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1.
Biomed Res Int ; 2021: 5541780, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33937393

RESUMO

Objective: This study is aimed at investigating the enriched functions of polymeric immunoglobulin receptor (PIGR) and its correlations with liver fibrosis stage. Methods: PIGR mRNA expression in normal liver, liver fibrosis, hepatic stellate cells (HSCs), and hepatitis virus infection samples was calculated in Gene Expression Omnibus (GEO) and Oncomine databases. Enrichment analysis of PIGR-related genes was conducted in Metascape and Gene Set Enrichment Analysis (GSEA). Logistic model and ROC curve were performed to evaluate the correlations between pIgR and liver fibrosis. Results: PIGR mRNA was upregulated in advanced liver fibrosis, cirrhosis compared to normal liver (all p < 0.05). PIGR mRNA was also overexpressed in activated HSCs compared to senescent HSCs, liver stem/progenitor cells, and reverted HSCs (all p < 0.05). Enrichment analysis revealed that PIGR-related genes involved in the defense response to virus and interferon (IFN) signaling. In GEO series, PIGR mRNA was also upregulated by hepatitis virus B, C, D, and E infection (all p < 0.05). After adjusting age and gender, multivariate logistic regression models revealed that high PIGR in the liver was a risk factor for liver fibrosis (OR = 82.2, p < 0.001). The area under curve (AUC), positive predictive value (PPV), negative predictive value (NPV), sensitivity, and specificity of PIGR for liver fibrosis stage >2 were 0.84, 0.86, 0.7, 0.61, and 0.90. Conclusion: PIGR was correlated with liver fibrosis and might involve in hepatitis virus infection and HSC transdifferentiation.


Assuntos
Biologia Computacional , Progressão da Doença , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Receptores de Imunoglobulina Polimérica/metabolismo , Regulação da Expressão Gênica , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Hepatite B/patologia , Hepatite B/virologia , Vírus da Hepatite B/genética , Humanos , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/genética , Modelos Logísticos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Imunoglobulina Polimérica/genética
2.
Molecules ; 26(5)2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33652602

RESUMO

Hepatitis B virus (HBV) is a circular, and partially double-stranded DNA virus. Upon infection, the viral genome is translocated into the cell nucleus, generating the covalently closed circular DNA (cccDNA) intermediate, and forming a mini chromosome. HBV HBx is a small protein displaying multiple roles in HBV-infected cells, and in different subcellular locations. In the nucleus, the HBx protein is required to initiate and maintain viral transcription from the viral mini chromosome. In contrast, HBx also functions in the cytoplasm, where it is able to alter multiple cellular functions such as mitochondria metabolism, apoptosis and signal transduction pathways. It has been reported that in cultured cells, at low expression levels, the HBx protein is localized in the nucleus, whereas at high expression levels, it accumulates in the cytoplasm. This dynamic subcellular distribution of HBx might be essential to exert its multiple roles during viral infection. However, the mechanism that regulates different subcellular localizations of the HBx protein is unknown. We have previously taken a bioinformatics approach to investigate whether HBx might be regulated via post-translational modification, and we have proposed that the multiple nucleocytoplasmic functions of HBx might be regulated by an evolutionarily conserved mechanism via phosphorylation. In the current study, phylogenetically conserved amino acids of HBx with a high potential of phosphorylation were targeted for site-directed mutagenesis. Two conserved serine (Ser25 and Ser41), and one conserved threonine (Thr81) amino acids were replaced by either alanine or aspartic acid residues to simulate an unphosphorylated or phosphorylated state, respectively. Human hepatoma cells were transfected with increasing amounts of the HBx DNA constructs, and the cells were analyzed by fluorescence microscopy. Together, our results show that the nucleocytoplasmic distribution of the HBx protein could be regulated by phosphorylation since some of the modified proteins were mainly confined to distinct subcellular compartments. Remarkably, both HBx Ser41A, and HBx Thr81D proteins were predominantly localized within the nuclear compartment throughout the different expression levels of HBx mutants.


Assuntos
Carcinoma Hepatocelular/genética , Hepatite B/genética , Neoplasias Hepáticas/genética , Transativadores/genética , Proteínas Virais Reguladoras e Acessórias/genética , Sequência de Aminoácidos/genética , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/virologia , Sequência Conservada/genética , Regulação Viral da Expressão Gênica/genética , Genoma Viral/genética , Células Hep G2 , Hepatite B/patologia , Hepatite B/virologia , Vírus da Hepatite B/genética , Vírus da Hepatite B/patogenicidade , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/virologia , Fosforilação/genética , Filogenia
3.
Mol Med Rep ; 23(5)2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33760167

RESUMO

Hepatitis B virus (HBV) is a leading cause of liver­related cancer. Progress has been made on the study of microRNA (miRNA or miR) function in HBV­related liver cancer. Hence, the objective of the present study was to determine the role and functional mechanism of miR­1271­5p in HBV­associated liver cancer. miR­1271­5p and aquaporin 5 (AQP5) expression at the mRNA level were measured by reverse transcription­quantitative PCR (RT­qPCR). The levels of hepatitis B e­antigen (HBeAg), hepatitis B surface antigen (HBsAg) and HBV DNA were assessed by ELISA or qPCR. Cell viability, apoptosis, migration and invasion were detected by Cell Counting Kit­8, flow cytometry or Transwell assay. The interaction of miR­1271­5p and AQP5 was predicted by TargetScan, and verified by dual­luciferase reporter assay and RNA binding protein immunoprecipitation assay. The protein levels of AQP5, Bax, Bcl­2, cleaved­caspase-3 and proliferating cell nuclear antigen were quantified by western blot analysis. Nude mouse tumorigenicity assay was conducted to examine the role of miR­1271­5p in vivo. miR­1271­5p was downregulated, while AQP5 was upregulated in HBV­related liver cancer cells and tissues. Overexpression of miR­1271­5p or AQP5 knockdown inhibited the levels of HBeAg, HBsAg and HBV DNA, blocked cell viability, migration and invasion, and induced apoptosis. AQP5 was confirmed to be a direct target of miR­1271­5p, and miR­1271­5p exerted its role through targeting AQP5. Overexpression of miR­1271­5p impeded tumor growth in vivo by weakening the expression of AQP5. In conclusion, miR­1271­5p blocked the progression of HBV­induced liver cancer by competitively targeting AQP5.


Assuntos
Aquaporina 5/genética , Vírus da Hepatite B/genética , Hepatite B/genética , Neoplasias Hepáticas/genética , MicroRNAs/genética , Animais , Apoptose/genética , Carcinogênese/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/virologia , Movimento Celular/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica/genética , Células Hep G2 , Hepatite B/patologia , Hepatite B/virologia , Antígenos de Superfície da Hepatite B/genética , Antígenos E da Hepatite B/genética , Vírus da Hepatite B/patogenicidade , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/virologia , Camundongos
4.
BMC Infect Dis ; 21(1): 228, 2021 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-33639860

RESUMO

BACKGROUND: Family with sequence similarity 26, member F (FAM26F) is an important innate immunity modulator playing a significant role in diverse immune responses, however, the association of FAM26F expression with HBV infection is not yet known. Thus, the current study aims to explore the differential expression of FAM26F in vitro in HepAD38 and HepG2 cell lines upon HBV infection, and in vivo in HBV infected individuals. The effects of antioxidant and calcium inhibitors on the regulation of FAM26F expression were also evaluated. The expression of FAM26F was simultaneously determined with well-established HBV infection markers: IRF3, and IFN-ß. METHODS: The expression of FAM26F and marker genes was analyzed through Real-time qPCR and western blot. RESULTS: Our results indicate that the differential expression of FAM26F followed the same trend as that of IRF3 and IFN-ß. The in vitro study revealed that, in both HBV infected cell lines, FAM26F expression was significantly down-regulated as compared to uninfected control cells. Treatment of cells with N-acetyl-L-cysteine (NAC), EGTA-AM, BAPTA-AM, and Ru360 significantly upregulated the expression of FAM26F in both the cell lines. Moreover, in in vivo study, FAM26F expression was significantly downregulated in all HBV infected groups as compared to controls (p = 0.0007). The expression was higher in the HBV recovered cases, probably due to the decrease in infection and increase in the immunity of these individuals. CONCLUSION: Our study is the first to show the association of FAM26F with HBV infection. It is proposed that FAM26F expression could be an early predictive marker for HBV infection, and thus is worthy of further investigation.


Assuntos
Cálcio/farmacologia , Hepatite B/genética , Glicoproteínas de Membrana/genética , Estresse Oxidativo/fisiologia , Adolescente , Adulto , Cálcio/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Sinalização do Cálcio/genética , Estudos de Casos e Controles , Linhagem Celular , Criança , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Hepatite B/imunologia , Hepatite B/metabolismo , Hepatite B/patologia , Vírus da Hepatite B/fisiologia , Humanos , Masculino , Glicoproteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Estresse Oxidativo/efeitos dos fármacos , Adulto Jovem
5.
Int J Mol Sci ; 22(1)2020 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-33375194

RESUMO

Infectious diseases represent a relevant issue in lung cancer patients. Bacterial and viral infections might influence the patients' prognosis, both directly affecting the immune system and indirectly impairing the outcome of anticancer treatments, mainly immunotherapy. In this analysis, we aimed to review the current evidence in order to clarify the complex correlation between infections and lung cancer. In detail, we mainly explored the potential impact on immunotherapy outcome/safety of (1) bacterial infections, with a detailed focus on antibiotics; and (2) viral infections, discriminating among (a) human immune-deficiency virus (HIV), (b) hepatitis B/C virus (HBV-HCV), and (c) Sars-Cov-2. A series of studies suggested the prognostic impact of antibiotic therapy administration, timing, and exposure ratio in patients treated with immune checkpoint inhibitors, probably through an antibiotic-related microbiota dysbiosis. Although cancer patients with HIV, HBV, and HCV were usually excluded from clinical trials evaluating immunotherapy, some retrospective and prospective trials performed in these patient subgroups reported similar results compared to those described in not-infected patients, with a favorable safety profile. Moreover, patients with thoracic cancers are particularly at risk of COVID-19 severe outcomes and mortality. Few reports speculated about the prognostic implications of anticancer therapy, including immunotherapy, in lung cancer patients with concomitant Sars-Cov-2 infection, showing, to date, inconsistent results. The correlation between infectious diseases and immunotherapy remains to be further explored and clarified in the context of dedicated trials. In clinical practice, the accurate and prompt multidisciplinary management of lung cancer patients with infections should be encouraged in order to select the best treatment options for these patients, avoiding unexpected toxicities, while maintaining the anticancer effect.


Assuntos
Infecções Bacterianas/complicações , COVID-19/complicações , Carcinoma Pulmonar de Células não Pequenas/complicações , Carcinoma Pulmonar de Células não Pequenas/terapia , Imunoterapia , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/terapia , Viroses/complicações , Síndrome de Imunodeficiência Adquirida/complicações , Síndrome de Imunodeficiência Adquirida/imunologia , Síndrome de Imunodeficiência Adquirida/patologia , Síndrome de Imunodeficiência Adquirida/terapia , Antibacterianos/administração & dosagem , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/patologia , COVID-19/tratamento farmacológico , COVID-19/patologia , Carcinoma Pulmonar de Células não Pequenas/microbiologia , Carcinoma Pulmonar de Células não Pequenas/virologia , HIV/efeitos dos fármacos , Hepatite B/complicações , Hepatite B/imunologia , Hepatite B/patologia , Hepatite C/complicações , Hepatite C/tratamento farmacológico , Hepatite C/patologia , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/microbiologia , Neoplasias Pulmonares/virologia , Microbiota/efeitos dos fármacos , Microbiota/imunologia
6.
PLoS Pathog ; 16(8): e1008793, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32866189

RESUMO

Transmission to chimpanzees of a precore hepatitis B virus (HBV) mutant implicated in acute liver failure (ALF) in humans did not cause ALF nor the classic form of acute hepatitis B (AHB) seen upon infection with the wild-type HBV strain, but rather a severe AHB with distinct disease features. Here, we investigated the viral and host immunity factors responsible for the unusual severity of AHB associated with the precore HBV mutant in chimpanzees. Archived serial serum and liver specimens from two chimpanzees inoculated with a precore HBV mutant implicated in ALF and two chimpanzees inoculated with wild-type HBV were studied. We used phage-display library and next-generation sequencing (NGS) technologies to characterize the liver antibody response. The results obtained in severe AHB were compared with those in classic AHB and HBV-associated ALF in humans. Severe AHB was characterized by: (i) the highest alanine aminotransferase (ALT) peaks ever seen in HBV transmission studies with a significantly shorter incubation period, compared to classic AHB; (ii) earlier HBsAg clearance and anti-HBs seroconversion with transient or undetectable hepatitis B e antigen (HBeAg); (iii) limited inflammatory reaction relative to hepatocellular damage at the ALT peak with B-cell infiltration, albeit less extensive than in ALF; (iv) detection of intrahepatic germline antibodies against hepatitis B core antigen (HBcAg) by phage-display libraries in the earliest disease phase, as seen in ALF; (v) lack of intrahepatic IgM anti-HBcAg Fab, as seen in classic AHB, but at variance with ALF; and (vi) higher proportion of antibodies in germline configuration detected by NGS in the intrahepatic antibody repertoire compared to classic AHB, but lower than in ALF. This study identifies distinct outcome-specific features associated with severe AHB caused by a precore HBV mutant in chimpanzees, which bear closer resemblance to HBV ALF than to classic AHB. Our data suggest that precore HBV mutants carry an inherently higher pathogenicity that, in addition to specific host factors, may play a critical role in determining the severity of acute HBV disease.


Assuntos
Anticorpos Anti-Hepatite B/metabolismo , Vírus da Hepatite B/metabolismo , Hepatite B/metabolismo , Imunoglobulina M/metabolismo , Falência Hepática Aguda/metabolismo , Animais , Modelos Animais de Doenças , Hepatite B/patologia , Antígenos do Núcleo do Vírus da Hepatite B/metabolismo , Humanos , Falência Hepática Aguda/patologia , Pan troglodytes
7.
PLoS One ; 15(8): e0238078, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32845895

RESUMO

BACKGROUNDS AND AIMS: Because of the known limitations of ultrasonography (US) alone, we re-evaluated whether complimentary testing for serum alpha-fetoprotein (AFP) is helpful in surveilling for hepatocellular carcinoma (HCC) in high-risk populations. METHODS: We included, from a hospital-based cancer registry, 1,776 asymptomatic adults who were surveilled biannually with the AFP test and US and eventually diagnosed with HCC between 2007 and 2015. Based on the screening results, these patients were divided into three groups: AFP (positive for AFP only; n = 298 [16.8%]), US (positive for US only; n = 978 [55.0%]), and AFP+US (positive for both; n = 500 [28.2%]). We compared the outcomes of the three groups, calculating the survival of the AFP group both as observed survival and as survival corrected for lead-time. RESULTS: In terms of tumor-related factors, the separate AFP and US groups were more likely to have early stage HCC and to receive curative treatments than the combined AFP+US group (Ps<0.05). The AFP group had significantly better overall and cancer-specific survival than the AFP+US group after adjusting for covariates (adjusted hazard ratios [HRs] 0.68 and 0.62, respectively). In analyses correcting for lead-time in the AFP group (doubling time 120 days), the respective adjusted HRs for the AFP group were unchanged (0.74 and 0.67), but they were no longer significant after additional adjustment for tumor stage and curative treatment (0.87 and 0.81). CONCLUSIONS: HCC cases detected by the AFP test without abnormal ultrasonic findings appear to have better survival, possibly as a result of stage migration and the resulting cures. Complementary AFP surveillance, together with US, could be helpful for at-risk patients.


Assuntos
Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , alfa-Fetoproteínas/análise , Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/mortalidade , Detecção Precoce de Câncer , Feminino , Hepatite B/patologia , Humanos , Cirrose Hepática/complicações , Cirrose Hepática/diagnóstico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Razão de Chances , Modelos de Riscos Proporcionais , Sistema de Registros , Fatores de Risco , Taxa de Sobrevida , Ultrassonografia
8.
PLoS One ; 15(8): e0237586, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32785260

RESUMO

This study investigated the kinetics of estimated glomerular filtration rate (eGFR) and quantitative hepatitis B surface antigen (qHBsAg) in telbivudine (LdT)-treated chronic hepatitis B (CHB) patients whose treatment was subsequently adjusted with the adding on adefovir or by switching to tenofovir disoproxil fumarate (TDF) as rescue. Of 295 CHB patients initially treated with LdT, 102 of them who subsequently receiving either adding-on adefovir (group A, n = 58) or switching to TDF (group B, n = 44) for more than 24 months were enrolled. Serial eGFR and qHBsAg levels (3 to 6 monthly) in both LdT monotherapy and rescue therapy periods were analyzed retrospectively. Subsequent decline of qHBsAg especially in rescue therapy period were noted (p<0.001 and p = 0.068 in group A and B). However, patients in group B achieved a significant increase of eGFR (p = 0.010) in LdT monotherapy period but had a significant decline of eGFR (p<0.001) in rescue therapy period. In contrast, patients in group A maintained eGFR levels in both periods. Meanwhile, switch to TDF (hazard ratio: 3.036; 95% confidence interval: 1.040-8.861; p = 0.042) was the sole factor related to the decrease of eGFR>20% from baseline. Both rescue therapies achieved subsequent declines of qHBsAg over time but caused different changes in eGFR. LdT-based rescue therapy maintained eGFR but TDF switching therapy descended eGFR. Therefore, it is essential to monitor patient's renal function intensively when switching from LdT to TDF as a rescue strategy.


Assuntos
Antivirais/farmacologia , Taxa de Filtração Glomerular/efeitos dos fármacos , Antígenos de Superfície da Hepatite B/metabolismo , Vírus da Hepatite B/metabolismo , Hepatite B/patologia , Telbivudina/farmacologia , Feminino , Seguimentos , Hepatite B/metabolismo , Hepatite B/virologia , Vírus da Hepatite B/efeitos dos fármacos , Humanos , Cinética , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos
9.
PLoS One ; 15(8): e0236704, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32790777

RESUMO

The hepatitis B virus (HBV) envelope is composed of a lipid bilayer and three glycoproteins, referred to as the large (L), middle (M), and small (S) hepatitis B virus surface antigens (HBsAg). S protein constitutes the major portion of the viral envelope and an even greater proportion of subviral particles (SVP) that circulate in the blood. Recombinant S proteins are currently used as a preventive vaccine, while plasma fractions isolated from vaccinated people, referred to as hepatitis B immune globulin (HBIG), are used for short-term prophylaxis. Here, we characterized a recombinant human IgG1 type anti-S antibody named Lenvervimab regarding its binding property to a variety of cloned S antigens. Immunochemical data showed an overall consistent avidity of the antibody to S antigens of most viral genotypes distributed worldwide. Further, antibody binding was not affected by the mutations in the antigenic 'a' determinant found in many clinical variants, including the immune escape mutant G145R. In addition, mutations in the S gene sequence that confer drug resistance to the viral polymerase did not interfere with the antibody binding. These results support for a preventive use of the antibody against HBV infection.


Assuntos
Anticorpos Anti-Hepatite B/imunologia , Antígenos de Superfície da Hepatite B/genética , Vírus da Hepatite B/metabolismo , Imunoglobulinas/imunologia , Sequência de Aminoácidos , Reações Antígeno-Anticorpo , Linhagem Celular , Farmacorresistência Viral , Genótipo , Células Hep G2 , Hepatite B/patologia , Hepatite B/virologia , Anticorpos Anti-Hepatite B/metabolismo , Antígenos de Superfície da Hepatite B/química , Antígenos de Superfície da Hepatite B/imunologia , Vírus da Hepatite B/genética , Vírus da Hepatite B/isolamento & purificação , Humanos , Imunoglobulinas/genética , Imunoglobulinas/metabolismo , Polimorfismo de Nucleotídeo Único , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/isolamento & purificação
10.
J Cancer Res Ther ; 16(3): 619-623, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32719277

RESUMO

Introduction: Patients receiving treatment for head-and-neck squamous cell carcinoma (HNSCC) also may have coexisting viral infections caused by HIV, HBV, and HCV (seropositive). There is scarce literature regarding the clinical presentation and treatment outcomes for these patients with coexisting viral infections (seropositive HNSCC). We conducted this study to assess the clinical presentation and treatment outcomes (overall survival [OS] and disease-specific survival [DSS]) of seropositive HNSCC patients. Methodology: This was a retrospective cohort study on seropositive HNSCC patients registered at our center from 2012 to 2014. The viral infections were identified by the presence of the antibodies to these viruses in the patient's blood samples. Results: Out of the 19,137 HNSCC patients registered, 156 patients had HBV, HCV, and/or HIV infection. Among these, HBV infection was the most common (n = 86/156, 55.1%) followed by HIV infection (n = 36/156, 23.1%) and HCV infection (n = 29/156, 18.6%). The oral cavity was the most common subsite involved. Majority of these patients presented at an advanced stage (advanced T stage - 71.8% and node positive - 62.2%). The majority of the patients received curative-intent treatment (65.4%). The OS at 3 years for these HNSCC patients with coexisting HIV, HBV, and HCV infection was 60%, 62.6%, and 57.5%, respectively, and their DSS at 3 years was 58.8%, 78.6%, and 53.8%, respectively. Conclusions: Seropositive patients with HNSCC often present in the advanced stage but have a good survival if treated appropriately.


Assuntos
Soropositividade para HIV/epidemiologia , Neoplasias de Cabeça e Pescoço/epidemiologia , Hepatite B/epidemiologia , Hepatite C/epidemiologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Anticorpos Anti-HIV/sangue , Soropositividade para HIV/imunologia , Soropositividade para HIV/patologia , Soropositividade para HIV/virologia , Neoplasias de Cabeça e Pescoço/sangue , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/virologia , Hepatite B/imunologia , Hepatite B/patologia , Hepatite B/virologia , Anticorpos Anti-Hepatite B/sangue , Hepatite C/imunologia , Hepatite C/patologia , Hepatite C/virologia , Anticorpos Anti-Hepatite C/sangue , Humanos , Índia/epidemiologia , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço/sangue , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia , Taxa de Sobrevida
11.
Anticancer Res ; 40(7): 3983-3990, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32620641

RESUMO

BACKGROUND/AIM: Few studies have studied micro hepatic vein invasion in hepatocellular carcinoma (HCC). We explored the correlation between hepatic vein invasion and hepatitis B/C virus infection. PATIENTS AND METHODS: Between April 2000 and February 2018, 869 patients underwent liver resection for HCC at a single center. The patients were divided into two groups: those with micro hepatic vein invasion (VV+) and those without (VV-). The clinical data, overall survival (OS) and correlations with the presence of hepatitis B and C viruses were investigated. RESULTS: There were 817 VV- patients and 43 VV+ patients. OS was 66.2 months for VV- patients and 9.9 months for VV+ patients (p=0.0010). VV+ patients had significantly higher levels of serum HBV DNA (p=0.016). CONCLUSION: HCC patients with micro hepatic vein invasion showed significantly shorter OS. A higher level of HBV DNA appears to be a risk factor for micro hepatic vein invasion.


Assuntos
Carcinoma Hepatocelular/patologia , Veias Hepáticas/patologia , Neoplasias Hepáticas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos Virais/sangue , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/virologia , DNA Viral/sangue , Feminino , Hepacivirus/genética , Hepacivirus/imunologia , Hepatite B/patologia , Hepatite B/virologia , Vírus da Hepatite B/genética , Vírus da Hepatite B/imunologia , Hepatite C/patologia , Hepatite C/virologia , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Adulto Jovem
12.
PLoS One ; 15(5): e0233702, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32442221

RESUMO

Liver fibrosis is a manifestation of chronic liver injury. It leads to hepatic dysfunction and is a critical element in the pathogenesis of cirrhosis and hepatocellular carcinoma. The activation of hepatic stellate cells (HSC) plays a central role in liver fibrogenesis of different etiologies. To elucidate the molecular mechanism of this phenomenon, it is important to analyze the changes in gene expression that accompany the HSC activation process. In this study, we isolated quiescent and activated HSCs from control mice and mice with CCl4-induced liver fibrosis, respectively, and performed RNA sequencing to compare the differences in gene expression patterns between the two types of HSCs. We also reanalyzed public gene expression data for fibrotic liver tissues isolated from patients with HBV infection, HCV infection, and nonalcoholic fatty liver disease to investigate the gene expression changes during liver fibrosis of these three etiologies. We detected 146 upregulated and 18 downregulated genes in activated HSCs, which were implicated in liver fibrosis as well. Among the overlapping genes, seven transcription factor-encoding genes, ARID5B, GATA6, MITF, PBX1, PLAGL1, SOX4, and SOX9, were upregulated, while one, RXRA, was downregulated. These genes were suggested to play a critical role in HSC activation, and subsequently, in the promotion of liver fibrosis. We undertook the RNA sequencing of quiescent and activated HSCs and analyzed the expression profiles of genes associated with HSC activation in liver fibrotic tissues from different liver diseases, and also aimed to elucidate the changes in gene expression patterns associated with HSC activation and liver fibrosis.


Assuntos
Hepacivirus/metabolismo , Células Estreladas do Fígado/metabolismo , Vírus da Hepatite B/metabolismo , Hepatite B/metabolismo , Hepatite C/metabolismo , Cirrose Hepática/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Animais , Linhagem Celular , Regulação da Expressão Gênica , Células Estreladas do Fígado/patologia , Células Estreladas do Fígado/virologia , Hepatite B/patologia , Hepatite C/patologia , Humanos , Cirrose Hepática/patologia , Masculino , Camundongos , Hepatopatia Gordurosa não Alcoólica/patologia , Fatores de Transcrição/biossíntese
13.
Aliment Pharmacol Ther ; 51(12): 1406-1416, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32390175

RESUMO

BACKGROUND: Virus, host factors and their interplay influence Hepatitis B surface Antigen serum levels during Hepatitis B Virus (HBV) infection course and treatment. AIM: To study the Pre-S/S circulating quasispecies in a cohort of untreated, HBeAg negative, genotype-D, HBsAg carriers. METHODS: We studied 260 carriers: 71 with HBeAg negative infection (ENI; HBV-DNA ≤2000 IU/mL); 42 Grey Zone (GZ; HBV-DNA ≤20 000 IU/mL); 82 chronic hepatitis (CH) and 65 cirrhosis (CI) (HBV-DNA > 20 000 IU/mL). Population sequencing was applied to identify Pre-S/S gene mutations responsible for any amino acid substitution or potential biological/antigenic implications (M-muts) on HBsAg. RESULTS: HBsAg serum levels were lower in ENI + GZ than in CH + CI (2.61 [-1.10/4.06] vs 3.62 [2.41/4.92] log10 IU/mL, P < 0.001) and in CI than CH (3.48 [2.41/4.38] vs 3.66 [2.57/4.92] log10 IU/mL, P < 0.001). M-muts were found in 73 (28.1%) cases: 5 (7.0%) ENI, 3 (7.1%) GZ, 26 (31.7%) CH, 39 (60.0%) CI (P < 0.001) and mostly in Pre-S2 (17.6%) than Pre-S1 (5.8%) and Small-S (10.8%; P < 0.001). Overall HBsAg serum levels were higher in carriers with M-muts (3.56 [0.95/4.38] vs 3.17 [-1.10/4.92] log10 IU/mL, P < 0.001), but comparable in carriers with or without M-mut when considering separately ENI + GZ (2.84 [0.95/3.89] vs 2.61 [-1.10/4.06] log10 IU/mL, P = 0.330] and CH + CI (3.57 [2.67/4.38] vs 3.63 [2.41/4.92] log10 IU/mL, P = 0.37). Infection phase (ß: 0.422, P < 0.001), age (ß: -0.260, P < 0.001), ALT (ß: -0.103, P = 0.045), liver stiffness (ß: -0.118, P = 0.039) and HBV-DNA (ß: 0.384, P < 0.001), but not M-mut were independently associated with HBsAg serum levels. CONCLUSIONS: In HBeAg negative, genotype-D, carriers Pre-S/S heterogeneity increases with severity of liver disease, but does not influence HBsAg serum levels, that in low viraemic carriers are associated with an effective control of HBV.


Assuntos
Antígenos de Superfície da Hepatite B/sangue , Antígenos E da Hepatite B/sangue , Hepatite B/sangue , Quase-Espécies , Adolescente , Adulto , Idoso , Portador Sadio/sangue , Portador Sadio/virologia , Estudos de Coortes , DNA Viral/sangue , Progressão da Doença , Feminino , Genótipo , Hepatite B/patologia , Hepatite B/virologia , Antígenos de Superfície da Hepatite B/análise , Antígenos E da Hepatite B/genética , Vírus da Hepatite B/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Testes Sorológicos , Viremia/sangue , Viremia/virologia , Adulto Jovem
14.
BMC Med Genet ; 21(1): 88, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32357928

RESUMO

BACKGROUND: Interleukin (IL) 28B polymorphisms encoding pro-inflammatory and anti-inflammatory cytokines trigger diverse clinical outcome of hepatitis virus infection. However, there is controversy concerning the association of IL28B polymorphisms with the outcome of hepatitis B virus (HBV) infection, with several studies obtaining inconsistent results. We performed a meta-analysis to evaluate the role of 3 single nucleotide polymorphisms (SNPs) rs12979860, rs12980275 and rs8099917 in the progression of HBV infection, overall and by ethnicity. METHODS: Searched PubMed, Embase and Wiley Online Library electronic databases using 'interleukin 28B', 'IL 28B', 'IL 28B polymorphism', 'hepatitis B virus', 'HBV', and performed meta- analysis for rs12979860, rs12980275 and rs8099917 in Asian and Caucasian populations under the dominant recessive and allele model. RESULTS: Eighteen studies were found in total and used for this meta-analysis, including 5587 cases and 4295 controls. The IL28B polymorphism rs12979860 had no association with HBV persistence (CC vs CT + TT: OR = 0.86, 95% CI = 0.76-1.00; TT vs CT + CC: OR = 1.14, 95% CI = 0.76-1.70; T vs C: OR = 1.03, 95% CI = 0.94-1.13). Similarly, neither rs12980275 nor rs8099917 had associations with HBV persistence (rs12980275 in AA vs AG + AA: OR = 1.15, 95% CI = 0.96-1.38; rs8099917 in TT vs GT + GG: OR = 1.15, 95% CI = 0.96-1.39). There was also no significant association of IL28B polymorphisms with persistent HBV infection in Asians or Chinese. There was no evidence of an association of rs12979860 with the HBV-related hepatocellular carcinoma susceptibility (T vs C: OR = 1.53, 95% CI = 0.96-2.43). CONCLUSION: IL28B polymorphisms had no association with the outcome of HBV infection overall, nor in the Asians and the Chinese. These 3 SNPs might not be relevant to the development of HBV infection.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Hepatite B/genética , Interferons/genética , Grupo com Ancestrais do Continente Asiático/genética , Feminino , Genótipo , Hepatite B/patologia , Hepatite B/virologia , Vírus da Hepatite B/patogenicidade , Humanos , Interleucinas/genética , Masculino , Polimorfismo de Nucleotídeo Único/genética
15.
Am J Trop Med Hyg ; 103(1): 169-174, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32431268

RESUMO

Hepatitis D virus (HDV) genotype III is endemic in the western Amazon basin and is considered to cause the most severe form of chronic viral hepatitis. Recently, noninvasive fibrosis scores to determine the stage of liver fibrosis have been evaluated in individuals positive for HDV genotype I, but their utility in HDV genotype III-positive patients is unknown. In this retrospective study conducted in an outpatient viral hepatitis referral clinic in the Brazilian Amazon region, the aspartate aminotransferase (AST) to Aspartate aminotransferase to Platelet Ratio Index (APRI) and Fibrosis Index for Liver Fibrosis (FIB-4) values were calculated and compared with histological fibrosis stages. Among the 50 patients analyzed, the median age at liver biopsy was 35.6 years, 66% were male, and all had compensated liver disease. Histological staging revealed fibrosis stages 0, 1, 2, 3, and 4 in four (8%), eight (16%), 11 (22), 11 (22%), and 16 (32%) patients, respectively. The area under the receiver operating curve (AUROC) of AST-to-alanine aminotransferase (ALT) ratio, APRI, and FIB-4 for detection of significant fibrosis (F ≥ 2) was 0.550 (P = 0.601), 0.853 (P < 0.001), and 0.853 (P < 0.0001), respectively. Lower AUROC values were obtained for cirrhosis: the AST-to-ALT ratio was 0.640 (P = 0.114), APRI was 0.671 (P = 0.053), and FIB-4 was 0.701 (P = 0.023). The optimal cutoff value for significant fibrosis for APRI was 0.708 (sensitivity 84% and specificity 92%) and for FIB-4 was 1.36 (sensitivity 76% and specificity 92%). Aspartate aminotransferase to Platelet Ratio Index and FIB-4 were less useful to predict cirrhosis. In contrast to recent reports from Europe and North America, both APRI and FIB-4 may identify significant fibrosis in HDV-III-infected patients from northwestern Brazil.


Assuntos
Vírus da Hepatite B/patogenicidade , Hepatite B/diagnóstico , Hepatite D/diagnóstico , Vírus Delta da Hepatite/patogenicidade , Cirrose Hepática/diagnóstico , Adulto , Alanina Transaminase/metabolismo , Área Sob a Curva , Aspartato Aminotransferases/metabolismo , Biomarcadores/análise , Plaquetas/patologia , Plaquetas/virologia , Brasil , Doença Crônica , Coinfecção , Feminino , Hepatite B/enzimologia , Hepatite B/patologia , Hepatite B/virologia , Hepatite D/enzimologia , Hepatite D/patologia , Hepatite D/virologia , Humanos , Cirrose Hepática/enzimologia , Cirrose Hepática/patologia , Cirrose Hepática/virologia , Masculino , Pessoa de Meia-Idade , Pacientes Ambulatoriais , Contagem de Plaquetas , Curva ROC , Estudos Retrospectivos , Sensibilidade e Especificidade , Índice de Gravidade de Doença
16.
Am J Trop Med Hyg ; 103(1): 175-182, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32394881

RESUMO

Chronic hepatitis C virus (HCV) infection can lead to liver cirrhosis and hepatocellular carcinoma. To eliminate HCV infection in an endemic area, an epidemiological baseline of the current HCV infection in the population is required. We therefore aimed to evaluate the HCV burden in the Thai Province of Phetchabun, which has the highest HCV infection rate in the country. Toward this, a province-wide district-based representative sampling of 4,769 individuals ages 35-64 years previously shown to represent high-risk age-groups were tested for anti-HCV antibodies using the automated chemiluminescent microparticle assays. Active HCV infection and subsequent genotyping were determined from serologically reactive samples by amplification of the HCV core gene. We found that 6.9% (327/4,769) were anti-HCV positive, of which 75.8% (248/327) had detectable HCV RNA and 5.8% (19/327) were in the presence of hepatitis B virus coinfection. Nucleotide sequencing and phylogenetic analysis revealed that HCV genotype 6 was the most prevalent (41%, 101/248), followed by genotype 3 (31%, 78/248), and genotype 1 (28%, 69/248). Socioeconomic and demographic factors including male gender, education, and agricultural work were associated with HCV seropositivity. From these results, we defined the regional HCV genotypes and estimated the HCV burden necessary toward the implementation of pan-genotypic direct-acting antivirals, which may be appropriate and effective toward the diversity of genotypes identified in this study. Micro-elimination of HCV in Phetchabun may serve as a model for a more comprehensive coverage of HCV treatment in Thailand.


Assuntos
Doenças Endêmicas/estatística & dados numéricos , Hepacivirus/genética , Hepatite B/epidemiologia , Hepatite C Crônica/epidemiologia , RNA Viral/genética , Adulto , Anticorpos Antivirais/sangue , Doença Crônica , Coinfecção , Erradicação de Doenças/organização & administração , Monitoramento Epidemiológico , Feminino , Genótipo , Hepacivirus/classificação , Hepatite B/diagnóstico , Hepatite B/patologia , Hepatite B/virologia , Vírus da Hepatite B/classificação , Vírus da Hepatite B/genética , Hepatite C Crônica/diagnóstico , Hepatite C Crônica/patologia , Hepatite C Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Tipagem Molecular , Filogenia , Prevalência , Tailândia/epidemiologia , Carga Viral/genética
17.
Sci Rep ; 10(1): 6470, 2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-32286332

RESUMO

The conjugation of polysaccharides with an effective carrier protein is critical for the development of effective bacterial polysaccharide vaccines. Therefore, the identification and optimization of carrier proteins to induce an effective immune response is necessary for developing a combined vaccine. In the current study, we utilized hepatitis B virus surface antigen (HBsAg) as a novel carrier protein combined with a capsular polysaccharide molecule to develop a new pneumococcal conjugated vaccine. The specific antibodies and T cell immune response against the capsular polysaccharide and HBsAg in the mice immunized with this conjugated vaccine were evaluated. In addition, the unique gene profiles of immune cells induced by this conjugated vaccine in the immunized mice were analyzed. Our results demonstrated that the vaccine consisting of pneumonia type 33 F capsular polysaccharide (Pn33Fps) conjugated with HBsAg can induce strong specific immune responses against both antigens in vivo in immunized mice. Furthermore, the conjugated vaccine induced higher expression of genes related to the activation of immunity and higher antibody titers against Pn33Fps and HBsAg in mice than those obtained via vaccination with a single antigen. Analyses of the dynamic expression changes in immunity-related genes in mice immunized with Pn33Fps_HBs, Pn33Fps, or HBsAg indicated the potent immunogenicity of the conjugated vaccine. In addition, a pathological evaluation of the organs from immunized mice further suggested that the conjugated vaccine is safe. Together, these results indicate that a conjugated vaccine consisting of Pn33Fps with HBsAg is a novel and effective vaccine.


Assuntos
Antígenos de Superfície da Hepatite B/imunologia , Vírus da Hepatite B/imunologia , Vacinas Pneumocócicas/imunologia , Animais , Feminino , Regulação da Expressão Gênica , Hepatite B/genética , Hepatite B/imunologia , Hepatite B/patologia , Imunidade , Camundongos Endogâmicos BALB C , Especificidade de Órgãos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Linfócitos T/imunologia , Vacinação
18.
Oncogene ; 39(18): 3774-3789, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32157216

RESUMO

Hepatitis B virus (HBV) infection plays an important role in hepatocarcinogenesis, especially in hepatocellular carcinoma (HCC). Long non-coding RNAs (lncRNAs) have emerged as crucial biomarkers and regulators in many cancers. Novel lncRNAs involved in the initiation and progression of HBV-related hepatocellular carcinoma (HCC) need to be investigated. Here, we report that the long non-coding RNA LINC01352 is markedly downregulated by HBV/HBx (HBV X protein) in HCC cells and clinical samples. The LINC01352 expression level in HCC is an independent prognostic factor for survival. We found that HBx suppresses LINC01352 promoter activity by forming a complex with the estrogen receptor (ERα). Furthermore, using a combination of in vitro and in vivo studies, we confirmed that HBx promotes HCC cell growth and metastasis by inhibiting LINC01352 expression. Further investigation revealed that the downregulation of LINC01352, which acts as an endogenous sponge, increases the expression of miR-135b, leading to the reduced production of adenomatous polyposis coli (APC), consequently activating Wnt/ß-catenin signalling to facilitate tumour progression. These findings strongly suggest that the LINC01352-miR-135b-APC axis regulated by the HBx/ERα complex acts as an important pathogenic factor for tumour progression, which may help provide a theoretical basis for the identification of new therapeutic targets for HBV-related HCC.


Assuntos
Proteína da Polipose Adenomatosa do Colo/genética , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , Idoso , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/virologia , Linhagem Celular Tumoral , Receptor alfa de Estrogênio/genética , Feminino , Hepatite B/complicações , Hepatite B/genética , Hepatite B/patologia , Hepatite B/virologia , Vírus da Hepatite B/genética , Vírus da Hepatite B/patogenicidade , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas/genética , Transdução de Sinais/genética , Transativadores/genética , Proteínas Virais Reguladoras e Acessórias/genética
19.
Int J Mol Med ; 45(4): 1261-1269, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32124952

RESUMO

The authors' previous studies demonstrated that the major renal damage from hepatitis B virus infection is HBx­induced apoptosis of renal tubular epithelial cells. Cordyceps sinensis is one of the most valuable of traditional Chinese medicines and is extensively used to treat chronic renal diseases. However, there is no research on the potential renal protective effect of C. sinensis on HBx­induced apoptosis of renal tubular cells. The protective effect and underlying mechanism of C. sinensis were examined using a renal tubular epithelial cell line stably overexpressing HBx. HK­2 cells were stably transfected with pCMV­HBx to establish HBx­overexpression in an in vitro cell model and HK­2 cells transfected with an empty vector were generated as a control. The effect of C. sinensis on cell proliferation and apoptosis, the phosphatidylinositol­3­kinase (PI3K)/protein kinase B (Akt) signaling pathway, and the enzyme activity of caspase­3 and caspase­9 was measured. The present study demonstrated that HBx transfection inhibited cell proliferation; increased apoptosis, caspase­3 and caspase­9 activity; and increased the activity of the PI3K/Akt pathway. Treatment with C. sinensis attenuated all of these HBx­induced responses. HBx triggered apoptosis and activated the PI3K/Akt signaling pathway in HK­2 cells. C. sinensis treatment significantly attenuated the effect of HBx, at least in part by suppressing the PI3K/Akt signaling pathway.


Assuntos
Apoptose , Cordyceps/química , Vírus da Hepatite B/metabolismo , Hepatite B/metabolismo , Túbulos Renais Proximais/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transativadores/metabolismo , Proteínas Virais Reguladoras e Acessórias/metabolismo , Linhagem Celular , Hepatite B/patologia , Humanos , Túbulos Renais Proximais/patologia
20.
Adv Exp Med Biol ; 1179: 71-107, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31741334

RESUMO

More than 95% of adult infected with HBV show acute self-limited infection and eventually eliminate the virus. In contrast, about 90% of people exposed to HBV in early childhood develop chronic infection. The specificity of the virus and the host's antiviral immune responses together determine the outcome of HBV infection. It is generally believed that viral genome variation, viral titers, and inhibition of viral components against the host immune system are associated with persistent infection and liver damage. The dysfunction of innate immune cells (NK cells, monocyte/macrophages, NKT cells, etc.) and adaptive immune cells (antigen-presenting cells, T cells, B cells) is a key factor leading to virus clearance failure and liver inflammation. In this chapter, we summarize these viral factors and host factors in acute and chronic hepatitis B and update recent understanding of the immune-tolerant phase and pathological mechanisms associated with age and vertical transmission. This will help us to understand more fully the mechanisms of chronic HBV infection and liver injury and to develop combined treatment strategies of direct antiviral drugs for HBV life cycle and immunomodulators.


Assuntos
Vírus da Hepatite B , Hepatite B , Antivirais/uso terapêutico , Hepatite B/tratamento farmacológico , Hepatite B/imunologia , Hepatite B/patologia , Hepatite B/virologia , Vírus da Hepatite B/genética , Vírus da Hepatite B/imunologia , Hepatite B Crônica/imunologia , Hepatite B Crônica/patologia , Hepatite B Crônica/virologia , Humanos , Carga Viral
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