Network pharmacology analyses of the antithrombotic pharmacological mechanism of Fufang Xueshuantong Capsule with experimental support using disseminated intravascular coagulation rats.

ETHNOPHARMACOLOGICAL RELEVANCE Fufang Xueshuantong (FXST) Capsule is developed on a traditional Chinese medicine remedy, with a four-herb formula of Panax notoginseng, Radix astragali, Salvia miltiorrhizae and Radix scrophulariaceae. It has been used for treatment of the clinic cardiovascular disease for many years. MATERIALS AND METHODS Due to its complexity of compositions and polypharmacological effects, it often complicates understanding of the mechanisms of action. In the present work, we have constructed an integrated model of system pharmacology to investigate the polypharmacological mechanisms of FXST formulation for treatment of thrombosis disease. RESULTS The predicted results showed that 22 ingredients in FXST were closely associated with 41 protein targets related to blood coagulation, fibrinolysis and platelet aggregation. Through analysis of the compound-protein target association, significant cross-targets between each herb indicated the multiple active chemical ingredients might interact with the same target simultaneously and thus explained the synergistic mechanisms of the principle of Traditional Chinese medicines (TCMs) as ''Jun (emperor) - Chen (minister) - Zuo (adjuvant) - Shi (courier)''. To validate the polypharmacological effects predicted by our network pharmacology (NetPharm) analysis, we have carried out experimental investigation the effects of FXST on the disorders of the blood coagulation system in a lipopolysaccharide-induced disseminated intravascular coagulation (DIC) rat model. The results showed that FXST could significantly ameliorate the activation of coagulation system, which is congruent with the cross-target prediction by NetPharm approach. CONCLUSIONS The combined investigations provide more insight into better understanding of the pharmacological mechanisms of FXST, and may also offer an alternative avenue to further explore the chemical and pharmacological basis of TCMs.

[1]  C. Trenor,et al.  Thrombosis and inflammatory bowel disease: A call for improved awareness and prevention , 2011, Inflammatory bowel diseases.

[2]  Baojun Xu,et al.  A comparative study on anticoagulant activities of three Chinese herbal medicines from the genus Panax and anticoagulant activities of ginsenosides Rg1 and Rg2 , 2013, Pharmaceutical biology.

[3]  Junmei Wang,et al.  GPCR Structure-Based Virtual Screening Approach for CB2 Antagonist Search , 2007, J. Chem. Inf. Model..

[4]  K. Aksu,et al.  Inflammation-induced thrombosis: mechanisms, disease associations and management. , 2012, Current pharmaceutical design.

[5]  A. Barabasi,et al.  Drug—target network , 2007, Nature Biotechnology.

[6]  A. Buckle,et al.  Control of the coagulation system by serpins , 2005, The FEBS journal.

[7]  C. Park,et al.  Efficacious and orally bioavailable thrombin inhibitors based on a 2,5-thienylamidine at the P1 position: discovery of N-carboxymethyl-d-diphenylalanyl-l-prolyl[(5-amidino-2-thienyl)methyl]amide. , 2003, Journal of medicinal chemistry.

[8]  J. Bajorath,et al.  Docking and scoring in virtual screening for drug discovery: methods and applications , 2004, Nature Reviews Drug Discovery.

[9]  K. Mann,et al.  Biochemistry and Physiology of Blood Coagulation , 1999, Thrombosis and Haemostasis.

[10]  D. Campbell,et al.  The renin-angiotensin and the kallikrein-kinin systems. , 2003, The international journal of biochemistry & cell biology.

[11]  Attenuating effect of Fufang Xueshuantong Capsule on kidney function in diabetic nephropathy model , 2012, Journal of Natural Medicines.

[12]  Bo Zhang,et al.  Traditional Chinese medicine network pharmacology: theory, methodology and application: Traditional Chinese medicine network pharmacology: theory, methodology and application , 2014 .

[13]  P. Shannon,et al.  Cytoscape: a software environment for integrated models of biomolecular interaction networks. , 2003, Genome research.

[14]  Hu Hu,et al.  Salvianolic acid A inhibits platelet activation and arterial thrombosis via inhibition of phosphoinositide 3‐kinase , 2010, Journal of thrombosis and haemostasis : JTH.

[15]  C. Hack.  Derangements of coagulation and fibrinolysis in infectious diseases. , 2003, Contributions to microbiology.

[16]  H. Koga,et al.  Antagonist of the Type-1 ANG II receptor prevents against LPS-induced septic shock in rats , 2009, Intensive Care Medicine.

[17]  R. Iyengar,et al.  Systems pharmacology: network analysis to identify multiscale mechanisms of drug action. , 2012, Annual review of pharmacology and toxicology.

[18]  F. Cipollone,et al.  Cyclooxygenase and prostaglandin synthases in atherosclerosis: recent insights and future perspectives. , 2008, Pharmacology & therapeutics.

[19]  M. Levi,et al.  Pathogenesis and treatment of DIC. , 2005, Thrombosis research.

[20]  J. Thachil,et al.  Guidelines for the diagnosis and management of disseminated intravascular coagulation , 2009, British journal of haematology.

[21]  J. Thachil,et al.  Guidance for diagnosis and treatment of disseminated intravascular coagulation from harmonization of the recommendations from three guidelines , 2013, Journal of thrombosis and haemostasis : JTH.

[22]  Liwei Guo,et al.  Systematic review of recent advances in pharmacokinetics of four classical Chinese medicines used for the treatment of cerebrovascular disease. , 2013, Fitoterapia.

[23]  C. Kitchens.  Thrombocytopenia and thrombosis in disseminated intravascular coagulation (DIC). , 2009, Hematology. American Society of Hematology. Education Program.

[24]  R. Bick.  Disseminated Intravascular Coagulation: A Review of Etiology, Pathophysiology, Diagnosis, and Management: Guidelines for Care , 2002, Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis.

[25]  Ming-Hui Chen,et al.  Effects of quercetin on LPS-induced disseminated intravascular coagulation (DIC) in rabbits. , 2013, Thrombosis research.

[26]  Shao Li,et al.  Traditional Chinese medicine network pharmacology: theory, methodology and application. , 2013, Chinese journal of natural medicines.

[27]  W. Hacke,et al.  State-of-the-Art Review: Anticoagulation: The Present and Future , 2001 .

[28]  Xiuping Chen,et al.  Material Basis of Chinese Herbal Formulas Explored by Combining Pharmacokinetics with Network Pharmacology , 2013, PloS one.

[29]  P. Gettins,et al.  Activation of antithrombin as a factor IXa and Xa inhibitor involves mitigation of repression rather than positive enhancement , 2009, FEBS letters.

[30]  C. Cerletti,et al.  Parnaparin, a low-molecular-weight heparin, prevents P-selectindependent formation of platelet-leukocyte aggregates in human whole blood , 2007, Thrombosis and Haemostasis.

[31]  J. Hirsh,et al.  Heparin and low-molecular-weight heparin: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. , 2004, Chest.

[32]  Hyun Chul Lee,et al.  Therapeutic Effects of Water Soluble Danshen Extracts on Atherosclerosis , 2013, Evidence-based complementary and alternative medicine : eCAM.

[33]  T. Nakao,et al.  Pharmacogenomics of cardiovascular pharmacology: molecular network analysis in pleiotropic effects of statin -- an experimental elucidation of the pharmacologic action from protein-protein interaction analysis. , 2008, Journal of pharmacological sciences.

[34]  Ajay N. Jain.  Effects of protein conformation in docking: improved pose prediction through protein pocket adaptation , 2009, J. Comput. Aided Mol. Des..

[35]  K. Hajjar,et al.  Molecular mechanisms of fibrinolysis , 2005, British journal of haematology.

[36]  A. Hopkins.  Network pharmacology: the next paradigm in drug discovery. , 2008, Nature chemical biology.

[37]  R. Rosenberg.  Role of heparin and heparinlike molecules in thrombosis and atherosclerosis. , 1985, Federation proceedings.

[38]  Hua Yu,et al.  A Systematic Prediction of Multiple Drug-Target Interactions from Chemical, Genomic, and Pharmacological Data , 2012, PloS one.

[39]  W. Hacke,et al.  Anticoagulation: the present and future. , 2001, Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis.

[40]  Xue Xu,et al.  Network pharmacology-based prediction of the active ingredients and potential targets of Chinese herbal Radix Curcumae formula for application to cardiovascular disease. , 2013, Journal of ethnopharmacology.

[41]  S. Olson,et al.  Kinetic evidence that allosteric activation of antithrombin by heparin is mediated by two sequential conformational changes. , 2010, Archives of biochemistry and biophysics.

[42]  A. Lau,et al.  Antiplatelet and anticoagulant effects of Panax notoginseng: comparison of raw and steamed Panax notoginseng with Panax ginseng and Panax quinquefolium. , 2009, Journal of ethnopharmacology.

[43]  B Dahlbäck.  Blood coagulation. , 2000, Lancet.

[44]  Ajay N. Jain,et al.  Customizing scoring functions for docking , 2008, J. Comput. Aided Mol. Des..

[45]  K. Chang,et al.  The effects of higenamine on LPS-induced experimental disseminated intravascular coagulation (DIC) in rats. , 2002, Planta medica.

[46]  K. Miyamoto,et al.  Induction of Vasoactive Substances Differs in LPS-Induced and TF-Induced DIC Models in Rats , 2002, Thrombosis and Haemostasis.

[47]  A. Rezaie.  Heparin-binding exosite of factor Xa. , 2000, Trends in cardiovascular medicine.

[48]  Trey Ideker,et al.  Cytoscape 2.8: new features for data integration and network visualization , 2010, Bioinform..

[49]  Xi Lin,et al.  A novel fibrinogenase from Agkistrodon acutus venom protects against DIC via direct degradation of thrombosis and activation of protein C. , 2012, Biochemical pharmacology.

[50]  N. Mackman,et al.  Role of the extrinsic pathway of blood coagulation in hemostasis and thrombosis. , 2007, Arteriosclerosis, thrombosis, and vascular biology.

[51]  B. Engelmann,et al.  Thrombosis as an intravascular effector of innate immunity , 2012, Nature Reviews Immunology.

[52]  Yonghua Wang,et al.  A Systems Biology Approach to Understanding the Mechanisms of Action of Chinese Herbs for Treatment of Cardiovascular Disease , 2012, International journal of molecular sciences.

[53]  S. Lewis.  British Committee for Standards in Haematology , 1969 .

[54]  S. Olson,et al.  Heparin Enhances the Specificity of Antithrombin for Thrombin and Factor Xa Independent of the Reactive Center Loop Sequence , 2001, The Journal of Biological Chemistry.

[55]  Zhi-xiang Shen,et al.  Dissection of mechanisms of Chinese medicinal formula Realgar-Indigo naturalis as an effective treatment for promyelocytic leukemia , 2008, Proceedings of the National Academy of Sciences.

[56]  Bin Wu,et al.  Antithrombotic effect of a novel protein from Fusarium sp. CPCC 480097 in a rat model of artery-vein bypass thrombosis , 2012, Pharmaceutical biology.

[57]  Xiang-Qun Xie,et al.  3D structural model of the G‐protein‐coupled cannabinoid CB2 receptor , 2003, Proteins.

[58]  K. Miyamoto,et al.  Selective inducible nitric oxide synthase inhibition attenuates organ dysfunction and elevated endothelin levels in LPS‐induced DIC model rats , 2005, Journal of thrombosis and haemostasis : JTH.