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

By Ronald Ross Watson and Victor R Preedy

Dietary Interventions in Gastrointestinal Diseases: Foods, Nutrients and Dietary Supplements provides valuable insights into the agents that affect metabolism and other health-related conditions in the gastrointestinal system. It provides nutritional treatment options for those suffering from gastrointestinal diseases including Crohn’s Disease, Inflammatory Bowel Disease, Ulcerative Colitis and Allergies, among others. Information is presented on a variety of foods, including herbs, fruits, soy and olive oil, thus showing that changes in intake can change antioxidant and disease preventing non-nutrients and affect gastrointestinal health and/or disease promotion.

This book serves as a valuable resource for biomedical researchers who focus on identifying the causes of gastrointestinal diseases and food scientists targeting health-related product development.

• Provides information on agents that affect metabolism and other health-related conditions in the gastrointestinal tract
• Explores the impact of composition, including differences based on country of origin and processing techniques to highlight compositional differences and their effect on the gastrointestinal tract
• Addresses the most positive results from dietary interventions using bioactive foods to impact gastrointestinal diseases, including reduction of inflammation and improved function of organs

• Language: English
• Publisher: Academic Press
• Release date: Jan 10, 2019
• ISBN: 9780128144695

Book preview

Dietary Interventions in Gastrointestinal Diseases

Foods, Nutrients, and Dietary Supplements

Editors

Ronald Ross Watson

Victor R. Preedy

Table of Contents

Cover image

Title page

Copyright

List of Contributors

Biography

Acknowledgments

Section I. Background and Overview of Diet and GI Tract Health

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

1. Plant Family and Phytochemicals

2. Carvacrol

3. Dietary Phytochemicals in Gastric Cancer Chemoprevention

4. Gastric Cancer

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

1. Introduction

2. Chronic Idiopathic Constipation

3. Antidiarrheal Effects of Fiber

4. Fiber and Irritable Bowel Syndrome

5. Overall Conclusions for Fiber and Laxation, Antidiarrheal, and Irritable Bowel Syndrome

Chapter 3. Dietary Interventions and Inflammatory Bowel Disease

1. Introduction

2. Nutritional Issues/Common Problems in Inflammatory Bowel Disease

3. Nutritional Assessment

4. Nutritional Interventions in Inflammatory Bowel Disease

5. Some Popular Dietary Intervention in Inflammatory Bowel Disease

6. Conclusions

Chapter 4. The Gastrointestinal System and Obesity

1. Introduction

2. Gastrointestinal Regulation of Food Intake

3. Complication of Obesity in Gastrointestinal Tract

4. Treatment of Obesity Focused in the Gastrointestinal Tract

5. Conclusions

Chapter 5. Constipation: A Symptom of Chronic Food Intolerance?

1. Introduction

2. Chronic Constipation

3. Emerging Views of Pediatric Chronic Constipation

4. Adverse Food Reactions and Chronic Constipation

5. Conclusion

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

1. Introduction

2. Reflux Hypersensitivity and Functional Heartburn

3. Functional Dyspepsia

4. Irritable Bowel Syndrome and Functional Constipation

5. Summary

Chapter 7. Vitamin D and Quality of Life of Patients With Irritable Bowel Syndrome

1. Introduction

2. Health-Related Quality of Life of Irritable Bowel Syndrome Patients

3. Functions of Vitamin D

4. Vitamin D Deficiency in Irritable Bowel Syndrome

5. Vitamin D and Quality of Life in Irritable Bowel Syndrome

6. Discussion

7. Conclusions

List of Abbreviations

Section II. Nutrition and GI Tract

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

1. Introduction

2. Gut Barrier Dysfunction in the Development of Alcoholic Liver Disease

3. Zinc Metabolism and Function

4. Zinc Deficiency in Alcoholic Liver Disease

5. Zinc Intervention for Alcoholic Liver Disease

6. Conclusion

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

1. Introduction

2. Crohn’s Disease

3. Nutritional Impact of Chron’s Disease in Children

4. Exclusive Enteral Nutrition

5. Mechanisms of Action of Exclusive Enteral Nutrition

6. Conclusions

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

1. Introduction

2. Gut Microbiota

3. Gut Microbiota and Liver

4. Liver Diseases and Role of Gut Microbiota

5. Dietary Intervention Strategies for Liver Diseases

6. Future Prospects

List of Abbreviations

Section III. Probiotics, Prebiotics, Symbiotics in Intestinal Functions

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

1. Introduction

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

3. Probiotics and Its Antimicrobial Role in Reduction of Enteric Bacterial Pathogen Growth

4. Combined Effect of Pre- and Probiotic and Its Limitation

5. Feasible Alternative to Overcome the Limitation of Symbiotic

6. Conclusion

Chapter 12. The Role of Prebiotics in Disease Prevention and Health Promotion

1. Concept of Prebiotics

2. Modulation of Gut Microbiota

3. Prebiotics Effects in Human Health

4. Synbiotic Approach

5. Insight Into Prebiotics Effect on the Growth of Harmful Bacteria

6. Conclusions and Future Directions

Chapter 13. Probiotics From Food Products and Gastrointestinal Health

1. Introduction

2. Probiotic Concept

3. Mechanisms of Action of Probiotics

4. Dietary Interventions of Probiotics in Gastrointestinal Disorders

5. Probiotic Functional Foods, Status, and Claims

6. Conclusions

List of Abbreviations

Chapter 14. Prebiotics for Gastrointestinal Infections and Acute Diarrhea

1. Introduction

2. Gastrointestinal Infections

3. Prebiotics: Types and Mechanisms of Action

4. Prebiotics in Gastrointestinal Diseases

5. Conclusions

List of Abbreviations

Chapter 15. Probiotics and Applications to Constipation

1. The Role of Microbiota in Gut Motility

2. Gut Microbiota and Gastrointestinal Health

3. Microbiota Alterations in Functional Constipation

4. Probiotics in the Management of Functional Constipation

5. Conclusions

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

1. Introduction

2. Preparation of Fermented Rice Bran for Ammonia Reduction in Shark Meat

3. Effect of Fermented Rice Bran on Ammonia Content and Preference Ranking in Shark and Other Fish Meat

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

5. Protective Effects of FRB in DSS-Induced IBD Model ICR Mice

6. Conclusion

Section IV. Microbes and GI Tract

Chapter 17. Zataria multiflora and Gastrointestinal Tract Disorders

1. Introduction

2. Beneficial Effects of ZM on Different Gastrointestinal Tract Diseases

2.7. Road Mapping for Future Studies and Conclusion

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

1. Introduction

2. Cocoa Composition

3. Cocoa and Gut Microbiota

4. Cocoa and the Intestinal Immune System

5. Cocoa in Gastrointestinal Disease and Food Hypersensitivity

6. Conclusions

List of Abbreviations

Section V. Foods and Macro Dietary Materials in GI Function

Chapter 19. High-Fiber Diets in Gastrointestinal Tract Diseases

1. Basic Concepts: Dietary Fiber

2. Gastrointestinal Tract and Microbiota Interaction

3. Stomach and Gastritis

4. Inflammatory Bowel Disease

5. Mucositis

6. Conclusion

Chapter 20. Dietary Interventions in Fatty Liver

1. Introduction

2. Soy

3. Egg

4. Nuts

5. Probiotics, Prebiotics, and Synbiotics

6. Seal Oil (N-3 Polyunsaturated Fatty Acids)

7. Flaxseed

8. Curcumin

9. Resveratrol

10. Pomegranate

11. Onion

12. Conclusion

Chapter 21. Rice Bran Usage in Diarrhea

1. Overall Health Benefits of Rice Bran Dietary Supplement

2. Dietary Rice Bran Supplementation in Reducing Diarrhea

3. Mechanisms for Rice Bran Usage in Reducing Diarrhea

4. Future Perspective

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

1. Introduction

2. Sources of Milk Organisms

3. Contamination in the Mammary Glands

4. Contamination Sources in the External Environment

5. Contamination From Handling and Storage Equipment

6. Microbial Composition of Milk From Different Sources

7. Important Microorganisms Found in Raw Milk

8. Impact of Storage Conditions and Treatments

9. Biopreservative Potential of Raw Milk Microorganisms

10. Human Health Association

11. Pathogenic Bacteria Found in Milk

12. Health-Promoting Bacteria

13. Conclusion

Chapter 23. Polyphenols in the Prevention of Ulcerative Colitis: A Revisit

1. Introduction

2. Curcumin, the Active Component of Turmeric

3. Resveratrol

4. Quercetin

5. Kaempferol

6. Ellagic Acid

7. Rutoside or Rutin

8. Green Tea Polyphenols in Colitis

9. Grape Seed Polyphenols

10. Silymarin

11. Polyphenols of Apple

12. Cocoa

13. Conclusions

Index

Copyright

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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

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

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

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

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

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

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

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

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

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

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

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

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

Nwadiuto Nwamaioha,     Food and Nutritional Sciences Program, 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

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

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

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

B.R. Southwell

Surgical Research Group, Murdoch Children’s Research Institute, Melbourne, Australia

Department of Paediatrics, University of Melbourne, Melbourne, Australia

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

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

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

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

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

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

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

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

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

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 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.

Section I

Background and Overview of Diet and GI Tract Health

Outline

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

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

Chapter 3. Dietary Interventions and Inflammatory Bowel Disease

Chapter 4. The Gastrointestinal System and Obesity

Chapter 5. Constipation: A Symptom of Chronic Food Intolerance?

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

Chapter 7. Vitamin D and Quality of Life of Patients With Irritable Bowel Syndrome

Chapter 1

Plant Family, Carvacrol, and Putative Protection in Gastric Cancer

Ayse Gunes Bayir¹, Huriye Senay Kiziltan², and 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

Abstract

Gastric cancer (GC) is one of the most common cancer types of gastrointestinal system within the five most common causes of all cancers in the world. The etiology of GC is multifactorial, which includes dietary and nondietary factors. Also, a parallel relationship exists between Helicobacter pylori infection and GC. Additionally, it has been reported the absence of tumor suppressor genes in GC cases especially p53 gene. Although there are advances in diagnosis and treatment with effective drugs of GC, resistance to chemotherapy may be developed in patients. Therefore, it is important to take preventive and chemopreventive measures to ward of GC. Many studies on natural products have been performed to investigate the anticancer and chemopreventive effects of phytochemicals. They are classified as polyphenols, terpenoids, alkaloids, phytosterols, and organosulfur compounds. Polyphenolic compounds are generally known to exhibit antioxidant properties, while high doses of these substances have shown to play an important role in induction of apoptosis, suppression of cell proliferation, migration, and invasion of cancer cells. Carvacrol is a monoterpenic phenol, which is found in many aromatic plants from the family Lamiaceae. Some in vitro and in vivo studies revealed that carvacrol has the bioactivity actions. It has been reported that carvacrol has also antioxidant and prooxidant properties depending on its concentration. Carvacrol at lower concentrations has the property of an antioxidant that scavenges the free radicals namely reactive oxygen species (ROS) and so protects the cells against oxidative stress. Carvacrol at higher concentrations activates the production of ROS in cells, which may result in DNA damage, apoptosis, and cell death. Therefore, plants or their chemical compounds such as carvacrol seem to be a good candidate for GC prevention or chemoprevention.

Keywords

Carvacrol; Chemoprevention; Gastric cancer; Phytochemicals; Polyphenols

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 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.

Figure 1.1  Classification of phytochemicals.

Figure 1.2  Roles of blocking and suppressing phytochemical agents.

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

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 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 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 - mitogen-activated 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

ROS, reactive oxygen species.

Carvacrol also significantly inhibited both the early (neurogenic pain) and the late (inflammatory pain) phases of formalin-induced licking with inhibition percentage values of 56.8% (100  mg/kg) for the neurogenic phase and 41.2% (25  mg/kg), 73.8% (50  mg/kg), and 99.7% (100  mg/kg) for the inflammatory phase.²⁸ In another study, carvacrol has been shown to attenuate mechanical hypernociception and inflammatory response in carrageenan-induced pleurisy and mouse model.⁸⁵ This compound significantly decreases TNF-α levels in pleural lavage and suppresses the recruitment of leukocytes without altering the morphological profile of these cells. Carvacrol (1, 10, and 100  μg/mL) also significantly reduced (P  <  .001) the lipopolysaccharide-induced nitrite production in vitro and did not produce cytotoxicity in the murine peritoneal macrophages in vitro. It seems to be carvacrol-induced antiinflammatory activity through the suppression of COX-2 expression, the activation of the peroxisome proliferator-activated receptors α and γ, and the inhibition of the production and actions of nitric oxide.⁸⁶ In generally, this compound might be potentially interesting in the development of novel tools for management and/or treatment of painful conditions, including those related to inflammatory and prooxidant states.

2.6.7. Hepatoprotective Effect

D-galactosamine is a well-established hepatotoxicant in rats, which induces a diffuse type of liver injury closely resembling human viral hepatitis with oxidative stress playing a role in the pathogenesis.⁸⁷ In vivo model for D-galactosamine induced liver injury (D-GaIN) was used in studies to investigate the hepatoprotective effect of carvacrol. Oral administration of carvacrol (80  mg/kg body weight) to rats during 21  days induces restoring the concentrations of lipid peroxidation products, lipids content in the kidney, liver, and blood plasma to its normal values.⁸⁸ The mechanism of the hepatoprotective effects of carvacrol against D-GalN is associated with its protection against the structural integrity of the hepatocellular membrane and the prooxidant/antioxidant balance in the liver.⁸⁹ On the other hand, a lack of glucose and oxygen in cells can result in ischemia when blood flow to an organ was insufficient or stopped.⁹⁰ Especially, in many surgical operations, ischemia occurring during hepatectomy (minimum 60  min in Pringle maneuver) causes serious tissue injury. Reperfusion following ischemia can occur in the passage of toxic products to the systemic circulation with worsening liver damage. Moreover, oxidants formed and circulated as a result of ischemia/reperfusion in another organ bring about negative effects especially in the lungs and the liver. In such cases, carvacrol may protect rats against ischemia/reperfusion–induced liver injury.

2.6.8. Antispasmodic and Antitussive Effect

It has been reported that carvacrol may reduce the contractions caused by acetylcholine, carbachol, histamine, 1,1-dimethyl-4-phenylpiperazinium iodide, and BaCl2 in guinea pig ileum.⁹¹ This compound can also act as a noncompetitive antagonist against the rat vas deferens contractions induced by the L-noradrenaline.⁹² Carvacrol has also the spasmolytic effect on tracheal chains of guinea pigs, which is not due to β2-adrenergic stimulation, histamine H1, and muscarinic blocking effect.⁹³ The mechanism of the indirect action of spasmolytic activity may be induced by inhibition of the nerve action potential in the postganglionic nerve fiber.⁹¹

2.6.9. Antiobesity Effect

Obesity is defined as abnormal or excessive body fat accumulation, which has the negative effect on health, leading to increased health problems.⁹⁴ It is associated with increased risk of developing metabolic syndrome, type 2 diabetes mellitus, and cardiovascular disease, leading to higher all-cause mortality. In a study, different doses of carvacrol exposed to mouse embryo 3T3-L1 cells caused an inhabiting of fat accumulation between cells and adipocyte differentiation.⁹⁵ In the same work, mice fed with 0.1% carvacrol-supplemented high-fat diet (HFD) showed decreasing body weight, visceral fat pad weights, and lowering plasma lipid levels. It was suggested that carvacrol prevents HFD-fed mice from the obesity and seems to inhibit visceral adipogenesis probably by suppressing bone morphogenic protein-, fibroblast growth factor 1-, and galanin-mediated signaling. It also attenuates the production of proinflammatory cytokines in visceral adipose tissues by inhibiting Toll-like receptor 2 (TLR2)- and TLR4-mediated signaling. More detailed studies are needed because of the limited studies on antiobesity effect of carvacrol.

3. Dietary Phytochemicals in Gastric Cancer Chemoprevention

MNNG-induced rat GC model resembles human GC.⁷ Therefore, it could be used a good model for the experimental GC researches.⁷,⁴¹ It was shown that some dietary agents such as curcumin, eugenol, folic acid, genistein, lycopene, naringenin, S-allyl cysteine, tea polyphenols, and epigallocatechin-3-gallate possess chemopreventive effects in the MNNG-induced GC model.⁷ The mechanism of action encompasses the inhibition of cell proliferation, angiogenesis, induction of apoptosis, and DNA damage, which include many gene targets such as caspases, PCNA, VEGF, COX-2, NF-κB, etc.

4. Gastric Cancer

Gastric or stomach cancer is one of the most common cancers in the world. In the case of cancer-related deaths, it is also in the third place.⁹⁶ The stomach cancer constitutes about 10% of all cancers. It is the second most common type of cancer in the world. In the last 30–50  years, there is a decrease in the rate of this disease in western societies. In some countries, such as Japan and Colombia, stomach cancer is still more common.⁹⁷

4.1. Anatomy and Physiology

The stomach is located between the upper abdomen, the liver, the pancreas, and the spleen (Fig. 1.4). It is rich in lymph glands. Stomach cancer is most commonly found in the antrum and one-third distal region of the small curvature region of stomach (Fig. 1.5). It is lesser seen in one-third proximal segment.⁹⁸–¹⁰⁰

4.2. Epidemiology of Gastric Cancer

It is still a very common cancer, though there is a decline in stomach cancer rate in recent years. According to GLOBOCAN 2012 data, 723,000 people die from cancer every year in the world, out of which 8.8% is related to stomach cancer. Half of the stomach cancer deaths are in Eastern Asia and most of them are from China.¹⁰¹ GC can be diagnosed earlier with the development of new diagnostic methods. Japan and Korea were seen with most stomach cancer cases.¹⁰²,¹⁰³ There are two main types of gastric adenocarcinoma, epidemic intestinal type and endemic infiltrative type.⁹⁷–¹⁰⁶

4.3. Etiology of Gastric Cancer

Many dietary and environmental factors have been revealed in chronic gastritis, which can lead to chronic atrophic gastritis, intestinal metaplasia, dysplasia, and eventually (10% risk) stomach cancer.¹⁰⁶ Additionally, some vitamins and mineral deficiencies can cause from chronic gastritis to intestinal metaplasia.¹⁰⁷ There has been an increase in the incidence of proximal GC within the last 15  years. Proximal adenocarcinomas have a lower 5-year survival rate.¹⁰⁰ Intestinal metaplasia, a type of mucin produced by intestinal metaplasia cells, is distinguished into two main groups such as complete (type I) and incomplete (type II).⁹⁷ Stomach ulcers are the chronic benign ulcers that rarely become cancerous, but cancer-related ulcers may be benign. After partial gastrectomy, atrophic gastritis and intestinal metaplasia can develop in the remaining gastric mucosa. Polyps should be removed because of increased risk for GC. In general, one of the most common causes of GC is infectious agents. Especially, Helicobacter pylori infection is an important risk factor for noncardiac-associated GC.¹⁰⁸ If HER2 concentration is present in intestinal-type stomach cancer, the progression of the disease becomes faster and worse.¹⁰⁹ In recent years, Epstein–Barr virus has also been shown to be an important agent in some types of stomach cancer.¹¹⁰ Cardiac tumors have different etiologic factors that are different from noncardiac tumors.¹¹¹ Intratumoral hypoxia or low-oxygen availability is an important factor in accelerating the progression of the disease in many types of cancer and GC.¹¹²

Figure 1.4  Anatomic location of the stomach.

Figure 1.5  Tumor locations of gastric cancer.

4.4. Pathology of Gastric Cancer

The majority of stomach tumors originate from stomach layer mucosa or other components, rarely from muscle, fat, and lymphoid origin (Fig. 1.6). Ninety-five percent of tumors are adenocarcinomas, whereas the remains of stomach cancers include the metastatic tumors of lymphomas, carcinoids, leiomas, liposarcomas, and leiomyosarcomas.⁹⁷–⁹⁹ The adenocancer of stomach are well differentiation and undifferentiation 60% and 40% of tumors, respectively. Macroscopically, 20% of early stomach cancer is swollen type and 80% depressed type. In advanced gastric carcinoma, the tumor invaded to serosal layer. A rare histological species, neuroendocrine tumors, may be good, bad, or mixed differentiation. Stomach lymphomas constitute to less than 5% form of stomach tumors. Non-Hodgkin’s lymphoma is the most common disease except lymph nodes. The most pathologic type is diffuse histiocytic cell type.¹¹³ H. pylori involvement is known in MALT-type lymphoma. Stomach sarcoma is 13% of malignant tumors of the stomach. Leiomyosarcoma, angiosarcoma, fibrosarcoma, and liposarcoma are the most common sarcoma types. Most common metastatic tumor of stomach was malignant melanoma-related metastases. Other metastatic tumors of stomach are Kaposi’s sarcoma, lung, liver, over, testis, and colon metastases.⁹⁷–⁹⁹ Stomach carcinoids are very rare, which arise from enterochromaffin cells in the gastrointestinal tract.

4.5. Types of Gastric Cancer

Cardiac tumors are located in proximal stomach (Fig. 1.5). It is more severe in Asia and its treatment differs from distal GC. It is generally worse and faster.¹⁰⁴,¹¹¹ Intestinal type of stomach cancer is mostly located in the antrum of the distal stomach and it has usually better and slow outcome.¹⁰⁶ Types I and IIa are well differentiated, whereas types IIb and IIc are moderate and varying in degree. Type III is more frequently and poorly differentiated or undifferentiated histologic type. Macroscopy of early stomach cancer is shown in Fig. 1.7. The lesion is seen to be multicentric at 10% (Japan 8%, Europe 0%–15%), and early stomach cancer is seen only at 13% rate.⁹⁷–⁹⁹ In GC patients, 60% has a good differentiation and 40% undifferentiation pathology. Macroscopically, early stomach cancer is 20% swollen and 80% submerged, and superficial, i.e., superficial, are rare. Type III is the most common type in the United States, while type IIc (30%) is the most common type in Japan. In early stage of GC, mucosal localization and lymph node metastasis are found in 7.5%–10%.⁹⁷–⁹⁹ In advanced gastric carcinoma, the tumor has advanced