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[PMID]:29377912
[Au] Autor:Robertson MJ; Soibam B; O'Leary JG; Sampaio LC; Taylor DA
[Ad] Endereço:Scientific Stem Cell, Texas Heart Institute, Houston, Texas, United States of America.
[Ti] Título:Recellularization of rat liver: An in vitro model for assessing human drug metabolism and liver biology.
[So] Source:PLoS One;13(1):e0191892, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Liver-like organoids that recapitulate the complex functions of the whole liver by combining cells, scaffolds, and mechanical or chemical cues are becoming important models for studying liver biology and drug metabolism. The advantages of growing cells in three-dimensional constructs include enhanced cell-cell and cell-extracellular matrix interactions and preserved cellular phenotype including, prevention of de-differentiation. In the current study, biomimetic liver constructs were made via perfusion decellularization of rat liver, with the goal of maintaining the native composition and structure of the extracellular matrix. We optimized our decellularization process to produce liver scaffolds in which immunogenic residual DNA was removed but glycosaminoglycans were maintained. When the constructs were recellularized with rat or human liver cells, the cells remained viable, capable of proliferation, and functional for 28 days. Specifically, the cells continued to express cytochrome P450 genes and maintained their ability to metabolize a model drug, midazolam. Microarray analysis showed an upregulation of genes involved in liver regeneration and fibrosis. In conclusion, these liver constructs have the potential to be used as test beds for studying liver biology and drug metabolism.
[Mh] Termos MeSH primário: Fígado/citologia
Modelos Animais
Farmacocinética
[Mh] Termos MeSH secundário: Animais
Reatores Biológicos
Adesão Celular
Proliferação Celular
Meios de Cultura
Matriz Extracelular
Hepatócitos/efeitos dos fármacos
Hepatócitos/metabolismo
Seres Humanos
Técnicas In Vitro
Ratos
Ratos Sprague-Dawley
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Culture Media)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180130
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0191892


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[PMID]:28456663
[Au] Autor:Singh S; Anupriya MG; Sreekumar E
[Ad] Endereço:Molecular Virology Laboratory, Rajiv Gandhi Centre for Biotechnology (RGCB), Thycaud P.O., Thiruvananthapuram 695014, Kerala, India.
[Ti] Título:Comparative whole genome analysis of dengue virus serotype-2 strains differing in trans-endothelial cell leakage induction in vitro.
[So] Source:Infect Genet Evol;52:34-43, 2017 Aug.
[Is] ISSN:1567-7257
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:The role of genetic differences among dengue virus (DENV) in causing increased microvascular permeability is less explored. In the present study, we compared two closely related DENV serotype-2 strains of Cosmopolitan genotype for their in vitro infectivity phenotype and ability to induce trans-endothelial leakage. We found that these laboratory strains differed significantly in infecting human microvascular endothelial cells (HMEC-1) and hepatocytes (Huh7), two major target cells of DENV in in vivo infections. There was a reciprocal correlation in infectivity and vascular leakage induced by these strains, with the less infective strain inducing more trans-endothelial cell leakage in HMEC-1 monolayer upon infection. The cells infected with the strain capable of inducing more permeability were found to secrete more Non-Structural protein (sNS1) into the culture supernatant. A whole genome analysis revealed 37 predicted amino acid changes and changes in the secondary structure of 3' non-translated region between the strains. But none of these changes involved the signal sequence coded by the C-terminal of the Envelope protein and the two glycosylation sites within the NS1 protein critical for its secretion, and the N-terminal NS2A sequence important for surface targeting of NS1. The strain that secreted lower levels of NS1 and caused less leakage had two mutations within the NS1 protein coding region, F103S and T146I that significantly changed amino acid properties. A comparison of the sequences of the two strains with published sequences of various DENV strains known to cause clinically severe dengue identified a number of amino acid changes which could be implicated as possible key genetic differences. Our data supports the earlier observations that the vascular leakage induction potential of DENV strains is linked to the sNS1 levels. The results also indicate that viral genetic determinants, especially the mutations within the NS1 coding region, could affect this critical phenotype of DENV strains.
[Mh] Termos MeSH primário: Vírus da Dengue/fisiologia
Células Endoteliais/virologia
Hepatócitos/virologia
Proteínas não Estruturais Virais/genética
[Mh] Termos MeSH secundário: Regiões 3' não Traduzidas
Animais
Permeabilidade Capilar
Linhagem Celular
Vírus da Dengue/genética
Células Endoteliais/citologia
Variação Genética
Genoma Viral
Hepatócitos/citologia
Seres Humanos
Estrutura Secundária de Proteína
Análise de Sequência de RNA
Proteínas não Estruturais Virais/química
Proteínas não Estruturais Virais/secreção
Replicação Viral/fisiologia
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (3' Untranslated Regions); 0 (NS1 protein, Dengue virus type 2); 0 (Viral Nonstructural Proteins)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170501
[St] Status:MEDLINE


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[PMID]:29441966
[Au] Autor:Zhao H; Meng W; Li Y; Liu W; Fu B; Yang Y; Zhang Q; Chen G
[Ti] Título:The protective effects of CHIR99021 against oxidative injury in LO2 cells.
[So] Source:Pharmazie;71(11):629-635, 2016 11 02.
[Is] ISSN:0031-7144
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Hepatic ischemia-reperfusion injury is one of the most important factors for the prognosis of liver transplantation and hepatic surgery. It was reported that glycogen synthase kinase-3 (GSK-3) regulated injury response during ischemia-reperfusion. In this study, we investigated the protective effects of the GSK-3 inhibitor CHIR99021 against hepatic ischemia-reperfusion injury. A H2O2-induced oxidative injury model using LO2 cells was established. LO2 cells were divided into four groups, including blank control group, CHIR99021 control group treated with CHIR99021 alone, H2O2-injury group treated with H2O2 and protection group treated with H2O2 plus CHIR99021. Cell viability, cell apoptosis or necrosis was determined. Meanwhile, mitochondrial membrane potential, lipid peroxidation, cellular ROS levels, SOD activity, and serum contents of ALS and AST were measured. Protein and mRNA expressions were also detected. The results showed that a cell oxidative injury model was established by treating LO2 cells with 200 µmol/L H2O2 for 6 h. Cells exposed to H2O2 resulted in a significant decrease of cell viability and increase of cell apoptosis, which was accompanied by increasing ROS levels, disruption of mitochondrial membrane potential, excessive lipid peroxidation, reduction of SOD activity, and increased levels of ALT and AST. Treatment with CHIR99021 significantly protected LO2 cells against H2O2-induce oxidative injury by inhibiting the changes of above oxidative injury related indicators. Moreover, CHIR99021 treatment significantly reversed H2O2-induced decrease in p-GSK-3ßSer9 , Bcl-2, Bcl-xl, survivin and ß-catenin expression, whereas it significantly attenuated H2O2-induced increase in caspase-3, cleaved caspase-3 and p-JNK protein expression. In conclusion, CHIR99021 protected LO2 cells against H2O2-induced oxidative injury through reducing GSK-3ß activity and apoptosis, with underlying mechanisms involved in stabilizing mitochondrial membrane potential, attenuating cellular ROS generation, suppressing mitochondria-mediated apoptotic pathway, and activation of GSK-3ß/ß-catenin signaling pathway.
[Mh] Termos MeSH primário: Citoproteção/efeitos dos fármacos
Hepatócitos/efeitos dos fármacos
Estresse Oxidativo/efeitos dos fármacos
Piridinas/farmacologia
Pirimidinas/farmacologia
[Mh] Termos MeSH secundário: Antioxidantes/metabolismo
Apoptose/efeitos dos fármacos
Linhagem Celular
Sobrevivência Celular/efeitos dos fármacos
Doença Hepática Induzida por Substâncias e Drogas/enzimologia
Doença Hepática Induzida por Substâncias e Drogas/patologia
Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle
Quinase 3 da Glicogênio Sintase/biossíntese
Quinase 3 da Glicogênio Sintase/genética
Seres Humanos
Peróxido de Hidrogênio/farmacologia
Potencial da Membrana Mitocondrial/efeitos dos fármacos
Necrose
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antioxidants); 0 (Chir 99021); 0 (Pyridines); 0 (Pyrimidines); BBX060AN9V (Hydrogen Peroxide); EC 2.7.11.26 (Glycogen Synthase Kinase 3)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180215
[St] Status:MEDLINE
[do] DOI:10.1691/ph.2016.6714


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[PMID]:28463419
[Au] Autor:Lin C; Khetani SR
[Ad] Endereço:School of Biomedical Engineering, Colorado State University, Fort Collins, Colorado.
[Ti] Título:Micropatterned Co-Cultures of Human Hepatocytes and Stromal Cells for the Assessment of Drug Clearance and Drug-Drug Interactions.
[So] Source:Curr Protoc Toxicol;72:14.17.1-14.17.23, 2017 May 02.
[Is] ISSN:1934-9262
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Drug clearance rates from the body can determine drug exposure that can affect efficacy or toxicity. Thus, accurate prediction of drug clearance during preclinical development can help guide dose selection in humans, but animal testing is not always predictive of human outcomes. Because hepatic drug metabolism is a rate-limiting step in the overall clearance of many drugs, primary human hepatocytes (PHHs) in suspension cultures or monolayers are used for drug clearance predictions. Yet, the precipitous decline in drug metabolism capacity can lead to significant underestimation of clearance rates, particularly for low turnover compounds that have desirable one-pill-a-day dosing regimens. In contrast, micropatterned co-cultures (MPCCs) of PHHs and fibroblasts display phenotypic stability for several weeks and can help mitigate the limitations of conventional cultures. Here, we describe protocols to create and use MPCCs for drug clearance predictions, and for modeling clinically-relevant drug-drug interactions that can affect drug clearance. © 2017 by John Wiley & Sons, Inc.
[Mh] Termos MeSH primário: Técnicas de Cocultura/métodos
Interações Medicamentosas
Hepatócitos/metabolismo
Preparações Farmacêuticas/metabolismo
Células Estromais/metabolismo
[Mh] Termos MeSH secundário: Células 3T3
Animais
Técnicas de Cultura de Células
Meios de Cultura
Fibroblastos/metabolismo
Hepatócitos/ultraestrutura
Seres Humanos
Taxa de Depuração Metabólica
Camundongos
Fenótipo
Células Estromais/ultraestrutura
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Culture Media); 0 (Pharmaceutical Preparations)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE
[do] DOI:10.1002/cptx.23


  5 / 27390 MEDLINE  
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[PMID]:28463418
[Au] Autor:Liu C; Sekine S; Song B; Ito K
[Ad] Endereço:Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
[Ti] Título:Use of Primary Rat Hepatocytes for Prediction of Drug-Induced Mitochondrial Dysfunction.
[So] Source:Curr Protoc Toxicol;72:14.16.1-14.16.10, 2017 May 02.
[Is] ISSN:1934-9262
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Mitochondrial dysfunction plays a central role in drug-induced liver injury. To evaluate drug-induced mitochondrial impairment, several isolated mitochondria- or cell line-based assays have been reported. Among them, culturing HepG2 cells in galactose provides a remarkable method to assess mitochondrial toxicity by activating mitochondrial aerobic respiration. We applied this assay to primary rat hepatocytes by culturing cells in galactose and hyperoxia to enhance the evaluation of metabolism-related drug-induced mitochondrial toxicity. Conventional culture of primary hepatocytes under high-glucose and hypoxic conditions could force cells to switch energy generation to glycolysis. By contrast, cells cultured in galactose and hyperoxia could maintain energy generation from mitochondrial aerobic respiration, which is consistent with physiological conditions, and consequently improve the susceptibility of cells to mitochondrial toxicants. Measuring the toxicities of test compounds in primary rat hepatocytes cultured in modified conditions provides a useful model to identify mitochondrial dysfunction-mediated drug-induced hepatotoxicity. © 2017 by John Wiley & Sons, Inc.
[Mh] Termos MeSH primário: Hepatócitos/efeitos dos fármacos
Doenças Mitocondriais/induzido quimicamente
Doenças Mitocondriais/patologia
[Mh] Termos MeSH secundário: Animais
Respiração Celular
Doença Hepática Induzida por Substâncias e Drogas
Meios de Cultura
Metabolismo Energético
Previsões
Galactose/metabolismo
Hepatócitos/enzimologia
Hiperóxia/metabolismo
L-Lactato Desidrogenase/análise
Consumo de Oxigênio
Cultura Primária de Células
Ratos
Ratos Sprague-Dawley
Testes de Toxicidade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Culture Media); EC 1.1.1.27 (L-Lactate Dehydrogenase); X2RN3Q8DNE (Galactose)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE
[do] DOI:10.1002/cptx.24


  6 / 27390 MEDLINE  
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[PMID]:28463417
[Au] Autor:Tolosa L; Gómez-Lechón MJ; Donato MT
[Ad] Endereço:Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe (IIS-La Fe), Valencia, Spain.
[Ti] Título:A Multi-Parametric Fluorescent Assay for the Screening and Mechanistic Study of Drug-Induced Steatosis in Liver Cells in Culture.
[So] Source:Curr Protoc Toxicol;72:14.15.1-14.15.11, 2017 May 02.
[Is] ISSN:1934-9262
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Human hepatic cells have been used for drug safety risk evaluations throughout early development phases. They provide rapid, cost-effective early feedback to identify drug candidates with potential hepatotoxicity. This unit presents a cell-based assay to evaluate the risk of liver damage associated with steatogenic drugs. Detailed protocols for cell exposure to test compounds and for the assessment of steatosis-related cell parameters (intracellular lipid content, reactive oxygen species production, mitochondrial impairment, and cell death) are provided. A few representative results that illustrate the utility of this procedure for the screening of drug-induced steatosis are shown. © 2017 by John Wiley & Sons, Inc.
[Mh] Termos MeSH primário: Fígado Gorduroso/induzido quimicamente
Fígado Gorduroso/patologia
Fígado/citologia
[Mh] Termos MeSH secundário: Morte Celular/efeitos dos fármacos
Células Cultivadas
Doença Hepática Induzida por Substâncias e Drogas
Hepatócitos/metabolismo
Seres Humanos
Metabolismo dos Lipídeos/efeitos dos fármacos
Mitocôndrias Hepáticas/efeitos dos fármacos
Espécies Reativas de Oxigênio/metabolismo
Toxicologia/métodos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Reactive Oxygen Species)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE
[do] DOI:10.1002/cptx.20


  7 / 27390 MEDLINE  
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[PMID]:28468836
[Au] Autor:Yoshikado T; Toshimoto K; Nakada T; Ikejiri K; Kusuhara H; Maeda K; Sugiyama Y
[Ad] Endereço:Sugiyama Laboratory, RIKEN Innovation Center, RIKEN, Kanagawa, Japan (T.Y., K.T., Y.S.); DMPK Research Laboratories Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma, Saitama, Japan (T.N.); and Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Univer
[Ti] Título:Comparison of Methods for Estimating Unbound Intracellular-to-Medium Concentration Ratios in Rat and Human Hepatocytes Using Statins.
[So] Source:Drug Metab Dispos;45(7):779-789, 2017 Jul.
[Is] ISSN:1521-009X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:It is essential to estimate concentrations of unbound drugs inside the hepatocytes to predict hepatic clearance, efficacy, and toxicity of the drugs. The present study was undertaken to compare predictability of the unbound hepatocyte-to-medium concentration ratios (K ) by two methods based on the steady-state cell-to-medium total concentration ratios at 37°C and on ice (K ) and based on their initial uptake rates (K ). Poorly metabolized statins were used as test drugs because of their concentrative uptake via organic anion-transporting polypeptides. K values of these statins provided less interexperimental variation than the K values, because only data at longer time are required for K K values for pitavastatin, rosuvastatin, and pravastatin were 1.2- to 5.1-fold K in rat hepatocytes; K values in human hepatocytes also tended to be larger than corresponding K To explain these discrepancies, theoretical values of K and K were compared with true K (K ), considering the inside-negative membrane potential and ionization of the drugs in hepatocytes and medium. Membrane potentials were approximately -30 mV in human hepatocytes at 37°C and almost abolished on ice. Theoretical equations considering the membrane potentials indicate that K values for the statins are 0.85- to 1.2-fold K , whereas K values are 2.2- to 3.1-fold K , depending on the ratio of the passive permeability of the ionized to nonionized forms. In conclusion, K values of anions are similar to K when the inside-negative membrane potential is considered. This suggests that K is preferable for estimating the concentration of unbound drugs inside the hepatocytes.
[Mh] Termos MeSH primário: Hepatócitos/metabolismo
Inibidores de Hidroximetilglutaril-CoA Redutases/metabolismo
[Mh] Termos MeSH secundário: Animais
Transporte Biológico/fisiologia
Seres Humanos
Fígado/metabolismo
Masculino
Potenciais da Membrana/fisiologia
Transportadores de Ânions Orgânicos/metabolismo
Permeabilidade
Pravastatina/metabolismo
Quinolinas/metabolismo
Ratos
Ratos Sprague-Dawley
Rosuvastatina Cálcica/metabolismo
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors); 0 (Organic Anion Transporters); 0 (Quinolines); 83MVU38M7Q (Rosuvastatin Calcium); KXO2KT9N0G (Pravastatin); M5681Q5F9P (pitavastatin)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180307
[Lr] Data última revisão:
180307
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170505
[St] Status:MEDLINE
[do] DOI:10.1124/dmd.116.074823


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[PMID]:28458469
[Au] Autor:Ryu J; Lee JW
[Ad] Endereço:Department of Pharmacy, Research Institute of Pharmaceutical Sciences, Tumor Microenvironment Global Core Research Center, Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
[Ti] Título:TM4SF5-Mediated Roles in the Development of Fibrotic Phenotypes.
[So] Source:Mediators Inflamm;2017:5108525, 2017.
[Is] ISSN:1466-1861
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Transmembrane 4 L six family member 5 (TM4SF5) can form tetraspanin-enriched microdomains (TERMs) on the cell's surface. TERMs contain protein-protein complexes comprised of tetraspanins, growth factor receptors, and integrins. These complexes regulate communication between extracellular and intracellular spaces to control diverse cellular functions. TM4SF5 influences the epithelial-mesenchymal transition (EMT), aberrant multilayer cellular growth, drug resistance, enhanced migration and invasion, circulation through the bloodstream, tumor-initiation property, metastasis, and muscle development in zebrafish. Here, current data on TM4SF5's roles in the development of fibrotic phenotypes are reviewed. TM4SF5 is induced by transforming growth factor 1 (TGF 1) signaling via a collaboration with epidermal growth factor receptor (EGFR) activation. TM4SF5, by itself or in concert with other receptors, transduces signals intracellularly. In hepatocytes, TM4SF5 expression regulates cell cycle progression, migration, and expression of extracellular matrix components. In CCl -treated mice, TM4SF5, -smooth muscle actin ( -SMA), and collagen I expression are observed together along the fibrotic septa regions of the liver. These fibrotic phenotypes are diminished by anti-TM4SF5 reagents, such as a specific small compound [TSAHC, 4'-( -toluenesulfonylamido)-4-hydroxychalcone] or a chimeric antibody. This review discusses the antifibrotic strategies that target TM4SF5 and its associated protein networks that regulate the intracellular signaling necessary for fibrotic functions of hepatocytes.
[Mh] Termos MeSH primário: Fibrose/metabolismo
Proteínas de Membrana/metabolismo
[Mh] Termos MeSH secundário: Actinas/metabolismo
Animais
Fibrose/genética
Hepatócitos/metabolismo
Seres Humanos
Proteínas de Membrana/genética
Camundongos
Receptor do Fator de Crescimento Epidérmico/genética
Receptor do Fator de Crescimento Epidérmico/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Actins); 0 (Membrane Proteins); 0 (TM4SF5 protein, human); EC 2.7.10.1 (Receptor, Epidermal Growth Factor)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180306
[Lr] Data última revisão:
180306
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170502
[St] Status:MEDLINE
[do] DOI:10.1155/2017/5108525


  9 / 27390 MEDLINE  
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[PMID]:28456632
[Au] Autor:Laidlaw SM; Marukian S; Gilmore RH; Cashman SB; Nechyporuk-Zloy V; Rice CM; Dustin LB
[Ad] Endereço:Kennedy Institute of Rheumatology, The University of Oxford, Oxford, United Kingdom; Peter Medawar Building for Pathogen Research, The University of Oxford, Oxford, United Kingdom.
[Ti] Título:Tumor Necrosis Factor Inhibits Spread of Hepatitis C Virus Among Liver Cells, Independent From Interferons.
[So] Source:Gastroenterology;153(2):566-578.e5, 2017 Aug.
[Is] ISSN:1528-0012
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND & AIMS: Tumor necrosis factor (TNF) is an inflammatory cytokine expressed by human fetal liver cells (HFLCs) after infection with cell culture-derived hepatitis C virus (HCV). TNF has been reported to increase entry of HCV pseudoparticles into hepatoma cells and inhibit signaling by interferon alpha (IFNα), but have no effect on HCV-RNA replication. We investigated the effects of TNF on HCV infection of and spread among Huh-7 hepatoma cells and primary HFLCs. METHODS: Human hepatoma (Huh-7 and Huh-7.5) and primary HFLCs were incubated with TNF and/or recombinant IFNA2A, IFNB, IFNL1, and IFNL2 before or during HCV infection. We used 2 fully infectious HCV chimeric viruses of genotype 2A in these studies: J6/JFH (clone 2) and Jc1(p7-nsGluc2A) (Jc1G), which encodes a secreted luciferase reporter. We measured HCV replication, entry, spread, production, and release in hepatoma cells and HFLCs. RESULTS: TNF inhibited completion of the HCV infectious cycle in hepatoma cells and HFLCs in a dose-dependent and time-dependent manner. This inhibition required TNF binding to its receptor. Inhibition was independent of IFNα, IFNß, IFNL1, IFNL2, or Janus kinase signaling via signal transducer and activator of transcription. TNF reduced production of infectious viral particles by Huh-7 and HFLC, and thereby reduced the number of infected cells and focus size. TNF had little effect on HCV replicons and increased entry of HCV pseudoparticles. When cells were incubated with TNF before infection, the subsequent antiviral effects of IFNs were increased. CONCLUSIONS: In a cell culture system, we found TNF to have antiviral effects independently of, as well as in combination with, IFNs. TNF inhibits HCV infection despite increased HCV envelope glycoprotein-mediated infection of liver cells. These findings contradict those from other studies, which have reported that TNF blocks signal transduction in response to IFNs. The destructive inflammatory effects of TNF must be considered along with its antiviral effects.
[Mh] Termos MeSH primário: Antivirais/farmacologia
Hepacivirus/efeitos dos fármacos
Hepatite C/tratamento farmacológico
Interferons/farmacologia
Fator de Necrose Tumoral alfa/farmacologia
[Mh] Termos MeSH secundário: Carcinoma Hepatocelular/virologia
Linhagem Celular Tumoral
Genótipo
Hepacivirus/genética
Hepatócitos/efeitos dos fármacos
Hepatócitos/virologia
Seres Humanos
Janus Quinases/metabolismo
Fígado/citologia
Neoplasias Hepáticas/virologia
Receptores do Fator de Necrose Tumoral/metabolismo
Replicon/efeitos dos fármacos
Transdução de Sinais/efeitos dos fármacos
Fator de Necrose Tumoral alfa/metabolismo
Replicação Viral/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antiviral Agents); 0 (Receptors, Tumor Necrosis Factor); 0 (Tumor Necrosis Factor-alpha); 9008-11-1 (Interferons); EC 2.7.10.2 (Janus Kinases)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:180307
[Lr] Data última revisão:
180307
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170501
[St] Status:MEDLINE


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[PMID]:28460646
[Au] Autor:Markusic DM; Nichols TC; Merricks EP; Palaschak B; Zolotukhin I; Marsic D; Zolotukhin S; Srivastava A; Herzog RW
[Ad] Endereço:Department of Pediatrics, University of Florida, Gainesville, FL, 32610, USA. dmarkusic@ufl.edu.
[Ti] Título:Evaluation of engineered AAV capsids for hepatic factor IX gene transfer in murine and canine models.
[So] Source:J Transl Med;15(1):94, 2017 May 01.
[Is] ISSN:1479-5876
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Adeno-associated virus (AAV) gene therapy vectors have shown the best outcomes in human clinical studies for the treatment of genetic diseases such as hemophilia. However, these pivotal investigations have also identified several challenges. For example, high vector doses are often used for hepatic gene transfer, and cytotoxic T lymphocyte responses against viral capsid may occur. Therefore, achieving therapy at reduced vector doses and other strategies to reduce capsid antigen presentation are desirable. METHODS: We tested several engineered AAV capsids for factor IX (FIX) expression for the treatment of hemophilia B by hepatic gene transfer. These capsids lack potential phosphorylation or ubiquitination sites, or had been generated through molecular evolution. RESULTS: AAV2 capsids lacking either a single lysine residue or 3 tyrosine residues directed substantially higher coagulation FIX expression in mice compared to wild-type sequence or other mutations. In hemophilia B dogs, however, expression from the tyrosine-mutant vector was merely comparable to historical data on AAV2. Evolved AAV2-LiC capsid was highly efficient in hemophilia B mice but lacked efficacy in a hemophilia B dog. CONCLUSIONS: Several alternative strategies for capsid modification improve the in vivo performance of AAV vectors in hepatic gene transfer for correction of hemophilia. However, capsid optimization solely in mouse liver may not predict efficacy in other species and thus is of limited translational utility.
[Mh] Termos MeSH primário: Capsídeo/metabolismo
Dependovirus/genética
Fator IX/genética
Técnicas de Transferência de Genes
Engenharia Genética
[Mh] Termos MeSH secundário: Animais
Cães
Vetores Genéticos/metabolismo
Hemofilia B/genética
Hepatócitos/metabolismo
Fígado/metabolismo
Lisina/genética
Masculino
Camundongos Endogâmicos BALB C
Camundongos Endogâmicos C57BL
Modelos Animais
Mutação/genética
Transdução Genética
Tirosina/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
42HK56048U (Tyrosine); 9001-28-9 (Factor IX); K3Z4F929H6 (Lysine)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE
[do] DOI:10.1186/s12967-017-1200-1



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