Department of Pharmacology, Guangxi Medical University, Nanning, 530021, China.
Department of Pharmacology, Guangxi Medical University, Nanning, 530021, China.
Biomed Pharmacother. 2019 Jul;115:108901. doi: 10.1016/j.biopha.2019.108901. Epub 2019 May 9.
An ingredient was isolated from Acanthus ilicifolius and identified as 4-hydroxy-2(3H)-benzoxazolone (HBOA). Its protective effects and underlying mechanism on liver fibrosis were investigated. Briefly, rats were intragastrically administrated with 50% CCl twice a week for 12 weeks to induce liver fibrosis. Meanwhile, the animals were treated with various medicines from weeks 8 to 12. Then the histological change, serum biochemical index, inflammatory factors and hepatocyte apoptosis were detected. Moreover, the TGF-β1/Smads, NF-κB and ERK signaling pathways were also detected to illustrate the underlying mechanism. The results showed that HBOA significantly ameliorated CCl-induced liver injury and collagen accumulation in rats, as evidenced by the histopathologic improvement. Moreover, HBOA markedly decreased hepatocyte apoptosis by regulating the expression levels of caspase-3, -9 and -12, as well as the Bcl-2 family. The mechanism study showed that HBOA significantly decreased the expressions of α-smooth muscle actin (α-SMA) and collagen and inhibited the generation of excessive extracellular matrix (ECM) components by restoring the balance between matrix metalloproteinases (MMPs) and its inhibitor (TIMPs). HBOA markedly alleviated oxidative stress and inflammatory cytokines through inhibiting the NF-κB pathway. In addition, HBOA significantly down-regulated the levels of TGF-β1, Smad2/3, Smad4 and up-regulated the level of Smad7, inhibiting the TGF-β1/Smads signaling pathway. Moreover, HBOA significantly blocked the ERK signaling pathway, leading to the inactivation of hepatic stellate cells. This study suggests that HBOA exerts a protective effect against liver fibrosis via modulating the TGF-β1/Smads, NF-κB and ERK signaling pathways, which will be developed as a potential agent for the treatment of liver fibrosis.
从獐牙菜中分离得到一种成分，鉴定为 4-羟基-2(3H)-苯并恶唑酮（HBOA）。研究了其对肝纤维化的保护作用及其作用机制。简而言之，大鼠每周两次经胃内给予 50% CCl 诱导肝纤维化 12 周。同时，从第 8 周到第 12 周，动物接受各种药物治疗。然后检测组织学变化、血清生化指标、炎症因子和肝细胞凋亡。此外，还检测了 TGF-β1/Smads、NF-κB 和 ERK 信号通路，以阐明其作用机制。结果表明，HBOA 可显著改善 CCl 诱导的大鼠肝损伤和胶原堆积，组织病理学改善证实了这一点。此外，HBOA 通过调节 caspase-3、-9 和 -12 以及 Bcl-2 家族的表达水平，显著减少肝细胞凋亡。机制研究表明，HBOA 通过恢复基质金属蛋白酶（MMPs）及其抑制剂（TIMPs）之间的平衡，显著降低α-平滑肌肌动蛋白（α-SMA）和胶原的表达，抑制细胞外基质（ECM）成分的过度产生。HBOA 通过抑制 NF-κB 通路显著减轻氧化应激和炎症细胞因子。此外，HBOA 还显著下调 TGF-β1、Smad2/3、Smad4 的水平，上调 Smad7 的水平，抑制 TGF-β1/Smads 信号通路。此外，HBOA 还显著阻断 ERK 信号通路，导致肝星状细胞失活。本研究表明，HBOA 通过调节 TGF-β1/Smads、NF-κB 和 ERK 信号通路，对肝纤维化发挥保护作用，有望开发为治疗肝纤维化的潜在药物。
