HUGO ID Detailed Result 14874

HUGO ID 14874
Symbol NOX5
Name NADPH oxidase, EF-hand calcium binding domain 5
#Occurrence 76
#Paper 6

 

PMID Match String Actual String Score Flanking text Edited by Edit
17853944NOX5Nox50.9Seven known NADPH oxidases (Nox1, Nox1 Nox2 Nox3 Nox4 Nox5 Duox1 and Duox2 are thought to play important roles in 
10525172nadph oxidasenadph oxidase1.0 be formed as a by product of the mitochondrial respiratory chain generated primarily by autoxidation of flavoproteins [ 78 ] fig 4 or during the respiratory burst of phagocytes via the activation of nadph oxidase [ 48 ].  
10525172nadph oxidasenadph oxidase1.0s primary neuronal insult can activate microglial cells and initiate the second step of the neurodegenerative process by induction of type ii nos which produces large amounts of no and stimulation of nadph oxidase which produces o 2 _amp_#x2212; .  
16014720nadph oxidasenadph oxidase1.0for instance nadph oxidase and inducible nitric oxide synthase inos which are major sources of inflammatory oxidants are upregulated in damaged areas in both pd and the 1 methyl 4 phenyl 1 2 3 6 tetrahydropyridine mptp model o 
16014720nadph oxidasenadph oxidase1.0studies of mice deficient in nadph oxidase or inos indicate that superoxide radical o 2 and no contribute to the mptp induced neurodegenerative process liberatore et al. 1999 ; wu et al. 2003 .  
16014720nadph oxidasenadph oxidase1.0remarkably detectable changes in inos expression and enzymatic activity are also confined to ventral midbrains of mptp injected mice liberatore et al. 1999 whereas activation of nadph oxidase is observed in both ventral midbrains and striata of these animals wu et al. 2003 .  
16877542nadph oxidasenadph oxidase1.0herein we show that nadph oxidase the main reactive oxygen species producing enzyme during inflammation is activated in spinal cords of als patients and in spinal cords in a genetic animal model of this disease.  
16877542nadph oxidasenadph oxidase1.0we demonstrate that inactivation of nadph oxidase in als mice delays neurodegeneration and extends survival.  
16877542nadph oxidasenadph oxidase1.0we also show that nadph oxidase derived oxidant products damage proteins such as insulin like growth factor 1 igf1 receptors which are located on motor neurons.  
16877542nadph oxidasenadph oxidase1.0nadph oxidase is up regulated in inflamed spinal cords of als mice.  
16877542nadph oxidasenadph oxidase1.0to determine the role of nadph oxidase in motor neuron degeneration we first evaluated its expression at different stages of the disease in transgenic mice expressing mutant human sod1 with a substitution of glycine to alanine in position 
16877542nadph oxidasenadph oxidase1.0expression 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 .  
16877542nadph oxidasenadph oxidase1.0the levels of the p67 phox subunit that contains the nadph binding site of the nadph oxidase complex 10 were increased in membrane fractions of spinal cord extracts from symptomatic transgenic sod1 g93a mice fig 1 c indicating that this cytosolic subunit did translocate to the plasma membran 
16877542nadph oxidasenadph oxidase1.0conversely none of these nadph oxidase alterations were seen in age matched nontransgenic littermates fig 1 a _amp_#x02013; e .  
16877542nadph oxidasenadph oxidase1.0consistent 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 
16877542nadph oxidasenadph oxidase1.0nadph oxidase causes protein oxidation in transgenic sod1 g93a mice.  
16877542nadph oxidasenadph oxidase1.0we further characterized the status of spinal cord nadph oxidase in transgenic sod1 g93a mice by probing for formation of ros and evidence of protein oxidation.  
16877542nadph oxidasenadph oxidase1.0nadph oxidase induction and neuronal protein carbonylation in sporadic als.  
16877542nadph oxidasenadph oxidase1.0we then sought to determine whether the nadph oxidase alterations identified in transgenic sod1 g93a mice were also present in human sporadic als the most common form of the disease 1 .  
16877542nadph oxidasenadph oxidase1.0next we explored the contribution of nadph oxidase activation on the disease phenotype in the sod1 g93a mouse model of als.  
16877542nadph oxidasenadph oxidase1.0in addition to the prolonged survival inactivation of nadph oxidase did mitigate neurodegeneration.  
16877542nadph oxidasenadph oxidase1.0nadph oxidase impairs the insulin like growth factor 1 igf1 /akt pathway in transgenic sod1 g93a mice.  
16877542nadph oxidasenadph oxidase1.0we then explored whether nadph oxidase mediated protein modifications might promote neurodegeneration in als by damaging essential surviving pathways for motor neurons such as igf1.  
16877542nadph oxidasenadph oxidase1.0to test the idea that nadph oxidase derived ros could impair igf1 pathway function an in vitro cell system using the neuron like cell lines sh sy5y and imr32 was used.  
16877542nadph oxidasenadph oxidase1.0however both the alteration of igf1 mediated akt phosphorylation and the loss of cell viability mediated by lps activated microglia were counteracted by the specific nadph oxidase inhibitor apocynin fig 5 c d and f .  
16877542nadph oxidasenadph oxidase1.0germane 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 .  
16877542nadph oxidasenadph oxidase1.0agreeing 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 .  
16877542nadph oxidasenadph oxidase1.0conversely in transgenic sod1 g93a mice paralleling the worsening of the als phenotype there was an intensification of spinal cord microgliosis accompanied by an up regulation and activation of nadph oxidase.  
16877542nadph oxidasenadph oxidase1.0corroborating this view are the levels of protein carbonyls which were markedly elevated in spinal cord extracts of symptomatic transgenic sod1 g93a mice for the most part in a nadph oxidase dependent manner fig 1 .  
16877542nadph oxidasenadph oxidase1.0evidence of microgliosis nadph oxidase up regulation and protein carbonylation was also found in postmortem spinal cords from human sporadic als cases fig 2 supporting the conclusion that the occurrence of inflammation mediated oxidative  
16877542nadph oxidasenadph oxidase1.0our 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 3 .  
16877542nadph oxidasenadph oxidase1.0consequently the attenuated phenotype seen in transgenic sod1 g93a /gp91 phox_amp_#x02212; mice is attributable to the lack of nadph oxidase activity and not to either an impaired microglial response or expression of the human sod1 g93a transgene.  
16877542nadph oxidasenadph oxidase1.0these data provide compelling evidence that nadph oxidase contributes to the degeneration of motor neurons in als.  
16877542nadph oxidasenadph oxidase1.0however 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 neuroprotection in als patients.  
16877542nadph oxidasenadph oxidase1.0all cells not motor neurons only which are located in the vicinity of activated microglia may indiscriminately have their plasma membrane proteins and lipids damaged by nadph oxidase derived ros.  
16877542nadph oxidasenadph oxidase1.0in this study we indeed found that receptors for igf1 were primarily expressed on motor neurons in mouse spinal cords fig 8 and that the igf1 signaling pathway was impaired by a nadph oxidase dependent mechanism in symptomatic transgenic sod1 g93a mice fig 4 .  
16877542nadph oxidasenadph oxidase1.0although igf1 per se did not seem to be damaged by inflammation nadph oxidase did stimulate the oxidative modification of igf1 receptors fig 4 .  
16877542nadph oxidasenadph oxidase1.0ggregate show that several molecular events that are normally elicited by ligation of the igf1 receptor including autophosphorylation and akt phosphorylation were indeed abated by ros in a microglial nadph oxidase dependent manner.  
16877542nadph oxidasenadph oxidase1.0our data also show that microglial nadph oxidase by impairing the igf1 signaling pathway renders sh sy5y cells in our in vitro system more prone to die upon exposure to a hostile environment such as that emulated by lps activated microglial conditi 
16877542nadph oxidasenadph oxidase1.0in our study however we did not find any evidence that the rescue of the igf1 pathway by abrogating nadph oxidase was associated with muscle hypertrophy fig 3 .  
16877542nadph oxidasenadph oxidase1.0microglial nadph oxidase stimulates carbonylation of spinal cord motor neurons in transgenic sod1 g93a mice.  
16877542nadph oxidasenadph oxidase1.0nadph oxidase is up regulated and associated with motor neuron carbonylation in the spinal cord of sporadic als patients.  
16877542nadph oxidasenadph oxidase1.0modulation of the igf1/akt pathway by nadph oxidase derived ros.  
16877542nadph oxidasenadph oxidase1.0among the microglia derived mediators that could promote neurodegeneration are reactive oxygen species ros produced by the enzyme nadph oxidase complex 7 .  
16877542nadph oxidasenadph oxidase1.0in light of these facts we undertook the study of nadph oxidase in both human als and one of its genetic models.  
16877542nadph oxidasenadph oxidase1.0our results for both human and mouse postmortem tissues indicate that spinal cord microgliosis in als is accompanied with an up regulation of nadph oxidase.  
16877542nadph oxidasenadph oxidase1.0furthermore by using mutant deficient mice in functional nadph oxidase as well as in neuron like cell culture systems we provide compelling evidence that supports the concept that this microglial ros generating enzymatic complex promotes spinal cord motor neuron degener 
17018025nadph oxidasenadph oxidase1.0however simultaneous activation of inos to produce nitric oxide and nadph oxidase to produce resulted in massive microglia mediated neuronal death mander and brown 2005 .  
17853944nadph oxidasenadph oxidase1.0here we show that disrupting either of these nadph oxidase genes nox1 or nox2 significantly delayed the progression of motor neuron disease in a sod1 g93a transgenic mouse model of als.  
17853944nadph oxidasenadph oxidase1.0nadph oxidase activities were analyzed by measuring the rate of superoxide generation using a chemiluminescent lucigenin based system 27 with modification as previously described 28 .  
17853944nadph oxidasenadph oxidase1.0the initial slope of the luminescence curve rlu/min was used to calculate the rate of luminescence product formation and compared between samples as an index of nadph oxidase activity.  
17853944nadph oxidasenadph oxidase1.0figure 1 deletion of nadph oxidase genes nox1 or nox2 enhances survival and survival index in als mice and significantly reduces superoxide production in spinal cords of end stage sod1 g93a mice.  
18598679nadph oxidasenadph oxidase1.0nadph oxidase was activated upon lps challenge and apocynin the selective inhibitor of this enzyme prevented inflammation mediated toxicity to motor neurons suggesting that nadph oxidase may play a critical role in motor neuron death caused by lps induced inflammation.  
18598679nadph oxidasenadph oxidase1.0nadph oxidase acting as the functional enzyme in the respiratory burst generates ros not as a byproduct but rather as the primary function of the enzyme system bedard and krause 2007 .  
18598679nadph oxidasenadph oxidase1.0recent studies indicate that ros produced by nadph oxidase could promote neurodegeneration [block and hong 2005] and [li et al. 2005] but the role of nadph oxidase in als remains largely unexplored.  
18598679nadph oxidasenadph oxidase1.0to study the involvement of reactive oxygen species in inflammation induced effects nadph oxidase selective inhibitor apocynin 0.5 and 1_amp_#xa0;mm was coapplied with lps 30_amp_#xa0;_amp_#x3bc;g/ml for 2_amp_#xa0;weeks in the culture medium.  
18598679nadph oxidasenadph oxidase1.0nadph oxidase subunits gp91 phox p47 phox and il 1_amp_#x3b2; mrna expression were evaluated by semiquantitative rt pcr using gapdh gene as internal standard.  
18598679nadph oxidasenadph oxidase1.0 c representative bands of nadph oxidase subunits gp91 phox and p47 phox mrna expression in slices treated with medium alone or 30_amp_#xa0;_amp_#x3bc;g/ml lps for 2_amp_#xa0;weeks after 1_amp_#xa0;week in culture.  
18598679nadph oxidasenadph oxidase1.0nadph oxidase inhibitor apocynin prevented lps induced toxicity to motor neurons.  
18598679nadph oxidasenadph oxidase1.0nadph oxidase and il 1_amp_#x3b2; mrna expression in spinal cord slices treated with lps  
18598679nadph oxidasenadph oxidase1.0we also investigated the message levels of nadph oxidase subunits gp91 phox and p47 phox .  
18598679nadph oxidasenadph oxidase1.0nadph oxidase also known as phagocytic oxidase phox is a dormant enzyme in resting cells composed of two membrane bound components gp91 phox and p22 phox and several cytosolic components including p47 phox p40 pho 
18598679nadph oxidasenadph oxidase1.0due to its particular construction the functional change of nadph oxidase relies more importantly on subcellular distribution of cytosolic subunits.  
18598679nadph oxidasenadph oxidase1.0so we next investigated the function of nadph oxidase at protein level and whether it was required for neurotoxicity induced by lps mediated inflammation.  
18598679nadph oxidasenadph oxidase1.0we first determined whether nadph oxidase formed an assembled and activated enzyme complex upon lps challenge.  
18598679nadph oxidasenadph oxidase1.0two weeks after application of lps cytosolic subunit p47 phox translocated to the plasma membrane fig 6 a indicating that nadph oxidase became activated.  
18598679nadph oxidasenadph oxidase1.0next we examined the effect of nadph oxidase inhibitor apocynin which significantly reduced lps induced phox cytosolic subunit p47 phox translocation to the cell membrane fig 6 a .  
18598679nadph oxidasenadph oxidase1.0nadph oxidase is a membrane bound enzyme consisting of multiple subunits.  
18598679nadph oxidasenadph oxidase1.0in addition nadph oxidase derived ros can mediate proinflammatory gene expression and lead to the production of inflammatory cytokines qin et al. 2004 .  
18598679nadph oxidasenadph oxidase1.0nadph oxidase is therefore considered a key factor in oxidative stress and inflammatory processes both of which are implicated in the pathogenesis of als.  
18598679nadph oxidasenadph oxidase1.0we speculated that nadph oxidase might mediate the toxicity to motor neurons.  
18598679nadph oxidasenadph oxidase1.0this hypothesis is supported by two recent reports that nadph oxidase is up regulated in the spinal cords of als patients and sod1 g93a transgenic mice wu et al. 2006 and deletion of either nox1 or nox2 gene significantly slowed disease progression and improved surviva 
18598679nadph oxidasenadph oxidase1.0in the present study we found that nadph oxidase was activated as indicated by the up regulation of membranous subunit gp91 phox mrna expression and the translocation of cytosolic component p47 phox to the membrane following lps challenge.  
18598679nadph oxidasenadph oxidase1.0more importantly lps induced inflammation mediated toxicity to motor neurons was markedly ameliorated by the nadph oxidase inhibitor apocynin.  
18598679nadph oxidasenadph oxidase1.0these data provide evidence that nadph oxidase plays an important role in mediating motor neuron injury under inflammatory conditions.  
18598679nadph oxidasenadph oxidase1.0nadph oxidase contributes to the demise of motor neurons caused by lps induced inflammation.