Liver fibrosis is characterized by the excessive accumulation of extracellular matrix proteins, which can lead to cirrhosis and liver cancer. Metabolic dysfunction-associated steatosis liver diseases are common causes of liver fibrosis, sharing a similar pathogenesis with carbon tetrachloride (CCl₄) exposure. This process involves the activation of hepatic stellate cells (HSCs) into myofibroblasts. However, the detailed mechanism and effective treatment strategies require further investigation. In this study, we uncovered a negative correlation between VDR expression and YAP within HSCs. Subsequently, we demonstrated that VDR exerted a downregulatory influence on YAP transcriptional activity in HSCs. Intriguingly, activation VDR effectively inhibited the culture induced activation of primary HSCs by suppressing the transcriptional activity of early YAP. Furthermore, in vivo results manifested that hepatic-specific deletion of YAP/TAZ ameliorates CCl4-induced liver fibrosis, and nullified the antifibrotic efficacy of VDR. Importantly, a YAP inhibitor rescued the exacerbation of liver fibrosis induced by hepatic-specific VDR knockout. Moreover, the combined pharmacological of VDR agonist and YAP inhibitor demonstrated a synergistic effect in diminishing CCl4-induced liver fibrosis, primary HSCs activation and hepatic injury in vivo. These effects were underpinned by their collective ability to inhibit HSC activation through AMPK activation, consequently curbing ATP synthesis and HSCs proliferation. In conclusion, our results not only revealed the inhibition of VDR on YAP-activated liver stellate cells but also identified a synergistic effect of VDR agonist and YAP inhibitor in an AMPKα-dependent manner, providing a practical foundation for integration of multi-targeted drugs in the therapy of CCl4-induced hepatic fibrosis.

A total hip arthroplasty (THA) can improve quality of life, but loosening of the hip prosthesis is a complex problem in which vitamin D may also play a role. The Vitamin D Receptor (VDR) is involved in the response of cells to the action of vitamin D, and its genetic variability raises the question of whether individual differences could influence the risk of prosthesis loosening. The aim of this study was to investigate the relationship between VDR single nucleotide polymorphisms (SNPs) (ApaI, BsmI, FokI and TaqI) and the serum VDR and 25(OH)D levels in three groups of patients: (1) arthroscopy patients after THA without loosening of the prosthesis (CA-Control Arthroplasty), (2) patients after THA with loosened hip prostheses (L-Loosening) and (3) the control group (C-Control). Our results suggest that the genotypes tt of TaqI, BB of BsmI, and FF of FokI may influence the VDR effect in patients with loosened protheses. Our results showed that the ACAC haplotype (AtBF) was over two times more frequent in the L group than in CA + C: OR =2.35 [95% CI 1.44-3.83; p = 0.001]. There was no significant correlation between the VDR and serum 25(OH)D levels, but there were differences between studied groups.

Alzheimer\'s disease is a neurodegenerative disorder with polygenic etiology. Genetic risk variants for Alzheimer\'s disease differ among populations. Thus, discovering them in each population is clinically important. A total of 118 patients and 97 controls for VDR rs11568820 and 88 patients and 100 healthy controls for MTHFR C677T polymorphism were genotyped to evaluate the association of these polymorphisms with late-onset Alzheimer\'s disease in the Iranian population, along with their impacts on the response to Rivastigmine treatment. The VDR C allele was significantly associated with Alzheimer\'s disease and provided protection against it (P = 0.003, RR = 1.14, 95% CI 1.04-1.24), while the T allele increased susceptibility (P = 0.003, RR = 1.93, 95% CI 1.23-3.02). These results were also considerable upon excluding the effect of APOE ε4 allele. The Prevalence-corrected Positive Predictive Value was 1.71% for the VDR CC genotype and 4% for the VDR CT genotype, indicating lower and almost twofold higher chances of developing Alzheimer\'s disease, respectively. No significant correlation was observed between MTHFR C677T and Alzheimer\'s disease. Based on our pharmacogenetic study, MTHFR T allele carriers lacking APOE ε4 allele showed a better response to Rivastigmine treatment after a 2-year follow-up. Moreover, patients with VDR CC genotype displayed milder Alzheimer\'s disease, particularly when coincided with the APOE ε4 allele. The VDR rs11568820 polymorphism affects both Alzheimer\'s disease risk and the response to Rivastigmine in Iranian patients. Also, MTHFR C677T polymorphism may play a role in the response to Rivastigmine, through a pathway that needs to be elucidated in future studies.

Vitamin D possesses a crucial role in preserving bone health, modulating the immune system responses, and supporting various physiological functions throughout the body. Chronic atrophic autoimmune gastritis (CAAG) constitutes an autoimmune condition marked by inflammation and damage to the stomach cells, often resulting in a decreased ability to absorb certain nutrients, including vitamin B12 and iron. Although, vitamin D is not directly affected by this condition, the sufficiency of this micronutrient seems to have important implications for overall health and management of the disease. The aim of the current review was to assess the incidence and related features of vitamin D deficiency in patients with CAAG and to elucidate the complex regulatory role of this nutrient, in an effort to improve patient outcomes. Vitamin D greatly contributes to the regulation of the immune system. In patients with CAAG, the immune system attacks the stomach lining; thus, the maintenance of a healthy and balanced immune response is important. In autoimmune conditions such as CAAG, where inflammation plays a decisive role in disease progression, vitamin D could potentially exert a role in managing and controlling the associated symptoms. Adequate vitamin D levels may help in regulating the immune response and reducing inflammation. In addition, patients with CAAG are at risk of nutrient deficiencies, including vitamin B12 and iron, which can lead to anemia and bone health issues. As vitamin D is critical for calcium absorption and bone health, assurance of sufficient levels of this micronutrient can be beneficial in preventing or mitigating bone-related complications. In conclusion, regular monitoring of vitamin D levels, among other nutrients, and appropriate supplementation, when necessary, can help improve overall health and well-being in these patients.

Background: The etiopathogenesis of inflammatory bowel disease (IBD) is still unclear. Prior studies suggest genetic components that may influence the incidence and severity of the disease. Additionally, it was shown that low levels of serum vitamin D may have an impact on the clinical course of the disease due to its effect on the immunological system. Methods: We aimed to investigate the correlation between the incidence of vitamin D receptor (VDR) gene polymorphisms (rs11568820, rs10735810, rs1544410, rs7975232, and rs731236, commonly described as Cdx2, FokI, Bsm, ApaI, and TaqI, respectively) and vitamin D concentration with the clinical course of IBD (disease activity, extent of the intestinal lesions). Data were obtained from 62 patients with IBD (34 with Crohn\'s disease, 28 with ulcerative colitis), aged 3-18 years, and compared with controls (N = 47), aged 8-18 years. Results: Although there was no difference in the incidence of individual genotypes between the study groups (IBD, C) in all the polymorphisms examined, we described a significant increase in the chance of developing IBD for heterozygotes of Cdx2 (OR: 2.3, 95% CI 0.88-6.18, p = 0.04) and BsmI (OR: 2.07, 95% CI 0.89-4.82, p = 0.048) polymorphisms. The mean serum 25OHD level in patients with IBD was significantly higher compared with the controls (19.87 ng/mL vs. 16.07 ng/mL; p = 0.03); however, it was still below optimal (>30 ng/mL). Furthermore, a significant correlation was found between vitamin D level and TaqI in patients with IBD (p = 0.025) and patients with CD (p = 0.03), as well as with the BsmI polymorphism in patients with IBD (p = 0.04) and patients with CD (p = 0.04). A significant correlation was described between the degree of disease activity and genotypes for the FokI polymorphism in patients with UC (p = 0.027) and between the category of endoscopic lesions and genotypes for the Cdx2 polymorphism also in patients with UC (p = 0.046). Conclusions: The results suggest a potential correlation of VDR gene polymorphism with the chance of developing IBD, and the clinical course of the disease requires further studies in larger group of patients. Vitamin D supplementation should be recommended in both children with inflammatory bowel disease and in healthy peers.

Several single nucleotide polymorphisms (SNPs) of the vitamin D receptor (VDR) have been observed in association with susceptibility to various pathologies, including autism, major depression, age-related changes in cognitive functioning, and Parkinson\'s and Alzheimer\'s diseases. This study aimed to establish the association between Fok1/Apa1 polymorphic variants and anxious/depressive symptoms in nonclinical adolescents from central Italy, with the goal of identifying the risk of developing both symptoms. We found no significant difference in genotype distribution or dominant/recessive models of Fok1/Apa1 VDR polymorphic variants between subjects with anxious/depressive symptoms and controls. HN9.10e cell lines carrying the AA genotype for Fok1 and the CC genotype for Apa1 responded better to treatment with vitamin D3 than cell lines carrying the AG genotype for Fok1 and CA genotype for Apa1. Cell lines carrying the GG genotype for Fok1 and the AA genotype for Apa1 did not respond at all, suggesting avenues for future studies in both the general population and individuals with mental and/or neuropsychiatric disorders. These studies suggest that the level of response to vitamin D3 administered to prevent and/or treat mental or neurological disorders could depend on the polymorphic variants of the vitamin D receptor.

A sedentary lifestyle and physical inactivity leads to metabolic syndrome-associated comorbidities involving abdominal obesity, type 2 diabetes, hyperlipidaemia associated Cardiovascular Diseases (CVDs), and Metabolic dysfunction-associated fatty liver disease (MAFLD). In this study, we evaluated the novel hepato/cardio/adipo-protective role of Quercetin via Vitamin D Receptor, and elucidated its underlying mechanisms in reducing lipotoxicity, inflammation and fibrosis in high calorie diet induced metabolic syndrome. Male Swiss albino mice were fed with western diet and sugar water for multiple time intervals. Anti-lipotoxicity, anti-inflammatory, and anti-fibrotic effect of Quercetin was assessed by Oil Red O, H&E and TMS staining at different time points. The lipid profile, mRNA expression of inflammatory markers (TNF- α, IL-1β, IL-6 and MCP-1), fibrotic markers (α-SMA, COL1A1, COL1A2), adiponectin, AdipoR2, and VDR expression levels were measured from RNA pools of adipose, liver and heart tissues. Also, lipid-lowering and anti-steatohepatitic effects of Quercetin was assessed using mouse 3T3-L1 adipocytes, rat H9c2 cardiac cells, and human HepG2 hepatocytes. Our results indicate that, western diet fed mice with Quercetin ameliorated lipid profile and lipotoxicity. Histopathological examination and gene expression data revealed that Quercetin reduced hepatic and cardiac inflammation and fibrosis-associated markers. Interestingly, Quercetin treatment increased the serum levels of adiponectin and mRNA expressions of AdipoR2 and VDR. In-vitro experiments revealed the reduction in lipid accumulation of 3T3-L1 and fatty-acid-treated hepatic and cardiac cells following Quercetin treatment. These findings indicate that Quercetin exhibits a protective role on multiple organs through VDR activation and subsequent Adipo/AdipoR2 signaling in metabolic syndrome associated obesity, hepatic injury, and cardiac dysfunction.

Carbon tetrachloride (CCl4) has a wide range of toxic effects, especially causing acute liver injury (ALI), in which rapid compensation for hepatocyte loss ensures liver survival, but proliferation of surviving hepatocytes (known as endoreplication) may imply impaired residual function. Yes-associated protein (YAP) drives hepatocytes to undergo endoreplication and ploidy, the underlying mechanisms of which remain a mystery. In the present study, we uncover during CCl4-mediated ALI accompanied by increased hepatocytes proliferation and YAP activation. Notably, bioinformatics analyses elucidate that hepatic-specific deletion of YAP substantially ameliorated CCl4-induced hepatic proliferation, effectively decreased the vitamin D receptor (VDR) expression. Additionally, a mouse model of acute liver injury substantiated that inhibition of YAP could suppress hepatocytes proliferation via VDR. Furthermore, we also disclosed that the VDR agonist nullifies CCl4-induced ALI alleviated by the YAP inhibitor in vivo. Importantly, hepatocytes were isolated from mice, and it was spotlighted that the anti-proliferative impact of the YAP inhibitor was abolished by the activation of VDR within these hepatocytes. Similarly, primary hepatic stellate cells (HSCs) were isolated and it was manifested that YAP inhibitor suppressed HSC activation via VDR during acute liver injury. Our findings further elucidate the YAP\'s role in ALI and may provide new avenues for protection against CCl4-drived acute liver injury.

Pharmacokinetic changes induced by radiation following radiotherapy (\"RT-PK\" phenomenon) are of great significance to the effectiveness and safety of chemotherapeutic agents in clinical settings. The aims of this study were to clarify the organic anion transporters (Oats) involved in the \"RT-PK\" phenomenon of bestatin in rats following X-ray irradiation and to elucidate its potential mechanism via vitamin D signalling. Pharmacokinetic studies, uptake assays using rat kidney slices and primary proximal tubule cells, and molecular biological studies were performed. Significantly increased plasma concentrations and systemic exposure to bestatin were observed at 24 and 48 h following abdominal X-ray irradiation, regardless of oral or intravenous administration of the drugs in rats. Reduced renal clearance and cumulative urinary excretion of bestatin were observed at 24 and 48 h post-irradiation in rats following intravenous administration. The uptake of the probe substrates p-aminohippuric acid and oestrone 3-sulfate sodium in vitro and the expression of Oat1 and Oat3 in vivo were reduced in the corresponding models following irradiation. Moreover, the upregulation of the vitamin D receptor (Vdr) in mRNA and protein levels negatively correlated with the expressions and functions of Oat1 and Oat3 following irradiation. Additionally, elevated plasma urea nitrogen levels and histopathological changes were observed in rats after exposure to irradiation. The \"RT-PK\" phenomenon of bestatin occurs in rats after exposure to irradiation, possibly resulting in the regulation of the expressions and activities of renal Oats via activation of the Vdr signalling pathway.

Vitamin D signals through the vitamin D receptor (VDR) to induce its end-organ effects. Hepatic stellate cells control development of liver fibrosis in response to stressors and vitamin D signaling decreases fibrogenesis. VDR expression in hepatocytes is low in healthy liver, and the role of VDR in hepatocyte proliferation is unclear. Hepatocyte-VDR null mice (hVDR) were used to assess the role of VDR and vitamin D signaling in hepatic regeneration. hVDR mice have impaired liver regeneration and impaired hepatocyte proliferation associated with significant differential changes in bile salts. Notably, mice lacking hepatocyte VDR had significant increases in expression of conjugated bile acids after partial hepatectomy, consistent with failure to normalize hepatic function by the 14-day time point tested. Real-time PCR of hVDR and control livers showed significant changes in expression of cell-cycle genes including cyclins D1 and E1 and cyclin-dependent kinase 2. Gene expression profiling of hepatocytes treated with vitamin D or control showed regulation of groups of genes involved in liver proliferation, hepatitis, liver hyperplasia/hyperproliferation, and liver necrosis/cell death. Together, these studies demonstrate an important functional role for VDR in hepatocytes during liver regeneration. Combined with the known profibrotic effects of impaired VDR signaling in stellate cells, the studies provide a mechanism whereby vitamin D deficiency would both reduce hepatocyte proliferation and permit fibrosis, leading to significant liver compromise.