Skip to main content
SpringerLink
Log in

Antioxidative, anti-inflammatory, and matrix metalloproteinase inhibitory activities of 20(S)-ginsenoside Rg3 in cultured mammalian cell lines

  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

Ginsenoside Rg3 is one of ginsenosides that are the well-known bioactive principles of Panax ginseng. Among the two stereoisomeric forms of Rg3, 20(S)-ginsenoside Rg3 [20(S)-Rg3] is predominant. 20(S)-Rg3 is capable of suppressing the nitric oxide (NO), reactive oxygen species (ROS) and prostaglandin E2 (PGE2) productions induced by lipopolysaccharide (LPS) in RAW264.7 macrophage cells in a concentration-dependent manner. In the same stimulated macrophages, 20(S)-Rg3 was able to suppress matrix metalloproteinase-9 (MMP-9) activity and suppress cyclooxygenase-2 (COX-2) expression. It suppressed the production of some proinflammatory cytokines, such as TNF-α, IL-1β and IL-6, and the cell mobility enhanced by LPS in the macrophage cells. 20(S)-Rg3 displayed suppressive effect on the ROS level but not on the NO level, and down-regulating effect on MMP-9 but not on MMP-2 in non-stimulated HaCat keratinocytes. 20(S)-Rg3 also exhibited suppressive effect on the MMP-9 gelatinolytic activity enhanced in the HaCat keratinocytes stimulated with tumor necrosis factor-α (TNF-α), one of the major proinflammatory cytokines. However, 20(S)-Rg3 was not able to modulate the NO level even in the presence of TNF-α. Taken together, anti-inflammatory and related antioxidative and MMP-9 inhibitory activities of 20(S)-Rg3, the major stereoisomeric form of ginsenoside Rg3, are confirmed in macrophage and keratinocyte cell lines.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

Abbreviations

20(S)-Rg3:

20(S)-Ginsenoside Rg3

COX-2:

Cyclooxgenase-2

DCF:

Dichlorofluorescein

LPS:

Lipopolysaccharide

MMP:

Matrix metalloproteinase

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

NO:

Nitric oxide

ROS:

Reactive oxygen species

TNF-α:

Tumor necrosis factor-α

References

  1. Christensen LP (2009) Ginsenosides chemistry, biosynthesis, analysis, and potential health effects. Adv Food Nutr Res 55:1–99

    Article  PubMed  CAS  Google Scholar 

  2. Hien TT, Kim ND, Kim HS, Kang KW (2010) Ginsenoside Rg3 inhibits tumor necrosis factor-alpha-induced expression of cell adhesion molecules in human endothelial cells. Pharmazie 65(9):699–701

    PubMed  CAS  Google Scholar 

  3. Jiang JW, Chen XM, Chen XH, Zheng SS (2011) Ginsenoside Rg3 inhibit hepatocellular carcinoma growth via intrinsic apoptotic pathway. World J Gastroenterol 17(31):3605–3613

    Article  PubMed  CAS  Google Scholar 

  4. Chen QJ, Zhang MZ, Wang LX (2010) Gensenoside Rg3 inhibits hypoxia-induced VEGF expression in human cancer cells. Cell Physiol Biochem 26(6):849–858

    Article  PubMed  CAS  Google Scholar 

  5. Liu TG, Huang Y, Cui DD, Huang XB, Mao SH, Ji LL, Song HB, Yi C (2009) Inhibitory effect of ginsenoside Rg3 combined with gemcitabine on angiogenesis and growth of lung cancer in mice. BMC Cancer 9:250

    Article  PubMed  Google Scholar 

  6. Xu TM, Cui MH, Xin Y, Gu LP, Jiang X, Su MM, Wang DD, Wang WJ (2008) Inhibitory effect of ginsenoside Rg3 on ovarian cancer metastasis. Chin Med J (Engl) 121(15):1394–1397

    CAS  Google Scholar 

  7. Chen J, Peng H, Ou-Yang X, He X (2008) Research on the antitumor effect of ginsenoside Rg3 in B16 melanoma cells. Melanoma Res 18(5):322–329

    Article  PubMed  CAS  Google Scholar 

  8. Kim M, Ahn BY, Lee JS, Chung SS, Lim S, Park SG, Jung HS, Lee HK, Park KS (2009) The ginsenoside Rg3 has a stimulatory effect on insulin signaling in L6 myotubes. Biochem Biophys Res Commun 389(1):70–73

    Article  PubMed  CAS  Google Scholar 

  9. Sherman MP, Aeberhard EE, Wong VZ, Griscavage JM, Ignarro LJ (1993) Pyrrolidine dithiocarbamate inhibits induction of nitric oxide synthase activity in rat alveolar macrophages. Biochem Biophys Res Commun 191:1301–1308

    Article  PubMed  CAS  Google Scholar 

  10. Royall JA, Ischiropoulos H (1993) Evaluation of 2′,7′-dichlorofluorescin and dihydrorhodamine 123 as fluorescent probes for intracellular H2O2 in cultured endothelial cells. Arch Biochem Biophys 302:348–355

    Article  PubMed  CAS  Google Scholar 

  11. Kleiner DE, Stetler-Stevenson WG (1994) Quantitative zymography: detection of picogram quantities of gelatinases. Anal Biochem 218:325–329

    Article  PubMed  CAS  Google Scholar 

  12. Yang CF, Shen HM, Ong CN (1999) Protective effect of ebselen against hydrogen peroxide-induced cytotoxicity and DNA damage in HepG2 cells. Biochem Pharmacol 57:273–279

    Article  PubMed  CAS  Google Scholar 

  13. Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254

    Article  PubMed  CAS  Google Scholar 

  14. Bastos GN, Silveira AJ, Salgado CG, Picanço-Diniz DL, do Nascimento JL (2008) Physalis angulata extract exerts anti-inflammatory effects in rats by inhibiting different pathways. J Ethnopharmacol 118:246–251

    Article  PubMed  CAS  Google Scholar 

  15. Jachak SM (2006) Cyclooxygenase inhibitory natural products: current status. Curr Med Chem 13(6):659–678

    Article  PubMed  CAS  Google Scholar 

  16. Eberhardt W, Huwiler A, Beck KF, Walpen S, Pfeilschifter J (2000) Amplification of IL-1 beta-induced matrix metalloproteinase-9 expression by superoxide in rat glomerular mesangial cells is mediated by increased activities of NF-kappa B and activating protein-1 and involves activation of the mitogen-activated protein kinase pathways. J Immunol 165(10):5788–5797

    PubMed  CAS  Google Scholar 

  17. Johansson N, Westermarck J, Leppä S, Häkkinen L, Koivisto L, López-Otín C, Peltonen J, Heino J, Kähäri VM (1997) Collagenase 3 (matrix metalloproteinase 13) gene expression by HaCaT keratinocytes is enhanced by tumor necrosis factor alpha and transforming growth factor beta. Cell Growth Differ 8(2):243–250

    PubMed  CAS  Google Scholar 

  18. Holvoet S, Vincent C, Schmitt D, Serres M (2003) The inhibition of MAPK pathway is correlated with down-regulation of MMP-9 secretion induced by TNF-alpha in human keratinocytes. Exp Cell Res 290(1):108–119

    Article  PubMed  CAS  Google Scholar 

  19. Yuan HD, Quan HY, Zhang Y, Kim SH, Chung SH (2010) 20(S)-Ginsenoside Rg3-induced apoptosis in HT-29 colon cancer cells is associated with AMPK signaling pathway. Mol Med Report 3(5):825–831

    PubMed  CAS  Google Scholar 

  20. Min JK, Kim JH, Cho YL, Maeng YS, Lee SJ, Pyun BJ, Kim YM, Park JH, Kwon YG (2006) 20(S)-Ginsenoside Rg3 prevents endothelial cell apoptosis via inhibition of a mitochondrial caspase pathway. Biochem Biophys Res Commun 349(3):987–994

    Article  PubMed  CAS  Google Scholar 

  21. Tian J, Zhang S, Li G, Liu Z, Xu B (2009) 20(S)-ginsenoside Rg3, a neuroprotective agent, inhibits mitochondrial permeability transition pores in rat brain. Phytother Res 23(4):486–491

    Article  PubMed  CAS  Google Scholar 

  22. Liu JP, Lu D, Nicholson RC, Li PY, Wang F (2011) Toxicity of a novel anti-tumor agent 20(S)-ginsenoside Rg3: a 26-week intramuscular repeated administration study in Beagle dogs. Food Chem Toxicol 49(8):1718–1727

    Article  PubMed  CAS  Google Scholar 

  23. Tang W, Zhang Y, Gao J, Ding X, Gao S (2008) The anti-fatigue effect of 20(R)-ginsenoside Rg3 in mice by intranasally administration. Biol Pharm Bull 31(11):2024–2027

    Article  PubMed  CAS  Google Scholar 

  24. Park MW, Ha J, Chung SH (2008) 20(S)-Ginsenoside Rg3 enhances glucose-stimulated insulin secretion and activates AMPK. Biol Pharm Bull 31(4):748–751

    Article  PubMed  CAS  Google Scholar 

  25. Mochizuki M, Yoo YC, Matsuzawa K, Sato K, Saiki I, Tono-oka S, Samukawa K, Azuma I (1995) Inhibitory effect of tumor metastasis in mice by saponins, ginsenoside-Rb2, 20(R)- and 20(S)-ginsenoside-Rg3, of red ginseng. Biol Pharm Bull 18(9):1197–1202

    Article  PubMed  CAS  Google Scholar 

  26. Kim JH, Lee JH, Jeong SM, Lee BH, Yoon IS, Lee JH, Choi SH, Kim DH, Park TK, Kim BK, Nah SY (2006) Stereospecific effects of ginsenoside Rg3 epimers on swine coronary artery contractions. Biol Pharm Bull 29(2):365–370

    Article  PubMed  CAS  Google Scholar 

  27. Wei X, Chen J, Su F, Su X, Hu T, Hu S (2012) Stereospecificity of ginsenoside Rg3 in promotion of the immune response to ovalbumin in mice. Int Immunol 24(7):465–471

    Article  PubMed  CAS  Google Scholar 

  28. Wei X, Su F, Su X, Hu T, Hu S (2012) Stereospecific antioxidant effects of ginsenoside Rg3 on oxidative stress induced by cyclophosphamide in mice. Fitoterapia 83(4):636–642

    Article  PubMed  CAS  Google Scholar 

  29. Singh VK, Mehrotra S, Narayan P, Pandey CM, Agarwal SS (2000) Modulation of autoimmune diseases by nitric oxide. Immunol Res 22:1–19

    Article  PubMed  CAS  Google Scholar 

  30. Kang KS, Kim HY, Yamabe N, Park JH, Yokozawa T (2007) Preventive effect of 20(S)-ginsenoside Rg3 against lipopolysaccharide-induced hepatic and renal injury in rats. Free Radic Res 41(10):1181–1188

    Article  PubMed  CAS  Google Scholar 

  31. Hien TT, Kim ND, Pokharel YR, Oh SJ, Lee MY, Kang KW (2010) Ginsenoside Rg3 increases nitric oxide production via increases in phosphorylation and expression of endothelial nitric oxide synthase: essential roles of estrogen receptor-dependent PI3-kinase and AMP-activated protein kinase. Toxicol Appl Pharmacol 246(3):171–183

    Article  CAS  Google Scholar 

  32. Bertram C, Hass R (2008) Cellular responses to reactive oxygen species-induced DNA damage and aging. Biol Chem 389(3):211–220

    Article  PubMed  CAS  Google Scholar 

  33. Nordberg J, Arner ES (2001) Reactive oxygen species, antioxidants, and the mammalian thioredoxin system. Free Radic Biol Med 31:1287–1312

    Article  PubMed  CAS  Google Scholar 

  34. Acharya A, Das I, Chandhok D, Saha T (2010) Redox regulation in cancer: a double-edged sword with therapeutic potential. Oxid Med Cell Longev 3(1):23–34

    Article  PubMed  Google Scholar 

  35. Cuzzocrea S (2006) Role of nitric oxide and reactive oxygen species in arthritis. Curr Pharm Design 12:3551–3570

    Article  CAS  Google Scholar 

  36. Jaeschke H (2011) Reactive oxygen and mechanisms of inflammatory liver injury: present concepts. J Gastroenterol Hepatol 26(Suppl 1):173–179

    Article  PubMed  CAS  Google Scholar 

  37. Visse R, Nagase H (2003) Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res 92:827–839

    Article  PubMed  CAS  Google Scholar 

  38. Oshita Y, Koga T, Kamimura T, Matsuo K, Rikimaru T, Aizawa H (2003) Increased circulating 92 kDa matrix metalloproteinase (MMP-9) activity in exacerbations of asthma. Thorax 58(9):757–760

    Article  PubMed  CAS  Google Scholar 

  39. Yue PY, Wong DY, Wu PK, Leung PY, Mak NK, Yeung HW, Liu L, Cai Z, Jiang ZH, Fan TP, Wong RN (2006) The angiosuppressive effects of 20(R)- ginsenoside Rg3. Biochem Pharmacol 72(4):437–445

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by a grant of the Korea Healthcare Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (Grant No.: A103017). This study was supported in part by Kangwon National University. The authors are grateful to Ms. Seul-Hee Lee and Ms. A Rum Park for her technical assistance.

Conflict of interest

The authors report no conflicts of interest to disclose.

Author information

Authors and Affiliations

  1. Department of Biochemistry, College of Natural Sciences, Kangwon National University, 192-1 Hyoja-2-dong, Chuncheon, 200-701, Korea

    Yu-Mi Shin, Woo-Yong Choi & Chang-Jin Lim

  2. Department of Anatomy, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-749, Korea

    Hyun-Joo Jung

Authors
  1. Yu-Mi Shin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hyun-Joo Jung
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Woo-Yong Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chang-Jin Lim
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Chang-Jin Lim.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shin, YM., Jung, HJ., Choi, WY. et al. Antioxidative, anti-inflammatory, and matrix metalloproteinase inhibitory activities of 20(S)-ginsenoside Rg3 in cultured mammalian cell lines. Mol Biol Rep 40, 269–279 (2013). https://doi.org/10.1007/s11033-012-2058-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-012-2058-1

Keywords

Search

Navigation