川芎提取物通过靶向 CTCF-c-MYC-H19 通路预防肝纤维化

IF 4.7 4区 医学 Q1 CHEMISTRY, MEDICINAL
Yajing Li , Fanghong Li , Mingning Ding , Zhi Ma , Shuo Li , Jiaorong Qu , Xiaojiaoyang Li
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引用次数: 0

摘要

目的肝纤维化被广泛认为是几乎所有慢性肝病的并发症。川芎是预防脑血管、妇科和肝脏疾病的传统中药。我们之前的研究发现,川芎提取物能显著降低肝星状细胞(HSCs)的胶原收缩力。本研究旨在比较不同的 CX 提取物对胆管结扎(BDL)诱导的肝纤维化的保护作用,并探讨其可能的内在机制。利用网络药理学确定了 CX 抗肝纤维化的潜在靶点。通过血清学检测和组织病理学评估来评价胆管增生和肝纤维化。结果通过四甲基吡嗪、阿魏酸和森久内酯 A 鉴别了不同的 CX 提取物。根据网络药理学分析,通过合并 CX 和肝纤维化的候选靶点,得到了 42 个重叠靶点。在 BDL 诱导的小鼠模型中,不同的 CX 水提取物、生物碱提取物和邻苯二甲酸酯提取物(CXAE、CXAL 和 CXPHL)能显著抑制弥漫性重度胆管增生,从而通过降低 CCCTC 结合因子(CTCF)-c-MYC-长非编码 RNA H19(H19)通路抑制肝纤维化。同时,CX 提取物,尤其是 CXAL 和 CXPHL 还能抑制 CTCF-c-MYC-H19 通路,并抑制胆管细胞在牛磺胆酸盐(TCA)、石胆酸盐(LCA)和转化生长因子 beta(TGF-β)刺激下的导管反应,胆管增殖标志物的减少也说明了这一点。结论我们的数据支持不同的 CX 提取物,尤其是 CXAL 和 CXPHL,通过抑制 CTCF-c-MYC-H19 通路显著缓解肝纤维化和胆管增生,为 CX 的抗纤维化机制提供了新的见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Chuanxiong Rhizoma extracts prevent liver fibrosis via targeting CTCF-c-MYC-H19 pathway

Objective

Hepatic fibrosis has been widely considered as a conjoint consequence of almost all chronic liver diseases. Chuanxiong Rhizoma (Chuanxiong in Chinese, CX) is a traditional Chinese herbal product to prevent cerebrovascular, gynecologic and hepatic diseases. Our previous study found that CX extracts significantly reduced collagen contraction force of hepatic stellate cells (HSCs). Here, this study aimed to compare the protection of different CX extracts on bile duct ligation (BDL)-induced liver fibrosis and investigate plausible underlying mechanisms.

Methods

The active compounds of CX extracts were identified by high performance liquid chromatography (HPLC). Network pharmacology was used to determine potential targets of CX against hepatic fibrosis. Bile duct hyperplasia and liver fibrosis were evaluated by serologic testing and histopathological evaluation. The expression of targets of interest was determined by quantitative real-time PCR (qPCR) and Western blot.

Results

Different CX extracts were identified by tetramethylpyrazine, ferulic acid and senkyunolide A. Based on the network pharmacological analysis, 42 overlap targets were obtained via merging the candidates targets of CX and liver fibrosis. Different aqueous, alkaloid and phthalide extracts of CX (CXAE, CXAL and CXPHL) significantly inhibited diffuse severe bile duct hyperplasia and thus suppressed hepatic fibrosis by decreasing CCCTC binding factor (CTCF)-c-MYC-long non-coding RNA H19 (H19) pathway in the BDL-induced mouse model. Meanwhile, CX extracts, especially CXAL and CXPHL also suppressed CTCF-c-MYC-H19 pathway and inhibited ductular reaction in cholangiocytes stimulated with taurocholate acid (TCA), lithocholic acid (LCA) and transforming growth factor beta (TGF-β), as illustrated by decreased bile duct proliferation markers.

Conclusion

Our data supported that different CX extracts, especially CXAL and CXPHL significantly alleviated hepatic fibrosis and bile duct hyperplasia via inhibiting CTCF-c-MYC-H19 pathway, providing novel insights into the anti-fibrotic mechanism of CX.

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来源期刊
Chinese Herbal Medicines
Chinese Herbal Medicines CHEMISTRY, MEDICINAL-
CiteScore
4.40
自引率
5.30%
发文量
629
审稿时长
10 weeks
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