title: Systems pharmacology dissection of multi-scale mechanisms of action for herbal medicines in stroke treatment and prevention.
abstract: Annually, tens of millions of first-ever strokes occur in the world; however, currently there is lack of effective and widely applicable pharmacological treatments for stroke patients. Herbal medicines, characterized as multi-constituent, multi-target and multi-effect, have been acknowledged with conspicuous effects in treating stroke, and attract extensive interest of researchers although the mechanism of action is yet unclear. In this work, we introduce an innovative systems-pharmacology method that combines pharmacokinetic prescreening, target fishing and network analysis to decipher the mechanisms of action of 10 herbal medicines like Salvia miltiorrhizae, Ginkgo biloba and Ephedrae herba which are efficient in stroke treatment and prevention. Our systematic analysis results display that, in these anti-stroke herbal medicines, 168 out of 1285 constituents with the favorable pharmacokinetic profiles might be implicated in stroke therapy, and the systematic use of these compounds probably acts through multiple mechanisms to synergistically benefit patients with stroke, which can roughly be classified as preventing ischemic inflammatory response, scavenging free radicals and inhibiting neuronal apoptosis against ischemic cerebral damage, as well as exhibiting lipid-lowering, anti-diabetic, anti-thrombotic and antiplatelet effects to decrease recurrent strokes. Relying on systems biology-based analysis, we speculate that herbal medicines, being characterized as the classical combination therapies, might be not only engaged in multiple mechanisms of action to synergistically improve the stroke outcomes, but also might be participated in reducing the risk factors for recurrent strokes.
authors.affiliation: Key laboratory of Industrial Ecology and Environmental Engineering (MOE), Faculty of Chemical, Environmental and Biological Science and Technology, Dalian University of Technology, Dalian, Liaoning, China.
authors.forename: Jingxiao
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Key laboratory of Industrial Ecology and Environmental Engineering (MOE), Faculty of Chemical, Environmental and Biological Science and Technology, Dalian University of Technology, Dalian, Liaoning, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: College of Life Sciences, Northwest A & F University, Yangling, Shaanxi, China; Center of Bioinformatics, Northwest A & F University, Yangling, Shaanxi, China.
authors.forename: Xuetong
authors.initials: X
authors.lastname: Chen
authors.affiliation: Key laboratory of Industrial Ecology and Environmental Engineering (MOE), Faculty of Chemical, Environmental and Biological Science and Technology, Dalian University of Technology, Dalian, Liaoning, China.
authors.forename: Yanqiu
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Key laboratory of Industrial Ecology and Environmental Engineering (MOE), Faculty of Chemical, Environmental and Biological Science and Technology, Dalian University of Technology, Dalian, Liaoning, China.
authors.forename: Shuwei
authors.initials: S
authors.lastname: Zhang
authors.affiliation: College of Life Sciences, Northwest A & F University, Yangling, Shaanxi, China; Center of Bioinformatics, Northwest A & F University, Yangling, Shaanxi, China.
authors.forename: Yonghua
authors.initials: Y
authors.lastname: Wang
mesh_terms: D018938:Caco-2 Cells; D062313:Databases, Pharmaceutical; D004353:Drug Evaluation, Preclinical; D005786:Gene Expression Regulation / Q000187:drug effects; D029001:Herbal Medicine; D006801:Humans; D058990:Molecular Targeted Therapy; D000069437:Pharmacological Phenomena; D028321:Plant Preparations / Q000494:pharmacology* / Q000627:therapeutic use*; D010946:Plants, Medicinal; D027561:Salvia miltiorrhiza; D031364:Scutellaria baicalensis; D020521:Stroke / Q000188:drug therapy* / Q000517:prevention & control*; D049490:Systems Biology / Q000379:methods*; D032070:Uncaria
chemical_list: D028321:Plant Preparations
references.citation: Brief Bioinform. 2014 Sep;15(5):710-33
references.pmid: 23736100
references.citation: Stroke. 2003 May;34(5):1333-4
references.pmid: 12702834
references.citation: J Cereb Blood Flow Metab. 2000 Mar;20(3):452-7
references.pmid: 10724108
references.citation: Int J Mol Sci. 2012;13(6):6964-82
references.pmid: 22837674
references.citation: J Chem Inf Comput Sci. 2001 Nov-Dec;41(6):1488-93
references.pmid: 11749573
references.citation: Nucleic Acids Res. 2012 Jan;40(Database issue):D876-80
references.pmid: 22075997
references.citation: Nat Biotechnol. 2007 Feb;25(2):197-206
references.pmid: 17287757
references.citation: Med Res Rev. 2007 Jan;27(1):133-48
references.pmid: 16888751
references.citation: Cochrane Database Syst Rev. 2004 Oct 18;(4):CD004295
references.pmid: 15495099
references.citation: Brain Res Rev. 2007 Apr;54(1):34-66
references.pmid: 17222914
references.citation: J Mol Biol. 1997 Apr 4;267(3):727-48
references.pmid: 9126849
references.citation: Curr Opin Neurol. 1995 Feb;8(1):15-23
references.pmid: 7749511
references.citation: J Ethnopharmacol. 2013 Apr 19;146(3):773-93
references.pmid: 23415946
references.citation: PLoS One. 2012;7(5):e37608
references.pmid: 22666371
references.citation: Free Radic Biol Med. 2005 Jul 1;39(1):81-90
references.pmid: 15925280
references.citation: Proc Natl Acad Sci U S A. 2001 Jan 30;98(3):1294-9
references.pmid: 11158633
references.citation: Mol Inform. 2011 Apr 18;30(4):376-85
references.pmid: 27466954
references.citation: Acta Pharmacol Sin. 2003 Feb;24(2):97-101
references.pmid: 12546715
references.citation: J Cereb Blood Flow Metab. 2002 Feb;22(2):215-22
references.pmid: 11823719
references.citation: Acta Pharmacol Sin. 2000 May;21(5):463-6
references.pmid: 11324448
references.citation: J Pharm Sci. 2004 Dec;93(12):3103-10
references.pmid: 15514985
references.citation: Fitoterapia. 2012 Jun;83(4):617-26
references.pmid: 22406453
references.citation: Life Sci. 2005 Oct 21;77(23):2964-76
references.pmid: 15982670
references.citation: Biochem Pharmacol. 2006 Dec 15;72(12):1680-9
references.pmid: 16999937
references.citation: Trends Pharmacol Sci. 1999 May;20(5):191-6
references.pmid: 10354613
references.citation: J Nutr. 2007 Oct;137(10):2190-5
references.pmid: 17884996
references.citation: Mol Pharmacol. 2007 Jul;72(1):62-72
references.pmid: 17429005
references.citation: Exp Brain Res. 2009 Feb;193(1):109-18
references.pmid: 18936923
references.citation: Trends Pharmacol Sci. 2007 May;28(5):244-9
references.pmid: 17416424
references.citation: Stroke. 2003 Dec;34(12):2922-9
references.pmid: 14605324
references.citation: Stroke. 2007 Jun;38(6):1973-9
references.pmid: 17463317
references.citation: Chin Med. 2010 Jun 21;5:22
references.pmid: 20565944
references.citation: Drug Discov Today. 2012 Apr;17(7-8):296-309
references.pmid: 22134007
references.citation: Lab Anim Res. 2013 Jun;29(2):63-9
references.pmid: 23825478
references.citation: J Cereb Blood Flow Metab. 2012 Apr;32(4):585-97
references.pmid: 22293990
references.citation: Zhongguo Yao Li Xue Bao. 1992 Mar;13(2):126-30
references.pmid: 1317985
references.citation: Cochrane Database Syst Rev. 2005 Oct 19;(4):CD003691
references.pmid: 16235335
references.citation: Integr Biol (Camb). 2013 Feb;5(2):351-71
references.pmid: 23168537
references.citation: Life Sci. 2002 Apr 21;70(21):2467-80
references.pmid: 12173411
references.citation: Eur J Pharmacol. 2006 Nov 7;549(1-3):166-72
references.pmid: 16989810
references.citation: Trends Neurosci. 1997 Mar;20(3):132-9
references.pmid: 9061868
references.citation: Neurosci Res. 2011 Mar;69(3):214-22
references.pmid: 21145362
references.citation: Genome Res. 2003 Nov;13(11):2498-504
references.pmid: 14597658
references.citation: PLoS One. 2012;7(9):e43918
references.pmid: 22962593
references.citation: Neuropharmacology. 2007 Mar;52(3):1024-33
references.pmid: 17204294
references.citation: Expert Opin Drug Discov. 2012 Oct;7(10):863-75
references.pmid: 22992175
references.citation: J Chem Inf Model. 2007 Jul-Aug;47(4):1395-404
references.pmid: 17569522
references.citation: Clin Pharmacol Ther. 2012 Oct;92(4):414-7
references.pmid: 22992668
references.citation: J Agric Food Chem. 2008 Dec 24;56(24):11621-30
references.pmid: 19053389
references.citation: Nucleic Acids Res. 2012 Jan;40(Database issue):D1128-36
references.pmid: 21948793
references.citation: Stroke. 2002 Mar;33(3):831-6
references.pmid: 11872911
references.citation: FASEB J. 2006 Jun;20(8):1185-7
references.pmid: 16641198
references.citation: Nat Genet. 1999 Jul;22(3):281-5
references.pmid: 10391217
references.citation: Nat Rev Neurosci. 2003 May;4(5):399-415
references.pmid: 12728267
references.citation: Nucleic Acids Res. 2011 Jan;39(Database issue):D1055-9
references.pmid: 21097881
references.citation: Stroke. 2007 Jun;38(6):1734-6
references.pmid: 17463306
references.citation: Agents Actions Suppl. 1995;46:41-50
references.pmid: 7610990
references.citation: Drug Metab Dispos. 2003 Dec;31(12):1507-19
references.pmid: 14625347
references.citation: Neurochem Res. 2010 Nov;35(11):1725-32
references.pmid: 20680459
references.citation: Neurochem Res. 2012 Jul;37(7):1560-7
references.pmid: 22447574
references.citation: Arch Pharm Res. 2008 Sep;31(9):1166-71
references.pmid: 18806960
references.citation: Curr Med Chem. 2012;19(12):1830-45
references.pmid: 22376038
references.citation: Int J Mol Sci. 2010 Jan 08;11(1):107-23
references.pmid: 20162004
references.citation: Adv Drug Deliv Rev. 2002 Mar 31;54(3):355-66
references.pmid: 11922952
references.citation: PLoS One. 2007 Dec 19;2(12):e1321
references.pmid: 18091994
references.citation: Annu Rev Pharmacol Toxicol. 2012;52:505-21
references.pmid: 22235860
references.citation: J Mol Model. 2002 Dec;8(12):337-49
references.pmid: 12541001
references.citation: Life Sci. 2001 Jan 12;68(8):903-12
references.pmid: 11213360
references.citation: Arch Pharm Res. 2009 May;32(5):773-9
references.pmid: 19471893
references.citation: Allergol Int. 2007 Jun;56(2):113-23
references.pmid: 17384531
references.citation: J Ethnopharmacol. 2010 Oct 28;132(1):15-27
references.pmid: 20736055
references.citation: J Immunol. 2011 Aug 1;187(3):1458-66
references.pmid: 21709150
references.citation: Clin Hemorheol Microcirc. 2004;31(2):97-103
references.pmid: 15310944