黄芪丹参及其有效成分配伍对动脉粥样硬化模型ApoE-/-小鼠肝脏代谢影响的组学研究

Study of Huangqi(Astragali Radix)-Danshen(Salvia Miltiorrhiza)and Its Effective Components in Atherosclerosis Apo^(E-/-)Mice Based on Liver Metabolism

目的:探究黄芪丹参及其有效成分配伍对ApoE基因敲除(Apo^(E-/-))小鼠动脉粥样硬化(AS)模型肝脏代谢的影响,明确配伍成分抗AS的共同代谢机制。方法:给予Apo^(E-/-)小鼠高脂饮食14 d,建立AS模型,取同周龄C57BL/6Cnc小鼠10只作空白组。AS模型制备成功后随机分为模型组、黄芪甲苷-丹酚酸B组、黄芪-丹参组各10只。黄芪甲苷-丹酚酸B组予黄芪甲苷4 mg/kg+丹酚酸B 25 mg/kg腹腔注射,黄芪-丹参组予黄芪颗粒1.56 g/kg+丹参颗粒0.78 g/kg(折合生品药量)灌胃,空白组和模型组给予等体积生理盐水灌胃,连续给药12周。末次给药后取小鼠肝组织,采用超高效液相色谱-四极杆-飞行时间质谱仪(UHPLC-QTOF-MS)非靶标代谢组学技术对样本中内源性物质进行模式识别、分析、鉴定,筛选回调差异代谢物及其富集的代谢通路,分析黄芪甲苷与丹酚酸B配伍和黄芪丹参配伍之间的共性。结果:干预前后黄芪甲苷-丹酚酸B组和黄芪-丹参组小鼠肝脏代谢轮廓明显分离,琥珀酸和蛋氨酸是两配伍组共同回调差异代谢物,共同富集三羧酸循环,丙氨酸、天冬氨酸和谷氨酸代谢及半胱氨酸和蛋氨酸代谢通路。结论:黄芪甲苷与丹酚酸B配伍和黄芪丹参配伍均可改善AS模型小鼠肝脏代谢紊乱,琥珀酸和蛋氨酸是两配伍组共性发挥的潜在生物标志物,其共同抗AS代谢机制可能是促进体内能量代谢和氨基酸类代谢。

Objective:To investigate the effect of the compatibility of Astragali Radix and Salviae Miltiorrhizae and its effective components on liver metabolism in Apo^(E-/-)mouse model of atherosclerosis (AS),and to clarify the common metabolic mechanism of anti AS between compatibility. Methods:Apo^(E-/-) mice were given a high-fat diet to establish AS model for 14 days. C57BL/6Cnc mice of the same age as blank group. After the model was successfully prepared,10 mice in each group were randomly divided into model group,AstragalosideⅣ-Salvianolic acid B(AsⅣ+ SalB) group,and Aastragali Radixs-Salvia miltiorrhiza(A-S) group. AsⅣ+SalB group was given AsⅣ 4 mg/kg + SalB 25 mg/kg by intraperitoneal injection. A-S group was given Aastragali Radixs granules 1.56 g/kg + Salvia miltiorrhiza granules 0.78 g/kg(equivalent to crude drug quantity) by gavage. The blank group and the model group were given equal volumes of saline by gavage. The administration was continued for 12 weeks. After the administration,the liver tissue was removed,UHPLC-QTOF-MS non-target metabonomics technology was used for pattern recognition,analysis,identification,and screening of the endogenous substances in the liver tissue samples of each group of mice. Screen callback differential metabolites and the enriched metabolic pathways,analyze the compatibility between AsⅣ+SalB and A-S. Results:The liver metabolism profile of the mice in the two compatibility groups was significantly separated before and after the intervention. Succinic acid and methionine were the common callback differential metabolites of AsⅣ+ SalB and A-S group to enrich the tricarboxylic acid cycle,alanine acid,aspartic acid and glutamate metabolism,cysteine and methionine metabolism pathways. Conclusions:The compatibility of AsⅣ+ SalB and A-S can be both to improve the metabolic disorder in AS model mice. Succinic acid and methionine are the potential biomarkers of the two compatibility groups. The common anti-AS mechanism may be promoted energy metabolism and amino acid metabolism in the vivo,the potential pharmacological effects may be related to anti-inflammatory,antioxidant and protection of vascular endothelium.