RESUMO
The in vivo antifibrotic effect of a fucoidan extract (FE) from Sargassum fluitans Borgesen was evaluated in a carbon tetrachloride-induced liver damage model in rats over twelve weeks. Chemical analysis showed the FE to contain carbohydrates, sulfates, uronic acids, protein, phenols, and to have a molecular weight of ~60 kDa. Physiological, biochemical, histological and genetic assays were done. Daily oral administration of FE (50 mg/kg) reduced liver enzymatic activity, liver infiltration of inflammatory cells, collagen fiber deposition and gene expression cytokines such as interleukin beta 1 (IL-ß1), tumor necrosis factor alpha (TNF-α), transforming growth factor beta 1 (TGF-ß1), Smad-3, Smad-2, collagen 1 alpha 1 (col1α1) and tissue inhibitor of metalloproteinase 1 (TIMP-1). It also increased RNA expression of Smad-7 and metalloproteinase 2 and 9 (MMP2 and MMP9). The fucoidan extract exhibited an antifibrotic effect mediated by the inhibiting TGF-ß1/Smad pathway, as well as anti-inflammatory effects.
Assuntos
Cirrose Hepática/tratamento farmacológico , Extratos Vegetais/farmacologia , Polissacarídeos/química , Sargassum/química , Animais , Tetracloreto de Carbono/toxicidade , Intoxicação por Tetracloreto de Carbono/tratamento farmacológico , Intoxicação por Tetracloreto de Carbono/genética , Intoxicação por Tetracloreto de Carbono/patologia , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Fígado/efeitos dos fármacos , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/patologia , Extratos Vegetais/química , Polissacarídeos/farmacologia , Ratos , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad/genética , Proteína Smad3/genética , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta1/genéticaRESUMO
Carbon tetrachloride (CCl4) is a model for studying free radical-induced liver injury and screening hepato-protective drugs. Numerous studies have reported the involvement of oxidative stress in CCl4-induced liver damage and the hepato-protective effects mediated by different antioxidants. The present study examined the effects of diphenyl diselenide, (PhSe)2, on hepatotoxicity induced by CCl4 in rats. To this end, male Wistar rats received (PhSe)2 by oral route at the dosage of 31.2 mg/kg for one or two days. After the second day of treatment, rats received CCl4 orally in a single dose. The liver and kidney were utilized for determination of histopathology, biochemical [aspartate (ALT) and alanine (AST) aminotransferases, alkaline phosphatase (ALP), total bilirrubin (TB) and gamaglutamyl transferase (GGT)] and toxicological parameters [thiobarbituric reactive species (TBARS) levels, catalase activity, ascorbic acid, nonprotein thiols (NPSH) and aminolevulinate dehydratase (-ALA-D) activity]. Repeated administration of (PhSe)2 caused a marked potentiation of hepatotoxicity induced by CCl4 exposure, as manifested by an increase in biochemical parameters (AST, ALT, ALP, GGT and BT) and severe alteration in histopathology. This study also demonstrated a potentiation of TBARS levels and a consequent depletion of important antioxidant defenses including catalase and ascorbic acid. Pre-treatment with a single dose of (PhSe)2 prevented the effect of strychnine, a substrate for CYPs, abolishing lethality in mice. This result indicates that (PhSe)2 prevented animal death, suggesting an activator action of (PhSe)2 in CYPs. This study clearly indicates that (PhSe)2 potentiated acute hepatic damage induced by CCl4.
Assuntos
Derivados de Benzeno/administração & dosagem , Derivados de Benzeno/farmacologia , Tetracloreto de Carbono/toxicidade , Fígado/efeitos dos fármacos , Compostos Organosselênicos/administração & dosagem , Compostos Organosselênicos/farmacologia , Administração Oral , Alanina Transaminase/sangue , Animais , Ácido Ascórbico/análise , Ácido Ascórbico/metabolismo , Aspartato Aminotransferases/sangue , Bilirrubina/sangue , Intoxicação por Tetracloreto de Carbono/metabolismo , Intoxicação por Tetracloreto de Carbono/patologia , Catalase/análise , Catalase/metabolismo , Creatinina/análise , Sinergismo Farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/metabolismo , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Sintase do Porfobilinogênio/análise , Sintase do Porfobilinogênio/metabolismo , Ratos , Ratos Wistar , Substâncias Reativas com Ácido Tiobarbitúrico/análise , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Ureia/sangue , gama-Glutamiltransferase/sangueRESUMO
The aim of this study was to investigate the possible beneficial effects of amburoside A, AMB [4-(O-beta- D-glycopyranosyl)benzyl protocatechoate], against carbon tetrachloride (CCl (4)) toxicity in rats. AMB is a phenol glucoside from the Brazilian medicinal plant Amburana cearensis, popularly used for the treatment of respiratory tract affections. Acute AMB (25 and 50 mg/kg, I. P. or P. O.) treatments of CCl (4)-intoxicated rats significantly inhibited the increase in serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, as compared to the group treated with CCl (4) only. Histological studies showed less centrolobular necrosis and inflammatory cell infiltrates in the liver of animals treated with AMB plus CCl (4), when compared to the group treated with CCl (4) alone. In hepatic tissues, AMB at both doses inhibited CCl (4)-induced thiobarbituric acid-reactive substances (TBARS) formation, indicating a blockade of CCl (4)-induced lipid peroxidation. AMB also reversed the decrement in glutathione contents of hepatic tissues in CCl (4)-intoxicated rats. Furthermore, it restored catalase activity to normal values, which was significantly increased after CCl (4) treatment. Our results indicate that CCl (4)-induced oxidative damage in hepatic tissues is reversed by AMB treatment. The protective effect of AMB is probably due to the phenolic nature of this glucoside.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Fabaceae/química , Glucosídeos/uso terapêutico , Fitoterapia , Extratos Vegetais/uso terapêutico , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Tetracloreto de Carbono , Intoxicação por Tetracloreto de Carbono/tratamento farmacológico , Intoxicação por Tetracloreto de Carbono/metabolismo , Intoxicação por Tetracloreto de Carbono/patologia , Catalase/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/patologia , Glucosídeos/isolamento & purificação , Glutationa/metabolismo , Fígado/enzimologia , Fígado/metabolismo , Fígado/patologia , Masculino , Extratos Vegetais/química , Ratos , Ratos Wistar , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismoRESUMO
The genotoxic effect of two tanshinones isolated from roots of Hyptis martiussi Benth (Labiatae) was studied using V79 (Chinese hamster lung) cells by the alkaline comet assay and micronucleus test. Tanshinones were incubated with the cells at concentrations of 1, 3, 6 and 12 microg/mL for 3 h. Tanshinones were shown to be quite strongly genotoxic against V79 cells at all tested concentrations. The data obtained provide support to the view that tanshinones has DNA damaging activity in cultured V79 cells under the conditions of the assays.
Assuntos
Antioxidantes/uso terapêutico , Intoxicação por Tetracloreto de Carbono/prevenção & controle , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Flavonoides/uso terapêutico , Animais , Análise Química do Sangue , Intoxicação por Tetracloreto de Carbono/patologia , Catalase/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Fígado Gorduroso/induzido quimicamente , Fígado Gorduroso/patologia , Glutationa/metabolismo , Glutationa Transferase/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/patologia , Masculino , Malondialdeído/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais , Ratos , Ratos Sprague-Dawley , Superóxido Dismutase/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismoRESUMO
Flavonoids are reported to exhibit a wide variety of biological effects, including antioxidant and free radical-scavenging activities. Evidence of oxidative reactions is often associated with various chronic disease processes characterized by accumulation of connective tissue. This study was aimed to investigate the protective effects of chronic administration of the flavonoid quercetin (150 micromol/kg body wt/day intraperitoneally) in rats with carbon tetrachloride-induced fibrosis. In animals rendered cirrhotic by administration of carbon tetrachloride for 16 weeks, cell necrosis, fibrosis, and inflammatory infiltration were found. Histological abnormalities were accompanied by a higher hepatic content of collagen and thiobarbituric acid-reactive substances. Expression of inducible nitric oxide synthase (iNOS) was significantly increased in the liver. Treatment with quercetin during 3 weeks improved liver histology and reduced collagen content, iNOS expression, and lipid peroxidation. Those effects were associated with an increased total peroxyl radical-trapping antioxidant capacity of liver. We conclude that quercetin is effective in this model of liver damage.
Assuntos
Intoxicação por Tetracloreto de Carbono/patologia , Flavonoides/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Cirrose Hepática Experimental/patologia , Quercetina/farmacologia , Animais , Colágeno/metabolismo , Radicais Livres/metabolismo , Injeções Intraperitoneais , Fígado/efeitos dos fármacos , Fígado/patologia , Cirrose Hepática Experimental/induzido quimicamente , Masculino , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase Tipo II , Peróxidos/metabolismo , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismoRESUMO
1. The aim of the present study was to develop an experimental model of liver cirrhosis in rabbits using CCl4 and phenobarbital. 2. Liver cirrhosis was induced in male New Zealand white rabbits (n = 10) by intragastric administration of CCl4 once weekly starting 14 days after the addition of phenobarbital to the drinking water (50 mg/day). Controls received phenobarbital only (n = 7). Alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT), albumin and bilirubin levels were determined throughout CCl4 treatment. The initial dose of CCl4 was 20 microg and subsequent doses were calculated to maintain AST and ALT levels between 400 and 800 IU/L for the duration of treatment (16 weeks). Indocyanine green (ICG) clearance was performed before and at the end of CCl4 treatment. Animals were killed at 16 weeks and three fragments of each liver lobe were processed for histological examination. A semiquantitative score was used to evaluate the development of fibrosis. 3. Cirrhosis developed in 80% of rabbits treated with CCl4. These animals did not gain weight compared with controls (P < 0.05). A significant reduction of ICG clearance was observed in CCl4-treated rabbits compared with controls (P < 0.05). The AST, ALT, bilirubin and gamma-GGT levels were elevated in CCl4-treated rabbits. 4. In conclusion, this model is successful in producing liver cirrhosis and may be useful in studies investigating metabolic, immunological or biochemical changes during the evolution of chronic liver disease.
Assuntos
Cirrose Hepática Experimental/induzido quimicamente , Animais , Intoxicação por Tetracloreto de Carbono/metabolismo , Intoxicação por Tetracloreto de Carbono/patologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Modelos Animais de Doenças , Cirrose Hepática Experimental/metabolismo , Cirrose Hepática Experimental/patologia , Masculino , Fenobarbital , CoelhosRESUMO
BACKGROUND/AIMS: The present study was undertaken to determine whether colchicine has a beneficial effect in the prevention of hepatic cirrhosis when it is given simultaneously with CCl4. METHODOLOGY: Wistar rats were employed as experimental animals and divided into 6 groups: Group I received saline solution, Group II, saline solution and mineral oil; Group III, colchicine (10 micrograms/100 g) and mineral oil; Group IV, colchicine (10 micrograms/100 g) and CCl4; Group V, colchicine (5 micrograms/100 g) and CCl4; and, Group VI received saline solution and CCl4. The effect of colchicine was evaluated by liver function tests, serum total proteins, electrolytes and histological evaluation. RESULTS: The results demonstrated higher values of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and total bilirubin in groups IV and V when compared with group VI (p < 0.05). No difference between group VI and groups IV and V was observed in histological evaluation, serum total proteins and electrolytes (p < 0.05). CONCLUSIONS: Colchicine, as given in this study, did not have any protective effect in the prevention of cirrhosis induced by carbon tetrachloride.
Assuntos
Intoxicação por Tetracloreto de Carbono/patologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Colchicina/farmacologia , Cirrose Hepática Experimental/prevenção & controle , Animais , Doença Hepática Induzida por Substâncias e Drogas/patologia , Relação Dose-Resposta a Droga , Humanos , Fígado/patologia , Cirrose Hepática Experimental/patologia , Testes de Função Hepática , Ratos , Ratos WistarRESUMO
A histopathological evaluation was performed on liver of rats treated with carbon tetrachloride (CCl4) and 25,50 and 100 mg/kg of Cuban red propolis (RP) extract. Additionally, alanine aminotransferase (ALT) in serum and liver triglycerides were determined in all animals. The morphometric study included the count of ballooned cells at the zone III of the Rappaport acini and the assessment of a software program to estimate the extension of steatosis area. A significant reduction of ballooned cells count in liver was observed at three dose levels of RP extract with respect to rats treated only with CCl4. Also, a certain reduction of steatosis degree as well as decreased concentration of liver triglycerides and ALT activity were found in three groups of rats treated with RP extract and CCl4 in relation to those treated with the hepatotoxin. Taken together, the histopathological and biochemical findings show hepatoprotective effects of RP extract in CCl4-induced liver damage in rats, probably due to the antioxidant effect of RP.
Assuntos
Antioxidantes/farmacologia , Intoxicação por Tetracloreto de Carbono/patologia , Tetracloreto de Carbono/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/patologia , Flavonoides/farmacologia , Sequestradores de Radicais Livres/farmacologia , Fígado/efeitos dos fármacos , Própole/farmacologia , Alanina Transaminase/metabolismo , Animais , Antioxidantes/uso terapêutico , Intoxicação por Tetracloreto de Carbono/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Cuba , Fígado Gorduroso/induzido quimicamente , Fígado Gorduroso/patologia , Flavonoides/uso terapêutico , Sequestradores de Radicais Livres/uso terapêutico , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/patologia , Masculino , Própole/química , Própole/uso terapêutico , Ratos , Software , Triglicerídeos/metabolismoRESUMO
We have previously reported that the endocytosis of rat plasma kallikrein (RPK) by hepatocytes is a calcium-independent and beta-galactoside-dependent mechanism. We now report the clearance of RPK by the liver of four groups of rats: normal, inflamed (48 h ex-turpentine) and two groups chronically treated with CCl4 (52 mg/kg per week, intragastrically, for 9-12 weeks). Each liver was isolated, exsanguinated and perfused at 37 degrees C with 30 mL of BSA-Krebs-Henseleit-bicarbonate medium containing 10 nmol/L RPK. Although all rats received the same mild CCl4 treatment, the liver histology showed that they evolved either to severe hepatitis (serum alanine aminotransferase [ALT] 4852 +/- 885 U/L, parenchymatous necrosis in the perivenous region) or to compensated cirrhosis (serum ALT 209 +/- 42 U/L, vigorous fibrous encircling regeneration nodules); neither jaundice nor ascites was noted. The results show that serum albumin was not altered among the groups and that: the acute-phase response by itself (inflamed group) increased RPK clearance rate (3.01 +/- 0.59 mL/min) as compared with the normal group (1.85 +/- 0.14 mL/min); the CCl4 treatment, although induced an acute-phase response, decreased (P < 0.01) RPK clearance rates (0.80 +/- 0.11 mL/min hepatitis group and 0.98 +/- 0.10 mL/min cirrhosis group). These findings suggest that the hepatic clearance rate of plasma kallikrein is an early indicator of liver injury.