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1.
Adv Exp Med Biol ; 1207: 497-528, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32671772

RESUMO

Autophagy plays an important role in the physiology and pathology of the liver. It is involved in the development of many liver diseases such as α-1-antitrypsin deficiency, chronic hepatitis virus infection, alcoholic liver disease, nonalcoholic fatty liver disease, and liver cancer. Autophagy has thus become a new target for the treatment of liver diseases. How to treat liver diseases by regulating autophagy has been a hot topic.


Assuntos
Autofagia , Hepatopatias , Autofagia/efeitos dos fármacos , Hepatite Crônica , Humanos , Hepatopatias/tratamento farmacológico , Hepatopatias Alcoólicas , Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Deficiência de alfa 1-Antitripsina
2.
Praxis (Bern 1994) ; 109(9): 677-686, 2020 Jul.
Artigo em Alemão | MEDLINE | ID: mdl-32635847

RESUMO

Ethyl-Toxic Steatohepatitis, the "Quiet Killer" - from Inflamed Fat to Multi-Organ Failure Abstract. The spectrum of the alcohol-associated liver disease (ALD) includes the potentially reversible simple fatty degeneration of the liver (AFLD), ethyl-toxic steatohepatitis (ASH), and the ethyl-toxic liver cirrhosis. Despite an interdisciplinary andn intensive care approach, alcohol-associated steatohepatitis (ASH), clinically characterized by jaundice and SIRS, may, in case of a fulminant course and due to the limited therapeutic options, have a mortality rate of up to 40 % . In highly selected cases, if the basic medical care of corticosteroids combined with N-acetylcysteine fails, a liver transplantation might be discussed, which occasionally shows a satisfactory long-term course. With the presented case we would like to raise awareness about the underlying disease, emphasize prevention, and summarize the most important facts for the clinical practice.


Assuntos
Fígado Gorduroso Alcoólico , Fígado Gorduroso , Hepatopatias Alcoólicas , Transplante de Fígado , Humanos
4.
Lancet Public Health ; 5(6): e316-e323, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32504584

RESUMO

BACKGROUND: Alcohol-related liver disease is the leading indication for liver transplantation in the USA. After remaining stable for over three decades, the number of deaths due to alcohol-related liver disease has been increasing as a result of increased high-risk drinking. We aimed to project trends in alcohol-related cirrhosis and deaths in the USA up to 2040 and assess the effect of potential changes in alcohol consumption on those trends. METHODS: In this modelling study, we developed a multicohort state-transition (Markov) model of high-risk alcohol drinking patterns and alcohol-related liver disease in high-risk drinking populations born in 1900-2016 in the USA projected up to 2040. We used data from the National Epidemiologic Survey on Alcohol and Related Conditions, National Institute of Alcohol Abuse and Alcoholism, US National Death Index, National Vital Statistics System, and published studies. We modelled trends in alcohol-related liver disease under three projected scenarios: the status quo scenario, in which current trends continued; a moderate intervention scenario, in which trends in high-risk drinking reduced to 2001 levels under some hypothetical moderate intervention; and a strong intervention, in which trends in high-risk drinking decreased by 3·5% per year under some hypothetical strong intervention. The primary outcome was to project deaths associated with alcohol-related liver disease from 2019 to 2040 for each pattern of alcohol consumption under the different scenarios. FINDINGS: Our model closely reproduced the observed trends in deaths due to alcohol-related liver disease from 2005 to 2018. Under the status quo scenario, age-standardised deaths due to alcohol-related liver disease are expected to increase from 8·23 (95% uncertainty interval [UI] 7·92-9·29) per 100 000 person-years in 2019 to 15·20 (13·93-16·19) per 100 000 person-years in 2040, and from 2019 to 2040, 1 003 400 (95% CI 896 800-1 036 200) people are projected to die from alcohol-related liver disease, resulting in 1 128 400 (1 113 200-1 308 400) DALYs by 2040. Under the moderate intervention scenario, age-standardised deaths due to alcohol-related liver disease would increase to 14·49 (95% UI 12·55-14·57) per 100 000 person-years by 2040, with 968 100 (95% UI 845 600-975 900) individuals projected to die between 2019 and 2040-35 300 fewer deaths than under the status quo scenario (a 3·5% decrease). Whereas, under the strong intervention scenario, age-standardised deaths due to alcohol-related liver disease would peak at 8·65 (95% UI 8·12-9·51) per 100 000 person-years in 2024 and decrease to 7·60 (6·96-8·10) per 100 000 person-years in 2040, with 704 300 (95% CI 632 700-731 500) individuals projected to die from alcohol-related liver disease in the USA between 2019 and 2040-299 100 fewer deaths than under the status quo scenario (a 29·8% decrease). INTERPRETATION: Without substantial changes in drinking culture or interventions to address high-risk drinking, the disease burden and deaths due to alcohol-related liver disease will worsen in the USA. Additional interventions are urgently needed to reduce mortality and morbidity associated with alcohol-related liver disease. FUNDING: American Cancer Society and the Robert Wood Johnson Health Policy Research Fellowship.


Assuntos
Hepatopatias Alcoólicas/epidemiologia , Hepatopatias Alcoólicas/mortalidade , Humanos , Modelos Estatísticos , Prevalência , Estados Unidos/epidemiologia
5.
Toxicol Lett ; 331: 65-74, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32492475

RESUMO

Although disturbance of the methionine cycle and sequent decrease in hepatic methylation capacity are known to be important factors in the development of alcoholic liver injury, the underlying mechanisms are not fully understood. Here, we investigated the importance of the methylation of protein phosphatase 2A (PP2A) in alcoholic liver disease (ALD). We found that the severity of ethanol-induced liver injury and the extent of demethylation of PP2A catalytic C subunit (PP2Ac) were reduced after treatment with betaine, a methyl donor involved in the methionine-homocysteine cycle. These results suggest that PP2Ac methylation is decreased due to a broad decrease in hepatic methylation capacity after exposure to ethanol. Moreover, we found that the reduction in PP2Ac methylation led to increased degradation of the regulatory Bα subunit, thus promoting the phosphorylation and nuclear exclusion of Forkhead box O1 (FOXO1) and reducing FOXO1 transcriptional activity. Ultimately, the reduced activity of FOXO1 led to increased expression of TXNIP, which caused hepatic lipid accumulation. Our findings suggest that the reduction of PP2A methylation, a result of decrease hepatic methylation capacity, played an important role in ethanol-induced lipid accumulation via down-regulation of PP2A/Bα and FOXO1 phosphorylation.


Assuntos
Etanol/toxicidade , Proteína Forkhead Box O1/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatopatias Alcoólicas/metabolismo , Fígado/efeitos dos fármacos , Proteína Fosfatase 2/metabolismo , Animais , Linhagem Celular , Hepatócitos/metabolismo , Fígado/metabolismo , Fígado/patologia , Hepatopatias Alcoólicas/patologia , Masculino , Metilação , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação
6.
Proc Natl Acad Sci U S A ; 117(21): 11667-11673, 2020 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-32393626

RESUMO

Alcohol-related liver disease (ALD) accounts for the majority of cirrhosis and liver-related deaths worldwide. Activation of IFN-regulatory factor (IRF3) initiates alcohol-induced hepatocyte apoptosis, which fuels a robust secondary inflammatory response that drives ALD. The dominant molecular mechanism by which alcohol activates IRF3 and the pathways that amplify inflammatory signals in ALD remains unknown. Here we show that cytoplasmic sensor cyclic guanosine monophosphate-adenosine monophosphate (AMP) synthase (cGAS) drives IRF3 activation in both alcohol-injured hepatocytes and the neighboring parenchyma via a gap junction intercellular communication pathway. Hepatic RNA-seq analysis of patients with a wide spectrum of ALD revealed that expression of the cGAS-IRF3 pathway correlated positively with disease severity. Alcohol-fed mice demonstrated increased hepatic expression of the cGAS-IRF3 pathway. Mice genetically deficient in cGAS and IRF3 were protected against ALD. Ablation of cGAS in hepatocytes only phenocopied this hepatoprotection, highlighting the critical role of hepatocytes in fueling the cGAS-IRF3 response to alcohol. We identified connexin 32 (Cx32), the predominant hepatic gap junction, as a critical regulator of spreading cGAS-driven IRF3 activation through the liver parenchyma. Disruption of Cx32 in ALD impaired IRF3-stimulated gene expression, resulting in decreased hepatic injury despite an increase in hepatic steatosis. Taken together, these results identify cGAS and Cx32 as key factors in ALD pathogenesis and as potential therapeutic targets for hepatoprotection.


Assuntos
Junções Comunicantes/metabolismo , Fator Regulador 3 de Interferon/metabolismo , Hepatopatias Alcoólicas/metabolismo , Nucleotidiltransferases/metabolismo , Adulto , Animais , Apoptose , Feminino , Hepatócitos/metabolismo , Humanos , Fígado/citologia , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Nucleotidiltransferases/genética , Transdução de Sinais
7.
Lancet Gastroenterol Hepatol ; 5(5): 485-493, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32277901

RESUMO

Alcohol-related liver disease has become the leading indication for liver transplantation in the USA, partly due to an increase in the prevalence of high-risk drinking behaviour and alcohol use disorder, particularly among young women. Achieving sustained alcohol abstinence might not only prevent the development and progression of alcohol-related liver disease, but could also lead to clinically significant improvements, even in the advanced stages of disease. In this Series paper, we discuss the diagnosis and outpatient management of alcohol-related liver disease, with an emphasis on treatment options for alcohol use disorder and the assessment of nutritional status.


Assuntos
Assistência Ambulatorial/métodos , Hepatopatias Alcoólicas/diagnóstico , Hepatopatias Alcoólicas/terapia , Abstinência de Álcool , Comorbidade , Diagnóstico Diferencial , Humanos , Hepatopatias Alcoólicas/complicações , Hepatopatias Alcoólicas/patologia , Desnutrição/etiologia , Desnutrição/terapia , Programas de Rastreamento , Avaliação Nutricional , Estado Nutricional , Apoio Nutricional
8.
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
9.
J Dairy Sci ; 103(5): 3937-3949, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32171514

RESUMO

Morbidity and mortality as a result of liver disease are major problems around the world, especially from alcoholic liver disease (ALD), which is characterized by hepatic inflammation and intestinal microbial imbalance. In this study, we investigated the hepatoprotective effects of camel milk (CM) in a mouse model of acute ALD and the underlying mechanism at the gut microbiota and transcriptome level. Male Institute of Cancer Research mice (n = 24; Beijing Weitong Lihua Experimental Animal Technology Co. Ltd., China) were divided into 3 groups: normal diet (NC); normal diet, then ethanol (ET); and normal diet and camel milk (CM), then ethanol (ET+CM). Analysis of serum biochemical indexes and histology revealed a reduction in hepatic inflammation in the ET+CM group. Sequencing of 16S rRNA showed that CM modulated the microbial communities, with an increased proportion of Lactobacillus and reduced Bacteroides, Alistipes, and Rikenellaceae RC9 gut group. Comparative hepatic transcriptome analysis revealed 315 differentially expressed genes (DEG) in the ET+CM and ET groups (150 upregulated and 165 downregulated). Enrichment analysis revealed that CM downregulated the expression of inflammation-related (ILB and CXCL1) genes in the IL-17 and tumor necrosis factor (TNF-α) pathways. We conclude that CM modulates liver inflammation and alleviates the intestinal microbial disorder caused by acute alcohol injury, indicating the potential of dietary CM in protection against alcohol-induced liver injury.


Assuntos
Camelus , Etanol/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Hepatopatias Alcoólicas/metabolismo , Hepatopatias Alcoólicas/microbiologia , Leite/fisiologia , Transcriptoma , Animais , Modelos Animais de Doenças , Inflamação/metabolismo , Lactobacillus/genética , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microbiota , RNA Ribossômico 16S , Fator de Necrose Tumoral alfa/metabolismo
10.
Transplant Proc ; 52(3): 900-904, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32151390

RESUMO

INTRODUCTION: Distance from a liver transplant (LT) center does not affect post-transplant outcomes. Rural areas have lower rates of listing and receiving solid organ transplants. The aim of this study was to investigate trends in referral for LT based on physician-dependent variables. METHODS: An online survey was distributed to a cohort of physicians. Questions pertained to physician demographics, including age, specialty, practice location, and training at an LT center. Distances to the nearest transplant center was calculated based on zip code. Variables studied included length of sobriety, patient age, and body mass index required for transplant evaluation. Responses were analyzed using univariate ordinal logistic regression models and multivariable analyses. RESULTS: In the study, 299 physician respondents were analyzed. Physicians without LT center training were 2.05 (confidence interval [CI] 1.33-3.17) times more likely to require longer duration of sobriety. As distance increased from a transplant center, the odds of requiring longer sobriety increased by 1.43 (CI 1.11-1.83) times. Gastroenterologists (GIs) and transplant hepatologists (THs) showed significant differences in referral candidacy for patients with alcohol-related liver disease (P < .0001). When compared to GIs/THs, primary care physicians were 2.11 times (CI 0.97-4.58) more likely to require a longer duration of sobriety. No significant physician-dependent variables were found in respect to patient age or body mass index. DISCUSSION: Our study demonstrates that physician-dependent variables exist in referral for transplant evaluation. GIs and THs were more likely to refer higher-risk patients, which suggests a disparity in referral of patients with alcohol-related liver disease to transplantation depending on access to subspecialty care.


Assuntos
Hepatopatias Alcoólicas/cirurgia , Transplante de Fígado , Padrões de Prática Médica/estatística & dados numéricos , Encaminhamento e Consulta/estatística & dados numéricos , Adulto , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários , Adulto Jovem
11.
Chem Biol Interact ; 321: 109044, 2020 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-32151596

RESUMO

Overconsumption of alcohol could lead to severe liver injury that connects with oxidative stress, apoptosis, and inflammatory response. Previously, we proved that p-coumaric acid prevents ethanol induced reproductive toxicity; however, p-coumaric acid (PCA) on ethanol mediated hepatotoxicity has not been examined yet. In our work, we sought to study the potential of PCA in contradiction of ethanol induced hepatoxicity which linking with MAPKs, apoptosis, oxidative stress, and Nrf2 signaling. Foremost, we found that PCA could protect ethanol induced both L-02 and HepG2 hepatic cells by inhibiting cytotoxicity, ROS production, mitochondrial depolarization, and nuclear fragmentation. Also, in vivo experiments showed that the ethanol increasing the lipid markers (TBARS, CD) and depletes the antioxidants thereby increased phosphorylation of JNK, ERK, and p38 in rat liver tissues. Interestingly, PCA treatments inhibit ethanol exposed lipid markers and depletion of antioxidants, which directs the inhibition of MAPKs activation in rat liver tissues. We also noticed that the PCA protected ethanol induced apoptosis and liver markers by inhibiting the expression of Bax, caspases; AST, ALT, ALS, and LDH in liver tissue. Overall, the ameliorative consequence of PCA on ethanol induced oxidative stress and apoptosis was achieved by suppressing the expression of CYP2E1 and overexpressing Nrf2 and its target protein HO-1 in rat liver tissue. As a result, PCA was marked to be an effective antioxidant with notable hepatoprotection by inhibiting MAPKs and apoptosis signaling via enhancing Nrf2 signaling.


Assuntos
Hepatopatias Alcoólicas/metabolismo , Hepatopatias Alcoólicas/prevenção & controle , Propionatos/farmacologia , Animais , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular , Modelos Animais de Doenças , Etanol/toxicidade , Células Hep G2 , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/lesões , Fígado/metabolismo , Hepatopatias Alcoólicas/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Substâncias Protetoras/farmacologia , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
14.
Lancet Gastroenterol Hepatol ; 5(3): 245-266, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31981519

RESUMO

BACKGROUND: Cirrhosis and other chronic liver diseases (collectively referred to as cirrhosis in this paper) are a major cause of morbidity and mortality globally, although the burden and underlying causes differ across locations and demographic groups. We report on results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 on the burden of cirrhosis and its trends since 1990, by cause, sex, and age, for 195 countries and territories. METHODS: We used data from vital registrations, vital registration samples, and verbal autopsies to estimate mortality. We modelled prevalence of total, compensated, and decompensated cirrhosis on the basis of hospital and claims data. Disability-adjusted life-years (DALYs) were calculated as the sum of years of life lost due to premature death and years lived with disability. Estimates are presented as numbers and age-standardised or age-specific rates per 100 000 population, with 95% uncertainty intervals (UIs). All estimates are presented for five causes of cirrhosis: hepatitis B, hepatitis C, alcohol-related liver disease, non-alcoholic steatohepatitis (NASH), and other causes. We compared mortality, prevalence, and DALY estimates with those expected according to the Socio-demographic Index (SDI) as a proxy for the development status of regions and countries. FINDINGS: In 2017, cirrhosis caused more than 1·32 million (95% UI 1·27-1·45) deaths (440 000 [416 000-518 000; 33·3%] in females and 883 000 [838 000-967 000; 66·7%] in males) globally, compared with less than 899 000 (829 000-948 000) deaths in 1990. Deaths due to cirrhosis constituted 2·4% (2·3-2·6) of total deaths globally in 2017 compared with 1·9% (1·8-2·0) in 1990. Despite an increase in the number of deaths, the age-standardised death rate decreased from 21·0 (19·2-22·3) per 100 000 population in 1990 to 16·5 (15·8-18·1) per 100 000 population in 2017. Sub-Saharan Africa had the highest age-standardised death rate among GBD super-regions for all years of the study period (32·2 [25·8-38·6] deaths per 100 000 population in 2017), and the high-income super-region had the lowest (10·1 [9·8-10·5] deaths per 100 000 population in 2017). The age-standardised death rate decreased or remained constant from 1990 to 2017 in all GBD regions except eastern Europe and central Asia, where the age-standardised death rate increased, primarily due to increases in alcohol-related liver disease prevalence. At the national level, the age-standardised death rate of cirrhosis was lowest in Singapore in 2017 (3·7 [3·3-4·0] per 100 000 in 2017) and highest in Egypt in all years since 1990 (103·3 [64·4-133·4] per 100 000 in 2017). There were 10·6 million (10·3-10·9) prevalent cases of decompensated cirrhosis and 112 million (107-119) prevalent cases of compensated cirrhosis globally in 2017. There was a significant increase in age-standardised prevalence rate of decompensated cirrhosis between 1990 and 2017. Cirrhosis caused by NASH had a steady age-standardised death rate throughout the study period, whereas the other four causes showed declines in age-standardised death rate. The age-standardised prevalence of compensated and decompensated cirrhosis due to NASH increased more than for any other cause of cirrhosis (by 33·2% for compensated cirrhosis and 54·8% for decompensated cirrhosis) over the study period. From 1990 to 2017, the number of prevalent cases more than doubled for compensated cirrhosis due to NASH and more than tripled for decompensated cirrhosis due to NASH. In 2017, age-standardised death and DALY rates were lower among countries and territories with higher SDI. INTERPRETATION: Cirrhosis imposes a substantial health burden on many countries and this burden has increased at the global level since 1990, partly due to population growth and ageing. Although the age-standardised death and DALY rates of cirrhosis decreased from 1990 to 2017, numbers of deaths and DALYs and the proportion of all global deaths due to cirrhosis increased. Despite the availability of effective interventions for the prevention and treatment of hepatitis B and C, they were still the main causes of cirrhosis burden worldwide, particularly in low-income countries. The impact of hepatitis B and C is expected to be attenuated and overtaken by that of NASH in the near future. Cost-effective interventions are required to continue the prevention and treatment of viral hepatitis, and to achieve early diagnosis and prevention of cirrhosis due to alcohol-related liver disease and NASH. FUNDING: Bill & Melinda Gates Foundation.


Assuntos
Carga Global da Doença/tendências , Hepatite B/complicações , Hepatite C/complicações , Cirrose Hepática/epidemiologia , Cirrose Hepática/etiologia , Adulto , África ao Sul do Saara/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Ásia Central/epidemiologia , Análise Custo-Benefício/métodos , Avaliação da Deficiência , Diagnóstico Precoce , Egito/epidemiologia , Europa Oriental/epidemiologia , Feminino , Hepatite B/epidemiologia , Hepatite B/prevenção & controle , Hepatite C/epidemiologia , Hepatite C/prevenção & controle , Humanos , Cirrose Hepática/mortalidade , Cirrose Hepática/prevenção & controle , Hepatopatias Alcoólicas/complicações , Hepatopatias Alcoólicas/epidemiologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Prevalência , Anos de Vida Ajustados por Qualidade de Vida , Fatores de Risco , Singapura/epidemiologia , Fatores Socioeconômicos
16.
Cell ; 180(2): 218-220, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31978341

RESUMO

Alcoholic hepatitis is a severe alcohol-associated liver disease with minimal treatment options. A recent study by Duan et al. uncovers that the exotoxin-secreting gut bacterium Enterococcus faecalis is a critical contributor to alcoholic hepatitis. This bacterium can now be eliminated with a bacteriophage, suggesting a new way to treat this life-threatening disease.


Assuntos
Bacteriófagos , Microbioma Gastrointestinal , Hepatite Alcoólica , Hepatopatias Alcoólicas , Enterococcus faecalis , Humanos
17.
18.
J Agric Food Chem ; 68(5): 1237-1247, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-31722525

RESUMO

Alcoholic liver injury, known as the most general result of chronic alcohol intake, is induced by inflammatory responses, which is activated by intestine-derived endotoxins formed from intestinal dysbiosis. The hepatoprotective activity of rice bran phenolic extract (RBPE) on ethanol-fed mice was investigated for the first time in this study, and the underlying mechanism was explored from gut microbiota, barrier function, and hepatic inflammation. Mice were fed an alcohol-containing liquid diet alone or in mixture with RBPE for 8 weeks. RBPE treatment mitigated ethanol-induced liver damage, evidenced by the declined lipid profile levels and hepatic function markers. Moreover, ethanol intake induced intestinal microbiota dysbiosis, which was attenuated by RBPE supplementation. RBPE treatment improved the alcohol-induced decrease in the expression of ZO-1, Claudin-1, Claudin-4, and Reg3g, revealing the ameliorative effect of RBPE on intestinal barrier dysfunction. Furthermore, RBPE treatment repressed the alcohol-induced trigger of the hepatic endotoxin-TLR4-NF-κB pathway, followed by the mitigated liver inflammation. The findings indicate that RBPE supplementation ameliorates intestinal microbiota dysbiosis and barrier dysfunction, inactivates the endotoxin-TLR4-NF-κB pathway, and represses inflammatory responses in liver, and therefore, intake of RBPE or brown rice may be an effective way to mitigate alcoholic liver injury.


Assuntos
Disbiose/tratamento farmacológico , Mucosa Intestinal/microbiologia , Hepatopatias Alcoólicas/prevenção & controle , NF-kappa B/imunologia , Oryza/química , Fenóis/administração & dosagem , Extratos Vegetais/administração & dosagem , Receptor 4 Toll-Like/imunologia , Animais , Disbiose/genética , Disbiose/imunologia , Disbiose/microbiologia , Endotoxinas/efeitos adversos , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Fígado/efeitos dos fármacos , Fígado/imunologia , Hepatopatias Alcoólicas/genética , Hepatopatias Alcoólicas/imunologia , Hepatopatias Alcoólicas/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/genética , Substâncias Protetoras/administração & dosagem , Receptor 4 Toll-Like/genética
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