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)

Neutrophil adherence to endothelium is partially mediated by the expression of endothelial leukocyte adhesion molecule-1 (ELAM-1) on endothelial cells activated by agents such as lipopolysaccharide (LPS) and phorbol myristate acetate (PMA). To elucidate molecular mechanisms involved in the induction of ELAM-1 on endothelial cells, we investigated the effect of the NADPH oxidase inhibitor, apocynin (4-hydroxy-3-methoxyacetophenone), on ELAM-1 mRNA expression in human umbilical vein endothelial cells (HUVEC) by Northern blot analysis. Apocynin downregulated both LPS- and PMA-induced ELAM-1 mRNA expression in a dose-dependent manner. Our results suggest NADPH oxidase might play a key role in ELAM-1 mRNA expression in HUVEC.
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PMID:Effect of NADPH oxidase inhibition on endothelial cell ELAM-1 mRNA expression. 137 59

We investigated the role of reactive oxygen species in ozone-induced airway hyperresponsiveness (AHR) in Brown Norway rats. Airway responsiveness to inhaled acetylcholine (ACh) and bradykinin (BK) and inflammatory cell recruitment in bronchoalveolar lavage fluid (BALF) were measured in vivo. Neutral endopeptidase (NEP) activity assay and measurement of BK-receptor binding sites in Brown Norway rat lungs were carried out in vitro. Apocynin (5 mg/kg), an inhibitor of superoxide anion-generating NADPH oxidase, was administered perorally 30 min before a 3- or 6-h exposure to 3 ppm of ozone, and the animals were studied 18-24 h postexposure. Ozone induced increases in airway responsiveness to ACh and BK and in neutrophil counts in BALF. Apocynin inhibited the increase in airway responsiveness to BK but not to ACh without affecting the neutrophil counts in BALF. The antioxidants allopurinol and deferoxamine prevented ozone-induced AHR to both ACh and BK but did not reduce neutrophil counts. To further examine the mechanisms of ozone-induced AHR to BK, we measured NEP activity and the density of BK receptors in vitro after ozone exposure. Ozone exposure had no significant effect either on NEP activity or on the affinity and the number of BK receptors in lungs from rats treated with or without apocynin. We conclude that superoxide anions released from inflammatory cells in the airway may be involved in ozone-induced AHR. Inactivation of NEP or upregulation of BK receptors do not appear to be involved, but the possibility of localized changes cannot be excluded.
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PMID:Ozone-induced airway hyperresponsiveness: role of superoxide anions, NEP, and BK receptors. 777 93

We investigated the role of endogenous nitric oxide (NO) and superoxide anions in recombinant human interleukin-1 beta (rhIL-1 beta)-induced bronchial hyperresponsiveness (BHR) and neutrophilia in Brown-Norway rats. Aminoguanidine (100 mg/kg/d) administered subcutaneously for 3 d, an inhibitor of inducible NO synthase, L-arginine (100 mg/kg/d administered subcutaneously for 3 d, a specific precursor for the synthesis of NO, and apocynin (5 mg/kg/orally), an inhibitor of superoxide anion (O2-)-generating NADPH oxidase in macrophages and neutrophils, were administered prior to administration of rhIL-1 beta (500 U) intratracheally. Aminoguanidine in addition to another inhibitor of NO synthase, NW-nitro-L-arginine methyl ester (L-NAME) 100 mg kg/d administered subcutaneously for 3 d augmented bronchial responsiveness to inhaled bradykinin (BK) but not to acetylcholine (ACh), an effect reversed by L-arginine. rhIL-1 beta-treated rats also demonstrated BHR to BK but not to ACh, associated with neutrophilia in bronchoalveolar lavage fluid (BALF). rhIL-1 beta-induced BHR and neutrophilia were neither further increased by aminoguanidine nor inhibited by L-arginine. Apocynin, however, significantly inhibited rhIL-1 beta-induced BHR but not the BALF neutrophilia. Suppression of NO generation and generation of O2- from macrophages and infiltrating neutrophils may be important in rhIL-1 beta-induced airway hyperresponsiveness to bradykinin.
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PMID:Role of nitric oxide and superoxide anions in interleukin-1 beta-induced airway hyperresponsiveness to bradykinin. 792 31

Reactive oxygen species (ROS) produced by NADPH oxidase activation in neutrophils play a major role in mediating sepsis-induced acute lung injury. To provide insight into whether the NADPH oxidase inhibitor apocynin might attenuate oxidant-induced lung injury, we examined the effect of apocynin on (1) sepsis-induced lung injury in guinea pigs, (2) ROS generation by LPS-stimulated neutrophils measured by chemiluminescence (CL), and (3) LPS-stimulated neutrophil-mediated human umbilical vein endothelial cell (HUVEC) injury assessed by 51Cr release. Sepsis-induced lung injury in guinea pigs was assessed by comparing 125I-labeled albumin concentrations in lung tissue and bronchoalveolar lavage (BAL) fluid relative to plasma (L/P and BAL/P), lung wet-to-dry weight ratios, and the number of neutrophils in BAL fluid. The lung wet-to-dry weight ratio, L/P, and the number of neutrophils in BAL fluid decreased after pretreatment and post-treatment with apocynin. BAL/P decreased upon pretreatment but not upon post-treatment with apocynin. Apocynin at concentrations from 10 to 100 micrograms/ml significantly reduced LPS-stimulated neutrophil CL and neutrophil-mediated HUVEC 51Cr release. We conclude that the NADPH oxidase inhibitor apocynin attenuates (1) sepsis-induced lung injury in guinea pigs, (2) neutrophil ROS generation measured by CL, and (3) neutrophil-mediated HUVEC injury assessed by 51Cr release.
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PMID:Effect of the NADPH oxidase inhibitor apocynin on septic lung injury in guinea pigs. 795 74

Secretory leukocyte protease inhibitor (SLPI) is a potent proteinase inhibitor produced in the lung. Stimulated neutrophils at sites of inflammation can inactivate SLPI by myeloperoxidase-mediated oxidation of the methionine residue in the active site of SLPI. Apocynin is a selective inhibitor of NADPH oxidase and may therefore protect SLPI against neutrophil-mediated oxidative inactivation. The aim of the present study was to determine the effect of apocynin on the efficacy of SLPI in preventing experimental emphysema. To investigate the effect of apocynin on emphysema without SLPI treatment, three groups of eight hamsters each received drinking water containing apocynin at concentrations of 2, 20, and 200 micrograms/ml, respectively. Emphysema was induced in these hamsters by intratracheal instillations of 500 micrograms of lipopolysaccharide (LPS) twice a week for 4 wk. In hamsters that received 200 micrograms/ml apocynin, the development of emphysema was reduced by 26.2% (p = 0.01). Other apocynin concentrations had no effect. The experiment was repeated, with SLPI added to the treatment. Of a total of six groups of hamsters, four groups (three with apocynin and one with solvent) received twice-weekly doses of a mixture of 500 micrograms of LPS and 1 mg SLPI in 200 microliters saline in the trachea for 4 wk. In addition, each LPS instillation was followed 24 and 48 h later by an instillation containing 1 mg of SLPI. Apocynin (20 and 200 micrograms/ml) improved the protective effect of SLPI from 37 to 64% and 79%, respectively (p < 0.01). We conclude that oral administration of apocynin can improve the efficacy of SLPI in preventing LPS-induced emphysema.
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PMID:Apocynin improves the efficacy of secretory leukocyte protease inhibitor in experimental emphysema. 795 25

In this study we tested the hypothesis that the pentose phosphate pathway (PPP) participates in the meiotic induction of mouse oocytes. The electron acceptors methylene blue, phenazine ethosulfate (PES), and pyrroline-5-carboxylate (P5C) oxidize NADPH to NADP and activate the NADP-dependent enzymes of the PPP. Each of these compounds triggered a dose-dependent increase in meiotic maturation in hypoxanthine-arrested cumulus cell-enclosed oocytes during 17- to 18-h cultures. More than 96% of the oocytes underwent germinal vesicle breakdown (GVB) at the highest concentrations of P5C and PES tested (250 and 1 microM, respectively) as compared to only 45-52% of control oocytes. P5C was also stimulatory to denuded oocytes. Analysis of energy substrates in microdrop cultures revealed a 3.6-fold increase in glucose consumption by PES-treated oocyte-cumulus cell complexes that was associated with stimulation of GVB. On the other hand, 2-deoxyglucose, which interferes with glucose utilization, prevented the induction of maturation brought about by P5C. Apocynin and diphenyleneiodonium, inhibitors of NADPH oxidase, prevented meiotic maturation in the presence or absence of FSH. Gonadotropin-induced maturation was also prevented by 6-aminonicotinamide (6-AN) and dehydroepiandrosterone (DHEA), inhibitors of the two NADP-dependent enzymes of the PPP, and this was accompanied by suppression of glucose consumption. Phosphoribosyl-pyrophosphate (PRPP) is an important compound required in purine metabolism and can be formed from the end product of the oxidative arm of the PPP, ribose-5-phosphate. Ribose, which can be metabolized to PRPP, increased PRPP synthesis in complexes and induced meiotic maturation when added to hypoxanthine-arrested cumulus cell-enclosed oocytes in glucose-free medium in both the presence and absence of FSH. PRPP levels within complexes were also increased by glucose and FSH, but were reduced by hypoxanthine, 6-AN, and DHEA. In addition, exogenous PRPP stimulated maturation in hypoxanthine-arrested oocytes. These results support the proposition that glucose metabolism through the PPP is important in the meiotic induction mechanism and may involve the generation of PRPP that acts, at least in part, through the purine metabolizing pathways.
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PMID:Meiotic induction in cumulus cell-enclosed mouse oocytes: involvement of the pentose phosphate pathway. 954 44

Reactive oxygen species (ROS) are thought to be involved in the pathogenesis of multiple sclerosis (MS) and experimental allergic encephalomyelitis (EAE). In this study we showed that the phagocytosis of myelin by macrophages triggers the production of ROS. We also demonstrated that ROS play a crucial role in the myelin phagocytosis. Blocking the ROS production with NADPH oxidase inhibitors (100 microM DPI or 10 mM Apocynin) essentially prevented the phagocytosis of myelin. Furthermore, scavenging of ROS with catalase (H2O2) or mannitol (OH-) decreased the phagocytosis of myelin by macrophages, whereas superoxide dismutase (O2-) did not show this effect. In addition, Lipoic acid (LA), a non-specific scavenger of ROS, also decreased the phagocytosis of myelin by macrophages. In our results, we demonstrate for the first time that ROS appear to play a regulatory role in the phagocytosis of myelin.
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PMID:Reactive oxygen species are required for the phagocytosis of myelin by macrophages. 991 81

Cultured human endothelial cells (EC) exposed to atherogenic low-density lipoprotein levels have increased reactive oxygen species (ROS) generation. The enzyme responsible for this ROS production elevation is unknown. We have examined for the presence of a functional leukocyte-type NADPH oxidase in EC to elucidate whether this enzyme could be the ROS source. The plasma membrane fraction of disrupted EC showed a reduced-minus-oxidized difference spectra with absorption peaks identical to those observed in the spectra of the leukocyte NADPH oxidase component, cytochrome b558. Western-blot analysis, using anti-gp91 -phox. anti -p22-phox. anti -p47-phox. and anti -p67-phox antibodies, demonstrated the protein expression of NADPH oxidase subunits in EC. Reverse transcriptase-polymerase chain reaction (RT-PCR) showed the mRNA expression of gp91-phox, p22-phox, p47-phox, and p67-phox in EC. Sonicates from unstimulated EC produced no measurable superoxide; whereas, exogenously applied arachidonic acid activated superoxide generation in a manner that was dependent upon the presence of NADPH and both membrane and cytosolic fractions combined. Apocynin, a specific leukocyte NADPH oxidase inhibitor, was shown by Western-blot analysis of membrane and cytoplasmic fractions to inhibit the translocation of p47-phox to the membrane of stimulated EC. These findings support the presence of a functionally active leukocyte-type NADPH oxidase in EC. NADPH oxidase could be the major cellular ROS source in EC perturbation, which has been hypothesized to be a major contributing factor in the pathogenesis of atherosclerosis.
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PMID:Identification of a functional leukocyte-type NADPH oxidase in human endothelial cells :a potential atherogenic source of reactive oxygen species. 1059 57

Apocynin (4-hydroxy-3-methoxy-acetophenone) inhibits NADPH oxidase in activated polymorphonuclear (PMN) leukocytes, preventing the generation of reactive oxygen species. To determine if apocynin attenuates ischemia-reperfusion lung injury, we examined the effects of apocynin (0.03, 0.3, and 3 mM) in isolated in situ sheep lungs. In diluent-treated lungs, reperfusion with blood (180 min) after 30 min of ischemia (ventilation 28% O(2), 5% CO(2)) caused leukocyte sequestration in the lung and increased vascular permeability [reflection coefficient for albumin (sigma(alb)) 0.47 +/- 0.10, filtration coefficient (K(f)) 0.14 +/- 0.03 g. min(-1). mmHg(-1). 100 g(-1)] compared with nonreperfused lungs (sigma(alb) 0.77 +/- 0. 03, K(f) 0.03 +/- 0.01 g. min(-1). mmHg(-1). 100 g(-1); P < 0.05). Apocynin attenuated the increased protein permeability at 0.3 and 3 mM (sigma(alb) 0.69 +/- 0.05 and 0.91 +/- 0.03, respectively, P < 0. 05); K(f) was decreased by 3 mM apocynin (0.05 +/- 0.01 g. min(-1). mmHg(-1). 100 g(-1), P < 0.05). Diphenyleneiodonium (DPI, 5 microM), a structurally unrelated inhibitor of NADPH oxidase, worsened injury (K(f) 0.32 +/- 0.07 g. min(-1). mmHg(-1). 100 g(-1), P < 0.05). Neither apocynin nor DPI affected leukocyte sequestration. Apocynin and DPI inhibited whole blood chemiluminescence and isolated PMN leukocyte-induced resazurin reduction, confirming NADPH oxidase inhibition. Apocynin inhibited pulmonary artery hypertension and perfusate concentrations of cyclooxygenase metabolites, including thromboxane B(2). The cyclooxygenase inhibitor indomethacin had no effect on the increased vascular permeability, suggesting that cyclooxygenase inhibition was not the explanation for the apocynin results. Apocynin prevented ischemia-reperfusion lung injury, but the mechanism of protection remains unclear.
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PMID:Effect of the NADPH oxidase inhibitor apocynin on ischemia-reperfusion lung injury. 1089 70

Glucocorticoids are known to promote apoptosis of eosinophils, normal and neoplastic lymphoid cells, and blastic cells in some patients with acute myeloid leukemia. We investigated the biochemical signal transduction pathways, in particular, the generation of reactive oxygen species (ROS) and activation of caspases in dexamethasone (DEX)-induced apoptosis of eosinophils, and we compared them with those in DEX-sensitive myeloid and lymphoid leukemia cell lines. The GC-receptor antagonist completely abolished DEX-induced apoptosis of eosinophils and leukemia cells. Among inhibitors related to the ROS system, diphenylene iodonium (DPI), a nicotinamide adenine dinucleotide diphosphate (NADPH) oxidase inhibitor, strongly inhibited both spontaneous and DEX-induced apoptosis of eosinophils at concentrations as low as 0.2 to 2 mumol/L, while promoting apoptosis of leukemia cells in a dose-dependent manner. Apocynin, another NADPH oxidase inhibitor, and antioxidants did not affect the apoptosis of eosinophils or leukemia cells. DEX treatment did not change intracellular production of O2- and H2O2, and it decreased the extracellular release of O2- in both cells. These results suggest little or no involvement of ROS generation in DEX-induced apoptosis of both cells. Although among peptide-based caspase inhibitors, only z-VAD-FMK, a broad caspase inhibitor, partially inhibited the apoptosis of eosinophils and leukemia cells, DEX treatment increased the activities of caspases 2-, 3-, 6-, and 8-like proteases assessed by colorimetry in both cells, suggesting the involvement of a similar caspase activation pathway in DEX-induced apoptosis in both cells. DPI markedly reduced caspase 3-like activity in eosinophils, while augmenting the activity in leukemia cells, indicating that DPI acts upstream of caspase 3 activation opposingly in both cells. Thus, the action of DPI in eosinophils seems peculiar in respect to apoptosis induction, and DPI appears to exert an influence on unknown targets rather than those involved in NADPH oxidase inhibition.
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PMID:Glucocorticoid-induced apoptotic pathways in eosinophils: comparison with glucocorticoid-sensitive leukemia cells. 1090 53


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