Integrated Transcriptomics and Reverse Pharmacophore Mapping-based
Network Pharmacology to Explore the Mechanisms of Natural Compounds
against Doxorubicin-induced Cardiotoxicity

Junfeng       Zhu; Xiaojiao       Yi; Haiying       Ding; Like       Zhong; Luo       Fang

doi:10.2174/1386207324666210816122629

Abstract

Background: Doxorubicin-Induced Cardiotoxicity (DIC) has greatly limited the clinical benefits of this frontline drug in oncotherapy. Drug combination with Natural Compounds (NCs) that possess potency against DIC is considered as a promising intervention strategy. However, the Mechanisms of Action (MoAs) underlying such drug interactions remain poorly understood. The aim of this study was to systematically pursuit of the molecular mechanisms of NCs against DIC.

Methods: First, the gene expression signatures of DIC were characterized from transcriptomics datasets with doxorubicin-treated and untreated cardiomyocytes using differentially expressed gene identification, functional enrichment analysis, and protein-protein interaction network analysis. Secondly, reverse pharmacophore mapping-based network pharmacology was employed to illustrate the MoAs of 82 publicly reported NCs with anti-DIC potency. Cluster analysis based on their enriched pathways was performed to gain systematic insights into the anti-DIC mechanisms of the NCs. Finally, the typical compounds were validated using Gene Set Enrichment Analysis (GSEA) of the relevant gene expression profiles from a public gene expression database.

Results: Based on their anti-DIC MoAs, the 82 NCs could be divided into four groups, which corresponded to ten MoA clusters. GSEA and literature evidence on these compounds were provided to validate the MoAs identified through this bioinformatics analysis. The results suggested that NCs exerted potency against DIC through both common and different MoAs.

Conclusion: This strategy integrating different types of bioinformatics approaches is expected to create new insights for elucidating the MoAs of NCs against DIC.

Keywords: Doxorubicin-induced cardiotoxicity, natural compounds, mechanism of action, gene expression profile, bioinformatics, network pharmacology.

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[1] 
Arcamone, F.; Cassinelli, G.; Fantini, G.; Grein, A.; Orezzi, P.; Pol, C.; Spalla, C. Adriamycin, 14-hydroxydaunomycin, a new antitumor antibiotic from S. peucetius var. caesius. Biotechnol. Bioeng.,  1969, 11(6), 1101-1110.
[http://dx.doi.org/10.1002/bit.260110607] 
[2] 
Zhang, L.; Wang, X.J.; Feng, M.W.; Zhang, H.; Xu, J.; Ding, J.J.; Cheng, Z.J.; Qian, L.M. Peptidomics analysis reveals peptide PDCryab1 inhibits doxorubicin-induced cardiotoxicity. Oxid. Med. Cell. Longev.,  2020, 9(2), 7182428.
[http://dx.doi.org/10.1155/2020/7182428] 
[3] 
Cagel, M.; Grotz, E.; Bernabeu, E.; Moretton, M.A.; Chiappetta, D.A. Doxorubicin: nanotechnological overviews from bench to bedside. Drug Discov. Today,  2017, 22(2), 270-281.
[http://dx.doi.org/10.1016/j.drudis.2016.11.005] 
[4] 
Yu, J.; Wang, C.X.; Kong, Q.; Wu, X.X.; Lu, J.J.; Chen, X.P. Recent progress in doxorubicin-induced cardiotoxicity and protective potential of natural products. Phytomedicine,  2018, 40, 125-139.
[http://dx.doi.org/10.1016/j.phymed.2018.01.009] 
[5] 
Shaikh, F.; Dupuis, L.L.; Alexander, S.; Gupta, A.; Mertens, L.; Nathan, P.C. Cardioprotection and second malignant neoplasms associated with dexrazoxane in children receiving anthracycline chemotherapy: a systematic review and meta-analysis. J. Natl. Cancer Inst.,  2016, 108(4), djv357.
[http://dx.doi.org/10.1093/jnci/djv357] 
[6] 
Kalen, A.L.; Wagner, B.A.; Sarsour, E.H.; Kumar, M.G.; Reedy, J.L.; Buettner, G.R.; Barua, N.C.; Goswami, P.C. Hydrogen peroxide mediates artemisinin-derived C-16 carba-dimer-induced toxicity of human cancer cells. Antioxidants (Basel),  2020, 9(2), 108.
[http://dx.doi.org/10.3390/antiox9020108] 
[7] 
Abushouk, A.I.; Ismail, A.; Salem, A.M.A.; Afifi, A.M.; Abdel-Daim, M.M. Cardioprotective mechanisms of phytochemicals against doxorubicin-induced cardiotoxicity. Biomed. Pharmacother.,  2017, 90, 935-946.
[http://dx.doi.org/10.1016/j.biopha.2017.04.033] 
[8] 
Hosseini, A.; Sahebkar, A. Reversal of doxorubicin-induced cardiotoxicity by using phytotherapy: a review. J. Pharmacopuncture,  2017, 20(4), 243-256.
[http://dx.doi.org/10.3831/KPI.2017.20.030] 
[9] 
Ojha, S.; Al Taee, H.; Goyal, S.; Mahajan, U.B.; Patil, C.R.; Arya, D.S.; Rajesh, M. Cardioprotective potentials of plant-derived small molecules against doxorubicin associated cardiotoxicity. Oxid. Med. Cell. Longev.,  2016, 2016, 5724973.
[http://dx.doi.org/10.1155/2016/5724973] 
[10] 
Yi, X.J.; Zhu, J.F.; Zhang, J.H.; Gao, Y.; Chen, Z.J.; Lu, S.H.; Cai, Z.W.; Hong, Y.J.; Wu, Y.J. Investigation of the reverse effect of Danhong injection on doxorubicin-induced cardiotoxicity in H9c2 cells: Insight by LC-MS based non-targeted metabolomic analysis. J. Pharm. Biomed. Anal.,  2018, 152, 264-270.
[http://dx.doi.org/10.1016/j.jpba.2018.02.012] 
[11] 
Lv, X.X.; Yu, X.H.; Wang, Y.Y.; Wang, F.Q.; Li, H.M.; Wang, Y.P.; Lu, D.X.; Qi, R.B.; Wang, H.D. Berberine inhibits doxorubicin-triggered cardiomyocyte apoptosis via attenuating mitochondrial dysfunction and increasing Bcl-2 expression. PLoS One,  2012, 7(10), e47351.
[http://dx.doi.org/10.1371/journal.pone.0047351] 
[12] 
Liu, Z.W.; Luo, Z.H.; Meng, Q.Q.; Zhong, P.C.; Hu, Y.J.; Shen, X.L. Network pharmacology-based investigation on the mechanisms of action of Morinda officinalis How in the treatment of osteoporosis. Comput. Biol. Med.,  2020, 127, 104074.
[http://dx.doi.org/10.1016/j.compbiomed.2020.104074] 
[13] 
Zhang, W.J.; Xue, K.Y.; Gao, Y.G.; Huai, Y.; Wang, W.; Miao, Z.P.; Dang, K.; Jiang, S.F.; Qian, A.R. Systems pharmacology dissection of action mechanisms of Dipsaci Radix for osteoporosis. Life Sci.,  2019, 235, 116820.
[http://dx.doi.org/10.1016/j.lfs.2019.116820] 
[14] 
Huang, Q.; Liu, R.; Liu, J.; Huang, Q.; Liu, S.; Jiang, Y.P. Integrated network pharmacology analysis and experimental validation to reveal the mechanism of anti-insulin resistance effects of Moringa oleifera Seeds. Drug Des. Devel. Ther.,  2020, 14, 4069-4084.
[http://dx.doi.org/10.2147/dddt.S265198] 
[15] 
Wang, X.; Shen, Y.H.; Wang, S.W.; Li, S.L.; Zhang, W.L.; Liu, X.F.; Lai, L.H.; Pei, J.F.; Li, H.L. PharmMapper 2017 update: a web server for potential drug target identification with a comprehensive target pharmacophore database. Nucleic Acids Res.,  2017, 45(W1), W356-W360.
[http://dx.doi.org/10.1093/nar/gkx374] 
[16] 
Liu, B.; Fu, X.Q.; Li, T.; Su, T.; Guo, H.; Zhu, P.L.; Tse, A.K.W.; Liu, S.M.; Yu, Z.L. Computational and experimental prediction of molecules involved in the anti-melanoma action of berberine. J. Ethnopharmacol.,  2017, 208, 225-235.
[http://dx.doi.org/10.1016/j.jep.2017.07.023] 
[17] 
Chen, S.J.; Cui, M.C. Systematic understanding of the mechanism of salvianolic acid a via computational target fishing. Molecules,  2017, 22(4), 644.
[http://dx.doi.org/10.3390/molecules22040644] 
[18] 
Huang, J.; Liang, Y.; Tian, W.; Ma, J.; Huang, L.; Li, B.; Chen, R.; Li, D. Antitumor activity and mechanism of robustic acid from Dalbergia benthami Prain via computational target fishing. Molecules,  2020, 25(17), 3919.
[http://dx.doi.org/10.3390/molecules25173919] 
[19] 
Lv, C.; Wu, X.T.; Wang, X.; Su, J.; Zeng, H.W.; Zhao, J.; Lin, S.; Liu, R.H.; Li, H.L.; Li, X.; Zhang, W.D. The gene expression profiles in response to 102 traditional Chinese medicine (TCM) components: a general template for research on TCMs. Sci. Rep.,  2017, 7(1), 352.
[http://dx.doi.org/10.1038/s41598-017-00535-8] 
[20] 
Yu, G.C.; Wang, L.G.; Han, Y.Y.; He, Q.Y. clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS,  2012, 16(5), 284-287.
[http://dx.doi.org/10.1089/omi.2011.0118] 
[21] 
Chen, Q.F.; Xia, J.G.; Li, W.; Shen, L.J.; Huang, T.; Wu, P. Examining the key genes and pathways in hepatocellular carcinoma development from hepatitis B virus-positive cirrhosis. Mol. Med. Rep.,  2018, 18(6), 4940-4950.
[http://dx.doi.org/10.3892/mmr.2018.9494] 
[22] 
Zhu, J.F.; Yi, X.J.; Zhang, Y.W.; Pan, Z.F.; Zhong, L.K.; Huang, P. Systems pharmacology-based approach to comparatively study the independent and synergistic mechanisms of Danhong injection and Naoxintong capsule in ischemic stroke treatment. Evid. Based Complement. Alternat. Med.,  2019, 2019, 1056708.
[http://dx.doi.org/10.1155/2019/1056708] 
[23] 
Maillet, A.; Tan, K.; Chai, X.; Sadananda, S.N.; Mehta, A.; Ooi, J.; Hayden, M.R.; Pouladi, M.A.; Ghosh, S.; Shim, W.; Brunham, L.R. Modeling doxorubicin-induced cardiotoxicity in human pluripotent stem cell derived-cardiomyocytes. Sci. Rep.,  2016, 6, 25333.
[http://dx.doi.org/10.1038/srep25333] 
[24] 
Burridge, P.W.; Li, Y.F.; Matsa, E.; Wu, H.; Ong, S.G.; Sharma, A.; Holmström, A.; Chang, A.C.; Coronado, M.J.; Ebert, A.D.; Knowles, J.W.; Telli, M.L.; Witteles, R.M.; Blau, H.M.; Bernstein, D.; Altman, R.B.; Wu, J.C. Human induced pluripotent stem cell-derived cardiomyocytes recapitulate the predilection of breast cancer patients to doxorubicin-induced cardiotoxicity. Nat. Med.,  2016, 22(5), 547-556.
[http://dx.doi.org/10.1038/nm.4087] 
[25] 
Magdy, T.; Schuldt, A.J.T.; Wu, J.C.; Bernstein, D.; Burridge, P.W. Human induced pluripotent stem cell (hiPSC)-derived cells to assess drug cardiotoxicity: opportunities and problems. Annu. Rev. Pharmacol. Toxicol.,  2018, 58, 83-103.
[http://dx.doi.org/10.1146/annurev-pharmtox-010617-053110] 
[26] 
Takeda, M.; Miyagawa, S.; Fukushima, S.; Saito, A.; Ito, E.; Harada, A.; Matsuura, R.; Iseoka, H.; Sougawa, N.; Mochizuki-Oda, N.; Matsusaki, M.; Akashi, M.; Sawa, Y. Development of in vitro drug-induced cardiotoxicity assay by using three-dimensional cardiac tissues derived from human induced pluripotent stem cells. Tissue Eng. Part C Methods,  2018, 24(1), 56-67.
[http://dx.doi.org/10.1089/ten.TEC.2017.0247] 
[27] 
Cheng, X.L.; Liu, D.; Xing, R.N.; Song, H.X.; Tian, X.X.; Yan, C.H.; Han, Y.L. Orosomucoid 1 attenuates doxorubicin-induced oxidative stress and apoptosis in cardiomyocytes via Nrf2 signaling. BioMed Res. Int.,  2020, 2020, 5923572.
[http://dx.doi.org/10.1155/2020/5923572] 
[28] 
Wang, W.; Fang, Q.; Zhang, Z.H.; Wang, D.W.; Wu, L.J.; Wang, Y. PPARα ameliorates doxorubicin-induced cardiotoxicity by reducing mitochondria-dependent apoptosis via regulating MEOX1. Front. Pharmacol.,  2020, 11, 528267.
[http://dx.doi.org/10.3389/fphar.2020.528267] 
[29] 
Ito, H.; Miller, S.C.; Billingham, M.E.; Akimoto, H.; Torti, S.V.; Wade, R.; Gahlmann, R.; Lyons, G.; Kedes, L.; Torti, F.M. Doxorubicin selectively inhibits muscle gene expression in cardiac muscle cells in vivo and in vitro. Proc. Natl. Acad. Sci. USA,  1990, 87(11), 4275-4279.
[http://dx.doi.org/10.1073/pnas.87.11.4275] 
[30] 
Rodrigues, P.G.; Miranda-Silva, D.; Costa, S.M.; Barros, C.; Hamdani, N.; Moura, C.; Mendes, M.J.; Sousa-Mendes, C.; Trindade, F.; Fontoura, D.; Vitorino, R.; Linke, W.A.; Leite-Moreira, A.F.; Falcão-Pires, I. Early myocardial changes induced by doxorubicin in the nonfailing dilated ventricle. Am. J. Physiol. Heart Circ. Physiol.,  2019, 316(3), H459-H475.
[http://dx.doi.org/10.1152/ajpheart.00401.2018] 
[31] 
Yarmohammadi, F.; Rezaee, R.; Karimi, G. Natural compounds against doxorubicin-induced cardiotoxicity: A review on the involvement of Nrf2/ARE signaling pathway. Phytother. Res.,  2020, 2020, 1-13.
[http://dx.doi.org/10.1002/ptr.6882] 
[32] 
Tang, Q.; Xiong, W.; Ke, X.X.; Zhang, J.; Xia, Y.; Liu, D.X. Mitochondria-associated protein LRPPRC exerts cardioprotective effects against doxorubicin-induced toxicity, potentially via inhibition of ROS accumulation. Exp. Ther. Med.,  2020, 20(4), 3837-3845.
[http://dx.doi.org/10.3892/etm.2020.9111] 
[33] 
Wang, P.X.; Lan, R.; Guo, Z.; Cai, S.D.; Wang, J.J.; Wang, Q.; Li, Z.Y.; Li, Z.Z.; Wang, Q.Q.; Li, J.Y.; Wu, Z.K.; Lu, J.; Liu, P.Q. Histone demethylase JMJD3 mediated doxorubicin-induced cardiomyopathy by suppressing SESN2 expression. Front. Cell Dev. Biol.,  2020, 8, 548605.
[http://dx.doi.org/10.3389/fcell.2020.548605] 
[34] 
Ichikawa, Y.; Ghanefar, M.; Bayeva, M.; Wu, R.X.; Khechaduri, A.; Naga Prasad, S.V.; Mutharasan, R.K.; Naik, T.J.; Ardehali, H. Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation. J. Clin. Invest.,  2014, 124(2), 617-630.
[http://dx.doi.org/10.1172/jci72931] 
[35] 
Schriml, L.M.; Arze, C.; Nadendla, S.; Chang, Y.W.; Mazaitis, M.; Felix, V.; Feng, G.; Kibbe, W.A. Disease Ontology: a backbone for disease semantic integration. Nucleic Acids Res.,  2012, 40, D940-D946.
[http://dx.doi.org/10.1093/nar/gkr972] 
[36] 
Zhao, Y.; Li, Q.; Zhao, W.J.; Li, J.; Sun, Y.; Liu, K.; Liu, B.L.; Zhang, N. Astragaloside IV and cycloastragenol are equally effective in inhibition of endoplasmic reticulum stress-associated TXNIP/NLRP3 inflammasome activation in the endothelium. J. Ethnopharmacol.,  2015, 169, 210-218.
[http://dx.doi.org/10.1016/j.jep.2015.04.030] 
[37] 
Auyeung, K.K.; Han, Q.B.; Ko, J.K. Astragalus membranaceus: a review of its protection against inflammation and gastrointestinal cancers. Am. J. Chin. Med.,  2016, 44(1), 1-22.
[http://dx.doi.org/10.1142/S0192415X16500014] 
[38] 
Jia, Y.Y.; Zuo, D.Y.; Li, Z.Q.; Liu, H.M.; Dai, Z.N.; Cai, J.Y.; Pang, L.L.; Wu, Y.L. Astragaloside IV inhibits doxorubicin-induced cardiomyocyte apoptosis mediated by mitochondrial apoptotic pathway via activating the PI3K/Akt pathway. Chem. Pharm. Bull. (Tokyo),  2014, 62(1), 45-53.
[http://dx.doi.org/10.1248/cpb.c13-00556] 
[39] 
Zhu, F.F.; Yin, Y.Y.; Li, W.P.; Li, W.Z.; Wu, G.C.; Gong, H.L.; Zhang, W. Protective effect of extract of astragalus against injury induced by hypoxia/reoxygenation in hippocampus neuron. Chin. Pharmacol. Bull.,  2009, 25(2), 213-216.
[http://dx.doi.org/10.3321/j.issn:1001-1978.2009.02.020] 
[40] 
Yang, Y.F.; Li, Y.; Wang, J.H.; Sun, K.; Tao, W.Y.; Wang, Z.Z.; Xiao, W.; Pan, Y.Q.; Zhang, S.W.; Wang, Y.H. Systematic investigation of Ginkgo Biloba leaves for treating cardio-cerebrovascular diseases in an animal model. ACS Chem. Biol.,  2017, 12(5), 1363-1372.
[http://dx.doi.org/10.1021/acschembio.6b00762] 
[41] 
van Nimwegen, M.J.; Huigsloot, M.; Camier, A.; Tijdens, I.B.; van de Water, B. Focal adhesion kinase and protein kinase B cooperate to suppress doxorubicin-induced apoptosis of breast tumor cells. Mol. Pharmacol.,  2006, 70(4), 1330-1339.
[http://dx.doi.org/10.1124/mol.106.026195] 
[42] 
Wang, X.P.; Li, C.; Wang, Q.Y.; Li, W.L.; Guo, D.Q.; Zhang, X.F.; Shao, M.Y.; Chen, X.; Ma, L.; Zhang, Q.; Wang, W.; Wang, Y. Tanshinone IIA restores dynamic balance of autophagosome/autolysosome in doxorubicin-induced cardiotoxicity via targeting Beclin1/LAMP1. Cancers (Basel),  2019, 11(7), 910.
[http://dx.doi.org/10.3390/cancers11070910] 
[43] 
Guo, Z.H.; Yan, M.; Chen, L.; Fang, P.F.; Li, Z.H.; Wan, Z.M.; Cao, S.; Hou, Z.Y.; Wei, S.S.; Li, W.Q.; Zhang, B.K. Nrf2-dependent antioxidant response mediated the protective effect of tanshinone IIA on doxorubicin-induced cardiotoxicity. Exp. Ther. Med.,  2018, 16(4), 3333-3344.
[http://dx.doi.org/10.3892/etm.2018.6614] 
[44] 
Jiang, B.H.; Zhang, L.; Wang, Y.C.; Li, M.; Wu, W.Y.; Guan, S.H.; Liu, X.; Yang, M.; Wang, J.C.; Guo, D.A. Tanshinone IIA sodium sulfonate protects against cardiotoxicity induced by doxorubicin in vitro and in vivo. Food Chem. Toxicol.,  2009, 47(7), 1538-1544.
[http://dx.doi.org/10.1016/j.fct.2009.03.038] 
[45] 
Zhang, M.Q.; Zheng, Y.L.; Chen, H.; Tu, J.F.; Shen, Y.; Guo, J.P.; Yang, X.H.; Yuan, S.R.; Chen, L.Z.; Chai, J.J.; Lu, J.H.; Zhai, C.L. Sodium tanshinone IIA sulfonate protects rat myocardium against ischemia-reperfusion injury via activation of PI3K/Akt/FOXO3A/Bim pathway. Acta Pharmacol. Sin.,  2013, 34(11), 1386-1396.
[http://dx.doi.org/10.1038/aps.2013.91] 
[46] 
Glauser, D.A.; Schlegel, W. The emerging role of FOXO transcription factors in pancreatic beta cells. J. Endocrinol.,  2007, 193(2), 195-207.
[http://dx.doi.org/10.1677/joe-06-0191] 
[47] 
Zhang, X.; Tang, N.; Hadden, T.J.; Rishi, A.K. Akt, FoxO and regulation of apoptosis. Biochim. Biophys. Acta,  2011, 1813(11), 1978-1986.
[http://dx.doi.org/10.1016/j.bbamcr.2011.03.010] 
[48] 
Jiramongkol, Y.; Lam, E.W. FOXO transcription factor family in cancer and metastasis. Cancer Metastasis Rev.,  2020, 39(3), 681-709.
[http://dx.doi.org/10.1007/s10555-020-09883-w] 
[49] 
Shi, Y.; Moon, M.; Dawood, S.; McManus, B.; Liu, P.P. Mechanisms and management of doxorubicin cardiotoxicity. Herz,  2011, 36(4), 296-305.
[http://dx.doi.org/10.1007/s00059-011-3470-3] 
[50] 
Chandrasekhar, Y.; Phani Kumar, G.; Ramya, E.M.; Anilakumar, K.R. Gallic acid protects 6-OHDA induced neurotoxicity by attenuating oxidative stress in human dopaminergic cell line. Neurochem. Res.,  2018, 43(6), 1150-1160.
[http://dx.doi.org/10.1007/s11064-018-2530-y] 
[51] 
Al Zahrani, N.A.; El-Shishtawy, R.M.; Asiri, A.M. Recent developments of gallic acid derivatives and their hybrids in medicinal chemistry: A review. Eur. J. Med. Chem.,  2020, 204, 112609.
[http://dx.doi.org/10.1016/j.ejmech.2020.112609] 
[52] 
Ryu, Y.; Jin, L.; Kee, H.J.; Piao, Z.H.; Cho, J.Y.; Kim, G.R.; Choi, S.Y.; Lin, M.Q.; Jeong, M.H. Gallic acid prevents isoproterenol-induced cardiac hypertrophy and fibrosis through regulation of JNK2 signaling and Smad3 binding activity. Sci. Rep.,  2016, 6, 34790.
[http://dx.doi.org/10.1038/srep34790] 
[53] 
Ola-Davies, O.E.; Olukole, S.G. Gallic acid protects against bisphenol A-induced alterations in the cardio-renal system of Wistar rats through the antioxidant defense mechanism. Biomed. Pharmacother.,  2018, 107, 1786-1794.
[http://dx.doi.org/10.1016/j.biopha.2018.08.108] 
[54] 
Ekinci Akdemir, F.N.; Yildirim, S.; Kandemir, F.M.; Tanyeli, A.; Küçükler, S.; Bahaeddin Dortbudak, M. Protective effects of gallic acid on doxorubicin-induced cardiotoxicity; an experimantal study. Arch. Physiol. Biochem.,  2019, 2019, 1-8.
[http://dx.doi.org/10.1080/13813455.2019.1630652] 
[55] 
Lee, E.R.; Kim, J.Y.; Kang, Y.J.; Ahn, J.Y.; Kim, J.H.; Kim, B.W.; Choi, H.Y.; Jeong, M.Y.; Cho, S.G. Interplay between PI3K/Akt and MAPK signaling pathways in DNA-damaging drug-induced apoptosis. Biochim. Biophys. Acta,  2006, 1763(9), 958-968.
[http://dx.doi.org/10.1016/j.bbamcr.2006.06.006] 
[56] 
Hughes, C.E.; Nibbs, R.J.B. A guide to chemokines and their receptors. FEBS J.,  2018, 285(16), 2944-2971.
[http://dx.doi.org/10.1111/febs.14466] 
[57] 
Haybar, H.; Shahrabi, S.; Deris Zayeri, Z.; Pezeshki, S. Strategies to increase cardioprotection through cardioprotective chemokines in chemotherapy-induced cardiotoxicity. Int. J. Cardiol.,  2018, 269, 276-282.
[http://dx.doi.org/10.1016/j.ijcard.2018.07.087] 
[58] 
He, J.; Zhu, N.L.; Kong, J.; Peng, P.; Li, L.F.; Wei, X.L.; Jiang, Y.Y.; Zhang, Y.L.; Bian, B.L.; She, G.M.; Shi, R.B. A newly discovered phenylethanoid glycoside from Stevia rebaudiana Bertoni affects insulin secretion in rat INS-1 islet β cells. Molecules,  2019, 24(22), 4178.
[http://dx.doi.org/10.3390/molecules24224178] 
[59] 
Wang, X.L.; Wang, X.; Xiong, L.L.; Zhu, Y.; Chen, H.L.; Chen, J.X.; Wang, X.X.; Li, R.L.; Guo, Z.Y.; Li, P. Salidroside improves doxorubicin-induced cardiac dysfunction by suppression of excessive oxidative stress and cardiomyocyte apoptosis. J. Cardiovasc. Pharmacol.,  2013, 62(6), 512-523.
[http://dx.doi.org/10.1097/FJC.0000000000000009] 
[60] 
Yin, Z.W.; Zhao, Y.R.; Li, H.P.; Yan, M.W.; Zhou, L.; Chen, C.; Wang, D.W. miR-320a mediates doxorubicin-induced cardiotoxicity by targeting VEGF signal pathway. Aging (Albany NY),  2016, 8(1), 192-207.
[http://dx.doi.org/10.18632/aging.100876] 
[61] 
Godo, S.; Shimokawa, H. Endothelial functions. Arterioscler. Thromb. Vasc. Biol.,  2017, 37(9), e108-e114.
[http://dx.doi.org/10.1161/atvbaha.117.309813] 
[62] 
Zhang, L.F.; Liu, L.Y.; Li, X. MiR-526b-3p mediates doxorubicin-induced cardiotoxicity by targeting STAT3 to inactivate VEGFA. Biomed. Pharmacother.,  2020, 123, 109751.
[http://dx.doi.org/10.1016/j.biopha.2019.109751] 
[63] 
Zhang, H.L.; Zhang, A.L.; Guo, C.F.; Shi, C.Z.; Zhang, Y.; Liu, Q.; Sparatore, A.; Wang, C.Q. S-diclofenac protects against doxorubicin-induced cardiomyopathy in mice via ameliorating cardiac gap junction remodeling. PLoS One,  2011, 6(10), e26441.
[http://dx.doi.org/10.1371/journal.pone.0026441] 
[64] 
Totland, M.Z.; Rasmussen, N.L.; Knudsen, L.M.; Leithe, E. Regulation of gap junction intercellular communication by connexin ubiquitination: physiological and pathophysiological implications. Cell. Mol. Life Sci.,  2020, 77(4), 573-591.
[http://dx.doi.org/10.1007/s00018-019-03285-0] 
[65] 
Martins-Marques, T.; Catarino, S.; Gonçalves, A.; Miranda-Silva, D.; Gonçalves, L.; Antunes, P.; Coutinho, G.; Leite Moreira, A.; Falcão Pires, I.; Girão, H. EHD1 modulates Cx43 gap junction remodeling associated with cardiac diseases. Circ. Res.,  2020, 126(10), e97-e113.
[http://dx.doi.org/10.1161/circresaha.119.316502] 
[66] 
Pecoraro, M.; Ciccarelli, M.; Fiordelisi, A.; Iaccarino, G.; Pinto, A.; Popolo, A. Diazoxide improves mitochondrial connexin 43 expression in a mouse model of doxorubicin-induced cardiotoxicity. Int. J. Mol. Sci.,  2018, 19(3), 757.
[http://dx.doi.org/10.3390/ijms19030757] 
[67] 
Pecoraro, M.; Pala, B.; Di Marcantonio, M.C.; Muraro, R.; Marzocco, S.; Pinto, A.; Mincione, G.; Popolo, A. Doxorubicin-induced oxidative and nitrosative stress: Mitochondrial connexin 43 is at the crossroads. Int. J. Mol. Med.,  2020, 46(3), 1197-1209.
[http://dx.doi.org/10.3892/ijmm.2020.4669] 

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DOI https://dx.doi.org/10.2174/1386207324666210816122629	Print ISSN 1386-2073
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Combinatorial Chemistry & High Throughput Screening

Integrated Transcriptomics and Reverse Pharmacophore Mapping-based Network Pharmacology to Explore the Mechanisms of Natural Compounds against Doxorubicin-induced Cardiotoxicity

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