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Structure, Activation, and Regulation of NOX2: At the Crossroad between the Innate Immunity and Oxidative Stress-Mediated Pathologies

ANTIOXIDANTS (2023)

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Article Immunology

NOX2 oxidase inhibitor GSK2795039 possess antiviral activity against H1N1 influenza A virus in vitro and vivo

Ning Xue et al.

Summary: By using a novel inhibitor GSK2795039, we investigated the roles of NOX2 in host inflammatory response and IAV replication. The drug significantly reduced H1N1 virus induced NOX2 activity and ROS release, as well as decreased the expression of pro-inflammatory cytokines. In vivo experiments showed that suppression of NOX2 improved the survival rate of mice infected with H1N1 virus and reduced viral burden. Our data demonstrated a critical role for NOX2 in the establishment of H1N1 infection and subsequent inflammatory reactions, suggesting that GSK2795039 may be a potential therapeutic drug for IAV infection.

MICROBIAL PATHOGENESIS (2023)

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Article Pharmacology & Pharmacy

Chemical synthesis of a reported p47phox/p22phox inhibitor and characterization of its instability and irreproducible activity

Jie Zang et al.

Summary: The NOX2 multi-subunit complex is a major source of reactive oxygen species, and inhibiting its activity by targeting the p47phox subunit shows therapeutic potential. The small molecule LMH001 was shown to inhibit the p47phox/p22phox interaction and reduce NOX2 activity, but our findings suggest that it is chemically unstable and unable to effectively inhibit the interaction. This information is crucial for researchers studying NOX2 biology.

FRONTIERS IN PHARMACOLOGY (2023)

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Article Hematology

NADPH oxidase 2 limits amplification of IL-1(3-G-CSF axis and an immature neutrophil subset in murine lung inflammation

Zhimin Song et al.

Summary: The deficiency of NOX2 in neutrophils leads to excessive inflammation in chronic granulomatous disease (CGD), which is associated with recurrent infections and tissue damage. In this study, excessive production of LTB4 by NOX2-deficient neutrophils was found to drive elevated lung neutrophil infiltration. IL-1β and G-CSF were identified as critical signals that amplify and sustain neutrophil accumulation in CGD mice. Neutrophils were the primary source of IL-1β in the airways, and the increased number of neutrophils in CGD mice led to elevated local and plasma G-CSF. Elevated G-CSF promoted increased granulopoiesis and mobilized the release of an immature neutrophil subset from the marrow, which exhibited a more proinflammatory transcriptome. These findings highlight NOX2 as a key regulator of neutrophil number, subsets, and function in inflammation.

BLOOD ADVANCES (2023)

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Article Cardiac & Cardiovascular Systems

Rosuvastatin Alleviates Coronary Microembolization-Induced Cardiac Injury by Suppressing Nox2-Induced ROS Overproduction and Myocardial Apoptosis

Yuanyuan Cao et al.

Summary: The study found that rosuvastatin mitigates coronary microembolism (CME)-induced cardiac injury by inhibiting Nox2-induced ROS overproduction and alleviating p53/Bax/Bcl-2-dependent cardiomyocyte apoptosis.

CARDIOVASCULAR TOXICOLOGY (2022)

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Article Neurosciences

The Methylglyoxal/RAGE/NOX-2 Pathway is Persistently Activated in the Hippocampus of Rats with STZ-Induced Sporadic Alzheimer's Disease

Ana Paula Moreira et al.

Summary: Alzheimer's disease (AD) is the main cause of dementia in humans, and the intracerebroventricular administration of streptozotocin (STZ) can simulate cognitive deficits, beta-amyloid accumulation, and tau phosphorylation, which are characteristic of AD. Methylglyoxal may serve as a precursor of advanced glycated end products that activate RAGE and contribute to neuroinflammation by activating NOX-2. Increased microglial activity may contribute to synaptic dysfunction and pruning.

NEUROTOXICITY RESEARCH (2022)

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Review Genetics & Heredity

Bacterial Response to Oxidative Stress and RNA Oxidation

Andre F. Seixas et al.

Summary: Bacteria face oxidative stress caused by Reactive Oxygen Species (ROS), and have developed strategies to protect cells and combat RNA oxidation. RNA oxidation can lead to structural and functional damage, resulting in harmful consequences for cell survival. However, bacteria have evolved RNA quality control pathways to eliminate oxidized RNA.

FRONTIERS IN GENETICS (2022)

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Article Medicine, Research & Experimental

Novel potential NOX2 inhibitors, Dudleya brittonii water extract and polygalatenoside A inhibit intracellular ROS generation and growth of melanoma

Hyungkuen Kim et al.

Summary: Reactive oxygen species (ROS) play a crucial role in regulating the proliferation, metastasis, and drug resistance of melanoma, and the inhibition of NOX2 and cytosolic ROS by Dudleya brittonii water extract (DBWE) and its bioactive substance polygalatenoside A may contribute to the prevention and treatment of melanoma. DBWE also inhibits mitochondrial activity, lipid metabolism, and cell cycle in B16-F10 melanoma cells.

BIOMEDICINE & PHARMACOTHERAPY (2022)

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Article Hematology

Impaired p47phox phosphorylation in neutrophils from patients with p67phox-deficient chronic granulomatous disease

Sahra Amel Belambri et al.

Summary: This study discovered that p67phox and p40phox are novel regulators of p47phox phosphorylation at specific sites, which is essential for superoxide production by phagocytes and immune response.

BLOOD (2022)

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Article Cell Biology

NOX2-derived hydrogen peroxide impedes the AMPK/Akt-mTOR signaling pathway contributing to cell death in neuronal cells

Ruijie Zhang et al.

Summary: Research shows that PD toxins induce neuronal apoptosis by generating H2O2 through NOX2, hindering the AMPK/Akt-mTOR signaling pathway. Inhibiting NOX2 or using antioxidants may help alleviate neuronal loss caused by oxidative stress.

CELLULAR SIGNALLING (2022)

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Article Pharmacology & Pharmacy

Hydrogen Attenuates Thyroid Hormone-Induced Cardiac Hypertrophy in Rats by regulating angiotensin II type 1 receptor and NADPH oxidase 2 mediated oxidative stress

Hongxiao Yang et al.

Summary: This study demonstrated a protective effect of hydrogen on levothyroxine-induced cardiac hypertrophy in rats by regulating angiotensin II type 1 receptors and NOX2-mediated oxidative stress.

EUROPEAN JOURNAL OF PHARMACOLOGY (2022)

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Article Plant Sciences

Ginsenoside Rg1 attenuates cerebral ischemia-reperfusion injury due to inhibition of NOX2-mediated calcium homeostasis dysregulation in mice

Yuli Han et al.

Summary: Ginsenoside Rg1 has been shown to have a significant neuroprotective effect in cerebral ischemia-reperfusion injury (CIRI), attenuating neuronal damage by inhibiting oxidative stress, calcium overload, and neuroinflammation.

JOURNAL OF GINSENG RESEARCH (2022)

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Article Biochemistry & Molecular Biology

Inhibition of endothelial Nox2 activation by LMH001 protects mice from angiotensin II-induced vascular oxidative stress, hypertension and aortic aneurysm

Lampson M. Fan et al.

Summary: LMH001, a small chemical compound, effectively inhibits the activation of endothelial Nox2 and superoxide production induced by AngII by blocking the interaction between phosphorylated p(47phox) and p(22phox). It shows potential as a therapeutic candidate for oxidative stress-related cardiovascular diseases.

REDOX BIOLOGY (2022)

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Article Immunology

Ursolic acid alleviates Kupffer cells pyroptosis in liver fibrosis by the NOX2/NLRP3 inflammasome signaling pathway

Yipeng Wan et al.

Summary: This study reveals that ursolic acid can attenuate KC pyroptosis in liver fibrosis by inhibiting the NOX2/NLRP3 inflammasome signaling pathway.

INTERNATIONAL IMMUNOPHARMACOLOGY (2022)

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Article Immunology

Neutrophil and Macrophage NADPH Oxidase 2 Differentially Control Responses to Inflammation and to Aspergillus fumigatus in Mice

Rachel A. Idol et al.

Summary: This study investigates the relative roles of macrophage and neutrophil NOX2 in the host response to Aspergillus fumigatus. The results show that macrophage NOX2 limits germination of inhaled A. fumigatus conidia, while reduced neutrophil NOX2 enhances inflammation to fungal cell walls and promotes fungal growth.

JOURNAL OF IMMUNOLOGY (2022)

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Article Cardiac & Cardiovascular Systems

KMT2B-dependent RFK transcription activates the TNF-?/NOX2 pathway and enhances ferroptosis caused by myocardial ischemia-reperfusion

Yuanyuan Cao et al.

Summary: The study revealed that KMT2B was upregulated in patients with acute myocardial infarction, and KMT2B knockdown could reduce myocardial infarct area and cell apoptosis, as well as suppress the release of pro-inflammatory proteins and ferroptosis. KMT2B promotes MIRI-induced cellular injury and ferroptosis by inducing RFK transcription and mediating the TNF-alpha/NOX2 axis.

JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY (2022)

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Article Oncology

NADPH Oxidase 2 Has a Crucial Role in Cell Cycle Progression of Esophageal Squamous Cell Carcinoma

Hiroki Shimizu et al.

Summary: This study revealed the association of NOX2 expression with cell proliferation, cell cycle, and prognosis in esophageal squamous cell carcinoma. NOX2 may serve as a biomarker and therapeutic target for this type of cancer.

ANNALS OF SURGICAL ONCOLOGY (2022)

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Article Biology

Structure of human phagocyte NADPH oxidase in the resting state

Rui Liu et al.

Summary: Phagocyte oxidase is crucial for the host defense against pathogens. This study reveals the structure of the NOX2-p22 complex, indicating the importance of cytosolic factors in activating the complex.

ELIFE (2022)

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Article Neurosciences

NADPH oxidase 2 activity in Parkinson's disease

Matthew T. Keeney et al.

Summary: Mitochondrial dysfunction and oxidative stress play important roles in the pathogenesis of Parkinson's disease, and mitochondrially-generated superoxide can activate NOX2. The study found that both neuronal and microglial NOX2 are highly activated in substantia nigra in chronic conditions, but only neuronal NOX2 is activated in acute and sub-acute models, suggesting its primary role in the early stages of the disease.

NEUROBIOLOGY OF DISEASE (2022)

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Article Biochemistry & Molecular Biology

Dexmedetomidine Attenuates Apoptosis and Neurological Deficits by Modulating Neuronal NADPH Oxidase 2-Derived Oxidative Stress in Neonates Following Hypoxic Brain Injury

Xiaohui Chen et al.

Summary: Dex provides neuroprotection against neonatal hypoxic brain injury by suppressing neuronal NOX2 activation and reducing oxidative stress.

ANTIOXIDANTS (2022)

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Review Cell Biology

Regulation of Neutrophil NADPH Oxidase, NOX2: A Crucial Effector in Neutrophil Phenotype and Function

Marie-Helene Paclet et al.

Summary: This article reviews the multiple roles of NOX2 in neutrophil functions, with a focus on the description of its components and their assembly mechanisms. It also explains the role of energy metabolism and phosphoinositides in regulating NADPH oxidase activity.

FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY (2022)

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Article Immunology

Stress level of glucocorticoid exacerbates neuronal damage and Aβ production through activating NLRP1 inflammasome in primary cultured hippocampal neurons of APP-PS1 mice

Liu Yang et al.

Summary: Chronic glucocorticoid exposure can accelerate neuronal damage and beta-amyloid production by activating oxidative stress and NLRP1 inflammasome, leading to the deterioration of Alzheimer's disease. Inhibition of NLRP1 inflammasome may be an important strategy in improving chronic glucocorticoid-induced neuronal injury.

INTERNATIONAL IMMUNOPHARMACOLOGY (2022)

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Article Cell Biology

A dual Keap1 and p47phox inhibitor Ginsenoside Rb1 ameliorates high glucose/ox-LDL-induced endothelial cell injury and atherosclerosis

Zi-Chao Wang et al.

Summary: This study found that Ginsenoside Rb1 can inhibit oxidative stress in endothelial cells by directly targeting Keap1 and p47(phox), which leads to the activation of Nrf2 and disruption of the NOX2 complex.

CELL DEATH & DISEASE (2022)

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Article Multidisciplinary Sciences

Structure of the core human NADPH oxidase NOX2

Sigrid Noreng et al.

Summary: This study reveals the core structure of NOX2, rationalizes disease-causing mutations, and suggests potential avenues for selective NOX2 pharmacological modulation.

NATURE COMMUNICATIONS (2022)

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Article Biochemistry & Molecular Biology

The Sodium-Glucose Co-Transporter-2 (SGLT2) Inhibitors Reduce Platelet Activation and Thrombus Formation by Lowering NOX2-Related Oxidative Stress: A Pilot Study

Pasquale Pignatelli et al.

Summary: This study demonstrates that gliflozins have antiplatelet and antithrombic effects in patients with T2D, potentially through the modulation of oxidative stress, platelet activation, and thrombus formation.

ANTIOXIDANTS (2022)

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Article Cell Biology

p67phox-derived self-assembled peptides prevent Nox2 NADPH oxidase activation by an auto-inhibitory mechanism

Edna Bechor et al.

Summary: This study identified a novel mechanism of inhibiting NADPH oxidase activity using self-assembled peptides, which bind specifically to p67(phox) and deplete it, leading to the inhibition of oxidase activity.

JOURNAL OF LEUKOCYTE BIOLOGY (2021)

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Article Immunology

Clinical, functional and genetic characterization of 16 patients suffering from chronic granulomatous disease variants - identification of 11 novel mutations inCYBB

M. Mollin et al.

Summary: Chronic granulomatous disease (CGD) is a rare inherited disorder characterized by a lack of NADPH oxidase activity in phagocytes. The X-linked form, X91-CGD, caused by mutations in the CYBB gene, is the most common. Through clinical, functional, and genetic characterizations of 16 cases, new mutations were identified and their pathological impacts were investigated. Low NADPH oxidase activity correlated with milder clinical forms of CGD, while X91(0)-CGD and X91(+)-CGD cases remained the most severe clinically.

CLINICAL AND EXPERIMENTAL IMMUNOLOGY (2021)

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Article Biology

Aβ initiates brain hypometabolism, network dysfunction and behavioral abnormalities via NOX2-induced oxidative stress in mice

Anton Malkov et al.

Summary: The activation of NADPH oxidase 2 (NOX2) is identified as the primary mechanism behind A beta(1-42)-related glucose hypometabolism and network dysfunction. Inhibiting NOX2 may prevent the pathological changes associated with AD-related brain glucose hypometabolism.

COMMUNICATIONS BIOLOGY (2021)

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Review Biochemistry & Molecular Biology

Implication of Nicotinamide Adenine Dinucleotide Phosphate (NADPH) Oxidase and Its Inhibitors in Alzheimer's Disease Murine Models

Leticia Guadalupe Fragoso-Morales et al.

Summary: Alzheimer's disease is a major human dementia characterized by memory loss associated with oxidative stress in brain cells. Overexpression of NADPH oxidase in AD leads to the production of large amounts of reactive oxygen species, damaging brain cells and vasculature, making it a potential therapeutic target for AD.

ANTIOXIDANTS (2021)

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Article Cardiac & Cardiovascular Systems

Myocardial infarction coincides with increased NOX2 and Nε-(carboxymethyl) lysine expression in the cerebral microvasculature

Amber Korn et al.

Summary: The study found a significant increase in CML and NOX2 levels in the brain microvasculature of patients with MI, which may contribute to mental health disorders associated with MI.

OPEN HEART (2021)

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Article Plant Sciences

Ginsenoside Rg1 alleviates Aβ deposition by inhibiting NADPH oxidase 2 activation in APP/PS1 mice

Han Zhang et al.

Summary: The study found that Rg1 significantly improved cognitive impairments and neuronal damage in APP/PS1 mice, inhibited the generation of A beta, and reduced p-Tau levels. Additionally, Rg1 also decreased ROS levels and NOX2 expression.

JOURNAL OF GINSENG RESEARCH (2021)

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Article Immunology

NOX2 Deficiency Permits Sustained Survival of S. aureus in Macrophages and Contributes to Severity of Infection

Bettina Tosetti et al.

Summary: Studies have shown that macrophages deficient in NADPH oxidase 2 may have impaired ability to clear S. aureus, leading to increased bacterial survival and dissemination, particularly in causing liver abscesses. The use of intracellular antibiotics can eliminate S. aureus from the liver completely, highlighting the importance of targeting intracellular bacteria in the treatment of invasive S. aureus infections.

FRONTIERS IN IMMUNOLOGY (2021)

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Review Chemistry, Multidisciplinary

Rational Design of Peptide-Based Inhibitors Disrupting Protein-Protein Interactions

Xuefei Wang et al.

Summary: This review summarizes drug design strategies for protein-protein interactions (PPIs) targeting, specifically focusing on the development of peptide-based PPI inhibitors. Examples targeting well-known PPI targets such as Bcl-2 family members, p53-MDM2, and APC-Asef are presented to illustrate detailed schemes for peptide-based PPI inhibitor development and optimization. The review provides an overview of recent advances in drug discovery targeting PPIs through peptides or peptidomimetics, offering insights into future therapeutic agent development for historically challenging PPI systems.

FRONTIERS IN CHEMISTRY (2021)

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Article Biochemistry & Molecular Biology

Proprotein Convertase Subtilisin Kexin Type 9 Inhibitors Reduce Platelet Activation Modulating ox-LDL Pathways

Vittoria Cammisotto et al.

Summary: PCSK9i treatment reduces levels of LDL cholesterol, oxidized LDL, platelet activation, etc., by modulating NOX2 activity and reducing formation of oxidized LDL in patients with HeFH.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2021)

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Review Cell Biology

Protective Effects of Estrogen on Cardiovascular Disease Mediated by Oxidative Stress

Du Xiang et al.

Summary: Premenopausal women have lower risk of cardiovascular disease compared to men, while postmenopausal women have higher risk. Estrogen has a protective effect on the cardiovascular system by regulating oxidative stress, offering potential strategies for treating menopausal women with cardiovascular diseases.

OXIDATIVE MEDICINE AND CELLULAR LONGEVITY (2021)

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Article Multidisciplinary Sciences

A small molecule inhibitor of Nox2 and Nox4 improves contractile function after ischemia-reperfusion in the mouse heart

Ferenc L. M. Szekeres et al.

Summary: A new compound has been identified to partially inhibit the NADPH oxidase enzymes Nox 2 and 4, leading to improved contractility of cardiomyocytes and enhanced recovery of heart function after ischemia-reperfusion injury.

SCIENTIFIC REPORTS (2021)

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Article Cardiac & Cardiovascular Systems

Glutathione Infusion Before and 3 Days After Primary Angioplasty Blunts Ongoing NOX2-Mediated Inflammatory Response

Gaetano Tanzilli et al.

Summary: The study demonstrated that early and prolonged infusion of glutathione in patients with ST-segment-elevation myocardial infarction can significantly reduce inflammatory response, protect vital myocardial components, and improve left ventricular size and function during follow-up assessments.

JOURNAL OF THE AMERICAN HEART ASSOCIATION (2021)

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ANTIOXIDANTS (2021)

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Higenamine Attenuates Neuropathic Pain by Inhibition of NOX2/ROS/TRP/P38 Mitogen-Activated Protein Kinase/NF-κB Signaling Pathway

Bing Yang et al.

Summary: The study demonstrated that higenamine has significant antioxidant and anti-inflammatory properties, relieving pain caused by neuropathic pain and improving cell survival rate. By rebalancing the redox system, reducing inflammation levels, and activating key signaling pathways, higenamine can alleviate oxidative stress injury, inflammation, and apoptosis induced by neuropathic pain.

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Inhibition of LPS-induced Nox2 activation by VAS2870 protects alveolar epithelial cells through eliminating ROS and restoring tight junctions

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Celastrol attenuates angiotensin II mediated human umbilical vein endothelial cells damage through activation of Nrf2/ERK1/2/Nox2 signal pathway

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Resveratrol reduces vascular cell senescence through attenuation of oxidative stress by SIRT1/NADPH oxidase-dependent mechanisms

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Peroxiredoxin 6 Phosphorylation and Subsequent Phospholipase A2 Activity Are Required for Agonist-mediated Activation of NADPH Oxidase in Mouse Pulmonary Microvascular Endothelium and Alveolar Macrophages

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Direct evidence of a role for Nox2 in superoxide production, reduced nitric oxide bioavailability, and early atherosclerotic plaque formation in ApoE(-/-) mice

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Atorvastatin Inhibits gp91phox Circulating Levels in Patients With Hypercholesterolemia

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Augmented Superoxide Production By Nox2-Containing NADPH Oxidase Causes Cerebral Artery Dysfunction During Hypercholesterolemia

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FRONTIERS IN NEUROENDOCRINOLOGY (2008)

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Rheumatoid arthritis: The role of reactive oxygen species in disease development and therapeutic strategies

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ANTIOXIDANTS & REDOX SIGNALING (2007)

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Review Immunology

The microglial NADPH oxidase complex as a source of oxidative stress in Alzheimer's disease

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Novel Nox inhibitor VAS2870 attenuates PDGF-dependent smooth muscle cell chemotaxis, but not proliferation

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The superoxide-generating NADPH oxidase: structural aspects and activation mechanism

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Development of a virtual screening method for identification of frequent hitters in compound libraries

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Novel competitive inhibitor of NAD(P)H oxidase assembly attenuates vascular O2- and systolic blood pressure in mice

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CIRCULATION RESEARCH (2001)

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