背景:Jaceosidin(JA)是从蒿属中提取的天然黄酮,用作食品和传统药草。据报道它具有许多生物活性。然而,肝纤维化改善的调节机制尚不清楚.
目的:我们假设黄洋素酸(JA)调节肝纤维化和炎症。
方法:使用硫代乙酰胺(TAA)建立HF小鼠模型。体外,TGF-β诱导小鼠原代肝细胞和HSC-T6细胞,而小鼠腹膜巨噬细胞接受脂多糖(LPS)/ATP治疗。
结果:JA降低了TAA刺激的TAA治疗小鼠的血清转氨酶水平并改善了肝脏组织学病理学。此外,与肝星状细胞活化相关的促纤维化生物标志物的表达被JA下调。同样,JA下调残留样家族成员3(VGLL3)的表达,高迁移率族蛋白B1(HMGB1),toll样受体4(TLR4),和核苷酸结合域-(NOD-)样受体蛋白3(NLRP3),从而在TAA刺激的小鼠中抑制炎症反应并抑制成熟IL-1β的释放。此外,JA抑制LPS/ATP刺激的小鼠腹膜巨噬细胞中HMGB1释放和NLRP3/ASC炎性体激活。JA降低与肝星状细胞活化相关的促纤维化生物标志物的表达并抑制小鼠原代肝细胞中的炎性小体活化。它还下调了α-SMA和VGLL3的表达,并抑制了HSC-T6细胞中炎性小体的激活。Vgll3敲低后,TGF-β刺激的HSC-T6细胞中VGLL3和α-SMA表达水平降低。此外,在Vgll3沉默的HSC-T6细胞中,NLRP3和caspase-1的表达水平降低。JA增强了对Vgll3沉默的HSC-T6细胞的抑制作用。最后,Vgll3在HSC-T6细胞中的过表达影响α-SMA的表达水平,NLRP3和裂解的半胱天冬酶-1。
结论:JA通过VGLL3/HMGB1/TLR4轴抑制纤维化发生和炎症,有效调节肝纤维化。因此,JA可能是治疗肝纤维化的候选治疗剂。了解JA的作用机制是肝纤维化治疗的新方法。
BACKGROUND: Jaceosidin (JA) is a natural flavone extracted from Artemisia that is used as a food and traditional medicinal herb. It has been reported to possess numerous biological activities. However, the regulatory mechanisms underlying amelioration of hepatic fibrosis remain unclear.
OBJECTIVE: We hypothesized that jaceosidin acid (JA) modulates hepatic fibrosis and inflammation.
METHODS: Thioacetamide (TAA) was used to establish an HF mouse model. In vitro, mouse primary hepatocytes and HSC-T6 cells were induced by TGF-β, whereas mouse peritoneal macrophages received a treatment lipopolysaccharide (LPS)/ATP.
RESULTS: JA decreased serum transaminase levels and improved hepatic histological pathology in TAA-treated mice stimulated by TAA. Moreover, the expression of pro-fibrogenic biomarkers associated with the activation of liver stellate cells was downregulated by JA. Likewise, JA down-regulated the expression of vestigial-like family member 3 (
VGLL3), high mobility group protein B1 (HMGB1), toll-like receptors 4 (TLR4), and nucleotide-binding domain-(NOD-) like receptor protein 3 (NLRP3), thereby inhibiting the inflammatory response and inhibiting the release of mature-IL-1β in TAA-stimulated mice. Additionally, JA suppressed HMGB1 release and NLRP3/ASC inflammasome activation in LPS/ATP-stimulated murine peritoneal macrophages. JA decreases the expression of pro-fibrogenic biomarkers related to liver stellate cell activation and inhibits inflammasome activation in mouse primary hepatocytes. It also down-regulated α-SMA and
VGLL3 expressions and also suppressed inflammasome activation in HSC-T6 cells.
VGLL3 and α-SMA expression levels were decreased in TGF-β-stimulated HSC-T6 cells following
Vgll3 knockdown. In addition, the expression levels of NLRP3 and cleaved-caspase-1 were decreased in
Vgll3-silenced HSC-T6 cells. JA enhanced the inhibitory effects on
Vgll3-silenced HSC-T6 cells. Finally, Vgll3 overexpression in HSC-T6 cells affected the expression levels of α-SMA, NLRP3, and cleaved-caspase-1.
CONCLUSIONS: JA effectively modulates hepatic fibrosis by suppressing fibrogenesis and inflammation via the VGLL3/HMGB1/TLR4 axis. Therefore, JA may be a candidate therapeutic agent for the management of hepatic fibrosis. Understanding the mechanism of action of JA is a novel approach to hepatic fibrosis therapy.