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1.
World J Gastroenterol ; 25(16): 1950-1963, 2019 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-31086463

RESUMO

BACKGROUND: Chronic hepatitis B is a highly heterogeneous disease that can be divided into four phases: Immune tolerant (IT), immune active (IA), inactive carrier (IC) and hepatitis B envelope antigen (HBeAg)-negative hepatitis (ENEG). AIM: To investigate the immune status of natural killer (NK) and T cells in different phases of chronic hepatitis B. METHODS: The frequency, phenotype and function of circulating NK cells, as well as nonantigen-specific and hepatitis B virus (HBV)-specific T cell responses were detected by flow cytometry in healthy and HBV-infected subjects. RESULTS: The ability of NK cells to produce IFN-γ was markedly attenuated in HBV-infected patients overall but was less compromised in IC patients. Patients in the IT and IA phases also displayed significantly lower TNF-α production compared to healthy subjects. NK cells were phenotypically activated in the IA and ENEG phases, as evidenced by the upregulation of NKp44 in CD56bright NK cells and CD69 in CD56dim NK cells. Furthermore, global T-cells from the ENEG phase displayed a proinflammatory cytokine profile with upregulated IFN-γ and TNF-α expression, while this profile was suppressed in IT and IA patients. Finally, core and S antigen-specific T cell responses were significantly stronger after in vitro expansion in the IC phase compared to other phases. CONCLUSION: Our findings demonstrate the changes in immune response pattern during the natural history of HBV infection. Both NK and T cells are functionally impaired in the IT and IA phases. With the spontaneous clearance of HBeAg and hepatitis B surface antigen decline, NK cell cytokine production and HBV-specific T responses are partially restored in IC phase, and the ENEG phase is dominated by nonantigen-specific T cell responses.

2.
J Viral Hepat ; 26(10): 1146-1155, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31087479

RESUMO

Hepatitis B virus (HBV) infection continues to be a major public health issue worldwide. HBsAg loss is associated with functional remission and improved long-term outcome, and is considered to be a 'functional cure' (also referred to as clinical or immunologic cure) for chronic hepatitis B. This ideal goal of therapy can be achieved using optimized combination regimens with direct-acting antivirals [eg nucleos(t)ide analogues (NAs)] and immunomodulators [eg pegylated interferon alpha2a (Peg-IFN)] in selected patients with chronic hepatitis B. Among different combination therapies currently available, those with NA lead-in followed by Peg-IFN in virally suppressed patients has been demonstrated to be effective. This review provides an updated overview of the evidence supporting the use of combination therapies and summarizes expert consensus on the roadmap to attain functional cure for chronic hepatitis B patients.

3.
World J Gastroenterol ; 24(21): 2300-2310, 2018 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-29881239

RESUMO

AIM: To evaluate the differences in acute kidney injury (AKI) between acute-on-chronic liver failure (ACLF) and decompensated cirrhosis (DC) patients. METHODS: During the period from December 2015 to July 2017, 280 patients with hepatitis B virus (HBV)-related ACLF (HBV-ACLF) and 132 patients with HBV-related DC (HBV-DC) who were admitted to our center were recruited consecutively into an observational study. Urine specimens were collected from all subjects and the levels of five urinary tubular injury biomarkers were detected,including neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), liver-type fatty acid binding protein (L-FABP), cystatin C (CysC), and kidney injury molecule-1 (KIM-1). Simultaneously, the patient demographics, occurrence and progression of AKI, and response to terlipressin therapy were recorded. All patients were followed up for 3 mo or until death after enrollment. RESULTS: AKI occurred in 71 and 28 of HBV-ACLF and HBV-DC patients, respectively (25.4% vs 21.2%, P = 0.358). Among all patients, the levels of four urinary biomarkers (NGAL, CysC, L-FABP, IL-18) were significantly elevated in patients with HBV-ACLF and AKI (ACLF-AKI), compared with that in patients with HBV-DC and AKI (DC-AKI) or those without AKI. There was a higher proportion of patients with AKI progression in ACLF-AKI patients than in DC-AKI patients (49.3% vs 17.9%, P = 0.013). Forty-three patients with ACLF-AKI and 19 patients with DC-AKI were treated with terlipressin. The response rate of ACLF-AKI patients was significantly lower than that of patients with DC-AKI (32.6% vs 57.9%, P = 0.018). Furthermore, patients with ACLF-AKI had the lowest 90 d survival rates among all groups (P < 0.001). CONCLUSION: AKI in ACLF patients is more likely associated with structural kidney injury, and is more progressive, with a poorer response to terlipressin treatment and a worse prognosis than that in DC patients.


Assuntos
Lesão Renal Aguda/etiologia , Insuficiência Hepática Crônica Agudizada/complicações , Cirrose Hepática/complicações , Lipressina/análogos & derivados , Vasoconstritores/uso terapêutico , Lesão Renal Aguda/tratamento farmacológico , Lesão Renal Aguda/epidemiologia , Lesão Renal Aguda/urina , Insuficiência Hepática Crônica Agudizada/virologia , Adulto , Biomarcadores/urina , Progressão da Doença , Feminino , Vírus da Hepatite B/isolamento & purificação , Humanos , Túbulos Renais/patologia , Túbulos Renais/virologia , Cirrose Hepática/virologia , Lipressina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Terlipressina , Resultado do Tratamento
4.
J Huazhong Univ Sci Technolog Med Sci ; 34(3): 348-353, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24939297

RESUMO

Recently, suppressor of cytokine signaling-3 (SOCS3) has been shown to be an inducible endogenous negative regulator of Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway which is relevant in inflammatory response, while its functions in acute liver failure and HBV-induced acute-on-chronic liver failure (HBV-ACLF) have not been fully elucidated. In this study, we explored the role of SOCS3 in the development of mouse hepatitis virus strain 3 (MHV-3)-induced acute liver failure and its expression in liver and peripheral blood mononuclear cells (PBMCs) of patients with HBV-ACLF. Inflammation-related gene expression was detected by real-time PCR, immunohistochemistry and Western blotting. The correlation between SOCS3 level and liver injury was studied. Our results showed that the SOCS3 expression was significantly elevated in both the liver tissue and PBMCs from patients with HBV-ACLF compared to mild chronic hepatitis B (CHB). Moreover, a time course study showed that SOCS3 level was increased remarkably in the liver of BALB/cJ mice at 72 h post-infection. Pro-inflammatory cytokines, interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α, were also increased significantly at 72 h post-infection. There was a close correlation between hepatic SOCS3 level and IL-6, and the severity of liver injury defined by alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, respectively. These data suggested that SOCS3 may play a pivotal role in the pathogenesis of MHV-3-induced acute liver failure and HBV-ACLF.


Assuntos
Doença Hepática Terminal/virologia , Hepatite Viral Animal/virologia , Falência Hepática Aguda/virologia , Vírus da Hepatite Murina/fisiologia , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Adulto , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Western Blotting , Doença Hepática Terminal/genética , Doença Hepática Terminal/patologia , Feminino , Expressão Gênica , Hepatite Viral Animal/genética , Hepatite Viral Animal/patologia , Interações Hospedeiro-Patógeno , Humanos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/virologia , Falência Hepática Aguda/genética , Falência Hepática Aguda/patologia , Masculino , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Índice de Gravidade de Doença , Proteína 3 Supressora da Sinalização de Citocinas , Proteínas Supressoras da Sinalização de Citocina/sangue , Proteínas Supressoras da Sinalização de Citocina/genética , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Adulto Jovem
5.
Zhonghua Gan Zang Bing Za Zhi ; 19(11): 833-7, 2011 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-22433305

RESUMO

OBJECTIVE: To explore the mechanisms of a novel potassium channel gene named KCTD9 (potassium channel tetramerization domain containing 9) in model of fulminant viral hepatitis induced by murine hepatitis virus 3 (MHV-3). METHODS: 78 BALB/cJ mice(6 male) were randomly and equally assigned to two groups, model group of fulminant viral hepatitis induced by MHV3 and its control. 75 C3H/HeJ female mice were done into two groups, 39 for model group of chronic hepatitis induced by MHV3, 36 for control. Various samples including spleen, liver and lymphocytes from mice of two model groups and the controls were examined for KCTD9 expression by real time quantitative PCR and Immunohistochemistry. Independent-samples T test or one-way ANOVA were carried out in different groups. RESULTS: Increased expressions of KCTD9 mRNA was observed in livers of both model mice of fulminant viral hepatitis and chronic hepatitis. Compared with the control mice, the expressions of KCTD9 mRNA were up-regulated by 577.1-, 8.8-, 59.4- and 10.8-fold in hepatic NK cells, CD4+ T cells, CD8+ T cells and splenic NK cells respectively in model mice of fulminant viral hepatitis 48 hr post MHV-3 infection, whereas down-regulation by 43% and 69% in splenic CD4 + T cells and CD8+ T cells were found respectively. In contrast, in model mice of chronic viral hepatitis the expressions of KCTD9 mRNA were down-regulated by 71% and 51% in hepatic CD4+ T cells and NK cells, respectively. The expression of KCTD9 protein was mainly evidenced in infiltrative mononuclear cells of liver as shown by immunohistochemistry. Basal expression was also investigated and showed constitutive expression of KCTD9 in brain, thymus and other organs in BALB/cJ mice. CONCLUSION: A novel potassium channel gene KCTD9 was highly expressed in hepatic NK cells and T cells of fulminant hepatitis mice induced by MHV-3.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , Hepatite Viral Animal/metabolismo , Células Matadoras Naturais/metabolismo , Fígado/metabolismo , Canais de Potássio/metabolismo , Animais , Linfócitos T CD4-Positivos/imunologia , Feminino , Hepatite Viral Animal/imunologia , Hepatite Viral Animal/virologia , Células Matadoras Naturais/imunologia , Fígado/virologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Vírus da Hepatite Murina , Canais de Potássio/genética
7.
Zhonghua Gan Zang Bing Za Zhi ; 16(11): 835-9, 2008 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-19032868

RESUMO

OBJECTIVE: Studies have shown that potassium channel plays a pivotal role in T cell activation. The expression of potassium channel gene KCTD9 was evidenced being highly upregulated in patients with severe hepatitis B (SHB). To understand this phenomenon further, tissue and cellular expression profiles of KCTD9 were investigated in patients with SHB. METHODS: A rabbit peptide polyclonal antibody was prepared. Various samples including peripheral blood mononuclear cells (PBMCs); livers from patients with SHB or mild chronic hepatitis B, were examined for KCTD9 expression by quantitative real time PCR and immunohistochemistry staining (IHC). Confocal microscopy was used to illustrate the localizations of the expressions. RESULTS: Increased expression of KCTD9 was observed in PBMC in over 35.7% of the patients with SHB when compared with that of patients with mild chronic hepatitis B. In all patients, the relative value of increased KCTD9 mRNA was positively correlated with alanine aminotransferase, aspartate aminotransferase, total bilirubin and direct bilirubin but negatively with serum albumin. The expression was mainly located in hepatocytes, bile duct epithelial cells, Kupffer cells and inflammatory cells, and in the cytoplasm of PBMCs from the healthy individuals and patients with mild chronic hepatitis B, whereas in both cytoplasm and nuclei in those from patients with SHB. CONCLUSION: The increased expression of potassium channel gene KCTD9 correlates with disease severity in patients with viral hepatitis B.


Assuntos
Hepatite B Crônica/sangue , Monócitos/metabolismo , Canais de Potássio/metabolismo , Adulto , Feminino , Hepatite B Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Canais de Potássio/genética , RNA Mensageiro/genética , Adulto Jovem
8.
Zhonghua Yi Xue Za Zhi ; 83(8): 678-83, 2003 Apr 25.
Artigo em Chinês | MEDLINE | ID: mdl-12887828

RESUMO

OBJECTIVE: To identify the transcription factor(s) that is essential for activation of mfgl2 prothrombinase/fibroleukin gene in response to nucleocapsid protein of murine hepatitis virus type 3 (MHV-3). METHODS: Western blotting was performed to investigate whether HNF4 is expressed in macrophages of Ba1b/c mice where mfgl2 is expressed. Confocus microscope immunofluorescence was performed to show whether N protein of MHV enters into the nucleus of infected cells, which is a critical step for the N protein to facilitate its transactivation property. To facilitate the identification of three candidate factor(s) including hepatocyte nuclear factor 4 (HNF4)/liver factor A1 (LF-A1), cytomegalovirus immediate early gene 1.2 (IE1.2) regulatory element and granulocyte- macrophage colony stimulating factor (GM-CSF) in response to mfgl2 activation upon the stimulation of MHV-A59 N protein, gel mobility shift assay (GMSA), competition experiments and site directed mutagenesis were performed. RESULTS: Western blotting displayed that HNF4 was constitutively expressed in macrophages and did not show significant change under the stimulation of different MHV. Confocus microscope immunofluorescence clearly showed that N protein of MHV entered into the nucleus of infected cells. GMSA and competition experiments demonstrated binding to both HNF4 and IE1.2 fragments could be competed with the cold specific oligonucleotides but not with the same amount of non-specific oligos nucleotides. A super shift band was observed when HNF4 antibody was pre-incubated with the nuclear extracts indicating the interaction between the HNF4 element and mfgl2 promoter. Site directed mutagenesis of cis-elements HNF4 (pfgl2HNF4mut) and HNF4/IE1.2 (pfgl2HNF4/IE1.2mut) mutations abolished over 75% of transcription from wild-type mfgl2 promoter. However the pfgl2IE1.2mut displayed almost wild-type promoter activity (75% approximately 80%). CONCLUSIONS: The factor HNF4 binds to mfgl2 promoter and serves as an essential transcription factor for mfgl2/fibroleukin expression in response to MHV-3 N protein.


Assuntos
Proteínas de Ligação a DNA , Fibrinogênio/genética , Regulação da Expressão Gênica , Vírus da Hepatite Murina/patogenicidade , Proteínas do Nucleocapsídeo/fisiologia , Fosfoproteínas/fisiologia , Tromboplastina/genética , Fatores de Transcrição/fisiologia , Animais , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos , Feminino , Fator 4 Nuclear de Hepatócito , Camundongos , Camundongos Endogâmicos BALB C
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