| Hormesis | 1 |
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| Preface | 4 |
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| Contents | 7 |
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| About the Editors | 8 |
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| Contributors | 9 |
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| Hormesis: What It Is and Why It Matters | 11 |
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| Hormesis Is a Fundamental Feature of Biological Systems | 12 |
| Hormesis Is a Manifestation of a Fundamental Feature of Evolution | 14 |
| Cellular and Molecular Mediators of Hormetic Responses | 16 |
| Hormesis in Medicine: Dose and Frequency of Treatment Are Both Important | 17 |
| Are Beneficial Chemicals in Fruits and Vegetables Toxins Acting at Low Doses? | 19 |
| Hormesis Is Not Homeopathy | 20 |
| Implications of Hormesis for the Practices of Environmental Protection and Medicine | 20 |
| References | 21 |
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| Hormesis: Once Marginalized, Evidence Now Supports Hormesis as the Most Fundamental Dose Response | 24 |
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| Introduction | 25 |
| Historical Antipathies, Rather Than Science, Determined Which DoseResponse Model Would Dominate Biology | 26 |
| The Hormetic Dose-Response Relationship | 29 |
| The Hormesis Database | 31 |
| The Frequency of Hormesis in Toxicology and Pharmacology | 39 |
| Implications of Hormesis | 40 |
| Impact on Biological Concepts | 41 |
| Hormesis Measures Performance | 41 |
| Hormesis Provides Quantitative Estimates of Biological Plasticity | 41 |
| Adaptive Response/Preconditioning: Manifestations of Hormesis | 42 |
| Hormesis as an Expression of Allometry | 42 |
| Toxicological/Pharmacological Implications | 43 |
| Factors Affecting the Recognition of Hormetic Dose-Response Relationships | 43 |
| Use of Multiple Terms | 43 |
| Modest Stimulation and Historically Weak Study Designs | 43 |
| Control Group: High Variation | 43 |
| Low Background Disease Incidence | 44 |
| Lack of Temporal Component | 44 |
| Summary | 44 |
| Chemical Potency and Hormesis | 44 |
| Hormesis: A Novel Concept of Synergy/Potentiation | 45 |
| Interindividual Variation and Hormesis | 46 |
| Epidemiology and Hormesis | 47 |
| Hormesis and Medicine | 47 |
| Low-Dose Stimulation of Tumor Cells | 47 |
| Low-Dose Stimulation of Microbes by Antibiotics | 48 |
| Anxiolytic Drugs | 48 |
| Antiseizure Drugs | 49 |
| Memory-Enhancing Drugs | 49 |
| Stroke Medications | 50 |
| Osteoporosis | 50 |
| Hair Growth | 51 |
| Pulmonary Hypertension | 51 |
| Fibrotic Diseases (e.g., Dupuytren's Contracture) | 51 |
| Avoidance of Undesirable Side Effects | 51 |
| Environmental Risk Assessment | 52 |
| Discussion | 59 |
| References | 60 |
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| The Fundamental Role of Hormesis in Evolution | 66 |
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| Introduction | 66 |
| The Biphasic Dose Response and Evolution | 68 |
| Cellular and Molecular Hormetic Mechanisms | 71 |
| Hormesis and Evolutionary Strategies: Diversification and Specialization | 72 |
| Conclusions and Future Directions | 75 |
| References | 75 |
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| Transcriptional Mediators of Cellular Hormesis | 78 |
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| Introduction | 78 |
| Nature of Transcriptional Regulation | 79 |
| Hormetic Signaling Pathways | 80 |
| Nuclear Factor--Erythroid 2p45 (NF-E2)--Related Factor (Nrf2)/Antioxidant Response Element (ARE) Signaling Pathway | 81 |
| Nrf2, Keap1, and Regulation of the ARE Pathway | 81 |
| Hormetic Inducers of the Nrf2/ARE Pathway | 83 |
| Forkhead Box O (FOXO) Transcription Factors | 85 |
| FOXO, Oxidative Stress, and Longevity | 88 |
| The Nuclear Factor-B Pathway | 89 |
| NF-B as a Hormetic Transducer of Exercise | 90 |
| Heat-Shock Factor Pathway | 91 |
| Conclusions | 95 |
| References | 96 |
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| The Devil Is in the Dose: Complexity of Receptor Systemsand Responses | 103 |
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| Introduction | 103 |
| Classic and Modern Dynamic GPCR Models | 104 |
| Receptor System Complexities and Responses | 106 |
| Multiple G Protein Coupling | 106 |
| Allosteric Receptor Modulation | 107 |
| Receptor Desensitization | 109 |
| Receptor Dimerization | 110 |
| GPCRs and Receptorsome Structures | 111 |
| Conclusions | 112 |
| References | 113 |
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| Exercise-Induced Hormesis | 117 |
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| Introduction | 117 |
| Effects of Exercise on the Musculoskeletal System | 118 |
| Dose-Response Characteristics of Exercise Effects on Muscle | 118 |
| Duration-Dependent Effects of Exercise on Bone | 119 |
| Effects of Exercise on the Digestive System | 119 |
| Dose-Dependent Effects of Exercise on the Stomach | 119 |
| Hormetic Effects of Exercise in the Large and Small Intestine | 119 |
| Dose-Response Characteristics of Exercise Effects on the Liver | 119 |
| Duration-Dependent Effects of Exercise on the Pancreas | 120 |
| Effects of Exercise on the Reproductive System | 120 |
| Dose-Response Characteristics of Exercise Effects on Ovarian Function | 120 |
| Duration-Dependent Effects of Exercise on the Testis | 121 |
| Effects of Exercise on the Cardiorespiratory System | 121 |
| Duration-Dependent Effects of Exercise on the Heart | 121 |
| Dose-Dependent Effects of Exercise on the Lungs | 122 |
| Effects of Exercise on the Immune System | 122 |
| Dose-Response Characteristics of Exercise Effects on the Thymus | 122 |
| Hormetic Effects of Exercise on the Spleen | 122 |
| Exercise Effects on Circulating Cytokines Conform to the Theory of Hormesis | 123 |
| Effects of Exercise on the Brain | 123 |
| Duration-Dependent Effects of Exercise on Adult Neurogenesis | 123 |
| Dose-Response Characteristics of Exercise Effects on Dendritic Spines | 124 |
| Duration-Dependent Effects on Angiogenesis | 125 |
| Duration-Dependent Effects of Running on Neurotrophic Factor Expression | 125 |
| Conclusion | 126 |
| References | 127 |
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| Dietary Energy Intake, Hormesis, and Health | 131 |
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| Introduction | 131 |
| CR as a Hormetic Effector | 132 |
| CR and Cellular Stress Factors | 133 |
| CR Effects Upon Cytoki
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