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1.
JAMA ; 326(2): 165-176, 2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34255003

RESUMO

Importance: Alcohol-associated liver disease results in cirrhosis in approximately 10% to 20% of patients. In 2017, more than 2 million people had alcohol-associated cirrhosis in the US. Alcohol-associated liver disease is the primary cause of liver-related mortality and the leading indication for liver transplant, representing 40% to 50% of all liver transplant in high-income countries. Observations: Steatosis, alcoholic hepatitis, and fibrosis are the 3 pathologic findings that are associated with progression to cirrhosis, with highest risk in patients with alcoholic hepatitis. The amount and duration of alcohol consumption, female sex, obesity, and specific genetic polymorphisms such as patatin-like phospholipase domain protein 3, membrane bound O-acyltransferase, and transmembrane 6 superfamily member 2 genes are risk factors for alcohol-associated liver disease progression. Ten-year survival of patients with alcohol-associated liver disease is 88% among those who are abstinent and 73% for those who relapse to alcohol consumption. Symptomatic alcoholic hepatitis is characterized by rapid onset of jaundice and a 30% risk of mortality 1 year after diagnosis. Severe alcoholic hepatitis, defined as a modified discriminant function score greater than or equal to 32 or Model for End-Stage Liver Disease score (starts at 6 and capped at 40; worst = 40) greater than 20, is associated with the development of acute-on-chronic liver failure and multiorgan failure. Corticosteroid therapy is associated with improved 1-month survival from 65% in untreated patients to 80% in treated patients. Early liver transplant may be appropriate in highly select patients with severe alcoholic hepatitis who do not respond to medical therapy. In patients with decompensated cirrhosis, liver transplant should be considered if the Model for End-Stage Liver Disease score remains greater than 17 after 3 months of alcohol abstinence. Between 2014 and 2019, the proportion of patients waiting for liver transplantation who had alcohol-associated liver disease increased from 22% to 40%. Alcohol-associated cirrhosis accounted for approximately 27% of 1.32 million deaths worldwide related to cirrhosis in 2017. Conclusions and Relevance: Alcohol-associated liver disease is among the most common liver diseases and more than 2 million people in the US in 2017 had alcohol-associated cirrhosis. Corticosteroid therapy improves survival in select patients with severe alcoholic hepatitis. Liver transplantation is the most effective therapy in patients with decompensated liver disease.


Assuntos
Corticosteroides/uso terapêutico , Hepatopatias Alcoólicas , Transplante de Fígado , Fígado/patologia , Abstinência de Álcool , Consumo de Bebidas Alcoólicas/efeitos adversos , Feminino , Humanos , Fígado/metabolismo , Hepatopatias Alcoólicas/diagnóstico , Hepatopatias Alcoólicas/genética , Hepatopatias Alcoólicas/terapia , Masculino , Fatores de Risco , Índice de Gravidade de Doença
2.
Int J Mol Sci ; 22(13)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34202112

RESUMO

D-galactose (D-gal) administration causes oxidative disorder and is widely utilized in aging animal models. Therefore, we subcutaneously injected D-gal at 200 mg/kg BW dose to assess the potential preventive effect of thymoquinone (TQ) and curcumin (Cur) against the oxidative alterations induced by D-gal. Other than the control, vehicle, and D-gal groups, the TQ and Cur treated groups were orally supplemented at 20 mg/kg BW of each alone or combined. TQ and Cur effectively suppressed the oxidative alterations induced by D-gal in brain and heart tissues. The TQ and Cur combination significantly decreased the elevated necrosis in the brain and heart by D-gal. It significantly reduced brain caspase 3, calbindin, and calcium-binding adapter molecule 1 (IBA1), heart caspase 3, and BCL2. Expression of mRNA of the brain and heart TP53, p21, Bax, and CASP-3 were significantly downregulated in the TQ and Cur combination group along with upregulation of BCL2 in comparison with the D-gal group. Data suggested that the TQ and Cur combination is a promising approach in aging prevention.


Assuntos
Benzoquinonas/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Curcumina/farmacologia , Galactose/farmacologia , Miocárdio/metabolismo , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Benzoquinonas/química , Curcumina/química , Imuno-Histoquímica , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Especificidade de Órgãos , Ratos , Relação Estrutura-Atividade
3.
Int J Mol Sci ; 22(13)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202493

RESUMO

As a newly identified manganese transport protein, ZIP14 is highly expressed in the small intestine and liver, which are the two principal organs involved in regulating systemic manganese homeostasis. Loss of ZIP14 function leads to manganese overload in both humans and mice. Excess manganese in the body primarily affects the central nervous system, resulting in irreversible neurological disorders. Therefore, to prevent the onset of brain manganese accumulation becomes critical. In this study, we used Zip14-/- mice as a model for ZIP14 deficiency and discovered that these mice were born without manganese loading in the brain, but started to hyper-accumulate manganese within 3 weeks after birth. We demonstrated that decreasing manganese intake in Zip14-/- mice was effective in preventing manganese overload that typically occurs in these animals. Our results provide important insight into future studies that are targeted to reduce the onset of manganese accumulation associated with ZIP14 dysfunction in humans.


Assuntos
Encéfalo/patologia , Proteínas de Transporte de Cátions/deficiência , Dieta , Suscetibilidade a Doenças , Manganês/metabolismo , Doenças Metabólicas/etiologia , Doenças Metabólicas/metabolismo , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Fígado/metabolismo , Fígado/patologia , Manganês/efeitos adversos , Doenças Metabólicas/patologia , Doenças Metabólicas/prevenção & controle , Camundongos , Especificidade de Órgãos
4.
Int J Mol Sci ; 22(13)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202771

RESUMO

In this article, we review the biological and clinical implication of the Recruitment-Secretory Block ("R-SB") phenomenon. The phenomenon refers to the reaction of the liver with regard to protein secretion in conditions of clinical stimulation. Our basic knowledge of the process is due to the experimental work in animal models. Under basal conditions, the protein synthesis is mainly carried out by periportal (zone 1) hepatocytes that are considered the "professional" synthesizing protein cells. Under stimulation, midlobular and centrolobular (zones 2 and 3) hepatocytes, are progressively recruited according to lobular gradients and contribute to the increase of synthesis and secretion. The block of secretion, operated by exogenous agents, causes intracellular retention of all secretory proteins. The Pi MZ phenotype of Alpha-1-antitrypsin deficiency (AATD) has turned out to be the key for in vivo studies of the reaction of the liver, as synthesis and block of secretion are concomitant. Indeed, the M fraction of AAT is stimulated for synthesis and regularly exported while the Z fraction is mostly retained within the cell. For that reason, the phenomenon has been designated "Recruitment-Secretory Block" ("R-SB"). The "R-SB" phenomenon explains why: (a) the MZ individuals can correct the serum deficiency; (b) the resulting immonohistochemical and electron microscopic (EM) patterns are very peculiar and specific for the diagnosis of the Z mutation in tissue sections in the absence of genotyping; (c) the term carrier is no longer applicable for the heterozygous condition as all Pi MZ individuals undergo storage and the storage predisposes to liver damage. The storage represents the true elementary lesion and consequently reflects the phenotype-genotype correlation; (d) the site and function of the extrahepatic AAT and the relationship between intra and extracellular AAT; (e) last but not least, the concept of Endoplasmic Reticulum Storage Disease (ERSD) and of a new disease, hereditary hypofibrinogenemia with hepatic storage (HHHS). In the light of the emerging phenomenon, described in vitro, namely that M and Z AAT can form heteropolymers within hepatocytes as well as in circulation, we have reviewed the whole clinical and experimental material collected during forty years, in order to evaluate to what extent the polymerization phenomenon occurs in vivo. The paper summarizes similarities and differences between AAT and Fibrinogen as well as between the related diseases, AATD and HHHS. Indeed, fibrinogen gamma chain mutations undergo an aggregation process within the RER of hepatocytes similar to AATD. In addition, this work has clarified the intriguing phenomenon underlying a new syndrome, hereditary hypofibrinogenemia and hypo-APO-B-lipoproteinemia with hepatic storage of fibrinogen and APO-B lipoproteins. It is hoped that these studies could contribute to future research and select strategies aimed to simultaneously correct the hepatocytic storage, thus preventing the liver damage and the plasma deficiency of the two proteins.


Assuntos
Suscetibilidade a Doenças , Retículo Endoplasmático/metabolismo , Sistemas de Translocação de Proteínas/metabolismo , Animais , Animais Geneticamente Modificados , Biomarcadores , Modelos Animais de Doenças , Predisposição Genética para Doença , Humanos , Fígado/metabolismo , Fígado/patologia , Fígado/ultraestrutura , Redes e Vias Metabólicas , Erros Inatos do Metabolismo/genética , Erros Inatos do Metabolismo/metabolismo , Transporte Proteico , alfa 1-Antitripsina/genética , alfa 1-Antitripsina/metabolismo , Deficiência de alfa 1-Antitripsina/genética , Deficiência de alfa 1-Antitripsina/metabolismo
5.
Nat Commun ; 12(1): 4264, 2021 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-34253736

RESUMO

Single-cell RNA-seq reveals the role of pathogenic cell populations in development and progression of chronic diseases. In order to expand our knowledge on cellular heterogeneity, we have developed a single-nucleus RNA-seq2 method tailored for the comprehensive analysis of the nuclear transcriptome from frozen tissues, allowing the dissection of all cell types present in the liver, regardless of cell size or cellular fragility. We use this approach to characterize the transcriptional profile of individual hepatocytes with different levels of ploidy, and have discovered that ploidy states are associated with different metabolic potential, and gene expression in tetraploid mononucleated hepatocytes is conditioned by their position within the hepatic lobule. Our work reveals a remarkable crosstalk between gene dosage and spatial distribution of hepatocytes.


Assuntos
Fígado/metabolismo , Ploidias , Análise de Sequência de RNA , Análise de Célula Única , Animais , Biomarcadores/metabolismo , Núcleo Celular/metabolismo , Doença Crônica , Secções Congeladas , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Ontologia Genética , Hepatócitos/metabolismo , Fígado/patologia , Hepatopatias/patologia , Camundongos Endogâmicos C57BL , Regeneração , Células-Tronco/metabolismo , Fatores de Transcrição/metabolismo , Transcrição Genética
6.
Int J Mol Sci ; 22(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199599

RESUMO

Orphan nuclear receptor estrogen-related receptor γ (ERRγ) is an important transcription factor modulating gene transcription involved in endocrine control of liver metabolism. Transferrin receptor 2 (TFR2), a carrier protein for transferrin, is involved in hepatic iron overload in alcoholic liver disease (ALD). However, TFR2 gene transcriptional regulation in hepatocytes remains largely unknown. In this study, we described a detailed molecular mechanism of hepatic TFR2 gene expression involving ERRγ in response to an endocannabinoid 2-arachidonoylglycerol (2-AG). Treatment with 2-AG and arachidonyl-2'-chloroethylamide, a selective cannabinoid receptor type 1 (CB1) receptor agonist, increased ERRγ and TFR2 expression in hepatocytes. Overexpression of ERRγ was sufficient to induce TFR2 expression in both human and mouse hepatocytes. In addition, ERRγ knockdown significantly decreased 2-AG or alcohol-mediated TFR2 gene expression in cultured hepatocytes and mouse livers. Finally, deletion and mutation analysis of the TFR2 gene promoter demonstrated that ERRγ directly modulated TFR2 gene transcription via binding to an ERR-response element. This was further confirmed by chromatin immunoprecipitation assay. Taken together, these results reveal a previously unrecognized role of ERRγ in the transcriptional regulation of TFR2 gene expression in response to alcohol.


Assuntos
Hepatopatias Alcoólicas/genética , Fígado/efeitos dos fármacos , Receptor CB1 de Canabinoide/genética , Receptores de Estrogênio/genética , Receptores da Transferrina/genética , Álcoois/farmacologia , Animais , Ácidos Araquidônicos/farmacologia , Endocanabinoides/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Glicerídeos/farmacologia , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Humanos , Ferro/metabolismo , Fígado/metabolismo , Fígado/patologia , Hepatopatias Alcoólicas/metabolismo , Hepatopatias Alcoólicas/patologia , Camundongos , Regiões Promotoras Genéticas , Receptor CB1 de Canabinoide/agonistas , Deleção de Sequência/genética , Transferrina/genética , Transferrina/metabolismo
7.
World J Gastroenterol ; 27(24): 3581-3594, 2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34239271

RESUMO

BACKGROUND: Fasudil, as a Ras homology family member A (RhoA) kinase inhibitor, is used to improve brain microcirculation and promote nerve regeneration clinically. Increasing evidence shows that Rho-kinase inhibition could improve liver fibrosis. AIM: To evaluate the anti-fibrotic effects of Fasudil in a mouse model of liver fibrosis induced by thioacetamide (TAA). METHODS: C57BL/6 mice were administered TAA once every 3 d for 12 times. At 1 wk after induction with TAA, Fasudil was intraperitoneally injected once a day for 3 wk, followed by hematoxylin and eosin staining, sirius red staining, western blotting, and quantitative polymerase chain reaction (qPCR), and immune cell activation was assayed by fluorescence-activated cell sorting. Furthermore, the effects of Fasudil on hepatic stellate cells and natural killer (NK) cells were assayed in vitro. RESULTS: First, we found that TAA-induced liver injury was protected, and the positive area of sirius red staining and type I collagen deposition were significantly decreased by Fasudil treatment. Furthermore, western blot and qPCR assays showed that the levels of alpha smooth muscle actin (α-SMA), matrix metalloproteinase 2 (MMP-2), MMP-9, and transforming growth factor beta 1 (TGF-ß1) were inhibited by Fasudil. Moreover, flow cytometry analysis revealed that NK cells were activated by Fasudil treatment in vivo and in vitro. Furthermore, Fasudil directly promoted the apoptosis and inhibited the proliferation of hepatic stellate cells by decreasing α-SMA and TGF-ß1. CONCLUSION: Fasudil inhibits liver fibrosis by activating NK cells and blocking hepatic stellate cell activation, thereby providing a feasible solution for the clinical treatment of liver fibrosis.


Assuntos
Células Estreladas do Fígado , Metaloproteinase 2 da Matriz , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , Animais , Células Estreladas do Fígado/patologia , Células Matadoras Naturais , Fígado/patologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/prevenção & controle , Camundongos , Camundongos Endogâmicos C57BL , Fator de Crescimento Transformador beta1
8.
Int J Mol Sci ; 22(11)2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-34198853

RESUMO

In nonalcoholic steatohepatitis animal models, an increased lipid droplet size in hepatocytes is associated with fibrogenesis. Hepatocytes with large droplet (Ld-MaS) or small droplet (Sd-MaS) macrovesicular steatosis may coexist in the human liver, but the factors associated with the predominance of one type over the other, including hepatic fibrogenic capacity, are unknown. In pre-ischemic liver biopsies from 225 consecutive liver transplant donors, we retrospectively counted hepatocytes with Ld-MaS and Sd-MaS and defined the predominant type of steatosis as involving ≥50% of steatotic hepatocytes. We analyzed a donor Patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409 polymorphism, hepatic expression of proteins involved in lipid metabolism by RT-PCR, hepatic stellate cell (HSC) activation by α-SMA immunohistochemistry and, one year after transplantation, histological progression of fibrosis due to Hepatitis C Virus (HCV) recurrence. Seventy-four livers had no steatosis, and there were 98 and 53 with predominant Ld-MaS and Sd-MaS, respectively. In linear regression models, adjusted for many donor variables, the percentage of steatotic hepatocytes affected by Ld-MaS was inversely associated with hepatic expression of Insulin Induced Gene 1 (INSIG-1) and Niemann-Pick C1-Like 1 gene (NPC1L1) and directly with donor PNPLA3 variant M, HSC activation and progression of post-transplant fibrosis. In humans, Ld-MaS formation by hepatocytes is associated with abnormal PNPLA3-mediated lipolysis, downregulation of both the intracellular cholesterol sensor and cholesterol reabsorption from bile and increased hepatic fibrogenesis.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/genética , Lipase/genética , Proteínas de Membrana/genética , Proteínas de Membrana Transportadoras/genética , Hepatopatia Gordurosa não Alcoólica/genética , Adulto , Idoso , Feminino , Regulação da Expressão Gênica/genética , Hepacivirus/genética , Hepatócitos/virologia , Humanos , Gotículas Lipídicas/metabolismo , Gotículas Lipídicas/patologia , Gotículas Lipídicas/virologia , Fígado/metabolismo , Fígado/patologia , Fígado/virologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatopatia Gordurosa não Alcoólica/virologia , Polimorfismo de Nucleotídeo Único/genética , Estudos Retrospectivos
9.
Int J Mol Sci ; 22(12)2021 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-34199317

RESUMO

Empagliflozin, an established treatment for type 2 diabetes (T2DM), has shown beneficial effects on liver steatosis and fibrosis in animals and in humans with T2DM, non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH). However, little is known about the effects of empagliflozin on liver function in advanced NASH with liver fibrosis and without diabetes. This study aimed to assess the effects of empagliflozin on hepatic and metabolic outcomes in a diet-induced obese (DIO) and insulin-resistant but non-diabetic biopsy-confirmed mouse model of advanced NASH. Male C57BL/6JRj mice with a biopsy-confirmed steatosis and fibrosis on AMLN diet (high fat, fructose and cholesterol) for 36-weeks were randomized to receive for 12 weeks: (a) Empagliflozin (10 mg/kg/d p.o.), or (b) vehicle. Metabolic outcomes, liver pathology, markers of Kupffer and stellate cell activation and lipidomics were assessed at the treatment completion. Empagliflozin did not affect the body weight, body composition or insulin sensitivity (assessed by intraperitoneal insulin tolerance test), but significantly improved glucose homeostasis as assessed by oral glucose tolerance test in DIO-NASH mice. Empagliflozin improved modestly the NAFLD activity score compared with the vehicle, mainly by improving inflammation and without affecting steatosis, the fibrosis stage and markers of Kupffer and stellate cell activation. Empagliflozin reduced the hepatic concentrations of pro-inflammatory lactosylceramides and increased the concentrations of anti-inflammatory polyunsaturated triglycerides. Empagliflozin exerts beneficial metabolic and hepatic (mainly anti-inflammatory) effects in non-diabetic DIO-NASH mice and thus may be effective against NASH even in non-diabetic conditions.


Assuntos
Compostos Benzidrílicos/uso terapêutico , Glucosídeos/uso terapêutico , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Animais , Antígenos CD/metabolismo , Compostos Benzidrílicos/farmacologia , Biópsia , Composição Corporal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Modelos Animais de Doenças , Glucose/metabolismo , Glucosídeos/farmacologia , Homeostase/efeitos dos fármacos , Resistência à Insulina , Lactosilceramidas/metabolismo , Lipidômica , Fígado/efeitos dos fármacos , Fígado/patologia , Camundongos Endogâmicos C57BL , Camundongos Obesos , Hepatopatia Gordurosa não Alcoólica/patologia , Triglicerídeos/metabolismo
10.
Anticancer Res ; 41(7): 3419-3427, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230137

RESUMO

BACKGROUND/AIM: Liver metastases are among the principal mortality causes in cancer patients. Dendritic cell immunotherapies have shown promising results in some tumors by mediating immunological mechanisms that could be involved in liver metastases during primary tumor growth. The present study aimed to evaluate the impact of prophylactic dendritic cell vaccination on the liver of mice with 4T1 mouse breast carcinoma. MATERIALS AND METHODS: Adult female Balb/c mice were submitted or not to vaccination with dendritic cells before the induction of 4T1 tumor lineage. Liver tissues from mice were analyzed by flow cytometry (markers CD3, CD4, CD8, CD25, IL-10, IL-12, IL-17, TNF-α, IFN-γ, T-bet, GATA3, RORγt, and FoxP3) and hematoxylin-eosin. The dendritic cell vaccine was differentiated and matured ex vivo from the bone marrow. RESULTS: Prophylactic vaccination reduced areas of liver metastases (p=0.0049), induced an increase in the percentage of total T and cytotoxic T lymphocytes (p<0.0001), as well as FoxP3+ (p<0.0001). It also increased the levels of cytokines IL-10 and IL-17 in helper T lymphocytes (p<0.0001). CONCLUSION: The prophylactic dendritic cell vaccine changed the cell phenotype in the immune response of liver, and it was able to reduce metastases. Cytotoxic T cells and regulatory T lymphocytes were more present, likewise, the production of IL-10 and IL-7 simultaneously, demonstrating that the vaccine can induce a state of control of pro-inflammatory responses, which can provide a less favorable environment for metastatic tumor growth.


Assuntos
Neoplasias da Mama/imunologia , Vacinas Anticâncer/imunologia , Células Dendríticas/imunologia , Neoplasias Hepáticas/imunologia , Fígado/imunologia , Animais , Biomarcadores Tumorais/imunologia , Medula Óssea/imunologia , Neoplasias da Mama/patologia , Modelos Animais de Doenças , Feminino , Imunidade/imunologia , Imunoterapia/métodos , Fígado/patologia , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Endogâmicos BALB C , Linfócitos T Citotóxicos/imunologia , Linfócitos T Reguladores/imunologia , Vacinação/métodos
11.
Anticancer Res ; 41(7): 3657-3665, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230164

RESUMO

BACKGROUND/AIM: We attempted to stratify prognosis using the modified Journal of Hepato-Biliary-Pancreatic Sciences (mJHBPS) nomogram upon identification of colorectal liver metastasis (CRLM) and to investigate which strategy is better, surgery first (SF) or chemotherapy first (CF), in each risk group. PATIENTS AND METHODS: A total of 137 patients with CRLM who underwent resection of the primary tumor were included. Patients with brain, bone, or perihilar lymph node metastases were excluded. Patients were scored using the mJHBPS nomogram upon identification of CRLM. Prognosis was investigated using event-free survival (EFS) and overall survival (OS). RESULTS: The nomogram allowed stratification of patients using EFS and OS: low-risk (0-6 score, n=38), medium-risk (7-11 score, n=42), and high-risk (12≥ score, n=57). In the low-risk group, the EFS and OS of the CF group were significantly poorer than those of the SF group (p=0.019 and p=0.014, respectively). CF was an independent prognostic factor for both EFS and OS. CONCLUSION: The mJHBPS nomogram can stratify CRLM patients with sufficient differences in EFS and OS. SF was recommended for patients in the low-risk group.


Assuntos
Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Fígado/patologia , Idoso , Feminino , Humanos , Metástase Linfática/patologia , Masculino , Nomogramas , Pâncreas/patologia , Prognóstico , Intervalo Livre de Progressão , Estudos Retrospectivos
12.
Int J Mol Sci ; 22(12)2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34204274

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is the leading cause of liver disease worldwide, affecting both adults and children and will result, in the near future, as the leading cause of end-stage liver disease. Indeed, its prevalence is rapidly increasing, and NAFLD is becoming a major public health concern. For this reason, great efforts are needed to identify its pathogenetic factors and new therapeutic approaches. In the past decade, enormous advances understanding the gut-liver axis-the complex network of cross-talking between the gut, microbiome and liver through the portal circulation-have elucidated its role as one of the main actors in the pathogenesis of NAFLD. Indeed, evidence shows that gut microbiota is involved in the development and progression of liver steatosis, inflammation and fibrosis seen in the context of NAFLD, as well as in the process of hepatocarcinogenesis. As a result, gut microbiota is currently emerging as a non-invasive biomarker for the diagnosis of disease and for the assessment of its severity. Additionally, to its enormous diagnostic potential, gut microbiota is currently studied as a therapeutic target in NAFLD: several different approaches targeting the gut homeostasis such as antibiotics, prebiotics, probiotics, symbiotics, adsorbents, bariatric surgery and fecal microbiota transplantation are emerging as promising therapeutic options.


Assuntos
Suscetibilidade a Doenças , Trato Gastrointestinal/metabolismo , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Transdução de Sinais , Ácidos e Sais Biliares/metabolismo , Biomarcadores , Gerenciamento Clínico , Metabolismo Energético , Microbioma Gastrointestinal , Trato Gastrointestinal/microbiologia , Humanos , Fígado/patologia , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatopatia Gordurosa não Alcoólica/terapia , Permeabilidade , Medicina de Precisão/métodos
13.
Zhonghua Gan Zang Bing Za Zhi ; 29(6): 551-557, 2021 Jun 20.
Artigo em Chinês | MEDLINE | ID: mdl-34225430

RESUMO

Objective: To analyze and summarize the characteristics of liver pathology and their relation to clinical markers and further explore noninvasive markers of liver fibrosis in children with chronic hepatitis B. Methods: Data of 80 hospitalized children with chronic hepatitis B who underwent liver biopsy without antiviral treatment from 2011 to 2020 were retrospectively analyzed. Inflammation and liver fibrosis characteristics were analyzed in children of different ages and genders. Variables with good correlation with liver fibrosis stage were selected to establish a non-invasive diagnostic score of liver fibrosis in children. Measurement data was used to compare the t-test or rank sum test. Mantel-Haenszel χ (2) test was used for bidirectional ordered grouping data. Spearman's rank correlation test was used for rank correlation analysis. Receiver operating characteristic curve (ROC) was used to evaluate the diagnostic value of the newly established diagnostic score in children with liver fibrosis. Results: The median age of the children was 6.4 years. HBV DNA level was high (P50 = 7.6 log(10) IU/ml), and serum alanine aminotransferase (ALT) in P50 was 171 U/L (< ULN: 5 cases, ULN-2ULN: 10 cases, > 2 ULN: 65 cases). Pathological analysis showed that the incidence of liver tissue inflammation was 97.5%, and the proportion of patients with G≥2 was 42.5%, while S≥2 was 36.3%. The incidence rate of liver fibrosis and liver cirrhosis was 81.3%, and 1.3%, respectively. The changes in liver tissue inflammation and fibrosis were gradually aggravated with the increase of age, and the proportion of high-grade inflammation and liver fibrosis in male children was higher than that in female children. Serum levels of glutamyl transpeptidase (GGT), γ-glutamyltransferase/platelet ratio (GPR) and HBeAg had a good correlation with fibrosis stage (r(s) = 0.397, 0.389, and - 0.311) in children with chronic hepatitis B. The combination of GGT, GPR and HBeAg can establish a non-invasive diagnostic score for evaluating liver fibrosis in children. When the score is less than 1.5, it can be diagnosed as S0, and 1.5 ≤ score < 3.5, it can be diagnosed as S1; 3.5 ≤ score < 5.5, the diagnosis of fibrosis is S2; score≥ 5.5, the diagnosis of fibrosis is S≥3. The sensitivity and specificity were 80%, 83%, 86%, and 53%, 55%, 67%, respectively. Conclusion: The incidence of liver tissue inflammation in children with chronic hepatitis B with elevated and fluctuating transaminase levels is high, and the pathological changes of liver tissue aggravate with the age of the children. GGT, GPR and HBeAg have a good correlation with liver fibrosis in children with chronic hepatitis B. Therefore, combining the above-mentioned markers to establish a new noninvasive diagnostic score has certain diagnostic value for liver fibrosis stage S0-S3 in children with chronic hepatitis B.


Assuntos
Hepatite B Crônica , Cirrose Hepática/diagnóstico , Alanina Transaminase , Biomarcadores , Biópsia , Criança , Feminino , Hepatite B Crônica/complicações , Hepatite B Crônica/patologia , Humanos , Fígado/patologia , Cirrose Hepática/patologia , Masculino , Curva ROC , Estudos Retrospectivos
14.
Zhongguo Zhong Yao Za Zhi ; 46(11): 2865-2870, 2021 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-34296587

RESUMO

In order to investigate the effect of salidroside on inhibiting liver fibrosis and its relationship with CXC chemokine ligand 16(CXCL16) in vivo and in vitro, totally 45 C57 BL/6 J male mice were randomly divided into normal group, model group and salidroside group, with 15 mice in each group. The mice in model group and salidroside group were injected intraperitoneally with 15% carbontetrachloride(CCl_4) olive oil solution to establish liver fibrosis model, and the mice in normal group were injected intraperitoneally with the same dose of olive oil. Salidroside group was given with 100 mg·kg~(-1 )salidroside by gavage, while the normal group and model group received the same amount of double distilled water by gavage. All mice were sacrificed after 5 weeks of intragastric administration. The pathological changes of mouse liver were observed by hematoxylin-eosin(HE) staining, and the degree of liver fibrosis was observed by sirius red staining. The protein expressions of collagen Ⅰ(ColⅠ), α-smooth muscle actin(α-SMA), fibronectin(FN), CXCL16, phosphorylated Akt(p-Akt), Akt in liver tissues were detected by Western blot. Hepatic stellate cell line JS 1 was cultured in vitro and divided into control group, model group(100 µg·L~(-1) CXCL16) and salidroside group(100 µg·L~(-1) CXCL16+1×10~(-5) mol·L~(-1) salidroside). Cell migration was detected by cell scratch, the mRNA expressions of ColⅠ and α-SMA were detected by RT-PCR, and the protein expressions of p-Akt and Akt were detected by Western blot. As compared with the normal group, the protein expressions of ColⅠ, α-SMA, FN, CXCL16, and p-Akt in the model group were significantly increased, and salidroside could reduce the expression of these indicators(P<0.05 or P<0.01). In vitro, CXCL16 could promote the migration of JS 1, increase the mRNA expressions of ColⅠ and α-SMA in JS 1, and enhance Akt phosphorylation in JS 1(P<0.05 or P<0.01). As compared with the model group, salidroside could inhibit the migration of JS 1 induced by CXCL16(P<0.05), and reduce the high expression of ColⅠ and α-SMA mRNA and the phosphorylation of Akt in JS 1 induced by CXCL16(P<0.05). In conclusion, salidroside might attenuate CCl_4-induced liver fibrosis in mice by inhibiting the migration, activation and Akt phosphorylation of hepatic stellate cells induced by CXCL16.


Assuntos
Células Estreladas do Fígado , Cirrose Hepática , Animais , Tetracloreto de Carbono , Quimiocina CXCL16 , Glucosídeos , Fígado/patologia , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/genética , Masculino , Camundongos , Fenóis
15.
Nan Fang Yi Ke Da Xue Xue Bao ; 41(7): 1002-1011, 2021 Jul 20.
Artigo em Chinês | MEDLINE | ID: mdl-34308849

RESUMO

OBJECTIVE: To investigate the protective effect of Bao Gan Ning (BGN), a traditional Chinese medicinal formula, against CCl4-induced liver fibrosis in mice and explore the mechanism. METHODS: C57BL/6 mice were randomly divided into control group, liver fibrosis model group, positive control group and the low-, middle-, and high-dose BGN groups (n=10). In all but the control group, the mice were subjected to daily intraperitoneal injection of 25% CCl4 (in olive oil) to induce liver fibrosis and intragastric gavage of corresponding drugs. After 8 weeks, serum levels of ALT and AST were detected. Pathological examination of the liver was performed using HE and Sirius Red staining and α-SMA immunohistochemistry. The expression level of indoleamine 2, 3-dioxygenase 1 (IDO1) and phenotypic changes of hepatic DCs in the liver were measured. Another 18 mice were randomly divided into AAV9-NC, AAV9-IDO1 and high-dose BGN + AAV-IDO1 groups (n=6) for corresponding treatment, and 4 weeks later the deposit of hepatic IDO1 and phenotypic changes of the hepatic DCs were analyzed. RESULTS: Compared with those in the model group, serum AST and ALT levels decreased significantly in BGN group (P < 0.01). Obvious liver fibrosis was observed in the model group, while the mice treated with BGN showed obviously reduced cell necrosis and collagen proliferation in the liver with significantly lowered the expression levels of hepatic α-SMA and IDO1 (P < 0.05). The percentages of CD11C + DCs, CD11C +CD80 + DCs, CD11C +CD86 + DCs, CD11C +CD40 + DCs, CD11C +MHCII + DCs, CD3 + T cells, and CD3 +CD4 + T cells all increased significantly in BGN group as compared with the model group (P < 0.05). In mice with adenovirus-mediated IDO1 overexpression in the liver, BGN treatment significantly lowered the expression level of IDO1 (P=0.000) and increased the percentages of hepatic CD11C +CD40 + DCs, CD11C +MHCII + DCs and CD3 +CD4 + T cells (P < 0.05). CONCLUSION: BGN can effectively inhibit liver fibrosis in mice possibly by lowering the expression level of IDO1 in the liver, thus improving the function of hepatic DCs and subsequently promoting proliferation of T cells.


Assuntos
Cirrose Hepática , Fígado , Animais , Células Dendríticas , Fígado/patologia , Cirrose Hepática/tratamento farmacológico , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T
16.
Zhonghua Gan Zang Bing Za Zhi ; 29(6): 497-499, 2021 Jun 20.
Artigo em Chinês | MEDLINE | ID: mdl-34225422

RESUMO

Immune system cannot only help the body resist the attack of pathogens, but it also prevents the reaction to its own components. In addition, there is a delicate balance between immune defense and immune tolerance. Therefore, once the balance is broken, diseases may appear. Notably, the liver is a unique and important immune organ, and its immune function under physiological and pathological conditions has important research value.


Assuntos
Doenças Autoimunes , Hepatite Autoimune , Cirrose Hepática Biliar , Doenças Autoimunes/patologia , Hepatite Autoimune/patologia , Humanos , Tolerância Imunológica , Fígado/patologia , Cirrose Hepática Biliar/patologia
17.
Zhonghua Gan Zang Bing Za Zhi ; 29(6): 505-509, 2021 Jun 20.
Artigo em Chinês | MEDLINE | ID: mdl-34225424

RESUMO

Nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease in the world. Liver cirrhosis, liver cancer and a variety of extrahepatic chronic diseases are important risk factors for NAFLD. Currently, there is still a lack of effective therapeutic drugs. Liver inflammation is a key driving factor for the progression of NAFLD, so regulating liver inflammation may provide a potential means to delay and reverse the progression of nonalcoholic steatohepatitis (NASH). Studies have found that the gut-liver-immune axis plays an important role in the progression of NASH. Gut microbiota can use its metabolites to induce glycolipid toxicity, oxidative stress and intestinal barrier damage, while bacterial components such as lipopolysaccharides, peptidoglycans, bacterial DNA and extracellular vesicles can translocate into the liver through the damaged intestinal barrier, causing excessive activation of immune cells, thus aggravating liver inflammation and promoting the progress of NASH. This paper focuses on the gut-liver-immune axis to analyze the gut microbiota mediated liver immunity and its mechanism in the occurrence and development of NASH, so as to lay a theoretical foundation for the research and development of new therapeutic strategies for NASH.


Assuntos
Microbioma Gastrointestinal , Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Humanos , Fígado/patologia , Cirrose Hepática/patologia , Neoplasias Hepáticas/patologia , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/patologia
18.
Zhonghua Gan Zang Bing Za Zhi ; 29(6): 595-599, 2021 Jun 20.
Artigo em Chinês | MEDLINE | ID: mdl-34225438

RESUMO

Nonalcoholic fatty liver disease is becoming the main cause of global liver disease-related morbidity and mortality. Notably, its pathological mechanism is complicated and not yet fully understood. Therefore, immune regulation is undoubtedly an important link in its pathogenesis, especially the change of T lymphocyte subsets. This article introduces the research progress of T lymphocytes involved in steatosis, inflammation, fibrosis, malignant transformation and immunotherapy.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Fibrose , Humanos , Inflamação/patologia , Fígado/patologia , Hepatopatia Gordurosa não Alcoólica/patologia , Subpopulações de Linfócitos T
19.
Zhonghua Gan Zang Bing Za Zhi ; 29(6): 604-608, 2021 Jun 20.
Artigo em Chinês | MEDLINE | ID: mdl-34225440

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide and it includes simple fatty liver disease (NAFL), nonalcoholic steatohepatitis (NASH), liver cirrhosis, and hepatocellular carcinoma-related NASH. The degree of hepatic necrotizing inflammation and fibrosis is closely related to the long-term prognosis of NAFLD patients. Therefore, early monitoring of disease progression and intervention are of great significance. Liver biopsy, as an invasive test, has always been the gold standard for the diagnosis of NAFLD; however, it is not easy to carry out widely in clinical practice. With the development of omics-related research technologies, the potential application value of omics biomarkers such as genomics, transcriptomics, proteomics, glycomics, metabolomics, and so on in the diagnosis of NAFLD has gradually emerged. This review mainly summarizes the research progress of omics biomarkers for NAFLD.


Assuntos
Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Biomarcadores , Progressão da Doença , Humanos , Fígado/patologia , Cirrose Hepática/patologia , Neoplasias Hepáticas/patologia , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia
20.
Artigo em Chinês | MEDLINE | ID: mdl-34218553

RESUMO

Objective: To access the effects of evodiamine on carbon tetrachloride (CCl(4)) -induced liver fibrosis mice and study the mechanism based on modulating gut microbiota. Methods: From August 2019, 30 SPF male C57BL/6 mice were randomly divided into normal, model and evodiamine groups. Mice in control group received intraperitoneal injection of olive oil (2 ml/kg, twice per week) for 6 weeks. Mice in model and evodiamine groups received intraperitoneal injection of 20% CCl(4) (2 ml/kg, twice per week) for 6 weeks to induce liver fibrosis mice. Then, mice in evodiamine group received orally of evodiamine (18 mg/kg) for 4 weeks. The levels of serum alanine aminotransferase (ALT) , aspartate aminotransferase (AST) , albumin (ALB) and total protein (TP) were detected. The pathological changes of liver tissue were observed. The effects of evodiamine on the abundance and diversity of intestinal microflora in liver fibrosis mice were determined. The mRNA and protein expression levels of inflammatory factors[interleukin-6 (IL-6) , interleukin-1ß (IL-1ß) , and tumor necrosis factor α (TNF-α) ] in liver tissue were measured. Results: Compared with the normal group, the body weight, serum ALB and TP levels of the model group were decreased, the liver index, ALT and AST levels were increased, and the intestinal flora Shannon and Simpson indexes were decreased (P<0.01) . Compared with the normal group, the abundance of Lactobacillus, Akkermansia and Bacteroides in the feces of the model group decreased, while the abundance of Enterococcus and Lachnoclostridium increased (P<0.01) . Compared with the normal group, the mRNA and protein expressions levels of IL-6, IL-1ß, and TNF-α in the liver tissue of the model group were significantly increased (P<0.01) . Compared with the model group, evodiamine could reduce liver index and serum ALT and AST levels, increase ALB and TP levels (P<0.05) , improve inflammatory cell infiltration and fibrosis degree in liver tissue, and up regulate intestinal flora Shannon and Simpson indexes in liver fibrosis mice (P<0.05) . Compared with the model group, evodiamine could increase the abundance of Lactobacillus, Akkermansia, Bacteroides, and reduce the abundance of Enterococcus and Lachnoclostridiun (P<0.05) . Compared with the model group, evodiamine could reduce the mRNA and protein levels of IL-6, IL-1ß and TNF-α in liver tissue of liver fibrosis mice (P<0.05) . Conclusion: Evodiamine can ameliorate CCl(4)-induced liver fibrosis through modulating gut microbiota and inhibiting the inflammatory response in liver.


Assuntos
Tetracloreto de Carbono , Microbioma Gastrointestinal , Alanina Transaminase , Animais , Fígado/patologia , Cirrose Hepática/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Quinazolinas
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