Key Laboratory for Traditional Chinese Korean Medicine Research (State Ethnic Affairs), College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China.
School of Pharmaceutical Sciences, Josai University, Sakado, Saitama, Japan.
Phytomedicine. 2024 Dec;135:156144. doi: 10.1016/j.phymed.2024.156144. Epub 2024 Oct 9.
Astilbin (ATB), a natural dihydroflavonol compound, exists in many plants, processed and functional foods. ATB has multiple pharmacological effects, such as antioxidant, lipid-lowering, and hepatoprotective. However, its anti-hepatic fibrosis and mechanisms remain unclearly elucidated.
This study explored the effect of ATB against the hepatic fibrosis and its regulation of hepatic microenvironment by regulating hepatic stellate cells-macrophage crosstalk.
Thioacetamide (TAA) was intraperitoneal injected to establish hepatic fibrosis mice, and treated with ATB or curcumin by gavage, respectively. Hepatic stellate cells (HSCs) were stimulated with TGF-β or conditioned medium (CM) from LPS-induced THP-1, then cultured with ATB, PXR agonist or antagonist.
In TAA-induced mice, ATB improved histopathological changes, serum transaminases increase; alleviated extracellular matrix (ECM) deposition, epithelial-mesenchymal transformation (EMT), inflammatory infiltration, PTEN induced kinase 1 (PINK1)/Parkin-mediated mitophagy and activated pregnane X receptor (PXR) expression. In vitro, ATB significantly reduced ECM, inflammatory cytokines release, mitophagy, EMT, and activated PXR expression. ATB could increase PXR and decrease PINK1/Parkin, functioning as a PXR agonist. PXR deficiency in LX-2 could degrade the regulation of ATB on ECM, inflammation, EMT, and mitophagy. CM from LPS-induced THP-1 activated LX-2 and resulted in PXR decreasing, while ATB could regulate the crosstalk between HSCs and macrophages. Deficiency of PXR, whether in LX-2 or in macrophages, all weakened the inhibitory effect of ATB on α-SMA, EMT, inflammatory cytokines, and PINK1/Parkin signaling.
ATB ameliorated hepatic fibrosis by inhibiting HSCs activation, inflammation and EMT through PXR-mediated PINK1/Parkin signaling. Especially, ATB targeted the hepatic microenvironment between hepatic stellate cells and macrophages, which might be a promising strategy for the treatment of hepatic fibrosis.
紫云英苷（ATB）是一种天然二氢黄酮醇化合物，存在于许多植物、加工食品和功能食品中。ATB 具有多种药理作用，如抗氧化、降血脂和保肝。然而，其抗肝纤维化及其机制尚不清楚。
本研究通过调节肝星状细胞-巨噬细胞串扰，探讨 ATB 对肝纤维化的作用及其对肝微环境的调节。
腹腔注射硫代乙酰胺（TAA）建立肝纤维化小鼠模型，分别给予 ATB 或姜黄素灌胃治疗。用 TGF-β或 LPS 诱导的 THP-1 细胞条件培养基（CM）刺激肝星状细胞（HSCs），然后与 ATB、PXR 激动剂或拮抗剂共培养。
在 TAA 诱导的小鼠中，ATB 改善了组织病理学变化，血清转氨酶升高；减轻细胞外基质（ECM）沉积、上皮-间充质转化（EMT）、炎症浸润、PTEN 诱导激酶 1（PINK1）/Parkin 介导的自噬和激活孕烷 X 受体（PXR）表达。在体外，ATB 显著降低 ECM、炎症细胞因子释放、自噬、EMT 和激活的 PXR 表达。ATB 可增加 PXR 并降低 PINK1/Parkin，作为 PXR 激动剂。LX-2 中的 PXR 缺失可降解 ATB 对 ECM、炎症、EMT 和自噬的调节作用。LPS 诱导的 THP-1 的 CM 激活 LX-2 并导致 PXR 减少，而 ATB 可调节 HSCs 和巨噬细胞之间的串扰。无论在 LX-2 还是巨噬细胞中，PXR 的缺失均减弱了 ATB 对 α-SMA、EMT、炎症细胞因子和 PINK1/Parkin 信号的抑制作用。
ATB 通过 PXR 介导的 PINK1/Parkin 信号抑制 HSCs 激活、炎症和 EMT，改善肝纤维化。特别是，ATB 针对肝星状细胞和巨噬细胞之间的肝微环境，可能是治疗肝纤维化的一种有前途的策略。
