杨梦霞,芦殿荣,朱世杰,王宁军

• 1:中国中医科学院望京医院
• 2:北京中医药大学

摘要(Abstract)：

目的 通过网络药理学方法研究炙甘草汤治疗抗肿瘤药物致心脏毒性（ADIC）的作用机制。方法 利用TCMSP、TCMID和TCM Database@Taiwan数据库检索药物主要有效成分，利用Swiss Target Prediction数据库检索炙甘草汤靶点，通过GengCards和DisGeNet数据库检索ADIC疾病基因，并将药物作用靶点和疾病基因进行映射，通过Cytoscape软件进行可视化并筛选出核心基因，对潜在治疗靶点进行GO和KEGG通路分析。结果 炙甘草汤的主要有效成分有115个，包含1 004个靶点。ADIC基因有354个，其中119个是炙甘草汤治疗ADIC的潜在靶点。通过GO和KEGG通路分析发现炙甘草汤治疗ADIC是通过PI3K/Akt、HIF-1、TNF及TLR等信号通路发挥心脏保护作用。炙甘草汤治疗ADIC的重要基因为FOS、TNF、MAPK8和EGFR等。结论 通过网络药理学发现炙甘草汤治疗ADIC的作用机制涉及多靶点、多通路，可能与抗炎、促进血管生成和抑制心肌细胞凋亡等相关。

关键词(KeyWords)： 抗肿瘤药物致心脏毒性;炙甘草汤;网络药理学;作用机制

Abstract:

Keywords:

基金项目(Foundation): 国家自然科学基金项目（81973640）

作者(Author): 杨梦霞,芦殿荣,朱世杰,王宁军

参考文献(References)：

• [1] Romitan DM,Rǎdulescu D,Berindan-Neagoe I,et al. Cardiomyopathies and arrhythmias induced by cancer therapies[J].Biomedicines,2020,8(11):496.
• [2] Hao E,Mukhopadhyay P,Cao Z,et al. Cannabidiol protects against doxorubicin-induced cardiomyopathy by modulating mitochondrial function and biogenesis[J]. Mol Med,2015,21:38-45.
• [3] Lenneman CG,Sawyer DB. Cardio-Oncology:An update on cardiotoxicity of cancer-related treatment[J]. Circ Res,2016,118(6):1008-1020.
• [4]马腾，朱明军，王永霞，等.心脉隆注射液治疗蒽环类药物化疗后心脏毒性的Meta分析[J].中药新药与临床药理，2021,32(6):886-893.
• [5]李田宏，谢晓冬.抗肿瘤药物心脏毒性的中医药防治进展[J].中国肿瘤临床与康复，2019,26(4):510-512.
• [6]郭松霖，乔元勋，于淼，等.中医药防治化疗药物心脏毒性研究进展[J].中医学报，2021,36(8):1668-1673.
• [7]申兴勇，袁平.加减炙甘草汤对乳腺癌化疗致心脏毒性的临床观察及对心功能的保护作用分析[J].癌症进展，2018,16(1):106-109.
• [8]郭连英，王菊美，安菊岩，等.炙甘草汤联合含阿霉素新辅助化疗方案治疗乳腺癌疗效及对心脏功能的影响[J].现代中西医结合杂志，2017,26(35):3915-3917.
• [9]王凡，巩平.炙甘草汤预防蒽环类药物心脏毒性的临床观察[J].现代肿瘤医学，2016,24(16):2610-2614.
• [10]林方圆，田菲，韩佳彤，等.《伤寒论》理法方药治疗蒽环类化疗药物所致心脏毒性初探[J].山西中医，2020,36(10):1-4.
• [11]唐荣华.炙甘草汤治疗脉结代心动悸的体会[J].中国中医急症，2011,20(3):392-393.
• [12] Olorundare O,Adeneye A,Akinsola A,et al. Irvingia gabonensis seed extract:An effective attenuator of doxorubicinmediated cardiotoxicity in wistar rats[J]. Oxid Med Cell Longev,2020,2020:1602816.
• [13] Hwang SL,Kim HN,Jung HH,et al. Beneficial effects of beta-sitosterol on glucose and lipid metabolism in L6 myotube cells are mediated by AMP-activated protein kinase[J]. Biochem Biophys Res Commun,2008,377(4):1253-1258.
• [14] Fernandez ML,Vega-López S. Efficacy and safety of sitosterol in the management of blood cholesterol levels[J]. Cardiovasc Drug Rev,2005,23(1):57-70.
• [15] Crespo I,García-Mediavilla MV,Gutiérrez B,et al. A comparison of the effects of kaempferol and quercetin on cytokine-induced pro-inflammatory status of cultured human endothelial cells[J]. Br J Nutr,2008,100(5):968-976.
• [16] Espley RV,Butts CA,Laing WA,et al. Dietary flavonoids from modified apple reduce inflammation markers and modulate gut microbiota in mice[J]. J Nutr,2014,144(2):146-154.
• [17] Dabeek WM,Marra MV. Dietary quercetin and kaempferol:Bioavailability and potential cardiovascular-related bioactivity in humans[J]. Nutrients,2019,11(10):2288.
• [18] Wang M,Zhang WB,Zhu JH,et al. Breviscapine ameliorates hypertrophy of cardiomyocytes induced by high glucose in diabetic rats via the PKC signaling pathway[J]. Acta Pharmacol Sin,2009,30(8):1081-1091.
• [19] Pan Z,Sun X,Shan H,et al. MicroRNA-101 inhibited postinfarct cardiac fibrosis and improved left ventricular compliance via the FBJ osteosarcoma oncogene/transforming growth factor-β1 pathway[J]. Circulation,2012,126(7):840-850.
• [20] Avouac J,Palumbo K,Tomcik M,et al. Inhibition of activator protein 1 signaling abrogates transforming growth factor β-mediated activation of fibroblasts and prevents experimental fibrosis[J]. Arthritis Rheum,2012,64(5):1642-1652.
• [21] Hanna A,Frangogiannis NG. Inflammatory Cytokines and Chemokines as Therapeutic Targets in Heart Failure[J]. Cardiovasc Drugs Ther,2020,34(6):849-863.
• [22] Xu H,Yao Y,Su Z,et al. Endogenous HMGB1 contributes to ischemia-reperfusion-induced myocardial apoptosis by potentiating the effect of TNF-&alpha；/JNK[J]. Am J Physiol Heart Circ Physiol,2011,300(3):913-921.
• [23] Liu CJ,Lo JF,Kuo CH,et al. Akt mediates 17beta-estradiol and/or estrogen receptor-alpha inhibition of LPS-induced tumor necresis factor-alpha expression and myocardial cell apoptosis by suppressing the JNK1/2-NFkappaB pathway[J].J Cell Mol,2009,13(9B):3655-3667.
• [24] Mindur JE,Swirski FK. Growth factors as immunotherapeutic targets in cardiovascular disease[J]. Arterioscler Thromb Vasc Biol,2019,39(7):1275-1287.
• [25] Zhang Z,Yao L,Yang J,et al. PI3K/Akt and HIF-1 signaling pathway in hypoxia-ischemia(Review)[J]. Mol Med Rep,2018,18(4):3547-3554.
• [26] Bai WW,Xing YF,Wang B,et al. Tongxinluo improves cardiac function and ameliorates ventricular remodeling in mice model of myocardial infarction through enhancing angiogenesis[J]. Evid Based Complement Alternat Med,2013:813247.
• [27] Patten RD,Pourati I,Aronovitz MJ,et al. 17beta-estradiol reduces cardiomyocyte apoptosis in vivo and in vitro via activation of phospho-inositide-3 kinase/Akt signaling[J]. Circ Res,2004,95(7):692-699.
• [28] He Z,Opland DM,Way KJ,et al. Regulation of vascular endothelial growth factor expression and vascularization in the myocardium by insulin receptor and PI3K/Akt pathways in insulin resistance and ischemia[J]. Arterioscler Thromb Vasc Biol,2006,26:787-793.
• [29] Vidya MK,Kumar VG,Sejian V,et al. Toll-like receptors:Significance,ligands,signaling pathways,and functions in mammals[J]. Int Rev Immunol,2018,37(1):20-36.
• [30] M Perticone,R Zito,S Miceli,et al. Immunity,inflammation and heart failure:their role on cardiac function and iron status[J]. Front Immunol,2019,10:1-9.
• [31] LC O’Brien,E Mezzaroma,BW Van Tassell,et al. Interleukin-18 as a therapeutic target in acute myocardial infarction and heart failure[J]. Mol Med,2014,20:221-229.