The role of vitamin D and its receptors (VDR) in PKDL and VL remains uncharacterized at genetic level. This study aimed to explore the single nucleotide polymorphism of VDR gene (rs1544410, rs7975232, rs731236) in association with PKDL and VL infection. A significant difference was observed among VL and PKDL patients versus healthy group (p<0.0001) for Bsm1 polymorphism. The comparison of VL and PKDL patients versus healthy control of VDR genotypes AA and GA were found highly significant (p<0.0001). The risk for developing disease was 7.03 and 4.98 times greater in AA, while 2.49 and 2.97 times greater in GA in case of VL and PKDL patients, respectively. There was no statistical significant difference between VL and PKDL patients in VDR gene polymorphisms and allelic frequency (p>0.05). The RNA expression profile of VDR gene and CYP27B1 gene were upregulated in pretreated PKDL (1.4-1.6 fold), but in VL patients, CYP27B1 (2-3 folds) and VDR (1.5 fold) expression were down regulated. Vitamin D levels in VL patients were significantly lower (22.41 ± 10.57 ng/ml), than PKDL patients (42.19 ± 10.84 ng/ml) (p<0.01). However, no significant difference was observed in relation to the genetic data with age and sex for VL (p = 0.622) and PKDL (p = 0.786), clinical observations along with anthropometric indices. The Bsm1 gene polymorphisms may contribute in VL and PKDL infection as a risk factor.

Previous studies have shown that vitamin D deficiency was associated with both cardiac autonomic dysfunction and the development of diabetic foot (DF). However, the impact of vitamin D levels on heart rate variability (HRV) in individuals with DF, a high-risk group, remains unclear. We explored the association between vitamin D status and HRV in individuals with DF.

A total of 458 individuals with DF were assessed for vitamin D levels by 25-hydroxyvitamin D (25(OH)D) and evaluated for cardiovascular autonomic function using both time and frequency domains of the HRV measures. Multivariate regression analysis and restricted cubic spline regression were employed to examine the associations.

Vitamin D levels were positively associated with HRV indices in people with DF, including standard deviation of the normal sinus interval (SDNN), standard deviation of the 5-min average RR intervals (SDANN), low-frequency power (LF), high-frequency power (HF), and the LF/HF ratio (all p < 0.05). The associations between serum 25(OH)D and cardiac autonomic dysfunction were nonlinear. When 25(OH)D levels were < 50 nmol/L, the odds ratio (OR) for predicted cardiac autonomic dysfunction per SD increase in 25(OH)D was 0.56 (95% CI, 0.44-0.72). However, no significant effect was observed when 25(OH)D levels exceeded 50 nmol/L.

This study demonstrates that lower 25(OH)D levels are associated with reduced HRV in individuals with DF. Specifically, when 25(OH)D levels fall below 50 nmol/L, the risk of cardiac autonomic dysfunction in people with DF significantly increases.

Hyperactivation of osteoclasts has been identified as a significant etiological factor in several bone resorption-related disorders, including osteoporosis, periodontitis, arthritis, and bone metastasis of tumors. It has been demonstrated that the severity of these diseases is influenced by lipids that regulate osteoclast differentiation and activity through specific signaling pathways and cytokine levels. The regulatory mechanisms of different types of lipids on osteoclastogenesis vary across diverse disease contexts in bone resorption regulated by osteoclasts. This review presents an overview of the mechanisms underlying osteoclast formation and summarizes the pathways through which various lipids regulate osteoclastogenesis in different pathological contexts. We also discuss effective therapeutic strategies for osteolytic diseases based on modulation of lipid metabolism.

Perfluoroalkyl substances (PFASs) raise concerns about their environmental accumulation. Experimental data have suggested that PFASs interfere with bone metabolism from the early stages of life. However, mechanisms underlying this association are unclear. The aim of this study was to evaluate the possible association between environmental exposure to PFAS and vitamin D (VitD), serum calcium and parathyroid hormone (PTH) levels in subjects residing in high-exposure area of the Veneto Region of Italy. In this cross-sectional observational study, 1174 subjects who previously adhered to the 2016-2018 Regional Surveillance Plan for plasma levels of PFASs were recalled in 2023 and evaluated for demographic, anthropometrics and blood analyses. Data on nutritional habits and VitD supplementation were obtained by a dedicated questionnaire. Serum concentrations of PFASs, calcium, 25-hydroxy-vitamin D (25OH-VitD) and PTH were determined from blood sampling. Perfluorooctanoic acid (PFOA), perfluorooctanesulfonate (PFOS) and perfluorohexanesulfonic acid (PFHxS) were the only three PFASs, of 12, quantifiable in at least 90% of the samples and considered for further analyses. Generalized additive models, using linear regression and smoothing thin plate splines, detected a positive association between serum calcium and all considered PFAS (PFOA: β = 0.03; CI 95% 0.01-0.06; PFOS: β = 0.06; CI 95% 0.02-0.09, PFHxS: β = 0.04; CI 95% 0.01-0.06). Estimated degrees of freedom (EDF) analysis showed the approximately linear association between serum calcium with PFOA (EDF = 1.89) and PFHxS (EDF = 1.21), but not for PFOS (EDF = 3.69). Differently, PFAS levels showed no association with either 25-hydroxy-vitamin D or PTH, except for ln-transformed 25OH-D and PFOS (β = 0.04; CI 95% 0.00-0.08). Stratified analyses confirmed the positive association between all considered PFAS and calcium in subjects not taking a VitD supplementation. Results show that high exposure levels to PFAS may interfere with calcium metabolism, independently of lifestyle and dietary factors. Further elucidation on the mechanisms underlying calcium homeostasis disruption, including multiple binding-equilibrium with serum albumin, remains to be addressed.

2α-Functionalization of 1α,25-dihydroxyvitamin D3 (active vitamin D3) A-ring enhances binding affinity for the vitamin D receptor (VDR) and prolongs the half-life in target cells due to gaining resistance to CYP24A1-dependant metabolism. The wide variety of modified A-ring precursor enynes for Trost coupling with CD-ring bromoolefin were synthesized from d-glucose. The A-ring modification provided potent, selective biological activities without calcemic side-effects in vivo; for example, 2α-(3-hydroxypropyl)-19-nor-1α,25-dihydroxyvitamin D3 (MART-10) exhibits potent antitumor activity (0.3µg/kg/d, twice/week for 3 weeks) in nude mice inoculated with BxpC-3 cancer cells, 2α-[2-(tetrazol-2-yl)ethyl]-1α,25-dihydroxyvitamin D3 (AH-1) shows better bone-forming effects (0.02µg/kg/d, 5d/week for 4 weeks) in ovariectomized (OVX) rats as an osteoporosis model than natural active vitamin D3, and NS-74c exhibits potent VDR-antagonistic activity (IC50 7.4pM) in HL-60 culture cells. The A-ring modification was also applicable to the synthesis of stable 14-epi-19-nortachysterols, and their novel VDR binding mode was confirmed by X-ray co-crystallographic analysis. 25-Hydroxyvitamin D3 has two independent target molecules: VDR and a sterol regulatory element-binding protein (SREBP)/SREBP cleavage-activating protein (SCAP) complex, and 25-hydroxyvitamin D3 shows SREBP/SCAP inhibitory activity. The VDR-silent vitamin D analog KK-052 with selective SREBP/SCAP inhibitory activity in vivo was developed. A chemical library of side-chain fluorinated vitamin D analogs is currently under construction, and some analogs have shown potent anti-inflammatory activity and therapeutic effects on psoriasis model mice.

Deep learning is accelerating drug discovery. However, current approaches are often affected by limitations in the available data, in terms of either size or molecular diversity. Active deep learning has high potential for low-data drug discovery, as it allows iterative model improvement during the screening process. However, there are several 'known unknowns' that limit the wider adoption of active deep learning in drug discovery: (1) what the best computational strategies are for chemical space exploration, (2) how active learning holds up to traditional, non-iterative, approaches and (3) how it should be used in the low-data scenarios typical of drug discovery. To provide answers, this study simulates a low-data drug discovery scenario, and systematically analyzes six active learning strategies combined with two deep learning architectures, on three large-scale molecular libraries. We identify the most important determinants of success in low-data regimes and show that active learning can achieve up to a sixfold improvement in hit discovery when compared with traditional screening methods.

The relationships between 25-hydroxyvitamin D [25(OH)D] and calcium and age-related macular degeneration (AMD) are unclear.

This study aimed to investigate the causal role of 25(OH)D concentrations, calcium concentrations, and dietary supplements use of vitamin D and calcium on risk of AMD and its subtypes.

Independent genetic variants associated with 25(OH)D and calcium concentrations were used as instrumental variables in published genome-wide association studies (GWASs) of European ancestry. The bidirectional 2-sample Mendelian randomization (MR) analyses were performed using summary-level data from the UK Biobank and FinnGen datasets. Sensitivity analyses were conducted to ensure the robustness of the MR results. The meta-analyses were conducted using both fixed-effect and random-effect models to provide comprehensive and reliable estimates.

A standard deviation increase in calcium concentrations was linked to a 14%, 17%, and 13% reduction in the likelihood of developing AMD (95% confidence interval [CI]: 0.77, 0.97), wet AMD (95% CI: 0.73, 0.95), and dry AMD (95% CI: 0.75, 1.00), respectively. No significant causal relationships were detected between genetically predicted 25(OH)D concentrations and AMD and its subtypes (all P > 0.05). The combined analyses showed that higher calcium concentrations were associated with a reduced risk of overall AMD, with an odds ratio of 0.89 (95% CI: 0.81, 0.98).

This study provides evidence supporting the causal relationship between calcium concentrations and risk of AMD and its subtypes, which may have important implications for the prevention, monitoring, and treatment of AMD.

Diabetic retinopathy (DR) is one of the most common complications of diabetes worldwide. The aim of this study was to assess the prevalence of DR in hospitalized patients with type 2 diabetes (T2DM) in Tibet and to identify risk factors that may influence the occurrence of DR.

This was a cross-sectional study conducted in a third-class hospital in the Tibet Autonomous Region. The prevalence of DR in hospitalized patients with T2DM was measured. Univariate and multivariate logistic regression, restricted cubic spline (RCS) analysis and receiver-operating characteristic curve analysis were used to investigate the risk factors for DR.

The prevalence of DR was 29.3%. The duration of diabetes; concentrations of 25-OH-VitD3, hemoglobin, fasting insulin, alanine aminotransferase, total bilirubin, and creatinine; and HOMA-IR were significantly different between DR patients and non-DR patients (all P < 0.05). Univariate and multivariate logistic regression revealed that a longer duration of diabetes and lower 25-OH-VitD3 levels were associated with increased DR risk. RCS analysis suggested overall positive associations of the duration of diabetes and 25-OH-VitD3 concentrations with DR risk (P nonlinearity < 0.05). The turning points for the duration of diabetes and 25-OH-VitD3 concentrations were 5.1 years and 10.6 ng/mL, respectively. The sensitivity, specificity, and area under the receiver-operating characteristic curve for the combination of the duration of diabetes and 25-OH-VitD3 levels were 79.4%, 69.4% and 0.764, respectively.

Given the high prevalence of DR in hospitalized patients with T2DM in Tibet, vitamin D supplementation seems to be important in the prevention of DR to some degree.

In the development of diabetic nephropathy, pathological damage such as interstitial fibrosis and cell apoptosis often occur in renal tubules. In the present study, diabetic and control group mice were randomly treated with vitamin D3 or vehicle for 6 months. In addition, human renal tubular epithelial (HK-2) cells were cultured in high-glucose medium and treated with vitamin D3 or the oxidative inhibitor NAC. Immunohistochemistry, western blotting, quantitative PCR), and ELISA showed that vitamin D3 decreased the expression of α-smooth muscle actin and E-cadherin in renal tubular epithelial cells, improving interstitial fibrosis. It also downregulated the ratio of Bax/Bcl2 protein, alleviating apoptosis in renal tubular epithelial cells. Furthermore, vitamin D3 significantly inhibited oxidative stress response in renal tubular epithelial cells and blocked the (Thioredoxin Interacting Protein) TXNIP/NLRP3 inflammatory pathway. Therefore, vitamin D3 can protect renal tubular epithelial cells from fibrosis and apoptosis by inhibiting oxidative stress response and blocking the TXNIP/NLRP3 inflammatory pathway in diabetic nephropathy.

Magnesium levels may influence the effect of vitamin D levels on the body. This study aimed to assess the combined effect of magnesium status as reflected by magnesium depletion score (MDS) and vitamin D status on the risk of retinopathy.

This cross-sectional study included participants aged 40 years and older with complete information on vitamin D, MDS, and retinopathy assessment from the 2005-2008 National Health and Nutrition Examination Survey (NHANES). Logistic regression analysis was utilized to analyze the relationship of MDS and vitamin D with retinopathy and expressed as odds ratio (OR) and 95% confidence interval (CI).

Of these 4,953 participants included, 602 (9.53%) participants had retinopathy. Serum vitamin D levels ≤30 nmol/L (vs. >30 nmol/L) (OR = 1.38, 95%CI: 1.05-1.81) and MDS >2 points (vs. ≤2 points) (OR = 1.47, 95%CI: 1.01-2.16) were associated with higher odds of retinopathy. There was an interaction between MDS and vitamin D on the increased odds of retinopathy (OR = 2.29, 95%CI: 1.12-4.68, P interaction = 0.025). In different MDS groups, serum vitamin D levels ≤30 nmol/L increased the odds of retinopathy only in the MDS >2 group (OR = 2.90, 95%CI: 1.16-7.24), but not in the MDS ≤2 group (p = 0.293). Subgroups analyses demonstrated that the interaction between MDS and serum vitamin D on retinopathy was observed in males (OR = 6.88, 95%CI: 1.41-33.66, P interaction = 0.019), people with diabetes (OR = 3.43, 95%CI: 1.78-6.63, P interaction < 0.001), and people with body mass index (BMI) ≥25 kg/m2 (OR = 2.46, 95%CI: 1.11-5.44, P interaction = 0.028).

Magnesium plays a moderating role in the relationship between serum vitamin D and retinopathy. The protective effect of vitamin D against retinopathy was primarily present among those with inadequate magnesium levels.

There is a growing evidence suggesting the association of vitamin D deficiency (VDD) and cognitive impairment. In this study we evaluated the possible involvement of gut microbiota in the cognitive impairments mediated by VDD and investigated the effects of pharmacological treatment with the oxazoline derivative of the aliamide palmitoylethanolamide, 2-Pentadecyl-2-oxazoline (PEA-OXA). Mice were submitted to behavioural, biochemical and electrophysiological analysis to assess whether their vitamin D status affected cognitive performance together with gut microbiota composition. In VDD mice we found cognitive malfunctioning associated with reduced neuroplasticity, indicated by impaired long term potentiation, and neuroinflammation at the hippocampal level. Importantly, PEA-OXA counteracted the cognitive impairments and modified the biochemical and functional changes induced by VDD. Additionally, PEA-OXA treatment enhanced gut microbiota diversity, which tended to be decreased by VDD only in female mice, elevated the relative abundance of lactic and butyric acid-producing families, i.e. Aerococcaceae and Butyricicoccaceae, and reversed the VDD-induced decrease of butyrate-producing beneficial genera, such as Blautia in female mice, and Roseburia in male mice. These data provide novel insights for a better understanding of the cognitive decline induced by VDD and related gut dysbiosis and its potential therapeutic treatment.

We aimed to estimate the effects of temperature and total cloud cover before birth on newborn vitamin D status.

Prospective birth cohort.

This study included 2055 mother-newborn pairs in Wuhan, Hubei province, China. The data of temperature and total cloud cover from 30 days before birth were collected, and cord blood 25-hydroxyvitamin D [25(OH)D] were determined. Restricted cubic spline regression models, multiple linear regression models, and logistic regression models were applied to estimate the associations.

A "J" shaped curve was observed between temperature and vitamin D status, and an inverse "J" shaped curve was observed between total cloud cover and vitamin D status. Compared to the fourth quartile (75-100th percentile, Q4) of average temperature (30 days before birth), the odds ratio (OR) for Q1 (0-25th percentile) associated with the vitamin D deficiency occurrence (<20 ng/mL) was 3.63 (95% CI, 1.54, 8.65). Compared to Q1 of the average total cloud cover (30 days before birth), the OR associated with the occurrence of vitamin D deficiency was 2.38 (95% CI, 1.63, 3.50) for the Q4.

Low temperature and high cloud cover before delivery were significantly associated with an increased probability of vitamin D deficiency in newborns. The findings suggested that pregnancy women lacking sufficient sunlight exposure still need vitamin D supplement to overcome the potential vitamin D deficiency status.

Vitamin D is a crucial micronutrient, critical to human health, and influences many physiological processes. Oral and skin-derived vitamin D is hydroxylated to form calcifediol (25(OH)D) in the liver, then to 1,25(OH)2D (calcitriol) in the kidney. Alongside the parathyroid hormone, calcitriol regulates neuro-musculoskeletal activities by tightly controlling blood-ionized calcium concentrations through intestinal calcium absorption, renal tubular reabsorption, and skeletal mineralization. Beyond its classical roles, evidence underscores the impact of vitamin D on the prevention and reduction of the severity of diverse conditions such as cardiovascular and metabolic diseases, autoimmune disorders, infection, and cancer. Peripheral target cells, like immune cells, obtain vitamin D and 25(OH)D through concentration-dependent diffusion from the circulation. Calcitriol is synthesized intracellularly in these cells from these precursors, which is crucial for their protective physiological actions. Its deficiency exacerbates inflammation, oxidative stress, and increased susceptibility to metabolic disorders and infections; deficiency also causes premature deaths. Thus, maintaining optimal serum levels above 40 ng/mL is vital for health and disease prevention. However, achieving it requires several times more than the government's recommended vitamin D doses. Despite extensive published research, recommended daily intake and therapeutic serum 25(OH)D concentrations have lagged and are outdated, preventing people from benefiting. Evidence suggests that maintaining the 25(OH)D concentrations above 40 ng/mL with a range of 40-80 ng/mL in the population is optimal for disease prevention and reducing morbidities and mortality without adverse effects. The recommendation for individuals is to maintain serum 25(OH)D concentrations above 50 ng/mL (125 nmol/L) for optimal clinical outcomes. Insights from metabolomics, transcriptomics, and epigenetics offer promise for better clinical outcomes from vitamin D sufficiency. Given its broader positive impact on human health with minimal cost and little adverse effects, proactively integrating vitamin D assessment and supplementation into clinical practice promises significant benefits, including reduced healthcare costs. This review synthesized recent novel findings related to the physiology of vitamin D that have significant implications for disease prevention.

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.

Underlying mechanisms for hypercalciuria remain unknown in most cases; thus, the designation "idiopathic." We hypothesized that the vitamin D-inactivating enzyme, CYP24A1 contributes to the pathogenesis of hypercalciuria in kidney stone formers.

We conducted association analyses between CYP24A1 activity, estimated by the vitamin D metabolite diagnostic ratio (25(OH) vitamin D3/total 24,25 (OH)2 vitamin D ratio; VMDR), and the phenotype of participants in 2 observational cohorts of kidney stone formers, the Swiss Kidney Stone Cohort (SKSC) and the Bern Kidney Stone Registry (BKSR). Circulating 25(OH)- and 24,25 (OH)2 vitamin D were quantified using a validated liquid chromatography tandem mass spectrometry assay.

A total of 974 participants were included in the analysis. We found a positive association of VMDR (and hence negative association of CYP24A1 activity) with total (β 0.009 mmol/l; 95% confidence interval [CI]: 0.002, 0.016; P = 0.02) and ionized plasma calcium (β 0.005 mmol/l; 95% CI: 0.002, 0.008; P < 0.01), absolute and fractional excretion of urinary calcium (β 0.054 mmol/24h; 95% CI: 0.010, 0.097; P = 0.02 and β 0.046%; 95% CI: 0.018, 0.074; P < 0.01, respectively). Further, VMDR was associated with an increased likelihood of forming calcium oxalate dihydrate stones (Odds ratio [OR] 1.64; 95% CI: 1.22, 2.35; P < 0.01) and reduced bone mineral density (BMD) at the femoral neck (β -0.005 g/cm2; 95% CI: -0.010, -0.001; P = 0.04). The described associations became stronger when the analysis was confined to idiopathic calcium stone formers.

Our study reveals that CYP24A1 activity, estimated by VMDR, is associated with clinical traits previously linked to idiopathic hypercalciuria.

To investigate the regulatory effect and mechanism of Vitamin D receptor (VDR) on mitochondrial function in renal tubular epithelial cell under diabetic status.

The diabetic rats induced by streptozotocin (STZ) and HK-2 cells under high glocose(HG)/transforming growth factor beta (TGF-β) stimulation were used in this study. Calcitriol was administered for 24 weeks. Renal tubulointerstitial injury and some parameters of mitochondrial function including mitophagy, mitochondrial fission, mitochondrial ROS, mitochondrial membrane potential (MMP), mitochondrial ATP, Complex V activity and mitochondria-associated ER membranes (MAMs) integrity were examined. Additionally, paricalcitol, 3-MA (an autophagy inhibitor), VDR over-expression plasmid, VDR siRNA and Mfn2 siRNA were applied in vitro.

The expression of VDR, Pink1, Parkin, Fundc1, LC3II, Atg5, Mfn2, Mfn1 in renal tubular cell of diabetic rats were decreased significantly. Calcitriol treatment reduced the levels of urinary albumin, serum creatinine and attenuated renal tubulointerstitial fibrosis in STZ induced diabetic rats. In addition, VDR agonist relieved mitophagy dysfunction, MAMs integrity, and inhibited mitochondrial fission, mitochondrial ROS. Co-immunoprecipitation analysis demonstrated that VDR interacted directly with Mfn2. Mitochondrial function including mitophagy, mitochondrial membrane potential (MMP), mitochondrial Ca2+, mitochondrial ATP and Complex V activity were decreased dramatically in HK-2 cells under HG/TGF-β ambience. In vitro pretreatment of HK-2 cells with autophagy inhibitor 3-MA, VDR siRNA or Mfn2 siRNA negated the activating effects of paricalcitol on mitochondrial function. Pricalcitol and VDR over-expression plasmid activated Mfn2 and then partially restored the MAMs integrity. Additionally, VDR restored mitophagy was partially associated with MAMs integrity through Fundc1.

Activated VDR could contribute to restore mitophagy through Mfn2-MAMs-Fundc1 pathway in renal tubular cell. VDR could recover mitochondrial ATP, complex V activity and MAMs integrity, inhibit mitochondrial fission and mitochondrial ROS. It indicating that VDR agonists ameliorate renal tubulointerstitial fibrosis in diabetic rats partially via regulation of mitochondrial function.

The human host defense peptide LL-37 is a component of the innate immune defense mechanisms of the oral cavity against colonization by microbes associated with periodontal disease. We have previously shown that the active form of vitamin D, 1,25(OH)2D3, can induce the expression of LL-37 in gingival epithelial cells (GEC), and prevent the invasion and growth of periopathogenic bacteria in these cells. Further, experimental vitamin D deficiency resulted in increased gingival inflammation and alveolar bone loss. Epidemiological studies have shown associations between vitamin D deficiency and periodontal disease in humans, suggesting application of vitamin D could be a useful therapeutic approach. Further, since we have shown the local activation of vitamin D by enzymes expressed in the GEC, we hypothesized that we could observe this enhancement with the stable, and inexpensive inactive form of vitamin D, which could be further increased with epigenetic regulators.

We treated 3-dimensional primary cultures of GEC topically with the inactive form of vitamin D, in the presence and absence of selected histone deacetylase (HDAC) inhibitors. LL-37 mRNA levels were quantified by quantitative RT-PCR, and inhibition of invasion of bacteria was measured by fluorescence microscopy.

Vitamin D treatment led to an induction of LL-37 mRNA levels, as well as an inhibition of pro-inflammatory cytokine secretion. This effect was further enhanced by HDAC inhibitors, most strongly when the HDAC inhibitor, phenyl butyrate (PBA) was combined with Vitamin D3. This was observed both in solution and in a prototype gel formulation using sodium butyrate. Finally, this combination treatment led to an increase in the antimicrobial activity against infection by Porphyromonas gingivalis and Filifactor alocis, bacteria associated with periodontal lesions, as well as herpes simplex virus, which has also been shown to be associated with periodontal lesions.

Our results demonstrate that a combination of inactive vitamin D and sodium butyrate could be developed as a safe treatment for periodontal disease.

Mitochondrial dysfunction is an early event in Alzheimer's disease (AD) pathogenesis. To assess the impact of vitamin D3 (Vit.D) on neurogenesis, we investigated its role in mitigating cognitive impairment and mitochondrial dysfunction through calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2)-mediated phosphorylation of Sirtuin1 (SIRT1) in an aluminum-chloride-D-galactose (AlCl3-D-gal)-induced AD rat model. Rats were distributed into four groups: control, AlCl3 + D-gal (10 + 60 mg/kg, ip), Vit.D (500 IU/kg, po), and AlCl3 + D-gal+Vit.D. Novel object recognition (NOR), Morris Water Maze, and passive avoidance (PA) tests were used to measure memory abilities. The hippocampal tissue was used to assess vitamin D3 receptor (VDR) and peroxisome-proliferator-activated-receptor-γ-coactivator-1α (PGC-1α) expression by quantitative real-time polymerase chain reaction (qRT-PCR), CAMKK2, p-SIRT1, phosphorylated-AMP-activated protein kinase (p-AMPK), dynamin-related-protein-1 (Drp1), and mitofusin-1 (Mnf1) proteins by western blot and Ca2+ levels, endothelial nitic oxide synthase (eNOS), superoxide dismutase (SOD), amyloid beta (Aβ), and phospho tau (p-Tau) via enzyme-linked immunosorbent assay(ELISA) in addition to histological and ultrastructural examination of rat's brain tissue. Vit.D-attenuated hippocampal injury reversed the cognitive decline and Aβ aggregation, and elevated p-Tau levels in the AlCl3 + D-gal-induced AD rat model. In AlCl3 + D-gal-exposed rats, Vit.D induced VDR expression, normalized Ca2+ levels, elevated CAMKK2, p-AMPK, p-SIRT1, and PGC-1α expression. Vit.D reduced Drp1, induced Mnf1, increased mitochondrial membrane potential, preserved mitochondrial structure, restored normal mitochondrial function, and retained normal eNOS level and SOD activity in AlCl3 + D-gal rats. In conclusion, our findings proved that Vit.D may ameliorate cognitive deficits in AlCl3 + D-gal-induced AD by restoring normal mitochondrial function and reducing inflammatory and oxidative stress via CAMKK2-AMPK/SIRT1 pathway upregulation.

Older adults are prone to vitamin D3 (VD3) deficiency, which may impair their health. A high dose of VD3 (HDVD3 = 100,000 IU) could improve their 25-hydroxyvitamin D3 [25(OH)D] level and health outcomes. However, evidence for such a beneficial effect of HDVD3 in older adults coming from clinical trials is mixed.

To review the literature on the efficacy of a single dose of 100,000 IU of VD3 in older people.

We searched PubMed/Medline, Science Direct, and NIH's clinical trials registry for clinical studies on the effect of a single high dose of VD3 on various health outcomes in older people. We also performed a meta-analysis using the standardized mean difference to assess the effect of VD3 on its blood level. Due to expected high heterogeneity, its amount (i.e., tau2) was estimated using the DerSimonian-Laird estimator. To estimate tau2, the Q-test for heterogeneity and the I2 statistic were calculated.

Search results identify 13 studies that reported diverse health outcomes, such as lung and cardiovascular function, skin cancer progression, intensive care unit mortality, immune system response, and bone density. The meta-analysis showed a significant increase in 25(OH)D blood levels after treatment in 10 studies, with an average standardized mean difference of 2.60 ng/mL (95% CI: 2.07 to 3.13). Their results suggested that a single high dose of VD3 may benefit intensive care unit patients and skin cancer patients in remission. However, evidence for other beneficial health effects of HDVD3 was mixed due to high heterogeneity among studies.

A single high dose of VD3 may positively affect some health outcomes in older people, possibly due to its pleiotropic and immunomodulatory effects. However, the evidence needs to be more extensive and consistent, and more rigorous studies are required to confirm the benefits and safety of VD3 high doses in older patients.

A large body of research shows an association between higher body weight and low vitamin D status, as assessed using serum 25-hydroxyvitamin D concentrations. Vitamin D can be metabolised in adipose tissue and has been reported to influence gene expression and modulate inflammation and adipose tissue metabolism in vitro. However, the exact metabolism of vitamin D in adipose tissue is currently unknown. White adipose tissue expresses the vitamin D receptor and hydroxylase enzymes, substantially involved in vitamin D metabolism and efficacy. The distribution and concentrations of the generated vitamin D compounds in adipose tissue, however, are largely unknown. Closing this knowledge gap could help to understand whether the different vitamin D compounds have specific health effects in the setting of adiposity. This review summarises the current evidence for a role of vitamin D in adipose tissue and discusses options to accurately measure vitamin D compounds in adipose tissue using liquid chromatography tandem mass spectrometry (LC/MS-MS).

Hutchinson-Gilford Progeria syndrome (HGPS) serves as a prominent model for Progeroid syndromes, a group of rare genetic disorders characterized by accelerated aging. This review explores the genetic basis, clinical presentation, and complications of HGPS. HGPS is caused by mutations in the LMNA gene, resulting in the production of a defective structural protein, prelamin A. This protein contains a "CAAX" motif, where C represents cysteine, and its abnormal processing is central to the disease's pathology. HGPS leads to multiple organ systems being affected, including cardiovascular, skeletal, neurological, and dermatological systems, causing severe disability and increased mortality. Cardiovascular issues are particularly significant in HGPS and are crucial for developing therapeutic strategies. Recent advances in treatment modalities offer promise for managing HGPS. Farnesyltransferase inhibitors and genetic interventions, such as CRISPR-Cas9, have shown potential in mitigating progerin-associated symptoms, with encouraging results observed in preclinical and clinical studies. Additionally, emerging therapies such as rapamycin, sulforaphane, and MG132 hold promise in targeting underlying disease mechanisms. Comprehensive management approaches, including growth hormone therapy, retinoids, and dental care, are emphasized to enhance overall patient well-being. Despite progress, further research is essential to unravel the complex pathophysiology of Progeroid syndromes and develop effective treatments. Continued focus on therapies that address progerin accumulation and its downstream effects is vital for improving patient care and outcomes for individuals affected by HGPS and related disorders. This review highlights ongoing efforts to understand and combat Progeroid syndromes, aiming to alleviate the burdens imposed by these debilitating conditions.

The active form of vitamin D, 1,25D3, plays an important function in the metabolism of calcium. The recommended daily INTAKE of Calcium varies from 1300 mg/day during adolescence to 1200 mg/day after the age of 50 years. Similarly, for vitamin D, the recommended daily intake varies from 400 IU/day during adolescence to 1000 IU/day after the age of 70 years. There is an intricate inter-play of homeostasis of calcium led by vitamin D and PTH at various sites like intestine, kidney, and bones. The increased fracture risk due to bone loss and osteoporosis creates a burden on the patient, healthcare provider as well as the health system. As the population grows old worldwide gradually, the long-term sequelae like pain, loss of independence, and institutionalized care will become more pervasive. Behavioral change to incorporate a healthy lifestyle, including optimal calcium and vitamin D intake and physical exercise in adolescence, form the important foundation in the program for osteoporosis prevention.

Increased emphasis on lifestyle modification and nutrition should be given during times of increased bone loss in old age and after menopause.

Background: Although vitamin D deficiency has been studied in various populations, there are few data on its prevalence and associated factors among Moroccan women. Aim: To determine the prevalence of vitamin D deficiency and investigate its association with body mass index (BMI), waist circumference, and serum concentrations of parathyroid hormone, calcium, and phosphorus in a sample of Moroccan adult women. Methods: This is a cross-sectional study conducted at Mohammed V Military Hospital of Instruction, Rabat. Anthropometric measurements and biochemical analyses were performed using standard procedures Results: A total of 714 women aged 18-65 years participated in this study. The overall prevalence of vitamin D deficiency was 74.4%. Approximately 24% and 51% of women had severe and moderate vitamin D deficiency, respectively. Serum 25-hydroxyvitamin D (25(OH)D) concentrations were inversely correlated with BMI in vitamin D-deficient subjects (P = 0.036) and with parathyroid hormone 1-84 (PTH1-84) levels in the study sample (P = 0.010). PTH1-84 concentrations were greater among overweight/obese individuals compared to their non-overweight peers (P = 0.001) and tended to be higher among vitamin D-deficient women than vitamin D-sufficient women (P = 0.053). Conclusion: This study showed a very high prevalence of vitamin D deficiency in this sample of Moroccan women. Lower serum 25(OH)D levels were associated with increased BMI in vitamin D-deficient women and with elevated PTH1-84 levels among the study sample. Although these findings come from a convenience sample of women that attended a nutrition clinic, they underscore the urgent need to develop public health interventions to improve women's vitamin D status.

Osteoporosis is a prevalent bone disorder characterized by low bone mineral density (BMD) and deteriorated bone microarchitecture, leading to an increased risk of fractures. Vitamin D (VD), an essential nutrient for skeletal health, plays a vital role in maintaining bone homeostasis. The biological effects of VD are primarily mediated through the vitamin D receptor (VDR), a nuclear receptor that regulates the transcription of target genes involved in calcium and phosphate metabolism, bone mineralization, and bone remodeling. In this review article, we conduct a thorough literature search of the PubMed and EMBASE databases, spanning from January 2000 to September 2023. Utilizing the keywords "vitamin D," "vitamin D receptor," "osteoporosis," and "therapy," we aim to provide an exhaustive overview of the role of the VD/VDR system in osteoporosis pathogenesis, highlighting the most recent findings in this field. We explore the molecular mechanisms underlying VDR's effects on bone cells, including osteoblasts and osteoclasts, and discuss the impact of VDR polymorphisms on BMD and fracture risk. Additionally, we examine the interplay between VDR and other factors, such as hormonal regulation, genetic variants, and epigenetic modifications, that contribute to osteoporosis susceptibility. The therapeutic implications of targeting the VDR pathway for osteoporosis management are also discussed. By bringing together these diverse aspects, this review enhances our understanding of the VD/VDR system's critical role in the pathogenesis of osteoporosis and highlights its significance as a potential therapeutic target.

Colorectal cancer (CRC) is a growing concern due to its high morbidity and mortality, and the search for effective and less toxic active substances against inflammatory bowel diseases has been a hot topic in the research and development of drugs against CRC. It is reported that monotropein isolated from the roots of Morinda officinalis, can improve Dextran Sodium Sulfate (DSS)-induced ulcerative colitis in mice, but its therapeutic effects and mechanisms for CRC treatment are still to be investigated. In the present study, we first used molecular docking, BLI, CESTA, and DARTS methods to detest whether monotropein targets VDR proteins. In addition, we used tumor cell conditioned co-culture and four models of macrophage polarisation to investigate the regulation of four macrophage polarisations by monotropein using RT-PCR, IF and western blot. Furthermore, we further validated the target of action of monotropein for the treatment of Azoxymethane (AOM)/DSS induced colitis associated cancer (CAC) using knockout animals. Meanwhile, we further explored the mechanism of action of monotropein in regulating polarisation by detecting JAK/STAT1-related genes and proteins. Molecular docking and biofilm interference techniques showed that monotropein bound to the VDR, and additional results from CESTA and DARTS suggested that VDR proteins are targets of monotropein. Furthermore, in tumor cell conditioned co-cultures or LPS + IFN-γ induced RAW264.7 cells, VDR translocation to the nucleus was reduced, JAK1/STAT1 signaling pathway proteins were up-regulated, and macrophages were polarised towards the M1-type after monotropein intervention. Animal models in which normal VDR or myeloid VDR was knocked out confirmed that JAK1 levels in intestinal tissues were increased after monotropein intervention, macrophages were polarised towards the M1 type, and CAC paracarcinomas were ameliorated. Taken together, the present study concluded that monotropein inhibited colitis-associated cancers through macrophage polarisation regulated by VDR/JAK1/STAT1.

Vitamin D3 metabolites block lipid biosynthesis by promoting degradation of the complex of sterol regulatory element-binding protein (SREBP) and SREBP cleavage-activating protein (SCAP) independent of their effects on the vitamin D receptor (VDR). We previously reported the development of KK-052, the first vitamin D-based SREBP inhibitor that mitigates hepatic lipid accumulation without VDR-mediated calcemic action in mice. Herein we extend our previous work to synthesize KK-052 analogues. Various substituents were introduced to the phenyl ring of KK-052, and two KK-052 analogues were found to exhibit more potent SREBP/SCAP inhibitory activity than KK-052, whereas they all lack VDR activity. These new KK-052 analogues may be suited for further development as VDR-silent SREBP/SCAP inhibitors.

Vitamin D deficiency was thought to be associated with insulin resistance and metabolic-associated fatty liver disease (MAFLD). The aim of this study was to investigate the relationship between the triglyceride-glucose (TyG) index, a useful surrogate biomarker of insulin resistance, and vitamin D status in patients with MAFLD.

A total of 566 patients with MAFLD were included in this retrospective cross-sectional study. Clinical characteristics were compared between participants with and without vitamin D deficiency. The association between the TyG index and serum 25-hydroxyvitamin D [25(OH)D] levels was determined by Spearman correlation analysis and logistic regression analysis. The receiver operating characteristic curve (ROC) was used to assess the diagnostic efficacy of TyG index for vitamin D deficiency in MAFLD patients.

The TyG index levels were higher in the vitamin D deficient group than in the non-vitamin D deficient group, and serum 25(OH)D was negatively correlated with the TyG index. The TyG index was an independent risk factor for vitamin D deficiency in patients with MAFLD. The area under the curve (AUC) of the TyG index for the identification of vitamin D deficiency in MAFLD patients was 0.744 (95% CI: 0.701-0.787, p<0.001).

The TyG index is negatively associated with vitamin D status in patients with MAFLD. In patients with MAFLD, a higher TyG index may be an indication of a higher prevalence of vitamin D deficiency.

To study if active sun exposure among women affects the risk of developing GCA or PMR in a prospective cohort study with restricted latitudinal variability.

We linked the response to questions relating to sun exposure from the Melanoma Inquiry in Southern Sweden (MISS) prospective cohort study in women to the risk of developing GCA or PMR. Healthcare data were gathered from the Skåne Healthcare Register (SHR), covering all public healthcare consultations. The direct effect of active sun exposure on the risk of developing GCA or PMR was assessed using Cox proportional hazards models adjusted for covariates based on a directed acyclic graph.

A total of 14 574 women were included in the study; 601 women were diagnosed with GCA or PMR (144 and 457, respectively) during the follow-up time. Women with moderate or high sun exposure were not less likely to develop GCA or PMR compared with women that indicated they avoided sun exposure [hazard ratio (HR) 1.2 (CI 0.9, 1.6) and 1.3 (0.9, 1.9), respectively] when adjusted for diabetes, hyperlipidaemia, hypertension, smoking, obesity and stratified by age. Similar patterns were observed when studying only GCA [HR 1.2 (CI 0.7, 2.3) and 1.3 (0.7, 2.6)] and only PMR [HR 1.3 (CI 0.9, 1.8) and 1.4 (0.9, 2.0)].

Active sun exposure did not affect the risk of developing GCA or PMR in women in a cohort with restricted latitudinal variability.

Vitamin deficiencies can have adverse effects on health, including on the visual system. The ocular manifestations of a vitamin deficiency are related to the underlying biochemical function of the particular nutrient. While vitamin deficiencies are not common in developed counties, they are still prevalent in parts of the developing world and in specific, vulnerable populations. Vitamin deficiencies can cause or contribute to many ophthalmological conditions and eye diseases may even be the first presenting finding of a vitamin deficiency. As such, it is important for ophthalmologists to be aware of the ocular manifestations of vitamin deficiencies, especially given that the complications can be severe and effectively treated if identified early. This review summarizes the literature on the main vitamins known to have characteristic ocular manifestations: vitamins A, B1, B2, B9, B12, C, D, E and K. The function, epidemiology, manifestations, workup, and management of each vitamin is discussed in detail.

The regulation of mineral homeostasis involves the three mineralotropic hormones PTH, FGF23 and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). Early research efforts focused on PTH and 1,25(OH)2D3 and more recently on FGF23 have revealed that each of these hormones regulates the expression of the other two. Despite early suggestions of transcriptional processes, it has been only recently that research effort have begun to delineate the genomic mechanisms underpinning this regulation for 1,25(OH)2D3 and FGF23; the regulation of PTH by 1,25(OH)2D3, however, remains obscure. We review here our molecular understanding of how PTH induces Cyp27b1 expression, the gene encoding the enzyme responsible for the synthesis of 1,25(OH)2D3. FGF23 and 1,25(OH)2D3, on the other hand, function by suppressing production of 1,25(OH)2D3. PTH stimulates the PKA-induced recruitment of CREB and its coactivator CBP at CREB occupied sites within the kidney-specific regulatory regions of Cyp27b1. PKA activation also promotes the nuclear translocation of SIK bound coactivators such as CRTC2, where it similarly interacts with CREB occupied Cyp27b1 sites. The negative actions of both FGF23 and 1,25(OH)2D3 appear to suppress Cyp27b1 expression by opposing the recruitment of CREB coactivators at this gene. Reciprocal gene actions are seen at Cyp24a1, the gene encoding the enzyme that degrades 1,25(OH)2D3, thereby contributing to the overall regulation of blood levels of 1,25(OH)2D3. Relative to PTH regulation, we summarize what is known of how 1,25(OH)2D3 regulates PTH suppression. These studies suggest that it is not 1,25(OH)2D3 that controls PTH levels in healthy subjects, but rather calcium itself. Finally, we describe current progress using an in vivo approach that furthers our understanding of the regulation of Fgf23 expression by PTH and 1,25(OH)2D3 and provide the first evidence that P may act to induce Fgf23 expression via a complex transcriptional mechanism in bone. It is clear, however, that additional advances will need to be made to further our understanding of the inter-regulation of each of these hormonal genes.

Hepatic fibrosis poses a significant threat to human health due to excessive extracellular matrix (ECM) deposition leading to liver function damage. Ligand-activated vitamin D receptor (VDR) has been identified as an effective target for hepatic fibrosis, reducing ECM by inhibiting hepatic stellate cell (HSC) activation. Here, a series of novel diphenyl VDR agonists have been rationally designed and synthesized. Among these, compounds 15b, 16i, and 28m showed better transcriptional activity compared to sw-22, which was previously reported to be a potent non-secosteroidal VDR modulator. Moreover, these compounds exhibited outstanding efficacy to inhibit collagen deposition in vitro. In models of CCl₄-induced and bile duct ligation-induced hepatic fibrosis, compound 16i showed the most significant therapeutic effect by ultrasound imaging and histological examination. Moreover, 16i was able to repair liver tissue by reducing the expression levels of fibrosis genes and serum liver function indexes without causing hypercalcemia in mice. In conclusion, compound 16i is a potent VDR agonist with significant anti-hepatic fibrosis action both in vitro and in vivo.

Sarcopenia is a geriatric condition characterized by a progressive loss of skeletal muscle mass and strength, with an increased risk of adverse health outcomes (e.g., falls, disability, institutionalization, reduced quality of life, mortality). Pharmacological remedies are currently unavailable for preventing the development of sarcopenia, halting its progression, or impeding its negative health outcomes. The most effective strategies to contrast sarcopenia rely on the adoption of healthier lifestyle behaviors, including adherence to high-quality diets and regular physical activity. In this review, the role of nutrition in the prevention and management of sarcopenia is summarized. Special attention is given to current "blockbuster" dietary regimes and agents used to counteract age-related muscle wasting, together with their putative mechanisms of action. Issues related to the design and implementation of effective nutritional strategies are discussed, with a focus on unanswered questions on the most appropriate timing of nutritional interventions to preserve muscle health and function into old age. A brief description is also provided on new technologies that can facilitate the development and implementation of personalized nutrition plans to contrast sarcopenia.

Age-related macular degeneration (AMD) has been the leading cause of irreversible blindness in industrialized countries. Emerging data suggest that serum vitamin D levels may be associated with AMD but show mixed results. National-level population data on the relationship between vitamin D and AMD severities are still lacking.

We used data from the National Health and Nutrition Examination Survey (NHANES) 2005 to 2008. Retinal photographs were taken and graded for AMD stage. The odds ratio (OR) of AMD and its subtype was calculated after adjusting for confounding factors. Restricted cubic spline (RCS) analyses were used to explore potential non-linear relations.

A total of 5041 participants with a mean age of 59.6 years were included. After adjusting for covariates, participants with higher level of serum 25-hydroxyvitamin D [25(OH)D] had significantly greater odds of early AMD (OR, 1.65; 95% CI, 1.08-2.51) and decreased risk of late AMD (OR, 0.29; 95% CI, 0.09-0.88). When stratified by age, a positive association between the level of serum 25(OH)D and early AMD was present in the <60 years group (OR, 2.79; 95% CI, 1.08-7.29), whereas a negative relation between the level of serum 25(OH)D and late AMD was detected in the ≥60 years group (OR, 0.24; 95% CI, 0.08-0.76).

A higher level of serum 25(OH)D was related to increased risk of early AMD in those <60 years and decreased risk of late AMD in those ≥60 years.

Some observational studies have suggested a possible association between vitamin D deficiency and CKD. However, in most studies, the causality between low levels of vitamin D and risk of renal events could not be explained. We investigated the relationship between vitamin D deficiency and risk of severe CKD stage and renal event in a large-scale prospective cohort study.

We used data from a prospective cohort of 2,144 patients with available information on serum 25-hydroxyvitamin D (25(OH)D) levels at baseline from KNOW-CKD, 2011-2015 were included. Vitamin D deficiency was defined as serum 25(OH)D levels < 15 ng/mL. We performed a cross-sectional analysis to elucidate the relationship between 25(OH)D and CKD stage using baseline CKD patient data. We further examined a cohort analysis to clarify the association between 25(OH)D and risk of renal event. Renal event was a composite of the first occurrence of a 50% decline in eGFR from the baseline value or the onset of CKD stage 5 (initiation of dialysis or kidney transplantation) across the follow-up period. We also investigated the associations of vitamin D deficiency with risk of renal event according to diabetes and overweight status.

Vitamin D deficiency were significantly associated with an increased risk of severe CKD stage - 1.30-fold (95% CI: 1.10-1.69) for 25(OH)D. Deficiency of 25(OH)D with 1.64-fold (95% CI: 1.32-2.65) was related to renal event compared with the reference. Furthermore, vitamin D deficiency patients with presence of DM and overweight status also displayed higher risk than non-deficient patients for risk of renal event.

Vitamin D deficiency is associated with significantly increased risk of severe CKD stage and renal event.

Bile acids are major components of bile; they emulsify dietary lipids for efficient digestion and absorption and act as signaling molecules that activate nuclear and membrane receptors. The vitamin D receptor (VDR) is a receptor for the active form of vitamin D and lithocholic acid (LCA), a secondary bile acid produced by the intestinal microflora. Unlike other bile acids that enter the enterohepatic circulation, LCA is poorly absorbed in the intestine. Although vitamin D signaling regulates various physiological functions, including calcium metabolism and inflammation/immunity, LCA signaling remains largely unknown. In this study, we investigated the effect of the oral administration of LCA on colitis in a mouse model using dextran sulfate sodium (DSS). Oral LCA decreased the disease activity of colitis in the early phase, which is a phenotype associated with the suppression of histological injury, such as inflammatory cell infiltration and goblet cell loss. These protective effects of LCA were abolished in VDR-deleted mice. LCA decreased the expression of inflammatory cytokine genes, but this effect was at least partly observed in VDR-deleted mice. The pharmacological effect of LCA on colitis was not associated with hypercalcemia, an adverse effect induced by vitamin D compounds. Therefore, LCA suppresses DSS-induced intestinal injury in its action as a VDR ligand.

(1) Background: The objective of this study was to evaluate the morphometry of peri-implant bone tissue in orchiectomized rats, treated with vitamin D isolated or associated with teriparatide. (2) Methods: 24 rats were divided into 4 groups: ORQ-orchiectomy, without drug treatment, ORQ+D-orchiectomy, treated with vitamin D, ORQTERI-orchiectomy, treated with teriparatide and ORQTERI+D-orchiectomy, treated with teriparatide + vitamin D. Each animal received an implant in the tibial metaphysis. Euthanasia occurred 60 days after implant surgery. Computed microtomography (micro-CT) was performed to evaluate the parameters of volume and percentage of bone volume (BV, BV/TV), trabecular thickness (Tb.Th), number and separation of trabeculae (Tb.N, Tb.Sp) and percentage of total porosity (Po-tot). Data were subjected to 1-way ANOVA and Tukey post-test, with a significance level of 5%. (3) Results: For the parameters BV, BV/TV, Tb.Th, the ORQTERI+D group showed the highest values in relation to the other groups and for Po-tot, the lowest values were for ORQTERI+D. For Tb.Sp and Tb.N, there was no statistically significant difference when comparing intragroup results (p > 0.05). (4) Conclusions: It was possible to conclude that treatment with vitamin D associated with teriparatide increases bone volume and improves bone quality.

Vitamin D is a fat-soluble vitamin with multiple functions. However, the metabolism of people with different vitamin D concentrations is still unclear. Herein, we collected clinical data and analysed the serum metabolome of people with 25-hydroxyvitamin D (25[OH]D) ≥40 ng/mL (A), 30 ng/mL ≤25(OH)D <40 ng/mL (B) and 25(OH)D <30 ng/mL (C) by the ultra-high-performance liquid chromatography-tandem mass spectrometry method. We found that haemoglobin A1c, fasting blood glucose, fasting insulin, homeostasis model assessment of insulin resistance and thioredoxin interaction protein were enhanced, while HOMA-β was reduced with the decrease of 25(OH)D concentration. In addition, people in the C group were diagnosed with prediabetes or diabetes. Metabolomics analysis showed that seven, thirty-four and nine differential metabolites were identified in the groups B vs A, C vs A and C vs B, respectively. Metabolites associated with cholesterol metabolism and bile acid biosynthesis, such as 7-ketolithocholic acid, 12-ketolithocholic acid, apocholic acid, N-arachidene glycine and d-mannose 6-phosphate, were significantly upregulated in the C group compared with the A or B groups. In conclusion, the disorder of vitamin D metabolism may be related to cholesterol metabolism and bile acid biosynthesis. This study provided a basis for exploring the possible mechanism leading to abnormal vitamin D metabolism.