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)

Poly-L-histidine (PHSTD) of molecular weight 26,000 induced the generation of large amounts of superoxide (O2-) and hydrogen peroxide (H2O2) in human neutrophils (PMNs). Despite its low solubility at neutral pH, PHSTD was bound very rapidly to the PMN surfaces. Maximal generation of O2- took place with 4-5 X 10(-6) M of PHSTD, starting after a lag of about 25 sec and proceeding for 15-17 min at a rate of 150 nmol/10(7) PMNs/min, suggesting that this polycation is one of the most potent stimulators of O2- generation known, PHSTD was found to be non-toxic for PMNs even at millimolar concentrations. Generation of O2- by PHSTD depended on extracellular calcium; it was inhibited by calcium channel blockers and by trifluoperazine, and it triggered a sharp rise in intracellular calcium as determined by the Quin 2 fluorescence technique. The generation of both O2- and H2O2 by PHSTD was partially inhibited by cytochalasin B or (CYB, CYE). On the other hand, CYB markedly enhanced the generation of both O2- and H2O2 following stimulation of PMNs either by PHSTD, polyarginine, histone, or by antibody-opsonized group A streptococci. Electron microscopic analysis and NBT reduction tests revealed that both PHSTD and PHSTD-opsonized streptococci were avidly phagocytosed by PMNs. Since CYB totally inhibited internalization of both PHSTD and the PHSTD-opsonized streptococci, it was suggested that these agents stimulated oxygen radical generation mainly on the leukocyte surfaces. Complexes (CX) formed between PHSTD and polyanethole sulfonate (a strong polyanion) or between histone and the polyanion mimicked immune CX in their ability to trigger the generation of large amounts of O2- which were inhibited by CYB. Generation of O2- and chemiluminescence either by PHSTD or by PHSTD-opsonized streptococci were markedly inhibited by poly-L-glutamate, suggesting that PHSTD acted as a cationic agent which interacted via electrostatic forces with some negatively charged sites in the leukocyte membrane. Generation of H2O2 by PHSTD was also markedly inhibited by deoxyglucose, KCN, DASA, as well as by the lipoxygenase inhibitors nordihydroguaiaretic acid, phenidone, and propylgallate. On the other hand, cyclooxygenase inhibitors such as aspirin, indomethacin, and piroxicam were inactive, suggesting that arachidonic acid metabolism via lipoxygenase pathway might have been involved in the activation by PHSTD of the NADPH oxidase in PMNs.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Poly L-histidine. A potent stimulator of superoxide generation in human blood leukocytes. 282 Aug 76

A luminol-dependent non-opsonized zymosan-induced chemiluminescence method for phagocytes in small quantities of whole blood (40 microliters; final dilution: 1:14) is described. It was characterized with reference to cellular and humoral components, and also applied to isolated neutrophils, eosinophils and monocytes. Normal values for whole blood chemiluminescence and for neutrophils, eosinophils and monocytes are presented. From the chemiluminescence characteristic of distinct phagocytes and their frequency distribution pattern in whole blood, it is concluded that whole blood chemiluminescence has its source predominantly in neutrophils. The question as to the origin of chemiluminescence in phagocytes of whole blood and isolated neutrophils is investigated. The results support the importance of the myeloperoxidase-H2O2-halide system, but also go beyond this. The release of arachidonic acid by phospholipase A2 and of diacylglycerol and inositol trisphosphate by phospholipase C, the metabolism of arachidonic acid by the cyclooxygenase and lipoxygenase pathway, the activation of membrane NADPH oxidase by diacylglycerol and the calcium mobilisation by inositol trisphosphate are necessary for the chemiluminescence reaction. Inhibition of either mechanism suppresses the chemiluminescence response. The interaction of non-opsonized zymosan with plasma opsonins, phagocyte Fc- and complement receptors, respectively, for the initiation of chemiluminescence, was investigated. Non-opsonized zymosan initiates a chemiluminescence response in blood phagocytes in the absence of opsonin from the interaction of the zymosan polysaccharide component glucan with the complement receptor type 3. In the presence of plasma this receptor type also mediates the major chemiluminescence response brought about by the zymosan-coated cleavage products of complement fraction three, iC3b and to a minor degree C3b, while immunoglobulin G-coated zymosan interaction with the Fc-receptor is in this case of minor importance.
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PMID:Mechanisms of non-opsonized zymosan-induced and luminol-enhanced chemiluminescence in whole blood and isolated phagocytes. 344 Aug 57

The origin of luminol-dependent chemiluminescence (CL) in neutrophils stimulated by immune complexes (IC) was investigated. It was found that CL induced by soluble IC and aggregated human gamma globulin (AHG) was glucose-independent, while insoluble IC-induced CL was diminished in the absence of glucose. AHG-induced CL was not inhibited by superoxide dismutase, catalase or 2,5-dimethyl furan, but was suppressed in the presence of phenol, sodium benzoate, sodium formate and mannitol. The CL was also inhibited by inhibitors of arachidonic acid (AA) metabolism including 5,8,11,14-eicosatetraynoic acid, nordihydroguaiaretic acid, quinacrine, indomethacin and aspirin, and by prostaglandins E1 and E2, theophylline and dibutyryl cyclic AMP. Luminol-dependent CL was also studied in cell-free systems including AA plus soybean lipoxygenase, hydroperoxyeicosatetraenoic acid plus peroxidase and xanthine oxidase plus xanthine. Our results indicate that, in neutrophils exposed to soluble IC and AHG, CL is produced and this is closely linked to the formation of free radicals during the metabolism of AA. The radical(s) involved is likely to include the hydroxyl radical. In neutrophils stimulated by large aggregates of IC or micro-organisms, superoxide anion, H2O2 and singlet oxygen are also produced as a result of activation of NAD(P)H oxidase. These oxygen species function as oxidizing agents for AA metabolism and amplify the production of hydroxyl radical along the lipoxygenase (and possibly cyclooxygenase) pathway(s).
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PMID:Luminol-dependent chemiluminescence produced by neutrophils stimulated by immune complexes. 608 70

Human peripheral blood leukocytes, activated by phorbol myristate acetate, disrupt canine sarcoplasmic reticulum calcium transport, in vitro, by an oxygen-derived free radical mechanism. Activated leukocytes significantly depress Ca++ uptake activity and Ca++ -stimulated, Mg++ -dependent ATPase activity. The depression is completely inhibited by sodium-azide (0.1 mM) or the combination of superoxide dismutase (10 micrograms/ml) and catalase (10 micrograms/ml). Exogenous hydrogen peroxide (0.441-4.41 mM) uncoupled Ca++ uptake activity from ATP hydrolysis, and this effect was inhibited by catalase. Mannitol alone did not inhibit the effects of activated leukocytes, but superoxide plus mannitol (20-100 mM) resulted in normal ATPase activity, while Ca++ uptake remained depressed. In the presence of indomethacin and ibuprofen, activated leukocytes depressed Ca++ uptake and had no effect on ATPase activity. 2-Amino-methyl-4-t-butyl-6-iodophenol (MK-447) further depressed Ca++ uptake and partially inhibited the effect on ATPase activity. Indomethacin plus catalase completely inhibited the effects of activated leukocytes on cardiac sarcoplasmic reticulum. We conclude, first, that activated leukocytes depress canine cardiac sarcoplasmic reticulum Ca++ transport by an oxygen-free radical mechanism with the generation of hydrogen peroxide and hydroxyl radical. In addition to the classical membrane NADPH oxidase system, significant oxygen radical generation can occur through the cyclooxygenase pathway of arachidonic acid metabolism, and seems to be responsible for the generation of the hydroxyl radical.
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PMID:Hydrogen peroxide and hydroxyl radical mediation of activated leukocyte depression of cardiac sarcoplasmic reticulum. Participation of the cyclooxygenase pathway. 613 70

The luminol-dependent chemiluminescence (CL) of neutrophils phagocytosing zymosan is inhibited by superoxide dismutase (SOD), catalase, sodium benzoate, and 2,5-dimethyl furan. In the present report it is shown that inhibition by SOD and 2,5-dimethyl furan is diminished and removed, respectively, by the omission of glucose from the incubation medium. Zymosan-induced CL is also inhibited by inhibitors of arachidonic acid (AA) metabolism, including 5,8,11,14-eicosatetraynoic acid, nordihydroguaiaretic acid, quinacrine, indomethacin, and aspirin, by prostaglandins E1 and E2, theophylline, and dibutyryl cyclic AMP (cAMP), and by the addition of AA, sodium fluoride, and xanthine oxidase plus xanthine to the cell suspension. These findings lead us to postulate that the metabolism of AA via the lipoxygenase (and cyclooxygenase) pathway(s) is the source of CL observed in neutrophils after phagocytosis. Reactive oxygen species produced as a result of activation of NAD(P)H oxidase provide oxidizing agents for the oxidation of AA along these pathways. It is also suggested that elevated levels of cAMP induced by prostaglandins synthesized via the cyclooxygenase pathway may play a role in the regulation of the zymosan-induced CL response.
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PMID:The origin of chemiluminescence produced by neutrophils stimulated by opsonized zymosan. 668 3

When activated, phagocytes undergo a large burst of metabolic acid production. Deleterious cytosolic acidification is prevented by extrusion of H+ (equivalents) through specific transport systems, including a recently described H+ conductive pathway. The conductance can be activated by cytosolic acidification and by depolarization, events known to occur during phagocyte activation. It is possible, however, that the conductance is also directly stimulated by agonists or second messengers. In this report, spectroscopic and electrophysiological determinations were used to assess the effects of arachidonic acid (AA), a potent phagocyte stimulant, on the plasmalemmal H+ conductance of murine macrophages. AA greatly enhanced the slowly activating H+ currents and the cytosolic alkalinization triggered by depolarizing pulses. The H+ current in AA-treated cells appeared at more negative potentials and its activation and deactivation became faster. The ionic selectivity, outward rectification, and pharmacological properties of the stimulated current were identical to those of the basal current, suggesting that AA acts by facilitating the activation of the endogenous H+ conductive pathway, rather than by exerting a protonophoric effect. Experiments using specific inhibitors suggested that the effects of AA are not mediated by lipo- or cyclooxygenase. Comparison of the effects of a variety of fatty acids supported this conclusion. The order of potency to stimulate the conductance was: AA > palmitoleate approximately palmitelaidate > linoleate > oleate > elaidate. Saturated fatty acids were inactive. This sequence shows striking similarity with the ability of these lipids to stimulate the NADPH oxidase. The results indicate that, simultaneously with the activation of metabolic acid generation, phagocyte agonists also directly activate regulatory H+ extrusion, thereby favoring maintenance of intracellular pH in the physiological range.
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PMID:Arachidonic acid stimulates the plasma membrane H+ conductance of macrophages. 750 28

The dynamics and mechanisms of extracellular release of hydrogen peroxide (H2O2) from bovine pulmonary artery endothelial cells (EC) subjected to anoxia, hypoxia, and hypoxia followed by reoxygenation were examined using various inhibitors of enzymatic systems in intact cells and by direct measurement of H2O2 production from isolated EC plasma membranes. Extracellular H2O2 was measured with a fluorometric assay. EC exposed to hypoxia (3% O2) and anoxia (0% O2) released less H2O2 (29.6 +/- 1.3% and 4.2 +/- 0.7%, respectively) compared with EC exposed to normoxia (20% O2). The extracellular release of H2O2 from EC previously exposed to hypoxia for 24 h increased immediately after reoxygenation (20% O2) to 272 +/- 48%, as compared with EC exposed continuously to normoxia (100% release). Inhibition of xanthine oxidase (XO) by allopurinol did not reduce the release of H2O2 from cells exposed to normoxia or hypoxia followed by reoxygenation. Furthermore, inhibitors of cyclooxygenase (indomethacin), phospholipase A2 (quinacrine and chlorpromazine), nitric oxide synthase (L-arginine analogs), the mitochondrial electron transport chain (rotenone and cyanide), and cytochrome P-450 (methoxypsoralen) had no or minimal effect on this release. On the other hand, inhibitors of protein kinase C (calphostin and staurosporine) and NADPH oxidase (diphenyliodonium) reduced the release of H2O2 from EC in a dose-dependent manner in both exposure groups. In separate experiments, plasma membranes isolated from EC were found to produce H2O2 in the presence of NADH or NADPH as electron donors. This was inhibited by diphenyliodonium but not by allopurinol.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Release of hydrogen peroxide in response to hypoxia-reoxygenation: role of an NAD(P)H oxidase-like enzyme in endothelial cell plasma membrane. 752 30

The anti-rheumatic drug tenidap has been shown previously to attenuate superoxide production by activated neutrophils. Given the importance of leukocyte as well as endothelial cell derived superoxide in mediating inflammatory responses, the effects of tenidap on mammalian enzymes capable of generating superoxide were determined. Tenidap had no effect on the generation of superoxide by NADPH oxidase reconstituted from fractionated neutrophil lysates. However, significant inhibition of superoxide production by mixtures of hypoxanthine and xanthine oxidase was observed in the presence of 3-30 micrograms/mL tenidap. The kientics of xanthine oxidase inhibition by tenidap were non-competitive; the Ki of tenidap for xanthine oxidase was 11 micrograms/mL (34 microM). No inhibition of xanthine oxidase was observed in the presence of other known inhibitors of cyclooxygenase. Inhibition of xanthine oxidase may be a heretofore unrecognized mechanism of the antirheumatic effects of tenidap.
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PMID:Effects of tenidap on superoxide-generating enzymes. Non-competitive inhibition of xanthine oxidase. 757 42

In kidney epithelial cells, arachidonic acid and other fatty acids are important signal transduction molecules for G protein-coupled receptors. We now demonstrate that arachidonic acid induced a time- and dose-dependent activation of JNK, a member of the mitogen-activated protein kinase family, as assessed by phosphorylation of the transcription factor ATF-2. Increments in JNK activity were detectable at 5 microM arachidonic acid and plateaued at 30 microM. Activation was specific to arachidonic acid and linoleic acid, since other fatty acids of the n - 3 and n - 6 series and/or various degrees of saturation were without effect. Specific inhibitors of cyclooxygenase-, lipoxygenase-, and cytochrome P450-dependent metabolism did not affect arachidonic acid-induced JNK activity. We further demonstrated that the free radical scavenger N-acetylcysteine blocked arachidonic acid-induced JNK activation, while H(2)O(2), a reactive oxidative molecule, activated JNK in a dose-dependent manner, providing additional support for a redox mechanism. Moreover, arachidonic acid activated NADPH oxidase (EC 1.6.-.-, EC 1.6.99.-) in a dose-dependent manner, and the potency of superoxide generation paralleled that of JNK activation by other fatty acids. We conclude that in kidney epithelial cells arachidonic acid activates JNK by means of NADPH oxidase and superoxide generation, independent of eicosanoid biosynthesis.
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PMID:Arachidonic acid activates c-jun N-terminal kinase through NADPH oxidase in rabbit proximal tubular epithelial cells. 910 53

There is increasing evidence that oxidative stress is of pathophysiological importance in cardiovascular disease. Mechanical forces such as pulsatility may also contribute. Using human coronary artery smooth muscle cells (HCAS), we tested the hypothesis that stretch-induced cell proliferation is associated with oxidative stress. Stretch induced DNA synthesis in HCAS, and this was prevented by the antioxidants N-acetylcysteine and pyrrolidinedithiocarbamate (PDTC). Pulsatile stretch also increased superoxide production from HCAS in a time- and stretch dependent manner. Stretch-induced superoxide production was inhibited by diphenyleneiodoniumchloride, an NADPH oxidase inhibitor, and p-chloromercuriphenylsulfonic acid, an NADH oxidase inhibitor, but not by the xanthine oxidase inhibitor oxypurinol or the cyclooxygenase inhibitor indomethacin. In electrophoretic mobility shift assays, tumor necrosis factor-alpha activated nuclear factor-kappa B (NF-kappa B) with a peak at approximately 3 hours, whereas pulsatile stretch showed sustained activation during stimulation for up to 24 hours. The sustained activation of NF-kappa B was abolished by cotreatment with N-acetylcysteine or PDTC. Furthermore, treatment of HCAS with antisense p65 and p50 oligodeoxynucleotides of NF-kappa B inhibited stretch-induced DNA synthesis. We propose that pulsatile stretch increases oxidative stress and, in turn, promotes DNA synthesis via NF-kappa B in cultured human coronary artery smooth muscle cells.
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PMID:Pulsatile stretch stimulates superoxide production and activates nuclear factor-kappa B in human coronary smooth muscle. 935 51


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