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)

The biological actions of corticotropin-releasing hormone (CRH) in the human myometrium during pregnancy and labor are unknown. We hypothesized that CRH may modulate the nitric oxide system, and influence myometrial relaxation/contractility. Incubation of myometrial cells with CRH, but not urocortin II or urocortin III, for 8-16 h significantly induced mRNA and protein expression of endothelial and brain but not inducible nitric oxide synthase (NOS) isoforms. This action resulted in increased activity of soluble guanylate cyclase (GC(s)), demonstrated by the enhanced cGMP-producing capacity of the NO donor, sodium nitroprusside. CRH also caused acute activation of the membrane-bound GC, shown by increased basal or atrial natriuretic peptide (ANP)-stimulated cGMP production. These effects appeared to be mediated via the R1 receptors because the CRH receptor antagonists, astressin and antalarmin but not anti-sauvagine 30, could block them. The acute effects of CRH were significantly reduced by inhibition of protein kinase A (PKA) activity, suggesting it is partially PKA dependent. Activation of protein kinase C (PKC) resulted in significant inhibition of both ANP-and CRH-stimulated cGMP production, suggesting a direct effect of PKC on membrane-bound GC. In conclusion, CRH appears to have a dual effect on myometrial NOS/GC pathway, a short term effect predominantly mediated by PKA, and a long-term effect increasing constitutive NOS expression, mediated by a PKA-independent mechanism. This mechanism could potentially be active during human pregnancy, and, because cGMP stimulates myometrial relaxation, these findings further suggest that during pregnancy CRH primarily activates intracellular signals that contribute to the maintenance of myometrial quiescence.
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PMID:Up-regulation of nitric oxide synthase and modulation of the guanylate cyclase activity by corticotropin-releasing hormone but not urocortin II or urocortin III in cultured human pregnant myometrial cells. 1185 58

We have investigated the mechanisms by which prior exposure of mouse macrophages to lipopolysaccharides (LPS) induces a state of low responsiveness to subsequent exposure to IFN-gamma. We demonstrate that induction of this state requires both de novo gene expression and the suppression of phosphorylation events that lead to activation of transcription factor Stat1 alpha. These observations are mechanistically consistent with the known induction of suppressors of cytokine signaling (SOCS)-1 and SOCS-3 proteins by LPS. In this regard, we demonstrate that overexpression of either SOCS protein suppresses induction of the mouse inducible nitric oxide synthase (iNOS) gene promoter: apparently by suppressing interactions between Stat1 alpha and IFN-gamma activated sites present in both the iNOS, and interferon regulatory factor-1, gene promoters. The induction of SOCS-1 and SOCS-3 by LPS or IFN-beta (an autocrine/paracrine mediator of LPS-induced SOCS-1 mRNA synthesis)occurs by way of multiple protein kinase pathways that include protein tyrosine kinases, protein kinase C, and mitogen-activated protein kinases. These results provide insight that may allow discrimination between LPS-induced inhibition of macrophage functions that are detrimental to the host (e.g. continued exposure to LPS) versus those that might potentially be beneficial (e.g. exposure to subsequent agonists that induce more specific macrophage functions).
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PMID:Low responsiveness to IFN-gamma, after pretreatment of mouse macrophages with lipopolysaccharides, develops via diverse regulatory pathways. 1187 Jun 15

Cyclooxygenase-2 (COX-2) is known to mediate the cardioprotective effects of the late phase of ischemic preconditioning (PC); however, the signaling pathways involved in COX-2 induction following ischemic PC are unknown. In addition, although inducible nitric oxide synthase (iNOS) has been identified as a co-mediator of late PC together with COX-2, the interaction between iNOS and COX-2 in the heart is unknown. Using conscious rabbits, we found that the induction of COX-2 expression 24 hours after ischemic PC was blocked by pretreatment with inhibitors of protein kinase C (PKC), Src protein tyrosine kinases (PTKs), and nuclear factor-kappaB (NF-kappaB) but not by inhibitors of NOS or scavengers of reactive oxygen species (ROS). The selective iNOS inhibitors SMT and 1400W, given 24 hours after PC, abrogated the increase in myocardial prostaglandin E2 (PGE2) and 6-keto-PGF1alpha, whereas the selective soluble guanylate cyclase inhibitor ODQ had no effect. COX-2 selective inhibitors (celecoxib and NS-398) did not affect iNOS activity. These results demonstrate that (i) ischemic PC upregulates cardiac COX-2 via PKC-, Src PTK-, and NF-kappaB-dependent signaling pathways, whereas generation of NO and ROS is not necessary, and (ii) the activity of newly synthesized COX-2 following PC requires iNOS-derived NO whereas iNOS activity is independent of COX-2-derived prostanoids, indicating that COX-2 is located downstream of iNOS in the protective pathway of late PC. The data also indicate that iNOS modulates COX-2 activity via cGMP-independent mechanisms. To our knowledge, this is the first demonstration that iNOS-derived NO drives prostanoid synthesis by COX-2 in the heart. NO-mediated activation of COX-2 may be a heretofore unrecognized mechanism by which NO exerts its salubrious effects in the late phase of PC.
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PMID:Inducible nitric oxide synthase modulates cyclooxygenase-2 activity in the heart of conscious rabbits during the late phase of ischemic preconditioning. 1190 25

Cancer chemopreventive agents are designed to reduce the incidence of tumorigenesis by intervening at one or more stages of carcinogenesis. Recently, resveratrol, a natural product found in the diet of humans, has been shown to function as a cancer chemopreventive agent. Resveratrol was first shown to act as an antioxidant and antimutagenic agent, thus acting as an anti-initiation agent. Further evidence indicated that resveratrol selectively suppresses the transcriptional activation of cytochrome P-450 1A1 and inhibits the formation of carcinogen-induced preneoplastic lesions in a mouse mammary organ culture model. Resveratrol also inhibits the formation of 12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted mouse skin tumors in the two-stage model. The enzymatic activities of COX-1 and -2 are inhibited by resveratrol in cell-free models, and COX-2 mRNA and TPA-induced activation of protein kinase C and AP-1-mediated gene expression are suppressed by resveratrol in mammary epithelial cells. In addition, resveratrol strongly inhibits nitric oxide generation and inducible nitric oxide synthase protein expression. NF kappa B is strongly linked to inflammatory and immune responses and is associated with oncogenesis in certain models of cancer, and resveratrol suppresses the induction of this transcription factor by a number of agents. The mechanism may involve decreasing the phosphorylation and degradation of I kappa B alpha. At the cellular level, resveratrol also induces apoptosis, cell cycle delay or a block in the G(1) --> S transition phase in a number of cell lines. Thus, resveratrol holds great promise for future development as a chemopreventive agent that may be useful for several disorders. Preclinical toxicity studies are underway that should be followed by human clinical trials.
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PMID:Cancer chemopreventive activity of resveratrol. 1207 74

Using intestinal (Caco-2) monolayers, we reported that inducible nitric oxide synthase (iNOS) activation is key to oxidant-induced barrier disruption and that EGF protects against this injury. PKC-zeta was required for protection. We thus hypothesized that PKC-zeta activation and iNOS inactivation are key in EGF protection. Wild-type (WT) Caco-2 cells were exposed to H(2)O(2) (0.5 mM) +/- EGF or PKC modulators. Other cells were transfected to overexpress PKC-zeta or to inhibit it and then pretreated with EGF or a PKC activator (OAG) before oxidant. Relative to WT cells exposed to oxidant, pretreatment with EGF protected monolayers by 1) increasing PKC-zeta activity; 2) decreasing iNOS activity and protein, NO levels, oxidative stress, tubulin oxidation, and nitration); 3) increasing polymerized tubulin; 4) maintaining the cytoarchitecture of microtubules; and 5) enhancing barrier integrity. Relative to WT cells exposed to oxidant, transfected cells overexpressing PKC-zeta (+2.9-fold) were protected as indicated by decreases in all measures of iNOS-driven pathways and enhanced stability of microtubules and barrier function. Overexpression-induced inhibition of iNOS was OAG independent, but EGF potentiated this protection. Antisense inhibition of PKC-zeta (-95%) prevented all measures of EGF protection against iNOS upregulation. Thus EGF protects against oxidative disruption of the intestinal barrier by stabilizing the cytoskeleton in large part through the activation of PKC-zeta and downregulation of iNOS. Activation of PKC-zeta is by itself required for cellular protection against oxidative stress of iNOS. We have thus discovered novel biologic functions, suppression of the iNOS-driven reactions and cytoskeletal oxidation, among the atypical PKC isoforms.
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PMID:PKC-zeta prevents oxidant-induced iNOS upregulation and protects the microtubules and gut barrier integrity. 1222 51

Advanced glycosylation end products (AGEs) have been implicated in the pathogenesis of diabetic complications. Treatment of RAW 264.7 macrophages with bovine serum albumin (BSA)-derived AGEs caused dose- and time-dependent increases in nitrite production and inducible nitric oxide synthase (iNOS) expression. These effects were blocked by the nuclear factor-kappa B (NF-kappaB) inhibitor, pyrrolidone dithiocarbamate (PDTC). BSA-AGEs also stimulated the translocation of p65 NF-kappaB from cytosol to the nucleus. Electrophoretic mobility shift assay revealed that the NF-kappaB DNA-protein-binding activity was enhanced by AGEs. The tyrosine kinase inhibitor, genistein, the phosphatidylinositol-3-kinase (PI 3-K) inhibitor, LY 294002, the protein kinase C (PKC) inhibitor, Ro 31-8220, and the p38 mitogen-activated protein kinase (MAPK) inhibitor, SB 203580, all inhibited AGEs-stimulated iNOS expression, NO release, NF-kappaB translocation and NF-kappaB DNA binding activity. These results suggest that AGEs may activate NF-kappaB via an upstream signaling cascade composed of tyrosine kinase, PI 3-K, PKC, and p38 MAPK, resulting in the induction of iNOS expression in RAW 264.7 macrophages.
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PMID:Advanced glycosylation end products induce NF-kappaB dependent iNOS expression in RAW 264.7 cells. 1224 23

We have previously shown that overexpression of a dominant-negative (DN) mutant of protein kinase C-alpha (PKC-alpha) in RAW 264.7 macrophages inhibited lipopolysaccharide (LPS)-induced IL-1alpha, inducible nitric oxide synthase and cyclooxygenase-2 expression. This inhibition was not related to defective NF-kappaB nuclear translocation, suggesting that PKC-alpha might be involved in the modulation of other LPS-inducible transcription factors. In the present study, we have investigated the impact of PKC-alpha on the activation of AP-1 and NF-IL6 in LPS-treated RAW 264.7 macrophages. Electrophoretic mobility shift assays and luciferase reporter constructs revealed that LPS-induced AP-1 transcriptional activity was normal in DN PKC-alpha-overexpressing RAW 264.7 cells. In contrast, LPS-induced DNA-binding and transcriptional activities of NF-IL6 were inhibited in DN PKC-alpha-overexpressing RAW 264.7 cells and correlated with an impairment of NF-IL6 nuclear translocation. Conversely, overexpression of either wild-type PKC-alpha or a constitutively active PKC-alpha mutant significantly enhanced LPS-stimulated NF-IL6-dependent promoter activity. Finally, LPS-induced expression of two genes regulated by NF-IL6, namely IL-1beta and granulocyte colony-stimulating factor, was impaired in DN PKC-alpha-overexpressing RAW 264.7 cells. Taken together, these results suggest that regulation of NF-IL6 activity constitutes one of the mechanisms by which PKC-alpha modulates LPS-induced gene expression in the mouse macrophage cell line RAW 264.7.
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PMID:Modulation of lipopolysaccharide-induced NF-IL6 activation by protein kinase C-alpha in a mouse macrophage cell line. 1235 43

The action mechanisms of several chemopreventive agents derived from herbal medicine and edible plants have become attractive issues in cancer research. Tea is the most widely consumed beverage worldwide. Recently, the cancer chemopreventive actions of tea have been intensively investigated. It have been demonstrated that the active principles of tea were attributed to their tea polyphenols. Recently, tremendous progress has been made in elucidating the molecular mechanisms of cancer chemoprevention by tea and tea polyphenols. The suppression of various tumor biomarkers including growth factor receptor tyrosine kinases, cytokine receptor kinases, PI3K, phosphatases, ras, raf, MAPK cascades, N x FB, I x B kinase, PKA, PKB, PKC, c-jun, c-fos, c-myc, cdks, cyclins, and related transducing proteins by tea polyphenols has been studied in our laboratory and others. The I x B kinase (IKK) activity in LPS-activated murine macrophages (RAW 264.7 cells) was found to be inhibited by various tea polyphenols including (-) epigallocatechin-3-gallate (EGCG), theaflavin (TF-1), theaflavin-3-gallate (TF-2) and theaflavin-3,3'-digallate (TF-3). TF-3 inhibited IKK activity in activated macrophages more strongly than did the other tea polyphenols. TF-3 inhibited both IKK1 and IKK2 activity and prevented the degradation of I x B x and I x B x in activated macrophage cells. The results suggested that the inhibition of IKK activity by TF-3 and other tea polyphenols could occur by a direct effect on IKKs or on upstream events in the signal transduction pathway. TF-3 and other tea polyphenols blocked phosphorylation of IB from the cytosolic fraction, inhibited NFB activity and inhibited increases in inducible nitric oxide synthase levels in activated macrophage. TF-3 and other tea polyphenols also inhibited strongly the activities of xanthine oxidase, cyclooxygenase, EGF-receptor tyrosine kinase and protein kinase C. These results suggest that TF-3 and other tea polyphenols may exert their cancer chemoprevention through suppressing tumor promotion and inflammation by blocking signal transduction. The mechanisms of this inhibition may be due to the blockade of the mitogenic and differentiating signals through modulating EGFR function, MAPK cascades, NFkappaB activation as well as c-myc, c-jun and c-fos expression.
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PMID:Cancer chemoprevention by tea polyphenols through modulating signal transduction pathways. 1243 85

Brief periods of non-lethal ischemia and reperfusion render the myocardium more resistant to subsequent ischemia. This adaption occurs in a biphasic pattern: the first being active immediately and lasting for 2-3 hrs (early preconditioning), the second starting at 24 hrs until 72 hrs after the initial ischemia (delayed preconditioning) and requiring genomic activation with de novo protein synthesis. Early preconditioning is more potent than delayed preconditioning in reducing infarct size; delayed preconditioning also attenuates myocardial stunning. Early preconditioning depends on the ischemia-induced release of adenosine and opioids and, to a lesser degree, also bradykinin and prostaglandins. These molecules activate G-protein coupled receptors, initiate the activation of KATP channels and generation of oxygen radicals, and stimulate a series of protein kinases with essential roles for protein kinase C, tyrosine kinases and members of the MAP kinase family. Delayed preconditioning is triggered by a similar sequence of events, but in addition essentially depends on eNOS-derived NO. Both early and pharmacological preconditioning can be pharmacologically mimicked by exogenous adenosine, opioids, NO and activators of protein kinase C. Newly synthetized proteins associated with delayed preconditioning comprise iNOS, COX-2, manganese superoxide dismutase and possibly heat shock proteins. The final mechanism of protection by preconditioning is yet unknown; energy metabolism, KATP channels, the sodium-proton exchanger, stabilisation of the cytoskeleton and volume regulation will be discussed. For ethical reasons, evidence for ischemic preconditioning in humans is hard to provide. Clinical findings that parallel experimental ischemic preconditioning are reduced ST-segment elevation and pain during repetitive PTCA or exercise tests, a better prognosis of patients in whom myocardial infarction was preceded by angina, and reduced serum markers of myocardial necrosis after preconditioning protocols during cardiac surgery with cardiac arrest. The most promising approach to apply principles of ischemic preconditioning therapeutically appears to be the pharmacological recruitment of delayed protection, as recently demonstrated with intravenous nitroglycerine in patients undergoing PTCA 24 hrs later.
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PMID:Ischemic preconditioning. Experimental facts and clinical perspective. 1247 80

Nitrate reductasing and immunoblotting test were used to investigate the modulation of protein kinase C (PKC) activity in cultured rat vascular smooth muscle cells (VSMCs) with high concentration of insulin (HI) and the effect of HI on lipopolysaccharides + gamma-interferon (LPS + gamma-IFN)-induced nitric oxide (NO) production and inducible nitric oxide synthase (iNOS) expression with or without PKC inhibitor H7. The results were that membrane PKC activity preincubated with HI was significantly higher than that with the control group(P < 0.05), and NO production pretreated by HI was obviously lower than that of the control group(P < 0.01). PKC inhibitor H7 ameliorated the down-regulation of LPS + gamma-IFN induced NO production by high concentration of insulin. Immunoblotting test revealed a decrease induced by the high level insulin in the expression of iNOS in VSMCs. It is suggested that hyperinsulinism may activate PKC to partly inhibit the expression of iNOS and decrease NO production in VSMCs.
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PMID:[Effect of hyperinsulinism on NO production in vascular smooth muscle cells]. 1253 85


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