College of Pharmacy, Dalian Medical University, Western 9 Lvshunnan Road, Dalian, 116044, China.
College of Pharmacy, Dalian Medical University, Western 9 Lvshunnan Road, Dalian, 116044, China.
Free Radic Biol Med. 2021 Jun;169:99-109. doi: 10.1016/j.freeradbiomed.2021.03.035. Epub 2021 Apr 7.
Dioscin, one natural product, has various pharmacological actions. However, its effects on methotrexate (MTX)-induced hepatorenal damages still remain unknown. In the present study, the data manifested that dioscin restored the viabilities of L-02 and NRK-52E cells, reduced ALT, AST, Cr, BUN levels, and ameliorated histopathological changes of liver and kidney. Besides, dioscin decreased ROS levels in cells, and adjusted SOD, MDA, GSH and GSH-Px levels in rats. Dioscin reduced the expression levels of miR-145-5p which directly targeted Sirt5, and then regulated the expression levels of SOD1, Nrf2, Gst, Keap1, HO-1, GCLC and NQO1. MiR-145-5p mimic in cells deteriorated ROS levels and decreased Sirt5 expression to accentuate oxidative stress by regulating the expression levels of SOD1, Nrf2, Keap1, which were all reversed by dioscin. Moreover, MTX-induced hepatorenal damage were worsened in mice by Sirt5 siRNA or miR-145-5p agomir, which were also alleviated by dioscin. Dioscin relieved MTX-induced hepatorenal damages through regulating miR-145-5p-medicated oxidative stress, which should be considered as one effective drug to treat the disorder in future.
薯蓣皂苷，一种天然产物，具有多种药理作用。然而，其对甲氨蝶呤（MTX）诱导的肝肾功能损害的影响尚不清楚。在本研究中，数据表明薯蓣皂苷恢复了 L-02 和 NRK-52E 细胞的活力，降低了 ALT、AST、Cr 和 BUN 水平，并改善了肝和肾的组织病理学变化。此外，薯蓣皂苷降低了细胞内的 ROS 水平，并调节了大鼠 SOD、MDA、GSH 和 GSH-Px 水平。薯蓣皂苷降低了 miR-145-5p 的表达水平，miR-145-5p 可以直接靶向 Sirt5，然后调节 SOD1、Nrf2、Gst、Keap1、HO-1、GCLC 和 NQO1 的表达水平。细胞内 miR-145-5p 模拟物通过调节 SOD1、Nrf2、Keap1 的表达水平，加重 ROS 水平并降低 Sirt5 表达，从而加重氧化应激，薯蓣皂苷可逆转这一作用。此外，Sirt5 siRNA 或 miR-145-5p 激动剂可加重 MTX 诱导的肝肾功能损害，薯蓣皂苷也可减轻这种损害。薯蓣皂苷通过调节 miR-145-5p 介导的氧化应激缓解 MTX 诱导的肝肾功能损害，有望成为未来治疗该疾病的有效药物之一。
