NADPH oxidase-dependent and -independent mechanisms of reported inhibitors of reactive oxygen generation

Gatto, Gregory J.; Ao, Zhaohui; Kearse, Michael G.; Zhou, Mei; Morales, Cyndi R.; Daniels, Erin; Bradley, Benjamin T.; Goserud, Matthew T.; Goodman, Krista B.; Douglas, Stephen A.; Harpel, Mark R.; Johns, Douglas G.

doi:10.3109/14756366.2011.636360

Cited by 65 publications

(54 citation statements)

References 49 publications

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“…Among other NOX inhibitors tested in this study, only DPI, celastrol, and suramin showed inhibition across the cellfree assays independently of assay format, in agreement with previous reports suggesting that DPI is an irreversible inhibitor of NOX2 (14), that celastrol inhibits NOX2 directly and via binding to the p47 phox subunit (30), and that suramin also acts via binding to the NADPH binding site (21). While DPI and celastrol also demonstrated inhibitory activity in the cell-based assays, suramin was not active, perhaps due to lack of cell penetrance as has previously been suggested (60).…”

supporting

confidence: 92%

Discovery of GSK2795039, a Novel Small Molecule NADPH Oxidase 2 Inhibitor

Hirano¹,

Chen²,

Chueng³

et al. 2015

Antioxidants & Redox Signaling

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151

141

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Aims: The NADPH oxidase (NOX) family of enzymes catalyzes the formation of reactive oxygen species (ROS). NOX enzymes not only have a key role in a variety of physiological processes but also contribute to oxidative stress in certain disease states. To date, while numerous small molecule inhibitors have been reported (in particular for NOX2), none have demonstrated inhibitory activity in vivo. As such, there is a need for the identification of improved NOX inhibitors to enable further evaluation of the biological functions of NOX enzymes in vivo as well as the therapeutic potential of NOX inhibition. In this study, both the in vitro and in vivo pharmacological profiles of GSK2795039, a novel NOX2 inhibitor, were characterized in comparison with other published NOX inhibitors. Results: GSK2795039 inhibited both the formation of ROS and the utilization of the enzyme substrates, NADPH and oxygen, in a variety of semirecombinant cell-free and cellbased NOX2 assays. It inhibited NOX2 in an NADPH competitive manner and was selective over other NOX isoforms, xanthine oxidase, and endothelial nitric oxide synthase enzymes. Following systemic administration in mice, GSK2795039 abolished the production of ROS by activated NOX2 enzyme in a paw inflammation model. Furthermore, GSK2795039 showed activity in a murine model of acute pancreatitis, reducing the levels of serum amylase triggered by systemic injection of cerulein. Innovation and Conclusions: GSK2795039 is a novel NOX2 inhibitor that is the first small molecule to demonstrate inhibition of the NOX2 enzyme in vivo. Antioxid. Redox Signal. 23, 358-374.

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supporting

confidence: 92%

Discovery of GSK2795039, a Novel Small Molecule NADPH Oxidase 2 Inhibitor

Hirano¹,

Chen²,

Chueng³

et al. 2015

Antioxidants & Redox Signaling

Self Cite

151

141

View full text Add to dashboard Cite

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“…In a neutrophil-cell-free system, VAS2870 inhibited superoxide production with an IC 50 of 10.6 lM. These results appear inconsistent with findings from Gatto et al who reported lack of inhibition of Nox2 by VAS2870 in a semipurified enzyme preparation (58). This difference may be a consequence of the dynamics of complex assembly that is dependent on the order of addition of the stimulus.…”

contrasting

confidence: 70%

The Quest for Selective Nox Inhibitors and Therapeutics: Challenges, Triumphs and Pitfalls

Cifuentes-Pagano

Meijles

Pagano

2014

Antioxidants & Redox Signaling

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“…Additional effects of perhexiline include blockade of the NAD(P)H oxidase 2 (Nox2) complex, conveying beneficial anti-inflammatory effects (Gatto, et al, 2013;Kennedy, et al, 2006;Liberts, et al, 2007), and reduced expression of TXNIP (Ngo, et al, 2011). Moreover, a recent study reports that perhexiline activates Krüppel-like factor 14 (KLF14), which regulates lipid metabolism, reducing atherosclerotic lesion development in a mouse model .…”

Section: Carnitine Palmitoyltransferase 1 (Cpt1) Inhibitionmentioning

confidence: 99%

Cardiac metabolism — A promising therapeutic target for heart failure

Noordali

Loudon

Frenneaux

et al. 2018

Pharmacology & Therapeutics

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Both heart failure with reduced ejection fraction (HFrEF) and with preserved ejection fraction (HFpEF) are associated with high morbidity and mortality. Although many established pharmacological interventions exist for HFrEF, hospitalization and death rates remain high, and for those with HFpEF (approximately half of all heart failure patients), there are no effective therapies. Recently, the role of impaired cardiac energetic status in heart failure has gained increasing recognition with the identification of reduced capacity for both fatty acid and carbohydrate oxidation, impaired function of the electron transport chain, reduced capacity to transfer ATP to the cytosol, and inefficient utilization of the energy produced. These nodes in the genesis of cardiac energetic impairment provide potential therapeutic targets, and there is promising data from recent experimental and early-phase clinical studies evaluating modulators such as carnitine palmitoyltransferase 1 inhibitors, partial fatty acid oxidation inhibitors and mitochondrial-targeted antioxidants.Metabolic modulation may provide significant symptomatic and prognostic benefit for patients suffering from heart failure above and beyond guideline-directed therapy, but further clinical trials are needed.

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NADPH oxidase-dependent and -independent mechanisms of reported inhibitors of reactive oxygen generation

Cited by 65 publications

References 49 publications

Discovery of GSK2795039, a Novel Small Molecule NADPH Oxidase 2 Inhibitor

Discovery of GSK2795039, a Novel Small Molecule NADPH Oxidase 2 Inhibitor

The Quest for Selective Nox Inhibitors and Therapeutics: Challenges, Triumphs and Pitfalls

Cardiac metabolism — A promising therapeutic target for heart failure

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