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At least 433 records · Page 24Linked to original sources
PubMed2007

VDR-mediated gene expression patterns in resting human coronary artery smooth muscle cells.

Vitamin D analogs such as paricalcitol and calcitriol that activate the vitamin D receptor (VDR) provide survival benefit for Stage 5 chronic kidney disease (CKD) patients, possibly associated with a decrease in cardiovascular (CV)-related incidents. Phenotypic changes of smooth muscle cells play an important role in CV disease. The role of vitamin D analogs in modulating gene expression in smooth muscle cells is still not well understood. In this study, DNA microarray analysis of approximately 22,000 different human genes was used to characterize the VDR-mediated gene expression profile in human coronary artery smooth muscle cells (CASMC) at rest. Cells in serum free medium were treated with 0.1 microM calcitriol (1alpha,25-dihydroxyvitamin D(3)) or paricalcitol (19-nor-1alpha,25-(OH)(2)D(2)) for 30 h. A total of 181 target genes were identified, with 103 genes upregulated and 78 downregulated (>two fold changes in either drug treatment group with P < 0.01). No significant difference was observed between calcitriol and paricalcitol. Target genes fell into various categories with the top five in cellular process, cell communication, signal transduction, development, and morphogenesis. Twenty-two selected genes linked to the CV system were also impacted. Real-time RT-PCR and/or Western blotting analysis were employed to confirm the expression patterns of selected genes such as 25-hydroxyvitamin D-24-hydroxylase, Wilms' tumor gene 1, transforming growth factorbeta3, plasminogen activator inhibitor-1, thrombospondin-1 (THBS1), and thrombomodulin (TM). This study provides insight into understanding the role of VDR in regulating gene expression in resting smooth muscle cells.

Blotting, Western↗
PubMed1983

Calcium uptake by isolated rat intestinal cells.

Intestinal cells were isolated by a combination of mechanical and enzymatic means, and their calcium uptake was assayed by a rapid filtration procedure. Calcium uptake was a time- and concentration-dependent process that was markedly elevated at 25 and 37 degrees C, as compared to 0 degree C. Cells isolated from rat duodenum exhibited higher uptakes than cells from jejunum, which in turn took up more calcium than cells from the ileum. Duodenal cells from vitamin D-deficient animals took up less calcium than cells from vitamin D-replete cells. In vivo vitamin D repletion with 1,25-dihydroxyvitamin D3 raised calcium uptake by duodenal cells from treated animals toward that of cells from replete rats. Furthermore, calcium uptake by duodenal cells from vitamin D-deficient animals approximated that of ileal cells from replete rats. These findings with isolated cells parallel prior findings of tissue calcium transport and suggest that cellular calcium uptake may be related to the saturable component of intestinal calcium absorption. Isolated intestinal cells may therefore constitute one experimental model for the study of transcellular calcium transport.

Animals↗
PubMed2006

Alendronate and vitamin D2 for prevention of hip fracture in Parkinson's disease: a randomized controlled trial.

Incidence of a fracture, particularly in the hip joint, is high in elderly women with Parkinson's disease (PD), and this is due to the immobilization-induced bone resorption and vitamin D deficiency with reduced bone mineral density (BMD). The objective of this study was to address the possibility that treatment with alendronate and vitamin D2 may reduce the incidence of hip fractures in elderly women with PD. PD patients were randomly assigned to daily treatment with 5 mg alendronate (n = 144) or a placebo combined with 1,000 IU of vitamin D2 (n = 144) and followed for 2 years. Incidence of hip fractures in the two patient groups during the 2-year follow-up period was studied. At baseline, both groups of patients had low BMD with high levels of serum-ionized calcium and urinary deoxypyridinoline (D-Pyr). Hip fractures occurred in 14 patients in the placebo group and 4 in the alendronate group. The relative risk for hip fractures in the alendronate group as compared with the placebo group was 0.29 (95% CI, 0.10-0.85). The number of hip fracture per 1,000 patient-years was 14 and 49 for the alendronate and placebo groups, respectively. In the alendronate group, serum calcium and urinary D-Pyr levels decreased significantly during the follow-up period, while the levels in the placebo group were increased. BMD increased by 3.1% in the alendronate group and decreased by 2.8% in the placebo group (P < 0.01). Treatment with alendronate and vitamin D2 increases BMD in elderly women with PD and leads to the prevention of hip fractures.

Aged↗
PubMed2003

Growth inhibition and differentiation in human prostate carcinoma cells induced by the vitamin D analog 1alpha,24-dihydroxyvitamin D2.

BACKGROUND: Vitamin D has been suggested as a chemopreventive and therapeutic modality for prostate cancer. However, hypercalcemic toxicity has limited the use of 1alpha,25-dihydroxyvitamin D(3) (1,25-(OH)(2)D(3)) in clinical trials, prompting the search for analogs of vitamin D with less toxicity while retaining efficacy as a modality for cancer intervention. In this study, the less hypercalcemic vitamin D analog 1alpha,24-dihydroxyvitamin D(2) (1,24-(OH)(2)D(2)) was examined for its effects on cellular growth inhibition and differentiation induction in the LNCaP human prostate carcinoma cell line. METHODS: LNCaP cell growth was determined by quantifying DNA levels. Protein levels were determined using the ELISA method and immunoblotting. Levels of mRNA were determined using real-time quantitative reverse transcriptase PCR. RESULTS: LNCaP growth was decreased 50% by exposure to 0.01 nM 1,24-(OH)(2)D(2) after 96 hr in the presence of a growth stimulatory 0.1 nM dose of the androgen R1881. Prostate specific antigen (PSA) levels were increased 3.5-fold with 10 nM 1,24-(OH)(2)D(2) treatment compared to a 1.9-fold increase in PSA levels found with 10 nM 1,25-(OH)(2)D(3) under low androgen conditions. Neither 1,24-(OH)(2)D(2) nor 1,25-(OH)(2)D(3) affected the expression of cytokeratin 18 protein levels. Treatment with 10 nM 1,24-(OH)(2)D(2) alone produced a 1.3-fold increase in AR mRNA and a 2.2-fold increase in AR protein levels after 96 hr. Surprisingly, the addition of 1.0 nM R1881 alone or in combination with 10 nM 1,24-(OH)(2)D(2) produced an approximately 60% decrease in AR mRNA, whereas AR protein levels were increased 1.6-fold. CONCLUSIONS: Overall, 1,24-(OH)(2)D(2) was found to be at least as effective as 1,25-(OH)(2)D(3) at inhibiting growth and inducing differentiation markers in LNCaP prostate carcinoma cells and may thus prove useful in prostate cancer treatment.

Blotting, Western↗
PubMed1999

Physiological significance of C-28 hydroxylation in the metabolism of 1alpha,25-dihydroxyvitamin D(2).

In our previous study, we indicated for the first time that C-28 hydroxylation plays a significant role in the metabolism of 1alpha, 25-dihydroxyvitamin D(2) [1alpha,25(OH)(2)D(2)] by identifying 1alpha,24(S),25,28-tetrahydroxyvitamin D(2) [1alpha,24(S),25, 28(OH)(4)D(2)] as a major renal metabolite of 1alpha,25(OH)(2)D(2) [G. S. Reddy and K-Y. Tserng Biochemistry 25, 5328-5336, 1986]. The present study was performed to establish the physiological significance of C-28 hydroxylation in the metabolism of 1alpha, 25(OH)(2)D(2). We perfused rat kidneys in vitro with 1alpha, 25(OH)(2)[26,27-(3)H]D(2) (5 x 10(-10)M) and demonstrated that 1alpha,24(R),25-trihydroxyvitamin D(2) [1alpha,24(R),25(OH)(3)D(2)] and 1alpha,24(S),25,28(OH)(4)D(2) are the only two major physiological metabolites of 1alpha,25(OH)(2)D(2). In the same perfusion experiments, we also noted that there is no conversion of 1alpha,25(OH)(2)D(2) into 1alpha,25,28-trihydroxyvitamin D(2 )[1alpha,25,28(OH)(3)D(2)]. Moreover, 1alpha,24(S),25,28(OH)(4)D(2) is not formed in the perfused rat kidney when synthetic 1alpha,25, 28(OH)(3)D(2) is used as the starting substrate. This finding indicates that C-28 hydroxylation of 1alpha,25(OH)(2)D(2) occurs only after 1alpha,25(OH)(2)D(2) is hydroxylated at C-24 position. At present the enzyme responsible for the C-28 hydroxylation of 1alpha, 24(R),25(OH)(3)D(2) in rat kidney is not known. Recently, it was found that 1alpha,25(OH)(2)D(3)-24-hydroxylase (CYP24) can hydroxylate carbons 23, 24, and 26 of various vitamin D(3) compounds. Thus, it may be speculated that CYP24 may also be responsible for the C-28 hydroxylation of 1alpha,24(R),25(OH)(3)D(2) to form 1alpha, 24(S),25,28(OH)(4)D(2). The biological activity of 1alpha,24(S),25, 28(OH)(4)D(2), determined by its ability to induce intestinal calcium transport and bone calcium resorption in the rat, was found to be almost negligible. Also, 1alpha,24(S),25,28(OH)(4)D(2) exhibited very low binding affinity toward bovine thymus vitamin D receptor. These studies firmly establish that C-28 hydroxylation is an important enzymatic reaction involved in the inactivation of 1alpha,25(OH)(2)D(2) in kidney under physiological conditions.

Animals↗
PubMed2001

In vitro metabolism of 19-nor-1alpha, 25-(OH)2D2 in cultured cell lines: inducible synthesis of lipid- and water-soluble metabolites.

The active vitamin D analog, 19-nor-1alpha,25-dihydroxyvitamin D2 (19-nor-1alpha,25-(OH)2D2), has a similar structure to the natural vitamin D hormone, 1a,25-dihydroxyvitamin D3 (1alpha,25-(OH)2D3), but lacks the C10-19 methylene group and possesses an ergosterol/ vitamin D2 rather than a cholesterol/vitamin D3 side chain. We have used this analog to investigate whether any of these structural features has any effect upon the type and rate of in vitro metabolism observed. Using a vitamin D-target cell, the human keratinocyte, HPK1A-ras, we observed formation of a number of metabolites, three of which were purified by extensive HPLC and conclusively identified by a combination of GC-MS and chemical derivatization as 19-nor-1alpha,24,25-(OH) 3D2, 19-nor-1alpha,24,25,26-(OH) 4D2, and 19-nor-1alpha,24,25,28-(OH)4,D2. The first metabolite is probably a product of the vitamin D-inducible cytochrome P450, P450cc24 (CYP24), while the latter two metabolites are likely to be further metabolic products of 19-nor-1alpha,24,25-(OH)3D2. These hydroxylated metabolites resemble those identified by other workers as products of the metabolism of 1alpha,25-(OH)2D2 in the perfused rat kidney. It therefore appears from the similar metabolic fate of 19-nor-1alpha,25-(OH)2D2 and 1alpha,25-(OH)2D2 that the lack of the C10-19 methylene group has little effect upon the nature of the lipid-soluble metabolic products and the rate of formation of these products seems to be comparable to that of products of 1alpha,25-(OH)2D3 in vitamin D-target cells. We also found extensive metabolism of 19-nor-1alpha,25(OH)2D2 to water-soluble metabolites in HPK1A-ras, metabolites which remain unidentified at this time. When we incubated 19-nor-1alpha,25-(OH)2D2 with the liver cell line HepG2, we obtained only 19-nor-1alpha,24,25-(OH)3D2. We conclude that 19-nor-1alpha,25-(OH)2D2 is efficiently metabolized by both vitamin D-target cells and liver cells.

Carcinoma, Hepatocellular↗
PubMed2001

Calcitroic acid is a major catabolic metabolite in the metabolism of 1 alpha-dihydroxyvitamin D(2).

Calcitroic acid (1 alpha-hydroxy-23 carboxy-24,25,26,27-tetranorvitamin D(3)) is known to be the major water-soluble metabolite produced during the deactivation of 1 alpha,25-dihydroxyvitamin D(3). This deactivation process involves a series of oxidation reactions at C(24) and C(23) leading to side-chain cleavage and, ultimately, formation of the calcitroic acid. Like 1 alpha,25-dihydroxyvitamin D(3), 1 alpha,25-dihydroxyvitamin D(2) is also known to undergo side-chain oxidation; however, to date there has been no evidence suggesting that 1 alpha,25-dihydroxyvitamin D(2) undergoes side-chain cleavage. To investigate this possibility, we studied 1 alpha,25-dihydroxyvitamin D(2) metabolism in HPK1A-ras cells as well as the well characterized perfused rat kidney system. Lipid and aqueous-soluble metabolites were prepared for characterization. Aqueous-soluble metabolites were subjected to reverse-phase HPLC analysis. The major aqueous-soluble metabolite from both the kidney and cell incubations comigrated with authentic calcitroic acid on two reverse-phase HPLC columns of different chemistry. The putative calcitroic acid from the cell and kidney incubations was methylated and found to comigrate with methylated authentic standard on straight-phase and reverse-phase HPLC columns. The identity of the methylated metabolite from cell incubations was also confirmed by mass spectral analysis. These data show, for the first time, that calcitroic acid is a major terminal product for the deactivation of 1 alpha,25-dihydroxyvitamin D(2). Intermediates leading to the formation of the calcitroic acid in the 1 alpha,25-dihydroxyvitamin D(2) metabolism pathway are currently being studied.

Animals↗
PubMed1998

Calcium dobesilate increases endothelium-dependent relaxation in endothelium-injured rabbit aorta.

Calcium dobesilate (DOBE) is an orally administered angioprotective agent which is used in some vascular diseases such as diabetic retinopathy, although its mechanism of action is not yet fully understood. The aim of this work was to correlate previous rising single quote, left (low)in vitro' findings carried out in our laboratory with an rising single quote, left (low)ex vivo' model of endothelium-injury by overdose of vitamin D2. Male New Zealand White rabbits were used. The study was divided into two protocols. Protocol 1: 10 days of treatment; and Protocol 2: 30 days of treatment. Rabbits in each group were treated with vitamin D2 (200"000 IU day-1) for the first 2 days and two groups were subsequently treated with DOBE at different doses (50 mg kg-1 per day or 500 mg kg-1 per day). The concentration-response curve induced by NA (10(-8)-10(-4) M) in aorta arteries was shifted downwards in the groups treated with DOBE (in both Protocol 1 and 2), whereas only in Protocol 2 (30 days of treatment) was this curve affected in the hypervitaminic group. The endothelium-dependent relaxation induced by ACh (10(-8)-10(-5) M) decreased in the hypervitaminic groups (in both Protocol 1 and 2) but only in Protocol 2 (30 days of treatment) was the endothelium-dependent relaxation restored to normal (control, untreated group) in both DOBE-treated groups. The endothelium-independent relaxation induced by sodium nitroprusside (SNP) (10(-8)-10(-4) M) decreased in the hypervitaminic groups only in Protocol 1. We did not find differences in the DOBE-treated groups in any protocol compared with the control (untreated) group. These findings show evidence that DOBE restored endothelial functionality in endothelium-injured rabbit aorta only after 30 days of treatment. (c) 1998 The Italian Pharmacological Society.

Acetylcholine↗
PubMed1984

Metabolic bone disease associated with total parenteral nutrition.

Patients receiving long-term treatment with total parenteral nutrition often develop bony abnormalities characterized by patchy osteomalacia and low bone turnover. The patients present evidence of physiologic hypoparathyroidism, although low levels of iPTH cannot entirely explain the osteomalacia. Abnormally low serum levels of 1,25(OH)2-vitamin D have been demonstrated, but the significance of these reduced levels in the pathogenesis of the bone lesions is not defined. Aluminum has been detected in large quantities in the plasma, urine, and bone of some patients treated with TPN, and there is mounting evidence that aluminum may be associated with skeletal pathology, particularly osteomalacia. There is, however, no clear documentation that aluminum accumulation produces the skeletal lesions observed, although it could be a contributing factor. There has been the unusual empiric observation that the removal of vitamin D2 from the infusate is associated with a decrease in the quantity of unmineralized osteoid in TPN patients. A possible role of vitamin D2 in producing osteomalacia is not easy to understand since normal serum levels of 25(OH)-D2, the circulating form of vitamin D2, have been reported. The long-term consequences of intravenous nutritional support for many aspects of metabolism remain unknown. Administration into the systemic circulation of predetermined quantities of calcium and phosphorus via a route that bypasses their passage across the intestinal mucosa, the portal system and the liver may have adverse consequences. It is possible that bypassing homeostatic mechanisms may affect bone formation and metabolism or lead to alterations in vitamin D sterols. Alternatively, a deficiency of an essential trace metal or the accumulation of a toxic trace substance could be responsible for the bony abnormalities. Much remains to be clarified concerning calcium homeostasis and bone disease during total parenteral nutrition. Among various possible factors, it seems likely that the significance of the low levels of 1,25(OH)2-vitamin D and of the accumulation of aluminum in this condition will soon be clarified.

Adult↗