State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Bioactive Natural Product Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Bioactive Natural Product Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
Phytomedicine. 2020 Nov;78:153294. doi: 10.1016/j.phymed.2020.153294. Epub 2020 Jul 28.
BACKGROUND: Hepatic fibrosis is considered integral to the progression of chronic liver diseases, as it leads to the development of cirrhosis and hepatocellular carcinoma. The activation of hepatic stellate cells (HSCs) is the dominant event in hepatic fibrogenesis. The transforming growth factor-β1 (TGF-β1) and Yes-associated protein (YAP) pathways play a pivotal role in HSC activation, hepatic fibrosis and cirrhosis progression. Therefore, targeting the TGF-β/Smad and YAP signaling pathways is a promising strategy for antifibrotic therapy. PURPOSE: The present study investigated the protective effects of Physalin D (PD), a withanolide isolated from Physalis species (Solanaceae), against liver fibrosis and further elucidated the mechanisms involved in vitro and in vivo. STUDY DESIGN/METHODS: We conducted a series of experiments using carbon tetrachloride (CCl)- and bile duct ligation (BDL)-induced fibrotic mice and cultured LX-2 cells. Serum markers of liver injury, and the morphology, histology and fibrosis of liver tissue were investigated. Western blot assays and quantitative real-time PCR were used to investigate the mechanisms underlying the antifibrotic effects of PD. RESULT: PD decreased TGF-β1-induced COL1A1 promoter activity. PD inhibited TGF-β1-induced expression of Collagen I and α-smooth muscle actin (α-SMA) in human hepatic stellate LX-2 cells. PD significantly ameliorated hepatic injury, including transaminase activities, histology, collagen deposition and α-SMA, in CCl- or BDL-induced mice. Moreover, PD markedly decreased the expression of phosphorylated Smad2/3 in vitro and in vivo. Furthermore, PD significantly decreased YAP protein levels, and YAP knockdown did not further enhance the effects of PD, namely α-SMA inhibition, Collagen I expression and YAP target gene expression in LX-2 cells. CONCLUSION: These results clearly show that PD ameliorated experimental liver fibrosis by inhibiting the TGF-β/Smad and YAP signaling pathways, indicating that PD has the potential to effectively treat liver fibrosis.
背景：肝纤维化被认为是慢性肝病进展的组成部分，因为它导致肝硬化和肝细胞癌的发展。肝星状细胞（HSCs）的激活是肝纤维化发生的主要事件。转化生长因子-β1（TGF-β1）和 Yes 相关蛋白（YAP）通路在 HSC 激活、肝纤维化和肝硬化进展中发挥关键作用。因此，靶向 TGF-β/Smad 和 YAP 信号通路是抗纤维化治疗的一种有前途的策略。
目的：本研究旨在探讨来自茄科（茄科）黄灯笼属（Physalis）的甾体 Physalin D（PD）对肝纤维化的保护作用，并在体外和体内进一步阐明其相关机制。
研究设计/方法：我们使用四氯化碳（CCl）和胆管结扎（BDL）诱导的纤维化小鼠和培养的 LX-2 细胞进行了一系列实验。检测血清肝损伤标志物，以及肝组织的形态、组织学和纤维化。Western blot 检测和实时定量 PCR 用于研究 PD 抗纤维化作用的机制。
结果：PD 降低 TGF-β1 诱导的 COL1A1 启动子活性。PD 抑制 TGF-β1 诱导的人肝星状细胞 LX-2 细胞中 Collagen I 和α-平滑肌肌动蛋白（α-SMA）的表达。PD 显著改善 CCl 或 BDL 诱导的小鼠肝损伤，包括转氨酶活性、组织学、胶原沉积和α-SMA。此外，PD 显著降低了体外和体内磷酸化 Smad2/3 的表达。此外，PD 显著降低了 YAP 蛋白水平，并且 YAP 敲低不会进一步增强 PD 的作用，即在 LX-2 细胞中抑制α-SMA 抑制、Collagen I 表达和 YAP 靶基因表达。
结论：这些结果清楚地表明，PD 通过抑制 TGF-β/Smad 和 YAP 信号通路改善实验性肝纤维化，表明 PD 具有有效治疗肝纤维化的潜力。
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