Virtual Screening of the Multi-pathway and Multi-gene Regulatory Molecular Mechanism of Dachengqi Decoction in the Treatment of Stroke Based on Network Pharmacology

Author(s): Lishan Pei, Xia Shen, Yonggang Yan*, Conge Tan*, Kai Qu, Junbo Zou, Yanxia Wang, Fan Ping

Journal Name: Combinatorial Chemistry & High Throughput Screening
Accelerated Technologies for Biotechnology, Bioassays, Medicinal Chemistry and Natural Products Research

Volume 23 , Issue 8 , 2020


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Abstract:

Background: Stroke is ranked second among diseases that cause mortality worldwide. Owing to its complicated pathogenesis, no satisfactory treatment strategies for stroke are available. Dachengqi decoction (DCQD), a traditional Chinese herbal medicine, has been widely used in China for a long time, as it has a good effect on stroke. However, the molecular mechanism underlying this effect of DCQD is unclear.

Objective: In the present study, we aimed to reveal and explore the multi-pathway and multi-gene regulatory molecular mechanism of Dachengqi decoction in the treatment of stroke.

Methods: In this study, a network pharmacology method, in combination with oral bioavailability prediction and drug-likeness evaluation, was employed to predict the active ingredients of DCQD. The target genes of the active components and the traced pathways related to these target genes were predicted. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed using clusterProfiler software package on the R platform and ClueGo+CluePedia plug-ins. Finally, the key DCQD targets were verified using the Gene Expression Omnibus (GEO) dataset.

Results and Discussion: According to the ADME model, 52 active components were screened from 296 active components of DCQD. After prediction and screening, 215 stroke-related targets were obtained and analyzed via GO and KEGG analyses. GO analysis showed that DCQD targets were mainly involved in the regulation of oxidative stress, lipid metabolism, inflammation, and other biological processes. KEGG pathway analysis further revealed pathways involved in stroke, such as arachidonic acid metabolic, HIF-1 signaling pathway, estrogen signaling pathway, MAPK signaling pathway, PI3K-Akt signaling pathway, platelet activation pathway, VEGF signaling pathway, and cAMP signaling pathway. Network analysis revealed that DCQD might be involved in the regulation of lipid metabolism, blood pressure, inflammation, angiogenesis, neuroprotection, platelet aggregation, apoptosis, and oxidation in stroke treatment. GEO dataset analysis showed that DCQD’s therapeutic effects might be exerted via the bidirectional regulation principle.

Conclusion: Based on the methods of network pharmacology and GEO analysis, it was found that, during stroke treatment, DCQD regulates and controls multiple genes and multiple pathways in a synergistic manner, providing a new strategy for stroke treatment.

Keywords: Dachengqi decoction, ADME, stroke, molecular mechanism, bidirectional regulation, GEO verified.

[1]
Cao, H.Q.; Chen, G.; Dong, E.D. Ten-year review of cerebrovascular disease research funded by the national natural science foundation of China. Chin. J. Neurosurg., 2013, 29, 541-542.
[2]
Hou, S.; Zhang, H.; Li, B.; Luo, Y.; Han, Z.; Shang, S. Validation and evaluation of the core nursing outcomes evaluation system for inpatients with stroke. Int. J. Nurs. Knowl., 2019, 2019, 1-7.
[http://dx.doi.org/10.1111/2047-3095.12259 ] [PMID: 31697041]
[3]
Johnson, C.O.; Nguyen, M.; Roth, G.A. GBD 2016 Stroke Collaborators. Global, regional, and national burden of stroke, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol., 2019, 18(5), 439-458.
[http://dx.doi.org/10.1016/S1474-4422(19)30034-1 ] [PMID: 30871944]
[4]
Owens, B. Stroke. Nature, 2014, 510(7506), S1.
[http://dx.doi.org/10.1038/510S1a ] [PMID: 24964020]
[5]
Sacco, R.L.; Dong, C. Declining stroke incidence and improving survival in US communities: evidence for success and future challenges. JAMA, 2014, 312(3), 237-238.
[http://dx.doi.org/10.1001/jama.2014.7693 ] [PMID: 25027138]
[6]
Wang, J.Q.; Wang, B.L.; Yang, W.Q. Clinical observation on treatment of 30 cases of large area Cerebral Infarction with Dachengqi decoction. J. Emerg. Tradit. Chin. Med., 2009, 18(3), 348-371.
[7]
Ming, K. W.; Hong, C. X. Study on the mechanism of Dachengqi Decoction in treating acute cerebral hemorrhage. Chinese J. Integr. Med. Cardio-/Cerebrovascuiar Dis., 2006, 4(11), 986-987.
[8]
Hopkins, A.L. Network pharmacology. Nat. Biotechnol., 2007, 25(10), 1110-1111.
[http://dx.doi.org/10.1038/nbt1007-1110 ] [PMID: 17921993]
[9]
Hopkins, A.L. Network pharmacology: the next paradigm in drug discovery. Nat. Chem. Biol., 2008, 4(11), 682-690.
[http://dx.doi.org/10.1038/nchembio.118 ] [PMID: 18936753]
[10]
Shen, X.; Zhao, Z.; Luo, X.; Wang, H.; Hu, B.; Guo, Z. Systems pharmacology based study of the molecular mechanism of SiNiSan formula for application in nervous and mental diseases. Evid. Based Complement. Alternat. Med., 2016, 2016, 9146378.
[http://dx.doi.org/10.1155/2016/9146378 ] [PMID: 28058059]
[11]
Shen, X.; Zhao, Z.; Wang, H.; Guo, Z.; Hu, B.; Zhang, G. Elucidation of the anti-inflammatory mechanisms of bupleuri and scutellariae radix using system pharmacological analyses. Mediators Inflamm., 2017, 2017, 3709874.
[http://dx.doi.org/10.1155/2017/3709874 ] [PMID: 28190938]
[12]
Stamova, B.; Jickling, G.C.; Ander, B.P.; Zhan, X.; Liu, D.; Turner, R.; Ho, C.; Khoury, J.C.; Bushnell, C.; Pancioli, A.; Jauch, E.C.; Broderick, J.P.; Sharp, F.R. Gene expression in peripheral immune cells following cardioembolic stroke is sexually dimorphic. PLoS One, 2014, 9(7), e102550.
[http://dx.doi.org/10.1371/journal.pone.0102550 ] [PMID: 25036109]
[13]
Zou, R.; Zhang, D.; Lv, L.; Shi, W.; Song, Z.; Yi, B.; Lai, B.; Chen, Q.; Yang, S.; Hua, P. Bioinformatic gene analysis for potential biomarkers and therapeutic targets of atrial fibrillation-related stroke. J. Transl. Med., 2019, 17(1), 45.
[http://dx.doi.org/10.1186/s12967-019-1790-x ] [PMID: 30760287]
[14]
Xu, X.; Zhang, W.; Huang, C.; Li, Y.; Yu, H.; Wang, Y.; Duan, J.; Ling, Y. A novel chemometric method for the prediction of human oral bioavailability. Int. J. Mol. Sci., 2012, 13(6), 6964-6982.
[http://dx.doi.org/10.3390/ijms13066964 ] [PMID: 22837674]
[15]
Tao, W.; Xu, X.; Wang, X.; Li, B.; Wang, Y.; Li, Y.; Yang, L. Network pharmacology-based prediction of the active ingredients and potential targets of Chinese herbal Radix Curcumae formula for application to cardiovascular disease. J. Ethnopharmacol., 2013, 145(1), 1-10.
[http://dx.doi.org/10.1016/j.jep.2012.09.051 ] [PMID: 23142198]
[16]
Yang, S.Z. The Divine Farmers Materia Medica:(A Translation of the Shen Nong Ben Cao Jing); Blue Poppy Press: Boulder, Colorado, 1997.
[17]
Veith, L. The Yellow Emperor’s Classic of Internal Medicine, New ed; Berkeley and Los Angeles: University of California Press: Back Cover, 1972.
[18]
Li, Z.G.; Liu, X.R. Yellow Emperor’s Canon of Medicine Plain Conversation, World Book Inc.: Xi’ an, Shaanxi, 2005.
[19]
Cavalieri, S.; Rotoli, M. Huangdi Neijing: a classic book of traditional Chinese medicine. Recenti Prog. Med., 1997, 88(11), 541-546.
[PMID: 9446158]
[20]
Hao, Y.F.; Jiang, J.G. Origin and evolution of China Pharmacopoeia and its implication for traditional medicines. Mini Rev. Med. Chem., 2015, 15(7), 595-603.
[http://dx.doi.org/10.2174/1389557515666150415150803 ] [PMID: 25877600]
[21]
Gao, C.; Zhu, J.P. On ‘apoplexy’ in Chinese ancient medical books. Chin J. Tradit. Chin. Med. Pharm., 2014, 29(5), 1298-1303.
[22]
Tian, Y.Q.; Ding, P. Summary of pharmacological clinical and pharmaceutical research of dachengqi decoction. Zhonghua Zhongyiyao Xuekan, 2006, 24(11), 2134-2135.
[23]
Li, X.; Chu, S.; Liu, Y.; Chen, N. Neuroprotective effects of anthraquinones from rhubarb in central nervous system diseases. Evid. Based Complement. Alternat. Med., 2019, 2019, 3790728.
[http://dx.doi.org/10.1155/2019/3790728 ] [PMID: 31223328]
[24]
Li, M.; Du, Z.M. Research progress on pharmacological effects of aloe-emodin. Zhongguo Lin Chuang Yao Li Xue Za Zhi, 2015, 31(9), 765-768.
[25]
Tan, P.; Zhang, H.Z.; Li, Y.; Zhang, D.K.; Wang, J.B.; Xiao, X.H.; Liu, M. Preliminary study on antiplatelet aggregation of 10 anthraquinones in Rhei Radix et Rhizoma based on bioassay. Chin. Tradit. Herbal Drugs, 2018, 49(04), 859-865.
[26]
Zhang, S.J.; Zhong, L.Y. Research progress on chemical constituents and modern pharmacology of Magnolia officinalis. Zhong Yao Cai, 2013, 36(5), 838-843.
[27]
Liu, Y.P. Main ingredients of Mangnolia officinalis and general situation of its pharmacological action research. Chem. Intermediate., 2017, 5, 141-142.
[28]
Zhang, X.X.; Li, Z.Y.; Ma, Y.L.; Ma, S.C. Progress in research of traditional Chinese medicine Citrus aurantium. Zhongguo Zhongyao Zazhi, 2015, 40(2), 185-190.
[PMID: 26080542]
[29]
Zhang, L.; Zhang, X.; Zhang, C.; Bai, X.; Zhang, J.; Zhao, X.; Chen, L.; Wang, L.; Zhu, C.; Cui, L.; Chen, R.; Zhao, T.; Zhao, Y. Nobiletin promotes antioxidant and anti-inflammatory responses and elicits protection against ischemic stroke in vivo. Brain Res., 2016, 1636, 130-141.
[http://dx.doi.org/10.1016/j.brainres.2016.02.013 ] [PMID: 26874072]
[30]
Gao, H.H.; Gao, L.B.; Wen, J.M. Genetic polymorphisms in the ESR1 gene and cerebral infarction risk: a meta-analysis. DNA Cell Biol., 2014, 33(9), 605-615.
[http://dx.doi.org/10.1089/dna.2013.2270 ] [PMID: 24772998]
[31]
Castellano-Castillo, D.; Moreno-Indias, I.; Sanchez-Alcoholado, L.; Ramos-Molina, B.; Alcaide-Torres, J.; Morcillo, S.; Ocaña-Wilhelmi, L.; Tinahones, F.; Queipo-Ortuño, M.I.; Cardona, F. Altered adipose tissue DNA methylation status in metabolic syndrome: relationships between global dna methylation and specific methylation at adipogenic, lipid metabolism and inflammatory candidate genes and metabolic variables. J. Clin. Med., 2019, 8(1), 1-17.
[http://dx.doi.org/10.3390/jcm8010087 ] [PMID: 30642114]
[32]
Feige, J.N.; Gelman, L.; Michalik, L.; Desvergne, B.; Wahli, W. From molecular action to physiological outputs: peroxisome proliferator-activated receptors are nuclear receptors at the crossroads of key cellular functions. Prog. Lipid Res., 2006, 45(2), 120-159.
[http://dx.doi.org/10.1016/j.plipres.2005.12.002 ] [PMID: 16476485]
[33]
Zhao, J.; Lv, C.; Wu, Q.; Zeng, H.; Guo, X.; Yang, J.; Tian, S.; Zhang, W. Computational systems pharmacology reveals an antiplatelet and neuroprotective mechanism of Deng-Zhan-Xi-Xin injection in the treatment of ischemic stroke. Pharmacol. Res., 2019, 147, 104365.
[http://dx.doi.org/10.1016/j.phrs.2019.104365] [PMID: 31348992]
[34]
Oh, S.H.; Min, K.T.; Jeon, Y.J.; Kim, M.H.; Moon, J.S.; Kim, H.S.; Kim, W.C.; Kim, O.J.; Park, E.K.; Kim, N.K. Association between kinase insert domain-containing receptor gene polymorphism and haplotypes and ischemic stroke. J. Neurol. Sci., 2011, 308(1-2), 62-66.
[http://dx.doi.org/10.1016/j.jns.2011.06.012 ] [PMID: 21705026]
[35]
Geiseler, S.J.; Morland, C. The janus face of VEGF in stroke. Int. J. Mol. Sci., 2018, 19(5), 1-20.
[http://dx.doi.org/10.3390/ijms19051362 ] [PMID: 29734653]
[36]
Xu, X.; Bass, B.; McKillop, W.M.; Mailloux, J.; Liu, T.; Geremia, N.M.; Hryciw, T.; Brown, A. Sox9 knockout mice have improved recovery following stroke. Exp. Neurol., 2018, 303, 59-71.
[http://dx.doi.org/10.1016/j.expneurol.2018.02.001 ] [PMID: 29425963]
[37]
Chaturvedi, M.; Kaczmarek, L. Mmp-9 inhibition: a therapeutic strategy in ischemic stroke. Mol. Neurobiol., 2014, 49(1), 563-573.
[http://dx.doi.org/10.1007/s12035-013-8538-z ] [PMID: 24026771]
[38]
Liu, R.; Cao, S.; Hua, Y.; Keep, R.F.; Huang, Y.; Xi, G. CD163 expression in neurons after experimental intracerebral hemorrhage. Stroke, 2017, 48(5), 1369-1375.
[http://dx.doi.org/10.1161/STROKEAHA.117.016850 ] [PMID: 28360115]
[39]
Förstermann, U.; Sessa, W. C. Nitric oxide synthases: regulation and function. Eur Heart J, 2012, 33(7), 829-837-837a-837d.
[http://dx.doi.org/10.1093/eurheartj/ehr304]
[40]
Shi, W.L.; Yuan, R.; Xin, Q.Q.; Jin, Y.; Cong, W.H.; Chen, K.J. Oxidative stress and hypertension. Med. Recapitulate., 2018, 24(4), 642-650.
[41]
Mao, G.; Ren, P.; Wang, G.; Yan, F.; Zhang, Y. MicroRNA-128-3p protects mouse against cerebral ischemia through reducing p38α mitogen-activated protein kinase activity. J. Mol. Neurosci., 2017, 61(2), 152-158.
[http://dx.doi.org/10.1007/s12031-016-0871-z ] [PMID: 27905005]
[42]
Zhao, S.; Wu, D.X.; Chen, X.; Zhang, Y.L. Study on mechanism for treating ischemic stroke of Siegesbeckiae Herba based on network pharmacology. Zhongguo Zhongyao Zazhi, 2019, 44(13), 2727-2735.
[PMID: 31359683]
[43]
Koyuncuoğlu, T.; Arabacı Tamer, S.; Erzik, C.; Karagöz, A.; Akakın, D.; Yüksel, M.; Yeğen, B.Ç. Oestrogen receptor ERα and ERβ agonists ameliorate oxidative brain injury and improve memory dysfunction in rats with an epileptic seizure. Exp. Physiol., 2019, 104(12), 1911-1928.
[http://dx.doi.org/10.1113/EP087986 ] [PMID: 31608530]
[44]
Li, L.; Fan, X.; Zhang, X.T.; Yue, S.Q.; Sun, Z.Y.; Zhu, J.Q.; Zhang, J.H.; Gao, X.M.; Zhang, H. The effects of Chinese medicines on cAMP/PKA signaling in central nervous system dysfunction. Brain Res. Bull., 2017, 132, 109-117.
[http://dx.doi.org/10.1016/j.brainresbull.2017.04.006 ] [PMID: 28438669]
[45]
Chen, X.; Wang, S.Q.; Li, Y.M. Role of thromboxane A2 in ischemic stroke and its relevant drugs. Chin. J. Cardiovasc. Res., 2015, 13(2), 117-120.
[46]
Yu, Z.H.; Cai, M.; Xiang, J.; Zhang, Z.N.; Zhang, J.S.; Song, X.L.; Zhang, W.; Bao, J.; Li, W.W.; Cai, D.F. PI3K/Akt pathway contributes to neuroprotective effect of Tongxinluo against focal cerebral ischemia and reperfusion injury in rats. J. Ethnopharmacol., 2016, 181, 8-19.
[http://dx.doi.org/10.1016/j.jep.2016.01.028 ] [PMID: 26805466]
[47]
McManus, D.D.; Freedman, J.E. MicroRNAs in platelet function and cardiovascular disease. Nat. Rev. Cardiol., 2015, 12(12), 711-717.
[http://dx.doi.org/10.1038/nrcardio.2015.101 ] [PMID: 26149483]
[48]
King, S.M.; McNamee, R.A.; Houng, A.K.; Patel, R.; Brands, M.; Reed, G.L. Platelet dense-granule secretion plays a critical role in thrombosis and subsequent vascular remodeling in atherosclerotic mice. Circulation, 2009, 120(9), 785-791.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.108.845461 ] [PMID: 19687360]
[49]
Giannarelli, C.; Alique, M.; Rodriguez, D.T.; Yang, D.K.; Jeong, D.; Calcagno, C.; Hutter, R.; Millon, A.; Kovacic, J.C.; Weber, T.; Faries, P.L.; Soff, G.A.; Fayad, Z.A.; Hajjar, R.J.; Fuster, V.; Badimon, J.J. Alternatively spliced tissue factor promotes plaque angiogenesis through the activation of hypoxia-inducible factor-1α and vascular endothelial growth factor signaling. Circulation, 2014, 130(15), 1274-1286.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.114.006614 ] [PMID: 25116956]
[50]
Kofler, N.M.; Simons, M. Angiogenesis versus arteriogenesis: neuropilin 1 modulation of VEGF signaling. F1000Prime Rep., 2015, 7, 26.
[http://dx.doi.org/10.12703/P7-26 ] [PMID: 25926977]


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VOLUME: 23
ISSUE: 8
Year: 2020
Published on: 02 November, 2020
Page: [775 - 787]
Pages: 13
DOI: 10.2174/1386207323666200311113747
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