基于血浆代谢组学的山茱萸酒制后抗大鼠肝纤维化作用增强机制研究

Mechanism investigation on the enhanced anti-hepatic fibrosis effects in rats of Fructus Corni after wine-processing based on plasma metabonomics

运用代谢组学技术探究和鉴定山茱萸生、制品提取物抗大鼠肝纤维化的作用机制及代谢通路,并比较分析酒蒸山茱萸干预大鼠肝纤维化作用增强的潜在机制。将大鼠随机分为空白对照组、模型组、秋水仙碱组、山茱萸生品低、中、高剂量组以及山茱萸制品低、中、高剂量组,每组6只。皮下注射40%四氯化碳复制肝纤维化模型,造模第3周开始灌胃给药,给药6周后取大鼠血样及肝脏,进行药效指标检测及UHPLC-Q-TOF-MS/MS分析。药效学结果表明,山茱萸生、制品均具有抗大鼠肝纤维化的作用。代谢组学分析显示,与空白对照组相比,模型组经筛选鉴定得到24种与肝纤维化相关的潜在生物标志物,主要参与初级胆汁酸代谢、甘油磷脂代谢、戊糖和葡萄糖醛酸脂代谢、视黄醇代谢、花生四烯酸代谢。山茱萸生、制品水煎液对其中的10种生物标志物有着不同程度的回调作用,且制品作用优于生品。本研究从血浆代谢的角度阐明了山茱萸酒制增效的机制,为山茱萸的进一步开发及临床应用提供理论依据。

Metabonomics technology was employed to investigate and identify the mechanisms and metabolic pathways of the crude and wine-processed Fructus Corni extracts on anti-hepatic fibrosis effects in rats, and to compare and analyze the potential mechanism of enhanced interference of the wine-processed Fructus Corni on hepatic fibrosis effects in rats. The rats were randomly divided into the blank control group, the model group, the colchicine group, the crude Fructus Corni groups with low, medium, and high-doses, and the wine-processed Fructus Corni groups with low, medium, and high-doses, and there were six rats in each group. The hepatic fibrosis model was established by subcutaneous injection of 40% carbon tetrachloride, and the intragastric administration was performed at the third week of modeling. The blood and liver samples of rats were taken and carried out for pharmacodynamic index detection and UHPLC-Q-TOF-MS/MS analysis after intragastric administration for six weeks.The results of pharmacodynamic investigation showed that both the crude and wine-processed Fructus Corni had the effects of anti-hepatic fibrosis in rats. Metabonomics analysis indicated that, compared to the blank control group, the twenty-four potential biomarkers related to hepatic fibrosis were screened and identified in the model group, which mainly involved in primary bile acid metabolism, glycerol phospholipid metabolism, pentose and glucuronide metabolism, retinol metabolism, and arachidonic acid metabolism. The crude and wine-processed Fructus Corni extracts had different degrees of callback effects on the ten of the above potential biomarkers, and the effect of wine-processed Fructus Corni was better than that of crude one. The present study clarifies the mechanism of enhanced efficiency of wine-processed Fructus Corni from the perspective of plasma metabolism, and provides the theoretical foundation for further development and clinical application of Fructus Corni.