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The vitamin D receptor is highly expressed in the gastrointestinal tract where it transacts gene expression. With current limited understanding of the interactions between the gut microbiome and vitamin D, we conduct a cross-sectional analysis of 567 older men quantifying serum vitamin D metabolites using LC-MSMS and defining stool sub-Operational Taxonomic Units from16S ribosomal RNA gene sequencing data. Faith’s Phylogenetic Diversity and non-redundant covariate analyses reveal that the serum 1,25(OH) 2 D level explains 5% of variance in α-diversity. In β-diversity analyses using unweighted UniFrac, 1,25(OH) 2 D is the strongest factor assessed, explaining 2% of variance. Random forest analyses identify 12 taxa, 11 in the phylum Firmicutes, eight of which are positively associated with either 1,25(OH) 2 D and/or the hormone-to-prohormone [1,25(OH) 2 D/25(OH)D] “activation ratio.” Men with higher levels of 1,25(OH) 2 D and higher activation ratios, but not 25(OH)D itself, are more likely to possess butyrate producing bacteria that are associated with better gut microbial health. Here, the authors investigate associations of vitamin D metabolites with gut microbiome in a cross-sectional analysis of 567 elderly men enrolled in the Osteoporotic Fractures in Men (MrOS) Study and find larger alpha-diversity correlates with high 1,25(OH)2D and high 24,25(OH)2D and higher ratios of activation and catabolism.

Vitamin D and calcium in follicular fluid play an important role in modulating steroidogenesis, folliculogenesis, and oocyte quality determination. Both collaborate to produce top-quality embryos (TQE) during in vitro fertilization (IVF). In this study, we compared free 25(OH)D3 and calcium levels in follicular fluid between TQE and non-TQE groups. This cross-sectional study included women who underwent IVF procedures at tertiary hospitals in Bandung, Indonesia. Ovarian follicular fluid was collected during the ovum pick-up procedure. The examination of 25(OH)D3 levels, vitamin d -binding protein, and calcium in the follicles was done using an enzyme-linked immunosorbent assay (ELISA). Free 25(OH)D3 levels were calculated using the Vermeulen formula. A total of 173 samples met the study criteria, including 86 subjects in the TQE group and 87 subjects in the non-TQE group. There was a significant difference in free 25(OH)D3 follicular fluid levels between the TQE and non-TQE groups (p = 0.017); however, there was no significant difference in calcium levels between the two groups (p = 0.805). We also found that there was a significant association between free 25(OH)D3 follicular fluid levels and embryo quality (OR 3.05, 95% CI 1.46–6.38; p-value = 0.002); however, there was no significant association between follicular fluid calcium and embryo quality [p = 0.144 and OR, 1.74 (95% CI 0.82–3.68)]. The results suggest that free 25(OH)D3 and calcium in the follicular fluid act independently during steroidogenesis, folliculogenesis, and fertilization.

Pregnancy 25-hydroxyvitamin D [25(OH)D] concentrations are associated with maternal and fetal health outcomes. Using physiological human placental perfusion and villous explants, we investigate the role of the placenta in regulating the relationships between maternal 25(OH)D and fetal physiology. We demonstrate active placental uptake of 25(OH)D 3 by endocytosis, placental metabolism of 25(OH)D 3 into 24,25-dihydroxyvitamin D 3 and active 1,25-dihydroxyvitamin D [1,25(OH) 2 D 3 ], with subsequent release of these metabolites into both the maternal and fetal circulations. Active placental transport of 25(OH)D 3 and synthesis of 1,25(OH) 2 D 3 demonstrate that fetal supply is dependent on placental function rather than simply the availability of maternal 25(OH)D 3 . We demonstrate that 25(OH)D 3 exposure induces rapid effects on the placental transcriptome and proteome. These map to multiple pathways central to placental function and thereby fetal development, independent of vitamin D transfer. Our data suggest that the underlying epigenetic landscape helps dictate the transcriptional response to vitamin D treatment. This is the first quantitative study demonstrating vitamin D transfer and metabolism by the human placenta, with widespread effects on the placenta itself. These data demonstrate a complex interplay between vitamin D and the placenta and will inform future interventions using vitamin D to support fetal development and maternal adaptations to pregnancy.

Hypovitaminosis D is becoming a notable health problem worldwide. A consensus exists among several different medical societies as to the need for adequate levels of vitamin D for bone and general health. The correct method by which to restore normal vitamin D levels is still a matter of debate. Although cholecalciferol remains the most commonly distributed form of vitamin D supplementation worldwide, several drugs with vitamin D activity are available for clinical use, and making the correct selection for the individual patient may be challenging. In this narrative review, we aim to contribute to the current knowledge base on the possible and appropriate use of calcifediol—the 25-alpha-hydroxylated metabolite—in relation to its chemical characteristics, its biological properties, and its pathophysiological aspects. Furthermore, we examine the trials that have aimed to evaluate the effect of calcifediol on the restoration of normal vitamin D levels. Calcifediol is more soluble than cholecalciferol in organic solvents, due to its high polarity. Good intestinal absorption and high affinity for the vitamin-D-binding protein positively affect the bioavailability of calcifediol compared with cholecalciferol. In particular, orally administered calcifediol shows a much shorter half-life than oral cholecalciferol. Most findings suggest that oral calcifediol is about three- to five-fold more powerful than oral cholecalciferol, and that it has a higher rate of intestinal absorption. Accordingly, calcifediol can be particularly useful in treating diseases associated with decreased intestinal absorption, as well as obesity (given its lower trapping in the adipose tissue) and potentially neurological diseases treated with drugs that interfere with the hepatic cytochrome P-450 enzyme system, resulting in decreased synthesis of calcifediol. Up to now, there has not been enough clinical evidence for its use in the context of osteoporosis treatment.

Vitamin D and its metabolites exert anti-cancer properties in various cancers; however, their effects on cervical cancer remain largely unexplored. To investigate this gap, we exposed HeLa adenocarcinoma cervical cells to physiological and the growth inhibition 20% (GI20) concentration of 25-hydroxycholecalciferol, the precursor hormone of active 1,25-dihydroxycholecalciferol. We then assessed its impact on cell health, and the expression of the genes and proteins involved in the activation and catabolism of vitamin D at the cellular level by autocrine vitamin D metabolism via the vitamin D metabolizing system (VDMS). Cell health was evaluated by crystal violet and alamarBlue assays, while cell cycle progression and apoptotic cell death markers were assessed by flow cytometry. Gross morphology and ultrastructure were observed using brightfield microscopy and transmission electron microscopy. Gene and protein analyses of the autocrine VDMS were assessed using reverse transcription polymerase chain reaction and Western blot, respectively. Our findings reveal that 25(OH)D3 inhibits cell growth and induces apoptosis in HeLa cervical cells in a dose-dependent manner through the autocrine upregulation of CYP27B1 and VDR. These autocrine effects most likely promote the bioactivation of 25(OH)D3 and intracellular signaling of pro-apoptotic genomic pathways by liganded VDR. Furthermore, the upregulation of CYP24A1 at GI20 treatment likely increases the catabolism of 25(OH)D3 and 1,25(OH)2D3, and therefore may mitigate the anti-cancer action of the high-treatment dose. In summary, 25(OH)D3 holds immense potential as a complementary therapeutic treatment for cervical cancer.

Recent studies have suggested that vitamin D activities involve vitamin D receptor (VDR)-dependent and VDR-independent effects of 1α,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ) and 25-hydroxyvitamin D 3 (25(OH)D 3 ) and ligand-independent effects of the VDR. Here, we describe a novel in vivo system using genetically modified rats deficient in the Cyp27b1 or Vdr genes. Type II rickets model rats with a mutant Vdr (R270L), which recognizes 1,25(OH) 2 D 3 with an affinity equivalent to that for 25(OH)D 3 , were also generated. Although Cyp27b1 -knockout (KO), Vdr- KO, and Vdr (R270L) rats each showed rickets symptoms, including abnormal bone formation, they were significantly different from each other. Administration of 25(OH)D 3 reversed rickets symptoms in Cyp27b1 -KO and Vdr (R270L) rats. Interestingly, 1,25(OH) 2 D 3 was synthesized in Cyp27b1 -KO rats, probably by Cyp27a1. In contrast, the effects of 25(OH)D 3 on Vdr (R270L) rats strongly suggested a direct action of 25(OH)D 3 via VDR-genomic pathways. These results convincingly suggest the usefulness of our in vivo system.

Vitamin D hydroxylated at carbon 25 (25(OH)D) is generally recognized as a precursor of active vitamin D. Despite its low affinity for the vitamin D receptor (VDR), both deficient and excessive 25(OH)D levels are associated with poor clinical outcomes. Here we studied direct effects of 25(OH)D3 on the kidney using 25(OH)D-1a-hydroxylase (CYP27B1) knockout mice. The effects of 25(OH)D3 on unilateral ureteral obstruction were analyzed as proximal tubular cells and macrophages are two major cell types that take up 25(OH)D and contribute to the pathogenesis of kidney injury. Excess 25(OH)D3 in obstructed mice worsened oxidative stress and tubulointerstitial fibrosis, whereas moderate levels of 25(OH)D3 had no effects. The exacerbating effects of excess 25(OH)D3 were abolished in CYP27B1/VDR double-knockout mice and in macrophage-depleted CYP27B1 knockout mice. Excess 25(OH)D3 upregulated both M1 marker (TNF-α) and M2 marker (TGF-β1) levels of kidney-infiltrating macrophages. In vitro analyses verified that excess 25(OH)D3 directly upregulated TNF-α and TGF-β1 in cultured macrophages but not in tubular cells. TNF-α and 25(OH)D3 cooperatively induced oxidative stress by upregulating iNOS in tubular cells. Aggravated tubulointerstitial fibrosis in mice with excess 25(OH)D3 indicated that macrophage-derived TGF-β1 also had a key role in the pathogenesis of surplus 25(OH)D3. Thus, excess 25(OH)D3 worsens tubulointerstitial injury by modulating macrophage phenotype.

It has been shown that mammalian cytochrome P450scc can metabolize vitamin D3 to 20-hydroxyvitamin D3 (20(OH)D3) and 20,22(OH)2D3. To define the biological significance of this pathway, we tested the effects of 20(OH)D3 on the differentiation program of keratinocytes and on the expression of enzymes engaged in vitamin D3 metabolism. Immortalized HaCaT and adult human epidermal keratinocytes were used as a model and the effects of 20(OH)D3 were compared with those of 25(OH)D3 and 1,25(OH)2D3. 20(OH)D3 inhibited proliferation and caused G2/M arrest. 20(OH)D3 stimulated involucrin and inhibited cytokeratin 14 expression. The potency of 20(OH)D3 was comparable to that of 1,25(OH)2D3. 20(OH)D3 decreased the expression of cytochrome P450 enzyme (CYP)27A1 and CYP27B1, however, having only slight effect on CYP24. The effect of 20(OH)D3 was dependent on the vitamin D receptor (VDR). As shown by electrophoretic mobility shift assay, 20(OH)D3 stimulated the binding of nuclear proteins to the VDRE. Transfection of cells with VDR-specific siRNA decreased 20(OH)D3-stimulated transcriptional activity of the VDRE promoter and the expression of involucrin and CYP24 mRNA. Therefore, the above studies identify 20(OH)D3 as a biologically active secosteroid that induces keratinocyte differentiation. These data imply that the previously unreported pathway of vitamin D3 metabolism by P450scc may have wider biological implications depending, for example, on the extent of adrenal gland or cutaneous metabolism.

Vitamin D is essential for healthy skeletal growth and is increasingly recognised for its role in chronic disease development, inflammation and immunity. 25-hydroxyvitamin D (25(OH)D ) concentrations are an indicator of vitamin D status and are normally analysed in plasma or serum samples in clinical settings, while archaeological studies rely on the identification of skeletal markers of vitamin D deficiency, such as rickets. Here, we determined 25(OH)D concentrations in hair specimens ('locks') that had been sampled close to the root, aligned by cut end, and sliced into sequential segments from participants (n = 16), from Aberdeen, Scotland, using a modified protocol designed to minimise sample size. Concentrations were above detectable levels in 14 of 16 individuals, generating a (~ monthly) time-series of 25(OH)D concentrations, with fluctuating intra-hair trends consistent with the bioaccumulation of 25(OH)D . In three participants, fluctuations in intra-hair 25(OH)D appear linked to recent significant weight loss, potentially due to the release of stored 25(OH)D from adipose tissue and subsequent uptake in hair. For the remaining participants, no statistically-significant correlations were determined between mean hair 25(OH)D levels and self-reported data, including age, sex, BMI, vitamin D supplementation, frequency of oily fish consumption, and hours spent outside. For a subset of our cohort (n = 4) isotope analysis highlighted potential relationships between elevated δ O values (which can indicate season of hair growth) and 25(OH)D concentrations in some individuals, which may reflect seasonally-increased UVB exposure. We also present data from an archaeological individual from the same city, with the addition of further isotope analysis (carbon, nitrogen, sulphur) to characterise diet. Results suggest possible positive correspondence of 25(OH)D levels with season in this archaeological individual, and possibly with marine protein consumption, highlighting the potential use of this approach in characterising the relationship between past vitamin D levels and diet. While results are promising, we recognise the limits of this study in terms of sample size and use of self-reported data, and further work is needed to better understand the relationship between serum and hair 25(OH)D before this approach can further be developed as either a non-invasive medical test or an archaeo-investigative technique.

Vitamin D is predominantly sequestered in adipose tissue, where it is slowly mobilized under conditions of deficiency in vivo. However, the kinetics of its uptake, release, and interaction with its major metabolites, 25(OH)D and 1,25(OH) D , remain poorly understood. Given the close relationship between obesity, low-grade chronic inflammation, and disrupted vitamin D metabolism, a clearer understanding of these dynamics in adipocytes is essential. Thus, we sought to characterize time-dependent uptake and metabolites in differentiated human adipocytes. Human pre-adipocytes were differentiated in vitro and exposed to either vitamin D and 1,25(OH) D or the combination of vitamin D , 25(OH)D and 1,25(OH) D . Intracellular concentrations were quantified through HPLC at various time points. A separate efflux experiment assessed vitamin D release under basal and isoproterenol-stimulated conditions using H-vitamin D and scintillation counting. Vitamin D uptake showed a gradual and sustained increase over 96 h, suggesting ongoing accumulation within lipid-rich compartments. In contrast, 25(OH)D and 1,25(OH) D peaked rapidly within the first hour and declined sharply. Isoproterenol stimulation significantly enhanced vitamin D release into the extracellular medium from the adipocytes, indicating increased efflux during lipolytic activation. Adipocytes selectively retain vitamin D while rapidly clearing its hydroxylated forms. These findings highlight the distinct intracellular handling of vitamin D metabolites and suggest that tailored supplementation strategies-particularly in individuals with excess adiposity-may improve bioavailability and metabolic efficacy.