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PURPOSE: Administering Oxaliplatin prior to resection of colorectal liver metastases often induces a Sinusoidal Obstruction Syndrome (SOS), which can affect postoperative patient outcome. Bevacizumab (Anti-VEGF-A) can decrease the severity of SOS and the associated risk of postoperative liver failure. We investigated the impact of both Oxaliplatin (Oxali) and Bevacizumab on liver regeneration in a rat model. MATERIAL AND METHODS: Male Wistar rats underwent a 70% partial hepatectomy (PH) 3 days after a 2 ml intraperitoneal injection of either saline (controls, n = 17), or Oxaliplatin 10, 20 or 50 mg/kg, 5-Fluorouracil 100 mg/kg (5-FU) and Bevacizumab 5 or 10 mg/kg in various combinations (total 98 rats, 11 groups, n = 5-18/group). Liver regeneration was assessed by remnant liver weight recovery and cell proliferation by immunodetection of BrDU incorporation (days 1, 2, 3, 7). Hepatic mRNA expression levels of VEGF-A and of its 2 receptors (Flt-1 and KDR) were quantified by PCR technique. RESULTS: Liver regeneration was impaired for 3 days post PH by Oxali 20 alone and Oxali 10 + 5-FU, without any rescue effect by neither Bevacizumab 5 nor 10 mg/kg. Unlike in humans, there were no sinusoidal changes. VEGF-A mRNA expression and receptor 2 (KDR) expressions decreased 24 h post PH in a similar fashion in controls, Oxali 20 and Oxali 10 + 5-FU groups. All groups had recovered over 60% of their liver weight by day 7. CONCLUSION: Oxaliplatin causes early hepatocyte proliferation impairment post PH, unaffected by Bevacizumab and unexplained by changes in VEGF-A signalling in a Wistar rat model.
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Antineoplásicos/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Regeneración Hepática/efectos de los fármacos , Neoplasias Experimentales , Inhibidores de la Angiogénesis/uso terapéutico , Animales , Bevacizumab/uso terapéutico , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/secundario , Quimioterapia Combinada , Masculino , Compuestos Organoplatinos/uso terapéutico , Oxaliplatino , Ratas , Ratas WistarRESUMEN
AIM: Our previous study demonstrated that the endothelial lipase (EL) C.584C>T polymorphism (rs2000813, p.Thr111Ile) was significantly associated with diabetic retinopathy (DR). The present work was conducted to see if this specific variant of the EL gene was more specifically linked to the severity of DR. METHODS: This retrospective cohort study was based on a review of the institutional charts of 287 type 2 diabetes patients (mean age = 59.7 years; mean BMI = 29.0 kg/m(2); mean HbA1c=8.4%) genotyped for the EL C.584C>T polymorphism (rs2000813, p.Thr111Ile). The stage of DR was also determined for each genotype (CC, CT, TT). RESULTS: On univariate analysis, the minor allele homozygote TT variant was significantly associated with severe DR (OR: 4.3; 95% CI: 1.4, 13.1) compared with the major CC homozygote. No significant result was found for the CT heterozygote. Multivariate analysis revealed an increased risk for TT homozygotes to present with severe non-proliferative DR (OR: 8.09; 95% CI: 1.23, 53.1) or proliferative DR. Other associations were not significant. CONCLUSION: Minor allele homozygosity for this EL variant (c.584C>T) could be a significant risk factor for developing severe, sight-threatening disease due to proliferative DR. Further prospective studies of this EL polymorphism in a larger population sample are needed to confirm these results.
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Diabetes Mellitus Tipo 2/genética , Retinopatía Diabética/genética , Lipasa/genética , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Estudios RetrospectivosRESUMEN
Ras activation is a frequent event in human hepatocarcinoma that may contribute to resistance towards apoptosis. Salirasib is a ras and mTOR inhibitor that induces a pro-apoptotic phenotype in human hepatocarcinoma cell lines. In this work, we evaluate whether salirasib sensitizes those cells to TRAIL-induced apoptosis. Cell viability, cell death and apoptosis were evaluated in vitro in HepG2, Hep3B and Huh7 cells treated with DMSO, salirasib and YM155 (a survivin inhibitor), alone or in combination with recombinant TRAIL. Our results show that pretreatment with salirasib sensitized human hepatocarcinoma cell lines, but not normal human hepatocytes, to TRAIL-induced apoptosis. Indeed, FACS analysis showed that 25 (Huh7) to 50 (HepG2 and Hep3B) percent of the cells treated with both drugs were apoptotic. This occurred through activation of the extrinsic and the intrinsic pathways, as evidenced by a marked increase in caspase 3/7 (five to ninefold), caspase 8 (four to sevenfold) and caspase 9 (eight to 12-fold) activities in cells treated with salirasib and TRAIL compared with control. Survivin inhibition had an important role in this process and was sufficient to sensitize hepatocarcinoma cells to apoptosis. Furthermore, TRAIL-induced apoptosis in HCC cells pretreated with salirasib was dependent on activation of death receptor (DR) 5. In conclusion, salirasib sensitizes hepatocarcinoma cells to TRAIL-induced apoptosis by a mechanism involving the DR5 receptor and survivin inhibition. These results in human hepatocarcinoma cell lines and primary hepatocytes provide a rationale for testing the combination of salirasib and TRAIL agonists in human hepatocarcinoma.
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Apoptosis/efectos de los fármacos , Farnesol/análogos & derivados , Proteínas Inhibidoras de la Apoptosis/metabolismo , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Salicilatos/farmacología , Ligando Inductor de Apoptosis Relacionado con TNF/farmacología , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Caspasa 3/metabolismo , Caspasa 7/metabolismo , Caspasa 8/metabolismo , Caspasa 9/metabolismo , Línea Celular Tumoral , Farnesol/farmacología , Células Hep G2 , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Proteínas Inhibidoras de la Apoptosis/antagonistas & inhibidores , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Mitocondrias/metabolismo , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/genética , Proteínas Recombinantes/farmacología , Survivin , Ligando Inductor de Apoptosis Relacionado con TNF/genética , Ligando Inductor de Apoptosis Relacionado con TNF/metabolismoRESUMEN
BACKGROUND: Literature provides compelling evidence for the health benefits of n-3 polyunsaturated fatty acids (PUFA) consumption and low n-6/n-3 ratio, in particular, on inflammation and metabolic syndrome prevention and treatment. Consequently, recommendations were established for adequate n-3 PUFA supplies in the general population. The aim of our study was to evaluate the fatty acid (FA) profile in collective catering in relation to those recommendations. METHODS: We obtained composition of lunches provided by the Township of Lille (France) to children and adults, and of "standard", "low-fat" and "for diabetic" menus from the catering service of St Luc university hospital (Brussels, Belgium). The average proportions of fish, meat, oils, and dairy were used to estimate total, saturated, monounsaturated and polyunsaturated (n-6 and n-3) FA contents. We used official tables of foodstuffs composition provided by the French Agency for Food Safety, the project "Nutritional Composition of Aquatic Products", the French Institute for Nutrition, and the USDA National Nutrient Database for Standard Reference. French guidelines were taken as reference for daily recommended intakes. RESULTS: n-3 PUFA content in lunches provided by municipal catering and in in-hospital menus were slightly below recommended intakes. In the latter, n-3 PUFA enriched margarine contributed for 50% to daily intakes. Despite, the n-6/n-3 ratio was too high, especially in municipal catering (around 20), related to excessive n-6 PUFA supply. CONCLUSIONS: Our results highlight that meeting n-3 PUFA nutritional recommendation remains challenging for collective catering. A detailed analysis of provided menus represents a powerful tool to increase awareness and foster improvement in practice.
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Encuestas sobre Dietas , Ácidos Grasos Omega-3/administración & dosificación , Hospitales , Síndrome Metabólico/dietoterapia , Necesidades Nutricionales , Instituciones Académicas , Adulto , Niño , Preescolar , Conducta Alimentaria , Femenino , Humanos , Masculino , Síndrome Metabólico/prevención & control , Estudios RetrospectivosRESUMEN
Animal models are being used for several decades to study fibrogenesis and to evaluate the anti-fibrotic potential of therapies and strategies. Although immensely valuable for our understanding of pathophysiological processes, they remain models and none of them reproduces a human disease. Each model (meaning stimulus, design, strain and species) displays specific characteristics in the nature of the pathogenesis, the topography and the evolution of fibrosis. We review here the most used as well as some newly described but potentially interesting models including models for studying biliary, immune, alcohol-induced, NASH-associated and viral fibrosis and provide insight on underlying disease processes and practical details. We attempted to delineate the benefits, advantages, limitations and drawbacks of those models. We also report the new opportunities provided by genetically engineered mice for tracking and manipulating cells that participate to fibrosis. Finally, we emphasize the importance of adapting study design to the question addressed.
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Cirrosis Hepática/etiología , Modelos Animales , Animales , Hígado Graso/genética , HumanosRESUMEN
Together with that of obesity, the prevalence of non-alcoholic fatty liver disease is increasing. NAFLD is associated with insulin resistance and participate to the metabolic syndrome. A proportion of NAFLD patient will present a progressive disease characterized by, in addition to steatosis, hepatocellualr damage, chronic inflammation and progressive fibrosis and termed non-alcoholic steatohepatitis (NASH). NAHS is recognized as the hepatic complication of the metabolic syndrome. Its severity is related to fibrosis progression. Pathophysiological mechanisms underlying NASH remain ill-defined, the tools to identify NAFLD patients at risk for NASH progression and validate therapy are lacking. In this review, we concentrate on 2 aspects of NAFLD/NASH pathogenesis: the mechanisms of hepatic insulin resistance and the determinants of fibrosis in the context of metabolic syndrome.
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Hígado Graso , Ácidos Grasos no Esterificados/metabolismo , Hígado Graso/complicaciones , Hígado Graso/epidemiología , Hígado Graso/metabolismo , Hígado Graso/fisiopatología , Humanos , Hiperglucemia/etiología , Hígado/metabolismo , Cirrosis Hepática/etiología , Cirrosis Hepática/metabolismo , Enfermedad del Hígado Graso no Alcohólico , Obesidad/complicaciones , Transaminasas/metabolismo , Triglicéridos/metabolismoRESUMEN
Non-alcoholic fatty liver disease (NAFLD) ranges from steatosis and hepatic insulin resistance to non-alcoholic steatohepatitis (NASH), advanced fibrosis and cirrhosis. NAFLD is now considered as the hepatic manifestation of the metabolic syndrome, and both are triggered by mechanisms including inflammation, lipid overload and oxidative stress in adipose tissue and liver. Despite accumulation of numerous data on NAFLD physiopathology, therapeutic modulation of the pathways involved appear insufficiently efficient or associated with serious adverse effects. The increased prevalence of NAFLD and metabolic syndrome during the last decades was associated with deep modifications of dietary habits, especially increased fat intakes. Recent literature provides clues of increased saturated (SFA) and n-6 polyunsaturated fatty acids (PUFA) as well as reduced n-3 PUFA in the diet of NAFLD and NASH patients. Indeed, strong data support the detrimental role of high SFA and n-6/n-3 ratio as well as low monounsaturated fatty acids (MUFA) and n-3 PUFA on metabolic parameters, which are ameliorated by administration of n-3 PUFA and MUFA. Despite governments and health associations having revised their recommendations for n-3 PUFA intakes upward during the last decade, those are still inferior to levels proved of therapeutic efficiency and are still not reached in the general population. This short review discusses these issues and provides consequent pragmatic suggestions for enhanced dietary measures for prevention of NAFLD and metabolic syndrome in the general population.
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Grasas de la Dieta/administración & dosificación , Ácidos Grasos Monoinsaturados/administración & dosificación , Ácidos Grasos Omega-3/administración & dosificación , Hígado Graso/dietoterapia , Humanos , Enfermedad del Hígado Graso no AlcohólicoRESUMEN
The incidence of obesity worldwide has increased dramatically during recent decades. As a consequence, obesity and associated co-morbidities constitute a serious threat in public health. Substantial epidemiologic evidence indicates that obesity is associated with increased risk of death, and increased incidence and progression of several cancers. Particular attention will be brought here to digestive and liver cancers. Plausible mechanisms by which obesity might participate to increased promotion and progression of cancer will be developed including hyperinsulinemia, insulin resistance and the pro-oxidative pro-inflammatory milieu characterizing the metabolic syndrome. We will focus on the specific case of hepatocellular carcinoma since the highest increase in mortality in obese individuals has been observed for this malignancy. Epidemiological evidence will be reviewed. We will next attempt to offer explanation for the higher risk of HCC in obese individuals although, at this point in time, we have insufficient knowledge to point towards the preeminence of factors directly related to obesity or more tightly linked to NASH itself, the underlying liver disease.
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Carcinoma Hepatocelular/etiología , Neoplasias Hepáticas/etiología , Obesidad/complicaciones , Carcinoma Hepatocelular/fisiopatología , Humanos , Resistencia a la Insulina , Neoplasias Hepáticas/fisiopatología , Obesidad/fisiopatología , Factores de RiesgoRESUMEN
BACKGROUND: Aberrant activation of oncogenes, such as Ras, likely contributes to the development of hepatocarcinoma (HCC). AIMS/METHODS: We evaluated in vivo the effect of intraperitoneal injections of the Ras inhibitor S-trans, trans-farnesylthiosalicyclic acid (FTS) on Ras activation and the development of preneoplastic liver lesions in rats receiving weekly diethylnitrosamine (DEN) injections for 16weeks. Western blotting, quantitative PCR, immunohistochemistry, Tunel and caspase activity assays were used. RESULTS: FTS prevents liver nodule formation and reduces foci expressing the tumour marker GSTp. FTS abrogates DEN-induced Ras membrane activity, increases Tunel positive cells in transformed, GSTp-expressing hepatocytes, up-regulates caspase 3 and 8 activity, induces Fas, Fas ligand and JNK phosphorylation that occurs independently of TNFalpha and Trail. Cytochrome C release, Bax, Bcl2, Bcl-xl, Ki67 and nuclear cyclin D expression is not affected by FTS. CONCLUSIONS: FTS inhibits Ras activation and prevents preneoplastic liver nodule development by inducing apoptosis in transformed hepatocytes through activation of the Fas/Fas ligand system. FTS might be new molecule for HCC treatment.
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Antineoplásicos/uso terapéutico , Farnesol/análogos & derivados , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Genes ras , Hepatocitos/patología , Salicilatos/uso terapéutico , Animales , Apoptosis/efectos de los fármacos , Biomarcadores/análisis , Western Blotting/métodos , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/prevención & control , Caspasa 3/análisis , Caspasa 8/análisis , Dietilnitrosamina , Farnesol/uso terapéutico , Hepatocitos/efectos de los fármacos , Inmunohistoquímica , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/prevención & control , Masculino , Modelos Animales , Ratas , Ratas WistarRESUMEN
We report the case of a patient who exhibited severe acute hepatitis with symptomatic cholestasis for more than 3 months and bile duct injury following the prescription of atorvastatin. After withdrawal the drug, the patient's wellbeing slowly improves and biological features normalize in 4 months. Therapy aimed at treating severe liver steatosis and hypercholesterolemia. Atorvastatin is a highly effective 3-hydroxy-3 methylglutamyl- coenzyme A reductase (statin) used to lower low-density lipoprotein. Reported frequent adverse events of the medication include nausea, depression, myalgia, abdominal pain and abnormal liver function tests. Although abnormal liver function tests is not an uncommon side effect of the medication, more serious liver injury is rare. In a recent literature review, about ten cases of serious hepatotoxicity have been documented. In the typical presentation, the duration of exposure prior to hepatic toxicity is variable. Liver injury is generally of the mixed type. A prolonged cholestasis for more than 3 months has been seldom reported. Morphological changes includes canalicular cholestasis, feathery degeneration but no cholangiolitis nor cholangitis under the form of cytological and inflammatory changes at the level of interlobular bile ducts. This case report provides further evidence that among statins, atorvastatin may be implicated in drug-induced liver injury and indicates for the first time that such liver injury may be followed by prolonged cholestasis and interlobular bile duct injury. Atorvastatin has thus to be added to the list of medication potentially responsible for bile duct injury.
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Anticolesterolemiantes/efectos adversos , Conductos Biliares/efectos de los fármacos , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Colestasis/inducido químicamente , Ácidos Heptanoicos/efectos adversos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Pirroles/efectos adversos , Enfermedad Aguda , Atorvastatina , Humanos , Masculino , Persona de Mediana EdadRESUMEN
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Hepatocellular carcinoma (HCC) is increasing worldwide and is the fifth main cause of cancer-related death. HCC develops on a preneoplastic organ, the cirrhotic liver. Therefore, chemoprevention could play a role in the therapy of HCC. We evaluated the preventive effects of pioglitazone, a peroxisome proliferator-activated receptor gamma agonist, on the induction of early carcinogenic events. We monitored pre-neoplastic foci induced by a two-stage initiation/promotion model of hepatocarcinogenesis in rats, using diethylnitrosamine and acetylaminofluorene. Pioglitazone treatment was initiated the day after the first diethylnitrosamine injection. By quantitative morphometry and Western blot, we showed that pioglitazone significantly decreases the size of pre-neoplastic foci. Analysis of proliferation and apoptosis, assessed by immunohistochemistry, demonstrated decreased proliferation but no effect on cell death in rats treated with pioglitazone. These events were associated with an increased expression of the cyclin-dependent kinase inhibitor p27(kip1), compared to the non treated group. In conclusion, pioglitazone inhibits early carcinogenic transformation in a two-step rat model. As pioglitazone has a low toxicity profile, we believe it would be interesting to evaluate its effect in chemoprevention of HCC in humans in a clinical setting.
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Anticarcinógenos/uso terapéutico , Carcinoma Hepatocelular/prevención & control , Neoplasias Hepáticas/prevención & control , PPAR gamma/antagonistas & inhibidores , Tiazolidinedionas/uso terapéutico , 2-Acetilaminofluoreno/toxicidad , Animales , Apoptosis , Western Blotting , Carcinógenos/toxicidad , Proliferación Celular/efectos de los fármacos , Quimioprevención , Dietilnitrosamina/toxicidad , Inmunohistoquímica , Antígeno Ki-67 , Masculino , Pioglitazona , Ratas , Ratas WistarRESUMEN
AIM: Peroxisome proliferator activated receptor gamma (PPARgamma) agonists have been shown to prevent hepatic fibrosis in rodents. We evaluated the therapeutic antifibrotic potential of the PPARgamma agonist pioglitazone on established hepatic fibrosis. METHODS: Repeated injections of carbon tetrachloride (CCl4), a choline deficient diet, or bile duct ligation (BDL) were used to induce hepatic fibrosis in rats. Pioglitazone treatment was introduced at various time points. Therapeutic efficacy was assessed by comparison of the severity of hepatic fibrosis in pioglitazone treated versus untreated fibrotic controls. RESULTS: When introduced after two weeks of CCl4, pioglitazone reduced hepatic fibrosis, OH proline content, hepatic mRNA expression of collagen type I, and profibrotic genes, as well as the number of activated alpha smooth muscle actin positive hepatic stellate cells, compared with rats receiving CCl4 only, with no significant change in necroinflammation. When pioglitazone treatment was initiated after five weeks of CCl4, no antifibrotic effect was observed. Similarly, pioglitazone was associated with a reduced severity of fibrosis induced by a choline deficient diet when introduced early, while delayed treatment with pioglitazone remained ineffective. In contrast, pioglitazone failed to interrupt progression of fibrosis due to BDL, irrespective of the timing of its administration. CONCLUSION: In rats, the therapeutic antifibrotic efficacy of pioglitazone is limited and dependent on the type of injury, duration of disease, and/or the severity of fibrosis at the time of initiation of treatment.
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Hipoglucemiantes/uso terapéutico , Cirrosis Hepática Experimental/tratamiento farmacológico , Tiazolidinedionas/uso terapéutico , Animales , Conductos Biliares/patología , Tetracloruro de Carbono , Colina/administración & dosificación , Colágeno Tipo I/genética , Progresión de la Enfermedad , Ligadura , Cirrosis Hepática Experimental/inducido químicamente , Cirrosis Hepática Experimental/patología , Masculino , Pioglitazona , ARN Mensajero/análisis , Ratas , Ratas Sprague-Dawley , Factores de Tiempo , Resultado del TratamientoRESUMEN
UNLABELLED: Hypervitaminosis A-related liver toxicity may be severe and may even lead to cirrhosis. In the normal liver, vitamin A is stored in hepatic stellate cells (HSC), which are prone to becoming activated and acquiring a myofibroblast-like phenotype, producing large amounts of extracellular matrix. AIMS: In order to assess the relationship between vitamin A intake, HSC activation and fibrosis, we studied nine liver biopsies from patients belonging to a well-characterized series of 41 patients with vitamin A hepatotoxicity. METHODS: Fibrosis was underlined by Sirius-red staining, whereas activated HSC were immunohistochemically identified using an antibody against alpha smooth muscle actin. The volume density (Vv) of sinusoidal and total fibrosis and of sinusoidal and total activated HSC was quantified by the point-counting method. RESULTS: Morphology ranged from HSC hypertrophy and hyperplasia as the sole features to severe architectural distortion. There was a significant positive correlation between Vv of perisinusoidal fibrosis and the daily consumption of vitamin A (P=0.004). CONCLUSION: The close correlation between the severity of perisinusoidal fibrosis and the daily dose of the retinol intake suggests the existence of a dose-effect relationship.