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 relationship between plasma levels of 15-keto-13, 14-dihydroprostaglandin E2 (15K-H2-PGE2) and serum calcium levels was studied in nontumor-bearing rabbits and in rabbits bearing the VX2 carcinoma intramuscularly and intra-abdominally. The plasma levels of 15K-H2-PGE2 in the two groups of tumor-bearing animals did not vary significantly but was several fold greater than in nontumor-bearing rabbits. Rabbits bearing the VS2 carcinoma intramuscularly developed hypercalcemia between the second and third week after implantation of neoplastic tissue and remained hypercalcemic until they expired. The serum calcium levels in rabbits bearing the VX2 carcinoma intra-abdominally did not vary significantly from those of nontumor-bearing rabbits. The differences in the serum calcium levels in rabbits bearing the VX2 carcinoma at intramuscular and intra-abdominal implant sites may be related to different extents of metabolism by the lung and by the liver of prostaglandin E2 or other cyclooxygense of polyenoic fatty acids produced by the tumor.
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PMID:The site of VX2 tumor transplantation affects the development of hypercalcemia in rabbits. 738 59

We present two patients with subcutaneous fat necroses (SCFN) in whom endocrinologic studies revealed an association with elevated prostaglandin E (PGE) levels. A boy born after prolonged labor complicated by meconium aspiration developed erythematous, indurated plaques over the back, arms, buttocks, and cheeks at 4 days of age. A biopsy specimen of involved skin showed panniculitis with foci of necrotic adipocytes containing radially arranged, needle-shaped clefts and a granulomatous infiltrate in the septae. Laboratory studies revealed hypercalcemia of 13.6 mg/dl (normal 8.8-10.1 mg/dl), elevated 1.25-1.25(OH)2D3, and increased urinary excretion of PGE2. The child was hospitalized and treated with systemic steroids and diuretics, with resolution of SCFN and hypercalcemia. The second patient was a girl born with cyanotic heart disease. A diagnosis of Ebstein anomaly was made, and intravenous PGE1 was started to keep patent the ductus arteriosus. Four days later erythematous, indurated plaques were noted on the knee, back, and anterior chest. A skin biopsy specimen revealed SCFN. There was no associated laboratory abnormality. On discontinuing PGE1, no new lesions formed and the existing panniculitis resolved. These two cases demonstrate the association between SCFN and elevated PGE levels (endogenous in patient 1, exogenous in patient 2). No previous reports of SCFN after the administration of PGE1 have appeared in the literature.
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PMID:Subcutaneous fat necrosis, hypercalcemia, and prostaglandin E. 779 19

Human T-cell leukemia virus type I (HTLV-I) is the etiologic agent of adult T-cell leukemia (ATL), and hypercalcemia frequently associated with ATL is mediated by parathyroid hormone-related peptide (PTHRP). The present study was undertaken to clarify the role of cAMP second messenger system in the regulation of human PTHRP gene expression in ATL cells, using an HTLV-I-infected T-cell line, MT-2. Forskolin and dibutyryl cAMP (Bt2cAMP) caused a marked and transient increase in the steady-state level of PTHRP mRNA. The effects of these agents were dose-dependent, and the maximal effects were observed at 3 h. Nuclear runoff transcription assay showed that forskolin and Bt2cAMP caused an increase in the transcription rate of the human PTHRP gene. In contrast, the stability of PTHRP mRNA was only modestly increased by these agents. Forskolin and Bt2cAMP also increased the secretion of PTHRP by MT-2 cells, as determined by both a newly established immunoradiometric assay using two antibodies against human PTHRP-(1-34) and PTHRP-(50-83) and a radioimmunoassay using an antibody against human PTHRP-(109-141). Prostaglandin E1 (PGE1) caused a marked stimulation of intracellular cAMP production in MT-2 cells, whereas PGE2 and PGF2 alpha had only modest effects. The ability of these PGs to stimulate cAMP production correlated well with their ability to increase PTHRP mRNA level and the secretion of PTHRP. Indomethacin did not affect the basal level of cAMP production or PTHRP mRNA, suggesting that endogenous PG was not involved in the basal production of cAMP or PTHRP. When PGE1 was given to MT-2 cells together with interleukin 2, which is another stimulator of PTHRP gene expression, PTHRP secretion was synergistically stimulated. These results suggest that the transcription of the human PTHRP gene is enhanced through a cAMP-dependent pathway by PGE1 and that PGE1, as well as interleukin 2, plays an important role in the overexpression of the human PTHRP gene in HTLV-I-infected T cells leading to the development of hypercalcemia in ATL patients.
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PMID:Transcription of the gene for parathyroid hormone-related peptide from the human is activated through a cAMP-dependent pathway by prostaglandin E1 in HTLV-I-infected T cells. 838 Apr 5

The hypothesis that endogenous PGE2 mediates defective thick ascending limb (TAL) Cl reabsorption (percent delivered load: FRCl%) in rats with vitamin D-induced chronic hypercalcemia (HC) was tested by measuring FRCl% in loop segments microperfused in vivo in HC and control rats treated acutely with indomethacin (Indo) or its vehicle, and obtaining the corresponding outer medullary [PGE2]. Microperfusion conditions were developed in which FRCl% was exclusively furosemide sensitive. To determine the cellular mechanism, tubules were perfused acutely with forskolin (FSK), cAMP, or the protein kinase C inhibitor staurosporine (SSP). Outer medullary [PGE2] in HC rats was 9 to 10 times greater than control and could be normalized by Indo. FRCl% was 20% lower in HC rats infused with vehicle, and Indo, FSK, and cAMP returned FRCl% to normal despite sustained HC. Indo or FSK had no effect on FRCl% in control rats and Indo did not prevent inhibition of FRCl% by luminal PGE2 (1 microM). Luminal SSP (10(-7), 10(-8) M) in HC did not return FRCl% to control values. We conclude that impaired TAL FRCl% in HC occurs at a pre-cAMP site and is due to endogenous PGE2 and not to HC.
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PMID:Endogenous prostaglandin E2 mediates inhibition of rat thick ascending limb Cl reabsorption in chronic hypercalcemia. 839 Apr 79

In chronic hypercalcemia, inhibition of thick ascending limb sodium chloride reabsorption is mediated by elevated intrarenal PGE2. The mechanisms and source of elevated PGE2 in hypercalcemia are not known. We determined the effect of hypercalcemia on intrarenal expression of cytosolic phospholipase A2 (cPLA2), prostaglandin H synthase-1 (PGHS-1), and prostaglandin H synthase-2 (PGHS-2), enzymes important in prostaglandin production. In rats fed dihydrotachysterol to induce hypercalcemia, Western blot analysis revealed significant upregulation of both cPLA2 and PGHS-2 in the kidney cortex and the inner and outer medulla. Immunofluorescence localized intrarenal cPLA2 and PGHS-2 to interstitial cells of the inner and outer medulla, and to macula densa and cortical thick ascending limbs in both control and hypercalcemic rats. Hypercalcemia had no effect on intrarenal expression of PGHS-1. To determine if AT1 angiotensin II receptor activation was involved in the stimulation of cPLA2 and PGHS-2 in hypercalcemia, we treated rats with the AT1 receptor antagonist, losartan. Losartan abolished the polydipsia associated with hypercalcemia, prevented the increase in cPLA2 protein in all regions of the kidney, and diminished PGHS-2 expression in the inner medulla. In addition, losartan completely prevented the increase in urinary PGE2 excretion in hypercalcemic rats. Intrarenal levels of angiotensin II were unchanged in hypercalcemia. These data indicate that hypercalcemia stimulates intrarenal cPLA2 and PGHS-2 protein expression. Our results further support a role for angiotensin II, acting on AT1 receptors, in mediating this stimulation.
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PMID:Hypercalcemia stimulates expression of intrarenal phospholipase A2 and prostaglandin H synthase-2 in rats. Role of angiotensin II AT1 receptors. 932 57

Cachexia consists of a constellation of metabolic changes that occur in cancer patients, including the reduction of muscle and fat tissue, asthenia, anorexia, hypoglycemia and hypercalcemia. These syndromes complicate therapeutic intervention and decrease the quality of life of the patient. This review discusses the involvement of cytokines in cancer cachexia and describes the contribution of IL-6 and other cytokines to the wasting of C-26-bearing mice. The neutralization of IL-6 by antibody, or IL-6 receptor antagonism by suramin, significantly reduce the severity of key parameters of cachexia. The participation of several other factors (PGE2, IL-1, IL-10 and TNF-alpha) in the cellular communication between the C-26 tumor cell and tumor-infiltrating macrophages is also described.
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PMID:Inhibition of experimental cancer cachexia by anti-cytokine and anti-cytokine-receptor therapy. 938 67

We examined the effect on osteoclast formation of disrupting the prostaglandin G/H synthase genes PGHS-1 and-2. Prostaglandin E(2) (PGE(2)) production was significantly reduced in marrow cultures from mice lacking PGHS-2 (PGHS-2(-/-)) compared with wild-type (PGHS-2(+/+)) cultures. Osteoclast formation, whether stimulated by 1,25-dihydroxyvitamin D(3) (1,25-D) or by parathyroid hormone (PTH), was reduced by 60-70% in PGHS-2(-/-) cultures relative to wild-type cultures, an effect that could be reversed by providing exogenous PGE(2). Cultures from heterozygous mice showed an intermediate response. PGHS inhibitors caused a similar drop in osteoclast formation in wild-type cultures. Co-culture experiments showed that supporting osteoblasts, rather than osteoclast precursors, accounted for the blunted response to 1,25-D and PTH. This lack of response appeared to result from reduced expression of RANK ligand (RANKL) in osteoblasts. We cultured spleen cells with exogenous RANKL and found that osteoclast formation was 50% lower in PGHS-2(-/-) than in wild-type cultures, apparently because the former cells expressed high levels of GM-CSF. Injection of PTH above the calvaria caused hypercalcemia in wild-type but not PGHS-2(-/-) mice. Histological examination of bone from 5-week-old PGHS-2(-/-) mice revealed no abnormalities. Mice lacking PGHS-1 were similar to wild-type mice in all of these parameters. These data suggest that PGHS-2 is not necessary for wild-type bone development but plays a critical role in bone resorption stimulated by 1,25-D and PTH.
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PMID:Prostaglandin G/H synthase-2 is required for maximal formation of osteoclast-like cells in culture. 1072 51

Anti-bone resorption properties of the Korean herbal formulation, Honghwain (HHI; Carthamus tinctorius L. seed) was biochemically investigated. On processing bone metabolism, PGE2 accelerated production of IL-1beta in fetal mouse osteoblast and stimulated physiological activation substance, IL-1beta. The novel class of Src tyrosine kinase inhibitors, Herbimycin A (HERB) and HHI reduced COX-2 mRNA levels as well as PGE2 production induced by IL-1beta, TNF-alpha and IL-6. HHI inhibited in vitro and in vivo bone resorption by inhibition of phosphorylation of peptide substrates. HHI dose-dependently reduced the hypercalcemia induced in mice by IL-1beta and partly prevented bone loss and microarchitectural changes in young ovariectomized rats, showing that the protective effect on bone was exerted via the inhibition of bone resorption. These results indicate that the synergy between IL-beta, TNF-alpha, IL-6 on PGE2 production is due to an enhanced gene expression of COX-2 and that tyrosine kinase (s) are involved in the signal transduction of COX-2 in mouse calvarial osteoblasts. Thus, HHI as a possible Src family kinase inhibitor may be useful for the treatment of diseases associated with elevated bone loss.
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PMID:Inhibitory effect of Carthamus tinctorius L. seed extracts on bone resorption mediated by tyrosine kinase, COX-2 (cyclooxygenase) and PG (prostaglandin) E2. 1206 2

To reduce lithium-induced nephrogenic diabetes insipidus (lithium-NDI), patients with bipolar disorder are treated with thiazide and amiloride, which are thought to induce antidiuresis by a compensatory increase in prourine uptake in proximal tubules. However, thiazides induced antidiuresis and alkalinized the urine in lithium-NDI mice lacking the sodium-chloride cotransporter, suggesting that inhibition of carbonic anhydrases (CAs) confers the beneficial thiazide effect. Therefore, we tested the effect of the CA-specific blocker acetazolamide in lithium-NDI. In collecting duct (mpkCCD) cells, acetazolamide reduced the cellular lithium content and attenuated lithium-induced downregulation of aquaporin-2 through a mechanism different from that of amiloride. Treatment of lithium-NDI mice with acetazolamide or thiazide/amiloride induced similar antidiuresis and increased urine osmolality and aquaporin-2 abundance. Thiazide/amiloride-treated mice showed hyponatremia, hyperkalemia, hypercalcemia, metabolic acidosis, and increased serum lithium concentrations, adverse effects previously observed in patients but not in acetazolamide-treated mice in this study. Furthermore, acetazolamide treatment reduced inulin clearance and cortical expression of sodium/hydrogen exchanger 3 and attenuated the increased expression of urinary PGE2 observed in lithium-NDI mice. These results show that the antidiuresis with acetazolamide was partially caused by a tubular-glomerular feedback response and reduced GFR. The tubular-glomerular feedback response and/or direct effect on collecting duct principal or intercalated cells may underlie the reduced urinary PGE2 levels with acetazolamide, thereby contributing to the attenuation of lithium-NDI. In conclusion, CA activity contributes to lithium-NDI development, and acetazolamide attenuates lithium-NDI development in mice similar to thiazide/amiloride but with fewer adverse effects.
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PMID:Acetazolamide Attenuates Lithium-Induced Nephrogenic Diabetes Insipidus. 2671 28


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