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- Progesterone Enhances Calcitriol Antitumor Activity by Upregulating Vitamin D Receptor Expression and Promoting Apoptosis in Endometrial Cancer Cells. [JOURNAL ARTICLE]
- Cancer Prev Res (Phila) 2013 May 16.
Human studies suggest that progesterone and calcitriol may prove beneficial in preventing or inhibiting oncogenesis, but the underlying mechanism is not fully understood. The current study investigates the effects of progesterone, calcitriol and their combination on immortalized human endometrial epithelial cells and endometrial cancer cells and identifies their targets of action. Combination treatment with both agents enhanced vitamin D receptor expression and inhibited cell proliferation through caspase-3 activation and induction of G0/G1 cell cycle arrest with associated down-regulation of cyclins D1 and D3 and p27 induction. We used mass spectrometry-based proteomics to measure protein abundance differences between calcitriol-, progesterone-, or combination-exposed endometrial cells. A total of 117 proteins showed differential expression amongst these three treatments. Four proteins were then selected for validation studies: histone H1.4 (HIST1H1E), histidine triad nucleotide-binding protein 2 (HINT2), interferon-induced, double-stranded RNA-activated protein kinase (EIF2AK2), and Bcl-2-associated X protein (BAX). Abundance levels of selected candidates were low in endometrial cancer cell lines versus the immortalized endometrial epithelial cell line. All four proteins displayed elevated expression in cancer cells upon exposure to calcitriol, progesterone or the combination. Further BAX analysis through gain or loss of function experiments revealed that upregulation of BAX decreased cell proliferation by changing the BAX:BCL-2 ratio. Knock down of BAX attenuated progesterone- and calcitriol-induced cell growth inhibition. Our results showed that progesterone and calcitriol up-regulate the expression of BAX along with other apoptosis-related proteins, which induce inhibition of endometrial cancer cell growth by apoptosis and cell cycle arrest.
- Improved dosage form of the combined alendronate and calcitriol (Maxmarvil(®)) on the absorption of alendronate in Korean postmenopausal women. [JOURNAL ARTICLE]
- Arch Pharm Res 2013 May 17.
Alendronate is one of the most potent anti-osteoporotic agents for postmenopausal osteoporosis. However, high doses of alendronate cause esophageal irritation, myalgia, gastrointestinal discomfort and decrease of serum calcium level. Recently, Maxmarvil(®) was developed as an enteric-coated tablet containing alendronate (5 mg) and calcitriol (0.5 μg) to minimize these side effects of alendronate. In the present study, we evaluated the pharmacokinetic profile and examined the incidence of unfavorable effects after oral administration of Maxmarvil(®) in Korean healthy postmenopausal women without a previous history of fracture. In the in vitro dissolution test, alendronate was not released from Maxmarvil(®) in pH 1.2 phosphate buffer solution but released in pH 6.0 and 6.8 phosphate buffer solutions and completely dissolved in 30 min. After oral administration of Maxmarvil(®), three out of 18 (16.7 %) women showed mild adverse effects; two myalgia and one upper gastrointestinal discomfort without heartburn. Most of these complaints disappeared during the study without additional treatment. The peak (U max) and the average (U ave) urinary excretion rate of alendronate and the time to reach U max (T max) were 2.94 μg/h, 0.901 μg/h and 6.77 h, respectively. The total cumulative urinary excretion of alendronate (Ae0-24 h) was 21.6 μg (0.432 % of oral alendornate), which was similar to the reported values. Taken together, enteric-coated Maxmarvil(®) is less harmful for the esophagus and gastrointestinal mucosa, shows the same pharmacokinetic profile to conventional alendronate (70 mg) and improves the tolerability of medication in clinical practice.
- Correction of hypocalcemia allows optimal recruitment of FGF-23-dependent phosphaturic mechanisms in acute hyperphosphatemia post-phosphate enema. [JOURNAL ARTICLE]
- J Bone Miner Metab 2013 May 16.
Both parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) are phosphaturic hormones. These hormones should increase in response to phosphate excess. However, they also regulate serum calcium; PTH increases serum calcium concentration and FGF23 suppresses renal production of calcitriol, favoring hypocalcemia. We report the case of an 83-year-old woman with hyperphosphatemia and hypocalcemia resulting from phosphate-containing enemas. PTH and calcitriol increased in response to hypocalcemia, and FGF23 increased in response to hyperphosphatemia. Unexpectedly, peak FGF23 did not coincide with peak serum phosphate. Rather, peak FG23 was observed only after severe hypocalcemia was partially corrected with exogenous calcium administration, even though serum phosphate had been already decreasing for 32 h. Correction of severe hypocalcemia was thus associated with peak FGF23 values and with a precipitous decrease in PTH. Peak FGF23 was followed by an accelerated decrease in serum phosphate and significant phosphaturia. This clinical report is consistent with experimental data in rats showing a blunted FGF23 response to high phosphate in the presence of severe hypocalcemia. Thus, complementary experimental and clinical data suggest that partial correction of severe hypocalcemia is required for optimal FGF23-mediated phosphaturia, which takes place despite correction of PTH levels. We believe this the first human report suggesting blunting of the FGF23 response to high phosphate by severe hypocalcemia.
- Reciprocal regulation of calcium-/phosphate-regulating hormones in cyclists during the Giro d'Italia 3-week stage race. [JOURNAL ARTICLE]
- Scand J Med Sci Sports 2013 May 7.
Calcium and phosphate are essential for cell functions, and their serum concentrations result from the balance between intestinal absorption, bony storage, and urinary excretion. Fibroblast growth factor 23 (FGF23), expressed by osteocytes and osteoblasts, acts in the kidney, leading to hypophosphatemia and low 1,25-dihydroxycholecalciferol synthesis, but suppresses parathyroid function. The aim of this study was to explore the effects of a high-energy demanding cycling race on this bone-kidney-parathyroid axis. We studied nine cyclists during the 2011 Giro d'Italia stage race. Pre-analytical and analytical phases followed academic and anti-doping recommendations. Serum parathyroid hormone (PTH), 25(OH)D, total calcium, inorganic phosphorus, and plasma FGF23 were measured on days -1, 12, and 22 and corrected for changes in plasma volume. Dietary calcium and phosphorus, anthropometric parameters (height, weight, and body mass index) and indexes of metabolic effort (net energy expenditure, power output) were recorded. Dietary calcium and phosphorus intakes were kept at the same levels throughout the race. Twenty-five (OH)D, PTH, and calcium concentrations remained stable. FGF23 increased 50% with a positive correlation with the indexes of metabolic effort and, consequently, phosphorous decreased, although only in the first half. The strong metabolic effort acts on the bone-kidney-parathyroid system, and the rise in FGF23 plasma concentration might be aimed at maintaining calcium and phosphorus homeostasis.
- Effect of acute and chronic vitamin D administration on systemic renin angiotensin system in essential hypertensives and controls. [Journal Article]
- J Endocrinol Invest 2013 Apr; 36(4):216-20.
To investigate the systemic renin-angiotensin system (RAS) in essential hypertensives (EH) and controls (C) after short- and long-term vitamin D receptor activation.Ten consecutive EH (under controlled low-salt diet) and 10 C underwent calcitriol administration (0.25 μg bid) for 1 week (Group A). Eighteen consecutive EH under angiotensin II receptor antagonist therapy received a single oral dose of 300,000 IU of cholecalciferol and were followed up for 8 weeks (Group B).In basal conditions and at the end of the study (1 week in Group A and 8 weeks in Group B), plasma renin activity (PRA), plasma active renin, aldosterone, and angiotensin II were evaluated, as well as blood pressure, plasma 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH)2D], and PTH.In Group A, plasma 25(OH)D levels in EH and C were below the normal range, although lower levels were found in the former. No association between basal plasma 25(OH)D or 1,25(OH)2D levels and blood pressure values or RAS components was observed either in the whole group or in the two subgroups. Calcitriol administration did not affect any RAS parameter either in EH or in C. In Group B, cholecalciferol significantly increased 25(OH)D and 1,25(OH)2D levels without interfering with the angiotensin II receptor antagonist-induced increase in RAS components. No correlation was found between plasma 25(OH)D or 1,25(OH)2D levels and blood pressure values or RAS parameters before and after cholecalciferol administration.The present data suggest that, in our experimental conditions, vitamin D receptor activation is unable to influence systemic RAS activity.
- Mass spectrometry based proteomics identifies UPF1 as a critical gene expression regulator in Mono Mac 6 cells. [JOURNAL ARTICLE]
- J Proteome Res 2013 May 3.
5-Lipoxygenase (5-LO) catalyzes the two initial steps in the biosynthesis of leukotrienes, a group of inflammatory lipid mediators derived from arachidonic acid. Recently, we have demonstrated that 5-LO mRNA expression is regulated by alternative splicing and nonsense-mediated mRNA decay (NMD). In addition to this, 5-LO protein expression was reduced on translational level in UPF1 knockdown cells, suggesting that UPF1 has a positive influence on 5-LO translation. Therefore, a mass spectrometry based proteomics study was performed to identify compartment specific protein expression changes upon UPF1 knockdown in differentiated and undifferentiated MM6 cells. The proteomics analysis revealed that the knockdown of UPF1 results in numerous protein changes in the microsomal fraction (~ 21%) but not in the cytosolic fraction (< 1%). The results suggest that UPF1 is a critical gene expression regulator in a compartment specific way. During differentiation by TGFβ and calcitriol the majority of UPF1 regulated proteins were adjusted to normal level. This indicates that the translational regulation by UPF1 can potentially be cell differentiation dependent.
- Oral supplementation with Calcitriol, Calcidiol, Vitamin D 3 or moderate Sun Exposure? [JOURNAL ARTICLE]
- J Invest Dermatol 2013 May 2.
- Effects of Pamidronate and Calcitriol on the Set Point of the Parathyroid Gland in Postmenopausal Hemodialysis Patients with Secondary Hyperparathyroidism. [JOURNAL ARTICLE]
- Nephron Clin Pract 2013 Apr 25; 122(3-4):93-101.
Background/Aims:Secondary hyperparathyroidism may worsen after the administration of pamidronate in postmenopausal hemodialysis (HD) patients. The aim of this study was to evaluate the short-term effect of coadministration of calcitriol and pamidronate on dynamic parathyroid hormone (PTH) secretion.
Methods:Fifteen postmenopausal women undergoing regular HD with serum intact PTH levels of >200 pg/ml were enrolled. The PTH-ionized calcium (iCa) curve was evaluated by the response to hypo- and hypercalcemia induced with 1 and 4 mEq/l of dialysate calcium, respectively. Parameters were compared after pamidronate was administered and after coadministration of pamidronate and calcitriol. Changes in serum levels of maximal serum PTH (PTHmax), basal PTH (PTHbase) and minimal PTH (PTHmin) were evaluated.
Results:Pamidronate therapy resulted in a decrease in predialysis basal plasma iCa (p < 0.05) and an increase in PTHmax (p < 0.01), PTHbase (p < 0.01) and PTHmin (p < 0.01). The change in serum iCa and PTH was reversed after the coadministration of calcitriol and pamidronate.
Conclusion:Our study demonstrated that pamidronate therapy is associated with a reduced plasma iCa and increased PTH secretion. These adverse effects may be reversed by calcitriol. These findings suggest that in considering pamidronate treatment in postmenopausal patients with osteoporosis receiving HD, it might be safer to add calcitriol to prevent the increased PTH secretion.
- Calcitriol Imparts Neuroprotection In Vitro to Midbrain Dopaminergic Neurons by Upregulating GDNF Expression. [Journal Article]
- PLoS One 2013; 8(4):e62040.
During development a tightly controlled signaling cascade dictates the differentiation, maturation and survival of developing neurons. Understanding this signaling mechanism is important for developing therapies for neurodegenerative illnesses. In previous work we have sought to understand the complex signaling pathways responsible for the development of midbrain dopamine neurons using a proteomic approach. One protein we have identified as being expressed in developing midbrain tissue is the vitamin D receptor. Therefore we investigated the effect of the biologically active vitamin D3 metabolite, calcitriol, on primary fetal ventral mesencephalic cultures of dopamine neurons. We observed a dose responsive increase in numbers of rat primary dopamine neurons when calcitriol was added to culture media. Western blot data showed that calcitriol upregulated the expression of glial derived neurotrophic factor (GDNF). Blocking GDNF signaling could prevent calcitriol's ability to increase numbers of dopamine neurons. An apoptosis assay and cell birth dating experiment revealed that calcitriol increases the number of dopamine neurons through neuroprotection and not increased differentiation. This could have implications for future neuroprotective PD therapies.
- Calcitriol supplementation effects on Ki67 expression and transcriptional profile of breast cancer specimens from post-menopausal patients. [JOURNAL ARTICLE]
- Clin Nutr 2013 Apr 9.