Histopathological Characterization and Expression of Vitamin D Receptor in the Prostate of Healthy Dogs and Dogs with Prostatic Carcinoma
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Vitamin D Receptor (VDR) expression is implicated in human Prostatic Carcinoma (PC), but its role in canine PC is unclear. To investigate how VDR expression is affected by age and castration in healthy dogs and how it changes with PC, we evaluated prostates from 8-month-old (n = 5) or 6-year-old (n = 8) intact males, 1-8-year-old healthy castrated males (n = 4) and 8-15-year-old castrated males (n = 7) with PC, by performing histopathology, immunohistochemistry, and ELISA. The results showed that VDR expression in canine prostate increased in an age-dependent manner and decreased after castration compared with intact dogs at 6 years of age. Castrated dogs with PC showed increased VDR expression compared with healthy castrated dogs and VDR expression in PC differed according to the pattern of tumor proliferation. The findings suggest that prostatic VDR expression may be a useful prognostic marker and therapeutic target for canine PC.Keywords:
Histopathology
Prostate carcinoma
Abstract Background Vitamin D is a fat-soluble vitamin that regulates calcium and phosphorous homeostasis to maintain a healthy mineralized skeleton. It can also influence immune responses and has immunomodulatory properties. Vitamin D receptor (VDR) is a nuclear receptor that mediates the activities of the hormonal form of vitamin D. VDR polymorphisms can alter immunity and susceptibility to infections by modulating VDR expression and vitamin D activity. This study aimed to investigate the levels of serum vitamin D as well as four VDR polymorphisms: FokI, BsmI, ApaI, and TaqI in fifty children admitted to intensive care unit (ICU) with a diagnosis of sepsis and one-hundred age- and sex-matched healthy children. Methods Vitamin D levels were measured in serum, in both patients and controls, using an enzyme-linked immunosorbent assay (ELISA) approach. VDR polymorphisms were also studied in both groups using specific restriction enzymes. Results Vitamin D levels were low in both patients and controls. Moreover, serum levels were unaffected by VDR polymorphisms, and their distribution was similar in both groups. Neither the need for mechanical ventilation or inotropic treatment nor the sepsis outcome was impacted by serum vitamin D levels or VDR polymorphisms. Conclusion In children admitted to pediatric ICU, neither vitamin D levels nor VDR polymorphisms were associated with sepsis. Further larger studies including different types of sepsis are recommended.
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Liver disease
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There is substantial interest in whether vitamin D signaling plays a role in reducing risk for prostate cancer and in its use as a therapeutic target in prostate cancer. Vitamin D is synthesized in the skin through a UVB-mediated reaction and subsequently hydroxylated to form 1,25-dihydroxyvitamin D3, the ligand for the vitamin D receptor (VDR), a hormone activated transcription factor. Epidemiological studies correlating prostate cancer risk with reduced exposure to sunlight have suggested that vitamin D reduces risk, but the conclusions from studies of vitamin D metabolites have been variable. Similarly, despite promising results in preclinical studies, attempts to target VDR clinically have been less successful. This chapter reviews what is known regarding the actions of VDR in prostate and in prostate cancers and the evidence for activation of VDR as a strategy to reduce risk and/or treat prostate cancer. The chapter summarizes the evidence for a role in reducing prostate cancer risk and discusses the possibility that aberrant vitamin D metabolism contributes to the difficulties in correlating serum vitamin D metabolites with the level of VDR activation in cells. Also discussed are other mechanisms for resistance to the beneficial actions of VDR and strategies to optimize VDR activity.
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The bioactive vitamin D3, 1α,25(OH)2D3, plays a central role in calcium homeostasis by controlling the activity of the vitamin D receptor (VDR) in various tissues. Hypercalcemia secondary to high circulating levels of vitamin D3 leads to hypercalciuria, nephrocalcinosis and renal dysfunctions. Current therapeutic strategies aim at limiting calcium intake, absorption and resorption, or 1α,25(OH)2D3 synthesis, but are poorly efficient. In this study, we identify WBP4 as a new VDR interactant, and demonstrate that it controls VDR subcellular localization. Moreover, we show that the vitamin D analogue ZK168281 enhances the interaction between VDR and WBP4 in the cytosol, and normalizes the expression of VDR target genes and serum calcium levels in 1α,25(OH)2D3-intoxicated mice. As ZK168281 also blunts 1α,25(OH)2D3-induced VDR signaling in fibroblasts of a patient with impaired vitamin D degradation, this VDR antagonist represents a promising therapeutic option for 1α,25(OH)2D3-induced hypercalcemia.
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This review aims to provide an overview of the current understanding regarding the relationship between muscle function and vitamin D. For many years, the molecular mechanisms of vitamin D's action on muscle tissue have been understood to involve both genomic and non-genomic effects. 1,25-dihydroxyvitamin D3 (1,25(OH)2D) binds to its nuclear receptor to start the genomic effects, which alter messenger RNA gene transcription and consequently protein synthesis. The membrane-bound vitamin D receptor (VDR) mediates the quick non-genomic effects of vitamin D. The significance of VDR polymorphisms in the development of osteoporosis and genetic variations in the VDR are still up for debate disagreement and discussion. VDR polymorphisms have most recently been reported to have an impact on muscle function. The body gets 80–100% of the vitamin D it needs from the skin, which has a huge capacity for producing the nutrient. The generation of vitamin D in the skin can be significantly impacted by age, latitude, time of day, and pigmentation. Elderly people in northern latitudes frequently have hypovitaminosis D. Elemental calcium is generally advised for people who are deficient in calcium and vitamin D since it lowers hip fractures and other non-vertebral fractures. Considering the close relationship between high parathyroid hormone levels, low serum calcium, and vitamin D deficiency.
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Vitamin D receptor (VDR) executes the main biological functions of its ligand vitamin D. VDR/vitamin D plays critical roles in regulating host immunity, maintaining barrier functions, and shaping gut microbiome. Reduction of intestinal VDR has been reported in various diseases, including inflammatory diseases and colon cancer. However, it is always challenging to get biopsies to test the pathologic changes of VDR in intestine. In the current study, we reported a simple and sensitive quantitative PCR (qPCR) method to detect reduction of intestinal VDR using fecal samples. We validated this method in several experimental models, such as colitis, bacterial infection, and aging. We further correlated the qPCR data of VDR with the protein level of VDR in colon or serum 25 (OH)D3 in mice with different VDR status (VDR+/+, VDR+/-, and VDR−/−). Our data indicate that the qPCR method to test VDR using fecal samples could detect the expression level of intestinal VDR in various diseases. Our study highlights the feasibility, sensitivity, and simplicity of a molecular method to study the status of VDR as a biomarker.
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What is the central question of this study? Does exercise affect vitamin D receptor expression in T lymphocytes in young, middle-aged and older adults? What is the main finding and its importance? Moderate-intensity cycling exercise increases vitamin D receptor expression in vitamin D-deficient men, independent of age, presenting a strategy to combat the prevalence of vitamin D deficiency.Vitamin D plays a key role in the modulation of the immune system, mediated through the intracellular vitamin D receptor (VDR). Exercise has been shown to influence the activity and availability of the VDR. The aim of this study was to investigate the effect of age on basal immune cell (T-lymphocyte) VDR expression and the subsequent effect of acute aerobic exercise to modulate VDR expression in peripheral T cells. Thirty-five men were included in the study (mean ± SD: age 44 ± 17 years and body mass index 25.7 ± 3.1 kg/m2 ), separated into three age groups: 18-30 (n = 12), 31-45 (n = 11) and 60-75 years (n = 12). Participants completed two trials [control (CON) and aerobic exercise (AE)], with blood samples collected pre- and postexercise (0, 1 and 3 h). Peripheral blood T cells were isolated and analysed for VDR expression by flow cytometry. The results show that advanced age is associated with lower VDR expression in T cells (882 ± 274, 796 ± 243 and 594 ± 174 geomean in the 18-30, 31-45 and 60-75 year age groups, respectively). Acute AE was successful at acutely increasing VDR expression in T cells, irrespective of age. Advanced age corresponds to a lower T-cell VDR expression, which might be responsible for age-associated development of chronic conditions and autoimmunity. Exercise was successful in increasing VDR expression in T cells irrespective of age and independent of exercise-induced T-cell mobilization.
Immunosenescence
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Receptor expression
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Abstract Background: Several roles have been proposed for vitamin D and the vitamin D receptor (VDR) in prostate cancer (PCa) pathogenesis and progression. However, previous genetic epidemiologic studies have provided limited support linking VDR polymorphisms to PCa due to complexity of vitamin D metabolism and potential gene and environmental interactions. In this study, we investigated the association of VDR genotypes with PCa incidence and aggressiveness in African Americans (AAs) and European Americans (EAs) and if the associations were modified by behavioral and biological factors that influence serum vitamin D levels. Methods: The total of 810 AAs and 487 EAs from Chicago, IL and Washington, D.C. were included in this study. Seven single-nucleotide polymorphisms (SNPs) in and around the VDR gene and 105 ancestry informative markers were genotyped. We performed logistic regression analyses adjusting for relevant variables. Results: In EAs, TaqI (rs73136) and BsmI (rs1544410) minor alleles revealed a protective effect against PCa, while in AAs, FokI (rs2228570) was associated with overall PCa risk (OR=0.74, 95% C.I.: 0.57-0.96). The heterogeneous associations observed in our study could be due to difference in prevalence of vitamin D deficiency between AAs and EAS and effect modifications by behavioral and biological factors that affect serum vitamin D levels. Therefore, we investigated if behavioral and biological factors that influence serum vitamin D modified the associations between VDR polymorphisms and PCa, and we found evidence suggesting that these behavioral and biological factors modify the effect of VDR on PCa. In AAs, we observed statistically significant interaction between two VDR polymorphisms, FokI and TaqI, and vitamin D intake (PInteraction=0.01 and PInteraction=0.03 respectively). We also observed evidence of interactions between VDR gene variants and other behavioral and biological factors that lower serum vitamin D levels in both AAs and EAs. In AAs, calcium intake and skin pigmentation may modify the effects of VDR on PCa. In EAs, BMI may modify the effect of VDR. Conclusions: Although a larger sample size is necessary to confirm the observation, we demonstrated that vitamin D related behavioral and biological factors modify the effect of VDR genotypes on PCa. Impact: The VDR gene is involved in PCa pathogenesis and progression, and polymorphisms in VDR gene and vitamin D are likely to alter the function of the gene. Citation Format: Ken Batai, Adam B. Murphy, Ebony Shah, Chiledum Ahaghotu, Rick A. Kittles. Effect modifications of vitamin D receptor common polymorphisms association with prostate cancer by serum vitamin D related behavioral and biological factors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1278. doi:10.1158/1538-7445.AM2017-1278
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