RESUMEN
BACKGROUND: Whether direct-acting anti-viral therapy can reduce liver fibrosis and steatosis in patients with chronic hepatitis C virus (HCV) infection is unclear. AIMS: To evaluate changes in liver stiffness and steatosis in patients with HCV who received direct-acting anti-viral therapy and achieved sustained virological response (SVR). METHODS: A total of 198 patients infected with HCV genotype 1 or 2 who achieved SVR after direct-acting anti-viral therapy were analysed. Liver stiffness as evaluated by magnetic resonance elastography, steatosis as evaluated by magnetic resonance imaging-determined proton density fat fraction (PDFF), insulin resistance, and laboratory data were assessed before treatment (baseline) and at 24 weeks after the end of treatment (SVR24). RESULTS: Alanine aminotransferase and homeostatic model assessment-insulin resistance levels decreased significantly from baseline to SVR24. Conversely, platelet count, which is inversely associated with liver fibrosis, increased significantly from baseline to SVR24. In patients with high triglyceride levels (≥150 mg/dL), triglyceride levels significantly decreased from baseline to SVR24 (P = 0.004). The median (interquartile range) liver stiffness values at baseline and SVR24 were 3.10 (2.70-4.18) kPa and 2.80 (2.40-3.77) kPa respectively (P < 0.001). The PDFF values at baseline and SVR 24 were 2.4 (1.7-3.4)% and 1.9 (1.3-2.8)% respectively (P < 0.001). In addition, 68% (19/28) of patients with fatty liver at baseline (PDFF ≥5.2%; n = 28) no longer had fatty liver (PDFF <5.2%) at SVR24. CONCLUSION: Viral eradication reduces both liver stiffness and steatosis in patients with chronic HCV who received direct-acting anti-viral therapy (UMIN000017020).
Asunto(s)
Antivirales/uso terapéutico , Hepacivirus/efectos de los fármacos , Hepatitis C Crónica/tratamiento farmacológico , Cirrosis Hepática/tratamiento farmacológico , Hígado/patología , Respuesta Virológica Sostenida , Anciano , Estudios de Cohortes , Elasticidad , Diagnóstico por Imagen de Elasticidad , Femenino , Estudios de Seguimiento , Hepacivirus/genética , Hepatitis C Crónica/patología , Hepatitis C Crónica/virología , Humanos , Hígado/diagnóstico por imagen , Hígado/virología , Cirrosis Hepática/complicaciones , Cirrosis Hepática/patología , Cirrosis Hepática/virología , Masculino , Persona de Mediana Edad , Inducción de Remisión , Carga Viral/efectos de los fármacosRESUMEN
BACKGROUND: With the development of direct-acting anti-virals (DAAs), almost all patients with chronic hepatitis C virus (HCV) infection can achieve sustained viral response (SVR). AIM: To evaluate the short-term risk of HCC among patients with SVR by DAAs, including those with cirrhosis or previous HCC. METHODS: This large-scale, multicentre cohort study included 1,675 consecutive patients who achieved SVR by treatment with interferon-free sofosbuvir-based regimens, divided into groups with (n = 152) or without previous HCC (n = 1,523). The Kaplan-Meier method and Cox proportional hazard analysis were used to calculate the cumulative HCC incidence and related factors of HCC. RESULTS: During the follow-up period (median: 17 months), 46 (2.7%) patients developed HCC. The 1-year cumulative rates of de novo HCC were 0.4% and 4.9% for the noncirrhosis and cirrhosis groups respectively (log-rank test: P < 0.001). For cirrhotic patients, serum α-fetoprotein level at the end of treatment (EOT-AFP) was the strongest predictor of de novo HCC. The 1-year cumulative de novo HCC rates were 1.4% and 13.1% in the EOT-AFP < 9.0 ng/mL and ≥ 9.0 ng/mL groups (cut-off value) respectively (log-rank test: P < 0.001). The 1-year cumulative rates of HCC recurrence were 6.5% and 23.1% for the noncirrhosis and cirrhosis groups respectively (log-rank test: P = 0.023). For cirrhotic patients, previous HCC characteristics were significantly associated with HCC recurrence. In contrast, sex, age and metabolic features did not influence de novo HCC or recurrence. CONCLUSIONS: For cirrhotic patients after elimination of HCV, serum EOT-AFP level and previous HCC characteristics would be useful markers for predicting de novo HCC or recurrence.
Asunto(s)
Antivirales/uso terapéutico , Carcinoma Hepatocelular/epidemiología , Hepatitis C Crónica/tratamiento farmacológico , Neoplasias Hepáticas/epidemiología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Carcinoma Hepatocelular/patología , Estudios de Cohortes , Femenino , Hepacivirus/efectos de los fármacos , Humanos , Incidencia , Cirrosis Hepática/tratamiento farmacológico , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Factores de Riesgo , Adulto Joven , alfa-Fetoproteínas/análisisRESUMEN
Favourable efficacy and safety profiles for simeprevir in combination with pegylated interferon alpha (PEG-IFNα) and ribavirin (triple therapy) have been shown in clinical trials. This study was carried out to evaluate the effectiveness of simeprevir-based triple therapy for patients with prior telaprevir treatment failure. This multicentre, observational cohort consisted of 345 consecutive Japanese patients infected with HCV genotype 1b, including 20 who had experienced telaprevir-based triple therapy. Amino acid substitutions in the NS3/4A region were identified by direct sequencing at the time of relapse or breakthrough in treatment with telaprevir and at the initiation of treatment with simeprevir. Patients were stratified according to prior response to PEG-IFNα and ribavirin. Of the 20 patients with telaprevir treatment failure, 10 (50.0%) achieved sustained virological response at week 12 after the end of treatment (SVR12). For patients treatment naïve [3/4 (75.0%)] or with prior relapse [1/1 (100%)] or partial response [5/6 (83.3%)] to PEG-IFNα and ribavirin, almost all achieved SVR12, mainly because of the improvement of treatment adherence, especially to direct-acting antiviral agent and ribavirin. However, of the nine patients with prior null response to PEG-IFNα and ribavirin, only one (11.1%) achieved SVR12, despite all having received an adequate treatment dosage, and five (55.6%) achieved rapid virological response. The treatment outcome of simeprevir-based triple therapy for HCV genotype 1b patients with prior telaprevir failure depended on the prior response to PEG-IFNα and ribavirin. For patients with prior null response to PEG-IFNα and ribavirin, retreatment with simeprevir-based triple therapy is not a useful option.
Asunto(s)
Hepatitis C Crónica/tratamiento farmacológico , Interferón-alfa/uso terapéutico , Polietilenglicoles/uso terapéutico , Ribavirina/uso terapéutico , Simeprevir/uso terapéutico , Anciano , Antivirales/uso terapéutico , Proteínas Portadoras/genética , Quimioterapia Combinada , Femenino , Hepacivirus/clasificación , Hepacivirus/efectos de los fármacos , Hepacivirus/genética , Humanos , Interferón alfa-2 , Péptidos y Proteínas de Señalización Intracelular , Japón , Cirrosis Hepática/patología , Cirrosis Hepática/virología , Masculino , Persona de Mediana Edad , Oligopéptidos/uso terapéutico , Proteínas Recombinantes/uso terapéutico , Recurrencia , Simeprevir/efectos adversos , Insuficiencia del Tratamiento , Proteínas no Estructurales Virales/genéticaRESUMEN
BACKGROUND: Antiviral treatment is recommended for chronic hepatitis C patients with advanced fibrosis to reduce and prevent cirrhosis-related complications. AIM: To evaluate the efficacy and safety of telaprevir (TVR)-based triple therapy for patients with advanced fibrosis in a clinical practice setting. METHODS: This prospective, multicentre study consisted of 102 patients with advanced fibrosis (METAVIR score F3-4) who were infected with HCV genotype 1b. All received 12 weeks of TVR in combination with 24 weeks of pegylated interferon (PEG-IFN) α2b and ribavirin (RBV). RESULTS: The sustained virological response (SVR) rate was 69.6% (71 of 102). Notably, for treatment-naïve and prior relapse patients the SVR rate was over 80%. Previous treatment response, interleukin 28B polymorphism (rs8099917) and rapid virological response (undetectable HCV RNA at week 4) were independently associated with SVR. To achieve SVR, an adequate dosage of PEG-IFNα2b (≥1.2 µg/kg/week) and RBV (≥7.5 mg/kg/day) is preferable; however, the mean weight-adjusted TVR dosage had little impact on treatment outcome. Although severe blood cytopaenia and a dermatological disorder were frequently found, the rate of discontinuation due to adverse effects was 12.7%. The inosine triphosphatase CC allele (rs1127354) was independently associated with the development of severe anaemia, and lower serum albumin level (<35 g/L) was associated with the occurrence of infection. CONCLUSIONS: The great gain in the SVR rate by telaprevir-based triple therapy offsets the problems with adverse effects; thus, it should be considered as a potent treatment protocol for patients with advanced fibrosis, especially for those with treatment-naïve and prior relapse.
Asunto(s)
Antivirales/uso terapéutico , Hepatitis C Crónica/tratamiento farmacológico , Cirrosis Hepática/tratamiento farmacológico , Oligopéptidos/uso terapéutico , Anciano , Anemia/epidemiología , Anemia/etiología , Antivirales/administración & dosificación , Antivirales/efectos adversos , Quimioterapia Combinada , Femenino , Genotipo , Hepacivirus/genética , Hepacivirus/aislamiento & purificación , Hepatitis C Crónica/fisiopatología , Humanos , Interferón alfa-2 , Interferón-alfa/administración & dosificación , Interferón-alfa/efectos adversos , Interferón-alfa/uso terapéutico , Cirrosis Hepática/fisiopatología , Masculino , Persona de Mediana Edad , Oligopéptidos/administración & dosificación , Oligopéptidos/efectos adversos , Polietilenglicoles/administración & dosificación , Polietilenglicoles/efectos adversos , Polietilenglicoles/uso terapéutico , Estudios Prospectivos , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/uso terapéutico , Recurrencia , Ribavirina/administración & dosificación , Ribavirina/uso terapéutico , Resultado del TratamientoRESUMEN
Recent studies have demonstrated that several cellular factors are involved in entry of hepatitis C virus (HCV) into host cells. Detailed gene expression profiles of these factors in HCV-infected livers have not been reported for humans. Transcriptional levels of LDL receptor (LDLR), CD81, scavenger receptor class B type I (SR-BI), claudin-1, and occludin genes in liver samples from patients with chronic hepatitis C were investigated. Serum levels of LDL-cholesterol (LDL-C) and HCV core antigen were also evaluated, and expression of claudin-1 and occludin were immunohistochemically analyzed. Compared with normal liver, transcription of LDLR and claudin-1 genes was significantly suppressed (P < 0.0001) and occludin transcription was significantly up-regulated in HCV-infected livers (P < 0.0001). Significant positive correlations were found for LDLR versus occludin, LDLR versus claudin-1, occludin versus claudin-1, and CD81 versus SR-BI in HCV-infected (P = 0.0012, P < 0.0001, P = 0.0004, and P < 0.0001, respectively) and normal livers (P < 0.0001, P = 0.0051, P < 0.0001, and P < 0.0001, respectively). Positive correlation was observed between serum levels of HCV core antigen and LDL-C (P = 0.0147), with their levels negatively correlated to LDLR (P = 0.0270 and P = 0.0021, respectively). Immunohistochemically, hepatocellular expression of claudin-1 and occludin was increased in HCV-infected livers. Different levels of expression were demonstrated at the mRNA and protein levels for occludin and claudin-1 in HCV-infected and normal livers. Correlation of elements associated with viral entry was comparable in HCV-infected and normal livers.
Asunto(s)
Regulación de la Expresión Génica , Hepacivirus/fisiología , Hepatitis C Crónica/patología , Interacciones Huésped-Patógeno , Hígado/virología , Internalización del Virus , Adulto , Anciano , Antígenos CD/biosíntesis , LDL-Colesterol/sangre , Claudina-1 , Femenino , Perfilación de la Expresión Génica , Hepacivirus/patogenicidad , Hepatitis C Crónica/virología , Humanos , Inmunohistoquímica , Masculino , Proteínas de la Membrana/biosíntesis , Persona de Mediana Edad , Ocludina , Receptores de LDL/biosíntesis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Receptores Depuradores de Clase B/biosíntesis , Tetraspanina 28 , Proteínas del Núcleo Viral/sangreRESUMEN
OBJECTIVE: Bezafibrate (BF) has been used to treat biliary damage, particularly in patients with primary biliary cirrhosis (PBC), and its clinical efficacy has been demonstrated. The mechanism of action is thought to involve activation of the PPARalpha-MDR3-phospholipid (PL) secretion pathway. We tried to confirm this hypothesis in patients with hepatobiliary disease. METHODS: The levels of serum gamma-glutamyl transpeptidase and alkaline phosphatase, and those of bile components were examined before and after BF administration in patients with obstructive jaundice undergoing percutaneous transhepatic biliary drainage (PTBD). Hepatic expression of PPARalpha and MDR3 was quantified by real-time PCR in patients with PBC or non-alcoholic fatty liver disease (NAFLD). RESULTS: In patients with obstructive jaundice, BF decreased the serum levels of biliary enzymes and increased the bile concentration of PL. In patients with PBC or NAFLD, the expression levels of MDR3 were already up-regulated before starting the BF treatment. Although BF treatment did not further up-regulate MDR3 expression in NAFLD patients, PPARalpha expression was significantly increased. CONCLUSIONS: BF enhanced the secretion of PL into bile in cholestatic patients undergoing PTBD. However, in patients with PBC or NAFLD, diseases that represent cholesterol overload, MDR3 was already expressed at a high level to compensate for bile acids overproduction, and its expression was hardly affected by BF. In patients with chronic liver diseases such as PBC, BF may induce clinical effects via mechanisms independent of PL secretion.
Asunto(s)
Bezafibrato/farmacología , Hipolipemiantes/farmacología , Ictericia Obstructiva/tratamiento farmacológico , Fosfolípidos/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Fosfatasa Alcalina/sangre , Bezafibrato/uso terapéutico , Colestasis/tratamiento farmacológico , Colestasis/fisiopatología , Colestasis/cirugía , Drenaje/métodos , Hígado Graso/tratamiento farmacológico , Hígado Graso/fisiopatología , Femenino , Humanos , Hipolipemiantes/uso terapéutico , Ictericia Obstructiva/fisiopatología , Ictericia Obstructiva/cirugía , Cirrosis Hepática Biliar/tratamiento farmacológico , Cirrosis Hepática Biliar/fisiopatología , Masculino , Persona de Mediana Edad , PPAR alfa/genética , PPAR alfa/metabolismo , Reacción en Cadena de la Polimerasa , gamma-Glutamiltransferasa/sangreRESUMEN
An interventional navigation system designed for percutaneous abdominal therapies was proposed, and a pilot study was carried out to assess the proposed system. Integration of US to MRI-based segmentation and 3D display of tumours can help physicians deal with instabilities such as respiratory motion and soft tissue shift that are inherent in abdominal interventions. In addition to the 3D display of the needle and tumours, we adapted the system for the abdominal applications and incorporated a process to correct the mismatch in needle path between MRI and US. The preliminary results of phantom and animal experiments indicated that the proposed method could combine the advantages of both MRI and US. The time required to determine the optimal needle insertion path by using this system was significantly less than that required when either US or MRI guidance alone was employed. The developed system was applied in two patients who underwent PEIT therapy, and its clinical feasibility was partially confirmed.
Asunto(s)
Abdomen/cirugía , Imagen por Resonancia Magnética , Ultrasonografía , Anciano , Animales , Humanos , Procesamiento de Imagen Asistido por Computador , Imagenología Tridimensional , Neoplasias Hepáticas/cirugía , Masculino , Agujas , Fantasmas de Imagen , Cirugía Asistida por Computador/instrumentación , PorcinosRESUMEN
BACKGROUND: In HCV-related graft hepatitis, immunosuppression has been implicated in rapid progression to cirrhosis, a serious clinical issue. We investigated the effects of cyclosporine or tacrolimus on cell growth and collagen production by hepatic stellate cells (HSC), which play a role in hepatic fibrosis. MATERIALS AND METHODS: Cultured rat HSCs and human HSC-derived TWNT-4 cells were evaluated for proliferation, type I collagen, phosphorylation states of mitogen-activated protein kinases extracellular signal-regulated kinase 1/2; [MAPKs Erk1/2], c-Jun N-terminal kinase (JNK, p38), as well as the expression of collagen, matrix metalloproteinase-1 (MMP-1) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) genes. RESULTS: Cyclosporine suppressed cell growth and collagen production in a concentration-dependent manner. At clinically relevant concentrations of 0.125 micromol (150 ng/mL) cyclosporine significantly reduced collagen production per cell by more than 50%. Similarly, tacrolimus also reduced both collagen concentration and cell number; however, tacrolimus at a clinically relevant concentration of 12.5 nmol (10 ng/mL) did not significantly reduce collagen production. Treatment with cyclosporine reduced type I collagen and TIMP-1 expression and enhanced MMP-1 expression. Cyclosporine also inhibited phosphorylation strongly for JNK and p38, and weakly inhibited for Erk1/2. CONCLUSION: These findings demonstrated that cyclosporine suppresses cell growth and collagen production, suggesting that it may have an antifibrogenic effect.
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Colágeno Tipo I/biosíntesis , Ciclosporina/farmacología , Hepatocitos/fisiología , Animales , Células Cultivadas , Colágeno/metabolismo , Relación Dosis-Respuesta a Droga , Hepatocitos/efectos de los fármacos , Humanos , Inmunosupresores/farmacología , Ratones , Tacrolimus/farmacología , Inhibidor Tisular de Metaloproteinasa-1/metabolismoRESUMEN
none.
RESUMEN
BACKGROUND: We have demonstrated immunohistochemically that RCAS 1 antigen is expressed in biliary neoplasms. Serum RCAS 1 levels are also elevated in a high percentage of patients with intra-hepatic cholangiocarcinoma. AIM: The study was designed to determine whether serum levels of RCAS1 are of clinical significance as a tumour marker for biliary tract tumour, in comparison to CA19-9. PATIENTS AND METHODS: In 38 patients with biliary carcinoma (gallbladder carcinoma, extra-hepatic and intra-hepatic cholangiocarcinoma and ampullary carcinoma), we measured serum RCAS1 and CA19-9 levels. For control, serum samples from patients with benign biliary disease and healthy volunteers were also examined. RESULTS: We established a threshold value for RCAS1 of 17.5 U/ml, which permitted discrimination between malignant and non-malignant biliary diseases. In comparison to CA 19-9, serum RCAS1 was more sensitive and specific for malignancy, and was not influenced by cholestasis. RCAS1 levels varied with respect to the disease course and the effect of clinical treatment. CONCLUSIONS: Serum RCAS1 appears to be valuable as a diagnostic index for biliary carcinomas, as well as for evaluating the progression of cancers during therapy. We speculate that RCAS1 is a clinically more significant serum marker for biliary neoplasms than CA19-9.
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Antígenos de Neoplasias/sangre , Neoplasias del Sistema Biliar/diagnóstico , Colangiocarcinoma/diagnóstico , Conductos Biliares Extrahepáticos/patología , Neoplasias del Sistema Biliar/terapia , Biomarcadores de Tumor/sangre , Antígeno CA-19-9/sangre , Colangiocarcinoma/terapia , Ensayo de Inmunoadsorción Enzimática , Fluorouracilo/uso terapéutico , Humanos , Valor Predictivo de las PruebasRESUMEN
The purpose of this study was to analyze computed tomographic (CT) findings of hepatic lesions due to Ascaris suum infection. CT of the liver in three patients, all of whom had immunoserologically confirmed A. suum infection, were retrospectively reviewed. Twenty-five lesions were identified in total. Two radiologists analyzed CT findings in a consensus fashion, with particular interest in the margin, shape, and location of the lesions. Hepatic lesions were ill-defined (22 of 25), small (3-35 mm; average, 11 mm), and nodular (18 of 25) or wedge (three of 25) in shape. Most were located in periportal (16 of 25) or subcapsular (six of 25) regions. Hepatic nodules due to visceral larva migrans of A. suum were located mainly in periportal or subcapsular regions, which may represent periportal eosinophilic granuloma, its pathologic feature. The results were considered to represent the pathophysiology of this entity.
Asunto(s)
Ascariasis/diagnóstico por imagen , Ascaris suum , Larva Migrans Visceral/diagnóstico por imagen , Hígado/diagnóstico por imagen , Tomografía Computarizada por Rayos X , Adulto , Animales , Ascariasis/parasitología , Femenino , Humanos , Larva Migrans Visceral/parasitología , Hígado/parasitología , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
BACKGROUND/AIM: N1,N12-diacetylspermine (DiAcSpm), a diacetylpolyamine which was recently identified in urine, appeared to be a useful tumor marker for urogenital cancers. Here we examined the clinical significance of urinary DiAcSpm as a tumor marker for hepatocellular carcinoma (HCC). METHODS: Urine samples were collected from patients with HCC and benign liver diseases. Urinary levels of DiAcSpm were measured by ELISA, which was newly developed in order to analyze large numbers of samples. RESULTS: The appropriate threshold value was set at 325 nM/g x creatinine. The sensitivity of the DiAcSpm assay for HCC was 65.5% and the specificity calculated between HCC and liver cirrhosis was 76.0%. The percentage of DiAcSpm-positive HCC patients was similar to that for AFP or PIVKA-II. At more advanced clinical stages, the positive percentage of these three markers increased but the DiAcSpm levels appeared to move independently of AFP and PIVKA-II. In HCC patients, the DiAcSpm levels reflected the progression of disease or the effect of treatment. CONCLUSIONS: DiAcSpm levels were found to reflect the severity, activity or viability of HCC. Urinary DiAcSpm can therefore be considered one of the useful indexes for patients with HCC.
Asunto(s)
Carcinoma Hepatocelular/orina , Neoplasias Hepáticas/orina , Espermina/análogos & derivados , Espermina/orina , Biomarcadores/orina , Biomarcadores de Tumor , Creatinina/metabolismo , Ensayo de Inmunoadsorción Enzimática , Reacciones Falso Positivas , Humanos , Hígado/metabolismo , Cirrosis Hepática/orina , Poliaminas/orina , Precursores de Proteínas/orina , Protrombina/orina , Curva ROC , Sensibilidad y Especificidad , Factores de Tiempo , alfa-Fetoproteínas/orinaRESUMEN
A 66-year-old male, whose primary skin lesion in extramammary Paget's disease had been surgically resected 4 years previously, was hospitalized with liver metastases. Hepatic arterial infusion chemotherapy was carried out and the tumours clearly reduced in size. Serum levels of some common tumour markers were not elevated, even prior to therapy. We measured serum levels of a novel tumour-associated antigen, RCAS1, because its expression was detected in the tumour cells. The patient's serum RCAS1 level was elevated (22.0 U/mL) before therapy and fell during (10.5 U/mL) and after (5.0 U/mL) therapy. Therefore, serum RCAS1 levels may be valuable as a potential biomarker for monitoring therapeutic efficacy against Paget's disease.
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Antígenos de Neoplasias/sangre , Biomarcadores de Tumor/sangre , Neoplasias de los Genitales Masculinos/inmunología , Neoplasias Hepáticas/inmunología , Enfermedad de Paget Extramamaria/inmunología , Escroto , Neoplasias Cutáneas/inmunología , Anciano , Neoplasias de los Genitales Masculinos/patología , Humanos , Neoplasias Hepáticas/metabolismo , Masculino , Enfermedad de Paget Extramamaria/metabolismo , Neoplasias Cutáneas/patologíaRESUMEN
Mammalian homologues of DnaJ proteins, also known as Hsp40 proteins, are co-chaperonins that complement Hsp70 chaperone function. Using the yeast two-hybrid system, we cloned an apolipoprotein (apo) B mRNA editing complementation protein, called apobec-1-binding protein-2 (ABBP-2), and found that it is a Class II DnaJ homologue. ABBP-2 binds to apobec-1, the mammalian apoB mRNA editase, via its J domain and neighboring G/F domain. It is a ubiquitously expressed protein, and, by transfection analysis of GFP-ABBP-2, we found that the protein is located in both the nucleus and cytosol of transfected cells, with predominance in the nucleus. Down-regulation of ABBP-2 expression in cultured cells inhibits endogenous apobec-1-mediated apoB mRNA editing. Like other Hsp40 proteins, ABBP-2 binds to Hsp70 and has ATPase-stimulating activity. Apobec-1-mediated apoB mRNA editing activity of in vitro tissue extracts requires the presence of Hsp70/ABBP-2. Although exogenously added ATP is not required for editing activity, removal of the endogenous ATP present in these extracts, which disrupts ABBP-2-Hsp70 interaction, completely inhibits editing. ABBP-2 differs from previously described auxiliary proteins (ABBP-1, ACF, and GRY-RBP) in that it does not contain any RNA recognition motifs. Not only is ABBP-2 required for efficient apoB mRNA editing, this newly discovered apobec-1-binding protein may help determine the subcellular distribution and trafficking of apobec-1 via its interaction with the chaperonin Hsp70.
Asunto(s)
Apolipoproteínas B/genética , Proteínas de Choque Térmico/fisiología , Edición de ARN , ARN Mensajero/metabolismo , Proteínas de Unión al ARN/fisiología , Adenosina Trifosfato/metabolismo , Secuencia de Aminoácidos , Clonación Molecular , Regulación hacia Abajo , Proteínas Fluorescentes Verdes , Proteínas del Choque Térmico HSP40 , Proteínas de Choque Térmico/metabolismo , Ribonucleoproteína Heterogénea-Nuclear Grupo A-B , Hidrólisis , Proteínas Luminiscentes/metabolismo , Chaperonas Moleculares/química , Chaperonas Moleculares/genética , Chaperonas Moleculares/fisiología , Datos de Secuencia Molecular , ARN Mensajero/genética , Proteínas de Unión al ARN/química , Proteínas de Unión al ARN/genética , Proteínas Recombinantes de Fusión/metabolismo , Homología de Secuencia de Aminoácido , Fracciones Subcelulares/metabolismoRESUMEN
We studied the preventive effects of dimethyl sulfoxide (DMSO) on experimental hepatic fibrosis induced by dimethylnitrosamine (DMN) in rats. Treatment with DMN caused a significant decrease in body and liver weight. Oral DMSO (2 ml/kg daily for 4 weeks) essentially prevented this DMN-induced body and liver weight loss with no major side effects. DMSO suppressed the induction of hepatic fibrosis, as determined by histological evaluation, and reduced hepatic hydroxyproline. It also suppressed the expression of mRNA for type I collagen in the liver. Because hepatic stellate cells (HSC) are the major cellular source of the collagen in hepatic fibrosis, we examined the effects of DMSO on collagen production in vitro using rat primary HSC culture. However, it was found that DMSO did not inhibit the collagen production in vitro. We next evaluated the effects of DMSO on tumor necrosis factor alpha (TNFalpha) and nitric oxide (NO) production by Kupffer cells, because these factors represent major activator of HSC, and because monocyte-macrophage infiltration has been implicated as being pathogenetically important for hepatic fibrosis induced by DMN. DMSO inhibited lipopolysaccharide (LPS)-induced TNFalpha and NO production, and reduced TNFalpha mRNA levels. DMSO also suppressed the LPS-induced nuclear factor kappa B activation in a murine macrophage-like cell line. These results suggest that the inhibitory effects of DMSO on hepatic fibrosis may be primarily exerted via blocking of DMN-induced inflammation. These results also implied that DMSO may be potentially useful for preventing the development of hepatic fibrosis.
Asunto(s)
Dimetilsulfóxido/farmacología , Dimetilnitrosamina/administración & dosificación , Depuradores de Radicales Libres/farmacología , Hígado/efectos de los fármacos , Animales , Peso Corporal/efectos de los fármacos , Línea Celular , Células Cultivadas , Enfermedad Hepática Inducida por Sustancias y Drogas , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Fibrosis/inducido químicamente , Fibrosis/prevención & control , Regulación de la Expresión Génica/efectos de los fármacos , Hidroxiprolina/metabolismo , Macrófagos del Hígado/efectos de los fármacos , Macrófagos del Hígado/metabolismo , Lipopolisacáridos/farmacología , Hígado/metabolismo , Hígado/patología , Hepatopatías/patología , Hepatopatías/prevención & control , Luciferasas/genética , Luciferasas/metabolismo , Masculino , FN-kappa B/genética , Óxido Nítrico/metabolismo , Tamaño de los Órganos/efectos de los fármacos , Regiones Promotoras Genéticas/genética , ARN Mensajero/efectos de los fármacos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Índice de Severidad de la Enfermedad , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo , Pérdida de Peso/efectos de los fármacosRESUMEN
BACKGROUND: Primary hepatic carcinoid tumor (PHCT) is a extremely rare. The authors describe a patient with PHCT and review previously published cases of the disease. CASE REPORT: A 75-year-old man, presenting with weight loss and pain in the right upper abdomen, had multiple masses in both lobes of the liver. He was diagnosed as PHCT by radiological examination, laboratory findings with high levels of 5-hydroxyindoleacetic acid (5-HIAA) in the serum and urine, and histological findings including positive staining of tumor cells for Grimelius and chromogranin A. The patient received totally transcatheter arterial chemoembolization (TACE) five times over 27 months; this treatment provided excellent palliation and caused a decrease in urinary 5-HIAA levels. Fifty-three cases of PHCT have been reported in the English-language literature. RESULTS: Analysis of these published cases revealed that PHCT occurs in the middle age (mean age = 48.2 years) and is more frequent in females (males/females = 20/33 cases). Of the symptomatic patients, the major findings is abdominal pain, fullness, and/or a palpable mass (56% of symptomatic patients). In contrast, only 2 cases out of 53 presented with symptoms of typical carcinoid syndrome. In most cases, PHCT was detected as a hypervascular lesion by radiological examination. By histological analysis, 80% and 84% of the cases were positive for Grimelius silver stain and immunohistochemically positive for chromogranin A, respectively. Surgical resection is the treatment primarily recommended with an 18% of recurrence rate and a 74% of a survival rate after 5 years. For unresectable and recurrent cases, TACE may be recommended.
Asunto(s)
Tumor Carcinoide/diagnóstico , Neoplasias Hepáticas/diagnóstico , Anciano , Angiografía , Tumor Carcinoide/irrigación sanguínea , Tumor Carcinoide/diagnóstico por imagen , Humanos , Neoplasias Hepáticas/irrigación sanguínea , Neoplasias Hepáticas/diagnóstico por imagen , Imagen por Resonancia Magnética , Masculino , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: p160ROCK is a direct Rho target which mediates Rho-induced assembly of focal adhesions and stress fibers. We previously reported that Rho signaling pathways are involved in the activation of hepatic stellate cells (HSC) in vitro. The aim of the present study was to test the hypothesis that an inhibitor specific for p160ROCK (Y27632) could prevent experimental hepatic fibrosis induced by dimethylnitrosamine (DMN) in rats. METHODS: Y27632 was given orally at 30 mg/kg daily for 4 weeks after the first injection of DMN. The degree of fibrosis was evaluated by image analysis and also by measurements of collagen and hydroxyproline content in the liver. The expression of alpha-smooth muscle actin (alpha-SMA) in the liver and in the primary cultured HSC was also evaluated. Semi-quantitative RT-PCR was performed to evaluate the expression of type I collagen mRNA in the liver. RESULTS: Y27632 treatment significantly decreased the occurrence of DMN-induced hepatic fibrosis and reduced the collagen and hydroxyproline content and alpha-SMA expression in the liver. The expression of alpha-SMA in HSC was also suppressed in vitro. CONCLUSIONS: These findings indicate that inhibitors of the Rho-ROCK pathway might be useful therapeutically in hepatic fibrosis.
Asunto(s)
Amidas/farmacología , Dimetilnitrosamina , Inhibidores Enzimáticos/farmacología , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/prevención & control , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Piridinas/farmacología , Actinas/antagonistas & inhibidores , Animales , Peso Corporal/efectos de los fármacos , Colágeno/antagonistas & inhibidores , Colágeno/genética , Dimetilnitrosamina/farmacología , Hidroxiprolina/antagonistas & inhibidores , Péptidos y Proteínas de Señalización Intracelular , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Cirrosis Hepática/patología , Masculino , Músculo Liso/metabolismo , Tamaño de los Órganos/efectos de los fármacos , ARN Mensajero/antagonistas & inhibidores , Ratas , Ratas Wistar , Quinasas Asociadas a rhoRESUMEN
1. In the present study, we investigated the preventive effects of pirfenidone (PFD), an antifibrotic agent, on experimental hepatic fibrosis induced by dimethylnitrosamine (DMN) in rats. 2. Treatment with DMN caused a significant decrease in bodyweight and liver weight. Oral PFD (500 mg/kg daily for 4 weeks) essentially prevented this DMN-induced loss in bodyweight and tended to suppress the loss in liver weight. There were no significant differences in liver weight and serum L-alanine aminotransferase levels between PFD-treated and -untreated groups. Pirfenidone has no major side effects in vivo. 3. Pirfenidone suppressed the induction of hepatic fibrosis determined by histological evaluation and reduced hepatic hydroxyproline levels. Expression of mRNA for type I collagen and transforming growth factor-beta in the liver was also suppressed by PFD treatment. 4. Because hepatic stellate cells (HSC) are the major cellular source of extracellular matrix in hepatic fibrosis, we examined the effects of PFD on type I collagen production in vitro using rat primary HSC cultures. Pirfenidone inhibited collagen production in HSC culture in a dose-dependent manner. 5. These results demonstrate that the inhibitory effects of PFD against hepatic fibrosis may be due, at least in part, to blockade of collagen production by HSC and suggest that PFD may be potentially useful in the prevention of the development of hepatic fibrosis.
Asunto(s)
Dimetilnitrosamina , Cirrosis Hepática/prevención & control , Piridonas/farmacología , Animales , Northern Blotting , Peso Corporal/efectos de los fármacos , Colágeno/genética , Colágeno/metabolismo , Hidroxiprolina/metabolismo , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Masculino , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
RCAS1 has been reported as a tumor-associated antigen in uterine and ovarian carcinomas. In vitro studies on RCAS1 indicated that it might function as an apoptosis-inducing factor since binding between RCAS1 and its receptor induced apoptosis in receptor-expressing cells. In this study, 68 surgically resected samples of hepatocellular carcinoma (HCC) were prepared and RCAS1 expression was examined immunohistochemically, because RCAS1 was also positive in all HCC cell lines tested. Clinical and pathological parameters were then compared between RCAS1-positive and -negative HCC cases. As a result, RCAS1 is expressed in 26.5% of HCC cases and vascular invasion is observed at a much higher rate in the RCAS1-positive cases (72.2%) than in RCAS1-negative cases (24.0%). RCAS1 is not an antigen specific for gynecological cancers. In HCC cases, the RCAS1-positive percentage is not high, however, RCAS1-positive HCCs exhibited a trend towards invasive character.