Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanisms involved in platelet aggregation by a monoclonal antibody (mAb) P256 specific for the GPIIb-IIIa complex was investigated following metabolic 32P labelling of platelets. When compared with thrombin, inositol phosphates (InsP) production during P256-induced activation was delayed and no apparent peak, but a small and sustained production of [32P]-Ins(1,4,5)P3 and [32P]-Ins(1,3,4,5)P4, was observed between 20 and 90 s. [32P]-Ins(1,3,4)P3 was also produced with a maximum after 90 s. Addition of the ADP scavenger creatinine phosphate/creatine phosphokinase (CP/CPK) and of the cyclooxygenase inhibitor aspirin together with P256 almost totally abolished InsP formation, whereas platelet aggregation and protein phosphorylation were partially inhibited. F(ab')2 fragments of P256 also aggregated platelets but to a smaller extent than IgG, and without any measurable InsPs. To characterize further P256-induced activation, the phosphorylation of p43, the main substrate of protein kinase C (PKC) and the phosphorylation of tyrosine protein (P-Tyr) was also studied. PKC activation was smaller with P256-IgG than with thrombin but both thrombin and P265-IgG induced a similar profile of P-Tyr involving seven major bands, whereas P256-F(ab')2 only occasionally activated PKC but always significantly phosphorylated a 64,000 molecular weight P-Tyr. The data indicate that the binding of P256 to GPIIb-IIIa, in contrast with thrombin, does not initially lead directly to the activation of the phosphoinositide phospholipase C to produce InsP's but rather involves the activation of protein kinases and also both fragments F(ab')2 and Fc play a specific role in the platelet responses to the mAb. Only the crosstalk between the two pathways evoked by F(ab')2 and Fc respectively allows the activation of all platelet activation systems.
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PMID:Mechanisms involved in platelet activation induced by a monoclonal antibody anti glycoprotein IIb-IIIa: inositol phosphate production is not the primary event. 178 4

This study was to investigate the effects of ischemic preconditioning on endothelin-1-induced myocardial injury and the role of calcitonin gene-related peptide (CGRP) played in such effects. The rat hearts were perfused in a Langendorff mode. Heart rates (HR), coronary flow (CF), left ventricular pressure (LVP) and its first derivative (LV dp/dtmax) were recorded and creatinine phosphate kinase (CPK) from coronary effluent was measured. There were no changes in HR, CF, LVP, or LV dp/dtmax throughout the experiment in the control hearts. Endothelin-1 (100 pmol) significantly decreased HR and CF, impaired the cardiac function, and increased the CPK release. However, the HR, CF, LVP and LV dp/dtmax were significantly improved, while the CPK release was decreased in the preconditioned hearts. CGRP8-37, a selective CGRP receptor antagonist, abolished the cardioprotection of ischemic preconditioning, such as the cardiac function and the CPK release. A similar cardioprotection was observed in the hearts pretreated with CGRP. However, the CGRP-induced preconditioning-like protection was abolished in the presence of CGRP8-17 or 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine, an inhibitor of protein kinase C. The present study suggests that the cardioprotective effect of ischemic preconditioning on endothelin-1-induced myocardial injury is mediated by CGRP, and that the cardioprotection of CGRP-induced preconditioning is related to the activation of protein kinase C.
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PMID:The protective effects of ischemic and calcitonin gene-related peptide-induced preconditioning on myocardial injury by endothelin-1 in the isolated perfused rat heart. 889 Sep 31

Na+/H+ exchange (NHE) was measured as maximal initial velocity of pH-dependent H+ efflux from red cells into an alkaline medium containing Na+ in patients with insulin-dependent or noninsulin-dependent diabetes, with and without hypertension and in normoglycemic, essential hypertensives and normal controls (50 subjects in each subgroup). Maximal velocities of NHE were found in microalbuminuric patients in all subgroups, and NHE correlated with the rate of micro-albuminuria (r = 0.61, p = 0.02). Daily insulin requirements were greater in those with elevated NHE (84 +/- 8 vs 42 +/- 4 U/day). There was no correlation between NHE and levels of plasma glucose, HbA1 and plasma aldosterone and lipid profile and PRA. NHE was correlated with plasma prolactin (r = 0.51, p = 0.02) and PTH r = 0.24, p = 0.05). In uremic patients, NHE was inversely correlated with creatinine clearance (r = -0.48, p = 0.03). Since calphostin C, a selective inhibitor of protein kinase C, lowered increased NHE in vitro, the protein kinase C-dependent pathway of the exchanger regulation was concluded to be responsible for NHE activation in diabetes mellitus and essential hypertension.
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PMID:[Red cell Na+/H+ exchange and role of protein kinase C in its stimulation in diabetes mellitus, essential hypertension and nephropathy]. 922 70

Repetitive brief ischemic episodes (ischemic preconditioning, PC) result in transient intracellular acidosis and protect the heart from subsequent ischemic injury, potentially through a protein kinase C (PKC)-dependent mechanism. We hypothesized that repetitive brief acidification of the heart without concomitant ischemia would also protect the heart from ischemic injury via a PKC-dependent mechanism. Isolated rat hearts underwent 30 min of global ischemia following control perfusion (CTL), or after PC or repetitive acidosis (RA), in the presence of absence of chelerythrine, a specific PKC inhibitor. Intracellular pH, PCr and ATP were measured using 31P NMR spectroscopy, while intracellular sodium [Na]i was measured using 23Na spectroscopy. Na,K-ATPase activity was measured prior to ischemia and on reperfusion. Both PC and RA resulted in transient acidification prior to ischemia. Ischemic injury, as assessed by creatinine kinase (CK) release on reperfusion, was reduced in both the PC and RA hearts [63+/-14 and 16+/-4 IU/g dry weight (dw) respectively, v 705+/-72 IU/gdw for control P<0.001], and was associated with improved functional recovery on reperfusion. PC and RA each significantly reduced Na,K-ATPase activity prior to ischemia (8.18+/-0.47 and 7.76+/-0.54 micromol ADP/h/mg protein) when compared to control (11.05+/-0.54 micromol ADP/h/mg protein P<0.05), limited the rate of ATP depletion during ischemia, and resulted in more rapid normalization of [Na]i on reperfusion. Chelerythrine resulted in intermediate CK release in PC and RA hearts (443+/-48 and 375+/-72 IU/gdw, P<0.001 v PC, P<0.01 v control), but did not alter the rate of ATP depletion or [Na]i kinetics in either PC or RA hearts. PC and RA each protect the ischemic heart, having in common ATP preservation during ischemia and more rapid normalization of [Na]i on reperfusion. These effects, not modulated by protein kinase C, are consistent with the hypothesis that ATP preservation during ischemia provides enhanced substrate for sodium efflux via the Na,K-ATPase on reperfusion.
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PMID:Repetitive acidosis protects the ischemic heart: implications for mechanisms in preconditioned hearts. 1032 17

The 1-31 fragment of human PTH [hPTH-(1-31)NH2] has been shown, like hPTH-(1-34), to have anabolic effects on the skeletons of ovariectomized rats when given intermittently, but, unlike hPTH-(1-34), it does so without affecting serum calcium concentrations and does not activate the protein kinase C second messenger pathway in some target cells. To investigate the biochemical responses to hPTH-(1-31) in humans, we have directly compared it to hPTH-(1-34) during the course of slow infusions of each. Ten healthy adults, five men and five women, aged 26+/-5 yr (range, 22-37), each received 8-h continuous infusions of 8 pmol/kg.h hPTH-(1-34) and hPTH-(1-31) given in random order at least 2 weeks apart. During the infusions there were significant increases in both plasma and urinary cAMP (P < 0.05), but there were no differences in the responses between the two peptides (P = 0.362 for plasma; P = 0.987 for urine). There were also significant phosphaturic and natriuretic responses to the two peptides, which again were not different between peptides. During the infusion of hPTH-(1-34) serum ionized calcium (Ca2+) increased from 1.21+/-0.033 to 1.29+/-0.046 mmol/L (P < 0.01), and endogenous hPTH-(1-84) decreased from 29.6+/-9 to 15.0+/-5.7 pg/mL (P < 0.01), such that there was a negative correlation between them (r2 = 0.45). However, when hPTH-(1-31) was infused, neither serum Ca2+ (1.24+/-0.03 vs. 1.25+/-0.03) nor hPTH-(1-84) (26.8+/-5 vs. 30.7+/-12 pg/mL) was affected. Circulating concentrations of 1,25-dihydroxyvitamin D3 increased from 92+/-42 to 131+/-63 pmol/L (P < 0.05) during infusion of hPTH-(1-34) and from 92+/-27 to 110+/-42 pmol/L (P = NS) during hPTH-(1-31) infusion. There was also a significant increase in the urinary measure of type I collagen degradation of aminoterminal telopeptides from 78+/-45 to 101+/-51 nmol/mmol creatinine (P < 0.05) when hPTH-(1-34) was infused, but it was not affected (68+/-30 vs. 66+/-24 nmol/mmol creatinine) by hPTH-(1-31). Therefore, hPTH-(1-31) appears to be equivalent and equipotent to hPTH-(1-34) in the release of cAMP from target tissues and the renal handling of phosphate and sodium. However, at the doses employed, it does not increase serum calcium, is a weaker stimulator of the 25-hydroxyvitamin D-1alpha-hydroxylase, and does not induce rapid bone resorption.
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PMID:Comparison of the biochemical responses to human parathyroid hormone-(1-31)NH2 and hPTH-(1-34) in healthy humans. 1044 71

The thiazolidinedione compounds are well known hypoglycemic agents via increasing insulin-sensitivity. Herein, we provide the possibility that thiazolidinedione compounds could be useful for renal dysfunction through mechanism dependent or independent of its insulin-sensitizing action. In type 2 diabetes, troglitazone could reduce urinary albumin-creatinine ratio compared to metformin. Furthermore, we have shown that troglitazone was able to prevent diabetic glomerular dysfunction through inhibition of diacylglycerol-protein kinase C-extracellular signal-regulated kinase pathway in type 1 diabetic rats. Thus, thiazolidinediones might be effective agents for treating insulin-resistant diabetes as well as diabetes-induced kidney disease.
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PMID:[Kidney disease and insulin resistance--clinical impact of thiazolidinedione compounds for kidney disease]. 1070 73

Puromycin aminonucleoside (PAN) has been known to induce proteinuria. The increased generation of reactive oxygen species (ROS) has been implicated in this toxicity of PAN. We have reported that PAN increases the synthesis of methylguanidine (MG) and creatol which are the products of the reaction of creatinine and the hydroxyl radical in isolated rat hepatocytes. However, the mechanism for the increased ROS induced by PAN is still unclear. In this paper, we investigate the role of protein kinase C (PKC) on the PAN induced reactive oxygen generation in isolated rat hepatocytes. Isolated hepatocytes were incubated in Krebs-Henseleit bicarbonate buffer containing 3% BSA, 16.6 mM creatinine and tested reagents. MG and creatol were determined by high-performance liquid chromatography using 9,10-phenanthrenequinone for the post-labeling. PAN increased MG and creatol synthesis in isolated rat hepatocytes by 60%. 1-(5-Isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H-7), a PKC inhibitor, at 10 and 100 microM significantly inhibited MG and creatol synthesis with or without PAN. The inhibition rate is dose dependent from 10 to 100 microM. H1004, a reagent used as control for H-7, did not affect (at 10 microM) or increased little (at 100 microM) the synthesis of MG and creatol. Ro31-8425, a potent PKC inhibitor, significantly inhibited (at 10 microM) MG synthesis in the presence of PAN. PKC in the membrane fraction, a marker of PKC activation, increased over the initial concentration by a factor of 1.65-fold at 60 min incubation and 2.16-fold at 120 min with PAN, while it changed little without PAN. These results indicate that PAN activates PKC resulting in increased hydroxyl radical generation in isolated rat hepatocytes.
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PMID:The role of protein kinase C in the increased generation in isolated rat hepatocytes of the hydroxyl radical by puromycin aminonucleoside. 1079 14

Renal ischemic reperfusion (IR) injury is a significant clinical problem in anesthesia and surgery. Recently, it was demonstrated that both renal ischemic preconditioning (IPC) and systemic adenosine pretreatment protect against renal IR injury. In cardiac IPC, pertussis toxin-sensitive G-proteins (i.e., G(i/o)), protein kinase C (PKC), and ATP-sensitive potassium (K+(ATP)) channels are implicated in this protective signaling pathway. The aim of this study was to elucidate the signaling pathways that are responsible for renal protection mediated by both IPC and adenosine pretreatment. In addition, because A1 adenosine receptor antagonist failed to block renal IPC, whether activation of bradykinin, muscarinic, or opioid receptors can mimic renal IPC was tested because these receptors have been implicated in cardiac IPC. Rats were acutely pretreated with chelerythrine or glibenclamide, selective blockers of PKC and K+(ATP) channels, respectively, before IPC or adenosine pretreatment. Some rats were pretreated with pinacidil (K+(ATP)channel opener), bradykinin, methacholine, or morphine before renal ischemia. Twenty-four h later, plasma creatinine was measured. Separate groups of rats received pertussis toxin intraperitoneally 48 h before being subjected to the above protective protocols. IPC and adenosine pretreatment protected against renal IR injury. Pretreatment with pertussis toxin and chelerythrine abolished the protective effects of both renal IPC and adenosine. However, glibenclamide pretreatment had no effect on either renal IPC or adenosine-induced renal protection, indicating no apparent role for K+(ATP) channels. Moreover, pinacidil, bradykinin, methacholine, and morphine failed to protect renal function. Therefore, the conclusion is that cellular signal transduction pathways of renal IPC and adenosine pretreatment in vivo involve G(i/o) proteins and PKC but not K+(ATP) channels. Unlike cardiac IPC, bradykinin, muscarinic, and opioid receptors do not mediate renal IPC.
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PMID:Protein kinase C and G(i/o) proteins are involved in adenosine- and ischemic preconditioning-mediated renal protection. 1115 13

It has been reported that platelet aggregation in diabetic patients with microangiopathy is increased compared with healthy subjects. Chronic hyperglycemia is known to cause an increase in diacylglycerol level in various tissues. We examine whether protein kinase C (PKC) isoform content in platelets from diabetic patients is increased compared with healthy subjects, as previously described in the retina, aorta, and heart of diabetic rats. Platelet PKCalpha, beta and zeta immunoreactivity in cytosol, membrane and cytoskeleton (CS) fractions were analyzed by immunoblotting in 20 type 2 diabetic patients (who had been treated with diet alone, sulphonylureas or insulin, and whose condition was complicated with retinopathy, nephropathy, neuropathy and/or macroangiopathy) and in five healthy subjects. PKCalpha, beta and zeta immunoreactivity in cytosol, membrane and CS fractions in platelets from diabetic subjects were not significantly higher than those from healthy subjects. However, platelet PKCbeta immunoreactivity in cytosol fraction was significantly higher in diabetic patients with normal serum creatinine (Cr) level than in diabetic patients with abnormal Cr level (Cr > or =1.5 mg/dl) or in healthy subjects. Moreover, significant negative correlation between PKCbeta immunoreactivity in cytosol fraction of platelets and serum Cr level was found in diabetic patients (P < 0.05). To clarify the effect of treatment for diabetes, PKC isoform immunoreactivity in platelets was measured in type 2 diabetic patients treated with diet alone, sulphonylurea or insulin treatment. Serum creatinine level in diabetic patients with insulin treatment was significantly higher than in diabetic patients with sulphonylurea treatment and diet alone. In addition, PKCbeta immunoreactivity in diabetic patients with insulin treatment was significantly suppressed compared with that in patients treated by sulphonylurea treatment. These results suggest that chronic hyperglycemia may activate platelet PKCbeta isoform, and that insulin treatment may decrease platelet PKCbeta activity. Finally, not only PKCbeta antagonists, but also glycemic control by insulin may prevent development of diabetic microangiopathy.
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PMID:Platelet protein kinase C isoform content in type 2 diabetes complicated with retinopathy and nephropathy. 1130 14

Production of guanidinoacetic acid, a precursor of creatinine is known to be reduced by metabolic disturbance when kidney function is damaged, and thus it may be a sensitive marker of renal damage. Therefore, the urinary levels of guanidinoacetic acid, creatinine and creatine from patients with urinary tract neoplasm who received cisplatin treatment were measured by liquid chromatography-mass spectrometry. Following the administration of cisplatin, the urinary excretion of guanidinoacetic acid decreased significantly, and the low concentration was maintained for at least five days. The concentrations of creatinine and creatine gradually decreased until the third day after cisplatin administration, and slightly increased on the fifth day. As superoxide might be concerned in renal damage by cisplatin, the effect of cisplatin on superoxide generation was also investigated using human neutrophils. Cisplatin significantly enhanced phorbol 12-myristate 13-acetate-induced superoxide generation in a concentration-dependent manner, but had no effect on the superoxide generation induced by N-formyl-methionyl-leucyl-phenylalanine and arachidonic acid. The superoxide generation increased by cisplatin was inhibited by staurosporine, an inhibitor of protein kinase C, but was rather enhanced by genistein, an inhibitor of protein tyrosine kinase.
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PMID:Effect of cisplatin treatment on the urinary excretion of guanidinoacetic acid, creatinine and creatine in patients with urinary tract neoplasm, and on superoxide generation in human neutrophils. 1138 33


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