中国中药杂志

2021, v.46(20) 5320-5329

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基于肝脏代谢组学研究“瓜蒌-薤白”对ApoE~(-/-)小鼠动脉粥样硬化的影响
Study on effect of "Trichosanthis Fructus-Allii Macrostemonis Bulbus" on atherosclerosis in ApoE~(-/-) mice based on liver metabonomics

徐鹏博;丁立丹;仇静文;钟华;吴欢;周安;吴鸿飞;戴敏;
XU Peng-bo;DING Li-dan;QIU Jing-wen;ZHONG Hua;WU Huan;ZHOU An;WU Hong-fei;DAI Min;Anhui Province Key Laboratory of Research & Development of Chinese Medicine, Department of Pharmacy, Anhui University of Chinese Medicine;

摘要(Abstract):

采用超高效液相色谱-四极杆飞行时间质谱(UPLC-Q-TOF-MS)技术,研究"瓜蒌-薤白"药对对载脂蛋白E基因敲除(ApoE~(-/-))小鼠动脉粥样硬化(AS)肝脏内源性代谢物代谢紊乱的调控机制。利用高脂饮食建立小鼠AS模型,观察小鼠组织病理学变化,检测小鼠体质量、肝重以及肝脏中血脂水平和炎性因子等病理生化指标的含量,采用UPLC-Q-TOF-MS技术对小鼠肝脏样品进行代谢轮廓分析,结合偏最小二乘判别分析(PLS-DA)与正交偏最小二乘判别分析(OPLS-DA)等方法,筛选差异代谢物并进行鉴别,检测代谢通路上相关代谢酶LCAT、sPLA2、EPT1、ACER1的水平进行验证。结果显示,"瓜蒌-薤白"药对显著减少AS小鼠主动脉斑块及肝脏脂肪空泡面积,减轻肝脏脂滴积累;可降低AS小鼠肝脏系数,调控肝脏血脂水平并改善肝脏的炎性损伤;空白组、模型组以及给药组的代谢物能够显著区分,发现并初步鉴定了15种与AS相关的潜在生物标志物,"瓜蒌-薤白"药对能显著回调其中的7种,代谢通路分析筛选出2条与"瓜蒌-薤白"药对调节AS小鼠肝脏代谢紊乱相关的代谢途径,"瓜蒌-薤白"药对调控代谢途径中关键酶LCAT、sPLA2、EPT1、ACER1水平,推测"瓜蒌-薤白"药对可干预AS小鼠肝脏甘油磷脂及鞘脂代谢紊乱从而抑制AS疾病,其调控机制可能与其干预肝脏代谢途径关键酶LCAT、sPLA2、EPT1、ACER1的表达有关。
In this study, ultra-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry(UPLC-Q-TOF-MS)-based liver metabolomics approach was used to explore the mechanism of "Trichosanthis Fructus-Allii Macrostemonis Bulbus" in improving atherosclerosis(AS) of mice with apolipoprotein E gene knockout(ApoE~(-/-)). AS mouse model was induced by high-fat diet. The pathological and biochemical indexes such as the histopathological changes, body weight, liver weight, blood lipid level and inflammatory factors in the liver of mice were determined. The metabolic profiling of mice liver samples was performed with UPLC-Q-TOF-MS. Multiple statistical analysis methods including partial least squares discriminant analysis(PLS-DA) and orthogonal partial least squares discriminant analysis(OPLS-DA) were employed to screen and identify biomarkers. The levels of related enzymes including LCAT, sPLA2, EPT1 and ACER1 were detected. The results showed that "Trichosanthis Fructus-Allii Macrostemonis Bulbus" significantly reduced the areas of aortic plaque and fat vacuoles of liver in AS mice and decreased the accumulation of lipid droplets and liver coefficient. "Trichosanthis Fructus-Allii Macrostemonis Bulbus" also regulated the levels of blood lipid and inflammatory injury in the liver. The metabolites of the control group, the model group and the "Trichosanthis Fructus-Allii Macrostemonis Bulbus" group could be distinguished significantly. Fifteen potential biomarkers related to AS were discovered and preliminarily identified, seven of which could be regulated by "Trichosanthis Fructus-Allii Macrostemonis Bulbus" in a trend of returning to normal. Metabolic pathway analysis screened out two major metabolic pathways. "Trichosanthis Fructus-Allii Macrostemonis Bulbus" obviously regulated the levels of LCAT, sPLA2, EPT1 and ACER1. It was inferred that "Trichosanthis Fructus-Allii Macrostemonis Bulbus" could play a major role in AS treatment by regulating glycerophospholipid and sphingolipid metabolism disorders in the liver, with the mechanism probably relating to the intervention of the expression of LCAT, sPLA2, EPT1 and ACER1.

关键词(KeyWords): “瓜蒌-薤白”药对;ApoE~(-/-)小鼠;动脉粥样硬化;肝脏;代谢组学
"Trichosanthis Fructus-Allii Macrostemonis Bulbus" drug pari;ApoE~(-/-) mice;atherosclerosis;liver;metabolomics

Abstract:

Keywords:

基金项目(Foundation): 国家自然科学基金项目(81873038);; 安徽中医药大学科技创新基金项目(2020ZC10)

作者(Author): 徐鹏博;丁立丹;仇静文;钟华;吴欢;周安;吴鸿飞;戴敏;
XU Peng-bo;DING Li-dan;QIU Jing-wen;ZHONG Hua;WU Huan;ZHOU An;WU Hong-fei;DAI Min;Anhui Province Key Laboratory of Research & Development of Chinese Medicine, Department of Pharmacy, Anhui University of Chinese Medicine;

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