Browse > Article
http://dx.doi.org/10.1016/j.jgr.2017.09.001

Systems-level mechanisms of action of Panax ginseng: a network pharmacological approach  

Park, Sa-Yoon (Department of Physiology, College of Korean Medicine, Gachon University)
Park, Ji-Hun (Department of Physiology, College of Korean Medicine, Gachon University)
Kim, Hyo-Su (Department of Physiology, College of Korean Medicine, Gachon University)
Lee, Choong-Yeol (Department of Physiology, College of Korean Medicine, Gachon University)
Lee, Hae-Jeung (Department of Food and Nutrition, College of BioNano Technology, Gachon University)
Kang, Ki Sung (Department of Preventive Medicine, College of Korean Medicine, Gachon University)
Kim, Chang-Eop (Department of Physiology, College of Korean Medicine, Gachon University)
Publication Information
Journal of Ginseng Research / v.42, no.1, 2018 , pp. 98-106 More about this Journal
Abstract
Panax ginseng has been used since ancient times based on the traditional Asian medicine theory and clinical experiences, and currently, is one of the most popular herbs in the world. To date, most of the studies concerning P. ginseng have focused on specific mechanisms of action of individual constituents. However, in spite of many studies on the molecular mechanisms of P. ginseng, it still remains unclear how multiple active ingredients of P. ginseng interact with multiple targets simultaneously, giving the multidimensional effects on various conditions and diseases. In order to decipher the systems-level mechanism of multiple ingredients of P. ginseng, a novel approach is needed beyond conventional reductive analysis. We aim to review the systems-level mechanism of P. ginseng by adopting novel analytical framework-network pharmacology. Here, we constructed a compound-target network of P. ginseng using experimentally validated and machine learning-based prediction results. The targets of the network were analyzed in terms of related biological process, pathways, and diseases. The majority of targets were found to be related with primary metabolic process, signal transduction, nitrogen compound metabolic process, blood circulation, immune system process, cell-cell signaling, biosynthetic process, and neurological system process. In pathway enrichment analysis of targets, mainly the terms related with neural activity showed significant enrichment and formed a cluster. Finally, relative degrees analysis for the target-disease association of P. ginseng revealed several categories of related diseases, including respiratory, psychiatric, and cardiovascular diseases.
Keywords
network pharmacology; Panax ginseng; polypharmacology; traditional Asian medicine;
Citations & Related Records
Times Cited By KSCI : 16  (Citation Analysis)
연도 인용수 순위
1 Chen X, Lee TJ. Ginsenosides-induced nitric oxide-mediated relaxation of the rabbit corpus cavernosum. Br J Pharmacol 1995;115:15-8.   DOI
2 Lee MH, Jeong JH, Seo JW, Shin CG, Kim YS, In JG, Yang DC, Yi JS, Choi YE. Enhanced triterpene and phytosterol biosynthesis in Panax ginseng overexpressing squalene synthase gene. Plant Cell Physiol 2004;45:976-84.   DOI
3 Richter R, Basar S, Koch A, Konig WA. Three sesquiterpene hydrocarbons from the roots of Panax ginseng C.A. Meyer (Araliaceae). Phytochemistry 2005;66: 2708-13.   DOI
4 Kim JS. Investigation of phenolic, flavonoid, and vitamin contents in different parts of Korean Ginseng (Panax ginseng C.A. Meyer). Prev Nutr Food Sci 2016;21:263-70.   DOI
5 Han BH, Park MH, Han YN, Woo LK. Alkaloidal components of Panax ginseng. Archives of Pharmacal Research 1986;9:21-3.   DOI
6 Huong NT, Matsumoto K, Kasai R, Yamasaki K, Watanabe H. In vitro antioxidant activity of Vietnamese ginseng saponin and its components. Biol Pharm Bull 1998;21:978-81.   DOI
7 Chang TK, Chen J, Benetton SA. In vitro effect of standardized ginseng extracts and individual ginsenosides on the catalytic activity of human CYP1A1, CYP1A2, and CYP1B1. Drug Metab Dispos 2002;30:378-84.   DOI
8 Lee JJ, Kwon HK, Jung IH, Cho YB, Kim KJ, Kim JL. Anti-cancer activities of ginseng extract fermented with Phellinus linteus. Mycobiology 2009;37:21-7.   DOI
9 Hwang SH, Lee BH, Choi SH, Kim HJ, Won KJ, Lee HM, Rhim H, Kim HC, Nah SY. Effects of gintonin on the proliferation, migration, and tube formation of human umbilical-vein endothelial cells: involvement of lysophosphatidic-acid receptors and vascular-endothelial-growth-factor signaling. J Ginseng Res 2016;40:325-33.   DOI
10 Yue PY, Wong DY, Wu PK, Leung PY, Mak NK, Yeung HW, Liu L, Cai Z, Jiang ZH, Fan TP, et al. The angiosuppressive effects of 20(R)- ginsenoside Rg3. Biochem Pharmacol 2006;72:437-45.   DOI
11 Kim JW, Jung SY, Kwon YH, Lee JH, Lee YM, Lee BY, Kwon SM. Ginsenoside Rg3 attenuates tumor angiogenesis via inhibiting bioactivities of endothelial progenitor cells. Cancer Biol Ther 2012;13:504-15.   DOI
12 Choi KS, Song H, Kim EH, Choi JH, Hong H, Han YM, Hahm KB. Inhibition of hydrogen sulfide-induced angiogenesis and inflammation in vascular endothelial cells: potential mechanisms of gastric cancer prevention by Korean Red Ginseng. J Ginseng Res 2012;36:135-45.   DOI
13 Zhou H, Hou SZ, Luo P, Zeng B, Wang JR, Wong YF, Jiang ZH, Liu L. Ginseng protects rodent hearts from acute myocardial ischemia-reperfusion injury through GR/ER-activated RISK pathway in an endothelial NOS-dependent mechanism. J Ethnopharmacol 2011;135:287-98.   DOI
14 Kim TH, Lee SM. The effects of ginseng total saponin, panaxadiol and panaxatriol on ischemia/reperfusion injury in isolated rat heart. Food Chem Toxicol 2010;48:1516-20.   DOI
15 Aravinthan A, Kim JH, Antonisamy P, Kang CW, Choi J, Kim NS, Kim JH. Ginseng total saponin attenuates myocardial injury via anti-oxidative and anti-inflammatory properties. J Ginseng Res 2015;39:206-12.   DOI
16 Mi H, Muruganujan A, Casagrande JT, Thomas PD. Large-scale gene function analysis with the PANTHER classification system. Nat Protoc 2013;8:1551-66.   DOI
17 Rimar S, Lee-Mengel M, Gillis CN. Pulmonary protective and vasodilator effects of a standardized Panax ginseng preparation following artificial gastric digestion. Pulm Pharmacol 1996;9:205-9.   DOI
18 Hopkins AL. Network pharmacology: the next paradigm in drug discovery. Nat Chem Biol 2008;4:682-90.   DOI
19 Ru J, Li P, Wang J, Zhou W, Li B, Huang C, Li P, Guo Z, Tao W, Yang Y, et al. TCMSP: a database of systems pharmacology for drug discovery from herbal medicines. J Cheminform 2014;6:13.   DOI
20 Mi H, Huang X, Muruganujan A, Tang H, Mills C, Kang D, Thomas PD. PANTHER version 11: expanded annotation data from Gene Ontology and Reactome pathways, and data analysis tool enhancements. Nucleic Acids Res 2017;45: D183-9.   DOI
21 Elyakov G, Strigina L, Uvarova N, Vaskovsky V, Dzizenko A, Kochetkov N. Glycosides from ginseng roots. Tetrahedron Letters 1964;5:3591-7.   DOI
22 Tansakul P, Shibuya M, Kushiro T, Ebizuka Y. Dammarenediol-II synthase, the first dedicated enzyme for ginsenoside biosynthesis, in Panax ginseng. FEBS Lett 2006;580:5143-9.   DOI
23 Shin BK, Kwon SW, Park JH. Chemical diversity of ginseng saponins from Panax ginseng. J Ginseng Res 2015;39:287-98.   DOI
24 Kim DY, Yang WM. Panax ginseng ameliorates airway inflammation in an ovalbumin-sensitized mouse allergic asthma model. J Ethnopharmacol 2011;136:230-5.   DOI
25 Jung JH, Kang IG, Kim DY, Hwang YJ, Kim ST. The effect of Korean red ginseng on allergic inflammation in a murine model of allergic rhinitis. J Ginseng Res 2013;37:167-75.   DOI
26 Babayigit A, Olmez D, Karaman O, Bagriyanik HA, Yilmaz O, Kivcak B, Erbil G, Uzuner N. Ginseng ameliorates chronic histopathologic changes in a murine model of asthma. Allergy Asthma Proc 2008;29:493-8.   DOI
27 Lim CY, Moon JM, Kim BY, Lim SH, Lee GS, Yu HS, Cho SI. Comparative study of Korean White Ginseng and Korean Red Ginseng on efficacies of OVA-induced asthma model in mice. J Ginseng Res 2015;39:38-45.   DOI
28 Tran TV, Shin EJ, Ko SK, Nam Y, Chung YH, Jeong JH, Jang CG, Nah SY, Yamada K, Nabeshima T, et al. Mountain-cultivated ginseng attenuates phencyclidine-induced abnormal behaviors in mice by positive modulation of glutathione in the prefrontal cortex of mice. J Med Food 2016;19:961-9.   DOI
29 Tawab MA, Bahr U, Karas M, Wurglics M, Schubert-Zsilavecz M. Degradation of ginsenosides in humans after oral administration. Drug Metab Dispos 2003;31:1065-71.   DOI
30 Hasegawa H, Suzuki R, Nagaoka T, Tezuka Y, Kadota S, Saiki I. Prevention of growth and metastasis of murine melanoma through enhanced natural-killer cytotoxicity by fatty acid-conjugate of protopanaxatriol. Biol Pharm Bull 2002;25:861-6.   DOI
31 Ling WH, Jones PJ. Dietary phytosterols: a review of metabolism, benefits and side effects. Life Sci 1995;57:195-206.   DOI
32 Iwabuchi H, Kato N, Yoshikura M. Studies on the sesquiterpenoids of Panax ginseng C. A. Meyer. IV. Chem Pharm Bull (Tokyo) 1990;38:1405-7.   DOI
33 Kumar S, Pandey AK. Chemistry and biological activities of flavonoids: an overview. Sci World J 2013;2013, 162750.
34 Hu S, Han R, Mak S, Han Y. Protection against 1-methyl-4-phenylpyridinium ion (MPP+)-induced apoptosis by water extract of ginseng (Panax ginseng C.A. Meyer) in SH-SY5Y cells. J Ethnopharmacol 2011;135:34-42.   DOI
35 Dang H, Sun L, Liu X, Peng B, Wang Q, Jia W, Chen Y, Pan A, Xiao P. Preventive action of Kai Xin San aqueous extract on depressive-like symptoms and cognition deficit induced by chronic mild stress. Exp Biol Med (Maywood) 2009;234:785-93.   DOI
36 Zhu KY, Mao QQ, Ip SP, Choi RC, Dong TT, Lau DT, Tsim KW. A standardized Chinese herbal decoction, Kai-Xin-San, restores decreased levels of neurotransmitters and neurotrophic factors in the brain of chronic stressinduced depressive rats. Evid Based Complement Alternat Med 2012;2012, 149256.
37 Yan L, Hu Q, Mak MS, Lou J, Xu SL, Bi CW, Zhu Y, Wang H, Dong TT, Tsim KW. A Chinese herbal decoction, reformulated from Kai-Xin-San, relieves the depression-like symptoms in stressed rats and induces neurogenesis in cultured neurons. Sci Rep 2016;6, 30014.   DOI
38 Luo P, Dong G, Liu L, Zhou H. The long-term consumption of ginseng extract reduces the susceptibility of intermediate-aged hearts to acute ischemia reperfusion injury. PLoS One 2015;10, e0144733.   DOI
39 Van Kampen JM, Baranowski DB, Shaw CA, Kay DG. Panax ginseng is neuroprotective in a novel progressive model of Parkinson's disease. Exp Gerontol 2014;50:95-105.   DOI
40 Nah JJ, Hahn JH, Chung S, Choi S, Kim YI, Nah SY. Effect of ginsenosides, active components of ginseng, on capsaicin-induced pain-related behavior. Neuropharmacology 2000;39:2180-4.   DOI
41 Mogil JS, Shin YH, McCleskey EW, Kim SC, Nah SY. Ginsenoside Rf, a trace component of ginseng root, produces antinociception in mice. Brain Res 1998;792:218-28.   DOI
42 Yin H, Park SA, Park SJ, Han SK. Korean Red Ginseng extract activatesnon-NMDA glutamate and GABAA receptors on the substantia gelatinosa neurons of the trigeminal subnucleus caudalis in mice. J Ginseng Res 2011;35:219-25.   DOI
43 Zhang K, Wang F, Yang JY, Wang LJ, Pang HH, Su GY, Ma J, Song SJ, Xiong ZL, Wu CF. Analysis of main constituents and mechanisms underlying antidepressant-like effects of Xiaochaihutang in mice. J Ethnopharmacol 2015;175:48-57.   DOI
44 Lee JH, Lee JH, Lee YM, Kim PN, Jeong CS. Potential analgesic and antiinflammatory activities of Panax ginseng head butanolic fraction in animals. Food Chem Toxicol 2008;46:3749-52.   DOI
45 Wang Y, Chen Y, Xu H, Luo H, Jiang R. Analgesic effects of glycoproteins from Panax ginseng root in mice. J Ethnopharmacol 2013;148:946-50.   DOI
46 Suzuki T, Yamamoto A, Ohsawa M, Motoo Y, Mizukami H, Makino T. Effect of ninjin'yoeito and ginseng extracts on oxaliplatin-induced neuropathies in mice. J Nat Med 2017;71:757-64.   DOI
47 Zhu Y, Chao C, Duan X, Cheng X, Liu P, Su S, Duan J, Dong TT, Tsim KW. Kai-Xin-San series formulae alleviate depressive-like behaviors on chronic mild stressed mice via regulating neurotrophic factor system on hippocampus. Sci Rep 2017;7, 1467.   DOI
48 Yan S, You ZL, Zhao QY, Peng C, He G, Gou XJ, Lin B. Antidepressant-like effects of Sanyuansan in the mouse forced swim test, tail suspension test, and chronic mild stress model. Kaohsiung J Med Sci 2015;31:605-12.   DOI
49 Lee KJ, Ji GE. The effect of fermented red ginseng on depression is mediated by lipids. Nutr Neurosci 2014;17:7-15.   DOI
50 Kuribara H, Tomioka H, Takahashi R, Onozato K, Murohashi N, Numajiri T, Iwata H, Koya S. An antidepressant effect of Sho-ju-sen, a Japanese herbal medicine, assessed by learned helplessness model in mice. Phytother Res 2004;18:173-6.   DOI
51 Jeong HG, Ko YH, Oh SY, Han C, Kim T, Joe SH. Effect of Korean Red Ginseng as an adjuvant treatment for women with residual symptoms of major depression. Asia Pac Psychiatry 2015;7:330-6.   DOI
52 Kim YO, Lee HY, Won H, Nah SS, Lee HY, Kim HK, Kwon JT, Kim HJ. Influence of Panax ginseng on the offspring of adult rats exposed to prenatal stress. Int J Mol Med 2015;35:103-9.   DOI
53 Zhu Y, Duan X, Cheng X, Cheng X, Li X, Zhang L, Liu P, Su S, Duan JA, Dong TT, et al. Kai-Xin-San, a standardized traditional Chinese medicine formula, upregulates the expressions of synaptic proteins on hippocampus of chronic mild stress induced depressive rats and primary cultured rat hippocampal neuron. J Ethnopharmacol 2016;193:423-32.   DOI
54 Jeon BH, Kim CS, Park KS, Lee JW, Park JB, Kim KJ, Kim SH, Chang SJ, Nam KY. Effect of Korea red ginseng on the blood pressure in conscious hypertensive rats. Gen Pharmacol 2000;35:135-41.   DOI
55 Hong SY, Kim JY, Ahn HY, Shin JH, Kwon O. Panax ginseng extract rich in ginsenoside protopanaxatriol attenuates blood pressure elevation in spontaneously hypertensive rats by affecting the Akt-dependent phosphorylation of endothelial nitric oxide synthase. J Agric Food Chem 2012;60:3086-91.   DOI
56 Lei Y, Tao LL, Wang GL. Effect of extracts from Panax ginseng, Panax notoginseng, and Ligusticum chuanxiong on vascular smooth muscle cells of aging and hypertension rats. Zhongguo Zhong Xi Yi Jie He Za Zhi 2012;32:1374-9 [in Chinese].
57 Zhou W, Chai H, Lin PH, Lumsden AB, Yao Q, Chen CJ. Molecular mechanisms and clinical applications of ginseng root for cardiovascular disease. Med Sci Monit 2004;10:RA187-R192.
58 Rhee MY, Kim YS, Bae JH, Nah DY, Kim YK, Lee MM, Kim HY. Effect of Korean red ginseng on arterial stiffness in subjects with hypertension. J Altern Complement Med 2011;17:45-9.   DOI
59 Jeon BH, Kim CS, Kim HS, Park JB, Nam KY, Chang SJ. Effect of Korean red ginseng on blood pressure and nitric oxide production. Acta Pharmacol Sin 2000;21:1095-100.
60 Kang SY, Schini-Kerth VB, Kim ND. Ginsenosides of the protopanaxatriol group cause endothelium-dependent relaxation in the rat aorta. Life Sci 1995;56:1577-86.   DOI
61 Kim ND, Kang SY, Schini VB. Ginsenosides evoke endothelium-dependent vascular relaxation in rat aorta. Gen Pharmacol 1994;25:1071-7.   DOI
62 Shin W, Yoon J, Oh GT, Ryoo S. Korean red ginseng inhibits arginase and contributes to endothelium dependent vasorelaxation through endothelial nitric oxide synthase coupling. J Ginseng Res 2013;37:64-73.   DOI
63 Lee CH, Kim JH. A review on the medicinal potentials of ginseng and ginsenosides on cardiovascular diseases. J Ginseng Res 2014;38:161-6.   DOI
64 Park HJ, Kim DH, Park SJ, Kim JM, Ryu JH. Ginseng in traditional herbal prescriptions. J Ginseng Res 2012;36:225-41.   DOI
65 Kuk YB, Kim SC, Park SD, Park SK, Seo BY, Seo YB, Shin SS, Lee SI, Lee JC, CH L. Formula study. Younglimsa. 1999 [in Korean].
66 Xiang YZ, Shang HC, Gao XM, Zhang BL. A comparison of the ancient use of ginseng in traditional Chinese medicine with modern pharmacological experiments and clinical trials. Phytother Res 2008;22:851-8.   DOI
67 Choi J, Kim TH, Choi TY, Lee MS. Ginseng for health care: a systematic review of randomized controlled trials in Korean literature. PLoS One 2013;8, e59978.   DOI
68 Lee HW, Lim HJ, Jun JH, Choi J, Lee MS. Ginseng for the treatment of hypertension: a systematic review and meta-analysis of double-blind, randomized, placebo-controlled trials. Curr Vasc Pharmacol 2017;15:549.
69 Kim JH. Cardiovascular diseases and Panax ginseng: a review on molecular mechanisms and medical applications. J Ginseng Res 2012;36:16-26.   DOI
70 Yuan CS, Wang CZ, Wicks SM, Qi LW. Chemical and pharmacological studies of saponins with a focus on American ginseng. J Ginseng Res 2010;34:160-7.   DOI
71 Rhee YH, Ahn JH, Choe J, Kang KW, Joe C. Inhibition of mutagenesis and transformation by root extracts of Panax ginseng in vitro. Planta Med 1991;57: 125-8.   DOI
72 Attele AS, Wu JA, Yuan CS. Ginseng pharmacology: multiple constituents and multiple actions. Biochem Pharmacol 1999;58:1685-93.   DOI
73 Lee LS, Cho CW, Hong HD, Lee YC, Choi UK, Kim YC. Hypolipidemic and antioxidant properties of phenolic compound-rich extracts from white ginseng (Panax ginseng) in cholesterol-fed rabbits. Molecules 2013;18:12548-60.   DOI
74 Takahashi M, Yoshikura M. Studies on the components of Panax ginseng C.A. Meyer. V. On the structure of a new acetylene derivative "Panaxynol" (3). Synthesis of 1,9-(cis)-heptadecadiene-4,6-diyn-3-ol. Yakugaku Zasshi 1966;86:1053-6 [in Japanese].   DOI
75 Matsunaga H, Katano M, Yamamoto H, Fujito H, Mori M, Takata K. Cytotoxic activity of polyacetylene compounds in Panax ginseng C. A. Meyer. Chem Pharm Bull (Tokyo) 1990;38:3480-2.   DOI
76 Kong Y-H, Lee Y-C, Choi S-Y. Neuroprotective and anti-inflammatory effects of phenolic compounds in Panax ginseng CA Meyer. J Ginseng Res 2009;33: 111-4.   DOI
77 Zhou W, Wang J, Wu Z, Huang C, Lu A, Wang Y. Systems pharmacology exploration of botanic drug pairs reveals the mechanism for treating different diseases. Sci Rep 2016;6, 36985.   DOI
78 Yu H, Chen J, Xu X, Li Y, Zhao H, Fang Y, Li X, Zhou W, Wang W, Wang Y. A systematic prediction of multiple drug-target interactions from chemical, genomic, and pharmacological data. PLoS One 2012;7, e37608.   DOI
79 Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B, Ideker T. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 2003;13:2498-504.   DOI
80 Chen EY, Tan CM, Kou Y, Duan Q, Wang Z, Meirelles GV, Clark NR, Ma'ayan A. Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool. BMC Bioinformatics 2013;14:128.   DOI
81 Kanehisa M, Goto S, Kawashima S, Nakaya A. The KEGG databases at GenomeNet. Nucleic Acids Res 2002;30:42-6.   DOI