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)

Patients with severe leukocyte G6PD deficiency may present with impairment of NADPH oxidase activity and a history of recurrent infections, mimicking the phenotype of chronic granulomatous disease. We report herein a child with recurrent infections who initially received the diagnosis of G6PD deficiency. His erythrocyte G6PD activity was reduced: 1.8 U/g Hb (normal: 12.1 +/- 2.1 U/g Hb). Further studies revealed that G6PD activity in neutrophils, mononuclear leukocytes, and Epstein-Barr virus-transformed B-lymphocytes from the proband was similar to healthy controls. Molecular studies showed that the G6PD deficiency was due a 202 G-->A mutation, the A- variant common in African ethnic groups. The proband also exhibited severely impaired respiratory burst activity, as observed in X-linked CGD. Sequence analysis of genomic DNA showed a 264 G-->A substitution at the 3' splice junction of gp91-phox exon 3. The cDNA sequence showed a deletion of gp91-phox exon 3, giving rise to an unstable or nonfunctional mutant gp91-phox and to the phenotype of X-linked CGD. We propose that clinicians treating a patient with G6PD deficiency during a severe infection episode consider the possibility of temporary or permanent impairment of the phagocytes' microbicidal activity and the eventual association of G6PD deficiency and chronic granulomatous disease.
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PMID:Association of glucose-6-phosphate dehydrogenase deficiency and X-linked chronic granulomatous disease in a child with anemia and recurrent infections. 1497 96

We compared the immune defense of mice with chronic granulomatous disease (CGD mice) with that of wild-type C57BL/6 mice for their response to Sporothrix schenckii. A subcutaneous injection of 5 x 10(4) CFU S. schenckii strain IFM41598 into CGD mice resulted in systemic infection and death within 84 days. In contrast, injected C57BL/6 mice did not develop systemic infection and were able to survive through 100 days of observation. Differences in host resistance were analyzed in vitro. Neutrophils and macrophages obtained from CGD mice were found to allow greater growth of this organism than did those obtained from C57BL/6 mice. Moreover, macrophages obtained from immunized CGD mice were able to simply inhibit the growth of this fungus whereas macrophages obtained from immunized C57BL/6 mice killed the fungus within 48 h after phagocytosis. These results suggest that (i) the lack of NADPH oxidase function is a risk factor for lethal S. schenckii infection and (ii) superoxide anion and its reactive oxidative metabolites produced by neutrophils and macrophages are involved in fungistatic and fungicidal activities.
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PMID:Impaired host defense against Sporothrix schenckii in mice with chronic granulomatous disease. 1532

The NOX family of ROS-generating NADPH oxidases consists of 7 members: NOX1 to NOX5, DUOX1 and 2. NOX1 is predominantly found in the colon, where it possibly plays a role in the host defense. NOX2 is the phagocyte NADPH oxidase, a clearly established host defense enzyme. NOX3 is almost exclusively expressed in the inner ear, where it is involved in otoconia morphogenesis, but based on its localization might also play a role in the auditory system. NOX4, widely expressed in kidney, vascular cells, osteoclasts etc.; it might be a constitutively active enzyme, regulated on the level of gene expression but its precise physiological function remains unknown. NOX5, a Ca2+ activated enzyme is predominantly expressed in lymphoid tissues and testis, where it might be involved in signaling processes. DUOX1 is expressed in the thyroid and in respiratory epithelia, and DUOX2 in the thyroid and in gastrointestinal glandular epithelia. Both DUOX enzymes are involved in thyroid hormone synthesis, but possibly also in epithelial host defense.
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PMID:Tissue distribution and putative physiological function of NOX family NADPH oxidases. 1550 65

Chronic granulomatous disease is an inherited disorder in which phagocytes lack a functional NADPH oxidase and so cannot generate superoxide anions (O(2) (-)). The most common form is caused by mutations in CYBB encoding gp91 phox, the heavy chain of flavocytochrome b(558) (XCGD). We investigated 11 male patients and their families suspected of suffering from X-linked CGD. These XCGD patients were classified as having different variants (X91(0), X91(-) or X91(+)) according to their cytochrome b(558) expression and NADPH oxidase activity. Nine patients had X91(0) CGD, one had X91(-) CGD and one had X91(+) CGD. Six mutations in CYBB were novel. Of the four new X91(0) CGD cases, three were point mutations: G65A in exon 2, G387T in exon 5 and G970T in exon 9, leading to premature stop codons at positions Try18, Try125 and Glu320, respectively, in gp91 phox. One case of X91(0) CGD originated from a new 1005G deletion detected in exon 9. Surprisingly, four nonsense mutations in exon 5 led to the generation of two mRNAs, one with a normal size containing the mutation and the other in which exon 5 had been spliced. A novel X91(-) CGD case with low gp91 phox expression was diagnosed. It was caused by an 11-bp deletion in the linking region between exon 12 and intron 12, activating a new cryptic site. Finally, a new X91(+) CGD case was detected, characterized by a missense mutation Leu505Arg in the potential NADPH-binding site of gp91 phox. No clear correlation between the severity of the clinical symptoms and the sub-type of XCGD could be established.
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PMID:Characterization of six novel mutations in the CYBB gene leading to different sub-types of X-linked chronic granulomatous disease. 1553 31

Oxidative damage is thought to play a key role in the aging of various organ systems. In this study, we have therefore analyzed mRNA expression of ROS-generating NADPH oxidases in the aging stomach. Gastric biopsies of hospitalized geriatric patients were analyzed for histology (Sidney classification), and real-time PCR was used to quantify mRNA expression of the superoxide-generating NADPH oxidases NOX1, NOX2, and NOX5. We found that stomach biopsies of elderly patients expressed NOX5 and NOX2 mRNA, but not NOX1. The mRNA expression of NOX5 (a lymphocyte NADPH oxidase) neither depended on age nor on the results of the stomach histology. In contrast, mRNA expression of NOX2 (phagocyte NADPH oxidase) was a function of two variables. Increased NOX2 mRNA levels were observed in biopsies with signs of chronic inflammation (p=0.01). Interestingly, however, there was also an age-dependent increase in NOX2 mRNA levels (p=0.01). We conclude that in elderly patients the gastric mRNA expression of the ROS-generating enzyme NOX2 increases as a function of age, possibly contributing to stomach aging and gastric vulnerability of the elderly.
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PMID:Expression of mRNA for ROS-generating NADPH oxidases in the aging stomach. 1582 Jun 17

This study was aimed to characterize the mitochondrial and extra-mitochondrial oxygen consuming reactions in human CD34+ hematopoietic stem cells. Cell samples were collected by apheresis following pre-conditioning by granulocyte colony-stimulating factor and isolated by anti-CD34 positive immunoselection. Polarographic analysis of the CN-sensitive endogenous cell respiration revealed a low mitochondrial oxygen consumption rate. Differential absorbance spectrometry on whole cell lysate and two-dimensional blue native-PAGE analysis of mitoplast proteins confirmed a low amount of mitochondrial respiratory chain complexes thus qualifying the hematopoietic stem cell as a poor oxidative phosphorylating cell type. Confocal microscopy imaging showed, however, that the intracellular content of mitochondria was not homogeneously distributed in the CD34+ hematopoietic stem cell sample displaying a clear inverse correlation of their density with the expression of the CD34 commitment marker. About half of the endogenous oxygen consumption was extra-mitochondrial and completely inhibitable by enzymatic scavengers of reactive oxygen species and by diphenylene iodinium. By spectral analysis, flow cytometry, reverse transcriptase-PCR, immunocytochemistry, and immunoprecipitation it was shown that the extra-mitochondrial oxygen consumption was contributed by the NOX2 and NOX4 isoforms of the O2-*. producer plasma membrane NAD(P)H oxidase with low constitutive activity. A model is proposed suggesting for the NAD(P)H oxidase a role of O2 sensor and/or ROS source serving as redox messengers in the activation of intracellular signaling pathways leading (or contributing) to mitochondriogenesis, cell survival, and differentiation in hematopoietic stem cells.
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PMID:Characterization of mitochondrial and extra-mitochondrial oxygen consuming reactions in human hematopoietic stem cells. Novel evidence of the occurrence of NAD(P)H oxidase activity. 1588 63

Our laboratory previously demonstrated that X-linked chronic granulomatous disease (X-CGD) mice develop exaggerated inflammatory responses and form granulomas following intradermal challenge with sterile Aspergillus fumigatus (AF) hyphae. In this study, we examined the efficacy of retroviral-mediated gene transfer (RMGT) into X-CGD bone marrow stem cells in preventing this abnormal inflammatory response. Sterile AF or saline was injected subcutaneously into the ears of wild-type, female X-CGD carrier, X-CGD, or X-CGD mice chimeric for varying numbers of either wild-type or RMGT-corrected neutrophils. Intradermal AF induced marked inflammation at both 3 and 30 d in the X-CGD mice, but not in the carriers or the wild-type mice. Similar to wild-type mice, chimeric X-CGD mice with >20% oxidase-positive neutrophils displayed a minimal and self-limited inflammatory response. Inflammation in chimeric (both wild-type and RMGT-corrected) mice with <15% oxidase-positive neutrophils was also improved compared to X-CGD mice, although still abnormal. This is the first evidence that partial correction of NADPH oxidase activity by gene therapy is likely to be beneficial in reducing or preventing the chronic inflammatory complications of CGD patients if sufficient numbers of RMGT-corrected neutrophils are obtained.
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PMID:Gene correction reduces cutaneous inflammation and granuloma formation in murine X-linked chronic granulomatous disease. 1618 69

Reactive oxygen species produced by NADPH oxidase are involved in the neuronal death associated with various neurodegenerative disorders. However, the role of NADPH oxidase in neuronal differentiation has not been well characterized. In nondifferentiated PC12 cells, the mRNA level of NOX1, a catalytic subunit of NADPH oxidase expressed in nonphagocytes, was approximately 10 times higher than that of the phagocyte type subunit, NOX2 (gp91(phox)), while the transcript of another isoform, NOX4, was not detected. Following nerve growth factor (NGF)-induced neurite outgrowth, the mRNA level of NOX1 and NOX2 was progressively increased and decreased, respectively. The NGF-induced increase in NOX1 mRNA was mediated by TrkA and accompanied by increased intracellular superoxide, which was suppressed by NADPH oxidase inhibitors. Unexpectedly, these inhibitors and superoxide scavengers significantly enhanced NGF-induced neurite outgrowth. Enhanced neurite outgrowth was similarly demonstrated in cells depleted with the NOX1 transcript by stable expression of ribozymes targeted for the NOX1 mRNA sequence. Furthermore, NGF-induced expression of betaIII-tubulin was significantly augmented in cells treated with NADPH oxidase inhibitors or stably expressing ribozymes. Phosphatidylinositol-3 (PI3) kinase inhibitors, without affecting NGF-induced NOX1 expression, augmented NGF-induced neurite outgrowth but not in clones expressing ribozymes. Taken together, increased superoxide production by up-regulation of NOX1 may negatively regulate neuronal differentiation by suppressing excessive neurite outgrowth.
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PMID:NOX1/NADPH oxidase negatively regulates nerve growth factor-induced neurite outgrowth. 1667 16

Promyelocytic NB4 leukemia cells undergo differentiation to granulocytes following retinoic acid treatment. Here we report that tissue transglutaminase (TG2), a protein cross-linking enzyme, was induced, then partially translocated into the nucleus, and became strongly associated with the chromatin during the differentiation process. The transglutaminase-catalyzed cross-link content of both the cytosolic and the nuclear protein fractions increased while NB4 cells underwent cellular maturation. Inhibition of cross-linking activity of TG2 by monodansylcadaverin in these cells led to diminished nitroblue tetrazolium (NBT) positivity, production of less superoxide anion, and decreased expression of GP91PHOX, the membrane-associated subunit of NADPH oxidase. Neutrophils isolated from TG2(-/-) mice showed diminished NBT reduction capacity, reduced superoxide anion formation, and down-regulation of the gp91phox subunit of NADPH oxidase, compared with wild-type cells. It was also observed that TG2(-/-) mice exhibited increased neutrophil phagocytic activity, but had attenuated neutrophil chemotaxis and impaired neutrophil extravasation with higher neutrophil counts in their circulation during yeast extract-induced peritonitis. These results clearly suggest that TG2 may modulate the expression of genes related to neutrophil functions and is involved in several intracellular and extracellular functions of extravasating neutrophil.
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PMID:Tissue-transglutaminase contributes to neutrophil granulocyte differentiation and functions. 1676 14

To initiate adaptative cytotoxic immune responses, proteolytic peptides derived from phagocytosed antigens are presented by dendritic cells (DCs) to CD8+ T lymphocytes through a process called antigen "crosspresentation." The partial degradation of antigens mediated by lysosomal proteases in an acidic environment must be tightly controlled to prevent destruction of potential peptides for T cell recognition. We now describe a specialization of the phagocytic pathway of DCs that allows a fine control of antigen processing. The NADPH oxidase NOX2 is recruited to the DC's early phagosomes and mediates the sustained production of low levels of reactive oxygen species, causing active and maintained alkalinization of the phagosomal lumen. DCs lacking NOX2 show enhanced phagosomal acidification and increased antigen degradation, resulting in impaired crosspresentation. Therefore, NOX2 plays a critical role in conferring DCs the ability to function as specialized phagocytes adapted to process antigens rather than kill pathogens.
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PMID:NOX2 controls phagosomal pH to regulate antigen processing during crosspresentation by dendritic cells. 1683 68


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