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

다국어 초록 (Multilingual Abstract)

We previously reported the in vitro and in vivohepatoprotective and anti-fibrotic effects of PF2401-SF, astandardized fraction of Salvia miltiorrhiza, against acuteand subacute liver injury. The aim of this study was toinvestigate the effect of PF2401-SF on liver fibrosisinduced by thioacetamide (TAA), a chronic liver injurymodel (12 weeks) that closely resembles fibrosis and cirrhosisin humans. Hepatoprotective activity was indicatedby low serum levels of the markers aspartate aminotransferase and alanine amino transferase .In addition,compared to the TAA-group livers, the PF2401-SF-treatedliver tissues showed no fibrous tissue deposition in theportal areas, hepatocyte morphology more closely resemblingnormal tissue morphology, and significantly reducedcollagen deposition. Furthermore, downregulation of collagen1(a) and tissue inhibitor of metalloproteinase(TIMP)1 protein and mRNA expression also supportsPF2401-SF’s anti-fibrotic effect. We also observed reducedexpression of a-smooth muscle actin (a-SMA), an importantmarker of hepatic stellate cells (HSCs) activation. From these results, we conclude that PF2401-SF’s antifibroticmechanism in the TAA model involves reducedHSC activation, and may be mediated by downregulationof central markers of fibrosis, including collagen 1(a),TIMP1, and a-SMA.

참고문헌 (Reference)

1 Lee, T.Y., "Water-soluble extract of Salvia miltiorrhiza ameliorates carbon tetrachloride-mediated hepatic apoptosis in rats" 58 : 659-665, 2006

2 Elsharkawy, A.M, "The role and regulation of hepatic stellate cell apoptosis in reversal of liver fibrosis" 10 : 927-939, 2005

3 Friedman, S.L, "Seminars in medicine of the Beth Israel Hospital, Boston. The cellular basis of hepatic fibrosis. Mechanisms and treatment strategies" 328 : 1828-1835, 1993

4 Fallowfield, J.A., "Scar-associated macrophages are a major source of hepatic matrix metalloproteinase-13 and facilitate the resolution of murine hepatic fibrosis" 178 : 5288-5295, 2007

5 Wasser, S., "Salvia miltiorrhiza reduces experimental—induced hepatic fibrosis in rats" 29 : 760-771, 1998

6 Pallottini, V., "Rat HMG-CoA reductase activation in thioacetamide-induced liver injury is related to an increased reactive oxygen species content" 44 : 368-374, 2006

7 Bruck, R., "Protective effect of pyrrolidine dithiocarbamate in a rat model of liver cirrhosis" 24 : 169-176, 2004

8 Park, E.J, "Preventive effects of apurified extract isolated from Salvia miltiorrhiza enriched with tanshinone I, tanshinone IIA and cryptotanshinone on hepatocyte injury in vitro and vivo" 47 : 2742-2748, 2009

9 Parajuli, D.R., "PF2401-SF, standardized fraction of Salvia miltiorrhiza, induces apoptosis of activated hepatic stelate cells in vitro and in vivo" 18 : 2122-2134, 2013

10 Park, E.J., "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" 45 : 1891-1898, 2007

11 Galli, A, "Oxidative stress stimulates proliferation and invasiveness of hepatic stellate cells via a MMP2-mediated mechanism" 41 : 1074-1084, 2005

12 Rosenbloom, J., "Narrative review : Fibrotic diseases : Cellular and molecular mechanisms and novel therapies" 3 : 159-166, 2010

13 Luedde, T., "NF-kB in the liver-linking injury, fibrosis and hepatocellular carcinoma" 8 : 108-118, 2011

14 Parola, M., "Myofibroblast-like cells and liver fibrogenesis : emerging concepts in a rapidly moving scenario" 29 : 58-66, 2008

15 Iredale, J.P., "Models of liver fibrosis : exploring the dynamic nature of inflammation and repair in a solid organ" 3 : 539-548, 2007

16 Iredale, J.P., "Mechanisms of spontaneous resolution of rat liver fibrosis. Hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors" 102 : 538-549, 1998

17 Friedman, S.L., "Mechanisms of hepatic fibrosis and therapeutic implications" 1 : 98-105, 2004

18 Friedman, S.L., "Mechanisms of hepatic fibrosis" 134 : 1665-1669, 2008

19 Recknagel, R.O, "Mechanism of carbon tetracholride toxicity" 43 : 139-154, 1989

20 Bataller, R., "Liver fibrosis" 115 : 209-218, 2005

21 Pinzani, M., "Liver cirrhosis" 25 : 281-290, 2011

22 Honda, H., "Leptin is required for fibrogenic responses induced by thioacetamide in the murine liver" 36 : 12-21, 2002

23 Li, G.S., "In vitro and In vivo antifibrotic effects of rosmarinic acid on experimental liver fibrosis" 17 : 282-288, 2010

24 Thyagarajan, S.P., "Herbal medicines for liver diseases in India" 17 : 370-376, 2002

25 Lin, H.J., "Hepatoprotective effects of Yi Guan Jian, an herbal medicine, in rats with dimethylnitrosamine-induced liver fibrosis" 134 : 953-960, 2011

26 Benyon, R.C, "Expression of tissue inhibitor of metalloproteinases 1 and 2 is increased in fibrotic human liver" 110 : 821-831, 1996

27 Wang, C.H., "Electroporative a-MSH gene transfer attenuates thioacetamide-induced murine hepatic fibrosis by MMP and TIMP modulation" 13 : 1000-1009, 2006

28 Takahara, T, "Dual expression of matrix metalloproteinnase-2 and membrane-type 1-matrix metalloproteinase in fibrotic human livers" 26 : 1521-1529, 1997

29 Zhou, L., "Danshen : an overview of its chemistry, pharmacology, pharmacokineics and clinical use" 45 : 1345-1359, 2005

30 Iredale, J.P., "Cirrhosis : new research provides a basis for rational and targeted treatments" 327 : 143-147, 2003

31 Trebicka, J., "Atorvastatin attenuates hepatic fibrosis in rats after bile duct ligation via decreased turnover of hepatic stellate cells" 4 : 702-712, 2010

32 Hsu, Y.C., "Antifibrotic effects of Salvia miltiorrhiza on dimethylnitorsamine-intoxicated rats" 12 : 185-195, 2005

33 Zhao, Z., "A unique issue in the standardization of Chinese materia medica : processing" 76 : 1975-1986, 2010

34 Low, T.Y., "A proteomic analysis of thioacetamide induced hepatotoxicity and cirrhosis in rat livers" 12 : 3960-3974, 2004