Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: CAS:7440-70-2 (calcium)
 333,191 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The isolated perfused rat kidney was used to study the effects of parathyroid hormone-related protein (PTHrP) on renal cyclic AMP (cAMP) and electrolyte excretion. A perfusate of PTHrP(1-34) increased cAMP excretion from 0.14 +/- 0.09 (S.E.M.) nmol/l glomerular filtrate (GF) in controls to 24.67 +/- 5.14 (P less than 0.01) and decreased calcium excretion from 0.278 +/- 0.033 to 0.162 +/- 0.011 mumol/l GF (P less than 0.01). Human PTH(1-34) (0.7 nmol/l) caused no significant change in calcium excretion, whilst the rise in cAMP excretion was similar to that with PTHrP. PTHrP(1-34) (7 nmol/l) further increased cAMP production to 366.7 +/- 100.8 nmol/l GF (P less than 0.01), higher than the rise with hPTH(1-34) (7 nmol/l) which was 76.7 +/- 46.8 (P less than 0.05). With the higher concentrations of both peptides (7 nmol/l), calcium excretion was further reduced to 0.090 +/- 0.009 mumol/l GF (P less than 0.01), whilst phosphate excretion increased with both PTHrP and PTH. PTHrP (7 nmol/l) caused a fall in urinary pH compared with controls (P less than 0.05). At low and high concentrations of both hormones, urinary pH was lower with PTHrP than hPTH (P less than 0.01). Thus PTHrP, like PTH, acts on the kidney to increase cAMP and phosphate excretion and reduce calcium excretion, but PTHrP may be more effective. Disparate effects on urinary pH could be reflected in the clinical features of humoral hypercalcaemia of malignancy.
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PMID:Actions of synthetic parathyroid hormone-related protein(1-34) on the isolated rat kidney. 253 69

To elucidate the mechanism of humoral hypercalcemia elicited by human esophageal carcinoma cells (EC-GI), which constitutively produced interleukin-1 alpha (IL-1 alpha) and PTH-like factor, the effects of IL-1 alpha and PTH-related protein (PTH-rP) on bone resorption in vitro and on serum calcium concentrations in vivo were investigated. Nude mice transplanted with EC-GI cells invariably developed hypercalcemia, although their urinary cAMP excretion remained within the normal range. IL-1 alpha or PTH-rP-(1-34) stimulated 45Ca release from prelabeled fetal mouse forearm bones in a concentration-dependent manner, and when combined, IL-1 alpha and PTH-rP-(1-34) synergistically stimulated bone resorption in vitro. Injection of PTH-rP-(1-34) into mice three times a day for 2 days increased the serum calcium concentration in a dose-dependent manner. Continuous infusion of IL-1 alpha occasionally increased the serum calcium concentration. Simultaneous administration of IL-1 alpha at rates of 1-2.7 micrograms/day and PTH-rP-(1-34) at doses of 15-30 micrograms/day synergistically increased the serum calcium concentration in vivo. These findings suggest that PTH-rP and IL-1 alpha produced by the tumor cells were synergistically responsible for the humoral hypercalcemia observed in both the original patient and the tumor-bearing nude mice, and that at least two bone-resorbing factors [PTH-rP and another nonadenylate cyclase-stimulating bone-resorbing factor(s)] are active in patients with malignancy-associated hypercalcemia, in whom nephrogenous cAMP excretion is neither increased nor decreased.
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PMID:Parathyroid hormone-related protein and interleukin-1 alpha synergistically stimulate bone resorption in vitro and increase the serum calcium concentration in mice in vivo. 253 70

Induction of osteoclast-like multinucleated cells (MNCs) by various fragments of PTH-related protein (PTHrP) was examined in mouse marrow cultures. Osteoclast-like MNCs were defined as tartrate-resistant acid phosphatase (TRACP)-positive MNCs with calcitonin receptors. In all experimental protocols examined, PTHrP-(1-34) induced TRACP-positive MNCs at almost the same rate as PTH-(1-34). PTHrP-(1-29) was less potent than PTHrP-(1-34). PTHrP-(1-25) and PTHrP-(1-14) had no effect. PTHrP-(1-34) was more potent than PTH-(1-34) in increasing the accumulation of cAMP, but the former appeared to lose its activity more rapidly than the latter. Isobutylmethylxanthine increased the effect of PTHrP-(1-34) and PTH-(1-34) in inducing TRACP-positive MNCs. Furthermore, the calcium ionophore A23187 significantly increased the formation of TRACP-positive MNCs. The effect of PTH-(1-34) and PTHrP-(1-34) in inducing TRACP-positive MNCs was potentiated by adding A23187 but suppressed by adding verapamil simultaneously. The inhibition by verapamil was overcome by adding A23187. [Nle8,18,Tyr34]PTH-(3-34)amide inhibited the effect of not only PTH-(1-34) but also PTHrP-(1-34) in inducing both the accumulation of cAMP and the TRACP-positive MNC formation. These results show that PTHrP is a potent stimulator of osteoclast-like MNC formation to almost the same extent as PTH. It increases the number of osteoclast-like MNCs by a mechanism involving cAMP and calcium ions, and is most likely mediated through the same receptor. The controversial results of the bone-resorbing activity of PTH and PTHrP reported so far may be explained by the differences in the relative potencies of the respective hormones in increasing the intracellular cAMP and calcium ions and by the shorter half-life of PTHrP in culture medium.
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PMID:Parathyroid hormone (PTH)-related protein is a potent stimulator of osteoclast-like multinucleated cell formation to the same extent as PTH in mouse marrow cultures. 254 1

Peptides containing residues 1-34 of parathyroid hormone-related protein (PTHrP) and of bovine parathyroid hormone (bPTH), and recombinant full-length PTHrP(1-141) were infused i.v. into anaesthetized thyroparathyroidectomized rats to compare their action and potency on the renal handling of calcium, phosphate and cyclic AMP (cAMP) in vivo. All three peptides decreased the excretion of calcium and increased the excretion of phosphate and cAMP in the urine, with PTHrP(1-34) and PTHrP(1-141) having virtually equipotent effects. Thus the essential requirements for the major physiological activity of PTHrP on the kidney are contained within the 34 amino-terminal amino acids. For all three peptides, the lowest infusion rate that increased phosphate and cAMP excretion was 0.01 nmol/kg per h, whereas the lowest infusion rate that decreased calcium excretion was 0.025 nmol/kg per h for the PTHrP peptides and 0.1 nmol/kg per h for bPTH(1-34). The response to the PTHrP peptides was maximal at an infusion rate of 0.1 nmol/kg per h for both calcium and phosphate. Since the kidney is either equally sensitive to PTHrP and bPTH(1-34), or more sensitive to PTHrP than to bPTH(1-34), the hypercalcaemia of humoral hypercalcaemia of malignancy may develop because uncontrolled secretion of PTHrP increases the renal reabsorption of calcium to such an extent that even a modest increase in the inflow of calcium into the blood raises plasma calcium concentration.
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PMID:Actions of parathyroid hormone-related protein on the rat kidney in vivo. 254 49

Expression of a parathyroid hormone-like protein (PLP), which is associated with hypercalcemia in malignancy, has recently been localized to normal lactating mammary tissue. We examined the possibility of an extramammary role of PLP by measuring its levels in serum and milk of lactating women. The levels of PLP by radioimmunoassay in serum of lactating and nonlactating women were indistinguishable [4.2 +/- 1.8 and 3.6 +/- 1.0 pg equivalents (eq) of PLP-(1-34) amide per ml, respectively]. As PLP was undetectable in some serum samples, this result does not exclude the possibility that lactation results in a small increase in serum levels of PLP. In contrast, high concentrations of immunoreactive PLP [40,000-75,000 pg eq of PLP-(1-34) amide per ml] and correspondingly high concentrations of bioactive PLP were found in human, rat, and bovine milk. A variety of processed bovine milk products had a PLP content similar to that of fresh bovine milk, whereas infant formulas had lower concentrations, ranging down to undetectable. Although the physiological role of PLP in lactation is unknown, the data establish the presence of PLP in milk and suggest the possibility that PLP may be important in neonatal calcium homeostasis.
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PMID:High levels of a parathyroid hormone-like protein in milk. 255 Sep 32

A protein responsible for the biochemical syndrome similar to primary hyperparathyroidism associated with certain tumors has been recently characterized and its effects at the level of bone and kidney reported. However, the relative role of tubular reabsorption of calcium (Ca) and bone resorption in the pathogenesis of hypercalcemia induced by this factor is still debated. We investigated the effects of a synthetic amino-terminal fragment of parathyroid hormone-related protein [PTHrP-(1-34)] administered chronically by intraperitoneal osmotic minipumps in thyroparathyroidectomized (TPTX) rats. Clearance studies performed on day 6 of treatment after a 24 h fast revealed an increase in renal tubular reabsorption of Ca and a decrease in renal tubular reabsorption of phosphate (Pi), accompanied by an increase in cAMP excretion. PTHrP-(1-34) (90 pmol/h) stimulated bone resorption as evaluated by an increment in fasting urinary Ca excretion. Although the bone resorption inhibitor aminopropylidene diphosphonate fully corrected urinary Ca excretion and reduced plasma Ca from 3.04 +/- 0.07 to 2.44 +/- 0.21 mM (p less than 0.05), this latter value remained considerably higher than in TPTX control rats (1.54 +/- 0.12 mM, p less than 0.01). In contrast, when the agent WR-2721, which is known to decrease the renal tubular reabsorption of Ca by a PTH-independent mechanism, was given, a further drop in plasma Ca and an increase in urinary Ca excretion were observed. These findings are similar to those found in animals implanted with the hypercalcemic Leydig cell tumor.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of bone and kidney in parathyroid hormone-related peptide-induced hypercalcemia in rats. 255 91

A parathyroid hormone-related protein (PTHrP) has been invoked as being responsible for the humoral hypercalcemia of malignancy. Eight of the first 13 amino acids of PTHrP are identical with those in PTH, but there is no other significant homology. The PTHrP gene is located on chromosome 12, whereas that for PTH is on chromosome 11, and the two genes are probably related by a duplication process. Antisera against PTHrP(1-34), which cross-react poorly or not at all with PTH, and antisera against other parts of PTHrP not homologous to PTH were used in immunocytochemistry using a peroxidase-antiperoxidase method, to identify PTHrP in the cytoplasm of cells in a series of unselected parathyroid adenomata. The study was based on our evidence that PTHrP is produced by fetal parathyroid and may be the predominant calcium-regulating hormone in the mammalian fetus. Glands from five patients with parathyroid hyperplasia secondary to chronic renal failure also stained positively for PTHrP. No evidence was obtained for PTHrP in sections from five patients with primary parathyroid chief cell hyperplasia or in a small group of patients with the multiple endocrine neoplasia type 1 or type 2 syndromes.
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PMID:A novel parathyroid hormone-related gene product. 257 61

Parathyroid hormone-related protein (PTHrP), the peptide associated with humoral hypercalcemia of malignancy, has been identified in fetal and adult parathyroid glands. We here report a sub-clone of a rat parathyroid cell line which secretes a single peptide species corresponding in size to PTHrP(1-84). Biological activity of the secretion product was blocked by a specific antiserum against PTHrP, but not by parathyroid hormone (PTH) antiserum. Secretion of PTHrP by these cells was regulated by extracellular calcium in the physiological range. A single messenger RNA species for PTHrP was identified, though PTH mRNA could not be shown in these cells. Hybrid CAT genes containing 700-1000 bp of 5'-flanking DNA from the human PTH or PTHrP genes were transfected into these cells, and the PTHrP gene was expressed at 10-fold higher levels than the PTH gene. These cells thus provide a valuable model system for investigation expression of PTHrP in a non-transformed cell line.
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PMID:Production of parathyroid hormone-related protein by a rat parathyroid cell line. 261 35

Hypercalcemia is one of well-recognized paraneoplastic syndromes and occurs occasionally in patients with oral cancers. Because bone is the richest source of calcium in the body, it has been proposed that humoral bone resorbing factors which are released by tumors are responsible for the pathogenesis of hypercalcemia. In the present study, partial purification and identification of bone resorbing humoral factors were carried out employing VX2 squamous cell carcinoma which has been known to induce hypercalcemia in rabbits. In addition, extra- and intra-cellular mechanisms which are operating to confer autonomous growth on VX2 cancer cells were also studied. VX2 carcinoma induced marked hypercalcemia not only in rabbits but also in nude mice in parallel with tumor enlargement. Administration of indomethacin (INDO), a prostaglandin (PG) synthesis inhibitor, before onset of the hypercalcemia prevented an elevation of serum calcium levels and growth of the tumor. INDO, however, failed to decrease serum calcium levels and tumor growth when administered after development of the hypercalcemia and tumor enlargement. These results indicate that not only PGs but other humoral factors are involved in the pathogenesis of the hypercalcemia seen in VX2 cancer-bearing animals. VX2 cancer cells in culture retained their cancerous phenotypic properties, synthesized PGE2, PGF2 alpha and 6-keto PGF1 alpha and secreted highly levels of PGE2, a powerful bone resorber, into the culture medium in a time- and cell density-dependent manner. The culture supernatants also contained a trypsin- and heat-sensitive bone risorbing factor (BRF) with a molecular weight of approximately 20kD. BRF was presumed to be similar to parathyroid hormone related protein (PTHrP) from its biological and biochemical behaviors. Both PGE2 and PTHrP promoted VX2 cell growth, thus suggesting that these two substances are autocrine growth factors for VX2 cells. Calcium stimulated VX2 cell growth and secretion of PGE2 and BRF (PTHrP) in a concentration-dependent fashion. Stimulation of VX2 cell proliferation by PGE2 and PTHrP was closely correlated with a transient elevation of intracellular free calcium ion ([Ca2+]i). [Ca2+]i elevated transiently in response to PGE2 and PTHrP was shown to be supplied by influx of extracellular free calcium ion ([Ca2+]e) through calcium channel present in plasma membrane. Involvement of protein kinase C in autocrine growth stimulation of VX2 cells by PGE2 and PTHrP was unclear. These results demonstrate that PGE2 and PTHrP secreted by VX2 cancer cells not only induce hypercalcemia but promote VX2 cell growth as autocrine growth factors.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Mechanism of hypercalcemia associated with malignancy: interactions between induction of hypercalcemia and autonomous growth in VX2 cancer cells]. 263 47

Humoral hypercalcemia of malignancy is a common cause of malignancy-associated hypercalcemia. This syndrome is caused by the elaboration of a tumor-derived factor or factors that induce intense bone resorption and increased renal tubular calcium reabsorption. Recently, the PTHrP has been isolated from tumors associated with HHM, and a single copy gene directing its synthesis has been identified on human chromosome 12. Analysis of mRNA from tumor-derived tissue suggests a complex pattern of hybridizing transcripts, implicating alternative processing of this gene. However, the circulating form or forms of the protein have yet to be determined. Synthetic amino-terminal polypeptides of PTHrP in vivo and in vitro reproduce all of the essential features of HHM. Preliminary studies suggest that neutralizing antisera to this protein reverse the hypercalcemia in experimental models for HHM. Thus, it appears likely that this protein has a central pathogenic role in HHM. The development of antisera to this protein will aid in the detection and diagnosis of malignancy-associated hypercalcemia. Antagonists to this molecule may be helpful in treating this disorder.
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PMID:Humoral hypercalcemia of malignancy. The role of parathyroid hormone-related protein. 267 73


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