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)

Recent studies suggest that superoxide production by the NADPH/NADH oxidase may be involved in smooth muscle cell growth and the pathogenesis of hypertension. We previously showed that angiotensin II (Ang II) activates a p22phoxbased NADPH/NADH oxidase in cultured rat vascular smooth muscle cells and in animals made hypertensive by infusion of Ang II. To investigate the mechanism responsible for this increased oxidase activity, we examined p22phox mRNA expression in rats made hypertensive by implanting an osmotic minipump that delivered Ang II (0.7 mg/kg per day). Blood pressure began to increase 3 days after the start of Ang II infusion and remained elevated for up to 14 days. Expression of p22phox mRNA in aorta was also increased after 3 days and reached a maximum increase of 338 +/- 41% by 5 days after pump implantation compared with the value after sham operation. This increase in mRNA expression was accompanied by an increase in the content of the corresponding cytochrome (twofold) and NADPH oxidase activity (179 +/- 11% of that in sham-operated rats 5 days after pump implantation). Treatment with the antihypertensive agents losartan (25 mg/kg per day) or hydralazine (15 mg/kg per day) inhibited this upregulation of mRNA levels and activity. Furthermore, infusion of recombinant heparin-binding superoxide dismutase decreased both blood pressure and p22phox mRNA expression. In situ hybridization of aortic tissue showed that p22phox mRNA was expressed in medial smooth muscle as well as in the adventitia. These findings suggest that Ang II-induced hypertension activates the NADPH/NADH oxidase system by upregulating mRNA levels of one or several components of this oxidase system, including the p22phox, and that the NADPH/NADH oxidase system is associated with the pathology of hypertension in vivo.
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PMID:p22phox mRNA expression and NADPH oxidase activity are increased in aortas from hypertensive rats. 897 21

Salivary gland homogenates of the adult female mosquito Anopheles albimanus, but not those of Aedes aegypti, induced light production in the presence of NADPH and luminol, indicating a NADPH oxidase activity producing reactive oxygen species (superoxide anion) by the anopheline salivary homogenate. Superoxide production by the anopheline salivary homogenate was also confirmed by the NADPH-dependent, superoxide dismutase inhibitable, reduction of cytochrome c. The NADPH oxidase reaction measured by light production in the presence of luminol was inhibited by superoxide dismutase and catalase. Both NADH and NADPH were substrates for the production of oxygen reactive species by the salivary homogenate. Activity, as measured by luminol-dependent light emission, was enhanced one order of magnitude in the presence of 1.6 mg/ml of either phosphatidylserine or bovine serum albumin. Molecular sieving and hydroxyapatite chromatography of the salivary homogenate showed coelution of the NADPH oxidase activity with the previously reported salivary peroxidase activity. It is suggested that the salivary peroxidase of Anopheles albimanus has the ability of producing superoxide in the presence of NADPH, and this may provide the peroxidase with substrates necessary for peroxidation of vasoconstrictor amines such as serotonin, released by aggregating platelets at the site of mosquito probing and feeding.
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PMID:NAD(P)H-dependent production of oxygen reactive species by the salivary glands of the mosquito Anopheles albimanus. 899 93

Oocysts of Cryptosporidium parvum showed relatively low levels of SOD activity. The SOD which had a pI of 4.8 and an approximate molecular weight of 35 kDa appeared to be iron dependent. Catalase, glutathione transferase, glutathione reductase and glutathione peroxidase activity could not be detected, nor could trypanothione reductase. No NADH or NADPH oxidase activity could be detected, nor could peroxidase activity be demonstrated using o-dianisidine, guaiacol, NADPH or NADH as co-substrates. However, an NADPH-dependent H2O2 scavenging system was detected in the insoluble fraction.
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PMID:Anti-oxidant enzymes in Cryptosporidium parvum oocysts. 901 Oct 70

Nitric oxide (NO) reacts with heme-containing enzymes, including certain isoforms of cytochrome P450. Cytochrome P4502E1 (CYP2E1) is induced by ethanol and plays an important role in the toxicity of ethanol and other hepatotoxins. CYP2E1 is also very effective in generating reactive oxygen intermediates such as superoxide radical and H2O2, oxidizing ethanol to the 1-hydroxyethyl radical, and has a high NADPH oxidase activity. The effect of NO on CYP2E1 catalytic activity and generation of reactive oxygen intermediates was evaluated. Incubating liver microsomes isolated from rats treated with pyrazole to induce high levels of CYP2E1, with gaseous NO or NO released from a variety of NO donors such as SNAP, DEA/NO, spermine/NO, and GSNO, resulted in a loss of CYP2E1 catalytic activity with specific substrates such as p-nitrophenol or dimethylnitrosamine. Trapping of NO with hemoglobin resulted in protection of CYP2E1 activity against the inactivation by NO. There was no effect by analogues of the donors which do not release NO nor was there any effect by NO on NADPH-cytochrome P450 reductase activity. Inactivation of CYP2E1 by NO was not prevented by superoxide dismutase or catalase, suggesting that superoxide, H2O2, or peroxynitrite were not responsible for the actions of NO. The inactivated CYP2E1 was not degraded nor did it lose its epitope sites as shown by Western blot analysis. Associated with loss of CYP2E1 catalytic activity was a decrease in the formation of superoxide radical and H2O2, in microsomal lipid peroxidation catalyzed by low, but not high concentration of iron, and in consumption of NADPH. Oxidation of ethanol to the 1-hydroxyethyl radical was also inhibited by NO. ESR experiments indicated the formation of stable heme-NO complexes with CYP2E1. NO appears to compete with O2 and CO for binding to CYP2E1 as incubation with gaseous NO, or NO donors inhibited formation of the characteristic CO binding spectrum of P450. Microsomes isolated from a stably transfected HepG2 cell line expressing only CYP2E1 were also inactivated by NO, validating interaction of NO with this isoform of P450. These results indicate that NO inhibits CYP2E1 catalytic activity and generation of reactive radical intermediates. NO may prevent toxicity of agents which require bioactivation by P450 isoforms such as CYP2E1 and in generation of reactive intermediates by CYP2E1.
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PMID:Inhibition of rat and human cytochrome P4502E1 catalytic activity and reactive oxygen radical formation by nitric oxide. 901 19

This study was designed to determine the source of reactive oxygen species (ROS) and whether Kupffer cells modulate the injury of perfused rat liver after cold preservation. The livers of male Lewis rats pretreated with schizophyllan glucan (SPG) (10 mg/kg, SPG group) or gadolinium chloride (5 mg/kg; Gd group) and untreated rats (control group) were preserved in University of Wisconsin solution for 0, 12, and 24 hours at 4 degrees C and then perfused for 60 minutes with oxygenated Krebs-Henseleit bicarbonate buffer. Real-time chemiluminescence (CL) of the liver during perfusion was measured using a sensitive photomultiplier, and reperfusion injury was assessed by measuring lipid peroxidation and lactate dehydrogenase release. CL intensity reached a peak within 5 minutes of reperfusion, and superoxide dismutase completely inhibited this CL in all groups. In the control group, the total CL intensity was high after 24 hours of preservation. It significantly (P < .05 vs. control group) increased in the SPG group, while it decreased in the Gd group after 12 and 24 hours of preservation. The total CL intensity decreased by 70% (when diphenyliodonium chloride (100 micromol/L; an NADPH oxidase inhibitor) was added to the perfusate before preservation of untreated rats. Lipid peroxidation and lactate dehydrogenase release significantly (P < .05) deteriorated in the SPG group, while they ameliorated in the Gd group after 24 hours of preservation. These results demonstrate that Kupffer cells primarily generate superoxide anions and modulate the organ injury in the initial phase of reperfusion after cold preservation.
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PMID:Kupffer cells generate superoxide anions and modulate reperfusion injury in rat livers after cold preservation. 902 47

Apoptosis permits neutrophil recognition by macrophages, thereby not only limiting potential cytotoxicity but also promoting resolution of inflammation. A direct relationship between apoptosis and intracellular hydrogen peroxide (H2O2) production was observed in phorbol 12-myristate 13-acetate (PMA) -stimulated neutrophils aged in culture. A significant decrease in intracellular H2O2 production was observed in aging neutrophils at 12, 24, and 48 h. However, intracellular superoxide anion production in response to PMA stimulation was preserved up to 24 h, implying retention of intracellular signaling pathways leading to NADPH oxidase stimulation. A significant decrease in the cytoplasmic content and activity of Cu,Zn superoxide dismutase was responsible for the observed decline in intracellular H2O2 production in apoptotic neutrophils. Intracellular glutathione content also decreased concomitantly with H2O2 production. These observations indicate that onset of apoptosis in neutrophils is in part mediated by oxidative stress resulting from the down-regulation of key antioxidant defense systems of the cell, namely superoxide dismutase and glutathione.
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PMID:Defects in intracellular oxidative metabolism of neutrophils undergoing apoptosis. 910 35

1. The generation of superoxide anions (O2-) by intact pig coronary artery rings was measured using a lucigenin-enhanced chemiluminescence technique and a histochemical technique with Nitroblue Tetrazolium (NBT) staining. 2. Isolated arteries with intact endothelium generated O2- at a rate of 9.0 +/- 0.8 pmol min-1 (mg dry weight)-1; this rate was diminished by about 24% when the endothelium was removed. The NBT staining of arterial ring preparations showed formazan precipitation mainly in the intima. Arterial rings were pretreated with diethylthiocarbamate in order to inhibit Cu-Zn superoxide dismutase (SOD) activity which increased the O2- generation by 184 +/- 55% (n = 10; P < 0.01). Stimulation of protein kinase C with phorbol 12-myristate 13-acetate (5 microM) enhanced endothelium-dependent O2- generation by 136 +/- 20% (n = 19; P < 0.01). Neither stimulation with bradykinin or substance P, nor inhibition with NG-nitro-L-arginine methyl ester of endothelial nitric oxide synthase had a significant effect on O2- generation. In contrast, the inhibition of flavoproteins with diphenyliodonium decreased concentration-dependent O2- generation (IC50, 1.85 +/- 5.33 microM). Inhibition of tetrahydrobiopterin synthesis with 2,4-diamino-6-hydroxy-pyrimidine resulted in a reduced generation of O2- by about 55%. 3. The addition of 100 microM NADH and 100 microM NADPH resulted in an excessive generation of O2- at a rate of 0.68 +/- 0.03 and 0.26 +/- 0.01 nmol O2- min-1 (mg protein)-1, respectively, in the membrane fraction, but not in the cytosolic fraction, of homogenates obtained from arteries. 4. The results suggest that intact coronary arteries do generate O2- under basal conditions and that the endothelial layer significantly contributes to this phenomenon. This generation of O2- is greatly influenced by intrinsic SOD activity. It is suggested that basal vascular O2- generation is mainly due to membrane-bound NAD(P)H oxidase activity and/or tetrahydrobiopterin-dependent processes.
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PMID:Endothelial-derived superoxide anions in pig coronary arteries: evidence from lucigenin chemiluminescence and histochemical techniques. 914 21

We successfully detected the oxyradical production in human synovial A (macrophage-like) and B (fibroblast-like) cells by phorbol 12-myristate 13-acetate (PMA) using the luminol-chemiluminescence method. The PMA (0.1 microgram/ml)-induced photon generation was abolished by an O2- scavenger, superoxide dismutase, and an H2O2 scavenger, catalase, suggesting that the stimulus produced oxyradicals in synovial cells. Both of these responses were abolished by a protein kinase C (PKC) inhibitor, calphostine C, but unaffected by an intracellular Ca2+ chelator, BAPTA-AM, and Ca2+ removal from the extracellular medium. These findings suggest that synovial A and B cells produce oxyradicals through PKC-mediated and [Ca2+]i-independent mechanisms, probably through the activation of NADPH oxidase.
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PMID:Phorbol 12-myristate 13-acetate (PMA)-induced oxyradical production in rheumatoid synovial cells. 916 72

Superoxide (O-2) and nitric oxide (NO) act to kill invading microbes in phagocytes. In macrophages NO is synthesized by inducible nitric oxide synthase (iNOS, NOS 2) from L-arginine (L-Arg) and oxygen; however, O-2 was thought to be produced mainly by NADPH oxidase. Electron paramagnetic resonance (EPR) spin trapping experiments performed in murine macrophages demonstrate a novel pathway of O-2 generation. It was observed that depletion of cytosolic L-Arg triggers O-2 generation from iNOS. This iNOS-mediated O-2 generation was blocked by the NOS inhibitor N-nitro-L-arginine methyl ester or by L-Arg, but not by the noninhibitory enantiomer N-nitro-D-arginine methyl ester. In L-Arg-depleted macrophages iNOS generates both O-2 and NO that interact to form the potent oxidant peroxynitrite (ONOO-), which was detected by luminol luminescence and whose formation was blocked by superoxide dismutase, urate, or L-Arg. This iNOS-derived ONOO- resulted in nitrotyrosine formation, and this was inhibited by iNOS blockade. iNOS-mediated O-2 and ONOO- increased the antibacterial activity of macrophages. Thus, with reduced L-Arg availability iNOS produces O-2 and ONOO- that modulate macrophage function. Due to the existence of L-Arg depletion in inflammation, iNOS-mediated O-2 and ONOO- may occur and contribute to cytostatic/cytotoxic actions of macrophages.
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PMID:Superoxide and peroxynitrite generation from inducible nitric oxide synthase in macrophages. 919 73

The role of reactive oxygen species (ROS) in the pathophysiology of human sperm function has been emphasized in recent years. ROS production in semen has been associated with loss of sperm motility, decreased capacity for sperm-oocyte fusion and loss of fertility. There is a current presumption that the most prolific source of ROS in sperm suspensions is an NADPH oxidase located in leukocytes or in spermatozoa which produces superoxide which is further converted to peroxide by the action of superoxide dismutase. Hydrogen peroxide has been recognized as the most toxic oxidizing species for human spermatozoa, which are very sensitive to lipid peroxidation owing to the high content of polyunsaturated fatty acids in their plasma membrane, though this is not the sole mechanism by which sperm function might be impaired by ROS. Although the excessive production of ROS is detrimental to human spermatozoa, there is a growing body of evidence which suggests that ROS are also involved in the physiological control of some sperm functions. This review focuses on the nature and source of the ROS generated by human spermataozoa as well as their operational mechanisms and their effects, which may be detrimental or beneficial.
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PMID:Reactive oxygen species and human spermatozoa: physiology and pathology. 929 15


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