MitoQ Modulates Lipopolysaccharide-Induced Intestinal Barrier Dysfunction via Regulating Nrf2 Signaling

Abstract

Background. Gut barrier dysfunction with alterant mucosal permeability during sepsis is a challenge problem in clinical practice. Intestinal epithelial cells (IECs) are strongly involved in mucosal oxidative stress and inflammatory response. The current study aimed at investigating the effect of MitoQ, a mitochondrial targeted antioxidant, in the treatment of intestinal injury and its potential mechanism during sepsis. Methods. 30 minutes before sepsis induction by lipopolysaccharide (LPS) treatment, mice were treated with MitoQ. Intestinal histopathology, mucosal permeability, inflammatory cytokines, and mucosal barrier proteins were evaluated in the present study. Results. MitoQ pretreatment significantly decreased the levels of plasma diamine oxidase, D-lactate, and intestinal histological damage and markedly restored the levels of tight junction proteins (ZO-1 and occludin) following LPS challenge. Furthermore, MitoQ inhibited the LPS-induced intestinal oxidative stress and inflammatory response, evidenced by increased levels of intestinal superoxide dismutase and glutathione, and decreased levels of intestinal IL-1, IL-6, TNF-α, and nitric oxide levels. Mechanically, we found that MitoQ inhibited the oxidative stress via activating nuclear factor E2-related factor 2 (Nrf2) signaling pathway and its downstream antioxidant genes, including HO-1, NQO-1, and GCLM. Conclusions. MitoQ exerts antioxidative and anti-inflammatory effects against sepsis-associated gut barrier injury by promoting Nrf2 signaling pathway.

lncRNA OTUD6B-AS1 Exacerbates As2O3-Induced Oxidative Damage in Bladder Cancer via miR-6734-5p-Mediated Functional Inhibition of IDH2

“…Furthermore, the elevation of Nrf2 in cytoplasm induced by As 2 O 3 was further significantly enhanced by lncRNA OTUD6B-AS1; however, Nrf2 in the nucleus showed the opposite trend. This discovery was consistent with Li et al's report [ 37 ] and Zhang et al's study [ 38 ]. A marked increase in the generation of ROS exceeds the physiological capacity of SOD and GSH-Px, and the exhaustion of these enzymes reduces their activity, ultimately leading to oxidative damage.…”

Metabolic endotoxemia is dictated by the type of lipopolysaccharide

“…Conversely, injection of an equivalent dose of R. sphaeroides LPS did not alter blood plasma FITC compared to saline injected mice (Fig 3c). Bacteria produce the majority of circulating D-lactate, and elevated blood D-lactate is a surrogate marker of increased intestinal permeability (Liu et al, 2016;Zhang et al, 2020). We found that only E. coli LPS, but not LPS from R. sphaeroides, increased levels of blood plasma D-lactate (Fig 3d).…”

Protective Effect of Mitochondria-Targeted Antioxidants against Inflammatory Response to Lipopolysaccharide Challenge: A Review

“…SOD catalyzes the conversion of superoxide to hydrogen peroxide, which, in turn, is converted to water by glutathione peroxidase (GPx). Under oxidative stress, the expression of antioxidant genes is activated by translocation of nuclear factor E2-related factor 2 (Nrf2) from the cytoplasm to the nucleus [ 11 , 58 ].…”

“…The impairment of gut permeability is a serious consequence of dysbiosis. MitoQ has been shown to improve intestinal permeability and inhibit LPS-induced bacterial translocation via a decrease in oxidative stress and restoration of the level of tight junction proteins (occludin and ZO-1) in the gut epithelium [ 11 ]. The authors showed that MitoQ alleviates LPS-induced oxidative stress in intestinal epithelial cells, triggering the nuclear translocation of the nuclear factor Nrf2, which, in turn, stimulates the expression of its downstream antioxidant genes [ 11 ].…”

“…Considerable evidence indicates that oxidative stress and mitochondrial dysfunction are common features in the majority of inflammatory states and diseases, acute or chronic [ 9 , 10 , 11 ]. It is generally accepted that excessive generation of reactive oxygen/nitrogen species and mitochondrial injury driven by an uncontrolled inflammatory response play a central role in the genesis of multiple-organ failure observed in sepsis (for review, see [ 12 , 13 , 14 , 15 , 16 ]).…”