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1.
Lancet Gastroenterol Hepatol ; 5(5): 507-514, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32277903

RESUMO

The survival of patients with alcohol-related liver disease who receive a liver transplant has steadily improved to reach 80-85% at 1 year post-transplantation. The standard requirement for liver transplant-abstinence from alcohol for 6 months before transplantation-has been applied widely, but few data support the use of this rule as the sole criterion for selecting candidates for liver transplantation. When determining the suitability of a patient for transplantation, many liver transplant programmes now try to balance the period of abstinence against the risk of death associated with the severity of liver damage. Data accumulated since 2011 suggest that early liver transplantation (ie, transplantation without a specific period of abstinence) in patients with severe alcoholic hepatitis who do not respond to medical therapy is an effective therapeutic strategy. Further studies are needed to help refine the selection of patients with alcohol-related liver disease who have been abstinent for less than 6 months as suitable liver transplant candidates, and to improve the treatment of alcohol use disorder in those patients who have received a liver transplant.


Assuntos
Hepatopatias Alcoólicas/cirurgia , Transplante de Fígado , Seleção de Pacientes , Abstinência de Álcool , Consumo de Bebidas Alcoólicas/psicologia , Alcoolismo/complicações , Alcoolismo/terapia , Aloenxertos/patologia , Hepatite Alcoólica/cirurgia , Humanos , Hepatopatias Alcoólicas/etiologia , Hepatopatias Alcoólicas/psicologia , Período Pós-Operatório
3.
Food Chem Toxicol ; 136: 111075, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31877367

RESUMO

Alcohol-related liver disease (ALD) and drug-induced liver injury (DILI) are common causes of severe liver disease, and successful treatments are lacking. Autophagy plays a protective role in both ALD and DILI by selectively removing damaged mitochondria (mitophagy), lipid droplets (lipophagy), protein aggregates and adducts in hepatocytes. Autophagy also protects against ALD by degrading interferon regulatory factor 1 (IRF1) and damaged mitochondria in hepatic macrophages. Specifically, we will discuss selective autophagy for removal of damaged mitochondria and lipid droplets in hepatocytes and autophagy-mediated degradation of IRF1 in hepatic macrophages as protective mechanisms against alcohol-induced liver injury and steatosis. In addition, selective autophagy for removal of damaged mitochondria and protein adducts for protection against DILI is discussed in this review. Development of new therapeutics for ALD and DILI is greatly needed, and selective autophagy pathways may provide promising targets. Drug and alcohol effects on autophagy regulation as well as protective mechanisms of autophagy against DILI and ALD are highlighted in this review.


Assuntos
Autofagia , Doença Hepática Induzida por Substâncias e Drogas/fisiopatologia , Etanol/efeitos adversos , Hepatopatias Alcoólicas/fisiopatologia , Animais , Autofagia/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Humanos , Fator Regulador 1 de Interferon/genética , Fator Regulador 1 de Interferon/metabolismo , Hepatopatias Alcoólicas/etiologia , Hepatopatias Alcoólicas/genética , Hepatopatias Alcoólicas/metabolismo
4.
Int J Biol Macromol ; 141: 822-830, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31487518

RESUMO

Chronic hepatic injury caused by hepatitis B and C virus (HBV and HCV) infection, high fat diet and alcohol intake has increased to be the critical promoter of hepatocellular carcinoma (HCC). These high risk factors set into motion a vicious cycle of hepatocyte death, inflammation and fibrosis that finally results in cirrhosis and HCC after several decades. However, the treatment options for HCC are very limited. Therefore, early treatment of liver injury may reduce the incidence and probability of HCC or delay the progression of HCC. Substantial ongoing research has focused on nontoxic biological macromolecules, mainly polysaccharides, which possess prominent efficacies on hepatoprotective activity. Based on these encouraging observations, a great deal of effort has been devoted to discovering novel polysaccharides for the development of effective therapeutics for hepatic injury. This review focuses on the protective effects of polysaccharides on liver injury, including hepatitis virus infection, nonalcoholic steatohepatitis, alcoholic liver disease and other hepatic injuries, and describes the underlying mechanisms.


Assuntos
Hepatopatias/tratamento farmacológico , Polissacarídeos/farmacologia , Polissacarídeos/uso terapêutico , Substâncias Protetoras/farmacologia , Substâncias Protetoras/uso terapêutico , Animais , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Suscetibilidade a Doenças , Humanos , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/etiologia , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Hepatopatias/etiologia , Hepatopatias/patologia , Hepatopatias Alcoólicas/tratamento farmacológico , Hepatopatias Alcoólicas/etiologia , Hepatopatias Alcoólicas/metabolismo , Hepatopatias Alcoólicas/patologia , Polissacarídeos/química , Polissacarídeos/isolamento & purificação , Substâncias Protetoras/química , Substâncias Protetoras/isolamento & purificação
6.
Transplant Proc ; 51(6): 1934-1938, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31399178

RESUMO

Excessive alcohol consumption has a negative impact on graft survival after liver transplantation (LT). However, it is difficult to predict alcohol relapse before LT. This study surveyed the alcohol consumption of LT recipients to identify the risk factors for harmful drinking. We surveyed the alcohol consumption of LT recipients by using the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C). AUDIT-C scores ≥ 5 points in men and ≥ 4 points in women indicated a high risk for harmful and hazardous drinking. Excessive alcohol consumption was considered to be > 20 g per day. Ninety-nine LT recipients completely filled out the questionnaire. Alcohol consumption after LT was detected in 26 recipients (26.5%); 4 of them had alcoholic liver disease before transplantation and 22 did not have alcoholic liver disease. The amount of alcohol consumption per day significantly decreased after LT (alcohol consumption per day: 49.6 g before LT vs 8.1 g after LT, P < .05). Fourteen recipients (14.1%) consumed alcohol excessively after LT. The AUDIT-C score before LT and smoking were risk factors for excessive alcohol consumption in the multivariate analysis. To properly manage post-transplant recipients, assessing the risk of excessive alcohol consumption by using the AUDIT-C is necessary.


Assuntos
Alcoolismo/diagnóstico , Hepatopatias Alcoólicas/cirurgia , Transplante de Fígado/efeitos adversos , Medição de Risco/métodos , Adulto , Alcoolismo/complicações , Feminino , Sobrevivência de Enxerto , Humanos , Hepatopatias Alcoólicas/etiologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Período Pós-Operatório , Recidiva , Fatores de Risco , Inquéritos e Questionários
7.
Biomed Pharmacother ; 117: 109179, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31387182

RESUMO

Chronic alcohol consumption is a major cause of chronic liver disease worldwide. Adult zebrafish have emerged as a new vertebrate model of alcoholic liver disease. In previous research, a high dose of chronic ethanol treatment induced characteristic features of steatosis and hepatic injury in adult zebrafish, yet the ethanol concentration in that study was significantly higher than the lethal dose in humans. In the current study, we examined whether a low dose of chronic ethanol exposure in adult zebrafish induced the metabolic and pathological features seen in alcoholic liver disease. We found that chronic ethanol treatment at 0.2% ethanol (v/v) concentration for 4 weeks induced a significant elevation of serum glucose and triacylglycerol in adult zebrafish. In addition, serum alanine aminotransferase activity was significantly elevated after ethanol treatment. Histological analysis revealed steatosis and hepatocyte ballooning phenotype. Gene expression analysis using quantitative real-time PCR suggested that ethanol treatment induced inflammation, apoptosis, and fibrosis. In addition, we found significant increases in gene expression involved in glucose and lipid metabolism as well as mitochondrial biogenesis and function. Importantly, expression of genes involved in oxidative and endoplasmic reticulum stress, two major stress signaling pathways underlying hepatic injury in alcoholic liver disease, were highly upregulated in the livers of adult zebrafish after chronic ethanol treatment. In conclusion, we found that 4 weeks of low dose ethanol exposure leads to typical ethanol-induced liver disease, with pathological and gene expression patterns.


Assuntos
Etanol/administração & dosagem , Etanol/efeitos adversos , Fígado Gorduroso/induzido quimicamente , Hepatopatias Alcoólicas/etiologia , Fígado/efeitos dos fármacos , Alanina Transaminase/metabolismo , Animais , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Fígado Gorduroso/metabolismo , Inflamação/induzido quimicamente , Inflamação/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Hepatopatias Alcoólicas/metabolismo , Masculino , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Peixe-Zebra/metabolismo
8.
Ann Transplant ; 24: 359-366, 2019 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-31209197

RESUMO

BACKGROUND Alcohol use disorders affect 10% of the European population. Alcohol-related liver disease (ALD) is the most common indication for liver transplantation in Slovakia. The aim of this study was to determine the proportion of patients with ALD who received a liver transplant who had alcohol relapsed, and the risk factors for alcohol relapse, as well as to compare clinical outcomes according to relapse. MATERIAL AND METHODS A retrospective study of consecutive patients with ALD, who underwent liver transplantation in a single transplant center between May 2008 and December 2017. We included adult patients who received a liver transplant due to ALD and excluded those who died <1 month after liver transplantation. We recorded demographic and clinical characteristics, graft injury, and overall mortality and compared them between relapsers and abstainers. RESULTS During the study period, we reviewed 196 cases of liver transplantation in 191 patients. We excluded 87 patients for non-ALD etiology and 15 patients by predefined criteria. The final analysis was carried out in 89 patients, mean aged 55 years; 24.7% were female. We diagnosed relapse in 23 patients (26%) with harmful drinking in 52% and occasional drinking in 48% of relapsers. The independent risk factors associated with relapse were: smoking (OR=5.92, P=0.006), loss of social status (OR=7.61, P=0.002), and time after liver transplantation (OR=1.0008, P=0.015). Graft injury was more frequent in relapsers with 2 independent risk factors: occasional drinking (OR=12.7, P=0.0005), and harmful drinking (OR=36.6, P<0.0001); overall survival was unaffected. CONCLUSIONS We found relapse to alcohol drinking in 26% of patients who received a liver transplant for ALD. Risk factors associated with alcohol drinking relapse were time, cigarette smoking, and loss of social status. Graft injury was more frequent in relapsers, but mortality was similar between relapsers and non-relapsers.


Assuntos
Alcoolismo/cirurgia , Hepatopatias Alcoólicas/cirurgia , Alcoolismo/complicações , Feminino , Sobrevivência de Enxerto , Humanos , Hepatopatias Alcoólicas/etiologia , Transplante de Fígado , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Recidiva , Estudos Retrospectivos , Fatores de Risco
9.
Ann Hepatol ; 18(1): 6-10, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31113611

RESUMO

With the discovery of direct-acting antivirals and the prospective of viral hepatitis becoming curable, alcohol liver disease (ALD) is back to primetime. In the last 20 years, there have been many advances in the understanding of the biology, the psychology and the social and environmental factors associated with this long-known medical problem. Recent information about regional, ethnic, cultural and genetic factors seem to be relevant for the Latin American (LA) population. New approaches based on the new concepts and current information will render better results in the overall management of patients with this problem. Considering alcohol use disorder and ALD as part of the same entity managing it in a multidisciplinary approach seems to be best way to deal with this disease.


Assuntos
Alcoolismo/complicações , Etanol/efeitos adversos , Hepatopatias Alcoólicas/epidemiologia , Fígado/efeitos dos fármacos , Medição de Risco , Alcoolismo/epidemiologia , Saúde Global , Humanos , Incidência , Hepatopatias Alcoólicas/etiologia
10.
FASEB J ; 33(6): 7274-7288, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30857422

RESUMO

Alcoholic beverages, which are consumed widely in most parts of the world, have long been identified as a major risk factor for all liver diseases, particularly alcoholic liver disease (ALD). Recent compositional analyses suggest that Chinese baijiu (CB), a clear alcoholic liquid distilled from fermented grains, contains large amounts of small molecule bioactive compounds in addition to a significant amount of ethanol (EtOH). Here, in an experimental mouse model, we show that CB caused lower degrees of liver injury than pure EtOH by protecting against the decrease of the relative abundance of Akkermansia and increase of the relative abundance of Prevotella in the gut, thereby preventing the destruction of the intestinal barrier. Furthermore, we demonstrated that EtOH-induced alteration of the gut microbiota profoundly affected the host metabolome. Compared with EtOH feeding, CB feeding resulted in higher concentrations of functional saturated long-chain fatty acids and short-chain fatty acids. The additional mouse models of low dosages of EtOH and of blending baijiu validated that volatile compounds in CB can attenuate EtOH-induced liver damages. Our results provide supporting evidence that ALD was profoundly influenced by host-gut microbiota metabolic interactions and that small molecule organic compounds in CB could attenuate ALD.-Fang, C., Du, H., Zheng, X., Zhao, A., Jia, W., Xu, Y. Solid-state fermented Chinese alcoholic beverage (baijiu) and ethanol resulted in distinct metabolic and microbiome responses.


Assuntos
Bebidas Alcoólicas , Disbiose/induzido quimicamente , Etanol/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Hepatopatias Alcoólicas/etiologia , Fígado/efeitos dos fármacos , Metaboloma/efeitos dos fármacos , Bebidas Alcoólicas/toxicidade , Animais , Translocação Bacteriana/efeitos dos fármacos , Destilação , Disbiose/metabolismo , Disbiose/microbiologia , Etanol/toxicidade , Ácidos Graxos/metabolismo , Fígado Gorduroso Alcoólico/etiologia , Fígado Gorduroso Alcoólico/metabolismo , Fígado Gorduroso Alcoólico/microbiologia , Fermentação , Hepatopatias Alcoólicas/metabolismo , Hepatopatias Alcoólicas/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Distribuição Aleatória , Ribotipagem , Organismos Livres de Patógenos Específicos , Substâncias Reativas com Ácido Tiobarbitúrico/análise , Verrucomicrobia/efeitos dos fármacos , Verrucomicrobia/isolamento & purificação
11.
Food Chem Toxicol ; 126: 277-284, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30826410

RESUMO

Alcoholic liver disease (ALD), as one of the most common diseases, has become a global threat to human health. The aim of this study was designed to investigate the hepatoprotective effects of ginsenoside Rk3 against ALD and to discover the potential mechanisms of these protective effects. Mice were intragastrically administered 50% alcohol and treated with ginsenoside Rk3 (25 and 50 mg/kg) once per day for 6 weeks. The results indicated that ginsenoside Rk3 promoted hepatic function through significant downgrading AST and ALT levels in the serum, attenuating oxidative stress, and restoring antioxidant balance in hepatic tissue. Additionally, ginsenoside Rk3 significantly reduced the expression of inflammatory cytokines, such as NF-κB, TNF-α, IL-6, and IL-1ß in the mice. Furthermore, ginsenoside Rk3 supplementation significantly inhibited apoptotic protein expression in the liver. The present study clearly demonstrates that ginsenoside Rk3 exerts a protective effect against ALD-induced liver injury because of its antioxidant, anti-apoptotic, and anti-inflammatory activities. The findings from the present investigation show that ginsenoside Rk3 might be a promising candidate treatment agent against ALD.


Assuntos
Apoptose/efeitos dos fármacos , Etanol/efeitos adversos , Ginsenosídeos/administração & dosagem , Hepatopatias Alcoólicas/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/administração & dosagem , Animais , Humanos , Interleucina-6/genética , Interleucina-6/imunologia , Fígado/efeitos dos fármacos , Fígado/imunologia , Hepatopatias Alcoólicas/etiologia , Hepatopatias Alcoólicas/imunologia , Hepatopatias Alcoólicas/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , NF-kappa B/genética , NF-kappa B/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
12.
Mar Drugs ; 17(3)2019 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-30893931

RESUMO

Alcoholic liver disease (ALD) is a major cause of chronic liver disease worldwide. It is a complex process, including a broad spectrum of hepatic lesions from fibrosis to cirrhosis. Our previous study suggested that astaxanthin (AST) could alleviate the hepatic inflammation and lipid dysmetabolism induced by ethanol administration. In this study, a total of 48 male C57BL/6J mice were divided into 4 groups: a Con group (fed with a Lieber⁻DeCarli liquid diet), an AST group (fed with a Lieber⁻DeCarli liquid diet and AST), an Et group (fed with an ethanol-containing Lieber⁻DeCarli liquid diet), and a EtAST group (fed with an ethanol-containing Lieber⁻DeCarli liquid diet and AST). Then, comparative hepatic transcriptome analysis among the groups was performed by Illumina RNA sequencing. Gene enrichment analysis was conducted to identify pathways affected by the differentially expressed genes. Changes of the top genes were verified by quantitative real-time PCR (qRT-PCR) and Western blot. A total of 514.95 ± 6.89, 546.02 ± 15.93, 576.06 ± 21.01, and 690.85 ± 54.14 million clean reads were obtained for the Con, AST, Et, and EtAST groups, respectively. Compared with the Et group, 1892 differentially expressed genes (DEGs) (including 351 upregulated and 1541 downregulated genes) were identified in the AST group, 1724 differentially expressed genes (including 233 upregulated and 1491 downregulated genes) were identified in the Con group, and 1718 DEGs (including 1380 upregulated and 338 downregulated genes) were identified in the EtAST group. The enrichment analyses revealed that the chemokine signaling, the antigen processing and presentation, the nucleotide-binding and oligomerization domain (NOD)-like receptor signaling, and the Toll-like receptor signaling pathways enriched the most differentially expressed genes. The findings of this study provide insights for the development of nutrition-related therapeutics for ALD.


Assuntos
Organismos Aquáticos/química , Hepatopatias Alcoólicas/tratamento farmacológico , Substâncias Protetoras/farmacologia , Transcriptoma/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Etanol/administração & dosagem , Etanol/toxicidade , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Fígado/efeitos dos fármacos , Fígado/patologia , Hepatopatias Alcoólicas/etiologia , Hepatopatias Alcoólicas/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Substâncias Protetoras/uso terapêutico , Análise de Sequência de RNA , Transdução de Sinais/efeitos dos fármacos , Resultado do Tratamento , Xantofilas/farmacocinética , Xantofilas/uso terapêutico
13.
PLoS One ; 14(1): e0211415, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30695051

RESUMO

Alcoholic liver disease (ALD) is a worldwide health problem and hepatocyte apoptosis has been associated with the development/progression of ALD. However, no definite effective pharmacotherapy for ALD is currently available. Cilostazol, a selective type III phosphodiesterase inhibitor has been shown to protect hepatocytes from ethanol-induced apoptosis. In the present study, the underlying mechanisms for the protective effects of cilostazol were examined. Primary rat hepatocytes were treated with ethanol in the presence or absence of cilostazol. Cell viability and intracellular cAMP were measured. Apoptosis was detected by Hoechst staining, TUNEL assay, and caspase-3 activity assay. The roles of cAMP and AMP-activated protein kinase (AMPK) pathways in the action of CTZ were explored using pharmacological inhibitors and siRNAs. Liver from mice received ethanol (5 g/kg body weight) by oral gavage following cilostazol treatment intraperitoneally was obtained for measurement of apoptosis and activation of AMPK pathway. Cilostazol inhibited ethanol-induced hepatocyte apoptosis and potentiated the increases in cAMP level induced by forskolin. However, the anti-apoptotic effect of cilostazol was not reversed by an inhibitor of adenylyl cyclase. Interestingly, cilostazol activated AMPK and increased the level of LC3-II, a marker of autophagy. The inhibition of AMPK abolished the effects of cilostazol on LC3-II expression and apoptosis. Moreover, the inhibition of LKB1 and CaMKK2, upstream kinases of AMPK, dampened cilostazol-inhibited apoptosis as well as AMPK activation. In conclusion, cilostazol protected hepatocytes from apoptosis induced by ethanol mainly via AMPK pathway which is regulated by both LKB1 and CaMKK2. Our results suggest that cilostazol may have potential as a promising therapeutic drug for treatment of ALD.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Apoptose/efeitos dos fármacos , Cilostazol/farmacologia , Etanol/toxicidade , Hepatócitos/efeitos dos fármacos , Hepatopatias Alcoólicas/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Animais , Autofagia , Sobrevivência Celular , Células Cultivadas , Depressores do Sistema Nervoso Central/toxicidade , Ativação Enzimática , Hepatócitos/enzimologia , Hepatócitos/patologia , Hepatopatias Alcoólicas/etiologia , Hepatopatias Alcoólicas/metabolismo , Hepatopatias Alcoólicas/patologia , Masculino , Camundongos , Ratos , Ratos Sprague-Dawley , Transdução de Sinais
15.
Clin Liver Dis ; 23(1): 55-69, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30454833

RESUMO

Alcohol use disorder (AUD) is common in alcoholic liver disease (ALD) and intrinsic to its pathophysiology. Optimal treatment requires a multidisciplinary team approach and a working alliance between patients and providers. Diagnosing AUD involves a combination of thorough history taking, physical examination, screening questionnaires, and alcohol biomarkers. Alcohol biomarkers have advantages and limitations of use of which clinicians should be aware. AUD treatment is effective, multifaceted, and can be tailored to each individual. Available treatment modalities are myriad: motivational enhancement therapy, cognitive behavior therapy, 12-step facilitation, group therapies, intensive outpatient programs, inpatient and residential treatment, and relapse prevention medications.


Assuntos
Alcoolismo/reabilitação , Hepatopatias Alcoólicas/terapia , Abstinência de Álcool , Dissuasores de Álcool/uso terapêutico , Alcoolismo/complicações , Alcoolismo/diagnóstico , Alcoolismo/metabolismo , Biomarcadores/metabolismo , Humanos , Hepatopatias Alcoólicas/etiologia
16.
J Diabetes Res ; 2019: 6430486, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31915709

RESUMO

Diabetes mellitus (DM) is a common chronic disease affecting humans globally. During the last few years, the incidence of diabetes has increased and has received more attention. In addition to growing DM populations, DM complications are involving injuries to more organs, such as the heart and cerebral vessel damage. DM complications can reduce quality of life and shorten life spans and eventually also impede social and economic development. Therefore, effective measures to curb the occurrence and development of diabetes assist in improving patients' quality of life, delay the progression of DM in the population, and ease a social burden. The liver is regarded as an important link in the management and control of DM, including the alleviation of glucose metabolism and lipid metabolism and others via glucose storage and endogenous glucose generation from glycogen stored in the liver. Liver cirrhosis is a very common chronic disease, which often lowers the quality of life and decreases life expectancy. According to a growing body of research, diabetes shows a close correlation with hepatitis, liver cirrhosis, and liver cancer. Moreover, coexistence of liver complications would accelerate the deterioration of patients with diabetes. Liver cirrhosis and diabetes influence each other. Thus, in addition to pharmacological treatments and lifestyle interventions, effective control of cirrhosis might assist in a better management of diabetes. When it comes to different etiologies of liver cirrhosis, different therapeutic methods, such as antiviral treatment, may be more effective. Effective control of cirrhosis might be a strategy for better management of diabetes.


Assuntos
Complicações do Diabetes/terapia , Cirrose Hepática/terapia , Doença Crônica , Feminino , Hepatite B/complicações , Hepatite B/terapia , Hepatite C/complicações , Hepatite C/terapia , Humanos , Hepatopatias Alcoólicas/epidemiologia , Hepatopatias Alcoólicas/etiologia , Hepatopatias Alcoólicas/terapia , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/terapia
17.
World J Gastroenterol ; 24(45): 5063-5075, 2018 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-30568384

RESUMO

Alcoholic liver disease (ALD) is a major cause of acute and chronic liver injury. Extensive evidence has been accumulated on the pathological process of ALD during the past decades. However, effective treatment options for ALD are very limited due to the lack of suitable in vivo models that recapitulate the full spectrum of ALD. Experimental animal models of ALD, particularly rodents, have been used extensively to mimic human ALD. An ideal animal model should recapitulate all aspects of the ALD process, including significant steatosis, hepatic neutrophil infiltration, and liver injury. A better strategy against ALD depends on clear diagnostic biomarkers, accurate predictor(s) of its progression and new therapeutic approaches to modulate stop or even reverse the disease. Numerous models employing rodent animals have been established in the last decades to investigate the effects of acute and chronic alcohol exposure on the initiation and progression of ALD. Although significant progress has been made in gaining better knowledge on the mechanisms and pathology of ALD, many features of ALD are unknown, and require further investigation, ideally with improved animal models that more effectively mimic human ALD. Although differences in the degree and stages of alcoholic liver injury inevitably exist between animal models and human ALD, the acquisition and translational relevance will be greatly enhanced with the development of new and improved animal models of ALD.


Assuntos
Modelos Animais de Doenças , Etanol/toxicidade , Hepatopatias Alcoólicas/patologia , Fígado/patologia , Alcoolismo/complicações , Animais , Biomarcadores/análise , Humanos , Fígado/efeitos dos fármacos , Hepatopatias Alcoólicas/diagnóstico , Hepatopatias Alcoólicas/tratamento farmacológico , Hepatopatias Alcoólicas/etiologia , Camundongos , Ratos , Especificidade da Espécie
18.
Front Immunol ; 9: 2133, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30294325

RESUMO

Background and aims: Chronic ethanol exposure results in inflammation in adipose tissue; this response is associated with activation of complement as well as the development of alcohol-related liver disease (ALD). Adipose communicates with other organs, including liver, via the release of soluble mediators, such as adipokines and cytokines, characterized as the "adipose secretome." Here we investigated the role of the anaphaylatoxin receptors C3aR and C5aR1 in the development of adipose tissue inflammation and regulation of the adipose secretome in murine ALD (mALD). Methods: Wild-type C57BL/6 (WT), C3aR -/-, and C5aR1 -/- mice were fed Lieber-DeCarli ethanol diet for 25 days (6% v/v, 32% kcal) or isocaloric control diets; indicators of inflammation and injury were assessed in gonadal adipose tissue. The adipose secretome was characterized in isolated adipocytes and stromal vascular cells. Results: Ethanol feeding increased the expression of adipokines, chemokines and leukocyte markers in gonadal adipose tissue from WT mice; C3aR -/- were partially protected while C5aR1 -/- mice were completely protected. In contrast, induction of CYP2E1 and accumulation of TUNEL-positive cells in adipose in response to ethanol feeding was independent of genotype. Bone marrow chimeras, generated with WT and C5aR1 -/- mice, revealed C5aR1 expression on non-myeloid cells, likely to be adipocytes, contributed to ethanol-induced adipose inflammation. Chronic ethanol feeding regulated both the quantity and distribution of adipokines secreted from adipocytes in a C5aR1-dependent mechanism. In WT mice, chronic ethanol feeding induced a predominant release of pro-inflammatory adipokines from adipocytes, while the adipose secretome from C5aR1 -/- mice was characterized by an anti-inflammatory/protective profile. Further, the cargo of adipocyte-derived extracellular vesicles (EVs) was distinct from the soluble secretome; in WT EVs, ethanol increased the abundance of pro-inflammatory mediators while EV cargo from C5aR1 -/- adipocytes contained a greater diversity and more robust expression of adipokines. Conclusions: C3aR and C5aR1 are potent regulators of ethanol-induced adipose inflammation in mALD. C5aR1 modulated the impact of chronic ethanol on the content of the adipose secretome, as well as influencing the cargo of an extensive array of adipokines from adipocyte-derived EVs. Taken together, our data demonstrate that C5aR1 contributes to ethanol-mediated changes in the adipose secretome, likely contributing to intra-organ injury in ALD.


Assuntos
Tecido Adiposo/metabolismo , Etanol/efeitos adversos , Hepatopatias Alcoólicas/imunologia , Receptor da Anafilatoxina C5a/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Adipócitos , Adipocinas/imunologia , Adipocinas/metabolismo , Tecido Adiposo/citologia , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/imunologia , Anafilatoxinas/imunologia , Anafilatoxinas/metabolismo , Animais , Citocinas/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Etanol/administração & dosagem , Vesículas Extracelulares/imunologia , Vesículas Extracelulares/metabolismo , Feminino , Fígado/imunologia , Fígado/metabolismo , Hepatopatias Alcoólicas/etiologia , Hepatopatias Alcoólicas/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Cultura Primária de Células , Receptor da Anafilatoxina C5a/genética , Receptor da Anafilatoxina C5a/imunologia , Receptores Acoplados a Proteínas-G/genética , Receptores Acoplados a Proteínas-G/imunologia
19.
Redox Biol ; 18: 266-278, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30071471

RESUMO

Alcoholic liver disease (ALD) is a major chronic liver disease worldwide and can range from simple steatosis, inflammation to fibrosis/cirrhosis possibly through leaky gut and systemic endotoxemia. We investigated whether pomegranate (POM) protects against binge alcohol-induced gut leakiness, endotoxemia, and inflammatory liver damage. After POM pretreatment for 10 days, rats were exposed to 3 oral doses of binge alcohol (5 g/kg/dose) or dextrose (as control) at 12-h intervals. Binge alcohol exposure induced leaky gut with significantly elevated plasma endotoxin and inflammatory fatty liver by increasing the levels of oxidative and nitrative stress marker proteins such as ethanol-inducible CYP2E1, inducible nitric oxide synthase, and nitrated proteins in the small intestine and liver. POM pretreatment significantly reduced the alcohol-induced gut barrier dysfunction, plasma endotoxin and inflammatory liver disease by inhibiting the elevated oxidative and nitrative stress marker proteins. POM pretreatment significantly restored the levels of intestinal tight junction (TJ) proteins such as ZO-1, occludin, claudin-1, and claundin-3 markedly diminished after alcohol-exposure. In addition, the levels of gut adherent junction (AJ) proteins (e.g., ß-catenin and E-cadherin) and desmosome plakoglobin along with associated protein α-tubulin were clearly decreased in binge alcohol-exposed rats but restored to basal levels in POM-pretreated rats. Immunoprecipitation followed by immunoblot analyses revealed that intestinal claudin-1 protein was nitrated and ubiquitinated in alcohol-exposed rats, whereas these modifications were significantly blocked by POM pretreatment. These results showed for the first time that POM can prevent alcohol-induced gut leakiness and inflammatory liver injury by suppressing oxidative and nitrative stress.


Assuntos
Antioxidantes/uso terapêutico , Intestinos/efeitos dos fármacos , Hepatopatias Alcoólicas/prevenção & controle , Lythraceae , Nitratos/metabolismo , Preparações de Plantas/uso terapêutico , Animais , Antioxidantes/química , Apoptose/efeitos dos fármacos , Bebedeira/complicações , Feminino , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Inflamação/prevenção & controle , Mucosa Intestinal/metabolismo , Intestinos/patologia , Hepatopatias Alcoólicas/etiologia , Hepatopatias Alcoólicas/metabolismo , Hepatopatias Alcoólicas/patologia , Lythraceae/química , Estresse Oxidativo/efeitos dos fármacos , Permeabilidade/efeitos dos fármacos , Preparações de Plantas/química , Ratos Endogâmicos F344 , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismo , Junções Íntimas/patologia
20.
J Nutr Biochem ; 59: 49-55, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29960116

RESUMO

Zinc deficiency is a frequent complication of alcohol abuse for multiple reasons including poor intake, increased excretion, internal redistribution and altered transporters. Zinc deficiency has been postulated to play a role in the development/progression of alcoholic liver disease (ALD). This study aimed to relate serum zinc levels with alcohol intake, serum albumin concentration and markers of inflammation and liver injury. One hundred and eight male and female very heavy drinking (≥10 drinks/day) individuals without clinical evidence of ALD were grouped by serum zinc concentration: normal-zinc group (zinc level≥71 µg/dl) included 67 patients, and low-zinc group (zinc level<71 µg/dl) included 41 patients. Data were collected on demographics, drinking history in last 90 days (heavy drinking days, HDD90 and total drinks, TD90), lifetime drinking history (LTDH) and clinical/ laboratory assessments. Our data show that in a very well-characterized, chronically heavy-drinking population without clinical evidence of liver disease, about 40% of subjects had low serum zinc levels. Frequency of heavy drinking days (HDD90) was significantly higher in the low-zinc group. Total drinks in past 90 days, LTDH and HDD90 showed significant associations with low zinc levels. The group with the low serum zinc had a higher aspartate aminotransferase/alanine aminotransferase ratio (good marker of alcoholic liver disease). Those in the low-zinc group had the lower albumin levels, a marker of hepatic synthetic function, and the highest C-reactive protein level, a biomarker of inflammation.


Assuntos
Biomarcadores/sangue , Hepatopatias Alcoólicas/etiologia , Zinco/sangue , Adulto , Idoso , Alanina Transaminase/sangue , Alcoolismo/complicações , Aspartato Aminotransferases/sangue , Bilirrubina/sangue , Proteína C-Reativa/análise , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Albumina Sérica Humana/análise , Zinco/deficiência
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