Micronutrients in Health and Disease, Second Edition: 2nd Edition (Hardback) book cover

Micronutrients in Health and Disease, Second Edition

2nd Edition

By Kedar N. Prasad

CRC Press

528 pages | 12 B/W Illus.

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Description

Increased oxidative stress due to the production of excessive amounts of free radicals along with the effects of chronic inflammation plays a major role in the initiation and progression of most chronic diseases. In addition, increased release of glutamate plays a central role in the pathogenesis of various disorders.

This second edition of Micronutrients in Health and Disease proposes a novel concept that in order to simultaneously and optimally reduce oxidative stress, chronic inflammation, and glutamate, it is essential to increase levels of antioxidant enzymes as well as levels of dietary and endogenous antioxidant compounds at the same time. This is accomplished by activating the Nrf2 pathways and by increasing the levels of antioxidant compounds and B-vitamins through supplementation. This book proposes a mixture of micronutrients that achieves this above goal. The mixture of micronutrients together with modification in diet and lifestyle may reduce the risk of chronic diseases and in combination with standard care, may improve the management of these diseases.

KEY FEATURES

• Provides evidence in support of the idea that increased oxidative stress, chronic inflammation, and glutamate are involved in the pathogenesis of chronic diseases.

• Contains three new chapters on Huntington’s disease, Autism spectra, and Prion disease.

• Discusses the role of microRNAs in the pathogenesis of chronic diseases.

• Presents information on regulation of the expression of microRNAs by reactive oxygen species and antioxidants.

Micronutrients in Health and Disease, Second Edition serves as a valuable resource for those seeking to promote healthy aging and prevent and improved management of chronic diseases.

Reviews

The book is comprehensive. The coverage ranges from the basic fundamentals of

micronutrients with explanations regarding the role of the antioxidant system,

oxidative stress, inflammatory responses, and adaptive immunity to the

scientific rationale underlying the role of micronutrients in

promoting/preventing these biological responses and the mechanisms that

underlie them. There is a particularly useful description of the healthy aging

process versus the common adverse impact of chronic diseases associated with

aging, including rheumatoid and osteoarthritis as well as cardiovascular

diseases, diabetes, and cancer. Unique features include a chapter on the role

of micronutrients in protecting against lethal doses of ionizing radiation and

a concluding chapter listing 17 common misconceptions, the underlying

rationale, and the proposed explanation for its misinterpretation.

Table of Contents

Contents

Preface…………………………………………………………………………………………………………………………xxvii

Acknowledgments ………………………………………………………………………………………………………….xxix

Author ………………………………………………………………………………………………………………………….xxxi

Chapter 1 Basic Facts about Micronutrients ………………………………………………………………………1

Introduction ……………………………………………………………………………………………………1

Evolution of the Antioxidant System ………………………………………………………………….1

History of the Discovery of Micronutrients ………………………………………………………..1

Sources and Forms of Vitamins ………………………………………………………………………..2

Solubility of Micronutrients ……………………………………………………………………………..4

Distribution of Antioxidants in the Body ……………………………………………………………4

Storage of Antioxidants ……………………………………………………………………………………6

Can Antioxidants Be Destroyed during Cooking? ……………………………………………….6

Absorption of Antioxidants and Its Significance …………………………………………………6

Functions of Individual Antioxidants …………………………………………………………………7

Antioxidant Defense Systems ……………………………………………………………………………8

Antioxidant Enzymes ………………………………………………………………………………….8

Dietary Antioxidants …………………………………………………………………………………..8

Endogenous Antioxidants …………………………………………………………………………….8

Known Functions of Antioxidants …………………………………………………………………….8

Current Controversies about Antioxidants ………………………………………………………….9

Misuse of Antioxidants in Clinical Studies ………………………………………………………..9

Conclusions …………………………………………………………………………………………………. 12

References …………………………………………………………………………………………………… 12

Chapter 2 Basic Facts about Oxidative Stress, Inflammation, and the Immune System ………… 13

Introduction …………………………………………………………………………………………………. 13

Oxidative Stress ……………………………………………………………………………………………. 14

What Are Free Radicals? …………………………………………………………………………… 14

Types of Free Radicals ……………………………………………………………………………… 14

Formation of Free Radicals Derived from Oxygen and Nitrogen ……………………. 14

Oxidation and Reduction Processes ………………………………………………………………… 16

What Is Inflammation? ………………………………………………………………………………….. 16

Types of Inflammatory Reactions ………………………………………………………………. 17

Products of Inflammatory Reactions ……………………………………………………………….. 17

Cytokines ………………………………………………………………………………………………… 17

Complement Proteins ……………………………………………………………………………….. 18

Arachidonic Acid (AA) Metabolites …………………………………………………………… 18

Endothelial/Leukocyte Adhesion Molecules ……………………………………………….. 18

Immune System ……………………………………………………………………………………………. 18

What Is the Immune System? …………………………………………………………………………. 19

Innate Immunity …………………………………………………………………………………………… 19

Adaptive Immunity ……………………………………………………………………………………….20

Conclusions ………………………………………………………………………………………………….20

References …………………………………………………………………………………………………… 21

Chapter 3 Scientific Rationale of Current Trends in Clinical Studies of Micronutrients ………..23

Introduction ………………………………………………………………………………………………….23

Levels of Oxidative Stress and Chronic Inflammation in High-Risk Populations ….24

High-Risk Populations of Cancer ………………………………………………………………..24

High-Risk Populations of Coronary Artery Disease (CAD) ……………………………24

High-Risk Populations of Alzheimer’s Disease (AD) and Parkinson’s

Disease (PD) …………………………………………………………………………………………….24

Distributions and Function of Antioxidants ………………………………………………………25

Results of Clinical Trials with a Single Antioxidant in High-Risk Populations ……..26

Cancer ……………………………………………………………………………………………………..26

Coronary Artery Disease (CAD) …………………………………………………………………26

Alzheimer’s Disease (AD) and Parkinson’s Disease (PD) ………………………………27

Why the Use of a Single Antioxidant Produced Inconsistent Results …………………..28

Results of Clinical Studies with Multiple Dietary Antioxidants in Cancer ……………29

Results of Clinical Studies with Fat and Fiber …………………………………………………..30

Rationale for Using a Mixture of Micronutrients for Reducing the Risk and

Progression of Chronic Diseases ……………………………………………………………………..30

Proposed Mixture of Micronutrients for Reducing the Risk and Progression

of Chronic Diseases………………………………………………………………………………………. 31

Proposed Changes in Diet and Lifestyle for Reducing the Risk and Progression

of Chronic Diseases………………………………………………………………………………………. 31

Conclusions …………………………………………………………………………………………………. 32

References …………………………………………………………………………………………………… 32

Chapter 4 Micronutrients in Healthy Aging and Age-Related Decline in Organ Functions …… 35

Introduction …………………………………………………………………………………………………. 35

Trends of Aging Population ……………………………………………………………………………36

Evidence for Increased Oxidative Stress During Aging ……………………………………..36

Extracellular Sources for Production of Free Radicals ……………………………………….36

Cellular Sites of Production of Free Radicals …………………………………………………… 37

Oxidative Stress-Induced Age-Related Decline in Organelle Functions ……………….38

Mitochondrial Dysfunction ………………………………………………………………………..38

Impairment of Proteasome and Lysosomal-Mediated Proteolytic Activities ……. 39

Oxidative Stress-Induced Changes in Cell Culture Models ……………………………. 39

Oxidative Stress-Induced Changes in Animal Models ………………………………….. 39

Oxidative Stress-Induced Shortening of the Length of Telomere ……………………. 39

Evidence for Chronic Inflammation During Aging ……………………………………………40

Impaired Immune Function in Aging ………………………………………………………….40

Changes in the Antioxidant Defense Systems During Aging ……………………………… 41

Antioxidant Enzymes ……………………………………………………………………………….. 41

Changes in Antioxidant Enzymes Activities in Animals ……………………………….. 42

Changes in Antioxidant Enzymes Activities in Humans ……………………………….. 42

Changes in Dietary and Endogenous Antioxidants Levels …………………………………. 43

Vitamin C ……………………………………………………………………………………………….. 43

Glutathione ………………………………………………………………………………………………44

Vitamin E ………………………………………………………………………………………………..44

Coenzyme Q10 …………………………………………………………………………………………44

MicroRNAs in Aging ……………………………………………………………………………………. 45

MicroRNAs …………………………………………………………………………………………….. 45

MicroRNAs in Age-Related Diseases …………………………………………………………. 45

MicroRNAs and Their Target Proteins in Aged Animals ……………………………… 45

Oxidative Stress and Pro-inflammatory Cytokine Regulate Expression of

MicroRNAs …………………………………………………………………………………………….. 47

Antioxidants Regulate Expression of MicroRNAs ……………………………………….. 47

Effects of Individual Antioxidants on Age-Related Functional Deficits ………………. 47

Vitamin E ……………………………………………………………………………………………….. 47

Coenzyme Q10 …………………………………………………………………………………………48

Carotenoids and Zinc ………………………………………………………………………………..48

Melatonin …………………………………………………………………………………………………48

Flavonoids ………………………………………………………………………………………………..48

Glutathione and N-Acetylcysteine (NAC) …………………………………………………….48

Alpha-Lipoic Acid …………………………………………………………………………………….49

Multiple Dietary Antioxidants…………………………………………………………………….49

Studies with Individual Antioxidants on Age-Related Neurodegenerative

Diseases in Humans ………………………………………………………………………………………49

Regulation of Activation of Nrf2 …………………………………………………………………….50

Reactive Oxygen Species (ROS) Activates Nrf2 ……………………………………………50

Binding of Nrf2 with ARE in the Nucleus ……………………………………………………50

Existence of ROS-Resistant Nrf2 ………………………………………………………………..50

Antioxidants and Phytochemicals Activate ROS-Resistant Nrf2 ……………………. 51

L-Carnitine Activates Nrf2 by a ROS-Dependent Mechanism ………………………. 51

Activation of Nrf2 by MicroRNAs ……………………………………………………………… 51

Suppression of Chronic Inflammation …………………………………………………………….. 51

Proposed Mixture of Micronutrients for Healthy Aging and for Reducing

Age-Related Functional Deficits …………………………………………………………………….. 51

Proposed Changes in Diet and Lifestyle for Healthy Aging and for Reducing

Age-Related Functional Deficits …………………………………………………………………….. 52

Conclusions …………………………………………………………………………………………………. 52

References …………………………………………………………………………………………………… 53

Chapter 5 Role of Micronutrients in Prevention of Coronary Artery Disease and

Improvement of the Standard Therapy …………………………………………………………….63

Introduction ………………………………………………………………………………………………….63

Prevalence, Incidence, and Cost ………………………………………………………………………64

Evidence for Increased Oxidative Stress in CAD ………………………………………………64

Consequences of Increased Oxidative Stress ………………………………………………..65

Evidence for Increased Chronic Inflammation in CAD………………………………………65

Evidence for Increased Levels of Homocysteine in CAD ……………………………………66

MicroRNAs in CAD ……………………………………………………………………………………..66

MicroRNAs …………………………………………………………………………………………….. 67

Circulating MicroRNAs in CAD ……………………………………………………………….. 67

Cellular MicroRNAs in CAD ……………………………………………………………………..68

Oxidative Stress and Pro-inflammatory Cytokine Regulate Expression of

MicroRNAs ……………………………………………………………………………………………..69

Antioxidants Regulate Expression of MicroRNAs ……………………………………….. 70

Role of Antioxidants in CAD …………………………………………………………………………. 70

Animal Studies after Treatment with Antioxidants ………………………………………. 70

Epidemiologic Studies with Antioxidants ……………………………………………………. 70

Intervention Human Studies after Treatment with Antioxidants …………………….. 71

Vitamin E Alone Producing Beneficial Effects ……………………………………………. 74

Vitamin C Alone Producing Beneficial Effects ……………………………………………. 74

Dietary Antioxidants Producing No Effects or Adverse Effects …………………….. 74

Endogenous Antioxidants Producing No Effects or Beneficial Effects ……………. 76

Dietary and Endogenous Antioxidants with Cholesterol-Lowering Drugs …………… 76

Multiple Dietary Antioxidants with Cholesterol-Lowering Drugs ……………………….77

Resveratrol and Omega-3 Fatty Acids ………………………………………………………………77

Resveratrol ……………………………………………………………………………………………….77

Omega-3 Fatty Acids ………………………………………………………………………………… 78

Intervention Studies with B-Vitamins to Lower Homocysteine Levels ………………… 79

Potential Reasons for the Failure of Individual Micronutrients in Producing

Sustained and Consistent Benefits in CAD ……………………………………………………….80

Regulation of Activation of Nrf2 ……………………………………………………………………. 81

Reactive Oxygen Species (ROS) Activates Nrf2 …………………………………………… 81

Binding of Nrf2 with ARE in the Nucleus …………………………………………………… 81

Existence of ROS-Resistant Nrf2 in CAD …………………………………………………… 81

Antioxidants and Phytochemicals Activate ROS-Resistant Nrf2 ……………………. 81

L-Carnitine Activates Nrf2 by a ROS-Dependent Mechanism ………………………. 81

Activation of Nrf2 by MicroRNAs ………………………………………………………………82

Suppression of Chronic Inflammation ……………………………………………………………..82

Proposed Mixture of Micronutrients for Prevention and Improved

Management of CAD …………………………………………………………………………………….82

Proposed Changes in Diet and Lifestyle for Prevention and Improved

Management of CAD …………………………………………………………………………………….82

Prevention and Improved Management of CAD ………………………………………………..83

Primary Prevention ……………………………………………………………………………………83

Secondary Prevention ………………………………………………………………………………..83

Improved Management of CAD ………………………………………………………………….84

Conclusions ………………………………………………………………………………………………….84

References ……………………………………………………………………………………………………84

Chapter 6 Micronutrients in Prevention and Improvement of the Standard Therapy in

Diabetes ……………………………………………………………………………………………………….95

Introduction ………………………………………………………………………………………………….95

Incidence, Prevalence, and Cost ………………………………………………………………………96

Incidence ………………………………………………………………………………………………….96

Prevalence ………………………………………………………………………………………………..96

Cost …………………………………………………………………………………………………………96

Types of Diabetes ………………………………………………………………………………………….96

Type 1 Diabetes ………………………………………………………………………………………..96

Type 2 Diabetes ………………………………………………………………………………………..96

Gestational Diabetes ………………………………………………………………………………….97

Other Types of Diabetes …………………………………………………………………………….97

Pre-diabetes and Metabolic Syndrome ………………………………………………………..97

Complications of Diabetes ……………………………………………………………………………..97

Evidence for Increased Oxidative Stress in Diabetes………………………………………….97

Type 1 Diabetes ………………………………………………………………………………………..97

Type 2 Diabetes ………………………………………………………………………………………..98

Metabolic Syndrome …………………………………………………………………………………99

Evidence for Increased Chronic Inflammation in Diabetes …………………………………99

MicroRNAs in Diabetes ………………………………………………………………………………. 100

MicroRNAs …………………………………………………………………………………………… 100

Circulating MicroRNAs in Diabetes …………………………………………………………. 100

Cellular MicroRNAs in Diabetes (Humans) ………………………………………………. 102

Cellular MicroRNAs in Diabetes (Animal Models)…………………………………….. 103

Oxidative Stress and Pro-inflammatory Cytokines Regulate Expression

of MicroRNAs ……………………………………………………………………………………….. 103

Antioxidants Regulate Expression of MicroRNAs ……………………………………… 103

Reducing Oxidative Stress and Chronic Inflammation in Diabetes …………………… 104

Role of Antioxidants and Phytochemicals in Protecting Against Diabetes …………. 104

Vitamin A (Animal and Human Studies) …………………………………………………… 104

Vitamin C (Human Studies) …………………………………………………………………….. 104

Vitamin C (Animal Studies) …………………………………………………………………….. 105

Vitamin D3 (Animal Studies) …………………………………………………………………… 105

Vitamin E (Animal Studies) …………………………………………………………………….. 105

Vitamin E (Human Studies) …………………………………………………………………….. 106

Alpha-Lipoic Acid (Human Studies) …………………………………………………………. 106

Alpha-Lipoic Acid (Animal Studies) …………………………………………………………. 106

N-Acetylcysteine (Human Studies) …………………………………………………………… 107

N-Acetylcysteine (Animal Studies) …………………………………………………………… 107

L-Carnitine (Human Studies) …………………………………………………………………… 107

L-Carnitine (Animal Studies) …………………………………………………………………… 108

Coenzyme Q10 (Human Studies) ……………………………………………………………… 108

Coenzyme Q10 (Animal Studies) ……………………………………………………………… 109

Omega-3 Fatty Acids (Animal Studies) ……………………………………………………… 109

Omega-3-Fatty Acids (Epidemiologic Studies) …………………………………………… 110

Omega-3-Fatty Acids (Intervention Studies) ………………………………………………. 110

Antioxidant Mixtures (Human Studies) …………………………………………………….. 110

Antioxidant Mixture (Animal Studies) ……………………………………………………… 111

Folic Acid and Thiamine (Human Studies) ………………………………………………… 111

Folic Acid and Thiamine (Animal Studies) ……………………………………………….. 112

Chromium (Human Studies) ……………………………………………………………………. 112

Antioxidants with Diabetic/Cardiovascular Drugs and/or Insulin (Human

Studies) …………………………………………………………………………………………………. 112

Antioxidants with Diabetic/Cardiovascular Drugs and/or Insulin (Animal

Studies) …………………………………………………………………………………………………. 113

Treatments of Diabetes ………………………………………………………………………………… 113

Standard Treatments ……………………………………………………………………………….. 113

Aspirin (Human Studies) …………………………………………………………………………. 113

Aspirin Resistance ………………………………………………………………………………….. 114

Aspirin (Animal Studies)…………………………………………………………………………. 114

Potential Reasons for Inconsistent Results with Individual Micronutrients or

Aspirin ………………………………………………………………………………………………………. 114

Regulation of Activation of Nrf2 ………………………………………………………………….. 115

Reactive Oxygen Species (ROS) Activates Nrf2 …………………………………………. 115

Binding of Nrf2 with ARE in the Nucleus …………………………………………………. 115

Existence of ROS-Resistant Nrf2 in Diabetes …………………………………………….. 116

Antioxidants and Phytochemicals Activate ROS-Resistant Nrf2 ………………….. 116

L-Carnitine Activates Nrf2 by a ROS-Dependent Mechanism …………………….. 116

Activation of Nrf2 by MicroRNAs ……………………………………………………………. 116

Suppression of Chronic Inflammation …………………………………………………………… 116

Recommended Mixture of Micronutrients for the Prevention of Diabetes …………. 117

Recommended Changes in Diet and Lifestyle for the Prevention and

Improved Management of Diabetes ………………………………………………………………. 117

Prevention of Diabetes ………………………………………………………………………………… 117

Primary Prevention …………………………………………………………………………………. 117

Secondary Prevention ……………………………………………………………………………… 118

Improved Management of Diabetes ………………………………………………………….. 118

Conclusions ……………………………………………………………………………………………….. 118

References …………………………………………………………………………………………………. 118

Chapter 7 Micronutrients in Cancer Prevention …………………………………………………………….. 131

Introduction ……………………………………………………………………………………………….. 131

Incidence, Prevalence, Mortality, and Cost …………………………………………………….. 132

Proposed Stages of Carcinogenesis ……………………………………………………………….. 132

Two-Stage Model of Animal Carcinogenesis ……………………………………………… 132

Some Examples of Tumor Initiators and Tumor Promoters ………………………………. 133

Three-Stage Model of Human Carcinogenesis …………………………………………… 133

Diagrammatic Representation of Three-Stage Model of Human Carcinogenesis ……..133

Some Examples of Environmental-Related Carcinogens …………………………………. 134

Some Examples of Diet-Related Carcinogens ………………………………………………… 134

Some Examples of Diet-Related Cancer Protective Agents ………………………………. 135

Some Examples of Lifestyle-Related Carcinogens ………………………………………….. 135

Alcohol …………………………………………………………………………………………………. 135

Cell Phone …………………………………………………………………………………………….. 135

Smoking ………………………………………………………………………………………………… 136

Coffee and Caffeine ………………………………………………………………………………… 136

Evidence for Increased Oxidative Stress ………………………………………………………… 137

Evidence for Increased Chronic Inflammation ……………………………………………….. 137

MicroRNAs in Cancer Prevention ………………………………………………………………… 138

MicroRNAs …………………………………………………………………………………………… 138

Changes in MicroRNAs after Exposure to Chemical Carcinogens and

Oncogenic Virus …………………………………………………………………………………………. 138

Functions of Antioxidants Relevant to Cancer Prevention ……………………………….. 140

Antioxidants and Phytochemicals Regulate Expression of MicroRNAs …………….. 141

Reducing Oxidative Stress and Chronic Inflammation in Cancer Prevention ……… 141

Cell Culture Models ……………………………………………………………………………….. 141

Animal Models ………………………………………………………………………………………. 141

Epidemiologic Studies …………………………………………………………………………….. 142

Intervention Studies with Single Antioxidants (Lung Cancer) ……………………… 143

Intervention Studies with a Single Antioxidant (Other Cancers) …………………… 144

Intervention Studies with Multiple Dietary Antioxidants …………………………….. 144

Intervention Studies with Vitamin D and Calcium ……………………………………… 145

Intervention Studies with Folate and B-Vitamins ……………………………………….. 145

Intervention Studies with Fat and Fiber …………………………………………………….. 146

Intervention Studies with Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) ……..146

Potential Reasons for Inconsistent Results with Individual Micronutrients

or Aspirin in Cancer Prevention Studies ………………………………………………………… 146

Regulation of Activation of Nrf2 ………………………………………………………………….. 147

Reactive Oxygen Species (ROS) Activates Nrf2 …………………………………………. 147

Binding of Nrf2 with ARE in the Nucleus …………………………………………………. 147

Existence of ROS-Resistant Nrf2 in Cells Following Exposure to Carcinogens …….147

Antioxidants and Phytochemicals Activate ROS-Resistant Nrf2 ………………….. 148

L-Carnitine Activates Nrf2 by a ROS-Dependent Mechanism …………………….. 148

Activation of Nrf2 by MicroRNAs ……………………………………………………………. 148

Suppression of Chronic Inflammation …………………………………………………………… 149

Recommended Mixture of Micronutrients for the Prevention of Cancer ……………. 149

Recommended Changes in Diet and Lifestyle for the Prevention of Cancer ……….. 149

Proposed Cancer Prevention Strategies …………………………………………………………. 150

Primary Prevention …………………………………………………………………………………. 150

Secondary Prevention ……………………………………………………………………………… 150

Can Cancer with a Family History Be Prevented? ………………………………………….. 150

Problems Associated with Implementation of Dietary and Lifestyle

Recommendations ………………………………………………………………………………………. 150

Toxicity of Micronutrients ……………………………………………………………………………. 151

Conclusions ……………………………………………………………………………………………….. 151

References …………………………………………………………………………………………………. 152

Chapter 8 Micronutrients in Improvement of the Standard Therapy in Cancer ………………….. 163

Introduction ……………………………………………………………………………………………….. 163

MicroRNAs in Cancer Cells ………………………………………………………………………… 164

MicroRNAs …………………………………………………………………………………………… 164

MicroRNAs Acting as Tumor Suppressors or Anti-oncogenes …………………………. 165

Colon Cancer …………………………………………………………………………………………. 165

Gastric Cancer Cells ……………………………………………………………………………….. 165

Non-Small Cell Lung Cancer (NSCLC) ……………………………………………………. 165

Retinoblastoma ………………………………………………………………………………………. 166

Breast Cancer Cells ………………………………………………………………………………… 166

Hepatocellular Carcinoma ……………………………………………………………………….. 167

Bladder Cancer ………………………………………………………………………………………. 167

Cervical Cancer ……………………………………………………………………………………… 167

MicroRNAs Acting as Oncogenes ………………………………………………………………… 168

Bladder Cancer ………………………………………………………………………………………. 168

Lung Cancer ………………………………………………………………………………………….. 168

Non-Small-Cell Lung Cancer …………………………………………………………………… 168

Prostate Cancer, Gastric Cancer, and Esophageal Cancer ……………………………. 168

Cervical Cancer, Colorectal Cancer, and Breast Cancer ………………………………. 168

Nrf2 in Cancer Cells …………………………………………………………………………………… 169

Normal Cell Response to Activated Nrf2…………………………………………………… 169

High Expression of Nrf2 Promotes Cancer Growth and Drug-Resistant ……………. 169

Individual Antioxidants Inhibit Cancer Growth in the Presence of Elevated

Levels of Nrf2 ……………………………………………………………………………………………. 170

Luteolin ………………………………………………………………………………………………… 170

Pterostilbene ………………………………………………………………………………………….. 170

Antioxidants Activate ROS-Resistant Nrf2 ………………………………………………… 170

Synthetic Triterpenoid RTA 405 ………………………………………………………………. 171

Curcumin ………………………………………………………………………………………………. 171

Tert-Butylhydroquinone ………………………………………………………………………….. 171

Vitamin E Succinate ……………………………………………………………………………….. 171

Vitamin C ……………………………………………………………………………………………… 172

Vitamin A and Carotenoids ……………………………………………………………………… 173

Selenium ……………………………………………………………………………………………….. 173

N-Acetylcysteine (NAC) and Alpha-Lipoic Acid………………………………………… 173

Antioxidant-Induced Changes in Gene Expression Profiles in Cancer Cells ………. 173

Effects of Therapeutic Doses of Individual Antioxidants in Combination

with Radiation Therapy on Cancer Cells and Normal Cells ……………………………… 174

Cell Culture Studies ……………………………………………………………………………….. 174

Animal Studies ………………………………………………………………………………………. 174

Human Studies ………………………………………………………………………………………. 176

Effects of Therapeutic Doses of Individual Antioxidants in Combination

with Chemotherapeutic on Cancer Cells and Normal Cells ……………………………… 176

Cell Culture Studies ……………………………………………………………………………….. 176

Animal Studies ………………………………………………………………………………………. 179

Human Studies ………………………………………………………………………………………. 179

Reasons for Growth-Inhibitory Effects Antioxidants in the Presence of

Elevated Levels of Nrf2 ……………………………………………………………………………….. 179

Preventive Doses of Individual Antioxidants Reduce the Efficacy of

Therapeutic Agents …………………………………………………………………………………….. 180

Effects of Therapeutic Doses of Individual Antioxidants in Combination with

Experimental Therapies on Cancer Cells ……………………………………………………….. 180

Hyperthermia…………………………………………………………………………………………. 180

Sodium Butyrate and Interferon-Alpha2b ………………………………………………….. 181

Immunotherapy and Gene Therapy …………………………………………………………… 182

Proposed Mixture Therapeutic Doses of Antioxidants During Cancer Therapy ……182

Conclusions ……………………………………………………………………………………………….. 182

References …………………………………………………………………………………………………. 183

Chapter 9 Micronutrients in the Prevention and Improvement of the Standard Therapy for

Alzheimer’s Disease ……………………………………………………………………………………. 191

Introduction ……………………………………………………………………………………………….. 191

Prevalence, Incidence, and Cost of AD ………………………………………………………….. 192

Estimated Cost of Treatment of AD ………………………………………………………………. 193

Etiology of AD …………………………………………………………………………………………… 193

Neuropathology of AD ………………………………………………………………………………… 193

MicroRNAs in the Pathogenesis of AD …………………………………………………………. 193

MicroRNAs …………………………………………………………………………………………… 193

Changes in the Expressions of MicroRNAs in Human AD ………………………………. 194

Elevated Expressions of MicroRNAs ………………………………………………………… 194

Decreased Expressions of MicroRNAs ……………………………………………………… 195

Changes in MicroRNAs in Animal and Cell Culture AD Models …………………….. 196

Elevated Expressions of MicroRNAs ………………………………………………………… 196

Decreased Expression of MicroRNAs ………………………………………………………. 196

ROS and Pro-inflammatory Cytokines Regulate the Expressions of MicroRNAs ……197

ROS Upregulates the Expressions of MicroRNAs Causing Neurodegeneration …….197

ROS Downregulates the Expressions of MicroRNAs Causing

Neurodegeneration………………………………………………………………………………….. 198

Pro-inflammatory Cytokines Upregulate the Expressions of MicroRNAs

Causing Neurodegeneration …………………………………………………………………….. 198

Micronutrients Regulate the Expressions of MicroRNAs ………………………………… 199

Resveratrol Enhances the Expressions of MicroRNAs ………………………………… 199

Resveratrol Decreases the Expressions of MicroRNAs ……………………………….. 199

Isoflavone Increases the Expressions of MicroRNAs ………………………………….. 199

Genistein Decreases the Expressions of MicroRNAs …………………………………..200

Quercetin Enhances the Expressions of MicroRNAs …………………………………..200

Curcumin Decreases the Expressions of MicroRNAs ………………………………….200

Curcumin Enhances the Expressions of MicroRNAs …………………………………..200

Coenzyme Q10 Regulates the Expressions of MicroRNAs …………………………..200

Vitamin D3 Regulates the Expressions of MicroRNAs ………………………………..200

Nicotinamide (Vitamin-B3) Regulates the Expressions of MicroRNAs ………… 201

Selenium Regulates the Expressions of MicroRNAs …………………………………… 201

Vitamin E and Delta-Tocotrienol Regulate the Expressions of MicroRNAs …… 201

Vitamin A (Retinoic Acid) Regulates the Expressions of MicroRNAs ………….. 201

Vitamin C Regulates the Expression of a MicroRNA ………………………………….202

Sources of Free Radicals in the Normal Brain ………………………………………………..203

Evidence for Increased Oxidative Stress as an Early Event in the Initiation of AD ……203

Studies on Cell Culture Model of AD ………………………………………………………..203

Studies on Animal Models of AD ……………………………………………………………..204

Studies on Asymptomatic Individuals Carrying Mutated AD Specific Genes ……..204

Studies on Increased Oxidative Stress in an Early Phase of AD ……………………204

Studies on Increased Oxidative Stress in Established Human AD

(Autopsied Brain Tissue) ………………………………………………………………………………205

Studies on Increased Oxidative Stress in Established Human AD

(Peripheral Tissue) ……………………………………………………………………………………….205

Mitochondrial Dysfunction …………………………………………………………………………..206

Processes of Generating Beta-Amyloid Fragments (Aβ1-42) and Their Toxicity ………206

Oxidative Stress Increases Production of Beta Amyloids (Aβ1-42 Peptides) ……….206

Aβ1-42 Peptides Cause Neuronal Degeneration by Inducing Free Radicals ………..207

Mutations in AD Specific Genes Increases the Production of Beta-Amyloids ……..207

Oxidative Stress Increases Hyperphosphorylated Tau (P-Tau) Protein in AD ……..207

Oxidative Stress Inhibits Proteasome Activity in AD ………………………………………207

Evidence for Increased Levels of Markers of Chronic Inflammation in AD ………..208

Cholesterol-Induced Generation of Beta-Amyloids ………………………………………….209

Genetic Defects in Idiopathic AD ………………………………………………………………….209

Mutated AD Genes Induce Neurodegeneration by Producing of Beta-Amyloids … 210

Neuroglobin in AD ……………………………………………………………………………………… 211

Laboratory and Clinical Studies with Individual Micronutrients in AD …………….. 211

Alpha-Lipoic Acid ………………………………………………………………………………….. 211

Coenzyme Q10 ………………………………………………………………………………………. 212

Melatonin ………………………………………………………………………………………………. 212

Nicotinamide (Vitamin B3) ……………………………………………………………………… 212

Vitamin A, Vitamin E, and Vitamin C ……………………………………………………… 212

Serum Levels of Antioxidants ………………………………………………………………….. 213

B-Vitamins …………………………………………………………………………………………….. 213

Curcumin ………………………………………………………………………………………………. 214

Resveratrol …………………………………………………………………………………………….. 214

Ginkgo biloba and Omega-3 Fatty Acids …………………………………………………… 214

Green Tea Epigallocatechin-3-Gallate (EGCG) and Caffeine ………………………. 214

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) in AD ……………………………… 215

Potential Reasons for Inconsistent Results with Individual Micronutrients

or Aspirin in AD ………………………………………………………………………………………… 215

Activation of Nrf2 (Nuclear Factor-Erythroid-2-Related Factor 2) ……………………. 216

Nrf2 ……………………………………………………………………………………………………… 216

ROS Activates Nrf2 ………………………………………………………………………………… 216

ROS-Resistant Nrf2 ………………………………………………………………………………… 216

Antioxidants Activate ROS-Resistant Nrf2 ………………………………………………… 216

Binding of Nrf2 with ARE in the Nucleus ……………………………………………………… 216

Suppression of Chronic Inflammation …………………………………………………………… 216

Nrf2 in AD ……………………………………………………………………………………………. 216

Proposed Micronutrient Mixture for Optimally Reducing Oxidative Stress

and Chronic Inflammation in AD …………………………………………………………………. 217

Proposed Micronutrient Strategies for Prevention of AD …………………………………. 217

Primary Prevention for AD ……………………………………………………………………… 217

Can AD Symptoms Be Prevented or Delayed in Individuals Carrying Mutated

Gene? ………………………………………………………………………………………………………… 218

Secondary Prevention for AD ………………………………………………………………….. 218

Proposed Micronutrient Mixture for Improving the Management of AD …………… 218

Current Drug Therapy for AD………………………………………………………………….. 218

Proposed Micronutrient Mixture in Combination with Drug Therapy for AD ………219

Diet and Lifestyle Recommendations for AD …………………………………………………. 219

Conclusions ……………………………………………………………………………………………….. 219

References ………………………………………………………………………………………………….220

Chapter 10 Micronutrients for the Prevention and Improvement of the Standard Therapy

for Parkinson’s Disease ……………………………………………………………………………….. 235

Introduction ……………………………………………………………………………………………….. 235

Incidence, Prevalence, and Cost of PD …………………………………………………………..236

Etiology of PD …………………………………………………………………………………………….236

Neuropathology and Symptoms of PD …………………………………………………………… 237

Genetic of PD …………………………………………………………………………………………….. 237

PD Genes and Oxidative Stress ……………………………………………………………………..238

DJ-1 Gene ………………………………………………………………………………………………238

Alpha-Synuclein Gene …………………………………………………………………………….. 238

PTEN-Induced Putative Kinase 1 (PINK1) ……………………………………………….. 239

PARKIN Gene ………………………………………………………………………………………..240

MicroRNAs in the Pathogenesis of PD …………………………………………………………..240

MicroRNAs ……………………………………………………………………………………………240

Changes in the Expressions of MicroRNAs in Neuronal Cell Culture

Models of PD ……………………………………………………………………………………………240

1-Methyl-4-Phenylpyridinium (MPP+) Treatment……………………………………….240

6-Hydroxydopamine (6-OHDA) Treatment ……………………………………………….. 241

Rotenone Treatment ………………………………………………………………………………… 241

Changes in the Expressions of MicroRNAs in Animal Models of PD ……………….. 241

Changes in the Expressions of MicroRNAs in Human PD ……………………………….242

Changes in the Expressions of MicroRNAs in Impaired Non-motor

Symptoms in PD …………………………………………………………………………………………. 243

Reactive Oxygen Species (ROS) Regulates the Expressions of MicroRNAs in

Neuronal Cells ……………………………………………………………………………………………. 243

Pro-inflammatory Cytokines Upregulate the Expressions of MicroRNAs …………. 243

Antioxidants Regulate the Expressions of MicroRNAs ……………………………………. 243

Evidence for Increased Oxidative Stress in PD……………………………………………….. 243

Mitochondrial Dysfunction in PD ………………………………………………………………….244

Evidence for Increased Chronic Inflammation in PD ……………………………………….245

Evidence for Increased Glutamate in PD ………………………………………………………..245

Laboratory and Human Studies in PD after Treatment with Micronutrients ……….246

In Vitro Studies with Micronutrients………………………………………………………….246

Cell Culture Studies with Micronutrients …………………………………………………..246

Antioxidant Studies in Animal Models of PD …………………………………………….246

Antioxidant Studies in Human PD ………………………………………………………………… 247

Potential Reasons for Inconsistent Results with Individual Micronutrients in

AD Prevention Studies …………………………………………………………………………………248

Activation of Nrf2 (Nuclear Factor-Erythroid-2-Related Factor 2) …………………….249

Nrf2 ………………………………………………………………………………………………………249

ROS Activates Nrf2 ……………………………………………………………………………………..249

Nrf2 in PD ………………………………………………………………………………………………….250

Reducing Glutamate Release and Toxicity ………………………………………………………250

Proposed Micronutrient Mixture for Prevention and Improved

Management of PD ………………………………………………………………………………………250

Primary Prevention …………………………………………………………………………………. 251

Secondary Prevention ……………………………………………………………………………… 251

Current Treatments of PD ……………………………………………………………………………. 251

Proposed Micronutrient Mixture in Combination with Standard Therapy …………. 251

Diet and Lifestyle Recommendations for PD ………………………………………………….. 252

Conclusions ……………………………………………………………………………………………….. 252

References …………………………………………………………………………………………………. 252

Chapter 11 Micronutrients in Prevention and Improvement of the Standard Therapy in

Hearing Disorders ……………………………………………………………………………………….263

Introduction ………………………………………………………………………………………………..263

Prevalence and Cost …………………………………………………………………………………….264

Prevalence ………………………………………………………………………………………………264

Cost ……………………………………………………………………………………………………….264

Types of Hearing Disorders ………………………………………………………………………….264

Conductive Hearing Loss …………………………………………………………………………264

Sensorineural Hearing Loss ……………………………………………………………………..264

Tinnitus ………………………………………………………………………………………………….265

Meniere’s Disease (MD) …………………………………………………………………………..265

Agents or Health Conditions Causing Hearing Disorders …………………………………265

Measurements of Hearing Loss ……………………………………………………………………..266

Evidence for Increased Oxidative Stress in Hearing Disorders ………………………….266

Noise-Induced Oxidative Stress (NIHL) …………………………………………………….266

Noise and/or Vibration-Induced Oxidative Stress ……………………………………….. 267

xvi Contents

Cisplatin-Induced Oxidative Stress …………………………………………………………… 267

Advanced Age-Induced Oxidative Stress …………………………………………………… 267

Oxidative Stress in the Meniere’s Disease (MD) ………………………………………… 267

Evidence for Inflammation in Hearing Disorders ……………………………………………. 267

Noise-Induced Inflammation ……………………………………………………………………. 267

Gentamicin- and Cisplatin-Induced Inflammation ………………………………………268

Bacterial Infection-Induced Inflammation ………………………………………………….268

Health Conditions-Induced Inflammation …………………………………………………..268

Advanced Age-Induced Inflammation ……………………………………………………….268

Evidence for Increased Glutamate Level in Hearing Disorders………………………….268

Noise Releases Glutamate ………………………………………………………………………..268

Salicylate Activates Glutamate Receptor ……………………………………………………269

Aminoglycoside, Cochlea Ischemia, or Trauma-Induced Release

of Glutamate ……………………………………………………………………………………… 269

MicroRNAs in the Pathogenesis of Hearing Disorders …………………………………….269

MicroRNAs ……………………………………………………………………………………………269

Expression of MicroRNAs in the Normal Ears……………………………………………269

Alterations in MicroRNAs Expression in Hearing Disorders……………………………. 270

Changes in the Expressions of MicroRNAs in Age-Related Hearing Disorders …..270

Mutation in MicroRNA Induces Nonsyndromic Hearing Loss (NSHL) ………… 271

Changes in the Expressions of MicroRNAs in Noise-Induced Hearing Loss ………271

Changes in the Expressions of MicroRNAs in Kanamycin-Induced Hearing

Disorders……………………………………………………………………………………………….. 271

Changes in the Expressions of MicroRNAs in Damaged Auditory

Nervous System ……………………………………………………………………………………… 272

Oxidative Stress Regulates the Expression of MicroRNAs in Hearing Disorders …….273

Auditory Cells ……………………………………………………………………………………….. 273

Non-auditory Cells (Neurons and Non-neuronal Cells) ……………………………….. 273

Pro-inflammatory Cytokines Could Upregulate the Expressions of MicroRNAs

in Hearing Disorders …………………………………………………………………………………… 273

Antioxidants Could Regulate the Expressions of MicroRNAs in Hearing

Disorders …………………………………………………………………………………………………… 273

Studies on Antioxidants in Hearing Disorders………………………………………………… 274

Animal Studies ………………………………………………………………………………………. 274

Human Studies ………………………………………………………………………………………. 274

Potential Reasons for Suboptimal Beneficial Effects with Individual

Micronutrients in Hearing Disorders …………………………………………………………….. 275

Activation of Nrf2 (Nuclear Factor-Erythroid-2-Related Factor 2) ……………………. 276

Nrf2 ……………………………………………………………………………………………………… 276

Activation of Nrf2 During Acute Oxidative Stress ……………………………………… 276

Failure to Activate Nrf2 During Chronic Oxidative Stress …………………………… 276

Antioxidants Activate ROS-Resistant Nrf2 ………………………………………………… 276

Binding of Nrf2 with ARE in the Nucleus …………………………………………………. 276

Importance of Activation of Nrf2 in Auditory Cells …………………………………….277

Current Prevention and Treatments Strategies …………………………………………………277

Reducing Oxidative Stress Level ………………………………………………………………….. 278

Reducing Inflammation Level ………………………………………………………………………. 278

Reducing Glutamate Level …………………………………………………………………………… 278

Proposed Micronutrients for Simultaneously Reducing Oxidative Stress,

Inflammation, and Glutamate Levels in Hearing Disorders ……………………………… 278

Prevention of Hearing Disorders …………………………………………………………………… 278

Primary Prevention …………………………………………………………………………………. 278

Secondary Prevention ……………………………………………………………………………… 279

Improved Management ……………………………………………………………………………. 279

Conclusions ……………………………………………………………………………………………….. 279

References ………………………………………………………………………………………………….280

Chapter 12 Micronutrients in Improvement of the Standard Therapy in Posttraumatic

Stress Disorder (PTSD) ………………………………………………………………………………..289

Introduction ………………………………………………………………………………………………..289

Prevalence and Cost of PTSD ……………………………………………………………………….289

Symptoms of PTSD ……………………………………………………………………………………..290

Brain Pathology of PTSD …………………………………………………………………………….. 291

MicroRNAs in PTSD …………………………………………………………………………………..292

Evidence for Increased Oxidative Stress in PTSD ……………………………………………292

Evidence for Chronic Inflammation in PTSD ………………………………………………….293

Evidence for Increased Release of Glutamate and Decreased Levels

of GABA in PTSD……………………………………………………………………………………….294

Glutamate and GABA Levels in PTSD ……………………………………………………… 295

Studies on Antioxidants in PTSD ………………………………………………………………….295

Omega-3-Fatty Acids ………………………………………………………………………………. 295

Curcumin ……………………………………………………………………………………………….296

Resveratrol ……………………………………………………………………………………………..296

Pentoxifylline and Tempol ……………………………………………………………………….296

Flavonoids ………………………………………………………………………………………………296

Valproic Acid ………………………………………………………………………………………….296

Blueberry-Rich Diet ………………………………………………………………………………..296

Effect of Multiple Micronutrients in Veterans …………………………………………….297

Potential Reasons for the Failure of Individual Micronutrients in Producing

Consistent Benefits in Human ……………………………………………………………………….297

Activation of Nrf2 (Nuclear Factor-Erythroid-2-Related Factor 2) …………………….298

Nrf2 ………………………………………………………………………………………………………298

Activation of Nrf2 During Acute Oxidative Stress ………………………………………298

Failure to Activate Nrf2 During Chronic Oxidative Stress ……………………………298

Antioxidants Activate ROS-Resistant Nrf2 …………………………………………………298

Binding of Nrf2 with ARE in the Nucleus ………………………………………………….299

Proposed Micronutrient Mixture for Optimally Reducing Oxidative Stress,

Chronic Inflammation, and Glutamate Levels …………………………………………………299

Reducing Oxidative Stress ……………………………………………………………………….299

Reducing Chronic Inflammation ……………………………………………………………….299

Reducing Glutamate Release and Toxicity ………………………………………………….299

Prevention of PTSD ……………………………………………………………………………………..299

Primary Prevention of PTSD ……………………………………………………………………299

Secondary Prevention of PTSD …………………………………………………………………299

Standard Therapy in PTSD …………………………………………………………………………..300

Improved Management of PTSD……………………………………………………………………300

Diet and Lifestyle Recommendations for PTSD ………………………………………………300

Conclusions ………………………………………………………………………………………………..300

References …………………………………………………………………………………………………. 301

Chapter 13 Micronutrients in Improvement of the Standard Therapy in Traumatic Brain

Injury …………………………………………………………………………………………………………309

Introduction ………………………………………………………………………………………………..309

Incidence, Prevalence, and Cost of TBI …………………………………………………………. 310

Concussion in USA Population ………………………………………………………………… 310

National Football League (NFL) ………………………………………………………………. 310

High School and College Sports ……………………………………………………………….. 310

US Veterans …………………………………………………………………………………………… 310

US Civilian ……………………………………………………………………………………………. 311

Penetrating TBI (pTBI) ……………………………………………………………………………….. 311

US Troops ……………………………………………………………………………………………… 311

US Civilian ……………………………………………………………………………………………. 311

Cost …………………………………………………………………………………………………………… 311

Causes of Concussion ………………………………………………………………………………….. 311

Causes of Penetrating TBI (pTBI) …………………………………………………………………. 311

Acute Symptoms of Concussion ……………………………………………………………………. 312

Acute Symptoms of pTBI …………………………………………………………………………….. 312

Long-Term Health Consequences of TBI ……………………………………………………….. 312

Concussion …………………………………………………………………………………………….. 312

pTBI ……………………………………………………………………………………………………… 313

Neuropathology of TBI ……………………………………………………………………………….. 313

Concussion …………………………………………………………………………………………….. 313

pTBI ……………………………………………………………………………………………………… 313

Scoring System of Severity of TBI ………………………………………………………………… 314

MicroRNAs in Pathogenesis of TBI ……………………………………………………………… 314

MicroRNAs as Potential Biomarkers for TBI …………………………………………………. 315

Evidence for Increased Oxidative Stress in Concussion …………………………………… 316

Animal Models ………………………………………………………………………………………. 316

Humans …………………………………………………………………………………………………. 316

Evidence for Increased Inflammation in Concussion ……………………………………….. 316

Animal Models ………………………………………………………………………………………. 316

Humans …………………………………………………………………………………………………. 317

Evidence for Increased Glutamate Level in Concussion …………………………………… 317

Molecular Changes in the Brain after Concussion…………………………………………… 317

Evidence for Increased Oxidative Stress after pTBI ………………………………………… 318

Animal Models ………………………………………………………………………………………. 318

Humans …………………………………………………………………………………………………. 318

Oxidative Stress and Mitochondrial Dysfunction after pTBI ……………………………. 319

Animal Models ………………………………………………………………………………………. 319

Humans …………………………………………………………………………………………………. 320

Evidence for Increase Levels of Markers of Inflammation after pTBI ……………….. 320

Animal Models ………………………………………………………………………………………. 320

Humans …………………………………………………………………………………………………. 321

Evidence for Increased Glutamate Level after pTBI ………………………………………… 322

Animal Models ………………………………………………………………………………………. 322

Humans …………………………………………………………………………………………………. 322

Role of Matrix Metalloproteinases (MMPS) after Severe TBI………………………….. 323

Studies on the Effects of Single Antioxidants after TBI …………………………………… 323

Animal Models ………………………………………………………………………………………. 323

Humans ………………………………………………………………………………………………….324

Potential Reasons for Inconsistent Results with Individual Micronutrients

in Other Neurodegenerative Diseases …………………………………………………………….324

Activation of Nrf2 (Nuclear Factor-Erythroid-2-Related Factor 2) ……………………. 325

Nrf2 ……………………………………………………………………………………………………… 325

Activation of Nrf2 During Acute Oxidative Stress ……………………………………… 325

Failure to Activate Nrf2 During Chronic Oxidative Stress …………………………… 325

Antioxidants Activate ROS-Resistant Nrf2 ………………………………………………… 326

Binding of Nrf2 with ARE in the Nucleus …………………………………………………. 326

Nrf2 in TBI ………………………………………………………………………………………………… 326

Reducing Oxidative Stress Level ………………………………………………………………….. 326

Reducing Inflammation Level ………………………………………………………………………. 326

Reducing Glutamate Level …………………………………………………………………………… 326

Proposed Micronutrients for Reducing Oxidative Stress, Inflammation,

and Glutamate Levels in TBI ……………………………………………………………………….. 326

Toxicity of Ingredients in Proposed Micronutrient Preparation ………………………… 327

Prevention Studies with Proposed Micronutrient Mixture in TBI ……………………… 327

Primary Prevention …………………………………………………………………………………. 327

Secondary Prevention ……………………………………………………………………………… 327

Standard Therapy of TBI …………………………………………………………………………….. 328

Proposed Micronutrients in Combination with Standard Therapy …………………….. 328

Diet and Lifestyle Recommendations for TBI ………………………………………………… 329

Conclusions ……………………………………………………………………………………………….. 329

References …………………………………………………………………………………………………. 329

Chapter 14 Micronutrients in Prevention and Improvement of the Standard Therapy in

HIV/AIDS ………………………………………………………………………………………………….. 341

Introduction ……………………………………………………………………………………………….. 341

History, Prevalence, Incidence, and Cost of HIV/AIDS …………………………………… 342

History of HIV/AIDS ……………………………………………………………………………… 342

Prevalence of HIV Infection…………………………………………………………………….. 342

Incidence of HIV Infection ……………………………………………………………………… 342

Cost of Treating HIV Infection ………………………………………………………………… 343

Role of Immune Function in HIV Infection ……………………………………………………. 343

Micronutrient Deficiency Impairs Immune Function ………………………………………. 343

Illicit Drugs Impair Immune Function ……………………………………………………………344

Evidence for Increased Oxidative Stress Enhancing the Progression of HIV

Infection …………………………………………………………………………………………………….344

Evidence for Increased Inflammation Enhancing the Progression of HIV

Infection ……………………………………………………………………………………………………. 345

Evidence for Micronutrients Reducing Progression of HIV Infection ………………..346

Potential Reasons for Inconsistent Results with Micronutrients in Patients

with HIV/AIDS ………………………………………………………………………………………….. 347

Activation of Nrf2 (Nuclear Factor-Erythroid-2-Related Factor 2) …………………….348

Nrf2 ………………………………………………………………………………………………………348

Activation of Nrf2 During Acute Oxidative Stress ………………………………………348

Failure of ROS to Activate Nrf2 During Chronic Oxidative Stress ………………..348

Antioxidants Activate ROS-Resistant Nrf2 …………………………………………………348

Binding of Nrf2 with ARE in the Nucleus ………………………………………………….348

Nrf2 in Patients with HIV Infection ………………………………………………………………348

Reducing Oxidative Stress Level in HIV-Infected People …………………………………349

Reducing Inflammation Level in HIV-Infected People …………………………………….349

Proposed Micronutrient Mixture for Reducing Oxidative Stress and

Inflammation Levels in Patients with HIV Infection ………………………………………..349

Toxicity of Ingredients in Proposed Micronutrient Mixture ………………………………349

Primary Prevention Against HIV Infection ……………………………………………………. 350

Secondary Prevention for Reducing the Progression of HIV Infection ………………. 350

Treatments of HIV/AIDS …………………………………………………………………………….. 350

Antiviral Therapy in Reducing the Risk of Transmission From Mother to Infants …… 351

Proposed Micronutrient Mixture in Combination with Antiviral Drugs …………….. 351

Conclusions ……………………………………………………………………………………………….. 352

References …………………………………………………………………………………………………. 352

Chapter 15 Improved Management of Autism Spectrum Disorder (ASD) by Micronutrients ……..359

Introduction ……………………………………………………………………………………………….. 359

Prevalence and Cost of ASD ………………………………………………………………………… 359

Prevalence ……………………………………………………………………………………………… 359

Cost ………………………………………………………………………………………………………. 359

Environmental and Genetic Factors ………………………………………………………………. 359

Environmental Factors ……………………………………………………………………………. 359

Health Conditions ……………………………………………………………………………………360

Genetic Factors ……………………………………………………………………………………….360

Major Symptoms of ASD …………………………………………………………………………….. 361

Brain Changes in ASD ………………………………………………………………………………… 361

MicroRNAs in ASD ……………………………………………………………………………………. 362

MicroRNAs …………………………………………………………………………………………… 362

MicroRNAs in Serum …………………………………………………………………………….. 362

MicroRNAs in Saliva ……………………………………………………………………………… 362

MicroRNAs in Autopsied Brain Samples ………………………………………………….. 363

MicroRNAs in Cell Culture …………………………………………………………………….. 363

MicroRNAs in Animals ………………………………………………………………………….. 363

Evidence for Increased Oxidative Stress in ASD …………………………………………….. 363

Human Studies ………………………………………………………………………………………. 363

Cell Culture Models ………………………………………………………………………………..364

Evidence for Increased Inflammation in ASD …………………………………………………365

Imbalances Between Neuronal Excitation and Inhibition………………………………….365

Human Studies ……………………………………………………………………………………….365

Use of Single Antioxidants in the Management of ASD …………………………………..366

Human Studies ……………………………………………………………………………………….366

Animal Studies ……………………………………………………………………………………….366

Studies with Individual Antioxidants in Human Neurodegenerative Diseases ……. 367

Regulation of Activation of Nrf2 …………………………………………………………………..368

Reactive Oxygen Species (ROS) Activates Nrf2 ………………………………………….368

Binding of Nrf2 with ARE in the Nucleus ………………………………………………….368

Existence of ROS-Resistant Nrf2 ………………………………………………………………368

Antioxidants Activate ROS-Resistant Nrf2 …………………………………………………368

L-Carnitine Activates Nrf2 by a ROS-Dependent Mechanism ……………………..368

Activation of Nrf2 by MicroRNAs …………………………………………………………….368

Suppression of Chronic Inflammation ……………………………………………………………369

Inhibition of Release and Toxicity of Glutamate ……………………………………………..369

Drug Treatment in Human ASD ……………………………………………………………………369

Drug Treatment in Animal ASD Models ……………………………………………………….. 370

Proposed Mixture of Micronutrients for Improved Management of ASD ………….. 370

Conclusions ……………………………………………………………………………………………….. 370

References …………………………………………………………………………………………………. 371

Chapter 16 Micronutrients in the Management of Prion Disease ………………………………………. 379

Introduction ……………………………………………………………………………………………….. 379

Incidence of Prion Disease …………………………………………………………………………… 379

Types of Prion Disease ………………………………………………………………………………… 379

Modes of Transmission of Prion Disease to the Brain ………………………………………380

Pathological Changes in the Brain …………………………………………………………………380

Symptoms of Prion Disease …………………………………………………………………………. 381

Factors Facilitating Conversion of PrPc to PrPsc and Mechanisms of

Proliferation of PrPsc ………………………………………………………………………………….. 381

Effect of Mutations in PRNP Gene …………………………………………………………… 381

Role of Exosomes …………………………………………………………………………………… 381

Effects on Polymorphisms of PNRP Gene …………………………………………………. 382

Effects of Increased Oxidative Stress ………………………………………………………… 383

Oxidation of Methionine Residues in PrPc ………………………………………………… 383

Effects of PrPsc-Induced Inflammation in the Brain ……………………………………….. 383

Mechanisms of Neurotoxicity ……………………………………………………………………….384

MicroRNAs in Prion Disease ………………………………………………………………………..384

Studies with Individual Antioxidants and Phytochemicals in Models

of Prion Diseases …………………………………………………………………………………………386

Studies with Individual Antioxidants in Other Neurodegenerative Diseases ………. 387

Regulation of Activation of Nrf2 ………………………………………………………………….. 388

Reactive Oxygen Species (ROS) Activates Nrf2 …………………………………………. 388

Binding of Nrf2 with ARE in the Nucleus …………………………………………………. 388

Existence of ROS-Resistant Nrf2 in Prion Disease …………………………………….. 388

Antioxidants Activate of ROS-Resistant Nrf2 ……………………………………………. 388

L-Carnitine Activates Nrf2 by a ROS-Dependent Mechanism …………………….. 388

Activation of Nrf2 by MicroRNAs ……………………………………………………………. 388

Suppression of Chronic Inflammation …………………………………………………………… 389

Proposed Mixture of Micronutrients in Prevention and Improved

Management of Prion Disease ……………………………………………………………………… 389

Prevention of Prion Disease …………………………………………………………………….. 389

Improved Management of Prion Disease …………………………………………………… 389

Conclusions ……………………………………………………………………………………………….. 389

References ………………………………………………………………………………………………….390

Chapter 17 Micronutrients for Improved Management of Huntington’s Disease ………………….. 395

Introduction ……………………………………………………………………………………………….. 395

Incidence, Prevalence, and Cost of HD ………………………………………………………….. 396

Incidence and Prevalence ………………………………………………………………………… 396

Cost ………………………………………………………………………………………………………. 396

Signs and Symptoms …………………………………………………………………………………… 396

Pathology of the Brain in HD………………………………………………………………………..397

Human Studies ……………………………………………………………………………………….397

Animal Studies ……………………………………………………………………………………….397

Receptor Abnormalities in HD …………………………………………………………………….. 398

Dopamine Receptors ………………………………………………………………………………. 398

Cannabinoid Receptors ……………………………………………………………………………. 398

Adenosine Receptors ……………………………………………………………………………….399

Transcriptional Deregulation in HD ………………………………………………………………399

Histone Deacetylation ……………………………………………………………………………..399

Pre-translational Modification of Proteins in HD …………………………………………….400

MicroRNAs ……………………………………………………………………………………………400

MicroRNAs in Brain Cell Pathology and Protection ……………………………………400

MicroRNAs in Plasma …………………………………………………………………………….. 401

Post-translational Modification of Proteins in HD ……………………………………………402

Evidence for Increased Oxidative Stress as an Early Event in the Onset

of HD Symptoms …………………………………………………………………………………………402

Studies on Asymptomatic and Symptomatic Individuals ……………………………..402

Aggregation of HD Protein ………………………………………………………………………403

Studies on Animal Models of HD ……………………………………………………………..403

Studies on Cell Culture Models of HD ………………………………………………………403

Mitochondrial Dysfunction in Asymptomatic and Symptomatic

Individuals Carrying HD Gene …………………………………………………………………403

Evidence for Increased Chronic Inflammation in HD ………………………………………404

Studies on Asymptomatic and Symptomatic Individuals ……………………………..404

Studies on Animal Models of HD ……………………………………………………………..405

Increased Glutamate Levels and Glutamate Receptor Activation in HD …………….405

GABA Receptors in Asymptomatic and Symptomatic Individuals …………………….406

Use of Single Antioxidants, Phytochemicals, and B-Vitamins in the

Management of HD ……………………………………………………………………………………..406

Alpha-Tocopherol (Vitamin E) ………………………………………………………………….406

Vitamin C ………………………………………………………………………………………………406

N-Acetylcysteine (NAC)…………………………………………………………………………..406

Alpha-Lipoic Acid …………………………………………………………………………………..407

Coenzyme Q10 ……………………………………………………………………………………….407

L-Carnitine …………………………………………………………………………………………….407

Lycopene and Epigallocatechin …………………………………………………………………407

Melatonin ……………………………………………………………………………………………….407

Curcumin ……………………………………………………………………………………………….408

Resveratrol ……………………………………………………………………………………………..408

Ginkgo biloba Extract and Olive Oil ………………………………………………………….408

Probucol …………………………………………………………………………………………………408

B-Vitamins ……………………………………………………………………………………………..409

Studies with Individual Antioxidants in Other Human Neurodegenerative

Diseases ……………………………………………………………………………………………………..409

Regulation of Activation of Nrf2 ………………………………………………………………….. 410

Reactive Oxygen Species (ROS) Activates Nrf2 …………………………………………. 410

Binding of Nrf2 with ARE in the Nucleus …………………………………………………. 410

Existence of ROS-Resistant Nrf2 ……………………………………………………………… 410

Antioxidants Activate ROS-Resistant Nrf2 ………………………………………………… 410

L-Carnitine Activates Nrf2 by a ROS-Dependent Mechanism …………………….. 410

Activation of Nrf2 by MicroRNAs ……………………………………………………………. 411

Nrf2 in HD ………………………………………………………………………………………………… 411

Suppression of Oxidative Stress by Nrf2 and Antioxidants ………………………………. 411

Suppression of Chronic Inflammation by Nrf2 and Antioxidants ……………………… 411

Inhibition of Release and Toxicity of Glutamate by Antioxidants and

B-Vitamins………………………………………………………………………………………………411

Proposed Mixture of Micronutrients for Improved Management of HD…………….. 412

Prevention or Delaying the Onset of Symptoms by Proposed Micronutrient

Mixture? ……………………………………………………………………………………………………. 412

Proposed Micronutrient Mixture in Combination with Standard Treatment……….. 413

Current Treatments of HD …………………………………………………………………………… 413

Movement Disorder Drugs ………………………………………………………………………. 413

Antipsychotic Drugs ……………………………………………………………………………….. 413

Other Medications ………………………………………………………………………………….. 413

Medications for Psychiatric Disorders …………………………………………………………… 413

Antidepressants ……………………………………………………………………………………… 413

Mood-Stabilizing Drugs ………………………………………………………………………….. 413

Clinical Studies with Additional Drugs in HD ……………………………………………….. 414

Psychotherapy …………………………………………………………………………………………….. 414

Speech Therapy ………………………………………………………………………………………….. 414

Physical Therapy ………………………………………………………………………………………… 414

Conclusions ……………………………………………………………………………………………….. 414

References …………………………………………………………………………………………………. 415

Chapter 18 Micronutrients in Protecting Against Late Adverse Health-Effects

of Diagnostic Radiation Doses ……………………………………………………………………… 423

Introduction ……………………………………………………………………………………………….. 423

Sources of Background Radiation ………………………………………………………………….424

Dose-Estimate of Diagnostic Radiation Procedures and Per Capita Dose ………….. 425

Estimated Dose Received by Radiation Workers …………………………………………….. 427

Estimated Dose Received by Crews of Commercial Flight ………………………………. 427

Health Effects of Low Doses of Radiation ……………………………………………………… 427

Effects of Background Radiation on Human Health ……………………………………. 427

Induction of Mutations ……………………………………………………………………………. 428

Induction of Radiation-Induced Cancer …………………………………………………….. 428

Impact of Chemical and Biological Carcinogens, and Tumor Promoters

on Radiation-Induced Cancer …………………………………………………………………… 428

Models Used for Risk Estimates of Radiation-Induced Cancer…………………………. 429

Cancer Risks in Populations Exposed to Diagnostic Radiation Procedures ……….. 429

Adults and Children ……………………………………………………………………………….. 429

Cancer Risk in Children Exposed in Utero During Atomic Bombing

of Hiroshima and Nagasaki ……………………………………………………………………… 430

Risk of Childhood Cancer after Irradiation of Fetuses ………………………………… 430

Women Receiving Gonadal Doses of Radiation Before Conception ……………… 431

Cancer Risk Among Radiation Workers ………………………………………………………… 431

Cancer Risk in Military and Civilian Pilots and Flight Attendants …………………… 432

Cancer Risk Among Frequent Flyers …………………………………………………………….. 433

Risk of Low-Dose Radiation-Induced Nonneoplastic Diseases ………………………… 433

Reducing Oxidative Stress and Inflammation by Single Antioxidants in

Humans ………………………………………………………………………………………………. 433

Reducing Damage by Multiple Antioxidants in Humans …………………………………. 434

Proposed Strategy to Simultaneously Reduce Oxidative Stress and Inflammation …….. 434

Activation of Nrf2 (Nuclear Factor-Erythroid-2-Related Factor 2) ……………………. 434

Nrf2 ……………………………………………………………………………………………………… 434

Activation of Nrf2 During Acute Oxidative Stress ……………………………………… 435

Failure to Activate Nrf2 During Chronic Oxidative Stress …………………………… 435

Antioxidants Activate ROS-Resistant Nrf2 ………………………………………………… 435

Binding of Nrf2 with ARE in the Nucleus …………………………………………………. 436

Proposed Micronutrients for Simultaneously Reducing Oxidative Stress

and Inflammation ……………………………………………………………………………………….. 436

Conclusions ……………………………………………………………………………………………….. 436

References …………………………………………………………………………………………………. 437

Chapter 19 Micronutrients in Protecting Against Lethal Doses of Ionizing Radiation ………….443

Introduction ………………………………………………………………………………………………..443

Unit of Radiation Doses ……………………………………………………………………………….444

High-Dose Radiation-Induced Damage ………………………………………………………….444

Bone Marrow Syndrome ………………………………………………………………………….444

Gastrointestinal (GI) Syndrome ………………………………………………………………..445

Central Nervous System (CNS) Syndrome …………………………………………………445

High-Dose Radiation-Induced Damage to Organs ………………………………………445

Risk of Developing Cancer Among Survivors of High Doses of Radiation …………446

Risk of Developing Non-neoplastic Diseases Among Survivors of High

Doses of Radiation ………………………………………………………………………………………446

MicroRNAs in Radiation Damage …………………………………………………………………447

MicroRNAs ……………………………………………………………………………………………447

Irradiation Alters the Expression of MicroRNAs in Normal Cells …………………….447

MicroRNAs in Radiation-Induced Bystandard Effect ………………………………………449

MicroRNAs as Biomarkers of Radiation Damage ……………………………………………449

Brief History of Radiation Protection Studies …………………………………………………449

Radiation Protection Studies with Antioxidants in Cell Culture Models ……………. 450

Radiation Protection Studies with Antioxidants in Animal Models …………………… 450

Radiation Protection Study with a Mixture of Multiple Antioxidants

Administered Orally Before and after Irradiation in Sheep ……………………………… 451

Radiation Protection Study with a Mixture of Multiple Antioxidants

Administered Orally Before and after Irradiation in Rabbits ……………………………. 452

Radiation Protection Study with a Mixture of Multiple Antioxidants

Administered Orally Before Irradiation in Mice …………………………………………….. 453

Radiation Protection Study with a Mixture of Multiple Antioxidants

Administered Through the Diet Before and after Irradiation in Drosophila

Melanogaster ……………………………………………………………………………………………… 454

Radiation Protection Studies with Antioxidants in Humans …………………………….. 454

Rationale for Using Multiple Antioxidants in Radiation Protection …………………… 454

Activation of Nrf2 (Nuclear Factor-Erythroid-2-Related Factor 2) ……………………. 455

Nrf2 ……………………………………………………………………………………………………… 455

Activation of Nrf2 During Acute Oxidative Stress ……………………………………… 456

Activation of Nrf2 During Acute Phase of Irradiation …………………………………. 456

Failure to Activate Nrf2 During Radiation-Induced Chronic Phase of

Irradiation ……………………………………………………………………………………………… 456

Antioxidants Activate ROS-Resistant Nrf2 ………………………………………………… 456

Binding of Nrf2 with ARE in the Nucleus …………………………………………………. 456

Reducing Oxidative Stress Level for Radiation Protection ……………………………….. 457

Reducing Inflammation Level for Radiation Protection …………………………………… 457

Proposed Micronutrients for Radiation Protection ………………………………………….. 457

Guidelines for the Management of Large Number of People Irradiated

with Lethal Doses of Radiation …………………………………………………………………….. 457

Radiation Mitigating Agents ………………………………………………………………………… 458

Chemical Agents for Mitigating Radiation Injury …………………………………………… 458

Antibiotics, Blood, and Electrolytes ………………………………………………………….. 458

Erythropoietin ……………………………………………………………………………………….. 458

Statins …………………………………………………………………………………………………… 458

Cytokines and Growth Factors …………………………………………………………………. 458

Biological Agents for Mitigating Radiation Injury ………………………………………….. 459

Bone Marrow and Newborn Liver Cells Transplant ……………………………………. 459

The Chernobyl Experience in Treating Irradiated Individuals ………………………….. 459

Proposed Micronutrient Mixture for the Treatment of Bone Marrow Syndrome ………460

Proposed Micronutrient Mixture for the Treatment of GI Syndrome ………………….460

Conclusions ………………………………………………………………………………………………..460

References …………………………………………………………………………………………………. 461

Chapter 20 Micronutrients in Prevention and Improvement of the Standard Therapy in

Arthritis ……………………………………………………………………………………………………..469

Introduction ………………………………………………………………………………………………..469

Prevalence and Cost of Arthritis …………………………………………………………………… 470

Types of Arthritis ……………………………………………………………………………………….. 471

Rheumatoid Arthritis (RA) ……………………………………………………………………… 471

Osteoarthritis (OA) …………………………………………………………………………………. 471

Juvenile Rheumatoid Arthritis (JRA)………………………………………………………… 472

Evidence for the Role of Oxidative Stress ………………………………………………………. 472

Evidence for the Role of Inflammation ………………………………………………………….. 473

Role of Antioxidants in Arthritis ………………………………………………………………….. 475

Studies on Animal Models of Arthritis ……………………………………………………… 475

Human Cell Culture Models of Arthritis …………………………………………………… 476

Studies on Human RA and OA ………………………………………………………………… 477

Prevention Strategies …………………………………………………………………………………… 477

Potential Reasons for Inconsistent Results …………………………………………………. 477

Activation of Nrf2 (Nuclear Factor-Erythroid-2-Related Factor 2) ……………………. 478

Nrf2 ……………………………………………………………………………………………………… 478

Activation of Nrf2 During Acute Oxidative Stress ……………………………………… 478

Failure to Activate Nrf2 During Chronic Oxidative Stress …………………………… 478

Antioxidants Activate ROS-Resistant Nrf2 ………………………………………………… 478

Binding of Nrf2 with ARE in the Nucleus …………………………………………………. 479

Importance of Activation of Nrf2 in Arthritis ……………………………………………. 479

Reducing Oxidative Stress Level ………………………………………………………………….. 479

Reducing Inflammation Level ………………………………………………………………………. 479

Proposed Micronutrients for Simultaneously Reducing Oxidative Stress and

Inflammation in Arthritis …………………………………………………………………………….. 479

Primary Prevention of Arthritis ……………………………………………………………………. 479

Treatment Strategies of Arthritis …………………………………………………………………..480

Low-Dose Methotrexate (MTX) ……………………………………………………………….480

Anti-cytokines Therapy ……………………………………………………………………………480

Toxicity of MTX and Anti-cytokine Therapy ……………………………………………..482

Treatment with Glucosamine and Chondroitin ……………………………………………482

Treatment with Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) ……………..483

Treatment with Complementary Medicine ………………………………………………….483

Proposed Micronutrient Mixture in Combination with Standard Therapy

in Patients with Arthritis ………………………………………………………………………………483

Diet and Lifestyle Recommendations for High Risk Populations and Patients

with Arthritis ………………………………………………………………………………………………483

Conclusions ………………………………………………………………………………………………..483

References ………………………………………………………………………………………………….484

Chapter 21 Misconceptions about the Functions and Value of Antioxidants in Health and

Disease ……………………………………………………………………………………………………… 493

Introduction ……………………………………………………………………………………………….. 493

Misconception 1 …………………………………………………………………………………………. 493

Misconception 2 …………………………………………………………………………………………. 493

Misconception 3 ………………………………………………………………………………………….494

Misconception 4 ………………………………………………………………………………………….494

Misconception 5 ………………………………………………………………………………………….494

Misconception 6 ………………………………………………………………………………………….494

Misconception 7 ………………………………………………………………………………………….494

Misconception 8 …………………………………………………………………………………………. 495

Misconception 9 …………………………………………………………………………………………. 495

Misconception 10 ……………………………………………………………………………………….. 495

Misconception 11 ……………………………………………………………………………………….. 495

Misconception 12 ………………………………………………………………………………………..496

Misconception 13 ………………………………………………………………………………………..496

Misconception 14 ………………………………………………………………………………………..496

Misconception 15 ………………………………………………………………………………………..496

Misconception 16 ………………………………………………………………………………………..496

Misconception 17 ………………………………………………………………………………………..497

Conclusions ………………………………………………………………………………………………..497

Chapter 22 Dietary Reference Intakes of Selected Micronutrients ……………………………………..499

Introduction ………………………………………………………………………………………………..499

RDA (DRI) …………………………………………………………………………………………………499

Adequate Intake (AI) ………………………………………………………………………………. 518

Tolerable Upper Intake Level (UL) …………………………………………………………… 518

Conclusions ……………………………………………………………………………………………….. 519

Index ……………………………………………………………………………………………………………………………. 521

About the Author

Dr. Kedar N. Prasad obtained a Masters degree in Zoology from the University of Bihar, Ranchi, India, and a Ph.D. degree in Radiation Biology from the University of Iowa, Iowa City, in 1963. He received Post-doctoral training at the Brookhaven National Laboratory, Long Island. New York, and joined the Department of Radiology at the University of Colorado Health Sciences Center where he became Professor and Director for the Center for Vitamins and Cancer Research. He has published over 250 articles in peer-reviewed journals, and authored and edited 25 books in the area of radiation biology, nutrition and cancer, and nutrition and neurological diseases particularly Alzheimer’s disease and Parkinson’s disease. These articles were published in highly prestigious journals such as Science, Nature, and Proceedings of the National Academic of Sciences, USA. Dr Prasad has received several honors which include: Invitation by the Nobel Prize Committee to nominate a candidate for the Nobel Prize in Medicine for 1982; The 1999 Harold Harper Lecture at the meeting of the American College of Advancement in Medicine; An award for the best review of 1998-1999 on antioxidant and cancer; and 1999-2000 on antioxidants and Parkinson’s disease by the American College of Nutrition. He was a Fellow of the American College of Nutrition, and served as a President of the International Society of Nutrition and Cancer, 1992-2000. In 2017, he was invited to become the member of The Royal Society of Medicine, London. Currently, he is Chief Scientific Officer of the Engage Global.

Subject Categories

BISAC Subject Codes/Headings:
MED004000
MEDICAL / Alternative Medicine
MED060000
MEDICAL / Nutrition
TEC012000
TECHNOLOGY & ENGINEERING / Food Science