title: 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.
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.
authors.affiliation: Department of Chemistry & Biochemistry, School of Medicine, University of Rijeka, Rijeka, Croatia. robertd@medri.uniri.hr
authors.forename: Robert
authors.initials: R
authors.lastname: Domitrović
authors.forename: Hrvoje
authors.initials: H
authors.lastname: Jakovac
authors.forename: Vanja Vasiljev
authors.initials: VV
authors.lastname: Marchesi
authors.forename: Biljana
authors.initials: B
authors.lastname: Blažeković
mesh_terms: D000818:Animals; D001599:Berberine / Q000008:administration & dosage*; D002251:Carbon Tetrachloride / Q000009:adverse effects; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007546:Isoquinolines / Q000008:administration & dosage*; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018384:Oxidative Stress / Q000187:drug effects*; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D007546:Isoquinolines; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D001599:Berberine; D002251:Carbon Tetrachloride; D020778:Matrix Metalloproteinase 2; C039109:isoquinoline