How Can Synergism of Traditional Medicines Benefit from Network Pharmacology?

Haidan Yuan, Qianqian Ma, Heying Cui, Guancheng Liu, Xiaoyan Zhao, Wei Li, Guangchun Piao, Haidan Yuan, Qianqian Ma, Heying Cui, Guancheng Liu, Xiaoyan Zhao, Wei Li, Guangchun Piao

Abstract

Many prescriptions of traditional medicines (TMs), whose efficacy has been tested in clinical practice, have great therapeutic value and represent an excellent resource for drug discovery. Research into single compounds of TMs, such as artemisinin from Artemisia annua L., has achieved great success; however, it has become evident that a TM prescription (which frequently contains various herbs or other components) has a synergistic effect in effecting a cure or reducing toxicity. Network pharmacology targets biological networks and analyzes the links among drugs, targets, and diseases in those networks. Comprehensive, systematic research into network pharmacology is consistent with the perspective of holisticity, which is a main characteristic of many TMs. By means of network pharmacology, research has demonstrated that many a TM show a synergistic effect by acting at different levels on multiple targets and pathways. This approach effectively bridges the gap between modern medicine and TM, and it greatly facilitates studies into the synergistic actions of TMs. There are different kinds of synergistic effects with TMs, such as synergy among herbs, effective parts, and pure compounds; however, for various reasons, new drug discovery should at present focus on synergy among pure compounds.

Keywords: .; drug discovery; network pharmacology; synergistic effects; traditional medicines.

Conflict of interest statement

The authors have declared that there is no conflict of interest.

Figures

Figure 1
Figure 1
Synergistic effects in traditional medicines (TMs).
Figure 2
Figure 2
Traditional Chinese medicine (TCM) modernization and network pharmacology.
Figure 3
Figure 3
Drug discovery from traditional medicines (TMs).

References

    1. Abdullahi A.A. Trends and challenges of traditional medicine in Africa. Afr. J. Tradit. Complement. Altern. Med. 2011;8:115–123. doi: 10.4314/ajtcam.v8i5S.5.
    1. World Health Organization . General Guidelines for Methodologies on Research and Evaluation of Traditional Medicine. World Health Organization; Geneva, Switzerland: 2000.
    1. Qi F.H., Wang Z.X., Cai P.P., Zhao L., Gao J.J., Kokudo N., Li A.Y., Han J.Q., Tang W. Traditional Chinese medicine and related active compounds: A review of their role on hepatitis B virus infection. Drug Discov. Ther. 2013;7:212–224. doi: 10.5582/ddt.2013.v7.6.212.
    1. Mogami S., Hattori T. Beneficial effects of rikkunshito, a Japanese kampo medicine, on gastrointestinal dysfunction and anorexia in combination with Western drug: A systematic review. Evid.-Based Complement. Altern. Med. 2014;2014:519035. doi: 10.1155/2014/519035.
    1. Kim J.Y., Noble D. Recent progress and prospects in Sasang constitutional medicine: A traditional type of physiome-based treatment. Prog. Biophys. Mol. Biol. 2014;116:76–80. doi: 10.1016/j.pbiomolbio.2014.09.005.
    1. Parasuraman S., Thing G.S., Dhanaraj S.A. Polyherbal formation: Concept of ayurveda. Pharmacogn. Rev. 2014;8:73–80. doi: 10.4103/0973-7847.134229.
    1. Oliver S.J. The role of traditional medicine practice in primary health care within Aboriginal Australia: A review of the literature. J. Ethnobiol. Ethnomed. 2013;9 doi: 10.1186/1746-4269-9-46.
    1. Zhang A.H., Sun H., Qiu S., Wang X.J. Advancing drug discovery and development from active constituents of yinchenhao tang, a famous traditional Chinese medicine formula. Evid.-Based Complement. Altern. Med. 2013;2013:257909. doi: 10.1155/2013/257909.
    1. World Health Organization . WHO Traditional Medicine Strategy: 2014–2023. World Health Organization; Geneva, Switzerland: 2013.
    1. Fabricant D.S., Farnsworth N.R. The value of plants used in traditional medicine for drug discovery. Environ. Health Perspect. 2001;109:69–75. doi: 10.1289/ehp.01109s169.
    1. Ngo L.T., Okogun J.I., Folk W.R. 21st Century natural product research and drug development and traditional medicines. Nat. Prod. Rep. 2013;30:584–592. doi: 10.1039/c3np20120a.
    1. Li Y.T., Du L.P., Mei D. Progress in the study on the pharmacokinetics of Bicyclol. Med. Res. J. 2011;40:18–20.
    1. Yuan H.D., Ma Q.Q., Ye L., Piao G.C. The traditional medicine and modern medicine from natural products. Molecules. 2016;21:559. doi: 10.3390/molecules21050559.
    1. Guo D.A., Lu A., Liu L. Modernization of traditional Chinese medicine. J. Ethnopharmacol. 2012;141:547–548. doi: 10.1016/j.jep.2012.05.001.
    1. Xue R., Fang Z., Zhang M., Yi Z., Wen C., Shi T. TCMID: Traditional Chinese Medicine integrative database for herb molecular mechanism analysis. Nucleic Acids Res. 2013;41:D1089–D1095. doi: 10.1093/nar/gks1100.
    1. Yang Y., Zhang Z., Li S., Ye X., Li X., He K. Synergy effects of herb extracts: Pharmacokinetics and pharmacodynamic basis. Fitoterapia. 2014;92:133–147. doi: 10.1016/j.fitote.2013.10.010.
    1. Kao W.F., Hung D.Z., Tsai W.J., Lin K.P., Deng J.F. Podophyllotoxin intoxication: Toxic effect of Bajiaolian in herbal therapeutics. Hum. Exp. Toxicol. 1992;11:480–487. doi: 10.1177/096032719201100607.
    1. Ernst M. Harmless herbs? A review of the recent literature. Am. J. Med. 1998;104:170–178. doi: 10.1016/S0002-9343(97)00397-5.
    1. Zhang L.W., Li J. The present situation and development trend of the modernization of Chinese Materia Medica. J. Zhejiang Univ. (Med. Sci.) 2011;40:349–353.
    1. Xu S.J., Huang C.M., Liu X.H., Chen J.N. The connotation of modernization of traditional Chinese medicine and some problems. J. New Chin. Med. 2013;45:160–161.
    1. Zhang W.D. New research idea for the modernization of TCM experience of combining the medicinal chemistry of natural products with biology in natural products research. Chin. J. Nat. Med. 2008;6:2–5. doi: 10.3724/SP.J.1009.2008.00002.
    1. Xia Y.F., Liang G.P. The modernization of traditional Chinese medicine under the background of big data. Asia-Pacific Tradit. Med. 2015;11:1–3.
    1. Zhang L., Yan J., Liu X., Ye Z., Yang X., Meyboom R., Chan K., Shaw D., Duez P. Pharmacovigilance practice and risk control of Traditional Chinese Medicine drugs in China: Current status and future perspective. J. Ethnopharmacol. 2012;140:519–525. doi: 10.1016/j.jep.2012.01.058.
    1. Shaw D., Graeme L., Pierre D., Elizabeth W., Kelvin C. Pharmacovigilance of herbal medicine. J. Ethnopharmacol. 2012;140:513–518. doi: 10.1016/j.jep.2012.01.051.
    1. Liu J., Huang Y.M., Wang H. Research progress of network pharmacology. West China J. Pharm. Sci. 2014;29:723–725.
    1. Pool J.L. Is it time to move to multidrug combinations? Am. J. Hypertens. 2003;16:36–40. doi: 10.1016/j.amjhyper.2003.07.005.
    1. Hurwitz J.L., Zhan X., Brown S.A., Bonsignori M., Stambas J., Lockey T.D., Sealy R., Surman S., Freiden P., Jones B., et al. HIV-1 vaccine development: Tackling virus diversity with a multi-envelope cocktail. Front. Biosci. 2008;13:609–620. doi: 10.2741/2706.
    1. Li Y. Qinghaosu (artemisinin): Chemistry and pharmacology. Acta Pharmacol. Sin. 2012;33:1141–1146. doi: 10.1038/aps.2012.104.
    1. Zhang A., Sun H., Yuan Y., Sun W., Jiao G., Wang X. An in vivo analysis of the therapeutic and synergistic properties of Chinese medicinal formula Yin-Chen-Hao-Tang based on its active constituents. Fitoterapia. 2011;82:1160–1168. doi: 10.1016/j.fitote.2011.07.014.
    1. Lau K.M., Lai K.K., Liu C.L., Tam J.C.W., To M.H., Kwok H.F., Lau C.P., Ko C.H., Leung P.C., Fung K.P., et al. Synergistic interaction between Astragali Radix and Rehmanniae Radix in a Chinese herbal formula to promote diabetic wound healing. J. Ethnopharmacol. 2012;141:250–256. doi: 10.1016/j.jep.2012.02.025.
    1. Ncube B., Finnie J.F., Van Staden J. In vitro antimicrobial synergism within plant extract combinations from three South African medicinal bulbs. J. Ethnopharmacol. 2012;139:81–89. doi: 10.1016/j.jep.2011.10.025.
    1. Singh H., Prakash A., Kalia A.N., Majeed A.B. Synergistic hepatoprotective potential of ethanolic extract of Solanum xanthocarpum and Juniperus communis against paracetamol and azithromycin induced liver injury in rats. J. Tradit. Complement. Med. 2015;6:370–376. doi: 10.1016/j.jtcme.2015.07.005.
    1. Yi L.T., Xu Q., Li Y.C., Yang L., Kong L.D. Antidepressant-like synergism of extracts from magnolia bark and ginger rhizome alone and in combination in mice. Prog. Neuropsychopharmacol. Biol. Psychiatry. 2009;33:616–624. doi: 10.1016/j.pnpbp.2009.03.001.
    1. Li M.H., Xua Y., Yang W.J., Li J.K., Xu X.Y., Zhang X., Chen F.T., Li D.P. In vitro synergistic anti-oxidant activities of solvent-extracted fractions from Astragalus membranaceus and Glycyrrhiza uralensis. LWT—Food Sci. Technol. 2011;44:1745–1751. doi: 10.1016/j.lwt.2011.02.017.
    1. Liao Z.G., Liang X.L., Zhu J.Y., Zhao G.W., Yang M., Wang G.F., Jiang Q.Y., Chen X.L. Correlation between synergistic action of Radix Angelica dahurica extracts on analgesic effects of Corydalis alkaloid and plasma concentration of dl-THP. J. Ethnopharmacol. 2010;129:115–120. doi: 10.1016/j.jep.2010.03.005.
    1. Chicca A., Raduner S., Pellati F., Strompen T., Altmann K.H., Schoop R., Gertsch J. Synergistic immunomopharmacological effects of N-alkylamides in Echinacea purpurea herbal extracts. Int. Immunopharmacol. 2009;9:850–858. doi: 10.1016/j.intimp.2009.03.006.
    1. Uto T., Morinaga O., Tanaka H., Shoyama Y. Analysis of the synergistic effect of glycyrrhizin and other constituents in licorice extract on lipopolysaccharide-induced nitric oxide production using knock-out extract. Biochem. Biophys. Res. Commun. 2012;417:473–478. doi: 10.1016/j.bbrc.2011.11.143.
    1. Chen H.Y., Ye X.L., Cui X.L., He K., Jin Y.N., Chen Z., Li X.G. Cytotoxicity and antihyperglycemic effect of minor constituents from Rhizoma Coptis in HepG2 cells. Fitoterapia. 2012;83:67–73. doi: 10.1016/j.fitote.2011.09.014.
    1. Nagaprashantha L.D., Vatsyayan R., Singhal J., Fast S., Roby R., Awasthi S., Singhal S.S. Anti-cancer effects of novel flavonoid vicenin-2 as a single agent and in synergistic combination with docetaxel in prostate cancer. Biochem. Pharmacol. 2011;82:1100–1109. doi: 10.1016/j.bcp.2011.07.078.
    1. Wang L., Zhou G.B., Liu P., Song J.H., Liang Y., Yan X.J., Xu F., Wang B.S., Mao J.H., Shen Z.X., et al. Dissection of mechanisms of Chinese medicinal formula Realgar-Indigo naturalis as an effective treatment for promyelocytic leukemia. Proc. Natl. Acad. Sci. USA. 2008;105:4826–4831. doi: 10.1073/pnas.0712365105.
    1. Liu X., Zhou H. Application of Proteomics Technique in Study of Network Pharmacology. Prog. Pharm. Sci. 2014;38:89–96.
    1. Muqbil I., Bao G.W., El-Kharraj R., Shah M., Mohammad R.M., Sarkar F.H., Azmi A.S. Systems and Network Pharmacology Approaches to Cancer Stem Cells Research and Therapy. J. Stem Cell Res. Ther. 2012 doi: 10.4172/2157-7633.S7-005.
    1. Xiao Z.Y., Zhou W.X., Zhang Y.X. Network pharmacology-based strategy for antitumor drug discovery. J. Int. Pharm. Res. 2014;41:1–5.
    1. Hopkins A.L. Network pharmacology. Nat. Biotechnol. 2007;25:1110–1111. doi: 10.1038/nbt1007-1110.
    1. Peng X.F., Wang L., Bian Y.H. Network pharmacology research technologies and applications. J. Tianjin Univ. TCM. 2015;34:121–124.
    1. Zhou W.X. Research progress and development prospect of network pharmacology. Chin. J. Pharmacol. Toxicol. 2015;29:760–762.
    1. Elgoyhen A.B., Langguth B., Vanneste S., De Ridder D. Tinnitus: Network pathophysiology-network pharmacology. Front. Syst. Neurosci. 2012;6:1–12. doi: 10.3389/fnsys.2012.00001.
    1. Azmi A.S., Wang Z., Philip P.A., Mohammad R.M., Sarkar F.H. Proof of concept: Network and systems biology approaches aid in the discovery of potent anticancer drug combinations. Mol. Cancer Ther. 2010;9:3137–3144. doi: 10.1158/1535-7163.MCT-10-0642.
    1. Huang H., Wu X., Pandey R., Li J., Zhao G., Ibrahim S., Chen J.Y. C²Maps: A network pharmacology database with comprehensive disease-gene-drug connectivity relationships. BMC Genom. 2012;13:S17. doi: 10.1186/1471-2164-13-S6-S17.
    1. An L., Feng F. Network pharmacology-based antioxidant effect study of Zhi-zi-da-huang decoction for alcoholic liver disease. Evid.-Based Complement. Altern. Med. 2015;2015:492470. doi: 10.1155/2015/492470.
    1. Alaimo S., Pulvirenti A., Giugno R., Ferro A. Drug-target interaction prediction through domain-tuned network-based inference. Bioinformatics. 2013;29:2004–2008. doi: 10.1093/bioinformatics/btt307.
    1. Yang M., Chen J.L., Xu L.W., Ji G. Navigating traditional chinese medicine network pharmacology and computational tools. Evid.-Based Complement. Altern. Med. 2013;2013:731969. doi: 10.1155/2013/731969.
    1. Ke Z.P., Zhang X.Z., Ding Y., Cao L., Li N., Ding G., Wang Z.Z., Xiao W. Study on effective substance basis and molecular mechanism of qi-gui-tong-feng tablet using network pharmacology method. China J. Chin. Mater. Med. 2015;40:2837–2842.
    1. Hu Q.N., Deng Z., Tu W., Yang X., Meng Z.B., Deng Z.X., Liu J. VNP: Interactive Visual Network Pharmacology of Diseases, Targets, and Drugs. CPT Pharmacomet. Syst. Pharmacol. 2014;3:e105. doi: 10.1038/psp.2014.1.
    1. Li J., Lu C., Jiang M., Niu X., Guo H., Li L., Bian Z., Lin N., Lu A. Traditional Chinese medicine-based network pharmacology could lead to new multicompound drug discovery. Evid.-Based Complement. Altern. Med. 2012;2012:149762. doi: 10.1155/2012/149762.
    1. Yildirim M.A., Goh K.I., Cusick M.E., Barabási A.L., Vidal M. Drug—Target network. Nat. Biotechnol. 2007;25:1119–1126. doi: 10.1038/nbt1338.
    1. Zhao S., Iyengar R. Systems pharmacology: Network analysis to identify multiscale mechanisms of drug action. Annu. Rev. Pharmacol. Toxicol. 2012;52:505–521. doi: 10.1146/annurev-pharmtox-010611-134520.
    1. Liu Z.H., Sun X.B. Network pharmacology: New opportunity for the modernization of traditional Chinese medicine. Acta Pharm. Sin. 2012;47:696–703.
    1. Liu P., Duan J.A., Bai G., Su S.L. Network pharmacology study on major active compounds of si-wu decoction analogous formulae for treating primary dysmenorrhea of gynecology blood stasis syndrome. China J. Chin. Mater. Med. 2014;39:113–120.
    1. Jia D.M., He X.J., Jiang M., Yi X.L., Zhao N., Tan Y., Li L., Lv A.P. Prediction of molecular mechanism of Radix Angelicae Pubescentis in treatment of rheumatoid arthritis by network pharmacology. Liaoning J. Tradit. Chin. Med. 2015;42:1838–1841.
    1. Pei L., Bao Y., Liu S., Zheng J., Chen X. Material basis of Chinese herbal formulas explored by combining pharmacokinetics with network pharmacology. PLoS ONE. 2013;8:e57414. doi: 10.1371/journal.pone.0057414.
    1. Wu L., Wang Y., Li Z., Zhang B., Cheng Y., Fan X. Identifying roles of “Jun-Chen-Zuo-Shi” component herbs of QiShenYiQi formula in treating acute myocardial ischemia by network pharmacology. Chin. Med. 2014;9:24. doi: 10.1186/1749-8546-9-24.
    1. Zhang B., Wang X., Li S. An Integrative platform of TCM network pharmacology and its application on a herbal formula, Qing-Luo-Yin. Evid.-Based Complement. Altern. Med. 2013;2013:456747. doi: 10.1155/2013/456747.
    1. Shi S.H., Cai Y.P., Cai X.J., Zheng X.Y., Cao D.S., Ye F.Q., Xiang Z. A network pharmacology approach to understanding the mechanisms of action of traditional medicine: Bushenhuoxue formula for treatment of chronic kidney disease. PLoS ONE. 2014;9:e89123. doi: 10.1371/journal.pone.0089123.
    1. Li H., Zhao L., Zhang B., Jiang Y., Wang X., Guo Y., Liu H., Li S., Tong X. A network pharmacology approach to determine active compounds and action mechanisms of ge-gen-qin-lian decoction for treatment of type 2 diabetes. Evid.-Based Complement. Altern. Med. 2014;2014:495840. doi: 10.1155/2014/495840.
    1. Xu H., Zhang Y., Lei Y., Gao X., Zhai H., Lin N., Tang S., Liang R., Ma Y., Li D., et al. A systems biology-based approach to uncovering the molecular mechanisms underlying the effects of dragon's blood tablet in colitis, involving the integration of chemical analysis, ADME prediction, and network pharmacology. PLoS ONE. 2014;9:e101432. doi: 10.1371/journal.pone.0101432.
    1. Shi Q.L., Ma X.H., Yan L.L., Xu X.J., Sun H. Network pharmacological studies of huo-xiang-zheng-qi pill in treating functional dyspepsia. Chin. J. New Drugs. 2014;23:1371–1377.
    1. Wang L.L., Zhao X.P., Zhao Z.Y., Fan X.H., Li Z. Network pharmacology study of mechanism on xue-sai-tong injection against retinal vein occlusion. China J. Chin. Mater. Med. 2014;39:2322–2325.
    1. Pan Y., Li S.X., Huang D., Pan M.Q. Network pharmacology approach to predict the anti-cancer active ingredients of gan-fu-le against hepatocellular carcinoma. China J. Chin. Mater. Med. 2014;29:1490–1498.
    1. Yu X.C., Yang W., Wu B.L., Yang Y.X., Li C.Y. Predication of Anti-Diabetes Effects of Corydalis yanhusuo Alkaloids with Pharmacological Network Technology and Experimental Validation in ICR Mice. Chin. Pharm. J. 2014;49:913–918.
    1. Li S., Zhang B., Jiang D., Wei Y., Zhang N. Herb network construction and co-module analysis for uncovering the combination rule of traditional Chinese herbal formulae. BMC Bioinform. 2010;11:S6. doi: 10.1186/1471-2105-11-S11-S6.
    1. Gu J., Gui Y., Chen L., Yuan G., Xu X. CVDHD: A cardiovascular disease herbal database for drug discovery and network pharmacology. J. Cheminform. 2013;5:51. doi: 10.1186/1758-2946-5-51.
    1. Zhao Q.Q., Li X., Zeng M.L., Huang X.L., Yu H.Y. A network pharmacology based study of regulation effects of the main active components in hong-hua injection on cerebrovascular disease network. Chin. Pharm. J. 2015;50:1402–1407.
    1. Chen J., Gu J.F., Wang C.F., Yuan J.R., Zhao B.J., Zhang L., Cheng X.D., Feng L., Jia X.B. Structural components of Chinese medicine and pharmacology network: Systematical overall regulation on pathological network. China J. Chin. Mater. Med. 2015;40:758–764.
    1. Liu Q.S., Chen X.Y., Zhuang S.J. Research progress of gene expression profiles based on the application of it in traditional Chinese medicine network pharmacology. Lishizhen Med. Mater. Med. Res. 2014;25:502–504.
    1. Gu J., Gui Y., Chen L., Yuan G., Lu H.Z., Xu X. Use of natural products as chemical library for drug discovery and network pharmacology. PLoS ONE. 2013;8:e62839. doi: 10.1371/journal.pone.0062839.
    1. Hsin K.Y., Ghosh S., Kitano H. Combining machine learning systems and multiple docking simulation packages to improve docking prediction reliability for network pharmacology. PLoS ONE. 2013;8:e83922. doi: 10.1371/journal.pone.0083922.
    1. Gu J., Zhang H., Chen L., Xu S., Yuan G., Xu X. Drug-target network and polypharmacology studies of a Traditional Chinese Medicine for type II diabetes mellitus. Comput. Biol. Chem. 2011;35:293–297. doi: 10.1016/j.compbiolchem.2011.07.003.
    1. Li S., Zhang B., Zhang N. Network target for screening synergistic drug combinations with application to traditional Chinese medicine. BMC Syst. Biol. 2011;5:S10. doi: 10.1186/1752-0509-5-S1-S10.
    1. Zhang G.B., Li Q.Y., Chen Q.L., Su S.B. Network pharmacology: A new approach for Chinese herbal medicine research. Evid.-Based Complement. Altern. Med. 2013;2013:621423. doi: 10.1155/2013/621423.
    1. Zheng C.S., Lin Z.C., Xu H.F., Zeng J.W., Xu X.J., Liu X.X., Ye H.Z. Pharmacological research on osteoarthritis treated by tou-gu-xiao-tong capsule. J. Fujian Univ. TCM. 2011;21:43–47.
    1. Hoeng J., Deehan R., Pratt D., Martin F., Sewer A., Thomson T.M., Drubin D.A., Waters C.A., de Graaf D., Peitsch M.C. A network-based approach to quantifying the impact of biologically active substances. Drug Discov. Today. 2012;17:413–418. doi: 10.1016/j.drudis.2011.11.008.
    1. Zhao J., Fang H.Y., Zhang W.D. Bioinformatics approaches in research on network pharmacology of traditional Chinese medicine. Prog. Pharm. Sci. 2014;38:97–103.
    1. Hopkins A.L. Network pharmacology: The next paradigm in drug discovery. Nat. Chem. Biol. 2008;4:682–690. doi: 10.1038/nchembio.118.
    1. Chen Y., Zhu J., Lum P.Y., Yang X., Pinto S., MacNeil D.J., Zhang C., Lamb J., Edwards S., Sieberts S.K., et al. Variations in DNA elucidate molecular networks that cause disease. Nature. 2008;452:429–435. doi: 10.1038/nature06757.
    1. Wang J., Li X.J. Drug targets discovery based on dynamic signal transduction networks. Acta Pharm. Sin. 2010;45:1–8.
    1. Csermely P., Agoston V., Pongor S. The efficiency of multi-target drugs: The network approach might help drug design. Trends Pharmacol. Sci. 2005;26:178–182. doi: 10.1016/j.tips.2005.02.007.
    1. Mayer L.D., Janoff A.S. Optimizing combination chemotherapy by controlling drug ratios. Mol. Interv. 2007;7:216–223. doi: 10.1124/mi.7.4.8.
    1. Ihnatova I., Budinska E. ToPASeq: An R package for topology-based pathway analysis of microarray and RNA-Seq data. BMC Bioinform. 2015;16:350. doi: 10.1186/s12859-015-0763-1.

Source: PubMed

3
Iratkozz fel