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)

Neutrophils undergo constitutive apoptosis when aged ex vivo. Recent studies have indicated roles for Fas/CD95 and the nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase system in this process. We have investigated the role of protein kinase C (PKC) in neutrophil death. We show that there is proteolysis and activation of the novel isoform PKCdelta in aged neutrophils and that this process is accelerated by the addition of an agonistic Fas antibody. PKCdelta proteolysis occurs before the onset of any detectable features of apoptosis and pharmacologic inhibition of this enzyme inhibits neutrophil apoptosis. PKCdelta cleavage and activation is dependent on caspase-8/FADD-like interleukin-1beta converting enzyme (FLICE)-mediated processing of caspase-3/CPP32. Neutrophil survival is prolonged by the addition of broad spectrum (BD.fmk) or caspase-8 targeted (zIETD.fmk) peptide caspase inhibitors. Inhibition of PKCdelta does not prevent apoptosis triggered by factor withdrawal in immature hematopoietic cells, including normal human CD34(+) progenitors indicating that within a given lineage, the mechanisms of apoptosis may be differentiation-stage-specific. Ex vivo aging of neutrophils leads to the increasing production of reactive oxygen species and this is attenuated in cells treated with either caspase or PKCdelta inhibitors. Proteolytically activated PKCdelta acts as a molecular link between the Fas/CD95 receptor and the NADPH-oxidase system and plays a central role in regulating the process of neutrophil apoptosis.
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PMID:Caspase-mediated proteolysis and activation of protein kinase Cdelta plays a central role in neutrophil apoptosis. 1038 25

Nicotinamide, an amide derivative of vitamin B3, was found to inhibit the increase in ras expression, protein kinase C (PKC) activity, and diacylglycerol (DAG) levels in rats treated with N-nitrosodiethylamine (NDEA). It effectively modulated the carcinogen induced increase in the cytosol and the particulate PKC activities but not the nuclear PKC activity. The DAG levels were also modulated by the endobiotic. It may serve as an ideal modulator of carcinogenesis. Nicotinamide is currently under trial as a radio sensitizer, and inhibition of these parameters may be one of the ways in which it confers radiosensitivity.
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PMID:Modulation of NDEA activated ras expression and protein kinase C activity by nicotinamide. 1066 87

We examined involvement of the polyol pathway in high glucose-induced human coronary artery smooth muscle cell (SMC) migration using Boyden's chamber method. Chronic glucose treatment for 72 hours potentiated, in a concentration-dependent manner (5.6 to 22.2 mol/L), platelet-derived growth factor (PDGF) BB-mediated SMC migration. This potentiation was accompanied by an increase in PDGF BB binding, because of an increased number of PDGF-beta receptors, and this potentiation was blocked by the aldose reductase inhibitor epalrestat. Epalrestat at concentrations of 10 and 100 nmol/L inhibited high glucose-potentiated (22.2 mmol/L), PDGF BB-mediated migration. Epalrestat at 100 nmol/L inhibited a high glucose-induced increase in the reduced/oxidized nicotinamide adenine dinucleotide ratio and membrane-bound protein kinase C (PKC) activity in SMCs. PKC inhibitors calphostin C (100 nmol/L) and chelerythrine (1 micromol/L) each inhibited high glucose-induced, PDGF BB-mediated SMC migration. High glucose-induced suppression of insulin-mediated [(3)H]-deoxyglucose uptake, which was blocked by both calphostin C (100 nmol/L) and chelerythrine (1 micromol/L), was decreased by epalrestat (100 nmol/L). Chronic high glucose treatment for 72 hours increased intracellular oxidative stress, which was directly measured by flow cytometry using carboxydichlorofluorescein diacetate bis-acetoxymethyl ester, and this increase was significantly suppressed by epalrestat (100 nmol/L). Antisense oligonucleotide to PKC-beta isoform inhibited high glucose-mediated changes in SMC migration, insulin-mediated [(3)H]-deoxyglucose uptake, and oxidative stress. These findings suggest that high glucose concentrations potentiate SMC migration in coronary artery and that the aldose reductase inhibitor epalrestat inhibits high glucose-potentiated, PDGF BB-induced SMC migration, possibly through suppression of PKC (PKC-beta), impaired insulin-mediated glucose uptake, and oxidative stress.
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PMID:Aldose reductase inhibitor improves insulin-mediated glucose uptake and prevents migration of human coronary artery smooth muscle cells induced by high glucose. 1081 70

Zinc is one of the most abundant transition metals in the brain. A substantial fraction (10-15%) of brain zinc is located inside presynaptic vesicles of certain glutamatergic terminals in a free or loosely bound state. This vesicle zinc is released with neuronal activity or depolarization, probably serving physiologic functions. However, with excess release, as may occur in a variety of pathologic conditions, zinc may translocate to and accumulate in postsynaptic neurons, events which may contribute to selective neuronal cell death. Intracellular mechanisms of zinc neurotoxicity may include disturbances in energy metabolism, increases in oxidative stress, and activation of apoptosis cascades. Zinc inhibits glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and depletes nicotinamide adenine dinucleotide (NAD(+)) and adenosine triphosphate (ATP). On the other hand, zinc activates protein kinase C (PKC) and extracellular signal-regulated kinase (Erk-1/2), and induces NADPH oxidase; these events result in oxidative neuronal injury. Zinc can also trigger caspase activation and apoptosis via the p75(NTR) pathway. Interestingly, the converse-depletion of intracellular zinc-also induces neuronal death, but in this case, exclusively via classical apoptosis. In addition to the neurotoxic effect, zinc may contribute to the pathogenesis of chronic neurodegenerative disease. For example, in Alzheimer's disease (AD), mature amyloid plaques, but not preamyloid deposits, are found to contain high levels of zinc, suggesting the role of zinc in the process of plaque maturation. Further insights into roles of zinc in brain diseases may help set a new direction toward the development of effective treatments.
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PMID:Zinc and disease of the brain. 1183 57

The phagocyte nicotinamide adenine dinucleotide phosphate (reduced form) (NADPH) oxidase was functionally reconstituted in monkey kidney COS-7 cells by transfection of essential subunits, gp91(phox), p22(phox), p47(phox), and p67(phox). COS-7 cells express the essential small guanosine 5'-triphosphatase, Rac1. Transgenic COS-phox cells were capable of arachidonic acid-induced NADPH oxidase activity up to 80% of that of human neutrophils, and of phorbol myristate acetate (PMA)-induced activity up to 20% of that of neutrophils. Expression of all 4 phox components was required for enzyme activity, and enzyme activation was associated with membrane translocation of p47(phox), p67(phox), and Rac1. Expression of p47(phox) Ser303Ala/Ser304Ala or Ser379Ala phosphorylation-deficient mutants resulted in significantly impaired NAPDH oxidase activity, compared with expression of wild-type p47(phox) or the p47(phox) Ser303Glu/Ser304Glu phosphorylation mimic, suggesting that p47(phox) phosphorylation contributes to enzyme activity in the COS system, as is the case in neutrophils. Hence, COS-phox cells should be useful as a new whole-cell model that is both capable of high-level superoxide production and readily amenable to genetic manipulation for investigation of NADPH oxidase function. PMA-elicited superoxide production in COS-phox cells was regulated by activation of protein kinase C (PKC) and Rac. Although COS-7 cells differ from human neutrophils in PKC isoform expression, transient expression of major neutrophil isoforms in COS-phox cells did not increase PMA-induced superoxide production, suggesting that endogenous isoforms were not rate limiting. Val204 in p67(phox), previously shown to be required for NADPH oxidase activity under cell-free conditions, was found to be essential for superoxide production by intact COS-phox cells, on the basis of transfection studies using a p67(phox) (Val204Ala) mutant.
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PMID:Creation of a genetic system for analysis of the phagocyte respiratory burst: high-level reconstitution of the NADPH oxidase in a nonhematopoietic system. 1192 50

The effects of grepafloxacin on the release of cytokines, chemical mediators, hydrolytic enzyme activities, and lipoxygenation in zymogen A- or Staphylococcus aureus-stimulated human THP-1 monocytes were evaluated. Initially, consistent with stimulation of phagocytic mechanisms of the monocytes, increases in cyclic adenosine monophosphate (cAMP) release, nitric oxide [NO] release, and hydrogen peroxide [H(2)O(2)] release, with a small decrease in cellular pH, occurred within 2 h. Enzymatic activities associated with oxygen burst of phagocytic cells (e.g., protein kinase C and nicotinamide adenine dinucleotide phosphate, reduced (NADPH) oxidase) were elevated, suggesting that monocytes attempted to destroy the invading organism through an innate phagocytic cidal immunologic mechanism. After 1-2 h of exposure to grepafloxacin, the oxygen burst and the release of proinflammatory cytokines and chemical mediators were suppressed. After 4 h, suppression of n-acetyl glucosaminidase (NAG) and cathepsin D activities and lipid peroxidation occurred, suppressing the pathogen-induced spread of infection and inflammation. Release of tumor necrosis factor (TNFalpha), interleukin (IL)-1, IL-6, and IL-8 was inhibited by grepafloxacin in a concentration-dependent manner, suggesting a reduction in the acute-phase inflammatory responses initiated by cytokine release from monocytes. Later, S. aureus were killed through inhibition of DNA synthesis, consistent with a bacteriostatic effect. Drug action against invading organisms appears to occur through multiple processes. Modulation of the innate immune system occurs within the first hour, causing the activation of cytokines, chemical mediators, and hydrolytic enzymes. A second phase between 2-4 h appears to involve the suppression of cellular components involved in inflammation and the spread of the infection. The third response, an apparent bacteriostatic inhibition of DNA synthesis, causes bacterial death.
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PMID:In-vitro anti-inflammatory and immunomodulatory effects of grepafloxacin in zymogen A- or Staphylococcus aureus-stimulated human THP-1 monocytes. 1282 12

Psoriasis is an inflammatory disorder characterized by a T helper type 1 cell cytokine pattern. Increased expression of adhesion molecules, prominent neutrophil accumulation, and increased production of nitric oxide are characteristics of this disorder. Moreover, histamine and proteases are supposed to participate in the pathogenesis of psoriasis. Nicotinamide is an inhibitor of poly (ADP-ribose) polymerase-1 (PARP-1) that, through enhancement of nuclear kappa B-mediated transcription, plays a pivotal role in the expression of inflammatory cytokines, chemokines, adhesion molecules, and inflammatory mediators. Through interaction with CD38 and inhibition of IL-1, IL-12, and TNF-alpha production, nicotinamide produces a mild TH2 bias. Nicotinamide is a potent phosphodiesterase inhibitor and suppresses neutrophil chemotaxis and mast cell histamine release. It inhibits nitric oxide synthase mRNA induction and suppresses antigen-induced lymphocyte transformation. Nicotinamide increases the biosynthesis of ceramides, which upon degradation produce sphingosine. Sphingosine inhibits protein kinase C (PKC) and decreases basal cell proliferation dependent on PKC. Taken together, it can be reasoned that nicotinamide could be a useful addition to anti-psoriatic armamentarium. The combination of nicotinamide and thalidomide or methotrexate provided a powerful synergistic inhibition of murine collagen-induced arthritis. Nicotinamide decreased the methotrexate-induced hepatotoxicity. The above combinations may prove to have a powerful anti-psoriatic effect as well. As PARP inhibitors could exert anti-retroviral effect, nicotinamide could also be of special value in the treatment of HIV-infected psoriatics.
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PMID:Nicotinamide: a potential addition to the anti-psoriatic weaponry. 1289 Jun 90

The vasoactive amine histamine is found at high concentrations in the immune and inflammatory tissues. Earlier studies have revealed that histamine regulates the nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase-dependent formation of oxygen radicals by phagocytic cells. However, the effects of histamine on intracellular signal transduction mechanisms of relevance to oxidase regulation remain controversial. For this study, we investigated the effects of histamine on NADPH oxidase activity in human neutrophil granulocytes triggered by a lipoxin A4 receptor agonist [the hexapeptide Trp-Lys-Tyr-Met-Val-Met (WKYMVM), a formyl peptide receptor (FPR) agonist (the chemotactic tripeptide formylmethionyl-leucyl-phenylalanine (fMLF)) and an activator of protein kinase C (phorbol myristate acetate (PMA)]. We report that histamine, acting via H2-type histamine receptors (H2R), suppresses NADPH oxidase-dependent formation of oxygen radicals induced by WKYMVM and fMLF but not that induced by PMA. Peptide-induced mobilization of granule-localized complement receptor 3 (CR3) was unaffected by histamine suggesting that the inhibition specifically affected NADPH oxidase activation. Our data suggest that histamine downregulates FPRL1- and FPR-induced NADPH oxidase activity upstream of protein kinase C (PKC) and downstream of the separation of the peptide-induced signal into granule secretion and oxidase activation.
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PMID:Histamine inhibits neutrophil NADPH oxidase activity triggered by the lipoxin A4 receptor-specific peptide agonist Trp-Lys-Tyr-Met-Val-Met. 1295 Jun 78

The present study was designed to reexamine the muscarinic acetylcholine receptor subtype mediating carbachol-induced contraction of human urinary bladder and to investigate the underlying signal transduction. Based upon the nonselective tolterodine, the highly M(2)-selective (R)-4-[2-[3-(4-methoxy-benzoylamino)-benzyl]-piperidin-1-ylmethyl]piperidine-1-carboxylic acid amide (Ro-320-6206), and the highly M(3)-selective darifenacin and 3-(1-carbamoyl-1,1-diphenylmethyl)-1-(4-methoxyphenylethyl)pyrrolidine (APP), contraction occurs via M(3) receptors. The phospholipase C inhibitor 1-(6-[([17beta]-3-methoxyestra-1,3,5[10]-trien-17-yl)amino]hexyl)-1H-pyrrole-2,5-dione (U 73,122) (1-10 microM) did not significantly affect carbachol-stimulated bladder contraction. The phospholipase D inhibitor butan-1-ol relative to its negative control butan-2-ol (0.3% each) caused small but detectable inhibition of carbachol-induced bladder contraction. The Ca(2+) entry blocker nifedipine (10-100 nM) strongly inhibited carbachol-induced bladder contraction. In contrast, 1-[beta-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl]-1H-imidazole HCl (SK&F 96,365) (1-10 microM), an inhibitor of store-operated Ca(2+) channels, caused little inhibition. The protein kinase C inhibitor bisindolylmaleimide I (1-10 microM) did not significantly affected carbachol-induced bladder contraction. In contrast, trans-4-[(1R)-1-aminoethyl]-N-4-pyridinylcyclohexanecarboxamide (Y 27,632) (1-10 microM), an inhibitor of rho-associated kinases, concentration dependently and effectively attenuated the carbachol responses. We conclude that carbachol-induced contraction of human urinary bladder via M(3) receptors largely depends on Ca(2+) entry through nifedipine-sensitive channels and activation of a rho kinase, whereas phospholipase D and store-operated Ca(2+) channels contribute only in a minor way. Surprisingly, phospholipase C or protein kinase C do not seem to be involved to a relevant extent.
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PMID:Signal transduction underlying carbachol-induced contraction of human urinary bladder. 1476 32

The prevalence of diabetes mellitus is rising worldwide and has reached epidemic dimensions. Diabetes mellitus places patients at high cardiovascular risk. High blood glucose levels, altered insulin signaling, reactive oxygen species (ROS), inflammation, and protein kinase C activation might lead to a decrease in nitric oxide (NO) bioavailability. Diminished NO and enhanced oxidative stress play a central role in several pathophysiologic pathways, leading to vascular damage, such as endothelial dysfunction, vascular inflammation, atherosclerotic plaque formation and vulnerability, and promotion of a prothrombotic state. Possible sources of oxidative excess in diabetes are reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, xanthine oxidase, uncoupled NO synthase, and the mitochondria. Advances in understanding the pathophysiologic mechanisms leading to vascular damage in diabetes will result in discovery of new therapeutic targets, which should help reduce cardiovascular risk in these patients.
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PMID:Nitric oxide, oxidative excess, and vascular complications of diabetes mellitus. 1501 9


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