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Sepsis is a systemic inflammatory response syndrome caused by a dysregulated host response to infection. Peroxisome proliferator-activated receptor gamma (PPAR γ ) exerts anti-inflammatory and antioxidative properties. To investigate the potential effects of PPAR γ on sepsis-induced liver injury and determine the related mechanisms, C57BL/6 male mice were subjected to cecal ligation and puncture (CLP) to create a sepsis model which was treated with GW1929 or GW9662 to upregulate or downregulate the expression of PPAR γ . We found that upregulation of PPAR γ decreased the serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (TBIL), and liver pathological damage and improved the 5-day survival rate. Increased expression of PPAR γ also decreased sepsis-induced reactive oxygen species (ROS) by promoting the expression of Nrf2. In addition, upregulated PPAR γ inhibited the expression of the TXNIP/NLRP3 signaling pathway by reducing ROS-induced injury in the liver during sepsis, which further reduced NLRP3-mediated pyroptosis and the inflammatory response. The role of PPAR γ was further examined in in vitro experiments, where lipopolysaccharide- (LPS-) treated HepG2 and Hep3B cells were incubated with GW1929 or GW9662 to upregulate or downregulate the expression of PPAR γ . We found that upregulated PPAR γ ameliorated LDH release and improved cell viability. Our results indicated that increased expression of PPAR γ reduced ROS levels and inhibited the TXNIP/NLRP3 signaling pathway, resulting in decreased pyroptosis and reduced liver dysfunction during sepsis., Competing Interests: We declare that there is no conflict of interest regarding the publication of this article., (Copyright © 2022 Zeyu Li et al.)

Acetaminophen (APAP) overdose has been considered responsible for the drug-induced liver injury for many years. Ferroptosis is defined as an iron-dependent form of cell death associated with lipid peroxide accumulation. Ferroptosis is involved in APAP-induced acute liver failure, and UTI is an effective drug treatment for acute liver failure. Thus, we aimed to determine whether UTI protects the liver against APAP-induced acute liver failure by decreasing ferroptosis-induced lipid peroxide accumulation. C57BL/6 mice and LO2 cell line were treated with UTI before and after the exposure to APAP. Liver tissues and LO2 cells were collected for biochemical assessment of molecular parameters. APAP-induced upregulation of ferroptotic events (iron content), lipid hydroperoxides (ROS production, MDA, and 4-HNE), and depletion of GSH were effectively relieved by ferrostatin-1 (Fer-1), a ferroptosis inhibitor, and UTI. UTI blocked ferroptosis-induced lipid peroxide accumulation by promoting nuclear translocation of NRF2 to activate its downstream targets (HO-1). An increased expression or knockdown of of SIRT1 influenced the UTI effect on the NRF2 pathway and had an impact on lipid accumulation. Overall, UTI plays a role in mitigation of APAP-induced acute liver injury by inhibiting ferroptosis-induced lipid peroxide accumulation, and the effect of UT1 was mediated by the NRF2/HO-1 pathway and SIRT1 expression., Competing Interests: None., (AJTR Copyright © 2021.)

Cholestatic liver injury, due to obstruction of the biliary tract or genetic defects, is often accompanied by progressive inflammation and liver fibrosis. Methane-rich saline (MRS) has anti-inflammatory properties. However, whether MRS can provide protective effect in cholestatic liver injury is still unclear. In this study, Sprague-Dawley rats received bile duct ligation (BDL) to generate a cholestatic model followed by MRS treatment (10 mL/kg, ip treatment) every 12 h after the operation to explore the potential protective mechanism of MRS in cholestatic liver injury. We found that MRS effectively improved liver function, alleviated liver pathological damage, and localized infiltration of inflammatory cells. MRS treatment decreased the expression of hepatic fibrosis-associated proteins to alleviate liver fibrosis. Furthermore, MRS treatment suppressed the TLR4/NF- κ B pathway and further reduced the levels of proinflammatory factors. Downregulation of NF- κ B subsequently reduced the NLRP3 expression to inhibit pyroptosis. Our data indicated that methane treatment prevented cholestatic liver injury via anti-inflammatory properties that involved the TLR4/NF- κ B/NLRP3 signaling pathway., Competing Interests: We declare that there is no conflict of interest regarding the publication of this article., (Copyright © 2019 Zeyu Li et al.)