Xanthohumol protect against acetaminophen-induced hepatotoxicity via Nrf2 activation through the AMPK/Akt/GSK3β pathway.

Acetaminophen (APAP) is one of the world's popular and safe painkillers, and overdose can cause severe liver damage and even acute liver failure. The effect and mechanism of the xanthohumol on acetaminophen-induced hepatotoxicity remains unclear. The hepatoprotective effects of xanthohumol were studied using APAP-induced HepG2 cells and acute liver injury of mouse, seperately. In vitro, xanthohumol inhibited H2O2- and acetaminophen-induced cytotoxicity and oxidative stress. Xanthohumol up-regulated the expression of Nrf2. Further mechanistic studies showed that xanthohumol triggered Nrf2 activation via the AMPK/Akt/GSK3β pathway to exert a cytoprotective effect. In vivo, xanthohumol significantly ameliorated acetaminophen-induced mortality, the elevation of ALT and AST, GSH depletion, MDA formation and histopathological changes. Xanthohumol effectively suppressed the phosphorylation and mitochondrial translocation of JNK, mitochondrial translocation of Bax, the activation o cytochrome c, AIF secretion and Caspase-3. In vivo, xanthohumol increased Nrf2 nuclear transcription and AMPK, Akt and GSK3β phosphorylation in vivo. In addition, whether xanthohumol protected against acetaminophen-induced liver injury in Nrf2 knockout mice has not been illustated. Thus, xanthohumol exerted a hepatoprotective effect by inhibiting oxidative stress and mitochondrial dysfunction through the AMPK/Akt/GSK3β/Nrf2 antioxidant pathway.

Zhu L ，Fan X ，Cao C ，Li K ，Hou W ，Ci X ... -  《-》

Pterostilbene Reduces Acetaminophen-Induced Liver Injury by Activating the Nrf2 Antioxidative Defense System via the AMPK/Akt/GSK3β Pathway.

Pterostilbene (Pts), a natural dimethylated analog of resveratrol from blueberries, exerts antioxidative and anti-apoptotic effects in various diseases. This study aims to investigate the protective effects and mechanism of Pts against acetaminophen (APAP)-induced hepatotoxicity in vivo. C57BL/6 mice were treated with APAP or APAP+Pts. HepG2 cells were used to further explore the underlying mechanisms in vitro. The effects of Pts on hepatotoxicity were measured by commercial kits, Hematoxylin and Eosin (H&E) straining, TUNEL assay, Western blot analysis, and Flow cytometry assay. In vivo, Pts treatment effectively protected against APAP-induced severe liver injury by decreasing the lethality rate, the serum alanine transaminase (ALT) and aspartate aminotransferase (AST) levels, liver histological injury, liver malondialdehyde (MDA) formation and myeloperoxidase (MPO) levels and by increasing liver glutathione (GSH) and superoxide dismutase (SOD) levels. Moreover, in Pts-treated mice, the nuclear factor-erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway was activated; however, APAP-induced c-Jun NH2-terminal kinase (JNK) activation, mitochondrial Bcl-2 Associated X Protein (Bax) translocation, apoptosis-inducing factor (AIF) levels and cytochrome c release were attenuated. In vitro, Pts was found to reverse hydrogen peroxide (H2O2) -induced cytotoxicity, reactive oxygen species (ROS) production and apoptosis that depended on Nrf2 activation. Moreover, Pts induced a dose-dependent increase in the phosphorylation of AMP-activated protein kinase (AMPK), serine/threonine kinase (Akt), and glycogen synthase kinase 3β (GSK3β) in HepG2 cells. Moreover, Pts protect against APAP or H2O2-induced toxicity were effectively attenuated or abolished in HepG2 Nrf2-/- cells and Nrf2-/- mice. Our data suggest that Pts protects against APAP-induced toxicity by activating Nrf2 via the AMPK/Akt/GSK3β pathway.

Fan X ，Wang L ，Huang J ，Lv H ，Deng X ，Ci X ... -  《-》

Nrf2-mediated liver protection by esculentoside A against acetaminophen toxicity through the AMPK/Akt/GSK3β pathway.

Acetaminophen (APAP) overdose accounts for the majority of acute liver failure cases, and oxidative stress plays a key role in its toxic effects. Esculentoside A (EsA) has anti-oxidant activities, but its therapeutic potential for APAP hepatotoxicity remains unknown. This study aimed to assess the protective effects and mechanism of EsA against APAP-induced hepatotoxicity in vitro and in vivo. In vitro, EsA treatment inhibited APAP- or H2O2-induced cytotoxicity, H2O2 and O2- production, glutathione (GSH) depletion and apoptosis dependent on nuclear factor erythroid-2-related factor 2 (Nrf2) activation in HepG2 cells. Moreover, EsA significantly increased the phosphorylation of AMP-activated protein kinase (AMPK) and serine/threonine kinase (Akt), as well as glycogen synthase kinase 3 beta (GSK-3β) inhibitory phosphorylation at Ser9. Furthermore, an AMPK inhibitor (compound c) abolished the effects of EsA on AKT phosphorylation, GSK-3β inactivation, Nrf2 nuclear translocation and cytoprotection. With regard to APAP-induced acute liver injury, EsA attenuated the APAP-stimulated increases in the serum ALT and AST levels, as well as centrilobular necrosis and GSH depletion in the mice. In addition, it decreased the GSSG level, GSSG-to-GSH ratio, and the phosphorylation and mitochondrial translocation of c-Jun N-terminal kinase (JNK). Further, the protective potential of EsA against mitochondrial dysfunction was exhibited not only by inhibiting Bax mitochondrial translocation and the release of mitochondrial inter-membrane proteins, such as apoptosis-inducing factor (AIF), but also by activating Nrf2/HO-1. Collectively, our findings suggest that EsA has protective potential against APAP toxicity by potentiating the Nrf2-regulated survival mechanism through the AMPK/Akt/GSK3β pathway.

Wang L ，Zhang S ，Cheng H ，Lv H ，Cheng G ，Ci X ... -  《-》

Corilagin alleviates acetaminophen-induced hepatotoxicity via enhancing the AMPK/GSK3β-Nrf2 signaling pathway.

Lv H ，Hong L ，Tian Y ，Yin C ，Zhu C ，Feng H ... -  《Cell Communication and Signaling》

Shikonin Attenuates Acetaminophen-Induced Hepatotoxicity by Upregulation of Nrf2 through Akt/GSK3β Signaling.

Li H ，Chen Y ，Zhang J ，Chen X ，Li Z ，Liu B ，Zhang L ... -  《MOLECULES》