Search Results (50)

Background/aim: Vitamin D (VitD) has been implicated in neuroprotection, yet its role in Parkinson’s disease (PD) remains unclear. This systematic review and meta-analysis aimed to evaluate the association between VitD status, supplementation, and vitamin D receptor (VDR) gene polymorphisms with PD risk and outcomes. Methodology: Following PRISMA guidelines, we searched PubMed, Scopus, and Google Scholar through August 2025 for observational studies, clinical trials, and genetic association studies. Primary outcomes included serum VitD levels in PD versus healthy controls (HCs), prevalence of VitD insufficiency/deficiency, and effects of VitD supplementation on motor symptoms. Secondary outcomes assessed associations between VDR polymorphisms and PD susceptibility. Data were synthesized using random- and fixed-effects models, with heterogeneity and publication bias evaluated. PROSPERO (CRD420251133875). Results: Sixty-three studies (n ≈ 10,700 participants) met inclusion criteria. PD patients exhibited significantly lower VitD levels (SMD = −0.46; 95% CI: −0.51 to −0.41) and higher odds of insufficiency (OR = 1.52) and deficiency (OR = 2.20) compared to HC. Cohort data suggested sufficient VitD may reduce PD risk (HR = 0.83). Supplementation yielded modest, non-significant improvements in motor outcomes. Among 20 genetic studies, FokI (rs2228570) was most consistently associated with PD, while other VDR SNPs showed variable or null associations. Conclusions: VitD deficiency is common in PD and may influence disease risk and motor function. Current evidence indicates limited benefit of supplementation for motor outcomes, and genetic associations remain inconsistent. Full article

(1) Background: this study aimed to determine whether a serum parathyroid hormone (PTH) threshold of 40 pg/mL represents a clinically relevant risk factor for vitamin D (VitD) deficiency and reduced bone mineral density (BMD). It also investigated potential genetic interactions influencing PTH regulation and skeletal health in patients with periodontitis. (2) Methods: a cross-sectional analysis was conducted on 1038 periodontitis patients (35–75 years). Serum PTH, VitD, calcium (Ca), phosphate (P), and urinary parameters were assessed. Dual-energy X-ray absorptiometry (DXA) was used to evaluate BMD in 261 subjects. Vitamin D Receptor (VDR) and estrogen receptor alpha (ERα) polymorphisms were genotyped, and composite genetic risk scores were calculated. Statistical analyses included correlation tests, subgroup comparisons, and regression models. (3) Results: sixty-two percent of individuals had PTH > 40 pg/mL, which was associated with significantly lower 25(OH)D and Ca levels and reduced T-scores (p < 0.05). PTH levels negatively correlated with BMD (Pearson’s r = –0.159, p = 0.0105). Patients with higher ERα polymorphism scores showed increased PTH values (p < 0.05), while VDR variants demonstrated a positive but no significant trend. (4) Conclusions: a PTH threshold of 40 pg/mL identifies individuals at higher risk of VitD deficiency and skeletal fragility, even without overt hypercalcemia. Genetic factors, particularly ERα variants, may contribute to elevated PTH levels, suggesting value in integrating biochemical, densitometric, and genetic screening for early bone health risk stratification. Full article

Corneal fibrosis, a significant source of visual impairment, can result from keratocyte-to-myofibroblast transdifferentiation during wound healing. This study investigated the antifibrotic role of 1,25-dihydroxyvitamin D₃ (1,25 Vit D) and the lesser-known vitamin D, 24,25-dihydroxyvitamin D₃ (24,25 Vit D), in human and mouse corneal stromal cells (HSCs and MSCs) and in a Vit D receptor knockout (VDR KO) mouse model. Cells were treated with TGF-β1 ± Vit D metabolites and the expression of fibrotic and antifibrotic genes and proteins was evaluated. Both metabolites significantly reduced α-smooth muscle actin levels in HSCs, MSCs and organ-cultured mouse corneas (p < 0.05). They also upregulated the mRNA expression of BMP2, BMP6, BMPR2, and TGF-β3, as well as the protein expression of BMP6 and TGF-β3. VDR KO corneas subjected to alkali injury exhibited increased fibrotic responses and reduced CD45+ immune cell infiltration compared to wild-type controls. Notably, 24,25 Vit D exerted antifibrotic effects even in VDR KO cells, and the alternative 24,25 Vit D receptor FAM57B was expressed in all corneal cell layers. These results reveal consistent antifibrotic effects of both 1,25 and 24,25 Vit D across species, support the existence of VDR-independent mechanisms in the cornea, and offer new insights into potential therapeutic strategies for preventing corneal fibrosis. Full article

Sarcopenia is a progressive age-related musculoskeletal disorder characterized by loss of muscle mass, strength, and physical performance, contributing to functional decline and increased risk of disability. Emerging evidence suggests that vitamin D (Vit D) plays a pivotal role in skeletal muscle physiology beyond its classical functions in bone metabolism. This review aims to critically analyze the relationship between serum Vit D levels and sarcopenia in older adults, focusing on pathophysiological mechanisms, diagnostic criteria, clinical evidence, and preventive strategies. An integrative narrative review of observational studies, randomized controlled trials, and meta-analyses published in the last decade was conducted. The analysis incorporated international diagnostic criteria for sarcopenia (EWGSOP2, AWGS, FNIH, IWGS), current guidelines for Vit D sufficiency, and molecular mechanisms related to Vit D receptor (VDR) signaling in muscle tissue. Low serum 25-hydroxyvitamin D levels are consistently associated with decreased muscle strength, reduced physical performance, and increased prevalence of sarcopenia. Although interventional trials using Vit D supplementation report variable results, benefits are more evident in individuals with baseline deficiency and when combined with protein intake and resistance training. Mechanistically, Vit D influences muscle health via genomic and non-genomic pathways, regulating calcium homeostasis, mitochondrial function, oxidative stress, and inflammatory signaling. Vit D deficiency represents a modifiable risk factor for sarcopenia and functional impairment in older adults. While current evidence supports its role in muscular health, future high-quality trials are needed to establish optimal serum thresholds and dosing strategies for prevention and treatment. An individualized, multimodal approach involving supplementation, exercise, and nutritional optimization appears most promising. Full article

Background: In humans, vitamin D₃ synthesis follows a day–night rhythm due to its UV-B-dependent production. Results: As part of the VitDHiD intervention study, we identified 87 in vivo vitamin D target genes with circadian expression patterns in immune cells, forming a regulatory network centered on transcription factors and membrane receptors. These genes exhibit a narrow basal expression range, with 80% downregulated upon vitamin D₃ supplementation. Clustering analysis revealed six distinct gene groups, with the two most prominent clusters driven by the transcription factor CSRNP1 (cysteine- and serine-rich nuclear protein 1) and GAS7 (growth arrest-specific 7), a known differentiation inducer. Among the 25 VitDHiD study participants, we identified two subgroups distinguished by significant differences in the responsiveness of 14 in vivo vitamin D target genes. These genes encode transcription factors like CSRNP1, as well as metabolic enzymes and transporters, including NAMPT (nicotinamide phosphoribosyltransferase), PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3), and SLC2A3 (solute carrier family 2 member 3). Notably, all 14 genes possess a vitamin D receptor-binding enhancer within a reasonable distance of their transcription start site. Conclusions: These findings highlight a novel link between vitamin D signaling and circadian gene regulation, with potential implications for personalized supplementation strategies. Full article

Individual variations in the active form of vitamin D (Vit.D) arise from a combination of dietary intake, sun exposure, and genetic factors, making it complex and challenging to maintain optimal levels. Among Vit.D-related genes, variations in CYP2R1 and CYP27B1 influence Vit.D synthesis, CYP24A1 regulates its inactivation, and the Vit.D receptor (VDR) mediates Vit.D signaling. These genetic variations contribute to substantial differences in Vit.D concentrations and associated clinical effects. However, there has been a lack of comprehensive, simultaneous exploration of these key genes and their clinical implications. This review provides a systematic analysis of genetic variants in Vit.D-related P450 genes identified in human clinical studies, along with in silico predictions of their functional consequences. Since multiple genes seem to influence the body’s response to Vit.D, studying just one genetic variant may not fully explain Vit.D deficiency. A comprehensive evaluation of all Vit.D-related genes could offer valuable insights for advancing personalized medicine in Vit.D management. This study provides a foundation for developing a more personalized approach to Vit.D supplementation and regulation, guided by genetic information. Full article

Lymphomas represent a heterogeneous group of blood tumors, generally divided into non-Hodgkin lymphoma (NHL) (90% of all lymphomas) and Hodgkin lymphoma (HL). High-grade NHL can rapidly progress so that new strategies and potentially therapeutical options are needed. Recently, it was shown that Vitamin D (VitD) inhibits the growth of cancer cells, controls their invasion and metastasis, and strengthens the antitumor activity of various types of chemotherapeutic anticancer agents. Therefore, we reviewed the recent literature about the influence of VitD and its analogues (VDAs) on the treatment and the prognosis of B-cell lymphomas. As to the in vitro studies in different cell lines, VitD3 and VDAs enhanced the anti-proliferative efficacy of various chemotherapeutics and increased the expression of VitD receptor. In in vivo studies, blood levels of VitD were considered: higher values of plasma bioavailable VitD were correlated with better progression-free survival (PFS) and overall survival (OS), while an unfavorable PFS and OS were observed in VitD deficient groups. No clinical trial was made on the analogs, thus confirming the absence of in vivo positive role of these synthetic drugs. In conclusion, higher levels of circulating VitD are related to improved OS, reduced cancer-specific mortality, and better disease-free survival. VitD and analogs showed also positive effects in in vitro studies, while only VitD was able to improve clinical parameters. Furthermore, a complex approach with plant-based diet, adequate levels for motor exercise, and/or eventual VitD supplementation could be a valuable strategy to challenge lymphomas. Full article

Many health benefits are associated with Vitamin D (VitD), although deficiency is associated with poor health outcomes and the increased risk of cancer development. For example, many tissue-specific enzymes are involved in VitD metabolism, and mutations or deletions within Vitamin D receptor (VDR) genes are known to increase the cancer risk by altering their functions or bioavailability, although less is known about these phenomena in oral cancers. Using well-characterized, commercially available oral cell lines (OKF4, HGF-1, SCC4, SCC9, SCC15, SCC25, and CAL27), the mRNA expression of P450 cytochrome VitD metabolic enzymes and receptor genes by qPCR revealed differential results. One oral cancer line (SCC15) did not express either the Vitamin D receptor (VDR) or FOK1 polymorphism and was also least affected by VitD3 administration in growth assays. In contrast, most oral cancers were missing one or more hydrolase (CYP2R1 and CYP24A1) or hydrolate (CYP27A1 and CYP27B1) enzymes. SCC25 was missing both the hydrolate enzymes and was the most inhibited in the VitD3 growth assays, while SCC4 was missing both the hydroxylase enzymes and was the least inhibited by VitD2. These associations between mRNA expression (or lack thereof) and VitD3 and VitD2 responsiveness can be used to identify molecular targets, which may lead to effective screening tools for VitD-related, complementary and alternative therapies. Full article

Vitamin D receptor [VDR] expression promotes LL37 expression, possibly contributing to host defense. The hypothesis was that an increase in 25 hydroxyvitamin D [25vitD] could lead to enhanced VDR expression and increased LL-37 production, thereby contributing to improved prognosis in critically ill patients. Methods: A nonblinded, randomized controlled trial was conducted. A total of 207 patients admitted to ICU with severe SARS-CoV-2 pneumonia were included and received different doses of cholecalciferol (500 MU, 3 MU/day, no cholecalciferol) during their ICU and hospital stay. 25vitD levels as well as LL37 and monocytes’ VDR gene expression were evaluated on admission and after. Clinical evolution, ICU mortality, hospital mortality, and 60-day mortality were evaluated. Results: The median age was 57.7 years and the majority of patients were Caucasian [87.4%] and male [70.5%]. There was a significant difference in 25vitD levels between groups on the third [p = 0.002] and seventh [p < 0.001] days. Patients supplemented with 500 MU of cholecalciferol had a very significant increase in monocytes’ VDR gene expression and showed a better clinical evolution in the ICU, with a significant correlation to evolution factors. Higher LL37 on admission had a significant negative association with hospital and ICU mortality, lost after adjustment for comorbidities to a nearly significant association with ICU, hospital, and 60-day mortality. Conclusion: Supplementation with higher doses of cholecalciferol may contribute to a significant increase in 25vitD levels but not in LL37 levels. Higher LL37 levels on admission may be related to a decrease in ICU, hospital, and 60-day mortality. VDR gene expression in monocytes is much higher in patients supplemented with higher doses of cholecalciferol. Full article

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. Full article

Vitamin D receptors (VDRs) are present in almost all cells of the immune system, including B cells, T cells, NK (Natural Killer) cells, dendritic cells, and monocytes, as well as the epithelial cells of many organs such as the intestine, pancreas, prostate, lungs, and cardiomyocytes. In addition, some immune cells, including dendritic cells, macrophages, and B and T cells, can synthesize calcitriol by expressing 1α-hydroxylase. Upon binding to VDRs, vitamin D (Vit D) regulates the expression of genes involved in immune responses, including those encoding for cytokines. It modulates the production of pro-inflammatory cytokines while promoting the synthesis of anti-inflammatory cytokines. Vit D also affects the differentiation and maturation of cells of the immune system. By inhibiting the nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways, Vit D reduces the expression of pro-inflammatory genes. These effects highlight the potential of Vit D as a therapeutic agent in the management of inflammatory diseases, including autoimmune disorders, cardiovascular diseases, diabetes, metabolic syndrome, cancer, neurological diseases, depression, and inflammatory bowel disease. Full article

Vitamin D (vitD) deficiency (25-hydroxy-vitamin D < 50 nmol/L) is common in pregnancy and associated with an increased risk of adverse pregnancy outcomes. High-dose vitD supplementation is suggested to improve pregnancy health, but there is limited knowledge about the effects on placental vitD transport and metabolism and the vitD status of newborns. Comparing the current standard maternal supplementation, 10 µg/day to a 90 µg vitD supplement, we investigated placental gene expression, maternal vitD transport and neonatal vitD status. Biological material was obtained from pregnant women randomized to 10 µg or 90 µg vitD supplements from week 11–16 onwards. Possible associations between maternal exposure, neonatal vitD status and placental expression of the vitD receptor (VDR), the transporters (Cubilin, CUBN and Megalin, LRP2) and the vitD-activating and -degrading enzymes (CYP24A1, CYP27B1) were investigated. Maternal vitD-binding protein (VDBP) was determined before and after supplementation. Overall, 51% of neonates in the 10 µg vitD group were vitD-deficient in contrast to 11% in the 90 µg group. High-dose vitD supplementation did not significantly affect VDBP or placental gene expression. However, the descriptive analyses indicate that maternal obesity may lead to the differential expression of CUBN, CYP24A1 and CYP27B1 and a changed VDBP response. High-dose vitD improves neonatal vitD status without affecting placental vitD regulation. Full article

Human corneal fibrosis can lead to opacity and ultimately partial or complete vision loss. Currently, corneal transplantation is the only treatment for severe corneal fibrosis and comes with the risk of rejection and donor shortages. Sphingolipids (SPLs) are known to modulate fibrosis in various tissues and organs, including the cornea. We previously reported that SPLs are tightly related to both, transforming growth factor beta (TGF-β) signaling and corneal fibrogenesis. The aim of this study was to investigate the effects of sphingosine-1-phosphate (S1P) and S1P inhibition on specific TGF-β and SPL family members in corneal fibrosis. Healthy human corneal fibroblasts (HCFs) were isolated and cultured in EMEM + FBS + VitC (construct medium) on 3D transwells for 4 weeks. The following treatments were prepared in a construct medium: 0.1 ng/mL TGF-β1 (β1), 1 μM sphingosine-1-phosphate (S1P), and 5 μM Sphingosine kinase inhibitor 2 (I₂). Five groups were tested: (1) control (no treatment); rescue groups; (2) β1/S1P; (3) β1/I₂; prevention groups; (4) S1P/β1; and (5) I₂/β1. Each treatment was administered for 2 weeks with one treatment and switched to another for 2 weeks. Using Western blot analysis, the 3D constructs were examined for the expression of fibrotic markers, SPL, and TGF-β signaling pathway members. Scratch assays from 2D cultures were also utilized to evaluate cell migration We observed reduced fibrotic expression and inactivation of latent TGF-β binding proteins (LTBPs), TGF-β receptors, Suppressor of Mothers Against Decapentaplegic homologs (SMADs), and SPL signaling following treatment with I₂ prevention and rescue compared to S1P prevention and rescue, respectively. Furthermore, we observed increased cell migration following stimulation with I₂ prevention and rescue groups, with decreased cell migration following stimulation with S1P prevention and rescue groups after 12 h and 18 h post-scratch. We have demonstrated that I₂ treatment reduced fibrosis and modulated the inactivation of LTBPs, TGF-β receptors, SPLs, and the canonical downstream SMAD pathway. Further investigations are warranted in order to fully uncover the potential of utilizing SphK I₂ as a novel therapy for corneal fibrosis. Full article

Aging is the result of several complex and multifactorial processes, where several agents contribute to an increased intrinsic vulnerability and susceptibility to age-related diseases. The hallmarks of aging are a set of biological mechanisms that are finely regulated and strictly interconnected, initiating or contributing to biological changes and anticipating several age-related diseases. The complex network of cellular and intercellular connections between the hallmarks might represent a possible target for the research of agents with pleiotropic effects. Vitamin D (VitD) is known to have a positive impact not only on muscle and bone health but also on several extra-skeletal districts, due to the widespread presence of Vitamin D Receptors (VDRs). VitD and VDR could be molecules potentially targeting the hallmarks of the aging network. To date, evidence about the potential effects of VitD on the hallmarks of aging is scarce in humans and mainly based on preclinical models. Although underpowered and heterogeneous, in-human studies seem to confirm the modulatory effect of VitD on some hallmarks of aging and diseases. However, more investigations are needed to clarify the pleiotropic effects of VitD and its impact on the hallmark of aging, hopefully highlighting the courses for translational applications and potential clinical conclusions. Full article

Vitamin D3 (VitD3) plays a crucial role in various cellular functions through its receptor interaction. The biological activity of Vitamin D3 can vary based on its solubility and stability. Thus, the challenge lies in maximizing its biological effects through its complexation within cyclodextrin (βNS-CDI 1:4) nanosponges (NS) (defined as VitD3NS). Therefore, its activity has been evaluated on two different gut–brain axes (healthy gut/degenerative brain and inflammatory bowel syndrome gut/degenerative brain axis). At the gut level, VitD3-NS mitigated liposaccharide-induced damage (100 ng/mL; for 48 h), restoring viability, integrity, and activity of tight junctions and reducing ROS production, lipid peroxidation, and cytokines levels. Following intestinal transit, VitD3-NS improved the neurodegenerative condition in the healthy axis and the IBS model, suggesting the ability of VitD3-NS to preserve efficacy and beneficial effects even in IBS conditions. In conclusion, this study demonstrates the ability of this novel form of VitD3, named VitD3-NS, to act on the gut–brain axis in healthy and damaged conditions, emphasizing enhanced biological activity through VitD3 complexation, as such complexation increases the beneficial effect of vitamin D3 in both the gut and brain by about 50%. Full article