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- Characterization of an animal model of pregnancy-induced vitamin D deficiency due to metabolic gene dysregulation. [JOURNAL ARTICLE]
- Am J Physiol Endocrinol Metab 2013 Dec 10.
Objective: Vitamin D deficiency has been associated with pregnancy complications, such as preeclampsia, gestational diabetes, and recurrent miscarriage. Therefore, we hypothesized differences in vitamin D status between healthy (Sprague-Dawley (SD), and Lewis (LW)) and complicated (Brown Norway (BN)) rat pregnancies. Approach and Results: In SD, LW and BN rats, we analyzed the maternal plasma levels of the vitamin D metabolites 25-OH-D and 1,25-(OH)2-D at pre-pregnancy, pregnancy, and postpartum. Analysis of the active metabolite, 1,25-(OH)2-D, showed a 2-fold increase in pregnant SD and LW rats, but a near 10-fold decrease in pregnant BN rats compared to non-pregnant controls. BN rats had a pregnancy-dependent upregulation of CYP24a1 expression, a key enzyme that inactivates vitamin D metabolites. In contrast, the maternal renal expression of CYP24a1 in SD and LW rats remained constant throughout pregnancy. Analysis of the vitamin D receptor (VDR) indicated that LW and SD, but not BN, rats experience a pregnancy-induced 10-fold decrease in maternal renal VDR protein levels. Further analysis of bisulfite-converted and genomic DNA indicated that the observed differences in maternal renal regulation of CYP24a1 during pregnancy and lactation are not due to differences in CYP24a1 promoter methylation or single-nucleotide polymorphisms. Lastly, supplementation with 1,25-(OH)2-D significantly improved the reproductive phenotype of BN rats by increasing litter size, and maternal-fetal weight outcomes. Conclusions: We conclude that BN rats represent a novel animal model of pregnancy-specific vitamin D deficiency linked to pregnancy complications. Vitamin D deficiency in BN rats correlates with maternal renal CYP24a1 upregulation followed by CYP27b1 upregulation.
- Human pharmacokinetic profile of 1,25-dihydroxyvitamin D3-glycoside of herbal origin. [JOURNAL ARTICLE]
- J Steroid Biochem Mol Biol 2013 Dec 6.
A natural form of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), the active metabolite of vitamin D, was identified in glycosylated form in Solanum glaucophyllum (SG). Solbone P, an extract of SG with high and homogenous content of glycosylated 1,25(OH)2D3, was chemically characterized and produced under GMP conditions. Three different doses of glycosylated 1,25(OH)2D3 were given as single oral dose to 16 healthy volunteers in a first-in-man trial. The oral pharmacokinetic properties of 1,25(OH)2D3 of SG origin were established and the subjects were monitored until day 28 for safety reasons. This included regular monitoring of vital signs, electrocardiogram (ECG) data, calcium, phosphate and creatinine values. Subjects were exposed to up to the equivalent of a 40-fold level of the recommended human daily dose for synthetic 1,25(OH)2D3 (0.5μg/subject/day) without experiencing any untoward effects. When compared with the historically established pharmacokinetics profile of synthetic 1,25(OH)2D3, glycosylated 1,25(OH)2D3 of herbal origin exhibited delayed absorption characteristics. The phenomenon is species independent, as similar pharmacokinetic patterns were observed in rats and chickens. This modified release pattern may be attributed to the glycosylation of herbal 1,25(OH)2D3 because de-glycosylation by ubiquitous intestinal enzymes prior to intestinal uptake of the unmodified 1,25(OH)2D3 is the rate-limiting step. The major relevance of this finding is that the human pharmacokinetic profile of glycosylated 1,25(OH)2D3 of herbal origin is reminiscent of a delayed release formulation of free 1,25(OH)2D3, resulting in a wider therapeutic window, a potentially longer therapeutic effectiveness, and thus, a better pharmacologic tolerance. This article is part of a Special Issue entitled '16th Vitamin D Workshop'.
- Hypercalcemia due to giant cell myocarditis: a case report. [Journal Article]
- Prog Transplant 2013 Dec; 23(4):365-7.
Granulomatous diseases are a rare cause of hypercalcemia. The pathogenesis is presumed to be from endogenous production of 1,25-dihydroxyvitamin D by activated macrophages in granulomatous lesions, which harbor the 1α-hydroxylase enzyme. Herein the first case of hypercalcemia associated with giant cell myocarditis, an unusual type of granulomatous process, is reported. In this case, a patient with giant cell myocarditis had development of progressive heart failure and cardiorenal syndrome that required biventricular support. One year later, hypercalcemia associated with a relatively high 1,25-vitamin D level and a concomitantly suppressed parathyroid hormone level developed in the presence of stage 4 chronic kidney disease. Her other workup of hypercalcemia was unrevealing for vitamin D intoxication and multiple myeloma. Computed tomography of her chest showed no signs of hilar lymphadenopathy. Her calcium levels returned to normal with low-dose steroid therapy and have remained normal following a successful heart transplant. This case illustrates an unusual cause of hypercalcemia thought to be due to extrarenal calcitriol production associated with giant cell myocarditis.
- Endoscopic comparison of alendronate alone and the enteric-coated alendronate with calcitriol combination in postmenopausal Korean females. [Journal Article]
- Korean J Intern Med 2013 Nov; 28(6):694-700.
This study was performed to compare the mucosal findings after esophagogastroduodenoscopy in two groups before and after the use of alendronate only and following administration of the enteric-coated alendronate (5 mg) and calcitriol (0.5 µg) combined drug (Maxmarvil, Yuyu Co.).The study population consisted of 33 postmenopausal healthy female volunteers, aged 50 to 70 years (mean age, 58 ± 5) without gastrointestinal symptoms and with normal baseline endoscopic findings. Esophagogastroduodenoscopy was performed at baseline and was repeated 2 weeks later after daily intake of Maxmarvil (n = 17 subjects) or alendronate only (n = 16 subjects). Mucosal injury scores were reported by an endoscopist after 2 weeks of treatment with each medication schedule.Esophageal mucosal injuries developed in two of 16 subjects in the alendronate only group and 0 of 17 in the Maxmarvil group. Gastric mucosal injuries developed in eight subjects in the alendronate group and four subjects in the Maxmarvil group; this difference was statistically significant.The mucosal damage scores for the alendronate group (total score 24) were significantly higher than those for the Maxmarvil group (total score 9) in the esophagus and stomach. Therefore, this study suggested that enteric-coated Maxmarvil is less harmful to gastrointestinal mucosa than alendronate, and may improve the tolerability of osteoporosis medication in clinical practice.
- Eldecalcitol replaces endogenous calcitriol but does not fully compensate for its action in vivo. [JOURNAL ARTICLE]
- J Steroid Biochem Mol Biol 2013 Nov 26.
Calcitriol (1α,25-dihydroxyvitamin D3, 1α,25(OH)2D3) is an essential hormone that works in cooperation with parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF-23) to regulate calcium and phosphorus homeostasis. Previous in vivo studies in rats have shown that eldecalcitol, a vitamin D analog, is more active than calcitriol in stimulating calcium and phosphorus absorption in the intestine and in increasing serum FGF-23, but is not as active in suppressing blood PTH. However, those results are problematic because administration of exogenous eldecalcitol or calcitriol affects the synthesis and degradation of endogenous calcitriol, and competes for binding to vitamin D receptor (VDR) in target tissues. Therefore, we tried to evaluate the 'true biological activity in vivo' of each compound by comparing their biological activities with respect to their blood concentrations. In VDR gene knockout mice, calcitriol and eldecalcitol did not affect either serum or urinary calcium levels, and also did not induce the expression of target genes. These results indicate that the actions of eldecalcitol are mediated by VDR. In normal rats, concentrations of both calcitriol and eldecalcitol in the blood increased dose-dependently and had a linear correlation with administered dosage. The concentration of calcitriol in the blood was reduced by eldecalcitol treatment, falling to below the limit of detection at 0.1μg/kg eldecalcitol. Based on the concentration of each compound in the blood, eldecalcitol had approximately 1/4 to 1/7 the activity of calcitriol to increase serum calcium, FGF-23, and urinary calcium excretion, and to suppress blood PTH. Eldecalcitol dose-dependently increased urinary phosphorus excretion and reduced serum phosphorus. However, calcitriol did not change serum phosphorus. In accordance with serum chemistry and hormones, a concentration of eldecalcitol in the blood of 3-8 times that of calcitriol was required to stimulate target gene expressions in the kidneys (VDR, TRPV5, and calbindin-D28k) and bone (VDR, FGF-23, and RANKL). On the other hand, the blood concentrations of eldecalcitol needed to stimulate target genes in the intestine (TRPV6, calbindin-D9k, and VDR) were comparable to those of calcitriol. These results indicate that oral administration of eldecalcitol stimulates target gene expression in the intestine similarly to calcitriol, but to a much lesser extent than calcitriol in the kidneys and bones. The major finding of the present study is that eldecalcitol suppresses endogenous calcitriol and replaces it. However, it may not fully compensate for the action of calcitriol in vivo. This article is part of a Special Issue entitled '16th Vitamin D Workshop'.
- Should vitamin d supplementation be a regular part of asthma care? [Journal Article]
- Otolaryngol Clin North Am 2014 Feb; 47(1):97-108.
Vitamin D (vitD3) deficiency occurs frequently and has profound effects on health, especially asthma. This article examines how current knowledge of vitD3 actions and the worldwide distribution of vitD3 deficiency influences everyday clinical allergy practice. Within the limits of current knowledge, the article concisely explains the molecular nature of vitD3 actions, reviews key vitD3 research as it applies to clinical care, answers questions about the potential clinical impact of low vitD3 levels, and discusses use and safety of vitD3 supplements.
- Compound Screening and Transcriptional Profiling in Human Primary Keratinocytes: A Brief Guideline. [JOURNAL ARTICLE]
- Methods Mol Biol 2013 Nov 27.
Cultured human primary keratinocytes constitute suitable targets for in-depth evaluation of the proliferative or differentiative potential of compounds. There is, however, a double-edged and intrinsically inseparable transition from biological activity to cytotoxicity for any agent under investigation. For that reason, we here first of all present an established protocol for the isolation, cultivation, and analysis of primary foreskin-derived keratinocytes. Taking calcitriol as example, we then reveal how a straightforward photometric cell culture assay can be exploited to assess overall cell viability in response to increasing compound doses. With predetermined cellular cytotoxicity at hand, physiologically meaningful (sub-toxic) compound concentrations for subsequent stimulation of cells can be readily selected, and, in doing so, differentially expressed genes with biological significance can be reliably identified.
- Pseudoarthrosis and fracture: interaction between severe vitamin D deficiency and primary hyperparathyroidism. [Journal Article]
- Singapore Med J 2013 Nov; 54(11):e224-7.
A young woman with severe vitamin D deficiency presented with proximal muscle weakness, fragility fracture and pseudoarthrosis. On evaluation, she was found to have hypercalcaemia, a single parathyroid adenoma and an undetectable 25-hydroxyvitamin D level. She received parenteral cholecalciferol and subsequently underwent curative parathyroidectomy. Postoperatively, she had hungry bone syndrome, which she gradually recovered from with calcium and calcitriol replacement. Notably, her calcium levels were in the lower limit of normal range and associated with elevated alkaline phosphatase levels at postoperative Day 14. Follow-up for the next four years showed that the patient had remarkable symptomatic and radiological improvements. In this report, we discuss the pathophysiological interactions between vitamin D deficiency and associated primary hyperparathyroidism.
- Calcitriol reduces the occurrence of acute cellular rejection of liver transplants: a prospective controlled study. [Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't]
- Pharmazie 2013 Oct; 68(10):821-6.
To investigate the acute cellular rejection rate of liver transplant recipients taking or not taking calcitriol in a prospective, randomized, controlled clinical study.Primary liver transplant patients were randomized to receive the placebo (arm A), calcium gluconate (arm B) or calcium gluconate plus calcitriol (arm C). The composition of circulating T cell subpopulations was determined by flow cytometry at baseline and one week post transplant. The primary endpoint was acute cellular rejection rate at one month post transplant.Seventy-five liver transplant recipients were eligible, including 25 patients each in arm A, B and arm C. The mean baseline serum 25-(OH) vitamin D content was 12.5 +/- 3.0 (range, 2.5 to 19.5) ng/mL, with no statistical difference among the three arms. Among 7 (9.33%) patients who developed definite acute cellular rejection (Banff score > or = 6), only 1 (4%, 1/25) were from arm C while 6 (12%, 6/50) of them were from either arm A or B. The acute cellular rejection rate was 20% (5/25) for arm C, 32% (8/25) for arm A and 28% (7/25) for arm B (arm C vs. arm A or B, P < 0.05). Flow cytometric analysis showed that the proportion of circulating CD4+ CD25(high) CD(127-)(Treg) cells in arm C increased by 63.22% at one week post transplant (3.95 +/- 4.0%) compared to baseline (2.42 +/- 2.35%) (P < 0.05). No significant difference was observed in arm A or B (P > 0.05 in both vs. baseline). Furthermore, no significant difference was noted among the three arms in the proportion of CD4(+)CD45RA(-)CD45RO(+), CD4(+)CD25(low)CD45RA(+) and CD4(+)CD25(low)CD45RA(-) T cells at one week post transplant compared to baseline.Calcitriol has apparent beneficial effect on acute cellular rejection of liver transplants, which may be associated with increases in the proportion of circulating Treg cells.
- Uric acid suppresses 1 alpha hydroxylase in vitro and in vivo. [Journal Article]
- Metabolism 2014 Jan; 63(1):150-60.
Patients with gout have lower calcitriol levels that improve when uric acid is lowered. The mechanism of these observations is unknown. We hypothesized that uric acid inhibits 1-αhydroxylase.In vivo, Sprague Dawley rats were randomized to control (n=5), allantoxanamide (n=8), febuxostat (n=5), or allantoxanamide+febuxostat (n=7). Vitamin D, PTH, and 1-αhydroxylase protein were evaluated. In order to directly evaluate the effect of uric acid on 1-αhydroxylase, we conducted a series of dose response and time course experiments in vitro. Nuclear factor κ-B (NFκB) was inhibited pharmacologically. Finally, to evaluate the potential implications of these findings in humans, the association between uric acid and PTH in humans was evaluated in a cross-sectional analysis of data from the NHANES (2003-2006); n=9773.1,25(OH)2D and 1-αhydroxylase protein were reduced in hyperuricemic rats and improved with febuxostat treatment. Uric acid suppressed 1-αhydroxylase protein and mRNA expression in proximal tubular cells. This was prevented by NFκB inhibition. In humans, for every 1mg/dL increase in uric acid, the adjusted odds ratio for an elevated PTH (>65pg/mL) was 1.21 (95% C.I. 1.14, 1.28; P<0.0001), 1.15 (95% C.I. 1.08, 1.22; P<0.0001), and 1.16 (95% C.I. 1.03, 1.31; P=0.02) for all subjects, subjects with estimated GFR ≥60, and subjects with estimated GFR <60mL/min/1.73m(2) respectively.Hyperuricemia suppresses 1-αhydroxylase leading to lower 1,25(OH)2D and higher PTH in rats. Our results suggest this is mediated by NFκB. The association between uric acid and PTH in NHANES suggests potential implications for human disease.