1?,25(OH)2 Vitamin D3 Modulates Avian T Lymphocyte Functions without Inducing CTL Unresponsiveness.
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ABSTRACT:
SUBMITTER: Boodhoo N
PROVIDER: S-EPMC4765962 | biostudies-literature | 2016
REPOSITORIES: biostudies-literature
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Project description:Glioblastoma is one the most aggressive primary brain tumors in adults, and, despite the fact that radiation and chemotherapy after surgical approaches have been the treatments increasing the survival rates, the prognosis of patients remains poor. Today, the attention is focused on highlighting complementary treatments that can be helpful in improving the classic therapeutic approaches. It is known that 1α,25(OH)2 vitamin D3, a molecule involved in bone metabolism, has many serendipidy effects in cells. It targets normal and cancer cells via genomic pathway by vitamin D3 receptor or via non-genomic pathways. To interrogate possible functions of 1α,25(OH)2 vitamin D3 in multiforme glioblastoma, we used three cell lines, wild-type p53 GL15 and mutant p53 U251 and LN18 cells. We demonstrated that 1α,25(OH)2 vitamin D3 acts via vitamin D receptor in GL15 cells and via neutral sphingomyelinase1, with an enrichment of ceramide pool, in U251 and LN18 cells. Changes in sphingomyelin/ceramide content were considered to be possibly responsible for the differentiating and antiproliferative effect of 1α,25(OH)2 vitamin D in U251 and LN18 cells, as shown, respectively, in vitro by immunofluorescence and in vivo by experiments of xenotransplantation in eggs. This is the first time 1α,25(OH)2 vitamin D3 is interrogated for the response of multiforme glioblastoma cells in dependence on the p53 mutation, and the results define neutral sphingomyelinase1 as a signaling effector.
| S-EPMC7694157 | biostudies-literature
Project description:RationalePatients with chronic rhinosinusitis with nasal polyps (CRSwNP) have been shown to be vitamin D3 (VD3) deficient, which is associated with more severe disease and increased polyp size. To gain mechanistic insights into these observational studies, we examined the impact of VD3 deficiency on inflammation and VD3 metabolism in an Aspergillus fumigatus (Af) mouse model of chronic rhinosinusitis (Af-CRS).MethodsBalb/c mice were fed control or VD3 deficient diet for 4 weeks. Mice were then sensitized with intraperitoneal Af, and one week later given Af intranasally every three days for four weeks while being maintained on control or VD3 deficient diet. Airway function, sinonasal immune cell infiltrate and sinonasal VD3 metabolism profiles were then examined.ResultsMice with VD3 deficiency had increased Penh and sRaw values as compared to controls as well as exacerbated changes in sRaw when coupled with Af-CRS. As compared to controls, VD3 deficient and Af-CRS mice had reduced sinonasal 1α-hydroxylase and the active VD3 metabolite, 1,25(OH)2D3. Differential analysis of nasal lavage samples showed that VD3 deficiency alone and in combination with Af-CRS profoundly upregulated eosinophil, neutrophil and lymphocyte numbers. VD3 deficiency exacerbated increases in monocyte-derived dendritic cell (DC) associated with Af-CRS. Conversely, T-regulatory cells were decreased in both Af-CRS mice and VD3 deficient mice, though coupling VD3 deficiency with Af-CRS did not exacerbate CD4 or T-regulatory cells numbers. Lastly, VD3 deficiency had a modifying or exacerbating impact on nasal lavage levels of IFN-γ, IL-6, IL-10 and TNF-α, but had no impact on IL-17A.ConclusionsVD3 deficiency causes changes in sinonasal immunity, which in many ways mirrors the changes observed in Af-CRS mice, while selectively exacerbating inflammation. Furthermore, both VD3 deficiency and Af-CRS were associated with altered sinonasal VD3 metabolism causing reductions in local levels of the active VD3 metabolite, 1,25(OH)2D3, even with adequate circulating levels.
| S-EPMC5646812 | biostudies-literature
Project description:ObjectivesAssessment of Vitamin D status by measurement of 25-Hydroxyvitamin D (25-OH-D) is widely performed by immunoassay. Yet, the ability of these assays to detect Vitamin D2 (as 25-OH-D2) or Vitamin D3 (as 25-OH-D3) varies. It is important to recognize the ability of an assay to quantitate either form of 25-OH-D to evaluate Vitamin D status of supplemented patients. We evaluated detection of 25-OH-D2 and 25-OH-D3 by two assays in our medical center.Design and methodsThe Abbott Architect i1000 SR 25-OH Vitamin D assay and Roche Cobas 8000 Vitamin D assay were compared for their recovery of 25-OH-D2 or D3 from spiked serum samples. Samples with known endogenous concentrations of 25-OH-D2 or D3 by LC-MS/MS were also measured to calculate bias between our assays and LC-MS/MS.ResultsRecovery of 25-OH-D3 in spiked samples was similar by Architect (84-87%) and Cobas (90%). Recovery of 25-OH-D2 was lower than 25-OH-D3, and was poorer by Architect (37-40%) than by Cobas (69-71%). In measurement of samples with known 25-OH-D concentrations, performance of Architect and Cobas assays was similar for 25-OH-D3. However, at concentrations >50 nmol/L 25-OH-D2, the Architect assay exhibited large average negative bias (-27%).ConclusionsWhile the Architect and Cobas assays performed similarly in detection of 25-OH-D3, the Architect assay was significantly poorer at detecting 25-OH-D2 than Cobas, with poorer recovery and significant negative bias at higher concentrations of 25-OH-D2. This agrees with other studies, and indicates that caution should be used in interpreting Architect 25-OH-D results in patients supplemented with Vitamin D2.
| S-EPMC6695248 | biostudies-literature
Project description:Purpose:Oxidative stress affects the retinal pigment epithelium (RPE) leading to development of vascular eye diseases. Cholecalciferol (VIT-D) is a known modulator of oxidative stress and angiogenesis. This in vitro study was carried out to evaluate the protective role of VIT-D on RPE cells incubated under hyperoxic conditions. Methods:Cadaver primary RPE (PRPE) cells were cultured in hyperoxia (40% O2) with or without VIT-D (?-1, 25(OH) 2D3). The functional and physiological effects of PRPE cells with VIT-D treatment were analyzed using molecular and biochemical tools. Results:Vascular signaling modulators, such as vascular endothelial growth factor (VEGF) and Notch, were reduced in hyperoxic conditions but significantly upregulated in the presence of VIT-D. Additionally, PRPE conditioned medium with VIT-D induced the tubulogenesis in primary human umbilical vein endothelial cells (HUVEC) cells. VIT-D supplementation restored phagocytosis and transmembrane potential in PRPE cells cultured under hyperoxia. Conclusions:VIT-D protects RPE cells and promotes angiogenesis under hyperoxic insult. These findings may give impetus to the potential of VIT-D as a therapeutic agent in hyperoxia induced retinal vascular diseases.
| S-EPMC7325624 | biostudies-literature
Project description:Vitamin D is a fat-soluble vitamin that is metabolized by the liver into 25-hydroxyvitamin D [25(OH)D] and then by the kidney into 1,25-dihydroxyvitamin D [1,25(OH)2D], which activates the vitamin D receptor expressed in various cells, including immune cells, for an overall immunostimulatory effect. Here, to investigate whether oral supplementation of 25-hydroxyvitamin D3 [25(OH)D3], a major form of vitamin D metabolite 25(OH)D, has a prophylactic effect on influenza A virus infection, mice were fed a diet containing a high dose of 25(OH)D3 and were challenged with the influenza virus. In the lungs of 25(OH)D3-fed mice, the viral titers were significantly lower than in the lungs of standardly fed mice. Additionally, the proinflammatory cytokines IL-5 and IFN-γ were significantly downregulated after viral infection in 25(OH)D3-fed mice, while anti-inflammatory cytokines were not significantly upregulated. These results indicate that 25(OH)D3 suppresses the production of inflammatory cytokines and reduces virus replication and clinical manifestations of influenza virus infection in a mouse model.
| S-EPMC7400405 | biostudies-literature
Project description:BACKGROUND: The 1?,25-dihydroxy-3-epi-vitamin-D3 (1?,25(OH)2-3-epi-D3), a natural metabolite of the seco-steroid vitamin D3, exerts its biological activity through binding to its cognate vitamin D nuclear receptor (VDR), a ligand dependent transcription regulator. In vivo action of 1?,25(OH)2-3-epi-D3 is tissue-specific and exhibits lowest calcemic effect compared to that induced by 1?,25(OH)2D3. To further unveil the structural mechanism and structure-activity relationships of 1?,25(OH)2-3-epi-D3 and its receptor complex, we characterized some of its in vitro biological properties and solved its crystal structure complexed with human VDR ligand-binding domain (LBD). METHODOLOGY/PRINCIPAL FINDINGS: In the present study, we report the more effective synthesis with fewer steps that provides higher yield of the 3-epimer of the 1?,25(OH)2D3. We solved the crystal structure of its complex with the human VDR-LBD and found that this natural metabolite displays specific adaptation of the ligand-binding pocket, as the 3-epimer maintains the number of hydrogen bonds by an alternative water-mediated interaction to compensate the abolished interaction with Ser278. In addition, the biological activity of the 1?,25(OH)2-3-epi-D3 in primary human keratinocytes and biochemical properties are comparable to 1?,25(OH)2D3. CONCLUSIONS/SIGNIFICANCE: The physiological role of this pathway as the specific biological action of the 3-epimer remains unclear. However, its high metabolic stability together with its significant biologic activity makes this natural metabolite an interesting ligand for clinical applications. Our new findings contribute to a better understanding at molecular level how natural metabolites of 1?,25(OH)2D3 lead to significant activity in biological systems and we conclude that the C3-epimerization pathway produces an active metabolite with similar biochemical and biological properties to those of the 1?,25(OH)2D3.
| S-EPMC3069065 | biostudies-literature
Project description:Dysferlinopathies are a heterogenous group of autosomal recessive inherited muscular dystrophies caused by mutations in DYSF gene. Dysferlin is expressed mainly in skeletal muscle and in monocytes and patients display a severe reduction or absence of protein in both tissues. Vitamin D3 promotes differentiation of the promyelocytic leukemia HL60 cells. We analyzed the effect of vitamin D3 on dysferlin expression in vitro using HL60 cells, monocytes and myotubes from controls and carriers of a single mutation in DYSF. We also performed an observational study with oral vitamin D3 in a cohort of 21 carriers. Fifteen subjects were treated for 1 year and dysferlin expression in monocytes was analysed before and after treatment. Treatment with vitamin D3 increased expression of dysferlin in vitro. The effect of vitamin D3 was mediated by both a nongenomic pathway through MEK/ERK and a genomic pathway involving binding of vitamin D3 receptor to the dysferlin promoter. Carriers treated with vitamin D3 had significantly increased expression of dysferlin in monocytes compared with nontreated carriers (P < 0.05). These findings will have important therapeutic implications since a combination of different molecular strategies together with vitamin D3 uptake could increase dysferlin expression to nonpathological protein levels.
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Project description:AimTo examine the biological consequences and demographic factors that might affect the pharmacokinetics of vitamin D3 after a single high dose intervention in a young Chinese population with vitamin D insufficiency status.MethodsA total of 28 young subjects (25 to 35 years old) with vitamin D insufficiency status [serum 25(OH)D <30 ng/mL] was recruited in Shanghai, China. The subjects were orally administered a single high dose of vitamin D3 (300 000 IU). Baseline characteristics and blood samples were collected at d 0, 1, 2, 3, 7, 28, 56, 84 and 112 after the intervention. The blood biomarker levels were determined with standardized methods.ResultsThe intervention markedly increased the blood 25(OH)D3 levels within the first five days (mean Tmax=5.1±2.1 d) and sustained an optimal circulating level of 25(OH)D3 (≥30 ng/mL) for 56 d. After the intervention, body weight and baseline 25(OH)D3 levels were significantly correlated with circulating 25(OH)D3 levels. No adverse events and no consistently significant changes in serum calcium, creatinine, glucose, parathyroid hormone, vitamin D binding protein, or the urinary calcium/reatinine ratio were observed. However, there was a significant increase in phosphorus after the vitamin D3 intervention. Total cholesterol and triglyceride levels were decreased at the end of the trial.ConclusionThe pharmacokinetics of vitamin D after intervention were influenced by baseline 25(OH)D3 levels and the body weight of the subjects. The results suggest that a single high oral vitamin D3 intervention is safe and efficient for improving the vitamin D status of young Chinese people with vitamin D insufficiency.
| S-EPMC5099415 | biostudies-literature
Project description:Vitamin D deficiency in pregnant women and their offspring may result in unfavorable health outcomes for both mother and infant. A 25hydroxyvitamin D (25(OH)D) level of at least 75 nmol/L is recommended by the Endocrine Society. Validated, automated sample preparation and liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods were used to determine the vitamin D metabolites status in mother-infant pairs. Detection of 3-Epi25(OH)D3 prevented overestimation of 25(OH)D3 and misclassification of vitamin D status. Sixty-three percent of maternal 25(OH)D plasma levels were less than the recommended level of 25(OH)D at 3 months. Additionally, breastmilk levels of 25(OH)D decreased from 60.1 nmol/L to 50.0 nmol/L between six weeks and three months (p < 0.01). Furthermore, there was a positive correlation between mother and infant plasma levels (p < 0.01, r = 0.56) at 3 months. Accordingly, 31% of the infants were categorized as vitamin D deficient (25(OH)D < 50 nmol/L) compared to 25% if 3-Epi25(OH)D3 was not distinguished from 25(OH)D3. This study highlights the importance of accurate quantification of 25(OH)D. Monitoring vitamin D metabolites in infant, maternal plasma, and breastmilk may be needed to ensure adequate levels in both mother and infant in the first 6 months of infant life.
| S-EPMC7469027 | biostudies-literature
Project description:An adequate vitamin D status is essential to optimize muscle strength. However, whether vitamin D directly reduces muscle fiber atrophy or stimulates muscle fiber hypertrophy remains subject of debate. A mechanism that may affect the role of vitamin D in the regulation of muscle fiber size is the local conversion of 25(OH)D to 1,25(OH)2 D by 1α-hydroxylase. Therefore, we investigated in a murine C2C12 myoblast culture whether both 1,25(OH)2 D3 and 25(OH)D3 affect myoblast proliferation, differentiation, and myotube size and whether these cells are able to metabolize 25(OH)D3 and 1,25(OH)2 D3 . We show that myoblasts not only responded to 1,25(OH)2 D3 , but also to the precursor 25(OH)D3 by increasing their VDR mRNA expression and reducing their proliferation. In differentiating myoblasts and myotubes 1,25(OH)2 D3 as well as 25(OH)D3 stimulated VDR mRNA expression and in myotubes 1,25(OH)2 D3 also stimulated MHC mRNA expression. However, this occurred without notable effects on myotube size. Moreover, no effects on the Akt/mTOR signaling pathway as well as MyoD and myogenin mRNA levels were observed. Interestingly, both myoblasts and myotubes expressed CYP27B1 and CYP24 mRNA which are required for vitamin D3 metabolism. Although 1α-hydroxylase activity could not be shown in myotubes, after treatment with 1,25(OH)2 D3 or 25(OH)D3 myotubes showed strongly elevated CYP24 mRNA levels compared to untreated cells. Moreover, myotubes were able to convert 25(OH)D3 to 24R,25(OH)2 D3 which may play a role in myoblast proliferation and differentiation. These data suggest that skeletal muscle is not only a direct target for vitamin D3 metabolites, but is also able to metabolize 25(OH)D3 and 1,25(OH)2 D3 . J. Cell. Physiol. 231: 2517-2528, 2016. © 2016 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc.
| S-EPMC5111790 | biostudies-literature