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1.
Clinics (Sao Paulo) ; 75: e1670, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32935822

RESUMO

OBJECTIVES: Acoustic radiation force impulse (ARFI) elastography, the aspartate aminotransferase-to-alanine aminotransferase ratio (AAR), aspartate aminotransferase-to-platelet ratio index (APRI), and the fibrosis-4 (FIB-4) index are widely used to assess liver fibrosis. However, efficacies of these methods in the evaluation of hepatic functional reserve remain unclear. In this study, we investigated the relationship between ARFI elastography combined with either AAR, APRI, or FIB-4 index and Child-Pugh (CP) class for the evaluation of hepatic functional reserve in patients with chronic hepatitis B (CHB)-related cirrhosis. METHODS: The shear wave velocities of 104 patients with clinically confirmed CHB-related cirrhosis were determined using the ARFI; and clinical serum markers (e.g. ALT, AST, PLT) were used to calculate the AAR, APRI, and FIB-4 index. Cirrhosis patients were scored according to their CP class. The ARFI, AAR, APRI, and FIB-4 index were compared with the CP class. The efficacy of each indicator in diagnosis was analyzed using the receiver operating characteristic (ROC) curve and the ARFI combined with either the AAR, APRI, or FIB-4 index, which is used to predict decompensated cirrhosis. RESULTS: No significant differences were observed in gender and age among CP classes A, B, and C patients (p>0.05). The ARFI values and the AAR, APRI, and FIB-4 index of patients with CP classes A, B, and C were significantly different (p<0.05). With an increasing CP class, the ARFI, AAR, APRI, and FIB-4 values increased. The correlation between the ARFI and the CP class was stronger than that between the AAR, APRI, and FIB-4 index and the CP class. The area under the ROC curve for the diagnosis of decompensated cirrhosis using the ARFI was 0.841, which was higher than that for the AAR, APRI, and FIB-4 index. According to the area under the curve results, no significant differences were found when the ARFI was combined with either the AAR, APRI, or FIB-4 index and when the ARFI alone was used. CONCLUSIONS: The ARFI value has a strong correlation with the CP class. Therefore, ARFI elastography complements CP class in the assessment of the hepatic functional reserve in patients with CHB-related cirrhosis.


Assuntos
Acústica , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Técnicas de Imagem por Elasticidade , Cirrose Hepática/patologia , Biomarcadores/sangue , Biópsia , Criança , Técnicas de Imagem por Elasticidade/métodos , Feminino , Humanos , Fígado/patologia , Cirrose Hepática/sangue , Cirrose Hepática/diagnóstico por imagem , Masculino , Valor Preditivo dos Testes , Curva ROC , Sensibilidade e Especificidade , Índice de Gravidade de Doença
2.
Nat Commun ; 11(1): 4489, 2020 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-32895384

RESUMO

We report a covalent chemistry-based hepatocellular carcinoma (HCC)-specific extracellular vesicle (EV) purification system for early detection of HCC by performing digital scoring on the purified EVs. Earlier detection of HCC creates more opportunities for curative therapeutic interventions. EVs are present in circulation at relatively early stages of disease, providing potential opportunities for HCC early detection. We develop an HCC EV purification system (i.e., EV Click Chips) by synergistically integrating covalent chemistry-mediated EV capture/release, multimarker antibody cocktails, nanostructured substrates, and microfluidic chaotic mixers. We then explore the translational potential of EV Click Chips using 158 plasma samples of HCC patients and control cohorts. The purified HCC EVs are subjected to reverse-transcription droplet digital PCR for quantification of 10 HCC-specific mRNA markers and computation of digital scoring. The HCC EV-derived molecular signatures exhibit great potential for noninvasive early detection of HCC from at-risk cirrhotic patients with an area under receiver operator characteristic curve of 0.93 (95% CI, 0.86 to 1.00; sensitivity = 94.4%, specificity = 88.5%).


Assuntos
Biomarcadores Tumorais/isolamento & purificação , Carcinoma Hepatocelular/diagnóstico , Detecção Precoce de Câncer/métodos , Vesículas Extracelulares/genética , Neoplasias Hepáticas/diagnóstico , Idoso , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Estudos de Casos e Controles , Química Click/instrumentação , Química Click/métodos , Química Computacional , Simulação por Computador , Diagnóstico Diferencial , Dimetilpolisiloxanos/química , Progressão da Doença , Detecção Precoce de Câncer/instrumentação , Feminino , Células Hep G2 , Humanos , Dispositivos Lab-On-A-Chip , Biópsia Líquida/instrumentação , Biópsia Líquida/métodos , Cirrose Hepática/sangue , Cirrose Hepática/patologia , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , Técnicas Analíticas Microfluídicas/instrumentação , Técnicas Analíticas Microfluídicas/métodos , Pessoa de Meia-Idade , Nanoestruturas/química , Nanofios/química , Estadiamento de Neoplasias , RNA Mensageiro/genética , RNA Mensageiro/isolamento & purificação , Curva ROC , Reação em Cadeia da Polimerase Via Transcriptase Reversa/instrumentação , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos
3.
Medicine (Baltimore) ; 99(22): e19889, 2020 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-32481363

RESUMO

This study aimed to investigate the association between the degree of thoracic duct dilatation and the progression of chronic liver disease.In this cross-sectional and retrospective study, 179 patients (mean age, 60.9 years; 114 men) with chronic liver disease who underwent chest CT were enrolled. Dilatation of the left distal thoracic ducts (DTD) was measured and divided into the following 3 grades according to the maximum transverse diameter: grade 0, invisible thoracic duct; grade 1, visible duct with <5-mm diameter; grade 2, diameter of ≥5 mm. Statistical analyses were conducted using the binary logistic regression model.The proportion of grade 2 DTD was notably higher as the chronic liver disease progressed to cirrhosis. Visible DTD on chest CT was significantly related to the presence of cirrhosis (odds ratio [OR], 3.809; P = .027) and significant varix (OR, 3.211; P = .025). Grade 2 DTD was observed more frequently in patients with ascites (OR, 2.788; P = .039). However, 40% of patients with cirrhosis and ascites still exhibited no visible DTD while demonstrating significant amount of ascites, and their ascites were more predominant of recent onset and transient than that observed in other patients (85.7% vs 48.4%, P = .010 and 66.7% vs 29.0%, P = .009, respectively).The degree of thoracic duct dilatation is significantly associated with progression to cirrhosis and advancement of portal hypertension. Further, insufficient lymph drainage to DTD might contribute to the development of ascites.


Assuntos
Ascite/patologia , Cirrose Hepática/patologia , Ducto Torácico/patologia , Idoso , Ascite/etiologia , Doença Crônica , Dilatação Patológica , Progressão da Doença , Feminino , Humanos , Cirrose Hepática/complicações , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
4.
PLoS One ; 15(6): e0234038, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32492075

RESUMO

Extracellular adenosine triphosphate (eATP) released by damaged cells, and its purinergic receptors, comprise a crucial signaling network after injury. Purinergic receptor P2X7 (P2RX7), a major driver of NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation and IL-1ß processing, has been shown to play a role in liver injury in murine diet- and chemically-induced liver injury models. It is unclear, however, whether P2RX7 plays a role in non-alcoholic steatohepatitis (NASH) and which cell type is the main target of P2RX7 pharmacological inhibition. Here, we report that P2RX7 is expressed by infiltrating monocytes and resident Kupffer cells in livers from NASH-affected individuals. Using primary isolated human cells, we demonstrate that P2RX7 expression in CD14+ monocytes and Kupffer cells primarily mediates IL-1ß release. In addition, we show that pharmacological inhibition of P2RX7 in monocytes and Kupffer cells, blocks IL-1ß release, reducing hepatocyte caspase 3/7 activity, IL-1ß-mediated CCL2 and CCL5 chemokine gene expression and secretion, and hepatic stellate cell (HSC) procollagen secretion. Consequently, in a chemically-induced nonhuman primate model of liver fibrosis, treatment with a P2RX7 inhibitor improved histological characteristics of NASH, protecting from liver inflammation and fibrosis. Taken together, these findings underscore the critical role of P2RX7 in the pathogenesis of NASH and implicate P2RX7 as a promising therapeutic target for the management of this disease.


Assuntos
Inflamação/prevenção & controle , Cirrose Hepática/tratamento farmacológico , Antagonistas do Receptor Purinérgico P2X/uso terapêutico , Receptores Purinérgicos P2X7/metabolismo , Animais , Caspase 3/metabolismo , Células Cultivadas , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Células Estreladas do Fígado/citologia , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Inflamação/patologia , Interleucina-1beta/metabolismo , Macrófagos do Fígado/citologia , Macrófagos do Fígado/efeitos dos fármacos , Macrófagos do Fígado/metabolismo , Lipopolissacarídeos/farmacologia , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/patologia , Macaca fascicularis , Masculino , Monócitos/citologia , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Pró-Colágeno/metabolismo , Antagonistas do Receptor Purinérgico P2X/farmacologia , Receptores Purinérgicos P2X7/química , Receptores Purinérgicos P2X7/genética
5.
Proc Natl Acad Sci U S A ; 117(25): 14231-14242, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32513687

RESUMO

Transforming growth factor ß-activated kinase1 (TAK1) encoded by the gene MAP3K7 regulates multiple important downstream effectors involved in immune response, cell death, and carcinogenesis. Hepatocyte-specific deletion of TAK1 in Tak1 ΔHEP mice promotes liver fibrosis and hepatocellular carcinoma (HCC) formation. Here, we report that genetic inactivation of RIPK1 kinase using a kinase dead knockin D138N mutation in Tak1 ΔHEP mice inhibits the expression of liver tumor biomarkers, liver fibrosis, and HCC formation. Inhibition of RIPK1, however, has no or minimum effect on hepatocyte loss and compensatory proliferation, which are the recognized factors important for liver fibrosis and HCC development. Using single-cell RNA sequencing, we discovered that inhibition of RIPK1 strongly suppresses inflammation induced by hepatocyte-specific loss of TAK1. Activation of RIPK1 promotes the transcription of key proinflammatory cytokines, such as CCL2, and CCR2+ macrophage infiltration. Our study demonstrates the role and mechanism of RIPK1 kinase in promoting inflammation, both cell-autonomously and cell-nonautonomously, in the development of liver fibrosis and HCC, independent of cell death, and compensatory proliferation. We suggest the possibility of inhibiting RIPK1 kinase as a therapeutic strategy for reducing liver fibrosis and HCC development by inhibiting inflammation.


Assuntos
Carcinoma Hepatocelular/metabolismo , Hepatócitos/metabolismo , Inflamação/metabolismo , Cirrose Hepática/metabolismo , Neoplasias Hepáticas/metabolismo , MAP Quinase Quinase Quinases/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Animais , Biomarcadores Tumorais , Carcinogênese/genética , Carcinogênese/patologia , Carcinoma Hepatocelular/genética , Morte Celular , Quimiocina CCL2/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica , Hepatócitos/patologia , Inflamação/patologia , Cirrose Hepática/patologia , Neoplasias Hepáticas/genética , MAP Quinase Quinase Quinases/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Receptores CCR2/metabolismo
6.
Medicine (Baltimore) ; 99(23): e20616, 2020 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-32502037

RESUMO

Liver steatosis could affect the accuracy of FibroScan in patients with chronic hepatitis B (CHB) and nonalcoholic fatty liver disease (NAFLD). This study aimed to assess the accuracy and cut-off values of FibroScan for diagnosing liver fibrosis and cirrhosis in patients with concomitant CHB and NAFLD.A total of 116 patients with concomitant CHB and NAFLD who underwent FibroScan test and liver biopsy were retrospectively enrolled. Liver fibrosis was staged according to the METAVIR scoring system. Calculations of the areas under receiver-operating characteristic curves (AUROC) were performed and compared for the staging of liver fibrosis.The AUROCs for FibroScan, gamma-glutamyl transpeptidase to platelet ratio (GPR), aspartate aminotransferase to platelet ratio index (APRI), fibrosis index based on 4 factors (FIB-4), and NAFLD Fibrosis Score (NFS) were 0.87, 0.73, 0.69, 0.57, and 0.57 for the diagnosis of significant liver fibrosis (METAVIR ≥ F2); 0.89, 0.77, 0.75, 0.68, and 0.60 for severe liver fibrosis (METAVIR ≥ F3); and 0.94, 0.86, 0.80, 0.74, and 0.63 for cirrhosis (F4), respectively. The cutoff values of FibroScan for staging liver fibrosis with sensitivity at least 90% were: 8.0 kPa for significant liver fibrosis, and 10.5 kPa for cirrhosis. The cutoff values of FibroScan for staging liver fibrosis with specificity at least 90% were: 10.8 kPa for significant liver fibrosis, and 17.8 kPa for cirrhosis.FibroScan provides high value for the diagnosis of liver fibrosis and cirrhosis in patients with concomitant CHB and NAFLD.


Assuntos
Técnicas de Imagem por Elasticidade/normas , Hepatite B Crônica/complicações , Cirrose Hepática/diagnóstico por imagem , Hepatopatia Gordurosa não Alcoólica/complicações , Adulto , Biópsia , Feminino , Humanos , Cirrose Hepática/etiologia , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Retrospectivos , Índice de Gravidade de Doença , gama-Glutamiltransferase/sangue
7.
Nature ; 583(7814): 127-132, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32555459

RESUMO

Cellular senescence is characterized by stable cell-cycle arrest and a secretory program that modulates the tissue microenvironment1,2. Physiologically, senescence serves as a tumour-suppressive mechanism that prevents the expansion of premalignant cells3,4 and has a beneficial role in wound-healing responses5,6. Pathologically, the aberrant accumulation of senescent cells generates an inflammatory milieu that leads to chronic tissue damage and contributes to diseases such as liver and lung fibrosis, atherosclerosis, diabetes and osteoarthritis1,7. Accordingly, eliminating senescent cells from damaged tissues in mice ameliorates the symptoms of these pathologies and even promotes longevity1,2,8-10. Here we test the therapeutic concept that chimeric antigen receptor (CAR) T cells that target senescent cells can be effective senolytic agents. We identify the urokinase-type plasminogen activator receptor (uPAR)11 as a cell-surface protein that is broadly induced during senescence and show that uPAR-specific CAR T cells efficiently ablate senescent cells in vitro and in vivo. CAR T cells that target uPAR extend the survival of mice with lung adenocarcinoma that are treated with a senescence-inducing combination of drugs, and restore tissue homeostasis in mice in which liver fibrosis is induced chemically or by diet. These results establish the therapeutic potential of senolytic CAR T cells for senescence-associated diseases.


Assuntos
Envelhecimento/patologia , Senescência Celular/imunologia , Cirrose Hepática/terapia , Longevidade/imunologia , Neoplasias Pulmonares/terapia , Receptores de Antígenos Quiméricos/imunologia , Rejuvenescimento , Linfócitos T/imunologia , Adenocarcinoma/imunologia , Adenocarcinoma/patologia , Adenocarcinoma/terapia , Animais , Tetracloreto de Carbono , Feminino , Xenoenxertos , Humanos , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/imunologia , Cirrose Hepática/patologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Receptores de Antígenos Quiméricos/metabolismo , Receptores de Ativador de Plasminogênio Tipo Uroquinase/genética , Receptores de Ativador de Plasminogênio Tipo Uroquinase/metabolismo , Linfócitos T/metabolismo , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo
9.
Expert Opin Pharmacother ; 21(13): 1637-1650, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32543284

RESUMO

INTRODUCTION: Chronic liver disease is due to various causes of persistent liver damage and will eventually lead to the development of liver fibrosis. If no treatment is initiated, this condition may progress to cirrhosis and hepatocellular carcinoma. Current treatments comprise the elimination of the cause of injury, such as by lifestyle changes, alcohol abstinence, and antiviral agents. However, such etiology-driven therapy is often insufficient in patients with late-stage fibrosis/cirrhosis, therefore maintaining the need for efficient antifibrotic pharmacotherapeutic interventions. AREAS COVERED: The authors discuss the recent advances in the development of antifibrotic drugs, which target various pathways of the fibrogenesis process, including cell death, inflammation, gut-liver axis, and myofibroblast activation. Due to the significant burden of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), various agents which specifically target metabolic pathways and their related receptors/ligands have been developed. For some of them, e.g., obeticholic acid, advanced stage clinical trials indicate antifibrotic efficacy in NAFLD and NASH. EXPERT OPINION: Significant advances have been made in the development of novel antifibrotic pharmacotherapeutics. The authors expect that the development of combinatorial therapies, which combine compounds that target various pathways of fibrosis progression, will have a major impact as future etiology-independent therapies.


Assuntos
Cirrose Hepática/tratamento farmacológico , Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Ensaios Clínicos como Assunto , Progressão da Doença , Avaliação Pré-Clínica de Medicamentos , Humanos , Inflamação , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/etiologia , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Redes e Vias Metabólicas/efeitos dos fármacos , Terapia de Alvo Molecular , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia
10.
Toxicol Lett ; 332: 1-6, 2020 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-32579995

RESUMO

Non-alcoholic fatty liver disease (NAFLD) can be typically classified into two subgroups: non-alcoholic fatty liver and non-alcoholic steatohepatitis. Mouse models of NAFLD are useful tools for understanding the pathogenesis and progression of NAFLD and for developing drugs for its treatment. Here, we investigated the time-dependent changes in serum lipids and biochemical markers of hepatic function, hepatic inflammation, and fibrosis in mice fed a normal diet (ND) or a NAFLD diet (choline deficient, L-amino acid-defined, high-fat diet; CDAHFD) for 12 weeks. CDAHFD-fed mice showed significantly reduced serum levels of total cholesterol, triglyceride, and high-density lipoprotein cholesterol throughout the treatment period compared with ND-fed mice. The changes in aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and total bilirubin showed an inverse U-shaped curve in the CDAHFD-fed mice. The serum alkaline phosphatase levels decreased in both ND- and CDAHFD-fed mice in a time-dependent manner. Furthermore, CDAHFD-fed mice showed a significant increase in the number of inflammatory foci and hepatic fibrosis at 6-12 weeks, although inflammatory foci and hepatic fibrogenesis were observable at relatively early stages as well (1-4 weeks). In conclusion, the long-term profile of serological biomarkers, hepatic inflammation, and fibrosis in CDAHFD-fed mice identified in this study may provide a better understanding of NAFLD pathogenesis.


Assuntos
Hepatite/patologia , Cirrose Hepática/patologia , Fígado/patologia , Hepatopatia Gordurosa não Alcoólica/patologia , Animais , Biomarcadores/análise , Peso Corporal/efeitos dos fármacos , Colesterol/sangue , HDL-Colesterol/sangue , Dieta , Hepatite/sangue , Hepatite/enzimologia , Metabolismo dos Lipídeos , Fígado/enzimologia , Fígado/metabolismo , Cirrose Hepática/sangue , Testes de Função Hepática , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/enzimologia , Triglicerídeos/sangue
11.
J Infect Dis ; 222(5): 726-733, 2020 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-32563190

RESUMO

BACKGROUND: COVID-19 is a potentially severe disease caused by the recently described SARS-CoV-2. Whether liver fibrosis might be a relevant player in the natural history of COVID-19 is currently unknown. We aimed to evaluate the association between FIB-4 and the risk of progression to critical illness in middle-aged patients with COVID-19. METHODS: In this multicenter, retrospective study with prospective follow-up of 160 patients aged 35-65 years with COVID-19, FIB-4, clinical, and biochemical variables were collected at baseline. FIB-4 ≥2.67 defined patients with risk for advanced liver fibrosis. RESULTS: Risk for advanced fibrosis was estimated in 28.1% of patients. Patients with FIB-4 ≥2.67 more frequently required mechanical ventilation (37.8% vs 18.3%; P = .009). In multivariate analysis, FIB-4 ≥2.67 (odds ratio [OR], 3.41; 95% confidence interval [CI], 1.30-8.92), cardiovascular risk factors (OR, 5.05; 95% CI, 1.90-13.39), previous respiratory diseases (OR, 4.54; 95% CI, 1.36-15.10), and C-reactive protein (OR, 1.01; 95% CI, 1.01-1.02) increased significantly the risk of ICU admission. Bootstrap confirmed FIB-4 as an independent risk factor. CONCLUSIONS: In middle-aged patients with COVID-19, FIB-4 may have a prognostic role. The link between liver fibrosis and the natural history of COVID-19 should be evaluated in future studies.


Assuntos
Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/patologia , Cirrose Hepática/virologia , Pneumonia Viral/patologia , Adulto , Idoso , Betacoronavirus/genética , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/virologia , Feminino , Humanos , Cirrose Hepática/diagnóstico , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/virologia , Estudos Prospectivos , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença
12.
Arch Biochem Biophys ; 689: 108445, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32524998

RESUMO

Liver fibrogenesis is defined as a dynamic and highly integrated process occurring during chronic injury to liver parenchyma that can result in excess deposition of extracellular matrix (ECM) components (i.e., liver fibrosis). Liver fibrogenesis, together with chronic inflammatory response, is then primarily involved in the progression of chronic liver diseases (CLD) irrespective of the specific etiology. In the present review we will first offer a synthetic and updated overview of major basic concepts in relation to the role of myofibroblasts (MFs), macrophages and other hepatic cell populations involved in CLD to then offer an overview of established and emerging issues and mechanisms that have been proposed to favor and/or promote CLD progression. A special focus will be dedicated to selected issues that include emerging features in the field of cholangiopathies, the emerging role of genetic and epigenetic factors as well as of hypoxia, hypoxia-inducible factors (HIFs) and related mediators.


Assuntos
Cirrose Hepática/patologia , Fígado/patologia , Animais , Doença Crônica , Progressão da Doença , Epigênese Genética , Humanos , Inflamação/genética , Inflamação/patologia , Fígado/metabolismo , Cirrose Hepática/genética , Macrófagos/metabolismo , Macrófagos/patologia , Miofibroblastos/metabolismo , Miofibroblastos/patologia
13.
Life Sci ; 254: 117795, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32417373

RESUMO

AIMS: The primary focus of this study was to explore the effects of cyclic AMP response element-binding protein H (CREBH) on the development of nonalcoholic fatty liver disease (NAFLD). MATERIALS AND METHODS: CREBH knockout (KO) and wildtype (WT) mice were averagely divided into a methionine and choline-deficient (MCD) or high fat (HF) diet group and respective chow diet (CD) groups. Mice were sacrificed after 4-week treatment for MCD model and 24-week treatment for HF model. KEY FINDINGS: Characteristics of nonalcoholic steatohepatitis-related liver fibrosis in KO-MCD/HF group were verified by hepatic histological analyses. Compared with WT-MCD/HF group, levels of plasma ALT and hepatic hydroxyproline increased in KO-MCD/HF group. Significantly higher levels of MCP-1, αSMA, Desmin, COL-1, TIMP-1, TGF-ß1, TGF-ß2 were found while MMP-9 and FGF21 mRNA levels decreased in KO-MCD/HF group. There was also a distinct difference of mRNA levels of TNFα, CTGF and CCND1 in KO-HF group compared with controls. Protein levels of MCP-1, BAX, αSMA, COL-1, TGF-ß1 and SMAD2/3 significantly increased in KO-MCD/HF group and CCND1 was also upregulated in KO-HF group compared to their counterparts. SIGNIFICANCE: CREBH knockout may primarily regulate the TGF-ß1 signaling pathway via TGF-ß2 and FGF21 resulting in more severe inflammation and fibrosis in NAFLD.


Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Cirrose Hepática/genética , Hepatopatia Gordurosa não Alcoólica/genética , Fator de Crescimento Transformador beta/metabolismo , Alanina Transaminase/sangue , Animais , Deficiência de Colina , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/deficiência , Dieta Hiperlipídica , Fatores de Crescimento de Fibroblastos/biossíntese , Hidroxiprolina/metabolismo , Lipídeos/sangue , Cirrose Hepática/sangue , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Masculino , Metionina/deficiência , Camundongos , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Transdução de Sinais/genética
14.
Life Sci ; 255: 117818, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32445757

RESUMO

Activation of hepatic stellate cells (HSCs) is a central event in the pathogenesis of liver fibrosis and is characterized by the disappearance of lipid droplets. Although the exogenous supplementation of lipid droplet content can effectively reverse the activation of HSCs, the underlying molecular mechanisms are largely unknown. In our current study, we sought to investigate the role of lncRNA-H19 in the process of lipid droplets disappearance and to further examine the underlying molecular mechanisms. We found that the lncRNA-H19 level was increased in CCl4-induced fibrotic liver, which activated HSCs. Further research showed that hypoxia inducible factor-1α (HIF-1α) significantly increased lncRNA-H19 expression by binding to the lncRNA-H19 promoter at two hypoxia response element (HRE) sites located at 492-499 and 515-522 bp. Importantly, lncRNA-H19 knockdown markedly inhibited HSC activation and alleviated liver fibrosis, indicating that lncRNA-H19 may be a potential target for anti-fibrosis therapeutic approaches. Moreover, lncRNA-H19 knockdown could reverse the lipid droplet phenotype of activated HSCs, inhibiting the phosphorylated AMPKα-mediated lipid oxidation signaling pathway. The AMPK agonist AICAR promoted AMPKα phosphorylation and abrogated lipid droplets restoration in HSCs transfected with the lncRNA-H19 knockdown plasmid. Experimental molecular analysis showed that lncRNA-H19 triggered AMPKα to interact with LKB1 and resulted in AMPKα phosphorylation, which accelerating lipid droplets degradation and lipid oxidation. Taken together, our results highlighted the role of lncRNA-H19 in the metabolism of lipid droplets in HSCs, and revealed a new molecular target for alleviating liver fibrosis.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Células Estreladas do Fígado/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Cirrose Hepática/patologia , RNA Longo não Codificante/genética , Animais , Linhagem Celular , Técnicas de Silenciamento de Genes , Humanos , Gotículas Lipídicas/metabolismo , Cirrose Hepática/genética , Masculino , Camundongos , Camundongos Endogâmicos ICR , Elementos de Resposta/genética
15.
PLoS One ; 15(5): e0233702, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32442221

RESUMO

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


Assuntos
Hepacivirus/metabolismo , Células Estreladas do Fígado/metabolismo , Vírus da Hepatite B/metabolismo , Hepatite B/metabolismo , Hepatite C/metabolismo , Cirrose Hepática/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Animais , Linhagem Celular , Regulação da Expressão Gênica , Células Estreladas do Fígado/patologia , Células Estreladas do Fígado/virologia , Hepatite B/patologia , Hepatite C/patologia , Humanos , Cirrose Hepática/patologia , Masculino , Camundongos , Hepatopatia Gordurosa não Alcoólica/patologia , Fatores de Transcrição/biossíntese
16.
Mol Immunol ; 123: 32-39, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32413787

RESUMO

At present, most studies on the relationship between hepatitis B virus (HBV) and IL-33/ST2 axis focus on clinical detection, but the underlying molecular mechanisms of HBx and IL-33/ST2 axis regulation and Th cell function regulation have not been explored. In this study, serum samples of patients with chronic hepatitis B (CHB) and HBV-related liver cancer (HBV-HCC), and healthy controls, as well as the supernatant solutions of HL7702-WT, HL7702-NC, and HL7702-HBx cells were collected to detect the content of soluble ST2 (sST2). The contents of Th1 cytokines (TNF-α and TNF-γ) and Th2 cytokines (IL-6 and IL-10) in the supernatant of different co-culture groups were detected. The effects of GATA2 on ST2 promoter transcription were investigated by upregulation or interference with GATA2 expression, dual-luciferase reporting, and ChIP experiments. The combined detection of sST2 and FIB-4 was beneficial to the non-invasive diagnosis of liver fibrosis. HBx promotes sST2 expression in liver cells, upregulates Th2 cell function, and inhibits Th1 cell function through IL-33/ST2 axis. HBx interacts with GATA2 to influence the activity of ST2 promoter. Serum sST2 detection is an invaluable indicator for the assessment of the progress of HBV infectious diseases, and the IL-33/ST2 axis plays an important role in changing the cellular immune function caused by HBV infection.


Assuntos
Fator de Transcrição GATA2/fisiologia , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Fígado/efeitos dos fármacos , Fígado/metabolismo , Transativadores/farmacologia , Adulto , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/virologia , Estudos de Casos e Controles , Células Cultivadas , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Vírus da Hepatite B/fisiologia , Hepatite B Crônica/complicações , Hepatite B Crônica/genética , Hepatite B Crônica/patologia , Humanos , Interleucina-33/fisiologia , Fígado/patologia , Cirrose Hepática/genética , Cirrose Hepática/patologia , Cirrose Hepática/virologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
17.
Zhonghua Gan Zang Bing Za Zhi ; 28(4): 357-360, 2020 Apr 20.
Artigo em Chinês | MEDLINE | ID: mdl-32403890

RESUMO

Liver sinusoidal endothelial cells (LSECs) are not only important intermediary cells for substance exchange between blood and hepatocytes, but also important hepatic non-parenchymal cells to cause liver fibrosis and cirrhosis because of chronic liver injury factors. It mainly regulates the liver microcirculation and participates in the development of hepatic fibrosis by interacting with hepatic stellate cells (HSCs), hepatocytes, Kupffer cells and mediating hepatic stiffness and hepatic angiogenesis. Hence, clarifying these mechanisms will help to explore new targets and strategies for the treatment of liver fibrosis.


Assuntos
Células Endoteliais/citologia , Cirrose Hepática/patologia , Fígado/citologia , Células Estreladas do Fígado , Hepatócitos , Humanos , Macrófagos do Fígado , Fígado/patologia
18.
Nat Commun ; 11(1): 2362, 2020 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-32398673

RESUMO

Due to their bacterial ancestry, many components of mitochondria share structural similarities with bacteria. Release of molecular danger signals from injured cell mitochondria (mitochondria-derived damage-associated molecular patterns, mito-DAMPs) triggers a potent inflammatory response, but their role in fibrosis is unknown. Using liver fibrosis resistant/susceptible mouse strain system, we demonstrate that mito-DAMPs released from injured hepatocyte mitochondria (with mtDNA as major active component) directly activate hepatic stellate cells, the fibrogenic cell in the liver, and drive liver scarring. The release of mito-DAMPs is controlled by efferocytosis of dying hepatocytes by phagocytic resident liver macrophages and infiltrating Gr-1(+) myeloid cells. Circulating mito-DAMPs are markedly increased in human patients with non-alcoholic steatohepatitis (NASH) and significant liver fibrosis. Our study identifies specific pathway driving liver fibrosis, with important diagnostic and therapeutic implications. Targeting mito-DAMP release from hepatocytes and/or modulating the phagocytic function of macrophages represents a promising antifibrotic strategy.


Assuntos
Alarminas/imunologia , Células Estreladas do Fígado/imunologia , Hepatócitos/metabolismo , Cirrose Hepática/imunologia , Hepatopatia Gordurosa não Alcoólica/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Alarminas/metabolismo , Animais , Apoptose/imunologia , Modelos Animais de Doenças , Progressão da Doença , Feminino , Hepatócitos/citologia , Hepatócitos/imunologia , Humanos , Fígado/citologia , Fígado/efeitos dos fármacos , Fígado/imunologia , Fígado/patologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/patologia , Macrófagos/imunologia , Masculino , Camundongos , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Hepatopatia Gordurosa não Alcoólica/imunologia , Fagocitose/imunologia , Tioacetamida/toxicidade , Adulto Jovem
19.
AJR Am J Roentgenol ; 215(2): 382-389, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32432909

RESUMO

OBJECTIVE. The purposes of this study were to evaluate the outcome of new arterial phase enhancing nodules at MRI of cirrhotic livers, including clinical and imaging factors that affect progression to hepatocellular carcinoma (HCC), and to assess the diagnostic performance of Liver Imaging Reporting and Data System version 2018 (LI-RADSv2018) versus version 2017 (LI-RADSv2017) in categorizing these nodules. MATERIALS AND METHODS. A database search identified 129 new arterial phase enhancing, round, solid, space-occupying nodules in 79 patients with cirrhosis who underwent surveillance MRI. Three readers assessed the nodules for LI-RADS findings and made assessments based on the 2017 and 2018 criteria. Clinical information and laboratory values were collected. Outcome data were assessed on the basis of follow-up imaging and pathology results. Interreader agreement was assessed. Logistic regression and ROC curve analyses were used to assess the utility of the features for prediction of progression to HCC. RESULTS. Of the 129 nodules, 71 (55%) progressed to HCC. LI-RADSv2017 score, LIRADSv2018 score, and mild-to-moderate T2 hyperintensity were significant independent predictors of progression to HCC in univariate analyses. Serum α-fetoprotein level, hepatitis B or C virus infection as the cause of liver disease, and presence of other HCCs were significant predictors of progression to HCC in multivariate analyses. The rates of progression of LI-RADS category 3 and 4 observations were 38.1% and 57.6%, respectively, for LI-RADSv2017 and 44.4% and 69.9%, respectively, for LI-RADSv2018. CONCLUSION. New arterial phase enhancing nodules in patients with cirrhosis frequently progress to HCC. Factors such as serum α-fetoprotein level and presence of other HCCs are strong predictors of progression to HCC.


Assuntos
Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/etiologia , Cirrose Hepática/complicações , Cirrose Hepática/diagnóstico por imagem , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/etiologia , Fígado/diagnóstico por imagem , Fígado/patologia , Imagem por Ressonância Magnética/métodos , Artérias , Progressão da Doença , Feminino , Humanos , Cirrose Hepática/patologia , Imagem por Ressonância Magnética/instrumentação , Masculino , Pessoa de Meia-Idade , Projetos de Pesquisa , Estudos Retrospectivos
20.
Am J Gastroenterol ; 115(9): 1486-1495, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32453046

RESUMO

INTRODUCTION: Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death worldwide, affecting men to women at a ratio of about 4:1. Risk factors, characteristics, and outcomes for HCC in women in the United States remain poorly understood; therefore, we aim to explore gender differences further. METHODS: Patients diagnosed with HCC between January 2000 and June 2014 at 5 large centers were identified. Clinical information, tumor characteristics, and survival data were extracted manually. The presence of underlying cirrhosis was assessed based on published criteria. RESULTS: Of 5,327 patients with HCC in our cohort, 1,203 (22.6%) were women. There were important differences in the underlying etiology of liver disease between the 2 genders (P < 0.0001): women had a significantly higher frequency of nonalcoholic fatty liver disease (23% vs 12%) and lower frequency of alcoholic liver disease (5% vs 15%). The proportion of noncirrhotic HCC was significantly higher among women (17% vs 10%, P < 0.0001). Women had less-advanced HCC at presentation by tumor, node, metastasis staging (P < 0.0001) and a higher proportion within Milan criteria (39% vs 35%, P = 0.002). Women had a greater overall survival (2.5 ± 2.9 years vs 2.2 ± 2.7 years, P = 0.0031). DISCUSSION: The frequency of underlying nonalcoholic fatty liver disease and noncirrhotic HCC were significantly higher in women than men in this large cohort. Women presented with less-advanced HCC and had a greater overall survival. Further investigation is warranted to explore potential mechanisms and implications for these gender differences, especially with noncirrhotic HCC (see Visual Abstract, Supplementary Digital Content 1, http://links.lww.com/AJG/B535).


Assuntos
Carcinoma Hepatocelular/patologia , Cirrose Hepática/patologia , Hepatopatias Alcoólicas/patologia , Neoplasias Hepáticas/patologia , Hepatopatia Gordurosa não Alcoólica/patologia , Idoso , Carcinoma Hepatocelular/etiologia , Feminino , Humanos , Cirrose Hepática/complicações , Hepatopatias Alcoólicas/complicações , Neoplasias Hepáticas/etiologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/complicações , Fatores Sexuais
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