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.
Highlights
Drug-induced liver injury (DILI) is a significantly challenging clinical problem all over the world
400 mg/kg APAP successfully induced hepatotoxicity. Pathological changes, such as central necrosis, lymphocytic infiltration, intrahepatic hemorrhagic, and destruction of the liver structure, were observed in the APAP group, which were significantly alleviated in the APAP + 10 ml/kg methane-rich saline (MRS) and APAP + 20 ml/kg MRS groups (Figure 1(a))
A significant reduction was observed in the histopathological score in the APAP + 10 ml/kg MRS and APAP + 20 ml/kg MRS groups in comparison to that of the APAP group (p < 0:05) (Figure 1(e))
Summary
Drug-induced liver injury (DILI) is a significantly challenging clinical problem all over the world. Acetaminophen (APAP) overdose contributes to the incidence of more than half of acute liver failure cases and approximately 30% of mortality which is the most common cause of DILI in the western world [3]. The pathogenesis of DILI has not been fully elaborated yet. Various drugs or their toxic metabolites can directly affect the hepatic cells, they can induce excessive inflammation, oxidative stress, and mitochondrial injury, which amplify the damage through apoptosis or necrosis of hepatocytes [4,5,6,7,8].
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