Pharmaceutical College, Guangxi Medical University, Nanning, Guangxi, 530021, China.
Pharmaceutical College, Guangxi Medical University, Nanning, Guangxi, 530021, China; National Center for International Research of Bio-targeting Theranostics, Guangxi Medical University, Nanning, Guangxi, 530021, China.
Eur J Pharmacol. 2022 Feb 15;917:174749. doi: 10.1016/j.ejphar.2022.174749. Epub 2022 Jan 7.
Isovitexin (IVT) has been shown to have a potential therapeutic effect on acute liver injury (ALI), but its underlying mechanisms especially the targets remain unclear, which was investigated in the present study. Briefly, the targets of IVT were predicted by bioinformatics and then were verified by multiple examinations using molecular docking, cellular thermal shift assay (CETSA), and Lipopolysaccharide/D-Galactosamine (LPS/D-GalN)-induced ALI animal model. The bioinformatic analysis predicted that the target genes of IVT against ALI were enriched into the PI3K/Akt and ERS-related pathways, in which, molecular docking and CETSA examination verified that the binding sites of IVT likely were PTEN, PI3K and BiP. Furthermore, the possible targets were also verified by animal experiments. The results revealed that IVT significantly ameliorated the hepatic injury, as evidenced by the attenuation of histopathological changes and the reduction in serum aminotransferase and total bilirubin activities. In addition, IVT treatment led to the reduction of PTEN, BiP and ERS-related targets expressions, as well as the elevation of PI3K, Akt and mTOR expressions. Notably, IVT significantly decreased total hepatic m6A level and m6A enrichment of PTEN and BiP, suggesting IVT regulated PTEN and BiP by modulating m6A modification. To sum up, the results indicate that IVT significantly ameliorates ALI, which is attributed to its ability to regulate the PI3K/Akt pathway and ERS by targeting PTEN, PI3K and BiP via modification of m6A. Our finding demonstrates that IVT may be a promising natural medicine for the treatment of ALI.
异荭草苷（IVT）已被证明对急性肝损伤（ALI）具有潜在的治疗作用，但作用机制尤其是靶点仍不清楚，本研究对此进行了探讨。简而言之，采用生物信息学预测 IVT 的靶点，然后通过分子对接、细胞热转移分析（CETSA）和脂多糖/半乳糖胺（LPS/D-GalN）诱导的 ALI 动物模型进行多次验证。生物信息学分析预测，IVT 针对 ALI 的靶基因富集到 PI3K/Akt 和 ERS 相关途径中，其中分子对接和 CETSA 检测证实 IVT 的结合位点可能是 PTEN、PI3K 和 BiP。此外，还通过动物实验验证了可能的靶点。结果表明，IVT 显著改善了肝损伤，表现在组织病理学变化减轻，血清转氨酶和总胆红素活性降低。此外，IVT 治疗导致 PTEN、BiP 和 ERS 相关靶基因表达减少，以及 PI3K、Akt 和 mTOR 表达增加。值得注意的是，IVT 显著降低了总肝 m6A 水平和 PTEN 和 BiP 的 m6A 富集，表明 IVT 通过调节 m6A 修饰来调节 PTEN 和 BiP。总之，研究结果表明，IVT 可显著改善 ALI，这归因于其通过调节 m6A 修饰靶向 PTEN、PI3K 和 BiP 来调节 PI3K/Akt 通路和 ERS 的能力。我们的研究结果表明，IVT 可能是治疗 ALI 的一种有前途的天然药物。
