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)

Pregnane X receptor (PXR) is a member of the nuclear receptor superfamily that regulates target gene transcription in a ligand-dependent manner. The in vivo effects of lipopolysaccharide (LPS) on expression of PXR and its target gene cytochrome P450 3A (CYP3A) in mouse liver were investigated in this study. Mice were injected intraperitoneally with different doses of LPS (0.1-5.0 mg/kg). PXR and CYP3A11 mRNA levels were measured using reverse transcription polymerase chain reaction. Results indicate that LPS significantly inhibits the expression of PXR mRNA in a dose-dependent manner, followed by suppression of CYP3A11 mRNA in mouse liver. LPS also represses the upregulation of CYP3A11 mRNA levels and erythromycin N-demethylase (ERND) catalytic activity in mice pretreated with PXR ligands dexamethasone, rifampicin, mifepristone, and phenobarbital. LPS-induced downregulation of PXR and CYP3A11 mRNA in liver was significantly attenuated in mice pretreated with gadolinium chloride, a selective Kupffer cell toxicant. Pretreatment with a single dose of gadolinium chloride (10 mg/kg) also significantly attenuated LPS-induced downregulation of dexamethasone-, rifampicim-, mifepristone-, and phenobarbital-inducible, CYP3A11 mRNA expression and ERND activity in mouse liver. Furthermore, LPS-induced downregulation of PXR and CYP3A11 mRNA was significantly attenuated in mice pretreated with allopurinol, an inhibitor of xanthine oxidase, and diphenyleneiodonium chloride, an inhibitor of NADPH oxidase. Allopurinol and diphenyleneiodonium chloride pretreatment also attenuated the repressive effects of LPS on dexamethasone-, rifampicin-, mifepristone-, and phenobarbital-inducible CYP3A11 mRNA expression and ERND catalytic activity in mouse liver. However, aminoguanidine, a selective inhibitor of inducible nitric oxide synthase, has no effect on LPS-induced downregulation of PXR and CYP3A11 mRNA. Finally, LPS-induced downregulation of PXR and CYP3A11 mRNA was prevented in mice pretreated with either N-acetylcysteine or ascorbic acid. These antioxidants also prevented the repressive effects of LPS on dexamethasone-, rifampicin-, mifepristone-, and phenobarbital-inducible CYP3A11 mRNA expression and ERND catalytic activity in mouse liver. These results indicate that Kupffer cells contribute to LPS-induced downregulation of PXR and CYP3A in mouse liver. Reactive oxygen species, produced possibly by NADPH oxidase and perhaps by xanthine oxidase, are involved in LPS-induced downregulation of nuclear receptor PXR and its target gene CYP3A in mouse liver.
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PMID:Kupffer cells and reactive oxygen species partially mediate lipopolysaccharide-induced downregulation of nuclear receptor pregnane x receptor and its target gene CYP3a in mouse liver. 1518 91

The development and expression of effective adaptive immunity is currently thought to hinge entirely upon inductor and effector mechanisms furnished by cells of the innate immune system. An obligate intracellular bacterium, the causative agent of human granulocytic anaplasmosis, apparently defies this dogma: in a mouse model of infection, Anaplasma phagocytophilum is controlled by specific lymphocyte immunity even in the absence of Toll-like receptor (TLR)2, TLR4, the TLR-adaptor protein MyD88, inducible nitric oxide synthase or the gp91 component of the NADPH oxidase complex. A. phagocytophilum infection biology raises some interesting questions about the development of resistance to innate defense strategies by vector-borne pathogens, and challenges our current bias concerning the relative importance and the mode of interaction of the innate and adaptive arms of infection control in vertebrates.
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PMID:Commentary: adaptive immunity in the absence of innate immune responses? The un-Tolled truth of the silent invaders. 1521 27

Anaplasma phagocytophilum is an obligate intracellular bacterium that is related to rickettsial organisms and replicates in the hostile environment of neutrophils. Previous studies with SCID mice suggested that T and/or B cells are required for its control in vivo. Here, we used mice deficient for Toll-like receptor (TLR)2 and TLR4, MyD88, tumor necrosis factor, inducible nitric oxide synthase, or phagocyte NADPH oxidase (gp91(phox-/-)) to define the pathways that are critical for the recognition and the killing of this pathogen. Whereas SCID mice developed a 60-fold higher bacterial load in the blood compared to wild-type mice and succumbed to infection, all other gene-deficient mouse strains were fully capable in overcoming a systemic infection with A. phagocytophilum. From these data we conclude that effector mechanisms that are crucial to the defense against numerous other intracellular pathogens are dispensable for the control of A. phagocytophilum.
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PMID:Frontline: control of Anaplasma phagocytophilum, an obligate intracellular pathogen, in the absence of inducible nitric oxide synthase, phagocyte NADPH oxidase, tumor necrosis factor, Toll-like receptor (TLR)2 and TLR4, or the TLR adaptor molecule MyD88. 1521 26

Advanced glycation end products (AGEs) are closely linked to the development of diabetic atherosclerosis. The current study examines the induction of inducible nitric oxide (NO) synthase (iNOS) and heme oxygenase (HO)-1 expression by AGEs, as well as the signaling pathways involved and the interplay between these two enzymes. The stimulation of RAW 264.7 cells with 6.64 or 33.2 microg/ml AGEs leads to HO-1 protein expression, iNOS protein expression, and nitrite accumulation. AGEs lead to the phosphorylation of p42/44 and p38 mitogen-activated protein kinase (MAPK). The inhibition of p42/44 MAPK and protein kinase C prevented, whereas inhibition of p38 MAPK augmented, AGE-induced nitrite release and iNOS expression. In contrast, HO-1 expression was downregulated by inhibition of p38 MAPK. Furthermore, the expression of both proteins was prevented by coincubation with acetovanillone (NADPH oxidase inhibitor). AGE-induced iNOS expression was negatively regulated by stimulation of HO-1 expression with cadmium chloride or endogenous NO. Tin-protoporphyrin IX (HO-1 inhibitor) partially reversed the cadmium chloride-mediated downregulation of iNOS expression. The current study demonstrates that multiple signaling molecules are involved in AGE-stimulated iNOS and HO-1 expression. There also exists a downregulation of iNOS by its own product as well as the products of HO-1.
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PMID:Regulation of inducible nitric oxide synthase expression in advanced glycation end product-stimulated raw 264.7 cells: the role of heme oxygenase-1 and endogenous nitric oxide. 1522 Feb 9

The mechanisms underlying the inhibition of long-term potentiation (LTP) induction by amyloidbeta-peptide (Abeta) were investigated in the medial perforant path of the rat and mouse dentate gyrus in vitro. Evidence is presented in this study that the Abeta-mediated inhibition of LTP induction involves activation of microglia and production of reactive oxygen and nitrogen species. In control slices, Abeta strongly inhibited induction of NMDA receptor-dependent (NMDAR-dependent) LTP, although not induction of NMDAR-independent LTP or long-term depression (LTD). The inhibition of NMDAR-dependent LTP was prevented by minocycline, an agent that prevents activation of microglia. The involvement of inducible nitric oxide synthase (iNOS) was shown by the inability of Abeta to inhibit LTP induction in iNOS knock-out mice and also by the ability of two iNOS inhibitors, aminoguanidine and 1400W, to prevent the Abeta-mediated inhibition of LTP induction. The Abeta-mediated inhibition of LTP induction also was prevented by the superoxide scavenger superoxide dismutase applied together with catalase. Evidence for involvement of superoxide in the action of Abeta on LTP induction was shown by the ability of an inhibitor of NADPH oxidase to prevent the Abeta-mediated inhibition of LTP induction. The study thus provides evidence that the Abeta-mediated inhibition of LTP induction involves an inflammatory-type reaction in which activation of microglia results in the production of nitric oxide and superoxide and thence possibly peroxynitrite, a highly reactive oxidant.
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PMID:Beta-amyloid-mediated inhibition of NMDA receptor-dependent long-term potentiation induction involves activation of microglia and stimulation of inducible nitric oxide synthase and superoxide. 1524 Jul 96

The guanidine compound ME10092 (1-(3,4-dimethoxy-2-chlorobenzylideneamino)-guanidine), which possesses a strong cardioprotective effect to ischemia-reperfusion, was assessed for different pharmacological actions that may underlie its cardioprotective effect. In the living rat ME10092 decreased the blood pressure and heart rate in a dose-dependent manner. We found ME10092 to bind to alpha 1- and alpha 2-adrenoreceptors with moderate affinity (Ki values 1-4 microM), and to block adrenaline-elicited contractile responses in isolated guinea pig aortas. Our results indicate that ME10092 possesses a certain anti-oxidant profile. Thus, in a competitive manner and with low affinity it inhibited the bovine milk xanthine oxidase enzyme, as well as NAD(P)H oxidase driven oxyradical formation in membrane fractions isolated from the rat brain. By using electron paramagnetic resonance we here show that, after its systemic administration, ME10092 modulates the nitric oxide (NO) content in several tissues of the rat in a time-dependent manner. However, in vitro ME10092 inhibited the activities of nitric oxide synthases nNOS and eNOS, but not that of iNOS. Our data give evidence that the cardioprotective effect of ME10092 could be mediated through pharmacological mechanisms that include some modulation of NO production, as well as possible inhibition of radical formation during ischemia-reperfusion.
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PMID:Investigations on the pharmacology of the cardioprotective guanidine ME10092. 1524 98

Astrocytes and microglia, the two immune-regulatory cells of the central nervous system (CNS), are activated by a variety of pathogens and cytokines to elicit rapid transcriptional responses. This program of activation is initiated by a set of intracellular signaling cascades that includes mitogen-activated protein kinase (MAPK), nuclear factor (NF) kappaB, and Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathways. This study defines the critical role that NADPH oxidase(Phox)-derived reactive oxygen species (ROS) play in lipopolysaccharide (LPS)- and interferon (IFN)gamma-induced signaling cascades leading to gene expression in glial cells. Treatment of rat microglia and astrocytes with LPS and IFNgamma resulted in a rapid activation of Phox and the release of ROS followed by an induction of inducible nitric oxide synthase (iNOS) expression. iNOS induction was blocked by inhibitors of Phox, i.e., diphenylene iodonium chloride (DPI) and 4-(2-aminoethyl) benzenesulfonylfluoride (AEBSF), suggesting an involvement of ROS signaling in iNOS gene expression. Exogenous catalase but not superoxide dismutase suppressed the basal activity and completely blocked induced levels of NO/iNOS, suggesting that hydrogen peroxide is the ROS involved. Phox inhibitors and catalase also suppressed LPS/IFNgamma-induced expression of cytokines, i.e., interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)alpha and blocked LPS activation of MAP kinases (i.e., p38 MAPK, c-Jun N-terminal kinase and extracellular signal-regulated kinase), NFkappaB, and IFNgamma-induced STAT1 phosphorylation. A microglial cell line stably transfected with a mutant form of Phox subunit, i.e., p47(phox) W(193)R, and primary astrocytes derived from Phox-deficient mice showed attenuated ROS production and induction of iNOS in response to LPS/IFNgamma, further strengthening the notion that Phox-derived ROS are crucial for proinflammatory gene expression in glial cells.
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PMID:Redox regulation of glial inflammatory response to lipopolysaccharide and interferongamma. 1526 24

Although reactive oxygen species (ROS) participate in many cellular mechanisms, only few data exist concerning their involvement in physiological angiogenesis. The aim of the present work was to elucidate possible mechanisms through which ROS affect angiogenesis in vivo, using the model of the chicken embryo chorioallantoic membrane (CAM). Superoxide dismutase (SOD) and its membrane permeable mimetic tempol, dose dependently decreased angiogenesis and down-regulated inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production. The NADPH oxidase inhibitors, 4-(2-aminoethyl)-benzenesulfonyl fluoride (AEBSF) and apocynin, but not allopurinol, also had a dose dependent inhibitory effect on angiogenesis and NO production in vivo. Catalase and the intracellular hydrogen peroxide (H2O2) scavenger sodium pyruvate decreased, while H2O2 increased in a dose-dependent manner the number of CAM blood vessels, as well as the expression and activity of iNOS. Dexamethasone, which down-regulated NO production by iNOS and L-NAME, but not D-NAME, dose dependently decreased angiogenesis in vivo. These data suggest that antioxidants affect physiological angiogenesis in vivo, through regulation of NOS expression and activity.
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PMID:Antioxidants inhibit angiogenesis in vivo through down-regulation of nitric oxide synthase expression and activity. 1529 58

Quorum sensing triggers virulence factor expression in medically important bacterial pathogens in response to a density-dependent increase in one or more autoinducing pheromones. Here, we show that phagocyte-derived oxidants target these autoinducers for inactivation as an innate defense mechanism of the host. In a skin infection model, expression of phagocyte NADPH oxidase, myeloperoxidase, or inducible nitric oxide synthase was critical for defense against a quorum-sensing pathogen, Staphylococcus aureus, but not for defense against a quorum sensing-deficient mutant. A virulence-inducing peptide of S. aureus was inactivated in vitro and in vivo by reactive oxygen and nitrogen intermediates, including HOCl and ONOO(-). Inactivation of the autoinducer prevented both the up-regulation of virulence gene expression and the downstream sequelae. MS analysis of the inactivated peptide demonstrated that oxidation of the C-terminal methionine was primarily responsible for loss of activity. Treatment of WT but not NADPH oxidase-deficient mice with N-acetyl methionine to scavenge the inhibitory oxidants increased in vivo quorum sensing independently of the bacterial burden at the site of infection. Thus, oxidant-mediated inactivation of an autoinducing peptide from S. aureus is a critical innate defense mechanism against infection with this pathogen.
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PMID:Inactivation of a bacterial virulence pheromone by phagocyte-derived oxidants: new role for the NADPH oxidase in host defense. 1535 93

Human inducible nitric oxide synthase (iNOS) is most readily observed in macrophages from patients with inflammatory diseases like atherosclerosis. The aim of the present study was to find out the combined effect of male sex hormone; testosterone and apocynin (NADPH oxidase inhibitor) on cytokine-induced iNOS production. THP-1 cells were differentiated into macrophages by phorbol myristate acetate (PMA). Expression of iNOS was induced by the addition of cytokine mixture? Testosterone was added at different concentrations (10(-6)-10(-12) M) with apocynin (1 mM). Testosterone (10(-8), 10(-10) M) inhibited NOx production in cytokine-added THP-1 cells which was further confirmed by quantikine assay of iNOS protein and RT-PCR analysis. Testosterone treatment decreased 40% of superoxide anion production. Testosterone showed inhibition of NADPH oxidase, especially expression of p67phox and p47phox (cytosol subunits). Addition of testosterone with apocynin further decreased the expression of p67phox and p47phox subunits of NADPH oxidase. The findings of the present study suggest that, testosterone; the male androgen plays an important role in the prevention of atherogenesis. Even though apocynin does not have any role on NO production, addition of apocynin together with testosterone is effective in suppressing iNOS activity.
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PMID:Combined effect of testosterone and apocynin on nitric oxide and superoxide production in PMA-differentiated THP-1 cells. 1536 32


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