甜菜碱对实验性顺铂性肝损伤的改善作用；miRNA-34a 对 SIRT1/PGC-1α 信号通路的新影响,Journal of Biochemical and Molecular Toxicology

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甜菜碱对实验性顺铂性肝损伤的改善作用；miRNA-34a 对 SIRT1/PGC-1α 信号通路的新影响
Journal of Biochemical and Molecular Toxicology ( IF 3.2 ) Pub Date : 2021-03-04 , DOI: 10.1002/jbt.22753
Ismail El Shaffei ₁ , Ghada A Abdel-Latif ₂ , Doaa B Farag ₃ , Mona Schaalan ₄ , Rania M Salama ₂

Affiliation

抗癌剂顺铂 (CIS) 与激活氧化应激和炎症通路相关的肝毒性作用有关。CIS 诱导的氧化性 DNA 损伤降低了沉默调节蛋白 1 (SIRT1) 的活性，进而调节过氧化物酶体增殖物激活受体-γ 共激活因子 1-α (PGC-1α) 的活性。此外，microRNA-34a (miRNA-34a) 被证明会阻碍 SIRT1 和核因子红细胞 2 相关因子 2 (Nrf2) 的活性。因此，靶向这种途径可以减轻 CIS 诱导的肝毒性。Betanin (BET) 是一种从甜菜中提取的天然红色糖苷食用染料，据报道具有抗氧化功能。然而，其在 CIS 引起的肝损伤中的作用及其分子机制尚未完全阐明。因此，本研究的目的是通过 SIRT1/PGC-1α 信号通路研究 BET 对 CIS 诱导的急性肝毒性的改善作用，并说明 miRNA-34a 的影响。七十二只大鼠被分成六个相等的组：（1）对照，（2）BET，（3）CIS，（4）CIS/BET，（5）CIS/EX527，和（6）CIS/BET/EX527。BAX 和 BCL2 水平失调、AMP 活化蛋白激酶和 PGC-1α 表达水平降低以及 SIRT1 活性降低都证明了 CIS 诱导的肝损伤。因此，观察到 Nrf2 水平降低以及相关血红素加氧酶-1 和谷氨酸-半胱氨酸连接酶修饰亚基的表达。有趣的是，BET 通过降低 miRNA-34a 的表达和增强 SIRT1/PGC-1α 通路，成功地减轻了 CIS 引起的肝损伤。这些发现与分子对接结果和组织病理学图片一致。总之，目前的研究提供了 BET 通过调节 miRNA-34a 表达和 SIRT1/PGC-1α 信号级联对 CIS 诱导的肝损伤改善作用的新发现。

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Ameliorative effect of betanin on experimental cisplatin-induced liver injury; the novel impact of miRNA-34a on the SIRT1/PGC-1α signaling pathway

The anticancer agent, cisplatin (CIS), is associated with hepatotoxic effects related to activation of oxidative stress and inflammation pathways. CIS-induced oxidative DNA damage reduces sirtuin 1 (SIRT1) activity, which in turn, modulates the activity of peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α). Moreover, microRNA-34a (miRNA-34a) was shown to hinder both SIRT1 and nuclear factor erythroid 2-related factor 2 (Nrf2) activity. Thus, targeting such a pathway can alleviate CIS-induced hepatotoxicity. Betanin (BET) is a natural red glycoside food dye obtained from beets, which is reported to exhibit antioxidant function. However, its role in CIS-induced liver injury and the molecular mechanism has not been fully elucidated. Thus, the aim of this study was to investigate the ameliorative effect of BET on CIS-induced acute hepatotoxicity through the SIRT1/PGC-1α signaling pathway and illustrate the impact of miRNA-34a. Seventy-two rats were divided into six equal groups: (1) Control, (2) BET, (3) CIS, (4) CIS/BET, (5) CIS/EX527, and (6) CIS/BET/EX527. CIS-induced liver injury was evidenced by deregulated BAX and BCL2 levels, decreased levels of AMP-activated protein kinase and PGC-1α expression, and decreased SIRT1 activity. Consequently, reduced levels of Nrf2 and the expression of associated heme oxygenase-1 and glutamate-cysteine ligase modifier subunit were observed. Intriguingly, BET succeeded in reducing the CIS-induced liver injury through reducing miRNA-34a expression and enhancing the SIRT1/PGC-1α pathway. These findings coincide with the molecular docking results and the histopathological picture. In conclusion, the current research provided novel findings of the BET ameliorative effect on CIS-induced liver injury through modulating miRNA-34a expression and the SIRT1/PGC-1α signaling cascade.

更新日期：2021-03-04

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