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KMID : 1161420130160060518
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Journal of Medicinal Food
2013 Volume.16 No. 6 p.518 ~ p.528
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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
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Domitrovic Robert
Jakovac Hrvoje
Marchesi Vanja Vasiljev
Blazekovic Biljana
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Abstract
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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.
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KEYWORD
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α?smooth muscle actin, berberine, liver fibrosis, matrix metalloproteinases, transforming growth factor-β1, tumor necrosis factor-α
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