Non-alcoholic Beverages 9780128152706, 0128152702, 9780128157022

Table of contents :
Content: 1. Tea, the "Ambrosia" Beverage: Biochemical, Cellular, Molecular, and Clinical Evidences2. Essential Element Contents of Turkish Black Tea3. Functional Nonalcoholic Beverages: A Global Trend Toward a Healthy Life4. Hawk Tea, a Traditional and Healthy Natural Beverage in South China5. Development of Mixed Beverages Based on Tropical Fruits6. Tuba, a Fermented and Refreshing Beverage from Coconut Palm Sap7. Kefir-Type Drinks from Whey8. Physiochemical Characteristics, Nutritional Properties and Health Benefits of Sugarcane Juice9. Engineering and Biomedical Effect of Commercial Juices of Berries, Cherries, and Pomegranates with High Polyphenol Content10. Kombucha: A Promising Functional Beverage Prepared from Tea11. Engineered Soybean-Based Beverages and Their Impact on Human Health12. Potential Health Benefits of Fruit and Vegetable Beverage13. Kinetics of Phytochemicals Degradation During Thermal Processing of Fruit Beverages14. Toxicological Aspects of Ingredients Used in Nonalcoholic Beverages15. Functional and Traditional Nonalcoholic Beverages in Turkey

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NON-ALCOHOLIC BEVERAGES

NON-ALCOHOLIC BEVERAGES Volume 6: The Science of Beverages Edited by

ALEXANDRU MIHAI GRUMEZESCU ALINA MARIA HOLBAN

An imprint of Elsevier

Woodhead Publishing is an imprint of Elsevier The Officers’ Mess Business Centre, Royston Road, Duxford, CB22 4QH, United Kingdom 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States The Boulevard, Langford Lane, Kidlington, OX5 1GB, United Kingdom © 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. Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library ISBN 978-0-12-815270-6 (print) ISBN: 978-0-12-815702-2 (online) For information on all Woodhead publications visit our website at https://www.elsevier.com/books-and-journals

Publisher: Andre Gerhard Wolff Acquisition Editor: Patricia Osborn Editorial Project Manager: Jaclyn Truesdell Production Project Manager: Sojan P. Pazhayattil Cover Designer: Matthew Limbert Typeset by SPi Global, India

CONTRIBUTORS Munawar Abbas  Institute of Home and Food Sciences, Government College University Faisalabad, Faisalabad, Pakistan Cristóbal N. Aguilar  School of Chemistry, Autonomous University of Coahuila, Saltillo, México Semin Altuntas  Environmental Management and Auditing, Provincial Directorate of Environment and Urbanization, Samsun, Turkey José Miguel Arbonés-Mainar  Adipocyte and Fat Biology Laboratory (AdipoFat), Aragon Institute of Health Sciences (IACS), Hospital Universitario Miguel Servet, Zaragoza, Spain Sania Arif  Institute of Microbiology and Genetics, Georg-AugustUniversität, Göttingen, Germany J.A. Ascacio-Valdes  School of Chemistry, Autonomous University of Coahuila, Saltillo, México Ayse Dilek Atasoy  Department of Environmental Engineering, Harran University, Sanliurfa, Turkey Ahmet Ferit Atasoy  Department of Food Engineering, Harran University, Sanliurfa, Turkey Huma Bader-Ul-Ain  Institute of Home and Food Sciences, Government College University Faisalabad, Faisalabad, Pakistan Theeshan Bahorun  ANDI Centre of Excellence for Biomedical and Biomaterials Research, University of Mauritius, Réduit, Republic of Mauritius Aamina Batool  School of Chemical and Materials Engineering, National University of Sciences and Technology, Islamabad, Pakistan Semantee Bhattacharya  School of Chemical Sciences, Indian Association for the Cultivation of Science, Jadavpur, Kolkata, India Debanjana Bhattacharya  School of Nutrition and Food Sciences, Louisiana State University, Baton Rouge, LA, United States Christian Carpéné  Institute of Metabolic and Cardiovascular Diseases, National Institute of Health and Medical Research (I2MC, INSERM U1048), Toulouse; Université Paul Sabatier, Toulouse Cedex 4, France Guillermo Cásedas  Department of Pharmacy, Faculty of Health Sciences, Universidad San Jorge, Zaragoza, Spain Somnath Chakravorty  Department of Biochemistry and Molecular Biophysics, Kansas State University, Manhattan, KS, United States

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xiv  Contributors

Ömer Utku Çopur  Faculty of Agriculture, Department of Food Engineering, Uludag University, Bursa, Turkey Eduardo M. Costa  Universidade Católica Portuguesa, CBQF – Centro de Biotecnologia e Química Fina – Laboratório Associado, Escola Superior de Biotecnologia, Rua Arquiteto Lobão Vital, Porto, Portugal Larissa Morais Ribeiro da Silva  Department of Food Engineering, Federal University of Ceara, Fortaleza, Brazil Raimundo Wilane de Figueiredo  Department of Food Engineering, Federal University of Ceara, Fortaleza, Brazil Paulo Henrique Machado de Sousa  Department of Food Engineering, Federal University of Ceara, Fortaleza, Brazil Giovana Matias do Prado  Department of Food Engineering, Federal University of Ceara, Fortaleza, Brazil Shameem Fawdar  ANDI Centre of Excellence for Biomedical and Biomaterials Research, University of Mauritius, Réduit, Republic of Mauritius A.C. Flores-Gallegos  School of Chemistry, Autonomous University of Coahuila, Saltillo, México Ana Valquiria Vasconcelos Fonseca  Department of Food Engineering, Federal University of Ceara, Fortaleza, Brazil Ratan Gachhui  Department of Life Science and Biotechnology, Jadavpur University, Kolkata, India Hale Hapoglu  Faculty of Engineering, Chemical Engineering Department, Ankara University, Ankara, Turkey Xuejing Jia  College of Life Sciences, Sichuan Agricultural University, Ya’an; College of Food Science and Technology, Guangdong Ocean University, Zhanjiang, China Sana Khalid  Department of Pharmaceutical Sciences, Government College University Faisalabad, Faisalabad, Pakistan Nauman Khalid  School of Food and Agricultural Sciences, University of Management and Technology, Lahore, Pakistan Rao Sanaullah Khan  School of Food and Agricultural Sciences, University of Management and Technology, Lahore, Pakistan; Institute for Community (Health) Development, Universiti Sultan Zainal Abidin, Terengganu, Malaysia Balakrishnan Kunasundari  Faculty of Engineering Technology, Universiti Malaysia Perlis (UniMAP), Perlis, Malaysia Francisco Les  Department of Pharmacy, Faculty of Health Sciences, Universidad San Jorge, Zaragoza, Spain Víctor López  Department of Pharmacy, Faculty of Health Sciences, Universidad San Jorge, Zaragoza, Spain

Contributors  xv

L.L. López-López  School of Chemistry, Autonomous University of Coahuila, Saltillo, México Huey Shi Lye  Faculty of Science, Department of Agricultural and Food Science, Universiti Tunku Abdul Rahman, Jalan Universiti, Kampar, Malaysia Geraldo Arraes Maia  Department of Food Engineering, Federal University of Ceara, Fortaleza, Brazil Norliza Binti Shah Jehan Muttiah  Faculty of Science, Department of Biological Science, Universiti Tunku Abdul Rahman, Jalan Universiti, Kampar, Malaysia Sandrasekaran Naresh  Faculty of Engineering Technology, Universiti Malaysia Perlis (UniMAP), Perlis, Malaysia Darshini Narrain  ANDI Centre of Excellence for Biomedical and Biomaterials Research, University of Mauritius, Réduit, Republic of Mauritius Wahab Nazir  School of Food and Agricultural Sciences, University of Management and Technology, Lahore, Pakistan Mei Kying Ong  Faculty of Science, Department of Agricultural and Food Science, Universiti Tunku Abdul Rahman, Jalan Universiti, Kampar, Malaysia Gülşah Özcan-Sinir  Faculty of Agriculture, Department of Food Engineering, Uludag University, Bursa, Turkey Manuela Pintado  Universidade Católica Portuguesa, CBQF – Centro de Biotecnologia e Química Fina – Laboratório Associado, Escola Superior de Biotecnologia, Rua Arquiteto Lobão Vital, Porto, Portugal Piteesha Ramlagan  ANDI Centre of Excellence for Biomedical and Biomaterials Research; Department of Health Sciences, University of Mauritius, Réduit, Republic of Mauritius Gabriela Râpeanu  Faculty of Food Science and Engineering, Dunarea de Jos University of Galaţi, Galati, Romania R. Rodriguez-Herrera  School of Chemistry, Autonomous University of Coahuila, Saltillo, México Farhan Saeed  Institute of Home and Food Sciences, Government College University Faisalabad, Faisalabad, Pakistan A. Sainz-Galindo  School of Chemistry, Autonomous University of Coahuila, Saltillo, México Soumyadev Sarkar  Department of Life Science and Biotechnology, Jadavpur University, Kolkata, India Sara Silva  Universidade Católica Portuguesa, CBQF – Centro de Biotecnologia e Química Fina – Laboratório Associado, Escola Superior de Biotecnologia, Rua Arquiteto Lobão Vital, Porto, Portugal

xvi  Contributors

Nicoleta Stănciuc  Faculty of Food Science and Engineering, Dunarea de Jos University of Galaţi, Galati, Romania Hafiz Ansar Rasul Suleria  UQ Diamantina Institute, Translational Research Institute, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia; Department of Food, Nutrition, Dietetics and Health, Kansas State University, Manhattan, KS, United States Senem Suna  Faculty of Agriculture, Department of Food Engineering, Uludag University, Bursa, Turkey Canan Ece Tamer  Faculty of Agriculture, Department of Food Engineering, Uludag University, Bursa, Turkey Kokila Thiagarajah  Faculty of Science, Department of Biomedical Science, Universiti Tunku Abdul Rahman, Jalan Universiti, Kampar, Malaysia Florence Umuhoza  Institute of Metabolic and Cardiovascular Diseases, National Institute of Health and Medical Research (I2MC, INSERM U1048), Toulouse, France O.F. Vázquez-Vuelvas  Autonomous University of Coahuila, Colima, México Mariana Veiga  Universidade Católica Portuguesa, CBQF – Centro de Biotecnologia e Química Fina – Laboratório Associado, Escola Superior de Biotecnologia, Rua Arquiteto Lobão Vital, Porto, Portugal Glenise Voss  Universidade Católica Portuguesa, CBQF – Centro de Biotecnologia e Química Fina – Laboratório Associado, Escola Superior de Biotecnologia, Rua Arquiteto Lobão Vital, Porto, Portugal Mehmet Irfan Yesilnacar  Department of Environmental Engineering, Harran University, Sanliurfa, Turkey Perihan Yolci Ömeroğlu  Faculty of Agriculture, Department of Food Engineering, Uludag University, Bursa, Turkey Ming Yuan  College of Life Sciences, Sichuan Agricultural University, Ya’an, China

SERIES PREFACE Food and beverage industry accounts among the most developed sectors, being constantly changing. Even though a basic beverage industry could be found in every area of the globe, particular aspects in beverage production, processing, and consumption are identified in some geographic zones. An impressive progress has recently been observed in both traditional and modern beverage industries and these advances are leading beverages to a new era. Along with the cutting-edge technologies, developed to bring innovation and improve beverage industry, some other human-related changes also have a great impact on the development of such products. Emerging diseases with a high prevalence in the present, as well as a completely different lifestyle of the population in recent years have led to particular needs and preferences in terms of food and beverages. Advances in the production and processing of beverages have allowed for the development of personalized products to serve for a better health of overall population or for a particular class of individuals. Also, recent advances in the management of beverages offer the possibility to decrease any side effects associated with such an important industry, such as decreased pollution rates and improved recycling of all materials involved in beverage design and processing, while providing better quality products. Beverages engineering has emerged in such way that we are now able to obtain specifically designed content beverages, such as nutritive products for children, decreased sugar content juices, energy drinks, and beverages with additionally added health-promoting factors. However, with the immense development of beverage processing technologies and because of their wide versatility, numerous products with questionable quality and unknown health impact have been also produced. Such products, despite their damaging health effect, gained a great success in particular population groups (i.e., children) because of some attractive properties, such as taste, smell, and color. Nonetheless, engineering offered the possibility to obtain not only the innovative beverages but also packaging materials and contamination sensors useful in food and beverages quality and security sectors. Smart materials able to detect contamination or temperature differences which could impact food quality and even pose a hazardous situation for the consumer were recently developed and some are already utilized in packaging and food preservation.

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This 20-volume series has emerged from the need to reveal the current situation in beverage industry and to highlight the progress of the last years, bringing together most recent technological innovations while discussing present and future trends. The series aims to increase awareness of the great variety of new tools developed for traditional and modern beverage products and also to discuss their potential health effects. All volumes are clearly illustrated and contain chapters contributed by highly reputed authors, working in the field of beverage science, engineering, or biotechnology. Manuscripts are designed to provide necessary basic information in order to understand specific processes and novel technologies presented within the thematic volumes. Volume 1, entitled Production and management of beverages, offers a recent perspective regarding the production of main types of alcoholic and nonalcoholic beverages. Current management approaches in traditional and industrial beverages are also dissected within this volume. In Volume 2, Processing and sustainability of beverages, novel information regarding the processing technologies and perspectives for a sustainable beverage industry are given. Third volume, entitled Engineering tools in beverage industry dissects the newest advances made in beverage engineering, highlighting cutting-edge tools and recently developed processes to obtain modern and improved beverages. Volume 4 presents updated information regarding Bottled and packaged waters. In this volume are discussed some wide interest problems, such as drinking water processing and security, contaminants, pollution and quality control of bottled waters, and advances made to obtain innovative water packaging. Volume 5, Fermented beverages, deals with the description of traditional and recent technologies utilized in the industry of fermented beverages, highlighting the high impact of such products on consumer health. Because of their great beneficial effects, fermented products still represent an important industrial and research domain. Volume 6 discusses recent progress in the industry of Nonalcoholic beverages. Teas and functional nonalcoholic beverages, as well as their impact on current beverage industry and traditional medicine are discussed. In Volume 7, entitled Alcoholic beverages, recent tools and technologies in the manufacturing of alcoholic drinks are presented. Updated information is given about traditional and industrial spirits production and examples of current technologies in wine and beer industry are dissected. Volume 8 deals with recent progress made in the field of Caffeinated and cocoa-based beverages. This volume presents the great variety of

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such popular products and offers new information regarding recent technologies, safety, and quality aspects as well as their impact on health. Also, recent data regarding the molecular technologies and genetic aspects in coffee useful for the development of high-quality raw materials could be found here. In Volume 9, entitled Milk-based beverages, current status, developments, and consumers trends in milk-related products are discussed. Milk-based products represent an important industry and tools are constantly been developed to fit the versatile preferences of consumers and also nutritional and medical needs. Volume 10, Sports and energy drinks, deals with the recent advances and health impact of sports and energy beverages, which became a flourishing industry in the recent years. In Volume 11, main novelties in the field of Functional and medicinal beverages, as well as perspective of their use for future personalized medicine are given. Volume 12 gives an updated overview regarding Nutrients in beverages. Types, production, intake, and health impact of nutrients in various beverage formulations are dissected through this volume. In Volume 13, advances in the field of Natural beverages are provided, along with their great variety, impact on consumer health, and current and future beverage industry developments. Volume 14, Value-added Ingredients and enrichments of beverages, talks about a relatively recently developed field which is currently widely investigated, namely the food and beverage enrichments. Novel technologies of extraction and production of enrichments, their variety, as well as their impact on product quality and consumers effects are dissected here. Volume 15, Preservatives and preservation approaches in beverages, offers a wide perspective regarding conventional and innovative preservation methods in beverages, as well as main preservatives developed in recent years. In Volume 16, Trends in beverage packaging, the most recent advances in the design of beverage packaging and novel materials designed to promote the content quality and freshness are presented. Volume 17 is entitled Quality control in the beverage industry. In this volume are discussed the newest tools and approaches in quality monitoring and product development in order to obtain advanced beverages. Volume 18, Safety issues in beverage production, presents general aspects in safety control of beverages. Here, the readers can find not only the updated information regarding contaminants and risk factors in beverage production, but also novel tools for accurate detection and control.

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Volume 19, Biotechnological progress and beverage consumption, reveals novel tools used for advanced biotechnology in beverage industry production. Finally, Volume 20 entitled Nanoengineering in the beverage industry take the readers into the nanotechnology world, while highlighting important progress made in the field of nanosized materials science aiming to obtain tools for a future beverage industry. This 20-volume series is intended especially for researchers in the field of food and beverages, and also biotechnologists, industrial representatives interested in innovation, academic staff and students in food science, engineering, biology, and chemistry-related fields, pharmacology and medicine, and is a useful and updated resource for any reader interested to find the basics and recent innovations in the most investigated fields in beverage engineering.

Alexandru Mihai Grumezescu Alina Maria Holban

PREFACE The industry of nonalcoholic beverages is rapidly developing products to fulfill the requirements of the increasing and highly dynamic population. Tea and fruit-based drinks are gaining increased attention since they bring numerous health benefits surpassing the properties of commercial refreshments, which contain increased amounts of sugar, dyes, and numerous additives. This book has emerged from the need to discuss the recent trends in the development of nonalcoholic beverages, focusing on new advances in the research, biotechnology, and industry of tea and fruit-based drinks. This volume contains 15 chapters prepared by outstanding authors from Mauritius, Germany, Turkey, China, the United States, Pakistan, France, Brazil, México, Malaysia, Portugal, and Romania. The selected manuscripts are clearly illustrated and contain accessible information for a wide audience, especially food and beverage scientists, engineers, biotechnologists, biochemists, industrial companies, students, and also any reader interested in learning about the most interesting and recent advances in the field of beverage science. Chapter 1, entitled Tea, the “ambrosia” beverage: biochemical, cellular, molecular, and clinical evidences, prepared by Piteesha Ramlagan et  al., discuss the properties of tea (Camellia sinensis), which is the most commonly consumed beverage in the world with a steadily increasing production load every year. While it is an integral part of many people’s routine diet, it is also highly valued as a functional food due to its potential to mitigate chronic human diseases. This chapter comprehensively reviews the recent findings on the bioactivity of specific tea components in different diseased conditions. Particular emphasis is laid on its prophylactic effects at biochemical, cellular, molecular, and clinical levels accompanied by a description of the molecular mechanisms underlying the claimed health benefits. Chapter 2, Essential element contents of Turkish black tea, prepared by Ayse Dilek Atasoy et  al., aims to determine the essential element contents and metal concentrations in Turkish black tea infusions and to compare the composition of Turkish tea and others. Some metals found in tea are components of important enzymes or participants in a number of physiological processes, so they are considered essential for the proper functioning of the human body. Chapter  3, Functional nonalcoholic beverages: a global trend toward the healthy life, by Huma Bader-Ul-Ain et al., reports on the scientific advances in the emerging area of functional beverages with a

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focus on commercially available products, as well as on the potential health benefits related to their consumption. At present, beverages are by far the most active functional food category because of convenience and possibility to meet consumer demands for container contents, size, shape, and appearance, as well as ease of distribution and storage for refrigerated and shelf-stable products. Chapter  4, Hawk tea, a traditional and healthy natural beverage in South China, by Xuejing Jia et al., introduces the present resource situation, traditional and current process technology, phytochemical and pharmacological activities of Hawk tea, and hope to lay a scientific basis for developing and utilizing this local beverage. Hawk tea is a medicinal herbal and caffeine-free drink, and it is one of the most popular beverages in South China, attracting about 30 million consumers. Hawk tea has multiple bioactive components, such as free amino acids, vitamins, microelements, polysaccharides, polyphenols, and essential oils, especially flavonoids. Chapter 5, Development of mixed beverages based on tropical fruits, by Geraldo Arraes Maia et al., reviews the current progress made for the development of mixed fruits beverages, focusing on the importance of those products for the countries that process tropical fruits. The use of these fruits for developing a mixed beverage is essential, because they may have a high nutritional value increasing the composition of the final products and compensating the nutrients and flavor in the mixtures. Chapter 6, Tuba a fermented and refreshing beverage from coconut palm sap, by A.C. Flores-Gallegos et al., presents the tuba, a Mexican traditional Pacific Coast beverage, which is made from fermented sap that is extracted from the inflorescence of the coconut palm. The obtaining process of tuba involves four stages: preparation of the plant, cutting to start sap flow, collection, and fermentation. In this chapter, the obtaining process of tuba, its physical and chemical composition, its microbial content, and potential functional properties of this beverage are reviewed. Chapter  7, Kefir-type drinks from whey, by Semin Altuntas et  al., discusses the properties and benefits of whey-based kefir-type beverages, emphasizing on the nutrients in whey composition. Chapter  8, Physiochemical characteristics, nutritional properties, and health benefits of sugarcane juice, by Sania Arif et al., focuses on explaining the physiochemical properties, nutritional values, and health benefits of the sugarcane juice. Sugarcane juice is relished as a refreshing drink as it is nutritious and rich in vitamins, carbohydrates, and amino acids. The potent biological activities have rendered this juice a promising therapeutic agent for future studies. Chapter 9, Engineering and biomedical effect of commercial juices of berries, cherries, and pomegranates with high polyphenol content, by Christian Carpéné et  al., compares the polyphenol content of

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­cranberry (Vaccinium macrocarpon), blueberry (Vaccinium myrtillus), sour cherry (Punica granatum), and pomegranate (Punica granatum) juices, which are all currently emerging as functional beverages. It seems all these juices are not a source of resveratrol, the most known polyphenol found in red wines, but the phenolic compounds they contain are much more than mere antioxidant agents. Indeed, the major phenolic compounds of these juices, namely punicalagins, ellagic acid, phenolic acids, and kuromanine are protective for their plant of origin being endowed with superoxide radical scavenging activity and exhibiting bacteriostatic properties. Once ingested, these polyphenols interact with the activity of various enzymes in human tissues and with the intestinal microbiota. This chapter indicates that the polyphenols found in juices of berries, cherries or pomegranates should have beneficial effects on consumers not only in terms of antioxidant potential but also as a consequence of modulation of amine degradation and lipid handling potentially acting on the mood and on the adiposity of the consumers. Chapter 10, Kombucha: a promising functional beverage prepared from tea, by Somnath Chakravorty et  al., presents the properties of Kombucha tea, a refreshing beverage, obtained by fermenting sugared black tea, made from Camellia sinensis (L.) Kuntze leaves, with a consortium of yeast and predominantly acetic acid bacteria. In recent times, Kombucha tea has seen considerable increase in interest worldwide and can easily be said to be an emerging popular beverage. Of the various health benefits of Kombucha tea, its antimicrobial, antioxidant, antidiabetic, and anticancer benefits are most attractive and appealing to ever-increasing cohort of scientific investigators and entrepreneurs. The last decade saw noteworthy progress toward understanding the beneficial properties of this fermented tea. Chapter 11, Engineered soybean-based beverages and their impact on human health, by Sandrasekaran Naresh et al., deals with types of soybeans, nutritional profile, and soybean-based functional beverages with the addition of probiotics and fortification with selected ingredients. Evidences from the past studies associated with health benefits and safety assessment of soybean are also discussed. Chapter  12, Potential health benefits of fruit and vegetable beverages, by Mariana Veiga et al., aims to provide a comprehensive evaluation of the possibilities of fruit and vegetable beverages as well as characterize the main constituents responsible for the health benefits attributed to them. Fruits and vegetables are one of the pillars of a healthy diet. However, individuals frequently disregard their importance for the maintenance of health and the homeostatic balance and have considerably lower ingestions of these products than recommended by regulatory bodies. The preparation and/or commercialization of fruit and vegetable beverages (with balanced nutrient and

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phytonutrient profiles) may be an interesting alternative to the direct consumption of fruits and vegetables as it provides an easy and on the go solution for this problem. Chapter 13, Kinetics of phytochemicals degradation during thermal processing of fruits beverages, by Nicoleta Stănciuc et al., focuses on the authors’ own results regarding the thermal degradation mechanisms of some biologically active compounds from a wide range of economically important fruits such as plums, sweet and sour cherries, blackthorn, sea buckthorn, and elderberry. The discussion also includes an overview of the most important data from the literature concerning the thermal degradation mechanisms of phytochemicals from other fruits. The kinetic parameters are discussed in terms of selecting optimal conditions for processing of fruit beverages in food industry in order to preserve the functionality of the final products. Chapter 14, Toxicological aspects of ingredients used in nonalcoholic beverages, by Canan Ece Tamer et al., details the presence and formation of antinutrient and toxic compounds in nonalcoholic beverages such as coffee, tea, herbal teas, fruit juices, carbonated beverages, and their potential health risks. Antinutrients are defined as natural or synthetic components which can block the absorption of health beneficial and essential organic nutrients and inorganic minerals. They have an ability to bind to nutrients to keep their retention, respond with them to form indigestible compounds or inhibit digestive proteins. Chapter 15, Functional and traditional nonalcoholic beverages in Turkey, by Canan Ece Tamer et al., highlights composition of Turkish traditional beverages and their preparation methods. Moreover, recent research findings on their functional properties are discussed. The main ingredients of those traditional beverages are well known to be rich sources of antioxidant components that may provide protection against oxidative damage and thereby reducing the risk of several degenerative diseases, lowering total and LDL cholesterol levels, improving intestinal flora, and having antimicrobial activity. Therefore, those traditional beverages could certainly be considered as a promising functional drink which could regain their popularity among health-conscious consumers. Recent researches are supporting their nutraceutical and therapeutic effects as well. Alexandru M. Grumezescu University Politehnica of Bucharest, Bucharest, Romania Alina M. Holban Faculty of Biology, University of Bucharest, Bucharest, Romania

TEA, THE “AMBROSIA” BEVERAGE: BIOCHEMICAL, CELLULAR, MOLECULAR, AND CLINICAL EVIDENCES

1

Piteesha Ramlagan⁎,†, Darshini Narrain⁎, Shameem Fawdar⁎, Theeshan Bahorun⁎ *

ANDI Centre of Excellence for Biomedical and Biomaterials Research, University of Mauritius, Réduit, Republic of Mauritius †Department of Health Sciences, University of Mauritius, Réduit, Republic of Mauritius

1.1 Introduction Besides water, tea is the most commonly consumed beverage in the world (Carloni et al., 2013). It is appreciated for its aroma, taste, and cultural practices but more importantly for its health benefits (Kosińska and Andlauer, 2014). The different varieties of tea originate from the Camellia sinensis plant (Fig. 1.1) but are processed differently to produce six main varieties, namely black, green, white, yellow, oolong, and pu-erh (Kosińska and Andlauer, 2014). These teas are different in taste, appearance, and chemical composition (Chan et al., 2011). With a steadily increasing production load every year (5.3 billion kg for the year 2015) (Food and Agriculture Organization of the United Nations, 2015), about 78% of the world tea production accounts for black tea, 20% for green tea, and 2% for the other types of teas. Black tea is consumed worldwide while green, white, oolong, and pu-erh teas are consumed mainly in Asia although these are also becoming increasingly popular in Europe and North America over time (Kosińska and Andlauer, 2014). The surge in tea consumption, especially green tea, is attributed to numerous studies demonstrating their physiological benefits to human health. The prophylactic effects of tea consumption are mainly due to the presence of its secondary metabolites, mainly polyphenols (Da Salva Pinto, 2013). This chapter will comprehensively review the recent findings on the bioactivity of specific tea components

Non-alcoholic Beverages. https://doi.org/10.1016/B978-0-12-815270-6.00001-3 © 2019 Elsevier Inc. All rights reserved.

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2  Chapter 1 

Tea, the “Ambrosia” Beverage: Biochemical, Cellular, Molecular, and Clinical Evidences

Fig. 1.1  Tea plantation and fresh tea leaves.

under different diseased conditions. Particular emphasis will be laid on their prophylactic effects at biochemical, cellular, molecular, and clinical levels, accompanied by a description of the molecular mechanisms underlying the claimed health benefits.

1.2  Bioactive Components of Tea Polyphenols are aromatic ring-containing compounds, with at least one hydroxyl (OH) group. The structure of polyphenols varies greatly, from simple phenolic acid molecules to polymerized condensed tannin compounds. The major classes of polyphenols found in teas are phenolic acids and flavonoids. Phenolic acids consist of a single aromatic ring and are divided into hydroxybenzoic and hydroxycinnamic acids (Fig.  1.2) (Manach et al., 2004; Pandey and Rizvi, 2009). Phenolic acids and related compounds such as gallic acid, chlorogenic acid, p-coumaric acid, galloylquinic acid, caffeoylquinic acid, p-coumaroylquinic acid, galloyl glucose, and gallic acid methyl ester have been detected in teas (Table 1.1) (Lin et al., 2008; Zhao et al., 2011). Flavonoids are the most studied group of polyphenols and are the most abundant class of compounds in teas Hydroxybenzoic acid

Hydroxycinnamic acid R1

R1 O R2

R2

O

OH R3 R1 = R2 = R3 = OH : Gallic acid

OH R1 = H, R2 = OH : p-Coumaric acid

Fig. 1.2  Chemical structure of phenolic acids.

CHCHCOOH group

Table 1.1  Common Compounds Present in Teas Chemical Class

Compound Name

Tea Type

References

Hydroxybenzoic acid Hydroxycinnamic acids

Gallic acid Caffeic acid Chlorogenic acid p-Coumaric acid Theogallin 4-Galloylquinic acid 5-Galloylquinic acid Galloylglucose 1,6-Digalloylglucose 1,2,6-Trigalloylglucose Gallic acid methyl ester 3-p-Coumaroylquinic acid 4-p-Coumaroylquinic acid 5-p-Coumaroylquinic acid 3-Caffeoylquinic acid 4-Caffeoylquinic acid 5-Caffeoylquinic acid 3,5-Dicaffeoylquinic acid Caffeoylmalic acid Gallocatechin (+)-Catechin (−)-Epicatechin (−)-Epigallocatechin (−)-Epiafzelechin (−)-Methylepigallocatechin gallate

WT, YT, GT, OT, BT, PT WT, GT, BT, PT WT, YT, GT, BT, PT WT, GT, BT, PT WT, GT, OT, PT WT WT, YT, GT, OT, BT, PT WT, GT, PT WT, GT, BT, PT WT, GT, PT WT, GT, PT WT WT, OT, BT GT WT, GT, BT, PT WT, GT, PT WT, GT, PT GT WT, GT, PT WT, YT, GT, OT, BT, PT WT, YT, GT, OT, BT, PT WT, YT, GT, OT, BT, PT WT, YT, GT, OT, BT, PT GT WT, GT, OT, PT

Zhang et al. (2011) Zhang et al. (2011) and Zhao et al. (2011) Zhang et al. (2011) Zhao et al. (2011) Lin et al. (2008), Wang et al. (2010), and Zhao et al. (2011) Lin et al. (2008) Lin et al. (2008) and Zhang et al. (2011) Lin et al. (2008) and Zhao et al. (2011) Lin et al. (2008) and Zhao et al. (2011) Lin et al. (2008) and Zhao et al. (2011) Lin et al. (2008) and Zhao et al. (2011) Lin et al. (2008) Lin et al. (2008) Lin et al. (2008) Lin et al. (2008) and Zhao et al. (2011) Lin et al. (2008) and Zhao et al. (2011) Lin et al. (2008) and Zhao et al. (2011) Lin et al. (2008) Zhao et al. (2011) Lin et al. (2008) and Zhang et al. (2011) Zhang et al. (2011) Zhang et al. (2011) Zhang et al. (2011) Lin et al. (2008) Lin et al. (2008) and Zhao et al. (2011)

Phenolic acid relatives

Flavan-3-ols

Continued

Table 1.1  Common Compounds Present in Teas—cont’d Chemical Class

Compound Name

Tea Type

References

Galloylated flavan-3-ols

(+)-Catechin gallate Gallocatechin gallate (−)-Epicatechin gallate (−)-Epigallocatechin gallate (−)-Epiafzelechin gallate Epicatechin 3-O-benzoate Catechin-4α-epicatechin 3-O-gallate (−)-Epigallocatechin 3-O-(3″-Omethyl) gallate (−)-Methoxyepiafzelechin gallate (−)-Epicatechin-3-O-(4-O-methyl)gallate (−)-Epicatechin-3-O-phydroxybenzoate (−)-Epicatechin-3-O-cinnamate Theasinensin A Theasinensin B Theasinensin C Theasinensin D Theasinensin E Theasinensin F Theasinensin G Theaflavin Theaflavin-3-gallate Theaflavin-3′-gallate Theaflavin-3,3′-digallate Theaflavin-3,5,3′-trigallate Theaflavin-3,3′,5-trigallate Theaflavin-3,5,3′,5-tetragallate Theaflavate A Theaflavate B Thearubigin Theabrownin

GT, OT WT, YT, GT, OT, BT, PT WT, YT, GT, OT, BT, PT WT, YT, GT, OT, BT, PT WT, GT, OT, PT WT, GT, PT WT, GT, PT WT, GT, PT

Lin et al. (2008) Zhang et al. (2011) Zhang et al. (2011) Zhang et al. (2011) Lin et al. (2008) and Zhang et al. (2012) Zhao et al. (2011) Zhao et al. (2011) Zhao et al. (2011)

OT OT

Lin et al. (2008)

Flavan-3-ol derivatives

Flavan-3-ols oxidized products

OT OT OT, BT OT, BT OT, BT OT, BT OT, BT OT OT BT, OT, PT OT, BT BT WT, BT BT BT BT OT, BT OT BT, PT OT, BT, PT

Hashimoto et al. (1988) and Tanaka et al. (2003) Hashimoto et al. (1988) and Tanaka et al. (2003) Hashimoto et al. (1988) and Tanaka et al. (2003) Hashimoto et al. (1988) and Tanaka et al. (2003) Hashimoto et al. (1988) and Tanaka et al. (2003) Hashimoto et al. (1988) Hashimoto et al. (1988) Lin et al. (2008) and Wang et al. (2010) Lin et al. (2008) Chen et al. (2012) Lin et al. (2008) and Chen et al. (2012) Chen et al. (2012) Chen et al. (2012) Chen et al. (2012) Lin et al. (2008) Lin et al. (2008) Menet et al. (2004) and Wang et al. (2010) Wang et al. (2010)

Flavonols

Glycosylated flavonols

Kaempferol

WT, GT, OT, BT, PT

Quercetin Myricetin Myricetin rhamnodiglucoside Myricetin rhamnosylglucoside Myricetin rutinoside Myricetin galactoside Myricetin galactosylrutinoside Myricetin glucoside Quercetin glucorhamnoglucoside Quercetin rhamnodiglucoside Quercetin dirhamnoglucoside Quercetin rhamnoside Quercetin rhamnogalactoside Quercetin rhamnoglucoside Quercetin rutinoside (rutin) Quercetin galactoside Quercetin galactosylrutinoside Quercetin glucoside Quercetin glucosylrutinoside Kaempferol rhamnosylgalactoside Kaempferol dirhamnogalactoside Kaempferol glucorhamnoglucoside Kaempferol rhamnodiglucoside Kaempferol galactoside Kaempferol galactosylrutinoside Kaempferol dirhamnoglucoside Kaempferol rhamnosylrutinoside Kaempferol rutinoside Kaempferol glucoside Kaempferol glucosylrutinoside Kaempferol xylosylrutinoside

WT, GT, OT, BT, PT WT, GT, OT, BT, PT GT, OT OT, BT GT, OT, BT WT, YT, GT, OT, BT, PT GT WT, OT, BT GT, OT, BT GT, OT, BT WT, GT, OT, BT, PT WT, YT, GT, OT, BT, PT WT, GT, OT, BT, PT WT, YT, GT, OT, BT, PT WT, GT, OT, BT, PT WT, GT, OT, BT WT, GT, OT WT, YT, GT, OT, BT, PT WT, GT, OT, BT, PT OT, BT WT, GT, OT, BT, PT GT, OT GT, OT, BT WT, GT, OT, BT, PT WT, GT, OT WT, YT, GT, OT, BT, PT WT, GT, PT WT, GT, OT, BT, PT WT, YT, GT, OT, BT, PT WT, GT, OT, BT, PT OT

Lin et al. (2008), Zhao et al. (2011), Zhang et al. (2012), and Jiang et al. (2015) Zhao et al. (2011), Zhang et al. (2012), and Jiang et al. (2015) Peterson et al. (2005) and Jiang et al. (2015) Jiang et al. (2015) Lin et al. (2008) Jiang et al. (2015) Lin et al. (2008), Zhang et al. (2011), and Jiang et al. (2015) Lin et al. (2008) Lin et al. (2008) and Jiang et al. (2015) Jiang et al. (2015) Jiang et al. (2015) Zhao et al. (2011) and Jiang et al. (2015) Lin et al. (2008) and Zhang et al. (2011) Jiang et al. (2015) and Zhao et al. (2011) Zhang et al. (2011) Lin et al. (2008), Zhao et al. (2011). and Jiang et al. (2015) Lin et al. (2008) and Jiang et al. (2015) Lin et al. (2008) Zhang et al. (2011) and Jiang et al. (2015) Lin et al. (2008) and Zhao et al. (2011) Lin et al. (2008) Zhang et al. (2011) and Jiang et al. (2015) Jiang et al. (2015) Jiang et al. (2015) Lin et al. (2008), Zhao et al. (2011), and Jiang et al. (2015) Lin et al. (2008) Zhang et al. (2011) and Jiang et al. (2015) Zhao et al. (2011) Lin et al. (2008), Zhao et al. (2011), and Jiang et al. (2015) Zhang et al. (2011) and Jiang et al. (2015) Lin et al. (2008) and Zhao et al. (2011) Lin et al. (2008) Continued

Table 1.1  Common Compounds Present in Teas—cont’d Chemical Class

Compound Name

Tea Type

References

Acylated glycosylated flavonols

Quercetin 3-O-acylglycoside Quercetin 3-O-p-coumaroylgluco­ sylrhamnosylglactoside Quercetin 3-O-p-coumaroylglucosylrutinoside Kaempferol 3-O-acylglycoside Kaempferol 3-O-acetyl-dirhamnosylhexoside Kaempferol 3-O-pcoumaroyldirhamnosylhexoside Kaempferol 3-O-di-pcoumaroylrhamnosyldihexoside Kaempferol 3-O-pcoumaroylrhamnosyldihexoside Kaempferol 3-O-pcoumaroylglucosyl­ rhamnosylglactoside Kaempferol 3-O-p-coumaroylglucoside Kaempferol 3-O-6″-p-coumaroylglucoside Kaempferol 3-O-p-coumaroylglycoside Kaempferol 3-O-p-coumaroylhexoside Kaempferol 3-O-di-p-coumaroylhexoside Kaempferol 3-O-2″,6″-di-p-coumaroylglucoside

GT, OT, BT OT

Lin et al. (2008) Lin et al. (2008)

GT, OT, BT

Lin et al. (2008)

WT WT, GT, BT, PT

Lin et al. (2008) Lin et al. (2008) and Zhao et al. (2011)

WT, GT, OT, BT, PT

Lin et al. (2008) and Zhao et al. (2011)

WT

Lin et al. (2008)

OT

Lin et al. (2008)

WT, GT, OT, PT

Lin et al. (2008) and Zhao et al. (2011)

WT, GT, PT

Lin et al. (2008) and Zhao et al. (2011)

WT, GT, PT

Lin et al. (2008) and Zhao et al. (2011)

OT

Lin et al. (2008)

WT

Lin et al. (2008)

WT, GT, PT

Lin et al. (2008) and Zhao et al. (2011)

WT, GT, PT

Lin et al. (2008) and Zhao et al. (2011)

Flavones Glycosylated flavones

Proanthocyanidins

Alkaloids

Amino acids

Apigenin Luteolin 6,8-C-Diglucosylapigenin Apigenin 6-C glucosyl-8-C-arabinoside Apigenin 6-C-arabinosyl-8-C-glucoside Apigenin 6-C-pentosyl-8-C-hexoside Apigenin-8-C-glucose-rhamnose Vitexin 2″-glucoside or isomer Vitexin 2″-O-rhamnoside Apigenin 6,8-C-dipentoside Gallocatechin dimer Procyanidin dimer Gallocatechin catechingallate Procyanidin trimer Digallocatechin-catechin Theanine Theobromine Theophylline Caffeine Alanine Arginine Asparagine Aspartic acid Glutamic acid Isoleucine Histidine Leucine Phenylalanine Serine Theanine Threonine Tyrosine

WT, GT, OT, BT GT, OT, BT, PT WT GT, OT, BT

Peterson et al. (2005) and Zhao et al. (2011) Peterson et al. (2005) Lin et al. (2008) Lin et al. (2008)

WT, YT, GT, OT, BT, PT

Lin et al. (2008) and Zhang et al. (2011)

GT WT, YT, GT, OT, BT, PT OT, BT WT WT WT GT WT, GT, PT GT WT, GT, PT

Lin et al. (2008) Zhang et al. (2011) Lin et al. (2008) Lin et al. (2008) Lin et al. (2008) Lin et al. (2008) Lin et al. (2008) Lin et al. (2008) and Zhao et al. (2011) Lin et al. (2008) Lin et al. (2008) and Zhao et al. (2011) Lin et al. (2008) Lin et al. (2008) and Zhang et al. (2011) Lin et al. (2008) and Zhao et al. (2011) Zhang et al. (2011) Alcázar et al. (2007) Alcázar et al. (2007) Alcázar et al. (2007) Alcázar et al. (2007) Alcázar et al. (2007) Alcázar et al. (2007) Alcázar et al. (2007) Alcázar et al. (2007) Alcázar et al. (2007) Alcázar et al. (2007) Alcázar et al. (2007) Alcázar et al. (2007) Alcázar et al. (2007)

WT, YT, GT, OT, BT, PT WT, GT, OT, PT WT, YT, GT, OT, BT, PT WT, GT, OT, BT, PT WT, GT, OT, BT, PT WT, GT, OT, BT, PT WT, GT, OT, BT, PT WT, GT, OT, BT, PT WT, GT, OT, BT, PT WT, GT, OT, BT, PT WT, GT, OT, BT, PT WT, GT, OT, BT, PT WT, GT, OT, BT, PT WT, GT, OT, BT, PT WT, GT, OT, BT, PT WT, GT, OT, BT, PT

BT, black tea; GT, green tea; OT, oolong tea; PT, pu-erh tea; WT, white tea; YT: yellow tea.

8  Chapter 1 

Tea, the “Ambrosia” Beverage: Biochemical, Cellular, Molecular, and Clinical Evidences

(Zhang et al., 2011). They comprise two aromatic rings bound together by three carbon atoms to form an oxygenated heterocycle (Fig.  1.3A). Based on the heterocycle type involved, level of oxidation, site linking the B ring to the C ring, and pattern of substitution of the C ring (Xie and Chen, 2013), flavonoids are divided into different subclasses with flavonols and flavan-3-ols being more commonly present in teas. Flavonols can occur in glycosylated form while flavan-3-ols, the predominant subclass of flavonoid in tea, occur as aglycones. Polymerization of flavan-3-ols forms proanthocyanidins, also known as condensed tannin (Manach et al., 2004; Pandey and Rizvi, 2009). Some of the flavan3-ols present in teas are gallocatechin, (+)-catechin, (−)-epicatechin (EC) and (−)-epigallocatechin (EGC), (−)-epiafzelechin as well as galloylated flavan-3-ols, such as gallocatechin gallate (−)-epicatechin gallate (ECG), (−)-epigallocatechin gallate (EGCG), and (−)-epiafzelechin gallate (Fig.  1.3B). The flavonols kaempferol, quercetin, and myricetin along with their glycosylated and acylated glycosylated are also present in teas (Fig. 1.3C). Another subclass of flavonoid, flavone, is present in a lesser amount in tea. The two flavones reported are apigenin and luteolin (Fig. 1.3D) (Peterson et al., 2005). The proanthocyanidins (Fig. 1.3E) present in teas are gallocatechin dimer, procyanidin dimer, gallocatechin gallate, procyanidin trimer, and digallocatechin-catechin (Table 1.1) (Lin et al., 2008). Besides polyphenols, other compounds, including a­ lkaloids and amino acids, are present in teas. Alkaloids are basic nitrogencontaining compounds and are divided into two major groups: heterocyclic and nonheterocyclic. Most alkaloids occurring in nature are heterocyclic, that is, they have the nitrogen as part of a cyclic ring system. Heterocyclic alkaloids are further divided into different classes among which purine (or methylxanthine) alkaloids are more commonly present in teas. The purine alkaloids present in teas are caffeine (1,3,7trimethylxanthine) and theobromine (7-dimethylxanthine) (Fig.  1.4), which contribute to the bitter taste of tea (Evans, 2009).

1.3  Processing of Different Tea Varieties The composition of the bioactive compounds of a tea type is influenced by growth conditions such as soil profile, climatic conditions, growth altitude, genetic strain, horticultural practices, or plucking season. The processing of the teas during the manufacturing of the different types of teas also alters the bioactive compound content of the final product (Kosińska and Andlauer, 2014). On this basis, tea can be categorized into nonfermented (white, yellow, and green teas), semi-fermented (oolong tea), fully fermented (black tea), and postfermented (pu-erh tea). For the production of green and yellow teas, fresh tea leaves are plucked and withered. The leaves are heated using the pan-firing method to produce green tea while the drying method

Chapter 1  Tea, the “Ambrosia” Beverage: Biochemical, Cellular, Molecular, and Clinical Evidences  

Basic flavonoid structure 3′ 2′

4′

B

8

O

5′

7

A

6′

C

6

3 4

5

(A)

Flavan-3-ols

Flavan-3-ols gallate

moiety OH

HO

OH

Catechol

OH

OH HO

O R1

O R2

+ gallic acid

R1

O OH

OH

Pyrogallol

OH

moiety OH

R1 = β OH, R2 = H : (+)-Catechin

OH

R1 = α OH, R2 = H : (–)-Epicatechin

R1 = H : (–)-Epicatechin gallate

R1 = α OH, R2 = OH : (–)-Epigallocatechin

R1 = OH : (–)-Epigallocatechin gallate

(B) R1

Flavonols

R1

R2

HO

Flavones

R2

O R3

HO

O

OH OH

O OH

R1 = R3 = H, R2 = OH : Kaempferol R1 = R2 = OH, R3 = H : Quercetin

(C)

R1 = R2 = R3 = OH : Myricetin

O

R1 = H, R2 = OH : Apigenin R1 = R2 = OH : Luteolin

(D)

Fig. 1.3  Chemical structures of flavonoids. (A) Basic flavonoid structure, (B) chemical structures of major tea flavan-3-ols, (C) chemical structures of tea flavonols, (D) chemical structures of tea flavones, and

(Continued)

9

10  Chapter1 

Tea,the “Ambrosia”Beverage:Biochemical,Cellular, Molecular, and Clinical Evidences

(E)

Proanthocyanidins OH OH

HO

O R1 OH OH OH OH HO

n

O R1 OH OH OH OH HO

O R1

OH OH

Fig. 1.3–cont’d  C(E) structure of proanthocyanidins.

R1 = H or OH n = Number of flavanol monomers

Alkaloids O R1

O

R2 N

N

N

N

CH3 R1 = H, R2 = CH3 : Theobromine R1 = CH3, R2 = H : Theophylline R1 = R2 = CH3 : Caffeine

Fig. 1.4  Chemical structures of purine alkaloids in teas.

Chapter 1  Tea, the “Ambrosia” Beverage: Biochemical, Cellular, Molecular, and Clinical Evidences  

of yellow tea involves mild pan-firing until 40% of drying followed by 70% dryness at high temperature. The hot tea leaves are then packed and stored until dry. For the production of white tea, only buds with tiny and silvery hairs are plucked. These buds are sunshine withered and dried (Tables 1.2 and 1.3) (Kosińska and Andlauer, 2014). Overall, the three nonfermented teas have similar total catechin contents, with EGCG being the most abundant (Zhang et al., 2011). White tea has, however, higher levels of phenolic acid relatives and proanthocyanidins (Zhao et al., 2011). During the fermentation process, catechins are oxidized by polyphenol oxidase. In oolong tea, the fermentation process produces theasinensins following dimerization of catechins linked by a C}C bond between the B rings. The different theasinensins reported are theasinensins A, B, C, D, E, F, and G (Hashimoto et al., 1988; Weerawatanakorn et al., 2015). Theasinensins A, B, and C embed with R-biphenyl bonds while theasinensins D and E embed with S-biphenyl bonds (Fig. 1.5A) (Weerawatanakorn et al., 2015). In

Table 1.2  Processes During Tea Manufacturing Type of Tea

Process

White tea Yellow tea Green tea Oolong tea Black tea Raw pu-erh tea Ripened pu-erh tea

Withering in sun → drying Withering → firing at high temperature → slow drying Withering → pan firing → rolling/shaping → drying Withering → rolling → partial fermentation → drying Withering → rolling → fermentation → drying Withering → pan frying → rolling/shaping → sun drying → steaming and shaping Withering → rolling → pile fermentation → inoculation → steaming

Table 1.3  Effect of Tea Processing Steps Process

Effect

Withering Steaming/pan firing (dry heating) Rolling

Moisture removal and leaves softening Deactivation of enzymes involved in oxidation Leaves disruption and release of tea oils by disrupting tea leaves Access of enzymes to polyphenols for oxidation Enzymatic oxidation of polyphenols by polyphenol oxidase Stopping fermentation Inhibition of microbial growth due to reduction in moisture content

Fermentation (oxidation) Drying

11

12  Chapter1  Tea,the “Ambrosia”Beverage:Biochemical,Cellular, Molecular, and Clinical Evidences

Fig. 1.5  Chemical structures of major polyphenols produced following fermentation. (A) Theasinensins, and

Chapter 1  Tea, the “Ambrosia” Beverage: Biochemical, Cellular, Molecular, and Clinical Evidences  

Fig. 1.5–Cont’d  (B) theaflavins.

13

14  Chapter1 

Tea,the “Ambrosia”Beverage:Biochemical,Cellular,Molecular, andClinicalEvidences

black tea, the oxidation process results in formation of orange-red colored theaflavin dimers and a dark-brown colored thearubigin polymer. The most commonly known theaflavins are theaflavin, theaflavin-3-gallate, theaflavin-3′-gallate, and theaflavin-3,3′-digallate (Kosińska and Andlauer, 2014). Theaflavin trigallate and theaflavin tetragallate have also been detected in black tea (Chen et  al., 2012). The cooxidation of selected pair of catechins produces different theaflavins. For instance, EC cooxidizes with EGC to produce theaflavin (Fig. 1.5B) (He, 2017). Theaflavins can further be oxidized to potentially produce the polymeric thearubigins and these have also been detected in pu-erh tea (Wang et  al., 2010). The oxidation process further produces theabrownin, a bioactive compound mostly abundant in pu-erh tea (Weerawatanakorn et al., 2015) and present to a lesser extent in black tea (Gong et  al., 2010; Weerawatanakorn et al., 2015). The manufacturing of pu-erh tea occurs in two different ways to produce raw or ripened pu-erh tea. The processing of raw puerh tea is similar to that of green tea. However, the firing process is not complete; thus, the incomplete deactivation of enzymes results in oxidation for several years. Ripened pu-erh tea is produced by the piling of sun-dried leaves, inoculated with selected microorganisms and allowed to ripen for months. The fermented leaves are then steamed, compressed, and dried (Kosińska and Andlauer, 2014). Ripened puerh tea has a higher level of gallic acid but lower total catechin contents compared to raw pu-erh tea (Zhang et  al., 2012). The level of gallic acid is higher in black, oolong, and pu-erh teas compared to green tea as a consequence of oxidative degallation of phenolic esters during the fermentation process (Zuo et al., 2002). The tea types have thus different polyphenolic compounds with varying contents. The major polyphenols in the different teas are summarized in Fig. 1.6.

1.4  Antioxidant Properties of Tea Teas, both fresh and processed, are rich sources of antioxidants (Luximon-Ramma et al., 2006). Antioxidants confer numerous health benefits as they offer cellular protection against damages caused by reactive oxygen species (ROS) (Shahidi and Ambigaipalan, 2015). ROS are highly reactive oxygen radicals and nonradicals that damage macromolecules leading to the development of diseased conditions such as diabetes and associated complications, atherosclerosis, endothelial cell dysfunction, aging, and neurodegenerative diseases (Alfadda and Sallam, 2012; Mandel et al., 2008; Schaffer et al., 2012). Several in  vitro antioxidant assays have demonstrated that green teas have higher antioxidant activity than other tea types. One such assay is the 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical scavenging assay, which demonstrates that green tea

Chapter 1  Tea, the “Ambrosia” Beverage: Biochemical, Cellular, Molecular, and Clinical Evidences  

Fig. 1.6  Classification of major tea polyphenols.

15

16  Chapter1 

Tea,the “Ambrosia”Beverage:Biochemical,Cellular,Molecular, andClinicalEvidences

is nearly twice more potent than white and black teas (Carloni et al., 2013). In different assaying systems, including the ferric reducing antioxidant power (FRAP), oxygen radical absorbance capacity (ORAC), inhibition of 2,2′-azobis(2-methylpropionamidine)dihydrochloride (AAPH)-induced hemolysis in addition to scavenging of radicals [1,1-diphenyl-2-picryl-hydrazyl (DPPH), superoxide ( O2 •− ), and nitric oxide (NO•)] and nonradicals [hypochlorous acid (HOCl), hydrogen peroxide (H2O2)], green tea has more prominent antioxidant propensities compared to white and/or black teas (Camargo et al., 2016; Carloni et al., 2013; Pereira et al., 2014; Ramlagan et al., 2017a). The high antioxidant potential of green tea is attributed to the low level of fermentation as the antioxidant activities of the tea types are generally inversely correlated to the degree of fermentation. Nonfermented teas (green and white teas) have the highest level of antioxidants compared to fully fermented tea (black tea) (Camargo et al., 2016). Tea leaves are rich in catechins, which get oxidized during the fermentation step of manufacturing. This results in lower amount of catechins in the fermented tea while the nonfermented green tea preserves most of catechins (Chan et  al., 2011). As such, fermented black tea has lower total phenolic, flavonoid, and proanthocyanidin contents than nonfermented green tea (Ho et  al., 2010; Ramlagan et  al., 2017a) as a direct consequence of the manufacturing process (Carloni et al., 2013). In addition, the caffeine concentration decreases as the degree of fermentation increases from green tea to black tea (Kim et al., 2011). The high antioxidant potential of teas is positively correlated to the polyphenolic content mainly, more specifically to its abundance in catechins and derivatives. Among different polyphenols screened, (+)-catechin, EC, ECG, EGC, and EGCG are the most potent antioxidant compounds (Hatia et al., 2014). White and black teas are also potent antioxidants as these teas contain other polyphenolic compounds with significant antioxidant activities (Hatia et al., 2014). The antioxidant potential of the different teas is particularly determined by the individual composition of the extracts that confer specific structure-function properties (Bendary et al., 2013). Depending on their structure, polyphenols exert antioxidant activity by scavenging radicals via hydrogen atom transfer (HAT) or single electron transfer (SET) reactions from the antioxidant to the radical and by reducing metal ions, therefore inhibiting metal ion-catalyzed radical species formation (Bendary et  al., 2013; Huang et  al., 2005). During the process of HAT, hydrogen atom is transferred from the antioxidant to the radical (Eq. 1.1) while the SET reaction is based on the transfer of a single electron from the antioxidant to a radical (Eqs. 1.2– 1.4) or metal (Eq. 1.5), involving a redox reaction (Huang et al., 2005; Prior et al., 2005). During scavenging of free radicals, polyphenols are oxidized resulting in the generation of new radicals that are stabilized

Chapter 1  Tea, the “Ambrosia” Beverage: Biochemical, Cellular, Molecular, and Clinical Evidences  

by the resonance of the aromatic nucleus due to the delocalization of electrons (Cuvelier et al., 1992; Patel et al., 2010). Thus, the greater the number of aromatic rings in a compound, the higher is its antioxidant potential. R • + ArOH → RH + ArO•

(1.1)

R • + ArOH → R − + ArOH•+

(1.2)

ArOH•+ + H2 O → ArO• + H3 O+

(1.3)

R − + H3 O+ → RH + H2 O

(1.4)

Metal ( n ) + ArOH → Metal ( n − 1) + ArOH +

(1.5)

The number and configuration of H-donating hydroxyl groups in polyphenols are essential structural characteristics that modulate the antioxidant potential (Bendary et al., 2013). Hydroxybenzoic acids with one or two hydroxyl groups are less antioxidant that gallic acid, which contains three hydroxyl groups, thus with a higher ability to donate hydrogen atom and stabilize radicals (Cuvelier et  al., 1992). Hydroxycinnamic acids are more effective antioxidants than hydroxybenzoic acids as the latter’s carboxylate group has electron-­withdrawing properties, therefore affecting the H-donating abilities. Furthermore, the }CHCHCOOH group (Fig.  1.2) in hydroxycinnamic acids increases the H-donating ability and subsequently stabilizes radicals (Rice-Evans et  al., 1996). p-Coumaric acid, a hydroxycinnamic acid with one hydroxyl group at position 4, is a better antioxidant than the corresponding hydroxybenzoic acid, p-­hydroxybenzoic acid (Cuvelier et al., 1992). In flavonoids, increasing number of OH groups in the B ring results in increased antioxidant potential; catechol group-containing compounds are more potent than compounds with a single hydroxyl group while the pyrogallol structure in flavonoids exerts the highest antioxidant activity (Fig.  1.3B). Quercetin, with an additional OH group in the B ring than kaempferol, has more than threefold higher antioxidant activity than the latter. EGC, with a pyrogallol group, is more potent than (+)-catechin that has a catechol group. Esterification of (+)-catechin and EGC at the 3-OH group with gallic acid, to form ECG and EGCG, respectively (Fig.  1.3B), further increases their antioxidant potential (Rice-Evans et  al., 1996). In galloylated catechins, the gallic acid moiety contributes to the antioxidant activity of the compounds (Nanjo et al., 1999; Rice-Evans et al., 1996). Black tea is the poorest in catechins and derivatives, but still maintains high antioxidant capacity due to the presence of theaflavins and thearubigins produced following oxidation of catechins. These black tea polyphenols exert greater antioxidant

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•− a­ ctivity than catechins as they are better scavengers of O2 , singlet oxygen, H2O2, and •OH compared to EGCG (Wu et al., 2011). Unlike the different radicals and nonradicals scavenging activities, green tea is a less potent iron (II) (Fe2+) chelator compared to black tea (Carloni et al., 2013; Ramlagan et al., 2017a). The Fe2+ chelation is a measure of the inhibitory activity of teas against free radical production as via the Fenton reaction, Fe2+ generates free radicals. Instead of catechins, other polyphenolic compounds contribute to the chelating activity as adjacent carbonyl and hydroxyl functions, present in theaflavins, are involved in metal chelation (Carloni et al., 2013). The overall accrued antioxidant capacity of the teas would ultimately be the consequence of a synergistic effect of the polyphenols. As such, a combination of the tea-derived polyphenols for example, gallic acid, chlorogenic acid, quercetin, and rutin exerts higher antioxidant activity than the predicted values (Hajimehdipoor et al., 2014). In addition to the polyphenolic content, tea polysaccharides (TPSs) also exert antioxidant properties. Unlike polyphenols, the antioxidant activity of TPS is dependent on the degree of fermentation. As such, TPS from lightly fermented oolong tea and younger pu-erh tea have lower yield and antioxidant capacities compared to TPS from highly fermented oolong and pu-erh teas, respectively (Wang et  al., 2012; Xu et al., 2014). The TPSs are acid heteropolysaccharides bound with protein. The increasing degree of fermentation enhances the conjugation between polysaccharides and protein, thus leading to higher bioactivity (Wang et al., 2012; Xu et al., 2014). The hydroxyl group in polysaccharides is potentially responsible for this observed antioxidant activity (Tian et al., 2011). The antioxidant activity of polysaccharides is directly linked to the quantity of the sugar acid, uronic acid. The level of uronic acid in TPS is positively associated with degree of fermentation (Chen et al., 2004; Wang et al., 2012; Xu et al., 2014). Thus, the high contents of polysaccharides and uronic acid in highly fermented oolong and pu-erh teas account for their high antioxidant potential.

1.5  Tea as an Antidiabetic Agent Type II (T2DM) or noninsulin-dependent diabetes mellitus (NIDDM) is an endocrine disorder that is characterized by hyperglycemia and occurs due to insulin resistance, pancreatic β-cell dysfunction, or both (Asmat et al., 2016). Insulin resistance is a state of dysregulation of glucose homeostasis due to the reduced ability of insulin to stimulate glucose uptake in the peripheral tissues or to inhibit glucose production (Cheng et al., 2010). Chronic exposure of β cells to high glucose level leads to overproduction of ROS, which ­subsequently

Chapter 1  Tea, the “Ambrosia” Beverage: Biochemical, Cellular, Molecular, and Clinical Evidences  

reduces insulin expression and secretion, ultimately resulting in apoptosis. Chronic hyperglycemia also decreases DNA-binding activities of transcription factors that are involved in activation of insulin gene transcription, maintenance of β-cell function, pancreas development, and differentiation. β-Cells are susceptible to ROS attack due to low expression of endogenous antioxidant enzymes, catalase and glutathione peroxidase (Kaneto et al., 2010). Black and green teas have potent protective properties in subjects predisposed to T2DM. In a number of randomized and clinical trials, black and green tea consumption reduced the level of fasting plasma glucose and increased plasma antioxidant propensity (Bahorun et al., 2012; Toolsee et al., 2013). In diabetes research, streptozotocin (STZ) and alloxan (ALX) are the most common diabetogenic agents used to validate experiments. STZ is an antimicrobial agent while ALX is a synthesized pyrimidine derivative (Lenzen, 2008). These agents destroy pancreatic β cells, via ROS-mediated oxidative damage, resulting in decreased insulin secretion (Biswas et  al., 2017). In mice, injection of STZ induces increased blood glucose level, high glucose intolerance, and accumulation of lipid droplets in the liver. Treatment of mice with black or green teas exerts antidiabetic activities by activating different protective mechanisms at the cellular level. Black tea supplementation results in increased serum insulin level and threefold higher β cell function while green tea treatment suppresses insulin resistance in the diabetic mice (Tang et al., 2013). Supplementation of TPSs from green tea restores the glucose intolerance, counteracts the hyperinsulinemic condition, and decreases blood sugar level dose dependently by improving insulin sensitivity in STZ-induced diabetic mice. In the liver, TPS induces the expression of glucose transporter 4 (GLUT4), as a consequence of increased expressions of phosphatidylinositol 3-kinase (PI3K) and AKT [also known as protein kinase B (PKB)]. Following binding to its receptor, insulin induces phosphorylation of PI3K which, in turn, phosphorylates and activates AKT. The latter stimulates translocation of GLUT4, resulting in glucose uptake (Ramachandran and Saravanan, 2015) (Fig.  1.7A). TPS also exerts antiatherogenic potential in diabetic mice by reducing the levels of cholesterol, glycerides, and low-density lipoprotein (LDL) as well as increasing high-density lipoproteins (HDLs) level (Fig. 1.7B). STZ leads to reductions in the activities of the antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) in •− the liver and kidney of diabetic mice (Li et al., 2015). SOD converts O2 to H2O2 while CAT and GPx induce dismutation of H2O2 (Nimse and Pal, 2015). Supplementing diabetic mice with TPS, the ethyl acetate fraction of methanolic green tea or tea-derived polyphenols increased the activities of the enzymes in different organs (Biswas et  al., 2017; Hao et al., 2012; Li et al., 2015; Peng and Zhang, 2014). Moreover, STZ

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gTPS Glucose

gTPS GTf

Activities of SOD and CAT

GTf

Hex and G6PD activities

PI3K

Bcl-2 Bax

G6P

EGCG

AGEs

GLUT4

AKT

Glucose

Hemoglobin

Triglyceride Cholesterol LDL

Apoptosis

AGEs

GTf

ALP ALT

EGCG BT

(A)

(B) Rutin TPs gTPS

gTPS BT

gTPS GTf BT Rutin

BT Rutin TPs

EGCG

Activities of SOD, CAT and GPx Aldose reductase activity

EGCG AGEs

creatinine urea

TGF-β1

Rutin BT TPs

Smad 2/3 CTGF

Rutin

Accumulation of ECM

(C)

Trigger

Inhibit

Induce

Fig. 1.7  Protective effect of tea and tea-derived polyphenols in (A) liver, (B) blood vessel, and (C) kidneys in diabetes. BT, black tea; GTf, ethyl acetate fraction of methanolic green tea; gTPS, green tea polysaccharides; TPs, tea-derived polyphenols.

causes severe pathological changes, such as infiltration of lymphocytes, congestion in central vein, and necrosis in the pancreas, kidney, and liver while TPS and black tea have the ability to alleviate these pathologies (Bhattacharya et  al., 2013; Li et  al., 2015) (Fig.  1.7A and C). The ethyl acetate fraction of methanolic green tea reduces blood glucose level in diabetic rats by increasing serum insulin level as a consequence of the ability of the tea fraction to recover the size of the islets of Langerhans. An increased insulin level also counteracts the STZ-mediated decrease in expression of Hexokinase-I and activities of hexokinase and glucose-6-phosphate dehydrogenase along with rise in glucose-6-phosphatase in the liver and skeletal muscle (Fig. 1.7A). Hexokinase and glucose-6-phosphate dehydrogenase are enzymes involved in glycolysis while glucose-6-phosphatase is involved in gluconeogenesis (Biswas et al., 2017). The liver, which is an important or-

Chapter 1  Tea, the “Ambrosia” Beverage: Biochemical, Cellular, Molecular, and Clinical Evidences  

gan involved in glucose homeostasis, has decreased expression of the antiapoptotic gene B-cell lymphoma 2 (Bcl-2) and increased expression of the proapoptotic gene Bcl-2-associated X (Bax) in STZ-treated rats, indicating ROS-mediated cell death (Fig. 1.7A). The increase in Bcl-2 and reduction in Bax by the green tea fraction further emphasizes its antioxidant potential, thus preventing the pathogenesis of diabetic complications (Biswas et al., 2017). Following ALX injection, diabetic rats develop elevated blood glucose level. The supplementation of black tea to diabetic rats significantly reduces the blood glucose level (Bhattacharya et al., 2013; Kumar and Rizvi, 2015), with the level being restored to normal after 35 days of black tea supplementation (Kumar and Rizvi, 2015). Black tea decreases the glycosylated hemoglobin level (Bhattacharya et al., 2013) and increases the plasma and erythrocyte antioxidant levels (Kumar and Rizvi, 2015) (Fig.  1.7B). Black tea supplementation also reduces the risk of diabetic complications. It protects against liver damage by lowering the activities of alanine transaminase (ALT) and alkaline phosphatase (ALP), two enzymes that are involved in hepatocellular injury (Knudsen et al., 2016) (Fig. 1.7A). It counteracts the increase in levels of cholesterol, LDL, and triglycerides, thus reducing the risk of atherosclerosis (Fig. 1.7B). Black tea, in addition to tea-­derived polyphenols, reduces the levels of urea and creatinine, the markers of kidney dysfunction (Bhattacharya et al., 2013; Kumar and Rizvi, 2015). Tea-derived polyphenols also afford protection against kidney dysfunction by reducing the extent of glomerular and mesangial matrix expansion (Hao et al., 2012; Peng and Zhang, 2014).

1.5.1 Suppression of Postprandial Hyperglycemia Following food ingestion, the digestion process leads to postprandial hyperglycemia. Pancreatic α-amylase catalyzes the hydrolysis of starch into a mixture of linear and branched oligosaccharides such as maltose and maltotriose along with α-(1–6) and α-(1–4) oligoglucans. As they cannot be absorbed into the bloodstream, these oligosaccharides are further degraded by α-glucosidase to absorbable free glucose monosaccharides that enter the bloodstream following absorption (Sudha et al., 2011). Retardation in the rate of starch hydrolysis is a potent therapeutic approach to delay and/or prevent diabetes pathogenesis. Acarbose is currently being used for the treatment of postprandial hyperglycemia, with a lower concentration required to inhibit 50% of activity of α-amylase compared to that of α-glucosidase (Deng et al., 2015; Ramlagan et al., 2017a). The accumulation of undigested carbohydrate, as a consequence of high inhibition of α-amylase activity by acarbose, becomes a source for colon bacterial growth and fermentation. This results in side effects such as abdominal pain, bloating, cramping, diarrhea, and flatulence (Telagari and Hullatti, 2015).

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Pu-erh, oolong, green, and black teas reduce postprandial hyperglycemia by inhibiting the activities of the carbohydrate hydrolyzing enzymes in vitro (Deng et al., 2015; Ramlagan et al., 2017a; Sun et al., 2016). Different types of teas exert higher α-glucosidase inhibitory activity compared to acarbose and the level of inhibition is positively correlated to the degree of fermentation of the teas. Fully fermented black tea has greater α-glucosidase inhibitory activity than nonfermented green tea (Ramlagan et al., 2017a). TPSs from lightly fermented oolong and pu-erh teas are less potent α-glucosidase inhibitors compared to moderate and highly fermented TPS (Deng et  al., 2015; Wang et  al., 2012; Xu et al., 2014). In ALX-induced diabetic mice, pu-erh TPS decreases postprandial hyperglycemia with the degree of inhibition of the postprandial glucose level associated with aging time of the tea (Xu et al., 2014). Highly fermented TPS affords greater protection as it exerts higher reduction of blood sugar level compared to acarbose in vivo (Deng et al., 2015). TPS are poor inhibitors of α-amylase and the degree of fermentation does not alter their inhibitory activities (Deng et  al., 2015). Black and green teas also exert lower α-amylase inhibition compared to acarbose (Ramlagan et al., 2017a). The polyphenolic composition of the different teas is linked to their different α-amylase and α-glucosidase inhibitory activities. The activities of these carbohydrate hydrolyzing enzymes are inhibited by catechins and theaflavins, with galloyl substitution increasing the activities of the compounds. Galloylation of EC, EGC and theaflavin-­ forming ECG, EGCG, theaflavin-3-gallate, theaflavin-3′-gallate, and theaflavin-3,3′-digallate enhance the activities of the compounds (Hara and Honda, 1990; Matsui et  al., 2007; Sun et  al., 2016). The greater protection against postprandial hyperglycemia exerted by black tea compared to green tea is attributable to the theaflavin content. Theaflavins have better α-amylase inhibitory action than catechins (Hara and Honda, 1990; Sun et al., 2016) and are more potent α-glucosidase inhibitors than EC and EGC (Matsui et al., 2007). Flavonols, such as myricetin, quercetin, and kaempferol, along with flavan-3-ols exert higher inhibition of α-glucosidase than α-amylase (Tadera et al., 2006), thus supporting the highest α-glucosidase inhibitory activity by different tea types. These findings indicate that tea has the ability to decrease postprandial hyperglycemia by reducing production of absorbable free glucose through their strong α-glucosidase activities. Teas can also prevent the development of any side effects due to their minimal α-amylase inhibitory activity. Tea-derived polyphenols can, in addition, reduce the consumption of high amounts of acarbose. When acarbose is combined with green tea, green tea polyphenols, and EGCG, a lower concentration of acarbose is required to attain 50% α-amylase and α-glucosidase inhibitory activities compared to acarbose only (Gao et al., 2013).

Chapter 1  Tea, the “Ambrosia” Beverage: Biochemical, Cellular, Molecular, and Clinical Evidences  

1.5.2 Inhibition of Advanced Glycation End Products (AGEs) During a prolonged hyperglycemic state, reducing sugar molecules induce nonenzymatic glycation of proteins through covalent binding of their aldehyde or ketone groups to free amino groups of proteins (Singh et al., 2014). Glycation leads to the formation of reversible Schiff base adducts, which rearrange into stable Amadori products (Fig. 1.8) (Takeuchi et al., 2001). Over the time course, further rearrangements, auto-oxidation, oxidative degradation, hydrolysis of Schiff‘s bases, and/or Amadori products produce several highly reactive dicarbonyl intermediates (α-oxoaldehyde) such as 3-deoxyglucosone, glyoxal (GO), and methyl-glyoxal (MGO) (Ott et al., 2014; Singh et  al., 2014). These intermediate products in turn react with free amino groups, mainly lysine and arginine residues (Nagaraj et al., 2002), and consequently lead to irreversible formation of either fluorescent cross-linking AGEs, nonfluorescent cross-linking AGEs or noncross-linking AGEs [such as N-carboxymethyllysine (CML)] (Fig.  1.8) (Gkogkolou and Böhm, 2012; Singh et  al., 2014; Takeuchi et al., 2001). During the process of glycation, metal ion catalysis amplifies the rate of AGE formation (Sajithlal et al., 1998) and induces •− the production of ROS such as O2 and H2O2 (Nagai et  al., 1997; •− Smith and Thornalley, 1992). O2 produced oxidizes amino acid residues to form carbonyl derivatives (Dalle-Donne, 2006). In the presence of metal ions, such as Fe2+, H2O2 undergoes the Fenton ­reaction

Fig. 1.8  Formation of advanced glycation end products (AGEs).

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r­ esulting in hydroxyl radical (•OH) production. The latter is involved in cleavage of the C2}C3 bond of dicarbonyls leading to the formation of CML (Nagai et  al., 1997). In addition to proteins, DNA and lipids are also prone to glycation, which results in loss of their functions (Breyer et al., 2007; Bucala et al., 1994). Glycation of these macromolecules can contribute to progressive β cell deterioration. AGEs decrease the proliferation rate as well as increase apoptosis and necrosis of pancreatic cells. AGEs also impair the synthesis and secretion of insulin (Luciano Viviani et al., 2008). Albumin is the most abundant circulating protein in the plasma, with an antioxidant role due to the presence of thiol groups (Faure et  al., 2008). This protein undergoes increased glycation during diabetes mellitus leading to structural changes and impairment in its antioxidant properties (Roche et  al., 2008). In diabetics, there is increased albumin glycation, decreased albumin’s thiol groups, and associated reduced plasma total antioxidant status (Faure et al., 2008). Glycated proteins further undergo oxidation resulting in formation of oxidatively modified proteins such as protein carbonyl and advanced oxidation protein products (AOPP) (Sadowska-Bartosz et al., 2014). Carbonyl groups are formed on the side chains of protein while AOPP are cross-linked protein products containing dityrosine. The increased level of protein carbonyl and AOPP is inversely correlated with thiol groups and antioxidant status in type II diabetics. These modified proteins further exacerbate the diabetic condition as they induce deleterious downstream signaling pathways (Deokar et  al., 2016; Kar and Sinha, 2014; Pandey et al., 2010). A higher level of AOPP occurs in diabetics with micro- and macroalbuminuria or with retinopathy compared to diabetics with normoalbuminuria or without retinopathy, respectively (Ng et al., 2013; Piwowar et al., 2008). Black and green teas have the propensity to suppress the development of diabetic complications due to their ability to reduce levels of protein carbonyl and/or AOPP in bovine serum albumin (BSA) glycated with ribose or MGO (Ramlagan et al., 2017a). The reduction in the level of carbonyls by the teas is likely linked to their iron (II)-chelating activities (Carloni et  al., 2013; Ramlagan et al., 2017a) as AGE inhibitors chelate metals prior to the formation of reactive carbonyl compounds (Price et al., 2001). Reduction in fluorescent AGE level is a commonly used biomarker to evaluate the antiglycation potential of teas or tea-derived polyphenols. Black and green teas lower fluorescent AGE level in BSA glycated with glucose, ribose, and MGO (Ho et al., 2010; Ramlagan et al., 2017a). Polyphenolic compounds, such as hydroxybenzoic and hydroxycinnamic acids, exert antiglycation activity with gallic acid and chlorogenic acids showing prominent activities (Wu et al., 2010). (+)-Catechin, EC, ECG, EGC, EGCG, kaempferol, quercetin, and

Chapter 1  Tea, the “Ambrosia” Beverage: Biochemical, Cellular, Molecular, and Clinical Evidences  

rutin also decrease fluorescent AGE formation induced by different glycating agents in BSA (Li et al., 2014; Sadowska-Bartosz et al., 2014; Wu and Yen, 2005). The antiglycation properties of flavan-3-ols are influenced by the presence of the galloyl group as EGC, (+)-gallocatechin, and EC have lower AGE inhibition abilities than their galloylated counterparts. The sterical structure of the hydroxyl group at position 3 in the gallate-free catechins also helps to determine their antiglycative potential; (+)-gallocatechin and (+)-catechin with a β-hydroxyl group at the 3 position have higher AGE inhibitory activity than their isomers with an α-hydroxyl group (EGC and EC, respectively). The presence of the 5′-OH group in the gallate-free catechins with the same sterical structure is the determining factor for the anti-AGE activity of the compound such that (+)-gallocatechin has higher inhibition capacity than (+)-catechin (Nakagawa et  al., 2002). Moreover, myricetin, which has a 5′-OH group in the B ring, has higher inhibitory activity compared to quercetin (Matsuda et  al., 2003). This indicates that the antiglycation activity of a compound is also influenced by the level of hydroxylation. The O2 •− , H2O2, and •OH scavenging activities along with Fe2+-chelating potential of tea-derived polyphenols (Camargo et  al., 2016; Nanjo et al., 1999; Ramlagan et al., 2017a; Sun et al., 2012) potentially account for the AGE inhibitory properties. The supplementation of green tea to STZ-induced diabetic rats reduces the level of AGEs formed in the tail tendon. The low level of AGEs could potentially be linked to the decreased blood glucose level (Babu et al., 2008). In db/db mice, an in vivo model for diabetic dyslipidemia, accumulation of AGEs in kidneys is linked to albuminuria as a consequence of deposition of immunoglobulin G (IgG). IgG is accumulated in glomeruli due to increased levels of circulating antibodies targeting the modified proteins in diabetes (Yan et al., 2012). Supplementation of the db/db mice with pu-erh tea or (+)-catechin attenuates accumulation of AGEs in kidney, thus inhibiting deposition of IgG and reducing associated urinary albumin and urea excretions. Pu-erh tea and (+)-catechin have the ability to mitigate diabetic renal complications as they decrease serum creatinine level, glomerular cell loss, glomerular hypertrophy, and mesangial expansion (Yan et  al., 2012; Zhu et al., 2014). Pu-erh tea supplementation also aids in decreasing the weight of the db/db mice, thus reducing the risk of obesity (Yan et al., 2012). The level of MGO in kidneys is decreased by pu-erh tea and (+)-catechin, potentially due to their MGO trapping ability to form stable adducts (Yan et al., 2012; Zhu et al., 2014). Different polyphenols in tea, such as EC, EGC, ECG, EGCG, theaflavin, theaflavin-3-gallate, theaflavin-3′-gallate, theaflavin-3,3′-digallate, and quercetin have the ability to trap MGO, thus inhibiting the formation of AGEs (Li et  al., 2014; Lo et al., 2006; Sang et al., 2007).

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1.5.3 Inhibition of AGE Action Oxidative stress is a state of increased ROS production and an impaired antioxidant defense system (Schaffer et  al., 2012). Oxidative stress induces oxidative damage to macromolecules, which in turn generate secondary reactive species resulting in cellular dysfunction and contributing to the pathogenesis of micro- and macrovascular diabetic complications (Dalle-Donne, 2006). The onset of oxidative stress in diabetes has been associated with AGE formation. When bound to specific cell-surface receptors, the best known being the receptor for AGE (RAGE) (Kuniyasu et al., 2003), AGEs induce the overexpression of nicotinamide adenine dinucleotide phosphate-oxidase1 (NOX1), which stimulates ROS production (Ramlagan et al., 2017b). Excess of ROS attack polyunsaturated fatty acids leading to peroxidation of membrane lipids. This results in decreased membrane fluidity, inactivation of membrane bound proteins, and production of chemically reactive products such as malondialdehyde (MDA) and 4-­hydroxy-2-nonenal (HNE). These aldehydes react with DNA, proteins, and phospholipids, thus altering the functionality of these molecules (Dalle-Donne, 2006; Uchida, 2003). Protein oxidation due to oxidative stress promotes dysfunction by altering protein structure, cleaving the peptide backbone, forming cross-links, and modifying side chains (Dalle-Donne, 2006). Oxidation of glycated protein increases AGE formation, suggesting that oxidative stress accelerates AGE production, which contributes to the pathogenesis of diabetic complications (Sajithlal et al., 1998). Cellular DNA damage induced by ROS leads to DNA strand breakage and base modifications, such as formation of 8-hydroxy-2′-deoxyguanosine (8-OHdG) by hydroxyl radicals from the base 2′-deoxyguanosine (Cooke et al., 2003). 8-OHdG is involved in substitution mutations and gene transcription alteration, thus providing a link between diabetes and cancer (Lee and Chan, 2015). Pronounced DNA damage in diabetics contributes to the pathogenesis of diabetic complications as a higher level of 8-OHdG occurred in diabetic patients with complications than in patients without complications (Hinokio et al., 1999). In ALX-induced diabetic rats, ROS production along with levels of MDA and protein carbonyl are elevated in the pancreatic, heart, kidney, and liver tissues. The activities of SOD, CAT, GPx, glutathione S-transferase (GST), and glutathione reductase (GR) in the different tissues are low. As a consequence of the hyperglycemic condition in diabetic rats, the loss of activities of the antioxidant enzymes is potentially linked to the glycation of these proteins (Bhattacharya et al., 2013). In the pancreas, the ALX-induced ROS overproduction causes DNA fragmentation and elevates the protein level of cleaved caspase-3, a cysteine protease involved in apoptosis (Bhattacharya et al., 2013). ALX

Chapter 1  Tea, the “Ambrosia” Beverage: Biochemical, Cellular, Molecular, and Clinical Evidences  

also induces accumulation of plasma AOPP and increases activity of the erythrocyte plasma membrane redox system (PMRS) (Kumar and Rizvi, 2015), whereby an increase in PMRS activity helps to reduce oxidative stress (Singh et al., 2016). Supplementation of black tea to diabetic rats counteracts the oxidative stress state by reducing ROS, MDA, protein carbonyl, AOPP, DNA fragmentation, caspase-3 levels, and erythrocytes PMRS activity along with increasing activities of antioxidant enzymes (Fig. 1.9A) (Bhattacharya et al., 2013; Kumar and Rizvi, 2015). The protective effects of black tea are attributed to its antioxidant properties as ROS generated due to ALX toxicity damages macromolecules in the pancreas as well as other organs (Bhattacharya et al., 2013). EGCG also alleviates the oxidative stress state by increasing the glutathione (GSH)/glutathione disulfide (GSSG) ratio, a marker of carbonyl stress, in the liver, kidney, and adipose tissue of diabetic mice (Sampath et al., 2017). EGCG further affords protection by decreasing the accumulation of AGEs in the plasma, liver, kidney, adipose, and heart tissues (Fig. 1.7) (Sampath et al., 2016a, 2017). In STZ-induced diabetic rodents, tea-derived polyphenols inhibit glycation and lipid peroxidation by reducing levels of glycosylated hemoglobin (Fig. 1.7B) and MDA, respectively (Hao et al., 2012; Peng and Zhang, 2014). Apart from reducing the blood glucose level, rutin also decreases accumulation of AGEs, collagen, and laminin in diabetic rats. The accumulation of extracellular matrix components (ECMs), such as collagen and

Fig. 1.9  Protective effect of tea and tea-derived polyphenols in (A) pancreas and (B) lens in diabetes. BT, black tea; ChlA, chlorogenic acid; Quer, quercetin.

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laminin, in the glomeruli and the interstitium of kidney is a characteristic pathological change in diabetic nephropathy. Accumulation of the ECM components is mediated by transforming growth factor beta (TGF-β1). The latter induces expressions of mediators like connective tissue growth factor (CTGF) and Smad 2/3, which are involved in fibrosis. In diabetic rats, rutin reduces the expressions of CTGF and TGF-β1 in the renal cortex and inhibits activation of Smad 2/3 (Hao et al., 2012), thus decreasing the risk of developing diabetic nephropathy (Fig. 1.7C). In retinal pigmented epithelial cells, high level of glucose and MGO results in cell death and induces accumulation of fluorescent AGEs and CML. These deleterious effects of the glycating agents are inhibited by EC, ECG, EGCG, quercetin, and chlorogenic acid (Sampath et al., 2016a,b). EGCG and quercetin also reduce the activity of aldose reductase, an enzyme involved in the production of AGEs, caused by hyperglycemia (Fig. 1.9B) (Sampath et al., 2016a). EGCG has the ability to suppress the development of diabetic retinopathy as it delays the formation of cataracts and lowers the activity of aldose reductase in lens of diabetic mice (Fig. 1.9B). Aldose reductase activity is also decreased in the kidney (Fig. 1.7C) and heart by EGCG (Sampath et al., 2016a). EGCG, in addition to a blend of green, oolong, and pu-erh tea, also suppress liver damage by decreasing activities of plasma ALT and ALP (Fig. 1.7A) (Braud et al., 2017; Sampath et al., 2017). In addition to its role in the oxidation of macromolecules, ROS are also involved in the activation of mitogen-activated protein kinases (MAPKs), such as stress-activated protein kinases (SAPKs)/c-Jun N-terminal kinases (JNKs), extracellular signal-regulated kinases 1/2 (ERK 1/2), and p38 MAPKs (Gupta et  al., 1999; Lander et  al., 1995), and of nuclear factor kappa B (NFκB) (Lander et al., 1995). In the cytoplasm, NFκB is generally in an inactivated form due to its association with the inhibitor κB proteins (IκB). MAPK or ROS stimulation induces the phosphorylation of IκB by IκB kinases (IKK), which degrade the NFκB inhibitor resulting in transactivation of the transcription factor (Xie et al., 2013). In the nucleus, NFκB induces the transcription of proinflammatory cytokines (Hattori et  al., 2002; Naitoh et  al., 2001), adhesion molecules (Goldin et al., 2006), and growth factors (Sourris et al., 2008) leading to diabetic complications (Fig. 1.10). Black and green teas reduce AGE-induced ROS overproduction and associated accumulation of protein carbonyl and AOPP. Both teas also suppress AGE-mediated decrease in activities of SOD, CAT, and GPx. Black and green teas also exert antiinflammatory activity by inhibiting the increase in IL-6 secretion mediated by AGEs (Ramlagan et  al., 2017a). EGCG decreases AGE-induced tumor necrosis factor alpha (TNF-α) and matrix metalloproteinase 13 (MMP13) expression by reducing the activation of p38- and JNK-MAPK

Chapter 1  Tea, the “Ambrosia” Beverage: Biochemical, Cellular, Molecular, and Clinical Evidences  

o

AGE EGCG

AGE receptor

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Catechins BT GT

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NFκB

IκB ChIA

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IKB

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P

Degradation

Pro-inflammatory cytokines Vascular adhesion molecules growth factors

BT GT TP

Diabetes complications

Fig. 1.10  Signaling pathways of AGE-induced diabetic complications. BT, black tea; ChlA, chlorogenic acid; GT, green tea; GTP, green tea polyphenol; PT, pu-erh tea; TP, tea-derived polyphenol; and Quer, quercetin.

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pathways. EGCG also suppresses the activity of IKKβ and thus inhibits the AGE-mediated degradation of IκBα, nuclear translocation of the NFκB subunit, and DNA-binding activity of NFκB p65 (Rasheed et al., 2009). NFκB-driven transcription is inhibited by black and green teas. Individual polyphenolic compounds also demonstrate NFκB inhibitory activities with EGCG exerting the highest inhibition (Di Lorenzo et al., 2013). Quercetin decreases the gene expression of NFκB1 (Nair et al., 2006) and chlorogenic acid inhibits the activation of NFκB and degradation of IκB (Ruifeng et al., 2014). (+)-Catechin suppresses the high glucose-induced interleukin (IL)-1β secretion in addition to the activation of NFκB and ERK1/2 in a dose-dependent manner (Zhu et al., 2014). Green tea polyphenols also inhibit the AGE-induced activation of ERK1/2. They also exert antiatherogenic property by inhibiting the AGE-induced proliferation of VSMCs (Ouyang et al., 2004). AGE-mediated VSMC proliferation accelerates the formation of atherosclerosis and coronary restenosis (He et al., 2015) (Fig. 1.10). In db/db mice, (+)-catechins exert antiinflammatory action in the kidney by reducing the activation of NFκB and associated levels of TNF-α and IL-1β (Zhu et al., 2014). In diabetic mice, RAGE is overexpressed in the kidney. Pu-erh tea-, (+)-catechin-, and EGCG-treated diabetic mice have lowered RAGE expression as compared to untreated diabetic mice (Sampath et al., 2016a,b, 2017; Yan et al., 2012; Zhu et al., 2014). In type II diabetic patients, EGCG inhibits binding of RAGE to its ligand by inducing secretion of soluble RAGE (sRAGE) via ectodomain shedding of the receptor by metalloproteinases like A disintegrin and metalloproteinase-10 (ADAM10) (Huang et  al., 2013). EGCG increases the expression of ADAM10 and stimulates sRAGE secretion via increased cleaved RAGE (cRAGE) in monocytes exposed to high glucose. This results in reduced protein expression of RAGE. sRAGE competes with RAGE as a ligand decoy and hence reduces the AGE-RAGE-induced development of diabetic complications (Fig. 1.10) (Huang et al., 2013). sRAGE also suppresses the AGEinduced activation and DNA-binding activity of NFκB and lowers the degree of phosphorylation of p38- and ERK-MAPK along with associated reduction in IL-6 and IL-8 levels (Rasheed et al., 2011).

1.6  Protection Against Obesity Obesity is one of the most common nutritional diseases worldwide. It arises due to excess energy intake and low energy expenditure, resulting in increased fat accumulation in adipose tissue (Pan et al., 2016a). In 2016, at least 1.9 billion adults were overweight and 650 million were obese. Overweight is defined as a body mass index (BMI) of at least 25 kg/m2 while obesity is described as a BMI of at

Chapter 1  Tea, the “Ambrosia” Beverage: Biochemical, Cellular, Molecular, and Clinical Evidences  

least 30 kg/m2 (World Health Organization, 2017a). Obesity is linked to multiple pathophysiologies such as diabetes, cardiovascular disease (CVD), hypertension, and dyslipidemia (Hassan and El-Gharib, 2015; Pan et al., 2016a). Two drugs, orlistat and sibutramine, are currently being used for the management of obesity. However, these are associated side effects like head ache, insomnia, high blood pressure, and constipation (Hassan and El-Gharib, 2015). Thus, the use of natural products for the management of obesity remains a better alternative. Over the past decades, tea has been studied for its antiobesity effects both in vitro and in vivo. In women with central obesity, supplementation of high dose of green tea extract results in weight loss, without any side effects. Ad ­ ecreased waist circumference (Chen et  al., 2016; Toolsee et  al., 2013), total cholesterol, and LDL levels occur in obese participants (Chen et al., 2016). Green tea also suppresses mean arterial pressure in prediabetics (Toolsee et al., 2013). Under a high fat (HF) diet, supplementation of EGCG to mice reduces the elevated blood glucose level and body weight (Sampath et al., 2016a, 2017). The HF diet represents an obesity model as it induces adipose expansion due to the rapid weight gain causing intraabdominal or visceral fat accumulation (Heber et al., 2014). Rats under a high-fructose diet have elevated body weight as the high-fructose diet mediates several symptoms of metabolic syndrome including hyperlipidemia. The body and adipose tissue weights of obese rats are lowered following treatment with different tea types and tea-derived polyphenols (Braud et  al., 2017; Dong et  al., 2014; Heber et  al., 2014; Huang and Lin, 2012; Molina et al., 2015; Rocha et al., 2016; Uchiyama et al., 2011; Wu et al., 2016). In the adipose tissue of obese rats, black tea treatments reduce the size of lipid cells and number of fat cells (Wu et al., 2016). Green tea treatment also ameliorates insulin sensitivity in obese rats and increases GLUT4 expression (Rocha et al., 2016). In obesity, functional mature adipocytes arise from preadipocytes via adipogenesis. The different stages of adipogenesis are mesenchymal precursors, committed preadipocytes, growth-arrested preadipocytes, mitotic clonal expansion, terminal differentiation, and mature adipocytes. In the early stage of adipogenesis, the transcription factor CCAAT/enhancer-binding protein (C/EBP) induces the expression of peroxisome proliferator-activated receptors (PPAR) γ. C/EBP also regulates cell proliferation during mitotic clonal expansion. Between the growth-arrested preadipocytes and mitotic clonal expansion stages, D-types cyclins and cyclin-dependent kinase (Cdk) are involved in the transition from the G1 phase to S phase. During adipocyte differentiation, the transcription factor sterol regulatory element binding protein (SREBP) is involved in lipogenesis and lipid homeostasis. In the terminal differentiation stage, expression of enzymes involved in

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triglyceride synthesis and lipogenesis increases, resulting in fat accumulation in mature adipocytes (Pan et al., 2016b). Green tea, raw, and ripened pu-erh teas inhibits differentiation of 3 T3-L1 (an in vitro cellular model of preadipocyte) by suppressing gene expressions of C/EBPα and PPARγ (Fig. 1.11) (Cao et al., 2013; Yang et al., 2014). Green tea also inhibits lipid accumulation in adipocytes (Yang et al., 2014). In differentiating adipocytes, white tea reduces the mRNA expression of C/EBPα, C/EBPδ, PPARγ, and SREBP-1c as well as mediates lipolytic activity in adipocytes (Söhle et al., 2009). Tea catechins also have antiadipogenic activities. As such, (−)-catechingallate, EGC, ECG, and EGCG inhibit lipid accumulation and suppress the expression of C/EBPα and PPARγ2 in 3 T3-L1 cells (Furuyashiki et al., 2004; Lin et al., 2005). EGCG induces G0/G1 growth arrest by downregulating CDK and cyclin D1 protein levels (Hung et al., 2005). EGCG also selectively mediates apoptosis of mature adipocytes, sparing preadipocytes (Lin et al., 2005). In bovine mesenchymal stem cells induced to adipogenesis, EGCG prevents fat accumulation and induces apoptosis. EGCG further inhibits expressions of the adipogenic markers C/EBPα, PPARγ, SREBP-1c, fatty acid-binding protein 4, and stearoyl-CoA desaturase (Jeong et al., 2015; Lao et al., 2015). 3 T3-L1 mimics white adipose tissue (WAT) (Lee and Kang, 2017), which has deleterious consequences for metabolic health (Bartelt and Heeren, 2014). Browning of WAT, that is, accumulation of beige adipocytes in WAT forms brown adipose tissue (BAT). BAT controls glucose and triglyceride metabolisms and is involved in weight loss, increasing insulin sensitivity, and reducing hyperlipidemia (Bartelt and Heeren, 2014). The ethyl acetate fraction of white, green, oolong, and black tea induce browning of the 3 T3-L1

Fig. 1.11  Inhibitory activities of tea and tea-derived polyphenols against adipogenesis and on adipocytes. BT, black tea; CG, catechin gallate; GT, green tea; OT, oolong tea; PT, pu-erh tea; and WT, white tea.

Chapter 1  Tea, the “Ambrosia” Beverage: Biochemical, Cellular, Molecular, and Clinical Evidences  

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adipocyte (Fig. 1.11) (Lee and Kang, 2017), thus protecting against the deleterious effects of WAT. In animal studies, oolong, black, and pu-erh teas lower the WAT weight in addition to cholesterol level compared to untreated mice. The three teas stimulate the phosphorylation of AMP-activated protein kinase (AMPK) in WAT and BAT and increase the protein expression of insulin-like growth factor binding protein-1, a protein that reduces body weight, adiposity, and hyperglycemia. Oolong, black, and pu-erh teas further inhibit the PPARγ level and increase the mRNA level of adiponectin in WAT. Black and pu-erh teas induce AMPK activation and increase the expression of uncoupling proteins 1 (UCP-1), which is involved in energy consumption in adipose tissues (Yamashita et al., 2014). Consumption of black tea as well as black tea-derived polyphenol and TPS promotes lipid excretion and inhibits elevation in serum triglyceride level in  vivo (Ashigai et  al., 2016; Uchiyama et  al., 2011; Wu et al., 2016). The increased lipid excretion is potentially attributed to the pancreatic lipase inhibitory activity by black tea, thus resulting in low intestinal lipid absorption. Green, oolong, black, and pu-erh tea, TPS from black tea along with a blend of green, oolong, and puerh teas decrease serum as well as hepatic triglyceride, cholesterol, LDL, nonesterified fatty acid (NEFA), and lipid levels in obese animals (Braud et al., 2017; Huang and Lin, 2012; Rocha et al., 2016; Uchiyama et al., 2011; Wu et al., 2016) (Fig. 1.12). In the liver of obese rats, the total lipid content is correlated with increased lipid peroxidation.

Fig. 1.12  Protective role of tea and tea-derived polyphenols in obesity. BT, black tea; bTPS, black TPS; GT, green tea; OT, oolong tea; PT, pu-erh tea; and TF, theaflavin.

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The hepatic oxidative stress is alleviated by the blend of green, oolong, and pu-erh teas due to lowered MDA content via reduction in ROS production (Braud et  al., 2017) (Fig.  1.12). In high-fructose-fed rats, green, black, and pu-erh tea supplementation significantly inhibits the overexpression of fatty acid synthase (FAS), the enzyme involved in overproduction of hepatic triglyceride. These decreases are reliant on the tea-induced phosphorylation of AMPK (Huang and Lin, 2012), which inhibits the expression of lipogenic markers, including FAS (Fig.  1.12) (Srivastava et  al., 2012). HepG2 cells incubated with fatty acid have elevated intracellular lipid accumulation. Treatment with catechins, theaflavins, and their derivatives reduces the lipid content, with theaflavins exerting the highest protection. Among the different tea polyphenols, theaflavins are also the most potent inhibitors of triglyceride and cholesterol production. These antihepatic fat accumulation effects of black tea polyphenols are linked to the phosphorylation of AMPK that is mediated by liver kinase B1 (LKB1) pathway. Theaflavin-induced activated AMPK phosphorylates and inhibits the activity of acetyl-CoA carboxylase (ACC) and thus reduces the rate of fatty acid synthesis both in HepG2 cells and in the liver of rats under a HF diet (Fig. 1.12). Theaflavins as well as green tea induce fatty acid oxidation both in vitro and in vivo (Lin et al., 2007; Rocha et al., 2016). In HepG2 cells exposed to high glucose, green tea polyphenols enhance insulin-induced glucose and lipid metabolism by dose-dependently increasing glycogen synthesis and decreasing lipogenesis. Green tea polyphenols elevate the phosphorylation of glycogen synthase kinase 3β (GSK3β), which in turn mediates the phosphorylation of glycogen synthase (GS) that is involved in glycogen synthesis. Green tea polyphenols are also demonstrated to phosphorylate ACC via AMPK activation and lower lipid synthesis (Kim et al., 2013) (Fig. 1.12).

1.6.1 Antiinflammatory Potential The accumulation of fat is accompanied by immune system activation and recruitment of macrophages, resulting in increased circulating level of chemokines including monocyte chemoattractant protein 1 (MCP-1) (Fig. 1.13) (Tchernof and Després, 2013). In fat tissue, the HF diet induces an inflammatory state by upregulating MCP-1 expression, which is counteracted by decaffeinated extract from green, oolong, or black tea. Fat accumulation also mediates the release of proinflammatory cytokines due to hypoxia and adipocyte necrosis as a consequence of lowered microvessel density and blood circulation (Elias et al., 2012; Sung et al., 2013). Green tea-enriched extract promotes angiogenesis in fat tissue by increasing mRNA expressions of adiponectin and vascular endothelial growth factor A (VegfA). Black tea-enriched extract also stimulates angiogenesis by ­decreasing

Chapter 1  Tea, the “Ambrosia” Beverage: Biochemical, Cellular, Molecular, and Clinical Evidences  

Fig. 1.13  Antiinflammatory activity of tea and tea-derived polyphenol in obesity. BT, black tea; GT, green tea; OT, oolong tea; TF3, theaflavin-3,3′-digallate; and Quer, quercetin.

the gene overexpression of the inhibitor of angiogenesis, pigment epithelium-derived factor (Pedf ). The black tea extract concomitantly increases expression of vascular endothelial growth factor receptor 2 (Vegfr2), thus mediating the formation of new blood vessels. During obesity, angiogenesis in fat tissue exerts an antiinflammatory role by maintaining adipocyte perfusion (Heber et al., 2014) and by counteracting the state of hypoxia (Aprahamian, 2013). The proinflammatory microenvironment in obesity further promotes activation and infiltration of immune cells in adipose tissue (Fig. 1.13) (Johnson et al., 2012). Quercetin treatment alleviates the inflammatory response by reducing mast cell and macrophage recruitment in addition to decreasing levels of TNF-α, IL-6, and MCP-1 in adipose tissue and serum. Moreover, quercetin also exerts antiinflammatory activity by decreasing M1 macrophage (proinflammatory) number while increasing the number of M2 macrophages (antiinflammatory) (Johnson et  al., 2012; Dong

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et al., 2014). Quercetin also inhibits the expression of nitric oxide synthase 2 (NOS2), a marker for the M1 macrophage phenotype as well as induces expression of the marker for the M2 macrophage phenotype, macrophage galactose lectin 2 (MGL2) in adipose tissue and macrophages. Quercetin also inhibits IL-6, IL-1β, and MCP-1 expressions and enhances IL-10 level in macrophages. These antiinflammatory activities of quercetin occur via the activation of AMPK and phosphorylation and silent information regulator 1 (SIRT1) activation (Fig. 1.13) (Dong et al., 2014). In a coculture of 3 T3-L1 adipocyte and RAW264.7 macrophage system, theaflavin-3,3′-digallate shows antiinflammatory effect by inhibiting NO, MCP-1, TNFα, IL-6, and IL-1β levels as well as by inducing the production of IL-10 and adiponectin. Theaflavin-3,3′digallate also stimulates M2-like phenotype remodeling of macrophages from M1-like cells (Fig. 1.13). Theaflavin-3,3′-digallate further suppresses free fatty acid release through an AMPK-dependent pathway (Ko et  al., 2014) (Fig.  1.13). Lymphocytes from obese rats have increased proliferative capacity as a consequence of their preactivation. Free fatty acids, leptin, and high nutrient availability potentially activate the lymphocytes. When treated with green tea, the lymphocytes have lowered proliferative capacity. Green tea treatment further lowers levels of the proinflammatory markers IL-2, IL-6, IL-1β, and TNFα while inducing an increase in the antiinflammatory cytokine IL-10 content, as a potential consequence of increased adiponectin level. Green tea also exerts antiinflammatory activity by decreasing the mRNA expression of Toll-like receptor 4 (TLR4), which induces MAPK and NFκB pathways. In addition, green tea protects against the oxidative stress state by counteracting the elevated ROS and protein carbonyl levels in lymphocytes (Molina et al., 2015).

1.7  Protection Against Cardiovascular Disease CVD, since the past 15 years, is the leading cause of death worldwide. In 2015, this world’s biggest killer accounted for 15 million deaths (World Health Organization, 2017b). The risk factors of CVD include type II diabetes, obesity, hypertension, hypercholesterolemia, oxidative stress, inflammation, and endothelial dysfunction (Bøhn et al., 2012; Annuzzi et al., 2013). Teas, by virtue of their antioxidant, antiinflammatory, antidiabetic, and antiobesity activities help to reduce the risk of CVD. Teas also mitigate CVD by managing platelet function, reducing blood pressure, and suppressing endothelial dysfunction (Bøhn et al., 2012). The protective effects of tea consumption against CVD morbidity and mortality have been extensively studied. Tea and tea-derived

Chapter 1  Tea, the “Ambrosia” Beverage: Biochemical, Cellular, Molecular, and Clinical Evidences  

polyphenol consumption lowers the risk of ischemic heart disease, major coronary events (Li et  al., 2017), stroke (Kokubo et  al., 2013; Liang et al., 2009), and hypertension, and reduce CVD mortality (de Koning Gans et al., 2010; Dower et al., 2016; Kuriyama et al., 2006; Liu et al., 2016; Mineharu et al., 2011; Yang et al., 2004). Green tea supplementation also reduces the risk of development of coronary heart disease (CHD), with more prominent effects in obese or diabetic subjects (Tian et al., 2016). High polyphenol intake decreases some risk factors of CVD, that is, plasma glucose level, triglyceride content, and systolic blood pressure (Guo et al., 2016), thus indicating the beneficial effects of polyphenolic rich teas. As such, black tea consumption lowers triglyceride content, LDL/HDL plasma cholesterol ratio, and the inflammatory marker, C-reactive protein (Bahorun et al., 2010, 2012). In response to injury, functional impairment of the vascular endothelium occurs prior to the development of atherosclerosis (Grassi et  al., 2013). The progression of atherosclerosis, which involves the build-up of cholesterol and formation of fatty lesions in the arterial wall, is a key event in the development of CVD. Atherosclerosis results in vessel narrowing and constriction of normal blood flow. The rupture of the atherosclerotic lesion results in recruitment of circulating platelets, which are activated following binding of collagen in the extracellular matrix of endothelial cells to the collagen receptor of platelets. Additional circulating platelets are recruited to the growing thrombus by the activated platelets. This results in a platelet aggregate that forms a coronary thrombus. Platelets also induce an inflammatory response by recruiting leukocytes and progenitor cells to the site of injury (Bøhn et al., 2012). Polyphenols present in tea, such as EGCG, rutin, quercetin, (+)-catechin, and kaempferol, have ability to inhibit platelet aggregation (Choi et al., 2015, 2016; Mosawy et al., 2016; Sheu et al., 2004; Wright et al., 2010). Quercetin and (+)-catechin inhibit aggregation by potentially binding to ligands necessary for collagen-stimulated aggregation (Wright et al., 2010). Kaempferol and quercetin reduce platelet activation, decrease coagulation, and suppress thrombosis development (Choi et al., 2015, 2016). In apolipoprotein E (ApoE)−/− gene-knockout mice, lesion formation occurs at the aortic sinus and thoracic aortic region (Loke et al., 2010). ApoE−/− induces hypercoagulation and mediates atherosclerotic plaque stability (Borissoff et al., 2013). Atherosclerotic lesion formation is diminished with quercetin, theaflavin, (−)-epicatechin, chlorogenic acid, and (+)-catechin treatment in apoE−/− mice (Hayek et al., 1997; Loke et al., 2010). Quercetin attenuates lesion formation by increasing the expression of heme oxygenase-1 (HO-1), a protein that protects against inflammation during atherosclerosis. Quercetin and (−)-epicatechin reduce levels of the oxidative stress markers, F2•− isoprostanes and O2 . Quercetin and theaflavin prevent ­leukocyte

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recruitment and adhesion to endothelial cells by lowering the production of the chemotactic molecule leukotriene B4 (LTB4) and by reducing the plasma soluble P-selectin level (Fig.  1.14) (Loke et  al., 2010). EGCG treatment lowers vascular cell adhesion molecule 1 (VCAM-1) expression and inhibits P-selectin secretion in endothelial cells and thus reduces monocyte recruitment and adhesion (Ludwig et al., 2004; Mosawy et al., 2016; Pullikotil et al., 2012). It also prevents macrophage infiltration into the aorta of obese mice (Jang et al., 2013). The antiatherogenic activity of EGCG is achieved via the signaling pathway involving p38 MAPK, Nrf-2, and HO-1. Activation of p38 MAPK upregulates the expression of Nrf-2, which induces the expression of HO-1 and results in increased activity of HO-1. Elevated

Fig. 1.14  Protective role of tea and tea-derived polyphenols in CVD. BT, black tea; GT, green tea; OT, oolong tea; TF, theaflavin; and TB, thearubigins.

Chapter 1  Tea, the “Ambrosia” Beverage: Biochemical, Cellular, Molecular, and Clinical Evidences  

HO-1 levels are associated with low VCAM-1 expression (Pullikotil et  al., 2012). Kaempferol and quercetin also reduce VCAM-1, intracellular adhesion molecule 1 (ICAM-1), and E-selectin expressions in endothelial cells (Crespo et al., 2008) (Fig. 1.14). The endothelium synthesizes the vasoactive mediator nitric oxide (NO) by endothelial NO synthase (eNOS). NO has an antiinflammatory property as it prevents the adherence of leukocytes to the endothelial surface. It is also antithrombotic as it inhibits platelet adhesion and platelet aggregation. NO suppresses lesion formation by exerting antiproliferative effects on vascular smooth muscle cells. In addition, NO is a vasodilator molecule and regulates blood flow. In the presence of CVD risk factors, the endothelium undergoes structural and functional alterations, leading to low NO bioavailability (Grassi et al., 2013) and resulting in hypertension (Klinger et  al., 2013). The oxidative •− stress state in CVD decreases NO bioavailability as O2 reacts with − NO to form peroxynitrite (ONOO ). This powerful oxidant damages DNA, disrupts signaling pathways, and potentially inactivates certain proteins such as ion channels and enzymes due to tyrosine residue nitration (Koppula et al., 2012; Surh et al., 2001). ONOO− also induces the production of hydroxyl radicals thus increasing oxidative stress in CVD (Surh et al., 2001) and mediates vasoconstriction (Klinger et al., 2013). The oxidative stress state also elevates the level of angiotensin converting enzyme (ACE). ACE cleaves angiotensin I to produce angiotensin II, which causes vasoconstriction. ACE also induces the production of ROS, which in turn induces the phosphorylation of NFκB and results in the expression of proinflammatory markers (Siti et al., 2015). Gallic acid, chlorogenic acid, (+)-catechin, (−)-epicatechin, quercetin, kaempferol, epigallocatechin, and procyanidin dimer exert inhibitory action against ACE activity, with epigallocatechin and procyanidin dimer being more prominent inhibitors (Actis-Goretta et  al., 2006). Reduction in the activity of ACE reduces vasoconstriction and the ROS-induced inflammatory response. In stroke-prone spontaneously hypertensive rats (SHRSP), black and green tea polyphenols lower the systolic and diastolic blood pressure by enhancing NO-mediated vasodilatory tone. H2O2 is involved in the activation of myosin light chain (MLC), a major regulatory mechanism of smooth muscle contraction. The antihypertensive effect of black and green tea polyphenols is also mediated by the inhibition of smooth muscle contraction due to reduced expression of phosphorylated MLC as a consequence of increased expression of catalase, the scavenger of H2O2 (Negishi et al., 2004). Green tea, black tea, quercetin, catechins, theaflavins, and thearubigins enhance endothelial function by increasing the activation and activity of eNOS in endothelial cells (Aggio et al., 2013; Jochmann et al., 2008; Loke et al., 2010; Lorenz et al., 2009). The different treatments also promote vasorelaxation in precontracted

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aortic rings of rats by increasing the NO content (Aggio et  al., 2013; Jochmann et  al., 2008; Lorenz et  al., 2009). EGCG-induced NO production occurs via activation of fyn, which induces phosphorylation of the PI3K-AKT axis stimulating eNOS activation (Fig. 1.14) (Kim et al., 2007). In the vascular endothelium, insulin mediates vasodilator action. Obese mice are insulin resistant and have impaired endothelial function and vasodilation. EGCG supplementation increased insulin sensitivity in the obese mice and therefore afforded protection against endothelial dysfunction and vasocontraction (Jang et al., 2013). Numerous reports have demonstrated the accumulation of cholesterol, triglyceride, and LDL during obesity and diabetes (Braud et  al., 2017; Chen et  al., 2016; Huang and Lin, 2012; Knudsen et  al., 2016; Li et al., 2015; Wu et al., 2016). Cholesterol and triglyceride are transported from the liver to peripheral organs through LDL. To maintain cholesterol homeostasis, LDL is taken up into cells via the LDL receptor (Bøhn et al., 2012). High level of LDL causes its aggregation. Macrophages take up these aggregated LDL molecules at a faster rate and this results in foam cell formation (Fig. 1.14) (Hayek et al., 1997). These foam cells induce an inflammatory response in the blood vessel via release of cytokines (Bøhn et al., 2012). During oxidative stress, the oxidation of LDL occurs. Oxidized LDL (oxLDL) is taken up by macrophages via receptors that recognize oxLDL. The surplus of oxLDL loading transforms the macrophages into foam cells (Fig. 1.14) (Bøhn et al., 2012). oxLDL also alters endothelial function, induces platelet activation, impairs NO generation, mediates apoptosis of endothelial cells, stimulates proinflammatory and oxidative stress states, and thus promotes atherosclerosis (Kishimoto et al., 2013; Kostyuk et al., 2011; Mollace et al., 2015). Different types of tea-derived polyphenols have the ability to suppress LDL oxidation (Fig.  1.14) (Hayek et  al., 1997; Hodgson et  al., 2000; Leung et  al., 2001; Ohmori et  al., 2005). The galloylated catechins inhibit LDL oxidation by incorporating LDL (Suzuki-Sugihara et al., 2016). (+)-Catechin and quercetin inhibit aggregation of LDL by binding to LDL via formation of an ether bond (Hayek et al., 1997). In macrophages, (+)-catechin and quercetin reduce cellular uptake of LDL. (+)-Catechin and quercetin additionally increase paraoxonase (PON) activity (Hayek et  al., 1997). PON is a glycoprotein with antioxidant property when bound to LDL or HDL. PON reduces the oxidation of LDL and HDL, inhibits oxLDL-induced proinflammatory response, and hydrolyses H2O2 (Mogarekar et  al., 2016). Quercetin treatment counteracts the reduction in NO production and overproduction of O2 •− in endothelial cells exposed to oxLDL, thus inhibiting endothelial dysfunction (Kostyuk et  al., 2011). oxLDL induces a dose-dependent endothelial cell death and mediates increased ROS production. It also stimulates phosphorylation of p38 MAPK, nuclear translocation of NFκB, and expression of ICAM-1,

Chapter 1  Tea, the “Ambrosia” Beverage: Biochemical, Cellular, Molecular, and Clinical Evidences  

VCAM-1, and P-selectin. Myricetin and quercetin afford protection to endothelial cells exposed to oxLDL by inhibiting cell death and reducing ROS production and the inflammatory response (Yi et  al., 2012) (Fig. 1.14).

1.8  Neuroprotective Role of Tea Neurodegenerative diseases are characterized by a gradual loss of structure and function of the brain through death of neurons (building blocks of the central nervous system and spinal cord). The most common neurodegenerative diseases include Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS). AD is the first most common neurodegenerative disease, the sixth leading cause of death, and is among the top 10 that have no cure till date (Chastain and Moss, 2015). Currently, there are up to 32.8 millions of people suffering from AD worldwide (World Alzheimer’s Report, 2015). AD is characterized by the pathological aggregation of amyloid-β peptides (Aβ) and tau protein, both of which are toxic to neurons. Up to 10 million people worldwide are suffering from Parkinson’s disease, the second most common disease after AD (Parkinson News Today, 2017). PD is characterized by the loss of the neurotransmitter dopamine and neuronal degeneration in the substantia nigra (basal ganglia structure containing dopamine-­producing nerve cells). The most prevalent symptoms of these diseases include memory loss, forgetfulness, apathy, anxiety, agitation, and mood changes. The prevalence of such neurodegenerative diseases is increasing worldwide (Heemels, 2016) and is significantly deteriorating the health status and quality of life of patients (Batista and Pereira, 2016). Although environmental, genetic, and inflammatory factors contribute to the cause of neurodegenerative diseases, there is accumulating evidence that oxidative stress is the main causative factor (Aruoma et al., 2014; Kim et al., 2015). Brain tissue is particularly susceptible to oxidative stress due to its richness in polyunsaturated fatty acids—which can easily undergo lipid peroxidation (Federico et  al., 2012)—the high level of ATP consumption in brain (Uttara et al., 2009), and compromised antioxidant defense system in the brain (Niedzielska et al., 2016). While the exact molecular pathogenesis of neurodegeneration related to the disturbance of redox balance remains unclear (Liu et al., 2017), a vast number of studies have contributed to the understanding of the various mechanisms that can lead to neurodegeneration. The main cellular mechanisms include oxidative damage, mitochondrial dysfunction (Gandhi and Abramov, 2012; Hambright et  al., 2017; Pathak et  al., 2013), microglial activation (Durand et al., 2017; Lull and Block, 2010; Smith et al., 2012), and

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protein misfolding or aggregation (Kumar et al., 2016; Ludtmann and Abramov, 2016), most of which are interlinked (Fig.  1.15). Naturally occurring antioxidants as well as modified or synthetic compounds have been screened for biological activities that could be useful in the development of new therapies for diverse neurodegenerative conditions (Aruoma et  al., 2014). Teas have been widely studied for their putative antioxidant and antiinflammatory effects as well as their roles in the modulation of neurodegenerative diseases. Tea phytochemicals reported to exhibit neuroprotective effects include flavan-3-ols and oxidized products (catechins, theaflavins, and thearubigins), flavonol (myricetin), flavones (luteolin and apigenin), amino acids (l-theanine in green and black tea), vitamins (ascorbic acid, in green tea only), alkaloid methylxanthines (caffeine, theobromine, and theophylline), and phenolic acids. Reduction of Ca2+, upregulation of synaptic dysfunction related proteins, downregulation of apoptotic proteins

EGCG Theaflavin Luteolin L-Theanine Caffeine

EGCG myricetin

Activated microgllia Fc

Activated astrocyte

RAGE

EGCG sAPPα

Estrogen-α, PI3K/AKT, MAPK, IKK activation

Aβ aggregation CD36 Aβ

B/γ-secretase (e.g., BACE1)

α-secretase (e.g., ADAM9, 10), 17

EGCG luteolin

ATP

Ca

Ca

Apoptosis Ferroptosis Necrosis

Cell death

SOD

P P

P

2+

EGCG Restores

P

ROS

Protein mis or aggreg folding ation Ca 2+ dysre gulation

PKC activation

Caspase activation

Neuron

Cdk5, GSK-3b activation

Protein misfolding, Ca2– dysregulation

Mitochondrial 2+ dysfunction Ca

EGCG

EGCG, L-theanine

Lipid peroxidation, DNA damage

2+

Release of proinflammatory cytokines (TNF-α, IL-1β, IL-6, iNOS)

ERK1/p38 MAPK, NFκβ activation

ROS

APP

TLRs

GPx

EGCG

Tau tangles

Nucleus

Inflammatory and apoptotic genes

CAT

Compromised endogenous antioxidant system

ER stress

Nuclear DNA damage Neurodegeneration

GSK-3b, cAbl/GSK-3b, cAbI/FE65, activation

EGCG

Inflammation

Trigger Induce Inhibit

Fig. 1.15  Protective effects of tea bioactive compounds on neurodegeneration, with emphasis on Alzheimer’s disease.

Chapter 1  Tea, the “Ambrosia” Beverage: Biochemical, Cellular, Molecular, and Clinical Evidences  

EGCG exhibits its neuroprotective role through mechanisms including (1) downregulation of amyloid precursor protein (APP) and Aβ, (2) modulation of APP processing (Rezai-Zadeh et al., 2008, 2005)—through activation of α-secretase (nonamyloidogenic pathway) and inhibition of β-secretase activity (amyloidogenic pathway) (Okello et  al., 2004)—(3) inhibition of proinflammatory cytokine production (Li et al., 2006), (4) promotion of defense against oxidative stress and iron chelation, (5) restoration of levels of endogenous antioxidants (Li et al., 2006), (6) stabilization of mitochondrial function (Mandel et  al., 2008), and (7) downregulation of proapoptotic genes (Hou et  al., 2008) (Fig.  1.15). EGCG enhances maturation of ADAM10, thus promoting APP processing via the nonamyloidogenic pathway (α-secretase cleavage) (Obregon et al., 2006), the estrogen receptor-α/PI3K/AKT pathway, MAPK pathways (Baptista et  al., 2014), and the NF-κB mediated IKK pathway (Yang et al., 2011). EGCG also has an important role in inhibiting cdk-5 and GSK3β activation, preventing abnormal tau phosphorylation (Fig. 1.15). Catechins and theaflavins show different inhibitory abilities at varying mechanistic steps of the Aβ aggregation pathway. Catechins affect only the later stages of aggregation, suggesting that catechins may bind to a specific structure present in aggregates. On the other hand, theaflavins show inhibitory effects at every stage of aggregation, indicating a sequence-specific recognition. Furthermore, better Aβ aggregation inhibitory capabilities, for both polyphenol categories can be directly correlated with the number of gallate groups (Chastain and Moss, 2015). Additionally, EGCG inhibits microglial activationinduced neuronal injury in both AD and PD. Microglia (resident innate immune cells in the brain) are activated as an immune response to various stimuli, including even the smallest pathogen circulating in the brain, amyloid peptides, their precursor protein (APP), and neurofibrillary tau tangles (Zilka et al., 2012). In the early stages of AD, microglial activation can promote Aβ clearance via microglia’s scavenger receptors (SRs) (Yang et al., 2011) and hinder AD progression. The persistent microglial activation stimulated by Aβ via Fc receptors, toll-like receptors (TLRs) (Carty and Bowie, 2011), and AGE receptors, including CD36 and RAGE (Arancio et al., 2004; Bamberger et al., 2003; Wilkinson and El Khoury, 2012), can increase Aβ production and decrease Aβ clearance, ultimately causing neuronal damage. Inhibition of Aβ-induced microglial activation relieves the produc•− tion of inflammatory cytokines (TNF-α, IL-1β, IL-6, NO, and O2 ) (Liu and Bian, 2010), lowers Aβ deposition (Fleisher-Berkovich et al., 2010), and also improves behavior in vivo (Ralay Ranaivo et al., 2006). Such neuroprotective actions have been found to be exhibited by EGCG though inhibition of NO production, inducible nitric oxide synthase (iNOS), downregulation of cyclooxygenase-2 (COX-2) protein

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expression (Wu et  al., 2012), and TNFα expression (Cheng-Chung Wei et al., 2016) in microglial cells in vitro. Long-term administration of green-tea catechins lessened Aβ-induced cognitive impairment in animal models by increasing antioxidative defenses (Haque et  al., 2008). In addition, catechin gallates were shown to be neuroprotective against Aβ toxicity (Bastianetto et al., 2006). Phytochemicals in tea including flavan-3-ols, flavones, and phenolic acids can penetrate the blood-brain barrier (BBB) and exert neuroprotective effects. Much of orally ingested EGCG is hydrolyzed to EGC and gallic acid. EGC is then metabolized to 5-(3′,5′-dihydroxyphenyl)γ-­valerolactone (EGC-M5) and its conjugated forms, which are distributed to various tissues. LC-MS/MS analysis shows that these EGCG metabolites are stable for 0.5 h, suggesting that they may stably circulate in blood and reach the brain parenchyma via the BBB. EGC-M5, with smaller molecular size than EGCG, shows slightly higher permeability than EGCG and EGC (Pervin et al., 2017). Green tea-pill consumption (four pills of 500 mg each, per day) by patients for 2  months substantially decreases biomarkers of neurodegenerative oxidative stress, notably MDA concentration, 8-OHdG concentration, and carbonyl content concentration. In addition, green tea substantially increases the total antioxidant capacity of plasma concentrations and Mini-Mental State Examination scores, indicating improved cognitive functioning (Arab et al., 2016). Green tea extracts and EGCG improve cognitive dysfunction by antioxidant and antiinflammatory properties (Bitu Pinto et al., 2015) via upregulation of antioxidant protective enzymes, including SOD and CAT, two major oxygen radical species-metabolizing enzymes (Choi et al., 2012). Clinical trials and meta-analyses reveal that constant consumption of diets rich in polyphenols protect against chronic inflammatory diseases like neurodegenerative diseases in humans (Venigalla et al., 2016). Studies revealed EGCG to improve dopaminaergic degeneration and may be beneficial for Parkinson’s patients (Renaud et al., 2015). In a rat model for Parkinson’s, green-tea extract or EGCG reversed pathological and behavioral modifications, demonstrating neuroprotection by decreasing rotational and increasing locomotor activities (Bitu Pinto et al., 2015; Oz, 2017). Apart from EGCG, other flavonoids, such as the flavone luteolin, reduce toxic levels of Aβ and mitochondrial dysfunction in AD brains (Mao and Reddy, 2011). Luteolin is superior to quercetin in inhibition of monoamine oxidase-A (MAO-A) activity, which regulates serotonin metabolism (Bandaruk et  al., 2012). Myricetin inhibits Aβ aggregation—especially oligomerization—in  vitro (Ono et  al., 2003) and in vivo (Ono et al., 2012). Theaflavins show potential in inhibition of Aβ and α-synuclein fibrillogenesis (Grelle et al., 2011). Theaflavin

Chapter 1  Tea, the “Ambrosia” Beverage: Biochemical, Cellular, Molecular, and Clinical Evidences  

attenuates 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid (MPTP/p1)-induced apoptosis and neurodegeneration by increasing nigral tyrosine hydroxylase and dopamine transporter and reducing apoptotic markers such as caspase-3, 8, and 9 (Anandhan et al., 2012). l-Theanine, an amino acid present in large amounts in green and black teas, has antioxidative properties and neuroprotective effects through inhibition of both Aβ-induced oxidative stress and activation of the pathways, ERK1/p38 MAPK and NKκB (Kim et al., 2009). l-Theanine readily crosses the BBB where it exerts a variety of neurophysiological and neuropharmacological effects (Lardner, 2014). l-Theanine in as low as typical serving doses of tea (20 mg) (Kobayashi et  al., 1998; Nobre et  al., 2008; Song et  al., 2003) promotes relaxation without causing drowsiness by stimulating alpha brain wave activity that is normally associated with a wakeful relaxation state via the inhibition of cortical neuron excitation (Fernando et al., 2017). l-Theanine is a natural glutamate antagonist that may protect and prevent neuronal death (Kakuda, 2011). Death of hippocampal CA1 (cornus ammonis) pyramidal neurons by transient forebrain ischemia and death of the hippocampal CA3 region by kainite are prevented by the administration of l-theanine (Kakuda, 2002). l-Theanine and caffeine lead to improvements in cognition, enhanced speed, accuracy of attention-related performances, mental clarity, and alertness in mood as well as in work performance (Bryan et al., 2012). Caffeine has a dose-dependent effect and known to affect mood, attention, and cognition. Moderate doses of caffeine (200–300 mg/ day) improve the feeling of well-being and increase motivation and energy for work, while higher doses (>400 mg/day) induce anxiety, nausea, and nervousness (Fenu and Acquas, 2013). Caffeine is a nonselective blocker of A1 and A2a adenosine receptors that stimulate cholinergic neurons. Chronic caffeine administration was shown to have neuroprotective effects in a mouse model of AD, indicating that decreased Aβ production is a likely mechanism (Arendash et al., 2006). Moreover, both caffeine and adenosine A2a receptor antagonists prevent Aβ-induced cognitive deficits in mice (Dall'Igna et al., 2007). There is accumulating evidence of the putative prophylactic and therapeutic roles of tea in neurodegenerative diseases. Their rising prevalence warrants further research to identify and characterize natural bioactive compounds for use in the prevention and treatment of these diseases. To ensure effective use of novel neuroprotective compounds, it is also important to elucidate aspects of bioavailability to the specific targets in the brain as well as their intricate molecular mechanisms of action.

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1.9 Conclusion Tea is an integral part of the diet across the world and highly valued for its health benefits. Much of its prophylactic and curative effects are attributed to its polyphenolic richness. The phenolics and flavonoids present in tea are powerful antioxidants and provide protection against the underlying pathophysiological hallmarks of a number of chronic diseases such as diabetes, obesity, CVD, and neurodegeneration. Tea and tea-derived compound(s) afford protection to the pancreas, kidneys, liver, eye, adipose tissue, circulatory, and nervous systems via different mechanisms of action at the cellular level. The intricate signaling mechanisms have been partly elucidated but warrant further investigations due to the complexity of certain pathologies. Despite this, the different varieties of tea are gaining popularity as their health benefits are increasingly being recognized and accepted across the world.

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Chapter 1  Tea, the “Ambrosia” Beverage: Biochemical, Cellular, Molecular, and Clinical Evidences  

Pereira, V.P., Knor, F.J., Vellosa, J.C.R., Beltrame, F.L., 2014. Determination of phenolic compounds and antioxidant activity of green, black and white teas of Camellia sinensis (L.) Kuntze. Theaceae. Rev. Bras. Plantas Med. 16, 490–498. Pervin, M., Unno, K., Nakagawa, A., et  al., 2017. Blood brain barrier permeability of (−)-epigallocatechingallate, its proliferation-enhancing activity of human ­neuroblastoma SH-SY5Y cells, and its preventive effect on age-related cognitive dysfunction in mice. Biochem. Biophys. Rep. 9, 180–186. Peterson, J., Dwyer, J., Bhagwat, S., Haytowitz, D., Holden, J., Eldridge, A.L., Beecher, G., Aladesanmi, J., 2005. Major flavonoids in dry tea. J. Food Compos. Anal. 18, 487–501. Piwowar, A., Knapik-Kordecka, M., Szczecińska, J., Warwas, M., 2008. Plasma glycooxidation protein products in type 2 diabetic patients with nephropathy. Diabetes Metab. Res. Rev. 24, 549–553. Price, D.L., Rhett, P.M., Thorpe, S.R., Baynes, J.W., 2001. Chelating activity of advanced glycation end-product inhibitors. J. Biol. Chem. 276, 48967–48972. Prior, R.L., Wu, X., Schaich, K., 2005. Standardized methods for the determination of antioxidant capacity and phenolics in foods and dietary supplements. J. Agric. Food Chem. 53, 4290–4302. Pullikotil, P., Chen, H., Muniyappa, R., Greenberg, C.C., Yang, S., Reiter, C.E., Lee, J.W., Chung, J.H., Quon, M.J., 2012. Epigallocatechin gallate induces expression of heme oxygenase-1 in endothelial cells via p38 MAPK and Nrf-2 that suppresses pro-­ inflammatory actions of TNF-α. J. Nutr. Biochem. 23, 1134–1145. Ralay Ranaivo, H., Craft, J.M., Hu, W., Guo, L., Wing, L.K., Van Eldik, L.J., Watterson, D.M., 2006. Glia as a therapeutic target: selective suppression of human amyloid-beta-induced upregulation of brain proinflammatory cytokine production attenuates neurodegeneration. J. Neurosci. 26 (2), 662–670. Ramachandran, V., Saravanan, R., 2015. Glucose uptake through translocation and activation of GLUT4 in PI3K/Akt signaling pathway by asiatic acid in diabetic rats. Hum. Exp. Toxicol. 34, 884–893. Ramlagan, P., Rondeau, P., Planesse, C., Neergheen-Bhujun, V.S., Bourdon, E., Bahorun, T., 2017a. Comparative suppressing effects of black and green teas on the formation of advanced glycation end products (AGEs) and AGE-induced oxidative stress. Food Funct. https://doi.org/10.1039/c7fo01038a. Ramlagan, P., Rondeau, P., Planesse, C., Neergheen-Bhujun, V.S., Fawdar, S., Bourdon, E., Bahorun, T., 2017b. Punica granatum L. mesocarp suppresses advanced glycation end products (AGEs)- and H2O2-induced oxidative stress and pro-­inflammatory biomarkers. J. Funct. Foods 29, 115–126. Rasheed, Z., Anbazhagan, A.N., Akhtar, N., Ramamurthy, S., Voss, F.R., Haqqi, T.M., 2009. Green tea polyphenol epigallocatechin-3-gallate inhibits advanced glycation end product-induced expression of tumor necrosis factor-α and matrix ­metalloproteinase-13 in human chondrocytes. Arthritis Res. Ther. 11, https://doi.org/10.1186/ar2700. Rasheed, Z., Akhtar, N., Haqqi, T.M., 2011. Advanced glycation end products induce the expression of interleukin-6 and interleukin-8 by receptor for advanced glycation end product-mediated activation of mitogen-activated protein kinases and nuclear factor-κB in human osteoarthritis chondrocytes. Rheumatology (Oxford) 50, 838–851. Renaud, J., Nabavi, S.F., Daglia, M., Nabavi, S.M., Martinoli, M.G., 2015. Epigallocatechin3-gallate, a promising molecule for Parkinson’s disease? Rejuvenation Res. 18 (3), 257–269. Rezai-Zadeh, K., Shytle, D., Sun, N., Mori, T., Hou, H., Jeanniton, D., Ehrhart, J., Townsend, K., Zeng, J., Morgan, D., Hardy, J., Town, T., Tan, J., 2005. Green tea epigallocatechin-3-gallate (EGCG) modulates amyloid precursor protein cleavage and reduces cerebral amyloidosis in Alzheimer transgenic mice. J. Neurosci. 25 (38), 8807–8814.

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Chapter 1  Tea, the “Ambrosia” Beverage: Biochemical, Cellular, Molecular, and Clinical Evidences  

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Further Reading Choi, Y.T., Jung, C.H., Lee, S.R., Bae, J.H., Baek, W.K., Suh, M.H., Park, J., Park, C.W., Suh, S.I., 2001. The green tea polyphenol (−)-epigallocatechin gallate attenuates ­beta-amyloid-induced neurotoxicity in cultured hippocampal neurons. Life Sci. 70, 603–614.

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ESSENTIAL ELEMENT CONTENTS OF TURKISH BLACK TEA

2

Ayse Dilek Atasoy⁎, Mehmet Irfan Yesilnacar⁎, Ahmet Ferit Atasoy† *

Department of Environmental Engineering, Harran University, Sanliurfa, Turkey †Department of Food Engineering, Harran University, Sanliurfa, Turkey

2.1 Introduction Tea has gained the world’s taste in the past 2000 years as one of the most popular nonalcoholic beverages, next to water. The economic and social interest of tea is easily understood from the fact that about 18–20 billion cups of tea are consumed daily in the world (Mandiwana et al., 2011). Tea is grown in an area of 762,008 ha in Turkey. The annual tea production in Turkey and world was 212,400 and 5,345,523 tones, respectively. Black tea is generally processed by a fermentation method that allows for the effective action of polyphenol oxidase enzymes and this process causes the leaves to blacken. Drying is applied to stop the oxidation process, thereby resulting in a long-lasting, stable tea product (Robertson, 1992). The consumption of tea is regarded as an important source of several essential and nonessential elements, including major dietary elements (Ca, K, and Mg), minor and trace minerals (Cu, Fe, Mn, Na, Sr, and Zn), and heavy metals (Al, Cd, Cr, Ni, and Pb) (Szymczycha-Madeja et al., 2015). Tea drinking has both positive and negative impacts on human health (Dambiec et  al., 2013). The health benefits of tea have been well documented. The beverage of tea may be an important source of essential major or mineral dietary inorganic elements (BrzezichaCirocka et al., 2016). Although tea is considered a healthy beverage, we should keep in mind its potentially toxic effects, which have been neglected in the past (Polechonska et al., 2015). C. sinensis (tea tree) was reported as an aluminum-accumulating plant in previous research works (Mossion et al., 2008). It also tolerates and accumulates elevated quantities of F and Pb (Szymczycha-Madeja et al., 2015). Atasoy et al. (2016) studied the fluoride content of Turkish and Ceylon teas and the Non-alcoholic Beverages. https://doi.org/10.1016/B978-0-12-815270-6.00002-5 © 2019 Elsevier Inc. All rights reserved.

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64  Chapter 2  Essentıal Element Contents of Turkish Black Tea

average daily fluoride intake of the human body. They determined the fluoride content of Turkish and Ceylon black and green tea infusions (2 g/100 mL) using an ion selective electrode. They identified dental fluorosis in school-age children because of the excessive intake of fluoride with black tea and the high-fluorine drinking water. Industrial wastes, agricultural applications, mining activities, and emissions are the main pollution sources of metals in the environment. Traces of undesirable and toxic metals from these sources can easily contaminate tea plants. Tea is known as a healthful beverage with bioactive molecules and high antioxidant activity (Mejia et al., 2009). Antioxidant activity is defined “as an limitation of the oxidation of proteins, lipids, DNA or other molecules that occurs by blocking the propagation stage in oxidative chain reactions” and primary antioxidants directly scavenge free radicals, while secondary antioxidants indirectly prevent the formation of free radicals through Fenton’s reaction (Huang et al., 2005). Black tea leaves and infusions include flavonoids such as oligomeric theaflavins and thearubigins formed in the oxidation process. Flavonoids are the most abundant polyphenolic compounds in fresh tea leaves and extracts, and they are primarily responsible for the beneficial healthful properties of tea. They exhibit antioxidant, antiinflammatory, antiallergic, and antimicrobial properties (Pękal et al., 2013). For the production of green tea, freshly gathered leaves are rapidly fried to inactivate the enzyme polyphenol oxidase, as a result of preventing fermentation and producing a dry, constant product. The fresh leaves are allowed to wither to produce black tea, until their moisture grade is lowered to 55%). They determined the lowest K content in tea from Argentina and Vietnam and the highest in tea from Central India. Kumar et  al. (2005) and Soomro et  al. (2008) also reported high K concentration in Indian and Chinese teas, respectively. Kumar et  al. (2005) suggest that it may be specifically incorporated within a binding ligand in the tea leaves. Mahani and Maragheh (2011) observed that about 90% of the Na and K elements were extracted to tea infusions. They found a considerable amount of Mn in tea leaves. Despite the extraction efficiency of 50%, tea is a rich source of manganese. Average Cu and Zn concentrations in Turkish black tea infusions were determined to be 0.08 and 0.24 mg/L, respectively. Jin et al. (2008) claimed that people who consume large amounts of tea (e.g., 10 g of tea leaves per day) may not necessarily be at any risk as the daily intake of Cu from such tea drinking is less than 0.4 mg. This is true because the recommended daily consumption of Cu for adults as issued by the US Air Force is 1.5–3.0 mg (US AF, 1990). Welna et  al. (2012) reported that when total concentrations of elements in tea infusions are measured and considered, it appears that the intake of 1 L of tea per day may contribute 2.0%–6.4% of

Chapter 2  Essentıal Element Contents of Turkish Black Tea   69

Cu, 89.5%–290% of Mn, and 1.3%–2.1% of Zn to the respective RDAs (Recommended Dietary Allowance) of these elements. Average Al and Fe contents of Turkish black tea infusions were found to be 11.6 and 0.16 mg/L, respectively. Polechonska et al. (2015) analyzed black teas in Poland for Zn, Mn, Cd, Pb, Ni, Co, Cr, Al, and Fe concentrations both in dry material and their infusions. Generally, the most abundant trace metals in both types of tea were Al and Mn. They found a wide variation in percentage transfer of elements from the dry tea materials to the infusions. Fe was insoluble and only a small portion of this metal content was determined in the infusion. With respect to the acceptable daily intake of metals, they found the infusions of teas analyzed to be safe for human consumption. Numerous studies have demonstrated the presence of Al in tea due to the acidic soils where tea plants are grown (Karak and Bhagat, 2010) as well as through tea processing. Some studies have revealed the high capacity of the tea plant to accumulate aluminum (Al), a neurotoxic element; therefore, it is necessary to control the intake of food with high amounts of this metal. One study reported that black tea contains approximately sixfold more Al than green tea, and the extraction of Al in black teas was higher than in the green teas. Aluminum is the most specific inorganic element in tea plants and tea leaves contain relatively higher Al than other plants (Shu et al., 2003). The variations in Al content may be due to different soil conditions, different harvesting periods, and the influence of the water quality (Khizar et al., 2015). Most of the elements in cured tea leaves, especially metals ions, are complexed by flavonols, catechols, tannins, and PPs. The content of tannins is negatively correlated with concentrations of Al, Cr, Cu, Fe, and Mn in tea infusions due to the binding of these metals and the formation of their insoluble complexes. Among different elements, Al seems to be the most strongly associated with polyphenolic compounds in the tea matrix. The chelating activity of PPs and caffeine toward Cu, Fe, and Zn is also high but lower than that established for Al. The lowest degree of the complexation by PPs can be observed for Mn (Welna et al., 2012). Barone et al. (2016) investigated the trace elements (Hg, Cd, Pb, Cu, Zn, Ni, Fe, Cr, and Se) in green and black tea marketed in Italy. They found Fe to be the most abundant element followed by Zn, Cu, Se, Ni, and Cr, whereas Pb was the predominant among the analyzed nonessential elements followed by Hg and Cd. Mg and Ca contents of Turkish black tea were found to be 12.86 and 9.73 mg/L, respectively. It appears that Mg is also quite easily extracted as a component of chlorophyll. Another alkaline earth element, that is, Ca is strongly trapped inside plant cells and for that reason extraction efficiencies for these elements are relatively lower. Differences in extraction efficiencies for transition metals, for example, Cu, Fe, Mn, Ni,

70  Chapter 2  Essentıal Element Contents of Turkish Black Tea

and Zn, are difficult to explain, but they probably reflect the ionic and covalent characteristics of these elements (Matsuura et al., 2001). Na is one of the major constituents in black teas. In the present research, the average Na content was 6.54 mg/L. Soomro et al. (2008) and Yemane et al. (2008) noted higher Na contents in tea from China and Ethiopia (880 and 964 mg/kg, respectively). The percentage transfer of the total Na content to the infusion was lower than 65%, reported by Soomro et al. (2008). Szymczycha-Madeja et al. (2012) also classified Na as highly extractable (>55%). Both essential mineral elements and toxic metals are extracted into tea infusion. Studies showed that heavy metal contents of tea infusions were generally lower than those in tea leaves. Some trace elements are essential for the normal functioning of the human organism and several have health-promoting properties. The main sources of trace metals in plants are their growth media, nutrients, soil, and agrochemical inputs, including pesticides and fertilizers (Dambiec et al., 2013). The regular consumption of tea contributes to the daily dietary requirements of several essential elements. The highest metal content was affirmed in black tea while the lower metal content was in green tea and herbal tea (Mandiwana et al., 2011). Despite the high toxic element levels in some of tea leaf samples, trace element concentrations in infusions were measured to be at safe levels (Milani et al., 2016).

2.4 Conclusions Tea is a source of a large variety of essential and nonessential elements including major dietary metals (Ca, K, and Mg), minor and trace minerals (Cu, Fe, Mn, Na, Sr, and Zn), and heavy metals (Al, Cd, Cr, Ni, and Pb). It is considered a healthy beverage with bioactive molecules and high antioxidant activity. Generally, K was found as the most abundant macroelement in Turkish black tea followed by Mg, Al, Ca, Mn, and Na whereas Al was prominent among the trace metals tested, followed by Mn, Zn, Fe, Ni, and Cu. On the other hand, Cd, Cr, Hg, and Pb were not detected. While the tea plant has a strong potential to uptake and accumulate several elements from the soil, tea infusion may serve as a dietary source of different micronutrients for humans. However, different opinions also prevail about the safety of tea drinking by taking into consideration such nonessential or trace element accumulation in the human body. Tea is an Al-accumulating plant. It also tolerates and accumulates elevated quantities of F and Pb. For example, excessive intake of fluoride with black tea increased dental fluorosis cases in children. Thus, more focus should be placed on monitoring heavy metal contents in tea infusion and studying their health risk to tea consumers. The quality of tea plants and infusions should be determined to avoid overconsumption and their toxicities

Chapter 2  Essentıal Element Contents of Turkish Black Tea   71

in long-term use. Trace element contents of tea plants, their toxic effects, and intake by humans must be known. The origin of the tea as well as the water sources must also be regarded.

References APHA, 1998. Standard Methods for the Examination of Water and Wastewater, twentieth ed. American Public Health Association, Washington. Atasoy, A.D., Yesilnacar, M.I., Atasoy, A.F., 2016. Evaluation of fluoride concentration and daily intake by human from tea infusions. Harran Tarım ve Gıda Bilimleri Dergisi 20 (1), 1–6. Barone, G., Giacominelli-Stuffler, R., Storelli, M.M., 2016. Evaluation of trace metal and polychlorinated biphenyl levels in tea brands of different origin commercialized in Italy. Food Chem. Toxicol. 87, 113–119. Brzezicha-Cirocka, J., Grembecka, M., Szefer, P., 2016. Monitoring of essential and heavy metals in green tea from different geographical origins. Environ. Monit. Assess. 188, 183. Cabrera, C., Artacho, R., Giménez, R., 2006. Beneficial effects of green tea—a review. J. Am. Coll. Nutr. 25 (2), 79–99. Dambiec, M., Polechonska, L., Klink, A., 2013. Levels of essential and non-essential elements in black teas commercialized in Poland and their transfer to tea infusion. J. Food Compos. Anal. 31, 62–66. Huang, D., Ou, B., Prior, R.L., 2005. The chemistry behind antioxidant capacity assays. J. Agric. Food Chem. 53, 1841–1856. Jeszka-Skowron, M., Krawczyk, M., Zgola-Grzeskowiak, A., 2015. Determination of antioxidant activity, rutin, quercetin, phenolic acids and trace elements in tea infusions: influence of citric acid addition on extraction of metals. J. Food Compos. Anal. 40, 70–77. Jin, C.W., Du, S.T., Zhang, K., Lin, X.Y., 2008. Factors determining copper concentration in tea leaves produced at Yuyao County, China. Food Chem. Toxicol. 46 (6), 2054–2061. Karak, T., Bhagat, R.M., 2010. Trace elements in tea leaves, made tea and tea infusion: a review. Food Res. Int. 43 (9), 2234–2252. Khizar, H., Hira, I., Uzma, M., Uzma, B., Sobia, M., 2015. Tea and its consumption: benefits and risks. Crit. Rev. Food Sci. Nutr. 55 (7), 939–954. Kottiappan, M., Dhanakodi, K., Annamalai, S., Anandhan, S.V., 2013. Monitoring of pesticide residues in South Indian tea. Environ. Monit. Assess. 185, 6413–6417. Kumar, A., Nair, A.G.C., Reddy, A.V.R., Garg, A.N., 2005. Availability of essential elements in Indian and US tea brands. Food Chem. 89 (3), 441–448. Lin, L.-Z., Chen, P., Harnly, J.M., 2008. New phenolic components and chromatographic profiles of green and fermented teas. J. Agric. Food Chem. 56, 8130–8140. Liu, H., Deng, S., Li, Z., Yu, G., Huang, J., 2010. Preparation of Al–Ce hybrid adsorbent and its application for defluoridation of drinking water. J. Hazard. Mater. 179, 424–430. Mahani, M.K., Maragheh, M.G., 2011. Simultaneous determination of sodium, potassium, manganese and bromine in tea by standard addition neutron activation analysis. Food Anal. Methods 4, 73–76. Mandiwana, K.L., Panichev, N., Panicheva, S., 2011. Determination of chromium(VI) in black, green and herbal teas. Food Chem. 129, 1839–1843. Matsuura, H., Hokura, A., Katsuki, F., Itoh, A., Haraguchi, H., 2001. Multielement determination and speciation of major-to-trace elements in black tea leaves by ICPAES and ICP-MS with the aid of size exclusion chromatography. Anal. Sci. 2001 (17), 391–398.

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Mejia, E.G., Ramirez-Mares, M.V., Puangpraphant, S., 2009. Bioactive components of tea: cancer, inflammation and behavior. Brain Behav. Immun. 23, 721–731. Milani, R.F., Morgano, M.A., Cadore, S., 2016. Trace elements in Camellia sinensis marketed in southeastern Brazil: extraction from tea leaves to beverages and dietary exposure. LWT Food Sci. Technol. 68, 491–498. Mossion, A., Potin-Gautier, M., Delerue, S., Le Hecho, I., Behra, P., 2008. Effect of water composition on aluminium, calcium and organic carbon extraction in tea infusions. Food Chem. 106, 1467–1475. Pękal, A., Biesaga, M., Pyrzynska, K., 2013. Trace metals and flavonoids in different types of tea. Food Sci. Biotechnol. 22 (4), 925–930. Polechonska, L., Dambiec, M., Klink, A., Rudecki, A., 2015. Concentrations and solubility of selected trace metals in leaf and bagged black teas commercialized in Poland. J. Food Drug Anal. 23, 486–492. Robertson, A., 1992. In: Wilson, K.C., Clifford, M.N. (Eds.), The Chemistry and Biochemistry of Black Tea Production-the Non-Volatiles, Tea Cultivation to Consumption. Chapman and Hall, Springer, Netherlands, pp. 555–601. Shu, W.S., Zhang, Z.Q., Lan, C.Y., Wong, M.H., 2003. Fluoride and aluminium concentrations of tea plants and tea products from Sichuan Province, PR China. Chemosphere 52 (9), 1475–1482. Soomro, M.T., Zahir, E., Mohiuddin, S., Khan, A.N., Naqvi, I.I., 2008. Quantitative assessment of metals in local brands of tea in Pakistan. Pak. J. Biol. Sci. 11 (2), 285–289. Sucman, E., Bednar, J., 2012. Determination of fluoride in plant material using microwave induceed oxygen combustion. Czech J. Food Sci. 30 (5), 438–441. Szymczycha-Madeja, A., Welna, M., Pohl, P., 2012. Elemental analysis of teas and their infusions by spectrometric methods. Trends Anal. Chem. 35, 165–181. Szymczycha-Madeja, A., Welna, M., Pohl, P., 2015. Determination of essential and non-essential elements in green and black teas by FAAS and ICP OES simplified— multivariate classification of different tea products. Microchem. J. 121, 122–129. US AF (US Air Force), 1990. Copper. In: The Installation Program Toxicology Guide. vol. 5. Wright-Patterson Air Force Base, Ohio, pp. 1–43. Welna, M., Szymczycha-Madeja, A., Stelmach, E., Pohl, P., 2012. Speciation and fractionation of elements in tea infusions. Crit. Rev. Anal. Chem. 42 (4), 349–365. Yemane, M., Chandravanshi, B.S., Wondimu, T., 2008. Levels of essential and nonessential metals in leaves of the tea plant (Camellia sinensis L.) and soil of Wushwush farms, Ethiopia. Food Chem. 107 (3), 1236–1243.

FUNCTIONAL NONALCOHOLIC BEVERAGES: A GLOBAL TREND TOWARD A HEALTHY LIFE

3

Huma Bader-Ul-Ain⁎, Munawar Abbas⁎, Farhan Saeed⁎, Sana Khalid†, Hafiz Ansar Rasul Suleria‡,§ ⁎

Institute of Home and Food Sciences, Government College University Faisalabad, Faisalabad, Pakistan †Department of Pharmaceutical Sciences, Government College University Faisalabad, Faisalabad, Pakistan ‡UQ Diamantina Institute, Translational Research Institute, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia §Department of Food, Nutrition, Dietetics and Health, Kansas State University, Manhattan, KS, United States

3.1 Introduction Nowadays, functional foods and beverages have been extensively used for the management and treatment of certain diseases. Apart from the nutritional aspect, the production and utilization of functional foods and beverages as a health benefit is gradually increasing. Over the past few years, the quest for the provision of healthy foods and drinks has been amplified globally (Ozen, 2012). The emergence of functional foods commercially has reduced the discrepancy between pharmaceuticals and nutraceuticals (Eussen et  al., 2011). Hippocrates, the father of Western medicine, recognized the potential of certain foods for good health and very gracefully wrote that “Let food be thy medicine and medicine be thy food.” Presently, advancement in scientific research highlights the importance of diet and beverages to be used therapeutically in some pathological conditions (Otles and Cagindi, 2012). The philosophy behind functional foods and beverages is: “Focus on Prevention.” In recent years, beverages have become a well-known class of functional foods due to their capacity to fulfill the market standards for container dimensions and characterization, in addition to storage conditions for the products stable at room temperature as well as refrigeration and ease of distribution. Furthermore, they are remarkable for extracting commercial biological compounds such as essential Non-alcoholic Beverages. https://doi.org/10.1016/B978-0-12-815270-6.00003-7 © 2019 Elsevier Inc. All rights reserved.

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minerals, vitamins, antioxidant species, fatty acids, plant extractables, fibrous materials, prebiotic, and probiotic substances. A functional beverage is a nonalcoholic drink product and its formulation constituents may include one or more from the herbs, amino acids, vitamins, minerals, and crude vegetables or fruits categories (Sanguansri and Augustin, 2009; Wootton-Beard and Ryan, 2011; Kausar et al., 2012). Recent studies from the literature have highlighted the primary features of functional beverages such as (Ozen, 2012; Bigliardi and Galati, 2013; Lau et al., 2013) probiotic functional beverages (Prado et al., 2008; Granato et al., 2010a,b; Ozer and Kirmaci, 2010), fermentation based (Marsh et al., 2014), fruit and vegetable beverages (Sun-Waterhouse, 2011), energy beverages (Heckman et  al., 2010a,b; Committee on Nutrition and the Council on Sports Medicine and Fitness, 2011), and drinks used during sports/athletics (Committee on Nutrition and the Council on Sports Medicine and Fitness, 2011). However, no published citations of functional beverages provide a complete detailed picture of all the distinctive features (Table 3.1). Functional beverages vary according to availability in a geographical area, but they are an important part of the lifestyle for every region. Dairy beverages are more likely to be favored by Asian countries whereas US and European countries prefer products ranging from enhanced waters to juice beverages. Sports and energy beverages are enormously consumed in Mexico as well as South America. Functional beverages improve our everyday lives and their consumption is prevalent in most of the regions. Basically, they help us to enhance our nutritional status, keep the body hydrated, help to prevent pathological conditions, and may contribute to our athletic performance. In the past few years, there has been a rapid increase in the beverage industry and this is very clear by observing the grocery stores in North America. Consumers have more beverage choices than before, the number of beverages has increased and are of many kinds and very specific and representing an extension of an individual’s personality, including beverages that boost up the energy level, narrow waists, enhance cognition, prevent pain related to bone and joint problems, etc. Moreover, based on demographics there are some beverages used specifically for different age groups and sexes such as children, elders, and females. This diverse nature fuels consumer demand. Functional beverages are recognized with health benefits to organs such as the heart, gastrointestinal tract, joints, and enhanced immune functions (Sun-Waterhouse, 2011).

3.2  Global Market The rise in the functional food market has been associated with a steady increase of functional food product introductions. Sorenson and Bogue (2009) reported that there was a twofold increase in the

Chapter 3  Functional Nonalcoholic Beverages: A Global Trend Toward a Healthy Life   75

Table 3.1  Different Food and Beverages With Their Bioactive Compounds Diseases

Mechanism

Foods

Cancer

• Cell cycle arrest results in the activation of mitochondrial pathway • Modulation of oxidative stress, amelioration of inflammation • Antioxidant activity and antiinflammatory effects • Boost of cardiovascular system aspects, Inhibition of platelet aggregation, and Prevention of hyperhomocysteinemia • Disturbance of the balance between antioxidant defense mechanisms and the levels of reactive oxygen species (ROS), due to the induction of CVD, diabetics, and other metabolic syndromes • Due to the excess intake of foods

Fruit, vegetables, and dairy beverage

Cardiovascular diseases

Antioxidant activity

Obesity

Bioactive Compound

Reference

Catechins, caffeine, phytophenols, polyphenols, quercetin, and flavanols β-carotene polyphenols vitamin C Carotenoid riboflavin and vitamin B-12

Cooper et al. (2005a,b), Madkor et al. (2012), Demeule et al. (2002), Lin et al. (1999), Wang et al. (2015)

Fruits and vegetables juices

Phenolic compounds vitamins flavonoids

Gutteridge and Halliwell (2010), AlOlayan et al. (2014), Foroudi et al. (2014)

Fruit, vegetables, and dairy beverage

Anthocyanin polyphenolic content, essential amino acids

Gilbert et al. (2011), Bendtsen et al. (2013), Oliveira et al. (2013a,b)

Fruits and vegetables juices

market of these products between the years 2005 and 2009. Between 2008 and 2009, US was leading in these product launches with 881 products, followed by Japan, Italy, UK, Germany, and France. It is not possible to analyze the world's functional food markets, owing to the deficiency of a precise definition of functional food meeting the international standards (Ozen, 2012; Valls et al., 2013). Hence, functional food market studies of the world vary in sales. Under a strict definition, the market of functional food and beverages had a collective value of $19.4 billion (2007); however, with an extensive definition, this value is increased up to $41.9 billion. The world market for a broader definition of functionally active products contributing specific health

Habauzit et al. (2015), Poudyal et al. (2010), Appel et al. (1997), Eno et al. (2000)

76  Chapter 3  Functional Nonalcoholic Beverages: A Global Trend Toward a Healthy Life

benefits was $24.2 billion in 2011 (Valls et  al., 2013). According to Sloan, by 2015 global sales of these beverages were estimated at $130 billion. Due to the deficiency of accurate sales data, functional foods have unquestionably occupied the top position in the food industry. Valls et  al. (2013) described functional foods as the fastest-growing sector in 2008 with per annum growth of 10% comparable to 2%–3%. In 2005, the functional beverage market was valued at $25 billion and is among the rapidly growing sectors within the food industry (Marete et al., 2011) with an annual increase of 14% in the US between 2002 and 2007 (Kranz et al., 2010). Up till now, beverage sales in the US represented about 59% of the total food sector economy. (Sloan, 2012). Functional beverages are the emerging category in the nonalcoholic beverage industry. This increasing recognition of the beverage sector is due to mutual collaboration of carbonated soft drink industries and substantial money investment by different food and beverage firms. The per capita intake of functional beverages has increased to 66.4 gal in 2006; however, the carbonated soft drink sector has a decline in its per capita intake to 50.4 gal. A sharper rise of the functional beverage market became significant over the past few years. Consistent with Datamonitor, the universal nonalcoholic beverage market is valued at just below $500 billion, with Europe contributing to the major share of $189 billion. China has become the highest developing country with overall growth rate of 77% o in the last couple of years. Globally, trends related to functional beverages are very dissimilar, changing continuously across the world, because of the differences in demographics, culture, consumer demands, and acceptance. As the US probiotic dairy category enjoyed sharp growth rates in current years, these categories are quite conventional in value as compared to European markets. Likewise, the sports beverages are not a fully developed category except in the US and Japan, whereas energy drinks lead a lot of European beverage markets (Sorenson and Bogue, 2009). According to Euromonitor, the fruit and vegetable juice market was at the top with more than $10 billion in 2014 and the fortified sports drink market valued approximately $18 billion in 2008. According to reports by Euromonitor, in 2009 the energy beverage category has earned more than double in the past years, ranking at the top with $14 billion. In the past 20 years, the functional beverages category together with sports beverages as well as nutraceuticals has grown intensely, exceeding $9.7 billion in 2015 sales of US, with two trademarks covering almost 85% of total value (Heckman et  al., 2010a,b). The targeted consumer population of energy drinks is among teenagers and youngsters (Heckman et al., 2010a,b), with a study reporting that 51% of college students consume almost one energy drink per month (Malinauskas et al., 2007). Although annual sales of energy drinks remain insignificant in comparison to those of soft drinks and coffee,

Chapter 3  Functional Nonalcoholic Beverages: A Global Trend Toward a Healthy Life   77

it is thought that lax marketing regulations contribute to the inclination toward increased consumption. In 1997, there was increase in the energy drink consumption among children and youngsters in the US market, although the caloric proportion attributed to energy drinks is quite minimal as compared to other sweet beverages (Kit et al., 2013; Wang et al., 2008a,b). In 2011, the market sale of beverages was predicted at $8.1 billion. This sale has recouped its growth after facing a decay in 2009. Mintel estimates the achievement of 92% growth rate during 2011–2016 because of the consistent manufacturing of innovative products by highly reputed energy drink manufacturers like Red Bull, 5 Hour Energy, Rockstar, and Monster Energy. Many of these new products such as Rockstar Recovery, Monster Rehab, Rockstar 2X, and 5-h Energy Extra Strength already show signs of success, evidenced by impressive dollar sales growth in these line extensions.

3.3  Types of Functional Beverages 3.3.1 Dairy Beverages Milk is often regarded as natural food and dairy-based beverages are consumed as staple food in most regions of the world. Dairy beverages are an ultimate vehicle for the delivery of essential vitamins, minerals, fatty acids, antioxidants, proteins, plant sterols, and mainly probiotics. Commercially produced dairy beverages are enriched with most of these functional ingredients. As far as micronutrients are concerned, dairy sources fulfill > 20% of the daily requirement for calcium, magnesium, and potassium. They are also important sources of vitamins A, D, B2, and B12. These bioactive compounds form the basis of numerous functional products of high nutritive value with enrichment in vitamins and minerals. Well-known examples of products rich in minerals are Meiji Love R (Meiji Milk, Japan) and Zen R (Danone, Belgium) whereas Dairy Land Milk-2-Go R (Saputo, Canada) is an example of a viable dairy beverage with supplementary vitamins. Most of the commercial dairy beverages contain bioactive substances such as ω-3 fatty acids and its types α-linoleic acid, eicosapentanoic acid, and docosahexanoic acid, which are important for normal metabolism (Ozer and Kirmaci, 2010). Recent clinical reports showed that ω-3 acids may be beneficial in preventing the progression of epilepsy (Boroski et  al., 2012). Some common examples include Natrel Omega-3 R (Natrel, Canada) and Heart Plus R (PB Food, Australia). Conjugated linoleic acid has been reported to possess antioxidant and anticancerous activities (Ozer and Kirmaci, 2010). Natural Linea R (Corporacion Alimentaria Penanata S.A., Spain) is an example of a commercialized product with conjugated linoleic acid as a potential ingredient. Melatonin is a hormone naturally present

78  Chapter 3  Functional Nonalcoholic Beverages: A Global Trend Toward a Healthy Life

in living organisms. It regulates the circadian rhythm of the human body and is effective toward insomnia (Ozer and Kirmaci, 2010). An example of a commercial product with additional melatonin is NightTime Milk R from Cricketer Farm (UK) (Table 3.2). Proteins present in milk, particularly caseins, act as a source of bioactive peptides with varied actions on human physiology; these biologically active peptides can act as inhibitors of angiotensin-­ converting enzyme, which controls the transformation of angiotensin-I to angiotensin-II and down-regulation of bradykinin receptors by actively blocking the enzyme. The conversion results in elevated blood pressure, whereas blocking the enzyme decreases blood pressure (Ozer and Kirmaci, 2010). An example of a commercial beverage with added bioactive peptides is Evolus R from Valio Ltd. (Finland). It is valuable commercially because of the bioactive peptides produced by Lactobacillus helveticus from casein of milk (Prado et al., 2008).

Table 3.2  Dairy Beverages With Their Functional Perspectives Dairy beverages

Main Functional Ingredients

Health Benefits

Probiotics

Alleviation of lactose-intolerance symptoms, Treatment of viral and antibiotic-associated diarrhea

Vitamins

Minerals

L. acidophilus, L. rhamnosus, and L. casei A, D, B12, and riboflavin (vitamin B2) Magnesium Potassium

ω, 3 Fatty acids

Conjugated linoleic acid (CLA) Proteins Plant sterols

C18:3 n-3, ALA, C20:5 n-3, EPA, and (C22:6 n-3, DHA) N/A Milk caseins Phytosterols and phytostanols

Prevent and treat various diseases including heart problems, high cholesterol levels, eye, and skin disorders Helps boost the immune system, treat high blood pressure, prevent heart attack, and asthma As a vasodilator, potassium reduces the tension in the blood vessels, and ensures the proper distribution of oxygen to vital organ systems Useful in the prevention and treatment of epilepsy

Fighting cancer, blocking weight gain, and helping build muscle Act as a precursor of biologically active peptides with different physiological effects Shown potential in reducing cancers of the stomach, lung, ovaries, and breasts

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Plant sterols such as phytosterols and phytostanols exhibit remarkable features. There is an emerging evidence of the potential exhibited by phytosterols in reducing the incidence of cancers of the lung, breast, ovarian, and stomach cancers (Woyengo et al., 2009; Bradford and Awad, 2010; Gratten, 2013). Serum cholesterol levels are effectively reduced by the addition of plant stanols, as they slow down the absorption of all sterols from the gut (Ozer and Kirmaci, 2010). Tall oil obtained from the wood pulp industry and vegetable oil from deodorizer distillate possess sterols used in functional foods and nutritional supplementation. These enriched plant sterols can be used to obtain the suggested quantity of sterols for persons with cholesterol problems (Alemany-Costa et al., 2012). Raisio Benecol Ltd. (Finland), which holds the trademark of Benecol R, is the prominent brand among plant stanol-containing products. Dairy-based beverages are ideal vehicles for all these nutrients because low temperature during refrigeration keeps these ingredients active. Consequently, most fragile ingredients having a relatively short shelf life are prevented from degradation before ingestion. Therefore, the task is to select the potent functional nutrients and formulate an ideal composition. Dairy-based beverages can be formulated with photidylcholine, ω-3 fatty acids, and hydrolyzed collagen ingredients. Probiotics are living microorganisms that are administered in sufficient quantities to give a beneficial health effect to the host. Numerous health benefits are associated with probiotics. A few of them are mitigation of lactose-intolerance signs, management of diarrhea caused by antibiotics, masking the symptoms of antibiotic treatment with Helicobacter pylori, improvement of symptoms of atopic dermatitis in children, relief from symptoms of inflammable bowel disease and irritable bowel syndrome, and increasing the defense mechanism of the body (Saarela et  al., 2009). In the food sector, probiotic bacteria have gained a high market value created by positive health concerns (Talwalkar and Kailasapathy, 2004). For that reason, most of the dairy manufacturing companies add probiotic bacteria such as L. acidophilus, L. rhamnosus, and L. casei of lactobacilli and B. bifidum among bifidobacteria. Some examples of these products are Actimel R (Danone, France) with L. casei, Immunitas TM, Yakult R (Yakult Honsha Co, Japan) with L. casei, Shirota and CHAMYTO R (Nestle, France) with L. johnsonii and L. helveticus.

3.3.2 Energy Beverages Energy beverages, commonly known as energy drinks, are non­ alcoholic beverages commercially sold for providing nourishment and regulate performance, focus, and stamina (Gunja and Brown, 2012; Heckman et al., 2010a,b). In the 1960s, energy beverages were

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patented in Japan and then approached United States in 1997 and are now making its way in the UK, Brazil, and India. Energy drinks are commonly used beverages among youngsters and are mostly purchased by college students, sportsmen, and persons 21–35  years of age (Dikici et al., 2013). Studies have shown that 30% of young individuals use energy drinks and > 40% of athletes utilize energy drinks during training (Duncan and Hankey, 2013). There are lots of energy drinks on the market and many of them possess comparable ingredient profiles (Heckman et al., 2010a,b). Some common examples of these products are Red Bull R (Red Bull GmbH, Austria), Full Throttle R (Coca-Cola Co., USA), and Monster Energy R (Hansen Natural Corp., USA) (Higgins et al., 2017) (Table 3.3). The most common ingredients of energy drinks are usually water, sugar, caffeine, vitamins, minerals, and nonnutritive stimulants (e.g., guarana, ginseng, yerba mate, taurine, and inositol) that form

Table 3.3  Energy Beverages With Their Bioactive Compounds and Health Benefits Energy beverages

Main Functional Ingredients

Health Benefits

Caffeine

Enhance physical performance in adults by increasing aerobic endurance and strength Stimulatory effect, antioxidant activity Immune system stimulation, improved physical, and mental conditions Antioxidant capacity, weight management, and cancer prevention Supports the heart and cardiovascular system, helps athletes optimize their performance, and helps burn fat more easily Antiinflammatory actions and has been suggested in the treatment of epilepsy, heart failure, cystic fibrosis, and diabetes Used as an agent to phosphoric acid can be administered as oral treatment of common diseases and collagen, one of the building blocks and an ingredient of chondroitin sulfate Promotes strong, health hair, lowers cholesterol levels, treat depression, and mood swings Cell functioning Aid in body metabolism, water balance, and bone health, and effectively boost health in hundreds of other small ways

Nonnutritive stimulants

Guarana Ginseng Yerba mate l-Carnitine

Taurine

d-Glucuronolactone

Inositol Vitamins Minerals

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a ­composite (Heckman et al., 2010a,b; Higgins et al., 2010; Schneider and Benjamin, 2011). Recently, safety issues have risen about the major components of these drinks. The concentration of caffeine in energy drinks ranges commonly from 47 to 80 mg/8 oz. upto 207 mg/2 oz. obtained from various sources (Generali, 2013). Although adequate caffeine consumption is generally assumed to be harmless and advantageous for health (McLellan et al., 2016), research has not established any tolerance level in children and adolescents (Temple, 2009). Caffeine has been found to improve body functioning by delaying fatigue and increasing strength and stamina and improving reaction time. These properties are highly variable and dose-dependent (Committee on Nutrition and the Council on Sports Medicine and Fitness, 2011). Energy beverages also possess large quantities of artificial sweeteners. The content of sugar present in a single can of 500 mL of an energy drink is normally 54 g (Higgins et al., 2010). WHO have suggested the use of low sugar content as intake of high sugar leads to a declined health condition (World Health Organization, 2003). Guarana obtained from the Paullinia cupana plant, native to South America, possesses adequate quantity of caffeine, with 1 g of guarana equal to 40 mg of caffeine (Finnegan, 2003). Owing to the presence of a high percentage of caffeine, guarana is frequently utilized as a constituent in energy drinks for its stimulant effects (Heckman et al., 2010a,b; Scholey and Haskell, 2008). Xanthine alkaloids such as theobromine and theophylline, and higher quantities of tannins, saponins, and flavonoids, add to its bioactivity together with its antioxidant effect. On the contrary, increased concentration of caffeine and other methylxanthines multiplies the incidence of clinically significant toxicities (Zeidán-Chuliá et al., 2013). Ginseng is an herb, highly prevalent in Eastern Asia and North America, including China and Japan, as a cure for countless ailments and it increases life years. The possible health benefits of ginseng include stimulation of immune functions, improved mental disorders, acts as antidepressant, reduces stress and promotes relaxation, together with antioxidant and antiinflammatory activity (Committee on Nutrition and the Council on Sports Medicine and Fitness, 2011). On the other hand, this herb has numerous clinically significant interactions, depending on the amount and frequency of dose ingested (Gunja and Brown, 2012). Like guarana, Green Mate possesses a high caffeine content (78  mg/cup) (Heckman et  al., 2010a,b) and, in addition, it is helpful in weight management and it is known to exhibit antioxidant and anticancer properties (Heck and De Mejia, 2007). Taurine has been used in the management of epilepsy, cystic fibrosis, and heart problems, and to treat diabetes due to its antiinflammatory effect. Eight B vitamins, which are water soluble, are exclusively important for the cell to perform its functions. Vitamin B2, B3, B6, and

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B12 are B vitamins commonly used to boost energy levels (Heckman et  al., 2010a,b). Although these vitamins regulate various metabolic functions and act as coenzymes, people in the US already have the recommended amount of these vitamins in their body; consequently vitamins released by the energy drinks are excreted with urine, without contributing any beneficial effect (Heckman et al., 2010a,b). Other ingredients such as l-carnitine, d-glucuronolactone, and inositol are less studied; very few studies suggest moderate benefits. Alcohol usage in energy beverages is an interesting concern, due to which there is an increased incidence of alcohol-associated complications in adults. Such intake may be associated with alcohol dependence and toxicity accidents (Azagba et al., 2014). Consumption of energy beverages during exercise may cause deaths in the young population (Higgins et  al., 2017). Energy beverages are being used all over the world. Adverse cardiovascular events can be caused by endothelial dysfunction. Endothelial cells form the inner lining of blood vessels and regulate metabolic processes and enhance vascular resistance. Reduction in coronary blood flow may be associated with endothelial dysfunction, poor vascular reactivity, pro-thrombosis, pro-inflammation, and growth promotion (Higgins and Ortiz, 2014; Higgins and Babu, 2013). Athletic coaches and sectors should address the matter of energy beverages consumption with students under training and educate them about the risks and benefits. The adverse effects of excessive caffeine intake have been confirmed by various studies, but the useful effects of supplementary additives, such as taurine and glucuronolactone, are under research, and their combination in energy beverages is unproven. Consumption of energy beverages before or during training can have severe adverse effects, such as restlessness and irritability; elevation of blood pressure; and may cause dehydration. The long-lasting effects of energy beverages on the human body have not been recognized. Limited ingestion of energy beverages by healthy people does not produce major adverse effects, but binge consumption or with alcohol may cause adverse reactions. Individuals with medical issues, such as heart disease, should consult their physician before using energy beverages, because they may cause exacerbation of the symptoms.

3.3.3  Fruits and Vegetables Beverages In Switzerland, the recommended range of fruits and vegetables is 600 g/day, but, this average intake has been reducing to about 60%, almost 380 g/day. This gap can be filled by using products like fruits and vegetables shots by making drinking easier. However, the content of fibers and vitamin C is lower; so, they cannot replace fresh

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food completely and they possibly interfere with the physiology of the food intake. These products have their importance in a way that they supply energy equivalent to one fruit or vegetable portion (Clarisse and Giusti, 2008). Fruit juices might be the ultimate carriers for probiotics due to the presence of vital nutrients (Granato et al., 2010a,b). Commercial preparations include fruits like mango, strawberries, cranberry, cherries, peach, blueberry, pomegranate, apple, blackcurrant, acerola, guarana, grapes, kiwifruits, and bilberries (Sun-Waterhouse, 2011). In addition, watermelon and orange juices were used as suitable culture media for the growth of Lactobacillus to prepare beverage for users who are hypersensitive to dairy foodstuffs (Gaanappriya et al., 2013). Examples of such products are Rela R (Biogaia, Sweden), a fruit juice containing L. reuteri MM53; Gefilus R (Valio Ltd., Finland), a fruit drink with a 5-week shelf-life under refrigeration; Bioprofit R (Valio Ltd.), with L. rhamnosus GG and Propionibacterium freudenreichii ssp. shermanii JS; and Biola R (Tine BA, Norway), a juice drink having > 95% fruit and no sugar (Prado et al., 2008). Some nonprobiotic fruit and vegetable beverages with vitamin D or calcium are also available commercially. The aim is to enhance their nutritional value and utilization in the prevention of certain malnutritive diseases like rickets, osteomalacia, and osteoporosis (Tangpricha et al., 2003). Examples of commercialized fruitbased products are Tropicana Essentials R Orange Juice & Calcium (Tropicana, USA), and Minute Maid R with Calcium & Vitamin D (Minute Maid, USA); however, some vegetable-based beverages include Daily Greens (Bolthouse Farms, USA), which is a blend of spinach, cucumber, and kale with a hint of lemon; and Langers Tomato Juice Plus and L&A Tomato Juice (Langer Juice Co., Inc., USA), made of 100% pure tomato juice with no added sugar, high-fructose corn syrup, and artificial sweeteners. Over the past 50 years, there has been a lot of progress in the industrial processing of fruit and vegetables beverages with special focus on the design of equipment and processes that enhance the product yield without compromising on the quality. In the past, there were batch-system processes and demand-intensive human labor. In 1980s, with the evolution of digital controllers, the analog controllers were replaced and the whole food industry was revolutionized with increased affordability. In developed and developing countries, most industrial processes for beverages have been converted into semicontinuous or continuous processes and have been automated. Nonthermal processing is a valuable method for preserving fruit and vegetable beverages. The products obtained by these techniques have numerous gains like retentiveness of sensorial qualities and nutritive values, which are preferred to outdated thermal techniques. So far, only high-pressure nonthermal processing techniques have been

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implemented by the food industry. In additionally, pilot-scale testing is a basic requirement for nonthermal processing to become an alternative to thermal processing. In the same way, the use of natural antimicrobial agents for preservation of fruit juice and beverages is limited only to the laboratory, but it is expected that the remarkable applications of these compounds would lead to their extensive use in food industries. More precisely, the combined use of nonthermal processing methods and natural antimicrobial agents would be the key factor for fruit beverages preservation, due to the proven efficacy for inhibiting microorganisms and extension in shelf-life of fruit juices and beverages (Rupasinghe and Yu, 2012). Fruit and vegetable beverages delay the onset of Alzheimer's disease, even among patients with high risk factors. These findings may lead to a new way of inquiry in the prevention of Alzheimer's disease (Pop et al., 2006).

3.3.4 Sports Beverages Sports beverages are drinks intended to be consumed before or during exercise to counter dehydration and they are typically devoid of caffeine but are usually flavored. They provide carbohydrates, vitamins, electrolytes (such as sodium, magnesium, potassium, calcium, phosphate, and chloride), and some other nutritional stuff. Amino acids normally lessen fatigue and improve muscle function while vitamin B and subtypes enhance metabolism and generate energy for the body. Simple carbohydrates provide instant energy and complex carbohydrates can be used for persistent energy supply (Heckman et al., 2010a,b; Committee on Nutrition and the Council on Sports Medicine and Fitness, 2011). The efficacy and safety of these products are supported extensively in research articles (Costill, 1988; Maughan, 1991, 2003; Maughan and Noakes, 1991; Burke, 2001; Meyer et  al., 2013). Many sports drinks contain a combination of sucrose, glucose, fructose, and maltodextrin/glucose polymers. The significance of adding maltodextrins and glucose polymers is that they are less sweet in taste than common sugar, which allows a high carbohydrate level without making the product excessively sweet (Campbell, 2013). The higher intake of carbohydrates from sport drinks unnecessarily increases the number of calories without extra nutritional benefit. The consequences could be dental caries, increased weight, and low quality of diet (Committee on Nutrition and the Council on Sports Medicine and Fitness, 2011; Larson et  al., 2014). Some examples of commercially available products are Gatorade R (PepsiCo Inc., USA), Powerade R (Coca-Cola Co., USA), and Accelerade R (Pacific Health Laboratories Inc., USA). Sports beverages can certainly be assumed as a prime tool and are considered prior to water (Higgins et al., 2010). For example,

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Table 3.4  Sports Beverages With Bioactive Compounds and Health Benefits Sports beverages

Main Functional Ingredients

Health Benefits

Amino acids B vitamins Simple carbohydrates Complex carbohydrates Combination of glucose, fructose, sucrose, and maltodextrin/ glucose polymers

Used to slow fatigue and improve muscle function Used to boost metabolism and generate energy Used for a quick energy burst Used for sustained energy Increases overall daily caloric intake without significant additional nutritional value, dental caries, excess weight gain, and poor diet quality

cyclists who take sodium-containing drinks during a 3-h ride in hot weather have sustained plasma levels of sodium and produce less urine as compared to those who drink water only (Bunn, 2013) (Table 3.4). These drinks are intended to improve the athletic performance and hydration status of players taking part in sports demanding stamina. These beverages are being marketed to children, for whom these products are prohibited. The popularity of such products among children has grown at a higher rate. Worryingly, they consume them generally and not only during physical activity. Sports drinks are acidic in nature and have high sugar content. High sugar possesses the potential for dental caries and erosion, which is ignored by product-marketing companies (Broughton et al., 2016). During training and competition, athletes have electrolyte imbalance and dehydration due to sweat; as a result, they consume a lot of energy. The loss of liquid as a result of dehydration is proportional to a significant decrease in their performance. The consequences of dehydration are decrease in blood volume and sweat formation decrease and increase in body temperature. To compensate this elevation of temperature, the body needs to work much harder to regulate the blood circulation and more sweat production. Complications associated with the loss of essential electrolytes are muscle cramps, fatigue and exhaustion, and headaches. A suitable drink can replace the depleted levels of water and electrolytes. Sports drinks serve the same purpose but during the training period. An isotonic drink is a quick replacement of the liquid lost by sweat and delivers the carbohydrate needed (Ersoy and Ersoy, 2013).

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3.3.5  Functional Ingredients A functional ingredient is a bioactive substance used in the production of functional food products. Such biologically active substances can be found from diverse sources such as primary producers, marine environment, microbes, and inorganic mineral deposits. Functional ingredients have also been found in the food processing waste, which is economically beneficial to food processing units. These functional ingredients have been used for the manufacturing of nutraceuticals. Various separation and purification techniques are sometimes used to extract these compounds. The technique used depends upon the chemical structure and economical status of the target compound and the chemical nature of the source through which it may be derived. Old methods that have been utilized include solvent- and water-based extraction, subsequent filtration distillation, evaporation, followed by crystallization. However, more frequently, techniques such as ­supercritical CO2 fluid extraction, low-polarity-based extraction, membrane-based, and molecular distillation are in use. These alternate methods have many benefits in that they can be more efficient and less costly. Moreover, for the use of solvents, there is also an increasing ambiguity because despite meeting the food grades, they can produce chemical residues. According to health ethics, these cleaner technologies are considered useful because they predominantly diminish the use of solvents. The functional beverage category is a tremendously growing market. Beverages are the ultimate grab-and-go product, but now the trend has slightly changed; clients associate hydration with performance as a preventive measure for health disorders. Beverages are incorporating a new extensive line of functional ingredients such as nutraceuticals, zero-calorie sweeteners, and flavors that are not only good for health but also taste delightful. Due to the wide diversity of functional ingredients and product-development changes in market, beverages are much more innovative than can be imagined. Custom nutrient premixes are a prime approach to make a beverage product exceptional and pending the number of ingredients used, which is less probably mocked in the market. Functional ingredients comprise nutritional elements (vitamins, minerals, amino acids, fatty acids, nutraceuticals, etc.), stabilizers, flavoring agents, sweetening agents, colors, preservatives, and caffeine.

3.4  Health Concerns 3.4.1 Antiinflammation Tenacious inflammation is related to most chronic diseases including atherosclerosis and cardiovascular diseases (CVDs) (Cancalon and King, 2015). Some diets have significant effects for mitigating the

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risk of CVD. As far as the antiinflammatory effect of functional beverages is concerned, fruit juices have considerable roles in the reduction of inflammation. Some studies have confirmed the antiinflammatory effects of some fruit juices. Li et al. (2015) studied the effect of tomato juice rich in lycopene on monocyte chemoattractant protein-1 (MCP-1) and they found that tomato juice intake reduced MCP-1. Moreover, Noratto et al. (2015) reported that plum and peach juice is considered effective against cardiac dysfunction and heart failure leading to obesity-induced inflammation through reducing the protein levels of the active p-Iκ-Bα and p-NF-κBp65 subunits in heart tissue. mRNA levels of Iκ-Bα and TNF-α are significantly decreased by plum juice whereas mRNA levels of TNF-α are lowered by peach juice intake. In another study, C-reactive protein levels were reduced by the consumption of cranberry juice cocktail for two nonconsecutive 24-h dietary calls (Duffey and Sutherland, 2015). In addition, another fruit juice, that is, mandarin juice and red orange juice were found to reduce inflammatory markers such as tumor necrosis factor-α (TNF-α), high-sensitive C-reactive protein, and interleukins 1α and 6 (Codoner-Franch et al., 2013; Buscemi et al., 2012) but this orange juice did not lead to any remarkable effects on circulating cytokine levels or PAI-1 activity (Devaraj et al., 2011). On the other hand, some juices such as flavanones (naringenin glycosides) of grapefruit juice were not found to have antiinflammatory effects. The consumption of grape fruit juice did not positively affect inflammation biomarkers such as tumor necrosis factor-α (TNF-α), high-sensitive C-reactive protein, and interleukins 1α and 6 (Habauzit et al., 2015). Furthermore, Simao et al. (2013) found that consumption of folic acid containing reduced energy cranberry juice by metabolic syndrome patients increased folic acid and adiponectin but significantly decreased the homocysteine level. In the study of Huebbe et al. (2012), blackcurrant treatment was found to be effective against ­lipopolysaccharide-induced inflammation. Its consumption did not remarkably change the production of TNF-α or IL-1β in human subjects.

3.4.2 Antidiabetic Type 2 diabetes is one of the major risk factors leading to morbidity and mortality, which validates the growing interest of scientists. The worldwide prevalence of type 2 diabetes is mounting rapidly, especially in obese people. A recorded worldwide number of people with diabetes was 171 million in 2000 and this number is tending to increase and will reach at least 336 million in 2030 (WHO, 2003). However, the prevalence of occurrence of this disease needs some therapeutic potentials and strategies. Functional beverages especially fruits, vegetables, and dairy beverages have captured greater attention in this context.

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Fruits and vegetables beverages are important for decreasing the incidence and risk of an array of aberrations such as obesity, CVDs, and hypertension. Many researchers have studied the role of fruit and vegetables in reducing diseases risk (Bazzano et al., 2008). Both fruits and vegetables have therapeutic potential, but this potential varies widely owing to the nutrient content differences. Moreover, fruit juices could be important, but it is not widely studied. Kris-Etherton and Keen (2002) reported that fruit juices have considerable roles owing to their antioxidant activity, but they lack fiber, have more sugar content, and are less satiating. Imamura et  al. (2015) found that the chances of type 2 diabetes is enhanced through the consumption of sugar-­ sweetened beverages but artificially sweetened beverages and fruits juices as the alternatives of sugar-sweetened beverages positively decrease the incidence of these aberrations. Similarly, the consumption of milk and dairy beverages is a significant strategy to mitigate the onset of diseases, mainly obesity and type 2 diabetes, and improves body composition in adults. Furthermore, during energy restriction, the intake of dairy products facilitates weight loss, but this evidence is less clear during energy balance. In this way, milk and dairy products, especially fermented dairy products (e.g., cheese and yogurt) reduce the risk of type 2 diabetes.

3.4.3 Obesity As far as the effect of functional beverages against obesity is concerned, some fruits and vegetables are considered important in terms of weight management. Some fruit juices have significant potential against metabolic disorders and CVDs. In the study of Wu et al. (2013), it was found that mulberry (Morus australis Poir) and blueberry (Vaccinium ashei) juices were rich in anthocyanin and they were effective against obesity. It resulted in body weight reduction, down-­ regulation of serum cholesterol and inhibition of leptin secretion, lipid accumulation, and insulin resistance in high-fat diet mice. Moreover, consumption of plum and peach juice was found effective for the prevention of metabolic disorders induced by obesity and plum was important to reduce weight due to the presence of polyphenolic content that was three times more in plum than in peach. Furthermore, Oliveira et al. (2013a,b) reported that intake of green juice was more effective than simple water in weight reduction. In the study of Williams et al. (2017), an encapsulated fruit and vegetable juice concentrate showed a positive effect in the treatment of systemic inflammation and other risk factors for chronic disease in overweight and obese adults and resulted in improvement of the metabolic profile. In addition, dairy beverages have therapeutic potential in weight reduction owing to the high satiating effect of high-quality protein,

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which aids to reduce overconsumption of energy and therefore reduces the body fat stores (Gilbert et al., 2011; Bendtsen et al., 2013). This dairy protein is a good reservoir of essential amino acids, which are important for muscle protein synthesis, and thus helps to maintain the metabolically active muscle mass during weight loss (Astrup et al., 2011). Many researchers studied the role of dairy products for weight management, that is, weight loss, body composition improvement, body fat mass reduction, and lean body mass preservation during energy restriction in short-term studies (Abargouei et al., 2012; Chen et al., 2012; Booth et al., 2015). In addition, many researchers studied the perspectives in long-term studies, but the effectiveness was less on body composition, fat mass, and lean body mass (Chen et al., 2012; Booth et al., 2015).

3.4.4 Antioxidant Activity Oxidative stress is considered significant in the pathogenesis of diabetes-induced CVD, which is associated with an abnormal blood lipid profile, insulin resistance, and metabolic syndrome (Rains and Jain, 2011). Oxidative stress occurs due to a disturbance of the balance between antioxidant defense mechanisms and the levels of reactive oxygen species (ROS) (Gutteridge and Halliwell, 2010; Halliwell, 2009). Dietary supplementation with antioxidants, including vitamins and phenolic compounds obtained from plants, may help to maintain a desirable pro-oxidative/antioxidative balance (Papageorgiou et  al., 2013; Halliwell et  al., 2005). A variety of beverages has gained greater attention owing to their bioactive functionalities against many diseases, including diabetic disorders (Sabate and Wien, 2010; Calder, 2012). Although fruits and vegetables have therapeutic potential as antioxidants against cancer, antidiabetic, antiviral, bactericidal, antiinflammatory, and antiatherosclerotic agents are known (Stanner et al., 2004; Collins, 2005; Lau et al., 2007; Montonen et al., 2007; Liu, 2013a,b). Moreover, Rao (2003) found that flavonoids of fruits and vegetables are more efficient toward antagonizing oxidative damage in vivo and in vitro than antioxidant vitamins like vitamin E. In addition to the direct scavenging of free radicals, antioxidants in fruit and vegetables are able to protect against ROS-mediated oxidative damage by elevating cellular antioxidant capacity (Rubió et al., 2013). De Morais et al. (2013) reported that individuals consuming fruit- and vegetable-rich diet are at lesser risk of many chronic diseases. However, the exact mode of action of fruits- and vegetables-enriched diet against oxidative damage-related diseases is still unclear (Duthie et al., 2006). In the study of Betanzos-Cabrera et al. (2011), it was found that pomegranate has antioxidant and antiatherogenic effects owing to its polyphenol

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content. It resulted in LDL protection against cell-mediated oxidation. Serum paraoxonase activity was also checked, which was increased and led to the hydrolysis of lipid peroxides in oxidized lipoproteins and in atherosclerotic lesions (Gilchrist et al., 2013). Moreover, Potter et al. (2011) found that the consumption of fresh carrot juice significantly increases plasma total antioxidant capacity and significantly decreases plasma malondialdehyde production. In addition, in the study of Foroudi et al. (2014), intake of orange juice was effective in increasing plasma total antioxidant capacity and decreasing lipid peroxidation. Furthermore, plasma lipid oxidation (malondialdehyde concentration) was markedly upregulated (− 29%) and lipid peroxidation was remarkably reduced (+ 115%) after consuming antioxidant-rich juice daily. Oliveira et al. (2013a,b) compared the antioxidant effects of green juices (cucumber, cabbage, apple, lettuce, and orange) and orange juice and found that both juices exhibited antioxidant activities. In addition, green juice reduced the weight gain, catalase activity and lipoperoxidation. Codoner-Franch et  al. (2013) studied the synergistic effect of dried apples and mandarin juice in obese children and it was shown that the antioxidant capacity of plasma was increased whereas DNA oxidative damage was reduced. Furthermore, Huebbe et al. (2012) reported that blackcurrant treatment imposed a negative impact on inducible NO synthase in cultured macrophages and compared with untreated controls, levels of iNOS protein were reduced while levels of heme oxygenase 1 were increased, while consumption of blackcurrant elevated plasma ascorbic acid and radical-scavenging capacity in human subjects. In addition, in the study of Miglio et al. (2014), it was found that synergistic intake of antioxidant-rich fruit juice could prevent the increase in levels of uric acid and thiols induced by high-fat meals. In another study, it was shown that the ingestion of pomegranate juice increased the antioxidant defense mechanism against CCl4-induced reproductive toxicity (Al-Olayan et al., 2014).

3.4.5 Cardiovascular Diseases CVD is one of the top 10 etiologies of death worldwide. The number of people who died of this disease was about 17.5 million in 2012, which was 31% of all global deaths. Out of these 17.5 million, 7.4 million were died owing to coronary heart disease and 6.7 million died of stroke (WHO, 2012). In 2008, a rough European Union estimation of direct and indirect costs was performed and about €192 billion cost for CVD was found. CVDs include coronary heart disease and the cerebral vessels-related diseases, and these diseases are collectively responsible for half of the deaths in developed countries and 25% of deaths in developing countries (Soliman et  al., 2011). Various risk factors are

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involved in the occurrence of this disease including unhealthy diet and obesity, lack of physical activity, excess alcohol consumption, and smoking. Among these factors, inappropriate diet is most important risk factor (WHO, 2011; Esmailnasab et al., 2012). With respect to diet, functional beverages have captured greater attention in the treatment and prevention of CVDs. Among functional beverages, fruits and vegetables juices are considered important for their therapeutic potential against CVD and its related aberration such as coronary heart disease and the cerebro-­ vascular disease. Many studies have been performed for highlighting the role of fruits and vegetables and related juices in the prevention and cure of cardiovascular-related diseases. The consumption of these fruits and vegetables is found to be significantly effective in lowering the incidence of various chronic noncommunicable diseases. This attribute is owing to the presence of polyphenols and vitamins in fruits and vegetables. The intake of fruits and vegetables beverages is very common in many countries and it is the most efficient way to increase the consumption of fruits and vegetables. These beverages are found to affect the risk of CVD such as lowering blood pressure and improving the blood lipid profiles. The main mechanism behind the positive role against CVDs includes the antioxidant activity, antiinflammatory effects, boost of cardiovascular system aspects, inhibition of platelet aggregation, and prevention of hyperhomocysteinemia (Zheng et al., 2017). In the study of Li et  al. (2014), fruits and vegetables juice were found to be effective against vascular diseases due to the presence of phenolic compounds. Moreover, in the study of Poudyal et al. (2010), the potential of purple carrot juice and β-carotene to reverse the structural and functional changes in the rat model of metabolic syndrome was compared in rats suffering from endothelial dysfunction and it was found that both β-carotene and purple carrot juice were able to ­attenuate and improve endothelial dysfunction. Furthermore, the effect of Finnish berry juices including juices of lingonberry (Vaccinium vitis-idaea), cranberry (Vaccinium oxycoccos), and blackcurrant (Ribes nigrum) on blood pressure and vascular function of spontaneously hypertensive rats for eight weeks was checked. All these fruits were rich in polyphenols. The results revealed that cranberry resulted in impaired endothelium-dependent relaxation whereas long-term lingonberry juice treatment resulted in improvement of endotheliumdependent vasodilation (Kivimaki et al., 2011). In addition, in the study of Flammer et al. (2013), cranberry juice, rich in polyphenols, caused no significant change in peripheral endothelial function. In another study, pomegranate juice was assessed for its effect on endothelial function and it was found that endothelial adhesion molecule 1 (VCAM-1) was markedly down-regulated while E-selectin were up-regulated (Asgary et al., 2014). In the study of

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Habauzit et al. (2015), it was found that grapefruit juice consumption significantly lowered central aortic stiffness but did not affect endothelial function in micro- and macrocirculation due to the presence of flavanones. Moreover, Buscemi et  al. (2012) studied the effect of red orange juice intake on endothelial function and the endothelial function was significantly improved. Siasos et al. (2014) reported that consumption of concord grape juice can improve endothelial function and arterial tree vascular elastic properties. In the study of Khan et al. (2014), the effect of blackcurrant juice on vascular function was probed and it was found that flow-mediated dilatation and plasma vitamin C concentration were significantly increased. In addition, in the study of Poudyal et al. (2010), purple carrot juice was able to attenuate or reverse these changes. Carotenoid concentration was low in purple carrot juice; so, anthocyanins might be the main contributor of antioxidant and antiinflammatory properties to improve cardiovascular function. In the study of Ramli et  al. (2014), it was demonstrated that consuming red pitaya juice could reduce diastolic stiffness of the heart in rats. In addition, the blood pressure down-regulation effect of Carica papaya fruit juice was examined in male albino Wistar rats (Eno et al., 2000). A significant depression of arterial blood pressure (MAP) was produced by juice and hydrallazine, and juice produced more depression of MAP than hydrallazine in the hypertensive rats. In  vitro studies were conducted to explore the mechanism. Isolated rabbit arteries were used, and the results indicated that the juice produced relaxation of vascular muscle tone. It was concluded that C. papaya fruit juice could contain antihypertensive agents that exhibited mainly α-adrenoceptor activity. As far as the effect of dairy beverages on CVDs in concerned, the mechanisms by which dairy foods, regardless of fat content, may reduce the risk of CVD have not been fully elucidated. The milk fat component of dairy food contains over 400 unique fatty acids, many of which are not found in other foods (Jensen, 2002). Milk fat contains saturated, monounsaturated, and polyunsaturated fatty acids of varying chain lengths and configurations. The study of milk fatty acid chemistry is complex, and some studies have suggested that bioactive fatty acids in milk fat are responsible for antiinflammatory and improved metabolic effects (Mozaffarian et  al., 2013; Dilzer and Park, 2012). In addition, the minerals contained in dairy foods, such as calcium, magnesium, phosphorus, and potassium, have been implicated in the management of elevated blood pressure and the cardiometabolic syndrome (Rice et al., 2011). Furthermore, calcium from dairy food has been implicated in fecal fat excretion and the maintenance of healthy blood lipids (Lorenzen and Astrup, 2011). Dairy foods are complex, however, and more recent evidence indicates that the dairy food matrix may be just as important as its

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individual components (Astrup et  al., 2011). There are likely multiple mechanisms by which dairy consumption may help reduce CVD risk. Based on the totality of the evidence, it is recommended that Americans 9  years and older consume three servings of milk/ milk products, including milk, cheese, and yogurt, per day (Dietary Guidelines Advisory Committee, 2010). The mechanisms by which dairy products can exert certain effects on CVD are diverse, with divergent mechanisms suggesting both positive and negative influences. Dairy products are rich in minerals (calcium, potassium, and magnesium), protein (casein and whey), and vitamins (riboflavin and vitamin B-12) that can exert beneficial effects on CVD. On the other hand, saturated fat in dairy products can adversely influence CHD, although the effect of saturated fat on CHD risk depends on the source of calories (unsaturated fatty acids or carbohydrates) by which it is substituted to maintain energy balance (Jakobsen et al., 2009). There is some suggestion that low-fat dairy products may beneficially influence blood pressure (Toledo et al., 2009; Wang et al., 2008a,b). Studies have shown that the dietary approaches to stop hypertension (DASH) dietary pattern—which is high in fruit, vegetables, nuts, fish, and low-fat dairy products—lowers blood pressure effectively, which may in part be attributed to its relatively high content of low-fat dairy products (Appel et  al., 1997). Whether these effects on blood pressure can be specifically addressed by low-fat dairy products is not clear from DASH, but European guidelines on CVD prevention do recommend the DASH diet with low-fat dairy products, albeit such a recommendation is not yet fully evidence-based (Graham et al., 2007). Two meta-analyses (Elwood et al., 2004a,b, 2010) and 2 narrative reviews (German et al., 2009; Gibson et al., 2009) combined with individual studies produced conflicting conclusions. Combining evidence from different study designs (ecologic, case-control, and prospective) and different study populations (age, sex, country, and various mean milk intakes) may explain the conflicting results. Pooling different exposures (calcium and milk) and the use of inappropriate statistical methods could also lead to conflicting conclusions. However, energy and sports drinks have potential adverse effects on CVD with respective to their ingredients, mainly caffeine and sugars. Consuming these drinks reduces endothelial function and stimulates platelet activity through arachidonic acid-induced platelet aggregation in healthy young adults (Pommerening et al., 2015).

3.4.6 Anticancer Effect Cancer is one of the most overwhelming diseases and the major e­ tiology of mortality, regardless of the molecular basis of the disease and advances in treatment. It is reported that almost 30%–40%

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of all cancers can be prevented by lifestyle and dietary modification. Functional beverages are considered as one of the main therapeutic pillars for the treatment of cancer and its related complications. Among functional beverages, fruits and vegetables beverages have gained greater interest owing to the bioactive functionalities of bioactive compounds such as polyphenols and terpenes present in the fruits and vegetables. The mechanisms by which these compounds inhibit tumorigenesis include inhibition of tumor cell-mediated protease activity, attenuation of tumor angiogenesis, induction of cell cycle arrest, and promotion of apoptosis (Beidokhti, 2013). These fruits, vegetables, and beverages mainly include beetroot, tomato, rhubarb, pumpkin, chili pepper, avocado, pineapple, papaya, apricot, guava, apple, cherry, turmeric, raspberry, blueberry, lemon, orange, grapefruit, lime, green tea, and black tea. Among these, various fruits and vegetables such as watermelon, mango, pineapple, cherry, papaya, guava, and turmeric contain clear anticancer agents like lycopene, lupeol, bromelain, perillyl alcohol, lycopene, and lupeol, respectively. As far as the anticancer effects of beverages are considered, green tea is now renowned as the most effective cancer-preventive beverage (Suganuma et al., 2011). The consumption of green tea is associated with a lower risk of several types of cancer, including stomach, esophagus, and lung (Lin et al., 1999). In some studies, green tea had protective effects on stomach, bladder, skin (Demeule et  al., 2002), and breast cancer (Madkor et al., 2012; Demeule et al., 2002). Green tea has antimutagenic (Demeule et al., 2002; Gupta et al., 2002) and anticarcinogenic properties (Demeule et  al., 2002; Cai et  al., 2004; Cooper et al., 2005a,b). The anticancer effect of green tea is owing to the presence of an array of bioactive compounds including catechins, caffeine, phytophenols, polyphenols, quercetin, and flavanols. Karna et al. (2011) investigated that catechins present in green tea extracts have shown antioxidant, antiangiogenesis, and antiproliferative activities that are potentially relevant to the prevention and treatment of various forms of cancer (Cooper et al., 2005a,b) such as prostate cancer. These catechins are found to increase the anticancer activity of various anticancer drugs (Suganuma et al., 2011). In addition, in the study of Demeule et al. (2002), it was found that the consumption of green tea was associated with a reduced risk of cancer among nonsmoking women. Furthermore, caffeine present in green tea also has anticancer effects. The mechanism behind these effects is mediation of carcinogen metabolizing or detoxification by inhibition of carcinogen-induced mutagenesis, inducing cell cycle arrest and apoptosis or tea components targeting specific signal transduction pathways leading to AP-1 or NF-κB, which are transcription factors that have been shown to play a key role in carcinogenesis (Bode and Dong, 2003). Quercetin present

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in green tea enhanced the therapeutic effect of docetaxel in ­castration-resistant prostate cancer cells (Wang et al., 2015). Moreover, polyphenols are also considered as important compounds having antioxidant effects and the inhibition of 16 cancers (Zhang et al., 2013), such as (−)-epigallocatechin-3-O-gallate, induces apoptosis in acute myeloid leukemia cells. Catechins of green tea are flavanols, which have many health-related characteristics; they especially lower the cytotoxicity and cost of anticancer treatment, inhibit proliferation of breast cancer cells, and block carcinogenesis (Yousaf et al., 2014; Yu et al., 2014). Humans would be able to achieve consistent cancer prevention effects provided there is timely intervention of green tea catechins at appropriate high-dose levels (Zhang et al., 2014). Green tea and coffee consumption has protective effects on esophageal cancer (Zhang et  al., 2013). Therefore, green tea is the most economic and effective method of anticancer treatment. Black tea is also found effective against many types of cancer such as prostate, lung, and breast cancer due to the presence of bioactive moieties such as polyphenols (Mujtaba and Dou, 2012; Madkor et al., 2012). Black tea and theaflavins activate an array of apoptogenic signaling events, thereby ensuing reduced tumor growth. This beverage not only regresses tumors but also protects the intrinsic defense machineries of the host from cancer insult. Black tea even reduces ­tumor-induced hepatotoxicity and protects against oxidative damage generated by the developing tumor. Therefore, acting in a multifaceted manner, black tea and theaflavins can successfully bring about regression of the tumor and ensure survival of the host. Black tea regresses cancer by directly killing cancer cells and rejuvenating the host's suppressed defense machinery (Das et al., 2008). Epidemiological studies suggest a protective effect of tea consumption on some cancer types in humans (Shukla and Singh, 2007). Black tea has also been shown to inhibit tumorigenesis in animal model systems, including lung, colon, skin (Das et al., 2008; Bhattacharyya et al., 2003), fore-stomach, pancreas, liver, and esophagus of rodents by activating the detoxification systems of the host (Das et al., 2008). Morinda citrifolia L. (noni) is one of the most important traditional Polynesian medicinal plants (Baliga et al., 2011). Noni fruit juice made from the fruit of Indian mulberry has been reported to have a broad range of therapeutic effects, for example, antibacterial, antiviral, antifungal, anticancer, and antiinflammatory activities including analgesic and immunomodulating effects. Regarding scientific studies, there are reports that polysaccharide-rich substances in Noni fruit juice have immunomodulating effects and contributed to anticancer activity (Ratanavalachai et al., 2008). Furthermore, when the anticancer effect of dairy beverages is overviewed, it is found that milk consumption is prevalent in daily diets,

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and its lactase persistence is likely to have an independent origin in Tibetans (Peng et al., 2012). The milk protein α-casein would provide a more natural and nontoxic approach to the development of novel anticancer therapies. Some cheese whey components possess anticancer properties. The whey proteins mainly contain sulfur-containing amino-acids including cysteine and methionine, which are utilized in glutathione (a substrate for two classes of enzymes). Glutathione catalyzes detoxification compounds, binds mutagens and carcinogens, and facilitates their elimination from the body. The ability of lactoferrin to bind iron also plays significant role in colon cancer therapy by inducing apoptosis in tumor cells. Another most important compound, sphingomyceline (one of the most abundant whey-derived sphingolipids), has the therapeutic potential toward colon cancer inhibition. Lysine and proline, obtained from whey and caseins proteins, respectively, lead at various positions in anticancer peptides. These peptides are responsible for the anticancer activity of milk proteins and can be identified from fermented dairy products (Sah et al., 2015). Furthermore, bovine lactoferrin also plays a significant role in different types of cancer including colon cancer (Gill and Cross, 2000; Masuda et al., 2000). This potential is attributed to its iron-binding capacity. The mechanism behind this therapeutic effect is that free iron induces oxidative damage to the nucleic acid and acts as a mutagenic promotor. After this, when bovine lactoferrin binds iron in tissues, it reduces the risk of oxidant-induced carcinomas and colon adenocarcinomas. Although there is no scientific link between energy drinks and cancer, doctors advise against consuming too much caffeine and sugar, both of which are the main ingredients in energy drinks. Research finds that adults should have only one serving per day. Due to recent evidence linking daily energy drink intake to heart abnormalities and seizures, regular consumption of energy drinks is not recommended.

3.5 Conclusions The rise of demand in functional foods is the evidence of consumer awareness. Functional beverages are the subcategory of functional foods. The share of functional beverages in the global market is increasing gradually. The consumption of functional beverages has several advantages over traditional beverages including the prevention and cure of life style-related disorders.

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Further Reading E., Pons A., and Tur J. A.., 2012. Worldwide consumption of functional foods: a systematic review. Nutr. Rev. 70, 472–481. Ozer, B., Kirmaci, H., 2009. Functional milk and dairy beverages. Int. J. Dairy Technol. 63, 1–15.

HAWK TEA, A TRADITIONAL AND HEALTHY NATURAL BEVERAGE IN SOUTH CHINA

4

Xuejing Jia⁎,†, Ming Yuan⁎ ⁎

College of Life Sciences, Sichuan Agricultural University, Ya’an, China †College of Food Science and Technology, Guangdong Ocean University, Zhanjiang, China

4.1  Introduction to Hawk Tea Hawk tea, also named eagle tea, or laoying cha, has been used as a local drink for hundreds of years in China. It is one of the most popular beverages along the Yangtze River and its southern area in China, and there are more than 30 million drinkers. Hawk tea is made from the tree of the Lauraceae family and is different from green tea (Camelliaceae) (Lu et  al., 2001). These evergreen trees are much taller than Camellia sinensis, many of them more than 10 m high. Their young leaves have white, small and tiny hairs (Xiang and Lu, 1998). The first written record of Hawk tea is in the “Compendium of Materia Medica” (Li Shizhen, Ming dynasty, AD 1590), and is traditionally used as a hypolipidemic herb in rural areas (Wang et al., 2009). Qianwei County chronicles had recorded that Hawk tea became the usual drink of the local people in 1746. Hawk tea is mainly produced in southwest China, and Sichuan is the most important appellations. And the plant of Hawk tea in Sichuan showed higher genetic diversity (Han et al., 2014). Hawk tea of Shimian County in Sichuan was protected as a product of national geographical indication by the General Administration of Quality Supervision, Inspection, and Quarantine of the People’s Republic of China in 2012. Now, Hawk tea is considered as the best drink to beat the heat in the summer by the rural people in southwest China, and this practice has also gradually extended to the city. Hawk tea is commonly popularized in Spicy Bampa because of its character of a refreshing thirst quencher and a slightly sweet taste (Xu et al., 2012). Hawk-tea soup exudes a slight smell of aromatic camphor, and is reported to prevent food spoilage, abdominal distension, and sunstroke (Li and Zhang, 2005). Non-alcoholic Beverages. https://doi.org/10.1016/B978-0-12-815270-6.00004-9 © 2019 Elsevier Inc. All rights reserved.

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108  Chapter 4  Hawk Tea, a Traditional and Healthy Natural Beverage in South China

4.2  The Original Plants of Hawk Tea and Their Resources The raw materials and species of Hawk tea are shown in Fig. 4.1. Generally, the original plants of Litsea coreana Lévl var. lanuginose (Migo) Yang and P. H. Huang, Machilus chuanchieneneie S. K. Lee, and Actinodaphne cupularis (Hemsl.) (Litsea cupularis Hemsl.) can be used as a raw material for Hawk tea. L. coreana var. lanuginose attracts a wide popularity among the residents to the south of the Yangtze River. M. chuanchieneneie is consumed in Guizhou and Sichuan provinces. A. cupularis is intensively drunk in Guizhou, Sichuan, Guangxi, and Yunnan provinces. Due to the degree of abundant resources and applicable range, L. coreana var. lanuginose is considered as the main original plant of Hawk tea and is utilized commercially (Xu et al., 2012). Hawk tea is traditionally divided into three types according to the mature degree of the raw material. They are mature leaf Hawk tea, tender leaf Hawk tea, and bud Hawk tea. As shown in Fig. 4.2, their soup is amber. In general, after collection the raw materials of Hawk tea need to be fixed, rolled, and fired with a pan, and the products are obtained. Bai cha is made from tender leaves by drying in the wind or sunlight, and dashu cha is made from slices of the stems and decocted with water (Lu et al., 2001). Hawk teas can be divided into different grades according to their raw material. The top Hawk tea is the buds or a bud and two leaves and the soup color is light green. The first grade of Hawk tea is a bud and three leaves and the soup color is slight green. The middle grade of Hawk tea is a bud and four leaves and its infusion color is light yellow. The low grade of Hawk tea is young branches and the infusion color is yellow (Li, 1995).

Fig. 4.1  The natural resources, species, and processing methods of Hawk tea.

Chapter 4  Hawk Tea, a Traditional and Healthy Natural Beverage in South China   109

Fig. 4.2  The raw material and soup of four kinds of popular Hawk teas.

L. coreana var. lanuginose is distributed from 450 to 1350 m in the mountainous areas. It mainly grows in the secondary evergreen broad-leaved or bamboo forests; sometimes, just a big lonely tree stands in the courtyard or at the edge of the field. Hawk tea is a dioecious tree, and its rate of fruit is very low. The growth period of the fruit is almost as long as one year, and few seeds can be collected every year. Its embryos will go on to develop after fruits fall off the tree, and some chemical constituents of the seed coat can inhibit the germination of the seed. Therefore, L. coreana var. lanuginose can hardly propagate by its seeds (Shu et  al., 2013a). Because of gathering the buds excessively, there are often a lot of dead branches on the trees, and the growth of plant often has been severely affected. These trees cannot flower and bear fruit normally. Therefore, these populations can hardly renew by themselves, and artificial cultivation and propagation must be carried on to protect the natural resources and utilize them sustainably. In agricultural production, Hawk tea is usually reproduced by asexual propagation. The age of mother trees greatly affected the rooting rate of its spring shoots. The rooting rate of spring shoots from 35-yearold mother trees was 72.45%, which was higher than that of spring shoots from 20-year-old mother trees (63.10%) and 8-year mother trees (65.14%) (Wang et al., 2015). Treatment with 500 mg/L ABT rooting powder could improve the cutting survival rate of 5 cm new shoots with two buds and a leaf (Shu et al., 2013a).

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Tissue culture of plant could improve the seedling propagation speed, and a large number of seedlings could be obtained in a short period of time. Tissue culture of L. coreana var. lanuginose was explored. Surface sterilization was an essential step to avoid the pollution of explants. The best surface sterilization for explants was as follows: soaking with 75% ethyl alcohol for 30 s, treating with 0.1% mercuric chloride for 8 min, and washing with sterile water three times. Under this condition, the callus-inducing ratio could be 36.4% (Kuang et al., 2013). To avoid browning during the tissue culture process, the optimal raw materials were stems with axillary buds, which possessed a low browning rate when compared with leaves and buds. In addition, 0.8 g/L active carbon could strongly restrain tissue from browning and result in a low browning rate (12%) (Zhu, 2013).

4.3  Processing Technology of Hawk Tea The collection time of L. coreana var. lanuginose leaves is important to its chemical components (Han et al., 2014), and the period from March to May might be its appropriate harvest month due to its high total polyphenol content (Xiao et  al., 2015). There are four processing methods of Hawk tea. The traditional method is utilized in rural ­areas. Tender branches and buds of Hawk tea are collected and boiled with water, and dried naturally. The second way is like the green-tea method. In detail, new shoots of Hawk tea are collected and rinsed. Then, the material is fixed at 320°C for 15 min. After cooling, the shoots are fired at 80°C for 25 min and then cooled naturally. A semi-­ fermented method is also used in Hawk tea processing. New shoots of Hawk tea are collected and washed in an orderly manner, and the surface is dried. Then, the shoots are fixed at 300°C for 10 min, rolled at 35 r/min for 15 min, and fermented for 30 min. Lastly, the material is processed through pan firing at 80°C for 25 min (Xu et al., 2016). In some regions, Da shu cha is made directly from stem slices, but they must be boiled with water before drinking. Each processing method possesses different inclusions. As shown in Table  4.1, compared with the traditional method, the green-tea method and semi-fermented method provide better nutritional quality, showing supernal contents of water extracts, proteins, and tea polyphenols (Xu et al., 2016). Thus, to obtain the high quality of Hawk tea, the green-tea method and semifermented method would be the optimal processing technologies. Another important Hawk tea is sandy tea, which is the feces of a particular insect. The special insect is fed with the leaves of Hawk tea, and its feces are collected (Lu et al., 2001). Hawk tea-producing insects include Aglossa dimidiata, Pyralis farinalis, and Martyringa xeraula. The host plants contain L. coreana var. lanuginose and A. cupularis

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Table 4.1  The Major Constituents of Hawk Tea Processed by Different Methods Water extracts (%) Caffeine (%) Protein (%) Total ash (%) Tea polyphenols (%) Total flavonoids (%) Soluble sugar (%) Fat (%) Vitamin C (mg/g)

Traditional Method

Green-Tea Method

Semi Fermented Method

21.6 0 21.1 5.8 7.8 2.0 0.3 2.4 0.2

33.5 0 26.2 5.5 13.0 2.0 0.2 4.1 0.2

32.0 0.1 26.4 5.3 10.0 2.1 0.3 3.2 0.2

The data depicted in this table come from Xu, Q., Wang, J., Qi, X., Xi, P., Yao, S., 2016. Effects of processing method and maturity on biochemical characteristics of Hawk tea. Hubei Agric. Sci. 55, 660–664.

(Liu et al., 2015). Tender branches and buds of L. coreana var. lanuginose are collected in the spring, boiled with water for the “fixation” procedure, scooped up and cooled, put them in a basket and hung under the eaves; insects such as A. dimidiata, P. farinalis, and M. xeraula enter the basket and feed and excrete. After 10–12 months, the basket is taken down, the impurity is sifted and selected, the feces are dried in the air, and the sandy tea is obtained. Specially, insect Hawk tea can be produced in factories, based on L. coreana var. lanuginose. In fact, sandy tea contains high proteins, rich mineral elements, and plentiful essential amino acids and fatty acids, which is beneficial to the spleen, heat detoxification, and easement of blood pressure (Xu et al., 2000, 2013). The soup of insect Hawk tea is dark brown (Fig. 4.2), and insect Hawk tea shows many advantages, such as little dosage, strong tea flavor, and few tea dregs (Xu et al., 2000). Except for using as a beverage, insect Hawk tea is commonly used as precious gifts.

4.4  Phytochemicals of Hawk Tea In this part, we emphasize the recent progress of L. coreana var. lanuginose regarding the chemical constituents and its biological activity due to its potential application prospects and the availability of research references. Hawk tea is abundant in proteins, amino acids, sugars, and polyphenols, and is caffeine-free (Table 4.2) (Yu and Gu, 2001; Shu et al., 2013b). Hawk tea is rich in vitamins and amino acids

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Table 4.2  The Major Nutritional Constituents of Hawk Tea Water extracts (%) Caffeine (%) Protein (%) Total ash (%) Tea polyphenols (%) Free amino acids (%) Soluble sugar (%) Fat (%)

Litsea coreana var. lanuginose

Machilus chuanchieneneie

Actinodaphne cupularis

Sandy Tea

31.1 ND 0.9 5.2 12.5 14.8 0.3 5.1

33.0 0.2 12.5 4.9 11.1 0.05 3.5 1.92

25.6 ND 0.3 5.3 10.8 14.6 4.0 4.2

26.3 0.2 14.3 6.1 7.5 ND ND 1.0

ND, not detectable. The data depicted in this table come from Xu, Q.L., Sun, X.T., Li, M.J., Zhou, X.S., 2000. Study on chemical constituents of hawk tea and sandy tea. Guizhou Sci. 18, 191–195; Yu, J.P., Gu, L.Q., 2001. The chemical constituent of laoying tea from Guizhou. J. Plant Resour. Environ. 10, 61–62.

(Yu and Gu, 2001). Hawk tea from different plantations has different contents of trace elements, including Pb, Cd, Mn, Fe, Zn, and Ca (Gu and Peng, 2013). Extensive research had been carried out to elucidate the structures of active ingredients, like flavonoids, polyphenols, and essential oils, from L. coreana var. lanuginose using gas chromatography mass spectrometry (GC-MS), 1D and 2D nuclear magnetic resonance (NMR), and infrared spectrometry (IR). And flavonoids were identified as the crucial active component in Hawk tea (Ye and Yu, 2004). Many published papers reported that many compounds from L. coreana var. lanuginose had been isolated and classified (Agrawal et al., 2011; Kong et al., 2015; Wang et al., 2016; Jia et al., 2017). Here, the extraction methods and chemical compounds from L. coreana var. lanuginose are systematically summarized.

4.4.1 Extraction Technologies of Chemicals From Hawk Tea Flavonoids were crucial active components of L. coreana var. lanuginose. A large number of studies reported flavonoids were extracted and isolated from L. coreana var. lanuginose. The yield of flavonoids was about 2.93%, which was extracted using the Soxhlet extraction method and was measured using the colorimetric method (Yang et  al., 2011). When the extraction factors were optimized, the

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yield could be up to 6.19% (quercetin equivalents). Based on an orthogonal experiment, their extraction parameters were: ethanol concentration, 70%; ratio of liquid to material, 35 mL/g; extraction temperature, 60°C; extraction time, 90 min (Ji et al., 2011a). Some ancillary extraction methods are applied to improve the extraction efficiency and yield of flavonoids. With the ultrahigh-pressure extraction method, the optimum extraction parameters were: extraction pressure, 427 MPa; pressure holding time, 9 min; liquid-solid ratio, 41 mL/g; ethanol concentration, 70%. Under these conditions, the flavonoid yield was improved to about 6.23% (Ji et al., 2011d). Based on response surface methodology, microwave-assisted extraction could increase the flavonoid yield of mature leaf Hawk tea. The best extraction factors were: microwave time, 61 s; microwave power, 560 W; ratio of water to solid, 10 mL/g; and ethanol concentration, 80.3%. And the maximum yield of flavonoids was up to 6.52% under these conditions (Jia et al., 2014b). Cellulase was used to improve the extraction efficiency of flavonoids. The best extraction condition was: pH of enzyme solution, 5.0; the time of enzymatic hydrolysis, 120 min; enzymatic hydrolysis temperature, 50°C; and the concentration of cellulase, 0.4 mg/mL. And the yield of flavonoids was 2.68% under these extraction parameters (Yang, 2011). It was reported that the water-macroporous resin method got a higher flavonoid yield from L. coreana var. lanuginose leaves than the ethanol-n-butanol method, and it was accessible to an industrial scale (Lu et al., 2009). Saponins were one group of active components in L. coreana var. lanuginose, and their optimum extracting technological conditions were explored. The best ultrasound extraction parameters were: ultrasound power, 450 W; extraction time, 40 min; extraction temperature, 60°C; and solvent-sample ratio, 30 mL/g. The total saponins yield was up to 75.4 mg/g under these optimal extraction conditions (Wang et al., 2012b). In addition, the microwave-assisted extraction process was used to increase the total saponins yield, and the optimum extraction conditions were: liquid to material ratio, 40 mL/g; microwave power, 480 W; microwave time, 60 s; and ethanol volume, 60%. The total saponins yield was about 71.6 mg/g under these extraction parameters (ginsenoside Rg1 equivalents) (Zhang et al., 2012a). Furthermore, other components, including polyphenols, polysaccharides, and aqueous extracts, were also isolated from Hawk tea. The polyphenolic compounds were purified by polyamide chromatography, and their yield was about 18.06% (Shen et  al., 2010). Mature leaf Hawk tea with low price is the most abundant natural resources among all kinds of Hawk tea, and its polysaccharides were optimally extracted. The optimum extraction conditions were: extraction temperature, 88.9°C; extraction time, 128.2 min; and ratio of water to solid, 11.4 mL/g; the maximum yield was about 12.74% (Jia et  al., 2014a).

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The ultrasound-assisted method was applied to extract aqueous extracts from L. coreana var. lanuginose. Using the conditions, ultrasound power, 200 W, ultrasound temperature, 93°C, and ultrasound time, 16 min, the aqueous extracts yield was 38.84% (Li et al., 2013).

4.4.2  Primary Metabolic Products of Hawk Tea Some primary metabolites, including peptides and polysaccharides, showed high biological activities in  vitro. Aqueous extracts of bud Hawk tea, tender leaf Hawk tea, and mature leaf Hawk tea contained many bioactive constituents, such as proteins, vitamin C, and carbohydrates (Yuan et  al., 2014). The hydrolysates of protein from Hawk tea are rich in histidine, tyrosine, leucine, phenylalanine, and ­lysine, but tryptophan is not detected. These highly soluble hydrolysates could efficiently scavenge DPPH radicals, chelate irons, and emulsify liquid (Jia et  al., 2013a). Three crude polysaccharides from mature leaf Hawk tea, tender leaf Hawk tea, and bud Hawk tea were separately isolated. These polysaccharides showed different physicochemical properties and remarkable antioxidant activities against DPPH radical, ferric oxidation, hydroxyl radical, and erythrocyte hemolysis (Jia et al., 2013b). The polysaccharide fractions of mature leaf Hawk tea purified by chromatography of DEAE-52 were composed of arabinose, galactose, glucose, and mannose, and exhibited stronger antioxidant activities against ferric oxidation and the DPPH radical than crude polysaccharides (Jia et al., 2014a).

4.4.3  Secondary Metabolic Products of Hawk Tea A large number of secondary metabolic substances have been isolated from L. coreana var. lanuginose. The levels of kaempferol3-O-β-d-glucoside and total flavonoids in L. coreana var. lanuginose leaves were as high as 8 and 31%, respectively (Ma et  al., 2011). In addition, flavonoids were the major active ingredients of Hawk tea, and 29 monomeric compounds from the stems and leaves of L. coreana var. lanuginose were isolated and their structures were identified (Fig. 4.3). Six monomers, including quercetin-3-O-β-d-galactopyranoside (1), quercetin-3-O-β-d-glucopyranoside (2), kaempferol-3-O-β-dgalactopyranoside (3), kaempferol-3-O-β-d-glucopyranoside (4), catechin (5), and epicatechin (6), were the major constituents of flavonoids from L. coreana var. lanuginose (Chen et al., 2008). More compounds from the leaves of L. coreana var. lanuginose were isolated and identified by the following research studies, and include quercetin (7), kaempferol (8), phaseic acid (9), kaempferol3-O-β-d-rutinose (10), pinocembrin-7-O-β-d-glucopyranoside

(Continued)

Chapter 4  Hawk Tea, a Traditional and Healthy Natural Beverage in South China   115

Fig. 4.3  Structure of chemical components from L. coreana var. lanuginose. (1) quercetin-3-O-β-d-galactopyranoside; (2) quercetin-3-O-β-dglucopyranoside; (3) kaempferol-3-O-β-d-galactopyranoside; (4) kaempferol-3-O-β-d-glucopyranoside; (5) catechin; (6) epicatechin; (7) quercetin; (8) kaempferol; (9) phaseic acid; (10) kaempferol-3-O-β-d-rutinose; (11) pinocembrin-7-O-β-d-glucopyranoside; (12) aromadedrin-3-O-α-larabinopyranoside; (13) 2,4,6-trihydroxybutyrophenone-2-O-β-d-glucopyranoside; (14) adenoside;

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Fig. 4.3 cont’d  (15) (+)-isolariciresinal-9-O-β-d-glucopyranoside; (16) kaempferol-3-O-β-d-(6-O-trans-p-coumaroyl) glucopyranoside; (17) kaempferol3-O-β-d-(6-O-trans-p-coumaroyl) mannopyranoside; (18) protocatechuic acid; (19) kaempferol-3-α-l-rhamnose; (20) trans-p-coumaric acid; (21) n-butyl phthalate; (22) salicylic acid; (23) isophyllocoumarin; (24) isoepiphyllocoumarin; (25) phyllocoumarin; (26) epiphyllocoumarin; (27) 5-(2-phenylethyl)-3hydroxyphenol-1-O-β-d-glucopyranoside; (28) 6-(2-phenylethyl)-2,4-dihydroxy benzoic acid-2-O-β-d-glucopyranoside; and (29) chlorogenic acid.

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(11), aromadedrin-3-O-α-l-arabinopyranoside (12), 2,4,6trihydroxybutyrophenone-2-O-β-d-glucopyranoside (13), adenoside (14), (+)-isolariciresinal-9-O-β-d-glucopyranoside (15), kaempferol-3-O-β-d-(6-O-trans-p-coumaroyl) glucopyranoside (16), kaempferol-3-O-β-d-(6-O-trans-p-coumaroyl) mannopyranoside (17), protocatechuic acid (18), kaempferol-3-α-l-rhamnose (19), trans-p-coumaric acid (20), n-butyl phthalate (21), salicylic acid (22), isophyllocoumarin (23), isoepiphyllocoumarin (24), phyllocoumarin (25), epiphyllocoumarin (26), 5-(2-phenylethyl)-3-hydroxyphenol1-O-β-d-glucopyranoside (27), 6-(2-phenylethyl)-2,4-dihydroxy benzoic acid-2-O-β-d-glucopyranoside (28), and chlorogenic acid (29) (Yu et al., 2001b; Wang et al., 2014; Tang et al., 2013a,b; Zhang et al., 2012b; Meng et al., 2012; Tan et al., 2016). Besides the above monomeric compounds, other organic components in L. coreana var. lanuginose were also studied. The essential oils from L. coreana var. lanuginose leaves were analyzed, and they were mainly composed of decanal (71.53%), 10-undecenal (5.02%), n-nonaldehyde (3.95%), copaene (3.58%), dodecanoic acid, and ethenyl ester (2.63%) (Yu et al., 2001a).

4.5  Pharmacological Activities of Hawk Tea 4.5.1  Hepatoprotective Activity of Hawk Tea The hepatoprotective activity of L. coreana var. lanuginose was investigated via liver-injury rat models. Methanol extracts of Hawk tea could prevent hepatic damage induced by carbon tetrachloride in Sprague-Dawley rats. Application of 400 mg/kg methanol extracts decreased the level of cytokine, including IL-6 (interleukin-6), IFN-γ (interferon-γ), and TNF-α (tumor necrosis factor-α), in the serum of Sprague-Dawley rats. Moreover, methanol extracts reduced the mRNA and protein levels of some special genes in the liver related to inflammation, such as iNOS (inducible nitric oxide synthase), COX-2 (­cyclooxygenase-2), IL-1β, and TNF-α (Zhao, 2013). It was ­reported that Kaempferol-glucopyranoside from Hawk tea prohibited rat hepatic stellate cells from proliferating through the decrease in the mRNA levels of collagen I, collagen III, Smad2, and Smad3, and the increase in the mRNA level of Smad7 (Zhou et al., 2010b). Flavonoids from L. coreana var. lanuginose could remarkably protect the liver from damage. Total flavonoids of L. coreana var. lanuginose (TFLC) (200 mg/kg) significantly decreased the levels of triglycerides and malondialdehyde (MDA) in the serum and liver of nonalcoholic steatohepatitis rats, and meanwhile improved liver SOD (superoxide dismutase) activity (Ni et al., 2006). In addition, 200 mg/ kg of TFLC lowered serum alanine aminotransferase levels (ALT),

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t­ riglycerides, aspartate aminotransferase (AST), TNF-α, and total cholesterol, and dropped the levels of triglycerides, and total cholesterol and the excess accumulation of lipids in the liver. Furthermore, TFLC decreased the protein level of NF-κB and the mRNA level of TLR4 (Wang et  al., 2012a). Moreover, TFLC could effectively protect rats from alcoholic fatty liver disease. The application of 200 mg/kg TFLC to the alcoholic fatty liver rat lowered the levels of total cholesterol, triglycerides, TNF-α, low density lipoprotein (LDL)-cholesterol, insulin, and glucose in serum, and reduced the level of hepatic adipose ­differentiation-related protein (Hu et  al., 2012). In steatotic hepatocytes, 100 mg/L of TFLC down-regulated the activities of AST and ALT and the content of triglycerides, and reduced the mRNA level of peroxisome proliferator-activated receptor γ (PPARγ) and adipose ­differentiation-related protein (Hu et al., 2013). As much as 200 mg/kg of TFLC ameliorated liver injury in liver fibrosis rats, and decreased the levels of AST, ALT, laminin, hyaluronic acid, hydroxyproline, procollagenase IV, and procollagen III N-terminal peptide in serum, and down-regulated the expressions of collagen I, transforming growth factor β receptor 1 (TGF-βR1), transforming growth factor-β1 (TGF-β1), and α-smooth muscle actin (Huang et al., 2010). A total of 200 mg/kg of TFLC lowered the levels of AST, ALT, laminin, hyaluronic acid, procollagenase IV, procollagen III N-terminal peptide, leptin, collagen I, and TGF-β1 in the serum of CCl4-induced rat liver fibrosis, and down-regulated the mRNA and protein levels of TGF-βR1, leptin receptor (Ob-Rb), and Smad3 at the same time in the liver (Huang et al., 2012). Feeding with 200 mg/kg of TFLC for 4 weeks strongly reduced the levels of AST, ALT, TNF-α, and lipids accumulation in the serum of high fat diet-induced hepatic steatosis rats. Simultaneously, TFLC could upregulate the levels of insulin and leptin in serum, augment the levels of MDA, peroxisome proliferator-activated receptor α (PPARα), and SOD, and reduce the accumulation of liver lipids (Wang et al., 2009). Another study reported TFLC could enhance insulin resistance. TFLC (200 mg/kg) aggravated the condition of impaired glucose tolerance in hyperlipidemia and insulin resistance rats. TFLC remarkably suppressed the levels of total cholesterol, fasting serum glucose, triglycerides, insulin, low-density lipoprotein cholesterol, leptin, and free fatty acids in the serum, and enhanced the index of insulin sensitivity and the level of high-density lipoprotein (HDL) cholesterol (Lv et al., 2009).

4.5.2  Hypoglycemic Activity of Hawk Tea TFLC of Hawk tea could reduce blood glucose and was suggested to relieve hyperglycemia. Feeding streptozocin induced type 2 diabetic rat with TFLC (400 mg/kg), the activity of SOD and the level

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HDL cholesterol went up, and the level of serum free fatty acids and the body weight reduced, and total cholesterol, LDL cholesterol, triglycerides, MDA, and C-reactive protein declined. TFLC downregulated the level of protein tyrosine phosphatase 1B in liver as well (Lu et al., 2010). Feeding type 2 diabetic rat with 400 mg/kg dosage of TFLC could effectively down the serum levels of glycohemoglobin, fast blood glucose, fast blood insulin, total cholesterol, free fatty acids, LDLcholesterol and triglycerides in serum, and elevated the accumulation of MDA in liver. Furthermore, TFLC increased the serum HDL cholesterol level and liver SOD activity (Sun et al., 2010). Major active constituents of Hawk tea ethanol extracts were flavonoids, which strongly inhibited activity of α-glucosidase and the IC50 value was 0.12 mg/mL. And the analysis of enzyme kinetics exhibited that this inhibitory effect was reversible mixed-type, and the inhibitory constants for resolvase and enzyme-substrate complexes were 0.058 and 0.178 mg/mL, respectively (Gou et al., 2016b).

4.5.3 Antiinflammatory Activity of Hawk Tea Extensive research studies found that TFLC could disturb inflammation progress. Taking 50 mg/kg dosage of TFLC orally could remarkably alleviate primary and secondary paw swelling in complete Freund’s adjuvant-induced arthritis (AA) rats, and reduced concanavalin A or lipopolysaccharide(LPS)-induced splenocyte proliferation and the pathological damage of the knee joint. TFLC decreased the production of IL-1, TNF-α, and IL-6 and inhibited the expression of matrix metalloproteinases (MMP-9) in peritoneal macrophages. However, TFLC could improve the level of IL-2. TFLC showed a curative effect on AA rats through downregulating the inflammatory cytokine level and suppressing MMP-9 expression (Wang et al., 2007, 2008). A subsequent study indicated that 100 mg/ kg dosage of TFLC remitted secondary paw swelling and dropped the levels of IL-1β and TNF-α in AA rat serum, and reduced the TNF-α and mTOR complex 1 levels of peritoneal macrophages (Zhong et  al., 2014). For collagen II-induced arthritis rats, TFLC (50 mg/kg) diminished paw swelling and led to weight gain. In addition, TFLC (0.05 mg/L) lowered the IL-2 level of splenocytes and the mRNA level of IL-1 and TNF-α in peritoneal macrophages (Zhou et  al., 2010a). For LPS-activated peritoneal macrophages of the mouse, compounds 23–26 inhibited the accumulation of IL-1 and TNF-α (Tang et al., 2013b). For LPS-induced RAW 264.7 cells, compounds 27–28 down-regulated the levels of IL-1 and TNF-α (Tang et al., 2013a). These reports indicated that these organic chemicals from L. coreana var. lanuginose could potently inhibit inflammatory reactions.

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4.5.4 Antioxidant Activity of Hawk Tea The extracts of Hawk tea have notable antioxidant properties in vitro. The ethanol extracts of L. coreana var. lanuginose could efficiently scavenge, 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals, hydroxyl radicals, and 2,2’-azino-bis (3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) radicals, with EC50 values (concentration for 50% of maximal effect) of 0.06, 2.42, and 1.09 mg/mL, respectively. In addition, these extracts inhibited the peroxidation of linoleic acid, and their inhibition rate is up to 65.5% (Tan et al., 2016). Purified TFLC showed high activity to scavenge the DPPH radicals and reduce iron ions; the EC50 values are 18.17 μg/L and 77.52 g/L, respectively (Ji et al., 2011a). Some flavonoid monomers, including isoquercitrin, hyperin, quercetin, quercitrin, catechins, kaempferol, epicatechin, and chlorogenic acid, exhibited strong ability to eliminate the ABTS radicals (Meng et al., 2012). Total saponins of Hawk tea also showed a strong ability to mop up reactive oxygen compounds, such as DPPH radicals and reduced iron ions. As much as 160 μg/mL of total saponins from Hawk tea showed a very high scavenging rate, up to 93.53%, which was better than that of butylated hydroxytoluene (Zhang et al., 2012a). Moreover, aqueous extracts from the buds, and tender and mature leaves of L. coreana var. lanuginose all showed high activity to clean up DPPH radicals and strong reducing power to ferric ions, prevented erythrocyte hemolysis, and inhibited the formation of LDL-conjugated dienes (Yuan et  al., 2014). The aroma components of L. coreana var. lanuginose mainly contained decane and 7H-dibenzo[b,g]carbazole, and 2 mg/mL dosage showed the scavenging rate of 80% on DPPH and hydroxyl radicals (Zhao and Li, 2014). Volatile oils of L. coreana var. lanuginose, composed of camphene, α-pinene, limonene, linalool,1,8-cineole, germacrene B, and cis-nerolidol, could efficiently eliminate H2O2 and DPPH radicals, and their IC50 values were 0.176 and 0.142 mg/mL, respectively (Yu et al., 2016).

4.5.5 Antimicrobial Activity of Hawk Tea Ethanol extracts of mature leaf Hawk tea stimulated the growth of the intestinal anaerobic bacteria of mice, such as Lactobacillus and Bifidobacterium (Wu et al., 2012). The growth of Bacillus cereus, Staphyloccocus aureus, and Pseudomonas aeruginosa was inhibited by the methanol extracts of bud Hawk tea, with the minimum inhibitory concentration (MIC) values of 4.56, 3.48, and 4.78 mg/mL, respectively. Meanwhile, the methanol extracts from tender leaf Hawk tea showed certain antimicrobial activity against Escherichia coli and Bacillus subtilis, with MIC values of 3.91 and 3.26 mg/mL, respectively (Xiao et  al., 2017). TFLC with 40 mg/mL concentration significantly

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inhibited the growth of Proteusbacillus vulgaris, Bacillus anthraci, B. subtilis, and S. aureus (Ji et al., 2011c). Total saponins of Hawk tea with 25 mg/mL concentration also efficiently inhibited the growth of S. aureus, P. vulgaris, and Enterobacter aerogenes (Wang et al., 2012b). In addition, aqueous extracts from mature leaf Hawk tea regulated the number of aerobic bacteria, Enterococcus, and Enterobacterium, in the mouse gut (Wu et al., 2012). Volatile oils of Hawk tea showed considerable inhibitory activity on Gram-positive bacteria, such as Staphylococcus epidermidis, S. aureus, and Listeria monocytogenes, and Gram-negative bacteria, such as Salmonella typhimurium and E. coli, and the MICs of S. epidermidis, S. aureus, L. monocytogenes, S. typhimurium, and E. coli were 32, 64, 128, 64, and 128 μg/mL, respectively (Yu et al., 2016).

4.5.6 Other Pharmacological Activities of Hawk Tea The methanol extracts from L. coreana var. lanuginose leaves conspicuously inhibited HSV-1, and its IC50 value was 12.02 μg/mL. These ethanol extracts could directly deactivate the virus and prevent the attachment of virus on Vero cells (Xu et al., 2011). 400 μg/mL of ethanol extracts inhibited the growth of colon carcinoma HT-29 cells and human gastric carcinoma AGS cells, and 1.25 mg/mL of ethanol extracts showed antimutagenic properties (Zhao et al., 2008). Epigallocatechin gallate, extracted from Hawk tea, might interact with α-glucosidase and further inhibited its activity with an IC50 of 3.8 mg/mL (Li et al., 2010). A total of 800 μg/mL of aroma components from L. coreana var. lanuginose showed about 60% inhibitory activity against AGS human gastric adenocarcinoma cells and HT-29 human colon cancer cells (Zhao and Li, 2014). Injecting 200  mg/kg TFLC into the abdominal cavity of ­cyclophosphamide-treated mice notably upgraded the indices of carbon clearance and macrophage phagocytic values, and evidently increased the level of immunoglobulin G (IgG) and immunoglobulin M (IgM) in serum, the ratio of CD4+ and CD8+ T cells, the amount of hemolysin, and the accumulation of IL-2 (Hu et  al., 2007). For mouse testicular cancer I-10 cells, TFLC with 100 mg/mL enhanced the cytotoxicity of oxaliplatin through regulating gap junction and tumor cell apoptosis and upregulating the ratio of Bax/Bcl-2 and the expression of caspase-3/9 (Yu et al., 2014a). For mouse TM3 testicular Leydig cells, treatment with 20 μg/mL TFLC enhanced its gap junction intercellular communication (GJIC). TFLC strengthened the synergistic anticancer effect by improving the level of Connexin 43 (Cx43) protein and enhancing GJIC (Yu et al., 2014b). In focal cerebral ischemia/reperfusion injury rats, 100 mg/kg dosage of TFLC lowered the levels of MDA, nitrates, and nitrites and the activity of

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lactate dehydrogenase, and improved the level of glutathione and the activities of SOD and catalase. Therefore, TFLC relieved the cerebral ischemia-induced neurological deficits (Dong et al., 2013). The relatively low concentration (2.5 and 1.25 mg/mL) of the aqueous extracts from L. coreana var. lanuginose could effectively protect fibroblasts from UV irradiation. And its protective ability was better than aqueous extracts of green tea (Chen et al., 2005). Aqueous extracts of mature leaf Hawk tea, composed of 2.96% flavonoids and 4.64% polyphenols, efficiently scavenged nitrites and inhibited the production of nitrosamine, and their IC50 values were 0.06 and 0.25 mg/mL, respectively (Gou et al., 2016a).

4.5.7  Toxicity of Hawk Tea Only a few reports concentrated on the toxicity of Hawk tea, and they all placed concern on TFLC. The survival rates of normal hepatocytes were not affected obviously by 100 mg/L of TFLC treatment for 48 h (Hu et al., 2013). The experience of the mice suggested that the 10 g/kg dosage of TFLC was nontoxic and safe. Rats were fed TFLC (10 g/kg) for 14 days continuously, and their behavior and weight remained unchanged, and no detectable biomarkers of toxic responses were found (Wang et  al., 2008). Concerning the limited data on the toxicity of hawk tea extracts, further studies are highly demanded to evaluate the chronic and acute toxicity of the extracts and constituents from L. coreana var. lanuginose in animal models (Wang et al., 2008).

4.6  Application and Limitation of Hawk Tea Exciting developments have taken place in separating active ingredients from L. coreana var. lanuginose and their bioactivities were evaluated in vitro and in vivo. However, to improve the use and development of the Hawk tea resource, numerous potential work still need to be explored. (1) Besides total flavonoids, more constituents of L. coreana var. lanuginose should be discovered and their potential utilization value further investigated and their related molecular mechanisms uncovered. (2) To ensure the safety of utilization, it is necessary to evaluate the efficacy and toxicology of Hawk tea extracts through preclinical and clinical research systematically, in particular, to clarify the safety of Hawk tea. It is worth noting that a mixture of 6 monomeric flavonoids from Hawk tea showed remarkable hepatoprotection and antiinflammatory ability. TFLC has the potential to be explored as a promising therapeutic agent, like Gingko biloba flavonoids, a mixture of flavonoids, exhibited potently protective effects on dementia, hypertension, Alzheimer’s disease, and aging

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(Smith and Luo, 2004). (3) Hawk tea also could be developed as a functional food. Due to the diverse health benefits of Hawk tea extracts, we can exploit functional foods or drinks. For example, the powder of L. coreana var. lanuginose can be brewed as a beverage together with jujube. And this drink smells rich flavor and tastes very sweet (Ji et al., 2011b). Moreover, the powder of L. coreana var. lanuginose can be added into yoghurt. The extracts of L. coreana var. lanuginose leaves can largely enhance the amount of Streptococcus thermophilus, lactic acid bacteria, Lactobacillus casei, and Lactobacillus acidophilus (Ye et al., 2012). 0.2%–1% water extracts of Hawk tea enhanced the flavor and the taste of yogurt. More importantly, water extracts of Hawk tea improved the polyphenol level, the viscosity, and water-holding ability of yogurt (Liu et al., 2016). Natural pigments of L. coreana var. lanuginose leaves can be explored as food additives. These pigments exhibited different colors in diverse pH and metal ions solutions. More importantly, they were relatively stable against temperature variations (Ye and Yu, 2002). However, some questions should still deserve our attention regarding the utilization of L. coreana var. lanuginose extracts. The pharmacological utilization of flavonoids might be affected due to the low absorption rate. The transport of flavonoids from L. coreana var. lanuginose depended on a sodium-dependent glucose transporter. The flavonoid glucosides of L. coreana var. lanuginose, quercetin-3-O-β-dglucoside and kaempferol-3-O-β-d-glucoside, could be uptaken and transported by a sodium-dependent glucose transporter in Madin Darby canine kidney cells. And multidrug resistance associated protein 2 might decrease the absorption rate of these flavonoid glucosides (Chen et al., 2014). In summary, more efforts and attentions should be paid to the structure analysis of active constituents, function of nutrition, and pharmacology for L. coreana var. lanuginose. On the basis of the above properties, it can promote the development and utilization of this valuable beverage in functional foods and the pharmaceutical industry.

4.7 Conclusion Hawk tea is a caffeine-free beverage, and it attracts a large number of local consumers in the south of China. In conclusion, to obtain high quality of Hawk tea production, the best harvest time is from March to May and the suitable processing method is the green-tea or semi-­fermented method. Published studies suggested that L. coreana var. lanuginose was rich in flavonoid compounds and demonstrated obvious pharmacological properties, especially for antioxidant,

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­ epatoprotective, and antiinflammatory abilities. However, further h studies are highly expected to investigate the relationship between target compounds and their effective disease, which can dramatically accelerate the commercial application of L. coreana var. lanuginose.

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Xiao, X., Xu, L., Hu, H., Yang, Y., Zhang, X., Peng, Y., Xiao, P., 2017. DPPH radical scavenging and postprandial hyperglycemia inhibition activities and flavonoid composition analysis of Hawk tea by UPLC-DAD and UPLC-Q/TOF MSE. Molecules 22, 1622. Xu, L., Pan, H., Lei, Q., Xiao, W., Peng, Y., Xiao, P., 2013. Insect tea, a wonderful work in the Chinese tea culture. Food Res. Int. 53, 629–635. Xu, L., Xiao, W., Ma, P., Peng, Y., Zhang, X., Wang, W., Xiao, P., 2012. An Chinese old teaHawk tea. Mod. Chin. Med. 14, 60–62. Xu, M., Pei, Y., Xiang, Y.F., Lai, Z.C., Qu, C., Qian, C.W., Ren, Z., Zhang, Y.J., Yang, C.R., Kaio, K., Wang, Y.F., 2011. Study on the in vitro anti-HSV-1 activity of aqueous extract from Litsea coreana. Lishizhen Med. Mater. Med. Res. 22, 282–284. Xu, Q., Wang, J., Qi, X., Xi, P., Yao, S., 2016. Effects of processing method and maturity on biochemical characteristics of Hawk tea. Hubei Agric. Sci. 55, 660–664. Xu, Q.L., Sun, X.T., Li, M.J., Zhou, X.S., 2000. Study on chemical constituents of hawk tea and sandy tea. Guizhou Sci. 18, 191–195. Yang, X.F., 2011. Enzymatic extraction of total flavonoids from Litsea coreana. Southwest China J. Agric. Sci. 24, 2369–2371. Yang, X.F., Han, M., Hu, L., 2011. Determination of total flavonoids in Litsea coreana by spectrophotometric method. Southwest China J. Agric. Sci. 24, 1234–1235. Ye, H., Yu, J.P., 2002. The preliminary studies on a natural food pigment extracted from Hawk tea (Litsea coreana). Food Sci. 23, 41–43. Ye, H., Yu, J.P., 2004. The preliminary studies on antioxidation of three kinds of flavoniods from Litsea coreana. Chin. Crude Drug. 27, 113–116. Ye, M., Liu, D., Zhang, R., Yang, L., Wang, J., 2012. Effect of hawk tea (Litsea coreana L.) on the numbers of lactic acid bacteria and flavour compounds of yoghurt. Int. Dairy J. 23, 68–71. Yu, B., Zhang, D., Yan, X., Wang, J., Yao, L., Tan, L., Zhao, S., Li, N., Cao, W., 2016. Comparative evaluation of the chemical composition, antioxidant and antimicrobial activities of the volatile oils of Hawk tea from six botanical origins. Chem. Biodivers. 13, 1573–1583. Yu, B.B., Dong, S.Y., Yu, M.L., Jiang, G.J., Ji, J., Tong, X.H., 2014a. Total flavonoids of Litsea coreana enhance the cytotoxicity of oxaliplatin by increasing gap junction intercellular communication. Biol. Pharm. Bull. 37, 1315–1322. Yu, B.B., Tong, X.H., Dong, S.Y., Gu, Y.C., Jiao, H., Ji, J., Qu, B., 2014b. Total flavonoids of Litsea coreana decreases the cytotoxicity of oxaliplatin in TM3 Leydig cells via enhancing the function of gap junction. Natl. J. Androl. 20, 400–404. Yu, J.P., Gu, L.Q., 2001. The chemical constituent of laoying tea from Guizhou. J. Plant Resour. Environ. 10, 61–62. Yu, J.P., Gu, L.Q., Ren, S.X., 2001a. Study on the essential oil compositions of the leaves of Litsea coreana from Guizhou. Food Sci. 7, 63–64. Yu, J.P., Ye, H., Gu, L.Q., 2001b. The flavonoids from Litsea coreana. Acta Sci. Natur. Univ. Sunyatseni 40, 110–114. Yuan, M., Jia, X.J., Ding, C.B., Yuan, S., Zhang, Z.W., Chen, Y.E., 2014. Comparative studies on bioactive constituents in Hawk tea infusions with different maturity degree and their antioxidant activities. Sci. World J. 2014, 1–7. Zhang, L.W., Ji, H.F., Li, B., Wang, Y., Yan, Z.M., Yang, M.D., 2012a. Microwave extraction and antioxidant activity of total saponins from Litsea coreana. Hubei Agric. Sci. 51, 5151–5154. Zhang, Y.L., Tang, W.J., Tang, M.F., Lv, X.W., Yu, S.C., Li, J., 2012b. Chemical constituents of n-butanol fraction of Litsea coreana L. Anhui yi ke da xue xue bao. 47, 1063–1065. Zhao, X., 2013. Hawk tea (Litsea coreana Leve. var. lanuginose) attenuates CCl4-induced hepatic damage in Sprague-Dawley rats. Exp. Ther. Med. 5, 555–560. Zhao, X., Li, G., 2014. Study on component analysis and in  vitro functional effects of aroma components of Hawk tea in Sichuan Mengding region. Sci. Technol. Food Ind. 35, 83–86.

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Zhao, X., Shao, L.N., Zheng, Y.F., 2008. Antimutagenic and in vitro anticancer effect of Litsea coreana leve. var. lanuginisa. Food Eng. 4, 29–31. Zhong, J., Ma, T.T., Huang, C., Liu, H.Z., Chen, Z.L., Cao, L., Li, X.H., Li, J., 2014. Flavonoids from Litsea coreana decreases TNF-α secretion from peritoneal macrophages in ­adjuvant-induced arthritis rats via UPR pathway. Am. J. Chin. Med. 42, 905–919. Zhou, Q., Li, J., Wang, T.Y., Wang, X.H., 2010a. Effect of total flavonids of Litsea coreana Leve on cytokines production and immunity of peritoneal macrophage from ­collagen-induced arthritis. Chin. Pharm. Bull. 26, 353–358. Zhou, W.C., Li, J., Dai, K.K., Xiong, L., Huang, C., 2010b. Effect and mechanism of kaempferol-glucopyranoside from total flavonoids of Litsea coreana L. on the proliferation of hepatic stellate cells induced by TGF-β1. Anhui yi ke da xue xue bao. 45, 499–502. Zhu, X., 2013. Study on browning prevention in tissue culture of Litsea coreana Var Lanuginosa. J. Anhui Sci. Technol. Univ. 27, 33–36.

DEVELOPMENT OF MIXED BEVERAGES BASED ON TROPICAL FRUITS

5

Geraldo Arraes Maia, Larissa Morais Ribeiro da Silva, Giovana Matias do Prado, Ana Valquiria Vasconcelos Fonseca, Paulo Henrique Machado de Sousa, Raimundo Wilane de Figueiredo Department of Food Engineering, Federal University of Ceara, Fortaleza, Brazil

5.1 Introduction The increase in fresh fruit consumption has been observed all over the world. This increase is associated with the following factors: higher health care and nutritional aspects of food, advertising campaigns on the benefits of fruit and vegetable consumption, aging of the population (which broadens the consumer age group), tendency to release schedules and costs (which increases the substitution of meals for fast snacks), open consumer novelties (attracted by new products), and a consumer demand for new and different flavors. The Food and Agriculture Organization (FAO) has shown that the worldwide marketing of fruit products has grown more than five times in the last 15 years. Among developing countries, Brazil stands out for having the most expensive fruit production, which is concentrated in a small number of fruit species, which are grown and processed on a large scale (Brunini et al., 2002). World fruit production was responsible for the production of 773.8 million tons of fruit in 2012 (FAO FAOSTAT, 2017). The fruticulture is considered one of the most profitable agricultural segments, attracting attention not only from rural businessmen and farmers but also from government agencies. This activity has socioeconomic advantages, such as higher profitability, reduction of the rural exodus, and better remuneration for businessmen and workers, since it requires qualification of the labor force (Pereira et al., 2002).

Non-alcoholic Beverages. https://doi.org/10.1016/B978-0-12-815270-6.00005-0 © 2019 Elsevier Inc. All rights reserved.

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Along with fruit growing, the fruit-based beverage sector has been growing in recent years, due to the factors that are already shown in the increase in fruit consumption. There is a growing demand by consumers of industrial nations for a greater variety of fruits in their diet. This interest does not extend only to fresh tropical fruits, but also to processed juices. The impact of this demand on developing countries has promoted an increase in production and processing capacity, thus ensuring the supply of these products in the world market. Concerning the market fruit juice segment, the world market moves around the US$5.0 billion/year. Brazil is a significant exporter and occupies the eighth place in the ranking of the world exports of tropical juices. The international market for juices and their derivatives is in full development, which allows tropical countries to participate in new market niches, not traditional in the consumption of these products. Fruit juices are a popular choice of beverage for both adults and children because of its taste and color friendly and it has many health benefits associated with it. Despite the appeal for the consumption of fruit-based products, the category of juices (ready and concentrated) still has low penetration in the domestic market of soft drinks. Studies of mixed fruit nectars have been carried out for a long time. As early as 1949, works by Menzies and Kefford, quoted in Kefford and Vickery (1961) with mixtures of passion fruit and apple juices. However, there are few products in the market. Despite the great variety of tropical fruits with delightful exotic flavors, presenting an excellent market potential, there are few commercial products of tropical fruit blends. The food sector depends on consumers and their social behavior. As currently, more and more consumers are looking for healthy products, exotic fruits have been increasingly used, with excellent opportunities for innovation (Moura Neto et al., 2016). In this way, beverages with new flavors and aromas are currently being elaborated, having their chemical, physicochemical, and sensorial properties analyzed throughout the world, being considered a consumption trend. In addition to the fruit mixture in beverages, the addition of components with claimed functional properties has also been studied, aiming at the elaboration of enriched fruit drink. The use of a wide variety of components has been studied, and these should present functional and/or medicinal properties claims, consumed in conventional diets. The purpose of this work was to address the factors that influence the development of fruit blends, as well as to present research results concerning fruits mixtures and fruit products with the addition of components with claims of functional and/or health properties.

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5.2  Factors Involving Mixed Fruit Beverages Development 5.2.1 Fruits Composition and Market Demand The most abundant components in fruits are water and carbohydrates, but from the nutritional point of view, vitamins and minerals are considered. Fruit dietary fibers are also present that aid the passage of the gastrointestinal tract and the antioxidant compounds, which act to decrease or inhibit free radicals in the body, which can cause various diseases, such as some types of cancer. Also, the antioxidant activity may also be related to the delay of aging, in reductions in the occurrence of degenerative and cardiovascular diseases. Thus, fruits, as they contain various compounds, both nutritional and functional, are essential in the maintenance of the human organism, aiding directly in the well-being of the body and mind. In view of this, it is observed that there is a growing consumer demand for a greater variety of fruits in their diet motivated by a series of factors: higher health care and nutritional aspects of foods, growing sensitivity to ecological factors, advertising campaigns on the benefits of fruit consumption, aging of the population, which expands the older consumer group, tendency to release the hours and customs, and consumer open to new flavors, attracted by new products (Maia et al., 2007). A few years ago, the food industry tried to promote its sales through new drinks, usually with claims of functional properties. These can be divided into products that provide additional nutrients, particularly for individuals engaged in energy-intensive activities, and are referred to as sports drinks, and in fortified beverages, which are enriched with minerals, vitamins, fibers, and other functional ingredients. Fruit blends, which have the commercial appeal of being entirely natural, can also be classified into this class of beverages with functional claims, as they are rich in vitamins and minerals as well as phytochemical components. According to Zheng et al. (2017), many studies have indicated that consumption of fruits is positively related to lower incidence of several chronic diseases. The composition of fruit juices is different from that of the edible portion of fruits. Drinking fruit juices are very popular in many countries, and also an efficient way to improve consumption of these products. The health benefits associated with consumption of fruits were linked to different mechanisms of action, cited in Fig. 5.1, According to the authors, drinking juices might be a potential way to improve damage to health, especially mixtures of juices because they contain a variety of polyphenols, vitamins, and minerals from different fruits and vegetables.

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Fruit and vegetable juices Controlling body weight

Preventing hyperhomocysteinemia

Decreasing blood pressure

Anti-inflammation

Inhibiting platelet aggregation

Improving endothelial function

Li, S., Zhang, P., Zhou, T., Xu, D.P., Li, H.B., 2017. Effects and mechanisms of fruit and vegetable juices on cardiovascular diseases. Int. J. Mol. Sci. 18(3), 555.

Antioxidant effects

Fig. 5.1  The health benefits associated with consumption of fruits and juices were linked to different mechanisms of action. From Zheng, J., Zhou, Y.,

Improving blood lipids

Fruit juice, depending on the fruit used, has many minerals, trace minerals, and macro minerals, which address some important role in two general body functions: building and regulating. These drinks are directed to a group looking for new flavors, whether or not they are carbonated. Despite the high appeal and tradition that many pure fruit juices have, there are logical reasons for producing blends of pure juices and juice products that contain 2500 species in the plant kingdom (Ganjewala et  al., 2010). They were located in vacuoles in plant cells. When cell disruption occurs due to a mechanic process, the cyanogenic glycosides get in contact with β-glucosidases and α-­ hydroxynitrile lyases, which are endogenous enzymes, ending up the delivery of hydrogen cyanide (Zagrobelny et al., 2004). While cyanogenic glycosides act as crucial compounds against animals those only consumes plants as a chemical protector. They are toxicant and poisoner, which induce several symptoms such as anxiety, headache, dizziness, and confusion for humans (Zagrobelny et al., 2004; Ganjewala et al., 2010). Amygdalin is the most abundant cyanogenic glycosides which found in the seeds and kernels of some fruits, that is, apricot, almond, apple, cherry, plum, lemon, peach, and nectarine. Some of the seeds of mentioned fruit are not eaten directly as a food. However, fruits with high amount of cyanogenic glycosides containing seeds also have cyanogenic glycosides in the fruit flesh (Krafft et al., 2012). Acute cyanide infection has been identified after swallowing the apricot kernels (Sahin, 2011) and almonds (Sanchez-Verlaan et  al., 2011). When amygdalin contained seeds eaten hydrogen cyanide dispense at acidic stomach media (Speijers, 2014). Decreasing the cyanide amount in foods, many processing procedures, that is, crushing, soaking, fermentation, and drying applied. Even apple seeds are not eaten by people, apple juice is commonly generated from whole

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a­ pples without separating the seeds. This may cause break into pieces of seeds along juice processing and contaminate the juice (Bolarinwa et al., 2015). Apricot seeds have higher amygdalin content and comparatively easy deliver hydrogen cyanide than apple and peach. Amygdalin concentration of apricot varies between 0.1 and 4.1 mg/g as well as on the growing area and bitterness of seeds. Amygdalin is not toxic alone but after ingested it is hydrolyzed by β-glycosidase to obtain one molecule hydrogen cyanide, two molecules glucose, and one molecule benzaldehyde (Bolarinwa et al., 2015). There are three stages occur during enzymatic degradation of amygdalin. At the first stage, amygdalin lyase enzyme contributes to divide amygdalin into prunasin and glucose. After this split, prunasin is hydrolyzed to mandelonitrile by prunasin lyase. The final part is pulling apart mandelonitrile to benzaldehyde and hydrogen cyanide by hydroxynitrile lyase. While enzyme-assisted degradation of amygdalin to mandelonitrile happens in an acidic environment hydrolysis of mandelonitrile to benzaldehyde and hydrogen cyanide continues rapidly in alkaline media (Bolarinwa et al., 2014). The enzymatic hydrolysis of amygdalin is shown in Fig. 14.1. Enzyme-assisted degradation of amygdalin in plant foods occurs within 30 min to 6 h according to the level of maceration of the food sample. These enzymes optimally work at 20–40°C and can be deactivated at higher temperature. The stated average toxic dose of cyanide in humans has differed between 39.2 and 106.4 mg for 70 kg/person (Anonymous, 1997). Because it is sensitive to processes, there were no quantified amygdalin content found in food and processed foods (Bolarinwa et al., 2014). Voldřich and Kyzlink (1992) identified that stewed fruits had 3–4 mg/kg and canned stone fruits had 4 mg/kg hydrogen cyanide equivalents which are lower than acute toxicity level. Toydemir et  al. (2013) investigated the industrialized sour cherry nectar processing effects on phenolic compounds by comparing metabolites of fruits and nectars. According to their results, amygdalin was the sole component represented higher in the fruit, compared to the juices. Amygdalin may have been removed due to discard of cherry seeds. Even this compound broke down during process by heat treatments, products processed by novel technologies requires detailed investigation for possible amydalin content.

14.2.3 Caffeine Caffeine is one of the well-known alkaloids. The large group of alkaloid is classified into a number of subclasses that have similar configuration, and closely related plant varieties commonly contain alkaloids with similar molecular structures (Jerzykiewicz, 2007).

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Fig. 14.1  The enzymatic hydrolysis of amygdalin.

Caffeine is a methylated xanthine formed compound that develops naturally in highest levels in coffee, tea, and cacao merchandise. Caffeine neurologically invigorates almost all organs of the body. The most important cellular activity of caffeine is to stop receptors of adenosine. Blockage of these receptors by caffeine and the related purine, theophylline, therefore stimulates activities of the associated organs and tissues, including the central nervous system. Low amount of caffeine, that is, 200 mg for an adult causes central nervous system stimulation, relaxation of smooth muscles, cardiac muscle stimulation, and increased gastric release. Even normal amount of caffeine consumption is not anticipated to generate adverse effects, but excessive doses of caffeine (>10 mg/kg per day) may cause nervousness, tachycardia, hypertension, and arrhythmia. Adverse effects can also include vomiting, abdominal pain, agitation, and seizures. The oral

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LD50 for caffeine is approximately 200 mg/kg, or about 12 g/60 kg person which would provide quick drink of 50 cups of coffee. Some of the beverages, which are sold at large portions in common marketplace and cafes, either have naturally caffeine or added caffeine. Caffeine containing beverages most widely self-prescribed and used drug in modern society. People prefer to drink these beverages for headache medications instead of over-the-counter caffeine pills (Ragsdale, 2016). High amount of caffeine, as well as vitamins, herbal supplements, and sweeteners, founds in energy drinks. Most of the invigorate characteristic of energy drinks comes from caffeine content. Other ingredients such as guarana, kola nut, yerba mate, and cocoa, also have stimulant, cardiac, and hematologic activity (Seifert et al., 2013).

14.2.4 Citral Citral (3,7-dimethyl-2,6-octadienal) is a unsaturated aldehyde, commonly known and prefer for its distinct, acceptable, and ­lemon-like pleasant odor (Berk, 2016). Citral is a main component of citrus fruit's peel oil. It is especially found in orange peel. Citral is a mixture of neral and geranial which are monoterpene aldehydes (Maarse, 1991). Citral has been applied to food, cosmetics, and beverages as a natural ingredient for its passionate lemon aroma and flavor. Essential oils, which presenting citral have been demonstrated to show antimicrobial, antifungal, and antiparasitic characteristics, accomplishing citral a natural preservative (Zeng et al., 2015). Citral was proposed to investigate its possible carcinogenic effects due to its common use in foods, beverages, cosmetics, and other products. For this study, male and female rats and male mice were subjected to microencapsulated pure citral (500–4000 ppm) in their food for 14 weeks or 2 years. Researchers were not able to identify any data to prove carcinogenic activity of citral in rats and mice (Anonymous, 2003).

14.2.5 Dietary Fiber Dietary fiber identified as the eatable pieces of plants or analogs carbohydrates that are durable to ingestion in the people's duodenum with full or limited fermentation in the colon. This definition contains polysaccharides, oligosaccharides, lignin, and related plant elements. Further, the definition identifies the restrictions as functional materials which should “promote beneficial physiological effects including laxation, and/or blood cholesterol attenuation, and/or blood glucose attenuation” (Phillips and Cui, 2011). Since then, better classifications have evolved, including the possible ways on the basis of source, molecular structure, solubility in water, functional properties, as well as application areas (Dai and Chau, 2016; Li and Komarek, 2017).

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Some fiber sources lower the absorption and retention of many minerals due to exchange amount of unmethylated galacturonic acid leftover and phytic acid comes from cereal. Dietary fiber can act like ion exchangers and bind minerals, that is, calcium, magnesium, zinc, and phosphorus (Omaye, 2004). On the other hand, highly fermentable fibers such as pectin, various gums, resistant starches, cellulose, certain oligosaccharides like soy and fructooligosaccharides, inulin, and lactulose showed improved absorption in calcium, magnesium, and iron (Otles and Ozgoz, 2014; Mesias et al., 2015). Millet flours contain cyanide, tannins, and phytate as antinutritional factors. Some of the countries consume millet beverage such as oskikundu in Namibia (Taylor, 2004) and togwa in Tanzania (Oi and Kitabatake, 2003). Also, Zimbabwe has a traditional fermented beverage mixes milk and finger millet (Mugocha et al., 2000). Boza is a traditional beverage prepared by adding water to one or several of crumbs or flour of millet, rice, wheat, maize, and similar cereals which cleaned from foreign materials, and subjecting them to alcohol and lactic acid fermentations with adding white sugar. It is one of the important fermented food contain high amount of dietary fiber contributes to human nutrition (Uylaser et al., 2005).

14.2.6 Enzyme Inhibitors Enzyme inhibitors or antienzymes are couple low and high-­ molecular weight natural food compounds and foreign substances that affect the activity of several enzymes. The most important antienzymes are inhibitors of digestive enzymes, particularly inhibitors of proteases also known as antiproteases and less important group is inhibitors of saccharases (Velisek, 2014). Trypsin and chymotrypsin inhibitors are commonly present in legumes, vegetables, milk, wheat, and potatoes. Trypsin inhibitors are proteins that can attach and inefficient the digestive enzyme trypsin. The trypsin inhibitor identified in milk is merely damaged after 85°C heat application for at 1 h. Adequate soaking and heating of beans will stop the activity of trypsin inhibitors to a decent level. Heat treatment shows reduction on the impact of many toxins and digestibility-­ reducing substances. Temperature has been displayed to change the influence of detoxification procedures (Coffey et al., 1985). Inhibitory effect of enzymes present in milk and soymilk studied and researchers determined that fermentation by kefir grains can increase inhibitory upon linoleic acid peroxidation (Sabokbar et  al., 2015). In another study, researchers tried to lower naturally found trypsin inhibitors during soymilk production by using new systems (Geronazzo et al., 1998).

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14.2.7 Goitrogens Thiocyanate is an important dietary goitrogen. Thiocyanate is formed as a by-product of glucosinolate hydrolysis and as the main detoxification product of cyanide. Thiocyanate blocks active ingestion of inorganic iodide by the thyroid. It prevents the enzyme thyroperoxidase, thereby inhibiting the incorporation of iodine into thyroglobulin thereby contributing to the hyperthyroid effect of vegetables. Couple tropic foods with fiber contain many of cyanogenic glycosides that are detoxified as thiocyanate. These plants are cassava, millet, yam, sweet potato, corn, and lima beans. The toxic degree of thiocyanate from cassava use, plus the mixed effect of iodine and lack of selenium, is thought to lead to endemic goiter and to promote to endemic cretinism observed in parts of Africa (Shibamoto and Bjeldanes, 2009). Isothiocyanates are also another glucosinolate hydrolysis product that present in cruciferous vegetables. After isothiocyanates are divided, they create compounds that induce hypertrophy and hyperplasia of the thyroid gland (Shibamoto and Bjeldanes, 2009). Goitrin (l-5-vinyl-2-thiooxazolidone) is present in plants as the water-soluble component. Progoitrin is precursor of goitrin, because it is delivered from progoitrin with the assistance of thioglucosidase. High-temperature application damages thioglucosidase, so goitrin cannot be produced. Goitrin inhibits the thyroid hormones, that is, thyroxine and triiodothyronine. The goitrogenic effects of goitrin were increasement of the thyroid gland, decreases iodine uptake by the gland, and lower thyroxine synthesis (Shibamoto and Bjeldanes, 2009). Tea shows goitrogenic effect due to its flavonoids. The goitrogenic potential of green tea is higher than black tea because of the differences in catechin concentration (Chandra et al., 2010).

14.2.8 Lectins Lectins are mainly delivered in nature and show significant toxicities. The lectins partly responsible for protection of the plants against insects and herbivory by other organisms including humans since they have cytotoxic, fungitoxic, insecticidal, and antinematode features either in vitro or in vivo, and are toxic to higher animals (Shibamoto and Bjeldanes, 2009). Lectins are a group proteins and glycoproteins which can attach to certain carbohydrates. The glycoproteins are not digested in the gastrointestinal tract. Lectin binds the cell wall of carbohydrate constituents which cause aggregating or agglutination of the cells. This function is worked as a base for analysis of kind of red blood cells. When lectins attach to carbohydrate parts of epithelial cells around gut, the absorption of nutrients from the intestinal system become less and lead changes in bacterial flora. This situation causes

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enlargement and degradation of internal organs and adjusts the hormone and immune system (Vasconcelos and Oliveira, 2004). With the binding of lectin to the ribosome causes very toxic results. Lectins might agglutinate red blood cells. They are delicate to heat applications and become activeless at 100°C for 15 min (Shibamoto and Bjeldanes, 2009). Lectin is not commonly found in commercial beverages but it is identified in white bean-based beverage. Adequate soaking and heating process is used to inactivate lectins in beans for preventing the presence of this antinutrient in beverage (Beckius and Schaar, 2016).

14.2.9 Licorice Licorice is a traditional drink in Southeast Anatolia. As well as it is used in the food/herbal medicine industry. The active ingredient is glyceryl acetic acid which can cause hypokalemia, metabolic alkalosis, and hypertension similar to primer hyperaldestronism (Daniş et  al., 2015). Erkus et al. (2016) purposed infrequent complication of licorice root syrup usage. Consumption of licorice root syrup repeatedly and in excessive amounts might cause cardiac arrhythmia.

14.2.10 Oxalic Acids and Oxalate Oxalic acid lowers the availability of positively charged bivalent ions such as Ca, Mg, and/or Fe by forming insoluble complexes. Oxalates are commonly found in rhubarb, spinach, beets, potatoes, tea, coffee, and cocoa. Consumption of tea, especially with milk, was related with attentions for calcium deficiency by way of complexes. Oxalic acid and oxalates could show renal poisonousness at high level (Cheung and Mehta, 2015). People with kidney disease need to be considered to limit consumption of fruit and vegetable juices, which can have plenty of oxalates, to lower the possibility of oxalate toxicity and severe nephritic deterioration (Getting et al., 2013).

14.2.11 Phytic Acid Phytic acid, acknowledged as phytate in its salt form, is principally stored in the shape of phosphorus in several tissues. It is found in bran and germ of grains, legumes, nuts, and species and place as energy cache and an origin of cations and myoinositol, although is commonly recognized as an antinutrient. It counts almost 1%–5% of most of the cereals and legumes. Phytates are not absorbable by people or nonruminants, because the absence of phytase enzyme which is in charge for producing

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Starch

OH

Protein HO

OH O

P

O

O

P

O

O

O O

O

P

O +NH3

Ca2+

O

O

CH2

Mg2+

O

Protein

OH O

O

P OH

HO

O HO

P

P O

O

O HO2HC O

OH

O

O

(A)

n

Starch

Protein

Tannin

Protein

OH NH

O

HO

O

OH HO

O

OH

OH O

N

HN

OH

OH OH

HN

O OH

NH

O

HO

OH HO

O

(B)

OH

OH O

N

O

OH

O N

NH

O

OH

O

O N

HN

OH

O

OH Hydrophobic

OH

Hydrogen bonds

Fig. 14.2  Interaction of phytate with minerals, proteins, and starch (A) and interaction of tannin with proteins (B).

phosphoric acid and inositol. Interaction of phytate with minerals, proteins, and starch is presented in Fig. 14.2. Phytic acid is a powerful chelator of divalent minerals comprising copper, calcium, magnesium, zinc, and iron (Reddy and Sathe, 2002), capable of forming insoluble complexes with these minerals, thus lowering the bioavailability of critical minerals. Moreover, phytates can directly or indirectly connect to loaded batch of proteins

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and form protein-phytate complexes which negatively influence protein digestion and bioavailability. Further, fermentation and other processing methods are advantageous in lowering phytate contents (Doria et al., 2012). Phytic acid also shows preventing effect on kidney stones (Doria et al., 2012) and can regulate the cell cycle, preventing uncontrolled cell division and forcing malignant cells to apoptosis (Rebello et al., 2014).

14.2.12 Phosphoric Acid Phosphoric acid is an inorganic acid which show antimicrobial characteristics, the capability to buffer pH, and able to balance flavor. Carbonated beverages have phosphoric acid and commonly have a pH of 2.8–3.2. Consumption of phosphoric acid containing beverages in high amount may lead to decalcification of bones along with low amounts of calcium uptake to the body (Aghili et al., 2014). Increasing amount of extracellular phosphorus is the reason of endothelial dysfunction and medial calcification. Higher amounts of phosphorus consumption have been related with reduced blood pressure (Takeda et al., 2012).

14.2.13 Saponin Saponins are structurally amphipathic glycosides of the aglycone sapogenins. They are made up of nonpolar aglycones together with one or more monosaccharide subdivisions. Saponins may be divided into two main groups steroidal and triterpenoid saponins, based on their chemical structure. Saponins, water-soluble plant components that have ability to form soapy foam even at low concentrations, may present whole components of plants, even though their concentration is change depends on variety and growing stage. They are mostly present in an extensive diversity of plants used in the humans daily food, including in fruits, vegetables, grains, legumes, tea, and several medicinal herbs, that is, ginseng (Bora, 2014). Many of them have several health benefits, that is, antioxidant, antitumor, and antidiabetes effects (Yuan et  al., 2010). Saponins are generally harmless to mammals when ingested, however, they have antinutritional effects including growth impairment, reduce bioavailability of iron, and inhibit trypsin and chymotrypsin activity. They also have toxic effects which hemolyze red blood cells and cause diarrhea and vomiting (Onder and Kahraman, 2009). Saponins may increase the penetrability of intestinal mucosal cells, prevent the transport of active mucosal, and assist the progress of uptake of substances that are normally not ingested by affecting the cell membranes (Couto et al., 2015). Saponins are suggested for use in foods as antimicrobial and antiyeast agents and saponin products for food applications. Saponin

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­ resent in whole plant body of Ruellia tuberosa L., which is an p ­ingredient of rice-based fermented beverage, haria, mostly consumed in East-Central of India (Ghosh et al., 2014).

14.2.14 Tannins Tannins are polyphenolic compounds identified in many plants (Obiakor, 2001). They are placed mainly in the seed coat with small amount in the cotyledons (Rao, 2003). Highly polymerized proanthocyanidin compounds are accepted as condensed tannins, which are the second most largely found family of natural polyphenolic compounds, after lignins (Shadkami et al., 2009). Tannins have damaging effects as a result of their well interactions with protein. Tannins decrease protein digestibility as a result of inactivating digestive enzymes or producing complexes with substrate proteins in company with ionizable iron. This can lower the content of digestible iron from the diet and their binding to metal ions can avoid formation of free radicals and bioavailability (Reddy et al., 1985). Protein and tannin interaction is given in Fig. 14.2. Tannins can exhibit anticarcinogenic effects by way of their antioxidative capacity. Their ability for binding to metal ions can prevent formation of free radicals (Doria et al., 2012). Because they are water-soluble component, several processing methods have been shown to eliminate tannins. Soaking, cooking, and air-drying processes help to remove them from food (Rao, 2003). Obiakor (2001) detailed that decline in tannins were useful during fermentation processing. Plant tannins damage thiamin (Omaye, 2004). Pomegranate has a complex mixture of anthocyanins and hydrolyzable tannins. The structures of hydrolyzable tannins are categorized into gallotannins, ellagitannins, and gallagyl esters such as punicalagin and punicalin (Martin et al., 2009). Hurrell et  al. (1999) examined the relationship of different ­polyphenolic-containing beverages on iron absorption in people. They identified that black tea polyphenols, which are high in galloyl esters, are inhibitorier than the polyphenols from herbal teas, cocoa. Meaningful reduction concluded in iron bioavailability with tannin consumption (tea). Also, polyphenols present in tea and many tannin compounds were proposed to inhibit or prevent the activity of a carcinogen. Several tannin compounds have also been proved to lower the mutagenic activity of a few mutagens which generate oxygen-free radicals for communication with cellular large-scale molecules. The anticarcinogenic and antimutagenic capacity of these compounds might be associated with their antioxidative characteristics.

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14.2.15 Thujone Thujone is a monoterpene ketone naturally found in varying quantity in a several plants, for instance Salvia officinalis, Salvia sclarea, Tanacetum vulgare, Artemisia artemisia, and Thuja occidentalis L. (Pelkonen et al., 2013). While ketons generally are not toxic, thujone is the most toxic keton (Roslan, 2014). Thujone occurs naturally in two diastereomeric forms: (−)-α-thujone and (+)-β-thujone (Fig.  14.3). In regards to health effects, the existence of α-thujone or β-thujone in foods and beverages has been managed by regulations in different continents (Dolan et al., 2010). In addition, clinical tests to experimental animals have proved that α-thujone was more toxic than mixture of isomers (Waidyanatha et al., 2013). α-Thujone decreases the activity of 5-HT3 receptor, which plays a role in a variety of sympathetic, parasympathetic, and sensory functions in the peripheral and central nervous systems (Deiml et al., 2004). Sage is one of the important aromatic plants cultivated for culinary and medicinal reasons and it is mainly used as infusion. The amount of α- and β-thujone present in S. officinalis L. varies between different geographical regions, such as Estonia; 28.1%–36.9%, Ukraine, Scotland, and Belgium; 3.4%–14.2%, Russia; 23.3%, and Hungary; 25.2% (Christopoulou-Geroyiannaki and Masouras, 2015).

14.2.16 Vitamins High intake of vitamin A may conclude a lasting liver damage, overwhelmed growth and shows bone mineralization, cardiovascular risk, and repletion of iodine deficiency together with HIV infections. Anorexia, bulging fontanelles, hyperirritability, vomiting, headaches, dizziness, drowsiness, and erythematous swelling are the symptoms (Omaye, 2004). The highest tolerable intake level for adults is 3000 μg. A hepatic concentration of over that amount is counted as excessive, and directly related with clinical toxicity. Vitamin D is a fat-soluble vitamin. The high intake of this vitamin has concluded several toxic effects, including death. Broad vitamin D enrichment of foods and drinks from the 1930s to 1950s in the United States and Europe lead to described toxicity crisis. Hypercalcemia is the main symptom of vitamin D poisonous while gastrointestinal illnesses such as anorexia, diarrhea, nausea, and vomiting are early symptoms. Consumption of fish liver oils in high amount can show hypercalcemia, membrane damage, high tension, cardiac deficiency, nephritic failure, and hypochromic anemia. The several evidences on toxicity indicate that the lowest dose of vitamin D creating hypercalcemia in some adults is 1000 g (40,000 IU)/day of the vitamin D2 form (Vieth, 1999).

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Fig. 14.3  The overall scheme of the α-thujone metabolism and metabolites.

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Excessive quantity of vitamin E uptake might oppose vitamin K's performance in the blood coagulation pathway (Omaye, 2004). The recommended upper level of any supplements containing α-­ tocopherol is 1000 mg/day for adults. This is only for vitamin E supplements, not for food, because of the impossibility of that amount of vitamin E intake from food. There is no toxicity report identified for the natural form of vitamin K, but unnatural menadione has been shown to generate hemolytic anemia, hyperbilirubinemia, and kernicterus when managed in quantity of >5 mg/day to infants (Vieth, 1999).

14.2.17 Others Pyrrolizidine alkaloids are a branch of naturally occurring phytotoxins particularly biologically combined by angiosperms. Pyrrolizidine alkaloids are detected mainly in the Boraginaceae, Compositae, and Leguminosae. They are found in several grains, milk, eggs, honey, salad greens, and teas (Bodi et al., 2014). However, there is no regulation for limiting dehydro pyrrolizidine alkaloids amount in foods and beverages. Nowadays, these components commonly found high amount in teas and medicinal herbs in Europe (Bodi et al., 2014; Griffin et al., 2014; Mathon et al., 2014; Mädge et al., 2015). Other groups of alkaloids are present to contaminate food and feed merchandise is the tropane alkaloid (TA). They are secondary metabolites of various plant families containing Brassicaceae, Solanaceae, and Erythroxylaceae (EFSA, 2013). Although >200 different TAs have been identified, data on their occurrence in food and feed are limited (EFSA, 2013). Several TA intoxications due to consumption of contaminated herbal teas were reported in burdock root tea, nettle tea, comfrey tea and marshmallow tea, and Paraguay tea (EFSA, 2013; Shimshonia et al., 2015). Safrole is a phenylpropenic component forming up to 80% of the essential oil of sassafras root bark. This tree is used for medicinal and culinary reasons, particularly as a flavoring ingredient for beverages such as root beer. Safrole has also been shown to be a weak hepatocarcinogen. Also, myristicin (methoxy-safrole) and safrole demonstrated to generation hepatic DNA adducts in adult and fetal mice together (Poivre et al., 2017). Some of the herbs, which use in beverage production, show toxic effects. Yerba mate (Ilex paraguariensis) is commonly used in the preparation of traditional beverages in South American countries. Beyond that, yerba mate derivatives might be available in the form of energy drinks, energy teas, or weight reduction drinks in the Europe market. It is commonly used as substances that invigorate physical and mental weakness, treat hepatic and digestive diseases, arthritis, rheumatism, obesity, hypertension, and hypercholesterolemia. But, yerba

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mate may show carcinogenic polycyclic aromatic hydrocarbons originated from its process and these substances may lead to oropharyngeal cancer (Andrade et  al., 2012). Ephedra was a known herb with its traditional use in respiratory necessity. It was used in weight-loss dietary supplements, but adverse effects such as cardiovascular disorder, hepatotoxicity, neurotoxicity, and transient blindness arised later on (Ekor, 2014). Ginkgo biloba has been present in variety of products such as extracts, tea, and tablets which have been produce from the dried root. Even plant extracts seems be safe, but some adverse effects, that is, dizziness, restlessness, nausea, vomiting, diarrhea, and dermal sensitivity have been observed. Guarana is a variety of plant famous for its stimulant and medicinal properties. Guarana is commonly used as a beverage around Amazon. It has high content of caffeine, so show similar adverse effects (Schimpl et al., 2013).

14.3  Process-Induced Toxic Compounds 14.3.1 Acrylamide Acrylamide is a chemically occurred toxic compound that typically forms at high temperature in processed (fried, baked, and roasted) foods. One of the process-induced sources of acrylamide formation was roasting. Coffee is one of the most known products, that roasting is necessary to apply, contains important levels of acrylamide. Couple studies comprehend the mechanisms of acrylamide formation in coffee and coffee substitutes (Bagdonaite et  al., 2006; Kocadagli et  al., 2012; Cai et al., 2014). They offered more than one route for the generation of the toxic molecules (Guenther et al., 2007). When food product exposed to heating, there will be a reaction occur between asparagine and carbohydrates or carbonyl compounds for the formation of acrylamide in coffee and coffee substitutes (Mottram et  al., 2002; Stadler et  al., 2002). There was a positive correlation found between acrylamide formation and asparagine concentration in coffee (Bagdonaite et  al., 2008; Loaëc et  al., 2014a,b). Another acrylamide production mechanism may include intermediate products of thermally formed reactions, such as acrolein, acrylic acid, and 3-aminopropanamide (Yasuhara et al., 2003; Becalski et al., 2003; Yaylayan and Stadler, 2005). Acrolein and acrylic acid may contribute the generation of acrylamide subsequent reaction with ammonia. The 3-APA was a potential precursor of acrylamide in model media and potatoes, where it can be generated also through the biochemical decarboxylation of asparagine (Bagdonaite et al., 2006). In connection with high-roasting temperatures, pyrolytic reactions can comprehensibly show an additional pathway for acrylamide formation in coffee, similarly observed in bread. 5-Hydroxymethylfurfural

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(HMF), which is also formed during roasting, may present an active role in acrylamide production (Kocadagli et al., 2012; Cai et al., 2014). HMF could treat as an important precursor than sugars to generate acrylamide. So, any compound able to promote HMF formation would increase acrylamide generation (Cai et al., 2014). Many factors may affect acrylamide quantity in coffee and coffee products. These are vegetable type (i.e., coffee or noncoffee ingredients), coffee species, and to process interventions (i.e., roasting, formulation, and storage). According to the EFSA (2012), average concentrations of acrylamide in roasted coffee, collected and analyzed from 2007 to 2010, range between 197 and 256 μg/kg and instant coffee range between 229 and 1123 μg/kg. Upper levels may rise to 2223 and 8044 μg/kg, respectively. According to the results of >1500 coffee products collected and analyzed from 2010 to 2013, mean acrylamide content was stated 578 μg/kg in roasted coffee, while instant coffee and cereal-based coffee substitutes showed greater amounts (EFSA, 2014). These data are consistent with the results of recent studies showing that the acrylamide content in soluble coffee varied from 200 to 645 μg/kg with an average concentration of 472 μg/kg (Loaëc et al., 2014a,b; Mizukami et al., 2014). But the coffee is not directly consumed in the form of powder, it is use to prepare a beverage with water. As a result of this dilution, acrylamide concentration may decrease, but brewing with hot water allows acrylamide transfer into the water (Guenther et al., 2007). The formation of acrylamide is closely related with the time of roasting which shows the degree of roast. When roasting time increases rapidly, it will reach the maximum level and then decreases quickly (Senyuva and Gökmen, 2005; Guenther et al., 2007; Bagdonaite et  al., 2008; Taeymans et  al., 2004). CONTAM (EFSA panel on contaminants in the food chain) survey indicated that typical amount of acrylamide content was 374, 266, and 187 μg/kg in light, medium, and dark-roasted coffee, appropriately (EFSA, 2014). The lower acrylamide content at high degrees of roast appears when the amount of decline exceeds the rate of formation. This may be the result of the reaction of acrylamide with other reactive group existing in the coffee (Biedermann et  al., 2002). During roasting, acrylamide may act with coffee melanoidins. This situation may cause a reduction in acrylamide concentration (Pastoriza et al., 2012). Furthermore, acrylamide content in roasted beans and coffee brews was related with coffee species (Summa et al., 2007; Bagdonaite et al., 2008; Alves et al., 2010). For example, Robusta (Coffea canephora robusta) has more acrylamide content than Arabica (Coffea arabica). Bagdonaite et  al. (2008) obtained 708 ± 77 and 374 ± 86 ng/g acrylamide concentration in Robusta and Arabica coffees which roasted in small-scale convection roaster at 240°C for 7.5 min. Likely, Summa et al. (2007) found that

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acrylamide content in Robusta coffee after 9 min of hot air roasting at 236°C was around 250 ng/g, when Arabica was 150 ng/g. This variation may relate with chemical differences in species. A study stated that not only acrylamide content in Robusta was higher than Arabica but also the concentration of the undesired molecule decreased proportionally with increasing the degree of roast in both ground coffee and espresso brew. Also, lower extraction time allows lower transfer rate of acrylamide in espresso coffee (Alves et al., 2010). Other than coffee, Becalski et  al. (2003) studied the low-­ temperature formation of acrylamide in prune-based food products and beverages. They identified minimum 0.2 mg/kg acrylamide occurred in a prune juice heated for 24 h at 95°C. This study showed the possibility of acrylamide formation in an aqueous food system at temperatures below 120°C. The acrylamide content was determined in various tea products (green tea, roasted green tea, oolong tea, and black tea) and infusions. Researchers determined 190–570 and 247–1880 μg/kg (Mizukami et  al., 2006) acrylamide content in roasted green tea. They also reported acrylamide content lower than 100 μg/kg. Black and oolong teas are examined for acrylamide content and found 100 μg/kg. Also, 30 tea specimens (green tea, oolong tea, black tea, white tea, yellow tea, and Pu-erh tea) were analyzed for the acrylamide contents (Liu et al., 2008). While acrylamide has not been identified in white tea, it has been determined in other teas between 3 and 94 ng/g. Some researchers used a new technique to analyze acrylamide in herbs with liquid chromatography-tandem mass spectrometry (LC-MS/MS) and they identified 500 mg/kg) after processing and/or blending demonstrate an adulteration with invert syrup (Jeurings and Kuppers, 1980). Honey may use as an ingredient in several beverages, so the content of HMF in honey is an important factor for the final products' HMF content. A study reports that amount of HMF in chicory and coffee between 0.2–22.5 and 0.1–6 g/kg, respectively (Kanjahn et al., 1996). The highest determined furfural content was between 250 and 113 mg/kg in coffee and roasted chicory, respectively. Also, different amount of HMF content was stated in natural coffees between 26 and 120 mg/ kg and torrefacto coffee (coffee with sugar added before roasting) between 500 and 2300 mg/kg. Sensorial and nutritional properties of juices are affected by thermal treatments and inappropriate storage temperatures. The HMF concentration is almost zero in fresh, untreated fruit juice (Askar, 1984), but it increase in stored juices and has been associated with color and flavor decline. In apple sauce and grape jelly, the concentration of HMF has been known as an indicator of long-term storage quality (Shaw et al., 1996). Even though HMF is not present in fresh grapes, it can occur at the time of juice production due to thermal stress during heat processing. Grapes shows huge quantity to generate HMF compared to some fruits. This is related with the composition and contained sugar of grape juices. Malik et al. (1981) stated that nearly all commercial grape

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juices have measurable amount of HMF. Also an increasing level of HMF was observed in grape juice and citrus fruit juices (Lo-Coco et al., 1994). The Association of the Industry of Juices and Nectars from Fruits and Vegetables (AIJN) of the European Economic Community stated the concentration of HMF as an infinite criterias of quality (maximum 20 mg/L in fruit nectars and 25 mg/kg in concentrates) in the Code of Practice for the rating of fruits and vegetable juices (AIJN, 1996). Revision in process parameters such as heating system generation and modification could be considered as approach that may be used to avoid furan and HMF formation (Anese and Suman, 2013).

14.3.3 Benzene Benzene is an industrialized chemical which is commonly applied in producing plastics and some types of rubbers, detergents, drugs, and pesticides. While native sources of benzene include volcanoes and forest fires, it can detect in crude oil, petrol, and cigarette smoke. Benzene can be formed in food media as a consequence of process generated changes developing from chemical conversions caused by higher heat application, ionizing radiation, and the response of added or naturally found precursors. Benzene might enter into food as an environmental pollutant or as a contaminant of food ingredients or flavors when the good manufacturing practices leaving out (Stadler and Lineback, 2009). Plastic cook wares are also sources of benzene as a result of its migration into food (Jickells et al., 1990). Benzene formation may occur due to pyrolysis of organic matter during roasting foods at high temperatures. This occurrence was a result of either the recombination of intermediates or by the degradation of compounds containing a benzene moiety ex. phenylalanine. Benzene also can be present in the food by the reason of smoking or grilling over an open flame, specifically with wood or charcoal. Imperceptible amount of benzene formation can happen in some irradiated foods under certain conditions and presently is known to form from oxidative and radiolytic splitting of phenylalanine (Sommers et al., 2006). Some researchers describe low level benzene production from irradiation of model solutions of benzoate and experimentally prepared foods preserved with benzoate (Zhu et al., 2004). Benzene may also be present in soft drinks at really low concentrations. In the early 1990s, benzene was found at very little amounts in beverages that have both ascorbic acid and sodium benzoate. Salt or ester of benzoic acid may be either naturally found or used in soft drinks as an antimicrobial agent. Ascorbic acid also may be spontaneously happening or used as a preservative or nutrient. Various researchers explained that under specific circumstances, benzene can

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be occurred in beverages containing benzoate and ascorbic acid (Salviano dos Santos et al., 2015). Loch et al. (2016) questioned that if benzaldehyde containing cherry flavor causes any benzene formation in juice. According to the researchers' suggestion, juice mixtures having either benzoic acid or benzaldehyde together with ascorbic acid should be prevented.

14.3.4  Biogenic Amines Biogenic amines composed principle by bacterial decarboxylation of amino acids and high concentrations may cause health problems for people. According to their chemical composition, they can be classified into aliphatic, aromatic, and heterocyclic biogenic amines and based on their number of amino groups, they can be grouped as monoamines, diamines, or polyamines (Esselen and Schrenk, 2017). Boza is a valuable fermented food which contributes to human nutrition; however, production conditions of boza in terms of microbial flora, pH value, raw materials used in production, and bad sanitation conditions allow biogenic amine formation. Yegin and Üren (2008) determined 11 biogenic amines in the samples collected from several manufacturers in Turkey. While putresin, spermidine, and tiramines were found in all samples, total biogenic amine contents were between 25 and 69 mg/kg. Coşansu (2009) also determined total biogenic amine substance in 21 boza samples range 1.67–101.14 mg/kg. Eating or drinking of boza is