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:1.6.99.6 (NADPH oxidase)
10,295 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Phagosomes formed by neutrophils are much less acidic than those of other phagocytic cells. The defective acidification seen in neutrophils has been attributed to consumption of protons during the dismutation of superoxide, because a large, sustained acidification is unmasked when the cells are treated with inhibitors of the NADPH oxidase. Consumption of protons transported into the phagosome by dismutation would tightly couple the activities of the NADPH oxidase and the vacuolar type H(+)-pump (or V-ATPase). We tested the existence of the predicted coupling using microfluorimetry and digital imaging and found that the rate of superoxide generation was independent of the activity of the H(+)-pump. Moreover, we failed to detect the alkalinization predicted to develop through dismutation when the pump was inhibited. Instead, two other mechanisms were found to contribute to the inability of neutrophil phagosomes to acidify. First, the insertion of V-ATPases into the phagosomal membrane was found to be reduced when the oxidase is active. Second, the passive proton (equivalent) permeability of the phagosomal membrane increased when the oxidase was activated. The increased permeability cannot be entirely attributed to the conductive H(+) channels associated with the oxidase, since it is not eliminated by Zn(2+). We conclude that the NADPH oxidase controls the phagosomal pH by multiple mechanisms that include reduced proton delivery to the lumen, increased luminal proton consumption, and enhanced backflux (leak) into the cytosol.
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PMID:Determinants of the phagosomal pH in neutrophils. 1174 29

Proton (equivalents) are primary participants in the control and potency of the NADPH oxidase. Both the cytosolic and intraphagosomal pH are influenced during oxidase activation, and maintenance of the optimal environment requires the coordinated action of a series of sophisticated, highly regulated H(+) transporters, including the Na(+)/H(+) exchange, vacuolar H(+)-ATPase, and H(+)-conductive pathway(s). In addition, protons that are produced during some of the NADPH oxidase reactions then are substrates for the dismutation of superoxide, which precedes production of additional bactericidal agents. In this review, pH homeostasis is shown in conjunction with the NADPH oxidase to present an integrated picture of leukocyte physiology during the phagocytic response.
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PMID:Modulation of the cytosolic and phagosomal pH by the NADPH oxidase. 1197 Aug 44

Chronic inappropriate (relative to dietary Na+ intake) elevations in circulating aldosterone (ALDO), termed aldosteronism, are associated with remodeling of intramural arteries of the right and left heart. Lesions appear at week 4 of treatment with ALDO and 1% dietary NaCl in uninephrectomized rats (ALDOST) and include invading monocytes, macrophages and lymphocytes with intracellular evidence of oxidative and nitrosative stress, myofibroblasts, and perivascular fibrosis. In this study, we tested the hypothesis that an immunostimulatory state with activated circulating peripheral blood mononuclear cells (PBMCs) precedes this proinflammatory and profibrogenic cardiac phenotype and is initiated by reduction in the cytosolic free Mg2+ concentration ([Mg2+]i). At 1 and 4 wk of ALDOST (preclinical and clinical stages, respectively), we monitored serum Mg2+, PBMC [Mg2+]i and cytosolic free [Ca2+] (via fluorimetry), and expressed genes (via microchip array) as well as markers of oxidative and nitrosative stress in plasma [alpha1-antiproteinase activity (alpha1-AP)] and cardiac tissue (immunohistochemical detection of gp91phox subunit of NADPH oxidase and 3-nitrotyrosine). Age- and gender-matched unoperated and untreated (UO) rats and uninephrectomized salt-treated (UN) rats served as controls. Serum [Mg2+] was unchanged by ALDOST. In contrast with UO and UN, [Mg2+]i and plasma alpha1-AP were each reduced (P < 0.05) at weeks 1 and 4. The decline in PBMC [Mg2+]i was accompanied by Ca2+ loading. Differential (twofold and higher) expression (up- and downregulation) in PBMC transcriptomes was present at week 1 and progressed at week 4. Involved were genes for the alpha1-isoform of Na+-K+-ATPase, the ATP-dependent Ca2+ pump, antioxidant reserves, inducible nitric oxide synthase, and PBMC activation with autoimmune responses. Expression of 3-nitrotyrosine and activation of gp91phox were seen in inflammatory cells that invaded intramural arteries. Thus early in aldosteronism (preclinical stage), an immunostimulatory state featuring activated circulating PBMCs with reduced ionized [Mg2+]i and oxidative and nitrosative stress precedes and may even predispose to coronary vascular lesions that first appear at week 4.
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PMID:Aldosteronism: an immunostimulatory state precedes proinflammatory/fibrogenic cardiac phenotype. 1286 May 67

Acute hemorrhage leads to a decrease in the phagocyte number and index, the NBT test parameters, and the NADPH oxidase activity and to an increase in the Ca2+ ATPase activity in polymorphonuclear leukocytes on the peripheral blood. Lysozyme produces effective correction of the above parameters of the functional-metabolic activity of these cells. The drug effect is mediated by cytokines of splenocytes sticking to the glass.
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PMID:[Effect of lysozyme on the functional and metabolic activity of polymorphonuclear leukocytes in the acute blood loss]. 1518 62

The pathophysiological mechanism of Salmonella enterica subsp. enterica serovar Typhimurium (Salmonella typhimurium) induced gastroenteritis is controlled by interplay of various cell signaling events. Adherence of this organism through type-1 fimbriae is known to be a vital prerequisite for the establishment of infection. In the present investigation male albino Wistar rats were immunized with purified type-1 fimbriae and challenged intragastrically with S. typhimurium. Electrolyte transport and level of different second messengers were studied in four different groups of animals. Transepithelial fluxes of Na+ and Cl- revealed absorption in immunized-challenged group as observed in case of control and immunized group while secretion was observed in infected group. Ca2+ and 3-0-methyl-D-glucose fluxes did not show any change. Significant increase in the level of intracellular Ca2+, cAMP, membrane form of protein kinase C, prostaglandins, NADPH oxidase, glucose-6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase, total oxygen free radicals, reactive nitrogen intermediates, citrulline and lipid peroxidation was found in the infected group. However, in the immunized-challenged group, the values of all the parameters were found to be same as that of control as well as immunized groups. Na+, K(+)-ATPase and calmodulin levels were found to be unaltered in all the groups of animals. Thus, the immunization with type-1 fimbriae has been found to be quite effective leading to the prevention of multiple physiologic derangements in isolated ileal cells suggesting the protective role of the fimbriae.
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PMID:The effect of type-1 fimbrial immunization on gut pathophysiological response in rats infected with Salmonella enterica subsp. enterica serovar Typhimurium. 1601 47

Hypertonicity activates the transcription factor tonicity-responsive enhancer/osmotic response element binding protein (TonEBP/OREBP), resulting in increased expression of genes involved in osmoprotective accumulation of organic osmolytes, including glycine betaine, and in increased expression of osmoprotective heat shock proteins. Our previous studies showed that high NaCl increases reactive oxygen species (ROS), which contribute to activation of TonEBP/OREBP. Mitochondria are a major source of ROS. The purpose of the present study was to examine whether mitochondria produce the ROS that contribute to activation of TonEBP/OREBP. We inhibited mitochondrial ROS production in HEK293 cells with rotenone and myxothiazol, which inhibit mitochondrial complexes I and III, respectively. Rotenone (250 nM) and myxothiazol (12 nM) reduce high NaCl-induced ROS over 40%, whereas apocynin (100 microM), an inhibitor of NADPH oxidase, and allopurinol (100 microM), an inhibitor of xanthine oxidase, have no significant effect. Rotenone and myxothiazol reduce high NaCl-induced increases in TonEBP/OREBP transcriptional activity (ORE/TonE reporter assay) and BGT1 (betaine transporter) mRNA abundance ranging from 53 to 69%. They inhibit high NaCl-induced TonEBP/OREBP transactivating activity, but not its nuclear translocation. Release of ATP into the medium on hypertonic stress has been proposed to be a signal that triggers cellular osmotic responses. However, we do not detect release of ATP into the medium or inhibition of high NaCl-induced ORE/TonE reporter activity by an ATPase, apyrase (20 U/ml), indicating that high NaCl-induced activation of TonEBP/OREBP is not mediated by release of ATP. We conclude that high NaCl increases mitochondrial ROS production, which contributes to the activation of TonEBP/OREBP by increasing its transactivating activity.
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PMID:Mitochondrial reactive oxygen species contribute to high NaCl-induced activation of the transcription factor TonEBP/OREBP. 1630 54

Immune cells such as macrophages and neutrophils provide the first line of defence of the immune system using phagocytosis, cytokine and chemokine synthesis and release, as well as Reactive Oxygen Species (ROS) generation. Many of these functions are positively coupled with cytoplasmic pH (pHi) and/or phagosomal pH (pHp) modification; an increase in pHi represents an important signal for cytokine and chemokine release, whereas a decrease in pHp can induce an efficient antigen presentation. However, the relationship between pHi and ROS generation is not well understood. In immune cells two main transport systems have been shown to regulate pHi: the Na+/H+ Exchanger (NHE) and the plasmalemmal V-type H+ ATPase. NHE is a family of proteins which exchange Na+ for H+ according to their concentration gradients in an electroneutral manner. The exchanger also plays a key role in several other cellular functions including proliferation, differentiation, apoptosis, migration, and cytoskeletal organization. Since not much is known on the relationship between NHE and immunity, this review outlines the contribution of NHE to different aspects of innate and adaptive immune responses such as phagosomal acidification, NADPH oxidase activation and ROS generation, cytokine and chemokine release as well as T cell apoptosis. The possibility that several pro-inflammatory diseases may be modulated by NHE activity is evaluated.
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PMID:The sodium/hydrogen exchanger: a possible mediator of immunity. 1693 May 75

Hydrophobic bile salts activate NADPH oxidase through a ceramide- and PKCzeta-dependent pathway as an important upstream event of bile salt-induced hepatocyte apoptosis. The mechanisms underlying bile salt-induced ceramide formation have remained unclear to date and thus were studied in rat hepatocytes. Proapoptotic bile salts, such as taurolithocholylsulfate (TLCS), lowered the apparent pHves within seconds from 6.0 to 5.6 in an FITC-dextran-accessible endosomal compartment that also contains acidic sphingomyelinase. Simultaneously, a rapid decrease in N-(ethoxycarbonylmethyl)-6-methoxyquinolinium bromide (MQAE) fluorescence was observed, suggestive of an increase in cytosolic [Cl-], which is known to activate vacuolar-type H+-ATPase. No vesicular acidification or increase in cytosolic [Cl-] was found in response to the non-apoptotic bile salt taurocholate or the anti-apoptotic bile salt tauroursodesoxycholate. Inhibition of TLCS-induced endosomal acidification by bafilomycin or 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid largely abolished the TLCS-induced ceramide-formation and downstream ceramide-dependent processes, such as p47phox-serine phosphorylation, NADPH oxidase activation, CD95 activation and apoptosis. These responses were also abolished after knockdown of acidic sphingomyelinase in rat hepatocytes. In conclusion, hydrophobic, proapoptotic bile salts stimulate ceramide formation through chloride-dependent acidification of endosomes, with subsequent activation of acidic sphingomyelinase. Our data suggest that changes in ion homeostasis underlie the stimulation of ceramide formation in response to hydrophobic bile acids as an important upstream event of bile salt-induced apoptosis.
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PMID:Hydrophobic bile salts trigger ceramide formation through endosomal acidification. 1726 Oct 82

This study examined the effect of leptin on renal ouabain-resistant Na(+)-ATPase, which drives the reabsorption of about 10% of sodium transported in the proximal tubule. Chronic leptin administration (0.25 mg/kg s.c. twice daily for seven days) increased Na(+)-ATPase activity by 62.9%. This effect was prevented by the coadministration of superoxide dismutase mimetic, tempol, or the NADPH oxidase inhibitor, apocynin (2 mM in the drinking water). Acutely administered NO donors decreased Na(+)-ATPase activity. This effect was abolished by soluble guanylate cyclase inhibitor, ODQ, but not by protein kinase G inhibitors. Exogenous cGMP reduced Na(+)-ATPase activity, but its synthetic analogues, 8-bromo-cGMP and 8-pCPT-cGMP, were ineffective. The inhibitory effect of NO donors and cGMP was abolished by EHNA, an inhibitor of cGMP-stimulated phosphodiesterase (PDE2). Exogenous cAMP analogue and dibutyryl-cAMP increased Na(+)-ATPase activity and abolished the inhibitory effect of cGMP. Finally, the administration of superoxide-generating mixture (xanthine oxidase+hypoxanthine) increased Na(+)-ATPase activity. The results suggest that nitric oxide decreases renal Na(+)-ATPase activity by stimulating cGMP, which in turn activates PDE2 and decreases cAMP concentration. Increased production of reactive oxygen species may lead to the elevation of Na(+)-ATPase activity by scavenging NO and limiting its inhibitory effect. Chronic hyperleptinemia is associated with increased Na(+)-ATPase activity due to excessive oxidative stress.
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PMID:Regulation of renal ouabain-resistant Na+-ATPase by leptin, nitric oxide, reactive oxygen species, and cyclic nucleotides: implications for obesity-associated hypertension. 1749 45

Serotonin (5-HT) stimulates smooth muscle cell growth through 5-HT receptors and the 5-HT transporter (5-HTT), and has been associated with pulmonary hypertension (PH). Platelet-derived growth factor receptors (PDGFR) have also been associated with PH. We present evidence for the first time that 5-HT transactivates PDGFRbeta through the 5-HTT in pulmonary artery (PA) SMCs. Inhibition of PDGFR kinase with imatinib or AG1296 blocks 5-HT-stimulated PDGFRbeta phosphorylation. 5-HTT inhibitors and the Na+/K+-ATPase inhibitor ouabain, but not 5-HT2 and 5-HT1B/1D receptor inhibitors, block PDGFRbeta activation by 5-HT. Notably, 5-HTT binds the PDGFRbeta upon 5-HT stimulation and the 5-HTT inhibitor fluoxetine blocks both the binding and PDGDRbeta activation. Activation of PDGFRbeta may occur through oxidation of a catalytic cysteine of tyrosine phosphatase. 5-HT-activated PDGFRbeta phosphorylation is blocked by the antioxidant N-acetyl-L-cysteine and the NADPH oxidase inhibitor, DPI. Inhibition of PDGFR kinase with imatinib or AG1296 significantly inhibits SMC proliferation and migration induced by 5-HT in vitro. Infusion of 5-HT by miniosmotic pumps enhances PDGFRbeta activation in mouse lung in vivo. In summary, these results demonstrate that 5-HT transactivates PDGFRbeta in PASMCs leading to SMC proliferation and migration, and may be an important signaling pathway in the production of PH in vivo.
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PMID:The 5-HT transporter transactivates the PDGFbeta receptor in pulmonary artery smooth muscle cells. 1750 74


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