ABSTRACT
AIM: To evaluate the effect of genistein on the fibrosis and matrix degradation caused by experimentally induced fibrosis in rats. METHODS: Hepatic fibrosis was brought about by chronic administration of carbon tetrachloride to rats. To evaluate the effect of genistein on liver fibrosis and function, total collagen content and proteolytic activity in the liver were quantified. Urokinase-type plasminogen activator (uPA) expression during experimental fibrosis was localized by immunohistochemistry. Histopathological changes were evaluated using light and electron microscopy. RESULTS: Animals with fibrosis and treated with genistein showed an important reduction (73%) in hepatic collagen content as well as an improvement in liver function (p < 0.001). Genistein increased the capacity of the liver to degrade type I collagen and Matrigel (3.1- and 3.7-fold, respectively; p < 0.001) in animals with liver fibrosis. Genistein increased the number of uPA-immunoreactive cells. The increase in the uPA expression correlated with an increase in proteolytic activity. Histological analysis revealed a reduction in the number of fiber septa in pericentral and perisinusoidal areas. Transmission electron micrographs of livers from animals with fibrosis and treated with genistein showed a reduction in the number of hepatic stellate cells activated and a smaller number of collagen fibers. CONCLUSION: Genistein is able to improve the liver after injury and fibrosis induced by chronic administration of carbon tetrachloride. This finding suggests that genistein has antifibrogenic potential and could therefore be useful for treating chronic liver disease.
Subject(s)
Genistein/therapeutic use , Liver Cirrhosis/prevention & control , Liver , Peptide Hydrolases/metabolism , Protein Kinase Inhibitors/therapeutic use , Urokinase-Type Plasminogen Activator/biosynthesis , Animals , Carbon Tetrachloride , Collagen Type I/metabolism , Disease Models, Animal , Genistein/administration & dosage , Genistein/pharmacology , Immunohistochemistry , Liver/drug effects , Liver/enzymology , Liver/metabolism , Liver/ultrastructure , Liver Cirrhosis/enzymology , Liver Cirrhosis/metabolism , Liver Cirrhosis/pathology , Liver Function Tests , Male , Microscopy, Electron, Transmission , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/pharmacology , Rats , Rats, WistarABSTRACT
Among the eight Calophyllum species found on the American continent, Calophyllum brasiliense is the most widely distributed. Chemical analysis of this species has shown the presence of xanthones with cancer chemopreventive properties and antifungal activity. Recently, three new coumarins with antineoplastic properties have been found. In this study, we have evaluated the biological effects of the antiproliferative activity of coumarins isolated from C. brasiliense on the survival, cell cycle and apoptosis of cells in-vitro and their antitumour effects in mice. The cytological study showed that coumarins from C. brasiliense reduce the survival of BMK cells (baby mouse kidney cells) by inducing apoptosis and, to a lesser degree, necrosis. The cell cycle was arrested in S-phase and the division of BMK cells was inhibited. Coumarins had caused a reduction of experimental tumours in 83% of animals by the end of the treatment. Therefore, coumarins have the potential to be used alone or in combination with other antineoplastic drugs, and they might increase the effectiveness of other treatments for cancer.
Subject(s)
Antineoplastic Agents/pharmacology , Calophyllum/chemistry , Coumarins/pharmacology , Plant Extracts/pharmacology , Animals , Antineoplastic Agents/isolation & purification , Apoptosis/drug effects , Cell Cycle/drug effects , Cell Proliferation/drug effects , Cell Survival/drug effects , Coumarins/isolation & purification , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Female , Mice , Mice, Inbred BALB C , Mitosis/drug effects , Necrosis , Neoplasms/drug therapy , Plant Extracts/isolation & purification , Plants, Medicinal/chemistry , Vincristine/pharmacologyABSTRACT
Fibrosis accompanies most chronic liver disorders and is a major factor contributing to hepatic failure. Therefore, the need for an effective treatment with the aim of modifying the clinical course of this disease is evident. The aim of this work is to determine whether genistein, which has been shown to modulate the physiology and pathophysiology of liver, is able to decrease experimental liver fibrosis and cholestasis. In male Wistar rats, the common bile duct was ligated. Administration of genistein (5 microg rat-1, day-1, p.o.) began four weeks after biliary obstruction and continued for a further four weeks. The liver was used for histological and ultrastructural analysis and for collagen quantification (hydroxyproline content). The degradation of Matrigel(R) and collagen type I was determined in homogenized liver. Bilirubins and enzyme activities were measured in serum. Genistein was able to improve normal liver histology, ultrastructure, collagen content, and biochemical markers of liver damage. It also increased Matrigel(R) and collagen type I degradation. In summary, the present report shows that genistein inhibits the fibrosis and cholestasis induced by prolonged biliary obstruction in the rat. Genistein has therapeutic potential against liver fibrosis.
