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)

Human peripheral blood polymorphonuclear leukocytes were perincubated with cystathionine and cystathionine metabolites found in the urine of the patients with cystathioninuria. Among the cystathionine metabolites, cystathionine ketimine significantly enhanced the N-formyl-methionyl-leucyl-phenylalanine-induced superoxide generation, but cystathionine and cyclothionine did not enhance the superoxide generation. Cystathionine ketimine also enhanced superoxide generation induced by opsonized zymosan but not those induced by arachidonic acid and phorbol myristate acetate. Superoxide generation induced by cystathionine ketimine was inhibited by genistein, an inhibitor of tyrosine kinase, and was enhanced by 1-(5-isoquinoline-sulfonyl)-2-methyl-piperazine, an inhibitor of protein kinase C.
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PMID:Effect of cystathionine ketimine on the stimulus coupled responses of neutrophils and their modulation by various protein kinase inhibitors. 857 64

We examined the effects of okadaic acid, a protein phosphatase 1 and 2A inhibitor, on superoxide generation in human neutrophils. Superoxide generation induced by fMLP was inhibited by low-dose okadaic acid (10-100 nM), but it had no effect on superoxide synthesis by PMA, and the fMLP-induced rise of the intracellular Ca2+ concentration was not affected by low-dose okadaic acid. These findings suggested that the inhibitory mechanism of okadaic acid might involve PKC-independent and Ca(2+)-independent pathways in fMLP induced NADPH oxidase activation. Both fMLP-stimulated phosphorylation of serine residues in p47phox and its translocation to the plasma membrane were suppressed by low-dose okadaic acid. On the other hand, PMA-induced phosphorylation and translocation of p47phox were not affected by such a low dose of okadaic acid. These findings suggested that fMLP induced phosphorylation of serine residues in p47phox was regulated by protein phosphatase 2A, and its phosphorylation was necessary for translocation and superoxide generation in fMLP-activated human neutrophils.
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PMID:Involvement of protein phosphatase 2A in PKC-independent pathway of neutrophil superoxide generation by fMLP. 865 38

The effect of prostaglandin F2 alpha (PGF2 alpha) on superoxide radical production by macrophages was studied in pseudopregnant rats. Peritoneal macrophages prepared on day 7 or 13 of pseudopregnancy (psp) were incubated with various doses of PGF2 alpha for 90 min, and the production of superoxide radical was measured by the cytochrome C reduction method. PGF2 alpha significantly stimulated superoxide radical production by macrophages on day 13 of psp, but not on day 7 of psp. The pretreatment of macrophages with an inhibitor of protein kinase C (H7), Ca2+ channel blocker (Verapamil), Ca2+ chelators (EGTA, BAPTA), and an inhibitor of GTP-binding protein (pertussis toxin) prevented the stimulatory effects of PGF2 alpha on superoxide radical production. In conclusion, PGF2 alpha stimulated superoxide radical production by macrophages through the intracellular signal transduction pathway including activation of protein kinase C through the GTP-binding protein and Ca2+ influx, which would play important roles in the luteolytic process in psp rats.
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PMID:[Involvement of stimulatory effect of prostaglandin F2 alpha on superoxide radical production by macrophages in corpus luteum regression]. 875 99

New quinolone (NQ) antimicrobials may influence the functions of polymorphonuclear leukocyes (PMNs). Fleroxacin (FLRX), one of the newer NQs which has a long half-life in blood and a strong bactericidal effect, was examined for its influence on superoxide production by PMNs. Augmentation of superoxide production by PMNs when stimulated with phorbol myristate acetate (PMA) and formyl-methionyl-leucyl-phenylalanine (fMLP) was observed following the addition of 25, 50, 100 and 200 micrograms/ml of FLRX. In addition, the effects of staurosporine and H-7, inhibitors of protein kinase C (PKC), and of genistein, a tyrosine kinase (TK) inhibitor, on FLRX-enhanced superoxide production were examined. Superoxide production augmented by FLRX was diminished by the addition of staurosporine and H-7, when PMNs were stimulated with PMA, and by the addition of genistein, when PMNs were stimulated with fMLP. These results suggest that FLRX augments superoxide production by PMNs through enhancing the activities of phosphorylation by PKC or TK within the signal transduction pathway in PMNs.
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PMID:Fleroxacin enhancement of superoxide production by polymorphonuclear leukocytes: the role of protein kinases. 880 96

Several authors have shown that neutrophil generation of reactive oxygen species (ROS) declines with advancing age. Similar changes have also been suggested in monocytes. In both cases alterations in second messenger activity have been implicated as the most likely explanation for these observations. The aim of this study was to investigate the effect of age on phagocyte ROS generation, stimulated by the direct activation of protein kinase C (PKC). Venous blood was drawn from normal healthy subjects, cells were separated on a double density gradient into mononuclear and polymorphonuclear (pmn) cells. Phorbol myristate acetate (PMA) was employed as a cell stimulus. Superoxide generation was measured by cytochrome c reduction and myeloperoxidase (MPO) products by measurement of peak luminol chemiluminescence (CL). Fifty-eight subjects, 25 males and 33 females, were studied, median age 49 years (range 26-88 years). Polymorphonuclear cell superoxide generation was significantly higher in males and there was a trend towards higher pmn MPO product generation in males. Using Spearman's ranked correlation coefficient, monocyte superoxide generation was negatively correlated with age (r = -0.473, P < 0.001). No changes in the generation of MPO products was found. There were also trends towards a negative correlation of pmn cytochrome c reduction and peak luminol CL with age in males but not females. Since PMA directly activates protein kinase C, reduced monocyte superoxide generation with increasing age appears to be related to alterations in the ROS generating system downstream of the cell receptor. Impaired monocyte superoxide generation may have implications for non-specific defence against certain infections and early tumour growth in the elderly. Factors underlying these changes in monocyte function therefore require further study.
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PMID:Age-related changes in non-receptor dependent generation of reactive oxygen species from phagocytes of healthy adults. 914 66

The anti-ischemic effects of organic nitrates are rapidly attenuated due to the development of nitrate tolerance. The mechanisms underlying this phenomenon likely involve several independent factors. As a vasodilator, nitroglycerin activates compensatory neurohumoral mechanisms such as the renin-angiotensin system and increases catecholamine and vasopressin levels, all of which may attenuate its vasodilator potency. Tolerance may be also due to the inability of the vessel to dilate after prolonged treatment with the nitrate. More recent experimental studies have challenged traditional tolerance concepts by demonstrating that tolerance is not associated with sulfhydryl group depletion, reduced nitroglycerin biotransformation, or desensitization of the target enzyme guanylyl-cyclase. Experimental and clinical observations suggest that tolerance may be the consequence of intrinsic abnormalities of the vasculature, including enhanced endothelial production of oxygen-derived free radicals secondary to an activation of NAD(P)H-dependent oxidases and an activation of PKC. Superoxide degrades nitric oxide derived from nitroglycerin (NTG) while C activation causes enhanced sensitivity of the vasculature to circulating neurohormones such as catecholamines, angiotensin II, and serotonin, all of which may compromise the vasodilator potency of NTG. Interestingly, these vascular consequences of in vivo NTG treatment such as superoxide production and PKC activation can be mimicked in vitro by incubating cultured endothelial and smooth muscle cells with angiotensin II. Furthermore, nitrate tolerance and rebound following sudden cessation of prolonged NTG therapy can be prevented by concomitant treatment with high-dose angiotensin-converting enzyme inhibition, angiotensin type 1 receptor blockade, or antioxidants such as hydralazine. Thus one can conclude that neurohumoral counterregulatory mechanisms such as increased circulating levels of angiotensin II may be at least in part responsible for tolerance mechanisms at the cellular level.
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PMID:Evidence for a role of oxygen-derived free radicals and protein kinase C in nitrate tolerance. 942 22

Different mechanisms have been proposed for the activity of the Bcl-2 proto-oncogene product. A bona fide antioxidant activity and a pro-oxidant setting up of the cell have been suggested using different experimental models, yet many uncertainties exist about the biochemical mechanism of Bcl-2 action. In the present paper, we report the characterization of the cellular response to mild oxidative stress of a cultured cell line of immortalized keratinocytes (HaCaT), overexpressing the Bcl-2 oncogene product. A sublethal oxidative stress was induced by 1 h treatment with 200 microM tert-butyl-hydroperoxide (t-BOOH). Following peroxide treatment, the formation of reactive oxygen species was lower in Bcl-2 expressing cells, suggesting a better capacity to counter oxidative stress. Total Superoxide Dismutase activity was induced by oxidative t-BOOH treatment in bcl-2 transfected cells, which also accumulated less damage to membrane lipids and proteins, as assessed by TBA-RS and carbonyl formation respectively. On the other hand, the formation of 4-hydroxy-nonenal, a more specific marker of peroxidative damage to polyunsaturated fatty acids, was higher in bcl-2 transfected cells than in control cells. Bcl-2 over-expression was also associated with significant changes in the fatty acid composition of cell membranes. Transfected cells presented a higher proportion of mono-unsaturated fatty acids and omega6 poly unsaturated fatty acids and a lower proportion of penta-enoic PUFA, thus resulting in a higher unsaturation index with respect to control cells. Changes in protein kinase C activity were also associated to bcl-2 expression, possibly resulting from the differences in membrane fatty acid composition. These data may be an important background for the understanding of Bcl-2 involvement in the control of apoptotic response as well as in the induction of antioxidant cell defenses against oxidative stress.
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PMID:Bcl-2 overexpression in the HaCaT cell line is associated with a different membrane fatty acid composition and sensitivity to oxidative stress. 943 18

In response to activation of phagocytic cells and during inflammatory disorders, some proteases and very reactive oxygen species are produced. These proteases and oxidants are involved in many diseases like tissue injury or atherosclerosis. We have shown in vitro that verapamil, a calcium channel blocker, had antielastase and antioxidant properties. This drug inhibited the release of elastase by neutrophils in a dose-dependent manner when these cells were stimulated by phorbol-myristate-acetate (PMA), by N-formyl-methionyl-leucylphenylalanine (fMLP) and by the calcium ionophore A23187 (Ca.I). In addition, verapamil inhibited superoxide anion when human neutrophils were stimulated by PMA, fMLP, dioctanoylglycerol (DiC8), Ca.I or by opsonised zymosan (OZ). Verapamil did not act by scavenging elastase or oxidants as demonstrated in cell-free models which showed no direct antielastase or antioxidant effect involved by verapamil. Superoxide anion and elastase inhibition by verapamil has been considered to the mobilization of cytosolic calcium and inhibition of protein kinase C. The results suggest that verapamil might contribute help the development and progression of atheroma where oxidants and elastase are involved.
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PMID:Verapamil inhibits elastase release and superoxide anion production in human neutrophils. 951 2

Monocytes, separated from peripheral blood, preincubated with a mixture of polycyclic aromatic hydrocarbons (PAHs) show an enhanced production of superoxide ions (O2-.) when the cells are stimulated with phorbol 12-myristate 13-acetate (PMA, direct activator of protein kinase C). When opsonized-zymosan is used as a stimulus (receptor-dependent stimulus), no enhanced production of O2-. is observed. Superoxide production increases dose dependently up to a PAH concentration of 5 microg/ml. Although the effect was rather small (125-145% of the control value), it was significant and reproducible. Similar enhancing activity was also observed in the production of hydrogen peroxide (H2O2) excluding an inhibitory effect of PAHs on the enzyme superoxide dismutase (SOD). Since the effect is related to the concentration of PMA and in the absence of stimulus, the O2-. is undetectable in both the control and in the PAHs-treated cells, it is concluded that the over production of O2-. is due to an increased activity of the NADPH oxidase.
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PMID:Polycyclic aromatic hydrocarbons enhance the production of phorbol 12-myristate 13-acetate-induced superoxide ions in human monocytes. 957 4

Periodontal disease, a frequent complication of diabetes mellitus, is the major cause of tooth loss. However, studies on neutrophil function in patients with this condition have yielded contradictory findings. The NADPH oxidase activity of 40 diabetic patients with periodontosis who were on metabolic control was evaluated and compared with that in 40 healthy subjects. Superoxide anion production was measured by a photometric method, with NBT reduction at 490 nm in a microplate reader and by a microscopic method, with a percentage of positive PMNs with granules of formazan in the cytoplasm. When the PMN respiratory burst was activated by phorbol myristate acetate (PMA), a protein kinase C (PKC) soluble activator, superoxide production of diabetics (4.31 +/- 1.67 A x 10(-3)/min) and normal subjects (4.25 +/- 1.25 A x 10(-3)/min) was comparable by photometric method, whereas a significantly defective response to opsonized zymosan was observed when the microscopic method was used (58 +/- 17% in diabetics and 66 +/- 18% in controls; p = 0.05). Therefore in patients with diabetes the impact on PMN function is of multifactorial origin, and is probably correlated to the glucose level and to glycation of PMN protein, such as NADPH oxidase or myeloperoxidase. Alternatively, glucose in PMN may be reduced by aldose reductase to polyols, and this pathway requires NADPH, the coenzyme for the respiratory burst. Moreover, we found that superoxide production in response to opsonized zymosan was reduced in diabetic patients. The activation of protein tyrosine kinase (PTK) is an important mechanism underlying transmembrane signaling and, moreover, protein tyrosine phosphorylations, stimulated by zymosan receptor-mediated activation, might be caused by the activation of specific PTK, whereas activation by PMA is probably mediated through another PKC type.
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PMID:Respiratory burst of neutrophils in diabetic patients with periodontal disease. 970 64


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