Department of Pharmacology, School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China.
Guangzhou Key Laboratory of Construction and Application of New Drug Screening Model Systems, Guangdong Pharmaceutical University, Guangzhou 510006, China.
Molecules. 2018 Dec 29;24(1):110. doi: 10.3390/molecules24010110.
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.
对乙酰氨基酚（APAP）过量诱导的急性肝损伤主要是由于氧化应激的过度增加。核因子-红细胞 2 相关因子 2（Nrf2）在减轻 APAP 肝毒性方面起着重要作用。紫草素（SHK）在多种正常细胞系中增强 Nrf2。然而，SHK 是否能保护肝脏免受 APAP 诱导的毒性仍然不清楚。本研究发现 SHK 能抵抗 APAP 诱导的肝毒性，并逆转血清丙氨酸/天冬氨酸转氨酶（ALT/AST）、肝髓过氧化物酶（MPO）活性和活性氧（ROS）的水平，同时增强 APAP 处理小鼠的肝脏谷胱甘肽（GSH）水平。SHK 挽救了细胞活力并减少 GSH 耗竭，但中和了 APAP 处理的人正常肝 L-02 细胞中的氧化应激。从机制上讲，SHK 在蛋白水平上而非在 mRNA 水平上增加了 APAP 暴露时的 Nrf2 表达。抑制 Nrf2 阻断了 SHK 在 APAP 处理的肝细胞中的作用。此外，SHK 通过刺激 PI3K/Akt 通路来改善 Nrf2 的稳定性，从而抑制 GSK-3β。体内研究证实了 SHK 对 APAP 的肝脏保护作用与 Akt/GSK-3β/Nrf2 通路密切相关。总之，本研究表明 SHK 通过 PI3K/Akt/GSK-3β 通路上调 Nrf2 来防止 APAP 肝毒性。因此，SHK 可能是一种有前途的治疗 APAP 诱导的肝损伤的候选药物。
