The effect of vitamin D2 supplementation on vitamin D levels in humans: A time and dose-response meta-analysis of randomized controlled trials.

BACKGROUND: Inconsistencies exist regarding the influence of vitamin D2 (ergocalciferol) supplementation on serum vitamin D levels. These inconsistencies could be attributed to numerous factors, such as dosage, baseline vitamin D levels, and duration of intervention. Hence, this dose-response meta-analysis of randomized controlled trials was conducted to assess the efficacy of vitamin D2 supplementation on vitamin D levels. METHODS: Relevant studies were searched in PubMed/Medline, Web of Science, Embase, and Scopus, from their inception to 3 January 2023. Variable alterations were considered to calculate the pooled weighted mean difference (WMD) with 95% confidence interval (CI) using the random effects model. RESULTS: Pooled results from 33 study arms demonstrated that Vitamin D2 treatment significantly increases total vitamin D concentrations (WMD: 11.47 ng/mL, 95 %CI: 9.29 to 13.64, p < 0.001), 25(OH)D2 concentrations (WMD: 11.40 ng/mL, 95 %CI: 4.72 to 18.09, p = 0.001), and 1,25(OH)D concentrations (WMD: 5.61 ng/mL, 95 %CI: 0.74 to 10.48, p = 0.024), but decreases 25(OH)D3 concentrations (WMD: -4.63 ng/mL, 95 %CI: -6.46 to -2.81, p < 0.001). In subgroup analyses, increase in total vitamin D concentrations was more significant in vitamin D2 doses >2000 IU/day (WMD: 13.82 ng/mL), studies with duration ≤12 weeks (WMD: 12.53 ng/mL), participants aged ≥60 years (WMD: 14.40 ng/mL), and trials with basal 25(OH)D concentrations <20 ng/mL (WMD: 11.47 ng/mL). CONCLUSIONS: This meta-analysis indicates that the supplementation of vitamin D2 significantly increases the serum concentrations of total vitamin D, 25(OH)D2, and 1,25(OH)D, but decreases 25(OH)D3 concentrations. Careful consideration of patient characteristics, dosage, and treatment duration is recommended for vitamin D2 supplementation.

Vitamin D/VDR attenuate cisplatin-induced AKI by down-regulating NLRP3/Caspase-1/GSDMD pyroptosis pathway.

Vitamin D/Vitamin D receptor (VDR) has been shown to inhibit the NF-κB-mediated inflammatory effects. Up-regulation of the NLRP3(Recombinant NLR Family, Pyrin Domain Containing Protein 3)/Caspase-1/GSDMD (Gasdermin D) pathway through NF-κb is one of the key mechanisms leading to pyroptosis. This study aims to explore the effects of vitamin D/VDR on the pyroptosis pathway in cisplatin induced acute kidney injury (AKI) models. Our results showed that in wide type mice, renal function loss, tissue injury and cell death induced by cisplatin were alleviated by pretreatment of high-dose paricalcitol(a VDR agonist) accompanied with up-regulated VDR and decreased expression of NLRP3, GSDMD-N, Cleaved-Caspase-1 and mature Interleukin- 1ß (features of pyroptosis). While, in VDR knock out mice, cisplatin induced more severer renal injury and further increased pyroptosis related protein than the wild type mice and the effect of paricalcitol were also eliminated. In tubular cell specific VDR-over expressing mice, those renal injury index as well as pyroptosis phenotype were significantly reduced by low-dose paricalcitol pretreatment with upregulated VDR expression compared with WT mice. In vitro data using gain and lose function experiments in Human tubular epithelial cell (HK-2) were consistent with the observation as in vivo work. Our further experiments in both animal and cell culture work has found that the level of IκBα(Inhibitor of NF-κB) were decreased and the nuclear level of NF-κB p65 of renal tubular cells were increased after cisplatin injury while VDR activation by paricalcitol could reverse up-regulation of nuclear NF-κB p65 with reduced cell pyroptosis. These data suggested that vitamin D/VDR could alleviate cisplatin-induced acute renal injury partly by inhibiting NF-κB-mediated NLRP3/Caspase-1/GSDMD pyroptosis.

The Therapeutic Effect of Active Vitamin D Supplementation in Preventing the Progression of Diabetic Nephropathy in a Diabetic Mouse Model.

BACKGROUND: Diabetic nephropathy (DN) is one of the most common microvascular complications of diabetes and is the leading cause of end-stage renal disease (ESRD) and replacement therapy worldwide. Vitamin D levels in DN patients are very low due to the decrease in the synthesis and activity of 1-α hydroxylase in the proximal tubule cells and decrease in the vitamin D receptor abundance. To date, few studies have shown the antioxidant effects of 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] on hyperglycemia-induced renal injury. The selective activator of the vitamin D receptor, paricalcitol, reduces proteinuria and slows the progression of kidney injury. The precise mechanism through which vitamin D affects diabetic status and provides kidney protection remains to be determined. METHODS: Diabetes mellitus (DM) was induced in 94 8-week-old DBA/2J mice by intraperitoneal injection of streptozotocin (STZ). DM mice were randomly divided into receiving vehicle or treatment with paricalcitol, the active vitamin D analog, 1 week after DM induction or paricalcitol treatment 3 weeks after DM induction. An additional control group of healthy wild-type mice was not treated. Urine albumin, blood urea nitrogen, and creatinine levels were measured before and at the end of the paricalcitol treatment. Periodic acid-Schiff, immunohistochemistry staining, and western blot of the renal tissues of vitamin D receptor, villin, nephrin, and podocin expressions, were analyzed. RESULTS: Paricalcitol treatment restored villin, nephrin, and podocin protein levels that were downregulated upon DM induction, and reduced fibronectin protein level. Vitamin D receptor activation by paricalcitol may reduce proteinuria of DN in mice and alleviate high-glucose-induced injury of kidney podocytes by regulating the key molecules such nephrin-podocin. CONCLUSIONS: Paricalcitol treatment was associated with improved structural changes in type 1 diabetic mice including upregulation of vitamin D receptor expression, and decreased fibrosis markers such as fibronectin. These effects may contribute to the consistent benefit of vitamin D analog to slow the deterioration in glomerular function and reduce the risk of ESRD in patients with type 1 and 2 diabetes mellitus. Our results suggest that additional use of paricalcitol may be beneficial in treating patients with diabetes under standard therapeutic strategies.

Effects of additional dosage of vitamin D3, vitamin D2, and 25-hydroxyvitamin D3 on calcium and phosphorus utilization, egg quality and bone mineralization in laying hens.

Vitamin D is essential for the metabolism of calcium (Ca) and phosphorus (P) in birds. The objective of the study was to evaluate the effect of different isoforms of dietary vitamin D on Ca and P utilization, egg quality, and bone mineralization of laying hens. A total of 42 Lohmann white laying hens at 57 wk of age were randomly assigned to 7 dietary treatments for 6 wk. Dietary treatments were: 3,000 IU/kg Vit D3 as control, and control with additional 3,000 IU/kg 25-hydroxyvitamin D3 (T1), 9,000 IU/kg 25-hydroxyvitamin D3 (T2), 3,000 IU/kg vitamin D3 (T3), 9,000 IU/kg vitamin D3 (T4), 3,000 IU/kg of vitamin D2 (T5), or 9,000 IU/kg of vitamin D2 (T6). Egg production and egg quality were measured weekly. Fecal samples were collected at weeks 2 and 6 to measure Ca and P utilization. After 6 wk, the left tibia and femurs were collected to measure bone mineral density (BMD) and bone mineral content (BMC). A 1-way ANOVA with Tukey HSD means separation test was used for statistical analysis. There were no significant differences in egg production, egg quality, BMD, or BMC of tibia and femurs among the treatments (P > 0.05). T6 significantly reduced feed intake (P < 0.05). The apparent total tract digestibility (ATTD) of Ca was higher (P < 0.012) in treatments supplemented with additional vitamin D, irrespective of forms. The ATTD of P was higher (P < 0.0001) in T5 compared to the other treatments at both time points. The utilization of Ca and P by laying hens can be improved through the addition of different isoforms of vitamin D in diets. However, additional vitamin D supplementation to laying hens, regardless of forms, had no effect on either bone mineralization or measures of egg quality.

Vitamins D3 and D2 have marked but different global effects on gene expression in a rat oligodendrocyte precursor cell line.

BACKGROUND: Vitamin D deficiency increases the risk of developing multiple sclerosis (MS) but it is unclear whether vitamin D supplementation improves the clinical course of MS, and there is uncertainty about the dose and form of vitamin D (D2 or D3) to be used. The mechanisms underlying the effects of vitamin D in MS are not clear. Vitamin D3 increases the rate of differentiation of primary oligodendrocyte precursor cells (OPCs), suggesting that it might help remyelination in addition to modulating the immune response. Here we analyzed the transcriptome of differentiating rat CG4 OPCs treated with vitamin D2 or with vitamin D3 at 24 h and 72 h following onset of differentiation. METHODS: Gene expression in differentiating CG4 cells in response to vitamin D2 or D3 was quantified using Agilent DNA microarrays (n = 4 replicates), and the transcriptome data were processed and analysed using the R software environment. Differential expression between the experimental conditions was determined using LIMMA, applying the Benjamini and Hochberg multiple testing correction to p-values, and significant genes were grouped into co-expression clusters by hierarchical clustering. The functional significance of gene groups was explored by pathway enrichment analysis using the clusterProfiler package. RESULTS: Differentiation alone changed the expression of about 10% of the genes at 72 h compared to 24 h. Vitamin D2 and D3 exerted different effects on gene expression, with D3 influencing 1272 genes and D2 574 at 24 h. The expression of the vast majority of these genes was either not changed in differentiating cells not exposed to vitamin D or followed the same trajectory as the latter. D3-repressed genes were enriched for Gene Ontology (GO) categories including transcription factors and the Notch pathway, while D3-induced genes were enriched for the Ras pathway. CONCLUSIONS: This study shows that vitamin D3, compared with D2, changes the expression of a larger number of genes in OLs. Identification of genes affected by D3 in OLs should help to identify mechanisms mediating its action in MS.

Activation of vitamin D receptor attenuates high glucose-induced cellular injury partially dependent on CYP2J5 in murine renal tubule epithelial cell.

AIMS: Vitamin D and its receptor, vitamin D receptor (VDR), have renoprotection effect against diabetic nephropathy (DN). But the exact mechanism has not been fully elucidated. Epoxyeicosatrienoic acids (EETs) are cytochrome P450 (CYP) epoxygenase-derived metabolites of arachidonic acid, protecting against diabetes and DN. Herein, we hypothesized that activation of VDR attenuated high glucose-induced cellular injury in renal tubular epithelial cells partially through up-regulating CYP2J5 expression. MAIN METHODS: Streptozotocin (STZ) was injected to induce diabetic in wild type and Vdr-/- mice. The effects of VDR knockout and an activator of VDR, paricalcitol, on the renal injury were detected. In vitro, a murine kidney proximal tubule epithelial cell line BU.MPT induced by high glucose were treated with or without paricalcitol (30 mM) for 12 h or 24 h. KEY FINDINGS: The expression of CYP2J5 was significantly decreased both in wild type and Vdr-/- diabetic mice induced by STZ. The STZ-induced kidney architecture damage and apoptosis rate in Vdr-/- mice were more severe. In vitro, high glucose treatment strongly reduced the CYP2J5 expression and the synthesis of 14,15-EET in BU.MPT cells. Supplement of 14,15-EET significantly reduced the lactate dehydrogenase (LDH) release induced by high glucose in BU.MPT cells. Furthermore, treatment with paricalcitol attenuated cellular injury and restored the expression of CYP2J5 reduced by high glucose in BU.MPT cells. SIGNIFICANCE: We conclude that activation of VDR attenuates high glucose-induced cellular injury partially dependent on CYP2J5 in murine renal tubule epithelial cells and paricalcitol may represent a potential therapy for DN.

Antifibrotic effects of hypocalcemic vitamin D analogs in murine and human hepatic stellate cells and in the CCl4 mouse model.

Liver cirrhosis is a life-threatening consequence of liver fibrosis. The aim of this study was to investigate the antifibrotic potential of clinically available vitamin D analogs compared to that of calcitriol in vitro and in vivo. Murine hepatic stellate cells, Kupffer cells, and human LX-2 cells were treated with vitamin D analogs, and the profibrotic behavior of these cells was studied. In vivo liver fibrosis was induced using CCl4 until measurable fibrosis was established. Animals were then treated with calcitriol and paricalcitol. Vitamin D and its analogs showed antifibrotic effects in vitro. Treatment with active vitamin D (calcitriol, CAL) and its analogs reduced the protein expression of α-smooth muscle actin (α-SMA) in mHSC. In human LX-2 cells alfacalcidol reduced transforming growth factor-ß (TGF-ß) induced platelet-derived growth factor receptor-ß protein expression and contractility while paricalcitol (PCT), in its equipotent dose to CAL, reduced TGF-ß induced α-SMA protein expression, and ACTA2 and TGF-ß mRNA expression. No effects of a treatment with vitamin D and its analogs were observed in Kupffer cells. In vivo, PCT-treated mice had significantly lower calcium levels than CAL-treated mice. CAL and PCT reduced the hepatic infiltration of CD11b-positive cells and alanine transaminase levels, while PCT but not CAL significantly inhibited fibrosis progression, with a favorable side effect profile in the CCl4 model. We conclude that hypocalcemic vitamin D analogs should be considered in future studies investigating vitamin D for the treatment of liver fibrosis.

Paricalcitol accelerates BACE1 lysosomal degradation and inhibits calpain-1 dependent neuronal loss in APP/PS1 transgenic mice.

BACKGROUND: Recent studies have revealed that vitamin D deficiency may increase the risk of Alzheimer's disease, and vitamin D supplementation may be effective strategy to ameliorate the neurodegenerative process in Alzheimer's disease patients. Paricalcitol (PAL), a low-calcemic vitamin D receptor agonist, is clinically used to treat secondary hyperparathyroidism. However, the potential application of PAL for treating neurodegenerative disorders remains unexplored. METHODS: The APP/PS1 mice were intraperitoneally injected with PAL or vehicle every other day for 15 weeks. The ß-amyloid (Aß) production was confirmed using immunostaining and enzyme linked immunosorbent assay. The underlying mechanism was verified by western blot and immunostaining in vivo and in vitro. FINDINGS: Long-term PAL treatment clearly reduced ß-amyloid (Aß) generation and neuronal loss in APP/PS1 transgenic mouse brains. PAL stimulated the expression of low-density lipoprotein receptor-related protein 1 (LRP1) possibly through inhibiting sterol regulatory element binding protein-2 (SREBP2); PAL also promoted LRP1-mediated ß-site APP cleavage enzyme 1 (BACE1) transport to late endosomes, thus increasing the lysosomal degradation of BACE1. Furthermore, PAL diminished 8-hydroxyguanosine (8-OHdG) generation in neuronal mitochondria via enhancing base excision repair (BER), resulting in the attenuation of calpain-1-mediated neuronal loss. INTERPRETATION: The present data demonstrate that PAL can reduce Aß generation through accelerating BACE1 lysosomal degradation and can inhibit neuronal loss through suppressing mitochondrial 8-OHdG generation. Hence, PAL might be a promising agent for treating Alzheimer's disease. FUND: This study was financially supported by the Natural Science Foundation of China (U1608282).

Differential Effects of Oral Boluses of Vitamin D2 vs Vitamin D3 on Vitamin D Metabolism: A Randomized Controlled Trial.

CONTEXT: Vitamin D2 and vitamin D3 have been hypothesized to exert differential effects on vitamin D metabolism. OBJECTIVE: To compare the influence of administering vitamin D2 vs vitamin D3 on metabolism of vitamin D3. METHODS: We measured baseline and 4-month serum concentrations of vitamin D3, 25-hydroxyvitamin D3 [25(OH)D3], 25-hydroxyvitamin D2, 24R,25-dihydroxyvitamin D3 [24R,25(OH)2D3], 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3], and 4ß,25-dihydroxyvitamin D3 [4ß,25(OH)2D3] in 52 adults randomized to receive a total of four oral bolus doses of 2.5 mg vitamin D2 (n = 28) or vitamin D3 (n = 24) over four months. Metabolite-to-parent compound ratios were calculated to estimate hydroxylase activity. Pairwise before vs after comparisons were made to evaluate effects of vitamin D2 and vitamin D3 on metabolism of vitamin D. Mean postsupplementation metabolite-to-parent ratios were then compared between groups. RESULTS: Vitamin D2 was less effective than vitamin D3 in elevating total serum 25(OH)D concentration. Vitamin D2 suppressed mean four-month serum concentrations of 25(OH)D3, 24R,25(OH)2D3, 1α,25(OH)2D3, and 4ß,25(OH)2D3 and mean ratios of 25(OH)D3 to D3 and 1α,25(OH)2D3 to 25(OH)D3, while increasing the mean ratio of 24R,25(OH)2D3 to 25(OH)D3. Vitamin D3 increased mean four-month serum concentrations of 25(OH)D3, 24R,25(OH)2D3, 1α,25(OH)2D3, and 4ß,25(OH)2D3 and the mean ratio of 24R,25(OH)2D3 to 25(OH)D3. Participants receiving vitamin D2 had lower mean postsupplementation ratios of 25(OH)D3 to vitamin D3 and 1α,25(OH)2D3 to 25(OH)D3 than those receiving vitamin D3. Mean postsupplementation ratios of 24R,25(OH)2D3 to 25(OH)D3 and 4ß,25(OH)2D3 to 25(OH)D3 did not differ between groups. CONCLUSIONS: Bolus-dose vitamin D2 is less effective than bolus-dose vitamin D3 in elevating total serum 25(OH)D concentration. Administration of vitamin D2 reduces 25-hydroxylation of vitamin D3 and 1-α hydroxylation of 25(OH)D3, while increasing 24R-hydroxylation of 25(OH)D3.

Paricalcitol alleviates lipopolysaccharide-induced depressive-like behavior by suppressing hypothalamic microglia activation and neuroinflammation.

Depression is highly prevalent in patients suffering from chronic inflammatory diseases. Dysregulated neuroinflammation and concomitant activated microglia play a pivotal role in the pathogenesis of depression. Paricalcitol (Pari), a vitamin D2 analogue, has been demonstrated to exert anti-inflammative effects on renal and cardiovascular diseases. In this study, mice were pretreated with Pari before being induced to acute depression-like behaviors by systemic lipopolysaccharide (LPS) injection. To determine the therapeutic effects of Pari, alterations in acute body weight, sucrose preference, forced swimming and tail suspension tests were assessed. Then, alterations of pro-inflammation cytokine IL1-ß level and microglia activity in the hypothalamus, which are involved in the pathophysiology of depression, were examined. The results showed that Pari significantly alleviated systemic LPS injection induced depressive-like behaviors as shown by increased sucrose preference and decreased TST and FST immobility. Pari could specifically regulate microglia-mediated neuroinflammation process and local activity of renin-angiotensin system to exert its anti-depressant effects. This study demonstrated a potential for paricalcitol in treating depressive symptoms induced by systemic inflammation, particularly in patients with chronic hypertension.

Paricalcitol inhibits the Wnt/beta-catenin signaling pathway and ameliorates experimentally induced arthritis

Background/aim: The Wnt/ß-catenin pathway has important biological activities, including the differentiation of cells and joint formations. The aim of our study was to determine the effect of paricalcitol on experimentally induced arthritis. Materials and methods: Type II collagen combined with Freund's adjuvant was applied to induce arthritis in Wistar albino female rats. Paricalcitol (0.3 µg/kg daily) was subcutaneously injected starting 1 day after collagen applications (prophylactic group) or 1 day after the onset of arthritis (therapeutic group), until day 29. Results: The 29th day arthritis scores were lower compared to the 13th day scores in the paricalcitol groups (P < 0.05), while they were higher in the arthritis group (P < 0.05). Marked cartilage-bone destruction and extensive perisynovial inflammation were detected in the arthritis group. Decreased cartilage-bone destruction and perisynovial inflammation in the paws were observed in the paricalcitol groups. The tissue mRNA levels of DKK1, Wnt5a, and axin-2 were higher in the arthritis group than in the control group. In the paricalcitol groups, mRNA expressions were lower than in the arthritis group. Conclusion: The present study shows that the Wnt/ß-catenin signaling pathway is active in arthritis. Moreover, paricalcitol ameliorates arthritis via inhibiting the Wnt/ß-catenin pathway. Paricalcitol and the Wnt/ß-catenin pathway are candidates for research in human rheumatoid arthritis.

Effect of low-level 1800 MHz radiofrequency radiation on the rat sciatic nerve and the protective role of paricalcitol.

The nervous system is an important target of radiofrequency (RF) radiation exposure since it is the excitable component that is potentially able to interact with electromagnetic fields. The present study was designed to investigate the effects of 1,800 MHz RF radiation and the protective role of paricalcitol on the rat sciatic nerve. Rats were divided into four groups as control, paricalcitol, RF, and RF + paricalcitol. In RF groups, the rats were exposed to 1,800 MHz RF for 1 h per day for 4 weeks. Control and paricalcitol rats were kept under the same conditions without RF application. In paricalcitol groups, the rats were given 0.2 µg/kg/day paricalcitol, three times per week for 4 weeks. Amplitude and latency of nerve compound action potentials, catalase activities, malondialdehyde (MDA) levels, and ultrastructural changes of sciatic nerve were evaluated. In the RF group, a significant reduction in amplitude, prolongation in latency, an increase in the MDA level, and an increase in catalase activity and degeneration in the myelinated nerve fibers were observed. The electrophysiological and histological findings were consistent with neuropathy, and the neuropathic changes were partially ameliorated with paricalcitol administration. Bioelectromagnetics. 39:631-643, 2018. © 2018 Wiley Periodicals, Inc.

Vitamin D Attenuates Endothelial Dysfunction in Uremic Rats and Maintains Human Endothelial Stability.

Background Dysfunctional endothelium may contribute to the development of cardiovascular complications in chronic kidney disease ( CKD ). Supplementation with active vitamin D has been proposed to have vasoprotective potential in CKD , not only by direct effects on the endothelium but also by an increment of α-Klotho. Here, we explored the capacity of the active vitamin D analogue paricalcitol to protect against uremia-induced endothelial damage and the extent to which this was dependent on increased α-Klotho concentrations. Methods and Results In a combined rat model of CKD with vitamin D deficiency, renal failure induced vascular permeability and endothelial-gap formation in thoracic aorta irrespective of baseline vitamin D, and this was attenuated by paricalcitol. Downregulation of renal and serum α-Klotho was found in the CKD model, which was not restored by paricalcitol. By measuring the real-time changes of the human endothelial barrier function, we found that paricalcitol effectively improved the recovery of endothelial integrity following the addition of the pro-permeability factor thrombin and the induction of a wound. Furthermore, immunofluorescence staining revealed that paricalcitol promoted vascular endothelial-cadherin-based cell-cell junctions and diminished F-actin stress fiber organization, preventing the formation of endothelial intracellular gaps. Conclusions Our results demonstrate that paricalcitol attenuates the CKD -induced endothelial damage in the thoracic aorta and directly mediates endothelial stability in vitro by enforcing cell-cell interactions.

The effect of vitamin D2 supplementation on muscle strength in early postmenopausal women: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Low serum 25-hydroxyvitamin D [25(OH)D] has been shown to be associated with low muscle mass and loss of muscle strength, resulting in increased disability and frailty in older men and women. Vitamin D deficiency is common in postmenopausal women. The primary objective of the present study was to evaluate the effects of vitamin D supplementation on muscle strength in early postmenopausal women. The effects of vitamin D2 supplementation on muscle mass and muscle cross-sectional area (CSA) were secondarily investigated. METHODS: A 12-week, prospective, randomized, double-blind, placebo-controlled trial was conducted in early postmenopausal women (45-60 years old) with vitamin D deficiency (serum 25(OH)D < 20 ng/ml). A total of 88 subjects were randomized into group I: vitamin D2 supplement 40 000 IU/week (n = 44), or group II: placebo (n = 44). Serum 25(OH)D level, muscle strength, muscle mass and muscle CSA were assessed at baseline and 12 weeks after the supplementation. RESULTS: After 12 weeks of supplementation, 70% of women in group I achieved a sufficient level of serum 25(OH)D (>30 ng/ml). There were significant differences in changes of serum 25(OH)D levels between the two groups (p < 0.05). Muscle strength and muscle CSA in group I increased significantly after 12 weeks (p = 0.015, 0.045, respectively). However, there were no significant differences in the mean changes of muscle strength, muscle mass and muscle CSA between the two groups (p = 0.16, 0.89, 0.84, respectively). CONCLUSION: In this study, we found no obvious effect of vitamin D supplementation on the changes in muscle strength, muscle mass and muscle CSA when compared to placebo. However, there were significant changes in muscle strength and muscle CSA from baseline in the vitamin D supplementation group.

Etelcalcetide, A Novel Calcimimetic, Prevents Vascular Calcification in A Rat Model of Renal Insufficiency with Secondary Hyperparathyroidism.

Etelcalcetide, a novel peptide agonist of the calcium-sensing receptor, prevents vascular calcification in a rat model of renal insufficiency with secondary hyperparathyroidism. Vascular calcification occurs frequently in patients with chronic kidney disease (CKD) and is a consequence of impaired mineral homeostasis and secondary hyperparathyroidism (SHPT). Etelcalcetide substantially lowers parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF23) levels in SHPT patients on hemodialysis. This study compared the effects of etelcalcetide and paricalcitol on vascular calcification in rats with adenine-induced CKD and SHPT. Uremia and SHPT were induced in male Wistar rats fed a diet supplemented with 0.75% adenine for 4 weeks. Rats were injected with vehicle, etelcalcetide, or paricalcitol for 4 weeks from the beginning of adenine diet. Rats fed an adenine-free diet were included as nonuremic controls. Similar reductions in plasma PTH and parathyroid chief cell proliferation were observed in both etelcalcetide- and paricalcitol-treated rats. Serum calcium and phosphorus were significantly lower in etelcalcetide-treated uremic rats and was unchanged in paricalcitol-treated rats. Both serum FGF23 and aortic calcium content were significantly lower in etelcalcetide-treated uremic rats compared with either vehicle- or paricalcitol-treated uremic rats. The degree of aortic calcium content for etelcalcetide-treated rats was similar to that in nonuremic controls and corroborated findings of lack of histologic aortic mineralization in those groups. In conclusion, etelcalcetide and paricalcitol similarly attenuated progression of SHPT in an adenine rat model of CKD. However, etelcalcetide differentially prevented vascular calcification, at least in part, due to reductions in serum FGF23, calcium, and phosphorus levels.

Daily supplementation with 15 µg vitamin D2 compared with vitamin D3 to increase wintertime 25-hydroxyvitamin D status in healthy South Asian and white European women: a 12-wk randomized, placebo-controlled food-fortification trial.

Background: There are conflicting views in the literature as to whether vitamin D2 and vitamin D3 are equally effective in increasing and maintaining serum concentrations of 25-hydroxyvitamin D [25(OH)D], particularly at lower doses of vitamin D.Objective: We aimed to investigate whether vitamin D2 or vitamin D3 fortified in juice or food, at a relatively low dose of 15 µg/d, was effective in increasing serum total 25(OH)D and to compare their respective efficacy in South Asian and white European women over the winter months within the setting of a large randomized controlled trial.Design: A randomized, double-blind, placebo-controlled food-fortification trial was conducted in healthy South Asian and white European women aged 20-64 y (n = 335; Surrey, United Kingdom) who consumed placebo, juice supplemented with 15 µg vitamin D2, biscuit supplemented with 15 µg vitamin D2, juice supplemented with 15 µg vitamin D3, or biscuit supplemented with 15 µg vitamin D3 daily for 12 wk. Serum 25(OH)D was measured by liquid chromatography-tandem mass spectrometry at baseline and at weeks 6 and 12 of the study.Results: Postintervention in the 2 ethnic groups combined, both the vitamin D3 biscuit and the vitamin D3 juice groups showed a significantly greater absolute incremental change (Δ) in total 25(OH)D when compared with the vitamin D2 biscuit group [Δ (95% CI): 15.3 nmol/L (7.4, 23.3 nmol/L) (P < 0.0003) and 16.0 nmol/L (8.0, 23.9 nmol/L) ( P < 0.0001)], the vitamin D2 juice group [Δ (95% CI): 16.3 nmol/L (8.4, 24.2 nmol/L) (P < 0.0001) and 16.9 nmol/L (9.0, 24.8 nmol/L) (P < 0.0001)], and the placebo group [Δ (95% CI): 42.3 nmol/L (34.4, 50.2 nmol/L) (P < 0.0001) and 42.9 nmol/L (35.0, 50.8 nmol/L) (P < 0.0002)].Conclusions: With the use of a daily dose of vitamin D relevant to public health recommendations (15 µg) and in vehicles relevant to food-fortification strategies, vitamin D3 was more effective than vitamin D2 in increasing serum 25(OH)D in the wintertime. Vitamin D3 may therefore be a preferential form to optimize vitamin D status within the general population. This trial was registered at www.controlled-trials.com as ISRCTN23421591.

Differential effects of vitamin D2 and D3 supplements on 25-hydroxyvitamin D level are dose, sex, and time dependent: a randomized controlled trial.

BACKGROUND: Vitamin D (D) supplements are indispensable for its world-wide deficiency. Controversy continues on ergocalciferol (D2) and cholecalciferol (D3) relative potency as well as on dosing-schedule and sex role in raising 25-hydroxy D (25(OH)D) level, the best indicator of D status. METHODS: We randomized 279 adults to daily D2, D3, D2/D3, or placebo; 2-weekly D2 or D3; or 4-weekly D2 or D3 (250,000 IU over/140 days). Randomization sequence, stratified by body-mass-index (BMI) and sex, was concealed from study coordinators and participants who were then blinded to capsules' content. D2, D3, 25(OH)D2, and 25(OH)D3 Serum levels were determined blindly on days 0,1,2,3,4,7,14, and 2-weekly thereafter by high performance liquid chromatography assay. The results of 269 participants were available for analysis. Primary endpoint was area-under-the-curve (AUC) of 25(OH)D (25(OH)D2 + 25(OH)D3) adjusted for sex, BMI, and baseline 25(OH)D level. RESULTS: Mean(SD) age was 33.0(8.5) year, 41% were males, and 85% completed follow-up. Baseline 25(OH)D level was 39.8(11.9) and increased by 3.3(11.6) and 28.6(16.3) nmol/L, in the placebo and active-treatment groups, respectively. AUC from day 0 to 140 (AUC140) of 25(OH)D was 40% (D3 daily) to 55% (D3 2-weekly) higher with active-treatment than placebo (p < 0.001). 25(OH)D2 AUC140 was higher in daily than 2-weekly (17%, p = 0.006) and 4-weekly (20%, p = 0.001) D2-treated groups. 25(OH)D3 AUC140 was lower in daily than 2-weekly (11%, p = 0.002) and 4-weekly D3-treated groups (10%, p = 0.008). In D2-treated groups, there was 16.4 nmol/L decrease in 25(OH)D3 level that correlated (p < 0.001) with 25(OH)D2 level increase (r = 0.48) and baseline 25(OH)D level (r = 0.58), in one participant with measurable baseline 25(OH)D2 level, D3 caused a similar decrease in 25(OH)D2 level, while in the D2/D3-treated group, 25(OH)D3 level didn't increase. Incremental AUC from day 0 to 7 (AUC7) of D3 and 25(OH)D3 in D3-treated groups were 118-243% higher and 31-39% lower, respectively, than incremental AUC7 of D2 and 25(OH)D2 in D2-treated groups. Incremental AUC7 of D3 and 25(OH)D3 in D3-treated groups and D2 and 25(OH)D2 in D2-treated groups were higher in females than males (55, 13, 64, and 28%, respectively). Baseline 25(OH)D level predicted response to D2 and D3 (p < 0.001), whereas, BMI was significant predictor only for early response to D2. CONCLUSIONS: Effects of D2 and D3 supplements on 25 (OH)D level may be dosing-schedule and sex-dependent. D2-associated reduction in 25(OH)D3 level may be related to total 25(OH)D level rather than being D2-specific. D2 may be 25-hydroxylated faster than D3. TRIAL REGISTRATION: ClinicalTrial.gov identifier: NCT01170494 (registered July 25, 2010).

Antiproliferative Effects of 1α-OH-vitD3 in Malignant Melanoma: Potential Therapeutic implications.

Early detection and surgery represent the mainstay of treatment for superficial melanoma, but for high risk lesions (Breslow's thickness >0.75 mm) an effective adjuvant therapy is lacking. Vitamin D insufficiency plays a relevant role in cancer biology. The biological effects of 1α hydroxycholecalciferol on experimental melanoma models were investigated. 105 melanoma patients were checked for 25-hydroxycholecalciferol (circulating vitamin D) serum levels. Human derived melanoma cell lines and in vivo xenografts were used for studying 1α-hydroxycholecalciferol-mediated biological effects on cell proliferation and tumor growth. 99 out of 105 (94%) melanoma patients had insufficient 25-hydroxycholecalciferol serum levels. Interestingly among the six with vitamin D in the normal range, five had a diagnosis of in situ/microinvasive melanoma. Treatment with 1α-hydroxycholecalciferol induced antiproliferative effects on melanoma cells in vitro and in vivo, modulating the expression of cell cycle key regulatory molecules. Cell cycle arrest in G1 or G2 phase was invariably observed in vitamin D treated melanoma cells. The antiproliferative activity induced by 1α-hydroxycholecalciferol in experimental melanoma models, together with the discovery of insufficient 25-hydroxycholecalciferol serum levels in melanoma patients, provide the rationale for using vitamin D in melanoma adjuvant therapy, alone or in association with other therapeutic options.

Effects of Vitamin D Supplementation on Muscle Strength in Athletes: A Systematic Review.

Chiang, C-m, Ismaeel, A, Griffis, RB, and Weems, S. Effects of vitamin D supplementation on muscle strength in athletes: A systematic review. J Strength Cond Res 31(2): 566-574, 2017-The purpose of this systematic review of the literature was to investigate the effects of vitamin D supplementation on muscle strength in athletes. A computerized literature search of 3 databases (PubMed, MEDLINE, and Scopus) was performed. Included in the review were randomized controlled trials (RCTs), published in English, which measured serum vitamin D concentrations and muscle strength in healthy, athletic participants aged 18-45 years. Quality was assessed using the PEDro scale. Five RCTs and 1 controlled trial were identified, and quality assessment showed 5 trials were of "excellent quality" and 1 was of "good quality." Trials lasted from 4 weeks to 6 months and dosages ranged from 600 to 5,000 International Units (IU) per day. Vitamin D2 was found to be ineffective at impacting muscle strength in both studies wherein it was administered. In contrast, vitamin D3 was shown to have a positive impact on muscle strength. In 2 studies, strength outcome measures were significantly improved after supplementation (p ≤ 0.05). In the other 2 studies administering vitamin D3, there were trends for improved muscle strength. Specifically, improvements in strength ranged from 1.37 to 18.75%. Additional studies are needed to confirm these associations.

The effect of vitamin D on renin-angiotensin system activation and blood pressure: a randomized control trial.

OBJECTIVE: Disruption of vitamin D signaling in rodents causes activation of the rennin-angiotensin system (RAS) and development of hypertension. Observational studies in humans found lower circulating 25-hydroxyvitamin D [25(OH)D] is associated with increased RAS activity and blood pressure (BP). We performed the first randomized control trial to investigate the effects of vitamin D supplementation on the RAS in humans. METHODS: Vitamin D deficient, [25(OH)D ≤20 ng/ml), overweight individuals without hypertension were randomized into a double-blind, placebo-controlled trial of 8-weeks treatment with ergocalciferol or placebo. Kidney-specific RAS activity, measured using renal plasma flow response to captopril in high sodium balance, was assessed at baseline and 8 weeks, as was systemic RAS activity and 24-h ambulatory BP. RESULTS: In total, 84 participants completed the study. Mean 25[OH]D levels increased from 14.7 to 30.3 ng/ml in the ergocalciferol group, P value < 0.0001, and from 14.3 to 17.4 ng/ml in the placebo group, P value = 0.3. The renal plasma flow response to captopril was 33.9 ±â€Š56.1 ml/min per 1.73 m at baseline and 35.7 ±â€Š47.7 ml/min per 1.73 m at 8 weeks in the ergocalciferol group (P value = 0.83); and was 37.3 ±â€Š46.9 ml/min per 1.73 m at baseline and 35.9 ±â€Š26.2 ml/min per 1.73 m at 8 weeks in the placebo group (P value = 0.78). Ergocalciferol had no effect on PRA, AngII, or 24-h BP measurements. CONCLUSIONS: This trial found no benefit from correcting vitamin D deficiency on RAS activity or BP after 8 weeks. These findings are not consistent with the hypothesis that vitamin D is a modifiable target for lowering BP in vitamin D deficient individuals.