Resolution of Liver Fibrosis by Isoquinoline Alkaloid Berberine in CCl4-Intoxicated Mice Is Mediated by Suppression of Oxidative Stress and Upregulation of MMP-2 Expression

다국어 초록 (Multilingual Abstract)

Liver fibrosis is the result of chronic liver injury, and it represents a widespread medical problem. The aim of this study is to investigate the antifibrotic activity of isoquinoline alkaloid berberine in carbon tetrachloride (CCl4)-induced damage in mice. Hepatic fibrosis was induced by intraperitoneal (i.p.) administration of CCl4 (2 mL/kg, 20% v/v in olive oil) twice a week for 8 weeks. Berberine at the doses of 3 and 9 mg/kg and silymarin at the dose of 50 mg/kg were given i.p. once daily for the next 2 weeks. CCl4 intoxication increased the levels of serum transaminases and induced oxidative stress in the liver. Hepatic fibrosis was evidenced by a massive deposition of collagen, which coincided with increased expression of tumor necrosis factor (TNF)–α and transforming growth factor (TGF)–β1 and the activation of hepatic stellate cells. The high-dose berberine (9 mg/kg) ameliorated oxidative stress, decreased TNF-α and TGF-β1 expression, increased the levels of matrix metalloproteinase (MMP)–2, and stimulated the elimination of fibrous deposits. Berberine at the dose of 9 mg/kg exhibited stronger therapeutic activity against hepatic fibrosis than silymarin at the dose of 50 mg/kg. In vitro analyses show an important scavenging activity of berberine against oxygen and nitrogen reactive species. The results of this study suggest that berberine could ameliorate liver fibrosis through the suppression of hepatic oxidative stress and fibrogenic potential, concomitantly stimulating the degradation of collagen deposits by MMP-2.

참고문헌 (Reference)

1 Herna´ndez-Mun˜oz I, "Tumor necrosis factor alpha inhibits collagen alpha 1(I) gene expression in rat hepatic stellate cells through a G protein" 113 : 625-640, 1997

2 Bissell DM, "Transforming growth factor b and the liver" 34 : 859-867, 2001

3 Overall CM, "Transcriptional and posttranscriptional regulation of 72-kDa gelatinase/type IV collagenase by transforming growth factor-b1 in human fibroblasts" 266 : 14064-14071, 1991

4 Simeonova PP, "The role of tumor necrosis factor-a in liver toxicity, inflammation, and fibrosis induced by carbon tetrachloride" 177 : 112-120, 2001

5 Kuo CL, "The anti-inflammatory potential of berberine in vitro and in vivo" 203 : 127-137, 2004

6 Han YP, "TNF-a stimulates activation of pro-MMP2 in human skin through NF-jB mediated induction of MT1-MMP" 114 : 131-139, 2001

7 Lee CW, "TNF-a induces MMP-9 expression via activation of Src/EGFR, PDGFR/PI3K/Akt cascade and promotion of NF-kappaB/p300 binding in human tracheal smooth muscle cells" 292 : L799-L812, 2007

8 Janbaz KH, "Studies on preventive and curative effects of berberine on chemical-induced hepatotoxicity in rodents" 71 : 25-33, 2000

9 Tsukamoto H, "Roles of oxidative stress in activation of Kupffer and Ito cells in liver fibrogenesis" 10 : S50-S53, 1995

10 Muriel P, "Role of free radicals in liver diseases" 3 : 526-536, 2009

11 Zhao X, "Protective effects of berberine on doxorubicin-induced hepatotoxicity in mice" 35 : 796-800, 2012

12 Zhou JY, "Protective effect of berberine on antioxidant enzymes and positive transcription elongation factor b expression in diabetic rat liver" 82 : 184-189, 2011

13 Zhang BJ, "Protection by and anti-oxidant mechanism of berberine against rat liver fibrosis induced by multiple hepatotoxic factors" 35 : 303-309, 2008

14 Ruch RJ, "Prevention of cytotoxicity and inhibition of intracellular communication by antioxidant catechins isolated from Chinese green tea" 10 : 1003-1008, 1989

15 Zuo F, "Pharmacokinetics of berberine and its main metabolites in conventional and pseudo germ-free rats determined by liquid chromatography/ion trap mass spectrometry" 34 : 2064-2072, 2006

16 Parola M, "Oxidative stress-related molecules and liver fibrosis" 35 : 297-306, 2001

17 Friedman SL, "Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury" 275 : 2247-2250, 2000

18 Hwang JM, "Inhibitory effect of berberine on tert-butyl hydroperoxide- induced oxidative damage in rat liver" 76 : 664-670, 2002

19 Kimura K, "Immunopathogenesis of hepatic fibrosis in chronic liver injury induced by repeatedly administered concanavalin A" 11 : 1491-1500, 1999

20 Ishak K, "Histological grading and staging of chronic hepatitis" 22 : 696-699, 1995

21 Pradhan SC, "Hepatoprotective herbal drug, silymarin from experimental pharmacology to clinical medicine" 124 : 491-504, 2006

22 Feng Y, "Hepatoprotective effects of berberine on carbon tetrachloride-induced acute hepatotoxicity in rats" 5 : 33-, 2010

23 Ye X, "Hepatoprotective effects of Coptidis rhizoma aqueous extract on carbon tetrachlorideinduced acute liver hepatotoxicity in rats" 124 : 130-136, 2009

24 Domitrovic´ R, "Hepatoprotective activity of berberine is mediated by inhibition of TNF-a, COX-2, and iNOS expression in CCl4-intoxicated mice" 280 : 33-43, 2011

25 Chen IS, "Hepatoprotection of silymarin against thioacetamide-induced chronic liver fibrosis" 92 : 1441-1447, 2012

26 Iredale JP, "Hepatic stellate cell behavior during resolution of liver injury" 21 : 427-436, 2001

27 Shek FW, "Expression of transforming growth factor-b 1 by pancreatic stellate cells and its implications for matrix secretion and turnover in chronic pancreatitis" 160 : 1787-1798, 2002

28 Knittel T, "Expression of matrix metalloproteinases and their inhibitors during hepatic tissue repair in the rat" 113 : 443-453, 2000

29 Zhou X, "Expression of matrix metalloproteinase-2 and - 14 persists during early resolution of experimental liver fibrosis and might contribute to fibrolysis" 24 : 492-501, 2004

30 Hemmann S, "Expression of MMPs and TIMPs in liver fibrosis—a systematic review with special emphasis on anti-fibrotic strategies" 46 : 955-975, 2007

31 Watanabe T, "Dynamic change of cells expressing MMP-2 mRNA and MT1-MMP mRNA in the recovery from liver fibrosis in the rat" 35 : 465-473, 2001

32 Yokozawa T, "Coptidis Rhizoma: protective effects against peroxynitriteinduced oxidative damage and elucidation of its active components" 56 : 547-556, 2004

33 Yu Q, "Cell surface-localized matrix metalloproteinase- 9 proteolytically activates TGF-b and promotes tumor invasion and angiogenesis" 14 : 163-176, 2000

34 Birdsall TC, "Berberine: therapeutic potential of an alkaloid found in several medicinal plants" 2 : 94-103, 1997

35 Rackova L, "Antiradical and antioxidant activities of alkaloids isolated from Mahonia aquifolium. Structural aspects" 12 : 4709-4715, 2004

36 Blois MS, "Antioxidant determinations by the use of a stable free radical" 181 : 1199-1200, 1958

37 Keawpradub N, "Antioxidant and cytotoxic activities of Thai medicinal plants named Khaminkhruea: Arcangelisia flava, Coscinium blumeanum and Fibraurea tinctoria" 27 : 455-46, 2005

38 Rai S, "Antioxidant activity of Nelumbo nucifera (sacred lotus) seeds" 104 : 322-327, 2006

39 Luo A, "Antioxidant activities of berberine hydrochloride" 5 : 3702-3707, 2011

40 Domitrovic´ R, "Antifibrotic activity of anthocyanidin delphinidin in carbon tetrachloride-induced hepatotoxicity in mice" 272 : 1-10, 2010

41 Bradford MM, "A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding" 72 : 248-254, 1976