Search Results (888)

Neuropathic pain remains a major clinical challenge due to its complex pathophysiology and limited treatment efficacy. Recent evidence suggests that vitamin D, beyond its classical role in bone and mineral metabolism, exerts neuroprotective and immunomodulatory effects that may influence pain perception. This review synthesizes current findings on the relationship between vitamin D status and neuropathic pain, highlighting potential mechanisms such as modulation of neuroinflammation, regulation of neuronal excitability, and influence on neurotransmitter pathways. Observational studies frequently report an association between vitamin D deficiency and increased pain severity, while interventional trials indicate that supplementation may alleviate neuropathic symptoms in specific populations. However, results remain heterogeneous, and mechanistic studies are still emerging. Understanding the interplay between vitamin D and neuropathic pain could open new avenues for adjunctive therapeutic strategies and personalized medicine approaches. Further high-quality clinical trials and mechanistic research are warranted to clarify causality and optimize clinical applications. Full article

Background: Vitamin D receptor (VDR) polymorphisms have been widely investigated as genetic determinants of neurodegenerative diseases, yet findings remain inconsistent and population-dependent. Evidence from the Middle East, North Africa, and Türkiye (MENA&T) regions, which is characterized by widespread vitamin D deficiency and distinct genetic backgrounds, has not been comprehensively synthesized. Methods: We conducted a systematic review and meta-analysis evaluating associations between four common VDR polymorphisms (ApaI rs7975232, FokI rs2228570, TaqI rs731236, and BsmI rs1544410) and the risk of multiple sclerosis (MS), Parkinson’s disease (PD), and Alzheimer’s disease (AD) in MENA&T populations. Six databases were searched from inception to November 2025. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were estimated using fixed- and random-effects models across multiple genetic contrasts. Subgroup analyses by ethnicity were conducted for MS. Study quality was assessed using the Newcastle–Ottawa Scale (NOS), and the certainty of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE). Results: Nineteen unique case–control studies (20 reports), including 4744 participants, were included. For MS, the ApaI polymorphism showed consistent associations with increased risk across genetic models (random-effects ORs = 1.4–1.9), with stronger effects in Arab and Iranian populations and no association in Turkish cohorts. FokI showed associations with MS under selected genetic models, particularly recessive and homozygous contrasts, although findings were not consistent across all analytical approaches. TaqI showed model-dependent associations with substantial heterogeneity, while BsmI showed no significant association. For AD, a meta-analysis of two studies showed no significant associations. For PD, ApaI showed associations with increased risk across several models without heterogeneity; however, these findings were based on a limited number of studies. Overall certainty of evidence ranged from very low to moderate. Conclusions: In MENA&T populations, VDR ApaI polymorphism shows consistent evidence of association with MS susceptibility, while FokI may be associated under specific genetic models; evidence for AD and PD remains limited and should be considered exploratory. These findings highlight population-specific genetic heterogeneity and underscore the need for further large-scale studies to confirm these associations. These population-specific genetic associations underscore the importance of incorporating VDR genotyping into precision medicine frameworks for neurodegenerative disease risk stratification in MENA&T populations, where vitamin D deficiency is highly prevalent. Full article

Recurrent pregnancy loss (RPL) is a multifactorial reproductive disorder with important genetic, endocrine, immune, and metabolic determinants. Growing evidence links vitamin D deficiency and vitamin D receptor (VDR) gene polymorphisms to pregnancy complications, including RPL. A narrative review was conducted via a literature search in major databases: PubMed, EMBASE, Scopus, and Web of Science from January 2010 to January 2026, which synthesized observational studies on maternal 25-hydroxyvitamin D [25(OH)D] status and/or VDR polymorphisms in RPL, with predefined eligibility criteria and qualitative risk-of-bias assessment. Most studies focused on FokI (rs2228570) and the 3′ regulatory block BsmI/ApaI/TaqI. FokI is the most extensively studied VDR variant in RPL and showed the most consistent directional association compared with other variants, particularly in Asian and Middle Eastern populations, though the effect varied by study design, ancestry, and covariate adjustment. Contrary to that, investigations of BsmI/ApaI/TaqI loci were not consistent due to ancestry-specific linkage disequilibrium (LD). Genotype and vitamin D interaction effects were scarcely studied, with stratified analyses indicating a more significant genotype effect under vitamin D deficiency. From clinical practice perspectives, VDR polymorphisms may explain why some patients with RPL have a poor response to standard vitamin D supplementation. Women with the FokI f allele polymorphism associated with lower VDR activity require higher vitamin D dosing or earlier immunomodulatory support to achieve adequate endometrial receptivity. VDR variation, particularly FokI, may contribute to RPL susceptibility within an endocrine–immune–metabolic framework. Clinical translation will require standardized RPL definitions, concurrent 25(OH)D assessment, robust control for confounders, and analytical models that account for gene–environment interactions. Full article

Background/Objectives: The colonisation of Australia around 250 years ago left a significant enduring impact on the mental health of Aboriginal and Torres Strait Islander peoples. Vitamin D may play a role in modulating mental health as its receptors are present in the brain regions associated with mood and behaviour regulation. We aimed to conduct an exploratory study to investigate associations between serum 25-hydroxyvitamin D (25(OH)D) concentration and Kessler Psychological Distress Scale 5 (K5) [low/moderate vs. high/very high psychological distress] among Aboriginal and Torres Strait Islander peoples. Methods: We used cross-sectional data from the 2012–2013 Australian Aboriginal and Torres Strait Islander Health Survey. Binary logistic regression was used to test associations between serum 25(OH)D concentration and K5, adjusting for age, sex, education, remoteness, socioeconomic status, season, alcohol intake, and smoking (n = 1983). Results: There was no association between serum 25(OH)D concentration and K5 in the total population. In our exploratory analyses, higher serum 25(OH)D concentration (per 10 nmol/L) was significantly associated with 10% lower odds of high/very high levels of psychological distress among females. When stratified by remoteness, higher serum 25(OH)D concentration (per 10 nmol/L) was significantly associated with 11% lower odds of high/very high levels of psychological distress among those living remotely. Conclusions: The findings of this study suggest no association between serum 25(OH)D and K5 among the total population, but with some exploratory evidence of differences by sex and remoteness. Given the high prevalence of low vitamin D status among this population, promoting adequate vitamin D status remains an important public health issue. Full article

Survivors of childhood leukemia are at increased risk of long-term skeletal complications, including reduced bone mineral density (BMD). Vitamin D deficiency and genetic variations in the vitamin D receptor (VDR) gene are important factors influencing bone health, yet their combined effects remain insufficiently studied, particularly in North African populations. This case-control study included 130 survivors of childhood acute lymphoblastic leukemia (ALL) in remission (age range: 5–26 years) and 110 age- and sex-matched healthy controls recruited from Beni Messous Hospital. BMD was assessed at the lumbar spine and femoral neck using dual-energy X-ray absorptiometry and expressed as z-scores. Serum 25-hydroxyvitamin D levels were measured, and VDR polymorphisms (FokI, ApaI, and BsmI) were analyzed using PCR-RFLP. Hypovitaminosis D was observed in 43.85% of patients at diagnosis and 23.07% after remission. Survivors had significantly lower BMD compared with controls at both the lumbar spine (z-score: −4.26 ± 0.75 vs. 0 ± 1, p < 0.001) and femoral neck (−3.78 ± 0.45 vs. 0 ± 1, p < 0.001). Reduced BMD for age was identified in 30% of patients. Variant genotypes TT (FokI), AA (BsmI), and CC (ApaI) were more frequent in patients and were associated with lower BMD (p < 0.0001). These findings suggest that hypovitaminosis D and VDR polymorphisms may be associated with bone health in survivors of childhood leukemia. The coexistence of these factors may contribute to interindividual variability in BMD. Full article

Background/Objectives: Genetic generalized epilepsies (GGE) often remit in childhood, yet a subset of adults remain pharmacoresistant with substantial morbidity. The genetic basis of adult pharmacoresistant GGE is poorly defined. This descriptive study used whole-genome sequencing (WGS) to identify recurrent coding variants and pathways associated with pharmacoresistant adult GGE. Methods: WGS was performed in ten racially diverse adults (mean age 37.2 years; range 20–52) with electroencephalographically confirmed, pharmacoresistant GGE (mean onset 13.7 years). Analysis prioritized variants present in at least 80% of participants and which were either (i) missense variants predicted deleterious with ANNOVAR or (ii) loss-of-function variants predicted high-impact from snpEff. Pathway enrichment and overlap with a commercial clinical epilepsy gene panel were assessed. Results: Filtering identified 133 unique, deleterious coding variants across 69 genes shared by at least eight participants. Four genes (APOL4, KMT2C, SON, VDR) overlapped a clinical epilepsy panel, supporting the capacity of WGS to recover clinically relevant loci. Prioritized loci implicated gastrointestinal and metabolic regulators (e.g., MUC6, PNLIPRP2), chemosensory receptors (OR10D3, OR8U1, TAS2R19), neuroimmune mediators (LILRA2, SIGLEC12, OAS2), and ion transporters (KCNJ12, P2RX5, RHBG), consistent with multifactorial mechanisms of pharmacoresistance. Conclusions: This exploratory WGS study focused exclusively on adults with pharmacoresistant GGE, revealing shared high-impact variants and convergent pathways spanning absorption/metabolism, vitamin D signaling, immunity, and ion transport. Findings broaden the genetic landscape of pharmacoresistant GGE while motivating validation in larger, multiethnic cohorts. Full article

Background: Asthma is a heterogeneous chronic inflammatory airway disease characterized by recurrent exacerbations and variable airflow limitation. Epithelial-derived alarmins, particularly interleukin-33 (IL-33) and its receptor ST2, play key roles in type 2 inflammation. The soluble form of ST2 (sST2) acts as a decoy receptor regulating IL-33 signaling. Vitamin D is an important immunomodulator influencing airway inflammation, but its interaction with the IL-33/ST2 pathway remains unclear. Objective: To evaluate the association between serum IL-33, sST2, and 25-hydroxyvitamin D [25(OH)D] levels with asthma severity and exacerbation status, and to assess their potential as clinical biomarkers. Methods: This study enrolled 52 adult asthma patients (27 experiencing exacerbation and 25 in remission) and 28 healthy controls. Serum levels of IL-33 and sST2 were measured using enzyme-linked immunosorbent assays, while 25(OH)D concentrations were determined via electrochemiluminescence immunoassay. Results: Serum sST2 levels were significantly higher and 25(OH)D levels significantly lower in asthma patients compared with controls (p < 0.000 for both). Serum IL-33 levels did not differ significantly between groups (p > 0.05). During exacerbation, sST2 levels were markedly elevated compared with remission (p < 0.001), whereas vitamin D levels were significantly reduced (p = 0.038). A significant negative correlation was identified between sST2 and 25(OH)D (r = −0.333, p = 0.016). Conclusions: The presence of asthma and the severity of exacerbations are associated with elevated circulating sST2 levels and reduced vitamin D levels. These findings suggest a regulatory interaction between vitamin D and the IL-33/ST2 axis in airway inflammation and indicate that targeting this axis could be a potential therapeutic strategy. Full article

Atopic dermatitis (AD) is a chronic inflammatory skin disease increasingly prevalent in adults. Vitamin D plays an important role in regulating immune responses, cellular differentiation, and inflammation. Several single-nucleotide polymorphisms (SNPs) in the vitamin D receptor (VDR) gene have been suggested as biomarkers of AD susceptibility and severity. The aim of this study was to investigate six SNPs in the VDR gene (rs3847987, rs731236, rs7975232, rs1544410, rs2228570, and rs11168293) and their association with AD and blood biomarkers. Genotyping was performed in 91 adult patients with AD and 102 controls using real-time polymerase chain reaction. The genotype and allele distributions did not differ significantly between AD patients and controls. However, the G and T alleles of VDR rs731236 and rs1544410 were more frequently detected in individuals with serum 25-hydroxyvitamin D (25(OH)D) levels above 30 ng/mL. In contrast, the VDR rs7975232 C allele appears to be associated with lower odds of having a serum 25(OH)D level above 30 ng/mL. In genotype-stratified analysis, the T allele of VDR rs11168293 was more prevalent among individuals with eosinophil counts of 300 cells/μL. These findings suggest that VDR polymorphisms may contribute to variability in vitamin D status and inflammatory responses in adults with AD. Full article

Background/Objectives: The escalating crisis of antibiotic resistance and the inherent limitations of conventional antibiotics necessitate the development of innovative therapeutic strategies. Targeted drug delivery (TDD) offers a powerful approach to enhance efficacy, minimize systemic toxicity, and circumvent bacterial resistance. This systematic review aims to evaluate the potential of unique bacterial transport systems (BTSs), surface specific receptors and intracellular enzymes as platforms for TDD via the “Trojan Horse” strategy (THS). Methods: A comprehensive literature review was conducted, focusing on studies that investigated the specificity and mechanisms of BTSs responsible for the uptake of metabolites that are essential for and unique to bacteria. This includes an analysis of transport systems for siderophores, bacteria-specific sugars, cell wall components, D-amino acids, and vitamins. We assessed preclinical and clinical examples of drug conjugates utilizing these pathways, as well as emerging platforms such as bacteriophage-derived proteins, antibody–antibiotic conjugates, and bacterial extracellular vesicles (EVs). Results: BTSs demonstrate high specificity for their cognate substrates, providing effective molecular gateways for TDD of drugs photosensitizers and diagnostic probes in form of conjugates. The siderophore–cephalosporin conjugate cefiderocol represents a clinically validated example, having received FDA approval. Preclinical studies further reveal that conjugates utilizing sugars (e.g., maltose, trehalose) and vitamins (e.g., B12) can significantly enhance antibiotic uptake and activity against both Gram-positive and Gram-negative pathogens, including drug-resistant strains. Emerging platforms like bacteriophage endolysins and engineered EVs show promise for overcoming biological barriers such as bacterial outer membranes and intracellular host niches. Conclusions: The THS leveraging BTSs represents a clinically viable and promising avenue for next-generation antibacterial therapies. Advantages of BTS include overcoming bacterial resistance, such as reduced membrane permeability and efflux pumps, enabling the “revival” of antibiotics that are poorly permeable or toxic, increasing their local concentration at the target site and reducing side effects on host cells. While significant progress has been made, a striking disconnect persists between the hundreds of conjugates demonstrating potent in vitro activity and the limited agent that has achieved clinical use. This in vitro–in vivo gap reflects, in large part, the early stage of this field rather than a fundamental failure. Further research is critically needed not only to identify novel BTSs and optimize drug-linker chemistry, but also to systematically address the translational barriers—including poor pharmacokinetics, immunogenicity, and unexpected toxicity—that have prevented most promising candidates from advancing beyond preclinical evaluation. Full article

We synthesized two vitamin D₃ analogues, 3 and 4, which have a shortened or elongated fluoro-side-chain based on 24,24-difluoro-25-hydroxyvitamin D₃ (5) using an efficient convergent approach and studied their preliminary biological activity. Both analogues exhibited greater resistance to CYP24A1-mediated metabolism than the natural 25-hydroxyvitamin D₃ (6), although their stability was lower than that of 5. Analogue 3 showed an approximately 100-fold lower human vitamin D receptor (hVDR)-binding affinity compared with 5 and 6. Despite this marked reduction in VDR-binding affinity, it demonstrated an approximately 1.5-fold increase in VDR-ligand binding domain (LBD) transcriptional activation of the natural ligand 6. In contrast, analogue 4 displayed moderate VDR-binding affinity and VDR-LBD transactivation compared with 5 and 6. We found that compound 3 is a unique vitamin D analogue with a fluorinated and shortened side-chain, exhibiting low binding affinity for hVDR but potent transcriptional activity through VDR-LBD with its long half-life; thus, 3 may serve as a basic structural skeleton for advancing medicinal chemistry and drug discovery. Full article

Vitamin D3 deficiency is a common concern in dermatology and aging, yet its topical supplementation is restricted in the EU, and direct precursors are unstable. Stimulating the skin’s endogenous vitamin D3 biosynthesis using phytochemicals represents a promising alternative. This research reveals the potential of a natural Passiflora edulis (passion fruit) extract to stimulate vitamin D3 synthesis in the skin epidermis. An in silico screening of phytochemicals using molecular docking and Molecular Mechanics/Poisson–Boltzmann Surface Area (MM/PBSA) analysis was performed to identify compounds with affinity for the vitamin D receptor (VDR) and lathosterol oxidase, a key enzyme in the vitamin D3 biosynthesis pathway. While several flavonoids showed high predicted vitamin D receptor affinity, genistein, which has been reported to occur in P. edulis fruit extracts, exhibited favorable docking scores and was predicted to interact with the active site of lathosterol oxidase. Subsequent in vitro experiments on HaCaT keratinocytes and an ex vivo human skin model demonstrated that the P. edulis extract significantly increased vitamin D3 amount, both under UVB irradiation and, notably, in its absence. The P. edulis extract significantly increased vitamin D3 level in HaCaT keratinocytes by up to 274.04% without UVB exposure and demonstrated a synergistic effect with UVB, enhancing production by a further 61.41% compared to UVB alone (p < 0.001). In the ex vivo model, the extract alone increased vitamin D3 levels by 153.31%, and its combination with UVB resulted in a 54.82% higher yield compared to the UVB control (p < 0.01). These findings highlight the promising potential of P. edulis fruit extract as a natural cosmeceutical ingredient for enhancing cutaneous vitamin D3 synthesis, offering a novel approach to supporting skin health through dermatocosmetics. Full article

Background: Vitamin D is a secosteroid that exerts immunomodulatory and anti-proliferative effects through the vitamin D receptor (VDR). Because HER2-targeted therapies substantially improve prognosis in HER2-positive breast cancer and introduces a new mechanism of immunotherapy, we hypothesized that successful correction of vitamin D deficiency would be associated with improved disease-free survival (DFS) in patients treated with curative intent. Methods: We performed a retrospective interventional cohort study of patients with early-stage HER2-positive breast cancer treated at Cancer Treatment Centers of America Midwestern Regional Medical Center from 2008 to 2014. Eligible patients had baseline vitamin D deficiency (25-hydroxyvitamin D or D25 < 30 ng/mL), received trastuzumab-based therapy, and had ≥12 months follow-up. Patients received vitamin D3 supplementation (typically 2000–10,000 IU/day) with doses adjusted based on D25 level follow-up. Responders were defined as having achieved a mean D25 ≥ 30 ng/mL during the first year; non-responders remained <30 ng/mL DFS was analyzed using Kaplan–Meier and Cox models. Results: Of 196 patients, 129 (65.8%) were vitamin D-deficient at baseline. Among these, 76 (60.3%) achieved repletion while 50 (39.7%) remained deficient. Three did not have D25 follow-up obtained. Thirty-one DFS events occurred but no deaths. Responders demonstrated numerically improved outcomes (3-year DFS 90% vs. 85%). Non-responders had a 1.7-fold higher hazard of recurrence, and those who achieved the highest D25 levels (>50 ng/mL) had the most favorable DFS trends, suggesting a dose response. Conclusions: Failure to correct a vitamin D deficiency was associated with a 1.7-fold higher recurrence risk, although the relationship did not achieve statistical significance. A similar effect size was reported in another retrospective cohort of HER2-positive breast cancer that did achieve statistical significance, and a doubling of pCR rates was seen in two recently completed RCTs in 2025, with benefits particularly seen in the triple-negative and HER2-positive subtypes. Prospective trials evaluating optimized vitamin D repletion in HER2-positive breast cancer are warranted. Full article

Bone regeneration requires tight coordination between mesenchymal stem cells (MSCs), immune signaling, and extracellular matrix remodeling. Yet, how atypical immune receptors contribute to this process remains unclear. Here, we identify Toll-like receptor 10 (TLR10) as a key regulator of osteogenic differentiation in human adipose-derived MSCs. Herein, ASC/TERT1 MSCs were engineered to overexpress or silence TLR10 using lentiviral vectors, and osteogenic differentiation (0–14 days) was assessed by metabolic assays—RT-qPCR of COL1A2, ALPL and BGLAP—Alizarin Red S staining, and quantitative mass spectrometry. Enhancing TLR10 expression promoted osteogenic gene programs, extracellular matrix organization, metabolic adaptation, and robust matrix mineralization, whereas TLR10 suppression maintained proliferative states and impaired osteoblast maturation. Proteomic analyses revealed that TLR10 selectively activates osteogenic, ECM-remodeling, and vitamin D-responsive pathways, while restraining programs antagonistic to differentiation. Notably, active vitamin D induced TLR10 expression and partially restored osteogenesis in TLR10-deficient cells, indicating that TLR10 is associated with vitamin D-driven bone formation. Together, beyond its established role in innate immunity, TLR10 emerges as a vitamin D-responsive regulator of mesenchymal stem cell osteogenesis, highlighting a potential therapeutic axis to enhance bone regeneration and osteogenic outcomes. Full article

Background/Objectives: Periodontitis grade reflects differences in disease progression and risk, yet the underlying host-response signatures that distinguish grade B from grade C are not fully elucidated. Nuclear receptors involved in inflammation and tissue homeostasis may contribute to these biological differences. The present study aimed to evaluate the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ), retinoid X receptor-α (RXR-α), and vitamin D receptor (VDR) in gingival tissues from periodontally healthy individuals and from patients with grade B and grade C periodontitis, with the primary comparison focusing on grade-related differences within the same disease stage (stage 3). Methods: Forty-five participants were allocated to three groups: Group 1, healthy controls; Group 2, stage 3 grade B periodontitis; and Group 3, stage 3 grade C periodontitis. Clinical parameters, including plaque index (PI), gingival index (GI), and clinical attachment loss (CAL), were recorded. Fibroblast and inflammatory cell density, and immunohistochemical expression levels of PPAR-γ, RXR-α, and VDR were assessed on histological sections. Results: Compared with healthy controls, both periodontitis groups showed lower fibroblast cell counts and higher inflammatory cell counts. PPAR-γ expression was significantly higher in Group 3 than in the other groups, whereas RXR-α and VDR expression were higher in Group 1 than in Groups 2 and 3. Conclusions: These findings suggest that increasing disease grade within stage 3 periodontitis is associated with increased PPAR-γ expression, whereas RXR-α and VDR expression primarily distinguish healthy from diseased gingival tissues. This nuclear receptor profile may help explain biological differences between healthy, grade B and grade C periodontitis and support future risk-stratified host-modulatory approaches. Full article

Coronavirus disease-2019 COVID-19 exhibits marked inter-individual variability in susceptibility and clinical outcomes, suggesting a role for host genetic factors. Vitamin D exerts immunomodulatory effects through the vitamin D receptor (VDR), and genetic variation in the VDR gene may influence host responses to SARS-CoV-2 infection. This study aimed to investigate the association between VDR-gene polymorphisms—FokI (rs2228570), TaqI (rs731236), ApaI (rs7975232), and BsmI (rs1544410)—and COVID-19 susceptibility in the Kurdish population. The FokI polymorphism was significantly associated with COVID-19 susceptibility. Interestingly, the GG-genotype was more frequent among Patients than controls and was associated with increased odds of infection (OR = 9.00; 95% CI: 3.22–25.15; p < 0.0001), whereas the AG-genotype was associated with reduced susceptibility (OR = 0.33; 95% CI: 0.14–0.76; p = 0.001). Additionally, the G-allele was also more prevalent in Patients than controls (OR = 1.87; 95% CI: 1.21–2.89; p = 0.004). Similarly, the TaqI TT-genotype was more frequent among Patients and was associated with increased susceptibility (OR = 36.0; 95% CI: 11.2–115.8; p < 0.0001). In contrast, the ApaI AA-genotype was less frequent among Patients and was associated with reduced odds of COVID-19 susceptibility under a recessive model (OR = 0.15; 95% CI: 0.03–0.68; p = 0.003). Moreover, the BsmI polymorphism was monomorphic in both groups and therefore not informative. Genetic variation in the VDR gene, particularly at the FokI, TaqI, and ApaI loci, was associated with COVID-19 susceptibility in the case–control study, while BsmI showed no variations. These findings suggest that genetic variation in the VDR gene may contribute to inter-individual differences in susceptibility to SARS-CoV-2 infection in the Kurdish population. Larger studies incorporating functional validation and detailed clinical data are required to confirm these associations. Full article