School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China.
School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China; Medical School, Zhejiang University City College, Hangzhou, 310015, China.
J Ethnopharmacol. 2022 Oct 28;297:115535. doi: 10.1016/j.jep.2022.115535. Epub 2022 Jul 12.
Astragaloside IV, a glycoside derived from Astragalus membranaceus, has anti-renal fibrosis effects. However, its mechanism of action has not yet been fully elucidated.
The purpose of this study was to investigate the anti-fibrotic effect of AS-IV and to clarify its underlying mechanism.
The network pharmacology method, molecular docking and surface plasmon resonance (SPR) was used to identify potential targets and pathways of AS-IV. A unilateral ischemia-reperfusion injury (UIRI) animal model, as well as TGF-β1-induced rat renal tubular epithelial cells (NRK-52E) and renal fibroblasts (NRK-49F) were used to investigate and validate the anti-fibrotic activity and pharmacological mechanism of AS-IV. Network pharmacology was performed to construct a drug-target-pathway network. The anti-fibrosis effect of AS-IV was determined using hematoxylin-eosin (H&E) and MASSON staining, as well as immunostaining methods. qRT-PCR and western blotting were used to elucidate and validate the mechanism of AS-IV.
Network pharmacology revealed that the PI3K/AKT pathway is an important pathway in AS-IV. AS-IV inhibited the expression of α-SMA, collagen I, and fibronectin in NRK-52E, NRK-49F, and UIRI rats, and reduced serum creatinine and blood urea nitrogen levels in UIRI rats. AS-IV inhibited AKT phosphorylation, blocked GSK-3β phosphorylation, and restored GSK-3β activity, which contributed to the degradation of β-catenin, thereby preventing epithelial-mesenchymal transition (EMT).
Astragaloside IV alleviated renal fibrosis through the AKT1/GSK-3β pathway. In addition, our findings indicate that the network pharmacology method is a powerful tool for exploring the pharmacological mechanisms of drugs.
黄芪甲苷（IV）是从黄芪中提取的一种糖苷，具有抗肾纤维化作用。然而，其作用机制尚未完全阐明。
本研究旨在探讨 AS-IV 的抗纤维化作用，并阐明其潜在的作用机制。
采用网络药理学方法、分子对接和表面等离子体共振（SPR）技术，鉴定 AS-IV 的潜在靶点和通路。采用单侧缺血再灌注损伤（UIRI）动物模型以及 TGF-β1 诱导的大鼠肾小管上皮细胞（NRK-52E）和肾成纤维细胞（NRK-49F），研究和验证 AS-IV 的抗纤维化活性和药理学机制。构建药物-靶点-通路网络进行网络药理学分析。采用苏木精-伊红（H&E）和 Masson 染色以及免疫染色方法测定 AS-IV 的抗纤维化作用。采用 qRT-PCR 和 Western blot 技术阐明和验证 AS-IV 的作用机制。
网络药理学显示，PI3K/AKT 通路是 AS-IV 的重要通路。AS-IV 抑制 NRK-52E、NRK-49F 和 UIRI 大鼠中 α-SMA、胶原 I 和纤连蛋白的表达，并降低 UIRI 大鼠血清肌酐和血尿素氮水平。AS-IV 抑制 AKT 磷酸化，阻断 GSK-3β磷酸化，恢复 GSK-3β活性，促进β-catenin 降解，从而防止上皮间质转化（EMT）。
黄芪甲苷通过 AKT1/GSK-3β 通路缓解肾纤维化。此外，我们的研究结果表明，网络药理学方法是探索药物药理学机制的有力工具。
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