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Archive > Volume 16 Issue 1 > 2024,16(1):82-93. DOI:https://doi.org/10.1016/j.chmed.2023.07.003 Prev Next

川芎提取物通過靶向CTCF-c-MYC-H19通路緩解肝纖維化

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Chuanxiong Rhizoma extracts prevent liver fibrosis via targeting CTCF-c-MYC-H19 pathway

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    摘要:
    目的:肝纖維化被認(rèn)為是所有慢性肝病的共同后果。川芎是一種預(yù)防腦血管、婦科和肝臟疾病的傳統(tǒng)中草藥。我們前期研究發(fā)現(xiàn)，川芎提取物顯著降低肝星狀細(xì)胞的膠原收縮力。本研究旨在比較不同川芎提取物對(duì)膽管結(jié)扎誘導(dǎo)的肝纖維化小鼠的保護(hù)作用，并探討其可能的潛在機(jī)制。 方法:采用高效液相色譜法對(duì)川芎提取物的有效成分進(jìn)行鑒定。采用網(wǎng)絡(luò)藥理學(xué)方法確定川芎抗肝纖維化的潛在靶點(diǎn)。通過血生化檢查和組織病理學(xué)評(píng)估膽管增生和肝纖維化。通過實(shí)時(shí)熒光定量PCR和蛋白免疫印跡法檢測(cè)目標(biāo)基因和蛋白的表達(dá)水平。 結(jié)果:基于網(wǎng)絡(luò)藥理學(xué)分析，通過鏈接川芎與肝纖維化的候選靶點(diǎn)，得到42個(gè)重疊靶點(diǎn)。在膽管結(jié)扎誘導(dǎo)的小鼠模型中，川芎的不同提取物如生物堿和苯酞類提取物通過降低CCCTC結(jié)合因子(CTCF)-c-MYC-長(zhǎng)非編碼RNA H19 (H19)通路，顯著抑制膽管增生和肝纖維化。同時(shí)，川芎生物堿和川芎苯酞還能抑制CTCF-c-MYC-H19通路，抑制牛磺膽酸、石膽酸和轉(zhuǎn)化生長(zhǎng)因子β引起的膽管反應(yīng)。 結(jié)論:我們的研究表明川芎不同提取物，特別是川芎生物堿和川芎苯酞可通過抑制CTCF-c-MYC-H19通路顯著抑制膽管細(xì)胞過度增殖肝纖維化，為川芎的抗纖維化機(jī)制研究提供新的見解。

    Abstract:
    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-b), 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.

    關(guān)鍵詞:
    川芎;膽管細(xì)胞;膽管反應(yīng);肝纖維化;長(zhǎng)非編碼RNA H19

    Keywords:


    Project Supported:
    This work was supported by the Beijing Municipal Science & Technology Commission (No. 7212174); the National High-Level Talents Special Support Program to XL; National Key Research and Development Program on Modernization of Traditional Chinese Medicine (No. 2022YFC3502100); National Natural Science Foundation of China (No. 82004045 and No. 82274186).

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