Vitamin D deficiency is associated with poor outcomes and increased mortality in cirrhosis. Calcitriol, the active form of vitamin D3, has antioxidant and hepatoprotective properties; however, its effects on diethylnitrosamine (DEN)-induced liver fibrosis remain unclear. This study investigated the effects of calcitriol on oxidative stress, inflammation, and fibrogenesis in DEN-induced liver fibrosis rat model. Male Sprague-Dawley rats (n = 6/group) were assigned to four groups: control (CON), DEN, DEN + low-dose calcitriol (DEN + LVD3: 5 µg/kg BW), and DEN + high-dose calcitriol (DEN + HVD3: 10 µg/kg BW). Liver fibrosis was induced by weekly DEN injections (70 mg/kg, i.p.) for 8 weeks. Calcitriol was administered twice weekly (i.p.) throughout the experiment. Oxidative stress (hepatic malondialdehyde; MDA), liver injury (serum ALT, AST), hepatic inflammation (NF-κB p65), antioxidant gene expression (SOD-1, GPX-1), and fibrosis markers (TGF-β1, MMP-12, TIMP-1, α-SMA, collagen) were evaluated by biochemical assays, immunohistochemistry, qRT-PCR, western blotting and H&E and Sirius Red staining. Calcitriol significantly attenuated DEN-induced oxidative stress by decreasing hepatic MDA levels in a dose-dependent manner, and lowered serum ALT and AST levels. It partially enhanced hepatic antioxidant defenses by increasing SOD-1 expression toward control levels and upregulating GPX-1 expression. Calcitriol also markedly suppressed NF-κB p65 activation and fibrotic markers (TGF-β1, MMP-12, α-SMA, collagen), which corresponded with improved histopathological fibrosis scores. TIMP1 expression remained unchanged across all groups. Therefore, calcitriol attenuates DEN-induced liver fibrosis by reducing oxidative stress, suppressing inflammatory and fibrogenic signaling, and enhancing antioxidant defenses.

Denosumab is a human monoclonal antibody that inhibits RANKL, thereby suppressing osteoclast-mediated bone resorption and increasing bone mass in patients with osteoporosis. Although generally well tolerated, denosumab is associated with hypocalcemia, particularly in individuals with impaired calcium and vitamin D homeostasis. We report the case of a 40-year-old woman with a history of sleeve gastrectomy who developed severe, symptomatic hypocalcemia following a single dose of denosumab despite receiving vitamin D supplementation. She presented with neuromuscular symptoms, QTc prolongation, profound hypocalcemia, severe vitamin D deficiency, and marked secondary hyperparathyroidism. Her clinical course was notable for delayed onset, resistance to standard therapy, recurrent hypocalcemia after discharge, and the need for prolonged hospitalization with high-dose intravenous calcium, active vitamin D, and aggressive oral supplementation. This case highlights bariatric surgery as a major and underrecognized risk factor for severe and prolonged denosumab-induced hypocalcemia and underscores the importance of correcting nutritional deficiencies and implementing close biochemical monitoring when initiating denosumab in high-risk patients.

Vitamin K (VK), traditionally recognized for its role in coagulation, is increasingly implicated in extrahepatic processes, including glucose metabolism and calcium regulation. A suboptimal VK status is common in the general population and may limit these functions, yet evidence linking VK to glucose metabolism and other endocrine axes remains heterogeneous and incompletely synthesized. This narrative review integrates mechanistic, observational, and interventional evidence to examine the role of VK across the endocrine system, with particular emphasis on glucose metabolism. Mechanistic studies indicate that VK supports pancreatic β-cell function, modulates peripheral insulin sensitivity, and facilitates proper calcium distribution. Observational studies consistently associate a higher VK status with a lower risk of type 2 diabetes, while interventional studies suggest that VK supplementation may improve glucose metabolism, primarily in metabolically impaired populations. In bone and mineral metabolism, VK acts synergistically with calcitriol, with combined supplementation showing more consistent benefits in skeletal outcomes than either vitamin alone. Evidence for VK involvement in other endocrine axes, including reproductive and inflammatory pathways, remains limited and largely mechanistic. Overall, the available evidence supports a context-dependent role for VK in glucose metabolism, influenced by baseline nutritional and metabolic status and outcome selection, as well as a synergistic interaction with calcitriol and parathormone in calcium regulation. Future clinical studies should incorporate baseline VK status stratification, dynamic measures of insulin sensitivity, and adequately powered designs to clarify the therapeutic relevance of VK across endocrine and metabolic outcomes.

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.

Pancreatic ductal adenocarcinoma (PDAC) exhibits pronounced desmoplasia, primarily attributed to the activation of pancreatic stellate cells (PSCs) from a quiescent state (quiescent PSCs [qPSCs]) to an activated form (activated PSCs [aPSCs]), which facilitates tumor progression and therapeutic resistance. This study investigates the potential of the vitamin D3 (VD) analog calcipotriol (Cal) to modulate this activation process and its impact on PDAC cell malignancy, with a particular focus on the thrombospondin 1/cluster of differentiation 47 (THBS1/CD47) signaling axis. Through analyzing VDR mRNA expression in aPSCs versus PDAC cells, we found that aPSCs are more responsive to VD signaling. Treatment with Cal significantly reduced aPSC activation, as evidenced by decreased α-SMA expression and THBS1 secretion, thereby diminishing stromal support for PDAC cell proliferation, migration, and invasion. These changes were mediated by the inhibition of the THBS1/CD47 axis, highlighting a novel mechanism by which Cal disrupts the supportive tumor microenvironment. Our findings highlight the therapeutic potential of targeting aPSCs with VD analogs in PDAC, suggesting a new direction for treatments that aim to interrupt the desmoplastic reaction and thereby inhibit PDAC progression.

Retinoid X receptor (RXR) is an obligate heterodimerization partner for many nuclear receptors. In the absence of ligands, RXR occupies thousands of genomic regions, with its binding landscape predominantly determined by cell identity. In the presence of agonists of RXR or its partners, RXR occupancy is changed at a subset of binding regions. The characteristics of these ligand-responsive binding regions remain largely unexplored. We used ChIP-seq to profile RXR occupancy in PMA-differentiated THP-1 cells treated with agonists of RXR or partner receptors, including RARα, VDR, PPARδ, PPARγ, LXRs, and TR, or a 'cocktail' containing multiple agonists. The RXR agonist LG268 produced a stronger increase in RXR occupancy than any of the six partner-receptor agonists or their combination. The relevance of ligand-induced RXR peaks was confirmed by analyses of motif enrichment and RXR occupancy at regulatory elements of target genes. RXR binding was investigated in more detail in cells treated with the VDR agonist, calcitriol. Calcitriol markedly enhanced VDR binding, but the corresponding increase in RXR occupancy was less pronounced. We found that both ligand-induced and unresponsive RXR peaks were involved in gene regulation, and only a small subset (∼3%) of calcitriol-regulated genes exhibited decreases in both RXR binding and mRNA levels in response to combined agonist treatment. These results support a model in which RXR functions as a non-limiting module in a macrophage-like cell type, and interference between pathways is minimally attributable to RXR sequestration.

Fahr's syndrome is a rare neurological condition characterized by bilateral intracranial calcifications secondary to metabolic or endocrine abnormalities, most commonly hypoparathyroidism. This condition is distinct from Fahr's disease (primary familial brain calcification), which is genetically inherited. A 30-year-old South Asian Pakistani man presented with sudden-onset generalized tonic-clonic seizures and progressive cognitive decline. Neuroimaging revealed bilateral, symmetrical calcifications in the basal ganglia, thalami, cerebellar dentate nuclei, periventricular regions, and centrum semiovale. Laboratory evaluation revealed severe hypocalcemia, hypomagnesemia, and markedly reduced parathyroid hormone levels, consistent with hypoparathyroidism. The patient was treated with calcium supplementation, calcitriol, vitamin D, magnesium replacement, and antiepileptic therapy, resulting in clinical stabilization of the patient. Fahr's syndrome should be considered in young patients presenting with seizures and cognitive impairment when characteristic intracranial calcifications are identified. Early recognition and correction of metabolic abnormalities can improve the outcomes.

Cerebral ischemia is a major cause of death and long-term disability. NOD-like receptor protein 3 (NLRP3) inflammasome plays a central role in post-ischemic inflammation, with reactive oxygen species (ROS)-induced thioredoxin-interacting protein (TXNIP) activation contributing to its assembly. Calcitriol, the active form of vitamin D3, has anti-inflammatory and antioxidant properties. Here, we investigated the neuroprotective effects of calcitriol via modulation of the ROS/TXNIP/NLRP3 pathway in cerebral ischemia. We employed a rat model of transient middle cerebral artery occlusion (tMCAO) to induce ischemia/reperfusion (I/R) injury. Adult male Wistar rats (280-320 g) were randomly assigned to three experimental groups: sham, I/R, and calcitriol-treated. Calcitriol (1 µg/kg) was administered intraperitoneally at 30 min, 24 h, and 48 h post-surgery. At 72 h, neurological deficits and infarct volume were assessed. Oxidative stress was evaluated by measuring ROS, malondialdehyde (MDA), nitric oxide (NO), and total antioxidant capacity (TAC). ELISA was utilized to assay the levels of Interleukin-1 beta (IL-1β) and, Interleukin-18 (IL-18). Protein expression of TXNIP, NLRP3, ASC, and Caspase-1 was analyzed via Western blot, and neuronal injury was assessed using Nissl staining. Molecular docking was used to assess the interaction strength between calcitriol and NLRP3. Results showed that calcitriol significantly alleviated neurological impairments, reduced infarct size of stroke, lowered oxidative stress and pro-inflammatory markers, and downregulated NLRP3 inflammasome components and TXNIP. Histological analysis confirmed neuroprotection, and docking analysis revealed favorable binding of calcitriol to NLRP3's NACHT domain. The present study suggests that calcitriol mitigates I/R-induced neuroinflammation by targeting the ROS/TXNIP/NLRP3 signaling pathway.

The core function of the vitamin D receptor (VDR) is to mediate the biological effects of vitamin D and plays an important role in inhibiting adipocyte differentiation. However, previous studies have revealed that VDR has an independent effect-promoting lipogenesis-although the underlying mechanism remains unclear. In this study, we established a 3T3-L1 preadipocyte model overexpressing VDR and treated the cells with the peroxisome proliferator-activated receptor gamma (PPARγ) inhibitor GW9662 to explore the effects of VDR on adipocyte differentiation and lipogenesis in the absence of vitamin D and to verify the role of PPARγ in this process. Under vitamin D-free conditions, compared with normally induced differentiated cells, 3T3-L1 cells overexpressing VDR presented increased synthesis of fatty acids and triglycerides, elevated expression of PPARγ and its downstream adipogenic regulator C/EBPα, and increased expression of the mature adipocyte marker adiponectin, suggesting that enhanced expression of VDR promotes adipocyte differentiation and lipogenesis. After GW9662 intervention, the expression levels of VDR, PPARγ, C/EBPα, and adiponectin were significantly decreased in both the normal differentiation group and the VDR-overexpressing group. In conclusion, under vitamin D deficiency, increased VDR expression promotes adipocyte differentiation and lipogenesis, and these effects are at least partially mediated by the upregulation of PPARγ expression.

Pediatric sarcoidosis is a rare noninfectious granulomatous disease that can affect any organ. Diagnosis is challenging due to a lack of specific tests and highly variable symptoms that can resemble infectious processes or malignancy. We report a 16-year-old Caucasian girl with well-controlled type 1 diabetes mellitus (T1DM) who presented with 10 days of nausea, vomiting, and generalized abdominal pain and was incidentally found to have severe hypercalcemia and acute kidney injury (AKI). Further testing revealed high 1,25-dihydroxyvitamin D (calcitriol) and angiotensin-converting enzyme (ACE) levels, with suppressed parathyroid hormone (PTH) and normal PTH-related peptide (PTHrP). An extensive infectious workup was negative. Imaging demonstrated generalized lymphadenopathy, raising concern for lymphoma or granulomatous disease. Lymph node biopsy showed non-caseating granulomas consistent with sarcoidosis. She received corticosteroids and steroid-sparing agents, resulting in normalization of calcium and symptom resolution. This case illustrates a rare, high-risk pediatric sarcoidosis with multiorgan involvement and severe hypercalcemia, emphasizing the need for biopsy confirmation and multidisciplinary evaluation in distinguishing it from infection or malignancy.