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)

Aspergillus fumigatus, a common mold, rarely infects humans, except during prolonged neutropenia or in cases of chronic granulomatous disease (CGD), a primary immunodeficiency caused by mutations in the NADPH oxidase that normally produces fungicidal reactive oxygen species. Filamentous hyphae of Aspergillus are killed by normal, but not CGD polymorphonuclear leukocytes (PMN); however, the few studies on PMN-mediated host defenses against infectious conidia (spores) of this organism have yielded conflicting results, some showing that PMN do not inhibit conidial growth, with others showing that they do, most likely using reactive oxygen species. Given that CGD patients are exposed daily to hundreds of viable A. fumigatus conidia, yet considerable numbers of them survive years without infection, we reasoned that PMN use ROS-independent mechanisms to combat Aspergillus. We show that human PMN from both normal controls and CGD patients are equipotent at arresting the growth of Aspergillus conidia in vitro, indicating the presence of a reactive oxygen species-independent factor(s). Cell-free supernatants of degranulated normal and CGD neutrophils both suppressed fungal growth and were found to be rich in lactoferrin, an abundant PMN secondary granule protein. Purified iron-poor lactoferrin at concentrations occurring in PMN supernatants (and reported in human mucosal secretions in vivo) decreased fungal growth, whereas saturation of lactoferrin or PMN supernatants with iron, or testing in the presence of excess iron in the form of ferritin, completely abolished activity against conidia. These results demonstrate that PMN lactoferrin sequestration of iron is important for host defense against Aspergillus.
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PMID:Human polymorphonuclear leukocytes inhibit Aspergillus fumigatus conidial growth by lactoferrin-mediated iron depletion. 1747 66

Clinical use of human immunodeficiency virus protease inhibitors such as ritonavir may be associated with cardiovascular disease. The objective of this study was to determine the effects and molecular mechanisms of ritonavir on cholesterol efflux from human macrophage-derived foam cells, which is a critical factor of atherogenesis. Human THP-1 monocytes and peripheral blood mononuclear cells were preincubated with acetylated low-density lipoprotein and [(3)H]cholesterol to form foam cells, which were then treated with apolipoprotein A-I for cholesterol efflux assay. A clinically relevant concentration of ritonavir (15 mumol/L) significantly reduced cholesterol efflux from THP-1 and peripheral blood mononuclear cells to apolipoprotein A-I by 30 and 29%, respectively, as compared with controls. In addition, ritonavir significantly decreased the expression of scavenger receptor B1 and caveolin-1, whereas it significantly increased superoxide anion production and activated extracellular signal-regulated kinase (ERK) 1/2 in macrophages. Mitochondrial membrane potential was significantly reduced, whereas NADPH oxidase subunits were increased in ritonavir-treated macrophages. Consequently, the antioxidant seleno-l-methionine, the specific ERK1/2 inhibitor PD98059, or infection of a recombinant adenovirus encoding the dominant-negative form of ERK2 effectively blocked ritonavir-induced decrease of cholesterol efflux. Therefore, human immunodeficiency virus protease inhibitor ritonavir significantly inhibits cholesterol efflux from macrophages, which may be mediated by mitochondrial dysfunction, oxidative stress, ERK1/2 activation, and down-regulation of scavenger receptor B1 and caveolin-1.
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PMID:Human immunodeficiency virus protease inhibitor ritonavir inhibits cholesterol efflux from human macrophage-derived foam cells. 1787 77

CYBB encodes the gp91-phox protein of the phagocytic NADPH oxidase; the innate immunity-related enzymatic complex responsible for the respiratory burst. Mutations in CYBB can cause chronic granulomatous disease (CGD), a primary immunodeficiency characterized by ineffective microbicidal activity, for which over 150 family-specific mutations have been described. It is also plausible that common SNPs in CYBB alter the expression or function of gp91-phox, determining differences in susceptibility to complex disorders such as autoimmune or infectious diseases. We have resequenced the exons, UTRs, and intronic regions of CYBB in 102 ethnically diverse individuals and genotyped nine tag-SNPs in 942 individuals from 52 worldwide populations. The 28 observed SNPs (none of which nonsynonymous) reside on 28 haplotypes that can be collapsed into five clades. CYBB shows lower diversity than other X-chromosome genes and most of the between-population genetic variance was observed among Africans and non-Africans. The African population shows the highest diversity and the lowest linkage disequilibrium (LD). Because there is extensive shared LD among non-Africans, tag-SNPs can be effectively employed in gene-centric association studies and are portable across Eurasian and Native American populations. Comparison of CYBB coding sequences among mammals evidences the action of long-term purifying selection, which is stronger on the C-terminal cytosolic domain than on the N-terminal transmembrane domain of gp91-phox.
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PMID:CYBB, an NADPH-oxidase gene: restricted diversity in humans and evidence for differential long-term purifying selection on transmembrane and cytosolic domains. 1827 5

Chronic granulomatous disease (CGD) is an inherited disorder of pathogen killing by phagocytic leukocytes caused by mutations in NADPH oxidase subunits. Patients with CGD have life-threatening bacterial and fungal infections. Children's Medical Center at Tehran University is the referral center for immunodeficiency in Iran. During 2 years of study, 11 non-consanguineous families with clinically diagnosed CGD were referred to this center. In functional assays performed on neutrophils from affected children and their mothers; no activity or strongly decreased oxidase activity was detected in the patients' cells. In oxidase tests that scored this activity on a per-cell basis, a mosaic pattern was detected in the neutrophils from all 11 mothers. Western blot analysis revealed an X91 degrees phenotype in all patients. Mutation screening in the CYBB gene encoding gp91(phox) by SSCP analysis followed by sequencing showed nine different mutations, including two novel mutations. The present survey is the first study aimed to analyze the clinical features and the molecular diagnosis of X-CGD in Iranian patients.
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PMID:Molecular diagnosis of X-linked chronic granulomatous disease in Iran. 1832 77

Human immunodeficiency virus (HIV)-infected patients have a higher incidence of oxidative stress, endothelial dysfunction, and cardiovascular disease than uninfected individuals. Recent reports have demonstrated that viral proteins upregulate reactive oxygen species, which may contribute to elevated cardiovascular risk in HIV-1 patients. In this study we employed an HIV-1 transgenic rat model to investigate the physiological effects of viral protein expression on the vasculature. Markers of oxidative stress in wild-type and HIV-1 transgenic rats were measured using electron spin resonance, fluorescence microscopy, and various molecular techniques. Relaxation studies were completed on isolated aortic rings, and mRNA and protein were collected to measure changes in expression of nitric oxide (NO) and superoxide sources. HIV-1 transgenic rats displayed significantly less NO-hemoglobin, serum nitrite, serum S-nitrosothiols, aortic tissue NO, and impaired endothelium-dependent vasorelaxation than wild-type rats. NO reduction was not attributed to differences in endothelial NO synthase (eNOS) protein expression, eNOS-Ser1177 phosphorylation, or tetrahydrobiopterin availability. Aortas from HIV-1 transgenic rats had higher levels of superoxide and 3-nitrotyrosine but did not differ in expression of superoxide-generating sources NADPH oxidase or xanthine oxidase. However, transgenic aortas displayed decreased superoxide dismutase and glutathione. Administering the glutathione precursor procysteine decreased superoxide, restored aortic NO levels and NO-hemoglobin, and improved endothelium-dependent relaxation in HIV-1 transgenic rats. These results show that HIV-1 protein expression decreases NO and causes endothelial dysfunction. Diminished antioxidant capacity increases vascular superoxide levels, which reduce NO bioavailability and promote peroxynitrite generation. Restoring glutathione levels reverses HIV-1 protein-mediated effects on superoxide, NO, and vasorelaxation.
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PMID:Vascular oxidative stress and nitric oxide depletion in HIV-1 transgenic rats are reversed by glutathione restoration. 1845 25

Chronic granulomatous disease (CGD) is a primary immunodeficiency syndrome characterized by a greatly increased susceptibility to severe fungal and bacterial infections. CGD results from a failure of the reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzyme in the patient's phagocytes to produce superoxide. It is caused by mutations in any of four genes that encode the components of the NADPH oxidase. Investigation of CGD patients has identified the different subunits and the genes encoding them. Study of rare CGD variants has highlighted sequences involved in the structural stability of affected components or has provided valuable insights into their function in the oxidase activation mechanism. Functional and molecular CGD diagnosis tests are discussed in this review. Long-term antibiotic prophylaxis has been essential in fighting infections associated with CGD, but approaches based on hematopoietic stem cell transplantation and gene therapy offer great hope for the near future.
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PMID:Genetics and immunopathology of chronic granulomatous disease. 1859 38

This work investigated the functional role of nuclear factor-kappaB (NF-kappaB) in respiratory burst activity and in expression of the human phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase genes CYBB, CYBA, NCF1, and NCF2. U937 cells with a stably transfected repressor of NF-kappaB (IkappaBalpha-S32A/S36A) demonstrated significantly lower superoxide release and lower CYBB and NCF1 gene expression compared with control U937 cells. We further tested Epstein-Barr virus (EBV)-transformed B cells from patients with anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID), an inherited disorder of NF-kappaB function. Superoxide release and CYBB gene expression by EDA-ID cells were significantly decreased compared with healthy cells and similar to cells from patients with X-linked chronic granulomatous disease (X91(0) CGD). NCF1 gene expression in EDA-ID S32I cells was decreased compared with healthy control cells and similar to that in autosomal recessive (A47(0)) CGD cells. Gel shift assays demonstrated loss of recombinant human p50 binding to a NF-kappaB site 5' to the CYBB gene in U937 cells treated with NF-kappaB inhibitors, repressor-transfected U937 cells, and EDA-ID patients' cells. Zymosan phagocytosis was not affected by transfection of U937 cells with the NF-kappaB repressor. These studies show that NF-kappaB is necessary for CYBB and NCF1 gene expression and activation of the phagocyte NADPH oxidase in this model system.
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PMID:Essential role of nuclear factor-kappaB for NADPH oxidase activity in normal and anhidrotic ectodermal dysplasia leukocytes. 1947 Apr 38

Chronic-granulomatous disease (CGD) is a rare inherited primary immunodeficiency syndrome caused by a defective oxidative metabolism of phagocytic cells. Dysfunction of the membranous NADPH oxidase complex leads to a greatly increased susceptibility to severe fungal and bacterial infections, early in childhood. The most severe and frequent type of GCD is the X-linked transmitted form caused by mutations in the CYBB gene encoding the redox element of the oxidase complex, gp91phox or Nox2. However, very rare autosomal recessive CGD affecting other oxidase components than Nox2 are characterized by mild-clinical manifestations that could appear later at the adult age. Long-term antibiotic prophylaxis is essential to prevent infections associated with CGD, but approaches based on hematopoietic stem-cell transplantation and gene therapy offer valuable hope in a near future.
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PMID:[Chronic-granulomatous disease]. 1864 Jul 47

Chronic granulomatous disease (CGD) is an innate immunodeficiency due to a genetic defect in one of the NADPH-oxidase components. In the course of 21 years, 38 Israeli CGD patients were diagnosed with 17 gene mutations, seven of which were new. Clinical, functional, and molecular studies were accomplished. Although X-linked recessive (XLR)-CGD is worldwide the most common genotype of the disease (~70%), in our study only 11 patients (29%) suffered from XLR-CGD. In Israel, the higher incidence of the autosomal recessive (AR) form of CGD (63%) may be related to consanguineous marriages. In three patients (8%), all four proteins of the NADPH oxidase were present. Severe clinical expression was found both in the XLR and AR forms, but in general a milder disease was evident in AR-CGD, particularly in patients with p47(phox) deficiency. Despite early and aggressive therapy, a mortality rate of 26% was noted. Given that bone-marrow transplantation was successful in five of seven patients, it is recommended to perform it as early as possible before tissue damage is irreversible.
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PMID:Chronic granulomatous disease in Israel: clinical, functional and molecular studies of 38 patients. 1870 96

Previous reports have shown that the human immunodeficiency virus (HIV) regulatory protein Tat has both pro-oxidant and pro-inflammatory properties, suggesting that Tat might contribute to the neurological complications of HIV. However, the intracellular mechanisms whereby Tat triggers free radical production and inflammation, and the relationship between Tat-induced free radicals and inflammatory reactions, are still subject to debate. The present study was undertaken to evaluate the specific effects of Tat on NADPH oxidase in microglia and macrophages, and to determine the specific role of NADPH oxidase in Tat-induced cytokine/chemokine release and neurotoxicity. Application of Tat to microglia or macrophages caused dose- and time-dependent increases in superoxide formation that were prevented by both pharmacologic NADPH oxidase inhibitors and by specific decoy peptides (gp91ds). Furthermore, inhibition of NADPH oxidase attenuated Tat-induced release of interleukin-6 (IL-6), tumor necrosis factor alpha (TNF), and monocyte chemoattractant protein 1 (MCP-1), and decreased microglial-mediated neurotoxicity. Finally, macrophages derived from NADPH oxidase-deficient mice displayed reduced superoxide production, released lower levels of cytokines/chemokines, and induced less neurotoxicity in response to Tat compared to wild-type macrophages. Together, these data describe a specific and biologically significant signaling component of the macrophage/microglial response to Tat, and suggest the neuropathology associated with HIV infection might originate in part with Tat-induced activation of NADPH oxidase.
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PMID:NADPH oxidase drives cytokine and neurotoxin release from microglia and macrophages in response to HIV-Tat. 1871 50


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