Pathway as a Pharmacological Target for Herbal Medicines: An Investigation from Reduning Injection

As a rich natural resource for drug discovery, Traditional Chinese Medicine (TCM) plays an important role in complementary and alternative medical systems. TCM shows a daunting complexity of compounds featuring multi-components and multi-targets to cure diseases, which thus always makes it extremely difficult to systematically explain the molecular mechanisms adequately using routine methods. In the present work, to reveal the systematic mechanism of herbal formulae, we developed a pathway-based strategy by combining the pathways integrating, target selection, reverse drug targeting and network analysis together, and then exemplified it by Reduning injection (RDN), a clinically widely used herbal medicine injection, in combating inflammation. The anti-inflammatory effects exerted by the major ingredients of RDN at signaling pathways level were systematically investigated. More importantly, our predicted results were also experimentally validated. Our strategy provides a deep understanding of the pharmacological functions of herbal formulae from molecular to systematic level, which may lead to more successful applications of systems pharmacology for drug discovery and development.

[1]  U. Bhalla,et al.  Emergent properties of networks of biological signaling pathways. , 1999, Science.

[2]  Yonghua Wang,et al.  Deciphering the combination principles of Traditional Chinese Medicine from a systems pharmacology perspective based on Ma-huang Decoction. , 2013, Journal of ethnopharmacology.

[3]  Sun-Mee Lee,et al.  Genipin Attenuates Sepsis by Inhibiting Toll-Like Receptor Signaling , 2012, Molecular medicine.

[4]  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.

[5]  A. Hata,et al.  Targeting the TGFβ signalling pathway in disease , 2012, Nature Reviews Drug Discovery.

[6]  Anne E Carpenter,et al.  Small molecules discovered in a pathway screen target the Rho pathway in cytokinesis , 2010, Nature chemical biology.

[7]  G. Johnson,et al.  Mitogen-Activated Protein Kinase Pathways Mediated by ERK, JNK, and p38 Protein Kinases , 2002, Science.

[8]  Shao Li,et al.  A novel network pharmacology approach to analyse traditional herbal formulae: the Liu-Wei-Di-Huang pill as a case study. , 2014, Molecular bioSystems.

[9]  Huan Yang,et al.  The Akt/PKB pathway: molecular target for cancer drug discovery , 2005, Oncogene.

[10]  T. Thalhamer,et al.  MAPKs and their relevance to arthritis and inflammation. , 2007, Rheumatology.

[11]  A. Choi,et al.  Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway , 2000, Nature Medicine.

[12]  Hou Ming Xu,et al.  Safety of an injection with a mixture of extracts from Herba Artemisiae annuae, Fructus Gardeniae and Flos Lonicerae , 2009, Pharmacy World & Science.

[13]  P. Tak,et al.  NF-κB: a key role in inflammatory diseases , 2001 .

[14]  Chen Dong,et al.  MAP kinases in the immune response. , 2002, Annual review of immunology.

[15]  K. Kröncke,et al.  Nitric oxide: cytotoxicity versus cytoprotection--how, why, when, and where? , 1997, Nitric oxide : biology and chemistry.

[16]  J. Christman,et al.  Nuclear factor k B: a pivotal role in the systemic inflammatory response syndrome and new target for therapy , 1998, Intensive Care Medicine.

[17]  N. Mackman,et al.  LPS induction of gene expression in human monocytes. , 2001, Cellular signalling.

[18]  Wei Zhou,et al.  Systems pharmacology strategies for drug discovery and combination with applications to cardiovascular diseases. , 2014, Journal of ethnopharmacology.

[19]  Yubin Luo,et al.  Inhibition of monosodium urate crystal-induced inflammation by scopoletin and underlying mechanisms. , 2012, International immunopharmacology.

[20]  T. Maniatis,et al.  Site-Specific Phosphorylation of IκBα by a Novel Ubiquitination-Dependent Protein Kinase Activity , 1996, Cell.

[21]  P. Tak,et al.  NF-kappaB: a key role in inflammatory diseases. , 2001, The Journal of clinical investigation.

[22]  K. M. Rao MAP kinase activation in macrophages , 2001, Journal of leukocyte biology.

[23]  T. Maniatis,et al.  Site-specific phosphorylation of IkappaBalpha by a novel ubiquitination-dependent protein kinase activity. , 1996, Cell.

[24]  M. Netea,et al.  The role of TNF-alpha in chronic inflammatory conditions, intermediary metabolism, and cardiovascular risk. , 2007, Journal of lipid research.

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

[26]  B. Kamińska MAPK signalling pathways as molecular targets for anti-inflammatory therapy--from molecular mechanisms to therapeutic benefits. , 2005, Biochimica et biophysica acta.

[27]  Keith T Flaherty,et al.  Multiple signaling pathways must be targeted to overcome drug resistance in cell lines derived from melanoma metastases , 2006, Molecular Cancer Therapeutics.

[28]  Dennis Normile,et al.  Asian medicine. The new face of traditional Chinese medicine. , 2003, Science.

[29]  D. Normile The New Face of Traditional Chinese Medicine , 2003, Science.

[30]  Xue Xu,et al.  A Systems Biology Approach to Uncovering Pharmacological Synergy in Herbal Medicines with Applications to Cardiovascular Disease , 2012, Evidence-based complementary and alternative medicine : eCAM.

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

[32]  Chao Huang,et al.  Systems pharmacology in drug discovery and therapeutic insight for herbal medicines , 2014, Briefings Bioinform..

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

[34]  Jianxin Chen,et al.  Large-scale exploration and analysis of drug combinations , 2015, Bioinform..

[35]  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.

[36]  L. Luo,et al.  Chlorogenic acid inhibits lipopolysaccharide-induced cyclooxygenase-2 expression in RAW264.7 cells through suppressing NF-kappaB and JNK/AP-1 activation. , 2009, International immunopharmacology.

[37]  Sheng-Yang Wang,et al.  Anti-inflammation activities of essential oil and its constituents from indigenous cinnamon (Cinnamomum osmophloeum) twigs. , 2008, Bioresource technology.

[38]  Y. Surh,et al.  Molecular mechanisms underlying chemopreventive activities of anti-inflammatory phytochemicals: down-regulation of COX-2 and iNOS through suppression of NF-kappa B activation. , 2001, Mutation research.