Vitamin D Receptor Activation Research Articles

Protective Role of Vitamin D Receptor in Cerebral Ischemia/Reperfusion Injury In Vitro and In Vivo Model.

Vitamin D receptor (VDR) can prevent myocardial ischemia reperfusion injury (MIRI). Hence, we aimed to illuminate the effect of VDR on cerebral ischemia/reperfusion injury (CIRI). C57BL/6 mice and SK-N-SH cells were utilized to establish CIRI and cellular oxygen deprivation/reoxygenation (OGD/R) models. Mice were injected with 1 μg/kg Calcitriol or 1 μg/kg Paricalcitol (PC) and adenovirus-mediated VDR overexpression or knockdown plasmids. 2,3,5-triphenyl-tetrazolium chloride (TTC) and Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays were performed to measure the brain infarct volume and the apoptosis of cerebral cells. SK-N-SH cells were treated with 5 mM N-acetyl-L-cysteine (NAC) and transfected with VDR knockdown plasmid. Flow cytometry and Cell Counting Kit-8 (CCK-8) assays were employed to assess the apoptosis and cell viability. Enzyme-Linked Immunosorbent Assay (ELISA), quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR) and Western blot were exploited to quantify the levels of reactive species oxygen (ROS), other oxidative stress-related factors, VDR and apoptosis-related factors. The level of VDR in mouse cerebral tissue was elevated by CIRI (p < 0.001). CIRI-induced cerebral infarction (p < 0.001) and the apoptosis of cerebral cells (p < 0.001) in mice were mitigated by the activation of VDR. VDR overexpression abrogated while VDR silencing enhanced CIRI-induced infarction, oxidative stress and apoptosis of cerebral cells (p < 0.05). Furthermore, VDR silencing aggravated the oxidative stress and apoptosis in OGD/R-treated SK-N-SH cells (p < 0.05). NAC, a scavenger of oxidative stress, could reverse the effects of VDR silencing on apoptosis and oxidative stress in OGD/R-treated SK-N-SH cells (p < 0.01). VDR alleviates the oxidative stress to protect against CIRI.

Paricalcitol prevents MAPK pathway activation and inflammation in adriamycin-induced kidney injury in rats.

Activation of the mitogen-activated protein kinase (MAPK) pathway induces uncontrolled cell proliferation in response to inflammatory stimuli. Adriamycin (ADR)-induced nephropathy (ADRN) in rats triggers MAPK activation and pro-inflammatory mechanisms by increasing cytokine secretion, similar to chronic kidney disease (CKD). Activation of the vitamin D receptor (VDR) plays a crucial role in suppressing the expression of inflammatory markers in the kidney and may contribute to reducing cellular proliferation. This study evaluated the effect of pre-treatment with paricalcitol on ADRN in renal inflammation mechanisms. Male Sprague-Dawley rats were implanted with an osmotic minipump containing activated vitamin D (paricalcitol, Zemplar, 6 ng/day) or vehicle (NaCl 0.9%). Two days after implantation, ADR (Fauldoxo, 3.5 mg/kg) or vehicle (NaCl 0.9%) was injected. The rats were divided into four experimental groups: control, n = 6; paricalcitol, n = 6; ADR, n = 7 and, ADR + paricalcitol, n = 7. VDR activation was demonstrated by increased CYP24A1 in renal tissue. Paricalcitol prevented macrophage infiltration in the glomeruli, cortex, and outer medulla, prevented secretion of tumor necrosis factor-α, and interleukin-1β, increased arginase I and decreased arginase II tissue expressions, effects associated with attenuation of MAPK pathways, increased zonula occludens-1, and reduced cell proliferation associated with proliferating cell nuclear antigen expression. Paricalcitol treatment decreased the stromal cell-derived factor 1α/chemokine C-X-C receptor type 4/β-catenin pathway. Paricalcitol plays a renoprotective role by modulating renal inflammation and cell proliferation. These results highlight potential targets for treating CKD.

Yes-associated protein inhibition ameliorates carbon tetrachloride-induced acute liver injury in mice by reducing VDR

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.

2α-Substituted Vitamin D Derivatives Effectively Enhance the Osteoblast Differentiation of Dedifferentiated Fat Cells.

The active form of vitamin D3, 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3], is a principal regulator of calcium homeostasis through activation of the vitamin D receptor (VDR). Previous studies have shown that 2α-(3-hydroxypropyl)-1,25D3 (O1C3) and 2α-(3-hydroxypropoxy)-1,25D3 (O2C3), vitamin D derivatives resistant to inactivation enzymes, can activate VDR, induce leukemic cell differentiation, and increase blood calcium levels in rats more effectively than 1,25(OH)2D3. In this study, to further investigate the usefulness of 2α-substituted vitamin D derivatives, we examined the effects of O2C3, O1C3, and their derivatives on VDR activity in cells and mouse tissues and on osteoblast differentiation of dedifferentiated fat (DFAT) cells, a cell type with potential therapeutic application in regenerative medicine. In cell culture experiments using kidney-derived HEK293 cells, intestinal mucosa-derived CaCO2 cells, and osteoblast-derived MG63 cells, and in mouse experiments, O2C2, O2C3, O1C3, and O1C4 had a weaker effect than or equivalent effect to 1,25(OH)2D3 in VDR transactivation and induction of the VDR target gene CYP24A1, but they enhanced osteoblast differentiation in DFAT cells equally to or more effectively than 1,25(OH)2D3. In long-term treatment with the compound without the medium change (7 days), the derivatives enhanced osteoblast differentiation more effectively than 1,25(OH)2D3. O2C3 and O1C3 were more stable than 1,25(OH)2D3 in DFAT cell culture. These results indicate that 2α-substituted vitamin D derivatives, such as inactivation-resistant O2C3 and O1C3, are more effective than 1,25(OH)2D3 in osteoblast differentiation of DFAT cells, suggesting potential roles in regenerative medicine with DFAT cells and other multipotent cells.

Molecular investigation of vitamin D receptor (VDR) genetic variants and their impact on VDR mRNA and serum vitamin D levels in allergic rhinitis in an Indian population: A case-control study.

Vitamin D deficiency is widespread and poses a significant health concern, as emerging research links it to allergic diseases owing to its immunomodulatory functions. The optimal functioning of vitamin D and its activation depend on its nuclear receptor, vitamin D receptor (VDR). Genetic variants of VDR have been explored as potential factors in autoimmune and allergic diseases, with limited studies on their association with allergic rhinitis (AR). The present investigation aims to analyse the role of three VDR genetic variants - TaqI, FokI and BsmI - in AR susceptibility and their impact on VDR mRNA and serum vitamin D levels. A total of 550 subjects, consisting of 250 AR cases and 300 age- and gender-matched controls, underwent genotyping by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). VDR mRNA and vitamin D levels were determined by quantitative real-time PCR and chemiluminescence, respectively. Although TaqI did not exhibit significant differences, FokI demonstrated a noteworthy association with AR, particularly with the CC genotype (odds ratio [OR]: 3.34; confidence interval [CI]: 1.79-6.23). Similarly, BsmI revealed an increased risk for AR, with the GA+AA genotypes showing a 2.2-fold elevated risk (OR: 2.20; CI: 1.53-3.16). VDR mRNA expression was threefold lower in AR patients (p<.0001), accompanied by reduced serum vitamin D levels (p<.0001). In addition, CC (p=.01) and AA (p=.02) genotypes of FokI and BsmI were associated with reduced VDR mRNA levels, whereas TaqI showed no such association. Similarly, heterozygous genotypes of TaqI and FokI, as well as homozygous AA of BsmI, correlated with lower serum vitamin D levels (p<.001). This study emphasizes the intricate relationship among VDR genetic variations, altered VDR activity, immune modulation and vitamin D metabolism in AR. Further research involving diverse populations is crucial for confirming and generalizing these findings, paving the way for personalized therapeutic interventions in vitamin D-related disorders.

#849 Association between types of phosphate binders and fragility fractures in patients on hemodialysis

Abstract Background and Aims Fractures that affect life expectancy and quality of life are an important outcome in patients undergoing hemodialysis. In older patients on dialysis, osteoporosis is particularly associated with fractures. Therefore, management of calcium, parathyroid hormone and phosphorus is essential to promote bone health. However, no effective treatment against osteoporosis has been established in patients with advanced chronic kidney disease Some reports have suggested that the use of calcium-based phosphate binder was favorable in bone metabolism; however, its effect on fragile fractures remains unclear. In this study, we aimed to investigate the relationship between the use of Ca-containing phosphate binders (CPB) or non-Ca-containing phosphate binders (NCPB) and fractures in patients on hemodialysis. Method A retrospective cohort study was conducted including 556 patients who started hemodialysis at our hospital between March 2004 and March 2023, and could be followed up for at least 3 months. To assess the association of the use of phosphate binders CPB or NCPB with fragile fractures, a multivariate analysis was performed using the Cox proportional hazard model with factors related to fractures as covariates. Results The mean age of the patients was 66 years, with women accounting for 28%. For up to 3 years from hemodialysis initiation, CPB, NCPB, vitamin D receptor activators (VDRA), and calcimimetics were prescribed in 35%, 52%, 72%, and 18% of patients, respectively. Of the 556 patients, 72 developed fragile fractures. A univariate analysis of factors associated with fractures revealed that the hazard ratio (HR) for fragile fractures was 0.39 [0.22-0.64] in CBP users and 0.81 [0.31-0.81] in NCPB users and both were statistically significant fracture suppressors. Multivariate analysis adjusted for significant factors in univariate analysis (age; history of fractures; BMI; levels of serum phosphorus, C-reactive protein, serum magnesium, and hemoglobin; and use or non-use of VDRA) as the covariates, demonstrated that the use of CPB and NCPB was not significantly associated with fractures (HR: 0.58 [0.31–1.05], HR: 0.58 [0.33–1.03]). However, the use of any phosphate binders was a significant fracture preventive factor with an HR of 0.43 [0.24-0.77]. Conclusion Regarding fragile fractures in patients on hemodialysis, no superiority was observed among CPB and NCPB; however, the use of either phosphate binders could reduce the risk of fragility fracture occurrence.

Multiomics profiling reveals VDR as a central regulator of mesenchymal stem cell senescence with a known association with osteoporosis after high-fat diet exposure.

The consumption of a high-fat diet (HFD) has been linked to osteoporosis and an increased risk of fragility fractures. However, the specific mechanisms of HFD-induced osteoporosis are not fully understood. Our study shows that exposure to an HFD induces premature senescence in bone marrow mesenchymal stem cells (BMSCs), diminishing their proliferation and osteogenic capability, and thereby contributes to osteoporosis. Transcriptomic and chromatin accessibility analyses revealed the decreased chromatin accessibility of vitamin D receptor (VDR)-binding sequences and decreased VDR signaling in BMSCs from HFD-fed mice, suggesting that VDR is a key regulator of BMSC senescence. Notably, the administration of a VDR activator to HFD-fed mice rescued BMSC senescence and significantly improved osteogenesis, bone mass, and other bone parameters. Mechanistically, VDR activation reduced BMSC senescence by decreasing intracellular reactive oxygen species (ROS) levels and preserving mitochondrial function. Our findings not only elucidate the mechanisms by which an HFD induces BMSC senescence and associated osteoporosis but also offer new insights into treating HFD-induced osteoporosis by targeting the VDR-superoxide dismutase 2 (SOD2)-ROS axis.

VDR mRNA Expression And Serum Vitamin D Levels in Post-Covid Vaccinated Patients

The emergence of COVID-19 vaccines has reshaped the trajectory of the ongoing pandemic, offering hope for widespread immunity. Beyond conferring protection against SARS-CoV-2, these vaccines have exhibited intriguing immunomodulatory effects. This research explores the dynamic interplay among VDR mRNA expression levels, calcium (ionized and total), and intact parathyroid hormone (iPTH) concentrations in individuals post-COVID-19 vaccination. The Vitamin D Receptor (VDR) plays a pivotal role in immune regulation and is closely intertwined with calcium homeostasis. This study investigates the hypothesis that COVID-19 vaccination may induce alterations in VDR mRNA expression, subsequently influencing calcium metabolism and iPTH secretion. Our findings reveal dynamic shifts in VDR mRNA expression following COVID-19 vaccination, with distinct patterns observed across individuals. Concurrently, we observe ionized and total calcium levels alterations, hinting at potential links between VDR activity and calcium metabolism post-vaccination. Furthermore, iPTH levels exhibit intriguing fluctuations, suggesting a regulatory role of VDR in parathyroid hormone secretion. The integration of clinical outcomes and vaccine response data sheds light on the significance of these molecular and biochemical alterations. This research underscores the multifaceted impact of COVID-19 vaccination on VDR mRNA expression, calcium homeostasis, and iPTH regulation. Beyond the scope of vaccination, our findings may bear implications for immunomodulation in various disease contexts, particularly in individuals with pre-existing calcium-related disorders. In conclusion, our study unveils the intricate relationships among VDR mRNA expression, calcium levels, and iPTH concentrations in the context of post-COVID-19 vaccination. These discoveries extend our understanding of vaccine-induced immunomodulation and may pave the way for personalized vaccination strategies, while also opening new avenues for investigating the role of VDR in immune responses and calcium regulation beyond the pandemic.

Association of rs4516035 Polymorphism with Osteoporosis in the Southeastern Iranian Population: A Case-Control Study.

Genetic polymorphisms are known to play a crucial role in the development of osteoporosis. Vitamin D3 regulates bone homeostasis through the vitamin D receptor (VDR). Reduced VDR activity increases osteoporosis risk. Study Design: A case-control study. This case-control study investigated the potential association between six single-nucleotide polymorphisms (SNPs) within the VDR gene (rs11568820, rs4516035, rs2228570, rs1544410, rs7975232, and rs731236) and the occurrence of osteoporosis in Kerman province. The genotypes of the SNPs were analyzed using polymerase chain reaction-restriction fragment length polymorphism, tetra primer amplification refractory mutation system-PCR, and sequencing in two groups of osteoporosis patients (n=40) and controls (n=42). Additionally, the levels of calcium and vitamin D3 in the serum of the patients were measured, and the in silico analysis of the VDR structure and interaction was performed using I-TASSER, ProSA, PROCHECK, GeneMANIA, GTEx, and GPS 6.0. None of the patients exhibited calcium or vitamin D3 deficiencies. Among the six SNPs, only the T allele in rs4516035, which leads to a shorter variant called VDRA, showed a significant association with susceptibility to osteoporosis (odds ratio=3.061, P=0.007). The in silico analysis demonstrated that the 3D structure, expression, and post-transcriptional modification of VDRA are distinct from those of the more extended variant, VDRB1. VDRB1 is upregulated in sun-exposed skin, and its interactions with its partners differ from those of VDRA. Despite adequate vitamin D levels, the VDRA variant, which has lower activity, could increase the predisposition to osteoporosis in the studied population. These findings clarify the importance of genetic screening for personalized medicine and the effectiveness of prevention and treatment strategies.

Associations of vitamin D receptor activators and calcimimetics with falls and effect modifications by physical activity: A prospective cohort study on the Japan Dialysis Outcomes and Practice Patterns Study.

This study aimed to examine the associations of vitamin D receptor activators (VDRA) and calcimimetics use with falls. This is a prospective cohort study on hemodialysis patients in the Japan Dialysis Outcomes and Practice Patterns Study. We excluded those who were unable to walk. The associations of VDRA or calcimimetics use with falls and effect modifications by physical activity were analyzed using marginal structural models. In total, 1875 patients were included. VDRA and calcimimetics use was not associated with falls (risk ratio [95% CI]: 1.13 [0.84-1.51] and 1.02 [0.72-1.44]). The risk ratio for falls associated with VDRA use was lower among those with poor physical activity (p for interaction <0.1). Although vitamin D receptor activators and calcimimetics use was not associated with falls, the lower risk ratio for falls with vitamin D receptor activators use among those with poor physical activity suggests that vitamin D receptor activators use might be beneficial among these patients.

Modulation of the vitamin D receptor by traditional Chinese medicines and bioactive compounds: potential therapeutic applications in VDR-dependent diseases.

The Vitamin D receptor (VDR) is a crucial nuclear receptor that plays a vital role in various physiological functions. To a larger extent, the genomic effects of VDR maintain general wellbeing, and its modulation holds implications for multiple diseases. Current evidence regarding using vitamin D or its synthetic analogs to treat non-communicable diseases is insufficient, though observational studies suggest potential benefits. Traditional Chinese medicines (TCMs) and bioactive compounds derived from natural sources have garnered increasing attention. Interestingly, TCM formulae and TCM-derived bioactive compounds have shown promise in modulating VDR activities. This review explores the intriguing potential of TCM and bioactive compounds in modulating VDR activity. We first emphasize the latest information on the genetic expression, function, and structure of VDR, providing a comprehensive understanding of this crucial receptor. Following this, we review several TCM formulae and herbs known to influence VDR alongside the mechanisms underpinning their action. Similarly, we also discuss TCM-based bioactive compounds that target VDR, offering insights into their roles and modes of action.

Multicentre, open-label, randomised, controlled trial to compare early intervention with calcimimetics and conventional therapy in preventing coronary artery calcification in patients with secondary hyperparathyroidism (UPCOMING): a study protocol

IntroductionCoronary artery and heart valve calcification is a risk factor for cardiovascular death in haemodialysis patients, so calcification prevention should be started as early as possible. Treatment with concomitant calcimimetics...

VDR Activation Attenuates Renal Tubular Epithelial Cell Ferroptosis by Regulating Nrf2/HO-1 Signaling Pathway in Diabetic Nephropathy.

Diabetic nephropathy (DN) is a serious microvascular complication of diabetes. Ferroptosis, a new form of cell death, plays a crucial role in the pathogenesis of DN. Renal tubular injury triggered by ferroptosis might be essential in this process. Numerous studies demonstratethat the vitamin D receptor (VDR) exerts beneficial effects by suppressing ferroptosis. However, the underlying mechanism has not been fully elucidated. Thus, they verified the nephroprotective effect of VDR activation and explored the mechanism by which VDR activation suppressed ferroptosis in db/db mice and high glucose-cultured proximal tubular epithelial cells (PTECs). Paricalcitol (PAR) is a VDR agonist that can mitigate kidney injury and prevent renal dysfunction. PAR treatment could inhibit ferroptosis of PTECs through decreasing iron content, increasing glutathione (GSH) levels, reducing malondialdehyde (MDA) generation, decreasing the expression of positive ferroptosis mediator transferrin receptor 1 (TFR-1), and enhancing the expression of negative ferroptosis mediators including ferritin heavy chain (FTH-1), glutathione peroxidase 4 (GPX4), and cystine/glutamate antiporter solute carrier family 7 member 11(SLC7A11). Mechanistically, VDR activation upregulated the NFE2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) signaling pathway to suppress ferroptosis in PTECs. These findings suggested that VDR activation inhibited ferroptosis of PTECs in DN via modulating the Nrf2/HO-1 signaling pathway.

Impact of vitamin D resistance genes on vitamin D deficiency during pregnancy among the South Indian population

Increasing evidence suggests that vitamin D (Vit-D) could be pivotal in maintaining normal glucose homeostasis. Low levels of Vit-D in early pregnancy are associated with a higher risk of gestational diabetes mellitus (GDM). Though several reports have highlighted the prevalence of vit-D deficiency among pregnant women, its underlying cause has not yet been fully elucidated. In this connection, a few studies have found the development of resistance to Vit-D, including the levels of Vitamin D receptor (VDR) and transcription regulators that modify VDR action, as well as the bioavailability of Vit-D. We aimed to determine the levels of Vit-D resistance genes such as 25-HydroxyVit-D-24-hydroxylase (CYP24A1), VDR repressor genes (SNAIL and SMRT) and their association between Vit-D concentrations in early pregnancy, and the risk of gestational diabetes mellitus (GDM). A prospective observational study was conducted on healthy pregnant women (NGDM; n = 50) and GDM (n = 50) attending routine antenatal care at SRM Medical College Hospital, Chennai, recruited at 12 weeks of gestation. We found that the serum levels of Vit-D were low in GDM subjects and negatively correlated with the fasting glucose levels. Further, increased expressions of Vit-D resistance genes such as CYP24A1, SNAIL, and SMRT were observed in GDM subjects and negatively correlated with the serum levels of Vit-D. Furthermore, we have validated the data using the trophoblast cell line, BeWo, exposed to calcitriol under a hyperglycemic environment. Our finding showed that increased expression of Vit-D resistance genes in pregnancy may be associated with a greater risk of adverse pregnancy outcomes, including GDM.

TGF-β1 stimulation and VDR-dependent activation modulate calcitriol action on skeletal muscle fibroblasts and Smad signalling-associated fibrogenesis

Fibroblasts play a pivotal role in fibrogenesis after skeletal muscle injury. Excess fibrous formation can disrupt contractile functions and delay functional recovery. Although vitamin D receptor (VDR) is expressed explicitly in regenerating muscle compared with uninjured muscle, how calcitriol [1α,25(OH)2D3] directly regulates skeletal muscle primary fibroblast proliferation, the transition to myofibroblasts, and Smad signalling-associated fibrogenesis is currently unknown. Herein, the effects of calcitriol on cultured skeletal muscle primary fibroblasts of male C57BL/6 mice (aged 1 month old) were investigated. The percentage of BrdU+ nuclei in primary fibroblasts was significantly decreased after calcitriol treatment; however, the antiproliferative effect of calcitriol was diminished after TGF-β1 stimulation to induce fibroblast to myofibroblast transition. This suppressive effect was associated with significantly decreased VDR expression in TGF-β1-treated cells. In addition, Vdr siRNA transfection abolished the effects of calcitriol on the suppression of α-SMA expression and Smad2/3 signalling in myofibroblasts, supporting that its antifibrogenic effect requires VDR activation. Compared with calcitriol, the antifibrotic agent suramin could inhibit fibroblast/myofibroblast proliferation and suppress the expression of TCF-4, which regulates fibrogenic determination. Collectively, these findings suggest that profibrotic stimulation and VDR-dependent activation could modulate the effects of calcitriol on skeletal muscle fibroblast proliferation and fibrogenesis processes. Therefore, TGF-β1 and VDR expression levels are crucial determinants for the antifibrogenic effect of calcitriol on skeletal muscle after injury.

Vitamin D Receptor Activation Attenuates Olanzapine-Induced Dyslipidemia in Mice Through Alleviating Hepatic Endoplasmic Reticulum Stress.

The involvement of vitamin D (VD) signaling in atypical antipsychotics (AAPs)-induced metabolic disturbances has been previously established. This study aims to elucidate the role of VD in maintaining endoplasmic reticulum (ER) homeostasis and its impact on AAPs-induced metabolic adverse effects. Female C57BL/6 mice receive either calcitriol or vehicle one week prior to co-treatment with olanzapine (OLZ) for an additional four weeks. Metabolic parameters, hepatic ER homeostasis, and the SREBPs pathway are assessed through biochemical assays and protein expression profiling. HepG2 cells are transfected with vitamin D receptor (VDR) siRNA for VDR knockdown. OLZ-treated HepG2 cells are exposed to calcitriol to examine its effects on SREBPs and the unfolded protein response (UPR) pathways. VDR activation by calcitriol reduces OLZ-induced hepatic ER stress, leading to decreased SREBPs activity and lipid accumulation. Conversely, the knockdown of VDR in HepG2 cells diminishes the protective effects of calcitriol against OLZ-induced ER stress and SREBPs activation. This resulted in sustained UPR activation, elevated cleaved SREBPs levels, and increased lipid accumulation. These findings highlight an essential role of VDR signaling in the beneficial effects of VD on OLZ-induced metabolic side effects. Targeting VDR to resolve ER stress is likely an applicable therapeutic strategy for AAPs-induced metabolic disturbances.

Genomic signaling of vitamin D

It took several hundred million years of evolution, in order to develop the endocrine vitamin D signaling system, which is formed by a nuclear receptor, the transcription factor VDR (vitamin D receptor), its ligand, the vitamin D3 metabolite 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) and several metabolizing enzymes and transport proteins. Even within the nuclear receptor superfamily the affinity of VDR for 1,25(OH)2D3 is outstandingly high (KD = 0.1 nM). The activation of VDR by 1,25(OH)2D3 is the core mechanism of genomic signaling of vitamin D3, which results in the modulation of the epigenome at thousands of promoter and enhancer regions as well as finally in the activation or repression of hundreds of target gene transcription. In addition, rapid non-genomic actions of vitamin D are described, which are mechanistically far less understood. The main function of vitamin D is to keep the human body in homeostasis. This implies the control of calcium levels, which is essential for bone mineralization, as well as for pushing of innate immunity to react sufficiently strong to microbe infection and preventing overreactions of adaptive immunity, i.e., not to cause autoimmune diseases. This review will discuss whether genomic signaling is sufficient for explaining all physiological functions of vitamin D3.

VDR alleviates endothelial cell injury in arteriovenous fistula through inhibition of P66Shc-mediated mitochondrial ROS

To investigate the effects and mechanism of Vitamin D receptor (VDR) signaling on arteriovenous fistula (AVF) endothelial cell injury. Venous tissues of AVF stenosis patients were collected and analyzed, vascular morphology, reactive oxygen species (ROS), and the expression of VDR, P66Shc, fibronectin (FN), collagen-1 (Col-1) were detected. In addition, human umbilical vein endothelial cells (HUVECs) was used in in vitro studies. HUVECs was incubated with transforming growth factor-beta (TGF-β, 50 ng/ml). Aditionally, paricalcitol, VDR overexpression plasmid and Pin1 inhibitor Juglone were used to investigate the regulatory mechanism of VDR in mitochondrial ROS. The parameters of ROS (e.g. MitoSox) and the expression of FN, Col-1 were tested. Moreover, the mitochondrial translocation of P66Shc was analyzed. The expression of VDR was obviously decreased in the venous tissues of AVF stenosis patients. On the contrary, the expression of P66Shc, P-P66Shc, FN, Col-1 and 8-OHdG were increased significantly in the venous tissues of AVF stenosis patients (P < 0.05). In line with this, the level of mitochondrial ROS and the expression of P66Shc, P-P66Shc, FN, Col-1 increased obviously in HUVECs cells under TGF-β condition. Both VDR over-expression plasmid and Pin1 inhibitor Juglone could alleviate TGF-β induced endothelial injury. Mechanistically, VDR overexpression plasmid and Juglone could inhibit the expression of Pin1, and then restrain P66Shc mitochondrial translocation, eventually reduce the level of mitochondrial ROS. Our research indicated that activation of VDR could alleviate venous endothelial cell dysfunction through inhibiting Pin1-mediated mitochondrial translocation of P66Shc and consequently reducing mitochondrial ROS. It suggested that VDR signaling might be an effective target for AVF stenosis treatment.

Syntheses of 25-Adamantyl-25-alkyl-2-methylidene-1α,25-dihydroxyvitamin D3 Derivatives with Structure-Function Studies of Antagonistic and Agonistic Active Vitamin D Analogs.

The active form of vitamin D3, 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3], is a major regulator of calcium homeostasis through activation of the vitamin D receptor (VDR). We have previously synthesized vitamin D derivatives with large adamantane (AD) rings at position 24, 25, or 26 of the side chain to study VDR agonist and/or antagonist properties. One of them-ADTK1, with an AD ring and 23,24-triple bond-shows a high VDR affinity and cell-selective VDR activity. In this study, we synthesized novel vitamin D derivatives (ADKM1-6) with an alkyl group substituted at position 25 of ADTK1 to develop more cell-selective VDR ligands. ADKM2, ADKM4, and ADKM6 had VDR transcriptional activity comparable to 1,25(OH)2D3 and ADTK1, although their VDR affinities were weaker. Interestingly, ADKM2 has selective VDR activity in kidney- and skin-derived cells-a unique phenotype that differs from ADTK1. Furthermore, ADKM2, ADKM4, and ADKM6 induced osteoblast differentiation in human dedifferentiated fat cells more effectively than ADTK1. The development of vitamin D derivatives with bulky modifications such as AD at position 24, 25, or 26 of the side chain is useful for increased stability and tissue selectivity in VDR-targeting therapy.

A novel mesenchymal stem cell-based regimen for acute myeloid leukemia differentiation therapy.

Currently the main treatment of acute myeloid leukemia (AML) is chemotherapy combining hematopoietic stem cell transplantation. However, the unbearable side effect of chemotherapy and the high risk of life-threatening infections and disease relapse following hematopoietic stem cell transplantation restrict its application in clinical practice. Thus, there is an urgent need to develop alternative therapeutic tactics with significant efficacy and attenuated adverse effects. Here, we revealed that umbilical cord-derived mesenchymal stem cells (UC-MSC) efficiently induced AML cell differentiation by shuttling the neutrophil elastase (NE)-packaged extracellular vesicles (EVs) into AML cells. Interestingly, the generation and release of NE-packaged EVs could be dramatically increased by vitamin D receptor (VDR) activation in UC-MSC. Chemical activation of VDR by using its agonist 1α,25-dihydroxyvitamin D3 efficiently enhanced the pro-differentiation capacity of UC-MSC and then alleviated malignant burden in AML mouse model. Based on these discoveries, to evade the risk of hypercalcemia, we synthetized and identified sw-22, a novel non-steroidal VDR agonist, which exerted a synergistic pro-differentiation function with UC-MSC on mitigating the progress of AML. Collectively, our findings provided a non-gene editing MSC-based therapeutic regimen to overcome the differentiation blockade in AML.