Search Results (129)

The vitamin D receptor (VDR) acts as both a nuclear transcription factor and a non-genomic mediator that regulates a broad spectrum of physiological processes beyond calcium and phosphate homeostasis. VDR plays an important role in the modulation of ion channels across multiple tissues, including osteoblasts, renal and intestinal epithelial cells, neurons, and vascular smooth muscle. These regulatory mechanisms encompass genomic actions through vitamin D response elements in target genes—such as TRPV5, TRPV6, KCNK3, and KCNH1—as well as rapid, non-genomic actions at the plasma membrane involving protein disulfide isomerase A3 and associated signaling cascades. VDR-mediated transcriptional control of calcium, potassium, and chloride channels contributes to the fine-tuning of cellular excitability, calcium transport, and mitochondrial function. Evidence also implicates VDR–ion channel crosstalk in various pathological contexts, including renal cell carcinoma, breast and cervical cancers, pulmonary arterial hypertension, and osteoporosis. Understanding the molecular interplay between VDR and ion channels provides new perspectives on the pleiotropic effects of vitamin D and offers promising therapeutic opportunities in oncology, cardiovascular disease, and skeletal disorders. This review synthesizes previous and current evidence on the genomic and non-genomic mechanisms underlying VDR–ion channel regulation and highlights novel frontiers in vitamin D signaling relevant to human health and disease. Full article

Background/Objectives: Vitamin D (VD), through the interaction with its receptor (VDR), plays essential roles in the skin. VDR-mediated signaling prevents cancer development and improves prognosis, making it an appealing target for therapy. However, VD cutaneous synthesis begins with solar exposure, which is the first etiological factor for cutaneous cancer and increases oxidative stress (OS). This complicates the dermatologist’s perspective when advising photoprotective strategies while aiming to consider the benefits of VD signaling. In this context, and in the absence of cutaneous data to date, this research aims to address VDR dynamics in skin cells and tissue subjected to OS. It also explores the potential of a natural photoprotectant with antioxidant properties (a specific combination of Polypodium leucotomos and Aspalathus linearis extracts) in preventing VDR depletion. Methods: HaCaT cell cultures and skin explants were used as experimental models. OS was induced by treatments with hydrogen peroxide (H₂O₂). The proteins of interest (VDR and Nuclear Factor Erythroid 2-Related Factor 2 (NRF2)) were analyzed by immunostaining. Cell viability, nuclear counterstaining, and Haematoxylin/Eosin staining were used as cyto/histochemical controls. Results: In both experimental models, we observed the reduction of VDR under OS. Pre-treatments with the botanical ingredient preserved VDR levels from that decline, probably through a mechanism involving NRF2. Conclusions: Cutaneous VDR levels are altered under oxidative stress, and certain photoprotectants could preserve them. This opens the door to preserving the benefits of VDR signaling while preventing solar radiation damage, bringing a new viewpoint for designing future strategies in skin cancer prevention and treatment. Full article

Cashmere goats produce high-value fine fibers derived from secondary hair follicles; however, the molecular mechanisms underlying this trait remain incompletely understood. In this study, comparative transcriptome sequencing was performed on skin tissues from Inner Mongolian cashmere goats and normal goats to characterize gene expression differences associated with cashmere fiber production. High-quality RNA-seq data with strong mapping efficiency and reproducibility were obtained across all samples. Differential expression analysis identified 1543 significantly differentially expressed genes (DEGs) between cashmere and normal goats, including genes involved in hair follicle morphogenesis, epidermal differentiation, cell proliferation, and extracellular matrix organization. Multivariate analyses showed a clear transcriptomic separation between fleece types, indicating that fleece phenotype is the primary driver of variation in global gene expression. Functional enrichment revealed significant involvement of the Wnt, MAPK, and PI3K–Akt signaling pathways, and several biologically relevant regulators of hair follicle development and hair cycle control, including FGF5, SOX9, LHX2, and VDR, were differentially expressed. Gene fusion events were rare and showed no group specific patterns, whereas alternative splicing was widespread, with exon skipping as the predominant splicing event in goat skin. Overall, these results provide quantitative transcriptomic evidence linking signaling regulation, follicle development, and structural differentiation to secondary hair follicle activity and cashmere fiber formation, offering candidate genes and molecular pathways for functional validation and molecular breeding in cashmere goats. Full article

Vitamin D signaling via the vitamin D receptor (VDR) regulates calcium–phosphate homeostasis and extensive gene programs controlling cell proliferation, differentiation, immune tone, and metabolism. However, systemic use of the natural agonist 1α,25-dihydroxyvitamin D₃ (calcitriol) for extraskeletal indications is limited by dose-limiting hypercalcemia. This review summarizes VDR biology and the structural basis of ligand action, emphasizing how ligand-induced repositioning of helix 12 and altered coregulator recruitment can be exploited to engineer selective VDR modulators. We highlight medicinal chemistry strategies spanning secosteroidal analogs with side-chain or ring modifications and emerging non-seco scaffolds and discuss clinically established agents (e.g., calcipotriol and paricalcitol) alongside experimental “super-agonists”, partial agonists, and antagonists designed to widen the therapeutic window. Finally, we discuss current evidence for VDR targeting across cancer, metabolic disease, fibrosis, and immune-inflammatory disorders, including mechanisms of resistance such as dysregulated vitamin D metabolism and epigenetic repression. Structural and epigenomic insights are positioning next-generation VDR ligands as tissue- and pathway-biased therapeutics that may enable safer, mechanism-guided translation beyond bone and mineral indications. Full article

Vitamin D, a fat-soluble vitamin functioning as a hormone via the vitamin D receptor (VDR), is critical for calcium homeostasis and bone health. Vitamin D deficiency is linked to nutritional rickets, osteomalacia, and increased risk of non-communicable diseases such as cancer and diabetes. While serum 25(OH)D₃ is used to assess vitamin D status, its active form, 1α,25(OH)₂D₃, exerts context-dependent effects on calcium metabolism. Nonetheless, the therapeutic utility of native vitamin D is limited in certain pathologies. In chronic kidney disease (CKD), the renal conversion of 25(OH)D₃ to active 1α,25(OH)₂D₃ is compromised, necessitating the use of active synthetic analogs to bypass this metabolic defect. Furthermore, for dermatological and oncological disorders requiring supraphysiological dosing, synthetic analogs have been designed to dissociate beneficial anti-proliferative effects from the severe hypercalcemia induced by high-dose 1α,25(OH)₂D₃. VDR mediates transcriptional responses, modulated by co-regulators and chromatin remodeling complexes. Recent discoveries include non-genomic VDR pathways and SCAP (SREBP cleavage-activating protein)-dependent signaling that modulate lipid metabolism. Despite promising preclinical results, most synthetic VDR agonists fail to show efficacy in cancer therapy due to calcemic toxicity. However, compounds like eldecalcitol are effective in osteoporosis, especially in low-calcium-intake populations. Selective VDR modulators, akin to SERMs, exhibit tissue-specific effects. Moreover, novel VDR antagonists such as ZK168281 demonstrate potential to suppress hypercalcemia and vitamin D toxicity by inhibiting transcriptional activity and altering VDR localization. These agents may enable anti-inflammatory or anti-proliferative actions without calcemic risks. Understanding the nuanced biology of vitamin D and its analogs offers new avenues for therapeutic intervention beyond bone metabolism, including managing hyperparathyroidism, granulomatous diseases, and inflammation-associated disorders. Full article

Osteomyelitis (OM), an inflammatory condition of the bone tissue, is a complex orthopedic condition marked by chronic inflammation, diagnostic uncertainty, and recurrent infections. Despite standard treatments—including surgical debridement, antimicrobial therapy, and bone reconstruction—many patients continue to experience recurrence and treatment failure. Growing molecular evidence indicates that host genetic factors play a crucial role in shaping immune responses and influencing disease progression in OM. This narrative review synthesizes current knowledge from candidate gene single-nucleotide polymorphism (SNP) association studies to illustrate how specific genetic variations contribute to OM pathogenesis, diagnostic refinement, and treatment outcomes. We examined key immunogenetic variants within genes involved in inflammatory signaling, pathogen recognition, and neutrophil regulation. Our synthesis identifies a landscape of pro-inflammatory SNPs, such as IL-1β rs16944 and NLRP3 rs10754558, that are associated with increased susceptibility to chronic or post-traumatic OM, as well as SNPs that are associated with protective effects that may favor infection resolution, such as within the NOS2 and VDR genes. These SNP-driven differences in inflammasome activity, cytokine pathways, and oxidative stress responses highlight emerging opportunities for individualized therapeutic strategies. This review consolidates these variants, providing a genetic framework to analyze host susceptibility and differentiating high risk from protective genetic profiles. Integrating genomic insights into OM management represents a promising shift toward personalized medicine, enhancing diagnostic precision, informing targeted interventions, and improving prognostic assessment. Continued large-scale validation of candidate SNPs and translational genomic models will be essential to support their future clinical application. Full article

Introduction: Peripheral blood mononuclear cells (PBMCs) constitute a diverse population of cells involved in adaptive and innate immunity, playing an essential role in pathogen recognition, immune signaling, and immune response modulation. Vitamin D deficiency through the regulation of vitamin D receptor (VDR) and calcium-sensing receptor (CaSR) gene expression could influence the apoptotic functioning of PBMCs, which, despite its importance in the immune response, has not been sufficiently explored. Objectives: This research aimed to detect differences in the mRNA expression of CaSR, VDR, and apoptosis of PBMcs between elderly women with hip fractures and vitamin D deficiency and healthy young women, as well as in older women both at baseline and after administration of calcitriol. Methods: A case–control study involving 44 women (22 and 20, respectively) was conducted. The case group (hip fracture) was administered 2 µg/day of calcitriol for two weeks and a before-and-after comparison was made. The baseline gene expression of VDR and CaSR in PBMCs, as well as the effects of calcitriol on both the VDR/CaSR regulation and PBMC apoptosis, were studied in both groups. Serum bone biomarkers were also assessed. Results: No differences were observed in creatinine and calcium serum levels between the young and elderly osteoporotic women studied. Serum phosphorus and 25-hydroxyvitamin D (25(OH)D) were low in osteoporotic fractured women with vitamin D deficiency. In contrast, intact parathyroid hormone (PTH_1–84) and alkaline phosphatase were high, while no significant difference in calcitriol [l,25(OH)₂D₃] serum levels was observed. In elderly women, serum calcium, phosphorus, alkaline phosphatase, 25(OH)D, and calcitriol remained unchanged after intravenous calcitriol therapy; however, PTH_1–84 decreased after the treatment. In comparison to the young women, the elderly women showed decreased VDR and increased CaSR mRNA expression in PBMCs, as well as higher monocyte apoptosis. Conclusions: Calcitriol administration increased both VDR and CaSR mRNA expression in PBMCs and decreased PBMC apoptosis. Conclusions: The results obtained support the role of the vitamin D endocrine system as a regulator of the immune response and thus may contribute to explaining certain aspects of the immune dysfunction reported in individuals with vitamin D insufficiency. Full article

Microbiota-derived indoles and short-chain fatty acids (SCFAs) modulate intestinal immunity via the aryl hydrocarbon receptor (AhR) and vitamin D receptor (VDR). This review proposes an operational AhR–VDR axis—three testable models (sequential, parallel, reciprocal)—to explain how indoles (AhR) and SCFAs/vitamin D (VDR) may cooperate to drive IL-22–mediated repair, antimicrobial peptide production, autophagy, and tight-junction restoration. We critically evaluate prebiotics, probiotics, and postbiotics: prebiotics shift fermentation toward SCFAs but show context-dependent effects; probiotics can supply indole-type AhR ligands yet are strain-specific; postbiotics offer standardized ligand delivery but face formulation challenges. We distinguish Salmonella-specific findings (e.g., SCFA suppression of SPI-1) from general colitis data and prioritize molecular validation, temporal mapping, multi-omics responder stratification, and standardized postbiotic development for clinical translation. Full article

Background/Objectives: This review integrates evolutionary, metabolic, genetic, and nutritional perspectives to explain how sterol-derived vitamin D pathways shape human physiology and inter-individual variability in vitamin D status. Methods: The literature on sterol and vitamin D metabolism across animals, plants, fungi, and algae was synthesized with data from metabolomics databases, genome-wide association studies, RNA-seq resources (including GTEx), structural biology, and functional genomics. Results: Vitamin D₂ and vitamin D₃ likely emerged early in evolution as non-enzymatic photochemical sterol derivatives and were later co-opted into a tightly regulated endocrine system in vertebrates. In humans, cytochrome P450 enzymes coordinate vitamin D activation and degradation and intersect with oxysterol production, thereby linking vitamin D signaling to cholesterol and bile acid metabolism. Tissue-specific gene expression and regulatory genetic variants, particularly in the genes DHCR7, CYP2R1, CYP27B1, and CYP27A1, contribute to population-level differences in vitamin D status and metabolic outcomes. Structural analyses reveal selective, high-affinity binding of 1,25-dihydroxyvitamin D₃ to VDR, contrasted with broader, lower-affinity ligand recognition by LXRs. Dietary patterns modulate nuclear receptor signaling through distinct yet convergent ligand sources, including cholesterol-derived oxysterols, oxidized phytosterols, and vitamin D₂ versus vitamin D₃. Conclusions: Sterol and vitamin D metabolism constitute an evolutionarily conserved, adaptable network shaped by UV exposure, enzymatic control, genetic variation, and diet. This framework explains inter-individual variability in vitamin D biology and illustrates how evolutionary and dietary modulation of sterol-derived ligands confers functional flexibility to nuclear receptor signaling in human health. Full article

Neuroinflammation via the cyclic GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway and reduced hippocampal brain-derived neurotrophic factor (BDNF) expression are key mechanisms underlying stress-induced depression. Vitamin D3, acting through the vitamin D receptor (VDR), is known to possess immunomodulatory and neurotrophic properties, but its role under chronic stress remains unclear. This study investigated the effects of vitamin D3 on chronic unpredictable mild stress (CUMS)-induced neuroinflammation and neurotrophic deficits in male Wistar rats. Thirty-two rats were divided into four groups: control, CUMS only, CUMS + vitamin D3 (1000 IU/kg), and CUMS + vitamin D3 (10,000 IU/kg). Vitamin D3 was injected intramuscularly three times weekly for 28 days. Hippocampal mRNA expression of cGAS–STING pathway markers, BDNF, microglial activation marker Iba1, and pro-inflammatory cytokines was quantified by RT-qPCR, and relative expression was calculated using the 2^−ΔΔCt method. Serum vitamin D3 and corticosterone concentrations were measured by ELISA. CUMS significantly reduced serum vitamin D3, increased corticosterone, activated hippocampal cGAS–STING signaling, upregulated inflammatory mediators and Iba1, and suppressed VDR and BDNF mRNA expression (all p < 0.05). Vitamin D3 administration effectively restored serum vitamin D3, normalized corticosterone levels, attenuated cGAS–STING activation and inflammatory gene expression, reduced microglial activation, and enhanced hippocampal VDR and BDNF mRNA expression (all p < 0.05). These findings demonstrate that vitamin D3 alleviates CUMS-induced hippocampal inflammation and neurotrophic deficits through coordinated modulation of immune signaling and BDNF, highlighting its potential as a therapeutic approach for stress-related brain disorders. Full article

CYP24A1, a mitochondrial cytochrome P450 enzyme, plays a critical role in the catabolism of active vitamin D metabolites and is a key regulator of local vitamin D signaling in the small intestine. While traditionally studied in the context of renal physiology, increasing evidence highlights its distinct regulatory mechanisms and functional significance within the intestinal epithelium. This review explores the molecular architecture, tissue-specific expression patterns, and multifactorial regulation of CYP24A1 in enterocytes, encompassing nuclear receptor signaling, epigenetic and post-transcriptional control, and environmental influences such as inflammation, diet, and the gut microbiota. We discuss how intestinal CYP24A1 modulates the expression of vitamin D target genes involved in transcellular calcium absorption and epithelial barrier function, and how its dysregulation contributes to gastrointestinal disorders including inflammatory bowel diseases, celiac disease, microbiota dysbiosis, and colorectal cancer. In addition, we examine preclinical and translational evidence supporting CYP24A1 as a potential therapeutic target. Emerging strategies such as selective enzyme inhibitors, microbiota modulation, RNA-based technologies, and personalized supplementation approaches are considered in the context of restoring local vitamin D bioactivity and mineral homeostasis. Together, this review underscores the clinical importance of intestinal CYP24A1 and highlights novel opportunities for targeted interventions in vitamin D-responsive gastrointestinal pathologies. Full article

Obesity-associated adipose tissue dysfunction represents a key driver of metabolic disorders, including type 2 diabetes, cardiovascular diseases, and fatty liver disease. Emerging evidence highlights the vitamin D/vitamin D receptor (VD/VDR) axis as an important regulator of adipose tissue homeostasis. Beyond its classical role in mineral metabolism, vitamin D influences adipogenesis, inflammation, and insulin sensitivity, thereby modulating systemic metabolic health. In this review, we summarize the current understanding of the VD/VDR axis in adipose tissue biology, from molecular pathways controlling lipid turnover and immune responses to experimental and clinical evidence linking vitamin D status with obesity-related complications. We also discuss the role of genetic variability and tissue-specific VDR signaling in shaping metabolic outcomes. While results from supplementation trials remain inconsistent, maintaining adequate vitamin D levels appears crucial for the prevention of adipose tissue dysfunction and its cardiometabolic consequences. Future studies are warranted to define optimal strategies for harnessing the VD/VDR axis in therapeutic approaches to obesity and metabolic disease. Full article

Multiple sclerosis (MS) is a chronic autoimmune neurodegenerative disorder characterized by progressive demyelination and axonal degeneration within the central nervous system, driven by complex genomic and epigenomic dysregulation. Its pathogenesis involves aberrant DNA methylation patterns at CpG islands of numbers of genes like OLIG1 and OLIG2 disrupting protein expression at myelin with compromised oligodendrocyte differentiation. Furthermore, histone modifications, particularly H3K4me3 and H3K27ac, alter the promoter regions of genes responsible for myelination, affecting myelin synthesis. MS exhibits chromosomal instability and copy number variations in immune-regulatory gene loci, contributing to the elevated expression of genes for pro-inflammatory cytokines (TNF-α, IL-6) and reductions in anti-inflammatory molecules (IL-10, TGF-β1). Vitamin D deficiency correlates with compromised immune regulation through hypermethylation and reduced chromatin accessibility of vitamin D receptor (VDR) dysfunction and is reported to be associated with dopaminergic neuronal loss. Vitamin D supplementation demonstrates therapeutic potential through binding with VDR, which facilitates nuclear translocation and subsequent transcriptional activation of target genes via vitamin D response elements (VDREs), resulting in suppression of NF-κB signalling, enhancement of regulatory T-cell (T_reg) responses due to upregulation of specific genes like FOXP3, downregulation of pro-inflammatory pathways, and potential restoration of the chromatin accessibility of oligodendrocyte-specific gene promoters, which normalizes oligodendrocyte activity. Identification of differentially methylated regions (DMRs) and differentially expressed genes (DEGs) that are in proximity to VDR-mediated gene regulation supports vitamin D supplementation as a promising, economically viable, and sustainable therapeutic strategy for MS. This systematic review integrates clinical evidence and eventual bioinformatical meta-analyses that reference transcriptome and methylome profiling and identify prospective molecular targets that represent potential genetic and epigenetic biomarkers for personalized therapeutic intervention. Full article

Vitamin D plays a key role in pregnancy beyond calcium–phosphate regulation, modulating immune responses and glucose metabolism via the vitamin D receptor (VDR). Placental expression may be altered in gestational diabetes mellitus (GDM). This study aimed to assess placental VDR expression in GDM and evaluate its association with maternal vitamin D levels and clinical parameters. VDR expression in the placental tissue of 53 women with GDM and 26 healthy controls was assessed semi-quantitatively by immunohistochemistry. Maternal serum 25-hydroxyvitamin D (25(OH)D) levels, body mass index, weight gain, neonatal outcomes, and other variables were evaluated. Univariate and multivariate linear regression analyses were performed. VDR expression was significantly higher in the GDM group compared to controls (p = 0.0297 for mean, p = 0.0378 for median). No significant differences were observed in serum 25(OH)D concentrations between groups. Stepwise regression revealed that diabetes was the only independent predictor of VDR expression. Within the GDM subgroup, VDR expression was not associated with any clinical parameters, including maternal vitamin D status. Upregulated placental VDR in GDM may represent an adaptive response to metabolic stress. These findings suggest complex regulation of vitamin D signalling in diabetic pregnancies, warranting further investigation. Full article

Vitamin D is increasingly recognized as a key regulator of epithelial barrier integrity and mucosal immune homeostasis, with implications extending far beyond skeletal health. Through the vitamin D receptor (VDR), vitamin D regulates epithelial cohesion, innate immune responses, and tight-junction gene expression. This review explores the multifactorial role of vitamin D in modulating inflammation and preserving tissue barriers, with particular emphasis on its effects on tight junction (TJ) regulation and disease states characterized by barrier dysfunction, namely atopic dermatitis, psoriasis, inflammatory bowel disease (IBD), and celiac disease. In these settings, vitamin D/VDR signaling exerts protective actions by enhancing barrier structure, suppressing Th1/Th17-driven inflammation, modulating the gut and skin microbiome, and promoting epithelial repair. Animal studies and clinical data suggest that vitamin D supplementation can restore TJ expression, reduce disease activity, and improve clinical outcomes in both intestinal and dermatologic diseases. In the cardiovascular system, the role of vitamin D remains complex. While vitamin D influences endothelial function, insulin sensitivity, and systemic inflammation, supplementation trials yield mixed results, indicating a need for individualized approaches. Overall, this review synthesizes mechanistic, translational, and clinical data supporting vitamin D as a crucial modulator of barrier integrity and inflammation. These findings highlight its therapeutic relevance in chronic diseases characterized by immune dysregulation and epithelial disruption. Full article