Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Studies were carried out to compare the effects of parathyroid extract (PTE) on serum and urinary calcium (Ca) and phosphorus (P), serum 25-hydroxyvitamin D (25-OHD), serum 24,25-dihydroxyvitamin D (24,25(OH)2D), serum 1 alpha,25-dihydroxyvitamin D (1 alpha,25(OH)2D), and urinary cyclic AMP in two normal subjects, two patients with hypoparathyroidism (HP) and six patients with pseudohypoparathyroidism (PHP), some of whom were on suboptimal treatment with vitamin D. Two of the patients with PHP were studied while on long-term treatment with 1 alpha,25-(OH)2D3. Before PTE, serum 1 alpha, 25(OH)2D was at the lower limit of normal in one patient and was abnormally low in the other five patients. None of these individuals was on treatment with 1 alpha,25(OH)2D3. Serum 25-OHD and 24,25(OH)2D were either increased or at the upper limit of normal in the patients given vitamin D and were normal in the other patients. PTE lowered the serum P and increased the serum 1 alpha,25(OH)2D, serum and urinary Ca, urinary P, and urinary cyclic AMP in the normal subjects and patients with HP. In individual studies, changes in serum 1 alpha,25(OH)2D and serum Ca occurred in parallel before, during, and after PTE. In contrast, PTE had very little effect in the patients with PHP. Whereas there were highly significant positive correlations between serum 1 alpha,25(OH)2D in each of the normal subjects and patients with HP, there were significant correlations in only one of the patients with PHP. An increase in serum Ca in response to PTE was observed in one of the two patients with PHP who were on long-term treatment with 1 alpha,25(OH)2D3. In these individuals, PTE produced only slight increases in serum 1 alpha,25(OH)2D. Serum 25-OHD and 24,25(OH)2D were not changed by PTE in any of the subjects or patients. The results provide evidence that hypocalcemia in HP and PHP arises in part from low circulating 1 alpha,25-(OH)2D, and indicate that the lack of change in serum 1 alpha,25(OH)2D with PTE in patients with PHP is related to impaired renal adenylate cyclase and phosphaturic responses. These and previous results support the idea that diminished renal production of 1 alpha,25(OH)2D, because of a defect in the parathyroid hormone-responsive adenylate cyclase system, may be a contributing factor in the pathogenesis of the abnormal calcium metabolism in PHP.
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PMID:Demonstration of a lack of change in serum 1 alpha,25-dihydroxyvitamin D in response to parathyroid extract in pseudohypoparathyroidism. 741 19

The aim of the present work was to characterize at the molecular level the mechanism of PTH resistance in a rat model of secondary hyperparathyroidism resulting from vitamin D deprivation. PTH/PTH-related protein (PTHrp) receptor messenger RNA (mRNA) expression, assayed by ribonuclease protection analysis, was studied in the kidney, femoral epi/metaphysis, and diaphysis. In addition, in the kidney, PTH/PTHrp receptor mRNA expression was correlated to receptor function by measuring adenyl cyclase activity in crude renal membranes after stimulation by PTH (10(-10) - 10(-6) M), forskolin (0.1 and 0.2 mM), NaF (5 and 10 mM), and isoproterenol (1 and 10 microM). Four groups of rats were studied to investigate the effects of calcium, PTH, and/or vitamin D status. The first group received a control diet (D+D+). The second group received a diet deficient in vitamin D until death (D-D-). In the two other groups that also received a vitamin D-deficient diet, the hypocalcemia and the hyperparathyroidism were later corrected, by either vitamin D supplementation (D-D+) or lactose and high calcium diet (D-Ca+), 1 week before death. The results revealed a 2-fold decrease in the PTH-induced adenyl cyclase activity of the renal membranes in the D-D- rats compared to those in the three other groups. There was no significant difference in the four groups in adenyl cyclase activity stimulated by forskolin, NaF, and isoproterenol. The decrease in PTH-induced adenyl cyclase activity was associated with an approximately 2-fold increase in PTH/PTHrp receptor mRNA expression in the kidneys of the D-D- rats compared to controls. Normalization of PTH/PTHrp receptor mRNA expression was observed after vitamin D supplementation (D-D+ rats), but not after correction of the hypocalcemia and secondary hyperparathyroidism by oral lactose and calcium supplementation. In the epi/metaphysis, an approximately 2-fold increase in PTH/PTHrp receptor mRNA was also observed in the D-D- rats compared to the controls; this increase was partially corrected upon normalization of the calcemia and PTH levels with either vitamin D (D-D+ group) or lactose/calcium (D-Ca+ group). In the diaphysis, no change in the expression of PTH/PTHrp receptor mRNA was observed in any group.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Parathyroid hormone (PTH)/PTH-related protein receptor messenger ribonucleic acid expression and PTH response in a rat model of secondary hyperparathyroidism associated with vitamin D deficiency. 764 81

Iliac crest biopsies of normals, uremic patients and subjects with primary hyperparathyroidism (pHPT) were investigated. It appeared that serum 1,25- and 24,25-(OH)2-D3 correlated inversely with basal adenylate cyclase (AC) activity and relative PTH-stimulated AC, respectively. Net PTH-elicited AC (dPTH-AC) activation hence reflected individual vitamin D status. The combination variable serum PTH (s-PTH) x dPTH-AC x [H+] correlated well with resorption surface (RS) in both normals, patients with pHPT or subjects with uremia, while s-PTH, dPTH-AC activity or pH as single variables were only marginally related to RS. For all subjects analyzed, osteoid volume (OV) correlated positively with serum alkaline phosphatase but negatively with serum 1,25-(OH)2-D3. OV showed no correlation with dPTH-AC, while the relationship between OV and s-PTH was strong, suggesting that PTH stimulates osteoid deposition via some signalling pathway other than cAMP. In normals, OV was inversely proportional to s-PTH, due to homologous desensitization of this signalling system. Furthermore, s-PTH was negatively correlated with urine cAMP due to homologous desensitization of the effect of PTH on the kidney 25-(OH)-D3 1 alpha-hydroxylase. This phenomenon was absent in uremic patients. Evaluation of variables by artificial intelligence showed that the prototype uremic patient exhibited serum creatinine > 900 microM, RS > 0.12, pH between 7.15 and 7.34 and s-PTH x dPTH-AC x [H+] between 0.5 and 3.7 units with the distinguishability index 'very good' (< 5% overlap) towards normals. Average similarity of uremic patients with the prototype for normal subjects was only 22%. Cluster analysis of all the variables was conducted for comparison and yielded less clinically relevant information. Hence, emulation done by the expert system was superior and clearly indicates that present treatment modalities restore normal bone turnover only to a minor degree or not at all.
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PMID:PTH-stimulated adenylate cyclase activity and bone histomorphometry in iliac crest biopsies in the evaluation of uremic patients: a pilot study with the use of artificial intelligence. 816 16

We tested whether the protein kinase C (PKC) modulation of PTH-sensitive adenylate cyclase in ROS 17/2.8 cells is affected by the glucocorticoid dexamethasone and the vitamin D hormone 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. Basal and PTH- and forskolin-stimulated adenylate cyclase activities were determined in the presence or absence of 100 nM phorbol 12-myristate 13-acetate (PMA), the activator of PKC, in ROS 17/2.8 cells that had been previously cultured with or without dexamethasone or 1,25(OH)2D3. Dexamethasone treatment increased the basal, PMA-, PTH-, (PTH + PMA)- and (forskolin + PMA)-sensitive adenylate cyclase while 1,25(OH)2D3 decreased these effects. The stimulatory and inhibitory effects were dose-dependent with respect to dexamethasone and 1,25(OH)2D3, respectively. Dexamethasone increased, while 1,25(OH)2D3 decreased the maximal activity of both PTH-sensitive and PKC-modulated PTH-sensitive adenylate cyclase without affecting the half-maximal concentration (ED50) of PTH required for the activation of the enzyme. Additionally, dexamethasone, 1,25(OH)2D3 and PKC did not affect each other's ED50. Our results suggest that the effects of dexamethasone, 1,25(OH)2D3 and PKC on PTH-sensitive adenylate cyclase in ROS 17/2.8 cells are independent of each other.
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PMID:Modulation of parathyroid hormone-sensitive adenylate cyclase in ROS 17/2.8 cells by dexamethasone 1,25-dihydroxyvitamin D3 and protein kinase C. 827 78

Previously we demonstrated that bone resorption in uremic patients appears to be related to increased serum parathyroid hormone (PTH) and to osseous PTH-stimulated adenylate cyclase (AC), the latter being inversely correlated to serum 24,25-dihydroxyvitamin D3 [24,25(OH)2D3]. In this study, we continue to examine the possible modulatory role of vitamin D3 analogs on the progression of the uremic condition. Four groups of predialytic uremic patients received oral administrations of CaCO3 (control), 1,25-dihydroxy-vitamin D3 [1,25(OH)2D3] (0.25-0.50 microgram/day), 24,25(OH)2D3 (15 micrograms/day) or a combination of the two vitamin D3 analogs for 6 months. In the treatment groups receiving single or combined therapy, respectively, the low pretrial serum levels of 1,25(OH)2D3 were raised (p < 0.05) within upper normal range, while the serum levels of 24,25(OH)2D3 were increased (p < 0.05) to twice the average physiological level. Neither regimens alone resulted in significant changes in serum levels of calcium of PTH. 1,25(OH)2D3 moderately hampered bone formation by reducing serum alkaline phosphatase (ALP) by some 15%. 24,25(OH)2D3 significantly decreased (p < 0.01) bone PTH-AC up to 98% after 2 and 6 months. However, no correlation was found between serum 24,25(OH)2D3 and the bone turnover parameters serum ALP, serum osteocalcin and urine hydroxyproline/creatinine ratio. These parameters were all positively correlated (p < 0.05) to serum PTH, indicating an on-going bone turnover. These biochemical events strongly indicate that 24,25(OH)2D3 may retard the PTH-dependent progression in bone demineralization occurring in uremic patients. This effect is apparently not reduced by concomitant 1,25(OH)2D3 administration.
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PMID:Alterations in serum and urine parameters reflecting bone turnover in uremic patients during treatment with 1,25-dihydroxyvitamin D3 and 24,25-dihydroxyvitamin D3. 837 28

We investigated the effects of vitamin D3 on the signaling pathways by prostaglandin E2 (PGE2) in osteoblast-like MC3T3-E1 cells. The pretreatment with 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3), an active form of vitamin D3, significantly inhibited cAMP accumulation induced by 10 microM PGE2 in a dose-dependent manner in the range between 1 pM and 1 nM. This effect of 1,25-(OH)2D3 was dependent on the time of pretreatment up to 8h. 1,25-(OH)2D3 also inhibited the cAMP accumulation induced by NaF, a GTP-binding protein activator, or forskolin which directly activates adenylate cyclase. On the other hand, 1,25-(OH)2D3 significantly inhibited PGE2-induced IP3 formation in a dose-dependent manner between 10 pM and 1 nM. However, 1,25-(OH)2D3 had little effect on NaF-induced IP3 formation. The pretreatment with 24,25-dihydroxyvitamin D3, an inactive form of vitamin D3, affected neither cAMP accumulation nor IP3 formation induced by PGE2. These results strongly suggest that 1,25-(OH)2D3 modulates the signaling by PGE2 in osteoblast-like cells as follows: the inhibitory effect on the cAMP production is exerted at a point downstream from adenylate cyclase and the inhibitory effect on the phosphoinositide hydrolysis is exerted at the point between the PGE2 receptor and GTP-binding protein, probably Gi2.
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PMID:Effects of vitamin D3 on signaling by prostaglandin E2 in osteoblast-like cells. 839 50

We have previously established an uremic rat model which is suitable for investigating the effect of various treatment modalities on the progression of renal osteodystrophy [1]. Four months subsequent to 5/6 nephrectomy, animals were treated three times a week for 3 months with either vehicle, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], 1,25(OH)2D3 + 24,25-dihydroxyvitamin D3 [24,25(OH)2D3], 1,25(OH)2D3 + calcitonin (CT), or 1,25(OH)2D3 + 24,25(OH)2D3 + CT. At termination of the study, clinical chemistry, chemical composition, and mechanical properties of femurs, calvarial parathyroid hormone (PTH)-elicited adenylate cyclase (AC), and phospholipase C (PL-C) activities, femoral cross-sectional area, and bone histomorphometry were analyzed. The main findings were that 1,25(OH)2D3 +/- 24,25(OH)2D3 treatment enhanced elasticity as well as time to fracture at the femoral metaphysis. CT potentiated the increase in elasticity obtained by 1,25(OH)2D3 +/- 24,25(OH)2D3 treatment. Only 24,25(OH)2D3 administration rectified the supernormal PTH-stimulated uremic bone AC, and only 1,25(OH)2D3 medication normalized the diminished CT-elicited AC. The obliterated uremic bone PTH-sensitive PL-C was fully normalized by all drug regimens. Femoral shaft inner zone diameter was enhanced by uremia, however, all drug treatments normalized it. Ditto effect was registered with either drug treatment on the subnormal outer and inner zone widths. Histomorphometrical analyses showed that 1,25(OH)2D3 administration reduced both eroded and osteoid surfaces. Most prominently, adjuvant 24,25(OH)2D3 or CT administration potentiated the beneficial effect of 1,25(OH)2D3 on fibrosis and osteomalacia. We assert that vitamin D3 treatment markedly reverses the development of renal osteodystrophy, and CT potentiates the effect of vitamin D3.
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PMID:Vitamin D3 analogs and salmon calcitonin partially reverse the development of renal osteodystrophy in rats. 856 2

Chronic renal failure is characterized by a resistance to the hypercalcemic action of parathyroid hormone (PTH). This resistance probably involves several mechanisms, including a disturbance of vitamin D metabolism, a desensitization of the skeleton by high PTH levels, hyperphosphatemia, uremic toxins, and acidosis. We have explored the possibility that a downregulation of the recently cloned PTH/PTHrp receptor might also be involved. We found a marked decrease in the expression of the receptor mRNA in the kidney and the bone of uremic rats; other authors have found a decrease in the heart and the liver. The reduced expression in the kidney was accompanied by a diminished stimulability of renal adenylate cyclase activity, suggestive of a functional depression of the hormonal response in this target tissue. It is probable that the downregulation of the PTH/PTHrp receptor plays an important role in the skeletal resistance to the calcemic effect of PTII in chronic renal failure.
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PMID:Abnormal skeletal response to parathyroid hormone and the expression of its receptor in chronic uremia. 879 3

Agents that increase intracellular cAMP (cAMP elevating agents) and 1, 25(OH)2D3 inhibit the proliferation of many cell types. We investigated the combined effect of 1,25(OH)2D3 and cAMP elevating agents on exponentially growing mouse 3T3 fibroblasts. The following cAMP elevating agents were used: theophylline and pentoxyfilline, which inhibit cAMP-dependent phosphodiesterase; prostaglandin E2 which activates adenylate cyclase by a receptor-mediated mechanism; forskolin, which directly stimulates adenylate cyclase; and the cell permeable cAMP analogs 8-bromo cAMP and N6 benzoyl cAMP. 1,25(OH)2D3 and cAMP elevating agents were added to exponentially growing fibroblasts cultured in 96-well microtiter plates and cell number was monitored 3-7 d later. 1,25(OH)2D3 and the cAMP elevating agents as single agents inhibited the growth of the 3T3 cells. The combined treatment of the fibroblasts with 1,25(OH)2D3 and the cAMP elevating agents resulted in an antiproliferative effect that was more than additive. The synergistic interaction depended on the dose of 1,25(OH)2D3 and was apparent already at 10(-8) M of the hormone. The specificity of the effect of 1,25(OH)2D3 was demonstrated by the finding that 24,25-dihydroxyvitamin D3, a vitamin D metabolite with low affinity for the vitamin D receptor, did not affect the antiproliferative effect of cAMP elevating agents. From the synergistic interaction between 1,25(OH)2D3 and the cell permeable cAMP analogs, we infer that the site of interaction between the two signaling pathways is distal to the cAMP generating and degrading machinery.
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PMID:1,25-dihydroxyvitamin D3 and agents that increase intracellular adenosine 3',5'-monophosphate synergistically inhibit fibroblast proliferation. 915 48

The effects of prostaglandin E2, forskolin, and phorbol 12-myristate 13-acetate on cell proliferation, cell surface antigen expression, vitamin D-24-hydroxylase activity and vitamin D receptor (VDR) expression have been studied in an adherent variant (Ad-HL60) of the human HL60 promyelomonocytic leukemia cell line. Ad-HL60 cells have a more differentiated phenotype than the nonadherent HL60 cells from which they were derived and, unlike the parent cell line, constitutively express vitamin D-24-hydroxylase activity. Treatment of Ad-HL60 cells with 1 microM PGE2 resulted in a decrease in the rate of cell proliferation (cell numbers were approximately 23% of control values after 72 h treatment), a change in expression of leukocyte surface antigens (decreased CD13 and CD14, increased CD11b and CD49d expression), an increase in the synthesis of 24,25-dihydroxyvitamin D3 from substrate 25-hydroxyvitamin D3 (control 5.76 +/- 0.17, 72 h PGE2-treated cells 12.10 +/- 1.90 pmol/h/10(6) cells), and an increase in receptors for the active metabolite of vitamin D, 1 alpha,25-dihydroxyvitamin D3, from 3910 to 11285 receptors per cell in control and 7-day treated cells, respectively. Prostaglandin E2 may be acting via a mechanism involving cyclic AMP in these cells, as we have also demonstrated that 10 microM forskolin, an adenylate cyclase activator, has similar effects. Phorbol 12-myristate 13-acetate had little effect on any of the parameters measured in this cell line.
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PMID:Prostaglandin E2 regulates vitamin D receptor expression, vitamin D-24-hydroxylase activity and cell proliferation in an adherent human myeloid leukemia cell line (Ad-HL60). 1041 Mar 79


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