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Vitamin D is a lipid soluble steroid hormone, which plays a critical role in the calcium homeostasis, neuronal development, cellular differentiation, and growth by binding to vitamin D receptor (VDR). Associations between VDR gene polymorphism and Alzheimer's disease (AD), Parkinson's disease (PD), and mild cognitive impairment (MCI) risk has been investigated extensively, but the results remain ambiguous. The aim of this study was to comprehensively assess the correlations between four VDR polymorphisms (Fok I, Bsm I, Taq I, and Apa I) and susceptibility to AD, PD, and MCI. Crude odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to determine the relationship of interest. Pooled analyses suggested that the Apa I polymorphism decreased the overall AD risk, and the Taq I increased the overall PD susceptibility. In addition, the Bsm I and Apa I polymorphisms were significantly correlated with the overall MCI risk. Stratified analysis by ethnicity further showed that the Taq I and Apa I genotypes reduced the AD predisposition among Caucasians, while the Taq I polymorphism enhanced the PD risk among Asians. Intriguingly, carriers with the BB genotype significantly decreased the MCI risk in Asian descents, and the Apa I variant elevated the predisposition to MCI in Caucasians and Asians. Further studies are need to identify the role of VDR polymorphisms in AD, PD, and MCI susceptibility. [ABSTRACT FROM AUTHOR]

Background and aim: NK cells and NK-cell-derived cytokines were shown to regulate neutrophil activation in acute lung injury (ALI). However, the extent to which ALI regulates lung tissue-resident NK (trNK) activity and their molecular phenotypic alterations are not well defined. We aimed to assess the impact of 1,25-hydroxy-vitamin-D3 [1,125(OH)2D] on ALI clinical outcome in a mouse model and effects on lung trNK cell activations. Methods: Oleic acid (OA)-induced ALI in C57BL/6J mice and 1,25(OH)2D treatment 2×/2 weeks were performed. Lung tissue was harvested to assess alveolar I/II cell apoptosis and lung injury marker of Surfactant-Protein-D (SP-D). Pulmonary edema markers of epithelial sodium channel, cystic fibrosis transmembrane conductance regulator, and aquaporin 5 were assessed by RT-PCR. Lung trNK cells were assessed for activation markers of CD107a and NKp46, vitamin D receptor (VDR), and programmed cell death protein-1 (PD-1) via flow cytometry. The bronchoalveolar lavage fluid (BALF) obtained was investigated for soluble receptor for advanced glycation end products (sRAGE), inflammatory cytokines, soluble 1,25(OH)2D, and PDL-1. Naïve mice treated with DMSO (vehicle) were used as a control. Results: Flow cytometry analysis displayed a high apoptotic rate in alveolar I/II cells of threefold in ALI mice as compared to naïve mice. These findings were accompanied by elevated markers of pulmonary edema as well as lung injury markers of SP-D. Isolated lung trNK cells of the ALI mice exhibited reduced CD107a and NKp46 markers and cytotoxicity potentials and were correlated through significantly 2.1-fold higher levels of PD-1 and diminished VDR expressions as compared to naïve mice. BALF samples of ALI mice displayed high soluble PDL-1 and reduced soluble 1,25(OH)2D levels compared to naïve mice. 1,25(OH)2D treatment alongside OA led to a significant fourfold increase in the CD107a and NKp46 expressions to levels higher than the mice treated with the vehicle. Furthermore, 1,25(OH)2D ameliorates free radical scavengers of GSH, GPX, CAT, and GPx-1; decreased pro-inflammatory cytokines and soluble PDL-1; and increased soluble 1,25(OH)2D with amelioration in pulmonary edema markers and alveolar I/II apoptosis. Conclusion: Our results indicate 1,25(OH)2D's potential therapeutic effect in preventing clinical outcomes associated with ALI via regulating NK cells through inhibiting inflammatory cytokines and alleviating levels of PDL-1 and 1,25(OH)2D released by lung tissue. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Methods Results Conclusion Acral and mucosal melanomas, the most common sun‐shielded site melanoma subtypes in Asia and Indonesia, often yield poor prognoses. The invasion depth reflects their progressivity, and the pathogenesis is influenced by vitamin D receptor (VDR) status and CD8+ T‐Lymphocyte amount. This study aims to determine the association between the invasion depth of acral and mucosal melanomas with their VDR and CD8+ immunoexpression.A cross‐sectional observational study was conducted on 60 formalin‐fixed paraffin‐embedded (FPPE) samples, with equal representation in acral and mucosal melanoma groups from 2017 to 2021. The samples were assessed for the invasion depth and immunoexpression of VDR and CD8+. A chi‐square test with an alternative Exact–Fisher analysis was used to determine the association between the variables in both subtype groups.An association between VDR and CD8+ immunoexpression and invasion depth in acral melanoma (p value = 0.0001 and 0.009, respectively) was observed, while only VDR immunoexpression was associated with the invasion depth in mucosal melanoma (p‐value =0.004). Interestingly, no association was found between CD8+ immunoexpression and the invasion depth in mucosal melanoma (p = 0.640).The role of VDR and CD8+ T‐lymphocytes are inversely associated with melanoma depth in acral melanoma, while only VDR is associated with melanoma depth in mucosal melanoma. [ABSTRACT FROM AUTHOR]

Introduction and Aims: Vitamin D has an immunomodulatory property influencing the activity of NKT cells. We aimed to study the impact of osteopontin (OPN), a key driver of fibrosis, on NKT cells' vitamin D receptor (VDR) and activity alterations. Methods: Liver fibrosis was induced in BALB/C mice with carbon-tetrachloride (CCl4) for 8 weeks with either vitamin D [100 ng/kg] or InVivoMAb anti-mouse OPN [100 μg/kg] 2X/week started at week-4 of CCl4. The liver injury profile of serum ALT, AST, and inflammatory cytokines were evaluated. Histopathological findings were assessed via H&E staining and Sirius-Red staining. Fibrotic genes of αSMA, CREBP, and collagen III were assessed using RT-PCR. Fast blood sugar, insulin, liver cholesterol, and triglyceride were evaluated. Liver tissue-resident (tr)-NKT cells were obtained for VDR expressions, molecular pathways of p-STAT1 and P-STAT-5, and activation markers of CD107a and NKp46 using flow cytometry. Results: Following vitamin D treatment, H&E staining revealed reduced microvascular and macrovascular steatosis, while Sirius-Red staining showed less fibrosis accumulation in liver fibrosis mice than in untreated counterparts. Results were associated with a significant decrease in serum cytokines of IL-β/IL-6/IL-4/OPN/TNF-α and serum AST and ALT by 2-fold and 3-fold, respectively. Fibrotic markers showed an average 1.3-fold decrease in αSMA, CREB, and Col-III in liver fibrosis mice following vitamin D treatment. Quantitated liver cholesterol and triglycerides, serum insulin, and fasting blood sugar ameliorated their levels following vitamin D treatment in liver fibrosis mice. OPN-neutralizing antibody over-expressed VDR on trNKT cells and increased CD107a and NKp46 activities of 3.1 and 3.5 folds, respectively, associated with increasing in p-STAT1 and p-STAT5 phosphorylation. These results were accompanied with a decrease in hepatic-stellate-cell activation markers of αSMA, Col-III, and desmin. Conclusion: VDR expressions affect trNKT cells activity and could modulate progressions of liver fibrosis. Using an OPN-neutralizing antibody exhibited an antifibrotic effect by alleviating the liver injury profile through NKT cells. It is also suggested as an immunomodulatory target of liver fibrosis. [ABSTRACT FROM AUTHOR]

Objectives: To determine the effects of hyperandrogenemia and other phenotypic parameters on endometrial vitamin D receptor (VDR-X2 and VDR-X4) expression in women with polycystic ovary syndrome (PCOS) undergoing ovarian stimulation and total embryo freezing. Methods: Forty-four PCOS patients were divided into four phenotypes according to the criteria for hyperandrogenemia (HA), ovulatory dysfunction (OD), and polycystic ovary morphology (PCOM): phenotype A (HA+OD+PCOM), phenotype B (HA+OD), phenotype C (HA+PCOM), and phenotype D (OD+PCOM). Endometrial VDR expression was determined by real-time PCR and immunohistochemistry. Twenty age- and body mass index (BMI)-matched couples with male infertility were included as controls. Results: VDR-X2 and VDR-X4 expression levels were significantly lower in the PCOS group than in the control group. A significant downregulation was detected in the relative VDR-X2 and X4 expression in phenotypes A, B, and C compared to the control group. VDR-X2 and X4 expression in phenotype D was significantly higher than in phenotypes A and B. A significant negative correlation was detected among VDR-X2, VDR-X4, serum testosterone (T), androstenedione (A), DHEAS, and insulin resistance (IR). Multivariate analysis revealed that serum T, A, DHEAS, and IR levels were independently associated with both VDR-X2 and VDR X4 relative gene expression after adjusting for age and BMI. The VDR mRNA and immunoreactivity of each phenotype overlapped. The clinical pregnancy rates for each phenotype were similar. Conclusion: VDR expression in the endometria of patients with PCOS was defective. Hyperandrogenemia and insulin resistance are the key drivers of defective VDR expression in the endometrium of patients with PCOS. [ABSTRACT FROM AUTHOR]

Patients carrying APOL1 risk alleles (G1 and G2) have a higher risk of developing Focal Segmental Glomerulosclerosis (FSGS); we hypothesized that escalated levels of miR193a contribute to kidney injury by activating renin–angiotensin system (RAS) in the APOL1 milieus. Differentiated podocytes (DPDs) stably expressing vector (V/DPD), G0 (G0/DPDs), G1 (G1/DPDs), and G2 (G2/DPDs) were evaluated for renin, Vitamin D receptor (VDR), and podocyte molecular markers (PDMMs, including WT1, Podocalyxin, Nephrin, and Cluster of Differentiation [CD]2 associated protein [AP]). G0/DPDs displayed attenuated renin but an enhanced expression of VDR and Wilms Tumor [WT]1, including other PDMMs; in contrast, G1/DPDs and G2/DPDs exhibited enhanced expression of renin but decreased expression of VDR and WT1, as well as other PDMMs (at both the protein and mRNA levels). G1/DPDs and G2/DPDs also showed increased mRNA expression for Angiotensinogen and Angiotensin II Type 1 (AT1R) and 2 (AT2R) receptors. Protein concentrations of Brain Acid-Soluble Protein [BASP]1, Enhancer of Zeste Homolog [EZH]2, Histone Deacetylase [HDAC]1, and Histone 3 Lysine27 trimethylated [H3K27me3] in WT1-IP (immunoprecipitated proteins with WT1 antibody) fractions were significantly higher in G0/DPDs vs. G1/DPD and G2/DPDs. Moreover, DPD-silenced BASP1 displayed an increased expression of renin. Notably, VDR agonist-treated DPDs showed escalated levels of VDR and a higher expression of PDMMs, but an attenuated expression of renin. Human Embryonic Kidney (HEK) cells transfected with increasing APOL1(G0) plasmid concentrations showed a corresponding reduction in renin mRNA expression. Bioinformatics studies predicted the miR193a target sites in the VDR 3′UTR (untranslated region), and the luciferase assay confirmed the predicted sites. As expected, podocytes transfected with miR193a plasmid displayed a reduced VDR and an enhanced expression of renin. Renal cortical section immunolabeling in miR193a transgenic (Tr) mice showed renin-expressing podocytes. Kidney tissue extracts from miR193aTr mice also showed reduced expression of VDR and PDMMs, but enhanced expression of Renin. Blood Ang II levels were higher in miR193aTr, APOLG1, and APOL1G1/G2 mice when compared to control mice. Based on these findings, miR193a regulates the activation of RAS and podocyte molecular markers through modulation of VDR and WT1 in the APOL1 milieu. [ABSTRACT FROM AUTHOR]

Background: The clinical significance of the genetic influence of vitamin D receptor polymorphisms has still not been well-analyzed. Objectives: To verify whether rs1544410, rs7975232 and rs731236 polymorphisms are associated with a higher 10-year fracture risk in postmenopausal women. Methods: The study group was a subset of a pre-defined population as part of the broader epidemiological research called the RAC-OST-POL Study and consisted of 358 postmenopausal women, chosen randomly from Racibórz (Poland) inhabitants (mean baseline age 65 ± 6.9 years, BMI 31.2 ± 5.5 kg/m2). From all participants' medical history, data concerning co-morbidities, fracture history, the medication used, parental history of bone fractures, cigarettes and alcohol use were taken at baseline. Moreover, rs1544410, rs7975232 and rs731236 polymorphisms were analyzed. Next, over the following 10 years, participants were contacted once a year and questioned concerning new fractures events and their circumstances. Results: We did not find statistically significant main effects on the fracture incidence of single-polymorphism variants. However, there were some significant findings dependent on the co-existence of these polymorphisms and medical factors. Women with a positive history of parental fracture and configuration of CC rs7975232, AA rs731236 and CC rs1544410 had a higher fracture incidence. The risk of bone fracture was also significantly higher in the group of heterozygotes of AC rs7975232 if their BMI value was in the categories of normal weight or overweight, or if they were treated with calcium or vitamin D. Conclusions: Polymorphisms of rs1544410, rs7975232 and rs731236 are connected with the fracture incidence in postmenopausal women. Nevertheless, its influence should be considered with co-existing clinical factors, especially paternal fracture history, prior fracture, BMI value, any osteoporotic treatment or calcium/vit. D supplementation. [ABSTRACT FROM AUTHOR]

Introduction: Genetic polymorphisms who disturb the mineral homeostasis during tooth development and eruption are candidate to clarify the molecular mechanisms involved in changes in the tooth eruption chronology. In this study, we evaluate whether the FokI (rs2228570) and BglI (rs739837) polymorphisms in the Vitamin D receptor (VDR) gene are associated with changes in the chronology of eruption of permanent teeth. Material & method: This cross-sectional study randomly included 353 biologically unrelated children, both sexes, without systemic impairment or syndromes and history of trauma during the primary dentition. One operator perform the oral clinical examination. The tooth was considered erupted if there was a visible minimum of any tooth surface emerging from the mucosa. Genomic DNA was extracted from buccal epithelial cells from saliva samples. Genotyping was performed by Real-Time Polymerase Chain Reactions using TaqMan® technology. The average of the total number of erupted permanent teeth between the genotypes was compared by the Mann-Whitney test and multivariate Generalized Linear Models (GLM) (α = 5 %). β values with Confidence Interval (CI) 95 % were calculated. Results: The heterozygous adenine-guanine genotype of the FokI significantly decreases the number of erupted permanent teeth (β = −1.15; CI 95 % = −2.22 to −0.07; p = 0.036). In the stratified analysis for maxillary and mandibular teeth, this genotype was associated with a decrease in the number of erupted maxillary permanent teeth (β = −0.65; CI 95 % = −1.22 to −0.09; p = 0.023). BglI was not associated with permanent teeth eruption. Conclusion: The FokI, but not BglI, in the VDR may delay the eruption of permanent teeth.

AbstractLiujunzi decoction (LJZD) is commonly used to treat hepatitis B virus (HBV), though its active ingredients and mechanisms are not fully known. This study identified core targets and active components of LJZD for treating hepatitis B (HB) through network pharmacology, molecular docking, and molecular dynamics simulation. Screening from databases yielded 533 active components, 2619 targets for LJZD, and 2910 for HB, with 891 intersecting targets. STRING and CytoHubba analyses identified AR and VDR as core targets, with key pathways including PI3K-Akt and MAPK. The findings clarify LJZD’s multicomponent, multitarget mechanisms, supporting its clinical application for HB treatment. [ABSTRACT FROM AUTHOR]

Genetic polymorphisms who disturb the mineral homeostasis during tooth development and eruption are candidate to clarify the molecular mechanisms involved in changes in the tooth eruption chronology. In this study, we evaluate whether the FokI (rs2228570) and BglI (rs739837) polymorphisms in the Vitamin D receptor (VDR) gene are associated with changes in the chronology of eruption of permanent teeth. This cross-sectional study randomly included 353 biologically unrelated children, both sexes, without systemic impairment or syndromes and history of trauma during the primary dentition. One operator perform the oral clinical examination. The tooth was considered erupted if there was a visible minimum of any tooth surface emerging from the mucosa. Genomic DNA was extracted from buccal epithelial cells from saliva samples. Genotyping was performed by Real-Time Polymerase Chain Reactions using TaqMan® technology. The average of the total number of erupted permanent teeth between the genotypes was compared by the Mann-Whitney test and multivariate Generalized Linear Models (GLM) (α = 5 %). β values with Confidence Interval (CI) 95 % were calculated. The heterozygous adenine-guanine genotype of the FokI significantly decreases the number of erupted permanent teeth (β = −1.15; CI 95 % = −2.22 to −0.07; p = 0.036). In the stratified analysis for maxillary and mandibular teeth, this genotype was associated with a decrease in the number of erupted maxillary permanent teeth (β = −0.65; CI 95 % = −1.22 to −0.09; p = 0.023). BglI was not associated with permanent teeth eruption. The FokI, but not BglI, in the VDR may delay the eruption of permanent teeth. [Display omitted] [ABSTRACT FROM AUTHOR]

Previous studies have shown that paricalcitol (PA) has a protective effect on the kidneys. However, the exact molecular mechanism by which PA affects diabetic nephropathy (DN) progression remains uncertain. PBMCs of patients with DN were isolated, and CYP2J2 and VDR levels were detected by qPCR. Pearson correlation analysis was utilized to detect the relationship between uACR and CYP2J2 and VDR and between CYP2J2 and VDR. The protective effects of PA on DN have been examined by TUNEL, HE staining, ELISA, and Flow cytometry assays in STZ‐induced mice. Moreover, THP‐1 cells were stimulated with HG/LPS for in vitro studies. ELISA, qPCR, western blot, and Flow cytometry assays were utilized to assess the effects of PA on DN progression by regulating CYP2J2. The interaction between CYP2J2 and VDR was analyzed by CHIP‐qPCR and luciferase experiments. CYP2J2 and VDR levels were downregulated and uACR level was upregulated in DN patients. CYP2J2 and VDR were positively correlated in PBMCs. Both CYP2J2 and VDR are inversely correlated with uACR. Moreover, after PA treatment, 11, 12‐EET levels increased, inflammatory factor levels decreased, and M2 macrophage polarization was promoted in STZ‐induced mice and HG/LPS‐triggered THP‐1 cells. Depletion of CYP2J2 and VDR decreased 11, 12‐EET level, enhanced inflammatory factor levels, and inhibited M2 macrophage polarization, which were reversed by CYP2J2 overexpression in HG/LPS‐treated cells. Furthermore, VDR bound to the CYP2J2 promoter and promoted CYP2J2 transcriptional expression. The present work pointed out a new use for PA to inhibit DN progression by increasing EET level, inhibiting inflammatory response, and inducing M2 macrophage polarization via regulating the VDR/CYP2J2 axis. [ABSTRACT FROM AUTHOR]

Despite the recent development of improved methods of treating melanoma such as targeted therapy, immunotherapy or combined treatment, the number of new cases worldwide is increasing. It is well known that active metabolites of vitamin D3 and lumisterol (L3) exert photoprotective and antiproliferative effects on the skin, while UV radiation is a major environmental risk factor for melanoma. Thus, many natural metabolites and synthetic analogs of steroidal and secosteroidal molecules have been tested on various cancer cells and in animal models. In this study, we tested the anti-melanoma properties of several natural derivatives of vitamin D3 and L3 in comparison to 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). A significant decrease in melanoma cell proliferation and cell mobility was observed for selected derivatives, with (25R)-27-hydroxyL3 showing the highest potency (lowest IC50) in A375 cells but lower potency in SK-MEL-28 cells, whereas the parent L3 failed to inhibit proliferation. The efficacy (% inhibition) by 1,24,25(OH)3D3 and 1,25(OH)2D3 were similar in both cell types. 1,25(OH)2D3 showed higher potency than 1,24,25(OH)3D3 in SK-MEL-28 cells, but lower potency in A375 cells for the inhibition of proliferation. As for 1,25(OH)2D3, but not the other derivatives tested, treatment of melanoma cells with 1,24,25(OH)3D3 markedly increased the expression of CYP24A1, enhanced translocation of the vitamin D receptor (VDR) from the cytoplasm to the nucleus and also decreased the expression of the proliferation marker Ki67. The effects of the other compounds tested were weaker and occurred only under certain conditions. Our data indicate that 1,24,25(OH)3D3, which has undergone the first step in 1,25(OH)2D3 inactivation by being hydroxylated at C24, still shows anti-melanoma properties, displaying higher potency than 1,25(OH)2D3 in SK-MEL-28 cells. Furthermore, hydroxylation increases the potency of some of the lumisterol hydroxy-derivatives, as in contrast to L3, (25R)-27(OH)L3 effectively inhibits proliferation and migration of the human malignant melanoma cell line A375. [ABSTRACT FROM AUTHOR]

Vitamin D activates the vitamin D receptor (VDR), which dimerizes preferentially with the retinoid X receptor‐α (RXRα). This heterodimer connects with genetic elements responsive to vitamin D, inhibiting or stimulating gene activity. We performed Nanostring® analysis of VDR/RXRα to compare the mRNA expression of this heterodimer and their correlated transcriptomes in non‐melanoma skin cancer (basal cell carcinomas (BCC) and squamous cell carcinomas (SCC)) and melanocytic lesions (intradermal nevi (IN), and melanomas (MM)) with control skin. To evaluate VDR, RXRα and other 22 correlated genes in BCC, SCC, IN and MM, paraffin samples had their transcriptomes analysed using Nanostring®, a platform that allows multiple mRNA analyses. There were 46 samples, including 11 BCC, 10 SCC, 10 IN, 12 MM and 3 pools of control skins. Most mRNAs differed between the lesion groups and the control group. BCC and SCC NCOR2 were upregulated; in MM and IN, RXRγ was higher than in the control group. TP53, FOXO3 and MED1 showed a significant difference when we compared the BCC group to the SCC group. Melanoma and intradermal nevi differed only in AhR. VDR and RXRα were lower than the control in all groups. The panel shows a clear difference between the non‐melanocytic cancers and, on the other hand, a slight difference between the melanocytic lesions. The study of vitamin D's influence through its receptor and RXRα is an exciting issue for understanding the importance of this pathway, and the present study can impact the prevention and treatment strategies, mainly in non‐melanocytic tumours. [ABSTRACT FROM AUTHOR]

Background: A possible role of vitamin D epimers and metabolites in the measurement and response to treatment of vitamin D has been reported recently. Furthermore, the influence of underlying vitamin D receptor (VDR) genetic polymorphisms which have been linked to diseases such as obesity remains unclear. We therefore aimed to examine the influence of vitamin D3 and calcium supplements on vitamin D epimer and metabolite concentrations in subjects with and those without vitamin D receptor (VDR) gene polymorphisms. Methods: A total of 277 participants who were part of a randomized intervention trial of vitamin D3 and calcium or a placebo for 6 months had clinical and anthropometric assessments. Blood samples were taken for measurements of vitamin D, epimers and metabolites of vitamin D, four vitamin D receptor gene polymorphism SNPs, namely, BsmI, FokI, TaqI, and ApaI, metabolic and inflammatory markers, and related biochemical variables. Repeated-measures analysis of variance was used to assess the between-group difference in cumulative changes in vitamin D epimers and metabolites at 6 months after adjusting for the presence of the 4 VDR genotypes and allele gene polymorphisms. Results: Overall, 277 participants, with a mean (±SD) age of 41 ± 12 and 204 (74%) of whom were female, were included in the study. We found no statistically significant differences in vitamin D metabolites or (epimers) between male and females or younger subjects compared to those over 40 years of age except in 7C4 BL (p < 0.05). There was a statistically significant difference in 1,25(OH)2D3 concentrations between subjects with and those without genotypes AG and the allele G SNP2_Taql VDR gene polymorphism. Vitamin D3 concentrations were also significantly lower in subjects with the CC SNP3_Apal gene polymorphism compared to those without the CC SNP3 gene. No statistically significant effects were seen on vitamin D epimers and metabolites concentration in response to supplements before or after adjusting for the presence of the 4 VDR genotypes and allele gene polymorphisms. Conclusions: The CC SNP3 gene had statistically significant influence on vitamin D3 levels. Vitamin D and/or calcium supplements, however, had no effects on vitamin D epimer and metabolite concentration before or after adjusting for the presence of the 4 VDR genotypes and alleles. [ABSTRACT FROM AUTHOR]

Background: Preeclampsia is a leading cause of pregnancy-related maternal and fetal morbidity and mortality. Although its precise cause and prevention remain unclear, risk factors such as overweight and inadequate nutrient intake (e.g., calcium, folic acid, and vitamin D) are known to increase its incidence. Recent research has focused on the genetic predisposition to preeclampsia, identifying polymorphisms that may affect enzyme or receptor function. This study aims to review existing literature examining the relationship between genetic polymorphisms, BMI (body mass index), and nutrient levels in preeclampsia to develop more actionable therapeutic strategies. Methods: A systematic review was conducted to analyze studies on the nutrigenetic relationship between BMI, micronutrients, and preeclampsia. Results: A total of 17 studies investigating 12 genes related to BMI and 10 studies exploring 3 genes in relation to micronutrient levels were included in the analysis. Several polymorphisms associated with preeclampsia were found to be influenced by maternal BMI or serum vitamin levels. The interactions between certain gene variants and these factors suggest that both BMI and micronutrient status may modify the risk of developing preeclampsia in genetically predisposed individuals. Conclusions: Our findings emphasize the potential for reanalyzing existing data by categorizing based on genotype and nutrient levels. This approach could yield more personalized dietary and therapeutic recommendations for managing preeclampsia. In the future, genetic information may support the development of tailored nutritional counseling during pregnancy to mitigate preeclampsia risk. [ABSTRACT FROM AUTHOR]

Several auto-immune diseases have been linked to vitamin D deficiency as a contributing environmental factor. Its pleiotropic effects on the immune system, especially its essential role in maintaining immune tolerance, make the vitamin D pathway of great interest. In this study, we focused on Pemphigus foliaceous (PF) in Tunisian population. we aimed to quantify the Serum 25[OH]D levels using chemiluminescence assay and to analyze the differential expression of the VDR, CYP27B1 and CYP24A1 genes in the circulating blood cells and lesional skin tissue of PF patients using Q-PCR. A genetic explanation was then sought to explore any direct relationship between tag polymorphisms and the inherited features of PF. Results confirmed a vitamin D hypovitaminosis in Tunisian PF patients. Interestingly, a differential gene expression correlated to the disease stratification was noted. Indeed, at the systemic level, an upregulation of VDR and CYP27B1 genes was observed in healthy controls compared to PF patients. Notably, in lesional skin tissue, the clinical and serological remission phase was correlated with high transcriptional levels of the VDR gene and conversely a drop in expression of the CYP24A1 gene. Genetic analysis indicated the involvement of the most appealing polymorphisms, rs2228570 and poly (A) microsatellite, in PF etiopathogenesis. Indeed, CAC13 haplotype was associated with a higher risk of PF development. Our findings suggest that alterations in the vitamin D-VDR pathway may influence PF physiopathology, making this pathway a potential target for pharmacological modulation, especially for cortico-resistant PF patients. [ABSTRACT FROM AUTHOR]

Nanotechnology, now established as a transformative technology, has revolutionized medicine by enabling highly targeted drug delivery. The use of organic nanocarriers in drug delivery systems significantly enhances the bioavailability of vitamins and their analogs, thereby improving cellular delivery and therapeutic effects. Vitamin D, known for its crucial role in bone health, also influences various metabolic functions, such as cellular proliferation, differentiation, and immunomodulation, and is increasingly explored for its anticancer potential. Given its versatile properties and biocompatibility, vitamin D is an attractive candidate for encapsulation within drug delivery systems. This review provides a comprehensive overview of vitamin D synthesis, metabolism, and signaling, as well as its applications in customized drug delivery. Moreover, it examines the design and engineering of organic nanocarriers that incorporate vitamin D and discusses advances in this field, including the synergistic effects achieved through the combination of vitamin D with other therapeutic agents. By highlighting these innovations, this review provides valuable insights into the development of advanced drug delivery systems and their potential to enhance therapeutic outcomes. [ABSTRACT FROM AUTHOR]

Objective: This study investigates the predictive value and risk factors associated with different vitamin D receptor (VDR) and calcium-sensing receptor (CaSR) genotypes in asthma. Methods: From December 2020 to February 2023, we studied 86 asthma patients and 70 healthy controls, analyzing VDR single nucleotide polymorphisms (SNPs) (rs1544410 and rs731236) and CaSR SNPs (rs1801726 and rs1042636) using DNA extracted from whole blood. We compared genotype distributions, demographic data, lung function parameters, vitamin D levels, and immune and inflammatory markers between the two groups. Results: The study group exhibited higher frequencies of VDR rs1544410 genotype TT and allele T, and CaSR rs1801726 genotype GG and allele G, but lower frequencies of CaSR rs1042636 genotype GG and allele G compared with controls (p < 0.05). Additionally, patients in the study group showed elevated rates of family history/genetic predisposition, allergy history, smoking, and higher levels of neutrophils, interleukin (IL)-4, IL-6, IL-8, IL-10, IL-17, and interferon-gamma (IFN-γ ). They also demonstrated lower levels of FEV1, FVC, PEFR, and 25-(OH)-D (P < 0.05). Logistic regression identified several factors, including specific genotypes, family history, and biomarker levels, as significant asthma risk factors. Conclusion: VDR rs1544410 and CaSR rs1801726 and rs1042636 may serve as potential diagnostic markers for asthma, highlighting their role in assessing genetic predisposition and disease severity. [ABSTRACT FROM AUTHOR]

Objective: Tuberculosis (TB) is the leading cause of mortality worldwide. Previous studies have reported that TB susceptibility can be caused by vitamin D deficiency, which is affected by polymorphisms in the vitamin D receptor (VDR) gene. However, these results have been inconsistent. Therefore, we performed a meta-analysis to investigate the association between VDR polymorphisms and TB susceptibility. Methods: We systematically searched for relevant literature in PubMed, Embase, and Medline databases through December 31st, 2022. Inclusion and exclusion criteria were made to ensure that HIV-negative population is the targeted subjects. The pooled odds ratio (OR) and 95% confidence interval (CI) were then used to assess the strength of the association, and the quality of the included articles was evaluated using the Newcastle-Ottawa Scale. Potential sources of heterogeneity were evaluated based on subgroup and meta-regression analyses. Results: In our meta-analysis, we found that the FokI polymorphism in the VDR gene was associated with increased TB susceptibility in the allele and recessive genotype models (OR f vs. F = 1.235, 95%CI: 1.035-1.475; OR ff vs. Ff + FF = 1.317, 95%CI: 1.00-1.727. Further subgroup analysis based on ethnicity demonstrated the association with the risk of TB in all genotype models of the FokI polymorphism for Han population. Meta-regression analysis also indicated that ethnicity could be a potential source of heterogeneity in the FokI and BsmI polymorphisms in the VDR gene. However, publication year was another source of heterogeneity for the TaqI polymorphism. Conclusion: In summary, the FokI polymorphism in the VDR gene was found to increase the risk of TB in the HIV-negative population, both overall and in Asian populations. The findings presented in this paper could provide clues for preventing TB from the perspective of vitamin D supplementation, which is a controversial topic in the field of medicine and health. [ABSTRACT FROM AUTHOR]

Background and Objectives: Polycystic ovary syndrome (PCOS) is a frequent and complex multidisciplinary disorder. Data regarding the role of genes involved in vitamin D metabolism in PCOS are as-yet elusive but suggest an association of VDR (vitamin D receptor) and vitamin D levels with metabolic, endocrine and cutaneous manifestations. The aim of this study was to evaluate the association between VDR gene polymorphisms and cutaneous manifestations, to find a correlation between hormonal parameters, oxidative stress and skin manifestations in women with PCOS, and to determine the impact of VDR gene polymorphisms on these parameters. Materials and Methods: This case–control study included 39 controls and 46 women with PCOS, matched by age and BMI distribution. Acne, hirsutism, seborrhea, androgenetic alopecia, oxidative stress and androgen hormones were recorded. VDR gene polymorphisms ApaI, FokI and TaqI were examined by polymerase chain reaction restriction fragment length polymorphism, and the androgen hormone (total testosterone, DHEAS), SHBG and malondialdehyde levels were assessed. Results: The most frequent skin manifestations in PCOS cases were acne followed by seborrhea, hirsutism and androgenic alopecia. The VDR-FokI polymorphism CC genotype had a significant protective role in the odds of acne (OR = 0.11, 95% CI: [0.02, 0.70], p = 0.015, p-corrected = 0.040) and seborrhea (OR = 0.15, 95% CI: [0.03, 0.75], p = 0.019, p-corrected = 0.039). The results demonstrated a significant protective effect of the C allele on the odds of acne and seborrhea in PCOS cases. Moreover, the dominant genotype of VDR-TaqI could have a protective role against oxidative stress (lower MDA levels) compared to patients carrying the TT genotype. Conclusions: In summary, this is the first study to demonstrate that the FokI CC genotype may have a protective role against both acne and seborrhea in women with PCOS, while the VDR-TaqI dominant genotype is associated with diminished oxidative stress in PCOS patients. [ABSTRACT FROM AUTHOR]

IntroductionAge-related decline in muscle strength and performance significantly impact morbidity and mortality. Various factors including genetics have been investigated to better understand this decline. This study aimed to investigate longitudinal changes in physical performance and strength and their association with genetic variants in genes involved in the vitamin D pathway.MethodsThis longitudinal study was conducted in the Prishtina region, Kosovo, with community-dwelling adults over 40 years of age. Genomic DNA was extracted from saliva samples to assess single nucleotide polymorphisms in the vitamin D receptor (VDR) gene (rs7975232, rs2228570, rs731236, also referred to as ApaI, FokI, and TaqI, respectively) and the vitamin D binding protein (GC) gene (rs4588, rs2282679). Physical performance was assessed by isometric handgrip strength, 30-s chair stand, timed up and go and 6-min walk test. Vitamin D levels were assessed from blood samples only at follow-up.ResultsA total of 138 participants (65.1 ± 9.0 years, 52.2% female) were included. Over a 2.7-year period, significant declines in the 30-s chair stand test (p

Nuclear Receptors (NRs) comprise a superfamily of proteins with essential roles in cell signaling, survival, proliferation, and metabolism. They act as transcription factors and are subclassified into families based on their ligands, DNA-binding sequences, tissue specificity, and functions. Evidence indicates that in infectious diseases, cancer, and autoimmunity, NRs modulate immune and endocrine responses, altering the transcriptional profile of cells and organs and influencing disease progression. Chronic infectious diseases, characterized by pathogen persistence, are particularly notable for an exaggerated inflammatory process. Unlike acute inflammation, which helps the host respond to pathogens, chronic inflammation leads to metabolic disorders and a dysregulated neuro-immuno-endocrine response. Over time, disturbances in cytokine, hormone, and other compound production foster an unbalanced, detrimental defensive response. This complexity underscores the significant role of ligand-dependent NRs. Tuberculosis and Chagas Disease are two critical chronic infections. The causative agents, Mycobacterium tuberculosis and Trypanosoma cruzi, have developed evasion strategies to establish chronic infections. Their clinical manifestations are associated with disrupted immuno-endocrine responses, pointing to a potential involvement of NRs. This review explores the current understanding of NRs in regulating immune-endocrine interactions within the context Tuberculosis and Chagas Disease. These diseases remain significant global health concerns, particularly in developing countries, highlighting the importance of understanding the molecular mechanisms underlying host-pathogen interactions mediated by NRs.

Background and aimNK cells and NK-cell-derived cytokines were shown to regulate neutrophil activation in acute lung injury (ALI). However, the extent to which ALI regulates lung tissue-resident NK (trNK) activity and their molecular phenotypic alterations are not well defined. We aimed to assess the impact of 1,25-hydroxy-vitamin-D3 [1,125(OH)2D] on ALI clinical outcome in a mouse model and effects on lung trNK cell activations.MethodsOleic acid (OA)-induced ALI in C57BL/6J mice and 1,25(OH)2D treatment 2×/2 weeks were performed. Lung tissue was harvested to assess alveolar I/II cell apoptosis and lung injury marker of Surfactant-Protein-D (SP-D). Pulmonary edema markers of epithelial sodium channel, cystic fibrosis transmembrane conductance regulator, and aquaporin 5 were assessed by RT-PCR. Lung trNK cells were assessed for activation markers of CD107a and NKp46, vitamin D receptor (VDR), and programmed cell death protein-1 (PD-1) via flow cytometry. The bronchoalveolar lavage fluid (BALF) obtained was investigated for soluble receptor for advanced glycation end products (sRAGE), inflammatory cytokines, soluble 1,25(OH)2D, and PDL-1. Naïve mice treated with DMSO (vehicle) were used as a control.ResultsFlow cytometry analysis displayed a high apoptotic rate in alveolar I/II cells of threefold in ALI mice as compared to naïve mice. These findings were accompanied by elevated markers of pulmonary edema as well as lung injury markers of SP-D. Isolated lung trNK cells of the ALI mice exhibited reduced CD107a and NKp46 markers and cytotoxicity potentials and were correlated through significantly 2.1-fold higher levels of PD-1 and diminished VDR expressions as compared to naïve mice. BALF samples of ALI mice displayed high soluble PDL-1 and reduced soluble 1,25(OH)2D levels compared to naïve mice. 1,25(OH)2D treatment alongside OA led to a significant fourfold increase in the CD107a and NKp46 expressions to levels higher than the mice treated with the vehicle. Furthermore, 1,25(OH)2D ameliorates free radical scavengers of GSH, GPX, CAT, and GPx-1; decreased pro-inflammatory cytokines and soluble PDL-1; and increased soluble 1,25(OH)2D with amelioration in pulmonary edema markers and alveolar I/II apoptosis.ConclusionOur results indicate 1,25(OH)2D’s potential therapeutic effect in preventing clinical outcomes associated with ALI via regulating NK cells through inhibiting inflammatory cytokines and alleviating levels of PDL-1 and 1,25(OH)2D released by lung tissue.

ABSTRACT The vitamin D receptor (VDR) is a nuclear steroid receptor that regulates the expression of genes across various biological functions. However, the role of VDR in pseudorabies virus (PRV) infection has not yet been explored. We discovered that VDR positively influenced PRV proliferation because knockdown of VDR impaired PRV proliferation, whereas its overexpression promoted it. Additionally, we observed that PRV infection upregulated VDR transcription alongside 1,25-dihydroxyvitamin D3 (VD3) synthesis, contingent on p53 activation. Furthermore, VDR knockdown hindered PRV-induced lipid synthesis, implicating VDR’s involvement in this process. To decipher the mechanism behind VDR’s stimulation of lipid synthesis during PRV infection, we conducted RNA sequencing (RNA-seq) and found significant enrichment of genes in the Ca2+ signaling pathway. Measurements of Ca2+ indicated that VDR facilitated Ca2+ absorption. Moreover, the PI3K/AKT/mTORC1 and AMPK/mTORC1 pathways were also enriched in our RNA-seq data. Interfering with VDR expression, or chelating Ca2+ using BAPTA-AM, markedly impacted the activation of PI3K/AKT/mTORC1 and AMPK/mTORC1 pathways, lipid synthesis, and PRV proliferation. In summary, our study demonstrates that PRV infection promotes VDR expression, thereby enhancing Ca2+ absorption and activating PI3K/AKT/mTORC1- and AMPK/mTORC1-mediated lipid synthesis. Our findings offer new insights into strategies for PRV prevention.IMPORTANCEVitamin D, beyond its well-known benefits for bone health and immune function, also plays a pivotal role in regulating gene expression through its receptor, the vitamin D receptor (VDR). Although VDR’s influence spans multiple biological processes, its relationship with viral infections, particularly pseudorabies virus (PRV), remains underexplored. Our research illustrates a complex interplay where PRV infection boosts VDR expression, which in turn enhances Ca2+ absorption, leading to the activation of critical lipid synthesis pathways, PI3K/AKT/mTORC1 and AMPK/mTORC1. These findings not only deepen our understanding of the intricate dynamics between host molecular mechanisms and viral proliferation but also open avenues for exploring new strategies aimed at preventing PRV infection. By targeting components of the VDR-related signaling pathways, we can potentially develop novel therapeutic interventions against PRV and possibly other similar viral infections.

Colorectal cancer (CRC) is the third most prevalent cancer worldwide. Vitamin D receptor (VDR) gene mutations and Vitamin D deficiency contribute to CRC development and progression. Certain long non-coding RNAs (lncRNAs) directly inhibit VDR gene transcription, leading to VDR mutation. Thus, targeting oncogenic lncRNAs and VDR expression is a promising strategy for effective cancer treatment. Here, we green-synthesized Lactobacillus plantarum loaded nickel oxide nanoparticles (LpNiONPs) to assess their anticancer potential in CRC by targeting long non-coding RNA EIF3J- divergent transcript (lncRNA EIF3J-DT) and VDR. The potent bioactive component present in L. plantarum was identified via gas chromatography-mass spectrometry (GC–MS) analysis, and its interaction with VDR, as well as the functional interaction with lncRNA EIF3J-DT, were evaluated using the PyRx program and RPISeq-software, respectively. The LpNiONPs were characterized using UV–Vis spectroscopy, Zeta Potential, dynamic light scattering (DLS), fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), energy dispersive X-ray (EDX) and X-ray diffraction (XRD) techniques. The anticancer potential of LpNiONPs against HT-29 cells was assessed through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, scratch assay, 4′,6-diamidino-2-phenylindole (DAPI)/ acridine orange-ethidium bromide (AO-EtBr) staining experiments, and reverse transcriptase-PCR to evaluate the expression of lncRNA EIF3J-DT/VDR and apoptotic-related genes. The potent bioactive compound Pyrrolo (1,2-a) pyrazine-1,4-dione in L. plantarum strongly interacts with VDR, highlighting its drug design potential. The formation of LpNiONPs was confirmed via UV–Vis spectroscopy with an absorption peak at 394 nm. LpNiONPs were positively charged, monodispersed, and stable square-shaped nanoparticles. LpNiONPs show dose-dependent cytotoxicity and induced apoptosis, confirmed by staining images in HT-29 cells. Moreover, LpNiONPs downregulated lncRNA EIF3J-DT, CYP24-A1 and BCL2 genes while upregulating VDR, cas-3, cas-9 and BAX in HT-29 cells. These findings suggest that LpNiONPs exhibit anticancer activity by promoting VDR-associated apoptosis by inhibiting lncRNA EIF3J-DT in CRC cells.

This study aimed to determine the association of vitamin D serum blood levels and vitamin D gene polymorphism with the severity of coronary lesions in patients with stable coronary artery disease (CAD). Material and methods. 260 patients with stable CAD (average age was 58 years) were examined in the presented research. All patients were divided into two groups according to the SYNTAX score: low-risk patients with SYNTAX score ≤ 31 (n = 224) and high-risk patients with SYNTAX score > 31 (n = 36). For enzyme-linked immunosorbent assay and genetic analysis, peripheral blood was collected from the cubital vein into vacuum tubes containing coagulation activator and K3-EDTA, respectively. Serum blood level of 25-hydroxyvitamin D (DiaSource Diagnostics, Belgium) and 1,25-dihydroxyvitamin D (Immunodiagnostic Systems, Great Britain) were determined by enzyme-linked immunosorbent assay according to the manufacturers’ protocols. Genomic DNA was isolated by phenol-chloroform extraction method from whole blood. The quality and quantity of isolated DNA were assessed using NanoDrop spectrophotometer (Thermo Fisher Scientific, USA). Five polymorphic variants in the VDR (rs2228570 and rs73123) and GC (rs7041, rs1155563 and rs2298849) genes were selected for analysis. Genotyping was performed by real-time PCR in a 96-well plate with fluorescently labeled TaqMan probes. The quality of PCR was controlled by repeated genotyping of 10 % of the analyzed samples. Results. We found no statistically significant differences in serum blood level of the studied markers in patients from low-risk and high-risk groups. One polymorphic variant in the GC gene associated with the multiple coronary lesions (rs2298849) (odds ratio 2.26, 95 % confidence interval 1.28–3.99, p = 0.006) according to an additive inheritance model was identified. In addition, we determined the association between low serum blood level of 1,25-dihydroxyvitamin D in patients with CAD with multiple lesions of the coronary vascular system with A/A – A/G genotypes of the rs2228570 polymorphism in the VDR gene, A/A genotype of the rs7041 polymorphism and A/A genotype of the rs2298849 polymorphism in the GC gene. Conclusions. Allelic variants in the vitamin D metabolism genes are associated with the degree of coronary artery lesions assessed by the SYNTAX score in patients with stable CAD. Also, serum blood level of the active form of vitamin D (1,25-dihydroxyvitamin D) is less in carriers of homozygous genotypes for the major alleles of the VDR and GC genes.

According to recent data, vitamin D is classified as a substance with hormonal activity, which, in addition to classical, has “non-classical” effects caused by the complex relationship between vitamin D and effector cells of the immune system. This relationship is based on the expression of the vitamin D receptor (VDR) on immune cells, which is encoded by the corresponding VDR gene. Vitamin D receptor specifically binds the active form of vitamin D (1,25(OH)2D3). As a result, a D3-VDR complex is formed, which mediates the effects of vitamin D through the formation of intracellular signaling pathways that transform the activity of certain target genes. However, it is not entirely clear how vitamin D realizes its effects at the cellular and receptor levels. According to the literature, studies of recent decades have revealed a significant role of vitamin D and immune checkpoint receptors (PD-1 (programmed cell death), PD-L (PD ligand), CTLA (cytotoxic T lymphocyte associated protein)) in autoimmune diseases. This review outlines possible mechanisms for the interconnection of these pathways. A deeper understanding of the intercellular interactions mediated by ligand-associated activation of vitamin D receptors, D3-VDR complex and immune checkpoint receptors (PD-1, PD-L, CTLA) in inflammation may become the basis for the development of new strategies for the diagnosis, prognosis and treatment of various diseases

Abstract Background Recent studies have indicated the importance of muscle quality in addition to muscle quantity in sarcopenia pathophysiology. Intramuscular adipose tissue (IMAT), which originates from mesenchymal progenitors (MPs) in adult skeletal muscle, is a key factor affecting muscle quality in older adults, suggesting that controlling IMAT formation is a promising therapeutic strategy for sarcopenia. However, the molecular mechanism underlying IMAT formation in older adults has not been clarified. We recently found that the vitamin D receptor (VDR) is highly expressed in MPs in comparison to myotubes (P = 0.028, N = 3), indicating a potential role of vitamin D signalling in MPs. In this study, we aimed to clarify the role of vitamin D signalling in MP kinetics, with a focus on adipogenesis. Methods MPs isolated from mouse skeletal muscles were subjected to adipogenic differentiation conditions with or without vitamin D (1α,25(OH)2D3, 100 nM) for 7 days, and adipogenicity was evaluated based on adipogenic marker expression. For in vivo analysis, tamoxifen‐inducible MP‐specific VDR‐deficient (VdrMPcKO) mice were newly developed to investigate whether lack of vitamin D signalling in MPs is involved in IMAT formation. To induce muscle atrophy, VdrMPcKO male mice were subjected to tenotomy of the gastrocnemius muscle, and then muscle weight, myofibre cross‐sectional area, adipogenic marker expression, and fatty infiltration into the muscle were evaluated at 3 weeks after operation (N = 3–4). In addition, a vitamin D‐deficient diet was provided to wild‐type male mice (3 and 20 months of age, N = 5) for 3 months to investigate whether vitamin D deficiency causes IMAT formation. Results Vitamin D treatment nearly completely inhibited adipogenesis of MPs through Runx1‐mediated transcriptional modifications of early adipogenic factors such as PPARγ (P = 0.0031) and C/EBPα (P = 0.0027), whereas VDR‐deficient MPs derived from VdrMPcKO mice differentiated into adipocytes even in the presence of vitamin D (P = 0.0044, Oil‐Red O+ area). In consistency with in‐vitro findings, VdrMPcKO mice and mice fed a vitamin D‐deficient diet exhibited fat deposition in atrophied (P = 0.0311) and aged (P = 0.0216) skeletal muscle, respectively. Conclusions Vitamin D signalling is important to prevent fate decision of MPs towards the adipogenic lineage. As vitamin D levels decline with age, our data indicate that decreased vitamin D levels may be one of the causes of IMAT formation in older adults, and vitamin D signalling may be a novel therapeutic target for sarcopenia.

Abstract Objectives Specific miRNAs are evident to be overexpressed with age, lifestyle, and environmental changes. Previous studies reported miR‐124 overexpression in different scenarios in aged skin, age‐related cognitive impairment, ischemic heart disease, muscle atrophy, and fractures. Thus miR‐124 was considered to be a reliable miRNA target to establish a hypothesis on aging epigenome. Parallelly the hypothesis focuses on the expression of SIRT1 and VDR genes as a target for this specific miRNA expression as these genes were believed to be related to aging. This study aims to derive facts and evidence from past studies on aging. The objective was to establish a hypothetical linkage between miR‐124 with age‐related genes like SIRT1 and VDR. Methods An in silico search was performed in the TargetScan and miRbase databases to analyze the aging‐associated miRNAs and their gene targets, the Python seaborn library was used, and the results were represented in terms of a bar plot. Results Based on an in silico analysis and studies available in the literature, we identified that miR‐124‐3p.1 and miR‐124‐3p.2 targets 3′ UTR of VDR and SIRT1 genes, and hence thereby indicates that the miR‐124 can regulate the expression of these genes. Further, few in vitro research studies have observed that miR‐124 overexpression leads to the downregulation of VDR and SIRT1 gene expression. These results indicate that the suppression of these target genes accelerates early aging and age‐related disorders. Conclusions Overall, this study hypothesizes that the overexpression of miR‐124 diminishes the expression of VDR and SIRT1 genes, and thereby advances the process of aging, resulting in the development of age‐associated complications.

Atopic diseases, including atopic dermatitis (AD) and allergic asthma (AA), are characterized by complex immune responses involving various T cells subsets and their cytokine profiles. It is assumed that single nucleotide polymorphisms (SNPs) in the Vitamin D receptor (VDR) gene and the Vitamin D-binding protein (GC) gene are related to the action of Vitamin D and, consequently, play a role in regulating the immune response. However, there is not enough data to unequivocally support the hypothesis about the relationship between T cells profile and VDR or GC SNPs. Two hundred sixty-six subjects (aged > 18 years) were involved in the study: 100 patients with mild or moderate AD, 85 patients with mild or moderate AA, and 81 healthy individuals. Blood cell counts were determined by standard methods. Flow cytometric analysis was used to evaluate CD4+ T-helper (Th) cell subtypes: Th2, Th1, Th17, and T regulatory (Treg) cells in peripheral blood. Measurements of cytokines, total immunoglobulin E (IgE), and Vitamin D levels in serum were evaluated by ELISA. Significantly higher levels of Th1, Th2, and Th17 cells, along with lower levels of Tregs, were found in patients with atopic diseases compared to healthy individuals. Additionally, higher serum levels of interleukin (IL) 5, IL-17A, and transforming growth factor-β1 (TGF-β1), as well as lower levels of IL-10, were observed in patients with atopic diseases than in control. The study established associations between VDR SNPs and immune profiles: the AA genotype of rs731236 was associated with increased Th2 and Th17 cells and a higher Th1/Th2 ratio; the GG genotype of rs731236 was linked to decreased serum IL-10 and TGF-β1 levels; and the TT genotype of rs11168293 was associated with increased IL-10 levels. Additionally, the GG genotype of GC gene SNP rs4588 was associated with reduced Th2 and Th17 lymphocytes, while the TT genotype of rs4588 was linked to decreased IL-10 levels. Furthermore, the CC genotype of rs7041 was associated with higher levels of Th2, Th17, IL-10, and IL-35, as well as reduced levels of TGF-β1, while the GG genotype of rs3733359 was associated with reduced IL-10 levels. In conclusion, our study demonstrates that the Vitamin D receptor gene single nucleotide polymorphisms rs731236 and rs11168293, along with polymorphisms in the Vitamin D-binding protein gene (rs4588, rs7041, rs3733359), are significantly associated with variations in T cell profiles in atopy. These variations may play a crucial role in promoting inflammation and provide insight into the genetic factors contributing to the pathogenesis of atopy. [ABSTRACT FROM AUTHOR]

A total hip arthroplasty (THA) can improve quality of life, but loosening of the hip prosthesis is a complex problem in which vitamin D may also play a role. The Vitamin D Receptor (VDR) is involved in the response of cells to the action of vitamin D, and its genetic variability raises the question of whether individual differences could influence the risk of prosthesis loosening. The aim of this study was to investigate the relationship between VDR single nucleotide polymorphisms (SNPs) (ApaI, BsmI, FokI and TaqI) and the serum VDR and 25(OH)D levels in three groups of patients: (1) arthroscopy patients after THA without loosening of the prosthesis (CA—Control Arthroplasty), (2) patients after THA with loosened hip prostheses (L—Loosening) and (3) the control group (C—Control). Our results suggest that the genotypes tt of TaqI, BB of BsmI, and FF of FokI may influence the VDR effect in patients with loosened protheses. Our results showed that the ACAC haplotype (AtBF) was over two times more frequent in the L group than in CA + C: OR =2.35 [95% CI 1.44–3.83; p = 0.001]. There was no significant correlation between the VDR and serum 25(OH)D levels, but there were differences between studied groups. [ABSTRACT FROM AUTHOR]

Objective of the study was to find the association of vitamin D receptor (VDR) polymorphisms (Fokl, Taql and Apal) with vitamin D levels in diabetic foot ulcer (DFU) patients in South India. In this case–control study, plasma vitamin D levels and VDR genotype frequencies of 70 cases (DFU patients) were compared with 70 diabetic (diabetes mellitus [DM] [non‐DFU]) patients and 70 apparently healthy controls (HC) from South India. Plasma vitamin D levels were measured using the ELISA technique, and genotyping of VDR polymorphisms was carried out using real‐time polymerase chain reaction. Logistic regression was used to find the association between DFU versus HC and DFU versus DM traits. Association analysis was performed based on additive, dominant and recessive models with age and gender as covariates. A 45.7% of DFU patients have sufficient vitamin D levels than 48.6% and 40% of DM patients and HC, respectively. Linkage disequilibrium analysis for DFU versus HC and DFU versus DM traits shows that single nucleotide polymorphisms (SNPs) Taq1 (rs731236) and Apal (rs7975232) are in strong linkage disequilibrium in DFU patients. The alleles and genotype frequencies were similar in all three groups. Although the additive model does not show statistical significance, age and sex correlate with the three SNPs (Fokl, Taql and Apal). No association was found between VDR gene polymorphisms and vitamin D levels in DFU patients in Southern India. On the other hand, age and sex correlate with the three SNPs. [ABSTRACT FROM AUTHOR]

Concerns regarding toxicity and resistance of current drugs in visceral leishmaniasis have been reported. Antimicrobial peptides are considered to be promising candidates and among them human cathelicidin hCAP18/LL-37 showed significant parasite killing on drug-sensitive and resistant Leishmania promastigotes, in addition to its apoptosis-inducing role. Administration of hCAP18/LL-37 to infected macrophages also decreased parasite survival and increased the host favorable cytokine interleukin 12. However, 1,25-dihydroxyvitamin D3 (vitamin D3)-induced endogenous hCAP18/LL-37 production was hampered in infected THP-1 cells. Infection also suppressed the vitamin D3 receptor (VDR), transcription factor of hCAP18/LL-37. cAMP response element modulator (CREM), the repressor of VDR, was induced in infection, resulting in suppression of both VDR and cathelicidin expression. PGE2/cAMP/PKA axis was found to regulate CREM induction during infection and silencing CREM in infected cells and BALB/c mice led to decreased parasite survival. This study documents the antileishmanial potential of cathelicidin and further identifies CREM as a repressor of cathelicidin in Leishmania infection. [ABSTRACT FROM AUTHOR]

Background: The etiopathogenesis of inflammatory bowel disease (IBD) is still unclear. Prior studies suggest genetic components that may influence the incidence and severity of the disease. Additionally, it was shown that low levels of serum vitamin D may have an impact on the clinical course of the disease due to its effect on the immunological system. Methods: We aimed to investigate the correlation between the incidence of vitamin D receptor (VDR) gene polymorphisms (rs11568820, rs10735810, rs1544410, rs7975232, and rs731236, commonly described as Cdx2, FokI, Bsm, ApaI, and TaqI, respectively) and vitamin D concentration with the clinical course of IBD (disease activity, extent of the intestinal lesions). Data were obtained from 62 patients with IBD (34 with Crohn's disease, 28 with ulcerative colitis), aged 3–18 years, and compared with controls (N = 47), aged 8–18 years. Results: Although there was no difference in the incidence of individual genotypes between the study groups (IBD, C) in all the polymorphisms examined, we described a significant increase in the chance of developing IBD for heterozygotes of Cdx2 (OR: 2.3, 95% CI 0.88–6.18, p = 0.04) and BsmI (OR: 2.07, 95% CI 0.89–4.82, p = 0.048) polymorphisms. The mean serum 25OHD level in patients with IBD was significantly higher compared with the controls (19.87 ng/mL vs. 16.07 ng/mL; p = 0.03); however, it was still below optimal (>30 ng/mL). Furthermore, a significant correlation was found between vitamin D level and TaqI in patients with IBD (p = 0.025) and patients with CD (p = 0.03), as well as with the BsmI polymorphism in patients with IBD (p = 0.04) and patients with CD (p = 0.04). A significant correlation was described between the degree of disease activity and genotypes for the FokI polymorphism in patients with UC (p = 0.027) and between the category of endoscopic lesions and genotypes for the Cdx2 polymorphism also in patients with UC (p = 0.046). Conclusions: The results suggest a potential correlation of VDR gene polymorphism with the chance of developing IBD, and the clinical course of the disease requires further studies in larger group of patients. Vitamin D supplementation should be recommended in both children with inflammatory bowel disease and in healthy peers. [ABSTRACT FROM AUTHOR]

Backround. The aim of this study was to examine the expression levels of the Thioredoxin interacting protein (TXNIP), Vitamin D receptor (VDR), Human 8-oxoguanine DNA N-glycosylase 1 (hOGG1) genes in bladder cancer patients, according to clinical staging and determine the levels of potential therapeutic targets in serum samples. Material and Methods. Tissue and serum samples of patients who underwent transurethral resection (TUR) between 2017 and 2018 were obtained. Levels of TXNIP, hOGG1, and VDR genes were assessed using Real time-polymerase chain reaction (RT-PCR), while levels of Thioredoxin (Trx), 8-hydroxy-2' -deoxyguanosine (8-OHdG), and 1,25-dihydroxyvitamin D (25(OH)D3) were evaluated using the enzyme-linked immunosorbant assay (ELISA) method. Selenium levels were also measured using Optical Emission Spectroscopy (ICP-OES) in both tissue and serum samples. The protein-protein interactions and molecular and biological function of the proteins were assessed using Search Tool for the Retrieval of Interacting Genes/Proteins. Statistical analysis was conducted using IBM SPSS Statistics version 20.0. Results. The TXNIP gene showed higher expression in low-grade bladder cancer patients up to stage T1, but decreased in high-grade T1 and T2 stages. Both VDR and hOGG1 gene expressions were consistently lower across all clinical subgroups. No significant differences were found in serum 25(OH)D3, 8-OHdG, Hypoxia Inducible Factor 1 Alpha (HIF-1α), selenium (Se), and tissue Se levels. Conclusions. TXNIP mRNA expression was remarkably lower in advanced stages. VDR and hOGG1 expression were low in all bladder cancer subgroups. These parameters could serve as potential targets for preventing or treating bladder cancer. [ABSTRACT FROM AUTHOR]

Background and Objectives: Parathyroid adenoma is a distinct cause of primary hyperparathyroidism, with the vast majority being sporadic ones. Proteomic analysis of parathyroid adenomas has proposed a large number of related proteins. The aim of this study is to evaluate the immunohistochemical staining of ANXA2, MED12, MAPK1 and VDR in parathyroid adenoma tissue. Materials and Methods: Fifty-one parathyroid adenomas were analyzed for ANXA2, MED12, MAPK1 and VDR expressions. Tissue was extracted from formalin-fixed paraffin-embedded parathyroid adenoma specimens; an immunohistochemical study was applied, and the percentage of allocation and intensity were evaluated. Results: ANXA2 stained positively in 60.8% of all cell types, while MED12 had positive staining in 66%. MAPK1 expression was found to be negative in total, although a specific pattern for oxyphil cells was observed, as they stained positive in 17.7%. Finally, VDR staining was positive at 22.8%, based on nuclear staining. Conclusions: These immunohistochemical results could be utilized as biomarkers for the diagnosis of sporadic parathyroid adenoma. It is of great importance that a distinct immunophenotype of nodule-forming cells in a positive adenoma could suggest a specific pattern of adenoma development, as in hereditary patterns. [ABSTRACT FROM AUTHOR]

Vitamin D3 deficiency and insufficiency are becoming a common global issue for us, especially in the most industrially developed countries. The only acknowledged activity of vitamin D3 in vertebrates is to promote the absorption of calcium and, therefore, allow for the mineralization of bones. Accordingly, its deficiency is associated with diseases such as rickets. Other numerous vital functions associated with vitamin D3 are yet to be considered, and the function of vitamin D2 in plants is unknown. Thus, 100 years after its discovery, the importance of vitamin D still seems to be unacknowledged (except for rickets), with little attention given to its decrease throughout the world. In this review, I suggest that vitamin D deficiency and insufficiency may be linked to the westernized lifestyle in more developed countries. Furthermore, I suggest that, rather than the calcemic activity, the main function of vitamin D is, in general, that of strengthening living organisms. I conclude with the hypothesis that vitamin D deficiency may represent a marker for a greater risk of chronic inflammatory diseases and a shorter life expectancy. [ABSTRACT FROM AUTHOR]

Dentin is a permeable and complex tubular composite formed by the mineralization of predentin that mineralization and repair are of considerable clinical interest during dentin homeostasis. The role of Vdr, a receptor of vitamin D, in dentin homeostasis remains unexplored. The aim of the present study was to assess the impact of Vdr on predentin mineralization and dental repair. Vdr-knockout (Vdr−/−) mice models were constructed; histology and immunohistochemistry analyses were conducted for both WT and Vdr−/− mice. The finding revealed a thicker predentin in Vdr−/− mice, characterized by higher expression of biglycan and decorin. A dental injury model was employed to observe tertiary dentin formation in Vdr−/− mice with dental injuries. Results showed that tertiary dentin was harder to form in Vdr−/− mice with dental injury. Over time, heightened pulp invasion was observed at the injury site in Vdr−/− mice. Expression of biglycan and decorin was reduced in the predentin at the injury site in the Vdr−/− mice by immunohistochemistry. Taken together, our results imply that Vdr plays a regulatory role in predentin mineralization and tertiary dentin formation during dentin homeostasis. [ABSTRACT FROM AUTHOR]