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| 18219386 | NOX2 | Nox2 | 3.5 | Figure 1 Production of ROS by microglial Nox2 during inflammation is amplified by mutant SOD1 binding to Rac1 | |  |
| 18219386 | NOX2 | Nox2 | 3.5 | (through through deletion of the gene encoding either Nox1 or Nox2 an increase in survival was seen with Nox2 deletion proving | | |
| 18219386 | NOX2 | Nox2 | 3.5 | Nox1 or Nox2 an increase in survival was seen with Nox2 deletion proving to be of greater benefit than Nox1 deletion | | |
| 18219386 | NOX2 | Nox2 | 3.5 | Consistent with progressive microglial activation during disease Nox2 expression was upregulated in SOD1 G93A mice ( 13 14 | | |
| 18219386 | NOX2 | Nox2 | 3.5 | The Nox prototype Nox2 is the phagocytic Nox (also also known as gp91 phox | | |
| 18219386 | NOX2 | Nox2 | 3.5 | Nox2 contains an NADPH-binding site a FAD-binding site and 4 heme-binding | | |
| 18219386 | NOX2 | Nox2 | 3.5 | Nox2 is constitutively associated with the transmembrane Nox stabilizing protein p22 | | |
| 18219386 | NOX2 | NOX2 | 3.5 | all Nox family members require the same interacting partners but Nox1 and Nox2 are both p47 phox and Rac dependent ( | | |
| 18219386 | NOX2 | Nox2 | 3.5 | family members require the same interacting partners but Nox1 and Nox2 are both p47 phox and Rac dependent ( 15 | | |
| 18219386 | NOX2 | Nox2 | 3.5 | This scenario is consistent with protection observed by Nox2 deletion in other models of neurodegeneration in which inflammation has | | |
| 18219386 | NOX2 | Nox2 | 3.5 | In addition dopaminergic neurons cocultured with microglial cells lacking the Nox2 gene are more resistant to rotenone-induced neuronal death ( 18 | | |
| 18219386 | NOX2 | Nox2 | 3.5 | SOD1 interacts directly with Rac1 but not with the other Nox2 cytosolic regulators ( 20 | | |
| 18219386 | NOX2 | Nox2 | 3.5 | bound Rac1-GTP the form of Rac1 that is recruited to Nox2 upon activation | | |
| 18219386 | NOX2 | Nox2 | 3.5 | Thus only if SOD1 mutants increase Nox2 activity independently of their metalated state could mutant SOD1_amp_#x02013 enhanced | | |
| 18219386 | NOX2 | Nox2 | 3.5 | Decreasing ROS production by deleting Nox2 has already proven efficacious in ALS mice ( 13 14 | | |
| 18219386 | NOX2 | Nox2 | 3.5 | and in fact greater than _amp_#x02014 the deletion of the Nox2 gene in SOD1 G93A mice previously reported by the same | | |
| 18219386 | NOX2 | NOX2 | 3.5 | only the Nox proteins requiring these cytosolic activators which include Nox1 and Nox2 | | |
| 18219386 | NOX2 | Nox2 | 3.5 | Nox proteins requiring these cytosolic activators which include Nox1 and Nox2 | | |
| 18219386 | NOX2 | Nox2 | 3.5 | Although expression of Nox2 by neurons astrocytes and endothelial cells has been reported ( | | |
| 18219386 | NOX2 | Nox2 | 3.5 | and endothelial cells has been reported ( 15 staining for Nox2 in ALS mice only revealed accumulation in microglial cells ( | | |
| 18219386 | NOX2 | Nox2 | 3.5 | Of relevance for patients Nox2 upregulation has been reported in spinal cords of sporadic ALS | | |
| 18219386 | NOX2 | Nox2 | 3.5 | patients with SOD1 mutations generate similar or greater increases in Nox2 activity or expression | | |
| 18219386 | NOX2 | Nox2 | 3.5 | Two reported studies of ALS mice with a Nox2 deletion reached divergent conclusions one group described downregulation of microglial | | |
| 18219386 | NOX2 | Nox2 | 3.5 | Mutations altering the activity of Nox2 (or or other subunits of Nox are known to cause | | |
| 18219386 | CGD | CGD | 2.5 | of Nox are known to cause chronic granulomatous disease (CGD) CGD ( 15 which is characterized by severe and chronic infections | | |
| 18219386 | CGD | CGD | 2.5 | CGD patients are usually chronically administered antibiotics and IFN-_amp_#x003b3 | | |
| 18219386 | NOX2 | Nox2 | 3.5 | that interaction of metalated SOD1 with Rac1 serves to activate Nox2 and that mutant forms of SOD1 amplify production of ROS | | |
| 18219386 | NOX2 | Nox2 | 3.5 | mutant forms of SOD1 amplify production of ROS by locking Nox2 in its activated state Harraz and colleagues have advanced a | | |
| 16877542 | gp91 phox | gp91 phox | 1.0 | transgenic sod1 g93a mice [c57bl/6j tgn sod1 g93a 1gur dl ] were crossed with gp91 phox deficient mice b6.129s6 cybb tm1din . | | |
| 16877542 | gp91 phox | gp91 phox | 1.0 | primer sequences for gp91 phox glial fibrillary acidic protein macrophage antigen complex 1 and gapdh and pcr conditions are presented in supporting text . | | |
| 16877542 | gp91 phox | gp91 phox | 1.0 | expression of nadph oxidase in the spinal cord which carries the brunt of the pathology in this als model was determined by analyzing its catalytic subunit gp91 phox . | | |
| 16877542 | gp91 phox | gp91 phox | 1.0 | both gp91 phox message and protein contents in whole tissue extracts of spinal cord rose over time in transgenic sod1 g93a mice fig 1 a b d and e in concert with the development of a glial response fig 6 which is p | | |
| 16877542 | gp91 phox | gp91 phox | 1.0 | histological evaluation of the spinal cord of symptomatic transgenic sod1 g93a mice showed numerous gp91 phox positive cells primarily in the gray matter of the anterior horn fig 1 g whereas sparse staining was observed in the spinal cord of age matched nontransgenic controls fig 1 f . | | |
| 16877542 | gp91 phox | gp91 phox | 1.0 | consistent with nadph oxidase expression by professional phagocytes confocal microscopy demonstrated the colocalization of the gp91 phox subunit with a microglial marker the ricinus communis agglutinin lectin fig 1 h _amp_#x02013; j ; no gp91 phox colocalization was detected with the motor neuron marker nonphosphorylated neurofilament | | |
| 16877542 | gp91 phox | gp91 phox | 1.0 | subunit with a microglial marker the ricinus communis agglutinin lectin fig 1 h _amp_#x02013; j ; no gp91 phox colocalization was detected with the motor neuron marker nonphosphorylated neurofilament heavy chain or with the astrocyte marker glial fibrillary acid protein data not shown . | | |
| 16877542 | gp91 phox | gp91 phox | 1.0 | in contrast in symptomatic transgenic sod1 g93a mice carrying the wild type gp91 phox allele sod g93a /gp91 phox+ spinal cord ethidium fluorescence was intense fig 1 l and coincided anatomically with the areas of gp91 phox expression fig 1 g and microglial activation fig 6 . | | |
| 16877542 | gp91 phox | gp91 phox | 1.0 | + spinal cord ethidium fluorescence was intense fig 1 l and coincided anatomically with the areas of gp91 phox expression fig 1 g and microglial activation fig 6 . | | |
| 16877542 | gp91 phox | gp91 phox | 1.0 | symptomatic transgenic sod1 g93a /gp91 phox+ mice but not age matched sod1 g93a /gp91 phox_amp_#x02212; mice had increased levels of spinal cord protein carbonyl adducts compared with nontransgenic controls expressing either wild type or null | | |
| 16877542 | gp91 phox | gp91 phox | 1.0 | but not age matched sod1 g93a /gp91 phox_amp_#x02212; mice had increased levels of spinal cord protein carbonyl adducts compared with nontransgenic controls expressing either wild type or null mutant gp91 phox fig 1 n . | | |
| 16877542 | gp91 phox | gp91 phox | 1.0 | immunohistochemically the most robust labeling for protein carbonyl adducts occurred in spinal cord sections from sod1 g93a /gp91 phox+ mice at the level of cells with mixed morphology including large motor neurons fig 1 o _amp_#x02013; q . | | |
| 16877542 | gp91 phox | gp91 phox | 1.0 | consistent with the mouse data gp91 phox content was low fig 2 a and b and its immunoreactivity was faint in control postmortem spinal cords fig 2 d whereas gp91 phox content was _amp_#x02248;3 fold higher and its immunoreactivity robust in sporadic als spinal cords fig 2 e . | | |
| 16877542 | gp91 phox | gp91 phox | 1.0 | in the latter gp91 phox positive cells colocalized with the microglial associated antigen cd68 fig 2 f and were identified in all of the typical als loci of neurodegeneration including the anterior horn and the lateral cort | | |
| 16877542 | gp91 phox | gp91 phox | 1.0 | deletion of gp91 phox mitigates the disease phenotype in transgenic sod1 g93a mice. | | |
| 16877542 | gp91 phox | gp91 phox | 1.0 | transgenic sod1 g93a /gp91 phox_amp_#x02212; mice reached end stage paralysis defined as a loss of the righting reflex later than their transgenic sod1 g93a /gp91 phox+ counterparts fig 3 a which resulted in a longer lifespan of transgenic sod1 g93a /gp91 phox_amp_#x02212; mice log rank test = 15.3; p _amp_#x0003c; 0.001 . | | |
| 16877542 | gp91 phox | gp91 phox | 1.0 | compared with end stage transgenic sod1 g93a /gp91 phox+ mice age matched transgenic sod1 g93a /gp91 phox_amp_#x02212; mice had _amp_#x02248;50% more anterior horn motor neurons in the spinal cord fig 3 b _amp_#x02013; e and myelinated axons in the fifth | | |
| 16877542 | gp91 phox | gp91 phox | 1.0 | spinal cord microgliosis evidenced by macrophage antigen complex 1 immunostaining and levels of the glial cytokine il 1_amp_#x003b2; did not differ between age matched transgenic sod1 g93a /gp91 phox+ mice and sod1 g93a /gp91 phox_amp_#x02212; mice fig 7 which is published as supporting information on the pnas web site . | | |
| 16877542 | gp91 phox | gp91 phox | 1.0 | also not affected by the deficit of gp91 phox were the levels of human sod1 in transgenic sod1 g93a mice fig 7 or the size of muscle fibers in the fibularis and peroneus longus muscles in nontransgenic mice fig 3 t . | | |
| 16877542 | gp91 phox | gp91 phox | 1.0 | however protein carbonyl adducts were evident in the _amp_#x003b1; chain of the igf1 tyrosine kinase cognate receptor in the spinal cord of symptomatic transgenic sod1 g93a /gp91 phox+ mice fig 4 a and b ; similar results were obtained for the _amp_#x003b2; chain of igf1 receptor data not shown . | | |
| 16877542 | gp91 phox | gp91 phox | 1.0 | however there were fewer phospho igf1 receptor immunoreactive cells in spinal cord sections from symptomatic transgenic sod1 g93a /gp91 phox+ mice than from age matched sod1 g93a /gp91 phox_amp_#x02212; mice fig 4 c _amp_#x02013; e . | | |
| 16877542 | gp91 phox | gp91 phox | 1.0 | as fewer cells that were immunoreactive for a downstream target of akt phospho bad fig 4 h _amp_#x02013; j and smaller phospho bad:total bad ratios fig 4 k and l in symptomatic transgenic sod1 g93a /gp91 phox+ mice compared with their age matched sod1 g93a /gp91 phox_amp_#x02212; counterparts. | | |
| 16877542 | gp91 phox | gp91 phox | 1.0 | these data further support the idea that oxidative modification of igf1 receptor in symptomatic transgenic sod1 g93a /gp91 phox+ mice is associated with a range of molecular perturbations. | | |
| 16877542 | gp91 phox | gp91 phox | 1.0 | germane to the molecular basis of this deleterious effect on motor neurons is our finding that virtually all spinal cord microglial cells express the gp91 phox subunit of the oxidant producing enzyme nadph oxidase fig 1 . | | |
| 16877542 | gp91 phox | gp91 phox | 1.0 | agreeing with the fact that in nonactivated phagocytes nadph oxidase is quiescent 7 gp91 phox positive cells in spinal cords from 1 to 4 month old nontransgenic mice had a morphology of resting microglia and did not seem to produce ros figs 1 and 6 . | | |
| 16877542 | gp91 phox | gp91 phox | 1.0 | our results also show that abrogation of the gp91 phox subunit of nadph oxidase in transgenic sod1 g93a mice eliminates the production of microglial derived ros fig 1 m and importantly prolongs survival and retards neurodegeneration in this als model fig | | |
| 16877542 | gp91 phox | gp91 phox | 1.0 | deletion of gp91 phox in transgenic sod1 g93a mice did not alter the spinal cord microglial response or the expression of human sod1 in transgenic sod1 g93a mice fig 7 which is a known determinant of disease severity in t | | |
| 16877542 | gp91 phox | gp91 phox | 1.0 | however the magnitude of benefit afforded by gp91 phox deletion in transgenic sod1 g93a mice argues that targeting neuroinflammation by inhibiting just one of its mediators such as nadph oxidase may not be sufficient to produce robust and lasting neuropr | | |
| 16877542 | gp91 phox | gp91 phox | 1.0 | nevertheless whether transgenic sod1 g93a mice carrying the gp91 phox null mutation reach end stage paralysis later and exhibit an attenuated neurodegenerative process because of some effects at the skeletal muscle level is an interesting possibility that cannot be exc | | |
| 16877542 | gp91 phox | gp91 phox | 1.0 | a _amp_#x02013; e spinal cord gp91 phox mrna a and d and protein b and e in 1 month old asymptomatic to 4 month old end stage transgenic sod1 more ... | | |
| 16877542 | gp91 phox | gp91 phox | 1.0 | a and b immunoblots and bar graph for gp91 phox using spinal cord extracts from six normal controls and six age matched als patients. | | |
| 16877542 | gp91 phox | gp91 phox | 1.0 | deletion of gp91 phox increases lifespan and lessens neurodegeneration in transgenic sod1 g93a mice. | | |
| 16877542 | gp91 phox | gp91 phox | 1.0 | a survival comparison of transgenic sod1 g93a /gp91 phox+ mice red 122.0 _amp_#x000b1; 1.7 days; n = 19 and transgenic sod1 g93a /gp91 phox_amp_#x02212; littermates more ... | | |
| 18219386 | gp91 phox | gp91 phox | 1.0 | the nox prototype nox2 is the phagocytic nox also known as gp91 phox that generates o 2 _amp_#x02022;_amp_#x02013; not as a byproduct but as a primary function of the enzyme 15 . | | |