基于血浆代谢组学和网络药理学研究脑心通胶囊活血化瘀作用机制

基金项目:国家“重大新药创制”科技重大专项（No.2015ZX09501004-001-007）；国家自然科学基金资助项目（No.U1504827，No.82004082）；河南省中医药拔尖人才培养项目（豫中医科教〔2018〕35号）；张怀亮全国名老中医药专家传承工作室建设项目（No.国中医药人教函〔2018〕134号）

作者	单位
李伟霞，李曼曼，牛璐，张书琦，张辉，王晓艳，唐进法，李学林	1.河南中医药大学第一附属医院药学部河南省中药临床应用、评价与转化工程研究中心/河南省中药临床药学中医药重点实验室（郑州 450008）；2. 河南中医药大学呼吸疾病中医药防治省部共建协同创新中心（郑州 450046）；3.河南中医药大学药学院（郑州 450046）

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中文摘要:

目的运用代谢组学和网络药理学探讨脑心通胶囊活血化瘀的作用机制。方法 24只大鼠随机分为空白组、模型组和药物组，每组8只。药物组给予脑心通胶囊1.5 g/kg 灌胃，空白组和模型组灌胃给予等量的0.5%羧甲基纤维素钠溶液，每日早、晚各1次，共7次。实验第3天第5次给药后模型组和药物组给予肾上腺素（0.8 mg/kg两次）制备急性血瘀证模型。超高效液相色谱-四极杆-飞行时间质谱技术分析大鼠血浆代谢轮廓，采用Progenesis QI和Simca-P软件进行多元统计分析及差异内源性代谢物筛查，通过MetaboAnalyst数据库对代谢通路进行分析。通过MBRole 2.0数据库对差异内源性代谢物的作用靶标进行筛选，利用网络药理学方法对脑心通胶囊中主要活性成分及其作用靶标进行筛选，采用Cytoscape软件构建差异内源性代谢物-靶标-脑心通胶囊活性成分网络。结果正常组和模型组比较鉴定得到白三烯A4、21-脱氧皮质醇、7α-羟基-3-氧代-4-胆甾烯酸酯、17α，21-二羟基孕烯醇酮、1-磷酸鞘氨醇和鹅去氧胆酸6个差异内源性代谢物，涉及花生四烯酸代谢、类固醇激素的合成、初级胆汁酸的生物合成和鞘脂代谢四条代谢途径。脑心通胶囊中的47个活性成分可通过对4个差异内源性代谢物（白三烯A4、21-脱氧皮质醇、1-磷酸鞘氨醇和鹅去氧胆酸）的调节发挥活血化瘀作用，涉及花生四烯酸代谢、类固醇激素的合成和鞘脂代谢途径。结论本研究从代谢组学和网络药理学角度阐释了脑心通胶囊的活血化瘀作用机制，为脑心通胶囊的深入研究提供依据，为中成药的作用机制研究提供新思路。

英文摘要:

Objective To explore the mechanism of activating blood and removing stasis of Naoxintong Capsule by using metabolomics strategy and network pharmacology. Methods Twenty-four rats were randomly divided into blank group，model group and drug group，8 in each group. Drug group was gavaged Naoxintong Capsules at a dose of 1.5 g/kg，blank group and model group were gavaged with a equal volume of 0.5% sodium carboxymethyl cellulose solution，1 time in the morning and 1 time in the evening，7 times in totally. On the third day of the experiment，the model group and the drug group were given adrenaline twice at the dosage of 0.8 mg/kg to establish the acute blood stasis model after fifth gavaged. Ultra high performance liquid chromatography-quadrupole-time of flight-mass spectrometry technology was used to analyze the plasma metabolic profiles of rats. Progenesis QI and Simca-P were used for multivariate statistical analysis and differential endogenous metabolite screening，and metabolic pathways were analyzed by MetaboAnalyst database. The targets of endogenous metabolites were screened by MBRole 2.0 database，and the main active components of Naoxintong Capsule and their targets were screened by network pharmacology method. The network of endogenous metabolite，target，and active components of Naoxintong Capsule was constructed by Cytoscape. Results Compared with the blank group，6 potential differential endogenous metabolites including leukotriene A4，21-deoxycortisol，7α-hydroxy-3-oxo-4-cholestenoate，17α，21-dihydroxypregnenolone，sphingosine 1-phosphate and chenodeoxycholic acid were identified in model group，involving 4 metabolic pathways of arachidonic acid metabolism，steroid hormone biosynthesis，primary bile acid biosynthesis and sphingolipid metabolism. The 47 active components in Naoxintong Capsule could activate blood and remove stasis by regulating the 4 differential endogenous metabolites （leukotriene A4， 21-Deoxycortisol，Sphingosine 1-phosphate and Chenodeoxycholic acid），involving arachidonic acid metabolism，steroid hormone synthesis，and sphingolipid metabolism. Conclusion The mechanism of Naoxintong Capsule in activating blood and removing stasis is interpreted by metabolomics and network pharmacology，providing a basis for the in-depth study of Naoxintong Capsule and provides a new idea for the study of the mechanism of action of Chinese patent medicine.

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