Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 12 de 12
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Neurosci ; 37(12): 3181-3191, 2017 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-28213441

RESUMO

The secreted glycoprotein Reelin regulates embryonic brain development and adult brain functions. It has been suggested that reduced Reelin activity contributes to the pathogenesis of several neuropsychiatric and neurodegenerative disorders, such as schizophrenia and Alzheimer's disease; however, noninvasive methods that can upregulate Reelin activity in vivo have yet to be developed. We previously found that the proteolytic cleavage of Reelin within Reelin repeat 3 (N-t site) abolishes Reelin activity in vitro, but it remains controversial as to whether this effect occurs in vivo Here we partially purified the enzyme that mediates the N-t cleavage of Reelin from the culture supernatant of cerebral cortical neurons. This enzyme was identified as a disintegrin and metalloproteinase with thrombospondin motifs-3 (ADAMTS-3). Recombinant ADAMTS-3 cleaved Reelin at the N-t site. ADAMTS-3 was expressed in excitatory neurons in the cerebral cortex and hippocampus. N-t cleavage of Reelin was markedly decreased in the embryonic cerebral cortex of ADAMTS-3 knock-out (KO) mice. Importantly, the amount of Dab1 and the phosphorylation level of Tau, which inversely correlate with Reelin activity, were significantly decreased in the cerebral cortex of ADAMTS-3 KO mice. Conditional KO mice, in which ADAMTS-3 was deficient only in the excitatory neurons of the forebrain, showed increased dendritic branching and elongation in the postnatal cerebral cortex. Our study shows that ADAMTS-3 is the major enzyme that cleaves and inactivates Reelin in the cerebral cortex and hippocampus. Therefore, inhibition of ADAMTS-3 may be an effective treatment for neuropsychiatric and neurodegenerative disorders.SIGNIFICANCE STATEMENT ADAMTS-3 was identified as the protease that cleaves and inactivates Reelin in the cerebral cortex and hippocampus. ADAMTS-3 was expressed in the excitatory neurons of the embryonic and postnatal cerebral cortex and hippocampus. Cleavage by ADAMTS-3 is the major contributor of Reelin inactivation in vivo Tau phosphorylation was decreased and dendritic branching and elongation was increased in ADAMTS-3-deficient mice. Therefore, inhibition of ADAMTS-3 upregulates Reelin activity and may be a potential therapeutic strategy for the prevention or treatment of neuropsychiatric and neurodegenerative disorders, such as schizophrenia and Alzheimer's disease.


Assuntos
Proteínas ADAMTS/metabolismo , Moléculas de Adesão Celular Neuronais/metabolismo , Córtex Cerebral/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Hipocampo/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Pró-Colágeno N-Endopeptidase/metabolismo , Serina Endopeptidases/metabolismo , Transdução de Sinais/fisiologia , Animais , Células Cultivadas , Ativação Enzimática , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Camundongos Knockout , Ligação Proteica
2.
J Biol Chem ; 289(18): 12922-30, 2014 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-24644294

RESUMO

Reelin is a secreted glycoprotein that plays essential roles in the brain. Reelin is specifically cleaved at two distinct sites, called N-t and C-t, with the former being the major one. N-t cleavage can occur both in the extracellular space and in the endosomes, although the physiological importance of endosomal N-t cleavage has not been investigated. In this study, we first determined the exact N-t cleavage site catalyzed by a protease secreted by cerebral cortical neurons. Cleavage occurred between Pro-1244 and Ala-1245 within Reelin repeat 3. A Reelin mutant in which Pro-1244 was replaced with aspartate (Reelin-PD) was resistant to a protease secreted by cultured cerebral cortical neurons, and its biological activity stayed active longer than that of wild-type Reelin. Interestingly, Reelin-PD remained in the intracellular compartments longer than wild-type Reelin and persistently activated downstream signaling. Therefore, N-t cleavage of Reelin is required for halting the signaling machinery in the extracellular space as well as within endosomes of target neurons. We established a monoclonal antibody specific to uncleaved Reelin protein and found that it is localized in the vicinity of Reelin-producing cells, whereas the N-terminal fragment diffuses, or is transported, to distant regions. These data demonstrate that N-t cleavage of Reelin plays critical roles in regulating the duration and range of Reelin functions both in the extracellular milieu and in the intracellular compartments.


Assuntos
Ácido Aspártico/genética , Moléculas de Adesão Celular Neuronais/genética , Proteínas da Matriz Extracelular/genética , Mutação , Proteínas do Tecido Nervoso/genética , Prolina/genética , Serina Endopeptidases/genética , Transdução de Sinais/genética , Sequência de Aminoácidos , Animais , Ácido Aspártico/metabolismo , Sítios de Ligação/genética , Western Blotting , Moléculas de Adesão Celular Neuronais/metabolismo , Células Cultivadas , Endossomos/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Espaço Extracelular/metabolismo , Feminino , Células HEK293 , Humanos , Masculino , Camundongos , Dados de Sequência Molecular , Proteínas do Tecido Nervoso/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Peptídeo Hidrolases/metabolismo , Prolina/metabolismo , Proteólise , Homologia de Sequência de Aminoácidos , Serina Endopeptidases/metabolismo
3.
J Hepatol ; 55(2): 379-87, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21168456

RESUMO

BACKGROUND & AIMS: Specific induction of cell death in activated hepatic stellate cells (HSCs) is a promising therapeutic strategy for hepatic fibrosis. In this study, we evaluated the cell-killing effect of ursolic acid (UA), a pentacyclic triterpenoid, in activated HSCs both in vitro and in vivo. METHODS: Culture-activated rat HSCs were treated with UA (0-40µM), and the mechanisms of cell death were evaluated. The cell killing effect of UA on activated HSCs in rats chronically treated with thioacetamide (TAA) was detected by dual staining of TdT-mediated dUTP nick-end labeling (TUNEL) and smooth muscle α-actin (αSMA) immunohistochemistry, and resolution of hepatic fibrosis was evaluated. Further, the protective effects of UA on progression of hepatic fibrosis caused by TAA and bile duct ligation (BDL) were evaluated. RESULTS: UA induced apoptotic cell death in culture-activated HSCs, but not in isolated hepatocytes and quiescent HSCs. Mitochodrial permeability transition (MPT) preceded the cleavage of caspase-3 and -9 following UA treatment. UA also decreased phosphorylation levels of Akt, and diminished nuclear localization of NFκB in these cells. In rats pretreated with TAA for 6weeks, a single injection of UA induced remarkable increases in TUNEL- and αSMA-dual-positive cells in 24h, and significant regression of hepatic fibrosis within 48h. Moreover, UA ameliorated hepatic fibrogenesis caused by both chronic TAA administration and BDL. CONCLUSIONS: UA ameliorated experimental hepatic fibrosis most likely through specific induction of apoptosis in activated HSCs. It is therefore postulated that UA is a potential therapeutic reagent for resolution of hepatic fibrosis.


Assuntos
Apoptose/efeitos dos fármacos , Células Estreladas do Fígado/efeitos dos fármacos , Cirrose Hepática Experimental/tratamento farmacológico , Triterpenos/uso terapêutico , Animais , Ductos Biliares , Progressão da Doença , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Técnicas In Vitro , Ligadura , Cirrose Hepática Experimental/metabolismo , Cirrose Hepática Experimental/patologia , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Wistar , Tioacetamida/toxicidade
4.
Am J Physiol Gastrointest Liver Physiol ; 299(2): G329-37, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20539006

RESUMO

Despite pathophysiological similarities to alcoholic liver disease, susceptibility to acetaminophen hepatotoxicity in metabolic syndrome-related nonalcoholic steatohepatitis (NASH) has not been well elucidated. In this study, therefore, we investigated acetaminophen-induced liver injury in KK-A(y) mice, an animal model of metabolic syndrome. Twelve-week-old male KK-A(y) and C57Bl/6 mice were injected intraperitoneally with 300 or 600 mg/kg acetaminophen, and euthanized 6 h later. Liver histology was assessed, and hepatic expression of 4-hydroxy-2-nonenal was detected by immunohistochemistry. Levels of reduced glutathione were determined spectrophotometrically. Phosphorylation of c-Jun NH(2)-terminal kinase (JNK) was analyzed by Western blotting. Hepatocytes were isolated from both strains by collagenase perfusion, and cell death and oxidative stress were measured fluorometrically by use of propidium iodide and 5-(and-6)-chloromethyl-2'7'-dichloro-dihydrofluorescein diacetate acetyl ester, respectively. Acetaminophen induced more severe necrosis and apoptosis of hepatocytes in KK-A(y) mice than in C57Bl/6 mice and significantly increased serum alanine aminotransferase levels in KK-A(y) mice. Acetaminophen-induction of 4-hydroxy-2-nonenal in the liver was potentiated, whereas the levels of reduced glutathione in liver were lower in KK-A(y) mice. Acetaminophen-induced phosphorylation of JNK in the liver was also enhanced in KK-A(y) mice. Exposure to 20 microM tert-butyl hydroperoxide did not kill hepatocytes isolated from C57Bl/6 mice but induced cell death and higher oxidative stress in hepatocytes from KK-A(y) mice. These results demonstrated that acetaminophen toxicity is increased in diabetic KK-A(y) mice mainly due to enhanced oxidative stress in hepatocytes, suggesting that metabolic syndrome-related steatohepatitis is an exacerbating factor for acetaminophen-induced liver injury.


Assuntos
Acetaminofen , Analgésicos não Entorpecentes , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Complicações do Diabetes , Diabetes Mellitus/genética , Acetaminofen/farmacologia , Analgésicos não Entorpecentes/farmacologia , Animais , Morte Celular , Doença Hepática Induzida por Substâncias e Drogas/patologia , Diabetes Mellitus/metabolismo , Diabetes Mellitus/fisiopatologia , Suscetibilidade a Doenças , Ativação Enzimática/efeitos dos fármacos , Hepatócitos/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Estresse Oxidativo
5.
Hepatology ; 49(5): 1636-44, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19205029

RESUMO

UNLABELLED: Pathogenesis of metabolic syndrome-related nonalcoholic steatohepatitis (NASH) involves abnormal tissue-repairing responses in the liver. We investigated the effect of pioglitazone, a thiazolidinedione derivative (TZD), on hepatic regenerative responses in obese, diabetic KK-A(y) mice. Male KK-A(y) mice 9 weeks after birth underwent two-thirds partial hepatectomy (PH) after repeated intragastric injections of pioglitazone (25 mg/kg) for 5 days. Almost half of the KK-A(y) mice died within 48 hours of PH;however, mortality was completely prevented in mice pretreated with pioglitazone. In KK-A(y) mice, bromodeoxyuridine (BrdU) incorporation to hepatocyte nuclei 48 hours after PH reached only 1%; however, pioglitazone pretreatment significantly increased BrdU-positive cells to 8%. Cyclin D1 was barely detectable in KK-A(y) mice within 48 hours after PH. In contrast, overt expression of cyclin D1 was observed 24 hours after PH in KK-A(y) mice pretreated with pioglitazone. Hepatic tumor necrosis factor alpha (TNF-alpha) messenger RNA (mRNA) was tremendously increased 1 hour after PH in KK-A(y) mice, the levels reaching ninefold over C57Bl/6 given PH, whereas pioglitazone blunted this increase by almost three-fourths. Pioglitazone normalized hypoadiponectinemia in KK-A(y) mice almost completely. Serum interleukin (IL)-6 and leptin levels were elevated extensively 24 hours after PH in KK-A(y) mice, whereas the levels were largely decreased in KK-A(y) mice given pioglitazone. Indeed, pioglitazone prevented aberrant increases in signal transducers and activators of transcription (STAT)3 phosphorylation and suppressor of cytokine signaling (SOCS)-3 mRNA in the liver in KK-A(y) mice. CONCLUSION: These findings indicated that pioglitazone improved hepatic regeneration failure in KK-A(y) mice. The mechanism underlying the effect of pioglitazone on regeneration failure most likely involves normalization of expression pattern of adipokines and subsequent cytokine responses during the early stage of PH.


Assuntos
Hipoglicemiantes/farmacologia , Resistência à Insulina , Hepatopatias/tratamento farmacológico , Regeneração Hepática/efeitos dos fármacos , Tiazolidinedionas/farmacologia , Adipocinas/metabolismo , Animais , Glicemia , Complicações do Diabetes/tratamento farmacológico , Complicações do Diabetes/metabolismo , Hepatectomia , Hipoglicemiantes/uso terapêutico , Janus Quinases/metabolismo , Fígado/metabolismo , Hepatopatias/etiologia , Hepatopatias/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/complicações , Obesidade/metabolismo , PPAR gama/agonistas , Fosforilação/efeitos dos fármacos , Pioglitazona , RNA Mensageiro/metabolismo , Fator de Transcrição STAT3/metabolismo , Proteína 3 Supressora da Sinalização de Citocinas , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Tiazolidinedionas/uso terapêutico
6.
Proc Natl Acad Sci U S A ; 105(31): 10895-900, 2008 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-18667695

RESUMO

Chronic cholestasis often results in premature death from liver failure with fibrosis; however, the molecular mechanisms contributing to biliary cirrhosis are not demonstrated. In this article, we show that the death signal mediated by TNF-related apoptosis-inducing ligand (TRAIL) receptor 2/death receptor 5 (DR5) may be a key regulator of cholestatic liver injury. Agonistic anti-DR5 monoclonal antibody treatment triggered cholangiocyte apoptosis, and subsequently induced cholangitis and cholestatic liver injury in a mouse strain-specific manner. TRAIL- or DR5-deficient mice were relatively resistant to common bile duct ligation-induced cholestasis, and common bile duct ligation augmented DR5 expression on cholangiocytes, sensitizing mice to DR5-mediated cholangitis. Notably, anti-DR5 monoclonal antibody-induced cholangitis exhibited the typical histological appearance, reminiscent of human primary sclerosing cholangitis. Human cholangiocytes constitutively expressed DR5, and TRAIL expression and apoptosis were significantly elevated in cholangiocytes of human primary sclerosing cholangitis and primary biliary cirrhosis patients. Thus, TRAIL/DR5-mediated apoptosis may substantially contribute to chronic cholestatic disease, particularly primary sclerosing cholangitis.


Assuntos
Apoptose/imunologia , Colangite/metabolismo , Colestase/imunologia , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Animais , Anticorpos Monoclonais , Linhagem Celular Tumoral , Colangite/patologia , Colestase/metabolismo , Colestase/patologia , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Camundongos , Camundongos Mutantes , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/genética
7.
J Gastroenterol Hepatol ; 22 Suppl 1: S49-52, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17567465

RESUMO

Acetaminophen overdose causes liver injury by mechanisms involving glutathione depletion, oxidative stress and mitochondrial dysfunction. The role of apoptosis in acetaminophen-induced cell killing is still controversial. Here, our aim was to evaluate the mitochondrial permeability transition (MPT) as a key factor in acetaminophen-induced necrotic and apoptotic killing of primary cultured mouse hepatocytes. Acetaminophen (10 micromol/L) induced necrotic killing in approximately 50% of hepatocytes after 6 h and cyclosporin A (CsA), MPT inhibitor, temporarily decreased necrotic killing after 6 h, but cytoprotection was lost after 16 h. Confocal microscopy revealed mitochondrial depolarization and inner membrane permeabilization at approximately 4.5 h after acetaminophen. CsA delayed these changes indicative of the MPT to about 11 h after acetaminophen. TUNEL labeling and caspase 3 activation also increased after acetaminophen. Fructose (20 mmol/L, an ATP-generating glycolytic substrate) plus glycine (5 mmol/L, a membrane stabilizing amino acid) prevented nearly all necrotic cell killing but paradoxically increased apoptosis. In conclusion, acetaminophen induces the MPT and ATP-depletion-dependent necrosis or caspase-dependent apoptosis as determined, in part, by ATP availability from glycolysis.


Assuntos
Acetaminofen/toxicidade , Apoptose/fisiologia , Doença Hepática Induzida por Substâncias e Drogas , Acetaminofen/farmacocinética , Animais , Permeabilidade da Membrana Celular , Células Cultivadas , Ciclosporina/farmacologia , Glutationa/metabolismo , Camundongos , Microscopia Confocal , Mitocôndrias Hepáticas/efeitos dos fármacos , Necrose/patologia , Estresse Oxidativo
8.
J Gastroenterol Hepatol ; 22 Suppl 1: S87-92, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17567476

RESUMO

Obesity and insulin resistance are the key factors for progression of hepatic fibrosis in various chronic liver diseases including non-alcoholic steatohepatitis (NASH). Recently it has been shown that leptin plays a pivotal role in development of hepatic fibrosis. Leptin promotes hepatic fibrogenesis through upregulation of transforming growth factor-beta in Kupffer cells and sinusoidal endothelial cells. Further, leptin facilitates proliferation and prevents apoptosis of hepatic stellate cells. There is a paradox, however, in that ob/ob mice and Zucker rats, which are the obese and diabetic strains, had minimal profibrogenic responses in the liver, most likely because they lack leptin and its receptors. To establish a more clinically relevant model to study the mechanism of fibrogenesis under steatohepatitis, fatty changes and profibrogenic responses in the liver caused by methionine-choline deficiency (MCD) were investigated in the KK-A(y) mouse, which is an obese and diabetic strain. KK-A(y) mice developed more severe hepatic steatosis, inflammation and fibrosis induced by an MCD diet as compared to C57Bl/6 controls. Importantly, KK-A(y) mice lack physiological upregulation of adiponectin levels, suggesting that adiponectin plays a pivotal role not only in regulation of insulin sensitivity but also in modulation of inflammatory and profibrogenic responses in dietary steatohepatitis. Collectively, these findings support the hypothesis that the balance of adipocytokine expression is a key regulator for the progression of hepatic fibrosis in the setting of steatohepatitis.


Assuntos
Modelos Animais de Doenças , Fígado Gorduroso/fisiopatologia , Leptina/fisiologia , Adiponectina/farmacologia , Animais , Deficiência de Colina , Progressão da Doença , Fígado Gorduroso/metabolismo , Macrófagos do Fígado/metabolismo , Fígado/citologia , Cirrose Hepática/fisiopatologia , Metionina/deficiência , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo , Fator de Crescimento Transformador beta1/metabolismo , Regulação para Cima
9.
J Hepatol ; 46(2): 286-94, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17166617

RESUMO

BACKGROUND/AIMS: In this study, we investigated the effect of dalteparin sodium, a low molecular weight (LMW)-heparin, on hepatic fibrogenesis caused by chronic carbon tetrachloride (CCl4) administration in the rat. METHODS: Female Wistar rats were given a single, or repeated intraperitoneal injections of CCl4 (1ml/kg, twice per week) and dalteparin (50IU/kg, daily) for 7 weeks. RESULTS: Dalteparin did not prevent acute CCl4-induced hepatic necrosis and elevation in serum aminotransferases levels; however, proliferating cell nuclear antigen (PCNA)-positive hepatocytes were dramatically increased 24h after simultaneous administration of CCl4 and dalteparin. Interestingly, serum hepatocyte growth factor (HGF) levels 12h after injection of CCl4 were almost doubled when dalteparin was given simultaneously. Hepatic fibrosis following 7-week CCl4 treatment was markedly ameliorated by daily co-administration of dalteparin. Indeed, dalteparin largely inhibited CCl4-induction of smooth muscle alpha-actin expression, alpha1(I)procollagen and transforming growth factor (TGF)-beta1 mRNA levels in the liver. Further, dalteparin blunted platelet-derived growth factor (PDGF)-induced increases in 5-bromo-2'deoxyuridine (BrdU) uptake in 3-day cultured hepatic stellate cells (HSCs) in a dose-dependent manner. CONCLUSIONS: Dalteparin enhances hepatic regeneration and minimizes hepatic fibrogenesis caused by chronic CCl4 treatment. The mechanism underlying these effects most likely involves both up-regulation of HGF and inhibition of HSC proliferation.


Assuntos
Dalteparina/administração & dosagem , Heparina de Baixo Peso Molecular/administração & dosagem , Cirrose Hepática Experimental/prevenção & controle , Actinas/genética , Actinas/metabolismo , Animais , Tetracloreto de Carbono/toxicidade , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Feminino , Fibrose , Fator de Crescimento de Hepatócito/sangue , Hepatócitos/química , Hepatócitos/efeitos dos fármacos , Hepatócitos/patologia , Fígado/química , Fígado/efeitos dos fármacos , Fígado/patologia , Cirrose Hepática Experimental/induzido quimicamente , Regeneração Hepática/efeitos dos fármacos , Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Antígeno Nuclear de Célula em Proliferação/análise , RNA Mensageiro/análise , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo
10.
Hepatol Res ; 36(3): 217-28, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16920398

RESUMO

In this study, we investigated a dietary model of steatohepatitis caused by methionine- and choline-deficiency (MCD) in obese, diabetic KK-A(y) mice. Male KK-A(y) mice and C57Bl/6 mice were fed an MCD diet for up to 8 weeks, and liver pathology was evaluated. Hepatic steatosis and inflammatory infiltration were more prominent in KK-A(y) mice than in C57Bl/6 mice 4 weeks after feeding with MCD diet. MCD diet-induced increases in tumor necrosis factor (TNF)-alpha mRNA levels, as well as lipid peroxidation, in the liver were also potentiated significantly in KK-A(y) mice. Extended degree of hepatic fibrosis was observed in KK-A(y) mice as compared to C57Bl/6 mice 8 weeks after feeding with MCD diet. Indeed, alpha1(I)procollagen and transforming growth factor (TGF)-beta1 mRNA levels were significantly higher in KK-A(y) mice following dietary treatment. Serum adiponectin levels were elevated nearly two-fold when C57Bl/6 mice were given MCD diet for 4 weeks; however, serum adiponectin levels in KK-A(y) mice fed both the control- and MCD diet were the same, reaching the values almost 1/2 of those in C57Bl/6 mice. In conclusion, KK-A(y) mice exhibit increased susceptibility to MCD diet-induced steatohepatitis, where hypoadiponectinemia most likely plays a key role in exacerbation of both inflammatory and profibrogenic responses.

11.
Hepatol Res ; 35(1): 19-25, 2006 May.
Artigo em Inglês | MEDLINE | ID: mdl-16531110

RESUMO

In this study, we evaluated whether hepatic steatosis affects the viral response to interferon (IFN) and ribavirin combination therapy in Japanese patients with chronic hepatitis C (CHC). Eighty CHC patients treated with IFN alpha-2b and ribavirin for 24 weeks were evaluated retrospectively. Liver biopsy specimens were assessed histopathologically, and grade of steatosis was scored as follows: grade 0: <5%; grade 1: 5-33%; grade 2: 33-66%; grade 3: >66%. Sustained viral response (SVR) was defined as negative for HCV-RNA by high-sensitivity qualitative reverse transcription-polymerase chain reaction (RT-PCR) at 24 weeks post-treatment. Hepatic steatosis graded 2 and higher was seen in 28.8% patients, whose average BMI were significantly higher than those in grade 0 patients. Grade of steatosis was well correlated with elevation in serum aminotransferases and gamma-glutamyltranspeptidase (gamma-GTP) levels, but not with histological degree of inflammation and fibrosis. The SVR rates were significantly lower in the group with overt steatosis (grade 2/3) as compared to the group with less steatosis (grade 0/1), the values being 30.4% and 57.9%, respectively. Moreover, grade of steatosis was selected as an independent negative factor for SVR in multivariate analysis. In conclusion, hepatic steatosis is an important predictor of poor response to therapy of IFNalpha-2b and ribavirin in patients with CHC.

12.
Hepatol Res ; 33(2): 151-4, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16198623

RESUMO

Since non-alchoholic steatohepatitis (NASH) is often accompanied with metabolic syndrome comprising obesity, type-2 diabetes and hypertension, it is hypothesized that adipocytokines, insulin resistance and autonomic nervous system play crucial roles in disease progression of NASH. On the other hand, hepatic stellate cells (HSCs) have been shown to produce leptin when they get activated during hepatic fibrogenesis. Therefore, we investigated the role of leptin in fibrogenesis in the liver. Xenobiotics-induced liver fibrosis was extremely diminished in ob/ob mice and Zucker (fa/fa) rats, an inborn leptin- and leptin receptor (Ob-R)-deficient animal, respectively. Further, leptin increased transforming growth factor (TGF)-beta mRNA in isolated sinusoidal endothelial cells and Kupffer cells, suggesting that leptin promotes hepatic fibrogenesis through up-regulation of TGF-beta in the liver. Moreover, leptin augmented PDGF-dependent proliferation of HSCs by enhancing downstream intracellular signaling pathways via mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3 kinase (PI3K)/Akt. Taken together, it is postulated that leptin acts as a profibrogenic cytokine in sinusoidal microenvironment. These findings indicate that leptin is one of the key regulators for inflammation and progression of fibrosis in various chronic liver diseases including NASH.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA