Overview

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.

Full Product Details

Author:   Kedar N. Prasad
Publisher:   Taylor & Francis Ltd
Imprint:   CRC Press
Edition:   2nd edition
Weight:   2.400kg
ISBN:  

9781138500020

ISBN 10:   113850002
Pages:   528
Publication Date:   19 April 2019
Audience:   Professional and scholarly ,  Professional & Vocational
Format:   Hardback
Publisher's Status:   Active
Availability:   In Print  
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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

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.

Author Information

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.

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