Methane Alleviates Acetaminophen-Induced Liver Injury by Inhibiting Inflammation, Oxidative Stress, Endoplasmic Reticulum Stress, and Apoptosis through the Nrf2/HO-1/NQO1 Signaling Pathway

Abstract

Acetaminophen- (APAP-) induced hepatic injury is an important clinical challenge. Oxidative stress, inflammation, apoptosis, and endoplasmic reticulum stress (ERS) contribute to the pathogenesis. Methane has potential anti-inflammatory, antioxidant, and antiapoptotic properties. This project was aimed at studying the protective effects and relative mechanisms of methane in APAP-induced liver injury. In the in vivo experiment, C57BL/6 mice were treated with APAP (400 mg/kg) to induce hepatic injury followed by methane-rich saline (MRS) 10 ml/kg i.p. after 12 and 24 h. We observed that MRS alleviated the histopathological lesions in the liver, decreased serum aminotransferase levels, reduced the levels of inflammatory cytokines, suppressed the nuclear factor-κB expression. Further, we found that MRS relieved oxidative stress by regulating the Nrf2/HO-1/NQO1 signaling pathway and their downstream products after APAP challenge. MRS also regulated proteins associated with ERS-induced apoptosis. In the in vitro experiment, the L-02 cell line was treated with APAP (10 mM) to induce hepatic injury. We found that a methane-rich medium decreased the levels of reactive oxygen species (DHE fluorescent staining), inhibited apoptosis (cell flow test), and regulated the Nrf2/HO-1/NQO1 signaling pathway. Our data indicated that MRS prevented APAP-induced hepatic injury via anti-inflammatory, antioxidant, anti-ERS, and antiapoptotic properties involving the Nrf2/HO-1/NQO1 signaling pathway.

Impressic Acid Attenuates the Lipopolysaccharide-Induced Inflammatory Response by Activating the AMPK/GSK3β/Nrf2 Axis in RAW264.7 Macrophages

“…Nrf2 is a key signaling pathway that protects against inflammation by regulating the expression of antioxidant enzymes, including HO-1 and NOQ1 [ 34 ]. In particular, HO-1 exerts an anti-inflammatory effect by inhibiting NF-κB signaling via the production of carbon monoxide, a metabolite of the heme reaction [ 27 ].…”

Hydrogen: An Endogenous Regulator of Liver Homeostasis

“…However, genetically manipulating the H 2 S-producing enzymes in mammalian cells could not exclude the biological effects of endogenous H 2 S produced by sulphate-reducing bacteria in animals. In addition, CH 4 is another by-product of H 2 metabolism derived from methanogenic bacteria, and Mihaĺy Boros group found that CH 4 can also be produced by rat liver mitochondria, it has hepatic protective effects by exogenous supplement (Ghyczy et al, 2008;Ye et al, 2015;He et al, 2016;Strifler et al, 2016;Yao et al, 2017;Feng et al, 2019;Li et al, 2019a;Li et al, 2019b), however, the hepatic functions of endogenous CH 4 produced by methanogenic bacteria or by hepatocytes are not clear. As that H 2 , H 2 S, and CH 4 are endogenous gas molecules, they may exist as colonic gas mixture and transport into liver by blood circulation or free diffusion, H 2 S and CH 4 can also be produced in liver.…”

1‐O‐Hexyl‐2,3,5‐Trimethylhydroquinone Ameliorates the Development of Preeclampsia through Suppression of Oxidative Stress and Endothelial Cell Apoptosis

“…Dihydroethidium (DHE) staining was preformed to assess the ROS production as described in a previous study [ 27 ]. In addition, placenta tissues and HUVEC concentrations of superoxide dismutase (SOD), catalase (CAT) malondialdehyde (MDA), and glutathione (GSH) were measured using commercially available kits.…”