scholarly journals Redox Signaling of NADPH Oxidases Regulates Oxidative Stress Responses, Immunity and Aging

Antioxidants ◽  
2018 ◽  
Vol 7 (10) ◽  
pp. 130 ◽  
Author(s):  
Collin Ewald
Keyword(s):  
Oxidative Stress ◽  
Nadph Oxidase ◽  
Enzymatic Activity ◽  
Stress Responses ◽  
Healthy Aging ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Redox Signaling ◽  
Small Gtpases ◽  
Endoplasmic Reticulum Membrane ◽  
Nadph Oxidases

An accumulating body of evidence suggests that transient or physiological reactive oxygen species (ROS) generated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidases act as a redox signal to re-establish homeostasis. The capacity to re-establish homeostasis progressively declines during aging but is maintained in long-lived animals to promote healthy aging. In the model organism Caenorhabditis elegans, ROS generated by dual oxidases (Duox) are important for extracellular matrix integrity, pathogen defense, oxidative stress resistance, and longevity. The Duox enzymatic activity is tightly regulated and under cellular control. Developmental molting cycles, pathogen infections, toxins, mitochondrial-derived ROS, drugs, and small GTPases (e.g., RHO-1) can activate Duox (BLI-3) to generate ROS, whereas NADPH oxidase inhibitors and negative regulators, such as MEMO-1, can inhibit Duox from generating ROS. Three mechanisms-of-action have been discovered for the Duox/BLI-3-generated ROS: (1) enzymatic activity to catalyze crosslinking of free tyrosine ethyl ester in collagen bundles to stabilize extracellular matrices, (2) high ROS bursts/levels to kill pathogens, and (3) redox signaling activating downstream kinase cascades to transcription factors orchestrating oxidative stress and immunity responses to re-establish homeostasis. Although Duox function at the cell surface is well established, recent genetic and biochemical data also suggests a novel role for Duoxs at the endoplasmic reticulum membrane to control redox signaling. Evidence underlying these mechanisms initiated by ROS from NADPH oxidases, and their relevance for human aging, are discussed in this review. Appropriately controlling NADPH oxidase activity for local and physiological redox signaling to maintain cellular homeostasis might be a therapeutic strategy to promote healthy aging.

scholarly journals Redox Signaling of NADPH Oxidases Regulates Oxidative Stress Responses, Immunity, and Aging

2018 ◽  
Author(s):  
Collin Y. Ewald
Keyword(s):  
Oxidative Stress ◽  
Nadph Oxidase ◽  
Enzymatic Activity ◽  
Stress Responses ◽  
Healthy Aging ◽  
Model Organism ◽  
Redox Signaling ◽  
Small Gtpases ◽  
Endoplasmic Reticulum Membrane ◽  
Nadph Oxidases

An accumulating body of evidence suggests that physiological reactive oxygen species (ROS) generated by NADPH oxidases act as a redox signal to re-establish homeostasis, a capacity that progressively declines during aging, but is maintained in long-lived animals to promote healthy aging. In the model organism Caenorhabditis elegans, ROS generated by dual oxidases (Duox) are important for extracellular matrix integrity, pathogen defense, oxidative stress resistance, and longevity. The Duox enzymatic activity is tightly regulated and under cellular control. Developmental molting cycles, pathogen infections, toxins, mitochondrial-derived ROS, drugs, and small GTPases (RHO-1) can activate Duox (BLI-3) to generate ROS, whereas NADPH oxidase inhibitors and negative regulators, such as MEMO-1, can inhibit Duox to generate ROS. Three mechanisms-of-action have been discovered for the Duox/BLI-3-generated ROS: 1) enzymatic activity to catalyze cross-linking of free tyrosine ethyl ester in collagen bundles to stabilize extracellular matrices, 2) high ROS bursts/levels to kill pathogens, and 3) Redox signaling activating downstream kinase cascades to transcription factors orchestrating oxidative stress- and immunity responses to re-establish homeostasis. Although Duox function at the cell surface is well established, recent genetic and biochemical data also suggests a novel role for Duoxs at the endoplasmic reticulum membrane to control redox signaling. Evidence underlying these mechanisms initiated by ROS from NADPH oxidases and their relevance for human aging are discussed in this review. Appropriately controlling NADPH oxidase activity for local and physiological redox signaling to maintain cellular homeostasis might be a therapeutic strategy to promote healthy aging.

scholarly journals NADPH Oxidase as a Therapeutic Target for Oxalate Induced Injury in Kidneys

2013 ◽  
Vol 2013 ◽  
pp. 1-18 ◽  
Author(s):  
Sunil Joshi ◽  
Ammon B. Peck ◽  
Saeed R. Khan
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Nadph Oxidase ◽  
Tissue Injury ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Reactive Oxygen ◽  
Renal Tissue ◽  
Oxygen Species ◽  
Gene Expressions

A major role of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase family of enzymes is to catalyze the production of superoxides and other reactive oxygen species (ROS). These ROS, in turn, play a key role as messengers in cell signal transduction and cell cycling, but when they are produced in excess they can lead to oxidative stress (OS). Oxidative stress in the kidneys is now considered a major cause of renal injury and inflammation, giving rise to a variety of pathological disorders. In this review, we discuss the putative role of oxalate in producing oxidative stress via the production of reactive oxygen species by isoforms of NADPH oxidases expressed in different cellular locations of the kidneys. Most renal cells produce ROS, and recent data indicate a direct correlation between upregulated gene expressions of NADPH oxidase, ROS, and inflammation. Renal tissue expression of multiple NADPH oxidase isoforms most likely will impact the future use of different antioxidants and NADPH oxidase inhibitors to minimize OS and renal tissue injury in hyperoxaluria-induced kidney stone disease.

scholarly journals Nox2-derived oxidative stress results in inefficacy of antibiotics against post-influenza S. aureus pneumonia

2016 ◽  
Vol 213 (9) ◽  
pp. 1851-1864 ◽  
Author(s):  
Keer Sun ◽  
Vijaya Kumar Yajjala ◽  
Christopher Bauer ◽  
Geoffrey A. Talmon ◽  
Karl J. Fischer ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nadph Oxidase ◽  
Influenza Infection ◽  
Treatment Strategies ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Inflammatory Cells ◽  
Oxidase Inhibitor ◽  
Lung Damage ◽  
Surrounding Tissue ◽  
Staphylococcus Aureus Pneumonia

Clinical post-influenza Staphylococcus aureus pneumonia is characterized by extensive lung inflammation associated with severe morbidity and mortality even after appropriate antibiotic treatment. In this study, we show that antibiotics rescue nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (Nox2)–deficient mice but fail to fully protect WT animals from influenza and S. aureus coinfection. Further experiments indicate that the inefficacy of antibiotics against coinfection is attributable to oxidative stress–associated inflammatory lung injury. However, Nox2-induced lung damage during coinfection was not associated with aggravated inflammatory cytokine response or cell infiltration but rather caused by reduced survival of myeloid cells. Specifically, oxidative stress increased necrotic death of inflammatory cells, thereby resulting in lethal damage to surrounding tissue. Collectively, our results demonstrate that influenza infection disrupts the delicate balance between Nox2-dependent antibacterial immunity and inflammation. This disruption leads to not only increased susceptibility to S. aureus infection, but also extensive lung damage. Importantly, we show that combination treatment of antibiotic and NADPH oxidase inhibitor significantly improved animal survival from coinfection. These findings suggest that treatment strategies that target both bacteria and oxidative stress will significantly benefit patients with influenza-complicated S. aureus pneumonia.

scholarly journals Oxidative stress, NADPH oxidases, and arteries

2016 ◽  
Vol 36 (02) ◽  
pp. 77-88 ◽  
Author(s):  
Qi-An Sun ◽  
Nageswara Madamanchi ◽  
Marschall Runge
Keyword(s):  
Oxidative Stress ◽  
Diabetes Mellitus ◽  
Nadph Oxidase ◽  
Oxidativer Stress ◽  
Nadph Oxidases ◽  
Reaktive Sauerstoffspezies ◽  
Oxidativer Streß

ZusammenfassungDie Atherosklerose und ihre wichtigsten Komplikationen – Myokardinfarkt und Schlaganfall – sind die Hauptursachen für Tod und Behinderung in den USA und weltweit. Eine dramatische Zunahme bei Adipositas und Diabetes mellitus wird wahrscheinlich auch in Zukunft zu einer hohen Prävalenz kardiovaskulärer Erkrankungen (CVD) und deren Auswirkungen auf das Gesundheitswesen führen. Große Fortschritte gibt es bei der Entwicklung neuer Therapien zur Senkung der Inzidenz von Atherosklerose und CVD, besonders bei der Behandlung der Hypercholesterinämie und Hypertonie. Der gemeinsame mechanistische Nenner bei vielen Risikofaktoren für CVD ist oxidativer Stress. Erst seit kurzem verfügen wir über Methoden, um die Schnittstelle zwischen oxidativem Stress und CVD im Tiermodell zu untersuchen. Die wichtigste Quelle für reaktive Sauerstoffspezies (und damit für oxidativen Stress) in vaskulären Zellen sind die Formen der Nicotin - amidadenindinukleotidphosphat-Oxidase (NADPH-Oxidase). Die jüngsten Studien belegen eindeutig, dass 1. NADPH-Oxidasen im Tiermodell von grundlegender Bedeutung für Atherosklerose und Hypertonie sind und 2. der vaskuläre oxidative Stress, angesichts der gewebespezifischen Expression wichtiger Bestandteile der NADPH-Oxidase, ein Ziel bei der Prävention der CVD sein könnte.

scholarly journals Dextromethorphan Reduces Oxidative Stress and Inhibits Uremic Artery Calcification

2021 ◽  
Vol 22 (22) ◽  
pp. 12277
Author(s):  
En-Shao Liu ◽  
Nai-Ching Chen ◽  
Tzu-Ming Jao ◽  
Chien-Liang Chen
Keyword(s):  
Oxidative Stress ◽  
Nadph Oxidase ◽  
Vascular Calcification ◽  
Wistar Rats ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Oxidase Inhibitor ◽  
In Vivo Studies ◽  
Ros Production

Medial vascular calcification has emerged as a key factor contributing to cardiovascular mortality in patients with chronic kidney disease (CKD). Vascular smooth muscle cells (VSMCs) with osteogenic transdifferentiation play a role in vascular calcification. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitors reduce reactive oxygen species (ROS) production and calcified-medium–induced calcification of VSMCs. This study investigates the effects of dextromethorphan (DXM), an NADPH oxidase inhibitor, on vascular calcification. We used in vitro and in vivo studies to evaluate the effect of DXM on artery changes in the presence of hyperphosphatemia. The anti-vascular calcification effect of DXM was tested in adenine-fed Wistar rats. High-phosphate medium induced ROS production and calcification of VSMCs. DXM significantly attenuated the increase in ROS production, the decrease in ATP, and mitochondria membrane potential during the calcified-medium–induced VSMC calcification process (p < 0.05). The protective effect of DXM in calcified-medium–induced VSMC calcification was not further increased by NADPH oxidase inhibitors, indicating that NADPH oxidase mediates the effect of DXM. Furthermore, DXM decreased aortic calcification in Wistar rats with CKD. Our results suggest that treatment with DXM can attenuate vascular oxidative stress and ameliorate vascular calcification.

scholarly journals The Post-Ischemic Increase in GluA2 Ser880 Phosphorylation Involves NADPH Oxidase

2018 ◽  
Vol 4 (1) ◽  
pp. 170-181
Author(s):  
Darrell A. Jackson ◽  
Fanny Astruc-Diaz ◽  
Nicole M. Byrnes ◽  
Phillip H. Beske
Keyword(s):  
Oxidative Stress ◽  
Nadph Oxidase ◽  
Oxidase Activity ◽  
Hippocampal Slices ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Glucose Deprivation ◽  
Subunit Composition ◽  
Stress Signaling ◽  
Scaffolding Proteins ◽  
Nadph Oxidase Activity

Most 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl) propanoic acid receptors (AMPARs) expressed on adult hippocampal pyramidal neurons contain the edited form of GluA2 (Q607R) and are thus impermeable to Ca2+/Zn2+ entry.  Following ischemic injury, these receptors undergo a subunit composition change, switching from a GluA2-containing Ca2+/Zn2+-impermeable AMPAR to a GluA2-lacking Ca2+/Zn2+-permeable AMPAR. Recent studies indicate that an oxidative stress signaling pathway is responsible for the I/R-induced changes in AMPAR subunit composition.  Studies suggest that nicotinamide adenine dinucleotide phosphate-oxidase (NADPH oxidase), a superoxide generator, is the source that initiates the oxidative stress-signaling cascade during post-ischemic reperfusion. The objective of the present study was to determine if suppression of NADPH oxidase activity prevents the increase in phosphorylation and subsequent internalization of the GluA2 AMPAR subunit during reperfusion of post-ischemic hippocampal slices. In this study, we demonstrated that exposure of adult rat hippocampal slices to oxygen glucose deprivation/reperfusion (OGD/R) results in an increase in Ser880 phosphorylation of the GluA2 subunit.  The increase in Ser880 phosphorylation resulted in the dissociation of GluA2 from the scaffolding proteins Glutamate receptor-interacting protein 1 (GRIP1) and AMPAR binding protein (ABP), thus enabling the association of GluA2 with protein interacting with C kinase 1 (PICK1). OGD/R also resulted in an increase in the association of activated protein kinase C ? (PKC?) with PICK1. We have found that pharmacological inhibition of NADPH oxidase with apocynin diminishes the OGD/R-induced increase in activated PKC? association with PICK1 and subsequent Ser880 phosphorylation of GluA2. Suppression of NADPH oxidase activity also blunted OGD/R-induced decreased association of GluA2 with the scaffolding proteins GRIP1 and ABP.  Protein phosphatase 2A (PP2A), which regulates PKC? activity by dephosphorylating the kinase, was inactivated by OGD/R-induced increase in tyrosine phosphorylation of the phosphatase (Y307). Inhibition of NADPH oxidase activity ameliorated OGD/R-induced PP2A phosphorylation and inactivation. Our findings are consistent with a model of OGD/R-induced Ser880 phosphorylation of GluA2 that implicates NADPH oxidase mediated inactivation of PP2A and sustained PKC? phosphorylation of GluA2.

scholarly journals The Role of NADPH Oxidases and Oxidative Stress in Neurodegenerative Disorders

2018 ◽  
Vol 19 (12) ◽  
pp. 3824 ◽  
Author(s):  
Anuradha Tarafdar ◽  
Giordano Pula
Keyword(s):  
Oxidative Stress ◽  
Neurodegenerative Diseases ◽  
Neurodegenerative Disorders ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Ros Generation ◽  
Phagocytic Cells ◽  
Nadph Oxidases ◽  
Age Related ◽  
Recent Developments ◽  
Cerebrovascular Endothelial Cells

For a number of years, nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOX) was synonymous with NOX2/gp91phox and was considered to be a peculiarity of professional phagocytic cells. Over the last decade, several more homologs have been identified and based on current research, the NOX family consists of NOX1, NOX2, NOX3, NOX4, NOX5, DUOX1 and DUOX2 enzymes. NOXs are electron transporting membrane proteins that are responsible for reactive oxygen species (ROS) generation—primarily superoxide anion (O2●−), although hydrogen peroxide (H2O2) can also be generated. Elevated ROS leads to oxidative stress (OS), which has been associated with a myriad of inflammatory and degenerative pathologies. Interestingly, OS is also the commonality in the pathophysiology of neurodegenerative disorders, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). NOX enzymes are expressed in neurons, glial cells and cerebrovascular endothelial cells. NOX-mediated OS is identified as one of the main causes of cerebrovascular damage in neurodegenerative diseases. In this review, we will discuss recent developments in our understanding of the mechanisms linking NOX activity, OS and neurodegenerative diseases, with particular focus on the neurovascular component of these conditions. We conclude highlighting current challenges and future opportunities to combat age-related neurodegenerative disorders by targeting NOXs.

scholarly journals The Antioxidant 3H-1,2-Dithiole-3-Thione Potentiates Advanced Glycation End-Product-Induced Oxidative Stress in SH-SY5Y Cells

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Robert Pazdro ◽  
John R. Burgess
Keyword(s):  
Oxidative Stress ◽  
Nadph Oxidase ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Antioxidant Defenses ◽  
Chemical Induction ◽  
Advanced Glycation ◽  
Glycation End Products ◽  
Ros Formation ◽  
Endogenous Antioxidant ◽  
Neurite Degeneration

Oxidative stress is implicated as a major factor in the development of diabetes complications and is caused in part by advanced glycation end products (AGEs). AGEs ligate to the receptor for AGEs (RAGE), promoting protein kinase C (PKC)-dependent activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and superoxide radical generation. While scavenging antioxidants are protective against AGEs, it is unknown if induction of endogenous antioxidant defenses has the same effect. In this study, we confirmed that the compound 3H-1,2-dithiole-3-thione (D3T) increases reduced-state glutathione (GSH) concentrations and NADPH:quinone oxidoreductase 1 (NQO1) activity in SH-SY5Y cells and provides protection against H2O2. Surprisingly, D3T potentiated oxidative damage caused by AGEs. In comparison to vehicle controls, D3T caused greater AGE-induced cytotoxicity and depletion of intracellular GSH levels while offering no protection against neurite degeneration or protein carbonylation. D3T potentiated AGE-induced reactive oxygen species (ROS) formation, an effect abrogated by inhibitors of PKC and NADPH oxidase. This study suggests that chemical induction of endogenous antioxidant defenses requires further examination in models of diabetes.

Role of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in upregulation of intermediate-conductance Ca[superscript 2+] -activated K[superscript +] channels (K[subscript Ca]3.1) associated with atherosclerosis

2010 ◽  
Author(s):  
◽  
Hope Kara Anne Gole
Keyword(s):  
Oxidative Stress ◽  
Smooth Muscle ◽  
Coronary Artery ◽  
Nadph Oxidase ◽  
Nicotinamide Adenine Dinucleotide ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Phenotypic Modulation ◽  
Channel Activity ◽  
Coronary Smooth Muscle ◽  
Expression And Activity

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT REQUEST OF AUTHOR.] A key risk factor for the development of atherosclerosis is familial hypercholesterolemia (FH), a genetic disease characterized by elevated levels of low density lipoprotein (LDL). Studies have shown that oxidative stress and vascular smooth muscle cell (VSMC) phenotypic modulation play critical roles in the development and stability of atherosclerotic plaques. The key source of reactive oxygen species (ROS) contributing to oxidative stress in the vasculature is the enzymatic complex nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Upregulation of intermediateconductance Ca[superscript 2 +]-activated K[superscript +] channels (K[subscript Ca]3.1) and modification of NADPH oxidase activity have been shown to mediate phenotypic modulation of coronary smooth muscle cells (CSMC). It remains unclear, however, whether K[subscript Ca]3.1 expression and activity are altered in atherosclerotic coronary smooth muscle of individuals with FH, and whether NADPH oxidase plays a role in atherosclerosis through regulation of K[subscript Ca]3.1 channels. Our objective was thus twofold, 1) to determine whether K[subscript Ca]3.1 expression and activity are increased in CSMCs isolated from FH swine, and 2) to determine if NADPH oxidase plays a role in growth factor-induced upregulation of K[subscript Ca]3.1. Right coronary artery (RCA) sections from 2 year old FH swine showed a [approximate sign]15 fold increase in artery stenosis accompanied by significantly elevated triglyceride and cholesterol values. In the media of the diseased FH coronaries, there was a trend for increased K[subscript Ca]3.1mRNA expression and K[subscript Ca]3.1 protein expression was elevated [approximate sign]20% compared to control coronaries. In addition, K[subscript Ca]3.1 channel activity increased almost 2- fold in coronary artery cells isolated from FH swine compared to control animals. In cultured CSMCs, basic fibroblast growth factor (bFGF) increased superoxide (O[subscript 2] [superscript .-]) production which was inhibited by treatment with the NADPH oxidase inhibitor apocynin (Apo). Treatment with bFGF increased K[subscript Ca]3.1 mRNA levels [aproximate sign]2.5 fold in both right coronary artery (RCA) sections and CSMCs, while addition of Apo prevented the increase. Furthermore, inhibition of NADPH oxidase abolished the bFGF-induced increase in coronary smooth muscle K[subscript Ca]3.1 protein expression and CSMC K[subscript Ca]3.1 channel activity. Treatment with bFGF significantly increased activator protein-1 (AP-1) promoter activity which was inhibited by addition of Apo. RCA and CSMC express all four cardiovascular Nox isoforms (Nox1, Nox2, Nox4, Nox5) with Nox4 being the predominant isoform. Treatment with bFGF decreased Nox1, Nox2, and Nox4 CSMC message, while treatment with Apo increased the mRNA expression of all four isoforms. Knock down of Nox2 and Nox4 did not affect the K[subscript Ca]3.1 message response to bFGF or Apo. Consistent with our earlier findings of increased medial K[subscript Ca]3.1 expression in FH coronaries; whole vessel K[subscript Ca]3.1 mRNA expression was increased in FH coronary smooth muscle and Nox2 rather than Nox4 was the predominant Nox isoform. Our findings demonstrate that K[subscript Ca]3.1 is upregulated in coronary smooth muscle of FH swine and support previous research indicating K[subscript Ca]3.1 plays a key role in the development and progression of atherosclerosis. Our findings also provide novel evidence that NADPH oxidase contributes to VSMC phenotypic modulation associated with atherosclerosis through AP-1 transcriptional upregulation of K[subscript Ca]3.1.

scholarly journals A novel pathway spatiotemporally activates Rac1 and redox signaling in response to fluid shear stress

2013 ◽  
Vol 201 (6) ◽  
pp. 863-873 ◽  
Author(s):  
Yunhao Liu ◽  
Caitlin Collins ◽  
William B. Kiosses ◽  
Ann M. Murray ◽  
Monika Joshi ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Molecular Mechanisms ◽  
Fluid Shear Stress ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Redox Signaling ◽  
Hemodynamic Forces ◽  
Rac1 Gtpase ◽  
Embryonic Organ

Hemodynamic forces regulate embryonic organ development, hematopoiesis, vascular remodeling, and atherogenesis. The mechanosensory stimulus of blood flow initiates a complex network of intracellular pathways, including activation of Rac1 GTPase, establishment of endothelial cell (EC) polarity, and redox signaling. The activity of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase can be modulated by the GTP/GDP state of Rac1; however, the molecular mechanisms of Rac1 activation by flow are poorly understood. Here, we identify a novel polarity complex that directs localized Rac1 activation required for downstream reactive oxygen species (ROS) production. Vav2 is required for Rac1 GTP loading, whereas, surprisingly, Tiam1 functions as an adaptor in a VE-cadherin–p67phox–Par3 polarity complex that directs localized activation of Rac1. Furthermore, loss of Tiam1 led to the disruption of redox signaling both in vitro and in vivo. Our results describe a novel molecular cascade that regulates redox signaling by the coordinated regulation of Rac1 and by linking components of the polarity complex to the NADPH oxidase.

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