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Micronutrients in Health and Disease, Second Edition
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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 (A 1-42) and Their Toxicity .........206 Oxidative Stress Increases Production of Beta Amyloids (A 1-42 Peptides) ..........206 A 1-42 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 Activatio

About the Author

Dr. Kedar N. Prasad obtained a Masters degree in Zoology from the University of Bihar, Ranchi, India, and a Ph.D. degree in Radiation Biology from the University of Iowa, Iowa City, in 1963. He received Post-doctoral training at the Brookhaven National Laboratory, Long Island. New York, and joined the Department of Radiology at the University of Colorado Health Sciences Center where he became Professor and Director for the Center for Vitamins and Cancer Research. He has published over 250 articles in peer-reviewed journals, and authored and edited 25 books in the area of radiation biology, nutrition and cancer, and nutrition and neurological diseases particularly Alzheimer's disease and Parkinson's disease. These articles were published in highly prestigious journals such as Science, Nature, and Proceedings of the National Academic of Sciences, USA. Dr Prasad has received several honors which include: Invitation by the Nobel Prize Committee to nominate a candidate for the Nobel Prize in Medicine for 1982; The 1999 Harold Harper Lecture at the meeting of the American College of Advancement in Medicine; An award for the best review of 1998-1999 on antioxidant and cancer; and 1999-2000 on antioxidants and Parkinson's disease by the American College of Nutrition. He was a Fellow of the American College of Nutrition, and served as a President of the International Society of Nutrition and Cancer, 1992-2000. In 2017, he was invited to become the member of The Royal Society of Medicine, London. Currently, he is Chief Scientific Officer of the Engage Global.

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