The novel NADPH oxidase 4 selective inhibitor GLX7013114 counteracts human islet cell death in vitro

Abstract

It has been proposed that pancreatic beta-cell dysfunction in type 2 diabetes is promoted by oxidative stress caused by NADPH oxidase (Nox) over-activity. The aim of the present study was to evaluate the efficacy of novel Nox inhibitors as protective agents against cytokine- or high glucose + palmitate-induced human beta-cell death. The Nox2 protein was present mainly in the cytoplasm and was induced by cytokines. Nox4 protein immunoreactivity, with some nuclear accumulation, was observed in human islet cells, and was not affected by islet culture in the presence of cytokines or high glucose + palmitate. Nox inhibitors with partial or no isoform selectivity (DPI, dapsone, GLX351322, and GLX481372) all reduced ROS production of human islet cells exposed to high glucose + palmitate. This was paralleled by improved viability and reduced caspase 3 activation. The Nox1 selective inhibitor ML171 failed to reduce human islet cell death in response to both cytokines and high glucose + palmitate. The selective Nox2 inhibitor Phox-I2 also failed to protect against cytokines, but protected partially against high glucose + palmitate-induced cellular death. The highly selective Nox4 inhibitor GLX7013114 protected islet cells against both cytokines and high glucose + palmitate. However, as no osmotic control for high glucose was used, we cannot exclude the possibility that the high glucose effect was due to osmosis. It is concluded that Nox4 may participate in stress-induced islet cell death in human islets in vitro. We propose that Nox4 mediates pro-apoptotic effects in intact islets under stressful conditions and that selective Nox4-inhibition may be a therapeutic strategy in type 2 diabetes.

NOX4 activation is involved in ROS‐dependent Jurkat T‐cell death induced by Entamoeba histolytica

“…In particular, NOX4‐derived ROS is important for the survival of many cancer types . However, recent reports have suggested that NOX4 activity perturbs redox balance in cells, resulting in cell death . These reports are consistent with our result that NOX4 inhibition finally blocked the PS exposure and DNA fragmentation of Entamoeba ‐stimulated Jurkat T cells.…”

“…Treating high glucose–exposed cells with a NOX4 selective inhibitor or by NOX4 siRNA knockdown had suppressed ROS levels and death in retinal cells . In addition, NOX4 participation in the stress‐induced human islet cell death process has been demonstrated using a NOX4 inhibitor . Also, it has been reported that elevated NOX4 expression by ethanol induced ROS generation, which causes cell death in hepatocytes .…”

On the Clinical Pharmacology of Reactive Oxygen Species

“…The Swedish company Glucox Biotech AB is also focused on NOX4 inhibitors and is reported to be looking into diabetes, Marfan syndrome, stroke, and cancer. GLX351322 (Anvari et al, 2015), GLX7013107, and GLX7013114 (GLX114) (Wang et al, 2018b) are compounds that are likely to be covered by the substantial intellectual property portfolio in Glucox's name: WO/2016/133446, WO/2016/096720, WO/2014/064118, WO/2013/135803, WO/2008/008033, and WO/2003/087399. A remarkable range of less apparent indications for NOX inhibitors has been claimed by academia: cardiac arrhythmia (WO/2013/158782, University of California), muscular dystrophies (WO/2013/ 078261, University of Maryland), cataract and presbyopia (WO/2009/044294, Université de Genève), and a broad range of psychiatric disorders (WO/2009/ 052454, University of California).…”

The pandemic COVID-19: a tale of viremia, cellular oxidation and immune dysfunction

“…Thioredoxin - interacting protein which mediates high glucose-induced ROS production is upregulated by excessive glucose levels [ 19 ]. Insulin released due to high glucose levels results in hydrogen peroxide generation through activation of NOX4 [ 20 ]. Cardiovascular diseases such as cardiac arrhythmia, hypertension, atherosclerosis, cardiomyopathy and heart failure have also been linked to sugar induced-oxidative stress [ 18 ].…”