Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020437 (hypercalcemia)
 10,293 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The renin-angiotensin system (RAS) plays a central role in the pathogenesis of hypertension. Recently, we discovered that 1alpha,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] functions as a negative endocrine regulator of renin biosynthesis, which provides a molecular basis to explore the potential of Vitamin D analogs as renin inhibitors to control the RAS. To search for renin-inhibiting Vitamin D analogs, we screened 20 Vitamin D analog compounds using As4.1-hVDR cell (a juxtaglomerular cell line) culture by Northern blot and luciferase reporter assays. We found that the Gemini compounds, which have two side-chains at carbon-20 position, were particularly active in suppressing renin expression. Eight Gemini compounds were identified that were equally or 10- to 100-times more potent than 1,25(OH)(2)D(3) in renin inhibition. These Gemini compounds also potently stimulate 25-hydroxyvitamin D 24-hydroxylase expression in As4.1-hVDR cells. Administration of compound RO-27-5646 [1,25-dihydroxy-21-(3-methyl-3-hydroxy-butyl)-19-nor-cholecalciferol] in mice caused a marked reduction in renal renin mRNA expression without invoking severe hypercalcemia as seen in 1,25(OH)(2)D(3) treatment. These data establish in principle that Vitamin D analogs can indeed inhibit renin expression in vitro and in vivo, and support the notion that low calcemic Vitamin D analogs can potentially be used as therapeutic agents to control the RAS.
J Steroid Biochem Mol Biol 2005 Jun
PMID:Analogs of 1alpha,25-dihydroxyvitamin D(3) as novel inhibitors of renin biosynthesis. 1587 26

The CASR, a cell surface glycoprotein expressed in parathyroid gland and kidney, is critical for maintaining extracellular calcium homeostasis. The inherited disorders, familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT), are caused by inactivating mutations in the CASR gene. The CASR has an N-terminal, 19 amino acid signal peptide that is predicted to direct the nascent polypeptide chain, as it emerges from the ribosome, into the endoplasmic reticulum (ER). Here, we report the functional characterization of three CASR mutations identified in hypercalcemic/hyperparathyroid patients. The mutations, L11S, L13P and T14A, lie within the signal peptide hydrophobic core. When transiently transfected into kidney cells, L11S and L13P mutants demonstrated reduced intracellular and plasma membrane expression and signaling to the mitogen-activated protein kinase pathway in response to extracellular calcium relative to wild-type CASR and the T14A mutant. All mutant CASR RNAs translated into protein normally. In cotranslational processing assays, which test the functionality of the signal peptide in the early secretory pathway, the wild-type CASR and mutant T14A nascent polypeptides were targeted to microsomal vesicles, representing the ER, translocated into the vesicular lumen and underwent core N-glycosylation. In contrast, the L11S and L13P mutants failed to be inserted in the microsomes and undergo glycosylation. This is the first study examining the function of the CASR signal sequence and reveals that both L11S and L13P mutants are markedly impaired with respect to cotranslational processing, accounting for the observed parathyroid dysfunction.
Hum Mol Genet 2005 Jun 15
PMID:Impaired cotranslational processing of the calcium-sensing receptor due to signal peptide missense mutations in familial hypocalciuric hypercalcemia. 1587 34

Effective chemotherapy for pancreatic cancer is urgently needed. The aim of this study was to compare the anti-proliferative activity on pancreatic cancer cell lines of the vitamin D(3) analog, 22-oxa-1,25-dihydroxyvitamin D(3), maxacalcitol, with that of 1,25-dihydroxyvitamin D(3), calcitriol, with analysis of vitamin D receptor status and the G(1)-phase cell cycle-regulating factors. Antiproliferative effects of both agents were compared using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method and by measuring the tumor size of xenografts inoculated into athymic mice. Scatchard analysis of vitamin D receptor contents, and mutational analysis of receptor complementary DNA were performed. Levels of expression of cyclins, cyclin-dependent kinases and cyclin-dependent kinase inhibitors, p21 and p27, were analysed by western blotting. In vitro, maxacalcitol and calcitriol markedly inhibited the proliferation and caused a G(1) phase cell cycle arrest with the appearance of numerous domes. In vivo, maxacalcitol inhibited the growth of BxPC-3 xenografts more significantly than calcitriol, without inducing hypercalcemia. Responsive cells had abundant functional vitamin D receptors. However, Hs 766T, showing no response to either agent, had the second highest receptor contents with no abnormalities in its primary structure deduced by receptor complementary DNA. In the responsive cells, p21 and p27 were markedly up-regulated after 24h of treatment with both agents. In non-responsive cells, no such changes were observed. In conclusion, maxacalcitol and calcitriol up-regulate p21 and p27 as an early event, which in turn could block the G(1)/S transition and induce growth inhibition in responsive cells, and maxacalcitol may provide a more useful tool for the chemotherapy of pancreatic cancer than calcitriol because of its low toxicity.
J Steroid Biochem Mol Biol 2005 Oct
PMID:Inhibitory effect of 22-oxa-1,25-dihydroxyvitamin D3, maxacalcitol, on the proliferation of pancreatic cancer cell lines. 1603 15

Prostate cancer metastasizes almost exclusively into the bone whereby it induces primarily an osteoblastic response. Non-calcemic vitamin D analogs have been shown to inhibit proliferation of prostate cancer cells in culture and inhibit their growth as subcutaneous xenografts in mice. However, their effect on prostate cancer cell growth in the bone has not been examined. In the present study, we inoculated the osteoblastic prostate cancer cell line MDA-PCa 2b into the bone of male SCID mice and examined the effect of the low-calcemic hybrid analog 1alpha-hydroxymethyl-16-ene-26,27-bishomo-25-hydroxy vitamin D(3) (JK-1626-2) on their ability to induce bone lesions. We found that 7 weeks after inoculation of MDA-PCa 2b cells, 90% of the mice in the vehicle-treated group had significant bone lesions that were detectable by micro-computed tomography and characterized by thickening of the cortical bone and ossification of the epiphysis. Only 30% of the mice in the analog-treated group (daily injections of 4microg/kg, 5 days/week for up to 7 weeks) had detectable bone lesions. Histological examination of the decalcified tumor-bearing bones has shown that tumor cells completely replaced the bone marrow in the diaphysis, and destroyed the trabecular bone in the metaphysis in 90% of the vehicle-treated mice. In contrast, the metaphysis of 60% of analog-treated mice appeared normal, although tumor cells were still found in the diaphysis of 70% of the bones in the analog-treated group. There was no evidence of hypercalcemia in any of the analog-treated mice. In a co-culture, MDA-PCa 2b cells induced a profound mitogenic response in osteoblasts followed by enhanced differentiation. However, in the presence of the analog the mitogenic response of the osteoblasts to the malignant cells was significantly attenuated. These experiments led to the hypothesis that, in vivo, JK-1626-2 prevented the metastatic bone lesions by inhibiting the mitogenic response of osteoblasts to growth factors produced by MDA-PCa 2b cells.
J Steroid Biochem Mol Biol 2005 Oct
PMID:Inhibition of prostate cancer-meditated osteoblastic bone lesions by the low-calcemic analog 1alpha-hydroxymethyl-16-ene-26,27-bishomo-25-hydroxy vitamin D3. 1608 Dec 81

The non-classical effects of 1,25(OH)(2)D(3) create possible therapeutic applications for immune modulation (e.g. auto-immune diseases and graft rejection), inhibition of cell proliferation (e.g. psoriasis, cancer) and induction of cell differentiation (e.g. cancer). The major drawback related to the use of 1,25(OH)(2)D(3) is its calcemic effect, which prevents the application of pharmacological concentrations. Several analogs are now available that show modest to good selectivity with regard to specific effects (e.g. anticancer or immune effects or bone anabolism versus hypercalcemia) when tested in appropriate in vivo models. The molecular basis for this selectivity is only partially understood and probably a variable mixture of mechanisms.
J Steroid Biochem Mol Biol 2005 Oct
PMID:Mechanisms for the selective action of Vitamin D analogs. 1611 85

1Alpha,25-dihydroxyvitamin D3 [1alpha,25-(OH)2D3; calcitriol] is best known as a hormone involved in calcium homeostasis but is also a potent antiproliferative agent in many cell types, particularly epithelial cells. 1Alpha,25(OH)2D3 mediates its actions through a classic steroid hormone-like transcriptional mechanism by influencing the expression of hundreds of genes. Effects of 1alpha,25(OH)2D3 have been observed on expression of cell cycle regulators, growth factors and their receptors, apoptotic machinery, metastatic potential, and angiogenesis; all of which have some effect on hyperproliferative conditions. This minireview focuses on the anticancer potential of 1alpha,25(OH)2D3 and its analogues by summarizing the promising data from animal and human trials of 1alpha,25(OH)2D3 and some of the more interesting synthetic vitamin D analogues in the treatment of a variety of different animal cancer models and in human patients with advanced cancer. Optimal administration of vitamin D analogues is only just being achieved with high-dose intermittent administration overcoming bioavailability and hypercalcemia problems and combination therapy with cytotoxic agents (taxols and cisplatins), antiresorptive agents (bisphosphonates), or cytochrome P450 inhibitors being attempted. Although the potential of vitamin D as an antiproliferative drug has been realized in the treatment of psoriasis and in parathyroid cell hyperplasia associated with secondary hyperparathyroidism, the search for an anticancer treatment incorporating a vitamin D analogue remains elusive.
Mol Cancer Ther 2006 Apr
PMID:Promise of vitamin D analogues in the treatment of hyperproliferative conditions. 1664 49

Calcium-sensing receptor (CASR), expressed in parathyroid gland and kidney, is a critical regulator of extracellular calcium homeostasis. This G protein-coupled receptor exists at the plasma membrane as a homodimer, although it is unclear at which point in the biosynthetic pathway dimerization occurs. To address this issue, we have analyzed wild-type and mutant CASRs harboring R66H, R66C or N583X-inactivating mutations identified in familial hypocalciuric hypercalcemia/neonatal severe hyperparathyroid patients, which were transiently expressed in kidney cells. All mutants were deficient in cell signaling responses to extracellular CASR ligands relative to wild-type. All mutants, although as well expressed as wild-type, lacked mature glycosylation, indicating impaired trafficking from the endoplasmic reticulum (ER). Dimerized forms of wild-type, R66H and R66C mutants were present, but not of the N583X mutant. By immunofluorescence confocal microscopy of non-permeabilized cells, although cell surface expression was observed for the wild-type, little or none was seen for the mutants. In permeabilized cells, perinuclear staining was observed for both wild-type and mutants. By colocalization fluorescence confocal microscopy, the mutant CASRs were localized within the ER but not within the Golgi apparatus. By the use of photobleaching fluorescence resonance energy transfer microscopy, it was demonstrated that the wild-type, R66H and R66C mutants were dimerized in the ER, whereas the N583X mutant was not. Hence, constitutive CASR dimerization occurs in the ER and is likely to be necessary, but is not sufficient, for exit of the receptor from the ER and trafficking to the cell surface.
Hum Mol Genet 2006 Jul 15
PMID:Calcium-sensing receptor dimerizes in the endoplasmic reticulum: biochemical and biophysical characterization of CASR mutants retained intracellularly. 1674 May 94

Hyperparathyroidism (HPT) can be associated with muscle atrophy and weakness. Muscle atrophy is typically caused by increased muscle protein breakdown. The influence of HPT on calpains and the ubiquitin-proteasome pathway, which are important regulators of muscle proteolysis, is not yet known. We examined the expression in skeletal muscle of mu- and m-calpain and the ubiquitin ligases, atrogin-1 and MuRF1, in patients with primary HPT. A biopsy was obtained from the sternohyoid muscle in patients undergoing surgery for primary HPT (n=8) and in normocalcemic control patients undergoing thyroid surgery (n=11). mRNA levels for atrogin-1, MuRF1 and the calcium-regulated proteases, mu- and m-calpain, were determined by real-time PCR. Calpain activity was measured using the calpain-specific substrate, BODIPY-FL-casein, and by zymography. Serum calcium was 11.4+/-0.46 and 9.5+/-0.10 mg/dl in HPT and control patients, respectively (p<0.01). The corresponding phosphate levels were 2.7+/-0.2 and 3.6+/-0.1 mg/dl (p<0.05). Parathyroid hormone serum concentration was 286+/-103 pg/ml (range, 77-946 pg/ml) in patients with HPT and was not measured in control patients. There were no significant differences in mRNA levels for atrogin-1, MuRF1, mu- or m-calpain and in calpain activity between HPT and control patients. The results suggest that the ubiquitin-proteasome and calpain systems are not activated in skeletal muscle in patients with primary HPT, at least not in patients with moderate hypercalcemia.
Int J Mol Med 2006 Sep
PMID:The gene expression and activity of calpains and the muscle wasting-associated ubiquitin ligases, atrogin-1 and MuRF1, are not altered in patients with primary hyperparathyroidism. 1686 32

Germline knockout of the extracellular Ca2+ -sensing receptor (CaR) leads to a phenotype that includes severe hypercalcemia, hyperparathyroidism, relative hypocalciuria, skeletal abnormalities, retarded growth, and early postnatal death. To investigate the role of heterotrimeric G proteins in CaR signaling, we used cre/lox technology to delete the respective alpha-subunits of Gq and G11 selectively in parathyroid cells. Mice that were PTH-Cre(+/-); Gnaq(flox/flox); Gna11(-/-) (PTH-Galphaq/Galpha11 -double knockouts) were viable, but showed all the features of germline knockout of the CaR except hypocalcuria. Our results demonstrate the critical role of both Gq and G11 in mediating inhibition of PTH secretion by extracellular Ca2+.
Mol Endocrinol 2007 Jan
PMID:Parathyroid-specific double knockout of Gq and G11 alpha-subunits leads to a phenotype resembling germline knockout of the extracellular Ca2+ -sensing receptor. 1698

Although approximately half of patients undergoing hemodialysis receive activated forms of Vitamin D, the primary reason to initiate this therapy has rested solely on the management of secondary hyperparathyroidism. Secondary hyperparathyroidism is likely one of several consequences of Vitamin D deficiency, and only now have other consequences of Vitamin D deficiency emerged. Although previously viewed as a contributor to hypercalcemia and hyperphosphatemia, recent studies suggest Vitamin D may improve cardiovascular structure and function, improve vascular compliance, and reduce pro-inflammatory cytokines, all of which may contribute to the improved survival observed in retrospective studies examining the outcome of patients treated with activated Vitamin D compared to those who were not. The current review examines two recent large-scale studies of hemodialysis patients: one that demonstrated a survival advantage of paricalcitol over calcitriol, and a second that demonstrated a significant survival advantage of any intravenous Vitamin D formulation versus none. In both studies, the findings were independent of mineral and parathyroid hormone levels, suggesting "non-traditional" actions of Vitamin D contributed to the observed survival advantage. Potential steps moving forward in light of these observational studies are subsequently discussed.
J Steroid Biochem Mol Biol 2007 Mar
PMID:Vitamin D in patients with renal failure: a summary of observational mortality studies and steps moving forward. 1719 69


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