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雷公藤甲素(triptolide,TP)是从植物雷公藤中分离得到的活性最高的二萜内酯类化合物。它具有抗炎、免疫调节、抗肿瘤等多种药理活性,目前在国内外被广泛研究与应用。然而,雷公藤甲素的肝脏毒性,限制了它的临床应用。为探讨Notch1信号通路对雷公藤甲素所致肝细胞毒性的保护作用及其相关机制,减轻雷公藤甲素肝脏毒性提供理论依据。研究表明,雷公藤甲素可以导致张氏肝细胞(Chang liver cell)的氧化应激水平及细胞凋亡水平增加,同时明显抑制Notch1信号通路的激活。此外,通过外源性给予Notch1配体Jagged1激活Notch1信号通路,可以保护雷公藤甲素诱导的氧化应激损伤及细胞凋亡损伤,在这个过程中,Nrf2及其下游靶点HO-1的表达水平增加。而通过给予DAPT或siRNA干扰Notch1抑制Notch1信号通路,则加重雷公藤甲素的细胞毒性,同时抑制Nrf2信号通路的激活。进一步的研究表明,siRNA干扰Nrf2可以部分消除Jagged1对雷公藤甲素所致肝细胞毒性的保护作用。以上实验结果表明,激活Notch1信号通路可以保护雷公藤甲素诱导的肝细胞氧化应激损伤及细胞凋亡损伤,而Nrf2是发挥该保护作用的重要下游靶点。
Triptolide (TP) is the most active diterpene lactone isolated from the plant Tripterygium wilfordii. It has anti-inflammatory, immunomodulatory, anti-tumor and other pharmacological activity, is widely studied and applied at home and abroad. However, the hepatic toxicity of triptolide limits its clinical utility. To investigate the protective effect of Notch1 signal pathway on the cytotoxicity of triptolide-induced hepatotoxicity and its related mechanisms, and to provide a theoretical basis for alleviating the hepatic toxicity of triptolide. Studies have shown that triptolide can cause Chang liver cell oxidative stress and apoptosis levels increased, while significantly inhibiting Notch1 signaling pathway activation. In addition, extrinsic Notch1 ligand Jagged1 activates Notch1 signaling pathway to protect against triptolide-induced oxidative stress injury and apoptosis. In this process, the expression of Nrf2 and its downstream target HO-1 Increase in level. However, the inhibition of Notch1 signaling by interfering Notch1 with DAPT or siRNA increased the cytotoxicity of triptolide and inhibited the activation of Nrf2 signaling pathway. Further studies showed that siRNA interference with Nrf2 partially blocked the protective effect of Jagged1 on the cytotoxicity induced by triptolide. The above experimental results show that activation of Notch1 signaling pathway can protect triptolide-induced oxidative stress injury and apoptosis of hepatocytes, and Nrf2 is an important downstream target of this protection.