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CRC Press
528 pages | 12 B/W Illus.
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.
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.
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
