Cui Xiaoyan, Zhang Ronghua, Li Yufeng, Li Ping, Liu Yankun, Yu Xiaohan, Zhou Jing, Wang Luyao, Tian Xuetao, Li Hongjie, Zhang Shukun, Lan Tao, Li Xin, Zhang Guangling, Li Jingwu, Liu Zhiyong
Hebei Provincial Key Laboratory for Chronic Diseases, School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, 063210, China.
The Cancer Institute, Hebei Key Laboratory of Molecular Oncology, Tangshan People's Hospital, Tangshan, 063001, China.
J Ethnopharmacol. 2025 Jan 30;337(Pt 2):118910. doi: 10.1016/j.jep.2024.118910. Epub 2024 Oct 5.
As a compound of traditional Chinese medicine (TCM), Bie Jia Jian pill (BJJP) is extensively used to treat the clinical chronic liver disease. Nevertheless, the specific mechanism through which BJJP affects hepatic fibrosis (HF) remains unknown.
To explore the role and potential mechanism of BJJP involved in treating HF.
HF model of Sprague-Dawley (SD) rats was induced by a bile duct ligation (BDL). The function of BJJP involved in the intestinal microbiota (IM) and its metabolites in BDL-induced HF rats were explored through the 16S rRNA sequencing and untargeted metabolomics technologies. Network pharmacology was used to forecast mechanism underlying BJJP's anti-HF effects, which were validated in BDL-induced rats and trimethylamine N-oxide (TMAO)-induced LX-2 and HSC-T6 cells.
BJJP effectively ameliorated pathological liver damage, inflammation, and fibrosis of the BDL-induced HF rats. BJJP regulated IM diversity and composition and interfered with trimethylamine (TMA)-flavin monooxygenase 3 (FMO3)-TMAO process. In vitro, BJJP significantly inhibited the TMAO-induced activation of hepatic stellate cells (HSCs) (rat HSC cell line, HSC-T6; human HSC cell line, LX-2). Network pharmacology results demonstrated that PI3K/AKT signal pathway is crucially involved in BJJP treatment of HF. Further research revealed that BJJP inhibited the PI3K/AKT signal pathway in BDL-induced HF rats. Moreover, TMAO activated the PI3K/AKT pathway, whereas BJJP suppressed TMAO-induced activation. Subsequent intervention with 740Y-P (the PI3K agonist) successfully neutralized the repression effect on PI3K/AKT signal pathway by BJJP.
These results clearly show that BJJP attenuates HF by regulating the IM, as well as inhibiting PI3K/AKT pathway mediated by TMAO.
鳖甲煎丸（BJJP）作为一种中药复方，被广泛用于治疗临床慢性肝病。然而，BJJP影响肝纤维化（HF）的具体机制尚不清楚。
探讨BJJP在治疗HF中的作用及潜在机制。
通过胆管结扎（BDL）诱导Sprague-Dawley（SD）大鼠建立HF模型。采用16S rRNA测序和非靶向代谢组学技术，探讨BJJP对BDL诱导的HF大鼠肠道微生物群（IM）及其代谢产物的作用。运用网络药理学预测BJJP抗HF作用的潜在机制，并在BDL诱导的大鼠以及三甲胺N-氧化物（TMAO）诱导的LX-2和HSC-T-6细胞中进行验证。
BJJP有效改善了BDL诱导的HF大鼠的肝脏病理损伤、炎症和纤维化。BJJP调节了IM的多样性和组成，并干扰了三甲胺（TMA）-黄素单加氧酶3（FMO3）-TMAO代谢过程。在体外，BJJP显著抑制了TMAO诱导的肝星状细胞（HSCs）（大鼠HSC细胞系，HSC-T-6；人HSC细胞系，LX-2）的激活。网络药理学结果表明，PI3K/AKT信号通路在BJJP治疗HF中起关键作用。进一步研究发现，BJJP抑制了BDL诱导的HF大鼠中的PI3K/AKT信号通路。此外，TMAO激活了PI3K/AKT通路，而BJJP抑制了TMAO诱导的激活。随后用740Y-P（PI3K激动剂）进行干预，成功抵消了BJJP对PI3K/AKT信号通路的抑制作用。
这些结果清楚地表明，BJJP通过调节IM以及抑制TMAO介导的PI3K/AKT通路来减轻HF。
