基于整合药理学的舒冠颗粒治疗心绞痛分子机制研究
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摘要
该文对舒冠颗粒配伍应用的中医理论进行分析,并对其6种植物药何首乌、丹参、黄精、川芎、淫羊藿、红花进行网络药理学分析,借助整合药理学平台获取化学成分及药物作用靶点,通过ETCM数据库搜集适应症靶标。对舒冠颗粒的配伍、成分、作用靶标、通路进行分析,确定其可能的最优适应症。结果表明,舒冠颗粒治疗中医症候为胸痹,君药为丹参。网络药理学分析发现舒冠颗粒药物靶标富集结果与适应症冠心病、心绞痛以及动脉粥样硬化均相关,结合适应症靶标进一步分析,心绞痛可能为舒冠颗粒的最优适应症。舒冠颗粒中的229种成分,共涉及核心靶标109个,其中直接作用心绞痛疾病靶标2个(TNF和MMP9)。此外舒冠颗粒亦可通过MAPK,NFKB,GF等靶标间接干预心绞痛病程。涉及的心绞痛相关的主要通路为PI3K-Akt信号通路、RAS信号通路、TNF信号通路、雌激素信号通路以及糖异生信号通路,可干预心绞痛的多个环节如炎症反应、血脂代谢血管扩张等。
The paper analyzed the combined administration of traditional Chinese medicine Shuguan Granules, and studied its six plant herbs, namely Polygoni Multiflori Radix, Salviae Miltiorrhizae Radix et Rhizoma, Polygonati Rhizoma, Chuanxiong Rhizoma, Epomedii Folium, and Carthami Flos by network pharmacology analysis, in order to define chemical constituents and drugs targets through integrated pharmacology platform. Based on the results, indications of Shuguan Granules were collected through the ETCM database. Therefore, the present study could determine the potential optimal indications of the drug. The results showed that chest apoplexy was the main traditional Chinese medicine(TCM) symptom treated by Shuguan Granules, whose monarch drug was Salviae Miltiorrhizae Radix et Rhizoma. Network pharmacology analysis found that the target enrichment results of Shuguan Granules were related to the indications of coronary heart disease, angina and atherosclerosis. According to the indications, angina may be the best indication for Shuguan Granules. The 229 components in Shuguan Granules involved a total of 109 core targets, of which TNF and MMP9 were the direct targets to the angina disease. In addition, Shuguan Granules could also indirectly intervene in the progression of angina through MAPK, NFKB, GF and other targets. The main pathways involving angina pectoris are PI3 K-Akt signaling pathway, RAS signaling pathway, TNF signaling pathway, Estrogen signaling pathway and glycolysis/gluconeogenesis, which can intervene in many aspects of angina, such as inflammatory reaction, blood lipid metabolism and vasodilation.
The paper analyzed the combined administration of traditional Chinese medicine Shuguan Granules, and studied its six plant herbs, namely Polygoni Multiflori Radix, Salviae Miltiorrhizae Radix et Rhizoma, Polygonati Rhizoma, Chuanxiong Rhizoma, Epomedii Folium, and Carthami Flos by network pharmacology analysis, in order to define chemical constituents and drugs targets through integrated pharmacology platform. Based on the results, indications of Shuguan Granules were collected through the ETCM database. Therefore, the present study could determine the potential optimal indications of the drug. The results showed that chest apoplexy was the main traditional Chinese medicine(TCM) symptom treated by Shuguan Granules, whose monarch drug was Salviae Miltiorrhizae Radix et Rhizoma. Network pharmacology analysis found that the target enrichment results of Shuguan Granules were related to the indications of coronary heart disease, angina and atherosclerosis. According to the indications, angina may be the best indication for Shuguan Granules. The 229 components in Shuguan Granules involved a total of 109 core targets, of which TNF and MMP9 were the direct targets to the angina disease. In addition, Shuguan Granules could also indirectly intervene in the progression of angina through MAPK, NFKB, GF and other targets. The main pathways involving angina pectoris are PI3 K-Akt signaling pathway, RAS signaling pathway, TNF signaling pathway, Estrogen signaling pathway and glycolysis/gluconeogenesis, which can intervene in many aspects of angina, such as inflammatory reaction, blood lipid metabolism and vasodilation.
引文
[1] 肖海平.中西医结合治疗冠心病20例疗效观察[J]. 中国中医药现代远程教育, 2012, 10(15): 39.
[2] 王建湘, 程丑夫, 韩育明.舒冠滴丸对动脉粥样硬化兔CD40通路调节作用研究[J]. 中西医结合心脑血管病杂志, 2007, 5(10): 958.
[3] 欧阳杰湖.舒冠颗粒抗心绞痛作用的药效学研究[D].沈阳: 沈阳药科大学,2002.
[4] 许海玉, 刘振明, 付岩, 等.中药整合药理学计算平台的开发与应用[J].中国中药杂志, 2017, 42(18): 3633.
[5] Xu H,Zhang Y,Liu Z,et al. ETCM: an encyclopaedia of traditional Chinese medicine[J]. Nucleic Acids Res, 2018, doi: 10.1093/nar/gky987.
[6] 许海玉, 杨洪军.整合药理学:中药现代研究新模式[J].中国中药杂志, 2014, 39(3): 357.
[7] 李沐森, 郭文场, 刘佳贺.复齿鼯鼠的分布、形态及五灵脂的采收方法和药理作用[J]. 特种经济动植物, 2017, 20(2): 4.
[8] 邱清华, 邓绍云.五灵脂化学成分与药用研究进展[J]. 江苏科技信息, 2015(11): 76.
[9] Hsin K Y, Matsuoka Y, Asai Y, et al. SystemsDock: a web server for network pharmacology-based prediction and analysis[J]. Nucleic Acids Res, 2018, doi: 10.1093/nar/gkw335.
[10] 高佳明,吕明,解微微,等.中医药心脑血管疾病同治的方剂用药规律分析[J].中国中药杂志, 2019, doi: 10.19540/j.cnki.cjcmm.20181101.007.
[11] 尹婕,李琦,赵正,等.纤维化对动脉粥样硬化斑块稳定性的基础研究及相关药物应用[J].中国中药杂志, 2019, doi:10.19540/j.cnki.cjcmm.20181012.005.
[12] 杨倩, 李晓宇, 赵新妹, 等.含何首乌的中成药不良反应系统分析[J]. 中草药, 2017, 48(9): 1878.
[13] 龚彦胜, 李晓宇, 孙蓉.基于功效与药理作用川芎抗冠心病心绞痛的物质基础研究进展[J]. 中国药物警戒, 2011, 8(11): 675.
[14] 江蔚新, 侯明阳.红花药材中的化学成分及其药理作用[J]. 黑龙江医药, 2015(4): 732.
[15] 徐凌, 胡月琴. 黄精研究状况概述[J]. 齐齐哈尔医学院学报, 2014, 35(3): 414.
[16] 顾晴. 治疗冠心病中药的研究进展[J]. 实用心脑肺血管病杂志, 2011, 19(2): 240.
[17] 唐绪刚, 黄文权,姜利鲲.中药五灵脂对动脉粥样硬化大鼠细胞间黏附分子-1的影响[J]. 中国老年学杂志, 2008, 28(23): 2318.
[18] 蔡少青, 王璇, 尚明英, 等. 中药“显效理论”或有助于阐释并弘扬中药特色优势[J]. 中国中药杂志, 2015, 40(17):3435.
[19] Tsutsui H, Kinugawa S, Matsushima S. Mitochondrial oxidative stress and dysfunction in myocardial remodelling[J]. Cardiovasc Res, 2009, 81(3): 449.
[20] Teshima Y, Akao M, Li R A, et al. Mitochondrial ATP-sensitive potassium channel activation protects cerebellar granule neurons from apoptosis induced by oxidative stress[J]. Stroke, 2003, 34(7): 1796.
[21] 杨永宗, 易光辉, 万腊香, 等. L-精氨酸/一氧化氮抗动脉粥样硬化及其机理的研究[J]. 医学研究杂志, 2000(6): 12.
[22] 张慧平,柳景华. 非对称性二甲基精氨酸与冠心病的相关性研究进展[J]. 中国临床保健杂志, 2014(6): 667.
[23] Cusack M R, Marber M S, Lambiase P D, et al. Systemic inflammation in unstable angina is the result of myocardial necrosis[J]. J Am Coll Cardiol, 2002, 39(12): 1917.
[24] 张成杰, 安庆华, 郑玉明, 等. 不稳定型心绞痛患者NF-κB、TNF-α、IL-1及IL-6的表达与干预研究[J]. 滨州医学院学报, 2018(3): 168.
[25] Blankenberg S, Rupprecht H J, Poirier O, et al. Plasma concentrations and genetic variation of matrix metalloproteinase 9 and prognosis of patients with cardiovascular disease[J]. Circulation, 2003, 107(12): 1579.
[26] Lamendola P, Di F A, Tarzia P, et al. Coronary microvascular dysfunction: an update[J]. Recenti Prog Med, 2011, 102(9): 329.
[27] 吴易航,邓翠云.微血管性心绞痛发病机制及治疗研究进展[J]. 中外医疗, 2017, 36(14): 196.
[28] Liu H, Li Y, An Y, et al. Endothelium-independent hypoxic contraction is prevented specifically by nitroglycerin via inhibition of Akt kinase in porcine coronary artery[J]. Stem Cells Int, 2016(5): 2916017.
[29] Rws C, Leanderson P, Lundberg A K, et al. Lutein exerts anti-inflammatory effects in patients with coronary artery disease[J]. Atherosclerosis, 2017, 262: 87.
[30] Wu J, Liou S, Lin S, et al. Lercanidipine inhibits vascular smooth muscle cell proliferation and neointimal formation via reducing intracellular reactive oxygen species and inactivating Ras-ERK1/2 signaling[J]. Pharmacol Res, 2009, 59(1): 48.
[31] Kalra B,Roy V. Efficacy of metabolic modulators in ischemic heart disease: an overview[J]. J Clin Pharmacol, 2012, 52(3): 292.
[32] Chiara M, Ulisse G, Chiara S, et al. Nuclear factor kappa B in patients with a history of unstable angina: case re-opened[J]. Intern Emerg Med, 2018, 13(5):699.
[33] 候宁,吴东雪,刘敏,等.基于药性组合的丹参和红花的性效关系研究[J].中国中药杂志,2019,doi:10.19540/j.cnki.cjcmm.20180903.002.
[34] Cao J, Han Z, Tian L, et al. Curcumin inhibits EMMPRIN and MMP-9 expression through AMPK-MAPK and PKC signaling in PMA induced macrophages[J]. J Transl Med, 2014, 12(1): 266.
[35] Laskarin G, Persic V, Mi?kulin R, et al. Can we assess an acute myocardial infarction in patients with acute coronary syndrome according to diagnostic accuracy of heat shock proteins?[J]. Med Hypotheses, 2012, 79(5): 592.
[36] Clarke B, Spedding M, Patmore L, et al. Protective effects of ranolazine in guinea-pig hearts during low-flow ischaemia and their association with increases in active pyruvate dehydrogenase[J]. Brit J Pharmacol, 1993, 109(3): 748.
[37] 刘曼华,尹琼. 不稳定型心绞痛患者血管内皮生长因子水平变化及其相关因素分析[J]. 中国心血管病研究, 2017, 15(4): 342.
[38] 朱红, 张光彩, 蒋玉敏, 等. 多种细胞因子在冠心病诊断中的应用价值[J]. 中国美容医学杂志, 2011, 20(s5):50.
[39] 沈庆乐, 张存琪, 林闽溪, 等. 老年冠心病碱性成纤维细胞生长因子和纤维连接蛋白的变化[J]. 心血管康复医学杂志, 2004, 13(2):117.
[2] 王建湘, 程丑夫, 韩育明.舒冠滴丸对动脉粥样硬化兔CD40通路调节作用研究[J]. 中西医结合心脑血管病杂志, 2007, 5(10): 958.
[3] 欧阳杰湖.舒冠颗粒抗心绞痛作用的药效学研究[D].沈阳: 沈阳药科大学,2002.
[4] 许海玉, 刘振明, 付岩, 等.中药整合药理学计算平台的开发与应用[J].中国中药杂志, 2017, 42(18): 3633.
[5] Xu H,Zhang Y,Liu Z,et al. ETCM: an encyclopaedia of traditional Chinese medicine[J]. Nucleic Acids Res, 2018, doi: 10.1093/nar/gky987.
[6] 许海玉, 杨洪军.整合药理学:中药现代研究新模式[J].中国中药杂志, 2014, 39(3): 357.
[7] 李沐森, 郭文场, 刘佳贺.复齿鼯鼠的分布、形态及五灵脂的采收方法和药理作用[J]. 特种经济动植物, 2017, 20(2): 4.
[8] 邱清华, 邓绍云.五灵脂化学成分与药用研究进展[J]. 江苏科技信息, 2015(11): 76.
[9] Hsin K Y, Matsuoka Y, Asai Y, et al. SystemsDock: a web server for network pharmacology-based prediction and analysis[J]. Nucleic Acids Res, 2018, doi: 10.1093/nar/gkw335.
[10] 高佳明,吕明,解微微,等.中医药心脑血管疾病同治的方剂用药规律分析[J].中国中药杂志, 2019, doi: 10.19540/j.cnki.cjcmm.20181101.007.
[11] 尹婕,李琦,赵正,等.纤维化对动脉粥样硬化斑块稳定性的基础研究及相关药物应用[J].中国中药杂志, 2019, doi:10.19540/j.cnki.cjcmm.20181012.005.
[12] 杨倩, 李晓宇, 赵新妹, 等.含何首乌的中成药不良反应系统分析[J]. 中草药, 2017, 48(9): 1878.
[13] 龚彦胜, 李晓宇, 孙蓉.基于功效与药理作用川芎抗冠心病心绞痛的物质基础研究进展[J]. 中国药物警戒, 2011, 8(11): 675.
[14] 江蔚新, 侯明阳.红花药材中的化学成分及其药理作用[J]. 黑龙江医药, 2015(4): 732.
[15] 徐凌, 胡月琴. 黄精研究状况概述[J]. 齐齐哈尔医学院学报, 2014, 35(3): 414.
[16] 顾晴. 治疗冠心病中药的研究进展[J]. 实用心脑肺血管病杂志, 2011, 19(2): 240.
[17] 唐绪刚, 黄文权,姜利鲲.中药五灵脂对动脉粥样硬化大鼠细胞间黏附分子-1的影响[J]. 中国老年学杂志, 2008, 28(23): 2318.
[18] 蔡少青, 王璇, 尚明英, 等. 中药“显效理论”或有助于阐释并弘扬中药特色优势[J]. 中国中药杂志, 2015, 40(17):3435.
[19] Tsutsui H, Kinugawa S, Matsushima S. Mitochondrial oxidative stress and dysfunction in myocardial remodelling[J]. Cardiovasc Res, 2009, 81(3): 449.
[20] Teshima Y, Akao M, Li R A, et al. Mitochondrial ATP-sensitive potassium channel activation protects cerebellar granule neurons from apoptosis induced by oxidative stress[J]. Stroke, 2003, 34(7): 1796.
[21] 杨永宗, 易光辉, 万腊香, 等. L-精氨酸/一氧化氮抗动脉粥样硬化及其机理的研究[J]. 医学研究杂志, 2000(6): 12.
[22] 张慧平,柳景华. 非对称性二甲基精氨酸与冠心病的相关性研究进展[J]. 中国临床保健杂志, 2014(6): 667.
[23] Cusack M R, Marber M S, Lambiase P D, et al. Systemic inflammation in unstable angina is the result of myocardial necrosis[J]. J Am Coll Cardiol, 2002, 39(12): 1917.
[24] 张成杰, 安庆华, 郑玉明, 等. 不稳定型心绞痛患者NF-κB、TNF-α、IL-1及IL-6的表达与干预研究[J]. 滨州医学院学报, 2018(3): 168.
[25] Blankenberg S, Rupprecht H J, Poirier O, et al. Plasma concentrations and genetic variation of matrix metalloproteinase 9 and prognosis of patients with cardiovascular disease[J]. Circulation, 2003, 107(12): 1579.
[26] Lamendola P, Di F A, Tarzia P, et al. Coronary microvascular dysfunction: an update[J]. Recenti Prog Med, 2011, 102(9): 329.
[27] 吴易航,邓翠云.微血管性心绞痛发病机制及治疗研究进展[J]. 中外医疗, 2017, 36(14): 196.
[28] Liu H, Li Y, An Y, et al. Endothelium-independent hypoxic contraction is prevented specifically by nitroglycerin via inhibition of Akt kinase in porcine coronary artery[J]. Stem Cells Int, 2016(5): 2916017.
[29] Rws C, Leanderson P, Lundberg A K, et al. Lutein exerts anti-inflammatory effects in patients with coronary artery disease[J]. Atherosclerosis, 2017, 262: 87.
[30] Wu J, Liou S, Lin S, et al. Lercanidipine inhibits vascular smooth muscle cell proliferation and neointimal formation via reducing intracellular reactive oxygen species and inactivating Ras-ERK1/2 signaling[J]. Pharmacol Res, 2009, 59(1): 48.
[31] Kalra B,Roy V. Efficacy of metabolic modulators in ischemic heart disease: an overview[J]. J Clin Pharmacol, 2012, 52(3): 292.
[32] Chiara M, Ulisse G, Chiara S, et al. Nuclear factor kappa B in patients with a history of unstable angina: case re-opened[J]. Intern Emerg Med, 2018, 13(5):699.
[33] 候宁,吴东雪,刘敏,等.基于药性组合的丹参和红花的性效关系研究[J].中国中药杂志,2019,doi:10.19540/j.cnki.cjcmm.20180903.002.
[34] Cao J, Han Z, Tian L, et al. Curcumin inhibits EMMPRIN and MMP-9 expression through AMPK-MAPK and PKC signaling in PMA induced macrophages[J]. J Transl Med, 2014, 12(1): 266.
[35] Laskarin G, Persic V, Mi?kulin R, et al. Can we assess an acute myocardial infarction in patients with acute coronary syndrome according to diagnostic accuracy of heat shock proteins?[J]. Med Hypotheses, 2012, 79(5): 592.
[36] Clarke B, Spedding M, Patmore L, et al. Protective effects of ranolazine in guinea-pig hearts during low-flow ischaemia and their association with increases in active pyruvate dehydrogenase[J]. Brit J Pharmacol, 1993, 109(3): 748.
[37] 刘曼华,尹琼. 不稳定型心绞痛患者血管内皮生长因子水平变化及其相关因素分析[J]. 中国心血管病研究, 2017, 15(4): 342.
[38] 朱红, 张光彩, 蒋玉敏, 等. 多种细胞因子在冠心病诊断中的应用价值[J]. 中国美容医学杂志, 2011, 20(s5):50.
[39] 沈庆乐, 张存琪, 林闽溪, 等. 老年冠心病碱性成纤维细胞生长因子和纤维连接蛋白的变化[J]. 心血管康复医学杂志, 2004, 13(2):117.