Search Results (84)

Secondary hyperparathyroidism (SHPT) in chronic kidney disease often necessitates parathyroidectomy (PTX), but this definitive treatment can precipitate hungry bone syndrome (HBS)—a profound, prolonged hypocalcemia caused by the rapid skeletal uptake of minerals after surgery. HBS results from the abrupt cessation of parathyroid hormone (PTH)-driven bone resorption while bone formation continues, leading to intensive mineral deposition (mainly calcium) into chronically demineralized bone. Clinically, HBS ranges from asymptomatic biochemical disturbances to life-threatening hypocalcemia with tetany, seizures, and/or cardiac arrhythmias. This illustrative review synthesizes current knowledge of HBS pathogenesis and management in the context of SHPT. We detail how the high-turnover bone remodeling state of SHPT (osteitis fibrosa cystica) creates an expansive unmineralized osteoid pool that avidly mineralizes post-PTX. We also explore molecular mechanisms (e.g., RANKL/OPG dysregulation, Wnt/β-catenin activation, osteocyte-driven signals, and calcium-sensing receptor effects) that underpin this process. Key preoperative risk factors for HBS include very elevated PTH and alkaline phosphatase levels, large skeletal calcium deficits, younger patient age, and total PTX. We outline the typical postoperative course of HBS, phased from immediate acute hypocalcemia to a nadir and gradual recovery. Prevention and management strategies are emphasized, centered on vigilant monitoring and aggressive calcium and calcitriol supplementation, with preoperative optimization (e.g., vitamin D loading, calcimimetics) to mitigate severity. By enhancing risk stratification and perioperative care, clinicians can improve outcomes and safely navigate patients through this challenging complication of endocrine surgery. Full article

Vitamin D, long recognized for its essential role in calcium–phosphate balance and bone health, has increasingly been identified as a pleiotropic regulator of metabolic, cardiovascular, and renal function. Deficiency of vitamin D is widespread worldwide and has been linked to a higher risk of insulin resistance, type 2 diabetes, atherosclerosis, hypertension, and chronic kidney disease. Meta-analyses suggest that each 10 nmol/L (≈4 ng/mL) increase in serum 25-hydroxyvitamin D [25(OH)D] is associated with about a 4% lower risk of type 2 diabetes, whereas other analyses indicate an approximately 10% reduction in cardiovascular event risk per 10 ng/mL (≈25 nmol/L) increment in circulating 25(OH)D concentration. Clinical and epidemiological studies suggest that optimal 25(OH)D concentrations may protect against cardiometabolic and renal complications, though supplementation trials show heterogeneous outcomes depending on baseline vitamin D status, genetic background, and dosage. By synthesizing current knowledge, this work highlights vitamin D status as a potentially modifiable determinant of global disease burden and a target for preventive and therapeutic strategies. Full article

HER2-positive breast cancer is an aggressive subtype, often associated with shorter progression-free and overall survival. Estrogen receptor (ER) expression within this subtype leads to distinct growth patterns and treatment responses. Calcitriol, the active form of vitamin D, induces ERα expression in ER-negative breast cancer cells, thereby sensitizing them to the antiproliferative effects of antiestrogens. When combined with neratinib, calcitriol enhanced cell growth inhibition. Therefore, we investigated whether adding calcitriol to the combined treatment with antiestrogens and neratinib could further inhibit the proliferation of HER2-positive breast cancer cells, regardless of their ER status. The BT-474 (ER-positive/HER2-positive) and SK-BR-3 (ER-negative/HER2-positive) breast cancer cell lines were pretreated with calcitriol to modulate ER expression, followed by treatment with calcitriol in combination with neratinib, with or without antiestrogens. Proliferation assays, cell cycle analysis, and Western blotting were then performed to assess treatment effects. The results demonstrated that calcitriol and neratinib, per se, significantly inhibited cell proliferation in a concentration-dependent manner in the HER2-positive cell lines. Notably, calcitriol enhanced the antiproliferative response of combined neratinib and antiestrogen treatment. Calcitriol, alone or in combination, modulated vitamin D receptor and ERα expression, reduced AKT and ERK phosphorylation, and promoted G1 phase arrest. These findings support the potential of this combinatorial approach as a therapeutic strategy for HER2-positive breast cancer. Full article

Paraoxonase 1 (PON1) is an antioxidant enzyme that plays physio-pathological roles. Prior in silico analysis revealed the presence of response elements of the nuclear receptor superfamily in the PON1 promoter, comparable to glucocorticoid receptors (GR), the vitamin D receptor (VDR), and the pregnenolone X receptor (PXR). The aim of this study was to evaluate the effects of 1α,25-dihydroxyvitamin D₃, a ligand specific to VDR, on the expression and activity of PON1 in hepatocarcinoma cells (HepG2 cells). PON1 activities (arylesterase/AREase and lactonase/LACase) were determined by spectrophotometry. Quantitative real-time PCR was used to evaluate the effect of VDR and PXR on the mRNA levels of PON1 and CYP3A4 genes. Molecular models and dynamics simulations were built using specialized software. Treatments with 1α,25-dyhydroxyvitamin D₃ (calcitriol), its active hormonal form, resulted in an induction of PON1 mRNA and AREase activity compared to control cultures. These results suggest that calcitriol plays a role in the regulation of PON1 transcription and provide evidence that this hormone increases PON1 levels in HepG2 cells. In addition, the molecular modeling suggests that calcitriol enhances PON1 activity and this increase could be caused by direct interaction on the PON1 protein. This study shows the effects of calcitriol on PON1 expression, proposing a new molecular mechanism for the transcriptional regulation of PON1 through a process linked to VDR activation and direct interaction of calcitriol on the PON1 protein. Full article

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is the etiologic agent that causes the coronavirus disease (COVID-19) identified in Wuhan, in 2019. Men are more prone to developing severe manifestations than women, suggesting a possible crucial role of sex hormones. 17,β-Estradiol (E2) and 1,25 α dihydroxyvitamin D₃ (calcitriol) act upon gene pathways as immunomodulators in several infectious respiratory diseases. In this study, we aimed to evaluate the influence of E2 and calcitriol on the VSV-based pseudovirus SARS-CoV-2 and SARS-CoV-2 infection in vitro. We infected Vero E6 cells with the recombinant VSV-based pseudovirus SARS-CoV-2 and the SARS-CoV-2 viruses according to the pre-treatment and pre–post-treatment models. The Angiotensin-Converting Enzyme 2 (ACE2) and Vitamin D Receptor (VDR) gene expression did not change under different treatments. The VSV-based pseudovirus SARS-CoV-2 infection showed a significant decrease in the focus-forming unit count in the presence of E2 and calcitriol (either alone or in combination) in the pre-treatment model, while in the pre–post-treatment model, the infection was inhibited only in the presence of E2. Th SARS-CoV-2 infection highlighted a decrease in viral titres in the presence of E2 and calcitriol only in the pre–post-treatment model. 17,β-Estradiol and calcitriol can exert an inhibitory effect on SARS-CoV-2 infections, demonstrating their protective role against viral infections. Full article

Environmental exposure to per- and polyfluoroalkyl substances (PFASs) has been increasingly associated with skin disorders, including atopic dermatitis (AD); however, the underlying molecular mechanisms remain unclear. This study aimed to evaluate the effects of perfluorononanoic acid (PFNA) and perfluorooctanoic acid (PFOA)—two widely detected PFASs—on epidermal function and gene expression in Human Epithelial Keratinocyte, neonatal (HEKn). We assessed cell viability, morphology, and transcriptomic changes using in vitro assays and RNA-seq analysis from a neonatal cohort. PFASs induced dose-dependent cytotoxicity and downregulation of barrier-related genes. Ingenuity pathway analysis identified calcitriol as a suppressed upstream regulator. Functional validation revealed that calcitriol partially reversed the PFAS-induced suppression of antimicrobial peptide genes. These findings support the hypothesis that PFASs may contribute to AD-like skin pathology by impairing vitamin D receptor signaling and antimicrobial defense, and calcitriol demonstrates potential as a protective modulator. This study provides mechanistic insights into the impact of environmental toxicants on skin homeostasis and suggests a potential protective role for calcitriol in PFAS-induced skin barrier damage. Full article

Background/Objectives: Adequate vitamin D levels are essential for various physiological functions, including cell growth, immune modulation, metabolic regulation, DNA repair, and overall health span. Despite its proven cost-effectiveness, widespread deficiency persists due to inadequate supplementation and limited sunlight exposure. Methods: This systematic review (SR) examines the relationship between vitamin D and the reduction of cancer risk and mortality, and the mechanisms involved in cancer prevention. This SR followed the PRISMA and PICOS guidelines and synthesized evidence from relevant studies. Results: Beyond genomic actions via calcitriol [1,25(OH)₂D]-receptor interactions, vitamin D exerts cancer-protective effects through mitigating inflammation, autocrine, paracrine, and membrane signaling. The findings reveal a strong inverse relationship between serum 25(OH)D levels and the incidence, metastasis, and mortality of several cancer types, including colon, gastric, rectal, breast, endometrial, bladder, esophageal, gallbladder, ovarian, pancreatic, renal, vulvar cancers, and both Hodgkin’s and non-Hodgkin’s lymphomas. While 25(OH)D levels of around 20 ng/mL suffice for musculoskeletal health, maintaining levels above 40 ng/mL (100 nmol/L: range, 40–80 ng/mL) significantly lowers cancer risks and mortality. Conclusions: While many observational studies support vitamin D’s protective role in incidents and deaths from cancer, some recent mega-RCTs have failed to demonstrate this. The latter is primarily due to critical study design flaws, like recruiting vitamin D sufficient subjects, inadequate dosing, short durations, and biased designs in nutrient supplementation studies. Consequently, conclusions from these cannot be relied upon. Well-designed, adequately powered clinical trials using appropriate methodologies, sufficient vitamin D₃ doses, and extended durations consistently demonstrate that proper supplementation significantly reduces cancer risk and markedly lowers cancer mortality. Full article

Vitamin D plays a vital role in human physiology, including a crucial role in regulating bone metabolism and various extra-skeletal effects. Calcitriol exerts anti-inflammatory effects on monocytes and macrophages by increasing IL-10 production and decreasing the production of proinflammatory IL-1β, IL-6, tumor necrosis factor-α (TNF-α), receptor activator of nuclear factor kappa-Β ligand (RANKL), and cyclo-oxygenase-2 (COX-2). In addition, calcitriol also exerts important effects on adaptive immunity by downregulating MHC-II class and co-stimulatory molecules on antigen-presenting cells, but it also directly affects T lymphocytes. In multiple studies, the influence of vitamin D on eye diseases, including corneal diseases, has been demonstrated. Adequate vitamin D supplementation in patients with dry eye significantly improves tear quality and consequently heals the epithelial cells of the ocular surface. Pterygium is a fibrovascular growth of conjunctival tissue that histologically consists of superficial conjunctival epithelium and an underlying fibrovascular layer. The prevalence of pterygium depends on the region. In zones closer to the equator—“pterygium zone”, it is up to 22%, and outside of them it can be even less than 2%. While UV radiation is recognized as a primary risk factor, other factors, including vitamin D, may influence its development. This review aims to summarize the effects of vitamin D on the pathophysiological mechanism of pterygium and its possible therapeutic impact. Current research suggests that vitamin D is protective through its immunomodulatory and anti-inflammatory properties. Finally, there is still insufficient evidence of the therapeutic benefit of vitamin D in pterygium, and future large-scale randomized controlled studies are needed to elucidate the exact role of vitamin D in pterygium onset and recurrence as well as its potential therapeutic benefit. Full article

Since its discovery, vitamin D (VD) has been known for its implications in maintaining bone homeostasis. However, in recent years it has been discovered that the vitamin D receptor is expressed on different cells of the immune system and that these cells can locally produce the active form of this molecule, calcitriol, strongly suggesting that this vitamin might play a key role in both branches of the immune system, innate and adaptive. Recent evidence has demonstrated that VD participates in the different protective phases of the immune system against invading microorganisms, including in the activation and production of antimicrobial peptides, in the inactivation of replication of infectious agents, in the prevention of the exposure of cellular receptors to microbial adhesion, and, more importantly, in the modulation of the inflammatory response. In recent years, the world has witnessed major outbreaks of an ancient infectious disease, dengue fever; the emergence of a pandemic caused by an unknown virus, SARS-CoV-2; and the resurgence of a common respiratory infection, influenza. Despite belonging to different viral families, the etiological agents of these infections present a common trait: their capacity to cause complications not only through their cytopathic effect on target tissues but also through the excessive inflammatory response produced by the human host against an infection. This review outlines the current understanding of the role that vitamin D plays in the prevention of the aforementioned diseases and in the development of their complications through its active participation as a major modulator of the immune response. Full article

Background: Herpes simplex keratitis (HSK) is a disease characterized by the recurrent infection of the cornea, mainly due to infection caused by herpes simplex virus type 1. The suppression of recurrence can suppress progressive corneal scarring, ulcers, and perforation. Cornea contains vitamin D receptors (VDRs). VDR agonists show antimicrobial activity. Case presentation: In this case report, I describe two female patients aged 76 and 85 years old in whom the administration of a VDR agonist led to the suppression of the recurrence of HSK. The former patient had repeated HSK recurrence for over 10 years after the initial infection. The latter patient developed HSK immediately after vitrectomy, and her cornea remained susceptible to infection, resulting in recurrence. Both patients were trying to suppress recurrence by applying acyclovir ophthalmic ointment, but their medication adherence was declining. So, they switched to oral treatment with 0.5 μg of the VDR agonist per day, and since then, there has been no recurrence of HSK. Oral treatment with the VDR agonist is still ongoing. Conclusions: This report highlights the cases where ways were examined to improve medication adherence in elderly patients who had a risk of HSK recurrence. Both patients responded to VDR agonist treatment and were able to suppress recurrence. Full article

The active metabolite of vitamin D3, calcitriol (1,25D), is widely recognised for its direct anti-proliferative and pro-differentiation effects. However, 1,25D is calcaemic, which restricts its clinical use for cancer treatment. Non-calcaemic agonists of the vitamin D receptor (VDR) could be better candidates for cancer treatment. In this study, we examined the influence of the hydroxylated lithocholic acid derivative CAR-R on osteosarcoma (OS) cell (MG63) growth and differentiation. Treatment of MG63 cells with CAR-R inhibited growth under conventional and hypoxic conditions. Co-treating cells with CAR-R and a lysophosphatidic acid (LPA) analogue resulted in their differentiation, as supported by synergistic increases in alkaline phosphatase (ALP) activity. Under hypoxic conditions, however, this differentiation response was attenuated. The importance of observed increases in hypoxia inducible factors (HIFs) were investigated through targeted disruption using pharmacological and genetic approaches. Disruption elicited a reduction in ALP activity, suggesting an important role for HIFs in OS differentiation. Finally, we examined the expression of the VDR protein. Hypoxic MG63s expressed less VDR, with the levels increasing with CAR-R exposure. Whilst these findings are encouraging, future studies aimed at bolstering the pro-differentiating effect of CAR-R under hypoxic conditions are warranted if this agent is to gain traction in the treatment of OS. Full article

Background/Objectives: Vitamin D receptor (VDR) agonists are commonly used in clinical practice for their roles in calcium regulation and potential benefits in various diseases. However, their safety profiles, particularly for compounds available as food supplements, remain underexplored in real-world settings. This study aimed to analyze the safety profiles of VDR agonists using the EudraVigilance database, focusing on adverse drug reactions (ADRs) reported between 1 January 2004 and 23 June 2024. Methods: Data for ten VDR agonists were collected, de-duplicated, and analyzed to identify specific safety signals. Risk factors for specific ADRs were assessed using multiple logistic regression. Results: This study analyzed 5,369,581 reports in the EudraVigilance system, from which 17,947 reports (0.33%) involving 80,050 ADRs were linked to VDR agonists. The most-reported drugs were cholecalciferol (12,944 cases) and calcitriol (1355 cases). Serious ADRs were more prevalent with paricalcitol, alfacalcidol, and calcitriol than with cholecalciferol (p < 0.05). Hypercalcemia was a hallmark ADR for all VDR agonists, with the highest risk linked to dihydrotachysterol (ROR = 5668; 95%CI = 3332 to 9641; p < 0.0001), alfacalcidol (ROR = 965.7; 95%CI = 843.6 to 1106; p < 0.0001), and calcitriol (ROR = 726.0; 95%CI = 634.6 to 830.5; p < 0.0001). Logistic regression highlighted dehydration, overdose, and concomitant administration of calcium salts as major predictors of hypercalcemia. The co-administration of multiple VDR agonists was also found to increase hypercalcemia risk. However, the disproportionality analysis showed that only active VDR agonists (e.g., calcitriol, alfacalcidol) were associated with severe complications like renal and urinary disorders and cardiac issues due to hypercalcemia. Natural precursors (cholecalciferol, ergocalciferol) were more often linked to non-calcemic ADRs such as gastrointestinal symptoms, which were more prevalent in infants and children compared to adults. Conclusions: The safety profiles of VDR agonists differ significantly between compounds. Active derivatives require close monitoring for serious calcemia-related complications, whereas cholecalciferol is associated with less severe ADRs, primarily in at-risk populations. These findings highlight the need for targeted safety monitoring and further research into the real-world uses of VDR agonists. 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

Background/Objectives: Vitamin D is essential for bone health, immune function, and overall well-being. Numerous ecological, observational, and prospective studies, including randomized controlled clinical trials (RCTs), report an inverse association between higher serum 25-hydroxyvitamin D [25(OH)D; calcifediol] levels in various conditions, including cardiovascular disease, metabolic disorders such as diabetes and obesity, susceptibility to infection-related complications, autoimmune diseases, and all-cause mortality. Results: Vitamin D operates through two distinct systems. The endocrine system comprises the renal tubular cell-derived circulatory calcitriol, which primarily regulates calcium homeostasis and muscular functions. In contrast, intracellularly generated calcitriol in peripheral target cells is responsible for intracrine/paracrine system signaling and calcitriol–vitamin D receptor-mediated genomic effects. Government-appointed committees and health organizations have developed various clinical practice guidelines for vitamin D supplementation and management. However, these guidelines heavily relied on the 2011 Institute of Medicine (IoM) report, which focused solely on the skeletal effects of vitamin D, ignoring other body systems. Thus, they do not represent maintaining good overall health and aspects of disease prevention. Additionally, the IoM report was intended as a public health recommendation for the government and is not a clinical guideline. Discussion: New country- and regional-specific guidelines must focus on healthy nations through disease prevention and reducing healthcare costs. They should not be restricted to bone effect and must encompass all extra-skeletal benefits. Nevertheless, due to misunderstandings, medical societies and other governments have used faulty IoM report as a foundation for creating vitamin D guidelines. Consequently, they placed disproportionate emphasis on bone health while largely overlooking its benefits for other bodily systems, making current guidelines, including 2024, the Endocrine Society less applicable to the public. As a result, the utility of published guidelines has been significantly reduced for clinical practice and RCTs that designed on bone-centric are generate misleading information and remain suboptimal for public health and disease prevention. Conclusions: This review and its recommendations address the gaps in current vitamin D clinical practice guidelines and propose a framework for developing more effective, country and region-specific recommendations that capture the extra-skeletal benefits of vitamin D to prevent multiple diseases and enhance public health. Full article

Vitamin D plays an important pleiotropic role in maintaining global homeostasis of the human body. Its functions go far beyond skeletal health, playing a crucial role in a plethora of cellular functions, as well as in extraskeletal health, ensuring the proper functioning of multiple human organs, including the skin. Genes from the Grainyhead-like (GRHL) family code for transcription factors necessary for the development and maintenance of various epithelia. Even though they are involved in many processes regulated by vitamin D, a direct link between vitamin D-mediated cellular pathways and GRHL genes has never been described. We employed various bioinformatic methods, quantitative real-time PCR, chromatin immunoprecipitation, reporter gene assays, and calcitriol treatments to investigate this issue. We report that the vitamin D receptor (VDR) binds to a regulatory region of the Grainyhead-like 1 (GRHL1) gene and regulates its expression. Ectopic expression of VDR and treatment with calcitriol alters the expression of the GRHL1 gene. The evidence presented here indicates a role of VDR in the regulation of expression of GRHL1 and correspondingly a role of GRHL1 in mediating the actions of vitamin D. Full article