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New NADPH Oxidase 2 Inhibitors Display Potent Activity against Oxidative Stress by Targeting p22^phox-p47^phox Interactions.

ABSTRACT: NADPH oxidase (NOX2) is responsible for reactive oxygen species (ROS) production in neutrophils and has been recognized as a key mediator in inflammatory and cardiovascular pathologies. Nevertheless, there is a lack of specific NOX2 pharmacological inhibitors. In medicinal chemistry, heterocyclic compounds are essential scaffolds for drug design, and among them, indole is a very versatile pharmacophore. We tested the hypothesis that indole heteroaryl-acrylonitrile derivatives may serve as NOX2 inhibitors by evaluating the capacity of 19 of these molecules to inhibit NOX2-derived ROS production in human neutrophils (HL-60 cells). Of these compounds, C6 and C14 exhibited concentration-dependent inhibition of NOX2 (IC₅₀~1 µM). These molecules also reduced NOX2-derived oxidative stress in cardiomyocytes and prevented cardiac damage induced by ischemia-reperfusion. Compound C6 significantly reduced the membrane translocation of p47^phox, a cytosolic subunit that is required for NOX2 activation. Molecular docking analyses of the binding modes of these molecules with p47^phox indicated that C6 and C14 interact with specific residues in the inner part of the groove of p47^phox, the binding cavity for p22^phox. This combination of methods showed that novel indole heteroaryl acrylonitriles represent interesting lead compounds for developing specific and potent NOX2 inhibitors.

SUBMITTER: Treuer AV

PROVIDER: S-EPMC10376059 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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New NADPH Oxidase 2 Inhibitors Display Potent Activity against Oxidative Stress by Targeting p22<sup>phox</sup>-p47<sup>phox</sup> Interactions.

Treuer Adriana V AV Faúndez Mario M Ebensperger Roberto R Hovelmeyer Erwin E Vergara-Jaque Ariela A Perera-Sardiña Yunier Y Gutierrez Margarita M Fuentealba Roberto R González Daniel R DR

Antioxidants (Basel, Switzerland) 20230718 7

NADPH oxidase (NOX2) is responsible for reactive oxygen species (ROS) production in neutrophils and has been recognized as a key mediator in inflammatory and cardiovascular pathologies. Nevertheless, there is a lack of specific NOX2 pharmacological inhibitors. In medicinal chemistry, heterocyclic compounds are essential scaffolds for drug design, and among them, indole is a very versatile pharmacophore. We tested the hypothesis that indole heteroaryl-acrylonitrile derivatives may serve as NOX2 i ...[more]

PMID: 37507978

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Project description:BackgroundEpidemiological studies have evaluated the association between nicotinamide adenine dinucleotide phosphate (NADPH) oxidase p22(phox) C242T polymorphism and risk of ischemic cerebrovascular disease (ICVD), but the results remain inconclusive. This meta-analysis was therefore designed to clarify these controversies.Methodology/principal findingsSystematic searches of electronic databases Embase, PubMed and Web of Science, as well as hand searching of the references of identified articles and the meeting abstracts were performed. Statistical analyses were performed using software Review Manager (Version 5.1.7) and Stata (Version 11.0). The pooled odds ratios (ORs) with 95% confidence intervals (95%CIs) were performed. Fixed or random effects model was separately used depending on the heterogeneity between studies. Publication bias was tested by Begg's funnel plot and Egger's regression test. A total of 6 studies including 1,948 cases and 2,357 controls were combined showing no statistical evidence of association between NADPH oxidase p22(phox) C242T polymorphism and overall ICVD (allelic model: OR?=?1.08, 95%CI?=?0.93-1.26; additive model: OR?=?1.33, 95%CI?=?0.81-2.17; dominant model: OR?=?1.00, 95%CI?=?0.86-1.15; recessive model: OR?=?1.06, 95%CI?=?0.77-1.45). Significant association was found in large-artery atherosclerotic stroke subgroup (allelic model: OR?=?1.12, 95%CI?=?0.88-1.41; additive model: OR?=?1.36, 95%CI?=?0.60-3.09; dominant model: OR?=?1.25, 95%CI?=?0.74-2.11; recessive model: OR?=?2.17, 95%CI?=?1.11-4.23). No statistical evidence of significant association was observed for small-vessel occlusive stroke, as well as Asian subgroup and Caucasian subgroup. Statistical powers on the combined sample size (total and subgroup) were all lower than 80%.Conclusions/significanceThis meta-analysis indicates that NADPH oxidase p22(phox) C242T polymorphism is more associated with large-artery atherosclerotic stroke than small-vessel occlusive stroke. However, this conclusion should be interpreted with caution due to the small sample size. Larger sample-size studies with homogeneous ICVD patients and well-matched controls are required.

Project description:BackgroundSpaceflight or microgravity conditions cause myocardial atrophy and dysfunction, contributing to post-flight orthostatic intolerance. However, the underlying mechanisms remain incompletely understood and preventive approaches are limited. This study investigated whether and how losartan, a blocker of angiotensin-II receptor, preserved cardiomyocyte size and prevented myocardial dysfunction during microgravity.MethodAdult male mice were suspended with their tails to simulate microgravity. Echocardiography was performed to assess myocardial function. Heart weight and cardiomyocyte size were measured. NADPH oxidase activation was determined by analyzing membrane translocation of its cytosolic subunits including p47phox, p67phox and Rac1. Heart tissues were also assayed for oxidative stress, p47phox phosphorylation (Ser345), MuRF1 protein levels and angiotensin-II production.ResultsTail-suspension for 28 days increased angiotensin-II production in hearts, decreased cardiomyocyte size and heart weight, and induced myocardial dysfunction. Administration of losartan preserved cardiomyocyte size and heart weight, and prevented myocardial dysfunction in tail-suspended mice. These cardioprotective effects of losartan were associated with inhibition of p47phox phosphorylation (Ser345), NADPH oxidase and oxidative stress in tail-suspended mouse hearts. Additionally, the NADPH oxidase inhibitor, apocynin, also reduced oxidative stress, preserved cardiomyocyte size and heart weight, and improved myocardial function in tail-suspended mice. Furthermore, losartan but not apocynin attenuated tail-suspension-induced up-regulation of MuRF1 protein in mouse hearts.ConclusionsAdministration of losartan preserves cardiomyocyte size and prevents myocardial dysfunction under microgravity by blocking p47phox phosphorylation and NADPH oxidase activation, and by inhibiting MuRF1 expression. Thus, losartan may be a useful drug to prevent microgravity-induced myocardial abnormalities.

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New NADPH Oxidase 2 Inhibitors Display Potent Activity against Oxidative Stress by Targeting p22^phox-p47^phox Interactions.

Publications

New NADPH Oxidase 2 Inhibitors Display Potent Activity against Oxidative Stress by Targeting p22<sup>phox</sup>-p47<sup>phox</sup> Interactions.

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New NADPH Oxidase 2 Inhibitors Display Potent Activity against Oxidative Stress by Targeting p22phox-p47phox Interactions.

Publications

New NADPH Oxidase 2 Inhibitors Display Potent Activity against Oxidative Stress by Targeting p22<sup>phox</sup>-p47<sup>phox</sup> Interactions.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

New NADPH Oxidase 2 Inhibitors Display Potent Activity against Oxidative Stress by Targeting p22^phox-p47^phox Interactions.