Zhang Jin-Jin, Zhang Jia-Xin, Feng Qi-Yuan, Shi Li-Qiang, Guo Xin, Sun Hai-Ming, Song Jian
College of Pharmacy, Beihua University, Jilin, Jilin Province, 132013, China.
School of Pharmacy and Medicine, Tonghua Normal University, Tonghua, Jilin Province, 134001, China.
J Ethnopharmacol. 2025 Feb 10;338(Pt 3):119119. doi: 10.1016/j.jep.2024.119119. Epub 2024 Nov 16.
Citri Reticulatae Pericarpium (Chenpi) is a traditional Chinese medicine and recorded to have hepatoprotective therapeutic and condition value. Eriocitrin (ER) a natural compound isolated from Citri Reticulatae Pericarpium may ameliorate hepatic inflammation in chronic liver diseases.
The current study investigates the hepatoprotective effect and potential mechanism of ER against hepatic fibrosis.
The hepatic fibrosis mouse model was constructed by intraperitoneally injecting thioacetamide (TAA) for five weeks. Hepatic stellate cells (HSCs) were treated with transforming growth factor-β (TGF-β). Meanwhile, lipopolysaccharide/adenosine triphosphate (LPS/ATP) was given to excite the normal mouse bone marrow-derived macrophages (BMDMs), and thus the cells could acquire the conditioned medium. Moreover, LX-2 cells were administrated with PPARα knockdown vector (siRNA-PPARα).
RNA sequencing studies revealed that in mice induced by TAA, the PPARα/NOD-like receptor/neutrophil extracellular traps (NETs) significantly influence ER-based hepatic protection. In TAA-induced mice, ER could up-regulate PPARα and down-regulate NLRP1/NLRC4 and the development of NETs. Our findings indicated that ER significantly up-regulated PPARα, inhibited NLRP1/NLRC4 inflammasome in HSCs. Deficiency of PPARα in the activated LX-2 weakened the regulatory effect of ER on inhibiting the NLRP1/NLRC4 inflammasome. In addition, ER might hinder the activation of BMDMs and also obstruct IL-1β and IL-6 passage in the extracellular space.
The results indicated that ER decreased inflammation by controlling the PPARα-NLRP1/NLRC4 signaling pathway and inhibiting fibril formation. Collectively, our results underscore the therapeutic potential of ER in addressing hepatic fibrosis.
陈皮是一种传统中药，有记载称其具有肝脏保护治疗价值。从陈皮中分离出的天然化合物橙皮苷可能改善慢性肝病中的肝脏炎症。
本研究旨在探讨橙皮苷对肝纤维化的肝脏保护作用及潜在机制。
通过腹腔注射硫代乙酰胺（TAA）五周构建肝纤维化小鼠模型。用转化生长因子-β（TGF-β）处理肝星状细胞（HSCs）。同时，给予脂多糖/三磷酸腺苷（LPS/ATP）刺激正常小鼠骨髓来源的巨噬细胞（BMDMs），从而获得条件培养基。此外，用PPARα敲低载体（siRNA-PPARα）处理LX-2细胞。
RNA测序研究表明，在TAA诱导的小鼠中，PPARα/核苷酸结合寡聚化结构域样受体/中性粒细胞胞外陷阱（NETs）显著影响基于橙皮苷的肝脏保护作用。在TAA诱导的小鼠中，橙皮苷可上调PPARα并下调NLRP1/NLRC4以及NETs的形成。我们的研究结果表明，橙皮苷显著上调PPARα，抑制HSCs中的NLRP1/NLRC4炎性小体。活化的LX-2中PPARα的缺乏削弱了橙皮苷对抑制NLRP1/NLRC4炎性小体的调节作用。此外，橙皮苷可能会阻碍BMDMs的活化，也会阻碍细胞外空间中白细胞介素-1β和白细胞介素-6的传递。
结果表明，橙皮苷通过控制PPARα-NLRP1/NLRC4信号通路并抑制纤维形成来减轻炎症。总体而言，我们的结果强调了橙皮苷在治疗肝纤维化方面的治疗潜力。
