Whole Grains and their Bioactives: Composition and Health 9781119129479, 1119129478

Table of contents :
Cover
Whole Grains and their Bioactives:

Composition and Health
© 2019
Contents
List of Contributors
Part I:

Introduction
1 Introduction to
Whole Grains and Human Health
Part II: Whole Grains,
Whole Food Nutrition
2
Wheat
3 Oats
4 Rice
5 Corn
6 Barley
7 Rye
Part III:
Pseudo Cereal Grains, Whole Food Nutrition
8
Amaranth
9 Buckwheat
10 Quinoa
Part IV: Health-Promoting Properties of
Whole Grain Bioactive Compounds
11
Avenanthramides
12 ?-Glucans
13 Phenolic Acids
14 Carotenoids
15 Alkylresorcinols
16 Lignans
17 Phytosterols
18 Phytic Acid and Phytase Enzyme
Index

Citation preview

Whole Grains and their Bioactives

Whole Grains and their Bioactives Composition and Health

Edited by Jodee Johnson Associate Principal Scientist Quaker Oats Center of Excellence R&D Nutrition Senior Scientist at PepsiCo R&D Nutrition Barrington, IL, USA

Taylor C. Wallace Principal & CEO at Think Healthy Group, Inc. Adjunct Professor, Department of Nutrition and Food Studies George Mason University Fairfax, Virginia, USA

This edition first published 2019 © 2019 John Wiley & Sons Ltd All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by law. Advice on how to obtain permission to reuse material from this title is available at http://www.wiley.com/go/permissions. The right of Jodee Johnson and Taylor C. Wallace to be identified as the authors of this editorial material has been asserted in accordance with law. Registered Offices John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, USA John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK Editorial Office The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK For details of our global editorial offices, customer services, and more information about Wiley products visit us at www.wiley.com. Wiley also publishes its books in a variety of electronic formats and by print-on-demand. Some content that appears in standard print versions of this book may not be available in other formats. Limit of Liability/Disclaimer of Warranty While the publisher and authors have used their best efforts in preparing this work, they make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives, written sales materials or promotional statements for this work. The fact that an organization, website, or product is referred to in this work as a citation and/or potential source of further information does not mean that the publisher and authors endorse the information or services the organization, website, or product may provide or recommendations it may make. This work is sold with the understanding that the publisher is not engaged in rendering professional services. The advice and strategies contained herein may not be suitable for your situation. You should consult with a specialist where appropriate. Further, readers should be aware that websites listed in this work may have changed or disappeared between when this work was written and when it is read. Neither the publisher nor authors shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages. Library of Congress Cataloging-in-Publication Data Names: Johnson, Jodee, editor. | Wallace, Taylor C., editor. Title: Whole grains and their bioactives : composition and health / edited by Jodee Johnson, Taylor C. Wallace. Description: First edition. | Hoboken, NJ : Wiley, 2019. | Includes bibliographical references and index. | Identifiers: LCCN 2019003540 (print) | LCCN 2019004883 (ebook) | ISBN 9781119129462 (Adobe PDF) | ISBN 9781119129479 (ePub) | ISBN 9781119129455 (hardcover) Subjects: | MESH: Whole Grains–chemistry | Phytochemicals Classification: LCC QK861 (ebook) | LCC QK861 (print) | NLM WB 431 | DDC 572/.2–dc23 LC record available at https://lccn.loc.gov/2019003540 Cover Design: Wiley Cover Image: © Madlen/Shutterstock Set in 10/12pt WarnockPro by SPi Global, Chennai, India Printed and bound by CPI Group (UK) Ltd, Croydon, CR0 4YY 10 9 8 7 6 5 4 3 2 1

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Contents List of Contributors xv

Part I

Introduction 1

1

Introduction to Whole Grains and Human Health 3 Jodee Johnson and Taylor C. Wallace

1.1 1.2 1.3 1.4 1.5 1.6 1.6.1 1.6.2 1.6.3 1.6.4 1.6.5 1.7

History of Whole Grains 4 Who Consumes Whole Grains? 5 What are Whole Grains? 5 Components of Whole Grains 6 Whole Grain Bioactives 6 Health-Promoting Effects of Whole Grains 7 Body Weight Regulation 8 Gastrointestinal Tract Health 10 Type 2 Diabetes 11 Cardiovascular Diseases 12 Cancer 12 Conclusion 13 References 13

Part II

Whole Grains, Whole Food Nutrition

2

Wheat 21 Daniel D. Gallaher and James A. Anderson

2.1 2.2 2.3 2.4 2.4.1 2.4.1.1 2.4.1.2 2.4.1.3 2.4.1.4

Introduction 21 History of the Grain 21 Types 22 Nutritional Composition 25 Macronutrient Content 25 Protein 25 Digestible Carbohydrate 25 Dietary Fiber 26 Lipids 26

19

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Contents

2.4.1.5 2.4.2 2.4.3 2.5 2.5.1 2.5.2 2.5.2.1 2.5.2.2 2.6

Hulled Wheats 26 Micronutrient Content 27 Potential Bioactive Compounds 28 Health Effects on Chronic Diseases 30 Epidemiological Studies 30 Experimental Studies 31 Animal Studies 31 Clinical Studies 34 Conclusion 35 References 36

3

Oats 45 Yao Tang, Aaron Yerke and Shengmin Sang

3.1 3.1.1 3.1.2 3.1.3 3.1.4 3.2 3.2.1 3.2.2 3.2.3 3.2.4 3.2.5 3.2.6 3.2.7 3.2.8 3.2.9 3.2.10 3.3 3.3.1 3.3.2 3.3.3 3.3.4 3.3.5 3.3.6 3.4

Introduction 45 Origins and Evolutionary History 45 Taxonomy and Strains 45 Economic Importance and Traditional Oat Uses 46 Other Uses for Oats 46 Nutritional Composition 47 Fibers 47 Proteins and Amino Acids 48 Lipids 48 Minerals 50 Carotenoids 50 Vitamins 50 Phenolic Acids 51 Flavonoids 51 Avenanthramides 51 Saponins 51 Health Effects in Chronic Diseases 52 Oats and Cardiovascular Disease 52 Oats and Diabetes 52 Oats and Obesity 53 Oats and Digestive Health 53 Oats and Cancer 53 Oats and Itching 54 Conclusion 55 References 55

4

Rice 63 Nora Jean Nealon and Elizabeth P. Ryan

4.1 4.2 4.3 4.4 4.4.1 4.4.2

Introduction 63 History of Whole Grain Rice 63 Variety in Whole Grain Rice Quality and Preferences 64 Nutritional Composition and Bioactive Compounds in Whole Grain Rice Fiber 67 Lipids 67

64

Contents

4.4.3 4.4.4 4.4.5 4.5 4.5.1 4.5.2 4.6 4.7

Amino Acids 69 Vitamins and Minerals 72 Phytochemicals 76 Whole Grain Rice Consumption and Prevention Against Chronic Disease 77 Obesity, Cardiovascular Disease, and Type 2 Diabetes 77 Cancer 81 Whole Grain Rice Consumption and Protection Against Gut Pathogens 81 Conclusion 82 Acknowledgments 83 References 83

5

Corn 113 Siyuan Sheng, Tong Li and Rui Hai Liu

5.1 5.2 5.3 5.3.1 5.3.1.1 5.3.1.2 5.3.2 5.3.2.1 5.3.2.2 5.3.3 5.3.4 5.3.5 5.4 5.4.1 5.4.2 5.4.3 5.4.4 5.5

Introduction 113 Macro- and Micronutrients in Corn 114 Corn Phytochemicals 114 Phenolics 116 Phenolic Acids 116 Flavonoids 118 Carotenoids 119 Carotenes 119 Xanthophylls 121 Vitamin E 121 Phytosterols 121 Other Bioactive Compounds 124 Health Benefits 124 Cardiovascular Disease 124 Type 2 Diabetes 125 Obesity 126 Digestive Health 127 Conclusion 128 References 128

6

Barley 135 Clarence W. (Walt) Newman, Rosemary K. Newman and Christine E. Fastnaught

6.1 6.2 6.3 6.3.1 6.3.2 6.3.3 6.3.4 6.3.4.1 6.3.4.2 6.3.4.3

Introduction 135 The Beginning 135 The Whole Grain Barley Kernel 137 Anatomy and Structure 137 End-Use Classification 139 Basic Processing 139 Composition 140 Alkylresorcinols 140 β-Glucan and Total Fiber 142 Carotenoids 143

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Contents

6.3.4.4 6.3.4.5 6.3.4.6 6.3.4.7 6.3.4.8 6.3.4.9 6.4 6.4.1 6.4.2 6.4.3 6.4.4 6.4.5 6.4.6 6.4.7 6.5

Folic Acid 144 Lunasin 144 Phenolic Acids, Flavonoids 145 Phytic Acid 146 Phytosterols, Lignans 147 Tocols 147 Health Effects of Bioactive Compounds in Barley on Chronic Diseases 149 Barley β-Glucan Effect on Cardiovascular Diseases 149 Barley β-Glucan Effects on Diabetes and Blood Glucose 150 Barley β-Glucan Effects on Metabolic Syndrome 151 Barley Fiber and Cancer Prevention 152 Tocotrienol Effects on Health 152 Lunasin Effects on Cancer and Cholesterol Control 154 Barley Antioxidants and Human Health 154 Conclusion 156 References 156

7

Rye 169 Laila Meija and Indrikis Krams

7.1 7.2 7.3 7.4 7.5 7.5.1 7.5.2 7.6 7.7 7.8 7.8.1 7.8.2 7.8.3 7.8.4 7.9 7.9.1 7.9.2 7.9.3 7.9.4 7.10 7.11 7.11.1 7.11.2 7.11.3 7.12

Introduction 169 Types 171 Consumption 171 Epidemiological Studies of Rye Intake 171 Rye Products 172 Rye Bread 172 Other Rye Products 175 Nutritional Composition 177 Phytochemicals 178 Rye Fiber 178 Main Components of Rye Fiber 180 Effects of Food Processing 182 Lignans 183 Alkylresorcinols 185 Health Effects on Chronic Diseases 186 Metabolic Syndrome 186 Weight Management 187 Glucose and Insulin Metabolism 189 Blood Lipids and Fatty Acids 190 Gut Health 191 Cancer 192 Colorectal Cancer 193 Prostate Cancer 194 Breast Cancer 196 Conclusion 198 References 198

Contents

Part III

Pseudo Cereal Grains, Whole Food Nutrition

209

8

Amaranth 211 Aída Jimena Velarde-Salcedo, Esaú Bojórquez-Velázquez and Ana Paulina Barba de la Rosa

8.1 8.2 8.3 8.4 8.5 8.6 8.6.1 8.6.2 8.6.3 8.6.4 8.6.5 8.6.5.1 8.7 8.8 8.8.1 8.8.2 8.8.3 8.8.4 8.9 8.9.1 8.9.2 8.9.3 8.9.4 8.9.5 8.9.6 8.9.7 8.10

Introduction 211 History of Amaranth 212 Amaranth Genetic Diversity 213 Amaranth Plant Physiology 215 Amaranth Seed Morphology 216 Amaranth Seed Chemical Composition and Nutritional Properties 217 Minerals and Vitamins 218 Dietary Fiber 218 Carbohydrates 219 Fat, Tocopherols, and Phytosterols 220 Proteins 221 Biological Value of Amaranth Proteins 221 Phytochemical Compounds in Amaranth Seeds 223 Amaranth Seed Storage Proteins 224 Albumins 224 Globulins 224 Prolamins 224 Glutelins 225 Health Effects of Amaranth Grain 226 Amaranth Bioactive Peptides 227 Antihypertensive Properties 233 Hypolipidemic Effects 235 Anticancer Peptides 236 Antioxidant Properties 237 Antidiabetic Effect 238 Effect on the Immune System 239 Conclusion 240 References 240

9

Buckwheat 251 Juan Antonio Giménez Bastida, José Moisés Laparra Llopis and Henryk Zielinski

9.1 9.2 9.3 9.4 9.5 9.5.1 9.5.2 9.5.3 9.5.4 9.5.5 9.5.6

Introduction 251 History of the Grain 251 Nutritional Composition of Buckwheat 253 Metabolism and Bioavailability 254 Health Effects on Chronic Diseases 255 Hypocholesterolemic Activity 255 Anticancer, Antiinflammatory, and Antioxidant Activity 256 Antidiabetic Activity 257 Effects on the Vascular System 257 Neurodegenerative Diseases 258 Celiac Disease 258

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9.6

Conclusion 260 Acknowledgments 260 References 260

10

Quinoa 269 Beenu Tanwar, Ankit Goyal, Syed Irshaan, Vikas Kumar, Manvesh Kumar Sihag, Ami Patel and Intelli Kaur

10.1 10.2 10.3 10.3.1 10.3.2 10.3.3 10.4 10.4.1 10.4.2 10.4.3 10.4.4 10.4.5 10.5 10.5.1 10.5.2 10.5.3 10.5.4 10.5.5 10.5.6 10.5.7 10.6 10.6.1 10.6.2 10.6.3 10.6.4 10.7 10.8 10.9

Introduction 269 History of the Quinoa Grain 270 Types of Quinoa 270 White Quinoa 270 Red Quinoa 271 Black Quinoa 271 Nutritional Composition 271 Protein 271 Fat 273 Carbohydrates 273 Dietary Fiber 277 Vitamins and Minerals 277 Phytochemicals/Bioactives and Antinutritional Factors 277 Phenolic Compounds 278 Saponins 278 Betalains 285 Phytic Acid 285 Alkaloids 285 Trypsin Inhibitor Activity 286 Oxalates 286 Health Benefits 287 Quinoa and Cardiovascular Diseases, Obesity, and Diabetes 287 Quinoa and Anticarcinogenic Activity 292 Quinoa and Menopausal Disorders 292 Quinoa for Celiac Disease 293 Food Applications 294 Future Prospects 294 Conclusion 295 References 295

Part IV Health-Promoting Properties of Whole Grain Bioactive Compounds 307 11

Avenanthramides 309 Tianou Zhang and Li Li Ji

11.1 11.2 11.3 11.4

Introduction 309 Presence in Whole Grains 309 Chemical Structure and Biosynthesis 310 Effects of Processing 311

Contents

11.4.1 11.4.2 11.5 11.5.1 11.5.2 11.5.3 11.6 11.6.1 11.6.2 11.6.3 11.6.4 11.6.5 11.6.6 11.7

Avenanthramide Stability 311 False Malting Process 313 Absorption, Distribution, Metabolism, and Excretion 314 Bioaccessibility 314 Bioavailability 316 Biotransformation 319 Health Benefits 320 Antioxidant Activity 320 Antiinflammatory Activity 321 Antiatherosclerosis Activity 325 Anticancer Activity 328 Antiobesity Activity 329 Antiitch Activity 330 Conclusions and Future Research 330 References 331

12

𝛃-Glucans 339 Susan Tosh and S. Shea Miller

12.1 12.2 12.3 12.4 12.5 12.6

Introduction 339 Presence and Distribution in Whole Grains 340 Chemistry 342 Mechanisms of Action 344 Effects of Processing 348 Conclusion 350 References 351

13

Phenolic Acids 357 C-Y. Oliver Chen, Sérgio M. Costa and Klinsmann Carolo

13.1 13.2 13.3 13.4 13.5 13.6

Introduction 357 Presence of Phenolic Acids in Whole Grain 358 Factors Affecting Phenolic Acid Content in Grains 363 Bioaccessibility and Bioavailability of Grain Phenolic Acids 365 Health Benefits of Grain Phenolic Acids 366 Conclusion 370 References 371

14

Carotenoids 383 Elizabeth J. Johnson

14.1 14.2 14.3 14.3.1 14.3.2 14.3.3 14.3.4 14.4 14.5

Introduction 383 Chemistry 384 Presence in Whole Grains 384 Wheat 384 Rice 386 Corn 386 Barley 386 Dietary Databases 387 Bioavailability 387

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14.6 14.7

Effect of Processing, Storage, and Environment 388 Conclusion 389 References 389

15

Alkylresorcinols 393 Alastair B. Ross

15.1 15.2 15.3 15.4 15.5 15.5.1 15.5.2 15.5.3 15.6 15.7 15.8 15.9 15.9.1 15.9.2 15.9.3 15.10

Introduction 393 Chemistry and Nomenclature 393 Presence of Alkylresorcinols in Cereals 394 Effect of Food Processing on Alkylresorcinols 394 Measuring Alkylresorcinols 396 Spectrophotometric Methods 396 Chromatographic Methods 397 Future Method Development 397 Intake of Alkylresorcinols 397 Bioavailability and Pharmacokinetics of Alkylresorcinols 398 Biological Effects of Alkylresorcinols 398 Mechanisms of Action 399 Are Alkylresorcinols Antioxidants? 399 Enzyme Inhibitors 400 Effect on Gut Microbiota 400 Use of Alkylresorcinols and Their Metabolites as Biomarkers of Whole Grain Intake 400 Conclusion 402 References 402

15.11

16

Lignans 407 Iman Zarei and Elizabeth P. Ryan

16.1 16.2 16.3 16.3.1 16.4 16.5 16.6 16.7 16.8 16.9

Introduction 407 Presence in Whole Grains 408 Chemistry 408 Types of Lignans 410 Metabolism of Lignans by Human Gut Microbiota and Bioavailability 410 Biological Activities 413 Impact of Agronomic Factors on Lignan Content in Foods 414 Effect of Processing 414 Safety 415 Conclusion 415 Acknowledgments 420 References 420

17

Phytosterols 427 Dan Zhu, and Laura Nyström

17.1 17.2 17.2.1 17.2.2

Introduction 427 Chemistry 427 Free Phytosterols 427 Steryl Fatty Acid Esters 430

Contents

17.2.3 17.2.4 17.3 17.3.1 17.3.1.1 17.3.1.2 17.3.1.3 17.3.1.4 17.3.1.5 17.3.2 17.3.2.1 17.3.2.2 17.3.2.3 17.3.3 17.3.3.1 17.3.3.2 17.3.3.3 17.3.4 17.3.4.1 17.3.4.2 17.3.4.3 17.3.4.4 17.3.5 17.3.5.1 17.3.5.2 17.3.5.3 17.4 17.4.1 17.4.2 17.4.3 17.4.4 17.5 17.5.1 17.5.1.1 17.5.1.2 17.5.1.3 17.5.1.4 17.5.2 17.5.2.1 17.5.2.2 17.5.2.3 17.5.3 17.5.3.1 17.5.3.2 17.5.3.3 17.5.4 17.5.5

Steryl Phenolates 431 Steryl Glycosides and Acylated Steryl Glycosides Presence in Whole Grains 431 Total Phytosterols 431 Wheat 433 Barley 433 Rye 433 Oat 434 Other Grains 434 Free Phytosterols 434 Wheat 434 Corn 434 Other Grains 436 Steryl Fatty Acid Esters 436 Wheat 436 Corn 436 Other Grains 438 Steryl Phenolates 438 Steryl Ferulates in Wheat 438 Steryl Ferulates in Rice 440 Steryl Ferulates in Corn 440 Steryl Ferulates in Other Grains 440 Steryl Glycosides and Acylated Steryl Glycosides Wheat 442 Corn 442 Other Grains 442 Bioaccessibility and Bioavailability 442 Free Phytosterols 443 Steryl Fatty Acid Esters 444 Steryl Phenolates 444 Steryl Glycosides and Acylated Steryl Glycosides Mechanisms of Action 446 Cholesterol-Lowering Effect 446 Free Phytosterols 446 Steryl Fatty Acid Esters 447 Steryl Phenolates (Ferulates) 447 Steryl Glycosides and Acylated Steryl Glycosides Cancer Preventive Effect 448 Free Phytosterols 448 Steryl Phenolates (Ferulates) 448 Steryl Glycosides 449 Antiinflammatory Effect 449 Free Phytosterols 449 Steryl Phenolates (Ferulates) 449 Steryl Glycosides 450 Antioxidant Activity 450 Other Properties 451

431

440

445

447

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17.6 17.6.1 17.6.2 17.6.3 17.6.4 17.7

Effect of Processing 451 Mechanical Treatments 451 Thermal Treatments 452 Other Treatments 452 Oxidation of Phytosterols 453 Conclusion 454 References 454

18

Phytic Acid and Phytase Enzyme 467 Vikas Kumar, Amit K. Sinha and Kimia Kajbaf

18.1 18.2 18.3 18.3.1 18.3.2 18.4 18.5 18.5.1 18.5.2 18.5.3 18.5.4 18.6 18.7 18.7.1 18.7.2 18.7.3 18.7.4 18.8

Introduction 467 Food Sources of Phytic Acid 468 Phytase 469 General Description and Mode of Action 469 Generations of Phytases 470 Classification of Phytase 474 Factors Influencing Phytase Bioefficacy 474 Optimal pH/Gastrointestinal pH 475 Phytase Resistance against Digestive Proteases 475 Substrate Specificity 476 Dietary Ingredient Content 476 Source of Phytase 476 Beneficial Health Effects of Phytate 476 Phytate and Diabetes Mellitus 476 Coronary Heart Disease 477 Renal Lithiasis 477 Phytate and Cancer 477 Conclusion 478 References 478 Index 485

xv

List of Contributors James A. Anderson

Christine E. Fastnaught

Department of Agronomy and Plant Genetics University of Minnesota St Paul, MN USA

Phoenix Seed, Inc. Fargo, ND USA

Juan Antonio Giménez Bastida

Department of Clinical Pharmacology Vanderbilt University School of Medicine Nashville, TN USA Esau Bojórquez-Velázquez

Molecular Biology Department Instituto Potosino de Investigación Científica y Tecnológica A.C. San Luis Potosí Mexico Klinsmann Carolo

Antioxidants Research Laboratory Jean Mayer USDA Human Nutrition Research Center on Aging Tufts University Boston, MA USA Sérgio M. Costa

Antioxidants Research Laboratory Jean Mayer USDA Human Nutrition Research Center on Aging Tufts University Boston, MA USA

Daniel D. Gallaher

Department of Food Science and Nutrition University of Minnesota St Paul, MN USA Ankit Goyal

Department of Dairy Technology Mansinhbhai Institute of Dairy and Food Technology Mehsana, Gujarat India Syed Irshaan

Department of Food Process Engineering National Institute of Technology Rourkela, Odisha India Li Li Ji

Laboratory of Physiological Hygiene and Exercise Science (LPHES) School of Kinesiology University of Minnesota-Twin Cities Minneapolis, MN USA

xvi

List of Contributors

Elizabeth J. Johnson

Vikas Kumar

Friedman School of Nutrition and Science Policy Tufts University Boston, MA USA

Department of Animal and Veterinary Science Aquaculture Research Institute University of Idaho Hagerman, ID USA

Jodee Johnson

Quaker Oats Center of Excellence PepsiCo R&D Nutrition Barrington, IL USA Kimia Kajbaf

Department of Animal and Veterinary Science Aquaculture Research Institute University of Idaho Hagerman, ID USA Intelli Kaur

Department of Aquaculture and Fisheries University of Arkansas at Pine Bluff Pine Bluff, AR USA José Moisés Laparra Llopis

Group of Molecular Immunonutrition in Cancer Madrid Institute for Advanced Studies in Food Madrid Spain Tong Li

Department of Food Technology and Nutrition Lovely Professional University Phagwara India

Department of Food Science Cornell University Ithaca, NY USA

Indrikis Krams

Department of Food Science Cornell University Ithaca, NY USA

Institute of Ecology, University of Tartu Tartu Estonia Department of Zoology and Animal Ecology Faculty of Biology University of Latvia Riga Latvia

Rui Hai Liu

Laila Meija

Department of Sports and Nutrition R¯ıga Stradi¸nš University Pauls Stradi¸nš Clinical University Hospital Riga Latvia

Vikas Kumar

Department of Food Technology and Nutrition Lovely Professional University Phagwara India

S. Shea Miller

Ottawa Research and Development Centre Agriculture and Agri-Food Canada Ottawa, ON Canada

List of Contributors

Nora Jean Nealon

Ana Paulina Barba de la Rosa

Graduate Student Department of Environmental and Radiological Health Sciences College of Veterinary Medicine and Biomedical Sciences Colorado State University Fort Collins, CO USA

Molecular Biology Department Instituto Potosino de Investigación Científica y Tecnológica A.C. San Luis Potosí Mexico

Clarence W. (Walt) Newman

Plant & Soil Sciences Department Montana State University Bozeman, MT USA Rosemary K. Newman

Plant & Soil Sciences Department Montana State University Bozeman, MT USA Laura Nyström

Laboratory of Food Biochemistry Institute of Food, Nutrition and Health Zurich Switzerland C-Y. Oliver Chen

Antioxidants Research Laboratory Jean Mayer USDA Human Nutrition Research Center on Aging Tufts University Boston, MA USA Biofortis Research, Merieux NutriSciences Addison, IL USA Ami Patel

Department of Dairy Microbiology Mansinhbhai Institute of Dairy and Food Technology Mehsana, Gujarat India

Alastair B. Ross

Department of Food and Nutrition Science Department of Biology and Biological Engineering Chalmers University of Technology Gothenburg Sweden Elizabeth P. Ryan

Department of Environmental and Radiological Health Sciences College of Veterinary Medicine and Biomedical Sciences Colorado State University Fort Collins, CO USA Shengmin Sang

Center for Excellence in Post-Harvest Technologies North Carolina A&T State University Kannapolis, NC USA Siyuan Sheng

Department of Food Science Cornell University Ithaca, NY USA Manvesh Kumar Sihag

Department of Dairy Chemistry Mansinhbhai Institute of Dairy and Food Technology Mehsana, Gujarat India

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Amit K. Sinha

Aaron Yerke

Department of Aquaculture and Fisheries University of Arkansas at Pine Bluff Pine Bluff, AR USA

Center for Excellence in Post-Harvest Technologies North Carolina A&T State University Kannapolis, NC USA

Yao Tang

Center for Excellence in Post-Harvest Technologies North Carolina A&T State University Kannapolis, NC USA Beenu Tanwar

Department of Dairy Technology Mansinhbhai Institute of Dairy and Food Technology Mehsana, Gujarat India Susan Tosh

School of Nutrition Sciences Associate Dean Faculty of Health Sciences University of Ottawa ON Canada Aída Jimena Velarde-Salcedo

Molecular Biology Department Instituto Potosino de Investigación Científica y Tecnológica A.C. San Luis Potosí Mexico Taylor C. Wallace

Think Healthy Group, Inc. Department of Nutrition and Food Studies George Mason University Washington, DC USA

Iman Zarei

Department of Environmental and Radiological Health Sciences College of Veterinary Medicine and Biomedical Sciences Colorado State University Fort Collins, CO USA Tianou Zhang

Laboratory of Exercise and Sports Nutrition (LESN) Department of Kinesiology, Health and Nutrition The University of Texas at San Antonio San Antonio, TX USA Dan Zhu

Laboratory of Food Biochemistry Institute of Food, Nutrition and Health Zurich Switzerland Henryk Zielinski

Department of Chemistry and Biodynamics of Food Institute of Animal Reproduction and Food Research of the Polish Academy of Sciences Olsztyn Poland

1

Part I Introduction

3

1 Introduction to Whole Grains and Human Health Jodee Johnson 1, 2 and Taylor C. Wallace 3, 4 1

PepsiCo R&D Nutrition, Barrington, Illinois, USA Quaker Oats Center of Excellence 3 Think Healthy Group, Inc. 4 Department of Nutrition and Food Studies, George Mason University, Washington, DC, USA 2

The existing scientific literature base indicates that the consumption of whole grains has a beneficial effect on maintaining human health over the lifespan. However, to date, most of the supporting evidence on disease prevention has been derived from observational studies. For example, in a 1992 study of 31 208 individuals in the Adventist Health Study cohort, Fraser et al. [1] found that there was a 44% reduction in nonfatal coronary heart disease (CHD) and an 11% reduced risk of fatal CHD for participants who consumed 100% whole-wheat bread compared with those who ate white bread. In 1998, the Iowa Women’s Health Study investigators also found an almost one-third reduced risk of CHD death among individuals who consumed ≥1 serving of whole grains each day compared with those who did not consume whole-grain products [2]. In 2005, the US Institute of Medicine (IOM) Food and Nutrition Board published dietary reference intakes for dietary fiber, which were largely based on whole grain studies. An adequate intake for total fiber was set at 38 and 25 g/day for young men and women, respectively, based on the intake level observed to protect against CHD [3]. It is important to expand the number of clinical intervention studies that assess the effect(s) of specific whole grains and whole grain products, as variations in their nutritional composition (e.g., dietary fiber, micronutrient and bioactive contents), effects on glycemic load, and health-promoting properties vary. More recent data build on the existing evidence base and indicate that whole grain consumption is a good indicator of diet quality and nutrient intake [4, 5]. Studies show that consumption of whole grains as part of a balanced diet decreases the incidence of CHD and many other chronic diseases (e.g., including, but not limited to, obesity, type 2 diabetes, and certain types of cancers) and promotes gastrointestinal tract regularity and function [6, 7]. The potential health-promoting effects of whole grains likely stem from synergies exhibited by the large array of essential nutrients, dietary fibers and bioactives present in the food matrix. The wide range of protective components in whole grains and potential mechanisms for protection have also been described in the scientific literature [6, 7]. The 2015–2020 Dietary Guidelines for Americans (DGAs) indicate that the US population’s intake of total grains is close to target amounts; however, intakes do not meet Whole Grains and their Bioactives: Composition and Health, First Edition. Edited by Jodee Johnson and Taylor C. Wallace. © 2019 John Wiley & Sons Ltd. Published 2019 by John Wiley & Sons Ltd.

4

Whole Grains and their Bioactives

recommendations for whole grains and exceed the limits for refined grains [8]. Average intakes of whole grains are far below recommended levels across all age and sex groups. Approximately 60% of whole grain intake in the US is from individual food items, such as breakfast cereals and oats, rather than mixed dishes. The DGAs recommend that consumers shift their diet such that they consume 50% of their grains as whole grains [8]. This recommendation is based on (i) literature demonstrating the contribution of whole grains in helping individuals meet nutrient recommendations and (ii) US Department of Agriculture (USDA) Evidence Analysis Library reports (used by the 2010 Dietary Guidelines Advisory Committee to inform the 2010 DGAs [9]) showing effects of whole grain consumption on both cardiovascular disease (CVD) and type 2 diabetes. The USDA Evidence Analysis Library reports concluded that (i) there is a moderate body of evidence from large prospective cohort studies showing that whole grain intake is associated with an approximately 21% lower risk of CVD and (ii) limited evidence supports an association between whole grain intake and an approximately 26% lower risk of type 2 diabetes [10]. This chapter seeks to review the basics of whole grains, their bioactives, and related potential health-promoting properties.

1.1 History of Whole Grains With the advent of agriculture >10 000 years ago, whole grains became a central part of the human diet [11]. The majority of the world’s population has relied on whole grains as a major component of the diet for at least the last 4000 years. Refined grains were introduced to society within the last 100 years. Prior to the introduction of technologies used to process refined grains, gristmills were used to grind grains and produce limited amounts of flour. Gristmills were inefficient in completely separating the bran and germ from the white endosperm. In 1873, the roller mill was introduced; its widespread use was applied to satisfy increasing consumer demand for refined grain products. Introduction of the roller mill was a significant factor in the sharp decline in whole grain consumption observed from 1873 through the 1970s [11]. Health benefits of whole grains have been postulated since the fourth century, when Hippocrates coined the famous proverb “Let food be thy medicine and thy medicine be food.” In that era, whole cereal grains (particularly barley and wheat) were the principal food throughout the Mediterranean. For thousands of years, humans consumed these foods in whole form (e.g., whole wheat berries), in cracked grains (e.g., bulgur and couscous), and in bread or baked goods. Hippocrates’ healing diet consisted of eating whole grain barley, somewhat softly prepared, at every meal every day for a period of approximately 10 days. This practice became a widespread home remedy in early Western medicine. In the last 200 years, whole grain intake has been traditionally recommended to prevent constipation. The “fiber hypothesis” was first published in 1972, suggesting that large amounts of unrefined plant foods, especially those starchy foods rich in dietary fiber, may offer protection against type 2 diabetes and diseases of the large bowel [12, 13]. The inclusion of whole grains as part of a healthful diet has been a component of the DGAs since the first edition published by the USDA and the Department of Health and Human Services in 1980 [14].

Introduction to Whole Grains and Human Health

1.2 Who Consumes Whole Grains? Current dietary guidelines encourage consumers to increase intakes of both dietary fiber and whole grains. Since 2000, the DGAs have recommended that individuals consume at least 3 oz-equivalents of whole grain daily and that at least half of all total grains consumed should be whole [8]. Data from the 2009–2010 National Health and Nutrition Examination Survey (NHANES) show that whole grain intakes are approximately 0.57 oz-equivalents/day for children and 0.82 oz-equivalents/day for adults. Total dietary fiber intakes in the US are directly associated with whole grain intake [15]. Only about one-third of Americans aged >12 years meet the grain intake recommendation, and only 4% meet the current whole grain intake recommendations. Mean intakes of whole grains fall well below (less than one-third) intake recommendations for all age groups. Despite increased public health messaging and the growing number and availability of whole grain-containing products, data show that there have been no significant changes in whole grain intakes for any age group over the last decade [16]. Major sources of whole grains for the US population include ready-to-eat cereals, yeast bread/rolls, hot cereal, and popcorn [15, 16]. Whole grain intakes are shown to be highest at breakfast (53%) [16, 17], which is likely driven by ready-to-eat cereal intake. Intake at breakfast contributes 44%, 39%, and 53% of the total intakes of whole grains for children/adolescents, adults aged 19–50 years, and adults aged >51 years, respectively [17]. More than 19% of whole grain consumption is obtained through snack foods.

1.3 What are Whole Grains? According to the American Association for Cereal Chemistry International [18], whole grains consist of: intact, ground, cracked, or flaked fruit of the grain whose principal components, the starchy endosperm, germ, and bran, are present in the same relative proportions as they exist in the intact grain. Whole grains can be present as a complete food (e.g., oatmeal or brown rice) or used as an ingredient in food (e.g., whole-wheat flour in bread). What constitutes a whole grain food is yet to be defined, which creates unique challenges for manufacturers, researchers, regulatory agencies, and consumers [19]. Foods that are only partially composed of whole grains can be problematic when assessing population intakes, since relative proportions may be proprietary information to the manufacturer. US Food and Drug Administration (FDA) regulations state that in order for a manufacturer to use the whole grain health claim on a product label, the food must contain at least 51% whole grain ingredients by weight per reference amount customarily consumed (RACC). Whole wheat contains 11 g of dietary fiber/100 g; thus, the qualifying amount of dietary fiber required for a food to bear the prospective claim can be determined by the following formula: 11 g × 51% × RACC/100 [20]. The most common consumed grains include wheat, oats, rice, corn, and rye. Wheat accounts for about 70–75% of grain consumption in the United States.

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Although the term whole grain has been at least somewhat defined, what constitutes a “whole grain food” is less clear; a definition has not yet been developed and adopted for use by the USDA, FDA, Health Canada, or European Commission. In the United States, the USDA estimates a standard grain food serving size to be 1 oz-equivalent, whereas the FDA estimates this value to be approximately 30 g [21]. Experts agree that a specific definition for whole grain foods that incorporates a specific amount of whole grains per 30 g serving is needed [19]. Types of whole grains include whole wheat, whole oats/oatmeal, whole grain cornmeal, popcorn, brown rice, whole rye, whole grain barley, wild rice, buckwheat, triticale, bulgur (cracked wheat), millet, quinoa, and sorghum. Other less common whole grains include amaranth, emmer, farro, grano (lightly pearled wheat), spelt, and wheat berries.

1.4 Components of Whole Grains All grains have a bark-like protective hull, which encases the germ, endosperm, and bran. The germ contains the plant embryo. The endosperm, composed of approximately 50–75% starch, is the largest component of the whole grain and is the major energy supply for the embryo during germination. Surrounding the germ and endosperm is a protective covering known as the bran, which provides a barrier to damage from sunlight, pests, water, and so forth. Most micronutrients (i.e., vitamins and minerals) are located in the germ and bran; the endosperm contains very few micronutrients. The germ is relatively small and accounts for only approximately 4–5% of the dry weight of most grains such as wheat, oats, and barley. By contrast, the germ in corn contributes a much higher proportion. Whole grains are typically high in B vitamins (thiamin, niacin, riboflavin, and pantothenic acid), minerals (calcium, magnesium, potassium, phosphorus, sodium, and iron), and dietary fibers. Dietary bioactives are also largely located in the bran and germ. Whole grains provide unique and efficacious profiles of dietary bioactive compounds (e.g., avenanthramides in oats) that have been suggested to influence human health beyond basic nutrition. In most developed countries, whole grains are subjected to processing, which in turn can affect the composition, stability, bioavailability, and health-promoting properties of the bioactives present in any given food matrix. Refined grains are defined as grains that have been milled, a process that removes the bran and germ. Milling gives grains a finer texture and improves their shelf-life but it also removes most of their dietary fiber, iron, and many B vitamins. Examples of refined grain products include white flour, “degermed” corn meal, white bread, and white rice. As much as 75% of the dietary bioactives found in whole grains are lost during the refining process. Compared with refined grains, most whole grains provide higher amounts of protein, dietary fiber, and more than a dozen vitamins and minerals. Since the early 1940s, US regulations have mandated that refined flour must be enriched with some B vitamins (thiamin, riboflavin, and niacin) and iron [22]. In 1996, the FDA mandated that enriched grain products be fortified with folic acid to help women of childbearing age reduce the risk of neural tube defects during pregnancy [23].

1.5 Whole Grain Bioactives Many studies suggest that the health-promoting effects of whole grains extend beyond their dietary fiber content, with studies showing that even after controlling for fiber

Introduction to Whole Grains and Human Health

intake, the beneficial effects of whole grains and heart disease remain, at least to some extent. Although the dietary fiber and other essential nutrients present in whole grains likely account for a significant portion of the postulated health effects, dietary bioactives most certainly play a synergistic role in health maintenance and disease prevention. The National Institutes of Health Office of Dietary Supplements [24] defined dietary bioactives as “compounds that are constituents in foods and dietary supplements, other than those needed to meet basic human nutritional needs, which are responsible for changes in health status.” Most of the health-promoting dietary bioactives present in whole grains are found in the germ and bran fraction of the grain kernel and include, but are not limited to, phenolic compounds, phytosterols, tocols, dietary fibers (mainly β-glucans), lignans, alkylresorcinols, phytic acid, γ-oryzanols, avenanthramides, cinnamic acid, ferulic acid, inositols, and betaine. Although much research has focused on individual components of whole grains (e.g., specific dietary bioactives or fiber), epidemiological evidence suggests that the whole grain food offers the greatest protection against chronic disease compared to its individual components alone. Some dietary bioactives are specific to certain cereal grains, such as γ-oryzanol in rice, β-glucans in oats and barley, avenanthramides and saponins in oats, and alkylresorcinol in rye, although these compounds are also present in relatively lower amounts in other cereals such as wheat.

1.6 Health-Promoting Effects of Whole Grains Although evidence continues to emerge, observational studies consistently suggest that the consumption of 2–3 servings of whole grains daily is associated with beneficial health effects (primarily a reduced risk of CVD and type 2 diabetes). Under the provisions of the FDA Modernization Act 1997, a manufacturer may submit to the FDA a notification of a health claim based on an authoritative statement from an appropriate federal agency or the National Academy of Sciences (NAS) [20]. On March 10, 1999, General Mills Inc. submitted to the US FDA a notification containing a prospective claim about the relationship between whole grain foods and heart disease and certain cancers. The notification cited the following from the Executive Summary of the NAS report, Diet and Health: Implications for Reducing Chronic Disease Risk, as an authoritative statement: Diets high in plant foods – i.e., fruits, vegetables, legumes, and whole grain cereals – are associated with a lower occurrence of CHD and cancers of the lung, colon, esophagus, and stomach. [21, p. 8] Whole grains are rich sources of vitamins, minerals, dietary fiber, lignins, β-glucans, inulin, numerous phytochemicals, phytosterols, phytin, and sphingolipids [25–28]. Most bioactives in whole grains are derived from their unique bran and germ structure [25]. Current scientific research indicates that the different types of dietary bioactives present in whole grains (and other plant foods) work synergistically to promote health [26]. Plants synthesize many dietary bioactive compounds in response to environmental factors including, but not limited to, ultraviolet light, frost hardiness, and pathogens [29]. Once consumed, bioactives may retain their protective character and work as antioxidants or antiinflammatory agents in vivo [26]. The dietary bioactives responsible for health benefits associated with whole grains may also complement those contained in fruits and vegetables when consumed together [25–28].

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Although the totality of research suggests effects of whole grain bioactives on numerous chronic health outcomes, it is important to note that research on the efficacy and biological potential of many whole grain bioactives is limited to small short-term clinical trials and to population studies, which cannot be used to determine causality. Additional long-term clinical research is needed to confirm the effects of whole grain bioactives on established biological mechanisms and on both surrogate and clinical endpoints of chronic disease. Examples of dietary bioactives found in whole grains and their postulated physiological benefits are described below and summarized in Table 1.1.

1.6.1

Body Weight Regulation

Although whole grains contain similar energy (i.e., kilocalories) to refined grains, there is significant scientific evidence that consumption of whole grains may lead to reduced body fat and weight. Data from observational studies consistently indicate that consuming approximately three servings of whole grains per day is associated with a lower body mass index (BMI), smaller waist circumference, smaller waist-to-hip ratio, and lower abdominal, subcutaneous, and visceral adipose tissue volume [31, 32]. Prospective cohort studies also suggest that weight gain and increases in abdominal obesity are lower among individuals who consume higher amounts of whole grains [33, 34]. Data from the 1999–2004 NHANES (n = 13 276) suggest an association between consuming whole grains and having lower body weight, BMI, and waist circumference across all age groups [35]. A 2012 systematic review of randomized controlled trials (RCTs) and prospective cohort studies showed that individuals who consumed whole grains (compared to nonconsumers) often experienced less weight gain over 8–12 years of follow-up [32]. Consistent with this, a 2013 systematic review of small RCTs showed that consuming whole grains may decrease body fat percentage, waist circumference, and BMI [36]. Emerging evidence from clinical studies indicates that whole grain consumption may alter body fat distribution, independent of changes in weight, although the mechanism of action is yet to be identified [31]. Proceedings of a American Society for Nutrition-sponsored symposium on health benefits associated with whole grains noted that 14 human intervention studies showed that consuming higher amounts of whole grains was associated with lower BMI, three studies showed that consuming whole grains was associated with smaller waist circumference, and one study found that consuming whole grains was associated with lower abdominal fat in a dose-dependent manner [37]. Whole grains are also a major source of dietary fiber in the US diet. The IOM recommends that all individuals aged 3)(1-> 4)-bD-glucan from oats (Avena sativa L.). Cereal Chem. 72 (4): 335–340.

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34 Wang, Q. and Ellis, P.R. (2014). Oat 𝛽-glucan: physico-chemical characteristics in

35 36 37 38

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upregulation of ceramide synthesis induced by an oat lipid extract via the activation of PPAR pathways. Exp. Dermatol. 24 (4): 290–295. 107 FAO. Dietary protein quality evaluation in human nutrition. FAO Food and Nutrition Paper 92 (2011). Available at: www.fao.org/ag/humannutrition/3597802317b979a686a57aa4593304ffc17f06.pdf

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4 Rice Nora Jean Nealon 1,2 and Elizabeth P. Ryan 1,2 1 Department of Environmental and Radiological Health Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA 2 Colorado State University, Fort Collins, CO, USA

4.1 Introduction Domesticated rice (Oryza sativa) is a major staple crop in human food systems and is grown in over 114 countries [1]. Whole grain or “brown” rice, which consists of the germ, endosperm, and bran, is becoming increasingly recognized for its human health benefits even though most of the world consumes polished white rice. A growing body of research associates whole grain rice consumption with prevention of major chronic diseases including obesity, cardiovascular disease, type 2 diabetes, and colorectal cancer [2–5]. In the face of multidrug-resistant bacteria and ineffective vaccines, emerging evidence also suggests that the rice bran fraction of whole grain rice bolsters the host immune system, increases the growth of health-promoting intestinal bacteria, and contains antimicrobial compounds that work collectively to fight gut pathogens, including human rotavirus, human norovirus, and Salmonella enterica serovar typhimurium [6–9].

4.2 History of Whole Grain Rice Historically, since its domestication around 1000–14 000 years ago, rice was processed locally and crushed manually, so that it retained an appreciable amount of the bran layer [10]. However, technological advances in rice production and postharvest processing have led to the removal of bran, and these processes have been implicated in the increased global consumption of bran-free “white rice” [10]. The water-powered mills used in the late eighteenth century [11] have evolved into high-efficiency commercial milling systems that rapidly dehusk, polish (remove bran), and package rice to meet large-scale consumer demands [12]. Ultimately, white rice production causes an estimated 29.3 million tonnes of rice bran to be either discarded or used as animal feed each year [1]. Despite the numerous health benefits associated with brown rice consumption, consumers across many countries continue to prefer white rice [10, 13]. The reasons for Whole Grains and their Bioactives: Composition and Health, First Edition. Edited by Jodee Johnson and Taylor C. Wallace. © 2019 John Wiley & Sons Ltd. Published 2019 by John Wiley & Sons Ltd.

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this preference are multifactorial and include socioeconomic factors such as the cost of whole grain rice and the cultural perceptions of brown rice as a byproduct or animal feed [14]. Further, cooked white rice has a longer shelf-life and is considered to have improved taste and texture when compared to brown rice [10]. Consequently, whole grain rice remains underutilized, despite being a highly nutritious food. Increased consumption of whole grain rice will require acceptance by developing and developed countries alike to achieve the goal of improved health across the lifespan [10].

4.3 Variety in Whole Grain Rice Quality and Preferences The International Rice Gene Bank has recognized over 40 000 genetic varieties of Oryza sativa [15]. There are three genetically distinct varietal groups within O. sativa referred to as japonica, indica, and aus, that give rise to many of the rice varieties grown and consumed globally [16, 17]. Japonica varieties grow in subtropical and temperate climates [18], indica rice is grown in regions with tropical and subtropical climates, and aus is known for its drought tolerance and ability to grow in harsh climates [18, 19]. Whole grain rice from these varietal groups can be classified by grain size (short, medium or long), texture (sticky versus nonsticky), and aroma when cooked (aromatic and nonaromatic) [20]. Rice varieties are further classified by bran color which can vary greatly from shades of brown to pigmented purple, black, and red hues due in part to differences in phenolic compounds, which enhance the antioxidative, antimicrobial, and immune-boosting functions of whole grain rice [21–25]. Table 4.1 describes features for the major varieties of whole grain rice consumed globally. Long grain rice varieties have a long, slender appearance and are generally light and fluffy and do not stick together when cooked [20]. Medium and short grain rice varieties tend to retain more moisture when cooked, resulting in a sticky texture [20]. Some whole grain rice varieties, including the Indian-derived Basmati, Wehani, Himalayan rice, and Thai purple rice, have a distinct aroma and taste when cooked. The nutty flavors of Basmati, Wehani, and Himalayan and sweeter tastes of Thai purple rice are used in savory and dessert dishes respectively [20]. Collectively, whole grain rice qualities can influence their palatability and utility in human diets [28].

4.4 Nutritional Composition and Bioactive Compounds in Whole Grain Rice Whole grain rice consists of the bran, germ, and endosperm and contains a wide array of nutrients important to human health. The whole grain rice parts and types are displayed in Figure 4.1. Although whole grain rice has been reported to contain less total protein and fiber compared to other whole grains [29], it contains a unique combination of bioactive fibers, fats, amino acids/peptides (proteins), vitamins, and phytochemicals that have many established roles in human health promotion. The bran component of whole grain rice is the major fraction contributing to the overall nutritive value of the whole grain [30, 31]. Metabolomics, a field that involves the identification and analysis of many small compounds, has been used to analyze the large suites of components that make up whole

Table 4.1 Representative whole grain rice varieties and selected quality features. Whole grain rice varietiesa Long grain

Medium grain Short grain

Sweet

Wehani

Himalayan Colusari

Thai

Chinese

References

Long, slender

Long

Long, slender

Short, wide

[20, 26]

Short, wide

Texture

Light and fluffy

Moist, tender, Soft, sticky sticky

Aroma/ Flavor

Non-aromatic Non-aromatic Non-aromatic Non-aromatic Nutty

Nutty, “popcorn” aroma

Nutty

NonSweet aromatic

Non[20, 26] aromatic

Bran color

Brown

Brown

Red

Red/ Purple Burgundy

Black/ Deep purple

a)

Brown

Plump, round Plump, short Long

Basmati

Morphology Long, slender

Brown

Sticky

Light brown

Light and Light and fluffy fluffy

Red

Short, wide

Light and Moist, fluffy tender, sticky

Light and Moist, fluffy tender, sticky

Whole grain varieties were defined by the Whole Grain Council and include popular rice varieties consumed in their whole grain form.

[20, 26]

[20, 21, 27]

66

Whole Grains and their Bioactives

Whole Grain, “Brown” Rice Bran + Germ + Endosperm

Long Grain Varieties

Short Grain Varieties

Medium Grain Varieties

Milling to remove bran

Wide diversity in rice bran colors

Rice bran contains the majority of the fats, proteins, fibers, vitamins, and other phytochemicals in whole grain rice.

Figure 4.1 Whole grain rice processing. The whole grain brown rice contains the bran, germ, and endosperm and is commonly classified by grain length (short-, medium-, and long-grain rice). Quality traits influence culinary and palatability preferences for whole grain rice. The milling practices of whole grain rice yield rice bran, which naturally exists in a variety of colors.

grain rice and its rice bran fraction [2, 32–34]. Metabolomics utilizes different instrument platforms including, but not limited to, liquid and gas chromatography coupled with mass spectrometry, nuclear magnetic resonance spectroscopy, and Fourier transform infrared spectroscopy, and has identified multiple bioactive compounds spanning many chemical classes [2, 15, 21, 32–38]. Individual bioactive compounds in whole grain rice fall under the broader classifications of fibers, lipids (fats), amino acids, peptides, and phytochemicals, all of which can be integrated into networks of metabolic subpathways, such as fatty acids, branched chain amino acids, and phenolic compounds. Collectively and individually, whole grain rice compounds have demonstrated multiple roles for bolstering immunity, protecting the gastrointestinal tract, suppressing the growth of microbial pathogens, and protecting against chronic diseases [2–10]. Tables 4.2, 4.3 and 4.4 highlight these rice bran health-promoting compounds that have been reported in the literature. The methods used to prepare whole grain rice for consumption further influence its nutritive value and include parboiling, fermenting, soaking, steaming, roasting, baking, extrusion, and germination [39]. Of growing interest for nutrition is germinated

Rice

rice, whereby rice is soaked in water and sprouted [40]. This process increases the bioavailability of vitamins, minerals, dietary fiber, amino acids, and many chronic disease-protective compounds including ferulic acid, γ-oryzanol, and γ-amino butyric acid [40]. 4.4.1

Fiber

Cooked whole grain rice contains approximately 3.2 g/cup of fiber (soluble and insoluble), primarily located in the bran and the husk [3, 41, 42]. Digestible (soluble) fibers in whole grain rice are polymers containing many β-glucan moieties [43, 44]. Nondigestible (insoluble) fibers, the majority of which are arabinoxylan polymers, serve as the primary constituents of the plant cell wall [45], and help deliver bioactive compounds to the gut. Whole grain rice nondigestible fibers function as prebiotics, nutrient sources that promote the growth of gut native health-promoting probiotic intestinal flora including Lactobacillus spp., Bifidobacterium spp., and Ruminococcus spp., and enhance the metabolism of the established human probiotic supplement Saccharomyces boulardii [33, 37, 38, 46]. A growing area of research involves identifying how the small molecule composition of whole grain rice changes during fermentation with probiotics [37, 47]. Probiotics produce bioactive compounds from fiber fermentation in two major ways: as direct products of fiber decomposition or by indirectly breaking down the structural matrix of the whole grain rice to release small compounds spanning multiple chemical classes [37, 48]. In support of the concept that probiotic fermentation modulates rice bran bioactivity is an in vitro investigation by Ryan et al. which observed that S. boulardii-fermented rice bran contained higher amounts of galactose and d-fructose and lower amounts of free amino acids, lipids, vitamins, and phytochemicals when compared to nonfermented rice bran [47]. Compounds that were only identified in the fermented rice bran included palmitic acid, a novel disaccharide, and glucitol that varied in abundance across varieties. Furthermore, these fermented bran varieties differentially reduced the growth of neoplastic human B cells and exhibited enhanced cancer suppression when compared to their unfermented forms [47], suggesting that probiotics enhance the health-promoting functions of whole grain rice, and potentially do so by changing the abundance of small compounds in a variety-dependent manner. Supporting this concept are other in vitro and human clinical studies demonstrated that phenolic compounds bound to whole grain rice fibers, including phenolic acid and p-coumaric acid, exhibited antioxidative, immunomodulatory, antiviral and anticarcinogenic properties when applied to cells or following consumption of whole grain rice [49–52], suggesting that fermentation alters the structural matrix of whole grain to release health-promoting compounds [53]. Collectively, understanding the functions of probiotics in modulating bioactive compounds in rice bran remains an active area of research. 4.4.2

Lipids

There is approximately 1.96 g of lipid/cup of cooked whole grain rice, primarily in the bran and endosperm [41, 54, 55], and it is known for its distinct lipid composition compared to other cereal grains such as corn, wheat, and oat [38]. For example, rice bran oil is used globally in a variety of cooked dishes and is distinguished from other plant oils by its high total content of the fat-soluble vitamin E and plant sterol content [56]. Table 4.2

67

Table 4.2 Lipids identified in whole grain rice with selected spectra of bioactivity. Metabolite namea)

Antimi- Antidicrobialb) arrheal

Gut barrier protective

Immunomodulatory

Neuroendocrine activity

Antioxidative

Chemopreventive

Cardiovascular protective

References

Short, Medium, Long Chain FAc) Azelate

[57–60]

Laurate

[61–66]

Linoleate

[67–69]

Oleate/vaccenate

[67, 70–75]

Palmitate

[74, 76, 77]

Palmitoleate

[78, 79]

Stearate

[74, 80]

Heptanedioate (pimelate)

[81]

Maleate

[82]

Malonate

[83]

Linoleoyl ethanolamide

[84]

Palmitoyl ethanolamide

[85]

1-Linoleoylglycerol

[86]

2-Linoleoyl glycerol

[87, 88]

2-Oleoylglycerol

[89]

2-Palmitoylglycerol

[90–92]

3-Hydroxyoctanoate

[93, 94]

Glycerol

[95, 96]

12,13-Dihydroxyoctadecenoic acid (DiHOME)

[97]

13 + 9 Hydroxy-octadecadienoate

[98–100]

Pinitol

[101–106]

β-Sitosterol

[107–111]

DCAd)

ENCe)

Monoacyl-glycerol

Misc. Lipid

a) Selected bioactivities of compounds are notated with a rice grain image. Metabolites were distributed across multiple components of the rice plant including the germ, endosperm, and bran. b) Refers to compounds possessing antibacterial, antiviral, and/or antifungal properties. c) FA, fatty acid. d) DCA, dicarboxylic acid. e) ENC, endocannabinoid.

Rice

lists many lipid components that have been identified in whole grain rice through the efforts of multiple in vitro and human clinical studies and organizes them by reported health-promoting properties. Whole grain rice contains many types of lipids (the most common of which are known as fatty acids and sterols) including short-, medium-, and long-chain fatty acids, endocannabinoids, monoacylglycerols, and sterols. Some of the short- and long-chain fatty acids found naturally within rice bran include maleate, laurate, oleate, and palmitoleate, which collectively have established broad-spectrum bacteriostatic and bactericidal activity against Escherichia coli and Salmonella spp. [61, 67, 78, 82], highlighting the potential prophylactic capacity of whole grain rice against enteric pathogens. There are many other rice lipids that have been shown to possess immunomodulatory and/or neuromodulatory activities. One is 2-linoleoylglycerol, which is metabolized by the host into secondary metabolites that bind to neuroactive endocannabinoid receptors that systemically influence inflammation via lipoxygenase and cyclooxygenase regulation [87, 88]. Another is 2-palmitoylglycerol which modulates intestinal cannabinoid-1 receptor expression to impact gut motility [90–92]. Further, β-sitosterol binds to intestinal muscarinic and histaminergic receptors to exert antidiarrheal and immune-modulatory functions along the gastrointestinal tract [107]. β-Sitosterol has additional antioxidative, chemopreventive, and cardiovascular protective functions, as it prevents lipid peroxidation, reduces the growth of neoplastic cells, and functions as an antihyperlipidemic agent [107–111]. Through their collective actions on the gut, immune, cardiovascular and nervous system, lipids found in whole grain rice have broad-acting bioactivity with the potential to simultaneously influence intestinal and systemic health. 4.4.3

Amino Acids

While the bioactivity of whole grain rice fibers and fatty acids is well established, the protein content of rice is often underappreciated for its beneficial contributions to the overall diet [1, 41, 112, 113]. Cooked whole grain rice, primarily in its bran, contains around 5.3 g/cup protein by mass [41]. When whole grain rice proteins are digested, their amino acid building blocks can play multiple roles in human health promotion. Table 4.3 lists bioactive amino acids that were identified in whole grain rice including those within the arginine, glutamine, glutamate, histidine, tryptophan, sulfur-containing amino acid, branched chain amino acid, and peptide metabolism pathways. A recent investigation of the rice bran metabolome conducted by Zarei et al. concluded that ∼34% of the identified compounds were composed of amino acids that spanned arginine, branched chain, sulfur-containing, glutamate, tryptophan, histidine, tyrosine, and taurine classes, and 29 of these compounds were found to have a broad spectrum of reported bioactivities acting multisystemically [2]. A major way by which amino acids from whole grain rice exert functional bioactivity is via the neuroendocrine axis. An emerging area of research investigates how these dietary components influence the “gut–brain axis” and influence signaling between the neuroendocrine, gastrointestinal, immune, and central nervous systems [221]. Of particular interest here is γ-aminobutyric acid (GABA), of which 8.8–10.1 mg/100 g is naturally found in whole grain rice and which acts on enteric nerves to influence fluid balance, motility, and mucosal immunity [146, 222]. In turn, all these

69

Table 4.3 Amino acids identified in whole grain rice with selected spectra of bioactivity.

Metabolitea)

Gut NeuroeCardiobarrier ndocrine ImmunoAntio- Chemovascular Antimicrobialb) Antidiarrheal protective modulation modulatory xidant preventive protective References

Arginine Agmatine

[114–119]

Arginine

[120–124]

Citrulline

[125–129]

Ornithine

[130–132]

4-Guanidino butanoate

[133, 134]

Glutamate and Glutamine Glutamate

[135–139]

Glutamine

[140–145]

γ-Aminobutyrate

[146, 147]

Carboxyethyl-γaminobutyrate

[148, 149]

5-Oxoproline

[150]

Sulfur Amino Acid Cystathionine

[151]

Cysteine

[152–154]

S-Adenosylhomocysteine

[155, 156]

Taurine

[157–160]

Glutathione

[161–165]

Methionine sulfone

[166]

Histidine

[167–170]

N-acetylhistidine

[171]

Trans-urocanate

[172]

Histidine

Tryptophan Indoleacetate

[173, 174]

Indole-3-carboxylic acid

[175–179]

N-acetyltryptophan

[180, 181]

Picolinic acid

[182, 183]

Serotonin

[184–186]

N-acetylserotonin

[187–191]

BC-AAc) N-acetylleucine

[192, 193]

Norvaline

[194–196]

Tyrosine N-acetyl-L-tyrosine

[197, 198]

N-methyltyrosine

[199]

3-(4-Hydroxyphenyl) lactate

[200, 201]

Proline Proline

[202, 203]

Trans-4- hydroxy proline

[204]

Misc. AAd) N-acetylserine

[205]

Betaine

[206–208]

Alanine

[209, 210]

Glycine

[211]

Peptide

a)

γ-Glutamylvaline

[212]

Spermidine

[213–217]

Carnitine

[218–220]

Selected bioactivities of compounds are notated with a rice grain image. Metabolites were distributed across multiple components of the rice plant including the germ, endosperm, and bran. b) Refers to compounds possessing antibacterial, antiviral, antiparasitic, and/or antifungal properties. c) BC-AA, branched chain amino acid. d) Misc. AA = miscellaneous amino acid.

72

Whole Grains and their Bioactives

mechanisms may help reduce diarrhea, influence digestion, and provide protection against infectious agents [33]. Ongoing research indicates that germinating brown rice before consumption, defined as sprouting the rice grain into a seedling [223], increases GABA concentrations and improves palatability [224]. One rodent study observed that consumption of germinated brown rice components, particularly the GABA-rich fractions, favorably modulated glucose and insulin metabolism in a manner protective against type 2 diabetes [225]. Ongoing research on whole grain rice bioactive amino acids should continue to focus on their neuroactive functions at the level of the enteric nervous system and for systemic health promotion, and work to understand how cooking changes the abundance or bioavailability of different bioactive components. In addition to neuromodulatory functions, whole grain rice amino acids exhibit a wide array of antidiarrheal, antioxidant, and chemopreventive activities (see Table 4.3). For example peptide, polyamines, including spermine found naturally in whole grain rice, were found to work at the gut mucosal surface to influence luminal osmolality, which could potentially protect the host against osmotic and secretory diarrheal episodes [33]. Additionally, many aromatic amino acids, including the arginine derivative agmatine and the tryptophan derivative indolacetate, reduce the growth of colorectal cancer polyps and epithelial carcinomas respectively [114, 173], suggesting potential chemotherapeutic functions of rice bran components. Given that compared to healthy cells of the same tissue type, neoplastic cells have multiple, simultaneous alterations to amino acid metabolism [226], dietary-derived modulations to amino acid availability, such as those that occur through consumption of whole grain rice, may consequently influence cancer cell viability and growth potential [226]. In support of this are the many other amino acids identified in whole grain rice that have chemopreventive properties as described in Table 4.3. 4.4.4

Vitamins and Minerals

Vitamins (Table 4.4) and minerals from whole grain rice are another important class of bioactive components. Per cup, whole grain rice contains approximately 5.92 g of vitamin B and 0.34 g of vitamin E (in the form of α-tocopherol), and these vitamins are primarily found in the bran layer [41, 457]. The multiple water-soluble vitamins, including vitamins B3 (nicotinamide) and B6 (pyridoxine), act systemically to alter metabolism, modulate inflammation, improve levels of circulating blood lipids, lower blood pressure, alter neurological function, and reduce the risk of colorectal cancer [253–257, 267–270]. Various isoforms of the fat-soluble vitamin E, including α-tocopherol acetate, α-tocotrienol, β-tocopherol, δ-tocopherol, δ-tocopherol, γ-tocopherol and γ-tocotrienol, have been identified in the bran component of whole grain rice and add to its antioxidant activity by preventing lipid peroxidation and scavenging free radicals [227, 228, 233, 237, 240, 242]. A study by Forster et al. further established that the tocopherol and tocotrienol profile varies across different cultivars of rice, emphasizing the need to consider whole grain varietal differences in bioactive vitamin compounds [21]. Improving vitamin A content in whole grain rice remains a growing area of research. Although whole grain rice is naturally low in vitamin A, committed bioengineering efforts have created “golden rice,” which contains about 35 μg/g β-carotene [458]. Preliminary human clinical research in American adults demonstrated that five weeks of

Table 4.4 Vitamins/Cofactors and phytochemicals identified in whole grain rice with selected spectra of bioactivity.

Metabolitea

Neuroe Cardio Gut barrier Immuno ndocrine Antio Chemo vascular Antimicrobialb Antidiarrheal protective modulatory activity xidant preventive protective References

Vitamin E α-Tocopherol

[227–232]

α-Tocopherol acetate

[231, 233, 234]

α-Tocotrienol

[227, 235, 236]

β-Tocopherol

[237, 238]

δ-Tocopherol

[229, 236, 237, 239]

γ-Tocopherol

[229, 240, 241]

γ-Tocotrienol

[242–245]

Thiamine (B1)

[246–248]

Riboflavin (B2)

[249–252]

Nicotinamide (B3)

[253–259]

Nicotinate

[260–266]

Pyridoxine (B6)

[267–273]

Cobalamin (B12)

[274–277]

Pantothenic acid (B5)

[278–280]

Vitamin B

Other Vitamins/Cofactors Biotin

[281, 282]

Trigonelline

[283–285]

Threonic acid

[286–288]

Glucarate

[289, 290]

Choline

[291–293]

Folic acid

[294, 295]

Phytic acid

[296–300] (Continued)

Table 4.4 (Continued)

Metabolitea

Antimicrobialb

Antidiarrheal

Gut barrier protective

Immuno modulatory

Neuroe ndocrine activity

Antio xidant

Chemo preventive

Cardio vascular protective

References

Phenolics 4-Hydroxybenzoate

[301–303]

Apigenin

[304–309]

Astragalin

[310–315]

Benzoate

[316–319]

Caffeate

[320–323]

Chlorogenic acid

[320, 324–326]

Chrysoeriol

[327–332]

Hydroxycinnamic acid

[333, 334]

Phenyllactic acid

[335, 336]

Cinnamate

[337–340]

4-Hydrxoycinnamic acid

[341]

Ferulate

[342–347]

Indolin-2-one

[348]

Luteolin

[349–355]

Salicylate

[356–360]

Gentisate

[361–364]

Sinapic acid

[365–369]

Tartaric acid

[83, 370, 371]

Vanillate

[372–376]

Vanillin

[372, 377–380]

Catechins

[381–385]

Gallate

[386–392]

Cyanidin glucoside

[393–396]

Cyanidin rutinoside

[397–399]

Epicatechin

[400–405]

Eriodictyol

[406–408]

Hesperetin

[409, 410]

Isorhamnetin

[411–414]

Peonidin glucoside

[415–417]

Cycloartenol ferulate

[418, 419]

Protocatechuic acid

[420–422]

Malvidin

[423, 424]

Quercetin

[425–428]

α-Amyrin

[429–431]

Sitostanol

[432, 433]

Piperidine

[434–436]

Abscisate

[437–440]

Ergothioneine

[441, 442]

Quinate

[443–445]

Syringic acid

[446–450]

Acylated steryl glycoside

[451, 452]

Policosanol

[453, 454]

Tricin

[38, 455, 456]

PSc

Misc.

a)

Selected bioactivities of compounds are notated with a rice grain image. Metabolites were distributed across multiple components of the rice plant including the germ, endosperm, and bran. b) Refers to compounds possessing antibacterial, antiviral, and/or antifungal properties. c) PS, phytosterol.

76

Whole Grains and their Bioactives

consumption of 65–98 g/day of golden rice led to levels of blood retinol (the active form of vitamin A) supportive of healthy recommended daily intake values [458], suggesting that it could potentially be applied to global populations to address vitamin A deficiencies. Golden rice represents an instance where the whole grain rice genome was manipulated to enhance its human nutritional benefits, and supports that this technology could be applied to improve levels of other vitamins, minerals, and/or macronutrients in rice. However, when considering vitamin content in rice, it should be emphasized that processing whole grain rice to “white” rice reduces the amounts of some vitamins [13, 39], and consuming rice as a whole grain is necessary to derive these stated health benefits. Mineral content of whole grain rice has shown a range in the levels of calcium, sodium, potassium, magnesium, iron, and zinc [459], which are essential parts of human diets and function multisystemically to affect many aspects of health, including bone and cell membrane structure and function, fluid balance, metabolism, oxygen transport, and antioxidative processes [459–464]. Whole grain rice varietal differences in these micronutrients are thus an active area of investigation [459, 465]. Alongside beneficial micronutrients, there are emerging concerns that whole grain rice contains heavy metal cofactors including arsenic, mercury, cadmium, and lead [466, 467] that may negatively affect human health by interfering with uptake of other essential micronutrients such as zinc, facilitating neurological dysfunction in adults and in utero, impairing immune function, or possibly enhancing cancer risk [468–471]. However, before more extensive claims can be made, additional research is needed to distinguish the genetic versus agricultural contributions to rice heavy metal content, and how these different factors ultimately influence the bioavailability of these components to humans and animals. 4.4.5

Phytochemicals

Phytochemicals, compounds produced uniquely by plants as a result of normal metabolism, are also found in whole grain rice (see Table 4.4). Phytochemical classes span phenolic compounds, phytosterols and miscellaneous secondary metabolites including hormones, organic acids, and bioactive amines. Phytochemicals protect plants against oxidative damage and pathogenic infections [472, 473], suggesting that they have a broad range of bioactivity, and consequently the roles for many of these compounds in human health are still being evaluated. Many phytochemicals in whole grain rice, including 4-hydroxybenzoate, caffeate, chlorogenic acid, chrysoeriol, cinnamate, ergothioneine, ferulate, luteolin, quinate, syringic acid, and vanillin, collectively serve as antioxidants that scavenge free radicals and reduce lipid peroxidation, leading them to ultimately reduce inflammation and tissue damage [301, 320, 327, 337, 342, 349, 441, 443, 446]. For example, 4-hydroxybenzoate has been found to suppress cellular nitric oxide production to reduce inflammation in vitro [474]. Animal studies also suggest that ferulic acid, another antioxidant, could reduce the severity of ulcerative colitis by modulating mucosal leukocyte populations and cytokine production [475]. Whole grain rice phytochemicals also possess natural, broad-spectrum antimicrobial activity against gram-positive and -negative bacteria, fungi, and parasites, such as 4-hydroxybenzoate, α-amyrin, astragalin, benzoate, cinnamate, luteolin, syringic acid, tartaric acid, vanillate, and vanillin [302, 310, 316, 337, 350, 370, 372, 447]. These compounds collectively work to suppress pathogen growth (bacteriostatically) and

Rice

kill pathogens (bacteriocidally) [301, 320, 461, 469–473]. Given the global escalation of antimicrobial resistance, as well as variable vaccine efficacy against many other pathogens, the hypotheses and applications of how whole grain rice and rice bran phytochemicals can function as sustainable, global preventive antimicrobial agents merit continued attention.

4.5 Whole Grain Rice Consumption and Prevention Against Chronic Disease The global escalation in chronic diseases of dietary origin, including obesity, type 2 diabetes, cardiovascular disease, and colorectal cancer, is a major public health concern. A growing body of research aims to evaluate whole grain consumption in the management and prevention of these diseases. Tables 4.5 and 4.6 list human clinical trials in which whole grain rice consumption was used as part of a preventive measure or as a treatment for these major chronic diseases of global morbidity and mortality importance. 4.5.1

Obesity, Cardiovascular Disease, and Type 2 Diabetes

Obesity is a chronic metabolic imbalance affecting over 2 billion people globally [489] and the resultant chronic elevations in blood pressure, low-density lipoprotein (LDL) cholesterol, and total cholesterol predispose millions of individuals to cardiovascular disease, type 2 diabetes, and even some cancers [490–492]. Globally, cardiovascular disease is the leading cause of human mortality, accounting for an estimated 17.5 million deaths annually [493]. Consumption of whole grain rice and rice bran for the management and prevention of these conditions is highlighted in Table 4.5, and illustrates the capacity of whole grain rice to serve as a health-promoting food. Notably, multiple trials involving hypercholesterolemic and/or obese patients have demonstrated that consumption of 11.8–84 g/day of whole grain rice is associated with lower levels of total and LDL cholesterol, improved ratios of high-density lipoprotein (HDL) to total cholesterol, and modulations to levels of plasma apolipoproteins [481–484]. High ratios of HDL to LDL cholesterol and shifts in apolipoprotein metabolism work together to shift levels of atherosclerosis-associated triacylglycerides toward a profile associated with a lower cardiovascular disease risk [494, 495]. A 2014 survey by the World Health Organization estimates that over 422 million people are affected with type 2 diabetes globally and suggests that two of the largest risk factors are high blood glucose and obesity [496], suggesting dysregulated nutritional or metabolic components of this condition. If left unmanaged, type 2 diabetes can result in blindness, limb amputation, heart attack, stroke, and premature death [496]. However, dietary changes that promote weight loss and lower fasting blood glucose levels [496] can improve the long-term prognosis of type 2 diabetes. Increased whole grain rice intake, when compared to white rice or refined grains, can help to promote these changes, as shown in Table 4.5. Collectively, the studies evaluating whole grain rice and rice bran as part of the dietary management for type 2 diabetes show that consumption of 20–40 g/day of either brown rice or rice bran has been associated with weight loss, lower levels of postprandial blood glucose and improvements in serum markers of type 2 diabetes, including glycated hemoglobin, adiponectin, aspartate transaminase, and alanine transaminase [478–480].

77

Table 4.5 Whole grain rice or components evaluated in human clinical trials for obesity, diabetes, and cardiovascular disease prevention, control, or treatment. Chronic disease

Study design

Obesity

Prospective, cross-over, randomized, study

Obesity

Prospective, parallel, Pigmented rice randomized, bran with or double-blind, without sterols controlled study

Intervention Brown rice, white rice

Study population

Number of participants

Treatment and trial duration

Outcomes

References

Acute dose study: healthy Japanese men with and without metabolic syndrome (mean age 43 y). Age not reported for chronic dose study

n = 11 (acute dose), n = 27 (chronic dose)

Acute dose: 200 kcal/one day (14-d washout) Chronic dose: 8 wk (no washout, amount not reported)

Compared to white rice, brown rice lowered the postprandial glycemic response. Decreased total and low-density (LDL)-cholesterol and endothelial function also observed.

[476]

Overweight and obese American adult men and women (mean age 43 y)

n = 24

Three 30 g rice snack bars/day for 8 wk

Total cholesterol was significantly lower and LDL-cholesterol was trending lower in participants consuming rice bran with sterols compared to the placebo.

[477]

Type 2 diabetes Randomized, double-blind, placebo-controlled study

Fermented brown rice byproducts (“lees of brown rice”)

n = 30 Koreans (median age 50.1 y) with managed type 2 diabetes with a fasting blood glucose of 126 mg/dL or higher or a value of 200 mg/dL glucose or higher on an oral glucose tolerance test

40 g/d for 12 wk

Rice consumption lead to greater [478] reduction in waist circumference, aspartate transaminase and alanine transaminase compared to the control.

Type 2 diabetes Prospective, cohort study

Brown rice, white rice

American adults free n = 197 228 of diabetes, cardiovascular disease, and cancer (aged 26–87 y)

Portion groups: ≤1 serving/ month, 1–3 servings/ month, 1 serving/ week, 2– 4 servings/ week, ≥5 servings/ week

When adjusted for age, higher [479] consumption of white rice was associated with higher risk of type 2 diabetes, while higher consumption of brown rice was associated with a lower risk of developing type 2 diabetes.

Type 2 diabetes Prospective, randomized, placebo-controlled study

Heat-stabilized rice bran or placebo

Volunteers with type 2 n = 28 diabetes from Taiwan, China. (age not reported)

20 g/d for 12 wk

Rice bran consumption lowered [480] levels of postprandial blood glucose, glycated hemoglobin, and increased blood adiponectin concentrations when compared to a placebo.

Cardiovascular disease

Prospective, randomized, cross-over, controlled study

Rice bran-enriched foods (pasta, rice cakes, bread, sauce, cream soup)

Italian men (aged 18–60 y) with mild hypercholesterolemia and no history of cardiovascular disease

n = 24

30 g/d for 4 wk (including 3-wk adaptation and 3-wk washout)

Consumption of rice bran-enriched foods significantly lowered total and LDL cholesterol, apo A-I, total/high density lipoprotein (HDL) cholesterol and glucose compared to baseline.

[481]

Cardiovascular disease

Prospective, randomized, parallel, double-blind, placebo-controlled study

Heat-stabilized, full-fat rice bran processed from California medium-grain rice

Moderately hypercholesterolemic, nonsmoking, nonobese, American middle-class Caucasian males and females (aged 32–64 y)

n = 44

84 g/d for 6 wk

Rice bran consumption signfiicantly decreased total serum cholesterol, LDL cholesterol, and serum apolipoprotein B compared to rice starch placebo.

[482]

Cardiovascular disease

Prospective, double-blind cross-over study

Rice bran incorporated into bread and muffins

Mildly hypercholesterolemic men (age not reported)

n = 24

11.8 g dietary fiber/day for 4 wk

Compared to wheatbran, participants consuming rice bran had a higher ratio of plasma HDL cholesterol to total cholesterol and an increased ratio of apolipoprotein A-1 to B.

[483]

Cardiovascular disease

Prospective, randomized, parallel study

Defatted rice bran

Healthy, normolipemic American men and women (mean age 32.9 y)

n = 26

56–94 g/d for 5 wk (preceded by a 3-wk run-in)

Defatted rice bran had no effect on blood lipid levels.

[484]

Cardiovascular disease

Prospective, parallel, randomized, controlled study

Heat-stabilized rice bran incorporated into muffins and smoothies

Healthy American children aged 8–13y with elevated cholesterol

n = 38

15 g/d for 4 wk

Heat-stabilized rice bran had no significant effect on blood lipid levels.

[4]

Cardiovascular disease/obesity

Prospective, cross-over, randomized, controlled study

Brown rice, white rice

Overweight or obese Iranian women (mean age 32.6 y)

n = 40

150 g/d for 6 wk (2-wk washout)

Brown rice significantly reduced weight, waist and hip circumference, body mass index (BMI), diastolic blood pressure, and C-Reactive Protein.

[485]

Table 4.6 Whole grain rice consumption in human clinical trials involving cancer prevention and treatment. Cancer type

Study design

Study population

Number of participants

Treatment dosage and trial duration

Cervical

Randomized, prospective, placebo-controlled, double-blinded, pilot study

Outcomes

References

Rice bran hydrolyzed by Lentinula edodes (Daiwa Pharmaceutical Company)

Adults (20–75y) undergoing chemo/ radiotherapy in Japan

n = 20

3 g/d for entire duration of a patient’s chemotherapy/radiation treatments

Participants exhibited lower radiation-induced gastroenteritis scores when compared to the placebo group.

[486]

Colorectal

Randomized, prospective, controlled, single-blinded, pilot trial

Heat-stabilized rice bran

Healthy adults from the United States

n=7

30 g/d for 28 d

Participants exhibited higher [487] levels of probiotic commensals in their intestines and elevations in intestinal fatty acids and bile acids compared to a rice bran-free control group.

Colorectal

Randomized, prospective, controlled, single-blinded, pilot trial

Heat-stabilized rice bran

Overweight/ obese adults from the United States who were colorectal cancer survivors

n = 29

30 g/d for 28 d

Participants had decreased [5, 46] Firmicutes:Bacteroidetes ratio and increased propionate and acetate at 14 d, and increased gut bacterial diversity and increased dietary fiber intake at 28 d. Improved serum amyloid A levels were observed at 28 d.

Colorectal

Prospective, cohort study

Brown rice

Non-Hispanic California Seventh-Day Adventists from the United States

n = 2818

1 serving brown rice/week

Consumption of at least one serving of brown rice per week was associated with a 40% reduction in colon/rectal polyp formation.

Intervention

[488]

Rice

Although the mechanisms by which whole grain rice reduces diabetes risk are not yet fully established, preliminary in vitro studies suggest that rice bran components may contribute by stimulating adipocyte uptake of glucose and reducing catabolism of starch into glucose by interfering with α-amylase activity [497]. Taken together, these results suggest that increased dietary brown rice intake may be used as part of an effective dietary management strategy for type 2 diabetes, where bioactive whole grain rice components may act on multiple metabolic pathways to improve blood glucose metabolism. 4.5.2

Cancer

In the United States alone, colorectal cancer is the second and third leading cause of cancer-related death in men and women respectively, and in 2017 has an expected mortality of over 50 000 Americans [498]. Studies highlighting the complex role for whole grains in the diet, as related to management and prevention of colorectal cancer and other types of cancer, are listed in Table 4.6. Specifically, a prospective cohort study conducted by Tantamango et al. analyzed over 2000 survivors from the 1976–1977 and 2002–2004 Adventist Health Studies and found that consumption of at least one serving of brown rice per week was associated with a 40% reduction in colon/rectal polyp formation [488]. Recent in vitro and human studies have begun to characterize the mechanisms by which brown rice may control or prevent colorectal cancer, and they suggest that these effects may come from enhancing the numbers and function of beneficial intestinal microflora. For example, in a pilot randomized, controlled trial in adults with four weeks of rice bran consumption, there were higher levels of probiotic Bifidobacterium longum and elevated fatty acids compared to an analogous rice bran-free control group [487]. Additional studies suggest that whole grain rice consumption exposes the colonic environment to a suite of bioactive compounds with chemopreventive properties, including various tocopherols, β-sitosterol, ferulic acid derivatives and other phenolics, γ-oryzanol, arabinoxylans, β-glucans, and multiple fatty acids [21, 38, 499] that may act on commensal bacteria to promote health. In support of this is a study with adult colorectal cancer suvivors by Sheflin et al., who observed that two weeks of rice bran consumption was associated with a decreased Firmicutes:Bacteriodes ratio and elevated biomarkers of probiotic microbial metabolism, including increased propionate and acetate [487]. A decreased Firmicutes:Bacteriodes ratio is a marker of healthy colonic metabolism as many Firmicutes species produce fatty acids such as lactate, propionate, and butyrate [500]. These short-chain fatty acids, produced by gut microbial metabolism, stimulate helper T-regulatory cell production, reduce inflammation, maintain the gut barrier, and modulate colonic metabolism [501]. Overall, consumption of whole grain rice and rice bran merits investigation for dietary efficacy in the chemoprevention and treatment of cancer, notably colorectal cancer, at different levels of consumption in the diet and in populations with diverse dietary patterns and environmental risk factors.

4.6 Whole Grain Rice Consumption and Protection Against Gut Pathogens Emerging research exists for the ability of whole grain rice, particularly the rice bran fraction, to prevent infectious diseases affecting the gut. A primary focus has been on

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antidiarrheal properties of rice bran to combat human rotavirus and norovirus infections, which are the leading global causes of childhood diarrhea [6–8]. Currently, limited vaccine efficacy against human rotavirus and the lack of a human norovirus vaccine [8, 33] support the demand for alternative enteric disease prevention and management strategies. Rice bran consumption in germ-free pigs suggested that rice bran can reduce human rotavirus and norovirus diarrhea via direct antiviral, immunomodulatory, and gut barrier protective actions on the intestinal tract [6–8, 33]. These activities include increased production of mucosal-protective IgA antibodies, improved mucosal integrity during viral infections and production of antiinflammatory cytokines at the gut barrier [6–8, 33]. Furthermore, these investigations established that combining rice bran with a probiotic cocktail can enhance disease-fighting properties with a concurrent increase in probiotic growth [6–8], again supporting the concept that beneficial gut microbes can enhance the health-promoting properties of whole grain rice components. In a bacterial pathogen context, whole grain rice components, particularly rice bran, have been examined for protective effects against Salmonella. Investigations by Kumar et al., Ghazi et al., and Goodyear et al. support the ability of rice bran to reduce Salmonella enterica serovar Typhimurium growth and pathogenicity in murine and porcine models [9, 36, 502]. Goodyear et al. [502] and Ghazi et al. [36]observed the differential ability of rice bran varieties in reducing Salmonella invasion and replication and concluded that these differences could be explained in part by the distinct profiles of bioactive compounds found in each rice variety. Specifically, Lijiangxintuanheigu “LTH,” a pigmented rice bran, was found to more effectively suppress Salmonella infection into and intracellular replication within cells compared to Sanhuangzhan “SHZ,” a brown rice bran [36]. These enhanced effects of LTH were associated with higher levels of galactolipids, phospholipids, and flavonoids when compared to SHZ [36]. Related studies using a murine model of Salmonella infection saw simultaneous decreases in pathogen shedding and increased gut-native lactobacilli in the feces of mice fed heat-stabilized rice bran and suggested that whole grain rice components in the intestinal tract also modulated the activity of probiotic lactobacilli to reduce Salmonella infectivity [9, 503]. In support of this, a study by Nealon et al. concluded that rice bran enhanced the ability of probiotic Lactobacillus paracasei to suppress Salmonella growth, and used metabolomics to identify multiple small compounds, including medium- and long-chain fatty acids, a cyclic polyol lipid, sulfur amino acids and glutamate derivatives with established broad-spectrum bactericidal, bacteriostatic, and β-lactam-enhancing antimicrobial activities [37]. Collectively, these studies indicate that whole grain rice could potentially help to treat and prevent disease outbreaks caused by human enteric pathogens.

4.7 Conclusion Whole grain rice has enormous potential for increased consumption and to address nutritional and health concerns affecting people across the globe. This chapter highlights whole grain rice compounds with antioxidative, chemopreventive, antimicrobial and immune and neuromodulatory functions. Human clinical trials have demonstrated

Rice

the efficacy of whole grain rice consumption in the protection and management of obesity, type 2 diabetes, cardiovascular disease, and cancer. This nutritional and functional food perspective for whole grain rice and human health should especially encompass rice bran, as the unique suite of fibers, lipids, amino acids, vitamins, and phytochemicals contributes to the majority of these broad-spectrum bioactivities. The form in which whole grain rice is consumed, notably the amount and variety of the bran component must also be considered when evaluating the potential bioactivity of whole grain rice. This is readily emphasized by examining the prebiotic potential of whole grain rice, whereby rice bran components change during fermentation and enhance probiotic growth and function to provide broad-spectrum defense against bacterial and viral pathogens. Further, although whole grain rice is globally available, an increasing preference for white rice without consumption of the bran continues to present challenges in achieving nutritional security. Educating populations on a global scale is desperately needed to achieve the full potential of health benefits from whole grain rice, and ideally an increasing demand will spur development of ways to improve shelf-life. These initiatives to elevate consumption of whole grain rice and/or rice bran should not be perceived as daunting tasks, but are rather imperative action items because there is continued human dependency and interest in rice production and nutrition globally.

Acknowledgments Departmental funding support from Colorado State University and NIFA-USDA funds were used for the preparation and synthesis of this book chapter. The authors thank Katherine Li, Iman Zarei, and Alyssa Beck for technical content and editorial review.

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5 Corn Siyuan Sheng, Tong Li and Rui Hai Liu Department of Food Science, Cornell University, Ithaca, NY, USA

5.1 Introduction Corn, also known as maize (Zea mays L.), originated in America. It was discovered by a European explorer, Christopher Columbus, in 1492, and later introduced to Europe, China and all over the world within the following 100 years [1, 2]. Corn is one of the major global food sources. It contains significant amounts of bioactive compounds providing desirable health benefits beyond its role as a major source of food. Besides corn grain, sweet corn is considered as one of the most popular vegetables in North America, and its popularity has increased rapidly all over the world. Sweet corn is among the top six vegetables in per capita consumption in the United States [3]. In 2007, canned and frozen sweet corn ranked third of all vegetables in the American diet after canned tomatoes and frozen potatoes [4]. For a long time, phytochemicals in corn have received less attention than those in fruits and vegetables. The consumption of corn and its derived products, along with many other whole grain (WG) products, has been proven to be associated with a reduced risk of a variety of chronic diseases such as cardiovascular disease [5–8], type 2 diabetes [9–12], obesity [13, 14], some cancers [2, 15–21], and with the improvement of digestive tract health [22–24]. Health-promoting effects of phytochemicals, such as antioxidant activities and antiproliferative activities, in fruit and vegetables have been well studied [25–27]. However, the health benefits of the whole grains have long been underestimated. Whole grains are composed of intact, ground, cracked, or flaked caryopsis, in which the principal components, the starchy endosperm, germ, and bran, are present in the same relative proportions as existed in the intact caryopsis [28]. The health benefits of corn arise not only from basic nutrients such as carbohydrates, vitamins, and minerals, but also from unique phytochemicals such as phenolic acids. The major components of the corn kernel each contain a different phytochemical profile. Along with health-promoting compounds such as amylase in corn endosperm, a wide range of phytochemicals such as total phenolics and phenolic acids (vanillic acid, syringic acid, coumaric acid, ferulic acid, and caffeic acid) are found in corn bran and germ at high concentrations. Adom and Liu discovered that the majority of phytochemicals in corn with beneficial effects on human health are contained in the bran and germ Whole Grains and their Bioactives: Composition and Health, First Edition. Edited by Jodee Johnson and Taylor C. Wallace. © 2019 John Wiley & Sons Ltd. Published 2019 by John Wiley & Sons Ltd.

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and not the endosperm, with about 87% of total phenolic content (TPC) present in the bran and germ. Thus, corn flour with ground germ, endosperm, and bran contains higher bioactive compounds than refined cornstarch and refined corn oil [29, 30]. All corn types are rich in dietary fiber, vitamins (A, B, E, and K), minerals (magnesium, potassium, and phosphorus), phenolic acids and flavonoids, plant sterols, and other phytochemicals (lignins and bound phytochemicals). However, different varieties of corn contain significantly different phytochemical profiles in terms of flavonoids and carotenoids. Blue, red, and purple corn possess higher concentrations of anthocyanidins (up to 325 mg/100 g dry weight (DW) corn) including cyanidin derivatives (75–90%), peonidin derivatives (15–20%) and pelargonidin derivatives (5–10%), yellow corn is rich in carotenoids (up to 823 μg/100 g DW corn) including lutein (50%), zeaxanthin (40%), β-cryptoxanthin (3%), β-carotene (4%), and α-carotene (2%), and high-amylose corn is rich in amylose (up to 70% of all carbohydrates) [31–35]. Therefore, the consumption of combined corn varieties provides optimum nutritional benefits. The additive and synergistic effects of bioactive compounds in corn and other whole grains along with many other nutrients and phytochemicals in fruits and vegetables may be responsible for their health benefits in reduced risk of chronic diseases [36]. In 1995, a daily serving of 6–11 grain products was recommended; in the 2005 nutrition guidelines, whole grains were first mentioned; and most recently, the 2015 Dietary Guidelines for Americans recommend more than 170 g daily intake of grains, half of which should be in whole grain form. However, the average intake of whole grains in the US is less than one serving per day, and 90% of Americans do not meet the whole grain intake recommendations [13, 37]. This review will focus on the recent research on the major nutrients and phytochemicals in corn and their potential health benefits related to the prevention of chronic diseases.

5.2 Macro- and Micronutrients in Corn Every 100 g of corn provides 365 cal and every 100 g of sweet corn provides 86 cal. Carbohydrates and water are the main chemical substances in corn. Carbohydrate content in corn is close to 75% and in sweet corn is nearly 18%. Water content in corn is about 10% and in sweet corn is about 75%. Corn and sweet corn provide a wide variety of vitamins (carotenoids, thiamine, riboflavin, niacin, pyridoxine, folate, ascorbic acid, vitamins E and K), minerals (calcium, magnesium, phosphorus, potassium, sodium, and zinc) and resistant starches (RS2s). The nutrition profiles of corn and sweet corn are similar, with the only exception being vitamin C, which is only found in sweet corn. Lipids in corn and sweet corn are mostly present in mono- (30%) and polyunsaturated (50%) forms with a small portion of lipids in the saturated form (20%) (Table 5.1).

5.3 Corn Phytochemicals Phytochemicals are the bioactive nonnutrient chemical compounds found in plants such as fruits, vegetables, and whole grains, which may function in reducing the risk of chronic diseases [36]. Although it is estimated that at least 5000 dietary phytochemicals

Corn

Table 5.1 Nutrient profiles of corn and sweet corn (data reported on wet basis)a).

Units

White corn

Yellow corn

White sweet corn

Yellow sweet corn

Water

g/100 g

10.37

10.37

75.96

76.05

Energy

kcal/100 g

365

365

86

86

Protein

g/100 g

9.42

9.42

3.22

3.27

Total lipid (fat)

g/100 g

4.74

4.74

1.18

1.35

Carbohydrate, by difference

g/100 g

74.26

74.26

19.02

18.7

Fiber, total dietary

g/100 g

N.D.

7.3

2.7

2

Sugars, total

g/100 g

N.D.

0.64

3.22

6.26

Calcium, Ca

mg/100 g

7

7

2

2

Iron, Fe

mg/100 g

2.71

2.71

0.52

0.52

Magnesium, Mg

mg/100 g

127

127

37

37

Phosphorus, P

mg/100 g

210

210

89

89

Potassium, K

mg/100 g

287

287

270

270

Sodium, Na

mg/100 g

35

35

15

15

Zinc, Zn

mg/100 g

2.21

2.21

0.45

0.46

Minerals

Vitamins Vitamin C, total ascorbic acid

mg/100 g

0

0

6.8

6.8

Thiamin

mg/100 g

0.385

0.385

0.2

0.155

Riboflavin

mg/100 g

0.201

0.201

0.06

0.055

Niacin

mg/100 g

3.627

3.627

1.7

1.77

Vitamin B6

mg/100 g

0.622

0.622

0.055

0.093

Folate, DFE

μg/100 g

N.D.

19

46

42

Vitamin A, RAE

μg/100 g

0

11

0

9

Provitamin A, IU

IU/100 g

0

214

1

187

Vitamin E (α-tocopherol)

mg/100 g

N.D.

0.49

0.07

0.07

Vitamin K (phylloquinone)

μg/100 g

N.D.

0.3

0.3

0.3

Fatty acids, total saturated

g/100 g

0.667

0.667

0.182

0.182

Fatty acids, total monounsaturated

g/100 g

1.251

1.251

0.347

0.432

Fatty acids, total polyunsaturated

g/100 g

2.163

2.163

0.559

0.487

Lipids

DFE, dietary folate equivalent; IU, international unit; N.D., not determined; RAE, retinol activity equivalent. a) Data from USDA [38].

have been discovered already, it is believed that a high percentage of phytochemicals in foods still remain unknown [36]. Like many other grain products, phytochemicals in corn are also distributed mainly in the kernel and bran [29, 39]. Phytochemical composition varies among different types of corn. Carotenoids are concentrated in yellow and red corn, anthocyanins are concentrated in red, blue, purple and black corn, and phytosterols are concentrated in the kernel [40].

115

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O

OH O HO OH Phenols

Phenolic acids

Flavonoids

Figure 5.1 Structures of common phenolic compounds.

Corn has the highest total antioxidant activity (181.4 ± 0.86 μmol vitamin C equiv./g of grain) among all common grains such as rice, wheat, and oats. Phytochemicals are the major contributors to the total antioxidant activity in corn. Flavonoids and ferulic acids contribute to the total phenolics in corn and are directly related to the total antioxidant activity; 87% of them are in bound form [29]. Thermal processing increases the antioxidant activity of sweet corn by releasing bound phytochemicals. Dewanto et al. discovered that thermal-processed sweet corn had higher antioxidant activity than unprocessed sweet corn [41]. 5.3.1

Phenolics

Phenolics are defined as chemical substances possessing one or more aromatic rings with one or more hydroxyl groups in their structures [42]. They are commonly categorized as phenolic acids, flavonoids, stilbenes, coumarins, and tannins [42]. Flavonoids and phenolic acids are the major ones found in corn. TPC varies among different corn varieties, the range being 243.8 ± 4.6 to 320.1 ± 7.6 mg gallic acid equiv./100 g DW of corn. High-carotenoid corn (320.1 ± 7.6 mg gallic acid equiv./100 g DW of grain) has the highest TPC followed by yellow corn (285.8 ± 14.0 mg gallic acid equiv./100 g DW of corn), blue corn (266.2 ± 0.7 mg gallic acid equiv./100 g DW of grain), white corn (260.7 ± 6.1 mg gallic acid equiv./100 g DW of grain) and red corn (243.8 ± 4.6 mg gallic acid equiv./100 g DW of grain) [31]. Adom and Liu reported that generally, corn has the highest TPC (15.55 ± 0.60 μmol/g of grain) among all commonly consumed grains such as rice (7.99 ± 0.39 μmol/g of grain), oats (6.53 ± 0.19 μmol/g of grain), and wheat (5.56 ± 0.17 μmol/g of grain) (Figure 5.1) [29]. 5.3.1.1

Phenolic Acids

Phenolic acids are one of the major phytochemical components of corn. Phenolic acids can be subdivided into hydroxybenzoic acid and hydroxycinnamic acid derivatives (Figures 5.1 and 5.2) [36]. In corn, phenolic acids contribute to the sour, bitter, and astringent taste, at a taste level threshold of 40–90 ppm [43]. Natural phenolic acids such as trans-cinnamic acid and ferulic acid are considered as effective fungitoxicants for Aspergillus flavus and A. parasiticus in corn [44]. For hydroxybenzoic acids, vanillic acid, and syringic acid are detected in corn, and for hyrocinnamic acid, p-coumaric, ferulic and caffeic acid are detected in corn [45]. The structure of benzoic acids and cinnamic acids is displayed in Figure 5.2. Sosulski et al. reported that total phenolic acid content in yellow dent corn flour was 309 ppm, and cis- and trans-ferulic, p-coumaric and syringic acids were the

Corn

R1 R2

COOH R3 Benzoic acid derivatives

Substitutions R1

R2

R3

H OH

H H

Vannilic acid

H H CH3O

OH

H

Protocatechuic acid

H

OH

OH

Syringic acid

CH3O

OH

CH3O

Benzoic acid p-Hydroxybenzoic acid

(a) R1 R2

CH

CH

COOH

R3 Substitutions

Cinnamic acid derivatives

R1

R2

R3

Ferulic acid

CH3O

OH

H

Caffeic acid p-Coumaric acid

OH H

OH OH

H H

Sinapinic acid

CH3O

OH

CH3O

p-Coumaric acid Quinic acid

H OH

OH OH

H OH

(b)

Figure 5.2 Structures of common phenolic acids found in corn: (a) benzoic acid derivatives and (b) cinnamic acid derivatives. Source: Adapted from [18].

predominant phenolic acids in corn flour (Table 5.2). The distribution of free, soluble, and bound forms of different phenolic acids in corn flour is shown in Table 5.3 [46]. The phenolic acid found in the highest quantities in corn is ferulic acid which is mainly in the bound form linked to cell wall structural components such as cellulose, lignin, and proteins by ester bonds [18]. In contrast to the results reported by Sosulski et al., Adom and Liu reported that more ferulic acids present predominantly in bound form while the former research (see Tables 5.1 and 5.2) indicated lower contrast ratios of different form of ferulic acids. Total ferulic acid content in corn is 906.13 ± 9.09 μmol/100 g of grain; 98.9% of that is in bound form, 1% is in soluble conjugate form and only 0.1% is in free form [29]. From the data above, the bound, soluble conjugate, and free form ratio for ferulic acid is 100:1:0.1. Thus processing techniques such as thermal processing, pasteurization, fermentation, and freezing play a critical role in releasing bound phenolic acids and increasing their total antioxidant activity by 44% to reach the optimum nutrition value of corn [29, 41].

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Table 5.2 Free, soluble, and bound forms of different phenolic acids in yellow dent corn flour (data reported on dry weight basis) [46].

Phenolic acids

Free (ppm)

Soluble form (ppm)

Bound (ppm)

p-Hydroxybenzoic acid

0.3

1

trace

(p-Hydroxyphenyl) acetic acid

1.1

Trace

N.D.

Vannilic acid

1

2.7

N.D.

Protocatechuic acid

1.1

1.9

Trace

Syringic acid

1.1

10.4

Trace

Quinic acid

N.D.

N.D.

N.D.

cis-p-Coumaric acid

N.D.

Trace

N.D.

trans-p-Coumaric acid

6.2

12.7

Trace

cis-Ferulic acid

0.6

5.1

0.8

trans-Ferulic acid

5.1

44.9

208.6

Caffeic acid

Trace

Trace

4.5

cis-Ferulic acid

Trace

N.D.

N.D.

trans-Sinapic acid

N.D.

Trace

Trace

Chlorogenic acid

N.D.

N.D.

N.D.

Total

16.5

78.7

213.9

N.D., not determined.

Table 5.3 Major phenolic acids content in yellow, Mexican blue, American blue, and white corn (data reported on dry weight basis) [46, 47]. Ferulic acid (ppm)

Type of corn

p-Coumaric acid (ppm)

Yellow dent

18.9

265

American blue

N.D.

927

Mexican blue

1.3

202

White

6.6

2484

N.D., not determined.

5.3.1.2

Flavonoids

Flavonoids are the largest group of phenolic compounds in corn. Epidemiological studies have shown that high intake of flavonoids reduces the risk of chronic diseases, including cardiovascular disease (CVD), diabetes, and cancers [36]. The generic structure of flavonoids consists of two aromatic rings (A and B rings) linked by an oxygenated heterocycle ring, known as the C ring. Different structures in the C ring of flavonoids classify them into flavonols, flavones, flavanols, flavanones, anthocyanins, and isoflavonoids [42]. Flavonoid content varies among corn varieties; total flavonoid content in yellow corn is about 1.68 ± 0.17 μmol catechin equiv./g. Most flavonoids are in bound form (1.52 ± 0.03 μmol catechin equiv./g), with a small amount in the free form (0.16 ± 0.004 μmol catechin equiv./g) [29].

Corn

Anthocyanins are the group of water-soluble flavonoids in corn imparting the color of purple to pink, depending on the pH level and concentration. The pericarp contains the highest level of anthocyanins (up to 50%), and aleurone contains a small portion of anthocyanin [48]. The color of the corn kernel indicates the content of anthocyanins; purplish-red corn kernels contain the highest concentration of anthocyanins (141.7 mg anthocyanins/100 g flour), and blue corn kernels contain less anthocyanins (62.7 mg/100 g flour) [32]. Six major and 17 minor anthocyanins have been identified in purple corn. The structures of major anthocyanins found in purple corn are shown in Figure 5.3, including perlargonidin-3-glucoside, cyanidin3-glucoside, delphinidin-3-glucoside, peonidin-3-glucoside, petunidin-3-glucoside, and malvidin-3-rutinoside [49, 50]. Anthocyanins in colored corn may have a positive effect on digestive health. A 12-week animal study on black mice conducted by Wu et al. suggested that anthocyanins in purple corn reduced the risk of colon cancer by increasing fecal butyric acid content as well as lowering the body weight by 16.6% at 200 mg/kg treatment [51]. Other research supported these results [52, 53] and the proposed mechanism is that corn anthocyanins inhibit the synthesis of fatty acids and triacylglycerol by suppressing the mRNAs level of enzymes, thus decreasing the accumulation of triacylglycerol in liver and white adipose tissue. Among the anthocyanins in purple corn, cyanidin 3-O-β-D-glucoside possesses substantial health benefits such as antiinflammatory activity, beyond its antioxidant effect [54]. 5.3.2

Carotenoids

Carotenoids provide pigments with yellow, orange, and red colors. More than 600 carotenoids have been identified in nature. Their physiological functions in promoting health are as provitamin A and antioxidants. Carotenoids generally have a 40-carbon skeleton of isoprene units cyclized at one or both ends [18]. The majority of carotenoids that occur in nature are in trans form. Due to the long series of conjugated double bonds in the central part of its chemical structure, carotenoids have light-absorbing and unique singlet oxygen-quenching capability [55]. Carotenoids are oil-soluble substances, so the absorption of carotenoids requires 3– 5 g of fat/oils present in a meal. Processing such as mechanical homogenization and thermal processing may increase carotenoid bioavailability. In contrast, nonabsorbable fat-soluble compounds may reduce carotenoid bioavailability by one order of magnitude [56–58]. 5.3.2.1

Carotenes

β-Carotene, α-carotene, and β-cryptoxanthin are provitamin A carotenoids which means they can be converted to retinol (vitamin A) in the human body, whereas xanthophylls do not possess this function. Theoretically, one molecule of β-carotene can be converted into two molecules of retinol through enzymatic reactions mainly in the intestinal mucosa. Realistically, the conversion rate of provitamin A to retinol is lower; vitamin A conversion rates of β- and α-carotenoids are expressed in retinol equivalents (REs) based on in vivo tests where 1 RE = 1 μg retinol = 6 μg β-carotene or 12 μg α-carotene [59]. The conversion of provitamin A to retinol is driven by individual physical requirements, and regulation mechanisms inhibit conversion if retinol content in the human body is sufficient [60, 61].

119

OH

OCH3

HO

OH

OH

OH

HO

O

HO

O

OH

HO

O

O

O

O

O

OH

OH

HO

HO

HO

Peonidin-3-glucoside

Pelargonidin3-glucoside

Delphinidin-3-glucoside OCH3

OH

OCH3

O

HO

OH

HO

OH OH

OH

OH

OH

OH

OH

HO

O

OH

OH

O

HO

O

O

HO

OCH3

OH HO OH O

O

HO OH

HO

Petunidin-3-glucoside

OH

OH

HO OH

O

O

HO

OH OH

O

OH

O OH O

Cyanidin-3-glucoside O H3C HO

OH OH

Malvidin-3-rutinoside

Figure 5.3 Structure of common anthocyanins found in purple, red, and black corn. Source: Adapted from [49].

Corn

Table 5.4 Carotenoid content of white, yellow, red, blue, and high-carotenoid corn [31, 34]. Carotenoid content (𝛍g/100 g of dry weight of corn)

Type of corn

Lutein

Zeaxanthin

β-Cryptoxanthin

β-Carotene

α-Carotene

White

5.73 ± 0.18

6.01 ± 0.06

1.27 ± 0.06

4.92 ± 0.18

0.04 ± 0.1

Yellow

406.2 ± 4.9

353.2 ± 23.1

19.1 ± 1.2

33.6 ± 1.2

11.7 ± 1.8

Red

121.7 ± 12.1

111.9 ± 9.2

13.1 ± 1.8

20.2 ± 1.9

N.D.

Blue

5.17 ± 0.49

14.3 ± 1.0

3.41 ± 0.39

23.1 ± 2.1

N.D.

High carotenoid

245.6 ± 9.4

322.3 ± 10.7

23.1 ± 1.0

45.8 ± 3.9

N.D.

N.D., not determined.

5.3.2.2

Xanthophylls

Unlike other carotenoids, xanthophylls (lutein and zeaxanthin) cannot be converted into provitamin A. Lutein and zeaxanthin are selectively taken up into the macula region (yellow spot) in the eye where they absorb 90% of blue light (450–470 nm), thus preventing the short-wavelength light from reaching the critical part of eye and causing oxidative damage [18, 62]. The average xanthophyll concentration in corn (the sum of lutein, zeaxanthin, and β-cryptoxanthin) is 21.97 μg/g corn. Lutein is 15.54 μg/g corn, zeaxanthin is 5.84 μg/g corn, and β-cryptoxanthin is 0.54 μg/g corn [63]. De la Parra et al. measured the carotenoid content of white, yellow, red, blue, and high-carotenoid corn; their data are shown in Table 5.4 [31]. The chemical structures of major carotenoids identified in corn are shown in Figure 5.4. 5.3.3

Vitamin E

Vitamin E is a family of eight isomers (vitamers) with two types of structures: the tocopherols (α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol) and the tocotrienols (α-tocotrienol, β-tocotrienol, γ-tocotrienol, and δ-tocopherol). The generic structures of the two classes of vitamin E are composed of a 6-hydroxychroman group and a phytol side-chain made of isoprenoid units (Figure 5.5), with tocopherols and tocotrienols sharing a similar chemical structure with minor differences on the phytol side-chain. Tocopherols have saturated phytol side-chains while tocotrienols have carbon–carbon double bonds in the phytol side-chain [18]. The main functions of vitamin E in human body are maintaining membrane integrity and as an antioxidant. Compared with tocopherol, tocotrienol has greater effects in preventing cancer and CVDs [64–67]. Vitamin E also improves immune system function by repairing DNA damage [68]. All vitamin E vitamers are found in corn, with the exception of β-tocotrienol. Total vitamin E content is 66.9 mg/kg DW of yellow corn, including 3.7 mg/kg DW corn of α-tocopherol, 5.3 mg/kg DW corn of α-tocotrienol, 0.2 mg/kg DW corn of β-tocopherol, 45 mg/kg DW corn of γ-tocopherol (the major isomer in corn), 11.3 mg/kg DW corn of γ-tocotrienol, 1.0 mg/g DW corn of δ-tocopherol, and 0.4 mg/kg DW corn of δ-tocotrienol (Table 5.5) [69]. About 95% of vitamin E isomers are found in the germ faction of corn [70]. 5.3.4

Phytosterols

Phytosterols are a collective term for plant sterols and stanols with a similar structure to cholesterol, differing only in the side-chain groups [18]. They are the essential

121

122

Whole Grains and their Bioactives

(a)

(b)

HO (c) OH

HO

(d) OH

HO

(e)

Figure 5.4 Structures of carotenoids found in corn: β-carotene (a), α-carotene (b), β-cryptoxanthin (c), lutein (d), and zeaxanthin (e). Source: Adapted from [18].

components of plant cell walls and membranes. As minor constituents in corn oil, phytosterols are classified into subgroups: 4-demethylsterols, simple sterols, 4,4-dimethylsterols, 4-monomethylsterols, and sitosterols. The classification is based on the number of methyl groups at the C-4 position [71, 72]. Corn oil is rich in phytosterols (Figure 5.6); 56– 60% of phytosterols in corn oil occur as steryl esters, while esterified sterol content is much lower in other vegetable oils [73]. The majority of vegetable oils contain 1–5 g/kg of plant sterols, while corn oil contains 5.13–9.79 g/kg of plant sterols [74]. Crude corn oil contains a higher plant sterol content (8.09–15.57 g/kg) than the refined oil (7.15–9.52 g/kg) [74, 75]. In the corn kernel, the germ fraction contains the highest amount of oil (24.2–30.7%), while endosperm and pericarp fractions only contain 0.4–1.2% oil. Sitosterol is the predominant phytosterol found in corn, accounting for approximately 77–87% of all phytosterols extracted from corn, followed by campestanol, which accounts for 13–23%. Stigmasterol and 𝛿−5-avenasterol are found in trace amounts. The endosperm fraction contains the highest level of phytostanols [76]. High intakes of plant sterols (1.6 g per day) can

Corn R1 HO CH3 CH3 R2

O

H3C

H3C CH3

(S)

R3

Tocopherols R1 HO CH3

CH3

CH3

CH3 R2

O

(S)

(E)

R3

CH3

(E)

Tocotrienols Isomers

R1

R2

R3

α

CH3

CH3

CH3

γ

H

CH3

CH3

δ

H

H

CH3

Figure 5.5 Structures of tocopherols and tocotrienols found in corn. Table 5.5 Vitamin E content in yellow corn [69]. mg/kg of dry weight corn

α-Tocopherol

3.7

α-Tocotrienol

5.3

β-Tocopherol

0.2

γ-Tocopherol

45.0

γ-Tocotrienol

11.0

δ-Tocopherol

1.0

δ-Tocotrienol

0.4

Total

66.9

lower serum low-density lipoprotein (LDL) and total cholesterol concentrations without affecting high-density lipoprotein (HDL) cholesterol concentration in humans [77]. The proposed mechanism is that phytosterols and cholesterol compete to be a part of the micelle formation in the intestine, thus inhibiting the absorption of cholesterol [78].

123

124

Whole Grains and their Bioactives

H

H

H

H

H

HO

H

HO Sitosterol

Campesterol

H

H

H

H

H

H

HO

HO Stigmasterol

Delta5-Avenasterol

Figure 5.6 Structures of common plant sterols found in corn.

5.3.5

Other Bioactive Compounds

Besides the major bioactive compounds listed above, other bioactive compounds are found in corn [79]. For now, four types of resistant starches have been identified based on their structures, natures, and sources [80, 81]. Type 2 resistant starch (RS2), which is difficult to digest due to its granular structure, is the major resistant starch found in corn and present at a high level in high-amylose corn. Also, high-amylose corn (70% amylose) has almost the highest amylose content among all grains [82]. Due to the nature of starch granules, RS2 is resistant to digestion in the intestine, conferring abeneficial effect on colon health [83]. Lignin (lariciresinol, matairesinol, pinoresinol, and secoisolariciresinol) is a common bioactive found in all grains, with health benefits such as anticancer and antioxidant effects [84]. Secoisolariciresinol is present in corn at 12 μg/100 g DW and lariciresinol is present at 11 μg/100 g DW while matairesinol and pinoresinol are not present in corn [85].

5.4 Health Benefits Whole grain corn is rich in nutrients and bioactive compounds including fiber, vitamins, minerals, and phytochemicals. More and more scientific evidence suggests that the regular consumption of whole grains reduces the risk of developing chronic diseases, including CVD, type 2 diabetes, overweight and obesity, and digestive disorders. 5.4.1

Cardiovascular Disease

The World Health Organization (WHO) has reported that 17.7 million people died from CVD in 2015, and by 2030, 23 million people will die of CVD and related diseases

Corn

annually around the world [86]. Numerous recent epidemiological studies and interventional trials suggest a strong association between the increased consumption of whole grains and whole grain-derived products and reduced risk of CVD [5, 6, 8, 87, 88]. Tighe et al. reported on whole grain consumption and CVD in middle-aged people and found that daily consumption of three portions of whole grain foods lowered the risk of CVD by reducing blood pressure in a randomized controlled trial (RCT). The 233 participants were separated into three groups treated with refined, wheat, and oat plus wheat diets. After 16 weeks, significant decreases in both systolic and diastolic blood pressure in the oat plus wheat group were observed. The researchers suggested that the blood pressure-lowering effect was provided by the high amount of viscous soluble fiber (β-glucans) in whole grain [8]. Holloender et al. conducted a metaanalysis of RCTs and concluded that whole grains, including corn, rye, and brown rice, lowered the risk of CVD (20–25% reduction) when compared with refined grains. The mechanism is due to lowering LDL cholesterol and total cholesterol without increasing HDL cholesterol or triglycerides [88]. Mellen et al. reported a metaanalysis of seven prospective cohort studies with quantitative measures of dietary whole grains and clinical CVD outcomes. They found that consumption of whole grains (corn meal and popcorn, barley, buckwheat, millet, oatmeal, quinoa, brown rice, rye, and sorghum) (2.5 servings/day versuss 0.5 servings/day) was associated with a 21% lower risk of CVD (0.79, 95% confidence interval (CI) 0.73–0.85). In contrast, the consumption of refined grains, in which only the carbohydrate-rich endosperm was retained, was not associated with a reduced risk of CVD, suggesting that the bran and germ fractions carry more health benefits than the endosperm [7]. Campbell and Fleenor reported a case–control study on 22 obese young men and found that whole grains had a significant effect on reducing obesity-associated aortic stiffness, which could lead to CVD. This study suggested that the synergistic effects of phytonutrients, micronutrients, and macronutrients in whole grains contributed to the reduced risk of CVD. However, the fiber content did not contribute to the beneficial effects in this study [89]. Based on the data collected from two prospective cohort studies, 74 341 women in the Nurses’ Health Study (1984–2010) and 43 744 men in the Health Professionals Follow-Up Study (1986–2010), Wu et al. reported that with each whole grain serving, the pooled hazard ratio (HR) for CVD was 0.91 with 95% confidence, with each serving of bran-only intake, HR for CVD was 0.80, while with germ-only intake, no effect was observed. The whole grain products in this study included corn products such as whole cornmeal, whole corn flours, and popcorn. It was concluded that the intake of WGs, including whole corn products, is negatively associated with increased mortality of CVD [90]. Recent cohort studies and metaanalysis also suggested the negative association between whole grain intake and the risk of CVD [91–93]. 5.4.2

Type 2 Diabetes

It is estimated by the WHO that the number of people who live with diabetes increased from 108 million in 1980 to 422 million in 2014, and 1.5 million deaths were related to diabetes in 2014 [94]. Most people with diabetes have type 2 . A number of recent reviews [11, 12, 95, 96] and epidemiology studies [9, 10] have suggested that the consumption of whole grains and whole grain-derived products is associated with

125

126

Whole Grains and their Bioactives

reduced risk of type 2 diabetes. Dietary magnesium, fiber, and vitamin E, which participate in insulin metabolism, are found in whole grains. Regular consumption of these substances from whole grains may help regulate insulin levels. Also, whole grains may help regulate insulin levels by increasing satiety and lowering body mass index (BMI) [2]. High amylose content is positively associated with the high type 2 resistant starch content. Human studies with arepas, made of cornstarch, suggested that high-amylose corn consumption is associated with a lower metabolic response [97]. In this study, blood and serum insulin responses of people who consumed ordinary corn arepas were significantly higher than those who consumed high-amylose corn arepas, suggesting that the high amylose content in corn is responsible for the slower metabolic response [97]. Behall et al. reported that after five weeks of a high-amylose starch diet compared to an amylopectin starch diet, glucose and insulin responses were significantly lower [98]. In a long-term study, Behall et al. investigated 24 men, 10 of whom were healthy and acted as the control group and 14 of whom were hyperinsulinemic (HI) and acted as the treatment group. HI is not type 2 diabetes but is often seen in the early stage of the disease. Subjects consumed products made with either high-amylopectin (70% amylopectin, 30% amlyose) or high-amylose starch (70% amylose, 30% amylopectin). After 14 weeks, glucose response in both groups was similar, but the insulin response curves of the high-amylose group were much lower than the high-amylopectin group. Fasting triglyceride concentration was also much lower in the high-amylose group than the high-amylopectin group. The results suggest that long-term consumption of high-amylose cornstarch may have beneficial effects on people with HI and diabetes by normalizing insulin response [99]. A later research study conducted by Behall et al. on 25 healthy subjects, 13 men and 12 women, with different concentrations of amylose (30–70%), found similar results to the study above in that consumption of a high-amylose cornstarch meal lowered peak glucose levels. In addition, the results suggested that amylose content needs to be greater than 50% to have a significant effect on lowering glucose and insulin levels [100]. Resistant starch from corn has exhibited beneficial effects on reducing type 2 diabetes. Yamada et al. reported that daily consumption of 6–12 g of RS2, which is retrograded amylose, has beneficial effects on postprandial glucose and insulin levels [101]. High-amylose starch is a type of RS with amylose content usually ranging from 30–70% total weight. A study conducted by Maki et al. on the beneficial effects of resistant starch from high-amylose corn on overweight and obese adults (11 men and 22 women) suggested that RS2 from corn increased insulin sensitivity only in men, and women are less sensitive to changes in circulating free fatty acids [102]. 5.4.3

Obesity

In 2016, the estimated worldwide overweight and obese population was 1.9 billion and 650 million respectively [103].The number of people with obesity has nearly tripled since 1975. Results from short-term [14] and long-term [13] epidemiology studies indicate that the intake of whole grains and whole grain-derived foods is inversely associated with an increased risk of obesity. In a prospective cohort study, Liu et al. conducted research on the association between whole grains and dietary fiber intake and development of obesity in 74 091 US female nurses. Over the 12-year period, women who consumed more dietary fiber weighed

Corn

1.52 kg less than those who had only a slight increase in dietary fiber. Also, women who consistently consumed more whole grains weighted less than those who consumed less whole grain. The research also indicated that obesity was positively related to the intake of refined grains [13]. Higgins et al. conducted research on replacing total carbohydrates with 0–10.7% RS (retrograded amylose), which is abundant in high-amylose corn starch. The results indicated that replacement of 5.4% or more of total dietary carbohydrates with corn RS significantly increased postprandial lipid oxidation, suggesting that consumption of corn RS decreases fat accumulation [23]. Corn bran may have a benefit in lowering weight gain and obesity by promoting satiety. A study of satiety response to high-fiber muffins (8.0–9.6 g fiber) versus low-fiber food (1.6 g fiber) conducted by Willis et al. on 20 healthy men and women suggested that muffins with RS and corn bran had the most impact [104]. Oat and barley brans do not seem to exhibit a similar effect [105]. 5.4.4

Digestive Health

Daily consumption of 20 g RS has a beneficial effect on promoting digestive heath [106].Corn and corn-derived products are rich in RS, a form of insoluble dietary fiber. According to the United States Department of Agriculture (USDA) national nutrient database, 7.3 g of dietary fiber is present in every 100 g of white and yellow corn grain [38]. Less than 3% of the US population meets the intake recommendation of 14 g dietary fiber per 1000 kcal, or 25 g per day for adult women and 38 g per day for adult men [107]. RS has potential health benefits of enhancing laxation and fermentation, increasing uptake of minerals, serving as a prebiotic and reducing the symptoms of diarrhea. Most RSs survive through the digestive tract thus bringing more bioactive compounds to the colon [83, 108]. Compared with a starch-free diet, a diet containing 17–30 g/day corn RS increased stool wet weight by 2.7 g/day. RS in corn significantly increased fecal short-chain fatty acid excretion and the proportion of acetate in feces. RS increased laxative health through stimulation of biomass and sparing of nonstarch polysaccharide (NSP) breakdown [22]. Muir et al. conducted research on the effect of the combination of whole wheat bran (WB) with resistant starch in corn on fecal indexes [24]. The randomized block design study on 20 volunteers included three diets: control, WB only (12 g fiber/d), and combination of WB and corn resistant starch (RS) (12 g WB fiber/d and 22 g RS/d). Compared with the control group, the WB-only group resulted in a 22.90% increase of wet fecal output, 5.96% increase of butyrate concentration in daily excretion, 6.38% decrease of propionate concentration and 4.17% decrease of total short-chain fatty acids (SCFAs) in excretion. The WB and RS combined diet resulted in a 56% increase of wet fecal output, 79.47% increase of butyrate concentration, 17.02% decrease of propionate concentration and a 21.88% increase of total SCFAs in excretion. The WB-only diet did not show such a strong improvement of fecal indexes, suggesting a synergistic effect of the combination of whole grains and corn dietary fiber on digestive health [24]. An animal study found that consumption of RS from corn (161.15 g RS/kg) significantly shortened intestinal transit time in streptozotocin-induced diabetic rats compared to consumption of RS from rice (161.15 g RS/kg). Briefly, rats were separated into four groups: nondiabetic healthy animal with no-intervention diet as control; diabetic with no intervention; diabetic with corn RS intervention; diabetic with rice

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RS intervention. All groups consumed the same amount of food. The RS from corn, RS from rice, and diabetes groups showed positive results in that the body and organ weights were significantly reduced compared to the control and diabetes groups. The transit time at two weeks of feeding with RS corn was 15% shorter than RS rice and 31.11% shorter than the control group. When compared with the diabetes group, the transit time with RS corn was 26.41% shorter and with RS rice was 13.21% shorter [109].

5.5 Conclusion Although the consumption of corn can be traced back to the fifteenth century, it has gained increasing attention in recent decades globally due to being rich in nutrients and phytochemicals and having potential health-promoting benefits. Most phytochemicals in corn are present in the bran and germ fractions instead of the endosperm. Human clinical trials, epidemiological studies, and some animal studies have indicated that regular consumption of corn and derived products is associated with reduced risk of developing chronic diseases such as CVD, type 2 diabetes, and obesity. The high amylose content in corn contributes to digestive health by its resistance to digestion, thus bringing bioactive compounds to the colon. Therefore, increasing consumption of corn and other whole grains is a practical strategy to optimize health and reduce the risk of chronic diseases. Corn is rich in phytochemicals such as phenolic acids, flavonoids, carotenoids, and RS that are complementary to those in fruits, vegetables, and other whole grains when consumed together [44]. The benefits of RS in corn have been well studied; a moderate intake of RS (about 10 g/day) from cornstarch helps to reduce glucose and insulin response, and a higher intake of RS (20 g/day) from cornstarch promotes digestive health. There is a lack of research on many other corn phytochemicals such as phenolic acids and flavonoids. Further research on the health benefits of phytochemicals in corn and sweet corn is warranted.

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6 Barley Clarence W. (Walt) Newman 1 , Rosemary K. Newman 1 and Christine E. Fastnaught 2 1 2

Plant & Soil Sciences Department, Montana State University, Bozeman, MT, USA Phoenix Seed, Inc., Fargo, ND, USA

6.1 Introduction There is a controversy as to which of the cereal grains, barley, wheat, or rye, was the first to be utilized by humans. These three grains are all classified in the Triticeae tribe and were probably all utilized and gradually developed by the same people about the same time in various parts of Asia and Africa. It is fair to say that in ancient cultures, barley was a major source of fermented foods, especially in liquid form, as well as porridges and flat unleavened breads. Barley’s early first use as a food source was likely to provide sustenance and we can surmise from archeological evidence that ancient people recognized further benefits beyond a “full belly.” From our present knowledge of barley’s health-promoting constituents, we can also understand why it became a popular food ingredient in the diets of our ancestors. We have briefly summarized the evolution and use of barley first as a food but also as a medicinal supplement from ancient times to the present, followed by a discussion of recently reported research on bioactive compounds found in barley.

6.2 The Beginning Archeological evidence of food consumed by early mankind has been vigorously discussed in the literature providing a scenario of human endeavors to survive under obviously harsh conditions. According to Badr et al. [1], “Barley (Hordeum vulgare L.), is one of the founder crops of Old World agriculture.” The authors concluded from barley remnants found in archeological sites in the Fertile Crescent that “wild barley” (H. spontaneum C Koch) is the progenitor of “modern barley,” H. vulgare L., domestication occurring some 10 000 years ago. This conclusion supported earlier reports [2, 3]. Hordeum spontaneum C Koch can still be found growing wild in the Israel-Jordan area, as well as in other countries adjacent to the western Mediterranean , and eastward as far south as Tajikistan and the Himalayas [4, 5]. Although it was strongly suggested that the original site of barley cultivation was in the Fertile Crescent, Badr et al. [1] noted that Ethiopia, Morocco, the Himalaya Mountains, and Tibet have also been proposed Whole Grains and their Bioactives: Composition and Health, First Edition. Edited by Jodee Johnson and Taylor C. Wallace. © 2019 John Wiley & Sons Ltd. Published 2019 by John Wiley & Sons Ltd.

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as locations of barley domestication. In a later publication, Dai et al. [6] presented solid evidence that Tibet was an area where barley domestication occurred, supporting earlier contentions for a “multicentric” origin of barley [7]. Regardless of the exact location where barley originated, the important fact is that barley was an original food utilized by humans for nourishment and was vital for the development of many civilizations across the ages. Whether barley was “carried” to eastern Asia or whether there were genetic changes in wild barley as in the Fertile Crescent, it is now accepted that barley plants characteristic of H. vulgare Koch have grown in Tibet, China, and India for thousands of years [6]. Tsampa, a unique food developed in ancient Tibet, is still prepared today from ground barley and yak butter [8–10]. The Indus Valley in southern Asia was an important agricultural region where wheat and barley were staple foods of the Harappan civilization (3200–2000 BC). Ancient Indian physicians were successful in stabilizing the symptoms of diabetes over 2400 years ago. The effective treatment was similar to that of modern medicine – lose weight, increase exercise, and change diet. In the case of diet, patients were advised to substitute barley for white rice [11]. In ancient Egypt barley was used as a therapeutic agent for numerous maladies as well as being a major food [12]. Ethiopia has a long history of barley cultivation and agroecological and cultural practices dating back to 3000 BC. The diversity of barley types is not exceeded in any other region of comparable size [13, 14]. The first high-lysine barley cultivar identified was in an Ethiopian collection of hulless barleys [15]. Barley spread to Greece, Italy, and surrounding regions from the Fertile Crescent and North Africa. Famous philosophers and physicians of that era, Herodotus, Pliny the Elder, and Hippocrates, were supporters of the “medicinal” value of barley foods and drinks. Gladiators in the Roman Empire were called hordearii, which translates to “barley men.” These combat-hardened men believed that barley gave them greater strength and stamina than other grains [16]. Crop production, including barley, expanded north and eastward from the Aegean area, reaching the Caucasus and Transcaucasia regions during the fifth millennium BC. Early settlers living in the Caucasus Mountains were fond of a low-alcohol drink made from fermented hulless barley cakes called buza [17, 18]. There are records of barley foods among Neolithic cultures in many parts of Europe, including Stone Age people in Switzerland [19]. A type of ancient barley bread, bolon or boulon, survives in Jura, a mountainous region in France [20]. A landmark achievement occurred about 3000 BC with the introduction of barley into the British Isles from the European mainland. British coins carried pictures of barley bearing the Anglo-Saxon name for barley, barlych or bærlic. Barley became a major source of food and treatment for various illnesses and maladies afflicting the masses, especially the poor [12, 21]. In the Orkney Islands north of mainland Scotland, an ancient variety of six-rowed barley is currently grown called bere, a word believed to derive from the Old English bære tracing back to the Latin word farina for flour. According to Sturtevant [22], bere barley was cultivated in Greece and once grew wild between the Tigris and Euphrates rivers. Bere barley is thought to have been introduced to the Orkney Islands by Danish and/or Norse invaders in the eighth century or earlier [23]. The current use of bere barley is almost entirely for human foods, principally Scottish bannocks, breads, and biscuits. The composition of bere barley is not very different from modern covered barleys, with the exception of β-glucan content. Wholemeal bere

Barley

flour and white bere flour contain 3.2 and 2.7 g/100 g β-glucan respectively, which is approximately one-half of values reported for most barley meals [24]. In other countries of northern Europe, Norway, Sweden, Finland, and Denmark, barley was also a major dietary constituent. Hulless barley was introduced into Norway between 2000 and 1700 BC [25]. Vassgraut (water porridge) was a common food on the island of Senja in Troms, a far northern part of Norway. As in Scotland, barley porridge was a major food item in the diet of early settlers in Scandinavia [26, 27]. Professor Lars Munck has described daily food barley consumption in old Scandinavia as follows: At the beginning of the 20th century in Lunnede on the island of Fyn (Denmark), a common diet included porridge of barley grits cooked in milk or beer in the morning; meat broth with abraded barley eaten at noon; and barley grits cooked in sufficient amounts for the evening meal and to provide for the next day’s breakfast. This was an ancient practice, which continued for many years in Old Scandinavia [27]. Barley’s story in the Americas is only a fragment of time considering the history of barley’s contribution to people in Asia, Africa, and Europe. Columbus brought barley on his second voyage to the “Americas” in 1494, although it is not known if any seeds were planted. There is evidence of barley being produced in Mexico in the sixteenth century [28]. In records of exploration of the New World, barley was reported to have been introduced by two routes. It was brought to the East Coast colonies from England at the turn of the seventeenth century and into the southwest by Spanish explorers a few years later, where barley is believed to have been used primarily as animal feed. Brewing was the major use of barley on the East Coast and this continued as settlers moved westward. Beer production in the New World was a continuation of learned practices from European ancestors. Knowledge of microbial pollution was nonexistent until considerably recent times although brewing was an accepted method of producing potable drinks. Barley production is most always located near populated areas to provide the raw material for the breweries. There is little evidence of barley being used much as a food other than in liquid form (beer) in the early days of settlement of North or South America, but it can be assumed that some barley found its way into the cookpots, as in Europe. At present, the use of barley as a food is gradually increasing in North America. Approval of the health claim that barley helps to prevent coronary heart disease in the US [29], Europe [30], and Canada [31] has encouraged the food industry to introduce new barley products and to make consumers more aware of barley’s health benefits [32].

6.3 The Whole Grain Barley Kernel 6.3.1

Anatomy and Structure

The nutritional value and health-promoting potential of barley foods depend first on the composition of the kernel and second on processing in product preparation. Mechanical separation of the kernel during processing alters the components of the final products due to the marked differences in the anatomy and composition of the various parts of the kernel.

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Endosperm Cell Cell Walls Aleurone Layer Embryo

Testa Pericarp Hull

Figure 6.1 The barley seed longitudinal cross-section shows the thick endosperm cell walls that contain significant levels of fiber, i.e. β-glucans and arabinoxylans. This unique cereal characteristic produces both whole grain and refined (pearl) barley foods with significant bioactive compounds. Source: Reproduced with permission of Jonathan Reich.

There are hulless and covered barley types, a characteristic controlled by a single recessive gene (nud) located on chromosome 7H [33]. In covered types, the hulls (husks) are cemented to the pericarp, the outer layer of the caryopsis, while in hulless types these structures are loose and mostly (85–90%) removed at harvest. Barley hulls are composed of cellulose, arabinoxylan, lignin, and silica [34]. Hulls constitute 9–13% of kernel weight, due primarily to variety, kernel size, and the availability of moisture as kernels mature. In both covered and hulless types, the caryopsis is composed of the pericarp, testa (seed coat), aleurone layer, endosperm, and embryo (Figure 6.1). The pericarp is crushed during seed development in covered barley, whereas in hulless types it is less compressed. The testa lies below the pericarp covering the aleurone layer cells and endosperm, the major storage area of protein and starch. The endosperm contains a network of roundish, oblong, or globular cells extending from the outermost parts of the aleurone to the center of the starch endosperm. The endosperm cell walls of barley are uniquely different from other cereal grains in that they can be thick and contain significant levels of fiber, resulting in refined barley products that retain some of the beneficial bioactives typically associated only with a whole grain. The cell walls are made up of a complex matrix of nonstarch polysaccharides (NSP), primarily β-glucan (BG) and arabinoxylan (ABX), varying in proportion approximately three parts BG to one part ABX. This part of the kernel is the storehouse for energy, protein, enzymes, and other nutrients necessary for germination and growth of the plant. The embryo is possibly the most complex tissue of the kernel, making up a small portion of the total by weight. It is located on the dorsal side of the caryopsis at the end attached to the rachis. The embryo is attached to the endosperm by the scutellum, a connective tissue. Genetic material necessary for initiation of growth of the new plant is located in embryo cells along with subcellular constituents that include mitochondria, protein bodies, spherosomes, Golgi bodies, endoplasmic reticulum, and thin cell walls traversed by cytoplasmic threads. On a dry weight basis, an average mature barley

Barley

kernel consists of approximately 13% hulls, 2% pericarp plus testa, 5% aleurone, 76% starchy endosperm plus the subaleurone, and 3% germ plus scutellum [35]. 6.3.2

End-Use Classification

There are four types of barley defined by their end-use quality: malt, feed, food, and forage. While any barley can be malted, the genetic variability naturally found in barley allows selection of varieties for malting based on very specific attributes. Similarly, any barley can be used as food, but varieties with higher levels of bioactive compounds can be selected for human food consumption. As mentioned previously, hulless types are desirable as food because they retain all of the bioactives found in whole grain barley. A second characteristic which is important in food barley is the type of starch. Altered starch types are associated with higher β-glucan content [36–38]. When the biosynthetic pathway for normal starch is changed to produce either high-amylopectin (waxy) or high-amylose starch, total starch levels are reduced [39, 40]. This results in some excess glucose available for β-glucan biosynthesis. Very high levels of β-glucan can be found in some food barley varieties that have starch synthesis pathways severely inhibited [41–43]. However, grain yields tend to be low in these varieties. 6.3.3

Basic Processing

Covered barley can only be consumed if the tough, inedible hull is removed. Because of the irregular shape of the kernel, any processing to remove this hull also removes some of the important bioactive compounds found in the outer layers of the seed (bran). This basic process is called pearling [44]. Historically, the sequence of pearling may produce 2–3 distinct edible products depending on severity and length of the process; dehulled barley, pot barley, and pearl barley. In dehulling, part of the outer caryopsis (bran) is unavoidably removed with milling along with the hulls (≈10–15%). Pot barley is made with further removal of the bran in the milling process along with the germ (≈5–10%). Finally, removing another 5–10% of the outer kernel produces a white pearl barley [45]. The resulting products are thus quite different in composition and texture. Hulless barley has an obvious advantage, as most (≈90%) of the hulls are removed in combining thus requiring less postharvest cleaning prior to processing. There is a growing consensus that whole grains consist of the intact, ground, cracked or flaked kernel after removal of the inedible parts such as the hull and husk. And there is agreement that: the principal anatomical components – the starchy endosperm, germ, and bran – are present in the same relative proportions as they exist in the intact kernel. Small losses of components – that is, less than 2% of the grain/10% of the bran – that occur through processing methods consistent with safety and quality are allowed. [46]. Thus, the value of whole grain benefits has brought about a change in processing covered barley. The term pot barley now refers to dehulled barley which is processed to remove the inedible hull but modified to reduce the loss of bran and embryo. Hicks

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et al. [47] reported dehulling the covered variety “Thoroughbred” in 1- to 10-minute increments. They found that 12% of the grain weight was removed after six minutes with loss of 35% of the ash but only 1.8% and 0.7% of the β-glucan and starch. However, there are a number of different types of commercial and laboratory-scale “pearling” machines for which studies have reported greater losses during “dehulling” [48–51]. To further confound any conclusions, the natural variation found between varieties has to be understood. For example, Aldughpassi et al. [52] pearled six Canadian covered, normal starch barley varieties for 55–60 seconds, removing 11–12% of the grain (hull and some bran). It is notable that the total fiber varied from 12.8% to 20.5% in these “whole grain” barley products. In comparison, three hulless varieties that were not pearled varied from 13.3% to 18.9% total fiber. Understanding the loss of nutrients due to processing must account for these varietal and machine interactions and only then can general guidelines for “whole grain” barley be established. 6.3.4

Composition

Knowledge of the bioactive composition of whole grain barley has greatly increased during the past 10 years. One particular study, the HEALTHGRAIN project [53], compared 10 barley lines with 150 bread wheat lines and 40 other lines of small grain cereals (spelt, durum wheat, Triticum monococcum, Triticum dicoccum, oats, and rye). The lines were selected for diversity in their geographical origin, age, and characteristics and grown on a single site in Hungary in 2004–2005. Samples were harvested, milled, and analyzed for a range of phytochemicals (tocols, sterols, phenolic acids, folates, alkylresorcinols) and fiber components that are considered to have health benefits. The covered barley was not dehulled prior to analysis. In comparison to the other grains, the barley set of varieties was high in total fiber, β-glucan, total sterols, total tocols, and folate. They were relatively low in alkylresorcinols and conjugated phenolics, but similar to the other grains in total phenols, bound phenolics, and free phenolics (Table 6.1). 6.3.4.1

Alkylresorcinols

The alkylresorcinols (AR), 1,3-dihydroxy-5-n-alkylbenzenes, are phenolic lipids mainly found in the testa/pericarp in barley. Barley contains only small amounts in comparison to wheat and rye. Mattila et al. [54] reported 32 mg/kg in a sample of barley flour obtained from a retail store. While AR can clearly be used as a marker to detect whole grain wheat and rye consumption, it is not clear if that is true for barley [55]. Andersson et al. [56] reported detailed levels of bioactives including total AR and homologue content for each of the 10 barley lines used in the Hungarian HEALTHGRAIN study. The varieties included both covered (not dehulled) and hulless types as well as normal, waxy (high-amylopectin), and high-amylose starch types. The total AR content varied from 32.2 to 103.1 μg/g, with an average of 55 μg/g. Landberg et al. [57] reported an average of 90 μg/g of ARs from four varieties (covered, not dehulled) of barley grown in Hungary and analyzed by gas chromatography (GC). The predominant homologue in both studies was C25:0, representing 50% of the AR in all but one variety. Gómez-Caravaca et al. [58] reported a mean of 48 μg/g and similar homologue ratio for four covered varieties that were dehulled prior to grinding. These data do not suggest a significant relationship between AR content and hull presence or starch type.

Table 6.1 Ranges of concentrations of phytochemical and dietary fiber components in different grains.

Grain (# varieties)

𝛃-glucan

Total dietary fiber

Total tocols

Total sterols

Folate

Alkyl-resorcinols

Emmer, dicoccum (5)

Bound phenolics

Free phenolics

Total phenolics

𝛍g/g DM

mg/g DM

Barley (10)

Conjugated phenolics

31–62

170–275

42–71

880–1180

500–810

0–150

50–210

50–550

5–25

50–550

3–7

75–145

28–60

780–970

500–950

450–775

90–225

350–975

5–18

360–950

Durum wheat (10)

3–7

125–175

39–65

850–1140

610–910

150–600

175–450

250–850

5–25

250–850

Einkorn, monococcum (5)

3–7

100–150

40–72

950–1210

400–700

500–700

175–350

200–520

5–21

200–530

Oat (5)

40–52

125–250

3–39

580–720

480–630

0–50

100–325

50–650

45–115

50–675

Rye (10)

11–21

220–280

41–70

1020–1450

550–800

700–1500

140–360

180–750

10–35

200–750

Spelt (5)

5–9

120–155

38–52

870–990

480–670

430–800

100–200

200–620

5–17

200–625

Spring wheat (20)

4–9

125–200

33–75

750–980

320–770

200–600

25–310

350–780

5–18

250–800

Winter wheat (130)

5–10

125–210

25–82

650–980

350–800

200–775

30–280

180–900

5–35

180–900

DM, dry matter. Adapted with permission from Ward et al. [53]. The HEALTHGRAIN cereal diversity screen: Concept, results, and prospects. Journal of Agricultural and Food Chemistry, 56 (21), 9699–9709. Copyright 2008 American Chemical Society.

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6.3.4.2

𝛃-Glucan and Total Fiber

Whole grain barley foods can provide levels of β-glucan (soluble fiber) not found in any other whole grain. Barley varieties with normal (25% amylose) starch have a β-glucan content similar to oats, but the hulless, low-amylose varieties can have 1.5–4 times more β-glucan than oats. β-Glucan in barley has been studied extensively because of its positive effects on health as well as its negative effects in malting and in feeding some types of animals, especially broiler chicks and laying hens. However, a large cooperative study with three-week-old weanling pigs comparing barley to corn as the basal grain showed no difference in animal performance due to basal grain after four weeks. The research was conducted at six state research stations using locally grown barley and corn purchased through local feed stores. A total of 1206 piglets in 29 replicates were fed either corn or barley as basal grains in otherwise identical diets. Differences in performance were between stations (crop-growing environments) and not basal grain. The conclusion was that barley could be substituted for corn and a portion of the soybean meal in diets for young pigs [59]. A second smaller study at two of the stations indicated that increased levels of dietary β-glucans and dietary fiber increased survival and growth rates of two-week-old piglets (unpublished data, MAES Bozeman MT). A review in 2007 [60] compiled data on 351 diverse barley varieties and reported that β-glucan content ranged from 2.0% to 17.5%. Research in the past 10 years has added to our knowledge of β-glucan in barley, but the numbers have not drastically changed (Table 6.2). Data compiled from 25 additional studies that included 242 varieties found the range of β-glucan to be the same as earlier reported. It is interesting to note that the data compiled represent barley varieties grown on five continents: Africa, Asia, Australia, Europe, and North America. The combined data in Table 6.2 show obvious differences between the varieties classified by hull and starch type. Hulless types have only slightly more β-glucan than covered types, which is mainly due to the removal of the hull at harvest. The higher β-glucan levels found in waxy and high-amylose starch types that are hulless validate the importance of these types as “food” barley. The ultra-high β-glucan content found in some varieties having low starch content (often referred to as high-protein, shrunken endosperm) may prove to be even more beneficial but because of low yield of these varieties, economic value must be considered. Whole grain barley can also contribute to the total dietary fiber (TDF) recommended in a healthy diet. Insoluble dietary fiber (IDF) in barley is mainly found in the bran or pericarp/testa while the soluble dietary fiber (SDF, mainly β-glucan) is located in the endosperm cell walls (Figure 6.1). Table 6.2 shows that the TDF in barley ranges from 11% to 34%. In general, the average TDF found in the hulless varieties is lower than the covered varieties. However, the covered types will lose some of the IDF when dehulled. Most importantly, the range of TDF is similar in both types. This suggests that varieties containing appropriate levels of TDF can be selected for the food industry. β-Glucan in barley, as the fiber component of the endosperm cell walls, may not be decreased when the outer layers of the whole grain are removed. In fact, soluble fiber and β-glucan content can show increases from 5% to 45%, depending on the variety and level of dehulling or pearling [48, 70, 82]. Since other components are being removed, β-glucan becomes a larger proportion of the whole product.

Barley

Table 6.2 Mean and range of total dietary fiber and β-glucan content reported in diverse barley genotypes.

Genotype

Coveredc), normal starch

Dietary fiber (% dry wt)

Total 𝛃-glucan (% dry wt)

Na)

Nb)

Mean Range

Mean Range

References

136 20.51 15.0–32.2

288

4.17 2.0–6.0

[47, 48, 50, 56, 61–68]

9 15.40 11.3–20.5

45

4.11 2.6–6.4

[36, 50, 52, 69, 70]

25 13.86 11.0–23.5

120

4.94 3.0–6.7

[36, 39, 56, 61–63, 70–77]

Coveredc), waxy starch

4 21.13 20.0–22.4

17

6.13 4.7–7.9

[56, 61, 63]

Covered, dehulled, waxy starch

2 20.35 20.3–20.4

3

7.52 6.2–8.3

[70, 73]

Covered, dehulled, normal starch Hulless, normal starch

Hulless, waxy starch

33 16.16 13.1–22.4

93

7.19 4.4–11.4

Coveredc), normal starch, low starch content

—

— —

11

9.95 3.1–16.5

[66, 67]

Hulless, normal starch, low starch content

—

— —

3

6.90 5.9–8.0

[63]

Hulless, waxy starch, low starch content

2 33.70 33.4–34.0

4 16.60 14.7–17.5

[80]

Coveredc), high amylose starch

1

6.40 23.4

1

6.40 6.4

[56]

Hulless, high amylose starch

6 17.55 16.0–18.5

13

7.91 6.0–9.7

[36, 39, 63, 71, 81]

a) n = number of cultivars reported for total dietary fiber. b) n = number of cultivars reported for total β-glucan. c) Covered types were not dehulled prior to analysis.

6.3.4.3

Carotenoids

Carotenoids are natural pigments that form part of the antioxidant system in seeds. They are classified into two groups: carotenes and xanthophylls. The minor xanthophylls [83], lutein and zeaxanthin, are found in the bran, germ, and endosperm of barley [75]. The content of total carotenoids along with the amount of lutein and zeaxanthin reported in a few studies for barley and other grains are listed in Table 6.3. The studies have included both hulless and covered barley, and a few waxy starch varieties that have anthocyanins in the bran. Total carotenoid ranged from 0.7 to 4.54 mg/kg, lutein from 0.185 to 0.86 mg/kg, and zeaxanthin from 0.3 to 0.937 mg/kg. One study reported higher levels of lutein than zeaxanthin while the other two studies reported the opposite, zeaxanthin similar or higher than lutein. Ndolo and Beta [84] manually dissected hull, bran, germ, and endosperm of barley and reported that carotenoids as a percentage of total in the grain were highest in the bran, followed in order by lower levels in endosperm and germ tissue.

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The barley varieties studied by Siebenhandl-Ehn et al. [75] were all hulless but included black, white, blue, and purple seed. These colors are due to the anthocyanins found in the pericarp and aleurone. Those with black color had the highest levels of total carotenoids as well as lutein and zeaxanthin. In contrast, Ndolo and Beta [84] reported a purple variety with very high levels of carotenoids similar to durum wheat but still lower than corn. While these datasets are not large enough to allow conclusions on the effect of hull, starch, or seed color, the variation is significant, suggesting that selection for the highest levels for whole grain food barley could be possible and beneficial. 6.3.4.4

Folic Acid

Folate, a vitamin in the B-complex, is an essential coenzyme which is enriched in many refined food products because deficiency is associated with neural tube defects and risk of other diseases. Whole grains, including barley, contain levels of folate that must be considered prior to enriching a whole grain food. Andersson et al. [56] reported a range of 518–789 ng/g in 10 barley varieties. The two hulless varieties had 518 and 724 ng/g folate. Since folate is found in bran and embryo, some loss may occur in covered varieties upon dehulling. Similar levels, 587–918 ng/g, were reported in five Finnish covered varieties [49]. These authors reported that folate levels were reduced 33% upon dehulling. Giordano et al. [85] found consistent levels of folate in two covered varieties (653–732 ng/g) but a much higher level of 1033 ng/g was found in the hulless variety “Mona.” Once again, further screening of food barley varieties is warranted and screening for other classes of barley may prove useful for breeding purposes. 6.3.4.5

Lunasin

Barley contains additional compounds which may be classified as bioactive but may not have been investigated to the same degree as those already discussed. Lunasin is a unique 43-amino acid peptide first found in soybean seeds (500–8500 μg/g) and later found in barley (13–21 μg/g), wheat (211–290 μg/g), rye (733–1510 μg/g), and triticale grains (429–6458 μg/g) [86–89]. This peptide is a small subunit of 2S albumin which is Table 6.3 Total carotenoid, lutein, and zeaxanthin (mg/kg) content reported in diverse barley genotypes and other grains. References

Type of barley

Lutein

Zeaxanthin

Total

Panfili et al. [83]

3 Covered – mean

0.860

0.300

Siebenhandl-Ehn et al. [75]

29 Hulless – mean

0.416

0.576

1.50

– min

0.185

0.382

0.70

1.21

– max

0.751

0.937

2.98

Ndolo and Beta [84]

Purple barley

0.699

0.624

4.54

(manually dissected)

Normal barley

0.295

0.651

2.25

Panfili et al. [83]

Oat

0.23

0.12

0.36

Durum wheat (14 varieties)

2.65

0.26

3.05

Corn

0.87

6.43

11.14

Soft wheat (3 varieties)

1.31

0.14

1.50

Barley

a group of storage proteins that occur widely in seeds of dicotyledonous plants. Plants use these peptides as a source of nutrients during germination and seedling growth. Jeong et al. [90] reported 12.7–99 μg/g in nine Chinese barley varieties. Legzdina et al. [91] reported from 5 to 189 μg/g of lunasin in 22 barleys grown in Latvia over two years and under two types of management. They concluded that there was a significant effect of environment and genotypes on lunasin content and encouraged further screening of barley genotypes. Lunasin is one of the most promising of several peptides recently identified for its inherent antioxidative, antiinflammatory, anticancer properties [92]. 6.3.4.6

Phenolic Acids, Flavonoids

The major phenolic compounds identified in barley are phenolic acids, flavan-3-ols, anthocyanins, flavonols, and proanthocyanidins (also referred to as condensed tannins) [93]. The phenolic acids are classified as either benzoic acid derivatives (in barley predominantly p-hydroxybenzoic, vanillic, and protocatechuic acids) or cinnamic acid derivatives (in barley predominantly, p-coumaric, caffeic, ferulic, and chlorogenic acid) [94]. These compounds exist in three forms: free (associated with the bran), soluble conjugates, or bound (linked to cell wall polysaccharides). The content of these forms in barley and the individual phenolic acids have been reviewed extensively [95] but the interest in these compounds found in barley extracts and their associated antioxidant activity is apparent as more than 15 new studies have been published in recent years. The content of phenolic compounds in barley varies according to the literature, owing to the genotypes examined and crop-growing environment as well as extraction procedure applied. Shewry [95] compiled data from studies and reported a range of 112–675 μg/g for total phenolics in 27 samples (genotypes). However, bound phenolic acids extracted with alkali ranged from 629 to 1346 μg/g in 16 genotypes. In general, recent studies have reported a higher amount of total phenolics in the 118 genotypes analyzed, a range of 76–9317 μg/g (Table 6.4). Also, a few studies developing new extraction methods have reported even higher levels [93, 102, 103]. Data in Table 6.4 show that the hulless genotypes have a similar range of total phenolics as covered genotypes as well as free and bound phenolics. But, in looking at data for individual genotypes, Holtekjolen et al. [98] reported the covered genotypes had about a 1:1 ratio of free to bound phenolics. The single hulless genotype had a 2:1 ratio of free to bound phenolics. Siebenhandl-Ehn et al. [75] investigated 29 hulless genotypes having different pericarp/aleurone color. They observed that the white and blue hulless genotypes always had higher levels of free versus bound phenolics, with more than 50% having a 2:1 ratio. In contrast, the purple genotypes had a lower content of free versus bound phenolics. Individual phenolic acids are reported in only a few recent studies. Klepacka et al. [97] reported syringic and ferulic as the primary phenolic acids isolated by acid and enzyme hydrolysis in six covered genotypes in Poland. He˛s´ et al. [69] reported ferulic and coumaric as the primary phenolic acids in a covered genotype. Zhu et al. [101] reported ferulic and chlorogenic as the primary bound phenolic acids isolated by alkaline hydrolysis of four hulless genotypes. They reported chlorogenic and protocatechuic acid as the primary free phenolic acids with no ferulic acid detected in the soluble extracts. Flavan-3-ol content is reported in six recent studies. Covered genotypes (53) ranged from 434 to 2474 μg/g of flavan-3-ol [65, 69, 99, 101, 104] while hulless genotypes (9)

145

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Table 6.4 Range of total, free, and bound phenolic content (μg/g) reported in barley genotypes.

References

Number of genotypes

Analysisa)

TPCa)

Anwar et al. [96]

3 Covered

FC

980–1456

Siebenhandl-Ehn et al. [75]

29 Hulless

FC

4502–9317

Klepacka et al. [97]

6 Covered

FC/HPLC

761–1193

Holtekjolen et al. [98]

11 Covered, 1 hulless

FC

4810–6760

He˛s´ et al. [69]

1 Covered

FC

6800

Lahouar et al. [65]

4 Covered

FC

1950–2201

Abidi et al. [99]

37 Covered

FC

709–1951

Benito-Román et al. [78]

1 Hulless waxy

HPLC

TP-free

TP-bound

2169–5341

2045–4276

2300–3450

2230–3480

3300

Narwal et al. [100]

12 Covered

FC

1910–3890

710–1640

730–2740

Zhu et al. [101]

4 Hulless

FC/HPLC

3339–4680

1679–2820

1660–1990

Moza and Gujral [74]

9 Hulless

FC

2712–3481

a) FC, Folin-Ciocalteu; HPLC, high-performance liquid chromatography; TPC, total phenolic content.

ranged from 559 to 1097 μg/g [74]. These levels are slightly higher than those reviewed by Shewry [95]. Catechin represented 80% of the flavan-3-ol reported by He˛s´ et al. [69] and Zhu et al. [101] and 75% was identified as a free phenolic, that is, isolated in the soluble extract. Total anthocyanins in barley are typically reported as μg cyanidin-3-glucose/g and range from 0.6 to 376.0 [95, 101, 103]. The ranges of total anthocyanin content found in white, blue, black, and purple barley are listed in Table 6.5. The highest level of total anthocyanins is found in purple barley with no apparent effect of hull type. Kim et al. [105] identified the predominant pigments as cyanidin-3-glucoside in the purple genotypes and delphinidin-3-glucoside in the blue genotypes. 6.3.4.7

Phytic Acid

Dietary phytate found in the aleurone of grains can exhibit beneficial health effects but is also known as an antinutrient. The mechanism is the same in both cases. Phytic acid binds minerals, especially iron and zinc, which reduces absorption, but also reduces the oxidation of iron in the colon. Colonic bacteria produce oxygen radicals in appreciable amounts and iron is easily oxidized in the presence of these radicals. The dietary phytic acid forms an iron chelate that becomes catalytically inactive, thus suppressing oxidant damage to the intestinal epithelium and neighboring cells. Lopez et al. [106] reviewed many of the interactions which affect mineral absorption and suggested that individual dietary patterns must be considered in understanding the role of phytic acid. Kumar et al. [107] examined this concept further and concluded that the beneficial effects such as reduced risk of cancer, heart disease, diabetes, and renal stone formation must be balanced with knowledge of mineral absorption associated with a particular diet.

Barley

Table 6.5 Range of total anthocyanin (μg/g) content reported in barley genotypes.

References

Kim et al. [105] Siebenhandl-Ehn et al. [75]

Zhu et al. [101]

Type of barley

Number of genotypes

Range of total anthocyanin

Covered and hulless black

4

59.8–84.5

Covered and hulless purple

3

312.7–350.3 4.4–12.9

Hulless white

6

Hulless black

8

9.2–23.0

Hulless blue

8

7.3–19.6

Hulless purple

7

13.8–146.5

Hulless white

2

0.6–3.5

Hulless blue

1

6.0

Hulless black

1

89.8

Moza and Gujral [74]

Hulless

9

13.8–22.5

Shen et al. [103]

Hulless black

1

376.0

The phosphorus in whole grain barley is 70% phytic acid. A range of 2.37–6.46 mg/g has been reported for varieties and locations [108, 109]. Low phytate genes, lpa, are available and feed varieties have been developed that decrease the phytic acid by one-half while maintaining the level of phosphorus in the seed. Raboy et al. [109] recently reported competitive yields for these varieties. 6.3.4.8

Phytosterols, Lignans

Plant sterols and lignans are secondary plant metabolites that have health-promoting properties in the human diet. Phytosterols are best known for cholesterol reduction but also have potential to prevent cancer [110]. Total sterols in barley are concentrated in the outer layers of the grain and are associated with the lipids. They are reported to range from 567 to 1153 μg/g in studies that included covered and hulless varieties as well as varieties having waxy or high-amylose starch [50, 56, 95]. The range was similar for both the covered and hulless types, but the covered types were not dehulled, so some loss might be expected in processing for whole grain foods. Lignans are found in plants as natural defense substances but may have pharmacological bioactivity, including antioxidant, antitumor, and beneficial effects on cardiovascular disease [111]. Cereal lignans are mainly found in the bran layers. Smeds et al. [112] reported that upon removing the bran from wheat, only 9.6% of the total lignans in the whole grain remained. Bran removal in rye, oat, barley, and spelt wheat removes 60–75% of the lignans. This study reported that a local barley variety contained 10 major lignans and four minor. Four of these lignans were predominant: 7-hydroxymatairesinol acid, lariciresinol, syringaresinol, and totolactol. These are also the major forms found in wheat, rye, and sesame. 6.3.4.9

Tocols

Tocotrienols are a part of the lipid fraction in barley, other cereal grains, and other plants. There are four isomers, α, β, γ, and δ, of each of the tocotrienol and tocopherol

147

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Whole Grains and their Bioactives

Table 6.6 Mean and range of total tocopherol (tocopherol + tocotrienol) and % tocotrienol reported in diverse barley genotypes. Total tocopherols (𝛍g/g dry wt.) References

Cavallero et al. [114] Moreau et al. [115] Andersson et al. [56]

Number

Mean

Tocotrienol (% of total tocopherols) Range

Mean

Range

Covered

4

55.8

53.1–61.4

79.4

78.1–80.3

Hulless

2

52.1

51.0–53.1

74.8

71.2–78.3

Hulless

4

115.5

84.7–151.1

72.4

70.3–75.7

Covered

10

55.0

46.2–68.8

76.9

70.5–80.2

Hulless

2

55.0

48.9–61.0

76.1

73.4–78.7

Tsochatzis et al. [116]

Covered

12

26.6

19.5–31.1

69.2

60.9–76.7

Temelli et al. [117]

Covered

10

87.3

77.1–99.2

71.4

64.9–76.7

Hulless

10

101.0

53.8–124.9

68.9

62.1–73.1

Covered

21

77.2

50.8–102.4

79.5

65.9–85.9

Hulless

4

51.7

20.3–69.3

81.4

74.1–85.1

Do et al. [118] All studies combined

Covered

57

60.4

19.5–102.4

75.3

60.9–85.9

Hulless

22

75.1

20.3–151.1

74.7

62.1–85.1

compounds, which are referred to as “tocols.” These compounds consist of a chromanol ring with a 16 carbon chain. In α-tocopherol, which is vitamin E, the carbon chain is saturated and in α-tocotrienol there are three double bonds in the carbon chain [95]. Of the tocols, α-tocotrienol has the highest biological activity [113]. Tocotrienols (T3) provide 60–80% of the total tocol content in barley grain, with α-tocotrienol being the major component (70%). Tocols are concentrated in the embryo and outer layers of the barley kernel, particularly in the aleurone and subaleurone tissue [70]. Total tocopherol (tocopherol + tocotrienol) and % tocotrienol levels reported by six studies are compiled in Table 6.6. These studies represent recent data collected worldwide on a diverse group of barley varieties. The mean total tocopherol content, 67.8 μg/g, represents a range from 19.5 to 151.1 μg/g from 79 varieties. The hulless varieties had a higher mean total tocopherol content and a greater genotypic variation. The mean percent tocotrienols were similar across studies but the range of 60.9–85.9% suggests some genotypic variation. Temelli et al. [117] found the proportion of T3 was lower in the 10 hulless varieties analyzed because the α-tocopherol levels were higher but this was not reported in other studies. Andersson et al. [56] reported on 10 varieties, including two having waxy starch and one having high-amylose starch. These three varieties had the highest content of total tocopherol and tocotrienol. This was not the case for the single waxy variety analyzed by Moreau et al. [115]. This variation between studies could be a result of growing environments or genotypes but is probably an interaction between the two factors. Tsochatzis et al. [116] found significant environment effects on total tocols in 12 Greek varieties. An increase of α-tocotrienol at an environment using organic cultivation improved the proportion of T3 to total tocols among the 12 varieties, from 64.9% to 73.4%. Cavallero et al. [114] observed significant environment and environment × genotype interaction on total

Barley

tocopherol content of six varieties grown in four locations in Italy. It is interesting to note that the highest levels of tocopherols and tocotrienols were reported in North America [115, 117] but no conclusions can be drawn on environment versus genotype since the varieties studied are only grown in this region.

6.4 Health Effects of Bioactive Compounds in Barley on Chronic Diseases At least three decades ago, a food revolution occurred in the United States involving the medical profession, dietitians, and nutritionists, urging greater consumption of fruits and vegetables. “In 1982, the American Institute for Cancer Research (AICR) was founded to advance the simple but then radical idea that cancer could be prevented” [119]. The concept of diet modification to control numerous disease maladies has exploded, resulting in hundreds of research projects in the field of human health. Research on the effective constituents in all foods has resulted in numerous reports not only in North America but globally. Since food grains are a major part of the human diet, many investigations have been reported on these foods, including barley. Selected research reports on important bioactive compounds in barley are presented in an abbreviated form in this chapter. 6.4.1

Barley 𝛃-Glucan Effect on Cardiovascular Diseases

Barley, along with oats, has been recognized to have cholesterol-lowering properties due to its content of β-glucan, a part of the soluble fiber. The blood cholesterol-lowering function of barley has a direct influence on risk of coronary artery disease. Blood lipids, especially the low-density lipoprotein (LDL) fraction, are associated with heart attacks, according to the American Heart Association. As lipid-rich blood flows through the arteries, there is a build-up of plaque, composed of cholesterol, fat, and other substances, which narrows the openings. This produces high blood pressure, a stress on the heart, as well as increasing the possibility of clot formation. When the arteries feeding the heart muscle are involved, creating a blockage of blood supply to the heart, the event is called coronary heart disease or myocardial infarction. De Groot et al. [120] reported the cholesterol-lowering effect of rolled oats, simulating the results of a large number of studies summarized by Truswell [121]. Trowell [122] promoted the hypothesis that dietary fiber may play an important role in regulating serum cholesterol, but at that time, the focus was on wheat fiber [123]. The blood cholesterol-reducing property of barley was shown initially in poultry by Fisher and Griminger [124] and later confirmed by Fadel et al. [125]. Danielson et al. [126] reported on the hypocholesterolemic effect of barley milling fractions as related to gastrointestinal viscosity of chickens, and Mori [127] demonstrated the relationship of barley β-glucan and fecal excretion of lipids, with consequent lowering of blood cholesterol in rats. Wang et al. [128] showed that barley β-glucan was effective in lowering blood cholesterol in chicks and hamsters. The barley–cholesterol relationship was later reported in human subjects by Newman et al. [129, 130] and McIntosh et al. [131]. These studies used wheat foods as control products. Shortly thereafter in Japan, a series of studies comparing barley to rice were reported, confirming the earlier findings [132–134].

149

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Whole Grains and their Bioactives

Behall et al. [135, 136] also confirmed the finding that barley is effective in lowering blood cholesterol in human subjects. Since that period of research activity, there have been numerous studies in the US, Canada, and Europe confirming the original findings that consumption of barley will lower blood cholesterol. For example, a meta-analysis of controlled trials was reported on the lipid-lowering capacity of barley β-glucan. It was concluded that increased consumption of barley products should be considered as a dietary approach to reduce LDL cholesterol concentrations [137]. A review paper from Ireland [138] promoted the utilization of barley β-glucans as an ingredient in food formulations, particularly breads since bread is the staple food of most civilizations. 6.4.2

Barley 𝛃-Glucan Effects on Diabetes and Blood Glucose

Diabetes mellitus is a group of disorders characterized by abnormally high blood glucose levels in the blood. Maintaining blood glucose levels close to normal is important because continuous or frequent episodes of high glucose can damage body tissues, leading to complications such as atherosclerosis, kidney damage, neuropathy, and vision disorders. There are two major types of diabetes: insulin-dependent (type 1) and noninsulindependent diabetes (type 2). People with type 1 diabetes do not produce insulin and must take insulin daily to survive. In type 2 diabetes, insulin does not work correctly, called insulin resistance. As a result, the pancreas may produce less insulin, becoming insulin deficient. In either case the amount and type of carbohydrate foods consumed must be carefully monitored to maintain beneficial levels of blood glucose as well as a healthy body weight. Diabetes was first described in Egyptian manuscripts as early as 1500 BC. The disease was named diabetes, which means “to siphon or to flow through,” referring to the increased amount of urine produced by people with the disease. The word “mellitus,” meaning honeyed, was added later to indicate the presence of sugar in the urine. In 1921, Canadian researchers Banting and Best discovered insulin which could be injected in diabetic patients, in order to normalize blood glucose. Today, people with type 1 diabetes learn to frequently test their blood glucose levels, and determine the amount of insulin to inject to reach normal levels. Individuals with type 2 diabetes can usually control their blood sugar levels by controlling their carbohydrate intake and increasing physical exercise. The glycemic index (GI) is an alternative classification of foods that reflect their effect on blood sugar levels in comparison with a reference food [139]. Carbohydrate foods vary in the speed at which they are digested and absorbed. Foods that have a slow transmission are termed “lente” or slow carbs, and more rapidly metabolized foods are said to be “fast” carbs. The frequency and intensity of “fast” carb peaks directly send messages to the pancreas where insulin is produced. Insulin is released from the pancreas, and carried to receptors on target cells throughout the body. Thus, the conversion of glucose to useable energy in cells requires the presence of insulin. The GI system ranks carbohydrates at values between 1 and 100 with pure glucose given a value of 100. Individuals having either type 1 or type 2 diabetes mellitus benefit from foods with low GI values. Application of the GI system has been developed and promoted extensively by an Australian scientist, J. Brand-Miller [140]. Foster-Powell and Brand-Miller [141] published

Barley

GI values calculated for many foods in many studies. The average GI values of five major cereal grains reported in this study are as follows: rice (56), corn (68), wheat (41), rye (34), and barley (25). In a review of studies on blood glucose responses to oat and barley products, Tosh [142] concluded that products containing a minimum of 4 g of β-glucans and 30 g of available carbohydrate in a meal can be expected to reduce the postprandial blood glucose. 6.4.3

Barley 𝛃-Glucan Effects on Metabolic Syndrome

Metabolic syndrome has been recognized in modern medicine as a combination of three or more disorders that increase the risk of heart disease, diabetes, and stroke. Over one-third of Americans are affected by this syndrome according to the National Institutes of Health (www.nhlbi.nih.gov/health/topics). The characteristics accompanying comorbidities are increased abdominal circumference, hypertension, hyperglycemia, and elevated blood lipids (cholesterol). These conditions, individually and collectively, are serious health threats to people living in today’s industrialized countries. Barley has been shown in numerous studies to be an effective dietary agent in reducing and/or control of metabolic syndrome systems. The role of barley β-glucans in effective treatment and control of this dangerous health threat was thoroughly reviewed by El Khoury et al. [143]. In 1990, Sato et al. [144] reported that blood glucose levels in hospital patients were lower for those who consumed barley instead of rice. Shortly thereafter, results of an experiment were reported where normal and diabetic rats were fed diets of rice or barley [145]. Fasting blood levels in the diabetic rats fed barley were reduced to normal. In 1996 Liljeberg [146] reported that flatbreads and porridge made from a high β-glucan barley were consumer acceptable and effective in producing a lowered glycemic response when compared to these products made with white wheat flour. Several later studies confirmed findings that barley meals compared to wheat induced significantly lower blood glucose levels [147–149]. Many of the glycemic studies using barley soluble fiber (β-glucan) also studied satiety, which is logically related to delayed gastric emptying and slow nutrient absorption. Ames et al. [150] reported on glucose response in healthy volunteers for tortillas made from five different barley flours (produced by milling fractionation) varying in amylose, β-glucan, and IDF contents. Levels of amylose and IDF did not alter postprandial glucose and insulin, but high β-glucan (11 g) tortillas had a lower glucose and insulin response compared to low β-glucan tortillas (5 g). The GI of these high β-glucan tortillas was only 22 in comparison to 57 for tortillas made with whole grain barley flour. The study also reported that tortillas made with a high insoluble dietary barley fiber elicited an increase in glucagon-like peptide-1 (GLP-1) but not the satiety hormone peptide YY. However, studies utilizing longer dietary interventions do report decreases in hunger and energy intake at subsequent meals. Aoe et al. [151] reported that consumption of a high β-glucan barley with rice at breakfast resulted in less hunger and energy consumption at both lunch and dinner. Johansson et al. [152] reported that an evening meal that included barley kernels increased GLP-1 and also reduced perceived hunger and energy intake for 10.5–16 hours following the meal (breakfast and lunch the next day). Nilsson et al. [153] reported that a three-day intervention with barley kernel-based bread consumed once a day in the morning resulted in increased levels of gut hormones

151

152

Whole Grains and their Bioactives

involved in appetite regulation, metabolic control, and maintenance of gut barrier function. While further studies are needed, it is logical to suggest that the increase in satiety and lower food intake may help in the prevention of obesity. 6.4.4

Barley Fiber and Cancer Prevention

Barley has a balance of dietary fibers, mainly insoluble and soluble (β-glucan) but also resistant starch, that have been studied as cancer prevention compounds. After consumption of barley, these compounds progress through the small intestine into the large intestine undigested. In this environment they are subjected to fermentation by native microorganisms, resulting in the formation of three short-chain fatty acids (SCFAs): acetic, propionic, and butyric. Butyric is thought to be the most important of the three in serving as beneficial agents for colonic mucosa and providing energy for epithelial cells [81]. The increased acidic environment results in a smaller proportion of secondary bile acids believed to be promoting factors for inducing colon cancer. Simultaneous consumption of barley fiber including β-glucan and resistant starch from the high-amylose variety “Himalaya 292” was reported to increase SCFA production in the colon, thus providing colon cancer protection [154]. More recently Verbeke et al. [155] found that greater amounts of butyrate were produced in the colon of subjects consuming intact barley kernels versus barley porridge. The researchers concluded that a combination of NSP and resistant starch from the whole kernels produced the effect. Arena et al. [156] confirmed an enhanced probiotic performance of foods containing barley β-glucan in in vitro fermentation studies. Lahouar et al. [157] suggested a relationship between the greater colonic diversity seen in rats fed barley flour and a reduction in azoxymethane-induced aberrant crypt foci. While improved gastrointestinal health may be one mechanism to explain the cancer prevention attributes of barley, other mechanisms are being investigated using purified barley β-glucan. Ramburg et al. [158] published a systematic review of studies on immunologic effects of dietary polysaccharides. They reported four studies in mice consuming barley β-glucan extracts which showed decreased tumor growth and increased survival. Prior to this, Hong et al. [159] showed that fluorescein-labeled barley β-glucan molecules are transported from the intestinal system of mice by macrophages to the spleen, lymph nodes, and bone marrow. Yao et al. [160] reported similar results in mice, in that extracted barley β-glucan decreased tumor volume and weight. Ghavami et al. [161] reported that barley β-glucan protected HepG2 cells against radiation when the cells were pretreated with 1 μg/mL for 72 hours. The protection was measured as a decrease in cell death hypothesized as a function of an observed increase in DNA repair. In contrast, Jafaar et al. [162] reported evidence that purified barley β-glucan inhibited proliferation of endocrine-resistant breast cancer cells. In human trials, Modak et al. [163] have used barley β-glucan extracts in a Phase I clinical study in patients with chemoresistant neuroblastoma. In combination with murine anti-GD2 antibody 3F8, the β-glucan was well tolerated and showed antitneoplastic activity, warranting further study. 6.4.5

Tocotrienol Effects on Health

Qureshi et al. [164] reported that the cholesterol-lowering property of barley was due solely to tocotrienols. At that time, β-glucan had not been publicized as being

Barley

a contributing factor. However, Wang et al. [128] reported significant cholesterol reduction in chicks fed whole barley meal but not enzyme-treated barley meal. The enzyme treatment was β-glucanase which converts β-glucan to glucose. In contrast, Wang et al. [165] showed that hexane-extracted barley oil did reduce cholesterol in chicks fed 5 g/kg cholesterol when compared to corn oil or margarine. Finally, Wang et al. [166] reported a study in golden Syrian hamsters designed to show the relative importance of each hypothesized cholesterol-lowering component of barley. Whole barley was compared to defatted barley, barley oil, and β-glucanase-treated barley. Only the whole barley and defatted barley reduced cholesterol. In the past 15 years, the research on prevention and therapeutic roles of tocotrienols has exploded. Two recent reviews summarize the extent of research indicating the potential of tocotrienols in maintaining human health. Wong and Radhakrishnan [167] classified categories of protection provided by tocotrienol as antioxidant, anticancer (breast, liver, prostate, skin, pancreas, and cervix), cardioprotective, antidiabetic, and antiosteoporotic. The second widespread in-depth review focused on the pharmacologic potential of tocotrienols [168]. Ongoing active research involving the various types of tocotrienols includes the following: protective agents in treating cancer, diabetes, inflammatory conditions, and as antioxidants, immune stimulants, and protective agents in several systematic diseases. This report represented 225 research papers and reviews of state-of-the-art research. It should be noted that many studies cited used tocotrienols from sources other than barley, namely palm trees as well as other plants. It was pointed out that all isomers of tocotrienol, α, β, γ, and δ, share the same properties regardless of plant source. When compared, reports indicated that α-tocopherol is the most active of the four isomers. Tocotrienols are being actively investigated in the search for treatments for cancer, including pancreatic cancer which is difficult to treat and has a poor survival rate. Antiinflammation is another extremely new and important topic, whereby tocotrienols have been shown to suppress cell signaling pathways and other steps in the development of inflammation. Antidiabetic research with tocotrienols has shown improvement in glucose metabolism which aids in preventing complications of neuropathy and retinopathy. A newer area of study with tocotrienols that showed promising results is enhancement of the immune system. Studies on cardiovascular disease verify the prevention of hypercholesterolemia, as well as blood pressure management although human trials with barley tocotrienols are lacking [169]. In the neuroprotective area, studies with tocotrienols report positive activities against Parkinson’s disease, among other functions. Tocotrienol studies involving protection of bone metabolism under adverse conditions such as osteoporosis, Paget’s disease, and excessive use of tobacco have been reported. The ability of tocotrienols to protect the liver against various toxic factors has been reported. Promising results indicate the next step will be the start of clinical studies in end-stage liver diseases. Nephroprotective research studies with tocotrienol involved the evaluation of kidney response under disease conditions which usually result in renal damage, which showed promise. Lastly, tocotrienols were tested for their ability to protect against radiation damage and showed promising results. In conclusion, the authors of this review [168] indicated that tocotrienols are powerful metabolic compounds that must be seriously considered by institutions of medical science research.

153

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6.4.6

Lunasin Effects on Cancer and Cholesterol Control

As a cancer prevention compound, lunasin internalizes into mammalian cells within minutes of exogenous application and localizes in the nucleus after 18 hours. It then inhibits acetylation of core histones. A eugenic mechanism of action was proposed whereby lunasin selectively kills cells by binding to deacetylated core histones exposed by the transformation event, disrupting the dynamics of histone acetylation-deacetylation and leading to cell death. In spite of its cancer prevention activity, lunasin does not affect the growth rate of normal and established cancer cell lines [86]. Jeong et al. [90, 170] demonstrated the cancer chemopreventive action of lunasin in mammalian cells and in skin cancer mouse models. They confirmed the numerous published reports of lunasin’s bioactivity against cancer proliferation. These researchers also concluded that this small peptide, prevalent in barley, is bioavailable and bioactive and that the consumption of barley could play an important role in cancer prevention in populations where barley is regularly consumed. In addition to the role that lunasin may play in cancer prevention, Lule et al. [92] suggested the peptide could play a vital role in regulating cholesterol biosynthesis in the human body. The effect of lunasin is identical to statins but differs in mode of action. Lunasin increases the expression of sterol regulatory element-binding proteins for LDL production, that in effect enhances clearance of plasma LDL cholesterol [171, 172]. Since barley is reported to contain much lower levels of lunasin than are reported for other seeds, it is fair to say that barley lunasin probably plays a minor role in the positive metabolic effects attributed to this bioactive compound. 6.4.7

Barley Antioxidants and Human Health

An antioxidant is a molecule that prevents or inhibits the oxidation of other molecules either directly or indirectly. This is a protective mechanism for organisms, particularly when the oxidation process can initiate degenerative diseases. Oxidation is a chemical reaction that produces free radicals that are prone to chain reactions, which may damage cells. Oxidative materials are continually present in the human body in the form of free radicals. The sources of free radicals are normal metabolism plus external factors such as using (smoking) tobacco products. The free radicals can attack nucleic acids, proteins, or lipids in the body. If the oxidative attack on body tissues exceeds repair mechanisms, chronic diseases such as cancer or heart disease can be initiated. For example, atherosclerosis can be initiated by oxidation of LDL, leading to plaque and arterial blockage. Antioxidants were given considerable recognition in the 1980s, initially in relation to their existence in fruits and vegetables. In recent years, attention to cereal grains as sources of phytochemical compounds has rapidly increased worldwide. The European HEALTHGRAIN project initiated a collaborative study to evaluate cereal grains for bioactive compound composition. This research group examined 10 barley varieties for antioxidant and other health-promoting compounds [56]. Antioxidants identified in barley include fat-soluble vitamins including tocopherols and tocotrienols, phenolic compounds, flavonoids including proanthocyandins and anthocyandins, and alkylresorcinols [95].

Barley

There have been many reports in recent years analyzing barley grain for content of various antioxidant compounds. Two common Canadian malting barley varieties (Falcon and AC Metcalf ) were examined by Madhujith and Shahidi [173]. The barleys were separated into fractions by pearling, then extracted. In both varieties, the outermost fraction yielded the highest phenolic content. The barley extracts were evaluated for efficacy in scavenging peroxyl and hydroxyl radicals, effectiveness in inhibiting supercoiled DNA breakage, and potential of inhibiting growth of Caco-2 human colorectal adenocarcinoma cells. Percentage inhibition of cancer cells by barley fraction extracts ranged from 14% to 74% at 0.5 mg/mL concentration. The results indicated that the barley fractions tested contained significant antioxidant and antiproliferative activities on human cancer cells. Furthermore, both fractions from both varieties exhibited the ability to inhibit growth of cancer cells. Holtekjolen et al. [98] reported on phenolic content and corresponding antioxidant activities from whole grain flours of Norwegian barley varieties and two different pearling fractions of these barleys. The highest antioxidant content and activity were found in the hulls, gradually decreasing as the pearling process progressed. These findings indicate that extracts of barley pearlings could be a welcome addition in the fight to control and/or inhibit cancer cell proliferation. Gamel and Abdel-Aal [102] reported similar activity in whole grain and pearlings of Canadian and Egyptian varieties. Alu’datt et al. [174] reported an extensive study of bioactive compounds in barley grains obtained from the Agricultural Research Center for Technology Transfer in Jordan. Proteins were isolated from barley flour and fractionated. Phenolics were extracted from both flour and isolated protein fractions. Both free and bound phenolics from all the fractions and flour showed antioxidant activity, angiotensin converting enzyme (ACE) and α-amylase inhibiting activity. Further, the unextracted proteins were hydrolyzed and promising correlations were obtained between antioxidant activities, ACE inhibiting activity, and degree of hydrolysis of the barley proteins. The protein isolates and fractions containing phenolics were recommended for health-promoting applications. Zhu et al. [101] investigated the cellular antioxidant activity (CAA) and the antiproliferative and cytotoxic effects on HepG2 human liver cancer cells of barley phenolic extracts from four Chinese varieties. They reported that free phenolics had greater activity than bound phenolics and activity varied significantly among the four varieties. A strong correlation was observed between CAA and phenolic acid and flavonoid content. Confirmation of the presence of antioxidant compounds in barley and their ability to provide health-promoting activity has been shown repeatedly [103, 175]. Do et al. [118] focused on the antioxidant capacity and activity of vitamin E in 25 barley genotypes before and after storage for four months at 10 ∘ C. In that study, vitamin E content and/or antioxidant capacity was lower in hulless or colored barley varieties. Narwal et al. [100] found genotype and environment variation in antioxidant activity in 72 barley varieties using two different assays. They selected five genotypes based on high values in both assays for two years and grew them at six locations. At least one of the varieties was hulless. The antioxidant activity and the free phenolics were reported to be more influenced by the genotype, whereas the bound and the total phenolics were most influenced by the environment.

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Finally, two recent reviews [64, 94] on the topic indicate the breadth of scientific interest in antioxidant capacity of cereal grains in general. These reviews, in addition to presenting recent trends in antioxidant research, indicate a new view of nutritional quality of cereal-based foods. Nutritional studies with livestock on the feeding value of barley (especially for nonruminants) for over 100 years have downplayed barley’s thick, impervious, and undesirable hull. The hull was only recognized as a protective cover for the inner seed, but now the same compounds that protect the inner seed are being recognized for additional value to food for animals and the human race.

6.5 Conclusion The resurgence of barley as an important cereal food grain is due in large part to the current worldwide interest in food for health. The accumulating evidence of the “goodness” of barley foods for health, as well as being an excellent source of the basic nutrients, has stimulated research and development of new health-promoting barley food products and publication of dedicated barley cookbooks such as Go Barley: Modern Recipes for an Ancient Grain [176]. Intensive research has unearthed new facts about the numerous compounds inherent in the barley kernel that have been previously perceived as only necessary for germination, growth of the seedling plant and/or protection from invading organisms. In this chapter we present an abbreviated history of barley’s roles in sustaining and providing nourishment for the human race, followed by a description of inherent bioactive compounds in barley that support daily functions and health of the human body. The bioactive compounds include alkylresorcinols, β-glucan, carotenoids, flavonoids, folate, lignans, lunasin, phenolic acid, phytic acid, phytosterols, and tocols. We have presented confirmation of the positive roles played by these compounds and related isomers as reported in the scientific literature, including 179 research articles from a variety of respected and recognized scientific journals, texts, conference proceedings, and patents.

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(Hordeum vulgare L.) low phytic acid mutations have little or no effect on yield across diverse production environments. Plants 4: 225–239. Woyengo, T.A., Ramprasath, V.R., and Jones, P.J.H. (2009). Anticancer effects of phytosterols. Eur. J. Clin. Nutr. 63 (7): 813–820. Durazzo, A., Azzini, E., Turfani, V. et al. (2013). Effect of cooking on lignans content in whole-grain pasta made with different cereals and other seeds. Cereal Chem. 90 (2): 169–171. Smeds, A.I., Eklund, P.C., Sjoholm, R.E. et al. (2007). Quantification of a broad spectrum of lignans in cereals, oilseeds, and nuts. J. Agric. Food. Chem. 55 (4): 1337–1346. Andrikopoulos, N.K., Hassapidou, M.N., and Manoukos, A.G. (1989). The tocopherol content of Greek olive oils. J. Sci. Food Agric. 46: 503–509. Cavallero, A., Gianinetti, A., Finocchiaro, F. et al. (2004). Tocols in hull-less and hulled barley genotypes grown in contrasting environments. J. Cereal Sci. 39 (2): 175–180. Moreau, R.A., Wayns, K.E., Flores, R.A., and Hicks, K.B. (2007). Tocopherols and tocotrienols in barley oil prepared from germ and other fractions from scarification and sieving of hulless barley. Cereal Chem. 84 (6): 587–592. Tsochatzis, E.D., Bladenopoulos, K., and Papageorgiou, M. (2012). Determination of tocopherol and tocotrienol content of Greek barley varieties under conventional and organic cultivation techniques using validated reverse phase high-performance liquid chromatography method. J. Sci. Food Agric. 92 (8): 1732–1739. Temelli, F., Stobbe, K., Rezaei, K., and Vasanthan, T. (2013). Tocol composition and supercritical carbon dioxide extraction of lipids from barley pearling flour. J. Food Sci. 78 (11): C1643–C1650. Do, T.D.T., Cozzolino, D., Muhlhausler, B. et al. (2015). Antioxidant capacity and vitamin e in barley: effect of genotype and storage. Food Chem. 187: 65–74. AICR (2018). Our History. Arlington: American Institute for Cancer Research Available from: www.aicr.org/about/about_history.html. de Groot, A.P., Luyken, R., and Pikaar, N.A. (1963). Cholesterol-lowering effect of rolled oats. Lancet 282 (7302): 303–304. Truswell, A.S. (2002). Cereal and coronary heart disease. Eur. J. Clin. Nutr. 56: 1–14. Trowell, H. (1975). Coronary heart disease and dietary fiber. Am. J. Clin. Nutr. 28: 798–800. Rimm, E.B., Ascherio, A., Giovannucci, F. et al. (1996). Vegetable, fruit, and cereal fiber intake and risk of coronary heart disease among men. J. Am. Med. Assoc. 275: 447–451. Fisher, H. and Griminger, P. (1967). Cholesterol-lowering effects of certain grains and of oat fractions in the chick. Exp. Biol. Med. 126 (1): 108–111.

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125 Fadel, J.G., Newman, R.K., Newman, C.W., and Barnes, A.E. (1987). Hypocholes-

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terolemic effects of β-glucans in different barley diets fed to broiler chicks. Nutr. Rep. Int. 35: 1049–1058. Danielson, A.D., Newman, R.K., Newman, C.W., and Berardinelli, J.G. (1997). Lipid levels and digesta viscosity of rats fed a high-fiber barley milling fraction. Nutr. Res. 17: 515–522. Mori, T., 1990,. Chemical characterization and metabolic functions of soluble dietary fiber from select milling fractions of a hulless barley and its waxy starch mutant. MS thesis, Montana State University, Bozeman. Wang, L., Newman, R.K., Newman, C.W., and Hofer, P.J. (1992). Barley β-glucans alter intestinal viscosity and reduce plasma cholesterol concentrations in chicks. J. Nutr. 122: 2292–2297. Newman, R.K., Lewis, S.E., Newman, C.W. et al. (1989). Hypocholesterolemic effect of barley food on healthy men. Nutr. Rep. Int. 39: 749–760. Newman, R.K., Newman, C.W., and Graham, H. (1989). The hypocholesterolemic function of barley β-glucans. Cereal Foods World 34: 883–886. McIntosh, G.H., Whyte, J., McArthur, R., and Nestel, P.J. (1991). Barley and wheat foods: influence on plasma cholesterol concentrations in hypercholesterolemic men. Am. J. Clin. Nutr. 53 (5): 1205–1209. Ikegami, S., Tomita, M., Honda, S. et al. Effect of boiled barley-rice-feeding in hypercholesterolemic and normolipemic subjects. Plant Foods Human Nutr. 49: 317–328. Li, J., Kaneko, T., Qin, L.-Q. et al. (2003). Effects of barley intake on glucose tolerance, lipid metabolism, and bowel function in women. Nutrition 19: 926–929. Shimizu, C., Kihara, M., Aoe, S. et al. (2008). Effect of high beta-glucan barley on serum cholesterol concentrations and visceral fat area in Japanese men--a randomized, double-blinded, placebo-controlled trial. Plant Foods Human Nutr. 63 (1): 21–25. Behall, K.M., Scholfield, D.J., and Hallfrisch, J. (2004). Lipids significantly reduced by diets containing barley in moderately hypercholesterolemic men. J. Am. Coll. Nutr. 23 (9): 55–62. Behall, K.M., Scholfield, D.J., and Hallfrisch, J. (2004). Diets containing barley significantly reduce lipids in mildly hypercholesterolemic men and women. Am. J. Clin. Nutr. 80 (5): 1185–1193. AbuMweis, S.S., Jew, S., and Ames, N.P. (2010). β-glucan from barley and its lipid-lowering capacity: a meta-analysis of randomized, controlled trials. Eur. J. Clin. Nutr. 64 (12): 1472–1480. Sullivan, P., Arendt, E., and Gallagher, E. (2013). The increasing use of barley and barley by-products in the production of healthier baked goods. Trends Food Sci. Technol. 29 (2): 124–134. Jenkins, D.J.A., Wolever, T.M.S., Taylor, R.H. et al. Glycemic Index of foods: a physiological basis for carbohydrate exchange. Am. J. Clin. Nutr. 34: 362–366. Brand-Miller, J., Burani, J., and Foster-Powell, K. (2001). The Glucose Revolution Life Plan. New York: Marlowe. Foster-Powell, K. and Brand-Miller, J. (1995). International tables of glycemic index. Am. J. Clin. Nutr. 62: 871S–893S.

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142 Tosh, S.M. (2013). Review of human studies investigating the post-prandial

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blood-glucose lowering ability of oat and barley food products. Eur. J. Clin. Nutr. 67 (4): 310–317. El Khoury, D., Cuda, C., Luhovyy, B.L., and Anderson, G.H. (2012). Beta glucan: health benefits in obesity and metabolic syndrome. J. Nutr. Metab. 2012: 1–28. Sato, J., Oswa, I., Hattori, Y., and Oshida, Y. (1990). Effects of dietary fiber on carbohydrate metabolism – a study in healthy subjects and diabetic patients. Nagoya J. Health, Phys. Fitness Sports 13: 17–78. Ikegami, S., Tsuchihashi, F., Nakamurs, K., and Innama, S. (1991). Effect of barley on development of diabetes in rats. J. Jpn. Soc. Nutr. Food Sci. 44: 447–454. Liljeberg, H.G., Granfeldt, Y.E., and Bjork, I.M. (1996). Products based on high fiber barley genotype, but not on common barley or oats, lower postprandial glucose and insulin responses in healthy humans. J. Nutr. 126: 458–456. Bourdon, I., Yokayama, W., Davis, P. et al. (1999). Postprandial lipid, glucose, insulin and cholecystokinin responses in men fed barley pasta enriched with barley β-glucan. Am. J. Clin. Nutr. 69: 55–63. Poppitt, S.D., van Drunen, J.D.E., McGill, A.-T. et al. (2007). Supplementation of a high- carbohydrate breakfast with barley β-glucan improves postprandial glycaemic response for meals but not beverages. Asia Pac. J. Clin. Nutr. 16: 16–24. Yokayama, W.H., Hudson, C.A., Knuckles, B.E. et al. Effects of barley β-glucan in durum wheat pasta on human glycemic response. Cereal Chem. 74: 293–296. Ames, N., Blewett, H., Storsley, J. et al. (2015). A double-blind randomised controlled trial testing the effect of a barley product containing varying amounts and types fo fibre on the postprandial glucose response of healthy volunteers. Br. J. Nutr. 113: 1373–1383. Aoe, S., Ikenaga, T., Noguchi, H. et al. (2014). Effect of cooked white rice with high β-glucan barley on appetite and energy intake in healthy Japanese subjects: a randomized controlled trial. Plant Foods Human Nutr. 69: 325–330. Johansson, E.V., Nilsson, A.C., Ostman, E.M., and Bjorck, M.E. (2013). Effects of indigestible carbohydrates in barley on glucose metabolism, appetite and voluntary food intae over 16 h in healthy adults. Nutr. J. 12: 46–58. Nilsson, A.C., Johansson-Boll, E.V., and Bjorck, I.M.E. (2015). Increased gut hormones and insulin sensitivity index following a 3-d intervention with a barley kernel-based product: a randomised cross-over study in healthy middle-aged subjects. Br. J. Nutr. 114: 899–907. Bird, A.R., Vuaran, M.S., King, R.A. et al. (2008). Wholegrain foods made from a novel high-amylose barley variety (Himalaya 292) improve indices of bowel health in human subjects. Br. J. Nutr. 99 (5): 1032–1040. Verbeke, K., Ferchaud-Roucher, V., Preston, T. et al. (2010). Influence of the type of indigestible carbohydrate on plasma and urine short-chain fatty acid profiles in healthy human volunteers. Eur. J. Clin. Nutr. 64 (7): 678–684. Arena, P.M., Caggianiello, G., Fiocco, D. et al. (2014). Barley β-glucans-containing food enhances probiotic performances of beneficial bacteria. Int. J. Mol. Sci. 15: 3025–3039. Lahouar, L., Pochart, P., Ben Salem, H. et al. (2012). Effect of dietary fibre of barley variety ‘Rihane’ on azoxymethane-induced aberrant crypt foci development and on colonic microbiota diversity in rats. Br. J. Nutr. 108: 2034–2042.

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158 Ramburg, J.E., Nelson, E.D., and Sinnott, R.A. (2010). Immunomodulatory dietary

polysaccharides: a systematic review of the literature. Nutr. J. 9: 54–76. 159 Hong, F., Yan, J., Baran, J.T. et al. (2004). Mechanism by which orally administered

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β-1,3-glucans enhance the tumoricidal activity of anittumor monoclonal antibodies in murine tumor model. J. Immunol. 173: 797–806. Yao, F., Zhang, J.Y., Xiao, X. et al. (2017). Antitumor activities and apoptosis-regulated mechanisms of fermented barley extract in the transplantaion tumor model of human HT-29 cells in nude mice. Biomed. Environ. Sci. 30: 10–21. Ghavami, L., Goliaei, B., Taghizadeh, B., and Nikoofar, A. (2014). Effects of barley β-glucan on radiation damage in the human hepatoma cell line HepG2. Mutation Res./Genet. Toxicol. Environ. Mutagen. 775-776: 1–6. Jafaar, Z.M.T., Litchfield, L.M., Ivanova, M.M. et al. (2014). β-D-glucan inhibits endocrine-resistant breast cancer cell proliferation and alters gene expression. Int. J. Oncol. 44: 1365–1375. Modak, S., Kushner, B.H., Kramer, K. et al. (2013). Anti-GD2 antibody 3F8 and barley-derived (1 3), (1 4)-β-D-glucan. OncoImmunology 2: e23402-1–e23402-8. Qureshi, A.A., Burger, W.C., Peterson, D.M., and Elson, C.E. (1986). The structure of an inhibitor of cholesterol biosynthesis isolated from barley. J. Biol. Chem. 261 (23): 10544–10550. Wang, L., Newman, R.K., Newman, C.W. et al. (1993). Tocotrienol and fatty acid composition of barley oil and their effects on lipid metabolism. Plant Foods Human Nutr. 43: 9–17. Wang, L., Behr, S.R., Newman, R.K., and Newman, C.W. (1997). Comparative cholesterol-lowering effects of barley β-glucan and barley oil in golden syrian hamsters. Nutr. Res. 17 (1): 77–88. Wong, R.S.Y. and Radhakrishnan, A.K. (2012). Tocotrienol research: past into present. Nutr. Rev. 70 (9): 483–490. Ahsan, H., Ahad, A., Iqbal, J., and Siddiqui, W.A. (2014). Pharmacological potential of tocotrienols: a review. Nutr. Metab. 11 (1): 52. Idehen, E., Tang, Y., and Sang, S. (2017). Bioactive phytochemicals in barley. J. Food Drug Anal. 25: 148–161. Jeong, H.J., Lam, Y., and Lumen, B.O. (2002). Barley lunasin suppresses ras-induced colony formation and inhibits core histone acetylation in mammalian cells. J. Agric. Food. Chem. 50: 5903–5908. Galvez, A.L., 2010. Methods of using soy peptides to inhibit H3 acetylation, reduce expression of HMG CoA reductase, and increase LDL receptor and SP1 expression in a mammal. US Patent 7731995. Galvez, A.L. (2012). Identification of Lunasin as the active component in soy protein responsible for reducing LDL cholesterol and risk of cardiovascular disease. Circ. Res. 126, A106932. Madhujith, T. and Shahidi, F. (2008). Antioxidant and antiproliferative potential of pearled barley (Hordeum vulgarae). Pharm. Biol. 46 (1–2): 88–95. Alu’datt, M.H., Ereifej, K., Abu-Zaiton, A. et al. (2012). Anti-oxidant, anti-diabetic, and anti-hypertensive effects of extracted phenolics and hydrolyzed peptides from barley protein fractions. Int. J. Food Prop. 15 (4): 781–795.

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175 Oh, S., Kim, M.-J., Park, K.W., and Lee, J.H. (2015). Antioxidant properties of aque-

ous extract of roasted hulled barley in bulk oil or oil-in-water emulsion matrix. J. Food Sci. 80 (11): C2382–C2388. 176 Inglis, P. and Whitworth, L. (2014). Go Barley: Modern Recipes for an Ancient Grain. Victoria: Touchwood Editions.

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7 Rye Laila Meija 1 and Indrikis Krams 2, 3 1

Riga Stradi¸nš University, Riga, Latvia Institute of Ecology and Earth Sciences, University of Tartu, Tartu, Estonia 3 Department of Zoology and Animal Ecology, University of Latvia , Riga, Latvia 2

7.1 Introduction Understanding the origin and evolution of wild plant species is crucial in the development of new crops. The wild perennial rye (Secale montanum) is considered to be the ancestor of the cultivated rye (Secale cereale). S. montanum is a wild species found in southern Europe and nearby parts of Asia, and rye was found as a weed often growing in the fields of wheat and barley. Rye had most likely coevolved with other weeds for over 2000 years until its value as a crop was recognized. Many forms of perennial rye can still be found in Turkey, especially in eastern parts of the country, including S. montanum Guss var. anatolicum Boiss and S. montanum Guss var. vavilovi Grossh. Other centers of the wild races of rye are found in adjacent northwestern Iran and Transcaucasia, including the Armenian genetic diversity center [1, 2]. Wild rye is indigenous to Anatolia and it was domesticated there before the Neolithic at the dawn of agriculture. Rye migrated to Europe as a weed among other cereals, and the first records of rye in Europe are dated from the early Neolithic. It is suggested that rye came to central Europe via Anatolia and the Balkans together with other crops [1]. A competing hypothesis suggests that rye migrated across the Caucasus or even from areas east of the Caspian Sea [3]. Although in central Europe rye is known since 4440 BCE, the expansion of intensive cultivation of rye as a competitive crop took place in the Middle Ages. Rye belongs to the so-called “cold-season” cereals. It is cold resistant and can be grown in low-fertility soil. The main cultivation areas of rye are located in the northwestern parts of the eastern hemisphere. During the last decade, new rye varieties with higher quality and better disease resistance have been developed. Rye has long been considered to be a primitive crop with a rather low yield and weak straw. The positive features in cultivation practices included low requirements regarding soil and fertilization, as well as a relatively good overwintering ability. Therefore, rye has become an important and popular crop especially in areas with relatively poor soils such as Eastern Europe and countries around the Baltic Sea [4, 5].

Whole Grains and their Bioactives: Composition and Health, First Edition. Edited by Jodee Johnson and Taylor C. Wallace. © 2019 John Wiley & Sons Ltd. Published 2019 by John Wiley & Sons Ltd.

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Rye

7.2 Types Regarding ploidy (number of chromosome), rye types are diploid and tetrapoid. Rye can be differentiated regarding seasonal types into winter, spring, and alternative types (www.upov.int). There are two types of variety rye grown today – classic rye and the more high-yielding hybrid rye. Widely grown in northern Europe, hybrid rye is increasingly popular because of its excellent yield, flexible drilling dates, vigorous growth habit, and very early maturity.

7.3 Consumption Rye is a traditional part of northern and eastern European cuisine. Nearly 95% of global production takes place in the northern part of the area between the Ural Mountains and the Nordic Sea. Historically, the greatest rye producer was the former Soviet Union. Now, the largest producers are Germany, with 4.7 million tonnes, and Poland and the Russian Federation, with 3.4 million tonnes produced by each in 2013. The Nordic countries are relatively unimportant rye producers, and the yearly production fluctuates depending on weather conditions at the time of sowing and, to some extent, on overwintering conditions. Other considerable rye producers are Belarus, with 0.6 million tonnes, and Denmark, with 0.5 million tonnes. The least important producers in Europe are Estonia and Norway, with 21 900 and 11 400 tonnes respectively in 2013 according to FAOSTAT, the statistics division of the Food and Agriculture Organization of the United Nations. Of the 11 million tonnes of rye produced in Europe in 2011, about 45% was used for food, especially in areas around the Baltic Sea. The remainder was used for livestock feed. In 2011–2012, human consumption of rye was over 3 million tonnes in the EU countries. Around 44% of this was used as grain, while the rest was grown as forage crop [6]. In the EU countries, human annual consumption of rye is 7 kg per capita, which is considerably higher than the consumption of barley (1.4 kg per capita) and oat (2.0 kg per capita), and significantly lower than that of wheat (109.7 kg per capita). The highest consumption of rye is in Eastern Europe (11.5 kg per capita). Poland and Belarus had the highest consumption of rye in 2010 (annual consumption: 31.0 and 26.8 kg/ per (follow consistency capita, respectively). Nordic and Baltic countries (except Norway) have higher rye consumption than the EU average, with the highest consumption being in Denmark and Finland (annual consumption: 17.4 and 16.5 kg per capita, respectively). Rye consumption is very low in the US and China (annual consumption: 0.3 and 0.5 kg per capita, respectively) [6].

7.4 Epidemiological Studies of Rye Intake A study carried out in Sweden (national dietary survey) found that traditional bread types including whole grain rye bread are consumed by older age groups, whereas white bread consumption was associated with younger age groups, less education, the presence of children in the family, eating less fruit and vegetables and more candy and

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snacks. The opposite was seen for mainly whole grain bread consumers. Older age groups reported eating whole grain rye bread more often [7]. A Danish study evaluated the dietary intake of Danish adults in association with a diet quality index. Individuals were categorized into groups according to the diet quality index while their food intake was estimated. The intake of wholemeal bread, including rye bread, was highest in the highest quality quartile. Median intake of rye bread was 33 g/day in the lowest and 53 g/day in the highest quality group in men and 18 g/day in the lowest and 35 g/day in the highest dietary score group in women. Interestingly, total energy intake decreased with increasing diet quality score [8]. In Finland, users of rye bread make up to 85% of the population, and consumption among them is 105–124 g/day (men) and 67–78 g/day (women). This means that rye bread is the most important source of dietary fiber in Finland [9, 10]. In addition, it was observed that the educated female population slightly increased rye bread consumption at the end of the twentieth century [11]. A Scandinavian study showed that whole grain rye made up more than 70% of the total whole grain intake in Denmark, more than 50% in Sweden, but only 20% in Norway [12]. There are limited data about rye bread consumption in Latvia. A few studies on men above 45 years showed that rye bread consumption is habitual (74–81% consume rye bread) and that men consume 105–126 g of rye bread a day in Latvia [13]. Overall, the consumption of rye has decreased across the world during the last decades of the twentieth century. However, there is a growing trend that highly educated, health-conscious people accept rye as a part of their diet.

7.5 Rye Products 7.5.1

Rye Bread

Rye is most often consumed in the form of dark bread. Rye bread is usually made from whole grain flour. The germ part of the grain is often removed and the dietary fiber (DF) content is high. The amount of DF depends on the type of rye flour used in bread production and constitutes 6–16 g per 100 g of bread. Rye bread has historically been the most important source of energy, protein, and carbohydrate in the diet of Finnish and German farmers. As wheat, fat, and sugar became readily available, the consumption of rye declined considerably. But whole grain bread, including rye bread, is still an important part of a healthy Nordic and Baltic diet. The use of rye is mainly based on local traditional nutritional practices. Traditional rye bread is the dark sour bread known in Finland, the Baltics, Poland, Belarus, and the Russian Federation. This tradition has undergone a slight change in countries such as Sweden, Denmark, and Germany. Rye bread is typically prepared without the addition of fat, milk, or sugar, but every country or region has its own way of making rye bread − adding sugar and malt, for example, is typical in Latvia. Baking rye differs considerably from baking wheat. Rye proteins cannot form a continuous network nor an elastic dough, which is why starch and especially arabinoxylans are important for the rye bread’s structure [14]. Rye breads are darker and do not rise as much as wheat breads. The most typical way of baking rye in the Nordic and Baltic countries is the use of the sourdough method and whole grain rye flour [15]. In brief, the main ingredients

Rye

(wholegrain rye flour, water, and starter culture) are mixed and fermented for 8–18 hours. The starter culture is usually the seed from a previous sourdough batch with stable microflora, but commercial starters are also used nowadays. The aim is to achieve low pH. During the fermentation period, the lactic acid bacteria and the sourdough yeast grow, and due to the microbial activity and the enzymatic reactions of the microflora, flavor compounds are formed. The main components formed are lactic acid and acetic acid. After the fermentation, more flour, water, and other ingredients are added to the starter to make the dough. The dough is left to rise for a short period, after which the breads are shaped, left to rise again and baked. The sourdough technique reduces amylase activity of the flour, increases solubility and swelling capacity of the arabinoxylans and traditionally, the leavening of the dough. This provides the characteristic taste of rye bread − quite intense, sour, and bitter. The amount of phytate decreases during fermentation in the presence of lactic acid bacteria [14, 16]. Sourdough also prevents microbial spoilage and reduces the staling rate of the bread crumb [14]. Further, the sourdough process enhances the antioxidant capacity and bioavailability of many bioactive compounds, such as increasing the concentration of folates, total phenolic compounds and free phenolic compounds when rye grain germination is combined with sourdough fermentation. Historically, sourdough was made in wooden bowls at home and in bakeries. The bowls were not washed after use but were utilized as a starter for the next sourdough batch. Nowadays bakeries have their own sourdough starters which are maintained with great attention [14]. The flavor and texture of the bread depend on the flour type, other added ingredients, baking conditions and time, as well as the size and shape of the bread. Rye bread can be made using rye flour alone or by mixing it with wheat or other flours. Rye bread is made in different varieties – with added cracked whole rye grains, seeds (flaxseeds, sunflower seeds, etc.), carrots, dried fruits, and other components. Caraway seeds are traditionally added to rye bread in many countries. Wheat flour breads with added rye fiber are also an option. The shelf-life of preservative-free rye breads is often above one week, or a few days for sliced breads. Most rye breads are produced using the sourdough method, especially in Finland. Many kinds of rye bread are available, such as loaf bread with different shapes or round flat bread with a hole in the center (in western Finland). Flatbreads have recently become popular in Scandinavia, including bread containing rye grits or pieces of rye kernel. The Baltic countries traditionally have particular rye bread making technology, which is based on cooked (or scaled) rye flour. The sourdough is started by pouring water onto rye flour and stirring the slurry. It is followed by cooling during which dextrines and sugars are created by a partial hydrolysis of the gelatinized starch. They give sweetness to the bread. The sourdough starter is then added to the cooked flour and, finally, the rest of the flour is mixed into the dough. Traditionally, big ovens have been used with very high baking temperatures (up to 300 ∘ C at the beginning). Big loaves requiring long baking time (up to three hours) were commonly made. These breads had a very long shelf-life (up to two weeks) due to the very moist and chewy crumb caused by flour cooking and gelatinization. The weight of the breads was from 0.5 to 5 kg. Instead of cooking, the desired sweet taste can nowadays be achieved by adding syrup at the dough stage. Rye malt is often used in order to deliver enzymes to enhance the hydrolysis of the

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gelatinized starch into dextrines and sugars [14, 17]. Nowadays rye bread is mostly sold sliced or unsliced in packages between 300 and 700 g, but big unsliced loaves (2–3 kg) are also offered by small producers. The rye bread of Latvia, Salin¯at¯a rudzu rupjmaize, is registered in the EC Council regulation “on agricultural products and foodstuffs as traditional specialties guaranteed.” This special kind of bread produced strictly in a traditional way is naturally leavened from rye flour, with scalded flour, baked in a hearth oven with a smooth and glossy crust to which starch paste or water is applied after baking [18]. Another popular type of rye bread is crisp bread, which can be found in many European countries, the US, and Japan. Crisp bread was created in Swedish farmhouses in the nineteenth century in order for the bread to maintain its eating properties for a long time. Industrial production of crisp bread began at the beginning of the twentieth century. The basic ingredients in most crisp bread variants are the same as in most rye breads: sourdough, whole grain rye flour, water, yeast, and salt. Often additional ingredients, such as caraway or cardamom, are added. Rye with low amylase activity is required for crisp bread production. There are three different methods of rye crisp bread production: normal yeast fermented, sourdough fermented, and cold bread (without added yeast). In Scandinavia, crisp breads are usually fermented by yeast. Sourdough versions are used in Finland. The baking temperature is usually quite low (100–170 ∘ C) and baking time varies from 10 to 36 hours. Thin crisps are produced using dough fermentation for 1–2 hours, a short baking time and drying at the end of process. Crisp bread has a long shelf-life, at least a year, and is resistant to microbiological contamination due to its very low water content ( 0.05) effect of quinoa flour addition on bake loss, specific volume and protein content; however, bread prepared with the addition of 25% quinoa flour displayed higher sensory scores (4.96) than control (1.20) and other quinoa supplemented breads (2.48–3.48)

Turkut et al. [156]

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10.6.2

Quinoa and Anticarcinogenic Activity

Cancer is a generic term characterized by the growth of abnormal cells beyond their usual boundaries that can then invade adjoining parts of the body and/or spread to other organs. By modifying various risk factors, the prevalence of cancer can be reduced. Quinoa extract, rich in different saponins, flavonoids and phenolic compounds, has been shown to have anticarcinogenic activity in vitro and in vivo. Kuljanabhagavad et al. [87] isolated 20 triterpene saponins from quinoa, out of which four were 3β-[(O-β-d-glucopyranosyl-(1-3)-a-L-arabinopyranosyl)oxy]-23-oxoolean-12-en-28-oic acid β-D-glucopyranoside, 3β-[(O-β-d-glucopyranosyl-(1-3)α-L-arabinopyranosyl)oxy]-27-oxo-olean-12-en-28-oic acid β-D-glucopyranoside, 3-O-α-L-arabinopyranosyl serjanic acid 28-O-β-d-glucopyranosyl ester, and 3-O-β-D-glucuronopyranosyl serjanic acid 28-O-β-d-glucopyranosyl ester, which showed cytotoxic and apoptosis-inducing activity in vitro in HeLa cells. The anticarcinogenic properties of saponins extracted from different sources (including quinoa) have been comprehensively reviewed by Man et al. [157]. On the basis of findings from these studies, Man et al. [157] concluded that almost all the saponins induce apoptosis in tumor cells by various mechanisms such as inhibition of tumor angiogenesis by suppressing its inducer in the endothelial cells of blood vessels, cell cycle arrest of tumorous cells, downregulation of expression of the HCC tumor marker α-fetoprotein [158], damaging the mitochondrial membrane and cristae in human leukemia and pancreatic cancer cells, leading to the loss of transmembrane potential, increase of cytosolic calcium, and activation of calcium-dependent apoptosis [159], suppressing telomerase activity through transcriptional and posttranslational inhibition of tumor cells [160], inhibiting colon cancer cell proliferation by delaying cell cycle S-phase [161] and by modification of the immune system [162]. Recently, Hu et al. [163] isolated bioactive polysaccharides from quinoa seed using ultrasound-assisted technology and estimated its antitumor activity on human liver cancer SMMC 7721 cells and breast cancer MCF-7 cells. They observed a substantial cytotoxic effect of bioactive polysaccharides against cancer cells without any effect on normal cells. Phytoecdysteroids and flavonoids such as catechin, epicatechin, quercetin, kaempferol, luteolin, genistein, apigenin, myricetin, silymarin, etc. are also known as potential bioactive components possessing anticancer properties [71, 164]. Quinoa is the only staple crop containing phytoecdysteroids among all traditional Poaceae cereal crops [165]. 10.6.3

Quinoa and Menopausal Disorders

The deficiency of estrogen linked with sedentary activity and elevated lipid intake in postmenopausal women makes them susceptible to chronic diseases [88, 166] by gradually leading to a substantial increase in the levels of tumor necrosis factor (TNF)-α and interleukin (IL)-6. However, regular consumption of whole grains provides antiinflammatory, hypolipidemic, and antioxidant benefits [167, 168]. De Carvalho et al. [64] investigated the effects of consumption of quinoa flakes or corn flakes (25 g/day, 4 weeks) on inflammatory markers in 35 overweight postmenopausal women. The findings were reversed IL-6 serum levels, a marker of inflammation, along with a reduction of total cholesterol (191 ± 35 to 181 ± 28 mg/dL) and LDL cholesterol (129 ± 35 to

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121 ± 26 mg/dL), and the increase in GSH (1.78 ± 0.4 to 1.91 ± 0.4 mmol/L) in the quinoa flake group. Owing to the high fiber content in quinoa, it presented a significantly higher intake of fiber at the end of the intervention compared to the corn flakes group. Earlier, Ma et al. [169] also reported that increased consumption of fiber brings about a significant reduction in plasma concentrations of proinflammatory markers like IL-6 and TNF-α receptor, suggesting the protective effect of fiber intake, particularly from whole grains.

10.6.4

Quinoa for Celiac Disease

Celiac disease is becoming an increasingly recognized autoimmune disorder, caused by complete intolerance of gluten protein in wheat, rye, and barley. A wide range of literature has confirmed that there is a strong correlation between celiac disease and maldigestion and malabsorption of vitamins, minerals, and other nutrients [170]. Initially, it was thought that this disease was age specific, and characterized by diarrhea but after detailed studies, it became evident that weight loss, constipation, abdominal pain, vomiting, weakness, and failure to thrive are other major symptoms associated with celiac disease [171]. Other clinical manifestations are iron deficiency anemia, mineral deficiency (zinc, calcium, etc.), irritable bowel syndrome, infertility, reduced bone mineral density, dyspepsia, and enamel hypoplasia, etc. Currently, there is no cure or treatment for this disease except life-long adherence to gluten-free products [172, 173]. In such a situation, quinoa can serve as an alternative to wheat as part of the regular diet. It should be noted that not all varieties of quinoa are equally effective for celiac patients. For example, Penas et al. [174] characterized 11 quinoa varieties using immunoblotting techniques to evaluate their relevance for celiac subjects. The results revealed that out of 11 varieties, three (PC1 (Lampa Grande), PC2 (Puno), and PC30 (commercial sample)) were not suitable for celiac patients. Similarly, Zevallos et al. [25] studied in vitro variability in immune response caused by 15 varieties of quinoa in blood and duodenal biopsy samples collected from celiac patients. They observed that two quinoa cultivars, Ayacuchana and Pasankalla, stimulated T cell lines at similar levels as gliadin and caused secretion of cytokines from cultured biopsy samples; they concluded that out of 15 cultivars studied, these two cultivars caused hypersensitivity in some celiac patients. Taking all these findings into consideration, the authors conducted a similar in vivo experiment in 2014 in celiac patients [61]. They evaluated the gastrointestinal effects of consuming 50 g quinoa daily for six weeks. Gastrointestinal parameters such as villus height to crypt depth, surface-enterocyte cell height and all blood tests were observed within normal range except for mild hypocholesterolemic effects. In all, it was concluded that consumption of 50 g/day of quinoa was safe and well tolerated by celiac patients. Taking into account the nutritional composition of quinoa, it can be included in the formulation of gluten-free products which will be inherently beneficial to celiac patients, although clinical studies and preliminary in vitro screening of different quinoa varieties are necessary to confirm whether a specific variety is suitable for celiac patients.

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10.7 Food Applications Owing to its functional properties and being a gluten-free pseudocereal, quinoa has been extensively used in the formulation of functional food products. Breads (fermented/steamed), biscuits, snacks, pasta, edible films, and beverages are some of the recently developed food products using quinoa as an ingredient. Quinoa, being rich in dietary fiber and bioactives with antioxidant activities, holds great potential for the formulation of novel food products. It is also an ideal ingredient for inclusion in “composite flour technology” which is based on the incorporation of cereal/legume/millet flour to wheat flour for improved nutritional value. Alvarez-Jubete et al. [57] incorporated 50% quinoa flour into a wheat flour bread formulation and revealed improved nutritional and textural properties of the resultant bread. Rodriguez-Sandoval et al. [145] demonstrated decreased volume and bulkiness of wheat bread that included 10% and 20% quinoa flour. The quality characteristics of quinoa food products largely depend on the physicochemical attributes of its protein and starch components. Addition of quinoa protein to film derived from chitin improved the tensile strength and thermal stability of quinoa-chitosan transparent edible biodegradable film [41]. Modification of quinoa starch granules makes it appropriate to be used as a stabilizing agent in emulsions as well as production of edible films [44]. Incorporation of quinoa flour into wheat dough can modify its thermomechanical properties. For example, addition of quinoa flour to gluten-containing flour causes weakening of the cohesive bonds in the gluten matrix, leading to lower springiness and cooking stability of dough, which indicates low staling or aging of bread substituted with quinoa flour [145]. Quinoa incorporation also extends the longevity and reduces microbial spoilage of food products. Hager et al. [175] demonstrated a 95% staleness reduction in quinoa flour bread compared to wheat flour bread. Prolonged longevity of quinoa food products could be attributed to a lower degradation rate of starch molecules [176], while the presence of bioactives like polyphenols inhibits mold growth. Stikic et al. [19] revealed a 16% improvement in protein quality of bread made with 20% quinoa seeds compared to bread made with wheat flour alone. Chlopicka et al. [177] found that antioxidant activity, total phenols and flavonoid content increased by 11%, 11%, and 36% respectively upon the addition of 15% quinoa flour to wheat bread. Pineli et al. [23] developed protein-rich quinoa milk from quinoa seeds with a low glycemic index. Some of the recently developed functional food products using quinoa as an ingredient and their major findings have been summarized in Table 10.6.

10.8 Future Prospects Quinoa is emerging rapidly as a potential source of quality protein and a rich source of fiber, vitamins, minerals, and bioactives. Quinoa has been exploited in developing several gluten-free and nutrient-rich novel food products for general as well as targeted populations. Quinoa is being studied extensively for its nonconventional applications such as quinoa starch-based edible films and stabilizers and quinoa protein-based packaging films, etc. By using the composite flour approach, several types of products such as infant foods, bread, pasta, fermented foods, and beverages have been prepared.

Quinoa

However, several areas need more research including quinoa extruded products, protein supplements, protein concentrates, fermented beverages, and modified-starch and protein-based functional foods.

10.9 Conclusion In all, it can be concluded that quinoa is a promising source of nutrients and an alternative to wheat, barley, and rye for celiac patients. The presence of bioactives (phenolic acids, flavonoids, saponins, etc.), EAAs, higher amounts of vitamins and minerals, ω-3 fatty acids and the absence of gluten make quinoa suitable not only for those who cannot tolerate gluten, but also for the general population who are at risk of various chronic diseases. A number of studies have demonstrated that the consumption of quinoa might reduce the risk of CVDs, obesity, diabetes, cancer, and menopausal disorders.

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11 Avenanthramides Tianou Zhang 1 and Li Li Ji 2 1 Laboratory of Exercise and Sports Nutrition (LESN), Department of Kinesiology, Health and Nutrition, The University of Texas at San Antonio, San Antonio, TX, USA 2 Laboratory of Physiological Hygiene and Exercise Science (LPHES), School of Kinesiology, University of Minnesota-Twin Cities, Minneapolis, MN, USA

11.1 Introduction Oat avenanthramides (AVA) are a group of diphenolic acids found only in oats. They are most abundant in oat bran and subaleurone layers. AVA, first discovered as phytoalexin known to protect against crown rust in oats, demonstrate strong antioxidant capacity by removing free radicals during germination. AVA are relatively stable, but heating, alkaline conditions, and conventional processing may affect their contents. Oat AVA are bioaccessible and bioavailable to rats and humans, and have exhibited biological effects in vitro and in vivo. These health benefits include antioxidant, antiinflammatory, antiproliferative, antiitch, antiosteoclastogenic, and antiatherosclerotic properties in multiple cell lines, animal and human studies. Besides original AVA, the metabolites after biotransformation and their derivatives may also exhibit potential biological efficacies. The antioxidant and antiinflammatory effects of AVA make them potential candidates for sports nutrition supplements to alleviate muscle inflammation after heavy exercise. Although AVA show great potential as a nutraceutical agent, their low bioavailability may limit the response threshold in exerting their biological actions. However, a recently reported “false malting” process provided a solution by increasing overall AVA contents in oats. More epidemiologic or interventional human studies are required to further prove these health benefits and the mechanisms of action. The health benefits of AVA will not only promote oat consumption, but also stimulate the development of AVA-enriched oat products and nutraceutical supplements in the future.

11.2 Presence in Whole Grains Oat (Avena sativa), as a cereal grain, is widely consumed all over the world. Although oat consumption is much lower than that of wheat and rice, it has gained more and more attention due to its numerous health benefits [1]. In the past, cardiovascular protection from oats was mainly attributed to the soluble dietary fiber β-glucan by lowering cholesterol and lipoprotein [2–4]. But recently, other components in oat with similar health Whole Grains and their Bioactives: Composition and Health, First Edition. Edited by Jodee Johnson and Taylor C. Wallace. © 2019 John Wiley & Sons Ltd. Published 2019 by John Wiley & Sons Ltd.

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benefits have been further investigated, including vitamin E, phenolic compounds (e.g., AVA), phytic acids, sterols, and flavonoids [5]. Early research indicated that oat bran contained a high concentration of antioxidants [6]. Increasing oat consumption was associated with decreased serum lipid and cholesterol [7] and decreased low-density lipoprotein (LDL) oxidation in humans [8]. AVA are a group of oat-specific diphenolic acids [9]. They are biosynthesized in most milling fractions, but most abundant in the pearling fraction, which is the outer layer of the oat kernel, such as oat bran and subaleurone layers [7, 10–12], compared to the inner starchy endosperm layer [6, 13]. AVA was first discovered as phytoalexins with antimicrobial properties (inhibiting fungal germination in vivo) in response to infection. Although AVA are found in the highest concentrations in oat bran, they are also expressed throughout the oat grains, oat hull, and eggs of white cabbage butterflies [14]. AVA concentrations are affected by genotype, growing environment, and growing conditions in different years [15]. AVA in different cultivars are highly variable, reaching a total level ranging from 2 to 300 ppm in oat grains [16]. However, a false malting process can significantly elevate the total AVA concentrations 25–40-fold, ranging from about 900 to 2000 ppm in the whole groats [17].

11.3 Chemical Structure and Biosynthesis AVA were first identified as N-cinnamoylanthranilate alkaloids by Collins with nuclear magnetic resonance spectroscopy, mass spectrum, ultraviolet spectroscopy and hydrolytic techniques after high-performance liquid chromatography (HPLC) separation [9, 18]. As the name implies, the structure of AVA (Figure 11.1) includes an anthranilate derivative and a phenylpropanoid derivative linked by an amide (pseudopeptide) bond. Among all AVA compounds, AVA-A (-2p or Bp ), AVA-B (-2f or -Bf ), and AVA-C (-2c or -Bc ) are the major forms, with AVA-C being the most abundant [19]. Collins and Dimberg have used different nomenclature systems to name AVA [6, 9]. Collins named each AVA by assigning an alphabetic descriptor (e.g., AVA-A, -B, and -C, etc.), while Dimberg developed a more systematic nomenclature to assign an upper-case letter to the anthranilate derivative (e.g., B = 5-hydroxyanthranilic acid) and lower-case letter to the phenylpropanoid derivative (e.g., p = p-coumaric acid, f = ferulic acid, c = caffeic acid). Later, a modified Dimberg nomenclature used a numeric descriptor for the anthranilate derivative (e.g., 2 = 5-hydroxyanthranilic acid) [20]. AVA-A, -B, and -C differ in the moiety of cinnamic acid, with substituents of –H, –OCH3 , and –OH at position 3 (or R2 in Figure 11.1), respectively. Recently, another three AVA isomers have been reported, namely AVA-O, -P, and -Q corresponding to -A, -B, and -C in terms of position 3 but differing in the numbers of double bonds at the pseudopeptide linkage [21]. AVA-O, -P and -Q may be abundant in oats after the false malting process [22]. Functioning as a phytoalexin, oat biosynthesizes AVA in response to crown rust infection. Mayama et al. found that AVA-A and -B production was negatively related to fungus hyphae growth among a variety of oats with known crown rust resistance genes [23, 24]. The biosynthesis of AVA (Figure 11.2) originates from erythrose-4-phosphate (E-4-P) converted from pentose phosphate metabolism and phosphoenolpyruvate (PEP) produced from glycolysis [20]. These two products are catalyzed into

Avenanthramides

Figure 11.1 Chemical structure of AVA.

3-deoxy-D-arabioheptulosonate-7-phoshate (DAHP) by DAHP synthase and react in the shikimate pathway [25]. Chorismate is yielded after the shikimate pathway, producing either anthranilate by anthranilate synthase or prephenate by chorismate mutase (CM). The former compound is thereafter converted to tryptophan, while the latter becomes the precursor to tyrosine or phenylalanine via catalysis of prephenate dehydrogenase (PDH) or prephenate dehydratase (PDT). The conversion of phenylalanine (or tyrosine) into the phenylpropanoids is the next key step in AVA biosynthesis [20]. Phenylalanine ammonia lyase (PAL) mediates transformation of phenylalanine to trans-cinnamic acid, which is subsequently hydroxylated into p-coumaric acid catalyzed by cinnamic acid 4-hydroxylase (C4H, a P450 monooxygenase). P-coumarate 3-hydroxylase (C3H) hydroxylate p-coumaric acid at the 3 position yields caffeic acid (CA), which can be further converted into ferulic acid by caffeate O-methyl transferase (COMT). The CoA thioester of p-coumaric, ferulic, and caffeic acid can be generated under 4-coumarate CoA ligases (4CL, adenosine triphosphate (ATP)-dependent enzymes) or from p-coumaroyl-coA under p-coumarate-CoA 3-hydroxylase (CC3H) or caffeoyl-CoA O-methyl transferase (CCOMT). The key enzyme, hydroxycinnamoyl CoA:hydroxyanthranilate N-hydroxycinnamoyl transferase (HHT), catalyzes the final step of AVA biosynthesis, which is the acylation of anthranilic acid and derivatives by the CoA thioester of p-coumaric, ferulic, or caffeic acid [20].

11.4 Effects of Processing 11.4.1

Avenanthramide Stability

AVA stability is affected by environment, such as temperature, pH value, and other physical factors. Dimberg et al. examined the stability of oat AVA retention under heat treatment, various pH levels, and UV light irradiation [26]. Pure synthetic AVA compounds

311

Pentose phosphate Glycolysis

DAHPS

E4P PEP

DAHP

shikimate

O

chorismate CM

O OH

PAL

PDT

OH

prephenate

NH2 trans-cinnamic acid

L-phenylalanine

O

O

O OH HO

PDH

4CL

HO p-coumaric acid

HO H T

R1

O

CoA OH

SCoA

4CL HO

HO

COMT

HO

Figure 11.2 Biosynthesis of AVA.

OCH3

feruloyl-CoA

O O OH

SCoA

4CL HO

OCH3 ferulic acid

T HH

O

CoA OH

N H

HHT

Avenanthramides

CCOMT O

O

HO OH caffeoyl-CoA

OH caffeic acid

L-tyrosine

ScoA

H

O

NH2

p-coumaroyl-CoA CC3H

C3H

OH

SCoA

anthranilate synthase

C4H

NH2

anthranilic acid

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Avenanthramides

and five oat-based products were tested in this study. Results showed that AVA-A and AVA-B were stable under different pH values within three hours or even 24 hours of incubation. AVA-C was completely degraded in alkaline conditions and almost totally decomposed under heating (95–98 ∘ C) at pH 7. AVA-B was degraded to a minor extent after heating at pH 7 and 12, while AVA-A remained unaffected in different pH levels and heating treatment. AVA-C and caffeic acid (corresponding to cinnamic acid of AVA-C) breakdown might not be a simple acid–base decarboxylation reaction, because acidification treatment did not restore the compounds [26]. Thus, this decomposition might be due to the amide bond hydrolysis to yield 5-hydroxylanthranilic acid and caffeic acid [9]. All three types of AVA were stable and there was no tendency to isomerize under irradiation at 254 nm for 18 hours. AVA in five oat-based products (yeast bread, yeast-fermented tea cake, muffin, macaroni, and fresh pasta) were also evaluated and found to be stable in most products except fresh pasta after baking or boiling treatments. The increase of free AVA during processing might be due to de novo synthesis, a release of conjugated forms or increased extraction after processing [26]. However, these mechanisms need to be verified in future studies. Mattila et al. [19] reported AVA content in commercial grain products and showed that total AVA-A, -B, and -C were similar both in traditional raw oat flakes and precooked oat flakes for porridge (27 versus 26 ppm of fresh weight). A recent study also showed a modest effect on AVA contents by milling, but a significantly higher AVA content after flaking, kilning, and steel cutting processes, which might be attributed to the liberation of bound AVA from food matrix during the process [27]. The same study conducted by Li et al. also evaluated AVA contents in wet-cooked porridge, ready-to-eat (RTE) puffed cereals and snack bars, indicating that whole grain porridge contained the highest AVA compared to the other two oat products.

11.4.2

False Malting Process

AVA content in a variety of oats in North America ranges from 4 to 150 ppm, which is dependent on many internal and external factors, such as genotype, environment, crop year, and location [28]. Oat bran, or more specifically the aleurone layer (the outer layer of endosperm), is known to contain higher AVA levels than other parts of oats [29]. However, Mattila et al. found that commercial oat bran contained only 13 ppm of total AVA compared to oat flakes with 27 ppm [19]. The relatively low AVA content in the commercial oat bran might be attributed to lack of an AVA enrichment process, such as steeping, germination, and malting, etc. [19, 30]. Collins and Burrows [28] reported a new false malting method to increase AVA concentrations in oats. Malting is a process of soaking and germinating oat grains, leading to nutrient composition changes, whereas in false malting selected (dormant oat varieties) or pretreated (nondormant oat varieties with dry heat process) oat grain is conventionally malted but prevented from germinating. Generally, nondormant oats are dry-heated at 30–40 ∘ C for 48–72 hours followed by further dry-heating at 70 ∘ C for 144–168 hours. Then the oats are anaerobically steeped by soaking in water at 4–40 ∘ C for 12–18 hours. Finally, for the purpose of false malting, oats are incubated at a temperature at 4–40 ∘ C for 96–120 hours [28]. The false malting process in oats can yield total AVA levels as high as 900–2000 mg/kg [17, 20]. Since regular oat varieties contain a

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relatively low AVA content, this new technique allows consumers to consume threshold response levels of AVA (30–60 mg) based on daily oat consumption of 50 g oat bran [17].

11.5 Absorption, Distribution, Metabolism, and Excretion Absorption, distribution, metabolism, and excretion (ADME) events of xenobiotics are widely studied in toxicology, nutrition, and pharmacology. The phytochemicals contained in food or beverages go through several steps in the body after oral indigestion and dissolution in the gut fluids, including ADME. Absorption is the diffusion or transportation of a compound from the site of administration into the systemic circulation [31]. Although many phytochemicals have been identified, along with their respective transcellular transporters on intestinal epithelium, such as ATP binding cassette (ABC) and solute carrier (SLC) transporters [32, 33], the mechanism of AVA absorption is still unclear. Distribution is the diffusion or transportation of AVA from the intravascular (systemic circulation) to the extravascular space (body tissues) [31]. After the compound enters systemic circulation, AVA and its metabolites will be distributed to the organs and other sites of action, where biochemical reactions occur and produce their pharmacological effects. Metabolism is the biochemical conversion or biotransformation of the phytochemical [31]. Metabolism of AVA occurs in enterocytes or hepatocytes and can be divided into two phases: phase I reactions include oxidation, reduction, and hydrolysis. The purpose of phase I reactions is to increase the hydrophilicity of the molecule, and expose or add a functional group (such as a hydroxyl group) to facilitate phase II conjugation reactions [33]. Cytochrome P450-dependent mixed-function oxidases (CYPs) play key roles in oxidation. After modifications in phase I metabolism, compounds undergo conjugations in phase II metabolism, including glucuronidation, sulfation, and methylation (Figure 11.3), to generate more polar and hydrophilic compounds, which become ideal substrates for active transporters on cell membranes and finally are excreted from the body. β-Glucuronide formation can be catalyzed by uridine diphosphoglucuronosyl (UDP) transferases (UGTs), while sulfation and methylation can be catalyzed by sulfotransferases (SULTs) and methyltransferases (MTs). UDP-glucuronic acid, 3′ -phosphoadenosine-5′ -phosphosulfate (PAPS) and S-adenosylmethionine (SAM) are donors for glucuronidation, sulfation, and methylation reactions to convert into UDP, 3′ -phosphoadenosine-5′ -phosphate (PAP) and S-adenosylhomocysteine (SAH) [34]. Excretion is the elimination of the phytochemical compounds or their metabolites from the body via renal and biliary processes [31]. 11.5.1

Bioaccessibility

After ingesting or consuming oat products, phytochemicals (e.g., AVA) are released from the food matrix and dissolved in gastric or intestinal fluid in the gut lumen. Liberation of AVA is the first step before ADME events, which is the process involved in the release of a compound from the food matrix [31]. Bioaccessibility measures the fraction of a compound released from the food matrix in the gastrointestinal tract, which becomes available for the gut endothelium and enters the portal vein [35, 36].

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Figure 11.3 Glucuronidation, sulfation, and methylation of AVA.

Li et al. reported phenolic recovery and in vitro bioaccessibility of three different whole grain oat products to Caco-2 human intestinal cells [27]. Results showed that total AVA ranged from 9.9 to 207.5 μg/g dry weight in the experimental samples, accounting for 57.3–90.6% of the total free phenolic, while ferulic acid was the dominant bound phenolic compound. AVA contents were modestly higher (p < 0.05) after kilning, cutting, and flaking processes, indicating that these oat treatments may increase liberation of bound AVA from oat matrix. Oat groats were milled and prepared as wet cooked porridge (20% oat flour in boiling water) or ready-to-eat products (puffed cereals and snack bars). Relative bioaccessibility for wet cooked porridge for AVA ranged from 3.4% to 37.0%, which is significantly lower than the puffed oat cereal product made from the same oat flour (19.1% vs 83.8% for AVA-A, p < 0.05). These in vitro data demonstrated that food processing of oat cultivars to ready-to-eat products may increase oat AVA release from the food matrix and make them more bioaccessible to intestinal cells for absorption. In fact, previous studies revealed that food matrix ingredients, such as salt, fat, and dietary fibers, may increase phenolic compound digestion and bioaccessibility [37–39], which might be an explanation for the increased bioaccessibility of ready-to-eat products in this study [27].

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11.5.2

Bioavailability

The biological efficacy of AVA is largely dependent on its bioavailability. Bioavailability is a measurement of the extent to which a therapeutically active compound reaches the systemic circulation and is available at the site of action [40]. Chen et al. first examined the bioavailability of AVA after gavaging hamsters with saline containing 0.25 g oat bran phenol-rich powder (40 μmol phenolics), and collected blood from 20 to 120 minutes [8]. The phenol-rich powder contained AVA-A (2.50 μmol/g) and AVA-B (1.97 μmol/g). After gavaging an oral dose of 0.63 μmol AVA-A and 0.49 μmol AVA-B, the maximum concentrations in plasma (Cmax ) of these compounds were 0.04 and 0.03 μmol/L respectively, which appeared at 40 minutes (Tmax ) after administration. Most of AVA-A and -B were eliminated by 120 minutes. The same research team also compared the apparent relative bioavailability among eight different phenolic compounds and found AVA-A and -B had lowest bioavailability [8]. Another animal study conducted by Koenig et al. further examined the conjugated and free AVA in plasma, liver, heart, and gastrocnemius of rats after administering synthetic AVA-A, -B, and -C by oral gavage at a dose of 20 mg/kg body weight [41]. Glucuronidase-sulfatase was used to free AVA from conjugated forms after phase II metabolism in the liver [8, 42]. Free and conjugated AVA concentrations were quantified over a 12-hour period at 0, 2, 4, and 12 hours. Peak plasma AVA concentrations occurred at one hour after administration. Liver and heart showed a higher AVA-B concentration, but a lower AVA-A and AVA-C than plasma and a large proportion of detected AVA-B was in the conjugated form. This indicated that AVA-B might be taken up faster than AVA-A and -C, which are related to different hydroxycinnamic acid moieties [41, 42]. The interesting phenomenon found in heart was that a rebound in AVA-B and -C concentrations occurred at 4 and 12 hours after returning to baseline at 2 hours. The authors explained that the AVA rebound observed in heart might be due to an enhanced uptake in heart after initial and dominant uptake by liver and skeletal muscles in the first couple of hours. In the skeletal muscles, AVA concentrations are much lower than liver and heart up to 12 hours after oral gavage, with most fractions in the conjugated forms. Koenig first determined the uptake and distributions of AVA in different tissues and found that different AVA compounds were taken up differently. However, the rank order of plasma concentration by AVA type (A ≫ B > C) is the same in rats, hamsters, and human [8, 41, 42]. Although AVA bioavailability has been investigated in vivo with animal models, similar human studies are required to illustrate the pharmacokinetic properties of this compound. Chen et al. first studied the pharmacokinetic parameters of total (free plus conjugated) AVA-A, -B and -C among six human subjects after consuming 0.5 or 1 g AVA-enriched mixture (AEM) extracted from oats [42]. In this study, times to reach maximum concentration (Tmax ) of AVA-A, -B and -C were 2.30, 1.75, and 2.15 hours and half times (T1/2 ) for elimination were 1.75, 3.75, and 3 hours. AVA-A, -B, and -C contents in AEM were 154, 109, and 111 μmol/g, and plasma maximal concentrations (Cmax ) of total AVA after consuming 0.5 and 1 g AEM reached 112.9 and 374.6 nmol/L for AVA-A, 13.2 and 96.0 nmol/L for AVA-B, and 41.4 and 89.0 nmol/L for AVA-C. Bioavailabilities (area under the curve/oral dose) were also compared and AVA-A showed significant higher bioavailability than AVA-B and -C. Recently, Zhang et al. examined the appearance of AVA in plasma (Figure 11.4) after oral ingestion of oat AVA in oat cookies and estimated key pharmacokinetic

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parameters [43]. Male and female nonobese participants (n = 16) consumed three cookies made with oat flour containing high (229.6 mg/kg, H-AVA) or low (32.7 mg/kg, L-AVA) amounts of AVA, including AVA-A, AVA-B, and AVA-C compounds. Participants consumed the cookies in the morning after a 10-hour fast, and blood samples were collected at 0, 0.5, 1, 2, 3, 5, and 10 hours after ingestion. Plasma total (conjugated and free) AVA concentrations were quantified using ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-QToF-MS), and pharmacokinetic parameters for each AVA moiety were estimated. After participants consumed the oat cookies, AVA-A, AVA-B, and AVA-C were present at peak concentrations in plasma between 2 and 3 hours for the H-AVA group (2.50, 2.04, and 2.29 hours for Tmax ) and between 1 and 2 hours for the L-AVA group (1.80, 1.50, and 1.32 hours for Tmax ). Cmax for AVA-A, AVA-B, and AVA-C was higher in the H-AVA (8.39, 8.44, and 4.26 ng/mL) than in the L-AVA (1.98, 2.43, and 1.33 ng/mL) group. AVA-B demonstrated a longer half-life (4.23 and 4.60 hours in H-AVA and L-AVA groups) and slower elimination rate than AVA-A (2.16 and 2.44 hours) and AVA-C (2.71 and 2.87 hours). The authors concluded that AVA found naturally in oats are absorbed after oral administration in humans. AVA-B has the slowest elimination rate and the longest half-life compared to AVA-A and AVA-C, while AVA-C demonstrated the lowest plasma concentrations of all three. Further studies are needed to determine the mechanisms contributing to the different plasma time-concentration profiles of AVA. Chen et al. [42] first described the relative bioavailability of AVA in humans. AVA-A, AVA-B, and AVA-C concentrations in the AEM were 46.09, 35.89, and 35.00 mg/g, respectively. Thus, the doses of AVA-A, AVA-B, and AVA-C in the high dose (1 g AEM) group were ninefold, fourfold, and fourfold higher than those in the H-AVA group from the oat cookies study [43]. Also, maximum plasma concentrations after consumption of 1 g AEM were 112.1, 31.6, and 28.1 ng/mL for AVA-A, AVA-B, and AVA-C reported by Chen et al., which were 13-fold, fourfold, and sevenfold higher than those in the H-AVA group from the oat cookies study. However, key pharmacokinetic properties such as Tmax and T1/2 were similar between both studies. These differences between the studies can be explained by a difference in AVA dose. Chen et al. used an AEM containing high concentrations of AVA, whereas Zhang et al. used cookies made with natural oat flour containing lower concentrations of AVA. The difference in bioavailability and elimination among AVA could be chemical structure dependent. The absorption profile of AVA-B differs from that of AVA-A and -C, with AVA-B having the highest Cmax , longest T1/2 , and shortest Tmax . These differences might be related to the different hydroxycinnamic acid moieties in AVA-A (–H), AVA-B (–OCH3 ), and AVA-C (–OH). That is, as AVA-B is more hydrophobic than AVA-A and AVA-C, this may lead to a slower elimination rate [42]. However, Koenig et al. [41] found that AVA-B showed the fastest elimination rate in rats. This discrepancy between human and rat studies might be due to species differences in phase I and II metabolism [44]. Unfortunately, like all other phytochemicals [45], both of these clinical trials revealed relative low AVA absorption after ingestion [42, 43]. The limitation for the current bioavailability studies is the lack of determination of absolute and relative bioavailability of AVA, and intravenous AVA or comparable biological products are required to estimate these two parameters. Further investigations are needed to determine the absolute bioavailability of other AVA compounds and the mechanisms contributing to the different absorption and elimination profiles of various AVA.

Avenanthramides

11.5.3

Biotransformation

The most common AVA metabolites after phase II metabolism are glucuronidated-AVA and sulfated-AVA (Figure 11.3). Koenig et al. first measured free and conjugated forms of AVA after 20 mg/kg AVA-A, -B, and -C oral administrations in rats [41]. Results showed that more conjugated AVA than free AVA were detected in plasma, liver, heart, and skeletal muscles, meaning most ingested AVA were biotransformed in phase II metabolism. Methylation modification (Figure 11.3) of AVA can be catalyzed by methyltransferases and this process was reported by Walsh et al. who identified methylated metabolites of AVA in human plasma [46]. Twelve healthy subjects consumed 70 g muffin made with 20 g AVA-enriched oat bran or a placebo muffin containing no oats, and blood samples were collected at different time points. UPLC-QToF-MS was used and identified methylated AVA metabolites (AVA-A and -O) in human plasma (identity score ≥90). In addition, aglycone forms of AVA-A and -O were also identified (identity score ≥80). Pharmacokinetic properties of this new metabolite were also calculated, and Cmax was 14.0 ± 8.2 ng/mL AVA-O equivalents and Tmax was 1.9 ± 0.7 hours for methylated AVA-O. One possible explanation for the low bioavailability of AVA could be hydrolysis of ingested AVA. The amide bond on AVA could be cleaved or hydrolyzed [47], yielding anthranilic acid as 5-hydroxyanthranilic acid and cinnamic acid as p-coumaric acid, ferulic acid, and caffeic acid for AVA-A, -B, and -C respectively. Although there is no direct evidence to show AVA is hydrolyzed into these phenolic acids, parts of the increased plasma phenolic compounds might be from hydrolysis of AVA. In the oat cookies study, Zhang et al. (not published) also observed that concentrations of plasma caffeic acid (an AVA-C hydrolysis product) increased after oat cookie consumption, but not concentrations of AVA-A and AVA-B hydrolysis products. This might be additional evidence explaining low plasma concentration of AVA-C. They also found that Tmax of the phenolic acids in this study were similar to AVA in hamsters, both reaching at 40 minutes and essentially eliminating by 120 minutes [8]. This mechanism also partially explains why plasma concentrations of AVA-C were lower than those of AVA-A and AVA-B. Additionally, the transporters on intestinal endothelium carrying AVA for absorption might be another explanation for the relatively low bioavailability. However, mechanisms of AVA absorption are still unclear, so a Caco-2 human intestinal cell model is required to explore these transporters and designing synergies to improve the bioavailability of AVA might be a solution for this issue [45]. The microbiota in the human gastrointestinal tract plays a special role in catalyzing and metabolizing phytochemicals by specific gut bacteria. These bacteria contribute to a series of reactions, such as hydrolysis, reduction, ring cleavage, demethylation, dihydroxylation, etc. [34, 48]. Wang et al. investigated the biotransformation of AVA using in vitro and in vivo fermentation models [47]. In the human microbiota study, AVA-C was incubated in vitro with fecal slurries obtained from six human subjects. The in vitro fermentation results demonstrated that AVA-C is biotransformed and metabolized into (i) reduction product dihydroavenanthramide (DH)-2c; (ii) hydrolysis product caffeic acid (CA); and (iii) reduction of hydrolysis products DH-CA. Although major metabolites were identified, interindividual differences among the six human subjects in the metabolism of AVA-C were also found, shown as differences in AVA-C biotransformation rates and the formation of cleaved metabolites. The authors further showed these

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biotransformation processes were mainly metabolized by human microbiota, but not liver and intestinal microsome and S9 fractions [47, 49]. These studies show that individual differences in gut microbiota composition may lead to variations in AVA bioavailability, especially influencing the metabolism and bioavailability of AVA-C [47], which explains the low bioavailability of AVA-C in all three compounds [43]. In the mouse study, Wang et al. identified eight metabolites (5-hydroxyanthranilic acid, dihydrocaffeic acid, caffeic acid, dihydroferulic acid, ferulic acid, dihydroavenanthramide-C, dihydroavenanthramide-B, and avenanthramide-B) in the urine after intragastrically treated AVA-C (-2c) (200 mg/kg) in mice. Both in vitro and in vivo experiments showed that reduction of the C7′ –C8′ double bond as well as cleavage of its amide bond were the major metabolic routes of AVA-C [47].

11.6 Health Benefits 11.6.1

Antioxidant Activity

Oxidative stress plays a crucial role in numerous chronic diseases, and AVA have been shown to have protective effects by scavenging free radicals and exerting antioxidant capacities in vitro and in vivo [6, 8, 16, 50, 51]. AVA contain an α,β-unsaturated carbonyl group (O=CR)-Cα = Cβ -R, which is susceptible to neutrophilic attack and plays a role as Michael acceptor. Heme oxygenase catalyzes the degradation of heme, and the inducible form HO-1 is involved in the oxidative stress regulation and redox reactions [52]. HO-1 expression is regulated by the binding of nuclear factor erythroid 2-related factor 2 (Nrf-2) to antioxidant response element (ARE) on DNA at the transcriptional level [53]. However, Nrf-2/Keap-1 (Kelch-like ECH-associated protein 1) complex prevents the translocation of Nrf-2 from cytosol to the nucleus and initiates target mRNA expression [54]. Michael acceptor groups, such as the α,β-unsaturated carbonyl group in AVA, can react with cysteine sulfhydryl groups of Keap-1 and activate the Keap1-Nrf2-ARE signaling pathway, regulating downstream HO-1 mRNA expression [55]. Fu et al. investigated whether AVA could induce HO-1 expression through the activation of Nrf-2 translocation in HK-2 cells [56]. In this study, AVA-A, -B, and -C increased HO-1 expression in both a dose- and time-dependent manner. In addition, AVA-A, -B, and -C stimulated Nrf-2 translocation from cytoplasma to nucleus, showing at least 50% decrease of cytosolic Nrf-2 levels and a 2.5-fold increase in nuclear Nrf-2. However, the addition of N-acetylcysteine (NAC) decreased HO-1 expression induced by all three types of AVA, indicating that reactive oxygen species (ROS) are involved in the upregulation of HO-1. The authors further tested dihydro-AVA (loss of α,β-unsaturated carbonyl group after hydrogenation) and found no effect on HO-1 expression in HK-2 cells. These results demonstrated that AVA may act as an antioxidant in trapping ROS due to its specific α,β-unsaturated carbonyl structure on aromatic rings, which are commonly known to scavenge free radicals [16, 51, 57]. Osteoblasts and osteoclasts are bone cells regulating calcium homeostasis of bone formation and resorption, respectively. Pellegrini et al. [58] investigated the regulation of AVA-A, -B, and -C on osteoblast gene expression and survival in vitro. OB-6 osteoblastic cells were cultured with 0.01, 0.1, 1, 10, and 100 μM of AVA-A, -B, and -C, separately. Gene expression of the osteoblast markers osteocalcin, runx2, collagen 1, osterix,

Avenanthramides

and alkaline phosphatase were not affected by AVA, but receptor activator of nuclear factor κ-B ligand (RANKL), an indicator of osteoclast differentiation and activation [59], was not detected, which indicated reduced bone resorption. Low concentrations of AVA-B and -C (0.01 and 0.1 μM) increased osteoprotegerin (OPG, an antiosteoclastogenic cytokine) gene expression. To further evaluate the effect of various doses of AVA-B on basal and induced apoptosis in OB-6 cells, a proapoptotic agent, etoposide (50 μM), was used and cell viability was measured. Results showed that AVA-B did not affect basal levels of apoptosis of osteoblastic OB-6 cells, but protected etoposide-induced OB-6 cell apoptosis in a dose-dependent way. These in vitro data revealed that oat AVA may have an antiosteoclastogenic property and prevent cell apoptosis, which increases the survival of osteoblast. However, more in vivo studies need to be performed to further test this hypothesis. Antioxidant enzymes, such as superoxide dismutase (SOD) and glutathione peroxidase (GPx), play key roles in scavenging free radicals and balancing oxidative stress [60]. Ren et al. investigated the effects of oat AVA-rich extract on the activity and gene expression of antioxidant enzymes in D-galactose-induced oxidative stress in mice [61]. Three doses of AVA-rich extract (250, 500, 1000 mg/kg) were administered to the mice and antioxidant enzyme activity or gene expression was observed. AVA-A, -B, and -C concentrations in AVA-rich extract were 4.37%, 5.36%, and 6.07%, respectively. Results showed that administration of the extract reversed D-galactose-induced oxidative stress marked by a lipid peroxidation marker, hepatic malondialdehyde (MDA) concentration, and increased enzymatic activities and gene expressions of hepatic SOD and GPx. In the oat AVA bioavailability study, Chen et al. evaluated antioxidant capacity and lipid peroxidation in humans after acute oat AVA consumption [8]. It was shown that consuming 1 g AEM (AVA-A, -B, and -C concentrations in the AEM were 46.09, 35.89, and 35.00 mg/g) only elevated plasma GSH by 21% at 15 minutes of exercise, and by 14% at 10 hours after exercise, but had no effects on other antioxidant levels or lipid peroxidation. Liu et al. first conducted the long-term supplementation in human subjects, in which they administered oat AVA-enriched extract (OAE) capsules to 120 healthy subjects for one month and observed the long-term antioxidant effect [62]. Results showed that SOD activity was elevated by 7.3% and 8.4%, respectively, in groups taking four capsules (1.56 mg AVA) or eight capsules (3.12 mg AVA) per day. They also detected a significant increase on reduced glutathione (GSH) and a decreased MDA level by 17.9% and 28.1%. Lipid profiles, such as total cholesterol (TC), triglyceride (TG), and LDL cholesterol, were significantly reduced by 11.1%, 28.1%, and 15.1%, respectively, while high-density lipoprotein (HDL) cholesterol was increased by 13.2%. Although this study was not conducted in cardiovascular patients, it revealed for the first time the cardiovascular protective effects of oat AVA in humans. 11.6.2

Antiinflammatory Activity

Dihydroavenanthramide is an analog of AVA, with a reduced double bond at C7′ -C8′ positions (Figure 11.5). Wang et al. identified dihydroavenanthramide-B and -C as metabolites after intragastrically administering AVA-C (-2c) (200 mg/kg) in mice, indicating that reduction of AVA by gut microbiota is one of the metabolism pathways [47]. Lv et al. [63] reported that a synthetic AVA analog, dihydroavenanthramide-D (DHAvD), exerted protection on pancreatic β-cells. Interleukin (IL)-1β and interferon

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O

OH

OH H N

Figure 11.5 Chemical structure of dihydroavenanthramide D.

O

(IFN)-γ induced rat pancreatic β-cell (RINm5F) damage was restored by addition of 5 μM DHAvD, and these cytoprotective effects from DHAvD were caused by the inhibition of nitric oxide (NO) production via the suppression of iNOS expression. Since the NF-κB pathway is involved in the regulation of iNOS expression, this study further explored NF-κB translocation from cytoplasm to nucleus in rat pancreatic β-cell line RINm5F cells. The authors found that pretreatment with DHAvD suppressed cytokine-induced p65 and p50 complex (active NF-κB) translocation to nucleus and binding to DNA. Preventive effects of DHAvD were further assessed using isolated islets from rat and results were similar to the in vitro findings mentioned above. Type 1 diabetes is an autoimmune disease, initiated by destruction of pancreatic β-cells, which are responsible for secreting insulin in response to high glucose conditions [64]. In this study, islet functions were also tested using isolated islets treated by cytokines and a type 1 diabetes model induced by streptozotocin (STZ). Both models showed that islet functions were degenerated after cytokine or STZ treatments, with significantly lower insulin secretion and higher fasting glucose. However, DHAvD pretreatment or injection blocked this destructive effect and restored insulin secretion back to control levels. In addition, an animal model was used to investigate DHAvD protection against STZ-mediated type 1 diabetes in ICR mice. Prior injection with DHAvD (1.5 g/kg DHAvD daily for three days) inhibited the STZ-induced islet destruction and maintained islet cell function by restoring insulin secretion. The in vivo study also proved the same hypothesis tested in vitro that DHAvD can protect islets and pancreatic β-cells from destruction by inhibiting NF-κB activation, which leads to decreased iNOS expression and NO production. Yang et al. evaluated the effect of AVA-A, -B, and -C on inhibition of tumor necrosis factor-α (TNF-α)-induced NF-κB activation using mouse myoblast C2C12 cell lines [16]. Results showed that three AVA fractions (25–360 μM) suppressed NF-κB activation in a dose-dependent manner. EC50 values (half maximal effective concentration) for the inhibition of NF-κB activation were 64.3 μM for AVA-C, 29.3 μM for -B and 9.10 μM for -A, indicating -A has a stronger inhibitory effect than -C and -B, even though previous research showed -C has the strongest antioxidant capacity [7, 16]. Differences in antioxidant capacities and NF-κB inhibitory effects might be due to the structural variations among the three AVA [16]. This in vitro study further strengthens the data reported by Koenig et al. that AVA supplementation can alleviate muscle injury and inflammation among young and postmenopausal women after eccentric exercise, mainly through inhibiting NF-κB binding to DNA and decreasing ROS production [65, 66]. Physical activity, especially heavy exercise, induces production of ROS, leading to oxidative damage and inflammation [67]. Ji et al. first found that synthetic AVA supplementation (AVA-C) affected ROS production and antioxidant enzyme activities in female Sprague–Dawley rats [50]. 0.1 g/kg AVA-C was added to the diet for 50 days and the rats were subjected to acute exercise on the treadmill at 22.5 m/min, 10% grade for one hour. Results showed that AVA-C supplementation alleviated exercise-induced

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Figure 11.6 AVA protects against exercise-induced muscle inflammation and oxidative damage in rats.

ROS production in the soleus muscle (Figure 11.6a), and lipid peroxidation in the heart (Figure 11.6c), but enhanced lipid oxidation in the deep vastus lateralis muscle (DVL). For antioxidant enzymes, AVA-fed rats showed elevated SOD activity in the DVL (Figure 11.6b), liver, and kidney. In addition, GPx activity was upregulated in the heart and DVL after AVA-C supplementation. This study showed for the first time that AVA may attenuate exercise-induced ROS production and lipid peroxidation in selected body tissues of rodents and set the stage for studies in human subjects [65, 66]. Downhill running (DR) or downhill walking (DW), as a typical format of muscle eccentric contraction, can induce overproduction of ROS and inflammatory responses [68]. Delayed-onset muscle soreness (DOMS) is a symptom of exercise-induced muscle damage after unaccustomed eccentric exercise [69, 70]. The macrodamage is the initial response to mechanical stretching, accompanied with myofibril filament ruptures [69], and activation of pain receptors within muscle connective tissues leading to muscle soreness and swelling sensation [70, 71]. During 0–24 hours after eccentric exercise, adhesion molecules (i.e., intercellular adhesion molecules, ICAMs and vascular cell adhesion molecules, VCAMs) on the surface of endothelium are induced by proinflammatory cytokines (i.e., IL-1β and TNF-α) released from damaged muscle fibers. The release of chemoattractants and proinflammatory cytokines (i.e., IL-6, IL-8) attracts phagocytic cells (monocytes and neutrophils) to migrate to the injury site [72, 73].

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This process is accompanied by accumulation of neutrophils, monocytes, and M1 macrophages (promoting inflammation) in the injured muscle fibers, reaching peak concentrations between 24 and 48 hours [74]. These phagocytic cells engulf (degranulation and phagocytosis) cellular debris from damaged muscle fibers and release proteases, inflammatory cytokines, and reactive oxygen and nitrogen species (RONS) [72, 73]. The NF-κB pathway can be further activated by imbalanced oxidative stress and upregulated inflammatory marker expression (i.e., IL-1β, IL-6, TNF-α), amplifying inflammation signals [75]. After 72 hours, M1 macrophages convert into nonphagocytic M2 macrophages (antiinflammatory effects), reaching peak concentration at about 96 hours [73], and may remain elevated for several days after muscle injury [76]. M2 macrophages release antiinflammatory cytokines (i.e., IL-10) and growth factors to help muscle fiber regeneration and remodeling, with the involvement of satellite cells [73, 76]. Koenig et al. first demonstrated the antiinflammatory and antioxidant effects of AVA in humans [65]. A DW-induced inflammation model among postmenopausal women was established to test the long-term AVA supplementation effect. Subjects were divided into two different AVA doses, consuming 9.2 or 0.4 mg AVA/day. AVA was supplemented by ingesting two oat cookies per day for a period of eight weeks. AVA decreased ROS generation from neutrophil respiratory burst (NRB) at 24 hours post-DW and C-reactive protein (CRP) level 48 hours post-DW (Figure 11.7a). 1.8

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Figure 11.7 AVA exerts antioxidant and antiinflammation effects in human downhill exercise.

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Inflammatory response, such as mononuclear cell NF-κB binding to DNA, was inhibited (Figure 11.7b) and plasma interleukin (IL)-1β concentration was reduced in the AVA group. These changes might be due to increased blood-borne antioxidant defense, such as elevated plasma total antioxidant capacity (TAC) (Figure 11.7c) and erythrocyte SOD activity [65]. Another similar study published recently investigated the antioxidant and antiinflammatory effects of AVA in a DR model among young women [66]. The dietary regimen and exercise protocol were exactly the same as the previous DW study among postmenopausal women [65], except for the treadmill speed. Plasma creatine kinase (CK) and inflammation marker TNF-α increased after DR but were alleviated in both AVA and control groups. The AVA group suppressed NRB (ROS generation) at 24 hours post-DR (Figure 11.7d). Inflammation marker (IL-6) and monocyte NF-κB binding to DNA were lowered 24 hours post-DR in the AVA group compared to control group. This study observed a similar increase in plasma TAC after eight weeks dietary regimen as the previous DW study [65]. In addition, the AVA supplementation group increased plasma GSH:GSSG ratio in response to DR and decreased erythrocyte GPx activity. These results suggest that AVA may be used as potential sports nutrition supplements in reducing muscle inflammation induced by heavy exercise. 11.6.3

Antiatherosclerosis Activity

Atherosclerosis, a polygenic disease [77], is developed and progressed by impaired oxidative stress, elevated inflammation, and endothelial dysfunction [78]. As shown in Figure 11.8, under oxidative conditions, LDL is oxidized to oxidized low-density lipoprotein (oxLDL), a key step to stimulate adhesion molecule expressions, such as E-selectin, VCAMs and ICAMs, and subsequently attract immune cells, such as lymphocytes and monocytes [78–80]. Proinflammatory cytokines promote monocyte transmigration into the subendocardium and their subsequent differentiation into macrophage scavenger cells. After monocytes are differentiated into macrophages, they ingest oxLDL and form foam cells, leading to the formation of a fatty streak and eventually atherosclerotic fibrous plaque. Fatty streaks and macrophages secret proinflammatory cytokines such as TNF-α, IL-1β, IL-6, and IL-8, as well as monocyte chemotactic protein MCP-1, VCAM-1, and CRP, a systemic inflammatory marker, mainly through activation of the NF-κB pathway [81]. TNF-α and IL-6 may serve as markers of inflammation for the prediction of future cardiovascular risks [80, 82]. TNF-α promotes IL-6 and IL-8, as well as increasing ROS production via the mitochondrial respiration chain, forming a vicious circle [83]. IL-6 acts as a mitogenic stimulus and is responsible for the migration and proliferation of smooth muscle cells involved in atherosclerosis development [10, 84, 85]. These cytokines further induce the transition of vascular smooth muscle cells (VSMC) from the quiescent “contractile” state to the active “synthetic” state, leading to the migration and proliferation of VSMC [86], and contribute to plaque formation in atherosclerosis. Endothelial cells play another critical role in atherosclerosis development because they regulate blood flow and artery remodeling and repair. Endothelial dysfunction appears to be the initial sign of early atherosclerotic development due to decreased NO availability and increased vasoconstrictors such as angiotensin-II and endothelin-I under oxidative stress [87]. Increased oxidative stress inhibits NO production, leading

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Figure 11.8 AVA inhibits the development of atherosclerosis in multiple pathways.

to endothelial dysfunction and inflammation related to oxLDL [2, 79, 87]. In the presence of endothelial dysfunction, reduced endothelial flow-mediated vasodilation caused by NO impairs reactive hyperemia [88]. Liu et al. first tested the potential antiatherogenic activity of partially purified AEM in human aortic endothelial cells (HAEC) [10]. Pretreatment of HAEC with AEM for 24 hours significantly reduced monocyte-HAEC adhesion stimulated by IL-1β in a dose-dependent manner. No effects were shown after supplementation of HAEC with AEM in unstimulated cells, but pretreatment of HAEC with AEM at 20 and 40 μg/mL decreased the production of vascular adhesion molecules (ICAM-1, VCAM-1, and E-selectin) and proinflammatory cytokine productions (IL-6, IL-8, and MCP-1). However, lower concentration at 4 μg/mL AEM supplementation had an inhibitory effect on IL-6 production but no effect on other cytokines (IL-8 and MCP-1) in HAEC. In addition, these inhibitory effects were comparable to the positive control with 17 μg/mL vitamin E. This study demonstrated that AVA inhibits adhesion molecules and proinflammatory cytokines in HAEC, suggesting a possible mechanism by which oat consumption could reduce atherosclerosis. Guo et al. examined whether the inhibitory effect of AVA on the expression of proinflammatory cytokines was mediated through NF-κB-dependent transcription [89]. Confluent HAEC monolayers pretreated with AVA-enriched extract of oats, synthetic AVA-C, or CH3 -AVA-C (a methyl ester derivative of AVA-C) inhibited IL-1β-induced activation of the NF-κB pathway in a dose-dependent manner. To test whether the reduction of cytokine secretion (IL-6, IL-8, and MCP-1) was regulated at

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the transcriptional level, multiple approaches were used such as NF-κB DNA binding assay, NF-κB luciferase reporter assay, proteasome activity assay, and western blot analysis. It was verified that the inhibitory effects of AVA on NF-κB activation were mediated by inhibiting the phosphorylation of IκB kinase (IKK) and IκB, as well as reducing proteasome activity [89]. This study showed that the NF-κB pathway played a key role in the AVA-mediated regulation of proinflammatory cytokines from mRNA to protein levels in inflammatory diseases. Oat AVA also improved VSMC and HAEC functions by regulating NO production. In the development of atherosclerosis, VSMC are stimulated by chronic inflammation [86] and activated VSMC proliferate, migrate and thicken the intimal layer of arterial walls. Generation of the vasodilation agent NO by endothelial NO synthase (eNOS) is known to protect against cardiovascular dysfunction [2, 90]. Nie et al. examined the effects of AVA-C on NO production in VSMC and HAEC [91]. 120 μM AVA-C inhibited VSMC proliferation by 50% and increased doubling time from 28 to 48 hours. VSMC cell numbers were also inhibited by AVA-C (40, 80, and 120 μM) in a dose-dependent manner. AVA-C also significantly and dose-dependently increased NO production and eNOS mRNA expression in both VSMC and HAEC. This study first demonstrated that oat AVA manifests the possible endothelial protection mechanism by regulating eNOS gene expressions and affecting NO production. These results provide potential mechanistic evidence to support the findings that regular oat consumption is associated with a reduced risk of coronary heart disease [92, 93]. However, AVA concentrations in VSMC and HAEC in vivo after oral consumption of oat products may not reach this high level (40–120 μM, optimum concentrations for both high biological effects and low cytotoxicity in vitro) based on AVA contents of current oat products and relative low bioavailability after ingestion. Further studies determining signal pathways elucidating the upregulation of eNOS mRNA expression will help to clarify the mechanisms. Nie et al. [94] demonstrated an 80 μM AVA-C arrested cell cycle in G1 phase in a rat embryonic aortic smooth muscle cell line A10, showing decreased S phase cells and increased G0 /G1 phase cells. AVA-C treatment also suppressed FBS-induced hyperphosphorylation of pRb (phosphorylation of retinoblastoma protein) and associated cyclin D1, a crucial regulator for G1 -S phase transition [95]. AVA-C also elevated tumor suppressor p53 protein levels in a dose-dependent manner, and this led to the upregulation of p21cip1, a transcriptional target of p53 and regulator for G1 phase arrest [96]. This study is the first to demonstrate how AVA attenuates atherosclerosis from an aspect of antiproliferative effect on VSMC, and reveals the mechanisms are arresting G1 phase by upregulation of the p53-p21cip1 pathway as well as inhibition of pRb phosphorylation [94]. Atherosclerosis is a disease (Figure 11.8) triggered by multiple risk factors and progressed by impaired oxidative stress, elevated inflammation, and endothelial dysfunction [77, 78]. The most common lipid disturbances in humans with atherosclerosis include increased LDL with/without increased very low-density lipoprotein (VLDL) and decreased HDL/(LDL + VLDL) ratio [78]. The LDL receptor distributes cholesterol to both hepatic and extrahepatic tissues through internalizing LDL cholesterol and reduces free cholesterol. Thomas et al. recently showed that dietary oat AVA supplementation suppressed atherosclerosis in vivo in LDLr−/− mice fed a high-fat diet [97]. LDLr−/− mice were fed a regular (10 ppm AVA) diet or false malted oats (451 ppm AVA) for 16 weeks. While both

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dietary groups significantly (p < 0.05) decreased high fat-induced atheroma lesions in the aortic tricuspid valve, the high-AVA group significantly lowered the numbers of lesions in the descending aorta compared to the control group. However, VCAM-1 was not significantly reduced in the lesions of aortic valves in mice fed a high-fat diet containing high-AVA. More importantly, both regular and false malted oats decreased blood total cholesterol levels to a similar extent, indicating that the significant decrease in aortic lesions in the false malted oats group was attributed to higher AVA content rather than decreased cholesterol levels. 11.6.4

Anticancer Activity

Previous research has shown that high intake of whole grains reduces colon cancer risks [98, 99]. Chronic inflammation and cyclooxygenase-2 (COX-2) expression are associated with epithelial carcinogenesis and cancer cell proliferation, while AVA was shown to inhibit inflammatory pathways [16, 89, 100]. Guo et al. first examined the effect of AVA on the regulation of COX-2 expression and prostaglandin E2 (PGE2) in macrophages, colon cancer cell lines, and proliferation of human colon cancer cell lines [100]. In this study, AVA-enriched extract of oats showed no effect on COX-2 expression, but inhibited COX enzyme activity and PGE2 production in mouse peritoneal macrophages. AVA-enriched extract of oats and AVA-C individually suppressed cell proliferation of both COX-2-positive and -negative human colon cancer cell lines, but had no effects on COX-2 expression or PGE2 productions in COX-2-positive colon cancer cells. These results showed that reduction of colon cancer is mainly due to reduced macrophage PGE2 production and non-COX-dependent antiproliferative effects from AVA on colon cancer cells [100]. The Wnt/β-catenin signaling pathway has been shown to induce cell proliferation and cause tumor growth [101]. Wang et al. examined the effects of phytochemicals, including AVA, on modulating Wnt/β-catenin signaling using HeLa cells [102]. AVA-A and -B individually attenuated 30% transcriptional induction of Wnt signaling at 40 μM concentrations and only AVA-A showed significant and dose-dependent antiproliferative activity in stable Wnt reporter HeLa cells. Furthermore, this study revealed that AVA-A triggered cellular β-catenin protein degradation, decreased nuclear localization of β-catenin and suppressed downstream oncogenic effector c-myc expression. Although this study revealed AVA as a potential chemopreventive phytochemical, further research using in vivo models of cancer is necessary to strengthen these findings. Dihydroavenanthramide is an analog of AVA, with a reduced double bond at C7′ -C8′ positions. AVA-C can be biotransformed into reduction product dihydroavenanthramide (DH)-2c by the human microbiota [47]. Wang et al. also discovered that similar AVA metabolites DH-2c and DH-2f exert inhibitory effects on HCT-116 human colon cancer cells. They found that DH-2c could exhibit a stronger inhibitory activity than 2f, with respective half-inhibitory concentration (IC50 ) of 158 μM compared to 363 μM. DH-2f also showed stronger inhibitory effects than 2f, with IC50 of 257 μM compared to more than 400 μM. These results showed that biotransformation of AVA may retain their pharmacologic activities. Lv et al. first found the antiinflammatory effect of a new analog of AVA (dihydroavenanthramide-D, DHAvD) in pancreatic β-cells [63]. To further expand the application of this new synthetic compound, Lee et al. studied the effects of

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DHAvD on MCF-7 human breast cancer cells [103]. Invasion and metastasis [104] play crucial roles in the development of breast cancer and these processes require degradation of extracellular matrix (ECM) by matrix metalloproteinases (MMPs). Previous research showed MMP-9 is a key biomarker in the invasion and metastasis of human breast cancer [105, 106]. In this study, MMP-9 expression was elevated by 12-O-tetradecanoylphorbol-13-acetate (TPA), but was suppressed by DHAvD (5 μM). Mitogen-activated protein kinase (MAPK) pathway modulators (ERK and JNK) were suppressed by DHAvD, leading to inhibition of NF-κB and activator protein-1 (AP-1) binding to DNA induced by TPA. DHAvD treatment also reduced TPA-induced MCF-7 cell invasion by 88%, consistent with MMP-9 expression. This study revealed a new potential mechanism by which synthetic AVA compound DHAvD can suppress MMP-9 and invasion ability of MCF-7 breast cancer cells by inhibiting MAPK/NF-κB and MAPK/AP-1 pathways. MMPs were also found to be upregulated in human dermal fibroblasts exposed to ultraviolet B radiation, accompanied with overproduction of ROS. Kim et al. showed that DHAvD reduced UVB irradiation-induced photoageing by blocking ROS and MMP-1 and MMP-3 expression in human dermal fibroblasts [107]. 11.6.5

Antiobesity Activity

Caenorhabditis elegans is a small, free-living nematode and multicellular organism that conserves 65% of the genes associated with human disease [108, 109]. C. elegans has been widely used in obesity studies not only because it regulates feeding and satiety, but also because it possesses insulin signaling and lipid oxidation pathways [109]. Gao et al. [108] fed wild-type and null strains of C. elegans with various percentages of oat flakes (0.5%, 1.0%, or 3%) with and without 2% glucose, and the oat flakes contained 20.8 ppm total AVA (5.4 ppm -C, 8.8 ppm -B, 5.3 ppm -A, and 1.2 ppm -AA). Results showed that oat consumption decreased intestinal fat deposition and increased pharyngeal pumping rate, a marker of life span in C. elegans which is an aging-related neuromuscular behavior [110]. In addition, oat consumption also upregulated lipid metabolism-relevant mRNA expression (cholecystokinin receptor homolog, guanylyl cyclase-8 and carnitine palmitoyltransferase-1 and -2), showing an augmented β-oxidation and metabolic rate after oat consumption. However, additional 2% glucose reduced lipid metabolism gene expressions (increased intestinal fat deposition) in daf-16- and daf-16/daf-2-deficient mutants. Furthermore, principal component analysis showed that the above changes were related to daf-16, daf-2, and sir-2.1 genes, which are human homologs of forkhead box protein O (FOXO), insulin/insulin-like growth factor (IGF)-1 receptor, and NAD-dependent protein deacetylase sirtuin-1, respectively. The Daf-2 gene, coding for the insulin/IGF-1 receptor, negatively correlates with the life span of C. elegans in a DAF-16/FOXO-dependent manner [111], and increased life span can be reversed by hyperglycemia [108, 112]. These data suggested that oat consumption is beneficial in reducing fat accumulation, improving lipid metabolism induced by hyperglycemia, and finally increasing life span [108]. However, future studies investigating glucose and fatty acid metabolism of AVA in humans are necessary. Obesity is closely related to vascular dysfunction and atherosclerosis. The etiology of obesity is related to a chronic low-level inflammatory state and increased oxidative stress in adipose tissues of obese subjects [113, 114]. Previous in vitro and in vivo studies have revealed antioxidant and antiinflammatory capacities of oat AVA due to its inhibition

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of ROS generation and proinflammatory cytokine production [50, 89, 91, 94]. To evaluate the effects of AVA-enriched oats on inflammation in humans, McKay et al. [115] conducted a pilot study among 16 older overweight and obese subjects with central adiposity (BMI 28–38 kg/m2 ). A smoothie made with AVA-enriched oat bran (90 mg AVA, from false malted oat kernels) and a placebo diet were supplemented for eight weeks. Oat smoothie reduced inflammatory marker VCAM-1 concentrations by 13% at four weeks (p = 0.031) and by 10% at eight weeks (p > 0.05) compared to placebo. Serum amyloid A-1, an acute phase protein response to inflammation [116], was also reduced by 18% at four weeks and 43% at eight weeks, but the change was not significant. These pilot data revealed antiinflammatory effects of oat AVA in aged and overweight/obese subjects, and suggested that supplementing AVA in whole food format (i.e., AVA-enriched oat bran) may be an economical and feasible part of similar human feeding studies. 11.6.6

Antiitch Activity

AVA are shown to inhibit NF-κB pathways in HAEC and downregulate inflammatory marker expressions, such as TNF-α, IL-1, and IL-6. Sur et al. [117] first explored the effects of AVA extraction (100 ppm) on the NF-κB pathway in keratinocytes. AVA were found to inhibit TNF-α-induced degradation of IκB, accompanied with decreased phosphorylation of the p65 subunit of NF-κB. In addition, NF-κB luciferase reporter assay revealed that cells pretreated with AVA showed a 1.7-fold inhibition of TNF-α-induced NF-κB activation. This treatment also downregulated proinflammatory cytokine IL-8 production by 1.4-fold. These data revealed a new atopic application of AVA in dermatology to attenuate skin inflammation and itch, such as atopic dermatitis and eczema [118]. Sur et al. previously demonstrated that the NF-κB pathway could be inhibited in keratinocytes by as little as 100 ppm AVA [117]. In the same study, they established inflammation in murine models of contact hypersensitivity (oxazolone-induced ear edema), neurogenic dermatitis (resiniferatoxin-induced ear edema), and itching (48/80 histamine release compound-induced itch response). The contact hypersensitivity model showed that topical application of AVA with 2 and 3 ppm significantly reduced ear edema by 43% and 67%, respectively. The neurogenic dermatitis model with the same AVA doses revealed a 32% and 46% reduction in ear edema. The pruritus (itching) model resulted in scratching times reduced by 41% by applying 3 ppm AVA on the skin. These results, together with in vitro data in keratinocytes, showed that topical application of avenanthramides is effective in reducing NF-κB-mediated inflammation and itch response at relative low concentrations [117].

11.7 Conclusions and Future Research Natural products with pharmaceutical effects are desirable due to lower cost and fewer side-effects. Oat has been well known for its excellent dietary fibers and multiple nutrients for a long time, but its antioxidant and antiinflammatory effects have only recently been investigated. Dietary components such as AVA and β-glucan in oats modulate cholesterol homeostasis and systemic inflammation, and influence development of atherosclerosis [10]. Midwest states in the US are known national leaders for food industry and biomedical research products, and these states (i.e., Minnesota,

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Wisconsin, and Michigan) have relatively high oat production although hitherto the crop has been limited by its low commercial value. The discovery of benefits from AVA may lead to commercialization of high-AVA oat food products, as well as nutraceutical products. In addition, developing value-added products could boost oat growth and production and help local agriculture and world export. Besides natural AVA forms, derivatives of AVA also demonstrate therapeutic effects in multiple cell lines and these agents may have great potential for the pharmaceutical and nutraceutical industries. The future of AVA is bright, but more extensive clinical trials are required to determine the pharmacokinetic properties and potential therapeutic effects in humans. Although AVA demonstrates great potential as a novel antioxidant and antiinflammatory agent, the low absorption is still the biggest concern because biological efficacy largely depends on the concentration at the site of action. Thus, in addition to exploring greater benefits with synthetic compounds, new studies are necessary to establish recommended daily oat consumptions to achieve threshold response levels for health benefits. Currently, most studies are limited to cell cultures or animal models, focusing more on biomarkers than functional indicators. Therefore, clinical trials are urgently required to clarify potential benefits of AVA in the complicated body system. In addition, bioaccessibility studies using in vitro models may elucidate the absorption and transportation mechanisms of AVA and reveal potential transporters in the ADME events. Answering these questions and seeking other synergistic compounds to improve AVA absorption will be important to increase AVA bioavailability [45]. In vitro studies revealed that the antiinflammatory effects of AVA occur through inhibition of the NF-κB pathway [89]. This might provide us with greater opportunities to apply AVA and its derivatives to various pathological disorders, such as obesity, atherosclerosis, ischemic heart disease, and delayed-onset muscle soreness. NF-κB activation in muscle fibers escalates the process and provokes systemic inflammation that could have broad health outcomes such as muscle pain and chronic inflammation, leading to underperformance and fear of participation in exercise and sports [65, 119]. Pharmacological treatment has been controversial as it interrupts the normal healing process [120]. Thus, exercise physiologists and nutrition scientists are seeking a natural, inexpensive, and widely available dietary supplement with antioxidant and anti inflammatory effects. The future application of AVA in sports nutrition may lead to the development of patentable value-added products, such as cereal bars, capsules containing oat extracts, and sports drinks. In summary, oat AVA is an oat-specific phenolic compound which is bioavailable to humans. Antioxidant, antiinflammatory, and antiproliferative effects have been proven, revealing its great potential to alleviate chronic diseases and sports injury. Although health benefits have been shown in vitro and in vivo, more epidemiologic or interventional studies should be carried out to further substantiate these effects. Increasing oat consumption therefore not only provides health benefits but also has an economic impact with the potential to increase production and export.

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12 𝛃-Glucans Susan Tosh 1 and S. Shea Miller 2 1 2

Faculty of Health Sciences, School of Nutrition Sciences, University of Ottawa, Ottawa, Canada Ottawa Research and Development Centre,, Agriculture and Agri-Food, Ottawa, Canada

12.1 Introduction Although β-glucan technically refers to a large class of polysaccharides, including cellulose, callose, and curdlan, in the context of cereal chemistry, it generally refers to mixed-linkage (1-3),(1-4)- β-D-glucan. This soluble fiber component of oats, barley, wheat, and rye makes up 0.5–10% of the kernel weight (Table 12.1). There has been interest in cereal β-glucans, from a nutritional standpoint, since the 1980s, when the importance of soluble fiber in reducing low-density lipoprotein (LDL) cholesterol was established [13, 14]. LDL cholesterol is recognized as a biomarker of cardiovascular health, and reduction of LDL cholesterol is associated with a decreased risk of heart attack and stroke [15, 16]. Oat β-glucan has been identified as the bioactive component of oat bran, and a regulation allowing health claims linking the consumption of oat β-glucan and reduction of cholesterol for foods containing at least 0.75 g of oat β-glucan was passed by the US Food and Drug Administration (FDA) in 1997. In 2006, the regulation was amended to allow health claims for foods containing at least 0.75 g of barley β-glucan also [17]. Public interest in the health benefits of oat bran and other cereal fibers has waned since the 1980s but the science supporting the benefits of β-glucan in the diet remains strong. The most widely recognized health benefit of cereal β-glucan remains the lowering of LDL cholesterol by consumption of oat and barley β-glucans. A recent metaanalysis demonstrated that the majority of evidence supports the recommendation that consumption of 3 g per day of oat β-glucan significantly lowers both total and LDL cholesterol [18]. Statistical analysis of the evidence on barley also showed a significant effect on the reduction of total and LDL cholesterol [19]. The European Union [20, 21], Australia, and New Zealand [22], Canada [23, 24], and Malaysia [25] all currently allow health claims concerning the relationship between consumption of soluble fiber from oat and barley and LDL cholesterol reduction. All jurisdictions recommend consumption of at least 3 g of oat and/or barley β-glucan per day. The conditions of use for each of the jurisdictions are given in Table 12.2. In parallel with research on β-glucan and cholesterol reduction, the ability of oat and barley β-glucan to attenuate blood glucose levels has also been studied. Oat and barley Whole Grains and their Bioactives: Composition and Health, First Edition. Edited by Jodee Johnson and Taylor C. Wallace. © 2019 John Wiley & Sons Ltd. Published 2019 by John Wiley & Sons Ltd.

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Table 12.1 Characteristics of cereal β-glucans.

Cereal

𝛃-glucan content (% of kernel)

Solubilitya) in hot water (%)

Molecular weightb) (× 106 g/mol)

Tri:Tetra saccharide ratioc)

Oats

2–8%

70–75

2.5–3

1.5–2.3

Barley

2–10%

50–70

1.8–2.5

1.8–3.5

Rye

1.5–2.5%

10–20

1–1.3

1.9–3.0

Wheat

0.5–1.5%

80 ∘ C causes decomposition of certain phenolics. Dlamini et al. [102] and Altan et al. [103] respectively reported that extrusion cooking decreased phenolic contents in sorghum and barley. Interestingly, heating at 177 ∘ C for 20 minutes compared to no heating did not alter total anthocyanin content of purple wheat bran [104]. However, it should be noted that the destruction of anthocyanins in grains is generally anticipated during extrusion cooking [85]. Ionizing irradiation is a nonthermal technology effectively eliminating food-borne pathogens [105] and is a proven alternative to chemicals to control food safety [106]. However, irradiation with dosages effective for the intended purposes may modify the phenolics profile [107]. For example, Zhu et al. [108] reported that γ-irradiation decreased total phenolic acid (FA, p-CA, and SA) and anthocyanin (cyanidin-3-glucoside and peonidin-3-glucoside) contents in black, red, and white rice, but the reductions did not completely follow a dose-dependent profile. In contrast to this study, Horváthová et al. [109] and Suhaj et al. [110] observed that irradiation at certain doses increased antioxidant activities of some dietary plants, and Oufedjikh et al. [107] found that at low doses, γ-irradiation enhanced the synthesis of total phenolic compounds in citrus peels. Thus, the impact of irradiation on phenolic acid profile in grains may vary and remains to be elucidated.

Phenolic Acids

13.4 Bioaccessibility and Bioavailability of Grain Phenolic Acids Phenolic acids are present ubiquitously in plant foods. With an array of bioactivities ranging from antioxidation to antiinflammation and from modulation of signal transduction to inhibition of digestive enzymes for carbohydrates, their contributions to the health benefits of plant food consumption are well appreciated. However, their bioefficacy in target organs is greatly dependent on their bioavailability, which is mediated mainly by absorption, metabolism, deposition, and excretion after consumption [111]. The first step is the release of phenolics from food matrices for digestion and absorption, which is referred to as bioaccessibility. The magnitude of bioaccessibility is critical because the majority of phenolic acids are present in an insoluble, bound form [26, 112]. For example, ∼74% and 69% of total phenolics present in rice and corn, respectively, are bound tightly to cellulosic matrices, which deters their absorption in the small intestine and allows them to reach the colon where they can be released for absorption by the action of bacterial enzymes such as microbial esterases and xylanases [36, 113, 114]. Compared to phenolics in fruits and vegetables, phenolics in grains appear less bioavailable due to tight bonding with cellulosic matrixes through either ester bonds to arabinoxylan chains or ether bonds to lignin. Because the majority of grain phenolic acids may not be absorbed in the upper gastrointestinal tract, bacterially mediated release of grain-bound phenolics in the lower gastrointestinal tract and their consequent bioefficacy have become one of the research topics in the elucidation of the contribution of grain phenolic acids to health. For example, Hole et al. [115] reported that the fermentation of whole grain barley and oat groat flours using probiotic lactic acid bacteria strains significantly increased accessible phenolic acids. Grains generally undergo a variety of processes during food preparation, depending on the food culture and taste preferences, and these processes can have a significant impact on bioaccessibility and subsequent bioavailability. However, information in this regard is scarce. Hithamani and Srinivasan [116] evaluated bioaccessibility of phenolics in finger millet after cooking using roasting, pressure-cooking, open-pan boiling or microwave heating. They found that pressure-cooking enhanced the bioaccessibility of phenolic acids and flavonoids the most, following by open-pan boiling, roasting, and microwave heating. Nevertheless, it should be noted that pressure-cooking could result in greater degradation of the measured phenolic acids and flavonoids compared to a small change caused by the other three common domestic cooking methods. Further, the magnitude of the enhancement appeared larger for flavonoids than phenolic acids. Thus, it can be extrapolated that food processing and cooking can have a marked impact on bioavailability and bioefficacy of grain phenolics, with the magnitude of the influences depending on processes and phenolics. Whole grain consumption may only elicit minimal increases in circulating phytochemicals in consumers. As these changes in circulating phenolic levels are generally in low micromolar ranges and of short duration, it is unlikely that phenolic acids in grains can modulate systemic levels. For example, consumption of ∼93 g boiled wheat bran increased postprandial plasma total phenol content by 2% at 60 minutes post ingestion [117]. Harder et al. [118] reported that total urinary excretion of FA was 4.8 mg after consuming 10.2 mg ferulic acid from rye bran.

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13.5 Health Benefits of Grain Phenolic Acids Epidemiologic data have shown there was an inverse association between intake of phenolics and disease risk, such as CVD, type 2 diabetes, certain cancers, and neurodegenerative disorders [119–122], through multiple putative mechanisms of actions, including antioxidation, antiinflammation, glucoregulation, antiproliferation, and microbial modulation. Hypercholesterolemia and hypertriglyceridemia are two of the most recognizable risk factors for CVD and other metabolic disorders. In a metaanalysis including 24 clinical studies, Hollænder et al. [123] concluded that consumption of whole grain diets lowers low-density lipoprotein (LDL) cholesterol and total cholesterol and tends to lower triglycerides compared with consumption of nonwhole grain control diets, but does not affect high-density lipoprotein (HDL) cholesterol. Interestingly, they did not find a threshold dose or dose-dependent association. Among the grains, oats appeared to be the most effective for blood cholesterol reduction. With the global prevalence in overweight and obesity, type 2 diabetes has become a serious threat to human health in developing and developed countries. Diet is one of the most modified factors to diminish the risk and control development of diabetic complications. Aune et al. [22] reported in a metaanalysis of 13 cohort studies that increased intake of whole grains was associated with a reduced risk for type 2 diabetes, which was consistent with an inverse dose–response relationship between whole grain food intake and incidence of type 2 diabetes observed in the Women’s Health Initiative Observational Study [124]. Similarly, Ye et al. [25] found in a systematic review and metaanalysis using 45 prospective cohort studies and 21 randomized controlled trials that compared with never/rare whole grain consumers, those consuming 48–80 g whole grain/day had a ∼26% lower risk of type 2 diabetes, ∼21% lower risk of CVD, and less weight gain during the 8–13-year study period. Health benefits of whole grain consumption can also be extended to cancer, especially colorectal cancer. In a metaanalysis with six whole grain studies, Aune et al. [21] found a 20% reduction for each three servings (90 g/day) of whole grain consumption, and further reductions with higher intakes. Whole grains contain a plethora of essential vitamins and minerals, fiber, and other minor phytochemicals. Understanding the contributions of components in whole grains to observed health benefits is pivotal to developing food products for health promotion and prevention and to formulating sound dietary recommendations for the public. However, it may be too challenging to characterize which components of whole grains are responsible for protecting against diseases, even though the high nutrient density and fiber content in general are considered the leading contributors [125–127] and other nutrients may contribute to smaller degrees. Of the minor contributors, phytochemicals in whole grains may work with fibers and other essential nutrients in an additive/synergistic manner to maintain/improve health. Phenolic acids in plant foods have been appreciated for their biological, medicinal, and health properties. After reviewing preclinical data, Vinayagam et al. [127] indicated that phenolic acids, including FA, SA, p-CA, CA, and others, could modulate glucose metabolism via several mechanisms, such as inhibiting carbohydrate digestion and glucose absorption in the small intestine, stimulating insulin secretion and action, reducing glucose production and secretion from the liver. All these actions provide support for an antidiabetic potential of grain phenolic acids. However, clinical data confirming a direct

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link between phenolic acids and the mechanism of actions are lacking because no study has been conducted to characterize the glucoregulating effects of phenolic acids with a composition comparable to that in whole grains. The positive data obtained from clinical trials comparing whole grains to refined grains only suggest a potential contribution of phenolic acids in whole grains. For example, Giacco et al. [128] conducted a parallel design clinical trial including 61 older adults with metabolic syndrome to examine whether consumption of a whole grain diet for 12 weeks would improve postprandial glycemic response. They found that postprandial insulin response was diminished at the end of the whole grain intervention compared to the refined grains, whereas there was no change in postprandial glucose response. Similar to the unchanged blood glucose noted in this trial, the data from two recent clinical trials illustrated unchanged blood glucose after relatively short-term whole grain consumption. In a cross-over study with six-week intervention periods separated by a four-week washout, Ampatzoglou et al. [129] found that whole grain consumption (>80 g/day) did not affect fasting blood glucose, compared to refined grain (23 mmol/L inhibited the growth of pathogenic Listeria monocytogenes, L. innocua, L. grayi, and L. seeligeri. It is interesting that phenolic acids seem to exert larger antimicrobial potency than polyphenols, such as catechins and proanthocyanidin dimers [175]. This notion suggests the complexity of interactions between phenolics and microbiota as phenolics are subject to bacterially mediated catabolism to generate phenolic acids and the resulting phenolic acids in turn modulate bacterial profile.

13.6 Conclusion Phenolics are ubiquitously present in plant foods. Their intake is associated with reduced risk of many chronic diseases such as CVD, type 2 diabetes, and certain cancers. These health benefits are attributed mainly to an array of putative bioactions, including antioxidation, glucoregulation, antiinflammation, and anticarcinogenesis.

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Grains play an integral role in most diets because they are the primary energy source. Most common grains are generally consumed in refined forms, which are produced after the outer layer is removed. Compared to whole grain forms, refined grains contain a small amount of phenolic acids, as they are primarily present in the outer layer. In this chapter, the content of 10 main phenolic acids (hydroxycinnamic acids: trans-cinnamic, p-coumaric, caffeic, ferulic, and sinapic acids; and hydroxybenzoic acids: p-hydroxybenzoic, protocatechuic, gallic, vanillic, and syringic acids) in 11 grains (barley, buckwheat, corn, millet, oat, quinoa, rice, rye, sorghum, triticale, and wheat) has been discussed. Ferulic acid is the most abundant in all whole grains except buckwheat, oat, and triticale. In oat and triticale, ferulic acid is ranked in second with p-coumaric and caffeic acids being the top, respectively, and in buckwheat, it is not ranked in the top five. In buckwheat, protocatechuic and caffeic acids are predominant in descending order. The sum of the 10 phenolic acids ranges from 208.5 in quinoa to 1711.0 μg/g dry weight in triticale. There are many factors affecting phenolic acid content in whole grains, including variety (genetics) and differences in agro-climatic and postharvest factors. As grains are traditionally processed before consumption, these processes, such as thermal treatment (drying, steaming, and water boiling), extrusion cooking, and irradiation, have an impact on phenolic acid content. Although these processes are anticipated to decrease phenolic acid content, they may have a favorable effect on bioaccessibility and bioavailability because the majority of phenolic acids are bound tightly to cellulosic matrix. Phenolic acids in whole grains are bioavailable; however, their concentrations after absorption are in the lower micromolar ranges at best and they are rapidly eliminated from the body within a day. Phenolic acids exert multiple bioactions. However, such bioactions are generally illustrated by preclinical experiments and clinical evidence supporting the contribution of phenolic acids in whole grains to observed health benefits remains lacking. Recently, reciprocal interactions between the microbiota and poorly absorbed nutrients in the lower gastrointestinal tract in local and systemic health have drawn considerable attention. Phenolics in whole grains are poorly absorbed in the small intestine and continue to the colon, where they have interesting, complex interactions with the microbiota. On one hand, bacterially mediated catabolism breaks down phenolics to generate new phenolic acids, which may exert bioactions in addition to what the parental compounds have conferred. On the other hand, with their microbial modulating activity, phenolic acids in the colon have a potential to move the microbiota to a profile more beneficial to human health. In conclusion, phenolic acid content varies widely between grains, and adding whole grains to a healthy diet rich in fruits and vegetables will definitely increase the pool of phenolic acid. Consumption of whole grains is associated with reduced risk of chronic diseases. However, the extent to which phenolic acids in whole grains contribute to observed health benefits has yet to be elucidated.

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14 Carotenoids Elizabeth J. Johnson Friedman School of Nutrition and Science Policy, Tufts University, Boston, MA, USA

14.1 Introduction Carotenoids are a family of compounds containing over 600 fat-soluble plant pigments and are responsible for the yellow, orange, and red colors in most fruits, flowers, and vegetables [1]. Carotenoids are involved in the photosystem assembly through harvesting light and photoprotection, assisting in nonphotochemical quenching, and involved in the seed-setting process of plants [2]. Epidemiologic studies have shown that a diet rich in carotenoid foods reduces the risk of major diseases, including certain cancers, heart disease, and eye disease, and also maintains skin health [3–7]. The beneficial effects of carotenoids are attributed to a small portion of the hundreds of carotenoids found in nature, given that only about two dozen are found in human blood and tissue, and only two in the lens and macula of the retina. The major carotenoids in the human diet and tissues are β-carotene, α-caroten, e lycopene, β-cryptoxanthin, lutein, and zeaxanthin. In part, the protection afforded by carotenoids is thought to arise from their antioxidant activity [8, 9]. Carotenoids act as radical scavengers and singlet oxygen quenchers [10] and also have antiinflammatory actions [11–15]. Lutein and zeaxanthin are thought to have an additional role of absorbing damaging blue light that enters the eye to protect the ocular tissues [16]. Carotenoids are classified as xanthophylls (e.g., lutein, zeaxanthin, cryptoxanthin) or carotenes (e.g., β-carotene, α-carotene, lycopene). Certain carotenoids have vitamin A activity. The major dietary provitamin A carotenoids are β-carotene, α-carotene, and β-cryptoxanthin, with β-carotene having the highest activity [8]. Intake of 8.4 and 10.8 mg of dietary β-carotene would meet the Recommended Dietary Allowance (RDA) for women and men, respectively [17]. A major dietary carotenoid without vitamin A activity is lycopene. Higher lycopene intake (∼10 mg/d) has been found to be inversely associated with total prostate cancer and more strongly with lethal prostate cancer compared to low intakes (0–3.7 mg/d) [18]. Typical dietary intakes of β-carotene in the United States are about 2 mg/day. Lycopene intakes are about 5 mg/day [19]. Lutein and zeaxanthin intakes are reported together and are generally 60% of the RDA for children [32, 33]. In these studies the bioavailability was also shown to be comparable to β-carotene in oil capsules, which is a common vitamin A supplementation strategy. In addition to rice, other staple cereals (corn, wheat, sorghum) are being developed to introduce β-carotene [34]. 14.3.3

Corn

Perry et al. reported that lutein, zeaxanthin, α-carotene and β-carotene are carotenoids contained in cooked corn [35], with values of approximately 200 μg/100 g for both lutein and zeaxanthin and approximately 15 μg/100 g for α-carotene and β-carotene. The USDA database for cooked yellow corn reports the lutein and zeaxanthin content together with a value of 1000 μg/100 g [29] and β-carotene and β-cryptoxanthin values as 0.16 and 0.13 mg/100 g, respectively. The carotenoid content of 40 dried corn seed samples was reported to be 17.5 ± 1.7 μg/g for zeaxanthin, 11.5 ± 0.8 μg/g for lutein, and 3.7 ± 0.2 μg/g for β-cryptoxanthin [36]. Izumi-Nagai et al. [14] reported carotenoid content from the aleurone, germ, and endosperm fraction of corn. The only carotenoids found in the aleurone were lutein and zeaxanthin (16.1 ± 0.4 and 35.8 ± 0.2 μg/100 g, respectively). This was also true for the endosperm (136.9 ± 0.9 μg/100 g and 1367.1 ± 0.5 μg/100 g, respectively) and germ (7.2 ± 0.8 and 98.9 ± 0.7 μg/100 g, respectively). In sum, unlike many whole grains, zeaxanthin is the major carotenoid in whole corn although levels vary among studies. 14.3.4

Barley

Zawadzki et al. reported the total carotenoid content of barley to be 10.6 μg/g, comprising lutein, zeaxanthin, and β-carotene (6.3, 2.2, and 2.1 μg/g, respectively) [37]. Masisi et al. [26] reported carotenoid content from the aleurone, germ, and endosperm fraction of barley. The only carotenoids found in the aleurone were lutein and zeaxanthin (11.2 ± 0.5 and 1.2 ± 0.1 μg/100 g, respectively). This was also true for the germ which

Carotenoids

Table 14.1 Carotenoid content of whole grains (μg/100 g dry weight) [38]. 𝛂-Carotene 𝛃-Carotene 𝛃-Cryptoxanthin Lutein + Zeaxanthin Lycopene

Barley

0

13

0

160

0

Millet

0

26

0

220

0

Corn

33

30

0

884

0

Oats

0

0

0

180

0

Rice, brown 0

0

0

0

0 0

Rice, white

0

0

0

0

Sorghum

0

20

0

66

0

Teff

0

5

0

66

0

Triticale

0

6

0

215

0

Wheat

0

5

0

220

0

was remarkably high in zeaxanthin (lutein and zeaxanthin, 132.8 ± 0.4 μg/100 g and 1513.9 ± 0.5 μg/100 g, respectively). No carotenoids were detected in the endosperm.

14.4 Dietary Databases The Nutrient Coordinating Center at the University of Minnesota Nutrient Data System for Research (NDSR) provides dietary information to aid in the assessment of dietary intake of carotenoids [38]. It is a major resource for epidemiologic studies evaluating diet and health. Table 14.1 contains the carotenoid content of whole grains contained in this database which is compiled from other food and food nutrient databases and articles in scientific journals. Lutein + zeaxanthin (reported together) are the major carotenoids for all grains listed with the exception of brown and white rice, which do not contain carotenoids. β-cryptoxanthin and lycopene are not found in the whole grains in this database.

14.5 Bioavailability Carotenoids, being fat soluble, follow the same intestinal absorption path as dietary fat [8]. Carotenoids are released from food matrices and solubilized in the gut. This is done in the presence of fat and conjugated bile acids. Absorption is affected by the same factors that influence fat absorption. Release from the food matrix and dissolution in the lipid phase is an important initial step in intestinal absorption. Thus, absence of bile or any generalized malfunction of the lipid absorption system will interfere with absorption of carotenoids. Chylomicrons are responsible for the transport of carotenoids from the intestinal mucosa to the bloodstream via the lymphatics for delivery to tissues. Carotenoids are transported in the circulation exclusively by lipoproteins, predominantly by high- and low-density lipoproteins [39]. Factors related to the bioavailability of carotenoids contained in grains have not been evaluated

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in human studies. However, they should be similar to what is known for fruits and vegetables. Factors that affect the bioavailability of carotenoids from foods include cooking, chopping, and the presence of fat [40]. Kean et al. evaluated the bioavailability of carotenoids in corn and corn products using a simulated three-stage in vitro digestion process designed to measure transfer of carotenoids from the food matrix to bile salt lipid micelles (micellarization) [41]. Carotenoid content of maize fractions ranged from a low of 1.8–6.5 mg/kg in yellow maize bran to 12.0–17.9 mg/kg in yellow corn meal. The major carotenoids were lutein and zeaxanthin in maize milled fractions, accounting for ∼70% of total carotenoid content. Micellarization efficiency of lutein and zeaxanthin was similar from yellow corn meal extruded puff and bread (63% and 69%, respectively), but lower in yellow corn meal porridge (48%). Micellarization of lutein and zeaxanthin from whole yellow corn meal products was highest in bread (85%) and similar in extruded puff and porridge (46% and 47%, respectively). For extruded puffs and bread porridge, β-carotene micellarization was 10–23% and 40–63% respectively, suggesting that wet cooking influences bioaccessibility of β-carotene. These investigators performed similar studies in matured yellow endosperm sorghum varieties (P88 and P1222) [42]. Carotenoid bioaccessibility was generally higher from sorghum (63–81%) compared to maize (45–47%). Micellarization of xanthophylls (75%) was more efficient than that of carotenes (52%) in sorghum, while they were similar in maize (40–49%).

14.6 Effect of Processing, Storage, and Environment Depending on the processing method, the carotenoid concentration can be affected. Given that most grains are cooked for consumption, cooking may improve the bioavailability of carotenoids as this form of processing releases carotenoids from the food matrix [40]. Bread making is one of the most common processing methods for grain consumption. Leenhardt et al. found that the total carotenoid content decreased after mixing (incorporation of water and oxygen in the dough) during the bread-making process using whole grain durum, einkorn, whole grain wheat, and white wheat flour [10]. Individual carotenoids were not evaluated. The greatest loss was for whole grain wheat dough (66%) and the least was for whole grain einkorn (7%). The authors also reported that the losses were highly correlated with lipoxygenase activity, which oxidizes fat-soluble components such as carotenoids. The effect of storage temperature on carotenoid composition in durum wheat and tritordeum whole grain flours was investigated [43]. For both cereal genotypes, total carotenoid content significantly decreased throughout a 90-day storage period, following a temperature-dependent first-order kinetic model. Individual and total carotenoid content decay were similar for durum wheat, with a maximum decay at 50 ∘ C at the end of the storage period (94%). The lowest temperature tested was 4 ∘ C which had decreases of about 50% for all varieties evaluated. Location, growing season, and environmental stresses can trigger plant responses to regulate the synthesis of carotenoids [44]. Such plant reactions allow carotenoids to circumvent the harmful effects caused by light, drought, salinity, extreme temperatures,

Carotenoids

and pathogens. The range of carotenoid values for a given food among the databases likely reflects some of these environmental effects.

14.7 Conclusion In general, concentrations of carotenoids in grains are low when evaluated with respect to levels found in brightly colored fruits and vegetables. For β-carotene, α-carotene, cryptoxanthin, and lycopene, these differences are substantial. The exception may be for lutein/zeaxanthin which, although still relatively small for most whole grains (∼0.2 mg/100 g), could contribute dietary intakes which typically are 1–2 mg/d [19] but still fall short of the 6–10 mg/d level that is related to eye health [20, 45].

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of vitamin A. Am. J. Clin. Nutr. 89 (6): 1776–1783. 33 Tang, G., Hu, Y., Yin, S. et al. (2012). β-Carotene in golden rice is as good as

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β-carotene in oil at providing vitamin A to children. Am. J. Clin. Nutr. 96 (3): 658–664. Farré, G., Bai, C., Twyman, R.M. et al. (2011). Nutritious crops producing multiple carotenoids – a metabolic balancing act. Trends Plant Sci. 16 (10): 532–540. Perry, A., Rasmussen, H., and Johnson, E.J. (2009). Xanthophyll (lutein, zeaxanthin) content in fruits, vegetables and corn and egg products. J. Food Compos. Anal. 22: 9–15. Brenna, O.V. and Berardo, N. (2004). Application of near-infrared reflectance spectroscopy (NIRS) to the evaluation of carotenoids content in maize. J. Agric. Food Chem. 52 (18): 5577–5582. Zawadzki, F., do Prado, I.N., and Prache, S. (2013). Influence of level of barley supplementation on plasma carotenoid content and fat spectrocolorimetric characteristics in lambs fed a carotenoid-rich diet. Meat Sci. 94 (3): 297–303. Nutrition Coordinating Center, University of Minnesota Nutrition Data System for Research (NDSR). Minneapolis, MN: Nutrition Coordinating Center. Wang, W., Connor, S.L., Johnson, E.J. et al. (2007). Effect of dietary lutein and zeaxanthin on plasma carotenoids and their transport in lipoproteins in age-related macular degeneration. Am. J. Clin. Nutr. 85 (3): 762–769. Van Het Hof, K.H., West, C.E., Weststrate, J.A., and Hautvast, J.G. (2000). Dietary factors that affect the bioavailability of carotenoids. J. Nutr. 130 (3): 503–506. Kean, E.G., Hamaker, B.R., and Ferruzzi, M.G. (2008). Carotenoid bioaccessibility from whole grain and degermed maize meal products. J. Agric. Food Chem. 56 (21): 9918–9926. Kean, E.G., Bordenave, N., Ejeta, G. et al. (2011). Carotenoid bioaccessibility from whole grain and decorticated yellow endosperm sorghum porridge. J. Cereal Sci. 54: 450–459. Mellado-Ortega, E. and Hornero-Méndez, D. (2016). Carotenoid evolution during short-storage period of durum wheat (Triticum turgidum conv. durum) and tritordeum (×Tritordeum Ascherson et Graebner) whole-grain flours. Food Chem. 192: 714–723. Othman, R., Mohd Zaifuddin, F.A., and Hassan, N.M. (2014). Carotenoid biosynthesis regulatory mechanisms in plants. J. Oleo Sci. 63 (8): 753–760. Age-Related Eye Disease Study 2 Research Group (2013). Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration: the Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial. JAMA 309 (19): 2005–2015.

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15 Alkylresorcinols Alastair B. Ross Department of Food and Nutrition Science, Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden

15.1 Introduction Alkylresorcinols are phenolic compounds present in high amounts in whole grain wheat and rye, and since 2001 have been of especial interest due to their use as biomarkers of whole grain intake. Estimating whole grain intake is a major challenge in population-based studies that study the associations between diet and disease risk, because whole grain foods are extremely heterogeneous. One way of improving questionnaire-based estimation of whole grains is to use a biomarker of intake, which is a compound related to a food which can be measured in, for example, blood or urine. Alkylresorcinols are measurable in blood and their metabolites are measurable in both blood and urine. Both intact alkylresorcinols and their metabolites have a strong relationship with whole grain wheat and rye intake. More recently, there has been renewed interest in possible biological activities of alkylresorcinols. This chapter will summarize what is known about the amounts of alkylresorcinols in whole grains and the state of the art on their bioavailability and possible biological effects.

HO

OH

R

Figure 15.1 Basic structure of alkylresorcinols. The R group in cereals is quantitatively predominantly an odd numbered saturated hydrocarbon chain 17–25 carbons long, though even-numbered hydrocarbon chains, and many different hydrocarbon chain modifications have been identified.

15.2 Chemistry and Nomenclature Cereal alkylresorcinols are 1,3-dihydroxy-5-alkyl-benzene derivatives, with a long alkyl chain, generally ranging from 17 to 25 carbon units long (Figure 15.1). This combination of a polar dihydroxybenzene ring and a hydrophobic alkyl chain makes alkylresorcinols amphiphilic; that is, they can arrange themselves in a membrane-like manner at the interface between a water and oil mixture. This property has been the topic of research and may be fundamental for any bioactivity of alkylresorcinols. Whole Grains and their Bioactives: Composition and Health, First Edition. Edited by Jodee Johnson and Taylor C. Wallace. © 2019 John Wiley & Sons Ltd. Published 2019 by John Wiley & Sons Ltd.

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Alkylresorcinols are named based on the length of their alkyl chain in a similar manner to fatty acids. Thus, an alkylresorcinol with a 17-carbon long alkyl chain (heptadecylresorcinol) is commonly referred to as C17:0 or AR17:0.

15.3 Presence of Alkylresorcinols in Cereals In the edible parts of food crops, alkylresorcinols have been detected and measured in wheat, rye, barley and triticale grains [1], quinoa (Chenopodium quinoa) seeds [2], and mango flesh [3]. They have also been detected in rice seedlings [4], but not in rice grains [1]. Similarly, they are found in cashew nut shell liquid (CNSL), but not in cashew nuts [5]. Notably, the composition of the different chain-length homologues is different between each type of grain (Figure 15.2), as well as the overall number of different homologues. Wheat has around 95% saturated alkylresorcinols, while rye has around 20% mainly monounsaturated homologues. Rye has high amounts of homologues C17:0, C19:0, and C21:0, while in wheat C21:0 is the main homologue and in barley C25:0 is the highest. Recently, we discovered the presence of a wide range of alkylresorcinols in quinoa [2], including even-chain alkylresorcinols, methyl-alkylresorcinols, and branched-chain alkylresorcinols. The alkylresorcinols detected in mango flesh are C15 and C17 derivatives, and are present at around the same amount as barley [3]. Quantitatively, rye has the highest amount of alkylresorcinols, overlapping with wheat (Figure 15.3). Barley has low amounts, not much higher than refined wheat in some cultivars. In the context of overall cereal composition, the amount of alkylresorcinols is higher than many other phenolic compounds present in wheat and rye. A few early papers suggested that there were alkylresorcinols present in corn/maize and millet, based on relatively nonspecific dye-based measurements. When measured using sensitive and selective methods such as gas chromatography-mass spectrometry (GC-MS), no alkylresorcinols have been detected [1], suggesting that they are unlikely to be present in these cereals. In cereals, they are present in the outer bran fraction [1], and microscopy has targeted them to the pericarp layer [17]. This would suggest a role in plant defense, and recent work has suggested that the actual concentration within the outer layers is sufficient to inhibit the growth of fungal infections [18].

15.4 Effect of Food Processing on Alkylresorcinols Initially, it was thought that food processing such as baking destroyed some alkylresorcinols, as amounts of alkylresorcinols extracted from bread and extruded cereals were lower than in the flour before processing [19, 20]. By chance, it was found that the difference between alkylresorcinols in uncooked flour and cooked flour was due to the extraction procedure, and that alkylresorcinols are in fact very stable under different kinds of food-processing conditions [1]. Instead, it was hypothesized that alkylresorcinols form complexes with starch, with the hydrophobic alkyl chain interacting with the hydrophobic core of starch helices [1]. Alkylresorcinols are stable during bread baking [1] and pasta making [6]. To date, it is not known if alkylresorcinols have any other effect on food processing, although they

Alkylresorcinols C19:0 

Rye  C17:0 

C21:0

C23:0

C19:1 

C17:1 

C20:0  (IS) 

C25:0 

C21:1 

C15:0  C17:2 

C23:1 C19:2 

C21:2 

C25:1

C27:1  C27:0

C20:0 (IS) 

Barley  C25:0 

C21:0

C23:0

C19:0 

C17:0 

C21:0

Wheat 

C19:0 

C19:1  C17:0 

C20:0  (IS)  C21:1 

C23:0 C23:1

C25:0 

Figure 15.2 Liquid chromatographyfluorescence detector chromatograms of rye, barley, and wheat. The difference in the chain length homologues is conserved for each type of cereal and allows the homologue composition to be used as a fingerprint for each cereal. Rye contains approximately 20% unsaturated homologues compared to stigmasterol) and the double bond at C5/C6 (sitosterol > sitostanol) [71]. Phytosterols are known to inhibit cholesterol absorption; some studies show that the absorption is also inhibited between phytosterols. Sitosterol-enriched intake increased the concentration of sitosterol but reduced the concentration of campesterol in human serum. An elevated sitostanol intake, although plant stanols have very low absorption, still led to a reduced serum sitosterol and campesterol level [72]. The passage of sterols across the intestinal barrier has been well studied (Figure 17.3). Generally, within the intestinal lumen, the micellar-solubilized sterol moves through the diffusion barrier which overlays the surface of absorptive cells. Phytosterols have a higher affinity to micelles than cholesterol, so they displace cholesterol from micelles and reduce cholesterol absorption. The sterol influx transporter Niemann-Pick C1-like 1 (NPC1L1) is located at the apical membrane of the enterocyte, which actively facilitates the uptake of cholesterol and phytosterols by promoting the passage of sterols across the brush border membrane. In contrast, two adenosine triphosphate (ATP)-binding cassette half-transporters, ABCG5 and ABCG8, promote active efflux of sterols, especially absorbed phytosterols, from the enterocyte into the intestinal lumen for excretion. Defects of either of these cotransporters lead to the rare inherited disease of phytosterolemia. In the enterocyte, sterols are first esterified by intestinal acyl-CoA (cholesterol acyltransferase, ACAT2). Further, they are incorporated with triglycerides (TG) forming nascent chylomicrons, with the assistance of apolipoprotein B48 (apoB48) and microsomal triglyceride transfer protein (MTP). The chylomicrons are subsequently secreted into the lymph [73, 74]. Phytosterols are poor substrates for ACAT2, so after absorption only a very small part is esterified. Also the free phytosterols are poorly incorporated into chylomicrons [75]. Moreover, phytosterols are eliminated via the biliary route more

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Enterocyte

Intestinal lumen

Lymph apoB-48

TG

Sterol MTP

ABCG5/ ABCG8

TG

Chylomicrons

Micelles NPC1L1

Fatty acids

ACAT2

Figure 17.3 Intestinal sterol absorption. ABCG5/G8: adenosine triphosphate-binding cassette G5/G8; ACAT2: acyl coenzyme A (cholesterol acyltransferase); apoB-48: apolipoprotein B48; MTP: microsomal triglyceride transfer protein; NPC1L1: Niemann-Pick C1-like 1 protein; TG: triglycerides. Source: Modified from Wang [73] and von Bergmann et al. [74].

rapidly than cholesterol [71], so their absorption is overall much lower compared to cholesterol. 17.4.2

Steryl Fatty Acid Esters

For the steryl fatty acid esters, hydrolysis is suggested to occur during digestion and the products are subsequently absorbed. Half of them are hydrolyzed in the upper small intestine [1]. Miettinen et al. [76] suggested that effective hydrolysis of the esters occurred during intestinal passage, and hydrolysis of esters with unsaturated fatty acids was slightly preferred. Moreover, 90% of the phytosterols were found in unesterified form in feces [76]. Brown et al. [77, 78] studied whether the pancreatic cholesterol esterase, primarily responsible for hydrolyzing cholesterol ester, is able to hydrolyze various phytosterol esters in the digestive tract in vitro. They confirmed that this enzyme hydrolyzed esters in the following order: cholesterol > (sitosterol = stigmastanol) > stigmasterol; oleate (18:1) > (palmitate (16:0) = stearate (18:0)). Moreover, cholesterol esterase plays an important but discriminatory role in liberating free phytosterols to compete with cholesterol in micellar solubilization and absorption in vivo [77]. 17.4.3

Steryl Phenolates

Some animal studies related to the absorption and metabolism of steryl phenolates (mainly with γ-oryzanol) are available. Fujiwara et al. [79–81] studied the absorption and metabolism of 14 C-labeled γ-oryzanol in rabbits, dogs, and rats in vivo. The absorption in animal models was very low. In rats, radioactivity excreted in the urine during 72 hours after oral administration was 10% of the dosage (50 mg/kg), about 85% was recovered in feces, and only a small fraction (0.06%) was transferred to blood. In

Phytosterols

an in situ intestinal absorption and lymphatic transportation experiment, the authors observed that most of the absorbed radioactivity was transferred into the mesenteric vein (mostly as intact form of γ-oryzanol), but very little radioactivity was transported into the thoracic duct (also mostly as intact form), suggesting that steryl ferulates were absorbed mainly into blood via the portal vein system, not the lymph via thoracic duct. In urine, intact steryl ferulates were not detected. However, ferulic acid and related metabolites were identified as urinary metabolites of γ-oryzanol, suggesting that hydrolysis of steryl ferulate may occur in vivo [81]. Sterol phenolate absorption in humans has also been reported. In a study with healthy volunteers, after an oral dose of 600 mg γ-oryzanol, peak plasma concentration was 21–107 ng/mL (equivalent to 0.01–0.05% of the total administered dose); after repetitive oral doses of 100 mg three times a day for 10 days, the peak plasma concentration was 112 ng/mL (