RESUMO
BACKGROUND: The role of circRNAs in hepatocellular carcinoma (HCC) progression remains unclear. CircPIAS1 (circBase ID: hsa_circ_0007088) was identified as overexpressed in HCC cases through bioinformatics analysis. This study aimed to investigate the oncogenic properties and mechanisms of circPIAS1 in HCC development. METHODS: Functional analyses were conducted to assess circPIAS1's impact on HCC cell proliferation, migration, and ferroptosis. Xenograft mouse models were employed to evaluate circPIAS1's effects on tumor growth and pulmonary metastasis in vivo. Bioinformatics analysis, RNA immunoprecipitation, and luciferase reporter assays were utilized to elucidate the molecular pathways influenced by circPIAS1. Additional techniques, including RNA pulldown, fluorescence in situ hybridization (FISH), chromatin immunoprecipitation (ChIP), qPCR, and western blotting, were used to further explore the underlying mechanisms. RESULTS: CircPIAS1 expression was elevated in HCC tissues and cells. Silencing circPIAS1 suppressed HCC cell proliferation and migration both in vitro and in vivo. Mechanically, circPIAS1 overexpression inhibited ferroptosis by competitively binding to miR-455-3p, leading to upregulation of Nuclear Protein 1 (NUPR1). Furthermore, NUPR1 promoted FTH1 transcription, enhancing iron storage in HCC cells and conferring resistance to ferroptosis. Treatment with ZZW-115, an NUPR1 inhibitor, reversed the tumor-promoting effects of circPIAS1 and sensitized HCC cells to lenvatinib. CONCLUSION: This study highlights the critical role of circPIAS1 in HCC progression through modulation of ferroptosis. Targeting the circPIAS1/miR-455-3p/NUPR1/FTH1 regulatory axis may represent a promising therapeutic strategy for HCC.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos , Carcinoma Hepatocelular , Proliferação de Células , Ferroptose , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas , MicroRNAs , Proteínas de Neoplasias , RNA Circular , Animais , Feminino , Humanos , Masculino , Camundongos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Progressão da Doença , Ferroptose/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/metabolismo , MicroRNAs/genética , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , RNA Circular/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The immune mechanism underlying hepatitis B surface antigen (HBsAg) loss, particularly type I inflammatory response, during pegylated interferon-α (PEG-IFN) therapy remains unclear. In this study, we aimed to elucidate such immune mechanisms. Overall, 82 patients with chronic hepatitis B (CHB), including 41 with HBsAg loss (cured group) and 41 uncured patients, received nucleos(t)ide analogue and PEG-IFN treatments. Blood samples from all patients, liver tissues from 14 patients with CHB, and hepatic perfusate from 8 liver donors were collected for immune analysis. Jurkat, THP-1 and HepG2.2.15 cell lines were used in cell experiments. The proportion of IFN-γ+ Th1 cells was higher in the cured group than in the uncured group, which was linearly correlated with HBsAg decline and alanine aminotransferase (ALT) levels during treatment. However, CD8+ T cells were weakly associated with HBsAg loss. Serum and intrahepatic levels of Th1 cell-associated chemokines (C-X-C motif chemokine ligand [CXCL] 9, CXCL10, CXCL11, IFN-γ) were significantly lower in the cured patients than in patients with a higher HBsAg quantification during therapy. Serum from cured patients induced more M1 (CD68+CD86+ macrophage) cells than that from uncured patients. Patients with chronic HBV infection had significantly lower proportions of CD86+ M1 and CD206+ M2 macrophages in their livers than healthy controls. M1 polarization of intrahepatic Kupffer cells promoted HBsAg loss by upregulating the effector function of tissue-resident memory T cells with increased ALT levels. IFN-γ+ Th1 activates intrahepatic resident memory T cells to promote HBsAg loss by inducing M1 macrophage polarization.
Assuntos
Antígenos de Superfície da Hepatite B , Hepatite B Crônica , Fígado , Macrófagos , Células T de Memória , Células Th1 , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antivirais/uso terapêutico , Antivirais/farmacologia , Antígenos de Superfície da Hepatite B/imunologia , Vírus da Hepatite B/imunologia , Hepatite B Crônica/imunologia , Hepatite B Crônica/tratamento farmacológico , Interferon-alfa , Interferon gama , Fígado/imunologia , Macrófagos/imunologia , Células T de Memória/imunologia , Células Th1/imunologiaRESUMO
Acute-on-chronic liver failure (ACLF) is a severe disease with a high mortality. Macrophage-related inflammation plays a crucial role in ACLF development. Mesenchymal stem cells (MSCs) treatment was demonstrated to be beneficial in ACLF in our previous study; however, the underlying mechanisms remain unknown. Therefore, mouse bone marrow-derived MSCs were used to treat an ACLF mouse model or cocultured with RAW264.7/J774A.1 macrophages that were stimulated with LPS. Histological and serological parameters and survival were analyzed to evaluate efficacy. We detected changes of Mer tyrosine kinase (Mertk), JAK1/STAT6, inflammatory cytokines, and markers of macrophage polarization in vitro and in vivo. In ACLF mice, MSCs improved liver function and 48-h survival of ACLF mice and alleviated inflammatory injury by promoting M2 macrophage polarization and elevated Mertk expression levels in macrophages. This is significant, as Mertk regulates M2 macrophage polarization via the JAK1/STAT6 signaling pathway.
Assuntos
Insuficiência Hepática Crônica Agudizada , Células-Tronco Mesenquimais , Camundongos , Animais , Insuficiência Hepática Crônica Agudizada/metabolismo , Proteínas Tirosina Quinases/metabolismo , Macrófagos/metabolismo , Transdução de Sinais , Células-Tronco Mesenquimais/metabolismo , c-Mer Tirosina Quinase/genética , c-Mer Tirosina Quinase/metabolismoRESUMO
BACKGROUND: Acute-on-chronic liver failure (ACLF) is a major challenge in the field of hepatology. While mesenchymal stem cell (MSC) therapy can improve the prognosis of patients with ACLF, the molecular mechanisms through which MSCs attenuate ACLF remain poorly understood. We performed global miRNA and mRNA expression profiling via next-generation sequencing of liver tissues from MSC-treated ACLF mice to identify important signaling pathways and major factors implicated in ACLF alleviation by MSCs. METHODS: Carbon tetrachloride-induced ACLF mice were treated with saline or mouse bone marrow-derived MSCs. Mouse livers were subjected to miRNA and mRNA sequencing. Related signal transduction pathways were obtained through Gene Set Enrichment Analysis. Functional enrichment, protein-protein interaction, and immune infiltration analyses were performed for the differentially expressed miRNA target genes (DETs). Hub miRNA and mRNA associated with liver injury were analyzed using LASSO regression. The expression levels of hub genes were subjected to Pearson's correlation analysis and verified using RT-qPCR. The biological functions of hub genes were verified in vitro. RESULTS: The tricarboxylic acid cycle and peroxisome proliferator-activated receptor pathways were activated in the MSC-treated groups. The proportions of liver-infiltrating NK resting cells, M2 macrophages, follicular helper T cells, and other immune cells were altered after MSC treatment. The expression levels of six miRNAs and 10 transcripts correlated with the degree of liver injury. miR-27a-5p was downregulated in the mouse liver after MSC treatment, while its target gene E2f2 was upregulated. miR-27a-5p inhibited E2F2 expression, suppressed G1/S phase transition and proliferation of hepatocytes, in addition to promoting their apoptosis. CONCLUSIONS: This is the first comprehensive analysis of miRNA and mRNA expression in the liver tissue of ACLF mice after MSC treatment. The results revealed global changes in hepatic pathways and immune subpopulations. The miR-27a-5p/E2F2 axis emerged as a central regulator of the MSC-induced attenuation of ACLF. The current findings improve our understanding of the molecular mechanisms through which MSCs alleviate ACLF.
Assuntos
Insuficiência Hepática Crônica Agudizada , Células-Tronco Mesenquimais , MicroRNAs , Humanos , Camundongos , Animais , MicroRNAs/genética , MicroRNAs/metabolismo , Insuficiência Hepática Crônica Agudizada/genética , Insuficiência Hepática Crônica Agudizada/terapia , Insuficiência Hepática Crônica Agudizada/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Células-Tronco Mesenquimais/metabolismoRESUMO
BACKGROUND: Shenzhen has made great efforts to address the tobacco epidemic in the past decade. This study aims to evaluate the current status of the tobacco epidemic among adolescent in Shenzhen, China. METHODS: The multi-stage random cluster sampling method was used in the school-based cross-sectional study in 2019 and a total of 7,423 junior and high school (both senior and vocational) students were recruited. Information on cigarette use was collected by the electronic questionnaire. Logistic regression analysis was used to examine the associations between current cigarette use and associated factors. ORs with their 95% CIs were reported. RESULTS: The prevalence of current cigarette use among adolescents was 2.3%, with boys (3.4%) significantly higher than girls (1.0%). Smoking rates in junior high schools, senior high schools, and vocational senior high schools were 1.0%, 2.7%, and 4.1%, respectively. The results of multivariate logistic regression analysis indicated that gender, age, parental smoking, teachers smoking in schools, friends smoking, exposure to tobacco marketing, and misconceptions about cigarette use were associated factors for adolescent smoking behaviour. CONCLUSIONS: The prevalence of current smoking was relatively low among adolescent in Shenzhen, China. Personal characteristics, family, and school were associated with current adolescent smokers.
Assuntos
População do Leste Asiático , Fumar Tabaco , Adolescente , Feminino , Humanos , Masculino , Estudos Transversais , Prevalência , Fumar Tabaco/epidemiologiaRESUMO
BACKGROUND: Thyroid dysfunction has been reported in severe liver diseases. The aim of this study was to analyze the impact of serum thyroid-stimulation hormone (TSH) levels on the prognosis of patients with hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF). METHODS: This retrospective cohort study included 1,862 patients with HBV-related ACLF. Risk factors associated with 30-day and 90-day survival, hazard ratios (HRs), and 95% confidence intervals (CIs) for TSH were estimated using Cox proportional hazards regression. The Area Under the ROC curve (AUROC) analysis was carried out, and the cut-off values were calculated. After grouping by the cut-off value, survival was compared between the groups using the log-rank test. This study data is from the "Survival Cohort Study (SCS)", which has been registered at ClinicalTrials.gov (NCT03992898). RESULTS: Multivariate analysis indicated that an elevated TSH level was a highly significant predictor for 30-day survival (HR = 0.743, 95% CI: 0.629-0.878, P < 0.001) and 90-day survival (HR = 0.807, 95% CI: 0.717-0.909, P < 0.001). The AUROC of TSH level for 30-day and 90-day mortality were 0.655 and 0.620, respectively, with the same best cut-off values of 0.261 µIU/mL. Log-rank test showed that the group with higher TSH level had higher 30-day (78.5%, 95% CI: 76.1%-80.9% vs. 56.9%, 95% CI: 53.4%-60.4%; P < 0.001) and 90-day survival rate (61.5%, 95% CI: 58.6%-64.4% vs. 42.8%, 95% CI: 39.3%-46.3%; P < 0.001). Similar findings were observed in subgroups analysis. After adjusting for age and other risk factors, the higher level of TSH remained associated with 30-day survival (HR = 0.602, 95% CI: 0.502-0.721, P < 0.001) and 90-day survival (HR = 0.704, 95% CI, 0.609-0.814, P < 0.001). CONCLUSIONS: Serum TSH level significantly correlate with HBV-related ACLF patients' survival and may be of value for predicting 30-day and 90-day survival of patients with HBV-related ACLF.
Assuntos
Insuficiência Hepática Crônica Agudizada , Hepatite B Crônica , Hepatite B , Estudos de Coortes , Hepatite B/complicações , Vírus da Hepatite B , Hormônios , Humanos , Prognóstico , Curva ROC , Estudos Retrospectivos , Glândula Tireoide , TireotropinaRESUMO
Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is a severe and life-threatening complication, characterised by multi-organ failure and high short-term mortality. However, there is limited information on the impact of various comorbidities on HBV-ACLF in a large population. This study aimed to investigate the relationship between comorbidities, complications and mortality. In this retrospective observational study, we identified 2166 cases of HBV-ACLF hospitalised from January 2010 to March 2018. Demographic data from the patients, medical history, treatment, laboratory indices, comorbidities and complications were collected. The mortality rate in our study group was 47.37%. Type 2 diabetes mellitus was the most common comorbidity, followed by alcoholic liver disease. Spontaneous bacterial peritonitis, pneumonia and hepatic encephalopathy (HE) were common in these patients. Diabetes mellitus and hyperthyroidism are risk factors for death within 90 days, together with gastrointestinal bleeding and HE at admission, HE and hepatorenal syndrome during hospitalisation. Knowledge of risk factors can help identify HBV-ACLF patients with a poor prognosis for HBV-ACLF with comorbidities and complications.
Assuntos
Insuficiência Hepática Crônica Agudizada , Diabetes Mellitus Tipo 2 , Hepatite B Crônica , Hepatite B , Insuficiência Hepática Crônica Agudizada/etiologia , Insuficiência Hepática Crônica Agudizada/microbiologia , Comorbidade , Hepatite B/complicações , Hepatite B/epidemiologia , Vírus da Hepatite B , Hepatite B Crônica/complicações , Humanos , Prognóstico , Estudos Retrospectivos , Fatores de RiscoRESUMO
BACKGROUND: Respiratory epithelium expressing angiotensin-converting enzyme 2 (ACE2) is the entry for novel coronavirus (SARS-CoV-2), pathogen of the COVID-19 pneumonia outbreak, although a few recent studies have found different ACE2 expression in lung tissue of smokers. The effect of smoking on ACE2 expression and COVID-19 is still not clear. So, we did this research to determine the effect of smoking on ACE2 expression pattern and its relationship with the risk and severity of COVID-19. METHODS: The clinical data of COVID-19 patients with smoking and non-smoking were analyzed, and ACE2 expression of respiratory and digestive mucosa epithelia from smoker and non-smoker patients or healthy subjects were detected by immunohistochemical (IHC) staining. RESULTS: Of all 295 laboratory-confirmed COVID-19 patients, only 24 (8.1%) were current smokers with moderate smoking or above, which accounted for 54.2% of severe cases with higher mortality than non-smokers (8.3% vs. 0.4%, p = 0.018). Data analysis showed the proportion of smokers in COVID-19 patients was lower than that in general population of China (Z = 11.65, P < 0.001). IHC staining showed ACE2 expression in respiratory and digestive epithelia of smokers were generally downregulated. CONCLUSIONS: The proportion of smokers in COVID-19 patients was lower, which may be explained by ACE2 downregulation in respiratory mucosa epithelia. However, smoking COVID-19 patients accounted for a higher proportion in severe cases and higher mortality than for non-smoking COVID-19 patients, which needs to be noted.
Assuntos
COVID-19 , Peptidil Dipeptidase A , Enzima de Conversão de Angiotensina 2 , China/epidemiologia , Humanos , Peptidil Dipeptidase A/genética , SARS-CoV-2 , Fumar/efeitos adversosRESUMO
PURPOSE: The purpose of this study was to detect severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ribonucleic acid (RNA) in urine and blood specimens, and anal and oropharyngeal swabs from patients with confirmed SARS-CoV-2 infection, and correlated positive results with clinical findings. METHODS: Patients with confirmed SARS-CoV-2 infections were included in this study. Patients' demographic and clinical data were recorded. Quantitative real-time polymerase chain reaction was used to detect SARS-CoV-2 RNA in urine and blood specimens, and anal and oropharyngeal swabs. The study is registered at ClinicalTrials.gov (No. NCT04279782, 19 February, 2020). RESULTS: SARS-CoV-2 RNA was present in all four specimen types, though not all specimen types were positive simultaneously. The presence of viral RNA was not necessarily predictive of clinical symptoms, for example, the presence of viral RNA in the urine did not necessarily predict urinary tract symptoms. CONCLUSIONS: SARS-CoV-2 can infect multiple systems, including the urinary tract. Testing different specimen types may be useful for monitoring disease changes and progression, and for establishing a prognosis.
Assuntos
Canal Anal/virologia , Líquidos Corporais/virologia , COVID-19/diagnóstico , COVID-19/virologia , Orofaringe/virologia , SARS-CoV-2 , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , RNA Viral/genética , Reação em Cadeia da Polimerase em Tempo Real , SARS-CoV-2/classificação , SARS-CoV-2/genética , SARS-CoV-2/isolamento & purificaçãoRESUMO
AIM: To review and clarify the strengths and directions of associations between nephrolithiasis and hypertension (HTN), diabetes mellitus (DM) and gallstones (GS) given the inconsistent results reported in cohort studies. METHODS: Relevant literature was searched in PubMed and EMBASE from inception to July 2019, for cohort studies that examined the relationships between kidney stones and these three diseases among adults. Pooled relative risks (RRs) were calculated by maximally adjusted risk estimates using a random effect model. Subgroup analysis, meta-regression and sensitivity analysis were conducted whenever appropriate. RESULTS: Of 3537 papers, 21 articles with each including 1 to 3 cohorts were identified. In this meta-analysis, nephrolithiasis was reciprocally linked to HTN, DM and GS. Kidney stones were significantly associated with 31%, 33% and 46% higher risks of incident HTN, DM and GS whereas GS was associated with a significantly higher risk of nephrolithiasis (RR: 1.49; 95% CI, 1.28-1.73), followed by HTN (RR: 1.30; 95% CI, 1.11-1.52) and DM (RR: 1.18; 95% CI, 1.07-1.29). Also, females with DM (RR: 1.29; 95% CI, 1.08-1.55) were more likely to develop kidney stones than diabetic male patients (RR: 0.91; 95% CI, 0.75-1.10). CONCLUSION: Although additional studies are needed to confirm these findings and elucidate the mechanisms, this study revealed possible bidirectional associations between nephrolithiasis and HTN, diabetes and GS, which reinforced the notion of nephrolithiasis as a systemic disease that requires comprehensive investigations.
Assuntos
Diabetes Mellitus/epidemiologia , Cálculos Biliares/epidemiologia , Hipertensão/epidemiologia , Cálculos Renais/epidemiologia , Humanos , Medição de Risco/métodos , Medição de Risco/estatística & dados numéricos , Fatores de RiscoRESUMO
BACKGROUND: Dietary and lifestyle factors may play an important role in the increasing prevalence of nephrolithiasis. We aimed to review and quantify the associations between lifestyle factors and incident nephrolithiasis and suggest lifestyle changes for the primary prevention of nephrolithiasis. METHODS: PubMed, EMBASE, and Cochrane Library were searched up to May 2019, for observational studies and randomized controlled trials (RCTs) that assessed modifiable lifestyle factors and risk of nephrolithiasis in adults. Pooled relative risks (RRs) and 95% confidence intervals (CIs) were computed using a random effects model. The I2 statistic was employed to evaluate heterogeneity. Subgroup analysis, sensitivity analysis and meta-regression were also conducted whenever possible. RESULTS: Fifty relevant articles with 1,322,133 participants and 21,030 cases in total were identified. Prominent risk factors for incident stones were body mass index (1.39,1.27-1.52), dietary sodium (1.38, 1.21-1.56), fructose, meat, animal protein, and soda. In contrast, protective factors included fluid intake (0.55, 0.51-0.60), a Dietary Approaches to Stop Hypertension (DASH) style diet (0.69, 0.64-0.75), alcohol (0.69, 0.56-0.85), water, coffee, tea, vegetables, fruits, dietary fiber, dietary calcium (0.83, 0.76-0.90), and potassium. Vitamin D (1.22, 1.01-1.49) and calcium (1.16, 1.00-1.35) supplementation alone increased the risk of stones in meta-analyses of observational studies, but not in RCTs, where the cosupplementation conferred significant risk. CONCLUSIONS: Several modifiable factors, notably fluid intake, dietary patterns, and obesity, were significantly associated with nephrolithiasis. Long-term RCTs are required to investigate the cost-effectiveness of dietary patterns for stone prevention. The independent and combined effects of vitamin D and calcium supplementation on nephrolithiasis need further elucidation.
Assuntos
Consumo de Bebidas Alcoólicas , Dieta , Comportamento de Ingestão de Líquido , Estilo de Vida , Nefrolitíase/prevenção & controle , Prevenção Primária , Cálcio da Dieta , Bebidas Gaseificadas , Café , Abordagens Dietéticas para Conter a Hipertensão , Fibras na Dieta , Suplementos Nutricionais , Água Potável , Frutas , Humanos , Potássio na Dieta , Chá , Verduras , Vitamina DRESUMO
Mortality from hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF) is high due to limited treatment options. Preclinical and clinical investigations have proved that treatment with mesenchymal stromal cells (MSCs) is beneficial for recovery from liver injury. We hypothesized that the outcome of HBV-related ACLF would be improved by MSC treatment. From 2010 to 2013, 110 patients with HBV-related ACLF were enrolled in this open-label, nonblinded randomized controlled study. The control group (n = 54) was treated with standard medical therapy (SMT) only. The experimental group (n = 56) was infused weekly for 4 weeks with 1.0 to 10 × 105 cells/kg allogeneic bone marrow-derived MSCs and then followed for 24 weeks. The cumulated survival rate of the MSC group was 73.2% (95% confidence interval 61.6%-84.8%) versus 55.6% (95% confidence interval 42.3%-68.9%) for the SMT group (P = 0.03). There were no infusion-related side effects, but fever was more frequent in MSC compared to SMT patients during weeks 5-24 of follow-up. No carcinoma occurred in any trial patient in either group. Compared with the control group, allogeneic bone marrow-derived MSC treatment markedly improved clinical laboratory measurements, including serum total bilirubin and Model for End-Stage Liver Disease scores. The incidence of severe infection in the MSC group was much lower than that in the SMT group (16.1% versus 33.3%, P = 0.04). Mortality from multiple organ failure and severe infection was higher in the SMT group than in the MSC group (37.0% versus 17.9%, P = 0.02). CONCLUSION: Peripheral infusion of allogeneic bone marrow-derived MSCs is safe and convenient for patients with HBV-related ACLF and significantly increases the 24-week survival rate by improving liver function and decreasing the incidence of severe infections. (Hepatology 2017;66:209-219).
Assuntos
Insuficiência Hepática Crônica Agudizada/mortalidade , Insuficiência Hepática Crônica Agudizada/terapia , Vírus da Hepatite B/isolamento & purificação , Hepatite B/complicações , Transplante de Células-Tronco Mesenquimais/métodos , Insuficiência Hepática Crônica Agudizada/etiologia , Insuficiência Hepática Crônica Agudizada/fisiopatologia , Adulto , Causas de Morte , China , Feminino , Hepatite B/fisiopatologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Medição de Risco , Estatísticas não Paramétricas , Análise de Sobrevida , Transplante Homólogo , Resultado do TratamentoRESUMO
BACKGROUND: Many studies on T helper (Th)1, Th2, T regulatory and Th17 cells have been carried out in acute-on-chronic liver failure (ACLF). However, CD8(+) T cell, as a main participant in immune-mediated injuries and defense against microorganisms, has seldom been studied in ACLF. AIMS: The purpose of this study was to investigate the CD8(+) T cell function, and the outcomes of patients with severe hepatitis [SH; serum bilirubin (SB) ≥ 10 mg/dl and prothrombin activity (PTA) < 60 %]. METHODS: Thirty-six patients with chronic HBV-associated SH were included. Twenty normal chronic hepatitis B (CHB) patients (2 < SB < 10 (mg/dl) and PTA ≥ 60 %) and 28 healthy volunteers were enrolled as control groups. RESULTS: Twenty-six patients with SH were diagnosed with ACLF (SB ≥ 10 mg/dl and PTA ≤ 40 %). The non-recovered ACLFs (NR-ACLF) had higher HBV DNA loads than recovered ACLFs (R-ACLF) (6.03 ± 1.79 vs. 4.36 ± 1.61 (log10, IU/L)). The NR-ACLFs had the highest neutrophil:lymphocyte ratios (5.10 ± 2.37) (all P < 0.001; a = 0.05). The CHBs had higher perforin(+) and TCM (CD45RA(-)CD62L(hi)CCR7(+)) proportions [31.28 ± 19.51, 5.32 ± 3.57 (%)] compared to R-ACLFs (11.75 ± 15.35, 0.78 ± 0.76 (%); P = 0.004, 0.001, respectively), or NR-ACLFs (11.61 ± 5.79, 1.14 ± 0.67 (%); P = 0.006, 0.003). The non-ACLF SHs had higher CD38(+) proportions than R-ACLFs or NR-ACLFs (25.46 ± 8.02 vs. 16.24 ± 7.77 or 16.81 ± 6.30 (%), P = 0.039, 0.023). CONCLUSIONS: High neutrophil:lymphocyte ratios and a decrease in activated CD8(+) T cells may be related to poor outcomes in patients with SH.
Assuntos
Insuficiência Hepática Crônica Agudizada/imunologia , Linfócitos T CD8-Positivos/imunologia , Hepatite B/imunologia , Imunidade Adaptativa , Adulto , Citocinas/sangue , DNA Viral/sangue , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
Mediator, a large multisubunit protein complex, plays a pivotal role in gene transcription by linking gene-specific transcription factors with the preinitiation complex and RNA polymerase II. In the liver, the key subunit of the Mediator complex, Med1, interacts with several nuclear receptors and transcription factors to direct gene-specific transcription. Conditional knock-out of Med1 in the liver showed that hepatocytes lacking Med1 did not regenerate following either partial hepatectomy or treatment with certain nuclear receptor activators and failed to give rise to tumors when challenged with carcinogens. We now report that the adenovirally driven overexpression of Med1 in mouse liver stimulates hepatocyte DNA synthesis with enhanced expression of DNA replication, cell cycle control, and liver-specific genes, indicating that Med1 alone is necessary and sufficient for liver cell proliferation. Importantly, we demonstrate that AMP-activated protein kinase (AMPK), an important cellular energy sensor, interacts with, and directly phosphorylates, Med1 in vitro at serine 656, serine 756, and serine 796. AMPK also phosphorylates Med1 in vivo in mouse liver and in cultured primary hepatocytes and HEK293 and HeLa cells. In addition, we demonstrate that PPARα activators increase AMPK-mediated Med1 phosphorylation in vivo. Inhibition of AMPK by compound C decreased hepatocyte proliferation induced by Med1 and also by the PPARα activators fenofibrate and Wy-14,643. Co-treatment with compound C attenuated PPARα activator-inducible fatty acid ß-oxidation in liver. Our results suggest that Med1 phosphorylation by its association with AMPK regulates liver cell proliferation and fatty acid oxidation, most likely as a downstream effector of PPARα and AMPK.
Assuntos
Adenilato Quinase/metabolismo , Regulação Enzimológica da Expressão Gênica , Fígado/citologia , Subunidade 1 do Complexo Mediador/metabolismo , Complexo Mediador/metabolismo , Animais , Proliferação de Células , Ácidos Graxos/metabolismo , Células HEK293 , Células HeLa , Hepatócitos/citologia , Homeostase , Humanos , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Oxigênio/metabolismo , PPAR alfa/metabolismo , FosforilaçãoRESUMO
BACKGROUND AND AIM: Acute-on-chronic liver failure (ACLF) caused by hepatitis B virus (HBV) is a severe disease with high mortality. Immune injury plays an important role during the early stage of the disease. Our research aimed to investigate the safety and efficacy of dexamethasone therapy for patients with HBV-related ACLF. METHODS: A total of 134 inpatients with HBV-induced ACLF were enrolled from January 2009 to December 2012. All the patients received the standard medicine treatment (SMT), among whom 31 cases underwent additional dexamethasone injection for three times (dexamethasone treatment [DMT] Group). A total of 35 patients (SMT Group) matched for baseline characters served as controls. Both the groups were followed up for 12 weeks. The survival rates, liver functions, and complications were recorded. RESULTS: The 12-week cumulative survival rates were 45.7% (16/35)and 48.4% (15/31) for SMT Group and DMT Group, respectively, and no significant differences were found (P = 0.959). There were no dramatic differences in liver function and model for end-stage liver disease (MELD) score at 1, 2, 4, 8, and 12 weeks between two groups. There were no significant differences in the incidence of complications (i.e. infection, gastrointestinal bleeding, encephalopathy, hepatorenal syndrome, and ascites) from 1 to 12 weeks between Group SMT and Group DMT. More than 40 ages, MELD score more than 28 and encephalopathy were independent risk factors for the mortality of patients. CONCLUSIONS: Dexamethasone cannot improve liver functions and 12-week survival rates of patients with HBV-related ACLF. Age, MELD score, and encephalopathy are independent risk factors.
Assuntos
Dexametasona/uso terapêutico , Doença Hepática Terminal/tratamento farmacológico , Doença Hepática Terminal/etiologia , Glucocorticoides/uso terapêutico , Hepatite B/complicações , Falência Hepática Aguda/tratamento farmacológico , Falência Hepática Aguda/etiologia , Adulto , Fatores Etários , Encefalopatias , Dexametasona/administração & dosagem , Doença Hepática Terminal/mortalidade , Doença Hepática Terminal/fisiopatologia , Feminino , Seguimentos , Glucocorticoides/administração & dosagem , Humanos , Falência Hepática Aguda/mortalidade , Falência Hepática Aguda/fisiopatologia , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Índice de Gravidade de Doença , Taxa de Sobrevida , Fatores de Tempo , Resultado do TratamentoRESUMO
The liver is the largest glandular organ in the body and has a unique distribution of cells and biomolecules. However, the treatment outcome of end-stage liver disease is extremely poor. Single-cell sequencing is a new advanced and powerful technique for identifying rare cell populations and biomolecules by analyzing the characteristics of gene expression between individual cells. These cells and biomolecules might be used as potential targets for immunotherapy of liver diseases and contribute to the development of precise individualized treatment. Compared to whole-tissue RNA sequencing, single-cell RNA sequencing (scRNA-seq) or other single-cell histological techniques have solved the problem of cell population heterogeneity and characterize molecular changes associated with liver diseases with higher accuracy and resolution. In this review, we comprehensively summarized single-cell approaches including transcriptomic, spatial transcriptomic, immunomic, proteomic, epigenomic, and multiomic technologies, and described their application in liver physiology and pathology. We also discussed advanced techniques and recent studies in the field of single-cell; our review might provide new insights into the pathophysiological mechanisms of the liver to achieve precise and individualized treatment of liver diseases.
RESUMO
Background: The correlation between metabolic syndrome (MetS) and hepatitis B surface antigen (HBsAg) loss remains to be further elucidated, particularly in patients receiving pegylated interferon-α (PEG-IFN) treatment. Methods: 758 patients with low HBsAg quantification who had received nucleos(t)ide analog (NUC) therapy for at least one year and subsequently switched to or add on PEG-IFN therapy over an unfixed course were enrolled. 412 patients were obtained with baseline data matched. A total of 206 patients achieved HBsAg loss (cured group) within 48 weeks. Demographic and biochemical data associated with MetS were gathered for analysis. HepG2.2.15 cell line was used in vitro experiments to validate the efficacy of interferon-α (IFN-α). Results: The proportion of patients with diabetes or hypertension in the uncured group was significantly higher than in the cured group. The levels of fasting blood glucose (FBG) and glycated albumin remained elevated in the uncured group over the 48 weeks. In contrast, the levels of blood lipids and uric acid remained higher in the cured group within 48 weeks. Triglycerides levels and liver steatosis of all patients increased after PEG-IFN therapy. Baseline elevated uric acid levels and hepatic steatosis may be beneficial for HBsAg loss. IFN-α could induce hepatic steatosis and indirectly promote HBsAg loss by increasing triglyceride level through upregulation of acyl-CoA synthetase long-chain family member 1(ACSL1). Conclusions: IFN-α could induce liver steatosis to promote HBsAg loss by increasing triglyceride level through upregulation of ACSL1. Comorbid diabetes may be detrimental to obtaining HBsAg loss with PEG-IFN therapy in CHB patients.
RESUMO
BACKGROUND: Liver cancer stem cells (CSCs) contribute to tumor initiation, progression, and recurrence in hepatocellular carcinoma (HCC). The Wnt/ß-catenin pathway plays a crucial role in liver cancer stemness, progression, metastasis, and drug resistance, but no clinically approved drugs have targeted this pathway efficiently so far. We aimed to elucidate the role of COLEC10 in HCC stemness. METHODS: The Cancer Genome Atlas (TCGA) and the Clinical Proteomic Tumor Analysis Consortium (CPTAC) databases were employed to search for the association between COLEC10 expression and HCC stemness. Colony formation, sphere formation, side population, and limiting dilution tumor initiation assays were used to identify the regulatory role of COLEC10 overexpression in the stemness of HCC cell lines. Wnt/ß-catenin reporter assay and immunoprecipitation were performed to explore the underlying mechanism. RESULTS: COLEC10 level was negatively correlated with HCC stemness. Elevated COLEC10 led to decreased expressions of EpCAM and AFP (alpha-fetoprotein), two common markers of liver CSCs. Overexpression of COLEC10 inhibited HCC cells from forming colonies and spheres, and reduced the side population numbers in vitro, as well as the tumorigenic capacity in vivo. Mechanically, we demonstrated that overexpression of COLEC10 suppressed the activity of Wnt/ß-catenin signaling by upregulating Wnt inhibitory factor WIF1 and reducing the level of cytoplasmic ß-catenin. COLEC10 overexpression promoted the interaction of ß-catenin with the component of destruction complex CK1α. In addition, KLHL22 (Kelch Like Family Member 22), a reported E3 ligase adaptor predicted to interact with CK1α, could facilitate COLEC10 monoubiquitination and degradation. CONCLUSION: COLEC10 inhibits HCC stemness by downregulating the Wnt/ß-catenin pathway, which is a promising target for liver CSC therapy.