Modelling the influence of vitamin D and probiotic supplementation on the microbiome and immune response.

The intestinal microbiota play a critical role in human health and disease, maintaining metabolic and immune/inflammatory health, synthesising essential vitamins and amino acids and maintaining intestinal barrier integrity. The aim of this paper is to develop a mathematical model to describe the complex interactions between the microbiota, vitamin D/vitamin D receptor (VDR) pathway, epithelial barrier and immune response in order to understand better the effects of supplementation with probiotics and vitamin D. This is motivated by emerging data indicating the beneficial effects of vitamin D and probiotics individually and when combined. We propose a system of ordinary differential equations determining the time evolution of intestinal bacterial populations, concentration of the VDR:1,25(OH)2D complex in epithelial and immune cells, the epithelial barrier and the immune response. The model shows that administration of probiotics and/or vitamin D upregulates the VDR complex, which enhances barrier function and protects against intestinal inflammation. The model also suggests co-supplementation to be superior to individual supplements. We explore the effects of inflammation on the populations of commensal and pathogenic bacteria and the vitamin D/VDR pathway and discuss the value of gathering additional experimental data motivated by the modelling insights.

Cytomegalovirus results in poor graft function via bone marrow-derived endothelial progenitor cells.

Introduction: Poor graft function (PGF), characterized by myelosuppression, represents a significant challenge following allogeneic hematopoietic stem cell transplantation (allo-HSCT) with human cytomegalovirus (HCMV) being established as a risk factor for PGF. However, the underlying mechanism remains unclear. Bone marrow endothelial progenitor cells (BM-EPCs) play an important role in supporting hematopoiesis and their dysfunction contributes to PGF development. We aim to explore the effects of CMV on BM-EPCs and its underlying mechanism. Methods: We investigated the compromised functionality of EPCs derived from individuals diagnosed with HCMV viremia accompanied by PGF, as well as after infected by HCMV AD 169 strain in vitro, characterized by decreased cell proliferation, tube formation, migration and hematopoietic support, and increased apoptosis and secretion of TGF-ß1. Results: We demonstrated that HCMV-induced TGF-ß1 secretion by BM-EPCs played a dominant role in hematopoiesis suppression in vitro experiment. Moreover, HCMV down-regulates Vitamin D receptor (VDR) and subsequently activates p38 MAPK pathway to promote TGF-ß1 secretion by BM-EPCs. Discussion: HCMV could infect BM-EPCs and lead to their dysfunction. The secretion of TGF-ß1 by BM-EPCs is enhanced by CMV through the activation of p38 MAPK via a VDR-dependent mechanism, ultimately leading to compromised support for hematopoietic progenitors by BM EPCs, which May significantly contribute to the pathogenesis of PGF following allo-HSCT and provide innovative therapeutic strategies targeting PGF.

Serum 25-hydroxyvitamin D, genetic susceptibility and abdominal aortic aneurysm risk.

CONTEXT: The association of serum 25-hydroxyvitamin D [25(OH)D] and genetic polymorphisms of the vitamin D receptor (VDR), and the vitamin D binding protein (VDBP) with incident abdominal aortic aneurysm (AAA) remains uncertain. OBJECTIVE: To investigate whether serum 25(OH)D, genetic polymorphisms of VDR and VDBP, genetic susceptibility to AAA, and the interactions among these factors influence the risk of incident AAA. DESIGN: Retrospective cohort study. SETTING: UK Biobank. PARTICIPANTS: 447,529 participants without a diagnosis of prevalent aortic aneurysm or aortic dissection at baseline. EXPOSURE: Serum 25(OH)D concentration. MAIN OUTCOME MEASURE: Incident AAA. RESULTS: During a median follow-up of 12.5 years, 2,042 participants developed incident AAA. A significant inverse association between serum 25(OH)D and incident AAA was observed (per SD increment, HR, 0.92; 95%CI, 0.88-0.96), which was particularly pronounced in older individuals and those without diabetes (both P for interaction <0.05). Compared to participants with serum 25(OH)D ≥ 50 nmol/L, those with serum 25(OH)D between 25 and <50 nmol/L and <25 nmol/L exhibited a significant higher risk of incident AAA. In the 371,621 participants with genetics assessment, individuals carrying AA alleles of ApaI SNP had a significant increased risk of incident AAA compared to those carrying CC alleles (HR, 1.16; 95%CI, 1.02-1.32). The inverse association between serum 25(OH)D and incident AAA was stronger in individuals with intermediate or high genetic risk for AAA (P for interaction = 0.048). CONCLUSIONS: There was a significant inverse association between serum 25(OH)D and AAA incidence, particularly among individuals with higher genetic risk for AAA, older age, and without diabetics.

Triclocarban disrupts the activation and differentiation of human CD8+ T cells by suppressing the vitamin D receptor signaling.

Triclocarban (TCC) is a widely applied environmental endocrine-disrupting chemical (EDC). Similar to most of EDCs, TCC potentially damages the immunity of various species. However, whether and how TCC impacts the adaptive immunity in mammals has yet to be determined. Herein, we discovered that TCC disrupts the activation and differentiation of CD8+ T cells in primary human peripheral blood samples, purified CD8+ T cells, and in mice in vivo. Mechanistically, TCC might block the activation of the vitamin D receptor (VDR) and reduce the synthesis of cholesterol, a precursor of vitamin D, resulting in inhibition of VDR signaling due to the suppression of both its ligand and the receptor itself by TCC. Our findings elucidate the hazard and potential mechanisms of TCC in mammalian adaptive immunity and highlighted VDR as a potential therapeutic target for the immunodeficiency caused by TCC.

A study of the association of vitamin D receptor (VDR) as a predictive biomarker for immune checkpoint inhibitor therapy with immune invasion in colon adenocarcinoma.

Colon adenocarcinoma(COAD) is a primary and aggressive malignancy with the fifth highest mortality rate among cancers, and it is important to discover new strategies. The online database was used to analyze the correlation between Vitamin D receptor (VDR) and COAD, and further explore the immune infiltration and related gene networks.The expression and methylation levels of VDR was analyzed by using Timer database, GEPIA platform and UALCAN database. GeneMANIA database was used to analyze and obtain gene networks that are closely linked to VDR. UALCAN database was used to score the gene effects of VDR in colorectal cancer cell lines. The cBioPortal database was used for the detection of gene mutations. The survival curve analysis was carried out using the GEPIA database. The relationship between VDR expression and immune cell infiltration was analyzed by using the timer database and TISIDB database. TISIDB database was used to obtain VDR-related drug targets.The expression of VDR was significantly lower in COAD(p<0.05). The methylation level of VDR was significantly higher in COAD (p<0.05). The gene mutation rate of VDR in COAD was 2 %. OS and DFS were not associated with changes in the VDR gene in patients with COAD. VDR expression was correlated with CD4+T cell infiltration, macrophage infiltration, neutrophil infiltration, and dendritic cell infiltration. VDR has a clear correlation with ADORA2A, BTLA, CD160, CD244, CD274, CD96, CSF1R, CTLA4, HAVCR2, IL10, IDO1, LAG3, LGALS9, PDCD1, PDCD1LG2, PVRL2, TGFB1, TGFBR1, TIGIT and VTCN1.The expression of VDR is associated with immune infiltration in patients with COAD. VDR may be a new candidate biomarker for determining the level of immune infiltration and predicting immune checkpoint inhibitor therapy.

Analysis of Pancreatic Cancer Genetic Risk Factors in a Multi-Ethnic Population Sample.

Background: Pancreatic cancer (PC) has one of the highest mortality to incidence ratio of all cancers. Early identification of at-risk individuals should permit early diagnosis. Genome-wide association studies showed the association of several genetic variants with PC risk in multi-ethnic populations. Our objective was to examine the association of these genetic variants with PC in a population sample from Kuwait. Methods: DNA samples from 103 pancreatic ductal adenocarcinoma (PDAC) specimens and 132 healthy controls were used for genotyping ABO rs505922, BCAR1 rs7190458, LINC-PINT rs6971499, HNF1B rs4795218, VDR rs2228570 rs731236, and PRSS1 rs111033565 rs111033568 rs387906698 and rs267606982 using TaqMan genotyping assays, and VDR expression was performed by immunocytochemistry. Results: ABO rs505922C and VDR rs2228570A were associated with PDAC risk (odds ratio (OR): 1.55, 95% confidence interval (CI): 1.07 - 2.24, P = 0.027; OR: 1.64, 95% CI: 1.09 - 2.48, P = 0.024; respectively). An unweighted polygenic risk score (ABO rs505922, BCAR1 rs7190458, LINC-PINT rs6971499, and HNF1B rs4795218) was significantly associated with PDAC risk (ß: -0.11, 95% CI: -0.15 to -0.05, P < 0.001). VDR expression was downregulated or absent in most PDAC specimens regardless of VDR haplotype. Conclusion: ABO rs505922C and VDR rs2228570A are PDAC genetic risk factors in our population. Ethnicity influences the association of reported genetic PDAC risk factors and should be adjusted for when performing PDAC genetic risk estimations. Investigation of these genetic risk factors in other ethnic populations is a necessity to evaluate their PDAC risk prediction potential.

Vitamin D in Cancer Prevention and Treatment: A Review of Epidemiological, Preclinical, and Cellular Studies.

BACKGROUND: Inhibition of human carcinomas has previously been linked to vitamin D due to its effects on cancer cell proliferation, migration, angiogenesis, and apoptosis induction. The anticancer activity of vitamin D has been confirmed by several studies, which have shown that increased cancer incidence is associated with decreased vitamin D and that dietary supplementation of vitamin D slows down the growth of xenografted tumors in mice. Vitamin D inhibits the growth of cancer cells by the induction of apoptosis as well as by arresting the cells at the G0/G1 (or) G2/M phase of the cell cycle. Aim and Key Scientific Concepts of the Review: The purpose of this article is to thoroughly review the existing information and discuss and debate to conclude whether vitamin D could be used as an agent to prevent/treat cancers. The existing empirical data have demonstrated that vitamin D can also work in the absence of vitamin D receptors (VDRs), indicating the presence of multiple mechanisms of action for this sunshine vitamin. Polymorphism in the VDR is known to play a key role in tumor cell metastasis and drug resistance. Although there is evidence that vitamin D has both therapeutic and cancer-preventive properties, numerous uncertainties and concerns regarding its use in cancer treatment still exist. These include (a) increased calcium levels in individuals receiving therapeutic doses of vitamin D to suppress the growth of cancer cells; (b) hyperglycemia induction in certain vitamin D-treated study participants; (c) a dearth of evidence showing preventive or therapeutic benefits of cancer in clinical trials; (d) very weak support from proof-of-principle studies; and (e) the inability of vitamin D alone to treat advanced cancers. Addressing these concerns, more potent and less toxic vitamin D analogs have been created, and these are presently undergoing clinical trial evaluation. To provide key information regarding the functions of vitamin D and VDRs, this review provided details of significant advancements in the functional analysis of vitamin D and its analogs and VDR polymorphisms associated with cancers.

Inflammation and Vitamin D Receptor Polymorphism: Impact on All-Cause and Cardiovascular Mortality in Mexican Women on Dialysis.

Mineral bone disease (MBD) is common in dialysis patients. Genetics and the hormonal environment influence the clinical picture and outcomes of women. This study aimed to determine how these factors affect mortality. In 234 female dialysis patients on Continuous Ambulatory (48%) or Automated (29%) Peritoneal Dialysis or Hemodialysis (23%), MBD biochemical variables, as well as bone density and genetic Bsm1 polymorphism of vitamin D receptor (VDR) were performed at baseline. The cohort was followed-up by 17 (IQ range 15-31) months. According to VDR polymorphism, the distribution of patients was bb: 64% and BB+Bb: 36%. Fifty-five patients died from all-cause mortality; the hs-C-reactive protein level was the most significant risk in multivariate Cox analysis. Nineteen died from cardiovascular mortality. None of the variables were significant for cardiovascular mortality. Patients with bb plus inflammation had the highest risk in the analysis; the significance persisted after adjustment for age, diabetes, and parathyroid hormone levels HR 2.33 (95% CI, 1.01-8.33) and after further adjustment for time on dialysis, albumin, and Osteoprotegerin levels HR 3.49 (95% CI, 1.20-10.9). The presence of the bb genotype from VDR and inflammation had the highest risk of death from all-cause mortality in females on CAPD, APD, and HD patient.

Association of VDR Polymorphisms with Muscle Mass Development in Elite Young Soccer Players: A Pilot Study.

The vitamin D receptor (VDR) is an important candidate gene in musculoskeletal phenotypes. Polymorphisms in the VDR have been previously associated with several pathologies and muscular strength in athletes and elderly people; however, the literature reported contradictory results. The object of this research was to verify the association between the most studied VDR variants (rs2228570, rs7975232, and rs1544410) and the increase in muscle mass in elite young soccer players. A sample of 55 soccer players (15-18 years old) from a professional team were selected for this study. DNA was extracted by the salting-out method, and polymorphisms were genotyped by PCR-RFLP, followed by 2% agarose gel electrophoresis. To test the effect of the three SNPs (single nucleotide polymorphisms), a logistic regression analysis was applied. The body composition determination was carried out through the skinfold thickness method, and the muscular area of the arm and lower limb were calculated using the Frisancho formula. All three polymorphisms met the Hardy-Weinberg equilibrium (p > 0.05) and their frequencies fell within the worldwide variability. A significant correlation between rs1544410 and the increase in calf muscle mass was observed. Individuals carrying the A allele showed higher calf muscular mass than those carrying the G allele (p = 0.034). Moreover, a haplotype analysis applied to the two SNPs in linkage disequilibrium (rs7975232 and rs1544410) showed that the AG haplotype appeared negatively correlated to the calf muscle area. In conclusion, we confirm an association between VDR polymorphisms and muscular mass that could encourage the genetic screening of the VDR gene to identify a potential risk of injury and for individual nutritional interventions.

Discovery of vitexin as a novel VDR agonist that mitigates the transition from chronic intestinal inflammation to colorectal cancer.

Colitis-associated colorectal cancer (CAC) frequently develops in patients with inflammatory bowel disease (IBD) who have been exposed to a prolonged state of chronic inflammation. The investigation of pharmacological agents and their mechanisms to prevent precancerous lesions and inhibit their progression remains a significant focus and challenge in CAC research. Previous studies have demonstrated that vitexin effectively mitigates CAC, however, its precise mechanism of action warrants further exploration. This study reveals that the absence of the Vitamin D receptor (VDR) accelerates the progression from chronic colitis to colorectal cancer. Our findings indicate that vitexin can specifically target the VDR protein, facilitating its translocation into the cell nucleus to exert transcriptional activity. Additionally, through a co-culture model of macrophages and cancer cells, we observed that vitexin promotes the polarization of macrophages towards the M1 phenotype, a process that is dependent on VDR. Furthermore, ChIP-seq analysis revealed that vitexin regulates the transcriptional activation of phenazine biosynthesis-like domain protein (PBLD) via VDR. ChIP assays and dual luciferase reporter assays were employed to identify the functional PBLD regulatory region, confirming that the VDR/PBLD pathway is critical for vitexin-mediated regulation of macrophage polarization. Finally, in a mouse model with myeloid VDR gene knockout, we found that the protective effects of vitexin were abolished in mid-stage CAC. In summary, our study establishes that vitexin targets VDR and modulates macrophage polarization through the VDR/PBLD pathway, thereby alleviating the transition from chronic colitis to colorectal cancer.

A triple hormone receptor ER, AR, and VDR signature is a robust prognosis predictor in breast cancer.

BACKGROUND: Despite evidence indicating the dominance of cell-of-origin signatures in molecular tumor patterns, translating these genome-wide patterns into actionable insights has been challenging. This study introduces breast cancer cell-of-origin signatures that offer significant prognostic value across all breast cancer subtypes and various clinical cohorts, compared to previously developed genomic signatures. METHODS: We previously reported that triple hormone receptor (THR) co-expression patterns of androgen (AR), estrogen (ER), and vitamin D (VDR) receptors are maintained at the protein level in human breast cancers. Here, we developed corresponding mRNA signatures (THR-50 and THR-70) based on these patterns to categorize breast tumors by their THR expression levels. The THR mRNA signatures were evaluated across 56 breast cancer datasets (5040 patients) using Kaplan-Meier survival analysis, Cox proportional hazard regression, and unsupervised clustering. RESULTS: The THR signatures effectively predict both overall and progression-free survival across all evaluated datasets, independent of subtype, grade, or treatment status, suggesting improvement over existing prognostic signatures. Furthermore, they delineate three distinct ER-positive breast cancer subtypes with significant survival in differences-expanding on the conventional two subtypes. Additionally, coupling THR-70 with an immune signature identifies a predominantly ER-negative breast cancer subgroup with a highly favorable prognosis, comparable to ER-positive cases, as well as an ER-negative subgroup with notably poor outcome, characterized by a 15-fold shorter survival. CONCLUSIONS: The THR cell-of-origin signature introduces a novel dimension to breast cancer biology, potentially serving as a robust foundation for integrating additional prognostic biomarkers. These signatures offer utility as a prognostic index for stratifying existing breast cancer subtypes and for de novo classification of breast cancer cases. Moreover, THR signatures may also hold promise in predicting hormone treatment responses targeting AR and/or VDR.

1,25-Dihydroxyvitamin D Enhances the Regenerative Function of Lgr5+ Intestinal Stem Cells In Vitro and In Vivo.

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder in the intestines without a cure. Current therapies suppress inflammation to prevent further intestinal damage. However, healing already damaged intestinal epithelia is still an unmet medical need. Under physiological conditions, Lgr5+ intestinal stem cells (ISCs) in the intestinal crypts replenish the epithelia every 3-5 days. Therefore, understanding the regulation of Lgr5+ ISCs is essential. Previous data suggest vitamin D signaling is essential to maintain normal Lgr5+ ISC function in vivo. Our recent data indicate that to execute its functions in the intestines optimally, 1,25(OH)2D requires high concentrations that, if present systemically, can cause hypercalcemia (i.e., blood calcium levels significantly higher than physiological levels), leading to severe consequences. Using 5-bromo-2'-deoxyuridine (BrdU) to label the actively proliferating ISCs, our previous data suggested that de novo synthesized locally high 1,25(OH)2D concentrations effectively enhanced the migration and differentiation of ISCs without causing hypercalcemia. However, although sparse in the crypts, other proliferating cells other than Lgr5+ ISCs could also be labeled with BrdU. This current study used high-purity Lgr5+ ISC lines and a mouse strain, in which Lgr5+ ISCs and their progeny could be specifically tracked, to investigate the effects of de novo synthesized locally high 1,25(OH)2D concentrations on Lgr5+ ISC function. Our data showed that 1,25(OH)2D at concentrations significantly higher than physiological levels augmented Lgr5+ ISC differentiation in vitro. In vivo, de novo synthesized locally high 1,25(OH)2D concentrations significantly elevated local 1α-hydroxylase expression, robustly suppressed experimental colitis, and promoted Lgr5+ ISC differentiation. For the first time, this study definitively demonstrated 1,25(OH)2D's role in Lgr5+ ISCs, underpinning 1,25(OH)2D's promise in IBD therapy.

BsmI, ApaI and FokI variants of vitamin D receptor gene polymorphism as predictors of response to treatment in immune thrombocytopenia patients.

Vitamin D receptor (VDR) polymorphisms are linked with the incidence and severity of several autoimmune diseases. The current work aimed at evaluating if VDR rs1544410 (BsmI), rs7975232 (ApaI) and rs2228570 (FokI) gene polymorphisms could be predictors of response to steroid treatment in patients with immune thrombocytopenia (ITP). The study involved 75 steroid treatment responders and 75 resistant ITP patients. All participants were subjected to VDR BsmI, ApaI and FokI gene polymorphisms analysis through genotyping by RT-PCR. Carrying the FokI F allele was significantly associated with low vitamin D level and increased risk of developing steroid resistance. Interestingly, the tri-allelic haplotypes BAF and BaF were significantly only present in steroid resistant ITP patients. Thus, the present study suggests that VDR FokI F allele may contribute to ITP pathogenesis and resistance to steroid treatment. Knowing the genetic background of patients helps to individualize treatment to obtain a better outcome.

A double-blinded randomised control study to compare the effectiveness and safety of intralesional vitamin D3 with intralesional triamcinolone and its correlation with tissue expression of vitamin D receptors in patients with keloid.

Intralesional steroids commonly used for keloid treatment have adverse effects like cutaneous atrophy and telangiectasias. Safer and more effective therapies are needed. Preliminary studies suggest intralesional vitamin D as a potential alternative treatment. The aim of this study was to compare efficacy and safety of intralesional vitamin D with triamcinolone for keloids, and correlate tissue expression of vitamin D receptors (VDRs) with treatment outcomes. Sixty patients were randomly assigned to two groups: Group A (intralesional vitamin D) and Group B (intralesional triamcinolone). Four injections were given at 4-week intervals, with an 8-week follow-up. Biopsies were taken pre- and post-treatment to examine VDR expression levels and treatment response correlation. The primary outcome of interest was the proportion of patients achieving a 50% reduction in Vancouver Scar Scale (VSS). Secondary outcomes included incidence of adverse effects, and changes in VDR expression before and after treatment. Baseline VSS scores were 9.73 ± 1.01 (vitamin D group) and 10.13 ± 1.07 (triamcinolone group). After treatment, mean VSS decreased to 5.17 ± 0.59 (vitamin D group, p < 0.001) and 4.77 ± 0.77 (triamcinolone group, p < 0.001), with significantly better response in latter (p = 0.03). More than 50% reduction in VSS score was higher in the triamcinolone group (76.7% vs. 50%, p = 0.032). No recurrences were noted during the 8-week follow-up. Hypopigmentation (80% vs. 36.7%, p < 0.001) and atrophy (73.3% vs. 40%, p = 0.009) were more common in the triamcinolone group. No significant difference in pre- and post-treatment VDR receptor expression was observed in either group. Both triamcinolone acetonide and vitamin D were effective for keloids. Triamcinolone was more efficacious, whereas vitamin D was safer, suggesting it as a viable alternative for keloid management.

Association between partial remission phase in type 1 diabetes and vitamin D receptor Fok1 rs2228570 polymorphism.

OBJECTIVES: The aim of the current study was to assess the natural course of partial remission (PR) phase of type 1 diabetes (T1D) and to highlight the putative association between vitamin D receptor (VDR) (Fok1) gene polymorphism and PR phase. METHODS: Ninety participants with newly diagnosed T1D were followed up for a total of 12 months. The VDR (Fok1) rs2228570 gene polymorphism was genotyped using allelic discrimination (AD) assay. RESULTS: Fifty-four patients (60 %) reached PR with an average duration of 5.63 ± 2.9 months. Among remitters, the frequency of CC "FF" genotype and allelic frequency of C "F" were significantly higher (p<0.001). Furthermore, participants expressing "CC" genotype had earlier onset of PR and spent a significantly longer duration in remission (p<0.001). Younger age (p<0.001; OR 41.6; CI 12.12-142.99), absence of DKA (p<0.001; OR 16, CI 4.36-50.74), higher C-peptide levels (p<0.001; OR 19.55; CI 6.52-58.63), and presence of CC "FF" genotype of VDR (p<0.001; OR 6.74; CI 2.41-18.86) best predicted the overall occurrence of PR. CONCLUSIONS: Younger age, less extent of metabolic derangements, and expression of a CC "FF" genotype were found to influence the occurrence of PR. Data from the current study showed that the "C" allele could have a protective role on preserving residual ß-cell mass and could predict both onset and duration of PR among newly diagnosed T1D. These findings support the growing concept of future tailored precision medicine.

Vitamin D receptor gene rs2228570 (FOKI) polymorphism associated with essential hypertension in Iraqi patients.

OBJECTIVE: Aim: To understand how vitamin D receptor gene polymorphism (VDR rs2228570) affects blood pressure in Iraqi patients with essential hypertension in Al Diwaniya province. PATIENTS AND METHODS: Materials and Methods: This is a single-center observational cross-sectional descriptive study of 90 patients with essential hypertension. Using the PCRTETRA ARM technique, blood samples were genotyped and examined for the polymorphisms of FOKI (rs2228570) gene. RESULTS: Results: The most frequent allele was A (121, 67%) while the most frequent genotype was AG (55, 61%). There was no statistical difference between the actual and expected frequency distribution, according to Hardy-Weinberg equilibrium. The effect of VDR polymorphism rs 2228570 on blood pressure indicates (the mean systolic blood pressure in AA, AG, and GG carrier patients was 149, 150 and 166 respectively, P=0.29. On the other hand, the mean diastolic blood pressure in AA, AG, and GG carrier patients was 89, 89, and 94 respectively P=0.6) there was no statistically significant effect on systolic and diastolic blood pressure. CONCLUSION: Conclusions: there is no statistically significant effect of VDR rs2228570 on SBP and DBP (p = 0.6), vitamin D receptor gene polymorphism rs2228570 was related to vitamin D level.

Vitamin D receptor alleviates lipid peroxidation in diabetic nephropathy by regulating ACLY/Nrf2/Keap1 pathway.

The membrane lipid damage caused by reactive oxygen species(ROS) and various peroxides, namely lipid peroxidation, plays an important role in the progression of diabetic nephropathy (DN).We previously reported that vitamin D receptor(VDR) plays an active role in DN mice by modulating autophagy disorders. However, it is unclear whether the ATP-citrate lyase (ACLY)/NF-E2-related factor-2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1) pathway is associated with the reduction of lipid peroxidation by VDR in the DN model. We found that in the DN mouse model, VDR knockout significantly aggravated mitochondrial morphological damage caused by DN, increased the expression of ACLY, promoted the accumulation of ROS, lipid peroxidation products Malondialdehyde(MDA) and 4-hydroxy-2-nonenal (4-HNE),consumed the Nrf2/Keap1 system, thus increasing lipid peroxidation. However, the overexpression of VDR and intervention with the VDR agonist paricalcitol (Pari) can reduce the above damage. On the other hand, cellular experiments have shown that Pari can significantly reduce the elevated expression of ACLY and ROS induced by advanced glycation end products (AGE). However, ACLY overexpression partially eliminated the positive effects of the VDR agonist. Next, we verified the transcriptional regulation of ACLY by VDR through chromatin immunoprecipitation (ChIP)-qPCR and dual luciferase experiments. Moreover, in AGE models, knockdown of ACLY decreased lipid peroxidation and ROS production, while intervention with Nrf2 inhibitor ML385 partially weakened the protective effect of ACLY downregulation. In summary, VDR negatively regulates the expression of ACLY through transcription, thereby affecting the state of Nrf2/Keap1 system and regulating lipid peroxidation, thereby inhibiting kidney injury induced by DN.

Orchestra of ligand-activated transcription factors in the molecular symphony of SERPINE 1 / PAI-1 gene regulation.

Plasminogen activator inhibitor 1 (PAI-1) is a crucial serine protease inhibitor that prevents plasminogen activation by inhibiting tissue- and urokinase-type plasminogen activators (tPA, uPA). PAI-1 is well-known for its role in modulating hemocoagulation or extracellular matrix formation by inhibiting plasmin or matrix metalloproteinases, respectively. PAI-1 is induced by pro-inflammatory cytokines across various tissues, yet its regulation by ligand-activated transcription factors is partly disregarded. Therefore, we have attempted to summarize the current knowledge on the transcriptional regulation of PAI-1 expression by the most relevant xenobiotic and endocrine receptors implicated in modulating PAI-1 levels. This review aims to contribute to the understanding of the specific, often tissue-dependent regulation of PAI-1 and provide insights into the modulation of PAI-1 levels beyond its direct inhibition.

Vitamin D receptor polymorphisms associate with the efficacy and toxicity of radioiodine-131 therapy in patients with differentiated thyroid cancer.

BACKGROUND: Radioiodine-131 (I-131) therapy is the common postoperative adjuvant therapy for differentiated thyroid cancer (DTC) However, methods to evaluate the efficacy and toxicity of I-131 on DTC are still lacking. OBJECTIVE: To evaluate the association between vitamin D receptor (VDR) gene polymorphisms and the efficacy and toxicity of I-131 in DTC patients. METHODS: A total of 256 DTC patients who received I-131 therapy were enrolled. The patients were divided into effective group and ineffective group. 4 single nucleotide polymorphisms (SNPs) (rs7975232, rs731236, rs1544410 and rs10735810) of VDR were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) Cell counting kit-8 (CCK-8) and flow cytometry were used to detect the proliferation and apoptosis of thyroid cancer cells. RESULTS: Patients in effective group had more CC genotype of rs7975232 and GG genotype of rs10735810 compared with patients in ineffective group They were also independent factors for influencing the efficacy of I-131. PTC-1 and FTC-133 cells transfected with CC genotype of rs7975232 showed lower proliferative activity and higher apoptosis rate after being treated with I-131 In addition, patients with CC genotype at rs7975232 had fewer adverse reactions after I-131 treatment. CONCLUSIONS: VDR gene polymorphisms may be associated with the efficacy and toxicity of I-131 in DTC patients, which will help to personalize the treatment for patients.