Isoliquiritigenin alleviates LPS/ D-GalN-induced acute liver failure by activating the PGC-1α/ Nrf2 pathway to reduce oxidative stress and inflammatory response

[Display omitted] •ISL has a protective effect on LPS/D-GalN-induced acute liver failure.•ISL regulates the expression of genes involved in ROS production, inflammatory response and hepatocyte apoptosis.•ISL regulated the expression of PGC-1α, Nrf2, and the targeted-genes to improve the ability of a...

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Published inInternational immunopharmacology Vol. 100; p. 108159
Main Authors Wang, Lu, Wang, Xiaohui, Kong, Lina, Wang, Shuyuan, Huang, Kai, Wu, Jingjing, Wang, Changyuan, Sun, Huijun, Liu, Kexin, Meng, Qiang
Format Journal Article
LanguageEnglish
Published Netherlands Elsevier B.V 01.11.2021
Elsevier BV
Subjects
ALT
MDA
MPO
LPS
GSH
AST
ISL
H&E
SOD
ROS
Bax
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Summary:[Display omitted] •ISL has a protective effect on LPS/D-GalN-induced acute liver failure.•ISL regulates the expression of genes involved in ROS production, inflammatory response and hepatocyte apoptosis.•ISL regulated the expression of PGC-1α, Nrf2, and the targeted-genes to improve the ability of anti-oxidative stress and inhibit NLRP3 inflammasome.•ISL protects against acute liver failure through PGC-1α/Nrf2 axis dose-dependently in vivo and in vitro. Acute liver failure (ALF) is a dramatic liver disease characterized by large areas of inflammation. However, there are no available effective targeted drugs for ALF treatment. In the study, serum biochemical index and H&E were used to explore the amelioration of the liver histopathological changes. The oxidative stress kits, quantitative real-time PCR, western blot, immunohistochemistry, immunofluorescence staining, reactive oxygen species (ROS), and siRNA were used to elucidate the mechanisms underlying isoliquiritigenin (ISL) protection. The results showed that ISL significantly improved the liver pathological changes. Furthermore, ISL reduced oxidative stress by altering the expression of PGC-1α, Nrf2, HO-1, NQO1, Keap1, GCLC, and GCLM in damaged hepatocytes. Moreover, the levels of inflammation-related genes including NLRP3 inflammasome, IL-1β, IL-6, TNF-α, iNOS, and Mip-2 were repressed by ISL. In addition, ISL alleviated LPS/D-GalN-induced hepatocytes apoptosis by increasing the Bcl-2/Bax ratio and suppressing the expression of cleaved caspase-3. Further in vivo and in vitro evidence proved the involvement of the PGC-1α/Nrf2 signaling pathway in ISL protection. In conclusion, ISL improves the ability of anti-oxidative stress, alleviates inflammatory reaction, apoptosis, and inhibits NLRP3 inflammasome to protect lipopolysaccharide/D-galactosamine (LPS/D-GalN)-induced ALF through activating the PGC-1α/Nrf2 pathway, which provides the possibility for the treatment of ALF.
ISSN:1567-5769
1878-1705
DOI:10.1016/j.intimp.2021.108159