RESUMO
Hepatic fibrosis (HF) is a common complication of numerous chronic liver diseases, but predominantly results from persistent liver inflammation or injury. If left untreated, HF can progress and develop into liver cirrhosis and even hepatocellular carcinoma. However, the underlying molecular mechanisms of HF remain unknown. The present study aimed to investigate the role of 11ßhydroxysteroid dehydrogenase1 (11ßHSD1) during the development of hepatic fibrosis. An experimental rat model of liver fibrosis was induced using porcine serum. 11ßHSD1 gene expression levels and enzyme activity during hepatic fibrogenesis were assessed. 11ßHSD1 gene knockdown using small interfering RNA and overexpression were performed in LX2human hepatic stellate cells (HSCs). HSCs were stimulated with transforming growth factorß1 (TGFß1). Cell cycle distribution, proliferation, collagen secretion and 11ßHSD1 gene activity in HSCs were compared before and after stimulation. As hepatic fibrosis progressed, 11ßHSD1 gene expression and activity increased, indicating a positive correlation with typical markers of liver fibrosis. 11ßHSD1 inhibition markedly reduced the degree of fibrosis. The cell proliferation was increased, the number of cells in the G0/G1 phase decreased and the number of cells in the S and G2/M phases increased in the pSuper transfected group compared with the N group. In addition, the overexpression of 11ßHSD1 enhanced the TGFß1induced activation of LX2HSCs and enzyme activity of connective tissue growth factor. 11ßHSD1 knockdown suppressed cell proliferation by blocking the G0/G1 phase of the cell cycle, which was associated with HSC stimulation and inhibition of 11ßHSD1 enzyme activity. In conclusion, increased 11ßHSD1 expression in the liver may be partially responsible for hepatic fibrogenesis, which is potentially associated with HSC activation and proliferation.
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Células Estreladas do Fígado/citologia , Cirrose Hepática Experimental/patologia , Fator de Crescimento Transformador beta1/efeitos adversos , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/genética , Animais , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Regulação para Baixo , Técnicas de Silenciamento de Genes , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Humanos , Cirrose Hepática Experimental/etiologia , Cirrose Hepática Experimental/genética , Cirrose Hepática Experimental/metabolismo , Masculino , RatosRESUMO
BACKGROUND: Assessment of hepatic fibrosis stage in patients with chronic hepatitis B (CHB) is indispensable for prognosis evaluation and therapeutic regime. Noninvasive tests are fast, safe and cheap and need low technical requirements for diagnosing hepatic fibrosis in CHB patients. OBJECTIVES: Using the latent class model with a random-factor to estimate relative accuracy of noninvasive tests for the diagnosis of hepatic fibrosis without a gold standard in a large population with CHB. PATIENTS AND METHODS: A total of 544 patients with CHB were assessed for fibrosis stage by four noninvasive tests containing liver stiffness measurement (LSM), aspartate aminotransferase-to-platelet ratio index (APRI), fibrosis index based on 4 factors (FIB-4) and globulin and platelet (GP). The diagnostic evaluation was made by the latent class method with random effect which analyzed the clinical data above to assess the accuracy of four ways of noninvasive diagnosis. RESULTS: The latent class model with random effect permitted to conciliate the observed data and estimates of test performances. For significant fibrosis, the specificity/sensitivity were 83.24%/91.59% (APRI), 90.05%/95.57% (FIB-4), 75.11%/66.01% (LSM) and 71.13%/98.33% (GP), respectively. For cirrhosis, the specificity/sensitivity were 84.04%/17.91% (APRI), 89.86%/17.09 (FIB-4), 78.64%/37.07% (LSM) and 82.28%/37.07% (GP), respectively. CONCLUSIONS: FIB-4 confirmed the best value for diagnosis of significant fibrosis. APRI had a sub-optimal diagnosis accuracy for significant fibrosis. LSM showed the most balance diagnosis value for cirrhosis with the highest sensitivity and moderate specificity.
RESUMO
Patients with acute-on-chronic hepatitis B liver failure (HBV-ACLF) show high morbidity and mortality. Independent prognostic predictors of short-term HBV-ACLF mortality include the Child-Turcotte-Pugh (CTP) score, the model for end-stage liver disease (MELD) score, other MELD-based indices and the dynamic changes in these indices. The aims of this study were to evaluate the existing prognostic scores in a large cohort of HBV-ACLF patients and create a new predictive model. We retrospectively reviewed 392 HBV-ACLF patients from December 2008 to November 2011 and evaluated their 3-month survival. The predictive accuracy of CTP, MELD and MELD-based indices and the dynamic changes in the MELD-related scores (Δ scoring systems) upon admission and after two weeks of treatment were compared using the area under the receiver operating characteristic (ROC) curve method. Life-threatening factors and a series of bio-clinical parameters were studied by univariate and multivariate analyses. Among the existing scores, MELD had the best predictive ability. However, our new regression model provided an area under the curve of 0.930 ± 0.0161 (95% CI: 0.869 to 0.943), which was significantly larger than that obtained with the MELD score at admission and after two weeks of treatment as well as with the dynamic changes of the MELD score (0.819, 0.921, and 0.826, respectively) (Z=3.542, P=0.0004). In a large cohort of patients retrospectively reviewed for this study, our prognostic model was superior to the MELD score and is, therefore, a promising predictor of short-term survival in patients with HBV-ACLF.
Assuntos
Hepatite B/complicações , Falência Hepática/etiologia , Doença Aguda , Adulto , Doença Crônica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
BACKGROUND: Human UDP-glucuronosyltransferases (UGTs) are important membrane proteins located in endoplasmic reticulum, and play important roles in metabolism of a variety of endogenous and exogenous compounds. AIMS: To determine the influence of subtle difference in the structure of oleanolic acid and betulinic acid towards the inhibition towards the activity of UGT isoforms. METHODS: In vitro glucuronidation of 4-methylumbelliferone (4-MU) reaction was employed as the probe reaction to determine the inhibition of these two compounds towards UGTs' activity. RESULTS: The inhibition of capability of oleanolic acid towards UGT1A6 and UGT1A8 were higher than betulinic acid. However, no significant difference was observed for the inhibition of oleanolic acid and betulinic acid towards UGT1A7. Furthermore, concentration-dependent behaviour was determined for the inhibition of oleanolic acid and betulinic acid towards UGT1A6 and UGT1A8. At various concentrations of oleanolic acid and betulinic acid, the inhibition of oleanolic acid towards UGT1A6 and UGT1A8 was higher than betulinic acid. CONSLUSION: Given that UGT1A6 and UGT1A8 play key role in the the inhibition of oleanolic acid towards UGT1A6 and UGT1A8 will induce drug-drug interaction and the risk of diseases.
Assuntos
Glucuronosiltransferase/antagonistas & inibidores , Himecromona/metabolismo , Ácido Oleanólico/farmacologia , Triterpenos/farmacologia , Interações Medicamentosas , Humanos , Triterpenos Pentacíclicos , Ácido BetulínicoRESUMO
OBJECTIVE: To investigate the association between the change of IGF-2 level in serum after transcatheter arterial chemoembolization (TACE) and hepatocellular carcinoma (HCC) progression, especially in relation to metastasis. METHODS: IGF-2 in serum was measured by quantitative sandwich enzyme-linked immunosorbent assay before, 3 days and 4 weeks after TACE in 60 patients with HCC. The occurrence of HCC metastasis was also evaluated, 3 months after TACE. RESULTS: (1) The average serum level of IGF-2 in the 60 patients with HCC was 136.5 ± 87.3 pg/ml; (2) A tendency for increase was observed with heterogenous uptake of octreotide and portal vein thrombosis. Metastatic foci were found in 37/38 patients in the group with IGF-2 increasing (97.0%), in contrast to 3/22 (13.6%) patients with IGF-2 decrease. CONCLUSION: The increase of IGF-2 level in serum appears to be associated with the occurrence of metastatic HCC after TACE and chemotherapy.
Assuntos
Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/terapia , Quimioembolização Terapêutica/métodos , Fator de Crescimento Insulin-Like II/biossíntese , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/terapia , Octreotida/administração & dosagem , Antineoplásicos Hormonais/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Feminino , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , PrognósticoRESUMO
OBJECTIVE: To evaluate the protective effect of recombinant human granulocyte colony stimulating factor (rhG-CSF) on acute hepatic failure induced by galactosamine (D-GalN) and lipopolysaccharide (LPS) in mice, and to explore its mechanism. METHODS: The mice were intraperitoneally administered D-GalN (800 mg/kg) and LPS (10 microg/kg), and then were intraperitoneally injected either saline (the control group )or rhG-CSF at 300 microg/kg body weight (the therapy group) at 4 h, 2 h and 0 h before the D-GalN/LPS injection. The survival rate of the mice was estimated at 24 h after the D-GalN/LPS injection. The degree of hepatic injury was evaluated at 6 h after the D-GalN/LPS injection, and the levels of TNF-alpha, IFN-gamma, IL-6 and IL-10 mRNA were simultaneously measured by semiquantitative RT-PCR. RESULTS: The survival rate of the therapy group was significantly higher than that of the control group (68.4% vs 20%, P<0.01). As compared with the control group, the degree of liver injury in the therapy group significantly decreased (P<0.05), and the levels of TNF-alpha and IFN-gamma mRNA in the hepatic tissue also reduced remarkably (P<0.01, respectively), while the levels of IL-6 and IL-10 mRNA increased (P<0.01, respectively) at 6 h after the D-GalN/LPS injection. CONCLUSION: G-CSF can protect the mice from acute hepatic failure induced by D-GalN/LPS.