Yang Yunheng, Liu Yi, Cheng Yujie, He Honglin, Liang Ailing, Pan Zheng, Liu Yuanyuan, Chen Zhiwei
Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing, 400016, China.
Department of Radiological Medicine, School of Basic Medical Sciences, Chongqing Medical University, Chongqing, 400016, China.
J Transl Med. 2024 Dec 23;22(1):1138. doi: 10.1186/s12967-024-05955-5.
Scutellaria baicalensis Georgi, a traditional Chinese herb, is known for its various biological effects, including antibacterial, anti-inflammatory, antioxidative, and antitumor properties. However, the function and mechanisms of methanol extract of Scutellaria baicalensis Georgi (MESB) in treating hepatic fibrosis remain unclear.
This study utilized a CCl4-induced mouse model of hepatic fibrosis to assess the effects of MESB through histopathological analysis and serum tests. The anti-fibrosis mechanism of MESB was investigated using qPCR, Western blotting, RNA interference, proteomics, and metabolomics. Spatial metabolomics identified key components of MESB in liver tissue, while molecular docking determined their targets.
Treatment with MESB alleviated hepatic pathological changes and reversed hepatic fibrosis in the CCl4-induced models, as evidenced by decreased collagen fibers deposition, reduced expression of hepatic fibrosis markers COL1A1, FN, and PAI-1, and lowered serum levels of AST and ALT. In vitro, MESB inhibited the proliferation of LX-2 cells and the expression of hepatic fibrosis markers. Furthermore, MESB intervention modulated various pathways, particularly those involved in metabolic pathways. Subsequent metabolomics analysis demonstrated that MESB disrupted glycerophospholipid metabolism and suppressed arachidonic acid metabolism. MESB downregulated the expression of cPLA2 in LX-2 cells, leading to decreased production of arachidonic acid and its downstream inflammatory mediators. Meanwhile, MESB inhibited the expression of cPLA2 and its downstream NF-κB pathway in the liver tissues of models induced by CCl4. Additionally, silencing cPLA2 markedly reduced the expressions of COL1A1, FN, and PAI-1. Spatial metabolomics analysis confirmed the penetration of baicalein, wogonin and wogonoside into liver tissue. Further results indicated that baicalein and wogonin inhibited the expression of cPLA2, while baicalin and wogonoside do not exhibit this effect. Moreover, molecular docking suggested that baicalein and wogonin possess the potential to directly interact with cPLA2.
This study reveals that MESB is crucial in preventing hepatic fibrosis via the cPLA2-mediated arachidonic acid metabolic pathway, highlighting its key active components as potential drugs for fibrosis treatment.
黄芩是一种传统的中草药，以其多种生物学效应而闻名，包括抗菌、抗炎、抗氧化和抗肿瘤特性。然而，黄芩甲醇提取物（MESB）在治疗肝纤维化中的作用和机制仍不清楚。
本研究利用四氯化碳诱导的小鼠肝纤维化模型，通过组织病理学分析和血清检测来评估MESB的作用。采用qPCR、蛋白质印迹、RNA干扰、蛋白质组学和代谢组学研究MESB的抗纤维化机制。空间代谢组学确定了MESB在肝组织中的关键成分，而分子对接确定了它们的靶点。
在四氯化碳诱导的模型中，MESB治疗减轻了肝脏病理变化并逆转了肝纤维化，表现为胶原纤维沉积减少、肝纤维化标志物COL1A1、FN和PAI-1的表达降低，以及血清AST和ALT水平降低。在体外，MESB抑制LX-2细胞的增殖和肝纤维化标志物的表达。此外，MESB干预调节了各种途径，特别是那些参与代谢途径的途径。随后的代谢组学分析表明，MESB破坏了甘油磷脂代谢并抑制了花生四烯酸代谢。MESB下调了LX-2细胞中cPLA2的表达，导致花生四烯酸及其下游炎症介质的产生减少。同时，MESB抑制了四氯化碳诱导模型肝组织中cPLA2及其下游NF-κB途径的表达。此外，沉默cPLA2显著降低了COL1A1、FN和PAI-1的表达。空间代谢组学分析证实了黄芩素、汉黄芩素和汉黄芩苷渗透到肝组织中。进一步的结果表明，黄芩素和汉黄芩素抑制cPLA2的表达，而黄芩苷和汉黄芩苷没有这种作用。此外，分子对接表明黄芩素和汉黄芩素具有直接与cPLA2相互作用的潜力。
本研究表明，MESB通过cPLA2介导的花生四烯酸代谢途径在预防肝纤维化中起关键作用，突出了其关键活性成分作为纤维化治疗潜在药物的地位。
