Disease relevance of Ncf1

• Translocation of glomerular p47phox and p67phox by protein kinase C-beta activation is required for oxidative stress in diabetic nephropathy [1].
• There is a prominent increase in the SHR kidney of the mRNA, and protein expression of p47phox in the vasculature, macula densa, and distal nephron, which precedes development of hypertension [2].
• Kainate-induced status epilepticus resulted in a time-dependent translocation of NADPH oxidase subunits (p47phox, p67phox and rac-1) from hippocampal cytosol to membrane fractions [3].
• It is interesting that only ARB prevented abnormal iron deposition in the interstitium, corrected chronic hypoxia, reduced expressions of heme oxygenase and p47phox (a subunit of NADPHoxidase), and inhibited pentosidine formation (which correlates well with proteinuria) [4].
• The increased MPO activity and p47phox expression accompanied a translocation of indigenous E. coli into the mesenteric lymph node without a spread to other organs [5].

High impact information on Ncf1

• The disease-related allele of Ncf1 has reduced oxidative burst response and promotes activation of arthritogenic T cells [6].
• TLCS induced a rapid serine phosphorylation of the regulatory subunit p47phox, which was sensitive to inhibition of sphingomyelinase and protein kinase Czeta (PKCzeta) [7].
• Inhibitors of p47phox phosphorylation and p47phox protein knockdown abolished the TLCS-induced oxidative stress response and blunted subsequent CD95 activation [7].
• To determine if osteoclasts express NADPH-oxidase, a superoxide-generating enzyme found in phagocytic leukocytes, immunohistochemical studies were performed on tibia from 1-5-d-old rats using mAbs 449 and 48 and an antiserum specific for p47-phox [8].
• Immunohistochemical staining indicated the localization of NADPH oxidase proteins gp91phox, p22phox, p47phox, and p67phox almost exclusively in the adventitia of the rat aorta with no substantial staining in the media [9].

Biological context of Ncf1

• This has also been confirmed by previous linkage analyses involving the LEW/Ztm strain which shows that a QTL on chromosome 12, most likely caused by polymorphism of Ncf1, is the major regulatory gene but that other loci are contributing [10].
• Inconsistent susceptibility to autoimmunity in inbred LEW rats is due to genetic crossbreeding involving segregation of the arthritis-regulating gene Ncf1 [10].
• We recently identified a single-nucleotide polymorphism in the Ncf1 gene, a component of the NADPH oxidase complex, to be the cause of one of the strongest identified loci for arthritis severity in rats [10].
• By using an alternative approach, i.e., linkage analysis using relevant animal models we succeeded in finding the Ncf1 gene residing in the Pia4 quantitative trait locus to be responsible for the severity of pristane induced arthritis in rats [11].
• A cDNA encoding rat p47phox was cloned from rat spleen cDNA library, utilizing rapid amplification of cDNA ends [12].

Anatomical context of Ncf1

• Moreover, the LEW/Mol strain had higher production of radical oxygen species in peripheral blood leukocytes, a phenomenon most likely regulated by the polymorphisms in the Ncf1 gene [10].
• The open reading frame corresponded to 389 amino acids: It contained the phagocyte oxidase homology domain, two Src homology 3 domains and a proline rich region, all of which are conserved in mammalian p47phox sequences [12].
• Adenoviral-mediated PKC-beta(2) overexpression enhanced ROS generation by modulating the membranous translocation of p47phox and p67phox in cultured mesangial cells [1].
• In this study we proposed to determine whether angiotensin II stimulated NADPH oxidase activation and NADPH oxidase subunit p47-phox expression in H9C2 cardiac muscle cells [13].
• Leukotriene B4 mediates p47phox phosphorylation and membrane translocation in polyunsaturated fatty acid-stimulated neutrophils [14].

Associations of Ncf1 with chemical compounds

• Quercetin and Isorhamnetin Prevent Endothelial Dysfunction, Superoxide Production, and Overexpression of p47phox Induced by Angiotensin II in Rat Aorta [15].
• Furthermore, expression of p47phox of nicotinamide adenine dinucleotide phosphate oxidase, but not of p67phox, in PMN from SHR was higher than that in PMN from WKY [16].
• We expressed and purified rat p47phox as a glutathione S-transferase fusion protein, and found that the rat protein could replace human p47phox in a cell-free activation system for human NADPH oxidase, giving about half activity [12].
• To this end, first we examined the abundance of several components of reduced nicotinamide-adenine dinucleotide phosphate oxidase (identified as the major source of reactive oxygen species), including gp91phox/Nox2, p22phox, p47phox, and Nox3 using real-time PCR [17].
• Detection of increased intracellular ROS in HG by dichlorofluorescein was inhibited by catalase, diphenyleneiodonium, or p47phox antisense oligonucleotide [18].

Regulatory relationships of Ncf1

• Cia25 regulates MAS and disease severity during the mid-to-late stages of the disease course and may be accounted for by Ncf1 polymorphisms [19].
• The overexpression of dominant-negative p47phox in A10 cells suppressed lysoPC-induced ERK activation [20].

Other interactions of Ncf1

• Sequencing analyses of the Cia25 candidate gene Ncf1 revealed polymorphisms between DA and ACI [19].
• In contrast, expression of Nox1, gp91phox, p22phox, and p47phox did not differ between strains [21].
• Western blot analyses after subcellular fractionation revealed that l-arginine supplementation distinctly decreases membrane localization of p47phox protein, as it decreases total expression of Rac1 protein in DS rats with high salt loading [22].
• CONCLUSION: Activation of NADPH oxidase with translocation of p47phox to the membrane underlies the oxidative stress and limited NO generation, despite enhanced eNOS expression in a model of diabetic nephropathy [23].
• The aim of the present study was to examine the effect of dietary iron deficiency on cardiac ultrastructure, mitochondrial cytochrome c release, NOS (nitric oxide synthase) and several stress-related protein molecules, including protein nitrotyrosine, the p47phox subunit of NADPH oxidase, caveolin-1 and RhoA [24].

Analytical, diagnostic and therapeutic context of Ncf1

• Immunoblotting data showed that aldosterone (100 nmol/L for 3 h) increased p47phox and p67phox protein levels in the membrane fraction by approximately 2.1- and 2.3-fold, respectively [25].
• Kidneys of adult (10 weeks old) SHR had a significantly (P<0.01) greater mRNA for p47phox (SHR 0.81 +/- 0.05 versus WKY 0.37 +/- 0.01, arbitrary unit), which was confirmed by Western blotting (SHR 0.58 +/- 0.04 versus WKY 0.42 +/- 0.04, arbitrary unit; P<0.05) and by immunohistochemistry [2].
• Furthermore, PE increased p47phox expression (RT-PCR) [26].

References