Although there have been numerous observations of vitamin D deficiency and its links to chronic diseases, no studies have reported on how vitamin D status and vitamin D3 supplementation affects broad gene expression in humans. The objective of this study was to determine the effect of vitamin D status and subsequent vitamin D supplementation on broad gene expression in healthy adults. (Trial registration: ClinicalTrials.gov NCT01696409).

BACKGROUND We designed an association study among 267 cases of children with sepsis and 283 healthy controls, by genotyping 9 variants in the VDR gene. MATERIAL AND METHODS This was a hospital-based, case-control, genetic association study. In addition to 3 genetic modes of inheritance, haplotype and interaction analyses were employed to examine the prediction of VDR gene for pediatric sepsis. Effect-size estimates are expressed as odds ratio (OR) and 95% confidence interval (CI). RESULTS Two variants in the VDR gene, rs2107301 and rs2189480, were found to play a leading role in susceptibility to sepsis in children. The mutant homozygotes of rs2107301 (CC) and rs2189480 (CC) were associated with a reduced risk of sepsis compared with the corresponding wild homozygotes (OR: 0.44 and 0.43, 95% CI: 0.21-0.92 and 0.23-0.81, p: 0.03 and 0.009, respectively). The mutations of rs2107301-C and rs2189480-C alleles were associated with reduced sepsis risk. Haplotype C-C-C-C-C-T-C-A-G in the VDR gene was significantly associated with a 0.59-fold decreased risk of sepsis (95% CI: 0.12-0.76, p: 0.02). In the haplotype-phenotype analysis, significant association was noted for high-density lipoprotein, even after simulation correction (psim <0.05). CONCLUSIONS Taken together, our findings indicate that the VDR gene may be a sepsis-susceptibility gene in Chinese Han children.

Inadequate photosynthesis or oral intake of Vitamin D are associated with high incidence and mortality rates of breast cancer in ecological and observational studies, but the dose-response relationship in individuals has not been adequately studied.

Several studies have reported an association between low Vitamin D (VD) levels and Alopecia areata (AA), and suggested VD preparations as a potential therapy. VD has immunomodulatory function closely associated with a variety of skin diseases, but there is no conclusive evidence to support VD supplementation for patients with AA. Therefore, we will conduct a meta-analysis to collect and evaluate the efficacy and safety of VD supplementation in the treatment of AA.

We investigated multiple signaling pathways activated by CYP11A1-derived vitamin D3 hydroxymetabolites in human skin fibroblasts by assessing the actions of these molecules on their cognate receptors and by investigating the role of CYP27B1 in their biological activities. The actions of 20(OH)D3, 20,23(OH)2D3, 1,20(OH)2D3 and 1,20,23(OH)3D3 were compared to those of classical 1,25(OH)2D3. This was undertaken using wild type (WT) fibroblasts, as well as cells with VDR, RORs, or CYP27B1 genes knocked down with siRNA. Vitamin D3 hydroxymetabolites had an inhibitory effect on the proliferation of WT cells, but this effect was abrogated in cells with silenced VDR or RORs. The collagen expression by WT cells was reduced upon secosteroid treatment. This effect was reversed in cells where VDR or RORs were knocked down where the inhibition of collagen production and the expression of anti-fibrotic genes in response to the hydroxymetabolites was abrogated, along with ablation of their anti-inflammatory action. The knockdown of CYP27B1 did not change the effect of either 20(OH)D3 or 20,23(OH)2D3, indicating that their actions are independent of 1α-hydroxylation. In conclusion, the expression of the VDR and/or RORα/γ receptors in fibroblasts is necessary for the inhibition of both the proliferation and fibrogenic activity of hydroxymetabolites of vitamin D3, while CYP27B1 is not required.

Changes in the composition and ratio of the flora during colitis have been found to potentially affect ovarian function through nutrient absorption. However, the mechanisms have not been fully explored. To investigate whether colitis-induced dysbacteriosis of the intestinal flora affects ovarian function, mice were given dextran sodium sulfate (DSS) through drinking water. High-throughput sequencing technology was used to clarify the composition and proportion of bacterial flora as well as gene expression changes in the colon. Changes in follicle type, number, and hormone secretion in the ovary were detected. The results showed that 2.5% DSS could induce severe colitis symptoms, including increased inflammatory cell infiltration, severe damage to the crypt, and high expression of inflammatory factors. Moreover, vitamin A synthesis metabolism-related genes Rdh10, Aldh1a1, Cyp26a1, Cyp26b1, and Rarβ were significantly decreased, as well as the levels of the steroid hormone synthase-related proteins STAR and CYP11A1. The levels of estradiol, progesterone, and Anti-Mullerian hormone as well as the quality of oocytes decreased significantly. The significantly changed abundances of Alistipes, Helicobacter, Bacteroides, and some other flora had potentially important roles. DSS-induced colitis and impaired vitamin A absorption reduced ovarian function.

The aims of this randomized controlled double-blind clinical trial were to assess the impact of vitamin D supplementation on calcium metabolism and non-calcemic broad gene expression by relating them to the individual's responsiveness to varying doses of vitamin D3. Thirty healthy adults were randomized to receive 600, 4,000 or 10,000 IU/d of vitamin D3 for 6 months. Circulating parathyroid hormone (PTH), 25(OH)D, calcium and peripheral white blood cells broad gene expression were evaluated. We observed a dose-dependent increase in 25(OH)D concentrations, decreased PTH and no change in serum calcium. A plateau in PTH levels was achieved at 16 weeks in the 4000 and 10,000 IU/d groups. There was a dose-dependent 25(OH)D alteration in broad gene expression with 162, 320 and 1289 genes up- or down-regulated in their white blood cells, respectively. Our results clearly indicated that there is an individual's responsiveness on broad gene expression to varying doses of vitamin D3. Vitamin D3 supplementation at 10,000 IU/d produced genomic alterations several fold higher than 4,000 IU/d even without further changes in PTH levels. Our findings may help explain why there are some inconsistency in the results of different vitamin D's clinical trials.

Vitamin D level has been reported to be associated with psoriasis, atopic dermatitis, and vitiligo. However, its causal relationship with the risk of these three diseases remains unclear.

Patients with myelodysplastic syndrome and ring sideroblasts (MDS-RS) present with symptomatic anemia due to ineffective erythropoiesis that impedes their quality of life and increases morbidity. More than 80% of patients with MDS-RS harbor splicing factor 3B subunit 1 (SF3B1) mutations, the founder aberration driving MDS-RS disease. Here, we report how mis-splicing of coenzyme A synthase (COASY), induced by mutations in SF3B1, affects heme biosynthesis and erythropoiesis. Our data revealed that COASY was up-regulated during normal erythroid differentiation, and its silencing prevented the formation of erythroid colonies, impeded erythroid differentiation, and precluded heme accumulation. In patients with MDS-RS, loss of protein due to COASY mis-splicing led to depletion of both CoA and succinyl-CoA. Supplementation with COASY substrate (vitamin B5) rescued CoA and succinyl-CoA concentrations in SF3B1mut cells and mended erythropoiesis differentiation defects in MDS-RS primary patient cells. Our findings reveal a key role of the COASY pathway in erythroid maturation and identify upstream and downstream metabolites of COASY as a potential treatment for anemia in patients with MDS-RS.

Previous studies have suggested that vitamin D is associated with cardiovascular disease (CVD), however, the relationship between vitamin D levels and CVD risk is still unclear. The purpose of this study was to assess the relationship of serum concentration of 25-hydroxyvitamin D (25(OH)D) with CVD in rural residents of Henan province of China. Basic information and medical history were gathered through face-to-face surveys from July 2013 to August 2015, and biochemical indicators were gathered in a laboratory setting. Logistic and restricted cubic splines regression analyses were used to estimate odd ratios (ORs) and 95% confidence intervals (95%CI) of CVD. A total of 1078 participants were included, the mean serum 25(OH)D concentration was determined to be 25 ± 18 ng/ml, with 54.45% of the participants presenting vitamin D deficiency [25(OH)D < 20 ng/mL]. Moreover, the prevalence of CVD was 59.28% in the vitamin D deficient group, which was higher than in the insufficient (48.55%) and sufficient groups (52.78%). After adjusting for potential confounders, compared with the deficient group, the ORs (95%CI) of CVDs were 0.68 (0.50, 0.91) in the insufficient group and 0.81 (0.56, 1.16) in the sufficient group. A nonlinear (U-shaped) association was observed between the risk of CVD and 25(OH)D concentration. Further research suggested that the risk of CVD was higher in males than in females. In conclusion, a U-shape association between serum levels of 25(OH)D and the risk of CVD was identified in our study, suggesting a nonlinear relationship between vitamin D with the prevalence of CVD.

To investigate whether single nucleotide polymorphisms (SNPs) within 4 representative genes (VDR, GC, CYP2R1, and CYP24A1) encoding the core proteins involved in vitamin D production, degradation, and ligand-dependent signaling pathway are associated with gestational diabetes mellitus (GDM) in a Chinese population. A total of 1494 pregnant Han Chinese women (692 women with GDM and 802 women with normal glucose served as controls) were recruited through a 2-step approach. Participants were further divided into 2 groups according to body mass index before gestation (pre-BMI) (25 kg/m2). Nine SNPs (rs3733359, rs2282679, and rs16847024 in GC, rs2060793 and rs10741657 in CYP2R1, rs2248359 and rs6013897 in CYP24A1, rs11574143 and rs739837 in VDR) were genotyped using TaqMan allelic discrimination assays. The relationships between genotypes/alleles of a single locus as well as haplotypes of each gene and GDM were analyzed. We did not observe a significant difference in genotype frequency of each SNP between cases and controls. However, in the obese subgroup (pre-BMI ≥ 25 kg/m2), the risk allele-A of rs3733359 showed an association with increased risk of GDM (OR = 1.739, 95% CI = 1.066-2.837, P = 0.027). The GG-haplotype frequency of rs3733359 and rs2282679 in GC was modestly lower in the GDM group (OR = 0.848, 95% CI = 0.719-0.999, P = 0.048). Rs2060793 and rs10741657 were associated with insulin area under the curve (P = 0.028, P = 0.042, respectively), while rs739837 and rs6013897 demonstrated a correlation with fasting glucose (P = 0.019, P = 0.049, respectively). Additionally, rs2248359 displayed an association with leukocyte counts (B = 0.063 P = 0.033) and rs16847024 was related to high-sensitivity C-reactive protein levels (B = 0.086, P = 0.005). Our results indicate an association between GC variants and GDM, as well as a relation between a subset of loci in CYP2R1, CYP24A1, and VDR and clinical parameters related to GDM. Our findings may provide information for identifying biomarkers for early risk prediction of GDM and the pathways involved in disease progression.

Hydroxyderivatives of vitamin D3, including classical 1,25(OH)2D3 and novel CYP11A1‑derived hydroxyderivatives, exert their biological activity by acting as agonists on the vitamin D receptor (VDR) and inverse agonists on retinoid‑related orphan receptors (ROR)α and γ. The anticancer activities of CYP11A1‑derived hydroxyderivatives were tested using cell biology, tumor biology and molecular biology methods in human A431 and SCC13 squamous (SCC)‑ and murine ASZ001 basal (BCC)‑cell carcinomas, in comparison with classical 1,25(OH)2D3. Vitamin D3‑hydroxyderivatives with or without a C1α(OH) inhibited cell proliferation in a dose‑dependent manner. While all the compounds tested had similar effects on spheroid formation by A431 and SCC13 cells, those with a C1α(OH) group were more potent in inhibiting colony and spheroid formation in the BCC line. Potent anti‑tumorigenic activity against the BCC line was exerted by 1,25(OH)2D3, 1,20(OH)2D3, 1,20,23(OH)3D3, 1,20,24(OH)3D3, 1,20,25(OH)3D3 and 1,20,26(OH)3D3, with smaller effects seen for 25(OH)D3, 20(OH)D3 and 20,23(OH)2D3. 1,25(OH)2D3, 1,20(OH)2D3 and 20(OH)D3 inhibited the expression of GLI1 and β‑catenin in ASZ001 cells. In A431 cells, these compounds also decreased the expression of GLI1 and stimulated involucrin expression. VDR, RORγ, RORα and CYP27B1 were detected in A431, SCC13 and ASZ001 lines, however, with different expression patterns. Immunohistochemistry performed on human skin with SCC and BCC showed nuclear expression of all three of these receptors, as well as megalin (transmembrane receptor for vitamin D‑binding protein), the level of which was dependent on the type of cancer and antigen tested in comparison with normal epidermis. Classical and CYP11A1‑derived vitamin D3‑derivatives exhibited anticancer‑activities on skin cancer cell lines and inhibited GLI1 and β‑catenin signaling in a manner that was dependent on the position of hydroxyl groups. The observed expression of VDR, RORγ, RORα and megalin in human SCC and BCC suggested that they might provide targets for endogenously produced or exogenously applied vitamin D hydroxyderivatives and provide excellent candidates for anti‑cancer therapy.

Genome-wide association studies have mainly relied on common HapMap sequence variations. Recently, sequencing approaches have allowed analysis of low frequency and rare variants in conjunction with common variants, thereby improving the search for functional variants and thus the understanding of the underlying biology of human traits and diseases. Here, we used a large Icelandic whole genome sequence dataset combined with Danish exome sequence data to gain insight into the genetic architecture of serum levels of vitamin B(12) (B12) and folate. Up to 22.9 million sequence variants were analyzed in combined samples of 45,576 and 37,341 individuals with serum B(12) and folate measurements, respectively. We found six novel loci associating with serum B(12) (CD320, TCN2, ABCD4, MMAA, MMACHC) or folate levels (FOLR3) and confirmed seven loci for these traits (TCN1, FUT6, FUT2, CUBN, CLYBL, MUT, MTHFR). Conditional analyses established that four loci contain additional independent signals. Interestingly, 13 of the 18 identified variants were coding and 11 of the 13 target genes have known functions related to B(12) and folate pathways. Contrary to epidemiological studies we did not find consistent association of the variants with cardiovascular diseases, cancers or Alzheimer's disease although some variants demonstrated pleiotropic effects. Although to some degree impeded by low statistical power for some of these conditions, these data suggest that sequence variants that contribute to the population diversity in serum B(12) or folate levels do not modify the risk of developing these conditions. Yet, the study demonstrates the value of combining whole genome and exome sequencing approaches to ascertain the genetic and molecular architectures underlying quantitative trait associations.

1α,20S-Dihydroxyvitamin D3 [1,20S(OH)2D3], a natural and bioactive vitamin D3 metabolite, was chemically synthesized for the first time. X-ray crystallography analysis of intermediate 15 confirmed its 1α-OH configuration. 1,20S(OH)2D3 interacts with the vitamin D receptor (VDR), with similar potency to its native ligand, 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] as illustrated by its ability to stimulate translocation of the VDR to the nucleus, stimulate VDRE-reporter activity, regulate VDR downstream genes (VDR, CYP24A1, TRPV6 and CYP27B1), and inhibit the production of inflammatory markers (IFNγ and IL1β). However, their co-crystal structures revealed differential molecular interactions of the 20S-OH moiety and the 25-OH moiety to the VDR, which may explain some differences in their biological activities. Furthermore, this study provides a synthetic route for the synthesis of 1,20S(OH)2D3 using the intermediate 1α,3β-diacetoxypregn-5-en-20-one (3), and provides a molecular and biological basis for the development of 1,20S(OH)2D3 and its analogs as potential therapeutic agents.

Progesterone (PROG) has been shown to protect the brain from traumatic injury and is now in Phase III clinical trials. Our work shows that PROG's beneficial effects can be reduced in vitamin D hormone (VDH)-deficient subjects. VDH can modulate neuronal apoptosis, trophic factors, inflammation, oxidative stress, excitotoxicity, and myelin and axon repair. We investigated whether VDH combined with PROG could improve behavioral outcomes more than PROG alone in VDH-sufficient rats given bilateral contusions of the medial frontal cortex. PROG and different doses of VDH (1 μg/kg, VDH1; 2.5 μg/kg, VDH2; 5 μg/kg, VDH3) were injected intraperitoneally 1 h post-injury. Eight additional doses of PROG were given subcutaneously over 8 days with tapering over the last 2 days. Neurobehavioral tests, necrotic cavity, neuronal death and activation of astrocytes were evaluated 21 days post-injury. We found that PROG and PROG + VDH preserve spatial memory processing. VDH1 + PROG improved performance in acquisition more effectively than PROG alone, indicating that the low VDH dose is optimal for combination therapy. There were no significant differences in necrotic cavity size among the groups. The density of positive staining for reactive astrocytes (glial fibrillary acidic protein (GFAP)) increased and the cell bodies and processes of GFAP-positive cells were enlarged in the PROG + VDH1 group. Our data indicate that the combination of PROG and VDH is more effective than PROG alone in preserving spatial and reference memory, and that PROG plus low-dose VDH can activateGFAP reactions up to 21 days after injury. This effect may be one of the mechanisms underlying PROG's neuroprotective effects in combination with VDH.

To investigate the association between serum 25-hydroxyvitamin D levels and its effect on adverse clinical outcomes, and parameters of immune function and mortality due to a SARS-CoV-2 infection.

Periodontitis is a common oral inflammation, which is a risk factor for adverse pregnancy outcomes. Intakes of vitamin D and calcium are inversely associated with occurrence and progression of periodontitis. This study aims to assess the feasibility of a multi-component intervention, including provision of milk powder supplemented with calcium and vitamin D and periodontal therapy (PT), for improving maternal periodontal health and metabolic and inflammatory profiles of low-income Brazilian pregnant women with periodontitis.

This study investigated the effects of β-caryophyllene (BCP) on protecting bone from vitamin D deficiency in mice fed on a diet either lacking (D-) or containing (D+) vitamin D.

Cytochrome P450scc metabolizes vitamin D3 to 20-hydroxyvitamin D3 (20(OH)D3) and 20,23(OH)(2)D3, as well as 1-hydroxyvitamin D3 to 1alpha,20-dihydroxyvitamin D3 (1,20(OH)(2)D3). It also cleaves the side chain of 7-dehydrocholesterol producing 7-dehydropregnenolone (7DHP), which can be transformed to 20(OH)7DHP. UVB induces transformation of the steroidal 5,7-dienes to pregnacalciferol (pD) and a lumisterol-like compounds (pL).

We investigated the metabolism of vitamin D2 to hydroxyvitamin D2 metabolites ((OH)D2) by human placentas ex-utero, adrenal glands ex-vivo and cultured human epidermal keratinocytes and colonic Caco-2 cells, and identified 20(OH)D2, 17,20(OH)₂D2, 1,20(OH)₂D2, 25(OH)D2 and 1,25(OH)₂D2 as products. Inhibition of product formation by 22R-hydroxycholesterol indicated involvement of CYP11A1 in 20- and 17-hydroxylation of vitamin D2, while use of ketoconazole indicated involvement of CYP27B1 in 1α-hydroxylation of products. Studies with purified human CYP11A1 confirmed the ability of this enzyme to convert vitamin D2 to 20(OH)D2 and 17,20(OH)₂D2. In placentas and Caco-2 cells, production of 20(OH)D2 was higher than 25(OH)D2 while in human keratinocytes the production of 20(OH)D2 and 25(OH)D2 were comparable. HaCaT keratinocytes showed high accumulation of 1,20(OH)₂D2 relative to 20(OH)D2 indicating substantial CYP27B1 activity. This is the first in vivo evidence for a novel pathway of vitamin D2 metabolism initiated by CYP11A1 and modified by CYP27B1, with the product profile showing tissue- and cell-type specificity.