Dietary Interventions in Gastrointestinal Diseases: Foods, Nutrients, and Dietary Supplements 0128144688, 9780128144688

Table of contents :
Content: A. Background and overview of diet and GI tract health 1. Plant family, carvacrol and putative protection in gastric cancer 2. The Physics of Fiber in the Gastrointestinal Tract: Laxation, Antidiarrheal, and Irritable Bowel Syndrome 3. Dietary interventions and Inflammatory Bowel Disease 4. The Gastrointestinal system and obesity 5.Constipation: a symptom of chronic food intolerance? 6. Food, Nutrients and Dietary Supplements in Management of Disorders of Gut-Brain Interaction (DBGIs), formerly Functional Gastrointestinal Disorders (FGIDs) 7. Vitamin D and Quality of Life of Patients with Irritable Bowel Syndrome B. Nutrition and GI tract 8. Sealing the leaky gut represents a beneficial mechanism of zinc intervention for alcoholic liver disease 9. Exclusive Enteral Nutrition in Children with Crohn Disease: A Focused Nutritional Intervention 10. Gut Microbes in liver diseases: Dietary intervention for promoting hepatic health C. Probiotics, prebiotics, symbiotics in intestinal functions 11. Feasible options to control colonization of enteric pathogens with designed synbiotics 13. The Role of Prebiotics in Disease Prevention and Health Promotion 14. Probiotics from Food Products and Gastrointestinal Health 15. Prebiotics for gastrointestinal infections and acute diarrhea 16. Probiotics and applications to constipation D. Microbes and GI tract 17. New functional properties of fermented rice bran (FRB) in food processing and intestinal bowel disease model mice 18. Zataria multiflora and gastrointestinal tract disorders E. Foods and Macro dietary materials in GI function 19. Influence of the cocoa-enriched diet on the intestinal immune system and microbiota 20. High fiber diets in gastrointestinal tract diseases 21. Dietary interventions in fatty liver 22. Rice bran usage in diarrhea 23. Milk Bacteria and Gastrointestinal Tract: Microbial Composition of Milk 24. Polyphenols in the prevention of Ulcerative colitis: A revisit

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Dietary Interventions in Gastrointestinal Diseases

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Dietary Interventions in Gastrointestinal Diseases

Foods, Nutrients, and Dietary Supplements

Edited by

Ronald Ross Watson Victor R. Preedy

Academic Press is an imprint of Elsevier 125 London Wall, London EC2Y 5AS, United Kingdom 525 B Street, Suite 1650, San Diego, CA 92101, United States 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom Copyright © 2019 Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. 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: 978-0-12-814468-8 For information on all Academic Press publications visit our website at https://www.elsevier.com/books-and-journals

Publisher: Stacy Masucci Acquisition Editor: Stacy Masucci Editorial Project Manager: Megan Ashdown Production Project Manager: Mohanapriyan Rajendran Cover Designer: Mark Rogers Typeset by TNQ Technologies

Contents 2. The Physics of Fiber in the Gastrointestinal Tract: Laxation, Antidiarrheal, and Irritable Bowel Syndrome

List of Contributors xiii Biographyxvii Acknowledgmentsxix

Johnson W. McRorie Jr.

Section I Background and Overview of Diet and GI Tract Health

1. Plant Family, Carvacrol, and Putative Protection in Gastric Cancer



Ayse Gunes Bayir, Huriye Senay Kiziltan and Abdurrahim Kocyigit



1. Plant Family and Phytochemicals 3 1.1 General Properties of Dietary Phytochemicals3 1.2 Classification of Phytochemicals 3 1.3 Mechanisms of Phytochemicals in Cancer Chemoprevention 3 2. Carvacrol 4 2.1 Carvacrol as a Molecule 4 2.2 Carvacrol Sources 4 2.3 Chemical and Physical Properties of Carvacrol 5 2.4 Metabolism and Excretion of Carvacrol 5 2.5 Acute Toxicity of Carvacrol 5 2.6 Biological Activities of Carvacrol 5 3. Dietary Phytochemicals in Gastric Cancer Chemoprevention 9 4. Gastric Cancer 10 4.1 Anatomy and Physiology 10 4.2 Epidemiology of Gastric Cancer 10 4.3 Etiology of Gastric Cancer 10 4.4 Pathology of Gastric Cancer 11 4.5 Types of Gastric Cancer 11 4.6 Stages of Gastric Cancer 12 4.7 Clinical Symptoms 13 4.8 Diagnosis of Gastric Cancer 13 4.9 Treatments 13 References14







1. Introduction 19 2. Chronic Idiopathic Constipation 20 2.1 Most Fibers Have No Laxative Effect, and at Least Four Can Be Constipating 20 2.2 Insoluble Fiber/Wheat Bran and Laxation 20 2.3 Soluble Gel-Forming Fiber/Psyllium and Laxation 21 2.4 Misconceptions About Fiber and Laxation 21 2.5 Summary: Fiber and Laxation 22 3. Antidiarrheal Effects of Fiber 24 3.1 Fermented Fibers/Prebiotics and Treatment/Prevention of Diarrhea 24 3.2 Prebiotics: Traveler’s Diarrhea, Antibiotic-Associated Diarrhea, and Clostridium difficile–Associated Diarrhea24 3.3 Fermented Fibers/Prebiotics and Enteral Nutrition–Induced Diarrhea 24 3.4 Mixed Fibers and Enteral Nutrition–Induced Diarrhea 25 3.5 Gel-Forming Fibers and Treatment/Prevention of Diarrhea25 4. Fiber and Irritable Bowel Syndrome 26 4.1 Fermentable Fiber/Prebiotics and Irritable Bowel Syndrome 26 4.2 Insoluble Wheat Bran and Irritable Bowel Syndrome 26 4.3 Guar Gum and Irritable Bowel Syndrome27 4.4 Calcium Polycarbophil and Irritable Bowel Syndrome 27 4.5 Psyllium and Irritable Bowel Syndrome27

v

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4.6 Summary: Fiber and Irritable Bowel Syndrome 28 4.7 Recommendation to Begin Fiber Therapy Gradually 28 5. Overall Conclusions for Fiber and Laxation, Antidiarrheal, and Irritable Bowel Syndrome 28 References28



3. Dietary Interventions and Inflammatory Bowel Disease

Zeinab Mokhtari and Azita Hekmatdoost



5. Constipation: A Symptom of Chronic Food Intolerance?

1. Introduction 33 1.1 Clinical Manifestations and Complications of Inflammatory Bowel Disease 33 2. Nutritional Issues/Common Problems in Inflammatory Bowel Disease 34 2.1 Vitamin D Deficiency in Inflammatory Bowel Disease 34 2.2 Anemia in Inflammatory Bowel Disease34 3. Nutritional Assessment 35 4. Nutritional Interventions in Inflammatory Bowel Disease 35 5. Some Popular Dietary Intervention in Inflammatory Bowel Disease 35 5.1 Enteral Nutrition in Inflammatory Bowel Disease 35 5.2 Dietary Recommendations in Practice 37 6. Conclusions 38 References38

I. Kearsey, Y.I. Yik, B.R. Southwell and J.M. Hutson

4. The Gastrointestinal System and Obesity



Gerardo Calderón and Andrés Acosta











1. Introduction 1.1 Obesity: Definition, Epidemiology, and Pathophysiology 2. Gastrointestinal Regulation of Food Intake 2.1 The Gastrointestinal Tract in Regulation of Food Intake and Regulation of Energy Balance 3. Complication of Obesity in Gastrointestinal Tract 3.1 Oral Disease 3.2 Esophagus 3.3 Stomach 3.4 Small Intestine



43 43

1. Introduction 63 2. Chronic Constipation 63 2.1 Definition 63 2.2 Epidemiology 63 2.3 Etiology 64 2.4 Clinical Assessment 64 2.5 Current Management Practices 64 3. Emerging Views of Pediatric Chronic Constipation65 3.1 The Nuclear Colonic Transit Study 65 3.2 Colonic Dysmotility Subtypes 67 3.3 Slow-Transit Constipation 67 3.4 Rapid-Transit Constipation 68 4. Adverse Food Reactions and Chronic Constipation68 4.1 Adverse Food Reactions 68 4.2 Adverse Food Reactions (AFR’s) and Chronic Constipation 69 4.3 Exclusion Diet as a Management Strategy for Chronic Constipation 70 5. Conclusion 71 References71

6. Food, Nutrients, and Dietary Supplements in Management of Disorders of Gut–Brain Interaction, Formerly Functional Gastrointestinal Disorders

43

45 49 49 51 51 52

3.5 Colon 53 3.6 Anorectal 54 3.7 Pancreas 54 3.8 Liver Disease 54 4. Treatment of Obesity Focused in the Gastrointestinal Tract 54 4.1 Diets 55 4.2 Drugs 55 4.3 Bariatric Procedures 56 5. Conclusions 57 Disclosures57 References57

Amol Sharma and Jigar Bhagatwala





1. Introduction 73 2. Reflux Hypersensitivity and Functional Heartburn74 3. Functional Dyspepsia 75

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4. Irritable Bowel Syndrome and Functional Constipation 76 5. Summary 78 References79



7. Vitamin D and Quality of Life of Patients With Irritable Bowel Syndrome Amir Abbasnezhad and Razieh Choghakhori





1. Introduction 81 2. Health-Related Quality of Life of Irritable Bowel Syndrome Patients 81 3. Functions of Vitamin D 83 4. Vitamin D Deficiency in Irritable Bowel Syndrome 83 5. Vitamin D and Quality of Life in Irritable Bowel Syndrome 83 6. Discussion 85 7. Conclusions 86 List of Abbreviations 86 References86







9. Exclusive Enteral Nutrition in Children With Crohn’s Disease: A Focused Nutritional Intervention Andrew S. Day

Section II Nutrition and GI Tract



8. Sealing the Leaky Gut Represents a Beneficial Mechanism of Zinc Intervention for Alcoholic Liver Disease



Wei Zhong and Zhanxiang Zhou 1. Introduction 91 2. Gut Barrier Dysfunction in the Development of Alcoholic Liver Disease 92 2.1 Alcohol-Induced Gut Hyperpermeability92 2.2 Bacterial Translocation and Hepatic Signaling in Alcoholic Liver Disease 93 3. Zinc Metabolism and Function 94 3.1 Physiological Functions of Zinc 94 3.2 Regulation of Zinc Homeostasis 94 4. Zinc Deficiency in Alcoholic Liver Disease95 4.1 Occurrence of Zinc Deficiency in Alcoholic Liver Disease 95 4.2 Mechanisms of Alcohol-Induced Zinc Deficiency 96

4.3 Effects of Zinc Deficiency on the Liver97 4.4 Effects of Zinc Deficiency on the Gut Barrier 97 5. Zinc Intervention for Alcoholic Liver Disease 98 5.1 Dietary Zinc Supplementation Prevents Alcohol-Induced Endotoxemia and Intestinal Barrier Dysfunction 99 5.2 Dietary Zinc Supplementation Restores the Function of Intestinal HNF-4α100 5.3 Dietary Zinc Supplementation Reduces Endotoxin Levels in the Intestinal Lumen 100 6. Conclusion 100 References101













1. Introduction 107 2. Crohn’s Disease 107 3. Nutritional Impact of Chron’s Disease in Children 108 4. Exclusive Enteral Nutrition 109 4.1 Typical Exclusive Enteral Nutrition Protocol 109 4.2 Exclusive Enteral Nutrition and Induction of Remission 109 4.3 Other Benefits of Exclusive Enteral Nutrition 109 4.4 Adverse Effects of Exclusive Enteral Nutrition 110 4.5 EEN for Complicated CD 110 4.6 Maintenance EN to Maintain Remission/Prevent Relapse 110 5. Mechanisms of Action of Exclusive Enteral Nutrition 111 5.1 Putative Mechanisms of Action of Exclusive Enteral Nutrition 111 5.2 Exclusive Enteral Nutrition and the Intestinal Microbiota 111 5.3 EEN Has Direct Antiinflammatory Effects and Enhances Barrier Function in Epithelial Cells 111 6. Conclusions 112 References113

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10. Gut Microbes in Liver Diseases: Dietary Intervention for Promoting Hepatic Health



Aryashree Arunima, Jugal Kishore Das and Mrutyunjay Suar



1. Introduction 117 2. Gut Microbiota 117 2.1 Gut Homeostasis 118 2.2 Gut Dysbiosis 118 3. Gut Microbiota and Liver 119 3.1 Liver as Vascular Sentinel of the Immune System 119 3.2 Gut-Liver Axis 120 3.3 Factors Affecting the Gut Microbiota in Liver Disease 120 4. Liver Diseases and Role of Gut Microbiota 121 4.1 Nonalcoholic Fatty Liver Disease 121 4.2 Alcoholic Fatty Liver Disease 122 4.3 Hepatic Fibrogenesis 122 4.4 Hepatic Encephalopathy 122 4.5 Viral Hepatitis 122 4.6 Hepatocellular Carcinoma 123 4.7 Liver Cirrhosis 123 4.8 Inflammatory Bowel Diseases 123 5. Dietary Intervention Strategies for Liver Diseases 123 5.1 Probiotic Therapy 124 5.2 Probiotic-Based Intervention for Promoting Hepatic Health 124 5.3 Prebiotics 125 6. Future Prospects 126 List of Abbreviations 126 Acknowledgments127 References127





Section III Probiotics, Prebiotics, Symbiotics in Intestinal Functions



12. The Role of Prebiotics in Disease Prevention and Health Promotion Rabin Gyawali, Nwadiuto Nwamaioha, Rita Fiagbor, Tahl Zimmerman, Robert H. Newman and Salam A. Ibrahim

11. Feasible Options to Control Colonization of Enteric Pathogens With Designed Synbiotics



Mengfei Peng, Puja Patel, Vinod Nagarajan, Cassandra Bernhardt, Michael Carrion and Debabrata Biswas

1. Introduction 2. Probiotics and Its Role in the Prevention of Enteric Pathogen Colonization

2.1 Environment of the Gut Flora 136 2.2 Interaction Between Probiotics and Intestinal Epithelial Barrier 137 2.3 Strengthening of the Epithelial Barrier138 2.4 Application of Probiotics in Prevention of Enteric Bacterial Infections138 3. Probiotics and Its Antimicrobial Role in Reduction of Enteric Bacterial Pathogen Growth138 3.1 Probiotics Producing Antimicrobial Substances139 3.2 Antimicrobial Action by Probiotics 139 3.3 Antimicrobial Activity of Probiotics in Food Products 140 4. Combined Effect of Pre- and Probiotic and Its Limitation 140 4.1 The Combined Effects in Form of Synbiotics141 4.2 Mechanisms of Synbiotics in Preventing Enteric Diseases 141 4.3 The Double Inhibitory Actions by Synbiotics142 4.4 Limitations of Synbiotics Application142 5. Feasible Alternative to Overcome the Limitation of Symbiotic 143 5.1 Alternative Functional Ingredients to Probiotics 143 5.2 Limitation in Prebiotics and Potential Solutions 144 5.3 Antimicrobials’ Potential in Combinational Alternatives 144 6. Conclusion 144 Acknowledgments145 References145

135

136



1. Concept of Prebiotics 2. Modulation of Gut Microbiota 3. Prebiotics Effects in Human Health 3.1 Production of Short-Chain Fatty Acids 3.2 Colon Cancer 3.3 Inflammatory Bowel Disease 3.4 Cardiovascular Disease

151 152 153 153 154 155 156

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3.5 Type II Diabetes and Glycemic Control157 3.6 Weight Management 157 3.7 Immune Function 158 4. Synbiotic Approach 158 5. Insight Into Prebiotics Effect on the Growth of Harmful Bacteria 161 6. Conclusions and Future Directions 163 Acknowledgments163 References163

5. Conclusions 187 List of Abbreviations 187 References188

15. Probiotics and Applications to Constipation Elena Scarpato, Vincenzo Coppola and Annamaria Staiano

13. Probiotics From Food Products and Gastrointestinal Health



Murat Doğan, İsmail Hakkı Tekiner and Hilal DemirkesenBiçak







1. Introduction 169 2. Probiotic Concept 169 3. Mechanisms of Action of Probiotics 170 3.1 Antimicrobial Effects 170 3.2 Enhancement of Mucosal Barrier Integrity171 3.3 Immune Modulation 171 4. Dietary Interventions of Probiotics in Gastrointestinal Disorders 171 5. Probiotic Functional Foods, Status, and Claims 172 6. Conclusions 173 List of Abbreviations 173 References174

16. New Functional Properties of Fermented Rice Bran in Food Processing and Inflammatory Bowel Disease Model Mice Takashi Kuda



14. Prebiotics for Gastrointestinal Infections and Acute Diarrhea





1. The Role of Microbiota in Gut Motility193 2. Gut Microbiota and Gastrointestinal Health193 3. Microbiota Alterations in Functional Constipation194 4. Probiotics in the Management of Functional Constipation 194 5. Conclusions 195 References195

Ignasi Azagra-Boronat, Maria José Rodríguez-Lagunas, Margarida Castell and Francisco J. Pérez-Cano



1. Introduction 179 2. Gastrointestinal Infections 179 3. Prebiotics: Types and Mechanisms of Action 181 3.1 Definition and Types of Prebiotics 181 3.2 Mechanisms of Action in the Protection of Gastrointestinal Infections181 3.3 Microbiota-Dependent Mechanisms 181 3.4 Microbiota-Independent Mechanisms 183 4. Prebiotics in Gastrointestinal Diseases 183 4.1 In Vitro Evidences 183 4.2 Evidences in Animal Models of Infection 183 4.3 Prebiotics in Human Infections of the Gastrointestinal Tract 186







1. Introduction 197 2. Preparation of Fermented Rice Bran for Ammonia Reduction in Shark Meat 198 3. Effect of Fermented Rice Bran on Ammonia Content and Preference Ranking in Shark and Other Fish Meat 199 4. Dietary and Lifestyle Disease Indices and Cecal Microbiota in High-Fat Diet, Dietary Fiber-Free Diet, or DSS-Induced IBD Models in Closed Colony Mice 199 5. Protective Effects of FRB in DSS-Induced IBD Model ICR Mice 200 5.1 Total Phenolic Content and Antioxidant Properties 201 5.2 Immune Promotion and Antiinflammation Activity in Murine Macrophage RAW264.7 Cells 201 5.3 Protective Effects of FRB-AES in DSS-Induced IBD Model ICR Mice 203 6. Conclusion 204 Acknowledgments204 References204 Further Reading 206

xContents

Section IV Microbes and GI Tract 17. Zataria multiflora and Gastrointestinal Tract Disorders

Section V Foods and Macro Dietary Materials in GI Function

T. Shomali

19. High-Fiber Diets in Gastrointestinal Tract Diseases



Ana Letícia Malheiros Silveira, Adaliene Versiani Matos Ferreira and Mauro Martins Teixeira

1. Introduction 209 2. Beneficial Effects of ZM on Different Gastrointestinal Tract Diseases 210 2.1 Stomatitis and Intraoral Ulcers 210 2.2 Gastric or Duodenal Ulcers 210 2.3 Irritable Bowel Syndrome and Inflammatory Bowel Disease 210 2.4 Intestinal Infections 211 2.5 Colon Cancer Chemopreventive Effect211 2.6 Hepatoprotective Effects 211 2.7 Road Mapping for Future Studies and Conclusion 211 References212



18. Influence of a Cocoa-Enriched Diet on the Intestinal Immune System and Microbiota











1. Basic Concepts: Dietary Fiber 229 2. Gastrointestinal Tract and Microbiota Interaction230 3. Stomach and Gastritis 231 3.1 High-Fiber Diet in Gastritis 231 4. Inflammatory Bowel Disease 232 4.1 Microbiota and Inflammatory Bowel Disease 232 4.2 Dietary Fiber in Inflammatory Bowel Disease 233 5. Mucositis 238 5.1 Microbiota and Mucositis 239 5.2 Dietary Fiber in Mucositis 239 6. Conclusion 239 References240

Mariona Camps-Bossacoma, Malen Massot-Cladera, Francisco J. Pérez-Cano and Margarida Castell

20. Dietary Interventions in Fatty Liver

1. Introduction 213 2. Cocoa Composition 213 3. Cocoa and Gut Microbiota 214 3.1 Role of Cocoa Flavonoids on Cocoa Microbiota Influence 215 3.2 Cocoa Fiber and Microbiota 216 3.3 Cocoa Theobromine and Microbiota 216 4. Cocoa and the Intestinal Immune System217 4.1 Cocoa and the Intestinal Epithelium 217 4.2 Cocoa and the Intestinal Immunoglobulin A 217 4.3 Cocoa and Gut-Associated Lymphoid Tissue Populations 218 5. Cocoa in Gastrointestinal Disease and Food Hypersensitivity 219 5.1 Influence of Cocoa Intake in Intestinal Inflammation 219 5.2 Food Allergy 220 6. Conclusions 221 List of Abbreviations 222 References222

Zahra Yari and Azita Hekmatdoost

1. Introduction 245 2. Soy 245 3. Egg 246 4. Nuts 246 5. Probiotics, Prebiotics, and Synbiotics 246 6. Seal Oil (N-3 Polyunsaturated Fatty Acids) 247 7. Flaxseed 248 8. Curcumin 248 9. Resveratrol 248 10. Pomegranate 249 11. Onion 249 12. Conclusion 250 References250

21. Rice Bran Usage in Diarrhea Shaohua Lei and Lijuan Yuan

1. Overall Health Benefits of Rice Bran Dietary Supplement 257 2. Dietary Rice Bran Supplementation in Reducing Diarrhea 257 2.1 Diarrhea in Irritable Bowel Syndrome257

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2.2 Human Rotavirus–Induced Diarrhea 258 2.3 Human Noroviruses–Induced Diarrhea259 3. Mechanisms for Rice Bran Usage in Reducing Diarrhea 259 3.1 Antimicrobial and Antiviral Activities260 3.2 Prebiotic and Microbiota Modulatory Properties 260 3.3 Effects on Intestinal Immunity and Overall Health 260 4. Future Perspective 261 References261



22. Milk Bacteria and Gastrointestinal Tract: Microbial Composition of Milk

Aseel T. Issa and Reza Tahergorabi











1. Introduction 265 2. Sources of Milk Organisms 265 3. Contamination in the Mammary Glands265 4. Contamination Sources in the External Environment 265 5. Contamination From Handling and Storage Equipment 266 6. Microbial Composition of Milk From Different Sources 266 6.1 Cow Milk 266 6.2 Goat Milk 267 6.3 Sheep Milk 267 6.4 Buffalo Milk 267 6.5 Other Types of Milk 267 7. Important Microorganisms Found in Raw Milk 268 7.1  Lactococcus268 7.2  Bifidobacterium269 7.3  Lactobacillus269 7.4  Streptococcus269 7.5  Propionibacterium269 7.6  Leuconostoc269 7.7  Enterococcus269 7.8 Gram-Positive Subpopulations 270 7.9 Gram-Negative Subpopulations 270 7.10 Fungal Populations 270 7.11 Psychrotrophic 270



8. Impact of Storage Conditions and Treatments270 8.1 Cold Storage 270 8.2 Pasteurization 271 8.3 Bacteriophage 271 9. Biopreservative Potential of Raw Milk Microorganisms 272 10. Human Health Association 272 11. Pathogenic Bacteria Found in Milk 272 11.1  Listeria monocytogenes272 11.2  Staphylococcus aureus272 11.3  Escherichia coli272 11.4 Salmonella 273 11.5  Coxiella burnetii273 11.6  Mycobacterium bovis273 11.7 Brucella 273 11.8 Filamentous fungi 273 12. Health-Promoting Bacteria 273 13. Conclusion 273 Acknowledgments274 References274

23. Polyphenols in the Prevention of Ulcerative Colitis: A Revisit Elroy Saldanha, Arpit Saxena, Kamaljit Kaur, Faizan Kalekhan, Ponemone Venkatesh, Raja Fayad, Suresh Rao, Thomas George and Manjeshwar Shrinath Baliga







1. Introduction 277 2. Curcumin, the Active Component of Turmeric 277 3. Resveratrol 278 4. Quercetin 279 5. Kaempferol 279 6. Ellagic Acid 279 7. Rutoside or Rutin 280 8. Green Tea Polyphenols in Colitis 280 9. Grape Seed Polyphenols 282 10. Silymarin 282 11. Polyphenols of Apple 282 12. Cocoa 284 13. Conclusions 284 List of Abbreviations 284 References285

Index289

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List of Contributors Amir Abbasnezhad Nutritional Health Research Center, Razi Herbal Medicines Research Center, Lorestan University of Medical Sciences, Khorramabad, Iran

Michael Carrion Biological Sciences Program - Molecular and Cellular Biology, University of Maryland, College Park, MD, United States

Andrés Acosta Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Mayo Clinic, Rochester, MN, United States

Margarida Castell Secció de Fisiologia, Departament de Bioquímica i Fisiologia, Facultat de Farmàcia i Ciències de l’Alimentació, Universitat de Barcelona (UB), Barcelona, Spain; Institut de Recerca en Nutrició i Seguretat Alimentària (INSA-UB), Santa Coloma de Gramenet, Spain

Aryashree Arunima School of Biotechnology, KIIT University, Bhubaneswar, India Ignasi Azagra-Boronat Secció de Fisiologia, Departament de Bioquímica i Fisiologia, Facultat de Farmàcia i Ciències de l’Alimentació, Universitat de Barcelona (UB), Barcelona, Spain; Institut de Recerca en Nutrició i Seguretat Alimentària (INSA-UB), Santa Coloma de Gramenet, Spain Manjeshwar Shrinath Baliga Mangalore Institute of Oncology, Mangalore, India Ayse Gunes Bayir Department of Nutrition and Dietetics, Faculty of Health Sciences, Bezmialem Vakif University, Istanbul, Turkey Cassandra Bernhardt Department of Animal and Avian Sciences, University of Maryland, College Park, MD, United States Jigar Bhagatwala Section of Gastroenterology and Hepatology, Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA, United States Debabrata Biswas Department of Animal and Avian Sciences, University of Maryland, College Park, MD, United States; Biological Sciences Program - Molecular and Cellular Biology, University of Maryland, College Park, MD, United States; Center for Food Safety and Security Systems, University of Maryland, College Park, MD, United States Gerardo Calderón Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Mayo Clinic, Rochester, MN, United States Mariona Camps-Bossacoma Secció de Fisiologia, Departament de Bioquímica i Fisiologia, Facultat de Farmàcia i Ciències de l’Alimentació, Universitat de Barcelona (UB), Barcelona, Spain; Institut de Recerca en Nutrició i Seguretat Alimentària (INSA-UB), Santa Coloma de Gramenet, Spain

Razieh Choghakhori Nutritional Health Research Center, Razi Herbal Medicines Research Center, Lorestan University of Medical Sciences, Khorramabad, Iran Vincenzo Coppola Department of Translational Medical Sciences – Section of Paediatrics, University of Naples “Federico II”, Naples, Italy Jugal Kishore Das School of Biotechnology, KIIT University, Bhubaneswar, India Andrew S. Day Cure Kids Chair Paediatric Research, Department of Paediatrics, University of Otago Christchurch, Christchurch, New Zealand Hilal DemirkesenBiçak Istanbul Yeni Yüzyıl University, Department of Nutrition and Dietetics, Istanbul, Turkey Murat Doğan Istanbul Gelişim University, Department of Gastronomy and Culinary Arts, Istanbul, Turkey Raja Fayad Department of General Surgery, Father Muller Medical College, Mangalore, India Adaliene Versiani Matos Ferreira Department of Nutrition, Nursing School, Federal University of Minas Gerais, Belo Horizonte, Brazil Rita Fiagbor Food and Nutritional Sciences Program, North Carolina A&T State University, Greensboro, NC, United States Thomas George MBBS Student, Father Muller Medical College, Mangalore, India Rabin Gyawali Food and Nutritional Sciences Program, North Carolina A&T State University, Greensboro, NC, United States

xiii

xiv  List of Contributors

Azita Hekmatdoost Department of Clinical Nutrition and Dietetics, Faculty of Nutrition Sciences and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran

Vinod Nagarajan Department of Animal and Avian Sciences, University of Maryland, College Park, MD, United States

J.M. Hutson Surgical Research Group, Murdoch Children’s Research Institute, Melbourne, Australia; Urology Department, The Royal Children’s Hospital, Melbourne, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Australia

Nwadiuto Nwamaioha Food and Nutritional Sciences Program, North Carolina A&T State University, Greensboro, NC, United States

Salam A. Ibrahim Food and Nutritional Sciences Program, North Carolina A&T State University, Greensboro, NC, United States Aseel T. Issa High Point Clinical Trials Center, High Point, NC, United States Faizan Kalekhan Mangalore Institute of Oncology, Mangalore, India Kamaljit Kaur Exercise Science, Arnold School of Public Health, University of South Carolina, Columbia, SC, USA I. Kearsey Surgical Research Group, Murdoch Children’s Research Institute, Melbourne, Australia; Urology Department, The Royal Children’s Hospital, Melbourne, Australia Huriye Senay Kiziltan Department of Radiation Oncology, Faculty of Medicine, Bezmialem Vakif University, Istanbul, Turkey Abdurrahim Kocyigit Department of Medical Biochemistry, Faculty of Medicine, Bezmialem Vakif University, Istanbul, Turkey Takashi Kuda Department of Food Science and Technology, Tokyo University of Marine Science and Technology, Tokyo, Japan Shaohua Lei Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, United States

Robert H. Newman Department of Biology, North Carolina A&T State University, Greensboro, NC, United States

Puja Patel Biological Sciences Program - Molecular and Cellular Biology, University of Maryland, College Park, MD, United States Mengfei Peng Department of Animal and Avian Sciences, University of Maryland, College Park, MD, United States; Biological Sciences Program - Molecular and Cellular Biology, University of Maryland, College Park, MD, United States Francisco J. Pérez-Cano Secció de Fisiologia, Departament de Bioquímica i Fisiologia, Facultat de Farmàcia i Ciències de l’Alimentació, Universitat de Barcelona (UB), Barcelona, Spain; Institut de Recerca en Nutrició i Seguretat Alimentària (INSA-UB), Santa Coloma de Gramenet, Spain Suresh Rao Mangalore Institute of Oncology, Mangalore, India Maria José Rodríguez-Lagunas Secció de Fisiologia, Departament de Bioquímica i Fisiologia, Facultat de Farmàcia i Ciències de l’Alimentació, Universitat de Barcelona (UB), Barcelona, Spain; Institut de Recerca en Nutrició i Seguretat Alimentària (INSA-UB), Santa Coloma de Gramenet, Spain Elroy Saldanha Department of General Surgery, Father Muller Medical College, Mangalore, India Arpit Saxena Exercise Science, Arnold School of Public Health, University of South Carolina, Columbia, SC, USA Elena Scarpato Department of Translational Medical Sciences – Section of Paediatrics, University of Naples “Federico II”, Naples, Italy

Malen Massot-Cladera Secció de Fisiologia, Departament de Bioquímica i Fisiologia, Facultat de Farmàcia i Ciències de l’Alimentació, Universitat de Barcelona (UB), Barcelona, Spain; Institut de Recerca en Nutrició i Seguretat Alimentària (INSA-UB), Santa Coloma de Gramenet, Spain

Amol Sharma Section of Gastroenterology and Hepatology, Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA, United States

Johnson W. McRorie Jr. Procter & Gamble, Mason, OH, United States

Ana Letícia Malheiros Silveira Department of Nutrition, Nursing School, Federal University of Minas Gerais, Belo Horizonte, Brazil

Zeinab Mokhtari Department of Clinical Nutrition and Dietetics, Faculty of Nutrition Sciences and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran

T. Shomali Division of Pharmacology and Toxicology, Department of Basic Sciences, School of Veterinary Medicine, Shiraz University, Shiraz, Iran

B.R. Southwell Surgical Research Group, Murdoch Children’s Research Institute, Melbourne, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Australia

List of Contributors  xv

Annamaria Staiano Department of Translational Medical Sciences – Section of Paediatrics, University of Naples “Federico II”, Naples, Italy

Y.I. Yik Department of Pediatric surgery, University of Malaya, Kuala Lumpur, Malaysia

Mrutyunjay Suar School of Biotechnology, KIIT University, Bhubaneswar, India

Lijuan Yuan Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, United States

Reza Tahergorabi Food and Nutritional Sciences Program, College of Agriculture and Environmental Sciences, North Carolina Agricultural and Technical State University, Greensboro, NC, United States

Wei Zhong Center for Translational Biomedical Research, Department of Nutrition, School of Health and Human Sciences, University of North Carolina at Greensboro, Kannapolis, NC, United States

Mauro Martins Teixeira Department of Biochemistry and Immunology, Biological Sciences Institute, Federal University of Minas Gerais, Belo Horizonte, Brazil

Zhanxiang Zhou Center for Translational Biomedical Research, Department of Nutrition, School of Health and Human Sciences, University of North Carolina at Greensboro, Kannapolis, NC, United States

İsmail Hakkı Tekiner Istanbul Gelişim University, Department of Gastronomy, Istanbul, Turkey Ponemone Venkatesh Mangalore Institute of Oncology, Mangalore, India Zahra Yari Department of Clinical Nutrition and Dietetics, Faculty of Nutrition Sciences and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran

Tahl Zimmerman Food and Nutritional Sciences Program, North Carolina A&T State University, Greensboro, NC, United States

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Biography

Ronald R. Watson, PhD, attended the University of Idaho but graduated from Brigham Young University in Provo, Utah, with a degree in chemistry in 1966. He earned his PhD in biochemistry from Michigan State University in 1971. His postdoctoral schooling in nutrition and microbiology was completed at the Harvard School of Public Health, where he gained 2 years of postdoctoral research experience in immunology and nutrition. From 1973 to 1974, Dr. Watson served as an assistant professor of immunology and performed research at the University of Mississippi Medical Center in Jackson. He was an assistant professor of microbiology and immunology at the Indiana University Medical School from 1974 to 1978 and associate professor at Purdue University in the Department of Food and Nutrition from 1978 to 1982. In 1982, Dr. Watson joined the faculty at the University of Arizona Health Sciences Center in the Department of Family and Community Medicine of the School of Medicine. He is currently professor of health promotion sciences in the Mel and Enid Zuckerman Arizona College of Public Health. Dr. Watson joined the faculty at the University of Arizona Health Sciences Center in the Department of Family and Community Medicine of the School of Medicine. His primary appointment now is professor of health promotion sciences in the Mel and Enid Zuckerman Arizona College of Public Health. He has 14 patents on dietary supplement and health promotion. He continues to do research in animals and in clinical trials on dietary supplements and health. Dr. Watson is a member of national and international nutrition, immunology, cancer, and alcoholism research societies. His patents are for antioxidant polyphenols in several dietary supplements including passion fruit peel extract, with more pending. This results from more than 10 years of polyphenol research in animal models and human clinical trials. He had done research on mouse AIDS and immune function for 20 years. For 30 years, he was funded by the NIH and foundations to study dietary supplements in health promotion. Dr. Watson has edited more than 120 books on nutrition, dietary supplements and over-the-counter agents, and drugs of abuse as scientific reference books. He has published more than 500 research and review articles. Victor R. Preedy, BSc, PhD, DSc, FSB, FRCPath, FRSPH is attached to both the Diabetes and Nutritional Sciences Division and the Department of Nutrition and Dietetics. He is professor of Nutritional Biochemistry (Kings College London) and professor of Clinical Biochemistry (Hon: Kings College Hospital). He is also director of the Genomics Center and a member of the School of Medicine. Professor Preedy graduated in 1974 with an honours degree in Biology and Physiology with Pharmacology. He gained his University of London PhD in 1981. In 1992, he received his Membership of the Royal College of Pathologists and in 1993 he gained his second doctoral degree for his outstanding contribution to protein metabolism in health and disease. Professor Preedy was elected as a Fellow to the Institute of Biology in 1995 xvii

xviii Biography

and to the Royal College of Pathologists in 2000. Since then, he has been elected as a Fellow to the Royal Society for the Promotion of Health (2004) and the Royal Institute of Public Health (2004). In 2009, Professor Preedy became a Fellow of the Royal Society for Public Health. In his career, Professor Preedy has carried out research at the National Heart Hospital (part of Imperial College London) and the MRC Centre at Northwick Park Hospital. He has collaborated with research groups in Finland, Japan, Australia, USA, and Germany. Professor Preedy has a wide interest in diet–tissue interactions and especially micronutrients. He has lectured nationally and internationally. To his credit, Professor Preedy has published over 570 articles, which includes 165 peer-reviewed manuscripts based on original research, 90 reviews, and over 40 books and volumes.

Acknowledgments The work of Dr. Watson’s editorial assistant, Bethany L. Stevens, in communicating with authors and editors and working on the manuscripts was critical to the successful completion of the book. It is very much appreciated. Support for Ms. Stevens’ and Dr. Watson’ editing was graciously provided by the Natural Health Research Institute (www.naturalhealthresearch.org) and Southwest Scientific Editing & Consulting, LLC. The encouragement and support of Elwood Richard and Dr. Richard Sharpee was vital. Direction and guidance from Elsevier’s staff Pat Gonzalez was critical. Finally, the work of the librarian at the Arizona Health Science Library, Mari Stoddard, was vital and very helpful in identifying key researchers who participated in the book.

xix

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Section I

Background and Overview of Diet and GI Tract Health

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Chapter 1

Plant Family, Carvacrol, and Putative Protection in Gastric Cancer Ayse Gunes Bayir1, Huriye Senay Kiziltan2, Abdurrahim Kocyigit3 1Department

of Nutrition and Dietetics, Faculty of Health Sciences, Bezmialem Vakif University, Istanbul, Turkey; 2Department of Radiation Oncology, Faculty of Medicine, Bezmialem Vakif University, Istanbul, Turkey; 3Department of Medical Biochemistry, Faculty of Medicine, Bezmialem Vakif University, Istanbul, Turkey

1. PLANT FAMILY AND PHYTOCHEMICALS 1.1 General Properties of Dietary Phytochemicals Plant chemicals called as phytochemicals are more than 5000 bioactive nonnutrient compounds in plants, including fruits, vegetables, grains, and other plant foods.1 These compounds in plants are the secondary metabolites within the functions in reproduction, growth, defense mechanisms against pathogens, the taste, smell, and color of plants. They have a role in oxidative stress metabolism, which is important for the development and prevention of a wide range of chronic diseases.2 Therefore, plant foods containing phytochemicals may provide to reduce the risk of chronic diseases.

1.2 Classification of Phytochemicals Phytochemicals are classified as polyphenols, terpenoids, alkaloids, phytosterols, and organosulfur compounds (Fig. 1.1). The most commonly found and studied phytochemical classes are the polyphenols.3 Until now 8000 polyphenolic compounds are identified, which have antioxidant and prooxidant activities depending on their doses.4 Polyphenols at higher doses have shown to play an important role in induction of apoptosis, suppression of cell proliferation, migration, and invasion of cancer cells, whereas their lower doses scavenge the free radicals in cells. Chemical structure of polyphenols demonstrates one or more aromatic rings with one or more hydroxyl groups.5 They have been classified according to their chemical structure as phenolic acids, flavonoids, stilbenes, and isoflavones.

1.3 Mechanisms of Phytochemicals in Cancer Chemoprevention The use of many dietary agents, medicinal plants, and their phytochemicals as specific natural or synthetic chemical compounds in cancer prevention gained importance over the past few years.6 However, the cancer preventive effect of these compounds should be tested in in vitro and in vivo before their investigations in clinical studies. Therefore, the mechanism of chemoprevention in cancer encompasses to prevent, suppress, or reverse all of the cancer stages that involve initiation, promotion, and progression.7 Chemopreventive agents are classified into blocking and suppressing agents.8 Phytochemicals can play a role as blocking or suppressing agents in different stages of cancer (Fig. 1.2). On the other hand, some phytochemicals can interact as both blocking and suppressing agents in carcinogenesis. Blocking agents can block or reverse the initiation stage of cancerogenesis and inhibit the reach of procarcinogens into the target cells, the metabolic activation of the procarcinogens, or their, subsequently, interaction with macromolecules such as DNA, RNA, lipids, and proteins. Suppressing agents inhibit the malignant transformation of initiated cells in either the promotion or the progression stages of cancerogenesis. Both agents affect the cancerogenesis at the molecular and cellular levels, which include the activation or detoxification of procarcinogens by metabolizing enzymes, reparation of DNA damage, and progression of cell cycle.9 It was included hormonal and growth factor activity, cell proliferation, cell differentiation, apoptosis, expression and functional activation/inactivation of oncogenes, angiogenesis, and tumor metastasis. On the other hand, two important mechanisms of polyphenols in cancer chemoprevention are the antioxidant and prooxidant activities that occur depending on their concentrations.2 Polyphenols at higher concentrations induce the overgeneration of intracellular reactive oxygen species (ROS) that may cause damage of DNA and Dietary Interventions in Gastrointestinal Diseases. https://doi.org/10.1016/B978-0-12-814468-8.00001-6 Copyright © 2019 Elsevier Inc. All rights reserved.

3

4  SECTION | I  Background and Overview of Diet and GI Tract Health

FIGURE 1.1  Classification of phytochemicals.

FIGURE 1.2  Roles of blocking and suppressing phytochemical agents.

macromolecules in cells and induce apoptosis of cells. Lower concentrations of polyphenols activate the antioxidant defense system in cells by reducing ROS level, and so the normal cells were prevent from the carcinogenesis. However, the molecular and cellular effects of chemopreventive phytochemicals still remain incomplete. Hence the clinical significance and direct impact on organs and organ functions in patients are also still unknown.

2. CARVACROL 2.1 Carvacrol as a Molecule Carvacrol is a monoterpenoid phenol representing with the chemical formula of C6H3CH3(OH) (C3H7).10 Its formula was described according to International Union of Pure and Applied Chemistry as 2-methyl-5-propan-2-ylphenol. The structural formula of carvacrol is demonstrated in Fig. 1.3.

2.2 Carvacrol Sources Carvacrol is a compound of many aromatic plants that are usually used as spices in culinary and for therapy/prevention purposes in folk medicine. These aromatic plants are including oregano (Origanum vulgare, O. majorana, O. compactum, O. dictamnus, O. microphyllum, O. onites, and O. scabrum), thyme (Thymus vulgaris, T. glandulosus, T. zygis, and T. serpyllum), Spanish origanum (Thymbra capitata), pepperwort (Lepidium flavum), black cumin (Nigella sativa), and summer and winter savory (Satureja hortensis and S. montana).10–14 On the other hand, carvacrol can be synthesized by chemical and biotechnological methods.15–18

Plant Family, Carvacrol, and Putative Protection in Gastric Cancer Chapter | 1  5

OH

FIGURE 1.3  The chemical structure of carvacrol.

2.3 Chemical and Physical Properties of Carvacrol Carvacrol is a liquid and boils at 237–238°C.19 It can be volatile with steam. Its melting point is 1°C. Its highly lipophilic character can allow its solubility in carbon tetrachloride, ethanol, diethyl ether, and acetone. Because of its lipophilic character, carvacrol is insoluble in water. The density of carvacrol differs between 0.97 g/cm3 at 20°C and 0.975 g/cm3 at 25°C.

2.4 Metabolism and Excretion of Carvacrol A study revealed that carvacrol is the substrate of the UDP-glucuronosyltransferase isoform UGT1A4.20 It was reported that carvacrol can rapidly be metabolized and excreted in rats.21 Its excretion after 24 h was very limited and the molecule was found unchanged. After 48–72 h of carvacrol treatments of rats, no metabolites were observed. Ring hydroxylation of carvacrol molecule is the reason why the metabolism of this compound is very quick. The biological activities of polyhydroxylated compounds generally seem to be dependent on their chemical properties such as structure and lipophilicity, which can also affect their uptake into cells or influence their interaction with proteins and enzymes. Another study showed that oral feeding of carvacrol in pigs was almost completely absorbed in the stomach and proximal small intestine, whereas 29% degradation of carvacrol was observed in cecum.22

2.5 Acute Toxicity of Carvacrol The median lethal dose (LD50) of carvacrol in rats was reported as 810 mg/kg body weight when it was applied by oral gavage.23 The LD50 for intravenous, intraperitoneal, or subcutaneous applications of carvacrol to mice were 80, 73.3, and 680 mg/kg body weight, respectively.24 In dogs, the LD50 of intravenously administered carvacrol was 0.31 g/kg body weight.

2.6 Biological Activities of Carvacrol In the past few years, increasing use of carvacrol as food additives for flavoring substance or natural food preservative in the food packaging system and a lot of carvacrol’s biological activities have attracted the attention of researchers for its possible potential in clinical applications. The preventing free radicals and hazardous compounds from interacting with cellular DNA are associated with its wide range of biological activities. Therefore, in vitro and in vivo studies were performed to research its biological activities, which are presented below.

2.6.1 Antioxidant Activity Antioxidant substances scavenge the ROS namely free radicals, and so they protect the cells against cellular stress. Furthermore, they inhibit prostaglandin synthesis, induce drug-metabolizing enzymes, and show many biological activities such as protecting from DNA damage, enzyme-induced hepatotoxicity, inhibiting/preventing from cancer imitation, etc. The reason for antioxidant activity of carvacrol was the presence of hydroxyl group (OH) that linked to aromatic ring of carvacrol molecule.25 During the reaction of carvacrol molecule with free radicals, it donates hydrogen atoms to an unpaired electron and produces another radical which is generated at a molecule resonance structure. Carvacrol can interact with the phospholipid membrane of cells or low-density lipoprotein and reduce the lipid peroxidation and nitric oxide production, which leads to oxidative destruction of cellular membranes.26,27 Nitric oxide is produced from the spontaneous

6  SECTION | I  Background and Overview of Diet and GI Tract Health

decomposition of sodium nitroprusside that was effectively scavenged by carvacrol.26 Carvacrol presented a strong antioxidant potential according to the total radical-trapping antioxidant parameter /total antioxidant reactivity evaluation which its scavenger activity against nitric oxide and preventive effect against the lipid peroxidation in vitro.28 The higher antioxidant activity of carvacrol was verified by in vitro and in vivo studies. Carvacrol protects the human lymphocytes from the DNA damage induced by 2-amino-3-methylimidazo[4,5-f]-quinoline and Mitomycin C at concentrations below 0.05 mM,29 whereas from the genotoxic effects of 0.1 mM H2O2 at concentrations below 0.1 nM.30 On the other hand, 10 mg/L dose of carvacrol treatment induces significant increases of the total antioxidant capacity levels in cultured primary rat neuron cells.31 Another in vitro study showed that the intracellular ROS generation was lower when the mouse V79 fibroblast cells exposed to lower concentrations of carvacrol (1–25 μM), but the increased ROS was found at the highest concentration of carvacrol (100 μM).32 The antioxidant activity of carvacrol has also been reported in a limited number of in vivo studies. For example, the resistance against hydrogen peroxide–induced DNA damage in hepatic and testicular tissues was higher in rats when carvacrol in drinking water (at 30 and 60 mg/kg for 7 days or 15 and 30 mg/kg for 14 days) was given.33 Another studies also showed that carvacrol has the preventive effect against the lipid peroxidation and induces an increase of the endogenous antioxidant defense mechanisms in N-nitrosodiethylamine-induced hepatocellular carcinogenesis and antioxidant activity against galactosamine-induced hepatotoxicity in rats.34,35 All of the reported studies suggest that carvacrol showed both antioxidant activities depending on its different doses.

2.6.2 Prooxidant Activity Generally, phenolic compounds are shown the features of both an antioxidant and a prooxidant activity depending on their different doses.4 Prooxidants can induce oxidative stress either by generating ROS or by inhibiting or decreasing the antioxidant status of cells. The prooxidant activity of carvacrol seems to be related to the mitochondrial membrane damage by permeabilization, resulting in a prooxidant status and induction of apoptosis thereafter.36,37 It seems that the conversion of carvacrol from antioxidant to prooxidant occurs at its higher concentrations, which may result in cytotoxicity, genotoxicity, apoptosis, and/or necrosis following ROS generation.38 The strong reducing power of antioxidants may also affect metal ions, especially Fe+3 and Cu+2, increasing their ability to form highly reactive HO−.concentrations and potentially harmful radicals, originating from peroxides via Fenton’s reaction.39,40 An in vivo study demonstrated the oral application of carvacrol at a high dose (100 mg/kg body weight) in male Wistar rats.41 Significant changes in body weight and oxidative stress index for plasma and stomach tissues of rats were found in carvacrol-administered group in comparison with animals of the control group.

2.6.3 Antimicrobial Activity: Antiviral, Antibacterial, and Antifungal The mechanisms of antimicrobial activity of carvacrol are based on the hydrophilic character of this compound, which could be attributed to the interactions between the effective compounds and cell membrane of microorganisms.42 Antiviral activity of a compound was described as reducing or inhibiting viral diseases. It has been reported that carvacrol has the antiviral activity in the animal and human viral diseases such as human rotavirus, acyclovir-resistant herpes simplex virus type 1, human respiratory syncytial virus, the pandemic H1N1 virus, and human norovirus.43–45 Carvacrol influences a wide spectrum of antimicrobial activity against both Gram-positive and Gram-negative bacteria isolated from food and clinical specimens. This effect may be attributed to inhibit the growth or to reduce the number of pathogenic bacteria.46,47 These human and animal pathogen bacterias are Campylobacter, Pseudomonas, Escherichia coli, Salmonella, Methicillin-resistant Staphylococcus aureus, Streptococci, Listeria, Bacillus, and Fusarium.46,48,49 On the other hand, a combination of tetracycline and carvacrol has been shown to be very active in in vitro against Candida albicans and bacterial strains such as E. coli, Pseudomonas aeruginosa, Staphylococcus aureus, Bacillus cereus, and Bacillus bronchispti.50 The synergistic effect may be associated with the enhancement of the permeability of tetracycline through the bacterial cell wall. Furthermore, carvacrol showed bacteriostatic and bactericidal activities on food pathogens such as Vibrio cholerae, Campylobacter jejuni, E. coli, Listeria monocytogenes, Salmonella enterica serovar Typhimurium, S. aureus, Staphylococcus epidermidis, Lactobacillus sakei, P. aeruginosa, Pseudomonas putida, Streptococcus mutans, and Bacillus subtilis.48,51–54 Carvacrol is able to inhibit the growth of preformed bacterial biofilm and to interfere with biofilm formation on stainless steel surfaces.55 In such cases, carvacrol distributes into membranes to permeabilize and disrupt their ion gradients.56 Additionally, the existence of a free hydroxyl group of carvacrol and its effect on delocalized electron system through the reducing the gradient across the cytoplasmic membrane are important for its antibacterial activity.57 The antifungal activity of carvacrol may act through the membrane and cell wall disruption with morphological deformation, collapse, and deterioration of the conidia and/or hyphae, and the inhibition of ergosterol biosynthesis.58 Carvacrol exerts a broad spectrum of antifungal activity against fungi isolated from food and clinical specimens.59,60 The inhibitory

Plant Family, Carvacrol, and Putative Protection in Gastric Cancer Chapter | 1  7

activity of carvacrol was reported for Cladosporium spp., Aspergillus spp., Fusarium spp., and Penicillium spp., which are the most food-decaying fungi.61 Moreover, carvacrol could be considered as strong antifungal agents and proposed as therapeutic agents for oral candidiasis in immunosuppressed rats.62

2.6.4 Anticarcinogenic and Antiplatelet Effects Numerous in vitro studies showed that carvacrol has anticarcinogenic effect on different cell lines (Table 1.1). Anticarcinogenic effect of carvacrol can occur through its cytotoxic, apoptotic, and genotoxic activities. As many anticancer agents are known to be also mutagenic, this effect of carvacrol was in a dose-dependent manner.78 Carvacrol can inhibit the proliferation of human gastric adenocarcinoma (AGS) cells as a result of increased ROS generation–induced mitochondrial apoptosis pathway via the activation of Bax, caspase-3, and caspase-9 and decreased Bcl-2 gene expression in a dose-dependent manner.38 Carvacrol-induced mitochondrial pathway of apoptosis is characterized through the damaging mitochondrial membrane after its permeabilization.70–72 Additionally, carvacrol can also induce the inactivation of Poly (ADP-ribose) polymerase and selectively alter the phosphorylation state of members of the MAPK superfamily, decreasing phosphorylation of ERK1/2 and activating phosphorylation of p38 but not affecting c-Jun N-terminal kinase - mitogenactivated protein kinase phosphorylation. In vivo studies are limited to demonstrate the anticarcinogenic property of carvacrol. Although the mechanism of the antitumor activity of carvacrol was not investigated in a study, its inhibitory effect on angiogenesis was observed against the 9,10-dimethyl-1,2-benzanthracene–induced lung tumors in Wistar rats.79 It has been also shown that the tumor incidence in Wistar rats treated with the carcinogen 3,4-benzo[a]pyrene (B[a]P) incubated with carvacrol (976 mg/ mL) was 30% lower and an existence of significant prolongation in animal survival time in comparison with the tumor incidence in rats treated with B[a]P alone.75 The mechanism for the observed decrease of B[a]P carcinogenic potency is not clear. However, it was hypothesized that the chemical neutralizing of both substances is responsible because of reducing double bounds on K and L molecular regions of B[a]P. Carvacrol (15 mg/kg body weight) also exhibited the anticancer activity by suppression of the serum tumor marker enzymes, carcinoembryonic antigen, and α-fetoprotein in diethylnitrosamine (DEN)-induced hepatocellular carcinogenesis.80 In addition, carvacrol can modulate the instability of xenobiotic metabolizing enzymes and downregulate the expressions of Proliferating cell nuclear antigen (PCNA), Matrix metalloproteinase-2 (MMP-2)-2, and MMP-9. Further investigations are needed to understand the anticancer effect of carvacrol on different cancer types. Carvacrol exerts antiplatelet effect, which is functioning the inhibition of platelet activation/aggregation through the thromboxane A2 (TAX2) and the reduction of cyclooxygenase (COX).75 Generally, antiplatelet effect of different antioxidants is due to the neutralization of free radicals produced in COX pathway, resulting in low production of TAX2 and lower accessibility of glycoprotein IIb/IIIa platelet receptors to fibrinogen molecules.81

2.6.5 Chemopreventive Effect Chemoprevention is defined as use of natural or synthetic chemicals for controlling cancer through the reverse, suppression, or prevention of premalignancy from progression to invasive cancer.7 Chemopreventive potential of some polyphenols has been studied in the N-methyl-N-nitro-N-nitrosoguanidine (MNNG)–induced gastric cancer (GC) model on rats, but only a report exists on the chemopreventive effect of carvacrol in MNNG-induced GC model.On the other hand, carvacrol supplementation (15 mg/kg body weight) significantly attenuated the DEN-induced liver cancer in male Wistar albino rat model, most likely by protecting the antioxidant defense system and preventing lipid peroxidation and hepatic cell damage.32 Chemopreventive effect of carvacrol was also reported on 1,2-dimethylhydrazine (DMH)–induced experimental colon carcinogenesis in male Wistar rats.82 DMH-treated rats received a commercial pellet diet containing carvacrol (40 mg/kg body weight) and showed significantly decreasing tumor incidence and the number of aberrant crypt foci and bacterial enzymes with enhancement of colonic lipid peroxidation, glutathione peroxidase, superoxide dismutase, and catalase activities.

2.6.6 Antiinflammatory and Antihypernociceptive Effects During inflammation the activation and directed migration of leukocytes (neutrophils, monocytes, and eosinophils) from the venous system to sites of damage and tissue mast cells play a significant role that releases the mediators such as interleukins, cytokines, or tumor necrosis factor (TNF)-α.83 In addition, tissue damage and inflammation can induce hypersensitivity.84 Hypersensitivity of nociceptor induces the inflammatory hyperalgesia, also called hypernociception, in laboratory animals, characterized by increased pain sensitivity.

TABLE 1.1  Anticancer Activity of Carvacrol (CRV) Studied In Vitro and the Main Results Reported Experimental Model

Concentration Ranges

Main Results

References

Human lymphocytes

0.0005–2 mM

CRV > 0.05 mM induced DNA damage

30

Cultured primary rat neurons

0–400 mg/L

Dose-dependent cytotoxicity and genotoxicity

31

N2a neuroblastoma cells

0–400 mg/L

Dose-dependent cytotoxicity and genotoxicity

31

V79 Chinese hamster lung fibroblast cells

1–25 μM

CRV