Fan Xiaoye, Wei Wei, Huang Jingbo, Peng Liping, Ci Xinxin
Institute of Translational Medicine, The First Hospital, Jilin University, Changchun, China.
Department of Urology, The First Hospital of Jilin University, Changchun, China.
Front Pharmacol. 2020 Dec 8;11:579178. doi: 10.3389/fphar.2020.579178. eCollection 2020.
Cisplatin (CDDP) is a widely used drug for cancer treatment that exhibits major side effects in normal tissues, such as nephrotoxicity in kidneys. The Nrf2 signaling pathway, a regulator of mitochondrial dysfunction, oxidative stress and inflammation, is a potential therapeutic target in CDDP-induced nephrotoxicity. We explored the underlying mechanisms in wild-type (WT) and Nrf2 mice on CDDP-induced renal dysfunction . We found that Nrf2 deficiency aggravated CDDP-induced nephrotoxicity, and Daph treatment significantly ameliorated the renal injury characterized by biochemical markers in WT mice and reduced the CDDP-induced cell damage. In terms of the mechanism, Daph upregulated the SIRT1 and SIRT6 expression and . Furthermore, Daph inhibited the expression level of NOX4, whereas it activated Nrf2 translocation and antioxidant enzymes HO-1 and NQO1, and alleviated oxidative stress and mitochondrial dysfunction. Moreover, Daph suppressed CDDP-induced NF-κB and MAPK inflammation pathways, as well as p53 and cleaved caspase-3 apoptosis pathways. Notably, the protective effects of Daph in WT mice were completely abrogated in Nrf2 mice. Moreover, Daph enhanced, rather than attenuated, the tumoricidal effect of CDDP.
顺铂（CDDP）是一种广泛用于癌症治疗的药物，在正常组织中会产生主要副作用，如肾脏中的肾毒性。Nrf2信号通路是线粒体功能障碍、氧化应激和炎症的调节因子，是顺铂诱导的肾毒性的潜在治疗靶点。我们探讨了野生型（WT）和Nrf2基因敲除小鼠中顺铂诱导的肾功能障碍的潜在机制。我们发现，Nrf2基因缺失加剧了顺铂诱导的肾毒性，而瑞香素（Daph）治疗显著改善了以生化指标为特征的肾损伤，减少了顺铂诱导的细胞损伤。在机制方面，瑞香素上调了SIRT1和SIRT6的表达。此外，瑞香素抑制了NOX4的表达水平，同时激活了Nrf2易位以及抗氧化酶HO-1和NQO1，并减轻了氧化应激和线粒体功能障碍。此外，瑞香素抑制了顺铂诱导的NF-κB和MAPK炎症通路，以及p53和裂解的caspase-3凋亡通路。值得注意的是，瑞香素在WT小鼠中的保护作用在Nrf2基因敲除小鼠中完全消失。此外，瑞香素增强而非减弱了顺铂的杀肿瘤作用。
