Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.6.3.1 (NADPH oxidase)
11,281 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Both 1,2-diacyl- and 1-O-alkyl-2-acyl-sn-glycerols are released during stimulation of human polymorphonuclear leukocytes (PMNL). 1,2-Diacylglycerols have received intense interest as intracellular "second messengers" due to their ability to activate protein kinase C (Ca2+ phospholipid-dependent enzyme). However, little is known about bioactivities of the alkylacylglycerols. This study compared the ability of 1,2-diacyl- and 1-O-alkyl-2-acylglycerols to modulate the respiratory burst of stimulated PMNL, a response which depends on the activation of an NADPH oxidase to generate bactericidal species of reduced oxygen. Direct stimulation by N-formyl-Met-Leu-Phe caused an abrupt release of H2O2 which ceased within 2.5 min. Preincubation with diacylglycerols (1-oleoyl-2-acetylglycerol,5-30 microM, and 1,2-dioctanoylglycerol,2-5 microM) caused a decrease in lag time, 3-fold increase in initial rate of H2O2 release, and marked prolongation of the response to N-formyl-Met-Leu-Phe (features characteristic of a priming effect). Preincubation with alkylacylglycerols (1-O-delta 9-octadecenyl-2-acetylglycerol, 5-30 microM, and 1-O-octyl-2-octanoylglycerol, 20-50 microM) primed initiation (shortened lag time and increased velocity) but, in contrast to diacylglycerols, did not alter duration of H2O2 release. While low concentrations of diacylglycerols (5-30 microM) primed PMNL, higher concentrations (greater than or equal to 70 microM) stimulated the cells directly. In contrast, higher (70-100 microM) concentrations of alkylacylglycerols did not prime the responses but, in fact, inhibited priming (especially of duration) induced by diacylglycerol. The high concentrations of alkylacylglycerol also inhibited direct stimulation induced by high concentrations of diacylglycerol. Direct stimulation by high concentrations of diacylglycerol probably involves activation of protein kinase C, whereas alkylacylglycerol was found to inhibit activation of protein kinase C by diacylglycerol in vitro. Thus, diacylglycerols are complete priming agonists, altering both rate and duration of the response. In contrast, alkylacylglycerols may have biphasic, concentration-related effects in modulation of functions of PMNL. At low concentrations, they may facilitate initiation of functional events; however, as their concentration increases, they may serve to terminate responses. The distinct priming effects of these diglycerides also reveal that priming can involve at least two distinct events: 1) initiation and 2) prolongation.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Selective priming of rate and duration of the respiratory burst of neutrophils by 1,2-diacyl and 1-O-alkyl-2-acyl diglycerides. Possible relation to effects on protein kinase C. 319 43

A sensitive luminol-dependent chemiluminescence assay for H2O2 was developed for the indirect determination of the transient changes in NADPH oxidase activity associated with the respiratory burst of human neutrophils. A relatively large, controlled amount of horseradish peroxidase was used in combination with added luminol to rapidly remove and simultaneously detect H2O2 as soon as it is formed, thus preventing its accumulation during burst activity and minimizing the effects of side reactions. Cell-derived myeloperoxidase and possibly catalase were inhibited with 90 microM sodium azide to maintain the total catalytic activity toward H2O2 at a constant level. Chemiluminescence measurements of the respiratory burst activity of human neutrophils stimulated with N-formyl-Met-Leu-Phe (fMLP) were in good agreement with measurements made using an established fluorometric assay based on similar principles (P. A. Hyslop and L. A. Sklar (1984) Anal. Biochem. 141, 280-286). In contrast to fluorometry, the chemiluminescence progress curves reflect the instantaneous rather than the integrated levels of H2O2 at any time and are thus a more direct measure of the activity of the NADPH oxidase. This advantage, as well as higher signal-to-noise ratios and greater inherent sensitivity, distinguishes chemiluminescence as a means of following burst activity. The onset of fMLP-stimulated H2O2 generation was detectable by chemiluminescence within 2 s of stimulation (as opposed to more than double this time by fluorometry), showing that high sensitivity is an important consideration in evaluating respiratory burst kinetics. In contrast to fMLP stimulation, longer and concentration-dependent onset times were observed when phorbol myristate acetate was used as a stimulus.
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PMID:Chemiluminescence detection of H2O2 produced by human neutrophils during the respiratory burst. 342 6

The effect of modification of maleimide derivatives on superoxide production by guinea-pig neutrophils induced by a variety of different soluble stimuli was studied. Pretreatment of neutrophils by showdomycin, a very slowly penetrating-SH reagent, did not affect superoxide production by all of the stimuli used, suggesting no exposure of sulfhydryl groups involved in superoxide-generating system on the cell surface. Pretreatment with N-ethylmaleimide (MalNEt), a considerably penetrating-SH reagent, markedly inhibited superoxide production stimulated by formyl-methionyl-leucyl-phenylalanine (HCO-Met-Leu-Phe), cytochalasin E or digitonin, but not superoxide production stimulated by the ionophore A23187 or sodium fluoride. The oxygen consumption stimulated by HCO-Met-Leu-Phe or cytochalasin E was inhibited by MalNEt pretreatment, whereas the oxygen consumption stimulated by A23187 was not inhibited by MalNEt. The inhibition by MalNEt of superoxide production did not appear to be due to the interference with binding of the affected stimuli, since MalNEt pretreatment did not inhibit the release of lysozyme, granule enzyme, induced by HCO-Met-Leu-Phe, cytochalasin E or digitonin. Particulate fractions from MalNEt-pretreated neutrophils before exposure to the stimulus exhibited the inhibition of the enhancement of NADPH-dependent superoxide production induced by HCO-Met-Leu-Phe, cytochalasin E or digitonin, but not A23187, whereas treatment of neutrophils with MalNEt after activation by these stimuli had no effect on the NADPH oxidase activity in particulate fractions. Direct exposure of particulate fractions from A23187-stimulated neutrophils to MalNEt showed no actual susceptibility of NADPH oxidase to MalNEt inhibition. These findings suggest that the inhibitory effect of MalNEt is caused by the modification of the process of the activation by the affected stimuli of the superoxide system, probably NADPH oxidase and that at least two mechanisms exist for activation of superoxide-generating system in guinea-pig neutrophils on the basis of the susceptibility to MalNEt inhibition.
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PMID:Effect of maleimide derivatives on superoxide-generating system of guinea-pig neutrophils stimulated by different soluble stimuli. 609 85

We explored the effects of compounds known or proposed to affect microtubule functions on superoxide (O2-) production in human polymorphonuclear leukocytes stimulated by N-formyl-methionyl-phenylalanine (f-Met-Phe), calcium ionophore A23187 and phorbol myristate acetate. F-Met-Phe-induced O2- production was markedly potentiated not only by microtubule-disrupting agents, including colchicine, vincristine, vinblastine, nocodazole, podophyllotoxin and griseofulvin, but also deuterium oxide (2H2O), which is proposed to stabilize microtubules, and not affected by lumicolchicine. Ionophore A23187-induced O2- production was not influenced by colchicine, and markedly enhanced by 2H2O, whereas phorbol myristate acetate-induced O2- production was not influenced by colchicine, and slightly inhibited by 2H2O. 2H2O did not counteract the effects of colchicine and vice versa. Dibutyryl cyclic AMP and prostaglandin E1 inhibited O2- production stimulated by f-Met-Phe and ionophore A23187, whereas phorbol myristate acetate-induced O2- production was strongly resistant to the inhibitory effect of these agents. The enhancing effect of colchicine and 2H2O on f-Met-Phe-induced O2- production was abolished by dibutyryl cyclic AMP. Colchicine promoted concanavalin A cap formation, and 2H2O produced concanavalin A patch formation, whereas dibutyryl cyclic AMP did not affect the distribution of concanavalin A receptors. In addition, 2H2O and dibutyryl cyclic AMP did not interfere with the colchicine-induced concanavalin A cap formation. These findings suggest that f-Met-Phe, ionophore A23187 and phorbol myristate acetate may activate the oxidative metabolism of human polymorphonuclear leukocytes through different mechanisms, and that microtubule-disrupting agents, 2H2O and cyclic AMP agonists may affect the different steps of the activating system of NAD(P)H oxidase.
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PMID:Effect of microtubule-disrupting agents on superoxide production in human polymorphonuclear leukocytes. 629 8

Production of reactive oxygen intermediates (ROI) by the NADPH oxidase of neutrophils is a major mechanism of bacterial killing and, in pathologic circumstances, tissue damage. Integrins and selectins participate in neutrophil adhesion but may also play a role in intracellular signaling. The role of L-selectin in ROI production and Ca2+ signaling in suspended neutrophils was examined using the DREG series of anti-L-selectin antibodies. NADPH oxidase activation was assessed in three ways: H2O2 production using either scopoletin or dihydrorhodamine and O2- production using cytochrome c. Alterations in [Ca2+]i were measured using Fura 2-AM and fluorescence spectrophotometry. Cross-linking of L-selectin with DREG and 2 degrees antibody did not trigger production of H2O2 by itself but significantly enhanced the subsequent response to two soluble activating agents; the formyl peptide formyl-Met-Leu-Phe (fMLP) and tumor necrosis factor (TNF). Potentiation of the oxidative burst was observed using F(ab')2 fragments but not with irrelevant antibodies and was observed whether 2 degrees antibody was added before or after fMLP. Cross-linking of L-selectin also triggered a rise in [Ca2+]i, due, in part, to release from intracellular stores. The intracellular Ca2+ chelator BAPTA blocked both the rise in [Ca2+]i and the potentiation of the oxidative burst in response to fMLP or TNF. We conclude that cross-linking of L-selectin induces intracellular signals, including release of Ca2+, which may contribute to potentiation of the oxidative burst.
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PMID:Potentiation of the oxidative burst of human neutrophils. A signaling role for L-selectin. 751 34

Cytosolic components of the phagocyte NADPH oxidase (p47phox, p67phox, and Rac2) translocate to the plasma membrane on cell activation where they interact with a membrane-bound cytochrome b to generate superoxide anion. Phosphorylation reactions are known to be important for activity of NADPH oxidase. Translocation of Rac2, p47phox, and p67phox were all enhanced in formyl-Met-Leu-Phe-stimulated neutrophils treated with 50 nM of the protein phosphatase 1/2A inhibitor calyculin A. Rac translocation was blocked by the tyrosine kinase inhibitors genistein (50 microM) and herbimycin (17 microM), whereas movement of p47phox and p67phox were not inhibited. Cell-free analysis of Rac translocation also demonstrated that translocation of p47phox and p67phox were not linked to the movement or availability of Rac2. Thus, Rac2 does not appear to regulate NADPH oxidase by controlling movements of the cytosolic components to the membrane-associated enzyme but may exert its effect at the level of the assembled complex. Tyrosine kinase activity is required for translocation of Rac in the chemoattractant-stimulated human neutrophil.
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PMID:Dissociation of Rac translocation from p47phox/p67phox movements in human neutrophils by tyrosine kinase inhibitors. 761 2

Induction of specific heat shock (HS) proteins (HSP) has been described as a response of human monocytes to phagocytosis, and HSP may play protective roles in infection and immunity. Here we compared the stress response in monocytes and polymorphonuclear neutrophils during exposure to the classical inducers of HSP, i.e., HS and cadmium. We also investigated the stress response in these two phagocytic cells after particulate (phagocytosis) and nonparticulate [f-Met-Leu-Phe (FMLP)] activation of the respiratory burst enzyme NADPH oxidase. HS and cadmium induced stress protein synthesis in both cell types. In contrast, phagocytosis induced HSP in monocytes only, while FMLP did so in neutrophils only. This differential regulation of stress proteins might relate to physiological and functional differences between monocytes and neutrophils. With respect to functional effects of HS, we examined, in human monocytes and in neutrophils, the effect of HS on NADPH oxidase-mediated O2- generation as well as on phagocytosis, bacterial killing, and superoxide dismutase (SOD) activity. In monocytes, as in neutrophils, NADPH oxidase activity was inhibited by HS, while thermotolerance prevented this inhibition. Phagocytosis and bacterial killing were unaltered by HS. SOD activity transiently increased in monocytes but decreased in neutrophils upon exposure to HS. These observations indicate differential induction of HSP in human phagocytes and differential regulation of phagocytes' functions by HS.
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PMID:Differential induction of stress proteins and functional effects of heat shock in human phagocytes. 762 64

Daphnoretin, a dicoumarin isolated from Wikstroemia indica C.A. Mey. (Thymelaceae), induced superoxide anion (O2-) formation in rat neutrophils in a concentration-dependent manner. Addition of staurosporine reduced daphnoretin-induced respiratory burst. Removal of extracellular free Ca2+ by EGTA did not affect the respiratory burst of neutrophils in response to daphnoretin. Prior exposure of neutrophils to phorbol 12-myristate 13-acetate (PMA) or daphnoretin reduced the O2- formation caused by a subsequent challenge with PMA and daphnoretin, but potentiated the response caused by a subsequent addition of formyl-Met-Leu-Phe (fMLP). Like PMA, daphnoretin did not increase the [Ca2+]i during cell activation. In neutrophil suspension, daphnoretin increased the membrane associated protein kinase C activity. In the presence of Ca2+ and phosphatidyl-serine, daphnoretin also activated protein kinase C isolated from cytosolic fraction of resting neutrophils. Staurosporine inhibited the direct activation of protein kinase C caused by daphnoretin as well as by PMA. Daphnoretin reduced the [3H]Phorbol-12,13-dibutyrate ([3H]PDB) binding to the neutrophil cytosolic protein kinase C in a concentration-dependent manner with an IC50 value of 1.77 +/- 0.37 microM. These results indicate that daphnoretin, like PMA, may direct activation of protein kinase C which in turn activated NADPH oxidase and elicited respiratory burst.
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PMID:Daphnoretin-induced respiratory burst in rat neutrophils is, probably, mainly through protein kinase C activation. 777 78

In human polymorphonuclear leukocytes (PMNs), mitogen-activated protein kinases (MAPKs), also known as extracellular signal-regulated kinases (Erks), are activated within minutes upon stimulation with either chemoattractant formyl-Met-Leu-Phe (fMLP) or phorbol 12-myristate 13-acetate (PMA). This activation of MAPKs coincides with the formation of superoxide anion, which occurs through the activation of a multiple-component NADPH oxidase pathway. MAPKs have thus been suggested to be involved in signal transduction leading to the oxidative burst. To investigate whether MAPK activation plays a central role in the oxidative burst, we evaluated the effect of cAMP on MAPK activation induced by fMLP and PMA. cAMP inhibits many PMN functional responses, including the oxidative burst, and has recently been shown to reduce growth factor- and PMA-induced MAPK activities in a variety of cells. We found that in differentiated, neutrophil-like HL-60 cells, while cAMP reduced PMA-induced MAPK activation, it had no effect on fMLP-induced MAPK activation. Despite the presence of unchanged levels of activated MAPKs, the fMLP-induced oxidative burst was substantially diminished by cAMP. By contrast, O2-production induced by PMA remained the same even though MAPK activation was inhibited. In PMNs, although the levels of O2-induced by either 10 ng/ml or 100 ng/ml PMA were similar, only 100 ng/ml could stimulate MAPK activation, suggesting that the oxidative burst could occur in the absence of detectable activation of MAPKs. As in HL-60 cells, cAMP inhibited the O2-production in fMLP-stimulated PMNs but had no effect on MAPK activity. These results demonstrate that, while MAPK activation coincides with PMN activation, it can be dissociated from the oxidative burst.
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PMID:Dissociation of mitogen-activated protein kinase activation from the oxidative burst in differentiated HL-60 cells and human neutrophils. 779 73

1. The possible mechanisms of action of the inhibitory effect of gomisin C on the respiratory burst of rat neutrophils in vitro was investigated. 2. The peptide formyl-Met-Leu-Phe (FMLP) induced superoxide anion (O2-) formation and O2 consumption, which was inhibited by gomisin C in a concentration-dependent manner (IC50 21.5 +/- 4.2 micrograms ml-1 for O2- formation). Gomisin C also suppressed O2- formation and consumption at low concentrations of phorbol myristate acetate (PMA) with an IC50 value of 26.9 +/- 2.1 micrograms ml-1 for O2- formation. However, gomisin C did not affect the responses induced by a high concentration of PMA. 3. Gomisin C had no effect on O2- generation and uric acid formation in the xanthine-xanthine oxidase system, and failed to alter O2- generation during dihydroxyfumaric acid (DHF) autoxidation, indicating that it does not scavenge superoxide. 4. Like trifluoperazine (TFP), gomisin C attenuated the activity of PMA-activated neutrophil particulate NADPH oxidase in a concentration-dependent manner. 5. Gomisin C reduced the elevations of cytosolic free Ca2+ in neutrophils stimulated by FMLP in the presence or absence of EDTA. Cyclopiazonic acid (CPA) induced the release of Ca2+ from intracellular stores and this was also reduced by gomisin C. However, the Ca2+ influx pathway activated by CPA was not affected by gomisin C. 6. The cellular cyclic AMP level was markedly increased by forskolin, but not by gomisin C. Moreover, the inositol phosphate levels in FMLP-activated neutrophils were not affected by gomisin C. 7. These results show that the inhibitory action of gomisin C on the respiratory burst is not mediated by changes in cellular cyclic AMP or in inositol phosphates, or by scavenging O2- released from neutrophils, but may be mediated partly by the suppression of NADPH oxidase and partly by the decrease of cytosolic Ca2+ released from an agonist-sensitive intracellular store.
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PMID:Inhibition by gomisin C (a lignan from Schizandra chinensis) of the respiratory burst of rat neutrophils. 785 90


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