College of Electronic and Information Engineering, Shandong University of Science and Technology, Qingdao, Shandong Province 266000, China.
Qingdao Jinmotang Biotechnology Co., Ltd, Qingdao, Shandong Province 266000, China.
Phytomedicine. 2024 Jun;128:155502. doi: 10.1016/j.phymed.2024.155502. Epub 2024 Mar 10.
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.
HYPOTHESIS/PURPOSE: We hypothesized that jaceosidin acid (JA) modulates hepatic fibrosis and inflammation.
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.
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.
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.
Jaceosidin (JA) 是一种从青蒿中提取的天然黄酮类化合物，可用作食品和传统草药。据报道，它具有多种生物活性。然而，改善肝纤维化的调节机制尚不清楚。
假说/目的：我们假设 jaceosidin 酸 (JA) 调节肝纤维化和炎症。
使用硫代乙酰胺 (TAA) 建立 HF 小鼠模型。在体外，用 TGF-β诱导小鼠原代肝细胞和 HSC-T6 细胞，用脂多糖 (LPS)/三磷酸腺苷 (ATP) 处理小鼠腹腔巨噬细胞。
JA 降低了 TAA 刺激的 TAA 处理小鼠血清转氨酶水平，并改善了肝组织病理学。此外，JA 下调了与肝星状细胞激活相关的促纤维化生物标志物的表达。同样，JA 下调了 vestigial-like family member 3 (VGLL3)、高迁移率族蛋白 B1 (HMGB1)、Toll 样受体 4 (TLR4) 和核苷酸结合域样受体蛋白 3 (NLRP3) 的表达，从而抑制炎症反应并抑制 TAA 刺激小鼠中成熟-IL-1β 的释放。此外，JA 抑制了 LPS/ATP 刺激的小鼠腹腔巨噬细胞中 HMGB1 的释放和 NLRP3/ASC 炎性小体的激活。JA 降低了与肝星状细胞激活相关的促纤维化生物标志物的表达，并抑制了小鼠原代肝细胞中的炎性小体激活。它还下调了 α-SMA 和 VGLL3 的表达，并抑制了 HSC-T6 细胞中的炎性小体激活。在 TGF-β 刺激的 HSC-T6 细胞中，VGLL3 敲低后 VGLL3 和 α-SMA 的表达水平降低。此外，沉默 Vgll3 的 HSC-T6 细胞中 NLRP3 和裂解的 caspase-1 的表达水平降低。JA 增强了对沉默 Vgll3 的 HSC-T6 细胞的抑制作用。最后，HSC-T6 细胞中 Vgll3 的过表达影响了 α-SMA、NLRP3 和裂解的 caspase-1 的表达水平。
JA 通过抑制纤维化和炎症来有效调节肝纤维化，通过 VGLL3/HMGB1/TLR4 轴。因此，JA 可能是管理肝纤维化的候选治疗药物。了解 JA 的作用机制是肝纤维化治疗的一种新方法。
