bims-noxint 2021-10-17 papers

Issue of 2021‒10‒17
four papers selected by
Laia Caja Puigsubira
Uppsala University

Redox Biol. 2021 Oct 04. pii: S2213-2317(21)00319-0. [Epub ahead of print] 102159

The role of NADPH oxidases in infectious and inflammatory diseases.

Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOX) are enzymes that generate superoxide or hydrogen peroxide from molecular oxygen utilizing NADPH as an electron donor. There are seven enzymes in the NOX family: NOX1-5 and dual oxidase (DUOX) 1-2. NOX enzymes in humans play important roles in diverse biological functions and vary in expression from tissue to tissue. Importantly, NOX2 is involved in regulating many aspects of innate and adaptive immunity, including regulation of type I interferons, the inflammasome, phagocytosis, antigen processing and presentation, and cell signaling. DUOX1 and DUOX2 play important roles in innate immune defenses at epithelial barriers. This review discusses the role of NOX enzymes in normal physiological processes as well as in disease. NOX enzymes are important in autoimmune diseases like type 1 diabetes and have also been implicated in acute lung injury caused by infection with SARS-CoV-2. Targeting NOX enzymes directly or through scavenging free radicals may be useful therapies for autoimmunity and acute lung injury where oxidative stress contributes to pathology.

Keywords: Acute lung injury; Autoimmunity; COVID-19; Immunity; NADPH Oxidase; NOX; Superoxide

DOI: https://doi.org/10.1016/j.redox.2021.102159

Front Pharmacol. 2021 ;12 751845

Nox4 Promotes RANKL-Induced Autophagy and Osteoclastogenesis via Activating ROS/PERK/eIF-2α/ATF4 Pathway.

Jing Sun, Wugui Chen, Songtao Li, Sizhen Yang, Ying Zhang, Xu Hu, Hao Qiu, Jigong Wu, Shangcheng Xu, Tongwei Chu.

Receptor activator of nuclear factor-κB ligand (RANKL) has been found to induce osteoclastogenesis and bone resorption. However, the underlying molecular mechanisms remain unclear. Via conducting a series of biochemical experiments with in vitro cell lines, this study investigated the role and mechanism of NADPH oxidase 4 (Nox4) in RANKL-induced autophagy and osteoclastogenesis. In the current study, we found that RANKL dramatically induced autophagy and osteoclastogenesis, inhibition of autophagy with chloroquine (CQ) markedly attenuates RANKL-induced osteoclastogenesis. Interestingly, we found that the protein level of Nox4 was remarkably upregulated by RANKL treatment. Inhibition of Nox4 by 5-O-methyl quercetin or knockdown of Nox4 with specific shRNA markedly attenuated RANKL-induced autophagy and osteoclastogenesis. Furthermore, we found that Nox4 stimulated the production of nonmitochondrial reactive oxygen species (ROS), activating the critical unfolded protein response (UPR)-related signaling pathway PERK/eIF-2α/ATF4, leading to RANKL-induced autophagy and osteoclastogenesis. Blocking the activation of PERK/eIF-2α/ATF4 signaling pathway either by Nox4 shRNA, ROS scavenger (NAC) or PERK inhibitor (GSK2606414) significantly inhibited autophagy during RANKL-induced osteoclastogenesis. Collectively, this study reveals that Nox4 promotes RANKL-induced autophagy and osteoclastogenesis via activating ROS/PERK/eIF-2α/ATF4 pathway, suggesting that the pathway may be a novel potential therapeutic target for osteoclastogenesis-related disease.

Keywords: NOX4; PERK/eIF-2α/ATF4 pathway; RANKL; ROS; UPR; autophagy; osteoclastogenesis

DOI: https://doi.org/10.3389/fphar.2021.751845

Acta Pharmacol Sin. 2021 Oct 15.

Small molecule compound M12 reduces vascular permeability in obese mice via blocking endothelial TRPV4-Nox2 interaction.

Meng-Ru Gao, Peng Zhang, Jing Han, Chun-Lei Tang, Yi-Fei Zhu, Hao Kan, Hong-Juan Li, Xi-Ping Han, Xin Ma.

Transient receptor potential channel TRPV4 and nicotinamide adenine dinucleotide phosphate oxidase (Nox2) are involved in oxidative stress that increases endothelial permeability. It has been shown that obesity enhances the physical association of TRPV4 and Nox2, but the role of TRPV4-Nox2 association in obesity has not been clarified. In this study we investigated the function of TRPV4-Nox2 complex in reducing oxidative stress and regulating abnormal vascular permeability in obesity. Obesity was induced in mice by feeding a high-fat diet (HFD) for 14 weeks. The physical interaction between TRPV4 and Nox2 was measured using FRET, co-immunoprecipitation and GST pull-down assays. The functional interaction was measured by rhodamine phalloidin, CM-H2DCFDA in vitro, the fluorescent dye dihydroethidium (DHE) staining assay, and the Evans blue permeability assay in vivo. We demonstrated that TRPV4 physically and functionally associated with Nox2, and this physical association was enhanced in aorta of obese mice. Furthermore, we showed that interrupting TRPV4-Nox2 coupling by TRPV4 knockout, or by treatment with a specific Nox2 inhibitor Nox2 dstat or a specific TRPV4 inhibitor HC067046 significantly attenuated obesity-induced ROS overproduction in aortic endothelial cells, and reversed the abnormal endothelial cytoskeletal structure. In order to discover small molecules disrupting the over-coupling of TPRV4 and Nox2 in obesity, we performed molecular docking analysis and found that compound M12 modulated TRPV4-Nox2 association, reduced ROS production, and finally reversed disruption of the vascular barrier in obesity. Together, this study, for the first time, provides evidence for the TRPV4 physically interacting with Nox2. TRPV4-Nox2 complex is a potential drug target in improving oxidative stress and disruption of the vascular barrier in obesity. Compound M12 targeting TRPV4-Nox2 complex can improve vascular barrier function in obesity.

Keywords: Compound M12; Nox2; TPRV4; obesity; oxidant stress; vascular permeability

DOI: https://doi.org/10.1038/s41401-021-00780-8

Proc Natl Acad Sci U S A. 2021 Oct 19. pii: e2015666118. [Epub ahead of print]118(42):

Forestalling age-impaired angiogenesis and blood flow by targeting NOX: Interplay of NOX1, IL-6, and SASP in propagating cell senescence.

Yao Li, Damir Kračun, Christopher M Dustin, Mohamed El Massry, Shuai Yuan, Christian J Goossen, Evan R DeVallance, Sanghamitra Sahoo, Cynthia St Hilaire, Aditi U Gurkar, Toren Finkel, Adam C Straub, Eugenia Cifuentes-Pagano, Patrick J Pagano.

In an aging population, intense interest has shifted toward prolonging health span. Mounting evidence suggests that cellular reactive species are propagators of cell damage, inflammation, and cellular senescence. Thus, such species have emerged as putative provocateurs and targets for senolysis, and a clearer understanding of their molecular origin and regulation is of paramount importance. In an inquiry into signaling triggered by aging and proxy instigator, hyperglycemia, we show that NADPH Oxidase (NOX) drives cell DNA damage and alters nuclear envelope integrity, inflammation, tissue dysfunction, and cellular senescence in mice and humans with similar causality. Most notably, selective NOX1 inhibition rescues age-impaired blood flow and angiogenesis, vasodilation, and the endothelial cell wound response. Indeed, NOX1i delivery in vivo completely reversed age-impaired hind-limb blood flow and angiogenesis while disrupting a NOX1-IL-6 senescence-associated secretory phenotype (SASP) proinflammatory signaling loop. Relevant to its comorbidity with age, clinical samples from diabetic versus nondiabetic subjects reveal as operant this NOX1-mediated vascular senescence and inflammation in humans. On a mechanistic level, our findings support a previously unidentified role for IL-6 in this feedforward inflammatory loop and peroxisome proliferator-activated receptor gamma (PPARγ) down-regulation as inversely modulating p65-mediated NOX1 transcription. Targeting this previously unidentified NOX1-SASP signaling axis in aging is predicted to be an effective strategy for mitigating senescence in the vasculature and other organ systems.

Keywords: IL-6; NADPH oxidase; aging; endothelium; senescence

DOI: https://doi.org/10.1073/pnas.2015666118