Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 9 de 9
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Gut ; 2021 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-33431576

RESUMO

OBJECTIVE: Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) pathophysiology remains unclear. This study aims to characterise the molecular basis of HBV-ACLF using transcriptomics. METHODS: Four hundred subjects with HBV-ACLF, acute-on-chronic hepatic dysfunction (ACHD), liver cirrhosis (LC) or chronic hepatitis B (CHB) and normal controls (NC) from a prospective multicentre cohort were studied, and 65 subjects (ACLF, 20; ACHD, 10; LC, 10; CHB, 10; NC, 15) among them underwent mRNA sequencing using peripheral blood mononuclear cells (PBMCs). RESULTS: The functional synergy analysis focusing on seven bioprocesses related to the PBMC response and the top 500 differentially expressed genes (DEGs) showed that viral processes were associated with all disease stages. Immune dysregulation, as the most prominent change and disorder triggered by HBV exacerbation, drove CHB or LC to ACHD and ACLF. Metabolic disruption was significant in ACHD and severe in ACLF. The analysis of 62 overlapping DEGs further linked the HBV-based immune-metabolism disorder to ACLF progression. The signatures of interferon-related, neutrophil-related and monocyte-related pathways related to the innate immune response were significantly upregulated. Signatures linked to the adaptive immune response were downregulated. Disruptions of lipid and fatty acid metabolism were observed during ACLF development. External validation of four DEGs underlying the aforementioned molecular mechanism in patients and experimental rats confirmed their specificity and potential as biomarkers for HBV-ACLF pathogenesis. CONCLUSIONS: This study highlights immune-metabolism disorder triggered by HBV exacerbation as a potential mechanism of HBV-ACLF and may indicate a novel diagnostic and treatment target to reduce HBV-ACLF-related mortality.

2.
Stem Cell Res ; 47: 101900, 2020 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-32622343

RESUMO

BACKGROUND & AIMS: Biliary injury is one of the main pathological mechanisms of fulminant hepatic failure (FHF). Delta-like ligand 4 (DLL4)-mediated Notch activation contributes to reversing biliary injury; however, the specific role of DLL4 in biliary restoration is still unclear. This study aimed to determine whether human bone marrow mesenchymal stem cells (hBMSCs) can differentiate into biliary epithelial cells (cholangiocytes) in vitro and in vivo and to clarify the role of DLL4 in restoring damaged liver by enhancing cholangiocyte differentiation. METHODS: hBMSCs were transplanted into immunodeficient mice (FRGS) with FHF induced by the hamster-anti-mouse CD95 antibody JO2. The appearance of human cholangiocytes was evaluated in the generated hBMSC-FRGS mice by q-PCR expression, flow cytometry and immunohistochemistry. The potency of DLL4 in inducing cholangiocyte differentiation from hBMSCs was assessed by observing the cell morphology and measuring the expression of cholangiocyte-specific genes and proteins. RESULTS: Human KRT19- and KRT7-double-positive cholangiocyte-like cells appeared in hBMSC-FRGS mice at 12 weeks after transplantation. After these cells were separated and collected by fluorescent-activated cell sorting (FACS), there were high levels of expression of eight typical human cholangiocyte-specific genes and proteins (e.g., KRT19 and KRT7). Furthermore, hBMSC-derived cholangiocytes induced by DLL4 had a better shape with higher nucleus/cytoplasm ratios and showed a specific increase in the expression of cholangiocyte-specific genes and proteins (e.g., KRT19, KRT7, SOX9 and CFTR). CONCLUSIONS: Cholangiocytes can be efficiently differentiated from hBMSCs in vivo and in vitro. DLL4 restores damaged liver by enhancing cholangiocyte differentiation from hBMSCs and has the potential to be used in future clinical therapeutic applications.

3.
Hepatol Res ; 50(6): 656-670, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32134538

RESUMO

AIM: The artificial liver support system (ALSS) is recognized as a bridge to liver transplantation in hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) patients. However, patient survival remains unknown. We aim to assess the effects of ALSS on survival in HBV-ACLF patients. METHODS: The clinical data of HBV-ACLF patients receiving standard medical treatment (SMT) plus ALSS (ALSS group, n = 507) or only SMT (SMT group, n = 417) were collected for survival assessment. The main end-points were cumulative survival rates at days 21, 28, and 90. Four different rigorous analyses were carried out to reduce bias and confounding. RESULTS: In the entire cohort, the cumulative survival rates at days 21, 28, and 90 were significantly higher in patients who underwent ALSS treatment (73.3% vs. 59.6%, 69.2% vs. 56.6%, 56.5% vs. 49.1%, respectively, P < 0.01) than in those who underwent SMT only. In the 276-pair case-control matched cohort, a significantly higher survival rate was also observed in the ALSS group than in the SMT group on days 21, 28, and 90 (72.5% vs. 60.3%, 68.3% vs. 57.4%, 55.9% vs. 48.5%, respectively, P < 0.05), especially in patients with ACLF-1 and -2. By a multivariable-adjusted analysis, ALSS treatment was associated with a significantly lower risk of mortality, especially for ACLF-2 at days 21, 28, and 90. These findings were also confirmed through propensity score matching and inverse probability treatment weighting analysis. CONCLUSIONS: ALSS treatment can improve short-term survival and is associated with a significantly lower risk of short-term mortality in patients with HBV-ACLF, especially ACLF-2.

4.
Int J Med Sci ; 17(2): 263-273, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32038110

RESUMO

Background: Human bone marrow mesenchymal stem cell-derived hepatocyte-like cells (hBMSC-HLCs) are a promising alternative for primary human hepatocytes (HHs) for treating liver disease. However, the molecular characteristics of HLCs remain unclear. Here, we aimed to clarify the transcriptome characteristics of hBMSC-HLCs for future clinical application. Materials and Methods: hBMSCs were isolated from the bone marrow of healthy volunteers and differentiated into hepatocytes. mRNA sequencing was used in the transcriptome profiling of hBMSC-HLCs, with hBMSCs and HHs as controls. Results: hBMSC-HLCs exhibited a polygonal morphology, glycogen accumulation and albumin expression. A total of 630 upregulated and 1082 downregulated genes were observed in hBMSC-HLCs and HHs compared with undifferentiated hBMSCs. The upregulated genes were mainly involved in hepatic metabolism and inflammatory and immune responses. The downregulated genes were mainly associated with stem cell characteristics (multipotent differentiation, cell cycle regulation, etc.). Confirmatory qRT-PCR of 9 upregulated and 9 downregulated genes with log2 fold changes > 5 showed similar results. In vivo transdifferentiation of hBMSCs in pigs with fulminant hepatic failure confirmed the similarly upregulated expression of 5 hepatogenic genes (TDO2, HP, SERPINA3, LBP and SAA1), showing a 150-fold change in liver tissues at 7 days after hBMSC transplantation. These 5 genes mainly contributed to liver metabolism and inflammation. Conclusion: hBMSC-HLCs possess a hepatic transcriptome profile and express hepatic-specific genes in vitro and in vivo, which might be useful for future clinical applications. The five upregulated genes identified herein could be potential biomarkers for the characterization of hBMSC-HLCs.


Assuntos
Células da Medula Óssea/citologia , Células da Medula Óssea/metabolismo , Perfilação da Expressão Gênica/métodos , Hepatócitos/citologia , Hepatócitos/metabolismo , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Biomarcadores/metabolismo , Diferenciação Celular/fisiologia , Células Cultivadas , Humanos , RNA Mensageiro/metabolismo
5.
Aging (Albany NY) ; 12(4): 3962-3975, 2020 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-32096766

RESUMO

Inhibitors of the CDK family of proteins have been approved for the treatment of a variety of tumours; however, the development of new drugs administered in combination with CDK inhibitors is expected to improve the therapeutic effect. We identified the function of suppressor of cytokine signalling 1 (SOCS1) in hepatocellular carcinoma (HCC) cell models and the xenograft mouse model. When SOCS1 expression was artificially upregulated, HCC cell lines were arrested at the G1-S transition in the cell cycle. Interestingly, during this process, total CyclinD1 protein increased, but the effective proportion decreased. We found that the deficiency of CyclinD1 in the nucleus is probably due to the decrease in the stability of nuclear CyclinD1 caused by the ubiquitin-based degradation of P21, thus inhibiting the progression of the cell cycle to S phase. After P21 expression was increased, the levels of the component that inactivates CyclinD1 decreased as expected. It showed that P21 has a partial promoting effect on cancer. SOCS1 is a good indicator of prognosis, tumour size and long-term survival after resection. SOCS1 is expected to become a drug target in combined with CDK family inhibitors.

6.
Gut ; 68(11): 2044-2056, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-30700543

RESUMO

OBJECTIVE: Developing a small animal model that accurately delineates the natural history of hepatitis B virus (HBV) infection and immunopathophysiology is necessary to clarify the mechanisms of host-virus interactions and to identify intervention strategies for HBV-related liver diseases. This study aimed to develop an HBV-induced chronic hepatitis and cirrhosis mouse model through transplantation of human bone marrow mesenchymal stem cells (hBMSCs). DESIGN: Transplantation of hBMSCs into Fah-/-Rag2-/-IL-2Rγc-/- SCID (FRGS) mice with fulminant hepatic failure (FHF) induced by hamster-anti-mouse CD95 antibody JO2 generated a liver and immune cell dual-humanised (hBMSC-FRGS) mouse. The generated hBMSC-FRGS mice were subjected to assessments of sustained viremia, specific immune and inflammatory responses and liver pathophysiological injury to characterise the progression of chronic hepatitis and cirrhosis after HBV infection. RESULTS: The implantation of hBMSCs rescued FHF mice, as demonstrated by robust proliferation and transdifferentiation of functional human hepatocytes and multiple immune cell lineages, including B cells, T cells, natural killer cells, dendritic cells and macrophages. After HBV infection, the hBMSC-FRGS mice developed sustained viremia and specific immune and inflammatory responses and showed progression to chronic hepatitis and liver cirrhosis at a frequency of 55% after 54 weeks. CONCLUSION: This new humanised mouse model recapitulates the liver cirrhosis induced by human HBV infection, thus providing research opportunities for understanding viral immune pathophysiology and testing antiviral therapies in vivo.


Assuntos
Modelos Animais de Doenças , Hepatite B Crônica/etiologia , Cirrose Hepática/etiologia , Transplante de Células-Tronco Mesenquimais , Animais , Hepatite B Crônica/patologia , Humanos , Cirrose Hepática/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID
7.
Gut ; 67(12): 2181-2191, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-28928275

RESUMO

OBJECTIVE: The definition of acute-on-chronic liver failure (ACLF) based on cirrhosis, irrespective of aetiology, remains controversial. This study aimed to clarify the clinicopathological characteristics of patients with hepatitis B virus-related ACLF (HBV-ACLF) in a prospective study and develop new diagnostic criteria and a prognostic score for such patients. DESIGN: The clinical data from 1322 hospitalised patients with acute decompensation of cirrhosis or severe liver injury due to chronic hepatitis B (CHB) at 13 liver centres in China were used to develop new diagnostic and prognostic criteria. RESULTS: Of the patients assessed using the Chronic Liver Failure Consortium criteria with the exception of cirrhosis, 391 patients with ACLF were identified: 92 with non-cirrhotic HBV-ACLF, 271 with cirrhotic HBV-ACLF and 28 with ACLF with cirrhosis caused by non-HBV aetiologies (non-HBV-ACLF). The short-term (28/90 days) mortality of the patients with HBV-ACLF were significantly higher than those of the patients with non-HBV-ACLF. Total bilirubin (TB) ≥12 mg/dL and an international normalised ratio (INR) ≥1.5 was proposed as an additional diagnostic indicator of HBV-ACLF, and 19.3% of patients with an HBV aetiology were additionally diagnosed with ACLF. The new prognostic score (0.741×INR+0.523×HBV-SOFA+0.026×age+0.003×TB) for short-term mortality was superior to five other scores based on both discovery and external validation studies. CONCLUSIONS: Regardless of the presence of cirrhosis, patients with CHB, TB ≥12 mg/dL and INR ≥1.5 should be diagnosed with ACLF. The new criteria diagnosed nearly 20% more patients with an HBV aetiology with ACLF, thus increasing their opportunity to receive timely intensive management.


Assuntos
Insuficiência Hepática Crônica Agudizada/diagnóstico , Hepatite B Crônica/diagnóstico , Insuficiência Hepática Crônica Agudizada/etiologia , Insuficiência Hepática Crônica Agudizada/microbiologia , Insuficiência Hepática Crônica Agudizada/mortalidade , Adulto , Bilirrubina/sangue , Biomarcadores/sangue , China/epidemiologia , Feminino , Hepatite B Crônica/mortalidade , Humanos , Coeficiente Internacional Normatizado , Cirrose Hepática/complicações , Cirrose Hepática/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Índice de Gravidade de Doença
8.
Int J Infect Dis ; 59: 131-136, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28408253

RESUMO

Hepatitis B virus (HBV) infection is associated with an increased risk of hepatic cirrhosis, hepatocellular carcinoma, fulminant hepatitis and end-stage hepatic failure. Despite the availability of anti-HBV therapies, HBV infection remains a major global public health problem. Developing an ideal animal model of HBV infection to clarify the details of the HBV replication process, the viral life cycle, the resulting immunoresponse and the precise pathogenesis of HBV is difficult because HBV has an extremely narrow host range and almost exclusively infects humans. In this review, we summarize and evaluate animal models available for studying HBV infection, especially focusing on humanized chimeric mouse models, and we discuss future development trends regarding immunocompetent humanized mouse models that can delineate the natural history and immunopathophysiology of HBV infection.


Assuntos
Modelos Animais de Doenças , Hepatite B , Animais , Hepatite B/complicações , Vírus da Hepatite B/fisiologia , Humanos , Camundongos
9.
Gut ; 66(5): 955-964, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-26884426

RESUMO

OBJECTIVE: Stem cell transplantation provides a promising alternative for the treatment of fulminant hepatic failure (FHF). However, it lacks fundamental understanding of stem cells' activities. Our objective was to clarify stem cell-recipient interactions for overcoming barriers to clinical application. DESIGN: We used an in-house large-animal (pig) model of FHF rescue by human bone marrow mesenchymal stem cells (hBMSCs) and profiled the cells' activities. The control and transplantation groups of pigs (n=15 per group) both received a D-galactosamine (D-Gal) injection (1.5 g/kg). The transplantation group received hBMSCs via intraportal vein infusion (3×106 cells/kg) immediately after D-Gal administration. The stem cell-recipient interactions were quantitatively evaluated by biochemical function, cytokine array, metabolite profiling, transcriptome sequencing and immunohistochemistry. RESULTS: All pigs in the control group died within an average of 3.22 days, whereas 13/15 pigs in the transplantation group lived >14 days. The cytokine array and metabolite profiling analyses revealed that hBMSC transplantation suppressed D-Gal-induced life-threatening cytokine storms and stabilised FHF within 7 days, while human-derived hepatocytes constituted only ∼4.5% of the pig hepatocytes. The functional synergy analysis of the observed profile changes indicated that the implanted hBMSCs altered the pigs' cytokine responses to damage through paracrine effects. Delta-like ligand 4 was validated to assist liver restoration in both pig and rat FHF models. CONCLUSIONS: Our results delineated an integrated model of the multifaceted interactions between stem cells and recipients, which may open a new avenue to the discovery of single molecule-based therapeutics that simulate stem cell actions.


Assuntos
Transplante de Medula Óssea , Citocinas/sangue , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Falência Hepática Aguda/metabolismo , Falência Hepática Aguda/terapia , Proteínas de Membrana/metabolismo , Transplante de Células-Tronco Mesenquimais , Animais , Modelos Animais de Doenças , Galactosamina/farmacologia , Hepatócitos , Humanos , Fígado/patologia , Falência Hepática Aguda/patologia , Masculino , Comunicação Parácrina , Ratos , Ratos Sprague-Dawley , Taxa de Sobrevida , Suínos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...