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)

Chronic granulomatous disease is a group of rare x-linked or autosomal genetic disorders of the phagocytic NADPH oxidase system involved in host defence against various microorganisms. It is manifested by a common phenotype consisting of recurrent serious, life-threatening infection and granuloma formation. Following the finding that interferon gamma-1b (IFN gamma-1b) can potentiate phagocyte activity in some other disease states as well as restoring defective phagocyte NADPH oxidase system activity in at least some patients with chronic granulomatous disease, a large-scale placebo-controlled trial was undertaken with IFN gamma-1b in patients with chronic granulomatous disease. Long term treatment with a therapeutic dosage of IFN gamma-1b produced a significant reduction in the incidence of serious clinical events necessitating hospitalisation. The relative risk of serious infection and the number of days in hospital were each reduced by about two-thirds, and the mean duration of hospital stay by about one-third in those who did experience infection. The greatest therapeutic benefit was found in patients aged less than 10 years, but all patients were improved regardless of age, sex, use of prophylactic antibiotics or genetic pattern of inheritance. The drug was well tolerated with the commonest adverse effects (e.g. fever, headache, chills, injection site erythema) usually being mild, transient, and relieved by symptomatic treatment. IFN gamma-1b therefore provides an effective and well tolerated therapy for patients with chronic granulomatous disease, offering an important clinical advance in the treatment of this rare genetic disorder by improving the prognosis of its serious and life-threatening infectious sequelae.
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PMID:Interferon gamma-1b. A review of its pharmacology and therapeutic potential in chronic granulomatous disease. 137 55

Chronic granulomatous disease (CGD) is an inherited group of disorders in which phagocytic leukocytes (neutrophils, eosinophils, monocytes, and macrophages) fail to undergo a respiratory burst when stimulated. The products of the respiratory burst, which include superoxide and hypochlorous acid, play a critical role in killing pathogenic bacteria, fungi, and parasites. As a result of the failure to activate the respiratory burst in their phagocytes, most CGD patients suffer from severe recurrent infections. While all CGD patients share this severe defect, there is substantial heterogeneity in the molecular mechanisms responsible. The enzyme that catalyzes the respiratory burst, NADPH oxidase, has been extensively characterized and found to consist of at least four subunits: gp91-phox and p22-phox (the two subunits of a low potential cytochrome b that is the terminal electron carrier of the oxidase) as well as p47-phox and p67-phox (two cytosolic oxidase components). CGD is caused by a defect in any one of these four components, thus explaining the previously confusing genetic heterogeneity of this disorder. In approximately thirty reported cases, the underlying mutations involving these oxidase components have been identified. The current understanding of the molecular basis of CGD is reviewed in the context of a recently completed Phase III clinical trial establishing the efficacy of recombinant human interferon gamma in the treatment of CGD.
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PMID:Molecular basis of the autosomal recessive forms of chronic granulomatous disease. 155 99

We examined the potential of interferon gamma (IFN-gamma) to ameliorate the physiologic defect of chronic granulomatous disease (CGD) by studying its effects on CGD phagocyte superoxide generation, NADPH oxidase kinetics, cytochrome b559 content, and expression of X-CGD (the gene for the X-linked disease). Granulocytes and macrophages from three patients in two kindreds with "variant" X-linked CGD (i.e., with very low, but detectable, baseline superoxide-generating activity) responded to IFN-gamma with enhanced nitroblue tetrazolium reduction and two- to eightfold increases in superoxide generation. IFN-gamma did not augment the respiratory burst activity of phagocytes from patients with "classic" CGD (i.e., no detectable baseline superoxide generation) or autosomal variant CGD. Incubation of a responding patient's granulocytes with IFN-gamma nearly doubled the maximal velocity for the NADPH oxidase, but did not change its abnormal Michaelis constant. Although the interferon-treated CGD granulocytes produced superoxide at a rate 40% of normal, the cytochrome b spectrum remained undetectable. IFN-gamma treatment of cultured monocytes from an IFN-gamma-responsive CGD patient increased the steady state level of RNA transcripts from the X-CGD gene from barely detectable up to approximately 5% of normal.
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PMID:Recombinant interferon gamma augments phagocyte superoxide production and X-chronic granulomatous disease gene expression in X-linked variant chronic granulomatous disease. 282 Oct 69

Capability to release superoxide anion in response to phorbol myristate acetate by intact cells has been compared with Kinetic properties of NADPH oxidase by lysates of human monocytes and monocyte-derived macrophages. Maturation of monocytes in vitro is accompanied by substantial decrease of the capability to release superoxide anion in response to phorbol myristate acetate. Exposure of mature macrophages to recombinant interferon gamma enhances respiratory burst activity up to 3-4 fold. Modifications of NADPH oxidase accompany changes in the ability to release superoxide anion. The affinity of the oxidase for its substrate is higher in monocytes and gamma interferon treated macrophages, while Vmax is not changed.
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PMID:Activation by gamma interferon of human macrophage capability to produce toxic oxygen molecules is accompanied by decreased Km of the superoxide-generating NADPH oxidase. 300 Mar 67

We established the system to detect superoxide produced by Epstein Barr virus lymphoblastoid cell line (EB-LCL). Superoxide production of EB-LCL was evaluated by measuring chemiluminescence (CL) enhanced with addition of horseradish peroxidase (HRP). Using this system, we measured CL of EB-LCL established from 13 patients with chronic granulomatous disease (CGD) and 8 normal individuals. Significant elevation of CL was observed in all control EB-LCLs, however, no remarkable CL was seen in any patients' EB-LCLs. We examined the effect of recombinant human interferon gamma (rh-IFN-gamma) and granulocyte colony stimulating factor (G-CSF) on CL of EB-LCL in vitro. With addition of rh-IFN-gamma, CL of normal control EB-LCL was significantly enhanced (p < 0.05), on the other hand, G-CSF was shown to have no effect. No significant CL was observed in any CGD patients' EB-LCLs even with addition of rh-IFN-gamma or G-CSF. It was suggested that superoxide produced by EB-LCL detected in this system was dependent on the same NADPH oxidase system which presents in phagocyte.
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PMID:[Establishment of superoxide production assay system using Epstein-Barr virus transformed cell line with chemiluminescence]. 755 50

In chronic granulomatous disease (CGD), diminished or absent neutrophil NADPH oxidase function leads to recurrent pyogenic infections and granuloma formation. In a recent randomized, placebo-controlled trail, short-term prophylactic use of recombinant human interferon gamma (rIFN-gamma 1b) reduced the risk of serious infection in CGD patients by 67%, The current study evaluated the safety and effectiveness of long-term rIFN-gamma therapy in CGD patients. Patients were treated three times weekly with rIFN-gamma and evaluated semiannually. Serious infections (requiring hospitalization and parenteral antibiotic therapy), adverse clinical events, and measures of growth and development were noted. Thirty patients were evaluated for 12 months. The total average duration of rIFN-gamma therapy was 2.5 years. Three patients developed a total of four serious infections (0.13 infections per patient year). This rate compare favorably with rates of 1.10 and 0.38 infections per patient year found in the placebo and rIFN-gamma groups, respectively, during a previous study. Common adverse events were fever (23%), diarrhea (13%), and flu-like illness (13%). No serious adverse event was attributable to rIFN-gamma therapy and no obvious effects on growth and development were observed. rIFN-gamma is a safe and effective adjunctive therapy for reducing the frequency and severity of serious infections in CGD patients.
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PMID:Safety and effectiveness of long-term interferon gamma therapy in patients with chronic granulomatous disease. 867 77

Helicobacter pylori infection induces the appearance of inflammatory infiltrates, consisting mainly of neutrophils and monocytes, in the human gastric mucosa. A bacterial protein with neutrophil activating activity (HP-NAP) has been previously identified, but its role in infection and immune response is still largely unknown. Here, we show that vaccination of mice with HP-NAP induces protection against H. pylori challenge, and that the majority of infected patients produce antibodies specific for HP-NAP, suggesting an important role of this factor in immunity. We also show that HP-NAP is chemotactic for human leukocytes and that it activates their NADPH oxidase to produce reactive oxygen intermediates, as demonstrated by the translocation of its cytosolic subunits to the plasma membrane, and by the lack of activity on chronic granulomatous disease leukocytes. This stimulating effect is strongly potentiated by tumor necrosis factor alpha and interferon gamma and is mediated by a rapid increase of the cytosolic calcium concentration. The activation of leukocytes induced by HP-NAP is completely inhibited by pertussis toxin, wortmannin, and PP1. On the basis of these results, we conclude that HP-NAP is a virulence factor important for the H. pylori pathogenic effects at the site of infection and a candidate antigen for vaccine development.
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PMID:The neutrophil-activating protein (HP-NAP) of Helicobacter pylori is a protective antigen and a major virulence factor. 1079 Apr 19

Chronic granulomatous disease (CGD) is an inherited disorder of host defense against microbial infections caused by defective activity of the phagocyte NADPH oxidase. Based on an increase of neutrophil superoxide-generating ability in response to interferon gamma (IFN-gamma) in a single patient with CGD, multicentered group studies demonstrated a beneficial effect of prophylactic IFN-gamma. However, no apparent increase of the phagocyte superoxide generation was found in patients enrolled in these studies. The present report offers an additional kindred in whom an IFN-gamma-dependent increase in neutrophil superoxide production was observed in 3 affected patients. The defect in the CYBB gene for gp91-phox was identified as an otherwise silent mutation adjacent to the third intron of the CYBB gene that alters messenger RNA splicing. By molecular analysis, significant differences were found in the splicing pattern of CYBB gene transcripts in patient neutrophils between 1 and 25 days after administration of IFN-gamma. Furthermore, a complete transcript containing the missing exons could be detected in all specimens after the treatment. The changes in the splicing pattern of the transcripts and the prolonged effect on superoxide-generating ability of patient neutrophils indicate that IFN-gamma induced a partial correction of the abnormal splicing of CYBB gene transcripts in myeloid progenitor cells.
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PMID:Improved superoxide-generating ability by interferon gamma due to splicing pattern change of transcripts in neutrophils from patients with a splice site mutation in CYBB gene. 1143 14

Osteoclasts are the primary cells responsible for bone resorption. Osteoclast formation and bone resorption activities involve processes tightly controlled by a network of cytokines. The presence of interferon gamma (IFN-gamma) receptors on osteoclasts is a necessary prerequisite for IFN-gamma to directly affect osteoclastic activity. To date, the presence of the IFN-gamma receptor on osteoclasts has not been established. This study provides evidence that osteoclasts express the IFN-gamma receptor. Specific binding of IFN-gamma to the osteoclastic receptor stimulates osteoclastic superoxide generation. The p91 and p47 components of the NADPH oxidase increase after IFN-gamma stimulation and may account for the enhanced superoxide generation. Antisense experiments targeting p91 and p47 subunits abrogate the increased osteoclastic superoxide production stimulated by IFN-gamma. Thus, superoxide generation by osteoclasts is stimulated by activation of a functional IFN-gamma receptor on the osteoclast.
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PMID:Characterization of interferon gamma receptors on osteoclasts: effect of interferon gamma on osteoclastic superoxide generation. 1181 69

The superoxide-generating phagocytic NADPH oxidase is an important component of the innate immune response against microbial agents, and is involved in shaping the cellular response to a variety of physiological and pathological signals. One of the downstream targets of NADPH oxidase-derived radicals is the ubiquitous transcription factor NF-kappaB, which controls the expression of a large array of genes involved in immune function and cell survival. Here we show that NF-kappaB itself is a key factor in controlling NADPH oxidase expression and function. In monocytic and microglial cell lines, the expression of the NADPH oxidase subunit gp91(phox) was induced by lipopolysaccharide/interferon gamma treatment and was inhibited in cells constitutively expressing IkappaBalpha. Furthermore, inducible reactive oxygen species production was inhibited in IkappaBalpha overexpressing cells. gp91(phox) expression was very low in RelA(-/-) fibroblasts and could be induced by reconstituting these cells with p65/RelA. Thus, gp91(phox) expression is dependent on the presence of p65/RelA. We also found that gp91(phox) transcription is dependent on NF-kappaB and we identified two potential cis-acting elements in the murine gp91(phox) promoter that control NF-kappaB-dependent regulation. The findings raise the possibility of a positive feedback loop in which NF-kappaB activation by oxidative stress leads to further radical production via NADPH oxidase.
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PMID:NF-kappaB regulates phagocytic NADPH oxidase by inducing the expression of gp91phox. 1640 83


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