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Vitamin D - Physiology, Molecular Biology, and Clinical Applications
Michael F. Holick
Verlag Humana Press, 2010
ISBN 9781603273039 , 1160 Seiten
2. Auflage
Format PDF
Kopierschutz Wasserzeichen
Dedication
5
In Memoriam
7
Series Editor Introduction
9
Preface
13
ACKNOWLEDGMENTS
14
Contents
15
Contributors
21
Part I Introduction and Basic Biology
27
1 Vitamin D and Health: Evolution, Biologic Functions,and Recommended Dietary Intakes for Vitamin D
28
1 Evolutionary Perspective
29
1.1 The Calcium Connection
29
1.2 Photosynthesis of Vitamin D in the Skin
31
1.3 Metabolism of Vitamin D
31
2 Vitamin D Deficiency And Sources Of Vitamin D
31
2.1 Consequences of Vitamin D Deficiency on Skeletal Health
31
2.2 Sources of Vitamin D
33
2.3 Definition of Vitamin D Deficiency, Insufficiency, and Sufficiency
35
2.4 The Vitamin D Deficiency Pandemic
37
3 Recommended Adequate Dietary Intake Of Vitamin D
39
3.1 Birth to 6 Months
39
3.2 Ages 6--12 Months
41
3.3 Ages 1--8 Years
42
3.4 Ages 9--18 Years
42
3.5 Ages 19--50 Years
43
3.6 Ages 51--70 Years
43
3.7 Age 71 Years and Older
44
3.8 Pregnancy
45
3.9 Lactation
45
3.10 Tolerable Upper Intake Levels
46
4 Causes Of And Treatment Strategies For Vitamin D Deficiency
46
4.1 Causes
46
4.2 Strategies for Preventing and Treating Vitamin D Deficiency
46
5 Myths
51
5.1 Vitamin D Treatment Will Worsen Hypercalcemia in Hyperparathyroid Patients
51
5.2 Treatment with Vitamin D Will Increase Risk of Kidney Stones
52
5.3 Patients with Chronic Kidney Disease Do Not Need to Be Treated with Vitamin D Since They Cannot Activate It
52
5.4 Treatment with 50,000 IU of Vitamin D Long-Term Will Cause Vitamin D Intoxication
53
6 Conclusion
53
Acknowledgments
54
References
54
2 Photobiology of Vitamin D
59
1 Introduction
1
2 Historical Perspective
60
3 Vitamin D Fortification In Milk
61
4 Photosynthesis Of Previtamin D 3 In The Skin
63
4.1 Photoconversion of 7-DHC to Previtamin D 3
63
4.2 Conversion of Previtamin D 3 to Vitamin D 3
66
4.3 Translocation of Vitamin D 3 from the Skin into the Circulation
67
4.4 Photodegradation of Vitamin D 3
68
4.5 Photoisomers of Vitamin D 3
68
5 Regulation Of The Cutaneous Synthesis Of Previtamin D 3
68
5.1 Role of Melanin Pigmentation
68
5.2 Influence of Altitude, Latitude, Time of Day, and Weather Conditions on Previtamin D 3 Production
70
5.3 Effect of Aging on the Cutaneous Production of Previtamin D 3
74
5.4 Effect of Sunscreen Use and Clothing on Previtamin D 3 Formation
75
5.5 Influence of Season on 25(OH)D Levels in Nursing Home and Home Care Elderly
77
5.6 Tanning Bed Irradiation Enhances Vitamin D Status and Bone Mineral Density
78
6 SUMMARY
79
Acknowledgments
80
References
80
3 The Functional Metabolism and Molecular Biology of Vitamin D Action
85
1 Introduction
85
2 Overall Role Of The Vitamin D Hormone In Calcium And Phosphorus Homeostasis
86
3 Functional Metabolism
87
4 Regulation Of The Production And Catabolism Of 1,25(OH) 2 D
90
5 Molecular Mechanism Of Vitamin D Action
94
6 Analogs: Mechanisms Of Action
96
7 Function Of Vitamin D Not Related To Calcium And Phosphate Homeostasis
96
8 Vitamin D In Public Health
100
Bibliography
106
4 Metabolism and Catabolism of Vitamin D, Its Metabolites and Clinically Relevant Analogs
122
1 Metabolism Of Vitamin D 3 AND 25(OH)D 3
122
1.1 25- and 1-Hydroxylation
123
1.2 24-Hydroxylation
126
1.3 26-Hydroxylation and 26,23-Lactone Formation
127
2 CATABOLISM of 1,25(OH)2D3
127
2.1 C-24 Oxidation Pathway to Calcitroic Acid
127
3 Metabolism And Catabolism Of The Analogs Of Vitamin D
130
3.1 Activation of Prodrugs
130
3.2 Vitamin D 2
130
3.2.1 Dihydrotachysterol
131
3.2.2 1(OH)D2 and 1(OH)D 3
132
3.3 Metabolism-Sensitive Analogs
134
3.3.1 Cyclopropane Ring Containing Analogs of Vitamin D
134
3.3.2 Oxa-Group-Containing Analogs
137
3.4 Metabolism-Resistant Analogs
140
3.4.1 F 6 -1,25-(OH) 2 D
140
3.4.2 Unsaturated Analogs
141
4 Important Implications Derived From Metabolism Studies
143
4.1 Relative Importance of Metabolism in the Mechanism of Action of Vitamin D Analogs
143
4.2 Future Directions
146
4.2.1 Structural Aspects of Vitamin D-Related Cytochrome P450s
146
4.2.2 Hydroxylase Gene Knockouts
147
4.2.3 Future Vitamin D Analog Design and Development
147
Acknowledgements
148
References
148
5 The Molecular Biology of the Vitamin D Receptor
158
1 INTRODUCTION
158
2 The Vitamin D Receptor Gene
159
3 Molecular Analysis Of The Functional Domains Of The Vdr
162
3.1 The DNA-Binding Domain (DBD)
162
3.2 The Multifunctional C-terminal Domain
164
4 Molecular Mechanism Of Transcriptional Control By Vdr
166
4.1 VDR Interaction with Vitamin D-Responsive Elements
166
4.1.1 Vitamin D-Responsive Elements
166
4.1.2 A R ole for the 1,25(OH) 2 D L igand
167
4.1.3 Gene Regulation Through Negative Response Elements
168
4.1.4 A Role for the Unliganded VDR in Transcriptional Regulation
168
4.2 Communication Between VDR and the Transcriptional Machinery
169
REFERENCES
171
6 VDR and RXR Subcellular Trafficking
176
1 Significance Of Receptor Localization
176
2 Spatial And Temporal Control Of Nuclear Receptor Functions
178
3 Nuclear Import Mechanisms For Vdr And Rxr
182
4 Nuclear Export Mechanisms For Vdr And Rxr
186
5 Intranuclear Trafficking Of Vdr And Rxr
189
6 Summary And Conclusion
191
REFERENCES
192
7 Mechanism of Action of 1,25-Dihydroxyvitamin D3 on IntestinalCalcium Absorption and Renal Calcium Transport
197
1 Introduction
197
2 Intestinal Calcium Absorption
198
2.1 Overview
198
2.2 Effect of 1,25-Dihydroxyvitamin D 3 on Saturable, Transcellular Intestinal Calcium Absorption
198
2.2.1 Role of 1,25(OH) 2 D on the Entry of Calcium Across the Brush Border Membrane
199
2.2.2 Role of 1,25(OH) 2 D on Transcellular Movement of Calcium
200
2.2.3 Role of 1,25(OH) 2 D on Calcium Extrusion from the Intestinal Cell
200
2.3 Other Models of Intestinal Calcium Transport -- Nonsaturable, Paracellular Intestinal Calcium Absorption
201
2.4 1,25(OH) 2 D and Intestinal Phosphorus Absorption
201
3 Renal Calcium Transport
201
3.1 Overview
201
3.2 Effect of 1,25(OH) 2 D on Renal Calcium Transport
203
3.2.1 Current Understanding of the Role of 1,25(OH) 2 D
203
3.2.2 Role of Vitamin D-Dependent Calcium-Binding Proteins and TRPV5 in Renal Calcium Transport
204
3.2.3 Role of the Plasma Membrane Calcium Pump and the Na + /Ca 2+ Exchanger
204
3.3 Other Effects of 1,25(OH) 2 D in the Kidney
205
4 Summary
205
References
206
8 Biological and Molecular Effects of Vitamin D on Bone
210
1 Introduction
210
2 A Spectrum of Cellular Activities of 1,25(OH) 2 D Contributing to Bone Formation
211
2.1 Bone Tissue Organization, Vitamin D, and Osteoblasts
211
2.2 Skeletal Development
213
2.3 Vitamin D3 Promotes Cell Differentiation at Multiple Levels
214
3 The Role of Vitamin D in Coupling Osteoblast Activity to Osteoclast Differentiation for Bone Resorption
216
4 Vitamin D Regulation of Gene Expression During Bone Formation
218
4.1 Components of Vitamin D-Dependent Regulatory Complexes
218
4.2 Vitamin D-Mediated Gene Expression Within the Three-Dimensional Context of Nuclear Structure in Bone Cells
220
4.3 Vitamin D Receptor Coregulatory Factors Provide Gene-Specific Regulation
221
5 Conclusions and Future Directions
224
Acknowledgments
225
References
225
9 Biological and Molecular Effects of Vitamin D on the Kidney
231
1 The Kidney, The Vitamin D Endocrine System, And Disease Prevention
231
2 Essential Role Of The Kidney In Vitamin D Biological Actions
233
2.1 Renal Regulation of Systemic Calcitriol
233
2.1.1 Calcitriol Synthesis
233
2.1.2 Calcitriol Catabolism
235
2.2 Abnormal Calcitriol Production in CKD
235
3 Renal Uptake Of 25(Oh)D: Relevance In The Maintenance Of Normal Vitamin D Status
235
3.1 Essential Contribution of Megalin-Mediated Endocytosis to Calcitriol Production
235
3.2 Abnormal Uptake of 25(OH)D in CKD
236
3.3 Abnormal Renal 25(OH)D Uptake in CKD Contributes to Impaired Extrarenal Calcitriol Production
238
4 Renal Regulation Of Vdr Expression And Function
239
4.1 Calcitriol Regulation of VDR Expression
239
4.2 Abnormal Regulation of VDR Expression and Function in CKD
240
4.3 Impaired VDR Function in CKD
240
5 Vitamin D Regulation Of Kidney Function
241
5.1 Mineral Homeostasis
241
5.1.1 Calcitriol/VDR Regulation of Calcitriol Homeostasis
241
5.1.2 Calcitriol/VDR Control of Renal Handling of Calcium and Phosphate
242
5.2 Renal Calcitriol/VDR Actions Affecting the Cardiovascular System
243
5.3 Calcitriol/VDR Renoprotective Actions
244
Acknowledgments
248
References
248
10 Vitamin D and the Parathyroids
255
1 INTRODUCTION
255
2 THE PARATHYROID HORMONE GENE
256
2.1 The PTH Gene
256
2.2 The PTH mRNA
256
3 DEVELOPMENT OF THE PARATHYROID AND TISSUE-SPECIFIC EXPRESSION OF THE PTH GENE
256
4 PROMOTER SEQUENCES
257
5 REGULATION OF PTH GENE EXPRESSION
258
5.1 1,25-Dihydroxyvitamin D
258
5.1.1 Calreticulin and the Action of 1,25(OH)2D on the PTH Gene
260
5.1.2 Studies on Mice with VDR Gene Deletion
262
5.2 Calcium
263
5.2.1 Mechanisms of Regulation of PTH mRNA by Caclium
263
5.3 Phosphate
265
5.3.1Phosphate Regulates the Parathyroid Independently of Calcium and 1,25(OH)2D
265
5.4 Protein--PTH mRNA Interactions Determine the Regulation of PTH Gene Expression by Serum Calcium and Phosphate
266
5.4.1 Identification of the PTH mRNA 30 -UTR-Binding Proteins that Determine PTH mRNA Stability
266
5.4.2 A Conserved Sequence in the PTH m RNA 30-UTR Binds Parathyroid Cytosolic Proteins and Determines m RNA Stability in Response to Changes in Calcium and Phosphate
268
6 FIBROBLAST GROWTH FACTOR 23 AND THE PARATHYROID
268
7 SUMMARY
269
Acknowledgments
269
References
269
11 Diversity of Vitamin D Target Genes
275
1 INTRODUCTION
276
2 VDR IS A NUCLEAR RECEPTOR
276
2.1 The Nuclear Receptor Superfamily
276
2.2 Modular Structure of Nuclear Receptors
277
2.3 The VDR
277
3 VDR-BINDING SITES
277
3.1 DR3-Type VDREs
277
3.2 Other Types of VDREs
279
3.3 Chromatin and Co-factors
279
3.4 VDREs in the Chromatin Context
280
3.5 Negative VDREs
282
4 VDR TARGET GENES
283
4.1 Classical VDR Targets
283
4.2 VDR Targets in Cell Cycle Regulation
283
4.3 Relative Expression of VDR Target Genes
284
5 VDR TARGET GENE ANALYSIS
285
5.1 Transcriptome Analysis
285
5.2 ChIP Analysis
285
5.3 ChIP-Chip Assays
286
5.4 In Silico Screening of VDREs
287
6 CONCLUSIONS
288
Acknowledgments
289
REFERENCES
289
Part II Non-skeletal/Functions of Vitamin D
295
12Extrarenal Synthesis of 1,25-Dihydroxyvitamin D and Its Health Implications
296
1 INTRODUCTION
296
2 TISSUE DISTRIBUTION OF CYP27B1
297
3 REGULATION OF EXTRARENAL CYP27 b 1 EXPRESSION
301
4 FUNCTION OF EXTRARENAL CYP27B1
303
4.1 Regulation of Proliferation and Differentiation
303
4.2 Regulation of Hormone Secretion
305
4.3 Regulation of Immune Function
306
5 SUMMARY
308
REFERENCES
308
13 Vitamin D and the Innate Immunity
315
1 TUBERCULOSIS
315
1.1 Tuberculosis Overview
315
1.1.1 Innate Immunity
316
1.1.2 Toll-Like Receptors
316
1.1.3 Immunoactivity of 1,25-Dihydroxyvitamin D
317
1.1.4 Antimicrobial Peptides
318
1.2 Vitamin D Pathway and Tuberculosis
319
1.2.1 Role of 25-HydroxyvitaminD on the Innate Immune Response
320
1.2.2 History of Vitamin D, Sunshine, and Tuberculosis
322
1.2.3 Treatment of Tuberculosis with Vitamin D
322
REFERENCES
323
14 Vitamin D and Colon Cancer
329
1 INTRODUCTION
329
1.1 Colorectal Cancer Prevention by Vitamin D and Calcium: Molecular and Cellular Mechanisms
330
2 RELEVANCE OF ENDOGENOUS 1,25(OH)2 D SYNTHESIS FOR GROWTH CONTROL OF NORMAL AND NEOPLASTIC COLON EPITHELIAL CELLS
331
3 EXPRESSION OF CYP27B1 DURING INFLAMMATION AND TUMOR PROGRESSION
332
4 REGULATION OF VITAMIN D HYDROXYLASES, CYP27B1 AND CYP24A1
333
4.1 Regulation of Vitamin D Metabolism in the Gut Mucosa by Calcium
333
4.2 Regulation of the Vitamin D System by Estrogenic Compounds
334
4.3 Effect of Folate on CYP24A1 Expression
335
4.4 Epigenetic Regulation of CYP24A1 and CYP27B1 Activity
335
4.5 Regulation of CYP24A1 and CYP27B1 and Prevention of Colon Cancer
338
REFERENCES
338
15Mechanisms of Resistance to Vitamin D Action in Human Cancer Cells
342
Acknowledgments
349
REFERENCES
349
16Vitamin D and the Brain: A Neuropsychiatric Perspective
352
1 INTRODUCTION
352
2 Vitamin D And Brain Development
353
3 Brain Development In The Developmental Vitamin D (Dvd)-Deficient Rodent
354
4 Behaviour In The Dvd-Deficient Rat And Mouse
355
5 Vitamin D And Neuropsychiatric Disorders: Clues From Epidemiology
356
6 CONCLUSIONS
358
REFERENCES
358
17 Vitamin D Modulation of Adipocyte Function
362
1 INTRODUCTION
362
2 Ca2+ SIGNALING
363
3 Role Of The Nuclear Vitamin D Receptor
364
4 Calcitriol Regulation Of Adipocyte Apoptosis
365
5 Calcitriol Modulation Of Adipocyte Glucocorticoid Production
366
6 Calcitriol Regulation Of Cross Talk Between Adipocyte And Skeletal Muscle In Energy Metabolism
367
7 Calcitriol Regulation Of Adipocyte Oxidative Stress
369
8 Calcitriol Regulation Of Adipocyte Inflammatory Cytokine Production
369
9 Calcitriol Regulation Of AdipocyteMacrophage Cross Talk In Inflammation
370
10 CONCLUSION
371
REFERENCES
371
Part III Vitamin D Status Global Analysis
376
18 Determinants of Vitamin D Intake
377
1 INTRODUCTION
377
2 Dietary Guidelines: Past, Present, And Future Considerations
378
3 History And Use Of Dietary Reference Intakes For Vitamin D
379
4 The Tolerable Upper Intake Level
383
5 Estimated Vitamin D Intakes In Canada And The United States
383
6 Food Patterns And Dietary Sources Of Vitamin D
385
7 Vitamin D Fortification Of Food
389
8 Vitamin D Supplementation
393
9 Considerations For Public Health Action
394
REFERENCES
394
19 25-Hydroxyvitamin D Assays and Their Clinical Utility
399
1 INTRODUCTION
399
2 Vitamin D Physiology
399
3 Currently Available 25(Oh)D Assays
401
3.1 Chromatographic Assays
401
3.2 Immunochemical and Competitive Protein Binding Assays (CPBA)
405
3.3 Specimen Stability
406
3.4 Proficiency Testing and Assay Quality
406
3.5 Current Status of 25(OH)D Result Agreement
408
3.6 25(OH)D Variability
410
3.7 Definition of Low Vitamin D Status/Reporting of Circulating 25(OH)D Results
411
3.8 When Should 25(OH)D Be Measured?
412
4 CLINICAL UTILITY of 25(OH)D MEASUREMENT
413
5 CONCLUSIONS
413
REFERENCES
413
20 Health Disparities and Vitamin D
416
1 Introduction
416
2 Infant Mortality
419
3 Cardiovascular Disease
425
4 Cancer
428
5 Total Mortality
432
6 Diabetes
434
7 Tuberculosis
434
8 HIV/AIDS
435
9 Conclusion
435
ReferenceS
436
21 Vitamin D Deficiency in Canada
440
1 INTRODUCTION
440
2 Dietary Studies Of Vitamin D In Canadians
441
3 Studies Of Canadians Utilizing Measurements Of Serum 25(OH)D
442
3.1 Healthy Ambulatory Adults
442
3.2 Children
444
3.3 Aboriginal (First Nations and Inuit) Peoples
445
4 CONCLUSIONS
446
REFERENCES
446
22 Vitamin D Deficiency and Its Health Consequences in Northern Europe
449
1 INTRODUCTION
449
2 DEFINITION OF VITAMIN D INSUFFICIENCY AND DEFICIENCY
450
3 GEOGRAPHY AND SOLAR UV RADIATION
450
4 OVERVIEW OF VITAMIN D STATUS IN EUROPE
452
5 WHAT IS THE EFFECT OF LATITUDE ON VITAMIN D STATUS IN EUROPE?
452
6 NATIONAL NUTRITIONAL RECOMMENDATIONS AND DIET
453
7 FORTIFICATION POLICY IN NORTHERN EUROPE
454
8 SUPPLEMENTATION
460
9 INDIVIDUAL LIFESTYLE FACTORS
460
10 VITAMIN D INTAKES
461
11 PREVALENCE OF VITAMIN D INSUFFICIENCY
461
12 VITAMIN D STATUS IN DENMARK
461
13 CONCLUSION
462
REFERENCES
463
23 Vitamin D Deficiency and Consequences for the Health of People in Mediterranean Countries
466
1 INTRODUCTION
466
2 VITAMIN D STATUS IN MEDITERRANEAN POPULATIONS IN SPAIN AND OTHER EUROPEAN COUNTRIES
470
3 VITAMIN D STATUS IN MEDITERRANEAN POPULATIONS OF THE MIDDLE EAST AND NORTH AFRICAN COUNTRIES
473
REFERENCES
478
24 Vitamin D Deficiency in the Middle East and Its Health Consequences
481
1 INTRODUCTION
482
2 Nutritional Rickets
483
2.1 Nutritional Rickets in the Middle East
484
2.2 Non-skeletal Manifestations of Nutritional Rickets
486
2.3 Rickets in Immigrants from Middle East
487
3 Hypovitaminosis D
487
3.1 Mothers--Neonates--Infants
487
3.2 Children and Adolescents
495
3.3 Adults
496
3.4 Immigrants from Middle East
497
3.5 Impact of Hypovitaminosis D on Musculoskeletal Outcomes
497
4 Recommendations For Treatment
498
4.1 Rickets
498
4.2 Hypovitaminosis D
500
5 Conclusion
501
Acknowledgments
502
References
502
25Vitamin D Deficiency in the Middle East and Its Health Consequencesfor Adults
507
1 Introduction
507
2 Epidemiology
507
3 Etiology
510
4 Conclusions
513
References
513
26 Vitamin D Deficiency and Its Health Consequences in Africa
516
1 Introduction
516
2 The Continent Of Africa
517
2.1 Geography, Topography, Climate
517
2.2 Demography
518
2.3 Ultraviolet Radiation and Skin Pigmentation
518
2.4 Diet and Foodstuffs
519
3 Indicators Of Health And Burden Of Disease In Africa Which May Affect Or Be Affected By Vitamin D Status
522
3.1 Malnutrition
522
3.2 Vitamin D Intake
522
3.3 Low Calcium Intake
522
3.4 Fluorosis
523
3.5 Tropical Enteropathy
523
3.6 Malaria
523
3.7 HIV/AIDS
524
3.8 Tuberculosis
524
3.9 Non-communicable Disease
524
4 Health Consequences Of Poor Vitamin D Status In Africa
524
4.1 Rickets and Osteomalacia
525
4.2 Tuberculosis
525
4.3 HIV/AIDS
526
5 Studies Of Vitamin D Status In Africa
527
6 Conclusions
527
REFERENCES
534
27 Vitamin D Deficiency and Its Health Consequences in India
540
1 Introduction
540
2 Historical Background
541
3 Vitamin D Status In Adults
541
3.1 Vitamin D Deficiency and Bone Mineral Density
543
4 Vitamin D Status In Pregnancy And Lactation
544
5 Vitamin D Status In Neonates And Infants
545
6 Vitamin D Status In Indian Children
546
6.1 Clinical Evidence of Rickets
547
7 Serum 25(Oh)D Levels
547
7.1 Vitamin D Deficiency and Bone Mineral Density
548
7.2 Do We Have Protective Bioadaptation to Vitamin D Deficiency?
549
7.3 How to Tackle Vitamin D Deficiency
549
8 Conclusion
550
References
550
28 Vitamin D Deficiency, Rickets, and Fluorosis in India
554
1 Vitamin D Deficiency In India
554
2 Nutritional Rickets In India
562
2.1 Skeletal Fluorosis in India: An Endemic Disease
567
3 Pathogenesis Of Fluorotoxic Bone Disease
568
4 Calcium Vitamin DFluoride Interactions
569
REFERENCES
569
29 Vitamin D in Asia
573
1 Vitamin D In Asia
573
2 Northern Asia
573
2.1 Vitamin D Status
574
2.2 Consequences
574
2.3 Causes of Vitamin D Deficiency
577
3 Middle East
579
3.1 Vitamin D Status
579
3.2 Consequences
582
3.3 Causes of Vitamin D Deficiency
583
4 Southern Asia
584
4.1 Vitamin D Status
584
4.2 Consequences
584
4.3 Causes of Vitamin D Deficiency
590
5 Strategies To Improve Vitamin D Status
590
6 CONCLUSION
591
References
592
30 Vitamin D Deficiency and Its Health Consequences in New Zealand
598
1 INTRODUCTION
598
2 New Zealand Location, Climate, And Uv Exposure
599
3 Prevalence Of Low 25(Oh)D Levels
599
4 Determinants Of 25(Oh)D Levels
601
5 The Effects Of Seasonal Variation Of 25(Oh)D And Fat Mass On The Diagnosis Of Vitamin D Sufficiency
604
6 CONCLUSION
609
References
609
31 Toxicity of Vitamin D
611
1 Signs And Symptoms
612
2 Treatment
612
3 Mechanisms Of Toxicity
613
3.1 Hypersensitivity to Vitamin D
614
4 Mandated Safety Levels
614
5 Theoretical Noncalcemic Risks Of Vitamin D
616
6 Conclusion
617
References
618
Part IV Health Consequences of Vitamin D Deficiency and Resistance on Musculoskeletal Health
621
32 Vitamin D Deficiency in Pregnancy and Lactation and Health Consequences
622
1 Introduction
622
2 Maternal/Infant Calcium Homeostasis In Pregnancy
623
3 Contemporary Maternal Vitamin D Status In Pregnancy
623
4 Clinical Trials Of Vitamin D Supplementation In Pregnancy
624
5 Vitamin D And Fetal Development
627
6 Fetal Vitamin D Exposure And Immune Function
627
7 Fetal Vitamin D Exposure And Cardiac Development
628
8 Vitamin D And Pregnancy Health
628
9 Vitamin D Requirements For Mother And Infant During Lactation
629
10 The Mechanism Of Vitamin D In Human Milk
629
11 Maternal Vitamin D Supplementation During Lactation
630
12 Infant Vitamin D Supplementation During Lactation
631
13 Consequences Of Infant Vitamin D Status
631
14 Conclusion
632
References
633
33 Vitamin D Deficiency in Children and Its Health Consequences
639
1 Introduction
639
2 Prevalence Data
640
2.1 Newborns, Infants, and Toddlers
641
2.2 Older Children and Adolescents
641
2.3 Factors Influencing Vitamin D Status Throughout Childhood
642
3 Prevalence Of Vitamin D Deficiency In At-Risk Groups
643
3.1 Overweight
643
3.2 Epilepsy and Other Neurological Disorders
644
3.3 Inflammatory Bowel Disease, Celiac Disease, and Cystic Fibrosis
645
3.4 Hereditary Predisposition
645
4 Assessment Of Vitamin D Status
646
5 Supplementation
647
5.1 Supplementation in Infants
647
5.2 Supplementation in Children and Adolescents
649
6 Treatment
650
7 Conclusions
651
REFERENCES
651
34Dietary Calcium Deficiency and Rickets
657
1 INTRODUCTION
657
2 Calcium Homeostasis
658
3 Dietary Calcium Deficiency Rickets
661
3.1 Dietary Calcium Intakes
663
3.2 Intestinal Calcium Absorption
665
3.3 Vitamin D Requirements
666
3.4 Possible Genetic Influences
667
4 CONCLUSIONS
669
REFERENCES
670
35 Vitamin D in Fracture Prevention and Muscle Function and Fall Prevention
674
1 Introduction
674
2 Vitamin D: Its Role In Muscle Health
675
3 Desirable 25-Hydroxyvitamin D Status For Better Function And Lower Risk Of Sarcopenia
675
4 Vitamin D And Muscle Weakness
676
5 Vitamin D And Fall Prevention
676
6 Desirable 25-Hydroxyvitamin D Status For Better Bone Health
677
7 Importance Of Dose In Anti-Fracture Efficacy With Vitamin D
678
8 Summary
680
REFERENCES
680
36 Inherited Defects of Vitamin D Metabolism
683
1 Introduction
683
2 Pseudovitamin D Deficiency Rickets
684
3 Hereditary Vitamin D-Resistant Rickets
688
4 25-Hydroxylase Deficiency
690
REFERENCES
691
37Molecular Defects in the Vitamin D Receptor Associatedwith Hereditary 1,25-Dihydroxyvitamin D-Resistant Rickets (HVDRR)
694
1 Introduction
694
2 Hereditary 1,25-Dihydroxyvitamin D-Resistant Rickets (Hvdrr)
695
3 The Vitamin D Receptor
696
4 Cellular Basis Of Hvdrr
697
5 Molecular Basis For Hvdrr
698
5.1 Mutations in the VDR DNA-Binding Domain (DBD)
698
5.2 Mutations Causing Premature Termination of the VDR
701
5.2.1 Premature Stop Mutations
701
5.2.2 Splicing Mutations
702
5.3 Mutations in the VDR Ligand-Binding Domain (LBD)
702
5.3.1 Mutations That Affect 1,25(OH)2D Binding
702
5.3.2 Mutations That Affect VDR0RXR Heterodimerization
704
5.3.3 Mutations That Affect Coactivator Binding
704
5.4 Compound Heterozygous Mutations in the VDR
705
5.5 Other Mutations in the VDR
706
6 Therapy Of Hvdrr
706
6.1 General
706
6.2 Treatment with Vitamin D
707
6.3 Calcium Therapy
708
6.4 Lessons from the Therapy of HVDRR Cases
709
7 Alopecia
709
8 Concluding Remarks
710
References
711
38Receptor-Independent Vitamin D Resistance in Subhumanand Human Primates
718
1 Early Primate Evolution
718
2 Simian Bone Disease
720
3 Steroid Hormone Resistance In New World Primates
721
4 Outbreak Of Rickets in The New World Primate Colonies of the Los Angeles Zoo
722
5 Investigating the Biochemical Nature of Vitamin D Resistance in New World Primates
723
6 Vitamin D Response Element-Binding Protein
725
7 hn RNPC-Related Proteins as Multifunctional Regulators of Gene Expression: Beyond Transcription
726
8 Intracellular Vitamin D-Binding Protein
728
9 Summary
729
Acknowledgments
729
References
729
3925-Hydroxyvitamin D-1-Hydroxylase: Studies in Mouse Modelsand Implications for Human Disease
732
1 Introduction
732
2 Skeletal and Mineral Modulating Actions of 25-Hydroxyvitamin D 3 -1 -Hydroxylase as Determined by Genetic Mouse Models
734
2.1 Regulation of Calcium Absorption
735
2.2 Regulation of the 1(OH)ase and of the 24(OH)ase Enzymes
735
2.3 Parathyroid Gland Function
736
2.4 Development of the Cartilaginous Growth Plate
736
2.5 Bone and Cartilage Remodeling
737
2.6 Mineralization of Bone
738
2.7 1,25 Dihydroxyvitamin D as a Bone Anabolic Agent
738
2.7.1 1anabolic Effects in Older Animals
738
2.7.2 Anabolic Effects in Neonatal Animals
738
2.7.3 Anabolic Effects of Exogenous 1, 25(OH)2D
739
2.7.4 Interaction of Exogenous PTH and Endogenous 1,25(OH)2D in Exerting a Bone Anabolic Effect
740
3 Role of 25-Hydroxyvitamin D 3 -1 -Hydroxylase in Extra-Skeletal Actions of 1,25(OH) 2 D as Determined by Genetic Mouse Models
740
Acknowledgments
742
References
742
Part V Sunlight, Vitamin D and Cancer
746
40The Health Benefits of Solar Irradiance and Vitamin Dand the Consequences of Their Deprivation
747
1 Introduction
747
2 Scientific Methods Utilized
748
3 Application to Specific Health Conditions
750
3.1 Bone Health
750
3.2 Cancer
750
3.3 Infectious Diseases
753
3.4 Autoimmune Diseases
755
3.5 Metabolic Diseases
756
3.6 Cardiovascular Diseases
756
3.7 Alzheimer's Disease
757
3.8 Life Expectancy
757
3.9 Historical Review
757
4 Summary and Conclusion
758
References
759
41 Vitamin D Status, Solar Radiation and Cancer Prognosis
767
1 INTRODUCTION
767
2 skin synthesis and activation of vitamin d
768
3 Calculation Of Seasonal And Latitudinal Variations In Vitamin D Status
769
4 Serum Measurements Of Vitamin D Metabolites
770
5 Epidemiological Investigations Of Relative Risk Of Death From Breast, Colon And Prostate Cancer
772
6 Anti-Neoplastic Mechanisms Of Action
773
7 Summary
774
References
774
42 The Epidemiology of Vitamin D and Cancer Risk
778
1 Introduction
778
2 Colorectal Cancer
779
2.1 25(OH)D Level
779
2.2 Predicted 25(OH)D Level
782
2.3 Dietary Intake
783
2.4 Sun Exposure
783
2.5 Randomized Controlled Trial
783
3 Prostate Cancer
784
3.1 25(OH)Vitamin D
784
3.2 Predicted 25(OH)D Level
784
3.3 Vitamin D Intake
785
3.4 Sun Exposure
785
4 Breast Cancer
786
4.1 25(OH)Vitamin D
786
4.2 Vitamin D Intake
786
4.3 Sun Exposure
787
5 Pancreatic Cancer
787
5.1 25(OH)D Level
787
5.2 Predicted 25(OH)D
788
5.3 Vitamin D Intake
788
6 Esophageal And Gastric Cancers
788
6.1 25(OH)D Level
788
7 Ovarian Cancer
789
7.1 25(OH)D
789
7.2 Sun Exposure
789
8 Non-Hodgkin's Lymphoma (NHL)
789
8.1 Sun Exposure
789
9 Total Cancer
790
9.1 Circulating 25(OH)D
790
9.2 Predicted 25(OH)D
790
9.3 Randomized Trials (RCT)
791
10 Synthesis And Summary
791
REFERENCES
793
43 Vitamin D Deficiency and the Epidemiology of Prostate Cancer
797
1 INTRODUCTION
797
2 Prostate Cancer, Clinical Considerations
797
3 Synthesis Of Vitamin D Metabolites
798
4 Prostate Cancer And The Vitamin D Hypothesis
798
5 1,25(OH) 2 D Is Synthesized By Normal Prostate Cells
800
6 PROSTATE CANCER CELLS EXPRESS VDR BUT LOSE EXPRESSION OF 1 -OH ase
801
7 Vdr Polymorphisms
803
8 Serological Studies Of The Vitamin D Deficiency Hypothesis
803
9 Epidemiologic Studies Of Solar Exposure
804
10 Vitamin D Deficiency And Prostate Cancer: Potential Mechanisms
806
11 Serum Calcium And Prostate Cancer Risk
807
REFERENCES
808
44Vitamin D for Cancer Prevention and Survival
812
1 Introduction
812
2 Serum 25-Hydroxyvitamin D and Risk of Breast Cancer
813
3 Serum 25-Hydroxyvitamin D and Risk of Colon Cancer
818
4 Latitude, Ultraviolet B, Serum 25-Hydroxyvitamin D and Risk of Cancer of the Ovary
820
5 Vitamin D and Cancer of Other Sites
820
6 Randomized Trials
821
7 Future Potential For Cancer Prevention
823
8 Serum 25-Hydroxyvitamin D And Cancer Survival
824
9 Vitamin D And Global Cancer Prevention
824
10 DisjunctionNatural SelectionInvasion (Dni) Model
826
10.1 Natural Selection: Basis of Pathogenesis
826
10.2 Invasion
828
10.3 Role of Calcium and Dietary Factors
829
10.4 Implications for Cancer Treatment
831
11 Safety of Vitamin D for Cancer Prevention and As an Adjunct to Treatment
831
12 Geographic Distribution of Cancer and Environmental Factors
832
13 Summary
833
Acknowledgments
833
References
833
45 The Anti-cancer Effect of Vitamin D: What Do the Randomized Trials Show?
840
1 INTRODUCTION
840
2 Potential Mechanism Of Vitamin D Anti-Cancer Effects
841
3 Vitamin D And Calcium In Prevention Of Cancer
843
4 Randomized Trials Of Vitamin D Supplementation And Cancer
843
5 Levels Of 25(Oh)d For Cancer Prevention
845
6 Doses Of Vitamin D Supplementation For Cancer Prevention
845
7 SUMMARY
846
REFERENCES
847
46 Sunlight, Skin Cancer, and Vitamin D
850
1 The Most Important Negative Health Effect Of Solar Uv Exposure: Induction Of Skin Cancer
851
1.1 Non-melanoma Skin Cancer, Malignant Melanoma, and Solar UV Exposure
851
1.2 Photocarcinogenesis of Skin Cancer
851
2 Recommendations For Sun Protection In Skin Cancer Prevention Campaigns
856
3 A Challenging Perspective: Understanding And Fighting Vitamin D Deficiency
856
3.1 Vitamin D Deficiency -- A Serious and Underappreciated Health Problem
856
3.2 Consequent Sun Protection Increases the Risk of Vitamin D Deficiency
858
3.3 How Much Vitamin D Do We Need?
859
4 Conclusions
859
References
861
Part VI Vitamin D Deficiency and Chronic Disease
864
47 Vitamin D and the Risk of Type 1 Diabetes
865
1 MECHANISMS
865
2 Ecological Correlations
866
3 Animal Experiments
868
4 Studies In Humans
870
5 Genetic Studies
872
6 Conclusions
873
References
873
48 Vitamin D and Multiple Sclerosis
878
1 Introduction
878
2 Ms Epidemiology
879
3 Sun Exposure, Vitamin D, And Ms Risk
880
3.1 Database Analyses
881
3.2 Case--Control Studies
881
3.3 Longitudinal Studies
883
4 Seasonal Variations In Birth Patterns
886
5 Vitamin D And Ms Progression
886
6 Summary
887
REFERENCES
887
49 Vitamin D and Type 2 Diabetes
891
1 Epidemiology And Burden Of Type 2 Diabetes
891
2 Vitamin D Metabolism
892
3 Potential Mechanisms Of Action Of Vitamin D On Glucose Metabolism
892
3.1 Vitamin D and Pancreatic Beta-Cell Function/Insulin Secretion
892
3.2 Vitamin D and Insulin Sensitivity
894
3.3 Vitamin D and Systemic Inflammation
895
4 Evidence From Observational Human Studies
895
4.1 Seasonal Variation and Type 2 Diabetes
895
4.2 Case--Control and Cross-Sectional Studies of Vitamin D and Type 2 Diabetes
895
4.3 Prospective Studies of Vitamin D and Type 2 Diabetes
900
4.4 The Role of Calcium Intake and Type 2 Diabetes or the Metabolic Syndrome
905
4.5 Summary of Evidence from Human Observational Studies
906
5 Evidence From Intervention Human Studies
906
5.1 Effect of Vitamin D Supplementation on Type 2 Diabetes
906
5.2 Effect of Combined Vitamin D and Calcium Supplementation on Type 2 Diabetes
906
5.3 Summary of Evidence from Intervention Studies
911
6 Limitations In The Study Of Vitamin D
911
7 Optimal Intake Of Vitamin D And Calcium In Relation To Type 2 Diabetes
911
8 Conclusions And Future Directions
912
REFERENCES
912
50 Role of Vitamin D for Cardiovascular Health
917
1 Historical Review
917
1.1 Adverse Cardiovascular Effects from Very High Intake of vitamin D
917
1.2 Early Epidemiological Studies
918
2 Ecological Studies
918
2.1 Hypothesis That Sunlight and vitamin D Protect Against Cardiovascular Disease
918
2.2 Winter Excess in Cardiovascular Disease
919
3 Recent Epidemiological Studies
920
3.1 Observational Studies
920
3.2 Experimental Studies
921
4 Possible Cardio-Preventive Mechanisms Of vitamin D
922
4.1 Cardiac Function
922
4.2 Blood Pressure
923
4.3 Inflammatory Factors
924
4.4 Summary of Possible Mechanisms
925
REFERENCES
925
51 Vitamin D, Renin, and Blood Pressure
933
1 Introduction
933
2 Vitamin D, Blood Pressure, and Cardiac Functions: Evidence for a Connection
934
2.1 Epidemiological Evidence
934
2.2 Clinical Evidence
936
3 The ReninAngiotensin System: A Central Regulator of Blood Pressure
937
3.1 The RAS Cascade and Its Functions
937
3.2 Renin, the Rate-Limiting Enzyme of the RAS Cascade
938
3.3 Pharmacological Inhibition of the Renin--Angiotensin System
939
4 Vitamin D Regulation of the ReninAngiotensin System: Mechanism for the Connection?
940
4.1 Vitamin D: Negative Endocrine Regulator of the Renin--Angiotensin System
941
4.2 Mechanism of Renin Suppression
942
4.3 Vitamin D Analogs as Novel Renin Inhibitors
943
5 Conclusion
944
Acknowledgments
944
References
944
52 Role of Vitamin D and Vitamin D Analogs for Bone Health and Survival in Chronic Kidney Disease
950
1 Vitamin D and Metabolic Changes of Chronic Kidney Disease
950
2 Bone Disease and Vitamin D in Ckd
951
3 Osteitis Fibrosa Cystica
951
4 Adynamic Bone Disease
952
5 Osteomalacia
953
6 Vitamin D and Survival
953
7 Potential Mechanisms of a Cardiovascular Survival Benefit
955
8 Infectious Disease Survival and Vitamin D
957
9 Summary
957
References
957
53 Role of Vitamin D and Ultraviolet Radiation in Chronic Kidney Disease
961
1 Vitamin D Status in Chronic Kidney Disease
961
2 Vitamin D Supplementation in Chronic Kidney Disease
962
3 Vitamin D and Uv Radiation in Chronic Kidney Disease Patients on Haemodialysis (Own Experiences and Data)
962
4 Uv Trials With Patients on Haemodialysis
963
4.1 Whole-Body Irradiation
963
4.2 Partial-Body Irradiation
963
4.3 Vitamin D Metabolism During UVB Irradiation
966
4.4 Renal Osteodystrophy, Bone Mineral Density, and Bone Turnover
969
4.5 Physical Work Capacity and Blood Pressure
970
4.5.1 E rythropoiesis and UV R adiation in ESKD P atients
971
4.6 Heart Rate Variability and UV Radiation in ESKD Patients
972
4.7 UVB Radiation in Clinical Routine of a Dialysis Unit
972
5 Vitamin D and Uv Exposure in Prevention and Treatment of Chronic Kidney Disease
974
References
974
54 Role of Vitamin D in Rheumatoid Arthritis
978
1 INTRODUCTION
978
2 Rheumatoid Arthritis Disease Mechanism
979
2.1 Genetic Involvement
979
2.2 Rheumatoid Arthritis Immune System Involvement
979
3 Vitamin D And Rheumatoid Arthritis
980
3.1 Background
980
3.1.1 Immune System Effects of Vitamin D and Rheumatoid Arthritis
981
3.2 Joint Destruction in Rheumatoid Arthritis
982
3.3 Clinical, Animal, and Epidemiologic Studies of Vitamin D and Rheumatoid Arthritis
983
REFERENCES
985
55 Vitamin D, Respiratory Infections, and Obstructive Airway Diseases
989
1 Introduction
989
2 Respiratory Infections
991
3 Obstructive Airway Diseases
992
3.1 Asthma
992
3.2 Chronic Obstructive Pulmonary Disease
993
4 Childhood Wheezing
993
5 Vitamin D And Respiratory Infection
994
5.1 Tuberculosis
994
5.2 Epidemiologic Studies on Respiratory Infections
995
5.3 Preliminary Evidence from Interventional Trials
996
6 Vitamin D And Asthma
998
6.1 Asthma Pathogenesis
998
6.2 Asthma Control
999
6.3 Asthma Exacerbation
1000
7 Vitamin D And Copd
1000
7.1 COPD Pathogenesis
1000
7.2 Acute Exacerbations of COPD
1001
8 Potential Mechanisms
1001
8.1 Vitamin D and Innate Immunity
1001
8.2 Vitamin D and Adaptive Immunity
1002
8.3 Vitamin D, Atopy, and Allergies
1003
9 Future Research on Vitamin D, Respiratory Infections, and OAD s
1005
10 Conclusions
1007
Acknowledgments
1007
References
1008
Part VII Clinical Uses of Vitamin D Analogues
1014
56 Treatment of Immunomediated Diseases by Vitamin D Analogs
1015
1 INTRODUCTION
1015
2 ENHANCEMENT OF INNATE IMMUNE RESPONSES BY VDR AGONISTS
1016
3 MODULATION OF ADAPTIVE IMMUNE RESPONSES BY VDR AGONISTS
1017
3.1 Induction of Pro-tolerogenic Properties in Myeloid Dendritic Cells
1017
3.2 Modulation of Effector Lymphocytes
1018
3.3 Enhancement of Regulatory T Cells
1019
4 VITAMIN D DEFICIENCY IN AUTOIMMUNE AND OTHER IMMUNOMEDIATED DISEASES
1019
5 ANTI-INFLAMMATORY AND IMMUNOMODULATORY EFFECTS OF VDR AGONISTS IN AUTOIMMUNE AND IMMUNOMEDIATED DISEASES
1020
5.1 Rheumatoid Arthritis
1020
5.2 Systemic Lupus Erythematosus
1022
5.3 Type 1 Diabetes
1022
5.4 Experimental Allergic Encephalomyelitis
1023
5.5 Inflammatory Bowel Disease
1023
5.6 Immunomediated Prostatic Diseases
1024
6 DEVELOPMENT OF VDR AGONISTS FOR THE TREATMENT OF AUTOIMMUNE AND OTHER IMMUNOMEDIATED DISEASES
1025
REFERENCES
1026
57Clinical Utility of 1,25-Dihydroxyvitamin D3 and Its Analoguesfor the Treatment of Psoriasis
1032
1 THE VITAMIN D SYSTEM IN THE SKIN
1032
2 PSORIASIS: PATHOGENESIS, IMMUNOLOGY, AND HISTOLOGY OF SKIN LESIONS
1034
3 CLINICAL STUDIES OF VITAMIN D AND ANALOGUES IN PSORIASIS AND OTHER SKIN DISEASES
1035
3.1 Treatment of Scalp Psoriasis
1038
3.2 Treatment of Nail Psoriasis
1038
3.3 Treatment of Face and Flexures
1038
3.4 Treatment of Skin Lesions in Children
1039
3.5 Treatment of Psoriatic Lesions in HIV Patients
1039
3.6 Combination of Vitamin D Analogues with Other Therapies
1039
4 TREATMENT OF OTHER SKIN DISORDERS WITH VITAMIN D ANALOGUES
1040
4.1 Vitamin D and Ichthyosis
1040
4.2 Vitamin D and Scleroderma
1040
4.3 Vitamin D and Vitiligo
1040
4.4 Vitamin D and Skin Cancer
1041
4.5 Vitamin D and Other Skin Diseases
1041
5 BIOLOGICAL EFFECTS OF VITAMIN D AND ANALOGUES IN PSORIASIS
1041
6 PERSPECTIVES FOR THE EVALUATION OF NEW VITAMIN D ANALOGUES WITH LESS CALCEMIC ACTIVITY THAT CAN BE USED FOR THE TREATMENT OF HYPERPROLIFERATIVE SKIN DISORDERS
1043
REFERENCES
1045
58Affinity Alkylating Vitamin D Analogs as Molecular Probesand Therapeutic Agents
1050
1 Affinity And Photoaffinity Labeling Reagents as Molecular Probes of Enzymes and Receptors
1050
2 Affinity Alkylating Compounds as Therapeutic Agents
1051
3 Vitamin D and Its Metabolites: Biosynthesis, Properties, and Mechanism of Action
1052
4 Mineral Homeostatic and Cell-Regulatory Properties of 1,25(OH) 2 D
1053
5 Transcriptional Mechanism of 1,25(OH) 2 D
1054
6 Vdr and Its Ligand-Binding Domain (Vdr-Lbd)
1055
7 Affinity Labeling of Vdr from Endogenous Sources
1055
8 Affinity Labeling of Recombinant Vdr and Identification of a Contact Point
1057
9 Vdr-Affinity Alkylating Derivatives of 1,25(OH) 2 D AND 25(OH)D As Potential Therapeutic Agents
1058
10 Pharmacokinetic Property of 1,25(OH) 2 D as it Relates to its Therapeutic Activity
1058
11 1,25(OH) 2 D-3-Be, A Derivative of 1,25(OH) 2 D, with a Potential of Less Catabolic Degradation: Our Hypothesis
1059
12 Kinetic And Stoichiometric Studies With 1,25(OH) 2 D-BE AND VDR
1059
13 Antiproliferative Effects Of 1,25(Oh) 2 D-Be In Various Cancer Cells
1060
14 Molecular Mechanisms Related To The Growth-Inhibitory Effect Of 1,25(OH) 2 D-3-Be
1062
14.1 VDR-Related Mechanisms
1062
14.2 Additional VDR-Related and VDR-Unrelated Mechanisms
1065
15 Therapeutic Potential Of 1,25(OH) 2 D-3-Be And Related Compounds In Cancer
1069
16 Summary
1071
Acknowledgment
1071
References
1072
59Anti-inflammatory Activity of Calcitriol That Contributesto Its Therapeutic and Chemopreventive Effects in Prostate Cancer
1076
1 INTRODUCTION
1076
2 CALCITRIOL AND PROSTATE CANCER
1077
2.1 Anti-proliferative Effects of Calcitriol in PCa Cells
1077
2.2 Tumor Inhibitory Effects of Calcitriol in Animal Models of PCa
1078
3 MECHANISMS OF THE ANTI-PROLIFERATIVE EFFECTS OF CALCITRIOL
1078
3.1 Growth Arrest
1078
3.2 Apoptosis
1078
3.3 Differentiation
1079
3.4 Modulation of Growth Factor Actions
1079
3.5 Inhibition of Invasion, Metastasis, and Angiogenesis
1079
3.6 Novel Molecular Pathways of Calcitriol Actions in PCa Cells
1080
4 ANTI-INFLAMMATORY EFFECTS OF CALCITRIOL IN PROSTATE CANCER
1080
4.1 Regulation of Prostaglandin Metabolism and Signaling
1080
4.1.1 COX-2 and Prostate Cancer
1080
4.1.2 15-PGDH
1081
4.1.3 PG Receptors
1081
4.1.4 Calcitriol Effects on the PG Pathway in Prostate Cells
1082
4.1.5 Combination of Calcitriol and Non-steroidal Anti-inflammatory Drugs (NSAIDs)as a Therapeutic Approach in Prostate Cancer
1083
4.2 Induction of MKP5 and Inhibition of Stress-Activated Kinase Signaling
1084
4.3 Inhibition of NFB Activation and Signaling
1085
5 THE ROLE OF ANTI-INFLAMMATORY EFFECTS OF CALCITRIOL IN PROSTATE CANCER PREVENTION AND TREATMENT
1086
5.1 Inflammation and Prostate Cancer
1086
5.2 Calcitriol and Prostate Cancer Chemoprevention
1087
6 SUMMARY AND CONCLUSIONS
1087
REFERENCES
1088
Subject Index
1094
About the Editor
1146
About the Series Editor
1148