Therapeutic potential of NADPH oxidase 1/4 inhibitors

Teixeira, Graciosa Q.; Szyndralewiez, Cédric; Molango, Sophie; Carnesecchi, Stéphanie; Heitz, Freddy; Wiesel, Philippe; Wood, Jeanette M.

doi:10.1111/bph.13532

Cited by 130 publications

(141 citation statements)

References 216 publications

Supporting

Mentioning

135

Contrasting

Unclassified

Order By: Relevance

“…Unlike with NOX2 inhibition, little immunosuppression is observed and no spontaneous pathologies are found upon NOX4 inhibition or deletion (Aoyama et al, 2012). Moreover, it has progressed to clinical trials, showing great promise (Teixeira et al, 2016). …”

Section: Potential Treatments On Nox Activationmentioning

confidence: 99%

NOX Activation by Subunit Interaction and Underlying Mechanisms in Disease

Rastogi

et al. 2017

Front. Cell. Neurosci.

180

167

View full text Add to dashboard Cite

Nicotinamide adenine dinucleotide phosphate (NAPDH) oxidase (NOX) is an enzyme complex with the sole function of producing superoxide anion and reactive oxygen species (ROS) at the expense of NADPH. Vital to the immune system as well as cellular signaling, NOX is also involved in the pathologies of a wide variety of disease states. Particularly, it is an integral player in many neurological diseases, including stroke, TBI, and neurodegenerative diseases. Pathologically, NOX produces an excessive amount of ROS that exceed the body’s antioxidant ability to neutralize them, leading to oxidative stress and aberrant signaling. This prevalence makes it an attractive therapeutic target and as such, NOX inhibitors have been studied and developed to counter NOX’s deleterious effects. However, recent studies of NOX have created a better understanding of the NOX complex. Comprised of independent cytosolic subunits, p47-phox, p67-phox, p40-phox and Rac, and membrane subunits, gp91-phox and p22-phox, the NOX complex requires a unique activation process through subunit interaction. Of these subunits, p47-phox plays the most important role in activation, binding and translocating the cytosolic subunits to the membrane and anchoring to p22-phox to organize the complex for NOX activation and function. Moreover, these interactions, particularly that between p47-phox and p22-phox, are dependent on phosphorylation initiated by upstream processes involving protein kinase C (PKC). This review will look at these interactions between subunits and with PKC. It will focus on the interaction involving p47-phox with p22-phox, key in bringing the cytosolic subunits to the membrane. Furthermore, the implication of these interactions as a target for NOX inhibitors such as apocynin will be discussed as a potential avenue for further investigation, in order to develop more specific NOX inhibitors based on the inhibition of NOX assembly and activation.

show abstract

Section: Potential Treatments On Nox Activationmentioning

confidence: 99%

NOX Activation by Subunit Interaction and Underlying Mechanisms in Disease

Rastogi

et al. 2017

Front. Cell. Neurosci.

180

167

View full text Add to dashboard Cite

show abstract

“…Thus, a rigorously developed ROS assay is critical for monitoring of enzyme activity and assessing the effects of putative Nox inhibitors. However, only a limited number of Nox inhibitors are currently available [37,38]. We propose that one of the reasons for the slow progress is the lack of availability of specific and selective ROS assays.…”

Section: Opportunities In Nox Inhibitor Discoverymentioning

confidence: 99%

Recent developments in detection of superoxide radical anion and hydrogen peroxide: Opportunities, challenges, and implications in redox signaling

Kalyanaraman

Hardy

Podsiadly

et al. 2017

Archives of Biochemistry and Biophysics

111

View full text Add to dashboard Cite

In this review, some of the recent developments in probes and assay techniques specific for superoxide (O2•−) and hydrogen peroxide (H2O2) are discussed. Over the last decade, significant progress has been made in O2•− and H2O2 detection due to syntheses of new redox probes, better understanding of their chemistry, and development of specific and sensitive assays. For superoxide detection, hydroethidine (HE) is the most suitable probe, as the product, 2-hydroxyethidium, is specific for O2•−. In addition, HE-derived dimeric products are specific for one-electron oxidants. As red-fluorescent ethidium is always formed from HE intracellularly, chromatographic techniques are required for detecting 2-hydroxyethidium. HE analogs, Mito-SOX and hydropropidine, exhibit the same reaction chemistry with O2•− and one-electron oxidants. Thus, mitochondrial superoxide can be unequivocally detected using HPLC-based methods and not by fluorescence microscopy. Aromatic boronate-based probes react quantitatively with H2O2, forming a phenolic product. However, peroxynitrite and hypochlorite react more rapidly with boronates, forming the same product. Using ROS-specific probes and HPLC assays, it is possible to screen chemical libraries to discover specific inhibitors of NADPH oxidases. We hope that rigorous detection of O2•− and H2O2 in different cellular compartments will improve our understanding of their role in redox signaling.

show abstract

“…This specific Nox1 and Nox4 inhibitor has a K i from 100 to 150 nM in cell‐free assays, does not inhibit other isoforms of Nox, xanthene oxidase, or the neutrophil oxidative burst, does not scavenge ROS, and has been previously shown to reverse fibrosis and improve survival in a mouse model of idiopathic pulmonary fibrosis . Nox4 is also a potential therapeutic target in pre‐clinical models of disease in many other systems including the liver, kidney, brain, bone, skin, cardiovascular system, gastrointestinal tract, and eye, and several forms of cancer …”

mentioning

confidence: 99%

Acute Changes in NADPH Oxidase 4 in Early Post‐Traumatic Osteoarthritis

Wegner

Campos

Robbins

et al. 2019

Journal Orthopaedic Research

View full text Add to dashboard Cite

Knee injuries cause structural damage and acute inflammation that initiates the development of post‐traumatic osteoarthritis (PTOA). NADPH oxidase 4 (Nox4), a member of a family of enzymes that generates reactive oxygen species (ROS), plays a pivotal role in normal development of the musculoskeletal system, but may increase ROS production to harmful levels after joint injury. The role of ROS in both normal joint homeostasis and injury is poorly understood, but inhibition of excessive ROS production by Nox4 after joint injury could be protective to the joint, decreasing oxidative stress, and initiation of PTOA. Knee injuries were simulated using inflammatory cytokines in cultured primary human chondrocytes and a non‐invasive mouse model of PTOA in C57BL/6N and Nox4 knockout mice. There is an acute decrease in Nox4 activity within 24 h after injury in both systems, followed by a subsequent sustained low‐level increase, a novel finding not seen in any other system. Inhibition of Nox4 activity by GKT137831 was protective against early structural changes after non‐invasive knee injury in a mouse model. Nox4 knockout mice had significant differences in structural and mechanical properties of bone, providing further evidence for the role of Nox4 in development of joint tissues and biochemical response after joint injury. Nox4 plays a significant role in the acute phase after joint injury, and targeted inhibition of inflammation caused by Nox4 may be protective against early joint changes in the pathogenesis of PTOA. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2429–2436, 2019

show abstract

Therapeutic potential of NADPH oxidase 1/4 inhibitors

Abstract: This article is part of a themed section on Redox Biology and Oxidative Stress in Health and Disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.12/issuetoc.

Cited by 130 publications

References 216 publications

NOX Activation by Subunit Interaction and Underlying Mechanisms in Disease

NOX Activation by Subunit Interaction and Underlying Mechanisms in Disease

Recent developments in detection of superoxide radical anion and hydrogen peroxide: Opportunities, challenges, and implications in redox signaling

Acute Changes in NADPH Oxidase 4 in Early Post‐Traumatic Osteoarthritis

Contact Info

Product

Resources

About