Nrf2 signaling and autophagy are complementary in protecting lipopolysaccharide/d-galactosamine-induced acute liver injury by licochalcone A

Abstract

Licochalcone A (Lico A), isolated from Xinjiang licorice Glycyrrhiza inflate, has been shown to have antioxidative potential via the activation of nuclear factor-erythroid 2-related factor 2 (Nrf2) activation, which is involved in the prevention of acetaminophen-induced hepatotoxicity. The purpose of the current study was to further explore the protective effect of Lico A against lipopolysaccharide/d-galactosamine (LPS/GalN)-induced acute liver injury (ALI) and its underlying molecular mechanisms. Our results found that treatment with Lico A significantly reduced in LPS/GalN-induced hepatotoxicity by lessening lethality, alleviating histopathological liver changes, decreasing the alanine transaminase, and aspartate aminotransferase levels, attenuating the secretion of inflammatory cytokines, and regulating oxidative markers. Furthermore, Lico A efficiently alleviated LPS-induced inflammatory response by inhibiting TLR4-MAPK and -NF-κB, as well as the Txnip-NLRP3 signaling pathway. Meanwhile, Lico A induced the activation of Nrf2 and QSTM1 (P62) signaling and promoted autophagy involved in AMP-activated protein kinase (AMPK)-the transcription factor EB (TFEB) signaling, which may contribute to its hepatoprotective activity. Additional mechanistic investigations to evaluate the dependence of the hepatoprotective role of Lico A on Nrf2 revealed that a lack of Nrf2 promoted Lico A-induced autophagy, which contributed to the hepatoprotective effect of Lico A in Nrf2 −/− mice. In addition, cotreatment with autophagy inhibitor (3-methyladenine, 3-MA) alleviated but did not abrogate the hepatoprotective effect of Lico A, which may be attributed to its ability to activate Nrf2. Our study firstly suggests that Lico A has protective potential against LPS/GalN-induced hepatotoxicity, which may be strongly associated with activation of Nrf2 and autophagy.

Bicyclol Attenuates Acute Liver Injury by Activating Autophagy, Anti-Oxidative and Anti-Inflammatory Capabilities in Mice

“…In the CCl 4 + bicyclol 48 h group, the expression level of p-mTOR/mTOR decreased to approximately 43.6% and 72.3% that of the control and CCl 4 exposure group, respectively. The MAPK, including the c-Jun NH2-terminal kinase (JNK), ERK, and p38, has been considered the main signaling pathway relevant to acute inflammation, which is also involved in the process of autophagy and anti-oxidant activities (Song et al, 2015;Lv et al, 2019). Our results showed that respective level of p-JNK/JNK protein expression increased 1.7-fold at 48 h, p-ERK/ERK and p-p38/p38 increased 1.7-fold and 1.7-fold at 24 h CCl 4 exposure, but bicyclol treatment effectively inhibited MAPK phosphorylation, indicating multiple responses and pathways may be responsible for bicyclol-mediated hepatoprotective effect.…”

Cardamonin Reduces Acetaminophen-Induced Acute Liver Injury in Mice via Activating Autophagy and NFE2L2 Signaling

“…*p < 0.05 and **p < 0.01 vs. WT control group; # p < 0.05 and ## p < 0.01 vs. WT APAP group; † p < 0.05 and † † p < 0.01 vs. NFE2L2 −/− control group; § p < 0.05 and § § p < 0.01 vs. NFE2L2 −/− APAP group. permeability, massive neutrophil infiltration, and release of inflammatory mediators (Lv et al, 2019). Our results indicated that APAP significantly increased mortality, serum activities of ALT and AST, and severity of histopathological changes in the liver.…”

Editorial: Autophagy and Related Transcription Factors in Liver and Gut Diseases

“…Fan et al, in their original research article, report on isoorientin-mediated suppression of APAP-induced hepatotoxicity in mice via activation Nrf2 anti-oxidative pathway and the involvement of AMPK/Akt/GSK3b signaling. This hepatoprotective effect of isoorientin could be mediated by autophagy activation, as reported by others (Muhammad et al, 2018;Lv et al, 2019). The last article by Zhang et al conclude that salvianolic acid B inhibits activation of human primary hepatic stellate cells through downregulation of MEF2 (myocyte enhancer factor 2) signaling pathway, resulting in subsequent amelioration of stellate cellmediated hepatic fibrosis.…”