Skip to main content
SpringerLink
Log in

Anti-fibrotic effect of PF2401-SF, a standardized fraction of Salvia miltiorrhiza, in thioacetamide-induced experimental rats liver fibrosis

  • Research Article
  • Published:
Archives of Pharmacal Research Aims and scope Submit manuscript

Abstract

We previously reported the in vitro and in vivo hepatoprotective and anti-fibrotic effects of PF2401-SF, a standardized fraction of Salvia miltiorrhiza, against acute and subacute liver injury. The aim of this study was to investigate the effect of PF2401-SF on liver fibrosis induced by thioacetamide (TAA), a chronic liver injury model (12 weeks) that closely resembles fibrosis and cirrhosis in humans. Hepatoprotective activity was indicated by low serum levels of the markers aspartate amino transferase and alanine amino transferase .In addition, compared to the TAA-group livers, the PF2401-SF-treated liver tissues showed no fibrous tissue deposition in the portal areas, hepatocyte morphology more closely resembling normal tissue morphology, and significantly reduced collagen deposition. Furthermore, downregulation of collagen 1(α) and tissue inhibitor of metalloproteinase (TIMP)1 protein and mRNA expression also supports PF2401-SF’s anti-fibrotic effect. We also observed reduced expression of α-smooth muscle actin (α-SMA), an important marker of hepatic stellate cells (HSCs) activation. From these results, we conclude that PF2401-SF’s anti-fibrotic mechanism in the TAA model involves reduced HSC activation, and may be mediated by downregulation of central markers of fibrosis, including collagen 1(α), TIMP1, and α-SMA.

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

Similar content being viewed by others

References

  • Bataller, R., and D.A. Brenner. 2005. Liver fibrosis. The Journal of clinical investigation 115: 209–218.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Benyon, R.C., J.P. Iredale, S. Goddard, P.J. Winwood, and M.J. Athur. 1996. Expression of tissue inhibitor of metalloproteinases 1 and 2 is increased in fibrotic human liver. Gastroenterology 110: 821–831.

    Article  CAS  PubMed  Google Scholar 

  • Bruck, R., R. Schey, H. Aeed, A. Hochman, O. Genina, and M. Pines. 2004. Protective effect of pyrrolidine dithiocarbamate in a rat model of liver cirrhosis. Liver International 24: 169–176.

    Article  CAS  PubMed  Google Scholar 

  • Elsharkawy, A.M., F. Oakley, and D.A. Mann. 2005. The role and regulation of hepatic stellate cell apoptosis in reversal of liver fibrosis. Apoptosis 10: 927–939.

    Article  CAS  PubMed  Google Scholar 

  • Fallowfield, J.A., M. Mizuno, T.J. Kendall, C.M. Constandinou, R.C. Benyon, J.S. Duffield, and J.P. Iredale. 2007. Scar-associated macrophages are a major source of hepatic matrix metalloproteinase-13 and facilitate the resolution of murine hepatic fibrosis. The Journal of Immunology 178: 5288–5295.

    Article  CAS  PubMed  Google Scholar 

  • Friedman, S.L. 1993. Seminars in medicine of the Beth Israel Hospital, Boston. The cellular basis of hepatic fibrosis. Mechanisms and treatment strategies. New England Journal of Medicine 328: 1828–1835.

    Article  CAS  PubMed  Google Scholar 

  • Friedman, S.L. 2004. Mechanisms of hepatic fibrosis and therapeutic implications. Nature Clinical Practice Gastroenterology & Hepatology 1: 98–105.

    Article  Google Scholar 

  • Friedman, S.L. 2008. Mechanisms of hepatic fibrosis. Gastroenterology 134: 1665–1669.

    Article  Google Scholar 

  • Galli, A., G. Svegliati-Baroni, E. Ceni, S. Milani, F. Ridolfi, R. Salzano, M. Tarocchi, C. Grappone, G. Pellegrini, A. Benedetti, C. Surrenti, and A. Casini. 2005. Oxidative stress stimulates proliferation and invasiveness of hepatic stellate cells via a MMP2-mediated mechanism. Hepatology 41: 1074–1084.

    Article  CAS  PubMed  Google Scholar 

  • Honda, H., K. Ikejima, M. Hirose, M. Yoshikawa, T. Lang, N. Enomoto, T. Kitmura, Y. Takei, and N. Sato. 2002. Leptin is required for fibrogenic responses induced by thioacetamide in the murine liver. Hepatology 36: 12–21.

    Article  CAS  PubMed  Google Scholar 

  • Hsu, Y.C., Y.L. Lin, Y.T. Chiu, M.S. Shiao, C.Y. Lee, and Y.T. Huang. 2005. Antifibrotic effects of Salvia miltiorrhiza on dimethylnitorsamine-intoxicated rats. Journal of Biomedical Science 12: 185–195.

    Article  CAS  PubMed  Google Scholar 

  • Iredale, J.P. 2003. Cirrhosis: new research provides a basis for rational and targeted treatments. BMJ 327: 143–147.

    Article  PubMed Central  PubMed  Google Scholar 

  • Iredale, J.P. 2007. Models of liver fibrosis: exploring the dynamic nature of inflammation and repair in a solid organ. Journal of Clinical Investigation 3: 539–548.

    Article  Google Scholar 

  • Iredale, J.P., R.C. Benyon, J. Pickering, M. McCullen, M. Northrop, S. Pawley, C. Hovell, and M.J. Arthur. 1998. Mechanisms of spontaneous resolution of rat liver fibrosis. Hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors. Journal of Clinical Investigation 102: 538–549.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Lee, T.Y., H.H. Chang, G.J. Wang, J.H. Chiu, Y.Y. Yang, and H.C. Lin. 2006. Water-soluble extract of Salvia miltiorrhiza ameliorates carbon tetrachloride-mediated hepatic apoptosis in rats. Journal of Pharmacy and Pharmacology 58: 659–665.

    Article  CAS  PubMed  Google Scholar 

  • Li, G.S., W.L. Jiang, J.W. Tian, G.W. Qu, H.B. Zhu, and F.H. Fu. 2010. In vitro and In vivo antifibrotic effects of rosmarinic acid on experimental liver fibrosis. Phytomedicine 17: 282–288.

    Article  CAS  PubMed  Google Scholar 

  • Lin, H.J., J.Y. Chen, C.F. Lin, S.T. Kako, J.C. Cheng, H.L. Chen, and C.M. Chen. 2011. Hepatoprotective effects of Yi Guan Jian, an herbal medicine, in rats with dimethylnitrosamine-induced liver fibrosis. Journal of Ethnopharmacology 134: 953–960.

    Article  PubMed  Google Scholar 

  • Low, T.Y., C.K. Leow, M. Salto-Tellez, and M.C. Chung. 2004. A proteomic analysis of thioacetamide induced hepatotoxicity and cirrhosis in rat livers. Proteomics 12: 3960–3974.

    Article  Google Scholar 

  • Luedde, T., and R.F. Schwabe. 2011. NF-kB in the liver-linking injury, fibrosis and hepatocellular carcinoma. Nature reviews Gastroenterology & hepatology 8: 108–118.

    Article  CAS  Google Scholar 

  • Pallottini, V., C. Martini, A.M. Bassi, P. Romano, G. Nanni, and A. Trentalance. 2006. Rat HMG-CoA reductase activation in thioacetamide-induced liver injury is related to an increased reactive oxygen species content. Journal of Hepatology 44: 368–374.

    Article  CAS  PubMed  Google Scholar 

  • Parajuli, D.R., E.J. Park, X.H. Che, W.Y. Jiang, Y.C. Kim, D.H. Sohn, and S.H. Lee. 2013. PF2401-SF, standardized fraction of Salvia miltiorrhiza, induces apoptosis of activated hepatic stelate cells in vitro and in vivo. Molecules 18: 2122–2134.

    Article  CAS  PubMed  Google Scholar 

  • Park, E.J., Y.Z. Zhao, Y.C. Kim, and D.H. Sohn. 2007. PF2401-SF, standardized fraction of Salvia miltiorrhiza and its constituents, tanshinon I, tanshinone IIA, and cryptotansinone, protect primary cultured rat hepatocytes from bile acid-induced apoptosis by inhibiting JNK phosphorylation. Food and Chemical Toxicology 45: 1891–1898.

    Article  CAS  PubMed  Google Scholar 

  • Park, E.J., Y.Z. Zhao, Y.C. Kim, and D.H. Sohn. 2009. Preventive effects of apurified extract isolated from Salvia miltiorrhiza enriched with tanshinone I, tanshinone IIA and cryptotanshinone on hepatocyte injury in vitro and vivo. Food and Chemical Toxicology 47: 2742–2748.

    Article  CAS  PubMed  Google Scholar 

  • Parola, M., F. Marra, and M. Pinzani. 2008. Myofibroblast-like cells and liver fibrogenesis: emerging concepts in a rapidly moving scenario. Molecular Aspects of Medicine 29: 58–66.

    Article  CAS  PubMed  Google Scholar 

  • Pinzani, M., M. Rosselli, and M. Zuckermann. 2011. Liver cirrhosis. Best Practice & Research Clinical Gastroenterology 25: 281–290.

    Article  CAS  Google Scholar 

  • Recknagel, R.O., E.A. Glende, J. Dolak, and R.L. Waller. 1989. Mechanism of carbon tetracholride toxicity. Pharmacology & Therapeutics 43: 139–154.

    Article  CAS  Google Scholar 

  • Rosenbloom, J., S.V. Castro, and S.A. Jimenez. 2010. Narrative review: Fibrotic diseases: Cellular and molecular mechanisms and novel therapies. Annals of Internal Medicine 3: 159–166.

    Article  Google Scholar 

  • Takahara, T., K. Furui, Y. Yata, B. Jin, L.P. Zhang, S. Nambu, H. Sato, M. Seiki, and A. Watanabe. 1997. Dual expression of matrix metalloproteinnase-2 and membrane-type 1-matrix metalloproteinase in fibrotic human livers. Hepatology 26: 1521–1529.

    Article  CAS  PubMed  Google Scholar 

  • Thyagarajan, S.P., S. Jayaram, V. Gopalakrishnan, R. Hari, P. Jayakumar, and M.S. Sripathi. 2002. Herbal medicines for liver diseases in India. Journal of Gastroenterology and Hepatology 17: 370–376.

    Article  Google Scholar 

  • Trebicka, J., M. Hennenberg, M. Odenthal, K. Shir, S. Klein, M. Granzow, A. Vogt, H.P. Dienes, F. Lammert, J. Reichen, J. Heller, and T. Sauerbruch. 2010. Atorvastatin attenuates hepatic fibrosis in rats after bile duct ligation via decreased turnover of hepatic stellate cells. Journal of Hepatology 4: 702–712.

    Article  Google Scholar 

  • Wang, C.H., T.H. Lee, C.N. Lu, W.Y. Chou, K.S. Hung, A.M. Concejero, and B. Jawan. 2006. Electroporative α-MSH gene transfer attenuates thioacetamide-induced murine hepatic fibrosis by MMP and TIMP modulation. Gene Therapy 13: 1000–1009.

    Article  CAS  PubMed  Google Scholar 

  • Wasser, S., J.M. Ho, H.K. Ang, and C.E. Tan. 1998. Salvia miltiorrhiza reduces experimental—induced hepatic fibrosis in rats. Journal of Hepatology 29: 760–771.

    Article  CAS  PubMed  Google Scholar 

  • Zhao, Z., Z. Liang, K. Chan, G. Lu, E.L. Lee, H. Chen, and L. Li. 2010. A unique issue in the standardization of Chinese materia medica: processing. Planta Medica 76: 1975–1986.

    Article  CAS  PubMed  Google Scholar 

  • Zhou, L., Z. Zhu, and M.S. Chow. 2005. Danshen: an overview of its chemistry, pharmacology, pharmacokineics and clinical use. Journal of Clinical Pharmacology 45: 1345–1359.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by a Grant from Wonkwang University for Prof. Sung Hee Lee (2012).

Author information

Authors and Affiliations

  1. Institute of Pharmaceutical Research and Development, College of Pharmacy, Wonkwang University, Iksan, Jeonbuk, 570-749, Republic of Korea

    Daya Ram Parajuli, Yu-Zhe Zhao, Hao Jin, Jin Hua Chi, Si Yuan Li, Youn-Chul Kim, Dong Hwan Sohn & Sung Hee Lee

  2. BK21plus Program & Department of Smart Life-Care Convergence, Graduate School of Wonkwang University, Iksan, Jeonbuk, 570-749, Republic of Korea

    Hao Jin, Jin Hua Chi, Si Yuan Li & Sung Hee Lee

Authors
  1. Daya Ram Parajuli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yu-Zhe Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hao Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jin Hua Chi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Si Yuan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Youn-Chul Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Dong Hwan Sohn
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Sung Hee Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Dong Hwan Sohn or Sung Hee Lee.

Additional information

Daya Ram Parajuli, Yu-Zhe Zhao contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Parajuli, D.R., Zhao, YZ., Jin, H. et al. Anti-fibrotic effect of PF2401-SF, a standardized fraction of Salvia miltiorrhiza, in thioacetamide-induced experimental rats liver fibrosis. Arch. Pharm. Res. 38, 549–555 (2015). https://doi.org/10.1007/s12272-014-0425-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12272-014-0425-2

Keywords

Search

Navigation