Qin Bo-Feng, Gao Shan, Feng Qi-Yuan, Chen Wei, Sun Hai-Ming, Song Jian
College of Pharmacy, Beihua University, Jilin, Jilin Province 132013, China.
College of Pharmacy, Beihua University, Jilin, Jilin Province 132013, China.
Acta Histochem. 2023 Oct;125(7):152079. doi: 10.1016/j.acthis.2023.152079. Epub 2023 Jul 30.
HSCs (hepatic stellate cells) contribute to the excessive extracellular matrix (ECM) deposition plays a key role in the progression of hepatic fibrosis. The present study focused on the hepatoprotective effect of Ginsenoside Rc (Rc), one of the protopanaxadiol type ginsenoside, which has contributed to reverse activated HSCs to improve hepatic fibrosis via regulating Nur77-TLR4/MyD88 signaling pathway. We established the hepatic fibrosis model by intraperitoneal injection of carbon tetrachloride (CCl). And HSCs were stimulated with TGF-β, followed by silencing of Nur77, and then incubated in Rc. Rc significantly alleviated histopathological changes, reduced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Rc could upregulate the Nur77 and downregulate fibrosis markers in the liver of mice, including decreasing the expressions of α-SMA, Collagen-I, the ratio of TIMP-1/MMP-13. Rc significantly increased the expression of Nur77 and suppressed the production of ECM in HSCs. Rc inhibited TLR4 signaling pathway, consequently reversing the inflammatory response, including the production of MyD88, IRAK1, IRAK4 and IL-23. When Nur77 was knocked in TGF-β-stimulated HSCs, TLR4 and α-SMA production were increased. Rc suppressed these activatory effects in Nur77 knockdown HSCs. Rc reduced inflammatory reaction by regulating the Nur77-TLR4 signaling pathway while suppressing the fibrogenesis suggesting, underscoring a promising approach of Rc for the treatment in hepatic fibrosis. Targeting Nur77-TLR4 signaling in HSCs would be the potential strategy for Rc against hepatic fibrosis.
肝星状细胞（HSCs）在肝纤维化进展过程中，对细胞外基质（ECM）过度沉积起关键作用。本研究聚焦于原人参二醇型人参皂苷之一的人参皂苷Rc（Rc）的肝保护作用，其通过调节Nur77 - TLR4/MyD88信号通路，促使活化的肝星状细胞逆转，从而改善肝纤维化。我们通过腹腔注射四氯化碳（CCl）建立肝纤维化模型。用转化生长因子-β（TGF-β）刺激肝星状细胞，随后沉默Nur77，再用Rc孵育。Rc显著减轻组织病理学变化，降低血清丙氨酸氨基转移酶（ALT）和天冬氨酸氨基转移酶（AST）水平。Rc可上调小鼠肝脏中Nur77的表达，并下调纤维化标志物，包括降低α - SMA、I型胶原、TIMP - 1/MMP - 13的表达。Rc显著增加肝星状细胞中Nur77的表达并抑制细胞外基质的产生。Rc抑制TLR4信号通路，从而逆转炎症反应，包括MyD88、IRAK1、IRAK4和IL - 23的产生。当在TGF-β刺激的肝星状细胞中敲入Nur77时，TLR4和α - SMA的产生增加。Rc在Nur77基因敲低的肝星状细胞中抑制了这些激活作用。Rc通过调节Nur77 - TLR4信号通路减少炎症反应，同时抑制纤维化形成，这表明Rc在治疗肝纤维化方面是一种有前景的方法。靶向肝星状细胞中的Nur77 - TLR4信号通路可能是Rc抗肝纤维化的潜在策略。
