Anti-Thymocyte Globulin Treatment Augments 1,25-Dihydroxyvitamin D3 Serum Levels in Patients Undergoing Hematopoietic Stem Cell Transplantation

Application of anti-thymocyte globulin (ATG) is a widely used strategy for the prevention of graft-versus-host disease (GvHD). As vitamin D3 serum levels are also discussed to affect hematopoietic stem cell transplantation (HSCT) outcome and GvHD development, we analysed a possible interplay between ATG treatment and serum levels of 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 in 4 HSCT cohorts with different vitamin D3 supplementation. ATG is significantly associated with higher serum level of 1,25-dihydroxyvitamin D3 around HSCT (day -2 to 7, peri-transplant), however only in patients with adequate levels of its precursor 25-hydroxyvitamin D3. ATG exposure had no impact on overall survival in patients supplemented with high dose vitamin D3, but was associated with higher risk of one-year treatment-related mortality (log rank test p=0.041) in patients with no/low vitamin D3 supplementation. However, the difference failed to reach significance applying a Cox-model regression without and with adjustment for baseline risk factors (unadjusted P=0,058, adjusted p=0,139). To shed some light on underlying mechanisms, we investigated the impact of ATG on 1,25-Dihydroxyvitamin D3 production by human dendritic cells (DCs) in vitro. ATG increased gene expression of CYP27B1, the enzyme responsible for the conversion of 25-hydroxyvitamin D3 into 1,25-dihydroxyvitamin D3, which was accompanied by higher 1,25-dihydroxyvitamin D3 levels in ATG-treated DC culture supernatants. Our data demonstrate a cooperative effect of 25-hydroxyvitamin D3 and ATG in the regulation of 1,25-dihydroxyvitamin D3 production. This finding may be of importance in the context of HSCT, where early high levels of 1,25-dihydroxyvitamin D3 levels have been shown to be predictive for lower transplant related mortality and suggest that vitamin D3 supplementation may especially be important in patients receiving ATG for GvHD prophylaxis.

Effects of Vitamin D3 Supplementation and Resistance Training on 25-Hydroxyvitamin D Status and Functional Performance of Older Adults: A Randomized Placebo-Controlled Trial

Vitamin D status is associated with muscle strength and performance in older adults. To examine the additive effects of vitamin D3 supplementation during resistance training, 100 seniors (65–85 years) participated in a 16-week intervention. Besides a daily dose of 400 mg of calcium, participants received either 800 IU vitamin D3 per day (VDD), 50,000 IU vitamin D3 per month (VDM) or nothing (CON). After the initial loading phase of four weeks, all groups started a 10-week resistance training program. Assessments of 25-hydroxyvitamin D (25(OH)D) status, muscle strength endurance (30-s chair stand and arm curl tests), aerobic capacity (6-min walk test) and functional mobility (gait speed and timed up and go test) were undertaken at baseline, after four weeks and at the end of the study. 25(OH)D status significantly improved in VDD and VDM, but not in CON (time x group: p = 0.021), as 15.2% of CON, 40.0% of VDD and 61.1% of VDM reached vitamin D sufficiency (>30 ng/mL; p = 0.004). Chair stand test, arm curl test, 6-min walk test, gait speed and timed up and go test improved over the whole intervention period (p < 0.05), however only chair stand and arm curl test were selectively affected by resistance training (p < 0.001). Neither muscle strength endurance, nor functional mobility or aerobic capacity were modulated by vitamin D supplementation. Therefore, the mere amelioration of 25(OH)D status of older adults does not lead to an additive effect on muscular performance during RT.

Effects of dietary vitamin D3 supplementation on the growth performance, tissue Ca and P concentrations, antioxidant capacitiy, immune response and lipid metabolism in Litopenaeus vannamei larvae

An 8-week feeding trial was conducted to investigate the effects of dietary vitamin D3 supplementation on the growth performance, tissue calcium (Ca) and phosphorus (P) concentrations, antioxidant capacity, immune response and lipid metabolism in Litopenaeus vannamei larvae. A total of 720 shrimp (initial weight 0.50±0.01 g) were randomly distributed into six treatments, each of which had three duplicates of 40 shrimp per duplicate. Six isonitrogenous and isolipidic diets were formulated to contain graded vitamin D3 (0.18, 0.23, 0.27, 0.48, 0.57 and 0.98 mg/kg of vitamin D3, measured) supplementation levels. The results revealed that L. vannamei fed diet containing 0.48 mg/kg vitamin D3 achieved the best growth performance. Compared with the control group, supplementing 0.48 mg/kg vitamin D3 significantly increased (P<0.05) the activities of catalase, total antioxidative capacity, alkaline phosphatase and acid phosphatase in serum and hepatopancreas. Expression levels of antioxidant and immune related genes were synchronously increased (P<0.05). Carapace P and Ca concentrations were increased (P<0.05) with the increased vitamin D3 supplementation levels. Further analysis of lipid metabolism related genes expression showed that shrimp fed 0.48 mg vitamin D3 kg−1 diet showed the highest value in the expression of lipid synthesis related genes, while shrimp fed 0.98 mg vitamin D3 kg−1 diet showed the highest value in the expression of lipolysis related genes. In conclusion, the results of present study indicated that dietary supplementation of 0.48 mg/kg vitamin D3 could increase Ca and P concentrations, improve antioxidant capacity, immune response and influence lipid metabolism in L. vannamei.

Comparative Effect of Vitamin D3 and Carbenoxolone Treatments in Metabolic Syndrome Rats

Metabolic syndrome (MetS) is a cluster of cardiovascular risk factors including central obesity, hypertension, insulin resistance, dyslipidemia, and hyperglyemia. MetS is found to be a positive predictor of cardiovascular morbidity and mortality. The present study was planned to test the efficacy of vitamin D3 supplementation as compared to cortisol inhibition on MetS parameters. Wistar rats were allocated into four groups: controls, untreated MetS, and MetS treated with either vitamin D3 (10 μg/kg), or carbenoxolone (50 mg/kg). MetS was induced by combination of high fat diet and oral fructose. After the induction period (8 weeks), MetS was confirmed and treatment modalities started for a further 4 weeks. Compared to untreated MetS, vitamin D3 and carbenoxolone treated rats showed significant reduction in blood pressure, body mass index, lee index, waist circumference, retroperitoneal fat, and improvement of dyslipidemia. Meanwhile, treatment with carbenoxolone significantly lowered the elevated liver enzymes, vitamin D3 resulted in improved insulin sensitivity, enhanced glucose uptake by muscles and replenished glycogen content in the liver and muscles near control levels. In conclusion, although treatment with vitamin D3 or carbenoxolone reduced the risk factors associated with MetS, vitamin D3 was effective in ameliorating insulin resistance which is the hallmark of MetS.

The role of vitamin D in breast cancer risk and progression

The active form of vitamin D3, 1,25-dihydroxvitamin D3 [1,25(OH)2D3], is primarily known as a key regulator of calcium and phosphate homeostasis. It exerts its biological functions by binding to the vitamin D receptor (VDR), a transcription factor that regulates gene expression in vitamin D-target tissues such as intestine, kidney and bone. Yet, the VDR is expressed in many additional normal and cancerous tissues, where it moderates the antiproliferative, prodifferentiating and immune-modulating effects of 1,25(OH)2D3. Interestingly, several epidemiological studies show that low levels of 25(OH)D3, a biological marker for 1,25(OH)2D3 status, are associated with increased risk of breast cancer (BC) development. Mendelian randomization studies, however, did not find any relationship between single-nucleotide polymorphisms in genes associated with lower serum 25(OH)D3 and BC risk. Nevertheless, multiple in vitro and in vivo preclinical studies illustrate that 1,25(OH)2D3 or its less calcaemic structural analogues influence diverse cellular processes in BC such as proliferation, differentiation, apoptosis, autophagy and the epithelial-mesenchymal transition. Recent insights also demonstrate that 1,25(OH)2D3 treatment impacts on cell metabolism and on the cancer stem cell population. The presence of VDR in the majority of BCs, together with the various antitumoural effects of 1,25(OH)2D3, have supported the evaluation of the effects of vitamin D3 supplementation on BC development. However, most randomized controlled clinical trials do not demonstrate a clear decrease of BC incidence with vitamin D3 supplementation. However, 1,25(OH)2D3 or its analogues seem biologically more active, and may have more potential anticancer activity in BC upon combination with existing cancer therapies.

Effect of vitamin D on cognitive decline: results from two ancillary studies of the VITAL randomized trial

Low vitamin D levels have been associated with cognitive decline; however, few randomized trials have been conducted. In a trial, we evaluated vitamin D3 supplementation on cognitive decline. We included participants aged 60+ years (mean[SD] = 70.9[5.8] years) free of cardiovascular disease and cancer in two substudies in the VITAL 2 × 2 randomized trial of vitamin D3 (2000 IU/day of cholecalciferol) and fish oil supplements: 3424 had cognitive assessments by phone (eight neuropsychologic tests; 2.8 years follow-up) and 794 had in-person assessments (nine tests; 2.0 years follow-up). The primary, pre-specified outcome was decline over two assessments in global composite score (average z-scores of all tests); substudy-specific results were meta-analyzed. The pooled mean difference in annual rate of decline (MD) for vitamin D3 versus placebo was 0.01 (95% CI − 0.01, 0.02; p = 0.39). We observed no interaction with baseline 25-hydroxyvitamin-D levels (p-interaction = 0.84) and a significant interaction with self-reported race (p-interaction = 0.01). Among Black participants (19%), those assigned vitamin D3 versus placebo had better cognitive maintenance (MD = 0.04, 95% CI 0.01, 0.08, similar to that observed for Black participants 1.2 years apart in age). Thus, vitamin D3 (2000 IU/day cholecalciferol) supplementation was not associated with cognitive decline over 2–3 years among community-dwelling older participants but may provide modest cognitive benefits in older Black adults, although these results need confirmation.Trial registration ClinicalTrials.gov; VITAL (NCT01169259), VITAL-DEP (NCT01696435) and VITAL-Cog (NCT01669915); the date the registration for the parent trial (NCT01169259) was submitted to the registry: 7/26/2010 and the date of first patient enrollment in either of the ancillary studies for cognitive function in a subset of eligible VITAL participants: 9/14/2011.

Impact of vitamin D3 supplementation on the in vitro growth of mouse preantral follicles

Objective: We investigated the impact of vitamin D3 (VD3) supplementation during mouse preantral follicle culture in vitro and the mRNA expression of 25-hydroxylase (CYP2R1), 1-alpha-hydroxylase (CYP27B1), and vitamin D receptor (VDR) in mouse ovarian follicles at different stages.Methods: Preantral follicles were retrieved from 39 BDF1 mice (7–8 weeks old) and then cultured in vitro for 12 days under VD3 supplementation (0, 25, and 50 pg/mL). Follicular development and the final oocyte acquisition were assessed. Preantral follicles were retrieved from 15 other BDF1 mice (7–8 weeks old) and cultured without VD3 supplementation. Three stages of mouse ovarian follicles were obtained (preantral, antral, and ruptured follicles). Total RNA was extracted from the pooled cells (from 20 follicles at each stage), and then reverse transcriptase-polymerase chain reaction was performed to identify mRNA for CYP2R1, CYP27B1, and VDR.Results: The survival of preantral follicles, rates of antrum formation and ruptured follicles (per initiated follicle) and the number of total or mature oocytes were all comparable among the three groups. Both CYP2R1 and CYP27B1 were expressed in antral and ruptured follicles, but not in preantral follicles. VDR was expressed in all three follicular stages.Conclusion: VD3 supplementation in vitro (25 or 50 pg/mL) did not enhance mouse follicular development or final oocyte acquisition. Follicular stage-specific expression of CYP2R1, CYP27B1, and VDR was observed.

Rapid and Effective Vitamin D Supplementation May Present Better Clinical Outcomes in COVID-19 (SARS-CoV-2) Patients by Altering Serum INOS1, IL1B, IFNg, Cathelicidin-LL37, and ICAM1

Background: We aimed to establish an acute treatment protocol to increase serum vitamin D, evaluate the effectiveness of vitamin D3 supplementation, and reveal the potential mechanisms in COVID-19. Methods: We retrospectively analyzed the data of 867 COVID-19 cases. Then, a prospective study was conducted, including 23 healthy individuals and 210 cases. A total of 163 cases had vitamin D supplementation, and 95 were followed for 14 days. Clinical outcomes, routine blood biomarkers, serum levels of vitamin D metabolism, and action mechanism-related parameters were evaluated. Results: Our treatment protocol increased the serum 25OHD levels significantly to above 30 ng/mL within two weeks. COVID-19 cases (no comorbidities, no vitamin D treatment, 25OHD <30 ng/mL) had 1.9-fold increased risk of having hospitalization longer than 8 days compared with the cases with comorbidities and vitamin D treatment. Having vitamin D treatment decreased the mortality rate by 2.14 times. The correlation analysis of specific serum biomarkers with 25OHD indicated that the vitamin D action in COVID-19 might involve regulation of INOS1, IL1B, IFNg, cathelicidin-LL37, and ICAM1. Conclusions: Vitamin D treatment shortened hospital stay and decreased mortality in COVID-19 cases, even in the existence of comorbidities. Vitamin D supplementation is effective on various target parameters; therefore, it is essential for COVID-19 treatment.