in South Asia, whilst undernourishment is highest in the Caribbean. In a study by Girma and Genebo [209] in Ethiopia, children, adolescent, and reproductive age women were observed to be more vulnerable to malnutrition. It was due to lack of care, low diet, uneven distribution of food, and dietary taboos. It was found that SES, age, birth order, and birth interval determines child stunting. Education and income are considered as the two equally and commonly used SES indicators. In the previous cross-sectional studies, occupation was also regarded as an SES indicator [210,211]. Parent educational and occupational level taken together are found as important predictors of children’s educational and behavioral patterns [212
214].

Table 7.3 Socioeconomic Status Socioeconomic Status: Class

BG Prasad’s classification for 1961

Modified BG Prasad’s Classification for 2013

I (Upper) II (Upper Middle) III (Middle) IV (Lower-Middle) V (Lower)

Rs 100 and above Rs 50
99 Rs 30
49 Rs 15
29 Below Rs 15

Rs 5156 and above Rs 2578
5155 Rs 1547
2577 Rs 773
1546 Below Rs 773

Here, the last three socioeconomic classes have been considered; class V [Below Rs 773 5 Lower (socioeconomic) class], class IV [Rs 773-1546 5 Lower middle (socioeconomic) class] and class III [1547-2577 5 Middle (socioeconomic) class] [36]. Modified BG Prasad’s classification for 2013.

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7.10.2 SOCIOECONOMIC STRATIFICATION AND HEIGHT Height is generally influenced by the genetic and environmental factors, the correlation between height and income was also found to be significant in earlier studies. Better health accompanies better height in developing countries like India [215
217]. In a study carried out in China between 1992 and 2002, the average increase in height of children was found to be greater in urban than rural areas [218,219]. It was also opined that taller adolescent boys have a greater tendency to participate in sociocultural activities [220]. In a Swedish study performed in 1981, a reduction in mean height was found between the sons and daughters of unskilled salaried employees [221]. It had been suggested that taller people selectively move up the social class scale and there might be an increase in the difference in height among the social classes [222]. Around 70% of obese adolescents grow up into obese adults [223]. A negative association was found between BMI and SES where poor diet quality, lack of physical activity, or less food awareness were present [224]. Glick [225] analyzed women’s employment and their wards nutritional status with frequency of schooling. Stunting, underweight, and wasting were found to be 15%, 7.3%, and 3.6% among the children, respectively. Low prevalence of stunting and underweight might be associated with high SES. Government and nongovernment interventions were highly recommended to improve the socioeconomic condition. Underweight and stunting was prevalent in children of illiterate mothers (55.2% and 55.8%), in children of mothers having above primary education (41.0% and 42.9%). In employed mothers the picture was 77.4% and 80.6%, respectively; while in the case of unemployed mothers, it was 46.8% and 47.8%, respectively. Children of educated and financially independent mothers exhibit better nutritional status while children of poor mothers suffer nutritionally.

7.10.3 RELATIONSHIP OF SOCIOECONOMIC STATUS WITH WEIGHT AND BODY MASS INDEX; INFLUENCE OF OBESITY SES and BMI are negatively linked in most developed countries [226
229]. The opposite has been found in some (urban India and Ghana) [223,230] but not all developing countries. Dominance of obesity was less in Iran among high-income elderly [231] people. In Hong Kong, SES was found to be insignificant in controlling childhood BMI [232]. Parental income and education were poor predictors of BMI among adolescent girls in Iran [233]. Participants in the higher SE group were found to be more energetic than those in the lower SE class in previous studies [224]. SES and obesity were found to be positively correlated among the young generation (both boys and girls) in low-income countries or countries having low human development index (HDI). In middle-income countries or in countries with medium HDI, the correlation became mixed for young boys and generally negative for girls [234]. On the contrary, obesity in children was a dominant problem of the affluent in low- and middle-income countries. Earlier studies proved that the weight of adolescents in low- to middle-SES families is mostly related to the hike of fast food prices [235]. Mean BMI of adolescents aged 8 through 17 increased by 9.1% over the 1997
2000 period [235]. The adolescents have less consciousness regarding nutrition and food choice; fast foods are very alluring to them resulting in a higher BMI and obesity in adolescence and adulthood. Low- to middle-socioeconomic classes very often face that situation. Previous studies did not find any

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statistically significant relationship between fast food prices and weight among the adolescents from affluent educated ones [223]. Statistically significant negative correlation between fast food prices and adolescents’ BMI suggests that fast food taxes may be an effective tool for curbing excessive consumption of fast food and related overweight [235]. In low-income countries such as Bangladesh, India, and Vietnam, low obesity rates were found. Higher prevalence of obesity or a positive correlation between SES and obesity were recorded in upper-middle-income countries like Russia, Poland, and the Seychelles [234]. A study reported [236,237] a positive association of economic status with height, weight, WC, HC, and BMI. But some studies [227] showed a negative correlation between the same which became a characteristic of developing countries compared to developed countries [238,239]. The food insecurity level was correlated to BMI in low SE school-age urban adolescents of the United States [240].

7.10.4 INFLUENCE OF FAMILY EDUCATION ON CHILDS COGNITION AND ACADEMICS Literacy has increased in India, ascending to 74% from about 65% [241]. A child’s academic achievement was found to be affected by the home environment and family processes; providing a network of physical, social, and intellectual factors affected the student’s learning [242]. The families encouragement towards educational activities related to socioeconomic groups affects the child’s academic development. Many studies examined the relationships among those constructs and students’ achievements [243]. When parents’ education and occupation were taken together, they efficiently predicted the academic achievement of students [244]. The level of education usually determines income and occupation of the individual; also they determines the person’s status.

7.10.5 MATERNAL EDUCATION Maternal education [245], SES, family size, availability of food in time due to parents presence at home, and access to mass media reduces stunting and underweight at young ages [96]. Other common causes of malnutrition are impaired or poor utilization of nutrients and inadequacy of food. Poor socioeconomic environment has been proved to be detrimental for subjects’ nutrition. Poor water quality, sanitation, and pollution have consequences such as nematode infection [246]. Undernutrition in children begins with mother [247]. A mother’s own birth weight, food habits, standard of living throughout her life, especially during pregnancy, affect a child’s birth weight. Bhargava [248] analyzed that the nutritional deficiencies and other inadequacies affect children’s cognitive development and thus hampers the economic situation. Several studies were conducted to investigate the impact of factors like maternal education, nutritional knowledge, urbanization, presence of parents at home, and access to mass media on child nutritional status in Ghana, Africa [249,250]. Those revealed that mothers secondary education was very important for attaining their child’s height, weight, and to reduce rates of stunting, underweight, and wasting whereas infections, diarrhea, and fever increase their rates.

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The impact of mothers education on maternal and child health in three districts of Kerala was assessed by Mukherjee et al. [251]. Educated mothers exhibited a better child care from every aspect ensuring a better child growth. In a study conducted at Army School, Pune, mothers’ education, SES and family size were found to be significantly (at 0.05 level) associated with the nutritional status of the school children [252]. In a Kerala study by Thankappan et al. [253] based on maternal employment, all anthropometric parameters were found almost equivalent except midupper-arm circumference (MUAC). That result revealed the lower relevance of maternal employment with children and adolescent nutritional status. In a study by Haddad [254], an association was found between child nutrition and womens relative status in seven Asian countries, where, in comparison to men, the status of women is lowest in India, Pakistan, and Bangladesh. Gender equality has a positive control on a child’s growth and development. Maternal education plays a key role in the nutritional and educational status of children especially the daughters.

7.10.6 IMPACT OF WOMEN EMPOWERMENT ON CHILDREN In earlier studies, rural and urban differences seemed to be less important once parental education is controlled [235]. In particular, the maternal education is very important for their wards’ awareness, and the stage from primary to secondary level of schooling is more important than that of illiteracy to primary level of schooling. Higher schooling provides an exposure to Western culture in which women and children are given more importance [255]. Having an educated and empowered mother in developing countries is more important because children will be inspired from that and make her as an idol for themselves. It is expected that those children irrespective of being a boy or girl, will have a greater tendency to be highly educated and more empowered in terms of financial and mental independence [256]. Mukhopadhyay [257] examined household food insecurity out of poverty which results in uneven food distribution in developing countries. It can be concluded that female empowerment directly reduces malnutrition and increases academic availabilities, as well as especially gender inequality.

7.10.7 SOCIOECONOMIC STATUS, BIRTH ORDER, AND GENDER BIAS The Indian National Census in 2011 indicated an improvement in the sex ratio (overall) to 940 females per 1000 men from 933 women for every 1000 men [241]. Sex ratios had been found improved except in Jammu, Kashmir, Bihar, and Gujarat. But hopefully the gap is widening between and among children [258]. Haryana reported the lowest child sex ratio of 774 females per 1000 males [259]. Himachal Pradesh was also awarded as the best district by the Indian National Census in 2011, with a number of 1013 girls for every 1000 boys [241]. A positive effect of maternal education was found on height of the whole population and in mixed race and white males and females; no such obvious effect was observed in black or Asian races. Only in mixed race females was family income positively associated with height [260]. Gender preferences was not found towards girls in terms of height and stunting in Pakistan [261]. In India, a stronger child height gradient was found. Birth order did matter less among

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129

Bengali rural school children in a Bengali rural school children survey. Being born into larger households, children of higher birth order are further stunted and so are compensated with a larger nutritional investment by parents. Furthermore, birth order still matters at the end of the child’s growth period [256]. Birth order affects the early life for anthropometric and educational outcomes, but stops when children enter adulthood. In a study of weight [200] and BMI [262], it was revealed that first- and second-born children are taller and heavier than third- and later born children. The possible explanation of that fact may be the better environment of the first-born than the followers.

7.11 TECHNICAL ERROR MEASUREMENTS Technical error measurements (TEM) were computed and found to be within limits [263]. Therefore TEM were not incorporated in statistical analysis. TEM was calculated as: TEM 5 sq root of fðsum of D2 Þ=2Ng

(7.2)

where D, difference between two measurements; N, number of subjects measured.

7.12 STATISTICAL METHODS ADOPTED 7.12.1 THE ONE-WAY ANOVA ANALYSIS WITH TUKEY POST HOC TEST The one-way analysis of variance (ANOVA) [264,265] is used to determine whether there are any significant differences between the means of two or more independent (unrelated) groups. In this case the one-way ANOVA was used to understand whether characterizing variables differ for different integration levels (e.g., weak, moderately weak, medium, and high-integrated farming system). However, as the one-way ANOVA is an omnibus test statistic and cannot tell us which specific groups were significantly different from each other; it only tells us that at least two groups were different, overall difference between integrated farming system groups, but it does not tell which specific groups differed—post hoc tests do. That is why Tukey post hoc tests were performed to get the difference between different integration groups for each dimension of characterization. The mathematical model that describes the relationship between response and treatment for the one-way ANOVA is given by Yij 5 μ 1 τ i 1 εij

(7.3)

where Yij represents the j-th observation (j 5 1, 2,. . .ni) on the i-th treatment (i 5 1, 2, . . ., k levels). The errors eij are assumed to be normally and independently (NID) distributed, with mean zero and variance s2 e. m is always a fixed parameter and t1, t2, . . .tk are considered to be fixed parameters if the levels of treatment are fixed, and not a random sample from a population of possible levels. It is also assumed that m is chosen so that [264] X

τ i 5 0 i 5 1; . . .k holds

(7.4)

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7.12.2 CLASSIFICATION AND REGRESSION TREE (CART) ANALYSIS A classification problem consists of four main components. The first component is a categorical outcome or “dependent” variable. This variable is the characteristic which we hope to predict, based on the “predictor” or “independent” variables. Typical outcome variables are survival, need for surgery, and presence of myocardial infarction. The second components of a classification problem are the “predictor” or “independent” variables. These are the characteristics which are potentially related to the outcome variable of interest. In general, there are many possible predictor variables. The third component of the classification problem is the learning dataset. This is a dataset which includes values for both the outcome and predictor variables, from a group of patients similar to those for whom we would like to be able to predict outcomes in the future. The fourth component of the classification problem is the test or future dataset, which consists of subjects for whom we would like to be able to make accurate predictions [266].

7.12.2.1 Steps in CART According to Lewis [267], CART analysis consists of four basic steps. The first step consists of tree building, during which a tree is built using recursive splitting of nodes. Each resulting node is assigned a predicted class, based on the distribution of classes in the learning dataset which would occur in that node and the decision cost-matrix. The assignment of a predicted class to each node occurs whether or not that node is subsequently split into child nodes. The second step consists of stopping the tree building process. At this point a “maximal” tree has been produced, which probably greatly over fits the information contained within the learning dataset. The third step consists of tree “pruning,” which results in the creation of a sequence of simpler and simpler trees, through the cutting off of increasingly important nodes. The fourth step consists of optimal tree selection, during which the tree which fits the information in the learning dataset, but does not overfit the information, is selected from among the sequence of pruned trees.

7.12.3 PEARSONS CORRELATION TEST Correlation between two anthropometric variables is measured [265]. Pearson’s correlation coefficient (r) is used to measure the linear dependence between two variables X and Y giving a value between 11 and
1 inclusive, where 11 is total positive, 0 is linear and
1 is total negative correlation. Pearson’s correlation coefficient (r) when applied to a population is represented by “ρ” (rho). ρðx; yÞ 5 covðX; Y Þ=σxXσy;

(7.5)

where cov is the covariance; σ x 5 standard deviation of x; σ y 5 standard deviation of y. When Pearson’s correlation coefficient is applied to a sample, ρ is written as (r). From the above review of literature it is evident that various previous investigations had already been performed by national and international researchers. Their contribution became significant in the field of nutritional epidemiology. A few studies had also been done on the Bengali community of rural southern WB (North 24 Parganas). But when compared on a worldwide platform, there was a paucity of data of Bengali ethnicity in this age-group based on sexual dimorphism [88,98]. The researcher attempted to deal with several nutritional and health aspects with a selected section of students aged about 8
16 years of rural southern WB by means of Anthropometry which explains it in a well-accepted manner.

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FUNCTIONAL FOOD SECURITY FOR PREVENTION OF OBESITY AND METABOLIC SYNDROME

8

Sergey Chibisov1, Mukta Singh2, Ram B. Singh3, Ghazi Halabi4, Rie Horiuchi5 and Toru Takahashi6 1

Department of General Pathology and Pathological Physiology RUDN University, Moscow, Russia 2Department of Home Science, Mahila Maha Vidyalaya, Banaras Hindu University, Varanasi, Uttar Pradesh, India 3Halberg Hospital and Research Institute, Moradabad, Uttar Pradesh, India 4Halabi Cardiac Center, Aley, Lebanon 5 Mukogawa Women’s University, Nishinomiya, Japan 6Department of Human Environmental Medicine, Graduate School of Scences, Fukuoka University, Fukuoka, Japan

8.1 INTRODUCTION The worldwide prevalence of obesity is rising dramatically, from 5% for men and 8% for women in 1980, to 11% for men and 15% for women in 2014 [1]. The prevalence of obesity has doubled in 73 countries around the world and steadily increased in others since 1980, and health problems resulting from being overweight or obese now affect more than 2 billion people [1 4]. Increase in body weight in most people tends to accumulate during early and middle adulthood, which is a known risk factor for overall premature mortality, cardiometabolic disease, postmenopausal breast cancer, and colorectal cancer, and other chronic diseases [1]. The knowledge on health effects of weight gain across adulthood may facilitate weight control and development of recommendations for preventing weight gain during adulthood. A recent analysis of two major data sets indicated that even moderate weight gain in early and middle adulthood may be associated with an increased risk for a range of major noncommunicable diseases in later life, as well as a reduced likelihood of healthy aging [1,2]. The results in more than 90,000 women and 25,000 men revealed that a weight gain of between just 2.5 and 10 kg between early adulthood (18 21 years of age) and 55 years of age increased the risk for type 2 diabetes, hypertension, cardiovascular disease (CVD), obesity-related cancers, and death in both men and women. A moderate weight gain was linked to decreased odds of having a life free of chronic disease and cognitive and physical impairment. There are marked changes in the prevalence of diagnosed obesity, diabetes, and physical inactivity [5,6]. Although the last three decades have witnessed a decline in deaths from CVDs, in developed countries, the risk of these problems is increasing in developing countries. This trend may be mainly due to improved diet and lifestyle; decreased consumption of foods rich in salt and sugar, lower consumption of total and saturated fat, and greater intake of whole grains, fruits, vegetables and nuts. There may be an associated increase in moderate physical activity and The Role of Functional Food Security In Global Health. DOI: https://doi.org/10.1016/B978-0-12-813148-0.00008-6 © 2019 Elsevier Inc. All rights reserved.

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decline in tobacco consumption in high-income countries but a decline in such health behavior in developing countries [5,7 9]. Treatment of heart disease has also improved, and cholesterol, blood pressure, and smoking have lessened in developed countries, with some impact in some middle-income countries [5]. Unfortunately, rise in obesity and diabetes with poor adherence to healthy diet and moderate physical activity has partly disturbed the decreasing trend in CVDs [5,7]. In this context, the European Union “from farm to fork” approach, with sustainable agriculture, and community-supported agriculture are important. The involvement of initiatives of organic farming, that are also promoted by some in agriculture, common kitchens, restaurants, and food service, appear to be highly appreciable. There should be repeated emphasis by the WHO and FAO about functional food security indicating the role of food diversity with nutrient adequacy which was abundant in the Paleolithic diet, 40,000 years ago [7,8]. Therefore, the increased prevalence of obesity and related noncommunicable diseases, in developing and developed countries was associated with food security via Western-type foods and sedentary behavior. This review presents the evidence for the role of functional foods as a substitute to Western-type foods in the prevention of obesity and metabolic syndrome.

8.2 THE EPIDEMIC OF OBESITY AND METABOLIC SYNDROME Apart from high-income countries, obesity and the metabolic syndrome have also become major health problems in Southwest Asia, where undernutrition was preexisting about 50 years ago [9]. Undernutrition may have been eradicated in West Asia, but more than half of the urban population in South Asia has a body mass index (BMI) between 18.50 and 25.00 kg/m2 and underweight (BMI , 18.5 kg/m2) appears to be less than 10% in urban populations which may be due to dietary transition with an increase in dietary fat and sugar consumption [9,10]. There is a need to develop novel functional foods with the aim of prevention of the epidemic of obesity and metabolic syndrome [11 17]. The Five City Study from India included 6940 subjects (3433 women and 3507 men) aged 25 years and above. The findings showed that the overall prevalence of overweight (BMI 23.0 24.9 kg/m2) 33.5% (35.0% vs 32.0%, P , .05) and that of obesity (BMI 25 kg/m2 and above) was 6.8% (7.8% vs 6.2%, P , .05) and among women and men, respectively [17]. The overall prevalence of underweight (BMI , 18.5 kg/m2) was 5.5% (n 5 380), significantly more common in North and Central India compared to West and South India [17]. A recent study surprisingly showed that South Asia had the highest prevalence of underweight in 2014, 23.4% (17.8 29.2) in men and 24.0% (18.9 29.3) in women [16]. Data provided by these countries may have been collected before 1960 when undernutrition was common in these countries. This meta-analysis among more than 19.2 million adult participants (9.9 million men and 9.3 million women) included subjects from 186 of 200 countries. Global age-standardized mean BMI increased from 21.7 kg/m2 (95% credible interval 21.3 22.1) in 1975 to 24.2 kg/m2 (24.0 24.4) in 2014 in men, and from 22.1 kg/m2 (21.7 22.5) in 1975 to 24.4 kg/m2 (24.2 24.6) in 2014 in women [16]. If the present trends continue, by 2025, global obesity prevalence will reach 18% in men and surpass 21% in women; severe obesity will surpass 6% in men and 9% in women [16]. Regional mean BMIs in 2014 for men ranged from 21.4 kg/m2 in central Africa and south Asia to 29.2 kg/m2 (28.6 29.8) in Polynesia and Micronesia; for women the range was from 21.8 kg/m2 (21.4 22.3) in south Asia

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to 32.2 kg/m2 (31.5 32.8) in Polynesia and Micronesia. In a large cohort of 2.3 million adolescents, who were followed up for 42,297,007 person-years, 2918 of 32,127 deaths (9.1%) were from CVDs, including 1497 from heart attack, 528 from stroke, and 893 from sudden death. A BMI in the 50th to 74th percentiles, within the accepted normal range during adolescence was associated with increased CVD and all-cause mortality after 40 years of follow-up [15]. Overweight and obesity were strongly associated with increased CVD mortality in adulthood. Increased rate of cardiovascular mortality in adulthood were also observed among offspring with parental records of obesity [18]. It seems that young adulthood has been a neglected period of study in the development of obesity. The increased morbidity and mortality associated with excessive weight gain, indicate that efforts to prevent and control obesity in young adults should be accorded a high priority. The challenge would be that many individuals, particularly men between the ages of 20 and 39 years, do not feel unhealthy, because they do not have an apparent medical problem. It is interesting that obesity spreads along social and family networks, so young adult women may offer a focus for familybased interventions [2]. It is possible that reducing and preventing obesity and excessive weight gain in young adults provide a new target, and one that could offer an effective transgenerational approach for prevention. The knowledge about the role of transgenerational inheritance of obesity and other chronic diseases by epigenetic inheritance has confirmed that intervention at younger age of adulthood is crucial for the prevention of this epidemic of obesity. This cohorts analysis included 92,837 US women (97% white) in the Nurses’ Health Study (1976 June 30, 2012) and 25,303 US men in the Health Professionals Follow-Up Study (1986 January 31, 2012) [1]. The women gained a mean 12.6 kg over the course of 37 years, and men, gained a mean 9.7 kg over the course of 34 years [1,2]. After a mean follow-up of 1,561,919 person-years among women and 343,951 person-years among men, there were 9419 incident cases of type 2 diabetes, 39,585 of hypertension, 9399 of CVD, 9767 of obesity-related cancer, 9545 of cholelithiasis, 3090 of severe osteoarthritis requiring hip replacement, 41,600 cataract extractions, and 32,422 deaths. Apart from these findings, 10,919 women (21%) and 6041 men (34%) had a composite healthy aging outcome in 2010, defined as being free of 11 chronic diseases and major cognitive or physical impairment, at which point the mean age was 76.5 years in women and 70.9 years in men. Those subjects with moderate weight gain ($2.5 kg to ,10 kg) had a higher incidence of type 2 diabetes, with an incident rate ratio (IRR) of 1.89 in women and 1.75 in men, when compared with participants who had maintained a stable weight (weight loss # 2.5 kg or gain ,2.5 kg). A similar pattern for hypertension, with an IRR of 1.24 in women and 1.21 in men, and for CVD, with an IRR of 1.25 in women and 1.13 in men were also observed. A moderate weight gain was associated with an increased incidence of obesity-related cancer, at an IRR of 1.09 in women and 1.26 in men, but there was no significant association with overall cancer incidence. There were also associations between moderate weight gain and the incidence of cholelithiasis and severe osteoarthritis in women, but not in men. A moderate weight gain was associated with an odds ratio of achieving the composite health aging outmode of 0.78 in women and 0.88 in men compared with participants who maintained a stable weight as noted in a multivariate analysis. The pooled IRR per 5-kg weight gain was 1.31 for type 2 diabetes, 1.14 for hypertension, 1.08 for CVD, 1.06 for obesity-related cancer, 1.05 for overall mortality, and 1.08 for mortality among never smokers [1]. The strategies to prevent obesity should target young adults as well as children and adolescents. A recent analysis from 195 countries, reported that in 2015, 107.7 million

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children and 603.7 million adults were obese worldwide which constitute 30% of the world’s population [19]. The highest level of adult obesity was in Egypt at 35.3% and the highest level of childhood obesity was in the United States at 12.7%, among 20 most populous countries. Vietnam had the lowest rate of adult obesity and Bangladesh had the lowest rate of childhood obesity, both at approximately 1%. In many countries, obesity rates among children are rising faster than obesity rates in adults, particularly in China and India, which had the highest numbers of obese children. A high BMI contributed to 4 million deaths and 120 million disability-adjusted life-years globally. There was a relative increase of 28.3% in the rate of high BMI-related global mortality and a relative increase of 35.8% in the rate of disability-adjusted life-years from 1990 to 2015. CVD was the leading cause of death related to high BMI. In South Asians, there is a paradox because the prevalence of obesity and type 2 diabetes mellitus and risk of hypertension and coronary artery disease are higher in rural and urban populations with low rates of obesity [20 22]. The increased risk of metabolic syndrome among Southwest Asians is believed to be due to central obesity and insulin resistance; increased BMI above 23 kg/m2 is associated with central obesity [9,20 22]. BMI does not appear to be an indicator of exact risk of obesity among Southwest Asians in which waist circumference or waist/hip ratio may be a better predictor of risk [20 22].

8.3 NUTRITION IN TRANSITION AND FOOD SECURITY Nutrition in transition from poverty to affluence with economic development is associated with increased fast food restaurant establishments, which have experienced exponential global expansion in recent decades. This increased availability of fast foods has contributed to unhealthful diets with high calorie content; large portion sizes; and large amounts of processed meat, highly refined carbohydrates, sugary beverages, and unhealthy fats. In the food system transition, saturation of largechain supermarkets, displacing fresh local food and farm shops and serving as a source of highly processed foods, high-energy snacks, and sugary beverages is important for the epidemic of obesity [15 18]. The world undergoing epidemiological transition has experienced a livestock revolution, which leads to increased production of beef, pork, dairy products, eggs, and poultry. Based on the United Nations Food and Agriculture Organization data, this change has been especially dramatic in Asian countries. The nutrition transition is characterized with increased refinement of grain products. Milling and processing of whole grains to produce refined grains such as polished white rice and refined wheat flour reduces the nutritional content of grains, including their fiber, micronutrients, and phytochemicals and increases the glycemic index of these foods. “The biggest cause of early death in the world is not smoking or alcohol—it’s what you eat” (Staufenberg J, IHME News, USA, Oct 2015). This is a very truthful and bold statement indicating our failure to provide proper management of undernutrition. and food scarcity. The increase in food production without consideration of nutrient content has been the major cause of overnutrition due to food security resulting in an epidemic of obesity and metabolic syndrome which are risk factors of mortality and disability due to CVDs and cancer [15 18]. FAO’s latest estimates indicate that the world’s population suffering from undernourishment is around 12.5%, lower from almost half of the world’s population in 1947. This is a remarkable

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achievement, yet hunger remains prevalent among 868 million subjects and micronutrient deficiencies are commonly observed among an estimated 2 billion people. These subjects are candidates for an estimated 1.4 billion overweight subjects, including 500 million obese subjects, who are predisposed to cardiometabolic diseases. Increased availability of Western-type foods to provide food security can increase life expectancy to hardly 60 years or more, because it is associated not only with unhealthy diet but also sedentary behavior, as well as increase in tobacco alcohol intake, leading to emergence of cardiometabolic diseases as well as cancer, brain degenerative diseases, and osteoporosis [7,20 24]. The Western-type foods are characterized by refining, processing, high in calories with a higher content of sugar and salt but low in micronutrient. Animal foods such as red meat, preserved and processed meats, bread, biscuits, candies, cookies, chocolate, high-sugar foods and syrups are common examples of Western-type foods that are well known for having adverse effects on health. These foods and most deep-fried foods are also rapidly absorbed. Red meat, preserved and salted meats and snacks, plastic-containing foods such as Chinese rice, as well as foods with high content of trans fat, ω-6, and saturated fat have adverse effects on metabolism that lead to obesity and metabolic syndrome.

8.4 FUNCTIONAL FOOD SECURITY FOR PREVENTION OF OBESITY One major characteristic of functional food security is that they are high in nutrient density and low in calories that are protective to our health. Increased availability of such foods with high content of protective nutrients are also protective against diseases [25 32]. These foods can enhance life expectancy, to 68 years and more. Since these dietary patterns come with higher general education and health education, such people and communities are also prone to adopt other healthy lifestyles, such as no tobacco, moderate physical exercise, and a decline in alcohol consumption. These health behaviors may cause an optimal increase in body weight and waist/hip ratio or normal waist circumference, resulting in prevention of chronic diseases and health promotion [32]. There is no uniform agreement about the definition of Functional foods and Functional Farming (4 F). According to Singh’s group, Functional Foods are defined as foods which contain certain nutrients that can address some physiological mechanisms in our metabolism, thereby providing benefits. Functional farming (FF) may be defined as improvement in methods of farming that can provide increased production of functional foods which may be either by appropriate soil, or by genetic engineering or plant breeding, or via feeding experiments to animals [32]. It is possible that the major success in the prevention of obesity and metabolic syndrome can be achieved via functional food security in conjunction with increased physical activity, which is an effective measure for weight loss [7,25 31]. The most popular and traditional functional foods are given in Tables 8.1 and 8.2. There is consistent epidemiological evidence demonstrating that diets rich in nuts, vegetables, and fruits and lower in animal foods such as red meat and whole-fat dairy products can cause a significant decline in the risk of cardiometabolic diseases. The Western dietary patterns having high red meats, processed foods, refined grains, and sweets, and which are rich in bread, biscuits, pizza, candies, and syrups, increase the risk of these diseases [7,8,10,23]. A large cohort study from China, among 512,891 adults, aged 30 79 years was conducted with a follow up for 3.2 million

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Table 8.1 Functional Food Package for Prevention of Metabolic Syndrome (for vegetarian, replace with soya bean, cottage cheese and yogurt) Functional Foods

Amount (g/day)

Foods

Nutrient/Mechanism

Fruits Vegetables

200 300 200 300

Flavonoids, vit C, flavonoids Flavonoids, carotenoids

Nuts and seeds

30 50

Whole grains

400 500

Fish, sea foods Poultry Curd/yogurt Spices Fats and oils

50 100g

Apple, grapes, guava, berries Green leaves, gourds, onion spinach, tomato, garlic Walnuts, almond, peanuts Flex, Gram, beans, peas, millets soybean, pulses, porridge Salmon, any oily fish, e.g., mackerel

50 100 100 200 10 20 30 100

Egg-quail & hen, chicken, duck Prebiotic, probiotics Turmeric, fenugreek, cumin, coriander Olive, mustard/canola

Amino acids, ω-3 in walnut, low glycemic index, MUFA Flavonoids, amino acids, complex carbohydrates ω-3, amino acids, selenium, CoQ10 Amino acids, Immunity, gut microbiome Flavonoids, minerals Flavonoids, ω-3, MUFA

Olive and rape seed oil are known to decrease CVDs, diabetes, and all-cause mortality.

Table 8.2 Blend of Fats and Oils With Possible Beneficial Effects on Health Oils, /100 g Olive Oil (50%) Rape seed/canola oil (20%) Rice bran oil (10%) Sesame oil (10%) Flex seed oil (10%) Blended oil 5 total 100.13 g

Saturated fat 7.00 1.4

ω-6 fat 7.50 4.11

ω-3 fat 0.75 2.00

MUFA

Protective nutrient

36.00 13.00

Flavonoids, MUFA ω-3, MUFA

2.5 1.5 1.10 13.50

3.4 4.00 0.66 19.67

0.21 0.1 5.5 8.56

3.80 4.00 1.60 58.4

Oryzenol Phytosterol ω-3, 54% ω-6/ω-3ratio 5 2.29, resveratrol, oryzenol, phytosterol

Olive oil and rape seed oil are known to decrease cardiovascular diseases, diabetes, and all-cause mortality. No such evidence for other oils. MUFA 5 monounsaturated fatty acids.

person-years [24]. The results showed that 5173 deaths from CVDs, 2551 incident major coronary events (fatal or nonfatal), 14,579 ischemic strokes, and 3523 intracerebral hemorrhages were recorded among the 451,665 subjects who had no any history of these diseases at baseline. Increased consumption of fresh fruit daily was associated with lower levels of systolic blood pressure (by 4.0 mmHg) and in blood glucose levels (by 0.5 m mol/L (9.0 mg/dL)) (P , .001) [24]. The

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adjusted hazard ratios for regular intake versus no intake were 0.60 (95% CI: 0.54 to 0.67) for CVD death, and 0.66 (95% CI: 0.58 to 0.75), 0.75 (95% CI: 0.72 to 0.79), and 0.64 (95% CI: 0.56 to 0.74) for incident major coronary events, ischemic strokes, and intracerebral hemorrhages, respectively. Overall, 18.0% of participants reported consuming fresh fruit daily. A higher level of fruit consumption was associated with lower blood pressure and blood glucose concentrations and, largely independent of these and other dietary and nondietary factors, with a significantly lower risk of major CVDs [24]. It is well accepted that the Mediterranean-style dietary patterns include high consumption of functional foods (vegetables, legumes, whole grains, fruits, nuts, and olive oil), moderate consumption of fish and wine, and low consumption of red and processed meat and whole-fat dairy products; this is widely recognized as a healthy dietary pattern, rich in functional foods, and similar to the Paleolithic diet [7,25 32]. In Southern Europe, further observational studies also reported a lower risk of type 2 diabetes among populations who had better adherence to the Mediterranean-style diet among healthy subjects at entry to study or among subjects who survived after myocardial infarction [26]. In many countries, rice contributes to health by supplying dietary energy, proteins, and fat. Many different species of rice have been developed in Japan and other rice producing countries. Some varieties are expected to prevent various diseases, or to be used for dietary therapy [14]. The health effects of brown rice are empirically well known, and accumulating evidence about the physiological and pharmacological activity of rice bran strongly supports the use of brown rice in the dietary therapy. These could be categorized in the new concept, “medical rice.” For example, medical rice for obesity and diabetes because of its lower glycemic index compared to present rice.

8.5 INTERVENTION TRIALS WITH FUNCTION FOODS In most of the trials with functional foods, Mediterranean-style diets or whole grains are used in subjects with obesity and metabolic syndrome [28 31]. In a controlled study, among 404 patients with acute coronary syndromes, administration of Indo-Mediterranean-style diet was associated with significant decline in obesity and prediabetes [30] (Fig. 8.1). In another randomized, controlled intervention trial, 180 patients with metabolic syndrome were randomized to follow either a Mediterranean diet or a low-fat diet for 2.5 years [28]. At the end of the study, body weight decreased by 4.0 kg (8.8 lbs) in the Mediterranean diet group, compared to 1.2 kg (2.6 lbs) in the low-fat control group. Of all 180 subjects, 44% in the Mediterranean diet group still had metabolic syndrome, compared to 86% in the control group, indicating a significant decline in metabolic syndrome (Fig. 8.2). The Mediterranean diet group also had improvements in several risk factors: The endothelial function score improved in the Mediterranean diet group, but remained stable in the low-fat control group. Pro-inflammatory markers (hs-CRP, IL-6, IL-7. and IL-18) and insulin resistance decreased significantly in the Mediterranean diet group compared to low-fat diet group. In another study, data from 1224 subjects in the PREDIMED study were analyzed after 1 year, examining whether the diet helped individuals reverse the metabolic syndrome [29]. The prevalence of metabolic syndrome decreased by 6.7% in the Mediterranean diet plus olive oil group and by 13.7% in the Mediterranean diet plus nuts group. The results were statistically significant only for

100 90

8.2

80 70 60

55

52

50

Baseline After 2 years

40 30 20 10 0 Obesity

Diabetes

Prediabetes

(A)

90 80 70 60 50 Baseline After 2 years

40 30 20 10 0 Obesity

Type 2 diabetes

Prediabetes

(B)

FIGURE 8.1 (A) Effects of Indo-Mediterranean style diet on obesity and diabetes in patients with ACS. Values are n (%),  P , .01,  P , .001. (B) Effects of control diet on obesity and diabetes in patients with ACS. Values are n (%),  P , .01,  P , .001.

Prevalence of MetS, %

65

Olive oil, 6.7% decrease

Nuts, 13.7% decrease

Baseline 1 Year

60 55 50 45 40

MedDiet + V00

MedDiet + Nuts

Control Diet

FIGURE 8.2 Baseline and 1-year prevalence of the metabolic syndrome (MetS) by diet assignment. MedDiet indicates Mediterranean diet; VOO, virgin olive oil.  P , .05 versus control diet.

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the Mediterranean diet plus nuts group, suggesting that nuts appear to be better than olive oil in reducing metabolic syndrome [29]. Among 215 overweight, newly diagnosed type 2 diabetes patients, who had hemoglobin A1c (HbA1c) values less than 11%, treatment started either with Mediterranean diets or low-fat diet [31]. After 4 years, 44% of patients in the Mediterranean-style diet group and 70% in the low-fat diet group required treatment (absolute difference, 26.0% (95% CI: 31.1 to 20.1); hazard ratio, 0.63 (CI: 0.51 to 0.86); hazard ratio adjusted for weight change, 0.70 (CI: 0.59 to 0.90), P , .001). Participants assigned to the Mediterranean-style diet lost more weight and experienced greater improvements in some glycemic control and coronary risk measures than did those assigned to the low-fat diet. As compared with a low-fat diet, a low-carbohydrate, Mediterranean-style diet led to more favorable changes in glycemic control and coronary risk factors and delayed the need for antihyperglycemic drug therapy in overweight patients with newly diagnosed type 2 diabetes [33]. Several clinical trials that examined the effects of functional food-rich, energy-restricted diets together with increased physical activity in individuals with impaired glucose tolerance, a prediabetic stage, showed risk reductions between 30% and 70% [28 31,34]. The study of functional food consumption patterns among decedents dying from various causes revealed that functional food intakes were inversely associated with risk of mortality from CVDs and other chronic diseases [35]. The results of further studies provide convincing evidence that increased consumption of functional foods and lifestyle modification reduces the incidence of obesity and metabolic syndrome, among high-risk individuals [33,36 39]. Commonly available functional foods are: nuts—walnuts, all other nuts; oils—olive oil, mustard, canola, fish oil; vegetables—green leafy, gourds, lady finger, onion, garlic; fruits—grapes, apples, guava, papaya, musk melon, kiwi, tomato, strawberry berries; whole grains; pulses—gram, beans, kidney beans, peas; white meats—fish, chicken, etc.; “super-eggs”—ω-3, flavonol; dairy—curd/butter milk, butter milk/yogurt-microbiome; honey; herbs; seeds; soybeans; cocoa; flax seeds; tea; coffee; spices—fenugreek, turmeric, coriander, cumin, cloves (Table 8.1). The US Department of Agriculture and Human Services and the International College of Nutrition advise legislation regulating food composition available in the market, to reduce calories, salt, saturated fat, sugar, and to limit portion sizes [7,40]. Industrially produced trans fats should be eliminated [7,40]. For children, there should be legislation against marketing foods high in fat, sugar, and salt. Foods rich in sugar and saturated fat, and alcoholic drinks should be highly taxed. Water and healthy food should be available in schools and workplaces as well as at public places without any taxation. Regulation of location and density of fast food outlets may also be important measures to decrease the consumption of unhealthy foods. The PREDIMED trial show that there should be no guideline to limit fat intake, because high intake of olive oil which is normal content of diets and other fatty acids (41% en from total fat) was associated with a significant reduction in CVDs in Spain [34]. Hence, the US Department of Agriculture may be considering advocating no limitation in total fat intake but limitation in the quality of fat such as lower consumption of saturated fat and trans fat that are known to have adverse effects. The best composition of fatty acid in the oil could be achieved by blending the oils as given in other chapters. Recently, whey protein, which is known to possess all high class proteins—the highest among all food proteins—are considered to liberate fragments of amino acids and peptides on enzymatic hydrolysis [41]. The blending of oil may provide low omega-6/omega-3 fatty acid ratio in the diet which may cause lower risk of metabolic syndrome [42]. These peptides

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can promote health benefits in obesity, metabolic syndrome, the immune functions, and cardiovascular, nervous, and gastrointestinal systems. In brief, there is substantial evidence that increased consumption of functional foods can decrease obesity and metabolic syndrome, resulting in a decline in the obesity epidemic. The availability of low-cost functional food security can enhance the consumption of these foods, resulting in disease prevention and health promotion.

ACKNOWLEDGMENTS The authors would like to thank the International College of Nutrition for providing logistic support to write this article.

REFERENCES [1] Zheng Y, Manson JE, Yuan C, et al. Associations of weight gain from early to middle adulthood with major health outcomes later in life. JAMA 2017;318(3):255 69 http://jamanetwork.com/journals/jama/ fullarticle/10.1001/jama.2017.7092. Accessed July 18, 2017. [2] Dietz WH. Obesity and excessive weight gain in young adults: new targets for prevention. JAMA 2017;318(3):241 2 http://jamanetwork.com/journals/jama/article-abstract/2643743. Accessed July 18, 2017. [3] Shastun S, Chauhan AK, Singh RB, Singh M, Singh RP, Itharat A, et al. Can functional food security decrease the epidemic of obesity and metabolic syndrome? A viewpoint. World Heart J 2016;8 (3):273 80. [4] Friedrich MJ. Global obesity epidemic worsening. JAMA. 2017;318(7):603. Available from: https://doi. org/10.1001/jama.2017.10693. [5] Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, et al. Heart disease and stroke statistics—2015 update: a report from the American Heart Association on behalf of the American Heart Association Statistics Committee and Stroke Statistics Subcommittee Circulation 2016;131:e38 e360. [6] Geiss LS, Kirtland K, Lin J, et al. Changes in diagnosed diabetes, obesity, and physical inactivity prevalence in US counties, 2004-2012. PLoS One 2017;12 e0173428-e0173428. [7] Hristova K, Pella D, Singh RB, Dimitrov BD, Chaves H, Juneja L, et al. Sofia declaration for prevention of cardiovascular diseases and type 2 diabetes mellitus: a scientific statement of the international college of cardiology and international college of nutrition; ICC-ICN Expert Group. World Heart J 2014;6:89 106. [8] De Meester F. Wild-type land based foods in health promotion and disease prevention: the LDL-CC: HDL-CC model. In: De Meester F, Watson RR, editors. Wild Type Foods in Health Promotion and Disease Prevention. NJ: Humana Press; 2008. p. 3 20. [9] Shehab A, Elkilany G, Singh RB, Hristova K, Chaves H, Cornelissen G, et al. Coronary risk factors in Southwest Asia. Editorial, World Heart J 2015;7:21 3. [10] Chauhan AK, Singh RB, Ozimek L, Basu TK. Saturated fatty acid and sugar; how much is too much for health? A scientific statement of the International College of Nutrition. Viewpoint, World Heart J 2016;8:71 8.

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[11] Singh RB, Fedacko J, Vargova V, Niaz MA, Rastogi SS, Ghosh S. Effect of low ω-6/ω-3 ratio fatty acid Paleolithic style diet in patients with acute coronary syndromes. A randomized, single blind, controlled trial. World Heart J 2012;3:71 84. [12] Narsingrao BS, Deasthale YG, Pant KC. Nutrient Composition of Indian Foods. New Delhi: Indian Council of Medical Research; 1989. [13] Sreeramulu D, Reddy CVK, Raghunath M. Antioxidant activity of commonly consumed cereals, millets, pulses and legumes in India. Indian J Biochem Biophys 2009;46(1):112 15. [14] Watanabe S, Hirakawa A, Nishijima C, et al. Food as medicine: the new concept of “medical rice”. Adv Food Technol Nutr Sci Open J 2016;2(2):38 50. Available from: https://doi.org/10.17140/AFTNSOJ-2-129. [15] Twig G, Yaniv G, Levine H, Leiba A, Goldberger N, Derazne E, et al. Body-mass index in 2.3 million adolescents and cardiovascular death in adulthood. New Engl J Med 2016. Available from: https://doi. org/10.1056/NEJMoa1503840. [16] NCD Risk Factor Collaboration. Trends in adult body-mass index in 200 countries from 1975 to 2014: a pooled analysis of 1698 population-based measurement studies with 19
2 million participants. Lancet. 2016;387:1377 96. [17] Singh RB, Pella D, Mechirova V, Kartikey K, Demeester F, Tomar RS, et al. Prevalence of obesity, physical inactivity and undernutrition, a triple burden of diseases during transition in developing countries. Acta Cardiol 2007;62:119 27. [18] Davey Smith G, Sterne JAC, Fraser A, Tynelius P, Lawlor DA, Rasmussen F. The association between BMI and mortality using offspring BMI as an indicator of own BMI: large intergenerational mortality study. BMJ 2009;339:b5043. [19] GBD 2015 Obesity Collaborators. Health effects of overweight and obesity in 195 countries over 25 years. N Engl J Med 2017;(377):13 27. [20] Singh RB, Bajaj S, Niaz MA, Rastogi SS, Moshiri M. Prevalence of type 2 diabetes mellitus and risk of hypertension and coronary artery disease in rural and urban population with low rates of obesity. Int J Cardiol 1998;66(1):65 72. [21] Pella D, Thomas N, Tomlinson B, Singh RB. Prevention of coronary artery disease: the South Asian paradox. Lancet 2003;361:79 80. [22] Janus ED, Postiglione A, Singh RB, Lewis B, on behalf of the council on arteriosclerosis of the International Society and Federation of Cardiology. The modernization of Asia: implications for coronary heart disease. Circulation 1996;94:2671 3. [23] Kastorini CM, Panagiotakos DB. Dietary patterns and prevention of type 2 diabetes; from research to clinical practice; a systematic review. Curr Diabetes Rev 2009;5:221 7. [24] Du H, Li L, Bennett D, Guo Y, Key TJ, Bian Z, et al. China Kadoorie Biobank Study. Fresh fruit consumption and major cardiovascular disease in China. N Engl J Med 2016;374:1332 43. Available from: https://doi.org/10.1056/NEJMoa1501451. [25] Martı´nez-Gonz´alez MA, Bes-Rastrollo M, Serra Majem L, Lairon D, Estruch R, Trichopoulou A. Mediterranean food pattern and the primary prevention of chronic disease: recent developments. Nutr Rev 2009;67(Suppl. 1):S111 16. [26] Martı´nez-Gonz´alez MA, de la Fuente-Arrillaga C, Nunez-Cordoba JM, Basterra-Gortari FJ, Beunza JJ, Vazquez Z, et al. Adherence to Mediterranean diet and risk of developing diabetes: prospective cohort study. BMJ 2008;336:1348 51. [27] Mozaffarian D, Marfisi R, Levantesi G, Silletta MG, Tavazzi L, Tognoni G, et al. Incidence of newonset diabetes and impaired fasting glucose in patients with recent myocardial infarction and the effect of clinical and lifestyle risk factors. Lancet 2007;370:667 75. [28] Esposito K, Marfella R, Ciotola M, Di Palo C, Giugliano F, Giugliano G, et al. Effect of a Mediterranean-style diet on endothelial dysfunction and markers of vascular inflammation in the metabolic syndrome: a randomized trial. JAMA 2004;292(12):1440 6.

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[29] Salas-Salvado´ J, Fern´andez-Ballart J, Ros E, Martı´nez-Gonz´alez MA, Fito´ M, Estruch R, et al. Effect of a Mediterranean diet supplemented with nuts on metabolic syndrome status: one-year results of the PREDIMED randomized trial PREDIMED Study Investigators Arch Intern Med 2008;168(22):2449 58. Available from: https://doi.org/10.1001/archinte.168.22.2449. [30] Singh RB, Saboo B, Mahashwari A, bharadwaj K, Verma NS, et al. Effects of Indo-Mediterranean style diet and low fat diet on incidence of diabetes in acute coronary syndromes. World Heart J 2017;9:25 37. [31] Esposito K, Maiorino MI, Ciotola M, DiPalo C, Scognamiglio P, Gicchino M, et al. 11: effects of a Mediterranean-style diet on the need for anti-hyperglycemic drug therapy in patients with newly diagnosed type 2 diabetes: a randomized trial. Ann Intern Med 2009;151:306 14. [32] Singh RB, Takahashi T, Shastun S, Elkilany G, Hristova K, Shehab A, et al. The concept of functional foods and functional farming (4 F) in the prevention of cardiovascular diseases: a review of goals from 18th World Congress of Clinical Nutrition. J Cardiol Therapy 2015;2(4):273 8. Available from: http:// www.ghrnet.org/index.php/jct/article/view/. [33] De Lorgeril M, Salen P, Martin JL, Monjaud I, Delaye J, Mamelle N. Mediterranean diet, traditional risk factors and the rate of cardiovascular complications after myocardial infarction. Final report of the Lyon Diet Heart Study. Circulation 1999;99:779 85. [34] Estruch R, Ros E, Salas-Salvado´ J, Covas MI, Corella D, Aro´s F, et al. PREDIMED Study Investigators. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med 2013;368 (14):1279 90. [35] Singh RB, Visen P, Sharma D, Sharma S, Mondol R, Sharma JP, et al. Study of Functional Foods consumption patterns among decedents dying due to various causes of death. Open Nutra J 2015;8:16 28. [36] Singh RB, Rastogi SS, Singh R, Ghosh S, Niaz MA. Effects of guava intake on serum total and high density lipoprotein cholesterol levels and systemic blood pressures. Am J Cardiol 1992;70:1287 91. [37] Singh RB, Niaz MA, Sharma JP, Kumar R, Rastogi V, Moshiri M. Randomized, double-blind, placebocontrolled trial of fish oil and mustard oil in patients with suspected acute myocardial infarction: the Indian experiment of infarct survival—4. Cardiovasc Drugs Ther 1997;11:485 91. [38] Singh RB, Rastogi SS, Verma R, Bolaki L, Singh R, Ghosh S. An Indian experiment with nutritional modulation in acute myocardial infarction. Am J Cardiol 1992;69:879 85. [39] Singh RB, Rastogi SS, Verma R, Laxmi B, Singh R, Ghosh S, et al. Randomized, controlled trial of cardioprotective diet in patients with acute myocardial infarction: results of one year follow up. BMJ 1992;304:1015 19. [40] The 2015-2020 Dietary Guidelines for Americans. http://www.usda.gov/wps/portal/usda/ usdahome? contentid 5 2016/01/0005.xml, accessed 01.07.2016. [41] Dullius A, Goettert MI, Volken de Souza CF. Whey protein hydrolysates as a source of bioactive peptides for functional foods biotechnological facilitation of industrial scale-up. J Funct Foods 2018;42:58 74. [42] Singh RB, Fedacko J, Saboo B, Niaz MA, Maheshwari A, et al. Association of higher omega-6/omega-3 fatty acids in the diet with higher prevalence of metabolic syndrome in North India. MOJ Public Health 2017;6(6):00193. Available from: https://doi.org/10.15406/mojph.2017.06.00193.

CHAPTER

FUNCTIONAL FOOD SECURITY FOR PREVENTION OF DIABETES MELLITUS

9

Anuj Maheshwari1, Banshi Saboo2, Ram B. Singh3, Narsingh Verma4, Viola Vargova5, Dominik Pella5 and Daniel Pella5 1

BBDCODS, BBD University, Lucknow, Uttar Pradesh, India 2DiaCare and Hormone Institute, Ahmedabad, Gujarat, India 3Halberg Hospital and Research Institute, Moradabad, Uttar Pradesh, India 4KG Medical University, Lucknow, Uttar Pradesh, India 5Faculty of Medicine, PJ Safaric University, Kosice, Slovakia

9.1 INTRODUCTION Frequent urbanization and environmental changes including occupational transition from heavy labor to sedentary work with higher use of automobiles, rising computerization, and mechanization have actually led to type 2 diabetes as a global public health crisis [1 5]. Environmental changes and the economic rise are actually reasons behind the radical alterations in food production, processing, and distribution leading to the easy accessibility of unhealthy food. The epidemic of diabetes mellitus has developed together with increased obesity prevalence across the world [5,6]. Fast food restaurants are increasing exponentially across the globe. Easy availability of fast foods has actually led to unhealthful food habits with high calories, bigger portion sizes, more processed meat, with superrefined carbohydrates, sweet beverages, and unhealthful fats [3 5]. The second key component in the food system transition has been the saturation of large-chain supermarkets, which displace fresh traditional food and farm shops and serve as a source of highly processed foods, high-energy snacks, and sugary beverages that are poor in micronutrients, in most of the middle- and high-income nations on globe [5 7]. Rising production of beef, pork, dairy products, eggs, and poultry have also been revolutionized in most of the countries facing epidemiological transitions [1]. This change in food production has been dramatic in Asian countries which is based on the United Nations Food and Agriculture Organization (Fig. 9.1). After harvesting, whole grains are milled and processed to produce refined grains such as polished white rice and refined wheat flour. This processing not only reduces the nutritional content of grains, including micronutrients, but also their fibers and phytochemicals. Under the age of 60 years, diabetes has become a major cause of death, therefore investment for effective prevention of diabetes and its management has become mandatory to fight this global epidemic. Although diet has always been believed to play an important role in the causation of diabetes despite we never had enough data in the past. But in last 20 years a lot of evidence has been accumulated through multiple epidemiological studies, both cohort and randomized controlled trials, to successfully validate this idea

The Role of Functional Food Security In Global Health. DOI: https://doi.org/10.1016/B978-0-12-813148-0.00009-8 © 2019 Elsevier Inc. All rights reserved.

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FIGURE 9.1 Trends in sugar sales and consumption by region in 2014 (A), 2009 14 (B). Modified from websites of sugar sweetened beverages companies, nutrition facts panel and Euromonitor Passport International. Kcal 5 Kilo Calories.

[6 10]. In this review, we are trying to explore the role of diet in pathogenesis and development of diabetes as well as its possible use for prevention and management.

9.2 WORLD HEALTH ORGANIZATION ESTIMATES Overall global prevalence of diabetes is 8.3%, which constitutes 382 million people and it is expected to increase to 592 million by 2035 [5]. Expenditure occurring with regards to diabetes increased up to US$147 billion dollars in Europe and US$263 billion dollars in North America and Caribbean countries in 2013 [5]. An approximately fourfold increase has occurred in the number of people with diabetes from 1980 to 2014 and the more frustrating fact is the almost doubling in prevalence of diabetes among adults over 18 years of age from 4.7% in 1980 to 8.5% in 2014 [5]. Now it is rapidly increasing in middle- and low-income countries causing blindness, nephropathy, myocardial infarctions, strokes, and amputations. In the year 2015, 1.6 million death were estimated to occur directly due to diabetes. Fifty percent deaths of due to hyperglycemia are occurring before 70 years of age and it is expected to be the seventh leading cause of death by 2030 [5].

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The diabetes epidemic and its dynamics are changing because it is rapidly increasing in every country of the world, although it was considered a disease of the West. Although once it was a disease of affluence, it is now becoming common among the poor due to the changing definition of poor, who now have enough low-cost western foods and are now longer hungry. International Diabetes Federation estimates that two-thirds of further escalation of diabetes is expected to come from low- to middle-income countries by 2030. Apart from diabetes, the number of adults with IGT (Impaired Glucose Tolerance) is expected to touch 472 million by 2030 increasing health expenditure on diabetes to US$492 billion dollars in 2030 [3,9]. The continuously rising prevalence of diabetes and its comorbidities and complications may reverse the economic growth of developing nations.

9.3 THE ASIAN AND SOUTH ASIAN PARADOX There is the emergence of diabetes and CVDs in Asia, more so in South Asia, which may be due to a paradox [2,10,11]. Asia has 60% of the diabetic population which is attributable to its fast economic growth, urbanization, and frequently altered food habits leading to a change in nutritional status [3,5,9 12]. Asia has become an epicenter of the epidemic due to its huge population and rapid transformation from poverty to affluence because of fast economic development. Asians appear to have a thrifty genotype or epigenetic damage among fathers and for fathers which allow them to develop conservative mechanisms to adapt against food scarcity [2,10]. The Asian population is developing a tendency to have diabetes even at younger ages with lower BMI levels and low fat intakes than Caucasians, due to increased incidence of central obesity with a lot of visceral fat beyond body mass index of 23 kg/m2, which is a paradox [10]. The fat intake among Asians generally varies between 15% and 25% kcal/day but has now increased to 35% in a few countries. Out of the many factors contributing to the escalated diabetes epidemic in Asians, one may be the “normal-weight metabolically-obese” phenotype which develops due to epigenetic damage as well as heavy smoking, alcohol use with high intake of refined carbohydrates (e.g., white rice), and increased use of automobiles with reduced physical activity levels [10 12]. These factors have caused a tremendous rise in the prevalence of metabolic disorders, including diabetes, in a small span of time comparatively in India, China, Thailand, Philippines, and other countries of Asia. China has been estimated to have 92 million adults with diabetes and 148 million with prediabetes, indicating it has overtaken India as the epicenter of the diabetes epidemic across the globe. However, the prevalence of diabetes has risen around 20% in urban parts of southern India [2,5,6,10,12 15]. Nutritional deprivation during pregnancy and in childhood lays the foundation of obesity and diabetes which flares up when receiving overnutrition in later life, causing epigenetic damage that plays a key role in Asia’s diabetes epidemic.

9.4 RISK FACTORS OF TYPE 2 DIABETES Obesity, metabolic syndrome, physical inactivity, western diet, sedentary behavior, family history, and psychosocial stress are common risk factors of diabetes. Alcoholism and tobacco consumption

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can also predispose diabetes. Western diet associated with higher consumption of sugar and other refined carbohydrates, trans fat, saturated fat, and omega-6 fat; with underlying decreased intake of micronutrient rich foods, vegetables, whole grains, fruits, and nuts; in conjunction with low physical activity are major risk factors of obesity, metabolic syndrome, and diabetes [1 6]. Although advanced genome-wide association studies done recently have made us wiser in understanding the pathophysiology of diabetes, the genetic loci identified are not enough to give us the reason for the ethnic difference in the risk of diabetes. However, the interactions between food habits, lifestyle, and genetic background can explain the acceleration of development of diabetes in the context of rapid transition of food habits and quality of diet in Asian countries [2]. In India, diabetes is twoto threefold more common in urban areas, compared to rural villages where people in poverty are blessed to eat more whole grains, seasonal vegetables, mustard oil, and less Western foods, such as bread, buns, biscuits, and cola drinks, with the underlying lack of automobiles resulting in high physical activity [2,6,7]. In South India, the prevalence of diabetes is twofold greater due to lack of poverty, more foods, more automobiles, and high consumption of coconut oil, tobacco, and alcohol [6,13 15]. A cross-sectional study, including more than 3500 subjects ranging from 25 to 64 years of age with almost equal rural (49.48%): urban (50.51) participation and almost equal gender distribution in both the groups of rural and urban, has shown significantly higher prevalence of coronary artery disease, diabetes, and glucose intolerance in participants consuming lower dietary zinc. Hypertension, hypertriglyceridemia, and low level of HDL-C (high density lipoprotein cholesterol) were commoner in people with lower zinc intakes. Statistical analysis of this study has established the relation of Serum lipoprotein(a) and 2-hour plasma insulin levels with poor intake of zinc. Multivariate logistic regression has shown inverse relationship between zinc intake and CAD after adjusting for age. In urban subjects, serum zinc (odds ratio:men 0.77, women 0.57) was found to be a significant risk factor for CAD, like serum triglycerides, blood pressure, diabetes mellitus, central obesity, glucose intolerance, and low high-density lipoprotein cholesterol, but this association has not been observed in rural subjects. Thus in urban subjects lesser consumption of dietary zinc and low serum zinc levels have been associated with high prevalence of CAD, diabetes, and their multiple associated risk factors including hypertension, hypertriglyceridemia, and other factors suggestive of mild insulin resistance. In one other cross-sectional study performed in a city of India, Moradabad, and two adjoining villages, which included 566 elderly persons of 60 80 years grouped on the basis of level of insulin resistance mild, moderate, and high—CADs, diabetes, hypertension, hypertriglyceridemia, central obesity and associated co morbidities were more common with increasing insulin resistance and it was more significant in urban sunjects than rural. It has been supported by multivariate logistic regression analysis also after the age adjustment. Insulin resistance has been found to keep a significant inverse relationship with physical activity both in rural as well as in urban populations, but with high density lipoprotein cholesterol (HDL-C) only in urban subjects. While in rural subjects insulin resistance has been found to have significant association with CADs and glucose intolerance, though not with other risk factors. Even in low prevalence of obesity (0.9%) urban population, insulin resistance has been significantly associated with risks of cardiovascular disease and diabetes. There has been a clear significant association of diabetes, glucose intolerance, hypertension, hypertriglyceriodemia, and central obesity with insulin resistance and coronary diseases in urban but not in rural population,

9.4 RISK FACTORS OF TYPE 2 DIABETES

161

High blood glucose and type 2 diabetes mellitus are associated with a range of adverse health and cognitive outcomes [16]. Diet is the most important factor that contributes to high blood glucose and type 2 diabetes. This relationship between dietary patterns, fasting plasma glucose, and diabetes status has been examined in a sample of 209 subjects, aged 60 65 [16]. No significant association was observed between prudent diet and fasting plasma glucose levels, or type 2 DM. In contrast, an individual in the upper tertile for Western dietary score had a significantly greater risk of having diabetes as compared to an individual in the lower tertile for Western dietary score. However, there was no significant association between Western diet and fasting blood glucose. Western diet may be associated with type 2 diabetes through mechanisms beyond impacting blood plasma glucose directly. WHO has also emphasized the role of added sugar mediated by weight gain in being an important risk factor of diabetes [5]. Developing type 2 diabetes has been linked with consuming too much of the sweet stuff independent of weight gain. In new Australian-led research, data collected from the 40,000 people-strong Thai Cohort Study assessed correlation between sugar-sweetened beverage (SSB) consumption and incidence of type 2 diabetes [12,16]. The results revealed that women drinking one or more sugary beverage a day were at higher risk for developing type 2 diabetes. The correlation was mediated through obesity in some, but the risk was also identified without weight gain in others. It is possible that sugary products could be an ideal target for public health interventions for prevention of type 2 diabetes, as these possess no nutritional value, neither do they protect against disease. It has been estimated that over 4000 new patients of type 2 diabetes could be prevented every year in the Thai population if they avoided sugary drinks daily. In developed countries there is a reduction in sugar consumption due to more tax and use of alternatives to sugar (Fig. 9.1). Analyzing prospective cohort studies: the nurses health study (NHS), NHS II, and follow-up study of health professionals who were free of diabetes at baseline including 124,607 participants who were observed for more than 20 years [3]. During 2,093,416 person-years of follow-up, 9361 subjects were detected with type 2 diabetes mellitus. More than 10% reduction in AHEI (Alternative Healthy Eating Index) over 4 years was associated with increased risk of getting diabetes subsequently (pooled hazard ratio 1.34 (95% CI: 1.23 1.46)) with multiple adjustment, whereas more than 10% rise in AHEI score was associated with reduced risk (0.84 (0.78 0.90)). A better quality of diet has been found to be associated with a lower risk of getting diabetes compared to all the kinds of baseline diet quality status (P for trend # .001 for low, medium, or high initial diet quality) and baseline BMI, i.e., Body Mass Index (P for trend # .01 for BMI ,25, 25 29, or 30 kg/m2). Alteration in body weight explained 32% (95% CI: 24 41) of the association between AHEI changes (per 10% increase) and diabetes risk. In brief, a better quality of overall diet has been found to be better associated with a lower risk of type 2 diabetes, whereas its deterioration leads to greater risk. The association between diet quality changes and diabetes risk is not fully understood by body weight alterations. On reviewing cohort studies performed to see the effect of nutrient and food intake (except for alcohol) on occurrence of type 2 diabetes [17], including large number of subjects who were followed up ranging from 5.9 to 23 years, the number of diabetes cases were quite high with higher intakes of trans fatty acid and heme-iron, glycemic index, and glycemic load, while on other hand higher usage of vegetable fat, polyunsaturated fatty acid, dietary fiber (particularly cereal fiber), magnesium, and caffeine were significantly inversely correlated with the occurrence of type 2

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CHAPTER 9 FUNCTIONAL FOOD SECURITY FOR PREVENTION

Table 9.1 Functional Food Portfolio for Prevention of Metabolic Syndrome (for vegetarian, replace with soya bean, cottage cheese and yogurt) Functional Foods

Amount (g/day)

Foods

Nutrient/Mechanism Flavonoids, vitamin C, Flavonoids, carotenoids Amino acids, ω-3 in walnut, low glycemic index, MUFA Flavonoids, isoflavons, amino acids, complex carbohydrates ω-3, amino acids, selenium, CoQ10

Fruits Vegetables Nuts

200 300 200 300 30 50

Apple, grapes, guava, berries Green leaves, gourds Walnuts, almond, peanuts

Whole grains

400 500

Fish, sea foods Poultry Curd/yogurt Spices

50 100g

Gram, beans, peas, millets soybean, pulses, porridge Salmon, any oily fish, e g mackerel

50 100 100 200 10 20

Miscellaneous Fats and oils

5 10 g 30 100

Egg-quail & hen, chicken, duck Prebiotic, probiotics Turmeric, fenugreek, cumin, coriander Cocoa, tea, coffee Olive, mustard/canola

Amino acids, Immunity, gut microbiome Flavonoids, minerals Flavanols, polyphenols Polyphenols, Flavonoids, ω-3, MUFA

Olive and rape seed oil are known to decrease cardiometaboic diseases and all-cause mortality.

diabetes. Data on food consumption pattern has shown significantly reduced risk of getting type 2 diabetes with more intake of grain, particularly whole grain, and coffee, and significantly higher risk with processed meat consumption.

9.5 PREVENTION OF DIABETES BY FUNCTIONAL FOOD ADMINISTRATION Functional food provides specific health benefits apart from routine nutrition. They deliver additional or enhanced health benefits above their basic nutritional value. These range from cereals and bars enriched with folic acid to the “average” tomato or green tea. They must be differentiated from nutraceuticals which are more commonly sold in the form of a pill. Increased consumption of functional foods can prevent diabetes as well as its complications. Lifestyle modifications, which also include diet modifications, are proven for effective prevention and management of type 2 diabetes meelitus [18]. Plant-based diets are found to be more useful, with an emphasis on legumes, whole grains, vegetables, fruits, nuts, and seeds and avoiding animal products. Cohort studies have strongly supported this it. Plenty of observational and interventional studies provide enough evidence that plant-based diets not only help in the prevention and treatment of diabetes but also reduce key macrovascular and microvascular consequences. These benefits also depend upon the type and source of carbohydrates, i.e., refined versus unrefined; fats, i.e., saturated, polyunsaturated, monounsaturated, and trans; and protein, i.e., plant versus animal. Multiple propitious mechanisms are described to derive

9.5 PREVENTION OF DIABETES BY FUNCTIONAL FOOD ADMINISTRATION

163

FIGURE 9.2 Showing probability of remaining free of diabetes; more with Mediterranean diets containing nuts or olive oil, compared to low-fat diet. Modified from Salas-Salvado´ J, Bullo´ M, Babio N., et al. For the PREDIMED Study Investigators. Reduction in the incidence of type 2 diabetes with the Mediterranean diet. Diabetes Care 2011; 34: 14-19.

these benefits from plant-based diets: reducing insulin resistance, promoting healthy body weight, more fibers and phytonutrients, food microbiome interactions, and reducing saturated fat, advanced glycation end products, nitrosamines, and heme iron [18]. Since glucose toxicity is associated with oxidative stress, increased consumption of antioxidants in foods may be protective against complications of diabetes [19]. Enough evidence of epidemiological and randomized controlled studies shows that dietary interventions effectively prevent type 2 diabetes with lifestyle modifications and this is possible directly by the intake of greater functional foods: vegetables, whole grains, nuts, and fruits, as well as by decreasing body weight which decreases the risk of diabetes [20]. Functional food packages containing spices and millets, which are rich sources of flavonoids and minerals, are definitely different than others and promising (Table 9.1). PREDIMED study was a randomized, controlled trial among 418 nondiabetic inclusions who were examined after 4 years, looking at their risk of developing type 2 diabete mellitus [21]. The findings revealed that only 10% and 11% of the participants using the Mediterranean diet who were receiving diet plus nuts or diet plus olive oil became diabetic, respectively, as compared to 17.9% who developed diabetes in the low-fat control group (Fig. 9.2). The Mediterranean diet

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decreases the risk of type 2 diabetes mellitus by 52%. Another important study was where 215 overweight participants who were recently diagnosed type 2 diabetes but not yet been treated with antidiabetic medication, who had glycoselated hemoglobin (HbA1c) less than 11%. They were treated either with Mediterranean or low-fat diet [22]. After 4 years follow-up, 44% who kept on the Mediterranean-style diet and 70% who used the low-fat diet needed treatment (absolute difference, 26.0% (95% CI: 31.1 to 20.1); hazard ratio, 0.63 (CI: 0.51 to 0.86); hazard ratio adjusted for weight change, 0.70 (CI: 0.59 to 0.90), P , .001). Participants kept on the Mediterranean diet lost more weight and experienced greater improvements in hyperglycemias well as coronary risk measures, as compared to those using the low-fat diet. A low-carbohydrate, Mediterranean diet caused more favorable outcomes in glycemic control and CV risk factors delaying medications in overweight newly detected patients with type 2 diabetes as compared to those on low-fat diet [22]. Translating the research into practice can only stop an escalation of the diabetes epidemic but it needs to change the basic concept underlying public health policies, food and its distribution, building environments, and alteration of health systems. Primary prevention with healthy diet and lifestyle should be a preferred global public health priority. All the patients with prediabetes or those at risk of developing diabetes should be referred to an intensive behavioral lifestyle intervention program modeled on the Diabetes Prevention Program [23 25]. The purpose is to achieve and learn the behavioral methods via services using a cost-effective model with proposed implementation in 2018 (https://innovation.cms.gov/initiatives/medicare-diabetes-prevention-program/). An Indo-Mediterranean style diet, physical activity twice in a day and eating 5-6 times by dividing the meals are important diet and lifestyle changes for prevention of diabetes [23]. In brief, the Indo-Mediterranean diet, regular physical activity, meditation, yoga, maintaining normal body weight, and healthy mind with the avoidance of tobacco can prevent or delay the onset of type 2 diabetes. The consequences of diabetes can also be avoided or delayed with diet modifications, increased physical activity, medication, and regular screening and treatment for complications.

REFERENCES [1] Ezzati M, Riboli E. Behavioral and dietary risk factors for non-communicable diseases. N Engl J Med. 2013;369(10):954 64. [2] Singh RB, Bajaj S, Niaz MA, Rastogi SS, Moshiri M. Prevalence of type 2 diabetes mellitus and risk of hypertension and coronary artery disease in rural and urban population with low rates of obesity. Int J Cardiol 1998;66(1):65 72. [3] Ley SH, Pan A, Li Y, Manson JE, Willett WC, Sun Q, et al. Changes in overall diet quality and subsequent type 2 diabetes risk: three U.S. Prospective Cohorts. Diabetes Care 2016;39(11):2011 18. Available from: https://doi.org/10.2337/dc16-0574 Published online 2016 Sep 15. [4] Popkin BM, Hawkes C. Sweetening of the global diet, particularly beverages: patterns, trends, and policy responses. Lancet Diabetes Endocrinol 2016;4:174 86. [5] WHO. Diabetes fact sheet, updated July 2017. www.who.int/mediacentre/factsheets/fs312/en/ accessed, Oct 2017. [6] Singh RB, Beegom R, Rastogi V, Rastogi SS, Madhu SV. Diet, body mass index and prevalence of diabetes by questionnaire method in North and South India. J Diabetes Assoc India 1997;36:45 9.

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[7] Singh RB, Niaz MA, SRastogi S, Bajaj S, Gaoli Z, Shoumin Z. Current zinc intake and risk of diabetes and coronary artery disease and factors associated with insulin resistance in rural and urban populations of North India. J Am Coll Nutr 1999;17(6):564 70. [8] Russell WR, Baka A, Bjo¨rck I, Delzenne N, Gao D, Griffiths HR. Impact of diet composition on blood glucose regulation. Crit Rev Food Sci Nutr 2016;56:541 90. [9] Ley SH, Hamdy O, Mohan V, Hu FB. Prevention and management of type 2 diabetes: dietary components and nutritional strategies. Lancet 2014;383(9933):1999 2007. Available from: https://doi.org/ 10.1016/S0140-6736(14)60613-9. [10] Singh RB, Rastogi SS, Rao PV, et al. Diet and lifestyle guidelines and desirable levels of risk factors for prevention of diabetes and its vascular complications in Indians: a scientific statement of the International College of Nutrition. J Cardiovasc Risk. 1997;4:201 8. [11] Hristova K, Pella D, Singh RB, Dimitrov BD, Chaves H, Juneja L, et al. Sofia declaration for prevention of cardiovascular diseases and type 2 diabetes mellitus: a scientific statement of the international college of cardiology and international college of nutrition; ICC-ICN Expert Group. World Heart J 2014;6:89 106. [12] Papier K, D’Este C, Bain C, Banwell C, Seubsman S, Sleigh A, et al. Consumption of sugar-sweetened beverages and type 2 diabetes incidence in Thai adults: results from an 8-year prospective study’. Nutr Diabetes 2017;7:e283. [13] Saboo B, Singh RB, Maheshwari A, Verma NS, Istvan T, De Meester F, et al. Fats and oil for the heart and diabetes: eat as much as possible The International College of Nutrition Expert Group World Heart J 2016;8:295 301. [14] Tiwari RR, Deb PK, Debbarma A, et al. Risk factor analysis in self-reported diabetes in a rural Kerala population. Int J Diabet Dev Count 2008;28(3):91 4. Available from: https://doi.org/10.4103/09733930.44080. [15] Sadikot SM, Nigam A, Das S, Bajaj S, Zargar AH, Prasannakumar KM, et al. The burden of diabetes and impaired glucose tolerance in India using the WHO 1999 criteria: prevalence of diabetes in India study (PODIS). Diabetes Res Clin Pract. 2004;66:301 7. [16] Walsh EI, Jacka FN, Butterworth P, Anstey KJ, Cherbuin N. The association between Western and Prudent dietary patterns and fasting blood glucose levels in type 2 diabetes and normal glucose metabolism in older Australian adults. Heliyon 2017;3(6):e00315. Available from: https://doi.org/10.1016/j.heliyon.2017.e00315. [17] Murakami K, Okubo H, Sasaki S. Effect of dietary factors on incidence of type 2 diabetes: a systematic review of cohort studies. J Nutr Sci Vitaminol (Tokyo) 2005;51(4):292 310. [18] McMacken M, Shah S. A plant-based diet for the prevention and treatment of type 2diabetes. J Geriatric Cardiol: JGC 2017;14(5):342 54. Available from: https://doi.org/10.11909/j.issn.16715411.2017.05.009. [19] Wilson DW, Nash P, Buttar HS, Griffiths K, Singh R, De Meester F, et al. The role of food antioxidants, benefits of functional foods, and influence of feeding habits on the health of the older person: an overview. Antioxidants 2017;6:81. [20] Shastun S, Chauhan AK, Singh RB, Singh M, Singh RP, Itharat A, et al. Can functional food security decrease the epidemic of obesity and metabolic syndrome? A viewpoint. World Heart J 2016;8 (3):273 80. [21] Salas-Salvado´ J, Bullo´ M, Babio N, et al. For the PREDIMED Study Investigators. Reduction in the incidence of type 2 diabetes with the Mediterranean diet. Diabetes Care 2011;34:14 19. [22] Esposito K, Maiorino MI, Ciotola M, DiPalo C, Scognamiglio P, Gicchino M, et al. 11: effects of a Mediterranean-style diet on the need for anti-hyperglycemic drug therapy in patients with newly diagnosed type 2 diabetes: a randomized trial. Ann Intern Med 2009;151:306 14.

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[23] Singh RB, Saboo B, Mahashwari A, bharadwaj K, Verma NS, et al. Effects of Indo-Mediterranean style diet and low fat diet on incidence of diabetes in acute coronary syndromes. World Heart J 2017;9:25 37. [24] Ritchie ND, Sauder KA, Brady PP, Amura CA. Rethinking the National Diabetes Prevention Program for Low-Income Whites. Diabetes Care 2018;dc172230. Available from: https://doi.org/10.2337/dc172230 Feb. [25] Prevention or Delay of Type 2 Diabetes: Standards of Medical Care in Diabetes—2018. American Diabetes Association. Diabetes Care 2018; 41(Supplement 1): S51-S54.

FURTHER READING Singh RB, Rastogi SS, Postiglion A. Association of central obesity and insulin resistance with high prevalence of diabetes and cardiovascular disease in an elderly population with low fat intake and lower than normal prevalence of obesity: the Indian paradox. Coronary Artery Disease 1998;9(9):559 65.

CHAPTER

FUNCTIONAL FOOD SECURITY FOR PREVENTION OF CARDIOVASCULAR DISEASES

10

Jan Fedacko1, Shantanu Singhal2, Ram B. Singh3, Krasimira Hristova4, Arunporn Itharat5 and Ghazi Halabi6 1

Faculty of Medicine, PJ Safaric University, Kosice, Slovakia 2Amrita Institute of Medical Sciences, Kochi, Kerala, India 3Halberg Hospital and Research Institute, Moradabad, Uttar Pradesh, India 4University National Heart Hospital, Department of Noninvasive Functional Diagnostic and Imaging, Sofia, Bulgaria 5Department of Applied Thai Traditional Medicine, Faculty of Medicine, Thammasat University Center of Excellence in Applied Thai Traditional Medicine Research (CEATMR), Thammasat University, Thailand 6Halabi Cardiac Center, Aley, Lebanon

10.1 INTRODUCTION The effects of dietary fats on health have been proposed by ancient physicians; Sushruta in India, Confucious in China, and Hippocrates in Europe approximately in the 5th century BCE. Numerous studies have been published to emphasize the effects of fatty acids on blood biomarkers for decades. However, controversies exist on the effects of various types of fatty acids, especially saturated fatty acid (SFA), on cardiovascular diseases (CVDs) [1 4]. There is consistent evidence that types of fat in the food may have divergent effects on risk CVDs. Replacement of SFAs by unsaturated fats, especially omega-3 fatty acids may cause substantial decline in the CVDs risk [2]. PolyunSFAs such as ω-6 and ω-3 are associated with lower CVDs, although the effects of fish oil supplementation remains inconsistent. The 2015 20 Dietary Guidelines for Americans place greater emphasis on types of dietary fat than total amount of dietary fat and recommend replacing SFAs with unsaturated fats, especially polyunsaturated fatty acids for CVD prevention [4]. Hydrogenation of vegetable oils by the industry produces trans fatty acids that are known to increase CVD risk. Highly effective pharmacotherapy and high technology cardiac care have been major advancements for a significant reduction in morbidity and mortality due to CVDs. The decline in the mortality due to CVDs has also been attributed to improvement in food consumption patterns and other lifestyle changes [1 4]. Reduction in the intake of saturated fat, salt, and sugar, and increase in the intake of functional foods—vegetables, fruits and whole grains—with moderate physical activity and decrease in tobacco intake may have contributed to a decline in CVDs in high-income countries [1 6]. Unfortunately, the decline in CVDs is partly offset by an increase in obesity and type 2 diabetes, which may be on account of poor adherence to physical activity [6 8]. It is proposed that increased intake of genetically modified foods such as canola oil may have caused an increase in inflammation in the adipocytes resulting in increase in metabolic risk in most of the high-income countries which is evident from an experimental study [4]. In high-income The Role of Functional Food Security In Global Health. DOI: https://doi.org/10.1016/B978-0-12-813148-0.00010-4 © 2019 Elsevier Inc. All rights reserved.

167

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FIGURE 10.1 Transition from poverty to Food Security and Functional Food Security leading to health promotion and prevention of obesity.

countries, with some impact in some middle-income countries, the prevalence of hypercholesterolemia, hypertension, and tobacco intake have declined but hypertriglyceridemia should be higher due to the increase in obesity and diabetes [1 5]. The new initiatives of the European Union “From Farm to Fork” including sustainable agriculture, organic farming initiatives, and community-supported agriculture that is also promoted by some experts in the agriculture, food service, and restaurant communities, need appreciation because these approaches can provide functional food security in European Union countries. The role of diet and lifestyle factors to explain the causes of deaths due to CVDs and other chronic disease in 10 countries have been emphasized by the world heart Federation as well as by the Global Burden of Diseases study [7] (Fig. 10.1). Unfortunately, most experts and policy makers continue to be ignorant about functional food security characterized by food diversity and adequacy of nutrients that was abundant in the Paleolithic diet 40,000 years ago [1 3]. It should be reiterated that the epidemic of NCDs throughout the world has been closely linked to food security via westernized dietary patterns, physical inactivity, and rapid increase in the rate of obesity. This article aims to highlight the role of functional foods security in health promotion and prevention of CVDs.

10.2 EFFECTS OF DIET ON MORTALITY DUE TO CARDIOVASCULAR DISEASES The evaluation of the relationship between changes in diet quality over time and the risk of death have been assessed in a few studies [5]. In a cohort study, 47,994 women from the Nurses’ Health Study and 25,745 men from the Health Professionals Follow-up Study were included. Any alterations in the quality of diet were assessed over the preceding 12 years with the use of the Alternate Healthy Eating Index 2010 score, the Alternate Mediterranean Diet score, and the Dietary Approaches to Stop Hypertension (DASH) diet score. For all-cause mortality among participants

10.2 EFFECTS OF DIET ON MORTALITY

169

who had the greatest improvement in diet quality (0% 3% vs 13% 33% improvement), as compared with those who had a relatively stable diet quality, the hazard ratios in the 12-year period were the following: 0.91 (95% CI: 0.85 0.97) according to changes in the Alternate Healthy Eating Index score, 0.84 (95% CI: 0.78 0.91) according to changes in the Alternate Mediterranean Diet score, and 0.89 (95% CI: 0.84 0.95) according to changes in the DASH score [5]. A 20percentile increase in diet scores for improved quality of diet was significantly associated with a reduction in total mortality of 8% 17% with the use of the three diet indexes and a 7% 15% reduction in the risk of death from CVDs with the use of the Alternate Healthy Eating Index and Alternate Mediterranean Diet. For those subjects with a high-quality diet over a 12-year period, the risk of death from any cause was 14% (95% CI: 8 19) when assessed with the Alternate Healthy Eating Index score, 11% (95% CI: 5 18) when assessed with the Alternate Mediterranean Diet score, and 9% (95% CI: 2 15) when assessed with the DASH score, compared to subjects with consistently low diet scores over time. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990 2013 were assessed in a systematic analysis for the Global Burden of Disease Study [7]. This study showed that one-third of the totals occur because of CVDs. The World Heart Federation published a modeling plan for the heart of 25 by 25 for achieving the goal of decreasing premature deaths from CVDs in association with the American Heart Association [8]. Prevention of CVDs should be taken as a challenge which has also been supported by a scientific statement of the International College of Cardiology who give greater emphasis on functional food security [9]. Approximately 50 years ago, poverty and undernutrition were common in South Asia, among women and children. Decreased availability of food during in utero life and infancy allowed the new born to develop conservative mechanisms which increases the susceptibility of these subjects to central obesity, diabetes, and CVDs and diabetes on increased food availability due to rapid economic development and food security via Western-type foods [10 13]. The Five City study involved 6940 subjects (3433 women and 3507 men) aged 25 years and above. The overall prevalence of obesity (BMI 25 kg/m2 and above) was 6.8% (7.8% vs 6.2%, P , .05) and overweight (BMI 23.0 24.9 kg/m2) 33.5% (35.0% vs 32.0%, P , .05) among women and men, respectively [10]. Approximately half of these subjects had central obesity which started with increase in body mass index above 23 kg/m2. There is evidence that central obesity and insulin resistance develops more rapidly in people of South Asian origin, after the body mass index goes beyond 23 kg/m2. It is considered a paradox since these populations become highly susceptible to develop CAD and type 2 diabetes at a lower body mass index which is taken as normal in Caucasians [4,11 13]. Among 2.3 million adolescents, during 42,297,007 person-years of follow-up, 2918 of 32,127 deaths (9.1%) were from CVDs, including 528 deaths from stroke, 1497 from heart attack, and 893 from sudden death [14]. Within the accepted normal range of BMI in the 50th to 74th percentiles, during adolescence, it was associated with increased CVD and all-cause mortality after 15 years of follow-up [14]. Increased cardiovascular mortality, possibly via epigenetic inheritance has been observed in adulthood among subjects giving history of overweight and obesity among parents and off-springs [15]. Increased availability of functional foods at affordable cost may be useful in the prevention of these problems. According to the World Heart Federation, the key targets proposed by United Nations High Level Meeting (UN HLM), that by 2025, substantial reduction in the risk of premature death due to CVDs and other chronic diseases should be achieved by 25% by 2025 [8]. Since CVDs are the

170

CHAPTER 10 FUNCTIONAL FOOD SECURITY

largest contributor to global mortality, accounting for nearly half of the 36 million annual deaths, it is important CVDs and the risk factors should be carefully prevented [7]. It has been estimated how reduction of selected risk factors can influence mortality due to CVDs for different regions in 188 countries up to the year of 2025 [16]. If the targets of risk factors proposed by the UNO are achieved in the year 2025, counterfactual scenarios may be then constructed indicating CVD premature mortality, adjusting for joint effects of risk factors. It has been estimated that 7.8 million premature CVD deaths would occur in 2025 if current risk factor trends continue [16]. If these risk factors targets are achieved, the premature CVD deaths would be reduced to 5.7 million as a result of a 26% reduction for men and a 23% reduction for women in the global risk of premature CVD death. The decline in the prevalence of hypertension would cause the largest reduction in risk, followed by a reduction in tobacco intake for men and obesity for women. The UNO, target of a 25% reduction in premature CVD mortality by the year 2025 can be achieved in some countries in which efforts have been made to enhance functional food availability and physical activity at affordable cost. Similar goals are possible for other countries, if more aggressive approaches are used in all regions of the world. It has been presumed that some countries will see no change or even a rise in premature CVD mortality unless there is a decrease in CVD risk factors. Regional estimates have been developed by the Global Cardiovascular Disease Taskforce with the help from Institute for Health Metrics which reveal that .5 million premature CVD deaths among men and 2.8 million among women are projected worldwide by 2025 [16]. There may be decline in these deaths to 3.5 million and 2.2 million, respectively, if risk factor targets for blood pressure, diabetes mellitus, obesity, and tobacco use, are achieved by various countries and regions because global risk factor targets have variable effects, depending on region. It is known that, compared with maintaining current levels of body mass index and fasting plasma glucose United Nations targets for reducing systolic blood pressure and tobacco use have greater benefits on future occurrence of CVDs [8]. Reductions in multiple risk factors may have global impact if all the health professionals and governments in each country set priorities, implement cost-effective population wide strategies, and collaborate in public private partnerships across multiple sectors, including Ministry of Health, Agriculture, Food and Nutrition, Sports, and Housing [2,17 19].

10.3 FOOD SECURITY AND EMERGENCE OF CARDIOVASCULAR DISEASES The FAO has made tremendous efforts during nutritional transition from poverty to affluence and provided guidelines for increased availability of foods resulting in to food security for most populations of the world [1 4,7] (Fig. 10.1). The world population in 2016 is estimated to be growing at a rate of around 1.13% per year and the current average population change is estimated at around 80 million per year. The United Nations estimated that the world’s population will increase from 7.4 billion in 2016 to 8.1 billion in 2025, with most growth in developing countries and more than half in Africa. By 2050, the world population will reach 9.6 billion. There is marked reduction in death rates due to undernutrition and an emergence of morbidity and mortality due to CVDs which has been attributed to food security [7]. It is clear that the biggest cause of death in the world appears to be either less food causing deaths due to undernutrition or increased availability of food, i.e., food security causing deaths due to overnutrition and related diseases—CVDs, diabetes, and cancer [6 9,20 24] (Fig. 10.2).

10.3 FOOD SECURITY AND EMERGENCE OF CARDIOVASCULAR DISEASES

171

Both sexes, Age-standardized, 2013, Deaths per 100,000 n Ba p Ja

1

1

1

1

1

1

12

4

3

7

4

6

2

Low fruit

3

4

7

3

5

4

5

2

5

4

Smoking

4

5

9

2

7

6

13

6

4

5

Ambient particulate matter

5

7

16

10

13

9

6

7

14

10

High body-mass index

6

11

2

7

2

2

2

14

2

7

Low whole grains

7

13

11

5

10

15

12

8

7

9

High fasting plasma glucose

8

8

4

11

8

10

11

10

9

11

Household air pollution

9

6

8

20

8

3

3

an

a si

1

6

es h

us R

ad gl

n ta is

1

2

ria

il

e ig N

az Br

1

2

es ia

on

k Pa

d In S U

1

High sodium

d In ia

na hi C

High blood pressure

Lead

10

18

19

18

19

17

17

13

21

19

Low physical activity

11

9

5

9

6

13

8

9

11

6

High total cholesterol

12

3

3

6

3

5

9

12

3

3

Low omega-3

13

12

12

22

14

14

14

16

17

21

Low fiber

14

15

15

15

16

18

19

18

16

14

Low nuts and seeds

15

16

10

13

12

16

16

17

12

12

Alcohol use

16

20

20

19

21

22

15

21

8

16

Low vegetables

17

10

8

4

9

7

10

5

10

8

Low glomerular filtration

18

14

14

14

11

12

4

11

15

13

Low PUFA

19

17

18

16

18

19

18

19

18

15

Secondhand smoke

20

22

22

17

22

21

22

22

19

18

High trans fat

21

19

17

21

15

11

20

15

20

17

High processed meat

22

21

13

20

17

20

21

20

13

20

High sweetened beverages

23

23

21

23

23

23

23

23

22

22

FIGURE 10.2 Dietary factors and other risk factors in relation to mortality in the global burden of disease study. Modified from GBD, 2013 Mortality and Causes of Death Collaborators. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990 2013: a systematic analysis for the Global Burden of Disease Study 2013. The Lancet 2015;385:117 171. https://doi.org/10.1016/S0140-6736(14)61682-2.

In 1947, almost half of the world’s population had undernutrition, that has declined by more than 25% globally. However, it is a serious problem for FAO, because 868 million people remain hungry, an estimated 2 billion people suffer from one or more micronutrient deficiencies and an estimated 1.4 billion people are overweight, of whom 500 million are obese, which predisposes to type 2 diabetes and CVDs. It is apparent, therefore, that food security has been the priority of most of the health agencies such as FAO and, with little consideration for functional foods in the year 2017 [23]. It is likely that there was no hard data with FAO and WHO indicating that increased availability of western type foods may increase life expectancy for hardly 60 years or slightly more. These agencies may have presumed that some food whatever it may be is better than keeping people hungry. It is now clear that food security is mostly associated with unhealthy diet, physical inactivity, tobacco use, and alcohol consumption due to improvement in economic status. Thus food security in most countries of the world accept Japan has caused emergence of obesity, metabolic syndrome, diabetes, hypertension, atherosclerosis, carcinogenesis, degenerative diseases of brain, and osteoporosis [2,7 16]. The Western-type foods are the refined, high-energy and

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low-nutrient foods; salty or sugary, red meat, preserved and processed meats, bread, biscuits, candies, cookies, white chocolate, and sirups constitute the category of western type foods. These foods are rapidly absorbed due to their high glycemic index and have adverse effects on health, resulting in CVDs. Apart from rapidly absorbed foods, deep fried foods, red meat, preserved, salted meats and snacks, plastic-containing foods, Chinese rice, trans fat, and too much omega-6, saturated fat, and trans fat-rich foods are also unhealthy and may have adverse effects on cardiovascular function [2,19,20].

10.4 FUNCTIONAL FOOD SECURITY AND PREVENTION OF CARDIOVASCULAR DISEASES Functional foods and Functional Farming (FF) (4 F) is the most suitable solution for health promotion which should be adopted by the WHO and FAO for world health. Functional foods may be defined as foods which contain certain nutrients that can address some physiological mechanisms in our bodies, thereby providing benefits [18 20]. FF aims to produce functional foods either by appropriate soil, or by genetic engineering or plant breeding [20]. Feeding functional diet to animals can also provide functional animal foods such as egg, meat, and milk. Functional food security in conjunction with increased physical activity are effective measures, and weight loss is the main predictor of the success [1 4,17 20]. Fig. 10.2 denotes that functional foods were inversely associated with causes of death in 10 high populous countries. The role of functional foods has been realized by the World Health Organization and International College of Nutrition which has been reflected in their publications after 1990. Increased availability of foods at affordable cost, that are rich in protective nutrients and low in energy and macronutrients which have beneficial effects, may be defined as functional food security [1 4,17 20]. In general, such foods increase the life expectancy, to 68 years and more. There is evidence that functional food security may improve other health behaviors: health education, moderate physical activity, moderation in alcohol intake, no tobacco, leading to health promotion with reduction in NCDs. These changes in health behavior can enhance life expectancy above 80 years, because other primary and secondary risk factors are also prevented [4,7,17 24]. A cohort study in China included 512,891 adults, aged 30 79 years [22]. After follow-up, 5173 deaths from CVDs, 2551 incident major coronary events (fatal or nonfatal), 14,579 ischemic strokes, and 3523 intracerebral hemorrhages were recorded among the 451,665 participants. The recruited subjects revealed no history of CVDs or antihypertensive treatment at the outset. Increased consumption of fresh fruit daily showed lower systolic blood pressure (by 4.0 mm Hg) and blood glucose concentrations (by 0.5 m mol/L [9.0 mg/dL]) (P , .001). The association of the risk of acute heart attack was examined among 287 women, aged 22 69 years and 649 controls. The findings revealed that increased intake of functional food had significant inverse association for fish (0.6), carrots (0.4), green vegetables (0.6), and fresh fruit (0.4). However increased frequency of consumption of meat (odds ratio 1.5 for upper vs lower thirds of consumption), ham and salami (1.4), butter (2.3), total fat added to food (1.6), and coffee (2.8) showed no such effects [25]. The risk was below one for moderate alcohol consumption (0.7) and above one for heavier intake (1.2) indicating that alcoholism could be a risk factor of heart attack. It is possible that frequency of consumption of functional foods and Western-type foods may provide useful indicators

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of the risk of heart attack. It is likely that certain foods—fish, moderate alcohol, or vegetables and fruits—may have an independent protective role against risk of heart attack [25]. A heavy breakfast or dinner with Western diet has also been reported in another case-control study involving 202 patients with ACS. This study showed a significant (P , .02) increase in cardiac events in the second quarter of the day compared to other quarters, respectively (16.8%, 41.0%, 13.8%, 28.2% per quarter). Other risk factors were: Western diet 72.6%), emotional stress (45.5%), sleep deprivation (27.7%), cold climate (29.2%), hot climate (24.7%), large meals (47.5%), and physical exertion (31.2%) [26]. Several other studies have also reported an inverse association of functional food intake with risk of CVDs [26 30]. Tables 10.1 and 10.2 show some of the important functional foods consumed in Asia and other countries. The understanding about the Paleolithic diet can increase our knowledge about the concept of functional foods. The changes in the diet have occurred in the last 40,000 years during transition from Homo sapiens to modern men. Cohort studies have also revealed that diets that are rich in vegetables and low in red meat and whole-fat dairy products can cause reduced risk of CVDs and type 2 diabetes [1 7,21,22]. High consumption of functional foods (vegetables, legumes, whole grains, fruits, nuts, and olive oil), moderate consumption of fish and wine, and low consumption of red and processed meat and whole-fat dairy products are important characteristics of a traditional Mediterranean-style diet. It is widely recognized that increased content of such foods in the diets, is a healthy dietary pattern, similar to Paleolithic diet [1,17 24]. In Southern European countries, several cohort studies have revealed a lower incidence of CVDs and diabetes with increasing adherence to the Mediterranean-style diet in previously healthy individuals and in survivors of heart attacks [23,24]. In a previous case control study, six food items were assessed that were considered protective, among 171 patients with AMI and 171 matched controls. The findings revealed that the greater the

Table 10.1 Functional Food Package for Prevention of Cardiovascular Diseases (for vegetarian, replace with soya bean, cottage cheese, and yogurt) Functional Foods

Amount (g/day)

Foods

Nutrient/Mechanism

Fruits Vegetables Nuts

200 300 200 300 30 50

Apple, grapes, guava, berries Green leaves, gourds Walnuts, almond, peanuts

Whole grains

400 500

Fish, sea foods Poultry Curd/yogurt Spices Fats and oils

50 100 50 100 100 200 10 20 30 100

Gram, beans, peas, millets soybean, pulses, porridge Salmon, any oily fish, e g mackerel Egg-quail & hen, chicken, duck Prebiotic, probiotics Turmeric, fenugreek, cumin, coriander Olive, mustard/canola

Flavonoids, vit C, flavonoids Flavonoids, carotenoids Amino acids, ω-3 in walnut, low glycemic index, MUFA Flavonoids, amino acids, complex carbohydrates ω-3, amino acids, selenium, CoQ10 Amino acids, Immunity, gut microbiome Flavonoids, minerals Flavonoids, ω-3, MUFA

Olive and rape seed oil are known to decrease CVDs, diabetes and all-cause mortality.

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Table 10.2 Saboo’s and Singh’s Blend of Fats and Oils With Possible Beneficial Effects on Health Oils, /100 g Olive oil (50%) Rape seed/canola oil (20%) Rice bran oil (10%) Sesame oil (10%) Flax seed oil (10%) Blended oil 5 total 100.13 g

Saturated Fat

ω-6 Fat

ω-3 Fat

MUFA

Protective Nutrient

7.00 1.4

7.50 4.11

0.75 2.00

36.00 13.00

Flavonoids, MUFA ω-3,MUFA

2.5 1.5 1.10 13.50

3.4 4.00 0.66 19.67

0.21 0.1 5.5 8.56

3.80 4.00 1.60 58.4

Oryzenol Phytosterol ω-3, 54% ω-6/ω-3ratio 5 2.29, polyphenols, oryzenol, phytosterol

Olive oil and rape seed oil are known to decrease cardiovascular diseases, diabetes and all-cause mortality. No such evidence for other oils. MUFA 5 monounsaturated fatty acids.

score of food intakes, the lower the odds ratio of heart attack. The results showed that fiber, fruits, vegetables, fish, olive oil, and alcohol were inversely associated with the risk of heart attack [26]. It is possible that a Mediterranean diet that emphasizes olive oil, fiber, fruits, vegetables, fish, and alcohol and reduces meat/meat products, can be an effective measure for reducing the risk of myocardial infarction. Exclusion of refined cereals with a high glycemic load is an healthy elements of Mediterranean diet. In a more recent study, 760 patients, below age 79 years, having nonfatal AMI, were compared with 682 noncardiac subjects, unrelated with diet [27]. The consumption of anthocyanidins (OR 5 0.45, 95% CI: 0.26 0.78 for the highest vs the lowest quintile, (P trend 5 .003)) and flavonols (OR 5 0.65, 95% CI: 0.41 1.02, (P trend 5 .02)) were reported to be protective against heart attack [27]. It is possible that increased intake of anthocyanidins might have protected from the risk of AMI, despite allowance for alcohol, fruit, and vegetables, supporting a real inverse association. A previous study involving 54 AMI patient and 85 control subjects, showed that mean total cholesterol and triglycerides were significantly higher and mean nitrite level lower in the study group as compared with the control group. The frequency of lipoprotein(a) excess (. 30 mg/dL; 42.6% vs 24.7%; P , .05) and mean concentration of lipoprotein(a) (Lp[a], 6.4 mg/dL, 95% CI: 2.8 10.5; P , .05) was significantly greater in the AMI group compared with control subjects [29]. The incidence of cardiac events was significantly greater in the second quarter of the day; 6.00 12.00 hours, compared to other time structures. Large breakfasts were a predisposing factor for cardiac events in the second quarter of the day and it was significantly associated with metabolic reactions. There was a significant decline in all the acute phase reactants: Lp (a), triglycerides, blood glucose, plasma insulin, malondialdehyde, diene conjugates, TBARS and tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-6 levels, that were significantly greater during the acute phase. Serum nitrite and coenzyme Q revealed an increase at 4 weeks of follow-up when the acute reactions evoked by MI had been controlled [29]. It is proposed that acute reactions as a result or as circadian rhythms appear to be important in the pathogenesis of AMI as well as in

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the associated complications. A large breakfast in association with nitrite deficiency may further trigger the circadian rhythms [29]. The increased circadian rhythm of cardiovascular events have also been observed in another case-control study involving 202 patients with AMI. The findings revealed a significant (P , .02) increase in cardiac events in the second quarter of the day compared to other quarters, respectively (16.8%, 41.0%, 13.8%, 28.2% per quarter). The cardiac events were mostly after a heavy breakfast or dinner [30]. Emotional stress (45.5%), sleep deprivation (27.7%), cold climate (29.2%), hot climate (24.7%), large meals (47.5%), and physical exertion (31.2%) were neuropsychological triggers to predispose circadian rhythms. The study showed, a decrease in magnesium, potassium, vitamin A, E, C, and beta carotene combined with an increase in thiobarbituric acid-reactive substances (TBARS), MDA and diene conjugates, TNF-alpha and IL-6, all of which are indicators of oxidative damage and pro-inflammatory activity, respectively [29,30]. These triggering factors may increase sympathetic activity and decrease vagal tone, with underlying increased release of noradrenaline, aldosterone, plasma cortisol, angiotension-converting enzyme, IL-1, -2, -6, -18, and TNF-alpha, all of which are proinflammatory agents. There is concurrent deficiency of antioxidant vitamin A, E, and C and magnesium, potassium, melatonin, and IL-10 (an antiinflammatory agent). The INTERHEART, study, involving participants from 52 countries used the principlecomponent analysis technique, in which dietitians identified three major dietary patterns [31]. The Oriental diet included high intake of tofu and soy and other sauces; Western diet, high in fried foods, salty snacks, eggs, sweetened foods, and meat; and prudent diet, high in fruit and vegetables. The authors demonstrated an inverse association between the prudent pattern score and risk of ACS and a significant positive association between the Western pattern score and increased risk of ACS [31]. A dietary risk score was constructed based on seven food items on the food-frequency questionnaire (meat, salty snacks, fried foods, fruits, green leafy vegetables, cooked vegetables, and other raw vegetables) and found that a higher score (indicating a poor diet) was strongly associated with risk of ACS. The authors reported that 30% of MI could be explained by unhealthy diets worldwide, based on an arbitrary cut point of score: top three quartiles compared to bottom quartile. The INTERHEART study provides evidence that despite different food habits in various populations, reproducible patterns can be found in diverse regions of the world. The most important weakness of this study was that dietary assessment were done by different investigators in various countries and total food intakes were not assessed in any of the countries. The habitual intake of food eating patterns were quantified by statistical methods such as factor or cluster analysis or dietquality indexes based on prevailing dietary recommendations or healthful traditional diets, e.g., the Mediterranean diet, and Indo-Mediterranean diet which are open to bias. The study indicated a consistent association between the Western-type food intake, characterized with greater amount of animal foods, salty foods, refined starches, and sugar and fried foods, as well as butter and vegetable oils rich in omega-6 fat and low in fruits and vegetables, with risk of heart attack in various countries of the world. Most of these studies did not assess the role of global trade and marketing on dietary patterns, and their effects on biological risk factors such as endothelial dysfunction and inflammation, across different countries. [28 31]. However, most recent studies indicate that the modern trend of dietary convergence toward a Western-type of diet can play a major role in the globalization of risk factors of cardiometabolic diseases and other NCDs [28 31].

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10.5 INTERVENTION TRIALS WITH FUNCTION FOODS Intervention trials with functional foods are conducted using Indo-Mediterranean style foods or Mediterranean-style diets in subjects with CVDs or among those with high risk of CVDs [32 40]. Acute heart attack is a highly dynamic state which is characterized with highly pro-inflammatory milieu with severe neuro-endocrinological dysfunction, apart from myocardial damage [41 43]. There may be significant rise in free radical stress and inflammation, free fatty acids due to greater extent of sympathetic activity, dyslipidemia and deficiency of magnesium, potassium, coenzyme Q10, as well as in vitamin A, C, E, and beta-carotene during the cardiovascular event. Endothelial dysfunction can also occur due to increase in free fatty acids and endothelin 1 and reduction in bradykinin and nitric oxide which enhances the susceptibility for recurrent heart attacks after myocardial infarction. It is possible to prevent these complications by functional food administration in the form of a yogurt or vegetable soup rich in almonds and walnuts or by Mediterranean-style foods [41 43]. There may be worsening of the pro-inflammatory biomarkers with a deficiency of endogenous antioxidants such as super-oxide-dismutase, catalase, and ceruloplasmin. Deficiency of omega-3 fatty acids, magnesium, potassium, and flavanols in the tissues can increase the damage to cardiomyocytes which may predispose cardiac arrhythmias. Apart from myocardial damage, the atheromatous plaque in heart attack can sometimes turn to unstable or inflamed plaque, with split or rupture, exposing thrombogenic material, which activates platelets and the coagulation cascade and produces an acute thrombus. The patho- physiology of ACS or myocardial infarction is associated with a deficiency of antioxidants vitamins as well as flavonoids due to increased consumption of these nutrients by the cells. There is an opportunity to administer functional foods in patients with heart attack as soon as the patient can tolerate a Mediterranean-style soup developed from functional foods [33 35]. These foods in the form of soup or yogurt in a semisolid form are rapidly absorbed to counteract antioxidant deficiency which is protective for myocardial and endothelial cells. Among 404 patients with ACS, Indo-Mediterranean diet group was advised fruits, vegetable, whole grains, nuts, and mustard oil initially as soup and later on as foods after few days compared to standard diet regimen [33 35]. The results after follow up of 2 years revealed that the total mortality was 14.7% in the intervention diet group and 25.2% in the control group (P 5 .08) [35]. The results also showed that decreasing ω-6/ω-3 fatty acid ratio of the diet in the intervention group from 32.5 to 3.5 was associated with significant decline in total cardiac mortality, total cardiovascular mortality, and total mortality compared to control diet group. It is possible that high omega-3 fatty acids and flavanols during the acute dysfunction in the cardiomyocyte as well endothelial cells may influence clinical outcome. There were 605 patients with myocardial infarction, included in the Lyon Heart Study. They were randomly assigned to a Mediterranean-style diet of Crete or a prudent diet as per guidelines that are also followed by the American Heart Association [36,37]. The intervention diet provided a ratio of ω-6 to ω-3 of 4/1 which was achieved by substituting olive oil and rape seed oil margarine for corn oil. A lower ratio of ω-6/ω-3 in the diet in the Lyon Heart Study, led to a 70% decrease in total mortality at the end of 27 months [36]. Further follow up for 4 years also showed that the beneficial effects of diet were present in the intervention group [37]. The Indo-Mediterranean Diet Heart study comprised of in 1000 patients, with existing coronary disease or at high risk for

10.5 INTERVENTION TRIALS WITH FUNCTION FOODS

177

coronary disease. Half of the patients (n 5 499 vs 501) were administered a Indo-Mediterranean style foods, whole grains such as gram, peas, kidney beans, red bean, green and black beans, along with vegetables, fruits, walnuts, mustard oil as a source for ω-3 fat and the remaining 501 patients were advised to take a prudent diet advised by the NCEP step 1 diet in 1988 [38]. The mean consumption of ω-3 fatty acids was over two-fold greater in the Indo-Mediterranean diet group compared to control group (1.8 6 0.4 vs 0.8 6 0.2 g/day, P , .001) during the follow up of 2 years. This ratio of fatty acids, showed a marked decline in the intervention group, which was greater than that observed in the control group consuming control diet (9.1 6 12 vs 21 6 10, P , .001). The ω-6/ω-3 ratio of fatty acids was slightly higher at baseline in the intervention group than in the control group (39 6 12 vs 34 6 10) yet both these values are extremely high, reflecting a diet with a very high ω-6 content in presence of low ω-3 [38]. There was a significant decline in the total cardiac events, sudden cardiac death, and nonfatal MI in the Indo-Mediterranean diet group compared to the control group. In an earlier trial, Burr et al. also reported a 29% decline in total mortality including a decrease in sudden cardiac death in the group that received fish advice or took fish oil supplements (tuna or salmon oily fish) relative to the group that did not among patients with heart attacks [44]. In a three arm clinical trial, Singh et al. compared fish oil and mustard oil with control vegetable oils in patients with heart attack [39]. After a follow up of 1 year, there was a significant reduction in total cardiac events in the fish oil and mustard oil groups compared to control group patients with heart attack [39]. Modification of the consumption of fat components, by reducing the intake of omega-6 fatty acids is quite interesting but other nutrients should also be included in the diet which is possible by functional food administration. A lower omega-6/omega-3 ratio in the background diets and the dose of EPA and DHA could be an important nutrients in studies with conflicting results in intervention trials on the role of EPA and DHA in patients with ventricular arrhythmias showing a beneficial effect [45 51]. Dietary intake of fruits and vegetables can also improve microvascular function in hypertensive subjects in a dose-dependent manner [45] The study of functional food consumption patterns among decedents dying from various causes revealed that functional food intakes were inversely associated with risk of mortality from CVDs and other chronic diseases [20]. The results of further studies showing beneficial effects on microcirculation, ventricular premature beats, arrhythmias, inflammation, platelets function, and nitric oxide provide convincing evidence that increased consumption of functional foods and lifestyle modification can reduce the incidence of CVDs among high-risk individuals and AMI patients [45 51]. The beneficial effects of functional foods on the molecular mechanism of complications in patients with heart attack pose the possibility that functional food and herb extract, such as cocoa, green tea, apple, black grapes, guava juice should be tried among patients undergoing angioplasty to prevent restenosis. The beneficial effects of Mediterranean-style diet could be enhanced by adding guava fruit and millets into the diet due to their potential nutrient contents [52,53]. It seems that there should be no upper limit for fat intake, if the fats or oils are healthy, because increased consumption of olive oil and other fatty acids (41% en from total fat) was associated with a significant decline in CVDs compared to control group receiving high saturated fat diet in the PREDIMED study [40]. The PREDIMED diet included olive oil in the intervention group, whereas control group took optimal fat diet consumed in the Mediterranean countries. This primary prevention trial, also reported a significant decline in CVDs in the intervention group compared to control group [40].

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10.6 EFFECTS OF MEDITERRANEAN-STYLE DIETS IN HYPERTENSION AND STROKE The beneficial effects of Mediterranean-style diets extend to hypertension, stroke, and chronic heart failure [5 11]. A recent cohort study by Sotos-Prieto et al. showed that increased intake high DASH score diet was associated with significant decline in all cause and cause specific mortality including stroke mortality. The PREDIMED study also reported significant decline in stroke as well as diabetes and hypertension in the various substudies [40]. In a randomized, double-blind, placebo-controlled 8-week, clinical trial, 48 postmenopausal women, with pre- and stage 1 hypertension were randomly assigned to receive either 22 g freezedried blueberry powder or 22 g control powder. After a follow up of 8 weeks, systolic blood pressure and diastolic blood pressure (131 6 17 mm Hg [P , .05] and 75 6 9 mm Hg [P , .01], respectively, were significantly lower. The brachial-ankle pulse wave velocity (1401 6 122 cm/second; P , .01) was also significantly lower than baseline levels (138 6 14 mm Hg, 80 6 7 mm Hg, and 1498 6 179 cm/second, respectively), with significant (P , .05) group 3 time interactions in the blueberry powder group, whereas there were no changes in the group receiving the control powder. The levels of nitric oxide were greater (15.35 6 11.16 μmol/L; P , .01) in the blueberry powder group at 8 weeks compared with baseline values (9.11 6 7.95 μmol/L), without any changes in the control group [54]. It is possible that daily blueberry intake may reduce blood pressure and arterial stiffness, which may be due, in part, to increased nitric oxide production. In an earlier, randomized trial, 217 hypertensives received either 1600 kcal/day diet rich in fruits and vegetables and pulses (group A, n 5 108) or the optimal 2100 kcal/day diet (group B, n 5 109) [55]. Sodium intake and physical activity were kept similar in both groups. Intervention group A received significantly less energy leading to a 2.8 kg net reduction in mean weight in association with a significant net decrease in mean SBP and DBP (7.5/6.5 mm Hg) compared with nonsignificant changes in group B, after a follow up of 16 weeks. There was a significant net decrease in mean total cholesterol (7.0%), low-density lipoprotein-cholesterol (7.9%), and triglycerides (8.0%), with a significant net increase in high-density lipoprotein (HDL)-cholesterol (4.0%) in group A compared with group B. Glucose intolerance (8.0%) and central obesity (waist-hip girth ratio, 0.021) showed a significant net reduction compared with group B. Patients with central obesity and other associated disturbances showed maximal reduction in BP and other cardiovascular risk factors with a significantly greater increase in HDL-cholesterol. Mean doses of drugs were similar at entry to the study as well as after 16 weeks in both groups. It is possible that weight reduction due to a low caloric diet can moderate central obesity and associated disturbances in hypertensive subjects. Coronary risk factors and ambulatory blood pressure and heart rate monitoring for 3 7 days, every half hour, in 209 Asian Indians, revealed that fruit and vegetable intake were inversely associated with the MESOR (rhythm-adjusted mean) of systolic and diastolic blood pressure and heart rate, indicating that these foods can enhance heart rate variability and reduce excessive blood pressure variability [56]. These foods can also enhance the capability of the human body to adapt to environmental factors [56]. The effects of guava intake on serum total and HDL cholesterol concentrations and systemic blood pressure were examined among 61 patients with hypertension [53]. After a 12-week follow-up, there was a significant decline in both systolic and diastolic blood pressure and in blood lipoproteins without a decrease in HDL cholesterol. This study also reported a

REFERENCES

179

significant decline in oxidative stress which may be due to high intake of vitamin C and flavonoids present in the guava fruit. In a randomized trial, of 197 hypertensive patients, 97 were randomized to receive an intervention diet rich in fruits, vegetables, whole grains and nuts for comparison with 100 patients receiving a usual low-fat diet [57]. Half of the subjects in both groups had diuretic induced hypomagnesemia and hypokalemia, thus indicating the possibility that the deficiency of these cations predisposed these patients to an aggravation of hypertension requiring more drugs to lower blood pressure. After 1 year of followup, deficiency of magnesium and potassium was repaired by the dietary approaches and by giving more dietary potassium and magnesium to reduce the aggravation of hypertension [57]. The Sofia Declaration proposed by Hristova et al. and Singh et al. further emphasizes the role of nutrition in the management of hypertension and other CVDs [58,59]. These strategies are consistent with the DASH proposed by American experts [60]. A DASH diet, which is rich in fruits, vegetables, and low-fat dairy foods, is reportedly effective as first-line therapy in stage 1, isolated systolic hypertension [60]. The US Department of Agriculture and International College of Cardiology have suggested no limit for total fat intake but limit the intake of saturated fat, trans fat, and possibly also possibly omega-6 fat which are known to have adverse effects. The best composition of fatty acid in the oil could be achieved by blending the oils as given in Table 10.2. The blend of oils provides high omega-3 fatty acids, low omega-6 as well as increased content of oryzenol, phytosterol that are potential antioxidant administered via this blend of oils. Association of higher omega-6/omega-3 fatty acids in the diet with higher prevalence of CAD, hypertension and diabetes as well as metabolic syndrome has also been reported in a recent study [61]. However, recent meta-analysis of trials with fish oil showed no beneficial effects of omeg-3 fatty acids on CVDs [62], indicating that omega-3 fatty acids benefits only when administered as component of Mediterranean diet which is also rich in antioxidant rich vergin oil [63 65]. The virgin olive oil contains numerous phenolic compounds that exert potent anti-inflammatory actions among which oleocanthal has been found to be most potential. The anti-inflammatory activity of oleocanthal is as good as anti-inflammatory properties of ibuprofen [65]. In conclusion, cohort studies and intervention trials provide a proof that increased consumption of functional foods can cause significant decline in cardiovascular risk among patients with CVDs. Functional food security provided foods available at affordable cost can enhance the consumption of these foods, resulting in health promotion and global prevention of these diseases.

ACKNOWLEDGMENTS The authors would like to thank the International College of Cardiology for providing logistic support to write this article.

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[2] Hristova K, Pella D, Singh RB, Dimitrov BD, Chaves H, Juneja L, et al. Sofia declaration for prevention of cardiovascular diseases and type 2 diabetes mellitus: a scientific statement of the international college of cardiology and international college of nutrition; ICC-ICN Expert Group. World Heart J, 6. New York: Nova Publishers; 2014. p. 89 106. [3] De Meester F. Wild-type land based foods in health promotion and disease prevention: the LDL-CC: HDL-CC model. In: De Meester F, Watson RR, editors. Wild type foods in health promotion and disease prevention. Totowa, NJ: Humana Press; 2008. p. 3 20. [4] Wang DD, Hu F. Dietary fat and risk of cardiovascular disease: recent controversies and advances. Annu Rev Nutr 2017;37:423 46. Available from: https://doi.org/10.1146/annurev-nutr-071816-064614. Epub 2017 Jun 23. [4a] Pedersen T. Mouse Study: Canola oil linked to weight gain, memory decline in Alzheimer’s. Psych Central. Retrieved on December 21, 2017, from-https://psychcentral.com/news/2017/12/10/mouse-studycanola-oil-linked-to-weight-gain-memory-decline-in-alzheimers/129738.html. [5] Sotos-Prieto M, Bhupathiraju SN, Mattei J, fung TT, Li Y, Pan A, et al. Association of changes in diet quality with total and cause-specific mortality. N Engl J Med 2017;377:143 53. Available from: https:// doi.org/10.1056/NEJMoa1613502. [6] Chauhan AK, Singh RB, Ozimek L, Basu TK. Saturated fatty acid and sugar; how much is too much for health? A scientific statement of the International College of Nutrition. Viewpoint, World Heart J, 8. New York: Nova Publishers; 2016. p. 71 8. [7] GBD. Mortality and Causes of Death Collaborators. Global, regional, and national age-sex specific allcause and cause-specific mortality for 240 causes of death, 1990 2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 2015 2013;385:117 71. Available from: https://doi.org/ 10.1016/S0140-6736(14)61682-2. [8] Sacco RL, Roth GA, Reddy KS, Arnett DK, Bonita R, Gaziano TA, et al. The heart of 25 by 25: achieving the goal of reducing global and regional premature deaths from cardiovascular diseases and stroke: a modeling study from the American Heart Association and World Heart Federation. Circulation 2016 2016;133. Available from: https://doi.org/10.1161/CIR.0000000000000395. Published online before print May 9. [9] Expert Group, International College of Cardiology. The challenges of prevention of cardiovascular diseases. A scientific statement of the international college of cardiology. World Heart J 2016;8(4):281 8. [10] Singh RB, Pella D, Mechirova V, Kartikey K, Demeester F, Tomar RS, et al. Prevalence of obesity, physical inactivity and undernutrition, a triple burden of diseases during transition in developing countries The Five City Study Group Acta Cardiol 2007;62:119 27. [11] Singh RB, Bajaj S, Niaz MA, Rastogi SS, Moshiri M. Prevalence of type 2 diabetes mellitus and risk of hypertension and coronary artery disease in rural and urban population with low rates of obesity. Int J Cardiol 1998;66(1):65 72. [12] Pella D, Thomas N, Tomlinson B, Singh RB. Prevention of coronary artery disease: the South Asian paradox. Lancet 2003;361:79 80. [13] Janus ED, Postiglione A, Singh RB, Lewis B. On behalf of the council on arteriosclerosis of the International Society and Federation of Cardiology. The modernization of Asia: implications for coronary heart disease. Circulation 1996;94:2671 3. [14] Twig G, Yaniv G, Levine H, Leiba A, Goldberger N, Derazne E, et al. Body-mass index in 2.3 million adolescents and cardiovascular death in adulthood. New Engl J Med 2016;oa1503840. Available from: https://doi.org/10.1056/NEJM. [15] Davey Smith G, Sterne JAC, Fraser A, Tynelius P, Lawlor DA, Rasmussen F. The association between BMI and mortality using offspring BMI as an indicator of own BMI: large intergenerational mortality study. BMJ 2009;339:b5043.

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[16] Roth GA, Nguyen G, Forouzanfar MH, Mokdad AH, Naghavi M, Murray CJ. Estimates of global and regional premature cardiovascular mortality in 2025. Circulation. 2015 Sep 29;132(13):1270 82. [17] Itharat A, Onsaard E, Singh RB, Chauhan AK, Shehab O. Flavonoids consumption and the heart. World Heart J 2016;8:103 8 (Nova Publishers, NY). [18] The 2015 2020 Dietary Guidelines for Americans. http://www.usda.gov/wps/portal/usda/usdahome? contentid 5 2016/01/0005.xml, accessed 01.07.2016. [19] Singh RB, Takahashi T, Shastun S, Elkilany G, Hristova K, Shehab A, et al. The concept of functional foods and functional farming (4 F) in the Prevention of cardiovascular diseases: a review of goals from 18th world congress of clinical nutrition. J Cardiol Therapy 2015;2(4):273 8. Available from: http:// www.ghrnet.org/index.php/jct/article/view/. [20] Singh RB, Visen P, Sharma D, Sharma S, Mondol R, Sharma JP, et al. Study of functional foods consumption patterns among decedents dying due to various causes of death. The Open Nutra J, 8. USA: Bentham Science; 2015. p. 16 28. [21] Kastorini CM, Panagiotakos DB. Dietary patterns and prevention of type 2 diabetes; from research to clinical practice; a systematic review. Curr Diabetes Rev 2009;5:221 7. [22] Du H, Li L, Bennett D, Guo Y, Key TJ, Bian Z, et al. China Kadoorie Biobank Study. Fresh fruit consumption and major cardiovascular disease in China. N Engl J Med 2016;374:1332 43. Available from: https://doi.org/10.1056/NEJMoa1501451. [23] Shastun S, Chauhan AK, Singh RB, et al. Can functional food security decrease the epidemic of obesity and metabolic syndrome? A viewpoint. World Heart J, 8. New York: Novapublishers; 2016. p. 3. in press. [24] Shehab A, Elkilany G, Singh RB, Hristova K, Chaves H, Cornelissen G, et al. Coronary risk factors in Southwest Asia. Edit World Heart J, 7. New York: Novapublishers; 2015. p. 21 3. [24a] FAO of the UNO. Guidelines on assessing biodiverse foods in dietary intake surveys. 2017 http://www. fao.org/documents/card/en/c/5d2034ff-a949-482a-801c-44b7b675f1dd [25] Gramenzi A, Gentile A, Fasoli M, Negri E, Parazzini F, La Vecchia C. Association between certain foods and risk of acute myocardial infarction in women. BMJ 1990;300:771 3. [26] Martı´nez-Gonz´alez MA, Fern´andez-Jarne E, Serrano-Martı´nez M, Marti A, Martinez JA. Martı´nMoreno Mediterranean diet and reduction in the risk of a first acute myocardial infarction: an operational healthy dietary score. Eur J Nutr 2002;41(4):153 60. [27] Tavani A, Spertini L, Bosetti C, Parpinel M, Gnagnarella P, Bravi F, et al. Intake of specific flavonoids and risk of acute myocardial infarction in Italy. Public Health Nutr 2006;9(3):369 74. [28] Singh RB, Fedacko J, Sharma JP, et al. Association of inflammation, heavy meals, magnesium, nitrite and coenzyme q10 deficiency and circadian rhythms with risk of acute coronary syndromes. World Heart J, 2. New York: Novapublishers; 2012. p. 219 27. [29] Singh RB, Pella D, Sharma JP, Rastogi S, Kartikey K, Goel VK, et al. Increased concentrations of lipoprotein(a), circadian rhythms and metabolic reactions evoked by acute myocardial infarction, associated with acute reactions in relation to large breakfasts. Biomed Pharmacother 2004;58(Suppl 1):S116 22. [30] Singh RB1, Pella D, Neki NS, Chandel JP, Rastogi S, Mori H, et al. Mechanisms of acute myocardial infarction study (MAMIS). Biomed Pharmacother 2004;58(Suppl 1):S111 15. [31] Iqbal R, Anand S, Ounpuu S, Islam S, Zhang X, Rangarajan S, et al. On behalf of the INTERHEART Study Investigators. Dietary patterns and the risk of acute myocardial infarction in 52 countries: results of the INTERHEART study. Circulation 2008;118:1929 37. [32] Vogel RA. Eating vascular biology and atherosclerosis: a lot to chew on. Eur Heart J 2006;27:13 14. [33] Singh RB, Rastogi SS, Verma R, Bolaki L, Singh R. An Indian experiment with nutritional modulation in acute myocardial infarction. Am J Cardiol 1992;69:879 85. [34] Singh RB, Rastogi SS, Verma R, Laxmi B, Singh R, Ghosh S, et al. Randomized, controlled trial of cardioprotective diet in patients with acute myocardial infarction: results of one year follow up. BMJ 1992;304:1015 19.

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[35] Singh RB, Fedacko J, Vargova V, Niaz MA, Rastogi SS, Ghosh S. Effect of low ω-6/ω-3 ratio fatty acid Paleolithic style diet in patients with acute coronary syndromes. A randomized, single blind, controlled trial. World Heart J, 3. New York: Novapublishers; 2012. p. 71 84. [36] de Lorgeril M, Renaud S, Mamelle N, Salen P, Martin JL, Monjaud I, et al. Mediterranean alphalinolenic acid-rich diet in secondary prevention of coronary heart disease. Lancet 1994;343 (8911):1454 9 Erratum in: Lancet 1995,345 (8951):738. [37] De Logeril M, Salen P, Martin JL, Monjaud I, Delaye J, Mamelle N. Mediterranean diet, traditional risk factors and the rate of cardiovascular complications after myocardial infarction. Final report of the Lyon Diet Heart Study. Circulation 1999;99:779 85. [38] Singh RB, Dubnov G, Niaz MA, Ghosh S, Singh R, Rastogi SS, et al. Effect of an Indo-Mediterranean diet on progression of coronary disease in high risk patients: a randomized single blind trial. Lancet 2002;360:1455 61. [39] Singh RB, Niaz MA, Sharma JP, Kumar R, Rastogi V, Moshiri M. Randomized, double-blind, placebocontrolled trial of fish oil and mustard oil in patients with suspected acute myocardial infarction: the Indian experiment of infarct survival—4. Cardiovasc Drugs Ther 1997;11:485 91. [40] Estruch R, Ros E, Salas-Salvado´ J, Covas MI, Corella D, Aro´s F, et al. PREDIMED Study Investigators. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med 2013;368 (14):1279 90. [41] Esposito K, Giugiliano D. Diet and inflammation: a link to metabolic and cardiovascular diseases. Eur Heart J 2006;27:15 20. [42] Kelishadi R, Mirghaffari N, Poursafa P, Gidding SS. Lifestyle and environmental factors associated with inflammation, oxidative stress and insulin resistance in children. Atherosclerosis 2009; 203:311 19. [43] Esposito K, Marfella R, Ciotola M, Di Palo C, Giugliano F, Giugliano G, et al. Effect of a Mediterranean-style diet on endothelial dysfunction and markers of vascular inflammation in the metabolic syndrome: a randomized trial. JAMA 2004;292(12):1440 6. [44] Burr ML, Fehily AM, Gilbert JF, Rogers S, Holliday RM, Sweetnam PM, et al. Effect of changes in fat, fish and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART). Lancet 1989;2:757 76. [45] McCall DO, McGartland CP, McKinley MC, Patterson CP, Sharpe P, McCance CR, et al. Dietary intake of fruits and vegetables improves microvascular function in hypertensive subjects in a dose-dependent manner. Circulation 2009;119:2153 60. [46] Smith PJ, Blumenthal JA, Babyak MA, Georgiades A, Sherwood A, Sketch Jr MH, et al. Association between n-3 fatty acid consumption and ventricular ectopy after myocardial infarction. Am J Clin Nutr 2009;89:1315 20. [47] Campos H, Baylin A, Willett WC. Alpha-Linolenic acid and risk of nonfatal acute myocardial infarction. Circulation 2008;118:339 45. [48] Harris WS, Reid KJ, Sands SA, Spertus JA. Blood omega-3 and trans fatty acids in middle aged acute coronary syndrome patients. Am J Cardiol 2007;99:154 8. [49] Harper CR, Jacobson TA. Usefulness of omega-3 fatty acids and the prevention of coronary heart disease. Amer J Cardiol 2005;96:1521 9. [50] Leaf A, Albert CM, Josephson M, Steinhaus D, Kluger J, Kang JX, et al. Fatty Acid Antiarrhythmia Trial Investigators. Prevention of fatal arrhythmias in high-risk subjects by fish oil n-3 fatty acid intake. Circulation 2005;112:2762 8. [51] Zhao G, Etherton TD, Martin KR, Gillies PJ, West SG, Kris-Etherton PM. Dietary -linolenic acid inhibits pro-inflammatory cytokine production by peripheral blood mononuclear cells in hypercholesterolemic subjects. Am J Clin Nutr 2007;85:385 91.

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[52] Sreeramulu D, Reddy CVK, Raghunath M. Antioxidant activity of commonly consumed cereals, millets, pulses and legumes in India. Indian J Biochem Biophys 2009;46(1):112 15. [53] Singh RB, Rastogi SS, Singh R, Ghosh S, Niaz MA. Effects of guava intake on serum total and high density lipoprotein cholesterol levels and systemic blood pressures. Am J Cardiol 1992;70:1287 91. [54] Johnson SA, Figueroa A, Navaei N, Wong A, Kalfon R, Ormsbee LT, et al. Daily blueberry consumption improves blood pressure and arterial stiffness in postmenopausal women with pre- and stage 1-hypertension: a randomized, double-blind, placebo-controlled clinical trial. Acad Nutr Diet 2015;115 (3):369 77. Available from: https:doi.org/10.1016/j.jand.2014.11.001 Epub 2015 Jan 8. [55] Singh RB, Niaz MA, Bishnoi I, Singh U, begum R, Rastogi SS. Effect of low energy diet and weight loss on major risk factors, central obesity and associated disturbances in patients with essential hypertension. J Human Hypert 1995;9(5):355 62. [56] Singh RB, Cornelissen G, Otsuka K, Juneja L, Halberg F. Coronary risk factors and ambulatory blood pressures and heart rate in Asian Indians. Open Nutr J 2012;5:79 80. [57] Singh RB, Sircar AR, Rastogi SS, Singh R. Dietary modulators of blood pressures in hypertension. Euro J Clin Nutr 1990;44:319 27. [58] Hristova K, Singh RB, Cornelissen G, Fedacko J, Pella D, Chaves H, et al. For the International College of Cardiology. The challenges of new guidelines for management of hypertension: a view point of the International College of Cardiology. World Heart J 2015;7:103 8. [59] Singh RB. Prevalence and prevention of hypertension, diabetes mellitus, and coronary artery disease in India. A scientific statement of the Indian Society of Hypertension, International College of Nutrition and International College of Cardiology and Indian Consensus Group World Heart J 2010;2:31 44. [60] Moore TJ, Conlin PR, Ard J, Svetkey LP. DASH (dietary approaches to stop hypertension) diet is effective treatment for Stage 1 isolated systolic hypertension for DASH Collaborative Research Group Hypertension 2001;38:155 8. [61] Singh RB, Fedacko J, Saboo B, Niaz MA, Maheshwari A, et al. Association of higher omega-6/omega-3 fatty acids in the diet with higher prevalence of metabolic syndrome in North India. MOJ Public Health 2017;6(6):00193. Available from: https://doi.org/10.15406/mojph.2017.06.00193. [62] Aung T, Halsey J, Kromhout D, et al. Associations of omega-3 fatty acid supplement use with cardiovascular disease risks; Meta-analysis of 10 trials involving 77 917 individuals. JAMA Cardiol 2018;3 (3):225 34. Available from: https://doi.org/10.1001/jamacardio.2017.5205. [63] Slomski A. Vegetarian and mediterranean diets effective for weight loss. JAMA. 2018;319(16):1649. Available from: https://doi.org/10.1001/jama.2018.4738. [64] Voelker R. The Mediterranean diet’s fight against frailty. JAMA. 2018;. Available from: https://doi.org/ 10.1001/jama.2018.3653. [65] Lucas L, Russell A, Keast R. Molecular mechanisms of inflammation. Anti-inflammatory Benefits of virgin olive oil and the phenolic compound oleocanthal. Curr Pharm Des 2011;17. Available from: https://doi.org/10.2174/138161211795428911.

CHAPTER

EFFECTS OF WESTERN STYLE FOODS ON RISK OF NONCOMMUNICABLE DISEASES

11 Adrian Isaza

Everglades University, Tampa, FL, United States

11.1 OSTEOPOROSIS 11.1.1 NUTRITIONAL RISK FACTORS • • • •

Excess Excess Excess Excess

red meats soda coffee alcohol

11.1.1.1 Red meats Excess intake of dietary protein from red meat has been associated to osteoporosis. The Nurses’ Health Study of 1996 found an increase in risk for animal protein, but no association was found for consumption of vegetable protein. Women who consumed five or more servings of red meat per week showed an increased risk of forearm fracture compared with women who consumed red meat less than once per week [1]. The suggested mechanism for the catabolic action of protein derived from red meats over bone is attributed to its acid producing effect. Minerals found in bone may be displaced in order to maintain acid base balance. A study in 2004 showed that higher total protein intake was associated with a reduced risk of hip fracture in men and women 50 69 years of age but not in men and women 70 89 years of age [2]. A more recent study found that there is a small benefit of protein on bone health [3]. Another recent study concluded that a causal association between dietary acid load and osteoporotic bone disease was untenable. Furthermore, this study found that there is no evidence that an alkaline diet is protective of bone health [4]. The potential mechanism for the anabolic action of dietary protein over bone has been attributed to its effect on growth factors and calcium homeostasis. Dietary protein has been proposed to increase intestinal calcium absorption, stimulate the secretion of insulin-like growth factor-1 and reduce bone resorption [5,6]. The Role of Functional Food Security In Global Health. DOI: https://doi.org/10.1016/B978-0-12-813148-0.00011-6 © 2019 Elsevier Inc. All rights reserved.

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11.1.1.2 Soda Consumption of phosphorus-rich and calcium-poor foods has been linked to osteoporosis. A study in 1988 revealed that a diet containing 1660 mg of phosphorus and 420 mg of calcium for 8 days caused increased level of parathyroid hormone in both men and women. This study concluded that short-term ingestion of high phosphorus and low calcium diets resulted in an elevated PTH action in young adults [7]. One suggested mechanism for the catabolic action of high phosphorus in the form of phosphates over bone is attributed to its effect on PTH. Excessive phosphate intake can stimulate PTH which then causes bone resorption. Another suggested mechanism is associated with the acidity of phosphates. This mechanism suggests that increased excretion of acidic ions derived from phosphate, contributes to urine calcium excretion, demineralization of bone, and osteoporosis A more recent study concluded that higher phosphate intakes were associated with decreased urine calcium and increased calcium absorption. Moreover, this study found no evidence that phosphate intake contributes to loss of bone mass density or to bone calcium excretion in urine. Finally, the study concluded that there is no evidence that higher phosphate intakes are harmful to bone health [8].

11.1.1.3 Coffee Caffeine found in coffee and tea has been found to contribute to osteoporosis. The Framingham study of 1990 revealed that when consuming more than two cups of coffee per day (four cups of tea) there was an increased risk of fracture. Moreover, hip fracture risk was modestly increased with heavy caffeine use, but not when consuming one cup of coffee per day [9]. The Rancho Bernardo Study of 1994 revealed that lifetime consumption of two cups per day of caffeinated coffee was associated with decreased bone density in postmenopausal women who do not drink milk every day [10]. The suggested mechanism for the catabolic action of caffeine over bone is attributed to the calciuric effect of caffeine. It has been proposed that caffeine consumption promotes short-term urinary calcium excretion which lacks supporting evidence. A more recent study revealed that there is not enough evidence to support the association between coffee consumption and osteoporosis [11]. Another recent study found that daily intake of coffee is associated with an increased risk of fractures in women, but not in men [12].

11.1.1.4 Alcohol Alcohol has been proposed to be a contributing factor to osteoporosis. In 2005, one study found that alcohol intake was associated with osteoporosis. This study showed no significant increase in risk when consuming two units or less of alcohol daily. When consuming more than two units of alcohol daily an increased risk of any fracture was observed [13]. The suggested mechanism for the catabolic effect of alcohol over bone is associated with its direct impact on bone metabolism. It has been proposed that drinking alcohol inhibits bone formation. A more recent study found that people who consume 0.5 1.0 drinks daily have a lower risk of hip fracture. Moreover, this study concluded that there is available evidence supporting a positive effect of alcohol consumption on bone mass density, but a precise quantity hasn’t been determined [14].

11.2 DIABETES MELLITUS TYPE 2

187

The potential mechanism for the anabolic effect of alcohol over bone is explained by its effect on bone mass density. One particular study showed that moderate alcohol intake increases bone mass density. This study found that alcohol consumption of at least 7 oz (206.99 mL)/week is associated with an increase in bone mass density for postmenopausal women [15]. Alcohol consumption promotes the formation of estrone which preserves mineral composition in bone.

11.2 DIABETES MELLITUS TYPE 2 11.2.1 NUTRITIONAL RISK FACTORS • • • •

Excess Excess Excess Excess

processed meats soda/sugar sweetened beverages fast food/fried foods white rice

11.2.1.1 Processed meats Consumption of processed meats has been linked to diabetes mellitus type 2. In 2010, Micha et al. conducted a systematic review and meta-analysis of 20 studies and found that consumption of processed meats, but not red meats, is associated with higher incidence of diabetes mellitus. Processed meat intake was associated with 19% higher risk of diabetes mellitus [16]. In 2012, Micha et al. performed an update review of the evidence and concluded that there are strong associations of processed meat consumption with incident diabetes mellitus [17]. Recently in 2017, Schwingshackl et al. performed a systematic review and meta-analysis of prospective studies and found an increase of risk with increasing consumption of processed meats [18]. Recently, in 2017, Etemadi et al. conducted a population-based cohort study of 536,969 participants. This study showed increased risks of mortality and death due to nine different causes including diabetes mellitus type 2. This increased risk of mortality is associated with both processed and unprocessed red meat, accounted for, in part, by heme iron and nitrate/nitrite from processed meat [19].

11.2.1.2 Soda/sugar sweetened beverages Consumption of sweet drinks including soda has been found to increase the risk of developing diabetes mellitus. In 2007, Vartanian et al. conducted a systematic review and meta-analysis of 88 studies. This study concluded that soft drinks offer energy with little accompanying nutrition, displace other nutrient sources, and are linked to several key health conditions such as diabetes [20]. In 2010, Malik et al. conducted a meta-analysis of the evidence and found that a higher consumption of sugar-sweetened beverages is associated with development of metabolic syndrome and type 2 diabetes [21]. In 2015, Wang et al. conducted a meta-analysis of prospective studies and found that sugar-sweetened beverage intake was associated with an increased risk of type 2 diabetes [22]. Also in 2015, Imamura et al. conducted a systematic review and meta-analysis which concluded that habitual consumption of sugarsweetened beverages was associated with a greater incidence of type 2 diabetes, independently of adiposity [23].

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11.2.1.3 Fast food/fried foods A large intake of fast food or fried foods can cause diabetes mellitus type 2. Through the processes of oxidation, polymerization, and hydrogenation, the method of frying alters both foods and their frying medium. In 2015, Bahadoran et al. conducted a review of current studies and concluded frequent consumption of fast foods was accompanied with overweight and abdominal fat gain, impaired insulin and glucose homeostasis, lipid and lipoprotein disorders, induction of systemic inflammation, and oxidative stress. Higher fast food consumption also increases the risk of developmental diabetes and metabolic syndrome [24]. Also in 2015, Gadiraju et al. performed a review of the evidence and concluded that more frequent consumption of fried foods (i.e., four or more times per week) is associated with a higher risk of developing type 2 diabetes [25].

11.2.1.4 White rice Eating white rice has been associated with diabetes mellitus type 2. In 2012, Hu et al. conducted a systematic review and meta-analysis of prospective studies and found that higher consumption of white rice is associated with a significantly increased risk of type 2 diabetes, especially in Asian (Chinese and Japanese) populations [26]. In 2015, Izadi et al. conducted a systematic review which found a positive association between white rice intake and risk factors of cardiovascular disease including metabolic syndrome and type 2 diabetes [27].

11.3 CORONARY HEART DISEASE 11.3.1 NUTRITIONAL RISK FACTORS • • • •

Excess Excess Excess Excess

trans fat foods processed meats fast food/fried food sugar sweetened beverages/soda

11.3.1.1 Trans fat foods Trans fat or hydrogenated fat has been associated with coronary heart disease. In 2011, Bendsen et al. conducted a systematic review and meta-analysis of cohort studies which revealed that industrial trans fatty acids may be positively related to coronary heart disease [28]. In 2015, de Souza et al. conducted a systematic review and meta-analysis of observational studies which showed that trans fats are associated with all causes of mortality, total coronary heart disease, and coronary heart disease mortality [29].

11.3.1.2 Processed meats Processed meat has been linked to coronary heart disease. In 2010, Micha et al. performed a systematic review and meta-analysis and concluded that consumption of processed meats, but not red meats, is associated with higher incidence of coronary heart disease [16]. In 2012, Micha et al. conducted an updated review of the evidence which reinforced that there are strong associations of processed meat consumption with incident coronary heart disease [17].

11.4 COLORECTAL CANCER

189

Recently, in 2017, Etemadi et al. conducted a population based cohort study of 536,969 participants. This study showed increased risks of mortality and death due to nine different causes including coronary heart disease. This increased risk of mortality is associated with both processed and unprocessed red meat, accounted for, in part, by heme iron and nitrate/nitrite from processed meat [19].

11.3.1.3 Fast food/fried food Fast food/fried food appears to have a correlation with coronary heart disease. In 2014, Cahill et al. performed a prospective study of two cohorts. Fried-food consumption was assessed in 70,842 women and 40,789 men who were free of diabetes, cardiovascular disease, and cancer at baseline. This study found that frequent fried-food consumption was moderately correlated with incident coronary artery disease [30].

11.3.1.4 Sugar-sweetened beverages/soda Sugar-sweetened beverages including soda has been connected to coronary heart disease. In 2014, Huang et al. conducted a meta-analysis of four prospective studies which showed that consumption of sugar-sweetened beverages may increase risk of coronary heart disease, especially among men and American populations [31]. In 2015, Xi et al. performed a dose-response meta-analysis which revealed that a higher consumption of sugar-sweetened beverages was associated with a higher risk of hypertension and coronary heart disease [32].

11.4 COLORECTAL CANCER 11.4.1 NUTRITIONAL RISK •

Excess red and processed meats

11.4.1.1 Red and processed meats Both red and processed meat have been correlated with colorectal cancer. In 2011, Chan et al. performed a meta-analysis of prospective studies which revealed that a high intake of red and processed meat is associated with significant increased risk of colorectal, colon, and rectal cancers [33]. In 2015, Aykan conducted a systematic literature search of the available evidence and concluded that the accumulated evidence of prospective epidemiological studies and their metaanalyses shows that red meat and processed meat convincingly increases colorectal cancer risk by 20% 30% [34]. Recently, in 2017, Etemadi et al. conducted a population-based cohort study of 536,969 participants. This study showed increased risks of mortality and death due to nine different causes including colorectal cancer. This increased risk of mortality is associated with both processed and unprocessed red meat, accounted for, in part, by heme iron and nitrate/nitrite from processed meat [19].

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11.5 LUNG CANCER 11.5.1 NUTRITIONAL RISK •

Excess red and processed meats

11.5.1.1 Red and processed meats Both red and processed meats have been implicated with lung cancer. In 2012, Yang et al. performed a systematic review and meta-analysis of observational studies which concluded that a high intake of red meat may increase the risk of lung cancer by about 35% [35]. In 2014, Xue et al. conducted a dose-response meta-analysis of 33 studies which revealed that consumption of red and processed meat may be associated with the risk of lung cancer [36].

11.6 BLADDER CANCER 11.6.1 PROCESSED MEATS Processed meats were recently associated to bladder cancer. In 2018 Crippa, et al. conducted a dose-response meta-analysis of epidemiological studies. Based on both case control and cohort studies, the pooled relative risk increased for every 50 g increase of processed meat/day. The study concluded that processed meat may be positively associated with bladder cancer risk [37].

11.7 BREAST CANCER 11.7.1 PROCESSED MEATS A causal relationship between the consumption of processed meats and breast cancer has recently been investigated. In 2018 Anderson, et al. performed a general population cohort study and meta-analysis. Over a period of 7 years, 4819 out of 262,195 women developed breast cancer. This study showed that consumption of processed meat, but not red meat, may increase the risk of breast cancer [38].

11.8 OBESITY 11.8.1 NUTRITIONAL RISK •

Excess sugar sweetened beverages

11.8.1.1 Excess sugar sweetened beverages Recent research indicates there seems to be a positive correlation between excess consumption of sugar sweetened beverages and obesity. In 2018 Luger, et al. published a systematic review of 30 studies between 2013 and 2015 and found that consumption of sugar sweetened beverages is positively associated with or has an effect on obesity indices in children and adults [39].

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[20] Vartanian LR, Schwartz MB, Brownell KD. Effects of soft drink consumption on nutrition and health: a systematic review and meta-analysis. Am J Public Health 2007;97(4):667 75. [21] Malik VS, Popkin BM, Bray GA, Despr´es JP, Willett WC, Hu FB. Sugar-sweetened beverages and risk of metabolic syndrome and type 2 diabetes: a meta-analysis. Diabetes Care 2010;33(11):2477 83. [22] Wang M, Yu M, Fang L, Hu RY. Association between sugar-sweetened beverages and type 2 diabetes: a meta-analysis. J Diabetes Investig 2015;6(3):360 6. [23] Imamura F, O’connor L, Ye Z, et al. Consumption of sugar sweetened beverages, artificially sweetened beverages, and fruit juice and incidence of type 2 diabetes: systematic review, meta-analysis, and estimation of population attributable fraction. BMJ 2015;351:h3576. [24] Bahadoran Z, Mirmiran P, Azizi F. Fast food pattern and cardiometabolic disorders: a review of current studies. Health Promot Perspect 2015;5(4):231 40. [25] Gadiraju TV, Patel Y, Gaziano JM, Djouss´e L. Fried food consumption and cardiovascular health: a review of current evidence. Nutrients 2015;7(10):8424 30. [26] Hu EA, Pan A, Malik V, Sun Q. White rice consumption and risk of type 2 diabetes: meta-analysis and systematic review. BMJ 2012;344:e1454. [27] Izadi V, Azadbakht L. Is there any association between rice consumption and some of the cardiovascular diseases risk factors? A systematic review. ARYA Atherosclerosis 2015;11(Suppl 1):109 15. [28] Bendsen NT, Christensen R, Bartels EM, Astrup A. Consumption of industrial and ruminant trans fatty acids and risk of coronary heart disease: a systematic review and meta-analysis of cohort studies. Eur J Clin Nutr 2011;65(7):773 83. [29] De souza RJ, Mente A, Maroleanu A, et al. Intake of saturated and trans unsaturated fatty acids and risk of all cause mortality, cardiovascular disease, and type 2 Diabetes: systematic review and meta-analysis of observational studies. BMJ 2015;351:h3978. [30] Cahill LE, Pan A, Chiuve SE, et al. Fried-food consumption and risk of type 2 diabetes and coronary artery disease: a prospective study in 2 cohorts of US women and men. Am J Clin Nutr 2014;100 (2):667 75. [31] Huang C, Huang J, Tian Y, Yang X, Gu D. Sugar sweetened beverages consumption and risk of coronary heart disease: a meta-analysis of prospective studies. Atherosclerosis 2014;234(1):11 16. [32] Xi B, Huang Y, Reilly KH, et al. Sugar-sweetened beverages and risk of hypertension and CVD: a doseresponse meta-analysis. Br J Nutr 2015;113(5):709 17. [33] Chan DS, Lau R, Aune D, et al. Red and processed meat and colorectal cancer incidence: meta-analysis of prospective studies. PLoS One 2011;6(6):e20456. [34] Aykan NF. Red meat and colorectal cancer. Oncol Rev 2015;9(1):288. [35] Yang WS, Wong MY, Vogtmann E, et al. Meat consumption and risk of lung cancer: evidence from observational studies. Ann Oncol 2012;23(12):3163 70. [36] Xue X-J, Gao Q, Qiao J-H, Zhang J, Xu C-P, Liu J. Red and processed meat consumption and the risk of lung cancer: a dose-response meta-analysis of 33 published studies. Int J Clin Exper Med 2014;7 (6):1542 53. [37] Crippa A, Larsson SC, Discacciati A, Wolk A, Orsini N. Red and processed meat consumption and risk of bladder cancer: a dose response meta-analysis of epidemiological studies. Eur J Nutr 2018;57 (2):689 701. Available from: https://doi.org/10.1007/s00394-016-1356-0. [38] Anderson JJ, Darwis NDM, Mackay DF, et al. Red and processed meat consumption and breast cancer: UK Biobank cohort study and meta-analysis. Eur J Cancer 2018;90:73 82. [39] Luger M, Lafontan M, Bes-rastrollo M, Winzer E, Yumuk V, Farpour-lambert N. Sugar-sweetened beverages and weight gain in children and adults: a systematic review from 2013 to 2015 and a comparison with previous studies. Obes Facts. 2017;10(6):674 93.

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12 Pramod Kumar

Dean Academics Medical Sciences, TM University, Moradabad, Uttar Pradesh, India

12.1 INTRODUCTION Public awareness about diet, physical activity, and body weight as major risk factors for so called lifestyle diseases, e.g., heart diseases, diabetes, etc., is increasing. Cancer is also included in the above list because of its association with type of food and nutrition and body weight. The WHO helps to build capacity to prevent, detect, and manage food-borne risks by providing Codex Alimentarius guidelines and recommendations to ensure food is safe. The WHO helps through independent scientific assessments on microbiological and chemical hazards and assessing the safety of new technologies used in food production, such as genetic modification and nanotechnology. The International Food Safety Authorities Network (INFOSAN) was developed by the WHO and the UN Food and Agriculture Organization (FAO) to rapidly share information during food safety emergencies; promoting safe food handling through systematic disease prevention and awareness programmes [1]. World Health Organization (WHO) lists the following common risk factors for cancer [2]: • • • • • • •

Alcohol use Tobacco use Physical inactivity Dietary factors, including insufficient fruit and vegetable intake Overweight and obesity Environmental and occupational risks including ionizing and non-ionizing radiation [3] Chronic infections from Helicobacter pylori, hepatitis B virus (HBV), hepatitis C virus (HCV), and some types of human papilloma virus (HPV).

12.2 CANCER-CAUSING AGENTS 12.2.1 CHEMICAL CARCINOGENS Various chemicals and environmental toxins may to be responsible for changes in normal cellular DNA. The agents causing DNA mutations are called mutagens, and mutagens that cause cancers are called carcinogens [3]. The Role of Functional Food Security In Global Health. DOI: https://doi.org/10.1016/B978-0-12-813148-0.00012-8 © 2019 Elsevier Inc. All rights reserved.

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Some of the substances have been particularly linked to specific types of cancer. Tobacco smoking, associated with many forms of cancer, causes 90% of lung cancer. Tobacco contains carcinogens like nitrosamines and polycyclic aromatic hydrocarbons [3] and is related to cancers of lung, larynx, head, neck, stomach, bladder, kidney, esophagus, and pancreas. A prolonged exposure to asbestos fibers is associated with mesothelioma.

12.2.2 IONIZING RADIATIONS Radon gas radiations and prolonged exposure to ultraviolet radiation from the sun leads to melanoma and other skin malignancies. Radiation therapy given for one type of cancer may itself can be the cause of another type of cancer. Chest radiation therapy for lymphomas may cause breast cancer [3,4].

12.2.3 VIRAL AND BACTERIAL INFECTIONS Infections with pathogens cause liver cancers due to Hepatitis B and C infections; cervical cancer due to infections with Human Papilloma virus (HPV); Epstein Barr virus causes Burkitt’s lymphoma; and gastric or stomach cancer due to Helicobacter pylori infection [3].

12.2.4 GENETIC OR INHERITED CANCERS The genetic cancers are inherited breast cancer and ovarian cancer genes including BRCA1 and 2. The Li-Fraumeni syndrome includes defects in the p53 gene leading to bone cancers, breast cancers, soft tissue sarcomas, brain cancers, etc. Down’s syndrome patients may develop leukemia and testicular cancer [3,5].

12.2.5 HORMONAL CHANGES Prominent among these are changes in the female estrogen hormone levels. The excess of estrogens promotes uterine cancer [3].

12.2.6 IMMUNE SYSTEM DYSFUNCTION The impaired immunity in HIV infection may cause several cancers including Kaposi’s sarcoma, non-Hodgkin’s lymphoma, and HPV-associated malignancies, such as anal cancer and cervical cancer [3,6].

12.3 BODY WEIGHT According to American Institute of Cancer Research (AICR) obesity may increase risk for cancer of kidney, pancreas, endometrium, gallbladder, colorectal, postmenopausal breast, and a common variety of esophageal cancer called adenocarcinoma [6].

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12.4 CANCER CAUSING FOODS 1. Refined Sugar: The high fructose corn syrup and other refined sugars are the major cancercausing food. The brown sugar is highly refined sugar with the removed molasses added back in it for flavor and color. Refined sugars and foods prepared with them lead to major insulin spikes. The sugar is the best feed for the growth of cancer cells. So the oncologists are using diabetes medication to fight cancer cells. Also the majority of the sugar is made using genetically modified (GMO) sugar beets in USA. Organic honey, coconut sugar, or maple sugar may be better alternatives. 2. Genetically Modified Foods (GMOs): Presently the genetically modified crops constitute a major share of food supply. More than 90% of corn and soy are now genetically modified. This has become source of many debates because of inadequate testing done before including GMO foods. No one knows about their long-term effects on human health [7]. 3. Canned foods: Most cans are lined with a product called bisphenol-A (BPA), which genetically alters the brain cells of rats. Many plastic goods, thermal paper, water lines, and many dental composites also contain BPA. By sticking to fresh or frozen vegetables that have no added ingredients may be a safer way [7]. 4. Grilled Red Meat: Processed meats like hot dogs release a carcinogen called heterocyclic aromatic amines. Grilling red meat changes the chemical and molecular structure of the meat. Baking, broiling, or preparing meat in a skillet than on the grill is better. The increased risk of mortality and death associated with both processed and unprocessed red meat can be partly accounted for by heme iron and nitrate/nitrite from processed meat. There are reduced risks associated with substituting white meat, particularly unprocessed white meat [7]. 5. Salted, Pickled, and Smoked Foods: These products contain preservatives like nitrates to prolong their shelf life. These preservatives accumulate in the body, can cause cellular damage, and may lead to cancer and various other diseases. In case of foods cooked at high temperatures, the nitrates are converted to nitrites which are much more harmful. The pickled fermented foods prepared at home are safe. 6. Hydrogenated Oils: Vegetable oils are extracted from their source using various chemicals, treated chemically, and more chemicals are added to change the smell and taste. The vegetable oils are rich in omega-6 fats which may alter the structure of cell membranes [7] 7. Soda and Carbonated Beverages: The use of high fructose corn syrup, dyes, and various other chemicals makes sodas very harmful for health. They have zero nutritional value and the body is robbed of the nutrients from other foods. “Diet” label means consuming aspartame which is poisonous to human cells. 8. White Flour: Refining the flour removes its nutritional value. It is bleached with harmful chlorine gas to make it more appealing. The very high glycemic index of white flour spikes insulin levels without providing nutritional fuel. In the human body carbohydrates are converted to sugars so an excess of white flour causes increased insulin resistance. The carbohydrate sugars are the preferred fuel source for cancer cells [7]. 9. Farmed Fish: The fish farming involves raising an incredible number of fish in a crowded environment. Most of the commercially available fish comes from fish farms, which treat

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them with antibiotics, pesticides, and other carcinogenic chemicals to control the bacterial, viral, and parasitic outbreaks which may result from cramming so many fish in a small space. Farmed salmon fish also don’t have as much omega-3 as wild salmon [7]. 10. Microwave Popcorn: From the chemically lined bag to the actual contents, microwave popcorn is at the center of lung cancer debates. Most of the kernels and oil used are GMO; the fumes released from artificial butter flavoring contain diacetyl, which is toxic. Making organic popcorn the old fashioned way tastes better and doesn’t release toxic fumes [7]. The following measures can be taken in the kitchen & daily eating plan: Macrobiotic Diet Patients undergoing and recovering from cancer treatment may find macrobiotic dietary recommendations challenging and restrictive; they are limiting in terms of needed calories and protein required for maintaining body weight, strength, and energy [8]. Organic Foods Organic food is the food grown without pesticides or herbicides. There are various reasons to choose organic foods, but it is not yet confirmed that organic foods help reduce cancer risk more than nonorganic foods [8]. Juicing Various types of fruit and vegetable juices provide nutrition and naturally occurring phytochemicals to the diet. But solely relying on juices for nutrition in the cancer patients is not recommended. A diet containing enough protein and calories for maintaining body weight is advised during cancer treatment [8]. Vegetarian Diet In spite of it being a healthier alternative in general, but there is no clear evidence that a vegetarian diet is more protective against cancer. A vegetarian meal which includes a variety of vegetables and fruits, whole grains, and meat protein alternatives such as beans, eggs, tofu, fish, or small amounts of reduced fat cheese is advised in cancer patients [8]. Soy Foods and Soy Products The soy foods provide several key nutrients and phytochemicals known for their cancer prevention properties. Many soy foods containing dietary fiber lower the risk of colorectal cancer. Soy foods contain isoflavones which increases estrogen levels, implicated to increase breast cancer risk. However, the phytoestrogens which mimic the action of estrogen are very weak. The soy foods do not increase risk and in some cases, may lower it [8]. Nutrition and Diet and the Development of Cancer The diet, physical activity, and body weight are major risk factors for developing certain types of cancer. A healthy diet, staying physically active, and avoiding excess body fat increases the body’s ability to fight cancer. A healthy diet rich in a variety of vegetables, fruits, whole grains, and legumes (beans), and low in red and processed meat [7] can fight cancer. Such a diet provides vitamins, minerals, and protective and naturally occurring plant substances known as phytochemicals and defends the body against cancer and other diseases [8]. These nutrients and phytochemicals seek out toxins and remove them from the body before they can cause cell damage or leads to cancer. They make it easier for the body to make repairs at the cellular level, and help stop cancer cells from reproducing [8,9].

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12.4.1 CANCER PREVENTION American Institute of Cancer Research (AICR) recommends: 1. A normal range of body weight, maintaining it within the normal BMI range especially after the teenage years, avoiding weight gain or increases in waist circumference [8]. 2. Avoiding foods and drinks promoting weight gain: Consume fewer amounts of energy dense foods with high calories more than 225 275 calories per 100 grams. Avoid sugary soft drinks, sweetened ice tea, juice flavored drinks. Avoid baked foods such as desserts, cookies, and cakes; chips such as potato and corn; ice cream, milkshakes; processed meat, e.g., hotdogs, salami, pepperoni; fast food such as fries, fried chicken, and burgers. The packaged and processed foods are high in added sugars and fats [8,10]. AICR Recommends eating mostly foods of plant origin, eating at least five portions/servings of a variety of nonstarchy vegetables and fruits every day, e.g., one cup raw or cooked vegetables or one medium apple. Also eat whole grains and/or legumes (beans and lentils) with every meal [8]. Food Safety: The following is the food safety advice for people undergoing and recovering from cancer treatment [8]: 1. Frequent washing of hands with soap and running water for at least 20 seconds. Use an alcoholbased hand sanitizer for cleaning hands if soap and water are not available. 2. Wash or sanitize hands before eating, after handling garbage, touching pets, and after sweeping the floor or counters. 3. Keep kitchen surfaces, appliances, and utensils thoroughly cleaned, change or throw away the sponges and dish towels more often. 4. Separate and do not cross-contaminate the food items. Keep raw meat, poultry, seafood, and eggs away from ready to eat foods. Thoroughly cook the food at proper temperatures. If possible use a food thermometer to make sure foods are safely cooked. 5. The food must be properly wrapped and refrigerated promptly. Refrigerate the leftover food within 1 hour to limit growth of bacteria. The refrigerator settings should be between 34 F and 40 F, while the freezer must be set to 0 2 F or below. Do not use the refrigerated food after two hours of its removal from the refrigerator. 6. The frozen meat and poultry should be thawed in the refrigerator, microwave, or cold water. Do not leave the food out on in the open, check food product expiry dates, if in doubt throw it out [8].

12.4.2 ROLE OF DIET AND LIFESTYLE IN CANCER Research in the field of recommended nutrition and physical activity for cancer survivors so as to prevent or reduce the risk of cancer recurrence, secondary cancers, and other chronic diseases, is still in an early stage. The recent studies observed health benefits for cancer survivors who maintained a proper weight, consume a healthy diet, and were involved in regular physical activity [8].

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12.5 AICR GUIDELINES FOR CANCER PREVENTION AND RISK REDUCTION AICR’s report recommends a plant-based diet and physical activity to cancer survivors for reducing risk of cancer. A healthy weight may establish a biochemical status or anticancer environment which discourages cancer growth [8]. The aim should be to build more activity, like brisk walking, into a daily routine. A sedentary way of life leads to weight gain and obesity, increasing the risk for several types of cancer. The consumption of red meats, e.g., beef, pork, and lamb should be limited to 18 oz. or less per week; avoiding processed meat like cold cuts, bacon, sausage, and ham may lower the risk for colorectal cancer. The cancer survivors are at greater risk for other chronic diseases such as heart disease, so eating less red and processed meat is recommended. AICR recommends avoiding even small amounts of alcohol, since alcohol increases risk for cancers of the colon and rectum, breast, esophagus, mouth, and liver. Tobacco in any form is a major cause of cancer and should be entirely avoided [8]. The consumption of salty foods and foods processed with salt can be harmful, increasing risk of stomach cancer as well as high blood pressure. The processed foods, canned, frozen prepared items, fast foods, and other restaurant foods are the major source of salt [11]. Additional AICR Recommendations: The aim should be to meet nutritional needs through a balanced diet with a variety of foods alone, rather than taking supplements to reduce risk of cancer. The food and drink, and not the dietary supplements are the best source of nourishment. The nutrient rich whole food contains fiber, vitamins, minerals, and phytochemicals necessary for good health. Plant-based foods are the source of many cancer fighting compounds [8].

12.5.1 DIET AND NUTRITION’S IMPACT AT THE MOLECULAR LEVEL The phytochemicals impart a plant with color, aroma, and flavor and a protection from infection and predators. The phytochemicals may stimulate the immune system, slow the growth rate of cancer cells, and prevent DNA damage that can lead to cancer and other diseases as described in the following section suggesting that many phytochemicals are antioxidants protecting the cells of the body from oxidative damage from water, food, and the air. Eating a balanced diet which includes whole grains, legumes, nuts, seeds, and a variety of colorful fruits and vegetables provides the body with phytochemicals [8].

12.5.2 MOLECULAR BASIS OF CARCINOGENESIS INDUCED BY FOODS Cancer is a genetic disease, more specifically it is a disease that is caused by specific genes that develop mutations and it then leads to uncontrolled cellular division. With aging, body defense and natural immunity becomes poor, leading to increased exposure to environmental factors. Due to continued exposure of food-borne carcinogens, different organs or parts of the body do experience inflammation and oxidative stress (formation of lipid peroxides and oxidized proteins widely known as “free radicals”). Both these types of active radicals initiate deoxyribonucleic acid (DNA) mutation and lead to uncontrolled proliferation and ultimately carcinogenesis due to epigenetic changes [12]. The process in proliferation includes several metabolic pathways specific to exposure

12.5 AICR GUIDELINES FOR CANCER PREVENTION AND RISK REDUCTION

Aging mitochondrial dysfunction metabolic deregulation

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Environmental factors physical and chemical factors infectious agents Tissue injury

Inflammation

Oxidative stress Lipid peroxidation protein oxidation

Abnormal protein aggregation

Apoptotic pathway

DNA damage

Mutation

Stem cell activation

Aberrant cell cycle entry

Endothelial & macrophase cell damage

Neural cell death

Proliferative pathway

Mutant cell proliferation Atherogenesis

Neurodegeneration

Carcinogenesis

FIGURE 12.1 Roles of oxidative stress on epigenetic damage and carcinogenesis. Modified from Sharma R. Nutraceuticals and nutraceutical supplementation criteria in cancer: a literature survey. Open Nutraceut J 2009;2:92 106. Indian J Pharmacol 2003;35:363-72.

of food contaminants. Still today, research is in its infancy as to which food may have carcinogens and which food may arrest or slow down proliferation. It is an open active research area. Some of the reported major food induced carcinogenic mechanisms are shown in Fig. 12.1.

12.5.3 NUTRACEUTICALS Nutraceutical was first defined in 1989 by Stephen De Felico “as food, food ingredient or dietary supplement that demonstrates specific health or medical benefits including the prevention and treatment of disease beyond basic nutritional functions.” Later nutraceuticals emerged as potential cancer preventive natural sources from food [11]. Nutraceuticals are natural bioactive chemical compounds. They promote health, prevent disease, and may have semimedicinal properties. Nutraceuticals are found as natural products from (1) the food industry, (2) herbal and dietary supplements, (3) the pharmaceutical industry, and (4) the bioengineered microorganisms, agro products, or active biomolecules [12].

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The classification of nutraceuticals [13]: 1. Isoprenoid derivatives: Terpenoids, carotenoids, saponins, tocotrienols, tocopherols, terpenes. 2. Phenolic compounds: Couramines, tannins, ligrins, anthrocynins, isoflavones, flavonones, flavanoids. 3. Carbohydrate derivatives: Ascorbic acid, oligosaccharides, nonstarch polysaccharides. 4. Fatty acid and structural lipids: N-3 PUFA, CLA, MUFA, sphingolipids, lecithins. 5. Amino acid derivatives: Amino acids, allyl-S compounds, capsaicnoids, isothiocyanates, indols, folate, choline. 6. Microbes: Probiotics, prebiotics. 7. Minerals: Ca, Zn, Cu, K, Se [13]. Tripathi et al. reported the chemotherapeutic value of nutraceuticals in cancer [14]. Most of their cancer prevention evidence was observed in animal studies on phytochemicals, fat, flavones, phytoesterogens, isoflavonones, genestein, curcumin, capsaicin, epigallocatechin-3-gallate, gingerol, lycopene, antaoxidants, vitamins, and minerals [13,14]. Further, the food ingredients like lycopene, silbinin, shark cartilage, vitamin D were cited to decrease osteoporosis and bone pain,while green tea, Selenium and vitamin E, Grape seed extract, modified citrus, pectin, Soy, PC-SPES, were listed as prostate cancer protective food supplements [11,15].

12.6 ANIMAL STUDIES The inhibitory effect of nutraceuticals on cancer cell growth is based on observations of cultured cancer cell proliferation, enhanced apoptosis, antioxidant action, etc. The studies involving microMRI and immunostaining suggested the reduced apoptosis in experimental rat MCF-7 explanted breast and mice PC-3 explanted prostate animal tumors. The anticancer intervention to animals caused increased sodium and enhanced apoptosis of tumor cells and led to tumor shrinkage after 24 hours. There was observed a slow apoptosis rate (less nuclear beads), reduced proliferation, less cyst size, less necrosis, single-strand DNA breaks, and decreased carcinoma growth in treated animals [11,16]. The probable mechanisms of nutraceutical action suggested are immune modulatory, induced apoptosis, removal of free radicals, inhibited cell proliferation, and inhibited necrosis. The biochemical basis of the individual sources of these foods is still not explored due to their complex nature. The mechanism of nutraceutical action is based on active metabolites present in nutraceuticals [11]. 1. The glutathione is the most abundant protective constituent of antioxidant glutathione reductase enzyme in the liver. The glutathione functions as a substrate for the two key detoxification processes in the liver: a. Transforming toxins into water soluble forms; b. Neutralizing and conjugating with toxins for elimination through the gut or the kidneys. The best nutrition with liver cancer focuses on improving the body’s glutathione reserves [14]. 2. Some opioid-rich nutraceuticals inhibit the tumor and get rid of toxins such as heavy metals, chemicals, and digestive by-products. Tobacco plants may also help a person to fight against lymphoma [17].

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3. The soy isoflavone Haelan951 (genistein and genistin) was observed to have a chemopreventive action against cancer in humans [18]. 4. An active green tea constituent, epigallocatechin-3-gallate (EGCG) had an effect on chronic lymphocytic leukaemia B cells isolated from leukemic patients. These cells were resistant to apoptosis by secreting and binding vascular endothelial growth factor [16,19].

12.6.1 IMMUNOLOGICAL LOSS At a young age the cell-mediated immunity is active and strong, but it deteriorates with age. The major cytokines, including interleukins, TNF alpha, and NF KappaB, lose their synergy response and affect cell-mediated immunity by reducing the ability to synthesize enough IgG, IgM, IgD antibody molecules. Humoral immunity also gets affected by fewer helper and suppressor lymphocytes. A person over 60 years of age need a regular checkup for any sign of cancer and advised nutraceuticals as daily dietary supplements [11]. The National Cancer Institute recommendations are to eat at least five servings of brightly colored fruits and vegetables a day, to restrict ingestion of animal products (excluding farm bred fish), while consuming more vegetable sources of protein (e.g., beans), to consume cooked tomato sauces, and to ensure 200 mcg a day of selenium [20]. The FDA requires appropriate scientific evidence regarding safety of nutraceutical use as a daily prescription. Some of the recommendations for daily nutraceutical supplements are shown in Table 12.1.

12.6.2 MECHANISM OF CANCER PREVENTION BY NUTRACEUTICALS The role of nutraceuticals may be through reduced cell damage, delayed apoptosis (cell death), DNA interaction, reduced necrosis, cell proliferation, signaling, and maintaining metabolic integrity in the cancer tissue as cancer prevention mechanisms [21]. The biomarkers of cancer, e.g., metalloproteinases [22], vitamin D hydroxylase [23], DNA adducts [24], DNA methylases [25], along with polymorphism, superoxide dismutase, interleukins, omega-3 fatty acids, and induced neutropenia [11], have been shown to be potent indicators of nutraceutical chemopreventive mechanism.

12.6.3 NUTRACEUTICAL PROTECTION IN CANCERS A wider acceptance of nutraceuticals by both public and federal agencies has been observed since a few years. The major health hazards where nutraceuticals can be beneficial are cancer of breast, prostrate, colorectum, ovary, pancreas and skin. In recent reports a positive response was observed to different nutraceutical supplements and foods by cancer, e.g., bone cancer to soy isoflavins; breast cancer to lycopene, phytoestrogen; common cancer to cruciferous vegetables; colon cancer to nuts, fibers; gastric cancer to herbs; liver cancer to silbinin and citrus flavonoids; lung cancer to vitamin A and E; ovary cancer to vitamin A, D and antioxidants; pancreatic cancer to vitamins and isoflavins; and prostate cancer to lycopene, phytoestrogen [11]. The majority of available data on nutraceuticals in cancer comes from epidemiological health and population statistics. The reduced cancer incidence due to nutraceuticals still needs to be explored and proved. Greater hopes are anticipated in the future when bioengineered nutraceuticals may play a significant role in cancer prevention [11].

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Table 12.1 The FDA Approved Major Nutraceuticals With Recommended Quantity Nutraceuticals

Quantity Needed

Vitamin D Multivitamin-minerals Natural Vitamin E (4 tocopherols 14 tocotrienols) Selenium Coffee Aspirin or ibuprofen Chocolate (best if fat-free) Green tea Black tea Lycopene Fish (salmon) or EHA 1 DHA Soy “meat”, cheese, milk Broccoli, cabbage, cauliflower Blueberries Strawberries Orange Old-fashioned oatmeal Legumes (beans) Low-fat-blueberry yogurt Yellow vegetables Purple grape juice, or red wine Turmeric roots Herbs Garlic, soy products

400 IU a day (2000 IU) 1 pill daily Two 400 IU capsules a week (800 mg) 200 mcgs/ day Ad libitum Baby aspirin a day Up to 3 servings Up to 3 servings 1 serving Cooked tomato sauces Two servings a week Ad libitum Sulfhydrals ad libitum A few tablespoons a day 40 or 5 large a day One a day One ounce Two servings a week 2 or 3 times a week Ad libitum A glass a day Two capsules daily Two pills daily Ad libitum

Modified from R. Sharma. The caloric contribution of protein-containing foods, Open Nutraceut J, 2009;2:92 106. https://www. benthamopen.com. Accessed August 2017.

REFERENCES [1] Codex Standards. www.fao.org/fao-who-codexalimentarius/standards/en/. Accessed September 2017. [2] World Health Organization 2009. NMH Fact sheet January 2010. http://www.who.int/nmh/publications/ fact_sheet_cancers_en.pdf. Accessed August 2017. [3] Food and cancer. http://www.news_medical.net. Accessed August 2017. [4] Environmental causes of cancer. May 7, 2006. http://www.bu.edu/lovecanal/workshop/PresentRC0507.pdf [5] What causes cancer? Limpopo Department of Health and Social Development. http://www.dhsd.limpopo. gov.za/docs/What%20is%20Cancer.pdf. Accessed August 2017. [6] The Truth about Cancer: A Global Quest. http://www.thetruthaboutcancer.com. Accessed August 2017. [7] Etemadi A, Sinha R, Ward MH, et al. Mortality from different causes associated with meat, heme iron, nitrates, and nitrites in the NIH-AARP Diet and Health Study: population based cohort study. BMJ 2017;357.

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[8] Foods that Fight cancer. American Institute for Cancer Research https://www.aicr.com. Accessed August 2017. [9] The Office of The Dietary Supplements (ODS). National Institutes of Health: http://www.nlm.nih.gov/ medlineplus/dietarysupplements. Accessed August 2017. [10] World Cancer Research Fund/American Institute for Cancer Research. Food, Nutrition, Physical Activity, and the Prevention of Cancer: A Global Perspective. Washington, DC: AICR; 2007. [11] Sharma R. The caloric contribution of protein-containing foods. Open Nutraceut J 2009;2:92 106. Available from: https://www.benthamopen.com. Accessed August 2017. [12] Sharma R. Nutraceuticals and nutraceutical supplementation criteria in cancer: a literature survey. Open Nutraceut J 2009;2:92 106. Indian J Pharmacol 2003;35:363-72. [13] Malik A, Kumar P, Kaushik N, Singh A. The potential of nutraceuticals. Pharm Rev 2008;6(2). [14] Tripathi YB, Tripathi P, Arjmandi BH. Nutraceuticals and cancer management. Front Biosci 2005;10:1607 18. [15] Rackley JD, Clark PE, Hall HC, Lycopene Silbinin, cartilage Shark, Vitamin D. Vitamin D to decrease osteoporosis and bone pain, Green tea, Selenium and vitamin E, Grape seed extract, Modified citrus, pectin, Soy, PC-SPES are cited as prostate cancer protective food supplements. Urol Clin North Am 2006;33(2):237 46. [16] Lambert JD, Lee MJ, Lu H, et al. Epigallocatechin-3-Gallate is absorbed but extensively glucuronidated following oral administration to mice. J Nutr 2003;133:4172 7. [17] Sharma R, Katz JK. Taxoterechemo sensitivity evaluation in mice prostate tumor: validation and diagnostic accuracy of quantitative measurement of tumour characteristics by MRI, PET, and histology of mice tumor. Technol Cancer Res Treat 2008;3(7):155 268. [18] Beliveau R, Gingras D. Green tea: prevention and treatment of cancer by nutraceuticals. Lancet 2004;364:1021 2. [19] Cooper R, Morr´e DJ, Morr´e DM. Medicinal benefits of green tea: part II. review of anticancer properties. J Altern Complement Med 2005;11(4):639 52. [20] Watson RR. Functional foods and nutraceuticals in cancer prevention. Source: Cancer: Nutrition and Health Issues: National Institute of Health. National Cancer Institute. Ames Iowa State Press, Blackwell Publishing; 2003. Available from: www.nutrition.gov/nal_display/index.php? info_center 5 11&tax_level 5 2&tax. [21] Sandur SK, Pandey MK, Sung B, et al. Curcumin, demethoxycurcumin, bisdemethoxycurcumin, tetrahydrocurcumin and turmerones differentially regulate anti-inflammatory and anti-proliferative responses through a ROS independent mechanism. Carcinogenesis 2007;28(8):1765 73. [22] Katiyar SK. Matrix metalloproteinases in cancer metastasis: molecular targets for prostate cancer prevention by green tea polyphenols and grape seed proanthocyanidins. Endocr Metab Immune Disord Drug Targets 2006;6(1):17 24. [23] Cross HS, K´allay E. Nutritional regulation of extrarenal vitamin D hydroxylase expression - potential application in tumor prevention and therapy. Future Oncol 2005;1(3):415 24. [24] Mooney LA, Madsen AM, Tang D, et al. Antioxidant vitamin supplementation reduces benzo(a)pyreneDNA adducts and potential cancer risk in female smokers. Cancer Epidemiol Biomarkers Prev 2005;14 (1):237 42. [25] Mathers JC. Reversal of DNA hypomethylation by folic acid supplements: possible role in colorectal cancer prevention. Gut 2005;54(5):579 81.

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LOW PROTEIN RICE: MEDICAL RICE FOR CHRONIC KIDNEY DISEASE

13

Shaw Watanabe1, Keio Endo2, Masanori Nakajou3, Norihiro Takei3 and Shigeru Beppu3 1

President, Life Science Promoting Association, Tokyo, Japan 2Tokyo Medical and Dental University, Tokyo, Japan 3 Forica Foods Co. Ltd, Niigata, Japan

13.1 THE GLOBAL BURDEN OF CHRONIC KIDNEY DISEASE Chronic kidney disease (CKD) is an important public-health issue because of late complications and high health-care costs [1 3]. The prevalence is estimated to be 8% 16% worldwide. It is also linked to other major lifestyle-related diseases, such as diabetes, cardiovascular diseases, and hypertension [4]. CKD is defined as a reduced glomerular filtration rate (GFR), an increased urinary albumin excretion, or both [1]. Complications include: an increase in all-cause mortality and cardiovascular mortality, kidney-disease progression, acute kidney injury, cognitive decline, anemia, mineral and bone disorders, and fractures [5]. Recently, diabetes mellitus has become the most common cause of CKD worldwide [6]. The increasing prevalence of diabetes has made CKD the leading cause of end-stage renal disease (ESRD) in many countries [4]. Screening and adequate early interventions can prevent the progression of CKD toward ESRD [7,8]. The economic cost of diabetic kidney disease (DKD) will grow in enormous amounts, and strategies to prevent its onset or progression are urgently awaited. There is emerging evidence that changes in renal function occurring early in the course of diabetes predict future outcomes [9]. In Japan, population-based health checks include the screening of eGFR and urinary protein, allowing the detection of CKD at an early stage [10]. We have been monitoring changes in eGFR in a population-based cohort study in Saku municipality [11,12]. Typically, the eGFR decreased at a rate of 1 mL/year, when typical amounts (male 60 g/day, female 50 g/day) of proteins were consumed. In some people, however, the decrease in eGFR accelerated up to 5 mL per year (Fig. 13.1). The dietary habits of those participants featured a preference for broiled or baked beef or other meat dishes. All major nutrients are burnt in the body to produce energy, in a process whereby they are ultimately transformed into carbon dioxide and water. When protein intake is excessive, the excess of urea filtration and excretion through the kidneys damages the renal function. Accumulation of AGE and a kind of amino acid metabolites should influence the progression of CKD [13]. Hypothetically and clinically, a low-protein diet could prevent the drop in renal function seen in CKD.

The Role of Functional Food Security In Global Health. DOI: https://doi.org/10.1016/B978-0-12-813148-0.00013-X © 2019 Elsevier Inc. All rights reserved.

205

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CHAPTER 13 LOW PROTEIN RICE

eGFR Male

Female

90

90 percentile 75 percentile

60

median 25 percentile 10 percentile

30 40

50

60

70

80 40 Age

50

60

70

80 Age

FIGURE 13.1 Annual changes in a population-based cohort study. Usually a 1 mL/year decrease is observed, when the proper amount of proteins is consumed. If the protein intake increases, the decreasing rate of eGFR becomes steep up to 5 mL/year.

13.2 LOW-PROTEIN DIETARY THERAPY Whenever it is necessary to reduce the protein intake from whole meals, low-protein processed boiled rice is a convenient option. The Japanese Ministry of Health and Welfare recommends a daily protein intake of 50 and 60 g in women and in men, respectively. The protein intake that is clinically effective for CKD is about 0.5 g/kg body weight/day [14 16]. To achieve this objective, it would be necessary to decrease the protein consumption to less than 30 g/day for an individual weighing 60 kg. However, meals are less enjoyable when their high protein contents (from meat, fish, and eggs) is reduced, making long-term adherence to long-term protein restriction difficult. On the other hand, Japanese people using mainly rice as a staple food take as much as 30 g of daily protein from rice. In this case, low-protein diet therapy would become easier if we could reduce the fraction of proteins provided by rice. In the case of the MDRD Study, the insufficient intake of an energy source led to a failure to show the effectiveness of a low-protein diet [17]. For example, a patient put on a diet of 30 g protein/day and eating three cups (540 g in total) of nonprocessed common rice (2.5% of proteins) would receive 13.5 g of proteins from rice, i.e., 45% of 30 g protein intake. On the other hand, for the same patient eating the equivalent amount (540 g per day) of 1/20 protein rice (LPR), rice would make only 0.67 g, i.e., 2.25% of the protein intake. This would allow eating meat or fish for the remaining 97.7% of protein intake. It would thus become easier to maintain the feeling of satisfaction from meals, thereby improving adherence to diet therapy. In addition, the quality of the diet therapy would improve, by balancing the amino acid contents with side dishes and maintaining the energy intake at the same time [16]. Compared to common rice, LPR has similar qualities, such as a color, form, fragrance, and taste. We recommend the substitution of a plant protein, e.g., soy protein, for meat protein. Fortunately, there are many food stuffs of soy

13.5 PROCESSING OF PACKED LOW-PROTEIN RICE

207

protein, like tofu, natto, miso, etc. The low-protein diet therapy for the CKD patients is still under debate, but apparently it is becoming the mainstream of treatment [18 22].

13.3 PROCESSING OF LOW-PROTEIN RICE FOR HOSPITAL USE In the 1960s it became popular to support patients with severe dysphagia, by using nasogastric tube or gastrostomy feeding [23]. In 1972, Forica Foods Co. Ltd. started to make special foodstuffs for hospitals, such as canned concentrated nutritional liquid food. Flow food A was marketed in 1972 as a canned food product for the emergency room, based on the quality standards of the Tokyo Medical and Dental College for dense liquid food. Later, the rice content was adjusted to produce Liquid food A rice-gruel, in which rice had been enzymatically half digested and mixed with chicken eggs, carrots, milk, and some other raw materials to improve taste. In many hospitals all over Japan, Forica collected information about the performance of Liquid Food A in the functional improvement of dysphagia, as well as its use in diet therapy for kidney disease patients.

13.4 PACKED LOW-PROTEIN RICE In 1992, researchers at the Niigata Prefectural Food Research Institute reported a method to reduce rice protein, phosphate, and potassium by digestion of boiled rice with lactic acid bacteria. We implemented the same method to produce low-protein rice but there were many problems, such as the length of metabolizing period by lactic acid bacteria, the production costs, and the effects of lactic acid bacterium on other products by cross-contamination in the factory. Therefore, we modified the original technique by using specific acid proteases, and we succeeded in releasing packed boiled rice in which the protein contents was reduced to 1/3 of nonprocessed rice [24]. Japanese people prefer cooked rice to be elastic and not sticky. Unfortunately, after ordinary boil cooking, the enzymatically treated low-protein rice became sticky like rice cakes. To circumvent the problem, rice was cooked for a short time at superhigh temperature, uniformly heating all layers down to the core, and keeping the starch inside. In addition, to be kept at room temperature, the final product had to be sterilized at 121 C for 4 minutes, in accordance with the Japanese Food Hygiene Law Fo3.1.

13.5 PROCESSING OF PACKED LOW-PROTEIN RICE We further researched the most suitable combination of enzymes, to solve residual manufacturing problems in the processing of low-protein boiled rice. In 1995, the first product had a 1/3 protein mass contents, compared with nonprocessed rice, but the technique was improved to produce more options in protein contents: 1/5 in 1997, 1/10 in 2001, and currently 1/20 and 1/25. Before 2012, earlier packages had to be warmed with a home microwave oven. Fig. 13.2 shows the flow chart of the production of low-protein aseptic boiled rice. The complete assembly line involves the successive steps of: enzymatic treatment, cooking at high temperature, and automatic packaging system (Fig. 13.2). In 2012 we released a new low-protein rice in 5 kg packages for home use, which could be handled in an ordinary rice cooker.

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Assembly line of low-protein aseptic rice package Rinse free rice Enzymatic resolution Wash and dry Weigh and pack High pressure & temp Sealing Cooling Packing Shipment

FIGURE 13.2 Assembly line of low-protein aseptic rice.

Table 13.1 Nutrients in the Low Protein Rice (LPC) weight

energy

water

CH

protein

lipid

ash

Na

K

P

NaCl

PLC

g

kcal

g

g

g

g

g

mg

mg

mg

g

1/3 1/5 1/10 1/20 1/25

160 180 180 180 180

252 290 300 300 300

97.7 108.4 105.5 106.2 105.1

60.5 69.9 73.3 72.7 73.7

1.3 0.9 0.45 0.22 0.18

0.5 0.7 0.5 0.9 0.3B1.4

Tr 0.2 0.2 Tr 0.2

2 5 3 1B5 4

2 1 4 0.5 0

24 27 23 25 24

0 0 0 0 0

PLC, different concentration of protein in rice; CH, carbohydrate.

The stability and quality of the system produce packaged boiled rice with long palatable lowprotein aseptic contents, of equal quality to normal rice. Table 13.1 and Fig. 13.3 show the nutritional properties of current items in the PLC (Protein Low Content) series of low-protein processed boiled rice (Fig. 13.3A). The weight and energy contents of one package unit are stable from 1/10 to 1/25 LPR. The protein contents are strictly controlled, as well as the low potassium and phosphate concentrations (Fig. 13.3B). Glycemic of LPR is 20% lower than that of the original rice (Fig. 13.3C). This would be an additional benefit for diabetic patients to prevent postprandial hyperglycemia.

13.5 PROCESSING OF PACKED LOW-PROTEIN RICE

(A)

Various aseptic low protein rice packages

products

Protein content /100g rice Content

0.83g 160g

0.5g 180g

0.25g 180g

0.125g 180g

products

Protein content /100g rice Content

0.1g 180g

0.1g 150g

0.1g 180g For storage (3.5 yrs)

Nutrients in PLC low protein rice

(B)

Protein content

Energy 200 Energy (kcal)

Protein (%)

3

2

1

0

150 100 50 0

NT 1/3 1/5 1/10 1/20 1/25

NT 1/3 1/5 1/10 1/20 1/25

Potassium content 29

20

10

0

Phosphate content 40 Phosphate (mg)

Potassium (mg)

30

30 20 10 0

NT 1/3 1/5 1/10 1/20 1/25

FIGURE 13.3 (A and B) PLC rice packages and nutritional ingredients.

NT 1/3 1/5 1/10 1/20 1/25

209

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CHAPTER 13 LOW PROTEIN RICE

13.6 PEAK CONDITION PERIOD Kept in aseptic packages at normal room temperature, low-protein boiled rice of the PLC series has a palatable peak condition period of about 6 7 months. The preservation-related improvement depends on hygiene and sterilization management, and barrier properties of the wrapping. For use in disasters, a special packaging container was developed, extending the palatable period to 42 months or 3.5 years (Fig. 13.3A right lower part).

13.7 THE RESULTS OF THE PRODUCTION Low-protein aseptic packaged boiled rice (PLC series 1/3) was released in 1995. It was further developed to produce the 1/5, 1/10, 1/20 series, the latest product being the 1/25 since 2008. To date, the total amount of production has reached 74 million packages (Fig. 13.4). In addition, the introduction of new products with lower protein contents has influenced the amount of production of products released earlier (Fig. 13.5).

13.8 TIME TO INITIATE LOW-PROTEIN DIET Early clinical diagnosis of CKD is an opportunity to initiate a low-protein diet, even if subjective symptoms are still absent [25 29]. In the past, most of the patients used to learn about low-protein diet therapy within a medical institution or when it was provided as meals served in hospitals. Low-protein processed boiled rice was rarely sold over the counter, even though patients could obtain it by a mail order. It has been more than 20 years since low-protein aseptic packaged boiled rice of the PLC series has been used for CKD patients within medical institutions in Japan [30]. During this period, 1995

1998

2001

2004

2007

2010

2013

1/3 1995 1/5 1/10 1/20 1/25

2016

Total ‘(x1000) pack)

10,437 29,847

1997

15,763

2001 2004

13,720 2008

Total

FIGURE 13.4 Total amount of product shipping (PLC series low-protein aseptic package).

4,856 74,623

13.9 FUTURE PROBLEMS

211

Changes of sales products of different PLC by year 8000 7000 6000 5000 Total

4000

1/5

3000 2000 1000 0 1995

1/3

1/20

1/10

2000

2005

1/25

2010

2015

FIGURE 13.5 Changes in sales of different PLC products by year.

strictly controlled manufacturing conditions and food hygiene have guaranteed the security of the product. In addition, there has been no report about side-effects by long-term use of PLC rice. PLC low-protein processed boiled rice is valuable as a dietary therapy for CKD in the long term.

13.9 FUTURE PROBLEMS The number of CKD patients has been increasing, as a result of obesity and diabetes becoming frequent causes of CKD in Southeast Asia and other countries [31]. These regions of the world live mainly on boiled rice as a staple food. Therefore, diet therapy using low-protein processed boiled rice is more likely to contribute to limiting the burden of medical expenditures. On the other hand, Japanese people like to eat “Japonica” rice, but in many countries the texture and flavor of “Indica” rice are more popular. Further developments of the low-protein processing boiled rice technology would be necessary to adjust to regional preferences. Low-protein rice powder could become available for noodles, steamed buns, bread, and other foodstuffs [32]. In Southeast Asia, rice is the main staple food and contributes to the nourishment of the entire nation. The highly added value to farm products like low-protein boiled rice make the farm village rich, and it can also solve the lifestyle-related disease control of the city dweller. The dietary habit as the prevention of the diabetes-related kidney disease is important, and the development of the LPR for the purpose of the prevention is necessary. The grade of low protein diet for the prevention of chronic disease progression is still in debate. Kitada et al. [33] have demonstrated that a low protein diet (LPD), particularly a very-LPD (VLPD), improved renal tubulo-interstitial damage, inflammation and fibrosis, through the restoration of autophagy via the reduction of a mammalian target of rapamycin complex 1 (mTORC1) activity in type 2 diabetes and obese animal models. In their system a VLPD showed an more beneficial effect against advanced diabetic kidney disease (DKD). Their results were coincided with ours that less than 0.5 g/kg body weight VLPD clearly showed significantly longer survival.

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CHAPTER 13 LOW PROTEIN RICE

However, there is insufficient clinical data regarding the beneficial effects of a VLPD against DKD. Additionally, the patients with DKD are a high-risk group for malnutrition, such as protein– energy wasting, sarcopenia, and frailty. Recently, we have succeeded to make a low-protein dewaxed brown rice, so the nutritional problem could remarkably be improved. [34] As the future predicts, the development of a VLPD replacement therapy without malnutrition may be expected for reno-protection against the advanced stages of DKD, through the regulation of mTORC1 activity and adequate autophagy induction.

13.10 CONCLUSION CKD becomes more common with increasing age. After the age of 40, kidney filtration begins to decrease by approximately 1% per year. On top of the natural aging of the kidneys, many conditions which damage the kidneys are more common in older people, including diabetes, high blood pressure, and heart disease. This is important because CKD increases the risk of heart attack and stroke, and in some cases can progress to kidney failure requiring dialysis or transplantation. The appearance of microalbuminuria and/or low eGFR is the opportunity to start a low-protein diet to prevent complications and improve the future quality of life.

ACKNOWLEDGMENT The author thanks Drs. Sun JJ and Pachalee for their constructive discussions on clinical trials in Shanghai and Bangkok. We also thank Dr. Philippe Calain for his English editing and valuable suggestions.

REFERENCES [1] Jha V, Garcia-Garcia G, Iseki K, Li Z, Naicker S, Plattner B, et al. Chronic kidney disease: global dimension and perspectives. Lancet 2013;382(9888):260 72. Available from: https://doi.org/10.1016/S01406736(13)60687-X Epub 2013 May 31. [2] http://www.worldkidneyday.org/faqs/chronic-kidney-disease/ [3] Zhang QL, Rothenbacher D. Prevalence of chronic kidney disease in population-based studies: systematic review. BMC Public Health 2008;8:117. [4] Levey AS, Atkins R, Coresh J, Cohen EP, Collins AJ, Eckardt KU, et al. Chronic kidney disease as a global public health problem: approaches and initiatives - a position statement from Kidney Disease Improving Global Outcomes. Kidney Int 2007;72(3):247 59. [5] El Nahas M. The global challenge of chronic kidney disease. Kidney Int 2005;68:2918 29. [6] Zimmer P, Alberti KG, Shaw J. Global and societal implications of the diabetes epidemic. Nature 2001;414:782 7. [7] Atkins RC, Zimmet P. World Kidney Day 2010: diabetic kidney disease-act now or pay later. Am J Kidney 2010;55:205 8. [8] Bilous R. Microvascular disease: what does the UKPDS tell us about diabetic nephropathy? Diabet Med 2008;25(Suppl 2):25 9.

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[9] Shibuya K, Hashimoto H, Ikegami N, Nishi A, Tanimoto T, Miyata H, et al. Future of Japan’s system of good health at low cost with equity: beyond universal coverage. Lancet 2016;378(9798):1265 73. [10] Ninomiya T, Kiyohara Y, Tokuda Y, Doi Y, Arima H, Harada A, et al. Japan Arteriosclerosis Longitudinal Study Group. Impact of kidney disease and blood pressure on the development of cardiovascular disease: an overview from the Japan Arteriosclerosis Longtudinal Study. Circulation 2008;118:2694 701. [11] Morimoto A, Tatsumi Y, Deura K, Mizuno S, Ohno Y, Miyamatsu N, et al. Impact of impaired insulin secretion and insulin resistance on the incidence of type 2 diabetes mellitus in a Japanese population: the Saku study. Diabetologia 2014. Available from: https://doi.org/10.1007/s00125-013-2932-y. [12] Watanabe S, Morita A, Aiba N, Miyachi M, Sasaki S, Morioka M, et al. SCOP. Study design of the SAKU Control Obesity Program (SCOP). Anti-aging Med 2007;7:71 3. [13] Hasegawa S, Jao T-M, Inagi R. Dietary metabolites and chronic kidney disease. Nutrients 2017;9:358. Available from: https://doi.org/10.3390/nu9040358. [14] Watanabe S. Low protein-diet for the prevention of renal failure. Proc Jpn Acad Ser B 2017;93:1 977. Available from: https://doi.org/10.21813/pjab.93.001. [15] Mizuno S. A secondary analysis of Ideura Data of low protein diet practice for progressive chronic kidney disease patients. Clin Funct Nutr 2009;1(5):242 5. [16] Watanabe S, Noboru M, Yasunaga M, Ideura T. A cross-sectional study on the effects of long term very low protein diets in patients with chronic kidney disease. Serum and urine DEXA and amino acid profiles. Anti-aging Med. 2010;7(2):7 13. [17] Watanabe S. Evaluation of Modification of Diet in Renal Disease (MDRD) Study. Clin Funct Nutr 2009;1(5):238 41. [18] Kanazawa Y, Nakao T. Nutritional and dietary management of diabetic nephropaty: focus on low protein diets for stages 4 and 5 CKD. Clin Funct Nutr. 2009;1(3):31 4. [19] Piccoli GB, Capizzi I, Vigotti FN, Leone F, D’Alessandro C, Giuffrida D, et al. Low protein diets in patients with chronic kidney disease: a bridge between mainstream and complementary-alternative medicines?. BMC Nephrol 2016;8:17. Available from: https://doi.org/10.1186/s12882-016-0275-x. [20] Watanabe S. Effects of low carbohydrate diet for obesity control: meta-analysis. Clin Funct Nutr 2014;6 (6):300 3. [21] Saito J. Effects of low protein diet for chronic renal failure. Clin Funct Nutr 2009;1(5):251 6. [22] Japan Nephrology Society. Dietary recommendations for chronic kidney disease. Jpn J Renal Soc (Nichi-jin-kai-shi) 2014;56(5):553 99. [23] Morita A, Watanabe S. Dietary therapy for the elderly. Clin Funct Nutr 2011;3(4):186 90. [24] Egawa K. New development of rice processing by lactic acid fermentation. Nyu-san kin Gakkaishi 1997;7(2):72 8. [25] James MT, Hemmelgam BR, Tonelli M. Early recognition and prevention of chronic kidney disease. Lancet 2010;375:1296 309. [26] Rifkin ED, Katz R, Chonchol M, Fried LF, Cao J, de Boer IH, et al. Impaird kidney function and cardiovascular outcomes or mortality in the elderly. Nephrol Dial Transplant 2010;25:1560 7. [27] Grimm Jr. RH, Svendsen KH, Kasiske B. Proteinuria is a risk factor for mortality over 10 years of follow-up. MRFIT Research Group. Multiple Risk Factor Intervention Trial. Kidney Int 1997; Suppl.63:510 14. [28] Romundstad S, Holmen J, Kvenild K, Hallan H, Ellekjaer H. Microalbuminuria and all-cause mortallity in 2,089 apparently healthy individuals: a 44-year follow-up study. The Nord-Trondelag Health Study (HUNT), Norway. Am J Kidney Dis 2003;42:466 73. [29] Verhave JC, Gansevoort RT, Hillege HL, Bakker SJ, De Zeeuw D, de Jong PE. An elevated urinary albumin excretion predicts de novo development of renal function impairment in the general population PREVEND Study Group Kidney Int 2004;(Suppl. S18-S21).

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[30] Ministry of Health, Labour and Welfare, Standard of foods for diseased. 2007; www.mhlw.go.jp/shingi/ 2007/11/dl/s1121-13m.pdf. [31] Sun J-Q, Wang Y. Effects of low-protein rice on nutrition status and renal function in patients with chronic kidney disease: a pilot study. 2014. In; East-Asia Conference on Standardization of Rice Function, Kyoto, pp. 49-50. [32] Watanabe S, Hirakawa A, Nishijima C, Ohtsubo K, Nakamura K, Beppu S, et al. Food as medicine: the new concept of “medical rice”. Adv Food Technol Nutr Sci Open J 2016;2(2):38 50. Available from: https://doi.org/10.17140/AFTNSOJ-2-129. [33] Kitada M, Ogura Y, Monno I, Koya D. A low-protein diet for diabetic kidney disease: Its effect and molecular mechanism, an approach from animal studies. Nutrients 2018;10(5):544. Available from: https://doi.org/10.3390/nu10050544. [34] Watanabe S. Population-based strategy for preventing diabetes and its complications. Diabetes Res Open J. 2018;4(1):e1 e4. Available from: https://doi.org/10.17140/DROJ-4-e011.

CHAPTER

14

HIGH OMEGA-6/OMEGA-3 FATTY ACID RATIO DIETS AND RISK OF NONCOMMUNICABLE DISEASES: IS THE TISSUE, THE MAIN ISSUE?

Hilton Chaves1, Ram B. Singh2, Shairy Khan3, Agnieszka Wilczynska4 and Toru Takahashi5 1

Hospital das Clı´nicas, Federal University of Pernambuco, Recife, Brazil 2The Tsim Tsoum Institute, Krakow, Andrzej Frycz Modrzewski Krakow University, Krakow, Poland 3Department of Food Sciences, SNDT University, Pune, Uttar Pradesh, India 4Krakow University, Krakow, Poland 5Graduate School of Human Environmental Medicine, Fukuoka University, Fukuoka, Japan

14.1 INTRODUCTION The United Nation Member States proclaimed in April 2016 the UN Decade of Action on Nutrition 2016 25 (Nutrition Decade) [1]. This new initiative calls upon Food and Agriculture Organization and World Health Organization to lead implementation of the Nutrition Decade and reach its aim to accelerate implementation and the commitments of the 2nd International Congress of Nutrition [1]. The purpose is to achieve the global nutrition and diet-related noncommunicable diseases (NCD) targets by 2025, and contribute to the realization of the sustainable development Goals by 2030. The FAO of the United Nations guidelines emphasize to make full use of available food biodiversity to enhance the nutritional status of populations for which a better understanding of food biodiversity information in dietary intake is required [2]. Only a few national and regional food consumption surveys exist that report food biodiversity, particularly at the cultivar/breed level. The Nutrition Decade serves as an umbrella space for nutrition-related work along with crosscutting integrative areas based on the recommendations of the 2nd International Congress on Nutrition Framework for Action [1,2]. These recommendations are given in Table 14.1 along with other suggestions with an aim to provide functional food security for total health and world health. Omega-6 and omega-3 polyunsaturated fatty acids (PUFAs) are essential fatty acids which should be obtained from the diet [3 5], These fatty acids are not synthesized by humans and other mammals because of the lack of endogenous enzymes for omega-3 desaturation [3 8]. Recently, emergence of food industry as well as agribusiness and modern agriculture have contributed food security with Western diets that are rich in omega-6 PUFAs with very low levels of omega-3 PUFAs [3,4,4a]. These changes in the feeding of animals for animal foods and manufacturing of foods have led to unhealthy omega-6/omega-3 ratios of 20:1 to 50:1, instead of the 1:1 that was during evolution in humans [3 8]. Recently, some antiinflammatory products of omega-3 fatty acids that are known to cause imbalance between the pro- and antiinflammatory molecules were The Role of Functional Food Security In Global Health. DOI: https://doi.org/10.1016/B978-0-12-813148-0.00014-1 © 2019 Elsevier Inc. All rights reserved.

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CHAPTER 14 HIGH OMEGA-6/OMEGA-3 FATTY ACID

Table 14.1 Recommendations for Biodiversity of Foods to Provide Functional Food Security in Global Health 1. 2. 3. 4. 5. 6. 7. 8.

Sustainable resilient food systems for healthy diets rich in functional foods. Aligned health systems providing universal coverage of essential nutrition actions. Social and community protection and nutrition education. Trade and investment for improved nutrition. Safe and supportive environments for nutrition at all ages and for parents to improve health of the off-springs. Nutrition education of the food industry to produce functional foods. Use of epigenetic technology to produce novel functional foods, both for animal and plant foods. Genetic modification of food technology to be preferred for expensive functional foods such as walnuts, almonds, olive oil, with an aim of affordability, rather than for staples which are already inexpensive. 9. Strengthened governance and accountability for nutrition. 10. Feed for animals used for animal foods and soil for agriculture need worldwide attention to produce functional foods. Modified from FAO and WHO, 2017, Joint Fao/Who Food Standards Programme Codex Committee On Food Labelling 44th Session Asuncio´n, Paraguay, 16 20 October 2017. http://www.fao.org/fao-who-codexalimentarius/sh-proxy/en/? lnk 5 1&url 5 https%253A%252F%252Fworkspace.fao.org%252 Fsites%252Fcodex %252FMeetings%252FCX-714-44%252, accessed Nov 6,2017; FAO of the UNO. Guidelines on assessing biodiverse foods in dietary intake surveys.2017 http://www.fao. org/documents/card/en/c/5d2034ff-a949-482a-801c-44b7b675f1dd/.

investigated with reference to NCDs [9,10].This indicates that therapeutic strategies directed to suppress inappropriate inflammation and enhance the synthesis of antiinflammatory bioactive agents, can provide protection against NCDs. In the past three decades, total fat and saturated fat intake as a percentage of total calories has continuously decreased in western diets, while the intake of omega-6 fatty acid increased and the omega-3 fatty acid decreased, resulting in a large increase in the omega-6/omega-3 ratio from 1:1 during evolution to 50:1 today [3,4]. This change in the composition of fatty acids parallels a significant increase in the prevalence of overweight and obesity leading to an epidemic of NCDs. This review aims to examine the role of fatty acid ratio in the pathogenesis and prevention of NCDs.

14.2 DIETARY PATTERNS, HIGH OMEGA-6/OMEGA-3 FATTY ACIDS, AND MORTALITY Increased amounts of omega-6 fatty acids and a very high omega-6/omega-3 ratio, observed in Western diets, promote the pathogenesis of NCDs; including cardiovascular disease (CVD), cancer, and inflammatory and autoimmune diseases, whereas increased levels of omega-3 fatty acids with a lower omega-6/omega-3 ratio, exert suppressive effects [3 6]. In the secondary prevention of acute myocardial infarction (MI), a ratio of 4/1 was associated with a 70% decrease in total mortality in the Lyon heart study [11]. A ratio of 2.5/1 reduced rectal cell proliferation in patients with colorectal cancer, whereas a ratio of 4/1 with the same amount of omega-3 fatty acids showed neutral effect [5]. The lower omega-6/omega-3 ratio in women with breast cancer was associated with decreased risk. A ratio of 2 3/1 suppressed inflammation in patients with rheumatoid arthritis (RA), and a ratio of 5/1 had a beneficial effect on patients with asthma, whereas a ratio of 10/1 had

14.2 DIETARY OMEGA-6/OMEGA-3 FATTY ACIDS AND MORTALITY

219

adverse consequences [5]. These observations indicate that the optimal ratio may vary with the disease under consideration which is consistent with the fact that NCDs are multigenic, epigenetic, and multifactorial. Moreover, other protective or harmful nutrients present in the diet can also influence the risk of diseases and death. Mediterranean-style diets and Indo-Mediterranean-style diets have low omega-6 fatty acids and high omega-3 fatty acids with low omega-6/omega-3 fatty acid ratio [11 13]. It has been demonstrated that reduction in mortality achieved by such diets, possibly may be due to low omega-6/omega-3 fatty acid ratio in these diets [3 5]. In India, high omega-6/ omega-3 fatty acid ratio was associated with risk of NCDs [13] (Fig. 14.1). Only a few studies have evaluated the relationship between changes in diet quality over time and the risk of death [14]. In a cohort study among 47,994 women in the Nurses’ Health Study and 25,745 men in the Health Professionals Follow-up Study, changes in diet quality were assessed over the preceding 12 years with the use of the Alternate Healthy Eating Index 2010 score, the Alternate Mediterranean Diet score, and the Dietary Approaches to Stop Hypertension (DASH) diet score. For all-cause mortality among participants who had the greatest improvement in diet quality (0% 3% vs 13% 33% improvement), as compared with those who had a relatively stable diet quality, the hazard ratio in the 12-year period were the following: 0.91 (95% CI: 0.85 0.97) according to changes in the Alternate Healthy Eating Index score, 0.84 (95% CI: 0.78 0.91) according to changes in the Alternate Mediterranean Diet score, and 0.89 (95% CI: 0.84 0.95) according to changes in the DASH score [14]. A 20-percentile increase in diet scores for improved quality of diet was significantly associated with a reduction in total mortality of 8% 17% with the use of the three diet indexes and a 7% 15% reduction in the risk of death from CVDs with the use of the Alternate Healthy Eating Index and Alternate Mediterranean Diet. For those subjects with a high-quality diet over a 12-year period, the risk of death from any cause was 14% (95% CI: 8 19) when assessed with the Alternate Healthy Eating Index score, 11% (95% CI: 5 18) when assessed 500

471

450 400 Male

350 Death

300

Female

Total

291 250

250 200

180

150

163 131

115

100

97 95

77

60

50 0

192

175

49

87

54

23 26

Cardiovascular diseases

Cerebrovascular accidents

Diabetes

15 12 27

Cancers

Chronic lungs diseases

Renal diseases

Cirrohosis liver

FIGURE 14.1 Causes of deaths in India, due to high omega-6/omega-3 fatty acids induced noncommunicable diseases based on available records, according to classification by World Bank 2008. Modified from reference Fedacko J., Vargova V., Singh R.B., Anjum B., Takahashi T., Tongnuka M., et al. Association of high ω-6/ω-3 fatty acid ratio Diet with Causes of Death Due to Noncommunicable Diseases Among Urban Decedents in North India. Open Nutraceut J 2012;5:113 123.

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with the Alternate Mediterranean Diet score, and 9% (95% CI: 2 15) when assessed with the DASH score compared to subjects with consistently low diet scores over time. Majority of the cohort studies support an association between healthy dietary patterns identical with DASH diet or Mediterranean-style diets, and a decreased risk of death. [15 25]. Diet appears to be important factors in the pathogenesis of NCDs [26,27]. Results from recent studies suggest that improved diet quality, as assessed by means of the Alternate Healthy Eating Index 2010 score 12, the Alternate Mediterranean Diet score [22] and the DASH diet score, was associated with reductions of 8% 22% in the risk of death from any cause and reductions of 19% 28% in the risk of death from CVDs and 11% 23% in the risk of death from cancer [15 17]. In view of these studies, the 2015 Dietary Guidelines for Americans recommended the Alternate Healthy Eating Index, the Alternate Mediterranean Diet, and DASH as practical, understandable, and actionable diet plans for the public [25]. The FAO and WHO also support the same view and have joined hands to increase the functional food security, rather than food security [1,2]. Chronic NCDs are becoming increasingly significant causes of disability, premature death in both developing and newly developed countries, placing additional burdens on already overtaxed national health budgets [28 30]. According to WHO and World Bank, NCDs are the leading causes of mortality in the world, representing over 60% of all deaths worldwide [29]. Every year, at least about 2.8 million die from being overweight. High cholesterol accounts for roughly 2.6 million deaths and 7.5 million die because of high blood pressure. Of the 57 million global deaths in 2008, 36 million were due to NCDs (approximately 63% of total deaths worldwide). By 2030, deaths due to chronic NCDs are expected to increase to 52 million per year [29]. They pose a major challenge to the well-being and prosperity of populations across the world. particularly increases in low- and middle-income countries where access to appropriate, affordable, comprehensive care, timely diagnosis, and treatment is limited. In a recent meta-analysis, suboptimal intake of dietary factors was associated with an estimated 318,656 cardiometabolic deaths, representing 45.4% of cardiometabolic deaths [29a]. Increased consumption of sodium, insufficient intake of nuts/seeds, excess intake of processed meats, and low intake of seafood omega-3 fats were risk factors for highest proportions of deaths due to cardiometabolic diseases; heart diseases, stroke, or diabetes.

14.3 DIET AND RISK OF NONCOMMUNICABLE DISEASES It is clear that CVDs and cancers are leading causes of morbidity and mortality due to NCDs. However, NCDs are polygenic and multifactorial and pose a major challenge to the health, wellbeing, and prosperity of populations across the world. NCDs are known to cause unnecessary suffering, poverty, disability, and premature death [27 30]. The prevalence rates of major NCDs, i.e., CVD, cancer, type 2 diabetes, and chronic obstructive pulmonary diseases (COPD), are rapidly increasing in almost all countries and are now among the world’s biggest killers [27 31]. Singh’s group proposed, modifying the previous hypothesis, that overweight comes first in conjunction with inflammation, hyperinsulinemia, increased angiotensin activity, vascular variability disorders and central obesity followed by glucose intolerance, type 2 diabetes, hypertension, low HDL, and hypertriglyceridemia (metabolic syndrome) [27]. This sequence is followed by coronary artery disease (CAD), gallstones and cancers, and finally dental caries, gastrointestinal diseases, bone and

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joint diseases, degenerative diseases of the brain, and psychological disorders, during transition from poverty to affluence (Fig. 14.2). Western diets are primary risk factors of NCDs which are known to increase the risk by causing tissue inflammation [27 30]. Western diets are characterized by high omega-6 and low omega-3 fatty acid intake, whereas during the Paleolithic period when human’s genetic profile was established, there was a balance between omega-6 and omega-3 fatty acids in the diets [3 11,31,32]. There has been a rapid increase in the primary risk factors resulting in a marked increase in obesity which is a major risk factor of NCDs [4 7]. Recently, omega-6/omega-3 fatty acids ratio of diet and other nutrients have been found to be protective in the prevention and management of obesity which is the predictor of NCDs [3 8]. Further studies showed that Mediterranean-style diets such as DASH diet is protective against morbidity and mortality due to NCDs [14 27]. The contributing factors are multifaceted, complex, and include population aging, urbanization, the globalization of trade and marketing. The resulting progressive increase in unhealthy patterns of living, i.e., sedentary living, alcoholism, mental stress, and tobacco intake, in conjunction with Western diet predispose inflammation leading to NCDs [30] (Fig. 14.3). Reducing dietary saturated fat and replacing it with polyunsaturated fat is still the main dietary strategy to prevent these diseases [26]. The concept of myocardial preconditioning has opened new avenues to understand the complex interplay between the various lipids and the risk of CVDs. A lower intake of both saturated and omega-6 fatty acids and an optimal intake of omega-3 fatty acids is the main feature of Mediterranean diet [3 13,26]. However, a few studies have also reported a positive association between omega-6 and breast cancer risk but in contrast, omega-3 fatty acids do have anticancer properties [5]. It seems that certain polyphenols significantly increase the

FIGURE 14.2 The world food dynamics showing globalization of western diet and food security leading to emergence of noncommunicable diseases.

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Modern lifestyle

Intake of pro-inflammatory refined foods (higher ratio of W-6: W-3) & decreased physical activity

Oxidative stress

Obesity & metabolic syndromes

Inflammation

Future chronic noncommunicable diseases (NCD)

FIGURE 14.3 Consequence of intake of proinflammatory refined diet and development of chronic noncommunicable diseases (NCDs).

endogenous synthesis of omega-3 fatty acids, whereas high intake of omega-6 decreases it [26]. Therefore, the present high intake of omega-6 fat advised by the health agencies in many countries is definitely not the optimal strategy to prevent CVDs and cancers [25]. The United Nation High-Level Meeting (UN HLM) on NCDs held in September, 2011 has been very exciting [28,30]. The world’s heads of states and health ministers attended the meeting, creating a unique opportunity to advance globally the prevention and treatment of NCDs. We need an urgent and collective response because no country alone can address a threat of this magnitude. Despite tremendous progress in medical sciences, people and populations continue to die from NCDs [28 30]. In recognition of the global threat of NCDs, many experts feel that they know what needs to be done, and have set out five overarching actions (1) leadership; (2) prevention; (3) treatment; (4) international cooperation; and (5) monitoring and accountability. These proposed actions raise important questions. Do we know the causes of, and treatment for, NCDs? If we do not know the treatment why then are the best brains of the world and majority of the public funds thrown for the palliative treatment of these problems? The “Homo economicus” (leaders of the capitalist world) need to be educated thoroughly before we develop guidelines for prevention. Apart from physical and social health, mental and spiritual health of these leaders need to be addressed

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before we go ahead to prevent NCDs among various populations of the world. Such education is also necessary for “Homo economicus” business world, because the health of the employee is quite cost-effective for them. The possibility that excessive omega-6 fat intakes and subsequent series-2/4 eicosanoid synthesis may influence untoward physiological outcomes and increase the risk for a variety of chronic diseases is receiving more attention [3 11,31,32]. There is also evidence that Mediterranean-style diet which is rich in ω-3 fatty acids and which has similarity with Paleolithic diet can influence mental health related to gut-liver-brain-heart axis indicating its influence on mind-body connection [31]. Recent studies intended to evaluate the Mediterranean diet in the primary or secondary prevention of cardiovascular and other chronic degenerative diseases have been promising [16 26].

14.4 MODERN METHODS OF FOOD PRODUCTION AS RISK FACTOR OF NONCOMMUNICABLE DISEASES During the entire human history, populations have experienced changes in ecological relationships that have modified their diet and physical activity and eventually altered their disease pattern. Neolithic and industrial revolutions in late 18th and early 19th centuries, enabled mechanized food processing techniques and intensive livestock farming methods, leading to the production of refined and fattier forms of diet [33 35]. These methods of food production replaced the nutrient dense foods leading to a decline in micronutrient density. Modern diets contain a high amount of saturated fatty acids (SFAs), trans fat and ω-6 fat and lower amount of monounsaturated fatty acids (MUFAs) and ω-3 fat which cause inflammation, dyslipidemia and glucose intolerance [36 40]. Comparison of food and nutrient intake among hunter-gatherers and among Western and Asian populations show marked reduction in the consumption of ω-3 fatty acids, vitamins, antioxidants, essential and nonessential amino acids and significant increase in the intakes of carbohydrates (mainly refined), fat (saturated, trans fat, and linoleic acid), and salt compared to Paleolithic period [35 40]. Proponents of diet argue that excessive consumption of these novel Neolithic and industrial era foods is responsible for the current epidemics of metabolic syndromes in the United States and other contemporary Western populations [33 35]. In the last few decades, such diets have been adopted by an increased number of populations in the Western world as well as in the urban populations of middle-income countries predisposing the epidemic of NCDs. The rates of chronic NCDs such as CVD, cancer, type 2 diabetes, and COPD are rapidly increasing in developed countries as well as in developing countries. The contributing factors are multifaceted, complex, and include population aging, urbanization, the globalization of trade and marketing, and the resulting progressive increase in unhealthy patterns of living. Chronic diet-related disease prevalence can be explained by a mismatch and maladaptation of our ancient genome to a 21st century diet and other physical health conditions for which personal lifestyles, societal conditions associated with economic development are believed to be important risk factors. Studies on the evolutionary aspects of diet also indicate that major changes in diet have taken place in the last 150 years, particularly in the type and amount of essential fatty acids and in the antioxidant content of foods [34,35,37 39,41 46]. Experimental studies by Crawford et al. on wild animals compared to domesticated animals confirm the original observations of previous researchers; about the validity

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of high ω-3 fatty acids and low ω-6 fatty acids in the in the wild animals and evolutionary foods [39]. In 1990, WHO expert group advised to eat 400 g/day of fruits and vegetables for prevention of NCDs, which was also reiterated in 2003 due to evidence available from cohort studies [37]. Expert groups from many countries emphasized that new products from the agri-food industry and animal foods produced to produce excessive energy by increasing the size without consideration of nutrient content may have adverse effects on health [34,35,37 40,47,48].

14.5 INFLAMMATION IN THE TISSUE, MAY BE THE MAIN ISSUE? Eaton, with support from, Watson, de Meester, Singh, and Simopoulos are of the view that our genes today are very similar to the genes of our ancestors during the Paleolithic period 40,000 years ago, at which time our genetic profile was established [49 53]. However, our epigenome has altered considerably due to adverse effects of modern diet and lifestyle resulting in new phenotypes which are more susceptible to NCDs [54 57]. Our diet was considered quite healthy similar to hunter-gatherer’s diet due to optimal availability of omega-3 fatty acids and antioxidants which may be antiinflammatory [54,58]. The modern humans live in a nutritional environment that differs from that in which our genetic constitution was selected. Dietary changes, particularly in the type and amount of essential fatty acids, essential and nonessential amino acids, and in the antioxidant content of foods may predispose inflammation in the body tissues [41 43,53]. Inflammation appears to be important in host defenses against infectious agents and injury, as well as it also contributing to the pathophysiology of many chronic diseases. Interactions of cells in the innate immune system, adaptive immune system, and inflammatory mediators may be important in the acute and chronic inflammation that underlies diseases of many organs. A coordinated series of common effector mechanisms of inflammation contribute to tissue injury, oxidative stress, remodeling of the extracellular matrix, angiogenesis, and fibrosis in diverse target tissues. Inflammation may be at the base of many NCDs which is mediated by interaction of biological systems with environmental factors, including heliomagnetic fluctuations. Several studies have demonstrated that inflammatory response represents the “common soil” of the multifactorial diseases, encompassing both chronic inflammatory atherothrombotic and rheumatic disorders and a wide variety of conditions of NCDs [38 40,47,48] (Fig. 14.3). A balanced omega-6/omega-3 ratio is important for health and in the prevention and management of obesity [3]. The mechanisms, how omega-6 and omega-3 fatty acids elicit divergent effects on body fat gain through mechanisms of adipogenesis, browning of adipose tissue, lipid homeostasis, brain-gut-adipose tissue axis, and most importantly systemic inflammation are reported by many investigators [38 40,47,48]. Prospective studies clearly show an increase in the risk of obesity as the level of omega-6 fatty acids and the omega-6/omega-3 ratio increase in red blood cell (RBC) membrane phospholipids, whereas high omega-3 RBC membrane phospholipids decrease the risk of obesity [3 7]. Recent studies in humans show that in addition to absolute amounts of omega-6 and omega-3 fatty acid intake, the omega-6/omega-3 ratio plays an important role in increasing the development of obesity via both AA eicosanoid metabolites and hyperactivity of the cannabinoid system, which can be reversed with increased intake of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) [3 7]. Further studies also indicate, the clinical implications and

14.5 INFLAMMATION IN THE TISSUE, MAY BE THE MAIN ISSUE?

225

g/day

molecular mechanisms involved in the metabolism of lipoxins, resolvins, protectins, maresins and nitrolipids; the antiinflammatory products of omega-3 fatty acids were reviewed with reference to NCDs [9,10]. These antiinflammatory products may cause an imbalance between the pro- and antiinflammatory molecules in these diseases, which may be mediated by cell signaling. A high omega-6/omega-3 ratio diet was also noted among victims in India dying due to NCDs (Fig. 14.4). Increased amount of dietary fatty acids, viz., ω-6, trans fat, saturated fat, and lower ω-3 fat, could increase the synthesis of prostaglandins, thromboxanes, and leukotrienes in our body which may alter the effects of these signals on their normal target cells [38]. Increased consumption of rapidly absorbed high glycemic proinflammatory foods may activate the Nuclear Factor κB (NF-κB) signaling cascade and induce the secretion of antibacterial peptides and other defense mechanisms as well as proinflammatory transcription factors, e.g., AP 1 and EGR 1 [38]. Eicosanoids act as intercellular messengers and mediators of inflammation and immune reactivity [38]. The eicosanoids from arachidonic acid (AA) are biologically active in very small quantities and, if they are formed in large amounts, they contribute to the formation of thrombus and atheromas. They can also predispose to allergic and inflammatory disorders, particularly in susceptible people; and to proliferation of cells [38,39]. Because of the increased amounts of omega-6 fatty acids in the Western diet, the eicosanoid metabolic products from AA, specifically prostaglandins, thromboxanes, leukotrienes, hydroxy fatty acids, and lipoxins, are formed in larger quantities than 400 300 200 100 0

200

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d tu

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d cur

100 50 0

r ods utte r, b d fo e e t t n fi bu Re ed rifi ns fat a l C tra and

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FIGURE 14.4 Food consumption pattern among victims based on dietary diaries of the spouse. Modified from Fedacko J., Vargova V., Singh R.B., Anjum B., Takahashi T., Tongnuka M., et al. Association of high ω-6/ω-3 fatty acid ratio Diet with Causes of Death Due to Noncommunicable Diseases Among Urban Decedents in North India. Open Nutraceut J 2012;5:113 123.

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those formed from omega-3 fatty acids, specifically EPA [9,10,39]. Since the omega-6 fatty acid, AA (arachidonic acid, 20:4 n 6), found in abundance in various cells and tissues including serum phospholipid, they can be readily converted into proinflammatory eicosanoids and other products associated with inflammatory processes and chronic disorders in contrast to EPA [40]. The AA: EPA ratio in serum phospholipid has been studied in relation to the risk of chronic NCDs. These studies have indicated that the AA/EPA ratio in serum (or plasma) phospholipid correlates positively with clinical symptoms of depression [47,48]. Furthermore, higher ratios of AA:DHA were also observed to be associated with greater neuroticism [39]. Other experts have also implicated the abundance of the “summed” omega-6 relative to the omega-3 fatty acids in human plasma phospholipid with respect to chronic diseases [48]. However, most experts now agree that the cause of rogue inflammation in our body tissue may be due to the high omega-6 and omega-3 fatty acids ratio, in our diet. High ω-3 fatty acids may cause increased concentrations of antiinflammatory cytokines and enzymes that may produce antiinflammatory effects. One of the explanations for the harmful effect of abundance of omega-6 fatty acids in the diet has already been mentioned, viz., the effect of changes in the AA/(EPA 1 DHA) ratio in the lipids of the inner mitochondrial membrane causing fluidity. A high AA/(EPA 1 DHA) ratio leads to stiffening of the membrane and enhanced Ohmic resistance to the transport of electrons from complex I to cytochrome c oxidase. This reaction in turn may lead to enhancement of the rate of mitochondrial reactive oxygen species production [35]. Chronic inflammation may be involved in the pathogenesis of insulin resistance and type 2 diabetes mellitus in which oxidative stress is the underlying cause. Oxidative stress and inflammation can lead to subsequent insulin resistance, which places an increased risk for NCDs. Free fatty acids (FFA) and glucose induce inflammation via oxidative stress and have a cumulative independent effect which could be prevented by high omega-3 fatty acid rich diets [54,59]. Adipocytes have significant intrinsic inflammatory properties, apart from macrophages and are highly sensitive to infectious disease agents and cytokine-mediated inflammatory signals. It is possible that adipocytes are sensitive to the effects of TNF-α, which, through its TNF receptors, stimulates NF-κB, extracellular signal-regulated kinase, and mitogen-activated protein kinases PI-3 kinase and c-Jun-N-terminal kinase cascades [44]. In response to infectious and inflammatory signals, adipocytes have been shown to induce expression, of several acute phase reactants and mediators of inflammation. These are TNF-α, plasminogen activator inhibitor-1 (PAI-1), IL-1β, IL6, IL-8, IL-10, and IL-15, leukemia inhibitory factor, hepatocyte growth factor, Serum Amyloid A3, macrophage migration inhibitory factor, hapto-globin, complement factors B, D, C3, prostaglandin E2, and potential inflammatory modulators such as leptin, adiponectin, and resistin [45]. Although many of these activities are restricted to autocrine and paracrine effects, some of these cytokines secreted from adipocytes and adipose-resident macrophages make significant contributions to systemic inflammation. Obese hypertrophic adipocytes and stromal cells within adipose tissue directly augment systemic inflammation [46].

14.6 HIGH OMEGA-6/OMEGA-3 FATTY ACID RATIO AND INFLAMMATION People in south Asia have very high omega-6/omega-3 fatty acid ratio in the diet which could be up to 50:1 [59]. The ratio of long-chain ω-6 and long-chain ω-3 fatty acids in the tissues is also

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high in many of the Western societies which substantially increases the mortality and/or morbidity due to NCDs [11,12]. An out-of-balance diet, high in omega-6 fatty acids disrupts the balance of pro- and antiinflammatory agents in the body, promoting chronic inflammation which elevates the risk of NCDs. The higher the ratio of omega-6 to omega-3 fatty acids in platelet phospholipids, the higher is the death rate from CVD and type 2 diabetes mellitus [34,37,38]. Increased dietary intake of ω-6 fatty acids, particularly in the presence of low ω-3 fatty acids and CoQ10, is known to enhance increased production of biomarkers like thromboxane A2 (TXA2), leukotrienes, prostacyclin, interleukins-1 and -6, tumor necrosis factor-alpha, and C-reactive proteins (CRPs) and oxidative stress, which have adverse proinflammatory effects, resulting in NCDs [44 46,60 63] (Fig. 14.5).

FIGURE 14.5 Beneficial effects of omega-3 fatty acids by inhibiting inflammation in the prevention of noncommunicable diseases. Modified from google.

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A balance between the omega-6 and omega-3 fatty acids is a more physiologic state in terms of gene expression, eicosanoid metabolism, and cytokine production. CVD, diabetes mellitus, obesity, cancer, autoimmune diseases, RA, asthma, and depression are associated with increased production of thromboxane A2 (TXA2), leukotrienes, prostacyclin, interleukins-1 and 6, tumor necrosis factoralpha, and CRPs in the tissues which are cell signaling molecules. This increase in diet- and lifestyle-induced systemic inflammation mediates multiple pathogenic mechanisms in the possible associations between obesity, cardiovascular pathology, and the comorbidities such as dyslipidemia, type 2 diabetes mellitus, hypertension, and the metabolic syndrome. Biochemical research using stable isotope studies in subjects largely of European ancestry have indicated only a small proportion of dietary LA is converted to AA in humans suggesting that even in the presence of high linoleic (LA), there is limited capacity for it to be converted to AA [64 66]. However, studies over the past 5 years suggest genetic variability in the rate of conversion of LA to AA [67 71]. Importantly, certain genetic variants appear to be associated with higher levels of AA, systemic inflammation and inflammatory disorders. Recent studies on the relation between mitochondria and inflammation are posing new intriguing questions on the meaning of cellular fuel production in systemic inflammatory response syndrome, myocardial infarction, cerebral ischemia, and systemic and organ autoimmunity [72,73]. Mitochondrial constituents selectively activate an inflammatory state that regulates the processing and secretion of IL-1 and IL-18 [73]. Mitochondrial structures released by injured cells possibly prompt inflammation during heart, kidney, or brain ischemia-reperfusion injuries, in which local neutrophil activation and further tissue damage occur when the blood flow is restored. Immunomodulation by PUFA has been studied mainly in T lymphocytes and T cell-mediated diseases, but ω-3 PUFA have also been found to affect monocyte and macrophage functions [74]. Dietary PUFA seem to postpone diabetes development [75] and have considerable impact on gene expression in a variety of tissues, including adipose tissue, where they regulate genes involved in adipocyte differentiation and lipid metabolism [76,77]. Results of a recent animal study of db/db mice as well as lean nondiabetic mice (db/ 1 ) as treated with either low-fat standard diet (LF) or high-fat diets rich in (1) saturated/monounsaturated fatty acids (HF/S); (2) n 2 6 PUFA (HF/6); and (3) the latter including purified marine ω-3 PUFA (HF/3), together, clearly showed that many genes involved in inflammatory alterations were upregulated in db/db mice on HF/S compared with LF in parallel with phosphorylation of c-Jun N-terminal kinase (JNK). In parallel, adipose tissue infiltration with macrophages was markedly enhanced by HF/S. When compared with HF/S, HF/6 showed only marginal effects on adipose tissue inflammation. However, inclusion of ω-3 PUFA in the diet (HF/3) completely prevented macrophage infiltration induced by high-fat diet and changes in inflammatory gene expression, also tending to reduce JNK phosphorylation (P , .1) in diabetic mice despite unreduced body weight. Moreover, high-fat diets (HF/S, HF/6) downregulated expression and reduced serum concentrations of adiponectin, but this was not the case with ω-3 PUFA [78]. Thus, ω-3 PUFA seems to prevent adipose tissue inflammation induced by high-fat diet in obese diabetic mice, thereby dissecting obesity from adipose tissue inflammation. Many studies report that increased dietary intake of certain types of n-3 PUFAs (e.g., EPA and DHA) can divert cell metabolism towards less inflammatory eicosanoids, thereby modulating both the inflammatory response and the immune reactivity [79 81]. In clinical trials, omega-3 fatty acids inhibit the expression of proinflammatory genes, whereas omega-6 fatty acids have proinflammatory effects, resulting in significant decline in cardiovascular events [82,83]. Previous studies

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FIGURE 14.6 Pathway for the conversion of dietary omega-3 polyunsaturated fatty acid into fatty acids desaturases (FADS) in the tissues- protectants. Modified from Google images.

examined the effect of these fatty acids at the gene levels of immune signals and cytokines (protein immune messengers) that impact autoimmunity and allergy in blood cells and found that many key signaling genes that promote inflammation were markedly reduced compared to a normal diet, including a signaling gene for a protein called PI3K, a critical early step in autoimmune and allergic inflammation responses [84]. They developed a dietary intervention strategy in which 27 healthy humans were fed a controlled diet mimicking the ω-6/ω-3 ratios of early humans over 5 weeks. This study demonstrates, for the first time in humans, that large changes in gene expression are likely. This is an important mechanism by which PUFAs exert their potent clinical effects [84 86]. Thus, it is the omega-3 deficiency induced tissue changes which are ultimately responsible for pathogenesis of all types of inflammatory diseases. Fig. 14.6 shows the pathway for the conversion of dietary omega-3 PUFA into fatty acids desaturases in the tissues.

14.7 CHRONOLOGICAL CHANGES IN THE OMEGA-6/OMEGA-3 FATTY ACID RATIO OF DIETS The relative increase of omega-6/omega-3 fatty acid ratio in the food supply of Western societies has occurred after 1910 with industrialization and urbanization compared to the hunter-gatherers and Paleolithic period when diets were healthy [33,36,49 52,86,87]. It is known that during

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evolution, omega-3 fatty acids were found in all foods consumed, e.g., meat, wild plants, eggs, fish, nuts, and berries [3 13]. The proteins which were from both animal (running animals and eggs) and plant sources (green leaves and seeds), should have been composed of both essential and nonessential amino acids. The protein or amino acid intake was 2.5-fold greater (33% vs 13 %) in the Paleolithic diet compared to modern diet, respectively. Eaton and coworkers have estimated higher intakes for protein, calcium, potassium, and ascorbic acid and lower intake of sodium in the diet of late Paleolithic period than the current diets examined in the food chains in various countries [46,88,89]. Fig. 14.7 shows dietary transition from Paleolithic diet of Homo sapiens to modern man. Green leafy vegetables are also rich sources of antioxidants, magnesium, potassium, ω-3 fatty acids, flavonoids, and carotenoids which appear to be high in the Paleolithic diet [88,89]. Anthropological research suggests that our hunter-gatherer ancestors consumed omega-6 and omega-3 fats in a ratio of roughly 1:1. Between 1935 and 1939, the ratio of n 6 to n 3 fatty acids was reported to be 8.4:1. From 1935 to 1985, this ratio increased to 10.3:1 (a 23% increase). Other calculations put the ratio as high as 12.4:1 in 1985. Today in prudent diets, estimates of the ratio range from an average of 10:1 to 20:1, with a ratio as high as 50:1 in South Asia [46,59,88 92]. The beneficial effects of the Paleolithic dietary pattern may be because of low ω-6 fatty acids and high content of alpha-linolenic acid (ALA), antioxidants, flavonoids, vitamins and carotenoids which is similar to todays Mediterranean-style diets which have been demonstrated to decrease inflammation in the tissues [91]. An enormous increase in ω-6 fatty acid (about 20 50 g/day) in the diet is due to the production of oils from vegetable seeds. Increased intake of meat has resulted into greater intake of AA (0.2 1.0 mg/day), whereas the consumption of ALA has decreased

FIGURE 14.7 Evolutionary diet and changes during different periods of human development from Homo sapiens to modern man.

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(about 0.55 g/day) and the amounts of EPA and DHA are 48 and 72 mg/day respectively. Recent studies indicate that a prudent dietary pattern, similar to a Mediterranean-style diet may be protective against NCDs [14 27,46,88 101]. Further studies showed that a fruit and vegetable enriched diet can protect against MI and modulate microvascular function and ventricular premature beats [59,90,102 104].

14.8 OMEGA-6/OMEGA-3 FATTY ACID RATIO AND NONCOMMUNICABLE DISEASES Epidemiological studies indicate that total fat intake and the ratio of ω-6 to ω-3 PUFAs in the Western diet have increased significantly since the industrial revolution [7 13]. Excessive amounts of omega-6 PUFAs and a very high omega-6/omega-3 ratio, as is found in today’s Western diets, promote the pathogenesis of many diseases, whereas increased levels of omega-3 PUFA and a low omega-6/omega-3 ratio of diet, exert suppressive effects [10 13]. Saturated and MUFAs can be synthesized de novo and obtained from the diet, whereas the essential fatty acids, a group of PUFAs, cannot be synthesized in the body [103]. Mammalian cells, save for transgenic mice, cannot convert omega-6 to omega-3 fatty acids because they lack the converting enzyme, omega-3 desaturase, therefore, these essential fatty acids must be obtained from the diet. Moreover, SFA and trans fatty acids (TFA) elevate, PUFA decrease, and MUFA have beneficial effects, on total and low density lipoprotein cholesterol (LDL) as well as on HDL cholesterol. There has been an enormous increase in ω-6 fatty acid (about 30 g/day) in the diet due to the production of oils from vegetable seeds (corn, sunflower, safflower, soybean, and cotton). Diets with higher ω-6 to ω-3 ratios may contribute to the pathology of metabolic syndrome through inflammatory processes and other currently unrecognized mechanisms. Emerging research in animals and human studies indicate that eating excessive amounts of dietary omega-6 fat combined with insufficient amounts of omega-3 fats might be a risk factor for obesity [104]. Increased intake of omega-6 fats, may produce greater amounts of inflammatory compounds in the body tissues, and decreased availability of enzymes for omega-3 fats known to produce antiinflammatory molecules. The high omega-6 and low omega-3 fats profile in vegetable oils (as much as 200:1) is setting the stage for chronic inflammation in the body tissues Increased intake of total fat, TFA, SFA, and ω-6 fatty acids, refined carbohydrates and decreased intake of MUFA, ω-3 fatty acids, fiber, and phytochemicals may cause insulin resistance resulting in metabolic syndrome [85 87,105,106]. Diets rich in omega-6 fatty acids contribute to higher levels of the omega-6 fatty acid in the body tissues (the kidney and elsewhere). AA is metabolically converted to “eicosanoids” which have been implicated in promoting the formation of kidney stones and may be associated with detrimental effects on bone health. Metabolic syndrome includes abdominal obesity, atherogenic dyslipidemia (elevated triglycerides level and low HDL cholesterol), hypertension, and insulin resistance (with or without glucose intolerance). Omega-6 PUFA and TFA also decrease HDL cholesterol, and increase insulin resistance, free radical stress, and inflammation, which may enhance atherosclerosis [107 109]. Decreased consumption of ω-3 fatty acids and diets rich in animal proteins, saturated fats, and ω-6 vegetable oils are associated with a higher incidence of autoimmune disorders such as RA and systemic lupus erythematosus.

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Elevated levels of chemokines, such as “Regulated upon Activation, Normal T cell Expressed and Secreted” (RANTES), Monocyte Chemotactic Protein-1 (MCP-1), Macrophage Inflammatory Protein-1alpha (MIP-1alpha), and Macrophage Inflammatory Protein-1beta (MIP-1beta), have been found in RA and juvenile arthritis, and they may be associated with the pathogenesis of these diseases. These chemokines are implicated in the migration of specific leukocytes into the joints. Psychologic stress in humans induces overproduction of proinflammatory cytokines and eicosanoids as a result of an imbalance of omega-6 and omega-3 PUFA ratio in the peripheral blood [110]. A higher ratio of omega-6/omega-3 consumption is found associated with a significantly increased risk of Dry Eye Syndrome (DES). Increased concentrations of inflammatory cytokines, such as IL-1, IL-6, and TNF have also been found in tear film in patients with DES [111]. Miljanovic et al. investigated the relation of dietary intake of omega-3 fatty acids and the ratio of omega-6 to omega-3 with DES incidence in a large population of women participating in the Women’s Health Study [111,112]. Chronic intestinal disorders, such as inflammatory bowel disease, may also have low plasma n-3 PUFAs compared to normal subjects leading to increased production of inflammatory mediators [113]. Thus, a diet rich in omega-6 fatty acids shifts the physiological state to one that is prothrombotic and proaggregatory, with increases in blood viscosity, vasospasm, and vasoconstriction and decreases in bleeding time especially in patients with hypercholesterolemia, hyperlipoproteinemia, MI, other forms of atherosclerotic disease, diabetes, obesity, and hypertriglyceridemia as well as promotes the pathogenesis of many NCDs [108 113]. A lower ratio of omega-6/omega-3 fatty acids is desirable in reducing the risk of many of the chronic diseases [114 120]. A meta-analysis of randomized trials on the role of ω-3 fatty acids on adhesion molecules showed that these fatty acids can decrease inflammation [121]. Experimental and clinical studies further emphasize that tissue is the main issue rather than associated risk factors of chronic diseases [5,119 127]. Another experimental study also showed that increased availability of ω-6 fatty acid in the tissues enhances the formation of ω-3 fatty acids by the animals due to extraordinary capability of the animals to fight the adverse effects of ω-6 fatty acids [125]. However, humans do not have this capacity. The protective effects of prudent dietary patterns appear to be due to a low ω-6/ω-3 ratio of such diets because Western diet and South Asian diets have high ω-6/ω-3 ratio of 20 50 as shown in recent studies [5,59,120 127]. Tables 14.2 and 14.3 show the dietary patterns among victims dying due to NCDs and other disease. The consumption of fruits, vegetables, and nuts and prudent diet was inversely associated with risk of NCDs. High omega-6/omega-3 fatty acid ratio was positively associated with deaths due to NCDs (Table 14.3). Recent studies have proposed a protective role from dietary ω-3 PUFAs in human inflammatory bowel disease [128,129], given the knowledge that the biological effects of EPA and DHA encompass improving lipid profiles and reducing blood pressure [130,131], inhibiting the growth of tumor cells [132], and modulating symptoms in autoimmune and other inflammatory diseases [133 139]. PUFA, particularly those of the ω-3 fatty acids that are found in marine fish oils, exert immunomodulatory effects, e.g., in inflammatory joint and bowel diseases [137]. Dietary ratios of omega-3 to omega-6 PUFAs have been implicated in controlling markers of the metabolic syndrome, including insulin sensitivity, inflammation, lipid profiles and adiposity. A ratio of 2.5/1 reduced rectal cell proliferation in patients with colorectal cancer, whereas a ratio of 4/1 with the same amount of omega-3 PUFA had no effect. The lower omega-6/omega-3 ratio in women with breast cancer was associated with decreased risk. A ratio of 2 3/1 suppressed inflammation in patients with RA, and

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Table 14.2 Food Intakes and ω-6/ω-3 Fatty Acid Ratio of Diet in Relation to Causes of Death Based on Assessment by Dietary Diaries of the Spouse and Questionnaires Filled by the Nutritionist Causes of Death

Prudent Diet

Western-type Diet

892 6 252 806 6 237

202 6 22 256 6 28

1094 6 302 1062 6 198

7.93 6 2.8 7.26 6 2.7

31.3 6 5.3 38.2 6 6.6

715 6 241 757 6 245 705 6 202 617 6 188 605 6 175 0.045

412 6 53 437 6 47 405 6 41 505 6 55 522 6 61 0.048

1127 6 311 1194 6 318 1110 6 302 1122 6 325 1127 6 334 0.025

6.44 6 2.5 6.81 6 2.6 6.25 6 2.2 5.72 6 1.8 5.65 6 1.7 0.041

42.2 6 6.8 45.3 6 8.3 42.0 6 7.4 41.8 6 6.1 41.6 6 5.7 0.042

n 5 1385 Injury-accidents (n 5 215) Communicable Diseases. (n 5 372) NCDs Malignant (n 5 77) Circulatory(n 5 406) Chronic lung diseases (97) Kidney diseases (n 5 163 Diabetes (n 5 23) Kendall’s Γ

Score

ω-6/ω-3 Ratio

Men (Mean 6 Standard deviation) g/day

.n 5 837 Injury-accidents (n 5 139) Communicable diseases (n 5 194) NCDs (n 5 502) Malignant (n 5 54) Circulatory (n 5 240) Chronic lung diseases(n 5 95) Renal diseases (n 5 87) Diabetes (n 5 26) Kendall’s Γ

Total Foods

Women (Mean 6 Standard deviation) g/day 822 6 234 736 6 237

186 6 23 218 6 33

1008 6 224 954 6 201

8.40 6 2.2 7.51 6 1.9

25.5 6 5.7 34.5 6 5.6

657 6 197 655 6 205 660 6 180 565 6 155 553 6 146 0.041

186 6 23 218 6 33 305 6 35 382 6 48 380 6 130 387 6 135

962 6 221 987 6 218 1029 6 180 995 6 165 940 6 153 0.024

6.70 6 1.8 6.68 6 1.7 6.12 6 1.3 5.57 6 1.1 5.53 6 1.1 0.043

41.6 6 6.8 44.5 6 7.5 40.0 6 6.5 39.7 6 6.8 40.0 6 6.5 0.041

Values are number mean (Standard deviation),  P , .01,  P , .001. Modified Fedacko J., Vargova V., Singh R.B., Anjum B., Takahashi T., Tongnuka M., et al. Association of high ω-6/ω-3 fatty acid ratio Diet with Causes of Death Due to Noncommunicable Diseases Among Urban Decedents in North India. Open Nutraceut J 2012;5:113 123.

a ratio of 5/1 had a beneficial effect on patients with asthma, whereas a ratio of 10/1 had adverse consequences. These studies indicate that the effect of optimal ratio may vary with the disease under consideration [5].

14.9 OBESITY AND METABOLIC SYNDROME Cohort studies and cross-sectional surveys suggest that omega-3 fatty acid deficiency combined with excess intake of dietary omega-6 fats affects the liver function in a manner, which may lead to

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Table 14.3 Multivariate Logistic Regression Analysis for Association of Food and Nutrient Intakes With Risk of Death From Noncommunicable Diseases, After Adjustment of Age and Body Mass Index Among Men and Women Risk Factor Men

Women

Odds ratio, (95% confidence interval) Prudent foods 1.11 (1.06 1.18) FVL and nuts 1.07 (1.02 1.12) Western-type foods 1.02 (0.95 1.09) Meat and eggs 1.00 (0.94 1.06) Refined foods 0.98 (0.91 1.05) ω-6/ω-3 fat ratio 1.12 (1.01 1.19)

Odds ratio, (95% confidence interval) 1.09 (1.04 1.16) 1.05 (0.99 11) 1.00 (0.94 1.06) 0.98 (0.93 1.04) 0.95(0.89 1.02) 1.11 (1.00 1.18)



P value ,.01,  P , .001. OR, Odds ratio; FVL, fruit, vegetable, legume. Modified from Fedacko J., Vargova V., Singh R.B., Anjum B., Takahashi T., Tongnuka M., et al. Association of high ω-6/ω-3 fatty acid ratio Diet with Causes of Death Due to Noncommunicable Diseases Among Urban Decedents in North India. Open Nutraceut J 2012;5:113 123.

obesity [1,7 13]. Barghardt et al. [138] used dietary manipulation of ω-3 to ω-6 PUFA ratios in an animal model of metabolic syndrome and a related healthy line to assay feeding behavior and endocrine markers of feeding drive and energy regulation. Two related lines of rodents with a healthy and a metabolic syndrome phenotype were fed one of two isocaloric diets, comprised of either a 1:1 or a 1:30 ω-3 to ω-6 ratio for 30 days. Food intake and weight gain were monitored, and leptin, ghrelin, adiponectin, and a suite of hypothalamic neuropeptides involved in energy regulation were assayed following the dietary manipulation period. Serum levels of leptin, acylated-ghrelin and adiponectin, and mRNA levels of the anorexigenic hypothalamic neuropeptide, cocaine-amphetamine related transcript, showed differential, dietary responses with high capacity runners rats showing an increase in anorexigenic signals in response to unbalanced ω-3:6 ratios, while low capacity runners did not. Three generations of mice were fed isocaloric diets, in which ALA (the omega-3 precursor of EPA), was replaced with linoleic acid, the chief omega-6 polyunsaturated fat found in vegetable oils. The experimental group’s diet was lower in omega-3 fat with a higher omega-6 level, compared to the control group (0.16% calories vs 1.0% calories), and (12.3% calories vs 9.7% calories), respectively. The results clearly indicated that mice eating the experimental diet, had a significant increase in body weight with detrimental consequences on the liver, heart, and kidney, compared to mice fed the standard diet [140]. Moreover, adipogenesis was accompanied by a six-fold elevation of a key enzyme (stearyl-CoA desaturase), which is related to plasma triglycerides and fatty liver. An increase in the dietary omega-6/omega-3 fat ratio, upregulated the key gene required to make this enzyme.

14.10 CARDIOVASCULAR DISEASES The prevalence of CVDs has increased in parallel with the increase in linoleic acid and saturated fat intakes in many countries [7 15,139]. An enormous amount of medical literature testifies to the

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fact that fish oils prevent and may help to ameliorate or reverse atherosclerosis, angina, heart attack, congestive heart failure, arrhythmias, stroke, and peripheral vascular disease [141 147]. Fish oils help maintain the elasticity of artery walls, prevent blood clotting, reduce blood pressure, and stabilize heart rhythm [28,141 145,148,149]. An Italian study of 11,000 heart attack survivors found that patients supplementing their diet with fish oils markedly reduced their risk of another heart attack, a stroke, or death. Bypass surgery and angioplasty patients reportedly also benefit from fish oils. Fish oils are especially important for diabetics who have an increased risk of heart disease [113,146,147,150 155]. Clinical evidence suggests that EPA and DHA (EPA and DHA, the two omega-3 fatty acids found in fish oil) help reduce risk factors for heart disease, including high cholesterol and high blood pressure. Omega-3 fatty acids lower CRP more so than any other nutrient, which accounts for decreasing the risk for coronary heart disease. Strong inverse correlations between the summed total of omega3 fatty acids in serum phospholipid and all four ratios (omega-6:omega-3 (n-6:n-3), AA:EPA, AA: DHA, and AA:(EPA 1 DHA)) were found with the most potent correlation being with the omega6:omega-3 ratio (R250.96). The strongest inverse relation for the EPA 1 DHA levels in serum phospholipid was found with the omega-6:omega-3 ratio followed closely by the AA:(EPA 1 DHA) ratio at R250.88. It was estimated that 95% of the subjects would be in the “lower risk” category for coronary heart disease (based on total omega-3 $ 7.2%) with omega-6:omega-3 ratios ,4.5 and AA:(EPA 1 DHA) ratios ,1.4. The corresponding ratio cut-offs for a “lower risk” category for fatal ischemic heart disease (EPA 1 DHA $ 4.6%) were estimated at ,5.8 and ,2.1, respectively. A meta-analysis of randomized controlled trials in which 18 studies were included showed that ω-3 fatty acids can decrease inflammation [114]. Omega 3 PUFA supplementation reduced plasma concentration of soluble intercellular adhesion molecule-1 (sICAM-1; weighted mean difference (WMD): 5.17; 95% CI: 10.07, 0.27; P 5 .04) but had no significant effects on soluble vascular cell adhesion molecule-1 (WMD: 5.90; 95% CI: 17.63, 5.84; P 5 .32), soluble Pselectin (WMD: 1.53; 95% CI: 4.33, 1.28; P 5 .29), or soluble E-selectin (WMD: 0.46; 95% CI: 1.54, 2.46; P 5 .65). Subgroup analysis stratified by the subjects’ health status showed that ω-3 PUFA supplementation reduced sICAM-1 concentration in healthy subjects (WMD: 8.87; 95% CI: 15.20, 2.53; P 5 .006; heterogeneity test: I2 5 0%, P 5 .76) and in subjects with dyslipidemia (WMD: 15.31; 95% CI: 26.82, 3.81; P 5 .009; heterogeneity test: I2 5 26%, P 5 .26). The effect was identified in both healthy subjects and subjects with dyslipidemia, which supports the hypothesis that ω-3 PUFA can be supplemented as a primary or secondary means for preventing the development as well as the progression of athero-thrombosis [114,115,156].

14.11 DIABETES MELLITUS Among 13 studies of type 2 diabetes or the metabolic syndrome, that were assessed by metaanalysis, omega-3 fatty acids had a favorable effect on triglyceride levels relative to placebo but had no effect on total cholesterol, HDL cholesterol, LDL cholesterol, fasting blood sugar, or glycosylated hemoglobin [156] These results are consistent with the results of another meta-analysis for fish oil [156], which found significant triglyceride-lowering and LDL-raising effects and no significant effect on fasting blood glucose, glycosylated hemoglobin, total cholesterol, or HDL cholesterol

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among diabetics. Animal biosynthesis of high PUFA from linoleic, alpha-linolenic, and oleic acids is mainly modulated by the delta6 and delta5 desaturases through dietary and hormonal stimulated mechanisms. In experimental diabetes mellitus type-1, the depressed delta6 desaturase is restored by insulin stimulation of the gene expression of its mRNA. However, cAMP or cycloheximide injection prevents this effect. [157]. The depression of delta6 and delta5 desaturases in diabetes is rapidly correlated by lower contents of AA and higher contents of linoleic in almost all the tissues except brain. Environment factors, including maternal or infant dietary nutrition have been reported to have an influence on the pathogenesis of type 1 diabetes. [158]. Findings of the study to investigate the effect of maternal or postweaning offspring’s nutrition, in particular the essential fatty acid ratio (n-6/n-3) on the development of type 1 diabetes, suggest that n-6/n-3 ratio of the maternal diet during gestation and lactation rather than that of offspring after weaning strongly affects the development of overt diabetes in nonobese diabetic mice [158].

14.12 CANCER Epidemiological studies on the association of n-3 fatty acids and cancer, including correlation studies and migration studies, suggest a protective effect of n-3 fatty acids and a promoting effect of n6 fatty acids on cancer [159]. Therefore, the ratio of n-6 to n-3 may be more important than the absolute amount of n-3 PUFAs, as suggested by animal and human studies [159 161]. A number of studies have shown n-3 fatty acid protection in rodent models of breast cancer. These include dietary supplementation of mouse transplantable tumors [162] and human cell xenograft models [163,164] as well as chemically induced tumors in rats. A recent report showed that dietary DHAinduced reduction in mammary tumors in a rat model was accompanied by a 60% increase in the human breast cancer caretaker tumor suppressor susceptibility protein [165] responsible for DNA repair. Interestingly, n-3 fatty acid-enriched diets enhanced the efficiency of doxorubicin [166] and mitomycin C [167] in inhibiting tumor growth and strengthened the inhibitory effect of tamoxifen in estrogen dependent xenografts [168]. Bougnoux et al. [169] reported that dietary supplementation of breast cancer patients with DHA during anthracyclin chemotherapy had beneficial effects on time to progression, overall survival, and tolerance of side effects, particularly in a group of patients with high incorporation of DHA as measured in the plasma In these animals an n-3 fatty acid-enriched diet reduced tumor growth, retarded histopathologic progression and extended lifespan, whereas n-6 fatty acid supplementation had the opposite effect [161]. In addition, tumor growth was also retarded in this model by introduction of the fat-1 omega-3 desaturase which converts n-6 to n-3 fatty acids [161]. These studies point to a potential value of n-3 fatty acids as adjuvant to standard chemotherapy [169]. Several trials address the possibility that nutritional supplements containing n-3 PUFAs could stabilize weight loss or lead to weight gain in advanced cancer patients with cachexia [170 173]. Studies even demonstrated that the cancer cells expressing the omega-3 desaturase underwent apoptotic death whereas the control cancer cells with a high omega-6/omega-3 ratio continued to proliferate [174]. Recent studies supporting a protective role of n-3 PUFAs in cancer included case-control studies performed in Japan [175] and Scotland [176]. In the Japanese study, there was a trend for an inverse relationship between the risk of colorectal cancer and n-3 PUFA consumption, but this association was only statistically significant for

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distal colon cancer. In the Scottish study, significant dose-dependent reductions in colon cancer risk were associated with increased intake of total n-3 PUFAs as well as EPA or DHA taken separately. Prevention trials using n-3 supplements to reduce colorectal cancer risk have used cell proliferation in the colonic or rectal mucosa as an intermediate marker of cancer risk. A randomized double-blind trial found that administration of fish oil for 30 days to individuals with high risk for developing colon cancer reduced rectal mucosa proliferation to a level found in low risk population, with a concomitant increase in n-3 fatty acid and decrease in AA in the rectal mucosa [177]. A double-blind, crossover trial where healthy individuals were given a controlled basal diet supplemented with either fish oil or corn oil for 4 weeks showed that rectal cell proliferation, ornithine decarboxylase activity and PGE2 release were significantly lower during the fish oil period than the corn oil period [178]. An additional case-control study with measurement of blood fatty acid levels showed an inverse relationship between long-chain n-3 fatty acids and overall prostate cancer risk [179]. The results of this study to determine whether altering the dietary content of N-6 (n-6) and N-3 (n-3)PUFAs affects the growth of androgen-sensitive prostate cancer xenografts, found that tumor membrane fatty acid composition, and tumor cyclooxygenase-2 and prostaglandin E2 (PGE2) levels showed that tumor growth rates, final tumor volumes, and serum prostate-specific antigen levels were reduced in the n-3 group relative to the n-6 group. The n-6/n-3 fatty acid ratios in serum and tumor membranes were lower in the n-3 group relative to the n-6 group. In addition, n-3 group tumors had decreased cyclooxygenase-2 protein and mRNA levels, an 83% reduction in PGE2 levels, and decreased vascular endothelial growth factor expression.

14.13 CHRONIC PULMONARY DISEASES COPD, the fifth-leading cause of death worldwide, is characterized by chronic inflammation. A dietary supplement containing omega-3 PUFAs has antiinflammatory effects [180 185]. Observational studies report that leukotriene B4 levels in serum and sputum and tumor necrosis factor-α and interleukin-8 levels in sputum decreased significantly in the n-3 group [180]. Considerable interest in the possible value of omega-3 fatty acid supplementation in asthma was sparked by Horrobin’s hypothesis that the low incidence of asthma in Eskimos stems from their consumption of large quantities of oily fish, rich in omega-3 fatty acids [180]. Additional impetus for research came from observations that omega-3 fatty acids’ possible protective, or even therapeutic, effect might be afforded by their impact on mediators of inflammation thought to be related to the pathogenesis of asthma [95]. The only consistent impacts of omega-3 fatty acids on mediators of inflammation involved the suppression of leukotriene C4 [181 183] and of polymorphonuclear leukocyte chemotaxis in response to various stimuli [184,185]. The possible asthma-related benefits were associated with actively and markedly decreasing levels of omega-6 fatty acid intake concurrent with increasing the intake of omega-3 fatty acids. Given the interplay between proinflammatory omega-6 fatty acids, and the less proinflammatory omega-3 fatty acids, a ratio of 5/1 had a beneficial effect on patients with asthma [184]. Respiratory benefits might be attributable to changes in the status of mediators of inflammation such as leukotrienes and prostaglandins. Broughton et al. [184] studied the effect of omega-3 fatty acids at a ratio of omega-6/omega-3 of 10/1 to 5/1 in an asthmatic population in ameliorating methacholine-induced

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respiratory distress. With low omega-3 ingestion, methacholine-induced respiratory distress increased. With high omega-3 fatty acid ingestion, alterations in urinary 5-series leukotriene excretion predicted treatment efficacy and a dose change in 40% of the test subjects (responders) whereas the nonresponders had a further loss in respiratory capacity. A urinary ratio of 4-series to 5-series of ,1 induced by omega-3 fatty acid ingestion may predict respiratory benefit.

14.14 BONE HEALTH AND DISEASES It seems that epigenetic as well as genetic factors are responsible for about 70% of the variance in bone mass [186,187] in conjunction with other factors including nutrition, physical activity, and body mass index (BMI) [126,188]. The ω-6 and ω-3 fatty acids are currently being studied by Kartikey et al. to understand their effects on BMD and bone biology [126]. Numerous animal studies have shown that a higher ratio of ω-6 to ω-3 fatty acids is associated with detrimental effects on bone health, and a lower ratio is associated with healthy bone properties [189 193]. Animal studies have shown that dietary intake of long-chain omega-3 fatty acids may influence both bone formation and bone resorption [194,195] and an increase in periosteal bone formation [196]. Several animal studies have shown a positive effect of ω-3 on bone mineral density (BMD) and bone mineral content (BMC). Liu et al. [192] found significantly higher BMC in quail fed a fish oilsupplemented diet (high in n-3) compared with a soybean oil diet group (high in ω-6). Similarly, fish oil-supplemented rats had significantly higher BMD in the distal femur and proximal tibia than a corn oil-supplemented group (high ω-6) [197,198]. An increasing ratio of total dietary omega-6/ omega-3 fatty acids was also significant and independently associated with lower BMD at the hip in all women and at the spine in women not using hormone therapy. The dietary ratio of omega-6/ omega-3 fatty acids and BMD in older adults was studied in the Rancho Bernardo Study by Weiss et al. [199]. The study was carried out in 1532 community-dwelling men and women aged 45 90 years, between 1988 and 1992. The average intake of total omega-3 fatty acids was 1.3 g/day and the average ratio of total omega-6/omega-3 fatty acids was 8.4 in men and 7.9 in women. There was a significant inverse association between the ratio of dietary LA to ALA and BMD at the hip in 642 men, 564 women not using hormone therapy, and 326 women using hormone therapy. The results were independent of age, BMI, and lifestyle factors. An increasing ratio of total dietary omega-6/omega-3 fatty acids was also significant and independently associated with lower BMD at the hip in all women and at the spine in women not using hormone therapy. Animal models have suggested that omega-3 fatty acids may attenuate postmenopausal bone loss, indicating that the relative amounts of dietary omega-6 and omega-3 fatty acids may play a vital role in preserving skeletal integrity of old age. [199]

14.15 RHEUMATOID ARTHRITIS Most clinical studies examining omega-3 fatty acid and low in the inflammatory omega-6 fatty acids supplements for arthritis have focused on RA, an autoimmune disease. A ratio of 2 3/1 suppressed inflammation in patients with RA and helped reduce symptoms of RA, including joint pain

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and morning stiffness. The data obtained from the mice model study suggest that fish oil diets containing omega-3 fatty acids are beneficial in decreasing the levels of certain proinflammatory chemokines (RANTES and MCP-1) thereby delaying the onset of, and severity of, autoimmune symptoms [199] effects. One study suggests that people with RA who take fish oil may be able to lower their dose of nonsteroidal antiinflammatory drugs (NSAIDs) [200]. New Zealand green lipped mussel (Perna canaliculus), another potential source of omega-3 fatty acids, has been reported to reduce joint stiffness, pain, increase grip strength, and improve walking pace in a small group of people with osteoarthritis. An analysis of 17 randomized, controlled clinical trials looked at the pain relieving effects of omega-3 fatty acid supplements in people with RA or joint pain caused by inflammatory bowel disease and painful menstruation (dysmenorrhea) [201]. BRAIN HEALTH AND DEGENERATIVE DISEASES: (Depression, age-related memory loss, cognitive function impairment, Alzheimer) The human brain is one of the largest “consumers” of DHA and low DHA levels have been linked to low brain serotonin levels which again are connected to an increased tendency to depression, suicide, and violence [202 205]. Stoll and colleagues have shown that EPA and DHA prolong remission, i.e., reduce the risk of relapse in patients with bipolar disorder [202,205]. Kiecolt-Glaser et al. [204] studied depressive symptoms, omega-6/omega-3 fatty acid ratio and inflammation in older adults [205]. As the dietary ratio of omega-6/omega-3 increased, the depressive symptoms, increased. The authors concluded that diets with a high omega-6/omega-3 ratio may enhance the risk for both depression and inflammatory diseases. Long-chain omega-3 PUFA has also been reported to have a beneficial effect on attention-deficit/hyperactivity disorder and schizophrenia, and may be effective in managing depression in adults. Researchers at Harvard Medical School have successfully used fish oil supplementation to treat bipolar disorder (manic-depressive illness) and British researchers report encouraging results in the treatment of schizophrenia [204 210]. A high intake of fish has been linked to a significant decrease in agerelated memory loss and cognitive function impairment and a lower risk of developing Alzheimer’s disease. A recent study found that Alzheimer’s patients given an omega-3-rich supplement experienced a significant improvement in their quality of life [211 214] Other studies have shown that countries with a high level of fish consumption have fewer cases of depression. KIDNEY HEALTH AND DISEASES: (Urolithiasis) Patients who present with kidney stones often exhibit high urinary levels of calcium as a frequent abnormality. Use of DHA/EPA omega-3 via daily fish oil supplementation may reduce the urinary calcium and oxalate levels in hypercalciuric stone-formers. Omega-3 fatty acids were found to suppress AA levels in the body and the conversion of AA to its corresponding eicosanoids, relative to baseline levels, an average reduction of 29% was found in urinary calcium excretion within 6 months of dietary intervention with fish oil in 29 patients along with a significant decrease in urinary oxalate excretion when supplemented daily with 1200 mg of fish oil (containing DHA plus EPA) with an average folloω-up period of 9.9 months along with dietary advice [112]. VISION HEALTH AND OTHER DISEASES: (DES, Age-related macular degeneration). Inflammation of the lacrimal gland, the meibomian gland, and ocular surface plays a significant role in DES. Increased concentrations of inflammatory cytokines, such as IL-1, IL-6, and TNFalpha have been found in tear film in patients with DES 223. Miljanovic et al. [113] noted in the Women’s Health Study that a higher ratio of ω-6/ω-3 consumption was associated with a significantly increased risk of DES (OR: 2.51; 95% CI: 1.13, 5.58) for 15:1 versus ,4.1 (P for

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trend 5 .01). A higher dietary intake of ω-3 fatty acids is associated with a decreased incidence of DES in women and a high ω-6/ω-3 ratio involves a greater risk. Age-related macular degeneration (AMD) is the leading cause of vision loss among the geriatric population. Studies suggest that a higher dietary intake of omega-3 fatty acids is associated with a decreased incidence of DES in women and vice versa. Fish intake has been reported to have protective properties in lowering the risk of AMD (225 229), especially when LA intake was low [215,216]. In a study involving twins, Seddon et al. [217] showed that fish consumption and omega-3 fatty acid intake reduce the risk of AMD whereas cigarette smoking increases the risk for AMD. NEUROMUSCULAR DISEASES: (Injuries, muscle paralysis) Nerve damage from accidents and injuries can lead to pain, weakness, muscle paralysis which can leave people disabled. Omega-3 fatty acids could play an important role in preventing damage to nerves, and may help them to regenerate, speeding up recovery when damage does occur according to new research in mice. The study—published in The Journal of Neuroscience [218]—suggests that a high level of omega-3 PUFAs in the body could lead to protection of nerve cells and have beneficial effects on the recovery of nerves after a peripheral nerve injury. In a new study, Michael-Titus and her colleagues [218] looked at isolated mouse nerve cells and simulated the type of damage caused by accident or injury, by either stretching the cells or starving them of oxygen and found that a high level of omega-3 fatty acids provided significant protection and reduced the amount of cell death, which helped mice to recover from nerve injury more quickly and more fully—and that their muscles were less likely to waste following nerve damage. Omega-3 fatty acids (i.e., DHA) regulate signal transduction, gene expression, protect neurons from death, provide protection against reduced plasticity and impaired learning ability after traumatic brain injury [219]. Rats were fed a regular diet or an experimental diet supplemented with omega-3 fatty acids, for 4 weeks before a mild fluid percussion injury (FPI) was performed. FPI increased oxidative stress, and impaired learning ability in the Morris water maze [219]. This type of lesion also reduced levels of brain-derived neurotrophic factor, synapsin I, and cAMP responsive element-binding protein.

14.16 GUT HEALTH AND DISEASES Immunomodulation of the gut associated lymphoid tissue is a key issue in the clinical management of inflammatory bowel disease (IBD) [220] Eicosanoids such as leukotriene B4 (LTB4), thromboxane A2, or prostaglandin E2, and cytokines are implicated [221]. Most endogenously produced n-3 fatty acids appear to have therapeutic potential in ulcerative colitis and perhaps also in Crohn’s disease [222]. Although the clinical studies dealing with the use of n-3 PUFAs in IBD have yielded conflicting results, this is probably the result of discrepancies in patient selection and dosages used in the different protocols. PUFA supplementation in patients with proctocolitis has, however, been associated with a reduction in disease activity [223].

14.16.1 PROTECTIVE EFFECTS OF PALEOLITHIC-STYLE DIET ON NCDs The Mediterranean diet is a modern style of Paleolithic diet which emphasizes foods rich in omega-3 fatty acids (whole grains, fresh fruits and vegetables, fish, olive oil, garlic, moderate wine

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consumption) and MUFAs (olive oil, canola oil) and low in ω-6 fatty acids. It is much more balanced in terms of the omega-6 to omega-3 ratios. Paleolithic prudent dietary pattern appears to have beneficial effects because of low ω-6 fatty acids and high content of ALA, EPA, DHA, antioxidants, flavonoids, vitamins, and carotenoids present in the diet. Such diets may be protective against CVDs hypertension, CADs and stroke, type 2 diabetes, osteoporosis, and degenerative diseases of the brain [14 26]. Omega-3 fatty acids, such as ALA, are rich in mustard oil, walnuts, green leaves, whole grains, and seeds and EPA and DHA are rich in fish and fish oil and can protect against ventricular premature beats and MI [103,104]. Epidemiological studies showed that the Mediterranean Diet represents a healthy food model in the maintenance of the state of health and in the improvement of the quality of life. This diet could serve as an antiinflammatory dietary pattern which could protect from, or even treat, diseases that are related to chronic inflammation including type2 diabetes [224]. Several large epidemiological studies have shown that these diets are characterized by a low degree of energy density, prevent weight gain, and exert a protective effect on the development of type 2 diabetes, a condition that is partially mediated through weight maintenance [225]. The Mediterranean diet showed benefits on the incidence of cancer in healthy subjects, on the metabolic syndrome both in primary and secondary prevention, modifying numerous variables concerning CVDs, and even reduced the risk of relapse and mortality from acute coronary syndromes (ACSs). Increased olive oil consumption is implicated in a reduction in CVD, RA, modulates immune function, particularly the inflammatory processes associated with the immune system, and has a reduced risk of major chronic degenerative diseases, including Alzheimer’s Disease. Consumption of olive oil-rich diets increases the concentration of oleic acid in plasma membrane lipids of different rat and human cells, with beneficial consequences on membrane functionality [226 229]. In fact, the MD has been associated with changes in membrane structure and function. The changes in membrane properties induced by dietary lipids may have important consequences on blood pressure regulation. A currently ongoing randomized trial has revealed that the Mediterranean diet, rich in virgin olive oil (VOO) or nuts, reduces systolic blood pressure in high-risk cardiovascular patients. The study aims to assess the effect of a Mediterranean-style diet supplemented with nuts or virgin olive oil on erythrocyte membrane properties in 36 hypertensive participants after 1 year of intervention. After the intervention, the membrane cholesterol content decreased, whereas that of phospholipids increased in all of the dietary groups; the diminishing cholesterol: phospholipid ratio could be associated with an increase in the membrane fluidity. The results of the 3-month intervention on the first 772 patients entering the Prevencion con Dieta Mediterranea (PREDIMED) study showed, that compared with a low-fat diet, the Mediterranean diet rich in vergin olive oil (VOO) or nuts reduced systolic blood pressure, serum total cholesterol, triglyceride concentrations and increased serum high-density lipoprotein cholesterol concentration [230]. A high degree of adherence to the Mediterranean diet has been found to be related to lower concentrations of inflammation, endothelial dysfunction, and coagulation markers [5,61,82,86,231 236]. In a recent meta-analysis on more than 1.5 million people results showed that a higher adherence to the Mediterranean diet is associated with a significant reduced risk of incidence and mortality from all causes and from cardiovascular, neoplastic, and neurodegenerative diseases [110]. Randomized, controlled intervention trials also confirm that a Paleolithic-style diet can cause significant decline in morbidity and mortality due to cardiovascular events which may be because of the ALA present in such diet [115,116]. These findings need reemphasis because of new

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research evidence showing multiple functions of Paleolithic-style diet on cardiovascular functions and other NCDs [14 27,117 120]. The traditional diet of Crete (Greece) is consistent with the Paleolithic diet relative to the omega-6:omega-3 ratio. The Lyon Heart Study, which was based on a modified diet of Crete, had an omega-6:omega-3 ratio of 4:1 resulting in a 70% decrease in risk for cardiac death. Several of these studies were conducted when thrombolysis and angioplasty were not freely available for the treatment of ACS [117 120]. Therefore, it is not possible to conduct such studies again to demonstrate the role of diet in the prevention of ACS, although many other agencies now advise increased intake of fruits, vegetables, and nuts in the prevention of CVDs [117 120]. A recent review also reconfirmed the association of diet and nutrition with NCDs in the light of the UNO sponsored high level meeting held in September 2011 [118]. Epidemiological studies indicate that a prudent dietary pattern characterized by fruit, vegetable, legume and whole grain intake appears to be protective against NCDs [91 100]. The INTERHEART study, involving participants from 52 countries [100] examined the relationship between dietary patterns and risk of ACS. Consistent with previous studies in single withinpopulation cohort studies, the authors found an inverse association between the prudent pattern score and risk of ACS and a significant positive association between the Western pattern score and increased risk of ACS. No association of Oriental diet with risk of ACS was reported. A dietary risk score based on seven food items on the food-frequency questionnaire (meat, salty snacks, fried foods, fruits, green leafy vegetables, cooked vegetables, and other raw vegetables) was constructed by the authors. The investigators found that a higher score, indicating a poor diet was strongly associated with ACS risk and the subjects in the highest quartile of the score had nearly two-fold increased risk, even after adjustment for established coronary risk factors. On the basis of an arbitrary cut point of the score (top three quartiles vs the bottom quartile), the investigators estimated that 30% of MI could be explained by unhealthy diets worldwide. In a large, prospective, observational study, involving 72,113 female nurses who were free of CAD, stroke, diabetes, and cancer, Factor Analysis identified two dietary patterns from data collected on serial food frequency questionnaires [97]. One pattern, called prudent, was characterized by a high consumption of vegetables, fruit, legumes, fish, poultry, and whole grains. The other pattern, called Western, corresponded to a high consumption of red meat, processed meat, refined grains, French fries, sweets, and desserts. Individuals were classified by their level of adherence to both the prudent diet and the Western diet. After baseline data collection in 1984, folloω-up lasted 18 years, during which time 6011 deaths occurred (3139 (52%) as a result of cancer; 1154 (19%) resulting from CVD; and 1718 (29%) resulting from other causes). There was a 17% lower risk of total mortality among those who were most adherent to the prudent diet (highest vs lowest quintile of adherence), a 28% lower risk of CVD mortality, and 30% lower mortality from non-CVD, noncancer causes. Cancer was not associated with the inverse prudent dietary pattern. A comparison of the highest and lowest quintiles of adherence showed that consumption of the Western diet was associated with increased total mortality (21%), CVD mortality (22%), cancer mortality (16%), and mortality from non-CVD, noncancer causes (31%). Hence, except for cancer, risk relationships for the dietary patterns appear to be the inverse of each other: mortality thus was increased as adherence to the prudent diet decreased and adherence to the Western diet increased. In one crosssectional survey among 6940 subjects, above 25 years of age, fruit, vegetable and legume intake were inversely associated with risk of prehypertension and hypertension in five Indian cities [94]. A meta-analysis of cohort studies quantitatively assessed the relation between fruit and

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vegetable intake and incidence of CAD which reported relative risks (RRs) and corresponding 95% CI of CAD with respect to frequency of fruit and vegetable intake [98]. A total of 278 459 subjects (9143 CAD events) were included, with a median folloω-up of 11 years. The individuals who had less than 3 servings/day of fruit and vegetables, the pooled RR of CAD was 0.93 (95% CI: 0.86 1.00, P 5 .06) while those with more than 5 servings/day, the RR was 0.83 (0.77 0.89, P 5 .0001).This meta-analysis of prospective cohort studies demonstrated that increased consumption of fruit and vegetables, less than 3 to more than 5 servings/day is related to a 17% reduction, whereas increased intake to 3 5 servings/day is associated with a smaller and borderline significant reduction in CAD risk. These results provide evidence supporting that 5 or more servings per day of fruit and vegetables are needed to protect from CVD. Therefore, for prevention of CVDs, one should eat 400 g/day of fruits, vegetables, and nuts and another 400 g/day of legumes and other whole grains along with 30 50 g of canola oil 1 olive oil to protect our tissues which is the major issue [90,127]. Earlier validation studies found that two major patterns (the prudent and Western patterns) identified through Principal Components Analysis of food consumption data assessed by foodfrequency questionnaires were reproducible over time and correlated reasonably well with the patterns identified from diet records. The consistent association observed between the Western or unhealthy dietary pattern (high in animal products, salty snacks, refined starches and sugar and fried foods and low in fruits and vegetables) and ACS risk in different regions of the world from the INTERHEART study and other studies, as well as in our study, provide evidence of the adverse effects of globalization on human nutrition and chronic disease risk. However, this evidence is indirect because these studies did not specifically assess the impact of global trade and marketing on food consumption patterns across different countries [91 100]. Despite this weakness, most recent studies suggest that the current trend of dietary convergence toward a typical Western diet characterized by high ω-6/ω-3 ratio of fatty acids is likely to play a role in the globalization of obesity, CVD, diabetes, and cancer.

14.17 INTERVENTION TRIALS ON IMPACT OF LOW OMEGA-6/OMEGA-3 FATTY ACID PALEOLITHIC-STYLE DIET AND MORTALITY Observational Studies suggest an increased intake of high ω-6/ω-3 ratio Western-type foods and decline in prudent foods intake may be a risk factor for deaths due to NCDs. Cohort studies provide an association of diet with risk of CVDs and deaths. However, randomized, controlled intervention trials are necessary to provide a scientific proof that diet has a role in the prevention of CVDs [11,12,59,83,110,119,120]. Intervention trials, using the whole diet approach, so far produced, are also in line with this epidemiological evidence. The effect of Paleolithic-style diet was examined in patients (n 5 204 intervention group, n 5 202 control group) with ACSs, which showed significant decline in total cardiac events as well as in total mortality after 6 weeks and the benefit continued after 1 year [119]. Further follow-up for 2 years in this study, is different from the published work, because it places emphasis on the Paleolithic dietary patterns and ALA content of the diet being responsible for the significant greater survival in the intervention group compared to control group [59]. Dietary patterns before entry to the study showed higher ω-6/ω-3 ratio of 32.5 in the diets of both groups. Intervention group A was advised a Paleolithic style diet with ω-6/ω-3 fatty acid ratio of 4.3

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compared to standard diet group with ratio of 20. After a follow-up of 2 years, total mortality was significantly declined in the Paleolithic style diet group compared to control group. In the Lyon Diet Heart Study [11,127] 605 patients who had a MI were randomly assigned to a “Mediterranean-style” diet or a control diet resembling the American Heart Association Step I diet. The MD model supplied 30% of energy from fats and ,10% of energy from SFAs, whereas the intake of 18:3 (n-3) (α-linolenic acid) provided .0.6% of energy. After a mean follow-up of 27 months, the risk of new acute MI and episodes of unstable angina was reduced by B70% by the Mediterranean diet group [11]. Moreover, total mortality was also reduced by 70%. Long-term follow-up for 4 years also showed that the beneficial effects of diet were continued [127]. Singh et al. tested an “Indo-Mediterranean diet” in 1000 patients in India, with existing coronary disease or at high risk for coronary disease [110]. Half of the patients (n 5 499 vs 501) were administered a diet rich in fruits, vegetables, whole grains, walnuts, mustard and soy bean oil as a source for ω-3 fat and the remaining 501 patients were advised to take prudent diet advised by the National Cholesterol Education Program step 1 diet in 1988. [122]. At the end of a 2-year follow-up, the Paleolithic-style diet group consumed significantly more fruits, vegetables, and legumes than did the control group (537 6 127 vs 231 6 19 g/day) as well as more mustard and soy bean oil (31 6 6.5 vs 15.2 6 5.5 g/day). The mean intake of ALA was over two fold greater in the Paleolithic style diet group compared to control group (1.8 6 0.4 vs 0.8 6 0.2 g/day). The ω-6/ω-3 ratio of fatty acids was slightly higher at baseline in the intervention group than the control group (39 6 12 vs 34 6 10) yet both these figures are extremely high, reflecting a diet with a very high ω-6 content yet low ω-3 [110]. At the end of 2 years follow-up, this ratio showed a marked decline in the intervention group, which was greater than that observed in the control group consuming control diet (9.1 6 12 vs 21 6 10). The study endpoints significant declined in the total cardiac events, sudden cardiac death, and nonfatal infarction in the intervention group compared to the control group. Esposito et al. randomized 180 patients (99 men, 81 women) with metabolic syndrome to a Mediterranean-style diet, characterized with whole grains, vegetables, fruits, nuts, and olive oil versus a cardiac-prudent diet with fat intake ,30% [91]. After a follow-up of 2 years, subjects in the intervention diet showed greater weight loss, had lower C-reactive protein, and proinflammatory cytokine levels, had less insulin resistance, as well as lower total cholesterol and triglycerides and higher HDL cholesterol. The prevalence of metabolic syndrome was reduced to one half. The Japan Public Health Centre based study, showed that eating more ω-3 fatty acids by increased intake of fish was associated with significant reduction in CVD and cardiac mortality [126]. The diet and reinfarction trial [237] showed that modest intake of fish, 2 servings per week can cause significant decrease in total mortality and cardiovascular mortality. Since no benefit was observed in nonfatal infarction, the authors concluded that ω-ω-3 fatty acids may have prevented ventricular fibrillation by altering cardiomyocyte cell membrane phospholipids. There is experimental evidence indicating that the very long chain ω-ω-3 fatty acids in fish oil and fatty fish have an important effect on the pathogenesis of arrhythmias in the setting of myocardial ischemia and reperfusion both in vivo and in vitro [238] There is additional evidence from other studies indicating the role of ω-6/ω-3 ratio of fatty acids in the pathogenesis of NCD [5,13,61,82,86,111 113,121,122,124 148,150 245] A value of ω-6/ω-3 ratio of 1 2:1 has been shown to be the ratio in the traditional diet of Crete, where the concept of Mediterranean diet originated from [245]. Fedacko et al. reported the association of dietary patterns with causes of deaths among urban decedents in north India (1385 men, 837 women, aged 25 64 years). The

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score for intake of prudent foods was significantly greater and the ratio of ω-6/ω-3 fatty acids of the diet significantly lower for deaths due to “injury” and accidental causes compared to deaths due to NCD. Multivariate logistic regression analysis revealed that after adjustment for age, total prudent foods (OR,CI: 1.11; 1.06 1.18 men; 109; 1.04 1.16 women) as well as fruits, vegetables, legumes and nuts (1.07; 1.02 1.12 men; 1.05; 1.99 1.11 women) were independently, inversely associated whereas Western-type foods (1.02; 0.95 1.09 men; 1.00; 0.94 1.06 women); meat and eggs (1.00; 0.94 1.06 men; .098; 0.93 1.04 women) and refined carbohydrates (0.98; 0.91 1.05 men; 0.95; 0.89 1.02 women) and high ω-6/ω-3 ratio of fatty acids were positively associated with deaths due to NCD. Results further highlighted that NCDs such as malignant, circulatory, chronic lung disease, renal disease, and diabetes mellitus were common causes (57.0%) of death among both sexes. It also highlighted that 5.9% (n 5 131) deaths were due to cancers in the victims consuming high ω-6/ω-3 ratio of 42:1 diet. [13]. Several cohort studies and intervention trials suggest that increased consumption of functional foods like fruits, green leafy vegetables, nuts and legumes decreases the risk of CVD morbidity and mortality [14 27]. The potentially protective content of these foods include ALA, EPA, DHA polyphenols, folate, magnesium, calcium, potassium, fiber, vitamin E, carotenoids, arginine, taurine, cysteine, oleate, and favorable lysine to arginine and methionine to arginine ratios. Experimental studies also indicate that adipose tissue inflammation induced by high-fat diet in obese diabetic mice may be prevented by treatment with PUFAs [246]. A recent study has reported that increase in omega-6/omega-3 ratio of diet may be associated with CVDs and metabolic syndrome [247]. Further studies showed that vegetarian and Mediterranean style diets that are low in omega-6/ omega-3 fatty acid ratio, are effective in reducing body weight and the functional food security with these diets can prevent the epidemic of metabolic syndrome [248,249]. Recently, probiotics have been suggested as a treatment for the prevention of NAFLD due to new research in this area [63 66]. Omega-3 fatty acid supplementation may have beneficial effects in regulating hepatic lipid metabolism, adipose tissue function, platelet function, arrhythmias and inflammation [63]. Further studies indicate that supplementation with probiotics, prebiotics, and synbiotics has shown promising results against various enteric pathogens due to their unique ability to compete with pathogenic microbiota for adhesion sites [64 66]. These strategies may alienate pathogens or can modulate, stimulate and regulate the immune responses in the host by initiating the activation of specific genes in and outside the host intestinal tract. There may be increase in lifespan and improvement in gut microbiota leading to decrease in fatty acid deposition in the hepatocytes [65,66].

14.18 CONCLUSION Since inflammation is at the base of many chronic diseases, therefore, the balance of omega-6/ omega-3 fatty acids as primary and secondary prevention is an important mechanism in decreasing the risk for NCD. A more practical approach would be to consume foods with added health benefits that were found prevalent in ancestral diets as functional foods, in addition to a healthy lifestyle to help prevent chronic diseases. It is the tissue which is mainly involved in the mechanism of inflammation; hence it is the main issue in the pathogenesis and prevention of NCDs. In view of epigenetic and genetic variations, the optimal ω-6/ω-3 ratio would vary with the disease and population under consideration. If the tissue concentration of ω-6/ω-3 ratio is 1:1 along with other nutrients

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which are in the proper ratios, high LDL cholesterol (unoxidized) may be neutral without any evidence of endothelial dysfunction. The Mediterranean-style diets may prove to be even more enjoyable and considerably healthier in combating the obesogenic environment and in decreasing the risks of the NCDs of modern life than conventional, modern dietary recommendations. The time has come to return the omega-3 fatty acids into the food supply and decrease the omega-6 intake using functional food approach for prevention of NCDs.

ACKNOWLEDGMENTS The authors would like to thank the Tsim Tsoum Institute, Krakow, Poland for providing logistic support.

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[184] Broughton KS, Johnson CS, Pace BK, Liebman M, Kleppinger KM. Reduced asthma symptoms with n-3 fatty acid ingestion are related to 5-series leukotriene production. Am J Clin Nutr 1997;65:1011 17. [185] Eisman JA. Genetics of osteoporosis. Endocr Rev 1999;20:788 894. [186] Seeman H, Hopper JL, Bach LA, Cooper ME, Parkinson E, McKay J, et al. Reduced bone mass in daughters of women with osteoporosis. N Engl J Med 1989;320:554 8. [187] Cummings SR, Nevitt MC, Browner WS, Stone K, Fox KM, Ensrud KE, et al. Risk factors for hip fracture in white women. Study of Osteoporosis Fracture Research Group. N Engl J Med 1995;332:767 73. [188] Watkins BA, Li KY, Allen GD, Hoffman WE, Seifert MF. Dietary ratio of (n-6)/(n-3) polyunsaturated fatty acids alters the fatty acid composition of bone compartments and biomarkers of bone formation in rats. J Nutr 2000;130:2274 84. [189] Watkins B, Shen C, Allen K, Seifert M. Dietary (n-3) and (n-6) polyunsaturates and acetylsalicylic acid alter ex vivo PGE2 biosynthesis, tissue IGF-I levels, bone morphometry in chicks. J Bone Miner Res 1996;11:1321 32. [190] Liu D, Denbow DM. Maternal dietary lipids modify composition of bone lipids and ex vivo prostaglandin E2 production in early postnatal Japanese quail. Poult Sci 2001;80:1344 52. [191] Liu D, Veit HP, Denbow DM. Effects of long-term dietary lipids on mature bone mineral content, collagen, crosslinks, and prostaglandin E2 production in Japanese quail. Poult Sci 2004;83:1876 83. [192] Liu D, Veit HP, Wilson JH, Denbow DM. Long-term supplementation of various dietary lipids alters bone mineral content, mechanical properties and histological characteristics of Japanese quail. Poult Sci 2003;82:831 9. [193] Sakaguchi K, Morita I, Murota S. Eicosapentaenoic acid inhibits bone loss due to ovariectomy in rats. Prostaglandins Leukot Essent Fatty Acids 1994;50:81 4. [194] Iwami-Morimoto Y, Yamaguchi K, Tanne K. Influence of dietary n-3 polyunsaturated fatty acid on experimental tooth movement in rats. Angle Orthod 1999;69:365 71. [195] Li Y, Seifert MF, Ney DM, Grahn M, Grant AL, Allen KG, et al. Dietary conjugated linoleic acids alter serum IGF-1 and IGF binding protein concentrations and reduce bone formation in rats fed (n-6) or (n-3) fatty acids. J Bone Miner Res 1999;14:1153 62. [196] Das U. Interaction(s) between essential fatty acids, eicosanoids, cytokines, growth factors and free radicals: relevance to new therapeutic strategies in rheumatoid arthritis and other collagen vascular diseases. Prostaglandins Leukot Essent Fatty Acids 1991;44:201 10. [197] Bhattacharya A, Rahman M, Banu J, Lawrence RA, McGuff HS, Garrett IR, et al. Inhibition of osteoporosis in autoimmune disease prone MRL/mpj-fasIpr mice by n-3 fatty acids. J Am Coll Nutr 2005;24:200 9. [198] Venkatraman J, Meksawan K. Effects of dietary omega3 and omega6 lipids and vitamin E on chemokine levels in autoimmune-prone MRL/MpJ-lpr/lpr mice. J Nutr Biochem 2002;13(8):479. [199] Lau CS, Morley KD, Belch JJ. Effects of fish oil supplementation on non-steroidal anti-inflammatory drug requirement in patients with mild rheumatoid arthritis a double-blind placebo controlled study. Br J Rheumatol 1993;32(11):982 9. [200] Riediger ND, Othman RA, Suh M, Moghadasian MH. A systemic review of the roles of n-3 fatty acids in health and disease. J Am Diet Assoc 2009;109(4):668 79. [201] Locke CA, Stoll AL. Omega-3 fatty acids in major depression. World Rev Nutr Diet 2001;89:173 85. [202] Stoll AL, Severus WE, Freeman MP, Rueter S, Zboyan HA, Diamond E, et al. Omega 3 fatty acids in bipolar disorder: a preliminary double-blind, placebo-controlled trial. Arch Gen Psychiatry 1999;56:407 12.

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[225] Schro¨der H. Protective mechanisms of the Mediterranean diet in obesity and type 2 diabetes. J Nutr Biochem 2007;18(3):149 60 Epub 2006. [226] Pagnan A, Corrocher R, Ambrosio GB, Ferrari S, Guarini P, Piccolo D, et al. Effects of an olive-oilrich diet on erythrocyte membrane lipid composition and cation transport systems. Clin Sci (Lond) 1989;76:87 93. [227] V´azquez CM, Zanetti R, Santa-Marı´a C, Ruı´z-Guti´errez V. Effects of two highly monounsaturated oils on lipid composition and enzyme activities in rat jejunum. Biosci Rep 2000;20:355 68. [228] Perona JS, Vo¨gler O, S´anchez-Domı´nguez JM, Montero E, Escrib´a PV, Ruiz-Gutierrez V. Consumption of virgin olive oil influences membrane lipid composition and regulates intracellular signaling in elderly adults with type 2 diabetes mellitus. J Gerontol A Biol Sci Med Sci 2007;62:256 63. [229] Ruiz-Gutierrez V, Muriana FJ, Guerrero A, Cert AM, Villar J. Plasma lipids, erythrocyte membrane lipids and blood pressure of hypertensive women after ingestion of dietary oleic acid from two different sources. J Hypertens 1996;14:1483 90. [230] Estruch R, Martinez-Gonzalez MA, Corella D, Salas-Salvado J, Ruiz-Gutierrez V, Covas MI, et al. Effects of a Mediterranean-style diet on cardiovascular risk factors: a randomized trial. Ann Intern Med 2006;145:1 11. [231] Singh RB, Niaz MA, Ghosh S, Beegom R, Rastogi V, Sharma JP, et al. Association of trans fatty acids (vegetable ghee),and clarified butter(Indian ghee) intake with higher risk of coronary artery disease in rural and urban populations with low fat consumption. Int J Cardiol 1996;56:289 98. [232] Singh RB, Beegom R, Verma SP, Haque M, Singh R, Mehta AS, et al. Association of dietary factors and other coronary risk factors with social class in women in five Indian cities. Asia Pac J Clin Nutr 2000;9:298 302. [233] Singh RB, Niaz MA, Beegom R, Wander GS, Thakur AS, Rissam HS. Body fat percent by bioelectrical impedence analysis and risk of coronary artery disease among urban men, with low rates of obesity: the Indian paradox. J Amer Coll Nutr 1999;18:268 73. [234] Aratti P, Peluso G, Nicolai R, Calvani M. Polyunsaturated fatty acids: biochemical, nutritional and epigenetic properties. J Am Coll Nutr 2004;23:281 302. [235] Kumar SG, Das UN, Kumar KV, Tan BKH, Das NP. Effects of n-6 and n-3 fatty acids on the proliferation and secretion of TNF and IL-2 by human lymphocytes in vitro. Nutr Res 1992;12:815 20. [236] Burr ML, Fehily AM, Gilbert JF. Effects of changes in fat, fish and fiberfiber intakes on death and myocardial infarction: diet and Reinfarction Trial(DART). Lancet 1989;757 61. [237] Appel LJ. Dietary patterns and longevity. Circulation 2008;118:214 15. [238] Mclennan PL, Abeywardena MY, Charnock JS. Dietary fish oil prevents ventricular fibrillation following coronary occlusion and reperfusion. Am Heart J 1988;16:709 16. [239] Gaudio E, Taddei G, Vetuschi A, Sferra R, Frieri G, Ricciardi G. Dextran sulfate sodium (DSS) colitis in rats: clinical, structural, and ultrastructural aspects. Dig Dis Sci 1999;44:1458 75. [240] Wigmore SJ, Barber MD, Ross JA, Tisdale MJ, Fearon KC. Effect of oral eicosapentaenoic acid on weight loss in patients with pancreatic cancer. Nutr Cancer 2000;36:177 84 [PubMed: 10890028]. [241] Sun D, Krishnan A, Zaman K, Lawrence R, Bhattacharya A, Fernandes G. Dietary n-3 fatty acids decrease osteoclastogenesis and loss of bone mass in ovariectomized rats. J Bone Miner Res 2003;18:1206 16. [242] Cho E, Hung S, Willett W, Rimm EB, Seddon JM, Colditz GA, et al. Prospective study of dietary fat and the risk of age-related macular degeneration. Am J Clin Nutr 2001;73:209 18. [243] Smith W, Mitchell P, Leeder SR. Dietary fat and fish intake and age-related maculopathy. Arch Ophthalmol 2000;118:401 4. [244] Seddon J, Ajani U, Sperduto R. Dietary fat intake and age-related macular degeneration (ARVO abstract). Invest Ophthalmol Vis Sci 1994;35:2003.

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[245] Simopoulos A. Essential fatty acids in health and chronic diseases. Am J Clin Nutr 1999;70(suppl 1):360 9. [246] Todoric J, Loffer M, Huber J, Bilban M, Raimers M, Kadl A, et al. Adipose tissue inflammation induced by high fat diet in obese diabetic mice is prevented by polyunsaturated fatty acids. Diabetologia 2006;49:2109 19. Available from: https://doi.org/10.1007/s00125-006-0300-x. [247] Singh RB, Fedacko J, Saboo B, Niaz MA, Maheshwari A, et al. Association of higher omega-6/omega3 fatty acids in the diet with higher prevalence of metabolic syndrome in North India. MOJ Public Health 2017;6(6):00193. Available from: https://doi.org/10.15406/mojph.2017.06.00193. [248] Slomski A. Vegetarian and Mediterranean diets effective for weight loss. JAMA 2018;319(16):1649. Available from: https://doi.org/10.1001/jama.2018.4738. [249] Shastun S, Chauhan AK, Singh RB, Singh M, Singh RP, Itharat A, et al. Can functional food security decrease the epidemic of obesity and metabolic syndrome? A viewpoint. World Heart J 2016;8 (3):273 80.

FURTHER READING Fung TT, Malik V, Rexroad KM, Manson JE, Willett WC, Hu FB. Sweetened beverage consumption and risk of coronary heart in women. Am J Clin Nutr 2009;89:1037 42.

CHAPTER

FATTY ACIDS IN HUMAN DIET AND THEIR IMPACT ON COGNITIVE AND EMOTIONAL FUNCTIONING

15

Agnieszka Wilczynska and Andrzej Frycz Modrzewski Krakow University, Krakow, Poland

15.1 INTRODUCTION A change of the living environment, in particular one’s diet, is the main factor of a higher risk of the development of contemporary diseases. There is still a lack of scientifically proven explanations for the causes of the occurrence of certain disorders, which have been on the rise all over the world in recent years. Such disorders include dyslexia, autism, or attention deficit hyperactivity disorder. Despite a thorough investigation of the symptoms of mental diseases, no explicit etiology of depression or the nervous system conditions, such as Alzheimer disease, has been identified. Such conditions are designated as contemporary civilization or degenerative diseases (known as noncommunicable diseases) and are considered to be a growing threat to the contemporary man. The World Health Organization estimates that as much as 85% of the mortality rate in Europe is caused by degenerative diseases [1]. At the Global Forum for Health organized by the WHO in Geneva in 2010, experts estimated that mental illnesses and cerebral vascular diseases are going to be one of the most serious conditions burdening mankind in the year 2020. The DALY (disability adjusted life-years) index, which is used by the WHO, defines the life-years affected by disability or health impairment excluding a given person from a full social participation. Researchers find that a lack of physical activity, an improper diet, and stress combined with a genetic predisposition of the individuals have become a common and primary risk of the occurrence of the abovementioned issues. This article describes the scientific discoveries of the past two decades and aims to demonstrate the significance of the change in proportions between certain fatty acids (as a consequence of the diet change) for the selected areas of psychological (cognitive and emotional) functioning of the human being.

The Role of Functional Food Security In Global Health. DOI: https://doi.org/10.1016/B978-0-12-813148-0.00015-3 © 2019 Elsevier Inc. All rights reserved.

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15.2 CHANGES IN THE DIET: EVOLUTIONARY DIET VERSUS CONTEMPORARY DIET Our ancestors, who were hunter-gatherers had a completely different content of certain substances in the diet and hence in their tissues in comparison with the contemporary man. What is more important, they did not suffer from degenerative diseases, such as circulation and cerebral diseases, or mental disorders, at least not on the contemporary scale [1]. The evolutionary diet of our ancestors was characterized by a balance kept between polyunsaturated acids and saturated acids as well as by a balanced proportion between polyunsaturated acids omega-6/omega-3 equaling 1:1. Nowadays, we can speak about a complete disturbance of balance between saturated and polyunsaturated acids, whose quantity ratio equals 2:1, and between polyunsaturated fatty acids omega-6 and omega-3, which amounts to as high as 20 15:1. This inversion of proportion is considered to be the primary cause of the development of degenerative diseases [2,3,4]. It has been noted that costs connected with the treatment of a growing number of cerebral diseases and mental disorders associated with an improper diet have been rapidly increasing and even surpassed the expenditures on the treatment of other conditions. For instance, it is estimated that in the United Kingdom such costs amount to d77 billion annually, a similar situation of rising cost of treatment of mental disorders has also been observed in each of 25 member states of the European Union [5].

15.3 POLYUNSATURATED FATTY ACIDS: STRUCTURE AND FUNCTION Among the fatty acids present in the human body the following ones can be distinguished: saturated and unsaturated fatty acids, including mono- and polyunsaturated. Polyunsaturated fatty acids are built from a hydrocarbon chain of a different length with several double bonds. The bonds are separated by single methylene groups. The designation of a particular family (omega-3 or omega-6) of fatty acids depends on the position of the first double bond starting from the methylene group. The position of the first double bond (omega) distinguishes the omega-3 family, which includes alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), from the omega-6 family including linolenic acid (LA) and arachidonic acid (AA). It is estimated that these double bonds influence their flexibility and plasticity. The excess of omega-6 fatty acids in the diet is harmful to the organism. Both families compete for the same enzymes, therefore the food including mainly omega-6 fatty acids hampers the transformation of omega-3 fatty acids [2,3]. Fatty acids are indispensable for the proper functioning of the human body and play a significant role in the area of cognitive, social, and emotional functioning of the human being. It should be also emphasized that they constitute the main building substance of the brain and the nervous system as well as each cell of the organism (a component of the cellular membrane). The central and peripheral nervous systems contain fatty acids in very high concentration. Their general content is estimated to be over 60%. Each axon of the nervous system cell is surrounded by a myelin sheath (composed mainly of fat), whose quality has impact on neural transmission and the

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speed of the transmission of impulses. A too thin or damaged myelin sheath slows down (up to 50 times) or disables the communication between neurons. Polyunsaturated fatty acids constitute as much as 20% of the dry mass of the brain and over 30% of all fatty acids in the nervous system [6]. Numerous investigations indicate that omega-3 fatty acids (especially DHA) play an important role in the synthesis of neurotransmitters, their degradation and the processes of reuptake [7,8,9]. The research results confirm that the intake of omega-3 fatty acids by the mother during pregnancy and lactation has a positive impact on the child’s psychological development [10,11]. The decrease of the DHA content in the brain (monitored by means of a test of the proportion of fatty acids in blood) is connected with the reduction of capacity to learn, remember, as well as receive auditory and olfactory stimuli. It has also influence on the decrease of the size of neurons and delay of cellular migration in the developing brain. The change of the proportion of fatty acids in the diet and consequently in human tissues is associated with the increase of depressive and aggressive behavior as well as lowering of cognitive functions [5,12]. A lot points to the fact that polyunsaturated omega-3 fatty acids may be useful in the treatment and prevention of chronic inflammatory diseases. EPA is present in the brain cells in a small amount, however, it seems to play an important role due to its antiinflammatory action. It is also successfully used in the therapy of depression [13,14]. On the basis of DHA, numerous compounds are created. They also have an antiinflammatory and protective potential, similarly to AA, which is a representative of omega-6 acids [5]. The properties of omega-3 fatty acids were also appreciated as far as the increase of cognitive efficiency and mood regulation is concerned. The effectiveness of individual fatty acids in the organism is connected not so much with their presence as with the proportion between particular fatty acids [11,15].

15.4 DESCRIPTIVE RESEARCH A lot of evidence which has been collected over the past decade indicates that the level of omega-3 fatty acids in the daily diet influences cognitive functioning and emotional regulation in humans. Lawrence J. Whalley et al. [16,17] conducted observational research in which 350 participants took part. They were intellectually apt, born in 1936, and their intellectual capacity was diagnosed in 1947. At the turn of the year 2000 and 2001, the researchers measured their cognitive capacity as well as their diet, applied supplements, and risk factors of cardiovascular diseases. The results revealed that the intake of supplements to the diet was related to the level of intellectual efficiency in the examined persons. Moreover, this relationship did not depend on the differences of cognitive ability in childhood. In people at the age of 64 years, the researchers observed notable intellectual benefits resulting from a regular use of diet supplements, in particular fish oil. The differences between the results of the test group and control group were observed in tests including the Digit Symbol Subtest of Wechsler Adult Intelligence Scale—Revised (WAIS-R), the scale sensitive to the symptoms of cognitive aging and the symptoms of Alzheimer’s disease. The outcome produced considerably better results in the scope of attention focus as well as visual and spatial functions in participants in the test group. Blood samples were taken from all test participants. Significant

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correlations were observed between the level of IQ in the childhood and present concentration of omega-3 fatty acids in cellular membranes of the blood cells. In addition, significant correlations were revealed between IQ at the age of 64 and the proportion of AA/DHA fatty acids and omega6/omega-3 fatty acids in the blood. These results coincide with the outcomes of Norwegian research conducted by Eha Nurk and collaborators in a group of 2031 healthy participants over 70 years of age [18]. The research outcome showed that people who often ate fish ($10 g/day) obtained considerably better results in all cognitive capacity tests than people whose fish consumption was occasional (,10 g/day) (Kendrick Object Learning Test (KOLT); Trail Making Test, part A (TMT-A); a modified version of the Digit Symbol Test (m-DST); Block Design (m-BD), a modified version of the Mini-Mental State Examination (m-MMSE), an abridged version of the Controlled Oral Word Association Test (S-task)). The more the oilier/fatty kinds of fish were present in the participant’s diet, the stronger the effect. The relationship between omega-3 fatty acids concentration in the plasma and the cognitive efficiency in adults was also found by Carla Dullemeijer and collaborators [19]. The Dutch research revealed that the concentration of omega-3 fatty acids in the plasma may enable the prediction of a pace and degree of the decrease of cognitive capacity typical in people over 50 years of age. Over a period of 3 years, in a group of participants at the age of 50 70, it was observed that the people with a higher level of omega-3 fatty acids in the plasma showed a considerably smaller impairment of such cognitive functions as sensorimotor speed or mental processing speed than the people having lower concentration of omega-3 fatty acids. It is worth noting that the scientific circles are still searching for the evidence if the impairment of cognitive functions in elderly people is a pathological phenomenon or it is solely a result of the physiological process of ageing. Recent findings suggest that keeping a diet rich in fatty acids (particularly those from omega-3 group) may considerably slow down this process.

15.4.1 INTERVENTIONAL RESEARCH Interventional studies conducted by means of a double-blind method with placebo in the control group definitely ensure a higher possibility of the control of experimental variables. They enable monitoring of the changes in cognitive and emotional functioning at different levels of proportions of the fatty acids mixture and the total amount of the intake of polyunsaturated acids administered during the experiment. This method makes it possible to reduce the influence of many potential disturbing variables. One of the most interesting research results was found by Fontani and his collaborators in a group of healthy volunteers [20]. Italian researchers applied an experimental intervention, which included the administration of diet supplements containing 4 g of EPA 1 DHA to participants. They were examined daily and the variability of their cognitive, emotional, and physiological parameters was monitored. The participants (aged from 22 to 51), who were healthy as well as fully physically and mentally capable, were subjected to the tests measuring different types of attention. The following computer tests were used: Alert, Go/No-Go, Choice, Sustained Attention to examine both groups, namely the group taking omega-3 fatty acids and the placebo group. In order to assess potential changes in the scope of neuroelectric parameters the EEG and EMG measurements were applied. The participants’ mood was tested (using the POMS form—Profile of Mood States) as well as the reaction time in attention tests being noted. The tests were conducted at the beginning

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of the experiment and after 35 days of providing the supplements. The results of the test group which took the diet supplements were compared with the results obtained from the control group. Blood samples were taken to determine the proportion of AA/EPA, the level of cholesterol and triglycerides, HDL, LDL, and glycemia. The research results obtained by Fontani and collaborators revealed that the daily intake of 4 g of n-3 PUFA is connected with essential changes in the mood. The analysis of the Profile of Mood States in the experimental group showed a higher statistically significant result related to the level of vigor and a lower result related to the states like anger, anxiety, tiredness, depression, and embarrassment in comparison to the results obtained in the placebo group. Reaction time in attention tests was definitely reduced in the group with the supplements intake, which indicated the improvement of results after the completion of the supplements intake in the test group in comparison with a slower reaction time among participants in the control group. All EEG recordings after the completion of the experiment showed changes in the direction of low frequencies. The results confirm the hypothesis of a direct influence of omega-3 fatty acids on the central nervous system. However, it should be emphasized that the people who participated in the tests were healthy and the fact of supplementing their diet with omega-3 fatty acids improved their individual efficiency, including emotional and cognitive functioning. The abovementioned results [20] make it possible to conclude that a positive impact of such a diet on cognitive processes relates not only to elderly people being at risk of the decrease of their intellectual functions but it also refers to young people who do not show any clinical symptoms of the disease. Ingredients of the diet including EPA and DHA may improve intellectual processes and influence the mood regulation in each person. It should be noted that the administration of higher doses (e.g., $ 3 g daily) may not always produce positive effects due to the fact that both EPA and DHA very easily undergo peroxidation and fragmentation to cytotoxic compounds [21]. The authors of the studies describe the observed changes in the reaction time and other psychological variables as strong confirmation of the hypothesis of a direct impact of unsaturated fatty acids on the central nervous system. The relationship between the proportion of omega-3 and omega-6 fatty acids was also examined in a group of healthy adults with diagnosed dyslexia [22]. The advantages of the administration of an omega-3 supplement were observed in an experimental therapy of dyslexia and dyspraxia as well as in the youth and children with attention deficit hyperactivity disorder. However, as the authors state themselves, in spite of satisfactory initial results, this direction of studies requires continuation and verification of the efficiency of such a therapy [22,23,24,25,26,27]. Other studies observed that the intake of omega-3 fatty acids in food or in supplements is connected with a decreased risk of the impairment of cognitive functions [28] and dementia [29,30]. It was ascertained that fatty acids contribute to the improvement of cognitive functioning [31,32], memory, and functions related to learning [20], as well as mood [29]. They also have influence on the increase of vigor and the feeling of life quality [33]. If they are included in the traditional treatment of patients with affective disorders, they significantly decrease the symptoms of depression. Such a method is recommended at the University Hospital of Adult Psychiatry in Pozna´n by Prof. Janusz Rybakowski [34]. In addition to that, many other researchers confirm a significant relationship between the symptoms of depression and the proportion of fatty acids in blood [14,35,36,37,38,39]. Also the American Psychiatric Association recommends 1 gram daily of EPA 1 DHA as a supplement to the pharmacological treatment of depression [40].

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The researchers also discovered the importance of omega-3 fatty acids in the prevention and treatment of Alzheimer’s disease—a progressive degenerative disease of the central nervous system with neuronal loss, which is the most common among elderly people. Its most significant symptom is the loss of memory as well as the disorders of mood, cognitive functions, personality, and behavior. Despite numerous efforts, no efficient drug has been found to treat the disease or stop its development. Only the symptoms of Alzheimer’s disease are treated by focusing on memory disturbances and the improvement of cognitive functions. The signs of this disease include the presence of amyloid laminae (called also senile laminae or senile plaques) in the walls of blood vessels and gradual disappearance of the cerebral cortex. The results of the conducted studies suggested that polyunsaturated omega-3 fatty acids alleviate the symptoms of Alzheimer’s disease. It was proven that DHA strengthens the action of neurons protecting the dendrites against pathological changes. To conclude, omega-3 fatty acids have been considered to be one of the main factors decreasing the risk of the disease [41,42]. It should be noted that there were also research results which did not confirm the effect of omega-3 [13,14,43]. In interventional research by Karen M. Silvers and collaborators [44] no significant differences between the results of the group taking fish oils and the placebo group were observed. British researchers [45] performed a test using a double-blind method in a group of 190 participants who were administered EPA and DHA (1.5 g/day). The investigation tested the impact of supplements on the mood and cognitive functions in people with a small or moderate level of depression symptoms. After 12 weeks of participation in the project, no significant differences were found on the Depression Anxiety Stress Scale (DASS). The results of other measurements, for instance mood tests according to the Beck Depression Inventory, the tests of mental health, and cognitive functions showed a rather small dependence of changes on the undertaken diet intervention. In different research, the authors [13] conducted a systematic review of available interventional studies taking into consideration a random selection of group participants. The meta-analysis combined 12 investigations from eight medical databases. The analysis showed, among other issues, that the impact of omega-3 fatty acids on the mood was considerably higher in patients with a diagnosed major depressive episode than in patients with diagnosed mild symptoms of mood disorders or in healthy participants.

15.5 DIET AND ITS SUPPLEMENTS VERSUS IMPULSIVE BEHAVIOR The influence of omega-3 acids was described on the basis of the randomized controlled trials conducted in the group of people from a criminal environment. Professor Bernard Gesch from the University of Oxford has been researching for years the relations between nutrition and aggression; and has been trying to reduce criminal inclinations in prisoners by means of a diet. Gesch and his collaborators’ research involved 231 young prisoners from HM Prison Aylesbury (a penal institution for young offenders prone to violence). The diet of half of the participants was radically changed. They ate varied meals supplemented with vitamins, mineral salts, and indispensable unsaturated fatty acids (including 80 mg of the EPA and 44 mg of the DHA). The other participants’ diet was not changed and they were given placebo. Gesch’s studies provide empirical evidence that the test group of young inmates who took the supplements showed a considerable

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reduction in the level of aggression. The number of brutal incidents in this group fell on average by 37% (in the group of offenders from the control group the level of aggression did not change). What seems interesting is the fact that after the completion of the experiment the aggression level rose again [46]. Similar investigations were commissioned by the government and carried out independently at the National Institute on Alcohol Abuse and Alcoholism in Bethesda [47]. For three weeks, 2 g of omega-3 fatty acids was administered daily to 80 patients at the institute. The obtained results coincide with the results of Gesch’s research—the diet enriched with omega-3 fatty acids had an influence on the reduction of impulsive behavior. Previous studies done by Professor Joseph Hibbeln, who supervised the abovementioned research, also confirm this thesis (e.g., Ref. [48]). The statistical data gathered by Hibbeln indicate that people who ate a lot of fish in their childhood are less aggressive: 64% less often recorded in the police records and 35% less often commit offences [18,33,36].

15.6 CONCLUSIONS The majority of the so-far conducted studies proved a beneficial influence of fatty acids on the reduction of depression symptoms and the improvement of cognitive capacity. It was confirmed that the content of EPA/DHA in blood correlates with many variables of psychological functioning. Researchers emphasize that fatty acids (EPA and DHA) are essential not only for the development of the central nervous system and cognitive functioning but also for the regulation of emotions [5]. During the Global Summit on Nutrition, Health, and Human Behaviour (www.omega3summit. org)—a world meeting of the representatives of science, medicine, and food industry in 2011—the researchers published a consensus emphasizing that brain and cardiac diseases are becoming the greatest future challenge to mankind. The risk of increased incidence of the abovementioned diseases rises as a result of a shortage of long-chain omega-3 fatty acids (EPA 1 DHA). It was ascertained that the key variable, which is essential to the human health and thus should be examined, may be a certain proportion of fatty acids (omega3/omega6) in the tissues obtained from the fatty acids content of the applied diet. The study of neuronal nutrition and, in particular, its impact on brain function and behavior is relatively new. It is possible that gaps remain to be filled in our knowledge of the biochemical, physiological, psychological, and behavioral aspects of the effects of diet on brain function [49]. Aggression is an important feature of type A behavior as well as depression which are chronic inflammatory diseases occurring due to degeneration of amygdala [50,51]. It is possible that a deficiency of omega-3 fatty acids and flavonoids could be inversely associated with these modern mental disorders [50,51]. In brief, most researchers agree that further investigations are necessary in order to determine which content of individual ingredients is optimal for the proper functioning of the brain in healthy and ill people as well as children at different ages and in pregnant women. There is still no answer to the following questions: in what way, if other accompanying ingredients such as vitamins and flavonoids or amino acids, enable better assimilation of fatty acids? Can supplementation with EPA 1 DHA improve behavior, learning, and mood in a general population? And finally, what kind of mechanisms influence human psychological functioning through EPA/DHA? Maybe thanks to the so-far and new findings, it will be possible to increase the life quality also of healthy people. A

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solution recommended by preventive and therapeutic strategies consists of the application of a natural diet rich in polyunsaturated fatty acids, which may be a Mediterranean-style diet and only then supplementing it in a sensible way. The analysis of human behavior from a psychosomatic perspective makes it possible to see many psychological disorders and dysfunctions in a different dimension. The above-discussed dietary aspect, which is emphasized in prevention and therapy, is more and more often examined in the context of complex support of cognitive and emotional development of the human being.

REFERENCES [1] World Health Organization. The 2008 2013 Action Plan for the Global Strategy for the Prevention and Control of Non-communicable Diseases (Action Plan http://www.who.int/nmh/Actionplan-PC-NCD2008.pdf). [2] De Meester F. Progress in lipid nutrition: the columbus concept addressing chronic diseases. w- a balanced omega-6/omega-3 fatty acid ratio, cholesterol and coronary heart disease. In: Simopoulos AP, De Meester F, editors. Karger, Basel, 100. 2009. p. 110 21. [3] Simopoulos AP. Evolutionary aspects of diet and essential fatty acids. World Rev Nutr Diet 2001;88:18 27. [4] Singh R. Study of Nutrition, Anxiety, Stress and Behaviour in Relation to Cardiovascular Risk Factors in the Elderly Urban Population of Moradabad, India, Thesis for PhD, Department of Psychology, Gokuldas Girls College, Moradabad, Rohilkhand University, Bareilly, 2008. [5] Crawford MA, Bazinet RP i, Sinclair AJ. Fat intake and CNS functioning: aeging and disease. Ann Nutr Metab 2009;55:202 28. [6] Yehuda S, Rabinovitz S, Crasso RL, et al. The role of polyunsaturated fatty acids in restoring the aging of neuronal membrane. Neur Ageing 2002;23:843 85. [7] Delion S, Chalon S, Herault J, et al. Chronic dietary alpha-linolenic acid deficiency alters dopaminergic and serotinergic neurotransmission in rats. J Nutr 1994;124:266 76. [8] Delion S, Chalon S, Guilloteau G, et al. Alpha-linolenic acid deficiency alters age-related changes of dopaminergic and serotoninergic neurotransmission in the rat frontal cortex. J Neurochem 1996;66:1582 91. [9] Joseph JA, Shukitt-Hale B i, Lau FC. Fruit polyphenols and their effects on neuronal signaling and behavior in senescence. Ann N Y Acad Sci 2007;1100:470 85. [10] Helland IB, Smith L, Saarem K, et al. Maternal supplementation with very-long-chain Omega-3 fatty acids during pregnancy and lactation augments children’s IQ at four years of age. Pediatrics 2003;111:39 44. [11] McCann JC i, Ames BN. Is docosahexaenoic acid, an n-3 long-chain polyunsaturated fatty acid, required for development of normal brain function? An overview of evidence from cognitive and behavioral tests in humans and animals. Am J Clin Nutr 2005;82:281 95. [12] Hamazaki K, Hamazaki T, Inadera H. Effect of omega-3 fatty acids on aggression. in: omega-3 fatty acids in brain and neurological health. In: Watson RR, Meester F De, editors. 29. London: Elsevier; 2014. p. 359 64. [13] Appleton KM, Hayward RC, Gunnell D, et al. Effects of n-3 long-chain polyunsaturated fatty acids on depressed mood: systematic review of published trials. Am J Clin Nutr 2006;85:1665 6. [14] Appleton KM, Rogers PJ i, Ness AR. Updated systematic review and meta-analysis of the effects of n-3 long-chain polyunsaturated fatty acids on depressed mood. Am J Clin Nutr 2010;91:757 70. [15] Yehuda S, Rabinovitz S i, Mostofsky DI. Essential fatty acids are mediators of brain biochemistry and cognitive functions. J Neurosci Res 1999;56:565 70.

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[16] Whalley LJ, Fox HC, Waje KW, et al. Cognitive aging, childhood intelligence, and the use of food supplements: possible involvement of n-3 fatty acids. Am J Clin Nutr 2004;80:1650 7. [17] Whalley LJ, Deary IJ, Starr JM, et al. N-3 fatty acid erythrocyte membrane content, APOE ε4, and cognitive variation: an observational follow-up study in late adulthood. Am J Clin Nutr 2008;87:449 54. [18] Nurk E, Drevon CA, Refsum H, et al. Cognitive performance among the elderly and dietary fish intake: the Hordaland Health Study. Am J Clin Nutr 2007;86:1470 8. [19] Dullemeijer C, Durga J, Brouwer IA, et al. n-3 fatty acid proportions in plasma and cognitive performance in older adults. Am J Clin Nutr 2007;86:1479 85. [20] Fontani G, Corradeshi F, Felici A, et al. Cognitive and physiological effects of Omega-3 polyunsaturated fatty acid supplementation in healthy subjects. Eur J Clin Invest 2005;35:691 9. [21] Cichosz G, Czeczot H. Rzekomo zdrowe tłuszcze ro´slinne. Pol Merk Lek 2011;184:239. [22] Cyhlarova E, Bell JG, Dick JR, et al. Membrane fatty acids, reading and spelling in dyslexic and nondyslexic adults. Eur Neuropsychopharmacol 2007;17:116 21. [23] Richardson AJ I, Puri BK. A randomized double-blind, placebo-controlled study of the effects of supplementation with highly unsaturated fatty acids on ADHD-related symptoms in children with specific learning difficulties. Prog Neuropsychopharmacol Biol Psychiatry 2002;26:233 9. [24] Richardson AJ I, Montgomery P. The Oxford-Durham study: a randomized, controlled trial of dietary supplementation with fatty acids in children with developmental coordination disorder. Pediatrics 2005;115:1360 6. [25] Sinn N, Bryan J. Effect of supplementation with polyunsaturated fatty acids and micronutrients on learning and behavior problems associated with child ADHD. J Dev Behav Pediatr 2007;28:82 91. [26] Stevens LJ, Zentall SS, Deck JL, et al. Essential fatty acid metabolism in boys withattention-deficit hyperactivity disorder. Am J Clin Nutr 1995;62:761 8. [27] Vaisman N, Kaysar N, Zaruk-Adasha Y, et al. Correlation between changes in blood fatty acid composition and visual sustained attention performance in children with inattention: effect of dietary n-3 fatty acids containing phospholipids. Am J Clin Nutr 2008;87:1170 80. [28] King BM, Smith RL i, Frohman LA. Hyperinsulinemia in rats with ventromedial hypothalamic lesions: role of hyperphagia. Behav Neurosci 1984;98:152 5. [29] Heude B, Ducimetiere P i, Berr C. Cognitive decline and fatty acid composition of erythrocyte membranes the EVA Study. Am J Clin Nutr 2003;77:803 8. [30] Velasco AB, Tan ZS. Fatty acids and the aiging Brain. In: Watson, Meester F De, editors. Omega-3 Fatty Acids in Brain and Neurological Health. Ronald Ross, 17. London: Elsevier; 2014. p. 201 19. [31] Gamoh S, Hashimoto M, Sugioka K, et al. Chronic administration of docosahexaenoic acid improves reference memory-related learning ability in young rats. Neuroscience 1999;93:237 41. [32] Willats P. Long chain polyunsaturated fatty acids improve cognitive development. J Fam Health Care 2002;12:5 7. [33] Kalmijn S, van Boxtel MPJ, Ocke M, et al. Dietary intake of fatty acids and fish in relation to cognitive performance at middle age. Neurology 2004;62:275 80. [34] Chyłkiewicz J. Genetyczne archiwum X. Newsweek Polska 2008;40. [35] Appleton KM, Gunnell D, Peters TJ, et al. No clear evidence of an association between plasma concentrations of n-3 long-chain polyunsaturated fatty acids and depressed mood in a non-clinical population. Prostaglandins Leukot Essent Fatty Acids 2008;78:337 42. [36] Hibbeln JR. Fish consumption and major depression. Lancet 1998;351:1213. [37] Nemets B, Stahl Z i, Belmaker RH. Addition of omega-3 fatty acid to maintenance medication treatment for recurrent unipolar depressive disorder. Am J Psychiatry 2002;159:477. [38] Peet M, Murphy B, Shay J, et al. Depletion of omega-3 fatty acid levels in red blood cell membranes of depressive patients. Biol Psychiatry 1998;43:315 19. [39] Su KP, Huang SY, Chiu CC, et al. Omega-3 fatty acids in major depressive disorder. A preliminary double-blind, placebo-controlled trial. Eur Neuropsychopharmacol 2003;13:267 71.

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[40] Freeman MP, Hibbeln JR, Wisner KL, et al. Randomnized dose-ranging pilot trail of omega-3 fatty acids for postpartum depression. Acta Psychiatr Scand Suppl 2006;113:31 5. [41] Conquer JA, Tierney MC, Zecevic J, et al. Fatty acid analysis of blood plasma of patients with Alzheimer’s disease, other types of dementia, and cognitive impairment. Lipids 2000;35:1305 12. [42] Samieri C, Feart C, Letenneur L, et al. Low plasma eicosapentaenoic acid and depressive symptomatology are independent predictors of dementia risk. Am J Clin Nutr 2008;88:714 21. [43] Voigt RG, Llorente AM, Jensen CL, et al. A randomized, double-blind, placebo controlled trial of docosahexaenoic acid supplementation in children with attention deficit/hyperactivity disorder. J Pediatr 2001;139:189 96. [44] Silvers KM, Woolley CC, Hamilton FC, Watts PM, Watson RA. Randomised double-blind placebo-controlled trial of fish oil in the treatment of depression. Prost Leuk Ess Fatty Acids 2005;72:211 18. [45] Rogers PJ, Appleton KM, Kessler D, et al. No effect of n-3 long-chain polyunsaturated fatty acid (EPA and DHA) supplementation on depressed mood and cognitive function: a randomized controlled trial. Br J Nutr 2008;99:421 31. [46] Gesch B, Hammond SM, Hampson SE, et al. Influence of supplementary vitamins, minerals and essential fatty acids on the antisocial behavior of young adult prisoners: randomized, placebo-controlled trial. Br J Psychiatry 2002;181:22 8. [47] Hibbeln JR, Ferguson TA i, Blasbalg TL. Omega-3 fatty acid deficiencies in neurodevelopment, aggression and autonomic dysregulation: opportunities for intervention. Int Rev Psychiatry 2006;18:107 18. [48] Hibbeln JR. Seafood consumption, the DHA content of mothers milk and prevalence rates of postpartum depression: a cross-national, ecological analysis. J Affect Disord 2002;69:15 29. [49] Wilczynska A, Singh RB, De Meester F. Nutritional modulators of neuropsychiatric dysfunction. Open Nutr J 2011;4:52 60 1876 3960/. [50] Wilczynska A, Singh RB, Fedacko J, Singhal S, Gupta N, Gangwar C. Validation of type A behaviour questionnaire in relation to social class and coronary artery disease: The Indian rating scale for type A behaviour. J Cardiol Ther 2018;5(1):707 12. Available from: URL: http://www.ghrnet.org/index.php/ jct/article/view/2193. [51] Fekadu N, Shibeshi W, Engidawork E. Major depressive disorder: pathophysiology and clinical management. J Depress Anxiety 2016;6:255. Available from: https://doi.org/10.4172/2167-1044.1000255.

FURTHER READING Anderson G. Diet, neurotransmitters and brain function. Br Med Bull 1981;37:95 100. Issa AM, Mojica WA, Morton SC, et al. The efficacy of omega-3 fatty acids on cognitive function in aging and dementia: a systematic review. Dement Geriatr Cogn Disord 2006;21:88 96. Mazza M, Pomponi M, Janiri L, et al. Omega-3 fatty acids and antioxidants in neurological and psychiatric diseases: an overview. Prog Neuropsychopharmacol Biol Psychiatry 2007;31:12 26. Morris MC, Evans DA, Tangney CC, et al. Fish consumption and cognitive decline with age in a large community study. Arch Neurol 2005;62:1849 53. Neuringer M, Reisbick S i, Janowsky J. The role of omega-3 fatty acids in visual and cognitive development: current evidence and methods of assessments. J Pediatr 1994;125:39 47. Salem Jr N, Litman B, Kim HY, et al. Mechanisms of action of docosahexaenoic acid in the nervous system. Lipids 2001;36:945 59. Wilczy´nska-Kwiatek A, De Meester F, Singh RB, et al. Western diet and behavior: the columbus concept. In: De Meester F, Zibadi S, Watson RR, editors. Modern Dietary Fat Intakes in Disease Promotion. New York: Humana Press; 2010. p. 3 29.

CHAPTER

FATS AND OILS FOR HEALTH PROMOTION AND DISEASE PREVENTION

16

Banshi Saboo1, Ram B. Singh2, Kshitij Bhardwaj3, Anuj Maheshwari3, Narsingh Verma4, Viola Vargova5 and Daniel Pella5 1

DiaCare and Hormone Institute, Ahmedabad, Gujarat, India 2Halberg Hospital and Research Institute, Moradabad, Uttar Pradesh, India 3Division of Chronomedicine, KG Medical University, Lucknow, Uttar Pradesh, India 4 Department of Medicine, BBDCODS, BBD University, Lucknow, Uttar Pradesh, India 5Faculty of Medicine, PJ Safaric University, Kosice, Slovakia

16.1 INTRODUCTION Saturated fatty acids and trans fatty acids are highly stable and monounsaturated fatty acids (MUFA) are moderately stable against oxidation. However, polyunsaturated fatty acids (PUFA), such as omega-3 fatty acids and omega-6 fatty acids, are easily oxidized. The oxidation of fatty acids may be associated with free radical generation which enhances the atherogenic potential of total and low density lipoprotein (LDL) cholesterol [1,2]. The oxidation of lipids may be inhibited by endogenous antioxidants—superoxide dismutase, catalase and ceruloplasmin—as well as by dietary antioxidants—polyphenolics and flavonoids. Saturated fatty acids elevate, PUFA decrease, and MUFA have neutral effects on total and LDL cholesterol [1,2]. Increased consumption of total fat with saturated fat brings about an increase in total and LDL cholesterol as well as in high-density lipoprotein (HDL) cholesterol [3,4]. Trans fatty acids also bring about an increase in total and LDL cholesterol as well as C-reactive proteins with a decrease in HDL cholesterol, which have adverse effects [3 5]. Omega-6 fatty acids are known to decrease total and LDL cholesterol as well as HDL cholesterol and increase C-reactive protein, whereas omega-3 fatty acids decrease C-reactive protein and platelet aggregation and increase HDL cholesterol [5 8]. Stearic acid, a type of saturated fatty acid found in clarified butter, is known to increase HDL cholesterol and has antiplatelet effects, hence a limited amount of butter may be allowed, in subjects with a healthy lifestyle [4,7]. This review aims to highlight various fats and oils having beneficial effects on health.

16.2 CLINICAL AND EPIDEMIOLOGICAL EVIDENCE ON FATS AND OILS The Seven Country Study showed that the association of total serum cholesterol and mortality from coronary artery disease (CAD) is continuous and graded in all the cultures but it varied from one The Role of Functional Food Security In Global Health. DOI: https://doi.org/10.1016/B978-0-12-813148-0.00016-5 © 2019 Elsevier Inc. All rights reserved.

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culture to another culture [8]. The mortality rate due to CAD was positively associated with saturated fat intake and inversely associated with MUFA consumption, showing the highest risk among cultures in North America and northern Europe compared to Japan and Mediterranean countries [8]. It is clear that it is not the total fat intake but the quality of fat that may have been responsible for variation in risk. This indicates that eating excessive amounts of animal fat such as butter and meat would increase the risk of death due to CAD. However, consuming increased amounts of olive oil may lower the risk of CAD death [8]. This result constituted this study’s major information about the relation between diet and CAD. The most interesting finding was that a Japanese cohort consuming 25% of energy as fat, and a Greek cohort consuming 40% of energy as fat had the lowest and similar death rates from CAD as compared to American and European cohorts [8]. Further studies including randomized and controlled trials also reported that consuming canola oil and mustard/rape seed oil that are rich sources of omega-3 fatty acids can bring about a significant decline in cardiovascular events [9 18]. The Seven Countries Study also reported that the various Mediterranean cohorts of the study did not have the same risk of CAD death, despite apparently similar dietary habits; the risk was higher for former-Yugoslavians than for Greeks and higher for Italians than former Yugoslavians [8]. The diet and 15-year death rate among 15 cohorts of the Seven Countries Study, consisting of 11,579 men aged 40 59 years, revealed that 2288 died in 15 years and the death rate differed among cohorts [17]. Differences in mean age, blood pressure, serum cholesterol, and smoking habits could account for 46% of the overall variance in death rate from all causes, 80% from CAD, 35% from cancer, and 45% from stroke, but unrelated to physical activity. Dietary intakes were crucial in accounting for the differences in death rates among these countries [17]. The findings revealed that average percentage of dietary energy from saturated fatty acids was positively related to adverse cardiovascular outcomes, whereas the relationship to MUFA was inverse, and there was no relation to PUFA, proteins, carbohydrates, and alcohol. All-cause mortality and death rates due to CAD were low in cohorts with olive oil as the main fat intake, which is also proven to be beneficial in the PREDIMED Study [12]. The lack of relation of mortality to PUFA intake may be due to the fact that a separate assessment of omega-3 and omega-6 fatty acids was possibly not done and it may take longer follow-up to demonstrate adverse effects of omega-6 fatty acids on outcome. In a cross-sectional survey, 1769 rural (894 men and 875 women) and 1806 urban (904 men and 902 women) randomly selected subjects aged 25 64 years were recruited from North India [19]. The total prevalence of CAD was significantly higher in urban as compared to rural men (11.0% vs 3.9%) and women (6.9% vs 2.6%). Food consumption patterns showed that important differences in relation to CAD were a higher intake of total visible fat, milk and milk products, meat, eggs, sugar, and jaggery in urban than in rural subjects. Prevalence of CAD in relation to visible fat intake showed a higher prevalence rate with higher visible fat intake in both genders; the trend was significant for total prevalence rates in both rural and urban men and women. Subgroup analyses of urban (694 men and 694 women) and rural (442 men and 435 women) subjects consuming moderate to high fat diets showed that subjects eating trans fatty acids plus clarified butter or those consuming clarified butter as total visible fat had a significantly (P , .01) higher prevalence of CAD compared to those consuming clarified butter plus vegetable oils in both rural (9.8%, 7.1% vs 3.0%) and urban (16.2%, 13.5% vs 11.0%) men as well as in rural (9.2%, 4.5% vs 1.5%) and urban (10.7%, 8.8% vs 6.4%) women [19]. It was suggested that lower intake of total visible fat (20 g/day), decreased milk intake, increased physical activity, and cessation of smoking caused benefit to some populations in preventing CAD. It seems that most investigators were misguided

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by the AHA step 1 diet (total fat intake less than 30%en and saturated fat intake less than 10%en per day) as a means to prevent CAD [15]. It is clear that the observations, relative to this study, were that high total and saturated fat intake were reported to be significantly associated with serum total and LDL cholesterol, CAD and type 2 diabetes [20 22]. The guidelines of the International College of Nutrition also recommended a low-fat diet similar to the AHA step 1 diet but saturated fat intake was advised to be less than 7%en per day, which is similar to the step 2 diet [23]. In a case-control study consisting of 350 cases of acute myocardial infarction and 700 controls, the authors used conditional logistic regression to control for matching factors and other predictors of risk [24]. A significant and dose-dependent inverse association was found between vegetable intake and CAD risk. The inverse association was stronger for green leafy vegetables and for wholegrain cereals, showing that subjects consuming a median of 3.5 servings/ week had a 67% lower relative risk (RR: 0.33; 95% CI: 0.17 0.64; P for trend 5 .0001) than did those consuming 0.5 servings/week. The consumption of mustard oil, which is rich in α-linolenic acid, was associated with a lower risk than was use of sunflower oil (for use in cooking: RR: 0.49 (95% CI: 0.24 0.99); for use in frying, RR: 0.29 (95% CI: 0.13 0.64)). Thus it is the quality of fat rather than its quantity that is important in defining the risk or protection of dietary fat against CVDs and diabetes. A recent study examined the association of specific dietary fats with total and cause-specific mortality in two large ongoing cohort studies including 83,349 women from the Nurses’ Health Study and 42,884 men from the Health Professionals Follow-up Study [25]. Over 3,439,954 person-years of follow-up, 33,304 deaths were reported. The consumption of dietary total fat compared with total carbohydrates was inversely associated with total mortality. The hazard ratios of total mortality comparing extreme quintiles of specific dietary fats were: 1.08 (95% CI: 1.03 1.14) for saturated fat; 0.81 (95% CI: 0.78 0.84) for PUFA; 0.89 (95% CI: 0.84 0.94) for MUFA; and 1.13 (95% CI: 1.07 1.18) for trans-fat (P , .001 for all). Replacing 5% of energy from saturated fats with equivalent energy from PUFA and MUFA was associated with estimated reductions in total mortality of 27% (HR 5 0.73; 95% CI: 0.70 0.77) and 13% (HR 5 0.87; 95% CI: 0.82 0.93), respectively. Intake of omega-6 PUFA, especially linoleic acid, was inversely associated with mortality owing to most major causes, whereas marine omega-3 PUFA intake was associated with a modestly lower total mortality [25]. Other studies reported that increased intake of omega-6 fatty acids can have only nonsignificant adverse effects on mortality, which may be related to a reduction in HDL cholesterol and to an increase in inflammation [26]. A recent cohort study involving 133,335 subjects, aged 35 70 years, with follow-up of 7.3 years showed that increased intake of carbohydrates was associated with greater risk of total mortality [27]. Total fat and individual types of fat were related to lower total mortality. It is possible that assessment of dietary intakes of fatty acids as well as types of carbohydrates may have been improper in this multicenter study because experts assessing food intakes were different in each study. Total fat and types of fat were not associated with CVDs, myocardial infarction, or cardiovascular disease mortality, whereas saturated fat had an inverse association with stroke [27].

16.3 RANDOMIZED, CONTROLLED TRIALS The PREDIMED study involving 7447 high-risk subjects, in a primary prevention trial, revealed that a Mediterranean-style diet with approximately 42% dietary fat (mainly olive oil) compared

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Incidence composite cardiovascular end point

with 37% fat in the control group, can bring about a significant reduction in cardiovascular events after 4.8 years of follow-up [12]. The risk of combined CAD, stroke, and death from CVDs was reduced by 30% in the Mediterranean diet 1 olive oil group, and by 28% in the Mediterranean diet 1 nuts group (Fig. 16.1). This landmark study further provided a proof that changing the quality of fat characterized with high MUFA and polyphenolics in the olive oil can be superior to animal fat in the diet. Mustard and canola oils/rape seed oil and fish are rich in omega-3 fatty acids whereas olive oil is rich in polyphenolics 1 MUFA that are critical factors in providing benefits, despite greater consumption of dietary fat [12 14]. In a previous Indian experiment, among 504 patients with acute coronary syndrome (ACS), a low omega-6/omega-3 fatty acid ratio in the diet was associated with significant decline in mortality in a graded fashion (Fig. 16.2). It was clear at this point of time that Control diet

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FIGURE 16.1 Effects of Mediterranean-style diets containing either olive oil or nuts on cardiovascular endpoints. Modified from PREDIMED Study Investigators. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med 2013; 368(14): 1279-1290.DOI: 10.1056/NEJMoa1200303.

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FIGURE 16.2 Effects of Paleolithic-style diet with mustard oil in patients with acute coronary syndrome. Modified from Singh RB, Fedacko J, Vargova V, Niaz MA, Rastogi SS, Ghosh S. Effect of low W-6/W-3 ratio fatty acid Paleolithic style diet in patients with acute coronary syndromes. A randomized, single blind, controlled trial. World Heart J 2012; 3: 71-84.

a low-fat diet with 10% energy from saturated fat, advised by the American Heart Association and the National Cholesterol Education Program does not appear to be absolutely correct and is open to criticism [15]. Furthermore, another trial conducted in postmenopausal women confirmed that a low-fat dietary pattern does not significantly reduce the risk of CAD and stroke [16]. Since every country in the world follows the United States, there was global advice and publicity for consumption of a low-fat diet to prevent CVDs and diabetes, which may have brought about adverse effects. The Indo-Mediterranean diet heart study involving 1000 high risk patients with CAD used mustard oil in the intervention group compared to a low-fat diet in the control group. Follow-up after 2 years showed significant decline in CVDs in the intervention group compared to the control group (Fig. 16.3).

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FIGURE 16.3 Effects of mustard oil rich Indo-Mediterranean diet on cardiovascular events (based on Ref. [10]).

The Sydney Diet Heart Study and updated meta-analysis, included an intervention group (n 5 221) which had higher rates of death than controls (n 5 237) (all cause 17.6% vs 11.8%, hazard ratio 1.62 (95% confidence interval 1.00 2.64), P 5 .05; CVDs 17.2% vs 11.0%, 1.70 (1.03 2.80), P 5 .04; CAD 16.3% vs 10.1%, 1.74 (1.04 2.92), P 5 .04) [18]. These recovered data in an updated meta-analysis of linoleic acid intervention trials showed nonsignificant trends toward increased risks of death from CAD (hazard ratio 1.33 (0.99 1.79); P 5 .06) and CVDs (1.27 (0.98 1.65); P 5 .07). It is clear that advice to substitute polyunsaturated fats for saturated fats is a key component of worldwide dietary guidelines for CAD risk reduction. Unfortunately, clinical benefits of the most abundant PUFA, omega-6 linoleic acid, have not been established, hence substituting dietary linoleic acid in place of saturated fats increased the rates of death from all causes, CAD, and CVDs [18]. It is clear that an updated meta-analysis of linoleic acid intervention trials showed no evidence of benefit in CVDs. It has been proposed that these findings can provide important implications for worldwide dietary advice to substitute omega-6 linoleic acid, or polyunsaturated fats in general, for saturated fats. However, no randomized, controlled trial is available to provide a proof for such benefits. Moreover, meta-analysis is open to bias because they are financed by commercial companies. In the PREDIMED study, with 418 nondiabetic subjects receiving Mediterranean diet 1 olive oil or diet 1 nuts, compared to a low-fat diet, a three-arm substudy was conducted to determine the risk of having developed type 2 diabetes [28]. After a follow-up of 4 years, the Mediterranean diet groups, receiving either nuts or olive oil, showed significantly lower incidence of diabetes, compared to the low-fat diet or to a control group (10% and 11% vs 17.9%, P , .01) (Fig. 16.4). The Mediterranean diet reduced the risk of developing type 2

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5

FIGURE 16.4 Effects of Mediterranean-style diets in the PREDIMED study on new onset diabetes in the three groups. ´ Modified from Salas-Salvado´ J, Bullo´ M, Babio N, Martı´nez-Gonzalez MA´, Ibarrola-Jurado N, Basora J, et al., For the PREDIMED Study Investigators. Reduction in the incidence of type 2 diabetes with the Mediterranean diet. Diabetes Care 2011; 34: 14-19.

diabetes by 52%. The consumption of total fat in the Mediterranean-style diet groups was significantly higher (approximately 40%en vs 30%en per day) compared to the low-fat diet group [28]. Various types of dietary fats have divergent associations with different risk factors as well as with total and cause-specific mortality [16 19]. However, it may be advised to replace saturated fat and trans fat with MUFA and omega-3 fat. We do not agree with some experts to increase the content of omega-6 fatty acids above 7%en because of their adverse effects on HDL cholesterol,

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inflammation, and mortality [26,27]. Olive oil and nuts are rich in MUFA and antioxidants with little amount of omega-3 fatty acids, indicating that it is not a perfect oil but there is consistent evidence for its healthful effects on CVDs and other chronic diseases [12,28,31,32]. In a case control study among 848 subjects with ACS, olive oil intake was associated with possible benefit to these patients [32]. Canola oil and rape seed oil are rich in MUFA as well as in omega-3 fatty acids, which have been reported to decrease CVDs [9 11]. Rice bran oil and sesame oils contain antioxidants and have potential antioxidant activity, which is known to reduce total and LDL cholesterol, with beneficial effects on HDL cholesterol [29,30]. Moreover, blending oils may have synergestic antioxidant and hypolipidemic effects, providing greater beneficial effects. Therefore, the International College of Nutrition Expert Group advises a blend of oils for its healthful effects.

16.4 PROPOSAL FOR NEW BLEND OF FATS AND OILS Since, none of the fats and oils are perfect, containing all the protective nutrients, a blend of oils has been developed for the prevention of diseases (Table 16.1) [5]. This blend contains 50% olive oil as there is conclusive evidence for its benefit on CVDs mortality and reduction in diabetes [12,28]. Inclusion of mustard or rape seed oil is based on the Leon Heart study, Indian experiments, and the Indo-Mediterranean Diet Heart study [9 11,13]. Sesame oil (phytosterol), flax seed (alphalinolenic acid) oil, and rice bran oil (orygenol) do not have such evidence but they contain potential nutrients, which are known to provide benefit against risk factors for CVDs and diabetes [29,30]. Blending of sunflower oil, soybean oil, corn oil, and cotton seed oil is out of the question because these oils are rich in omega-6 fatty acids (linoleic acid), which are known to bring about inflammation, decrease HDL cholesterol, and may increase CVDs mortality [26,27]. High content of saturated fatty acids in coconut oil, butter, and Indian clarified butter (oxidized cholesterol) does not allow adding these fats and oils in the healthful blend. However, the presence of stearic acid (antiplatelet with increase in HDL) and the flavor of Indian clarified butter may be important for its inclusion in the new blend of oils, developed for south Asians. Table 16.1 Blend of Fats and Oils With Possible Beneficial Effects on Health Oils, /100 g

Saturated Fat

Omega6 fat

Omega3 fat

MUFA

Nutrient

Olive oil (50%) Rape seed/canola oil (20%) Rice bran oil (10%) Sesame oil (10%) Flexed seed oil (10%) Blended oil 5 total 100.13 g

7.00 1.4 2.5 1.5 1.10 13.50

7.50 4.11 3.4 4.00 0.66 19.67

0.75 2.00 0.21 0.1 5.5 8.56

36.00 13.00 3.80 4.00 1.60 58.4

Flavonoids, MUFA ω-3,MUFA Oryzenol Phytosterol ω-3, 54% ω-6/ω-3 ratio 5 2.29, resveratrol, oryzenol, phytosterol,

Olive oil and rape seed oil are known to decrease cardiovascular diseases, diabetes, and all-cause mortality. No such evidence for other oils. MUFA, monounsaturated fatty acids.

16.4 PROPOSAL FOR NEW BLEND OF FATS AND OILS

281

In view of the above listed results, the US Department of Health and Human Services is no longer advising to reduce total dietary fat intake, although a reduction in saturated fat has been advised [33]. However, some experts have urged the removal of the limits of total fat intake and to promote the consumption of healthy fat with low saturated fat in the guidelines [33,34]. The blend of rice bran oil and sunflower oil with antioxidant technology may bring about a significant decline in blood lipids and C-reactive proteins with a significant increase in HDL cholesterol, and thus, in turn, may help prevent CVDs [36]. Since a healthy diet with healthy fats and oil, and the lifestyle of the parents prevent cardiometabolic risk in the offspring, it is important to develop a healthy blend of oil for health promotion and diseases prevention [37].

16.4.1 FLAXSEED OIL BLEND Blending is an alternative to partial hydrogenation. This process reduces the percentage of unsaturated lenoleic and linolenic acids by a blend of flaxseed oil with palm oil in a stabilized ratio which helps in maintaining the overall oxidative stability and proper ratio of omega-3, omega-6, and omega-9 content in the blended product. Flaxseed oil is considered to be a rich source of alpha linolenic acid, lignans, fiber, protein, vitamins, and minerals. A growing number of cases of CVD and hypertension were related to an imbalance of necessary omega-3 and omega-6 fatty acids in our bodies. Fish is a great source of omega-3 but changes in our diet have cut out that source and besides, the nutrients in fish have also reduced in recent times because of the inferior feed it gets. For vegetarians, flax seed with 58% omega-3 is major source (Tables 16.2 and 16.3). A study 150 KGMU patient (100 of CVD and 50 of hypertension) was conducted over a one-and-a-half year span. The patients were kept on a single dose of blended flaxseed and palm oil (no other edible oil used in their food) for 6 months. They were asked to mix one spoon of the oil in their lentils and pulses and use it for mild frying [39 41] the obtained results (shown in Table 16.4) revealed a nonsignificant increase in serum LDL-c and VLDL-c concentration. On the Table 16.2 Fatty Acid Profile of Pure Oils and Oils of Flax Oil Blends.% Vegetable Oils

Oil Blends

Fatty Acids

Palm Oil

Flaxseed Oil

40% Palm Oil FPB2

60% Palm Oil FPB3

C12:0 C14:0 C16:0 C16:1 C17:0 C17:1 C18:0 C18:1 C18:2 C18:3

0.17 1.04 41.21 0.18 0.1 0.02 4.44 36.21 10.03 0.17

ND ND 5.71 0.07 ND ND 4.84 14.99 15.11 59.02

0.1 0.61 27.41 0.13 0.08 0.02 5.21 27.88 12.25 29.74

0.1 0.61 26.61 0.13 0.08 0.02 4.38 27.25 12.32 27.45

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CHAPTER 16 FATS AND OILS FOR HEALTH PROMOTION

Table 16.3 Effect of Flaxseed Oil Blend Administration on Weight and BMI of Control, CAD, and Hypertensive Patients (mg/dL) BMI

Weight

Subjects Groups

0 Month

6 Months

0 Month

6 Months

Control Hypertension CAD

25.56 6 1.53 22.37 6 2.5025 25.24 6 1.41

26.71 6 1.20 21.78 6 1.47 24.18 6 1.11

60.26 6 2.35 64.42 6 2.78 65.41 6 2.2

63.87 6 1.53 62.32 6 6.26 63.33 6 1.87

Values represent the mean 6 SE of 50 subjects each group, CAD 5 coronary artery disease. Significant at the level of (P # 0.05).

Table 16.4 Effect of Flax Seed Oil Administration on Serum HDL-c, LDL-c and VLDL-c Concentration in Normal and Hypertensive Patients (mg/dL) Subjects Groups Control Hypertensive 1 Blend CAD 1 Blend

VLDL (mg/dL)

LDL C (mg/dL)

HDL C (mg/dL)

0 Month

6 Months

0 Month

6 Months

0 Month

6 Months

20.65 6 1.65 23.76 6 1.65

19.98 6 2.65 20.18 6 2.65

115.11 6 1.30 109.11 6 2.78

120.20 6 1.41 108.20 6 2.01

40.11 6 1.30 38.11 6 1.87

41.20 6 1.71 43.20 6 2.1

27.14 6 1.65

22.98 6 2.65

97.11 6 2.00

98.20 6 1.86

36.11 6 2.30

46.20 6 2.28

CAD, coronary artery disease.

other hand, a significant increase in serum HDL-c Concentration was observed in the CAD group as well as in the hypertensive group. Flaxseed oil treatment resulted in a significant decrease in serum LDL-c and VLDL-c levels over the period of the experiment as compared to control group. Recent meta analysis of trials with fish oil showed no beneficial effects of omega-3 fatty acids on CVDs [42], indicating that omega-3 fatty acids benefit only when administered as a component of Mediterranean diet, that is rich in antioxidant extra virgin olive oil [42 44]. The virgin olive oil contains numerous phenolic compounds that exert potent antiinflammatory actions among which oleocanthal has been found to be most potential. The antiinflammatory activity of oleocanthal is as good as antiinflammatory properties of ibuprofen [44]. In brief, the food industry should take urgent steps to use healthy fats in developing new foods, aiming at providing a healthy diet rich in functional food and nutrients, to provide global functional food security [34 36]. It seems that blending of multiple oils is important because each oil may provide better antioxidant potential [36]. The challenge is how to provide optimal amounts of MUFA, omega-3 fat, and stearic acid as well as antioxidants (oryzenol and phytosterol) by the food industry because these MUFA and omega-3 fats are not as stable as saturated fat and trans fat which appear to have adverse effects [38]. Acknowledgments are due to International College of Nutrition and International College of Cardiology for providing logistic support to write this article.

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[17] Keys A, Menotti A, Karvonen MJ, Aravanis C, Blackburn H, Buzina R, et al. The diet and 15-year death rate in the seven countries study. Am J Epidemiol. 1986;124(6):903 15. [18] Ramsden CE, Zamora D, Leelarthaepin B, Majchrzak-Hong SF, Faurot KR, Suchindran CM, et al. Use of dietary linoleic acid for secondary prevention of coronary heart disease and death: evaluation of recovered data from the Sydney Diet Heart Study and updated meta-analysis. BMJ 2013;346:e8707 Cite this as: BMJ 2013;346:e8707. [19] Singh RB, Niaz MA, Ghosh S, Beegom R, Rastogi V, Sharma JP, et al. Association of trans fatty acids (vegetable ghee) and clarified butter (Indian ghee) intake with higher risk of coronary artery disease in rural and urban populations with low fat consumption. Int J Cardiol 1996;56:289 98. [20] Singh RB, Rastogi V, Niaz MA, Ghosh S, Sy RG, Janus ED. Serum cholesterol and coronary artery disease in populations with low cholesterol levels: the Indian paradox. Int J Cardiol 1998;65(1):81 90. [21] Singh RB, Sharma JP, Rastogi V, Raghuvanshi RS, Moshiri M, Verma SP, et al. Prevalence of coronary artery disease and coronary risk factors in rural and urban populations of north India. Eur Heart J 1997;18(11):1728 35. [22] Singh RB, Bajaj S, Niaz MA, Rastogi SS, Moshiri M. Prevalence of type 2 diabetes mellitus and risk of hypertension and coronary artery disease in rural and urban population with low rates of obesity. Int J Cardiol 1998;66(1):65 72. [23] Singh RB, Rastogi SS, Rao PV, Das S, Madhu SV, Das AK, et al. Diet and lifestyle guidelines and desirable levels of risk factors for the prevention of diabetes and its vascular complications in Indians: a scientific statement of The International College of Nutrition. Indian Consensus Group for the Prevention of Diabetes. J Cardiovasc Risk. 1997;4(3):201 8. [24] Rastogi T, reddy KS, Vaz M, Spiegelman D, Prabhakaran D, Willett WC, et al. Diet and risk of ischemic heart disease in India1,2,3. Am J Clin Nutr 2004;79:582 92. [25] Wang DD, Li Y, Chiuve SE, Stampher MJ, Manson JE, Rimm EB, et al. Association of specific dietary fats with total and cause-specific mortality. JAMA Intern Med 2016;176(8):1134 45. Available from: https://doi.org/10.1001/jamainternmed.2016.2417. [26] Naughton SS, Mathai ML, Hryciw DH, McAinch AJ. Linoleic acid and the pathogenesis of obesity. Prostaglandins Other Lipid Mediat 2016;. [27] Prospective Urban-Rural Epidemiology study investigators. Associations of fats and carbohydrate intake with cardiovascular disease and mortality in 18 countries from five continents (PURE): a prospective cohort study Lancet 2017 2017;Published Online . Available from: http://dx.doi.org/10.1016/S0140-6736 (17)32252-3. ´ , Ibarrola-Jurado N, Basora J, et al. For the [28] Salas-Salvado´ J, Bullo´ M, Babio N, Martı´nez-Gonz´alez MA PREDIMED Study Investigators. Reduction in the incidence of type 2 diabetes with the Mediterranean diet. Diabetes Care 2011;34:14 19. [29] Salehi EA, Sardarodiyan M. Bioactive phytochemicals in rice bran: processing and functional properties. Biochem Ind J 2016;10(3):101. [30] Harikumar KB, Sung B, Tharakan ST, Pandey MK, Joy B, Guha S, et al. Sesamin manifests chemopreventive effects through the suppression of NF-kappa B-regulated cell survival, proliferation, invasion, and angiogenic gene products. Mol Cancer Res 2010;8(5):751 61. Available from: https://doi.org/ 10.1158/1541-7786.MCR-09-0565. [31] Hunter KA, Crosbie LC, Horgan GW, Miller GJ, DuttaRoy AK. Effects of diets rich in oleic acid, stearic acid and linoleic acid on postprandial hemostatic factors in young healthy men. Brit J Nutr 2001;86:207 2015. [32] Kontogianni MD, Panagiotakos DB, Chrysohoou C, Pitsavos C, Zamplas A, Stephandes C. The impact of olive oil consumption pattern on the risk of acute coronary syndromes: The Cardio2000 Case Control study. Clin Cardiol 2007;30:125 9.

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DIETARY SUGAR INTAKE AND RISK OF NONCOMMUNICABLE DISEASES

17

´ Viliam Mojto1, Ram B. Singh2, Anna Gvozdjakova1, Maria Mojtova´ 3, Jarmila Kucharska´ 1, 4 ˇ ˇ a´ 1 and Toru Takahashi5 Poonam Jaglan , Olga Vancov 1

Pharmacobiochemical Laboratory of 3rd Internal Clinic Faculty of Medicine, Comenius University in Bratislava, Bratislava, Slovakia 2Halberg Hospital and Research Institute, Moradabad, Uttar Pradesh, India 3St. Elizabeth University of Health and Social Work, Bratislava, Slovakia 4Center of Nutrition Research, Panipat, Haryana, India 5 Department of Nutrition and Health Science, Faculty of Human Environmental Sciences, Fukuoka Women’s University, Fukuoka, Japan

17.1 INTRODUCTION Overweight and obesity are major risk factors for a number of noncommunicable diseases (NCDs) including type 2 diabetes, cardiovascular diseases (CVDs), chronic kidney disease, osteoporosis, and certain types of cancer [1 3]. Once considered a problem only in high-income countries, overweight and obesity are now dramatically on the rise in low- and middle-income countries, particularly in urban settings, caused by increased availability and greater intake of sugar-sweetened, high-fat foods [4 6]. Apart from obesity, increased intake of sugary products also predisposes to dental caries [7]. Modifiable risk factors such as unhealthy diet and physical inactivity, which are known to cause obesity and diabetes, are some of the most common causes of NCDs [8 10]. The World Health Organization states that reducing free sugars intake in adults may reduce the risk of NCDs [8]. A recent analysis from 195 countries, reported that in 2015, 107.7 million children and 603.7 million adults were obese worldwide which constitutes 30% of the world’s population [9]. The highest level of adult obesity was in Egypt at 35.3% and the highest level of childhood obesity was in the United States at 12.7%, among the 20 most populous countries. Vietnam had the lowest rate of adult obesity and Bangladesh had the lowest rate of childhood obesity, both at approximately 1%. In many countries, obesity rates among children are rising faster than obesity rates in adults, particularly in China and India, which had the highest numbers of obese children. A high BMI contributed to 4 million deaths and 120 million disability-adjusted life-years globally. NCDs are the leading causes of death and were responsible for 38 million (68%) of the world’s 56 million deaths in 2012. More than 40% (i.e., 16 million) of NCD-related deaths were premature (i.e., under the age of 70 years) and the majority of premature deaths (82%) occurred in low- and middle-income countries. There has been a worldwide increase in obesity during the past 30 years in both high-income and low-income countries, which may be due to dietary sugar and fat and decreased physical activity [11 15]. The Western type of diet, particularly sugary foods, is not The Role of Functional Food Security In Global Health. DOI: https://doi.org/10.1016/B978-0-12-813148-0.00017-7 © 2019 Elsevier Inc. All rights reserved.

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restricted to industrialized societies and the increase in obesity due to the Western diet and sedentary behavior is often faster in developing countries than in the developed world [11 13]. Obesity and overweight associated with CVDs, hypertension, stroke, coronary artery diseases (CAD), and type 2 diabetes may increase the risk morbidity and mortality among these patients [13 15]. Current obesity levels range from below 10% in China, India, Japan, and certain African nations, to over 75% in urban Samoa. But even in relatively low prevalence countries like India and China, rates are almost 20% in some cities. The estimated numbers of overweight and obese adults worldwide in 2005 were 937 million (922—951 million) and 396 million (388—405 million), respectively. It is further estimated that there would be 2.16 billion overweight people and 1.12 billion obese individuals by 2030, if the same trends continue [13]. Childhood obesity is already an epidemic in some areas and on the rise in others. Childhood obesity is one of the most serious public health challenges of the 21st century. Overweight and obese children are likely to stay obese into adulthood and more likely to develop NCDs like diabetes and CVDs at a younger age. In 2013, 42 million children under the age of 5 were overweight or obese. The vast majority of overweight or obese children live in developing countries, where the rate of increase has been more than 30% higher than that of developed countries. If current trends continue the number of overweight or obese infants and young children globally will increase to 70 million in 2025 [16]. Obesity prevalence in youths aged 12 17 has increased dramatically from 5% to 13% in boys and from 5% to 9% in girls between 1966 70 and 1988 91 in the United States [14,15,17]. The problem is global and increasingly extends into the developing world; e.g., in Thailand the prevalence of obesity in 5 12 year olds children rose from 12.2% to 15% 6% in just 2 years. The study from various regions of Slovakia included 101 obese children, aged 10 18 years (mean age: 12.58 6 2.26 years). The number of boys was 52 and of girls 49. The number of nonobese children was 20, aged 10 18 years, (mean age: 14.25 6 1.88 years, 11 boys and 9 girls). Fig. 17.1 shows significantly decreased concentration of antioxidant coenzyme Q10 (CoQ10 ) in obese boys and girls (P , .0001) compared with the nonobese children. HDL-cholesterol was significantly decreased in obese children (in boys 27.00%, in girls 27.7, P , .001 (Fig. 17.2) [18]. 1.2 Reference Nonobese children

Obese children

µmol/L

0.8

boys 0.4

0

FIGURE 17.1 Coenzyme Q10 concentration in plasma of nonobese and obese children.

girls

17.2 SUGAR AND THE CARDIOMETABOLIC DISEASES

289

2

mmol/L

1.5

Reference >1.16

Nonobese children

Obese children boys

girls

1

0.5

0

FIGURE 17.2 HDL-Cholesterol concentration in plasma of nonobese and obese children.

Obesity accounts for 2% 6% of total health care costs in several developed countries; some estimates put the figure as high as 7%. The true costs are undoubtedly much greater as not all obesity-related conditions are included in the calculations. The average male and female adult in the United States has gained 25 and 24 lbs, respectively, since 1962 [14,15,17]. In 2014, more than 1.9 billion adults, 18 years and older, were overweight. Of these over 600 million were obese. Overall, about 13% of the world’s adult populations (11% of men and 15% of women) were obese in 2014. In 2014, 39% of adults aged 18 years and over (38% of men and 40% of women) were overweight. The worldwide prevalence of obesity more than doubled between 1980 and 2014. Once considered a high-income country problem, overweight and obesity are now on the rise in low- and middle-income countries, particularly in urban settings. They continue to deal with the problems of a rapid upsurge in NCD risk factors such as obesity and overweight, particularly in urban settings. Most of the world’s population lives in countries where overweight and obesity kill more people than underweight. This includes all high-income and most middle-income countries [16]. New data from World Obesity show the global annual medical cost of treating obesity-related diseases is expected to reach US$1.2 trillion per year by 2025. Released for World Obesity Day (October 11, 2017), the data show that 2.7 billion adults globally are expected to suffer from obesity and overweight by 2025. Investing in the prevention, early intervention, and treatment of obesity will significantly reduce the costs of treating the various NCDs linked to obesity, such as heart disease, diabetes, liver disease, and various forms of cancer [19].

17.2 SUGAR AND THE CARDIOMETABOLIC DISEASES Dietary patterns among American adults indicate that they consume on average about 15% of their calories from sugars added to foods during processing which is about 37% of the added sugar consumed in sugar-sweetened beverages (SSB). The study projects that regularly drinking as little as one 12-ounce sugary soda a day may increase the risk of CVDs by about 30%, independent of total calories, obesity, or other risk factors [14]. There is a need to educate the population about it and to

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counsel patients about the health hazards associated with sugar consumption. Some recommendations have been made by certain health agencies about the safe limits of sugar intake but actually they are not safe but only less harmful [8]. Some of the important issues that have received renewed attention is the role of fructose and other sweetening agents [6]. Sugar is composed of fructose and glucose—the two main components of sucrose. However, fructose levels can vary widely in different forms of sugar, e.g., 45% 55% of sugar in some high-fructose corn sirups and 55% 65% in some fruit juices. Most experts agree that it is glucose that has important adverse effects on obesity as well as on other body tissues such as endothelial dysfunction [3 6]. However, fructose, which is metabolized in the liver, seems to have unique adverse effects, such as increased liver fat, uric acid, visceral fat, muscle fat, and triglycerides that are important in the pathogenesis of metabolic syndrome [3 5,20,21]. Concerning the mechanisms that induce these metabolic aberrations, most of the studies are in agreement with the fact that it is mainly fructose (free or as part of the sucrose molecule) that is the main driver of these metabolic aberrations, presumably primarily by inducing lipid synthesis in and release from the liver [22]. The fructose moiety is singled out to be the primary driver for the harms of sugars due to its unique endocrine signal and pathophysiological role. Prospective cohort studies have shown an association between fructose-containing sugars and cardiometabolic risk, CVD, and diabetes only when restricted to SSB. SSBs are a marker of an unhealthy lifestyle and their drinkers consume more calories, exercise less, smoke more, and have a poor dietary pattern [23]. Cohort studies indicate that the relations between body mass index and intake of SSB might be stronger in Hispanic and Asian subjects than in white individuals [3 5]. These findings suggest that further research in other populations especially in India and China, are required to find out why a modest increase in dietary fat and sugar is associated with rapid increase in central obesity and metabolic syndrome in developing countries [24,25]. It is proposed that increased sugar intake amplifies the risk of weight gain, diabetes, and many other cardiometabolic problems. Other beverages containing caloric sweeteners also have adverse health effects, but further research is needed to investigate the health effects of beverages containing low-calorie sweeteners, 100% fruit juices [6,26] and to determine whether routine consumption of nonnutritive sweeteners was associated with long-term adverse cardiometabolic effects. In the case of low calorie sweeteners’ effect on body weight, evidence from randomized controlled trials is clear and consistent in pointing to a modest benefit of low calorie sweeteners’ use in weight loss and maintenance [27,28]. Importantly, trials of longer duration have shown higher weight loss and maintenance with low calorie sweeteners’ use [29,30]. From 11,774 citations included seven trials (1003 participants; median followup 6 months) and 30 cohort studies (405 907 participants; median follow-up 10 years). In the included randomized controlled trials, nonnutritive sweeteners had no significant effect on BMI (mean difference 20.37 kg/m2; 95% CI 21.10 to 0.36; I2 9%; 242 participants). Consumption of nonnutritive sweeteners was associated with a modest increase in BMI (mean correlation 0.05, 95% CI 0.03 to 0.06; I2 0%; 21,256 participants). In the cohort studies, consumption of nonnutritive sweeteners was associated with increases in weight and waist circumference, and higher incidence of obesity, hypertension, metabolic syndrome, type 2 diabetes, and cardiovascular events [31]. In multivariable analyses there was no significant association comparing the highest to lowest quintiles of 100% fruit juice consumption (8 oz/day compared to none) and incident hypertension (HR 1.00, 95% CI 0.97 1.03) or diabetes (HR 0.96, 95% CI 0.90 1.03). There was also no significant association between whole fruit consumption (2.4 servings/day compared to 0.3 servings/day) and

17.2 SUGAR AND THE CARDIOMETABOLIC DISEASES

291

incident hypertension (HR 1.02, 95% CI 0.98 1.05) or diabetes (HR 1.03, 95% CI 0.96 1.10). Consuming moderate amounts of 100% fruit juice or whole fruit was not significantly associated with risk of hypertension or diabetes among postmenopausal US women [26]. There is evidence that high consumption of added sugar increases the risk of type 2 diabetes, obesity, and hypertension [11 13,22]. However, most studies focused only on SSB, and none looked at the relationship between added sugar intake and CVD mortality in a nationwide large population sample [14,15,17,32]. The American Heart Association has made stricter recommendations for intake of daily sugar; less than 100 calories a day (about 5% of total daily calories) for women and 150 calories a day (about 7.5% of total daily calories) for men. However, the International College of Nutrition does not recommend eating sugar but advises functional food supplements—raisins, dates, bananas, and grapes—in place of sugar [33,34]. Jaggery or unrefined sugar in a limited amount could be a better substitute for those following the advice by the health agencies; AHA advise 5.0% 7.5%, or up to 25% of total calories according to the Institute of Medicine, or less than 10% of total calories according to the World Health Organization. Yang et al. analyzed data from three National Health and Nutrition Examination Survey (NHANES) surveys and examined CVD mortality during a mean follow-up of 14.6 years [14]. The adjusted mean daily calories from added sugar went from 15.7% to 16.8% to 14.9% during the three time periods. The majority ( . 70% ) of the added sugar was provided from SSB (37.1%), grain-based desserts (13.7%), fruit drinks (8.9%), dairy desserts (6.1%), and candy (5.8%). The majority of the adults (71.4%) consumed 10% or more of calories from added sugar, and about 10% consumed 25% or more calories from sugar in the years 2005 to 2010 (Table 17.1). Multivariate logistic regression analysis revealed that after adjustment for age, sex, race/ethnicity, education, smoking, alcohol consumption, physical activity, antihypertensive medication, family history of CVD, Healthy Eating Index score, body-mass index (BMI), systolic BP, total serum cholesterol, and total calories, increased consumption of added sugar .10% of calories, was associated with significant increase in CVDs mortality (Table 17.1) [14]. The risk of CVD mortality becomes elevated once added sugar intake surpasses 15% of daily calories which may be equivalent to drinking one 20-ounce Mountain Dew soda in a 2000-calorie daily diet. New unsweetened truths about sugar indicated that the risk rises exponentially as sugar intake increases, peaking with a four-fold increased risk of CVD death for individuals who consume one-third or more of their daily calories in added sugar diet [15]. Despite no evidence of adverse events below 10% of calories, it is not logical to advise sugars as a chosen food. Singh et al. in a large, international epidemiologic study reported that drinking large amounts of sugary beverages was associated with an increased BMI, which in turn was linked with BMI-related deaths from diabetes, CVD, and cancer [32]. The researchers pointed that in 2010, 132,000 deaths from Table 17.1 Adjusted Hazard Ratio (95% CI) of Cardiovascular Disease Mortality for Different Percentages of Calories From Added Sugar [14] Hazard Ratio (Confidence Interval) 

P , .001.

0 10 Calories

10.0 25.0 Calories

25.0 and Above

1.00

1.30 (1.09 1.55)

2.75 (1.40 5.42)

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diabetes, 44,000 deaths from CVD, and 6000 deaths from cancer in the world could be attributed to drinking sugar-sweetened soft drinks, fruit juice, or sports beverages. It seems that three-quarters of these BMI-related deaths were from diabetes, which indicates that limiting sugary-beverage intake is an important step in reducing diabetes deaths [32]. The study reinforces the need for clinicians and other health professionals and policy makers to encourage patients to drink fewer sugary beverages. Further earlier studies also support that eating more sugar can predispose to obesity, metabolic syndrome, and deaths due to CAD and stroke [20,21,24,25,35]. The Global Burden of Disease study, data from 114 national dietary surveys, representing more than 60% of the world’s population, determined how changes in consumption of sugary drinks can influence BMI, resulting in CVD, diabetes, and seven obesity-related cancers—breast, uterine, esophageal, gallbladder, colorectal, kidney, and pancreatic cancer. They calculated the number of deaths from BMI-related CVD, diabetes, and cancer for men and for women aged 20 44, 45 64, and 65 and older based on WHO data. Chinese women were consuming the least sugary drink (8 oz vs 40 oz) compared to Cuban younger men, respectively, and the most of the deaths (78%) from excess sugary drinks were in low- and middle-income countries. The greatest numbers of deaths related to sugar intake (318 deaths per million adults) were in Mexico, one of the world’s highest per capita rates of drinking sweetened drinks. However, Japan, with one of the lowest percapita rates of imbibing these beverages, had the smallest number of deaths attributable to this risk factor (about 10 deaths per million adults). In 2010, drinking SSB was associated with about 38,000 deaths from diabetes in Latin American and Caribbean countries, 11,000 deaths from CVD in Eastern- and Central-Eurasian countries, and 25,000 deaths in the United States. Intake of SSB should generally be reduced as much as possible to improve the health of the population. Rather than just focusing on one energy source, we should consider the whole diet for health benefits. It is very important to increase the intake of food containing vitamin D. The Health professional Follow-Up Study [36] found that men with a low level of vitamin D3 were twice as likely to have a heart attack as men with an adequate level of vitamin D3. Low vitamin D3 levels are associated with a higher risk of heart failure, sudden cardiac death, stroke, overall CVD and cardiovascular death [37 41]. Worldwide, the vitamin D3 deficiencies can be found in the people of all continents, within all ethnic groups and/or ages. Some surveys suggest that almost half of the worlds population has inadequate blood levels of vitamin D3 [42 44]. Diets high in sugar but deficient in vitamin D may cause synergestic adverse effects on NCDs.

17.3 SUGAR PRODUCTS Approximately, 74% of products in the US food supply contain caloric or low-calorie sweeteners, or both [6]. In Chile, a rapid absolute growth in sales of SSB was noted per capita in 2014, see Fig. 17.3. Of all packaged foods and beverages purchased by a nationally representative sample of US households in 2013, 68% (by proportion of calories) contain caloric sweeteners and 2% contain low-calorie sweeteners. In North America, Australasia, and Western Europe many beverages are consumed containing low-calorie sweeteners; North America, Australia and New Zealand consume twice as many such beverages as do other regions, see Fig. 17.4.

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Chile Mexico USA Argentina Saudi Arabia Germany Netherlands Slovakia Austria Brazil Belgium Israel Ireland Canada Australia Poland United Arab Emirates Denmark South Africa Norway Venezuela Finland Czech Republic Portugal Peru New Zealand Turkey Sweden UK Hungary Colombia Spain Romania France Thailand Russia Italy Philippines Bulgaria Japan Switzerland South Korea Taiwan Ukraine Singapore Greece Malaysia Mainland China Morocco Egypt Hong Kong Vietnam Indonesia India 0

20

40

60

80

100

120

140

160

180

200

Calories sold per capita per day

FIGURE 17.3 Sales of beverages in the year 2009 14 in selected countries. Modified from Euromonitor Passport International, which were obtained from Nutrition Facts Panels, websites of sugar sweetened beverage companies. Kcal 5 kilocalories (Popkin BM, Hawkes C. Lancet Diabetes Endocrinol 2016; 4: 174-86.

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It is possible that the rest of the world will move towards this pervasiveness of added sugars in the food supply in the near future because health education to reduce manufacturing of and to eat fewer sugar containing products is still far from a universal education. A recent analysis of trends in sales of SSB around the world, in terms of calories sold per person per day and volume, shows that the four regions with the highest consumption are North America, Latin America, Australasia, and Western Europe [6], see Fig. 17.5. There is a need to intervene to tackle the high levels and continuing growth in sales of such beverages worldwide by taxation, in the same way alcohol consumption is decreased in some of the countries. Reduction of the consumption of SSB in the past few years, has been done by (B) Volume (mL) per person per day

(A) North America Australasia Western Europe Latin America Worldwide North Africa and Middle East Eastern Europe Sub-Saharan Africa Asia Pacific

120

North America Australasia

100

Western Europe Latin America Worldwide North Africa and Middle East

80 60

Eastern Europe Sub-Saharan Africa Asia Pacific

40 20

5

10

15

20

25

30

Volume (L) per person

20 0 20 0 0 20 1 0 20 2 0 20 3 0 20 4 0 20 5 0 20 6 0 20 7 0 20 8 0 20 9 1 20 0 1 20 1 1 20 2 1 20 3 14

0 0

Year

FIGURE 17.4 Sales of food beverages with only low calorie sweetners in 2014 and trends in 2000 14 (B). Modified from Euromonitor Passport International) (Popkin BM, Hawkes C. Lancet Diabetes Endocrinol 2016; 4: 174-86.

180

Sports and energy drinks Fruit drinks Caloric soft drinks

kcal per person per day

160 140 120 100 80 60 40 20

20 0 20 9 1 20 0 1 20 1 1 20 2 1 20 3 1 20 4 0 20 9 1 20 0 1 20 1 1 20 2 1 20 3 1 20 4 0 20 9 1 20 0 1 20 1 1 20 2 1 20 3 1 20 4 0 20 9 1 20 0 1 20 1 1 20 2 1 20 3 1 20 4 0 20 9 1 20 0 1 20 1 1 20 2 1 20 3 1 20 4 0 20 9 1 20 0 1 20 1 1 20 2 1 20 3 1 20 4 0 20 9 1 20 0 1 20 1 1 20 2 1 20 3 1 20 4 0 20 9 1 20 0 1 20 1 12 20 1 20 3 1 20 4 0 20 9 1 20 0 1 20 1 1 20 2 1 20 3 14

0

North America

Latin America

Australasia

Western Europe

Eastern Europe

North Africa and Middle East

Worldwide

Sub-Saharan Africa

Asia Pacific

FIGURE 17.5 Sales of beverages in the year 2009 14 in selected countries. Modified from Euromonitor Passport International, which were obtained from Nutrition Facts Panels, websites of sugar sweetened beverage companies. Kcal 5 kilocalories (Popkin BM, Hawkes C. Lancet Diabetes Endocrinol 2016; 4: 174-86.

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295

taxation (e.g., in Mexico); reduction of their availability in schools (India); restrictions on marketing of sugary foods to children; public awareness campaigns; and positive and negative front-ofpack labeling. Most of these actions are not specific to SSB, but do include them, see Fig. 17.6. The evidence of the effectiveness of these actions indicate that they are moving in the right direction, but governments and other health agencies should view them as a learning process and improve their design over time by involving World Health Organization advocacy. However, the absence of a consensus on the relation of beverages containing low-calorie sweeteners and fruit juices with cardiometabolic outcomes, which may be healthy substitutes for SSB are an integral part of policy design. It seems fruit juices may be allowed to some of the lower weight individuals, but the main agenda for population education should be to avoid sirups from the list of functional foods. Over the past several decades, the world has become increasingly aware of the role of added sugars, particularly in beverages, as a major driver of increased weight gain and diabetes. This problem is especially evident in high-income countries such as the United States, the United Kingdom, and Australia, where consumption of SSB increased throughout the 20th century [11 15]. The role of caloric sweeteners, such as nutritive sweeteners, and low-calorie sweeteners,

40

Pacific Islands Asia Eastern Europe Sub-Saharan Africa Middle East and North Africa Western Europe Australasia Latin America and the Caribbean North America

35

Number of countries

30 25 20 15 10 5 0 Taxation of sugarsweetened beverages

Mandatory Restrictions or restrictions and warnings on official voluntary advertising of guidelines on sugar-sweetened sugar-sweetened beverages beverages in schools

Public awareness campaigns on or including sugarsweetened beverages

Mandatory or official voluntary guideliness on front-of-pack labelling

FIGURE 17.6 Name of countries showing implementation policies on sugar-sweetened beverages. Modified from data from World Cancer Research Fund International NOURISHING database) (Popkin BM, Hawkes C. Lancet Diabetes Endocrinol 2016; 4: 174-86.

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such as nonnutritive sweeteners, is an important factor in weight gain, diabetes, and other cardiometabolic health problems. Popkin and Hawkes have grouped SSB into three categories: caloric soft drinks, fruit drinks, and sports and energy drinks. In the next decade, they plan to provide an in-depth analysis of trends for added caloric sweeteners and low-calorie sweeteners in both foods and beverages in the United States to find out global trends. In high-income countries, the past 25 years have seen a revolution in our understanding of the effect on cardiometabolic risk, of caloric sweeteners (including sugar) on energy intake, obesity, and diabetes. The relation between sugar and insulin control has been understood since the 1920s. The view that sugar is a danger to health was ignored by most of the health profession during the last three decades [2 4]. The consumption of SSB and other sugary products may increase substantially because the intake of caloric beverages in any form are not compensated for by an equivalent reduction in food intake [6]. There is evidence that free sugars contribute to the overall energy density of diets and higher intakes of free sugars may have adverse effects on the nutrient quality of the diet by providing significant energy without specific nutrients which may cause unhealthy weight gain and increased risk of obesity and various NCDs, particularly dental caries which is the most prevalent NCD globally. Free sugars include monosaccharides and disaccharides added to foods and beverages by the manufacturer, cook ,or consumer, and sugars naturally present in honey, sirups, fruit juices, and fruit juice concentrates.

17.4 MECHANISMS Sugar, sirups, and refined foods with added sugar are rapidly absorbed causing oxidative stress with an increase in superoxide anions, free fatty acids, and pro-inflammatory transcription factors—nuclear factor (NFkB) and activating protein 1—which are known to cause endothelial dysfunction and damage the other tissue in the brain, liver, heart, and beta cells of pancreas causing insulin resistance [1 3]. Oxidative stress, nitric oxide synthase, oxidative phosphorylation, and coenzyme Q damage contribute to the chronic complications of diabetes mellitus. Hyperglycemia also favors an increased expression of inducible nitric oxide synthase (iNOS), which is accompanied with increasing nitric oxide (NO) generation. NO can react with superoxide anion to produce peroxynitrite, which in turn can increase lipid peroxidation, protein nitration, and LDL oxidation, affecting several signal transduction pathways. These metabolic changes are involved in the development of early diabetic injury before the evolution of late complications. Hyperglycemia causes oxidative stress due to increased mitochondrial superoxide anion production, nonenzymatic glycation of proteins and glucose autooxidation. Increased superoxide anion production by hyperglycemia could damage mitochondria and mitochondrial DNA (mtDNA). MtDNA depletion was identified in diabetic complications. Excess superoxide production is accompanied with increased nitric oxide generation in endothelial cells. High glucose concentration leads also to an increase of reducing equivalents such as NADH and FADH2 within mitochondria. Their uptake from the cytoplasm occurs by various mitochondrial redox shuttles as well as by increasing uptake of pyruvate. Pyruvate as a substrate for mitochondrial oxidative phosphorylation participates in ATP production from ADP and inorganic phosphate. The increased cytosolic ATP/ADP ratio causes closure of the plasma membrane KATP channels and depolarizes the beta-cell. After depolarization of the plasma

REFERENCES

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membrane, calcium influx into beta-cells leads to secretion of insulin. Mitochondrial dysfunction results in impaired glucose-stimulated insulin secretion. An increased amount of contact sites on mitochondria in the diabetic heart can contribute to etiopathogenic mechanisms involved in chronic DM complications [45 47]. It seems that SSB are associated with excess weight gain which actually increases the risk of death from diabetes, CVD, and cancer. Refined carbohydrates, especially sugar-sweetened beverages, increase the risk of CVD [48]. The AHA recommends that adults don’t exceed 450 calories (36 oz) a week from SSB. The American Diabetes Association stated that nonnutritive artificial sweeteners can be a tool to help people lower their added sugar and calorie intake, as long as they don’t eat extra calories to compensate for the lower calories in the diet drinks. The International College of Nutrition and International College of Cardiology also warn against the adverse effects of added sugar on CVDs [33]. Because added sugar is also linked to increase in glycated hemoglobin which is an indicator of increased risk of CVDs [34]. WHO’s efforts is to achieve their global target set action plan to halt the rise in diabetes and obesity and reduce the burden of premature death due to NCDs to 25% by the year 2025 [49]. Acknowledgments are due to International College of Nutrition and International College of Cardiology for providing logistic support to write this article.

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CHAPTER

MODERN EGGS, NOT WILD TYPE EGGS, PREDISPOSE RISK OF CARDIOVASCULAR DISEASE, DIABETES AND CANCER?

18

Dominic Pella1, Jan Fedacko2, Daniel Pella2, Viola Vargova2, Vilium Mojto3 and Ram B. Singh4 1

Department of Cardiology, East Slovak Institute of Cardiovascular Diseases, Kosice, Slovakia 2Faculty of Medicine, PJ Safaric University, Kosice, Slovakia 3Pharmacobiochemical Laboratory of 3rd Internal Clinic Faculty of Medicine, Comenius University in Bratislava, Bratislava, Slovakia 4The Tsim Tsoum Institute, Krakow, Andrzej Frycz Modrzewski Krakow University, Krakow, Poland

18.1 INTRODUCTION Cardiovascular diseases (CVDs)—hypertension, coronary artery disease (CAD), stroke, diabetes mellitus, and cancer—which are commonly called noncommunicable diseases (NCDs) have become a public health problem. According to WHO data, NCDs have become major causes of death in both middle-income and high-income countries [1]. NCDs, principally CVD, cancer, chronic respiratory disease, and diabetes mellitus caused 35 million deaths, which were 60% of total deaths in the year 2005. CVDs are the leading chronic diseases, with 17 million deaths [1]. Deaths due to diabetes are usually recorded as being deaths due to heart disease, stroke, and renal failure [2 4]. Majority of these deaths (80%) occurred in low- and middle-income countries. In one recent study [2], all-cause mortality were infectious diseases (41.1%) and NCDs as the cause of death were common among 60.00% of the victims dying due to various causes. The Indian study revealed that NCDs as the cause of deaths (60.2%) were: circulatory diseases (29.1%), heart attacks (10.0%), stroke (7.8%), valvular heart disease (7.2%), sudden cardiac death and inflammatory cardiac disease, each, 2.0%), type 2 diabetes (2.2%), malignant neoplasm (5.8%), injury (14.0%) including accidents; fire and falls and poisonings, were also quite common causes of death. Countries with the greatest number of cardiovascular deaths, are found throughout Eastern Europe, Central Asia, the Middle East, South America, sub-Saharan Africa, and Oceania. However, the steep declines experienced by the United States, Canada, Australia, New Zealand, Japan, South Korea, and countries in Western Europe over the past two decades have begun to taper off and plateau. It seems that trends in CVD mortality are no longer declining for high-income regions and low- and middle-income countries are also seeing more CVD-related deaths. Further evidence indicate that western diet is important in the pathogenesis of deaths due to NCDs, whereas Mediterranean style foods are protective [3,4]. The key ingredients of Mediterranean type diets include olive oil, fresh fruits and vegetables, protein-rich legumes, fish, poultry including eggs and The Role of Functional Food Security In Global Health. DOI: https://doi.org/10.1016/B978-0-12-813148-0.00018-9 © 2019 Elsevier Inc. All rights reserved.

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Table 18.1 Nutrients Contents in Eggs Nutrient

White

Yolk

% Total in White

% Total in Yolk

Protein Fat Calcium Magnesium Iron Phosphorus Potassium Sodium Zinc Copper Manganese Selenium Thiamin Riboflavin Niacin Pantothenic acid. B6 Folate B12 Vitamin A Vitamin E Vitamin D Vitamin K DHA and AA Carotenoids

3.6 g 0.05g 2.3 mg 3.6 mg 0.03 mg 5 mg 53.8 mg 54.8 mg 0.01 mg 0.008 mg 0.004 mg 6.6 mcg 0.01 mg 0.145 mg 0.035 mg 0.63 mg 0.002 mg 1.3 mcg 0.03 mcg 0 IU 0 mg 0 IU 0 IU 0 0 mcg

2.7g 4.5g 21.9 mg 0.85 mg 0.4 mg 66.3 mg 18.5 mg 8.2 mg 0.4 mg 0.013 mg 0.009 mg 9.5 mcg 0.03 mg 0.09 mg 0.004 mg 0.51 mg 0.059 mg 24.8 mcg 0.331 mcg 245 IU 0.684 mg 18.3 IU 0.119 IU 94 mg 21 mcg

57 1 9.5 80.8 6.2 7 74.4 87 0.2 38 30.8 41 3.2 61.7 89.7 11 3.3 5 8.3 0 0 0 0 0 0

43 99 90.5 19.2 93.8 93 25.6 13 99.8 62 69.2 59 96.8 48.3 9.3 89 96.7 95 91.7 100 100 100 100 100 100

whole grains with moderate amounts of wine and red meat. The composition of an egg given in Table 18.1, shows that that it is quite rich in proteins, vitamins, and minerals and have a few antioxidants. The eggs and red meat from running animals are healthy whereas those from animals domesticated at farm houses and given feeds made by the industry, may have adverse effects on meat, eggs and milk [5 10]. These modern type foods are integral parts of Western diet [11,12,13a]. This review examines the association of egg intake with risk of NCDs.

18.2 DIET AND MORTALITY DUE TO NONCOMMUNICABLE DISEASES Only a few studies have evaluated the relationship between changes in diet quality over time and the risk of death [14]. In a cohort study among 47,994 women in the Nurses’ Health Study and 25,745 men in the Health Professionals Follow-up Study, changes in diet quality were assessed over the preceding 12 years with the use of the Alternate Healthy Eating Index 2010 score, the

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Alternate Mediterranean Diet score, and the Dietary Approaches to Stop Hypertension (DASH) diet score. For all-cause mortality among participants who had the greatest improvement in diet quality (0% 3% vs 13% 33% improvement), as compared with those who had a relatively stable diet quality, the hazard ratio in the 12-year period were the following: 0.91 (95% CI: 0.85 0.97) according to changes in the Alternate Healthy Eating Index score, 0.84 (95% CI: 0.78 0.91) according to changes in the Alternate Mediterranean Diet score, and 0.89 (95% CI: 0.84 0.95) according to changes in the DASH score [4]. A 20-percentile increase in diet scores for improved quality of diet was significantly associated with a reduction in total mortality of 8% 17% with the use of the three diet indexes and a 7% 15% reduction in the risk of death from CVDs with the use of the Alternate Healthy Eating Index and Alternate Mediterranean Diet. For those subjects with a high-quality diet over a 12-year period, the risk of death from any cause was 14% (95% CI: 8 19) when assessed with the Alternate Healthy Eating Index score, 11% (95% CI: 5 18) when assessed with the Alternate Mediterranean Diet score, and 9% (95% CI: 2 15) when assessed with the DASH score compared to subjects with consistently low diet scores over time. Majority of the cohort studies support an association between healthy dietary patterns identical with DASH diet or Mediterranean style diets, and a decreased risk of death [14 16]. Diet appears to be important factors in the pathogenesis of NCDs [14 27]. Results from recent studies suggest that improved diet quality, as assessed by means of the Alternate Healthy Eating Index 2010 score [12], the Alternate Mediterranean Diet score [22], and the Dietary Approaches to Stop Hypertension (DASH) diet score, was associated with reductions of 8% 22% in the risk of death from any cause and reductions of 19% 28% in the risk of death from CVDs and 11% 23% in the risk of death from cancer. [25 27]. It is clear from these studies that Mediterranean-style diets may be protective against deaths due to NCDs. In most of these studies, poultry is considered in the prudent diet. All the other diets are similar or part of the Mediterranean-style diet which is considered highly prudent, traditionally includes fruits, vegetables, whole grains, nuts, olive oil, fish with poultry, and lower intake of red meats (Table 18.2).

18.3 NUTRITION IN TRANSITION AND DEVELOPMENT OF NCDs Dietary intakes and lifestyle have Westernized significantly in the last century with modernization of the world; intake of refined carbohydrates, saturated fat, trans fat, and ω-6 fat increased and that of ω-3 fatty acids and flavonoids decreased [10 12,13a]. However, diets of hunter-gatherers during the Paleolithic times comprised mainly of fruits, vegetables, seeds, whole grains, egg, fish, and Table 18.2 Components of the Mediterranean-Style Foods • • • • • •

Eating plant-based foods; fruits and vegetables, whole grains, legumes, and nuts Replacing butter and clarified butter or lard with healthy fats, such as olive oil Using herbs and spices instead of salt to flavor foods Eating fish and poultry at least twice a week Drinking red wine in moderation (optional) No advice for red meat which may not exceed more than a few times a month

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wild-animal meat which were low in omega-6 and high in omega-3 fatty acids along with antioxidants polyphenols and flavonoids, vitamins and minerals, and amino acids [9 13]. Economic development in middle- and high-income countries, during transition from poverty to affluence, has been associated with industrialization and urbanization, domestication of animals in farm houses, development of feeds for animals in factories (Table 18.1). There is decreased physical activity due to use of automobiles and increased intake of ready prepared Western foods— bread, biscuits, candies, sirups, preserved foods as well as animal foods like eggs and red meat from domesticated animals. Use of natural and synthetic versions of estrogen, progesterone, and testosterone hormones by the farm houses (although not permitted) causes rapid increase in animal’s weight, increased size of eggs, and increased amount of milk. These drugs boost production of growth-stimulating hormones that help the animal convert feed into muscle, fat, and other tissues more efficiently than they would naturally. This artificial plumping process boosts the amount of meat, eggs, and milk that farmers can sell per animal. The consumption of meat, egg and milk from these animals may cause inflammation among human populations, leading to obesity and NCDs much more rapidly compared to food consumption from normally fed animals. (http://www. businessinsider.com/farmers-fatten-cattle-hormone-implants-2016-4?IR 5 T). The hunter-gatherer diets had paradox because they were meat based, yet nonatherogenic because animal meat was from running animals who take their feeds from natural environment [8 10]. Feeding experiments have demonstrated that flax seed as animal feed can increase the content of omega-3 fatty acids in egg, milk, and meat [9,10].

18.4 WESTERN DIET, PRUDENT DIET, AND POULTRY Commonly used prudent foods are, fruits, vegetables, whole grains, nuts, fish, and olive oil and mustard oil or canola oil. Egg, chicken meat, and sea foods are also considered prudent foods by most of the experts [9 11]. For example, residents of Greece average six or more servings a day of antioxidant-rich fruits and vegetables [28 30]. In the Mediterranean region, grains are typically whole grain and usually contain very few unhealthy trans fats, or saturated fat and bread is an important part of the diet [29]. However, throughout the Mediterranean region, bread is eaten plain or dipped in olive oil hence its adverse effects if any are neutralized by flavonoids present in olive oil. Eating bread with butter or margarine, which contains saturated or trans fats may have adverse effects on glycemia, free fatty acids, and lipoproteins. Nuts are another part of a healthy Mediterranean-style diets which are high in fat, but most of the fat is healthy monounsaturated type and there is high content of omega-3 fatty acids in walnuts consumed in Mediterranean region. Since nuts are high in calories, they may be eaten in large amounts to avoid other energy rich foods such as red meat and refined carbohydrates, which are considered unhealthy. In a meta-analysis, on the role of diet in metabolic syndrome [29], the authors conducted a systematic review and random effects of epidemiological studies and randomized controlled trials, including 50 original research studies (35 clinical trials, two prospective, and 13 cross-sectional), with 534,906 participants, were included in the analysis [29]. The combined effect of prospective studies and clinical trials showed that adherence to the Mediterranean diet was associated with reduced risk of metabolic syndrome (log hazard ratio: 0.69, 95% CI: 1.24 1.16). Additionally,

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results from clinical studies (mean difference, 95% CI) revealed the protective role of the Mediterranean diet on components of metabolic syndrome, like waist circumference, diastolic blood pressure, and blood glucose. The results from epidemiological studies also confirmed those of clinical trials. It is possible that this dietary pattern can be easily adopted by all population groups and various cultures and cost-effectively serve for primary and secondary prevention of the CVDs and other chronic diseases. Sofi et al. conducted another meta-analysis of cohort prospective studies that investigated the effects of adherence to the Mediterranean diet on diseases [30]. The study showed that a 2-point increase in adherence to the Mediterranean style foods was associated with a significant reduction of overall mortality (relative risk (RR) 5 0.92; 95% CI: 0.90, 0.94), CVDs incidence or mortality (RR 5 0.90; 95% CI: 0.87, 0.93), cancer incidence or mortality (RR 5 0.94; 95% CI: 0.92, 0.96), and neurodegenerative diseases (RR 5 0.87; 95% CI: 0.81, 0.94). This updated meta-analysis confirmed, in a larger number of subjects and studies, the significant and consistent protection provided by adherence to the Mediterranean diet in relation to the occurrence of major chronic degenerative diseases. The Northern Manhattan Study, among 2568 participants (mean age 69.6 6 10 y; 64% women; 55% Hispanic, 21% white, and 24% black) reported a higher score on a 0 9 scale represented increased adherence to an Mediterranean diet rich in fruit, vegetables, whole grains, fish, poultry and olive oil [31]. Over a mean follow-up of 9 y, 518 vascular events accrued (171 ischemic strokes, 133 myocardial infarctions, and 314 vascular deaths). The Mediterranean diet score was inversely associated with risk of the composite outcome of ischemic stroke, MI, or vascular death (P-trend 5 .04) and with vascular death specifically (P-trend 5 .02). Moderate and high Mediterranean diet scores were marginally associated with decreased risk of MI and vascular events without any effect on stroke. In another study involving 72,113 female nurses who were free of CAD, stroke, diabetes, and cancer, prudent food consumption pattern was characterized by a high consumption of vegetables, fruit, legumes, fish, poultry, and whole grains [32]. The other pattern, called Western, corresponded to a high consumption of red meat, processed meat, refined grains, French fries, sweets, and desserts. After 18 years of follow up, 6011 deaths occurred (3319 (52%) as a result of cancer; 1154 (19%) resulting from CVD; and 1718 (29%) resulting from other causes. There was a 17% lower risk of total mortality among those who were most adherent to the prudent diet (highest versus lowest quintile of adherence), a 28% lower risk of CVD mortality, and 30% lower mortality from nonCVD, noncancer causes. Cancer was not associated with the inverse prudent dietary pattern. A comparison of the highest and lowest quintiles of adherence showed that consumption of the Western diet was associated with increased total mortality (21%), CVD mortality (22%), cancer mortality (16% nonsignificant), and mortality from non-CVD, noncancer causes (31%). The Greek Epic Prospective cohort study with Greek segment comprising of 23,349 men and women, not previously diagnosed with cancer, CAD, or diabetes, with documented survival status until June 2008 [33]. After a mean follow-up of 8.5 years, 652 deaths from any cause had occurred among 12 694 participants with Mediterranean diet scores 0 4 and 423 among 10,655 participants with scores of 5 or more. After potential confounders were controlled, higher adherence to a Mediterranean diet was associated with a statistically significant reduction in total mortality. Moderate ethanol consumption 23.5%, low consumption of meat and meat products 16.6%, high vegetable consumption 16.2%, high fruit and nut consumption 11.2%, high monounsaturated to saturated lipid ratio 10.6%, and high legume consumption 9.7% were individual components of the Mediterranean diet contributing to this association. It is possible that moderate consumption of

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ethanol, low consumption of meat and meat products, and high consumption of vegetables, fruits and nuts, olive oil, and legumes were highly protective and minimal contributions were found for cereals and dairy products, possibly because they are heterogeneous categories of foods with differential health effects, and for fish and seafood which are consumed less often in Greece. The INTERHEART study, involving participants from 52 countries examined the relationship between dietary patterns and risk of heart attack [34]. No association of Oriental diet with risk of heart attack was reported. A dietary risk score based on seven food items on the food-frequency questionnaire (Western; meat, salty snacks, fried foods, prudent; fruits, green leafy vegetables, cooked vegetables, and other raw vegetables, poultry) was constructed by the authors. The investigators found that a higher score, indicating a poor diet was strongly associated with heart attack risk and the subjects in the highest quartile of the score had nearly two-fold increased risk, even after adjustment for established risk factors. On the basis of an arbitrary cut-point of the score (top three quartiles versus the bottom quartile), the investigators estimated that 30% of heart attacks could be explained by unhealthy diets worldwide. The INTERHEART study is the first large study to quantify eating patterns in all geographic regions of the world. It provides evidence that despite different food habits in various populations, reproducible patterns can be found in diverse regions of the world. These findings are important because there has been a concern that dietary patterns derived through a data-driven approach such as Principal Components Analysis may be highly unstable and nonreproducible because of very different eating habits in different populations. Hence, except for cancer, risk relationships for the prudent and Western dietary patterns appear to be the inverse of each other: Mortality thus was increased as adherence to the prudent diet decreased and adherence to the Western diet increased. In the dietary-patterning analysis, habitual intake patterns are typically quantified by statistical methods such as Factor or Cluster Analysis or diet-quality indexes based on prevailing dietary recommendations or healthful traditional diets, e.g., the Mediterranean diet, the Japanese diet, and the Indo-Mediterranean diet. The Lyon Heart study using Mediterranean style diet high is omega-3 fatty acids included poultry in the diet but the IndoMediterranean diet heart study did not include poultry as healthy component of diet [35,36]. Diet and Re-infarction trial using fish 50 75 g twice weekly) and the Lyon heart study were the first to demonstrate that total mortality can be reduced without reduction in LDL cholesterol [35,37]. In all above studies except Indian experiment of Infarct Survival and the Indo-Mediterranean Diet Heart study, poultry, egg and chicken, has been considered prudent. However, in both trials, heart attack patients were advised to eat only fruits, vegetables, nuts, whole grain, curd, and mustard oil which resulted in significant decline in total cardiovascular events [36,38]. It is possible that if poultry is excluded from prudent food category, the results of above studies may be much better. The role of wild type of poultry in the evolutionary diet has also been appreciated by other investigators [39,40].

18.5 EGG CONSUMPTION AND RISK OF NONCOMMUNICABLE DIAEASES Eggs, chicken, and sea foods have been considered components of prudent diets by most of the experts [41 45]. Egg, fish, other sea foods, and meat from running animals are also components of Paleolithic diets [9,10]. However, the egg and chicken that are produced today appear to be

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different from those that were consumed by the hunter-gatherers. Egg is a rich source of protein, fat, saturated and cholesterol along with other nutrients (Table 18.3) [9,10]. Cohort studies on the association between egg consumption and risk of type 2 diabetes mellitus (2DM), CVDs, and cancer have been inconsistent [27 31]. Since eggs are a good source of protein and micronutrients and are inexpensive, it is important to clarify their role in the risk of diabetes, CVDs, and cancer. In a meta-analysis, 13 cohort studies or case control studies that evaluated the relationship between egg consumption and breast cancer risk were included [41]. The meta-analysis results showed that egg consumption was associated with increased breast cancer risk (RR 1.04, 95% CI: 1.01 1.08). Subgroup analyses showed egg consumption was also associated with increased breast cancer risk based on cohort studies (RR 1.04, 95% CI: 1.00 1.08), among European population (RR 1.05, 95% CI: 1.01 1.09), Asian population (RR 1.09, 95% CI: 1.00 1.18), postmenopausal population (RR 1.06, 95% CI: 1.02 1.10), and those who consumed $ 2, # 5/week (RR 1.10, 95% CI: 1.02 1.17), but not in case-control studies (RR 1.06, 95% CI: 0.97 1.15), among American population (RR 1.04, 95% CI: 0.94 1.16), premenopausal population (RR 1.04, 95% CI: 0.98 1.11), and those who consumed $ 1, ,2/week (RR 1.04, 95% CI: 0.97 1.11) or .5 eggs/ week (RR 0.97, 95% CI: 0.88 1.06). This meta-analysis revealed that egg consumption was associated with increased breast cancer risk among the European, Asian and postmenopausal population and those who consumed 2 and more eggs/week. There is evidence that that egg intake may be implicated in the etiology of sex hormone-related cancers, but the dose-response association is not clear [42]. The linear dose-response meta-analysis for breast cancer, observed a nonsignificantly increased risk (RR for an increase of 5 eggs consumed/week: 1
05, 95% CI: 0
99, 1
11, n 16,023 cases). Evidence for nonlinearity was not statistically significant (P nonlinearity 5 0
50, n 15,415 cases) but consuming 5 eggs or more/week was significantly associated with an increased risk of breast cancer compared with no egg consumption, with the summary RR being 1
04 (95% CI: 1
01, 1
07) for consuming 5 eggs/week and 1
09 (95% CI: 1
03, 1
15) for consuming about 9 eggs/week. The summary RR for an increase of 5 eggs consumed/week was 1
09 (95% CI: 0
96, 1
24, n 2636 cases) for ovarian cancer; 1.47 (95% CI: 1
01, 2
14, n 609 cases) for fatal prostate cancer, with evidence of small-study effects (P Egger 5 0
04). No evidence was found for an association with the risk of total prostate cancer. A dose-response meta-analysis of prospective cohort studies to find out the association between egg consumption and risk of CAD and stroke [43]. The meta-analysis included 3,081,269 person years and 5847 incident cases for CAD, and 4,148,095 person years and 7579 incident cases for stroke. The summary RR of CAD for an increase of one egg consumed per day was 0.99 (95% CI: 0.85 1.15; P 5 0.88 for linear trend) without heterogeneity among studies (P 5 0.97, I(2) 5 0%). For stroke, the combined RR for an increase of one egg consumed per day was 0.91 (0.81 1.02; P 5 .10 for linear trend) without heterogeneity among studies (P 5 .46, I(2) 5 0%). In a subgroup analysis of diabetic populations, the RR of CAD comparing the highest with the lowest egg consumption was 1.54 (1.14 2.09; P 5 .01). In addition, people with higher egg consumption had a 25% (0.57 0.99; P 5 .04) lower risk of developing hemorrhagic stroke. No evidence of a curve linear association was seen between egg consumption and risk of CAD or stroke (P 5 .67 and P 5 .27 for nonlinearity, respectively). It is clear that higher intake of eggs (up to one egg per day) is not associated with increased risk of CAD or stroke. The risk of CAD increase among diabetic patients and reduced risk of hemorrhagic stroke associated with higher egg consumption in subgroup analyses warrant further studies.

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CHAPTER 18 MODERN EGGS, NOT WILD TYPE EGGS

Table 18.3 Nutrition in Transition and Emergence of Noncommunicable Diseases in Developing Countries Pattern 3: Receding Food Scarcity & Poverty

Pattern 4: More Food, Less Exercise- Homo economicus

Pattern 5: Healthy Behavior-Homo modestis

Cereals predominant, diet less varied

Fewer starchy staples; more fruit, vegetables, animal protein; low variety continues

More fat (animal products, trans fat, w-6 fat), sugar, processed foods; less fiber, less w-3 fat and flavonoids

Robust, lean population; few nutritional deficiencies

Children and women suffer most from low fat intake, nutritionaldeficiency disease emerge, stature declines

Continued MCHa nutrition problems, many deficiencies disappear, weaning diseases emerge, stature grows

Economy

Huntergatherers

Agriculture, animal husbandry, homemaking begin; shift to monocumono cultures

Household

Primitive, onset of fire

Labor-intensive, primitive technology begins (clay cooking vessels)

Second agricultural revolution (crop rotation, fertilizer), Industrial Revolution, women join labor force Primitive water systems, clay stoves, cooking technology advances

Obesity, problems for elderly (osteoporosis, fractures etc.), type 2 diabetes, hypertension, stroke, heart attack, brain degeneration, psychological disorders, cancer Fewer jobs with heavy physical activity, service sector and mechanization, household technology revolution

Income and assets

Subsistence, primitive stone tools

Subsistence, few tools

Higher-quality fats, reduced refined carbohydrates, more whole grains, fruit, vegetables rich in w-3 and flavonoids Reduction in body fat and obesity, and NCDs, improvement in bone health; epigenetic modulation and transgenerational epigenetic inheritance -natural selection. Service sector mechanization and industrial robotization dominate, increase in leisure exercise offsets sedentary jobs Significant reduction in food preparation costs as a result of technologic change Decrease in income growth, increase in home and leisure technologies

Homo sapiens Diet Patterns

Pattern 1: HunterGatherers

Pattern 2: Food ScarcityPoverty

Nutrition profile / diet

Plants, lowfat wild animals, diet diversity by collecting foods

Nutritional status

Increases in income disparity and agricultural tools industrialization

Household technology mechanizes and proliferates

Rapid growth in income and income disparities, technology proliferation

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Table 18.3 Nutrition in Transition and Emergence of Noncommunicable Diseases in Developing Countries Continued Homo sapiens Diet Patterns

Pattern 1: HunterGatherers

Pattern 2: Food ScarcityPoverty

Professional skill/ Education Demographic profile / Mortality

Hunting

Stock breeding, cultivation

Low fertility, high mortality, low life expectancy

Age of Malthus; high natural fertility, short life expectancy, high infant and maternal mortality

Age structure

Young population

Young, very few elderly

Housing

Rural, low density

Rural, a few small, crowded cities

Food processing

Nonexistent

Food storage begins

Pattern 3: Receding Food Scarcity & Poverty

Pattern 4: More Food, Less Exercise- Homo economicus

Pattern 5: Healthy Behavior-Homo modestis

Industry, intensive agriculture Mortality declines slowly, then rapidly; fertility static, then declines; small, cumulative population growth, which later explodes Chiefly young, shift to older population begins

Processed unhealthy foods increased Life expectancy hits unique levels (ages 60 70), huge decline and fluctuations in fertility (e.g., postwar baby boom)

Functional foods availability increases Life expectancy extends to ages of 70 and 90 years, disabilityfree period increases

Rapid decline in fertility, rapid increase in proportion of elderly person Dispersal of urban population decrease in rural green space

Increases in the proportion of elderly .75 years of age

Numerous foodtransforming technologies

Technologies create functional foods and food constituent substitutes (e.g., macronutrient substitutes)

Chiefly rural, move to cities increases, international migration begins, megacities develop Storage processes (drying, salting) begin, canning and processing technologies emerge, food refining and milling

Lower-density cities rejuvenate, increase in urbanization of rural areas encircling cities

a MCH denoted maternal and child health. As modified from Popkin BM. Global nutrition dynamics; the world is shifting rapidly toward a diet linked with noncommunicable diseases. Am J Clin Nutr 2006:83:289-298.

The association of egg consumption with CVD and diabetes was examined by conducting a meta-analysis of prospective cohort studies which included a total of 22 independent cohorts from 16 studies [44]. The number of participants ranged from 1600 to 90,735 and in follow-up time

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from 5.8 to 20.0 year. Comparison of the highest category ($1 egg/day) of egg consumption with the lowest (,1 egg/week or never) resulted in a pooled HR (95% CI) of 0.96 (0.88, 1.05) for overall CVD, 0.97 (0.86, 1.09) for CAD, 0.93 (0.81, 1.07) for stroke, 0.98 (0.77, 1.24) for CAD mortality, 0.92 (0.56, 1.50) for stroke mortality, and 1.42 (1.09, 1.86) for type 2 diabetes. However, egg consumption may be associated with an increased incidence of type 2 diabetes among the general population and CVD comorbidity among diabetic patients. Another meta-analysis of published prospective cohort studies was conducted to evaluate the relation of egg consumption with the risk of 2DM among 12 cohorts for a total of 219,979 subjects and 8911 cases of 2DM [45]. Comparing the highest with the lowest category of egg intake, pooled multivariate RRs of diabetes were 1.09 (95% CI: 0.99, 1.20) using the fixed-effect model and 1.06 (95% CI: 0.86, 1.30) using the randomeffect model. There was evidence for heterogeneity (I2 5 73.6%, P , .001). The stratification by geographic area, revealed, a 39% higher risk of diabetes (95% CI: 21%, 60%) comparing highest with lowest egg consumption in US studies (I2 5 45.4%, P 5 .089) and no elevated risk of diabetes with egg intake in non-US studies (RR 5 0.89; 95% CI: 0.79, 1.02 using the fixed-effect model, P , .001 comparing United States with non-US studies). In a dose-response assessment using cubic splines, elevated risk of diabetes was observed in US studies among people consuming $ 3 eggs/ week but not in non-US studies. The findings noted no relation between infrequent egg consumption and diabetes risk but suggests a modest elevated risk of diabetes with $ 3 eggs/week that is restricted to US studies. However, in determining associations, of egg intake with cardiometabolic diseases, principal components analysis is commonly used method to define dietary patterns using food consumption information to identify common underlying dimensions (factors or patterns) of food intake. The method aggregates specific food items based on the degree to which these food items are correlated with each other. A summary score for each pattern is then derived and can be used to examine relationships between various eating patterns and outcomes of interest such as CAD, diabetes mellitus, stroke and other chronic diseases. Earlier validation studies found that 2 major patterns (the prudent and Western patterns) identified through analysis of food consumption data assessed by food frequency questionnaires were reproducible over time and correlated reasonably well with the patterns identified from diet records [33,34]. The consistent association observed between the Western or unhealthy dietary pattern (high in animal products, particularly red meat and preserved meat as well as eggs, salty snacks, refined starches and sugar and fried foods, and low in fruits and vegetables) and ACS risk in different regions of the world from the INTERHEART study and other studies, provide consistent evidence of the adverse effects of globalization on human nutrition and NCDs risk. However, this evidence is indirect because these studies did not specifically assess the impact of global trade and marketing on food consumption patterns across different countries [31 33,41 49]. A meta-analysis of new onset heart failure following exposure to egg consumption was conducted among four prospective cohorts for a total of 105,999 subjects and 5,059 cases of new onset heart failure [50]. Comparing the highest ($1/day) to the lowest category of egg consumption, pooled RR of heart failure was 1.25 (95% CI: 1.12 1.39; P 5 .00). The findings suggests an elevated risk of incident heart failure with frequent egg consumption. Despite a few weaknesses, most recent studies suggest that the current trend of dietary convergence toward a typical Western diet rich in eggs, and red meat characterized with high ω-6/ω-3 ratio of fatty acids, low in flavonoids, fruits, vegetables, and nuts is likely to play a role in the globalization of obesity, diabetes, CVDs, and cancers [31 49]. It is possible that adding nuts and

REFERENCES

311

omega-3 fatty acids and flavonoids to modern foods might prevent the adverse effects of eggs and other unhealthy foods. In a recent meta-analysis, 12 studies were included, involving 9513 cases and 181,906 controls. Six of these were prospective cohort studies, and six were case-control studies [42]. The risk of breast cancer significantly decreased in women with high intake of flavonols (RR 5 0.88, 95% CI: 0.80 0.98) and flavones (RR 5 0.83, 95% CI: 0.76 0.91) compared with that in those with low intake of flavonols and flavones. Furthermore, summary RRs of three casecontrol studies stratified by menopausal status suggested flavonols, flavones, or flavan-3-ols intake is associated with a significant reduced risk of breast cancer in postmenopausal while not in premenopausal women. It seems that the intake of flavonols and flavones, but not other flavonoid subclasses or total flavonoids, is associated with a decreased risk of breast cancer, especially among postmenopausal women. It is possible that feeding tea leaves to hens may increase flavanols levels in eggs and meat of the hen which may be healthy. A recent randomized trial showed that dietary cholesterol from eggs appears to regulate endogenous synthesis of cholesterol in such a way that the LDL-C/HDL-C ratio is maintained [51]. In brief, it is possible that eating three eggs and more per week can increase the risk of diabetes in populations living in United States. However, in diabetic subjects and high risk populations for diabetes, may have greater risk of CVDs on eating three eggs or more in a week. The findings also revealed that egg consumption is not associated with the risk of CVD and cardiac mortality in the general population. A high egg intake may be associated with a modestly elevated risk of breast cancer, and a positive association between egg intake and ovarian and fatal prostate cancers cannot be ruled out. Feeding of flax seeds and tea leaves to hen may provide wild-type eggs and meat which may be healthy.

ACKNOWLEDGMENTS The authors would like to thank the International College of Cardiology for providing logistic support to write this article.

REFERENCES [1] WHO. Mortality and burden of disease estimates for WHO Member States in 2008. Geneva: World Health Organization; 2010. [2] Singh RB, Fedacko J, Vargova V, Kumar A, Mohan A, Pella D, et al. Singh’s verbal autopsy questionnaire for assessment of causes of death, social autopsy, tobacco autopsy, and dietary autopsy based on medical records and interview. Acta Cardiol 2011;66:471 81. [3] Hristova K, Pella D, Singh RB, et al. Sofia declaration for prevention of cardiovascular diseases and type 2 diabetes mellitus: a scientific statement of the international college of cardiology and international college of nutrition; ICC-ICN Expert Group. World Heart J 2014;6:89 106. [4] Cordain Loren, Eaton SB, Sebastian A, Mann N, Lindeberg S, Watkins BA, et al. Origins and evolution of the Western diet: health implications for the 21st century. Amer J Clin Nutrition. 2005;81(2):341 54 PMID 15699220.

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[5] Kris Etherton PM, Taylor DS, Yu-Poth S, Huth P, Moriarty K, Fischel v, et al. Polyunsaturated fatty acids in food chain in United States. Am J Clin Nutr 2000;71(1):179S 88S. [6] Christophersen OA, Haugh A. Animal products, diseases and drugs: a plea for better integration between agricultural sciences, human nutrition and human pharmacology. Lipids Health Disease 2011;10:16. Available from: https://doi.org/10.1186/1476-571x-10-16. [7] Simopoulos AP. New products from the agri-food industry: the return of n-3 fatty acids into the food supply. Lipids 1999;34(Suppl):S297 301. [8] Cordain L, Eaton SB, Brand Miller J, Mann N, Hill K. The paradoxical nature of hunter-gatherer diets: meat based, yet non-atherogenic. Eur J Clin Nutr 2002;56(Suppl):S42 52. [9] DeMeester F. Wild-type land based food in health promotion and disease prevention. TheColumbus Concept. In: De Meester F, Watson RR, editors. Wild type food in health promotion and disease prevention. Totova, NJ: Humana Press; 2008. p. 3 20. [10] De Meester F. Progress in lipid nutrition. In: Simopoulos AP, De Meester F, editors. A balanced omega6/omega-3 fatty acid ratio. Cholesterol and coronary heart disease. World Rev Nutr Diet, 100. Basel: Karger; 2009. p. 110 2. [11] Singh RB, Kumar A, Neki NS, Pella D, Rastogi SS, Basu TK, et al. Diet and lifestyle guidelines and desirable levels of risk factors for prevention of cardiovascular disease and diabetes among elderly subjects. A revised scientific statement of the International College of Cardiology and International College of Nutrition-2011. World Heart J 2011;3:305 20. [12] Carrera-Bastos P, Fintess-Villaba M, O’Keefe JH, Lindeberg S, Cordain L. The Western diet and life style and diseases of civilization. Clin Cardiol 2011;2:15 35. [13] Singh RB, Takahashi T, Nakaoka T, Otsuka K, Toda E, Shin HH, et al. Nutrition in transition from Homo sapiens to Homo economicus. Open Nutra J 2013;6:6 17. [13a] To da E, Singh RB, Takahashi T, Alam SE, De Meester F, Wilczynska A, et al. Paleolithic-style diet and coronary artery disease: the tissue is the issue? Am Med J 2012;3(2):183 93. ISSN 1949-0070 r 2012 Science Publications. [14] Sotos-Prieto M, Bhupathiraju SN, Mattei J, fung TT, Li Y, Pan A, et al. Association of changes in diet quality with total and cause-specific mortality. N Engl J Med 2017;377:143 53. Available from: https:// doi.org/10.1056/NEJMoa1613502. [15] George SM, Ballard-Barbash R, Manson JE, et al. Comparing indices of diet quality with chronic disease mortality risk in postmenopausal women in the Women’s Health Initiative Observational Study: evidence to inform national dietary guidance. Am J Epidemiol 2014;180:616 25. [16] Harmon BE, Boushey CJ, Shvetsov YB, et al. Associations of key diet-quality indexes with mortality in the Multiethnic Cohort: the Dietary Patterns Methods Project. Am J Clin Nutr 2015;101 587 97. [17] Reedy J, Krebs-Smith SM, Miller PE, et al. Higher diet quality is associated with decreased risk of allcause, cardiovascular disease, and cancer mortality among older adults. J Nutr 2014;144:881 9. [18] Yu D, Sonderman J, Buchowski MS, et al. Healthy eating and risks of total and cause-specific death among low-income populations of African-Americans and other adults in the southeastern United States: a prospective cohort study. PLoS Med 2015;12(5):e1001830. [19] Boggs DA, Ban Y, Palmer JR, Rosenberg L. Higher diet quality is inversely associated with mortality in African-American women. J Nutr 2015;145:547 54. [20] Akbaraly TN, Ferrie JE, Berr C, et al. Alternative Healthy Eating Index and mortality over 18 y of follow-up: results from the Whitehall II cohort. Am J Clin Nutr 2011;94:247 53. [21] Atkins JL, Whincup PH, Morris RW, Lennon LT, Papacosta O, Wannamethee SG. High diet quality is associated with a lower risk of cardiovascular disease and all-cause mortality in older men. J Nutr 2014;144:673 80.

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[22] Fung TT, Rexrode KM, Mantzoros CS, Manson JE, Willett WC, Hu FB. Mediterranean diet and incidence of and mortality from coronary heart disease and stroke in women. Circulation 2009;119:1093 100. [23] Estruch R, Ros E, Salas-Salvado´ J, et al. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med 2013;368:1279 90. [24] Mursu J, Steffen LM, Meyer KA, Duprez D, Jacobs Jr DR. Diet quality indexes and mortality in postmenopausal women: the Iowa Women’s Health Study. Am J Clin Nutr 2013;98:444 53. [25] Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics— 2015 update: a report from the American Heart Association. Circulation 2015;131(4):e29 322. [26] De Lorgeril M, Salen P. New insights into the health effects of dietary saturated and omega-6 and omega-3 polyunsaturated fatty acids. BMC Med 2012;10(50). Available from: https://doi.org/10.1186/ 1741-7015-10-50. [27] Pella D, Singh RB, Otsuka K, Chiang CA, Joshi SR. Nutritional predictors and modulators of insulin resistance. J Nutr Environ Med 2004;14(1):3 16. [28] Singh RB, Fadecko J, Pellad D, De Meester F, Moshiri M, Aroussy WE. Superfood dietary approaches for acute myocardial infarction. World Heart J 2010;2:13 23. [29] Kastorini CM, Milionis HJ, Esposito K, Giugliano D, Goudevenos JA, Panagiotakos DB. The effect of Mediterranean diet on metabolic syndrome and its components. JACC 2011;57:1299 313. [30] Sofi F, Abbate R, Gensini GF, Casini A. Accruing evidence about benefits of adherence to Mediterranean diet on health: an updated systematic review with meta-analysis. Am J Clin Nutr 2010. Available from: https://doi.org/10.3945/ajcn.2010.29673. [31] Gardener H, Wright CB, Gu Y, Demmer RT, Boden-Albala D, Alkind MSV, et al. Mediterranean style diet and risk of ischemic stroke, myocardial infarction and vascular death: the Northern Manhattan Study. Am J Clin Nutr 2011;94:1458 64. [32] Heidemann C, Schulze MB, Franco OH, et al. Dietary patterns and risk of mortality from cardiovascular disease, cancer, and all causes in a prospective cohort of women. Circulation 2008;118:230 7. [33] Trichopolou A, Bamia C, Trichopolou D. Anatomy of health effects of Mediterranean diet. Greek EPIC prospective cohort study. BMJ 2009;338:b2337. Available from: https://doi.org/10.1136/bmj.b2337. [34] Iqbal R, Anand S, Ounpuu S, et al. Dietary patterns and the risk of acute myocardial infarction in 52 countries. Circulation 2008;118:1929 37. [35] Singh RB, Dubnov G, Niaz MA, Ghosh S, Singh R, Rastogi SS, et al. Effect of an Indo-Mediterranean diet on progression of coronary disease in high risk patients: a randomized single blind trial. Lancet 2002;360:1455 61. [36] de Lorgeril M, Renaud S, Mamelle N, Salen P, Martin JL, Monjaud I, et al. Mediterranean alphalinolenic acid-rich diet in secondary prevention of coronary heart disease. Lancet 1994;343 (8911):1454 9. Erratum in: Lancet 1995,345 (8951):738. [37] Burr ML, Fehily AM, Gilbert JF. Effects of changes in fat, fish and fibre intakes on death and myocardial infarction: diet and Reinfarction Trial(DART). Lancet 1989;757 61 ii. [38] Singh RB, Rastogi SS, Verma R, Laxmi B, Singh R, Ghosh S, et al. Randomized, controlled trial of cardioprotective diet in patients with acute myocardial infarction: results of one year follow up. BMJ 1992;304:1015 19 59.40. [39] Lindeberg S. Food and western disease: health and nutrition from an evolutionary perspective. Chichester, UK: Wiley-Blackwell; 2010. [40] Eaton SB, Eaton SB III, Sinclair AJ, Cordain I, Mann NJ. Dietary intake of long chain polyunsaturated fatty acids during the Paleilithic period. In Simopoulos AP edition. The return of w-3 fatty acids in the food supply. Land based Animal Food Products and their Health Effects. World Rev Nutr Dietetics 1998;83:12-23.

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[41] Si R, Qu K, Jiang Z, Yang X, Gao P. Egg consumption and breast cancer risk: a meta-analysis. Breast Cancer 2014 May;21(3):251 61. Epub 2014 Feb 7. [42] Keum N, Lee DH, Marchand N, Oh H, Liu H, Aune D, et al. Egg intake and cancers of the breast, ovary and prostate: a dose-response meta-analysis of prospective observational studies. Br J Nutr 2015 Oct 14;114(7):1099 107. Epub 2015 Aug 21. [43] Rong Y, Chen L, Zhu T, Song Y, Yu M, Shan Z, et al. Egg consumption and risk of coronary heart disease and stroke: dose-response meta-analysis of prospective cohort studies. BMJ 2013 Jan 7;346:e8539. Epub 2013 Jan 7. [44] Shin JY, Xun P, Nakamura Y, He K. Egg consumption in relation to risk of cardiovascular disease and diabetes: a systematic review and meta-analysis. Am J Clin Nutr 2013 Jul;98(1):146 59. Epub 2013 May 15. [45] Djouss´e L, Khawaja OA, Gaziano JM. Egg consumption and risk of type 2 diabetes: a meta-analysis of prospective studies. Am J Clin Nutr 2016 Jan 6; pii: ajcn119933. [Epub ahead of print]. [46] Hui C, Qi X, Qianyong Z, Xiaoli P, Jundong Z, Mantian M. Flavonoids, flavonoid subclasses and breast cancer risk: a meta-analysis of epidemiologic studies. PLoS One 2013;8(1):e54318. Epub 2013 Jan 18. [47] Popkin BM. Global nutrition dynamics; the world is shifting rapidly toward a diet linked with noncommunicable diseases. Am J Clin Nutr 2006;83:289 98. [48] Keum N, Greenwood DC, Lee DH, Kim R, Aune D, Ju W, et al. Adult weight gain and adiposityrelated cancers: a dose-response meta-analysis of prospective observational studies. J Natl Cancer Inst 2015 Mar;107(3). Epub 2015 Jan 24. [49] Wang DD, Li Y, Chiuve SE, Hu FB, Willett WC. Improvements in US diet helped reduce disease burden and lower premature deaths, 1999-2012; overall diet remains poor. Health Affairs (Millwood) 2015;34(11):1916 22. [50] Khawaja O, Singh H, Luni F, Kabour A, ali SS, Taleb M, et al. Egg consumption and incidence of heart failure: a meta-analysis of prospective cohort studies. Front Nutr 27 March 2017. Available from: https://doi.org/10.3389/fnut.2017.00010. [51] Lemos BS, Medina-Vera I, Blesso CN, Fernandez ML. Intake of 3 eggs per day when compared to a choline bitartrate supplement, downregulates cholesterol synthesis without changing the LDL/HDL ratio. Nutrients 2018;10(2):258. Available from: https://doi.org/10.3390/nu10020258.

CHAPTER

COCOA CONSUMPTION AND PREVENTION OF CARDIOMETABOLIC DISEASES AND OTHER CHRONIC DISEASES

19

Anna Gvozdjakova1, Reema Singh2, Ram B. Singh2, Toru Takahashi3, Jan Fedacko4, ´ Krasimira Hristova5, Agnieszka Wilczynska6, Maria Mojtova´ 7 and Viliam Mojto1 1

Pharmacobiochemical Laboratory of 3rd Internal Clinic Faculty of Medicine, Comenius University in Bratislava, Bratislava, Slovakia 2Halberg Hospital and Research Institute, Moradabad, Uttar Pradesh, India 3Graduate School of Human Environment Science, Fukuoka Women’s University, Japan 4Faculty of Medicine, PJ Safaric University, Kosice, Slovakia 5Department of Noninvasive Functional Diagnostic and Imaging, University National Heart Hospital, Sofia, Bulgaria 6Krakow University, Krakow, Poland 7St Elizabeth University of Science and Social Work, Bratislava, Slovak

19.1 INTRODUCTION Noncommunicable diseases (NCDs), such as cardiovascular disease (CVD), coronary artery disease (CAD) and stroke, diabetes mellitus, cancer, and neuropsychiatric diseases, remain the leading cause of morbidity and mortality worldwide [1,2]. The global prevalence of diabetes is rising progressively and is estimated to increase from 366 million cases in the year 2011 to 552 million cases in 2030 [3]. These cardiometabolic diseases (CMDs) need effective prevention guidelines to improve public health and to relieve the social and economic burdens of NCDs. Nutritional factors and other lifestyle elements involved in the prevention and control of CMDs should be evaluated to provide functional foods for prevention and management of these diseases. Chocolate is rich in cocoa which is a potential antioxidant used by the food industry to provide flavor and is a highly popular dietary food throughout the world. Recently, cocoa and chocolates containing cocoa have gained increasing attention for their potential benefits in CMDs [4 10]. A number of experimental and clinical studies have indicated a protective role of chocolate against oxidative stress, inflammation, endothelial dysfunction, and atherogenesis [4]. In recent meta-analyses of feeding trials, the beneficial effects of cocoa and cocoa containing foods have been emphasized, supporting the favorable impact of cocoa consumption on CMDs, blood pressure (BP), lipid profiles, flow-mediated dilatation (FMD), and insulin sensitivity and diabetes [5 10]. There is consistence evidence that cocoa consumption can improve vascular function, but the evidence showing reduced risk of CMDs is weaker. However, the overall results on the role of cocoa in CMDs remain inconclusive. The beneficial effects of hot chocolate on health and NCDs are considered secondary, although

The Role of Functional Food Security In Global Health. DOI: https://doi.org/10.1016/B978-0-12-813148-0.00019-0 © 2019 Elsevier Inc. All rights reserved.

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these are recently reported in the world class journals. However, cocoa chocolate is consumed mainly for taste and flavor in most of the countries of the world. This review aims to highlight pertinent prospective studies to comprehensively evaluate the role of chocolate in prevention of CMDs.

19.2 HISTORICAL VIEW ON COCOA The 16th century explorers and early civilizations considered cocoa an enjoyable drink [1]. Cocoa was admired by the Emperor Montezuma (16th century),who named it a divine drink. Cocoa can increase the resistance of body and inhibits fatigue and a single cup of cocoa drink may allow a man to work throughout the day [11]. The botanical name of the cocoa tree is Theobroma cacao, derived from the Greek words theo (god) and broma (drink), and therefore Incas considered it, the drink of gods [12]. In Honduras, archeologists uncovered elaborately designed bowls that are believed to have been used by the Aztecs to drink liquid cocoa thousands of years ago [12 14]. In the language of the Aztecs (Nahuatl) this drink was called chocolatl (“xocolatl” comprising “xococ” (sour or bitter) and “atl” meaning water or drink from the cocoa tree). However, T. cacao was known much earlier, perhaps originally consumed by the Paleo-tribal Indian gatherers of Mesoamerica as an infusate. The evidence regarding cocoa consumption by Incas, Aztecs, and Mayans is abundant and early consumption can be traced to the Mokaya and other pre-Olmec people. Cacao beverages date back even earlier (1900 BC) [12 14]. Recent studies indicate that it has beneficial biochemical and clinical effects as well as being an enjoyable drink. In the 19th and for a large part of the 20th century, chocolate was considered a luxury item and its consumption was considered to have adverse effects on health because it was sugar-sweetened which is a part of Western diet and lifestyle [11]. Western diet in conjunction with ordinary chocolate intake may be associated with dental caries, obesity, high BP, and diabetes; hence many physicians currently tend to warn patients about the potential health hazards of consuming large amounts of chocolate-based energy rich foods [11,15]. Native Indians were consuming as a unsweetened drink of raw and dried cocoa powder which is rich in polyphenolic flavonoids [11 14]. The product was sweetened after it was commercialized in European countries. Other processing methods were used by the food industry to decrease its bitterness and to achieve European taste and flavor. The flavanol content of cocoa, which is most likely polyphenolic having potential antioxidant effects, were reduced due to this modification. It seems that all chocolates with cocoa are not equal in bioactivity. A high cocoa consumption by native Indians could be difficult with presently available chocolate products. The cocoa products should be duly fortified and bioactivity examined to achieve more effective highly bioavailable cocoa chocolates. Further studies are needed on its (plant) epidemiology and manufacturing to demonstrate if there are any interactions with co-ingredients.

19.3 BENEFICIAL EFFECTS OF COCOA In Kuna Indians, a native population living on islands off the coast of Panama, cocoa was consumed for its protective effects. The Kuna belong to one of the few cultures that are protected against the age-dependent increase in BP and the development of arterial hypertension. The recent

19.3 BENEFICIAL EFFECTS OF COCOA

319

discovery of biologically active phenolic compounds in cocoa has changed the above perception and stimulated research on its effects on various biological markers: oxidative stress, blood lipids, insulin resistance, BP, atherosclerosis and ageing [5,16 23]. Cocoa flavonol appears to have potential beneficial effects against the risk of, metabolic syndrome, hypertension, blood lipids, stroke, CAD, cancer, cognitive function, and dementia [5,16 34]. Polyphenolics including flavonoids share a common chemical structure: C6-C3-C6 (Figs. 19.1 and 19.2). Flavonoids can be classified into: flavonols, flavones, isoflavones, flavanones, anthocyanidins, and flavanols [35 38]. Fruits and vegetables are rich sources of flavanols (also called flavan-3-ols) which are well known to provide protective effects against deaths due to NCDs [15]. Cocoa is consumed as chocolates, cakes, biscuits, and bread but the highest content is present in bread Table 19.1. Flavanols occur as the monomers epicatechin and catechin, which are the main flavanols in fruits [35 37]. These

FIGURE 19.1 Cocoa fruit and leaves.

FIGURE 19.2 Effects of cocoa epicatechin on biomarkers of health and disease.

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CHAPTER 19 COCOA CONSUMPTION

monomers can form links between C4 and C8, allowing them to assemble as dimers, oligomers, and polymers of catechins, the so-called procyanidins [27]. Procyanidins are also known as condensed tannins, which, through the formation of complexes with salivary proteins, are responsible for the bitterness of cocoa [35]. Major sources of flavonols are certain teas, grape juice, wine, various berries, and especially cocoa (Table 19.2).

19.4 PHARMACOKINETICS The flavanol content and the total antioxidant capacity in plasma increase after oral consumption of flavonol [25,26]. However, if cocoa is consumed with milk or if cocoa is ingested as milk chocolate, these effects appear to be markedly reduced, but the finding is controversial [28 30]. Table 19.1 Nutrient Composition of Cocoa and Chocolates Nutrient

Cocoa

Chocolates

Flavonoids, μg/g Flavanols 1 procyanidins, μg/g Falvanol (catechin, epicatechin), μg/g Axtioxidant activity (ORAC), mmol Trolox equivalents Total fat, g/g Total carbohydrates, g/g Total proteins, g/g Total Cholesterol, mg/g

200 1055 (dry powder) 1400 (Cocoa liquor) 336 956 (dry powder) 40 (Cocoa liquor) 0.045 (dry powder) 0.070 (dry powder) 0.080 (dry powder) ,3 (dry powder)

700 1700 460 610 6.7 13 0.326 0.587 0.004 0.1

ORAC, oxygen radical absorbance capacity (Ref. [9 12]).

Table 19.2 Flavonoid Contents in Various Foods Foods Beans Apricots Cherries Peaches Blackberries Apples Green tea Black tea Red wine Cider Chocolate

Flavanol Content (mg/kg or mg/L) 350 550 100 250 50 220 50 140 130 20 120 100 800 60 500 80 300 40 460 610

19.5 MECHANISMS OF ACTION

321

The highest plasma peak concentrations of flavanols are obtained 2 3 hours after ingestion in a dose-dependent manner and are still measurable after 8 hours [28,31,32]. The smaller the polyphenol is, the higher the concentration in blood, so it is the molecular size of the flavonol that also matters. A single measurement of plasma levels at 2 hours may be a check for compliance [33]. There is limited usefulness of this measure in finding out the bioavailability and bioactivity of flavonols. The metabolic conversion of flavonols in the intestinal cells, liver, and other tissues; their binding to proteins; their accumulation in cells; and the urinary elimination rate are important to find out bioactivity [33,34]. The quantity of flavanols markedly decreases during the conventional chocolate manufacturing process from fresh cocoa seeds to the final product [35]. Roasting and fermentation may also reduce the final flavanol content of foods and the flavanol concentrations may depend on the soil in which the plant is grown [36]. It should be noted that milk chocolate has the lowest flavanol content compared with cocoa powder and dark chocolate [37].

19.5 MECHANISMS OF ACTION The potential mechanisms of actions of cocoa flavanols on various body systems to provide benefits against CMDs have been explored (Fig. 19.3). Inhibition of free radical stress, activation of nitric oxide (NO), antiplatelet and antiinflammatory effects are important mechanisms of actions of cocoa flavonols. These actions may improve endothelial function, lipid levels, BP, and insulin resistance, resulting in better clinical outcomes [39]. Among these beneficial effects of cocoa, the improvement in endothelial function, characterized with a continuous, smooth, nonthrombogenic surface of all blood vessels that exhibit a highly selective permeability in their healthy state, appears to be most important. The endothelium synthesizes and releases a broad range of vasoactive substances. The structural atherosclerotic changes may develop long after functional impairment of the vascular endothelium in response to injury by the oxidants and toxicants which impair the release of NO, synthesized by endothelial NO synthase (eNOS) from L-arginine, in the

FIGURE 19.3 Mechanism of action of cocoa epicatechin showing release of nitric oxide.

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presence of the cofactor the tetrahydrobiopterin [40]. The circulating blood or receptor ligand substances such as acetylcholine, bradykinin, or serotonin induce shear stress responsible for the release of NO from the endothelial cells [41]. NO causes vasodilation as well as inhibits adhesion of leukocyte and migration, smooth muscle cell proliferation, and prevents platelet dysfunction. Decrease in eNOS expression and/or NO bioavailability may result in dysfunction of the endothelium predisposing to atherothrombosis [42] (Fig. 19.4). After diffusion from endothelial to vascular smooth muscle cells, within a few seconds it augments intracellular cGMP levels and leads to relaxation of vascular smooth muscle cells [43]. Epidemiological studies indicate that forearm endothelial dysfunction is predictive of coronary vascular dysfunction and predisposes future coronary events [44 46]. There is evidence that increased consumption of flavanol-rich red wine, black tea, and green tea can enhance endothelial function among patients with CAD [47 50]. An experimental study in rats indicated that cocoa can induce NO-dependent vasodilation [51]. Cocoa can also cause vasodilation in the finger or forearm circulation of healthy subjects [52 54] and among patients with coronary risk factors including diabetes mellitus [55 59] (Table 19.3). High flavanol diet on long-term consumption may cause an increased release of NO metabolites consistent with an augmented NO production or diminish its degradation [54]. Epicatechins are known to closely mimic the vascular effects of flavanol-rich cocoa in humans, indicating that these antioxidants represent the primary mediator of the beneficial effect of cocoa flavanols on vascular function [54]. In vitro experiments in cultured endothelial cells and rat aorta indicate that plant extracts rich in flavanoids enhance eNOS activity [60 62]. Further study showed that incubation of endothelial cells with flavonoidrich red wine upregulates eNOS mRNA and protein expression, most likely via stabilization of OH OH O

HO

OH OH

Epicatechins Inhibit inflammation

Blood pressure reduction

Improved vascular function Reduced platelet reactivity

FIGURE 19.4 Effects of epicatechin on clinical and biochemical risk factors.

Improved insulin sensitivity

19.5 MECHANISMS OF ACTION

323

Table 19.3 Effects of Cocoa on Endothelial Function Authors

Year

n

Karim et al. 77

2000

5

Fisher et al.78

2003

Engeler et al.79

Animals/ Patient

Duration

Intervention

Outcome

Arotic rings from rats

Immediately

Procyanidins derived from cocoa

27

Healthy people

5d

Flavanol-rich cocoa (821 mg/d)

2004

21

Healthy subjects

2 wk

Schroeter et al.80

2006

16

Healthy subjects, isolated rabbit rings

High-flavonoid chocolates (213 mg procyanidins,46 mg epicatechin) versus low-flavonoid chocolate Drink with high flavonoid content

Endothelium-derived relaxation mediated by activation of NOS Peripheral vasodilatation, improvement in vasodilator response to ischemia assessed by pulse-wave amplitude on the finger Improvement in flow mediated vasodilatation of the brachial artery, increase in epicatechin concentrations

Heiss et al.81

2003

26

Patients with at least 1 CV risk factor

2h (crossover)

Flavanol-rich cocoa drink (100 ml)

Hermann et al.82

2006

20

Healthy smokers

2h

40 g commercially available dark chocolate versus white chocolate

Grassi et al.83

2005

20

Patients with untreated essential hypertension

15d (crossover)

100 g dark chocolate (21.91 mg catechin,65.97 mg epicatechins) versus flavanol free white chocolate

Improvement in flowmediated vasodilatation paralleled the appearance of flavanols in plasma; enough to mediate ex vivo vasodilatation; pure epicatechins mimic vascular effects of cocoa; high-flavanol diet causes high urinary excretion of NO metabolites Improvement in flowmediated vasodilatation, increase in levels of nitrosated and nitrosylated species Increase in flowmediated vasodilatation of the brachial artery, improvement in antioxidant status and platelet function Increase in flowmediated vasodilatation of the brachial artery, decrease in blood pressure and LDL cholesterol, increase in insulin sensitivity. (Continued)

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CHAPTER 19 COCOA CONSUMPTION

Table 19.3 Effects of Cocoa on Endothelial Function Continued Authors

Year

n

Animals/ Patient

Heiss et al.85

2005

11

Balzer et al.86

2008

Flammer et al.54

Duration

Intervention

Outcome

Smokers

2h (crossover)

41

Diabetes

4 wk

100 ml cocoa drink with high (17618 mg) or low (,11 mg) flavanol content Drink with high flavanol content

2007

22

Heart transplant recipients

2h

Grassi et al.84

2008

19

2 wk

Shina et al.87

2009

39

Hypertensives, impaired glucose tolerance patients Healthy subjects

Grassi et al.88

2012

12

healthy volunteers

3 days

Increase in flowmediated vasodilatation and circulating NO pool, increase in flavanol metabolites Improvement in flowmediated vasodilatation (acute and chronic) Induction of coronary vasodilation, improvement in coronary endothelial function and platelet function Improvement in flowmediated vasodilatation, insulin sensitivity, β-cell function, and blood pressure Improvement in coronary circulation as measured by coronary velocity flow reserve Improved flow-mediated dilation, wave reflections, and endothelin-1

2 wk

40 gm commercially available dark chocolate versus flavonoid-free placebo chocolate Flavanol-rich dark chocolate

45 gm commercially available dark chocolate versus white chocolate 100 g/d dark chocolate

eNOS mRNA [63]. It is known that endothelial cells can produce up to three-fold more bioactive NO compared to control cells [63]. Similarly, cocoa flavanols can induce NOS in vitro and can lower vascular arginase activity in human endothelial cells in vitro, thus augmenting the local levels of L-arginine [64,65]. Further studies indicate that epicatechin elevates NO in endothelial cells via inhibition of NADPH oxidase [66] and pure dietary flavonoids quercetin and epicatechin augment NO products and reduce endothelin-1 acutely in healthy men [67]. A recent study [32] indicates that low-dose epicatechin, which does not have significant antioxidant activity, may be also protective. The mechanism by which low-dose epicatechin induces this effect is unknown. It is possible that low-dose epicatechin mediates cardiac protection via opioid receptor activation. In this experimental study among C57BL/6 mice, there were 10 groups with a control group. Administration of epicatechin (1 mg/kg) or other inhibitors (5 mg/kg) was done by oral gavage or intraperitoneal injection, respectively, daily for 10 days. In the experiment, coronary artery occlusion was induced for 30 minutes followed by 2 hours of reperfusion, and infarct size was determined via planimetry. Compared with control mice, there was a significant decrease in infarct size in epicatechin- and epicatechin 1 nor-BNI-treated mice. Naloxone, naltrindole, and

19.7 CLINICAL STUDIES

325

5-HD were able to block this protection. Epicatechin and epicatechin 1 nor-BNI increased the phosphorylation of Src, Akt, and IκBα. There was a concurrent decreasing effect on the expression of c-Jun NH2-terminal kinase and caspase-activated DNase. These results are consistent with opioid receptor stimulation and subsequent cardiac protection. The effects were attenuated by naloxone, naltrindole, and 5-HD attenuated. It is clear that action of epicatechin is mediated by the opioid receptors, possibly through the δ-opioid receptor to produce cardiac protection from ischemiareperfusion injury. These beneficial effects of cocoa and dark chocolate have been observed also in the epidemiological studies [68 74].

19.6 PLATELET DYSFUNCTION Platelet dysfunction may predispose atherothrombotic vascular disease. Apart from providing micronutrients, certain fruits and vegetables and legumes rich in polyphenolics and flavonoids may also protect against thrombosis [15,75]. The antiplatelet effects of cocoa have been demonstrated in many studies [76 78]. Within hours of ingestion, cocoa decreases ADP/collagen activated, platelet-related primary hemostasis. The antiplatelet effects may be explained, at least in part, by a reduction in the ADP-induced expression of the activated conformation of glycoprotein IIb/IIIa surface proteins. In vitro experiment indicates that catechin and epicatechin reduce glycoprotein IIb/ IIIa expression, thereby exerting antiplatelet effects [67]. In a clinical study among healthy volunteers, 100 g dark chocolate intake reduced platelet aggregation [79]. This effect was not observed among subjects eating white chocolate or milk chocolate [79]. Cocoa decreases platelet aggregation as well as platelet adhesion [79 82]. Dark chocolate intake among young healthy smokers may decrease platelet adhesion as assessed by a shear stress-dependent platelet test [82]. Stearic acid, a saturated fat found in Indian clarified butter as well as in chocolate, reduces mean platelet volume, an index of platelet activation, in humans [80,81].

19.7 CLINICAL STUDIES Epidemiological studies, in particular observations in native Kuna Indians living on Central American islands, suggest that cocoa-rich products reduce cardiovascular mortality [15,68 70]. The Kunas consume enormous amounts of cocoa daily which may be rich in salt similar to Indian rural populations with enormous physically demanding occupations. Clinical studies revealed that the Kunas indeed have lower BP values and no age-dependent decline in kidney function [69,70]. Randomized controlled trials (RCTs) and cohort studies further confirm that polyphenolic antioxidant flavonoid consumption can be beneficial in CMDs and degenerative diseases of the brain. It is believed that the high content of polyphenolic antioxidants in some fruit, vegetables, whole grains, nuts, dark chocolate, and tea may contribute to their cardioprotective effects. In a recent study [15], death records of 2222 (1385 men and 837 women) decedents, aged 25 64 years, were examined. Causes of death, clinical data, and food intakes were assessed using data from verbal autopsy questionnaires. Compared to deaths due to NCD, the scores for intake of prudent foods—fruits, vegetables, whole grains, nuts, chocolate—were significantly higher and the ratio of omega-6/omega-3

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fatty acids of the diet significantly lower for deaths due to accidents. After adjustment for age, regression analysis revealed that Western type foods (1.02; 0.95 1.09 men; 1.00; 0.94 1.06 women); meat and eggs(1.00; 0.94 1.06 men; 0.98; 0.93 1.04 women) and refined carbohydrates (0.98; 0.91 1.05 men, 0.95; 0.89 1.02 women) and high omega-6/omega-3 ratio of fatty acids were positively associated whereas total prudent foods (OR,CI: 1.11;1.06 1.18 men; 1.09;1.04 1.16 women) as well as fruits, vegetables, legumes, and nuts (1.07; 1.02 1.12 men; 1.05; 1.99 1.11 women) were independently, inversely associated with deaths due to NCDs. The findings indicated that polyphenolic flavanoids and omega-3 fatty acids may be protective against deaths due to NCDs. The Zutphen Elderly Study [24] in a cross-sectional analysis, reported that cocoa consumption was inversely related to BP. In a prospective analysis, the study showed that intake of cocoa was associated with a reduction of cardiovascular and all-cause mortality [24]. Among 470 elderly men free of chronic diseases, this report highlighted the protective effects of cocoa intake. After adjustment for age, body mass index, lifestyle factors, drug use, food, and caloric intake, the risk of cardiovascular mortality for men in the highest tertile of cocoa intake was reduced by 50% compared with the lowest tertile (P 5 .004).The adjusted relative risk (RR) for allcause mortality was 0.53 (95% CI: 0.39 0.72; P 5 .001). In the native population, mortality resulting from cardiovascular events is significantly lower compared with other Pan-American citizens (9.2 3.1 vs 83.4 0.7 age-adjusted deaths per 100,000) [61]. It is possible that the factors involved are environmental rather than genetic because this protection is lost on migration to urban Panama City, where other cocoa food products with a lower flavanol content are used [69]. In the Iowa Women’s Health Study [72], among 34,489 postmenopausal women who were free of CVDs were examined. After 16 years of follow-up, foods rich in flavonoids were associated with a decreased risk of death caused by CAD. There was a significant inverse association between chocolate consumption and CVDs mortality after multivariate adjustment. Cocoa is highly rich in flavonoids—catechin, epicatechin, and procyanidins—which predominate in antioxidant activity [73]. The tricyclic structure of the flavonoids determines antioxidant effects that scavenge reactive oxygen species (ROS), chelate Fe2 1 and Cu 1 , inhibit enzymes, and upregulate antioxidant defenses. The epicatechin content of cocoa upregulates NO production, this is primarily responsible for its favorable impact on vascular endothelium. Other beneficial effects are mediated through antiinflammatory effects of cocoa polyphenols, and modulated through the activity of NF-κB. Cocoa can stimulate changes in redox-sensitive signaling pathways involved in gene expression and the immune response. It may also protect neurons from injury and inflammation as well as protect the skin from oxidative damage from UV radiation in topical preparations. Cocoa consumption has beneficial effects on satiety, cognitive function, and mood and regular intake has been found to improve cognitive function in elderly subjects with mild memory dysfunction, which is mostly due to (micro-)vascular dysfunction [11,33].

19.8 OBESITY The commercially available chocolates in the market have high fat content which may enhance dietary energy intake leading to obesity and dyslipidemia [30,31]. An excess intake of energy via such

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chocolate (about 500 kcal/100 g) may predispose gain in weight, that is a risk factor for hypertension, stroke, dyslipidemia, CAD, and diabetes. However, a study in 49 healthy women showed no weight gain after daily consumption of 41 g chocolate, 60 g almonds, or almonds and chocolate together for 6 weeks [30]. It is possible that weight gain may occur only with higher amounts of daily chocolate intake with very high fat content. In this study, the primary objective was to identify potentially synergistic or additive effects of combining consumption of dark chocolate with almonds as part of a low-fat diet on serum lipids and pro-inflammatory biomarkers of obesity and atherosclerosis. The biomarkers were intercellular adhesion molecule (ICAM), vascular adhesion molecule, and high-sensitivity C-reactive protein. The duration of the study was 6 weeks among 49 women with normal serum cholesterol, and a four-armed parallel design was used. Women were randomized to one of three treatments: chocolate (41 g/d), almonds (60 g/d), chocolate and almonds, or control (no chocolate or almonds). All women improved dietary intakes in accordance with guidelines, and no subjects gained or lost weight. Serum cholesterol concentrations showed no changes after 6 weeks; however, triacylglycerol levels were reduced by approximately 21%, 13%, 19%, and 11% (P , .05), in the chocolate, almond, chocolate and almond, and control groups, respectively. Circulating ICAM levels decreased significantly by 10% in the treatment group consuming chocolate only (P 5 .027). Vascular adhesion molecule and high-sensitivity C-reactive protein levels showed no abnormality in any treatment group. It seems, that the consumption of chocolate and almonds as part of the Therapeutic Lifestyle Changes diet for 6 weeks showed no harmful effects in healthy women; all dietary modifications improved serum triacylglycerol levels, and consumption of chocolate, reduced the levels of circulating ICAM.

19.9 INSULIN RESISTANCE, DIABETES MELLITUS, AND VASCULAR DISEASE The antioxidant activity of cocoa may directly influence insulin resistance by protecting beta cells of pancreas against free radicals resulting in increased insulin release. Decrease in insulin resistance in turn, reduces the risk for type 2 diabetes mellitus. However, as cocoa is predominantly consumed as energy-dense chocolate, potential detrimental effects of overconsumption exist, including increased risk of weight gain. Overall, research to date suggests that the benefits of moderate dark chocolate consumption or cocoa intake is likely to outweigh the risks of increased energy intake and sugar-induced hyperglycemia, oxidative stress, hypertriglyceridemia, and free fatty acids. It seems that chocolate’s potential benefits should be explored in outcome studies looking at these biomarkers and NCDs—diabetes mellitus, dementia, heart attack, stroke, cancer, and death [5,12 18]. The overall prognosis among patients with diabetes mellitus is unfavorable due to deteriorated cardiovascular function, despite optimal control of hyperglycemia by optimal drug therapy [59]. Epidemiological data indicate that diets rich in flavanols are associated with a reduced cardiovascular risk. This study examined the feasibility and efficacy of a dietary intervention based on daily intake of flavanol-containing cocoa for improving vascular function of patients with type 2 diabetes patients on optimal drug therapy [59]. The study included 10 diabetic patients, in which vascular function were assessed as FMD of the brachial artery, plasma levels of flavanol metabolites, and

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tolerability after an acute, single-dose ingestion of cocoa, containing increasing concentrations of flavanols (75, 371, and 963 mg). In a subsequent efficacy study, changes in vascular function in 41 medicated diabetic patients were assessed after a 30-day, thrice-daily dietary intervention with either flavanol-rich cocoa (321 mg flavanols per dose) or a nutrient-matched control (25 mg flavanols per dose). Both studies were undertaken in a randomized, double-blind fashion. Primary and secondary outcome measures included changes in FMD and plasma flavanol metabolites, respectively. A single ingestion of flavanol-containing cocoa was dose-dependently associated with significant acute increases in circulating flavanols and FMD (at 2 hours: from 3.7% 0.2% to 5.5% 0.4%, P 5 .001). A 30-day, thrice-daily consumption of flavanol-containing cocoa increased baseline FMD by 30% (P 5 .0001), while acute increases of FMD upon ingestion of flavanolcontaining cocoa continued to be manifest throughout the study. Treatment was well tolerated without evidence of tachyphylaxis. Endothelium-independent responses, BP, heart rate (HR), and glycemic control were unaffected. In hypertensive patients with impaired glucose tolerance (IGT), the effect of flavanol-rich dark chocolate (FRDC) on endothelial function, insulin sensitivity, b-cell function, and BP was examined [56,57]. After a run-in phase, 19 patients with hypertension with IGT (11 males, 8 females; 44.8 6 8.0 y) were randomized to receive isocalorically either dark or flavanol-free white chocolate (FFWC) at 100 g/d for 15 days. After a washout period, patients were switched to the other treatment. Clinical and 24-hour ambulatory BP was determined by sphygmometry and oscillometry, respectively. FMD, oral glucose tolerance test (OGTT), serum cholesterol and C-reactive protein, and plasma homocysteine were evaluated after each treatment phase. Dark chocolate but not white chocolate intake reduced insulin resistance (homeostasis model assessment of insulin resistance; P 5 .0001) and increased insulin sensitivity (quantitative insulin sensitivity check index, insulin sensitivity index (ISI), ISI(0); P ,.05) and beta cell function (corrected insulin response CIR(120); P 5 .035). Systolic (S) and diastolic (D) BP decreased (P 5 .0001) after dark chocolate (SBP, 3.82 6 2.40 mm Hg; DBP, 3.92 6 1.98 mm Hg; 24-hour SBP, 4.52 6 3.94 mm Hg; 24-hour DBP, 4.17 6 3.29 mm Hg) but not after white chocolate. Dark chocolate also increased FMD (P 5 .0001) and decreased total cholesterol (TC) ( 6.5%; P , .0001), and low-density lipoprotein (LDL) cholesterol ( 7.5%; P ,.0001). Changes in insulin sensitivity (Delta ISI Delta FMD: r 5 0.510, P 5 .001; Delta QUICK1 Delta FMD: r 5 0.502, P 5 .001) and beta-cell function (D CIR(120) Delta FMD: r 5 0.400, P 5 .012) were directly correlated with increases in FMD and inversely correlated with decreases in BP (Delta ISI Delta 24-hour SBP: r 5 0.368, P 5 .022; Delta ISI Delta 24-hour DBP: r 5 0.384, P 5 .017). Thus, dark chocolate ameliorated insulin sensitivity and beta-cell function, decreased BPs, and increased FMD in IGT hypertensive patients. These findings indicate that flavanol-rich, low-energy cocoa food products may have a positive impact on CVD risk factors. Another study aimed to test the hypothesis that consumption of cocoa may simultaneously lower BP, improve endothelial dysfunction, and ameliorate insulin resistance in subjects with essential hypertension [58]. This randomized, placebo-controlled, double blind, crossover trial examined the effects of a flavanol-rich cocoa drink (150 mL twice a day, 900 mg flavanols/d) in 20 individuals with essential hypertension. Antihypertensive medications were discontinued before study enrollment. After a 7-day cocoa-free run-in period, cocoa or flavanolpoor placebo (28 mg flavanols/d) treatment for 2 weeks was followed by a 1-week washout and then crossover to the other treatment arm. BP was measured thrice weekly. At baseline and after each treatment period, the authors [58] assessed insulin sensitivity (hyperinsulinemic isoglycemic

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glucose clamp) and insulin-stimulated changes in brachial artery diameter and forearm skeletal muscle capillary recruitment (Doppler ultrasound with or without microbubble contrast). Cocoa treatment for 2 weeks increased insulin-stimulated changes in brachial artery diameter when compared with placebo (median percentage increase from baseline (25th 75th percentile):8.3 (4.2 11.3) compared with 5.9 ( 0.3 to 9.6); P 5 .04). Nevertheless, cocoa treatment did not significantly reduce BP or improve insulin resistance and had no significant effects on skeletal muscle capillary recruitment, circulating plasma concentrations of adipocytokines, or endothelial adhesion molecules. Daily consumption of flavanol-rich cocoa for 2 weeks was not sufficient to reduce BP or improve insulin resistance in human subjects with essential hypertension. It is clear that there is a controversy on the role of cocoa flavanol in the treatment of hypertension and insulin resistance. Therefore, a meta-analysis of studies was conducted to find out the cumulative results of epidemiological studies and controlled trials. In an earlier meta-analysis published in 2011 [21], in which the association between chocolate consumption and the risk of outcomes related to cardiometabolic disorders were reported, the primary outcomes were CAD, stroke, type 2 diabetes, and metabolic syndrome [21] (Fig. 19.5). This meta-analysis assessed the risk of developing these disorders by comparing the highest and lowest

Study Any cardiovascular disease Buijsee et al 200615 Mink et al 200772 Janszky et al 2009 Janszky et al 2009 Buijsee et al 2010 Djosee et al 2010 Subtotal (I2 = 81.2%, P71

FIGURE 24.1 Frequency of dietary supplements use among US citizens by age. Data originate from National Health and Nutrition Examination Survey 2003 2006 (7).

24.3.1 THE PRODUCT RANGE There is a wide range of ingredients and products covered by nutraceuticals. In some cases ingredients are to be found in registered pharmaceuticals and nutrition supplements as well (e.g., probiotics, omega-3 fatty acids, glucosamine, melatonin, lutein, vitamins, minerals, etc.). In other cases the effect on health status may be well demonstrated, however clinical studies have not been done or only with low power. Examples are lycopene, creatine, resveratrol, conjugated linoleic acid, etc. Most representatives of the nutraceuticals group were introduced as specialty supplements. The European dietary supplements market in 2015 is ca. h14 billion. The biggest market is Italy (h1.424 million), followed by Russia (h888 million) and Germany (h967 million) [15]. For 2020 an expansion by 14% (0% 21% according to countries) is expected. The US DS market is ca three to eight times bigger and reached in 2015 the US$40 121 billion according to various sources. Ingredients according to purpose of use of nutraceuticals are categorized as follows (in bracket data of CRN Survey, 2011): 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.

Supplement the diet (42%) Boost immunity (32%) Enhanced energy (31%) Bone health (30%) Heart heath, decrease cholesterol (29%) Prevent health problems (26%) Healthy joints, prevent arthritis (20%) Skin, hair, and nails (17%) Bowel and colon health, digestive health (15%) Weight loss, weight management (14%) Eye health (13%) Mental health and concentration (13%)

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Novel nutraceuticals are being developed as add-on supplements for youngsters, who actively take part in sports, gymnastics, and various forms of trainings, and other consumers, also from the vulnerable groups, such as small children, old people, pregnant women, patients with chronic illnesses. Their safety is paramount important.

24.4 SAFETY ASPECTS OF NUTRACEUTICALS Nutraceuticals are taken by hundreds of millions and they are fine even if the products are not approved by health authorities. In the majority of cases nutraceuticals’ main ingredients are identical to those of pharmaceuticals. Certain ingredients of the nutraceuticals can however carry minor or major health risks. In a recent survey based on 3667 cases it was extrapolated that ca. 25,000 emergency department admissions per year can be attributed to dietary supplements in the United States [16]. 90% of the patients have minor problems and will be discharged in 1 day but nearly 10% (c. 2500 individuals) have to be hospitalized. Distribution of gender is 58% females and 42% males. Youngsters (20 34 years) and small children (under 4 years) are the most at jeopardy. The first risk factor to mention is the raw material, which does not necessarily conform with the pharmacopoeia. Here one can see impurities as well as contaminations but fraudulent practices are also explored [17]. Moreover due to the more liberal control processes during and after production, failures are less frequently discovered and if so, not always followed by a strict withdrawal process. This is the reason why one can read reports on serious harms as well. As health authorities don’t control regularly safety of commercialized nutraceuticals or dietary supplements, scientists, scientific institutions and non-governmental bodies keep check on the safety of dietary supplements. Recently eg. US Preventive Services Task Force (USPSTF) evaluated the risk of dose recommendtions of vitamin D with or without calcium supplementation. They concluded that current evidence is insufficient to assess the balance of the benefits and harms of vitamin D and calcium supplementation for the prevention of fractures in community-dwelling asymptomatic men and premenopausal women. But USPSTF found adequate evidence that daily supplementation with 400 IU or less of vitamin D and 1000 mg or less of calcium has no benefit for the primary prevention of fractures in community-dwelling postmenopausal women [18]. Further risks arise due to the impurities. In case of herbal dietary supplements heavy metals, eg. mercury content can be a source of additional risk. Recently a publication from Poland drow attention to this type of contamination [19]. It worth mentioning that recording patients’ use of dietary and herbal supplements is an important factor in patients safety. However, doctors often forget to query patients if they use DS, and forget all about putting this into the medical files. Recently it was reported that there is an incidence of 7.5% DS use recorded in patients medical documentation [20]. The records are of importance because of the potential interactions, too. Prescription medications and DSs often share similar enzymatic pathways for their metabolism. But “harmless” products as multivitamins alone or with minerals can cause problems under certain conditions (gravidity, small children, chronic illnesses, etc.) if they were administered continuously. Moreover, timing of nutraceuticals can also influence the effectiveness [21]. It is joyful that a recent meta-analysis of randomized, controlled clinical studies demonstrate the safety of these products used for more than 10 years in mixed population [22].

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24.5 SOME EXAMPLES In a recent US survey the most consumed specialty supplements are omega-3 fatty acids, second are the fibers, and third are probiotics (Fig. 24.2). Here we give a brief overview about the features and safety conditions of them. 1. Fish oil All fish oil products are mixtures of fatty acids (FAs) containing high proportion of n-3 polyunsaturated fatty acids (PUFAs). Main ingredient: polyunsaturated fatty acids including the only repersentative of the n-6 series, the linoleic acid—precursor of arachidonic acid, source of prostaglandins, leukotrienes and thromboxanes—and n-3 series incl. alpha-linolenic acid furthermore highly unsaturated fatty acids ( . C20; HUFA) like eicosapentaenic acid (EPA), docosapentaenic acid (DPA), and docosahexaenic acid (DHA). The n-6 FA content of native fish oil (e.g., cod liver oil) is less than 5%, the n-3 content is, in contrast, 20% 25%. Fish oil preparations usually contain concentrates. Inflammation is a common physiological reaction of the body. Under pathological conditions regulation of inflammation leads to excessive or ongoing inflammation. Great proportion of proinflammatory cytokines are derived from the cell membrane. The grade of inflammation depends on the ratio of omega-6 and omega-3 fatty acids. Today general daily food contains 5 20 3 more omega-6 HUFA than omega-3 HUFA [23]. The optimal n-3 : n-6 ratio is about 1: 2 [24]. Therefore ingestion of EPA- and DHA-rich food or supplements is more important in order to balance the fatty acid intake. Enrichment of blood with omega-3 FAs can be done by pharmaceuticals and nonpharmaceuticals as well. For a long time there was just one fish oil product (Lovaza/ Omacor) approved by the FDA. Over the last decade, several prescription omega-3 fatty acid

Use in 2015 (%)

20

Use in 2016 (%)

18 16 14 12 10 8 6 4 2 0 n-3 FA

Fiber

Probiotics

FIGURE 24.2 The use of specialty supplement categories in US citizens. CRN Consumer Survey 2015 and 2016.

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products have been approved based on clinical intervention trials [25]. There are, on the other hand, other brands of n-3 fatty acid products (fish oil, krill oil, alkal, oils, etc.) available OTC, without approval of the regulatory agent. Most of them belong to nutraceuticals. Main indications for prescription n-3 FA drugs are hypertriglyceridemia and neurological disorders because modifications of the PUFAs composition of the cell membrane has a large effect on the membrane permeability [26]. But in the intensive therapy and in surgery—e.g., in certain inflammatory conditions—n-3 supplementation is fully accepted, however in general medicine results are controversial [27 29]. In the case of oral supplementation there is a therapeutic dose of 2 g/day or above, which could result in antiinflammatory effect. n-3 PUFAs have local and systemic actions. For instance at high doses ( . 2 g EPA 1 DHA) cardiovascular curative and preventive actions can be proven (effects on lipid profile but also on endothelium, on immune cells, on platelet aggregation, on proinflammatory cytokines, etc.). But lower dose of PUFA consumption has also very high impact because it seems n-3 PUFA ingestion may block or diminish gastrointestinal absorption of saturated fatty acids [30]. The sporadic consumption of n-3 FA also can modify n-3 levels in body stores, the more EPA 1 DHA intake the better storage basis [31]. Nutraceuticals, dietary supplements, fortified foods, and other nonpharmaceuticals contain less highly unsaturated fatty acids, i.e., mainly EPA 1 DHA [32]. Even if their recommendations for daily dose are less than mentioned for pharmaceuticals, manufacturers and distributors of n-3 FA containing dietary supplements usually suggest the same effects for their products, without proof referring to the particulate product. There are concerns regarding the content, quality, and purity of n-3 FA dietary supplements as omega-3 fatty acids are very reactive to oxidation. Oxidative reactions can lead to significant quality deficits in this type of products. 2. Prebiotics (Fiber) Prebiotics are defined as resistant (in the small intestine nondigestible) plant-derived carbohydrates that are poorly absorbed or metabolized. They are, however, fermentable in the colon and promote the proliferation of local lactic acid producing microbes. Prebiotics are part of the dietary fibers. Well-known prebiotic ingredients are oligosaccharides (fructo- and galacto-oligosaccharides and inulin), pectin, guar gum, and resistant starch. Main characteristics are the water-solubility, the fermentability in the colon, the viscosity, and the water-holding capacity. In the case of nutraceuticals it is important to be resistant to gastric and intestinal juice as well as to bile acids [33]. They act in the colon as substrates for the majority of beneficial bacteria to produce short-chain fatty acids (SCFA), improve reduction of the colonpH, and are selective stimulants to proliferation. Prebiotics exert their action via SCFAs by providing energy to mucosal cells, by stimulation of mucosal blood flow, mucosal cell proliferation, and gut bacteria. SCFAs act also at antioxidative (ROS scavenger), antiinflammatory (reduce pro-inflammatory cytokines and PGE2) and antiproliferative (regulation of gene expression, signal transduction, apoptosis) agents. From a clinical point of view few direct benefits could be demonstrated by prebiotic intervention because in the majority of studies concomitant agents (usually probiotics) were present [34]. Best results appeared from the field of metabolic disorders. Benefits in appetite reduction, in glucose intolerance, and in hypercholesteremia seem to be proven. Metaanalysis verified beneficial effect of prebiotics in EN-induced diarrhea, too [35]. Possible benefits were demonstrated in the prevention of colon

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cancer, relief from GI-inflammation, and lowering of risk for cardiovascular diseases [36]. After all prebiotics are usually used together with probiotics (5synbiotics) and the effect of such fixed combination (also available as nutraceuticals) has been proven in several clinical studies. As clinical studies with separate prebiotics are very scarce, adverse effects are rarely reported, if so, they are not typical and not enough for statistical evaluation. In general it can be stated that all prebiotics labeled as nutraceuticals must be GRAS (Generally Recognized As Safe). Manufacturers take the responsibility for the health claims appearing on the label. 3. Probiotics Probiotics are—according to the WHO and FAO joint statement—live microorganisms that when administered in adequate amounts confer a health benefit on the host [37]. Utilization of these microbes in the healthcare system and food industry is multiple, as probiotic drugs, probiotic foods, probiotic medical foods, probiotic dietary supplements, probiotic infant formulas, probiotic animal feed, etc. are presently marketed. They are used mainly via oral administration/consumption but there are other dosage forms as well. There are products containing probiotics alone and probiotics with prebiotics (synbiotics), but several other combinations, like probiotic 1 multivitamin, probiotic 1 minerals are also popular. Due to the various non-consolidated regulations in the field of probiotics worldwide, recently publications urged stringent regulation of non-pharmaceutiucal probiotics. The “umbrella concept” and trademark low arise problems that must be soved in order to keep the safety of this group of nutraceuticals [38]. Probiotics as nutraceuticals are of higher value because these products mimic the drugs, therefore basic requirements of medicinal raw material (strain identity for phenotype and genotype, purity, high viability, colony-forming capability, resistance against acidity and the digestive enzymes, etc.) as well as the manufacturing processes are usually similar. Dosage forms contain 106 1010 bacteria per unit. The probiotic microbes administered orally will colonize the gut in some hours. Various mechanisms by which probiotics could be of benefit have been suggested. Major mechanisms of action of the probiotic products are the production of antimicrobial agents, competition with pathogens for binding sites, antagonism on gastrointestinal pathogen microbes, modification of toxins and/or toxin-receptors, and immunmodulation. The specific action is strain-dependent. As the human microbiome is originally very diverse ( . 500 species in the colon) in the case of dysbiosis reduction in total microbe numbers, change in composition of microbiota, and shrinking of diversity is to be observed [39]. In restoring the eubiosis probiotics demonstrated significant benefits. Main indications are a. b. c. d. e. f. g. h.

Diarrhea (acute diarrhea, travelers diarrhea, antibiotic-induced diarrhea) Lactose intolerance IBS and IBD (ulcerative colitis, pouchitis, Crohn’s disease) Helicobacter pylori infection Metabolic diseases (diabetes mellitus, dyslipidemia, obesity) Immunity (allergic conditions) Respiratory tract infections Mental health and neurological conditions

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The therapeutic interventions—in optimal situations—are led by the disease-related benefits of the various strains. Unfortunately today we have not enough information about the diseasespecific effectivity of the strains but more and more studies verify the usefulness or uselessness of specific strains in certain diseases. Based on the forthcoming literature we know that, e.g., in acute dysbiosis use of Lactococcus acidophylus, Lactococcus rhamnosus, Lactococcus casei, and Lactococcus reuteri resulted in definitive favorable clinical improvement. Or in Colitis ulcerosa positive therapeutic effects have been published with Lactococcus acidophylus, Lactococcus bulgaricus, Lactococcus casei, Lactococcus plantarum, Bifidobacterium breve, Bifidobacterium lactis, Bifidobacterium infantis, and Streptococcus thermophilus strains. And the knowledge in this field is getting broader and broader [40 42], however the comparable studies and the randomized controlled studies are missing, due to the dietary supplement status of the most probiotic products. Most of the manufacturers are not really interested in sponsoring big multicentric studies that could reveal the details of actions of certain strains. Safety issues of the probiotics arise from time to time. Despite the FDA designation GRAS having been applied to certain probiotic organisms when added to food, some systematic safety studies have reported risks, especially in vulnerable populations [43]. With respect to the huge amount of consumed probiotics the risk is very small. But as more and more manufacturers produce probiotic articles, the risk is not negligible, therefore vigilance of pharmacists and medical doctors is well-founded during every discussion with patients being on probiotic therapy [44]. The risk is present in products where raw materials are purchased from any manufacturer and the producer of the final product uses health claims according to other producers’ health claims. It is important to know that the results of a certain strain are not “interchangeable.” The second risk is the patients nonadherence. Should the patient not take the proper dosage (e.g., lower dose), beneficial results will not come [45].

24.6 CONCLUSION Nutraceuticals represent a special group of healthcare products: not pharmaceuticals and not really dietary supplements but somewhere in between. Even if nutraceutical products are not approved by the health authorities, their effects are similar to pharmaceuticals. The similarity and the reliability depends on the manufacturer. Consumers and patients take nutraceuticals as drugs. Therefore healthcare professionals, medical doctors, and pharmacists should also take into account during counseling that nutraceuticals are not approved pharmaceuticals and effectiveness and adverse effects may be different from pharmaceuticals having the same ingredients. The deviations should be reported to the competent persons in order to avoid unnecessary hazards.

REFERENCES [1] Lockwood B. Nutraceuticals. 2nd ed London Grayslake (USA): Pharmaceutical Press; 2007. [2] Aronson JK. Defining’nutraceuticals’: neither nutritious nor pharmaceutical. Br J Clin Pharmacol 2017;83:8 19.

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[23] Beydoun MA, Fanelli Kuczmarski MT, Beydoun HA, et al. Association of the ratios of n3 to n6 dietary fatty acids with longitudinal changes in depressive symptoms among US women. Am J Epidemiol 2015;181(9):691 705. Available from: https://doi.org/10.1093/aje/kwu334. [24] Simopoulos AP, Leaf A, Salem Jr N. Workshop ont he essentiality of and recomended dietary intake for omega-6 and omegy-3 fatty acids. J. Am Coll Nutr 1999;18(5):487 9. [25] Fialkow J. Omega-3 fatty acid formulations in cardiovascular disease: dietary supplements are not substitutes for prescription products. Am J Cardiovasc Drugs 2016;16:229 39. [26] Husted KS, Bouzinova EV. The importance of n-6/n-3 fatty acids ratio in the major depressive disorder. Medicina (Kaunas) 2016;52(3):139 47. [27] Barros KV, Cassulino AP, Schalch L, et al. Supplemental intravenous n-3 fatty acids and n-3 fatty acid status and outcome in critically ill elderly patients int he ICU receiving enteral nutrition. Clin Nutr 2013;32(4):599 605. Available from: https://doi.org/10.1016/j.clnu.2012.10.016. [28] Marventano S, Kolscz P, Castellano S, et al. A review of recent evidence in human studies of n3 and n6 PUFA intake on cardiovascular disease, cancer and depressive disorders: does the ratio really metter? Int J Food Sci Nutr 2016;66(6):611 22. [29] Weimann A, Braga M, Carli F, et al. SPEN guideline: clinical nutrition in surgery. Clin Nutr 2017;36 (3):623 50. [30] Yang Q, Wang S, Ji Y, et al. Dietary intake of n-3 PUFAs modifies the absorption, distribution and bioavailability of fatty acids int he mous gastrointestinal tract. Lipids Health Dis 2017;16:10. Available from: https://doi.org/10.1186/s12944-016-099-9. [31] Browning LM, Walker CG, Mander AP, et al. Incorporation of eicosapentaenoic and docosahexaenoic acids into lipid pools when given as supplements providing doses equivalent to typical intakes of oily fish. Am J Clin Nutr 2012;96:748 58. [32] Calder PC. Omega-3 polyunsaturated fatty acids and inflammatory processses: nutrition or pharmacology? Brit J Clin Pharmacol 2012;75(3):645 62. [33] Kuo S-M. The interplay between fiber and the intestinal microbiome in the inflammatory response. Adv Nutr 2013;4(1):16 28. Available from: https://doi.org/10.3945/an.112.003046. [34] Kellow NJ, Coughlan MT, Reid CM. Metabolic benefits of dietary prebiotics in human subjects: a systematic review of randomized controlled studies. Brit J Nutr 2014;111:1147 61. [35] Zaman MK, Chin K-F, Rai V, Majid HA. Fiber and prebiotic supplementation in enteral nutrition: a systematic review and meta-analysis. World J Gastroenterol 2015;21(17):5372 81. Available from: https:// doi.org/10.3748/wjg.v21.j17.5372. [36] Pandey KR, Naik SR, Vakil VB. Probiotics, prebiotics and synbiotics a review. J Food Sci Technol 2015;52(12):7577 87. [37] Report of a Join FAO/WHO Expert Consultation on Evaluation of Health and Nutritional Properties of Prebiotics in Food including Powder Milk with Live Lactic Acid Bacteria. Cordoba, Argentina, 2001. https://www.fao.org/3/a-a0512e.pdf [38] de Simone C. The unregulated probiotic market. Clin Gastroenterol Hepatol 2018; Available from: http://doi.org/10.1016/j.cgh.2018.01.018. [39] Carding S, Verbeke K, Vipond DT, et al. Dysbiosis of the gut microbiota in disease. Microb Ecol Health Dis 2015;26:26191 9. [40] Dolan KE, Finley HJ, Burns KM, et al. Probiotics and disease: a comprehensive summary Part 1, Mental and neurological health. Integr Med (Encinitas) 2016;15(5):46 58. [41] Parker EC, Gossard CM, Dolan KE, et al. Probiotics and disease: a comprehensive summary Part 2, Commercially produced cultured and fermented foods commonly available in the United States. Integr Med (Encinitas) 2016;15(6):22 30.

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CHAPTER

TRIGONA PROPOLIS AND ITS POTENCY FOR HEALTH AND HEALING PROCESS

25

Ahmad Sulaeman1, Al Mukhlas Fikri1, Nurbani Kalsum2 and Mahani Mahani3 1

Department of Community Nutrition, Faculty of Human Ecology, Bogor Agricultural University, Bogor, Indonesia Department of Agricultural Technology, State Polytechnic of Lampung, Lampung, Indonesia 3Department of Food Industrial Technology, Faculty of Agroindustrial Technology, Padjajaran University, West Java, Indonesia

2

25.1 INTRODUCTION Propolis is a substance produced by honey bees and plays a role in the construction of the nest, if there is a shortage then the hive will not be perfect. Due to its sticky texture like glue, propolis is also called bee glue. Propolis in a hive is used by worker bees to close crevices, caulking cracks, minimizing and closing holes [1]. Propolis may be produced by various kind of bees, both stinging bees like Apis spp. and by stingless bees like Trigona spp. Propolis is produced by collecting resin from various plants. Resins are collected from buds, skins, or other parts of the plant, then resins are mixed with saliva and enzymes in the bees to become new resins different from their original resins [2]. Then these resins are mixed with wax and flower pollen, and made into elastic structures, so-called propolis. They use this sticky material for adaptation and protection. It is used to strengthen and repair the honeycomb. They also use it against microorganism to lower the incidence of bacteria and molds within the hive. The human beings have used these functions for pharmaceutical uses [3]. Kro´l et al. [4] reviewed more than 50 articles and found that propolis possesses antibacterial, antiviral, antifungal, anticancer, antiinflammation, and antioxidant properties. Many researchers have explored the characteristics of propolis and its health benefits. However, most of the studies were conducted on propolis from Apis species. Meanwhile, studies on propolis from stingless bee like from Trigona spp. are still rare. In this chapter, we focus on the potency of propolis from Trigona spp for immunomodulators, antituberculosis, and antiemesis. The latter term is the least explored function, however, it is very useful to support the other functions. In addition, we show our study on the diversity of Indonesian propolis, including the distribution of bee species, source of resin, phytochemical profiling, and antioxidant activity and toxicity level among propolis from several provinces of Indonesia.

The Role of Functional Food Security In Global Health. DOI: https://doi.org/10.1016/B978-0-12-813148-0.00025-6 © 2019 Elsevier Inc. All rights reserved.

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CHAPTER 25 TRIGONA PROPOLIS AND ITS POTENCY FOR HEALTH

25.2 TRIGONA SPECIES DISTRIBUTION AND PLANT ORIGIN There are so many species of stingless bee around the world. In Indonesia, our identification found more than 30 species of stingless bee around the archipelagos, especially from Trigona species. Most of them are still wild and underutilized. We have observed Trigona species in 10 provinces of Indonesia that have beensuccessfuly cultivated. Among them, there are eight species that productively yield propolis (Table 25.1). The distribution of Trigona species are quite diverse. Tetragonula laeviceps is the most widespread species, over four provinces: Banten, Jawa Barat, Jawa Tengah and Kalimantan Selatan. Tetragonula laeviceps tends to colonize in Java island, while Heterotrigona itama spreads over three provinces, namely Kalimantan Barat, Kalimantan Timur, and Kalimantan Selatan. There are indications Heterotrigona itama is an endemic species in Kalimantan island. Tetragonula fuscobalteata species spreads across NTB and Maluku which are the eastern provinces of Indonesia. However, the other species found only in one province. The resins composing the Trigona propolis are collected by the Trigona bee from various plants. We identified that there are at least 31 kind of plants as the source of the collected resin. Based on our observation, Trigona bee in Sulawesi Selatan is the species that has the highest propolis production. Mango is the source plant with the highest resin contribution because it spreads over nine provinces, i.e., Sumatra Utara, Banten, Jawa Barat, Jawa Tengah, Kalimantan Timur, Kalimantan Selatan, Nusa Tenggara Barat, Sulawesi Selatan, and Maluku. Jackfruit is the second source plant and spreads across eight provinces, i.e., Sumatera Utara, Banten, Jawa Barat, Jawa Tengah, Kalimantan Timur, Kalimantan Selatan, Nusa Tenggara Barat, and Maluku. The other source plants are avocado, acacia, cempaka, jackfruit, cocoa, mahogany, and soursop.

Table 25.1 List of Trigona Bee Species Cultivated in 10 Provinces of Indonesia (Sulaeman et al. [5]) Amount of Species

No.

Province Origin

Trigona Bee Species

1. 2. 3. 4. 5. 6. 7.

Sumatera Utara Banten Jawa Barat Jawa Tengah Kalimantan Barat Kalimantan Timur Kalimantan Selatan Sulawesi Selatan Nusa Tenggara Barat Maluku

Tetragonula minangkabau, Sundatrigona moorei Tetragonula laeviceps Tetragonula laeviceps Tetragonula laeviceps Heterotrigona itama Heterotrigona itama Heterotrigona itama, Tetragonula laeviceps, Geniotrigona thorasica Geniotrigona insica, Lepidotrigona terminate Tetragonula fuscobalteata

2 1

Tetragonula fuscobalteata

1

8. 9. 10.

2 1 1 1 1 1 3

25.3 BIOLOGICAL ACTIVITIES AND CHEMICAL COMPOSITION

427

25.3 BIOLOGICAL ACTIVITIES AND CHEMICAL COMPOSITION 25.3.1 CHEMICAL CONTENT OF PROPOLIS The nature of biological activity of propolis is related to the origin of the plant [6]. This is caused by the fact that its composing components are largely derived from plants. Kumazawa et al. [7] suggests that flavonoids in propolis are ascertained to have origins as flavonoids in plants. The quantity and quality of the chemical components of propolis is influenced by bee species and resin source vegetation, which may differ across provinces in Indonesia. According to Bankova et al. [1] this difference in chemical composition will greatly affect the ability of its biological activity. The main chemical groups found in propolis resin includes phenolic acids or esters, flavonoids (flavones, flavanones, flavonols, dihiroflavonol and chalcones), terpenoids, aldehydes and aromatic alcohols, fatty acids, stilbene, and b-steroids. Chemically, the propolis component is very complex and it is rich in terpene compounds, benzoic acid, caffeine acid, cinnamic acid, and phenolic acids. Propolis also contains many phenol compounds, especially flavonoids [8]. Flavonoids are a group of chemical compounds known to have antioxidant activity, especially the ability for free radical scavenging and metal chelating properties [9]. Phenol compounds are commonly present in plants and reported to have a wide range of bioactivity abilities including antioxidant activity. [10] One of the phenol bonds in propolis is Caffeic Acid Phenethyl Ester (CAPE) which reaches 50% of the total components. CAPE is an active flavonoid side that works to maximize scavenger activity against free radicals by decreasing the activity of hydroxyl radicals (KOH) so that it becomes less reactive [11]. According to Kumazawa et al. [7] phenol content is thought to be responsible for the main antioxidant function in propolis. In addition to the presence of phenol and flavonoids, propolis also contains important nutrients such as vitamins and minerals especially vitamin B1, B2, B6, C, and E. Propolis also contains 16 essential amino acids needed for cell regeneration. Of all the amino acids present in propolis, arginine and proline are the most common, about 45.8%. Propolis contains all minerals, except sulfur. Iron (Fe) and zinc (Zn) are the most dense. This mineral content is strongly influenced by the environment where plants grow. Based on previous research, it was concluded that the different composition of propolis was influenced by the origin of propolis [1].

25.3.2 PHYTOCHEMICAL PROFILE OF PROPOLIS TRIGONA SPP. FROM THREE REGIONS IN INDONESIA We tried to show the diversity of the phytochemical profile of Indonesian Trigona spp. propolis from three regions of Indonesia. We did it using gas chromatography-mass spectrometry (GC-MS). GC-MS analysis of ethanol extracts of propolis of Trigona spp. from Sulawesi Sealatan, Kalimantan Selatan, and Banten provinces shows peaks indicating the presence of phytochemical compounds with retention times and percent of different areas. From the comparison of the mass spectrum of compounds with WILEY7 and NIST library ver.2.0, phytochemical components were characterized and identified by retention time (RT), molecular weight (MW), molecular formula, and concentration.

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CHAPTER 25 TRIGONA PROPOLIS AND ITS POTENCY FOR HEALTH

The chemical composition of Indonesian propolis varies greatly among different samples. It supports several previous studies [12 17]. The main compounds identified in samples from three regions of Indonesia include triterpenoids, n-alkanes, n-fatty alcohols, n-alkanols, aromatics, naliphatics, methyl carboxylates, phenols, and ketoaldehyde. A total of 14 peaks showed in the chromatogram GC-MS ethanol extract of propolis Trigona spp. which originated from the Sulawesi Selatan region, among which there was an approximate percentage of structural similarity of $ 95% (Table 25.3). Of the 14 peaks, there were 12 different bioactive compounds including octadecane (11.87%), (Z)-9-Octadecen-1-ol (1.79%), pentatriacontane (1.49% and 0.23%), limonene (1.53%), tricosane (0.9%), 1-heptacosanol (0.77%), heptacosane (0.48% and 12:22%), 1-hexadecanol (0.64%), 1-hexadecene (0.37%), dioctyl adipate (12:32%), hexadecane (0:16 %), and 2-methyl-butanoic acid (0.12%). Among these compounds, six compounds are reported to have biological activity such as limonene (C10H16), hexadecane (C16H34), 1-hexadecanol (C16H34O), dioctyl adipate (C22H42O4), heptacosane (C27H56), and 1-heptacosanol (C27H56O). Various phytochemical compounds of propolis Trigona spp. originating from the Sulawesi Selatan region that provide biological activity are shown in Table 25.2. Table 25.2 Phytochemical Components of Extract Ethanol of Propolis Trigona spp. From Several Regions of Indonesia (Kalsum et al. [18]) Chemical Components Sulawesi Selatan

Kalimantan Selatan

Banten

No.

Molecular Formula

Component Namea

Molecular Formula

Component Namea

Molecular Formula

Component Namea

1.

C5H10O2

CH6SI2

Methyl-Silane

C10H16

Limonene

2.

C10H16

2-methylbutanoic acid Limonene

C2H4O2

Acetic acid

C8H10O

3.

C16H32

1-Hexadecane

C4H6O3

C15H32

4.

C16H34

Hexadecane

C5H8O3

5.

C16H34O

1-Hexadecanol

C6H10O3

6.

C18H36O

C16H32O2

7. 8. 9. 10. 11. 12. 13. 14.

C35H72 C22H42O4 C23H48 C27H56 C18H38 C35H72 C27H56 C27H56O

(Z)-9Octadecen-1-ol Pentatriacontane Dioctyl adipate Tricosane Heptacosane Octadecane Pentatriacontane Heptacosane 1-Heptacosanol

2-oxo-methyl ester propanoic acid 1-(acetyloxy)-2Propanone 1-(acetyloxy)- 2Butanone Hexadecanoic acid

2,6-dimethylPhenol Pentadecane

C23H48 C23H48 C44H90

Tricosane Tricosane Tetratetracontane

a

The data had an approximate $ 95% of structural similarities.

C16H32O2

C23H48

Hexadecanoic acid Bis(2-ethylhexyl) phthalate Tricosane

C29H60 C44H90

Nonacosane Tetratetracontane

C24H38O4

25.3 BIOLOGICAL ACTIVITIES AND CHEMICAL COMPOSITION

429

From GC-MS analysis of propolis from Kalimantan Selatan, it is known that nine peaks of them have a percentage estimation of structural similarity of $ 95% (Table 25.4). Of the nine peaks, there are eight different bioactive compounds including tricosane (0.96% and 0.42%), hexadecanoic acid (0.92%), tetratetracontane (0.87%), acetic acid (0.86%), methyl-silanes (0.77%), 1- (acetyloxy)2-propanone (0.16%), 2-oxo-methyl ester propanoic acid (0.15%), and 1-(acetyloxy)-2-butanone (0.09%). Among these compounds, three compounds are reported to have biological activity including acetic acid (C2H4O2), hexadecanoic acid (C16H32O2), and tetratetracontane (C44H90). Phytochemical compounds of propolis Trigona spp. originating from Kalimantan Sealatan providing biological activity can be seen in Table 25.2. Based on the GC-MS chromatogram analysis of extract ethanol propolis of Trigona spp. from Banten, there are eight peaks with an approximate percentage of structural similarity of $ 95% (Table 25.4). Of the eight bioactive compounds, the indicated compounds were nonacosane (4.80%), tetratetracontane (2.78%), bis(2-ethylhexyl)phthalate (1.79%), hexadecanoic acid (1.06%), tricosane (0.78%), limonene (0.51%), pentadecane (0.41%), and 2,6-dimethyl-phenol (0.26%). Among these compounds, five compounds are reported to have biological activity including limonene (C10H16), hexadecanoic acid (C16H32O2), bis(2-ethylhexyl)phthalate (C24H38O4), nonacosane (C29H60), and tetratetracontane (C44H90). Phytochemical compounds of propolis Trigona spp. originating from the Banten region that provide the biological activity are shown in Table 25.2. Terpenoid, in monoterpenoid form, is the main compound of the Trigona propolis samples from Indonesia. The relative concentrations of this substance range from 0.51% to 1.53%. Limonene is also found in propolis samples from Argentina, Uruguay, and Croatia. Acetic acid found in this propolis sample, was also found in propolis samples from China [19]. The presence of monoterpenoids (especially limonene) may act as immunomodulatory agents, antioxidants, antibacterials, antiinflammatories, antialzheimers, and more. The main source of monoterpenoid in propolis is clearly derived from the surrounding vegetation. Therefore, the determination of the chemical composition of regional vegetation should be considered, as it would be useful to investigate the pharmacologically active components of local plants as well as from propolis. Compared with the findings of this study, two samples of ethanol extract of Turkish propolis reported containing 24 and 18 chemical compounds while 20 chemical compounds were found in Brazilian red propolis ethanol extract [20,21]. It should be noted that the tricosane (C23H48) found is present in all three propolis Trigona spp. and was also detected in Portuguese and Indian propolis [21 23]. While octadecane (C18H38) is the highest phytochemical compound (11.87%) found in propolis in this study, it was also found to be present in Turkish and Iranian propolis [23,24]. The limonene compounds (C10H16), a major component found in propolis from South Sulawesi (1.53%) and Banten (0.51%), are also the main volatile compounds found from Argentina (the Andean region), Brazil (Rio Grande do Sul), Croatia, and Uruguay. [19] Table 25.3 shows the biological activities of each component contained in propolis collected from three regions of Indonesia.

25.3.3 ANTIOXIDANT ACTIVITY AND TOXICITY OF PROPOLIS Antioxidant activity and toxicity level of propolis from all provinces are presented in Table 25.4. Propolis from Sulawesi Selatan (Trigona insica) had the highest antioxidant activity, while propolis from Sumatera Utara (Trigona minangkabau) had the lowest antioxidant activity. The results of

Table 25.3 The Activity of Components Identified in Samples of Ethanol Extract of Propolis From Three Regions in Indonesia Using GC-MS (Kalsum et al. [18]) Sample of Propolis

No.

Group Compound

Compound

Molecular Formula

1.

Hydrocarbons monoterpenes

Limonene

C10H16

O

2. 3. 4. 5. 6.

Hydrocarbons alkanes Hydrocarbons alkanes Alkanes Fatty alcohol Fatty alcohol

Hexadecane Heptacosane Tetratetracontane 1-Hexadecanol 1-Heptacosanol

C16H34 C27H56 C44H90 C16H34O C27H56O

O O

7.

Hydrocarbon aromatic

Hexadecanoic acid

C16H32O2

Sulawesi

Kalimantan

Banten

Biological Activitiesa

O

immunomodulator, antioxidant, antibacterial, antiinflamatory, antiadenomic, antialzheimer, antiasthma, anticancer, antiesophagitic, antiflu, antilithic, antilymphomic, antimetastatic, antimutagen, antiobessity, antiseptic, antispasmodic, antitumor, antiacetylcholinesterase, antiallergy, antiangiogenic, antiatherogenic, anticarcinomic, antinociceptive, antitussive, apoptotic, candidistatic, chemopreventive, cholesterolytic, detoxican, enterocontractan, expectoran, flavor, fungistat, GST-inducer, herbicida, histaminic, insecticida, insectifugal, IL-6-inhibitor antioxidant, antimicroba antibacterial antioxidant, hypoglycemia antioxidant antioxidant, antimicrobial, anticancer, nematicidial antioxidant, antiandrogen, flavor, hemolytic 5-alpha reductase inhibitor, hypocholesterolemic, nematicida, pesticide, lubricant

O

O

O

O

O O

8.

Aliphatic acids

Acetic acid

C2H4O2

9. 10. 11.

Carboxylic acid ester Hydrocarbon alifatic Phthalates

C22H42O4 C29H60 C24H38O4

12.

Carbocylic acid

13.

Hydrocarbon aromatic

14. 15.

Hydrocarbon alkanes Alpha Ketoaldehide

16.

Fenol

17.

Fenolic Ester

18. 19. 20. 21.

Acyclic olefins Hydrocarbon alkanes Hydrocarbon alkanes Fatty alcohol

22.

Organo metalic

Dioctyl adipate Nonacosane Bis(2ethylhexyl) phthalate 2-oxo-methyl ester Propanic acid 2-methylButanoic acid Pentadecane 1-(acetyloxy)-2Propanone 2,6-dimethylPhenol 1-(acetyloxy)-2Butanone 1-Hexadecene Octadecane Tricosane (Z)-9-Octadecen1-ol Methyl-Silane

a

Dr. Duke’s Phytochemical and Ethnobotanical Databases.

O O O O O

C4H6O3

C5H10O2

flavor and taste taste flavor and taste

O

flavor and taste

O

C6H10O3

CH6SI2

O O

C8H10O

C16H32 C18H38 C23H48 C18H36O

flavor

O

C15H32 C5H8O3

O O O O

antibacterial; antibiotic; antisalmonella; antivaginitic; expectorant; asidulan; fungicide antibacterial antimutagen antimutagen, antileukemia

O

O

flavor

O

no no no no

activity activity activity activity

reported reported reported reported

no activity reported

432

CHAPTER 25 TRIGONA PROPOLIS AND ITS POTENCY FOR HEALTH

Table 25.4 Antioxidant Activity and Toxicity of Trigona Propolis From Various Provinces of Indonesia [25] No.

Province Origin of Propolis

Bee Species

IC 50 (ppm)

LC 50 (ppm)

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14.

Sumatra Utara Sumatra Utara Banten Jawa Barat Jawa Tengah Kalimantan Barat Kalimantan Timur Kalimantan Selatan Kalimantan Selatan Kalimantan Selatan Sulawesi Selatan Sulawesi Selatan Nusa Tenggara Barat Maluku

T. minangkabau S. moorei T. laeviceps T. laeviceps T. laeviceps H. itama H. itama H. itama T. laeviceps G. thorasica G. insica L. terminate T. fuscobalteata T. fuscobalteata

1378.95 208.92 150.83 574.85 283.05 227.54 939.98 636.61 580.40 905.06 100.05 467.93 477.88 218.65

621.49 55.09 , 50.00 521.74 615.84 802.26 451.32 270.60 838.05 . 1000.00 854.75 656.41 624.34 932.63

toxicity testing indicate that propolis from Banten had the highest level of toxicity, while propolis with the lowest level of toxicity came from Kalimantan Selatan (Trigona thorasica). Propolis from Kalimantan Selatan (Trigona insica) might be the most safe propolis. In contrast, those consuming propolis from Banten should be aware of its toxicity. Nevertheless, the high toxicity level may be linked to the anticancer properties. Investigating anticancer properties of propolis from Banten, therefore, may be useful.

25.4 PROPOLIS AS IMUNOMODULATORY AGENTS Propolis has attracted the interest of researchers in recent decades due to its biological and pharmacological properties, such as antimicrobial [26 28], immunomodulators, antiinflammatory [28], and antioxidants [7]. Propolis of Trigona spp. which contains limonene is thought to have an immunomodulatory effect which through in vitro studies showed that D-limonene increased the production of peritoneal macrophage NO in tumor-induced mice [29]. According to Draganova-Filipova [30], at low concentrations CAPE is able to activate T lymphocytes, which exhibit antiapoptotic effects in B lymphocytes, and does not affect NK cells.

25.4.1 PROPOLIS PROSPECT AS IMMUNOMODULATOR As one form of functional food, i.e., food that has physiological properties for the body, such as improving immunity, the prospects of immunomodulators from natural ingredients vary. Some articles have provided information on the influence of propolis on the body’s immune system.

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Immunomodulatory tests include tests with positive controls, such as lipopolysaccharide (LPS), concanavalin A (Con A), phorbol miristate acetate (PMA), cytokines (IFN-γ), or others to compare the efficiency of propolis. Cyclophosphamide is commonly used as an immunosuppressive drug, and has been used in vivo both as a negative control and also to investigate the immunorestorative performance of poplar propolis [31 33]. Such immunomodulatory performance of Brazilian green propolis, through the administration of ethanol extract of propolis (200 mg/kg) in mice for 3 days can increase innate immunity, activating the early work of the body’s immune response through upregulating expression of TLR-2 and TLR-4 and production of proinflammatory cytokines by macrophages and spleen cells (IL-1 and IL-6), improves the introduction of microorganisms and lymphocyte activation by presenting antigen cells [33]. Brazilian green propolis (2.5 and 5 mg/kg) also increases hydrogen peroxide (H2O2), in favor of the killing of microorganisms. [34] The antiinflammatory action of propolis has been reported by several researchers, using different experimental models [35 38]. Taking propolis (200 mg/kg) in the short term (3 days) to mice may inhibit IFN-γ production in splenocyte cultures [39]. In addition, in the C57BL/6 mice treated with green propolis Brazil (200 mg/kg) for 14 days showed inhibition of IL-1, IL-6, IFN-γ, IL-2, and IL10 production of spleen cells, and showed its antiinflammatory activity after it was discovered that cytokines regulate and perpetuate a chronic inflammatory picture of some diseases [40,41]. Brazilian green propolis 10% stimulates antibody production [42]. Giving CAPE (5, 10, and 20 mg/kg) in BALB/c mice also increased the production of antibodies [43], but in addition to the influence of each element, the synergistic effects of some compounds may be responsible for various pharmacological activities against propolis. Kujumgiev et al. [44] state that the biological nature of common propolis is due to the natural mixture of its components, and the sole element of propolis has no greater activity than the whole extract. These data strongly suggest the capacity of adjuvant propolis in conjunction with the vaccine. For example, Fischer et al. [45] linked Brazilian propolis (5 mg/dose) to the inactivated vaccine Suid herpesvirus type 1 (SuHV-1), proving that mice inoculated with SuHV-1 vaccine plus aluminum hydroxide and propolis showed higher antibody titers. Propolis is also efficient as adjuvant for inactivated vaccine against Aeromonas hydrophila in koi fish, due to the phagocytic activity of these fish and serum antibodies against A. hydrophila are higher than nonadjuvant fish vaccine [46]. The effect of propolis on immobilizing animal stress changes is also investigated. In acute stress, Brazilian green propolis (200 mg/kg for 3 days) improved TLR-2 and TLR-4 expression, increased the introduction of microorganisms during stressful conditions, and increased IL-4 production, supporting humoral immune response [47]. In the study of Conti et al. [48], the administration of cinnamic acid 5, 10, 25, 50, and 100 mg/mL in peripheral blood mononuclear cells (PBMC) downregulated TLR-2, HLA-DR, and CD80 and upregulated expression of human monocytes TLR-4. High concentrations of cinnamic acid (100 mg/mL) inhibit the production of TNF-α and IL-10, whereas the same concentration can induce high fungicid activity against Candida albicans. Production of TNF-α and IL-10 decreased by blocking TLR-4, whereas the fungicide activity of monocytes was not affected by blocking TLRs. In chronic stress mice, the treatment of Brazilian green propolis (200 mg/kg for 7 days) potentially produces H1 through macrophages and neutralizes the changes found in the spleen [49]. Brazilian green propolis (200 mg/kg for 14 days) also provides immunomodulatory activity in melanoma mice to chronic stress [40,41]

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The mechanism of propolis as an antiinflammatory has been studied by some researchers who found that propolis can reduce inflammation due to the presence of CAPE and quertecin content that contribute to suppression of T cell activity. CAPE is able to inhibit Nuclear Transcription Kappa Factor B (NF-κB) and IL-2 stimulant which spur the proliferation of the work of the T cell itself, whereas quercetin may affect the cyclooxygenase pathway. Both compounds are equally responsible for blocking lipooxygenase and cyclooxygenase [50].

25.4.2 THE INFLUENCE OF TRIGONA SPP. PROPOLIS ON MACROPHAGE PHAGOCYTOSIS ACTIVITY AND PRODUCTION OF NITRIC OXIDE (NO) The influence of Trigona spp. propolis to macrophage stimulated by different treatments are shown in Table 25.5. The provision of propolis as an immunomodulatory effect on macrophage phagocytosis index was seen from the increase in the average index of phagocytic macrophages when given at 0.16% when compared to the negative control and showed a slight increase in the average index phagocytes of macrophages when administered at 0.48% when compared with positive controls (not significantly different). This suggests that propolis is an immunomodulator, potentially increasing the phagocytic index of peritoneal macrophages of mice when administered within a specified period, and slightly increases the power of phagocytic index of peritoneal macrophages when administered in higher amounts. This is because the properties of propolis as an immunomodulator; when given in small doses it can potentially improve macrophage phagocytic index averages [52]. These results suggest that peritoneal macrophages have been enabled by the provision of propolis Trigona spp., as demonstrated by improving phagocytosis. There is strong suspicion that compounds contained in propolis Trigona spp. such as limonene, are able to work on activating macrophages. Several other studies have shown that some components in propolis, such as caffeic acid phenethyl ester, cinnamic acid, and artepillin C, are also capable of activating macrophages in vitro and in vivo [51]. Literature data showed that the essential oil of Eucalyptus globulus, which contains p-cymene which is a member monoterpene, is also capable of inducing macrophage response and p-cymene can also stimulate phagocytosis by binding to the receptor TLR4 [53]. As shown in Table 25.6, propolis is able to increase NO production in macrophages by different treatments. NO production increased significantly with different concentrations of propolis (0.16%, 0.48%, and 1.44%) similar to that observed in CAPE (0.5%—a positive control). At 0.48% and Table 25.5 Influence of Propolis Trigona spp. on the Ability of Macrophage Phagocytosis [51] Group

Phagocytosis Percent (%)

Phagocytosis Index

Phagocytosis Efficiency

CAPE (positive control) Aquadest (negative control) Propolis 0.16% Propolis 0.48% Propolis 1.44%

87.20 6 1.25 52.73 6 12.45c 80.67 6 5.54b 88.40 6 4.63a 90.07 6 3.73a

51.23 6 1.31 45.19 6 1.13c 45.73 6 1.02b 51.67 6 0.68a 52.38 6 1.46a

0.59 6 0.02a 0.86 6 0.29c 0.57 6 0.05b 0.59 6 0.03a 0.58 6 0.04a

a

a

The numbers followed by the same letter in the same column states no significant difference at the test level of 5%.

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Table 25.6 Effect of Propolis Trigona spp. on the Production of NO Macrophages [51] Group

NO (μM/L)

CAPE (positive control) Aquadest (negative control) Propolis 0.16 % Propolis 0.48 % Propolis 1.44 %

184.164 6 0.79b 176.79 6 5.61c 187.104 6 1.14b 195.866 6 0.78a 198.034 6 1.15a

The numbers followed by the same letter in the same column states no significant difference at the test level of 5%

1.44%, it was significantly different with negative control group and positive control and dose group 0.16%. It is possible that 0.48% and 1.44% are able to activate NO production by macrophages. According to Goel et al. [54] without induction, NO is produced at a level that can not be detected, and the induction with LPS resulted in significant increase in NO production. Nitric oxide is a mediator associated with cell activation that contributes to the death or inhibition of various pathogens [55]. In our study, it was found that at 0.16% propolis has been able to induce NO production. These results are consistent with other studies showing that NO has an important regulatory role in various types of inflammatory processes. Limonene is reported to suppress the production of TNF-α, thus becoming a strong antiinflammatory agent especially in skin inflammatory conditions [56]. In vitro studies have shown that D-limonene increases the production of peritoneal macrophage NO in tumor-induced mice [29]. One indication of activated macrophages is the formation of nitric oxide (NO) from L-arginine by nitric oxide synthase (NOS). Nitric oxide is a free radical in the form of inorganic gas and is able to penetrate the membrane layer. NO plays an important role in many physiological functions, one of which is a key mediator of nonspecific immunity. NO is toxic to pathogenic bacteria because NO can inhibit the enzyme ribonucleotide reductase and interfere with DNA synthesis. NO can also inactivate enzymes that bind to iron and sulfur such as Nicotinamide Adenine Dinucleotide (NADH) and ubiquinone oxidoreductase. Although NO itself is quite toxic and naturally reactive, NO can easily bind to other molecules such as oxygen and produce stable and nontoxic nitrates and nitrites [57] Inhibition of NF-κB activation can be the molecular basis of antiinflammatory properties of propolis [58]. Therefore, this study considers the possibility that limonene may be one of the most important ingredients in propolis of Trigona spp. from Indonesia, which plays a role in activating macrophages and increasing NO production.

25.4.3 THE INFLUENCE OF PROPOLIS TRIGONA SPP. ON CYTOKINE PRODUCTION (TNF-α, IFN-γ, AND IL-2) The difference in cytokine production can be seen in Table 25.7 where propolis is able to increase cytokine production in rat blood serum by different treatments. This shows the provision of propolis extract successfully stimulates the immune response in this study. Propolis 0.16% significantly

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CHAPTER 25 TRIGONA PROPOLIS AND ITS POTENCY FOR HEALTH

Table 25.7 Effect of Propolis Trigona spp. on Cytokine Production [50] Group

TNF-α (pg/mL)

IFN-γ (pg/mL)

IL-2 (pg/mL)

CAPE (positive control) Aquadest (negative control) Propolis 0.16% Propolis 0.48% Propolis 1.44%

4.996 6 0.51 12.426 6 0.68a 4.055 6 1.20c 4.724 6 0.48c 9.826 6 1.41b

37.145 6 1.35 45.015 6 2.49a 42.865 6 0.85a 35.264 6 1.49b 32.615 6 0.75c

58.813 6 1.50a 50.741 6 1.77b 56.173 6 5.74a 59.913 6 2.27a 61.017 6 8.57a

c

b

The numbers followed by the same letter in the same column states no significant difference at the test level of 5%.

increased production of IL-2 cytokines and decreased production of TNF-α and decreased IFN-γ cytokine production although not significantly. The results showed that the average number of IL-2 due to immunomodulatory activity of ethanol extract extract of Trigona spp. propolis in Sprague Dawley white rats with 0.16%, 0.48%, and 1.44% of the total IL-2 significantly increased compared with the negative control group. While the mean number of IFN-γ and TNF-α was significantly decreased compared with the negative control group. Activation of macrophages through the release of cytokines by the lymphocyte of the macrophage release pathways in the body’s immune system is not only through the arachidonic acid pathway but also through the cytokines produced by the lymphocytes. Cytokines are a small protein that many cells release and they act like hormones, through the receptors on the surface of the target cell. Cytokines have properties, among others: one cytokine has an effect on various cells, various cytokines have the same overlapping effect, two or more cytokines show a greater effect than only additive effects, and one cytokine can prevent the effects of other cytokines [59]. Of the secondary metabolite content of Trigona spp. in the form of chemical compounds, one of them is monoterpenoid (limonene). The results of the Lappas and Lappas [60] study concluded that D-limonene, limonene-1-2-diol, and perillic acid significantly inhibited proinflammatory activity of CD41 and CD81 T lymphocytes and had cytotoxic potential. The results of Hamada et al. [61] showed that D-limonene has the potential to work on lymphokines (IFN-γ) produced by T cells that will stimulate phagocyte cells to perform phagocytic responses and may stimulate lymphocyte proliferation, increase T-cell count, and increase secretion of IL-12. D-limonene may increase the production of IL-2, one of the cytokines essential for lymphocyte proliferation. Based on research by Yoon et al. [56], D-limonene and its metabolites can increase phagocytes and can significantly increase IL-2. IL-2 is one of the many cytokines that regulate the immune response, functioning as a mitogen for T cells, potentially increasing the proliferation and function of T cells, B cells, and NK cells, improving antigen formation and increasing the production and release of other cytokines. Activated macrophages produce and release products including several cytokines, inorganic reactive radicals, reactive oxygen intermediates, and reactive nitrogen with biological activity. In our study, peritoneal macrophages exposed to active propolis compounds showed the production of cytokines. Proinflammatory cytokines are essential to initiate an inflammatory process that causes tissue damage. These cytokines induce tissue damage and reduce the capacity to repair damaged

25.4 PROPOLIS AS IMUNOMODULATORY AGENTS

437

tissue by stimulating the production of other mediators [62]. Cellular bacteria activate NK cells by inducing expression of NK cell activating ligand on the surface of infected cells, or dendritic cell stimulation and IL-12 production by macrophages which are strong mecrophage activating cytokines. NK cells produce IFN-γ which in turn activates macrophages and enhances the ability of macrophages to kill the bacteria they ingest [63]. In our study, it was found that propolis of Trigona spp. was able to reduce production of proinflammatory cytokines, such as IFN-γ and TNF-α, and increase production of antiinflammatory cytokines, such as IL 2. Thus, it can be assumed that in ethanol extract propolis has an active compound that acts as an antiinflammatory agent in response to the presence of superantigens resulting in toxic shock mice infected with S. aureus bacteria. The production of IL-2 can be stimulated by the presence of immunomodulatory compounds and involves the role of a differentiated T cell into Th cells capable of producing IL-2 that can activate other immune systems. The combined results show the immunomodulator activity of propolis extract.

25.4.4 THE INFLUENCE OF PROPOLIS TRIGONA SPP. ON THE PRODUCTION OF ANTIBODIES (IGG) Effect of different administration of propolis Trigona spp. can stimulate antibody production as shown in the Table 25.8. The production of IgG antibodies increased significantly by administering different concentrations of propolis (0.16%, 0.48%, and 1.44%). Provision of 0.16% propolis, has significantly been able to increase the production of antibodies when compared with the giving of distilled water (negative control). The treatment of propolis 0.48% was not significantly different from that observed for CAPE (positive control). Serum IgG content increased dramatically in mice receiving 0.48% propolis Trigona spp. from Indonesia compared with other treatments (0.16% and 1.44%). Immunoglobulin G is the main immunoglobulin formed on antigen stimulation. IgG generally coats the microorganisms so that the particles are more easily phagocytosed; besides that IgG is also able to neutralize toxins and viruses [63]. Serum antibody levels continue to rise for several weeks and then decrease. The first antibody formed is IgM, followed by IgG, IgA, IgD, and IgE [63]. There was a decrease in the treatment group of propolis 0.16% and 1.44% as well as in the negative control group (aquadest). Provision of doses that exceed the effective dose can be toxic, so the administration of propolis extract Trigona spp. which exceeds the maximal doses leads to a Table 25.8 Effect of Propolis of Trigona spp. on the Production of Antibodies [51] Group

IgG (ng/mL)

Kontrol (before intervention) CAPE (positive control) Aquadest (negative control) Propolis 0.16% Propolis 0.48% Propolis 1.44%

12.191 6 0.31a 13.459 6 0.56a 8.193 6 0.24d 10.717 6 0.80c 13.733 6 0.44a 11.853 6 0.31b

The numbers followed by the same letter in the same column states no significant difference at the test level of 5%.

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CHAPTER 25 TRIGONA PROPOLIS AND ITS POTENCY FOR HEALTH

reduction in the expression of the immune response due to the immunosuppressant mechanism of the immune system. The influence of antigens/foreign bodies through T cells and B cells proliferates and differentiates into plasma cells capable of forming and releasing Ig (Immunoglobulin) with the same specificity as receptors present on the surface of precursor cells. Immunoglobulin G is found in serum. Propolis contains alkaloid compounds, flavonoids, triterpenoids, and saponins. The tendency of elevated levels of IgG in the administration of 0.48% propolis is due to the immunomodulatory terpenoid content of ethanol extract propolis of Trigona spp. from Indonesia. As stated by Wagner et al. [64], generally terpenoids, alkaloids, or polyphenols have immunomodulatory properties. Provision of terpenoid compounds can increase the production of total antibodies, antibodies that produce cells in the spleen, cellular bone marrow, and positive α-esterase cells significantly compared with normal animals exhibiting potentiation effects on the immune system [65].

25.5 PROPOLIS AS ANTITUBERCULOSIS 25.5.1 PROPOLIS AND ITS POTENTIAL TO ACCELERATE NUTRITIONAL STATUS IN TB PATIENT Pulmonary tuberculosis (TB) is a global infectious disease and the second leading cause of death after HIV infection. Antituberculosis drugs (ATD) have been used as treatment in TB patients. However, it has a side-effect, which is hepatotoxic effects [66,67]. It leads to decreaseed appetite, nausea, dizziness, insomnia, fever, and weight loss [68 70], thus resulting in decreased nutritional status. Unfortunately, nutritional status strongly supports the healing process [71]. Some studies suggest that propolis has hepatoprotective action [72 74]. Wahyunitisari et al. [75] found that propolis has the ability to act against TB infection and has a synergizing effect with ampicillin, gentamycin, streptomycin, rifampicin, isoniazid, cloxacyllin, and ethambutol to kill mycobacterium tuberculosis [76 78]. The synergy effect of propolis with those antibiotics potentially accelerates the healing process. Our studies examined the potency of propolis to accelerate nutritional status improvement in TB patients. We administered a standard treatment in accordance with the Ministry of Health of Repucblic of Indonesia guideline for TB treatment. However, we added low and high concentration of propolis in the treatments for 6 months (Table 25.9). Table 25.9 The Treatment of Intervention Group P0 P1 P2

Intensive Stage Everyday for 56 Days RHZE (150/75/400/275) 1 Propolis

Advanced Stage 3 Times a Week for 16 Weeks RH (150/150) 1 Propolis

(4 tablets of 4FDC 1 20 drops of placebo propolis) (4 tablets of 4FDC 1 20 drops of 6% propolis) (4 tablets of 4FDC 1 20 drops of 30% propolis)

(4 tablets of 2FDC 1 20 drops of placebo propolis) (4 tablets of 2FDC 1 20 drops of 6% propolis) (4 tablets of 2FDC 1 20 drops of 30% propolis)

RHZE, rifampicin, isoniazide, pyrazinamid, ethambutol; FDC, fixed Dose Combination. The dose of ATD used was dosage for adult patients according to the National Guidelines for Tuberculosis Control (MoH of RI 2014).

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439

The ARB conversion of each group was quite different. In P0 group, the conversion was occured in the week 6, which was only in one subject (7.1%). In the next week, there were another ARB conversion of four subjects and this continued until all of the subjects had a negative test of ARB conversion in month 6. The average period of conversion in this group was 10 weeks. Similarly, P1 group conversion was occurred in week 6 (7.1%). In week 7, there was another conversion and this continued until the conversion for all subjects (100.0%) was reached in month 3. The average period of conversion in P1 group was 8 weeks. The conversion time was 100% shorter than the P0 group. In contrast, P2 group conversion occured earlier than the others. 26.7% of subjects experienced conversion in week 3. This group took only 3 months to achieve 100% of full conversion. The average period of conversion in P2 group was 5 weeks (Table 16). Based on this result, the supplementation of 20 drops of 30% liquid propolis to ATD treatment were beneficial in accelerating the healing process of TB patients (Table 25.10). Table 25.10 The Average Period of TB Subject Conversion P0, P1, and P2 Groups Period Week

Group

Month

0

1

2

3

4

5

6

7

8

3

4

5

6

0

0

0

0

0

0

1 1

3 4

5 9

4 13

0 13

0 13

1 14

7.1

28.6

64.3

92,9

92.9

92.9

100.0

P0 group, n 5 14 Conversion (n) Accumulation (n) Accumulation percentage (%) Average period of conversion

10 weeks

P1 group, n 5 14 Conversion (n) Accumulation (n) Accumulation percentage (%)

0

0

0

0

0

0

1 1

4 5

6 11

3 14

0 14

0 14

0 14

7.1

35.7

78.6

100.0

100.0

100.0

100.0

Average period of conversion

8 weeks

P2 group, n 5 15 Conversion (n) Accumulation (n) Accumulation percentage (%) Average period of conversion

0

0

0

4 4

6 10

3 13

0 13

1 14

0 14

1 15

0 15

0 15

0 15

26.7

66.7

86.7

86.7

93.3

93.3

100.0

100.0

100.0

100.0

5 weeks

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CHAPTER 25 TRIGONA PROPOLIS AND ITS POTENCY FOR HEALTH

P0

1.6

P1

1.2

BMI changes

1.2

0.8

1

1

1.3

0.2

0.4

0.3

0.4

–0.1

0

0.1

0.2 0.4

0.5

1.5

1

1

0.9

0

–0.4 M0 M1 M2 M3 M4 M5 M6 M7 M8

B3

–0.8

–0.5

B4 –0.4

–1.2 –1.5

1.4

0.5

–0.2

–1.6

1.4

1 1

0.8 0

P2

–1.4 –1.4

–1.2

–1.1 –1

B5

B6

–0.3 –0.2

–0.9

–1.6

Measurement time

FIGURE 25.1 BMI changes during treatments.

Propolis has a good ability to against mycobacterium tuberculosis infection. This result was in line with Wahyunitisari et al. [75], Scazzocchio et al. [76], Scheller et al. [77], Krol et al. [78], Syamsudin et al. [79], and Pranandaru et al. [80]. They stated that propolis synergized with ATD against mycobacterium infection. Diterpen, triterpen, and sesquiterpen and its derivates in propolis have antimycobacterial activity [81]. In addition, Toreti et al. [82] reviewed compounds in propolis which acted as antibacterials and antibiotics, such as flavanones, flavones, phenolic acids and esters, prenylated p-coumaric, labdane diterpenes, prenylated flavonones, and prenylated benzophenones. BMI was one of adult nutritional status indicator. The P0 group experienced decreased BMI since the beginning of intervention and did not recover until the end of intervention (6 months). The final BMI was 0.2 from baseline. These data showed that intensive ATD administration (daily ATD administration) strongly decreased the nutritional status of TB patients. In the P1 group, BMI decreased during the first 3 weeks and started to increase in week 4 (10.1). In the month 6, BMI had achieved 10.9. Unlike other groups, the P2 group directly experienced BMI increasing from the beginning of intervention and continued until the end of intervention (11.5). Our results indicated the P2 group experienced a rapid nutritional status improvement during TB treatments (Fig. 25.1).

25.6 ANTIEMETIC EFFECT OF PROPOLIS In addition to previously described functons, propolis has an antiemetic effect. Unfortunately, it has not been extensively explored. Emesis, nausea, and/or vomiting, is an unpleasant state which is a manifestation of several conditions including pregnancy, toxicants ingestion, and a side-effect of medication, surgery, and cancer chemotheraphy [83]. There are several part of body involved in emesis induction, including chemoreceptor trigger zone (CTZ), vestibular center, vagal nerve and central nervous system (CNS) [84]. They possess several receptors that may be activated by emetogenic subctances. The receptors are dopamine (D2), 5-HT3, neurokinin-1 (NK1), muscarinic acetylcholine (AChM), histamine (H1), and opioid receptors.

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441

Regarding antiemetic effect, several compounds had been successfully isolated by Eda et al. [85]. The compounds are propionic acid, cinamic acid, lupeol, aromadendrane, and dehydrohautriwaic acid. Nevertheless, propolis content is widely diverese and depends on plants of resin sources, bee species, and season [6]. It brings a difficulty in standardization of biological activity of propolis. However, the researchers have tried to investigate the diversity of propolis content around the world. This section discuss the potenty of propolis in prgenancy. Especially in the first trimester, pregnant mothers frequently experience emesis. According to Kramer et al. [86] who conducted a longitudinal study in Canada, they found that the prevalence of pregnant women who experienced emesis in first trimester was 63.3%. The etiology is still unclear, however, it could lead to a severe condition. Decreased appetite during emesis would reduce calory, nutrition intake, and body weight gain. Veenendal et al. [87] concluded that pregnant mothers who frequently experience nausea and vomiting tend to deliver babies with low birthweight (LBW) and premature. Propolis is a safe herb for normal physiological conditions. Animal studies confirm propolis is safe with a nonobserved adverse effect level (NOAEL) 5000 mg/kg bodyweight/day [88]. MennitiIppolito et al. [89] surveyed suspected adverse reaction of propolis from 2002 to 2007 in Italia. They found only 18 cases of allergic reaction and disgestive tract problem. Unfortunately, its safety in preganancy has not been examined. Is there any teratogenic effect? Our team is still investigating.

25.6.1 POTENTIAL ANTIEMETIC EFFECT OF PROPOLIS IN PREGNANCY The antiemetic effect of propolis is a less explored function. We have an interest in these issue because of its other functions. Propolis is like a superpower herb. It possesses a lot of biological activities. Our present issue completes the former function of propolis. For example, propolis administration could improve patient’s cancer status by its apoptosis inducer activity. The patient also experinces emesis during medication therefore this new emerging issue is very useful. Beside that, antiemesis propolis in pregnancy also probably brings a beneficial effect. Antimicrobial, antidiabetic, and antioxidant functions are important to keep a mother healthy. Treatment of emesis during pregnancy depends on its severity. Pharmacological and nonpharmacological approaches can be done. Nonpharmacological treatments such as dietary changes in small portions but often, emotional support, acupressure, and acupuncture. Pharmacological approach can be given in the form of vitamin B6 and doxylamin, metoclopramide, corticosteroids, antihistamines and anticholinergics, and antiemetics [90] However, the adverse effect of the drug is still a problem. Nowdays, consumers tend to consume natural products. They believe it to be safer than phamacological intervention. Natural products such as propolis are widely used for any treatment of disease. Propolis demand is relatively high and well-known around the world beacuse of its superpower functions. Here, we will discuss our interest in the antiemetic effect of propolis. Although still lacking data, we try to elaborate its function from any point of view. For the first time, the antiemetic effec of propolis was published by Eda et al. [85]. They used Brazilian propolis with several solvents. Their research is basic research because they isololated the potential compounds that possess antiemetic activity. Water and methanol extract of Brazilian propolis showed 50.9% and 44.9% of inhibition of retching in young chickens, respectively. Table 25.11 shows the result of their research.

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CHAPTER 25 TRIGONA PROPOLIS AND ITS POTENCY FOR HEALTH

Table 25.11 Antiemetic Effects of Each Extract on Copper Sulfate-Induced Emesis in Young Chicks Drug Control Water extract Control MeOH sol. 

Dose (mg/kg) 300 100

No. of Young Chicks

No. of Retches

5 6 5 6

45.8 6 3.01 22.5 6 1.77 53.2 6 2.48 29.3 6 1.61

Inhibition (%) 50.9 44.9

P , .001, significantly different from the control value.

Antagonic action to nausea and vomiting receptors is a way of treating the emesis [84]. Eda et al. [85] isolated six compounds with antiemetic effect. They are dehydrohautriwaic acid, (Z)-3(2,2-dimethyl-2H-1-benzopyran-6-yl)-2propenoic acid, aromadandrane-4β,10α-diol, (E)-3-(2,2dimethyl-2H-1-benzopyran-6-yl)-2propenoic acid, lupeol, and dihydrocinamic acid. They have antagonic properties of δ (enkephalinergic) receptors, dopamine inhibition, and antagonistic effects against 5-HT3, 5HT4, and or NK1 receptors. We also conducted the research on the antiemetic effect of Indonesian propolis (unpublished data). We have examined propolis from three provinces of Indonesia. Our research found that Indonesian propolis also possesses an antiemetic effect. Water extract showed higher antiemetic activity than ethanol extract. It is in line with Eda et al. [85]. We speculated that there is a water soluble compound that is a strongly antiemetic subtance. Linked to our objective, the safety issue of propolis is raised when we are recommending it to be antiemetic product. Until now, toxicological studies examine the safety of propolis only in normal physiological conditions either in human or animal. Pregnant mothers are particularly vulnerable to foreign subtances because it affects not only themselves but also the embryo. No study has investigated the safety level of propolis in a preganant condition. Therefore, we still need further research about it before we can recommend propolis as an alternative for emetic treatment.

25.6.2 WHAT NEXT RESEARCH MUST BE CONDUCTED? Although still limited data, animal assays show propolis has antiemetic effects. Like the other question in propolis study, the solvent is a critical problem to claim the antiemetic activity level. We have conducted the comparative research that indicates that water extract showed higher antiemetic activity. As per the research by Eda et al. [85] six compounds had been isolated as an antiemetic. For the next research, we recommend to investigate the comparision of those six compounds between water and ethanol extract. On the other hand, new compounds may be isolated from water extract that have not been detected before. To be an antiememetic in pregnancy, we must pay attenton to propolis safety level. No study has been evaluated in pregnancy either in animal or human assay. However, Jung et al. [91] said that caffeic acid phenethyl ester (CAPE), an active ingredient of propolis, had selective estrogen effects. CAPE did not increase the growth of MCF-7 estrogen receptor-positive breast cancer cells, but was a modulator in a healthy cell. Nevertheless, we need further advanced study to confirm the

REFERENCES

443

safety level of propolis in pregnancy. In addition, propolis content is not only CAPE but also a lot of other chemical compounds that may be risky for pregnant mother. Recently, propolis extract has been demonstrated to synergistically enhance the efficacy of antibiotics, especially those acting on cell wall synthesis such as vancomycin and oxacillin, against drug-resistant microorganisms [93]. It is possible that majority of the beneficial effects of propolis on body functions may due to presence of polyphenols; phenolic acids; caffeic, coumaric, ferulic, and isoferulic [94].This study reported that overall, flavones and flavonols ranged from B20% up to B36% in the glyceric extract, while flavanones and diidroflavonols were between B28% and B41%. The content of glycolic and hydroalcoholic extracts were found to be richer in the total polyphenols content. The antioxidant properties determined for the four preparations, revealed that it is strictly related to the polyphenols content for propolis products whose composition is quite comparable [94]. A more recent experimental study showed that propolis of Chihuahua possesses hypoglycaemic and antioxidant activities and can alleviate clinical and biochemical manifestations of diabetes mellitus [95]. These effects may be directly related to the chemical contents of propolis; pinocembrin, quercetin, naringin, naringenin, kaempferol, acacetin, luteolin, and chrysin because most of the compounds identified in propolis are reportedly active in terms of the antioxidant parameters; superoxide dismutase, catalase, and glutathione peroxidase. It seems that studies on the efficacy of propolis which is a unique resinous aromatic substance produced by honeybees from different types of species of plants, are promising and it has been effective in the treatment of several pathological conditions [93,96]. Finally, propolis is considerebly influenced by the environment. Different regions, seasons, honeybee species will produce different content of propolis. Biological activity mapping could be a research topic. The mapping needs a standard method of sampling, extraction, and analysis and then we could compare propolis biological activity. Actually, those standard methods are already available from Bankova et al. [92].

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[73] Hashmi N, Muhammad F, Javed I, Khan JA, Khan MZ, Khaliq T, et al. Nephroprotective effects of Ficus religiosa linn (peepal plant) stem bark against isoniazid and rifampicin induced nephrotoxicity in albino rabbits. Pak Vet J 2013;33:330 4. [74] Cevik MU, Acar A, Tanriverdi H, Varol S, Arikanoglu A, Yucel Y, et al. Toxic effects of isoniazid and rifampicin on rat brain tissue: the preventive role of caffeic acid phenethyl ester. Int J Pharmacol 2012;8:555 60. [75] Wahyunitisari MR, Mertaniasih NM, Rachmawati D. Antimicrobial activities of andrographolide and propolis against intracellular Mycobacterium tuberculosis phagocytosed by monocytes derived macrophages. Folia Medica Indones 2006;42:22 7. [76] Scazzocchio F, D’Auria FD, Alessandrini D, Pantanella F. Multifactorial aspects of antimicrobial of propolis. Microbiol Res 2006;161(4):327 33. [77] Scheller S, Dworniczak S, Waldemar-Klimmek K, Rajca M, Tomczyk A, Shani J. Synergism between Ethanolic Extract of Propolis (EEP) and anti-tuberculosis drugs on growth of mycobacteria. Naturforsch C. 1999;54(7-8):549 53. [78] Krol W, Scheller S, Shani J, Pietsz G, Czuba Z. Synergistic effect of ethanolic extract of propolis and antibiotics on the growth of Staphylococcus aureus. Arzneimittelforschung 1993;43(5):607 9. [79] Syamsudin DRM, Kusmardi. Immunomodulatory and in vivo Antiplasmodial Activities of Propolis Extracts. Glob J of Pharmacol 2008;2(3):37 40 2008. [80] Pranandaru HA, Sembodo J, Choirina, Wijaya FK, Sewaka SW. Propolis Sebagai Suplemen Bagi Penderita Tuberkulosis Dewasa. PKM Penelitian 2010, Dikti Kemendikbud, 2011. [81] Cantrell CL, Franzblau SG, Fischer NH. Antimycobacterial plant terpenoids. Planta Med 2001;67:685 94. [82] Toreti VC, Sato HH, Pastore GM, Park YK. Recent Progress of Propolis for Its Biological and Chemical Compositions and Its Botanical Origin Volume eCAM. Hindawi Publishing Corporation; 2013. p. 1 3. [83] Hussain M, Raza MS, Khan RM, Nawaz S. In vivo assessment of antiemetic potential of crude extract of Vetiveria zizanioides (Linn.); chick emesis model. Int J Pharm Sci 2015;5(3):1068 71 88 (Ahmed et al. 2013). [84] Ahemd S, Hasan MM, Ahmed ES, Mahmood AZ, Azhar I, Habtemariam S. Antiemetic effects of bioactive natural productsd 2013 Phytopharmacology 2013;4(3):390 433. [85] Eda M, Hayashi Y, Kinoshita K, Koyama K, Takashi K, Akutu K. Anti-emetic principles of water extract of Brazilian propolis. Pharm Biol 2005;43(2):184 8. [86] Kramer J, Kramer J, Bowen A, Stewart N, Muhajarine N. Nausea and vomiting of prgenancy: prevalence, severity and realtion to psychosocial health. Am J Matern Child Nurs 2013;38(1):21 7. [87] Veenendaal M, Abeelen A, Painter R, van der Post J, Roseboom T. Consequences of hyperemesis gravidarum for offspring: a systematic review and meta-analysis. Int J Obst and Gynaecol 2011;118:1302 13. [88] Ramadan A, Soliman G, Mahmoud SS, Nofal SM, Abdel-Rahman RF. Evaluation of the safety and antioxidant activitites of Crocus sative and propolis ethanolic extracts. J Saudi Chem Soc 2012;16:13 21. [89] Menniti-Ippolito F, Mazzanti G, Vitalone A, Firenzuoli F, Santuccio C. Surveillance of suspected adverse reaction to natural health products, the case of propolis. Drug Saf 2008;31(5):419 23. [90] Quinlan JD, Hill DA. Nausea and vomiting of pregnancy. Am Fam Physician 2003;68(1):121 8. [91] Jung B, Kim M, Kim H, Kim D, Sang J, Her S, et al. Caffeic acid phenethyl ester, a component f beehive propolis, is a novel elective estrogen receptor modulator. Phytothee Res 2010;24:295 3000. [92] Bankova V, Bertelli D, Borba R, Conti JB, Cunha DBD, Banert C, et al. Standrad methods for Apis mellifera propolis research. J Api Res 2016;56:1 49. [93] Issam A-A, Zimmermann S, Reichling J, Wink M. Antimicrobial activities of european propolis collected from various geographic origins alone and in combination with antibiotics. Medicines 2018;5:2. Available from: https://doi.org/10.3390/medicines5010002.

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[94] Galeotti F, Maccari F, Fachini A, Volpi N. Chemical composition and antioxidant activity of propolis prepared in different forms and in different solvents useful for finished products. Foods 2018;7. Available from: https://doi.org/10.3390/foods7030041. [95] Rivera-Yan˜ez N, Rodriguez-Canales M, Nieto-Yan˜ez O, et al. Hypoglycaemic and antioxidant effects of propolis of chihuahua in a model of experimental diabetes Evidence-Based Complementary Altern. Med. 2018;Article ID 4360356, 10 pages, 2018. Available from: https://doi.org/10.1155/2018/4360356. [96] da Silva LM, de Souza P, Jaouni SKA, Harakeh S, Golbabapour S, de Andrade SF. Propolis and its potential to treat gastrointestinal disorders Evidence-Based Complementary Altern. Med. 2018;Article ID 2035820, 12 pages, 2018. Available from: https://doi.org/10.1155/2018/2035820.

FURTHER READING Kalsum N, Sulaeman A, Setiawan B, Wibawan IWT. Effect of liquid propolis Trigona spp. to the immune response of Sprague Dawley mice infected with Sthapylococcus aureus. JGP 2017;12(1):1 8. Kartal M, Kaya S, Kurucu S. GC-MS analysis of propolis samples from two different regions of Turkey. Z Naturforsch C. 2002;57(9-10):905 9.

CHAPTER

THE ROLE OF BEE PRODUCTS IN THE PREVENTION AND TREATMENT OF CARDIOMETABOLIC DISORDERS: CLINICO-PHARMACOLOGICAL AND DIETARY STUDY

26

Svetoslav Handjiev1,3, Teodora Handjieva-Darlenska2 and Aneliya Kuzeva3 1

Medical University of Sofia, Bulgaria 2Medical University of Sofia, BASORD, Bulgaria 3Bulgrian Association of the Study of Obesity and Related Diseases (BASORD), BASORD, Bulgaria

26.1 INTRODUCTION Epidemiological studies indicate that cardiometabolic diseases (CNDs) have become a worldwide cause of morbidity and mortality, despite tremendous advancements in drug therapy. Diet and lifestyle changes are important in the pathogenesis and prevention of these problems [1]. The honey bee (Apis mellifera L.) is known to collect propolis, which is a sticky, resinous material, from various plants and mix it with wax and other secretions [2,3]. There are several biological functions of propolis that have been reported including cytotoxic, antimicrobial, antiviral, free radical scavenging, anti-inflammatory, local anesthetic, hepatoprotective, antitumor, and immune system stimulating [4 7]. Propolis is widely used in popular medicine and apitherapy, with extensive use in food and beverages to improve health and prevent diseases in Eastern European countries [2,3,5]. Propolis has a complex chemical composition which depends on from which plant source it is derived [6]. The samples of propolis have been analyzed and have identified at least 300 different compounds [7,8]. The biological activities are mainly attributed to the phenolic components such as flavonoids in all their forms (flavonols, flavones, flavonones, dihydroflavonols, and chalcones), terpenes, beta-steroids, aromatic aldehydes, and alcohols [7,8]. The mechanism of propolis polyphenols can be summarized as potential antioxidants with a significant ability of scavenging reactive oxygen species (ROS) and radical reactive nitrogen species (RNS) to decrease the xanthine oxidase reaction. They also chelate metal ions involved in the process of free radical generation and disrupt the cascade of reactions, leading to the peroxidation of lipids and synergistic action with other antioxidants [9,10]. The medical application of propolis has led to increased interest in its chemical composition and potential clinical use in humans.

The Role of Functional Food Security In Global Health. DOI: https://doi.org/10.1016/B978-0-12-813148-0.00026-8 © 2019 Elsevier Inc. All rights reserved.

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CHAPTER 26 THE ROLE OF BEE PRODUCTS IN THE PREVENTION

It is well known that increased intake of the Western diet is associated with oxidative stress and inflammation with high lipid peroxides produced through a free radical chain process of autoxidation of lipids containing polyunsaturated fatty acids; their formation by ROS action has been implicated in the pathogenesis of CMDs [1]. The apidietetics is the main part of the apitherapy—prevention and treatment with nutritional regiment, enriched with different bee products. The modern apidietetics comprises of bee products in combination with the main nutritional ingredients such as proteins, fats, carbohydrates, vitamins, salts, etc. The bee products are milestones for the healthy Balkan nutrition, the so-called the Balkan diet [11 14]. Our studies emphasize the important role of apidietetics (nutritional regiment, enriched with propolis, honey, royal jelly, bee pollen, laclarville, etc.) in the prevention and treatment of CMDs. The aim of this chapter is to clarify the effect of bee products on the parameters of metabolism and the cardiovascular vascular diseases while treating obesity and metabolic disorders.

26.2 EFFECTS OF BEE PRODUCTS ON CARDIOMETABOLIC DISEASES 26.2.1 CLINICAL STUDIES The majority of the evidence on the role of bee products in diseases is experimental. Hence any data available in humans should be considered important. In a clinical study among 68 individuals (29 males and 39 females) with average age of 40.2 years and average values of BMI 31.4kg/m2, a hypocaloric and normoprotein diet was administered, consisting daily of 99 g proteins, 47 g fats, and 158 g carbohydrates, enriched by bee products (propolis, bee pollen, and royal jelly) [13]. Parameters of metabolism and the cardiovascular system (body mass, lean body mass, fat tissue mass, serum lipids, blood sugar, uric acid, arterial pressure and pulse rate before and after loading, functional tests) have been studied. After the treatment was concluded a reduction of the body mass by 5.76 kg was established, as an improvement of the lean body mass/fat tissue mass ratio. Total cholesterol decreased with an average of 25.3% (from 7.82 to 5.90 mmol/L), the level of triglycerides dropped by 49,7% (from 3.42 to 1.72 mmol/L). Blood sugar, uric acid, atherogenic index, and the cardiovascular tests also changed favorably (Tables 26.1 and 26.2). Table 26.1 Clinical Data Among Subjects With Obesity. Values Are Means Parameter

BMI

FM

LBM

LBM/FM

VBM

W

H

W/H

SD

Before treatment After treatment

35.4 31.9

39.4 35.2

60.6 64.8

1.53 1.84

14.1 12

109 96

120.2 113.2

0.91 0.85

27 24.2

BMI, body mass index; FM, fat mass; LBM, lean body mass; VBM, visceral body mass; W, Waist; H, hips; SG, sagittal diameter.

Table 26.2 Blood Lipids and Blood Pressures Among Obese Subjects. Values Are Means

Before treatment After treatment

Total Cholesterol (mm/L)

LDL (mol/L)

6,72  5.52



4.42 3.26

Triglycerides (mmol/L) 

2.34 1.72

Lipid status and blood pressure was also ameliorated for this period;  P , .05.

SBP (mmHg) 

160 145

DBP (mmHg) 

95 85

26.5 COMMENTS

451

26.3 SECOND STUDY The study was performed on 1276 persons (501 females and 775 males), 36.2 mean age [14]. They all passed through anthropometric measurements of body weight and relative body mass and through examination of their actual nutrition habits. In part of them we measured blood pressure, cholesterolemia, triglyceridemia, glycemia, and 146 mean electrocardiographic evaluations of ischemic heart disease were carried out. Various hypoenergetic regimens of nutrition enriched with propolis, bee pollen, royal jelly, multiflower honey, pectin, and fibers were tested. Out of 1276 only 455 (36.4%) subjects had a normal body mass index (BMX), 40.3% overweight while 23.3% had severe obesity. Metabolic syndrome is characterized with android obesity, leading to diabetes, hyperlipidemia, hypertension, which are early degenerative cardiovascular risk factors. It is possible that about two-thirds (63.6%) have serious anthropometric and metabolic risk factors which need treatment. We examined various diets (enriched by bee products) in the course of treatment and prevention of those metabolic diseases that are coronary risk factors. In their gist all these diets may be reduced to lowered energetic content: in the range of 1200 1400 kcal per day, the optimal amount of protein being 80 100 g per day, as well as lowering fats (50 60 g per day) and carbohydrates (150 200 g per day). Diets of this kind result in a reduction of overweight, the relative body mass, glycemia, triglyceridemia, as well as systolic and diastolic blood pressures. Addition of physical activity to diet therapy increases the beneficial effects of diet and bee products lead to improvement in the cardiovascular and respiratory systems.

26.4 THIRD STUDY On the base of our studies we created a series of dietary products for prevention and treatment of obesity and metabolic syndrome—containing a mixture of propolis, multiflavored honey, bee pollen, various herbs, and bioactive substances. Our hypothesis is that the bee product (especially propolis) has an effect on the stomach mucosa—on the secretion of the stomach hormone ghrelin. Thus, there is a positive effect on the metabolic pathways. The effects of food supplements enriched with bee products have been examined among another 302 individuals (171 females and 131 males) diagnosed with obesity [15]. The mean age was 46.3 years and the mean BMI 32.8 kg/m2. After allergy examination, the food supplement was prescribed as follows-40 drops thrice daily, 15 minutes before meals for 5 days, then 60 drops at 10 AM and at 4.00 PM, twice daily in a cup of tea. The results after treatment with the bee product supplements are illustrated in Tables 26.1 and 26.2.

26.5 COMMENTS All the three studies show the beneficial role of bee products (propolis, bee pollen, and royal jelly) in the treatment of obesity and metabolic syndrome as well as a decline in cardiovascular risk factors which are important for the early prevention of atherosclerosis. Our study demonstrates that

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CHAPTER 26 THE ROLE OF BEE PRODUCTS IN THE PREVENTION

the dietary menus, enriched with pectin, fibers, propolis, fruit, and vegetable juices reduce the coronary risk and ameliorate the metabolic parameters among shift and night transport workers. There is substantial evidence of the benefits of propolis on human health [2]. However, the majority of the studies have been conducted using animal models. In a recent study, the chemical characterization and clinical evaluation of the effects of the oral administration of propolis solution on the oxidative status and modulation of lipids in a human population in Talca, Chile has been examined. This double-blind, placebo-controlled clinical trial included eligible subjects (n 5 67) randomized in two groups: propolis (n 5 35) and placebo (n 5 32). In the propolis group, there was a significant increases in HDL-c from 53.9 6 11.9 to 65.8 6 16.7 mg/dL (P , .001) from baseline to 90 days. Compared to placebo subjects, consumption of propolis induced a net increase in GSH levels (P , .0001) and a decrease (P , .001) in TBARS levels in the propolis group [2]. It is possible that the use of propolis may have positive effects on oxidative status and improvement of HDL-c, both of which contribute to a reduced risk of CMDs. Flavonoids are bioactive, polyphenolic, noncaloric, nonnutrient compounds—which are ubiquitous in fruits, vegetables, and other vascular plants and cannot be synthesized by humans. Flavonoids are present in relatively high amounts in the diets of US and European populations, who have total intakes of flavonoids that vary from B200 to 400 mg/day. Animal and clinical studies suggest that intakes of certain flavonoid classes reduce risk of CVDs. Consequently some experts have recommended increased intakes of flavonoid rich diets for preventive of CMDs. A meta-analysis including 20 publications from 12 prospective cohorts evaluated associations between flavonoid intakes and incidence or mortality from CVDs among adults in Europe and the United States [16]. The most common outcome was coronary artery disease (CAD) mortality, and four of eight cohort studies reported significant inverse associations for at least one flavonoid class. Three cohorts reported that increased consumption of flavonoid was associated with lower risk of incident stroke. In 11 studies, the most common flavonoid classes examined were flavones and flavonols combined and only one study examined all seven flavonoid classes. The flavonol and flavone classes were most strongly associated with lower CAD mortality and evidence for protection from other flavonoid classes and CVD outcomes was limited. In view of the diverse functions of flavonoids and polypolyphenol, it could be an attractive alternative for the treatment of multifactorial diseases such as brain degeneration, where a multitude of cellular pathways are disrupted. The underlying mechanisms of polyphenols for nutrition or therapeutic applications must be further consolidated, however there is strong evidence of their beneficial impact on brain function during aging [17].

26.6 FLAVONOID INTAKE AND MORTALITY Epidemiological studies have suggested that flavonoid intake is associated with a decreased risk of coronary heart disease and cardiovascular disease (CVD). There are many epidemiological studies on flavonoid intake and mortality, but no comprehensive investigation has yet been conducted. To quantitatively assess the association between flavonoid intake and mortality from CVD and allcauses, we performed a meta-analysis of prospective cohort studies. In a previous meta-analysis from 16 cohorts of the Seven Countries Study in whom flavonoid intake at baseline around 1960

26.6 FLAVONOID INTAKE AND MORTALITY

453

was estimated by flavonoid analysis of equivalent food composites that represented the average diet in the cohorts [18]. Mean intake of antioxidant flavonoids was inversely associated with mortality from CAD and explained about 25% of the variance in CAD rates in the 16 cohorts. In multivariate analysis, intake of saturated fat (73%; P 5 0.0001), flavonoid intake (8%, P 5 .01), and percentage of smokers per cohort (9%; P 5 .03) explained together, independent of intake of alcohol and antioxidant vitamins, 90% of the variance in CAD rates. Flavonoid intake was not independently associated with mortality from other causes. It is possible that average flavonoid intake may partly contribute to differences in CAD mortality across populations, but it does not seem to be an important determinant of cancer mortality [18]. A total of 15 prospective cohort studies that examined the association between flavonoid intake and mortality from CVD and all-causes were identified [19]. The pooled RR of CVD mortality for the highest versus lowest category of flavonoid intake was 0.86 (95% CI: 0.75, 0.98). All classes of flavonoids, except flavonols and isoflavones, showed significant inverse associations with mortality due to CVDs. A nonlinear association was found between flavonoid intake and CVD mortality in the dose-response analysis and for total mortality, a high intake of flavonoids was associated with lower total mortality (pooled RR 5 0.86, 95% CI: 0.73, 1.00). It is possible that a high intake of flavonoids is associated with reduced risk of mortality from CVD and all causes in men and women. These results support current recommendations of high fruit and vegetables intake as a part of a healthy diet. Previous epidemiologic studies assessing the association between dietary total flavonoids intake and the risk of mortality from CVD and all causes have yielded inconsistent results. Therefore, another meta-analysis was conducted in a dose-response meta-analysis to investigate this association which included 10 studies [20]. The relative risk (RR) of all-cause mortality for the highest versus lowest category of total flavonoids intake was 0.82 (95% CI: 0.72 0.92). An analysis by dose-response revealed that those consuming 200 mg/day of total flavonoids had the lowest risk of all-cause mortality. A marginally significant association was found between dietary total flavonoids consumption and risk of death from CVD (summary RR: 0.85; 95% CI: 0.70 1.03; P 5 .099) and coronary heart diseases (summary RR: 0.74; 95% CI: 0.54 1.02; P 5 .069), respectively. It is possible that the meta-analysis provides strong evidence for the recommendation of consuming flavonoids-rich food to reduce risks of mortality from all causes as part of a healthy diet among general adults [20]. Fruit and vegetable intake that are rich sources of flavonoids and vitamins which have been demonstrated to be inversely associated with greater risk of CVD, total cancer, and all-cause mortality in a systematic review and dose-response meta-analysis of prospective studies [21]. Clinical and experimental studies suggested the chemopreventive effects of flavonoids on carcinogenesis. However, numbers of epidemiologic studies assessing dietary flavonoids and breast cancer risk have yielded inconsistent results. The association between flavonoids, flavonoid subclasses (flavonols, flavan-3-ols, etc.) and the risk of breast cancer lacks systematic analysis [22]. A recent meta-analysis included 12 studies, involving 9513 cases and 181,906 controls, six of which were prospective cohort studies, and six were case-control studies [21]. The risk of breast cancer significantly decreased in women with high intake of flavonols (RR 5 0.88, 95% CI: 0.80 0.98) and flavones (RR 5 0.83, 95% CI: 0.76 0.91) compared with that in those with low intake of flavonols and flavones. A summary of RRs of three case-control studies stratified by menopausal status suggested flavonols, flavones, or flavan-3-ols intake to be associated with a significant reduced risk of

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CHAPTER 26 THE ROLE OF BEE PRODUCTS IN THE PREVENTION

breast cancer in post-menopausal while not in premenopausal women. It is possible that the intake of flavonols and flavones, but not other flavonoid subclasses or total flavonoids, is associated with a decreased risk of breast cancer, especially among post-menopausal women [22]. In earlier studies, antioxidant vitamin deficiency was considered to be important in the pathogenesis of atherosclerosis and CVD [23]. Epidemiological studies show that vitamin A, E, and C and beta-carotene as well as folic acid and selenium were inversely associated with risk of morbidity and mortality due to CVDs and cancer. However, randomized, controlled intervention trials showed no evidence of benefit in CVDs and cancers; but adverse effects were observed in some of the important studies [23]. Hence, there is no evidence to support the use of vitamins in the prevention of CVDs and cancer. However, the majority of the studies on the role of vitamins and minerals show vitamin and mineral rich diets to be protective against CMDs. It is possible that beneficial effects of a vegetarian or a Mediterranean diet on body weight and metabolic syndrome, could be because of high content of flavonoids and omega-3 fatty acids as well as vitamins and minerals in the diets [24 26]. It is possible that along with the traditional remedies, honey, propolis, bee pollen, royal jelly, sucker jelly, bee venom may be used as apitherapy that has a remarkable medicinal pool. Some authors proposed that the 21st century is the century of apitherapy. E. Petkov emphasized that bee pollen (respectively perga) has healing properties to reduce interference in the metabolism of lipods and is used in the diet to improve the quality of life and as part of the complex treatment of android obesity and metabolic syndrome. The authors together with all our studies demonstrate the positive effect firstly of the propolis and also of all other bee products in the management of metabolic disorders. The bee products do not present side effects in the patients participating in our studies. In brief, the results demonstrate that food supplements enriched with honey, propolis, bee pollen, and royal jelly exhibit a healing effect in obese persons. Apidietetics has the capacity to reduce the risk of CMDs, including hyperlipidemias, high blood pressure, and atherogenesis.

REFERENCES [1] Hristova K, Pella D, Singh RB, Dimitrov BD, Chaves H, Juneja L, et al. Sofia declaration for prevention of cardiovascular diseases and type 2 diabetes mellitus: a scientific statement of the international college of cardiology and international college of nutrition; ICC-ICN Expert Group. World Heart J 2014;6:89 106. [2] Mujica V, Orrego R, P´erez J, et al. The role of propolis in oxidative stress and lipid metabolism: a randomized controlled trial. eCAM 2017;2017:4272940. Available from: https://doi.org/10.1155/2017/ 4272940. [3] Fuliang HU, Hepburn HR, Xuan H, Chen M, Daya S, Radloff SE. Effects of propolis on blood glucose, blood lipid and free radicals in rats with diabetes mellitus. Pharmacol Res 2005;51(2):147 52. Available from: https://doi.org/10.1016/j.phrs.2004.06.011. [4] Bankova VS, De Castro SL, Marcucci MC. Propolis: recent advances in chemistry and plant origin. Apidologie 2000;31(1):3 15. Available from: https://doi.org/10.1051/apido:2000102. [5] Toreti VC, Sato HH, Pastore GM, Park YK. Recent progress of propolis for its biological and chemical compositions and its botanical origin. eCAM 2013;2013:13. Available from: https://doi.org/10.1155/2013/ 697390.697390 [PMC free article] [PubMed] [Cross Ref].

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[6] Salatino A, Fernandes-Silva CC, Righi AA, Salatino MLF. Propolis research and the chemistry of plant products. Nat Product Rep 2011;28(5):925 36. Available from: https://doi.org/10.1039/c0np00072h. [7] Mani F, Damasceno HCR, Novelli ELB, Martins EAM, Sforcin JM. Propolis: effect of different concentrations, extracts and intake period on seric biochemical variables. J Ethnopharmacol 2006;105 (1 2):95 8. Available from: https://doi.org/10.1016/j.jep.2005.10.011. ´ lvarez JA. Functional properties of [8] Viuda-Martos M, Ruiz-Navajas Y, Fern´andez-Lo´pez J, P´erez-A honey, propolis, and royal jelly. J Food Sci 2008;73(9):R117 24. Available from: https://doi.org/ 10.1111/j.1750-3841.2008.00966.x. [9] Kurek-Go´recka A, Rzepecka-Stojko A, Go´recki M, Stojko J, Sosada M, Swierczek-Zieba G. Structure and antioxidant activity of polyphenols derived from propolis. Molecules. 2014;19(1):78 101. Available from: https://doi.org/10.3390/molecules19010078. [10] Borys JM, Graca P, Gregorio M, Handjiev SV, et al. EPODE for the Promotion of Health Equity, Cachan cedex France, Lavoisier, 2015, 11-195. http://www. Lavoisier [11] European Coalition Against Obesity, Warsaw, 2017, https://stopobesity.eu/?lang 5 en, accessed nov 2017. [12] Glavce C, Milici N, Popescu-Spineni D, Iancu E. Mondialisation du comportament alimentaire et l’obesite Sofia Mondialisation des comportaments alimentaires et facteurs de risques pour l’obesite et le diabe`te. Simel Press Edt; 2012. p. 42 52. [13] Handjiev SV, Dimitrova V, Atanasov SV. Role of the apidietetics in the treatment of obesity. VI ISORD 2000;167. [14] Handjiiev SV. The Balkan diet (Balkan antioxydative healthy food) in the prevention and treatment of metabolic syndrome. Second Balkan Congress on obesity. Albena; 2006. p. 32 5. [15] Handjiev SV. Childhood obesity and nutrition in the children age in Bulgaria. Milano: EANS; 2017. [16] Peterson JJ, Dwyer JT, Jacques PF, McCullough ML. Do flavonoids reduce cardiovascular disease incidence or mortality in US and european populations? Nutr Rev 2012;70(9):491 508. Available from: https://doi.org/10.1111/j.1753-4887.2012.00508.x. [17] Figueira I, Menezes R, Macedo D, Costa I, Nunes dos Santos C. Curr Neuropharmacol 2017;15 (4):562 94. [18] Hertog MG, Kromhout D, Aravanis C, Blackburn H, Buzina R, Fidanza F, et al. Flavonoid intake and long-term risk of coronary heart disease and cancer in the seven countries study. Arch Intern Med 1995;155(4):381 6. [19] Kim Y, Je Y. Flavonoid intake and mortality from cardiovascular disease and all causes: A metaanalysis of prospective cohort studies. Clin Nutr ESPEN 2017;68 77. Epub 2017 Apr 28. [20] Liu XM, Liu YJ, Huang Y, Yu HJ, Yuan S, Tang BW, et al. Dietary total flavonoids intake and risk of mortality from all causes and cardiovascular disease in the general population: A systematic review and meta-analysis of cohort studies. Mol Nutr Food Res 2017;61(6). Epub 2017 Feb 22. [21] Aune D, Giovannucci E, Boffetta P, Fadnes LT, Keum NN, Norat T, et al. Fruit and vegetable intake and the risk of cardiovascular disease, total cancer and all-cause mortality—a systematic review and dose-response meta-analysis of prospective studies. Int J Epidemiol 2017;46(3):1029 56. Available from: https://doi.org/10.1093/ije/dyw319 1 June. [22] Hui C, Qi X, Qianyong Z, Xiaoli P, Jundong Z, Mantian M. Flavonoids, flavonoid subclasses and breast cancer risk: a meta-analysis of epidemiologic studies PLoS One 2013;8(1):e54318. Epub 2013 Jan 18. PLoS One. 2013;8(1):e54318. Available from: https://doi.org/10.1371/journal.pone.0054318. Epub 2013 Jan 18. [23] Darlenska HD, Handjiev S, Hristova K, Singh RB. Antioxidant vitamins and the heart. World Heart J 2014;6:179 84.

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[24] Slomski A. Vegetarian and Mediterranean diets effective for weight loss. JAMA 2018;319(16):1649. Available from: https://doi.org/10.1001/jama.2018.4738. [25] Shastun S, Chauhan AK, Singh RB, Singh M, Singh RP, Itharat A, et al. Can functional food security decrease the epidemic of obesity and metabolic syndrome? A viewpoint. World Heart J 2016;8 (3):273 80. [26] Singh RB, Fedacko J, Saboo B, Niaz MA, Maheshwari A, et al. Association of higher omega-6/omega-3 fatty acids in the diet with higher prevalence of metabolic syndrome in North India. MOJ Public Health 2017;6(6):00193. Available from: https://doi.org/10.15406/mojph.2017.06.00193.

FURTHER READING Handjieva-Darlenska T, Roville-Sausse S, Handjiev SV. Nutrition et sant´e. Sofia: Edition Simel Press; 2016. p. 59 60. 2016;49-56. Karadjov Y. Therapeutic effect of bee products. XIX ISORD 2011;79 80. Milici N. Comportements alimentaires d´esordonn´es. Mondialisation des comportaments alimentaires et facteurs de risques pour l’ob´esit´e et le diabe`te. Sofia: Simel Press Edt; 2016978-619-183-042-8. p. 36 49. NCD Risk Factor Collaboration (NCD-RisC). Trends in adult body-mass index in 200 countries from 1975 to 2014: a pooled analysis of 1698 popula-tion- based measurement studies with 19.2 million participants. Lancet Lond Engl 2016;387(10026):1377 96. Petkov E. Bee perga food supplement in patients with android obesity and metabolic syndrome. VIII ISORD 2009;75 6.

CHAPTER

MILLETS AS FUNCTIONAL FOOD, A GIFT FROM ASIA TO WESTERN WORLD

27

Ram B. Singh1, Shairy Khan2, Anil K. Chauhan3, Meenakshi Singh4, Poonam Jaglan5, Poonam Yadav3, Toru Takahashi6 and Lekh R. Juneja7 1

Halberg Hospital and Research Institute, Moradabad, Uttar Pradesh, India 2Department of Food Science, SNDT University, Pune, Uttar Pradesh, India 3Center of Food Science and Technology, Institute of Agricultural Sciences & Institute of Technology, Banaras Hindu University Varanasi, Varanasi, Uttar Pradesh, India 4Sr. Principal Scientist, Research, Project Planning and Business Development Directorate CSIR, New Delhi, India 5Center of Nutrition Research, Panipat, Haryana, India 6Graduate School of Human Environment Science, Fukuoka University, Fukuoka, Japan 7Department of Research and Development, Rohto Co Limited, Osaka, Japan

27.1 INTRODUCTION Millets are a group of highly variable small-seeded grasses, widely grown around the world as cereal crops or grains for fodder as well as for food. Millets are important crops in the semiarid tropics of Asia and Africa with 97% of millet production in developing countries [1 3]. The crop is primarily grown on marginal lands in dry areas in temperate, subtropical, and tropical regions. The crop is favored due to its productivity and short growing season under dry, high-temperature conditions. Millets have been important food staples in human history, particularly in Asia and Africa. They have been in cultivation in East Asia for the last 10,000 years [4]. Millets are indigenous to many parts of the world and pearl millet is the most widely grown millet, which is an important crop in India and parts of Africa [4]. The most important species are pearl millet, finger millet, proso millet, and foxtail millet and pearl millet accounts for almost half of global millet production in the world. In terms of cropped area and contributions to food security in regions of Africa and Asia pearl millet is the most important species of millets. Proso millet is used for bird seed in the developed countries and for food in some parts of Asia. In China and Eastern Europe, foxtail millet is an important crop. Finger millet is widely produced in the cooler, higher-altitude regions of Africa and Asia both as a food crop and as a preferred input for traditional beer. The other species (barnyard, kodo, and little millets, the fonios and teff) are locally important food grains restricted to smaller regions or individual countries. The various species differ in their physical characteristics, quality attributes, soil and climatic requirements, and growth duration. Food security has been a major concern to the world’s population that is highly dependent on grains. Millets are nutritionally superior as their grains contain high amount of proteins, minerals, flavonoids, polyphenols, and vitamins. Millets could be used to combat micronutrient malnutrition by biofortification of staple crops. Interestingly, HarvestPlus The Role of Functional Food Security In Global Health. DOI: https://doi.org/10.1016/B978-0-12-813148-0.00027-X © 2019 Elsevier Inc. All rights reserved.

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CHAPTER 27 MILLETS AS FUNCTIONAL FOOD

group realized the importance of millet biofortification and released conventionally bred high iron pearl millet in India to tackle iron deficiency. Since millets are a rich source of essential and nonessential amino acids, vitamins, and minerals, as well as antioxidants and fiber, these grains could be important functional foods for prevention of noncommunicable diseases. This review aims to highlight the role of millets as functional food for worldwide use.

27.2 PRODUCTION OF MILLETS In developing countries, mainly in Asia and Africa, millet production accounts for about 94% of global output, estimated at some 28 million tons (1992 94 average). Of this, pearl millet accounts for about 15 million tons, foxtail millet for 5 million tons, proso millet for 4 million tons, and finger millet for over 3 million tons [1 4]. Millets are produced by small-scale farmers for household consumption and localized trade and pearl millet, in particular, is critically important for food security in some of the world’s hottest, driest cultivated areas. In the developed countries, only limited quantity of millets are produced primarily for a high-value specialty market as bird seed because its value has not yet been explored by the nutrition scientists. Table 27.1 shows the areas of yield and production by region of millets in the world as per the Food and Agriculture Organization. India is the leading producer of millets accounting for about 80% of the global millet production [5]. The world total production of millet grains at last count as per FAO, was 762,712 metric tons and the top producer was India with an annual production of 334,500 tons (43.85%) Millets are commonly called small seeded grasses, which include various species of millets; pearl millet (Pennisetum glaucum(L.) R. Br.), finger millet (Eleusine coracana (L.) Gaertn), foxtail millet (Setaria italica (L.) Beauv), proso millet (Panicum miliaceum L.), barnyard millet (Echinochloa spp.), kodo millet (Paspalum scrobiculatum), and little millet (Panicum sumatrense). Among the millets, pearl millet occupies 95% of the production. Foxtail millet (S. italica (L.) P. Beauv) is the second largest crop among the millets, cultivated for food in semiarid tropics of Asia and as forage in Europe, North America, Australia, and North Africa [1]. The sixth largest crop under cultivation serving as the primary food for rural populations of East and Central Africa and southern India is finger millet (Fig. 27.1). Proso millet is a shortseason crop cultivated in drier regions of Asia, Africa, Europe, Australia, and North America. Barnyard millet is the fastest growing among the millets with a harvesting period of 6 weeks which is predominantly cultivated in India, China, Japan, and Korea for food as well as fodder. Kodo millet is native to the tropical and subtropical regions of Africa and was domesticated in India 3000 years ago. Little millet was domesticated in the Eastern Ghats of India occupying a major portion of the diet of the tribal people and spread to Sri Lanka, Nepal, and Myanmar. In developed countries, millets are considered cheap food and the food industry ignores the use of millet in staple bread. There is a need to educate the food industry about the nutrient quality of millets and to use it as functional food for prevention of metabolic syndrome. Table 27.2 shows the millet utilization by type, region, and selected countries indicating that more than 90% of millet produced is being used as food in developing countries. Use of millets as animal feed is mostly in developed countries indicating that it is considered as a poor man’s food.

Table 27.1 Millet Area, Yield, and Production by Region Area (million ha)

Developing countries Africa Northern Africa Sudan Western Africa Burkina Faso Ghana Cote d’Ivoire Mali Niger Nigeria Senegal Togo Central Africa Cameroon Chad Eastern Africa Ethiopia Kenya Tanzania Uganda Zimbabwe Southern Africa Asia Near East Far East China India Myanmar

Yield (ton/ha)

Production (million tons)

1979 81

1989 91

1992 94

1979 81

1989 91

1992 94

1979 81

1989 91

1992 94

34.70 11.50 1.10 1.10 8.30 0.80 0.18 0.06 0.64 3.01 2.40 0.93 0.12 0.63 0.13 0.36 1.46 0.23 0.08 0.45 0.30 0.35 0.09 22.98 0.19 22.79 3.98 17.84 0.18

34.40 15.80 1.05 1.05 12.60 1.21 0.19 0.08 1.19 4.19 4.50 0.90 0.13 0.79 0.06 0.54 1.33 0.25 0.10 0.23 0.38 0.27 0.11 18.29 0.18 18.41 2.25 15.19 0.17

35.60 18.50 1.96 1.95 14.00 1.24 0.20 0.08 1.20 4.87 5.20 0.89 0.13 0.93 0.05 0.59 1.46 0.25 0.09 0.32 0.41 0.25 0.21 16.99 0.15 16.84 1.90 13.95 0.20

0.68 0.67 0.40 0.40 0.67 0.49 0.64 0.58 0.72 0.44 1.04 0.60 0.36 0.59 0.75 0.50 0.89 0.90 1.05 0.80 1.59 0.43 0.41 0.69 1.02 0.68 1.45 0.51 0.45

0.73 0.66 0.18 0.18 0.68 0.54 0.64 0.61 0.69 0.34 1.04 0.64 0.51 0.51 1.06 0.40 0.97 0.95 0.67 0.94 1.53 0.50 0.49 0.79 0.58 0.78 1.74 0.64 0.69

0.75 0.61 0.28 0.28 0.64 0.64 0.82 0.84 0.61 0.38 0.89 0.61 0.50 0.48 1.01 0.47 0.91 1.05 0.65 0.71 1.57 0.27 0.18 0.89 0.78 0.89 1.93 0.77 0.66

23.67 7.68 0.44 0.44 5.52 0.39 0.12 0.04 0.46 1.31 2.50 0.56 0.04 0.37 0.10 0.18 1.31 0.20 0.08 0.36 0.47 0.15 0.04 15.75 0.19 15.56 5.79 9.19 0.08

25.00 10.46 0.19 0.19 8.55 0.65 0.12 0.05 0.82 1.43 4.67 0.58 0.07 0.40 0.06 0.22 1.29 0.24 0.07 0.22 0.58 0.14 0.06 14.45 0.10 14.35 3.92 9.76 0.12

26.60 11.36 0.55 0.55 9.00 0.79 0.17 0.07 0.73 1.86 4.62 0.55 0.06 0.45 0.06 0.28 1.33 0.27 0.06 0.23 0.63 0.07 0.04 15.17 0.12 15.05 3.67 10.70 0.13 (Continued)

Table 27.1 Millet Area, Yield, and Production by Region Continued Area (million ha) 1979 81 Nepal Pakistan Central America and the Carribean South America Argentina Developed countries Australia United States CIS2 World Modified from FAO, 1979 81.

1989 91

Yield (ton/ha)

1992 94

Production (million tons)

1979 81

1989 91

1992 94

1979 81

1989 91

1992 94

0.12 0.51 0.00

0.20 0.44 0.00

0.21 0.43 0.00

0.99 0.50 0.00

1.16 0.41 0.00

1.14 0.44 0.00

0.12 0.25 0.00

0.23 0.18 0.00

0.24 0.19 0.00

0.20 0.20 2.94 0.03 0.09 2.79 37.60

0.04 0.04 4.13 0.03 0.15 3.92 38.60

0.04 0.04 2.49 0.03 0.15 2.27 38.10

1.21 1.21 0.65 1.00 1.20 0.63 0.68

1.49 1.49 0.88 0.88 1.20 0.87 0.74

1.53 1.53 0.72 1.05 1.20 0.68 0.74

0.25 0.25 1.93 0.03 0.11 1.76 25.70

0.06 0.06 3.64 0.03 0.18 3.40 28.65

0.06 0.06 1.79 0.03 0.18 1.54 28.38

27.3 NUTRIENT COMPOSITION OF MILLETS

461

FIGURE 27.1 Production of millets in Asia, Africa, and the rest of the world. Modified from FAO.

27.3 NUTRIENT COMPOSITION OF MILLETS In several developing countries such as India, China, and some countries of Africa, there is an interest to develop policy statements about drought-tolerant grains and that it should be grown in areas that have water scarcity. Some of the countries have earmarked funds to scientific research for purposes of improving and increasing millet production and utilization as food [1]. Millet is one of the most important drought-resistant crops and the sixth cereal crop in terms of world agriculture production. Millet grains are now receiving specific attention from these developing countries in terms of utilization as food as well as from some developed countries in terms of its good potential in the manufacturing of bioethanol and biofilms. The chemical composition and nutrient content depends on the species and the soil in which millets are grown [2 4]. Millets are known as coarse cereals beside maize (Zea mays), sorghum (Sorghum bicolor), oats (Avena sativa), and barley (Hordeum vulgare). Millet is known as ragi and mandia in the Bastar region of Chhattisgarh (India) and offers both nutritional and livelihood security for human beings and also feed security for diverse livestock populations in dryland regions of rural India. Table 27.3 shows nutrient composition of millets compared to other grains. Despite superior quality of millets, only pearl millet has been prioritized as the crop of choice for iron biofortification in India. There is vast potential to

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CHAPTER 27 MILLETS AS FUNCTIONAL FOOD

Table 27.2 Utilization of Millets by Type, Region and Selected Countries, 1992 94 Average Direct Food (‘000 tons) Developing countries Africa Burkina Faso Chad Ethiopia Mali Niger Nigeria Senegal Sudan Tanzania Uganda Asia China India Central America and the Caribbean South America Developed countries North America Europe CIS Oceania World

Feed (‘000 tons)

Other Uses (‘000 tons)

Total (‘000 tons)

Per Caput Food Use (kg/year)

21776 8673 683 217 108 658 1440 3315 505 364 177 517 13103 3277 9216 0

966 187 2 0 0 3 17 100 5 20 2 20 748 327 283 0

3767 2328 126 41 153 119 259 1155 83 76 53 95 1433 257 1100 0

26509 11188 811 258 260 781 1716 4570 593 460 233 633 15284 3861 10599 0

5.08 13.40 68.52 33.73 1.97 74.63 162.45 31.50 61.61 14.14 6.41 25.93 4.17 2.74 10.23 0.00

0 513 0 0 504 0 22289

31 970 180 4 736 1 1936

6 323 0 1 316 0 4090

37 1805 180 5 1555 1 28314

0.00 0.40 0.00 0.00 1.73 0.00 4.00

Modified from FA0.

utilize the minor millets for biofortification which can be achieved through two strategies: (1) by enhancing the accumulation of nutrients in milled grains and (2) by reducing the antinutrients to increase the bioavailability of minerals, vitamins, and flavonoids. Millet yield is highest in Asia followed by Africa as given in Fig. 27.2. Micronutrients project has focused primarily on seven major staple crops (rice, beans, cassava, maize, sweet potato, pearl millet, and wheat) targeting three important micronutrients; Fe, Zn, and vitamin A. In resource-poor countries of Asia and Africa, millets provide 75% of total calorie intake next to cereal grains with an average annual production of 14.2 and 12.4 million tons. Biofortification is a food-based approach to overcome the nutrient starvation by delivering nutrientdense crops to the doorsteps of poor populations. Biofortification Challenge Program (BCP) under HarvestPlus-Consultative Group for International Agricultural Research (CGIAR) Millets are

27.3 NUTRIENT COMPOSITION OF MILLETS

463

Table 27.3 Nutrient Composition of Millets Compared to Other Cereals (per 100 g edible portion; 12% moisture) Food

Proteina (g)

Fat (g)

Ash (g)

Fiber (g)

Carhohydrate (g)

(kcal)

Rice (brown) Wheat Maize Sorghum Pearl millet Finger millet Foxtail millet Common millet Little millet Barnyard millet Kodo millet

7.9 11.6 9.2 10.4 11.8 7.7 11.2 12.5 9.7 11.0 9.8

2.7 2.0 4.6 3.1 4.8 1.5 4.0 3.5 5.2 3.9 3.6

1.3 1.6 1.2 1.6 2.2 2.6 3.3 3.1 5.4 4.5 3.3

1.0 2.0 2.8 2.0 2.3 3.6 6.7 5.2 7.6 13.6 5.2

76.0 71.0 73.0 70.7 67.0 72.6 63.2 63.8 60.9 55.0 66.6

362 348 358 329 363 336 351 364 329 300 353

All values except protein are expressed on a dry weight basis. (Modified from Hulse and others (1980); United States National Research Council/National Academy of Sciences (1982); USDA/HNIS (1995); FAO (2012).

FIGURE 27.2 Millet yield in Asia, Africa, and the rest of the world. Modified from FAO 2015.

464

CHAPTER 27 MILLETS AS FUNCTIONAL FOOD

nutritionally superior to rice and wheat as they contain a high amount of proteins, dietary fibers, iron, zinc, calcium, phosphorus, potassium, vitamin B, and essential amino acids. Most agricultural and food scientists consider the presence of phytates, polyphenols, and tannins as antinutrients which may reduce the mineral bioavailability by chelating multivalent cations like Fe21, Zn21, Ca21, Mg21, and K1. However, it should be noted that polyphenols and tannins are potential antioxidants which have been demonstrated to decrease noncommunicable diseases. It seems that predominance of the antinutritional factors like phytates has thus rendered the orphan status to millets in terms of global economic importance. Application of genetic engineering and genome editing tools to facilitate nutrient accumulation in edible portions and to block the biosynthesis of antinutrients is needed to improve millets as functional food.

27.4 DEVELOPMENT OF MILLETS AS FUNCTIONAL FOODS Millets are now called ragi by the affluent class and consumed as functional food for weight reduction due to the high content of fiber and proteins which provide the satiety. Millets are also rich in iron, magnesium, and calcium as well as B vitamins, apart from polyphenols and flavonoids [6,7]. Calcium and magnesium are important essential macromineral that are required in relatively large quantities in the diet for maintaining cellular function and overall health. Young children, pregnant and nursing women, as well as elderly populations in marginalized and poorest regions of the world are at highest risk of calcium malnutrition [7]. In the elderly population calcium deficiency manifests in the form of osteoporosis and osteopenia and improved dietary intake of calcium may be the most cost-effective way to meet such deficiencies. Finger millet (Eleusine coracana (L.) Gaertn.), a crop with inherently higher calcium content in its grain, is an excellent candidate for understanding genetic mechanisms associated with calcium accumulation in grain crops. Millets can be developed as food-based nutraceuticals in the form of highly personalized medicine or therapeutic agents due to the high content of minerals and flavonoids and amino acids [6 8]. Finger millet (Eleusine coracana (L.) Gaertn.) is a crop with a potentially tremendous but underexplored source of nutraceutical properties as compared to other regularly consumed cereals. According to the 2017 agenda of the FAO and WHO in the era of growing divide and drawback of food security via food diversity, these characteristics of millets should be harnessed to develop finger millet as a novel functional food [8,9]. Apart from this, introgression of these traits into other staple crops can improve the well-being of the general population by providing abundant functional foods on a global scale. The importance of biofortification of finger millet in the context of universal health and nutritional crisis appears to be important for the western world as well as for lowerand middle-income countries. The role of recent biotechnological research offers enrichment of its nutritional value and these developments can be commissioned in the field of nutritional biology by opening new avenues for future research on millets [7]. Unfortunately, most of the crop improvement strategies are directed toward staple cereals such as rice, wheat, maize etc., whereas attention on minor cereals such as finger millet (Eleusine coracana (L.) Gaertn.) and expensive functional foods lags far behind, especially in developing countries [10]. Millets are important staple for several semiarid and tropical regions of the world with excellent nutraceutical properties as well as ensuring functional food security in such areas even

27.5 NUTRITIONAL SIGNIFICANCE

465

during harsh environment. Increased production of millets can be used to export it to developed countries for functional food security, if food industry is educated to use millets in manufacturing modern foods for modern communities [10]. Only limited studies have been conducted for the genetic improvement of finger millets, its nutritional significance in providing minerals, calories, and protein makes it an ideal model for nutrition-agriculture research. An improved genetic manipulation of finger millets for resistance to both abiotic and biotic stresses, as well as for enhancing nutrient content will be very effective in millet improvement [10].

27.5 NUTRITIONAL SIGNIFICANCE Research has identified the molecular basis of waxy starch in foxtail millet, proso millet, and barnyard millet to facilitate their use in infant foods. In view of the close genetic-relatedness to cereals, comparative genomics has helped in deciphering quantitative trait loci and genes linked to protein quality in finger millet. Recently, transgenic expression of zinc transporters resulted in the development of high-zinc grain while transcriptomics revealed various calcium sensor genes involved in uptake, translocation, and accumulation of calcium in finger millet. RNA interference and genome editing tools (zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and clustered regularly interspaced short palindromic repeats (CRISPR)) need to be employed to reduce phytate which is antinutrient. In a nutritional biochemical study, a central composite rotatable design was applied to analyze the effects of independent variables (soaking time (ST), germination time (Gt) and temperature (GT)) on responses (antioxidant activity (AoxA), total phenolic contents (TPC) and flavonoid contents (TFC)) [3]. The findings revealed that with increase in ST, Gt, and GT, then AoxA, total phenolic content (free/bound), and total flavonoid contents (free/bound) of foxtail millet increased significantly. The best combination of germination bioprocess variables for producing optimized germinated foxtail millet flour with the highest AoxA (90.5%), total phenol content (45.67 mg gallic acid equivalent (GAE)/100 g sample) and total flavonoid content (30.52 43.96 mg RU/g sample) were found with soaking time of 15.84 minutes having germination temperature of 25 C. The optimized germinated foxtail millet flour was nutritionally rich as it produced higher protein (14.32 g/100 g), dietary fiber (27.42 g/100 g), calcium (25.62 mg/kg), iron (54.23 mg/kg), magnesium (107.16 mg/kg), and sodium (69.45 mg/kg) per kg as compared to ungerminated foxtail millet flour [3]. Foxtail millet (Setaria italica), also called Kangni, tenai, kakun, and navane, is generally grown as a rain-fed crop in India, as well as China and Bangladesh. It has been reported that foxtail millet has many nutritional and medicinal properties and is recommended in ayurvedic and unani products by the practitioners [11]. Foxtail millet is nonglutinous, like buckwheat and quinoa, and is a nonacid-generating food, henceit is considered to be an easily digestible food [12]. Millets act as a potential functional food ingredient and a supplementary protein source to most cereals, due to the high lysine content [13]. The availability of minerals increases during germination which may be due to the catabolism of antinutrients like polyphenol and saponins which hinder the bioavailability of minerals. It has been also described that germination of foxtail millet for 3 days resulted in production of high concentration of minerals [14]. It is possible that consumption of sprouts as

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CHAPTER 27 MILLETS AS FUNCTIONAL FOOD

functional food can be considered very important in reducing oxidative stress-induced NCDs, due to the presence of antioxidant phenolics and flavonoids [14]. A negligible amount of research on its antioxidant property has been carried out by researchers mainly on foxtail millet commercially available, which is utilized in various forms for human consumption [11,15]. A recent study, investigated the natural antioxidants in edible flours of small millets. Total carotenoids content varied from 78 to 366 μg/100 g in the millet varieties with an average of 199 1 77, 78 1 19, 173 1 25, and 366 1 104 μg/100 g in finger, little, foxtail, and proso millets, respectively [15]. HPLC analysis of vitamin E indicated a higher proportion of γ- and α-tocopherols; however, it showed lower levels of tocotrienols in the millets. Total tocopherol content in finger and proso millet varieties were higher (3.6 4.0 mg/100 g) than in foxtail and little millet varieties (B1.3 mg/ 100 g). Total antioxidant capacity in finger, little, foxtail, and proso millets were 15.3 1 3.5, 4.7 1 1.8, 5.0 1 0.09, and 5.1 1 1.0 mM TE/g, respectively. It is possible that edible flours of small millets are good sources of endogenous antioxidants [15]. In economically developed countries of the world, foxtail millet is more commonly used as bird feed [16]. The physicochemical and health-functional properties of foxtail millet, and the processing technologies employed to improve these properties and develop more palatable food products is underway in these countries. However, the western world is not looking toward using this gift from Asia as a functional food for prevention of NCDs. Foxtail millet contains significant levels of protein, fiber, mineral, and phytochemicals, tannin and polyphenols. Antinutrients, such as phytic acid, present in this millet can be reduced to negligible levels by using suitable processing methods. The millet is also reported to possess hypolipidemic, low-glycemic index, and antioxidant characteristics. It is now receiving increased research and commercial attention, especially because its cultivation is not too demanding from the point of view of agricultural inputs and it can grow in difficult terrains. Foxtail millet has a promising role to play in enhancing nutritional and functional food security in the western world by improving taste and flavor without losing its biochemical protective effects [16 18]. Millets could be mixed with cake, cookies, bread, and biscuits to provide proteins and micronutrients. The authors have used ragi, which is a common name for all the millets, for making Indian type of bread called chapatti which is quite palatable. The most important contents of foxtail millet are substantial concentrations of protein, fiber, mineral, and phytochemicals as well as anti-nutrients such as phytic acid and tannin [19 21]. This millet is also reported to possess hypolipidemic, low-glycemic index, and antioxidant characteristics with beneficial effects on libido. In brief, millets have important potential to be used as functional food worldwide. There is a need to conduct more research to decrease phytate content and increase antioxidant potential by modulating phenolics and flavonoids which are considered important for the prevention of NCDs.

REFERENCES [1] Vinoth K, Ravidran R. Biofortification in Millets: a sustainable approach for nutritional security front. Plant Sci 2017. Available from: https://doi.org/10.3389/fpls.2017.00029 23 January. [2] Hadimani NA, Malleshi NG. Studies on milling, physico- chemical properties, nutrient composition and dietary fibre content of millets. J Food Sci Technol 1993;30:17 20.

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[3] Sharma S, Saxena DC, Riar CS. Antioxidant activity, total phenolics, flavonoids and antinutritional characteristics of germinated foxtail millet (Setaria italica). Cogent Food Agri 2015;1. Available from: http://dx.doi.org/10.1080/23311932.2015.1081728. [4] Lu H, Zhang J, Liu KB, Wu N, Li Y, Zhou K, et al. Earliest domestication of common millet (Panicum miliaceum) in East Asia extended to 10,000 years ago. Proc Natl Acad Sci USA 2009;106(18):7367 72. [5] Food and Agricultural Organization, World food and agriculture Rome, 2015. http://www.fao.org/3/ai4691e.pdf, accessed Nov 2017. [6] Kumar A, Metwal M, Kaur S, Gupta AK, Puranik S, Singh S, et al. Nutraceutical value of finger millet [Eleusine coracana (L.) Gaertn.], and their improvement using omics approaches. Front Plant Sci 2016;7:934. Available from: https://doi.org/10.3389/fpls.2016.00934. Published online 2016. [7] Puranik S, Kam J, Sahu PP, Yadav R, Srivastava RK, Ojulong H, et al. Harnessing finger millet to combat calcium deficiency in humans: challenges and prospects. Front Plant Sci 2017;8:1311. Epub 2017 Jul 26. [8] Joint FAO/WHO Food Standards Programme Codex Committee on Food Labelling 44th Session Asuncio´n, Paraguay, 16 20 October 2017. http://www.fao.org/fao-who-codexalimentarius/sh-proxy/en/ ?lnk 5 1&url 5 https%253A%252F%252Fworkspace.fao.org%252.Fsites%252Fcodex %252FMeetings% 252FCX-714-44%252, accessed Nov 6, 2017. [9] FAO of the UNO. Guidelines on assessing biodiverse foods in dietary intake surveys, 2017. http://www. fao.org/documents/card/en/c/5d2034ff-a949-482a-801c-44b7b675f1dd/. [10] Gupta SM, Arora S, Mirza N, Pande A, Lata C, Puranik S, et al. Finger millet: a “certain” crop for an “uncertain” future and a solution to food insecurity and hidden hunger under stressful environments. Front Plant Sci, 8. 2017. p. 643. Epub 2017 Apr 25. [11] Adekunle AA. Agricultural innovation in sub-Saharan Africa: Experiences from multiple stakeholder approaches. Ghana: Forum for Agricultural Research in Africa; 2012. 9988-8373-2-4. [12] Prashant SH, Namakkal SR, Chandra TS. Effect of the antioxidant properties of millet species on oxidative stress and glycemic status in alloxan-induced rats. Nutr Res 2005;2005(25):1109 20. [13] Mohamed TK, Zhu K, Issoufou A, Fatmata T, Zhou H. Functionality, in vitro digestibility and physicochemical properties of two varieties of defatted foxtail millet protein concentrates. Int J Mol Sci 2009;10:5224 38. [14] Silva LR, Pereira MJ, Azevedo J. Glycine max (L.) Merr., Vigna radiata L. and Medicago sativa L. Sprouts: a natural source of bioactive compounds. Food Res Int 2013;50:167 75. Available from: https://doi.org/10.1016/j.foodres.2012.10.025. [15] Asharani VT, Jayadeep A, Malleshi NG. Natural antioxidants in edible flours of selected small millets. Int J Food Propert 2010;13:41 50. [16] Sharma N, Niranjan K. Foxtail millet: properties, processing, health benefits, and uses. Food Rev Int 2017;1 35. Available from: http://dx.doi.org/10.1080/87559129.2017.1290103. [17] Yano A, Takakusagi M, Oikawa K, Nakajo S, Sugawara T. Xanthophyll levels in foxtail millet grains according to variety and harvesting time. Plant Prod Sci 2017;20(1):136 43. [18] Wu Y, Lin Q, Cui T, Xiao H. Structural and physical properties of starches isolated from six varieties of millet grown in China. Int J Food Properies 2014;17:2344 60. [19] Kaur L, Kumar K, Kumar R, Yadav AN. October 7 8 Role of millets as functional food. National conference on technology on food systems. Sangrur, Punjab, India: Department of Food Engineering and Technology; 2016. [20] Sharma N, Niranjan K. Foxtail millets: properties, processing, health benefits and uses. Food Rev Interna 2018;34:329 63.

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[21] Sharma N, Goyal SK, Alam T, Fatma S, Niranjan K. Effect of germination on the functional and moisture sorption properties of high pressure-processed foxtail millet grain flour. Food Bioprocess Technol 2018;11(1):209 22.

FURTHER READING Coulibaly A, Chen J. Evaluation of energetic compounds, antioxidant capacity, some vitamins and minerals, phytase and amylase activity during germination of foxtail millet. Am J Food Technol 2011;6:40 51. Devi PB, Vijayabharathi R, Sathyabama S, Malleshi NG, Priyadarisini VB. Health benefits of finger millet (Eleusine coracana L.) polyphenols and dietary fiber: a review. J Food Sci Technol 2011. Available from: https://doi.org/10.1007/s13197-011-0584-9.

CHAPTER

FENUGREEK (TRIGONELLA FOENUM-GRAECUM L.): DISTRIBUTION, GENETIC DIVERSITY, AND POTENTIAL TO SERVE AS AN INDUSTRIAL CROP FOR THE GLOBAL PHARMACEUTICAL, NUTRACEUTICAL, AND FUNCTIONAL FOOD INDUSTRIES

28

Saikat K. Basu1, Peiman Zandi2 and William Cetzal-Ix3 1

Department of Biological Sciences, University of Lethbridge, Lethbridge, AB, Canada 2Institute of Environment and Sustainable Development in Agriculture, Chinese Academy of Agricultural Sciences, Beijing, P.R. China 3 ´ Campeche, Mexico ´ Istituto Tecnolo´gico de China,

28.1 INTRODUCTION Fenugreek (Trigonella foenum-graecum L.) is an aromatic, medicinal plant rich in several important phytochemicals. Historically, fenugreek has been used as an important traditional, multipurpose medicinal herb in the Indian Ayurvedic Systems as well as in the treatment of both humans and animal subjects in Traditional Chinese Medicinal Practices and Tibetan Medicinal Practices for several centuries [1 4]. The species name “foenum-graecum” literally translates “Greek hay” suggesting that fenugreek was well known as a forage crop even in the distant past [1,3,5 8]. The plant is traditionally grown in major parts of South Asia, Middle East, North Africa, and Mediterranean Europe as a spice crop; and as an ingredient of the famous East Indian curries or as a part of the traditional curry mix powder of the Indian subcontinent. It is a very well-known traditional spice commonly known to South Asians and South Asian diaspora spread across the globe. Fenugreek constitutes an important ingredient of the traditional curry-mix powders and hence a significant cuisine of traditional Indian faith and practices across the planet [5,6,8]. Historically fenugreek has been grown as a forage crop in parts of Mediterranean Eurasia, Russia, North Africa, and the Middle East, and later spread to other parts of the world including The Role of Functional Food Security In Global Health. DOI: https://doi.org/10.1016/B978-0-12-813148-0.00028-1 © 2019 Elsevier Inc. All rights reserved.

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CHAPTER 28 FENUGREEK (TRIGONELLA FOENUM-GRAECUM L.)

the vast Indian subcontinent or to major parts of South Asia [1,2,4]. Fenugreek is an annual, forage legume belonging to the legume family of Fabaceae (Leguminosae) like alfalafa (Medicago sativa L.), commonly known as the “Queen of Forages.” It is dicotyledonous angiosepermic annual legume plant belonging to the Order Fabales, Family Fabaceae and is closely related to well-known forage crop, alfalfa (M. sativa). Fenugreek is a selfpollinated herb with an indeterminate growth habit, suggesting that the plant continues to grow throughout the growing season [3,9 11]. Hence, fenugreek continues to flower in the field until there is frost or any desiccant is specifically applied (Fig. 28.1). Fenugreek produces fine branches and subbranches, bearing light green compound trifoliate leaves with pale yellow to white small papilionaceous flowers either terminal or axillary in position. The plant varies in height from 15 45 cm; with dryland (rainfed) plants shorter in height compared to irrigated ones. The plant produces profuse long single pods varying in length between 10 and 15 cm bearing on average 18 20 seeds. Often double pods are also observed under natural field conditions [2,12]. The pods are long and curved with small hairs on the surface. The pods are greenish to slightly purplish when young and turn brownish at maturity [11,13]. However, plants raised from seeds treated with physical or chemical mutagens produce large numbers of double pods, increasing the production of pods and hence seeds per plant [12]. Seeds are greenish when young but turn hard, solid brown or golden brown in color at maturity (Fig. 28.2). Due to indeterminate growth habit the plant continues to grow throughout the season and hence often is not suitable for short growing seasons unless specialized, short cultivars suitable for short growing seasons are developed. Application of seed chemical mutagens (ethyl methane sulphonate, dimethyl sulfoxide, cholchicine) are reported producing varieties with determinate growth habit, larger seed, higher seed oil constituents, and better profile of several phytochemicals [9,10,13 15]. The plant is reported to exhibit high Genotype X Environment interactions (G X E effect) under various environmental parameters across diverse geographical regions and climatic regimes [5,6,15]. Being an annual forage legume it could be also used as green, organic manure and can be used in local crop cycles as a natural nitrogen enricher of the soil [16 18]. As a commercial industrial crop and being a dryland crop can help in water preservation. Forage quality of fenugreek is comparable to alfalfa and unlike the later is known to be bloat free. It supports muscle growth and promotes better animal carcass weight [19]. The seeds are an essential source of galactagogue. Both seeds [20] and leaves [12] are rich in several phytochemicals; and are predominantly hence used for medicinal as well as culinary purposes. Fenugreek seed is also used in producing synthetic maple syrup [12,21]. Due to the presence of such phytochemicals, fenugreek has been found to be a useful crop for the phytochemical, nutraceutical, and functional food industries in addition to producing forage and seed as direct agronomic products [14]. Fenugreek is used as hay, silage, straight grazing, or swath grazing [1,12,22]. Although a dryland crop, fenugreek does well under irrigation for both forage and seed production [23]. Fenugreek is easy to establish and can be used in both long and short crop rotational cycles with other local crops for fixing atmospheric nitrogen in the soil. The crop is particularly susceptible to fungal leaf spot and powdery mildew diseases under moist and humid conditions [24]; other bacterial, viral, and insect diseases have also been reported. Fenugreek do not develop canopy to reduce weed growth until several weeks post-seeding; and yield could be impacted by competing annual grasses or broad-leaf weeds [11,13,25].

28.1 INTRODUCTION

473

FIGURE 28.1 (A) Fenugreek seed; (B) Germinating seeds; (C) Seedlings; (D) Crop under rainfed conditions; (E) Cattle grazing on forage fenugreek; and (F) Fenugreek under irrigation.

474

CHAPTER 28 FENUGREEK (TRIGONELLA FOENUM-GRAECUM L.)

FIGURE 28.2 (A) Fenugreek trifoliate compound leaf; (B) Fenugreek plant close up infected with Powdery mildew; (C) Fenugreek seed multiplication trial in Iran for use as nutraceutical and functional food; (D) Overnight soaked fenugreek seed, rich source of phytochemicals used in nutraceutical and functional food industry, and (E) Fenugreek seedlings germinated following hydropnics under lab conditions.

28.2 TAXONOMY OF TRIGONELLA

475

Fenugreek is an important medicinal and aromatic plant containing rich sources of a number of significant phytochemicals [15,20,23]. The most important phytochemicals reported from the seed as well as leaves of fenugreek are as follows: steroidal sapogenin (diosgenin, tigogenin, yamogenin), flavonoids, alkaloids (fenugreekine), complex carbohydrate (galactommanan), essential amino acid (4-hydroxyisoleucine) to mention only a few [1,15]. Fenugreek seeds contain several polyphenolic flavonoids, such as trigonelline, quercetin, phytic acid, and saponins [26]. The seeds also comprise mucilaginous fiber, lysine, LTR (L-tryptophan-rich) proteins, and some other rare chemicals (e.g., fenugreekine, coumarin, folic acid, phytic acid, nicotinic acid, sapogenins, trigonelline, scopoletin), which are believed to have their presumed efficacy in cases of therapeutic actions; they may inhibit cholesterol absorption and decrease blood sugar concentrations [20,27]. The presence of such a wide diversity of medicinally important phytochemicals, make this crop an attractive resource as well as an opportunity for the global pharmaceutical, nutraceutical, and functional food industries [14,28]. The plant has been used as a medicinal herb in major ancient civilizations of the Eurasian region including both the Chinese as well as Indus valley civilizations [11,13,25]. For centuries, fenugreek has been used in treating various human and animal ailments in the Indian Ayurvedic medicinal practices; as well as in Tibetan and traditional Chinese medicinal applications. Modern clinical trials have also established significant medicinal properties of fenugreek seed and leaves on study animals and human subjects in comparison to untreated control groups [1,18,20,29]. The plant has been found to be extremely useful in reducing high blood sugar (i.e., triglyceride percentage, fasting and postprandial blood glucose) and high cholesterol (i.e., total cholesterol, low-density lipoprotein (LDL) cholesterol) levels in both laboratory animals and human subjects [20]. In addition it has been found to have antipyretic, antioxidant, antimicrobial, antileukemic, and antineoplastic properties [11,29]. Several longer-term clinical trials have shown that seed extracts of fenugreek have the potency both to slow enzymatic digestion of carbohydrates, to modulate Glucagon-like Peptide-1(GLP-1) signaling, and to reduce insulin concentrations and glycated hemoglobin (HbA1c) [20]. The GLP-1 analogs have been proved to positively account for curing type 2 diabetes [20]. Such important medicinal properties further illustrate the importance and potential for fenugreek as a crop to the global pharmaceutical, nutraceutical, and functional food industries [14].

28.2 TAXONOMY OF TRIGONELLA The genus Trigonella L. belongs to the subtribe Trifolieae (Fabaceae), together with the genera Medicago Inc., Trifolium L., and Melilotus L. This subtribe is monophyletic within “vicioid clade,” their taxa are morphologically characterized by trifoliate leaves with stipules adnate to the stem that do not cover entirely it [4]. Trigonella is the genus within this subtribe with more taxa and high economic importance; this genus is monophyletic and includes annual or perennial aromatic herbs that are characterized by a campanulate or tubular sepals with two (large) and three (small) equal lobes, diadelphous stamens, uniform anthers, terminal stigma, and ovary with numerous ovules [4]. Taxa are widely distributed in the dry regions around Mediterranean, West of Asia, Europe, North and South Africa, North America, and South Australia [30]. The exact number of taxa accepted in the Trigonella depends on unresolved names, accepted synonymies, and authors,

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CHAPTER 28 FENUGREEK (TRIGONELLA FOENUM-GRAECUM L.)

for example, Linnaeus listed 260 species [31], other authors recognized between 62 and 128 species [32 37]. The most recent study based on Small [38] indicates that the genus currently includes 62 species [4]. However, The Plant List [39] listed 98 taxa accepted, 97 unresolved names, three misapplied names, and 27 accepted synonymies. Trigonella has a wide diversity of species with potential economic (Table 28.1), including among these T. foenum-graecum which is the most popular species in the genus by its countless uses and properties. Also, different species of fenugreek were assigned several potential uses by different authors; however, some currently are synonymous (Table 28.1) or belong to other genera. For example, T. monspeliaca is a synonym for Medicago monspeliaca (L.) Trautv [22]., T. polycerata for Medicago orthoceras (Kar. & Kir) Trautv [16,17,21,22]., and T. radiata Boiss. For Medicago radiata L [40].

Table 28.1 Diversity of Species of Fenugreek With Several Potential Economic Uses Taxa

Uses

References

T. anguina Delile T. arabica Delile T. baccarinii Chiov. (Syn. T. marginata Baker) T. balansae Boiss. & Reut. T. caerulea (L.) Ser. T. calliceras Fischer ex M. Bieb. T. coerulescens Hal´acsy T. corniculata Sibth. & Sm. T. cretica (L.) Boiss. T. foenum-graecum L. T. glabra subsp. uncata (Boiss. & Noe) Lassen (Syn. T. uncata Boiss. & Noe) T. glabra Thunb. T. hamosa Del. ex Smith T. laciniata L. T. lilacina Boiss. T. maritima Poir T. occulta Ser. T. spicata Sm. T. spinosa L. T. spruneriana Boiss (Syn. T. sibthorpii Boiss.) T. stellata Forssk. T. suavissima Lindl.

FO, IR, NU FO, IR, NU FO, IR, UN

[22] [22] [22]

FO, IR, NU, PH IR, ME, PH, SP PH FO, IR, UN CO, FO, IR, NU, PH PH FO, IR, ME, NU, PH ME

[16,22] [16,17,22] [16] [22] [16,17,22] [16] [16,17,41] [17]

FO, FO, FO, PH PH FO, FO, FO, FO,

[22] [22] [22] [40] [16] [16,17,22] [16,22] [22,40] [22]

IR, NU IR, UN IR, UN

IR, ME, NU, PH IR, NU, PH IR, NU, PH IR, NU

FO, IR, NU IR

[22] [22]

CO, comestible; IR, insect repellent; FO, forage; ME, medicinal; NU, nutraceutics; PH, pharmaceutical; SP, species.

28.3 FENUGREEK DISTRIBUTION AND GLOBAL GENETIC DIVERSITY

477

Most of these species (T. foenum-graecum, T. caerulea, T. corniculata, T. hamosa, T. balansae, T. laciniata, T. marginata, T. occulta, T. anguina, T. arabica, T. glabra, T. stelata, T. coerulenses, T. spinosa, T. sibthorpii, T. spicata, etc.) are rich in protein, vitamins, and amino acids [22], while the seeds and the fresh material are used as forage, especially for cattle, mainly in the eastern Mediterranean area. In particular, T. arabica and T. stelata are grazed by animals in the desert areas of the Sahara, Palestine, and the Dead Sea [40]. Several species of Trigonella (T. foenum-graecum, T. balansae, T. corniculata, T. maritima, T. spicata, T. coerulea, T. occulta, T. polycerata, T. calliceras, T. cretica, etc.) contain some interesting, from the pharmaceutical point of view, phytochemical compounds belonging to steroids, flavonoids, and alkaloids [42] and efforts are being made to use some of them as a source of these constituents, especially of the steroidal diosgenin [16]. Seeds of these species also yield choline, a semicrystalline white saponin, a lactation-stimulating oil, and various gums [40]. The alkaloid trigonelline has been isolated from plant parts, mainly seeds of T. caerulea, T. cretica, T. foenum-graecum, T. lilacina, T. radiata, T. spinosa [40] and T. polycerata [21]. This pyridine alkaloid is known for its hypoglycemic and hypocholesterolaimic properties [21]. Some of these species are also used in traditional as well as veterinary medicine for different diseases, alone or in combination with other remedies: T. occulta, T. polycerata, and T. uncata are included among the Indian herbals along with T. foenum-graecum [17]. The well developed endosperm of most of the species is rich in the polysaccharide mucilage (galactomannan) that has wide uses in industry including in pharmaceuticals and cosmetics. In some parts of Pakistan and India T. corniculata is used for different purposes: its young tops are currently used as a green vegetable, the dried herb as a flavoring agent, and its seeds for the treatment of swellings and bruises [17]. Chopped foliage of the species T. caerulea (sweet trefoil) is used in Switzerland for flavoring green cheeses: Schabzieger, Chapsiger, and Serred Vert. In some parts of Tirol sweet trefoil is used for flavoring the bread called Brotwnrze. Sweet trefoil is also employed as a condiment in soups and potatoes, as a decoction for tea, and as flavoring in Chinese tea [40]. Hardman and Fazli [17] report that in Switzerland sweet trefoil has also been used in herbal medicine.

28.3 FENUGREEK DISTRIBUTION AND GLOBAL GENETIC DIVERSITY Fenugreek is an old world crop and is currently known to have a wide global distribution (Figs. 28.3 and 28.4, Table 28.2). Genetic diversity is one of the most important criteria from the production aspect of a crop. Rich genetic diversity is essential for the long-term agricultural qualitative and quantitative success of a crop or for the purpose of a crop introduction into a new but tentatively suitable agro-climatic condition or for screening for a high yielding or early maturation trait(s) or for identifying potential disease resistant germplasms for developing a new economically viable and productive cultivar for successful commercial release [23,29,31]. The richness of genetic variabilities within various populations or subpopulations or even tribes or subtribes of plant groups or plant families are essential features for screening for genetic diversity. High genetic variability is also essential for developing cultivars through multilocation trials or even for looking for developing locally adapted cultivars. In other words, wide genetic variability or genetic diversity is important for any crop development program [1,9,10,17,31,40].

478

CHAPTER 28 FENUGREEK (TRIGONELLA FOENUM-GRAECUM L.)

FIGURE 28.3 Fenugreek crop distribution. (A) Map showing the continents of Europe, Asia, Africa, and Oceania; and (B) map showing North and South Americas.

28.3 FENUGREEK DISTRIBUTION AND GLOBAL GENETIC DIVERSITY

479

FIGURE 28.4 Diversity of fenugreek cultivars around the globe. (A) Fenugreek grown in Egypt; (B) Field plot showing fenugreek forage and seed yield trial in Iran; (C) Dried fenugreek foliage at a spice shop in Jordan; (D) Fenugreek seeds from China; (E) Fenugreek cultivation in Vietnam; (F) Fenugreek crop production in India; (G) Fenugreek under dryland production system in Pakistan; (H) Fenugreek crop from Australia; and (I) Fenugreek seeds from Brazil.

480

CHAPTER 28 FENUGREEK (TRIGONELLA FOENUM-GRAECUM L.)

Table 28.2 Current Global Distribution of Fenugreek Crop Areas of Distribution

Countries

Europe

Russia, United Kingdom, France, Spain, Portugal, Greece, Italy, Sweden, Germany, Switzerland, Austria, Hungary, Poland, Ukraine, Romania, Croatia, Slovenia Egypt, Morocco, Tunisia, Algeria, Sudan, Libya Ethiopia, Eritrea Kenya, South Africa Turkey, Israel, Lebanon, Jordan, Syria, Saudi Arabia, Bahrain, Qatar, UAE, Kuwait, Oman, Yemen, Iraq, Iran Afghanistan, Turkmenistan, Azerbaijan China, Taiwan India, Pakistan, Nepal Australia Canada, United States Argentina

North Africa Horn of Africa Sub Saharan Africa Middle East Central Asia Far East South Asia Oceania North America South America

Fenugreek is an ancient, old world crop that is now being introduced under new crop introduction programs in several countries across Asia, Africa, the Americas, and EU with suitable agroclimatic regimes to find new and alternative crops to resist agricultural productivity challenges due to Global Warming and Climate Change [13]. For example, the cultivar “Tristar” released in Canada is late maturing, hence the seed quality and yield can vary considerably over years and locations. It is capable of consistent production targeting most semiarid regions of the continent of North America; however, yearly fluctuations across different locations are also reported [2]. Hence the need for developing locally adapted cultivars of fenugreek to deal with the challenges of high GE effect. Fenugreek too is reported to be rich in different species distributed in different countries across major continents and also known to possess significant genetic diversity [28,31,40]. A demonstration of wide genetic diversity of fenugreek cultivars, germplasms, landraces, and other varieties has been presented in Table 28.2. Genetically diverse fenugreek cultivars could be commercially released for low input agriculture systems of economically underdeveloped countries of Asia, Africa, and Latin America [25]. The plant breeding groups around the globe currently working on the fenugreek improvement has the important goal of releasing locally adapted cultivars for specific agro-climatic regions with stable forage and seed yield along with enriched chemical constituents useful for human health and nutrition [2,12]. The immediate objectives of most fenugreek breeding programs have been to develop high yielding, disease resistant, and early maturing genotypes suitable for special climatic regions so as to produce high quality seed every year [31,40]. The majority of fenugreek breeders use physical and chemical mutation breeding, field and greenhouse testing including multilocation trials, for the purpose of developing locally adapted cultivars for this potential multipurpose crop [9,10]. It will be important to exploit the natural genetic and ecotype variabilities associated with fenugreek populations and subpopulations across the globe for producing forage and seed as well as

28.3 FENUGREEK DISTRIBUTION AND GLOBAL GENETIC DIVERSITY

481

pharmaceutical, nutraceuticals, and functional food and products [23,29,31]. Several fenugreek crop variants around the planet demonstrate the wide range of population-specific yield trends for specific crop products like seed, leaves, and different phytochemicals [9,10,43]. It is important to recognize that selection for stable and consistent yields within different agronomic ecoregions to grow fenugreek could allow the development of nutraceutical and functional food with distinctive, efficient, and reliable health and food values in addition to forage and seed production. India is currently the largest producer of the crop; but due to high internal market demand, India hardly makes any exports. Hence, there is great opportunity for supplying fenugreek seed in the international global markets for various agricultural as well as industrial needs for this crop [12,18]. Fenugreek has been an Old World crop; and hence the predominance of agricultural productivity for fenugreek is more commonly observed in the Old World countries compared to the New World [1,21] (Table 28.2). We refer to these areas, regions, localities, and countries as the traditional fenugreek producing countries. The highest number of fenugreek cultivars is reported from India, Pakistan, and China; followed by North African countries (Egypt, Tunisia, Morocco, Algeria, Libya, Sudan), Horn of Africa (Ethiopia, Eritrea), sub-Saharan African nations (Kenya, South Africa), Middle East nations (Turkey, Israel, Oman, Jordan, Syria, Yemen, Iran, Iraq), and European countries (United Kingdom, France, Italy, Spain, Portugal, Germany, Greece, Romania, Slovenia, Poland, Austria, Switzerland, Hungary, Azerbaijan). Recently, other parts of the world have also shown active interest in the production of fenugreek; most notably being the continents of North America (Canada and the United States), South America (Argentina), and Oceania (predominantly the island continent of Australia) (Table 28.4). Among nontraditional fenugreek producing countries, Canada has been actively pursuing fenugreek production with “Tristar” being released as the first North American cultivar [2]. The United States has also followed closely with Mexico just starting to show some interest in the production of the crop. Dry semiarid parts of the United States and Mexico; as well as the American and the Canadian prairies are suitable areas for fenugreek production in the continent [2,11,25]. Australia has also shown active interest in fenugreek production and has slowly transformed into an important fenugreek producing country with several new cultivars in the pipeline. The Mediterranean region with its warmer climate has always been a traditional fenugreek producing region and thus extends and expands further into the North African and Middle East agro-climatic zones [1,25]. A further extension of the fenugreek producing region is also observed in the Horn of Africa with one of the largest producing areas observed across South Asia (India, Pakistan, Nepal) and China. Parts of Central Asia like Afghanistan and Turkmenistan and Far Eastern corners of Asia like Taiwan have also been traditional fenugreek producing countries; expanding the fenugreek producing zone from Australia across the vast Eurasia and Africa recently to the Americas. The farthest stretch of the fenugreek producing region is reported to be in the Canary Islands (Macronesia) an autonomous archipelago of Spain off the southern coast of Morocco [44,45]. Based on suitable, similar, or nearly similar agro-climatic conditions, we humbly suggest the following global areas across all the major continents as future potential fenugreek production areas (Fig. 28.3, Table 28.3). Given that diversity indices bring more information than only the number of species represented, they serve as a valuable facility that gives permission to biologists to appraise diversity in an specific ecological community, landscape, or region, and explain its numerical structure [46]. In

482

CHAPTER 28 FENUGREEK (TRIGONELLA FOENUM-GRAECUM L.)

Table 28.3 Potential Fenugreek Production Areas Areas of Distribution

Countries

Europe

Malta, Gibraltar, Monaco, Albania, Cyprus, Montenegro, Georgia, Ukraine, Belorussia, Moldavia, Bulgaria, Macedonia, Serbia, Bosnia-Herzegovina, Kosovo Algeria, Libya, Western Sahara, The Horn of Africa (Somalia and Djibouti), and several sub-Saharan African nations Azerbaijan, Armenia, Georgia, Mongolia, Tajikistan, Uzbekistan, Kyrgyzstan, Kazakhstan Japan, S. Korea Bangladesh, Bhutan, Sri Lanka, Maldives, Myanmar, Thailand, Vietnam, Cambodia, Laos PDR, Brunei-Darussalam, Singapore, the Philippines, Indonesia, Malaysia, Papua and New Guinea, East Timor Pacific Islands Mexico, Nicaragua, Guatemala, Panama, El Salvador, Belize, Honduras, Costa RicaSuriname, Guyana, Ecuador, Colombia, Venezuela, Brazil, Uruguay

Africa Central Asia Far East South and South East Asia Oceania North AmericaSouth America

Table 28.4 we have gathered all of the reported accessions, cultivars, lines, masses, and varieties (hereinafter called diversification) of fenugreek plant in various geographical regions. According to the dataset presented, fenugreek crop has a total of 1090 diversification distributed in 45 countries across the continents (Figs. 28.3 and 28.4). The accompanying pie chart (Fig. 28.5) also reveals a straightforward pattern, in terms of both where and to what fraction the plant possesses genetic diversity/richness. As expected, the variation in fenugreek diversification is not equally diverse. The highest relative abundance belongs to India (36.79%), followed by Ethiopia (13.94%) and Oman accounts for only 7.06% (Table 28.4, Fig. 28.5). There are various indices or quantitative measures taken into account to quantify how many different species are in a given dataset. A diversity index also reflects how evenly or basic individuals are distributed among those species [46,113]. When the number of fenugreek diversification (our type of interest) or their evenness increases, the value of the diversity index increases as well. As seen in Table 28.4 the highest diversification richness refers to Indian subcontinent (401 accessions) with an extraordinary variety of climatic zones; varying from tropical in the south to temperate and alpine in the Himalayan north. For a given number of fenugreek diversification, the value of diversity index is augmented when all accessions, lines, masses, and varieties are equally abundant [114,115]. Our data simply represent the number of fenugreek diversifications cultivated or wildly grown regardless of their available quantities and/or their specific geological positions. Climatic and ago-ecological situations are assumed to have the greatest influence [46,116] on fenugreek biodiversity. Most commonly, fenugreek cultivation occurs in almost every zone where there is arable land and a favorable climate. In a region like Ethiopia with three main climatic zones including dega (cold), weyna dega (warm), and kola (dry) [117] we have 152 diversifications of fenugreek that accounts for 13.94% of total relative frequency as compared to the rest of the given countries. Likewise, a hot desert climatic country such as Oman lies in the third place having more than 77 reported diversifications

28.3 FENUGREEK DISTRIBUTION AND GLOBAL GENETIC DIVERSITY

483

Table 28.4 List of Fenugreek Accessions, Lines, Masses or Varieties Reported Worldwide Origin

Accessions, Lines, Masses and Varieties

References

Azerbaijan Syria

44744 19 X, D 19, H-26, A150297, A297, SA 35687, SA 34579 (T. filipes Boiss.), SA 34549 (T. spinosa L.), SA 34532 (T. spicata Sm.), SA 16848 (T. caelesyriaca Boiss.), SA 14518 (T. mesopotamica Hub.-Mor.), SA 14491 (T. coerulescens (M. Bieb.) Halacsy), 39345, 33664, 37865 Ardestan, Azna (T. elliptica), Esfahan (T. persica), Ahvaz, Borazjan, Broojerd, Khash, Khorasan (Qaen and Boshroi T. foenum graecum), Haji Abad (T. uncata), Minab (T. uncata), Khoramabad, Zanjan (Eejrood- T. monatha), Semnan, Shiraz, Yazd (Taft- T. elliptica), Ghaenat, Karaj (T. foenum graecum), Kashan (T. persica), Kerman, Javanrood (T. monatha), Kermanshah(T. monantha, T. persica), Miandoab (T. coerulescens) Neyshaboor, Rafsenjan (T. foenum graecum), Yasooj1, Yasooj2, Ilam, Mazandaran, PI138687, PI143504, Shahrerey, Kakan, Cisakht, Araqi, PI138687 (CN 19118), PI143504 (CN 19062), Tristar (CN 19118), L3312 (CN 19062), TMP 8675, A150147, A147, SA 35684, SA 34542 (T. spinosa), SA 32223(T. macrorrhyncha Boiss.), SA 16834 (T. mesopotamica), SA 16134 (T. filipes), TMP 8685, Tiranche, Jahrom, 5310 (T. elliptica, Shurjestan-Fars), 770 (T. elliptica, Avaj-Qazvin), 162 (T. elliptica, Hossein Abad-Fars), 76 (T. elliptica, Gazal Park-Tehran) SA 34528 (T. cylindracea Desv.), SA 19767 (T. caelesyriaca), SA 14519 (T. mesopotamica), SA 14514 (T. strangulata Boiss.), SA 14501 (T. spicata), 110364, 66620 PAK 020978, PAK 021703, PAK 022254, PAK 021131, PAK 021156, PAK 021330, PAK 021675, PAK 021986, PAK 021748, PAK 021711, PAK 021696, PAK 021117, PAK 022260, PAK 022257, PAK 022219, PAK 021908, PAK 021900, PAK 021889, PAK 021882, Donated,21879, 20595, 21947, 21857, 20593, 11122 (T. corniculata Sibth. & Sm.), PI269994 (CN 19066), Kasuri methi, Methi No.47, Methi No.14, Co-1, UM-34, UM-35, Prabha (NLM), Qusoori, TMP 8717, TMP 8718, 117722, 117702, 42107 F75, F86, PI211636, Geminiflora (Bunge), PI 211636 (CN 19065), TMP 8707, T. griffithii Boiss., Variety micrantha Gilli, T. afghanica Vassilcz., Bot., T. ascendens (Nevski) Afan. & Gontsch., T. verae Sirj., Repert., T. salangensis Vassilcz., T. pycnotricha Rech. f., T. pamirica Boriss., Bot., T. laxiflora Aitch. & Baker, Trans., T. bactriana Vassilcz., Bot., T. badachschanica Aphan., T. cashemiriana Camb., T. ˇ edelbergii (Sirj. & Rech.f.), T. emodi Benth., T. freitagii

[47] [47 53]

Iran

Iraq

Pakistan

Afghanistan

[48,49,51,52,54 61]

[51,62]

[47,49,56,64 68]

[47,49,54,56,67,68,69]

(Continued)

484

CHAPTER 28 FENUGREEK (TRIGONELLA FOENUM-GRAECUM L.)

Table 28.4 List of Fenugreek Accessions, Lines, Masses or Varieties Reported Worldwide Continued Origin

Accessions, Lines, Masses and Varieties

References

Vassilcz., T. gharuensis Rech.f., T. grandiflora Bunge, T. heratensis Rech.f., T. ionantha Rech.f., T. ˇ kafirniganica Vassilcz., T. koeiei Sirj. & Rech.f., 34107 Italy Canada

India

F96, Ali corte, Ali Lunghe, A150238 AC Tristar, AC Amber, Quatro MP 30, X92-23-32T (X92), QUATRO (CN 19069), X92-23-3(CN 19071), ZT-5(CN 19070), LRCF0802, LRCF0803, LRCF0804, LRCF0805, LRCF0806, LRCF0808, LRCF0809, LRCF0811, LRCF0813, LRCF0814, LRCF0815, LRCF0816, LRCF0819, LRCF0820, LRCF0821, L3308 (source), F18, PI 9095, L3538, L3673 (T. caerulea (L.) Ser.), L3683 (CN 19069), AMBER, NGC 2001(source), PI229626 (source), L3314, L3685 (CN 19071), L3684 (CN 19070), F17, TMP 1065, TMP 8738 (source/ T. caerulea), TMP 8750 (source/ T. caerulea), TMP 8752 (source/ T. caerulea), Canagreen, Canafen, SA 32208 (T. cretica (L.) Boiss.), SA 32202 (T. calliceras Fisch. ex M. Bieb.), CDC Quatro, AAFC F70, IT, LRC3375, LRC3708, PI 143505 (source), PI 229636, L3075, L3097 (source), L3103 (source), L3107 (source) Rajasthan Methi-1(RMt-1), RMt-143, RMt-361, RMt351, RMt-303, RMt-305, NRCSS-AM-1, NRCSS-AM2, Gujarat Methi-1(GM-1), Gujarat Methi-2 (GM-2), GM 351, LFC 84, CO-1,CO-2, Rajendra Kranti, Rajendra Khushba, Lam selection-1, Hisar Sonali, Hisar Suvarna, Hisar Mukta, Hisar Madhvi, HM-350, Pant Ragini, Pusa Early Bunching (HM-57), Pusa Kasuri, Indian temple, F80, L3068 (CN 19123), L3172, L3177, L3689, L3690, L3691, L3692, L3693, L3694, L3180, L3695, L3696, L3697, L3698, L3699, L3700, L3701, L3702, L3703, L3704, L3705, L3706, L3707, L3708, L3709, L3710, L3711, L3712, L3713, L3714, L3715, L3716, L3717, L3718, L3719, L3720, L3721, UM-9, UM-17, UM-18, UM-23, UM-25, UM-26, UM27, UM-32, UM-33, UM-36, UM-50, UM-52, UM-58, UM-67, UM-70, UM-75, UM-77, UM-79, UM-83, UM-84, UM-105, UM-112, UM-113, UM-114, UM115,UM-116, UM-117, UM-118, UM-120, UM-121, UM-122, UM-123, UM-125, UM-128, UM-129, UM130, UM-131, UM-132, UM-133, UM-135, UM-138, UM-143, UM-144, CVT UM-5, CVT UM-17, CVT UM-32, CVT UM-34, CVT UM-35, CVT UM TC 2336, CVT TG 1084, CVT GF 1, CVT CC, CVT NLM, NLM, Local check, RG-07, TG-3, TG-13, TG18, TG-24, TG-34, UM-5, UM-6, UM-17, UM-20, UM-34, UM-35, UM-38, NI-01, MP-14, Local Bobes, Pusa Earlier, Bangalore-Local, IC-99, T-8, IC-74,

[52,67] [1,2,7,12,49,51,54,56,67,68,70,71 75]

[31,47 49,51 54,56,68,73,76 92]

28.3 FENUGREEK DISTRIBUTION AND GLOBAL GENETIC DIVERSITY

485

Table 28.4 List of Fenugreek Accessions, Lines, Masses or Varieties Reported Worldwide Continued Origin

Accessions, Lines, Masses and Varieties

References

Green trailing, HFM 1, HFM 7, HFM 8, HFM 13, HFM 14, HFM 17, HFM 18, HFM 19, HFM 20, HFM 22, HFM 25, HFM 27, HFM 29, HFM 30, HFM 34, HFM 37, HFM 39, HFM 54, HFM 61, HFM 63, HFM 65, HFM 116, Metha, IC-373449, IC-396616, IC396625, IC-448828, IC-448830, IC-448832, IC448833, IC-448834, IC-448835, IC-448837, TMP 8686, TMP 8689, TMP 8687, MMT-5, A150182, Hebar, A169, SA 33871 (T. balansae Boiss. & Reut.), Ajmer Fenugreek-1, DFC-1, DFC-2, DFC-3, DFC-4, DFC-5, DFC-6, DFC-7, Panta Ragini, IC 143851, IC 144225, IC 332236, IC 371755, IC 433589, Azad (from West Bengal), IL1 (AGR 548), IL2 (Methi Local), IL3 (Shalimar Improved), AM 1. var. obcordata Wall., DMM-49, VRS-VEE-1071, DARLSS-68, DARL-SS-216, VRS-VFE-1167, DARL-SS103, DMRS-237, VRE-VFE-1992, VDVSS-174, VRBVFE-1476, DARL-SS-150, DARL-SS-145, DMRS107, DARL-SS-44, KJ-186, VDVSS-123, DARL-VK588, DARL-SS-36, DMRS-78, DMRS-72, DARL-SS211, KHH-654, DARL-SS-168, VRB-VFE-2016, KHH-603, VRB-VFE-1791, DMM-56, DMM-520, KHH-185, VV-254, DARL-SS-413, DARL-140, VDVSS-155, VDVSS-74, VDVSS-159, DMRS-161, VV-204, DARL-SS-330, VV-229, DMRS-256, VRSVFE-1056, DARL-VP-1400, DARL-VP-1383, DARLVP-1369, DARL-VP-1363, DARL-VP-1357, DARLVP-1352, RKS-RAA-156, DARL-VP-1191, VR-VFC2188, VRVFE-2204, VR-VFE-2207, VR-VFE-2326, LOCAL ALMORA, KASHMIRI, LOCAL PITHORAGARH, SPECIAL, KASURI, KASTURI, DESHI (T. corniculata), LOCAL (T. corniculata), NDM, NDM-1, NDM-2, NDM-8, NDM-7, NDM-6, NDM-5, NDM-4, NDM-3, NDM-10, NDM-11, NDM12, NDM-13, NDM-14, NDM-15, NDM-18, NDM-19, NDM-20, NDM-21, NDM-22, NDM-23, NDM-24, NDM-25, NDM-26, NDM-27, NDM-28, NDM-29, NDM-30, NDM-31, NDM-32, NDM-33, UM-351, IC 001978-9, IC 016837, IC 266838, IC 332188, IC 397328, IC 397961, IC 398004, IC 398093, IC 398123, IC 398173, IC 398738, IC 398823, IC 411629, IC 411675, IC 411691, IC 411695, IC 411797, IC 421923, IC 433586, IC 441817, IC 467950, IC 538804, IC 538817, IC 143816 (source/no passport data), IC 143821, IC 143845, IC 143850, IC 143889, IC 143890, IC 144245, IC 144260, IC 144275, IC 144276, IC 144290, IC 144291, IC 144331, IC 149350, IC 311282, IC 377911, IC 467951, KSS 1(source/no passport data), AM 10, AM 35, AM 293, PEB, IC 143900 (T. (Continued)

486

CHAPTER 28 FENUGREEK (TRIGONELLA FOENUM-GRAECUM L.)

Table 28.4 List of Fenugreek Accessions, Lines, Masses or Varieties Reported Worldwide Continued Origin

Accessions, Lines, Masses and Varieties

References

corniculata,(source/no passport data), 33886, 33088, 33366, 33092, 33374, 33888, 40058, HM-267, HM281, HM-279, HM-282, HM-278, HM-271, HM-258-1, HM-280, HM-258, HM-280-1, HM-259, HM-277, HM277-1, HM-273, HM-260, RM-33, RM-27, RM-195, RM-187, RM-185, RM-16, RM-190, RM-14, RM-15, RM-13, RM-18, RM-186, RM-199, RM-189, RM-28, RM-70, RM-424, RM-198, RM-10, ACC-001, ACC002, ACC-003, ACC-017, ACC-010, ACC-009, ACC006, ACC-004, ACC-012, ACC-013, ACC-007, ACC020, ACC-021, ACC-019, CL-32-17, AFG-3, AFG-6, AFG-5, BZ-19, AL1-1-2 Turkey

Egypt

Greece England

France Ethiopia

F70, TMP 8692, TMP 8691, TMP 8690, TMP 8704, PI 206486, PI 206901 (T. caerulea), A150293, Sel. no.18, Sel. no.3, SA 34544 (T. kotschyi Boiss.), SA 32198 (T. caerulea), SA 26689 (T. spicata), SA 16074(T. filipes), SA 12543 (T. brachycarpa Fisch. ex M. Bieb.), SA 12521 (T. schlumbergeri Boiss.), SA 5056 (T. plicata Boiss.), Gurarslan, T. kotschyi (variety not available), T. cilicica Hub.-Mor. (variety not available), T. aurantiaca, T. arenicola, T. fischeriana, T. tenuis, T. cancellata (HA 3757), T. astroits (HA 3804), T. halophila (HA 4555), T. crassipes (HA 3791), T. rigida (HA 4737), T. carica (HA 3366), T. arcuata (HA 3746), T. monantha subsp. monantha, T. monantha subsp. noeana, T. rostrata (Boiss. & Balansa) Boiss., T. isthmocarpa Boiss. & Balansa, T. rhytidocarpa Boiss. & Balansa, T. cephalotes Boiss. & Balansa, T. procumbens (Besser) Reichp., T. capitata Boiss. Gharbin-6, TMP 8679, TMP 8698, Giza-3, A277, SA 35686, SA 34593 (T. arabica Delile), Egypt0, Egypt1, Giza-2, Giza-30, Giza-6, Giza 126, Giza 1, 33894, 356812 Ionia, PI199264 (CN 19064), SA 33025, SA 33011, SA 32999, SA 13285 (T. balansae) Barbara, Margaret, Paul, Fluorescent (RH 2602), Ethiopian (RH 2699), Kenyan (RH 2698), Moroccan (RH 2701), RH 3112, RH 3113, RH 3114, RH 3116, RH 3117, RH 3119, RH 3120, RH 3122, RH 3109/32, RH 3109/33, RH 3109/42, RH 3110/66, RH 3129, RH 3118, RH 3115, RH 3109/39, RH 31093/37, L3679(CN 19138), L3674(CN 19132/ T. caerulea), 42625 Gouta, Gers, L3682(CN 19151) PI195691(CN 19063), RH 2475, RH 2278, M08, TMP 8696, A150198, 53072, 53030, 53032, 53075, 216897, 53006, 53064, 53065, 230072, 230073, 234028, 53056, 53057, 53059, 234033, 237511, 207599, 234024, 234025, 234026, 212775, 212776, 236622, 53050,

[49,51,52,56,73,91 94]

[31,47 49,51,73,95 99]

[31,51,56] [2,31,47,54]

[31,53] [31,47,49,52,56,100,101]

28.3 FENUGREEK DISTRIBUTION AND GLOBAL GENETIC DIVERSITY

487

Table 28.4 List of Fenugreek Accessions, Lines, Masses or Varieties Reported Worldwide Continued Origin

Accessions, Lines, Masses and Varieties

References

239062, 53017, 230880, 234030, 234031, 234034, 241140, 53005, 53066, 207376, 207370, 53086, 53087, 53088, 53106, 212550, 53007, 215261, 53009, 207360, 53014, 53102, 215729, 215731, 226090, 53019, 213110, 213115, 53096, 53016, 53020, 53022, 51012, 219250, 223350, 223351, 223352, 223353, 216898, 232194, 236992, 53060, 53063, 53091, 212876, 212878, 237984, 239727, 234032, 235133, 234023, 53071, 53080, 53097, 53107, 53079, 53098, 53099, 212777, 215334, 215335, 239061, 239063, 239064, 53018, 208680, 230536, 230540, 53062, 53108, 53109, 207356, 207367, 53003, 212552, 214942, 229245, 229246, 239073, 53010, 53008, 207391, 215585, 53104, 53105, 212658, 53012, 53013, 213111, 213112, 213114, 213117, 239068, 239065, 208679, 237982, 53103, 235134, 226091, 212779, 53061, 53021, 53026, 239066, 236621, 212549, 53074, 216899, Challa, 212657, 213109, 205176, 207365, 53078, 215096, 53023, 229247, 53002, 232195, 212877, 53085, 53100, 215406, 230070, 215405, 230883, 234029, 234027, 207359, 223349, 212656, 33660, 238247 Kenya Morocco Spain

China

Libya

RH 2591 RH 2283, PI577711(CN 19067), A150265, A265, SA 32194 (T. anguina Delile) PI577713 (CN 19068), Chiadoncha, Blidet, Obanos, PI 244288 (T. caerulea), A150264, SA 32220 (T. gladiata Steven ex M. Bieb.), SA 32200 (T. caerulea) L3375, H 003, H 133, H 134, H 135 (T. cancellata Desf), H 137, H 138, H 002, H 001 (T. orthoceras Kar. & Kir.), (Tongxin, Ningxia I), (Tongxin, Ningxia II), (Taole, Ningxia), (Pengyang, Ningxia), (Longde, Ningxia I), (Tongxin, Ningxia III), (Qingtongxia, Ningxia), (Xiji, Ningxia), (Pingluo, Ningxia), (Tongxin, Ningxia IV), (Guyuan, Ningxia), (Longde, Ningxia II), (Haixi, Qinghai), (Taihe, Anhui), (Fengning, Hebei), (Shanxian, Henan), (Bayannaoer, Inner Mongolia), (Yunnan), (Yishui, Shandong), (Zhangye, Gansu), (Etuoke, Inner Mongolia), (Xining, Qinghai), (Yumen, Gansu), (Sunwu, Heilongjiang), (Hangkong, Ningxia), (Duizhao, Ningxia), (Bameng, Inner Mongolia), (Qianqi, Inner Mongolia), (Lanzhou, Gansu), (Wuwei, Gansu), (Etuokeqianqi, Inner Mongolia), 33086 (West China), 33089 (West China), 34583 (West China) Ghahkamon, SA 32195 (T. anguina), SA 9841 (T. maritima Delile ex Poir.), SA 9840 (T. coerulescens), 355761

[31] [31,48,51,52,54,56] [49,51 53,56]

[47,54,56,102 105]

[47,51,53]

(Continued)

488

CHAPTER 28 FENUGREEK (TRIGONELLA FOENUM-GRAECUM L.)

Table 28.4 List of Fenugreek Accessions, Lines, Masses or Varieties Reported Worldwide Continued Origin

Accessions, Lines, Masses and Varieties

References

Hungary Romania

Ovari 4, Ovari Gold, PSZ.G.SZ L3681(CN 19150), Tfg-15-PN,Tfg-18-PN, De Muntenia, Tfg-6-SC, Tfg-5-PN, Tfg-15-PN, Tfg-18PN, Tfg-4-PN, Tfg-17-PN, Tfg-14-PN, Tfg-6-PN, Tfg3-PN, Tfg-16-PN, Tfg-13-PN L3680 (CN 19139), SA 32209 (T. cretica) L3678 (CN 19137), L3677 (CN 19136), L3672 (CN 19130), 33392 L3676 (CN 19135), 33787 L3675 (CN 19133) L3671 (CN 19129), PI 345743 (T. caerulea), SA 32224 (T. schlumbergeri) TMP 8714, Dilba, 425579 TMP 8706, Local (in Kathmandu Valley) PI 186283 (T. caerulea), A150118 (source), A150000 (source), SA 35940 (T. suavissima Lindl.), SA 32597 (T. suavissima), SA 32197 (T. caerulea), SA 27514 (T. suavissima) A150212, SA 34597 (T. stellata Forssk.), SA33810 (T. hierosolymitana Boiss.), SA 14511 (T. arabica), SA 5043 (T. caelesyriaca) SA 5045 (CPI 19633/ T. balansae), SA 5048 (T. cretica), SA 5045 (T. balansae) Sidi Khiar II, Kssar, Douar Lehmailia I, Douar Lehmailia II, Tel Elgozlan II, Sidi Khiar I, Borj Berrzig, Tel Gozlan II, Ben Bechir, Sidi Hamed, Beja I, Beja II, Beja II, Beja IV, Nefza I, Nefza II, Nefza III, Mater I, Mater II, Mater III, Mater IV, Mater V, Mhamdia I, Mhamdia II, Mhamdia III, Bizerte, Manzel Temim I, Manzel Temim II, Manzel Temim III, Manzel Temim IV, Manzel Temim V, Sidi Maaouia, Zaouia, Merguaz, Dakhla I, Dakhla II, Dakhla III, Manzel Habib I, Manzel Habib II, Elkef, Nebeur, 4681 Nakhichevanskaya Shambala, SA 32203 (T. coerulescens), SA 6142 (T. grandiflora) Paul, Barbara, Ionia, Margaret SA 919 (T. arabica), Israel I, Israel II F-2, F-3, F-17, F-31, F-35, F-94, F-98, F-104 [Batinah South, 14 accessions, Interior, 13 accessions, Sharqiya, 12 accessions and Dhahira and Buraimi, 10 accessions// F-109, F-105, F-100, F-97, F-92, F-91, F-89, F-86, F-83, F-82, F-80, F-79, F-78, F-76, F-75, F-60, F-61, F-62, F50, F-52, F-47, F-49, F-46, F-36, F-38, F-34, F-35, F-29, F-30, F-26, F-27, F-20, F-21, F-23, F-14, F-16, F-10, F12, F-6, F-8, F-5, F-1], 312, 63, 136, 153, 160, 209, 235, 240, 122, 97, 2, 17, 31, 35, 49, 212, 246, 260, 274, 304

[53] [54,73,106]

Switzerland Germany Poland Austria USA Yemen Nepal Australia

Jordan

Sweden Tunisia

Russia Slovenia Israel Oman

[51,54] [47,54] [47,54] [54] [49,51,54] [47,49,73] [49,107] [49,51,52]

[51,52]

[51,108] [47,73,109]

[51,73] [73] [51,105] [62,110]

28.3 FENUGREEK DISTRIBUTION AND GLOBAL GENETIC DIVERSITY

Table 28.4 List of Fenugreek Accessions, Lines, Masses or Varieties Reported Worldwide Continued Origin

Accessions, Lines, Masses and Varieties

References

Algeria Sudan

30856, 42104 Abu Hamad, Berber, Damar I, Damar II, Dongola, Habashy, Hindy, Rubatab, Baladi, 37067 T. glabra (Thunb) Sir. T. hamosa Forssk (variety not available) EC 520255 4970 34252 43305

[47] [47,111,112]

South Africa Taiwan Eritrea Ukraine Turkmenistan Portugal

[76] [76] [85] [47] [47] [47]

FIGURE 28.5 Pie chart indicating relative frequency of fenugreek diversification distributed across different countries.

489

490

CHAPTER 28 FENUGREEK (TRIGONELLA FOENUM-GRAECUM L.)

distributed across the Eastern Hijaz subcontinent with low annual rainfall and high temperature during summer and big differences in its day/night temperatures [118]. These are evident indications of the high degree of tolerance of the semiarid crop to unfavorable circumstances [119]. Irrespective of desert (nonarable) regions, it is clear that fenugreek plant enjoys a great diversity across different latitudes. Species richness is mostly highlighted in tropical/ subtropical regions such as India and Ethiopia. In Turkey, Pakistan, Iran, Tunisia, China, and Canada we have relatively high genetic diversity. Among which, throughout Turkey and the northern part of Iran and Tunisia is a Mediterranean climate suitable for crop plants, especially forage cultivation. Central and South Eastern part of China are likely best suited for fenugreek cultivation. Even though in the literature it is mostly documented that the plant is a fairly tolerant herb to frost and very low temperature, however, Canada is allocated nearly 4.95% of the relevant frequency among other nations (Table 28.4). The observed diversification richness in North America might be relevant to intense inbreeding activities done to enable the crop to thrive during the frost-free period. Undoubtedly, the Indian subcontinent is the largest producer of fenugreek worldwide, and due to its particular climatic conditions accounts for the highest genetic variation not only for the multipurpose (medicinal/aromatic or even forage) crop but in other areas.

28.4 CONCLUSION Fenugreek has great potential for growth in dryland (rainfed) localities with little support of irrigation. However, the crop performs well under irrigation; therefore being suitable for sustainable agriculture due to its water conservation properties and as such reduces the cost of production for farmers. Being a predominantly dryland crop, fenugreek is an attractive crop for the low input agricultural systems for developing and underdeveloped nations of Asia, Africa, and Latin America. Dry or semiarid areas or pockets can serve as potential new areas for fenugreek production with suitable agro-climatic conditions within these continents. Furthermore, being an annual legume, it can easily fix atmospheric nitrogen to the soil. Hence, it is a potential crop for reclamation of otherwise agriculturally unsuitable or marginal lands for potential agricultural productivity and transforming unsuitable lands into agriculturally productive areas for poor and marginal farmers who may not have access to land for agricultural activity. Fenugreek can also be incorporated into the short growing cycles of local crops to enrich the soil nitrogen quality naturally. It could also be made an integrated part of organic agricultural practices. Fenugreek, in short is a multipurpose crop that can either be grown as forage, spice, or medicinal herb, as well as a crop for the pharmaceutical, nutraceutical, and functional food industries for the presence of several important phytochemicals in its seeds and leaves. Hence, fenugreek is considered as a chemurgic crop due to its industrial applications and being suitable for the low input agricultural system of developing and underdeveloped nations. It has been reported that global warming and climate change will have significant impacts on agricultural productivity across the planet. Therefore, it is important to actively look for opportunities to introduce new climate resilient crops like fenugreek for tropical, subtropical, and subtemperate agro-climatic regions to boost agricultural production by cultivating new nonconventional or new nontraditional crops for agriculturally unexplored or under explored areas in addition to the

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conventional crops or traditional crops of the region. However, it is important to note that since high Genetic X Environment interactions have been reported for fenugreek germplasms across the globe, it will be best to develop locally adapted cultivars for optimal yield. The genetics, metabolic mechanisms, and special adaptations allow fenugreek to work as an active nitrogen-fixer with low water requirement and allow the crop to grow in semiarid climatic regimes under low input agriculture system practices in several poor developing and underdeveloped nations. Semiarid plants like fenugreek are well adapted to survive in areas with little rainfall and hence can be looked upon as climate resilient, water saving, energy and resource efficient multiuse crop for poor agriculturally dependent countries around the globe with semiarid climate. Fenugreek has the potential to develop into a popular, drought-resistant, bioenergy crop under suitable climatic conditions. Above all, the presence of medicinally important rich phytochemicals makes fenugreek an appealing industrial crop for the global pharmaceutical, nutraceutical, and functional food industries.

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[56] [57] [58] [59]

[60] [61]

[62] [63]

[64] [65] [66] [67] [68]

[69]

[70]

[71]

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[91] Martin E, Akan H, Ekici M, Aytac¸ Z. Karyology of ten Turkish Trigonella L. (Leguminosae) species from section Cylindricae Boiss. Turk J Bot. 2010;34:485 94. [92] Martin E, Akan H, Ekici M, Aytac Z. Karyotype analyses of ten sections of Trigonella (Fabaceae). Comp Cytogen 2011;5:105 21. [93] Tunc¸tu¨rk R. The effects of varying row spacing and phosphorus doses on the yield and quality of fenugreek (Trigonella foenum-graecum L). Turk J Field Crops 2011;16:142 8. [94] C ¸ eter T, Pinar NM, Akan H, Ekici M, Aytec¸ Z. Comparative seed morphology of Trigonella L. species (Leguminosae) in Turkey. Afr J Agric Res. 2012;7:509 22. [95] Ping L, Hongwei M, Yinxia Z, Hailin Z. Study on the characteristics of seed and seedling in Trigonella foenum-graecum from different provenances. J Agric Sci. 2008;29:1 5. [96] Ahmed MA, Ibrahim OM, Badr EA. Effect of bio and mineral phosphorus fertilizer on the growth, productivity and nutritional value of fenugreek (Trigonella foenum graecum L.) in newly cultivated land. Res J Agric Biol Sci. 2010;6:339 48. [97] Marie-Christine RS, Shreef GNG. Post-prandial responses to different bread products based on wheat, barley and fenugreek or ginger or both in healthy volunteers and their effect on the Glycemic index of such products. J Am Sci. 2010;6:89 96. [98] Ahmad AG, Ebtsam El-Housini A, Hassanein MS, Nabila Zaki M. Influence of organic and biofertilizer on growth and yield of two fenugreek cultivars grown in sandy soil. Aust J Basic Appl Sci. 2012;6:469 76. [99] Hussein MM, Safi-Naz SZ. Influence of water stress on photosynthetic pigments of some fenugreek varieties. J Appl Sci Res. 2013;9:5238 45. [100] Fikreselassie M, Zeleke H, Alemayehu N. Genetic variability of Ethiopian fenugreek (Trigonella foenum-graecum L.) landraces. J Plant Breed Crop Sci. 2012;4:39 48. [101] Amberber M, Argaw M, Asfaw Z. The role of home gardens for in situ conservation of plant biodiversity in Holeta Town, Oromia national regional state, Ethiopia. Int J Biodivers Conserv. 2013;6:8 16. [102] Liu P, Zhang LI, Ma HW, Li YK, Kang G. Genetic diversity in germplasm resources of Trigonella foenum-graecum based on biological characters. Chinese Traditional and Herbal Drugs. 2009;40:630 4. Available from: http://en.cnki.com.cn/Article_en/CJFDTOTAL-ZCYO200904043.htm. Accessed March 11, 2016. [103] Li P, Li YK, Li XH, Ma HW. Allozyme variation and genetic diversity in Trigonella foenum-graecum L. Acta Botany Boreal-Occident Sinica 2010;30:1780 5. [104] Deng CH, Cui DF, Yang HI, Li FF, Fang Y. Studies on morphological characters and numerical classification of Medicago L. and Trigonella L. species. J Plant Res Environ. 2010;19:1 11. [105] Zhangjun W, Ping L, Cui I, Yunxia Z. Analysis of genetic diversity using RAPD in the germplasm resources of Trigonella foenum-graecum Linn. Journal of Ningxia University (Natural Science Edition) 2011;32:74 7. [106] Floria F, Ichim MC. Valuable Fenugreek (Trigonella foenum-graecum L.) mutants induced by Gamma rays and Alkylating agents. Plant Mutat Rep. 2006;1:31 2. [107] Ali M, editor. Dynamics of vegetable production, distribution and consumption in Asia. Shanhua, Taiwan: Asian Vegetable Research and Development Center (AVRDC) publication; 2000. [108] Dundas IS, Nair RM, Verlin DC. First report of meiotic chromosome number and karyotype analysis of an accession of Trigonella balansae (Leguminosae). New Zealand J Agric Res 2006;49:55 8. Available from: https://doi.org/10.1080/00288233.2006.9513693. [109] Marzougui N, Guasmi F, Boubaya A, Elfalleh W, Lachieheb B, Ferchichi A, et al. Assessment of Tunisian Trigonella foenum-graecum diversity using physiological parameters. J Food Agric Environ. 2009;7:427 31.

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CHAPTER

FUNCTIONAL AND THERAPEUTIC APPLICATIONS OF SOME IMPORTANT SPICES

29

Amit Krishna De1 and Minakshi De2 1

Indian Science Congress Association, Kolkata, West Bengal, India 2Surendranath College, Kolkata, West Bengal, India

29.1 INTRODUCTION The literature of Ancient Asia is a treasure trove of information related to the problems of health and diseases. One such important antiquity, besides the ayurvedic treaties like Charaka Sushrita, Vhagbhat (Asthanga Hridaya) Samhita, and Bhowprakash, is particularly the India vedic literature, which are four in number. The vedic literature (2500 BC) is the source of information that contributes to the development of Ayurveda where different parts of the plants have been mentioned to be used as medicines. In ancient India natural herbs including spices were consumed either as food or used as medicines in order to maintain proper sanitation, health and hygiene, and increase longevity of life. In medieval Asia, besides fine textiles and ivory, spices were considered to be highly important. In this respect, India has been considered as the “Kingdom of spices.” In ancient economics, spices were ranked with precious inventories of royal possessions. Pepper was regarded as the “Black gold of India” and the “King of Spices,” while cardamom was the “Queen of spices.” Spices have been used since ages in tribal and folk medicines and different traditional forms of ancient medicine like Ayurvedic, Unani, and Sino-Tibetan systems. In Ayurveda specially, spices contribute a major amount for the treatment of major disorders of the body and are officially recognized as a drug material in the pharmacopoeia of several countries like India, China, United States, and Europe. They are used as carminatives, antiseptics, or musking the unpleasant taste of drugs. Homoeopathic medicine has been using spices as one of the major ingredients in most of their preparations. In this respect, some major spices like chilli, pepper, ginger, garlic, bishops weed, cumin, coriander, turmeric, mustard, asafoetida, fenugreek, onion, fennel, anise, cinnamon, tamarind, etc., play a major role. Spices were also used in perfumes, offerings, medicine, preservatives, flavors, cultural marks, cosmetics, in perfumery, soap manufacturing, pesticides, and as condiments. Natural red and yellow color prepared from red chilli, turmeric, and saffron, respectively, were used as dyes. Spices were some of the most valuable items of trade in the ancient and medieval world. India is well known as one of the largest producers, consumers, and exporters of spices and spice products. India grows over 50 spices in different parts as compared to 86 spices in the world. India consumes a considerable quantity of spices and still exports around 218,000 225,000 tons of The Role of Functional Food Security In Global Health. DOI: https://doi.org/10.1016/B978-0-12-813148-0.00029-3 © 2019 Elsevier Inc. All rights reserved.

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spice products each year. There are about 86 species of spices grown in different parts of the world. Many of them are grown in India and other Asian countries. Around 52 spices have been identified by the Spices Board, India. The important spices of India are given below (Table 29.1).

29.2 MEDICINAL PROPERTIES OF SPICES Spices are parts of plants, such as roots, buds, flowers, barks, and seeds, which can be obtained from a large number of different plants. The flavor of spices comes from volatile oils and also fixed oils and small amounts of resins. Sometimes a blend of alcohols, phenols, esters, organic acids, alkaloids, and sulfur contribute to the flavor. Spices also contain the usual components of plant products such as protein, carbohydrates, fiber, minerals, tannins, and vitamins. Natural colors extracted from spices are contributing a lot towards the exports of the country. Spices play a very important role in human health and disease. Apart from serving a critical role in Indian cuisine, spices are now revealing important properties in preventing or combating ailments including cancer, arthritis, diabetes, rheumatism, metabolic and immunological disorders. Even in the modern day Western allopathic system, spices provide about one-third of the medicines or the patent compounds. Even today, spices are used as medicines and are playing significant roles in the development of the national economy. The antiproliferative, antihypercholesterolemic, antidiabetic, antiinflammatory effects of spices have overriding importance, as the key health concern of mankind nowadays is diabetes, cardiovascular diseases, arthritis, and cancer. Spices or their active compounds could be used as possible ameliorative or preventive agents for these health disorders. Most of the available spices in India have been studied in detail and their active constituents have been identified. Some of the important active principles are mentioned in Table 29.2. Spices are prone to spoilage by insect or microbial attack. Hence, spice oils containing all the active ingredient of spices are extracted or marketed. This is done by steam distillation of ground spices. Oleoresins are obtained by solvent extraction of ground spices. Acetone, isopropanol, methanol, hexane, etc., are used as solvents. Processed products of spices are convenient to use, free from contamination, have better storage life, and easy to transport. In curries, bakery products, pickles, processed meat, beverages, liquors, etc., spices are used as flavoring agents varying or enhancing the flavor. Sometimes spices can help mask the flavor of foods; some spices possess antioxidant properties while others are used as carminatives. Some spices are used as preservatives; others like clove and mustard prevent food spoilage due to their antimicrobial properties. Many spices also possess important physiological and medicinal properties. Besides antimicrobial properties, spices also have (1) antiinflammatory, (2) analgesic, (3) antioxidant, (4) antiobesity, (5) antipollutant, and (6) antimutagenic properties. Based on the recent reports and studies carried out in our laboratory, spices can be grouped according to their biological activities and medicinal properties. These properties of spices justify their traditional uses in various folklore and ancient medicines in different cultures and customs.

29.2 MEDICINAL PROPERTIES OF SPICES

501

Table 29.1 Spices Available in India Name

Botanical Name

Parts of Plant

1. Cardamom (small) (large) 2. Pepper 3. Chilli 4. Ginger 5. Turmeric 6. Coriander 7. Cumin 8. Fennel 9. Fenugreek 10. Celery 11. Aniseed 12. Bishop’s weed 13. Caraway 14. Dill 15. Cinnamon 16. Cassia 17. Garlic 18. Curry leaf 19. Kokam 20. Mint 21. Mustard 22. Parsley 23. Pomegranate seed 24. Saffron 25. Tejpat 26. Pepper long 27. Star anise 28. Vanilla 29. Sweet flag 30. GreaterGalanga 31. Horse radish 32. Caper 33. Clove 34. Asafoetida 35. Cambodge 36. Hyssop 37. Juniper berry 38. Bay leaf 39. Lovage 40. Marjoram

Electtaria cardamomum Linn Amomum subulatum Roxb Piper nigrum Linn Capsicum frutescens Linn Zingiber officinale Roscoe Curcuma longa Linn Coriandrum sataivum Linn Cuminum cyminum Linn Foeniculum vulgare P. miller Trigonella foenumgraecum Linn Apium graveolens Linn Pimpinella anisum Linn Trachyspermum anisum Linn Carum carvi Linn Anethum graveolens Linn Cinnamomum zeylanicum Blume Cinnamomum aromaticum Nees Allium sativum Linn Murraya koenigii Linn Garcina indica Choisy Mentha piperita Linn Brassica jaucea Linn Petroselinum crispum Punica granatum Linn Crocus sativus Linn Cinnamomum tamala Nees Piper longum Linn Illicium verum J D Hooker Vanilla fragrans Ames Syn. Acorus calamus Linn Alpinia galanga Linn Armoracia rusticana Gaertner Capparis spinosa Linn Syzgium aromaticum Linn Ferula asafoetida Linn Garcinia cambogia Gaertner Hyssopus officinalis Linn Juniperus communis Linn Laurus nobilis Linn Levisticum officinale Koch Marjorana hortensis

Fruit Fruit Fruit Fruit Rhizome Rhizome Leaf & seed Fruit Fruit Seed Fruit Fruit Fruit Fruit Fruit & Seed Bark Bark Bulb Leaf Fruit Leaf Seed Seed Seed Stigma Leaf Fruit Fruit Pod Rhizome Rhizome Rhizome Fruit Bud Resin Pericarp Leaf Berry Leaf Leaf Leaf (Continued)

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Table 29.1 Spices Available in India Continued Name

Botanical Name

Parts of Plant

41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52.

Myristica fragrans Houttuyn Myristica fragrans Houttuyn Ocimum basilicum Linn Papaver somniferum Linn Pimenta dioca Linn Rosmarinus officinalis Linn Salvia officinalis Linn Satureja hortensis Linn Thymus vulgaris Linn Origanum vulgare Linn Artemisia dracunculus Linn Tamarindus indica Linn

Seed Aril Leaf Seed Fruit Leaf Leaf Stem, leaf fruit Leaf Leaf Fruit

Nutmeg Mace Basil Poppy seed All Spice Rosemary Sage Savory Thyme Oregano Tarragon Tamarind

Spices Board, Cochin.

Table 29.2 Active Principle(s) of some major Spices Major Spice

Some Important Active Constituents(s)

Basil Chilli

methyl cinnamate, methyl chavicol, ocimene,cineole, linalool capsaicinoids, caffeic acid, chlorogenic acid, coumaric acid, feluric acid, hesperidin, quarcetin, rutin piperine,germacrene, limonene, pinene, alpha-phellandrene beta-caryophyllene gingerols, gingerdione, 6-shogaol, galanolactone eugenol, gallic acid cuminaldehyde, α-pinene, safranol, linalool, thymol linalool, caffeic acid, ferulic acid, gallic acid, chlorogenic acid allicin, ajoene, allyl sulfides propenylsulfides anethole, methyl chavicol, p-methoxyphenol acetone thymol, carvacrol, p-cymene, gamma-terpinene allyl isothiocyanate cinnamaldehyde, ethyl cinnamate, eugenol, beta- caryophyllene, linalool, and methylchavicol thymol, eugenol thymol, carvacrol anethole, fenchone, foeniculin anethole, protocatechuic acid phellandrene, carvone curcuminoids (curcumin and demethoxycurcumin) trigonellin, galactomannan, 4-hydroxy-isoleucine, saponin carvacrol, flavonoid, p-cynene-2,3-diol, rosmarinic acid

Pepper Ginger Clove Cumin Coriander Garlic Onion Anise Bishops weed Mustard Cinnamon Sage Oregano Fennel Star anise Dill Turmeric Fenugreek Thyme

29.2 MEDICINAL PROPERTIES OF SPICES

503

29.2.1 ANTIMICROBIAL PROPERTIES Scientists have demonstrated that the same chemical compounds that protect the spice plants from their natural enemies are at work today in foods from parts of the world where before refrigeration food-spoilage microbes were an even more serious threat to human health. People who enjoyed food with antibacterial spices probably were healthier, especially in hot climates. Indeed, in hot countries nearly every meat-based recipe calls for at least one spice, and most include many spices, especially the potent spices, whereas in cooler counties substantial fractions of dishes are prepared without spices, or with just a few. As a result, the estimated fraction of food-spoilage bacteria inhibited by the spices in each recipe is greater in hot than in cold climates. Scientific experiments since the late 19th century have documented the antimicrobial properties of some spices, herbs, and their components. Studies in the past decade confirm that the growth of both gram-positive and gram-negative foodborne bacteria, yeast, and mold can be inhibited by garlic, onion, cinnamon, cloves, thyme, sage, and other spices. Effects of the presence of these spices/herbs can be seen in food products such as pickles, bread, rice, and meat products. Thus, it is observed that higher levels of spices are necessary to inhibit growth in food than in culture media. Spices and herbs have been used for thousands of years by many cultures to preserve foods. Some spices are used as preservatives in pickles and also prevent food spoilage. Spices that have been shown from our laboratory to have an inhibitory effect on various microorganisms include cumin, cinnamon, black cumin, clove, onion, Bishop’s weed (ajowain), chilli, garlic, celery, basil, tejpat, nutmeg, small cardamom, caraway, turmeric, tamarind, aniseed, black pepper, horseradish, pomegranate seeds, cambodge, mustard, rosemary, thyme, oregano, and star anise [1 5]. Some of these spices, either in the form of powder, extract, or extracted oil are known to control microbial spoilage of food [6,7]. Reports are available on the antimicrobial principles from the volatile oil of black cumin. The essential oil of small cardamom has been studied as an antimycotic agent against mycotoxigenicmoulds. It has been observed that large cardamom also inhibited growth of some bacteria. Clove oil has been found to be active against many nonpathogenic and pathogenic bacteria and fungi. It has been found that oil of mustard is antimicrobial in nature. Chilli has been found to possess antimicrobial properties. Cumin, clove, thyme, and cinnamon contain different antimicrobial agents. Ginger inhibits the growth of many microbes. Carvacrol, the main fungicidal component of savory has been found to inhibit the growth of some fungus. Essential oils from spices like ginger, coriander, basil, etc., have been found to show various degrees of inhibition against bacterial growth. Inhibitory effects of anethole and eugenol on the growth and toxin production of A. parasiticus have also been observed. Capsaicin from Chilli acts as a potent inhibitor of the gastric pathogen, Helicobacter pylori. Garlic extract also inhibits the growth of many aerobic bacteria and prevents bacterial growth in bacterial wilt disease in tomato. The high antimycotic activities of four different of spices, viz. Chinese cassia, clove, thyme oil, and cinnamon, may be used for preservation of agricultural commodities. Cinnamon, cardamom, and thyme oil are highly active against the growth of Gramnegative and Gram-positive bacteria. Reports of bacterostatic and fungistatic activities of volatile oil from cinnamon have also been found. Inhibition of growth and germination of Clostridium botulinum by essential oil of clove, thyme, black pepper, garlic, onion, and cinnamon have been recorded.

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Cinnamon contains a lot of manganese, iron, dietary fiber, and calcium. Cinnamon contains derivatives, such as cinnamaldehyde, cinnamic acid, cinnamate, and numerous other components such as polyphenols which show antioxidant, antiinflammatory, antidiabetic, antimicrobial, anticancer effects [8]. Oil of anise is also used in soap making and the toilette industry. It is also utilized in perfuming satchels or school bags, dental preparations, and mouthwashes. It finds an important application in the preparation of lacquers or varnishes. Recently it has been shown that anise seeds and root have estrogenic activity in rats. The oil of anise is used as an antiseptic for the treatment of cholera and has fungicidal properties. An alcoholic extract of aniseed kills fungi and is thus useful in fungal skin diseases. Essential oils of Pimpinellaanisum, Chamomillarecutita L., Thymus vulgaris, and Origanum vulgare L. showed antifungal activity [9]. Recently some spices, such as clove, oregano, thyme, cinnamon, and cumin, have been shown to possess significant antibacterial and antifungal activities against food spoilage bacteria like Bacillus subtilis and Pseudomonas fluorescens, pathogens like Staphylococcus aureus and Vibrio parahaemolyticus, harmful fungi like Aspergillus flavus, even antibiotic resistant microorganisms such as methicillin resistant Staphylococcus aureus [10,11]. In a study cardamom, cumin, and dill weed essential oils were evaluated for their antibacterial activities against Campylobacter jejuni and Campylobacter coli. The results supported high efficiency of all three to inhibit Campylobacter spp. by impairing the bacterial cell membrane. Turmeric has a wide medicinal use especially in Ayurvedic and homoeopathic medicine. Externally it is used for removing edemas or swellings, stabilizing or stopping painful sensations, helping in coloration of skin, and is rather helpful in cleaning wounds. It is useful in urinary disorders, blood anaemia, indigestion, and loss of taste. It is extensively referred to in “Charaka Samhita” as scarifying and destructive of itching and skin diseases including leprosy. Turmeric is effective against respiratory disorders. Clinical trials on patients indicate that turmeric can cause relief to patients suffering from bronchitis and asthma. This clearly also clarifies the use of turmeric as an Ayurvedic medicine for treatment of cough, cold attacks, and even asthma. Turmeric oil applied on the chest, the back and the belly, as well as the throat relieves asthmatic bouts and chronic coughing. Turmeric, both raw and dried, is considered beneficial for skin diseases. The juice of raw rhizomes is used as an antiparastic for many skin infections. The protective effect of curcuminoids from turmeric on epidermal skin cells under oxygen radical stress has recently been reported. An aqueous extract containing total active constituents of turmeric is useful in treating gallstones and gall complaints. Turmeric has wide uses as an antimicrobial and antiseptic agent. The antimicrobial property of essential oil from turmeric against pathogenic bacteria and fungi has been reported [1]. Curcumin has been found to have antiinflammatory, antioxidant, hepatoprotective, and choleretic properties [12,13]. Recent studies indicate that turmeric has potent antioxidant activity due to the phenolic character of curcumin. It is one of the few spices with antioxidant properties that can protect against harmful mutagens.

29.2.2 ANALGESIC/ANTIINFLAMMATORY/ANTIOXIDANT PROPERTIES Spices are rich in antioxidants, and scientific studies suggest that they are also potent inhibitors of tissue damage and inflammation caused by high levels of blood sugar and circulating lipids.

29.2 MEDICINAL PROPERTIES OF SPICES

505

Because spices have very low calorie content and are relatively inexpensive, they are reliable sources of antioxidants and other potential bioactive compounds in diet. The Indian traditional medical systems use turmeric for wound healing, rheumatic disorders, gastrointestinal symptoms, deworming, rhinitis, and as a cosmetic [12]. Studies in India have explored its antiinflammatory, cholekinetic, and antioxidant potentials with the recent investigations focusing on its preventive effect on precarcinogenic, antiinflammatory, and antiatherosclerotic effects in biological systems both under in vitro and in vivo conditions in animals and humans. Both turmeric and curcumin were found to increase detoxifying enzymes, prevent DNA damage, improve DNA repair, decrease mutations and tumor formation, and exhibit antioxidative potential in animals. Many clinical trials have been conducted to determine the effectiveness of Extracts of Curcuma species curcumin in osteoarthritic patients. Patients with osteoarthritis showed improvement in pain, physical function, and quality of life after taking curcumin. They also reported reduced concomitant usage of analgesics and side effects during treatment. In vitro studies demonstrated that curcumin could prevent the apoptosis of chondrocytes, suppress the release of proteoglycans and metal metalloproteases and expression of cyclooxygenase, prostaglandin E-2, and inflammatory cytokines in chondrocytes. The antiinflammatory role of curcumin has been utilized in treating osteoarthritis. Ginger has been used as a pain killer. It can cure all types of pain. In headache, ginger ointment made by rubbing dry ginger with a little water on a grinding stone and applied to the forehead affords relief. It allays toothache when applied to the gum. In the case of earache, a few drops of ginger juice give relief. Assay-guided isolation was found to give three new compounds, e.g., Cassumurins A, B, and C, having both antioxidant and antiinflammatory activities from the rhizomes of a tropical ginger Zingibercassumunar. Numerous studies have documented the antioxidant, antiinflammatory, and immunomodulatory effects of spices, which might be related to prevention and treatment of several types of cancers, including lung, liver, breast, stomach, colorectum, cervix, and prostate cancers. Several spices are potential sources for prevention and treatment of cancers, such as turmeric, black cumin, ginger, garlic, saffron, black pepper, and chilli pepper, which contain several important bioactive compounds, such as curcumin, thymoquinone, piperine, and capsaicin. The main mechanisms of action include apoptosis, inhibiting proliferation, migration and invasion of tumors, and sensitizing tumors to radiotherapy and chemotherapy [14]. Star anise has antimicrobial properties. It has been found to prevent growth of both pathogenic and nonpathogeic bacteria and also inhibit fungal and yeast activity [2,3]. Extensive studies have indicated that anethole and derivatives of anethole may be responsible for the above antimicrobial properties of star anise. Anethole is the main fragrance and bioactive compound of anise, fennel, and star anise spices and more than other 20 plant species. It is widely used as a flavor agent in the food industry and other industries, e.g., in cosmetics, perfumery, and pharmaceuticals. In the last few years, various studies have revealed multiple beneficial effects of anethole for human health, such as antiinflammatory, anticarcinogenic and chemopreventive, antidiabetic, immunomodulatory, neuroprotective, or antithrombotic, that is mediated by the modulation of several cell signaling pathways, mainly NF-kB and TNF-α signaling, and various ion channels [15,16]. Some commonly used Indian spices (anise, cardamom, Ceylon cinnamon, and clove) along with their purified components (anethole, eucalyptol, cinnamaldehyde, and eugenol, respectively) were studied and it was found that spices as a whole are more potent antioxidants than their purified

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active components, perhaps reflecting the synergism among different phytochemicals present in spice extracts [17]. Indians have been using spices to stop spoilage of cooked foods. This can be explained on the basis of their antioxidant properties. Recent studies indicate that capsaicin from chilli, piperine from pepper, gingerone from ginger, curcumin from turmeric, thymol from bishops weed, etc., have a lot of antioxidant properties. Extensive studies from our laboratory have shown that pretreatment of rats with capsaicin or chilli extract protected the pulmonary system against free radical induced damages produced from gaseous irritants like formaldehyde, nitrogen dioxide, sulfur dioxide, carbon tetrachloride, dicholoromethane, and smoke [18 21]. Cigarette smoke in particular causes clastogenicity and DNA-strand breakage in mice bone marrow cells which may be prevented by treatment with capsaicin. Moreover liposomes exposed to UV radiation produced peroxidation which was reduced by capsaicin application [22]. These results prove the antioxidant properties of capsaicin [21a]. The antioxidant activity of the spice compounds in mammalian system involve one or more of the following: (1) free radical scavenging; (2) suppressing of lipid peroxidation; (3) enhancing the antioxidant molecules in tissues; (4) stimulating the activities of endogenous antioxidant enzymes; (5) inhibition of the activity of inducible nitric oxide synthase; (6) inhibition of LDL oxidation; (7) inhibition of enzymes of arachidonate metabolism-5-lipoxygenase and 2-cyclooxygenase enzymes [23].

29.2.3 ANTIDIABETIC AND HYPOCHOLESTEROLEMIC PROPERTIES Some spices are also known to exert several beneficial physiological effects including the antidiabetic influence. Among the spices, fenugreek seeds, garlic, onion, and turmeric have been experimentally documented to possess antidiabetic potential. In a limited number of studies cumin seeds, ginger, mustard, curry leaves, and coriander have been reported to have effects on hypoglycemia [23]. Coriander has been documented as a traditional treatment for cholesterol and diabetes patients. In a study, coriander seeds were incorporated into diet and the effect of the administration of coriander seeds on the metabolism of lipids was studied in rats fed with a high-fat diet and added cholesterol. There was significant increase in beta-hydroxy, beta-methyl glutaryl CoA reductase, and plasma lecithin cholesterol acyl transferase activity noted in the experimental group. The level of low density lipoprotein (LDL) 1 very low density lipoprotein (VLDL) cholesterol decreased while that of high density lipoprotein (HDL) cholesterol increased in the experimental group compared to the control group. The increased activity of plasma LCAT enhanced degradation of cholesterol to fecal bile acids and neutral sterols appeared to account for its hypocholesterolemic effect [24]. In another study, administration of turmeric or curcumin to diabetic rats reduced the blood sugar, Hb, and glycosylated hemoglobin levels significantly. Turmeric and curcumin supplementation also reduced the oxidative stress encountered by the diabetic rats. Moreover, the activity of SDH (sorbitol dehydrogenase), which catalyzes the conversion of sorbitol to fructose, was lowered significantly on treatment with turmeric or curcumin. These results also appeared to reveal that curcumin was more effective in attenuating diabetes mellitus related diseases [25] Many spices and herbs are known to have effects on hypoglycemia. Cumin belonging to the family Apiaceae is widely used in Ayurvedic medicine for the treatment of dyspepsia, diarrhea, and

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jaundice. In a recent study oral administration of cumin for 6 weeks to diabetic rats resulted in significant reduction in blood glucose and an increase in total hemoglobin and glycosylated hemoglobin. It also prevented a decrease in body weight and significant reduction in plasma and tissue cholesterol, phospholipids, free fatty acids, and triglycerides. Supplementation with cumin diabetic rats significantly reduced the fatty changes and inflammatory cell infiltrates [26]. Garlic and onion are two other spices that have been widely tested for their antidiabetic potential. The hypoglycemic potency of garlic and onion is attributed to the disulfide compounds present in them, di (2-propenyl) disulfide and 2-propenylpropyl disulfide, respectively, which cause direct or indirect stimulation of insulin secretion by the pancreas [23]. In addition, they may also have insulin-sparing action by protecting from sulfhydryl inactivation by reacting with endogenous thiolcontaining molecules such as cysteine, glutathione, and serum albumins. Onion, fenugreek, turmeric, and red pepper are found to be effective as hypocholesterolemic agents under various conditions of experimentally induced hypercholesterolemia / hyperlipidemia. Fenugreek seeds were hypocholesterolemic in rats with hyperlipidemia induced by either high fat or a high cholesterol diet [13] Consumption of garlic or garlic oil has been associated with a reduction in total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels. In a retrospective study, death records of 2222 (1385 men and 837 women) decedents, aged 25 64 years, out of 3034 death records, were randomly selected and studied by verbal autopsy questionnaires [27]. All the risk factors and protective factors were assessed by questionnaires which were completed with the help of the victim’s spouse and a local treating doctor, by a trained scientist. The prevalence of optimal prudent foods intake behavior—fruit, vegetable, nuts, and legume ( . 250 g/day) intake—were observed among 51.4% (n 5 712) men and 50.4% (n 5 422) women. Western-type food ( . 255 g/day) intake was observed among 63.2% (n 5 875) of men and 59.9% (n 5 502) of women. The prevalence of optimal functional food intake was significantly greater among men compared to women (19.4% vs 14.6%, P , .01). Functional food intake including nuts intake and spices (turmeric, cumin, coriander, fenugreek) intake (,5 g/day) was inversely associated with deaths due to NCDs.

29.3 CONCLUSION The term “folk medicine” refers to the traditional beliefs, practices, and materials that people use to maintain health and cope with diseases, outside of an organized relationship with academic, professionally recognized, and established medical systems and treatments. Natural medicine in the home is more than just first aid for common and minor ailments. It can be preventive, using some of the most common items to protect against illness. Modern research—particularly over the last three decades—is now justifying the use of spices which have been used for centuries in both folk medicine and traditional cookery. Traditional folk and home remedies tend to work on the body by allowing it to heal itself and keep strong and healthy without any side effects. As research into the active constituents of herbs continues, increasing numbers of ancient treatments and tonics are being rediscovered and recognized and brought back into widespread use. Much of the pharmacopoeia of academic medicine, including those from spices has been derived from folk remedies.

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Recently, multinational drug companies of developed countries are paying more and more attention to herbal medicine for their low cost, more sustainable curative value, and less or no side effects. The recent controversy over the patenting of the healing property of turmeric in the United States (and subsequent revoking of patent after strong representation by CSIR, India) and a number of patents on medicinal plants are examples of the importance and economic issue of Indian herbs and spices for human health care. In the context of the UN declaration of “Health for All,” spices are expected to play a greater role. India with its vast tropical and Himalayan biodiversity of medicinal plants has recently attracted renewed world attention in search of novel bioactive substances from plants. On the other hand, a lack of public awareness coupled with a leaning towards Western lifestyle and a dependence more and more on synthetic medicines are leading to the loss of both faith in such systems of medicine and also of biodiversity. The lack of proper trained experienced herbal doctors and strict standardization and drug rules for herbal medicines complicates the situation. With developing techniques in gene patenting and intellectual property rights, it is now high time to assess, document, and conserve our valuable gift of nature as heritage for the benefit of man. Different genetic stocks and species of spices are to be identified using modern techniques and an all-out effort should be made to conserve them, before it is too late. Results indicate that spices have a dual type of action showing inflammation, pain, heat, redness and swelling on acute treatment, and antiinflammation, analgesia, antimicrobial, antioxidant, and antimutagenic actions on long term treatment. Recent studies indicate that spices at low dose are beneficial for human health. To summarize, extensive studies with spices have clearly identified their traditional role in medicine. Daily consumption of spices at low doses shows beneficial effects in the long run. The therapeutic prospects of spices indicate that they can be used as (1) antiinflammatory agents, (2) analgesic agents, (3) antioxidant agents, (4) antimicrobial agents, (5) antiobesity agents, (6) antipollutant, and (7) antimutagenic agents. Hence, spices may be the main natural source of therapeutic agents in near future. Medicines from such a cheap source as spices, which are, consumed daily, may help to shape the future health of mankind. Spices significantly contribute to human health and may be considered as the first ever functional food. By making foods palatable without salt and fat, spices assist in reduced daily intake of sodium and meeting healthy fat intake. Spices thus deserve to be considered as the natural and necessary component of daily nutrition, beyond their role in imparting taste and flavor to the food.

REFERENCES [1] De M, De AK, Banerjee A. Antimicrobial screening of some Indian spices. Phytother Res 1999;13:166. [2] De M, De AK, Mukhophadhyay R, Banerjee AB. Antimicrobial actions of Illicium verum. Ars Pharm 2001;42(3-4):211 22. [3] De M, De AK, Sen P, Banerjee AB. Antimicrobial properties of star anise (Illicium verum Hooker.f). Phytother Res 2002;16:94. [4] De M, De AK, Mukhopahyay R, Banerjee AB, Miro M. Antimicrobial actions of cumin (Cuminum cyminum). Ars Pharm 2003;44(3):257.

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[5] De M, De AK. Antimicrobial activities of Indian Spices with special reference to Bishops weed, Cumin and Star Anise. Asian J Exp Sci 2014;28(1):13 21. [6] Meena MR, Sethi VJ. Antimicrobial activity of essential oil from spices. Food Sci Technol 1994;31:68 71. [7] Karapinar M, Aktug SE. Inhibition of food borne pathogens by thymol, eugenol, menthol and anethole. Int J Food Microbiol 1987;4(2):161 6. [8] Hariri M, Ghiasvand R. Cinnamon and chronic diseases. Adv Exp Med Biol 2016;929:1 24. [9] Felˇso¨ciov´a S, Kaˇca´ niov´a M, Horsk´a E, Vukovi N, Hleba L, Petrov´a J, et al. Antifungal activity of essential oils against selected terverticillatepenicillia. Ann Agric Environ Med 2015;22(1):38 42. [10] Liu Q1, Meng X, Li Y, Zhao CN, Tang GY, Li HB. Antibacterial and antifungal activities of spices. Int J Mol Sci 2017;18:6 Jun 16. [11] Mutlu-Ingok A, Karbancioglu-Guler F, Cardamom Cumin. Chemical compositions, antimicrobial activities, and mechanisms of action against Campylobacter spp and Dill Weed Essential Oils Molecules 2017;22(7) Jul 15. [12] De AK. Spices: traditional uses and medicinal properties. New Delhi: Asian Books Private Limited Darya Ganj; 2004. 110 002. [13] De AK. Spices: Elixir of Life, 2011 Originals (Low Priced Edition,) B 2, Vardhaman, Delhi 110 052. [14] Zheng J, Zhou Y, Li Y, Xu DP, Li S, Li HB. Spices for prevention and treatment of cancers. Nutrients 2016;8:8 Aug 12. [15] Aprotosoaie AC, Costache II, Miron A. Anethole and its role in chronic diseases. Adv Exp Med Biol 2016;929:247 67. [16] De AK. The genus foeniculum. In: Jordral MM, editor. Illicium, Pimpinella and Foeniculum. Florida: CRC Press; 2004. [17] Patra K, Jana S, Mandal DP, Bhattacharjee S. Evaluation of the antioxidant activity of extracts and active principles of commonly consumed Indian spices. J Environ Pathol Toxicol Oncol 2016;35 (4):299 315. [18] De AK, Ghosh JJ. Capsaicin pretreatment protects free radical induced rat lung damage on exposure to gaseous chemical irritants. Phytother Res 1989;3:159. [19] De AK, Ghosh JJ. Short and long term effects of capsaicin on pulmonary antioxidant enzyme defence system. Phytother Res 1989;3:182. [20] De AK, Ghosh JJ. Effect of short term capsaicin on formalin and nitrogen dioxide induced changes in lipid peroxidation and anti-oxidant enzymes in rat lung. Phytother Res 1991;5:88. [21] De AK, Ghosh JJ. Capsaicin action modulates lipid peroxidation induced by different irritants. Phytother Res 1993;7:273. [21a] De AK. CAPSICUM. New Fetter Lane, London EC4P 4EE, U.K: Taylor & Francis; 200011 CAPSICUM. New Fetter Lane, London EC4P 4EE,U.K: Taylor & Francis; 2003. [22] De AK, Mandal TK, Ghosh JJ. Effect of ultra violet radiation induced lipid peroxidation in liposomal membrane: modification by capsaicin. Phytother Res 1993;7:87. [23] Srinivasan K. Plant foods in the management of diabetes mellitus: spices as beneficial antidiabetic food adjuncts. Int J Food Sci Nutr 2005;56(6):399 414. [24] Dhanapakiam P, Joseph JM, Ramaswamy VK, Moorthi M, Kumar AS. The cholesterol lowering property of coriander seeds (Coriandrumsativum): mechanism of action. J Environ Biol 2008;29(1):53 6. [25] Arun N, Nalini N. Efficacy of turmeric on blood sugar and polyol pathway in diabetic albino rats. Plant Foods Hum Nutr 2002;57(1):41 52. [26] Dhandapani S, Subramanian VR, Rajagopal S, Namasivayam N. Hypolipidemic effect of Cuminumcyminum L. on alloxan-induced diabetic rats. Pharmacol Res 2002;46(3):251 5.

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[27] Singh RB, Visen P, Sharma D, Sharma S, Mondal R, Sarma JP, et al. Study of functional foods consumption patterns among decedents dying due to various causes of death. 2015; 8:16-28.

FURTHER READING Krishnaswamy K. Traditional Indian spices and their health significance. Asia Pac J Clin Nutr 2008;17(Suppl. 1):265 8.

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ALTERED CIRCADIAN ENERGY METABOLISM AND CHRONOBIOLOGICAL RISK FACTORS OF CHRONIC DISEASES

Germaine Cornelissen Halberg Chronobiology Center, University of Minnesota, Minneapolis, MN, United States

In memory of Franz Halberg, who ushered in the new discipline of chronobiology by statistically documenting the partly genetic nature of circadian rhythms, by providing methods for their analysis, and by amassing a critical mass of evidence for the ubiquity of their manifestation. He demonstrated the critical importance of the feeding schedule as well as the lighting regimen as major synchronizers of circadian rhythms, showing that access to a single daily meal could make the difference between life and death in the singly-housed mouse model of potentially fatal interactions between hunger, cold, and rhythms, and that in humans it makes the difference between body weight gain or body weight loss. The field has exploded ever since Franz’s first experiments, now that a molecular basis has provided a mechanism for their existence, the importance of which has just been recognized by the Nobel Assembly at the Karolinska Institutet that awarded the 2017 Nobel Prize in Physiology or Medicine jointly to Jeffrey C. Hall, Michael Rosbash and Michael W. Young “for their discoveries of molecular mechanisms controlling the circadian rhythm.”

30.1 INTRODUCTION: CRITICAL IMPORTANCE OF CIRCADIAN RHYTHMS Extensive studies by Halberg with collaborators worldwide accumulated a body of evidence documenting the ubiquity and critical importance of circadian (and other) rhythms [1 3]. Most variables in most organisms are circadian rhythmic. Moreover, the response of these organisms to a given intervention also changes predictably in a circadian-rhythmic fashion. Examples of external stimuli to which a circadian stage-dependent response was documented include noise, Xirradiation, a variety of drugs, and periodontal surgery [4 8]. The response to a single daily “meal” also depends on the circadian stage when food is made available. The response rhythm is so large that meal timing can make the difference between life and death in a mammalian model of potentially fatal interactions between hunger, cold, and rhythms, namely the singly-housed mouse abruptly restricted to a single daily “meal.” Survival of

The Role of Functional Food Security In Global Health. DOI: https://doi.org/10.1016/B978-0-12-813148-0.00030-X © 2019 Elsevier Inc. All rights reserved.

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this mouse model depends on the timing of the “meal” in relation to a regimen of light and darkness alternating at 12-hour intervals: most singly-housed mice (but not multiply-housed mice) die when they have access to food for 4 hours during the first part of the light (rest) span each day, but if food is only available during 4 hours in the early part of the dark (active) span, most of the mice survive [9,10]. In humans, Halberg showed that weight loss is associated with consuming a single daily meal as breakfast-only but not as dinner-only, whether fixed 2000-calorie or free-choice daily meals are used [11,12]. The difference between a calorie consumed at breakfast versus dinner can in part be accounted for by the circadian rhythm in diet-induced thermogenesis [13] and by changes in the internal time relations among ubiquitous rhythms characterizing the entire metabolic, notably endocrine, system [11,14]. The timing of cortisol moved least by the change from a single daily meal as dinner versus breakfast, by contrast to other hormones such as insulin, growth hormone, and glucagon [11,14].

30.2 PARTLY ENDOGENOUS CIRCADIAN RHYTHMS ARE SYNCHRONIZED BY 24-HOUR ENVIRONMENTAL CYCLES Halberg was the first to statistically document the partly genetic nature of circadian rhythms and to relate it to the hypothalamus. He showed that in the absence of environmental time cues, the period free-runs, deviating slightly but statistically significantly from 24 hours [1 3]. Whereas shamoperated control mice had on the average consistently high blood eosinophil counts in the middle of the daily light span and low counts during the dark span, blinded C mice and mice born anophthalmic showed the same pattern in one study and an opposite pattern a few weeks later, suggesting that the circadian period differed somewhat from 24 hours [15]. This result was verified based on longitudinal records of around-the-clock measurements of rectal temperature. Temperature peaked on the average about every 24 hours in the sham-operated control mice, but these temperature peaks occurred earlier and earlier each day in the blinded mice, corresponding to a circadian period shorter than 24 hours [15]. These studies not only established the phenomenon of free-running, they also documented that the eyes serve as transducers for the primary environmental synchronizer, the 24-hour cycle of light alternating with darkness. The role of the lighting regimen as synchronizer of circadian rhythms was further illustrated by showing in several stocks of mice that the daily periodicity in the number of circulating tail blood eosinophils and in rectal temperature may be reversed by the inversion of the lighting regimen [16]. The importance of the feeding schedule as another important synchronizer of circadian rhythms was first noted by Halberg as he counted eosinophils to answer the question whether an adrenocortical activation could be used to treat breast cancer and prolong life. Eosinophil counts were depressed by fasting (or “stress”), achieved by a 50% reduction in dietary carbohydrates and fats in C3H mice with a high incidence of breast cancer [3]. But as Halberg started experiments earlier in the day to handle larger groups of animals to verify whether steroids (that depress eosinophil cell counts and perhaps mitoses) could be a mechanism through which caloric restriction and ovariectomy act in reducing cancer incidence, the difference in eosinophil counts vanished.

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He interpreted the lack of a difference as stemming from a phase difference between the caloricrestricted and the fully-fed groups, which postulate was confirmed when another experiment starting even earlier on even larger groups of animals yielded opposite results [3]. Food intake can become a dominant synchronizer of circadian rhythms, as seen when manipulating a diet with a 50% reduction in calories from carbohydrate and fat yet with the full availability of protein, vitamins and minerals, all comparable to amounts in a control diet. That timerestricted feeding can override the otherwise dominant lighting schedule was shown indirectly with respect to the adrenocortical cycle in Halberg’s studies of blood eosinophil cells [17], as well as with corticosterone determination. The finding that under conditions of relative starvation, the gut can override the hypothalamus has later been extended to circadian aspects of the liver, lung and pancreas [18,19].

30.3 CIRCADIAN RHYTHMS AND CALORIC RESTRICTION In addition to the internal desynchronization (altering aspects of carbohydrate and lipid metabolism) brought about by meal feeding, Halberg’s experiments also documented that food restriction lowers circulating eosinophil counts and amplifies the circadian rhythm of blood eosinophil counts in mice [17]. As compared to mice fed ad libitum, the amplitude of circadian rhythms was generally increased when food intake was restricted to a single daily “meal” [20,21], as shown for variables such as rectal temperature, corticosterone, and liver glycogen. Life span studies of caloric restriction in mice showed that the life span was longer and that tumors (mostly mammary) appeared later and were less prevalent in food-restricted mice than in control mice fed ad libitum, irrespective of the pattern of food availability [22]. Suggested factors contributing to the effect of food restriction on survival consisted of a lower body temperature, a reduced overall metabolic rate, and increased circadian amplitude [22]. That a lower temperature brought about by calorie restriction may underlie beneficial effects in retarding senescence and increasing longevity is also apparent from a comparison of the temperature response of 28 different strains of singly-housed female mice fed 60% of their ad libitum intake [23]. The highly statistically significant variation (ranging from 1.5 to 5.0 C) among the different strains reportedly could not be accounted for by differences in loss of thermoregulation, ad libitum adiposity, sensitivity to hypothermia, motor activity, or absolute food intake [23], in agreement with another report that low body temperature improves health and longevity independently of caloric restriction [24]. The above results illustrate the critical importance of circadian rhythms in understanding how food intake relates to longevity and health. It is now generally recognized that caloric restriction is the only intervention that has been repeatedly demonstrated to prolong life spans across taxa [25] and to reduce cancer incidence in mammals [26]. This knowledge could serve as a founding block for fighting today’s major civilization diseases. The larger circadian amplitude of core body temperature brought about by calorie restriction achieved by time-restricted feeding reflects a strengthening of the circadian system. The feeding schedule may more readily synchronize organs such as the liver, muscles, fat tissue, beta cells, and the gut, all involved in glucose metabolism. Appropriately resetting peripheral rhythms could constitute an important mediator of longevity in calorie-restricted animals [27]. Transgenic αMUPA

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mice exhibiting spontaneously reduced eating live longer as compared to their FVB/N wild-type controls and have large-amplitude, appropriately reset circadian rhythms, notably in clock gene expression in the liver, feeding time, and body temperature [28]. Caloric restriction, and possibly also intermittent fasting (food available ad libitum every other day), may synchronize the circadian system in the suprachiasmatic nuclei (SCN) [29].

30.4 CIRCADIAN CLOCK GENES When both suprachiasmatic nuclei are destroyed, the circadian rhythm in telemetered temperature from freely moving animals exhibits a great amplitude reduction and a circadian phase advance [30,31]. A critical core of clock genes identified in the SCN is thought to orchestrate the circadian system. Core circadian “clock” genes are defined as genes whose protein products are necessary components for the generation and coordination of circadian rhythms. Evidence for a genetic basis of circadian rhythms at the molecular level in higher eukaryotes started with the discovery of the period (per) locus in Drosophila melanogaster in 1971 [32]. Analysis of per circadian mutants and additional mutations on Drosophila clock genes led to a model consisting of positive and negative autoregulatory feedback loops of transcription and translation. These molecular mechanisms underlying the circadian system earned Jeffrey C Hall, Michael Rosbash, and Michael W Young the 2017 Nobel Prize in Physiology and Medicine some 60 years after the partly genetic basis of circadian rhythms was posited by Franz Halberg. Similar models of positive and negative autoregulatory feedback loops of transcription and translation were later described in mammals and other organisms [33]. CLOCK and BMAL1 are transcriptional activators that bind the enhancer sequences of Per and Cry (Cryptochrome) [34]. In turn, PER and CRY proteins accumulate in the cytoplasm and translocate to the nucleus to inhibit CLOCK:BMAL1 [34]. SIRT1, a NAD-dependent deacetylase, interacts directly with CLOCK and deacetylates BMAL1 and PER [35]. In addition, the nutrient sensor AMPK directly phosphorylates and destabilizes CRY1 [36], and acts upstream of PER. AMPK can in turn coordinate SIRT1 activity [37], participating with the core circadian clock machinery in an intricate nutrient-sensing signaling loop that is now starting to be unraveled at the whole-organism level [25]. AMPK has been referred to as an “energy sensor” because it binds to and is coordinated by both AMP and ATP. AMPK coordinates a multitude of metabolic processes. One of its downstream targets is the mammalian target of rapamycin (mTOR), a positive effector of cell growth and division [38]. Genetic manipulations in flies leading to increased dTOR signaling, specifically in a subset of the central pacemaker neurons, significantly lengthen the circadian period of locomotor activity, whereas mutations reducing AKT activity shorten the circadian period [39]. In the mouse SCN, TOR is coordinated by circadian function [40]. Conserved nutrient-sensing pathways are integrated into the circadian clock network, likely to ensure organism-wide time function and survival [25]. Alterations in the circadian clock machinery have been linked to a host of disease conditions, from cancer [41] to addiction [42] and cardiovascular disease [43]. Their role in relation to obesity [44] and diabetes [45] is particularly noteworthy since circadian clocks are tightly coupled to cellular metabolism as they share a number of nutrient-sensing pathways [46]. Disease risk

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elevation and the presence of overt disease are also often associated with a weakened circadian system, with reduced circadian amplitude and a less tightly synchronized circadian system [47].

30.5 CLOCK GENES AND NUTRIENT-SENSING PATHWAYS Primary nutrient-signaling pathways known to modulate life span include insulin/insulin-like growth factor and target of rapamycin (TOR) [25]. Reductions in TOR activity enhance life span and mimic the effects of caloric restriction. Mice lacking ribosomal S6 protein kinase 1 (S6K1), a downstream component of the TOR pathway, have a longer life span and exhibit resistance to agerelated pathologies. In humans, increased insulin sensitivity, evidenced by reduction in plasma insulin, IGF-1, and plasma glucose concentrations, is a hallmark of increased longevity [25]. Longevity outcomes from caloric restriction in humans may, however, depend on the genetic background, the age of onset of caloric restriction, and the composition of the diet [25]. Molecular pathways thought to be involved in obesity, diabetes, and the metabolic syndrome include the AMP-activated protein kinase (AMPK) and mTOR since they are implicated in metabolism and also impinge on the circadian system [38,48]. Coordinating a multitude of metabolic processes, AMPK maintains cellular energy functioning through repression of a number of energy-consuming processes with simultaneous enhancement of energy-producing processes. By identifying essential pathways, it is believed that aging interventions will delay and prevent disease onset for many chronic conditions of adult and old age [49]. The mTOR inhibitor RAD001 (everolimus) was reported to have beneficial effects on immunosenescence in elderly volunteers [50]. The oral antidiabetic drug metformin, which activates AMPK in the liver, was also reported to decrease cardiovascular disease risk, cancer incidence, and overall mortality as compared to other antidiabetic drugs [49,50].

30.6 CIRCADIAN RHYTHMS AND METABOLISM Several studies shed light on the link between the circadian system and metabolism, accounting for the beneficial effects of time-restricted feeding. In one study [51], mutation in the circadian clock gene Per1, which affects a conserved phosphorylation site, led mice to consume more food during the rest span, predisposing them to metabolic diseases. Another study [52] showed that the feeding pattern of mice fed a high-fat diet ad libitum is altered, mice consuming small meals throughout the 24-hour day, including during their usual rest span. Yet another study [53] indicated that by restricting access to the high-fat diet only during the night (active span), both diet-induced obesity and obesity in Per1 mutant mice can be prevented. These results support Halberg’s early finding [11,12,14] that meal timing may serve as an effective clinical intervention, now further substantiated by additional recent human studies showing that earlier meal timing is associated with improved effectiveness of weight-loss therapy in overweight and obese patients [54,55]. However important circadian rhythms are, they represent only one periodic component in the broad time structure that constitutes life. The need to consider the broader time structure as a whole

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is illustrated in the role of Bmal1’s influence on longevity. The timing of expression of the core clock gene Bmal1 was reported to influence its effects on aging and survival [56]. While prenatal deletion of Bmal1 in mice disrupts clock-dependent oscillatory gene expression and behavioral rhythmicity coincident with reduced body weight, impaired hair growth, abnormal bone calcification, eye pathologies, neurodegeneration, and a shortened life span, mice in which the gene is knocked out after birth do not exhibit many of these aging-related phenotypes, suggesting that the circadian clock gene plays different roles during embryogenesis and after birth [56].

30.7 CIRCADIAN DISRUPTION AND METABOLIC DISORDERS The murine gastrointestinal tract contains functional clock genes, which are molecular core components of the circadian clock. Clock genes are expressed rhythmically throughout the gastrointestinal tract [57]. Daytime feeding in nocturnal rodents is a strong synchronizer of gastrointestinal clock genes. Clock gene expression is shifted at the RNA and protein level but not in the SCN [57]. Alterations in clock gene expression in a mouse model of diabetes are most pronounced in those organs that are intimately associated with food processing and metabolism. The effects of acute and chronic STZ-induced diabetes on period genes were assessed in the stomach body, proximal and distal colon, liver, kidney, and lung of C57BL/6J mice [58]. While rhythmicity in expression of per2 and per3 persisted in all organs, per2 and per3 expression of STZ-injected mice was generally phase delayed within the gastrointestinal tract but not within the kidney or lung as compared with vehicle-injected mice. The circadian rhythm in food intake had a larger amplitude in diabetic mice than in control mice. Mouse models of diabetes and obesity (e.g., Bmal12/2 and Per22/2 mice), where glucose function is altered, exhibit altered circadian behavior [25]. This bidirectional relationship between circadian disruption and metabolic pathologies is also observed in humans. Diabetic patients exhibit a reduced circadian amplitude of glucose tolerance and insulin secretion [59]. Conversely, a higher incidence of metabolic diseases and cardiovascular events is observed among shift workers [60]. Genomic variations in clock genes have been associated with obesity and metabolic syndrome in humans [61]. Circadian rhythms in fasting blood glucose, body temperature, and heart rate are progressively disrupted in association with metabolic dysfunction and the development of prediabetes and type 2 diabetes mellitus in overweight middle-aged (40 69 years old) subjects [62]. Increasing average and dampened circadian amplitudes of body temperature and heart rate were found in association with adverse changes in metabolic state. Increased nocturnal body temperature and a phase delay of its circadian variation, together with a deviant circadian profile of heart rate and a phase advance of the circadian rhythms in heart rate and fasting blood glucose were early signs of the prediabetes metabolic state. In the presence of type 2 diabetes mellitus, the circadian rhythm in fasting blood glucose was no longer detectable, and the circadian amplitudes of body temperature and heart rate were greatly diminished [62]. Restricted feeding improves overall health, notably metabolic function [53,63,64]. The timing and amount of food consumed affects not only body weight and insulin sensitivity, but also the circadian pattern of clock genes expression in the liver and the activity of nutrient sensing pathways

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such as TOR, AMPK, and SIRT1 [53,64,65]. While food restricted mice have desynchronized peripheral circadian rhythms, their SCN pacemaker remains intact [48,53,63].

30.8 INTERVENTIONAL STUDIES BASED ON CALORIC RESTRICTION REGIMENS Although research efforts have mainly focused on how specific components of foodstuffs affect health, relatively little is known about a more fundamental aspect of diet, namely the frequency and circadian timing of meals, and potential benefits of intermittent spans with no or very low energy intake [48]. Intermittent energy restriction spans as short as 16 hours can improve health indicators and counteract disease processes. Underlying mechanisms are thought to involve a metabolic shift to fat metabolism and ketone production and the stimulation of adaptive cellular stress responses that prevent and repair molecular damage [48]. Three experimental dietary regimens have been considered [48]: • • •

caloric restriction, involving a reduction (by 20% 40%) in daily calorie intake, while meal frequency is not changed; intermittent energy restriction, consisting of intermittently (e.g., 2 days/week) fasting or greatly reducing daily calorie intake (e.g., 500 calories/day); and time-restricted feeding, involving limiting the daily intake of calories to a 4- to 6-hour time window.

Intermittent feeding was common by hunter-gatherer anthropoids, including those living today [66]. Physical and mental fitness during extended times without food may have been very important in human evolution. Many adaptations for an intermittent food supply are conserved among mammals, including organs for the uptake and storage of rapidly mobilizable glucose (liver glycogen stores) and longer-lasting energy substrates, such as fatty acids in adipose tissue [48]. Caloric restriction has long been shown to be associated with a longer life span across species and to reduce cancer incidence in mammals [25,26,67]. Intermittent energy restriction was also reported to forestall and even reverse disease processes in animal models of various cancers, cardiovascular disease, diabetes, and neurodegenerative disorders [68 70]. Patterns of intermittent energy restriction have even now been patented as a method of improving longevity and/or alleviating a symptom of aging or preventing age-related diseases [71]. Intermittent fasting can markedly reduce obesity, insulin resistance, and hepatic steatosis by selectively promoting the beiging of white adipose tissue via modulation of the gut microbiota [72]. Some of the mechanisms thought to underlie protective effects of intermittent energy restriction against injury and disease include adaptive stress response, bioenergetics related in part to a metabolic shift to ketogenesis, inflammation, and improved repair and removal of damaged molecules and organelles, related in part to autophagy, which is also linked to the nutrient-responsive mTOR pathway [48]. Cyclic gene expression in the liver was reportedly much higher in mice fed a ketogenic instead of the usual chow diet, whereas an opposite effect took place in ileal intestinal epithelial cells. The ketogenic diet was also associated with an enriched PPARα signaling pathway, likely related to circadian-periodic changes in serum concentrations of β-hydroxyl-butyrate, a ketone body inhibiting histone deacetylases [73].

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The American Heart Association issued a statement on the implications of meal timing and frequency for cardiovascular disease prevention [74]. Cardiometabolic health effects of specific eating patterns, such as skipping breakfast, intermittent fasting, meal timing and frequency, are reviewed, considering that eating styles can affect obesity, lipid profile, insulin resistance, and blood pressure.

30.9 CONCLUDING REMARKS Health promotion goes hand in hand with addressing issues related to aging. As in the case of metabolic disorders, reduced circadian amplitude is a feature of aging [47]. In an attempt to offset social and economic consequences of the current shift in the aging segment of the population, geroprotectors (substances that slow aging, repair age-associated damage, and extend healthy life span) are being developed to prevent and treat age-related pathologies [50]. Criteria for potential geroprotectors include an increased life span, amelioration of human aging biomarkers, and improving health-related quality of life, with minimal side effects at therapeutic dosage; evolutionary conservatism of mechanism of action and reproducibility of geroprotective effects on different model organisms are added desiderata [50]. Among nonpharmacologic interventions affecting life span and aging biomarkers are physical exercise and caloric restriction. Caloric restriction delays aging both in rodents and primates and improves aging biomarkers in humans, including body mass index, blood pressure, glucose, insulin, and lipids. Moreover, caloric restriction decreases risks of aging-associated diseases, such as diabetes and cardiovascular disease [50]. Caloric restriction can be achieved through intermittent fasting, a pattern of eating that cycles between fasting and nonfasting. Some of the most promising strategies that could be tested in humans for their effects on health span have been reviewed: They include dietary interventions mimicking chronic dietary restriction, drugs that inhibit the growth hormone/IGF-I axis, drugs that inhibit the mTOR S6K pathway and drugs that activate AMPK or specific sirtuins [49]. SIRT1, which declines with age in the suprachiasmatic nuclei [75], is required for high-magnitude circadian transcription of several core clock genes [34]. Host health is also increasingly recognized to depend on microbiota in the gut, and their structure is apparently shaped by diet, as shown by lifelong caloric restriction on both high-fat and lowfat diet in mice [76]. Caloric restriction enriched phylotypes positively correlated with life span and reduced phylotypes negatively correlated with life span. Aging, metabolic disorders, as well as other disease conditions are associated with circadian disruption, characterized by a weakened circadian system. By contrast, large-amplitude circadian rhythms are hallmarks of health and longevity. A lowered metabolism being implicated in obesity, meal timing (if not overall caloric restriction) presents itself as an appealing lifestyle option available to increase metabolism and reduce body weight [47]. Physiological monitoring of variables such as temperature, heart rate, blood pressure, and blood glucose is becoming increasingly easier to perform noninvasively and may represent one way to assess the effectiveness of interventions aimed at improving health span.

SUPPORT Halberg Chronobiology Fund.

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31

Maria Abramova1, Ram B. Singh2, Sergey Chibisov1, Germaine Cornelissen2, Toru Takahashi2, Vaishali Singh3 and Dominik Pella2 1

Division of Chronobiology and Chronomedicine, People’s Friendship University of Russia, Moscow, Russia East Slovak Institute of Cardiovascular Sciences, Kosice, Slovakia 3Halberg Hospital and Research Institute, Moradabad, India

2

31.1 INTRODUCTION Experimental and clinical studies indicate that impairment of the central nervous system due to Western diet, lifestyle, and mental stress, such as cognitive impairment, depression, vulnerability to stress, wrong body image, low self-esteem, and dysregulation of hedonic hunger contribute to the development of obesity [1 4]. The link between all the three pathways—mental disorders, circadian disruption, and hypothalamic dysfunction—with obesity and cancer is likely to be independent and bidirectional [1 6]. Brain inflammation and imbalance of neuronal plasticity caused by dysregulation of metabolic signals are candidates which cause mental disorders associated with obesity leading to noncommunicable diseases (NCDs), including cancers [5 7] (Fig. 31.1). Industrialization and urbanization may be associated with increased exposure to electric light and reduced availability and exposure to sunlight due to extensive living inside buildings, resulting in deficiency of antioxidants, vitamins, omega-3 fatty acids and minerals as well as functional foods in the diet, which are risk factors of cancer. Electric lighting in the built environment is quite different from solar radiation in intensity, spectral content, and timing during the 24-hour day, which may cause circadian dysfunction [1 4]. Humans evolved over millions of years with the day-night pattern of solar radiation as the primary circadian cue. Daily entrainment of the human circadian clock is necessary for good human health, which may be disturbed due to night awakening during shift work resulting in NCDs, including cancers [1,2]. Rotating night shifts, in conjunction with other lifestyle factors, disrupt circadian rhythms and may have a wide range of physiologic, psychological, and social effects, leading to behavioral changes and biological dysfunctions among night shift workers [8 15]. Suppression of melatonin by exposure to light at night causing circadian disruption may be one reason for the higher rates of breast, prostate, and colorectal cancers in the developed world [16,17]. Experimental evidence and limited human evidence allowed the International Agency for Research on Cancer (IARC) to classify circadian disruption of sleep as a probable human carcinogen, group 2A. In the present review, we examine the evidence about brain-related pathways in relation to functional food intake in the pathogenesis of carcinogenesis. The Role of Functional Food Security In Global Health. DOI: https://doi.org/10.1016/B978-0-12-813148-0.00031-1 © 2019 Elsevier Inc. All rights reserved.

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FIGURE 31.1 Pathways for interactions of environmental factors with lifestyle factors causing cancers.

31.2 CIRCADIAN DISRUPTION Disruption of circadian rhythms influences many biological and metabolic processes within the body and results in different NCDs, such as cancer, cardiovascular diseases (CVDs), and neurodegenerative diseases. Circadian regulatory pathways may generate rhythmic epigenetic modifications and the formation of circadian epigenomes [2]. Circadian rhythms are endogenous rhythms that are generated to synchronize physiology, metabolism, and behavior with 24-hour environmental cues. These rhythms are regulated by both external cues and molecular clock mechanisms in almost all living cells. Epigenetic modifications such as hyomethylation, hypermethylation, and histone modification due to circadian disruption may also be involved in the transformation of normal cells into carcinogenic cells. An epigenetic basis for the carcinogenic effects of circadian disruption involves circadian genes and regulatory proteins. The current evidence related to the epigenetic modifications that result in circadian disruption appears to be important for carcinogenic effects of circadian disruption in different types of cancers.

31.3 CIRCADIAN DISRUPTION OF SLEEP AND CARCINOGENESIS Epidemiological studies have reported that shift work may be associated with higher risk of some NCDs, including CVD, type 2 diabetes, and certain types of cancers [1 4]. It has been reported

31.3 CIRCADIAN DISRUPTION OF SLEEP AND CARCINOGENESIS

527

FIGURE 31.2 During the regulation of appetite and metabolism, pro-opiomelanocortin neurons (POMC) inhibit feeding, and neuropeptide-Y (NPY) neurons stimulate feeding that is diminished by fasting and AgRP, agouti-related protein. Modified from Singh RB, Gupta S, Dherange P, De Meester F, Wilczynska A, Alam SE, et al. Metabolic syndrome: a brain disease. Can J Physiol Pharmacol. 2012;90(9):1171-1183. doi: 10.1139/y2012-122.

that the rotating night shift at least for three nights per month for 15 or more years may increase the risk of colorectal cancer [1 11] (Figs. 31.2 and 31.3). Epidemiological studies have addressed numerous health concerns, in particular circadian disruptions associated with shift work. The International Agency for Research on Cancer (IARC) has provided the incentive for epidemiological studies which investigate “probable” cancer hazards [1,18,19]. Disruption of circadian rhythms causes epigenetic modifications, which may alter cell proliferation and subsequently result in oncogenesis and cancer [16,17,20 25]. Circadian disruption has been implicated in the development of different human cancers. There is evidence that a deficiency and disruption of melatonin rhythms is related to carcinogenesis [17]. Many of these circadian disruptions are due to dramatic changes resulting from industrialization and the development of societies and consequent changes in lifestyle over the past few hundred years [1 4,26]. Epigenetic changes can be the result of several environmental factors, including repeated circadian disruption due to long-term shift work.

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FIGURE 31.3 Mechanism of inflammation and subcellular remodeling via antiinflammatory endogenous molecules.

Table 31.1 Circadian Disruption of Circadian Gene Expression and Risk of Various Cancers Type of Cancer

Type of Genes

Head and neck squamous cell carcinoma (HNSCC) Breast cancer

PER1, PER2, PER3, CRY1, CRY2, CKIε, BMAL1, and TIM

Chronic myeloid leukemia (CML) Chronic lymphocytic leukemia (CLL) Ovarian cancer Colorectal cancer (CRC) Prostate cancer Non small cell lung cancer (NSCLC) Gastric cancer

NPAS2, CLOCK, CRY2, TIMELESS, PER1, PER2, CRY1, and BMAL1 CRY1, CRY2, PER1, PER2, PER3, CKIε, and BMAL1 PER1, PER2, BMAL1, Wee1, Cyclin D1, and Myc BMAL1 BMAL1 PER1, PER2, PER3, CKIε, CRY1, CRY2, BMAL1, CLOCK, and NPAS2 PER1 PER2 and CRY1

NPAS2, neuronal PAS domain protein 2; CLOCK, circadian locomotor output cycles kaput; CRY2, cryptochrome.

Studies on shift workers have demonstrated changes in the DNA methylation of their genes [16]. Since 15% 20% of workers worldwide have shift work schedules, the IARC and other agencies reported that shift work may be a carcinogenic factor in humans [18,19]. Table 31.1 shows circadian disruption induced genetic damage causing circadian gene expression predisposing risk of various cancers.

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529

Circadian rhythm synchronization occurs due to the regulation of core clock genes as well as from the regulation of various clock-controlled genes, including several cell cycle genes. In view of the associations between the circadian clock and cell metabolism, circadian disruption results in abnormal cell metabolism which is important in the mechanisms of carcinogenesis and can result in multitumorigenesis [27 30]. Carcinogenesis and tumorigenesis include cellular oscillators and clock machinery in conjunction with disruption of the expression of clock genes which have also been reported in patients with cancers [31]. The core clock genes PER1 and PER2 are known as tumor suppressor genes, and their knockdown results in the doubling of tumor number and cancer growth [32]. However, overexpression of these genes decreases tumor number and cancer growth transcriptional silencing of the BMAL1 gene through hypermethylation of its promoter CpG island as reported in hematologic malignancies. Circadian rhythm disruption may predispose up- or downregulation of several genes and proteins, which when combined lead to carcinogenesis, indicating that suppression of melatonin production due to forced exposure to light increases L1-induced genomic instability and consequently promotes carcinogenesis [33]. There is evidence that melatonin synthesis may be regulated by some long noncoding RNAs (lncRNAs) directly and indirectly, and that the abundance of these lncRNAs can alter the circadian cycles [34]. Circadian disruption may also alter melatonin expression and consequently promote carcinogenesis by changing the abundance of certain lncRNAs [34].

31.4 DIET AND CARCINOGENESIS: A DYSFUNCTION OF THE BRAIN Western diet, characterized by refined carbohydrates, highly saturated ω-6 and trans fatty acids, and low levels of ω-3 fatty acids and other long-chain polyunsaturated fatty acids (PUFA), particularly in association with lower levels of antioxidant vitamins and flavonoids, is pro-inflammatory and may cause metabolic syndrome [1,9,35]. Metabolic syndrome may be a disease of the brain which can occur due to Western diet-induced damage of the arcuate nucleus and POMC neurons [9]. Western diet and eating late at night can also damage the circadian clock machinery leading to circadian disruption resulting in the metabolic syndrome and other NCDs, such as cancers [1,9,12]. Night shift working, sedentary behavior, and psychosocial stress can further increase the inflammation by increased sympathetic activity, with increased secretion of catecholamine and cortisol, which are known to increase oxidative stress and may damage certain areas of the brain, which may result from increased intake of Western diets [1,2,36 45]. Increase in free radicals may damage the neurons as well as the macrophages and the liver which may release pro-inflammatory cytokines [41 45]. The pro-inflammatory cytokines, in conjunction with an underlying deficiency of long-chain PUFA, and polyphenolics, may damage the arcuate nucleus as well as neuropeptide-Y and pro-opiomelanocortin (POMC) neurons and insulin receptors in the brain [40 45]. This is particularly common during fetal life, infancy, and childhood, resulting in their dysfunction. Of the total fatty acids in the brain, 30% 50% are long-chain PUFA, which are incorporated in the cell membrane phospholipids [40]. Omega-3 fatty acids are also known to enhance parasympathetic activity and increase the secretion of the antiinflammatory cytokines interleukin (IL)-4 and IL-10 as well as acetylcholine in the hippocampus, and other areas of the brain that may be protective [36,40]. Increased intake of Western foods may also cause lower intake of polyphenolics and omega-3 fatty acids which may reduce endogenous antiinflammatory products in the body [46,47].

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Epidemiological studies indicate that there is an altered eating behavior among night shift workers as well as in those with chronic psychosocial stress, possibly due to sleep deprivation, which may be a manifestation of an altered relationship between internal 24-hour rhythms and the external work schedule or sleeping pattern of these subjects [1,9,36,40]. Eating behavior might be altered by working shifts, especially when night work is involved, due to a diverse range of biological, social, and cultural factors [1,12,16,18,26]. Eating at night may cause disturbances of intestinal motility, affecting the digestion, absorption, and utilization of pharmacological drugs and nutrients [1,18,26]. Western diets characterized by refined carbohydrates, ω-6 fat, trans fat, and highly saturated fat diets particularly low in ω-3 fats, antioxidants, vitamins, and essential and nonessential amino acids may have greater adverse effects on physiological functions, leading to poor availability of protective nutrients and health molecules (resolvins, protectins, lipoxins, and nitrolipids) produced by physiology and metabolism [46]. There is evidence that shift work affects circadian distribution of food intakes, regularity of meals, and the number of meals eaten during different phases of shift cycles [1,12,16]. Further studies have examined dietary patterns in shift workers and reported that a lower intake of energy and nutrients in female shift workers, compared to day workers, may be observed because of less frequent and poorer quality, mostly ready-prepared Western foods. The frequency of eating per day was significantly higher in night shift workers, although these workers had a reduced energy intake during the 8-hour night shifts [47,48]. In 2002, a detailed questionnaire survey revealed a preference for fried food which was significantly more frequent in shift workers (46% vs 42%) than in day workers [49]. However, there was no significant difference in the preference for either sweet or salty food; therefore, the preference for fried food was another potential factor associated with night shift. A cross-sectional survey examined the associations of various nutrients and dietary factors as well as food groups with creatinine-adjusted first morning urinary melatonin (6-sulfatoxymelatonin; aMT6s) concentrations [50]. Although no specific nutrients were associated with altered concentrations of melatonin, the findings suggest that several specific foods, including red meat, could affect cancer risk through the lowering of melatonin concentrations [50]. A recent study was aimed at exploring factors influencing food choice and dietary intake in shift workers [51]. Six focus groups (n 5 41) were conducted to establish factors affecting dietary intake while at work. Dietary intake was assessed using repeated 24-hour dietary recalls (n 5 19) and interviews were audio recorded, transcribed verbatim, and interpreted using thematic analysis. The findings showed increased consumption of discretionary foods and limited availability of healthy food choices on night shift [51]. Energy intakes (kJ/day) did not differ between days that included a day or night shift but greater energy density of the diet was observed on night shift compared with day shift. In a clinical study involving 39 day workers and 123 night shift workers, the scores for meal contents and temporal eating patterns in rotating shift workers were significantly higher than those in day workers [52]. The ME score of rotating shift workers was significantly lower, indicating greater eveningness/less morningness among rotating shift workers. Multivariate linear regression revealed that the ME score was significantly negatively associated with temporal eating patterns and showed a negative association with the score for meal contents at a trend level, while current work shift was not significantly correlated with the scores. Eating behaviors for rotating shift workers may be associated with a more unbalanced diet and abnormal temporal eating patterns; the associations may be accounted for by diurnal preference rather than by rotating shift work. Night shift working in conjunction with altered dietary patterns may damage the arcuate

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nucleus, POMC neurons, and circadian clock machinery, resulting in greater risk of cancers. These findings support the hypothesis of association of diet with carcinogenesis as brain dysfunction. In a cross-sectional study, 395 non-Saudi female nurses completed a questionnaire from November 2013 to January 2014 that included items relating to stress and eating behavior using the Dutch Eating Behavior Questionnaire (DEBQ) [53]. For all eating styles, stress and shift duty influenced the amount of food nurses consumed, but was more significant under a restrained eating style. Under this eating style, a significantly higher percentage of nurses reported eating more fast food, snacks, and binging, while fruits and vegetables were the least likely to be eaten under stress. Highly stressed nurses were more likely to present with abnormal restrained eating (odds ratio (OR) 5 1.52, P 5 .004), emotional (OR 5 1.24; P 5 .001), and external (OR 5 1.21; P 5 .001) DEBQ scores. Working nighttime shift duty was positively associated with restrained eating (OR 5 1.53; P 5 .029) and emotional eating (OR 5 1.24; P 5 .001), but negatively associated with external eating (OR 5 0.45; P 5 .001).

31.5 DIET, INFLAMMATION, AND SUBCELLULAR REMODELING NCDs are associated with low-grade systemic inflammation with an increase in pro-inflammatory cytokines and reactive oxygen species, reactive nitrogen species, and pro-inflammatory eicosanoids, in conjunction with a decline in the cellular antioxidants, antiinflammatory cytokines, and certain PUFAs. The reduction in these cytokines with a decline in omega-3 PUFA may cause reduction in their antiinflammatory products, such as lipoxins (LXs), resolvins (Rvs), protectins, maresins, and nitrolipids [46]. In carcinogenesis and other chronic diseases, there may be imbalance between the pro- and antiinflammatory molecules, indicating that treatment may be directed to suppress inappropriate inflammation by these molecules, thus leading to recovery from these diseases [46]. This suggests that both local and systemic delivery of these agents and/or their more stable synthetic analogs may be protective against these diseases by causing subcellular remodeling of neurons, endothelial cells, cardiomyocytes, and hepatocytes (Fig. 31.3). There is evidence that inflammation is a protective response that eliminates harmful stimuli and restores tissue homeostasis, whereas the failure to resolve inflammation leads to the development of malignancies [54]. Immune cells in the tumor inflammatory microenvironment endow cancer cells with their specific hallmarks, including mutations, metabolic reprograming, angiogenesis, invasion, and metastasis. Targeting the inflammatory microenvironment with antiinflammatory drugs (e.g., aspirin) or by enhancing antitumor immunity (e.g., chimeric antigen receptor T cell therapy) may be promising in carcinogenesis. The proposal of pro-resolving strategy based on the discovery of potent, endogenous, specialized pro-resolving mediators such as lipoxins, resolvins, protectins, and maresins via a dual antiinflammatory approach, can inhibit carcinogenesis. The cellular and molecular mechanisms of inflammation resolution and cancer immunity and the pro-resolution strategy in cancer treatment and prevention are not well known. In an experimental study, antiinflammatory and pro-resolving circuits, and the temporal and differential changes in self-resolving murine exudates were examined using mass spectrometrybased proteomics and lipidomics [55]. Aspirin-triggered lipoxin A4 analog reduced Ψmax, resolvin E1 decreased both Ψmax and Tmax, whereas 10,17S-docosatriene reduced Ψmax, Tmax, and shortened Ri [55]. Also, aspirin-triggered lipoxin A4 analog markedly inhibited

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pro-inflammatory cytokines and chemokines at 4 hours (20% 50% inhibition), whereas resolvin E1 and 10,17S-docosatriene’s inhibitory actions were maximal at 12 hours (30% 80% inhibition). Aspirin-triggered lipoxin A4 analog also evoked release of the antiphlogistic cytokine TGF-β. These results characterize the first molecular resolution circuits and their major components activated by specific novel lipid mediators (i.e., resolvin E1 and 10,17S-docosatriene) to promote resolution [55].

31.6 DIET, PSYCHOSOCIAL STRESS, AND CANCERS Psychosocial stress disorders, including depression, are under the influence of a variety of biological and environmental factors, such as Western diet, sedentary behavior, affluence, sleep deprivation, alcoholism, and tobacco consumption [56 58]. However, there are remarkable differences in how patients respond to treatment which may be due to lifestyle factors. There is a strong need to find out biological markers that could be used to better predict and enhance responses to antidepressant treatments for prevention of NCDs, including cancers. Diet is known to influence cancer, neuronal function, and psychosocial dysfunction, including depression [56 60]. The fatty acid composition of the Western diet, which has a high ratio of ω-6:ω-3 PUFA, is associated with higher concentrations of pro-inflammatory cytokines, prostaglandins, and leucotriens, which are known to increase the incidence of depression and cancers [61,62]. The brain is rich in lipids, and dietary fatty acids act within specific brain regions to regulate processes that impact emotional behavior [61]. Increasing blood concentrations of certain fats, such as ω-3s, via dietary intervention may serve as an adjunct to improve the efficacy of antidepressants, and prevent carcinogenesis. Further research indicates that most of the existing studies regarding fatty acids and depression-related brain regions has focused on ω-3s, as compared to ω-6s, monounsaturated, and saturated fats [59]. Psychosocial stress has also emerged as one of the key factors associated with carcinogenesis, growth, and metastasis [58,59]. Most studies on nutrition, stress, and cancer have mainly focused on cancer progression due to the inconsistent results of cancer etiology caused by emotional stress [56 60]. Depression is closely linked to stress and induces hypothalamic pituitary adrenal (HPA) axis activation as well as sympathetic nervous system (SNS) down to immune cell surveillance. The neuroendocrine system is activated by psychological stress/depression, which is associated with cancer occurrence and metastasis. A recent study included 582 young patients with breast cancer and 540 controls with benign breast disease [59]. The risk factors for breast cancer in young women included age at first birth, history of breast cancer in an immediate family member, history of genital surgery, active and passive smoking in daily life or the environment, weekly intake of soy products, use of household cooking oil, disharmonious marital status, frequent depression, and negative emotional experiences (OR 5 1.15, 95% CI: 1.03 1.29). Further studies may provide the basis for risk assessment and preventive interventions for early onset breast cancer. In a meta-analysis including various studies (11 covered stroke, nine covered depression, and eight covered cognitive impairment; only one pertained to Parkinson’s disease), high adherence to Mediterranean diet was consistently associated with reduced risk for stroke, depression, and cognitive impairment [60]. Similarly, moderate adherence to the Mediterranean diet was also associated with reduced risk for

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depression and cognitive impairment, whereas the protective trend concerning stroke was only marginal. Subgroup analyses highlighted the protective actions of high adherence in terms of reduced risk for ischemic stroke, mild cognitive impairment, dementia, and particularly Alzheimer’s disease. Concerning depression, the protective effects of high adherence seemed independent of age, whereas the favorable actions of moderate adherence seemed to fade away with more advanced age in depression [60]. Adherence to a Mediterranean diet may contribute to the prevention of a series of brain diseases. Another meta-analysis including 10 studies, involving 227,852 subjects, was carried out to qualitatively summarize the evidence regarding association of fruit and vegetable intake with risk of depression in the general population [63]. This study also included eight studies involving 218,699 participants for vegetable intake with risk of depression. This meta-analysis indicated that fruit and vegetable consumption might be inversely associated with the risk of depression. In a further metaanalysis, dietary patterns most commonly found were traditional/healthy patterns, Western/ unhealthy patterns, and Mediterranean patterns [64]. The findings suggest a protective effect of healthy and Mediterranean patterns, as well as a potential positive association of Western patterns and depression. Dietary patterns may influence the onset of depression, but no firm conclusion can be drawn at this point. More research is needed to clarify the diet depression relationship, preferably in the form of strong prospective studies [61,62,64,65]. A recent study reported deficiency of omega-3 fatty acid as a risk factor of depression [61].

31.7 EFFECTS OF SLEEP DEPRIVATION ON DIET AND LIFESTYLE FACTORS Dietary changes are also common in night shift workers because light, including artificial light, has a range of effects on human physiology and behavior and can therefore alter human physiology and metabolism when inappropriately timed. The internal rhythms can become desynchronized from both the external environment and internally with each other, impairing our ability to sleep and wake at the appropriate times and compromising physiologic and metabolic processes [1,9]. There is increased consumption of ready-prepared foods rich in calories, refined carbohydrates, and total fat, trans fat, and ω-6 fat which are well-known risk factors of obesity and other chronic diseases [10 12]. Apart from dietary changes, night shift workers tend to avoid spare time physical activity, and there is a tendency to consume more tobacco and alcohol and eat more ready-prepared foods due to increased hunger. In a longitudinal observational study in nurses that incorporated two 5-year spans between 1980 and 1985 (n 5 363) and 1985 90 (n 5 285) [66], weight gains exceeding 5 and 7 kg were more frequent in nurses on night work compared to daytime work during 1985 90. The subjects of the study differed from those in Niedhammer’s study as they were male workers engaged in alternating shift work. Morikawa et al. [67] conducted a longitudinal cohort study over a 10-year span in 1529 Japanese male workers and reported significantly increased body mass index in shift workers during the observation span. The type of job schedule was significantly associated with all three BMI endpoints (5% increase in body mass index: for comparison between alternating shift workers and regular day workers, OR 5 1.14; 95% CI: 1.06 1.23); 7.5% increase in body mass index: OR 5 1.13; 95% CI: 1.03 1.24; 10% increase: OR 5 1.13; 95% CI: 1.00 1.28). Body mass index at study entry was

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also positively associated with the 5%, 7.5%, and 10% increases in body mass index during the study [68]. Lifestyle alterations such as eating habits and exercise in conjunction with disruption of circadian rhythm may have contributed to shift work-related weight gain, which is known to predispose to cancers. Kivimaki et al. [69] examined the association between the shift work and health habits among 689 nurses aged 22 60 years, working night and day shifts [68]. There was an increased incidence of smoking and overweight among those who worked during the night, compared to those who worked only daytime hours. Persson et al. [70] conducted qualitative interviews with 27 nurses (2 men and 25 women) between the ages of 25 and 63 to determine the impact of night work on diet and exercise habits. They reported eating food high in sugar in order to override the feelings of tiredness. Sweetened foods and ready-prepared rapidly absorbed food were readily consumed due to ease of access compared to an alternatively healthy snack. In addition, nurses reported that it was difficult to select healthy foods the day after working the night shift [70]. Other lifestyle behavior also changes with sleep deprivation. Alcohol drinking habits are usually assumed to be a risk factor for obesity and cancers as alcohol itself is high in calories and drinkers also tend to eat high-calorie meals [70]. Night shift workers are more likely to smoke and drink alcohol during night shift work, in order to pass their time and stay awake during work. A study in Japanese male workers found that drinking alcohol more than five times per week decreased the risk of developing obesity compared to abstinence, which may be due to moderate drinking [70]. Sleep deprivation such as night shift work may cause melatonin deficiency which is a potential endogenous antioxidant known for inhibiting carcinogenesis [71 74]. Melatonin can also prevent epigenetic inheritance of cancers due to antiproliferative effects and by protecting the DNA [73,74].

31.8 FUNCTIONAL FOODS FOR PREVENTION OF CANCERS The association of diet with stress, sleep deprivation, and circadian rhythm is important because the Western diet may be carcinogenic, whereas the Mediterranean-style diet may be protective against carcinogenesis [59 61,63 65]. Overall cancer incidence has been observed to be lower in Mediterranean countries compared to that in Northern countries, such as the United Kingdom and the United States, indicating that a Mediterranean-style diet rich in functional foods may be protective [75]. There is increasing evidence that adherence to a Mediterranean dietary pattern correlates with reduced risk of several cancer types and cancer mortality. In addition, specific aspects of the Mediterranean diet, such as high consumption of fruit and vegetables, whole grains, and low processed meat intake, are inversely associated with risk of tumor pathogenesis at different cancer sites. Evidence is available regarding the association between the Mediterranean diet and cancer risk from clinical trials, prospective cohort studies, and casecontrol studies [75,76]. Observational studies provide new evidence suggesting that high adherence to a Mediterranean diet is associated with reduced risk of overall cancer mortality as well as a reduced risk of incidence of several cancer types (especially cancers of the colorectum, aerodigestive tract, breast, stomach, pancreas, prostate, liver, and head and neck). Breast cancer is the leading type of cancer in women; its incidence has increased by more than 20% worldwide since 2008 [75 77]. Some observational studies have suggested that the Mediterranean diet may reduce the risk of breast cancer.

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The PREDIMED study is a 1:1:1 randomized, single-blind, controlled field trial conducted at primary health care centers in Spain. From 2003 to 2009, 4282 women aged 60 80 years and at high CVD risk were recruited after invitation by their primary care physicians [76]. Participants (n 5 4152) were randomly allocated to a Mediterranean diet supplemented with extra-virgin olive oil, a Mediterranean diet supplemented with mixed nuts, or a control diet. After a median followup of 4.8 years, 35 confirmed incident cases of breast cancer were identified. Observed rates (per 1000 person-years) were 1.1 for the Mediterranean diet with extra-virgin olive oil group, 1.8 for the Mediterranean diet with nuts group, and 2.9 for the control group. The multivariable-adjusted hazard ratios versus the control group were 0.32 (95% CI: 0.13 0.79) for the Mediterranean diet with extra-virgin olive oil group and 0.59 (95% CI: 0.26 1.35) for the Mediterranean diet with nuts group. In analyses with yearly cumulative updated dietary exposures, the hazard ratio for each additional 5% of calories from extra-virgin olive oil was 0.72 (95% CI: 0.57 0.90). The results suggest a beneficial effect of a Mediterranean diet supplemented with extra-virgin olive oil in the primary prevention of breast cancer. These results come from a secondary analysis of a previous trial and are based on few incident cases and, therefore, need to be confirmed in longer-term and larger studies. Mediterranean-style diets are rich in functional foods such as fruits, vegetables, whole grains, walnuts, almonds, olive oil, fish, and poultry, with limited consumption of red meat. Such diets are also protective against neuropsychiatric diseases, CVDs, and diabetes [1,9,16,75,76]. A recent study investigated the relationship between adherence to the Mediterranean diet and risk of postmenopausal breast cancer (and estrogen/progesterone receptor subtypes, ER/PR) [77]. In the Netherlands Cohort Study, 62,573 women aged 55 69 years provided information on dietary and lifestyle habits in 1986. Follow-up for 20.3 years showed that adherence to this diet was estimated through the alternate Mediterranean Diet Score excluding alcohol. Multivariate casecohort analyses were based on 2321 incident breast cancer cases and 1,665 subcohort members with complete data on diet and potential confounders. A statistically significant inverse association between Mediterranean diet adherence and risk of ER negative (ER ) breast cancer had a hazard ratio of 0.60 (95% CI: 0.39 0.93) for high versus low Mediterranean diet adherence (Ptrend 5 .032) [77]. In meta-analyses, summary HRs for high versus low diet adherence were 0.94 for total postmenopausal breast cancer, 0.98 for ER 1 , 0.73 for ER and 0.77 for ER PR breast cancer. These findings support an inverse association between Mediterranean diet adherence and, particularly, receptor negative breast cancer. The researchers looked at data from a study involving more than 60,000 women aged 55 69 over a 20-year period. At the start of the study, details of the women’s diet, physical activity, and other cancer-related risk factors were collected. The researchers then compared the diets of more than 2000 women who went on to develop breast cancer with a selected group of similar women who didn’t develop the cancer. Overall, there was no link between a Mediterranean diet and breast cancer risk. However, the researchers found women whose diet was most like a Mediterranean diet were 40% less likely to develop one particular type of breast cancer: estrogen receptor-positive breast cancer. As with all studies of this type, it is difficult to separate out the effects of diet and other lifestyle factors, such as exercise and smoking. This makes it difficult to be certain that the differences in risk are the result of the Mediterranean diet alone. In a meta-analysis from 10 prospective large studies, 68,222 subjects, aged 35 years and above, free of CVD and cancer, were examined [78]. Main outcome measures were death from all causes

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(n 5 8365), CVDs including cerebrovascular disease (n 5 3382), all cancers (n 5 2552), and deaths from external causes (n 5 386). After a mean follow-up of 8.2 years, a dose-response association between psychological distress across the full range of severity and an increased risk of mortality with hazard ratio of 1.20 (95% CI: 1.13 1.27; scores 4 6: 1.43, 1.31 1.56; and scores 7 12: 1.94, 1.66 2.26; P , .001 for trend) were observed [78]. A similar association was found for CVD deaths and deaths from external causes. Cancer death was only associated with psychological distress at higher levels. Psychological distress was associated with increased risk of mortality from several major causes in a dose-response pattern. Risk of mortality was raised even at lower levels of distress. In a recent meta-analysis, single nucleotide polymorphisms (SNPs) of 17 circadian genes reported by three GWAS meta-analyses dedicated to: Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Consortium included cases, n 5 15,748; controls, n 5 18,084), prostate (Elucidating Loci Involved in Prostate Cancer Susceptibility (ELLIPSE) Consortium; cases, n 5 14,160; controls, n 5 12,724) and lung carcinoma (Transdisciplinary Research In Cancer of the Lung (TRICL) Consortium; cases, n 5 12,160; controls, n 5 16,838) in patients. The findings via adapted rank truncated product analysis-based gene and pathway analysis, support the hypothesis that circadian pathway genetic variation is involved in cancer predisposition indicating that brain dysfunction could be an important pathway for development of cancer [79]. In brief, while the Western diet can predispose chronic diseases such as cancer, depression, and emotional stress, eating a Mediterranean diet may inhibit breast cancer risk by 40% in postmenopausal women and has beneficial effects in carcinogenesis. Such diets are also protective against brain-related psychosocial stress and circadian disruption-induced oxidative stress and inflammation.

ACKNOWLEDGMENT The International College of Nutrition who provided logistic support to write this article.

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[63] Liu X, Yan Y, Li F, Zhang D. Fruit and vegetable consumption and the risk of depression: a metaanalysis. Nutrition 2016;32:296 302. [64] Lai JS, Hiles S, Bisquera A, Hure AJ, McEvoy M, Attia J. A systematic review and meta-analysis of dietary patterns and depression in community-dwelling adults. Am J Clin Nutr 2014;99:181 97. [65] Rahe C, Unrath M, Berger K. Dietary patterns and the risk of depression in adults: a systematic review of observational studies. Eur J Nutr 2014;53:997 1013. [66] Niedhammer I, Lert F, Marne MJ. Prevalence of overweight and weight gain in relation to night work in a nurses’ cohort. Int J Obes Relat Metab Disord 1996;20:625 33. [67] Morikawa Y, Nakagawa H, Miura K, Soyama Y, Ishizaki M, Kido T, et al. Effect of shift work on body mass index and metabolic parameters. Scand J Work Environ Health 2007;33:45 50. [68] Suwazono Y, Dochi M, Sakata K, Okubo Y, Oishi M, Tanaka K, et al. A longitudinal study on effect of shift work on weight gain in male Japanese workers. Obesity 2008;16:1887 93. [69] Kivimaki M, Kuisma P, Virtanen M, Elovainio M. Does shift work lead to poorer health habits? A comparison between women who had always done shift work with those who had never done shift work. Work Stress 2001;15(1):3013. [70] Watari M, Uetani M, Suwazono Y, Kobayashi E, Kinouchi N, Nogawa K. A longitudinal study of the influence of smoking on the onset of obesity at a telecommunications company in Japan. Prev Med 2006;43:107 12. [71] Hill SM, Blask DE. Effects of the pineal hormone melatonin on the proliferation and morphological characteristics of human breast cancer cells (MCF-7) in culture. Cancer Res 1988;48:6121 6. [72] Cos S, Fernandez F, Sanchez-Barcelo EJ. Melatonin inhibits DNA synthesis in MCF-7 human breast cancer cells in vitro. Life Sci 1996;58:2447 53. [73] Cos S, Fernandez R, Guezmes A, Sanchez- Barcelo EJ. Influence of melatonin on invasive and metastatic properties of MCF-7 human breast cancer cells. Cancer Res 1998;58:4383 90. [74] Mediavilla MD, Cos S, Sanchez-Barcelo EJ. Melatonin increases p53 and p21WAF1 expression in MCF-7 human breast cancer cells in vitro. Life Sci 1999;65:415 20. [75] Schwingshackl L, Hoffmann G. Does a Mediterranean-type diet reduce cancer risk?. Curr Nutr Rep. 2016;5:9 17. Available from: https://doi.org/10.1007/s13668-015-0141-7. [76] Toledo E, Salas-Salvado´ J, Donat-Vargas C, Buil-Cosiales P, Estruch R, Ros E, et al. Mediterranean diet and invasive breast cancer risk among women at high cardiovascular risk in the PREDIMED trial: a randomized clinical trial. JAMA Intern Med. 2015;175(11):1752 60. Available from: https://doi.org/ 10.1001/jamainternmed.2015.4838. [77] van den Brandt PA, Schulpen M. Mediterranean diet adherence and risk of postmenopausal breast cancer: results of a cohort study and meta-analysis. Int J Cancer 2017;140(10):2220 31. [78] Russ TC, Stamatakis E, Hamer M, Starr JM, Kivimaki M, Batty GD. Association between psychological distress and mortality: individual participant pooled analysis of 10 prospective cohort studies. BMJ 2012;345. Available from: https://doi.org/10.1136/bmj.e4933 Published 31 July 2012) Cite this as: BMJ 2012;345:e4933. [79] Mocellin S, Tropea S, Benna C, Rossi CR. Circadian pathway genetic variation and cancer risk: evidence from genome-wide association studies. BMC Med 2018;16:20. Available from: https://doi.org/ 10.1186/s12916-018-1010-1.

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ANTIOXIDANT DIETS AND FUNCTIONAL FOODS PROMOTE HEALTHY AGING AND LONGEVITY THROUGH DIVERSE MECHANISMS OF ACTION

32

Sanit Wichansawakun1 and Harpal S. Buttar2 1

Division of Clinical Nutrition, Department of Internal Medicine, Thammasat University, Bangkok, Thailand Department of Pathology and Laboratory Medicine, Faculty of Medicine, University of Ottawa, Ontario, Canada

2

LIST OF ABBREVIATIONS AD AMPK BMI CR CRP CVDs DHA DNMT EGCG eNOS EPA FAD FOS FOXO GI GOS GSH HAT HDAC HDL HDM HMT hTERT IGF-1 IL

Alzheimer’s disease adenosine monophosphate-activated protein kinase body mass index caloric restriction c-reactive protein cardiovascular diseases docosahexaenoic acid DNA methyltransferase epigallocatechin-3-gallate endothelial nitric oxide synthase eicosapentaenoic acid fasting on alternative day fructo-oligosaccharides forkhead transcription factor family O glycemic index galacto-oligosaccharides glutathione histone acetyltrasferase histone deacetylase high-density lipoprotein histone demethylase histone methyltransferase human telomerase reverse transcriptase insulin-like growth factor-1 interleukine

The Role of Functional Food Security In Global Health. DOI: https://doi.org/10.1016/B978-0-12-813148-0.00032-3 © 2019 Elsevier Inc. All rights reserved.

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LDL MCT Med-diet miRNA MTHFR mTOR NCDs NF-KB PUFA QoL ROS RSV SFN SIRT-1 TNF TOR WAT

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low-density lipoprotein medium-chain triglycerides Mediterranean-type diet micro-RNA methylenetetrahydrofolate reductase mammalian target of rabamycin noncommunicable diseases nuclear factor kappa B polyunsaturated long chain fatty acid quality of life reverse oxidative stress resveratrol sulforaphane sirtuin-1 tumor necrosis factor target of rabamycin white adipose tissue

Based on long-term historical data, humans nowadays enjoy longer life spans than that of their ancestors. The Guinness Book of World Records has listed a person who had the longest life span and lived up to the age of 122 years [1]. Looking back to the past couple of centuries, longevity has increased worldwide due to medical advances, reduced infant mortality, improved socioeconomic conditions, good sanitation, and healthy nutrition. Even in Africa, where malnutrition is rampant and people suffer from serious infections, men and women live longer these days compared to the past century [2,3]. However, it has been observed that both nature and nurture play significant roles to promote healthy aging and longevity. For instance, early life environment, socioeconomic conditions, availability of healthy foods, and lifestyle factors can contribute greatly to the development of chronic diseases that impact on our aging and life span in adulthood life [4]. It is now recognized that maternal health and nutrition contribute heavily in fetal programming and its intrauterine growth. Premature delivery and low birthweight contribute to cardiovascular pathology [5], as well as pre- and postnatal development that subsequently impact on the offspring’s health and longevity [6,7]. It is therefore imperative that the healthcare providers should remain cognizant of the fact that maternal fetal health plays an important role in reducing the incidence of noncommunicable diseases (NCDs) during postnatal life, and healthy aging and longevity. Also, it is the duty of the mother to keep active and eat healthy foods during pregnancy, and reduce the risk of stress on the intrauterine guest. According to the WHO, the number of elderly seniors ( . 60 70 years) has increased continuously during the past 60 years, and the projected global increase of elderly population will be 56% from 901 million to 1.4 billion people between 2015 and 2030 [8]. It is estimated that in 2030, the number of 80-year-old persons will become three times greater than in 2015 [8]. Although there is a worldwide increase in life expectancy resulting from the advancement of health care system, improved nutrition, better sanitation, and socioeconomic status, the elderly people are also facing increased incidences of NCDs, such as diabetes mellitus, obesity, cardiovascular diseases (CVDs), neurodegenerative disorders, and cancers. The NCDs not only increase the health care costs and pose an economic burden in developed and developing countries, but also result in poor quality of

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life (QoL) among the elderly folks, especially in poor countries [9 11]. There is an overwhelming evidence that both genetic and epigenetic factors contribute to the occurrence of NCDs, including a number of lifestyle factors (cigarette smoking, sedentary habits), unhealthy dietary habits, heavily salted foods, sugar-loaded beverages, malnutrition, and lack of micronutrients (vitamins and trace elements). Many epidemiological studies and meta-analyses have focused on the specific food nutrients (e.g., Mediterranean-type diet), nutritional supplements, intake of functional foods and probiotics, and lifestyle modifications that slow the onset of aging and reduce age-related illnesses, and consequently promote healthy aging, longevity, and improvement of QoL among the elderly people.

32.1 PROPOUNDED THEORIES OF MECHANISMS OF AGING The exact mechanisms of aging or gerontology-retarded senescence remain unknown. Recently, da Costa et al. have published an excellent review on the theories of aging, mechanisms, and future prospects of senescence [12]. The proposed theories of aging, including mechanisms involved that take into consideration both intrinsic and extrinsic factors, are depicted in Figs. 32.1 and 32.2. Briefly, the primary or intrinsic senescence is an independent deterioration in physical structure and biological functions with increasing age. In elderly persons, there is a reduction in skeletal muscle mass and total body protein, increased percentage of total body fat and increased accumulation in abdominal fat [13], reduced bone mineral density and joint problems, accompanied by decline in cardiac, pulmonary, renal, hepatic, gut, eye, brain, skin, and immune function [14]. It is believed that these dysfunction mechanisms are programmed in our genes [12]. The aging process seems to result from an increase in oxidative stress produced by cellular mitochondrial metabolism and excessive production of free oxygen radicals (reactive

FIGURE 32.1 Mechanism of aging.

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FIGURE 32.2 The theories of senescence induced by various mechanisms.

oxygen species (ROS)) which cause cell membrane and DNA damage [12,15,16]. Under normal physiologic conditions, the mitochondrial ROS are produced continuously through aerobic metabolism for cell signaling, but small amounts of ROS can escape and cause cellular oxidative stress [16,17]. In fact, the lack of neutralization of ROS gives rise to oxidative stress [18]. Endogenous antioxidants that can scavenge free radicals include glutathione and enzymes (catalase, superoxide dismutase) produced internally, and dietary antioxidants like vitamin C, E, and β-carotene. Elements like selenium, zinc, copper, and iron-binding proteins such as ferritin and transferrin contribute to antioxidant defense by quenching free radicals and inhibiting lipid peroxidation [19,20]. The Mediterranean-style of diet containing fruits, nuts, vegetables and foods rich in antioxidants reduces the risk of CVDs, type 2 diabetes, and NCDs by lowering cellular oxidative stress [21 23]. If not promptly neutralized by the antioxidant systems, ROS can attack intracellular lipids, proteins, nucleic acids, and other macromolecules which can lead to epigenetic modifications, genetic mutations, and carcinogenesis [12,15]. Imbalance between ROS and the antioxidative stress defense systems in cells creates excessive oxidative stress and triggers inflammatory conditions that cause cardiovascular and neurodegenerative diseases, diabetes mellitus, and cancer. This functional imbalance between the oxidant versus antioxidant can cause physiological cell death or apoptosis and may also initiate the process of nonfunctioning cells or the cellular aging process in the body. However, some endogenous or exogenous conditions can result in excessive production of oxidative stress causing DNA damage of normal cells [20,24]. For example, accumulation of amyloid and other cellular metabolites can cause deterioration in structure and function of vital organs [25]. This phenomenon may not only be involved in causing the NCDs but also onset early aging [26]. While the human cells have abilities to repair their DNA, however, this DNA repair function may be impaired during oxidative stress [12,13]. The diagrammatic representation of oxidative stress theory is illustrated in Fig. 32.3.

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FIGURE 32.3 Diagramatic represention of oxidative stress theory.

At the end of our chromosomes, there are telomere caps protecting the DNA from fraying or fusion, and telomere cap damage can cause genetic defects [12,15]. During every cell division, telomeres are shortened, and subsequently the cells are no longer able to replicate causing senescence [27]. In addition, extrinsic factors of aging, namely polluted environment, reduced physical activity, psychological stress, unhealthy dietary habits, intake of high fatty, salty or sugar loaded foods, or calorie-dense foods cause chronic diseases [27,28]. These factors also increase adipokines, cytokines, and plasma free fatty acids production from changes in fatty acid metabolism resulting in the progressive deterioration in cellular structure and function [13,29,30].

32.2 MITOCHONDRIAL-GENERATED REACTIVE OXYGEN SPECIES AND LONGEVITY Mitochondria play an important role in aerobic metabolism process, and their function involves cellular oxygen transportation [15,31]. Based on oxidative stress theory, excessive production of ROS can lead to the progression of aging. It has been found that a greater amount of ROS production occurs in highly aerobic tissues such as heart, brain, liver, and kidney during electron transportation at mitochondria and these tissues represent the marked changes during aging. Even though endogenous antioxidants (glutathione, catalase, superoxide dismutase) are known to scavenge free radicals to protect cells from aging, the beneficial effects of exogenous antioxidants supplementation to fight the process of aging warrants further investigations. A few studies have shown that antioxidant-increased levels in tissues from dietary supplements cannot enhance the maximum life span potential in mammals [31]. Moreover, the tissue levels of endogenous antioxidants and antioxidant enzymes levels in tissues inversely correlate with the mammal’s maximum life span potential. In contrast, the rate of mitochondrial ROS production may be one of the main factors that contributes to the aging process and predicts the maximum life span potential [31]. It appears that the lower production of mitochondrial ROS instead of having higher amount of

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endogenous antioxidants may be crucial for animal and human longevity. As opposed to short-lived species, a lower rate of mitochondrial ROS production has been detected in long-lived species [31]. There is some evidence that mitochondrial ROS production may be a signal for antiaging effect. For example, in Caenorhabditis elegans, an increased production of mitochondrial ROS and enhanced signaling extended life span in this species [16]. Also, the mitochondrial signaling gets involved in other homeostatic pathways like wound healing and survival under hypoxemia situation. Because mitochondrial ROS is a by-product of mitochondrial oxidative metabolism, the type of diet (lipid, carbohydrate, and fat), and fuel load may be a factor in determining the aging process [16].

32.3 ANTIAGING AND DISEASE PREVENTION PROPERTIES OF FOODS Unfortunately, people living longer lives face some health disadvantages: namely increased risks of NCDs such as CVDs, cancers, chronic pulmonary diseases, neuroendocrine and metabolic disorders, type 2 diabetes, hypertension, hyperlipidemia, brain degenerative diseases (dementia, Alzheimer disease), osteoarthritis and joint pains, gastrointestinal and blabber problems [24]. Sometimes these chronic disorders result in prolonged illness, morbidity, and high mortality [24]. Learning about the holistic approaches that cultivate health education and health promotion, healthy diets, and therapy through social medicine among the elderly could help to slow the progression of aging and enhance the chances of healthy longevity [20,26,32,33]. In order to promote good health and well-being, the consumption of antioxidant foods and nutrients, omega-3 fatty acids, low-fat dairy products, moderate exercise (about 30 min/day), and lifestyle changes are important because all these factors contribute heavily in the NCDs prevention [34,35]. Many researchers have proposed dietary interventions, moderate physical activity, smoking cessation, restriction of caloric and sodium intake for the management and prevention of heart attack and stroke, atherosclerosis, type 2 diabetes, obesity, osteoarthritis, and other chronic abnormalities [34 36]. It has been argued that holistic approaches are needed for health education and health promotion among children and adults [34,36]. Emerging evidence suggests that diets containing flavonoids, carotenoids, antioxidants, and antiinflammatory agents decrease oxidative stress and consequently reduce the risk of CVDs, cancer, and chronic diseases multifactorial in origin [35 37]. Mediterranean-type diets rich in whole grains, fruits and vegetables, legumes, olive oil, fish and omega-3 fatty acids, low-fat dairy products, and moderate red wine consumption are linked with improved serum lipid concentrations and lower incidence of CVDs, type 2 diabetes, and NCDs [21]. Ingestion of phytosterol-enriched foods, vitamins, minerals, and amino acids (tryptophan, tyrosine, cysteine) assist to improve overall health beyond basic nutritional functions. Dietary supplements containing flavonoids and antioxidants seem to modulate gene and protein expression and thereby modify endogenous metabolic pathways and homeostasis, and consequently reduce the risk of NCDs multifactorial in origin. Improvement of nutrition also appears to induce epigenetic changes that help to induce good health and prolong life span. Nutrition-induced epigenetic changes may enhance DNA methylation, histone modifications, and noncoding RNA [38 40], resulting in adapting gene expression that respond to signals from external and internal environment [41].

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32.4 DNA METHYLATION DNA methylation controls many gene expression processes in our bodies by the addition of methyl-end (CH3) to 5-position of cytosine [40]. This action causes X-chromosome inactivation or silencing of germline-specific genes as well as production of cancer cells [38,42]. Under high oxidative stress, DNA methylation can happen more frequently. Theoretically speaking, the more DNA methylation occurs, the lesser gene transcription will happen because the attachment of methyl group to DNA acts like a “dimmer switch” that slows the activity of genes. This mechanism has been proposed for a gene that encodes human telomerase reverse transcriptase (hTERT) [40]. Substances like folate, vitamin B12, selenium, bioflavonoids, and polyphenols present in green tea are known to modulate DNA methylation [38,43]. Epigallocatechin-3-gallate (EGCG), epicatechin, and ganistein found in polyphenols and quercetin, fisetin. and myricerin present in bioflavonoids can decrease DNA methylation and assist to promote health and longevity. [40].

32.5 HISTONE MODIFICATION Histones are highly alkaline proteins found in eukaryotic cell nuclei and play an important role in gene regulation. An active gene is less bound by histone, whereas an inactive gene is highly bound by histone [40]. Acetylation of the histone tail increases transcriptional activity of the gene promoter region [40]. It is postulated that the activities of enzymes involved in the posttranslational modification of histone such as histone acetyltransferase (HAT), histone methyltransferase (HMT), histone deacetylases (HDAC), and histone demethylases (HDM) may be influenced by dietary ingredients. For instance, polyphenols from garlic and cinnamon can inhibit HDAC activity, resulting in posttranslational modification of histone protein [44]. Also, polyphenols from green tea and copper can inhibit the activity of HAT, whereas EGCG can inhibit HMT activity [40]. It appears that life span may be prolonged by inhibiting the activities of histonerelated enzymes.

32.6 MICRO-RNAs OR NONCODING RNAs MODIFICATION BY DIET Micro-RNA (miRNA) also plays a role in the alterations of posttranscriptional gene expression [38 40,42]. The miRNA can bind to complementary sequences on messenger RNA (mRNA), causing posttranscriptional gene silencing [38]. Moreover, miRNA can produce DNA methylation and histone modification [38]. The consumption of fat, protein, alcohol, and vitamin E has an impact on the expression of miRNA. It has been reported that polyphenols from anthocyanin, curcumin, genistein, and quercetin, fish oil, and retinoic acid can modulate the expression of miRNA, resulting in cancer therapy [38,45,46]. The anticancer effect of retinoic acid has been shown in the treatment of acute promyelocytic leukemia with chemotherapy and all-trans-retinoic acid [38].

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32.7 MISCELLANEOUS DIETARY INTERVENTIONS FOR ANTIAGING AND LONGEVITY Since the proposed theory of shortening telomeres is associated with many chronic diseases and cause of senescence, many studies have been done to address this issue and to find out the way to stabilize telomeres or to improve the activity of telomerase enzyme, consequently resulting in good health and expansion of life span [27]. Several investigators have shown that mental, emotional, and physical health is related to this genetic mechanism. Consumption of Mediterranean-style diet [28,47,48], Okinawa diet [49 51], as well as the practice of caloric restriction (CR) or intermittent alternative fasting [13,52,53] have shown positive effects on human health and well-being by this proposed mechanism. Also, some dietary supplements containing antioxidants have had positive impacts on the telomeres, causing increase in life span. For example, intake of folate, vitamin B, D, E, C, zinc, polyphenolic compounds from resveratrol, grape seed, and curcumin have a potential role in CVDs and cancer prevention [26,28]. In addition, several antioxidant foods with antiinflammatory properties such as tuna, salmon, herring, mackerel, halibut, anchovies, cat-fish, flax and sesame seeds, kiwi, black raspberries, green tea, broccoli, sprouts, red grapes, tomato, olive oil, omega-3 fatty acids, nuts and seeds, vegetables and fruit, probiotics, herbs, and spices reduce the risk of NCDs and improve overall health [27,54 56]. The increase in life span was first noticed in yeast via inactivation of protein kinase, namely target of rapamycin (TOR) [40]. Also, in mammalian species and humans, mammalian TOR (mTOR) can regulate cell growth. Inactivation of mTOR signaling pathway supports autophagy and expands life span [57]. Insulin, some growth and stress factors (temperature change, oxidative stress), and leucine amino acid can activate mTOR, whereas, caffeine, hypoxia, and DNA damage inhibit mTOR activity [40,58]. A class III NAD1 dependent histone deacetylase (HDAC) such as sirtuin-1 (SIRT-1) is an important nutrient sensor enzyme related to metabolism that has shown interesting effects on increasing the life span in animal models [59,60]. SIRT-1 activity is regulated by the NAD/NADH ratio that indicates oxygen consumption and the redox respiratory chain. Because it is known that HDAC is associated with slowing the aging process, SIRT-1 has been followed as another answer to fighting the aging process [40]. Activation of SIRT-1 has been observed in yeast, and animals during food restriction state, which can help in expanding their life span [61]. Polyphenol discovered in resveratrol is an important mediator in the antiaging process by its action as a SIRT-1 mimic [40,46]. The mammalian forkhead transcription factor family O (FOXO) factors, are involved in controlling apoptosis, cell differentiation, and the expression of DNA repairing genes and oxidative stress resistance. Polyphenols from black tea can mimic the actions of insulin/insulin-like growth factor 1 (IGF1) signaling pathway on FOXO factors resulting in promoting longevity [62,63]. CR is the most studied dietary intervention in many animal models. CR has shown to extend life and improve health by decreasing the incidence of type 2 diabetes, CVDs, neurodegenerative diseases, and cancers [40,58]. CR also promotes longevity by modulating the signaling pathways of adiponectin, insulin/IGF1, adenosine monophosphate-activated protein kinase (AMPK), mTOR, FOXO, and sirtuins [15]. It has been suggested that adaptive stress responses may prevent apoptosis and stimulate autophagy [57]. The role of CR is to decrease the amount of caloric intake by 10% 30% from usual intake, but does not cause malnutrition because of deficiency of

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vitamins, minerals, or some essential nutrients [64 67]. Moreover, CR together with exercise can lead to reductions in total body fat, improvement of lipid profiles, including decreased plasma low-density lipoprotein (LDL)-cholesterol, total cholesterol/high-density lipoprotein (HDL) ratio, and c-reactive protein (CRP) levels which are the major coronary heart disease risk factors [13,68]. Additionally, CR causes an increase in adiponectin level, and decreases plasma insulin and IGF-1. Overall, CR can be beneficial for health by promoting fatty acid oxidation and decreasing lipid accumulation, and reduce the risk of obesity [64,67,69]. Some patients find it difficult to follow CR intervention, therefore, CR mimicking has been studied in many ways. Combination of exercise with CR by reducing caloric intake by 12.5% instead of 25% in traditional CR has shown similar positive health outcomes. There is no significant difference in fasting insulin levels, DNA damage, and muscle mitochondrial gene expression [38]. Fasting on alternate day (FAD) is another way for mimicking CR intervention. However, results cannot be compared to CR because of the different duration of the study, viz, 20 weeks of FAD versus 6 months to 6 years of CR. The results obtained from CR subjects did not show any significant changes in biomarkers specific to lipid profiles and oxidative stress in FAD [38]. A dietary intervention to control the quantity of dietary proportion instead of the amount of overall calories intake is known as dietary restriction (DR). This may be another method to mimic CR. The DR studies have been performed with fruit flies, worms, and rodents [70]. Most results of DR originate from observational studies, and animal findings. The carbohydrate and fat DR investigation failed to decrease the oxidative stress [38]. Thus, neither carbohydrate nor lipid restrictions are effective alternatives to CR. Nevertheless, protein restriction seems to mimic CR in rodents. Such study showed an increase in the maximum life span by 20% [31]. The protein DR study with methionine restriction in diet seems to show benefits on longevity [71,72]. The methionine rich foods are nuts, beans, meat protein, cheese, fish, shellfish, soy, eggs, and dairy products. The recommended intake of methionine is 10.4 mg/kg/day [73,74]. Methionine-restricted diet has shown the benefits on methylenetetrahydrofolate reductase (MTHFR) gene mutations because methionine restriction helps to reduce homocysteine accumulation level in the body. Further studies are needed to evaluate the effects of limiting dietary methionine and inhibiting cancer cells and extension of life span. The methionine effect might occur from increased insulin sensitivity, improved lipid metabolism, and decreased systemic inflammation [73 76]. However, there are studies stating that humans require lesser caloric energy when they get older, but the requirement of protein intake may increase [77,78]. This is a cautionary point of protein and methionine restriction, as decreased intake of methionine can lead to reducing the overall amount of protein intake. In fact, protein is essential for building and repairing tissues, producing antibodies and hormones, and enzymes synthesis, therefore, limiting methionine and protein may pose a negative impact on the elderly’s health. Loss of muscle mass and their function is known as sarcopenia, which can cause increased morbidity and mortality in elderly subjects [78,79]. Based on evidence gathered from several studies, it appears that intake of protein is essential for elderly individuals, and older people may require more dietary protein than younger adults to keep good health and functionality, and to promote recovery when they are sick [80]. The European Union Geriatric Medicine Society (EUGMS) recommended that in order to help older people ( . 65 years) with normal kidney function (GFR .30 mL/min/1.73 m2) and to maintain lean body mass and function, the average amount of protein intake should increase to at least 1.0 to 1.2 g/kg/day and may increase up to 1.5 g/kg/day in exercising or very active elders [81,82].

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Resveratrol (RSV), a polyphenol derived from the skin of red grapes is one of the most studied nutrients as a CR mimetic in animal models [38,83]. A moderate dose (25 30 mg/kg/day) of RSV can activate AMPK which is associated in the same pathway of SIRT-1 [83]. This action of RSV has shown beneficial effect in mitochondrial function both in in vitro and in vivo studies [84]. Six-week supplementation of 20% trans RSV(about RSV 40 mg/day) extracted from Polygonum cuspidatum 200 mg inhibited the binding of nuclear factor kappa B (NF-κB), reduced ROS generation, decreased tumor necrosis factor (TNF)-α and interleukin-6 (IL-6) levels in mononuclear cells. Also, there was a reduction of plasma TNF-α levels and CRP. However, no significant changes in cholesterol, triglycerides, or leptin levels were observed in the treatment group [32]. The RSV supplementation showed an increase in mRNA expression of the NAD(P)H dehydrogenase and glutathione S-transferase-p1 genes, thereby indicating strong antioxidant effects. By upregulating the activity of endothelial nitric oxide synthase (e-NOS), RSV caused vasodilatation and increased blood flow in the cardiovascular system [85]. However, RSV supplement did not show any improvement in cognitive function [86]. Further investigations on the biological effects of RSV are warranted to enhance our understanding about the long-term safety and efficacy of RSV in humans. Other nutrients like sulforaphane (SFN) found in cruciferous vegetables such as kale, cabbage, Brussels sprouts, and broccoli, EGCG found in green tea, and genistein found in soy, also are characterized as dietary compounds of the epigenetic diet and proposed as CR mimicking agents [13,38,40] Dietary patterns consist of combination of foods rather than a single nutrient and their intake reduces the risk of NCDs [50]. One well-known and widely used dietary pattern is Mediterranean-type diet (Med-diet). It was alluded to earlier that Med-diet meals contain olive oil as the main source of unsaturated fat, high amount of fresh fruits and vegetables, nuts, nonrefined grains and legumes, moderate to high amount of fish and poultry, and moderate to low amount of dairy products, and low amount of red meat, as well as moderate amount of red wine [87]. It is documented through clinical trials that people who follow Med-dietary pattern have better health status and live longer than who follow Western dietary pattern [87]. Med-diet pattern is also associated with reduced risk of CVDs, diabetes mellitus, and other age-related disorders [54,87,88]. In addition, Med-diet has a protective impact on the telomere length via antiinflammatory and antioxidant mechanisms [87,89]. It has been reported that in high risk cardiovascular people, this dietary pattern could help to keep longer telomeres [87]. The Okinawa dietary pattern has been studied in a large number of healthy aging and centenarian population [49,50]. The Okinawa diet is high in vegetables and soy intake, but low in fat and diary products. Specifically, the Okinawa diet contains high amount of vegetables and fruits, especially sweet potato, green-leafy or yellow-root vegetables, soy and legume, small servings of fish, noodles, and lean meat. Also, it is flavored with herbs, spices, cooking oil, and very low in sugary deserts/sweets [50]. The specific characteristics of Okinawa diet are low in calories, high in fiber from vegetables and legumes, moderate consumption of fish, low intake of meat and dairy products, low intake of unhealthy fat (low in saturated fatty acids, high in mono- and poly-unsaturated fatty acid), and the emphasis is on low glycemic index (GI) carbohydrates, which contributes to slower increasing in plasma glucose compared to glucose ingestion, and moderate alcohol consumption. The investigators who have analyzed the results of this dietary pattern are of the opinion that the benefits of Okinawa diet in causing longevity may be from the high amount of dietary fiber, low GI carbohydrates, and high antioxidant levels from vitamin A and C, potassium, iron, calcium, low sodium, and low levels of fat and cholesterol. These nutritional properties of the Okinawa diet seem to decrease the risk of chronic diseases, cancers, and CVDs.

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32.8 IMPACT OF ANTIOXIDANT FOODS AND ANTIINFLAMMATORY AGENTS ON NONCOMMUNICABLE DISEASES PREVENTION Diabetes-induced hyperglycemia and metabolic disorder seem to be the main culprit for causing cellular oxidative stress and release of ROS that initiates and/or promotes an inflammatory process in the arterial wall and causes endothelial dysfunction, atherosclerosis, myocardial infarction, and CVDs [24,90]. Also, there is a link between oxidative stress following heart attack and myocardial damage, known as ischemia reperfusion-induced cardiac injury, which increases further risk of mortality and morbidity. Reduction of oxidative stress by dietary interventions and antioxidant supplements having free radical scavenging and antiinflammatory properties can play a pivotal role in CVDs and cancer prevention, improvement of QoL, and help to delay the aging process and increase life span. To prevent sustained oxidative stress and chronic inflammation, the antioxidants effects of wide variety food ingredients have been studied in animal models and humans. Table 32.1 shows examples of beneficial health outcomes associated with phytochemicals, vitamins, and trace elements. They include β-carotene, vitamin C and E, omega-3 fatty acid, selenium supplements, or bioactive substances like resveratrol, Epigallocatechin-3-gallate (EGCG), catechins, or tea polyphenol, lycopene, curcumin, sulphoraphane, genestin, and Ginkgoo biloba, as well as carotenoids and coenzyme Q10 present in vegetables to mitigate CVDs, cancer, and chronic diseases through their antioxidant and antiinflammatory actions [91,92]. The results of many studies did not indicate effective doses of supplements that reduce the risk of CVDs. Conversely, findings of some studies revealed negative effects of supplements in CVD prevention due to increased mortality rate [93]. A large number of studies have failed to show clear benefit of antioxidant supplements in a healthy population [20]. Small doses of dietary supplements may be beneficial for some individuals, while high-doses of antioxidants may be harmful due to increased cardiovascular problems and high mortality, e.g., β-carotene supplementation in smokers and vitamin E supplementation in undernourished elderly may be disadvantageous [20]. Trace amounts of selenium may have positive effects in decreasing oxidative stress and antiinflammation, but selenium supplementation has not revealed any significant benefits either on lipid profiles or in reducing CV mortality [94]. Selenium is involved in the synthesis of antioxidant glutathione (GSH). Omega 3-polyunsaturated long chain fatty acid (PUFA), containing eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), possesses antiinflammatory effect, and may also have antithrombotic and antiarrhythmic effects. Omega-3 PUFA at 1 3 g doses has shown benefits in lipid profiles and reduced cardiovascular risk in patients. However, a meta-analysis failed to show any beneficial effect for treating CVDs [95]. In contrast, phytochemicals derived from fruits and vegetables have depicted significant benefit in the prevention and treatment of CVDs [20,92]. Studies with many potential bioactive ingredients from foods containing β-carotenoid, flavonoid, resveratrol, and polyphenols have demonstrated significant benefits in the primary and secondary prevention of CVDs [20,26,92,96]. During the last 25 30 years, obesity and type 2 diabetes have become major public health problems in developed and developing countries. The incidence of obesity has continually increased in children and adults during the past few decades. In 2013, about 33% of the world population was considered overweight or obese and this number is still increasing each year [97]. While the total body composition of lean adult men or women consists of about 20% white adipose tissue (WAT), this tissue can increase to .40% in obese humans (BMI 30 35). White adipocytes secrete a wide

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Table 32.1 Examples of Beneficial Health Outcomes Associated With Phytochemicals, Vitamins, and Trace Elements Substances

Sources

Outcomes

Comments

Beta-carotene

Foods and dietary supplements



Vitamin C

Foods and dietary supplements Foods and dietary supplements Supplements 1 3 g/d DHA

Negative outcomes on cardioprotective, neuroprotective, anticancer, decreased mortality increased risk of lung cancer espectially in smokers Cancer prevention

Vitamin E Omega-3 EPA/ DHA Selenium Resveratrol

Polyphenols EGCG catechins Lycopene Flavonoid Anthocyanin Curcumin Sulforaphane Genistein Ginkgo biloba

Foods and dietary supplements Food: grape/red wine Dietary supplements Black and green tea Tomato Food (dark black color vegetables and fruits esp. berries) Turmeric Cruciferous vegetables Soybeans Plant leaves Supplement 120 160 mg

Positive outcome could be found only in animal studies on anticancer issues.

Cancer prevention Decreased mortality Antithrombotic Antiarrhythmic Antiinflammation Neuroprotective Cancer prevention 1 /Cardioprotective Cancer prevention 1 /- Cardioprotective Cancer prevention Antioxidant and Cancer prevention Antiinflammation Improve lipid profiles Cancer prevention Cancer protection Antioxidant Antiinflammation Cancer prevention Improves cognitive function



Positive outcomes can be found in animal studies.

Caution: May cause herb drug interaction with antiplatelet and anticoagulant effects

range of adipokines and inflammatory cytokines/interleukin (IL6, IL8) and estrogen/testosterone hormone. Adipokines regulate appetite, insulin sensitivity, angiogenesis, blood pressure, and immune response. Mild to moderate degree of oxidative stress and chronic inflammation is caused by the accumulation of WAT [76,98]. Obesity-induced upregulation of inflammatory cytokines is linked with pathological conditions such as atherosclerosis, CVDs, diabetes mellitus, metabolic syndrome, and various cancers. Metabolic syndrome consists of a cluster of disorders observed in diabetics and excessively obese patients (BMI .35) and produces insulin resistance, impairment in glucose tolerance, hyperlipidemia, and hypertension that causes CVDs and other chronic abnormalities [98]. Currently, the management and treatment of obesity includes lifestyle modifications consisting of increased physical

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activity, decreased calories intake, and antiobesity drugs, as well as bariatric surgery based on BMI indications. In addition to lifestyle modification in every patient, consumption of functional foods and nutraceuticals has been recommended in order to modulate inflammatory processes leading to an increased successful rate of weight loss and obesity-related disease control. The antiobesity role of flavonoids and anthocyanins has been studied in mice and the findings suggest that these substances help to control inflammation and weight gain in mice, however, in obese healthy humans there was no benefit of weight loss [98 100]. It has been reported that anthocyanins from dark or black color fruits and vegetables may decrease inflammatory markers and improve lipid profiles [98,101]. Catechins and EGCG from green tea may assist to control weight gain and benefit obese patients due to their effect on the upregulation of beta-oxidation-related gene and downregulation of lipogenic enzyme expression in liver as well as increased glucose uptake and fatty acid oxidation in muscles [98]. Further, ingredients of green tea may inhibit digestive enzymes, resulting in decreased lipid absorption [98]. In addition, green tea may inhibit maturation processes of adipocytes and enhance apoptosis of preadipocytes and adipocytes [98]. However, clinical relevance of green tea extract in causing weight loss and prevention of disease has not been shown in humans. Resveratrol has shown cardioprotective, neuroprotective, antiinflammatory, and glucose lowering effects in humans, whereas it failed to show any benefits on weight control. Very high daily dose of resveratrol (3.0 g/day) causes liver injury as indicated by increased level of liver alanine-transferase. Further studies need to be done with lower doses of resveratrol to evaluate its antiobesity potential [98]. Saturated trans, n-3, n-6, and n-9 fatty acids can improve lipid profiles and have antiinflammatory effects. In obese subjects, only medium-chain saturated fatty acid or medium-chain triglycerides (MCT) help to decrease visceral adiposity, increase secretion of adiponectin, improve insulin sensitivity and lipid profiles by reduced LDL-c [98]. The antiobesity effects of other functional foods such as minor olive oil components, EPA and DHA, and caffeine have been studied in animal models, but no clinical studies have been done in humans [26,98]. The incidence of neurodegenerative diseases such as dementia and Alzheimer’s disease (AD) has markedly escalated in elderly people. Although genetic factors are considered the primary cause of these diseases, aging processes related to chronic inflammation and oxidative stress may contribute to their pathogenesis [102]. Accumulation of β-amyloid peptide is found in AD. Apart from the advanced age, genetic-related apolipoprotein-E4 as well as nongenetic influences such as elevated serum cholesterol, high intake of saturated fatty acids, and excessive use of alcohol seems to be collectively involved in the pathogenesis of dementia, AD. It has been found that elevated homocysteine, and increased oxidative stress also contribute to the occurrence of brain degenerative disorders [102]. Therefore, plant-derived antioxidant phytochemicals, functional foods, Med-diet type, and Okinawa-type diets may have significant roles in the prevention, management, or treatment of the neurodegenerative diseases. Dietary phytochemicals such as catechins, anthocyanin, curcumin, resveratrol, polyphenols in green tea, grapes, peanuts, berries, and turmeric have been proposed to prevent neurodegenerative diseases [46,102]. Some antioxidant substances like vitamin C, E, carotenoid, zinc, and selenium have been proposed for AD prevention [20,102]. Well designed, placebocontrolled clinical studies in an adequate number of patients are needed to evaluate the safety and efficacy of antioxidants and antiinflammatory agents reported in this review. It has been suggested that vitamin D supplement and omega-3 fatty acids containing EPA and DHA may prevent or slow progression of AD [102]. Ginkgo biloba is a well-tried herbal remedy that is recommended to prevent and treat neurodegenerative diseases. The bioactive ingredients extracted from Ginkgo biloba

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are ginkgolides, sesquiterpene derivative, bilobalide, isoginkgetin, and flavonoids [103]. Its usefulness as a memory and cognition enhancer is still controversial because it does not show any beneficial effects in the healthy population. However, in mild to moderate cognitive impairment, dosages of 120 160 mg of ginkgo extract have revealed some improvement in cognitive function. Side effects include headache, gastrointestinal disturbance, and bleeding as well as interactions with antiplatelet or anticoagulant drugs (aspirin, warfarin, ticlopidine, clopidogrel, dipyridamole) causing increased risk of internal bleeding [103]. Therefore, therapeutic application of Ginkgo biloba requires caution with underlying diseases treated with anticoagulant drugs. Cancers are chronic diseases which put the financial burden on both patients and healthcare providers. According to WHO, 14 million people are diagnosed with a new cancer every year and about two-thirds of these patients die each year [104]. Cancers are caused by multifactorial etiology that involves both genetic and nongenetic mechanisms, however, still there are many unknowns for cancer origin and the underlying processes of cancer development are complex [20]. The contributing risk factors of cancers have shown association between lifestyles and dietary patterns. There is overwhelming evidence that high consumption of fruits and vegetables, legumes and whole grains, low consumption of red meat and processed salty foods, and less sugar can reduce the overall risk of cancers [105,106]. The recommended amount of different fruits and vegetables for cancer prevention is about 600 g/day [105]. Genetic polymorphisms can influence cancer response, and it has been suggested that healthy dietary habits may have an impact on the genetic polymorphisms [20]. As oxidative stress is linked with many chronic inflammatory diseases, food antioxidants and their antiinflammatory ingredients may enhance the prevention of CVDs, cancers, and other chronic diseases. Russo et al. [106] have recently emphasized that antioxidant polyphenols present in fruits and vegetables can protect against cancer and dietary interventions can reduce cancer mortality and morbidity. Elevated serum levels of antioxidant vitamins E, C, and β-carotene may help to lower the incidence of cancers, however, this effect is seen only when these vitamins are taken from dietary sources. The negative impact of vitamin supplements cannot be underestimated, because consumption of β-carotene supplement caused an increased incidence of lung cancer and deaths, especially in smokers and male asbestos workers [106 108]. With respect to the therapeutic effectiveness of antioxidant dietary compounds, the findings of different studies pertaining to cancer risk are still controversial and conflicting, since cancers are very complex diseases and many factors are involved in their pathogenesis. Nevertheless, many bioactive compounds present in natural diets have shown positive effects in cancer prevention and treatment through epigenetic changes [109,110]. For example, EGCG and polyphenol of green tea showed epigenetic effect by inhibiting DNA methyltransferase (DNMT) activity, thereby causing the reversal of tumor suppressor epigenetic silencing of cancer cells as well as inducing apoptosis in cancer cells [109,111]. EGCG can produce downregulation of telomerase activity, and this action may help to fight cancer [39]. Cruciferous vegetables containing SFN can inhibit HDAC and DNMT1 activity, and elicit proapoptotic and antiproliferative effects, leading to cancer protection [39,112]. In addition, other phytochemicals such as curcumin (turmeric), resveratrol (grapes and red wine), and genistein (soybeans) have shown their epigenetic potential in cancer prevention [39,40,109]. Polyphenol, flavonoid, and ECGC are the most studied antioxidants in laboratory animals and humans. Even though administration of several dietary compounds have shown positive outcomes in animals inflicted with cancer, the clinical trials in humans have revealed ambiguous anticancer effects, thus the clinical significance of results obtained remains uncertain [106]. Since the administration of purified antioxidants present in dietary supplements have

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shown more negative than positive effects in humans, no recommendation for antioxidant supplementation can be made for prophylactic cancer prevention in the healthy population. It appears that the intake of a mixture of antioxidants, dietary fibers, and other natural ingredients present in fruits and vegetables, together with changes in lifestyle, may be more effective in the prevention of cancer and other chronic diseases in humans. At present, dietary guideline encourages people to consume different types of fruits and vegetables at least five portions/day [20,92].

32.9 ROLE OF GUT MICROBIOTA, PROBIOTICS, AND PREBIOTICS IN HEALTHY AGING There is growing evidence that the gut microbiota play an important role to maintain good heath, including immune homeostasis, antiinflammation, metabolic function, and neuroendocrine effects in the host’s body. The human gastrointestinal tract, especially the large intestine, harbors about 100 trillion microorganisms (weighing almost 1.5 kg) of diverse species of bacteria, viruses, fungi, archaea, and bacteriophage particles [98]. The intestinal microbes play an important role in nutrients absorption, fermentation of food, stimulation of immune system, and maintenance of gut epithelium barrier function to protect our body from pathogens invasion [113]. Compositions and diversity of gut microorganisms vary in different individuals and at each stage of life [114]. At birth, the composition and diversity of gut microbiota depends on the delivery route. For example, gut microbiomes of vaginally delivered infants seem to be similar to their maternal vaginal organisms, whereas gut microbiomes of cesarean section delivered babies are more similar to maternal skin microbiota [114]. Patterns of gut microbiota in adults are established after 3 years of age and remain stable during adulthood and elderly life [115]. The majority of organisms in adulthoods are Bacteroidetes (B) and Firmicutes (F) [115,116]. However, the ratio of F/B changes when we get older. In elderly folks, there is a large number of Bacteroides compared to younger people who have a higher proportion of Firmicutes [113]. Research data show that the ratio of F/B may influence our health and contribute to many chronic diseases [115]. Health-related changes in the gut microbial composition have been observed in different states of health, viz., more diverse type organisms are encountered in healthy people compared to sick individuals [114]. Recently, Vaiserman and colleagues reported that gut microbiota may be a player in the aging process and may modify life span or longevity [115]. These investigators found that antiinflammatory Firmicutes show a decrease in elderly persons, whereas Bacteroides become more dominant and may contribute to age-related diseases. Even though, the composition of intestinal organisms remains almost similar in younger adults and elderly (70 years-old), the composition of gut microbiota is markedly different in centenarians. Interestingly enough, in relatively younger elderly, there is 10-fold increase in Eubacterium limosum in centenarians, which is the signature bacteria of long life [115]. Gut microbial composition can be modified by diet, lifestyle, antibiotics, environment, and chronic diseases. For instance, different compositions of gut microbiota are noticed in obese and nonobese subjects. Further, it has been observed that the Western-style diet, which contains high fat and sugar, can increase the population of Bacteroidetes, whereas a high fiber diet enhances the amount of Firmicutes [114,117]. The changes in gut microbiota pattern may also affect the host energy metabolism, causing obesity-related metabolomic disorders [114,118]. Dietary patterns (Med-type diet, Okinawa-type diet) can cause alterations in the composition of gut microbiota.

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For example, CR, a well-known dietary intervention used to enhance longer health span and life span, can change the composition of gut microbiota [115]. Alterations in gut microorganisms composition or function have been detected in type 2 diabetes, wherein nutritional interventions may impact on gut microbiota and help to control inflammation and energy homeostasis in diabetic patients [119]. Taken together, the findings of the abovementioned studies suggest that changes in gut microbiota occur with age and dietary interventions, and manipulation of the gut microorganisms may be promising targets and novel therapeutic approaches for boosting host immune function, energy homeostasis, gut barrier functions, reduction of age-related diseases, and promotion of life span. It is well known that probiotics and prebiotics can modulate the composition of gut microbiota and change the biodiversity of health-promoting species in the gut. Probiotics consist of live bacteria present in foods like yogurt, cheese, and buttermilk that confer health benefits on the host. Probiotic foods may reduce the symptoms of irritable bowel syndrome or some types of inflammatory bowel disease and diarrhea from antibiotics. Prebiotics are indigestible oligosaccharides that promote the growth and activities of beneficial bacteria especially in lactic bacteria family in the gut. Synbiotics contain a synergistic combination of prebiotics and probiotics. If someone is unable to consume probiotics due to lactose intolerance, then he/she should look for Lactobacillus and Bifidobacterium in the food ingredients list. Currently, probiotics and prebiotics are being promoted as useful dietary supplements for creating homeostasis of the ecosystem of microorganisms in the colon which is the most metabolically active organ in the body [113]. The nondigestible ingredients of prebiotics promote the growth or activity of one or a limited number of host organisms in the colon and provide benefits to the host’s well-being. Prebiotics are nondigestible food ingredients (e.g., non starch polysaccharides and oligosaccharides) and reach the colon as major substrates for the growth of gut microbiomes [116,120,121]. Three well-known prebiotics are inulin fructo-oligosaccharides (FOS) and galactooligosaccharides (GOS). FOS is able to modify the gut flora composition in favor of bifidobacteria that improve metabolic functions and enhance nonspecific immune responses. Inulin is found in chicory onion, garlic, tomato, and banana. Consumption of FOS containing foods promotes healthy body weight and reduces gut inflammatory disorders by selectively increasing the growth of bifidobacterium [118,121,122]. GOS also increases the number of bifidobacterium, and may also decrease the number of bacteroides [121]. World Gastroenterology Organisation Global guidelines on probiotics and prebiotics in 2017 indicated that consuming short-chain FOS 5 g/day or GOS 3.5 g/day may have control irritable bowel syndrome (evident suggestion in level 2) [123]. Probiotics can resist the effect of lower gastric pH, survive from bile salts and pancreatic enzymes, and after reaching the colon are able to attach to colon epithelium to confer benefit to the host [124 126]. Bifidobacterium and Lactobacillus are two well-known probiotics recommended for improving health and gut immunity [116,124]. Fermented milk, yogurt, and cheese are excellent natural source of probiotics. Yogurt and fermented milk containing several strains of lactic acid bacteria have been tested for various human health issues. Animal studies showed antiinflammatory effects of probiotics resulting from gut cytokine IL-10 induced from the increased population of bifidobacteria [117]. It was reported that the probiotics inhibit cancerous growth in the murine colon through their antiinflammatory action and by increasing the release of IL-10 and by decreasing the activity of procarcinogenic enzymes in the gut [117]. The animal experiments provide some useful clues that regular intake of probiotics may reduce the risk of colon cancer in humans.

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32.10 CONCLUSIONS The primary intent of this review was to identify the potential role of dietary interventions and their underlying mechanisms for the prevention of NCDs, including CVDs, cancers, and brain degenerative disorders associated with genetic and nongenetic factors, oxidative stress, and inflammation that impact upon healthy aging and longevity. Excessive production of ROS and sustained oxidative stress can also cause genetic defects, endogenous inflammation, atherosclerosis, and metabolomic distortion of body homeostasis, and these effects consequently enhance the occurrence of NCDs, including CVDs, diabetes, and cancer. In addition, we have briefly described the benefits of physical activity and lifestyle changes that promote good health. The clinical and epidemiological studies in humans and preclinical investigations in animal models provide strong evidence that dietary interventions can ameliorate chronic stress through antioxidant and antiinflammatory properties, and consequently reduce the risk of cancer, CVDs, diabetes mellitus, obesity, neurodegenerative disease, and other NCDs. The regular intake of healthy food products, including pre- and probiotics, would help to promote good health and well-being, quality of life, and extended life span. The Med-type and Okinawatype diets as well as functional foods containing antioxidants and antiinflammatory agents, and high in fiber content, have proven beneficial in the prevention of CVDs, diabetes mellitus, obesity, cancers, neurodegenerative disorders, and chronic diseases multifactorial in origin. Emerging evidence suggests that dietary supplements containing flavonoids and antioxidants modulate gene and protein expression and thereby modify endogenous metabolic pathways and homeostasis, and consequently reduce the risk of NCDs. Lifestyle modifications such as regular physical activity (about 30 min/day), restriction of caloric intake, lesser amounts of saturated fat and red meat, low sodium chloride, smoking cessation, and moderate alcohol consumption are recommended for improving cardiovascular health and quality of life. The holistic approaches of healthy dietary habits, moderate physical activity, and reduction of psychological stress tend to provide better quality of life, assist to improve overall health, and promote healthy aging and longevity.

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CHAPTER

BENEFICIAL USES OF CINNAMON IN HEALTH AND DISEASES: AN INTERDISCIPLINARY APPROACH

33

Maria Leonor Tavares da Silva1, Maria Alexandra Sardinha Bernardo1, Jaipaul Singh2 and Maria Fernanda de Mesquita1 1

Centro de Investigac¸a˜o Interdisciplinar Egas Moniz, Instituto Superior de Cieˆncias da Sau´de Egas Moniz, Monte de Caparica, Caparica, Portugal 2School of Forensic and Applied Sciences, University of Central Lancashire, Preston, United Kingdom

33.1 INTRODUCTION Herbs and spices have been used for hundreds of years in cuisine for their aromatic properties to enhance the flavor and aroma of food, beverages, chocolates, and liquors [1]. Beyond their culinary uses, herbs and spices have also been used due to their potential functional properties as therapeutic approaches to a number of diseases [2]. Cinnamon is an indigenous spice, belonging to the Lauracea family and it was discovered by the Portuguese in the 16th century in Sri Lanka. Cinnamon was imported to Europe during 16th and 17th centuries. There are several species of Cinnamomum [1,3] including Cinnamomum verum (sym. C. zeylanicum), commonly called “true” cinnamon or Ceylon cinnamon, which is a native from Sri Lanka, or Cinnamomun cassia, which originates from different sources. Other species include Chinese cinnamon (syn. C. aromaticum), a native of China andVietnam; Indonesian cassia (syn. C. burmannii), originating from Sumatra and Java regions; Indian cassia (syn. C. tamala), originating from North Eastern India; and Saigon cassia (syn. C. loureiroi) from Vietnam. Fig. 33.1 shows a typical cinnamon bark (A) and the powder (B). Generally, the bark is golden brown and this can be pulverized into powder. This spice has been shown to possess several functional properties. Some of these properties included a possible protective function in type 2 diabetes mellitus (Allen, Schwartzman et al., 2013), cardiovascular diseases [2], cancer (Lu et al., 2010), and neurological disease [4]. These functional properties of cinnamon are attributed to the antioxidant activity of its bioactive compound—polyphenols, which have been demonstrated to act beneficially in glycemic control [5], lipid profile [6], antiinflammatory activity (Koteswara et al., 2007), and antimicrobial action [7]. This chapter emphasizes the functional properties of cinnamon in health and diseases as one of the most commonly used spices.

The Role of Functional Food Security In Global Health. DOI: https://doi.org/10.1016/B978-0-12-813148-0.00033-5 © 2019 Elsevier Inc. All rights reserved.

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CHAPTER 33 BENEFICIAL USES OF CINNAMON IN HEALTH AND DISEASES

FIGURE 33.1 Images showing (A) bark and (B) powder of cinnamon.

33.2 CHEMICAL COMPOSITION OF CINNAMON The main cinnamon compounds are procyanidin type-A polymers, cinnamic acid, cinnamaldehyde, and coumarin [8,9]. However, it is important to remember that the concentrations of these compounds could depend on different factors, such as species, tree section and its growth stages, and the extraction process, which could consequently influence cinnamon functional properties [8,10]. The main bioactive compounds depend on cinnamon species [8] namely, Cinnamomum verum or Cinnamomun cassia, in which C. cassia demonstrates higher coumarin content [11]. Cinnamon composition also varies upon the tree section (top, center, and lower segments) and on the different growth stages [10]. The top and center segments of the cinnamon bark would be more efficient for oil extraction than the whole bark [10] and at 12-years-old, the cinnamon bark oil has the highest yield in trans-cinnamaldeyde [12]. The bark products have a minimum of this compound at 1-year of growth (33.95%) and a maximum at 6-years of growth (76.4%) [10]. The quantities of each compound also depend on the different solvents used in the extraction process. Table 33.1 shows the major compounds of different species of cinnamon according to the different cinnamon extract and analytical chemical methods, namely highperformance liquid chromatography (HPLC), liquid-chromatography-mass spectrometry (LC-MS), and gas chromatography-mass spectrometry (GC-MS) employed in each study (Fig. 33.2).

33.3 CINNAMON POLYPHENOLS AND ITS ANTIOXIDANT ACTIVITY Culinary spices, especially cinnamon, have been the focus of interest due to their possession of antioxidant and antiinflammatory effects, which are all attributed to high polyphenol contents

33.3 CINNAMON POLYPHENOLS AND ITS ANTIOXIDANT ACTIVITY

567

Table 33.1 Major Compounds Found in Different Cinnamon Species According to Extract and Analytical Methods Cinnamon Extracts

References

Species

(Yang, Chen et al., 2007) [8] [10]

C. cassia

[5] [12]

C. zeylanicum

Aqueous Oil

[8]

C. wilsoni C. mairei C. loureirii C. burmannii

Methanolic

[9]

Aqueousmethanolic Methanolic Oil

Aqueous

[13]

Methanolic

[14]

Oil

[15]

C. osmophloeum

Oil

Major Compounds Identified Protocatechuic acid, ( )-epicatequin, cinamic acid, cinnamaldehyde and eugenol Coumarin, cinnamic acid, cinnamaldehyde, and eugenol Cis-cinnamaldehyde (1.43%), trans-cinnamaldehyde (60%), copaene (7.37%), cinnamyl alcohol acetate (1.18%), gamma-muurolene (1.56%), 2methoxycinnamaldehyde (1.85%), alpha-muurolene (1.92%), beta-bisabolene (1.25%), (1)-delta-cadinene (2.92%), trans-alpha-bisabolene (2.54%), and tetradecanal (0.83% Cinnamyl alcohol and cinnamaldehyde Cinnamaldehyde (97.7%), α-copaene (0.8%), α-amorphene (0.5%), and cadinene (0.9%) Cinnamaldehyde and eugenol Cinnamaldehyde and eugenol Coumarin, cinnamic acid, and cinnamaldehyde Procyanidin Type-A oligomers; chlorogenic acid, ferulic acid, t-cinnamic acid, guiacol, cinnamic acid methyl ester, homovanillic acid, cinnamide, isovanillic acid cinnam, 2-methoxy-cinnamaldehyde, cinnamyl alcohol, 3-methoxy-l-tyrosine, clove oil, 4-oxo-4h-1benzopyan-carboxylic acid, p-coumaric acid, resveratrol, o-coumaric acid, vanillic acid, curcumin, vanillin azine, and eugenol Procyanidin B1 (0.7%), procyanidin B2 (5.12%), procyanidin trimer (13.76%), (1)-catechin (2.61%), procyanidin dimer (1.27%), procyanidin tetramer (2.35%), (-)-epicatechin (1.02%), (E)-cinnamic acid (2.69%), (E)-cinnamaldehyde (62.18%), and (S)cinnamaldehyde (1.95%) Camphor (1.79%), 4-terpineol (0.50%), cinnamaldehyde (2.70%), δ-elemene (2.32%), α-cubebene (1.56%), α-ylangene (0.52%), caryophylene (1.23%), epibicyclosesquiphellandrene (0.44%), calarene (0.94%), β-guaiene (2.14%), aromadendrene (1.47%), α-humulene (0.43%), santalene (0.77%), α-amorphene (5.39%), valencene (0.60%), α-murolene (2.40%), γ-cadinene (0.50%), δ-cadinene (5.98%), patchoulene (0.25%), α-calacorene (1.71%), cyclopentadecane (1.29%), cariophylnenyl alcohol (0.49%), γ-eudesmol (1.28%), T-cadinol (1.15%), α-eudesmol (1.63%), pentadecanol (0.96%), isocurcumenol (0.55%), palmitic acid (2.48%), and elaidinsaeure (7.71%). Linalool (40.24%), trans-cinnamyl acetate (11.71%), camphor (9.38%), cinnamaldehyde (6.87%), 3-phenyl2-propenal (4.06%), caryophyllene (2.65%), coumarin (2.13%)

Analytical Methods HPLC HPLC GC-MS

HPLC GC-MS HPLC HPLC HPLC HPLC

GC-MS and LCMS

GC-MS

GC/MS

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CHAPTER 33 BENEFICIAL USES OF CINNAMON IN HEALTH AND DISEASES

FIGURE 33.2 shows the chemical structures of the main cinnamon compounds including procyanidin type-A polymers, cinnamic acid, cinnamaldehyde, and coumarin.

[16]. Polyphenols are secondary metabolites of the plants and participate against oxidative process. These compounds are contained in different foods and have been of much interest due to their potential health benefits [17,18]. Cinnamon extract and its different isolated bioactive compounds have been demonstrated to possess a potential source of natural antioxidants [19] exhibiting strong free radicals scavenger activity in in vitro models [20,21]. Cinnamon polyphenols have been shown to enchance the superoxide dismutase action, improving the scavenging of oxygen free radicals in organisms and protecting the tissues against oxidative stress injury [22]. Aqueous cinnamon extract (ACE) showed a high total phenolic content (2286.3 mg/L gallic acid) [23], which has been associated with antioxidant activity [24]. The addition of 3 g of cinnamon to mousse increases 3.5 times the phenolic content compared with mousse without cinnamon [25]. In addition, a custard tart containing 3 g of C. burmannii showed high antioxidant activity and revealed 4.4 times more capacity of free radical scavenging compared with custard tart alone [26]. Cinnamon tea can significantly decrease oxidative stress by inhibiting lipid peroxidation level in health subjects [27] and in obese subjects (Roussel et al., 2009). In addition, proanthocyanidins are bioactive components of cinnamon and they have been shown to prevent the formation of advanced glycation-end products (AGEs) [28].

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33.4 FUNCTIONAL PROPERTIES OF CINNAMON ON HUMAN HEALTH Cinnamon has been attributed a high importance due to its antioxidant properties, which may contribute to beneficial effects on human health, protecting against non-communicable diseases [29]. These medicinal benefits include lowering blood glucose [30] and serum cholesterol levels [31], and exerting both antiinflammatory [32] and antimicrobial effects [33].

33.4.1 HYPOGLYCEMIC EFFECT To date, different Cinnamomum species have been shown to improve glycemic response in healthy and type 2 diabetic subjects. In a recent study, it was shown that cinnamon burmannii tea can significantly lower postprandial maximum glucose concentration and variation of maximum glucose concentration on nondiabetic adults [23]. Moreover, cinnamon powder demonstrated beneficial effects after addition to high-sugar foods, decreasing the postprandial blood glucose area under the curve (AUC) [26,34]. In diabetic subjects, administration of aqueous cinnamon extract with oral antidiabetics, three times per day over 4 months seems to decrease fasting blood glucose (FBG) [35]. However, a meta-analysis suggested that Cinnamomum cassia supplementation did not exhibit an improvement on glycemic control in type 2 diabetes mellitus [36]. Based on animal evidence, cinnamaldehyde administration decreased fasting blood glucose levels (FBG) and improved hyperinsulinemia levels [37]. These effects were also observed with cinnamon polyphenols administration in type 1 diabetic animals [38]. Moreover, this bioactive compound of cinnamon could also be beneficial in diabetes disease through decreased glycosylated hemoglobin (HbA1c) [37]. Proantocyanidins, present in aqueous cinnamon extract, have also been reported to have beneficial hypoglyaemic effect [39]. There are several proposed mechanisms for the hypoglycemic effect of cinnamon and its isolated compounds. These include insulin-mimetic action via signaling pathway regulations [40,41]. Cinnamon tea compounds enhanced the GLUT4 translocation by improving glucose uptake in muscle and adipose tissue [5]. Cinnamon extract also promotes glycogen synthesis via downregulation of phosphoenolpyruvate carboxykinase (PEPCK) in the liver [42]. Another possible mechanism of action of cinnamon and its bioactive compounds relating to its hypoglycemic effect is related to a decrease in intestinal glycosidase activity thereby, affecting glucose absorption and postprandial blood glucose level [43].

33.4.2 LIPID LOWERING EFFECT Several studies also have shown that cinnamon can not only lower blood glucose level, but also improve the lipid profile. In animal studies, cinnamon administration can improve lipid profile by decreasing the total cholesterol (TC), triglycerides (TG), and increasing high-density lipoprotein [44]. In spite of these results, human data revealed some controversial results regarding the effect of cinnamon on the lipid profile. According to different studies, either aqueous cinnamon extract or cinnamon powder has little or no beneficial effect on cholesterol comparing to control group [35,45,46]. However, in diabetic patients, the administration of Cinnamon cassia by capsule demonstrated a significantly decreased of TC, TG, and low-density lipoprotein (LDL) after 40 days [47].

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A possible cellular mechanism of action of cinnamon in lowering cholesterol effect is related to lipid metabolism regulation in enterocyte. Cinnamon seems to decrease cholesterol absorption and fatty acid in gut cells through Niemann-Pick c1-like 1 and Cd36 mRNA receptors inactivation, respectively. In addition, the spice also downregulates the chylomicron synthesis [41].

33.4.3 ANTIINFLAMMATORY ACTIVITY Different studies reported an antiinflammatory activity of cinnamon, suggesting beneficial functional properties in the prevention of a number of diseases. Oral administration of aqueous C. cassia extract decreases tumor necrosis factor-α (TNF-α) and interleukin (IL-6) [32]. In a study by Guo et al (2006), they reported that cynnamaldehyde can decrease IL-1β and furthermore, induces gene expression upregulation of cyclooxygenase (COX). Cinnamaldehyde can suppress the proinflammatory nuclear transcription factor NF-kB, which has an important role in inflammation process via signal transduction pathway modulation, IkB kinases (IKKs), ERK kinase, and p38 MAPK [48]. Another possible mechanism suggests that cinnamaldehyde suppresses toll-like receptor 4 activation and inhibits ligand-independent NFkB activation [49]. Similarly, the bark extracts from Cinnamomum osmophloeum induces an inhibition of IL-12 [50]. Although obtaining these promising results in animal models, data from human studies revealed no significant changes in the IL-6 by cinnamon administration compared to the placebo group [51]. In an animal model, 2-methoxycinnamaldehyde, a bioactive compound of cinnamon, has been shown to protect myocardial injuries due to its antiinflammatory properties [52]. Moreover, cinnamic aldehyde and cinnamic acid components also show a cardioprotective effect in ischemic myocardial injury in animals through increases in nitric oxide levels and reciprocal decreases on blood concentrations of TNF-α and IL-6 [53].

33.4.4 IN VITRO ANTIMICROBIAL PROPERTIES In addition to the functional properties of cinnamon described earlier, the spice has also been used in traditional medicine due to its antimicrobial activity by inhibiting pathogen agent growth [54]. One isolated compound of cinnamon extract is cynnamaldehyde and it has been shown to possess antibacterial action, particularly to Staphylococcus aureus, a Gram-positive bacteria [7]. These authors reported that this compound inhibits the cell membrane function, protein synthesis, and nucleic acids synthesis of the pathogenic agent leading to their destruction [7]. An in vitro study showed a high antibacterial activity of C. zeylanicum bark extracts against Klebsiella pneumonia 13883, Bacillus megaterium NRS, Pseudomonas aeruginosa ATCC 27859, S. aureus 6538P, Escherichia coli ATCC 8739, Enterobacter cloacae ATCC 13047, Corynebacterium xerosis UC 9165, and Streptococcus faecalis DC 74 [55]. According to Yap et al. (2013), cinnamon bark can be used effectively as potential natural therapies with conventional antibiotic as a treatment strategy to antibiotic resistance [56]. Cinnamon bark oil also revealed an antibacterial activity against Gram-negative bacteria (E. coli O157:H7, Yersinia enterocolitica O9, Proteus spp., and K. pneumonia) [57].

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33.5 BIOAVAILABILITY OF CINNAMON COMPOUNDS In spite of cinnamon’s high polyphenols content, its biological properties depend on their bioavailability, which can be influenced by many factors, namely, the food preparations process, metabolism, and administration forms [58,59]. Regarding food preparations process, investigations showed that cinnamon cooked (simmered for 1 hour) contained more total phenolic content compared to cinnamon uncooked. However, although there was a slightly increase in phenolic compounds, the thermal process did not seem to affect its antioxidant and antiinflammatory capacity based on percentage of COX-2 inhibition [16]. Moreover, these authors also revealed that the digestion process could also influence cinnamon properties. An in vitro model showed that cooking, followed by digestion, can decrease significantly its antioxidant capacity, but increased significantly its antiinflammatory capacity. Despite these effects, the total phenolic content was not significantly altered by the digestion process [16]. It is interesting to note that there is a significantly strong positive correlation between the total phenolic content and the antioxidant capacity for uncooked, cooked, and digested cinnamon. Baker et al (2013) suggested that the antioxidant capacity of cinnamon may contribute to its antiinflammatory properties. Cinnamon can also be administrated through different forms and routes, which can also influence its bioavailability. The oral bioavailability of cinnamon oil can be improved by liquid loadable table administration due to its poor water soluble property, making it more efficient in disease treatment. The results from animal studies revealed that blood glucose level and HbA1c are significantly decreased with cinnamon oil capsulated as liquid tablets, which is not verified by only cinnamon oil alone [59].

33.6 CINNAMON ADVERSE EFFECTS Some cinnamon constituents have been associated with risky health effects. Coumarin is a compound of cinnamon that has been reported to possess pharmacological activity, such as, antiinflammatory, antioxidant, antihyperglycemic, antiadipogenic, antibacterial, and anticancer properties [60]. However, data from human studies have indicated that this bioactive compound, when exposed to high doses, can result in a considerable hepatotoxicity [61]. In this context, the European Food Safety Authority (EFSA) established a tolerable daily intake (TDI) value of 0,1 mg/ kg body weigh per day to health assessment of coumarin [62]. Coumarin, after oral intake, is rapidly metabolized in the human liver reaching a very low concentration in systemic circulation [63]. This compound of cinnamon is catalyzed by cytochrome P450 2A6 (CYP2A6) to 7-hydroxycoumarin (7OHC), which is also rapidly excreted by urine [64]. The bioavailability of coumarin depends on different factors, such as forms of administration (capsule or contained in cinnamon), dietary applications, and different kinetics [65]. Data from human studies showed that oral intake of coumarin from cinnamon tea produced the fastest uptake of 7-hydroxycoumarin (7OHC) into the plasma, approximately 30 minutes after administration. This is followed by oral intake of coumarin from cinnamon powder containing foods (rice pudding) and coumarin intake from capsule (coumarin-isolated or cinnamon powder)

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[65]. According to these authors, this result suggests that coumarin dissolved in water is rapidly transported to the small intestine for absorption following oral ingestion [65]. The relative extent of coumarin absorption (measured as 7OHC excretion within 8 hours) also is demonstrated to have the highest values (66.1%) by cinnamon tea administration. The coumarin showed lower absorption when administrated in a capsule as coumarin-isolated (62.8%) or cinnamon (56%) and when administrated cinnamon in rice pudding (54.7%). The coumarin administration in capsule form or foods may need more time for the capsule to break down to form molecules, which can be absorbed by the gut. Moreover, the cinnamon powder might have a component which interferes with coumarin absorption since it does not transfer to aqueous solution (tea) [65]. In addition, 105 minutes after administration, 7OHC plasma levels demonstrated the lowest plasma values for cinnamon tea and cinnamon powder in rice pudding revealed that the 7OHC plasma levels from noncapsule administration is more rapidly metabolized, compared to capsule administration. The urinary excretion within the observation period of 8 hours of 7OHC metabolite was demonstrated to be 80.3% on cinnamon tea, 73.4% on cinnamon in rice pudding, 70.5% on cinnamon capsules, and 58.8% on coumarin capsules. These data clearly revealed that more excretion of coumarin seemed to occur when administrated by noncapsule administration [65]. It is also important to note that coumarin content depends on the species of cinnamon. Cinnamomum cassia demonstrated a high content of coumarin (2650 7017 mg/kg) in contrast with Cinnamomum verum samples, which showed very low (trace) coumarin content. An analysis of cinnamon containing bakery food products on the European market demonstrated that several cases of coumarin content seemed to exceed the European Union limits [11]. In Europe, United States, and Canada the species Cinnamomum cassia is used more widely than Cinnamomum verum (true cinnamon or Ceylon cinnamon). In the United States, cinnamon from C. burmannii corresponded to 90% of imported cinnamon [66]. In conclusion, this short review outlined briefly the functional properties of cinnamon and its isolated compounds in health and diseases. It also described some adverse effects when employed in large quantities.

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[64] Khayyat MH, Vahdati-mashhadian N, Eghbal S. Inter-individual variability of coumarin 7-hydroxylation (CYP2A6 activity) in an Iranian population. Iran J Basic Med Sci 2013;16:610 14. [65] Abraham K, Pfister M, Wo¨hrlin F, Lampen A. Relative bioavailability of coumarin from cinnamon and cinnamon-containing foods compared to isolated coumarin: a four-way crossover study in human volunteers. Mol Nutr Food Res 2011;55(4):644 53. [66] Wang Y-H, Avula B, Nanayakkara NPD, Zhao J, Khan IA. Cassia cinnamon as a source of coumarin in cinnamon-flavored food and food supplements in the United States. J Agric Food Chem 2013;61 (18):4470 6 8.

FURTHER READING Allen RW, Schwartzman E, Baker WL, Coleman CI, Phung OJ. Cinnamon use in type 2 diabetes: an updated systematic review and meta-analysis. Annu Fam Med 2013;11(5):452 9. Lu J, Zhang K, Nam S, Anderson A, Jove R, Wen W. Novel angiogenesis inhibitory activity in cinnamon extract blocks VEGFR2 kinase and downstream signaling. Carcinogenesis 2010;31(3):481 8. Roussel A-M, Hininger I, Benaraba R, Ziegenfuss TN, Anderson RA. Antioxidant effects of a cinnamon extract in people with impaired fasting glucose that are overweight or obese. J Am Coll Nutr 2009;28 (1):16 21. Yang J, Chen L-H, Zhang Q, Lai M-X, Wang Q. Quality assessment of cortex cinnamomi by HPLC chemical fingerprint, principle component analysis and cluster analysis. J Sep Sci 2007;30(9):1276 83.

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DEVELOPMENTS ON THE APPLICATIONS AND THE SUITABILITY OF FUNCTIONAL FERMENTED SOUR SOBYA AS A VIABLE SOURCE OF NOVEL PROBIOTICS IN THE MANAGEMENTS OF GASTROINTESTINAL DISORDERS AND BLOOD LIPID PROFILES

34

Laila Hussein1 and Ram B. Singh2 1

2

Department of Nutrition, National Research Center, Cairo, Egypt Halberg Hospital and Research Institute, Moradabad, Uttar Pradesh, India

34.1 INTRODUCTION The impact of the intestinal microbial community on human health is currently an expanding field of research. The colon is viewed as a metabolic organ and the human colonic microbial flora is estimated to weigh about 1 3 kilograms and may contain 1016 1017 colony forming units representing more than 500 strains with a wide variety of functions in nutrition, immunology and metabolism [1]. Culture-independent methods for characterizing the microbiota, together with a molecular phylogenetic approach to organizing life’s diversity provided a fundamental breakthrough in allowing researchers to compare microbial communities across environments within a unified phylogenetic context. The concept of the human microbiome was first introduced to the scientific community by Lederberg [2], who defined it as the ecological community of commensal, symbiotic, and pathogenic microorganisms that literally share the body space and are determinants of health and disease. The remarkable diversity of the human colonic microbiota at the level of bacterial species and phylotypes has become apparent from 16 S rRNA based analyses [3]. Gut microbiota is mainly composed of seven bacterial divisions, namely, Firmicutes, Bacteroides, Proteobacteria, Fusobacteria, Verrucomicrobia, Cyanobacteria ,and Actinobacteria; whereby, phylotypes Firmicutes and Bacteroides are among the most abundant species. Typical human colonic microbiota from a given fecal sample measured by The Role of Functional Food Security In Global Health. DOI: https://doi.org/10.1016/B978-0-12-813148-0.00035-9 © 2019 Elsevier Inc. All rights reserved.

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sequencing 16 S rRNA contains hundreds of phylotypes [4] and samples from different unrelated individuals show limited overlap in the phylotypes present. Identifiable core sets of genes and pathways are a more highly conserved microbiome and are shared in each individual than microbial composition. Unlike the human genome, its gene pool can be induced by changing the environmental conditions, such as food intake, affecting the composition and function of the intestinal microbiota. The Perturbations of core microbial functions, rather than core microbial communities, may be associated with alterations in physiological or disease states [5 7].

34.2 POST-NATAL DEVELOPMENT OF GUT MICROBIOTA Born sterile, the neonatal period is crucial for undergoing intestinal colonization within a few days by different types of bacteria (Fig. 34.1). The Gestational age, type of delivery, and feeding affect the stool flora of young infants. One of the most important tasks of postnatal development is

FIGURE 34.1 Dependence of the composition of gut microbiota from the stage of life.

34.2 POST-NATAL DEVELOPMENT OF GUT MICROBIOTA

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the acquisition from the environment of an intestinal microbiota capable of performing beneficial functions, while at the same time developing a mucosal immune system capable of tolerating desirable community members and also discouraging pathogens. Infants born vaginally apparently acquire their gut flora from maternal vaginal and fecal flora, but the environment also contributes. For the colonization of infants born by cesarean delivery (CD), gut colonization is delayed in infants, and intestinal colonization is consequently abnormal for several weeks. A study included 64 healthy newborn infants of healthy mothers; 34 vaginal delivery (VD) infants and 30 infants by elective CD were enrolled for follow up fecal examination [8]. The results demonstrated that the fecal flora of infants born by CD with prophylactic antibiotics administered to the mother is very different from that of infants delivered vaginally. The greatest differences were seen in the bacteria of the Bacteroides fragilis group, which was only half that of infants in the VD group (36% and 76%, respectively; p 5 0.009). The long-lasting changes seen in the primary gut flora of infants born by CD could be the result of one or both of the two abnormal components of their birth [8], CD itself or the prophylactic ampicillin administered to the mother 2 hours before the elective CD. Ampicillin is very poorly protein-bound and crosses the placenta readily: maternal and fetal serum ampicillin levels equilibrate within 1 hour after intravenous administration. The infants born by CD had a higher colonization rate of Clostridium perfringens than the VD group of infants at 1 month (57% and 17%, respectively). The presence of Clostridium perfringens in the gut is associated with an increased incidence of gastrointestinal signs, such as flatulence, distended abdomen, foulsmelling stools, and diarrhea. Normal intestinal flora has immunostimulatory functions and when probiotic bacteria belonging to the normal intestinal flora have been administered orally to children in association with diarrhea, an increase in antigen-specific and nonspecific IgA and IgM responses has been detected. Secretory IgA and IgM are the main humoral mediators of mucosal immunity in cooperation with a variety of innate protective mechanisms. Well-functioning mucosal immunity is a prerequisite for health, because the mucosal surfaces are favored as portals of entry by most infectious agents, allergens, and carcinogens. Favier et al. in 2002, using genomic PCR analysis, characterized the gut microbiota from birth and found that soon thereafter, bacterial colonization of a previously infant gut intestinal tract begins [9]. The gut microbiome of a vaginally delivered full-term breastfed infant is rapidly colonized immediately after delivery and it was dominated by bifidobacteria after just a few days on a milk diet. Bifidobacteria represent up to 80% in infants and are regarded among the beneficial members of the human gut microflora. Bifido bacteria have enzymes suited to extracting energy from milk oligosaccharides, production of short-chain fatty acids, and lowering of the pH in the colon, favoring colonization by anaerobes. Bifidobacteria have been shown to inhibit the growth of pathogenic bacteria, modulate the immune system, produce digestive enzymes, repress the activities of rotavirus, and restore microbial integrity of the gut microbiota following the antibiotics therapy [9]. The very early colonization by Enterobacteria and Streptococcus appearance in feces generates a low redox environment that allows anaerobic bacterial species to flourish. A more diverse microbiota develops after dietary supplementation commences. In contrast, the intestines of formula-fed infants are colonized by members of a variety of bacterial genera, including entero bacterial genera, Streptococcus, Bacteroides, and Clostridium, in addition to members of the genus Bifidobacterium. This characteristic succession continues until after weaning, when a dense, complex, more stable microbiota becomes established. Although exposure to microorganisms at different stages of infant development shapes the assembly of the microbiome, clearly, the diet at these

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stages also plays a major role. The addition of solid food to the infant diet is accompanied by the appearance of a more diverse community of bacteria, capable of digesting starch, fiber, complex plant polysaccharides, sulfated glycoproteins, and mucins. A complex diet encourages the establishment of a mature microbiota capable of performing a diverse set of metabolic tasks. Odamaki et al. studied the abundance of genus-like groups of three age clusters, infant, adult and elderly-related reshaping of gut microbiota [10]. The authors reported higher relative abundance of Actinobacteria and Clostridia in infant and adult cluster, while the elderly cluster showed significantly higher abundances of Bacteroidetes, Beta proteobacteria, and Delta proteobacteria. Bifidobacteria counts decline during old age, coinciding with a proliferation of other bacterial groups, including clostridia and members of the Enterobacteriaceae family. Consequently, increasing bifidobacterial counts may be advantageous for controlling the proliferation of certain undesirable bacteria [11]. Elements of a modern lifestyle, such as diet, domestic hygiene, urbanization, antibiotic usage, and family size, may represent proxy markers of environmental influence on the composition of the microbiota colonizing the host in early life [12,13]. The most comprehensive study to date of gut bacterial communities in multiple geographic locations was demonstrated by a study comparing healthy children, from 1 to 6 y of age, in Burkina Faso and Italy [14]. The Burkina Faso diet was low in fat, low in animal protein, and high in starch, fiber, and plant polysaccharides; the Italian diet was high in fat, animal protein, starch, and simple sugars but low in fiber. The microbiota of children being breastfed resembled each other more than older children from either country, but the microbiota of the older children were clearly differentiated by country of origin. The genera found exclusively in the Burkina Faso children (Xylanibacter, Prevotella, Butyrivibrio, and Treponema) have genomes rich in enzymes for fermenting the indigestible plant polysaccharides xylan, xylose, and carboxymethylcellulose; Another study compared Amerindians from Venezuela, rural Malawians, and urban Americans [15]. The phylogenetic composition of all fecal samples was determined by sequencing 16 S rRNA gene amplicons; a subset of 110 samples was subjected to shotgun sequencing to characterize genomic functional capability. In all countries, children had more interpersonal variation in composition than adults, and the phylogenetic composition coalesced toward an adult-like configuration over the first 3 y from birth. The early loss of Enterobacteriaceae, the gain in infants of oligosaccharidedegrading anaerobes and methanogenic bacteria, and the decline in relative abundance of Bifidobacterium longum with age appeared to be universal. Significant differences in microbiota were found between the three countries, with the US population being most distinct [15]. The adults had gut microbial genes for metabolizing dietary folate, while the gut microbes of babies were enriched in genes for de novo folate synthesis, reflecting the dependence of children on bacterial vitamin production prior to dietary intake of plant material. Microbial genes for B12 biosynthesis increased with age; because certain bacteria are the primary source of B12, the acquisition of those species in childhood is essential to avoid B12 deficiency. In terms of differences between geographic locations, in the non-US cohorts, microbial vitamin B was more active. Recently, the distal gut microbiota composition and functions and intestinal metabolites of Egyptian and US teenagers were profiled by shotgun sequencing [16]. The results showed that all Egyptian gut microbial communities belonged to the Prevotella enterotype, whereas all but one of the U.S. samples was of the Bacteroides enterotype. The intestinal environment of Egyptians was characterized by higher levels of short-chain fatty acids, a higher prevalence of microbial polysaccharide degradation-encoding genes, and a higher proportion of several polysaccharide-degrading

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genera. Egyptian gut microbiota also appeared to be under heavier bacteriophage pressure. In contrast, the gut environment of US children was rich in amino acids and lipid metabolism-associated compounds; contained more microbial genes encoding protein degradation, vitamin biosynthesis, and iron acquisition pathways; and was enriched in several protein and starch-degrading genera. Levels of 1-methylhistamine, a biomarker of allergic response, were elevated in US guts, as were the abundances of members of Faecalibacterium and Akkermansia, two genera with recognized anti-inflammatory effects. The revealed corroborating differences in fecal microbiota structure and functions and metabolite profiles between Egyptian and US teenagers are with the nutrient variation between Mediterranean and Western diets [16]. Egyptian children consumed a Mediterranean diet rich in plant foods, US children consumed a Western diet high in animal protein, fats, and highly processed carbohydrates. Consistent with the consumed diets, Egyptian gut samples were enriched in polysaccharide-degrading microbes and end products of polysaccharide fermentation, and US gut samples were enriched in proteolytic microbes and end products of protein and fat metabolism. Thus, the intestinal microbiota might be selected on the basis of the eaten diets, which can open opportunities to affect gut health through modulation of gut microbiota with dietary supplementations.

34.3 MALNUTRITION IN CHILDREN AND IMPACT ON THE COMPOSITION AND FUNCTION OF THE GUT MICROBIOTA A handful of studies have characterized the microbiota of healthy children, even fewer have addressed malnourished child. Globally, one in ten child deaths result from diarrheal disease during the first 5 years of life [17]. Alterations in the micobiomes of Indian malnourished and stunted children were reported [18]. The microbiota of stunted Indian children was enriched in inflammogenic bacteria belonging to the Proteobacteria phylum, whereas Bifidobacteria longum was abundant in the gut of nonstunted children [19]. Children suffering from malnutrition had alterations in the gut microbiome, which delayed the normal development of the gut microbiota in early childhood or forced it toward an altered composition that lacks the required functions for healthy growth and/or increases the risk for intestinal inflammation [20]. Marked differences were reported in phylogenetic composition of the microbiota from Bangladesh acutely malnourished children 2 3 y old whose, gut Proteobacteria were 9.2 times higher compared with that present in healthy children. The α-diversity (complexity within a sample) of the microbiota was significantly lower among the malnourished children, while species-rich intestinal communities are more resistant to invasion by pathogens. The antibiotic treatment was detrimental on the status of children suffering from chronic nutritional deficits or repeated enteric infections and could be at risk of developing a stable degraded microbiota as a result of persistent stressors. One of the difficulties in comparative studies of the microbiota is the number of variables potentially influencing community composition. To reduce confounders, Smith et al. enrolled 315 Malawi twin pairs children over the first 3 y of their lives, because at this age twins shared both genetics, diet, and exposure to environmental microbial reservoirs; nine well-nourished twin pairs and 13 pairs discordant for kwashiorkor were selected for in-depth functional metagenomic analysis of their fecal microbiomes [21]. The investigators showed that the microbiomes of the healthy

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twins followed a developmental trajectory of progression toward older children’s microbiota, those of the kwashiorkor twins failed to mature (http://www. unicef.org/Malawi/children.html. Fecal samples were collected from a cohort of children with consistently healthy growth from birth up to 24 months, to monitor and regress the relative abundances of the fecal bacteria against the age of the child at the time of sample collection [22].The authors developed an index consisting of a set of the 24 most “age-discriminatory” (most significantly age correlated) taxa, which became the basis for a model, which defines “microbiota age.” Based on the parameter, two novel metrics were derived, “relative microbiota maturity” (the difference between the microbiota age of a child and the microbiota age of healthy children of the same chronological age) and a “microbiota-for-age z score.” The model was verified by applying it to a second cohort of Bangladeshi children and then to a previous study of healthy children in Malawi, suggesting that it may have a universal utility. Stunting may also be viewed as an adaptive response in which, under conditions of starvation, height gain is sacrificed in order to sustain weight and energy. (Fig. 34.2) Intestinal barrier integrity is maintained by tight junction proteins between adjacent epithelial cells and increased intestinal permeability has been associated with dysbiosis. Dysbiosis is a state characterized by alteration in microbiota composition consisting of absence of the species that efficiently process foods, or produce short-chain fatty acids, and could lead to malnutrition even in the face of adequate food intake [23]. The damage could be from any number of causes, including viral, bacterial, or parasitic infection or environmental toxins [23]. Microbiota lacking the organisms linked to decreased mucosal inflammation or induction of antimicrobial peptides could result in reduced nutrient absorption secondary to chronic inflammation. In turn, inflammation can promote the growth of Enterobacteriaceae [24,25]. In the developing world where protein deficiency is common, protein malnutrition can result in changes in the colonic microbiota that are not manifested until the epithelium incurs some form of damage. Conversely, malnutrition has been shown to result in dysbiosis [26].

FIGURE 34.2 Dietary and environmental factors leading to progression of leaky gut (dysbiosis).

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The presence of pathogenic bacteria can cause epithelial damage and/or diarrhea, with a deleterious effect on absorption. Certain hydrogen-scavenging bacteria produce hydrogen sulfide, which can be toxic to the epithelium. Dysbiosis has been linked to a number of disease states and is quantified by a “Microbial Dysbiosis Index” [22,27].

34.4 MICROBIOTA-BASED THERAPEUTIC INTERVENTIONS Three approaches to microbiota manipulation are currently available: probiotics, prebiotics, and synbiotics. Today foods are not intended to only satisfy hunger and to provide necessary nutrients for humans but also to prevent nutrition-related diseases and improve physical as well as mental well-being of the consumers. The consumers expect specific properties of food and create a demand for food products associated with health benefits. Health promotion and disease prevention are increasingly recognized as crucial to Europe’s health challenges. Modern nutritional science is providing ever more information on the functions and mechanisms of specific food components in health promotion and/or disease prevention [28] Today’s busy lifestyles are also driving modern biotechnology to the use of fermentation, extraction, encapsulation, fat replacement, and enzyme technology to produce new health food ingredients, reduce or remove undesirable food components, add specific nutrient or functional ingredients, modify food compositions, mask undesirable flavors, or stabilize ingredients. Designing effective preventive strategies aiming at reducing the risk of chronic diseases is a cost-effective safer initiative for primary and second prevention [29]. Ensuring the food safety is an integral part of food security alongside the entire agrifood chain to reduce food-borne illnesses and outbreaks that account for 50% of the identified indirect drivers of food insecurity. (Fig. 34.3)

34.5 PROBIOTICS The original observation of the positive role played by certain bacteria was first introduced by the Russian scientist Metchnikoff, a professor at the Pasteur Institute in Paris and Nobel laureate, who observed that Bulgarian farmers who lived largely on milk fermented by lactic-acid bacteria (LAB) were exceptionally long-lived. Based on these facts, Metchnikoff proposed that consumption of fermented milk would “seed” the intestine with harmless lactic-acid bacteria and decrease the intestinal pH and that this would stop the production of the toxic compounds including phenols, indols, and ammonia produced from proteolytic bacteria such as clostridia and responsible for what he called “intestinal auto-intoxication,” which caused the physical changes associated with old age. Lactobacillus bulgaricus and Streptococcus thermophilus are well-known LAB and starters of yoghurt with great industrial value [30] Tissier who also worked at the Pasteur Institute discovered and isolated the Bifidobacterium spp. in 1899 and later 34 Bifidobacterium isolates have been isolated from baby feces among which six showed antilisterial activity against Listeria monocytogenes. Bifidobacteria belongs to the Bifidobacteriaceae family and the Actinobacteria class and it was detected in 85% of the infants in 108 to 1011log10 colonies forming units per g feces [31,32,33]. Bifidobacterium thermophilum was also isolated from infant feces with moderate tolerance to oxygen and was tolerant up to 47 C.

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FIGURE 34.3 Molecular structure of the intracellular junction of intestinal epithelial cells. The tight junctions (TJs), multiple protein complexes, locate at the apical ends of the lateral membranes of intestinal epithelial cells. The TJ complex consists of transmembrane and intracellular scaffold proteins. The transmembrane proteins (claudins, occludin, and junctional adhesion molecules [JAMs]) create a permselective barrier in the paracellular pathways. The intracellular domains of the transmembrane proteins interact with the intracellular scaffold proteins such as zonula occludens (ZO) proteins, which in turn anchor the transmembrane proteins to the actin cytoskeleton (Reference: 84. Lee SH, Intestinal permeability regulation by tight junction: Implication on inflammatory bowel diseases. Intest Res. 2015;13:11 18.

Bifidobacteria represent a commensal group among the GIT-resident (mucosa-adherent) bacteria, which constitutes 80% of the infant and less than 10% of the human adult microbiota. The presence of Bifidobacterium in the gut is often associated with health-promoting effects [34]. Clinical benefits from treating diarrhea in infants with Bifidobacteria are related to competitive colonization of Bifido to the invading pathogenic proteolytic bacteria. Probiotics were first introduced in 1953 and were defined as microbially derived factors that stimulate the growth of other microorganisms. In 1989 Roy Fuller and Gibson [34]. suggested a definition of probiotics which has been widely used: “A live microbial feed supplement which beneficially affects the host animal by improving its intestinal microbial balance,” emphasizing the requirement of viability for probiotics and introducing the aspect of a beneficial effect on the host. Guidelines for the optimum uses of probiotics were reported by a FAO/WHO joint working group [35]. Lactobaccilli and Bifido are the most popular

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Table 34.1 Suggested Beneficial Actions of Probiotics on the Host Serial

Beneficial Actions

1 2 3 4 5 6 7 8 9 10 11

Antimicrobial activity Colonization resistance Immune effects Adjuvant effect Cytokine expression Stimulation of phagocytosis by peripheral blood leukocytes Secretory IgA Antimutagenic effects Antigenotoxic effects Influence on enzyme activity Enzyme delivery

probiotic species available on the market today reported to regulate inflammation, suggesting their ability to modulate the function of immune-related cells [36]. Microbial metabolites may possess genotoxic, mutagenic, or carcinogenic activity and contribute subsequently to the development of cancer over a period of long-term exposure. It is the recognition of the effects of colonizing microbes in association with the human body, and the combination of wanting to encourage the positive and discourage the negative activities of commensal bacteria. Furthermore some infections, once thought to be benign and self-limiting or readily treatable with antibiotics, are now recognized as more serious health threats. Campylobacter jejuni is now believed to be the leading cause of bacterial gastroenteritis. Other food-borne pathogens have become prevalent and life-threatening, including Shiga-like Escherichia coli strains. Multiple antibiotic resistance is a continual threat in the battle against once treatable infections. Vaginosis is now recognized to be associated with lowbirthweight infants, preterm delivery. Demographic trends have indicated the increase in populations of the immune compromised, including the elderly, organ transplant recipients, chemotherapy patients and many others. Because of these emerging microbial threats, a safe, low-risk approach that adds a barrier to microbial infection or to the negative influences of indigenous colonizing microbes may be significant to human health. Probiotic bacteria have been suggested to play a role in a variety of health effects, and mechanisms proposed for mediating these effects are numerous and are given in Table 34.1. Numerous commercial probiotics products are on the retail markets and they are produced by different multinational companies as shown in Table 34.2.

34.6 TRANSCRIPTIONAL CHANGES AS FUNCTION OF PROBIOTIC BACTERIA INTAKE The 21st century will witness the mutation of nutrition research from molecular nutrition to nutritional systems biology. Indeed, nutrigenomics is already deciphering the interaction of food with human organisms and nutrigenetics is evaluating the contribution of individual genetic

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Table 34.2 List With the Most Commonly Used Probiotics and the Respective Manufacturers Serial Number

Commercial Trade Name

Manufacturer

1 2 3 4 5 6 7 8 9 10

B.bifidoanimalis lactis (activia) L. casei strain dn-114001 () B. animalis dn 173010 L. johnsonii la7 L. acidophilus ncfm L. reuteri L. plantarum 299 v L. rhamnosus 271 L. rhamnosus gg L. caseishirota

Danone Danisco Danisco Nestle Nestle Biogaia Probi ab Probi ab Valio Yakult

configurations to this interaction. An in vivo study was carried out to assess probiotic mechanisms on duodenal mucosal transcriptional responses of healthy adults after 6 h of continuous infusion of one of the three widely used probiotic strains Lactobacillu acidophilus, L. casei, and L. rhamnosus in dosages of 1010 CFU. According to the information provided by the ConnMap analyses and data bases person-to-person variation in gene expression showed the largest determinant of differences between transcriptomes, while genes that play central roles in regulatory networks showed little variation between individuals [37]. The investigators found that consumption of L. rhamnosus GG and its secreted proteins coregulate epithelial homeostasis and may promote innate immune responses against intestinal infections.

34.7 THE USE OF PROBIOTICS IN RESTORING THE GUT PERMEABILITY (GUT TIGHT JUNCTION) The healthy intestinal mucosa represents a large efficient absorptive surface with a powerful barrier (gut barrier function 5 intestinal permeability) to permeation of potential food antigens and bacteria invading the body. Tight junctions are highly regulated macromolecular structures that link epithelial cells to one another forming an intracellular barrier. Bacterial metabolism of dietary and endogenous substances generates wide range of metabolites that may have beneficial or harmful effects on the host [38]. Hence, bacteria and their community structure affect mucus barrier properties. Higher levels of Proteobacteria and TM7 bacteria in the distal colon mucus mice were characterized by a penetrable mucus layer in ways that can have implications for health and disease [39,40]. Epidemiological data pointed out that probiotics may induce beneficial changes in intestinal tight junction integrity by reducing the levels of microorganisms such as E. coli, and Salmonella that attack tight junctions. Restoration and maintenance of the tight junctions, restrict pathogens into the bloodstream. Asymptomatic Egyptian children are characterized with significant demarcated variations in the intestinal permeability (IP) and absorptive

34.7 THE USE OF PROBIOTICS IN RESTORING THE GUT PERMEABILITY

589

FIGURE 34.4 Individual initial and final urinary lactulose:mannitol ratio among the control and the probiotic groups.

capacity compared with age-matched Europeans. Evidence has demonstrated the important implication of geography, the environmental factors, and the gross domestic product per capita on the absorptive capacity; and their association with a higher recovery of urinary lactulose [41,42] A dietary intervention study was carried out to evaluate the impact of the probiotic Lactobacillus acidophilus L1a on upregulating the disordered intestinal function among Egyptian children [43] Free-living children of both sexes with mean age of 11 years were recruited and consumed daily the probiotic in yoghurt matrix for 42 days. The daily serving provided 1012 colonies forming units in the yoghurt matrix. At days zero and 42 the standard urinary lactulose mannitol dual test (LMDT) was carried out on all children as the criteria of assessment. Urinary L and M were analyzed by liquid chromatography for calculating [L] / [M] ratio based on amounts excreted in the urine as % of the intakes. The results showed that one-third of the children had [L/ M] .5.3 and the dietary intervention with L. acidophilus L1a in yoghurt matrix restored the IP to the normal ranges between 2 3 as shown in the figure below (Figure 34.4). Normal [IP] expressed as %L/M recovery are in the range of 2 3 in 4-year-old children [44,45]. Mohammad et al. evaluated further the impact of the same probiotic Lactobacillus acidophilus L1a in yoghurt matrix on improving the biochemical status of vitamin B12 and folate, and the metabolic marker total homocysteine (t-Hcy) at the end of the 42-day dietary intervention [44]. Blood samples were collected at days zero and 42 for the microbiological assays of plasma vitamin B12

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and folate and the fluorescence polarization immunoassay of t-Hcy. The results showed that initially 33.3% of the children were presented with biochemical vitamin B12 deficiency (,208 pg/mL equivalent to ,220 pmoles/L), while one-fifth (21%) were biochemically deficient in folate (,3 ng/mL folate/ml plasma or 0.68 nmoles/L). The 42-day dietary intervention with probiotic La1 yoghurt resulted in significant improvements in the mean levels of plasma vitamin B12 (P ,0.05) and folate (P ,0.01) among the studied children compared with the respective baseline data. Fifty percent of the children were presented with high plasma t-Hcy ( . 15.0 mmol/L), which was reduced significantly (P , 0.05) at the termination of the 42-day dietary intervention, compared with the respective initial mean levels. The fact that the biochemical status of the vitamins improved following the intake of the probiotic LAB is in line with earlier studies reporting that the bacterial flora in the colon produce all of the B vitamins. Based on their findings, the authors concluded that the consumption of the probiotic L. acidophilus La1, a natural inhabitant of the nonpathogenic gut flora still used in different foodstuffs, successfully manipulated the colonic microflora, leading to an improvement in the overall nutritional status of the children under study. The main cause for getting pediatric diarrhea is the ingestion of food not having the appropriate standard regarding the hygienic condition. The hygienic standard of a food is based on the processing and handling of the food, as well as on the conditions of the raw materials. A food item prepared from water contaminated with pathogenic microorganisms will successively be contaminated, and poses a health risk. The probiotics Lactobacillus rhamnosus GG and the yeast Saccharomyces boulardi are the two most commonly used probiotics in the management of diarrhea. Meta-analyses of clinical studies reported that oral intake Lactobacillus rhamnosus GG as a probiotic consistently shortened the diarrheal phase of rotavirus infection by one day with no reported adverse events [45]. The outcome of these studies could provide more insights in specific health benefits brought by fermented foods produced by controlled fermentation, including so called locally sourced probiotics [46]. Antibiotic-associated diarrhea (AAD) results from an imbalance in the colonic microbiota caused by antibiotic therapy. Microbiota alteration changes carbohydrate metabolism with decreased short-chain fatty acid absorption and an osmotic diarrhea as a result. Another consequence of antibiotic therapy leading to diarrhea is overgrowth of potentially pathogenic organisms such as Clostridium difficile. Efficacy of probiotic AAD prevention is dependent on the probiotic strain(s) and on the dosage used. Some probiotics have been shown to be beneficial in preventing and treating various forms of gastroenteritis. They reduce both the frequency of stools and duration of illness. Up to a 50% reduction of AAD occurrence has been found with no side-effects in any of the reported studies. Fermented milk products (such as yogurt) also reduce the duration of symptoms. However, caution should be exercised when administering probiotic supplements to immunocompromised individuals or patients who have a compromised intestinal barrier. Probiotic treatment can reduce the incidence and severity of AAD as indicated in several meta-analyses. From the ecological perspective, a single bacterial strain is not likely to radically alter the established intestinal community, which in adults typically consists of hundreds of different species-level phylotypes that represent approximately ten bacterial phyla, vastly dominated by Firmicutes, Bacteroidetes. Further documentation of these findings through randomized, double blind, placebo-controlled trials are warranted. The introduction of probiotics as dietary functional fermented supplements has been seen as a means to ensure a reduction in different aspects of malnutrition and promote nutrition in various forms [48]. Its use is currently an attractive strategy to upregulate disordered intestinal function and

34.8 PROBIOTIC INFLUENCE ON PLASMA LIPID PROFILE PARAMETERS

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to improve nutritional status. Experiments into the benefits of probiotic therapies suggest a range of potentially beneficial medicinal uses for probiotics. For many of the potential benefits, research is limited and only preliminary results are available. Recent research on the molecular biology and genomics of Lactobacillus has focused on the interaction with the immune system, anticancer potential, and potential as a biotherapeutic agent in cases of antibiotic-associated diarrhea, travelers’ diarrhea, pediatric diarrhea, inflammatory bowel disease, and irritable bowel syndrome. All effects can only be attributed to the individual strain(s) tested. Testing of a supplement does not indicate benefit from any other strain of the same species, and testing does not indicate benefit from the whole group of LAB (or other probiotics). Bifidobacterium animalis is the most common probiotic species used in foods, as it possesses the highest tolerance to oxygen and acids. The continued adaptation of this species to the fermented dairy environment resulted in the evolution of a subspecies of B. animalis subsp. lactis strain Bb-12, which is commercially available as a probiotic on the retail market and is exclusively supplied by Chr. Hansen Inc., a worldwide supplier of fermentation cultures. Bifidobacteria are generally believed to contribute to good intestinal health, and attempts have been made to increase their numbers in the intestine by including them in certain foods as probiotics. They are frequently included in yogurts together with prebiotics, such as inulin or fructo oligosaccharides, the combination of which can be referred to as a symbiotic yogurt. Studies on Bifidobacteria Bb-12 ingestion reported it maintained the intestinal microbial balance and it is implicated in the prevention and treatment of diarrhea, the development and maintenance of a healthy microbiota in low-weight preterm infants, the stimulation of certain immune responses of the phagocytic activity in peripheral blood samples, and treatment of atopic eczema in infants

34.8 PROBIOTIC INFLUENCE ON PLASMA LIPID PROFILE PARAMETERS AND GUT MICROBIOTA METABOLISM Hypercholesterolemia and hypertension are the main risk factors for cardiovascular disease and are considered the leading cause of death all over the world. According to the World Health Organization (WHO) about 23.6 million people will be affected by cardiovascular disease by the year 2030. Pharmacological agents that effectively reduce cholesterol levels are available for the treatment of high cholesterol; however, they are expensive and are known to have severe side effects [47]. The promotion of a healthy lifestyle with nonpharmacological means is a preventive measure strategy aiming at ideal CV health [48]. Some studies have shown that the intestinal microbiota can regulate host lipid metabolism via numerous microbial activities. The daily consumption of 300 g/day of yoghurt supplemented with L. acidophilus 145 and B. longum 913 by 29 women for 21 weeks was associated with significant increase in the level of HDL-cholesterol with a concomitant significant decrease in the ratio of LDL/ HDL-C. The hypocholesterolemic effect was demonstrated following the consumption of wild Lactobacillus fermented milk with probiotic activities and the reduction included concentration of total cholesterol (TC) and LDL-C [49]. Lactobacillus plantarum strains are potential probiotic cultures with cholesterol-lowering activity for the management of hypercholesterolemia. Lactobacillus rhamnosus GG is also one of the most widely used probiotic bacteria that is assumed to interact with the host via binding to human mucus via its extracellular pili. A study was carried out on a group of

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healthy volunteers to assess the abundance of microbial species in their gut prior and after three weeks consumption of 250 mL drink supplemented with the probiotic Lactobacillus rhamnosus GG (1.55 3 109 CFU/250 mL) and the authors showed that average excretion of L. rhamnosus GG in the probiotic group was more than 1000-fold higher than that in the placebo group [50]. When the authors integrated lipid profiling with the microbiota data sets, they found that the daily intake of L. rhamnosus GG did not alter the serum lipids or resulted in any changes in the biochemically determined cholesterol and triglyceride levels of the healthy, normolipidemic adults analyzed in their study [50]. The investigators identified mainly members of the Firmicutes, Actinobacteria, and Proteobacteria that were involved in the absorption and metabolism of the dietary and endogenous lipids The antihypertensive activity of L. helveticus-fermented sour milk has been demonstrated in human subjects with different cholesterol levels [51] and the antihypertensive activity was attributed to the production of angiotensin-I converting enzyme inhibitory (ACE-I) tripeptides such as isoleucyl-prolyl-proline (IPP) and valyl-prolyl-proline (VPP) from the milk protein casein by the proteolytic activity of L. helveticus strains. The two probiotics bacteria strains KII13 and KHI1 isolated from fermented cow milk were reported to produce bioactive tripeptides and their probiotic properties were studied in vitro and in vivo [52,53]. A feeding study on induced hypercholesterolemicmices showed that dietary L. helveticus KII13supplements for 7 weeks lowered the plasma cholesterol level by 13%. An investigation was carried out on Egyptian adults to test the hypocholesterolemic activity of the intake of functional fermented sour sobya porridge. The 170 g daily portion size served to each volunteer contained 5.0 3 109 CFU diverse Lactobacilli and 1.7x109 CFU Saccharomyces cerecisae. Average fecal excretion of L. rhamnosus GG reached 46-fold higher than that in the control group, suggesting that L. rhamnosus survived the gastric transit (Labib et al., unpublished data). Furthermore, significant reduction in the plasma levels of total cholesterol, HDL cholesterol, LDL-C, and the atherogenic index was demonstrated among the sour sobya group than that in the control group (Table 34.3). In addition, the 3-week intervention with functional fermented sour sobya effectively reduced the plasma tHcy concentrations compared to respective baseline level [54]. Blood tHcy is a very important biomarker of cardiovascular diseases and high levels of tHcy

Table 34.3 Effect of 3-Week Dietary Intervention With Functional Fermented Sour Sobya on the Concentrations of Plasma Lipid Chemistry and Total Homocysteine Among Healthy Adults, Ref 53 Parameter

Initial

Terminal (21 d)a

P

Triglycerides, mmoles/L Total cholesterol, mmoles/L HDL-C, mmoles/L LDL- C, mmoles/L LDL/HDL ratio Atherogenic index (AI) Hcyc, μmol/L

1.2 6 0.2 5.0 6 0.3 1.0 6 0.1 3.5 6 0.3 3.6 6 0.5 4.1 6 0.5 16.5 6 1.2

1.0 6 0.2 4.5 6 0.3 1.7 6 0.1 2.7 6 0.4 1.7 6 0.2 1.8 6 0.2 12.3 6 0.8

0.12 0.026 0.002 0.005 0.001 0.001 0.003

Daily intake of 170 g functional fermented sour sobya providing 5 x 109 CFU diverse lactic acid bacteria (LAB) and 1.7 3 109 CFU Sacharomyces cerivisiae. a

34.9 PROBIOTIC INFLUENCE ON IMPROVEMENT

593

are considered an independent risk factor for heart disease. Initial plasma tHcy level (18 6 4 μmol/L), was higher than the respective reported values of 7.5 and 9.8 μmol/L for American women and men 20 29 years, respectively [55]. The finding denotes that the sour sobya product can lend itself in the dietary management of disorders of lipid metabolism. The body of research on the effects of culture-containing dairy products or probiotic bacteria on cholesterol levels has yielded equivocal results. Since 1974, 13 studies have been published evaluating blood lipids in human subjects consuming fermented milk products, with a total of 465 subjects (302 of those subjects were in three studies). Statistically significant lowering of total cholesterol ranged from 5.4% to 23.2% and of LDL cholesterol from 9% to 9.8%. The studies conducted to date have been criticized for failure to stabilize baselines before the onset of the feeding protocol, small sample size, short study duration, unreasonably large fermented milk intake requirements, and failure to control for diet and physical activity of subjects. Of the studies showing significant results on the lowering of either total cholesterol or LDL, the duration did not exceed 6 weeks. A meta-analysis implies that probiotic intake can lower the total and LDL cholesterol [56].The mechanisms for the effect of probiotic bacteria on reduction of serum cholesterol are based on the ability of certain probiotic Lactobacilli and Bifidobacteria to deconjugate bile acids enzymatically, increasing their rates of excretion—several mechanisms of cholesterol reduction by probiotics have been proposed and the high bile salt hydrolase (BSH hypothesis) activity of the probiotics are among the proposed mechanisms [57,58]. Because cholesterol is a precursor of bile acids, this could lead to reduction in serum cholesterol because cholesterol molecules are converted to bile acids to replace those lost through excretion. If this mechanism operated in the control of serum cholesterol levels, one concern is the conversion of deconjugated bile acids into secondary bile acids by colonic microbes. Another proposed mechanism, postulated that 3-hydroxy-3-methyl glutaric acid (HMG) present in fermented milk inhibits hydroxy methyl glutaryl CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis. Explanations for the controversy are many; the strain-specificity and their effects on lipid metabolism are likely to vary between different strains and the identification of bacteria that potentially affect the athreogenic index may provide important clinical implications for dyslipidemic individuals. Definition of the active property of a probiotic product is essential to understand shelf life issues and efforts to maximize shelf life must be focused on maintaining optimal levels of this ingredient, whether as the intact, viable cell, some cell component(s), a metabolic end product, or a combination of these. From the ecological perspectives, a single bacterial strain is not likely to radically alter the established intestinal community, which in adults typically consists of hundreds of different species-level phylotypes that represent approximately 10 bacterial phyla, vastly dominated by Firmicutes and Bacteroidetes.

34.9 PROBIOTIC INFLUENCE ON IMPROVEMENT OF INTESTINAL IMMUNE CELL FUNCTION Secretory IgA (sIgA) secreted by B cells, mucus and antimicrobial peptides are the first line of defense in protecting the intestinal epithelium from microbial invasion. Secretory IgA can coat the luminal microbiota and maintain homeostasis in the mucosal barrier. A study in healthy humans,

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indicated that 24% 74% of fecal bacteria are coated with sIgA. Consumption of some probiotics in humans was shown to increase secretory fecal immunity [59]. The immune modulatory activity of Lactobacillus bulgaricus ME-552 (ME552) and Streptococcus thermophilus ME-553 (ME553 were evaluated in vivo and the production of both the interferon γ (IFN-γ) and interleukin 17 (IL-17) were enhanced by cluster of differentiation (CD) 4 1 T cells from Peyer’s patches (PPs).

34.10 PREBIOTICS Prebiotics are indigestible food supplements that provide nutrition to desirable gut commensals, encouraging their growth. Fructoologosaccharides (FOS) and inulin are polymers of D-fructose joined by β (2 1) bonds with an α (1 2 ) linked glucose at the terminal end of the molecule. Molecules with degree of polymerization (DP) between 3 and 10 are referred to as oligofructose or FOS and those with DP between 8 and 65 are known as inulin. Inulin occurs naturally in a range of plants such as chicory, garlic, onion, Jerusalem artichoke, and others. It is part of everyday human diet and according to US statistical data estimated daily intakes for inulin and FOS averaged 2.6 and 2.5 g, respectively [60]. Inulin is not hydrolyzed by digestive enzymes in the upper gastrointestinal tract and reached the colon intact, where it is selectively fermented by Bifido bacteria. Inulin ingestion promoted the growth and increased fecal Bifido levels [61]. Starch is highly digestible across the whole gastrointestinal tract, with the most resistant starches (RSs) being completely fermented in the large intestine [62] Diets high in resistant starch (RS) have been shown to benefit insulin sensitivity, possibly mediated by bacterial fermentative activity in the colon [63]. Microbial breakdown of NSP also releases bound phytochemicals into the colon [64] Dietary fibers such as resistant starch, plant cell wall materials, and oligosaccharides that escape digestion by host enzymes reach the colon and serve as substrates for microbial fermentation [65]. These plant fibers have a major impact on the gut microbial ecosystem as they serve as growth substrates for gut bacteria and are fermented to short-chain fatty acids (SCFAs) [66]. Diets containing RS and nondigestible polysaccharides (NSP) offer potential benefits in the prevention of colorectal cancer through the delivery of fermentation acids, in particular butyrate, to the distal colon [67]. The time courses show that most diet-driven changes occurred rapidly, being detectable within 3 4 days, and were reversed equally rapidly. These kinetics appear consistent with immediate effects of dietary residue upon relative bacterial growth rates in the colon that are subsequently reflected in fecal samples as colonic contents turnover, assuming mean transit colonic times of around 60 h. Fimicutes bateria related to R-ruminococci were preferentially associated with resistant starches suggesting that they have an important role in the breakdown of particulate substrates [68]. Daily consumption of novel fibers polydextrose or soluble corn fiber (SCF) in 21 g dosages to adults for three week resulted in significant increases in Lactobacilli and Faecalibacterium prausnitzii, the well-known butyrate producer with strong anti-inflammatory properties only among the group consuming soluble dietary fiber [69]. Principal component analysis clearly indicated a distinct clustering of individuals consuming supplemental fibers. The data demonstrate a beneficial shift in the gut microbiome of adults consuming fibers polydextrose or soluble corn fiber, with potential application as prebiotics.

34.12 TRADITIONAL FERMENTED FOODS RICH IN HOME SOURCE

595

34.11 SYNBIOTICS Synbiotics are the simultaneous administration of a combination of pre- and probiotics. Its use is currently an attractive strategy to upregulate disordered intestinal function, improve gut health and reinforce the immunological response against pathogenic bacteria. A randomized controlled study was carried out on 46 healthy volunteers aged 35 years to evaluate the efficiency of inulin plus the strain B. animalis subsp. Lactis Bb-12 (B109 to 1010 CFU/serving) in yoghurt matrix on the counts of the fecal bacteria Bifidobacteria, Clostridia, and Enterobacteria at days zero and 21. The results demonstrated that there were no significant differences between the synbiotic and the placebo groups in numbers of Bifidobacteria, Clostridia, or Enterobacteria during any of the feeding periods [70]. The only published trial of synbiotics in malnutrition is the PRONUT study [71]. A cohort of 795 Malawi children aged 5 168 months, of whom 40% were seropositive for HIV, were fed the standard synbiotic (four Lactobacillus strains and four prebiotic fermentable bioactive fibers). Ready to use therapeutic foods (RUTF) treatment and the results demonstrated no effect on outcomes. According to the authors, confounding factors for failure to respond was 7-day administration of cotrimoxazole, with 50% also receiving additional parenteral antibiotics. Two of the four probiotic organisms were demonstrated to be sensitive to cotrimoxazole. Another factor was the wide age span of the children, presenting at potentially different microbiota ages was also confounding [72].The gastrointestinal microbiome plays a crucial role in human gastrointestinal and host health, because it affects the metabolism and development of the immune system and provides protection against pathogens while modulating gastrointestinal development. Despite its benefits, the gut microbiome has been associated with complex diseases such as obesity, diabetes, colon cancer, and inflammatory bowel disease (IBD). The associated lowering of intestinal pH had been implicated as the underlying protective mechanism of synbiotics [73]. Fecal transplantation has been highly effective in treatment of Clostridium difficile infection; this approach has not yet been accepted by the public domain and needs more development [73].

34.12 TRADITIONAL FERMENTED FOODS RICH IN HOME SOURCE PROBIOTIC BACTERIA STRAINS There is a growing interest in functional food which can beneficially affect one or more target functions in the body in a way that is relevant either to promoting the state of well-being and health and/or reducing the risk of disease. Fermentation is the “slow decomposition process of organic substances induced by microorganisms or enzymes, of plant or animal origin.” and the changes caused by fermentation can be advantageous. Another definition of fermented foods includes the exposure of the foods to the action of micro-organisms or enzymes so that desirable biochemical changes cause significant modification to the food. However, to the microbiologist, the term”fermentation” describes a form of energy-yielding microbial metabolism in which an organic substrate, usually a carbohydrate, is incompletely oxidized, and an organic carbohydrate acts as the electron acceptor. Sahlin [74] produced and characterized the properties of fermented cereal water slurries, a common base for the production of gruels. Lactic acid bacteria controlled fermentation is a relatively efficient food preservation process which gives beneficial results, and is therefore a

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highly appropriate technique for use in developing countries and remote areas where access to sophisticated equipment is limited. By tradition, LAB are the most commonly used microorganisms for preservation of foods. These bacteria have the ability to produce lactic acid from carbohydrates. Nearly all food fermentations are the result of more than one microorganism, either working together or in a sequence, but growth is generally initiated by bacteria, followed by yeasts. Quality, safety, and acceptability of traditional fermented foods may be significantly improved through the use of starter cultures selected on the basis of multifunctional considerations [75]. Experience has shown that back slopping (inoculating the materials to kick-start fermentation with residue from a previous batch) accelerates the initial phase of fermentation. In many traditional processes, starter cultures are not purchased, but an effective means of achieving a similar goal, is to recycle material from a previous successful batch which helps to initiate a new process, shorten the fermentation process, and reduce the risk of fermentation failure. Spontaneous fermentations in the absence of back-slopping or a starter culture have been applied for millennia and identified through trial and error, and much small-scale fermentation in developing countries is still conducted this way. However, it takes longer and can be associated with a high risk for failure [76]. Lactic acid fermented food produce organic acids in an environment below pH 4 in fermented cereal; conditions where pathogenic microorganisms normally found in food will not be able to grow. The importance of LAB is associated mainly with their safe metabolic activity while growing in foods utilizing available sugar for the production of organic acids and other metabolites. Their common occurrence in foods and feeds coupled with their long-lived use contributes to their natural acceptance as GRAS (Generally Recognised As Safe) for human consumption [76]. However, there are many kinds of fermented foods in which the dominating processes and end products are contributed by a mixture of endogenous enzymes and other microorganisms like yeast and mold. Very often, a mixed culture originating from the native microflora of the raw materials is in action in most of the food fermentation processes. The enterotoxinogenic Escherichia coli cannot withstand the acidic environment produced in this process. FAO encourages more in-depth research work to elucidate the functional activities of fermented food pertinent to each community [77]. Sour sobya is a traditional Egyptian fermented porridge prepared from rice flour, milk, and sugar. Cultured fermented sour sobya (SS) is produced through symbiotic fermentation of lactic acid bacteria, mainly Lactobacillus rhamnosus, and yeast and the final pH of the product is very stable ranging between pH 3.5 3.6. The product possesses in vitro high antimicrobial activities against seven pathogenic bacteria [78]. In vivo the product possesses antioxidative activities [79] and anticholesterolemic activities, as mentioned above [54].

34.13 PROBIOTIC PRODUCTS

A GLOBAL MARKET OVERVIEW

Research on probiotics consists of experiments done with dozens of different bacterial strains and combinations of strains used at different doses in human studies with dozens of different research endpoints. The positive results from human volunteer or clinical studies, even in the absence of compelling mechanistic studies, provide validity to the probiotic concept. Functional food

34.13 PROBIOTIC PRODUCTS

A GLOBAL MARKET OVERVIEW

597

consumption is seen as a major industry trend benefiting global probiotics market growth and the probiotics market size was US$36.6 billion in terms of ingredient sales in 2015. Bio-yoghurt foods are relevant on the food market with a steady increase in consumption rate throughout the world. The backdrop to these efforts is the rapidly expanding marketing worldwide of probiotic-containing products. Experts in this field acknowledge that a prerequisite for successful probiotic research and development is developing fundamental knowledge of intestinal bacteria and their interactions with each other and their host. These efforts to understand the role probiotic bacteria may play in human health are justifiable apart from the interest in yet another functional ingredient for purchasing dollars from an increasingly health conscious consumer [80]. It is questionable if these bacteria are going to make a substantive benefit in the health of the average consumer. In the United States, the National Yogurt Association ((NYA) allows yogurt manufacturers use of its “Live active culture seal” on products that contain 108 viable cultures per gram at time of manufacture. Probioticcontaining food products list bacterial genera and species added as live cultures, but make no mention of the numbers of probiotic bacteria present in the product per serving. California and Oregon are unique in that they legislate a minimum requirement for L. acidophilus-containing fluid milk products (106/mL) and this seal is of little value in assuring consumers of effective probiotic levels. In practice, fluid milk products (with their short shelf life and near-neutral pH) provide the expected levels of probiotic bacteria (108 viable cultures per species (L. acidophilus, L. casei, L. reuteri, Bifidobacterium species, among others). Results from yogurt products show a greater range in levels of viable probiotic bacteria. Labeling has been criticized for overstating the level of viable bacteria, for inaccurately indicating the species of probiotic bacteria present, and for the presence of species of bacteria not listed on the label (e.g., Enterococcus). There is a need for the probiotics industry to focus on delivery of high potency doses of appropriate bacteria in these products [81]. Not all probiotic bacteria are identical and strain specificity is quite critical. Strains of the same species could be expected to differ in traits such as stability, expression of enzymes, extent and types of inhibitors produced, carbohydrate fermentation patterns, acid producing ability, resistance to acid and bile, ability to colonize the gastrointestinal tract, and perhaps most importantly clinical efficacy. Positive research, especially clinical and mechanistic research, conducted on a specific strain is required to prove efficacy. This also contributes substantially to the commercial value of the probiotic strain. Industrial scale of a particular defined starter culture which has been developed under controlled conditions is of first preference so that the qualities of the finished product could be consistently maintained day after day. The use of indigenous foods as potential vehicles for delivering beneficial bacteria has great potential for prophylactic and therapeutic use in resource poor countries [82]. Kort et al. [83] have described the creation of a novel probiotic formulation of two lactic acid bacteria that is affordable and practical for use in resource-challenged communities in Africa [83] An essential feature of the formulation is the strain Streptococcus thermophilus C106 which complements the disability of L. rhamnosus yoba 2012 to grow in milk by degrading casein and lactose. The entire production process has been validated and is carried out in rural areas and only requires the sachet, milk, a sauce pan, and a source of heat. The freeze-dried strains stored in moisture-proof sachets remain active over a period of at least 2 years and food safety of seed cultures and sensory evaluation of dairy and cereal based fermentations were reported [46]. The content of the seed cultures were routinely tested by selective enumeration methods: Listeria mono cytogenes were examined according to ISO 11290-2, Enterobacteriaceae yeast and molds according to ISO 7954 (1987), and

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nonlactic-acid bacteria according to a validated colony count technique from Eurofins Food Testing BV, Heerenveen, The Netherlands. Typical sensory aspects such as color, structure, firmness, sweetness, sourness, and taste were evaluated by a panel in Uganda in agreement with local practices. Whitening ability and whey separation were also evaluated for the fermented milk products. According to the same investigators, their initiative provides a means to bring highly nutritious, health-promoting food to people around the world who currently have no access to probiotic benefits. The concentration of B vitamins as a result of the fermentation process showed three-fold increase of vitamin B1 or thiamine, while the other B vitamins remained at similar concentrations to those found prior to fermentation. In addition, detoxification is a well-accepted benefit of some food fermentations since L. rhamnosus GG has been shown to bind and neutralize toxins known to contaminate foods, leading to a reduction of their uptake in the gastrointestinal tract as they are secreted with L rhamnosus GG during defecation [84]. In addition, probiotic L. rhamnosus GR-1 supplemented yogurt has been shown to lower mercury and arsenic uptake in children and pregnant women [85]. Recent studies indicate that supplementation with probiotics, prebiotics, and synbiotics has shown promising results against various enteric pathogens due to their unique ability to compete with pathogenic microbiota for adhesion sites [86 88]. These strategies may alienate pathogens or can modulate, stimulate and regulate the immune responses in the host by initiating the activation of specific genes in and outside the host intestinal tract. There may be increase in lifespan and improvement in gut microbiota leading to decrease in fatty acid deposition in the hepatocytes [86,87]. Nutrigenomics as a technology will lead in the future away from a one-size-fits-all nutrition and exploration of this area towards products that are more closely matched to nutritional requirement.

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[71] Kerac M, Bunn J, Seal A, Thindwa M, Tomkins A, Sadler K, et al. Probiotics and prebiotics for severe acute malnutrition (PRONUT study): a double-blind efficacy randomised controlled trial in Malawi. Lancet. 2009;374:136 44. [72] Gupta SS, Mohammed MH, Ghosh TS, KanungoS, Nair GB, Mande SS. Metagenome of the gut of a malnourished child. Gut Pathog 2011;3:7 15. [73] de Groot PF, Frissen MN, de Clercq NC, Nieuwdorp M. Fecal microbiota transplantation in metabolic syndrome: History, present and future. Gut Microbes. 2017;8:253 67. [74] Sahlin P. Fermentation as a method of food processing production of organicacids, pH-development and microbial growth in fermenting cereals. Lund Inst Technol., Lund Univ; 1999. p. 65. [75] Holzapfel WH. Appropriate starter culture technologies for small scale fermentation in developing countries. Intern J Food Microbiol 2002;75:197 212. [76] Aguirre M, Collins MD. Lactic acid bacteria and human clinical infection. J Appl Bacteriol 1993;75:95 107. [77] FAO 1999. Fermented cereals: A global perspective. FAO Agric Services Bulletin No. 138, Rome. [78] Fouad M, Moustafa A, Hussein L, Roumeyla R. In-vitro antioxidant and antimicrobial activities of selected fruit and vegetable juices and fermented dairy products commonly consumed in Egypt. RJPBC 2015;5:6541 50. [79] Gouda M, Moustafa A, Hussein L, Hamza M. Three week dietary intervention ususing apricots, pomegranate juice or/and fermented sour sobya and impact on ibibiomarkers of antioxidative activity, oxidative stress and erythrocytic glutathione transferase activity among adults. Nutr J 2016;15:52 61. [80] Sanders MA. Considerations for use of probiotic bacteria to modulate human he health. J Nutr 2000;130:384S 90S. [81] Hamilton-Miller JM, Shah S. Deficiencies in microbiological quality and labelling of probiotic supplements. Int J Food Microbiol. 2002;72:175 6. [82] Franz CM, Huch M, Mathara JM, Abriouel H, Benomar N, Reid G, et al. H81. Holzapfel WH. African fermented foods and probiotics. Int J Food Microbiol 2014;190:84 96. [83] Kort R, Westerik N, MarielaSL, Douillard FP. A novel consort of Lactobacillus rhrhamnosus and Streptococcus thermophilus for increased access to functional fefermented foods. Microb Cell Factory 2015;14:195 209. [84] Lahtinen SJ, Haskard CA, Ouwehand AC, Salminen SJ, Ahokas J. Binding of aflatoxin B1 to cell wall components of Lactobacillus rhamnosus strain GG. Food Addit Contam 2004;21:158 64. [85] Bisanz JE, Enos MK, Mwanga JR, Changalucha J, Changalucha J, Burton J, et al. Randomized openlabel pilot study of the influence of probiotics and the gut microbiome on toxic metal levels in Tanzanian pregnant women and school children. MBio. 2014;5:e01580. [86] Sharma K, Pooranachithra M, Balamurugan K, Goel G. Multivariate analysis of increase in life span of Caenorhabditis elegans through intestinal colonization by indigenous probiotic strains. Probiot Antimicrob Proteins. 2018 May 1;. Available from: https://doi.org/10.1007/s12602-018-9420-0. [87] Zhang Y, Tang K, Deng Y, Chen R, Liang S, Xie H, et al. Effects of shenling baizhu powder herbal formula on intestinal microbiota in high-fat diet-induced NAFLD rats. Biomed Pharmacother. 2018 Apr 3;102:1025 36. Available from: https://doi.org/10.1016/j.biopha.2018.03.158. [88] Kerry RG, Patra JK, Gouda S, Park Y, Shin HS, Das G. Benefaction of probiotics for human health: a review. J Food Drug Anal 2018;. Available from: https://doi.org/10.1016/j.jfda.2018.01.002.

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SAFETY OF PROBIOTICS IN HEALTH AND DISEASE

35

Eric Banan-Mwine Daliri1, Byong H. Lee1,2 and Deog H. Oh1 1

Department of Food Science and Biotechnology, Kangwon National University, Chuncheon, South Korea 2 Department of Microbiology/Immunology, McGill University, Montreal, QC, Canada

35.1 INTRODUCTION The International Scientific Association for Probiotics and Prebiotics define probiotics as “live microorganisms that, when administered in adequate amounts, confer a health benefit on the host” [1]. For centuries, probiotics have been applied as food and dairy ingredients. However, there is growing interest in the use of probiotics for disease prevention and treatment in recent years. The rapid advancement of the field of probiotics is due to the global progress in understanding how the human microbiota influences health and disease [2] and the need for effective approaches to shape a healthier microbiota. There is evidence that probiotics effectively modulate the immune system, enhance epithelial barrier functions, control serum cholesterol levels, treat diarrhea, and have many other health effects [2,3]. However, despite their preventive and therapeutic effects, probiotic consumption may not be completely safe and may pose some risks. Yet, due to the numerous beneficial effects of probiotics, their adverse side effects have been overlooked [4]. For this reason, many countries have regulations that guide probiotic use and market authorization. In Canada, live bacteria cultures used in food must meet the Food and Drug regulations or must have a long history of safe use. Probiotics are categorized as natural health products under the approval controlled by the Canadian Food and Drugs Act of the Natural Health Products Regulations. The Food Directorate of Health Canada requires that information about whether or not probiotics carry transferable antimicrobial genes be disclosed. Probiotics in food products are also required to be viable and genetically stable so as to perform their intended purpose throughout the shelf life (https://www.canada.ca/en/health-canada/services/food-nutrition/legislation-guidelines/ guidance-documents/guidance-document-use-probiotic-microorganisms-food-2009.html accessed on 10-6-2017). In India, probiotics are characterized as functional foods and are regulated by the Prevention of Food Adulteration Act and the Food and Drug Administration (FDA). The authorities require that the possibility of undesirable side effects of probiotics be assessed before they are accepted for human consumption. In addition, studies on the acute, subacute, and chronic toxicity that may occur as a result of consuming extremely large amounts of the probiotic must be carried out. The hemolytic ability of probiotics or their ability to produce mammalian toxins must also be reported [5]. The Role of Functional Food Security In Global Health. DOI: https://doi.org/10.1016/B978-0-12-813148-0.00034-7 © 2019 Elsevier Inc. All rights reserved.

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In the United States, probiotics are considered as dietary supplements and are regulated by the FDA’s Center for Food Safety and Applied Nutrition under the Dietary Supplement Health and Education Act of 1994 (https://www.fda.gov/Food/DietarySupplements/UsingDietarySupplements/ default.htm accessed on 10-6-207). However, probiotics that are intended to diagnose, prevent, cure, treat, or mitigate human diseases are regulated as drugs and biological products by the USFDA’s Center for Biologics Evaluation and Research and an Investigational New Drug application is required to follow clinical studies in human volunteers. Although over-the-counter probiotics are generally regarded as safe in healthy individuals, the authorities require that clinical studies be carried out to assess the impact of such probiotics in immunocompromised individuals. It is also required that probiotic products be screened for the presence of extraneous and undesirable microbes. For this reason, the USFDA currently uses recombinant phage lysins as reagents for determining harmful contaminants that may be present in probiotic products (https://www.fda.gov/ biologicsbloodvaccines/scienceresearch/ucm493702.htm). In the EU, the European Food and Feed Cultures Association and International Dairy Federation jointly produced an inventory of microorganisms with documented history of use in food until 1997 and updated the list in 2012 [6]. The authorities accept the presumed safety of some microorganisms that meet the Qualified Presumption of Safety (QPS) status [7]. The QPS is a general risk evaluation method applied by the European Food Safety Authority to already reported biological agents to simplify risk assessments across different scientific panels. If the microorganism is not recognized as QPS, a complete assessment of its safety must be carried out according to regulatory requirements.

35.2 POTENTIAL SIDE EFFECTS OF PROBIOTIC CONSUMPTION Despite the numerous benefits of probiotic consumption, a joint report by the World Health Organization (WHO) and the Food and Agriculture Organization (FAO), suggests that probiotics could be involved in deleterious metabolic activities and/or produce host-deleterious metabolites, cause systemic infections, induce inappropriate immune responses in vulnerable populations, and may possess transferable antibiotic resistant genes to pathogens [8]. It is therefore recommended that new probiotic strains be tested for their resistance to antibiotics, hemolytic and toxin producing potentials, and their potential deleterious metabolic activities.

35.2.1 DELETERIOUS METABOLIC ACTIVITIES AND/OR HOST-DELETERIOUS METABOLITES 35.2.1.1 Bile Salt Hydroxylase The ability of probiotics to promote metabolic activities in their hosts implies that they could as well influence other metabolic activities that may be harmful to the host. For instance, many studies have reported the presence of bile salt hydrolase (BSH) genes in some probiotics [9]. Such bacteria including Bifidobacterium, Pediococcus species, and Lactobacillus species secrete BSH which deconjugates primary bile salts and reduces cholesterol reabsorption in hosts [10 12]. In a randomized controlled trial to study the cholesterol lowering ability of probiotics, subjects who consumed

35.2 POTENTIAL SIDE EFFECTS OF PROBIOTIC CONSUMPTION

605

L. reureri NCIMB 30242 recorded an increase in mean plasma deconjugated bile acids by 1 nmol/ L and decreased LDL-C by 11.64% over 9 weeks [13]. However, excessive deconjugation or dehydroxylation of primary bile salts in the small bowel by 7α-dehydroxylase active strains could yield toxic and/or mutagenic secondary bile salts. The toxicity of secondary bile salt may result in reduced normal gut microflora leading to mucosal inflammation and diarrhea [14]. Excessive bile salt deconjugation in the small intestine could also result in small bowel overgrowth syndrome and excessive accumulation of bile acids could lead to colon cancer development [15,16].

35.2.1.2 Gut Epithelia Binding and Mucin Degradation The ability of probiotics to bind to gut epithelia wall is important for their colonization [17] and pathogen-binding inhibition [2]. However, although many probiotics have been reported to be non mucin-degrading [18,19], some strains of Bifidobacterium bifidum and Bifidobacterium longum possess afcA and engBF genes which express mucin-degrading glycosidases in the presence of mucin [20]. Probiotics such as L. rhamnosus and L. paracasei subsp. paracasei secrete glycosidases and arylamidase which can breakdown human glycoproteins and lyse human fibrin clots [17]. Bacteria with such properties may compromise gut barrier integrity and also cause endocarditis. Excessive degradation of gut mucin by probiotics could enhance bacteria translocation into the blood and other organs [18]. Probiotic translocation has been reported in low-birthweight [21], preterm [22 24], immunocompromised [25], patients with organ failure [26,27], and patients with dysfunctional gut barrier. In a randomized double-blind placebo-controlled trial involving 296 patients with severe pancreatitis, the researchers studied the ability of a probiotic cocktail to prevent infectious complications in the subjects. High mortality rate was recorded among subjects who consumed the probiotics, which was attributed to bowel ischemia. Bowel ischemia is a process of insufficient blood supply of the small or large bowel with the consequences ranging from a transient, totally reversible attack to a lethally catastrophic event. To account for the observation, the researchers proposed that consumption of the probiotic bacteria might have increased the oxygen demand in the gut mucosa, an environment that already had reduced blood flow. The probiotics might have also caused inflammation in the small intestine resulting in reduced blood flow. There are other cases where critically ill adults [28] and infants [29] consuming probiotics experienced increase in infectious complications. Indeed, as the compromised gut integrity of such patients may cause bacteria translocation yet, the possible role in breaking down gut glycoproteins needs be further investigated.

35.2.1.3 Toxic Secondary Metabolites Probiotic secondary metabolites may have adverse effects on their host. Neu et al. [30] reported that P. luteoviolacea S4060 (a fish probiotic) produced pentabromopseudilin which was toxic to Artemia sp. and Caenorhabditis elegans. Although such findings have not yet been reported in mammals, the study shows the possibility of probiotics to produce toxic secondary metabolites that may harm the host. Also, certain probiotics especially Lactobacillus species are capable of producing biogenic amines when incorporated in foods [31,32]. Intake of high levels of biogenic amines could be erroneously considered to be allergic reactions as their signs and symptoms are similar. It is therefore important that probiotics are screened for their tendency to produce such harmful metabolites.

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35.2.1.4 D(2)-Lactate Humans produce L(1)-lactic acid from carbohydrate metabolism, whereas D(2)-lactate is produced in the body by bacterial metabolic activities [33,34]. Humans poorly metabolize and excrete D(2)-lactate and its accumulation in the blood can cause D(2)-lactate acidosis, a common symptom observed in short bowel syndrome [35]. Although not all probiotics may directly produce D(2)-lactate, many lactobacilli possess a DL-lactate racemase enzyme which converts L (1)-lactate to D(2)-lactate [36,37]. D(2)-lactate acidosis is mostly reported in patients with short gut syndrome and consumption of certain probiotics among this population has been reported to cause D(2)-lactate associated encephalopathy [38,39]. For this reason, the type of probiotics administered to a given population must be carefully selected to prevent such situations where their metabolites may adversely affect their hosts.

35.2.2 SYSTEMIC INFECTIONS Several cases of sepsis have been reported in humans administered with L. rhamnosus [26,40 42], Lactobacillus casei var. casei [43], L. acidophilus [44 46], and Bifidobacterium sp [21,23,24,47]. Several other reports of peritonitis [48], endocarditits [49,50], chest infection [51,52], leukocytosis [53], and bicuspid aortic valve infections have been reported among consumers of Lactobacillus sp. [54,55] and Streptococcus. Weber et al. [56] have compiled published cases of human bacteremia due to Bifidobacterium species. One case of Lactobacillus jensenii-associated empyema has been reported [43]. Many cases of fungemia have also been reported in humans treated with the probiotic Saccharomyces cerevisiae [57,58] and Saccharomyces boulardii (Table 35.1). A few randomized control studies have been carried out on the safety of mixed probiotic strains (Table 35.2). In almost all the cases reported, the subjects involved had severe underlying conditions such as severe heart conditions in the case of endocarditis and the presence of catheter in the case of septicemia. Ford et al. [97] have demonstrated the ability of some streptococci to aggregate human platelets by a mechanism that requires the cyclo-oxygenase pathway in the presence of glycoprotein Ib and glycoprotein IIb/IIIa. Some lactobacilli isolated from infective endocarditis have high hydrophobicity and show strong platelet aggregation ability due to the abundance of hydrophobic extracellular proteins [98]. The direct involvement of bacteria in platelet aggregation is believed to play a role in the progression of infective endocarditis [99]. In a 4-year Finish study to assess the possibility of lactobacilli to cause serious infections, the researchers monitored the frequency of bacteremia due to Lactobacillus species in southern Finland. Out of 3317 blood culture isolates, Lactobacillus was isolated in eight patients (five of whom had severe conditions disposing them to bacteremia). None of the eight bacteria isolates corresponded to dairy strains [100]. In a second study, however, 12 out of 5912 blood cultures were lactobacilli, yet, none of the isolates was identical to dairy strains [101]. It is probable that the normal gut commensals might have traversed the gut epithelia of immunocompromised subjects who were part of the study. Meanwhile, many studies have recorded no cases of infection or side effects when probiotics were consumed by critically ill patients, patients who had undergone surgery or had autoimmune diseases [102], as well as Acquired Immunodeficiency Syndrome patients [103,104].

Table 35.1 Cases of Adverse Effects During Probiotic Administration in Humans References

Patient

Purpose

Sanyal and Bhandari [59]

Chronic renal failure

Not reported

Griffiths et al. [60]

A defective bicuspid aortic valve, severe aortic insufficiency, and a dilated left ventricle Acute leukemia

Adverse Effects

Number of Cases

Source of Isolate

Treatment

Outcome

Several episodes of CAPD peritonitis Endocarditis

1

Peritoneal dialysis fluid

Erythromycin cure 8 Rifampicin, 3 1 week

Recovery

1

Blood

Ampicillin, Gentamicin, 3 6 weeks Penicillin 1 Tobramycin

Recovery

Septicemia

3

Imipenem, Erythromycin, 3 3 weeks (lst episode) Penicillin x 6 weeks (2nd episode) Probiotic stopped, Vancomycin, ciprofloxacin and liposomal amphotericin administered Probiotic stopped, CVC removed, ceftriaxone, ampicillin administered CVC removed, ampicillin, gentamicin administered Probiotic stopped, ampicillin administered Probiotic stopped, CVC removed, penicillin, gentamicin administered Probiotic stopped, ampicillin 1 gentamicin, pivampicillin 1 probenecid

Recovery

L. rhamnosus

Severe aplastic anemia

Not reported

Sepsis

1

Broncho alveolar lavage, throat and stool cultures Blood

Kunz et al. [63]

Short bowel cholestasis

To prevent SIBO

Bacteremia

2

Blood

De Groote et al. [64] Land et al. [65]

Short bowel

To treat rotavirus To treat AAD

Bacteremia

1

Blood

Bacteremia

1

Blood

To treat AAD

Bacteremi, endocardits

1

Blood

To increase friendly bacteria in the gut

Endocarditis

1

Blood

Chomarat and Espinouse [61] Kalima et al. [62]

Mackay et al. [66]

Cerebral palsy, microcephaly Cardiac stenosis

Mild mitral valve regurgitation

Death

Recovery

Recovery Recovery Recovery

Recovery

(Continued)

Table 35.1 Cases of Adverse Effects During Probiotic Administration in Humans Continued Patient

Purpose

Adverse Effects

Number of Cases

Source of Isolate

Lortholary et al. [67]

Defective cardiac aorta

NR

Endocarditis

1

Aorta valve tissue

Chong et al. [68] Tenebaum and Warner [69] Naude et al. [70]

Dental procedure

NR

Endocarditis

1

Blood

NR

NR

Endocarditis

1

Blood

Penicillin, streptomycin 3 4 wks

Recovery

Mitral incompetence

NR

Endocarditis

1

Blood

Penicillin 1 Tobramycin, ampicillin 1 netilmicin administered

Death

Probiotic stopped, amphotericin B, fluconazole administered Probiotic stopped, amphotericin B, fluconazole administered Probiotic stopped, amphotericin B, fluconazole administered Probiotic stopped, amphotericin B, fluconazole administered Probiotic stopped, CVC removed, caspofungin administered Probiotic stopped, CVC removed, fluconazole administered CVC removed, fluconazole administered

Recovery

References

Treatment

Outcome

Beta-lactam antibiotics and aminoglycosides administered Penicillin G

Recovery

L. casei

Recovery

Saccharomyces boulardii Zunic et al. [71]

Colectomy, Sepsis

Prevent AAD

Fungemia

1

Blood

Pletincx et al. [72]

Pneumonia, Enteritis

Prevent diarrhea

Fungemia

1

Blood

Viggiano et al. [73]

Burns

Prevent diarrhea

Fungemia

1

Blood

Fredenucci et al. [74]

Pneumonia

Prevent diarrhea

Fungemia

1

Blood

Lolis et al. [75]

Pneumonia

Prevent diarrhea

Fungemia

1

Blood

Niault et al. [76]

Pulmonary disease

Prevent diarrhea

Fungemia

1

Blood

Riquelme et al. [77]

Neurosurgery

Prevent diarrhea

Fungemia

1

Blood

Recovery

Recovery

Recovery

Recovery

Recovery

Death

Hennequin et al. [78]

Cystic fibrosis, Ileal atresia

Prevent diarrhea

Fungemia

1

Blood

HIV/AIDS, Lymphoma

To treat diarrhea

Fungemia

1

Blood

Esophageal cancer

Treat AAD

Fungemia

1

Blood

Pulmonary disease

Prevent diarrhea

Fungemia

1

Blood

Cesaro et al. [79]

Leukemia

Prevent AAD

Fungemia

1

Blood

Perapoch et al. [80]

Cardiopathy

Treat diarrhea

Fungemia

1

Blood

Lherm et al. [81]

Cardiac arrest

Prevent diarrhea Prevent diarrhea

Fungemia

1

Blood

Fungemia

1

Blood

Fungemia

1

Blood

Fungemia

1

Blood

Fungemia

1

Blood

Fungemia

1

Blood

Fungemia

1

Blood

Fungemia

1

Blood

Aortic surgery

Stroke Respiratory failure Peritonitis

Prevent diarrhea Prevent diarrhea Prevent diarrhea

Lherm et al. [81] Lungarotti et al. [82]

Respiratory failure Preterm infant

Prevent diarrhea Prevent SIBO

Lestin et al. [83]

Diabetes Foot necrosis

Treat CDAD

Probiotic stopped, CVC removed, amphotericin B administered Probiotic stopped, amphotericin B, fluconazole administered Probiotic stopped, CVC removed, fluconazole administered Probiotic stopped, CVC removed, fluconazole administered Probiotic stopped, CVC removed, amphotericin B administered Probiotic stopped, CVC removed, amphotericin B administered Probiotic stopped, CVC changed administered Probiotic stopped, CVC changed, fluconazole administered Probiotic stopped, CVC changed Probiotic stopped, CVC administered Probiotic stopped, CVC changed, amphotericin B administered Probiotic stopped, CVC changed Probiotic stopped, CVC removed, amphotericin B administered Probiotic stopped

Recovery

Recovery

Recovery

Recovery

Recovery

Recovery

Death Death

Recovery Recovery Death

Recovery Recovery

Death

(Continued)

Table 35.1 Cases of Adverse Effects During Probiotic Administration in Humans Continued References

Patient

Purpose

Adverse Effects

Number of Cases

Source of Isolate

Treatment

Outcome

Cherifi et al. [84] Henry et al. [85] Burkhardt et al. [86]

C. difficile, anorexia nervosa Oropharyngeal cancer

Prevent CDAD

Fungemia

1

Blood

Fluconazole administered

Recovery

Treat diarrhea

Fungemia

1

Blood

Recovery

Tetraparesis

Prevent diarrhea

Fungemia

1

Blood

Thygesen et al. [87]

C difficile infection, short bowel syndrome

Treat C difficile diarrhea

Fungemia

1

Blood

Probiotic stopped, amphotericin B Probiotic stopped, fluconazole, voriconazole administered Probiotic stopped, amphotericin B administered

Recovery

Death

35.2 POTENTIAL SIDE EFFECTS OF PROBIOTIC CONSUMPTION

611

Table 35.2 Randomized Controlled Trials of Mixed Probiotic Strains and Their Adverse Effects References

Probiotic

Study Population

Adverse Effects

Rayes et al. [88]

Lactobacillus plantarum 299 and fiber 8 3 1010 cells/day Ecologic 641 (Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus salivarius, Lactococcus lactis, Bifidobacterium bifidum, and Bifidobacterium lactis) 1010 cells/day Ergyphilus, 2 3 1010 lactic acid bacteria, mostly Lactobacillus rhamnosus GG, once a day Ecologic 641 (Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus salivarius, Lactococcus lactis, Bifidobacterium bifidum, and Bifidobacterium lactis) 1010 cells/day Lactobacillus acidophilus (LAVRI-A1)

90 Adults in ICU Surgical unit (Pancreato duodenectomy) Adults with severe acute pancreatitis in ICU

Pneumonia, Abdominal cramps, distention in 20% 30% of the patients Mortality (24/152 patients) and bowel Ischemia (9/144 patients)

Critically ill patients in ICU

Increased mortality rate among nonsevere sepsis patients who consumed probiotics Increased bacterial translocation and enterocyte damage in patients with organ failure

Besselink et al. [89]

Barraud et al. [90]

Besselink et al. [91]

Taylor et al. [92]

Kopp et al. [93]

Lactobacillus GG

Ligaarden et al. [94]

L. plantarum MF1298 (1010 cfu)

Van Gossum et al. [95]

Lactobacillus johnsonii, LA1, Nestl´e (1010 colonyforming units, cfu) L. acidophilus La5 and B. animalis subsp lactis Bb12

Ivey et al. [96]

Patients with predicted severe acute pancreatitis

Newborns of women with allergy Pregnant women from families with one or more member (mother, father, or child) with an atopic disease IBS patients

Crohn’s disease patients who have undergone ileocecal resection Overweight men and women over 55 years

Probiotic consumption increased allergen sensitization in infants Increased rate of recurrent episodes of wheezing bronchitis among children born by the women under the study Increased abdominal discomfort, stool frequency, bloating, incompetent bowel movement and diarrhea Increased risk of severe recurrence among patients taking probiotics Probiotic consumption resulted in a significantly higher fasting glucose

612

CHAPTER 35 SAFETY OF PROBIOTICS IN HEALTH AND DISEASE

35.2.3 INAPPROPRIATE IMMUNE RESPONSES IN VULNERABLE POPULATIONS Probiotics can stimulate the nonspecific immune response in humans [105 108]. This is because the cell walls of Gram-positive bacteria contain peptideglycan polysaccharide complexes which can activate immune cells. An earlier study by Gill et al. [109] showed that consumption of Lactobacillus rhamnosus HN001 or Bifidobacterium lactis HN019 for 3 weeks increased the levels of CD56-positive lymphocytes in peripheral circulation and also increased PBMC tumoricidal activity in the elderly. Meanwhile, subjects who were fed with only milk (without the probiotics) had significantly lower levels of immune stimulation. Also, consumption of probiotic Bifidobacterium lactis HN019 with low-fat milk significantly increased the levels of helper (CD41), and activated (CD251) T lymphocytes and natural killer cells relative to those who consumed only low-fat milk [110]. In a recent study, administration of a multistrain probiotic to HIV-1 patients (twice daily for 6 months) induced an increase in the levels of Th17 cell subsets and a reduction in the levels of CD41 and CD81 T-cell subsets relative to a control group. Though probiotics may improve the immunological integrity of the intestinal mucosa barrier immune activations may only be part of the probiotic’s adaptation mechanism in the host [111]. However, due to the cell wall peptidoglycan, probiotic consumption could induce side effects such as fever [112], chronic inflammation, rheumatoid arthritis [113 115], cardioangiitis [116,117], and hepatobiliary lesions [113] as seen in animal studies. Yet, up to date, no adverse immunological side effects have been reported from oral administration of probiotics among humans. Certain probiotics have been shown to stimulate immune cell proliferation and activity to enhance immune response against pathogens [105,118]. In contrast, other probiotics suppress overreaction of the immune system, by suppressing effector cells and inducing tolerance mechanisms [112,118,119]. Therefore, classification of specific probiotic structural and functional relationships in target populations will minimize the possibility of triggering adverse harmful effects in the host. There is also a need for long-term studies concerning the potential of existing probiotics to induce inappropriate immune response in a large population of vulnerable subjects such as the aged, newborns, pregnant women, and people with other immunocompromised conditions. The effect of a probiotic on the immune system would depend on the outcome of the complex interactions between the microbial signals, the genetic make-up of the host and other environmental factors (Table 35.3).

35.2.4 ANTIBIOTIC RESISTANCE GENE TRANSFER The rise in antibiotic resistant infections has become an important global health concern as many bacteria continue to develop resistance against available antibiotics. Susceptible bacteria develop resistance to antibiotics either by genetic mutations or by acquiring resistance via horizontal gene transfer from other strains [133]. Many lactobacilli are known to be intrinsically resistant to aminoglycosides [134] while bifidobacteria are intrinsically resistant to streptomycin, gentamicin [135], and mupirocin [136]. However, probiotics with antibiotic resistant genes encoded by plasmids and transposons could be transferred to other members of the gut microbial ecosystem [137]. Mobilizable plasmids have been identified in L. plantarum 5057 (tetracycline resistance plasmid pMD5057) [138], L. plantarum M345 (erythromycin resistance plasmid pLFE1) [139], and L. fermentum ROT1 (dalfopristin- and erythromycin-resistance plasmid pLME300) [140]. Conjugative transposons have also been identified in E. faecium (Tn5233), E. faecalis (Tn916, Tn918, Tn920,

35.2 POTENTIAL SIDE EFFECTS OF PROBIOTIC CONSUMPTION

613

Table 35.3 Antibiotic Resistance Gene Transfer Among Lactic Acid Bacteria and Other Bacteria Antibiotic Resistant Gene

Bacteria Involved

References

tet(M) gene

From Lactobacillus plantarum to Lactococcus lactis BU-2-60 and to Enterococcus faecalis JH2-2 From Lactobacillus plantarum to Lactococcus lactis subsp. lactis From Lactobacillus alimentarius to Enterococcus faecalis JH2-2 From Lactobacillus sakei subsp. sakei to Enterococcus faecalis JH2-2 Lactobacillus plantarum to Enterococcus faecalis JH2-2 Lactobacillus reuteri to Enterococcus faecalis JH2-2 From Enterococcus faecalis to Escherichia coli Lactobacillus plantarum to Enterococcus faecalis From Lactobacillus reuteri to Enterococcus faecium From Enterococcus faecium to Enterococcus faecalis From Enterococcus faecalis to Lactobacillus fermentum From Enterococcus faecalis to Lactococcus lactis subsp.lactis Bu2-60 From Lactobacillus ivanovii to Enterococcus faecalis From Streptococcus faecalis to Lactobacillus plantarum From Lactobacillus lactis to Enterococcus faecalis JH2-2 From Streptococcus avium to Lactobacillus casei From Enterococcus faecalis RE25 to Listeria innocua, and Lactococcus lactis

Toomey et al. [120]

tet(M) gene tet(M) gene tet(M) gene erm(B) gene Plasmid pAM beta 1 (erythromycin resistance) Plasmid pAT191 (Kanamycin resistance) tet(M) and erm(B)genes Plasmid pAMβl (erythromycin resistance) Plasmid pAMβl (erythromycin resistance) Plasmid pAMβl (erythromycin resistance) Plasmid pAMβ1 (erythromycin resistance) tet(M) gene Plasmid pAMβ1 (erythromycin and lincomycin resistance) tet(M) gene (Tetracycline resistance) Plasmid pAMβ1 (erythromycin and lincomycin resistance) Plasmid pRE25 (resistant to aminoglycosides, lincosamides, macrolides, chloramphenicol, andstreptothricin)

Gevers et al. [121]

Tannock [122] and Morelli et al. [123] Doucet-Populaire et al. [124] Jacobsen et al. [125] McConnell et al. [126]

Kleinschmidt et al. [127] Pourshaban et al. [128] Shrago et al. [129] Boguslawska et al. [130] Gibson et al. [131] Schwarz et al. [132]

AAD, antibiotic-associated diarrhea; CDAD, clostridium difficile-associated diarrhea; Cfu, colony-forming unit; ICU, intensive care unit; NR, not reported; SIBO, small intestinal bacterial overgrowth; IBS, irritable bowel syndrome.

Tn925, Tn2702), and Lc. lactis (Tn5276, Tn5301) which can be used for antibiotic gene transfer [141]. This property is of particular concern because such resistant genes can be transferred to pathogens and make antimicrobial treatment difficult. Many studies have shown the ability of lactic acid bacteria to transfer antibiotic resistant genes within themselves and to pathogenic bacteria.

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Mater et al. have reported the ability of an Enterococcus strain to transfer a vancomycin resistance gene (Van A) to L. acidophillus in mice gut [135]. Several studies have shown the ability of animal Enterococcus faecium to transfer VanA genes to human Enterococcus faecalis in vivo [142,143]. Also Lactobacillus reuterii can transfer the macrolide resistance plasmid pAMl to Enterococcus faecium, and also from Enterococcus faecium to Enterococcus faecalis in the gut [126]. In another study, Enterococcus faecalis in food transferred high-level gentamicin resistance to E. coli in the gut [144], while aminoglycoside and macrolide resistance was transferred among Enterococcus faecium strains through conjugation in the gut [145]. Doucet-Populaire et al. [146] have also reported the ability of Enterococcus faecalis to transfer conjugative transposon Tn1545 (kanamycin, erythromycin, and tetracycline resistance) to Listeria monocytogenes in mice gut. The complex nature and diversity of the microbiota in the gut makes it difficult to detect horizontal gene transfer, but the conditions of the large intestine allows for transduction, natural transformation, and bacteria conjugation [147]. Therefore, although many antibiotic-resistant strains such as E. faecium have a long history of safe use in foods, it is imperative that the genetics of such antibiotic resistance in probiotics be critically studied.

CONCLUSION Many health professionals advocate the consumption of probiotics due to their ability to treat, prevent, or mitigate disease. Despite their numerous health effects, the necessity of probiotic safety data cannot be ignored. Most of the documented adverse side effects were case reports and only several randomized control trials have reported incidence of adverse side effects. Although probiotic consumption among healthy individuals is safe, administration among immunocompromised individuals should be used with caution. Lactobacillus rhamnosus and Saccharomyces boulardii seem to have the most record of sepsis and fungemia, respectively, in immunocompromised individuals, patients with short bowel syndrome, premature infants, patients with central venous catheters, and patients with cardiac valve disease. Since different probiotic strains may have different effects in health and disease, the effect of one strain cannot be generalized to other strains. It is important that clinical trials involving probiotics include active surveillance for cases of adverse effects associated with the probiotic.

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[127] Kleinschmidt J, Soeding B, Teuber M, Neve H. Evaluation of horizontal and vertical gene transfer and stability of heterologous DNA in Streptococcus thermophilus isolated from yogurt and yogurt starter cultures. Syst Appl Microbiol 1993;16(2):287 95. [128] Pourshaban M, Ferrini AM, Mannoni V, Oliva B, Aureli P. Transferable tetracycline resistance in Listeria monocytogenes from food in Italy. J Med Microbiol 2002;51(7):564 97. [129] Shrago A, Chassy B, Dobrogosz W. Conjugal plasmid transfer (pAM beta 1) in Lactobacillus plantarum. Appl Environ Microbiol 1986;52(3):574 6. [130] Boguslawska J, Zycka-Krzesinska J, Wilcks A, Bardowski J. Intra-and interspecies conjugal transfer of Tn916-like elements from Lactococcus lactis in vitro and in vivo. Appl Environ Microbiol 2009;75 (19):6352 60. [131] Gibson EM, Chace NM, London SB, London J. Transfer of plasmid-mediated antibiotic resistance from streptococci to lactobacilli. J Bacteriol 1979;137(1):614 19. [132] Schwarz FV, Perreten V, Teuber M. Sequence of the 50-kb conjugative multiresistance plasmid pRE25 from Enterococcus faecalis RE25. Plasmid 2001;46(3):170 87. [133] Munita JM, Arias CA. Mechanisms of antibiotic resistance. Microbiol Spect 2016;4(2). Available from: https://doi.org/10.1128/microbiolspec.VMBF-0016-2015. [134] Wong A, Saint Ngu DY, Dan LA, Ooi A, Lim RLH. Detection of antibiotic resistance in probiotics of dietary supplements. Nutr J 2015;14(1):95. [135] Mater DD, Langella P, Corthier G, Flores M-J. A probiotic Lactobacillus strain can acquire vancomycin resistance during digestive transit in mice. J Mol Microbiol Biotechnol 2008;14(1-3):123 7. [136] Serafini F, Bottacini F, Viappiani A, et al. Insights into physiological and genetic mupirocin susceptibility in bifidobacteria. Appl Environ Microbiol 2011;77(9):3141 6. [137] van Schaik W. The human gut resistome. Phil Trans R Soc B 2015;370(1670) 20140087. [138] Danielsen M, Wind A. Susceptibility of Lactobacillus spp. to antimicrobial agents. Int J Food Microbiol 2003;82(1):1 11. [139] Feld L, Bielak E, Hammer K, Wilcks A. Characterization of a small erythromycin resistance plasmid pLFE1 from the food-isolate Lactobacillus plantarum M345. Plasmid 2009;61(3):159 70. [140] Gfeller KY, Roth M, Meile L, Teuber M. Sequence and genetic organization of the 19.3-kb erythromycin-and dalfopristin-resistance plasmid pLME300 from Lactobacillus fermentum ROT1. Plasmid 2003;50(3):190 201. [141] Sharma P, Tomar SK, Goswami P, Sangwan V, Singh R. Antibiotic resistance among commercially available probiotics. Food Res Int 2014;57:176 95. [142] Bourgeois-Nicolaos N, Moubareck C, Mangeney N, Butel MJ, Doucet-Populaire F. Comparative study of vanA gene transfer from Enterococcus faecium to Enterococcus faecalis and to Enterococcus faecium in the intestine of mice. FEMS Microbiol Lett 2005;254(1):27 33. [143] Moubareck C, Bourgeois N, Courvalin P, Doucet-Populaire F. Multiple antibiotic resistance gene transfer from animal to human enterococci in the digestive tract of gnotobiotic mice. Antimicrob Agents Chemother 2003;47(9):2993 6. [144] Sparo M, Urbizu L, Solana M, et al. High-level resistance to gentamicin: genetic transfer between Enterococcus faecalis isolated from food of animal origin and human microbiota. Lett Appl Microbiol 2012;54(2):119 25. [145] Lester CH, Frimodt-Moller N, Hammerum AM. Conjugal transfer of aminoglycoside and macrolide resistance between Enterococcus faecium isolates in the intestine of streptomycin-treated mice. FEMS Microbiol Lett 2004;235(2):385 91. [146] Doucet-Populaire F, Trieu-Cuot P, Dosbaa I, Andremont A, Courvalin P. Inducible transfer of conjugative transposon Tn1545 from Enterococcus faecalis to Listeria monocytogenes in the digestive tracts of gnotobiotic mice. Antimicrob Agents Chemother 1991;35(1):185 7. [147] Mizan S, Lee MD, Harmon BG, Tkalcic S, Maurer JJ. Acquisition of antibiotic resistance plasmids by enterohemorrhagic Escherichia coli O157: H7 within rumen fluid. J Food Prot 2002;65(6):1038 40.

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FURTHER READING Aliakbarpour H, Chamani M, Rahimi G, Sadeghi A, Qujeq D. The Bacillus subtilis and lactic acid bacteria probiotics influences intestinal mucin gene expression, histomorphology and growth performance in broilers. Asian-Australas J Anim Sci 2012;25(9):1285. Cassone M, Serra P, Mondello F, et al. Outbreak of Saccharomyces cerevisiae subtype boulardii fungemia in patients neighboring those treated with a probiotic preparation of the organism. J Clin Microbiol 2003;41 (11):5340 3. Georgieva R, Yocheva L, Tserovska L, et al. Antimicrobial activity and antibiotic susceptibility of Lactobacillus and Bifidobacterium spp. intended for use as starter and probiotic cultures. Biotechnol Biotechnol Equip 2015;29(1):84 91.

CHAPTER

BIOACTIVE OLIVE OIL POLYPHENOLS IN THE PROMOTION OF HEALTH

36

Nancy B. Ray1, Kyle D. Hilsabeck1, Tom C. Karagiannis2 and D. Elizabeth McCord1 1

McCord Research, Coralville, IA, United States 2Monash University, Epigenomic Medicine, Central Clinical School, The Alfred Centre, Prahran, VIC, Australia

36.1 INTRODUCTION Olive polyphenols are part of the minor components that comprise approximately 2% of the total weight of olive oil. They are found in the unsaponifiable fraction that includes the phenolic alcohols, hydroxytyrosol and tyrosol, and the secoiridoids, oleuropein and oleocanthal [1,2], with the latter two responsible for the pungent and throat-irritating qualities of olive oil, respectively [1,3,4]. This chapter review will focus on these polyphenols due to the substantial quantity of evidence that exists concerning these compounds in relation to human health as discussed in recent reviews [5,6]. The concentration of polyphenols in olive oil is dependent upon the olive tree variety, the stage of ripening and extraction, as well as storage conditions and other variables [1,7]. Olive oil is a main component of the Mediterranean diet that has been shown to have various positive health effects [8], and olive polyphenols have been associated with many of the beneficial effects of olive oil on health including antioxidant, antiinflammatory, enhanced wound healing, and digestive health, as well as effects against diabetes, osteoporosis, heart disease, neurological disease, and cancer [7 12]. In fact, it has been proposed that extra-virgin olive oil (EVOO) fits the definition of a functional food due to its “clinically proven and documented health benefits for the prevention, management or treatment of chronic disease” [13] (Fig. 36.1). The polyphenols found in olive oil, like other polyphenols are produced by the olive tree during stress to protect the olive fruit and other parts of the tree from pests and microbial infections [1] Interestingly, the polyphenols found in olive oil including hydroxytyrosol, oleuropein, tyrosol, and oleocanthal are also antioxidants that help prevent autooxidation of the oil [14,15]. Hydroxytyrosol, which is produced from oleuropein by hydrolysis, has the strongest antioxidant effect of the polyphenols found in EVOO [16], and tyrosol has the weakest antioxidant effect [17].

36.2 ORAL BIOAVAILABILITY AND METABOLISM OF OLIVE POLYPHENOLS Most important polyphenols from olive oil include the phenolic alcohols hydroxytyrosol and tyrosol as well as the secoiridoids oleuropein and ligstroside as glycosides and aglycones [18]. Olives also The Role of Functional Food Security In Global Health. DOI: https://doi.org/10.1016/B978-0-12-813148-0.00036-0 © 2019 Elsevier Inc. All rights reserved.

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FIGURE 36.1 Accumulating evidence suggests that olive oil polyphenols have various beneficial effects, represented by the arrows directed at eight highlighted areas of health.

contain phenolic acids (benzoic and cinnamic acids), lignans (pinoresinols), and flavonoids (apigenin and luteolin); however, this section will focus on the phenolic alcohols and secoiridoids as they have more research behind them. The absorption and bioavailability of olive polyphenols has predominately been conducted on hydroxytyrosol, tyrosol, and oleuropein and their derivatives, but the findings have been somewhat inconsistent, conflicting, and sometimes controversial [18]. The metabolic pathways of hydroxytyrosol, tyrosol, and oleuropein are further complicated by the fact that there are endogenous sources of these compounds and/or their metabolites as part of natural dopamine metabolism. Hydroxytyrosol, also referred to as 3,4-dihydroxyphenyethanol (DOPET), is a known metabolite of dopamine, as are many of the hydroxytyrosol metabolites including homovanillic acid (HVA), HVA1c, 3,4-dihydroxyphenylacetic acid (DOPAC), and 3,4-dihydroxyphenyl acetaldehyde (DOPAL) [19,20]. Hydroxytyrosol and other metabolites can freely pass through the blood brainbarrier making it somewhat difficult to separate endogenous production from exogenous sources in pharmacokinetic studies [18,20,21]. The majority of in vivo data on olive polyphenols has been completed in rat models and some research has indicated as much as a 25-fold increase in excretion of metabolites when comparing rats to humans [18]. It is also notable that many of the studies in both rats and humans have utilized preparations that are enriched with polyphenols, and may not represent the typical exposure from regular consumption of standard olive oil preparations [18]. Some forms of olive polyphenols are susceptible to hydrolysis in low pH environment of the stomach, however it appears that significant portions of these compounds can survive into the small intestines where most absorption occurs [18]. Hydroxytyrosol and tyrosol are predominantly absorbed in the small intestine; however, oleuropein is absorbed mostly in the colon following bioconversion by intestinal bacteria [22].

36.3 ANTIOXIDANT AND ANTIINFLAMMATORY PROPERTIES

625

Olive polyphenols are absorbed into the bloodstream relatively well following oral administration; however, most of the compounds are subject to significant first-pass hepatic metabolism that potentially reduces their distribution and bioavailability throughout the body. However, researchers have identified dose-dependent effects throughout the body leading many investigators to believe that several of the metabolites have biological activity. Some hypothesize that certain metabolites such as glucuronide and sulfate conjugates may even function as depot forms of the polyphenols, slowly releasing the free polyphenols into the bloodstream [20]. As mentioned before, the research is clouded by the fact that many of the polyphenols and metabolites are endogenously produced as a part of normal dopamine metabolism, so there is still significant research needed to better understand the complexities. Typically, olive polyphenols are quickly absorbed in 5 10 minutes after administration, with more efficient absorption observed with oil-based formulations versus water-based [21]. While some of the polyphenol derivatives and conjugates may persist longer by certain mechanisms including binding to circulating lipoproteins, free-circulating hydroxytyrosol has a short 1 2 minutes half-life before being excreted by the kidneys [21]. There is significant absorption of most olive polyphenols and their derivatives into the bloodstream, however it is hard to pinpoint the exact bioavailability and activity without further research in human models. However, dose-dependent increases in plasma levels, urinary excretion, and biochemical effects have been identified, indicating that oral administration can deliver olive polyphenols into the bloodstream with subsequent biochemical activity throughout the body by the polyphenols and/or their derivatives. The average consumption of olive oil per capita per day in the three Mediterranean countries where it is consumed the most (Greece, Italy, and Spain) is approximately 42 mL/day with Greece having the highest consumption per capita of approximately 55 mL/day [23] The full extent of oral bioavailability is still in need of further research.

36.3 ANTIOXIDANT AND ANTIINFLAMMATORY PROPERTIES Many health issues including type 2 diabetes mellitus, vascular disease, and neurodegenerative diseases are associated with oxidative stress [24,25]. Oxidative stress occurs when cells are unable to eliminate free radicals known as reactive oxygen species (ROS) using the natural antioxidant defense system that includes glutathione and defense enzymes such as superoxide dismutase (SOD) and hydrogen peroxidase (HO)-1 [26,27]. When cells undergo oxidative stress, they express genes encoding detoxifying enzymes in the cytoplasm, under the control of the nuclear factor erythroid 2-related factor 2 (Nrf2), such as glutathione S-transferase (GST) and HO-1 [27]. Mitochondria, the powerhouses of cells, produce free radicals including ROS during metabolism and can contribute substantially to oxidative stress when damaged or dysfunctional [28]. The mitochondrial antioxidant system is regulated by the forkhead box “O” (FOXO) transcription factor, FOX03a that activates manganese (Mn) SOD [27]. As mentioned, hydroxytyrosol, oleuropein, tyrosol, and oleocanthal possess antioxidant activity. Hydroxytyrosol has been found to activate Nrf2, FOXO3a, and MnSOD, as well as decrease mitochondrial dysfunction [27,29]. In addition, hydroxytyrosol and oleuropein have been shown to upregulate Nfr2 and activate HO-1 [30,31].

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Oxidative stress is associated with inflammation and ROS can activate signaling pathways and transcription factors involved in inflammatory cascades, including NFkB, a key transcription factor involved in inflammation regulation [32]. All of the antioxidant olive polyphenols previously mentioned also possess antiinflammatory activities [4,9,33,34]. In fact, hydroxytyrosol has been shown to inhibit activation of NFkB [21], which upregulates many inflammatory cytokines during the acute phase of inflammation, including IL-1, IL-6, and TNF-alpha. Inflammation is the body’s response to infection and injury, and accumulating evidence indicates that it plays an important role in many diseases including diabetes, arthritis, cancer, and cardiovascular disease [35,36]. Markers of inflammation include matrix metalloproteinases (MMPs), C-reactive protein (CRP), and cyclooxygenase (COX)-2, an enzyme that produces prostaglandins, which help mediate the inflammatory response [35 37]. Interestingly, oleocanthal was observed to have irritating qualities similar to the NSAID, ibuprofen, and was found to inhibit COX-1 and COX-2 enzymes, mimicking the antiinflammatory activity of ibuprofen [38]. Hydroxytyrosol has also been shown to decrease the level of COX-2 messages [39], and oleuropein has been found to inhibit the production of inflammatory cytokines and lipoxygenase (involved in prostaglandin metabolism) activity [33,40]. Recently, tyrosol has also been shown to have antiinflammatory activity, partially induced by preventing the phosphorylation of NFkB signaling proteins [34].

36.4 IMMUNE CELL RESPONSES AND WOUND HEALING During inflammation induced by invading pathogens or injury, sensor cells including mast cells, dendritic cells, and macrophages detect infection or tissue damage and express inflammatory mediators including inflammatory cytokines. Neutrophils are recruited from the circulation and certain inflammatory cytokines induce the liver to produce acute phase proteins such as CRP. Normally, a transition from neutrophil to monocyte/macrophage recruitment results in the removal of debris, resolution of inflammation, and initiation of tissue repair. If the inflammatory trigger is not removed, chronic inflammation and chronic wounds may occur. In addition, some health conditions have less distinct inflammatory triggers including diabetes, obesity, neurodegenerative diseases, and cancer that are associated with chronic inflammation [41]. Oral olive oil administration has resulted in reduced inflammation and enhanced wound healing [42,43]. Hydroxytyrosol and oleuropein have been shown to increase wound healing by increasing cell endothelial cell migration (even with high glucose simulating diabetic wounds) and have been found to increase angiogenesis (unpublished results from our laboratory). Endothelial cell repair and wound healing has also been correlated with Nrf2 activation or nuclear accumulation and increased HO-1 expression [30,31]. Evidence for hydroxytyrosol and oleuropein reversing endothelial dysfunction, which occurs with diabetes, has also been found [14,31]. In addition, evidence indicates that mast cells regulate wound healing in diabetes [44] and that therapies that inhibit mast cell degranulation (including histamine release) could improve wound healing in diabetes. Interestingly, hydroxytyrosol and oleuropein have both been shown to inhibit mast cell degranulation [45]. Antimicrobial properties of olive polyphenols are likely to benefit wound healing. Hydroxytyrosol and/or oleuropein have been shown to inhibit the growth of wound pathogens including Staphylococcus aureus and Candida albicans [46,47].

36.6 CANCER

627

36.5 DIGESTIVE HEALTH The potential impacts of olive polyphenols in digestive health are particularly interesting because the polyphenols have direct contact with the gastric and intestinal mucosa, allowing for direct cellular exposure while avoiding the first-pass hepatic metabolism previously discussed. Studies have demonstrated that several of the olive polyphenols and/or derivatives can passively diffuse into enterocytes quite readily [18,48]. The mucosa, therefore, does not rely on increasing plasma levels to observe some of the researched benefits, though there is likely added benefit from circulating polyphenols and derivatives. Olive oil polyphenols can also directly impact digestive health by promoting an intestinal microbiome that supports intestinal immune homeostasis, which expands the potential benefits to a broad spectrum of disease processes known to be tied into this system [49,50]. The findings that topical application of olive polyphenols can improve wound healing processes and is also relevant in digestive health as oral administration of the polyphenols can serve as a topical application to the gastric and intestinal mucosa [51,52]. The implications are that topical would healing properties have utility in restoring damaged and inflamed mucosa. The combination of systemic effects paired with direct topical effects on mucosa, modulation of microbiome, and immunemodulation all contribute to the observed benefits of olive polyphenols in a wide variety of digestive issues including IBS, Crohn’s disease, ulcerative colitis, and even cancer [53 55].

36.6 CANCER Cancer is a complex disease that involves the transformation of normal cells into malignant cells that can grow beyond normal boundaries, forming tumors and frequently invading other tissues or spreading. The increased proliferation of cancer cells compared to normal cells is due to the lack of growth regulation that is found in normal cells. In addition, normal cells monitor DNA damage that may occur and arrest their growth until the damage is repaired, or if unable to repair damage, activate apoptosis. Cancer cells, however, are fairly resistant to apoptosis [56,57]. VOO consumption and the incidence of many forms of cancer including colon, breast, and skin cancer have been inversely correlated [7]. In fact, a systematic review and meta-analysis that included 13,800 patients came to the conclusion that olive oil consumption is inversely related to cancer prevalence [58]. The anticancer properties of olive oil polyphenols have recently been reviewed [7,56]. Some anticancer mechanisms and targets of olive polyphenols are summarized in Table 36.1 including cytoskeleton disruption [59], lysosomal membrane permeabilization [60], C-Met signaling inhibition [61,62], and epidermal growth factor receptor (EGFR) downregulation and degradation [63]. Many studies have demonstrated antiproliferative and proapoptotic effects of oleuropein with different cancer types including studies involving breast, colorectal, lung, leukemia, and prostate cancer cell lines (unpublished results from our laboratory) [3]. Other studies have also shown that hydroxytyrosol decreases proliferation and induces apoptosis in various types of cancer cells including breast, prostate, as well as in various leukemia cell lines (unpublished results from our laboratory) [9,11,64]. In fact, oleuropein and hydroxytyrosol have invariably been found in

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CHAPTER 36 BIOACTIVE OLIVE OIL POLYPHENOLS IN THE PROMOTION

Table 36.1 Some Anticancer Mechanisms and Targets of Olive Oil Phenols Mechanism

Effect

Cancer Cells

Target

Polyphenol

References

Estrogen competition Cytoskeleton disruption

Proliferation inhibition Proliferation, migration, inhibition Apoptosis, necrosis

Breast

Estrogen receptor Actin filaments

Oleuropein, hydroxytyrosol Oleuropein

[73]

Lysosome

Oleocanthal

[63]

Breast, prostate

C-Met kinase

Oleocanthal

[64,65]

Colon

EGFR

Hydroxytyrosol

[66]

Lysosomal membrane permeabilization C-Met signaling inhibition EGFR down regulation, degradation

Proliferation, migration, invasion inhibition Proliferation inhibition

Leukemia, renal, breast, colorectal melanoma Prostate, breast, pancreatic

[62]

numerous studies to have these effects (inhibition of proliferation and induction of apoptosis) in cancer cells without affecting normal cells [36]. In addition, oleocanthal has been shown to induce death or inhibit proliferation and/or migration and invasion of breast, colon, prostate, or pancreatic cancer cell lines, as well as multiple myeloma cells [60,61,65]. In animal model studies, orally delivered oleuropein induced complete soft tissue sarcoma tumor regression [59] and in another study, decreased the incidence and volume of skin tumors [66]. Hydroxytyrosol delivered orally, was shown to decrease breast tumor volume [21]. In addition, oleocanthal treatment was found to suppress tumor cell growth in a model of breast cancer [61]. As mentioned, various olive polyphenol anticancer activities have been demonstrated, including those involving apoptosis. Cancer cells have greater ROS production due to their higher metabolism [67], and olive polyphenols including hydroxytyrosol and oleuropein can induce prooxidative effects in cancer cells that lead to apoptosis. Interestingly, one hypothesis (xenohormesis) proposes that polyphenols produced by plants under stress might also activate stress responses in humans, including oxidative stress responses that protect against diseases such as cancer [36]. Cancer is an inflammatory disease and NFkB plays an important role in many inflammatory pathways [35]. Evidence indicates that the olive polyphenols, oleuropein, and hydroxytyrosol can inhibit NFkB and modulate these pathways that are related to inflammatory cytokine, COX-2, and iNOS production in various cancer types. Interestingly, therapies that inhibit COX-2 have decreased breast cancer risk and have had proapoptotic effects in a breast cancer cell line [36]. The tumor suppressor gene, p53, mediates apoptosis following damage to cellular DNA. In an important study, oleuropein was shown to induce apoptosis in breast cancer cells via a p53-dependent pathway [68]. High levels of estrogen are linked with breast cancer development. An interesting mechanism proposed to explain certain anticancer activities of hydroxytyrosol and oleuropein on breast cancer cells, highlights the fact that these polyphenols have an aromatic ring analogous to estradiol that could compete with estrogen [69].

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Inhibition of a heat shock protein is involved in an additional olive polyphenol anticancer activity. Interestingly, oleocanthal was found in a study to inhibit Hsp90, a key target in cancer therapy [70]. Cells exposed to stress, including wounding, produce heat-shock proteins (HSPs) whose primary role is in aiding protein folding and maintaining the structures and functions of the proteins that they chaperone. Molecular chaperones protect proteins under stress that results in their unfolding, and their expression and activities are substantially increased in a variety of cancer types, resulting in the suppression of apoptosis [71]. Oleocanthal had a proapoptotic effect on leukemia cells in the aforementioned study with only a slight decrease in the viability of normal cells, which is typical of other Hsp90 inhibitors [4].

36.7 CARDIOVASCULAR DISEASE There are many etiologies behind the various forms of cardiovascular disease, however there are some common motifs that all tend to include components of inflammation, endothelial dysfunction, and metabolic impairments associated with metabolic syndrome, obesity, and/or dyslipidemia [72,73]. Accumulating evidence suggests that olive oil polyphenols can influence these processes, indicating that polyphenols have tremendous potential in addressing the causative and contributing factors in a wide variety of cardiovascular disorders [8,11]. In fact, olive polyphenols are thought to play a significant role in the improved cardiovascular health observed in adherents to Mediterranean diets that incorporate significant amounts of olives and olive oil [74]. Some examples of the effects of olive oil polyphenols against cardiovascular disease are summarized in this section including the observation that hydroxytyrosol was able to reverse chronic inflammation and oxidative stress that can lead to the development of cardiovascular, hepatic, and metabolic syndrome from a high-carbohydrate and high-fat diet [75]. Polyphenols have also been shown to improve vascular function and reduce inflammation and fibrosis in heart tissues, reduce left ventricle stiffness, and improve aortic reactivity, while simultaneously improving abdominal fat deposition, plasma triglycerides, total cholesterol, glucose tolerance, and insulin sensitivity [75,76]. Moreover, the antiinflammatory and antioxidant properties of oleuropein appear to contribute to the antithrombotic and antiatherogenic properties of oleuropein, which has also been shown to have beneficial effects in dyslipidemia and preventing LDL oxidation [33]. In addition, studies in hypertensive patients have shown therapeutic benefits from high-phenolic olive oil that was not observed with low-phenolic olive oil, leading researchers to attribute the observed effects to the natural polyphenols [77]. Moreover, oleuropein has been shown to demonstrate cardioprotective effects following ischemia and doxorubicin-induced cardiomyopathy [8]. Finally, there have been some clinical trials that have examined the effects of olive oil on cardiovascular disease and related health problems, including diabetes, that have indicated that the consumption of olive oil can provide protection against various aspects of cardiovascular disease [1,7].

36.8 DIABETES People with type 2 diabetes mellitus have an increased risk of cardiovascular disease, neurodegenerative disorders, retinopathy, impaired wound healing, and cancer. Throughout this chapter, we

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have or will discuss the impact olive polyphenols can have in each of those conditions, and the benefits are observed in the diabetic patient as well. Many of the studies that attribute benefits of olive polyphenols in people with diabetes have done so due to the aforementioned reasoning, however there is also evidence suggesting the polyphenols have more direct effect on sugar metabolism, fasting glucose levels, glycosylated hemoglobin (HbA1C), and BMI [8,17,78]. In addition, oleuropein has recently been shown to protect beta cells from cytotoxicity induced by amylin amyloids that are characteristic of type 2 diabetes [79].

36.9 NEURODEGENERATIVE DISEASE There is a continuously increasing body of evidence implicating oxidative and inflammatory processes, as well as mitochondrial dysfunction in a variety of neurological and neurodegenerative disorders [80,81]. Naturally, due to their well-documented antiinflammatory and antioxidant properties, olive polyphenols are increasingly being investigated for their potential neuroprotective effects [82]. Hydroxytyrosol has been shown to increase genetic expression of key cellular antioxidants that protect brain cells from free radical damage that contributes to neurodegenerative processes [29,83]. Hydroxytyrosol has also been shown to protect against mitochondrial dysfunction [28] including in rat brains [84]. Oleuropein has demonstrated protective effects on dopaminergic neurons located in the substantia nigra, implying possible roles in preventing or treating Parkinson’s disease [33]. Oleuropein also interacts with some of the biochemical processes behind the formation and deposition of betaamyloid plaques and Tau proteins associated with Alzheimer’s Disease, with promising studies showing possible protective effects [33]. In addition, oleocanthal has been found to enhance amyloid-beta clearance from the brains of mice [85,86]. Moreover, oleocanthal was found to interfere with Tau aggregation [87].

36.10 OSTEOPOROSIS AND BONE LOSS Bone formation and maintenance is regulated by bone-producing osteoblasts and bone-reabsorbing osteoclasts, and imbalance of these processes can result in diseases including osteoporosis [88], which has the lowest incidence in the Mediterranean region where the Mediterranean diet is common [89]. Interestingly, EVOO phenolic extracts have been shown to increase osteoblastic cell proliferation [90]. In addition, olive oil oral supplementation has been found to increase bone thickness and density in ovariectomized mice [91,92], and hydroxytyrosol has been found to suppress bone loss in ovariectomized mice [93]. Importantly, female patients 30 50 years of age who had hysterectomies were provided with 50 mL of olive oil per day or nothing (control) in a study where it was found that bone density decreased in the control group, but not in the treatment group [92]. Estrogen deficiency is a major factor contributing to osteoporosis, however oxidative stress and inflammation are thought to play critical roles as well, and notably, patients with inflammatory diseases including inflammatory bowel disease, rheumatoid arthritis, and chronic obstructive pulmonary disease experience decreased bone mass and increased fractures. In fact, inflammatory

REFERENCES

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mediators have been found to affect bone remodeling, and antiinflammatory therapies have positive effects on bone fragility markers [12].

36.11 RESPIRATORY HEALTH Olive polyphenols have been shown to play a role in reducing oxidative stress and modulating inflammatory responses in the lungs [94,95]. Studies have shown a variety of positive effects including reductions in inflammatory markers, improved lung function, and fewer exacerbations of conditions like COPD, emphysema, and asthma [94].

36.12 CONCLUSION The positive health effects of the Mediterranean diet have indicated that olive oil, a main component, may also have various positive health effects, which in recent years have been investigated and substantiated. Here, we have reviewed evidence for many of these health effects including against diabetes, cancer, and heart disease. There are numerous other favorable effects of olive oil polyphenols on health that were not reviewed such as against arthritis, obesity, and liver disease. Although evidence is rapidly accumulating to support the beneficial health effects of olive oil polyphenols, more human trials may be needed before the general public is convinced and willing to incorporate olive oil into their diet, suggesting that olive polyphenol supplementation is important.

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CHAPTER

FUNCTIONAL FOOD SECURITY FOR OSTEOPOROSIS, CARCINOGENESIS, ATHEROSCLEROSIS AND BRAIN DEGENERATION

37

Kumar Kartikey1, Garima Singh1, Deepak Sah2, Ram B. Singh1, Amrat K. Singh3, Toru Takahashi4 and Agnieszka Wilczynska5 1

Halberg Hospital and Research Institute, Moradabad, Uttar Pradesh, India 2Shah Nursing Home, Moradabad, Uttar Pradesh, India 3Neuron Hospital, Kanth Road, Moradabad, Uttar Pradesh, India 4Graduate School of Human Environment Science, Fukuoka University, Fukuoka, Japan 5The Tsim Tsoum Institute, Krakow, Andrzej Frycz Modrzewski Krakow University, Krakow, Poland; Krakow University, Krakow, Poland

37.1 INTRODUCTION Diet and lifestyle factors, such as Western diet, physical inactivity, mental stress, tobacco use, alcohol intake, and positive family history, are important risk factors of noncommunicable diseases including cardiovascular diseases (CVDs), cancers, and neuropsychiatric diseases [1 3]. CVDs, in particular atherosclerosis, may be associated with osteoporosis resulting in increased rates of bone and joint diseases (osteoporosis) and cancers (carcinogenesis), directly by causing inflammation as well as due to gene and environment interactions (Fig. 37.1). The increased prevalence of NCDs is characterized by inflammation which is important in the pathogenesis of atherosclerosis, osteoporosis, and carcinogenesis and suggests that inflammation, caused by excessive and inappropriate innate immune system (IIS) activity, due to unhealthy diet and lifestyle factors, is unable to respond appropriately to danger signals that are new in the context of evolution [1 4]. This leads to unresolved or chronic inflammatory activation in the body leading to autonomic nervous system dysfunction resulting in atherosclerosis, osteoporosis, and carcinogenesis as well as neuronal degeneration. CAD is a major cause of death among postmenopausal women from the onset of menopause which is closely related to the onset of coronary atherosclerosis and osteoporosis as well as psychological disorders. This review aims to describe the association of these chronic diseases.

The Role of Functional Food Security In Global Health. DOI: https://doi.org/10.1016/B978-0-12-813148-0.00037-2 © 2019 Elsevier Inc. All rights reserved.

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CHAPTER 37 FUNCTIONAL FOOD SECURITY FOR OSTEOPOROSIS

Pathway for development of Risk Factors of Osteoporosis due to interaction of gene and environment?. (modified from singh et al 1 Environmental risk factors Behavioral risk factors No prayer & meditation Urbanization Alcoholism-tabacco Globalization Physical inactivity Industrialization Circadian disruption Pollution,modernization Psychosocial stress Biological risk factors

High oxidative stress High blood glucose, Antioxidant and calcium deficiency High inflammatory. cytokines. High cancer markers Blood pressure variability

Non communicable diseases

Atherosclerosis. Joint dis & osteoporosis Hypertension, stroke carcinogenesis Obesity and Type 2 diabetes Neuropsychiatric diseases.

FIGURE 37.1 Pathway for development of osteoporosis, atherosclerosis, carcinogenesis, and brain degeneration.

37.2 ASSOCIATION OF RISK FACTORS AND OSTEOPOROSIS The risk factors associated with CAD in postmenopausal women, which are critical for reducing related mortality, along with associated healthcare costs, are important to emphasize the association of hormones with atherosclerosis and osteoporosis. The prevalence of CAD has risen in tandem with increased life expectancy and with the emergence of chronic diseases. Hence, the number of postmenopausal women who suffer from CAD is expected to increase over time in conjunction with increases in osteoporotic fractures and cancers. Previous studies have demonstrated that osteoporosis and atherosclerosis have common etiological factors and mechanisms, suggesting that the presence of osteoporosis is a predictor of atherosclerosis [2 4]. Recent studies indicate that decreased bone mineral density (BMD) is associated with vascular calcification, which has been found to be a predictor of overall CAD incidence and mortality. Several prospective studies have reported that low BMD and bone loss are risk factors for CAD-related mortality. Fig. 37.2 shows the threshold of atherosclerosis and carcinogenesis in apparently healthy subjects. A population-based cohort study involving 19,456 patients aged 45 years or older who had no history of CAD and had a diagnosis of osteoporosis were identified as the osteoporosis cohort in Taiwan [2]. The patients in the comparison cohort were randomly selected and frequency matched according to age, sex, and year of index date at a 1:1 ratio. Both cohorts were followed from the index date until a new diagnosis of CAD was made. Baseline variables, comorbidities, and intakes of bisphosphonate and estrogen prescriptions were collected. The overall incidence of CAD was 23.5 (per 1000 person-years) for the osteoporosis cohort and 16.7 for the comparison cohort, with a mean follow-up of 6.54 years and 6.63 years, respectively. The hazard ratio (HR) for developing CAD during follow-up was 1.30 (95% CI: 1.23 1.38) for the osteoporosis cohort compared with the

37.2 ASSOCIATION OF RISK FACTORS AND OSTEOPOROSIS

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FIGURE 37.2 Threshold of atherosclerosis in patient with infarction and carcinogenesis.

comparison cohort after adjusting for age, gender, comorbidities, and estrogen medication. Patients with osteoporosis who received treatment with bisphosphonates or with both bisphosphonates and estrogen exhibited a significantly lower risk for CAD (adjusted HR 5 0.37 and 0.23) than those who did not receive either of these two medications. A retrospective review of 252 postmenopausal women who had visited a health promotion center for a routine checkup were examined for bone mineral density (BMD) of the lumbar spine (L1 L4) and femoral neck using dual-energy X-ray absorptiometry. Coronary atherosclerosis was assessed using 64-row multidetector computed tomography [3]. Participants were divided into normal BMD and osteopenia-osteoporosis groups, according to the T-scores of their lumbar spine or femoral neck. Participants with osteopenia-osteoporosis had a significantly higher proportion of coronary atherosclerosis than did those with normal BMD at the lumbar spine (P 5 .003) and femoral neck (P 5 .004). Osteopenia-osteoporosis at the lumbar spine (odds ratio (OR), 2.86; 95% CI: 1.12 7.27) or femoral neck (OR, 3.35; 95% CI: 1.07 10.57) was associated with coronary atherosclerosis, after controlling for age and cardiovascular risk factors. The findings revealed that decreased BMD is associated with coronary atherosclerosis in healthy postmenopausal women, independent of age and cardiovascular risk factors. Postmenopausal women with decreased BMD may have a higher risk of developing coronary atherosclerosis as well as cancers. In the pathogenesis of variant angina, focal spasm of the epicardia coronary arteries is variably associated with atherosclerotic coronary disease [4]. Although not previously reported, administration of the endothelin antagonist bosentan (bisphosphonates) resulted in complete resolution of her symptoms which were refractory to commonly used antianginals, and these symptoms recurred when the drug was inadvertently withdrawn, confirming the agent’s efficacy. There is convincing

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evidence for a reduction in risk of osteoporosis, carcinogenesis, neuronal plasticity, and atherosclerosis with increased intake of dietary vitamin D and calcium, omega-3 fatty acids, flavonoids, and physical activity, and for an increased risk with high intake of Western diet and sedentary behavior [1 9]. No study has examined the role of nutrients among post-operative outcome in patients with osteoporotic hip fracture. Dietary calcium, vitamin D, ω-3 fatty acid, and magnesium deficiency have been studied in the pathogenesis of osteoporosis (known to predispose fractures), as well as in atherosclerosis [4]. However, the role of ω-3 fatty acid metabolism in the pathogenesis of osteoporosis has not been studied thoroughly, although several studies are available to indicate that ω-3 fatty acids are cardioprotective and antithrombotic and can protect against neuronal degeneration and carcinogenesis [7 10]. Millions of people around the world are suffering from osteoporosis. It is characterized by low bone mass and microarchitectural deterioration of bone tissue, leading to bone fragility and a consequent increase in risk of fracture [1 3]. The incidence of vertebral and hip fractures increases exponentially with advancing age while that of risk of fractures levels off after the age of 60 years [3]. Osteoporosis fractures are a major cause of morbidity and disability in older people and, in the case of hip fractures, can lead to premature death [1 4]. Such fractures impose a considerable economic burden on health services in both developed and developing countries [4]. Worldwide variation in the incidence and prevalence of osteoporosis is difficult to determine because of problems with definition and diagnosis. The most useful way of comparing osteoporosis prevalence between populations is to use fracture rates in older people. However, because osteoporosis is usually not life-threatening, quantitative data from developing countries are scarce, despite this, the current consensus is that approximately 1.66 million hip fractures occur each year worldwide, that the incidence is set to increase four-fold by 2050, because of the increasing numbers of older people, and that the age-adjusted incidence rates are many times higher in affluent developed countries than in sub-Saharan Africa and Asia [1 4]. Recent studies [5,6] indicate that hip fractures are two- to fivefold more common among patients with CVD which poses the possibility that both problems may have a common unifying hypothesis for their pathogenesis, to account for the cause of this association. The role of ω-3 fatty acids and the body mind interaction in relation to atherosclerosis and osteoporosis need further consideration.

37.3 DIET AND RISK OF OSTEOPOROSIS, ATHEROSCLEROSIS, CARCINOGENESIS In the last few decades, our knowledge about the global dimensions of noncommunicable diseases (NCD), including osteoporosis, carcinogenesis, and CVDs had tremendous growth [1 8]. Recent studies indicate that there is coexistence of nutritional deficiencies and appreciable overnutrition in the form of central obesity and overweight in developing countries and in developed countries onequarter of the population is obese, which may be risk factors for CVD and osteoporosis [1 6]. Hip fractures rates are highest in Caucasian women living in temperate climates, slightly lower in women from Mediterranean and Asian countries, and are lowest in women in Africa [1 4]. The lower incidence of hip fractures in these countries indicates that differences in diet and lifestyle appear to be important in the pathogenesis and prevention of osteoporosis and hip fractures, similar to

37.3 DIET AND RISK OF OSTEOPOROSIS, ATHEROSCLEROSIS

643

FIGURE 37.3 Nutritional modulators of inflammation.

atherosclerosis [9 13]. Experimental and clinical studies [13 16] indicate that the high intake of ω-6 and low ω-3 fatty acids in the diet contribute to the development of CVD as well as osteoporotic hip fractures and cancers by enhancing inflammation (Fig. 37.3). Recently, increased intake of fruits, vegetables, legumes, fish, and nuts that are rich in ω-3 fatty acids (alpha-linolenic acid) have been found to be protective against risk of CVD and osteoporosis, which poses the possibility that these foods and nutrients may protect against fracture and CVD and provide better quality of life [13 20]. High-protein diets and physical activity also protect against osteoporosis-induced fractures and CVD. These protective factors are also beneficial against depression and memory dysfunction, indicating that body mind interaction appears to be important in the prevention of these diseases. In the pathogenesis of NCDs, it is possible, that overweight comes first in conjunction with inflammation, hyperinsulinemia, increased angiotensin activity, vascular variability disorders, and central obesity, followed by glucose intolerance, type 2 diabetes, hypertension, low HDL, and hypertriglyceridemia (metabolic syndrome) [9,10]. This sequence is followed by CAD, gallstones, and cancers and finally dental caries, gastrointestinal diseases, degenerative diseases of the brain and psychological disorders, and bone and joint diseases. We suggest that this sequence also includes osteoporosis, during transition from poverty to affluence. These NCDs may be associated with increased production of thromboxane A2, leucotrienes, interleukins-1 and -6, tumor necrosis factor-alpha and C-reactive protein. Increased dietary intake of ω-6 fatty acids and low ω-3 fatty acids are known to enhance these risk factors and risk of all these diseases, by having adverse proinflammatory effects, whereas increased ω-3 fatty acids and some of the other nutrients are protective against inflammation [9 20] (Fig. 37.3). There is evidence [21] that depression and dementia may be associated with atherosclerosis as well as osteoporosis because of a unifying hypothesis that inflammation characterized with high concentrations of C-reactive protein, IL-6, IL-1, and TNF-alpha can predispose all the three chronic diseases of affluence (Fig. 37.2).

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In a clinical study among 25 patients, aged 40 70 years; half of the subjects were men [6]. Prosthetic surgery, Austin Moores Prosthesis, and Bipolar Prosthesis were used in all the patients. They were hospitalized and followed-up daily for various complications during hospitalization and at weekly follow-up for 12 weeks. Quality of life was assessed by a 6-min walk test and the distance walked was recorded. We recorded 4-hourly blood pressure measurements, heart rate, respiratory rate, and temperature to study their time-adjusted variations for early diagnosis of infections, and vascular complications. One-fifth of the patients had indicated high risk of CVD. Of 25 patients, one patient developed acute myocardial infarction and another one had a stroke. Popliteal vein thrombosis and thrombo-phlebitis were observed in approximately one-third of the patients. Most vascular injuries have been reported to occur during revision surgery, and since there is an increase in the number of revisions being performed, the incidence of vascular injuries may show increase. Subjects taking statins may have less osteoporosis and less vascular complications. Approximately 95% patients had osteoporosis which was the commonest cause of hip joint fracture. The fracture was associated with low intake of protein in the diet and sedentary behavior. Larger studies would be necessary to find out the incidence of vascular complications of hip joint surgery and its association with CVDs. Synnerby and colleagues suggested that clinicians should be aware of the considerably increased rate of hip fracture in both genders, especially after a recent hospitalization for CVD [5]. Osteoporosis and CVD are prevalent in elderly individuals, but until recently have been regarded as independent age-related disorders. Recent research indicates commonalities between the disorders— for example, bone and vasculature are regulated by several shared factors, in which calcification of the vascular walls in many ways resembles the bone formation and bone resorption process. Similarly, bisphosphonates are known to decrease the progression of osteoporosis, as well as also prevent the development of atherosclerosis and reduce total mortality rate; while cholesterollowering statins that reduce risk of CVD are thought to reduce the risk of osteoporotic fractures. In the same report, the researchers examined data from the Swedish Twin Registry, which contains 31,936 twin members born between 1914 and 1944, who were followed-up from the time of their 50th birthday [5]. By examining the National Patient Registry, the investigators found that individuals with CVD had a significantly increased prevalence of hip fractures than those with no CVD. The crude absolute rate of hip fractures in individuals without a history of CVD was 1.2 per 1000 person-years. This compared with a rate of 12.6 after a diagnosis of heart failure, 12.6 after a diagnosis of stroke, 6.6 after a diagnosis of peripheral atherosclerosis, and 5.2 after a diagnosis of ischemic heart disease. Corresponding hazard ratios (HR) for hip fracture after a diagnosis of CVD were 5.09, 4.40, 3.20, and 2.32 for stroke, heart failure, peripheral atherosclerosis, and ischemic heart disease, respectively, compared with patients with no CVD. The researchers then looked at identical twin pairs where one co-twin had CVD and the other did not. They found that the unaffected cotwins had a significantly increased risk for hip fracture when compared with unaffected twin pairs, at HRs of 3.74 for “pseudo exposure” to heart failure and 2.29 for pseudo exposure to stroke. The authors pointed out that most of the overall increased rate of hip fracture after heart failure (and part of the increased risk after stroke) appears to be accounted for by genes or by early environmental sharing (i.e., not individual lifestyle habits or other individual-specific environmental factors). However, it is known that environmental factors can enhance the expression of genes responsible for CVD, heart failure, and osteoporosis due to increased consumption of ω-6 fat, trans fat, and refined carbohydrates.

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645

The associations of dietary pattern and ω-6/ω-3 fatty acid ratio of the diet were examined with hip joint fractures [8]. Sixty cases having a fracture of the neck of the femur and 95 control subjects above 50 years of age were included in this case control study. Dietary intakes were obtained by 3-day assessment of food intakes by questionnaires among patients with fractures (n 5 50) as well as among 95 control subjects. Cytokines were measured by chemoluminescence enzyme immunometric assay (immulite automated analyzer) kit (DPC Los Angelis, CA, USA). Regression analysis was done to find out the association of risk factors with hip fractures. Among 60 cases, the fracture was more common in males than in females. Fruits, vegetables, and legume (165 6 12.6 vs 205 6 15.8 g/day, P , .03) as well as milk products (milk, curd, butter, etc.) consumption (205 1 25.8 vs 318 6 31.5 g/day, P , .05) were significantly lower and ω-6-rich oil intake was significantly higher among patients with fractures compared to control subjects, respectively. Omega3 fatty acid intakes were significantly lower among patients with fractures (0.45 6 0.74 g/day, P , .05). Osteoporosis (92.0%), trivial trauma (92.0%), physical inactivity (80.0%), diabetes mellitus (21.6%) were common among patients with hip fracture. Multivariate logistic regression analysis showed that the intakes of fruit, vegetable, and legume (odds ratio 0.89, CI: 0.83 0.98, P , .05), physical activity (OR 0.74, CI: 0.66 0.82, P , .05), ω-3 fatty acids intake (OR 0.95, 0.85 1.09, NS) were inversely associated with fracture, whereas ω-6/ω-3 ratio (OR 1.33, CI: 1.18 1.47, P , .01), interleukin-6, (OR 1.11, CI: 1.02 1.19, P , .05), and tumor necrosis factoralpha (OR 1.09, CI: 1.01 1.17, P , .05) were positively associated with fracture. This study showed that increased consumption of fruit, vegetable and legume, milk products and ω-3 fatty acid, and low ω-6/ω-3 ratio diet, as well as physical activity may be protective against hip joint fractures. In a single-blind, randomized trial, the interactions of calcium, dihomogamalinolenic acid (DGLA) 1 eicosapentaenoic acid (EPA) was examined compared to coconut oil 1 calcium in women with osteoporosis. All subjects were living in an institution for elderly and fed lowcalcium, nonvitamin D-enriched foods and had similar exposure to sunlight. Markers of bone formation or degradation and bone mineral density (BMD) were measured at the outset and after 6, 12, and 18 months. After 18 months, osteocalcin and deoxypyridinoline concentrations decreased significantly in both groups, indicating a reduction in bone turnover, whereas bone-specific alkaline phosphatase increased, indicating beneficial effects of calcium given to all the patients. Lumbar and femoral BMD showed that lumbar spine density remained the same in the treatment group, but decreased 3.2% in the placebo group. Femoral bone density increased 1.3% in the treatment group but decreased 2.1% in the placebo group. During the second stage of 18 months with all women receiving intervention treatment, lumbar spine density increased 3.1% among patients who remained on active intervention and 2.3% among those women who switched from placebo to active treatment; femoral BMD in the latter group showed an increase of 4.7%. Terano studied 40 elderly women with age-related osteoporosis who were divided into four groups. They were administered daily for 16 weeks one of four treatment regimens in each group: 4 g evening primrose oil, 4 g fish oil, 4 g of a fish and evening primrose oil mixture, or 4 g olive oil placebo, while no other medication/supplements or special foods was taken during the trial. In this study, fish oil increased serum calcium, osteocalcin, and collagen and decreased ALP. Evening primrose oil alone had no significant effects, but the positive results from the fish oil group were also seen in the fish oil plus evening primrose oil group. Evening primrose oil may have synergistic effects with fish oil. Evening primrose oil also contains ALA which is metabolized in our body into EPA and docosahaxaenoic acid (DHA), long-chain ω-3 fatty acids present in fish oil. A case control

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study reported that depression may be associated with reduced bone mineral density (BMD) [21]. In this study, 24 women with a history of major depression were compared with another 24 age-, race-, and body mass index-, postmenopausal status-matched control women. There was a significant lower BMD in patients with depression compared to controls. Deficiency of ω-3 fatty acids may be a common link between depression and osteoporosis among these subjects, both prevalent among elderly populations. These studies indicate that ω-3 fatty acids appear to be important in bone health and in the prevention of osteoporosis and support our findings that increased ratio of ω-6/ω-3 fatty acids or deficiency of ω-3 fatty acids may be a risk factor for osteoporosis and hip fractures [8,18,19,21]. The role of polyunsaturated fatty acids in the pathogenesis of osteoporosis and hip fracture may be provided from the experimental studies [22 25]. In an experimental study, 15 rats were fed identical diets except that the ω-6/ω-3 ratio differed. Safflower oil and fish oil were mixed to produce ω-6/ω-3 ratios of 23.8, 9.8, 2.6, and 1.2 [22]. There was a significant increase in PGE2 and ALP with decrease in ω-6/ω-3 ratio in the rat liver and bone tissue [22]. The high concentration of ALP indicated better reabsorption of bone and moreover 1.2 ω-6/ω-3 ratio diets showed higher rate of bone formation. In another study [23], an increased production of PGE2 in tibia of chicks given a semipurified diet containing soya bean oil, high in ω-6 fat was associated with a lower rate of bone formation compared with that of chicks fed a low dietary ratio of ω-6/ω-3 fatty acids. In a further study [24], rats fed a lower dietary ratio of ω-6/ω-3 fat showed increased bone marrow cellularity and bone strength. These studies indicate that ω-6/ω-3 fatty acid ratio of diet appears to be important in bone metabolism, and may be responsible for fracture due to trivial trauma in our patients. It is possible, that dietary fatty acids modulate the fatty acid composition and PGE2 production in these tissues by altering fatty acid composition of membrane phospholipids resulting into improvement in cell function. The bone is highly active metabolic tissue that continues to change throughout life. Bone remodeling occurs up to 20% which is the process of bone growth associated with maintaining a fixed adult bone mass. Older bone tissue is destroyed (reabsorbed) and replaced by new bone tissue in a cyclical process. However, in osteoporosis, the basic cause is that reabsorption becomes greater ahead of bone formation, resulting in a net bone loss. Diets higher in ω-6/ω-3 fatty acids are associated with greater PGE2 which have adverse effects [22 24]. Whereas low ω-6/ω-3 ratio diet may provide low PGE2 which stimulates bone formation by increased production of insulin like growth factor, which is a powerful growth stimulator for bone and muscle, growth may be further enhanced by simultaneous treatment with coenzyme Q10 which is potent antioxidant and bioenergetic agent present in the mitochondria of muscles. PGE2 also mediates the effects of vitamin D, TNF-alpha, and growth factors which are known to enhance bone reabsorption which results into osteoporosis [22 25]. There was a positive association of pro-inflammatory cytokines, IL-6 and TNF-alpha, in patients with hip fracture, in presence of ω-3 fatty acids in the diet. Therefore it is possible that ω-3 fatty acids modulates PGE2 as well as pro-inflammatory cytokines, TNF-alpha and IL-6, which are known to enhance PGE2, resulting in to marked increase in bone reabsorption [25]. Inflammation may be important in the pathogenesis of osteoporosis, atherosclerosis, depression, and dementia and these problems are related to diet and lifestyle factors. Our genes appear to be similar to the genes of our ancestors during the Paleolithic period 40,000 years ago, the time when our genetic profile was established. Man appears to live in a nutritional environment which completely differs from that for which our genetic constitution was selected. However, only during the last 100 160 years have dietary intakes changed significantly, causing increased intake of saturated fatty acids (SFA) and linoleic acid, and decrease in ω-3 fatty acids,

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from grain-fed cattle, tamed at farm houses, rather than meat from running animals. There is marked reduction in consumption of ω-3 fatty acids, vitamins, polyphenols, minerals, and proteins, and significant increase in the intakes of carbohydrates (mainly refined), fat (saturated, trans fat, linoleic acid), and salt compared to the Paleolithic period. These changes in the diet can damage our genes present in neurons, osteocytes, endothelial cells, and other cells which interact with environmental factors leading to osteoporosis, atherosclerosis, brain degeneration as well as carcinogenesis. The brain is quite rich in ω-3 PUFAs and several studies suggest a role for ω-3 PUFAs in neurotransmitter synthesis, degradation, release, reuptake, and binding [26]. Fatty acids belong to the phospholipid group and, consequently, are part of all biological membranes. The membrane’s fluidity, which is of crucial importance for its functioning, depends on its lipid components. Phospholipids composed of chains of polyunsaturated fatty acids increase the membrane fluidity because, by binding some chains, double bonds prevent them from compacting themselves perfectly. In addition, membrane fluidity is determined by the phospholipids/free cholesterol ratio, as cholesterol increases membrane viscosity. DHA deficit is associated with dysfunctions of neuronal membrane stability and transmission of serotonin, norepinephrine, and dopamine, which might be related to the etiology of the mood and cognitive dysfunction of depression [26]. On the other hand, EPA is essential to balance the immune function and physical health by reducing the proportion of arachidonic acid (AA, C20:4ω6) in cell membrane and prostaglandin E2 (PGE2) synthesis. A diet based on a high proportion of essential polyunsaturated fatty acids allows a higher incorporation of cholesterol in the membranes to balance their fluidity, which, in turn, would contribute to lower blood cholesterol levels and inflammation and lower risk of CVD, osteoporosis, and neuropsychological disorders [20 26]. Recent results from the PREDIMED studies indicate that Mediterranean-style diets can cause significant decline in CVDs, type 2 diabetes and cancer [27 29]. The beneficial effects of Mediterranean style diets may be because of increased intake of fruits, vegetables, nuts, fish, poultry, and olive oil with very little red meat, the foods, which have low glycemic index [27 29]. Most of these foods possess increased content of polyphenolic flavonoids, carotenoids, omega-3 fatty acids, antioxidants, vitamins and minerals as well as essential and nonessential amino acids [30 33]. Increased consumption of nuts has been demonstrated to cause significant decline in allcause mortality [34], whereas a greater intake of fresh fruits was associated with significant decline in CVDs in China [35]. Increased consumption of fruits, vegetables and antioxidants can also decrease free radical-induced oxidation of blood lipids and other tissues leading to significant decline in free radical generation which may cause decrease in atherosclerosis and carcinogenesis [36 38]. In a randomized trial in patients with myocardial infarction, treatment with antioxidant vitamins E, C, and beta-carotene for 4 weeks was associated with significant decline in oxidative stress with a nonsignificant decline in cardiovascular events [38].

37.4 OXIDATIVE STRESS, ANTIOXIDANTS, AND CELL DAMAGE Free radical stress occurs when the production of free radicals through a number of cellular events exceeds the ability of the cell’s antioxidant defense to eliminate these oxidants [37,38]. These free radicals have the ability to change the integrity of, and thus, damage several biomolecules, such as DNA, proteins, and lipids [37 40]. There is increasing evidence that oxidative stress is responsible for the

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pathophysiology of the aging process and may also be involved in the pathogenesis of atherosclerosis, neurodegenerative diseases, carcinogenesis, osteoporosis, and diabetes. The extent of free radical damage increases in a deficiency of endogenous antioxidants as well as if there is antioxidant polyphenol deficiency in the diet. Since functional foods are rich sources of antioxidants, vitamins, omega-3 fatty acids, it poses the possibility that that these foods can prevent oxidative damage. Recently, ROS were shown to be responsible for the development of osteoporosis [39,40]. Experimental studies have shown that oxidative stress diminishes the level of bone formation by reducing the differentiation and survival of osteoblasts and it has been reported that ROS activate osteoclasts and thus, enhance bone resorption [40]. Further evidence from a few clinical studies have also revealed that ROS and/or antioxidant systems might play a role in the pathogenesis of bone loss and a number of studies have shown that antioxidants have a fundamental role in preventing postmenopausal osteoporosis. For instance, estrogens, whose antioxidant activity is essential in protecting women of reproductive age from CVD, stimulate osteoblastic activity through specific receptors, thus favoring bone growth [40]. Antioxidant deficiency has been shown to have adverse effect on bone mass; treatment with bisphosphonate which is an antioxidant has been found to be protective [39,40]. A recent review emphasized that atherosclerosis and osteoporosis have similar molecular pathways involving bone and vascular mineralization, estrogen deficiency, parathyroid hormone, homocysteine, lipid oxidation products, inflammatory process, as well as vitamin D and K. Treatment with statins, biphosphonates, beta-blockers and experimental dualpurpose therapies based on the biological linkage of the above entities may simultaneously benefit bone loss and vascular disease, which could be beyond the process of ageing [41]. The mean carotid intima media thickness (CIMT) revealed no difference between postmenopausal women with and without osteoporosis [42]. Risk of elevated CIMT in postmenopausal women with osteoporosis was comparable to that of postmenopausal women without osteoporosis. There was no significant difference between the two groups in terms of the presence of plaque. In brief, it is possible that increased consumption of pro-inflammatory foods in conjunction with sedentary behavior may be associated with free radical stress and inflammation which may predispose atherosclerosis, osteoporotic fractures, carcinogenesis, neurodegenerative diseases, depression, and dementia. Increases in inflammation may explain the pathogenesis of increased rates of hip fractures after developing CVD and cancers. Increased consumption of functional foods—fruits, vegetables, legumes, nuts, yogurt, milk, cottage cheese, olive oil, canola oil, or mustard oil—may be protective against CVDs, cancers, hip fractures, and neurodegenerative diseases.

ACKNOWLEDGMENTS International College of Nutrition for support to present this study.

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[24] Atkinson TG, Barker HJ, Mechling Gill KA. Incorporation of long chain n-3 fatty acids in tissues and enhanced bone marrow cellularity with docosahexaenoic acid feeding in post weaning Fischer 344 rats. Lipids 1997;32:293 302. [25] Tashjian AH, Voelkel EF, Lazzaro M, Goad D, Bosma T, Levine L. Tumor necrosis factor-alpha (cachectin) stimulates bone reabsorption in mouse calvaria via a prostaglandin mediated mechanism. Endocrinology 1997;120:2029 36. [26] Crawford MA, Bazinet RP, Sinclair AJ. Fat intake and CNS functioning: ageing and disease. Ann Nutr Metab 2009;55:202 28. [27] Estruch R, Ros E, Salas-Salvado´ J, Covas MI, Corella D, Aro´s F, et al. PREDIMED Study Investigators. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med 2013;368 (14):1279 90. [28] Toledo E, Salas-Salvado´ J, Donat-Vargas C, Buil-Cosiales P, Estruch R, Ros E, et al. Mediterranean diet and invasive breast cancer risk among women at high cardiovascular risk in the PREDIMED trial: a randomized clinical trial. JAMA Intern Med 2015;5(11):1752 60. Available from: https://doi.org/10.1001/ jamainternmed.2015.4838. ´ , Ibarrola-Jurado N, Basora J, et al. [29] Salas-Salvado´ J, Bullo´ M, Babio N, Martı´nez-Gonz´alez MA PREDIMED Study Investigators. Reduction in the incidence of type 2 diabetes with the Mediterranean diet. Diabetes Care 2011;34:14 19. [30] Shastun S, Chauhan AK, Singh RB, Singh M, Singh RP, Itharat A, et al. Can functional food security decrease the epidemic of obesity and metabolic syndrome? A viewpoint. World Heart J 2016;8 in press. [31] Singh RB, Hristova K, Fedacko J, Singhal S, Khan S, Wilson DW, et al. Antioxidant vitamins and oxidative stress in chronic heart failure. World Heart J 2015;7:257 64. [32] Rajoria A, Kumar J, Chauhan AK. Anti-oxidative and anti-carcinoginic role of Lycopene in human health: a review. J Dairying, Foods & Home Science 2010;29:3 4. [33] Itharat A, Onsaard E, Singh RB, Chauhan AK, Shehab O. Flavonoids consumption and the heart. World Heart J 2016;8 in press. ´ , Ros E, Corella D, Estruch R, et al. [34] Guasch-Ferr´e M, Bullo´ M, Martı´nez-Gonz´alez MA Frequency of nut consumption and mortality risk in the PREDIMED nutrition intervention trial PREDIMED study group BMC Medicine 2013;16(11):164. Available from: https://doi.org/10.1186/ 1741-7015-11-164. [35] Du H, Li L, Bennett D, Guo Y, Key TJ, Bian Z, et al. China Kadoorie Biobank Study. Fresh fruit consumption and major cardiovascular disease in China. N Engl J Med 2016;374:1332 43. Available from: https://doi.org/10.1056/NEJMoa1501451. [36] Fito´ M, Guxens M, Corella D, S´aez G, Estruch R, de la Torre R, et al. PREDIMED Study Investigators. Effect of a traditional Mediterranean diet on lipoprotein oxidation. JAMA Internal Medicine 2007;167 (11):1195 203. Available from: https://doi.org/10.1001/archinte.167.11.1195. [37] Singh RB, Niaz MA, Agarwal P, Begom R, Rastogi SS. Effect of antioxidant-rich foods on plasma ascorbic acid, cardiac enzyme, and lipid peroxide levels in patients hospitalized with acute myocardial infarction. J Am Diet Assoc 1995;95(7):775 80. [38] Singh RB, Niaz MA, Rastogi SS, Rastogi S. Usefulness of antioxidant vitamins in suspected acute myocardial infarction (the Indian experiment of infarct survival-3). Am J Cardiol 1996;77(4):232 6. [39] Little CH, Combet E, McMillan DC, Horgan PG, Roxburgh CSD. The role of dietary polyphenols in the moderation of the inflammatory response in early stage colorectal cancer. Criti Rev Food Sci Nutr 2017;57(11):2310 20 2017.

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[40] Rao LG, Kang N, Rao AV. In: Rao V, editor. Polyphenol antioxidants and bone health: a review, Phytochemicals - A Global Perspective of Their Role inNutrition and Health. InTech; 2012. Available from. Available from: http://www.intechopen.com/books/phytochemicals-a-global-perspective-oftheirrole-in-nutrition-and-health/phytochemical-antioxidants-and-bone-health-a-review. [41] Anagnostis P, Karagiannis A, Kakafika AI, Mikhailidis DP. Atherosclerosis and osteoporosis: agedependent degenerative processes or related entities? Osteoporosis Int 2018;20:197 207. [42] Sothornwit J, Somboonporn SW, Soontrapa S, Kaewrudee SS, Wongwiwotchai J, Soontrapa S. Carotid intima-media thickness and osteoporosis in postmenopausal women: a cross-sectional study. Climecteric 2018;280 5. Available from: https://doi.org/10.1080/13697137.2018.1439916.

CHAPTER

38

MODERNIZATION OF POLICY FOR FOOD MANUFACTURING AND FARMING MAY BE NECESSARY FOR GLOBAL HEALTH

Ram B. Singh1,2, Jagdish P. Sharma3, Toru Takahashi4, Lekh R. Juneja5, Ronald R. Watson6, Rukam S. Tomar7, Mukta Singh8, Poonam Jaglan9, Meenakshi Singh10, Ester Halmy11, Anil K. Chauhan12 and Ekasit Onsaard13 1

The Tsim Tsoum Institute, Krakow, Poland 2Formerly, Food and Agriculture Organization, Bankok, Thailand JM Maternity Hospital, Seohara, Bijnore, Uttar Pradesh, India 4Graduate School of Human Environment Science, Fukuoka Women’s University, Japan 5Department of Health Promotion Sciences, Health Sciences Center, Osaka, Japan 6College of Public Health, School of Medicine, Tucson, United States 7Department of Plant Breeding and Genetic Engineering, Junagarh Agricultural University, Junagarh, Gujarat, India 8Department of Home Science, Mahila Maha Vidyalaya, Banaras Hindu University, Varanasi, Uttar Pradesh, India 9Center of Nutrition Research, Panipat, Haryana, India 10Division of Food Standard, CSIR, New Delhi, India 11Obesity Research Center, Budapest, Hungary 12Center of Food Science and Technology, Institute of Agricultural Sciences & Institute of Technology, Banaras Hindu University Varanasi, Varanasi, Uttar Pradesh, India 13Department of Foods, Ratchathani University, Ratchathani, Thailand 3

38.1 INTRODUCTION There is extensive literature emphasizing how diet causes and prevents diseases [1 3]. Majority of the experts agree that diet, changes in human behavior and government policies on food production and urbanized housing can improve physical, mental, social, and spiritual health [1 3]. Diet and lifestyle modification causes healthy dietary patterns, leading to decreased omega-6/omega-3 fatty acids ratio and increase in antioxidant flavonoids, vitamins, minerals, as well as amino acids in the tissues, resulting in a healthy human being [1 3]. Several original research studies have been published in the last few years by notable investigators from all over the world, giving the same message, that a Mediterranean-style diet, particularly with low omega-6/omega-3 ratio of fatty acids near 1:1, may be protective [4 10]. The nutrient consumption pattern during various stages of evolution and the evolutionary diet, are shown in Fig. 38.1 which reveal changes in food and nutrient consumption pattern and development of diseases, indicating that NCDs are the creation of Homo economicus societies [2,11]. It seems that health agencies such as the Food and agriculture Organization (FAO), World Health Organization (WHO), and International College of Nutrition should advise governments to make food policy which allows increased production of healthy foods and discourage the production of unhealthy energy-rich foods. Most experts agree that the worldwide increase in morbidity The Role of Functional Food Security In Global Health. DOI: https://doi.org/10.1016/B978-0-12-813148-0.00038-4 © 2019 Elsevier Inc. All rights reserved.

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FIGURE 38.1 Nutrient intakes among Homo sapiens, Homo erectus, hunter gatherers, and Homo economicus. Modified from Singh RB, Takahashi T, Nakaoka T, Otsuka K,Toda E, Shin HH, et al. Nutrition in transition from Homo sapiens to Homo economicus. Open Nutra J 2013;6:6 17.

and mortality due to NCDs, is taking away resources, funds, and brains that could have been allocated for human development [10]. The prevalence rates of major NCDs—cardiovascular disease (CVD), cancer, type 2 diabetes, and chronic obstructive pulmonary diseases (COPD)—are rapidly increasing in almost all countries and are now among the world’s biggest killers [9,10]. NCDs are polygenic and multifactorial and pose a major challenge to the health, well-being, and prosperity of populations across the world, and cause unnecessary suffering and premature death [10 15]. The contributing factors are multifaceted and complex, including health behavior related to population ageing, urbanization, the globalization of trade and marketing, and the resulting progressive increase in unhealthy patterns of diets and living [11 16]. This review emphasizes the role of alteration in policy for food production by manufacturing and farming in the prevention of NCDs and in health promotion.

38.2 MODERN FOODS WITH ADVERSE EFFECTS ON HEALTH Western diets characterized with preserved and processed foods including bacon, sausage, and ham are once again found to be key foods driving the association between meat consumption and the world’s most common diseases [4]. This large cohort study, involving 10 countries and almost half a million men and women, reported that high consumption of processed meat by middle-aged adults was associated with a nearly two-fold greater risk of all-cause mortality, compared with low

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consumption, over a mean of 12 years. Risk of cardiovascular death, after rigorous modeling, was increased by more than 70% among people eating more than 160 g/day, as compared with those eating 10 19.9 g/day. Risk of cancer deaths was also 43% higher among the highest consumers of processed meats. The interesting point was that a signal of increased mortality was seen among the highest consumers of red meat in general, the risk for red meat was much lower than that of processed meats and lost statistical significance after correction for measurement error. With the same adjustments and corrections, high processed-meat consumption was associated with an 18% greater risk of all-cause mortality. It seems that processed meats tend to contain more peroxidized fatty acids, including saturated fat and salt, than unprocessed meat (where the fat is often trimmed off), as well as more oxidized cholesterol and additives, as part of the smoking or curing process, which may be carcinogenic or precursors to carcinogenic processes and atherogenic. Heme iron is another mechanism, which may interact with oxidized products linking meat consumption to cardiovascular disease (CVD) risk. Eating unhealthy diets goes hand in hand with other unhealthy behaviors, including smoking, low physical-activity levels, and low consumption of fruits and vegetables leading to NCDs [1 15]. In a further study involving black and white Americans aged 45 years or older between 2003 and 2007, the factor analysis identified five dietary patterns: “Convenience” (Chinese and Mexican foods, pasta, pizza); “Plant-based” (fruits, vegetables, legumes); “Southern” (fried foods, organ meats, sweetened beverages); “Sweets/Fats” (desserts, added sugars, sweet snacks); and “Alcohol/ Salads” (alcohol, fats, vegetables) [5]. Subjects with a higher adherence to the Southern dietary pattern, experienced a 41% increased risk of stroke (comparing Q4 to Q1: HR 5 1.41; 95% CI: 1.07, 1.85). However, higher adherence to the plant-based pattern was associated with a 29% reduction in stroke risk (comparing Q4 to Q1: HR 5 0.71; 95% CI: 0.55, 0.91). The trend across quartiles was ,0.001 indicating a dose response for adherence to each pattern. Adding socioeconomic status, smoking, physical activity, and total energy (calories) intake to the models attenuated the association but the direction remained the same and persisted in subgroup analysis examining only ischemic strokes. The Convenience, Sweets, and Alcohol patterns were not associated with stroke risk. The study suggests that foods common to US Southern cuisine such as fried foods and sweetened beverages may increase the risk of stroke, while diets rich in legumes, fruits, vegetables, and fish may reduce stroke risk. It is possible that interventions focusing on increasing plant-based foods and fish while reducing fried foods and sweetened beverages are needed for prevention of CVDs and health promotion [5]. In view of the above evidence from two large cohort studies, many more people may be considering a switch to vegetarianism, because processed and unprocessed meat consumption has been reported to be associated with a significantly increased risk of all-cause CVD mortality and death from cancer [4,5]. After adjustment for multiple risk factors, eating one additional serving of meat daily was associated with a 16% increase in the risk of cardiovascular mortality and a 10% increased risk of death from cancer. The PREDIMED Study which is a randomized, controlled intervention trial, comprised of a total of 7447 persons, aged 55 80 years; including 57% women [6]. A primary end-point event occurred in 288 participants. The multivariable-adjusted hazard ratios were 0.70 (95% CI: 0.54 to 0.92) and 0.72 (95% CI: 0.54 to 0.96) for the group assigned to a Mediterranean diet with extra-virgin olive oil (96 events) and the group assigned to a Mediterranean diet with nuts (83 events), respectively, versus the control group (96 and 83 vs 109 events). Among high risk subjects, a Mediterranean diet supplemented with extra-virgin olive oil or

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nuts caused significant decline in the incidence of major cardiovascular events [6]. The Sydney Diet Heart Study included 458 men aged 30 59 years with a recent coronary event [7]. The intervention group received replacement of dietary saturated fats (from animal fats, common margarines, and shortenings) with omega-6 linoleic acid (from safflower oil and safflower oil polyunsaturated margarine). Controls received no specific dietary instruction or study foods and all nondietary aspects were designed to be equivalent in both groups. An intention to treat, survival analysis approach to compare mortality outcomes by group showed that the intervention group (n 5 221) had higher rates of death than controls (n 5 237) (all cause 17.6% vs 11.8%, hazard ratio 1.62 (95% CI: 1.00 2.64), P 5 .05; cardiovascular disease 17.2% versus 11.0%, 1.70 (1.03 2.80), P 5 .04; CAD 16.3% versus 10.1%, 1.74 (1.04 2.92), P 5 .04). Inclusion of these recovered data in an updated meta-analysis of linoleic acid intervention trials showed nonsignificant trends toward increased risks of death from CAD (hazard ratio 1.33 (0.99 1.79); P 5 .06) and CVDs (1.27 (0.98 1.65); P 5 .07). It is clear that dietary linoleic acid supplementation in place of saturated fats increased the rates of death from all causes, as well as CAD and CVD. An updated meta-analysis of linoleic acid intervention trials showed no evidence of cardiovascular benefit. These are the complications of meta-analysis and funded research. These findings may have important implications for worldwide dietary advice to substitute omega-6 linoleic acid, or omega-3 fatty acids or polyunsaturated fats in general to alter the ω-6/ω-3 ratio to 1:1 [3]. In a randomized clinical trial among 406 patients, acute coronary syndromes (ACS),was diagnosed following WHO criteria [8]. The experimental intervention group received Paleolithic-style diet characterized by fruits, vegetables, whole grains, almonds, and walnuts and the control group fat modified according to the National Cholesterol Education Program Step 1 (prudent) diet. Main outcome measures were compliance with experimental diets at one year and all-cause mortality and its association with omega-6/omega-3 fatty acid ratio after a follow-up of 2 years. The experimental group received significantly greater amount of fruits, vegetables and whole grains, almonds, walnuts, and mustard oil and lower amount of refined bread, biscuits and sugar, and butter and clarified butter compared to the control diet group at 1 year of follow-up. Intervention group was also advised fish and forbidden red meat intake. Total adherence score to Paleolithic-style diet and prudent diet were significant in both the groups. Omega-6/omega-3 fatty acid ratio of the diet which was much higher before entry to the study (32.5 6 3.3), was brought down to significantly lower content in the Paleolithic-style diet group A (n 5 204, compared to control group diet B (n 5 202) at entry to the study (3.5 6 0.76 vs 24.0 6 2.4 kJ/day, P , .001). The fatty acid ratio remained significantly much lower in the experimental group compared to control group after one year of follow up (4.4 6 0.56 vs 22.3 6 2.1 kJ/day, P , .001). Total mortality was 14.7% in the Paleolithic-style diet group and 25.2% in the control group, after a follow-up of 2 years. The association omega-6/ omega-3 ratio of fatty acids with mortality showed a gradient in both the groups independently, as well as among total number of deaths. A lower omega-6/omega-3 ratio of fatty acids from 1 10 was associated with a significantly lower mortality whereas increase in omega-6/omega-3 fatty acid ratio to more than 10 was associated with an increasing trend in mortality; 1.7% at ratio less than 5 and 19.9% at ratio 30 (Fig. 38.2). In another study, randomly selected records of death of 2222 (1385 men and 837 women) decedents, aged 25 64 years, were examined by examining the records of deaths [9] (Table 38.1). The score for intake of prudent foods was significantly greater and the ratio of omega-6/omega-3 fatty acids of the diet significantly lower for deaths due to “injury” and accidental causes compared to deaths due to noncommunicable diseases (NCD).

38.3 NUTRIENTS IMBALANCES WITH ADVERSE EFFECTS

657

FIGURE 38.2 Effect of low ω-6/ω-3 fatty acid ratio diet on mortality. Modified from Singh RB, Fedacko J, Vargova V, Pella D, Niaz MA, Ghosh S. Effect of low W-6/W-3 fatty acid ratio Paleolithic style diet in patients with acute coronary syndromes: a randomized, single blind, controlled trial, World Heart J 2012;4:71 84.

Multivariate logistic regression analysis revealed that after adjustment for age, total prudent foods (OR,CI: 1.11;1.06 1.18 men; 109;1.04 1.16 women) as well as fruits, vegetables, legumes, and nuts (1.07; 1.02 1.12 men; 1.05; 1.99 1.11 women) were independently, inversely associated whereas Western-type foods (1.02; 0.95 1.09 men; 1.00; 0.94 1.06 women), meat and eggs (1.00 0.94 1.06 men; 0.98; 0.93 1.04 women), and refined carbohydrates (0.98; 0.91 1.05 men, 0.95; 0.89 1.02 women) and high omega-6/omega-3 ratio of fatty acids were positively associated with deaths due to NCDs. Increased intake of high omega-6/omega-3 ratio Western-type foods and decline in prudent foods intake may be a risk factor for deaths due to NCDs.

38.3 NUTRIENTS IMBALANCES WITH ADVERSE EFFECTS Concerns regarding nutrient deficiencies and toxicities have been raised because of the acknowledged capability of food manufacturing by the food industry. Genetic engineering, feeding special foods and nutrients to pregnant animals, and adding nutrients to soil are important technology/ methods to markedly change the composition of foods. Modifications of food composition must consider the potential impact on nutrient deficiencies, toxicities, interactions, and/or other imbalances that can influence human health. Alteration of essential nutrients from foods or, more likely, their enhancement, has the potential of influencing the risk of nutrient deficiencies or toxicities, respectively, in the general or subsets of the population, depending on exposure patterns. It should be noted that to date most nutrient toxicities are due to the addition of nutrient levels in excess of normal physiologic needs, achieved through fortification or due to the excessive consumption of nutrient supplements (https://www.nap.edu/read/10977/chapter/7). Cohort studies and intervention trials clearly indicate that processed meat and red meat containing more peroxidized fatty acids, including saturated fat and salt, as well as more oxidized cholesterol

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Table 38.1 Food Intakes and ω-6/ω-3 Fatty Acid Ratio of Diet in Relation to Causes of Death Based on Assessment by Dietary Diaries of the Spouse and Questionnaires Filled by the Nutritionist Causes of Death

Prudent Diet Western

n 5 1385 Injury-accidents (n 5 215) Communicable Diseases. (n 5 372) NCDs Malignant (n 5 77) Circulatory (n 5 406) Chronic lung diseases (97) Kidney diseases (n 5 163) Diabetes (n 5 23) Kendall’s ȶ

Total Foods

Score

ω-6/ω-3 Ratio

Men (Mean 6 Standard deviation) g/day 892 6 252

202 6 22

1094 6 302 1062 6 198

7.93 6 2.8 31 7.26 6 2.7

806 6 237

256 6 28

38.2 6 6.6

715 6 241 757 6 245 705 6 202

412 6 53 437 6 47 405 6 41

1127 6 311 1194 6 318 1110 6 302

6.44 6 2.5 6.81 6 2.6 6.25 6 2.2

42.2 6 6.8 45.3 6 8.3 42.0 6 7.4

617 6 188

505 6 55

1122 6 325

5.72 6 1.8

41.8 6 6.1

605 6 175 0.045

522 6 61 0.048

1127 6 334 0.025

5.65 6 1.7 0.041

41.6 6 5.7 0.042

n 5 837 Injury-accidents (n 5 139) Communicable diseases (n 5 194) NCDs(n 5 502) Malignant (n 5 54) Circulatory (n 5 240) Chronic lung diseases (n 5 95) Renal diseases (n 5 87) Diabetes (n 5 26) Kendall’s ȶ

Western-Type Diet

31.3 6 5.3

Women (Mean 6 Standard deviation) g/day 822 6 234

186 6 23

1008 6 224

8.40 6 2.2

25.5 6 5.7

736 6 237

218 6 33

954 6 201

7.51 6 1.9

34.5 6 5.6

657 6 197 655 6 205 660 6 180

305 6 35 332 6 41 382 6 48

962 6 221 987 6 218 1029 6 180

6.70 6 1.8 6.68 6 1.7 6.12 6 1.3

41.6 6 6.8 44.5 6 7.5 40.0 6 6.5

565 6 155 553 6 146 0.041

380 6 130 387 6 135 0.067

995 6 165 940 6 153 0.024

5.57 6 1.1 5.53 6 1.1 0.043

39.7 6 6.8 40.0 6 6.5 0.041

Values are mean (Standard deviation),  5 P , 0.01,  5 P , 0.001. by comparison of food consumption among victims dying due to NCDs and with victims dying of injury and accidents among both sexes. Modified from Fedacko J, Vargova V, Singh RB, Anjum B, Takahashi T, Tongnuka M, et al. Association of high w-6/w-3 fatty acid ratio diet with causes of death due to non-communicable diseases among urban decedents in North India. Open Nutra Jour 2012;5:113 123.

and additives, as part of the smoking or curing process, may be carcinogenic or precursors to carcinogenic processes and atherogenic [3]. Heme iron is another mechanism, which may interact with oxidized products linking meat consumption to cardiovascular disease (CVD) risk. All rapidly absorbed foods, particularly sweetened and sugary beverages, such as such as syrups and cola drinks, refined starches—biscuits, bread, cookies, white chocolates—can cause obesity and metabolic syndrome. High omega-6/omega-3 fat ratio in the foods, trans fat, and saturated fat are known to have adverse

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659

effects on blood lipids, oxidative stress, and inflammation resulting in NCDs [3 5]. Food manufacturing policies should restrict the use of nutrients having adverse effects.

38.4 THE AGENDA FOR FOOD INDUSTRY There is enough scientific evidence for a robust case to develop functional foods by the food industry for prevention of NCDs. Such products should have similar effects on human nutrition and metabolism as natural Paleolithic-style foods or Mediterranean-style foods, without any adverse effects of foods additives, food preservation, and food processing. There is a need to educate the food industry and agriculture scientists to develop functional foods characterized with low glycemic index and optimal amount of soluble fiber, vitamins, minerals, antioxidant flavonoids, essential and nonessential amino acids, and a balanced ratio of omega-6/omega-3 fatty acids, similar to the notional Paleolithic diet [15 17]. In earlier studies, these foods and nutrients rich in the Paleolithic-style and Mediterranean-style diets have been found to be protective against NCDs [15 17]. It is advised that a change in food production policy is desirable to produce foods which are rich in above nutrients and can simulate Paleolithic foods. There is a need to use food production technology for developing new inexpensive healthy foods in place of almonds, walnuts, vegetables, and fruits which should be available at affordable cost. Farmers should be given subsidies to grow more vegetables and pulses as well as fruits which should be preserved and stored at no cost to farmers to maintain the affordable cost of these foods. A recent study also showed that there was a significant decrease in the prudent food consumption among victims dying due to NCDs compared to those dying due to other causes [4] (Table 38.1). The food industry should explore the possibility of adding or blending these nutrients which have been reported to have nitric oxide activating effects and other protective effects [15 22]. Dietary supplements such as resveratrol and epicatechin present in wines and fruit juices and flavanols-rich cocoa, as well as ω-3 fatty acids, can protect against adverse effects of food processing. Some of the spices such as turmeric, cumin, chilies, garlic, and onion are rich in antioxidants and could be incorporated in the functional foods making them more functional and healthy. They also provide additional beneficial effects on cardiovascular health, insulin resistance, and memory dysfunction [14 17]. In a recent meta-analysis of randomized controlled trials, supplementation with probiotics in critically ill adult patients was found to be associated with a reduction in the incidence of ICU-acquired pneumonia and ICU length of stay [23]. Data from a total of 13 trials including 1439 patients were included in the analysis. While probiotic administration was not associated with a significant reduction in ICU (OR 5 0.85) or hospital (OR 5 0.90) mortality, or shorter duration of mechanical ventilation ( 0.18 days) or a shorter hospital length of stay ( 0.45 days), probiotics were associated with a reduction in incidence of ICU-acquired pneumonia (OR 5 0.58) and shorter stay in the ICU ( 1.49 days). This study indicates that this approach appears to be useful for the food industry to develop superfoods by further modifications of probiotics with omega-3 fatty acids, flavanols by adding cocoa, walnuts, and black raisins. In a systematic review of studies which included the results from 14 human studies (seven prospective, three cross-sectional, one controlled, three case-control) and 13 animal studies, found that dietary omega-6 to omega-3 fatty acid ratio can influence brain composition [24], Alzheimer’s disease pathology, and behavior (as according to animal studies), and revealed an association between

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the omega-6 to omega-3 ratio, cognitive decline, and incidence of dementia. This review supports growing evidence of a positive association between the dietary omega-6/omega-3 ratio and the risk of Alzheimer’s disease. In a recent study involving 3457 children aged 8 15 years, out of which 354 had reduced birth weight [25], systolic blood pressure was found to be 1.1 mm Hg higher in those with reduced (less than 10th centile) compared with normal birth weight, and pulse pressure was significantly higher (3.4 mm Hg) in children with reduced birth weight. Those with reduced birth weight who were in the highest tertile of EPA and DHA intake were found to have significantly lower systolic blood pressure ( 4.9 mm Hg) and pulse pressure ( 7.7 mm Hg), than those with normal birth weight. These data are consistent with the hypothesis that long-chain omega-3 fatty acids reduce blood pressure in those with impaired fetal growth. It is possible that a change of policy aimed at producing functional foods and functional crops can provide adequate functional foods for prevention of NCDs [26 28]. More efforts are required to educate the people and industry on protective effects of wines, spices, and herbs to consider adding nitric oxide activating agents like epicatechin and flavones as well as omega-3 fatty acids in alcohol to provide additional beneficial effects. Apart from the food industry, agriculture should be made functional by developing functional foods, using plant breeding and genetic engineering to enhance protective nutrients in the foods.

38.5 FOOD SAFETY, FROM FARM TO FORK, IN THE EUROPEAN UNION Food standard and safety are regulated by government authorities in many countries which should include health professionals to advise the government about regulation of food content in the manufactured foods. In the European Union, every European citizen has the right to know how the food he eats is produced, processed, packaged, labeled, and sold.(https://ec.europa.eu/food /overview_en). The central goal of the European Commission’s Food Safety policy is to ensure a high level of protection of human health regarding the food industry. Applying an integrated approach from farm to fork covering all sectors of the food chain is the guiding principle of the commission. The objective of the animal health policy is to raise the health status and improve the conditions of the animals, in particular foodproducing animals by better sanitation livestock, whilst permitting intra-community trade and imports of animals and animal products in accordance with the appropriate health standards and international obligations. It should be ensured that animals do not endure avoidable pain or suffering and obliges the owner/keeper of animals to respect minimum welfare requirements. The European Union legislation aims at the promotion of free trade in breeding animals and their genetic material considering the sustainability of breeding programs and preservation of genetic resources. This is done by setting of international phyto-sanitary and quality standards for plants and plant products, and the harmonized protection of “green resources.” The guidelines also state the use of pesticides, plant variety rights, or genetically modified organisms that are regulated by the European Union (Novel Food Catalogue http://ec.europa.eu/food/safety/novel_food/catalogue/search/public/ index.cfm).

38.6 POLICY FOR DEVELOPING FUNCTIONAL FOODS The association of food and Western diseases from an evolutionary point of view indicates that sustainable human development may be difficult due to the conservative mechanisms developed

38.7 THE FUNCTIONAL FOOD MARKET

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during food scarcity [1 3]. Moreover genetically modified foods which are high in energy and low in nutrient density may have greater adverse effects [30]. There is no uniform definition of functional foods. Functional foods may be defined as foods which contain certain nutrients that can address some physiological mechanisms in our bodies thereby providing benefits. Functional foods are characterized with high nutrient density and low energy which can influence physical and mental performance as well as psychosocial behaviors that are characteristics of total health, including cardiovascular health [2,3,26,29]. The majority of functional foods are rich in omega-3 fatty acids, vitamins, polyphenolics, minerals as well as in essential and nonessential amino acids and lower in energy [1 4,9,11] Functional farming (FF) means that foods produced by farming either by appropriate soil, or by genetic engineering or plant breeding should be functional foods. A world policy to produce enormous amounts of functional foods via the food industry and FF worldwide can increase the dimension of the increased consumption of functional foods and their benefits on total health in general, as well as global health [2,3,26]. The challenge facing food manufacturers in the food industry is to develop functional foods; slowly absorbed bread, biscuits, cakes, candies, syrups etc. which should also be rich in nutrients and low in density. A similar approach is expected from FF to grow foods which should be slowly absorbed and have a low glycemic index with high nutrient content, although FF alone cannot serve the demand. Genetically modified foods may be developed rapidly to counteract undernutrition but these foods should be slowly absorbed and rich in nutrients because increased consumption of such foods may predispose obesity and metabolic syndrome [3 26,29,30]. It seems that a policy should be made to use genetic modification technology for developing expensive functional foods such as walnuts and almonds and blueberries to make them available at affordable cost [30]. Large-scale use of fertilizers and biotechnology for rapid growth of crops for greater yield of foods, refining and processing of foods, storing and distributing them have become widespread in the continuous search for a better economic model in high income and middle income countries [26]. This approach for individual patients as well as for populations and other methods, may be a roadmap for the future, provided the aim is to achieve functional food security rather than just food security [26 29]. These existing evidences strengthen the hypothesis that the effect of functional food intervention could be modulated by baseline conditions of the subjects which could be useful for sustainable human development [28].

38.7 THE FUNCTIONAL FOOD MARKET According to Leatherhead Food Research report, the international functional food and drink market was worth US$24.22 billion in 2010, with an expected growth of 4% 5% in the next few years. There is a forecast from experts that the international functional food market would have a value of US$29.75 billion by 2014. Japan is currently the largest market for functional foods, with a value share over 38%,. A direct comparison may be difficult, because Japan’s Foods for Specific Health Use includes not only foods with health claims but, also, those with purported medicinal benefits, such as herbal remedies. The United States follows Japan with 31.1% of the global market (up some 31% compared to 2006), and Europe comes in third place with 28.9% of the market. The estimates for the size of the US functional foods market may vary according to the definitions used. The funds allotted for research on functional foods are rapidly increasing in Europe, indicating the

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FIGURE 38.3 Funds allotment and expenditure in food science in Europe. Modified from http:/www. preparedfoods.com.

great future of functional food industry (Fig. 38.3). The risk benefit assessment including main challenges, combines chemical and microbial risk assessment with risk and benefit assessment in nutrition [31]. These challenges may be related to, data, health metrics, interdisciplinarity, methods and applications. It is clear that the United States and European markets are driving growth, since there are still some relatively undeveloped sectors compared to the more mature Japanese market. Some of the recent global growth in functional foods is appearing in less developed markets, such as China, India, Latin America, and Southeast Asia, although they are the home of the majority of the natural functional foods. The global functional foods market is dominated by dairy products, with sales valued at US$9.23 billion in 2010, equivalent to more than 38% of the overall industry. It continues to hold a strong position in Europe, and functional dairy products due to probiotic yogurt drinks are also making much headway in the United States. The Actimel and Activia brands now account for about a quarter of market leader Danone’s annual revenue. In brief, the food industry needs drastic changes to produce and promote slowly absorbed functional foods containing low omega-6/omega-3 fatty acid ratio, high vitamins, antioxidants, fiber, flavanols, and essential and nonessential amino acids, preferably by using foodstuffs rich in these ingredients. Food science technology should be used to produce new inexpensive foods such as walnuts, almonds, vegetables, pulses, and fruits to reduce their cost. The public and industry should demand tax subsidies to lower the cost of such foods. Health education of the food industry to

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manufacture healthy foods at affordable cost should be given greater emphasis by the governments and such efforts should be rewarded because the future market appears to be quite big.

ACKNOWLEDGMENTS International College of Nutrition and The Tsim Tsoum Institute for providing logistic support to write this article.

REFERENCES [1] De Meester F, Zibadi S, Watson RR. Available from: www.springer.com. Modern dietary fat intakes in disease promotion. New York: Humana Press, Springer; 2010. [2] DeMeester F. Wild-type land based foods in health promotion and disease prevention: the LDL-CC: HDL-CC model. Wild Type Foods in Health Promotion and DiseasePrevention, editors Fabien DeMeester and RR Watson. NJ: Humana Press; 2008. p. 3 20. [3] De Meester F, Watson RR, Zibadi S. Available from: www.springer.com. Omega-6/3 fatty acids;functions, sustainability strategies and perspectives. New York: Humana Press, Spernger; 2012. [4] Rohrmann S, Overvad K, Bueno-de-Mesquita HB, et al. Meat consumption and mortality. Results from the European Prospective Investigation into Cancer and Nutrition. BMC Med 2013. [5] Judd SE, Orlando Gutierrez O, Kissela BM, et al. Southern diet pattern increases risk of stroke while plant-based pattern decreases risk of stroke in the REGARDS study. International Stroke Conference 2013; February 7, 2013; Stroke. 2013;44:A144. [6] PREDIMED Study Investigators. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med 2013; February 25, 2013, http://dx.doi.org/10.1056/NEJMoa1200303. [7] Ramsden CE, Zamora D, Leelarthaepin B, Majchrzak-Hong SF, Faurot KR, Suchindran CM, et al. Use of dietary linoleic acid for secondary prevention of coronary heart disease and death: evaluation of recovered data from the Sydney Diet Heart Study and updated meta-analysis. BMJ 2013;346:e8707 Cite this as: BMJ 2013;346:e8707. [8] Singh RB, Fedacko J, Vargova V, Pella D, Niaz MA, Ghosh S. Effect of low W-6/W-3 fatty acid ratio Paleolithic style diet in patients with acute coronary syndromes: a randomized, single blind, controlled trial. World Heart J 2012;4:71 84. [9] Fedacko J, Vargova V, Singh RB, Anjum B, Takahashi T, Tongnuka M, et al. Association of high w-6/ w-3 fatty acid ratio diet with causes of death due to non-communicable diseases among urban decedents in North India. Open Nutra Jour 2012;5:113 23. [10] WHO. Mortality and burden of disease estimates for WHO Member States in 2008. Geneva: World Health Organization; 2010. [11] Singh RB, Takahashi T, Nakaoka T, Otsuka K, Toda E, Shin HH, et al. Nutrition in transition from Homo sapiens to Homo economicus. Open Nutra J 2013;6:6 17. [12] Moodie R, Stuckler D, Monteiro C, Sheron N, Thamarangsi, Lincoln P. Profits and pandemics: prevention of harmful effects of tobacco, alcohol, and ultra-processed food and drink industries Casswel S on Behalf of the Lancet NCD Group Lancet, Early Online Publ 2013. Available from: https://doi.org/ 10.1016/S0140-6736(12)62089. [13] The “Heart Disease and Stroke Statistics. Update” and the need for a national cardiovascular surveillance system. Circulation 2013;(127):21 3 2013.

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[14] U. S. Health In International Perspective. Shorter Lives, Poorer Health. National Academy of Sciences, USA 2013. (For the report on US health disadvantagesee http://www.nap.edu/catalog.php? record_id 5 13497; For the US prevention strategysee http://www.healthcare.gov/prevention/nphpphc/ strategy/report.pdf. [15] Editorial. Wealth but not health in USA. Lancet 2013;381:177. http://dx.doi.org/10.1016/S0140-6736 (13)60069-0. [16] Singh RB, Anjum B, Takahashi T, Martyrosyan DM, Pella D, De Meester F, et al. Poverty is not the absolute cause of deaths due to non-communicable diseases. World heart J 2012;3:221 31. [17] Toda E, Toru T, Singh RB, Alam SE, et al. Can low w-6/w-3 ratio Paleolithic style diet stop cardiovascular diseases? Tissue is the Issue. Am Med J 2012;3:183 93. [18] De Lorgeril M, Renaud S, Mamelle N, et al. Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coronary heart disease. Lancet 1994;343(8911):1454 9. [19] Singh RB, Dubnov G, Niaz MA, Ghosh S, Singh R, Rastogi SS, et al. Effect of an Indo-Mediterranean diet on progression of coronary disease in high risk patients: a randomized single blind trial. Lancet 2002;360:1455 61. [20] Singh RB, Rastogi SS, Ghosh S, Niaz MA, Singh R, Verma R. Randomised controlled trial of cardioprotective diet in patients with recent acute myocardial infarction results of one year follow up. BMJ 1992;304:1015 19 PMID: 1586782. [21] Singh RB, Kumar A, Neki NS, Pella D, Rastogi SS, Basu TK, et al. Diet and lifestyle guidelines and desirable levels of risk factors for prevention of cardiovascular disease and diabetes among elderly subjects. A Revised Scientific Statement of the International College of Cardiology and International College of Nutrition-2011. World Heart J 2011;3:305 20. [22] Hristova K, Nakaoka T, Otsuka K, Fedacko J, Singh R, Singh RB, et al. Perspectives on chocolate consumption and risk of cardiovascular diseases and cognitive function. Open Nutr J 2012;5:207 12. [23] Barraud D, Bollaert PE, Gibot S. Impact of the Administration of probiotics on mortality in critically ill Adult patients: a meta-analysis of randomized controlled trials. Chest 2013;143:646 55. [24] Loef M, Walach H. The omega-6/omega-3 ratio and dementia or cognitive decline: a systematic review on human studies and biological evidence. J Nutr Gerontol Geriatr 2013;32:1 23. [25] Skilton MR, Raitakari OT, Celermajer DS. High intake of dietary long-chain ω-3 fatty acids is associated with lower blood pressure in children born with low birth weight: NHANES 2003-2008 Hypertension. 2013;[Epub ahead of print] PMID. Available from: 23460284. [26] Singh RB, De Meester F, Wilczynska A, Takahashi T, Juneja L, Watson RR. Can a changed food industry and agricultural policy prevent cardiovascular and other chronic diseases? World Heart J 2013;5:1 8. [27] Hristova K, Shiue I, Pella D, Singh RB, Chaves H, Basu TK, et al. Sofia declaration on transition of prevention strategies for cardiovascular diseases and diabetes mellitus in developing countries: a statement from the International College of Cardiology and the International College of Nutrition. Nutrition 2014. Available from: https://doi.org/10.1016/j.nut.2013.12.013. [28] FAO, UNO. The State of Food and Agriculture: sustainable Food Systems for Food Security and Nutrition http://www.fao.org/docrep/meeting/ 028/mg413e01.pdf, accessed 2017. [29] Singh RB, Takahashi T, Shastun S, Elkilany G, Hristova K, Shehab A, et al. The concept of functional foods and functional farming (4 F) in the prevention of cardiovascular diseases: a review of goals from 18th World Congress of Clinical Nutrition. J Cardiol Therapy 2015;2(4):341 4. [30] Mishra S, Singh RB. Physiological and biochemical significance of genetically modified foods, an overview. Open Nutra J 2013;6:18 26. [31] Nauta MJ, Andersen R, Pilegard K, Pires SM, et al. Meeting the challenges in the development of riskbenefit assessment of foods. Trends Food Sci Technol 2018;76:90 100.

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EPIGENETIC MODULATION OF NUTRITIONAL FACTORS IN PLANTS, ANIMALS, AND HUMANS: A NEW APPROACH FOR DEVELOPING FUNCTIONAL FOODS

Rie Horiuchi1, Ram B. Singh2, Toru Takahashi3, Saikat K. Basu4 and Rukam S. Tomar5 1

Mukogawa Women’s University, Nishinomiya, Japan 2The Tsim Tsoum Institute, Krakow, Andrzej Frycz Modrzewski Krakow University, Krakow, Poland 3Graduate School of Human Environment Science, Fukuoka, Japan 4 Department of Biological Sciences, University of Lethbridge, Lethbridge, AB, Canada 5Department of Genetics, Junagarh Agricultural University, Junagarh, Gujarat, India

39.1 INTRODUCTION Epigenetic variation in DNA methylation can provide an evolutionarily and ecologically important source of phenotypic variation among individuals and can act as a mechanism of adaptation [1 3]. The epigenome is a multitude of chemical compounds that can cross-talk to the genome to alter its biology and biochemistry as well as physiology and metabolism to achieve capability for the survival of the fittest [2,3]. Darwin’s theory on evolution of the Origin of Species proposed: “Natural selection can act only by taking advantage of slight successive variations; it can never take a leap, but must advance by the shortest and slowest steps.” In 1942, Julian Huxley brought Darwin’s concept into the 20th century and incorporated a knowledge of genes in the light of Gregor Mendel’s experiments on inheritance. However, in both the concepts, there is no reference to epigenome and epigenetic damage or epigenetic modulation, which can change the phenotypes in such a way, to look like as if it is a genetic change due to natural selection. Such phenotypes of plants and animals are likely to have unique characteristics in nutrient content which may be exploited as functional foods. More recently, Barbara McClintock discovered transposable elements where parts of the genome can jump around and cause mutations or alter the gene expression, skewing Mendelian ratios and inheritance patterns. The genotype manifests due to interactions of environment on genome as well as on epigenome, which result in phenotypes [1 3]. The environmental factors in general and nutrition in particular have thus been implicated in the pathobiology of genetic variations and epigenetic damage-induced inheritance, leading to emergence of chronic diseases of affluence: cardiovascular diseases (CVDs), type 2 diabetes, cancer, bone and joint diseases, and degenerative diseases of brain [3 10] (Fig. 39.1). There is a need to assess that increase in chronic The Role of Functional Food Security In Global Health. DOI: https://doi.org/10.1016/B978-0-12-813148-0.00039-6 © 2019 Elsevier Inc. All rights reserved.

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FIGURE 39.1 Effects of environmental factors on behavioral and epigenetic biomarkers and development of noncommunicable diseases.

diseases is due to epigenetic inheritance leading to development of phenotypes such as pro-inflammatory cytokines or due to interaction of thrifty gene (developed during scarcity) with environmental factors, such as excess of fat and refined carbohydrates in a diet [11 15]. Epigenetic inheritance or epigenetic modulation can also alter the function of foods of both animal and plant origin, due to alterations in the nutrient content of the cell which are under influence of the soil and water that are important for the growth of the plants [11,16]. Therefore, genetic variations in the plant cell appear to be basic determinants of the nutrient content of fruits, leaves, and seeds of the plant foods which may be important for health promotion. Similarly, nutrient content of the animal foods can also alter due to epigenetic variations which need to be defined for inclusion of the food in functional food category [11,16]. In earlier studies, feeding experiments have been conducted to change the content of nutrient in animal foods such as egg of a hen after feeding flex seeds and tea leaves [11,16]. This review aims to highlight the role of epigenetics in the interaction of gene and environment which could be exploited in the development of foods and functional foods.

39.2 EPIGENETIC MECHANISMS OF EVOLUTION OF FUNCTIONAL FOODS Functional foods can evolve directly from plants that are provided nutrient rich soil and water used for growth of the plants. It has been proposed that dramatic adaptations can occur in the form of major morphological changes in the plants and animals, which appear to be similar to changes

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in structure from prehistoric man to modern day man and various human races [1 3]. These adaptations may be common among animals as well as among plants that may be used as functional foods. It is possible that maladaptations of the genome may be responsible for the development of genetic diseases or new species of plants and animals [1 3]. In many species of plants and animals, new phenotypes have been observed to occur rapidly in the last 100 years due to the rapid changes in the environment [1 11]. It is proposed that plants and animals with some level of genetic variations evolve via changes in gene frequency and gene sequence, induced mostly by natural selection or by epigenetic inheritance [1 10]. The progress in evolutionary biology, biochemistry, genomics, developmental biology, systems biology, and the impact of the environment on genes concerning mechanism of evolution have grown significantly [3 11]. It is possible that some lineages have greater “evolvability” than others, independent of how much baseline genetic variation is present. Heritable phenotype variations may depend on the biology and biochemistry of the genes as well as on their status of DNA methylation and hypomethylation of the epigename [7]. Epigenome showing histone, DNA, and chromosome is given in Fig. 39.2. Epigenetic mechanisms, such as DNA methylation and histone modification, can cause stable alterations in gene

FIGURE 39.2 Epigenome showing histone, DNA, and chromosome which are methylated due to oxidative stress and inflammation. Modified from www.genome.gov.

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activity without any changes in the underlying DNA sequence. DNA methylation is associated with silencing of transposons, imprinting and silencing of both transgenes and endogenous genes. DNA methylation can cause heritable phenotypic modifications in the absence of changes in DNA sequence. Nutritional factors—choline, pyrodoxin, vitamin B12, omega-3 fatty acids, folic acid, etc.—if given during pregnancy can trigger DNA methylation, which may have evolutionary consequences, even in the absence of sequence variation. However, it remains largely unknown to what extent environmentally induced methylation changes are transmitted to offspring, and whether observed methylation variation is truly independent. In mammals, resetting of DNA methylation takes place during early embryonic development [7 16]. In plants a considerable proportion of DNA methylation marks can be stably transmitted from parents to offspring for development of segregating phenotypes, depending on micronutrient content in the parent or offspring tissues. In one experiment [5], genetically identical apomictic dandelion (Taraxacum officinale) plants were exposed to different ecological stresses, and apomictic offspring were raised in the common unstressed environment. Only methylationsensitive amplified fragment length polymorphism markers were used to screen genome-wide methylation alterations triggered by stress treatments to assess the heritability of induced changes. These changes may be translated into quality and quantity of nutrient content of the fruits, leaf, or seed of the plant that are determinant of the functions of the foods, available for human consumption. In a previous study, a yeast prion provided a mechanism for genetic variation and diversity of phenotype indicating that nearly half of the conditions having the prion (PSI) led to significant phenotypic effects in some of the strains, which uncovered previously-hidden phenotypic variation in the yeast cells [6]. The low ω-6/ω-3 fatty acid ratio with high amino acids, flavonoids, and coenzyme Q10 present in the cell membrane to which species adapted during evolution, may have beneficial effects on DNA methylation and therefore on this phenotypic diversity, resulting in diversity of functional foods [7 16]. The prion (PSI) can pass from mother to daughter yeast cells when they divide either mitotically or meiotically despite lineages where they revert back to nonprion state selection, resulting in beneficial adaptations [6]. The “natural selection” may not actually be “natural” but it is our ignorance about the environmental factors that are causing phenotypic variations by altering the composition of the epigenome. This may be clearer from the evidence on the facilitation of genetic variation in a perspective of functional foods which are known to cause health promotion and decline in phenotypes related to diseases. The enrichment of nutrients may be accomplished by feeding domesticated birds and other animals, a diet close to that of their wild ancestor [11,16 20]. The diet of these animals may include a wider range of seeds and green vegetation, than is normally the case in modern farming practice. After long-term feeding, the eggs or milk or meat of these animals becomes rich in omega-3 fatty acids and polyphenolics that are obtained from the feed. In experiments with hens, Sim used flax seeds and other experts used tea leaves to enhance omega-3 fatty acids and flavonols in the hens eggs [11,16]. These experts did not study the epigenome of the animals but it is quite possible that feeding may have caused epigenetic modulation.

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39.3 INTERACTION OF ENVIRONMENTAL FACTORS AND GENETIC VARIATIONS AMONG HUMANS Our ancestors, approximately 15 million years ago, ate mostly fruits, vegetables, and seeds and honey containing little or no fat. They adapted by evolving a mutation for conversion of fructose from the fruit-based diet to fat for metabolic functions, which allowed them to survive seasonal periods of famine, when the fruit and vegetable plants were scarce. This epigenetic inheritance of fat accumulating phenotype, has become an adverse genetic variation for the modern man, although it was protective for the survival of our ancestors. It is proposed that from high fructose corn syrups and sugar, the refined starches are rapidly converted to fat in the modern man because of this mutation, resulting in obese phenotype causing obesity, insulin resistance, type 2 diabetes, and CVD. Since the diet of ancient man was rich in micronutrients, adverse effects of fructose rich foods were inhibited by these functional foods. Similar epigenetic inheritance has been observed among populations when they migrate from rural areas to urban environment and from developing countries of South Asia to the western world [1 3]. The South Asians are known to be highly susceptible for central obesity, type 2 diabetes, insulin resistance, and CVDs [1]. A complex set of physical and chemical factors, coming into play during development, which can influence structures and functions, are beyond simple genome to phenotype translation [6 11]. There are complex gene interactions and sudden morphological reorganizations occurring during development, and in experiments and natural setups, there may be discordance between genotype and phenotype [1 3,6 11].

39.4 NUTRIENTS AND THE AGOUTI GENE EXPERIMENT Nutritional modulation of epigenetic inheritance has been demonstrated in the yellow agouti mouse, an epigenetic biosensor for nutritional and environmental changes. These fat and yellow mice owe their appearance to an epigenetic modification that removes methyl groups from the normally methylated agouti gene [10]. In a developing mouse fetus, if the above modification occurs shortly after fertilization, the baby mouse may exhibit the yellow fur and obese phenotype with greater risk of developing cancer and diabetes [10]. However, the genetic code remains unchanged from normal mice. In this study, the nutrient intake was altered to serve as methyl group donors in mouse mothers, to cause methylation or demethylation of the agouti gene. Increased supplementation of choline, betaine, folic acid, and vitamin B12 in the diet of pregnant yellow agouti mice was able to decrease the incidence of deleterious phenotypes in offspring, by donating methyl groups and allowing for the remethylation of the agouti gene. If these mice were born with the agouti phenotype, they can pass that deleterious epigenetic trait to their offspring, regardless of their diet during pregnancy. This study indicates that nutrients can cause phenotypic changes which can pass on through cell division and mating to the offspring due to their possible influence on (natural) selection [10]. It is likely therefore, that we are what we eat and what our parents ate, and potentially what our grandparents ate.

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It may be also important to point out that we are not only “what we eat” but also “we are when we eat” and when our father and grandfather were eating [11,16]. There is a need to study the effects of low ω-6/ω-3 ratio diet, with high arginine, taurine, cysteine, coenzyme Q10 on the remethylation of the agouti gene and their effects on phenotypic variations. This approach can be exploited for food production from animal sources by feeding them green leaves, seeds, and grass from wild sources [16 20]. The above mode of inheritance needs to penetrate more than a few generations before it can earn a place in the evolutionary concept. Epigenetic inheritance appears to be widespread but it does not mean that it lasts and causes “evolutionarily” important effects. It is not clear until now, that if epigenetic changes are not stable for 20 to 30 generations, it would be relevant to evolution. Several experiments related to epigenetics are underway to establish the role of environmental factors in inheritance. Observing inheritance in three to four or more generations among patients of obesity, type 2 diabetes, hypertension, and coronary artery disease appears to be important which would be clear from the following cases. CASE 1: In 1975, we examined a patient with obesity (body mass index 27 kg/m2) and type 2 diabetes mellitus whose father also had a history of diabetes mellitus and died suddenly. This 48-year-old patient while under treatment developed tightness in the chest and myocardial ischaemia. He was treated and recovered but after a few months died of a sudden cardiac failure. His 40-year-old son who was also obese and had type 2 diabetes mellitus while under treatment also died of a sudden cardiac failure. Diet and lifestyle history showed that they have/had a wholesale business of selling clarified butter (anhydrous milk fat) during the time of the first generation, clarified butter and hydrogenated fat, during the second generation which continued during the third generation. All these three generations were sedentary and were consuming more than 40% of calories from clarified butter which may have caused inheritance of deleterious phenotypes in the offspring, resulting in type 2 diabetes and sudden death. The adverse effects of trans fat (unsaturated fats with trans-isomer fatty acids and oxidized cholesterol present in the clarified butter) consumed by the last three generations, on pro-inflammatory cytokines are well known [12 14]. Effects of oxidative stress and inflammation on epigenome are shown in Fig. 39.3. Inflammation has also been demonstrated to cause genetic damage leading to DNA methylation, histone modification, and RNA alterations [13]. Furthermore, sedentary behavior enhances inflammation by its adverse effects on adiponectin-, leptin- and brain-derived neurotrophic factors, which are antiinflammatory [12 16]. Inflammation could be important in the pathobiology of epigenetic inheritance. Currently, we are following the son (fourth generation) who is 30 years old, who has also been consuming clarified butter and high ω-6/ω-3 ratio diet by using sunflower oil and he continues to lead a sedentary life. CASE 2 (an ongoing observation): A 45-year-old obese man presented in 1975 with hypertension ( . 150/95 mmHg) and albuminuria and family history of hypertension and stroke causing death of his father. He had a heart attack in 1985 and died of a sudden cardiac failure after few months. His son presented with obesity (body weight 147 kg) and hypertension at the age of 29 years in 1995 and has developed heart hypertrophy by 2010. He had bariatric surgery which resulted in to body weight of 95 kg. His prediabetes and hypertension disappeared with regression of hypertrophy.

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FIGURE 39.3 Effects of oxidative stress and inflammation on epigenetic alterations. Modified from Google.

39.5 THE EVOLUTIONARY DIET, ENVIRONMENT, AND HEALTH Recently fossil studies from Germany on material from Jebel Irhoud, Morocco, revealed a mosaic of features with early or recent anatomically modern humans and more primitive neurocranial and endocranial morphology [12]. This study documents that early stages of the Homo sapiens clade in which key features of modern morphology were established, involved possibly the whole African continent, rather than Ethiopia alone, approximately 315,000 years ago. A fundamental view of evolution has been that the genetic makeup of contemporary humans shows only minor difference from that of the modern human, who appeared in Africa during the ancient period [12,13,16]. However, during the past 50,000 years, the human evolution has been comparatively rapid as revealed by the molecular geneticists [12]. Since 10,000 years ago, there have been marked changes in the food supply with the development of agriculture, it is of interest that there has been only a little change in our genes, during the past 10 centuries which may be due to the presence of ω-3 fatty acids, amino acids, vitamins, and minerals in our diet and without any dramatic changes in the environment [12 15]. However, there must have been some structural

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modifications in individual DNA sequences, and altered gene regulation and in the epigenome. A major effect in epigenetics would include DNA methylation, translational histone and noncoding RNA modifications that epigenetic modifications have major functional changes [15,16]. Although similar to genetic features of DNA heritability, epigenetic mechanisms may differ with potential reversibility by environmental and nutritional factors, which make them potentially crucial for their role in complex and multifactorial diseases. Increased evolutionary rapidity in humans compared with rates for other primates, has resulted from unprecedented demographic expansion, which has provided a far larger pool of mutations, upon which natural selection can operate. The human diaspora which has exposed humans to environmental changes appears to be quite different from those of their ancestral land in Africa and this rapid change may predispose deleterious epigenetic inheritance [13 17]. Our genes appear to be similar to the genes of our ancestors during the Paleolithic period (40,000 years ago), the time when our genetic profile was established. It was only during the last 100 160 years that dietary intakes and environment have changed significantly, causing increased intake of saturated fatty acids (SFA), trans fat, and linoleic acid, and a decrease in ω-3 fatty acids, from grain fed cattle, tamed at farmhouses, rather than meat from running animals [14]. The food and nutrient intake among hunter-gatherers and during the Paleolithic period showed no remarkable differences. However, after industrialization, there is a marked reduction in consumption of ω-3 fatty acids, vitamins, antioxidants, and proteins and a significant increase in the intake of carbohydrates (mainly refined), fat (saturated, trans fat, linoleic acid), and salt compared to the Paleolithic period [1 4,12 19]. There are also marked changes in the environmental factors, salt intake, and quality of food and nutrients which, in turn, may have deleterious effects on epigenetic inheritance, resulting in chronic diseases [16 22].

39.6 EGGS AS FUNCTIONAL FOODS, AFTER FEEDING FUNCTIONAL FOODS Nature recommends to ingest fatty acids in a balanced ratio (polyunsaturated: saturated: ω-6:ω3 5 1:1) as part of a dietary lipid pattern in which monounsaturated fatty acids is the major fat (P: M:S 5 1:6:1). These ratios represent the overall distribution of fats in a natural untamed environment (www.columbus-concept.com). Circulating plasma fatty acids, such as ω-6/ω-3 fatty acid ratio, gives an indication of pro-inflammatory status of blood vessels. Of major importance appear to be the essential dietary nutrients (essential amino acids, fatty acids, antioxidant vitamins, flavonoids and minerals) and the functional component of the regimen (diet, sport, spiritualism, etc.), because these factors may be important in the epigenetic modulation and regulation. It is not clear how these nutrients are incorporated in egg yolk? Can feeding-induced epigenetic modulation play some role? The conventional eggs are standard supermarket eggs which are produced from the chickens that are usually raised in an overfilled hen house or a cage and never see the light of day. They are usually fed grain-based crap, supplemented with vitamins and minerals and may also be treated with antibiotics and hormones. However, organic eggs or Columbus eggs are not treated with antibiotics or hormones and receive organic feed and may have limited access to the outdoors [11,16,20,23]. Pastured eggs are produced from chickens that are allowed to roam free, eating

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plants and insects (their natural food) along with some commercial feed. Omega-3 enriched eggs are basically like those of conventional chickens, except that their feed is supplemented with an omega-3 source like flax seeds and may have had some access to the outside. Feeding 10%, 20%, and 30% flaxseed to laying hens for a 28-day period and collecting eggs for analysis in the last 3 days of the period causes large increases in omega-3 fatty acids in the eggs at all levels of flax seed administration [23a]. Cheronian and Sim fed flax seed to laying hens at 8% and 16% in diets which were supplemented with pyridoxine and demonstrated increased omega-3 fatty acids in the eggs, and brain tissue of embryos and chicks from the hens fed the ground flaxseed [23b]. The longer chain omega-3 fatty acids were deposited exclusively in the phospholipids and the fatty acid content of chicks was significantly altered by egg yolk lipids. Cherian and Sim also found that elongation of omega-3 fatty acids occurs during incubation [23b]. However, Chu and Kummerow were the first to feed linseed oil and reported higher levels of linolenic acid in the chickens [23c]. Sim was awarded Singh’s felicitation award during the World Congress of Clinical Nutrition at Banff, Canada in 2002. A study compared the fatty acid composition of three types of eggs: conventional, organic, and omega-3 enriched [20]. Omega-3 eggs had 39% less arachidonic acid, an inflammatory omega-6 fatty acid that most people eat too much of. Omega-3 eggs had five times as much omega-3 as the conventional eggs. There was very little difference between organic and conventional eggs. It is clear that hens fed an omega-3 enriched diet lay eggs that are much higher in omega-3 than conventional eggs [20,23]. Eggs from pastured hens are more nutritious than the conventional eggs at the supermarket. They are higher in vitamin A and E and omega-3 fatty acids and lower in cholesterol and saturated fat [20,23,24]. The advantages of simultaneous enrichment of eggs, milk, or meat, with other nutrients, i.e., vitamin E, carotenoids, selenium, and DHA, include better stability of polyunsaturated fatty acids during egg storage and cooking, high availability of such nutrients as vitamin E and carotenoids, absence of off-taste, and an improved antioxidant and omega-3 status of people consuming these eggs. Having reviewed the relevant scientific literature, it is concluded that designer eggs rich in omega-3 and antioxidants, can be considered as a new type of functional food [23,24], It is possible that by feeding animals with nutritious feeds, there is enrichment of eggs, milk, or meat [23,24]. This method can provide the animal foods—egg, milk, and meat—with low saturated fat and cholesterol, high omega-3, vitamins E, A, minerals, and selenium. The pigment enriched eggs and many more types of the modified or enriched animal foods can easily be obtained for the specific purposes by this method. A recent study revealed that mineral nutrient composition of vegetables, fruits, and grains is not declining due to changes in soil [25]. Allegations of decline due to agricultural soil mineral depletion are unfounded because some high-yield varieties show a dilution effect of lower mineral concentrations. It seems that changes are within natural variation ranges and are not nutritionally significant; hence, eating the recommended daily servings can provide adequate nutrition. However, this study examined only minerals without mention of other nutrients which can alter due to epigenetic modulation of epigenome of seeds grown in deficient soil. It is important to develop wild-type feed for animals which should be rich in omega-3 fatty acids, antioxidants, minerals, amino acids, and other nutrients [26]. The content of flax seed in layer feed should not exceed 10%, because a layer of 15% adversely affects feed conversion and weight of the product such as egg from hen which may be due to antiestrogenic effects [27]. Such diets can be used in other

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animals like lamb, pigs, cow, buffalo for producing healthy meats and milk. There is a need to study the epigenome among animals receiving such feeds to demonstrate the effects on epigenetic marks or epigenetic regulation. Previous studies also indicate that food and nutrient intake, energy expenditure, and body adiposity are regulated by physiology and metabolism of foods and nutrients [18 21]. Central and peripheral signals from central and peripheral areas communicate information about the current state of energy balance and food quality, to key brain regions, including the hypothalamus and brain stem [19]. Hunger and satiety represent coordinated responses to these signals, which include neural and hormonal messages from the gut. Our understanding of how neural and hormonal brain gut signaling regulates energy homeostasis has advanced considerably and it is possible that gut brain body connection may be regulated by genes and epigenes. Gut hormones have various physiological functions that include specifically targeting the brain to regulate appetite. New research suggests that gut hormones can be used to specifically regulate energy homeostasis in humans, and offer a target for genetic modulation. Epigenetics alterations have also been observed in patients with hypertension and gut hormones under the influence of probiotics can prevent the development of CVDs including hypertension [19].

39.7 EPIGENETIC MODULATION IN PLANTS FOR FOOD PRODUCTION Epigenetic modulation is characterized with alteration in chromatin structure, remodeled histone proteins, or methylated DNA, often mediated by environmental factors, and can pass from parent to offspring without changing the actual sequence of the inherited genome. If epigenetic inheritance plays any role in evolutionary change, it should be possible to demonstrate that the changes are stable causing heritable effects through several generations and which can be associated with alteration in the biochemical content of plant or animal foods [8,11,16]. In an experiment, two groups of genetically identical Arabodopsis plants (Brassicaceae) were exposed to either hot or cold conditions for P and F1 generations [9]. The next generation (F2) from both groups was grown at a normal temperature, but the offspring (F3) from both groups were grown in either hot or cold conditions. The F3 plants, grown in hot conditions and descended from P and F1 plants, also grown in hot conditions produced five-fold more seeds compared to F3 plants grown in hot conditions but descended from cold-treated ancestors [9]. These mutations may have occurred due to epigenetic factors affecting flower productions and early stage seed survival, due to molecular adaptations in these plants. There is a need to study biochemistry of seeds and leaves to find out if the increase in the quantity of seeds was also associated with an increase in certain nutrients in the seeds, which can improve the quality of seeds to consider as if they are functional foods. Plants require at least 14 minerals, including macronutrients nitrogen (N), phosphorus (P), potassium (K), calcium (Ca), magnesium (Mg), and sulfur (S) and the micronutrients chlorine (Cl), boron (B), iron (Fe), manganese (Mn), copper (Cu), zinc (Zn), nickel (Ni), and molybdenum (Mo) [28]. However, selenium and chromium also appear to be important for plant growth because they are rich in certain foods. Crop production is often limited by low phytoavailability of essential mineral elements and/or the presence of excessive concentrations of potentially toxic mineral elements,

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such as sodium (Na), Cl, B, Fe, Mn, Al, Hg, As, Pb, and Cd in the soil solution. The activities of key transport proteins determine species-specific tissue and cellular ionomes. Some of the minerals in the soils that are toxic need to be avoided but minerals have an important role in plant physiology [28]. Iron is needed for chlorophyll formation and oxygen transfer. Without adequate iron, leaves turn yellow, but leaf veins remain green. Adding too much lime in the soil, can lead to an iron deficiency. Manganese works as a channel for a variety of enzymes and is essential for chlorophyll formation. Deficiency of manganese causes a variety of indicators depending on the type of plant. The most common signs include yellowing of leaves with green veins or grayish-white specks that appear on the leaves. Excess of manganese may deplete iron in the soil and cause symptoms similar to those exhibited with a lack of manganese. Boron works as a vehicle for the interchange of sugars, for reproduction, and for cellular intake of water. Deficiency of boron causes plant distortion with hollow stems and malformed fruits as well as scorched, curled, and sometimes mottled leaves. Zinc is important for the production of proteins or amino acids which affects how big plants grow and whether or not they mature. Zinc deficiency produces less fruit and brings about yellowing of leaves between veins often accompanied by purple or dead spots with small, deformed leaves growing close together which could be a manifestation of epigenetic damage [28]. Copper is also important for the production of proteins and plays an important role in reproduction. Copper deficiency causes bluish-green leaves that might wither or never unfold. It may cause rosettes on growing tips. Molybdenum is vital to nitrate enzymes and the formation of root nodules in beans and peas. Lack of molybdenum causes the leaves to produce yellow mottling and dead spots and often growing tips are distorted or killed. Lack of the right amount of chlorine in soil might affect carbohydrate metabolism and photosynthesis as well as cause stubby roots and wilting. It is proposed that deficiency of certain of these nutrients, such as zinc and copper, can have adverse effects on amino acid metabolism leading to epigenetic damage and supplementation can be beneficial. Epigenetic gene regulation affects genome integrity by maintaining, over generations, silencing in repetitive sequences and transposons [29]. In plants, epigenetic regulation plays a key role in phenomena such as genomic imprinting and paramutation [30 37] mainly, by enforcing a silenced chromatin state through DNA methylation and/or chromatin modifications, leading to gene silencing. The silenced states are then maintained trans-generationally by epigenetic machinery [35]. Several components involved in the maintenance of transcriptional gene silencing have been identified in plants, the detailed mechanisms that may be distinct among different plant species are not fully understood. Technological advances in plant epigenetics are providing unprecedented opportunities to monitor chromatin modifications, gene expression, and genome structure [29 41]. Many classical epigenetic phenomena such as transposable element inactivation, imprinting, para-mutation, transgene silencing, and co-suppression are first documented in plants [31 37]. Recent studies have demonstrated that plants are heavily dependent upon changes in gene expression in order to respond to environmental stimuli, and chromatin-based regulation of gene expression is likely crucial for these responses [29 34]. The level of chromatin “resetting” during sexual reproduction appears to be lower in plants in comparison with animal species [29,30]. It potentially allows inheritance of epimutations acquired during plant life and many plant species can propagate asexually and produce vegetative clones, providing opportunities for mitotic inheritance of epigenetic states leading to

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important traits [29 33]. Study of nutrient contents in these new traits and how to alter nutrient contents, may be the future of functional food production. Epigenetic marks in the form of DNA methylation can influence cytosines in different sequence contexts such as CG, CHG, and CHH (where H is any base other than G) and at different types of loci in plant genomes. The silencing of transposons, that are called genomic parasites, which invade the genome of their hosts may be an important mechanism of epigenetic regulation [29,30]. The repetitive nature of transposons and the fact that they generate large insertion/deletion polymorphisms among genotypes has led to difficulties in monitoring the link between transposon polymorphism and variation in DNA methylation. Epigenetic silencing influences the vast majority of transposons that are highly methylated [30,31]. Eukaryotic genomes consist of two types of DNA, genic and intergenic, where the genic regions are associated with an open euchromatic state, and the inactive, intergenic regions are associated with a closed heterochromatic state. Segregation of the genome into active and repressed regions requires complex sets of enzymes to direct appropriate, context-specific activity of RNA polymerases. It is possible that a conflict would emerge at the boundaries of intergenic and genic regions, where regions of genetic repression must cooperate or at least not interfere with the expression of genes and epigenes. The mammalian and plant DNA methylation is restricted to symmetrical CG sequences, but plants also have significant levels of cytosine methylation in the symmetric context CHG (where H is A, C, or T) and even in asymmetric sequences. Cytosine DNA methylation is a heritable epigenetic mark present in many eukaryotic organisms is performed by DNA-methyltransferases that catalyze transfer of a methyl group from S-adenosyl-l-methionine to cytosine bases in DNA (Fig. 39.4). The CHH methylation is maintained due to RNA dependent methylation of DNA (RdDM) and requires the plant-specific RNA polymerases IV and V (Pol IV and V), respectively. Polymerase IV generates precursor transcripts of 24-nt small RNAs (sRNAs) that target scaffold transcripts from polymerase V, by sequence complementarity and recruit the domains rearranged methyltransferase 2 [31]. Zhang and coworkers demonstrated a new link between RdDM and the chromatin remodeling factor PICKLE (PKL) indicating that PKL is required for the accumulation of transcripts generated by Polymerase V and for the positioning of Polymerase V-stabilized nucleosomes at a subset of RdDM target loci [32]. The results link nucleosome positioning with the initiation of RdDM, consistent with the previously proposed role of SWI/SNF chromatin remodeling complexes in establishing positioned nucleosomes on specific loci primed for RdDM [33]. The plant development is regulated by PICKEL and, in particular, regulates the access of Polycomb-group proteins to its targets as well as SWI/SNF complexes also having a role in the development of plants [34]. A recent study indicates that the SWI/SNF complex core subunit BAF60 regulates access of the Phytochrome Interacting Factor 4 (PIF4) to nucleosome-free regions [35]. It is possible that the dual functional role of chromatin-remodeling factors in regulating plant development and RdDM may have both processes more closely connected than is widely appreciated. The gene body methylation (gbM) indicating to the moderate levels of CG methylation found within the exons of transcribed genes, correlates with intermediate levels of expression [36]). More recent studies also reveal that nutritional restriction or supplementations from conception to antenatal period or during natality can influence the nutrient content of meat, milk, and egg of the offspring by epigenetic modulation [42–44]. A recent study showed that the prenatal restriction diet can affect the activity of genes involved in epigenetic mechanisms in the liver across multiple

39.7 EPIGENETIC MODULATION IN PLANTS FOR FOOD PRODUCTION

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FIGURE 39.4 Elucidation of epigenetics and RNA regulation due to stress and increase in micronutrient-rich seed production. Modified from Google web.

generations [43]. Restricted feeding also revealed the global histone H3 acetylation in fetal liver. Another study reported that exposure to endocrine-disrupting chemicals, during prenatal and early postnatal periods, can alter normal physiology and increase susceptibility to noncommunicable diseases like obesity [44]. It is possible that such animal foods may have proinflammatory effects on increased consumption of such foods by the healthy population. In brief, the evolution of foods occurred with human evolution. The evolutionary diets were rich in vegetables, roots, fruits, seeds, milk, and honey. Fish and meats were also available to early men. These foods are rich in omega-3 fatty acids, antioxidants, vitamins, flavonoids, and minerals as well as amino acids. However, supplementation of omega-6:omega-3 fatty acids to achieve a ratio of 1:1 in the tissues with optimal choline, betaine, folic acid, and vitamin B12 as well as other essential amino acids, antioxidants and vitamins can modulate methylation of DNA resulting in reduction in phenotypes for health or disease by epigenetic regulation. Feeding diets high in omega-3 fatty acids and other nutrients to animals can increase these nutrients in the egg, milk, and muscle and may modulate the epigenome with beneficial effects. Further research is necessary to demonstrate the role of nutrition in the epigenetic regulation for the development of new functional foods and a new perspective for health promotion [21,22,29 41]).

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ACKNOWLEDGMENTS Tsim Tsoum Institute, Krakow, Poland and International College of Nutrition for the support to produce this work.

REFERENCES [1] Singh RB, Mori H. Risk factors for coronary heart disease: synthesis of a new hypothesis through adaptation. Med Hypoth 1992;39:334 41. [2] Mishra S, Singh RB, Dwivedi SP, De Meester F, Rybar R, Pella D, et al. Effects of nutraceuticals on gene expression. Open Nutra J 2009;2:70 80. [3] Singh RB. Darwin, evolution and origin of species. Open Nutr J 2009;2:86 7. [4] Singh RB, Singh AK, Alam SE, De Meester F, Fedacko J, Dharwadker S, et al. In: Meester F De, Watson RR, Zibadi S, editors. Effects of omega-3 fatty acids in genetic expressions. In Nutrition in Health, Omega-6/3 Fatty Acids. New York: Humena Press, r Springer Science 1 Business Media; 2013. p. 27 52. Available from: https://doi.org/10.1007/978-1-62703-215-5_3. [5] Verhoeven KJF, Jansen JJ, van Dijk PJ, Biere A. Stress induced DNA methylation, changes and their heritability in asexual dendilions. New Phyto 2010;1108 18. [6] True HL, Lindquist SL. A yeast prion provides a mechanism for genetic variation and Phenotypic diversity. Nature 2000;407:477 83. [7] Badyaey A. The beak of the other finch: coevolution of genetic covariance structure and developmental modularity during adaptive evolution. Phil Trans Royal Soc 2010;365:1111 26. [8] Jablonka F, Raz G. Transgenerational epigenetic inheritance: prevalence, mechanisms and implications for the study of heredity and evolution. Q Rev Biol 2009;84:131 76. [9] Whittle CA, Otto SP, Johnston MO, Krochko JE. Adaptive epigenetic memory of ancestral temperature regime in Arabidopsis thaliana. Botany 2009;87:650 7. [10] Waterland RA, Jirtle RL. Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol Cell Biol 2003;23:5293 300. [11] De Meester F. The wild type egg, an empirical approach to a reference pattern for dietary fatty acids in human nutrition. In: De Meester F, Watson RR, editors. Wild type foods in health promotion and disease prevention. Humena Press; 2008. [12] Hublin JJ, Ben-Ncer A, Bailey SE, Freidline SR, Neubauer S, Skinner MM, et al. New fossils from Jebel Irhoud, Morocco and the pan-African origin of Homo sapiens. Nature 2017;546:289 92. Available from: https://doi.org/10.1038/nature22336. [13] Puri BK, Stannard JP. The essentiality of eicosapentaenoic acid in breast milk. In: Meester Fabien De, Watson RR, editors. Wild type foods in health promotion and disease prevention. Humena Press; 2008. [14] Simopolous AP. Genetic variation and dietary response: nutrigenetics/ nutrigenomics. Asia Pac J Clin Nutr 2002;11:S117 28. [15] Eaton S.B., Eaton S.B. III, Sinclair A.J., Cordain I., Mann N.J. Dietary intake of long chain polyunsaturated fatty acids during the Paleolithic period. In Simopoulos AP edition. The return of w-3 fatty acids in the food supply. Land based Animal Food Products and their Health Effects. World Rev Nutr Dietetics 1998; 83: 12-23. [16] Surai PF, Speake BK. The natural fatty acid composition of eggs of wild birds and the consequences of domestication. In: De Meester F, Watson RR, editors. Wild type foods in health promotion and disease promotion. Humena Press; 2008.

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[17] Kwiatek AW, Singh RB, De Meester F. Nutrition and behaviour: the role of w-3 fatty acids. Open Nutra J 2010;3:119 28. [18] Bensatti P, Peluso G, Nicolai R, Calvani M. Polyunsaturated fatty acids: biochem- ical, nutritional and epigenetic properties. J Am Coll Nutr. 2004;23:281 302. [19] Singh RB, Lee JY, Fedacko J, Niaz MA, Takahashi T, Elkilany G, et al. Epigenetic inheritance of hypertension. World Heart J 2016;8:79 88. [20] Karsten HD, Patterson PH, Stout R, Crews G. Vitamins A, E and fatty acid composition of the eggs of caged hens and pastured hens. Renew Agri Food Systems 2010;25:45 54. [21] Tokunaga M, Takahashi T, Singh RB, De Meester F, Wilson DW. Nutrition and Epigenetics. Med Epigenet 2013;1:70 7. Available from: https://doi.org/10.1159/000355220. [22] Thanan R, Oikawa S, Hiraku Y, Ohnishi S, Ma N, Pinlaor S, et al. Oxidative stress and its significant roles in neurodegenerative diseases and cancer. Int J Mol Sci 2015;16(1):193 217. Available from: https://doi.org/10.3390/ijms16010193. [23] Samman S, Kung P, Carter LM, Foster J, Ahmad ZI, Phuyal JL, et al. Fatty acid composition of certified organic, conventional and omega-3 eggs. Food Chem 2009;116:911 14. [23a] Cherian G, Sim JS. Effect of feeding full fat flax and canola seeds to laying hens on the fatty acid composition of eggs, embryos and newly hatched chicks. Poultry Sci 1991;70:917 22. [23b] Cherian G, Sim JS. Net transfer and incorporation of yolk n-3 fatty acids into developing chick embryos. Poultry Sci 1993;72:98 105. [23c] Chu TK, Kummerow FA. The deposition of linolenic acid in chickens fed linseed oil. Poultry Sci 1950;29:846 51. [24] Ewing, W.R. Poultry Nutrition. The W. R. Ewing Company, Pasadena, California, 1963. [25] Singh VP, Pathak V, Akhilesh V. Modified or enriched eggs: a smart approach in egg industry: a review. Am J Food Technol 2012;7:266 77. [26] Marles RJ. Mineral nutrient composition of vegetables, fruits and grains: the context of reports of apparent historical declines. J Food Compo Anal 2017;56:93 103. [27] Coucke L. Columbus feed around the world; selection of ingredients and potential influence on future international strategy for crop selection. In: Meester F De, Watson RR, editors. Wild type foods in health promotion and disease prevention. New Jersay: Humena Press; 2008. p. 537 44. [28] Eder K, roth-Maiyer DA, Kirchgessner M. Laying performance and fatty acid composition of egg yolk lipids and hens fed diets with various amounts of ground or whole flax seeds. Arch Furgeflugelkunde 1998;62:223 8. [29] White PJ, Brown PH. Plant nutrition for sustainable development and global health. Ann Bot 2010;105 (7):1073 80. Available from: https://doi.org/10.1093/aob/mcq085. [30] Kohler C, Springer N. Plant epigenomics—deciphering the mechanisms of epigenetic inheritance and plasticity in plants. Gen Biol 2017;18:132. Available from: https://doi.org/10.1186/s13059-017-1260-9. [31] Daron J, Slotkin RK. EpiTEome: simultaneous detection of transposable element insertion sites and their DNA methylation levels. Gen Biol 2017;18:91. [32] Matzke MA, Mosher RA. RNA-directed DNA methylation: an epigenetic pathway of increasing complexity. Nat Rev Genet 2014;15:394 408. [33] Yang R, Zheng Z, Chen Q, Yang L, Huang H, Miki D, et al. The developmental regulator PKL is required to maintain correct DNA methylation patterns at RNA-directed DNA methylation loci. Gen Biol 2017;18:103. [34] Zhu Y, Rowley MJ, Bohmdorfer G, Wierzbicki AT. A SWI/SNF chromatin-remodeling complex acts in noncoding RNA-mediated transcriptional silencing. Mol Cell 2013;49:298 309. [35] Han SK, Wu MF, Cui S, Wagner D. Roles and activities of chromatin remodeling ATPases in plants. Plant J 2015;83:62 77.

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[36] J´egu T, Veluchamy A, Ramirez-Prado JS, Rizzi-Paillet C, Perez M, Lhomme A, et al. The Arabidopsis SWI/SNF protein BAF60 mediates seedling growth control by modulating DNA accessibility. Gen Biol 2017;18:114. [37] Zilberman D. An evolutionary case for functional gene body methylation in plants and animals. Gen Biol 2017;18:87. [38] Picard CL, Gehring M. Proximal methylation features associated with nonrandom changes in gene body methylation. Gen Biol 2017;18:73. [39] Bewick AJ, Niederhuth CE, Ji L, Rohr NA, Griffin PT, Leebens-Mack J, et al. The evolution of CHOMOMETHYLASES and gene body DNA methylation in plants. Gen Biol 2017;18:65. [40] Wollmann H, Stroud H, Yelagandula R, Tarutani Y, Jiang D, Jing L, et al. The histone H3 variant H3.3 regulates gene body DNA methylation in Arabidopsis thaliana. Gen Biol 2017;18:94. [41] Blackledge NP, Rose NR, Klose RJ. Targeting Polycomb systems to regulate gene expression: modifications to a complex story. Nat Rev Mol Cell Biol 2015;16:643 9. [42] Skjærven KH, Jakt LM, Fernandes JMO, Dahl JA, Adam A-C, Klughammer J, et al. Parental micronutrient deficiency distorts liver DNA methylation and expression of lipid genes associated with a fatty-liver-like phenotype in offspring. Sci Rep 2018;8. Available from: https://doi.org/10.1038/s41598-018-21211-5. [43] Nowacka-Woszuk J, Szczerbal I, Malinowska AM, Chmurzynska A. Transgenerational effects of prenatal restricted diet on gene expression and histone modifications in the rat. PLoS One 2018;13(2): e0193464. Available from: https://doi.org/10.1371/journal.pone.0193464. [44] Junge KM, Leppert B, Jahreis S, Wissenbach DK, Feltens R, Gru¨tzmann K, et al. MEST mediates the impact of prenatal bisphenol A exposure on long-term body weight development. Clin Epigenet 2018;10:58.

FURTHER READING Zhou Y, Romero-Campero FJ, Gomez-Zambrano A, Turck F, Calonje M. H2A monoubiquitination in Arabidopsis thaliana is generally independent of LHP1 and PRC2 activity. Gen Biol 2017;18:69.

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40

Ram B. Singh1, Aditya K. Gupta2, Jan Fedacko3, Lekh R. Juneja4, Peter Jarcuska5 and Daniel Pella6 1

Halberg Hospital and Research Institute, Moradabad, Uttar Pradesh, India 2Department of Medicine, Rajshree Medical College, Bareilly, Uttar Pradesh, India 3Faculty of Medicine, PJ Safaric University, Kosice, Slovakia 4 Global Head of International Business, R&D, Rohto Pharmaceutical Co.,Ltd, Osaka, Japan 5 ˇ arik, ´ Department of Gastroenterology, University of P.J. Saf Faculty of Medicine and University Hospital L. 6 Pasteur, Koˇsice Faculty of Medicine, PJ Safaric University, Kosice, Slovakia

40.1 INTRODUCTION The occurrence of cancer or cardiovascular diseases (CVDs) or diabetes is dependent on the interplay between the genome and the epigenome, which together interact with environmental factors, including nutrition [1]. The study of nutrition is complex as it is influenced by numerous variables that may have variable effects due to other environmental factors [1,2]. Exposures to Western diet or Mediterranean-style diets can have consequences for health or diseases, years or decades later and this raises questions about the mechanisms through which such exposures are “remembered” and how they result in altered disease risk [2 4]. There is growing evidence that epigenetic mechanisms may mediate the effects of nutrition and may be causal for the development of common complex (or chronic) diseases. Epigenetics encompasses changes to marks on the genome as well as on associated cellular machinery, that are copied from one cell generation to the next, which may alter gene expression, but which do not involve changes in the primary DNA sequence [1 3]. Change in paternal grandmothers’ early food supply can influence mortality due to CVDs of the female grandchildren, which is called transgenerational epigenetic inheritance [5,6] Epigenetic alteration is the non-Mendelian inheritance of DNA modifications that may influence gene expression on one or more alleles [6]. These epigenetic changes are heritable from cell to cell and may be heritable from parent to offspring [6]. Epigenetic marks may be acquired throughout life and some of the marks can be potentially reversible [7,8]. However, once some of the characteristics are established, they may remain stable throughout life and into the next generations [9]. These are more common with less pronounced, nutrition-induced epigenetic variation which may occur throughout the life course [10]. Most experts agree that there are critical windows during early development during which epigenetic marks are cleared and then reestablished, and it is not surprising that an embryo would be particularly vulnerable to environmental influences during this time [10]. The Role of Functional Food Security In Global Health. DOI: https://doi.org/10.1016/B978-0-12-813148-0.00040-2 © 2019 Elsevier Inc. All rights reserved.

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Further studies indicate that oxidative stress can damage the epigenome as well as genome, which appears to be a major regulator of epigenetic gene regulation via modification of DNA methylation, histones, and microRNAs in the epigenome [11]. The epigenome means surface of the genes, whereas genome means involvement of DNA sequences. The knowledge of epigenome and genome has provided both the biological link and a potential molecular explanation between oxidative stress and cardiovascular/ metabolic diseases and cancer [11]. Oxidative stress promotes DNA damage of the epigenome as well as genome and may also contribute to the development of cardiometabolic diseases (CMDs), including type 2 diabetes, neurodegenerative diseases, CVDs, and cancer [11]. Exogenous antioxidants obtained from the diet, mainly vitamin C, vitamin E, zinc, selenium, flavonoids, polyphenols, and carotenoids as well as omega-3 fatty acids, have an important role in reducing oxidative stress and also DNA damage. It seems likely that the therapeutic dose of omega-3 fatty acids will depend on the risk factor of the disease as well as on degree of severity of disease resulting from the genetic predisposition. A lower ratio of omega-6/omega-3 fatty acids is more desirable in reducing the risk of many of the NCDs of high prevalence in Western societies, as well as in the developing countries who are rapidly adopting Western dietary habits [1 3]. It has been proposed that human beings evolved on a diet with a ratio of omega-6 to omega-3 essential fatty acids (EFA) of B1 whereas in Western diets the ratio is 15/1 16.7/1 and in Asia the ratio may be 1:50. It is possible that high omega-3 fatty acids can protect the genome as well as epigenome [12 17]. Endogenous antioxidants include the enzymes catalase, glutathione peroxidase, and superoxide dismutase. Oxidative stress is a result of an imbalance between the production and accumulation of reactive species and the organisms capacity to manage those using endogenous and exogenous antioxidants. Nutrigenetics is a field of science that examines the interactions between diet and genetic variation. Individual genetic variation can affect proteins involved in the uptake, utilization, and metabolism of dietary antioxidants. It may alter their serum levels and subsequent contribution to modulation of oxidative stress in the tissues. This review aims to elucidate the interaction between genetic as well as epigenetic variations, nutrient status, and development of noncommunicable diseases (NCDs).

40.2 NUTRITION AND GENETIC VARIATIONS Nutritional status indicates how nutrients can maintain normal and stable body homeostasis at the level of the cell, tissues, and organs. The mechanism of nutrient-dependent interactions at the genetic molecular, protein production, and metabolic profile levels is important for cell function [12 14]. There is evidence from the Human Genome Project about the science of nutritional genomics to discover multiple mutual relations between genes, nutrition, and diseases [14]. Sequencing of the human genome revealed significant genetic heterogeneity within human populations observed by finding out the sequencing of human genome. Millions of single-nucleotide polymorphisms (SNPs) have been found to have a relation to nutrition [15]. It is possible that accommodating the SNPs, in the involved genes in metabolism of drugs, environmental agents, or dietary components, may highly affect the individual response to exposure to these agents, including diet [15,16] (Fig. 40.1).

40.2 NUTRITION AND GENETIC VARIATIONS

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FIGURE 40.1 Epigenomics; DNA inaccessible gene-turned off, DNA accessible-gene turned on.

Most experts agree with the aforesaid four proposals of nutritional genomics [16 25]. 1. Diet ingredients change the gene structure and/or gene expression, and consequently, the human genome. 2. Some of the genes, dependent on dietary factors in its regulation may initiate the commencement, extent, advancement, and progression of chronic NCDs. 3. The equilibrium between health and disease can be explained by individual variations in genotype indicating greater susceptibility in populations with poor in utero-undernutrition or protection as in Japanese populations. 4. Diet is considered be a critical predisposing factor for many diseases in some individuals under particular conditions.

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The body homeostasis is maintained by interaction between nutrition, metabolism, and gene expression. Nutrition related or dependent disorders are polygenic and appear to be the result of a mixture of nutrients [17,18]. For person-to-person divergence in response to diet, genetic variation may be the basis. In nutrigenetics, there is focus on how genetic variation influences gene expression and recognizing genetic variants as risk factors for human nutrition dependent disorders, such as NCDs [19]. There is an interacting two-way relationship between nutrition and the human genome which defines and marks the gene expression as well as metabolic response [20]. The genetic background of the subject can define the nutrient state, metabolic response, and susceptibility to diet-dependent or related health disorders [16]. The nutrients may also regulate the transcription factors that modify the gene expression, up or down, and consequently adjust the metabolic responses at the molecular level [16]. Therefore, the interplay of results between nutrition and the human genome has led to production of new definitions; nutrigenetics, and nutrigenomics [13]. It is suggested that the science of nutrigenetics is involved in handling the mechanism by which genetic variations define the risk of individual to diseases and daily requirements of nutrients [20]. Nutrigenetics is also involved in cellular metabolic response and behavior towards the bioactive dietary components or nutritional therapy, the main target of that is to clarify the impact of the gene variability on the interaction between nutrients and diseases. The science of nutrigenomics is directed to review and study the genome-wide impact of nutrition. Its interests include functional effect of various food components on the (-omes) branch of science including genome, transcriptome, proteome, and metabolome [20]. Nutrigenomics are clearly distinguished through the mechanisms of interactions between nutrients and genes that determine the risk of development of diseases and nutrigenetics explores the interaction between nutrients and genes [21]. Nutrigenomics also characterizes the impact of all aspects of nutrients as food-based, dietary limitation, or nutritional supplementary agents, on the gene expression. The interest in the genome-wide effects of nutrients on transcriptome, proteome, and metabolome in cells, tissues, or organisms is also part of nutrigenomics. The genes that can influence the risk of diet-dependent diseases are also identified via nutrigenomics. It may also be useful in understanding how nutrients can affect the metabolic pathways and how these regulations can be inhibited in the early phase of diet-related and diet-dependent diseases [21]. Therefore, nutrigenomics also aims to understand how these dietary signatures have an impact on the cellular function and the balance of the internal environment tissues within the whole body [22]. The manner of gene expression, protein expression, and metabolite production as a result of exposure to nutrient and represented it by dietary signature are also important components of nutrigenomics [22 25].

40.3 NUTRITION AND EPIGENETIC VARIATIONS Dietary and other environmental factors induce epigenetic alterations which may have important consequences for development of NCDs including cancer [3 10]. It is known that the epigenome is under the influence of dietary, lifestyle, and environmental determinants of risk of NCDs. It is proposed that effects of these exposures might be mediated, at least in part, via epigenetic mechanisms. All the recognized epigenetic marks—DNA methylation, histone modification, and

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microRNA (miRNA) expression—are influenced by environmental exposures, including diet, tobacco, alcohol, physical activity, stress, environmental carcinogens, genetic factors, and infectious agents which play important roles in the etiology of NCDs [5 10]. Some of these epigenetic modifications change the expression of tumor suppressor genes and oncogenes and, therefore, may be causal for tumorigenesis. However, further work is required to understand the mechanisms of carcinogenesis, atherosclerosis, osteoporosis, and brain degeneration through which specific environmental factors produce epigenetic changes or genetic changes. Identification of those changes which are likely to be causal in the pathogenesis of cancer and other NCDs that are secondary, or bystander, effects are also important [3 10]. In view of the plasticity of epigenetic marks in response to oxidative stress and inflammation; cancer or other NCDs-related exposures, such epigenetic marks are attractive candidates for the development of surrogate endpoints which could be used in dietary or lifestyle intervention studies for cancer prevention before development of a full picture of cancer or other NCD (Fig. 40.2). There is a need for future research to focus on identifying epigenetic marks which are (1) validated as biomarkers for the cancer under study; (2) readily measured in easily accessible tissues,

FIGURE 40.2 Showing epigenetic marks; DNA methylation, histone modification, and mRNA alteration.

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for example, blood, buccal cells, or stool; and (3) altered in response to dietary or lifestyle interventions for which there is convincing evidence for a relationship with risk of NCDs including cancer. The most important epigenetic marks are closely interacting mechanisms, including DNA methylation, histone modifications, and noncoding microRNAs (miRNA) which, together, are responsible for regulating gene expression not only during cellular differentiation in embryonic and fetal development but also throughout the life course [2 10]. In fact, numerous dietary factors, including micronutrients and nonnutrient dietary components, such as genistein and polyphenols, can modify epigenetic marks. Effects of altered dietary supply of methyl donors on DNA methylation are plausible explanations for the observed epigenetic changes, but to a large extent, the mechanisms responsible for diet epigenome health relationships remain to be discovered. Also, only little is known about which epigenomic marks are most labile in response to dietary exposures. Given the plasticity of epigenetic marks and their responsiveness to dietary factors, there is potential for the development of epigenetic marks as biomarkers of health for use in intervention trials. Since the epigenome can be modified, unlike genome, hence some epigenetic risk markers have the potential to be reversed. Such modifications take place by means of drugs, diet, or environmental exposures. It is widely accepted that epigenetic modifications take place during early embryonic and primordial cell development, but it is also important that we gain an understanding of the potential for such changes later in life. These “later life” epigenetic modifications in response to dietary intervention are the most important biomarkers of health or diseases. The epigenetic modifications investigated include DNA methylation, histone modifications, and the influence of microRNAs. Therefore, the epigenotype could be used to predict susceptibility to certain cancers and other CMDs as well as to assess the effectiveness of dietary modifications to reduce such risk. The influence of diet or dietary components on epigenetic modifications and the impact on cancer and CMDs initiation or progression has been assessed but the evidence is very scarce. Early life exposure to famine and colorectal cancer risk and Western diet and stress predisposing epigenetic damage resulting in cancer and mental diseases, respectively, have been reported [26,27].

40.4 THE HUMAN GENOME The International HapMap Project was launched to identify large-scale SNP-mapping ventures, for the regions of the genome underlying phenotypic variation and disease susceptibility [28,29] (hapmap.ncbi.nlm.nih.gov). A haplotype map of the human genome can be developed due to elucidation of the entire human genome. The haplotype map, or “HapMap,” is a tool that allows researchers to find genes and genetic variations that affect health and disease. The DNA sequence of any two subjects is 99.5% identical but the variations may greatly affect an individual’s risk of diseases. Sites in the DNA sequence where individuals differ at a single DNA base are called SNPs. Sets of nearby SNPs on the same chromosome are inherited in blocks. This pattern of SNPs on a block is a haplotype. Blocks may contain a large number of SNPs, but a few SNPs are enough to uniquely identify the haplotypes in a block. The HapMap is a map of these haplotype blocks and the specific SNPs that identify the haplotypes are called tag SNPs. The HapMap is a powerful resource for studying the genetic factors contributing to variation in response to environmental factors, in susceptibility to infection, and in the effectiveness of and adverse responses to drugs and vaccines.

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Using just the tag SNPs, researchers are able to find chromosome regions that have different haplotype distributions in the two groups of people, those with a disease or response and those without. Each region is then studied in more detail to discover which variants in which genes in the region contribute to the disease or response, leading to more effective interventions. However, SNPs are only part of the picture, because most scientists understand that structural differences—including deletions, duplications, inversions, and copy-number variants—encompass millions of bases of DNA, and are at least as important as SNPs in contributing to genomic variation in humans [30]. We know that gains or losses of large swaths of DNA—known as copy number variants (CNVs)—are common features of the human genome. Recently, genome-wide studies identified a few hundred CNVs, but because of the techniques used, researchers could detect only large-scale differences of roughly 50 kb and greater [12]. The interaction of environmental factors such as radiation, pollutants, magnetic forces, and nutritional factors or dietary modulators with SNPs and CNVs need to be studied more clearly [30]. The genetic variation between people was largely pinned on simple sequence differences known as SNPs. We now know close to 700 finer-scale CNVs within the human genome [12]. These researchers looked for odd patterns in the existing HapMap SNP data, to uncover deletion “footprints” and discovered apparent violations of Mendelian inheritance, while others inspected clusters of SNPs that are out of expected equilibrium frequencies, and other genotyping errors [28,30]. These experts also showed that deletions and their neighboring SNPs are tightly linked, indicating that most polymorphic deletions have ancient origins. The role of ω-3 fatty acids or ω-6: ω-3 on deletion SNPs and CNVs need further studies [29]. The large number of segregating deletions indicates stability of the genome and extent of genomic dynamism and to the wave of structural variations. Deletion polymorphisms appear to be a “binary CNVs,” because only two possible states exist in an individual. The genomic region is either there or it’s not. Deletions, however, make up only a small subset of a much larger number of CNVs and structural variants in general. Online database of Genomic Variants (http://projects. tcag.ca/variation), which, as of May 2010 contained 34,229 individual variants greater than 100 bp. It is possible that the patterns observed were true for unique regions of the genome, but they’re not necessarily true for complex regions where deletions reoccur with high frequencies. Therefore, scientists are using different methods to find structural variants today. This approach helped construct an unbiased genome-wide CNV map, and discovered around 1500 CNVs greater than 1 kb covering 12% of the genome.

40.5 THE GENES There are various phases in human life; formative phase, growth phase, maturation phase and senescent phase. Each one of them is being characterized by specific heritable genetic information [2 5]. The vital roles of genes can be best understood through the total package of chromatin rather than individual gene [2 4]. Studying monozygotic twins, whose genomic DNA and chromatin complexes are indistinguishable, can show the influence of environment and diet on gene function which are independent of each other. Designer genes dictate the barricading of cells and cellular recognition during development. There are tissue-specific genes responsible for cellular

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differentiation and organogenesis [30]. Housekeeping genes maintain the basic requirements of the cells and their epigenome diverges with changes in food intake, physical activity, and stress. Chromatin is a DNA protein complex in higher organisms. Its diameter is 30 nm, whereas the diameter of DNA is 2 nm. The chromatin appears as a diffuse mass within the nucleus during the interphase of a cell. The new field of epigenetics has emerged with a greater impact on cellular transgeneration profiles, primarily dealing with the health perspectives. This refers to the heritable changes in the gene expression that occur without a change in DNA sequence. Epigenesis implies a fundamental regulatory system beyond nucleotide sequence information of DNA, emphasizing that Mendel’s alleles are not merely coding DNA portions. The human genome contains nearly 40,000 genes and they tend to express in specific cells at precise times. The region of the genomic DNA comprising of a function-specific nucleotide sequence makes up a gene. Each unit of histone (nuclear proteins) octamer is wrapped by genomic DNA, either in a compact or relaxed conformation. These units are called nucleosomes. The region of the chromosome which possesses the compact chromatin is known as the heterochromatin and the relaxed one euchromatin. The temporal status of the gene in either of these conformations appears to be important because environmental modulation of genes is quite possible. The genes are dormant when chromatin is condensed and they are expressed if chromatin is relaxed. Therefore, it seems that genetic functions are dependent on the chromatin conformation. It is possible that by altering nutritional environment, the activity and conformation of the chromatin may be altered, which may result in genetic expression along with relaxation of chromatin. The wild foods and nutraceuticals—ω-3 fatty acids, antioxidants, essential amino acids, vitamins, and minerals—are important determinant of enzymes, hence these foods and nutrients can suppress the expression of genes that have adverse effects.

40.6 METHYLATION OF GENES The chromatin complex can influence enzymatic machineries,such as methyltransferases, histone deacetylases, histone acetylases, histone methyltransferases, and methyl binding chromatin protein. In cellular function, a gene is made either awake or silent depending upon specific posttranslational modifications of histones on one side and methylation of cytosine of phenotype guanine (CpG) islands in the promoter region of a gene on the other side. This results in a distinct trait, for example, CpG island methylator phenotype, which are nucleotides in DNA. The unmethylated clusters of CpG pairs may be seen in tissue-specific genes and housekeeping genes and are footprints for transcription factors. The DNA methylation patterns reprogram cells and tissues in the overall context of individual’s life. The epigenetic mechanisms regulate gene accessibility and expressivity depending upon environmental factors. There is evidence that chromatin is a physiological template and modifies histones by covalent coupling with methyl or acetyl groups, resulting in dysregulation or commitment for cellular differentiation. It can establish, maintain, and propagate patterns of gene expression, by organizing epigenetic marks. There is a strong correlation between tissue-specific expression and nonmethylation of non-CpG islands; maspin gene, a tumor suppressor gene. Several chromatin regulatory proteins are dynamic and are continuously recruited, bound, and ejected which may be due to environmental factors like dietary proteins, antioxidants, and vitamins.

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The cytosine methylation, histone modifications, and nucleosomal remodeling are closely related and under the influence of nutrient and nutraceutical environment in the body. Each nucleosome contains a characteristic histone octamer constituted by histones dimer proteins of chromatin; H1, H2A, H2B, H3, and H4 (Fig. 40.2). The amino acids lysine and arginine residues that are involved in chromatin modification are in relatively higher proportion among histones. Lysine is important for establishing an epigenetic program and its residues (K) on H3 and H4 are prone for post-translational alterations. Methylation of K9, which means lysine is at 9th position in the histone protein molecule, and K27 in H3 are the epigenetic marks for silenced chromatin. Loss of acetylation at K16 and trimethylation at K20 in H4 are the epigenetic marks for cancer. It is possible that lysine- and arginine-containing foods or supplementation of these nutraceuticals can influence epigenetic marks and methylation of chromatin, resulting in protection of genes. Most of the methyl marks on histone have some biological message, called epigenetic information that is maintained through the cell cycle. Methylated lysine residues of histones appear to be important epigenetic markers which may be modulated by nutrients; ω-6/ω-3 fatty acids and others [25,29].

40.7 OMEGA-3 FATTY ACIDS AND GENE INTERACTIONS It is known that the enzymes FADS1 and FADS2 can break down omega-6 and omega-3 fatty acids for our bodies to use for brain development and controlling inflammation [24 26,31]. In a recent study, the team identified a mutation, rs66698963, in the gene responsible for expressing FADS 1 and FADS 2 [23]. An insertion mutation, characterized by extra base pairs, caused an increase in the production of the two enzymes and a better ability to produce fatty acids from plants, hence it was dubbed the vegetarian allele. The researchers looked at how this insertion varied between 234 primarily vegetarian Indians and 311 meat-eating Americans (mostly from Kansas). They found that insertions existed in 68% of the Indians but only 18% of Americans, which makes sense considering the group of Indians used in the study had practiced vegetarianism for thousands of years. Then, armed with data from the 1000 Genome Project, they discovered that the vegetarian allele existed in 70% of South Asians, 53% of Africans, 29% of East Asians, and just 17% of Europeans [23]. This study is the first to connect an insertion allele with vegetarian diets, and the deletion allele with a marine diet. The two genetic variations probably emerged early in our evolutionary history, when people around the world migrated to different environments. They ate a plant-based diet sometimes and sometimes they ate a marine-based diet, and in different time periods these different alleles were adaptive. This study indicates that people of Indian origin are more susceptible to adverse effects of animal foods, compared to Caucasians who have a different allele. The elucidation of interaction between genetic variations and nutritional status, in particular omega-6/omega-3 fatty acid ratio may have important implications for public health through the identification of individuals and populations who could benefit from dietary intervention and supplementation with nutrients. A greater understanding of which nutrient could promote more protection and increase DNA repair may be important as a strategy to avoid the earlier development of NCDs. Recent studies indicate that the optimal ratio of ω-6 and ω-3 fatty acids may vary within the pathogenesis of a disease under consideration. This is consistent with the fact that NCDs are polygenic and multifactorial. Modern diets are deficient in omega-3 fatty acids, and have excessive

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amounts of omega-6 fatty acids compared with the diet on which human beings evolved and their genetic patterns were established. Excessive amounts of omega-6 polyunsaturated fatty acids (PUFAs) and a very high omega-6/omega-3 ratio, as is found in today’s modern diets, promote the pathogenesis of NCDs, including CVD, cancer, and inflammatory and autoimmune diseases, whereas increased levels of omega-3 PUFA (a lower omega-6/omega-3 ratio) exerts suppressive effects. In the secondary prevention of CVD, a ratio of 4/1 was associated with a 70% decrease in total mortality. A ratio of 2.5/1 reduced rectal cell proliferation in patients with colorectal cancer, whereas a ratio of 4/1 with the same amount of omega-3 PUFA had no effect. The lower omega-6/omega-3 ratio in women with breast cancer was associated with decreased risk. A ratio of 2 3/1 suppressed inflammation in patients with rheumatoid arthritis, and a ratio of 5/1 had a beneficial effect on patients with asthma, whereas a ratio of 10/1 had adverse consequences. It is possible that the intake of wild foods rich in ω-3 and low in ω-6 fatty acids as well as may be protective, whereas western diet and lifestyle may enhance the expression of genes related to NCDs. Our genes or pathways are most likely regulated by microRNA [2 4]. It is difficult to tell which miRNA sequences might be responsible. It has been possible now to apply a simple and accurate real-time polymerase chain reaction (PCR) technique to identify miRNA expression patterns that correlate with biological phenotypes of the disease. CVD, diabetes, obesity, and cancer are polygenic in nature and their prevalence and mortality vary depending upon genetic susceptibility and presence of phenotype risk factors [1 6]. It is possible that the majority of the human beings are deviate, and may inherit risk as well as may have interaction of nature and nurture [1 4]. There may be a sequence in the development of NCDs due to rapid changes in diet and lifestyle which are known to enhance the expression of harmful genes. Overweight and central obesity come first in conjunction with deficiency of angiotensin, and adiponectin, hyperinsulinemia, increase in interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha), followed by premetabolic syndrome, hyperlipidemia, diabetes and insulin resistance, hypertension, and gallstones. Coronary artery disease (CAD) and cancer come later and finally there is emergence of dental caries, gastrointestinal diseases, neuropsychiatric disorders, and bone and joint diseases. Nutritional environment can influence the heritability of the variant phenotypes that are dependent on the nutrient for their expression. If the nutrition during pregnancy and fetal life is inadequate, it may create an adverse nutritional environment, decreasing the possibility of explaining the cause by a single gene variant, because of adaptations. It seems that single gene variants may be useful models to measure the other determinants of genetic diseases [4 8]. Among NCDs, the genetic variance in cancer appears to have greater genetic component than it is in CAD, hypertension, obesity, and diabetes [4 10]. In the prevention of diseases, the aim should be to inhibit the expressions of genotypes which result in phenotype risk factor. The result may be best if the treatment begins during the antenatal period and infancy, because there is evidence that the lipoprotein (a) phenotype can change during childhood and possibly also during pregnancy. Iron and energy deficiency during pregnancy may cause development of conserving mechanisms in the mother and the fetus, which may be harmful during infancy on modest increases in these nutrients. The conservation of iron may increase free radical generation, and can damage the genes. However, energy conservation may result in central obesity on modest increase in food intakes, due to interaction of gene and environmental factors. The role of time structure for feeding may also influence the functioning of genes [9 11]. Foods rich in micronutrient and low ω-6/ω-3 ratio of fatty acids, consumed in the morning may prevent the expression of

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harmful genes responsible for platelet aggregation, inflammation, and oxidative stress which are greater in the morning. However, excess consumption of refined foods may cause increased generation of superoxide which may damage the genes, resulting in further increase in the adverse biological environment in the second quarter of 24 hours, in our body. There is evidence that the tissue composition of PUFAs is important to health and depends on both dietary intake and metabolism controlled by genetic polymorphisms that should be taken into consideration in the determination of nutritional requirements [10,25,32,33]. Therefore, at the same dietary intake of linoleic acid (LA) and alpha-linolenic acid (ALA), their respective health effects may differ due to genetic differences in metabolism. Delta-5 and delta-6 desaturases, FADS1 and FADS2, respectively, influence the serum, plasma, and membrane phospholipid levels of LA, ALA and long-chain PUFAs during pregnancy and lactation may influence an infant’s IQ, atopy, and CAD risk [24,25,31]. At low intakes of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), polymorphisms at the 5-lipoxygenase (5-LO) level increase the risk for CAD whereas polymorphisms at cyclooxgenase-2 increase the risk for prostate cancer. At high intakes of LA the risk for breast cancer increases. EPA and DHA influence gene expression. In future, intervention studies on the biological effects of LA, ALA, and LC-PUFAs, and the effects of genetic variants in FADS1 and FADS2, 5-LO and cyclooxygenase-2 should be taken into consideration both in the determination of nutritional requirements and risk of NCDs. Furthermore, genome-wide association studies need to include environmental exposures and include diet in the interaction between genetic variation and disease association In experimental studies, if animals are administered high omega-6 diet, they develop genetic protection by producing excess of more omega-3 fatty acids [34,35]. In several studies, dietary PUFAs have been demonstrated to influence gene transcription, modulate fatty acid deposition in liver, adipocyte, and improve mitochondrial function and genetic expressions [36 42]. The delta-5 and delta-6 desaturases, encoded by the FADS1 and FADS2 genes, are rate-limiting enzymes in PUFA biosynthesis. SNP in the FADS gene cluster region have been associated with both PUFA concentrations in plasma or erythrocyte membrane phospholipids and cholesterol concentrations in recent genome-wide association studies [33,42]. Genetic variations in the FADS gene cluster region interact with dietary intakes of ω-3 and ω-6 fatty acids, to affect plasma total, HDL, and non-HDLcholesterol concentrations. Dietary intakes of ω-3 and ω-6 PUFAs, plasma concentrations of total and HDL cholesterol, and rs174546, rs482548, and rs174570 in the FADS gene cluster region were measured in 3575 subjects in the second survey of the Doetinchem Cohort Study [29]. Significant associations between rs174546 genotypes and total and non-HDL-cholesterol concentrations were observed in the group with a high intake of ω-3 PUFAs (. or 5 0.51% of total energy; P 5 .006 and .047, respectively) but not in the low-intake group (P for interaction 5 .32 and .51, respectively). The C allele was associated with high total and non-HDL-cholesterol concentrations. Furthermore, the C allele was significantly associated with high HDL-cholesterol concentrations in the group with a high intake of ω-6 PUFAs (. or 5 5.26% of total energy, P 5 .004) but not in the group with a low intake (P for interaction 5 .02). Genetic variation in the FADS1 gene potentially interacts with dietary PUFA intakes to affect plasma cholesterol concentrations, which should be investigated further in other studies. The genes encoding delta (5)- and delta(6)-desaturases (FADS1/FADS2 gene cluster) were reported to be associated with ω-3 and ω-6 fatty acid proportions in human plasma, tissues, and milk. Docosahexaenoic acid (DHA) can be supplied especially by dietary fish or fish oil and

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synthesized from alpha-linolenic acid through a pathway involving these desaturases [43]. It has been evaluated whether FADS gene variants modify the effect of maternal fish and fish-oil intake on plasma and milk DHA proportions. FADS1 rs174561, FADS2 rs174575, and intergenic rs3834458 SNPs were genotyped in 309 women from the KOALA Birth Cohort Study in The Netherlands. Plasma was collected at week 36 of pregnancy, and milk was collected at 1 month postpartum. Fish and fish-oil intake was assessed by using a food-frequency questionnaire at 34 week of pregnancy and updated for the week of milk collection. Gene-diet interactions were tested by linear regression analysis. DHA proportions were lower in women homozygous for the minor allele than in women who were homozygous for the major allele (DHA proportions in plasma phospholipids: P , .01; DHA proportions in milk: P , .05). Fish intake ranged from 0 to 2.5 portions of fatty fish/week, and 12 women took fish-oil supplements during pregnancy. DHA proportions in plasma phospholipids increased with increasing fish and fish-oil intake, irrespective of the genotype. DHA proportions in milk increased only with fish and fish-oil intake in the major-allele carriers. Lower proportions of DHA in milk from women who were homozygous for the minor allele could not be compensated for by increasing fish and fish-oil intake, possibly because of limited incorporation into milk. Polymorphisms of the human delta-5 (FADS1) and delta-6 (FADS2) desaturase genes have been recently described to be associated with the level of several long-chain ω-3 and ω-6 PUFAs in serum phospholipids [44]. This study had genotyped 13 SNPs located on the FADS1-FADS2FADS3 gene cluster (chromosome 11q12-13.1) in 658 Italian adults (78% males; mean age 59.7 6 11.1 years) participating in the Verona Heart Project. Polymorphisms and statistically inferred haplotypes showed a strong association with arachidonic acid (C20:4n-6) levels in serum phospholipids and in erythrocyte cell membranes (rs174545 adjusted P value for multiple tests, P , .0001 and P , .0001, respectively). Other significant associations were observed for linoleic (C18:2n-6), alpha-linolenic (C18:3n-3) and eicosadienoic (C20:2n-6) acids. Minor allele homozygotes and heterozygotes were associated to higher levels of linoleic, alpha-linolenic, eicosadienoic, and lower levels of arachidonic acid. No significant association was observed for stearidonic (C18:4n-3), eicosapentaenoic (C20:5n-3) and docosahexaenoic (C22:6n-3) acids levels. The observed strong association of FADS gene polymorphisms with the levels of arachidonic acid, which is a precursor of molecules involved in inflammation and immunity processes, suggests that SNPs of the FADS1 and FADS2 gene region are worth studying in diseases related to inflammatory conditions or alterations in the concentration of PUFAs. Several physiological processes, such as visual and cognitive development in early life, are dependent on the availability of long-chain polyunsaturated fatty acids (LC-PUFAs) [45]. Furthermore, the concentration of LC-PUFAs in phospholipids has been associated with numerous complex diseases like CVD, atopic disease, and metabolic syndrome. The level and composition of LC-PUFAs in the human body is mainly dependent on their dietary intake or on the intake of fatty acid precursors, which are endogenously elongated and desaturated to physiologically active LCPUFAs. The delta-5 and delta-6 desaturase are the most important enzymes in this reaction cascade. In the last few years, several studies have reported an association between SNPs in the two desaturase encoding genes (FADS1 and FADS2) and the concentration of omega-6 and omega-3 fatty acids. It is clear that beside nutrition, genetic factors play an important role in the regulation of LC-PUFAs as well. Current knowledge of the impact of FADS genotypes on LC-PUFA and lipid metabolism and their influence on infant intellectual development, neurological conditions,

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metabolic disease as well as CVD is important. Tissue availability of PUFAs depends on dietary intake and metabolic turnover and has a major impact on human health. Strong associations between variants in the human genes fatty acid desaturase 1 (FADS1, encoding Delta-5 desaturase) and fatty acid desaturase 2 (FADS2, encoding Delta-6 desaturase) and blood levels of PUFAs and long-chain PUFAs (LC-PUFAs) have been reported [46]. The most significant associations and the highest proportion of genetically explained variability (28%) were found for arachidonic acid (20:4n-6), the main precursor of eicosanoids. Subjects carrying the minor alleles of several SNPs had a lower prevalence of allergic rhinitis and atopic eczema. Therefore, blood levels of PUFAs and LC-PUFAs are influenced not only by diet, but to a large extent also by genetic variants common in a European population. These findings have been replicated in independent populations. Depending on genetic variants, requirements of dietary PUFA or LC-PUFA intakes to achieve comparable biological effects may differ. We recommend including analyses of FADS1 and FADS2 polymorphism in future cohort and intervention studies addressing biological effects of PUFAs and LC-PUFAs. Recent genome-wide association studies (GWASs) showed that SNPs in FADS1/FADS2 were associated with plasma lipid concentrations in populations with European ancestry. A recent study, investigated the associations between the SNPs in FADS1/FADS2 and plasma concentrations of triglycerides, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) in two Asian groups, i.e., Japanese and Mongolians [47]. The genotype of rs174547 (T/ C), found to be associated with triglyceride and HDL-C concentrations in the GWAS, was determined in 21,004 Japanese and 1,203 Mongolian individuals. Genotype-phenotype association was assessed by using multiple linear regression models, assuming an additive model of inheritance. The copy number of the rs174547C allele was significantly associated with increased triglyceride levels (P 5 1.5 3 10( 6)) and decreased HDL-C levels (P 5 .03) in the Japanese population. On the other hand, in the Mongolian population, the rs 174547C allele copy number was strongly associated with decreased LDL-C levels (P 5 2.6 3 10( 6)), but was not associated with triglyceride and HDL-C levels. The linkage disequilibrium pattern and haplotype structures of SNPs around the FADS1/FADS2 locus showed no marked dissimilarity between Japanese and Mongolian individuals. The present data indicate that the FADS1/FADS2 locus can be added to the growing list of loci involved in polygenic dyslipidemia in Asians. Furthermore, the variable effects of FADS1/ FADS2 on plasma lipid profiles in Asians may result from differences in the dietary intake of PUFAs, which serve as substrates for enzymes encoded by FADS1/FADS2. Since nutrients have interactions with genes, it poses the possibility that a genetic cause may explain the continued appearance of nutritional disease in the population by nutritional silencing of phenotype expression [2 9]. Nutrients which can influence genes are given in Table 40.1. Nutrients, which can modulate concerned genes or genetic determinants, are given in Table 40.2. PUFAs (ω-6 and ω-3), milk, calcium, vitamin, iron, ascorbate, and saturated fat have been found to modulate gene expression in various experimental studies [4 8]. Apparently healthy subjects may be walking around with broken copies of genes because several insertion and deletion polymorphisms land in the coding regions of genes. Some individuals homozygous for one of the most commonly deleted genes, UGT2B17, may have lower levels of urinary testosterone, suggesting that steroid users might often pass undetected in current athletic doping tests simply based on their DNA [18]. There is only a limited information of a subset of the complete view of structural variations. Many current hybridization probes can reliably detect some CNVs, and two newly developed

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Table 40.1 Nutraceuticals and Nutrients Having Possible Influence on Genes Nutrient

Effects

Refined carbohydrates (sugar and refined starches) Trans fatty acids Excess of saturated fat Excess of linoleic acid Omega-3 fatty acids Monounsaturated fatty acids Calcium, magnesium, potassium, iron Zinc, copper, selenium, chromium manganese, molybdenum, cobalt Coenzyme Q10, carnitine Lead, mercury, arsenic, cadmium, fluoride Excess of iron Vitamin A and beta-carotene Pyridoxine, thiamin, riboflavin, cynacobalamin, nicotinic acid, folic acid Vitamin E Vitamin C Vitamin D Vitamin K Fiber, (polysaccharides) Amino acids; arginine, taurine, cystein

Adverse Adverse Adverse Adverse Beneficial Beneficial Benefcial Beneficial Beneficial Adverse Adverse Beneficial Beneficial Beneficial Beneficial Beneficial Beneficial Beneficial beneficial

Table 40.2 Dietary Modulators of Genes and Genetic Determinants Genes and Genetic Determinants

Nutrients

1. 2. 3. 4. 5.

Polyunsaturated fatty acids [PUFA] Fat synthesis Milk Fat Calcium

Hepatic gene expression Hormonal regulating gene encoding enzyme Lactose intolerance and lactase Gastrointestinal lipase gene expression Gastrointestinal hormone gene expression, Calcium mRNA-translation in cells 6. Adipocyte gene expression 7. Ferritin synthesis 8. Apolipoprotein B mRNA editing

Vitamin A Iron PUFA, insulin, T3

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genotyping platforms from Affymetrix and Illumina include CNV probes in combination with SNP probes. There is a need to design more comprehensive microarray chips dedicated to genome-wide structural variation. This goal might not be far off, because by next year, we may see the first arrays targeted specifically toward structural variation, which may tell us more specifically the role of drugs, wild foods or western foods on genetic variations. The phenotypic expression for health or disease would depend on phenotype and environment, as well as on genotype and upon structural variations of genes. There is interaction of specific nutrient with the genetic code possessed by all nucleated cells which may cause nutritional modulation of genetic expression for health or disease. There is a limited food supply such as in the rural population of developing countries and lower social classes in urban areas, which also have greater physical activity due to physically demanding occupations [1,2]. There is also in utero undernutrition due to wide spread malnutrition during pregnancy common in developing countries which can predispose epigenetic damage [9]. These interactions predispose the biological mechanisms to adapt and develop survival gene which may modulate genotype for increased survival. In urban populations of developing countries and immigrants from developing to developed countries, better food supply, usually Western diet, may be associated with phenotypic expression for disease [5,8]. The thrifty gene utilizes the energy with a better capability resulting in obesity on a modest increase in energy intake and sedentary behavior. Fatty acids are metabolized more efficiently and misdirected to the arterial wall for cell membranes and there is better storage of iron resulting in free radical stress which may damage the genetic code (Table 40.1). The health status of gene CNVs or SNPs, whether single or polymorphic appear to be important in the manifestation of health or CAD, hypertension or diabetes and obesity (Table 40.2). Increased intake of energy may cause obesity due to expression of obesity genes, which is a major cause of CVD. In one study [20], subjects were 383 consecutive patients with angiographically confirmed CAD and 368 non-CAD subjects adjusted for age and BMI in the Japanese population. SNPs in the adiponectin gene were determined by Taqman PCR method or a PCR-based assay for the analysis of restriction fragment length polymorphism. The plasma adiponectin concentration was measured by enzyme-linked immunosorbent assay. Among SNPs, the frequency of I164T mutation was significantly higher in CAD subjects (2.9%) than in the control (0.8%, P , .05). The plasma adiponectin levels in subjects carrying the I164T mutation were significantly lower than in those without the mutation, and were independent of BMI. In contrast, SNP94 and SNP276, which are reported to be associated with an increased risk of type 2 diabetes, were associated neither with CAD

Table 40.3 Survival Gene and Development of Genotype Gene Expression

Environmental Factor

Phenotypic Expression

1. 2. 3. 4. 5. 6.

Excess of food supply Low iron vegetarian diet low cholesterol Exposure to enough food

Obesity Anemia atherosclerosis Central obesitydiabetes

Thrifty gene Conservation of iron Lipoprotein transport In utero- undernutrition Early childhood nutrition Growth spurt

rapid changes in lifestyle.

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CHAPTER 40 EFFECTS OF DIET AND NUTRIENTS ON EPIGENETIC

prevalence nor with plasma adiponectin level. Subjects with I164T mutation exhibited a clinical phenotype of the metabolic syndrome. Genetic and environmental risk factors of CAD and the dietary modulators are given in Table 40.3.

40.8 TELOMERE A link of early adversity and cellular aging has been observed showing small telomere length and early severe social deprivation [33]. Telomeres are stretches of noncoding DNA at the ends of chromosomes that shorten with each cell division. In adults, shorter telomeres have previously been associated with aging, CVD, and cognitive decline, as well as oxidative and psychological stress [5]. Recent research has suggested that adults with adverse experiences as kids tended to have shorter telomeres than controls [1,2], but to date, no studies have looked at the more immediate impacts of childhood deprivation. It has been assumed that early and/or chronic adversity would have a deleterious effect on telomere length. The health of telomere appears to be determined by their brightness and length which in turn is affected by telomerase enzyme. Long sizes of telomeres are associated with longevity. Diet, physical activity, stress, and yoga pranayam may also influence the biology and function of telomeres and telomerase enzyme. Since Mediterranean diet rich in ω-3 fatty acids and low in ω-6 fatty acids can decrease mortality due to NCDs, this poses the possibility that this diet may also enhance the size and brightness of telomeres. In healthy cells, telomere length is highly regulated, giving the cell a predetermined life span. However, in view of the nature of the telomeric DNA strings of repeated nucleotides, these so-called telomeric sisters’ chromatid exchanges can be dangerous by making it easy for the DNA to slip. This can cause the chromatids to exchange DNA sections of unequal length, resulting in one daughter telomere that is much shorter and one that is much longer. The daughter cell that gets the shorter end, could be more susceptible as it has fewer divisions, worth of telomere reserves. On the other hand, the daughter cell that gets the longer end will live longer. This is the first step in a process known as telomere elongation, a pathway of telomere maintenance activated in some tumor types that allows cancerous tissue to keep dividing beyond the normal lifespan of a cell. Another way tumor cells elongate their telomeres is by upregulating telomerase, which is present in about 85% of tumors of malignant origin. Telomerase is an enzyme which could be under the influence of diet and lifestyle factors. A high ω-6/ω-3 ratio in the tissues may have adverse effects on telomerase and telomeres length and brightness. However, a low ratio of ω-6/ω-3 fatty acids in the tissue may enhance the brightness and size of telomeres [25,29] (Fig. 40.3). While Rap1 is clearly essential for suppressing telomeric sister chromatid exchanges as a part of the shelterin complex, this is a redundant suppression pathway. The role for Rap1 could only be seen when the researchers looked in cell cultures where another protein known as Ku had also been knocked out. Once we know which protein, either alone or in combination, is dedicated to which pathway, we can begin to try to understand the mechanism by which these proteins act. The protein in question is part of a complex called shelterin, which prevents a potentially dangerous type of DNA repair that can shorten telomeres and therefore cause cells to age quickly. Alternatively, the repair process can help elongate telomeres in cancer cells, allowing them to proliferate. This protein

40.8 TELOMERE

697

FIGURE 40.3 Showing telomeres at the end of chromosome in white color.

is required in the complex to repress one of the two DNA repair pathways that can act on DNA ends. It’s important for cells to repress this, because it can be dangerous for telomeres, leading to abrupt changes in telomere length which can kill the cells or reset telomere length. Accelerated telomere length attrition has been associated with psychological stress and early adversity in adults; however, no studies have examined whether telomere length in childhood is associated with early experiences. The Bucharest Early Intervention Project [5] is a unique randomized controlled trial of foster care placement compared with continued care in institutions. As a result of the study design, participants were exposed to a quantified range of time in institutional care, and represented an ideal population in which to examine the association between a specific early adversity, institutional care and telomere length. We examined the association between average relative telomere length, telomere repeat copy number to single gene copy number (T/S) ratio and exposure to institutional care quantified as the% of time at baseline (mean age 22 months) and at 54 months of age that each child lived in the institution. A significant negative correlation between T/S ratio and percentage of time was observed. Children with greater exposure to institutional care had significantly shorter relative telomere length in middle childhood. Gender modified this main effect. The percentage of time in institutional care at baseline significantly predicted telomere length in females, whereas the percentage of institutional care at 54 months was strongly predictive of telomere length in males. This is the first study to demonstrate an association between telomere length and institutionalization, the first study to find an association between adversity and telomere length in children, and contributes to the growing literature linking telomere length and early adversity. However, there is a need to adjust diet and physical activity and prayer which may have beneficial or adverse effects on telomeres. While a Western diet high in trans fat and ω-6 fat and sedentary behavior can decrease the length and functioning of the telomeres, a Mediterranean diet, moderate physical activity, and possibly regular active prayer or pranayam breathing may have beneficial effects on telomeres.

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CHAPTER 40 EFFECTS OF DIET AND NUTRIENTS ON EPIGENETIC

40.9 CLOCK GENES AND CARDIAC EVENTS IN THE MORNING? There is a need to identify genes that express according to time structure, because more than half of the cardiovascular events (stroke, sudden cardiac death and heart attacks), other vascular variability disorders (VVDs), including blood pressure variability, coronary constriction, endothelial dysfunction, rise in blood pressure and heart rate occur between 8.00 AM and 11.00 AM. It is known that the signature of a circadian gene is characterized in such a way, that its expression levels oscillate once each day according to time structure [10,11]. In earlier studies, a total of 458 unique genes were identified. They all used essentially the same fly stocks, the same lab protocols for isolating RNA, and the same Affymetrix GeneChip technologies. Seven genes were found in common among all five studies, and these included most, but not all, of the known pacemaker genes. We still need to find out about the hundreds of other genes, which may be responsible for coronary thrombosis, that occurs in the second quarter of 24 hours and which may be related to sleep and wake cycle. Keegan and Allada who discovered a list of 214 genes, more than half of which were not found in the earlier studies, are important [30,48]. The types of genes they found also ran the gambit of functions, from protein kinases to ion channels. Further studies are needed to find out, how many of these genes could be responsible for increased concentration of superoxide anion and proinflammatory cytokines; IL-6, IL-18, IL-1,2, and TNF-alpha that may be determinant of a rupture of hot coronary plaque, resulting in heart attack, sudden death, and stroke in the morning. Because Western foods may enhance the expression of these genes and wild foods may be protective. It is clear that Keegan and Allada’s technique added a key element: an ANOVA test that screened the list of candidate genes and tossed out those whose expression levels did not significantly peak and trough over 24 hours [48]. It seems that this method drastically reduced the number of genes, and when they combined all five data sets, they uncovered a suite of new genes whose activity levels cycled on a daily basis. It is possible, that a cosinar analysis of various genes, according to time structure, may throw further light on the characterization of clock genes discovered by these investigators. Such analysis appears to be quite important because increased consumption of refined starches and sugar in the breakfast, increases generation of superoxide anion in the leucocytes and mononuclear cells, FFA, as well as higher amount and activity of nuclear factorkB(NF-kB), a transcriptional factor regulating the activity of at least 125 genes, most of which are pro-inflammatory [24]. Table 40.4 shows the gene status and phenotype expressions.

40.10 HIGH OMEGA-6/OMEGA-3 FATTY ACIDS RATIO AND GENETIC DAMAGE Omega-6 fatty acid is known to cause oxidative stress and inflammation, therefore, excess of ω-3 fatty acid up to a ratio of 1:1 is being advised for suppression of adverse effects of ω-6 fatty acids in diets with high ω-6/ω-3 ratio [25]. Inflammatory processes that are at the basis of such phenotype have in the long run deleterious effects on homeostasis and health. Those genetically predisposed develop the disease with age and under certain conditions, transfer the disease to their offspring, constitutionally. In South Asians, there is marked increase in ω-6/ω-3 fatty acids ratio to 50 due to

40.10 HIGH OMEGA-6/OMEGA-3 FATTY ACIDS RATIO

699

Table 40.4 Gene Status and Phenotypic Expression for Health or Disease 1. 2. 3. a. b. c. d. e. f. g. h. 4.

Expressed at birth, e.g., phenyl ketonuria. Nonevident clinically but expressed, e.g., glucose Expressed with change in diet and lifestyle Obesity and central obesity on increase in energy Noninsulin dependent diabetes mellitus-energy Hypercholestrolemias and LDL receptors-SF, TF Lipoprotein [a], coenzyme Q10, trans fatty acids Homocystenemia, pyridoxine, folic acid, B12 Iron storage free radical stress ACE gene coenzyme Q10 6-phosphate deficiency evident on fava bean intake Nonexpressed.

increased intake of vegetable oils, which may be a cause of their increased susceptibility to CAD and diabetes, because of the interaction of gene and environment. Fatty acid metabolism appears to be important in the pathogenesis, progression and prevention of CVDs [19 28,30,31,49,50]. The functions of EPA, DHA, and AA appear to have competition in metabolism. Increased intake of fish or fish oil can antagonize AA from membrane phospholipids in practically all cells, platelets, erythrocytes, neutrophils, monocytes, endothelial, arterial smooth muscle, and liver cells, which is protective [4 7]. Diets in both developing and industrialized countries have become rich in ω-6 fatty acids, which enhances the production of eicosanoid metabolic products whereas ω-3 fatty acids are known to have least of these adverse effects. These eicosanoids are biologically active and may cause thrombosis, atherosclerosis, as well as allergies and inflammatory disorders. However, ω-3 fatty acids lead to a state of increased production of prostanoids, antivasoconstrictive and anti-inflammatory products which may have beneficial effects via genetic modulations. The genetic and environmental risk factors common in others are also common in south Asians, increasing their predisposition to CAD Several candidate proteins have been identified in the search for the signaling pathway involved to study the effects of specific nutrients on gene transcription. The metabolic path-ways and cellular growth are under continuous influence of dietary ω-6 and PUFA as well as highly USFA [36]. While supplementation of long chain PUFA (e.g., EPA) enhances mitochondrial and peroxisomal fatty acid oxidation; [37 40] linoleate consumption suppresses the hyperproliferation of keratinocytes associated with essential fatty acid deficiency, arachidonate promotes cellular growth in chemically induced mammary cancer and stimulates in vitro the conversion of pre-adipocytes to adipocytes [41]. Omega-3 fatty acid rich diets can modulate mRNAs, encoding several lipogenic enzymes within hours of feeding of the animals [38,39]. If ω-3 PUFA remains in the diet, these effects are sustained. The fatty acids act like a hormone to control the activity or abundance of key transcription factors. It seems that some fatty acids can act as hormones that control the activity of transcription factors. It is possible that fatty acids are passive energy-providing molecules as well as also being metabolic regulators.

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Application of molecular biology techniques indicated that PUFA elicit changes in gene expression that precede changes in membrane composition by directly governing the activity of nuclear transcription factors [42,51,52]. Fish oil feeding decreases mature sterol regulatory elementbinding Protein 1 (SREBP-1) by downregulation of SREBP-1c mRNA in mouse liver [42]. A previous experiment reported fatty acid CoA esters as ligands of hepatic nuclear factor-4 [52]. PUFA regulation of gene transcription occurred within a matter of minutes: such a time frame was too rapid to be explained simply by changes in membrane composition and altered hormone release or signaling, but is most consistent with a ligand mediated event. Recent research indicates novel perspectives for deeper understanding of energy metabolism and therapeutic interventions. Peroxisome proliferater-activated receptor-α [PPAR-α] was the first transcription factor identified as a prospective fatty acid receptor [32]. PPAR-α plays a role in the regulation of an extensive network of genes involved in glucose and lipid metabolism. In animal models, ω-6 and ω-3 fatty acids are potent inducers of fatty acid oxidation and potent suppressors of fatty acid and triacylglycerol synthesis. It is possible that PUFA are potent PPAR activators [37,40,53]. Experimental studies revealed that, in animals fed with a diet rich in 20-carbon and 22-carbon PUFA, the expression of the genes may be associated with high rates of fat oxidation and reduced body fat deposition. It has been established that the 5’ flanking regions of genes encoding carnitine palmitoytransferase, acyl-CoA oxidase, mitochondrial hydroxymethylglutaryl-CoA synthase, fatty acyl-CoA synthetase, and mitochondrial uncoupling proteins all contain DNA recognition sequences for PPAR [37]. However, studies with the PPAR-α null mouse have shown that PPAR-α is not the sole transcription factor involved in mediating fatty acid effects on gene transcription. Desvergne and Wahli, reported that activated PPAR-γ induces lipoprotein lipase and fatty acid transporters and enhances adipocyte differentiation as well as inhibits the function of the transcription factor NF-kB and cytokines, and therefore COX-2 expression [54]. PPAR-γ also binds 20:5 ω-3. In experimental studies, drug-induced activation of PPAR-α and PPAR-γ, reduces lipid levels in muscle and adipose tissue and improves insulin sensitivity [55,56]. Omega-3 PUFA are weak agonists of PPAR as compared with drug agonists (e.g., thiazolidinediones), these fatty acids have significant effects on insulin sensitivity in various tissues, particularly skeletal muscle [55]. PPAR requires the formation of heterodimers with retinoid X receptors (RXR), in order to bind with DNA and activate transcription. Apart from PPAR family (PPAR-α, -β, -γ1, and -γ2) several other transcription factors have been identified as targets for fatty acid regulation. These are hepatic nuclear factor-4α (HNF-4α), sterol regulatory element-binding protein (SREBP), liver X receptors (LXRα and β), retinoid X receptors (RXR-α), and NF-kB [17,40 42,51]. PUFA antagonize oxysterol activation by liver X receptors (LXR)-α in HEX 293 and hepatoma cell lines by interfering with oxysterol binding. The targets for fatty acid regulation may be the liver X receptors (LXR-α and LXR-β) [51]. LXRs bind oxysterols and regulate the expression of genes involved in hepatic bile acid synthesis. It plays an important role in lipogenesis, via regulation of transcription of the gene, encoding the SREBP-1c isoform. This is a transcription factor required for the insulin-mediated induction of hepatic fatty acid and triglyceride synthesis [54]. PUFA also suppresses the nuclear content of SREBP -1c. The hierarchy for fatty acid regulation of mRNA SREBP-1c levels is 20:5n-3 5 20:4n-6 . 18:2n-6 . 18:1n-9.

40.11 MECHANISMS OF EPIGENETIC AND GENETIC EXPRESSIONS

701

40.11 MECHANISMS OF EPIGENETIC AND GENETIC EXPRESSIONS Oxidative states exert a significant influence on a wide range of biological and molecular processes and functions including the genome and epigenome [11,49,50]. If the oxidative stress and free radicals are enhanced, pathological phenomena can occur, in the form of the generation of reactive oxygen species (ROS) in the tissue microenvironment or in the systemic circulation which can be detrimental [11]. The epidemic of NCDs of Western societies, such as CVDs, obesity, and diabetes correlate with the imbalance of redox homeostasis. A special emphasis on the epigenome will highlight the effect on epigenetic regulation of human’s current life habits, external and environmental factors, including food intake, tobacco, air pollution, and antioxidant-based approaches. Additionally, the strategy to quantify oxidative states in humans in order to determine which biological marker could best match a subject’s profile. The physiological cellular redox state can be defined as a fine and suitable balance achieved by the correct proportion of ROS within the cell microenvironment. The overall redox events are functional for living cells and equally involved in the cellular physiological maintenance and in response to a wide range of internal and external cues. ROS are intrinsic biological effectors of important mechanisms such as cell proliferation and differentiation, cell cycle progression, host defense, apoptosis, and migration, which indicate their fundamental role in living cells [49,50]. Basic investigations on the pathophysiological role of cellular oxidative states on disease have been clinically confirmed [49,50]. There is a causal connection between enhanced ROS and increased risk of CVD in the form of endothelial dysfunction [50]. Endothelium has been demonstrated to have multiple roles in vascular homeostasis including tone, angiogenesis, remodeling, maintenance of blood fluidity, and as the first line of defense against systemic oxidative stress and inflammation [28,30,49,50]. Cellular stress can occur due to nutrient deficiencies or excesses, pollutants, and radiation. The patterns of DNA methylation differ in response to specific nutrients, inherited genetic polymorphisms, and exposure to environmental factors [2 4,11]. Nutrients and nutraceuticals provide the methyl group, which are added to DNA via folate and methionine pathways. It is not yet clear which methyl mark accounts for aging or development of diseases. The packaging and function of human genome are controlled by epigenetic mechanisms [5 10]. The DNA sequence of humans appears to be under strong influence of genome and packed chromatin which facilitate for the differential expression of genes [12 15]. The epigenome alters with aging and may interact with nutrients and nutraceuticals, physical activity, mental stress, tobacco consumption and alcohol consumption and environmental pollutants. CVD, diabetes, and cancer may involve proteins that interpret cytosine methylation signals and epigenetic changes may precede genetic changes in the arterial and vascular cells due to different biochemical factors like glycemia, hyperinsulinemia and pro-inflammatory cytokines. The DNA hypomethylation activates the concerned genes, for example, oncogenes in cancer, and initiate chromosomal instability. However, DNA hypermethylation may also initiate silencing of protective genes resulting in cancers. These methylation patterns can develop molecular epigenetic markers for variety of cancers. Cellular stress during replication also induces many small deletions and duplications in the genome, adding fuel for human diversity and disease. Replication stress is known to be hazardous for the cell, and is thought to contribute to aging and cancer. But exactly how stress causes DNA

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damage has remained unclear. Human mouse hybrid cells exposed to an antibiotic that inhibits DNA polymerase and induces mitotic stress, lead to a high frequency of submicroscopic deletions at a particular genomic site with elevated susceptibility to DNA damage [12 15]. Exposition of human fibroblast to the same stressful conditions, compared the stressed out cells with their normal counterparts appears to be interesting. It has revealed a suite of sequence copy number changes— deletions and duplications—between the stressed sample and control DNA. The deletions varied from 25 to around 1300 kb, while the duplications were slightly larger, ranging from 143 to around 2800 kb. In one instance, the researchers observed the same deletion in two independent cell lines, indicating that there might be a predictable pathway to stress-induced DNA damage. Sequencing of the deletions’ breakpoint junctions revealed that they were all characterized by short equivalent DNA sequences called microhomologies. This pattern is consistent with a particular form of DNA repair that uses microhomologies to mend DNA damage, known as nonhomologous end joining rather than other genetic fix-it methods that rely on matching DNA templates. Since the observed deletions and duplications closely resembled CNVs seen in screens of human diversity, as well as spontaneous DNA changes implicated in diseases such as cancer, stress during cell division is likely a major contributor to both normal and aberrant genomic copy number changes.

40.12 EFFECTS OF NUTRITION ON GENETIC AND EPIGENETIC EXPERSSIONS Mediterranean or Indo-Mediterranean diets or any other diet supplemented with olive, corn, soybean, or walnut oil at ,20% of total calories suppress hepatic lipogenic gene expression by suppressing the transcription of many genes involved in de novo lipogenesis including fatty acid synthase, stearoyl CoA desaturase-1, L-Pyruvate kinase, and S14 protein [51]. It is possible that fatty acid regulation of hepatic de novo lipogenesis and fatty acid oxidation was not mediated through a common factor, i.e., PPAR-α [55]. Coupling this action with the PUFA-mediated induction of PPAR-α-regulated genes shifts hepatic metabolism away from lipid synthesis and storage toward lipid oxidation [51]. This mechanism prevents lipotoxicity associated with lipid overload. All glycolytic and lipogenic genes that are suppressed by dietary PUFA do not contain recognition sites for SREBP-1c. It seems that PUFA regulation of the SREBP-1c isoform appears to be a key player in PUFA suppression of lipogenic genes [42,51]. The nucleus of the liver cells may have a second PUFA-regulated transcription factor. Hepatic nuclear factor-4 (HNF-4) may be most suitable to complete above role [52]. HNF-4 is also a member of the steroid receptor super family. Like PPARs, HNF-4 appears to enhance the promoter activity of selected genes such as fatty acid synthase. This enhancer activity is suppressed when PUFA esters bind to the ligand domain of the HNF-4. A sequence is also a component of the PUFA response region of the pyruvate kinase gene, apart from, an HNF-4 recognition. In a recent study, transcriptional profiling of sir2 mutants by RNA-seq revealed a major overlap with genes regulated by the nuclear receptor Hepatocyte Nuclear Factor 4 (HNF4) [57]. Drosophila HNF4 mutants display diabetic phenotypes similar to those of sir2 mutants, and protein levels for dHNF4 are reduced in sir2 mutant animals. Sir2 also exerts these effects by deacetylating and stabilizing dHNF4 through protein interactions. Increasing dHNF4 expression in sir2 mutants is sufficient to rescue their insulin signaling defects, defining this nuclear receptor as an important downstream effector of Sir2 signaling [57]. Table 40.5 shows the genetic and environmental risk factors of cardio-metabolic diseases.

40.12 EFFECTS OF NUTRITION ON GENETIC

703

Table 40.5 Genetic and Environmental Risk Factors of Cardiometabolic Diseases Genetic Determinants

Environmental Risk Factors

1. Family history at ,50 years of age 2. Total and LDL cholesterol and Apo A 1 and APO A II LEVELS 3. HDL cholesterol, Apo A 1 and Apo, A II levels 4. Apo A-IV-1/1 5. Apo E polymorphism 6. Lipoprotein [a] 7. LDL receptor activity 8. Thrombosis, coagulation parameters 9. Triglycerides and HDL levels 10. RFL is in DNA at the Apo A-1/Apo C-III and Apo B loci and other DNA marker 11. Hypertension 12. Noninsulin dependent diabetes mellitus 13. Obesity and central obesity 14. Insulin levels and response 15. Heterozygosity for homocyteinuria

1. 2. 3. a. b. c. d. e. f. g.

Smoking Sedentary lifestyle Diet Excess High total and saturated fat High trans fatty acids High ω-6 fatty acids High sucrose Low ω -3 fatty acids Low antioxidant

h. Low coenzyme Q10 levels i. Low folic acid j. Low pyridoxine and B12

4. Chronic anxiety disorders.

Transfection studies using primary hepatocytes have failed to show that TR or thyroid hormone response elements are major targets for PUFA regulation of these genes. An exception to this is seen when ω-3 PUFA activate PPAR-α, leading to a sequestration of RXR. PPAR requires the formation of heterodimers with RXR and inhibition of gene transcription through the interference with T3 action at the thyroid hormone response elements [55,56]. It seems that several T3-regulated hepatic genes are suppressed by PUFA particularly ω-3 fatty acids. NCX1.3 is more sensitive to inhibition by ALA than NCX1.1. In addition, only ω-3 PUFA inhibits NCX1.1, but several classes of fatty acids inhibit NCX1.3 [58]. The differential sensitivity of NCX isoforms to fatty acids may have important implications as therapeutic approaches for hypertension, heart failure and arrhythmias. A recent study showed that the risk of CAD associated with a variant of chromosome 9p21 is increased in the presence of poor glycemic control in patients with type 2 diabetes, indicating that all diabetics may not have similar risk of vascular disease [59]. A new bioinformatics method for pinpointing an individual DNA profile within an aggregation of 1000 or more DNA samples has been developed which may revolutionize nutrient modulation of genetic expressions [28]. The method uses SNPs, genetic irregularities regularly used to study human disease and genetic variation, as markers to probe a mixture of DNA for an individual’s genetic signature. It may be possible to provide individual advice of a suitable nutrient or wild foods for genetic modulation of the concerned allele in the genome in near future. A recent study showed that the prenatal restriction of diet can affect the activity of genes involved in epigenetic mechanisms in the liver across multiple generations [60]. Restricted feeding also revealed the global histone H3 acetylation in fetal liver. Another study reported that exposure to endocrine-disrupting chemicals, or drugs during

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prenatal and early postnatal periods, can alter normal physiology and increase susceptibility to noncommunicable diseases like obesity and diabetes [61]. In brief, polymorphisms of the human delta-5 (FADS1) and delta-6 (FADS2) desaturase genes have been recently described to be associated with the level of several long-chain ω-3 and ω-6 PUFAs in serum phospholipids indicating alteration of genetic sequence by nutrients. Sequencing of the human genome revealed significant genetic heterogeneity within human populations due to nutritional modulators of millions of SNPs. It is possible that accommodating the SNPs in the involved genes in metabolism of drugs, environmental agents, or dietary components may highly affect the individual response to exposure to these agents. All the recognized epigenetic marks— DNA methylation, histone modification, and miRNA expression—are influenced by diet and other environmental exposures, right from cell differentiation during the embryonic stage to the later life span resulting in NCDs. Dietary factors, including micronutrients and nonnutrient dietary components such as genistein and polyphenols, can modify epigenetic marks. Effects of altered dietary supply of methyl donors on DNA methylation are plausible explanations for the observed epigenetic changes, but to a large extent, the mechanisms responsible for diet epigenome health relationships remain to be discovered for a early diagnosis of diseases. The findings from various studies indicate that nutrients and wild foods that are rich in ω-3 fatty acids and possibly antioxidant flavonoids and polyphenols, can modulate genetic and epigenetic function and gene expression and may be important in the pathogenesis and prevention of NCDs.

ACKNOWLEDGMENTS International College of Nutrition, International College of Cardiology, and The Tsim Tsoum Institute for support to write this article.

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[50] Siti HN, Kamisah Y, Kamsiah J. The role of oxidative stress, antioxidants and vascular inflammation in cardiovascular disease (a review). Vascu Pharmacol 2015;71:40 56 2015. [51] Mater MK, Thelen AP, Pan DA, Jump DB. Sterol response element-binding protein 1c (SREBP 1c) is involved in the poly-unsaturated fatty acid suppression of Hepatic S14 Gene Transcription. J Biol Chem 1999;274:32725 32. [52] Hertz R, Magenheim J, Berman I, Bar-Tana J. Fatty acid CoA esters are ligands of hepatic nuclear factor-4. Nature 1998;392:512 16. [53] Juge-Aubry CE, Gorla-Bajsczak A, Pernin A, Lemberger T, Wahli W, Burger AG, et al. Peroxisome proliferator-activated receptor mediates cross-talk with thyroid hormone receptor by competition for retinoid X receptor. Possible role of a leucine zipper-like heptad repeat. J Biol Chem 1995;270:18117 22. [54] Desvergne B, Wahil W. Peroxisome proliferator activated receptors: nuclear control of metabolism. Endocr Rev 1999;20:649 88. [55] Ye JM, Doyle PJ, Iglesias MA, Watson DG, Cooney GJ, Kraegen EWW. Peroxisome proliferatoractivated receptor (PPAR)- alpha activation lowers muscle lipid and improves insulin sensitivity in high fat-fed rats: comparison with PPAR-gamma activation. Diabetes 2001;50:411 17. [56] Guerre-Millo M, Gervois P, Raspe E, Madsen E, Poulain P, Derudas B, et al. Peroxisome proliferatoractivated improve insulin sensitivity and reduce adiposity. J Biol Chem 2000;275:16638 42. [57] Palu RA, Thummel CS. Sir2 acts through hepatocyte nuclear factor 4 to maintain insulin signaling and metabolic homeostasis in drosophila. PLoS Genet 2016;12(4):e1005978. Available from: https://doi.org/ 10.1371/journal.pgen.1005978 eCollection 2016 Apr. [58] Ander BP, Hurtado C, Raposo CS, et al. Differential sensitivities of the NCX1.1 and NCX1.3 isoforms of the Na 1 Ca2 1 exchanger to a´ -linolenic acid. Cardiovasc Res 2007;73:395 403. [59] Doria A, Wojcik J, Xu R, et al. Interaction Between Poor Glycemic Control and 9p21 Locus on Risk of Coronary Artery Disease in Type 2 Diabetes. JAMA 2008;300(20):2389 97. Available from: https:// doi.org/10.1001/jama.2008.649. [60] Nowacka-Woszuk J, Szczerbal I, Malinowska AM, Chmurzynska A. Transgenerational effects of prenatal restricted diet on gene expression and histone modifications in the rat. PLoS One 2018;13(2): e0193464. Available from: https://doi.org/10.1371/journal.pone.0193464. [61] Junge KM, Leppert B, Jahreis S, Wissenbach DK, Feltens R, Gru¨tzmann K, et al. MEST mediates the impact of prenatal bisphenol A exposure on long-term body weight development. Clin Epigenet 2018;10:58.

FURTHER READING Houstis N, Rosen ED, Lander ES. Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature 2006;440:944 8. Ohashi K, Ouchi N, Kihara S, et al. Adiponectin I164T mutation is associated with the metabolic syndrome and coronary artery disease. J Am Coll Cardiol 2004;43:1195 200. Ulrev CL, Liu L, Andrews LG, et al. The impact of metabolism on DNA and methylation. Hum Mol Genet 2005;14(supple 1):139 47.

Index Note: Page numbers followed by “f” and “t” refer to figures and tables, respectively.

A AA. See Arachidonic acid (AA) AAD. See Antibiotic-associated diarrhea (AAD) ABPM. See Ambulatory blood pressure monitoring (ABPM) Abstinence, 533 534 ACE. See Aqueous cinnamon extract (ACE) ACE-I. See Angiotensin-I converting enzyme inhibitory (ACE-I) Acetic acids, 381 382 Acetylcholine, 321 322 AChM. See Muscarinic acetylcholine (AChM) ACS. See Acute coronary syndrome (ACS) Action as antioxidant, free radical scavenger, 374 Acute coronary syndrome (ACS), 98 99, 241, 276 277, 656 657 Acute heart attack, 176 Acute myocardial infarction, 275 AD. See Alzheimer’s disease (AD) Adenocarcinoma, 194 Adenosine monophosphate-activated protein kinase (AMPK), 516 517, 548 549 Adipocytes, 226 ADMA. See Asymmetric dimethylarginine (ADMA) Administration forms, 571 Admixture, 72 Advanced glycation-end products (AGEs), 205, 373, 568 Adverse effect of food security, 52 53 of Tamasic foods, 80 81 Aerobic metabolism process, 545 546 Aeromonas hydrophila, 433 Affluence, 73 77 Affymetrix, 693 695 Affymetrix GeneChip technologies, 698 African undernutrition, 111 Age-related macular degeneration (AMD), 239 240 Age(ing), 318 320 age-discriminatory taxa, 583 584 age-independent classification, 116 age-independent measurements, 112 113 BMI for, 118 119 BP variation with, 121 122 height for, 116 117 mechanisms, 543 545, 543f theories of senescence induced by mechanisms, 544f at menarche, 123 124 weight for, 116 AGEs. See Advanced glycation-end products (AGEs)

Agouti gene experiment, 669 670 Agricultural/agriculture, 8 food and agricultural transition, 4 policy, 339 products, 35 Agro-climatic conditions, 481 AHEI. See Alternative Healthy Eating Index (AHEI) AI. See Augmentation index (AI) AICPI. See All India consumer price index (AICPI) AICR. See American Institute of Cancer Research (AICR) ALA. See Alpha-linolenic acid (ALA) Alcohol(ism), 172 173, 186 187 Alfalafa (Medicago sativa L.), 471 472 All India consumer price index (AICPI), 125 All-cause mortality nut consumption and risk, 348 353, 351f nut consumption neurodegenerative disease, 353f nut intake and mortality due to respiratory diseases and diabetes, 352f nut intake and risk of cardiovascular diseases and total cancer, 350f of coronary disease and stroke, 349f Allium sativum. See Garlic (Allium sativum) Almonds, 354, 360t, 361t Alpha-linolenic acid (ALA), 53, 230 231, 262, 354, 359, 642 643, 691 5-Alpha-reductase inhibitor (5α-reductase inhibitor), 387 Altered circadian energy metabolism circadian clock genes, 516 517 circadian disruption and metabolic disorders, 518 519 circadian rhythms and caloric restriction, 515 516 circadian rhythms and metabolism, 517 518 clock genes and nutrient-sensing pathways, 517 critical importance of circadian rhythms, 513 514 interventional studies based on caloric restriction regimens, 519 520 partly endogenous circadian rhythms, 514 515 Alternate Healthy Eating Index score, 99, 219 220, 302 303 Alternate Mediterranean Diet score, 99, 219 220 Alternative Healthy Eating Index (AHEI), 161 Alzheimer disease, 261 Alzheimer’s disease (AD), 266, 553 554 Ambulatory blood pressure, 178 179 Ambulatory blood pressure monitoring (ABPM), 120 121, 354 AMD. See Age-related macular degeneration (AMD) American Heart Association, 291, 520 American Institute of Cancer Research (AICR), 194, 197

709

710

Index

American Institute of Cancer Research (AICR) (Continued) guidelines for cancer prevention and risk reduction, 198 200 American Psychiatric Association, 265 Amino acids, 457 458, 464 derivatives, 200 lysine, 689 2-Amino-1-methyl-6-phenylimidazo(4,5-b)-pyridine (PhIP), 382 384 Amla. See Stargoose berry Ampicillin, 580 581 AMPK. See Adenosine monophosphate-activated protein kinase (AMPK) aMT6s. See 6-Sulfatoxymelatonin (aMT6s) Anabolic effect of alcohol, 187 Analgesic effect of spices, 500 Analgesic/antiinflammatory/antioxidant properties, 504 506 Analysis of variance (ANOVA), 129 Anethole, 505 Angiogenesis, 385 Angiotensin-I converting enzyme inhibitory (ACE-I), 592 Animal and in vitro experiment, 382 385 bone, 385 breast, 382 384 prostate and angiogenesis, 385 Animal assays, 442 Animal cells, 15 Animal studies, 200 201 immunological loss, 201 mechanism of cancer prevention by nutraceuticals, 201 nutraceutical protection in cancers, 201 Anise, oil of, 504 ANOVA. See Analysis of variance (ANOVA) Anthocyanidins, 318 320 Anthropometric assessment, 112 113 Anthropometric indicators, 116. See also Physiometric indicators BMI for age, 118 119 CI, 120 height for age, 116 117 of malnutrition, 113 waist height ratio, 119 120 WAZ, 116 weight for height, 117 WHR, 119 Anthropometry, 115, 122 Antiaging and disease prevention properties of foods, 546 miscellaneous dietary interventions for, 548 550 Antibiotic resistance, 612 614 gene transfer, 612 614, 613t Antibiotic-associated diarrhea (AAD), 590 Antibodies production, 437 438, 437t

Anticancer intervention, 200 effect of retinoic acid, 547 Anticarcinogenic fatty acid, 21 Antidiabetic properties, 506 507 Antiemesis, 425 Antiemetic effect of propolis, 440 443, 442t potential antiemetic effect of propolis in pregnancy, 441 442 research, 442 443 Antihypertensive activity of L. helveticus-fermented sour milk, 592 Antiinflammatory/antiinflammation, 555 556 action of propolis, 433 activity, 570 agents, 551 555 effects, 321 322, 415 416, 500 properties, 625 626 Antimicrobial properties, 500, 503 504 of olive polyphenols, 626 in vitro, 570 Antimutagenic properties, 500 Antinutrients, 466 Antiobesity, 500 Antioxidant activity (AoxA), 429 432, 432t, 465 cinnamon polyphenols and, 566 568 of cocoa, 327 of spice compounds, 506 Antioxidant diets antiaging and disease prevention properties of foods, 546 impact of antioxidant foods and antiinflammatory agents, 551 555 DNA methylation, 547 histone modification, 547 miRNA or noncoding RNAs modification by diet, 547 miscellaneous dietary interventions for antiaging and longevity, 548 550 mitochondrial-generated reactive oxygen species and longevity, 545 546 propounded theories of mechanisms of aging, 543 545 role of gut microbiota, probiotics, and prebiotics in healthy aging, 555 556 Antioxidant(s), 282, 322 326, 374, 457 458, 546, 647 648 antioxidant-rich foods, 115 116 compounds, 15 deficiency, 647 648 effect, 500 food impact, 551 555 olive polyphenols, 626 properties, 625 626 systems, 647 648 Antioxidative stress defense systems, 543 544 Antiplatelet, 321 322 effects, 325

Index

Antipollutant effect, 500 Antiproliferative effects of oleuropein, 627 628 Antituberculosis, 425 and potential to accelerate nutritional status in TB patient, 438 440 propolis as, 438 440 Antituberculosis drugs (ATD), 438 AoxA. See Antioxidant activity (AoxA) Apiaceae, 506 507 Apidietetics, 449 450, 454 Apigenin, 20 Apis mellifera L. See Honey bee (Apis mellifera L.) Apis species, 425 Aqueous cinnamon extract (ACE), 568 Arabodopsis plants, 674 Arachidonic acid (AA), 225 226, 262, 692 AA:EPA ratio in serum phospholipid, 225 226 eicosanoid metabolites, 224 225 Area under curve (AUC), 569 Arginine residues, 689 Arjunolic acid, 374 Aromatic plant, 475 Ascorbic acid, 366 Ashwagandha, 49 Asian paradox, 159 Asian population, 159 Aspergillus flavus, 504 Asthanga Hridaya. See Vhagbhat Samhita Asymmetric dimethylarginine (ADMA), 357 358 ATD. See Antituberculosis drugs (ATD) Atherogenesis, 317 318 Atheromatous plaque in heart attack, 176 Atherosclerosis, 318 320, 335 336, 454, 639, 640f, 642 647 atherosclerotic coronary disease, 641 642 Atherothrombosis, 332 Athreogenic index, 593 Attention deficit hyperactivity disorder, 261 Aubios process, 399 AUC. See Area under curve (AUC) Augmentation index (AI), 330 Autism disorder, 261 Autophagy, 519 Ayurvedic/Ayurveda, 49, 499 treaties, 499 Aztecs, 318

B B vitamins, 597 598 Bacillus megaterium NRS, 570 Bacillus subtilis, 504 Back slopping, 596 Bacterial infections, 194

711

Bacterial metabolism, 588 589 Bacteroides enterotype, 582 583 Bacteroidetes (B), 555 556 Balkan diet, 449 450 BAP. See Bone alkaline phosphatase (BAP) Barley (Hordeum vulgare), 461 462 Barnyard millet (Echinochloa spp.), 458 BBCE cells. See Bovine brain capillary endothelial cells (BBCE cells) BCP. See Biofortification Challenge Program (BCP) Bee glue, 425 Bee pollen, 451 452, 454 Bee products comments, 451 452 effects of bee products on cardiometabolic diseases, 450 flavonoid intake and mortality, 452 454 second study, 451 third study, 451 Bee venom, 454 Beef, 21 Benzoic acid-rich fruit, 19 20 Beverage market, 13 14 Bifido species, 585 587 Bifidobacteria, 397, 581 582, 585 587 Bifidobacterium animalis, 590 591 Bifidobacterium spp., 556, 585 587, 604 605 B. bifidum, 397, 403, 605 B. breve, 417 418 B. infantis, 417 418 B. lactis, 417 418 B. longum, 582 583, 605 B. thermophilum, 585 587 culture, 397, 403 Bile salt hydrolase (BSH), 593, 604 605 Bioactive components from dairy food and potential benefits, 18t from oil seed and cereal food and potential benefits, 17t from vegetable food and potential benefits, 17t Bioactive compounds, 566 Bioactive olive oil polyphenols in promotion of health antioxidant and antiinflammatory properties, 625 626 cancer, 627 629 cardiovascular disease, 629 diabetes, 629 630 digestive health, 627 immune cell responses and wound healing, 626 neurodegenerative disease, 630 oral bioavailability and metabolism, 623 625 osteoporosis and bone loss, 630 631 respiratory health, 631 Bioavailability of cinnamon compounds, 571 Biochemical assessment, 113 Biochemical risk factors, nuts effects on, 354 356 Biofortification, 462 464

712

Index

Biofortification Challenge Program (BCP), 462 464 Biofuel production, 8 Biological activities and chemical composition, 427 432 antioxidant activity and toxicity of propolis, 429 432 chemical content of propolis, 427 phytochemical profile of propolis Trigona spp., 427 429 Biological factor, 532 Biological markers, 318 320 of cancer, 201 Birth order, 128 129 Bisphenol-A (BPA), 195 Bisphosphonate, 647 648 bLF. See Bovine lactoferrin (bLF) Block Design (m-BD), 264 Blood lipids, 318 320 in human, 593 reduction in, 332 Blood pressure (BP), 112 113, 120, 317 320 relation of blood pressure with body mass index, 121 relationship of BP with WC, 121 variation with age, 121 122 Blood tHcy, 592 593 Blood brain barrier, 624 BMAL1, 516 517 BMC. See Bone mineral content (BMC) BMI. See Body mass index (BMI); Body Mind Index (BMI) Body fat, 124 Body mass index (BMI), 26 27, 58, 112 113, 116, 122, 146 148, 159, 169, 197, 238, 290 291, 373, 440, 440f, 451 for age, 118 119 menarche effect on height, weight, and BMI, 122 123 relation of blood pressure with, 121 relationship of SES with weight and BMI, 126 127 Body Mind Index (BMI), 81 82 Body weight, 194 Bone, 385 387 health and diseases, 238 and joint diseases, 87 loss, 630 631 Bone alkaline phosphatase (BAP), 386 Bone mineral content (BMC), 238, 640, 645 646 Boron (B), 674 675 Boston standards, 116 Bovine brain capillary endothelial cells (BBCE cells), 385 Bovine lactoferrin (bLF), 382 384 Bowel ischemia, 605 BP. See Blood pressure (BP) BPA. See Bisphenol-A (BPA) Brachial-ankle pulse wave velocity, 178 Bradykinin, 321 322

Brain dysfunction circadian disruption, 526 of sleep and carcinogenesis, 526 529 diet and carcinogenesis, 529 531 inflammation, and subcellular remodelling, 531 532 psychosocial stress, and cancers, 532 533 effects of sleep deprivation on diet and lifestyle factors, 533 534 functional foods for prevention of cancers, 534 536 pathways for interactions of environmental factors, 526f Brain health and degenerative diseases, 239 Brassica supplementation, 53 Bread, 304 Breast, 382 384 British Herbal Manufacturers’ Association, 411 Broccoli, 19 Brotwnrze, 477 BSH. See Bile salt hydrolase (BSH) Bucharest Early Intervention Project, 696 697 Burkina Faso diet, 582 Burkitt’s lymphoma, 194

C C allele, 691 CAD. See Coronary artery disease (CAD) Caenorhabditis elegans, 545 546, 605 Caffeic acid phenethyl ester (CAPE), 427, 442 443 Caffeine, 186 Calcium (Ca), 13 14, 20 21, 464, 674 675 Caloric or low-calorie sweeteners, 292 Caloric restriction (CR), 548 circadian rhythms and, 515 516 interventional studies based on, 519 520 Caloric soft drinks, 295 296 Caloric sweeteners, 295 296 Calories, 6 Campylobacter spp, 504 C. coli, 504 C. jejuni, 504, 585 587 Cancer, 18 20, 87, 97 98, 193, 236 237, 287, 301, 317 318, 390, 526, 532 533, 536, 627 629 anticancer mechanisms and targets of olive oil phenols, 628t biomarkers, 201 cancer-causing agents chemical carcinogens, 193 194 genetic cancers, 194 hormonal changes, 194 immune system dysfunction, 194 ionizing radiations, 194 viral and bacterial infections, 194

Index

functional foods for prevention, 534 536 mortality, 348 350 nutraceutical protection in, 201 nutrition in AICR guidelines for cancer prevention and risk reduction, 198 200 animal studies, 200 201 body weight, 194 cancer causing foods, 195 197 role of diet and lifestyle, 197 Cancer prevention, 197 AICR guidelines for cancer prevention and risk reduction, 198 200 diet and nutrition’s impact at molecular level, 198 molecular basis of carcinogenesis induced by foods, 198 199 nutraceuticals, 199 200 by mechanism nutraceuticals, 201 Candida albicans, 626 Candidate proteins, 699 Canned foods, 195 hyperactivity of, 224 225 Canola oil, 167, 279 280, 304 CAPE. See Caffeic acid phenethyl ester (CAPE) Capsaicin, 503 Carbohydrates, 94 95, 99 100, 162, 200, 449 450, 548 549 Carbonated beverages, 195 Carcinogenesis, 526 531, 639, 640f, 641f, 642 647 induced by foods, molecular basis, 198 199 roles of oxidative stress, 199f Carcinogens, 193 Cardamom, 499 Cardiac events, 698 Cardiometabolic diseases (CMDs), 289 292, 291t, 310, 317 318, 329 330, 449, 682. See also Noncommunicable diseases (NCDs) bee products effects, 450 blood lipids and blood pressures, 450t clinical data among subjects with obesity, 450t clinical studies, 450 Cardiometabolic health effects, 520 Cardiometabolic risk effect, 296 Cardiovascular diseases (CVDs), 4 5, 10 11, 14 15, 20, 36 37, 47, 66, 71 72, 77 79, 87, 93 94, 112 113, 120 121, 145, 167, 218 219, 234 235, 280, 287 288, 301, 317 318, 347, 452 453, 526, 542 543, 629, 639, 653 655, 657 659, 665 666, 681. See also Noncommunicable diseases (NCDs) functional food security for prevention, 172 175 effects of diet on mortality, 168 170 effects of Mediterranean-style diets in hypertension and stroke, 178 179 food security and emergence, 170 172

713

intervention trials with function foods, 176 177 transition from poverty to food security and functional food security, 168f Cardiovascular system, 450 Carotenoids, 95 96, 551 CART analysis. See Classification and regression tree analysis (CART analysis) Carvacrol, 503 Catabolic effect of alcohol, 186 Catalase, 273 Catechin, 20, 325 326, 339 Catecholamine, 529 Cathepsin D activity, 405 CD. See Cesarean delivery (CD); Cluster of differentiation (CD) Cell damage, 647 648 Cell wall peptidoglycan, 612 Cellular aging process, 543 544 Cellular damage, 374 Cellular stress, 701 Central nervous system (CNS), 262 263, 440, 525 Central obesity (CO), 115 Centriwhey process, 398 Cereals processing, 38 Cerebral diseases, 262 Cerebral ischemia, 334 335 Ceruloplasmin, 273 Cervical cancer, 194 Cesarean delivery (CD), 580 581 Ceylon cinnamon, 565 CF. See Correction Factor (CF) CFVR. See Coronary flow velocity reserve (CFVR) CGIAR. See Consultative Group for International Agricultural Research (CGIAR) Chalcones, 449 Chamomillarecutita L., 504 Chapsiger, 477 Charaka Samhita, 504 CHD. See Coronary heart disease (CHD) Cheese, 397, 403 405 preconcentration of cheese-milk, 402 production per country, 406, 407t Chemical carcinogens, 193 194 content of propolis, 427 preservation of quarg cheese by using, 403 Chemical composition antioxidant activity and toxicity of propolis, 429 432 chemical content of propolis, 427 of cinnamon, 566 chemical structures of main cinnamon compounds, 568f compounds found in different cinnamon species, 567t phytochemical profile of propolis Trigona spp., 427 429 Chemoluminescence enzyme immunometric assay, 645

714

Index

Chemoreceptor trigger zone (CTZ), 440 Chest radiation therapy, 194 CHH methylation, 676 Chicken meat, 304 Childhood obesity, 115, 288 Children, women empowerment impact on, 128 Chili, 503 Chinese cinnamon, 565 Chlorine (Cl), 674 675 Chocolate, 317 318, 320t, 334 335 Cholesterol, 593 lowering effect, 570 Choline, 72, 667 668 Chromatin, 687 688 Chronic diseases, 13, 21, 46, 99 100, 337 338, 531 Chronic infections, 193 Chronic inflammation, 225 226 Chronic intestinal disorders, 232 Chronic kidney disease (CKD), 119 120, 205, 287 global burden of, 205 population-based cohort study, 206f Chronic lung diseases, 80 Chronic NCDs, 220, 222f Chronic obstructive pulmonary diseases (COPD), 220 221, 237 238, 653 654 Chyavanprash, 49 CI. See Conicity index (CI) Cigarette smoke, 506 Cinnamaldehyde, 566, 569 570 Cinnamic acid, 566, 570 Cinnamic aldehyde, 570 Cinnamomum species, 569 C. burmannii, 568 C. cassia, 565 566, 569, 572 C. osmophloeum, 570 C. verum, 565 566, 572 Cinnamomum zeylanicum bark, 570 Cinnamon, 504 adverse effects, 571 572 burmannii tea, 569 in health and diseases bioavailability of cinnamon compounds, 571 chemical composition of cinnamon, 566 polyphenols and antioxidant activity, 566 568 powder, 569, 572 tea compounds, 569 functional properties on human health, 569 570 antiinflammatory activity, 570 hypoglycemic effect, 569 lipid lowering effect, 569 570 in vitro antimicrobial properties, 570 Cinnamon bark, 566, 570 oil, 570 CIR. See Corrected insulin response (CIR)

Circadian clock genes, 516 517 Per1, 517 Circadian disruption, 525 526 and metabolic disorders, 518 519 of sleep and carcinogenesis, 526 529 of circadian gene expression and risk of cancers, 528t mechanism of inflammation and subcellular remodelling, 528f regulation of appetite and metabolism, POMC, 527f Circadian regulatory pathways, 526 Circadian rhythms, 518 and caloric restriction, 515 516 critical importance, 513 514 and metabolism, 517 518 synchronization, 529 Citrus fruits, 19 c-Jun N-terminal kinase (JNK), 228 CKD. See Chronic kidney disease (CKD) Classification and regression tree analysis (CART analysis), 130 Climacteric symptoms, 385 386 Climate change, 480 food production and changes in relative global production of crops and animals, 10f estimates of cereal production, utilization, and stocks, 9f estimates of global progress in food consumption pattern, 11f Clinical and biochemical risk factors, nuts effects on, 354 356 Clinical assessment, 113 Clock genes, 517 518, 698 CLOCK transcriptional activator, 516 Clostridium botulinum, 503 Clostridium difficile, 590, 595 Clostridium perfringens, 580 581 Clove oil, 503 Cluster analysis, 99 100 Cluster of differentiation (CD), 594 Clustered regularly interspaced short palindromic repeats (CRISPR), 465 CMDs. See Cardiometabolic diseases (CMDs) CMO. See Common Market Organization (CMO) CNS. See Central nervous system (CNS) CNVs. See Copy number variants (CNVs) CO. See Central obesity (CO) Coarse cereals beside maize (Zea mays), 461 462 Cochran meta-analysis of RCTs, 331 Cocoa consumption and prevention agricultural policy, 339 beneficial effects of cocoa, 318 320, 319f clinical studies, 325 326 drug development, 338 339 dysfunction of endothelium, 333 334

Index

functional food development, 339 historical view on cocoa, 318 hypertension, 330 332 insulin resistance, diabetes mellitus, and vascular disease, 327 330 mechanisms of action, 321 325 effects of cocoa on endothelial function, 323t memory dysfunction and dementia, 335 337 obesity, 326 327 other chronic diseases, 337 338 pharmacokinetics, 320 321 platelet dysfunction, 325 reduction in blood lipids, 332 stroke, 334 335 Cocoa flavanols, 321 322 Cocoa/chocolate effects, 330 Coenzyme Q (CoQ), 174 175 CoQ10, 226 227, 288, 288f, 551 Coffee, 186 Cognitive function, 318 320 Cognitive functioning, 261, 263 264 impairment in elderly people, 264 Cognitive impairment, 525 Cohort studies, 243, 657 659 COLI. See Cost-of-living index (COLI) Colon, 579 580 Colorectal cancer, 594 nutritional risk, 189 red and processed meats, 189 Columbus eggs, 672 673 Common Market Organization (CMO), 30 “Common soil” of multifactorial diseases, 224 Communicable diseases, 63, 80, 93 94 Complex diseases, 595 Computed tomography (CT), 115, 120 Concanavalin A (Con A), 432 433 Condensed tannins. See Procyanidins Conicity, 120 Conicity index (CI), 112 113, 120 Conjugated linoleic acid (CLA). See Anticarcinogenic fatty acid ConnMap analyses, 587 588 Consultative Group for International Agricultural Research (CGIAR), 462 464 Consumer awareness, 375 Contemporary diet, 261 262 Controlled trials of nut consumption, 357 361 effect of almonds and walnut rich diet on cardiac events after 1 year, 361t on oxidative stress, vitamins, and cardiac damage, 361t in patients with acute myocardial infarction, 360t Controlled trials with Mediterranean-style diets, 101 104 Conventional eggs, 672 673 COPD. See Chronic obstructive pulmonary diseases (COPD)

715

Copper (Cu), 674 675 Copy number variants (CNVs), 687 CoQ. See Coenzyme Q (CoQ) Core clock gene Bmal1, 517 Coriander, 506 Coronary artery disease (CAD), 93, 99 100, 160, 220 221, 273 274, 287 288, 301, 317 318, 329 330, 347, 452, 639, 690 Coronary atherosclerosis, 640 641 Coronary disease, 52 Coronary flow velocity reserve (CFVR), 333 Coronary heart disease (CHD), 16, 18, 120 121. See also Cardiovascular diseases (CVDs) nutritional risk factors, 188 189 fast food/fried food, 189 processed meats, 188 189 sugar-sweetened beverages/soda, 189 trans fat foods, 188 Coronary risk factors, 58, 178 179 Corrected insulin response (CIR), 328 329, 333 Correction Factor (CF), 125 Cortisol, 529 Cost-of-illness approach, 58 60 Cost-of-living index (COLI), 125 Coumarin, 566, 571 572 COX. See Cyclooxygenase (COX) CpG methylation. See Cytosine-phosphate-guanine methylation (CpG methylation) CR. See Caloric restriction (CR) Cranberry, 19 20 C-reactive proteins (CRPs), 46, 226 227, 273, 548 549, 626 CRISPR. See Clustered regularly interspaced short palindromic repeats (CRISPR) Crop, 457 plants, 490 production, 674 675 CRPs. See C-reactive proteins (CRPs) Cruciferous vegetables, 19 Cryptochrome (Cry), 516 CT. See Computed tomography (CT) CTZ. See Chemoreceptor trigger zone (CTZ) Culinary spices, 566 568 Cultivation, 71 72 Culture-independent methods, 579 580 Cultured fermented sour sobya (SS), 596 Cumin, 506 507 Curcuma species, 505 Curcumin, 504 505 Curing process, 654 655 CVDs. See Cardiovascular diseases (CVDs) Cyclic gene expression, 519 Cyclooxygenase (COX), 570 COX-2, 626, 628 Cyclophosphamide, 432 433

716

Index

CYP24 expression, 384 CYP27B1 expression, 384 CYP2A6. See Cytochrome P450 2A6 (CYP2A6) Cysteine, 546 Cytochrome P450 2A6 (CYP2A6), 571 Cytokines, 432 433, 435 437 Cytosine DNA methylation, 676 Cytosine methylation, 689 Cytosine-phosphate-guanine methylation (CpG methylation), 72, 688

D Daidzein, 386 Daidzin, 381 382 Daily blueberry intake, 178 Dairy products, 20 21 DALY. See Disability adjusted life-years (DALY) DASH. See Dietary Approaches to Stop Hypertension (DASH) DASS. See Depression Anxiety Stress Scale (DASS) Data-driven approach, 98 99 DBP. See Diastolic blood pressure (DBP) DEBQ. See Dutch Eating Behavior Questionnaire (DEBQ) Decade of Action on Nutrition, 25 Degree of polymerization (DP), 594 Dehydrohautriwaic acid, 442 Deleterious metabolic activities bile salt hydroxylase, 604 605 gut epithelia binding and mucin degradation, 605 D( )-lactate, 606 toxic secondary metabolites, 605 Deletion polymorphisms, 687 Delta-5 desaturases, 691 Delta-6 desaturases, 691 Dementia, 335 337, 643 Deoxypyridinoline (DPD), 386 Deoxyribonucleic acid (DNA), 198 199 damage, 198, 627 methylation, 72, 547, 667 668 epigenetic variation in, 665 mutations, 193 “Dependent” variable, 130 Depression, 525, 532, 536, 643 Depression Anxiety Stress Scale (DASS), 266 DES. See Dry Eye Syndrome (DES) Designer genes, 687 688 Desynchronization, internal, 515 Detoxification, 200, 597 598 DGLA. See Dihomogamalinolenic acid (DGLA) DHA. See Docosahaxaenoic acid (DHA) dHNF4. See Drosophila HNF4 mutants (dHNF4) Diabetes, 120 121, 157, 280, 287, 289, 291 292, 365 366, 451, 518, 629 630

diabetes-induced hyperglycemia, 551 prevention, 373 374 Diabetes epidemic and dynamics, 159 Diabetes mellitus, 205, 235 236, 296 297, 301, 317 318, 322 324, 327 330 functional food security for prevention of Asian and South Asian paradox, 159 PF diabetes prevention by functional food administration, 162 164 risk factors of type 2 diabetes, 159 162 trends in sugar sales and consumption by region, 158f world health organization estimates, 158 159 Diabetes mellitus type 2 nutritional risk factors, 187 188 fast food/fried foods, 188 processed meats, 187 soda/sugar sweetened beverages, 187 white rice, 188 Diabetic kidney disease (DKD), 205 Diabetic nephropathy, 373 Diarrhea prevention, 373 Diarroea, 114 Diastolic blood pressure (DBP), 329 330, 387 Diet(s), 157, 161, 168, 261, 325 326, 451, 529 533, 581 582, 594, 639 clock genes and cardiac events, 698 changes in, 261 262 development, and disease, 58 diet-quality indexes, 99 100 dietary modulators of genes and genetic determinants, 694t effects of nutrition on genetic and epigenetic expressions, 702 704 on mortality to cardiovascular diseases, 168 170 epigenetic marks; DNA methylation, histone modification, 685f epigenomics; DNA inaccessible gene-turned off, 683f genes, 687 688 methylation, 688 689 status and phenotypic expression for health or disease, 699t genetic and environmental risk factors of cardiometabolic diseases, 703t high omega-6/omega-3 fatty acids ratio and genetic damage, 698 700 human genome, 686 687 label, 195 and lifestyle in cancer, 197 linked NCDs, 77 79 mechanisms of epigenetic and genetic expressions, 701 702 and mortality, 46 47 to NCDs, 302 303 NCDs, 356

Index

dietary transition and emergence, 88t failure of global health community to preventing, 90 91 noncoding RNAs modification by, 547 nutrition and epigenetic variations, 684 686 and genetic variations, 682 684 impact at molecular level, 198 nutraceuticals and, 694t omega-3 fatty acids and gene interactions, 689 696 randomized, controlled trials with Mediterranean-style diets, 101 104 and risk of NCD, 220 223 of osteoporosis, atherosclerosis, carcinogenesis, 642 647 role in metabolic syndrome, 304 305 sleep deprivation effects on, 533 534 and supplements, 266 267 survival gene and development of genotype, 695t telomere, 696 697, 697f world nutritional dynamics and risk of diseases, 91 100 Dietary application, 405 Dietary Approaches to Stop Hypertension (DASH), 168 169, 219 221 diet, 73 77, 95 96, 179, 302 303 score, 99 Dietary assessment, 113 Dietary dimensions, 356 Dietary factors, 355 Dietary fibers, 594 enrichment with, 403 Dietary flavonoids, 335 336 Dietary intake, 303 304, 530 531, 645 of fruits and vegetables, 177 of omega-3 fatty acids, 232 Dietary interventions, 546 Dietary patterns, 149, 175, 289 290, 310, 550, 645 globalization and, 47 49 Dietary phytochemicals, 553 554 Dietary protein, 185 Dietary PUFA, 228 Dietary restriction (DR), 548 549 Dietary sugar intake and risk of NCDs childhood obesity, 288 HDL-cholesterol concentration in plasma of nonobese, 289f mechanisms, 296 297 sugar and cardiometabolic diseases, 289 292 products, 292 296 Dietary Supplement Health and Education Act (1994), 603 604 Dietary supplements (DSs), 411 412, 413f, 603 604, 659 Dietary transitions, 73 77 Dietary-patterning analysis, 99 100, 306 Digestion process, 571

717

Digestive health, 627 Dihomogamalinolenic acid (DGLA), 645 Dihydroflavonols, 449 3,4-Dihydroxyphenyethanol (DOPET). See Hydroxytyrosol 3,4-Dihydroxyphenyl acetaldehyde (DOPAL), 624 3,4-Dihydroxyphenylacetic acid (DOPAC), 624 “Dimmer switch”, 547 Disability adjusted life-years (DALY), 261 Disease prevention properties of foods, 546 Disruption of circadian rhythms, 526 Distal gut microbiota, 582 583 Diversity indices, 481 482 Indonesian propolis, 425 of phytochemical profile, 427 DKD. See Diabetic kidney disease (DKD) DNA. See Deoxyribonucleic acid (DNA) DNA methyltransferase (DNMT), 554 555 DNMT. See DNA methyltransferase (DNMT) Docosahaxaenoic acid (DHA), 177, 224 225, 262 263, 415 416, 551, 645 646, 691 692 Docosapentaenic acid (DPA), 415 416 10,17S-Docosatriene, 531 532 DOPAC. See 3,4-Dihydroxyphenylacetic acid (DOPAC) DOPAL. See 3,4-Dihydroxyphenyl acetaldehyde (DOPAL) Dopamine (D2), 440 DP. See Degree of polymerization (DP) DPA. See Docosapentaenic acid (DPA) DPD. See Deoxypyridinoline (DPD) DR. See Dietary restriction (DR) Drosophila clock genes, 516 Drosophila HNF4 mutants (dHNF4), 702 Drosophila melanogaster, 516 Drug development, 338 339 Dry Eye Syndrome (DES), 232 DSs. See Dietary supplements (DSs) dTOR signaling, 516 Dual burden of malnutrition, 115 116 Dual-energy X-ray absorptiometry, 640 641 Dutch Eating Behavior Questionnaire (DEBQ), 531 Dysbiosis, 584 585 Dyslexia disorder, 261 Dyslipidemia, 235, 326 327

E Eaten diets, 582 583 Economic burden of NCDs, 57, 60 62 diet, development, and disease, 58 dietary pattern transition from poverty, 61f food consumption pattern in LMIC and HIC, 59f food consumption pattern with increase in gross domestic product, 60f

718

Index

Economic burden of NCDs (Continued) economic cost of overnutrition and related diseases, 62f food wastage prevention to reducing cost of food production, 65 66 NCDs impacts, 58 60 in low-income countries, 63 reduction of economic cost, 63 65 Economic development, 44 46, 61 Economic growth approach, 58 60 ED agents. See Endocrine disrupting agents (ED agents) Education, 103 104, 125 EFA. See Essential fatty acids (EFA) EFSA. See European Food Safety Authority (EFSA) EGCG. See Epigallocatechin-3-gallate (EGCG) EGFR. See Epidermal growth factor receptor (EGFR) Eggs, 301 302, 304 consumption and risk of NCDs, 306 311 as functional foods, 672 674 nutrients contents in, 302t Eicosanoids, 225 226, 240, 698 699 Eicosapentaenoic acid (EPA), 177, 224 225, 262, 415 416, 551, 645, 691 Emotional functioning, 261 Emotional stress, 536 EN-induced diarrhea, 416 417 End-stage renal disease (ESRD), 205 Endocrine disrupting agents (ED agents), 124 Endogenous antioxidants, 273, 545 546, 682 Endogenous circadian rhythms, partly, 514 515 Endothelial cell repair, 626 Endothelial dysfunction, 176, 289 290, 317 318, 357 358, 626 Endothelial function cocoa effects on, 323t score, 151 153 Endothelial NO synthase (eNOS), 321 322, 550 Endothelium, 701 dysfunction, 333 334 Energy intakes, 530 531 eNOS. See Endothelial NO synthase (eNOS) Enterobacter cloacae, 570 Enterococcus faecalis, 612 614 Enterococcus faecium, 612 614 Enterococcus strain, 612 614 Enterodiol, 53 Enterolactone, 53 Environmental cycles, synchronized by 24-hour, 514 515 Environmental factor, 532 Environmental transitions, 87 Enzyme transglutaminase, quarg cheese produced with, 405 Eosinophil counts, 514 515 EPA. See Eicosapentaenoic acid (EPA) EPIC model of WHO, 58 60

EPIC-NL Study, 97 98 Epicardia coronary arteries, 641 642 Epicatechin(s), 20, 322 326, 322f, 339, 659 epicatechin-3-gallate, 20 Epidemic of diabetes mellitus, 157 of NCDs, 168 of obesity and metabolic syndrome, 146 148 Epidemiological studies, 73, 334 335 Epidemiological transition, 148 Epidemiology of nutraceuticals, 412 414 Epidermal growth factor receptor (EGFR), 205, 627 Epigallocatechin, 20 Epigallocatechin-3-gallate (EGCG), 20, 201, 547, 551 Epigenetic alteration, 681 damage, 665 expression effects of nutrition on, 702 704 mechanism, 701 702 factors, 542 543 information, 689 inheritance, 666, 669 mechanisms of evolution of functional foods, 666 668 modifications, 526 modulation, 665 666 of epigenome of seeds grown in deficient soil, 673 674 in plants for food production, 674 677 regulation, 675 silencing, 676 variations in DNA methylation, 665 nutrition and, 684 686 Epigenome, 73, 665, 667f, 681 Epstein Barr virus, 194 Equol, 53, 379, 386 ER/PR. See Estrogen/progesterone receptor subtypes (ER/PR) ERK kinase, 570 ERRγ. See Estrogen-related receptor γ (ERRγ) Escherichia coli, 19 20, 373, 570, 588 589, 596 E-selectin, 357 358 ESRD. See End-stage renal disease (ESRD) Essential fatty acids (EFA), 682 Estrogen, 53 deficiency, 630 631 replacement, 390 Estrogen-related receptor γ (ERRγ), 385 Estrogen/progesterone receptor subtypes (ER/PR), 535 EU. See European Union (EU) Eubacterium limosum, 555 556 Eucalyptus globulus, 434 EUGMS. See European Union Geriatric Medicine Society (EUGMS) Eukaryotic cell nuclei, 547

Index

Eukaryotic genomes, 676 European Commission’s Food Safety policy, 660 European Food Safety Authority (EFSA), 571 European Union (EU), 25 26 agenda, 30 36 final estimates of food production in India (2016 17), 36 fruit and vegetable production in, 32t funds allotment to food science, 34f grapes and wine production, 34 olives and olive oil production, 35 “From Farm to Fork” approach, 145, 168 legislation, 660 European Union Geriatric Medicine Society (EUGMS), 548 549 Eurostat, 33 Evolutionary adaptations, 73 Evolutionary diet, 261 262 environment, and health, 671 672 evolution of man, 72 globalization of wealth without health, 79 82 nutrition in transition and diet linked NCDs, 77 79 nutritional transition from H. erectus to H. modestis, 73 77 primary risk factors and genetic variations, 73 EVOO. See Extra-virgin olive oil (EVOO) Excessive eating, 122 Exogenous antioxidants, 545 546, 682 Extra-virgin olive oil (EVOO), 623 Extrinsic factors, 543 544

F FAD. See Fasting on alternate day (FAD) FADS. See Fatty acids desaturases (FADS) Faecalibacterium prausnitzii, 594 Family education influence on child’s cognition and academics, 127 FAO. See Food and Agriculture Organization (FAO) Farmed fish, 195 196 Farmers, 87 FAs. See Fatty acids (FAs) Fast foods, 157, 188 189 Fasting blood glucose (FBG), 569 Fasting on alternate day (FAD), 548 549 Fats, 94 95, 99 100, 162, 449 450, 548 549 for health promotion and disease prevention clinical and epidemiological evidence, 273 275 flaxseed oil blend, 281 282 proposal for new blend of fats and oils, 280 282, 280t randomized, controlled trials, 275 280 Fatty acids (FAs), 273, 415 416, 695 in human diet changes in diet, 261 262 descriptive research, 263 266

719

diet and supplements vs. impulsive behavior, 266 267 polyunsaturated fatty acids, 262 263 precursors, 692 693 and structural lipids, 200 Fatty acids desaturases (FADS), 229f, 691 enzyme FADS1, 689, 691 692 FADS2, 689, 691 692 FBG. See Fasting blood glucose (FBG) FDA. See Food and Drug Administration (FDA) Fecal enzymes, 20 21 Fecal transplantation, 595 Feeding functional diet to animals, 172 schedule, 514 516 Fenugreek (Trigonella foenum-graecum L.), 471 distribution and global genetic diversity, 477 490 current global distribution of fenugreek crop, 480t diversity of fenugreek cultivars around globe, 479f fenugreek crop distribution, 478f list of fenugreek accessions, lines, masses, 483t pie chart indicating relative frequency of fenugreek diversification, 489f potential fenugreek production areas, 482t fenugreek seed; germinating seeds; seedlings, 473f fenugreek trifoliate compound leaf, 474f seeds, 507 taxonomy of Trigonella, 475 477 Fermentation, 595 598 Fermented milk products, 590 Fertilizers, 51 FF. See Functional farming (FF); Functional foods (FF) FFA. See Free fatty acids (FFA) FFF. See Functional food factor (FFF) FFWC. See Flavanol-free white chocolate (FFWC) “Fiber Mini”, 49 51 Fibers, 416 417, 451, 457 458, 464 fiber-rich foods, 6 polydextrose, 594 Finger millet (Eleusine coracana (L.) Gaertn), 457 458, 464 Firmicutes, 555 556, 594 Fish, 20, 172 173, 281, 304 oil, 415 416 feeding, 700 omega-3 fatty acids, 276 277 Five City study, 169 Flavan-3-ols, 318 320 Flavanol-free white chocolate (FFWC), 328 329 Flavanols, 318 321 Flavanones, 318 320 Flavones, 318 320, 449 Flavonoids, 20, 29, 49, 318 320, 320t, 336 337, 374, 427, 452, 464, 466, 546, 623 624

720

Index

Flavonoids (Continued) intake and mortality, 452 454 omega-3 fatty acids in Japanese and Mediterranean traditional diets, 71 72 Flavonols, 318 320, 449 Flavonones, 449 Flaxseed, 18 oil blend, 281 282, 281t, 282t Flow-mediated dilatation (FMD), 317 318, 357 358 Fluid percussion injury (FPI), 240 FMD. See Flow-mediated dilatation (FMD) FML process. See Forschungsinstitute fur Milch und Lebensmittel process (FML process) Foam mat drying, 375 “Foenum-graecum” species, 471 Folic acid, 72, 667 668 Food and Agriculture Organization (FAO), 25, 52, 58, 148 149, 170, 193, 347, 397, 604, 653 654 agenda, 11 13 estimates for functional foods production, 27 29 joint statement, 417 Food and Drug Administration (FDA), 201, 410, 603 Food processing and food industry role in functional food processing, 36 40 food-processing, 37 fruit and vegetable processing, 38 milk processing, 38 processing of cereals, pulses and oil seeds, 38 technological choices for value addition, 38 40 vegetable oil production, 39f Food security, 3 6, 21, 457 458 adverse effects, 52 53 and emergence of cardiovascular diseases, 170 172 dietary factors and other risk factors, 171f functional food package for prevention of cardiovascular diseases, 173t Saboo’s and Singh’s blend of fats and oils, 174t nutrition in transition and, 148 149 Food(s), 217 218, 223 224, 301 302 agenda for food industry, 659 660 and agricultural transition, 4 antiaging and disease prevention properties, 546 availability, 43 in cancer AICR guidelines for cancer prevention and risk reduction, 198 200 animal studies, 200 201 body weight, 194 cancer causing foods, 195 197 cancer-causing agents, 193 194 consumption, 3 pattern, 82, 305, 310 diversity, 145 146 food-borne pathogens, 585 587

food-spoilage bacteria, 503 intake, 515 preparations process, 571 processing, 37 production, 653, 659 and climate change, 8 9 safety, 197, 585, 660 science technology, 662 663 spoilage bacteria, 504 supplements, 411 system transition, 94 95, 148, 157 wastage prevention to reducing cost of food production, 65 66 conflict of interest statement, 66 Forage crop, 471 Forage quality of fenugreek, 472 Forkhead transcription factor family O (FOXO), 548, 625 Forschungsinstitute fur Milch und Lebensmittel process (FML process), 399 FOS. See Fructo-oligosaccharides (FOS) FOX03a, 625 FOXO. See Forkhead transcription factor family O (FOXO) Foxtail millet (Setaria italica), 465 466 Foxtail millet, 457 458, 466 Foxtail millet (Setaria italic (L. ) Beauv), 458 FPI. See Fluid percussion injury (FPI) Free fatty acids (FFA), 225 226, 296 297 Free oxygen radicals, 543 544 Free radicals, 198 199 quenching, 543 544 stress, 647 648 Freeze drying process, 375 Freeze-dried strains, 597 598 Fried foods, 188 189 consumption, 189 Fructo-oligosaccharides (FOS), 385, 556, 594 Fructose, 19 20, 289 290 moiety, 290 Fruits, 30, 162 163, 172 173, 304, 318 320, 365 366, 366f drinks, 295 296 powders, 375 processing, 38 production in EU, 32t Functional attributes, enhancement of, 402 Functional farming (FF), 43, 149, 172, 661 Functional fermented sour sobya gut microbiota malnutrition in children and impact on compositions, 583 585 post-natal development, 580 583 microbiota-based therapeutic interventions, 585 prebiotics, 594 probiotics, 585 587

Index

influence on improvement of intestinal immune cell function, 593 594 influence on plasma lipid profile parameters, 591 593 products, 596 598 in restoring gut permeability, 588 591 synbiotics, 595 traditional fermented foods rich in home source probiotic bacteria strains, 595 596 Functional food administration, PF diabetes prevention by, 162 164 functional food portfolio for prevention of metabolic syndrome, 162t probability of remaining free of diabetes, 163f Functional food factor (FFF), 380 381 Functional food security, 4 6, 179 association of risk factors and osteoporosis, 640 642 diet and risk of osteoporosis, atherosclerosis, carcinogenesis, 642 647 oxidative stress, antioxidants, and cell damage, 647 648 for prevention of cardiovascular diseases, 172 175 effects of diet on mortality due to cardiovascular diseases, 168 170 effects of Mediterranean-style diets in hypertension and stroke, 178 179 food security and emergence of cardiovascular diseases, 170 172 intervention trials with function foods, 176 177 transition from poverty to food security and, 168f for prevention of diabetes mellitus Asian and South Asian paradox, 159 PF diabetes prevention by functional food administration, 162 164 risk factors of type 2 diabetes, 159 162 trends in sugar sales, 158f world health organization estimates, 158 159 for prevention of obesity and metabolic syndrome, 149 151, 150t blend of fats and oils with possible beneficial effects, 150t epidemic of obesity and metabolic syndrome, 146 148 intervention trials with function foods, 151 154 nutrition in transition and food security, 148 149 Functional food-rich diet, 81 82 Functional foods (FF), 10 11, 21, 43, 49 51, 95 96, 375 antiaging and disease prevention properties of foods, 546 availability estimation agenda of GBD, 26 27 estimates of FAO for functional foods production, 27 29 European Union agenda, 30 36 food processing and role of food industry in functional food processing, 36 40 functional food intake and risk of mortality, 26f functional foods estimation with reference to nutrients, 29 30

721

WHO agenda, 27 impact of antioxidant foods and antiinflammatory agents, 551 555 consumption, 72, 90, 596 597 development, 339 by food manufacturing, 13 15 DNA methylation, 547 effects of environmental factors, 666f of oxidative stress and inflammation on epigenetic alterations, 671f eggs as, 672 674 elucidation of epigenetics and RNA regulation, 677f epigenetic mechanisms of evolution, 666 668 epigenetic modulation in plants for food production, 674 677 estimation with reference to nutrients, 29 30 evolutionary diet, environment, and health, 671 672 FAO estimates for, 27 29 food consumption per day/person in grams, 28t histone modification, 547 industries, 472, 475 intake, 507 interaction of environmental factors and genetic variations among humans, 669 longevity miscellaneous dietary interventions for antiaging and, 548 550 mitochondrial-generated reactive oxygen species and, 545 546 market, 15 16, 661 663 millets as development of millets as functional foods, 464 465 nutrient composition of millets, 461 464, 463f, 463t nutritional significance, 465 466 production of millets, 458 460, 459t, 461f, 462t miRNA or noncoding RNAs modification by diet, 547 in NCDs, 25 26 and nutrients, 355 nutrients and agouti gene experiment, 669 670 packages, 162 163 for metabolic syndrome prevention, 45t policy for developing, 660 661 for prevention of cancers, 534 536 propounded theories of mechanisms of aging, 543 545 role of gut microbiota, probiotics, and prebiotics in healthy aging, 555 556 Functional foods and functional farming (4 F), 43, 49 51, 53, 149, 172 adverse effects of food security, 52 53 diet and mortality, 46 47 globalization and dietary patterns, 47 49 modern trends in diets and development, 44 46 blend of fats and oils, 45t

722

Index

Functional foods and functional farming (4 F) (Continued) functional food package for prevention of metabolic syndrome, 45t industry Effects on quality of foods, physical activity, 44t Fungemia, 606

G G X E effect. See Genotype X Environment interactions (G X E effect) Galacto-oligosaccharides (GOS), 556 Gallic acid equivalent (GAE), 465 Garlic (Allium sativum), 19, 503, 507 Gas chromatography-mass spectrometry (GC-MS), 382, 427, 430t, 566 Gastrectomized rats, 385 Gastric cancer, 194 Gastrointestinal microbiome, 595 Gastrointestinal signs, 580 581 Gastrointestinal tract, 594, 597 598 GBD. See Global Burden of Disease (GBD) gbM. See Gene body methylation (gbM) GC-MS. See Gas chromatography-mass spectrometry (GCMS) GCP. See Good Clinical Practice (GCP) GDP. See Gross domestic product (GDP) Gender bias, 128 129 Gene body methylation (gbM), 676 677 Gene(s), 687 688 interactions, 689 696 Generally Recognized As Safe (GRAS), 416 417, 596 Genetic cancers, 194 Genetic diversity, 477, 480 Genetic engineering, 3 Genetic expression effects of nutrition on, 702 704 mechanism, 701 702 Genetic factors, 542 543, 692 693 Genetic modification, 51 Genetic polymorphisms, 554 555 Genetic variations, 73, 682 684 Genetically modified (GMO), 195 foods, 195, 661 sugar beets, 195 Genistein, 386 Genistin, 381 382 Genome, 681 editing tools, 465 Genome-wide association studies (GWASs), 159 160, 693 Genomic parasites, 676 Genomic PCR analysis, 581 582 Genotype X Environment interactions (G X E effect), 472 Genotype-phenotype association, 693 Germination, 465 466

Germination temperature (GT), 465 Germination time (Gt), 465 GFR. See Glomerular filtration rate (GFR) GHI. See Global hunger index (GHI) GI. See Glycemic index (GI) Ginger, 503, 505 Ginkgo biloba, 553 554 GIT-resident bacteria, 585 587 Global burden of CKD, 205 Global Burden of Disease (GBD), 6, 26 27 agenda, 26 27 study, 99 Global food availability for global health FAO agenda, 11 13 food and agricultural transition, 4 production and climate change, 8 9 security and functional food security, 4 6 functional food development by food manufacturing, 13 15 market, 15 16 natural, 16 21 total functional foods available for consumption, 10 11 total world population and total food availability, 6 8 Global food production, 37 Global genetic diversity, fenugreek distribution and, 477 490 Global health community failure of global health community to preventing NCDs, 90 91 Global hunger index (GHI), 110 Global nutritional dynamics, 100 Global pandemic of obesity, 44 Global pharmaceutical, 475 Global trading system, 8 Global warming, 480 Globalization and dietary patterns, 47 49 of diets dietary transition and emergence of NCDs, 88t failure of global health community to preventing NCDs, 90 91 randomized, controlled trials with Mediterranean-style diets, 101 104 world nutritional dynamics and risk of diseases, 91 100 of wealth without health, 79 82 Globesity, 115 Glomerular filtration rate (GFR), 205 Glucagon-like Peptide-1 signaling (GLP-1 signaling), 475 Glucose sirups, 375 Glucose toxicity, 162 163 Glucosinolates, 19, 21 Glucuronic acid, 374 GLUT4 translocation, 569 Glutathione (GSH), 200, 551

Index

Glutathione S-transferase (GST), 625 Glycated hemoglobin, 296 297 Glycemic index (GI), 550 Glycitin, 381 382 GMO. See Genetically modified (GMO) GMP. See Good Manufacturing Practice (GMP) Good Clinical Practice (GCP), 412 Good Manufacturing Practice (GMP), 411 GOS. See Galacto-oligosaccharides (GOS) Grading of Recommendations, Assessment, Development, and Evaluation (GRADE), 329 330, 334 Grain-based diet, 58 Gram-negative bacteria, 570 Grapes, 20 and wine production, 34 GRAS. See Generally Recognized As Safe (GRAS) Greek epic potential heart study, 52 53 Green leafy vegetables, 230 231 Green resources, 660 Green tea catechins, 20 Grilled red meat, 195 Gross domestic product (GDP), 58 GSH. See Glutathione (GSH) GST. See Glutathione S-transferase (GST) Gt. See Germination time (Gt) Guava (Psidium gujava), 365 366, 366f, 367t, 375 bio defensive properties, 366 372 enriched functional foods bio defensive properties, 366 372 technological challenges, 375 therapeutic potential, 373 374 fruits, 366 juice, 365 366 mousse, 375 powder, 375 therapeutic potential, 373 374 action as antioxidant, free radical scavenger, 374 prevention of diabetes and obesity, 373 374 prevention of diarrhea and metabolic disorders, 373 Gut epithelia binding and mucin degradation, 605 Gut health and diseases, 240 243 protective effects of paleolithic-style diet on NCDs, 240 243 Gut microbial ecosystem, 612 614 Gut microbiome, 595 Gut microbiota, 555 556, 579 580 malnutrition in children and impact on composition and function, 583 585 dietary and environmental factors, 584f metabolism, 591 593 post-natal development, 580 583 Gut permeability, probiotics in restoring, 588 591 Gut tight junction, 588 591 GWASs. See Genome-wide association studies (GWASs)

723

H H1. See Histamine (H1) Habitual food consumption patterns, 99 100 Habitual intake patterns, 306 Haplotype map (HapMap), 686 687 Harmful additives, 37, 39 40 Harmful fungi, 504 HarvestPlus-CGIAR Millets, 462 464 HAT. See Histone acetyltransferase (HAT) Hazard ratio (HR), 389 390, 640 641, 644 HbA1c. See Hemoglobin A1c (HbA1c) HBV. See Hepatitis B virus (HBV) 7OHC. See 7-Hydroxycoumarin (7OHC) HC. See Hip circumference (HC) HCV. See Hepatitis C virus (HCV) HDAC. See Histone deacetylase (HDAC) HDI. See Human development index (HDI) HDL. See High-density lipoprotein (HDL) HDL-C. See High-density lipoprotein cholesterol (HDL-C) HDM. See Histone demethylases (HDM) Health agencies, 171 172, 653 654 behavior, 73, 82, 103 104, 172, 653 654 community, 90 education, 80 globalization of wealth without, 79 82 hazards, 289 290 systems, 27 Healthy aging, gut microbiota, probiotics, and prebiotics in, 555 556 Healthy diet, 110 Healthy food, 13 14, 37 Healthy intestinal mucosa, 588 Healthy traditional diets, 99 100 Heart disease, 198, 234 235, 289, 301, 592 593 blood tHcy, 592 593 fish oils and, 234 235 Heart rate (HR), 178 179, 327 328 Heat-shock proteins (HSPs), 629 Height for age, 116 117 index, 112 113 menarche effect on, 122 123 socioeconomic stratification and, 126 Helicobacter pylori, 193 194, 503 Heme iron, 95, 654 655, 657 659 Hemoglobin A1c (HbA1c), 153 Hepatic nuclear factor-4 (HNF-4), 702 HNF-4α, 700 Hepatitis B virus (HBV), 193 Hepatitis C virus (HCV), 193

724

Index

Herbs, 21, 356, 548, 565 fenugreek, 471 garlic, 19 propolis, 441 Heterochromatin, 687 688 Heterocyclic aromatic amines, 195 Heterotrigona itama, 426 HIC. See High-income countries (HIC) High blood glucose, 161 High DASH score diet, 178 High Level Meeting (HLM), 91 High omega-6/omega-3 fatty acid ratio beneficial effects of omega-3 fatty acids, 227f bone health and diseases, 238 cancer, 236 237 causes of deaths in India, 219f chronological changes, 229 231 COPD, 237 238 CVD, 234 235 diabetes mellitus, 235 236 diet and risk of NCD, 217 223 dietary patterns and mortality, 218 220 food consumption pattern, 225f food intakes and ω-6/ω-3 fatty acid ratio of diet, 233t and genetic damage, 698 700 gut health and diseases, 240 243 and inflammation, 226 229 inflammation in tissue, 224 226 modern methods of food production, 223 224 multivariate logistic regression analysis for food and nutrient intakes, 234t and NCD, 231 233 obesity and metabolic syndrome, 233 234 recommendations for foods biodiversity, 218t rheumatoid arthritis, 238 240 world food dynamics, 221f High-density lipoprotein (HDL), 273, 332, 374, 506, 548 549 High-density lipoprotein cholesterol (HDL-C), 160, 178, 356, 693 High-fat diets, 228 High-income countries (HIC), 58, 66, 92 93 economic development in, 304 food consumption pattern in, 59f High-performance liquid chromatography (HPLC), 466, 566 analysis of vitamin E, 466 Highly unsaturated fatty acids (HUFA), 415 416 Hip circumference (HC), 112 113, 122 Hip fractures, 642, 645 646 Histamine (H1), 440 Histone acetyltransferase (HAT), 547 Histone deacetylase (HDAC), 547 548 Histone demethylases (HDM), 547 Histone methyltransferase (HMT), 547 Histone modification, 526, 547, 667 668, 689

HLM. See High Level Meeting (HLM) HMG. See 3-Hydroxy-3-methyl glutaric acid (HMG) HMT. See Histone methyltransferase (HMT) HNF-4. See Hepatic nuclear factor-4 (HNF-4) Home source probiotic bacteria strains, traditional fermented foods rich in, 595 596 Homo economicus, 77 80, 222 223 populations, 46 Homo erectus, 71 72 nutritional transition from Homo erectus to, 73 77 Homo habilis, 71 72 Homo modestis, 82 nutritional transition from Homo erectus to, 73 77 Homo sapiens, 46, 72 73, 173 Homoeopathic medicine, 499 Homovanillic acid (HVA), 624 Honey, 71 72, 87, 454, 669 quarg cheese preparation by adding, 401 Honey bee (Apis mellifera L.), 425, 449 Hormonal changes, 194 Host-deleterious metabolites, 604 606 bile salt hydroxylase, 604 605 D( )-lactate, 606 gut epithelia binding and mucin degradation, 605 toxic secondary metabolites, 605 Hot flash and climacteric symptoms, 385 386 Housekeeping genes, 687 688 HPA axis. See Hypothalamic pituitary adrenal axis (HPA axis) HPLC. See High-performance liquid chromatography (HPLC) HPV. See Human Papilloma virus (HPV) HR. See Hazard ratio (HR); Heart rate (HR) HSPs. See Heat-shock proteins (HSPs) hTERT. See Human telomerase reverse transcriptase (hTERT) HUFA. See Highly unsaturated fatty acids (HUFA) Human colonic microbiota, 579 580 Human development index (HDI), 126 Human evolution, 72 Human genome, 72, 579 580, 686 687 Human health, functional properties of cinnamon on, 569 570 Human microbiome, 579 580 Human microbiota, 603 Human Papilloma virus (HPV), 193 194 HPV-associated malignancies, 194 Human telomerase reverse transcriptase (hTERT), 547 Human umbilical vein endothelial cells (HUVE cells), 385 HUVE cells. See Human umbilical vein endothelial cells (HUVE cells) HVA. See Homovanillic acid (HVA) HVA1c, 624 Hydrocarbon chain, 262 Hydrogen peroxidase (HO)-1, 625 Hydrogen-scavenging bacteria, 585

Index

Hydrogenated fat foods. See Trans fat(s), foods Hydrogenated oils, 37, 195 Hydrogenation of vegetable oils, 167 3-Hydroxy-3-methyl glutaric acid (HMG), 593 7-Hydroxycoumarin (7OHC), 571 572 Hydroxyl radicals (•OH), 427 1,25-D3 24-Hydroxylase, 384 Hydroxytyrosol, 623 628, 630 Hyomethylation, 526 Hypercholesterolemia, 356 358, 591 Hypercholesterolemicmices, 592 Hyperglycemia, 82, 158, 296 297, 335 336 Hyperlipidemia, 82, 451 Hypermethylation, 526 Hyperplasia, 390 Hypertension, 93, 112 113, 120 121, 160, 287 288, 290 291, 301, 330 332, 355, 387, 451, 591 Mediterranean-style diets effects in, 178 179 Hypertriglyceridemia, 160 Hypocholesterolemic properties, 506 507 Hypoglycemic effect, 569 Hypokalemia, 179 Hypomagnesemia, 179 Hypothalamic dysfunction, 525 Hypothalamic pituitary adrenal axis (HPA axis), 532

I I164T mutation, 695 696 I3C. See Indole-3 carbinol (I3C) IAP. See Indian Academy of Pediatrics (IAP) IARC. See International Agency for Research on Cancer (IARC) IBD. See Inflammatory bowel disease (IBD) ICAM. See Intercellular adhesion molecule (ICAM) IFN-γ. See Interferon γ (IFN-γ) IFPRI. See International Food Policy Research Institute (IFPRI) IFs. See Isoflavones (IFs) IGF1. See Insulin/insulin-like growth factor 1 (IGF1) IGG. See Immunoglobulin G (IGG) IGT. See Impaired glucose tolerance (IGT) IHME. See Institute of Health Metrics and Evaluation (IHME) IIS. See Innate immune system (IIS) IkB kinases (IKKs), 570 IL. See Interleukin (IL) Illumina, 693 695 Immune cells, 531 532 responses and wound healing, 626 Immune homeostasis, 555 556 Immune system dysfunction, 194 Immunocompromised individuals, probiotics in, 603 604 Immunoglobulin G (IGG), 437 438

725

Immunoglobulins IgA, 581 582 IgM, 581 582 Immunological loss, 201, 202t Immunomodulation of gut associated lymphoid tissue, 240 by PUFA, 228 Immunomodulators, 425 effects of spices, 505 prospect as immunomodulator propolis, 432 434 Impaired glucose tolerance (IGT), 159, 328 329 Impulsive behavior, 266 267 Imunomodulatory agents, propolis as, 432 438 influence of propolis Trigona spp. on cytokine production, 435 437 on production of antibodies, 437 438 influence of Trigona spp. propolis, 434 435 propolis prospect as immunomodulator, 432 434 In vitro antimicrobial properties of cinnamon, 570 Incident rate ratio (IRR), 147 Income, SES indicators, 125 “Independent” variables, 130 India final estimates of food production, 36 leading producer of millets, 458 spices in, 501t Indian Academy of Pediatrics (IAP), 116 Indian Ayurvedic Systems, 471 Indian cassia (C. tamala), 565 Indian spices, 505 506 Indian traditional medical systems, 505 Indigenous foods, 597 598 Individual health security, 91 Indo-Mediterranean diet, 52 53, 73 77, 95 96, 99 100, 164, 176, 244, 306 Indo-Mediterranean Diet Heart study, 176 177, 280 Indo-Mediterranean foods, 46 Indo-Mediterranean-style diets, 151 153, 218 219 Indoctrination, 103 104 Indole-3 carbinol (I3C), 19 Indoles, 19 Indonesian cassia (C. burmannii), 565 Inducible nitric oxide synthase (iNOS), 296 297 Industrialization, 4, 71 77, 87, 94 95, 525 Infectious diseases, 114 Inflammation, 82, 225 226, 317 318, 335 336, 415 416, 531 532, 584, 626, 630 631, 639, 642 643, 643f high omega-6/omega-3 fatty acid ratio and, 226 229 markers of, 626 in tissue, 224 226 Inflammatory bowel disease (IBD), 240, 417, 595 Inflammatory processes, 698 699 INFOSAN. See International Food Safety Authorities Network (INFOSAN)

726

Index

Inherited cancers. See Genetic cancers Innate immune system (IIS), 639 iNOS. See Inducible nitric oxide synthase (iNOS) Institute of Health Metrics and Evaluation (IHME), 25 27 Insulin resistance, 160, 225 226, 318 320, 327 330 Insulin sensitivity index (ISI), 328 329 Insulin/insulin-like growth factor 1 (IGF1), 548 Intercellular adhesion molecule (ICAM), 326 327 Interferon γ (IFN-γ), 435 437, 593 594 INTERHEART study, 80 81, 98 99, 175, 242, 306 Interleukin (IL), 174 175, 359, 529 IL-1, 46 IL-2, 435 437 IL-6, 46, 550, 570, 690 IL-17, 593 594 Intermittent energy restriction, 519 Intermittent fasting, 515 516, 519 Intermittent feeding, 519 International Agency for Research on Cancer (IARC), 525 528 International College of Nutrition, 51, 172, 653 654 International Diabetes Federation, 159 International Food Policy Research Institute (IFPRI), 110 International Food Safety Authorities Network (INFOSAN), 193 International HapMap Project, 686 687 International Scientific Association for Probiotics and Prebiotics, 603 International Year of Pulses (IYP), 12 13, 29 Interquartile range (IQR), 52 Intervention trials, 657 659 with function foods, 151 154, 176 177 baseline and 1-year prevalence of metabolic syndrome, 152f Interventional research, 264 266 Interventional studies based on caloric restriction regimens, 519 520 Intestinal auto-intoxication, 585 Intestinal barrier integrity, 584 Intestinal immune cell function improvement, probiotic influence on, 593 594 Intestinal immune homeostasis, 627 Intestinal microbes, 555 556 Intestinal microbial community, 579 580 Intestinal microbiota, 582 583, 591 592 Intestinal permeability (IP), 588 589 Intrinsic factors, 543 544 Inulin, 403, 590 591, 594 Ionizing radiations, 194 IP. See Intestinal permeability (IP) IPP. See Isoleucyl-prolyl-proline (IPP) IQR. See Interquartile range (IQR) Iron (Fe), 427, 674 675

IRR. See Incident rate ratio (IRR) Ischemia reperfusion-induced cardiac injury, 551 ISI. See Insulin sensitivity index (ISI) ISO 7954 standard, 597 598 ISO 11290 2 standard, 597 598 Isoflavones (IFs), 318 320, 379 chemical structure, 380f health effects and safety of animal and in vitro experiment, 382 385 bone, 385 breast, 382 384 epidemiology, 379 381 metabolism and measurement, 381 382 prostate and angiogenesis, 385 randomized clinical trial and metaanalysis, 385 387 safety, 388 390 supplement, 388 multiple functions, 381t pharmacokinetics, 383f and polyamines for PHI-induced breast cancer in rats, 384f Isoleucyl-prolyl-proline (IPP), 592 Isoprenoid derivatives, 200 Isothiocyanates, 19 IYP. See International Year of Pulses (IYP)

J Japan Public Health Centre based study, 244 245 Japanese diet, 73 77, 95 96, 306, 379 JNK. See c-Jun N-terminal kinase (JNK) Juicing, 196 Juvenile arthritis, 231 232

K Kaempferol, 20 Kakun. See Foxtail millet (Setaria italica) Kangni. See Foxtail millet (Setaria italica) Kaposi’s sarcoma, 194 Karnal Haryana method, 400 Keegan and Allada’s technique, 698 Kendrick Object Learning Test (KOLT), 264 Ketogenic diet, 519 KHI1, probiotics bacteria strains, 592 Kidney health and diseases, 239 KII13, probiotics bacteria strains, 592 “Kingdom of spices”, 499 Kitchen & daily eating plan, 196 Klebsiella pneumonia 13883, 570 Kodo millet (Paspalum scrobiculatum), 458 KOLT. See Kendrick Object Learning Test (KOLT) Ku protein, 696 697 Kwashiorkor, 114

Index

L LA. See Linoleic acid (LA) LAB. See Lactic acid bacteria (LAB) Labeling, 597 598 D( )-Lactate, 606 Lactate dehydrogenase (LDH), 359 361 Lactic acid bacteria (LAB), 397, 585, 596 Lactobaccilli species, 556, 585 587, 604 605 L. acidophilus, 375, 397, 403, 587 588 L. acidophilus L1a, 589 L. brevis, 38 L. bulgaricus, 585 L. bulgaricus ME-552, 593 594 L. casei, 397, 401, 403, 587 588 L. casei Shirota, 15 16 L. plantarum, 591 592 L. rhamnosus, 38, 596 L. rhamnosus GG, 590 592 L. rhamnosus, 587 588 Lactobacillus helveticus-fermented sour milk, 592 Lactobacillus jensenii-associated empyema, 606 Lactococcus acidophylus, 417 418 Lactococcus bulgaricus, 417 418 Lactococcus casei, 417 418 Lactococcus plantarum, 417 418 Lactococcus reuteri, 417 418 Lactococcus rhamnosus, 417 418 Lactose absorption, 405 406 food consistency effects of quarg in lactose malabsorption, 406 hydrolysis in high heated milk affecting physical properties, 400 401 Lactulose mannitol dual test (LMDT), 589 Lancet Commission, 8 9 LBW. See Low birthweight (LBW) LC-MS. See Liquid-chromatography-mass spectrometry (LCMS) LC-PUFAs. See Long-chain polyunsaturated fatty acids (LCPUFAs) LDH. See Lactate dehydrogenase (LDH) LDL. See Low density lipoprotein (LDL) LDL cholesterol. See Low density lipoprotein cholesterol (LDL cholesterol) Lead, 124 Leatherhead Food Research report, 661 662 Leuconostoc citrovorum, 395 397 Leucotrienes, 46 Leukotriene B4 (LTB4), 240 LF. See Low-fat (LF) Li-Fraumeni syndrome, 194 LIC. See Low-income countries (LIC) Life span studies of caloric restriction in mice, 515

727

Lifestyle factors, 168, 532, 542 543, 639 modifications, 162 sleep deprivation effects on, 533 534 Light at night, 525 Lighting regimen, 514 Lignans, 18, 379, 623 624 Limonene, 429 Linoleic acid (LA), 228, 262, 280, 415 416, 691 Lipids, 221 222 lowering effect, 569 570 reduction in blood lipids, 332 Lipopolysaccharide (LPS), 432 433 Lipoprotein(a) (Lp(a)), 174 175, 690 691 Liposomes, 506 Lipoxins (LXs), 531 5-Lipoxygenase (5-LO), 691 Liquid-chromatography-mass spectrometry (LC-MS), 566 Listeria monocytogenes, 612 614 Little millet (Panicum sumatrense), 458 Liver cancers, 194, 201 Liver X receptors (LXR), 700 Livestock revolution, 148 LMDT. See Lactulose mannitol dual test (LMDT) LMIC. See Lower middle-income countries (LMIC) lncRNAs. See Long noncoding RNAs (lncRNAs) 5-LO. See 5-Lipoxygenase (5-LO) Locally sourced probiotics, 590 Long noncoding RNAs (lncRNAs), 529 Long-chain omega-3 PUFA, 239 Long-chain polyunsaturated fatty acids (LC-PUFAs), 692 693 Low birthweight (LBW), 441 Low density lipoprotein (LDL), 273, 328 329, 374, 506, 548 549, 569 Low density lipoprotein cholesterol (LDL cholesterol), 16, 231, 356, 387, 475, 591 592, 693 Low height-for-age, 116 Low omega-6/omega-3 fatty acid paleolithic-style diet, intervention trials on impact of, 243 245. See also High omega-6/omega-3 fatty acid ratio Low protein rice (LPR), 206 207 global burden of CKD, 205 low-protein dietary therapy, 206 207 packed, 207 peak condition period, 210 processing for hospital use, 207 processing of packed, 207 209 low-protein aseptic rice, 208f nutrients in low protein rice, 208t results of production, 210 changes in sales, 211f total amount of product shipping, 210f time to initiate low-protein diet, 210 211

728

Index

Low ω-3 fatty acids, 226 227 Low-calorie sweeteners, 295 296 Low-dose epicatechin, 324 325 Low-fat (LF), 228 Low-income countries (LIC), 52, 127 Low-protein diet, 210 211 Low-protein dietary therapy, 206 207 Lower middle-income countries (LMIC), 58, 63, 77 79 LPS. See Lipopolysaccharide (LPS) LTB4. See Leukotriene B4 (LTB4) LTR. See L-tryptophan-rich (LTR) L-tryptophan-rich (LTR), 475 Lung cancer, 190 Luteolin, 20 LXR. See Liver X receptors (LXR) LXs. See Lipoxins (LXs) Lycopene, 18 19, 374 Lyon Diet Heart Study, 53, 244 Lyon Heart Study, 218 219, 241 242 Lysine, 689

M Macrobiotic diet, 196 Macronutrients, 99 100, 172, 674 675 Macrophage Inflammatory Protein-1alpha (MIP-1alpha), 231 232 Macrophage Inflammatory Protein-1beta (MIP-1beta), 231 232 Macrophage phagocytosis activity, 434 435, 434t Magnesium (Mg), 464, 674 675 Magnetic Resonance Imaging (MRI), 115 Malignant diseases, 80 Malnourishment, 115 Malnutrition, 25, 113, 115, 542, 584. See also Undernutrition anthropometric indicators of, 113 in children and impact on composition and function of gut microbiota, 583 585 dual burden of, 115 116 Malonic acids, 381 382 Maltodextrin, 375 MAM. See Moderate acute malnutrition (MAM) Mammalian target of rapamycin (mTOR), 516, 548 Mammary tumor model, 21 Man evolution, 72 Mandia. See Millets Manganese (Mn), 625, 674 675 MAP. See Mean blood pressure (MAP) Marasmus, 114 Maresins, 531 Markers of inflammation, 626 Mast cell degranulation, 626 Maternal education, 127 128 Maternal fetal health, 542

Matrix metalloproteinases (MMPs), 626 Mayans, 318 m-BD. See Block Design (m-BD) MCA. See Middle cerebral artery (MCA) MCP-1. See Monocyte Chemotactic Protein-1 (MCP-1) MCT. See Medium-chain triglycerides (MCT) MDGs. See Millennium development goals (MDGs) MDRD study. See Modification of Diet in Renal Disease study (MDRD study) m-DST. See Modified version of Digit Symbol Test (m-DST) 6-ME. See 6-Methoxyequol (6-ME) Mean blood flow velocity (MFV), 335 Mean blood pressure (MAP), 120 121 Med-diet pattern, 550 Medicago sativa L. See Alfalafa (Medicago sativa L.) Medical costs, 58 60 Medical rice, 151 for chronic kidney disease global burden of CKD, 205 low-protein dietary therapy, 206 207 packed, 207 peak condition period, 210 processing for hospital use, 207 processing of packed, 207 209 results of production, 210 time to initiate low-protein diet, 210 211 Medicinal drug registration/authorization, 411 Medicinal plant, 475 Medicinal products, 410 Mediterranean diet, 46, 53, 73 77, 95 100, 149 151, 163 164, 173 174, 218 219, 221, 240 241, 278 279, 279f, 301 304, 303t, 306, 356 358, 532 535, 582 583, 629, 655 656 effects in hypertension, 178 179 in stroke, 178 179 randomized controlled trials with, 101 104 effect of ω-3 fatty acid rich Paleolithic style diet, 101t fatty acid consumption in Paleolithic style diet group and standard diet group, 102t numbers and rate ratios for end points in Paleolithic style diet group and standard diet, 102t Mediterranean style diet. See Mediterranean diet Medium-chain triglycerides (MCT), 552 553 Melatonin deficiency, 533 534 Memory dysfunction, 335 337 Menarche age at menarche, 123 124 effect on height, weight, and BMI, 122 123 effect on WC, WHR, and waist height ratio, 123 nutrition impact on, 122 Mental disorders, 262, 525 Mental stress, 525 Messenger RNA (mRNA), 359, 547

Index

Metaanalysis, 385 387, 593 bone, 386 387 hot flash and climacteric symptoms, 385 386 hypertension, 387 LDL-cholesterol, 387 prostate, 387 Metabolic disorder, 449 450, 551 circadian disruption and, 518 519 prevention of, 373 Metabolic function, 555 556, 669 Metabolic syndrome, 4 5, 10 11, 231 234, 329 330, 451, 552 553 functional food security for prevention of obesity and, 149 151, 150t blend of fats and oils, 150t epidemic of obesity and metabolic syndrome, 146 148 intervention trials with function foods, 151 154 nutrition in transition and food security, 148 149 Metabolism circadian rhythms and, 517 518 and measurement, 381 382 of olive polyphenols, 623 625, 624f parameters, 450 Metabolome, 684 Methionine effect, 548 549 2-Methoxycinnamaldehyde, 570 6-Methoxyequol (6-ME), 385 Methyl group, 701 Methylation DNA, 547 of genes, 688 689 of K9, 689 Methylenetetrahydrofolate reductase (MTHFR), 548 549 1-Methylhistamine, 582 583 MFV. See Mean blood flow velocity (MFV) MI. See Myocardial infarction (MI) Micro-RNA (miRNA), 547, 684 686 Microbes, 200 gut, 582 intestinal, 555 556 Microbial Dysbiosis Index, 585 Microbial metabolites, 585 587 Microbial vitamin B, 582 Microbiota α-diversity of, 583 584 of children, 582 malnutrition, 583 585 microbiota-based therapeutic interventions, 585 “Microbiota-for-age z score”, 583 584 Microhomologies, 701 702 Micronutrients, 73 77, 674 675 project, 462 464 Microorganisms, 503, 588 589 Microwave popcorn, 196

729

Mid-upper-arm circumference (MUAC), 112 113, 128 Middle cerebral artery (MCA), 335 Milk processing, 38 Millennium development goals (MDGs), 110 Millets, 162 163 as functional food development of millets as functional foods, 464 465 nutrient composition of millets, 461 464, 463f, 463t nutritional significance, 465 466 production of millets, 458 460, 461f Minerals, 95 96, 200, 301 302, 454, 457 458, 464 MIP-1alpha. See Macrophage Inflammatory Protein-1alpha (MIP-1alpha) MIP-1beta. See Macrophage Inflammatory Protein-1beta (MIP-1beta) miRNA. See Micro-RNA (miRNA) Miscellaneous dietary interventions for antiaging and longevity, 548 550 Mitochondria(l), 625 antioxidant system, 625 dysfunction, 296 297 and inflammation, 228 mitochondrial-generated reactive oxygen species and longevity, 545 546 oxidative metabolism, 545 546 ROS, 545 546 Mitochondrial DNA (mtDNA), 296 297 MMPs. See Matrix metalloproteinases (MMPs) m-MMSE. See Modified version of Mini-Mental State Examination (m-MMSE) Moderate acute malnutrition (MAM), 115 Moderate weight gain, 147 148 Modern diets, 223 224 Modern foods with adverse effects on health, 654 657 Modern lifestyle, 582 Modern men, 73 77 Modern nutritional science, 585 Modernization of policy for food manufacturing and farming agenda for food industry, 659 660 food intakes and ω-6/ω-3 fatty acid ratio of diet, 658t food safety, 660 functional food market, 661 663 funds allotment and expenditure in food science, 662f low ω-6/ω-3 fatty acid ratio diet effect on mortality, 657f modern foods with adverse effects, 654 657 nutrient intakes, 654f nutrients imbalances with adverse effects, 657 659 policy for developing functional foods, 660 661 Modification of Diet in Renal Disease study (MDRD study), 206 Modified version of Digit Symbol Test (m-DST), 264 Modified version of Mini-Mental State Examination (mMMSE), 264 Molecular chaperones, 629

730

Index

Molecular weight (MW), 427 Molybdenum (Mo), 674 675 Monocyte Chemotactic Protein-1 (MCP-1), 231 232 Monounsaturated fatty acid (MUFA), 223 224, 273, 282, 356, 359 Mortality diet and, 46 47 diet effects on mortality due to CVD, 168 170 flavonoid intake and, 452 454 Mouse models of diabetes and obesity, 518 MRI. See Magnetic Resonance Imaging (MRI) mRNA. See Messenger RNA (mRNA) mtDNA. See Mitochondrial DNA (mtDNA) MTHFR. See Methylenetetrahydrofolate reductase (MTHFR) mTOR. See Mammalian target of rapamycin (mTOR) MUAC. See Mid-upper-arm circumference (MUAC) Mucin degradation, 605 MUFA. See Monounsaturated fatty acid (MUFA) Multiflower honey, 451 Multiple antibiotic resistance, 585 587 “Multiregional” model, 72 Multivariate linear regression, 530 531 Multivariate logistic regression analysis, 244 245 Murine gastrointestinal tract, 518 Muscarinic acetylcholine (AChM), 440 Muscular growth, 114 Mustard and canola oils/rape seed oil, 276 277 Mustard oil, 275, 277f, 304 Mustard seed cake, 44 46 Mutagens, 193, 472 MW. See Molecular weight (MW) Myocardial damage, 176 Myocardial infarction (MI), 176, 218 219 Myricetin, 20 Myrosinase, 19

N n-3 polyunsaturated fatty acids, 18, 228 229, 236 237 NAD-dependent deacetylase, 516 NADH. See Nicotinamide Adenine Dinucleotide (NADH) NAMS. See North American Menopause Society (NAMS) Nanofiltration (NF), 402 preconcentration of cheese-milk by, 402 National Centre for Health Statistics (NCHS), 117 National Cholesterol Education Program, 656 657 National Dairy Research Institute (NDRI), 397t preparation of quarg cheese by, 400 National Family and Health Survey (NFHS), 112 National food security, 5 6 National Health and Nutrition Examination Survey (NHANES), 291 National Nutrition Monitoring Bureau (NNMB), 112 National Yogurt Association (NYA), 596 597

Natural antioxidant defense system, 625 Natural foods, 36 37 Natural functional foods, 16 21, 37. See also Nutraceuticals beef, 21 bioactive components from dairy food and potential benefits, 18t from oil seed and cereal food and potential benefits, 17t from vegetable food and potential benefits, 17t broccoli and other cruciferous vegetables, 19 citrus fruits, 19 cranberry, 19 20 dairy products, 20 21 fish, 20 flaxseed, 18 garlic, 19 oats, 16 17 soy, 18 tea, 20 tomatoes, 18 19 wine and grapes, 20 Nausea receptor, 442 Navane, 465 466 NCDs. See Noncommunicable diseases (NCDs) NCHS. See National Centre for Health Statistics (NCHS) NCX1.3, 703 704 NDRI. See National Dairy Research Institute (NDRI) Nematode infection, 127 Neolithic Revolution, 73 Neurodegenerative diseases, 526, 630 Neuroendocrine effects, 555 556 Neuroendocrine system, 532 Neurokinin-1 (NK1), 440 Neuromuscular diseases, 240 Neuropeptide-Y, 529 Neuropsychiatric diseases, 87, 317 318 Neutrophils, 626 New Zealand green lipped mussel (Perna canaliculus), 238 239 NF. See Nanofiltration (NF) NF-κB. See Nuclear factor κB (NF-κB) NFHS. See National Family and Health Survey (NFHS) NHANES. See National Health and Nutrition Examination Survey (NHANES) NHS. See Nurses health study (NHS) Nickel (Ni), 674 675 Nicotinamide Adenine Dinucleotide (NADH), 435 NID distribution. See Normally and independently distribution (NID distribution) Nitrate-rich vegetables, 339 Nitric oxide (NO), 296 297, 321 322, 321f, 434 435, 435t Nitric oxide synthase (NOS), 435 Nitrogen, 674 675 Nitrolipids, 531 NK1. See Neurokinin-1 (NK1)

Index

NNMB. See National Nutrition Monitoring Bureau (NNMB) NO. See Nitric oxide (NO) NOAEL. See Nonobserved adverse effect level (NOAEL) Non-Hodgkin’s lymphoma, 194 Noncoding RNAs modification by diet, 547 Noncommunicable diseases (NCDs), 6, 25, 43, 57, 77 79, 87, 91, 217, 261, 287 288, 301, 308t, 317 318, 347, 507, 525, 542, 639, 642 643, 653 654, 656 657, 682. See also Cardiometabolic diseases (CMDs); Cardiovascular diseases (CVDs) diet, nut intake, and risk, 356 diet and mortality due to, 302 303 diet and risk, 220 223 diet linked, 77 79 diet effects and lifestyle on body composition, 79f dietary transition and emergence, 88t economic burden, 60 62 diet, development, and disease, 58 economic cost of overnutrition and related diseases, 62f food wastage prevention to reducing cost of food production, 65 66 egg consumption and risk, 306 311 failure of global health community, 90 91 current situation, 91t identify impacts of, 58 60 in low-income countries, 63 modern methods of food production as risk factor, 223 224 nutrition in transition and development, 303 304 omega-6/omega-3 fatty acid ratio and, 231 233 prevention, 551 555 reduction of economic cost of, 63 65 western style foods effects on risk of colorectal cancer, 189 coronary heart disease, 188 189 diabetes mellitus type 2, 187 188 lung cancer, 190 osteoporosis, 185 187 Nondialyzable polymeric compound, 19 20 Nondigestible polysaccharides (NSP), 594 Nonhomologous end joining, 701 702 Nonlactic-acid bacteria, 597 598 Nonmedical costs, 58 60 Nonnutritive sweeteners, 295 296 Nonobserved adverse effect level (NOAEL), 441 Nonstarter lactobacilli enhanced flavor of quarg, 404 Nonsteroidal antiinflammatory drugs (NSAIDs), 238 239 Normal intestinal flora, 580 581 Normal-weight metabolically-obese, 159 Normally and independently distribution (NID distribution), 129 130 North American Menopause Society (NAMS), 388 North Karelia Project, 95 96 NOS. See Nitric oxide synthase (NOS)

731

Novel foods, 51 Nrf2. See Nuclear factor erythroid 2-related factor 2 (Nrf2) NSAIDs. See Nonsteroidal antiinflammatory drugs (NSAIDs) NSP. See Nondigestible polysaccharides (NSP) Nuclear factor erythroid 2-related factor 2 (Nrf2), 625 Nuclear factor κB (NF-κB), 225 226, 296 297, 434, 550, 628, 698 Nucleosomal remodeling, 689 Nucleosomes, 687 688 Nurses health study (NHS), 161 Nurses’ Health Study, 95, 185 Nut intake of NCDs, 356 Nutraceuticals, 162, 199 200, 409 410, 472, 475, 701. See also Natural functional foods effectiveness, 411 412, 414 epidemiology, 412 414 product range, 413 414 examples, 415 418 mechanism of cancer prevention by, 201 protection in cancers, 201 safety, 411 412, 414 sphere of products, 409 412 supplements, 411 Nutrients, 19, 71 72, 530, 669 670, 682, 693 695, 701 composition of millets, 461 464, 463f, 463t functional foods estimation with reference to, 29 30 food production in EU, 31t functional food portfolio for health promotion and disease prevention, 30t production of nuts and pulses, 32t imbalances with adverse effects, 657 659 nutrient-sensing pathways, 517 Nutrigenetics, 682, 684 Nutrigenomics, 598, 684 Nutrition(al), 25, 113, 682 686 biochemical study, 465 in cancer AICR guidelines for cancer prevention and risk reduction, 198 200 animal studies, 200 201 body weight, 194 cancer causing foods, 195 197 cancer-causing agents, 193 194 deprivation, 159 and diet and development of cancer, 196 factors, 317 318, 667 668 health education, 92 93 immunodeficiency, 115 impact on puberty and menarche, 122 management of blood glucose levels, 99 100 marasmus, 115 requirements, 412 significance, 465 466 stunting, 116

732

Index

Nutritional challenges of school children anthropometric indicators, 116 120 classification of nutritional status, 113 116 GHI, 110 MDGs, 110 nutritional epidemiology, 111 113 physiometric indicators, 120 122 puberty and menarche, 122 124 sociodemographic factors, 124 129 South Asian Enigma, 111 statistical methods, 129 130 TEM, 129 Nutritional epidemiology, 111 112 aim, 112 classification, 112t cross sectional studies, 112 steps of cross-sectional studies, 112 methods to measure, 112 113 Nutritional risk colorectal cancer, 189 factors coronary heart disease, 188 189 diabetes mellitus type, 187 188 osteoporosis, 185 187 lung cancer, 190 Nutritional status classification, 113 116 dual burden of malnutrition, 115 116 overnutrition, 115 purpose and theories of classification, 116 undernutrition, 114 115 of present generation, 110 Nutritional status acceleration in TB patient, 438 440 Nutritional transition, 47, 77 79, 103 104 and development of NCDs, 303 304 estimated fatty acid consumption, 75t ethnic differences in fatty acid levels, 76t fatty acids ratio in diets, 77t and food security, 148 149 from H. erectus to H. modestis, 73 77 nutrient composition in Late Paleolithic society, 76t nutrient intake, 74t in Paleolithic societies, 78f Nutritive sweeteners, 295 296 Nuts, 162 163, 304 consumption effects controlled trials of nut consumption, 357 361 diet, nut intake, and risk of NCDs, 356 effects of nuts on clinical and biochemical risk factors, 354 356 and risk of all-cause mortality, 348 353 NYA. See National Yogurt Association (NYA)

O Oats (Avena sativa), 16 17, 461 462 Obesity, 10 11, 44, 46, 87, 115, 121 122, 167, 233 234, 287 288, 326 327, 365 366, 451, 517 in children, 126 functional food security for prevention metabolic syndrome, 149 151, 150t blend of fats and oils with beneficial effects on health, 150t epidemic, 146 148 intervention trials with function foods, 151 154 nutrition in transition and food security, 148 149 genes, 695 696 global pandemic, 44 menarche effect on height, weight, and BMI relation with, 122 123 obesity-induced upregulation of inflammatory cytokines, 551 552 obesity-related diseases, 118 prevention, 373 374 Observational studies, 243 OC. See Osteocalcin (OC) O-desmethylangolensin (O-DMA), 381 382 OGTT. See Oral glucose tolerance test (OGTT) Oil. See also Olive oil of anise, 504 canola oil, 167, 279 280, 304 cinnamon bark oil, 570 clinical evidence, 273 275 clove, 503 epidemiological evidence, 273 275 for health promotion and disease prevention clinical and epidemiological evidence, 273 275 flaxseed oil blend, 281 282 proposal for new blend of fats and oils, 280 282, 280t randomized, controlled trials, 275 280 hydrogenated, 37, 195 mustard, 275, 277f, 304 seeds processing, 38 sesame, 279 280 turmeric, 504 vegetable, 195, 698 699 Okinawa dietary pattern, 550 Oleanolic acid, 374 Oleocanthal, 623, 626 630 Oleoresins, 500 Oleuropein, 623 628, 630 antiinflammatory and antioxidant properties, 629 Oligofructose, 594 Olive oil, 276 277, 304, 623 oral supplementation, 630 polyphenols, 629 production, 35, 35f

Index

Olive polyphenols, 623, 628 630 anticancer activities, 628 oral bioavailability and metabolism, 623 625, 624f Omega-3 acids, 266 267 enriched eggs, 672 673 fat, 282 PUFA, 700 Omega-3 fatty acids (n-3 fatty acids), 14 15, 20, 29, 71 72, 223 224, 228 229, 240 241, 262, 265, 273, 303 304, 667 668, 689 696, 698 699 metabolism, 641 642 omega-3 fatty acid-rich Mediterranean diet, 359 361 Omega-6 fatty acids, 223 224, 228 229, 262, 265, 273, 698 699 Omega-6/omega-3 fatty acids ratio, 176 177, 325 326, 672 balanced, 224 225 of diet, 645 One-way ANOVA analysis with Tukey post hoc test, 129 Onion, 507 Online database of Genomic Variants, 687 Opioid receptors, 440 Opioid-rich nutraceuticals, 200 Oral bioavailability of cinnamon oil, 571 and metabolism of olive polyphenols, 623 625, 624f Oral glucose tolerance test (OGTT), 328 329 Oral olive oil administration, 626 Organic eggs, 672 673 Organic foods, 196 Oriental diet, 175 Oriental dietary pattern, 98 99 Origanum vulgare L., 504 Oryzenol, 282 Osteocalcin (OC), 386 Osteoporosis, 18, 287, 630 631, 639, 640f diet and risk, 642 647 nutritional risk factors, 185 187 alcohol, 186 187 coffee, 186 red meats, 185 soda, 185 186 risk factors association and, 640 642 “Out of Africa” model, 72 Ovariectomy (OVX), 385 Overeating, 80 81 Overnourishment, 115 Overnutrition, 115 116 Overweight, 121, 287 288 OVX. See Ovariectomy (OVX) Oxidative injury, 374 Oxidative states, 701

733

Oxidative stress, 82, 224 227, 296 297, 317 320, 335 336, 529, 543 544, 625 626, 630 631, 647 648, 682 theory, 543 544, 545f

P p38 MAPK, 570 Packaged foods, 36 37 PAI-1. See Plasminogen activator inhibitor-1 (PAI-1) Paleolithic diet, 53, 73 77, 173 Paleolithic period, 71 73 Paleolithic-style diet, 101 103. See also Western-type diets protective effects of Paleolithic-style diet on NCDs, 240 243 Panicum sumatrense. See Little millet (Panicum sumatrense) Pasteurized quarg (QP), 406 Pastured eggs, 672 673 Pathogenic bacteria, 585 Pathogens, 504 PBMCs. See Peripheral blood mononuclear cells (PBMCs) PCI. See Per capita monthly income (PCI) PCM. See Protein calorie malnutrition (PCM) PCOOH. See Phosphatidyl choline peroxide (PCOOH) PCPT. See Prostate Cancer Prevention Trial (PCPT) PCR. See Polymerase chain reaction (PCR) Peak condition period, 210 Peanuts, 348 350 Pearl millet (Pennisetum glaucum(L.) R. Br.), 457 458 Pearsons correlation test, 130 Pectin, 451 Pediatric diarrhea, 590 Pediococcus species, 604 605 PEM. See Protein energy malnutrition (PEM) 3-Penten-2-ol and 2-butenyl acetate, 366 PEOOH. See Phosphatidyl ethanolamine peroxide (PEOOH) PEPCK. See Phosphoenolpyruvate carboxykinase (PEPCK) PEPI trial. See Postmenopausal Estrogen and Progestin Interventions trial (PEPI trial) Peptides, 153 154 Per capita monthly income (PCI), 125 PER protein, 516 Per1, circadian clock gene, 517 Peripheral blood mononuclear cells (PBMCs), 359, 433 Peripheral nervous systems, 262 263 Perna canaliculus. See New Zealand green lipped mussel (Perna canaliculus) Peroxisome proliferater-activated receptor-α (PPAR-α), 700 Peroxisome proliferater-activated receptor-γ (PPAR-γ), 700 Peroxynitrite, 296 297 Peyer’s patches (PPs), 594 PF diabetes prevention by functional food administration, 162 164 PGE2. See Prostaglandin E2 (PGE2)

734

Index

Pharmacokinetics, 320 321 Pharmacological agents, 591 Phenol compounds, 427 Phenolic acids, 374, 623 624 Phenolic compounds, 21, 200, 374 Phenotypic expression for health or disease, 695, 699t PhIP. See 2-Amino-1-methyl-6-phenylimidazo(4,5-b)-pyridine (PhIP) Phorbol miristate acetate (PMA), 432 433 Phosphatidyl choline peroxide (PCOOH), 384 Phosphatidyl ethanolamine peroxide (PEOOH), 384 Phosphoenolpyruvate carboxykinase (PEPCK), 569 Phosphorus, 674 675 Physiological cellular redox state, 701 Physiometric indicators. See also Anthropometric indicators blood pressure, 120 relation of BP with body mass index, 121 relationship of BP with WC, 121 variation of BP with age, 121 122 Phytic acid, 466, 475 Phytoalexin, 20 Phytochemicals, 21, 196, 198, 471 472, 551, 552t profile of propolis Trigona spp., 427 429 Phytochrome Interacting Factor 4 (PIF4), 676 677 Phytoestrogens, 53, 379 380, 387 Phytosterol, 282 PI3K, 228 229 PICKLE (PKL), 676 Pickled foods, 195 PIF4. See Phytochrome Interacting Factor 4 (PIF4) Pimpinellaanisum, 504 PKL. See PICKLE (PKL) Placebo-controlled clinical trial, 452 Plant breeding, 3 groups, 480 cells, 15 foods, 21 plant-based diets, 162 163 products, 500 sterols, 14 15 technological advances in plant epigenetics, 675 676 Plasma cholesterol concentrations, 691 Plasminogen activator inhibitor-1 (PAI-1), 226 Platelet dysfunction, 321 322, 325 PLC. See Protein low content (PLC) PMA. See Phorbol miristate acetate (PMA) Pneumonia, 114 Pol IV and V. See Polymerases IV and V (Pol IV and V) Polybrominated agents, 124 Polygonum cuspidatum, 550 Polymerase chain reaction (PCR), 689 690 Polymerases IV and V (Pol IV and V), 676

Polyphenolic(s), 275 276, 318 320, 336 337 flavonoids, 318 Polyphenols, 20, 320 321, 339, 565, 623, 628 629. See also Olive polyphenols Polypolyphenol, 452 Polyunsaturated fatty acids (PUFAs), 217 218, 228, 262 263, 273, 359, 415 416, 449 450, 529, 551, 646, 689 690 PolyunSFAs, 167 POMC. See Pro-opiomelanocortin (POMC) POMS. See Profile of Mood States (POMS) Popliteal vein thrombosis, 644 Population health education, 91 92 population-based cohort study, 189 studies, 73, 87 Post-natal development of gut microbiota, 580 583, 580f Postmenopausal Estrogen and Progestin Interventions trial (PEPI trial), 390 Potassium, 674 675 Poultry, 304 306 Poverty, 73 77, 80 PPAR-α. See Peroxisome proliferater-activated receptor-α (PPAR-α) PPs. See Peyer’s patches (PPs) Prasads classification of SES, 114 Preagricultural humans diet, 87 Prebiotic(s), 416 417, 594 activity, 374 enrichment of quarg cheese with prebiotic attributes, 403 in healthy aging, 555 556 “Predictor” variables, 130 Pregnancy, potential antiemetic effect of propolis in, 441 442 Prevencion con Dieta Mediterranea study (PREDIMED study), 53, 99, 153 154, 163 164, 177 178, 241, 275 276, 535, 655 656 Prevention of Food Adulteration Act, 603 Prevotella enterotype, 582 583 Price indices, 33 Primary risk factors, 73 Principle-component analysis technique, 98 100, 175, 594 Prion (PSI), 668 Pro-atherogenic foods, 58 Pro-inflammatory cytokines, 436 437 markers, 151 153 transcription factors, 296 297 Pro-opiomelanocortin (POMC), 529 Proanthocyanidins, 568 Proantocyanidins, 569 Probiotic L. rhamnosus GR-1 supplemented yogurt, 597 598

Index

Probiotic(s), 14 15, 20 21, 38, 417, 585 587, 588t, 590 591 bacteria, 585 587, 596 597 strains, 592 culture, 397 enrichment of quarg cheese with probiotic attributes, 403 in healthy aging, 555 556 influence on improvement of intestinal immune cell function, 593 594 influence on plasma lipid profile parameters, 591 593 organisms, 397 potential side effects of probiotic consumption, 604 614 antibiotic resistance gene transfer, 612 614 immune responses in vulnerable populations, 612 metabolic activities, 604 606 systemic infections, 606 611 products, 596 598 quarg cheese, 403 in restoring gut permeability, 588 591 safety in health and disease, 603 traditional fermented foods rich in home source probiotic bacteria strains, 595 596 Processed meats, 187 190 Procyanidins, 318 320, 326 type-A polymers, 566 Product range, 413 414 Product sphere, 409 412 Profile of Mood States (POMS), 264 265 PRONUT study, 595 Propolis Trigona spp., 425, 441, 449, 451 452, 454 antiemetic effect, 440 443 antioxidant activity and toxicity, 429 432 as antituberculosis, 438 440 chemical content, 427 on cytokine production, 435 437, 436t as imunomodulatory agents, 432 438 on production of antibodies, 437 438 from regions in Indonesia, 427 429, 428t Proso millet (Panicum miliaceum L.), 457 458 Prostacyclin, 46 Prostaglandin E2 (PGE2), 236 237, 646 647 Prostaglandins, 626 Prostate, 385, 387 Prostate Cancer Prevention Trial (PCPT), 387 Protectins, 531 Protein calorie malnutrition (PCM), 115 116 “Protein Digestibility Corrected Amino Acid Score” method, 18 Protein energy malnutrition (PEM), 114 115 Protein low content (PLC), 208, 209f Protein(s), 99 100, 162, 301 302, 449 450, 464 deficiency, 584 Proteolytic bacteria, 585 Proteome, 684

735

Proteus spp., 570 Prudent diets, 101 103, 175, 304 307 globalization and protection from NCDs, 95 100 pattern, 98 99 pattern, 242 243 Pseudomonas aeruginosa ATCC 27859, 570 Pseudomonas fluorescens, 504 Psidium gujava. See Guava (Psidium gujava) Psychologic stress in humans, 232 Psychological stress/depression, 532 533 PTH, 186 Puberty determinants of pubertal development, 124 nutrition impact on, 122 PUFAs. See Polyunsaturated fatty acids (PUFAs) Pulse(s), 13, 29 crops, 13 processing, 38 Pyridoxine, 72 Pyrodoxin, 667 668

Q QBM cultures. See Quarg buttermilk cultures (QBM cultures) QoL. See Quality of life (QoL) QP. See Pasteurized quarg (QP) QPS. See Qualified Presumption of Safety (QPS) Qualified Presumption of Safety (QPS), 604 Qualitative methods, 111 112 Quality of life (QoL), 542 543 Quarg buttermilk cultures (QBM cultures), 406 Quarg cheese. See Quark cheese Quarg yogurt (QY), 406 Quark cheese, 395 396 application based on end use, 402 characteristics, 396 397 composition of skim milk, 397t factors affecting preparation, 400 401 by adding honey and effects, 401 heating affects physical properties, 400 lactose hydrolysis in high heated milk, 400 401 functional properties, 397 398 microbiology, 397 preparation method, 396f, 398 401 general method, 398 399 preparation of quarg cheese by NDRI, 400 production of quarg cheese using two-stage continuous fermenter, 399 yield of quarg and whey protein recovery, 399t quarg filtration technology, 401 402 preconcentration of cheese-milk by NF, 402 recent advances in preparation, 402 406 cathepsin D activity in quarg, 405

736

Index

Quark cheese (Continued) cheese production per country, 406, 407t enhancement of functional attributes, 402 enrichment of quarg cheese with prebiotic and probiotic attributes, 403 enrichment with dietary fibers, 403 food consistency effects of quarg in lactose malabsorption, 406 lactose absorption by postweaning rats, 405 406 nonstarter lactobacilli enhanced flavor, 404 physiological effects and dietary application, 405 preservation of quarg cheese by using chemicals, 403 rennet enzyme effect on proteolysis and bitterness, 404 thermization effect on quality of quarg, 406 “Queen of Forages”. See Alfalafa (Medicago sativa L.) Quercetin, 20, 475 QY. See Quarg yogurt (QY)

R RA. See Rheumatoid arthritis (RA) Radiation therapy, 194 RAGE. See Receptor for advanced glycation end products (RAGE) Ragi, 461 462, 464, 466 Randomized controlled/clinical trials (RCTs), 275 280, 290 291, 325 326, 385 387 bone, 386 387 effects of Mediterranean-style diets containing either olive oil, 276f of mustard oil rich Indo-Mediterranean diet, 278f of paleolithic-style diet with mustard oil, 277f hot flash and climacteric symptoms, 385 386 hypertension, 387 LDL-cholesterol, 387 of mixed probiotic strains, 611t prostate, 387 Randomized trials with Mediterranean-style diets, 101 104 RANTES. See Regulated upon Activation, Normal T cell Expressed and Secreted (RANTES) Rap1 knockout mice, 696 697 Rape seed oil, 279 280 RBC. See Red blood cell (RBC) RCTs. See Randomized controlled/clinical trials (RCTs) RdDM. See RNA dependent methylation of DNA (RdDM) Reactive nitrogen species (RNS), 449 Reactive oxygen species (ROS), 326, 374, 449, 543 544, 625, 701 Ready to use therapeutic foods treatment (RUTF treatment), 595 Receptor for advanced glycation end products (RAGE), 373 Red blood cell (RBC), 224 225 Red meats, 185, 189 190, 301 302, 304

Red wine, 20 Redox-sensitive signaling pathways, 326 REDUCE. See Reduction by Dutasteride of Prostate Cancer Events (REDUCE) Reduction by Dutasteride of Prostate Cancer Events (REDUCE), 387 Reduction in blood lipids, 332 Refined carbohydrates, 304 Refined foods, 296 297 Refined grains, 44 46, 73 77, 94 95, 157 Regulated upon Activation, Normal T cell Expressed and Secreted (RANTES), 231 232 Relative humidity (RH), 403 “Relative microbiota maturity”, 583 584 Relative risks (RRs), 242 243, 275, 304 305, 325 326, 453 Rennet, 398, 404 enzyme effect on proteolysis and bitterness, 404 Resistant starches (RSs), 594 Resolvins (Rvs), 531 Respiratory health, 631 Resveratrol (RSV), 20, 550, 659 Retardation, 116 Retention time (RT), 427 Retinoid X receptors (RXR), 700 RXR-α, 700 RH. See Relative humidity (RH) Rheumatoid arthritis (RA), 218 219, 231 232, 238 240 Rice, 151 bran oil, 279 280 RNA dependent methylation of DNA (RdDM), 676 RNA interference, 465 RNS. See Reactive nitrogen species (RNS) ROS. See Reactive oxygen species (ROS) Royal jelly, 451 452, 454 16 S rRNA gene sequences, 388 RRs. See Relative risks (RRs) rs66698963 mutation, 689 RSs. See Resistant starches (RSs) RSV. See Resveratrol (RSV) RT. See Retention time (RT) RUTF treatment. See Ready to use therapeutic foods treatment (RUTF treatment) Rvs. See Resolvins (Rvs) RXR. See Retinoid X receptors (RXR)

S S6 protein kinase 1 (S6K1), 517 Saccharomyces boulardii, 590, 606 Saccharomyces cerevisiae, 606 Saigon cassia (C. loureiroi), 565 Salmonella species, 588 589 Salts, 449 450 SAM. See Severe acute malnutrition (SAM)

Index

Saponins, 475 Sarcopenia, 548 549 Saturated fats, 278 279 Saturated fatty acids (SFA), 93 94, 167, 223 224, 273, 359, 646 647, 672 SBP. See Systolic BP (SBP) Scanning electron microscopy (SEM), 400 SCCS. See Southern Community Cohort Study (SCCS) SCD. See Sudden cardiac death (SCD) SCF. See Soluble corn fiber (SCF) SCFA. See Short-chain fatty acids (SCFA) Schabzieger, 477 SCN. See Suprachiasmatic nuclei (SCN) SD classification, 116 SDGs. See Sustainable development goals (SDGs) SDH. See Sorbitol dehydrogenase (SDH) Sea foods, 304 Secretory IgA (sIgA), 593 594 Seed chemical mutagens, 472 Selective estrogen receptor modulator (SERM), 382 SEM. See Scanning electron microscopy (SEM) Sensory aspects, 597 598 SEP. See Socioeconomic pattern (SEP) Sepsis, 606 Sequencing 16 S rRNA, 579 580, 582 SERM. See Selective estrogen receptor modulator (SERM) Serotonin, 321 322 Serred Vert, 477 Serum HDL-c concentration, 281 282, 282t LDL-c concentration, 281 282, 282t nitrite, 174 175 VLDL-c Concentration, 281 282, 282t zinc, 160 SES. See Socioeconomic status (SES) Sesame oils, 279 280 Setaria italica. See Foxtail millet (Setaria italica) Severe acute malnutrition (SAM), 115 Sexual maturation, 123 SFA. See Saturated fatty acids (SFA) SFN. See Sulforaphane (SFN) SG. See Soya germ (SG) Shanghai Men’s Health Study (SMHS), 351 353 Shanghai Women’s Health Study (SWHS), 351 353 Shelterin, 696 697 Shiga-like Escherichia coli strains, 585 587 Short-chain fatty acids (SCFA), 416 417, 594 Short-chain oligosaccharides, 15 sICAM-1. See Soluble intercellular adhesion molecule-1 (sICAM-1) sIgA. See Secretory IgA (sIgA) Singh’s and Saboo’s functional food portfolio, 29, 30t

737

Single-nucleotide polymorphisms (SNPs), 682, 686 687 SNP276, 695 696 SNP94, 695 696 Sino-Tibetan systems, 499 Sir2, 702 Sirtuin-1 (SIRT-1), 516, 548 Sirups, 296 297 Skeletal maturation assessment, 116 Sleep, 90 91 circadian disruption, 526 529 deprivation, 530 effects on diet and lifestyle factors, 533 534 Small RNAs (sRNAs), 676 Small seeded grasses, 458 SMHS. See Shanghai Men’s Health Study (SMHS) Smoked foods, 195 Smoking, 654 655 SNPs. See Single-nucleotide polymorphisms (SNPs) SNS. See Sympathetic nervous system (SNS) Soaking time (ST), 465 Social class(es), 73 80, 92 93, 100 Sociodemographic factors, 124 129 family education influence on child’s cognition and academics, 127 maternal education, 127 128 relationship of SES with weight and BMI, 126 127 SES birth order, and gender bias, 128 129 classification, 125 socioeconomic stratification and height, 126 women empowerment impact on children, 128 Socioeconomic pattern (SEP), 115, 118 119 Socioeconomic status (SES), 58, 114, 124, 125t, 351 353 birth order, gender bias and, 128 129 classification, 125 relationship of SES with weight and BMI, 126 127 Socioeconomic stratification, 125 and height, 126 SOD. See Superoxide dismutase (SOD) Soda, 185 186 beverages, 195 soda/sugar sweetened beverages, 187 Sodium (Na), 674 675 Sofia Declaration, 46, 179 Soluble corn fiber (SCF), 594 Soluble intercellular adhesion molecule-1 (sICAM-1), 235 Sorbitol dehydrogenase (SDH), 506 Sorghum (Sorghum bicolor), 461 462 Sour sobya (SS), 596 South Asian Enigma, 111 South Asian paradox, 159 Southern Community Cohort Study (SCCS), 351 353

738

Index

Soy, 18, 379 380 animal and in vitro experiment, 382 385 bone, 385 breast, 382 384 prostate and angiogenesis, 385 epidemiology, 379 381 foods, 196, 379 health effects and safety, 379 metabolism and measurement, 381 382 products, 196 protein, 387 randomized clinical trial and metaanalysis, 385 387 safety, 388 390 supplement, 388 Soy isoflavone Haelan951, 201 Soy-based IFs, 388 Soya germ (SG), 382 384 SPD. See Spermidine (SPD) Spermidine (SPD), 382 384 Spice(s), 162 163, 499, 565 active principles, 502t analgesic/antiinflammatory/antioxidant properties, 504 506 antidiabetic and hypocholesterolemic properties, 506 507 antimicrobial properties, 503 504 crop, 471 in India, 501t medicinal properties, 500 507 Sports and energy drinks, 295 296 Spray drying, 375 SREBP. See Sterol regulatory element-binding protein (SREBP) SREBP-1c isoform, 700, 702 sRNAs. See small RNAs (sRNAs) SS. See Cultured fermented sour sobya (SS); Sour sobya (SS) SSA. See Sub-Saharan Africa (SSA) SSB. See Sugar-sweetened beverages (SSB) ST. See Soaking time (ST) Staphylococcus aureus, 504, 570, 626 S. aureus 6538P, 570 Star anise, 505 Starch, 594 Stargoose berry, 49 Starter culture, 397 Statistical methods, 99 100 CART analysis, 130 one-way ANOVA analysis with Tukey post hoc test, 129 Pearsons correlation test, 130 Stearic acid, 282 Stearyl-CoA desaturase, 233 234 Steptococcus cremoris, 395 397 Steroidal sapogenin, 475 Sterol regulatory element-binding protein (SREBP), 700 SREBP-1, 700 Stingless bees, 425

Stomach cancer. See Gastric cancer Streptococcus faecalis DC 74, 570 Streptococcus mutans, 373 Streptococcus thermophilus, 417 418, 585 C106 strain, 597 598 ME-553, 593 594 Stroke, 93, 287 288, 301, 317 318, 329 330, 329f, 332, 334 335 Mediterranean-style diets effects in, 178 179 Structural variation, 693 695 “Stunting”, 116 117, 126, 583 584 Sub-Saharan Africa (SSA), 63 Subcellular remodelling, 531 532 Sucker jelly, 454 Sudden cardiac death (SCD), 355 356 Sugar, 289 292, 296 297 intake, 291 products, 292 296 refined, 195 Sugar-sweetened beverages (SSB), 161, 189, 289 290 Suid herpesvirus type 1 (SuHV-1), 433 Sulawesi Selatan, 429 432 6-Sulfatoxymelatonin (aMT6s), 530 Sulforaphane (SFN), 550 Sulfur (S), 674 675 Sumatera Utara (Trigona minangkabau), 429 432 Sun exposure, 90 91 Sunrise sector, 37 Superoxide anions, 296 297 Superoxide dismutase (SOD), 273, 625 Supplements diet and, 266 267 of soy and IFs, 388 Suprachiasmatic nuclei (SCN), 515 516 Sustainable development goals (SDGs), 347 Sustainable food system, 25 26 Sweet trefoil, 477 SWHS. See Shanghai Women’s Health Study (SWHS) Sydney Diet Heart Study, 278 279 Symbiotic yogurt, 590 591 Sympathetic nervous system (SNS), 532 Synbiotics, 595 Systemic infections, 606 611, 607t, 611t Systolic BP (SBP), 328 329, 331, 333, 387

T Tag SNPs, 686 687 TALENs. See Transcription activator-like effector nucleases (TALENs) Taqman PCR method, 695 696 Target of rapamycin (TOR), 516 517, 548 TB. See Tuberculosis (TB)

Index

TBARS. See Thiobarbituric acid-reactive substances (TBARS) TC. See Total cholesterol (TC) TDI. See Tolerable daily intake (TDI) Tea, 20 Technical error measurements (TEM), 129 Telomerase, 696 Telomere, 696 697, 697f elongation, 696 Telomere repeat copy number to single gene copy number ratio (T/S ratio), 696 697 Telomeric sisters’ chromatid exchanges, 696 TEM. See Technical error measurements (TEM) Tenai. See Foxtail millet (Setaria italica) Terpenoid, 429 Tetragonula fuscobalteata, 426 Tetragonula laeviceps, 426 Tetrahydrobiopterin, 321 322 TFA. See Trans fatty acids (TFA) TFC. See Total flavonoid contents (TFC) TG. See Triglyceride (TG) t-Hcy. See Total homocysteine (t-Hcy) Theobroma cacao, 318 Thermization, 398 effect on quality, 406 process, 396 Thiobarbituric acid-reactive substances (TBARS), 175 Thrombo-phlebitis, 644 Thromboxane A2 (TXA2), 46, 226 228 Thymus vulgaris, 504 Time-resolved fluorescence immunoassays (TR-FIAs), 382 Time-restricted feeding, 519 Tirol sweet trefoil, 477 TMT-A. See Trail Making Test, part A (TMT-A) TNF. See Tumor necrosis factor (TNF) Tobacco. See also Smoking plants, 200 smoking, 194 Tolerable daily intake (TDI), 571 Tomatoes, 18 19 TOR. See Target of rapamycin (TOR) Total cholesterol (TC), 328 329, 569, 591 592 Total flavonoid contents (TFC), 465 Total functional foods for consumption, 10 11, 12t Total homocysteine (t-Hcy), 589 590 Total phenolic contents (TPC), 465 Toxic secondary metabolites, 605 TPC. See Total phenolic contents (TPC) TR-FIAs. See Time-resolved fluorescence immunoassays (TRFIAs) Trace elements, 551, 552t Traditional fermented foods rich in home source probiotic bacteria strains, 595 596 Traditional Korean diet, 47, 95 96

739

Traditional whole-grain-based diets, 63 Trail Making Test, part A (TMT-A), 264, 335 336 Trans fat(s), 39, 223 224 foods, 188 Trans fatty acids (TFA), 231, 273 Transcription activator-like effector nucleases (TALENs), 465 Transcriptome, 684 Transfection studies using primary hepatocytes, 703 704 Transgenerational epigenetic inheritance, 681 Transgenic αMUPA mice, 515 516 Transglutaminase, 405 Transposable elements, 665 666 Transthoracic Doppler echocardiography (TTDE), 333 Tree nuts, 348 350 Tricosane, 429 Triglyceride (TG), 332, 569 Trigona insica, 429 432 Trigona minangkabau. See Sumatera Utara (Trigona minangkabau) Trigona spp., 434 435 biological activities and chemical composition, 427 432 distribution and plant origin, 426 and potency for health and healing process, 425 propolis antiemetic effect of, 440 443 as antituberculosis, 438 440 as imunomodulatory agents, 432 438 toxicity of, 429 432, 432t Trigona thorasica, 429 432 Trigonella foenum-graecum, 476 Trigonella foenum-graecum L. See Fenugreek (Trigonella foenum-graecum L.) Trigonella L., 475 476 taxonomy, 475 477, 476t Trigonella monspeliaca, 476 Trigonelline, 475 “True” cinnamon, 565 Tryptophan, 546 T/S ratio. See Telomere repeat copy number to single gene copy number ratio (T/S ratio) Tsim Tsoum concept, 81 82 TTDE. See Transthoracic Doppler echocardiography (TTDE) Tuberculosis (TB), 438, 439t potential to accelerate nutritional status in TB patient, 438 440, 438t Tukey post hoc test, one-way ANOVA analysis with, 129 Tumor necrosis factor (TNF), 359, 550 TNF-α, 46, 174 175, 226, 435 437, 570, 690 Tumor suppressor genes, 529 p53, 628 Tumorigenesis, 529 Turmeric, 504 505 oil, 504

740

Index

Two-stage continuous fermenter, production of quarg cheese using, 399 TXA2. See Thromboxane A2 (TXA2) Type 2 diabetes, 10 11, 87, 93, 161, 167, 287, 306 307, 329 330 risk factors, 159 162 Type 2 diabetes mellitus (2DM). See Type 2 diabetes Tyrosine, 546 Tyrosine protein kinase, inhibition of, 382 Tyrosol, 623 624, 626

U UF Quarg, 401 UGT2B17 gene, 693 695 Ultrafiltration, 398 399 UN HLM. See United Nations High Level Meeting (UN HLM) Unani, 499 Undernutrition, 57, 63, 111, 114 115, 117. See also Malnutrition in children, 127 MAM, 115 PEM, 114 115 SAM, 115 Underweight, 117, 126 Unhealthy behaviors, 79 80 diets, 44 46 United Nations Decade of Action on Nutrition, 347 United Nations Food and Agriculture Organization data, 148 United Nations High Level Meeting (UN HLM), 169, 222 223 Upper-middle-income countries, 77 79, 127 Urbanization, 4, 27 29, 71 77, 87, 94 95, 525 Urinary excretion, 572 Urolithiasis, 239 Ursolic acid, 374 US Department of Agriculture and Human Service, 153 154 US Department of Agriculture and International College of Cardiology, 179 US Department of Health and Human Services, 281 US Preventive Service Task Force, 81 82

V Vaginal delivery (VD), 580 581 Vaginosis, 585 587 Value-added functional food products, 10 11 Valyl-prolyl-proline (VPP), 592 Vascular disease, 327 330 Vascular variability disorders (VVDs), 698 Vasodilation, 321 322 VD. See Vaginal delivery (VD)

Vegetable(s), 30, 162 163, 172 173, 304, 318 320 oils, 195, 698 699 processing, 38 production in EU, 32t sector, 33 34 Vegetarian diet, 196 Very low density lipoprotein (VLDL), 506 Vhagbhat Samhita, 499 Vibrio parahaemolyticus, 504 “Vicioid clade”, 475 476 Viral infections, 194 Virgin olive oil (VOO), 241, 627 Vision health and other diseases, 239 Vitamin(s), 95 96, 301 302, 449 450, 454, 457 458, 551, 552t vitamin B12, 72, 667 668 vitamin C, 49 vitamin D, 13 14 VLDL. See Very low density lipoprotein (VLDL) Vomiting receptor, 442 VOO. See Virgin olive oil (VOO) VPP. See Valyl-prolyl-proline (VPP) VVDs. See Vascular variability disorders (VVDs)

W WAIS-R. See Wechsler Adult Intelligence Scale—Revised (WAIS-R) Waist circumference (WC), 112 113, 121 menarche effect, 123 relationship of BP with, 121 Waist height ratio (WHtR), 112 113, 119 120 menarche effect, 123 Waist hip ratio (WHR), 112 113, 119 menarche effect, 123 Walnuts, 354, 357 358, 360t, 361t Wasting, 117 WAT. See White adipose tissue (WAT) WAZ. See Weight for age (WAZ) WB. See West Bengal (WB) WC. See Waist circumference (WC) Wechsler Adult Intelligence Scale—Revised (WAIS-R), 263 264 Weight, 117 for height, 117 index, 112 113 loss, 514 menarche effect, 122 123 relationship of SES with weight and BMI, 126 127 Weight for age (WAZ), 116 117 West Bengal (WB), 113 Western allopathic system, 500

Index

Western diet(s), 46, 80 81, 159 161, 175, 221, 304 306, 318, 449 450, 525, 529, 532, 534, 536, 582 583, 654 655 Western dietary patterns, 27, 98 99, 149 151, 306 Western style food effects on risk of NCDs colorectal cancer, 189 coronary heart disease, 188 189 diabetes mellitus type 2, 187 188 lung cancer, 190 osteoporosis, 185 187 Western-style diets, 356 Western-type diets, 94 95, 175. See also Paleolithic-style diet globalization of Western-type diets and health, 93 95 Western-type foods, 6, 90, 148 149, 171 172 Westfalia lactal process, 398 Westfalia thermoprocess, 398 Whey protein, 153 154 WHI trial. See Women’s Health Initiative trial (WHI trial) White adipose tissue (WAT), 551 552 White flour, 195 White rice, 188 WHO. See World Health Organization (WHO) Whole grains, 162 163, 176 177, 304, 379 380 Wholesale Price Index (WPI), 125 WHR. See Waist hip ratio (WHR) WHtR. See Waist height ratio (WHtR) Wild foods, 87 Wild type eggs and meat, 311 of poultry in evolutionary diet, 306 Wine, 20 Winter cherry. See Ashwagandha Women empowerment impact on children, 128 Women’s Health Initiative trial (WHI trial), 390 World Economic Forum, 63 65 World Health Assembly, 91 World Health Organization (WHO), 51 52, 61, 95 96, 171 172, 193, 261, 287, 295, 347, 397, 417, 591, 604, 653 654

741

agenda, 27 estimates, 158 159 World Heart Federation, 169 170 World nutritional dynamics and risk of diseases, 91 100, 92f globalization of prudent diets and protection from NCDs, 95 100 globalization of Western-type diets and health, 93 95 World Obesity Day, 289 World population and global food availability FAO agenda, 11 13 food and agricultural transition, 4 production and climate change, 8 9 security and functional food security, 4 6 functional food development by food manufacturing, 13 15 market, 15 16 natural functional foods, 16 21 total functional foods available for consumption, 10 11 total world population and total food availability, 6 8 Wound healing, 626 WPI. See Wholesale Price Index (WPI)

X Xenohormesis, 628

Y Yakult Honsha, 15 16 Yersinia enterocolitica O9, 570 Yogurt, 590 lactose absorption by postweaning rats from, 405 406 symbiotic, 590 591

Z Zinc (Zn), 427, 674 675 Zinc finger nuclease (ZFN), 465 Zingibercassumunar, 505