Molecular Mechanisms Related to Responses to Oxidative Stress and Antioxidative Therapies in COVID-19: A Systematic Review

Abstract

The coronavirus disease (COVID-19) pandemic is a leading global health and economic challenge. What defines the disease’s progression is not entirely understood, but there are strong indications that oxidative stress and the defense against reactive oxygen species are crucial players. A big influx of immune cells to the site of infection is marked by the increase in reactive oxygen and nitrogen species. Our article aims to highlight the critical role of oxidative stress in the emergence and severity of COVID-19 and, more importantly, to shed light on the underlying molecular and genetic mechanisms. We have reviewed the available literature and clinical trials to extract the relevant genetic variants within the oxidative stress pathway associated with COVID-19 and the anti-oxidative therapies currently evaluated in the clinical trials for COVID-19 treatment, in particular clinical trials on glutathione and N-acetylcysteine.

N-acetylcysteine Reduces Inflammasome Activation Induced by SARS-CoV-2 Proteins In Vitro

“…The hyper-inflammatory syndrome of severe COVID-19 patients is accompanied by elevated oxidative stress [ 45 ]. In fact, serum levels of antioxidant thiols and GSH, among others, are decreased and inversely correlated with COVID-19 severity, while reactive nitric and oxygen species are overexpressed and correlated with COVID-19 severity [ 45 ].…”

“…The hyper-inflammatory syndrome of severe COVID-19 patients is accompanied by elevated oxidative stress [ 45 ]. In fact, serum levels of antioxidant thiols and GSH, among others, are decreased and inversely correlated with COVID-19 severity, while reactive nitric and oxygen species are overexpressed and correlated with COVID-19 severity [ 45 ]. In this work, we evaluated the expression and the balance between the anti-oxidant transcription factor Nrf2 and the oxidant NOX4 cell membrane protein since the increase in NOX4/Nrf2 ratio has been associated with lung fibrosis [ 46 ], important sequelae of COVID-19 [ 47 ].…”

“…An explanation of these apparently contradictory results could be discussed by the fact that SARS-CoV-2 produces an exaggerated inflammatory response, and these inflammatory proteins elevate ROS levels that are able to increase inflammation, thus producing a positive feedback loop. In this regard, ROS can activate Nf-κB and NLRP3, thus elevating the even more, the inflammation [ 45 ]. Although we have observed induction of NOX4 by mosaic (S-E-M) after 24 h of stimulation, the experimental conditions and ROS readouts (up to 24 h), together with the elevation of Nrf2, can explain the undetectable in vitro ROS production.…”

“…In this regard, NAC has been postulated as a potential treatment for COVID-19 because of the antioxidant, anti-inflammatory, and anti-viral properties. In COVID-19 patients, high doses of NAC (600–1200 mg/day) may prevent the severe symptoms of COVID-19 in observational and case-report studies, although negative results have also been reported in interventional studies, which have encouraged scientists to conduct a broad number of NAC clinical trials in COVID-19 patients which are currently ongoing [ 45 ]. Mechanistically, NAC is a direct ROS scavenger, a source of sulfhydryl (SH) groups that elevates thiol groups and increases levels of GSH.…”

“…I t is known that ROS activates Nf-κB that induces NLRP3 expression. In addition, ROS can directly promote NLRP3 assembly and activation [ 45 ]. In this work, we showed for the first time the effects of NAC on the inhibition of SARS-CoV-2 mosaic (S-E-M) protein-induced NLRP3/ASC/CASP1 and IL-1β/IL-18 inflammasome activation as well as the inhibition of pro-inflammatory cytokines IL-6, IL-8 and TNFα in human macrophages and bronchial epithelial cells.…”