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

Abstract

Acetaminophen (APAP) overdose-induced acute liver damage is mostly due to overwhelmingly increased oxidative stress. Nuclear factor-erythroid 2-related factor2 (Nrf2) plays an important role in alleviating APAP hepatic toxicity. Shikonin (SHK) enhances Nrf2 in multiple lines of normal cells. Nevertheless, whether SHK protects against APAP-induced liver toxicity remains undefined. This study found SHK defended APAP-induced liver toxicity, as well as reversed the levels of serum alanine/aspartate aminotransferases (ALT/AST), liver myeloperoxidase (MPO) activity, and reactive oxygen species (ROS), while it enhanced the liver glutathione (GSH) level in APAP-treated mice. SHK rescued the cell viability and GSH depletion, but neutralized oxidative stress in APAP-treated human normal liver L-02 cells. Mechanically, SHK increased Nrf2 expression in the exposure of APAP at the protein level but not at the mRNA level. Inhibition of Nrf2 blocked the SHK effect in APAP-treated hepatocytes. Furthermore, SHK improved Nrf2 stability through stimulating PI3K/Akt pathway, thus inhibiting GSK-3β. In vivo studies confirmed the close correlation of liver protection of SHK against APAP and Akt/GSK-3β/Nrf2 pathway. In conclusion, this study reveals that SHK prevents APAP hepatotoxicity by upregulation of Nrf2 via PI3K/Akt/GSK-3β pathway. Therefore, SHK may be a promising candidate against APAP-induced liver injury.

Baicalin ameliorates neuroinflammation-induced depressive-like behavior through inhibition of toll-like receptor 4 expression via the PI3K/AKT/FoxO1 pathway

“…Recently, Zhang et al discovered that baicalin exerts neuroprotective effects via inhibiting the activation of GSK3β in a rat model of depression [71]. There is evidence suggesting that glycogen synthase kinase-3 (GSK3) β is a downstream molecule of PI3K/AKT [72], and the activation of PI3K/AKT results in the increase of p-GSK3β and then inhibits the activation of GSK3β. We also investigated this molecular mechanism in CUMS mice as described in Fig.…”

Ginsenoside Rb1 alleviates liver injury induced by 3‐chloro‐1,2‐propanediol by stimulating autophagic flux

“…In recent years, phytochemicals have been found to alleviate acute liver injury through a variety of pathways, including Nrf2 signaling pathway (Li et al., 2018b; Reisman et al., 2009), IL‐1β and IL‐6 inflammatory signaling pathway (Liu et al., 2019), and JNK signaling pathway. Recent studies by Zhao et al.…”

“…In recent years, phytochemicals have been found to alleviate acute liver injury through a variety of pathways, including Nrf2 signaling pathway (Li et al, 2018b;Reisman et al, 2009), IL-1β and IL-6 inflammatory signaling pathway (Liu et al, 2019), and JNK signaling pathway. Recent studies by Zhao et al (2020) showed that inhibiting of JNK activation is an effective way to prevent TNF-α and ROSinduced hepatocyte apoptosis, and the natural compound NOB could alleviate Con-A induced hepatocyte apoptosis by inhibiting JNK activation.…”

Roles of Cofactors in Drug-Induced Liver Injury: Drug Metabolism and Beyond

“…On the other hand, Nrf2 inhibitors undermine ADS and potentiate DILI. In mice co-treated with APAP and brusatol, a Nrf2 inhibitor, more serious liver injury together with a lower GSH level and a higher ROS level were observed when compared to that of APAP alone group (Chan et al, 2001;Li et al, 2019).…”