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There is still controversy about whether to continue antiviral therapy (AVT) after delivery, especially for pregnant women in the immune tolerance (IT) phase. In this study, a retrospective cohort study was conducted to explore the relationship between hepatitis B e antigen (HBeAg) decline rate (%) from mid-pregnancy to delivery and HBeAg seroconversion postpartum among patients using nucleos(t)ide analogs (NAs) to prevent mother-to-child transmission (MTCT), with the goal of identifying the ideal candidates for postpartum AVT continuation. This retrospective cohort study included 151 postpartum women. Univariate and multivariable logistic regression analyses were conducted to assess the association between the HBeAg decline rate (%) from mid-pregnancy to delivery and HBeAg seroconversion postpartum. Receiver operating characteristic (ROC) analysis was utilized to evaluate the predictive capacity of the HBeAg decline rate (%) and determine the optimal cut-off point. The univariate analysis revealed a significant association between the HBeAg decline rate (%) and HBeAg seroconversion postpartum (OR 1.068, 95% CI: 1.034-1.103, p < .001). In the multivariate regression analysis, adjusting for age, hepatitis B surface antigen (HBsAg) titre (log10 IU/mL) at mid-pregnancy, HBeAg titre (log10 S/CO) at mid-pregnancy, and hepatitis B virus (HBV) DNA load decline rate (%) from mid-pregnancy to delivery, the HBeAg decline rate(%) remained significantly associated with HBeAg seroconversion postpartum (OR 1.050, 95% CI: 1.015-1.093, p = .009). Then HBeAg decline rate (%) was treated as a categorical variable (tertiles) for sensitivity analysis. In the three distinct models, taking Tertile1 as a reference, women in Tertile3 still had a 4.201-fold (OR 4.201, 95% CI: 1.382-12.773, p = .011) higher risk of developing HBeAg seroconversion (p for trend <.05) after adjusting above covariates. The area under the curve (AUC) was 0.723 (95% CI: 0.627-0.819). The optimal cut-off value was 5.43%, with a sensitivity of 0.561, specificity of 0.791, and Youden's index of 0.352.A higher HBeAg decline rate (%) from mid-pregnancy to delivery independently correlated with an increased risk of HBeAg seroconversion postpartum. This decline rate can serve as a valuable clinical indicator for predicting HBeAg seroconversion.
Assuntos
Antígenos E da Hepatite B , Período Pós-Parto , Complicações Infecciosas na Gravidez , Soroconversão , Humanos , Feminino , Gravidez , Antígenos E da Hepatite B/sangue , Adulto , Estudos Retrospectivos , Complicações Infecciosas na Gravidez/imunologia , Complicações Infecciosas na Gravidez/tratamento farmacológico , Antivirais/uso terapêutico , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/imunologia , Adulto Jovem , Curva ROC , Hepatite B/imunologia , Vírus da Hepatite B/imunologiaRESUMO
BACKGROUND: The purpose of this study was to evaluate the diagnostic value of the GeneXpert® MTB/RIF (Xpert®), Auramine O staining method, and Lowenstein-Jensen medium for bacteriologically confirmed pulmonary tuberculosis and explore the effects of the sputum bacillary load (SBL) and qRTâPCR threshold cycle (Ct) value on the detection methods. METHODS: We retrospectively analysed the results in the Department of Infectious Disease for 49 months. The χ2 test was used to compare the performances of each method, receiver operating characteristic curve analysis was used to determine the optimal cut-off values, and the factors associated with a false-negative result from Xpert® were analysed by logistic regression. RESULTS: Simultaneous analysis of 980 sputum specimens showed that the positive detection rate of Xpert® did not increase with increasing SBL, and there were differences between the three when SBL ≤ 1 + (all P < 0.05). There was a good negative correlation between the Ct value and the SBL (P < 0.0001). Age was an independent risk factor for false-negative Xpert® results (P = 0.029), and when Ct < 16, the diagnostic sensitivity and specificity were both 100.00%. The optimal cut-off Ct values for resegmentation based on the drug resistance classification were < 18.6, 18.6-34.1, and > 34.1 cycles. CONCLUSIONS: Xpert® was not affected by SBL but it was by age, and it is more advantageous when SBL ≤ 1 + . The results regarding rifampicin resistance were reliable, and the novel Ct segmentation was a practical and more clinically meaningful classification method for diagnosing rifampicin resistance. These findings will help improve physicians' ability to accurately diagnose TB.
Assuntos
Antibióticos Antituberculose , Bacillus , Mycobacterium tuberculosis , Tuberculose Pulmonar , Humanos , Rifampina/farmacologia , Rifampina/uso terapêutico , Estudos Retrospectivos , Mycobacterium tuberculosis/genética , Antibióticos Antituberculose/uso terapêutico , Escarro , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/tratamento farmacológico , Sensibilidade e Especificidade , FirmicutesRESUMO
In the past, hepatic stellate cells (HSCs) were considered to be noninflammatory cells and to contribute to liver fibrosis by producing extracellular matrix. Recently, it was found that HSCs can also secrete cytokines and chemokines and therefore participate in hepatic inflammation. Autophagy participates in many immune response processes in immune cells. It is unclear whether autophagy is involved in inflammatory cytokine induction in HSCs. MAPK p38, Ulk1 phosphorylation, and the Ulk1-Atg13 complex were analyzed in HSC-T6 cells after LPS treatment. The relationship between autophagy inhibition and inflammation was investigated in primary rat HSCs. We discovered that LPS inhibited autophagy through MAPK p38. The activation of MAPK p38 induced Ulk1 phosphorylation, which disrupted the Ulk1-Atg13 complex and therefore inhibited autophagy. Furthermore, in primary rat HSCs, we demonstrated that autophagy inhibition regulated IL-1ß induction, which depended on the MAPK p38/Ulk1 pathway. Our results reveal a continuous signaling pathway, MAPK p38-Ulk1 phosphorylation-Ulk1-Atg13 disruption, which inhibits autophagy and induces IL-1ß expression in HSCs.NEW & NOTEWORTHY LPS inhibits autophagy in a concentration- and dose-dependent manner in HSC-T6 cells. MAPK p38 induces phosphorylation of Ulk1, which disrupts the Ulk1-Atg13 complex and is therefore required for the inhibition of autophagy by LPS. LPS induces IL-1ß expression via the MAPK p38/Ulk1 pathway in HSCs.
Assuntos
Células Estreladas do Fígado , Lipopolissacarídeos , Animais , Autofagia , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/genética , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Citocinas/metabolismo , Células Estreladas do Fígado/metabolismo , Inflamação/metabolismo , Interleucina-1beta , Lipopolissacarídeos/metabolismo , Lipopolissacarídeos/farmacologia , Fosforilação , Ratos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Persistent hepatic damage and chronic inflammation in liver activate the quiescent hepatic stellate cells (HSCs) and cause hepatic fibrosis (HF). Several microRNAs regulate the activation and proliferation of HSCs, thereby playing a critical role in HF progression. Previous studies have reported that miR-188-5p is dysregulated during the process of HF. However, the role of miR-188-5p in HF remains unclear. This study investigated the potential role of miR-188-5p in HSCs and HF. Firstly, we validated the miR-188-5p expression in primary cells isolated from liver of carbon tetrachloride (CCl4 )-induced mice, TGF-ß1-induced LX-2 cells, livers from 6-month high-fat diet (HFD)-induced rat and 4-month HFD-induced mice NASH models, and human non-alcoholic fatty liver disease (NAFLD) patients. Furthermore, we used miR-188-5p inhibitors to investigate the therapeutic effects of miR-188-5p inhibition in the HFD + CCl4 induced in vivo model and the potential role of miR-188-5p in the activation and proliferation of HSCs. This present study reported that miR-188-5p expression is significantly increased in the human NAFLD, HSCs isolated from liver of CCl4 induced mice, and in vitro and in vivo models of HF. Mimicking the miR-188-5p resulted in the up-regulation of HSC activation and proliferation by directly targeting the phosphatase and tensin homolog (PTEN). Moreover, inhibition of miR-188-5p reduced the activation and proliferation markers of HSCs through PTEN/AKT pathway. Additionally, in vivo inhibition of miR-188-5p suppressed the HF parameters, pro-fibrotic and pro-inflammatory genes, and fibrosis. Collectively, our results uncover the pro-fibrotic role of miR-188-5p. Furthermore, we demonstrated that miR-188-5p inhibition decreases the severity of HF by reducing the activation and proliferation of HSCs through PTEN/AKT pathway.
Assuntos
Células Estreladas do Fígado/citologia , Cirrose Hepática/prevenção & controle , MicroRNAs/antagonistas & inibidores , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Adulto , Animais , Apoptose , Proliferação de Células , Células Cultivadas , Feminino , Regulação da Expressão Gênica , Células Estreladas do Fígado/metabolismo , Humanos , Cirrose Hepática/etiologia , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , PTEN Fosfo-Hidrolase/genética , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , RatosRESUMO
BACKGROUND: A series of evidence revealed that body mass index was an important confounding factor in the research of uric acid and ischemic heart disease/hypertension. The objective of this study was to investigate whether obesity status can modify the association between serum uric acid and the severity of liver damage in NAFLD, and the possible interactive effect of hyperuricemia and obesity. METHODS: We conducted a cross-sectional study in a total of 557 ultrasound diagnosed-NAFLD. The hepatic steatosis and liver fibrosis were quantitatively evaluated by transient elastography. Hyperuricemia was defined as serum uric acid > 420 µmol/L in men, > 360 µmol/L in women and obesity was defined as body mass index ≥ 25 kg/m2. The adjusted OR values of hyperuricemia and obesity were analyzed by multivariate logistic regression analysis, and the additive model was used to investigate the possible interactive effect. RESULTS: Multivariate regression analysis showed that hyperuricemia was associated with serious hepatic steatosis (1.74[1.09-2.79]) and elevated ALT (2.17[1.38-3.41]), but not with advanced fibrosis (1.61[0.91-2.85]). The association was further investigated in different BMI group. Hyperuricemia was associated with higher odds of serious hepatic steatosis (2.02[1.14-3.57]) and elevated ALT (2.27[1.37-3.76]) only in obese NAFLD, not in non-obese subjects. Similarly, patients with hyperuricemia had higher odds of advanced fibrosis in obese subjects (2.17[1.13-4.18]), not in non-obese subjects (0.60[0.14-2.70]). Furthermore, there was an additive interaction between hyperuricemia and obesity on the odds of serious hepatic steatosis (AP: 0.39[0.01-0.77]) and advanced fibrosis. (AP: 0.60[0.26-0.95]). CONCLUSIONS: Hyperuricemia and obesity had a significantly synergistic effect on the hepatic steatosis and fibrosis. Thus, management of uric acid may need to be targeted in obese NAFLD.
Assuntos
Hiperuricemia , Hepatopatia Gordurosa não Alcoólica , Índice de Massa Corporal , Estudos Transversais , Feminino , Humanos , Hiperuricemia/complicações , Hiperuricemia/epidemiologia , Masculino , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Obesidade/complicações , Obesidade/epidemiologia , Ácido ÚricoRESUMO
BACKGROUND & AIMS: There is limited evidence on the efficacy and safety of nucleos(t) ide analogues (NAs) in the treatment of HBV-ACLF. Our objective was to evaluate the outcomes among TAF, TDF and ETV, three first-line antivirals against chronic hepatitis B, in patients with HBV-ACLF. METHODS: Patients with HBV-related ACLF were recruited and received daily TAF (25 mg/d), TDF (300 mg/d) and ETV (0.5 mg/d). They were prospectively followed-up. The primary endpoint was overall survival at week 12 and week 48, the secondary endpoints were virological response and biochemical response. RESULTS: Forty gender and age matched eligible subjects were recruited and divided into three groups: TAF group, TDF group and ETV group. By week 48, 8 (80%) patients in TAF group, 6 (60%) patients in TDF group and 17 (85%) patients in ETV group survived without liver transplantation (P = 0.251). After 4 weeks of NAs treatment, all three groups showed paralleling reduction of HBV DNA levels. All three groups presented similar biochemical responses at week 4, patients treated with TAF showed a priority in total bilirubin reduction, albumin and cholesterol maintenance. Additionally, although there was no significant difference in changes of serum urea, serum creatinine, serum cystatin C and estimated GFR among the three groups by treatment week 4, TDF showed unfavorable renal safety even in short -term treatment. The treatment using NAs was well-tolerated and there was no serious drug-related adverse event reported. CONCLUSIONS: TAF, TDF and ETV are of similar efficacy and safety in short-term and long-term treatment of HBV-ACLF. TRIAL REGISTRATION: This study is ongoing and is registered with ClinicalTrials.gov , NCT03640728 (05/02/2019).
Assuntos
Insuficiência Hepática Crônica Agudizada/tratamento farmacológico , Antivirais/uso terapêutico , Hepatite B Crônica/tratamento farmacológico , Adenina/análogos & derivados , Adenina/uso terapêutico , Adulto , Alanina , Guanina/análogos & derivados , Guanina/uso terapêutico , Vírus da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/genética , Humanos , Masculino , Pessoa de Meia-Idade , Tenofovir/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: HBV-resistant mutants in treatment-naïve patients may lead to antiviral treatment failure. It is not clear if HBV mutants are present in pregnant women and about the influence of the preexisting mutants on the short-term antiviral therapy during pregnancy. METHOD: We enrolled 73 pregnant women with high HBV DNA load and telbivudine (TBV) treatment during pregnancy in this retrospective study. The UDPS was used to detect the HBV mutations before and after the TBV treatment. RESULTS: Before TBV treatment, the complexity of HBV quasispecies of all subjects was 0.40 ± 0.09; 41.1% (30/73) and 53.4% (39/73) subjects had rtM204I/V and rtN236 T/A detected, respectively; and 9.6% (7/73) patients had more than 20% frequency mutation of rtM204I/V, which was also similar with high frequency of rtN236 T/A mutation (41.1% vs. 53.4%, P=0.136; frequencies >20%: 9.6% vs. 5.5%, P=0.347). After TBV treatment, 71.2% (52/73) subjects had HBV DNA load ≥ 103 IU/mL at delivery. Among them, 75.0% of patients with rtM204I positive had HBV DNA load ≥103 IU/mL at delivery, which was comparable with the subjects without rtM204I (75.0% vs. 70.8%, P=0.710). No changes were found in the frequencies and the complexity of HBV quasispecies of rtM204I mutation after the TVB treatment. CONCLUSION: The prevalence of preexisting drug-resistant mutations among pregnant women was high using UPDS. However, the preexisting HBV mutation had limited influence on the efficacy of short-term TBV treatment, and TBV treatment during late pregnancy seemed not to increase the risk of emerging HBV-resistant mutants.
RESUMO
Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related mortality worldwide. The expression of nitric oxide synthase (NOS) and the inhibition of autophagy have been linked to cancer cell death. However, the involvement of serum nitric oxide (NO), the expression of NOS and autophagy have not been investigated in HCC. In the present study, we first established that the NO level was significantly higher in hepatitis B virus-related HCC than in the liver cirrhosis control (53.60 ± 19.74 vs 8.09 ± 4.17 µmol/L, t = 15.13, P < 0.0001). Using immunohistochemistry, we found that the source of NO was at least partially attributed to the expression of inducible NOS and endothelial NOS but not neuronal NOS in the liver tissue. Furthermore, in human liver cancer cells, NO-induced apoptosis and inhibited autophagy. Pharmacological inhibition of autophagy also induced apoptosis, whereas the induction of autophagy could ameliorate NO-induced apoptosis. We also found that NO regulates the switch between apoptosis and autophagy by disrupting the Beclin 1/Vps34 association and by increasing the Bcl-2/Beclin 1 interaction. Overall, the present findings suggest that increased NOS/NO promotes apoptosis through the inhibition of autophagy in liver cancer cells, which may provide a novel strategy for the treatment of HCC.
Assuntos
Apoptose/fisiologia , Autofagia/fisiologia , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Óxido Nítrico/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Proteína Beclina-1/metabolismo , Feminino , Humanos , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismoRESUMO
Mother-to-child transmission (MTCT) is a major obstacle in the elimination of hepatitis B virus (HBV) infection. Telbivudine (LdT) and tenofovir disoproxil fumarate (TDF) are the two most common antiviral medicines for preventing MTCT. However, the efficacy and safety of LdT and TDF in preventing HBV vertical transmission during the second to third trimester have not been compared rigorously. Therefore, we carried out a prospective multicentre cohort study of chronic hepatitis B in mothers with HBV DNA > 106 IU/mL, receiving LdT or TDF during the second to third trimester. Among the 893 mothers enrolled, 857 (LdT/TDF/untreated group (NTx) = 396/325/136) completed consecutive follow-up with 854 infants (LdT/TDF/NTx = 395/323/136). LdT and TDF treatment resulted in a similar decrease of HBV DNA in mothers at delivery. Multivariate analysis indicated that only HBsAg titre at the baseline correlated with viral DNA decrease (P = 0.015). With intention-to-treat analysis, MTCT rates in the LdT, TDF and NTx group were 4.41%, 2.42% and 22.08%, respectively. An increasing vertical transmission rate was found to be closely associated with higher HBsAg titre, 5.32% and 17.65% infection rate was estimated in infants born to mothers with HBsAg > 4 and >5 log10 IU/mL, respectively. No serious side effects were reported in either mothers or infants. LdT and TDF treatments were well tolerated and showed comparable efficacy in reducing MTCT. Higher risk of MTCT was shown in pregnant women with HBsAg > 4 log10 IU/mL.
Assuntos
Antivirais/uso terapêutico , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/transmissão , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Telbivudina/uso terapêutico , Tenofovir/uso terapêutico , Adulto , Antivirais/efeitos adversos , DNA Viral/sangue , Feminino , Antígenos de Superfície da Hepatite B/sangue , Vírus da Hepatite B/isolamento & purificação , Humanos , Gravidez , Complicações Infecciosas na Gravidez/tratamento farmacológico , Estudos Prospectivos , Telbivudina/efeitos adversos , Tenofovir/efeitos adversos , Resultado do Tratamento , Carga Viral , Adulto JovemRESUMO
We previously found that genetic factors are associated with a familial predisposition for developing liver cirrhosis and hepatocellular carcinoma during chronic hepatitis B virus (HBV) infection. Autophagy has been shown to play a role in HBV replication and the course of disease. More than 190 host genes have been identified that modify the process of autophagy, but which of these genes are involved in chronicity of HBV infection and how this occurs remains unclear. Chronic hepatitis B (CHB) patients were recruited to investigate the expression of autophagy-modulating genes in peripheral blood mononuclear cells (PBMCs). mRNA prepared from PBMCs from members of two families with clustering HBV infection, including 11 CHB patients and nine healthy spouses, was hybridized to high-density oligonucleotide arrays. Immunoblot analysis was used to determine the level of autophagy. Of the 192 autophagy-modulating genes, 18 were found to be differently expressed. Of these, 11 displayed decreased expression in CHB patients, while seven displayed increased expression compared to those in healthy controls. Functional analysis showed that these genes are closely involved in initiation, nucleation, elongation of phagophores, formation of autophagosomes, transportation to lysosomes, and the process of degradation. Western blot analysis revealed inhibited autophagy in PBMCs based on decreased lipidation of LC3II. A differential expression profile of autophagy-modulating genes was observed, and decreased autophagy in PBMCs could be closely associated with chronicity of HBV infection, suggesting a novel strategy for the treatment of patients with chronic HBV infection.
Assuntos
Proteínas Relacionadas à Autofagia/genética , Autofagia/genética , Redes Reguladoras de Genes/genética , Hepatite B Crônica/genética , Leucócitos Mononucleares/fisiologia , Autofagossomos/fisiologia , Análise por Conglomerados , Feminino , Vírus da Hepatite B/patogenicidade , Hepatite B Crônica/virologia , Humanos , Lisossomos/fisiologia , Masculino , RNA Mensageiro/genéticaRESUMO
BACKGROUND: Sofosbuvir is the keystone of direct antiviral agents for the chronic hepatitis C (CHC). The safety of sofosbuvir in patients with stage 4-5 chronic kidney disease (CKD) needs further observation in real world. CASE PRESENTATION: Thirty-three patients with stage 5 CKD and hepatitis C virus (HCV) infection from 2 hemodialysis centers accepted sofosbuvir based treatment as we reported previously. Serum potassium concentrations were tested every 4 weeks or on demand. Ten of 33 patients showed recurrence of hyperkalemia. We summarized the characteristics of hyperkalemia occurrence in these 10 patients. Overall, 24 episodes of hyperkalemia were observed in these 10 patients, 21 were under treatment and 3 were after treatment. Patients with or without hyperkalemia before sofosbuvir treatment didn't show significantly differences in the median frequencies of hyperkalemia episodes during the observation period (3.5 vs. 2, p = 0.264). CONCLUSIONS: Patients with stage 5 CKD and HCV infection treated with sofosbuvir based regimens, even halved sofosbuvir, should be taken caution and closely monitoring serum potassium and renal function is necessary.
Assuntos
Antivirais/uso terapêutico , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Hiperpotassemia/induzido quimicamente , Hiperpotassemia/epidemiologia , Insuficiência Renal Crônica/complicações , Adulto , Idoso , Estudos de Coortes , Quimioterapia Combinada , Feminino , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/epidemiologia , Sofosbuvir/uso terapêutico , Resposta Viral SustentadaRESUMO
Liver sinusoids serve as the first line of defense against extrahepatic stimuli from the intestinal tract. Hepatic stellate cells (HSCs) are pericytes residing in the perisinusoidal space that integrate cytokine-mediated inflammatory responses in the sinusoids and relay these signals to the liver parenchyma. Oxidative stress has been shown to promote inflammation during acute liver failure (ALF). Whether and how oxidative stress is involved in HSC inflammation during ALF remains unclear. Level of systemic oxidative stress is reflected by superoxide dismutase (SOD). Thus, ALF patients were recruited to investigate the correlation between plasma SOD levels and clinical features. Liver tissues were collected from chronic hepatitis patients by biopsy and from ALF patients who had undergone liver transplantation. SOD2 expression and HSCs activation were investigated by immunohistochemistry. Inflammation, mitophagy, and apoptosis were investigated by immunoblot analysis and flow cytometry in HSCs treated with lipopolysaccharide (LPS) and reactive oxygen species (ROS) donors. The plasma SOD level was significantly increased in patients with ALF compared with those with cirrhosis (444.4 ± 23.58 vs. 170.07 ± 3.52 U/ml, P < 0.01) and was positively correlated with the Model for End-Stage Liver Disease-Na score ( R2 = 0.4720, P < 0.01). In vivo observations revealed that SOD2 immunostaining was increased in ALF patients and mice models, and in vitro experiments demonstrated that LPS/ROS promoted inflammation via inhibiting mitophagy. Moreover, the regulation of inflammation was apoptosis independent in HSCs. LPS-induced increases in oxidative stress promote inflammation through inhibiting mitophagy in HSCs during the process of ALF, providing a novel strategy for the treatment of patients with ALF. NEW & NOTEWORTHY Here we demonstrate that the serum superoxide dismutase (SOD) level is significantly increased in patients with acute liver failure (ALF), and, correlated with the Model for End-Stage Liver Disease-Na score, SOD level dropped in the remission stage of ALF. We identify that, in liver tissue from ALF patients and mice models, manganese-dependent SOD was overexpressed, and show lipopolysaccharide/H2O2 inhibits mitophagy via reactive oxygen species in hepatic stellate cells (HSCs). We show that inhibited mitophagy promotes inflammation in HSCs, whereas mitophagy inducer rescues HSCs from lipopolysaccharide-induced inflammation.
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Hepatite Crônica , Falência Hepática Aguda , Fígado/metabolismo , Animais , Apoptose/fisiologia , Células Estreladas do Fígado/metabolismo , Hepatite Crônica/metabolismo , Hepatite Crônica/patologia , Humanos , Peróxido de Hidrogênio/metabolismo , Inflamação/metabolismo , Falência Hepática Aguda/metabolismo , Falência Hepática Aguda/patologia , Camundongos , Mitofagia , Estresse Oxidativo/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/sangue , Superóxido Dismutase/metabolismoRESUMO
Hepatitis B virus (HBV) infections and adverse outcome have been demonstrated to show characteristics of familial clustering. The aim of this study was to investigate the prevalence of different HBV genotypes, HBV sub-genotypes, and Pre-S mutations associated with familial HBV infection clusters with unfavorable prognoses. Families presenting with clustered HBV infections and unfavorable prognoses were enrolled in this study. Non-clustered HBV-infected individuals were used as the control group. DNA extracted from patient serum samples was used to facilitate characterization of the HBV genotypes, HBV sub-genotypes, and Pre-S mutations by phylogenetic analysis. The Pre-S/S gene was successfully amplified in 83 patients from the clustering group and 105 patients from the sporadic group. The prevalence of genotype C in the clustering group (71/83, 85.54%) was significantly higher than in the sporadic group (77/105, 73.33%) (P = 0.042). The prevalence of sub-genotype C2 in the clustering group (33/83, 39.76%) was also higher than in the sporadic group (21/105, 20%) (P = 0.003). Analyses of functional mapping of pre-S sequences showed that the prevalence of the mutation in the S promoter site (nt 3045-3189 of pre-S1 domain) was significantly increased in the clustering group compared with the sporadic group (15.7% vs. 3.8%) (P = 0.009). This study suggests that genotype C, especially sub-genotype C2, may be associated with the progression of HBV infection in familial clustering infection cohorts with unfavorable prognoses. We also observed that the natural occurrence of S promoter mutations in the clustering group was significantly prevalent.
Assuntos
Análise por Conglomerados , Saúde da Família , Genótipo , Vírus da Hepatite B/classificação , Vírus da Hepatite B/genética , Hepatite B/epidemiologia , Epidemiologia Molecular , Adulto , Idoso , China/epidemiologia , Estudos Epidemiológicos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
BACKGROUND & AIMS: We previously found that hepatic stellate cell activation induced by autophagy maintains the liver architecture to prevent collapse during acute liver failure. Nitric oxide has shown to induce hepatic stellate cell apoptosis. Whether and how nitric oxide is involved in acute liver failure and autophagy remains unclear. METHODS: Acute liver failure patients were recruited to investigate the correlation between plasma nitric oxide levels and clinical features. Liver tissues were collected from chronic hepatitis patients by biopsy and from acute liver failure patients who had undergone liver transplantation. The expression of nitric oxide synthases and hepatic stellate cell activation (alpha-SMA), and autophagic activity (LC3) were investigated by immunohistochemistry. Autophagy and apoptosis were investigated by immunoblot analysis, confocal microscopy, and flow cytometry in hepatic stellate cells treated with nitric oxide donors. RESULTS: Plasma nitric oxide level was significantly increased in patients with acute liver failure compared to those with cirrhosis (53.60±19.74 µM vs 19.40±9.03 µM, Z=-7.384, P<.001) and positively correlated with MELD-Na score (r=.539, P<.001), implicating nitric oxide in acute liver failure. At least some Nitric oxide was produced by overexpression of inducible nitric oxide synthases and endothelial nitric oxide synthases, but not neuronal nitric oxide synthases in the liver tissue. In vivo observation revealed that autophagy was inhibited in hepatic stellate cells based on decreased LC3 immunostaining, and in vitro experiments demonstrated that Nitric oxide can inhibit autophagy. Moreover, nitric oxide promoted hepatic stellate cell apoptosis, which was rescued by an autophagy inducer. CONCLUSIONS: Increased nitric oxide synthases/ nitric oxide promotes apoptosis through autophagy inhibition in hepatic stellate cells during acute liver failure, providing a novel strategy for the treatment of patients with acute liver failure.
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Apoptose , Autofagia , Células Estreladas do Fígado/citologia , Falência Hepática Aguda/sangue , Óxido Nítrico/sangue , Adulto , Animais , Feminino , Hepatite Crônica/complicações , Humanos , Fígado/patologia , Cirrose Hepática/complicações , Falência Hepática Aguda/patologia , Falência Hepática Aguda/cirurgia , Transplante de Fígado , Masculino , Pessoa de Meia-Idade , Óxido Nítrico Sintase/metabolismoRESUMO
Although food processing can alter food allergenicity, the impact of extrusion processing on in vivo hazelnut allergenicity is unknown. Here, we tested the hypothesis that extrusion processing will alter the immune activation properties of hazelnut protein (HNP) in mice. Soluble extrusion-processed HNP (EHNP) was prepared and evaluated for immune response using an established transdermal sensitization mouse model. Mice were sensitized with identical amounts of EHNP versus raw HNP. After confirming systemic IgE, IgG1 and IgG2a antibody responses, oral hypersensitivity reaction was quantified by hypothermia shock response (HSR). Mechanism was studied by measuring mucosal mast cell (MMC) degranulation. Compared to raw HNP, the EHNP elicited slower but similar IgE antibody (Ab) response, lower IgG1 but higher IgG2a Ab response. The EHNP exhibited significantly lower oral HSR as well as MMC degranulation capacity. These results demonstrate that the extrusion technology can be used to produce soluble HNP with altered immune activation properties.
Assuntos
Corylus/química , Manipulação de Alimentos , Hipersensibilidade a Noz/imunologia , Nozes/química , Proteínas de Plantas/imunologia , Animais , Formação de Anticorpos , Corylus/imunologia , Modelos Animais de Doenças , Feminino , Imunoglobulina E/imunologia , Imunoglobulina G/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Hipersensibilidade a Noz/prevenção & controle , Nozes/imunologia , Proteínas de Plantas/isolamento & purificaçãoRESUMO
BACKGROUND & AIMS: Acute liver failure (ALF) is a condition with high mortality and morbidity. Fibrosis in chronic liver disease was extensively researched, whereas fibrosis and underlying mechanism in acute liver failure remains unclear. METHODS: Hepatitis B virus related ALF patients were recruited to investigate if there was ongoing fibrosis by liver histology and liver stiffness measurement(LSM) analysis as well as fibrosis markers assay. Sera HMGB1 were kinetically detected in progression and remission stage of ALF. Hepatic stellate cell(HSC) activation by HMGB1 was explored by testing mRNA and protein level of α-SMA and collagen 1a1 by using qPCR and western blot. Autophagy induction by HMGB1 was explored by LC3-II conversion, autophagy flux and fluorescence. RESULTS: Firstly, ongoing fibrosis in progression stage of ALF was confirmed by histological analysis, LS measurement as well as fibrosis markers detection. HSC activation and autophagy induction in explanted liver tissue also revealed. Next, kinetic monitoring sera HMGB1 revealed elevated HMGB1 in progression stage of ALF vs HBsAg carrier, and drop back to base level in remission stage. Thirdly, rHMGB1 dose dependently activated HSCs, as indicated by increased mRNA and proteins level in α-SMA and collagen 1a1. Moreover, autophagy was induced in HSC treated with rHMGB1, as illustrated by increased LC3 lipidation, elevated autophagy flux and GFP-LC3 puncta. CONCLUSIONS: Acute liver failure is accompanied by ongoing fibrosis, HSC activation and autophagy induction. Increased HMGB1 activates HSC via autophagy induction. Those findings integrate HMGB1, HSCs activation, autophagy into a common framework that underlies the fibrosis in ALF.
Assuntos
Células Estreladas do Fígado/patologia , Hepatite B/complicações , Cirrose Hepática/diagnóstico , Falência Hepática Aguda/diagnóstico , Fígado/patologia , Actinas/genética , Actinas/metabolismo , Animais , Autofagia , Biomarcadores/sangue , Biópsia , Células Cultivadas , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Cadeia alfa 1 do Colágeno Tipo I , Progressão da Doença , Técnicas de Imagem por Elasticidade , Proteína HMGB1/sangue , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/virologia , Hepatite B/diagnóstico , Humanos , Fígado/metabolismo , Fígado/virologia , Cirrose Hepática/sangue , Cirrose Hepática/genética , Cirrose Hepática/patologia , Cirrose Hepática/virologia , Falência Hepática Aguda/sangue , Falência Hepática Aguda/genética , Falência Hepática Aguda/patologia , Falência Hepática Aguda/virologia , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Valor Preditivo dos Testes , Estudos Prospectivos , Ratos , Transdução de SinaisRESUMO
The hepatitis B virus (HBV) whole-X gene comprises the HBV X gene and the 168-bp region immediately upstream. Although the functions of HBx in hepatocarcinogenesis are well known, the activity of the HBV whole-X protein (HBwx), with 56 additional amino acids, has not yet been explored. In this study, proteomic and bioinformatic analysis was done to determine the protein interaction profiles of HBwx and HBx and to describe their functions in carcinogenesis. A total of 203 proteins were identified that interacted with HBwx, of which 149 were unique, the rest interacting also with HBx, and 73% (148/203) of these proteins are involved in carcinogenesis. Gene ontology (GO) analysis showed that HBwx- and HBx-interacting proteins are involved in different processes, the former mainly in biosynthetic processes (glycolysis, cell-cycle functions, and protein folding), and the latter mainly in localization, viral transcription, biological adhesion and angiogenesis. Pathway networks analysis revealed that proteins interacting with HBx participate mainly in oxidative phosphorylation, localization, the cytoskeleton, and cell adhesion. In contrast, more-specific functional analysis showed that proteins interacting with HBwx are involved in apoptosis and survival, cell-cycle functions, glycolysis, and gluconeogenesis (Pathway Maps); to cellular macromolecular complex assembly, protein folding and mRNA metabolic process (GO Processes); and to regulation of protein folding in the endoplasmic reticulum and cytoplasm, transcription, cell cycle G2-M and cytoskeleton rearrangement (Process Networks). In conclusion, this study shows that HBwx functions in carcinogenesis in a way that is different from that of HBx.
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Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/virologia , Vírus da Hepatite B/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/virologia , Transativadores/metabolismo , Motivos de Aminoácidos , Carcinoma Hepatocelular/genética , Biologia Computacional , Vírus da Hepatite B/química , Vírus da Hepatite B/genética , Humanos , Neoplasias Hepáticas/genética , Ligação Proteica , Proteômica , Transativadores/química , Transativadores/genética , Proteínas Virais Reguladoras e AcessóriasRESUMO
INTRODUCTION: The absence of predictive models for early latent tuberculosis infection (LTBI) progression persists. This study aimed to create a screening model to identify high-risk LTBI patients prome to active tuberculosis (ATB) reactivation. METHODOLOGY: Patients with confirmed ATB were enrolled alongside LTBI individuals as a reference, with relevant clinical data gathered. LASSO regression cross-validation reduced data dimensionality. A nomogram was developed using multiple logistic regression, internally validated with Bootstrap resampling. Evaluation included C-index, receiver operating characteristic (ROC) curve, and calibration curves, with clinical utility assessed through decision curve analysis. RESULTS: The final nomogram incorporated serum albumin (OR = 1.337, p = 0.046), CD4+ (OR = 1.010, p = 0.004), and CD64 index (OR = 0.009, p = 0.020). The model achieved a C-index of 0.964, an area under the ROC curve of 0.962 (95% CI: 0.926-0.997), sensitivity of 0.971, and specificity of 0.910. Internal validation showed a mean absolute error of 0.013 and 86.4% identification accuracy. The decision curve indicated substantial net benefit at a risk threshold exceeding 10% (1: 9). CONCLUSIONS: This study established a biologically-rooted nomogram for high-risk LTBI patients prone to ATB reactivation, offering strong predictability, concordance, and clinical value. It serves as a personalized risk assessment tool, accurately identifying patients necessitating priority prophylactic treatment, complementing existing host risk factors effectively.
Assuntos
Tuberculose Latente , Nomogramas , Humanos , Tuberculose Latente/diagnóstico , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Adulto Jovem , Medição de Risco/métodos , Curva ROC , Tuberculose/diagnóstico , Tuberculose/complicações , Fatores de RiscoRESUMO
ABSTRACT: Chronic hepatitis B virus (HBV) infection is a global public health concern. Existing antiviral drugs, including nucleos(t)ide analogs and interferon-α, can suppress HBV replication and improve the prognosis. However, the persistence of covalently closed circular DNA (cccDNA), the integration of HBV-DNA into the host genome, and compromised immune responses impede the successful treatment of hepatitis B. While achieving a functional cure of HBV remains elusive with the current treatment methods, this is the goal of new therapeutic approaches. Therefore, developing novel antiviral drugs is necessary for achieving a functional or complete cure for chronic hepatitis B. In recent years, substantial progress has been made in drug discovery and development for HBV infection. Direct-acting antiviral agents such as entry inhibitors, capsid assembly modulators, subviral particle release inhibitors, cccDNA silencers, and RNA interference molecules have entered clinical trials. In addition, several immunomodulatory agents, including toll-like receptor agonists, therapeutic vaccines, checkpoint inhibitors, and monoclonal antibodies, are also making their way toward clinical use. In this review, we summarize the recent progress and limitations of chronic hepatitis B treatment and discuss perspectives on approaches to achieving functional cure. Although it will take some time for these new antiviral drugs to be widely used in clinical practice, combination therapy may become a preferable treatment option in the future.
RESUMO
In recent years, abnormal m6A alteration in hepatocellular carcinoma (HCC) has been a focus on investigating the biological implications. In this study, our objective is to determine whether m6A modification contributes to the progression of HBV-related HCC. To achieve this, we employed a random forest model to screen top 8 characteristic m6A regulators from 19 candidate genes. Subsequently, we developed a nomogram model that utilizes these 8 characteristic m6A regulators to predict the prevalence of HBV-related HCC. According to decision curve analysis, patients may benefit from the nomogram model. The clinical impact curves exhibited a robust predictive capability of the nomogram models. Additionally, consensus molecular subtyping was employed to identify m6A modification patterns and m6A-related gene signature. The quantification of immune cell subsets was accomplished through the implementation of ssGSEA algorithms. PCA algorithms were developed to compute the m6A score for individual tumors. Two distinct m6A modification patterns, namely cluster A and cluster B, exhibited significant correlations with distinct immune infiltration patterns and biological pathways. Notably, patients belonging to cluster B demonstrated higher m6A scores compared to those in cluster A, as determined by the m6A score metric. Furthermore, the expression of IGFBP3 proteins was validated through immunofluorescence, revealing their pronounced lower expression in tumor tissues. In summary, our study underscores the importance of m6A modification in the advancement of HBV-related HCC. This research has the potential to yield novel prognostic biomarkers and therapeutic targets for the identification of HBV-related HCC.