Vitamin D And Its Receptor Research Articles

Vitamin D status, vitamin D receptor gene polymorphism, and haplotype in patients with cutaneous leishmaniasis: Correlation with susceptibility and parasite load index.

CL endemicity was reported worldwide including in Saudi Arabia, imposing a major challenge on the health authorities. Vitamin D and its receptor (VDR) are key modulators of the immune response where the VDR is expressed. A remarkable lack of data exists in humans about the contribution of vitamin D and polymorphisms of the VDR gene in protozoan infections, especially cutaneous leishmaniasis (CL). This is the first work conducted to assess the relationship between vitamin D status, polymorphisms of the VDR gene (BsmI, ApaI, TaqI, and FokI), and VDR haplotype with parasite tissue load and susceptibility to CL. Fifty-two patients with confirmed CL (21 patients receiving vitamin D medication and 31 patients not receiving it) and 46 control subjects participated in this cross-sectional investigation. VDR genotyping was determined by restriction fragment length polymorphism analysis. Serum levels of 25-OH vitamin D were assessed using the ELISA method in all participants. The skin biopsy quantified the parasite load based on the Ridley parasitic index. The mean serum level of 25-OH vitamin D in CL patients who were not receiving vitamin D therapy was significantly lower compared to CL patients on vitamin D therapy and controls (p <0.001 for both) and CL patients with no history of vitamin D therapy had a significantly higher frequency of vitamin D deficiency compared to CL patients on vitamin D therapy and controls (p < 0.05). Compared to CL patients with no history of vitamin D therapy, CL patients receiving vitamin D therapy had a significantly lower mean size of the lesion and RPI (p = 0.02, .03 respectively). The frequency of genotype "aa" and its "a" allele in ApaI SNP of VDR was significantly lower in CL patients compared to controls (p = 0.006 and 0.03 respectively). However, patients with CL had a considerably greater frequency of the "A" allele than the controls (p = 0.03), suggesting its role in CL susceptibility. There was no statistically significant difference between the two groups in the genotype and allele frequency distributions of BsmI, TaqI, and FokI (p > 0.05). When compared to controls, CL cases had a considerably greater frequency of the "B-A-T-F" haplotype (p = 0.04), and a significantly lower frequency of the "B-a-T-F" haplotype (p = 0.01) suggesting that these haplotypes may have the potential susceptibility or protection against CL respectively. The "Aa" genotype in ApaI SNP of VDR had considerably lower levels of vitamin D with higher parasite load compared to the "AA" and: aa" genotypes (p = 0.02,0.02 respectively). A significant negative correlation was found between the parasite load and 25-OH vitamin D levels (r2 = -0.53, p< 0.001). According to these findings, vitamin D levels and "ApaI" VDR gene polymorphisms could affect the parasite load and susceptibility to infection, whereas BsmI, FokI, and TaqI polymorphisms did not. Correction of vitamin D levels may aid in CL management.

Vitamin D inhibits osteosarcoma by reprogramming nonsense-mediated RNA decay and SNAI2-mediated epithelial-to-mesenchymal transition.

Osteosarcomas are immune-resistant and metastatic as a result of elevated nonsense-mediated RNA decay (NMD), reactive oxygen species (ROS), and epithelial-to-mesenchymal transition (EMT). Although vitamin D has anti-cancer effects, its effectiveness and mechanism of action against osteosarcomas are poorly understood. In this study, we assessed the impact of vitamin D and its receptor (VDR) on NMD-ROS-EMT signaling in in vitro and in vivo osteosarcoma animal models. Initiation of VDR signaling facilitated the enrichment of EMT pathway genes, after which 1,25(OH)2D, the active vitamin D derivative, inhibited the EMT pathway in osteosarcoma subtypes. The ligand-bound VDR directly downregulated the EMT inducer SNAI2, differentiating highly metastatic from low metastatic subtypes and 1,25(OH)2D sensitivity. Moreover, epigenome-wide motif and putative target gene analysis revealed the VDR's integration with NMD tumorigenic and immunogenic pathways. In an autoregulatory manner, 1,25(OH)2D inhibited NMD machinery genes and upregulated NMD target genes implicated in anti-oncogenic activity, immunorecognition, and cell-to-cell adhesion. Dicer substrate siRNA knockdown of SNAI2 revealed superoxide dismutase 2 (SOD2)-mediated antioxidative responses and 1,25(OH)2D sensitization via non-canonical SOD2 nuclear-to-mitochondrial translocalization leading to overall ROS suppression. In a mouse xenograft metastasis model, the therapeutically relevant vitamin D derivative calcipotriol inhibited osteosarcoma metastasis and tumor growth shown for the first time. Our results uncover novel osteosarcoma-inhibiting mechanisms for vitamin D and calcipotriol that may be translated to human patients.

The role of vitamin D receptor gene polymorphism in the development of necrotizing enterocolitis.

Vitamin D and its receptor (VDR) effects on the gastrointestinal system are among its most critical multisystemic effects. This study aimed to reveal that VDR gene polymorphisms may constitute a risk factor for necrotizing enterocolitis (NEC). VDR Fok1-Bsm1-Apa single-nucleotide polymorphisms were analyzed in the NEC group (n = 74) and the control group (n = 147). Among 1112 babies at and below 36 weeks of gestational age who were hospitalized between January 2013 and December 2016 with a diagnosis of prematurity, 74 of a total of 148 patients who developed NEC during follow-up (NEC group) were included in the study. When NEC was diagnosed according to clinical and radiological findings and staged using Modified Bell criteria, 9 (12.1%) of 74 babies were stage 1A, 13 (17.5%) stage 1B, and 5 (6.7%) stage 2A, 33 (44.5%) stage 2B, 7 (9.4%) stage 3A, 7 (9.4%) stage 3B. Of 964 babies who did not develop NEC during follow-up, 147 were included as the control group in the study. Genotyping of VDR polymorphisms was assayed by real-time PCR. From 221 premature babies in the NEC and control groups, 2 ml peripheral blood was taken appropriately and meticulously into an EDTA tube. DNA was isolated from these blood samples. DNA amplification was performed using a thermal cycler (Applied Biosystems GeneAmp PCR System 9600). When the two groups were compared in terms of the prevalence of VDR Fok1 C/T genotype, it was found that TT genotype increased the risk of NEC by 2.697 times, and there was a significant relationship between TT genotype and the risk of NEC (p = 0.041). Multivariable logistic regression analysis was performed in terms of gestational age, birth weight, VDR gene polymorphism data between NEC and the control group. According to the analysis results, TT polymorphism, increased the risk of disease 4.5 times (p = 0.033). Fok 1 C > T polymorphism in the VDR gene plays a role in the development of NEC. Identifying the risk groups by detecting gene polymorphisms that cause increased susceptibility to NEC may assist in the follow-up of these patients and in making early treatment decisions for them. In this study examining the non-bone effects of the genetic differences in vitamin D metabolism in premature babies, Fok 1 polymorphism has been observed to be an essential risk factor for NEC. This is the first study in our country that has investigated the relationship between VDR gene polymorphism and necrotizing enterocolitis among the Turkish population. Identifying the risk groups by detecting gene polymorphisms that cause increased susceptibility to NEC may assist in the monitoring of these patients and in making early treatment decisions for them.

Vitamin D-VDR Novel Anti-Inflammatory Molecules-New Insights into Their Effects on Liver Diseases.

There is consistent evidence that vitamin D deficiency is strongly associated with liver dysfunction, disease severity, and poor prognosis in patients with liver disease. Vitamin D and its receptor (VDR) contribute to the regulation of innate and adaptive immune responses. The presence of genetic variants of vitamin D- and VDR-associated genes has been associated with liver disease progression. In our recent work, we summarized the progress in understanding the molecular mechanisms involved in vitamin D–VDR signaling and discussed the functional significance of VDR signaling in specific cell populations in liver disease. The current review focuses on the complex interaction between immune and liver cells in the maintenance of liver homeostasis and the development of liver injury, the interplay of vitamin D and VDR in the development and outcome of liver disease, the role of vitamin D- and VDR-associated genetic variants in modulating the occurrence and severity of liver disease, and the therapeutic value of vitamin D supplementation in various liver diseases. The association of the vitamin D–VDR complex with liver dysfunction shows great potential for clinical application and supports its use as a prognostic index and diagnostic tool.

The role of vitamin D receptor polymorphisms in the course of chronic hepatitis C infection.

BackgroundVitamin D and its receptor (VDR) exert important immunoregulatory functions that contribute to liver homeostasis. The aim of this study was to investigate the influence of FokI, ApaI, BsmI and TaqI VDR polymorphisms on cirrhosis development and laboratory variables in patients with chronic hepatitis C (CHC).MethodsA total of 48 patients were enrolled in this retrospective, observational study and underwent genotype analysis; their medical records were examined to obtain relevant data.ResultsThe cumulative rate of progression to cirrhosis during the course of CHC was 31.3% after a median period of 11 years from diagnosis. Importantly, in multivariate analysis, FokI ff (adjusted hazard ratio [aHR] 13.6, 95% confidence interval [CI] 2.51-73.73; P=0.002) and ApaI aa (aHR 4.69, 95%CI 1.13-19.43; P=0.033) genotypes were independently associated with progression to cirrhosis. The presence of the aa genotype was also associated with higher liver stiffness measurements measured by transient elastography compared to the AA/Aa genotype (12.3kPa interquartile range [IQR] 9.6-17.3 vs. 7.1kPa IQR 5.6-11.1; P=0.012). In addition, higher HCV RNA and lower serum albumin levels were observed in patients with the tt genotype of the TaqI polymorphism compared to TT/Tt carriers, and in patients with the aa genotype compared to AA/Aa carriers. In haplotype analysis, no association was found between any haplotype and disease progression.ConclusionsIn patients with CHC, laboratory parameters are influenced by VDR polymorphisms and the development of cirrhosis is related to homozygosity for the dominant trait of ApaI and FokI variants.

Vitamin D-Liver Disease Association: Biological Basis and Mechanisms of Action.

Vitamin D plays a major role in hepatic pathophysiology, demonstrated by studies showing that it actively inhibits liver fibrosis and that its deficiency is associated with liver dysfunction and severity of liver diseases. Vitamin D and its receptor (VDR) are involved in the regulation of innate and adaptive immune responses and emerging evidence suggests that they contribute to liver homeostasis by exerting antiproliferative, anti-inflammatory and antifibrotic activities. Over the last decades, extensive research has been focused on the identification of the biochemical and molecular pathways that mediate vitamin D-VDR cellular and genomic actions through which vitamin D regulates the expression of target genes and modulates the progression of liver diseases. In this review, we discuss the recent advances in our understanding of the molecular mechanisms involved in vitamin D-VDR signaling and how genetic variants influence inflammatory responses and fibrogenic outcomes. The delineation of the biological basis of the association between vitamin D and liver disease progression is important for the development of novel treatment strategies for liver diseases.

Potential role of vitamin D receptor-related polymorphisms in bronchopulmonary dysplasia

BackgroundThe potential contribution of vitamin D and its receptor (VDR) to bronchopulmonary dysplasia (BPD) in preterm neonates is still unknown. The objective of the study was to test the relationship between VDR Taq 1 and Fok 1 gene polymorphisms and BPD in preterm neonates. VDR Fok 1 and Taq 1 gene polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis.ResultNo statistically significant differences of genotypic distributions and allele frequencies of Fok 1 and Taq 1 VDR polymorphisms were detected between cases and controls. Moreover, no risk association was detected between both polymorphisms and BPD development in preterm neonates. Homozygous mutant (ff) genotype was the least frequent genotype among BPD and non-BPD groups (2.6%, 13.0% respectively) (p = 0.1). The same was detected for the mutant (CC) genotype frequency in both groups (10.5% and 15.2%, respectively). However, Taq 1 VDR polymorphism was significantly associated with the severity of BPD, as the genotypes with mutant allele C (CC +CT) were more frequent among severe cases (52.2%).ConclusionFok 1and Taq 1 VDR polymorphisms have no role in BPD development in preterm neonates. However, the presence of a mutant allele of Taq 1 VDR polymorphism may be associated with a more severe form of the disease.

Association of vitamin D receptor gene polymorphisms with rheumatoid arthritis

IntroductionRheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease of unknown etiology which causes progressive deterioration of the joints, leading to severe pain and functional disability. Vitamin D and its receptor (VDR) play a significant part in the onset of autoimmune diseases such as RA. The purpose of this study was to evaluate the association between VDR gene polymorphisms and risk of developing RA.Material and methodsA retrospective study was performed, including 214 RA cases and 748 controls of Caucasian origin. FokI (rs2228570), BsmI (rs1544410), TaqI (rs731236), ApaI (rs7975232) and Cdx2 (rs11568820) gene polymorphisms were analyzed by TaqManResultsThe recessive logistic regression model showed that the VDR FokIAA genotype was associated with lower risk of RA (p = 0.0255; OR = 0.58; 95% CI: 0.35–0.92). No other genetic polymorphism showed any association with RA in any of the models tested. Haplotype analysis revealed that the haplotypes ACGAG (p = 0.033; OR = 1.62; 95% CI: 1.04–2.53) and GTGCA (p &lt; 0.01; OR = 2.77; 95% CI: 1.53–4.98) for BsmI, Cdx2, FokI, ApaI and TaqI were associated with higher risk of RA.ConclusionsVDR FokI gene polymorphism showed a trend for risk of RA, taking into account the variables of gender, age and tobacco use, and preventing false positives. Among our patients we found no influence of VDR BsmI, TaqI, ApaI and Cdx2 on the risk of developing RA. However, haplotype analysis indicated that the haplotypes ACGAG and GTGCA were associated with higher risk of RA.

The Calcitriol/Vitamin D Receptor System Regulates Key Immune Signaling Pathways in Chronic Lymphocytic Leukemia.

Simple SummaryCalcitriol, the biologically active form of vitamin D, modulates a plethora of cellular processes following its receptor ligation, namely the vitamin D receptor (VDR). Epidemiological studies have linked low blood levels of vitamin D to adverse disease outcome in several B cell malignancies, including chronic lymphocytic leukemia (CLL), for as yet undetermined reasons. In this study, we sought to obtain deeper biological insight into the role of vitamin D in the pathophysiology of CLL. To this end, we investigated whether the calcitriol/VDR system is functional in CLL and analyzed key signaling pathways that are regulated by calcitriol supplementation, while also exploring the role of microenvironmental signals in the regulation of calcitriol/VDR system. Overall, we provide evidence that the calcitriol/VDR system is functional in CLL, regulating signaling pathways critical for cell survival/proliferation. Although microenvironmental triggers can modulate VDR expression and function, calcitriol appears to act independently, alluding to a potential clinical utility of vitamin D supplementation in CLL.It has been proposed that vitamin D may play a role in prevention and treatment of cancer while epidemiological studies have linked vitamin D insufficiency to adverse disease outcomes in various B cell malignancies, including chronic lymphocytic leukemia (CLL). In this study, we sought to obtain deeper biological insight into the role of vitamin D and its receptor (VDR) in the pathophysiology of CLL. To this end, we performed expression analysis of the vitamin D pathway molecules; complemented by RNA-Sequencing analysis in primary CLL cells that were treated in vitro with calcitriol, the biologically active form of vitamin D. In addition, we examined calcitriol effects ex vivo in CLL cells cultured in the presence of microenvironmental signals, namely anti-IgM/CD40L, or co-cultured with the supportive HS-5 cells; and, CLL cells from patients under ibrutinib treatment. Our study reports that the calcitriol/VDR system is functional in CLL regulating signaling pathways critical for cell survival and proliferation, including the TLR and PI3K/AKT pathways. Moreover, calcitriol action is likely independent of the microenvironmental signals in CLL, since it was not significantly affected when combined with anti-IgM/CD40L or in the context of the co-culture system. This finding was also supported by our finding of preserved calcitriol signaling capacity in CLL patients under ibrutinib treatment. Overall, our results indicate a relevant biological role for vitamin D in CLL pathophysiology and allude to the potential clinical utility of vitamin D supplementation in patients with CLL.

Association of Vitamin D and its Receptor (VDR) Gene Single Nucleotide Polymorphism (ApaI and TaqI) with Risk of Psoriasis

Introduction: Psoriasis is one of the skin related inflammatory diseases that affects a low percentage of population around the globe. Vitamin D through Vitamin D Receptor (VDR) also regulates the function of white blood cells in psoriasis. Mutations in VDR gene have shown abnormalities in immune responses like psoriatic arthritis. To determine the possible association between Vitamin D Receptor (ApaI and TaqI) gene polymorphism and psoriasis, a case-control study was designed and conducted at the Institute of Basic Medical Sciences (IBMS), Khyber Medical University (KMU) Peshawar and health units of Peshawar. Method: This multi-centre study included 220 samples (110 cases of psoriatic disease and 110 healthy controls). DNA was extracted using modified salting out protocol. VDR gene polymorphisms (TaqI and ApaI) were genotyped using amplification refractory mutation system using polymerase chain reaction (ARMSPCR) method. Results were statistically analyzed. Result: Our study showed significant association between VDR gene (TaqI, ApaI) polymorphisms and psoriasis with p-value of 0.009 (0.0019 and 0.0162) and odds ratios (95% confidence interval) for psoriasis of CC vs CT (TaqI) and AA vs AC (ApaI) were 2.963 (95% CI: 1.508-5.743) and 2.293 (95% CI:1.22-4.246) respectively. Conclusion: Findings indicate that VDR gene polymorphisms (TaqI, ApaI) are significantly associated with onset and progression of psoriasis, and mutations in these loci are risk factors for development of psoriasis. Key words: Psoriasis, VDR polymorphism, TaqI, ApaI, South Asia, Pakistan

Comparison of VDR Expression and Blood Vitamin D 1.25 (OH)2 Level between Cervical Cancer Patients and Normal Women

Background: Vitamin D and its receptor (VDR) play a crucial role in the development of gynecological cancers. This study aims to evaluate the VDR expression and blood vitamin D 1.25 (OH)2 levels in cervical cancer patients and healthy women.Methods: This is a cross-sectional study. In vitro quantitative examination (ELISA) was used for the measurement of vitamin D 1.25 (OH)2 and Sandwich-ELISA was applied for quantitative determination in vitro concentration of Human VDR in serum.Results: The number of research subjects consisting of 20 cervical cancer patients based on clinical and histopathological results and 20 women without cervical cancer based on clinical and pap smear results. The mean vitamin D 1.25 (OH)2 levels in the cervical cancer group of 209.23 ± 71.476 pg/mL were significantly lower than in the group of normal women of 339.79 ± 139.003 pg/mL (P=.001). The mean VDR expression in the cervical cancer group of 5.38 ± 5.478 ng/mL was significantly higher than the group of normal women of 1.89 ± 1.657 ng/mL (P=.018). The best cut-off value for vitamin D levels is 239.25 pg/mL (sensitivity 70% and specificity 75%). The cut-off value for VDR expression is 2.23 ng/mL (sensitivity 60% and specificity 75%). Low vitamin D levels increase the risk of cervical cancer incidence by 2.7 times greater, and an increase in VDR expression increases the risk of cervical cancer incidence 2 times greater.Conclusions: The study results indicated a higher expression of VDR and lower levels of vitamin D 1.25 (OH)2 in cervical cancer compared to normal women. Low levels of vitamin D increase the risk of cervical cancer incidence by 2.7 times greater, and higher VDR expression increases the risk of cervical cancer incidence 2 times greater.

Vitamin D Signaling in Inflammation and Cancer: Molecular Mechanisms and Therapeutic Implications.

Vitamin D and its active metabolites are important nutrients for human skeletal health. UV irradiation of skin converts 7-dehydrocholesterol into vitamin D3, which metabolized in the liver and kidneys into its active form, 1α,25-dihydroxyvitamin D3. Apart from its classical role in calcium and phosphate regulation, scientists have shown that the vitamin D receptor is expressed in almost all tissues of the body, hence it has numerous biological effects. These includes fetal and adult homeostatic functions in development and differentiation of metabolic, epidermal, endocrine, neurological and immunological systems of the body. Moreover, the expression of vitamin D receptor in the majority of immune cells and the ability of these cells to actively metabolize 25(OH)D3 into its active form 1,25(OH)2D3 reinforces the important role of vitamin D signaling in maintaining a healthy immune system. In addition, several studies have showed that vitamin D has important regulatory roles of mechanisms controlling proliferation, differentiation and growth. The administration of vitamin D analogues or the active metabolite of vitamin D activates apoptotic pathways, has antiproliferative effects and inhibits angiogenesis. This review aims to provide an up-to-date overview on the effects of vitamin D and its receptor (VDR) in regulating inflammation, different cell death modalities and cancer. It also aims to investigate the possible therapeutic benefits of vitamin D and its analogues as anticancer agents.

The Vitamin D Receptor as Tumor Suppressor in Skin.

Cutaneous malignancies including melanomas and keratinocyte carcinomas (KC) are the most common types of cancer, occurring at a rate of over one million per year in the United States. KC, which include both basal cell carcinomas and squamous cell carcinomas, are substantially more common than melanomas and form the subject of this chapter. Ultraviolet radiation (UVR), both UVB and UVA, as occurs with sunlight exposure is generally regarded as causal for these malignancies, but UVB is also required for vitamin D synthesis in the skin. Keratinocytes are the major cell in the epidermis. These cells not only produce vitamin D but contain the enzymatic machinery to metabolize vitamin D to its active metabolite, 1,25(OH)2D, and express the receptor for this metabolite, the vitamin D receptor (VDR). This allows the cell to respond to the 1,25(OH)2D that it produces. Based on our own data and that reported in the literature, we conclude that vitamin D signaling in the skin suppresses UVR-induced epidermal tumor formation. In this chapter we focus on four mechanisms by which vitamin D signaling suppresses tumor formation. They are inhibition of proliferation/stimulation of differentiation with discussion of the roles of hedgehog, Wnt/β-catenin, and hyaluronan/CD44 pathways in mediating vitamin D regulation of proliferation/differentiation, regulation of the balance between oncogenic and tumor suppressor long noncoding RNAs, immune regulation, and promotion of DNA damage repair (DDR).

Association of vitamin D receptor gene FokI and TaqI polymorphisms and risk of RDS

Background: Vitamin D and its receptor (VDR) have important roles in perinatal lung development. The objective of this study was to investigate the possible association between VDR FokI and TaqI polymorphism and development of respiratory distress syndrome (RDS) in preterm infants.Method: A total of 173 premature infants <34 weeks: 82 with RDS and 91 without RDS were enrolled. Genotyping of VDR polymorphisms was assayed by real-time PCR. Serum 25-hydroxyvitamin D (25-OHD) levels were measured by ELISA in blood samples that were obtained at the time of admission to the neonatal intensive care unit.Results: Gestational age (GA) was significantly lower in the RDS group compared with the controls. In univariate analysis, VDR TaqI CT and CC genotypes were associated with the increased risk of RDS (OR = 3.264, p = .001, 95% CI = 1.597–6.672 and OR = 5.222, p < .001, 95% CI = 2.165–12.597, respectively); while VDR FokI showed no association with RDS. In multivariate logistic regression analysis, variant TaqI genotype increased risk of RDS (p = 0.001, OR = 3.464, 95% CI = 1.655–7.251) independent of gestational age, birth weight and gender. 25-OHD levels in the RDS group were significantly lower compared with those in without the RDS group (p = .002). Serum 25-OHD levels were not significantly different among the different FokI and TaqI genotypes in RDS group.Conclusions: This is the first report of association of VDR polymorphism with RDS development in preterm neonates. Current study suggests that VDR TaqI polymorphism may be involved in predisposition to RDS in premature neonates. Further studies are needed to assess the contribution of vitamin D and VDR signaling to the pathogenesis RDS

Potential role of hypovitaminosis D in renal cell carcinoma patients treated with immune-checkpoint inhibitors.

50 Background: hypovitaminosis D is frequent in renal diseases but it was never reported in metastatic renal cell carcinoma (mRCC). The interaction between vitamin D and its receptor (VDR) has a key role for T-cell activation. Naïve T-cells do not express VDR and had very low expression of phospholipase C-γ1 (PLC-γ1), with low responsiveness to T-cell receptor (TCR). Initial TCR signaling induces VDR expression and upregulates PLC-γ1 via the kinase p38 pathway. VDR interaction with high concentrations of vitamin D and PLC-γ1 increase are required to trigger classical TCR signaling, increasing T-cell responsiveness. On these basis, we hypothesized that hypovitaminosis D could contribute to lower responsiveness to immune-checkpoint inhibitors (CKI). Methods: we assessed vitamin D levels of mRCC patients undergoing therapy with CKI, with the aim to reveal hypovitaminosis D, evaluate its prevalence and hypothesize its potential role in the outcome of treatment with CKI. Results: of 10 mRCC patients pretreated with tyrosine-kinase inhibitors, vitamin D levels assessed before the first treatment with nivolumab (anti-PD1 CKI) revealed deficiency in 80% of cases (8 patients). Hypovitaminosis D was severe ( &lt; 20 ng/ml) in 7 cases and moderate ( &lt; 30 ng/ml) in one. The 2 patients without deficiency (20%), had vitamin D values near to the lower limit of normality. Oral supplementation with cholecalciferol was given when necessary, likely confounding the possible influence of vitamin D deficiency on the outcome of CKI treatment. Vitamin D normal values after two months of therapy were recovered in the great majority of cases. Interestingly, the only patient who achieved a good objective response to treatment had normal values of vitamin D before therapy. Conclusions: hypovitaminosis D could have a relevant prevalence in mRCC patients. Considering the role of vitamin D in T-cell activation, assessment of its levels and initiation of a supplementation before immunotherapy should be considered to enhance responsiveness. On the basis of these observations, we are planning a perspective multicenter study to investigate the role of hypovitaminosis D in mRCC patients treated with CKI (PRoviDenCe study).

Vitamin D and inflammatory bowel disease.

Vitamin D deficiency has been recognized as an environmental risk factor for Crohn's disease since the early 80s. Initially, this finding was correlated with metabolic bone disease. Low serum 25-hydroxyvitamin D levels have been repeatedly reported in inflammatory bowel diseases together with a relationship between vitamin D status and disease activity. Subsequently, low serum vitamin D levels have been reported in various immune-related diseases pointing to an immunoregulatory role. Indeed, vitamin D and its receptor (VDR) are known to interact with different players of the immune homeostasis by controlling cell proliferation, antigen receptor signalling, and intestinal barrier function. Moreover, 1,25-dihydroxyvitamin D is implicated in NOD2-mediated expression of defensin-β2, the latter known to play a crucial role in the pathogenesis of Crohn's disease (IBD1 gene), and several genetic variants of the vitamin D receptor have been identified as Crohn's disease candidate susceptibility genes. From animal models we have learned that deletion of the VDR gene was associated with a more severe disease. There is a growing body of evidence concerning the therapeutic role of vitamin D/synthetic vitamin D receptor agonists in clinical and experimental models of inflammatory bowel disease far beyond the role of calcium homeostasis and bone metabolism.

Vitamin d receptor gene polymorphism and vitamin d plasma concentration: correlation with susceptibility to tuberculosis.

It is estimated that one third of the world's population were infected with M. tuberculosis, but only 10% of them have developed in to disease form. This subject refers to differences in host immune system activity against the tuberculosis. Vitamin D and its receptor (VDR) are important factors in the host innate immune system against the tuberculosis. In the present study VDR gene polymorphisms and its relationship with plasma vitamin D levels in susceptibility to tuberculosis have been investigated. The subjects were 84 patients with tuberculosis and 90 healthy controls. Vitamin D levels were measured in all study participants. DNA was isolated from the blood leukocytes of all groups and amplified by polymerase chain reaction (PCR). Then restriction fragment length polymorphism (RFLP) was performed on each PCR products to study the VDR gene polymorphisms. The statistical analyses were conducted using SPSS. There was no statistically significant relationship between polymorphisms of FokI, BsmI, ApaI and TaqI in VDR gene and susceptibility to tuberculosis. Vitamin D deficiency and susceptibility to tuberculosis were closely related (95% CI -0.08 - 4.7, P = 0.059). Also the relationship between plasma vitamin D levels and frequency of FokI-ff gene polymorphism was significant in all study participants (P = 0.045). When the genotype frequencies of VDR gene polymorphisms were analyzed with respect to plasma vitamin D levels, a significant association was seen. As an enhancement in plasma vitamin D levels in individuals (with FokI-ff genotype and low levels of vitamin D) may protect them against active tuberculosis.

Vitamin D Receptor Regulates High Glucose Induced Inflammation through Inhibition of NF-κBpathway

Inflammation is thought to contribute to the progression of diabetic nephropathy (DN). Vitamin D (VD) and its receptor (VDR) have beneficial function on the pathogenesis of DN by anti-inflammation. However, the underlying mechanism for VD and VDR to inhibit inflammation in DN is missing. The inflammation and activation of NF-κBpathway in HK-2 cells were fully analyzed after high glucose and VD supplementation. High glucose promoted obvious expression of monocyte chemoattractant protein (MCP)-1 and RANTES (CCL-5) by activation of NF-κBpathway. VD supplementation inhibited the inflammation induced by high glucose through VDR, which inactivated the NF-κBpathway. The inhibition of VDR by siRNA diminished the modulation of VD on inflammation induced by high glucose. VDR regulates high glucose induced inflammation by affecting NF-κBpathway.

Hypotheses and Emerging Facts: the Vitamin D Receptor Capacitor, Rheumatoid Arthritis and Beyond

As System-IN Failing, complex diseases such as autoimmune diseases (ADs) like rheumatic arthritis (RA), and the associated cancers remain as a challenge to thoroughly understand, though their common underlying mechanisms emerge. In this visionary article, we summarize some recent hypothesis-generating discussions on the Vitamin D and its receptor (VDR) capacitor for autoimmune diseases (ADs) and associated cancers, then update bioinformatics evidence along with latest progress in RA. We could conclude this may provide one unique angle to view the controversies surrounding the beneficial effects of Vitamin D supplementation.

Association of vitamin D receptor gene polymorphisms and bronchopulmonary dysplasia.

Vitamin D and its receptor (VDR) have important roles in perinatal lung development. The aim of this study was to investigate the relationship between VDR gene polymorphism and bronchopulmonary dysplasia (BPD) in preterm infants. VDR Fok I, Bsm I, Apa I, and Taq I polymorphisms were genotyped using restriction fragment length polymorphism in 109 preterm infants (47 with BPD, 62 without BPD). In univariate analysis, Ff (odds ratio (OR) = 3.937, P = 0.022, 95% confidence interval (CI) = 1.22-12.69) and ff (OR = 5.23, P = 0.004, 95% CI = 1.69-16.23) genotypes of Fok I were associated with the increased risk of BPD; whereas tt genotype of Taq 1 was associated with a protective effect against BPD (OR = 0.30, P = 0.04, 95% CI = 0.09-0.94). In multivariate logistic regression analysis, variant Fok 1 genotype increased risk of BPD (OR = 4.11, 95% CI = 1.08-15.68, P = 0.038) independent of patent ductus arteriosus, sepsis, mechanical ventilation, and surfactant treatment. Taq 1, Bsm 1, and Apa 1 polymorphisms did not have any effect. After adjusting for multiple confounders, VDR Fok 1 polymorphism was associated with the increased frequency of BPD. Further studies are needed to assess the contribution of VDR signaling to the pathogenesis of BPD and to determine if VDR polymorphisms may be suitable for identifying infants at high risk for BPD.