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)

Nitric oxide (NO) has been implicated in the "second-window" of ischemic preconditioning (PC). However, the identity of the end effector after initiation of preconditioning by NO is not known. It is likely that NO is involved in opening of mitochondrial ATP-sensitive potassium (mitoK(ATP)) channels. We hypothesized that NO is an important trigger for the opening of mitoK(ATP) channels in the late phase of preconditioning and inducible nitric oxide synthase (iNOS) up-regulation via NF kappa B plays a critical role in diazoxide-induced cardioprotection. To examine this, diazoxide (7 mg/kg) was administered to wild-type (WT) mice and mice lacking the gene 24 hours before 40 minutes of global ischemia. Hearts were perfused in a Langendorff mode and effects of activation of mitoK(ATP) channel and other interventions on functional, biochemical and pathological changes in ischemic hearts were assessed. In hearts from WT mice treated diazoxide, left-ventricular-developed pressure, end-diastolic pressure and coronary flow were significantly improved after ischemia/reperfusion (I/R); lactate dehydrogenase (LDH) release was also significantly decreased, while ATP contents were significantly higher. Administration of 5-HD, a specific blocker of mitoK(ATP) channel or l -NAME, an inhibitor of iNOS before I/R, during diazoxide-pretreatment completely blocked the late cardioprotection against ischemia. Late cardioprotection was also blocked by inhibition of either PKC- delta by rottlerin or NF kappa B by DDTC before diazoxide pretreatment. Diazoxide pretreatment significantly increased nuclear translocation of p65 which was blocked by protein kinase C (PKC) or nitric oxide synthase (NOS) inhibition. Diazoxide was totally inefffective in iNOS knockout mice. These results suggest that diazoxide activates NF kappa B via PKC signaling pathway and that leads to iNOS up-regulation after 24 hours. NO which is generated upon ischemic stress triggers the opening of mitoK(ATP)channel as an end effector of cardioprotection during late PC.
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PMID:Mitochondrial K(ATP) channel as an end effector of cardioprotection during late preconditioning: triggering role of nitric oxide. 1170 47

We have recently demonstrated protection against renal ischemic-reperfusion injury in vivo by A(1)- and A(2a)-adenosine receptor (AR) modulations. To further elucidate the signaling cascades of AR-induced cytoprotection against reperfusion/oxidant-mediated injury, immortalized human proximal tubule (HK-2) cells were treated with H(2)O(2). H(2)O(2) caused dose- and time-dependent HK-2 cell death that was measured by lactate dehydrogenase release and trypan blue dye uptake. Adenosine protected against H(2)O(2)-induced HK-2 cell death by means of A(1)- and A(2a)-AR activation. A(1)-AR-mediated protection involves pertussis toxin-sensitive G proteins and protein kinase C, whereas A(2a)-AR-mediated protection involves protein kinase A activation by means of cAMP and activation of the cAMP response element binding protein. Moreover, protein kinase A activators (forskolin and Sp-isomer cAMP) also protected HK-2 cells against H(2)O(2) injury. De novo gene transcription and protein synthesis are required for both A(1)- and A(2a)-AR-mediated cytoprotection as actinomycin D and cycloheximide, respectively, blocked cytoprotection. Chronic treatments with a nonselective AR agonist abolished the protection by adenosine. Moreover, chronic treatments with a nonselective AR antagonist increased the endogenous tolerance of HK-2 cells against H(2)O(2). We concluded that A(1)- and A(2a)-AR activation protects HK-2 cells against H(2)O(2)-induced injury by means of distinct signaling pathways that require new gene transcription and new protein synthesis.
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PMID:Adenosine attenuates oxidant injury in human proximal tubular cells via A(1) and A(2a) adenosine receptors. 1193 94

The objective was to analyze the mechanism of the protection induced by a nonalcoholic extract of red wine (RWE) on ischemia/reperfusion injury. Isovolumic perfused rat hearts were exposed after stabilization to a 20-min global ischemic period followed by 30 min of reperfusion in absence and presence of RWE infused prior to ischemia and early in reperfusion. In other hearts, 5-hydroxydecanoate (5-HD, 100 microM), a selective mitochondrial K(ATP) blocker, chelerythrine (1 microM), a protein kinase C blocker, or >L(G)-nitro->L-arginine methyl ester (>L-NAME), a nitric oxide synthase inhibitor, was administered prior to RWE infusion. Left ventricular developed pressure (LVDP), +dP/dtmax, and left ventricular end-diastolic pressure (LVEDP) were used to assess myocardial function. The lactate dehydrogenase release during reperfusion was measured. After the ischemic period, LVDP decreased to 61 +/- 4% and +dP/dtmax to 62 +/- 5% of baseline values at the end of reperfusion. The infusion of RWE resulted in a complete recovery of systolic function (LVDP = 102 +/- 4%; +dP/dtmax = 101 +/- 4%) and in an attenuation of the increase of LVEDP (20 +/- 3 mm Hg versus 42 +/- 4 mm Hg, p < 0.05). The treatment with RWE did not produce lactate dehydrogenase release during reperfusion. 5-HD and chelerythrine completely abolished the protection induced by RWE (mechanical and enzymatic). >L-NAME partially abolished the systolic improvement induced by RWE but returned lactate dehydrogenase loss to ischemic control values. The diastolic protection afforded by RWE was not altered by >L-NAME. These data are the first demonstration that mitochondrial K channels and nitric oxide are involved in the protection against ischemia/reperfusion conferred by a nonalcoholic RWE.
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PMID:Cardioprotection from ischemia/reperfusion induced by red wine extract is mediated by K(ATP) channels. 1219 29

The major objective of this study was to determine whether urocortin, a member of the corticotrophin-releasing factor (CRF) family, protects adult rat cardiomyocytes from ischemia that has been simulated by glucose deprivation and acidosis. When it was present during simulated ischemia, urocortin (0.1 microM) markedly attenuated the cellular injury, which was assessed by increases in creatine kinase and lactate dehydrogenase levels. This effect was comparable with that observed with adenosine (10 microM). The cardioprotective effect of urocortin was markedly attenuated by the protein kinase C inhibitor chelerythrine and by 5-hydroxydecanoate, an inhibitor of ATP-sensitive K(+) channels. Cardiomyocytes were also protected from injury by pretreatment with urocortin, either by incubation for 5 min with a subsequent 10-min recovery or incubation for 20 min with a 20-h recovery before simulated ischemia. Similar cardioprotective effects were observed with ischemic preconditioning protocols during both immediate and delayed phases. In conclusion, in adult cardiomyocytes, urocortin has immediate and delayed cardioprotective actions that mimic ischemic preconditioning. These actions are mediated via protein kinase C and ATP-sensitive K(+) channels.
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PMID:Cardioprotective action of CRF peptide urocortin against simulated ischemia in adult rat cardiomyocytes. 1238 60

The relative roles of mitochondrial (mito) ATP-sensitive K(+) (mitoK(ATP)) channels, protein kinase C (PKC), and adenosine kinase (AK) in adenosine-mediated protection were assessed in Langendorff-perfused mouse hearts subjected to 20-min ischemia and 45-min reperfusion. Control hearts recovered 72 +/- 3 mmHg of ventricular pressure (50% preischemia) and released 23 +/- 2 IU/g lactate dehydrogenase (LDH). Adenosine (50 microM) during ischemia-reperfusion improved recovery (149 +/- 8 mmHg) and reduced LDH efflux (5 +/- 1 IU/g). Treatment during ischemia alone was less effective. Treatment with 50 microM diazoxide (mitoK(ATP) opener) during ischemia and reperfusion enhanced recovery and was equally effective during ischemia alone. A(3) agonism [100 nM 2-chloro-N(6)-(3-iodobenzyl)-adenosine-5'-N-methyluronamide], A(1) agonism (N(6)-cyclohexyladenosine), and AK inhibition (10 microM iodotubercidin) all reduced necrosis to the same extent as adenosine, but less effectively reduced contractile dysfunction. These responses were abolished by 100 microM 5-hydroxydecanoate (5-HD, mitoK(ATP) channel blocker) or 3 microM chelerythrine (PKC inhibitor). However, the protective effects of adenosine during ischemia-reperfusion were resistant to 5-HD and chelerythrine and only abolished when inhibitors were coinfused with iodotubercidin. Data indicate adenosine-mediated protection via A(1)/A(3) adenosine receptors is mitoK(ATP) channel and PKC dependent, with evidence for a downstream location of PKC. Adenosine provides additional and substantial protection via phosphorylation to 5'-AMP, primarily during reperfusion.
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PMID:Receptor and non-receptor-dependent mechanisms of cardioprotection with adenosine. 1238 77

The aims of this study were to examine the enhancing effects of aloe-emodin anthrone (AEA) on the colonic membrane permeability of water-soluble and poorly permeable compounds and to clarify the mechanism of the permeation-enhancing activity of AEA. The permeation-enhancing activity of AEA was estimated from changes in the permeability coefficient of 5(6)-carboxyfluorescein (CF) in rat colonic mucosa using a Ussing-type chamber. Various inhibitors were used to investigate the mechanism of action of AEA. The structural change in the membrane and the cytotoxicity of AEA in the intestinal mucosa were evaluated by measuring the electrical resistance of the membrane (R(m)) and lactate dehydrogenase (LDH) activity, respectively. AEA significantly increased the permeation of CF in a dose-dependent manner. The enhanced permeability was significantly suppressed by a histamine H(1) receptor antagonist, pyrilamine, and a mast cell stabilizer, ketotifen, but not by a histamine H(2) receptor antagonist, cimetidine. The enhancing effect was also inhibited by an inhibitor of protein kinase C (PKC). Potential difference and short-circuit current values decreased, while R(m) values remained constant throughout the experiment. The addition of AEA to the mucosal solution decreased R(m) to 30%, but then remained constant. LDH activity with AEA was not significantly different from that of the control. In conclusion, AEA is a candidate for effective absorption enhancers without damage of the membrane and cytotoxicity. We propose that AEA stimulates mast cells within the colonic mucosa to release histamine, which probably bind to the H(1) receptor. The intracellular PKC route activated by H(1) receptor activation enhances the permeability of water-soluble and poorly permeable drugs via opening of tight junctions in rat colonic membrane.
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PMID:Permeation-enhancing effect of aloe-emodin anthrone on water-soluble and poorly permeable compounds in rat colonic mucosa. 1249 49

In this study, we have synthesized several compounds and examined their cytotoxic effects on human non-small cell lung cancer A549 cells. We found that GO-13 ((E,E)-2,5-bis[4-(3-dimethyl-aminopropoxy)styryl]-1,3,4-thiadiazole) is the most effective one by the MTT assay. Furthermore, the GO-13-induced apoptotic reaction was identified based on several criteria, such as negative release reaction of lactate dehydrogenase and positive labeling of annexin V and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) techniques. GO-13 induced the apoptosis in A549 cells in a concentration- and time-dependent manner. The data demonstrate that the regulations of p38 mitogen-activated protein kinase and protein kinase C was not involved in the GO-13-mediated mechanism. However, GO-13 significantly induced a down-regulation of Bcl-X(L) expression in a short-term treatment (less than 3hr), whereas stimulated up-regulation of Bax expression in a long-term treatment (24hr) indicating their involvement in GO-13 action. GO-13-mediated apoptosis is also positively correlated with the increase in caspase-3 activity. Worth noting is the fact that GO-13 did not modify the phosphorylation level of Akt/protein kinase B (PKB) until a 24-hr exposure was carried out indicating that the inhibition of Akt/PKB activation was involved in the late-phase apoptosis. Besides the anticancer activity, GO-13 also showed equivalent anti-angiogenic activity in the nude mice angiogenesis model. In summary, we conclude that GO-13 is the most effective anticancer compound in our screening tests. It induced the early-phase apoptosis in A549 cells via the Bcl-X(L) down-regulation, and that of the late-phase through up-regulation of Bax expression as well as inhibition of Akt/PKB activation.
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PMID:Investigation of anticancer mechanism of thiadiazole-based compound in human non-small cell lung cancer A549 cells. 1281 71

Intestinal epithelial cells are constantly stimulated by reactive oxidant metabolites (ROMs) in inflamed mucosa. Monochloramine (NH2Cl), a cell-permeant ROM, is particularly relevant to the pathogenesis of inflammation in the gastrointestinal tract. Nuclear speckles, a unique nuclear subcompartment, accumulate a family of proteins, namely, serine- and arginine-rich (SR) proteins. They play important roles in regulation of pre-mRNA splicing. Currently, little is known about the link between inflammatory stimulation and the pre-mRNA splicing process, although gene expression is changed in inflamed tissues. The present study was designed to investigate whether stimulation of human colonic epithelial cells (HT-29 and Caco-2 cell lines) with NH2Cl affects nuclear speckles and their components. By indirect immunofluorescence, nuclear speckles have been shown to undergo rapid aggregation after NH2Cl stimulation. By utilizing Western blotting, SRp30 (a subset of SR proteins) in intestinal epithelial cells was found to be phosphorylated after NH2Cl treatment, whereas other SR proteins were not responsive to NH2Cl stimulation. The cytotoxic effect of NH2Cl was excluded by both negative lactate dehydrogenase assay and propidium iodide staining. Therefore, NH2Cl-induced morphological changes on nuclear speckles and phosphorylated SRp30 do not result from intestinal epithelial injury. Furthermore, the effect of NH2Cl on nuclear speckles and SRp30 was blocked by bisindolylmaleimide I, a selective PKC inhibitor. Together, the available data suggest that stimulation of intestinal epithelial cells with NH2Cl results in a consequent change on pre-mRNA splicing machinery via a distinctive signal pathway involving activation of PKC. This effect may contribute to oxidant-induced pathophysiological changes in the gastrointestinal tract.
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PMID:Monochloramine induces reorganization of nuclear speckles and phosphorylation of SRp30 in human colonic epithelial cells: role of protein kinase C. 1282

In the present study, we investigated whether a novel benzopyranylindol analogue, KR-31466 (KR466) (1-[(2S,3R,4S)-3,4-dihydro-2-dimethoxymethyl-3-hydroxy-2-methyl-6-nitro-2H-1-benzopyran-4-yl]-1H-indole-2-carboxylic acid ethyl ester) can attenuate hypoxic injury in heart-derived H9c2 cells and, if so, whether the protective effect of KR466 is mediated through mitochondrial ATP-sensitive potassium (mtK(ATP)) opening. The treatment of H9c2 cells with KR466 (3 - 30 microM) significantly reduced hypoxia-induced cell death in a concentration-dependent manner, as shown by lactate dehydrogenase release and propidium iodide-uptake. In addition, KR466 (10 microM) significantly reduced the increase in hypoxia-induced TUNEL-positive cells, suggesting its anti-apoptotic potential in H9c2 cells. The protective effects of KR466 were abolished by 5-hydroxydecanoate, a specific blocker of the mtK(ATP) channel, suggesting the involvement of the mtK(ATP) channel in the protective effect of KR466. A specific inhibitor of protein kinase C (PKC), chelerythrine (3 microM), significantly attenuated the protective effect of KR466 against hypoxia-induced cardiac cell death. In conclusion, our results suggest that KR466 can protect H9c2 cells from hypoxia-induced death through mtK(ATP) channel opening and PKC activation.
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PMID:KR-31466, a benzopyranylindol analog, attenuates hypoxic injury through mitochondrial K(ATP) channel and protein kinase C activation in heart-derived H9c2 cells. 1283 50

Excitotoxicity through stimulation of N-methyl-d-aspartate (NMDA) receptors contributes to neuronal death in brain injuries, including stroke. Several lines of evidence suggest a role for protein kinase C (PKC) isoforms in NMDA excitotoxicity. We have used specific peptide inhibitors of classical PKCs (alpha, beta, and gamma), novel PKCs delta and epsilon, and an atypical PKCzeta in order to delineate which subspecies are involved in NMDA-induced cell death. Neuronal cell cultures were prepared from 15-day-old mouse embryos and plated onto the astrocytic monolayer. After 2 weeks in vitro the neurons were exposed to 100 micro m NMDA for 5 min, and 24 h later the cell viability was examined by measuring the lactate dehydrogenase release and bis-benzimide staining. While inhibitors directed to classical (alpha, beta, and gamma) or novel PKCs (delta or epsilon) had no effect, the PKCzeta inhibitor completely prevented the NMDA-induced necrotic neuronal death. Confocal microscopy confirmed that NMDA induced PKCzeta translocation, which was blocked by the PKCzeta inhibitor. The NMDA-induced changes in intracellular free Ca2+ were not affected by the peptides. In situ hybridization experiments demonstrated that PKCzeta mRNA is induced in the cortex after focal brain ischemia. Altogether, the results indicate that PKCzeta activation is a downstream signal in NMDA-induced death of cortical neurons.
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PMID:Prevention of NMDA-induced death of cortical neurons by inhibition of protein kinase Czeta. 1287 85


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