Objectives To study the active components and targets of Salvia miltiorrhixa Bge-Hedysarum multijugum Maxim in the treatment of diabetic cardiomyopathy based on network pharmacology and bioinformatics technology, and to construct lncRNA-miRNA-mRNA transcription network.
Methods The TCMSP database was used to retrieve the chemical constituents and targets of Salvia miltiorrhixa Bge-Hedysarum multijugum Maxim; diabetic cardiomyopathy and autophagy related targets were obtained through CTD and GeneCards database screening; protein-protein interaction network was constructed through STRING database and the core targets were screened by five algorithms for the Hubba plugin in Cytoscape software; the gene ontology and kyoto encyclopedia of genes and genomes enrichment analysis of the targets were carried out through the Metascape database; the core component-core targets-core signaling pathway network were constructed used bioinformatic platform; Discovery Studio Client 19.1.0 software was used for molecular docking; the miRNAs regulated upstream of target mRNA was predicted and the core miRNAs was screened through Target Scan Human, miRDB and miRTarBase databases; StarBase database was used to predict lncRNAs with miRNA competitive binding, and to screen the core lncRNA, and to construct competitive endogenous RNA network.
Results The active ingredients in Salvia miltiorrhixa Bge-Hedysarum multijugum Maxim that regulate autophagy and prevent diabetic cardiomyopathy were salvianolic acid J, tanshinone ⅡB, tanshindiol A and Isomucronulatol 7-O-glucoside, etc; its core targets included SRC and GRB2, etc; the core pathways included PI3K/AKT, FoxO and AGE-RAGE signaling pathways, etc; 12 miRNAs related to core targets were screened, including miR-4731-5p and miR-503-5p,etc; there were five core lncRNAs, including NEAT1 and XIST, etc.
Conclusions The Salvia miltiorrhixa Bge-Hedysarum multijugum Maxim may exert synergistic effects through regulating autophagy, which can affect processes such as cell apoptosis, oxidative stress, and glucose metabolism, and achieve the effect of preventing and treating diabetic cardiomyopathy.
1.Dewanjee S, Vallamkondu J, Kalra RS, et al. Autophagy in the diabetic heart: a potential pharmacotherapeutic target in diabetic cardiomyopathy[J]. Ageing Res Rev, 2021, 68: 101338. DOI: 10.1016/j.arr.2021.101338.
2.Kiencke S, Handschin R,von Dahlen R, et al. Pre-clinical diabetic cardiomyopathy: prevalence, screening, and outcome[J]. Eur J Heart Fail, 2010, 12(9): 951-957. DOI: 10.1093/eurjhf/hfq110.
3.Zhang W, Xu W, Feng Y, et al. Non-coding RNA involvement in the pathogenesis of diabetic cardiomyopathy[J]. J Cell Mol Med, 2019, 23(9): 5859-5867. DOI: 10.1111/jcmm.14510.
4.Jia G, Hill MA, Sowers JR. Diabetic cardiomyopathy: an update of mechanisms contributing to this clinical entity[J]. Cir Res, 2018, 122(4): 624-638. DOI: 10.1161/CIRCRESAHA.117.311586.
5.Wu X, Liu Z, Yu XY, et al. Autophagy and cardiac diseases: therapeutic potential of natural products[J]. Med Res Rev, 2021, 41(1): 314-341.DOI: 10.1002/med.21733.
6.樊一波, 文颖娟. 糖尿病心肌病中医药治疗刍议[J]. 陕西中医药大学学报, 2018, 41(4): 123-125, 130. [Fan YB, Wen YJ. Discussion on Traditional Chinese medicine treatment of diabetic cardiomyopathy [J]. Journal of Shaanxi College of Traditional Chinese Medicine, 2018, 41(4): 123-125, 130.] DOI: 10.13424/j.cnki.jsctcm.2018.04.038.
7.尤良震, 潘海娥, 代倩倩, 等. 糖尿病心脏病中医病机述要[J]. 中医杂志, 2021, 62(12): 1013-1019. [You LZ, Pan HE, Dai QQ, et al. Pathogenesis of diabetic heart disease in traditional Chinese medicine[J]. Journal of Traditional Chinese Medicine, 2021, 62(12): 1013-1019.] DOI: 10.13288/j.11-2166/r.2021.12.001.
8.王亚运, 许生, 张琪. 基于伤寒论中消渴日久病及于心治法的刍议[J]. 实用妇科内分泌杂志, 2017, 4(21): 50-51. [Wang YY, Xu S, Zhang Q. Based on the theory of typhoid fever,quenching thirst, long-term illness, and the treatment of the heart[J]. Journal of Practical Gynecologic Endocrinology, 2017, 4(21): 50-51.] DOI: 10.16484/j.cnki.issn2095-8803.2017.21.035.
9.陈方敏. 糖尿病心脏病中医药文献研究与方药证治规律探微[D]. 广州: 广州中医药大学, 2010.
10.朱宇溪, 周慢, 赵兴旺, 等. 糖尿病心肌病的中医治疗进展[J]. 四川中医, 2017, 35(5): 218-220. [Zhu YX, Zhou M, Zhao XW, et al. Advances in TCM treatment of diabetic cardiomyopathy[J]. Journal of Sichuan Traditional Chinese Medicine, 2017, 35(5): 218-220.] DOI: CNKI:SUN:SCZY.0.2017-05-085.
11.徐怡, 陈途, 陈明. 丹参的化学成分及其药理作用研究进展[J]. 海峡药学, 2021, 33(5): 45-48. [Xu Y, Chen Y, Chen M. Research progress of chemical constituents and pharmacological effects of Salvia miltiorrhiza Bunge[J]. Strait Pharmaceutical Journal, 2021, 33(5): 45-48.] DOI: 10.3969/j.issn.1006-3765.2021.05.015.
12.李奔, 赵泉霖, 王贞贞, 等. 黄芪、当归防治糖尿病性心肌病研究概况[J]. 山东中医药大学学报, 2022, 46(3): 406-410. [Li B, Zhao QL, Wang ZZ, et al. Research overview of Huangqi(Astragali Radix) and Danggui(Angelicae Sinensis Radix) in prevention and treatment of diabetic cardiomyopathy[J]. Journal of Shandong University of Traditional Chinese Medicine, 2022, 46(3): 406-410.] DOI: 10.16294/j.cnki.1007-659x.2022.03.021.
13.辛高杰, 付建华, 李磊, 等. 中药调控自噬与缺血性心脏病关系的研究进展[J]. 中国中药杂志, 2020, 45(16): 3784-3789. [Xin GJ, Fu JH, Li L, et al. Research progress of traditional Chinese medicine in regulating autophagy and ischemic heart disease[J]. China Journal of Chinese Materia Medica, 2020, 45(16): 3784-3789.] DOI: 10.19540/j.cnki.cjcmm.20200113.401.
14.Salmena L, Poliseno L, Tay Y, et al. A ceRNA hypothesis: the rosetta stone of a hidden RNA language?[J]. Cell, 2011, 146(3): 353-358. DOI: 10.1016/j.cell.2011.07.014.
15.Rupaimoole R, Slack FJ. MicroRNA therapeutics: towards a new era for the management of cancer and other diseases[J]. Nat Rev Drug Discov, 2017, 16(3): 203-222. DOI: 10.1038/nrd. 2016.246.
16.Yang L, Zhang X, Li H, et al. The long noncoding RNA HOTAIR activates autophagy byupregulating ATG3 and ATG7 in hepatocellular carcinoma[J]. Mol BioSyst, 2016, 12(8): 2605-2612. DOI: 10.1039/c6mb00114a.
17.Jing Z, Ye X, Ma X, et al. SNGH16 regulates cell autophagy to promote Sorafenib Resistance through suppressing miR-23b-3p via sponging EGR1 in hepatocellular carcinoma[J]. Cancer Med, 2020, 9(12): 4324-4338. DOI: 10.1002/cam4.3020.
18.Chin CH, Chen SH, Wu HH, et al. cytoHubba: identifying hub objects and sub-networks from complex interactome[J]. BMC Syst Biol, 2014, 8 Suppl 4(Suppl 4): S11. DOI: 10.1186/1752-0509-8-S4-S11.
19.严斐斐, 张超, 王艾丽, 等. 二甲双胍调控PI3K/Akt通路对心肌缺血再灌注模型大鼠心肌细胞自噬的影响研究[J]. 中国药师, 2019, 22(11): 1980-1985. [Yan FF, Zhang C, Wang AL, et al. Effect of metformin on the autophagy of myocardial cells in myocardial ischemia-reperfusion model rats by regulating P13K/Akt pathway[J]. China Pharmacist, 2019, 22(11): 1980-1985.] DOI: 10.3969/j.issn.1008-049X.2019.11.004.
20.Waghela BN, Vaidya FU, Ranjan K, et al. AGE-RAGE synergy influences programmed cell death signaling to promote cancer[J]. Mol Cell Biochem, 2021, 476(2): 585-598. DOI: 10.1007/s11010-020-03928-y.
21.王新东, 卞勇, 祁晓霞. 黄芪丹参水煎液激活AMPK上调自噬抑制ISO诱导的大鼠心肌重构[J]. 中药材, 2017, 40(10): 2433-2436. [Wang XD, Bian Y, Qi XX. Astragalus and Salvia Miltiorrhiza decoction activates AMPK up-regulates autophagy and inhibits ISO-induced myocardial remodeling in rats[J]. Journal of Chinese Medicinal Materials, 2017, 40(10): 2433-2436.] DOI: 10.13863/j.issn1001-4454.2017.10.044.
22.叶婷, 马国庆, 魏明慧, 等. 黄芪多糖对糖尿病心肌病大鼠AMPK-mTOR通路的调控机制研究[J]. 世界中医药, 2022, 17(7): 977-982. [Ye T, Ma GQ, Wei MH, et al. [Regulation mechanism of Astragalus Polysaccharides on diabetic cardiomyopathy rats by AMPK-mTOR pathway[J]. World Chinese Medicine, 2022, 17(7): 977-982.] DOI: 10.3969/j.issn.1673- 7202.2022.07.014.
23.Roskoski R Jr. Src protein-tyrosine kinase structure and regulation[J]. Bio Biophys Res Commun, 2004, 324(4): 1155-1164. DOI: 10.1016/j.bbrc.2004.09.171.
24.Yang X, Xu S, Su Y, et al. Autophagy-Src regulates Connexin43-mediated gap junction intercellular communication in irradiated HepG2 cells[J]. Radiat Res, 2018, 190(5): 494-503. DOI: 10.1667/RR15073.1.
25.Li G, Li Y, Zheng SF, et al. Autophagy in pulmonary macrophages mediates lung inflammatory injury via c-Src tyrosine kinase pathway activation during mechanical ventilation[J]. Eur Rev Med Pharmacol Sci, 2019, 23(4): 1674-1680. DOI: 10.266355/eurrev_201902_ 17129.
26.Bongartz H, Gille K, Hessenkemper W, et al. The multi-site docking protein Grb2-associated binder 1 (Gab1) enhances interleukin-6-induced MAPK-pathway activation in an SHP2-, Grb2-, and time-dependent manner[J]. Cell Commun Signal, 2019, 17(1): 135. DOI: 10.1186/s12964-019-0451-2.
27.Wang J, Sun X, Wang X, et al. Grb2 induces cardiorenal syndrome type 3: roles of IL-6, cardiomyocyte bioenergetics, and Akt/mTOR pathway[J]. Front Cell Dev Biol, 2021, 9: 630412. DOI: 10.3389/fcell.2021.630412.
28.Bravo-San Pedro JM, Gómez-Sánchez R, Niso-Santano M, et al. The MAPK1/3 pathway is essential for the deregulation of autophagy observed in G2019S LRRK2 mutant fibroblasts[J]. Autophagy, 2012, 8(10): 1537-1539. DOI: 10.4161/auto.21270.
29.Zhu Y, Yang T, Duan J, et al. MALAT1/miR-15b-5p/MAPK1 mediates endothelial progenitor cells autophagy and affects coronary atherosclerotic heart disease via mTOR signaling pathway[J]. Aging (Albany NY), 2019, 11(4): 1089-1109. DOI: 10.18632/aging.101766.
30.Zhang P, Zheng Z, Ling L, et al. w09, a novel autophagy enhancer, induces autophagy dependent cell apoptosis via activation of the EGFR-mediated RAS-RAF1-MAP2K-MAPK1/3 pathway[J]. Autophagy, 2017, 13(7): 1093-1112. DOI: 10.1080/15548627.2017.1319039.
31.Chen S, Li F, Xu D, et al. The function of RAS mutation in cancer and advances in its drug research[J]. Curr Pharm Des, 2019, 25(10): 1105-1114. DOI: 10.2174/1381612825666190506 122228.
32.Pan W, Zhong Y, Cheng C, et al. MiR-30-regulated autophagy mediates angiotensin II-induced myocardial hypertrophy[J]. PloS one, 2013, 8(1): e53950. DOI: 10.1371/journal.pone.0053950.
33.Nandi SS, Duryee MJ, Shahshahan HR, et al. Induction of autophagy markers is associated with attenuation of miR-133a in diabetic heart failure patients undergoing mechanical unloading[J]. Am J Transl Res, 2015, 7(4): 683-696. https://pubmed.ncbi.nlm.nih.gov/26064437/.
34.Nandi SS, Zheng H, Sharma NM, et al. Lack of miR-133a decreases contractility of diabetic hearts: a role for novel cross talk between tyrosine aminotransferase and tyrosine hydroxylase[J]. Diabetes, 2016, 65(10): 3075-3090. DOI: 10.2337/db16-0023.
35.Chen C, Yang S, Li H, et al. Mir30c is involved in diabetic cardiomyopathy through regulation of cardiac autophagy via BECN1[J]. Mol Ther Nucleic Acids, 2017, 7: 127-139. DOI: 10.1016/j.omtn.2017.03.005.
36.He Y, Cai Y, Pai PM, et al. The causes and consequences of miR-503 dysregulation and its impact on cardiovascular disease and cancer[J]. Front Pharmacol, 2021, 12: 629611. DOI: 10.3389/fphar.2021.629611.
37.Miao Y, Wan Q, Liu X, et al. miR-503 is involved in the protective effect of phase II enzyme inducer (CPDT) in diabetic cardiomyopathy via Nrf2/ARE signaling pathway[J]. Bio Med Res Int, 2017, 2017: 9167450. DOI: 10.1155/2017/9167450.
38.Wei H, Li L, Zhang H, et al. Circ-FOXM1 knockdown suppresses non-small cell lung cancer development by regulating the miR-149-5p/ATG5 axis[J]. Cell Cycle, 2021, 20(2): 166-178. DOI: 10.1080/15384101.2020.1867780.
39.Pan Q, Su H, Hui D, et al. miR-149-5p can reduce myocardial apoptosis induced by myocardial ischaemia reperfusion by inhibiting the expression of IL-6[J]. Acta Medica Mediterranea, 2020, 36(1): 641-646. DOI: 10.19193/0393-6384_2020_1_101.
40.Zhuo C, Jiang R, Lin X, et al. LncRNA H19 inhibits autophagy by epigenetically silencing of DIRAS3 in diabetic cardiomyopathy[J]. Oncotarget, 2017, 8(1): 1429-1437. DOI: 10.18632/oncotarget.13637.
41.Han D, Zhou Y. YY1-induced upregulation of lncRNA NEAT1 contributes to OGD/R injury-induced inflammatory response in cerebral microglial cells via Wnt/β-catenin signaling pathway[J]. In Vitro Cell Dev Biol Anim, 2019, 55(7): 501-511. DOI: 10.1007/s11626-019-00375 -y.
42.李欣谕. 长链非编码RNA NEAT1调控肝癌细胞自噬的机制研究[D]. 沈阳: 中国医科大学, 2020.
43.Zhuang ST, Cai YJ, Liu HP, et al. LncRNA NEAT1/miR-185-5p/IGF2 axis regulates the invasion and migration of colon cancer[J]. Mol Genet Genomic Med, 2020, 8(4): e1125. DOI: 10.1002/mgg3.1125.
44.Zhou D, Gu J, Wang Y, et al. Long non-coding RNA NEAT1 transported by extracellular vesicles contributes to breast cancer development by sponging miRNA-141-3p and regulating KLF12[J]. Cell Biosci, 2021, 11(1): 68. DOI: 10.1186/s13578-021-00556-x.
45.Fan CB, Yan XH, Tian M, et al. Long non-coding RNA NEAT1 regulates Hodgkin's lymphoma cell proliferation and invasion via miR-448 mediated regulation of DCLK1[J]. Eur Rev Med Pharmacol Sci, 2020, 24(11): 6219-6227. DOI: 10.26355/eurrev_202006_21518.
46.李吉, 徐莹, 褚以忞, 等. lncRNA XIST-miR137-ATG5调节细胞自噬功能在肠癌细胞5-氟胞嘧啶耐药性中的作用[J]. 现代生物医学进展, 2020, 20(19): 3609-3615. [Li J, Xu Y, Chu YM, et al. LncRNA XIST-miR137-ATG5 mediate cell autophagy to attenuate 5-FU resistance in colorectal cancer cells to 5-FU[J]. Progress in Modern Biomedicine, 2020, 20(19): 3609-3615.] DOI: 10.13241/j.cnki.pmb.2020.19.002.
47.邢益桓, 付斌, 夏鹰. lncRNA XIST介导的ceRNA调控网络在恶性肿瘤中作用的研究进展[J]. 中国肿瘤生物治疗杂志, 2020, 27(9): 1062-1067. [Xing YH, Fu B, Xia Y. Research progress on the role of lncRNA XIST mediated ceRNA regulatory network in various malignant tumors[J]. Chinese Journal of Cancer Biotherapy, 2020, 27(9): 1062-1067.] DOI: 10.3872/j.issn.1007-385X.2020.09.016.
48.冯晓帆, 王艳杰, 刘羽茜, 等. 沉默LncRNA MALAT1对补脾益气法调节DE大鼠海马中I-κB、IL-6和PI3K表达的影响[J]. 中华中医药学刊, 2022, 40(10): 151-155. [Feng XF, Wang YJ, Liu YQ, et al. Effect of silencing LncRNA MALAT1 on regulating expressions of I-κB, IL-6 and PI3K in hippocampus of DE rats by Tonifying Spleen and Qi effects method[J]. Chinese Archives of Traditional Chinese Medicine, 2022, 40(10): 151-155.] DOI: 10.13193/j.issn.1673- 7717.2022.10.035.
49.曹亚莉, 李宏慧, 邵渊, 等. siRNA靶向沉默MALAT-1对鼻咽癌细胞增殖、凋亡及PI3K/ATK通路的影响[J]. 现代肿瘤医学, 2020, 28(6): 892- 896. [Cao YL, Li HH, Shao Y, et al. Effects of siRNA targeting silencing MALAT-1 on proliferation, apoptosis and PI3K/ATK pathway of nasopharyngeal carcinoma cells[J]. Journal of Modern Oncology, 2020, 28(6): 892- 896.] DOI: 10.3969/j.issn.1672-4992.2020.06.005.
50.Hu H, Wu J, Yu X, et al. Long noncoding RNA MALAT1 enhances the apoptosis of cardiomyocytes through autophagy modulation[J]. Biochem Cell Biol, 2020, 98(2): 130-136. DOI: 10.1139/bcb-2019-0062.
51.Sun R, Zhang L. Long non-coding RNA MALAT1 regulates cardiomyocytes apoptosis after hypoxia/reperfusion injury via modulating miR-200a-3p/PDCD4 axis[J]. Biomed Pharmacother, 2019, 111: 1036-1045. DOI: 10.1016/j.biopha.2018.12.122.
52.Wu A, Sun W, Mou F. lncRNAMALAT1 promotes high glucoseinduced H9C2 cardiomyocyte pyroptosis by downregulating miR1413p expression[J]. Mol Med Rep, 2021, 23(4): 259. DOI: 10.3892/mmr.2021.11898.
53.黄家喜, 鲍翠玉, 李晶. PI3K/AKT通路在糖尿病心肌病中的研究进展 [J]. 中国药理学通报, 2019, 35(9): 1202-1205. [Huang JX, Bao CY, Li J. Research progress of PI3K/Akt pathway in diabetic cardiomyopathy[J]. Chinese Pharmacological Bulletin, 2019, 35(9): 1202-1205.] DOI: 10.3969/j.issn.1001-1978.2019.09.005.