State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Bioactive Natural Product Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 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, China.
Phytomedicine. 2022 Dec;107:154466. doi: 10.1016/j.phymed.2022.154466. Epub 2022 Sep 20.
Liver fibrosis is a common scarring response and may ultimately lead to liver cancer, unfortunately, there is currently no effective antifibrotic drug approved for human use. Limonoids exhibit a broad spectrum of biological activities; however, the potential role of limonoids against fibrosis is largely unknown.
This study investigates the antifibrotic activities and potential mechanisms of TKF (3-tigloyl-khasenegasin F), a natural mexicanolide-type limonoid derivative.
STUDY DESIGN/METHODS: Two well-established mouse models (CCl challenge and bile duct ligation) were used to assess anti-fibrotic effects of TKF in vivo. Human hepatic stellate cell (HSC) line LX-2 and mouse primary hepatic stellate cells (pHSCs) also served as in vitro liver fibrosis models.
TKF administration significantly attenuated hepatic histopathological injury and collagen accumulation and suppressed fibrogenesis-associated gene expression including Col1a1, Acta2, and Timp1. In LX-2 cells and mouse pHSCs, TKF dose-dependently suppressed HSC activation and the expression levels of fibrogenic markers. Mechanistic studies showed that TKF inhibited Notch3-Hes1 and YAP signalings in vivo and in vitro. Furthermore, YAP inhibition or knockdown downregulated the Notch3 expression; however, Notch3 inhibition or knockdown did not affect the level of YAP in activated HSC. We revealed that TKF inhibited Notch3-Hes1 activation and downregulated hepatic fibrogenic gene expression via inhibiting YAP.
The therapeutic benefit of TKF against liver fibrosis results from inhibition of YAP and Notch3-Hes1 pathways, indicating that TKF may be a novel therapeutic candidate for liver fibrosis.
肝纤维化是一种常见的瘢痕反应，最终可能导致肝癌，但目前尚无有效的抗纤维化药物被批准用于人类。柠檬苦素类化合物表现出广泛的生物活性；然而，柠檬苦素类化合物在抗纤维化方面的潜在作用在很大程度上是未知的。
本研究旨在探讨天然墨西哥醇型柠檬苦素衍生物 TKF（3- 二氢糠基-4-甲氧基-6-氧代-7-色满酮）的抗纤维化活性及其潜在机制。
研究设计/方法：采用两种成熟的小鼠模型（CCl4 刺激和胆管结扎）体内评估 TKF 的抗纤维化作用。人肝星状细胞（LX-2）系和小鼠原代肝星状细胞（pHSCs）也被用作体外肝纤维化模型。
TKF 给药显著减轻肝组织学损伤和胶原积累，并抑制纤维化相关基因表达，包括 Col1a1、Acta2 和 Timp1。在 LX-2 细胞和小鼠 pHSCs 中，TKF 呈剂量依赖性抑制 HSC 激活和纤维化标志物的表达水平。机制研究表明，TKF 在体内和体外抑制 Notch3-Hes1 和 YAP 信号通路。此外，YAP 抑制或敲低下调 Notch3 表达；然而，Notch3 抑制或敲低并不影响激活的 HSC 中 YAP 的水平。我们揭示 TKF 通过抑制 YAP 抑制 Notch3-Hes1 激活和下调肝纤维化基因表达。
TKF 治疗肝纤维化的益处源于抑制 YAP 和 Notch3-Hes1 通路，表明 TKF 可能是肝纤维化的一种新型治疗候选药物。
