Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 799
Filtrar
1.
Life Sci ; 238: 116976, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31634464

RESUMO

AIM: The purpose of the present study was to elucidate the protective effect of histone deacetylase 6 inhibitor ACY1215 on autophagy pathway in acute liver failure (ALF). MAIN METHODS: Lipopolysaccharide (LPS) and d-galactosamine (D-Gal) were used to induce ALF model in C57BL/6 mice. D-Gal and tumor necrosis factor alpha (TNF-α) were applied in L02 cell. Autophagy inhibitor 3-MA and ACY1215 were conducted to induce 3-MA group, ACY1215 group and ACY1215+3-MA group. RESULTS: ACY1215 improved liver histological and functional changes in ALF mice model, whereas the autophagy inhibitor 3-MA aggravated liver tissue pathological and functional damage in ALF mice model group. The apoptotic levels (including apoptotic index/rate and apoptotic proteins) in ALF mice and L02 cell were ameliorated with treatment ACY1215. 3-MA accentuated the apoptotic levels in ACY1215 group. D-Gal/TNF-α could reduce L02 cell mitochondrial membrane potential (ΔΨm) in control group. ACY1215 increased the ΔΨm in ALF model. 3-MA also further reduced the ΔΨm in ACY1215 group. ACY1215 could induce autophagy in ALF mice and cell model group accompanied with an increase in expression of LC3-II and beclin-1 proteins and down-regulation of p62 protein. Moreover, the expression of LC3-II and beclin1 proteins were greatly reduced and the expression of p62 protein was ascended after intervention with 3-MA in ACY1215 group. SIGNIFICANCE: Histone deacetylase 6 inhibitor ACY1215 could protect acute liver failure mice and L02 cell by inhibiting apoptosis pathway through enhancing autophagy way.


Assuntos
Autofagia , Desacetilase 6 de Histona/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Falência Hepática Aguda/prevenção & controle , Substâncias Protetoras/farmacologia , Pirimidinas/farmacologia , Animais , Apoptose , Autofagia/efeitos dos fármacos , Células Cultivadas , Citocinas/metabolismo , Modelos Animais de Doenças , Lipopolissacarídeos/toxicidade , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/metabolismo , Falência Hepática Aguda/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais
3.
Jpn J Infect Dis ; 72(5): 347-349, 2019 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-31155601

RESUMO

An 84-year-old man with chronic renal failure, anemia, and diabetes was admitted for hemodialysis initiation. His vital signs were stable until the eighteenth hospital day, before acquiring an influenza A virus infection. Three days later, he died of septic shock with severe liver impairment. His leukocyte count, prothrombin time (PT-INR), and liver enzyme levels such as aspartate transaminase and alanine aminotransferase, were significantly increased. Hypercytokinemia was also observed. Autopsy revealed bilateral diffuse pneumonia with neutrophil infiltration. The liver showed extensive centrilobular hepatocyte necrosis. Immunohistochemistry for influenza A nucleoprotein revealed positivity in the ciliated columnar epithelium of the bronchi and negativity in the trachea, lungs, and liver. Hypoxic hepatitis is characterized by an abrupt and massive increase in aminotransferase levels (> 20 times upper normal limit) due to anoxic centrilobular hepatocyte necrosis. The occurrence of hypoxic hepatitis requires a pre-existing, chronic condition, such as anemia, causing reduced oxygen supply to the liver, followed by an acute decrease in hepatic oxygen supply, such as septic shock. Therefore, this report suggests that hypoxic hepatitis can be an important causative factor for acute liver failure associated with influenza virus infection.


Assuntos
Influenza Humana/complicações , Falência Hepática Aguda/diagnóstico , Falência Hepática Aguda/patologia , Choque Séptico/diagnóstico , Choque Séptico/patologia , Idoso de 80 Anos ou mais , Anemia/complicações , Autopsia , Complicações do Diabetes , Evolução Fatal , Humanos , Vírus da Influenza A , Falência Renal Crônica/complicações , Masculino , Choque Séptico/complicações
4.
Int J Mol Med ; 44(1): 335-345, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31059066

RESUMO

A newly synthesized ruthenium metal complex, TQ­5, exhibited antithrombotic and antiplatelet effects in our previous study. In the present study, the anti­inflammatory/hepatoprotective effects and mechanisms of action of TQ­5 were investigated in lipopolysaccharide (LPS)­induced RAW 264.7 macrophages in vitro and in acute liver injury in mice in vivo. The results demonstrated that TQ­5 suppressed the LPS­induced production of nitric oxide, tumor necrosis factor­α (TNF­α), interleukin­1ß (IL­1ß) and inducible nitric oxide synthase (iNOS), without inducing cytotoxicity or damaging the morphology of the RAW 264.7 macrophages. In addition, the role of TQ­5 in mediating mitogen­activated protein kinases and nuclear factor κB (NF­κB) pathways involved in the inflammation process of LPS­stimulated RAW264.7 cells was investigated. Although TQ­5 did not alter the phosphorylation of extracellular signal­related kinase, p38 or c­Jun N­terminal kinase in LPS­treated cells, it suppressed the phosphorylation of Akt in a concentration­dependent manner. TQ­5 significantly reversed the LPS­induced degradation of inhibitor of NF­κBα and phosphorylation of p65. The mRNA expression levels of iNOS, TNF­α and IL­1ß were also suppressed by TQ­5. TQ­5 improved LPS­induced liver injury in mice by inhibiting the expression of TNF­α, IL­1ß and iNOS and phosphorylation of NF­κBp65. These findings suggest that Akt/NF­κB signaling may be a promising target for TQ­5 to combat LPS­induced inflammation. Therefore, TQ­5 may act as a potential agent for the development of anti­inflammatory drugs to treat acute liver failure.


Assuntos
Complexos de Coordenação , Regulação para Baixo/efeitos dos fármacos , Lipopolissacarídeos/toxicidade , Falência Hepática Aguda , Macrófagos/metabolismo , NF-kappa B/metabolismo , Rutênio , Transdução de Sinais/efeitos dos fármacos , Animais , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/tratamento farmacológico , Falência Hepática Aguda/metabolismo , Falência Hepática Aguda/patologia , Macrófagos/patologia , Masculino , Camundongos , Células RAW 264.7 , Rutênio/química , Rutênio/farmacologia
5.
Mol Biol Rep ; 46(3): 3101-3112, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30977085

RESUMO

Chronic overuse of common pharmaceuticals, e.g. acetaminophen (paracetamol), often leads to the development of acute liver failure (ALF). This study aimed to elucidate the effect of cultured mesenchymal stem cells (MSCs) proteome on the onset of liver damage and regeneration dynamics in animals with ALF induced by acetaminophen, to test the liver protective efficacy of MSCs proteome depending on the oxygen tension in cell culture, and to blueprint protein components responsible for the effect. Protein compositions prepared from MSCs cultured in mild hypoxic (5% and 10% O2) and normal (21% O2) conditions were used to treat ALF induced in mice by injection of acetaminophen. To test the effect of reduced oxygen tension in cell culture on resulting MSCs proteome content we applied a combination of high performance liquid chromatography and mass-spectrometry (LC-MS/MS) for the identification of proteins in lysates of MSCs cultured at different O2 levels. The treatment of acetaminophen-administered animals with proteins released from cultured MSCs resulted in the inhibition of inflammatory reactions in damaged liver; the area of hepatocyte necrosis being reduced in the first 24 h. Compositions obtained from MSCs cultured at lower O2 level were shown to be more potent than a composition prepared from normoxic cells. A comparative characterization of protein pattern and identification of individual components done by a cytokine assay and proteomics analysis of protein compositions revealed that even moderate hypoxia produces discrete changes in the expression of various subsets of proteins responsible for intracellular respiration and cell signaling. The application of proteins prepared from MSCs grown in vitro at reduced oxygen tension significantly accelerates healing process in damaged liver tissue. The proteomics data obtained for different preparations offer new information about the potential candidates in the MSCs protein repertoire sensitive to oxygen tension in culture medium, which can be involved in the generalized mechanisms the cells use to respond to acute liver failure.


Assuntos
Acetaminofen/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/terapia , Meios de Cultivo Condicionados/metabolismo , Falência Hepática Aguda/etiologia , Falência Hepática Aguda/terapia , Células-Tronco Mesenquimais/metabolismo , Proteoma , Animais , Biomarcadores , Biópsia , Células Cultivadas , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Meios de Cultivo Condicionados/farmacologia , Citocinas/metabolismo , Modelos Animais de Doenças , Hipóxia/metabolismo , Falência Hepática Aguda/patologia , Masculino , Espectrometria de Massas , Células-Tronco Mesenquimais/citologia , Camundongos , Consumo de Oxigênio , Substâncias Protetoras/metabolismo , Substâncias Protetoras/farmacologia , Proteômica/métodos
6.
J Neuroinflammation ; 16(1): 69, 2019 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-30940161

RESUMO

BACKGROUND: Acute liver failure resulting from drug-induced liver injury can lead to the development of neurological complications called hepatic encephalopathy (HE). Hepatic transforming growth factor beta 1 (TGFß1) is upregulated due to liver failure in mice and inhibiting circulating TGFß reduced HE progression. However, the specific contributions of TGFß1 on brain cell populations and neuroinflammation during HE are not known. Therefore, the aim of this study was to characterize hepatic and brain TGFß1 signaling during acute liver failure and its contribution to HE progression using a combination of pharmacological and genetic approaches. METHODS: C57Bl/6 or neuron-specific transforming growth factor beta receptor 2 (TGFßR2) null mice (TGFßR2ΔNeu) were treated with azoxymethane (AOM) to induce acute liver failure and HE. The activity of circulating TGFß1 was inhibited in C57Bl/6 mice via injection of a neutralizing antibody against TGFß1 (anti-TGFß1) prior to AOM injection. In all mouse treatment groups, liver damage, neuroinflammation, and neurological deficits were assessed. Inflammatory signaling between neurons and microglia were investigated in in vitro studies through the use of pharmacological inhibitors of TGFß1 signaling in HT-22 and EOC-20 cells. RESULTS: TGFß1 was expressed and upregulated in the liver following AOM injection. Pharmacological inhibition of TGFß1 after AOM injection attenuated neurological decline, microglia activation, and neuroinflammation with no significant changes in liver damage. TGFßR2ΔNeu mice administered AOM showed no effect on liver pathology but significantly reduced neurological decline compared to control mice. Microglia activation and neuroinflammation were attenuated in mice with pharmacological inhibition of TGFß1 or in TGFßR2ΔNeu mice. TGFß1 increased chemokine ligand 2 (CCL2) and decreased C-X3-C motif ligand 1 (CX3CL1) expression in HT-22 cells and reduced interleukin-1 beta (IL-1ß) expression, tumor necrosis factor alpha (TNFα) expression, and phagocytosis activity in EOC-20 cells. CONCLUSION: Increased circulating TGFß1 following acute liver failure results in activation of neuronal TGFßR2 signaling, driving neuroinflammation and neurological decline during AOM-induced HE.


Assuntos
Córtex Cerebral/patologia , Encefalopatia Hepática/etiologia , Falência Hepática Aguda/complicações , Falência Hepática Aguda/patologia , Neurônios/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo II/deficiência , Fator de Crescimento Transformador beta1/sangue , Animais , Anticorpos/uso terapêutico , Azoximetano/toxicidade , Benzamidas/farmacologia , Carcinógenos/toxicidade , Linhagem Celular Transformada , Modelos Animais de Doenças , Encefalopatia Hepática/tratamento farmacológico , Inflamação/tratamento farmacológico , Inflamação/etiologia , Isoquinolinas/farmacologia , Fígado/metabolismo , Fígado/patologia , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Fagocitose/efeitos dos fármacos , Fagocitose/genética , Pirazóis/farmacologia , Piridinas/farmacologia , Pirróis/farmacologia , Receptor do Fator de Crescimento Transformador beta Tipo II/genética , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/imunologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
7.
Int Immunopharmacol ; 72: 348-357, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31030090

RESUMO

Atractylodin (ACD) possesses versatile biological and pharmacological activities, including antibacterial, anti-inflammatory and hepatoprotective properties. However, the protective effects of ACD on lipopolysaccharide (LPS) and d-galactosamine (GalN)-induced acute liver failure (ALF) as well as the underlying molecular mechanisms remain unclear. In this study, our findings showed that ACD treatment could reduce the high lethality rate; decrease the serum levels of alanine transaminase (ALT), aspartate aminotransferase (AST), monocyte chemoattractant protein (MCP)-1, interleukin-1ß (IL-1ß), IL-6 and tumor necrosis factor-α (TNF-α), and ameliorate the pathological hepatic damage of ALF. Furthermore, ACD pretreatment inhibited toll like receptor 4 (TLR4), nuclear factor kappa B (NF-κB), the mitogen-activated protein kinase (MAPK) and NOD-like receptor protein-3 (NLRP3) activation pathway. Moreover, our research showed that ACD could dramatically increase superoxide dismutase (SOD) and glutathione (GSH) production, and reduce COX-2, inducible nitric oxide synthase (iNOS), reactive oxygen species (ROS) and malondialdehyde (MDA) production through upregulating the expression of the anti-oxidative enzymes heme oxygenase-1 (HO-1) and quinone (NQO1), which were related to the induction of nuclear transcription factor 2 (Nrf2) nuclear translocation. These results indicated that ACD exhibited anti-inflammatory activity, which was associated with the inhibition of inflammatory mediator production via the downregulation of the NLRP3 inflammasome and TLR4-NF-κB/-MAPK signaling pathways, and the antioxidative effects of ACD were connected with GSH and SOD activation through upregulation of the Nrf2-mediated signaling pathways.


Assuntos
Anti-Inflamatórios/uso terapêutico , Furanos/uso terapêutico , Falência Hepática Aguda/tratamento farmacológico , Animais , Anti-Inflamatórios/farmacologia , Citocinas/metabolismo , Furanos/farmacologia , Galactosamina , Lipopolissacarídeos , Fígado/efeitos dos fármacos , Fígado/patologia , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/metabolismo , Falência Hepática Aguda/patologia , Masculino , Camundongos Endogâmicos C57BL , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo
8.
Int J Mol Sci ; 20(8)2019 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-31013780

RESUMO

Hepatocyte growth factor (HGF) is an endogenously expressed bioactive substance that has a strong anti-apoptotic effect. In this study, we biochemically and histologically characterized the effects of rh-HGF on in vitro human hepatocyte injury and mouse acute liver failure (ALF) models, both of which were induced by antibody-mediated Fas signaling. rh-HGF inhibited intracellular caspase-3/7 activation and cytokeratin 18 (CK-18) fragment release in both models. Histologically, rh-HGF dramatically suppressed parenchymal damage and intrahepatic hemorrhage. Among the laboratory parameters, prothrombin time (PT) was strongly preserved by rh-HGF, and PT was well correlated with the degree of intrahepatic hemorrhage. These results showed that the anti-apoptotic effect of rh-HGF on hepatocytes coincided strikingly with the suppression of intrahepatic hemorrhage. PT was considered to be the best parameter that correlated with the intrahepatic hemorrhages associated with hepatocellular damage. The action of rh-HGF might derive not only from its anti-apoptosis effects on liver parenchymal cells but also from its stabilization of structural and vasculature integrity.


Assuntos
Apoptose/efeitos dos fármacos , Coagulação Sanguínea/efeitos dos fármacos , Hemorragia/metabolismo , Fator de Crescimento de Hepatócito/farmacologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatopatias/metabolismo , Proteínas Recombinantes/farmacologia , Animais , Células Cultivadas , Modelos Animais de Doenças , Hemorragia/tratamento farmacológico , Hemorragia/etiologia , Humanos , Concentração Inibidora 50 , Hepatopatias/tratamento farmacológico , Hepatopatias/etiologia , Hepatopatias/patologia , Falência Hepática Aguda/sangue , Falência Hepática Aguda/tratamento farmacológico , Falência Hepática Aguda/etiologia , Falência Hepática Aguda/patologia , Masculino , Camundongos , Tempo de Protrombina , Receptor fas/metabolismo
9.
Autops. Case Rep ; 9(2): e2019089, Abr.-Jun. 2019. ilus, tab
Artigo em Inglês | LILACS | ID: biblio-1015106

RESUMO

Liver metastases are commonly found in advanced cancer patients; however, acute liver failure secondary to diffuse liver infiltration is rare. Small cell lung carcinoma accounts for 15% of lung carcinomas. We describe the ninth case of small cell lung carcinoma massively metastatic to the liver, reported in the scientific literature, with sudden clinical onset and death after a few days. An autopsy was performed to understand the cause of death.


Assuntos
Humanos , Masculino , Idoso , Carcinoma de Pequenas Células do Pulmão/patologia , Neoplasias Pulmonares/patologia , Autopsia , Falência Hepática Aguda/patologia , Hepatomegalia , Metástase Neoplásica
10.
Eur J Pharmacol ; 854: 338-346, 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-30902658

RESUMO

In clinic, there is still no drug that can significantly improve the survival rate of patients with acute liver failure (ALF). We have confirmed that recombinant human IL-1 receptor antagonist (rhIL-1Ra) significantly improves the survival rate of acetaminophen (APAP)-induced ALF mice by reducing hepatocellular apoptosis. Here, we investigated the mechanism of this and the key target cells of rhIL-1Ra. In vivo, APAP-induced ALF mice were treated with rhIL-1Ra and gadolinium chloride (Gdcl3), respectively. Survival rates of mice, serum IL-1Ra and IL-1ß levels, IL-1 receptor type I (IL-1RI) and CD163 expression in the livers, and the phagocytic activities of Kupffer cells (KCs) were investigated. Additionally, the proliferation of hepatocytes and KCs in co-culture conditions with the serum of ALF mice were investigated in vitro. In this study, a large number of activated large KCs were found in liver lobe region III. Both GdCl3 and rhIL-1Ra significantly decreased the quantity of large KCs. In all of the mice, hepatocytes and liver non-parenchymal cells other than KCs expressed low levels of IL-1RI, whereas large KCs expressed high levels of IL-1RI. The high ratio of endogenous IL-1Ra/IL-1ß was related to rhIL-1Ra function. Additionally, the phagocytic activities of KCs were significantly inhibited by GdCl3 and rhIL-1Ra. In vitro, the proliferation of hepatocytes in co-culture conditions were significantly inhibited by KCs. In conclusion, large KCs were the key target cells of rhIL-1Ra, and rhIL-1Ra could play its role of reducing hepatocellular apoptosis mainly by inhibiting the activities of KCs.


Assuntos
Apoptose/efeitos dos fármacos , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Macrófagos do Fígado/efeitos dos fármacos , Macrófagos do Fígado/patologia , Falência Hepática Aguda/tratamento farmacológico , Falência Hepática Aguda/patologia , Proteínas Recombinantes/farmacologia , Animais , Proliferação de Células/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Interleucina-1beta/metabolismo , Macrófagos do Fígado/metabolismo , Falência Hepática Aguda/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fagocitose/efeitos dos fármacos , Proteínas Recombinantes/uso terapêutico , Análise de Sobrevida
11.
Biologicals ; 58: 64-72, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30824230

RESUMO

This study investigated the correlation between the hepatic level of miR-122 and the extent of liver tissue regeneration in CCl4 induced liver injury mice model following transplantation of menstrual blood-(MenSCs) and bone marrow-derived stem cells (BMSCs). Hepatic miR-122 levels were significantly up-regulated following administration of CCl4 (P < 0.01). The significant positive correlations were observed between hepatic miR-122 and biochemical serum markers and the severity of liver injury in histopathological assessments (P < 0.01). Following stem cell therapy, all cell treated groups showed a significant down-regulation in miR-122 that was significantly correlated with improvement in histopathological features and biochemical markers (P < 0.01). Furthermore, the hepatic level of miR-122 was lower in the MenSCs-treated group compared with the BMSCs-treated group (P < 0.01) and in HPL cells-treated groups in reference to undifferentiated cells-treated groups (P < 0.05). These data suggest that miR-122 could be used as a potential predictor of outcome of liver injury after mesenchymal stem cell transplantation.


Assuntos
Regulação para Baixo , Falência Hepática Aguda , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/metabolismo , MicroRNAs/biossíntese , Adulto , Animais , Modelos Animais de Doenças , Feminino , Xenoenxertos , Humanos , Falência Hepática Aguda/metabolismo , Falência Hepática Aguda/patologia , Falência Hepática Aguda/terapia , Camundongos , Camundongos Endogâmicos BALB C
12.
Methods Mol Biol ; 1951: 189-207, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30825154

RESUMO

The NLRP3 inflammasome is a cellular sensor of danger signals such as extracellular ATP or abnormally accumulating molecules like crystals. Activation of NLRP3 by such compounds triggers a sterile inflammatory response that may be involved in numerous pathologies including rheumatoid arthritis, atherosclerosis, diabetes, and Alzheimer's disease. A better understanding of the mechanisms that govern NLRP3 inflammasome activation is an important step toward the development of novel therapeutic strategies to dampen over-activation of the immune system. Recent findings demonstrate that ligand-activated nuclear receptors regulate the NLRP3 inflammasome pathway, thus representing possible therapeutic targets. It is therefore important to assess the potential of these putative targets in the regulation of the NLRP3 inflammasome activation in the most appropriate pathophysiological models. Fulminant hepatitis (FH) results from massive hepatocyte apoptosis, hemorrhagic necrosis, and inflammation. Low doses of LPS in combination with the specific hepatotoxic agent D-galactosamine (D-GalN) promote liver injury in mice and induce the production of inflammatory cytokines associated with increased NLRP3 protein and caspase 1 activity, thus recapitulating the clinical picture of FH in humans. We provide a simple method to examine the involvement of nuclear receptors in NLRP3-driven fulminant hepatitis, consisting in the induction of FH, in the isolation of liver macrophages, and in the extraction and analysis of RNA content.


Assuntos
Hepatite/etiologia , Hepatite/metabolismo , Inflamassomos/metabolismo , Falência Hepática Aguda/etiologia , Falência Hepática Aguda/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Animais , Galactosamina/efeitos adversos , Expressão Gênica , Hepatite/patologia , Humanos , Macrófagos do Fígado/imunologia , Macrófagos do Fígado/metabolismo , Lipopolissacarídeos/efeitos adversos , Falência Hepática Aguda/patologia , Camundongos , Transdução de Sinais
13.
Drug Des Devel Ther ; 13: 589-600, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30809090

RESUMO

Objectives: Jie-Du-Hua-Yu (JDHY) granule is a combination of six traditional Chinese medicines with known therapeutic effect in treating acute liver failure (ALF). The aim of this study was to investigate the amelioration efficacy of JDHY in lipopolysaccharide/D-galactosamine (LPS/D-GalN)-induced ALF in rat and explore the possible molecular mechanism underlying the therapeutic efficacy. Materials and methods: The efficacy of JDHY was determined by assessing hepatic pathology and function in LPS and D-GalN challenged Wistar rat. We also evaluated the effect of JDHY on LPS-induced Kupffer cells by measuring inflammatory cytokines and determining the phenotypic function. By means of bioinformatics analysis of liver tissue and validation in Kupffer cells, we identified possible pathways involved in the pharmacologic action of mechanism of JDHY. Results: JDHY could attenuate LPS-induced liver injury in rat by inhibiting apoptosis and increasing hepatic activity. In vitro study showed that JDHY could decrease the production of proinflammatory cytokines (tumor necrosis factor-α, IL6, and interferon-γ), increase anti-inflammatory cytokines (IL10, IL13), and promote cell survival and proliferation, possibly due to inhibition of IκB/nuclear factor-κB (NF-κB) signaling pathway and expression of CD14 and CXCL2, which was consistent with the findings from bioinformatics analysis. Conclusion: Our results revealed that JDHY protected against LPS-induced liver damage both in vitro and in vivo, by inhibiting the NF-κB-mediated inflammatory pathway, indicating its potential function to treat liver diseases.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Falência Hepática Aguda/prevenção & controle , Medicina Tradicional Chinesa , Animais , Proliferação de Células/efeitos dos fármacos , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/isolamento & purificação , Galactosamina/farmacologia , Lipopolissacarídeos/farmacologia , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/patologia , Masculino , Ratos , Ratos Wistar
14.
Eur J Pharmacol ; 850: 150-157, 2019 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-30772394

RESUMO

The farnesoid X receptor (FXR) is a ligand-activated transcription factor that regulates genes involved in bile acid metabolism. Accumulating data demonstrate that FXR has an anti-inflammatory activity. The present study aimed to investigate the effect of obeticholic acid (OCA), a novel synthetic FXR agonist, on D-galactosamine (GalN)/lipopolysaccharide (LPS)-evoked acute liver injury. All mice except controls were intraperitoneally injected with GalN (300 mg/kg) plus LPS (2.5 µg/kg). Some mice were pretreated with OCA (10 mg/kg) 48, 24 and 1 h before GalN/LPS. As expected, pretreatment with OCA alleviated hepatocyte apoptosis at early and middle stages of GalN/LPS-induced acute liver failure. By contrast, pretreatment with OCA augmented hepatic injury and inflammatory cell infiltration at middle stage of GalN/LPS-induced acute liver failure. Additional experiment found that OCA inhibited hepatic NF-κB activation at early and middle stages of GalN/LPS-induced acute liver failure. Interestingly, OCA inhibited hepatic proinflammatory cytokine tnf-α and il-6 but upregulated hepatic anti-inflammatory cytokine il-10 at early stage of GalN/LPS-induced acute liver failure. By contrast, OCA suppressed hepatic anti-inflammatory cytokine tgf-ß and il-10 at middle stage of GalN/LPS-induced acute liver injury. These results suggest that FXR agonist OCA differentially regulates hepatic injury and inflammation at different stages of GalN/LPS-evoked acute liver failure.


Assuntos
Ácido Quenodesoxicólico/análogos & derivados , Galactosamina/farmacologia , Lipopolissacarídeos/farmacologia , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/tratamento farmacológico , Fígado/efeitos dos fármacos , Animais , Morte Celular/efeitos dos fármacos , Ácido Quenodesoxicólico/farmacologia , Ácido Quenodesoxicólico/uso terapêutico , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/tratamento farmacológico , Fígado/metabolismo , Fígado/patologia , Falência Hepática Aguda/genética , Falência Hepática Aguda/patologia , Camundongos , NF-kappa B/metabolismo
15.
Phytother Res ; 33(4): 1055-1064, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30701601

RESUMO

Tectorigenin has received attention due to its antiproliferation, anti-inflammatory, and antioxidant activities. In this study, we investigated the effects of tectorigenin on lipopolysaccharide (LPS)/D-galactosamine(D-GalN)-induced fulminant hepatic failure (FHF) in mice and LPS-stimulated macrophages (RAW 264.7 cells). Pretreatment with tectorigenin significantly reduced the serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), histological injury, apoptosis, and the mortality of FHF mice, by suppressing the production of inflammatory cytokines such as TNF-α and IL-6. Tectorigenin also suppressed the activation of the inflammatory response in LPS-stimulated RAW 264.7 cells. Tectorigenin-induced protection is mediated through its mitigation of TLR4 expression, inhibition of mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) pathway activation, and promotion of autophagy in FHF mice and LPS-stimulated RAW 264.7 cells. Therefore, tectorigenin has therapeutic potential for FHF in mice via the regulation of TLR4/MAPK and TLR4/NF-κB pathways and autophagy.


Assuntos
Autofagia/efeitos dos fármacos , Isoflavonas/farmacologia , Falência Hepática Aguda/prevenção & controle , Substâncias Protetoras/farmacologia , Receptor 4 Toll-Like/metabolismo , Animais , Apoptose/efeitos dos fármacos , Células Cultivadas , Humanos , Lipopolissacarídeos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Falência Hepática Aguda/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos
16.
Immunopharmacol Immunotoxicol ; 41(2): 192-198, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30721100

RESUMO

Context: Tamoxifen (TAM) ameliorates D-galactosamine/lipopolysaccharide (Gal/LPS)-induced acute liver failure (ALF) through its antioxidative effect; thus, this study was designed to determine whether the effectiveness of TAM is related to nuclear factor-κB (NF-κB) reactivation. Materials and methods: Experimental mice were injected with TAM once daily for 3 consecutive days intraperitoneally (i.p). Twelve hours after pretreatment, Gal/LPS was given to mice (i.p) for ALF induction. In the positive control group, N-acetylcysteine (NAC) was administered immediately after ALF establishment. Except for survival observation, other animals were sacrificed 7 h after Gal/LPS treatment. Survival and hepatic failure were evaluated. For the oxidation assessment, the reduced/oxidized glutathione (GSH/GSSG) ratio and hepatic superoxide dismutase (SOD) activity were analyzed using both colorimetry and Western blotting. Lastly, hepatic NF-κB activation was measured through Western blot analysis of p65 and IκBα. Results: The results indicated that pretreatment with TAM dramatically attenuated Gal/LPS-induced ALF, as demonstrated by improved survival (70%), decreased transaminase levels, and reversed histopathological manifestation. In addition, the hepatic GSH/GSSG ratio and SOD activity were decreased in the ALF model. However, to some degree, TAM and NAC effectively prevented this undesirable phenomenon in contrast to the ALF model. Western blotting revealed that compared with mice in the ALF model group, mice treated with TAM or NAC showed reactivation of hepatic NF-κB. Conclusions: Taking the results together with those of other studies, we conclude that TAM may attenuate Gal/LPS-induced ALF by antagonizing oxidative stress through NF-κB reactivation.


Assuntos
Galactosamina/toxicidade , Lipopolissacarídeos/toxicidade , Falência Hepática Aguda , Fígado/metabolismo , NF-kappa B/metabolismo , Tamoxifeno/farmacologia , Animais , Modelos Animais de Doenças , Fígado/patologia , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/tratamento farmacológico , Falência Hepática Aguda/metabolismo , Falência Hepática Aguda/patologia , Camundongos , Camundongos Endogâmicos BALB C
17.
Cell Commun Signal ; 17(1): 2, 2019 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-30630510

RESUMO

BACKGROUND: Acetaminophen (APAP) overdose-induced acute liver failure (ALF) is mainly resulted from uncontrolled oxidative stress. Nuclear factor-erythroid 2-related factor 2 (Nrf2), a key antioxidant transcription factor, is essential for alleviating APAP-induced hepatotoxicity. Corilagin (Cori) is a natural polyphenol compound that possesses effective antioxidant activity; however, the protective effect of Cori on APAP-induced hepatotoxicity is still unknown. The current study aimed to explore whether Cori could mitigate hepatotoxicity caused by APAP and the underlying molecular mechanisms of action. METHODS: Cell counting kit-8 (CCK-8) assays, Western blotting analysis, dual-luciferase reporter assays, a mouse model, CRISPR/Cas9 knockout technology, and hematoxylin-eosin (H & E) staining were employed to explore the mechanisms by which Cori exerts a protective effect on hepatotoxicity in HepG2 cells and in a mouse model. RESULTS: Our findings suggested that Cori efficiently decreased APAP-triggered the generation of reactive oxygen species (ROS) and cell death in HepG2 cells. Additionally, Cori significantly induced the expression of several antioxidant enzymes, and this induced expression was closely linked to the upregulation of Nrf2, inhibition of Keap1 protein expression, and promotion of antioxidant response element (ARE) activity in HepG2 cells. Moreover, Cori clearly induced the phosphorylation of AMP-activated protein kinase (AMPK), glycogen synthase kinase-3ß (GSK3ß), liver kinase B1 (LKB1) and acetyl-CoA carboxylase (ACC). Furthermore, Cori-mediated GSK3ß inactivation, Nrf2 upregulation and cytoprotection were abolished by an AMPK inhibitor (Compound C) in HepG2 cells. Lastly, we found that Cori inhibited APAP-induced hepatotoxicity and mediated the expression of many antioxidant enzymes; these results were reversed in Nrf2 -/- HepG2 cells. In vivo, Cori significantly protected against APAP-induced ALF by reducing mortality and alanine transaminase (ALT) and aspartate aminotransferase (AST) levels, attenuating histopathological liver changes, inhibiting myeloperoxidase (MPO) and malondialdehyde (MDA) levels, and increasing the superoxide dismutase (SOD) content and GSH-to-GSSG ratio as well as suppressing c-jun N-terminal kinase (JNK) phosphorylation. However, Cori-induced reductions in mortality, AST and ALT levels, and histopathological liver changes induced by APAP were clearly abrogated in Nrf2-deficienct mice. CONCLUSIONS: These findings principally indicated that Cori effectively protects against APAP-induced ALF via the upregulation of the AMPK/GSK3ß-Nrf2 signaling pathway.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Acetaminofen/efeitos adversos , Glucosídeos/farmacologia , Glicogênio Sintase Quinase 3 beta/metabolismo , Taninos Hidrolisáveis/farmacologia , Fígado/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Transdução de Sinais , Animais , Elementos de Resposta Antioxidante/genética , Morte Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glucosídeos/química , Células Hep G2 , Humanos , Taninos Hidrolisáveis/química , Fígado/efeitos dos fármacos , Fígado/lesões , Falência Hepática Aguda/tratamento farmacológico , Falência Hepática Aguda/patologia , Masculino , Camundongos Endogâmicos C57BL , Modelos Biológicos , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Substâncias Protetoras/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
18.
Gut ; 68(6): 1076-1087, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30670575

RESUMO

OBJECTIVE: Uncertainty about acute liver failure (ALF) pathogenesis limits therapy. We postulate that ALF results from excessive reactivation of a fetal liver programme that is induced in hepatocytes when acutely injured livers regenerate. To evaluate this hypothesis, we focused on two molecules with known oncofetal properties in the liver, Yes-associated protein-1 (YAP1) and Insulin-like growth factor-2 RNA-binding protein-3 (IGF2BP3). DESIGN: We compared normal liver with explanted livers of patients with ALF to determine if YAP1 and IGF2BP3 were induced; assessed whether these factors are upregulated when murine livers regenerate; determined if YAP1 and IGF2BP3 cooperate to activate the fetal programme in adult hepatocytes; and identified upstream signals that control these factors and thereby hepatocyte maturity during recovery from liver injury. RESULTS: Livers of patients with ALF were massively enriched with hepatocytes expressing IGF2BP3, YAP1 and other fetal markers. Less extensive, transient accumulation of similar fetal-like cells that were proliferative and capable of anchorage-independent growth occurred in mouse livers that were regenerating after acute injury. Fetal reprogramming of hepatocytes was YAP1-dependent and involved YAP1-driven reciprocal modulation of let7 microRNAs and IGF2BP3, factors that negatively regulate each other to control fate decisions in fetal cells. Directly manipulating IGF2BP3 expression controlled the fetal-like phenotype regardless of YAP1 activity, proving that IGF2BP3 is the proximal mediator of this YAP1-directed fate. CONCLUSION: After acute liver injury, hepatocytes are reprogrammed to fetal-like cells by a YAP1-dependent mechanism that differentially regulates let7 and IGF2BP3, identifying novel therapeutic targets for ALF.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Hepatócitos/metabolismo , Falência Hepática Aguda/metabolismo , Falência Hepática Aguda/patologia , Regeneração Hepática/genética , Fosfoproteínas/genética , Ubiquitina-Proteína Ligases/metabolismo , Análise de Variância , Animais , Biomarcadores/sangue , Estudos de Casos e Controles , Células Cultivadas , Hepatócitos/citologia , Humanos , Regeneração Hepática/fisiologia , Masculino , Camundongos , MicroRNAs/metabolismo , Reação em Cadeia da Polimerase em Tempo Real/métodos , Valores de Referência , Fatores de Transcrição , Regulação para Cima
19.
Int Immunopharmacol ; 68: 171-178, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30641432

RESUMO

Acute liver failure (ALF) is a distinct clinical syndrome with high mortality and characterized by metabolic derangements, neurological complication, and multiple failures. Flavonoids exert great biological properties on anti-oxidation, anti-inflammation, and anti-apoptosis. After lipopolysaccharide (LPS)/d-galactosamine (d-GalN) administration, five flavonoids inhibited oxidative activities with reducing nitric oxide synthase (iNOS), malondialdehyde (MDA), and improving catalase (CAT), superoxide dismutase (SOD), total antioxidant capacity (T-AOC), nuclear factor erythroid-derived 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). They reduced the serum levels of alanine and aspartate aminotransferase (ALT, AST) and pro-inflammatory cytokines, prevented the phosphorylation of IKK, IκBα, and NF-κB/p65 in the NF-κB signaling pathway. Additionally five flavonoids inhibited hepatocyte apoptosis through increasing Bcl-2/Bax ratio and suppressing the Caspase family proteins. Chrysin, luteolin, apigenin, hesperetin and 3', 4'-dimethoxy hesperetin have apparently hepato-protective effects against ALF induced by LPS/d-GalN. The study found, the C2C3 double bond at A ring, and the hydroxyl group of C3' or C4' at B ring increased the protective activities, however, the effect of hydroxymethylation at C3' and C4' was reversed. In addition, apigenin has good hepatoprotective effects and potential as a promising therapeutic agent for ALF in clinical application.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Flavonoides/uso terapêutico , Falência Hepática Aguda/tratamento farmacológico , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Flavonoides/química , Flavonoides/farmacologia , Galactosamina , Lipopolissacarídeos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/metabolismo , Falência Hepática Aguda/patologia , Masculino , Camundongos , NF-kappa B/metabolismo , Relação Estrutura-Atividade
20.
J Surg Res ; 236: 172-183, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30694753

RESUMO

BACKGROUND: Acute liver failure (ALF) from severe acute liver injury is a critical condition associated with high mortality. The purpose of this study was to investigate the impact of preemptive administration of γ-aminobutyric acid (GABA) on hepatic injury and survival outcomes in mice with experimentally induced ALF. MATERIALS AND METHODS: To induce ALF, C57BL/6NHsd mice were administered GABA, saline, or nothing for 7 d, followed by intraperitoneal administration of 500 µg of tumor necrosis factor α and 20 mg of D-galactosamine. The study mice were humanely euthanized 4-5 h after ALF was induced or observed for survival. Proteins present in the blood samples and liver tissue from the euthanized mice were analyzed using Western blot and immunohistochemical and histopathologic analyses. For inhibition studies, we administered the STAT3-specific inhibitor, NSC74859, 90 min before ALF induction. RESULTS: We found that GABA-treated mice had substantial attenuation of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive hepatocytes and hepatocellular necrosis, decreased caspase-3, H2AX, and p38 MAPK protein levels and increased expressions of Jak2, STAT3, Bcl-2, and Mn-SOD, with improved mitochondrial integrity. The reduced apoptotic proteins led to a significantly prolonged survival after ALF induction in GABA-treated mice. The STAT3-specific inhibitor NSC74859 eliminated the survival advantage in GABA-treated mice with ALF, indicating the involvement of the STAT3 pathway in GABA-induced reduction in apoptosis. CONCLUSIONS: Our results showed that preemptive treatment with GABA protected against severe acute liver injury in mice via GABA-mediated STAT3 signaling. Preemptive administration of GABA may be a useful approach to optimize marginal donor livers before transplantation.


Assuntos
Falência Hepática Aguda/prevenção & controle , Fígado/efeitos dos fármacos , Substâncias Protetoras/administração & dosagem , Ácido gama-Aminobutírico/administração & dosagem , Ácidos Aminossalicílicos/administração & dosagem , Animais , Benzenossulfonatos/administração & dosagem , Modelos Animais de Doenças , Galactosamina/toxicidade , Humanos , Injeções Intraperitoneais , Fígado/patologia , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Necrose/induzido quimicamente , Necrose/patologia , Necrose/prevenção & controle , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Resultado do Tratamento , Fator de Necrose Tumoral alfa/toxicidade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA