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Eur J Pharmacol:棘苷(SPI)通过靶向Nur77/ASK1/p38 MAPK信号通路抑制活化的肝星状细胞,减轻肝纤维化

2023-12-17 紫菀款冬 MedSci原创 发表于上海

肝纤维化是包括慢性病毒性肝炎、非酒精性脂肪性肝炎(NASH)、胆汁淤积性肝炎和肝硬化在内的各种慢性肝病的共同过程,主要是由肝细胞损伤引发的,随后是持续的炎症反应和细胞外基质(ECM)的过度产生。

背景:肝纤维化是包括慢性病毒性肝炎、非酒精性脂肪性肝炎(NASH)、胆汁淤积性肝炎和肝硬化在内的各种慢性肝病的共同过程,主要是由肝细胞损伤引发的,随后是持续的炎症反应细胞外基质(ECM)的过度产生肝纤维化是可逆和可治愈的,然而如果不及时治疗,它可能会发展为不可逆的肝硬化,并最终发展为肝细胞癌(HCC)。不幸的是,目前临床上尚无有效的方法来阻断肝纤维化的进展,这在世界范围内仍然是一个巨大的挑战。

棘苷(SPI)是一种主要从中药酸枣中分离得到的天然类黄酮c -糖苷。SPI已被证明对慢性炎症、神经系统疾病和癌症等具有抗炎、抗心肌纤维化等多种药理活性。SPI被证明可以通过抑制TGF-β1/Smad信号来减轻糖尿病心肌纤维化。

该研究旨在探索SPI是否可以成为治疗肝纤维化的潜在先导,并探索核孤儿受体Nur77(肝纤维化发展的负调节因子)是否在SPI的作用中起关键作用。

方法:建立α-SMA双荧光素酶报告系统,评价SPI对LX2和HSC-T6细胞肝星状细胞(HSC)活化的影响。采用CCl4诱导的小鼠肝纤维化模型,检测SPI抗肝纤维化的作用。采用Western blotting和qPCR检测Nur77、炎性细胞因子和胶原蛋白的表达水平。还分析了可能涉及的激酶途径。荧光滴定法证实了Nur77与SPI的亲和力。

结果:SPI能强烈抑制TGF-β1介导的LX2和HSC-T6细胞的活化,且呈剂量依赖性。SPI增加Nur77的表达,降低TGF-β1介导的ASK1和p38 MAPK的磷酸化水平,这可以通过敲除Nur77来逆转。SPI强烈抑制胶原沉积(COLA1),降低炎症因子(IL-6和IL-1β),随后改善CCl4诱导小鼠模型的肝功能。SPI可以直接与Nur77-LBD口袋中的R515和R563结合,Kd值为2.14 μM。

结论:SPI是酸枣的主要药理活性成分,该研究首次证明了SPI可以有效阻碍肝纤维化的进展,改善肝功能。在机制上,SPI可以直接与Nur77-LBD结合,通过ASK1/p38 MAPK信号级联抑制促炎和促纤维化反应。这些发现表明SPI可能是制定肝纤维化治疗新候选药物的潜在先导。

原始出处:

Lin G, Hong WB, Desheng Z, et al. Spinosin inhibits activated hepatic stellate cell to attenuate liver fibrosis by targeting Nur77/ASK1/p38 MAPK signaling pathway. Eur J Pharmacol. Published online December 12, 2023. doi:10.1016/j.ejphar.2023.176270

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    2023-12-17 1dea4a7em68(暂无匿称) 来自福建省

    谢谢分享

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    2023-12-17 jshbyywk2008 来自河北省

    肝纤维化是包括慢性病毒性肝炎、非酒精性脂肪性肝炎(NASH)、胆汁淤积性肝炎和肝硬化在内的各种慢性肝病的共同过程

    0

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    2023-12-17 屋顶瞄爱赏月 来自贵州省

    签到学习

    0

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