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

Stimulation of human SH-SY5Y neuroblastoma cells by a muscarinic receptor agonist, carbachol (CCh; 1 mM), elevated levels of free intracellular calcium and subsequently increased the production of reactive oxygen species (ROS). Quinuclidinylbenzilate (QNB) binding increased at 1 h after CCh, but returned back to the control level at 3 h. Production of ROS increased, however, during the 3 h time period. CCh also increased the translocation of protein kinase C (PKC) to the membrane. ROS production was completely blocked by atropine and a PKC inhibitor, Ro 31-8220. These results show that increased ROS production was a result of muscarinic receptor stimulation, and that PKC had an active role in this cellular stimulation. ROS production upon cellular stimulation by CCh was completely inhibited also by superoxide dismutase, and partially by catalase, indicating that the formation of superoxide anion dominated in cholinergic-induced generation of ROS in human neuroblastoma cells. These results also show that muscarinic stimulation causes sustained ROS production in human neuroblastoma cells. The slow increase in ROS production by CCh suggest a stepwise cascade of events leading to oxidative stress with a triggering role of cholinergic muscarinic receptors in this process.
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PMID:Cholinergic-induced production of reactive oxygen species in human neuroblastoma cells. 915 1

We successfully detected the oxyradical production in human synovial A (macrophage-like) and B (fibroblast-like) cells by phorbol 12-myristate 13-acetate (PMA) using the luminol-chemiluminescence method. The PMA (0.1 microgram/ml)-induced photon generation was abolished by an O2- scavenger, superoxide dismutase, and an H2O2 scavenger, catalase, suggesting that the stimulus produced oxyradicals in synovial cells. Both of these responses were abolished by a protein kinase C (PKC) inhibitor, calphostine C, but unaffected by an intracellular Ca2+ chelator, BAPTA-AM, and Ca2+ removal from the extracellular medium. These findings suggest that synovial A and B cells produce oxyradicals through PKC-mediated and [Ca2+]i-independent mechanisms, probably through the activation of NADPH oxidase.
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PMID:Phorbol 12-myristate 13-acetate (PMA)-induced oxyradical production in rheumatoid synovial cells. 916 72

Acidosis, energy depletion, overstimulation by excitatory amino acids, and free radical-mediated reactions are the major current concepts for the explanation of damage and death resulting from asphyxia. Impaired phosphorylation by protein kinase C (PKC) represents another mechanism incriminated for cell death. We used an unsophisticated perinatal asphyxia model to study heart protein kinases PKC and cyclin dependent kinase (CDK). Tissue pH, ATP, the antioxidant enzymes superoxide dismutase, catalase, and glutathion peroxidase, lipid peroxidation products, carbonyls, and aromatic hydroxylation were also tested. Electron spin resonance was applied to demonstrate the possible presence of radical adducts. An ELISA method was used to determine cell death. PKC activity and mRNA decreased with the length of the asphyctic periods and were paralleled by CDK and pH, whereas cell death gradually increased. No evidence was found for the involvement of active oxygen species or a radical adduct, and no energy depletion was observed. We conclude that impaired protein phosphorylation and/or acidosis may play a role in the pathobiochemistry of death from perinatal asphyxia in the rat.
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PMID:Decrease of heart protein kinase C and cyclin-dependent kinase precedes death in perinatal asphyxia of the rat. 919 29

We measured the production of reactive oxygen species (ROS) using luminol-horseradish peroxidase-induced chemiluminescence in mechanically dispersed cell suspensions from bovine corpus luteum (CL). Since other cell types besides luteal cells were present in crude cell suspensions from CL, cell preparations were purified by centrifugation on Percoll. Only cell suspensions that gave no significant response when stimulated with formyl-methionyl-leucyl-phenylalanine, a potent stimulator of ROS production by phagocytes, were used routinely. Basal ROS production by purified bovine luteal cell preparations was low but could be stimulated rapidly and in a dose-dependent manner by nanomolar concentrations of the protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA), though only in cells purified by fractionation on Percoll. Luteal ROS responses to PMA were quenched by returning bovine erythrocytes to purified luteal cells, or by exogenous catalase or superoxide dismutase. The magnitude of the response to PMA varied markedly from one luteal cell preparation to another but appeared to be unrelated to the stage of the luteal phase of the CL from which the cells were prepared. The luteal ROS response to PMA was blocked by staurosporine, an inhibitor of PKC. Although the inactive phorbol ester (4alpha-phorbol didecanoate; 4alphaPDD) alone had little or no effect on luteal ROS production, 4alphaPDD significantly potentiated the effects of submaximal concentrations of PMA in a dose-dependent manner. ROS production could also be stimulated by the Ca2+ ionophore A23187. This response was rapidly abolished by treatment with EDTA or EGTA. A23187 also augmented the response to submaximal PMA levels: however, pretreatment with 4alphaPDD did not significantly enhance the ROS response to A23187. In conclusion, we have shown that isolated bovine luteal cell suspensions are capable of generating a marked acute ROS response triggered by activation of PKC and/or elevation of cytosolic calcium.
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PMID:Protein kinase C- and Ca2+ ionophore-stimulated production of reactive oxygen species in mechanically dispersed isolated bovine luteal cells. 924 Oct 60

Age-related changes in the activities of acid and neutral cholesteryl ester hydrolases (ACEH and NCEH) and their activation by protein kinase A (PKA) and also by protein kinase C (PKC) were examined in the aortae of 4-, 8-, 12- and 20-week-old rats in relation to their aortic lipid and lipid peroxides and lipid contents. The physiological basal activity as well as total activities of the ACEH and NCEH activated by the two kinases, which were high in the aortae of the 4- and 8-week-old rats, decreased gradually with increasing age to about 40% (ACEH) and 50% (NCEH) by 20 weeks of age. The vitamin E intake and ad libitum-diet intake of the rats each modified the age-related decline of CEH activities. The aortic PKA and PKC activities were reflected by the CEH activities to some degree. The in vitro exposure of the aortic CEH to active oxygen (AO) generators revealed the PKC-mediated activation of CEH, which was inhibited by superoxide dismutase and catalase. These results suggested that the activities of ACEH and NCEH and their regulatory enzymes may be modulated by the dual effect of endogenous AO; an activation of CEH at low doses and an inactivation at high doses, or upon a long-term exposure in aging to a low level of endogenous AO.
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PMID:Age-related changes in the activation of aortic cholesteryl ester hydrolases by protein kinases in rats. 951 48

To evaluate the role of reactive oxygen species (ROS) in Shigella dysenteriae 1 toxin (STx) mediated intestinal infection, the ligated rabbit small intestinal loops were injected with STx. The enterocytes isolated from STx treated rabbit ileal loops had a significantly higher level of lipid peroxidation as compared to enterocytes isolated from control rabbit ileum. To study the role of second messengers in STx mediated intestinal damage, the in vivo and in vitro effects of modulators of lipid peroxidation of enterocytes were used. The presence of Ca2+-ionophore A23187 enhanced the extent of lipid peroxidation in enterocytes isolated from the control and STx treated rabbit ileum. However, 1-verapamil only marginally decreased the lipid peroxidation level of enterocytes isolated from STx treated rabbit ileum. The in vitro effect of modulators was in agreement with in vivo studies. Dantrolene significantly decreased the extent of lipid peroxidation of enterocytes isolated from STx treated rabbit ileum. PMA significantly increased the lipid peroxidation level of enterocytes isolated from control ileum. However, PMA could not further enhance the lipid peroxidation level of enterocytes isolated from STx treated rabbit ileum. The presence of H-7 significantly decreased the extent of lipid peroxidation of enterocytes isolated from STx treated rabbit ileum. In vitro effect of PMA and H-7 was in agreement with that of in vivo findings. The role of arachidonic acid metabolites, prostaglandins (PGs), in mediating STx induced lipid peroxidation was also studied. The presence of indomethacin (a PG synthesis inhibitor) significantly decreased the lipid peroxidation induced by STx. These findings suggest that lipid peroxidation induced by STx is mediated through cytosolic calcium. The increase in (Ca2+)i leads to activation of PKC. A significant decrease in the enterocyte levels of antioxidant enzymes superoxide dismutase, catalase and reduced glutathione in STx treated rabbit ileum as compared to control was seen. A significant decrease in vitamin E levels was also observed. This suggests that there is decreased endogenous intestinal protection against ROS in STx mediated intestinal infection which could contribute to enterocyte membrane damage that ultimately leads to changes in membrane permeability and thus to fluid secretion.
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PMID:Shigella dysenteriae type 1 toxin induced lipid peroxidation in enterocytes isolated from rabbit ileum. 954 97

It has been suggested that reactive oxygen species may be involved in the regulation of vascular tone. However, the underlying mechanisms remain to be elucidated. The present studies were designed to investigate the contractile effects of hydrogen peroxide (H2O2), one of the reactive oxygen species, on isolated ring segments of rat aorta with and without endothelium. H2O2 induced an endothelium-independent contraction in isolated rat aorta ring segments in a concentration-dependent manner at concentrations from 5 x 10(-6) to 5 x 10(-3) M. H2O2-induced contractions of denuded rat aorta rings were stronger than those on intact rat aorta segments. The contractile effects of H2O2 were inhibited completely by 1200 u/ml catalase. The presence of 1.0 microM Fe2+ or 10 microM proadifen, a cytochrome P450 monooxygenase inhibitor, potentiated the contractile effect of H2O2 on isolated rat aorta segments. 1 mM deferoxamine (a Fe2+ chelator) or 100 microM dimethyl sulfoxide (a hydroxyl radical scavenger) significantly attenuated the vessel contractions induced by hydrogen peroxide plus Fe2+ or hydrogen peroxide itself. Removal of extracellular Ca2+ ([Ca2+]0), addition of 5 microM verapamil, administration of a protein kinase C inhibitor (staurosporine), treatment with an inhibitor of protein tyrosine phosphorylation (genistein) or employment of 5.0 microM indomethacin resulted in a significant attenuation of the contractile responses of the vessels to H2O2. Pharmacological antagonists (e.g. a muscarinic acetylcholine receptor antagonist (atropine), an antagonist of histamine H1 receptors (diphenhydramine), an antagonist of histamine H2 receptors (cimetidine), an alpha-adrenoceptor antagonist (phentolamine), a beta-adrenoceptor antagonist (propranolol) and an antagonist of serotonin receptor (methysergide)) did not inhibit or attenuate the contractions induced by H2O2. Exposure of primary aortic smooth muscle cells to H2O2 (5 x 10(-6) to 5 x 10(-3) M) produced significant rises of intracellular Ca2+ ([Ca2+]i) within 20 s. Employment of 1.0 microM Fe2+ markedly enhanced the increment in [Ca2+]i in the smooth muscle cells. 10 microM proadifen treatment failed to alter the hydrogen peroxide-induced increment in [Ca2+]i of the smooth muscle cells. However, the presence of 5 microM indomethacin significantly attenuated the rise in [Ca2+]i in smooth muscle cells. The present results suggest that H2O2 can induce contractions of rat aorta segments, at pathophysiological concentrations, which are Ca2+-dependent. Hydroxyl radicals (.OH), cyclooxygenase products, protein kinase C and products of protein tyrosine phosphorylation appear to play some role in hydrogen peroxide-induced contractions. Metabolites catalyzed by cytochrome P450-dependent enzymes (upon treatment with hydrogen peroxide) appear to exert a vasodilator effect on rat aorta segments. Lastly, some unidentified mediators, produced by a cytochrome P450 inhibitor (proadifen), during hydrogen peroxide treatment, appear to play some role in contraction of vascular smooth muscle of rat aorta segments in vitro.
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PMID:Mechanisms of hydrogen peroxide-induced contraction of rat aorta. 960 Jun 52

Vibrio cholerae O139 has pandemic potential and it produces copious amounts of fluid secretion. The levels of various second messengers (intracellular Ca2+, cAMP, IP3, PKC) were measured to determine the cause of fluid secretion produced by this strain of V. cholerae. There was a significant increase in the levels of these second messengers in V. cholerae O139 treated ileum as compared to control ileum (enterocytes). Levels of these second messengers were also assessed in V. cholerae 569B induced fluid secretion in rabbit ileum and it was found that the levels were raised more in V. cholerae O139 treated ileum than in V. cholerae 569B treated rabbit ileum. The intestinal damage was assessed by measuring changes in the extent of lipid peroxidation of the enterocytes. Intracellular second messengers are known to raise the extent of lipid peroxidation. In V. cholerae O139 treated loops calcium ionophore A23187 enhanced the extent of lipid peroxidation whereas l-verapamil could only marginally decrease the lipid peroxidation. Dantrolene and H7 significantly decreased the extent of lipid peroxidation of enterocytes in V. cholerae O139 treated rabbit ileum. However, PMA could not enhance further the extent of lipid peroxidation in V. cholerae O139 treated rabbit ileum. So intracellular calcium and protein kinase C appear to be involved in intestinal damage caused by V. cholerae O139. Reactive oxygen species are responsible for causing tissue damage and the extent of oxidative damage depends on the balance between the pro-oxidants and the anti-oxidants. So the changes in the enterocytes' antioxidant level during V. cholerae O139 mediated intestinal infection was estimated. There was a significant decrease in the enterocyte level of the antioxidant enzymes SOD, catalase, glutathione peroxidase, glutathione reductase, glutathione transferase and glucose-6-phosphate dehydrogenase in V. cholerae O139 mediated intestinal infection. So a significant decrease in the levels of antioxidant defenses and a significant increase in the levels of second messengers appear to be important in mediating V. cholerae O139 induced lipid peroxidation which contributes to the changes in membrane permeability and thus to fluid secretion.
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PMID:Role of intracellular second messengers and reactive oxygen species in the pathophysiology of V. cholera O139 treated rabbit ileum. 963 66

Regeneration experiments in Hydra have shown that lithium long-term treatment apparently causes a transformation of prospective head into foot tissue. Although lithium ions are known to interfere with the PI-PKC signal-transduction system and evidence has been provided that this system plays a role in pattern formation in Hydra, its role in mediating the lithium effect on patterning is still obscure. The present study provides evidence that H2O2 and presumably also lipid hydroperoxides mediate the lithium effects. First, the perturbation of pattern formation is strikingly stronger in the strain Hydra vulgaris than in Hydra magnipapillata, and similar strain-specific differences are found in the long lasting accumulation of hydroperoxides following lithium treatment. Second, the antioxidant vitamins E and C, which suppress peroxide accumulation, and the H2O2-degrading enzyme catalase significantly protect H. vulgaris from lithium effects. Lithium treatment also negatively affects overall DNA synthesis in a similar strain-specific manner, which, however, cannot be rescued by antioxidant vitamins. The lithium-activated source of peroxide production differs from another source, which generates peroxide in untreated polyps of both strains. The results suggest that lithium treatment-induced peroxide accumulation in H. vulgaris provokes a cytotoxic response showing foot-like characteristics. Nevertheless, a role of peroxides as messengers in pattern forming processes can not be excluded.
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PMID:Hydroperoxides mediate lithium effects on regeneration in Hydra. 966 86

Apoptosis has been documented as a fundamental component of the life cycle of many cell types. One of the characteristics of this process is the cleavage of genomic DNA into oligonucleosomal fragments. The multifunctional cytokine TGF-beta 1 has been described to induce apoptosis in cultured hepatocytes although in this condition DNA fragmentation has not been detected. We investigated whether TGF-beta 1-induced apoptosis was associated with DNA fragmentation and was affected by PMA. Agarose gel electrophoresis of TGF-beta 1-treated hepatocytes shows a typical ladder-like pattern of DNA fragments and PMA, a selective stimulator of protein kinase C, diminishes the DNA fragmentation and cell death. It has been described that the antioxidant enzyme systems play an important role in the control of apoptosis and that the apoptogenic ability of TGF-beta 1 is through the inhibition of antioxidant enzyme expression in cultured hepatocytes [8]. However, PMA does not induce significant changes levels of manganese superoxide dismutase, copper-zinc superoxide dismutase and catalase mRNAs. Our data reveal that the attenuation of TGF-beta 1-induced DNA fragmentation by PMA is not associated with changes in the expression of antioxidant systems and is probably due selectively to the stimulation of protein kinases C.
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PMID:Effect of phorbol ester (PMA) on antioxidant enzyme expression in TGF-beta 1-induced apoptosis in primary cultures of hepatocytes. 969 11


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