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1.
Lancet ; 391(10138): 2417-2429, 2018 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-29861076

RESUMO

BACKGROUND: Evidence is scarce on the efficacy of long-term human albumin (HA) administration in patients with decompensated cirrhosis. The human Albumin for the treatmeNt of aScites in patients With hEpatic ciRrhosis (ANSWER) study was designed to clarify this issue. METHODS: We did an investigator-initiated multicentre randomised, parallel, open-label, pragmatic trial in 33 academic and non-academic Italian hospitals. We randomly assigned patients with cirrhosis and uncomplicated ascites who were treated with anti-aldosteronic drugs (≥200 mg/day) and furosemide (≥25 mg/day) to receive either standard medical treatment (SMT) or SMT plus HA (40 g twice weekly for 2 weeks, and then 40 g weekly) for up to 18 months. The primary endpoint was 18-month mortality, evaluated as difference of events and analysis of survival time in patients included in the modified intention-to-treat and per-protocol populations. This study is registered with EudraCT, number 2008-000625-19, and ClinicalTrials.gov, number NCT01288794. FINDINGS: From April 2, 2011, to May 27, 2015, 440 patients were randomly assigned and 431 were included in the modified intention-to-treat analysis. 38 of 218 patients died in the SMT plus HA group and 46 of 213 in the SMT group. Overall 18-month survival was significantly higher in the SMT plus HA than in the SMT group (Kaplan-Meier estimates 77% vs 66%; p=0·028), resulting in a 38% reduction in the mortality hazard ratio (0·62 [95% CI 0·40-0·95]). 46 (22%) patients in the SMT group and 49 (22%) in the SMT plus HA group had grade 3-4 non-liver related adverse events. INTERPRETATION: In this trial, long-term HA administration prolongs overall survival and might act as a disease modifying treatment in patients with decompensated cirrhosis. FUNDING: Italian Medicine Agency.


Assuntos
Albuminas/uso terapêutico , Ascite/terapia , Cirrose Hepática/tratamento farmacológico , Idoso , Ascite/etiologia , Diuréticos/administração & dosagem , Diuréticos/efeitos adversos , Quimioterapia Combinada , Feminino , Furosemida/administração & dosagem , Furosemida/efeitos adversos , Humanos , Hiperpotassemia/induzido quimicamente , Hiponatremia/induzido quimicamente , Estimativa de Kaplan-Meier , Cirrose Hepática/complicações , Cirrose Hepática/fisiopatologia , Masculino , Pessoa de Meia-Idade , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Paracentese , Qualidade de Vida , Anos de Vida Ajustados por Qualidade de Vida , Taxa de Sobrevida , Fatores de Tempo
2.
Int J Biochem Cell Biol ; 40(9): 1764-74, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18291705

RESUMO

Chemokines binding the CXCR3 receptor have been shown to inhibit angiogenesis via the CXCR3-B isoform, but the underlying molecular mechanisms are unknown. Aim of this study was to elucidate the effects of CXCR3-B on activation of members of the mitogen-activated protein kinase family, and to explore the relevance of defined signaling pathways to the angiostatic effects of CXCR3-B ligands. Human embryonic kidney (HEK) 293 cells were transfected with expression vectors encoding for CXCR3-A or CXCR3-B. In cells expressing CXCR3-A, CXCL10 (IP-10) at nanomolar concentrations induced activation of ERK, Akt, and Src, as previously described in human vascular pericytes. In HEK-293 cells expressing CXCR3-B, exposure to CXCL10 in the micromolar concentration range led to activation of the p38(MAPK) pathway, as indicated by phosphorylation of p38(MAPK) itself, and of MKK3/6 and MAPKAPK-2, that lie upstream and downstream of p38(MAPK), respectively. Similar results were obtained in cells stimulated with CXCL4 (PF4), a specific ligand of CXCR3-B. In contrast, CXCL4 was unable to activate p38(MAPK) in mock-transfected HEK-293 cells. Only a modest induction of ERK or JNK was observed upon CXCR3-B activation. In human microvascular endothelial cells, which selectively express CXCR3-B, in a cell cycle-dependent fashion, CXCL10 and CXCL4 increased the enzymatic activity of p38(MAPK). Pharmacologic inhibition of p38(MAPK) by SB302580 resulted in a significant increase in DNA synthesis and in reversal of the inhibitory action of CXCL10. In conclusion, the p38(MAPK) pathway is a downstream effector of CXCR3-B implicated in the angiostatic action of this chemokine receptor.


Assuntos
Proteínas Angiostáticas/metabolismo , Receptores CXCR3/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Linhagem Celular , Quimiocina CXCL10/metabolismo , Ativação Enzimática , Regulação da Expressão Gênica , Humanos , Fator Plaquetário 4/metabolismo , Isoformas de Proteínas/metabolismo , Transdução de Sinais
3.
Endocrinology ; 146(10): 4321-30, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15994351

RESUMO

FNC-B4 neuroblasts that express both neuronal and olfactory markers have been established and cloned. These cells express GnRH and both the endothelin-1 (ET-1) gene and protein and respond in a migratory manner to GnRH in a dose-dependent manner. Previous research has shown that FNC-B4 cells produce and respond to ET-1 by regulating the secretion of GnRH through endothelin type A receptors and by stimulating their proliferation through endothelin type B (ETB) receptors. In this study, we found that FNC-B4 cells are able to migrate in response to ET-1 through the involvement of ETB receptors. Combined immunohistochemical and biochemical analyses showed that ET-1 triggered actin cytoskeletal remodeling and a dose-dependent increase in migration (up to 6-fold). Whereas the ETB receptor antagonist (B-BQ788) blunted the ET-1-induced effects, the ETA receptor antagonist (A-BQ123) did not. Moreover, we observed that FNC-B4 cells were independently and selectively stimulated by ET-1 and GnRH. We suggest that ET-1, through ETB receptor activation, may be required to maintain an adequate proliferative stem cell pool in the developing olfactory epithelium and the subsequent commitment to GnRH neuronal migratory pattern. The coordinate interaction between ET receptors and GnRH receptor participates in the fully expressed GnRH-secreting neuron phenotype.


Assuntos
Endotelina-1/fisiologia , Hormônio Liberador de Gonadotropina/metabolismo , Neurônios/metabolismo , Condutos Olfatórios/fisiologia , Linhagem Celular , Endotelina-1/farmacologia , Humanos , Radioimunoensaio , Receptor de Endotelina B/fisiologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/efeitos dos fármacos
4.
Hepatology ; 45(5): 1290-7, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17464971

RESUMO

UNLABELLED: Measurement of hepatic venous pressure gradient (HVPG) is a standard method for the assessment of portal pressure and correlates with the occurrence of its complications. Liver stiffness measurement (LSM) has been proposed as a noninvasive technique for the prediction of the complications of cirrhosis. In this study, we evaluated the ability of LSM to predict severe portal hypertension compared with that of HVPG in 61 consecutive patients with HCV-related chronic liver disease. A strong relationship between LSM and HVPG measurements was found in the overall population (r=0.81, P<0.0001). However, although the correlation was excellent for HVPG values less than 10 or 12 mm Hg (r=0.81, P=0.0003 and r=0.91, P<0.0001, respectively), linear regression analysis was not optimal for HVPG values>or=10 mm Hg (r2=0.35, P<0.0001) or>or=12 mm Hg (r2=0.17, P=0.02). The AUROC for the prediction of HVPG>or=10 and >or=12 mm Hg were 0.99 and 0.92, respectively and at LSM cutoff values of 13.6 kPa and 17.6 kPa, sensitivity was 97% and 94%, respectively. In patients with cirrhosis, LSM positively correlated with the presence of esophageal varices (P=0.002), although no correlation between LSM and esophageal varices size was detected. The area under the ROC for the prediction of EV was 0.76 and at a LSM cutoff value of 17.6 kPa sensitivity was 90%. CONCLUSION: LSM represents a non-invasive tool for the identification of chronic liver disease patients with clinically significant or severe portal hypertension and could be employed for screening patients to be subjected to standard investigations including upper GI endoscopy and hemodynamic studies.


Assuntos
Elasticidade , Hepatite C Crônica/complicações , Hipertensão Portal/diagnóstico , Cirrose Hepática/complicações , Fígado/fisiopatologia , Adulto , Idoso , Técnicas de Diagnóstico do Sistema Digestório/efeitos adversos , Varizes Esofágicas e Gástricas/diagnóstico , Feminino , Veias Hepáticas , Humanos , Cirrose Hepática/fisiopatologia , Masculino , Pessoa de Meia-Idade , Análise de Regressão
5.
Am J Physiol Gastrointest Liver Physiol ; 290(1): G120-8, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16150872

RESUMO

Thrombopoietin (TPO), a cytokine that participates in the differentiation and maturation of megakaryocytes, is produced in the liver, but only limited information is available on the biological response of liver-derived cells to TPO. In this study, we investigated whether HepG2 cells express c-Mpl, the receptor for TPO, and whether TPO elicits biological responses and intracellular signaling in this cell type. Specific transcripts for c-Mpl were detected in HepG2 cells by RT-PCR, and expression of the protein was demonstrated by Western blot analysis and immunofluorescence. Exposure of HepG2 cells to TPO was associated with a dose-dependent increase in cell migration and chemoinvasion through Matrigel-coated filters. A checkerboard analysis showed that the effects of TPO on cell migration were dependent on both chemotaxis and chemokinesis. Exposure of HepG2 cells to TPO resulted in the activation of different members of the MAPK family, including ERK and JNK, as assessed using phosphorylation-specific antibodies and immune complex kinase assays. TPO also activated phosphatidylinositol 3-kinase (PI3K) and the downstream kinase Akt in a time-dependent manner. Finally, activation of c-Mpl was associated with increased activation of nuclear factor-kappaB. With the use of specific inhibitors, tyrosine phosphorylation and activation of PI3K were found to be required for the induction of migration in response to TPO. We conclude that TPO exerts biological actions on cultured hepatoblastoma cells via activation of c-Mpl and its downstream signaling.


Assuntos
Movimento Celular/efeitos dos fármacos , Hepatoblastoma/metabolismo , Hepatoblastoma/patologia , Transdução de Sinais/efeitos dos fármacos , Trombopoetina/farmacologia , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Ativação Enzimática , Regulação Neoplásica da Expressão Gênica , Humanos , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Ligação Proteica , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Receptores de Citocinas/genética , Receptores de Citocinas/metabolismo , Receptores de Trombopoetina , Trombopoetina/metabolismo
7.
J Hepatol ; 37(1): 39-47, 2002 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12076860

RESUMO

BACKGROUND/AIMS: Little is known about the role of fractalkine (CX3CL1) in the liver. The aim of this study was to investigate the expression patterns of fractalkine and its receptor CX3CR1 in normal human liver and in conditions of injury. METHODS: Distribution and expression of fractalkine and its receptor were investigated using immunohistochemistry, in situ hybridization, flow cytometry and reverse transcriptase-polymerase chain reaction. In vitro experiments were conducted in HepG2 cells. RESULTS: Both fractalkine and CX3CR1 were up-regulated during chronic injury, in areas of portal and lobular inflammation. In severe acute hepatitis, fractalkine and CX3CR1 were expressed at high levels not only in areas of inflammation but also in regenerating epithelial cells within bile duct-like structures, which showed co-expression of fractalkine and cytokeratin-7 or CX3CR1. The human hepatocarcinoma cell line HepG2 expressed fractalkine at the gene and protein level, and HepG2-conditioned medium was chemotactic for cells overexpressing CX3CR1. Transcripts for CX3CR1 were detected in HepG2, and exposure of these cells to recombinant fractalkine induced cell migration. CONCLUSIONS: This study shows that the fractalkine system is up-regulated during liver damage, and suggests that fractalkine may play a role in the recruitment and adhesion of inflammatory cells and in the biology of liver epithelial cells.


Assuntos
Carcinoma Hepatocelular , Quimiocinas CX3C/genética , Hepatite C/fisiopatologia , Neoplasias Hepáticas , Proteínas de Membrana/genética , Receptores de Quimiocinas/genética , Doença Aguda , Receptor 1 de Quimiocina CX3C , Quimiocina CX3CL1 , Células Epiteliais/fisiologia , Expressão Gênica/fisiologia , Humanos , Fígado/citologia , Fígado/fisiologia , Regeneração Hepática/fisiologia , Células Tumorais Cultivadas , Regulação para Cima
8.
Gastroenterology ; 124(2): 504-20, 2003 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-12557155

RESUMO

BACKGROUND & AIMS: Several lines of evidence indicate that aldosterone antagonists may exert direct antifibrogenic effects. The aim of this study was to evaluate the possible direct antifibrogenic effects of canrenone, the active metabolite of spironolactone, in activated human hepatic stellate cells. METHODS: The effects of canrenone were assessed on platelet-derived growth factor-induced mitogenic and chemotactic effects and the increased de novo synthesis of different extracellular matrix components induced by transforming growth factor-beta1. RESULTS: Canrenone dose-dependently reduced platelet-derived growth factor-induced cell proliferation and motility. This effect was not associated with either changes in the phosphorylation of platelet-derived growth factor receptor and phospholipase C gamma or in the activation of the Ras/extracellular signal-regulated kinase pathway, whereas it was accompanied by a dose-dependent inhibition of platelet-derived growth factor-induced phosphatidylinositol 3-kinase activity. In addition, canrenone inhibited the activity of the Na(+)/H(+) exchanger 1 induced by platelet-derived growth factor. The effect of canrenone on Na(+)/H(+) exchanger 1 activity was reproduced by phosphatidylinositol 3-kinase inhibitors, thus supporting an inhibitory action of canrenone on phosphatidylinositol 3-kinase activity. To further address this possibility, the action of canrenone was compared with that of 2 established Na(+)/H(+) exchanger 1 inhibitors: ethylisopropylamiloride and cariporide. Whereas ethylisopropylamiloride was able to inhibit platelet-derived growth factor-induced phosphatidylinositol 3-kinase activity, cariporide was without any effect. Both compounds reproduced the effects of canrenone on platelet-derived growth factor-induced mitogenesis and chemotaxis. Finally, canrenone was able to reduce transforming growth factor-beta1-induced de novo synthesis of procollagen type I/IV and fibronectin and thrombin-induced hepatic stellate cell contraction. CONCLUSIONS: These results indicate that canrenone may be active as an antifibrogenic drug.


Assuntos
Amilorida/análogos & derivados , Canrenona/farmacologia , Cirrose Hepática/prevenção & controle , Fígado/efeitos dos fármacos , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Aldosterona/metabolismo , Amilorida/farmacologia , Cálcio/metabolismo , Divisão Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Proteínas da Matriz Extracelular/biossíntese , Quinase 1 de Adesão Focal , Proteína-Tirosina Quinases de Adesão Focal , Guanidinas/farmacologia , Humanos , Concentração de Íons de Hidrogênio/efeitos dos fármacos , Membranas Intracelulares/metabolismo , Fígado/citologia , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Fator de Crescimento Derivado de Plaquetas/farmacologia , Proteínas Tirosina Quinases/metabolismo , Transdução de Sinais , Trocadores de Sódio-Hidrogênio/antagonistas & inibidores , Sulfonas/farmacologia , Trombina/farmacologia
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