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Sánchez-Martínez, Ruth, Alberto Zambrano, Ana I. Castillo, and Ana Aranda. "Vitamin D-Dependent Recruitment of Corepressors to Vitamin D/Retinoid X Receptor Heterodimers." Molecular and Cellular Biology 28, no. 11 (March 24, 2008): 3817–29. http://dx.doi.org/10.1128/mcb.01909-07.
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ABSTRACT Transcriptional regulation by nuclear receptors is mediated by recruitment of coactivators and corepressors. In the classical model, unliganded nonsteroidal receptors bind corepressors, such as the silencing mediator of thyroid and retinoid receptors (SMRT) or nuclear corepressor (NCoR), that are released upon ligand binding. We show here that, unlike other receptors, the heterodimer of the vitamin D receptor (VDR) with the retinoid X receptor (RXR) recruits NCoR and SMRT strictly in a VDR agonist-dependent manner. Binding of an agonist to VDR allows its partner receptor, RXR, to bind the corepressors. The RXR ligand has the opposite effect and induces corepressor release from the heterodimer. 1,25-Dihydroxy-vitamin D3 (VD3) causes recruitment of SMRT and NCoR to a VDR target promoter. Down-regulation of corepressors by means of small interfering RNA enhances transcriptional responses to VD3. These data reveal a new paradigm of SMRT and NCoR binding to nuclear receptors and demonstrate that these corepressors can function as physiological negative regulators of VD3-mediated transcription.
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Takeyama, Ken-Ichi, Yoshikazu Masuhiro, Hiroaki Fuse, Hideki Endoh, Akiko Murayama, Sachiko Kitanaka, Miyuki Suzawa, Junn Yanagisawa, and Shigeaki Kato. "Selective Interaction of Vitamin D Receptor with Transcriptional Coactivators by a Vitamin D Analog." Molecular and Cellular Biology 19, no. 2 (February 1, 1999): 1049–55. http://dx.doi.org/10.1128/mcb.19.2.1049.
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ABSTRACT The nuclear vitamin D receptor (VDR) is a member of a nuclear receptor superfamily and acts as a ligand-dependent transcription factor. A family of cotranscriptional activators (SRC-1, TIF2, and AIB-1) interacts with and activates the transactivation function of nuclear receptors in a ligand-dependent way. We examined interaction of VDR with these coactivators that was induced by several vitamin D analogs, since they exert differential subsets of the biological action of vitamin D through unknown mechanisms. Unlike other vitamin D analogs tested, OCT (22-oxa-1α,25-dihydroxyvitamin D3) induced interaction of VDR with TIF2 but not with SRC-1 or AIB-1. Consistent with these interactions, only TIF2 was able to potentiate the transactivation function of VDR bound to OCT. Thus, the present findings suggest that the structure of VDR is altered in a vitamin D analog-specific way, resulting in selective interactions of VDR with coactivators. Such selective interaction of coactivators with VDR may specify the array of biological actions of a vitamin D analog like OCT, possibly through activating a particular set of target gene promoters.
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Li, S. M., L. H. Ouyang, and D. G. Zhou. "Effects of vitamin D3 on expression of defensins, Toll-like receptors, and vitamin D receptor in liver, kidney, and spleen of Silky Fowl." Czech Journal of Animal Science 58, No. 1 (January 8, 2013): 1–7. http://dx.doi.org/10.17221/6519-cjas.
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The expression of avian β-defensins (AvBDs), Toll-like receptors (TLRs), and vitamin D receptor (VDR) following in vivo vitamin D<sub>3 </sub>injection was studied. Healthy 90-day Silky Fowls were abdominally injected with vitamin D<sub>3</sub> or untreated. Real-time PCR analyses revealed that injection of vitamin D<sub>3</sub> significantly (P < 0.05) up-regulated the expression of TLRs (TLR2, TLR5), VDR, AvBDs (AVBD-6, GAL-1), and 24-hydroxylase (CYP24A1) in the tissues (liver, spleen, and kidney) at various times 8–24 h post injection. These results suggest that expression of VDR, AvBDs, and TLRs seems to be induced by vitamin D<sub>3 </sub>and it was concluded that the tissues expressing TLRs and VDR respond to vitamin D<sub>3</sub> and in turn upregulate these tissues cellular functions to synthesize AvBDs. Intraperitoneal injection of vitamin D<sub>3</sub> likely resulted in enhancing the expression of AvBDs, TLRs, and VDR, which providedinsight into factors important for the control of the innateimmune response in the chickens.
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Takeshita, Akira, Yasunori Ozawa, and William W. Chin. "Nuclear Receptor Coactivators Facilitate Vitamin D Receptor Homodimer Action on Direct Repeat Hormone Response Elements." Endocrinology 141, no. 3 (March 1, 2000): 1281–84. http://dx.doi.org/10.1210/endo.141.3.7441.
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Abstract Vitamin D receptor (VDR) is a ligand-dependent transcription factor that regulates target gene expression. Although VDR forms stable heterodimer complex with retinoid X receptors (RXRs) on vitamin D-response elements (VDREs), it is still not clear whether VDR/RXR heterodimers are the only VDR complexes responsible for vitamin D-mediated gene transcription. In this report, we analyzed the effect of nuclear receptor coactivators (SRC-1 and TRAM-1) on VDR homodimer and VDR/RXR heterodimer formation by electrophoretic mobility shift assay. We found that VDR forms stable homodimers after interaction with the coactivators on a VDRE (DR+3). Of particular note, DR+4 and DR+5 hormone-response elements (HREs) may also support such interactions. Cotransfection experiments revealed further that the coactivators enhance ligand-induced VDR transcription on these elements. Our studies suggest the important role of VDR homodimers, in addition to VDR/RXR heterodimers, in vitamin D-induced transactivation. Thus, specific coactivator-VDR interactions on HREs may determine target gene transactivation.
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Bouillon, Roger, Geert Carmeliet, Lieve Verlinden, Evelyne van Etten, Annemieke Verstuyf, Hilary F. Luderer, Liesbet Lieben, Chantal Mathieu, and Marie Demay. "Vitamin D and Human Health: Lessons from Vitamin D Receptor Null Mice." Endocrine Reviews 29, no. 6 (October 1, 2008): 726–76. http://dx.doi.org/10.1210/er.2008-0004.
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Abstract The vitamin D endocrine system is essential for calcium and bone homeostasis. The precise mode of action and the full spectrum of activities of the vitamin D hormone, 1,25-dihydroxyvitamin D [1,25-(OH)2D], can now be better evaluated by critical analysis of mice with engineered deletion of the vitamin D receptor (VDR). Absence of a functional VDR or the key activating enzyme, 25-OHD-1α-hydroxylase (CYP27B1), in mice creates a bone and growth plate phenotype that mimics humans with the same congenital disease or severe vitamin D deficiency. The intestine is the key target for the VDR because high calcium intake, or selective VDR rescue in the intestine, restores a normal bone and growth plate phenotype. The VDR is nearly ubiquitously expressed, and almost all cells respond to 1,25-(OH)2D exposure; about 3% of the mouse or human genome is regulated, directly and/or indirectly, by the vitamin D endocrine system, suggesting a more widespread function. VDR-deficient mice, but not vitamin D- or 1α-hydroxylase-deficient mice, and man develop total alopecia, indicating that the function of the VDR and its ligand is not fully overlapping. The immune system of VDR- or vitamin D-deficient mice is grossly normal but shows increased sensitivity to autoimmune diseases such as inflammatory bowel disease or type 1 diabetes after exposure to predisposing factors. VDR-deficient mice do not have a spontaneous increase in cancer but are more prone to oncogene- or chemocarcinogen-induced tumors. They also develop high renin hypertension, cardiac hypertrophy, and increased thrombogenicity. Vitamin D deficiency in humans is associated with increased prevalence of diseases, as predicted by the VDR null phenotype. Prospective vitamin D supplementation studies with multiple noncalcemic endpoints are needed to define the benefits of an optimal vitamin D status.
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Thorne, James, and Moray J. Campbell. "The vitamin D receptor in cancer." Proceedings of the Nutrition Society 67, no. 2 (April 15, 2008): 115–27. http://dx.doi.org/10.1017/s0029665108006964.
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Over the last 25 years roles have been established for vitamin D receptor (VDR) in influencing cell proliferation and differentiation. For example, murine knock-out approaches have revealed a role for the VDR in controlling mammary gland growth and function. These actions appear widespread, as the enzymes responsible for 1α,25-dihydroxycholecalciferol generation and degradation, and the VDR itself, are all functionally present in a wide range of epithelial and haematopoietic cell types. These findings, combined with epidemiological and functional data, support the concept that local, autocrine and paracrine VDR signalling exerts control over cell-fate decisions in multiple cell types. Furthermore, the recent identification of bile acid lithocholic acid as a VDR ligand underscores the environmental sensing role for the VDR.In vitroandin vivodissection of VDR signalling in cancers (e.g. breast, prostate and colon) supports a role for targeting the VDR in either chemoprevention or chemotherapy settings. As with other potential therapeutics, it has become clear that cancer cells displayde novoand acquired genetic and epigenetic mechanisms of resistance to these actions. Consequently, a range of experimental and clinical options are being developed to bring about more targeted actions, overcome resistance and enhance the efficacy of VDR-centred therapeutics.
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Brown, Alex J., Adriana Dusso, and Eduardo Slatopolsky. "Vitamin D." American Journal of Physiology-Renal Physiology 277, no. 2 (August 1, 1999): F157—F175. http://dx.doi.org/10.1152/ajprenal.1999.277.2.f157.
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The vitamin D endocrine systems plays a critical role in calcium and phosphate homeostasis. The active form of vitamin D, 1,25-dihydroxyvitamin D3[1,25(OH)2D3], binds with high affinity to a specific cellular receptor that acts as a ligand-activated transcription factor. The activated vitamin D receptor (VDR) dimerizes with another nuclear receptor, the retinoid X receptor (RXR), and the heterodimer binds to specific DNA motifs (vitamin D response elements, VDREs) in the promoter region of target genes. This heterodimer recruits nuclear coactivators and components of the transcriptional preinitiation complex to alter the rate of gene transcription. 1,25(OH)2D3also binds to a cell-surface receptor that mediates the activation of second messenger pathways, some of which may modulate the activity of the VDR. Recent studies with VDR-ablated mice confirm that the most critical role of 1,25(OH)2D3is the activation of genes that control intestinal calcium transport. However, 1,25(OH)2D3can control the expression of many genes involved in a plethora of biological actions. Many of these nonclassic responses have suggested a number of therapeutic applications for 1,25(OH)2D3and its analogs.
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Ogbu, Destiny, Eric Xia, and Jun Sun. "Gut instincts: vitamin D/vitamin D receptor and microbiome in neurodevelopment disorders." Open Biology 10, no. 7 (July 2020): 200063. http://dx.doi.org/10.1098/rsob.200063.
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The gut microbiome regulates a relationship with the brain known as the gut–microbiota–brain (GMB) axis. This interaction is influenced by immune cells, microbial metabolites and neurotransmitters. Recent findings show gut dysbiosis is prevalent in autism spectrum disorder (ASD) as well as attention deficit hyperactivity disorder (ADHD). There are previously established negative correlations among vitamin D, vitamin D receptor (VDR) levels and severity of ASD as well as ADHD. Both vitamin D and VDR are known to regulate homeostasis in the brain and the intestinal microbiome. This review summarizes the growing relationship between vitamin D/VDR signalling and the GMB axis in ASD and ADHD. We focus on current publications and summarize the progress of GMB in neurodevelopmental disorders, describe effects and mechanisms of vitamin D/VDR in regulating the microbiome and synoptically highlight the potential applications of targeting vitamin D/VDR signalling in neurodevelopment disorders.
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Zwerina, Karin, Wolfgang Baum, Roland Axmann, Gisela Ruiz Heiland, Jörg H. Distler, Josef Smolen, Silvia Hayer, Jochen Zwerina, and Georg Schett. "Vitamin D receptor regulates TNF-mediated arthritis." Annals of the Rheumatic Diseases 70, no. 6 (March 17, 2011): 1122–29. http://dx.doi.org/10.1136/ard.2010.142331.
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ObjectiveReduced vitamin D intake has been linked to increased susceptibility to develop rheumatoid arthritis (RA) and vitamin D deficiency is associated with increased disease activity in RA patients. The pathophysiological role of vitamin D in joint inflammation is, however, unclear.MethodsTo determine the influence of absent vitamin D signalling in chronic arthritis, vitamin D receptor (VDR)-deficient mice were crossed with human tumour necrosis factor (TNF) transgenic mice (hTNFtg), which spontaneously develop chronic arthritis.ResultsClinical signs and symptoms of chronic arthritis were aggravated in hTNFtg mice lacking functional VDR signalling. Moreover, synovial inflammation was clearly increased in VDR−/−hTNFtg mice as compared to hTNFtg mice and was associated with an increased macrophage influx in inflamed joints. In vitro, VDR-deficient monocytes were proinflammatory and hyper-responsive to TNF stimulation associated with prolonged mitogen-activated protein kinase activation and cytokine secretion. Also, VDR−/− monocytes showed enhanced potential to differentiate into bone resorbing osteoclasts in vitro. In line, VDR−/−hTNFtg mice had significantly increased cartilage damage and synovial bone erosions.ConclusionsVDR plays an important role in limiting the inflammatory phenotype in a mouse model of RA. Absent VDR signalling causes a proinflammatory monocyte phenotype associated with increased inflammation, cartilage damage and bone erosion.
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Dusso, Adriana S., Alex J. Brown, and Eduardo Slatopolsky. "Vitamin D." American Journal of Physiology-Renal Physiology 289, no. 1 (July 2005): F8—F28. http://dx.doi.org/10.1152/ajprenal.00336.2004.
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The vitamin D endocrine system plays an essential role in calcium homeostasis and bone metabolism, but research during the past two decades has revealed a diverse range of biological actions that include induction of cell differentiation, inhibition of cell growth, immunomodulation, and control of other hormonal systems. Vitamin D itself is a prohormone that is metabolically converted to the active metabolite, 1,25-dihydroxyvitamin D [1,25(OH)2D]. This vitamin D hormone activates its cellular receptor (vitamin D receptor or VDR), which alters the transcription rates of target genes responsible for the biological responses. This review focuses on several recent developments that extend our understanding of the complexities of vitamin D metabolism and actions: the final step in the activation of vitamin D, conversion of 25-hydroxyvitamin D to 1,25(OH)2D in renal proximal tubules, is now known to involve facilitated uptake and intracellular delivery of the precursor to 1α-hydroxylase. Emerging evidence using mice lacking the VDR and/or 1α-hydroxylase indicates both 1,25(OH)2D3-dependent and -independent actions of the VDR as well as VDR-dependent and -independent actions of 1,25(OH)2D3. Thus the vitamin D system may involve more than a single receptor and ligand. The presence of 1α-hydroxylase in many target cells indicates autocrine/paracrine functions for 1,25(OH)2D3in the control of cell proliferation and differentiation. This local production of 1,25(OH)2D3is dependent on circulating precursor levels, providing a potential explanation for the association of vitamin D deficiency with various cancers and autoimmune diseases.
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Kharb, Simmi, Kanika Goel, and Rajesh Rajput. "Role of Vitamin D Receptor in Prediabetes." Open Diabetes Journal 10, no. 1 (August 19, 2020): 20–25. http://dx.doi.org/10.2174/1876524602010010020.
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Background: Recent epidemiological evidence points towards the potential association of vitamin D insufficiency with adverse metabolic risk and in the pathogenesis of cancer, cardiovascular diseases, type 2 diabetes and other diseases. Vitamin D exerts its action in a variety of cell types through vitamin D receptors. No reports are available in the literature regarding vitamin D and vitamin D receptor status in prediabetics. The present study was planned to compare serum 25-hydroxy vitamin D [25(OH)D] and vitamin D receptor (VDR) protein levels in prediabetic cases and normoglycemic controls. Methods: The present study was conducted in 80 persons who were divided into two groups, Study group (n= 40) comprised of diagnosed cases of prediabetes and control group (n=40) comprised of healthy normoglycemic controls. Serum 25-hydroxy vitamin D [25(OH)D] was analyzed by radioimmunoassay (RIA). Serum vitamin D receptor (VDR) protein was analyzed by sandwich enzyme immunoassay (ELISA). Results: Serum 25(OH) vitamin D levels were significantly decreased in prediabetic cases as compared to normoglycemic controls [p<0.001]. Serum Vitamin D receptor protein levels were highly significantly decreased in prediabetic cases as compared to normoglycemic controls [p<0.00]. Serum 25(OH)D levels showed a highly significant positive correlation with serum VDR levels in both the groups [p<0.001 at both levels]. Conclusion: The findings of the present study indicate that vitamin D and VDR can serve as a possible screening marker and target for modulation of the management and alleviating the progress and complications of diabetes.
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Shimada, Takashi, Yuji Yamazaki, Motoo Takahashi, Hisashi Hasegawa, Itaru Urakawa, Takeshi Oshima, Kaori Ono, et al. "Vitamin D receptor-independent FGF23 actions in regulating phosphate and vitamin D metabolism." American Journal of Physiology-Renal Physiology 289, no. 5 (November 2005): F1088—F1095. http://dx.doi.org/10.1152/ajprenal.00474.2004.
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FGF23 suppresses both serum phosphate and 1,25-dihydroxyvitamin D [1,25D] levels in vivo. Because 1,25D itself is a potent regulator of phosphate metabolism, it has remained unclear whether FGF23-induced changes in phosphate metabolism were caused by a 1,25D-independent mechanism. To address this issue, we intravenously administered recombinant FGF23 to vitamin D receptor (VDR) null (KO) mice as a rapid bolus injection and evaluated the early effects of FGF23. Administration of recombinant FGF23 further decreased the serum phosphate level in VDR KO mice, accompanied by a reduction in renal sodium-phosphate cotransporter type IIa (NaPi2a) protein abundance and a reduced renal 25-hydroxyvitamin D-1α-hydroxylase (1αOHase) mRNA level. Thus FGF23-induced changes in NaPi2a and 1αOHase expression are independent of the 1,25D/VDR system. However, 24-hydroxylase (24OHase) mRNA expression remained undetectable by the treatment with FGF23. We also analyzed the regulatory mechanism for FGF23 expression. The serum FGF23 level was almost undetectable in VDR KO mice, whereas dietary calcium supplementation significantly increased circulatory levels of FGF23 and its mRNA abundance in bone. This finding indicates that calcium is another determinant of FGF23 production that occurs independently of the VDR-mediated mechanism. In contrast, dietary phosphate supplementation failed to induce FGF23 expression in the absence of VDR, whereas marked elevation in circulatory FGF23 was observed in wild-type mice fed with a high-phosphate diet. Taken together, FGF23 works, at least in part, in a VDR-independent manner, and FGF23 production is also regulated by multiple mechanisms involving VDR-independent pathways.
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Gisbert-Ferrándiz, Laura, Jesús Cosín-Roger, Carlos Hernández, Dulce C. Macias-Ceja, Dolores Ortiz-Masiá, Pedro Salvador, Juan V. Esplugues, et al. "Diminished Vitamin D Receptor Protein Levels in Crohn’s Disease Fibroblasts: Effects of Vitamin D." Nutrients 12, no. 4 (April 1, 2020): 973. http://dx.doi.org/10.3390/nu12040973.
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Vitamin D (VD) deficiency has been associated to Crohn’s disease (CD) pathogenesis, and the exogenous administration of VD improves the course of the disease, but the mechanistic basis of these observations remains unknown. Vitamin D receptor (VDR) mediates most of the biological functions of this hormone, and we aim to analyze here the expression of VDR in intestinal tissue, epithelial cells, and fibroblasts from CD patients. The effects of VD on a fibroblast wound healing assay and murine intestinal fibrosis are also analyzed. Our data show diminished VDR protein levels in surgical resections and epithelial cells from CD patients. In intestinal fibroblasts isolated from damaged tissue of CD patients, we detected enhanced migration and decreased VDR expression compared with both fibroblasts from non-damaged tissue of the same CD patient or control fibroblasts. Treatment with VD increased VDR protein levels, avoided the accelerated migration in CD fibroblasts, and prevented murine intestinal fibrosis induced by the heterotopic transplant model. In conclusion, our study demonstrates diminished VDR protein levels associated with enhanced migration in intestinal fibroblasts from damaged tissue of CD patients. In these cells, VD accumulates VDR and normalizes migration, which supports that CD patients would benefit from the VD anti-fibrotic therapeutic value that we demonstrate in a murine experimental model.
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Li, Yixuan, Jiaqiang Huang, Jingxuan Wang, Mengjuan Ma, Yao Lu, Ran Wang, and Huiyuan Guo. "Lactoferrin Is a Potential Activator of the Vitamin D Receptor in Its Regulation of Osteogenic Activities in C57BL/6J Mice and MC3T3-E1 Cells." Journal of Nutrition 151, no. 8 (May 12, 2021): 2105–13. http://dx.doi.org/10.1093/jn/nxab105.
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ABSTRACT Background Lactoferrin (LF) has been shown to promote bone anabolism, and the vitamin D receptor (VDR) mediates the effects of vitamin D on bone. We hypothesized that LF improves bone health by increasing VDR expression. Objectives We sought to determine the role of VDR activation in LF-induced osteogenic activity in vivo and in vitro and the underlying molecular mechanisms. Methods Sixty male C57BL/6J mice (aged 4 wk) were randomly assigned into 6 groups and fed vitamin D–deficient (VDD; 0 IU/kg) or vitamin D–normal diet (VDN; 1000 IU cholecalciferol/kg) and administered placebo or LF (100 or 1000 mg/kg body weight) by gavage for 24 wk. Trabecular bone structure was analyzed using micro-CT, and VDR expression was assessed by immunohistochemistry. In vitro, MC3T3-E1 cells were treated with 100 μg LF/mL to evaluate its effect on VDR expression. Finally, the direct recruitment of LF to the Vdr promoter was confirmed by chromatin immunoprecipitation assay. In addition, cells were transfected with pGL3-basic Vdr vector for monitoring Vdr promoter activation using luciferase assays. Results LF supplementation at 100 and 1000 mg/kg revealed an ∼6.5% (P < 0.05) increase in bone mineral density in mice on VDD diet and exhibited an enhanced expression of VDR in bone compared with control. This increased expression of VDR was also observed in the bone of mice on the VDN diet, but the effect was more pronounced in VDD diet. In vitro, compared with the control group, Vdr mRNA expression was 18 times greater (P < 0.05) and peaked at 2 h posttreatment of LF. By cotransfection of the pGL3-basic Vdr vector, LF induced luciferase activity by 30% (P < 0.05) in MC3T3-E1 cells. Conclusions In vivo and in vitro, LF, a potential activator of VDR, promotes osteogenesis. This suggests that dairy products, which are rich in LF, may serve as a functional food to improve bone health.
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Xie, Zhongjian, Sandra Chang, Yuko Oda, and Daniel D. Bikle. "Hairless Suppresses Vitamin D Receptor Transactivation in Human Keratinocytes." Endocrinology 147, no. 1 (January 1, 2006): 314–23. http://dx.doi.org/10.1210/en.2005-1111.
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The vitamin D receptor (VDR) and its ligand 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] are required for normal keratinocyte differentiation. Both the epidermis and the hair follicle are disrupted in VDR-null mice. Hairless (Hr), a presumptive transcription factor with no known ligand, when mutated, disrupts hair follicle cycling similar to the effects of VDR mutations. Hr, like VDR, is found in the nuclei of keratinocytes in both epidermis and hair follicle. To investigate the potential interaction between Hr and VDR on keratinocyte differentiation, we examined the effect of Hr expression on vitamin D-responsive genes in normal human keratinocytes. Inhibition of Hr expression in keratinocytes potentiated the induction of vitamin D-responsive genes, including involucrin, transglutaminase, phospholipase C-γ1, and 25-hydroxyvitamin D-24-hydroxylase (24-hydroxylase) by 1,25(OH)2D3. Overexpression of Hr in human keratinocytes suppressed the induction of these vitamin D-responsive genes by 1,25(OH)2D3. Coimmunoprecipitation, DNA mobility shift assays, and chromatin immunoprecipitation revealed that Hr binds to VDR in human keratinocytes. Hr binding to the VDR was eliminated by 1,25(OH)2D3, which recruited the coactivator vitamin D receptor-interacting protein 205 (DRIP205) to the VDR/vitamin D response element complex. These data indicate that Hr functions as a corepressor of VDR to block 1,25(OH)2D3 action on keratinocytes.
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Apprato, Giulia, Camilla Fiz, Isabella Fusano, Loredana Bergandi, and Francesca Silvagno. "Natural Epigenetic Modulators of Vitamin D Receptor." Applied Sciences 10, no. 12 (June 14, 2020): 4096. http://dx.doi.org/10.3390/app10124096.
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Vitamin D plays an important role in every tissue due to its differentiating properties and the control of calcium homeostasis. The reversion of the epigenetic repression of the vitamin D receptor (VDR) could lead to an increased sensitivity of the cells to the beneficial activity of the hormone and could be exploited in many vitamin D-resistant diseases. In this study we analyzed the effects of three natural epigenetic modulators: sulforaphane, curcumin, and the products of the fermentative activity of probiotics. Sulforaphane and curcumin are inhibitors of the DNA methyltransferases (DNMT) and of the histone deacetylases (HDAC); it has been demonstrated that sulforaphane and curcumin increase VDR expression in intestinal epithelial cells and in a human liver cancer cell line, respectively. The anti-inflammatory properties associated with the probiotic administration in vivo can be linked to the increased activity of intestinal VDR. Butyrate, an inhibitor of HDAC and a known modulator of VDR expression, is the candidate byproduct of fermentation by gut microbiome that could mediate the enhanced expression of VDR triggered by probiotics in vivo. Many other natural compounds wait to be investigated and recognized as epigenetic modulators of VDR, thus opening promising therapeutic avenues for many diseases by natural means.
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Tsoumpra, Maria K., Shun Sawatsubashi, Michihiro Imamura, Seiji Fukumoto, Shin’ichi Takeda, Toshio Matsumoto, and Yoshitsugu Aoki. "Dystrobrevin alpha gene is a direct target of the vitamin D receptor in muscle." Journal of Molecular Endocrinology 64, no. 3 (April 2020): 195–208. http://dx.doi.org/10.1530/jme-19-0229.
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The biologically active metabolite of vitamin D, 1,25-dihydroxyvitamin D3 (VD3), exerts its tissue-specific actions through binding to its intracellular vitamin D receptor (VDR) which functions as a heterodimer with retinoid X receptor (RXR) to recognize vitamin D response elements (VDRE) and activate target genes. Upregulation of VDR in murine skeletal muscle cells occurs concomitantly with transcriptional regulation of key myogenic factors upon VD3 administration, reinforcing the notion that VD3 exerts beneficial effects on muscle. Herein we elucidated the regulatory role of VD3/VDR axis on the expression of dystrobrevin alpha (DTNA), a member of dystrophin-associated protein complex (DAPC). In C2C12 cells, Dtna and VDR gene and protein expression were upregulated by 1–50 nM of VD3 during all stages of myogenic differentiation. In the dystrophic-derived H2K-mdx52 cells, upregulation of DTNA by VD3 occurred upon co-transfection of VDR and RXR expression vectors. Silencing of MyoD1, an E-box binding myogenic transcription factor, did not alter the VD3-mediated Dtna induction, but Vdr silencing abolished this effect. We also demonstrated that VD3 administration enhanced the muscle-specific Dtna promoter activity in presence of VDR/RXR only. Through site-directed mutagenesis and chromatin immunoprecipitation assays, we have validated a VDRE site in Dtna promoter in myogenic cells. We have thus proved that the positive regulation of Dtna by VD3 observed during in vitro murine myogenic differentiation is VDR mediated and specific. The current study reveals a novel mechanism of VDR-mediated regulation for Dtna, which may be positively explored in treatments aiming to stabilize the DAPC in musculoskeletal diseases.
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Howarth, Deanna L., Sheran H. W. Law, Benjamin Barnes, Julie M. Hall, David E. Hinton, Linda Moore, Jodi M. Maglich, John T. Moore, and Seth W. Kullman. "Paralogous Vitamin D Receptors in Teleosts: Transition of Nuclear Receptor Function." Endocrinology 149, no. 5 (February 7, 2008): 2411–22. http://dx.doi.org/10.1210/en.2007-1256.
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The availability of multiple teleost (bony fish) genomes is providing unprecedented opportunities to understand the diversity and function of gene duplication events using comparative genomics. Here we describe the cloning and functional characterization of two novel vitamin D receptor (VDR) paralogs from the freshwater teleost medaka (Oryzias latipes). VDR sequences were identified through mining of the medaka genome database in which gene organization and structure was determined. Two distinct VDR genes were identified in the medaka genome and mapped to defined loci. Each VDR sequence exhibits unique intronic organization and dissimilar 5′ untranslated regions, suggesting they are not isoforms of the same gene locus. Phylogenetic comparison with additional teleosts and mammalian VDR sequences illustrate that two distinct clusters are formed separating aquatic and terrestrial species. Nested within the teleost cluster are two separate clades for VDRα and VDRβ. The topology of teleost VDR sequences is consistent with the notion of paralogous genes arising from a whole genome duplication event prior to teleost radiation. Functional characterization was conducted through the development of VDR expression vectors including Gal4 chimeras containing the yeast Gal4 DNA binding domain fused to the medaka VDR ligand binding domain and full-length protein. The common VDR ligand 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3] resulted in significant transactivation activity with both the Gal4 and full-length constructs of medaka (m) VDRβ. Comparatively, transactivation of mVDRα with 1α,25(OH)2D3 was highly attenuated, suggesting a functional divergence between these two nuclear receptor paralogs. We additionally demonstrate through coactivator studies that mVDRα is still functional; however, it exhibits a different sensitivity to 1α,25(OH)2D3, compared with VDRβ. These results suggest that in mVDRα and VDRβ have undergone a functional divergence through a process of sub- and/or neofunctionalization of VDR nuclear receptor gene pairs.
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Gascoyne, Duncan M., Linden Lyne, Hayley Spearman, Francesca M. Buffa, Elizabeth J. Soilleux, and Alison H. Banham. "Vitamin D Receptor Expression in Plasmablastic Lymphoma and Myeloma Cells Confers Susceptibility to Vitamin D." Endocrinology 158, no. 3 (December 21, 2016): 503–15. http://dx.doi.org/10.1210/en.2016-1802.
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Abstract Plasmablastic B-cell malignancies include plasmablastic lymphoma and subsets of multiple myeloma and diffuse large B-cell lymphomaDLBCL. These diseases can be difficult to diagnose and treat, and they lack well-characterized cell line models. Here, immunophenotyping and FOXP1 expression profiling identified plasmablastic characteristics in DLBCL cell lines HLY-1 and SU-DHL-9, associated with CTNNAL1, HPGD, RORA, IGF1, and/or vitamin D receptor (VDR) transcription. We demonstrated VDR protein expression in primary plasmablastic tumor cells and confirmed in cell lines expression of both VDR and the metabolic enzyme CYP27B1, which catalyzes active vitamin D3 production. Although Vdr and Cyp27b1 transcription in normal B cells were activated by interleukin 4 (IL-4) and CD40 signaling, respectively, unstimulated malignant plasmablastic cells lacking IL-4 expressed both VDR and CYP27B1. Positive autoregulation evidenced intact VDR function in all plasmablastic lines, and inhibition of growth by active vitamin D3 was both dependent on MYC protein inhibition and could be enhanced by cotreatment with a synthetic ROR ligand SR-1078. Furthermore, a VDR polymorphism, FOK1, was associated with greater vitamin D3–dependent growth inhibition. In summary, HLY-1 provides an important model of strongly plasmablastic lymphoma, and disruption of VDR pathway activity may be of therapeutic benefit in both plasmablastic lymphoma and myeloma.
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Bikle, Daniel D. "Vitamin D receptor, a tumor suppressor in skin." Canadian Journal of Physiology and Pharmacology 93, no. 5 (May 2015): 349–54. http://dx.doi.org/10.1139/cjpp-2014-0367.
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Vitamin D and calcium are well-established regulators of keratinocyte proliferation and differentiation. Therefore, it was not a great surprise that deletion of the vitamin D receptor (VDR) should predispose the skin to tumor formation, and that the combination of deleting both the VDR and calcium sensing receptor (CaSR) should be especially pro-oncogenic. In this review I have examined 4 mechanisms that appear to underlie the means by which VDR acts as a tumor suppressor in skin. First, DNA damage repair is curtailed in the absence of the VDR, allowing mutations in DNA to accumulate. Second and third involve the increased activation of the hedgehog and β-catenin pathways in the epidermis in the absence of the VDR, leading to poorly regulated proliferation with reduced differentiation. Finally, VDR deletion leads to a shift in the expression of long noncoding RNAs toward a more oncogenic profile. How these different mechanisms interact and their relative importance in the predisposition of the VDR null epidermis to tumor formation remain under active investigation.
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Abdurahman, Ahmed Abdulahi, Leila Khorrami-nezhad, and Khadijeh Mirzaei. "Vitamin D (FokI) Receptor Gene Polymorphism is associated with Vitamin D Deficiency and Chronic Musculoskeletal Pain. A meta-analysis." International Journal for Vitamin and Nutrition Research 87, no. 3-4 (May 1, 2017): 219–32. http://dx.doi.org/10.1024/0300-9831/a000569.
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Abstract. Background: Musculoskeletal pain is the most common chronic pain experienced by older adults. The aim of this study is to explore the associations between vitamin D (FOKI) receptor gene polymorphism (VDR) and vitamin D deficiency (VDD) and chronic musculoskeletal pain. Methods: Cross-sectional studies published in English from January 2000 to January 2015which reported prevalence of chronic pain (CP) and chronic musculoskeletal pain (CMP) were included in this systematic review and meta-analysis. A heat map was used to visualize and observe the correlation between VDR and CMP, CP and VDD. Results: 20 studies (N = 216,365) were included in the analysis, which showed an overall pooled prevalence estimate of CMP and CP as 30.6 per 100 (95 % CI: 30.59, 30.69) and 27.9 per 100 (95 % CI: 27.68, 28.24) respectively. The heat map clustering analysis visualizes the similarity between CP and CMP. Moreover, a direct correlation was observed between the three disease conditions (namely CMP, CP, and VDD) and FokI VDR polymorphism (FF). Spearman’s correlation analyses with adjusted r2 revealed that there is a statistically significant interaction effect of the FF genotype and VDD on CMP (r2 = 0.19, p = 0.03), a marginally significant interaction effect of the ff genotype and VDD on CMP (r2 = 0.11, p = 0.08). VDD was also associated with increased CMP (r2 = 0.19, p = 0.028). The pooled estimates of the prevalence of CMP in this review were found to be high. Conclusion: FokI VDR gene polymorphism (FF) plays an important role in the relationship between VDD and CMP.
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Lei, Min, Zhangsuo Liu, and Jia Guo. "The Emerging Role of Vitamin D and Vitamin D Receptor in Diabetic Nephropathy." BioMed Research International 2020 (July 13, 2020): 1–8. http://dx.doi.org/10.1155/2020/4137268.
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Diabetic nephropathy (DN), one of the most common and severe microvascular complications of diabetes mellitus (DM), is an important risk factor for DM patient’s death. Nowadays, DN has become the leading cause of end-stage renal disease (ESRD) in most countries without effective therapeutic methods. Recently, the renoprotective effects mediated by vitamin D (VD) and vitamin D receptor (VDR) have been evidenced. VD, a kind of steroid with the active form 1,25(OH)2D3, has been known for the crucial roles in the modulation of serum calcium and phosphorus concentrations. It exerts important functions by binding with its receptor VDR.VDR, a transcription factor located at chromosome 12 containing 9 exons, is one of the nonsteroid nuclear hormone receptor superfamily, which participates in transcriptional regulation of genes in tissue- and cell-specific ways. Increasing evidences have demonstrated that VD/VDR signaling pathway possesses a variety of kidney-protective effects in DN patients, such as antiproteinuria, antifibrosis, anti-inflammatory, and preventing podocyte damage. Although there are many studies on the role of the VD/VDR signaling pathway in DN, the effects and mechanisms still need to be further explained. This review summarized the multiple roles of VD/VDR in podocyte injury, tubule lesions, interstitial fibrosis, and inflammation, as well as the clinical applications about DN to explore much more and effective therapeutic methods for DN.
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Al-Ghafari, Ayat B., Khadijah S. Balamash, and Huda A. Al Doghaither. "Relationship between Serum Vitamin D and Calcium Levels and Vitamin D Receptor Gene Polymorphisms in Colorectal Cancer." BioMed Research International 2019 (August 26, 2019): 1–7. http://dx.doi.org/10.1155/2019/8571541.
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Background. Many epidemiological studies have shown that vitamin D deficiency is associated with various types of human cancers. The biological action of vitamin D and its metabolites is mediated by the transcription factor vitamin D receptor (VDR). The VDR gene is highly expressed in the colon and is involved in many biological functions. The aim of the current study was to assess the relationship between serum vitamin D metabolite and calcium levels with VDR polymorphisms in normal and colorectal cancer (CRC) patients. Methods. Fifty Saudi CRC patients and fifty controls were enrolled in the study. The levels of total vitamin D, 25(OH)D3, and calcium were measured in serum. Results. The homozygous genotype (aa) of the ApaI VDR polymorphism (rs7975232) was found to correlate with total serum vitamin D levels of CRC patients, while the heterozygous (Tt) TaqI VDR polymorphism (rs731236) was associated with serum calcium levels. In contrast, the BsmI and FokI VDR polymorphisms (rs1544410 and rs2228570, resp.) did not affect the serum levels of total vitamin D, 25-hydroxyvitamin D3, and calcium. Conclusion. Appropriate vitamin D levels were shown to be important in preventing the onset of CRC.
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Erdoğan, Murat, and Hüseyin Avni Fındıklı. "Novel biomarker for predicting sepsis mortality: vitamin D receptor." Journal of International Medical Research 49, no. 8 (August 2021): 030006052110347. http://dx.doi.org/10.1177/03000605211034733.
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Objective There are currently no studies on the role of vitamin D receptor (VDR) levels as a cause of or risk factor for sepsis. We aimed to establish the association between VDR levels and 28-day mortality in critically ill patients with sepsis. Methods This prospective cross-sectional observational study included 148 patients diagnosed with sepsis who were treated in the intensive care unit. We measured VDR levels, laboratory characteristics, and health scores and related them to survival. Results The 148 patients included 96 survivors and 52 non-survivors, with VDR levels of 1.92 and 1.36 ng/mL, respectively. Baseline VDR was a significant predictor of 28-day mortality, with an area under the curve of 0.778. A low VDR level was significantly associated with lower overall survival in patients with sepsis according to Kaplan–Meier curve analysis. VDR levels were also negatively correlated with lactate, C-reactive protein, acute physiological and clinical health evaluation (APACHE) II and sequential organ failure assessment (SOFA) scores, and disease severity. Conclusions VDR levels were associated with high 28-day mortality and negatively correlated with lactate, C-reactive protein, APACHE II and SOFA scores, and disease severity in patients with sepsis. VDR levels can predict poor outcomes in patients with sepsis.
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Rojanasrirat, Napatsanant, Somsak Suthutvoravut, Pattamawadee Yanatatsaneejit, and Anna Wongkularb. "Association Between Vitamin D Levels and Vitamin D Receptor FokI Polymorphism in Thai Postmenopausal Women With Osteoporosis." Ramathibodi Medical Journal 44, no. 1 (March 26, 2021): 1–10. http://dx.doi.org/10.33165/rmj.2021.44.1.246575.
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Background: Osteoporosis is a complex genetic disease, which is common among postmenopausal women. It is characterized by decreased bone mineral density (BMD) and increased bone fragility and fractures.
Objective: To study the association between serum vitamin D levels and vitamin D receptor (VDR) genetic FokI polymorphism in postmenopausal women with osteoporosis.
Methods: A total of 60 postmenopausal women who came for treatment at the menopausal clinic at Ramathibodi Hospital were enrolled. All of the patients had their BMD measured, and were determined serum vitamin D levels and VDR FokI polymorphism. Data were analyzed using chi-square and Fisher exact tests. The frequency of single nucleotide polymorphism (SNP) with risk of osteoporosis was compared.
Results: Among 60 postmenopausal women, 26 (43.3%) women were an osteoporotic group and 34 (56.7%) women were non-osteoporotic group. There were no significant differences in age, vitamin D levels, or VDR FokI polymorphism between the groups (P > .05). However, the TT genotype of VDR FokI polymorphism was significantly associated with vitamin D deficiency (< 20 ng/mL) (OR, 6.15; 95% CI, 1.51 - 25.14; P < .05).
Conclusions: Vitamin D levels and genotype of VDR FokI polymorphisms were similar between the osteoporotic and non-osteoporotic postmenopausal women. The TT genotype of VDR FokI polymorphism showed a significant association with vitamin D deficiency. Therefore, TT genotype of VDR FokI polymorphism may be used to predict risk of vitamin D deficiency.
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Tekeli, Seçkin Özgür, Feyza Yağmur Tekeli, Onur Erol, Hamit Yaşar Ellidag, Esin Eren, and Necat Yılmaz. "Serum vitamin D receptor levels in gestational diabetes mellitus." LaboratoriumsMedizin 42, no. 4 (August 28, 2018): 149–54. http://dx.doi.org/10.1515/labmed-2017-0149.
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AbstractBackgroundVitamin D affects glucose metabolism by increasing insulin secretion and insulin receptor expression. Also, it exerts these effects by binding to its primary receptor, the vitamin D receptor (VDR). In this preliminary study, we aimed to examine serum 25-(OH) vitamin D3and serum VDR levels in gestational diabetes mellitus (GDM) patients.MethodsBlood samples were obtained during 24–28 weeks of pregnancy from patients with GDM (n=30) and age, body mass index (BMI), and gestational age-matched control subjects (n=33). Both groups were examined for changes in the levels of glucose, insulin, glycated hemoglobin (bA1c), 25-(OH) vitamin D3and VDR.ResultsThere were no significant differences in serum 25-(OH) vitamin D3and fasting insulin levels between the control and GDM groups (p=0.115, p=0.182). But serum VDR levels were significantly higher in the GDM group than in the control group (p=0.001).ConclusionsAlthough there was no significant difference between the two groups regarding 25-(OH) vitamin D3levels, it is notable that VDR levels were higher in GDM patients. To further define the role of vitamin D in the prophylaxis and treatment of GDM, it may be useful to conduct more extensive studies on VDR.
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Karmila, Ariesta, Muhammad Nazir, Kiagus Yangtjik, and Yuwono Yuwono. "Serum vitamin D and vitamin D receptor gene FokI polymorphisms in children with tuberculosis." Paediatrica Indonesiana 55, no. 5 (October 1, 2015): 263. http://dx.doi.org/10.14238/pi55.5.2015.263-7.
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Background Vitamin D deficiency and vitamin D receptor (VDR) gene polymorphisms are strongly associated with tuberculosis (TB) susceptibility in countries with four seasons. As a country with sufficient sunlight for vitamin D production in skin, the incidence of TB in Indonesia remains high. Objective To assess for possible associations between the incidence of tuberculosis and serum vitamin D level, as well as VDR FokI polymorphisms in children. Methods A case-control study was conducted at the Department of Child Health, Dr. Mohammad Hoesin Hospital, Palembang from November 2011 to April 2012. Subjects were children with TB (the case) and children without TB who had been exposed to TB in the home (the control). Serum vitamin D [1,25(OH)2D3 or calcitriol] level was measured by immunodiagnostic system (IDS) 1,25-dihydroxy vitamin D enzyme immunoassay (EIA) kit. The VDR FokI polymorphisms were identified by polymerase chain reaction (PCR) and restriction-fragment length polymorphism (RFLP) analysis. Results Sixty subjects was divided equally into the case and control groups. The mean serum calcitriol level in the case group was significantly lower than that of the control group [105.5 (SD 66.9) pmol/L vs. 162.9 (SD 52.9) pmol/L, respectively; (P=0.001)]. We found 9 subjects with calcitriol deficiency, 8 in the TB group and 1 in the healthy contact group (OR 10.5; 95%CI 1.2 to 90.7) The VDR FokI polymorphism was seen in 28 subjects in the case group and 22 in the control group (OR 5.0; 95%CI 0.9 to 26.4). Conclusion Vitamin D (calcitriol) deficiency and lower serum levels are associated with higher risk of TB in children. The VDR gene FokI polymorphism also contributes to susceptibility for TB.
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Mayer, Otto, Jitka Seidlerová, Václava Černá, Alena Kučerová, Petra Karnosová, Markéta Hronová, Peter Wohlfahrt, et al. "Serum Vitamin D Status, Vitamin D Receptor Polymorphism, and Glucose Homeostasis in Healthy Subjects." Hormone and Metabolic Research 50, no. 01 (November 28, 2017): 56–64. http://dx.doi.org/10.1055/s-0043-122144.
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AbstractLow vitamin D status has been frequently associated with impaired glucose metabolism. We examined associations between 25-hydroxyvitamin D (25-OH-D) and several parameters of glucose homeostasis in virtually healthy subjects, and explored possible interaction with vitamin D receptor (VDR) polymorphism. Nondiabetic subjects without chronic medication or any known significant manifest disease were selected from large general-population based population survey. Insulin sensitivity and β cell secretion were calculated by homeostasis model assessment (HOMA) and soluble isoform of receptor for advanced glycation end-products (sRAGE) using commercial ELISA. Subjects were also genotyped for rs2228570 polymorphism of VDR. After adjustment for potential confounders, we observed a significant relationship between 25-OH-D and fasting glycemia (β coefficient=–5.904; p=0.002) or insulin sensitivity (β=0.042; p=0.001), but not with β cell secretion or sRAGE. We found also an interaction with VDR polymorphism. Subjects with low 25-OH-D and AA genotype had significantly lower insulin sensitivity than those with GG genotype plus highest 25-OH-D concentrations (107.3% vs. 183.9%, p=0.021). In conclusion, low vitamin D status was in virtually healthy subjects associated with decreased insulin sensitivity, namely in those with GG genotype of rs2228570 VDR polymorphism.
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Brożyna, Anna A., Tae-Kang Kim, Marzena Zabłocka, Wojciech Jóźwicki, Junming Yue, Robert C. Tuckey, Anton M. Jetten, and Andrzej T. Slominski. "Association among Vitamin D, Retinoic Acid-Related Orphan Receptors, and Vitamin D Hydroxyderivatives in Ovarian Cancer." Nutrients 12, no. 11 (November 19, 2020): 3541. http://dx.doi.org/10.3390/nu12113541.
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Vitamin D and its derivatives, acting via the vitamin D receptor (VDR) and retinoic acid-related orphan receptors γ and α (RORγ and RORα), show anticancer properties. Since pathological conditions are characterized by disturbances in the expression of these receptors, in this study, we investigated their expression in ovarian cancers (OCs), as well as explored the phenotypic effects of vitamin D hydroxyderivatives and RORγ/α agonists on OC cells. The VDR and RORγ showed both a nuclear and a cytoplasmic location, and their expression levels were found to be reduced in the primary and metastatic OCs in comparison to normal ovarian epithelium, as well as correlated to the tumor grade. This reduction in VDR and RORγ expression correlated with a shorter overall disease-free survival. VDR, RORγ, and RORα were also detected in SKOV-3 and OVCAR-3 cell lines with increased expression in the latter line. 20-Hydroxy-lumisterol3 (20(OH)L3) and synthetic RORα/RORγ agonist SR1078 inhibited proliferation only in the OVCAR-3 line, while 20-hydroxyvitamin-D3 (20(OH)D3) only inhibited SKOV-3 cell proliferation. 1,25(OH)2D3, 20(OH)L3, and SR1078, but not 20(OH)D3, inhibited spheroid formation in SKOV-3 cells. In summary, decreases in VDR, RORγ, and RORα expression correlated with an unfavorable outcome for OC, and compounds targeting these receptors had a context-dependent anti-tumor activity in vitro. We conclude that VDR and RORγ expression can be used in the diagnosis and prognosis of OC and suggest their ligands as potential candidates for OC therapy.
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Prüfer, Kirsten, and Julia Barsony. "Retinoid X Receptor Dominates the Nuclear Import and Export of the Unliganded Vitamin D Receptor." Molecular Endocrinology 16, no. 8 (August 1, 2002): 1738–51. http://dx.doi.org/10.1210/me.2001-0345.
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Abstract Liganded and unliganded vitamin D receptors (VDRs) carry out distinct functions; both types of functions require heterodimerization with retinoid X receptors (RXRs). Our recent studies with fluorescent protein chimeras of VDR and RXR, termed GFP-VDR, YFP-RXR, and RXR-BFP, indicated that RXR regulates VDR functions in part by regulating subcellular localization. Here we explored the mechanisms of this regulation. Photobleaching experiments demonstrated that YFP-RXR and both unliganded and liganded GFP-VDR shuttle constantly between nucleus and cytoplasm. To characterize RXR import, we identified a nuclear localization sequence (NLS) in the DNA-binding domain. Mutations in this NLS caused predominant cytoplasmic localization of nlsYFP-RXR and prevented transcriptional activity. The nlsRXR-BFP retained unliganded GFP-VDR in the cytoplasm and reduced baseline transcriptional activity. After calcitriol exposure, however, both GFP-VDR and nlsRXR-BFP entered the nucleus. We characterized receptor export rates and mechanisms using permeabilization experiments. Mutations in the calreticulin binding region slowed both GFP-VDR and YFP-RXR export. Coexpression of RXR-BFP slowed the export of unliganded GFP-VDR, whereas calcitriol treatment tripled the rate of GFP-VDR export. Treatment with leptomycin B, an inhibitor of CRM-1 receptor-mediated export, inhibited export of unliganded GFP-VDR but did not influence export of liganded GFP-VDR or YFP-RXR. Leptomycin B added before calcitriol similarly decreased hormone-induced luciferase activity but was ineffective when added subsequent to calcitriol. These results indicate that the unliganded and liganded VDR interact differently with the import and export receptors and with RXR. Most likely, the regulation of VDR nuclear import by RXR is essential for ligand-independent functions.
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Lin, Lin, Lei Zhang, Chao Li, Zhibo Gai, and Yunlun Li. "Vitamin D and Vitamin D Receptor: New Insights in the Treatment of Hypertension." Current Protein & Peptide Science 20, no. 10 (September 20, 2019): 984–95. http://dx.doi.org/10.2174/1389203720666190807130504.
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Vitamin D, as a natural medicine, is known to regulate calcium and phosphate homeostasis. But abundant research has shown that vitamin D also plays a regulatory role in autoimmunity, inflammation, angiogenesis and vascular cell activity. Since the vitamin D receptor (VDR) is widely distributed in vascular endothelial cells, vascular smooth muscle cells and cardiomyocytes, the role of vitamin D and VDR in hypertension has received extensive attention. Hypertension is a disease with high incidence and high cardiovascular risk. In recent years, both clinical trials and animal experiments have shown that vitamin D plays a regulatory role in decreasing blood pressure (BP) through inhibiting renin-angiotensin-aldosterone system activity, modulating function of vascular wall and reducing vascular oxidative stress. A growing body of data suggest that vitamin D deficiency is associated with increased cardiovascular disease risk in hypertension, even short-term vitamin D deficiency may directly raise BP and promote target organ damage. Due to the high correlation between vitamin D and hypertension, vitamin D supplementation therapy may be a new insight in the treatment of hypertension. The aim of this review will explore the mechanisms of the vitamin D and VDR in regulating the BP and protecting against the target organ damage.
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de la Fuente, Alerie Guzman, Oihana Errea, Peter van Wijngaarden, Ginez A. Gonzalez, Christophe Kerninon, Andrew A. Jarjour, Hilary J. Lewis, et al. "Vitamin D receptor–retinoid X receptor heterodimer signaling regulates oligodendrocyte progenitor cell differentiation." Journal of Cell Biology 211, no. 5 (December 7, 2015): 975–85. http://dx.doi.org/10.1083/jcb.201505119.
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The mechanisms regulating differentiation of oligodendrocyte (OLG) progenitor cells (OPCs) into mature OLGs are key to understanding myelination and remyelination. Signaling via the retinoid X receptor γ (RXR-γ) has been shown to be a positive regulator of OPC differentiation. However, the nuclear receptor (NR) binding partner of RXR-γ has not been established. In this study we show that RXR-γ binds to several NRs in OPCs and OLGs, one of which is vitamin D receptor (VDR). Using pharmacological and knockdown approaches we show that RXR–VDR signaling induces OPC differentiation and that VDR agonist vitamin D enhances OPC differentiation. We also show expression of VDR in OLG lineage cells in multiple sclerosis. Our data reveal a role for vitamin D in the regenerative component of demyelinating disease and identify a new target for remyelination medicines.
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Ashcroft, Stephen P., Joseph J. Bass, Abid A. Kazi, Philip J. Atherton, and Andrew Philp. "The vitamin D receptor regulates mitochondrial function in C2C12 myoblasts." American Journal of Physiology-Cell Physiology 318, no. 3 (March 1, 2020): C536—C541. http://dx.doi.org/10.1152/ajpcell.00568.2019.
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Vitamin D deficiency has been linked to a reduction in skeletal muscle function and oxidative capacity; however, the mechanistic bases of these impairments are poorly understood. The biological actions of vitamin D are carried out via the binding of 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) to the vitamin D receptor (VDR). Recent evidence has linked 1α,25(OH)2D3 to the regulation of skeletal muscle mitochondrial function in vitro; however, little is known with regard to the role of the VDR in this process. To examine the regulatory role of the VDR in skeletal muscle mitochondrial function, we used lentivirus-mediated shRNA silencing of the VDR in C2C12 myoblasts (VDR-KD) and examined mitochondrial respiration and protein content compared with an shRNA scrambled control. VDR protein content was reduced by ~95% in myoblasts and myotubes ( P < 0.001). VDR-KD myoblasts displayed a 30%, 30%, and 36% reduction in basal, coupled, and maximal respiration, respectively ( P < 0.05). This phenotype was maintained in VDR-KD myotubes, displaying a 34%, 33%, and 48% reduction in basal, coupled, and maximal respiration ( P < 0.05). Furthermore, ATP production derived from oxidative phosphorylation (ATPOx) was reduced by 20%, suggesting intrinsic impairments within the mitochondria following VDR-KD. However, despite the observed functional decrements, mitochondrial protein content, as well as markers of mitochondrial fission were unchanged. In summary, we highlight a direct role for the VDR in regulating skeletal muscle mitochondrial respiration in vitro, providing a potential mechanism as to how vitamin D deficiency might impact upon skeletal muscle oxidative capacity.
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Futawaka, Kumi, Tetsuya Tagami, Yuki Fukuda, Rie Koyama, Ayaka Nushida, Shoko Nezu, Hironori Yamamoto, Miyuki Imamoto, Masato Kasahara, and Kenji Moriyama. "Transcriptional activation of the wild-type and mutant vitamin D receptors by vitamin D3 analogs." Journal of Molecular Endocrinology 57, no. 1 (July 2016): 23–32. http://dx.doi.org/10.1530/jme-16-0048.
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The active form of vitamin D3 (1α,25(OH)2D3, also known as calcitriol) controls the expression of target genes via the vitamin D receptor (VDR). Vitamin D-dependent rickets type II (VDDRII) is a congenital disease caused by inactivating mutations in the VDR. The condition is treated with high doses of calcitriol, but the therapeutic effects of other synthetic VD3 analogs have not yet been investigated. In the present study, we analyzed the transcriptional activity of seven different VD3 analogs with VDRs carrying ligand-binding domain mutations identified in VDDRII patients. Wild-type VDR (WT-VDR) and seven mutant VDRs were expressed in TSA201 human embryonic kidney cells, HepG2 human liver cancer cells, and MC3T3-E1 mouse calvaria cells, and their transcriptional activation with VD3 analogs were analyzed by performing transient expression assays, western blotting, and quantitative real-time PCR. The results demonstrated that falecalcitriol stimulated significantly higher transcriptional activation of the WT-VDR and some mutant VDRs than did calcitriol. Calcitriol showed almost no transcriptional activation of the VDR with the I268T mutation identified in a severe case of VDDRII, whereas falecalcitriol caused a dose-dependent increase in the activation of this mutant VDR. Our findings demonstrate that falecalcitriol has a VDR activation profile distinct from that of calcitriol and may exhibit therapeutic effects even on difficult-to-treat VDDRII cases resistant to calcitriol. It is also possible that VDDRII patients responding to high doses of calcitriol could be appropriately treated with low doses of falecalcitriol.
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Saini, Amarjit, Linda Björkhem-Bergman, Johan Boström, Mats Lilja, Michael Melin, Karl Olsson, Lena Ekström, et al. "Impact of vitamin D and vitamin D receptor TaqI polymorphism in primary human myoblasts." Endocrine Connections 8, no. 7 (July 2019): 1070–81. http://dx.doi.org/10.1530/ec-19-0194.
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The CC genotype of the vitamin D receptor (VDR) polymorphism TaqI rs731236 has previously been associated with a higher risk of developing myopathy compared to TT carriers. However, the mechanistic role of this polymorphism in skeletal muscle is not well defined. The effects of vitamin D on patients genotyped for the VDR polymorphism TaqI rs731236, comparing CC and TT carriers were evaluated. Primary human myoblasts isolated from 4 CC carriers were compared with myoblasts isolated from four TT carriers and treated with vitamin D in vitro. A dose-dependent inhibitory effect on myoblast proliferation and differentiation was observed concurrent with modifications of key myogenic regulatory factors. RNA sequencing revealed a vitamin D dose–response gene signature enriched with a higher number of VDR-responsive elements (VDREs) per gene. Interestingly, the greater the expression of muscle differentiation markers in myoblasts, the more pronounced was the vitamin D-mediated response to suppress genes associated with myogenic fusion and myotube formation. This novel finding provides a mechanistic explanation to the inconsistency regarding previous reports of the role of vitamin D in myoblast differentiation. No effects in myoblast proliferation, differentiation or gene expression were related to CC vs TT carriers. Our findings suggest that the VDR polymorphism TaqI rs731236 comparing CC vs TT carriers did not influence the effects of vitamin D on primary human myoblasts and that vitamin D inhibits myoblast proliferation and differentiation through key regulators of cell cycle progression. Future studies need to employ strategies to identify the primary responses of vitamin D that drive the cellular response towards quiescence.
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Malloy, Peter J., and David Feldman. "Inactivation of the Human Vitamin D Receptor by Caspase-3." Endocrinology 150, no. 2 (February 1, 2009): 679–86. http://dx.doi.org/10.1210/en.2008-1217.
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Calcitriol actions are mediated by the vitamin D receptor (VDR), a nuclear transcription factor of the steroid-retinoid-thyroid nuclear receptor gene superfamily. Calcitriol inhibits the growth of many cells including cancer cells by inducing cell cycle arrest. In some cancer cell lines, calcitriol also induces apoptosis. In the LNCaP prostate cancer cell line, induction of apoptosis and caspase-3/7 activities by staurosporine (STS) abolished [3H]1,25-dihydroxy vitamin D3 binding and VDR protein, suggesting that the VDR may be targeted for inactivation by caspases during apoptosis. A potential caspase-3 site (D195MMD198S) was identified in the human VDR ligand-binding domain. Mutations D195A, D198A, and S199A were generated in the putative capase-3 cleavage site. In transfected COS-7 cells, STS treatment resulted in the cleavage of the wild-type (WT) VDR and S199A mutant VDR but not the D195A or D198A mutants. In in vitro assays, the WT VDR and S199A mutant VDR were cleaved by caspase-3, although the D195A and D198A mutants were resistant to caspase-3. In vitro, the WT VDR was also cleaved by caspase-6 and caspase-7 and in extracts of STS-treated LNCaP cells. In STS-treated LNCaP cells and human skin fibroblasts, the proteasome inhibitor MG-132 protected the VDR caspase cleavage fragment from further degradation by the 26S proteasome. The rat VDR that does not contain the caspase-3 cleavage site was not cleaved in STS-treated COS-7 cells. In conclusion, our results demonstrate that the human VDR is a target of caspase-3 and suggest that activation of caspase-3 may limit VDR activity. The vitamin D receptor contains a caspase-3 cleavage site in the ligand-binding domain that can be cleaved by caspase-3 in vitro and in intact cells.
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Garcia-Villalba, P., A. M. Jimenez-Lara, and A. Aranda. "Vitamin D interferes with transactivation of the growth hormone gene by thyroid hormone and retinoic acid." Molecular and Cellular Biology 16, no. 1 (January 1996): 318–27. http://dx.doi.org/10.1128/mcb.16.1.318.
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The thyroid hormone, retinoic acid (RA), and vitamin D regulate gene expression by binding to similar receptors which act as ligand-inducible transcription factors. Incubation of pituitary GH4C1 cells with nanomolar concentrations of vitamin D markedly reduces the response of the rat growth hormone mRNA to thyroid hormone triiodothyronine (T3) and RA. The stimulation of growth hormone gene expression by both ligands is mediated by a common hormone response element (TREGH) present in the 5'-flanking region of the gene, and the inhibition caused by vitamin D is due to transcriptional interference of the vitamin D receptor on this DNA element. No inhibition of the basal promoter activity by the vitamin was observed. The response to T3 and RA of a heterologous promoter containing this element, the palindromic T3- and RA-responsive sequence TREPAL, or a direct repeat of the same motif is also inhibited by vitamin D. In contrast, vitamin D strongly induces the activity of constructs containing a vitamin D response element, and neither T3 nor RA reduces vitamin D-mediated transactivation. Transfection with an expression vector for the retinoid X receptor alpha (RXR alpha) increases transactivation by T3 and RA but does not abolish the inhibition caused by the vitamin. Gel retardation experiments show that the vitamin D receptor (VDR) as a heterodimer with RXR weakly binds to the T3- and RA-responsive elements. Additionally, VDR displaces binding of T3 and RA receptors in a dose-dependent manner. Our data suggest the formation of TR-VDR and RAR-VDR heterodimers with RXR. The fact that the same response element mediates opposite effects of at least four different nuclear receptors provides a greater complexity and flexibility of the transcriptional responses to their ligands.
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Kwon, Hye-Joo. "Vitamin D Receptor Signaling Regulates Craniofacial Cartilage Development in Zebrafish." Journal of Developmental Biology 7, no. 2 (June 22, 2019): 13. http://dx.doi.org/10.3390/jdb7020013.
Full textAbstract:
Vitamin D plays essential roles in supporting the skeletal system. The active form of vitamin D functions through the vitamin D receptor (VDR). A hereditary vitamin-D-resistant rickets with facial dysmorphism has been reported, but the involvement of VDR signaling during early stages of craniofacial development remains to be elucidated. The present study investigated whether VDR signaling is implicated in zebrafish craniofacial cartilage development using a morpholino-based knockdown approach. Two paralogous VDR genes, vdra and vdrb, have been found in zebrafish embryos. Loss-of-vdra has no discernible effect on cartilage elements, whereas loss-of-vdrb causes reduction and malformation of craniofacial cartilages. Disrupting both vdra and vdrb leads to more severe defects or complete loss of cartilage. Notably, knockdown of vdrb results in elevated expression of follistatin a (fsta), a bone morphogenetic protein (BMP) antagonist, in the adjacent pharyngeal endoderm. Taken together, these findings strongly indicate that VDR signaling is required for early craniofacial cartilage development in zebrafish.
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Choi, Mihwa, Jun Ozeki, Masami Hashizume, Shigeaki Kato, Hisamitsu Ishihara, and Makoto Makishima. "Vitamin D Receptor Activation Induces Peptide YY Transcription in Pancreatic Islets." Endocrinology 153, no. 11 (November 1, 2012): 5188–99. http://dx.doi.org/10.1210/en.2012-1396.
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Abstract Peptide YY (PYY) is a peptide hormone secreted from L cells in the intestine after food intake and regulates appetite and intestinal function. PYY is also expressed in the pancreas, but the mechanisms of regulation of pancreatic PYY expression have not been elucidated. The vitamin D receptor (VDR) is a nuclear receptor for the active form of vitamin D3 and regulates numerous physiological processes. Because VDR is expressed in the pancreas, we investigated the role of pancreatic VDR activation and found that Pyy is a VDR target gene in the mouse pancreas. Treatment of mice with 1α-hydroxyvitamin D3 increased plasma PYY levels. VDR activation increased mRNA and protein expression of PYY in the pancreatic islets of mice and pancreatic endocrine cell lines but did not change intestinal PYY expression. 1α-Hydroxyvitamin D3-dependent induction of pancreatic and plasma PYY was abolished in VDR-null mice. We identified a functional vitamin D-responsive element in the mouse Pyy promoter using chromatin immunoprecipitation assay, EMSA, and luciferase promoter assay. Thus, Pyy is a tissue-specific VDR target gene. The pancreatic VDR-PYY pathway may mediate a regulatory function of vitamin D in the neuroendocrine system.
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Peräkylä, Mikael, Marjo Malinen, Karl-Heinz Herzig, and Carsten Carlberg. "Gene Regulatory Potential of Nonsteroidal Vitamin D Receptor Ligands." Molecular Endocrinology 19, no. 8 (August 1, 2005): 2060–73. http://dx.doi.org/10.1210/me.2004-0417.
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Abstract The seco-steroid 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3] is a promising drug candidate due to its pleiotropic function including the regulation of calcium homeostasis, bone mineralization and cellular proliferation, differentiation, and apoptosis. We report here a novel class of nonsteroidal compounds, represented by the bis-aromatic molecules CD4409, CD4420, and CD4528, as ligands of the 1α,25(OH)2D3 receptor (VDR). Taking the known diphenylmethane derivative LG190178 as a reference, this study provides molecular evaluation of the interaction of nonsteroidal ligands with the VDR. All four nonsteroidal compounds were shown to induce VDR-retinoid X receptor heterodimer complex formation on a 1α,25(OH)2D3 response element, stabilize the agonistic conformation of the VDR ligand-binding domain, enable the interaction of VDR with coactivator proteins and contact with their three hydroxyl groups the same residues within the ligand-binding pocket of the VDR as 1α,25(OH)2D3. Molecular dynamics simulations demonstrated that all four nonsteroidal ligands take a shape within the ligand-binding pocket of the VDR that is very similar to that of the natural ligand. CD4528 is mimicking the natural hormone best and was found to be in vitro at least five times more potent than LG190178. In living cells, CD4528 was only two times less potent than 1α,25(OH)2D3 and induced mRNA expression of the VDR target gene CYP24 in a comparable fashion. At a noncalcemic dose of 150 μg/kg, CD4528 showed in vivo a clear induction of CYP24 expression and therefore may be used as a lead compound for the development of therapeutics against psoriasis, osteoporosis, and cancer.
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Ellison, Tara I., Diane R. Dowd, and Paul N. MacDonald. "Calmodulin-Dependent Kinase IV Stimulates Vitamin D Receptor-Mediated Transcription." Molecular Endocrinology 19, no. 9 (September 1, 2005): 2309–19. http://dx.doi.org/10.1210/me.2004-0382.
Full textAbstract:
Abstract 1,25-Dihydroxyvitamin D3 [1,25-(OH)2D3] promotes intestinal absorption of calcium primarily by binding to the vitamin D receptor (VDR) and regulating gene expression. 1,25-(OH)2D3 also exerts rapid actions at the cell membrane that include increasing intracellular calcium levels and activating protein kinase cascades. To explore potential cross talk between calcium signaling elicited by the nongenomic actions of 1,25-(OH)2D3 and the genomic pathway mediated by VDR, we examined the effects of activated Ca2+/calmodulin-dependent kinases (CaMKs) on 1,25-(OH)2D3/VDR-mediated transcription. Expression of a constitutively active form of CaMKIV dramatically stimulated 1,25-(OH)2D3-activated reporter gene expression in COS-7, HeLa, and ROS17/2.8 cell lines. Metabolic labeling studies indicated that CaMKIV increased VDR phosphorylation levels. In addition, CaMKIV increased the independent transcription activity of the VDR coactivator SRC (steroid receptor coactivator) 1, and promoted ligand-dependent interaction between VDR and SRC coactivator proteins in mammalian two-hybrid studies. The functional consequences of this multifaceted mechanism of CaMKIV action were revealed by reporter gene studies, which showed that CaMKIV and select SRC coactivators synergistically enhanced VDR-mediated transcription. These studies support a model in which CaMKIV signaling stimulates VDR-mediated transcription by increasing phosphorylation levels of VDR and enhancing autonomous SRC activity, resulting in higher 1,25-(OH)2D3-dependent interaction between VDR and SRC coactivators.
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S. El-Shimi, Ola, Soheir A. Abdel Samea, Nahla M. Samy, and Sahar M. Fayed. "Association of Vitamin D Receptor Gene (FokI) (rs2228750) Polymorphism with Susceptibility to Tuberculosis." Egyptian Journal of Medical Microbiology EJMM29, no. 4 (October 1, 2020): 75–81. http://dx.doi.org/10.51429/ejmm29410.
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Background: Genetic susceptibility has been suggested as an important explanation for individual risk for tuberculosis. The association between vitamin D receptor (VDR) FokI gene polymorphisms and the risk of tuberculosis have been studied in several populations; but results were inconsistent. Objectives: This study aimed to determine the influence of vitamin D status and frequency of association of VDR FokI (rs2228570) polymorphism on susceptibility to pulmonary tuberculosis. Methodology: A case-control study was conducted between 40 pulmonary tuberculosis patients and 40 control subjects. Serum vitamin D level and VDR FokI gene (rs2228570) polymorphism were tested. Results: Tuberculosis patients had significant lower vitamin D level compared to controls (P = 0.002). Patients showed significantly higher frequencies of VDR FokI (rs2228750) Ff, ff genotypes and f allele than controls (P = 0.023, 0.014, <0.001 respectively) with significant lower vitamin D level in patients with ff compared to patients with FF or Ff genotypes (P = 0.017). Excess smoking, vitamin D insufficiency and VDR FokI (rs2228750) (Ff+ff) genotypes were found predictors for susceptibility to tuberculosis infection. Conclusion: vitamin D deficiency plays a role as a risk factor for tuberculosis and VDR FokI (rs2228750) polymorphism may be partially responsible for host susceptibility to human tuberculosis in Egyptians.
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Wu, Shaoping, Sonia Yoon, Yong-Guo Zhang, Rong Lu, Yinglin Xia, Jiandi Wan, Elaine O. Petrof, Erika C. Claud, Di Chen, and Jun Sun. "Vitamin D receptor pathway is required for probiotic protection in colitis." American Journal of Physiology-Gastrointestinal and Liver Physiology 309, no. 5 (September 1, 2015): G341—G349. http://dx.doi.org/10.1152/ajpgi.00105.2015.
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Low expression of vitamin D receptor (VDR) and dysfunction of vitamin D/VDR signaling are reported in patients with inflammatory bowel disease (IBD); therefore, restoration of VDR function to control inflammation in IBD is desirable. Probiotics have been used in the treatment of IBD. However, the role of probiotics in the modulation of VDR signaling to effectively reduce inflammation is unknown. We identified a novel role of probiotics in activating VDR activity, thus inhibiting inflammation, using cell models and VDR knockout mice. We found that the probiotics Lactobacillus rhamnosus strain GG (LGG) and Lactobacillus plantarum (LP) increased VDR protein expression in both mouse and human intestinal epithelial cells. Using the VDR luciferase reporter vector, we detected increased transcriptional activity of VDR after probiotic treatment. Probiotics increased the expression of the VDR target genes, such as antimicrobial peptide cathelicidin, at the transcriptional level. Furthermore, the role of probiotics in regulating VDR signaling was tested in vivo using a Salmonella-colitis model in VDR knockout mice. Probiotic treatment conferred physiological and histologic protection from Salmonella-induced colitis in VDR+/+mice, whereas probiotics had no effects in the VDR−/−mice. Probiotic treatment also enhanced numbers of Paneth cells, which secrete AMPs for host defense. These data indicate that the VDR pathway is required for probiotic protection in colitis. Understanding how probiotics enhance VDR signaling and inhibit inflammation will allow probiotics to be used effectively, resulting in innovative approaches to the prevention and treatment of chronic inflammation.
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Whitcomb, James P., Mary DeAgostino, Mark Ballentine, Jun Fu, Martin Tenniswood, JoEllen Welsh, Margherita Cantorna, and Mary Ann McDowell. "The Role of Vitamin D and Vitamin D Receptor in Immunity toLeishmania majorInfection." Journal of Parasitology Research 2012 (2012): 1–10. http://dx.doi.org/10.1155/2012/134645.
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Vitamin D signaling modulates a variety of immune responses. Here, we assessed the role of vitamin D in immunity to experimental leishmaniasis infection in vitamin D receptor-deficient mice (VDRKO). We observed that VDRKO mice on a genetically resistant background have decreasedLeishmania major-induced lesion development compared to wild-type (WT) mice; additionally, parasite loads in infected dermis were significantly lower at the height of infection. Enzymatic depletion of the active form of vitamin D mimics the ablation of VDR resulting in an increased resistance toL. major. Conversely, VDRKO or vitamin D-deficient mice on the susceptible Th2-biased background had no change in susceptibility. These studies indicate vitamin D deficiency, either through the ablation of VDR or elimination of its ligand, 1,25D3, leads to an increase resistance toL. majorinfection but only in a host that is predisposed for Th-1 immune responses.
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Aktürk, Tülin, Yaşar Turan, Nermin Tanik, Müjgan Ercan Karadağ, Hikmet Sacmaci, and Levent Ertugrul Inan. "Vitamin D, vitamin D binding protein, vitamin D receptor levels and cardiac dysautonomia in patients with multiple sclerosis: a cross-sectional study." Arquivos de Neuro-Psiquiatria 77, no. 12 (December 2019): 848–54. http://dx.doi.org/10.1590/0004-282x20190182.
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ABSTRACT Vitamin D is a pleiotropic steroid hormone that modulates the autonomic balance. Its deficiency has been described as an environmental risk factor for multiple sclerosis (MS). The aim of this study was to investigate the serum levels of vitamin D, vitamin D binding protein (VDBP) and vitamin D receptors (VDR) and to evaluate cardiac dysautonomia in MS patients due to bidirectional interaction between vitamin D and the autonomic nervous system. Methods: The current cross-sectional study was conducted on 26 patients with relapsing-remitting MS and on 24 healthy controls. Twenty-four-hour ambulatory blood pressure variability (BPV) was calculated and the participants were evaluated for orthostatic hypotension and supine hypertension. Serum levels of vitamin D, VDBP and VDR were measured. Results: The mean serum vitamin D level was significantly lower in MS patients than in controls (p = 0.044); however there was no significant difference in terms of VDR and VDBP levels between the groups. Supine hypertension and orthostatic hypotension were significant and the 24-hour systolic BPV was significantly decreased in patients with MS (p < 0.05) compared to controls. No correlation was found between vitamin D, VDBP and VDR with supine hypertension, orthostatic hypotension and systolic BPV values (p > 0.05). Also, there was a negative correlation between VDBP and the EDSS (p = 0.039, r = −0.406). Conclusion: There was no correlation between orthostatic hypotension, supine hypertension and systolic BPV values and serum vitamin D, VDBP and VDR in MS patients. Future prospective studies with large number of patients may help us to better understand the relationship between vitamin D and the autonomic nervous system.
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El Omri, Naoual, Fadwa Mekouar, Youssef Sekkach, Mohamed Jira, Mohamed El Qatni, Naoufal Assoufi, Salaheddine El Khader, Taoufik Amezyane, Driss Ghafir, and Rachid Eljaoudi. "Serum vitamin D and vitamin D receptor gene polymorphism in Moroccan patients with systemic lupus erythematosus." International Journal of Research in Medical Sciences 5, no. 3 (February 20, 2017): 811. http://dx.doi.org/10.18203/2320-6012.ijrms20170467.
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Background: Vitamin D plays an important role in the immunomodulation and could be involved in the development of autoimmune diseases such as systemic lupus erythematous (SLE). The study of the polymorphism of the Vitamin D Receptor (VDR) gene may be of interest in explaining the pathophysiology of SLE.Methods: In this study, we aimed to examine the characteristics of VDR gene BsmI polymorphism for the first time in Moroccan patients with SLE and their relationship with clinical manifestations of the disease. We also measured the serum level of 25-hyroxyvitamin D3 to assess its relation to such polymorphism.Results: The study included 66 SLE patients and 91 healthy controls. Our results showed that there were no differences observed in VDR genotypes and allelic distribution within the two groups. Both groups were in Hardy-Weinberg equilibrium, with no significant P values for the observed and expected genotype frequencies. 25-hyroxyvitamin D3 serum levels were the same in the two groups.Conclusions: Based on the results of the present study. We cannot verify any association between VDR gene BsmI polymorphism and SLE. This polymorphism could not be regarded as a genetic marker of the SLE. A larger study examining BsmI and other VDR gene polymorphisms is needed.
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Wang, Fuxin, Hsun-Ming Chang, Yuyin Yi, Yung-Ming Lin, Hong Li, and Peter C. K. Leung. "TGF-β1 promotes vitamin D-induced prostaglandin E2 synthesis by upregulating vitamin D receptor expression in human granulosa-lutein cells." American Journal of Physiology-Endocrinology and Metabolism 318, no. 5 (May 1, 2020): E710—E722. http://dx.doi.org/10.1152/ajpendo.00361.2019.
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There is increasing evidence showing the importance of vitamin D (Vit D) and its nuclear receptor, the Vit D receptor (VDR), in female reproductive health. Transforming growth factor-β1 (TGF-β1) and its functional receptors are expressed in human oocytes and granulosa cells that participate in follicular development and ovulation. Recently, Sma- and Mad-related protein 3 (SMAD3; a downstream effector of TGF-β1) has been proposed to mediate crosstalk between the Vit D and TGF-β1 signaling pathways, but this relationship has not been fully explored and has yet to be tested in human granulosa-lutein (hGL) cells. In this study, we showed that TGF-β1 significantly promoted the expression of VDR, and this stimulatory effect occurred through the activin receptor-like kinase 5 type I receptor-mediated SMAD3 and ERK1/2 signaling pathways in hGL cells. Additionally, we showed that Vit D increased the expression of cyclooxygenase 2 (COX-2) and the synthesis of prostaglandin E2 (PGE2) in a time- and dose-dependent manner. Furthermore, we demonstrated a synergistic effect of TGF-β1 and Vit D on the expression of COX-2 and synthesis of PGE2, and this effect could be attenuated by silencing the expression of VDR. Our findings indicate that TGF-β1 upregulates the expression of VDR, which promotes Vit D-induced COX-2 expression and subsequent PGE2 production by activating the SMAD3 and ERK1/2 signaling pathways in hGL cells.
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Segawa, Hiroko, Ichiro Kaneko, Setsuko Yamanaka, Mikiko Ito, Masahi Kuwahata, Yoshio Inoue, Shigeaki Kato, and Ken-ichi Miyamoto. "Intestinal Na-Pi cotransporter adaptation to dietary Pi content in vitamin D receptor null mice." American Journal of Physiology-Renal Physiology 287, no. 1 (July 2004): F39—F47. http://dx.doi.org/10.1152/ajprenal.00375.2003.
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Recent studies suggest that vitamin D may play a role in intestinal Na+-dependent phosphate transport adaptation to variable levels of dietary Pi. Therefore, the goal of the current study was to assess Na+-dependent Pi cotransport activity in transgenic mice to determine whether vitamin D is an essential mediator of this process. Intestinal brush-border membrane (BBM), Na+-dependent Pi cotransport activity was significantly decreased in vitamin D receptor (VDR) null [VDR (−/−)] mice compared with wild-type (VDR+/+) mice. While intestinal Na-Pi cotransporter (type IIb) mRNA levels were similar in VDR (−/−) and VDR (+/+) mice, type IIb Na-Pi cotransporter protein expression was markedly suppressed in VDR (−/−) mice compared with VDR (+/+) mice. Furthermore, Na-Pi cotransport activity in renal BBM was similar in VDR (−/−) and VDR (+/+) mice, but type IIa Na-Pi cotransporter protein expression was decreased in VDR (−/−) mice. After administration of a low-Pi diet, type IIb protein expression was significantly increased in VDR (+/+) and VDR (−/−) mice, and type IIb protein expression was present in the intestinal BBM of VDR (−/−) mice. These data demonstrate that intestinal Na-Pi cotransport adaptation to a low-Pi diet occurs independently of vitamin D.
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Ginting, R. N. A., Dwi Rita Anggraini, and M. S. Sitorus. "Vitamin D Receptor Immunoexpression in Benign and Malignant Prostate Tumors." Open Access Macedonian Journal of Medical Sciences 8, B (October 9, 2020): 949–51. http://dx.doi.org/10.3889/oamjms.2020.5148.
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BACKGROUND: Prostate cancer is a major health concern of men. Vitamin D can modulate innate or adaptive immune responses. The anticancer and anti-inflammatory effects of Vitamin D are mediated through gene transcription by Vitamin D receptor (VDR), including angiogenesis and tumor cell invasion. Targeted therapy in carcinoma prostate such as is as calcitriol is an alternative therapy for better treatment outcome.
METHODS AND MATERIALS: We investigated VDR immunoexpression in benign prostatic hyperplasia (BPH) and prostate adenocarcinoma. The cross-sectional study, categorical analysis of 60 paraffin blocks consist of 30 samples diagnosed as BPH, and 30 samples of prostate adenocarcinoma were divided three grading groups based on Patterns of Gleason: low, moderate, and high grade. Immunostaining was used to evaluate the VDR immunoexpression by histoscore.
RESULTS: The results showed that strong expression of VDR was 40% in BPH and 33.33% in prostate adenocarcinoma (p = 0.961). The strong expression of VDR in low, moderate, and high grade was 10%, 3.33%, and 20%, respectively. Statistically, there is no significant different (p = 0.906).
CONCLUSION: Positive immunoexpression of VDR affected the differentiation of prostatic adenocarcinoma.
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Sun, Jun, Juan Kong, Yingli Duan, Frances L. Szeto, Anne Liao, James L. Madara, and Yan Chun Li. "Increased NF-κB activity in fibroblasts lacking the vitamin D receptor." American Journal of Physiology-Endocrinology and Metabolism 291, no. 2 (August 2006): E315—E322. http://dx.doi.org/10.1152/ajpendo.00590.2005.
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1,25-Dihydroxyvitamin D [1,25(OH)2D3] is known to have anti-inflammatory activity; however, the molecular mechanism remains poorly defined. Here we show that the nuclear vitamin D receptor (VDR) is directly involved in the regulation of NF-κB activation, a pathway essential for inflammatory response. In mouse embryonic fibroblasts (MEFs) derived from VDR−/− mice, the basal level of κB inhibitor (IκB) α protein was markedly decreased compared with VDR+/− MEFs; however, degradation of IκBα and its phosphorylation in response to TNF-α treatment or Salmonella infection were not altered in VDR−/− cells, neither were the levels of IκB kinase-α and IκB kinase-β proteins. Consistent with IκBα reduction, p65 accumulation in the nucleus was markedly increased in unstimulated VDR−/− cells. In addition, the physical interaction between VDR and p65 was absent in VDR−/− MEFs, which may free p65 and increase its activity. Consequently, these alterations combined led to a marked increase in nuclear p65 DNA binding and NF-κB transcriptional activity; consistently, induction of IL-6 by TNF-α or IL-1β was much more robust in VDR−/− than in VDR+/− cells, indicating that VDR−/− cells are more susceptible to inflammatory stimulation. Therefore, cells lacking VDR appear to be more proinflammatory due to the intrinsic high NF-κB activity. The reduction of IκBα in VDR−/− MEFs may be partially explained by the lack of VDR-mediated stabilization of IκBα by 1,25(OH)2D3. This is supported by the observation that IκBα degradation induced by TNF-α was inhibited by 1,25(OH)2D3 in VDR+/− cells, but not in VDR−/− cells. Taken together, these data suggest that VDR plays an inhibitory role in the regulation of NF-κB activation.