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胡旭东,彭木子,陈铭,廖菁,陈聪.加味丹参饮预防心肌缺血再灌注损伤作用机制的网络药理学分析与实验验证研究[J].湖南中医药大学学报英文版,2023,43(3):473-482.[Click to copy
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| 加味丹参饮预防心肌缺血再灌注损伤作用机制的网络药理学分析与实验验证研究 |
| 胡旭东,彭木子,陈铭,廖菁,陈聪 |
| (湖南中医药大学中医学院, 湖南 长沙 410208;湖南中医药大学科技创新中心, 湖南 长沙 410208) |
| 摘要: |
| 目的 基于网络药理学预测加味丹参饮预防心肌缺血再灌注损伤（myocardial ischemia reperfusion injury, MIRI）的活性成分、作用靶点及信号通路，并进行实验验证研究。方法 通过TCMSP、UniProt等数据库搜集加味丹参饮相关成分及靶点；通过GeneCards、OMIM以及DRUGBANK数据库获取MIRI疾病相关靶点；利用STRING平台分析构建蛋白互作网络模型；通过Metascape平台分析“药物-成分-靶点”及其参与的生物学过程及信号通路，而后采用Cytoscape 3.7.1软件构建“加味丹参饮成分-MIRI靶点-通路”网络。加味丹参饮预防性给药灌胃1周后，采用结扎大鼠左前降支的方法，建立实验性MIRI大鼠模型。通过ELISA观察MIRI大鼠血清丙二醛（malonic dialdehyde, MDA）、肌酸激酶同工酶MB（creatinekinase-MB, CK-MB）、乳酸脱氢酶（lactate dehydrogenase, LDH）、超氧化物歧化酶（superoxide dismutase, SOD）水平，HE染色观测心肌病理改变，qRT-PCR、Western blot检测大鼠血清心肌组织环氧合酶2（prostaglandin-endoperoxide synthase 2, PTGS2）、蛋白激酶B1（akt serine/threonine kinase 1, Akt1）表达水平。结果 初步筛选获得加味丹参饮中的活性成分102个，药物疾病交集基因140个，核心靶点54个；其中，Akt1、原癌基因JUN（Jun proto-oncogene, JUN）、信号转导与转录激活因子3（signal transducer and activator of transcription 3, STAT3）、PTGS2等靶点可能与MIRI密切相关，富集分析预测加味丹参饮预防MIRI主要涉及调节癌症相关通路等20条通路，并且其中5条通路中Akt1处于PTGS2上游。动物实验结果显示，加味丹参饮能够显著提高MIRI大鼠血清MDA、CK-MB、LDH水平（P<0.05），同时降低SOD水平（P<0.05），抑制心肌组织中Akt1、PTGS2表达水平（P<0.05），减轻心肌组织坏死。结论 加味丹参饮可能同时抑制Akt1、PTGS2两个靶点，缓解过度心肌损伤，发挥预防MIRI作用。 |
| 关键词: 心肌缺血再灌注损伤 加味丹参饮 网络药理学 MIRI大鼠模型 作用机制 蛋白激酶B1 环氧合酶2 |
| DOI：10.3969/j.issn.1674-070X.2023.03.016 |
| Received:September 02, 2022 |
| 基金项目:国家自然科学基金青年项目（81704065）；宁夏自治区重点研发项目（2020BFH02003）；湖南省教育厅科学研究项目（20C1392、20C1416、19B415）；湖南省卫生健康委科研计划项目（202202084742）；湖南中医药大学科研基金重点项目（2021XJJJ003）；黄政德全国名老中医药专家传承工作室资助项目。 |
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| Network pharmacology analysis and experimental verification of mechanism of Jiawei Danshen Decoction in preventing myocardial ischemia-reperfusion injury |
| HU Xudong,PENG Muzi,CHEN Ming,LIAO Jing,CHEN Cong |
| (College of Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China;Institute of Innovation and Applied Research in Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China) |
| Abstract: |
| Objective To predict active constituents, drug targets, and signaling pathways of Jiawei Danshen Decoction (JWDSD) in the prevention of myocardial ischemia-reperfusion injury (MIRI) based on network pharmacology and to perform experimental validation. Methods The related constituents and targets of JWDSD were obtained from the Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and UniProt; the MIRI-related targets were obtained from GeneCards, OMIM and DrugBank databases; the protein-protein interaction (PPI) network model was analyzed and constructed by String platform; the “drug-component-target” and the involved biological processes and signaling pathways were analyzed by the Metascape platform, and then the “JWDSD component-MIRI target-pathway” network was constructed by Cytoscape 3.7.1 software. The MIRI rat model was established by ligating the left anterior descending artery of rats one week after preventive gavage administration of JWDSD. The serum malonic dialdehyde (MDA), creatinekinase-MB (CK-MB), lactate dehydrogenase (LDH) and superoxide dismutase (SOD) level of MIRI rats were observed with ELISA, the pathological change of myocardium of the rats was observed by HE staining, and the serum prostaglandin-endoperoxide synthase 2 (PTGS2) of rats myocardium and the expression level of akt serine/threonine kinase 1 (Akt1) were detected by qRT-PCR and Western blot. Results The total of 102 active constituents in JWDSD, 140 drug-disease intersection genes and 54 core targets were obtained by preliminary screening. Akt1, Jun proto-oncogene (JUN), signal transducer and activator of transcription 3 (STAT3), PTGS2 and other targets may be closely related to MIRI. KEGG enrichment analysis predicted that the prevention of MIRI by JWDSD mainly by the regulation of 20 pathways, including cancer-related pathways, and Akt1 is upstream of PTGS2 in 5 pathways. Animal experiment showed: JWDSD could significantly increase the serum levels of malondialdehyde (MDA), creatine kinase isoenzyme MB (CK-MB), and lactate dehydrogenase (LDH); meanwhile, it could decrease the level of superoxide dismutase (SOD) (P<0.05), inhibit the expression levels of Akt1 and PTGS2 in myocardial tissue and reduce myocardial tissue necrosis in MIRI rats (P<0.05). Conclusion JWDSD may inhibit Akt1 and PTGS2 targets at the same time, thereby alleviating excessive myocardial damage and preventing MIRI. |
| Key words: myocardial ischemia-reperfusion injury Jiawei Danshen Decoction network pharmacology MIRI rat model mechanism of action akt serine/threonine kinase 1 prostaglandin-endoperoxide synthase 2 |
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