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Toll-like receptor 4 polymorphisms and bacterial infections in patients with cirrhosis and ascites

World Journal of Hepatology 2018年第1期10卷 124-133页

作者： Edilmar Alvarado-Tapias Carlos Guarner-Argente Elida Oblitas Elisabet Sánchez Silvia Vidal eva román Mar Concepción Maria Poca Cristina Gely Oana Pavel Juan Camilo nieto Cándido Juárez Carlos Guarner Germán Soriano Department of Gastroenterology Hospital de la Santa Creu i Sant PauBarcelona 08025Spain Instituto de Salud Carlos III Institut de Recerca IIBSant PauUniversitat Autònoma de BarcelonaBellaterra(Cerdanyola del Vallès)08193Spain Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas(CIBERehd) Instituto de Salud Carlos IIIMadrid 28029Spain Department of Immunology Hospital de la Santa Creu i Sant PauBarcelona 08025Spain Escola Universitària d’Infermeria EUI-Sant Pau Hospital de la Santa Creu i Sant PauBarcelona 08025Spain

AIM To assess the relationship between the presence of toll-like receptor 4(TLR4) polymorphisms and bacterial infections in cirrhotic patients with ascites. METHODS We prospectively included consecutive patients with cirrhosis and ascites hospitalized during a 6-year period. Patients with human immunodeficiency virus(HIV) infection or any other immunodeficiency, patients with advanced hepatocellular carcinoma(beyond Milan's criteria) or any other condition determining poor short-term prognosis, and patients with a permanent urinary catheter were excluded. The presence of D299 G and/or T399 I TLR4 polymorphisms was determined by sequencing and related to the incidence and probability of bacterial infections, other complications of cirrhosis, hepatocellular carcinoma, and mortality during follow-up. A multivariate analysis to identify predictive variables of mortality in the whole series was performed. RESULTS We included 258 patients: 28(10.8%) were carriers of D299G and/or T399I TLR4 polymorphisms(polymorphism group) and 230 patients were not(wildtype group). The probability of developing any bacterial infection at one-year follow-up was 78% in the polymorphism group and 69% in the wild-type group(P = 0.54). The one-year probability of presenting infections caused by gram-negative bacilli(51% vs 44%, P = 0.68), infections caused by gram-positive cocci(49% vs 40%, P = 0.53), and spontaneous bacterial peritonitis(29% vs 34%, respectively, P = 0.99) did not differ between the two groups. The oneyear probability of transplant-free survival was 55% in the polymorphism group and 66% in the wild-type group(P = 0.15). Multivariate analysis confirmed that age, Child-Pugh score, active alcohol intake, previous hepatic encephalopathy, hepatocellular carcinoma and serum creatinine were associated with a higher risk of death during follow-up. COnCLUSIOn Genetic polymorphisms D299 G and/or T399 I of TLR4 do not seem to play a relevant role in the predisposition of cirrhotic patients with ascites to bacterial infections.

关键词： Cirrhosis Genetic polymorphisms Toll-like receptor 4 Bacterial infections Ascites

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Cytokine production in patients with cirrhosis and TLR4 polymorphisms

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World Journal of Gastroenterology 2014年第46期20卷 17516-17524页

作者： Juan Camilo nieto Elisabet Sánchez eva román Silvia Vidal Laia Oliva Carlos Guarner-Argente Maria Poca Xavier Torras Cándido Juárez Carlos Guarner German Soriano Department of Immunology Institut de Recerca-IIB Sant PauUniversitat Autònoma de Barcelona08025 BarcelonaSpain Department of Gastroenterology Hospital de la Santa Creu i Sant Pau08025 BarcelonaSpain Department of Gastroenterology Instituto de Salud Carlos Ⅲ Institut de Recerca-IIB Sant PauUniversitat Autònoma de Barcelona08025 BarcelonaSpain Department of Gastroenterology Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas08025 BarcelonaSpain Instituto de Salud Carlos Ⅲ Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas08025 BarcelonaSpain Department of Gastroenterology Escola Universitària d’Infermeria Sant Pau08025 BarcelonaSpain Department of Gastroenterology Universitat Autònoma de Barcelona08025 BarcelonaSpain

AIM:To analyze the cytokine production by peripheral blood cells from cirrhotic patients with and without TLR4 D299G and/or T399I polymorphisms.METHODS:The study included nine patients with cirrhosis and TLR4 D299G and/or T399I polymorphisms,and 10 wild-type patients matched for age,sex and degree of liver failure.TLR4 polymorphisms were determined by sequence-based genotyping.Cytokine production by peripheral blood cells was assessed spontaneously and also after lipopolysaccharide(LPS)and lipoteichoic acid(LTA)stimulation.RESULTS:Patients with TLR4 polymorphisms had a higher incidence of previous hepatic encephalopathy than wild-type patients(78%vs 20%,P=0.02).Spontaneous production of interleukin(IL)-6 and IL-10 was lower in patients with TLR4 polymorphisms than in wild-type patients[IL-6:888.7(172.0-2119.3)pg/m L vs 5540.4(1159.2-26053.9)pg/m L,Pn of tumor necrosis factor-α,IL-6 and IL-10 after LPS and LTA stimulation was similar in the two groups.COnCLUSIOn:TLR4 polymorphisms were associated with a distinctive pattern of cytokine production in cirrhotic patients,suggesting that they play a role in the development of cirrhosis complications.

关键词： Inflammatory response Hepatic encephalopathy Genet

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Preclinical evaluation of azathioprine plus buthionine sulfoximine in the treatment of human hepatocarcinoma and colon carcinoma

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World Journal of Gastroenterology 2011年第34期17卷 3899-3911页

作者： Borja Hernández-Breijo Jorge Monserrat Sara Ramírez-Rubio eva P Cuevas Diana Vara Inés Díaz-Laviada M Dolores Fernández-Moreno Irene D román Javier P Gisbert Luis G Guijarro Molecular Hepatic Toxicology Unit Biochemistry and Molecular Biology Department University of Alcalá Networked Biomedical Research Center of Hepatic and Digestive Diseases (CIBEREHD) Medicine Department University of Alcalá neuroendocrinology of Cannabinoid/Vanilloid System Unit Biochemistry and Molecular Biology Department University of Alcalá Gastroenterology Unit Hospital de la Princesa Institute of Health Research Princesa Networked Biomedical Research Center of Hepatic and Digestive Diseases (CIBEREHD)

AIM: To evaluate the efficacy and the safety of azathioprine (AZA) and buthionine sulfoximine (BSO) bylocalized application into HepG2 tumor in vivo.METHODS: Different hepatoma and colon carcinoma cell lines (HepG2, HuH7, Chang liver, LoVo, RKO, SW-48, SW-480) were grown in minimal essencial medium supplemented with 10% fetal bovine serum and 1% antibiotic/antimycotic solution and maintained in a humidified 37 ℃ incubator with 5% CO2. These cells were pretreated with BSO for 24 h and then with AZA for different times. We examined the effects of this combination on some proteins and on cellular death. We also studied the eff icacy and the safety of AZA (6 mg/kg per day) and BSO (90 mg/kg per day) in HepG2 tumor growth in vivo using athymic mice. We measured safety by serological markers such as aminotransferases and creatine kinase.RESULTS: The in vitro studies revealed a new mechanism of action for the AZA plus BSO combination in the cancer cells compared with other thiopurines (6-mercaptopurine, 6-methylmercaptopurine, 6-thioguanine and 6-methylthioguanine) in combination with BSO. The cytotoxic effect of AZA plus BSO in HepG2 cells resulted from necroptosis induction in a mitochondrial-dependent manner. From kinetic studies we suggest that glutathione (GSH) depletion stimulates c-Jun amino-terminal kinase and Bax translocation in HepG2 cells with subsequent deregulation of mitochondria (cytochrome c release, loss of membrane potential), and proteolysis activation leading to loss of membrane integrity, release of lactate dehydrogenase and DnA degradation. Some of this biochemical and cellular changes could be reversed by n-acetylcysteine (a GSH replenisher). In vivo studies showed that HepG2 tumor growth was inhibited when AZA was combined with BSO.COnCLUSIOn: Our studies suggest that a combination of AZA plus BSO could be useful for localizedtreatment of hepatocellular carcinoma as in the currently used transarterial chemoembolization method.

关键词：硫唑嘌呤结肠癌肝癌 HepG2细胞评价亚砜肿瘤生长临床

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