Browse > Article
http://dx.doi.org/10.1016/j.jgr.2019.12.003

Ginsenosides: potential therapeutic source for fibrosis-associated human diseases  

Li, Xiaobing (College of Basic Medicine, Henan University of Traditional Chinese Medicine)
Mo, Nan (College of Basic Medicine, Henan University of Traditional Chinese Medicine)
Li, Zhenzhen (Medical Research Center, The First Affiliated Hospital of Zhengzhou University)
Publication Information
Journal of Ginseng Research / v.44, no.3, 2020 , pp. 386-398 More about this Journal
Abstract
Tissue fibrosis is an eventual pathologic change of numerous chronic illnesses, which is characterized by resident fibroblasts differentiation into myofibroblasts during inflammation, coupled with excessive extracellular matrix deposition in tissues, ultimately leading to failure of normal organ function. Now, there are many mechanistic insights into the pathogenesis of tissue fibrosis, which facilitate the discovery of effective antifibrotic drugs. Moreover, many chronic diseases remain a significant clinical unmet need. For the past five years, many research works have undoubtedly addressed the functional dependency of ginsenosides in different types of fibrosis and the successful remission in various animal models treated with ginsenosides. Caveolin-1, interleukin, thrombospondin-1 (TSP-1), liver X receptors (LXRs), Nrf2, microRNA-27b, PPARδ-STAT3, liver kinase B1 (LKB1)-AMPK, and TGF-β1/Smads are potential therapy targeting using ginsenosides. Ginsenosides can play a targeting role and suppress chronic inflammatory response, collagen deposition, and epitheliale-mesenchymal transition (EMT), as well as myofibroblast activation to attenuate fibrosis. In this report, our aim was to focus on the therapeutic prospects of ginsenosides in fibrosis-related human diseases making use of results acquired from various animal models. These findings should provide important therapeutic clues and strategies for the exploration of new drugs for fibrosis treatment.
Keywords
Chinese herb medicines; Fibrosis; Ginseng; Ginsenosides; Therapeutics;
Citations & Related Records
Times Cited By KSCI : 7  (Citation Analysis)
연도 인용수 순위
1 Zhang K, Zhang J, Wang X, Wang L, Pugliese M, Passantino A, Li J. Cardioprotection of Sheng Mai Yin a classic formula on adriamycin induced myocardial injury in Wistar rats. Phytomedicine 2018;38:1-11.   DOI
2 Mutsaers HA, Olinga P. Editorial: organ fibrosis: triggers, pathways, and cellular plasticity. Front Med (Lausanne) 2016;3:55.
3 Xie XS, Yang M, Liu HC, Zuo C, Li Z, Deng Y, Fan JM. Influence of ginsenoside Rg1, a panaxatriol saponin from Panax notoginseng, on renal fibrosis in rats with unilateral ureteral obstruction. J Zhejiang Univ Sci B 2008;9:885-94.   DOI
4 Xie XS, Liu HC, Yang M, Zuo C, Deng Y, Fan JM. Ginsenoside Rb1, a panoxadiol saponin against oxidative damage and renal interstitial fibrosis in rats with unilateral ureteral obstruction. Chin J Integr Med 2009;15:133-40.   DOI
5 Xie XS, Liu HC, Wang FP, Zhang CL, Zuo C, Deng Y, Fan JM. Ginsenoside Rg1 modulation on thrombospondin-1 and vascular endothelial growth factor expression in early renal fibrogenesis in unilateral obstruction. Phytother Res 2010;24:1581-7.   DOI
6 Xiong J, Guo J, Huang L, Meng B, Ping Q. Self-micelle formation and the incorporation of lipid in the formulation affect the intestinal absorption of Panax notoginseng. Int J Pharm 2008;360:191-6.   DOI
7 Li T, Shu YJ, Cheng JY, Liang RC, Dian SN, Lv XX, Yang MQ, Huang SL, Chen G, Yang F. Pharmacokinetics and efficiency of brain targeting of ginsenosides Rg1 and Rb1 given as Nao-Qing microemulsion. Drug Dev Ind Pharm 2015;41:224-31.   DOI
8 Cai H, Wen X, Wen L, Tirelli N, Zhang X, Zhang Y, Su H, Yang F, Chen G. Enhanced local bioavailability of single or compound drugs delivery to the inner ear through application of PLGA nanoparticles via round window administration. Int J Nanomedicine 2014;9:5591-601.   DOI
9 Yun TK, Choi SY, Yun HY. Epidemiological study on cancer prevention by ginseng: are all kinds of cancers preventable by ginseng? J Korean Med Sci 2001;16(Suppl):S19-27.   DOI
10 Cui Y, Shu XO, Gao YT, Cai H, Tao MH, Zheng W. Association of ginseng use with survival and quality of life among breast cancer patients. Am J Epidemiol 2006;163:645-53.   DOI
11 Yennurajalingam S, Reddy A, Tannir NM, Chisholm GB, Lee RT, Lopez G, Escalante CP, Manzullo EF, Frisbee Hume S, Williams JL, et al. High-Dose Asian Ginseng (Panax Ginseng) for Cancer-Related Fatigue: A Preliminary Report. Integr Cancer Ther 2015;14:419-27.   DOI
12 Zhou B, Yan Z, Liu R, Shi P, Qian S, Qu X, Zhu L, Zhang W, Wang J. Prospective Study of Transcatheter Arterial Chemoembolization (TACE) with Ginsenoside Rg3 versus TACE Alone for the Treatment of Patients with Advanced Hepatocellular Carcinoma. Radiology 2016;280:630-9.   DOI
13 Sheng C, Peng W, Xia ZA, Wang Y, Chen Z, Su N, Wang Z. The impact of ginsenosides on cognitive deficits in experimental animal studies of Alzheimer's disease: a systematic review. BMC Complement Altern Med 2015;15:386.   DOI
14 Song L, Xu MB, Zhou XL, Zhang DP, Zhang SL, Zheng GQ. A preclinical systematic review of ginsenoside-rg1 in experimental Parkinson's disease. Oxid Med Cell Longev 2017;2017:2163053.
15 Wynn TA. Cellular and molecular mechanisms of fibrosis. J Pathol 2008;214:199-210.   DOI
16 Gourdie RG, Dimmeler S, Kohl P. Novel therapeutic strategies targeting fibroblasts and fibrosis in heart disease. Nat Rev Drug Discov 2016;15:620-38.   DOI
17 Kim JH, Yi YS, Kim MY, Cho JY. Role of ginsenosides, the main active components of Panax ginseng, in inflammatory responses and diseases. J Ginseng Res 2017;41:435-43.   DOI
18 Li B, Zhao J, Wang CZ, Searle J, He TC, Yuan CS, Du W. Ginsenoside Rh2 induces apoptosis and paraptosis-like cell death in colorectal cancer cells through activation of p53. Cancer Lett 2011;301:185-92.   DOI
19 Sun Y, Liu Y, Chen K. Roles and mechanisms of ginsenoside in cardiovascular diseases: progress and perspectives. Sci China Life Sci 2016;59:292-8.   DOI
20 Zheng Q, Bao XY, Zhu PC, Tong Q, Zheng GQ, Wang Y. Ginsenoside Rb1 for myocardial ischemia/reperfusion injury: preclinical evidence and possible mechanisms. Oxid Med Cell Longev 2017;2017:6313625.
21 Yun TK. Experimental and epidemiological evidence on non-organ specific cancer preventive effect of Korean ginseng and identification of active compounds. Mutat Res 2003;523-524:63-74.   DOI
22 Peng XD, Dai LL, Huang CQ, He CM, Yang B, Chen LJ. Relationship between anti-fibrotic effect of Panax notoginseng saponins and serum cytokines in rat hepatic fibrosis. Biochem Biophys Res Commun 2009;388:31-4.   DOI
23 Li SS, Ye JM, Deng ZY, Yu LX, Gu XX, Liu QF. Ginsenoside-Rg1 inhibits endoplasmic reticulum stress-induced apoptosis after unilateral ureteral obstruction in rats. Ren Fail 2015;37:890-5.   DOI
24 Levin A, Tonelli M, Bonventre J, Coresh J, Donner JA, Fogo AB, Fox CS, Gansevoort RT, Heerspink HJL, Jardine M, et al. Global kidney health 2017 and beyond: a roadmap for closing gaps in care, research, and policy. Lancet 2017;390:1888-917.   DOI
25 Rangarajan S, Bone NB, Zmijewska AA, Jiang S, Park DW, Bernard K, Locy ML, Ravi S, Deshane J, Mannon RB, et al. Metformin reverses established lung fibrosis in a bleomycin model. Nat Med 2018;24:1121-7.   DOI
26 Udomsinprasert W, Jittikoon J. Vitamin D and liver fibrosis: molecular mechanisms and clinical studies. Biomed Pharmacother 2019;109:1351-60.   DOI
27 Kim WR, Brown Jr RS, Terrault NA, El-Serag H. Burden of liver disease in the United States: summary of a workshop. Hepatology 2002;36:227-42.   DOI
28 Lim W, Mudge KW, Vermeylen F. Effects of population, age, and cultivation methods on ginsenoside content of wild American ginseng (Panax quinquefolium). J Agric Food Chem 2005;53:8498-505.   DOI
29 Du YG, Wang LP, Qian JW, Zhang KN, Chai KF. Panax notoginseng saponins protect kidney from diabetes by up-regulating silent information regulator 1 and activating antioxidant proteins in rats. Chin J Integr Med 2016;22:910-7.   DOI
30 Li SS, He AL, Deng ZY, Liu QF. Ginsenoside-Rg1 protects against renal fibrosis by regulating the Klotho/TGF-beta1/Smad signaling pathway in rats with obstructive nephropathy. Biol Pharm Bull 2018;41:585-91.   DOI
31 Du N, Xu Z, Gao M, Liu P, Sun B, Cao X. Combination of Ginsenoside Rg1 and Astragaloside IV reduces oxidative stress and inhibits TGF-beta1/Smads signaling cascade on renal fibrosis in rats with diabetic nephropathy. Drug Des Devel Ther 2018;12:3517-24.   DOI
32 Liu QF, Deng ZY, Ye JM, He AL, Li SS. Ginsenoside Rg1 protects chronic cyclosporin a nephropathy from tubular cell apoptosis by inhibiting endoplasmic reticulum stress in rats. Transplant Proc 2015;47:566-9.   DOI
33 Lim SW, Doh KC, Jin L, Jin J, Piao SG, Heo SB, Chung BH, Yang CW. Ginseng treatment attenuates autophagic cell death in chronic cyclosporine nephropathy. Nephrology (Carlton) 2014;19:490-9.   DOI
34 Doh KC, Lim SW, Piao SG, Jin L, Heo SB, Zheng YF, Bae SK, Hwang GH, Min KI, Chung BH, et al. Ginseng treatment attenuates chronic cyclosporine nephropathy via reducing oxidative stress in an experimental mouse model. Am J Nephrol 2013;37:421-33.   DOI
35 Xie XS, Yang M, Liu HC, Zuo C, Li HJ, Fan JM. Ginsenoside Rg1, a major active component isolated from Panax notoginseng, restrains tubular epithelial to myofibroblast transition in vitro. J Ethnopharmacol 2009;122:35-41.   DOI
36 Hou YL, Tsai YH, Lin YH, Chao JC. Ginseng extract and ginsenoside Rb1 attenuate carbon tetrachloride-induced liver fibrosis in rats. BMC Complement Altern Med 2014;14:415.   DOI
37 Han X, Song J, Lian LH, Yao YL, Shao DY, Fan Y, Hou LS, Wang G, Zheng S, Wu YL, et al. Ginsenoside 25-OCH3-PPD Promotes Activity of LXRs To Ameliorate P2X7R-Mediated NLRP3 Inflammasome in the Development of Hepatic Fibrosis. J Agric Food Chem 2018;66:7023-35.   DOI
38 Su GY, Li ZY, Wang R, Lu YZ, Nan JX, Wu YL, Zhao YQ. Signaling pathways involved in p38-ERK and inflammatory factors mediated the anti-fibrosis effect of AD-2 on thioacetamide-induced liver injury in mice. Food Funct 2019;10:3992-4000.   DOI
39 Beaven SW, Wroblewski K, Wang J, Hong C, Bensinger S, Tsukamoto H, Tontonoz P. Liver X receptor signaling is a determinant of stellate cell activation and susceptibility to fibrotic liver disease. Gastroenterology 2011;140:1052-62.   DOI
40 Wu YL, Wan Y, Jin XJ, Ouyang BQ, Bai T, Zhao YQ, Nan JX. 25-OCH3-PPD induces the apoptosis of activated t-HSC/Cl-6 cells via c-FLIP-mediated NF-kappaB activation. Chem Biol Interact 2011;194:106-12.   DOI
41 Bataller R, Brenner DA. Liver fibrosis. J Clin Invest 2005;115:209-18.   DOI
42 Geng J, Peng W, Huang Y, Fan H, Li S. Ginsenoside-Rg1 from Panax notoginseng prevents hepatic fibrosis induced by thioacetamide in rats. Eur J Pharmacol 2010;634:162-9.   DOI
43 Li JP, Gao Y, Chu SF, Zhang Z, Xia CY, Mou Z, Song XY, He WB, Guo XF, Chen NH. Nrf2 pathway activation contributes to anti-fibrosis effects of ginsenoside Rg1 in a rat model of alcohol- and CCl4-induced hepatic fibrosis. Acta Pharmacol Sin 2014;35:1031-44.   DOI
44 Lo YT, Tsai YH, Wu SJ, Chen JR, Chao JC. Ginsenoside Rb1 inhibits cell activation and liver fibrosis in rat hepatic stellate cells. J Med Food 2011;14:1135-43.   DOI
45 Tsai KD, Yang SM, Lee JC, Wong HY, Shih CM, Lin TH, Tseng MJ, Chen W. Panax notoginseng Attenuates Bleomycin-Induced Pulmonary Fibrosis in Mice. Evid Based Complement Alternat Med 2011;2011:404761.
46 Hong YA, Lim JH, Kim MY, Kim EN, Koh ES, Shin SJ, Choi BS, Park CW, Chang YS, Chung S. Delayed treatment with oleanolic acid attenuates tubulointerstitial fibrosis in chronic cyclosporine nephropathy through Nrf2/HO-1 signaling. J Transl Med 2014;12:50.   DOI
47 Richeldi L, Collard HR, Jones MG. Idiopathic pulmonary fibrosis. Lancet 2017;389:1941-52.   DOI
48 Zhang J, Li Q, Shao Q, Song J, Zhou B, Shu P. Effects of panax notoginseng saponin on the pathological ultrastructure and serum IL-6 and IL-8 in pulmonary fibrosis in rabbits. J Cell Biochem 2018;119:8410-8.   DOI
49 Zhan H, Huang F, Ma W, Zhao Z, Zhang H, Zhang C. Protective effect of ginsenoside Rg1 on bleomycin-induced pulmonary fibrosis in rats: involvement of caveolin-1 and TGF-beta1 signal pathway. Biol Pharm Bull 2016;39:1284-92.   DOI
50 Guan S, Liu Q, Han F, Gu W, Song L, Zhang Y, Guo X, Xu W. Ginsenoside Rg1 ameliorates cigarette smoke-induced airway fibrosis by suppressing the TGF-beta1/Smad pathway in vivo and in vitro. Biomed Res Int 2017;2017:6510198.
51 Yang L, Chen PP, Luo M, Shi WL, Hou DS, Gao Y, Xu SF, Deng J. Inhibitory effects of total ginsenoside on bleomycin-induced pulmonary fibrosis in mice. Biomed Pharmacother 2019;114:108851.   DOI
52 Cheng L, Sun X, Hu C, Jin R, Sun B, Shi Y, Cui W, Zhang Y. In vivo early intervention and the therapeutic effects of 20(s)-ginsenoside rg3 on hypertrophic scar formation. PLoS One 2014;9:e113640.   DOI
53 Yuan D, Xiang T, Huo Y, Liu C, Wang T, Zhou Z, Dun Y, Zhao H, Zhang C. Preventive effects of total saponins of Panax japonicus on fatty liver fibrosis in mice. Arch Med Sci 2018;14:396-406.   DOI
54 Cheng L, Sun X, Hu C, Jin R, Sun B, Shi Y, Zhang L, Cui W, Zhang Y. In vivo inhibition of hypertrophic scars by implantable ginsenoside-Rg3-loaded electrospun fibrous membranes. Acta Biomater 2013;9:9461-73.   DOI
55 Higashi T, Friedman SL, Hoshida Y. Hepatic stellate cells as key target in liver fibrosis. Adv Drug Deliv Rev 2017;121:27-42.   DOI
56 Chen XJ, Liu WJ, Wen ML, Liang H, Wu SM, Zhu YZ, Zhao JY, Dong XQ, Li MG, Bian L, et al. Ameliorative effects of Compound K and ginsenoside Rh1 on non-alcoholic fatty liver disease in rats. Sci Rep 2017;7:41144.   DOI
57 Wei X, Chen Y, Huang W. Ginsenoside Rg1 ameliorates liver fibrosis via suppressing epithelial to mesenchymal transition and reactive oxygen species production in vitro and in vivo. Biofactors 2018.
58 Park SM, Jung EH, Kim JK, Jegal KH, Park CA, Cho IJ, Kim SC. 20S-Protopanaxadiol, an aglycosylated ginsenoside metabolite, induces hepatic stellate cell apoptosis through liver kinase B1-AMP-activated protein kinase activation. J Ginseng Res 2017;41:392-402.   DOI
59 Berk BC, Fujiwara K, Lehoux S. ECM remodeling in hypertensive heart disease. J Clin Invest 2007;117:568-75.   DOI
60 Cui W, Cheng L, Hu C, Li H, Zhang Y, Chang J. Electrospun poly(L-lactide) fiber with ginsenoside rg3 for inhibiting scar hyperplasia of skin. PLoS One 2013;8:e68771.   DOI
61 Sun X, Cheng L, Zhu W, Hu C, Jin R, Sun B, Shi Y, Zhang Y, Cui W. Use of ginsenoside Rg3-loaded electrospun PLGA fibrous membranes as wound cover induces healing and inhibits hypertrophic scar formation of the skin. Colloids Surf B Biointerfaces 2014;115:61-70.   DOI
62 Tang M, Bian W, Cheng L, Zhang L, Jin R, Wang W, Zhang Y. Ginsenoside Rg3 inhibits keloid fibroblast proliferation, angiogenesis and collagen synthesis in vitro via the TGFbeta/Smad and ERK signaling pathways. Int J Mol Med 2018;41:1487-99.
63 Tark KC, Lee DW, Lew DH, Kang EH, Roh H, Lee MC. Effects of ginsenoside Rb1 on hypertrophic scar remodeling in rabbit model. Eur J Pharmacol 2015;750:151-9.   DOI
64 Dai JP, Chen XX, Zhu DX, Wan QY, Chen C, Wang GF, Li WZ, Li KS. Panax notoginseng saponins inhibit areca nut extract-induced oral submucous fibrosis in vitro. J Oral Pathol Med 2014;43:464-70.   DOI
65 Kabalak AA, Soyal OB, Urfalioglu A, Saracoglu F, Gogus N. Menometrorrhagia and tachyarrhythmia after using oral and topical ginseng. J Womens Health (Larchmt) 2004;13:830-3.   DOI
66 Gyongyosi M, Winkler J, Ramos I, Do QT, Firat H, Mcdonald K, Gonzalez A, Thum T, Diez J, Jaisser F, et al. Myocardial fibrosis: biomedical research from bench to bedside. Eur J Heart Fail 2017;19:177-91.   DOI
67 Nguyen MN, Kiriazis H, Gao XM, Du XJ. Cardiac fibrosis and arrhythmogenesis. Compr Physiol 2017;7:1009-49.
68 Kim JH. Pharmacological and medical applications of Panax ginseng and ginsenosides: a review for use in cardiovascular diseases. J Ginseng Res 2018;42:264-9.   DOI
69 Kim MK, Lee SK, Park JH, Lee JH, Yun BH, Park JH, Seo SK, Cho S, Choi YS. Ginsenoside Rg3 Decreases Fibrotic and Invasive Nature of Endometriosis by Modulating miRNA-27b: In Vitro and In Vivo Studies. Sci Rep 2017;7:17670.   DOI
70 Greenspan EM. Ginseng and vaginal bleeding. JAMA 1983;249:2018.   DOI
71 Oh KJ, Chae MJ, Lee HS, Hong HD, Park K. Effects of Korean red ginseng on sexual arousal in menopausal women: placebo-controlled, double-blind crossover clinical study. J Sex Med 2010;7:1469-77.   DOI
72 Gurtner GC, Werner S, Barrandon Y, Longaker MT. Wound repair and regeneration. Nature 2008;453:314-21.   DOI
73 Wynn TA. Fibrotic disease and the T(H)1/T(H)2 paradigm. Nat Rev Immunol 2004;4:583-94.   DOI
74 Rockey DC, Bell PD, Hill JA. Fibrosis-a common pathway to organ injury and failure. N Engl J Med 2015;372:1138-49.   DOI
75 Jun JI, Lau LF. Resolution of organ fibrosis. J Clin Invest 2018;128:97-107.   DOI
76 Stramer BM, Mori R, Martin P. The inflammation-fibrosis link? A Jekyll and Hyde role for blood cells during wound repair. J Invest Dermatol 2007;127:1009-17.   DOI
77 Hochreiter-Hufford A, Ravichandran KS. Clearing the dead: apoptotic cell sensing, recognition, engulfment, and digestion. Cold Spring Harb Perspect Biol 2013;5:a008748.   DOI
78 Weiskirchen R, Weiskirchen S, Tacke F. Organ and tissue fibrosis: molecular signals, cellular mechanisms and translational implications. Mol Aspects Med 2019;65:2-15.   DOI
79 Wynn TA, Vannella KM. Macrophages in tissue repair, regeneration, and fibrosis. Immunity 2016;44:450-62.   DOI
80 Thannickal VJ, Lee DY, White ES, Cui Z, Larios JM, Chacon R, Horowitz JC, Day RM, Thomas PE. Myofibroblast differentiation by transforming growth factor-beta1 is dependent on cell adhesion and integrin signaling via focal adhesion kinase. J Biol Chem 2003;278:12384-9.   DOI
81 Kim KK, Sheppard D, Chapman HA. TGF-beta1 signaling and tissue fibrosis. Cold Spring Harb Perspect Biol 2018;10.
82 Zhang YJ, Zhang XL, Li MH, Iqbal J, Bourantas CV, Li JJ, Su XY, Muramatsu T, Tian NL, Chen SL. The ginsenoside Rg1 prevents transverse aortic constriction- induced left ventricular hypertrophy and cardiac dysfunction by inhibiting fibrosis and enhancing angiogenesis. J Cardiovasc Pharmacol 2013;62:50-7.   DOI
83 Li CY, Deng W, Liao XQ, Deng J, Zhang YK, Wang DX. The effects and mechanism of ginsenoside Rg1 on myocardial remodeling in an animal model of chronic thromboembolic pulmonary hypertension. Eur J Med Res 2013;18:16.   DOI
84 Xu ZM, Li CB, Liu QL, Li P, Yang H. Ginsenoside Rg1 prevents doxorubicininduced cardiotoxicity through the inhibition of autophagy and endoplasmic reticulum stress in mice. Int J Mol Sci 2018;19.
85 Wei HJ, Yang HH, Chen CH, Lin WW, Chen SC, Lai PH, Chang Y, Sung HW. Gelatin microspheres encapsulated with a nonpeptide angiogenic agent, ginsenoside Rg1, for intramyocardial injection in a rat model with infarcted myocardium. J Control Release 2007;120:27-34.   DOI
86 Li Y, Wang L, Dong Z, Wang S, Qi L, Cho K, Zhang Z, Li N, Hu Y, Jiang B. Cardioprotection of salvianolic acid B and ginsenoside Rg1 combination on subacute myocardial infarction and the underlying mechanism. Phytomedicine 2019;57:255-61.   DOI
87 Siegel RK. Ginseng and high blood pressure. JAMA 1980;243:32.   DOI
88 Coon JT, Ernst E. Panax ginseng: a systematic review of adverse effects and drug interactions. Drug Saf 2002;25:323-44.   DOI
89 Miller LG. Herbal medicinals: selected clinical considerations focusing on known or potential drug-herb interactions. Arch Intern Med 1998;158:2200-11.   DOI
90 Scaglione F, Cattaneo G, Alessandria M, Cogo R. Efficacy and safety of the standardised Ginseng extract G115 for potentiating vaccination against the influenza syndrome and protection against the common cold [corrected]. Drugs Exp Clin Res 1996;22:65-72.
91 Siegel RK. Ginseng abuse syndrome. Problems with the panacea. JAMA 1979;241:1614-5.   DOI
92 Biswas T, Mathur AK, Mathur A. A literature update elucidating production of Panax ginsenosides with a special focus on strategies enriching the antineoplastic minor ginsenosides in ginseng preparations. Appl Microbiol Biotechnol 2017;101:4009-32.   DOI
93 Li L, Chen X, Li D, Zhong D. Identification of 20(S)-protopanaxadiol metabolites in human liver microsomes and human hepatocytes. Drug Metab Dispos 2011;39:472-83.   DOI
94 Xu LQ, Yu H, Yin SP, Zhang RX, Zhou YD, Li J. Liposome-based delivery systems for ginsenoside Rh2: in vitro and in vivo comparisons. J Nanopart Res 2015;17.
95 Han M, Sha X, Wu Y, Fang X. Oral absorption of ginsenoside Rb1 using in vitro and in vivo models. Planta Med 2006;72:398-404.   DOI
96 Liu H, Yang J, Du F, Gao X, Ma X, Huang Y, Xu F, Niu W, Wang F, Mao Y, et al. Absorption and disposition of ginsenosides after oral administration of Panax notoginseng extract to rats. Drug Metab Dispos 2009;37:2290-8.   DOI
97 Kapetanaki MG, Mora AL, Rojas M. Influence of age on wound healing and fibrosis. J Pathol 2013;229:310-22.   DOI
98 Zheng X, Wang S, Zou X, Jing Y, Yang R, Li S, Wang F. Ginsenoside Rb1 improves cardiac function and remodeling in heart failure. Exp Anim 2017;66:217-28.   DOI
99 Huynh K, Mcmullen JR, Julius TL, Tan JW, Love JE, Cemerlang N, Kiriazis H, Du XJ, Ritchie RH. Cardiac-specific IGF-1 receptor transgenic expression protects against cardiac fibrosis and diastolic dysfunction in a mouse model of diabetic cardiomyopathy. Diabetes 2010;59:1512-20.   DOI
100 Lo SH, Hsu CT, Niu HS, Niu CS, Cheng JT, Chen ZC. Ginsenoside Rh2 improves cardiac fibrosis via PPARdelta-STAT3 signaling in type 1-like diabetic rats. Int J Mol Sci 2017;18.
101 Romani L, Oikonomou V, Moretti S, Iannitti RG, D'adamo MC, Villella VR, Pariano M, Sforna L, Borghi M, Bellet MM, et al. Thymosin alpha1 represents a potential potent single-molecule-based therapy for cystic fibrosis. Nat Med 2017;23:590-600.   DOI
102 Plasschaert LW, Zilionis R, Choo-Wing R, Savova V, Knehr J, Roma G, Klein AM, Jaffe AB. A single-cell atlas of the airway epithelium reveals the CFTR-rich pulmonary ionocyte. Nature 2018;560:377-81.   DOI
103 Wong AS, Che CM, Leung KW. Recent advances in ginseng as cancer therapeutics: a functional and mechanistic overview. Nat Prod Rep 2015;32:256-72.   DOI
104 Ru W, Wang D, Xu Y, He X, Sun YE, Qian L, Zhou X, Qin Y. Chemical constituents and bioactivities of Panax ginseng (C. A. Mey.). Drug Discov Ther 2015;9:23-32.   DOI
105 Cho CW, Kim YC, Kang JH, Rhee YK, Choi SY, Kim KT, Lee YC, Hong HD. Characteristic study on the chemical components of Korean curved ginseng products. J Ginseng Res 2013;37:349-54.   DOI
106 Shibata S. Chemistry and cancer preventing activities of ginseng saponins and some related triterpenoid compounds. J Korean Med Sci 2001;16(Suppl):S28-37.   DOI
107 Wang QW, Yu XF, Xu HL, Zhao XZ, Sui DY. Ginsenoside Re improves isoproterenol-induced myocardial fibrosis and heart failure in rats. Evid Based Complement Alternat Med 2019;2019:3714508.
108 Shin BK, Kwon SW, Park JH. Chemical diversity of ginseng saponins from Panax ginseng. J Ginseng Res 2015;39:287-98.   DOI
109 Aung TN, Qu Z, Kortschak RD, Adelson DL. Understanding the effectiveness of natural compound mixtures in cancer through their molecular mode of action. Int J Mol Sci 2017;18.
110 Yun TK, Zheng S, Choi SY, Cai SR, Lee YS, Liu XY, Cho KJ, Park KY. Non-organspecific preventive effect of long-term administration of Korean red ginseng extract on incidence of human cancers. J Med Food 2010;13:489-94.   DOI
111 Zhang N, An X, Lang P, Wang F, Xie Y. Ginsenoside Rd contributes the attenuation of cardiac hypertrophy in vivo and in vitro. Biomed Pharmacother 2019;109:1016-23.   DOI
112 Yang L, Liu Q, Yu Y, Xu H, Chen S, Shi S. Ginsenoside-Rb3 inhibits endothelialmesenchymal transition of cardiac microvascular endothelial cells. Herz 2019;44:60-8.   DOI
113 Shen N, Li X, Zhou T, Bilal MU, Du N, Hu Y, Qin W, Xie Y, Wang H, Wu J, et al. Shensong Yangxin Capsule prevents diabetic myocardial fibrosis by inhibiting TGF-beta1/Smad signaling. J Ethnopharmacol 2014;157:161-70.   DOI
114 Chen D, Yu H, Mu H, Li G, Shen Y. Novel multicore niosomes based on double pH-sensitive mixed micelles for Ginsenoside Rh2 delivery. Artif Cells Nanomed Biotechnol 2014;42:205-9.   DOI
115 Artursson P, Ungell AL, Lofroth JE. Selective paracellular permeability in two models of intestinal absorption: cultured monolayers of human intestinal epithelial cells and rat intestinal segments. Pharm Res 1993;10:1123-9.   DOI
116 Yanni S, Thakker DR. Prodrugs: absorption, distribution, metabolism, excretion (ADME) issues. New York: Springer; 2007.