Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 6.813
Filtrar
1.
Hepatol Commun ; 8(7)2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38967588

RESUMO

BACKGROUND: Liver transplantation (LT) for alcohol-associated liver disease (ALD) is increasing and may impact LT outcomes for patients listed for HCC and other indications. METHODS: Using US adults listed for primary LT (grouped as ALD, HCC, and other) from October 8, 2015, to December 31, 2021, we examined the impact of center-level ALD LT volume (ATxV) on waitlist outcomes in 2 eras: Era 1 (6-month wait for HCC) and Era 2 (MMaT-3). The tertile distribution of ATxV (low to high) was derived from the listed candidates as Tertile 1 (T1): <28.4%, Tertile 2 (T2): 28.4%-37.6%, and Tertile 3 (T3): >37.6% ALD LTs per year. Cumulative incidence of waitlist death and LT within 18 months from listing by LT indication were compared using the Gray test, stratified on eras and ATxV tertiles. Multivariable competing risk regression estimated the adjusted subhazard ratios (sHRs) for the risk of waitlist mortality and LT with interaction effects of ATxV by LT indication (interaction p). RESULTS: Of 56,596 candidates listed, the cumulative waitlist mortality for those with HCC and other was higher and their LT probability was lower in high (T3) ATxV centers, compared to low (T1) ATxV centers in Era 2. However, compared to ALD (sHR: 0.92 [0.66-1.26]), the adjusted waitlist mortality for HCC (sHR: 1.15 [0.96-1.38], interaction p = 0.22) and other (sHR: 1.13 [0.87-1.46], interaction p = 0.16) were no different suggesting no differential impact of ATxV on the waitlist mortality. The adjusted LT probability for HCC (sHR: 0.89 [0.72-1.11], interaction p = 0.08) did not differ by AtxV while it was lower for other (sHR: 0.82 [0.67-1.01], interaction p = 0.02) compared to ALD (sHR: 1.04 [0.80-1.34]) suggesting a differential impact of ATxV on LT probability. CONCLUSIONS: The high volume of LT for ALD does not impact waitlist mortality for HCC and others but affects LT probability for other in the MMAT-3 era warranting continued monitoring.


Assuntos
Carcinoma Hepatocelular , Hepatopatias Alcoólicas , Neoplasias Hepáticas , Transplante de Fígado , Listas de Espera , Humanos , Transplante de Fígado/mortalidade , Transplante de Fígado/estatística & dados numéricos , Carcinoma Hepatocelular/cirurgia , Carcinoma Hepatocelular/mortalidade , Listas de Espera/mortalidade , Neoplasias Hepáticas/cirurgia , Neoplasias Hepáticas/mortalidade , Masculino , Feminino , Pessoa de Meia-Idade , Hepatopatias Alcoólicas/cirurgia , Hepatopatias Alcoólicas/mortalidade , Estados Unidos/epidemiologia , Adulto , Estudos Retrospectivos , Idoso
2.
BMC Public Health ; 24(1): 1841, 2024 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-38987717

RESUMO

BACKGROUND: There is a lack of national-level research on alcohol consumption and the epidemiology of alcoholic liver disease (ALD) in South Korea. This study aims to address the critical public health issue of ALD by focusing on its trends, incidence, and outcomes, using nationwide claims data. METHODS: Utilizing National Health Insurance Service data from 2011 to 2017, we calculated the population's overall drinking amount and the incidence of ALD based on ICD-10 diagnosis codes. RESULTS: From 2011 to 2017 in South Korea, social drinking increased from 15.7% to 16.5%, notably rising among women. High-risk drinking remained around 16.4%, decreasing in men aged 20-39 but not decreased in men aged 40-59 and steadily increased in women aged 20-59. The prevalence of ALD in high-risk drinkers (0.97%) was significantly higher than in social drinkers (0.16%). A 3-year follow-up revealed ALD incidence of 1.90% for high-risk drinkers and 0.31% for social drinkers. Women high-risk drinkers had a higher ALD risk ratio (6.08) than men (4.18). The economic burden of ALD was substantial, leading to higher healthcare costs and increased hospitalization. Progression rates to liver cirrhosis and hepatocellular carcinoma (HCC) in ALD patients were 23.3% and 2.8%, respectively, with no gender difference in cirrhosis progression. CONCLUSIONS: The study revealed a concerning rise in alcohol consumption among South Korean women and emphasizes the heightened health risks and economic burdens associated with high-risk drinking, especially concerning ALD and its complications.


Assuntos
Consumo de Bebidas Alcoólicas , Hepatopatias Alcoólicas , Humanos , República da Coreia/epidemiologia , Feminino , Masculino , Pessoa de Meia-Idade , Hepatopatias Alcoólicas/epidemiologia , Adulto , Consumo de Bebidas Alcoólicas/epidemiologia , Incidência , Adulto Jovem , Estudos de Coortes , Idoso , Prevalência
3.
Clin Transplant ; 38(7): e15381, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38940230

RESUMO

BACKGROUND: Alcohol-associated liver disease (ALD) is a leading indication for liver transplant (LT) in the United States. Rates of early liver transplant (ELT) with less than 6 months of sobriety have increased substantially. Patients who receive ELT commonly have alcohol-associated hepatitis (AH) and are often too ill to complete an intensive outpatient program (IOP) for alcohol use disorder (AUD) prior to LT. ELT recipients feel alienated from traditional IOPs. METHODS: We implemented Total Recovery-LT, a tailored virtual outpatient IOP specific for patients under evaluation or waitlisted for LT who were too ill to attend community-based alcohol treatment programs. The 12-week program consisted of weekly group and individual counseling delivered by a master's level Certified Addiction Counselor trained in the basics of LT.  Treatment consisted of 12-Step Facilitation, Motivational Interviewing, and Cognitive Behavioral Therapy. We report on program design, implementation, feasibility and early outcomes. RESULTS: From March 2021 to September 2022, 42 patients (36% female, 23 in LT evaluation, 19 post-transplant) enrolled across five cohorts with 76% (32/42) completing the program. Alcohol relapse was more common among noncompleters versus those who completed the program (8/10, 80% vs. 7/32, 22%, p = 0.002). History of trauma or post-traumatic stress symptoms were associated with lower likelihood of completion. Patients' desire for continued engagement after completion led to the creation of a monthly alumni group. CONCLUSIONS: Our integrated IOP model for patients with high-risk AUD in LT evaluation or post-transplant is well-received by patients and could be considered a model for LT programs.


Assuntos
Alcoolismo , Estudos de Viabilidade , Transplante de Fígado , Recidiva , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Seguimentos , Alcoolismo/complicações , Alcoolismo/terapia , Prognóstico , Adulto , Complicações Pós-Operatórias , Telemedicina , Hepatopatias Alcoólicas/cirurgia , Hepatopatias Alcoólicas/terapia , Hepatopatias Alcoólicas/complicações
4.
Adv Food Nutr Res ; 110: 243-274, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38906588

RESUMO

Alcohol intake has become one of the leading risks to human health and wellness, among which acute and/or chronic alcohol-induced liver injury is a leading threaten, with few therapeutic options other than abstinence. In recent years, studies suggested that certain bioactive peptides from food sources could represent natural and safe alternatives for the prevention of alcoholic liver injury. Hence, this chapter focus on the advanced research on bioactive peptides exerting hepatoprotective activity against alcoholic liver injury. The main sources of protein, strategies for the preparation of hepatoprotective hydrolysates and peptides, underlying mechanisms of peptides on hepatoprotection, and possible structure-activity relationship between peptides and hepatoprotective activity were summarized and discussed, aiming to give a systematic insight into the research progress of hepatoprotective peptides. However, more efforts would be needed to give a clearer insight into the underlying mechanisms and structure-activity relationship before using hepatoprotective peptides as functional food ingredients or dietary supplements.


Assuntos
Hepatopatias Alcoólicas , Peptídeos , Humanos , Hepatopatias Alcoólicas/prevenção & controle , Peptídeos/farmacologia , Peptídeos/química , Substâncias Protetoras/farmacologia , Animais , Relação Estrutura-Atividade , Fígado/efeitos dos fármacos
5.
Medicine (Baltimore) ; 103(25): e38315, 2024 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-38905402

RESUMO

Gegensan (GGS) has been reported for the treatment of alcoholic liver disease (ALD), but its therapeutic mechanism is still unclear. This paper aims to determine the therapeutic mechanism and targets of action of GGS on alcoholic liver disease utilizing network pharmacology and bioinformatics. The active ingredients in GGS were screened in the literature and databases, and common targets of ALD were then obtained from public databases to construct the network diagram of traditional Chinese medicine-active ingredient targets. Based on the common targets, Gene Ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed to find target enrichment pathways, and the core targets were screened out by combining differential analysis and protein-protein interaction network analysis. Molecular docking was performed to verify the binding effect between the core targets and the corresponding active ingredients. ALD and GGS have 84 common targets, corresponding to 91 active ingredients. After subsequent differential analysis and protein-protein interaction network analysis, 10 core targets were identified. Gene Ontology and KEGG enrichment analyses showed that the main BPs corresponding to the common targets included the response to lipopolysaccharide, inflammatory response, etc. The KEGG pathways involved in the regulation of the common targets included the lipid-atherosclerosis pathway and the alcoholic liver disease pathway, etc. Further molecular docking showed that the core targets CYP1A1, CYP1A2, CXCL8, ADH1C, MMP1, SERPINE1, COL1A1, APOB, MMP1, and their corresponding 4 active ingredients, Naringenin, Kaempferol, Quercetin, and Stigmasterol, have a greater docking potential. The above results suggest that GGS can regulate lipid metabolism and inflammatory response in the ALD process, and alleviate the lipid accumulation and oxidative stress caused by ethanol. This study analyzed the core targets and mechanisms of action of GGS on ALD, which provides certain theoretical support for the further development of GGS in the treatment of ALD, and provides a reference for the subsequent research on the treatment of ALD.


Assuntos
Biologia Computacional , Medicamentos de Ervas Chinesas , Hepatopatias Alcoólicas , Simulação de Acoplamento Molecular , Farmacologia em Rede , Mapas de Interação de Proteínas , Hepatopatias Alcoólicas/tratamento farmacológico , Hepatopatias Alcoólicas/metabolismo , Farmacologia em Rede/métodos , Humanos , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Biologia Computacional/métodos , Medicina Tradicional Chinesa/métodos , Ontologia Genética
6.
Gut Microbes ; 16(1): 2367342, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38889450

RESUMO

Alcohol-related liver disease (ALD) is recognized as a global health crisis, contributing to approximately 20% of liver cancer-associated fatalities. Dysbiosis of the gut microbiome is associated with the development of ALD, with the gut microbial metabolite urolithin A (UA) exhibiting a potential for alleviating liver symptoms. However, the protective efficacy of UA against ALD and its underlying mechanism mediated by microbiota remain elusive. In this study, we provide evidence demonstrating that UA effectively ameliorates alcohol-induced metabolic disorders and hepatic endoplasmic reticulum (ER) stress through a specific gut-microbiota-liver axis mediated by major urinary protein 1 (MUP1). Moreover, UA exhibited the potential to restore alcohol-induced dysbiosis of the intestinal microbiota by enriching the abundance of Bacteroides sartorii (B. sartorii), Parabacteroides distasonis (P. distasonis), and Akkermansia muciniphila (A. muciniphila), along with their derived metabolite propionic acid. Partial attenuation of the hepatoprotective effects exerted by UA was observed upon depletion of gut microbiota using antibiotics. Subsequently, a fecal microbiota transplantation (FMT) experiment was conducted to evaluate the microbiota-dependent effects of UA in ALD. FMT derived from mice treated with UA exhibited comparable efficacy to direct UA treatment, as it effectively attenuated ER stress through modulation of MUP1. It was noteworthy that strong associations were observed among the hepatic MUP1, gut microbiome, and metabolome profiles affected by UA. Intriguingly, oral administration of UA-enriched B. sartorii, P. distasonis, and A. muciniphila can enhance propionic acid production to effectively suppress ER stress via MUP1, mimicking UA treatment. Collectively, these findings elucidate the causal mechanism that UA alleviated ALD through the gut-microbiota-liver axis. This unique mechanism sheds light on developing novel microbiome-targeted therapeutic strategies against ALD.


Assuntos
Cumarínicos , Estresse do Retículo Endoplasmático , Microbioma Gastrointestinal , Hepatopatias Alcoólicas , Fígado , Camundongos Endogâmicos C57BL , Microbioma Gastrointestinal/efeitos dos fármacos , Animais , Camundongos , Fígado/metabolismo , Fígado/efeitos dos fármacos , Hepatopatias Alcoólicas/microbiologia , Hepatopatias Alcoólicas/metabolismo , Hepatopatias Alcoólicas/prevenção & controle , Masculino , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Cumarínicos/farmacologia , Cumarínicos/metabolismo , Disbiose/microbiologia , Humanos , Bactérias/metabolismo , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação
7.
Food Funct ; 15(13): 7124-7135, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38881239

RESUMO

Alcoholic liver injury has become a leading threat to human health, with complicated pathogenesis and limited therapeutic options. Our previous study showed that Musculus senhousei peptides (MSPs) exhibit protective potential against early-stage alcoholic liver injury, although the underlying mechanism is not yet clear. In this study, histopathological analysis, mRNA abundance of injury-associated biomarkers, the gut microbiota, and faecal metabolome were evaluated using a mouse model subjected to acute alcohol exposure, aiming to identify the mechanism by which MSP can alleviate alcoholic hepatotoxicity. The results showed that MSP intervention significantly ameliorated symptoms of liver injury (suppressed serum ALT increment, hepatic lipid accumulation, and neutrophil infiltration in liver tissue), and reversed the abnormal mRNA abundance of biomarkers associated with oxidative stress (iNOS), inflammation (TNF-α, IL-1ß, MCP-1, TNF-R1, and TLR4), and apoptosis (Bax and Casp. 3) in the liver. Moreover, MSP improved intestinal barrier function by increasing the expression of tight junction proteins (Claudin-1 and Claudin-3). Further analysis of faecal microbiota and metabolome revealed that MSP promoted the growth of tryptophan-metabolizing bacteria (Clostridiales, Alistipes, and Odoribacter), leading to increased production of indole derivatives (indole-3-lactic acid and N-acetyltryptophan). These results suggested that MSPs may alleviate alcohol-induced liver injury targeting the gut-liver axis, and could be an effective option for the prevention of alcoholic liver injury.


Assuntos
Microbioma Gastrointestinal , Hepatopatias Alcoólicas , Fígado , Camundongos Endogâmicos C57BL , Animais , Camundongos , Microbioma Gastrointestinal/efeitos dos fármacos , Masculino , Hepatopatias Alcoólicas/tratamento farmacológico , Hepatopatias Alcoólicas/metabolismo , Fígado/metabolismo , Fígado/efeitos dos fármacos , Peptídeos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Modelos Animais de Doenças
8.
Food Res Int ; 188: 114489, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38823872

RESUMO

Solanum nigrum L. (SN) berry is an edible berry containing abundant polyphenols and bioactive compounds, which possess antioxidant and antiinflammatory properties. However, the effects of SN on alcohol-induced biochemical changes in the enterohepatic axis remain unclear. In the current study, a chronic ethanol-fed mice ALD model was used to test the protective mechanisms of SN berries. Microbiota composition was determined via 16S rRNA sequencing, we found that SN berries extract (SNE) improved intestinal imbalance by reducing the Firmicutes to Bacteroides ratio, restoring the abundance of Akkermansia microbiota, and reducing the abundance of Allobaculum and Shigella. SNE restored the intestinal short-chain fatty acids content. In addition, liver transcriptome data analysis revealed that SNE primarily affected the genes involved in lipid metabolism and inflammatory responses. Furthermore, SNE ameliorated hepatic steatosis in alcohol-fed mice by activating AMP-activated protein kinase (AMPK), acetyl-CoA carboxylase (ACC), peroxisome proliferator-activated receptor α (PPAR-α). SNE reduced the expression of toll-like receptor 4 (TLR4), myeloid differentiation factor-88 (MyD88) nuclear factor kappa-B (NF-κB), which can indicate that SNE mainly adjusted LPS/TLR4/MyD88/NF-κB pathway to reduce liver inflammation. SNE enhanced hepatic antioxidant capacity by regulating NRF2-related protein expression. SNE alleviates alcoholic liver injury by regulating of gut microbiota, lipid metabolism, inflammation, and oxidative stress. This study may provide a reference for the development and utilization of SN resources.


Assuntos
Frutas , Microbioma Gastrointestinal , Metabolismo dos Lipídeos , Hepatopatias Alcoólicas , Estresse Oxidativo , Extratos Vegetais , Solanum nigrum , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Extratos Vegetais/farmacologia , Camundongos , Frutas/química , Solanum nigrum/química , Masculino , Hepatopatias Alcoólicas/metabolismo , Hepatopatias Alcoólicas/prevenção & controle , Camundongos Endogâmicos C57BL , Inflamação , Fígado/efeitos dos fármacos , Fígado/metabolismo , Receptor 4 Toll-Like/metabolismo , Modelos Animais de Doenças , PPAR alfa/metabolismo , Antioxidantes/farmacologia , Etanol
9.
Biochem Pharmacol ; 225: 116334, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38824967

RESUMO

Alcoholic liver injury (ALI) stands as a prevalent affliction within the spectrum of complex liver diseases. Prolonged and excessive alcohol consumption can pave the way for liver fibrosis, cirrhosis, and even hepatocellular carcinoma. Recent findings have unveiled the protective role of proline serine-threonine phosphatase interacting protein 2 (PSTPIP2) in combating liver ailments. However, the role of PSTPIP2 in ALI remains mostly unknown. This study aimed to determine the expression profile of PSTPIP2 in ALI and to uncover the mechanism through which PSTPIP2 affects the survival and apoptosis of hepatocytes in ALI, using both ethyl alcohol (EtOH)-fed mice and an EtOH-induced AML-12 cell model. We observed a consistent decrease in PSTPIP2 expression both in vivo and in vitro. Functionally, we assessed the impact of PSTPIP2 overexpression on ALI by administering adeno-associated virus 9 (AAV9)-PSTPIP2 into mice. The results demonstrated that augmenting PSTPIP2 expression significantly shielded against liver parenchymal distortion and curbed caspase-dependent hepatocyte apoptosis in EtOH-induced ALI mice. Furthermore, enforcing PSTPIP2 expression reduced hepatocyte apoptosis in a stable PSTPIP2-overexpressing AML-12 cell line established through lentivirus-PSTPIP2 transfection in vitro. Mechanistically, this study also identified signal transducer and activator of transcription 3 (STAT3) as a direct signaling pathway regulated by PSTPIP2 in ALI. In conclusion, our findings provide compelling evidence that PSTPIP2 has a regulatory role in hepatocyte apoptosis via the STAT3 pathway in ALI, suggesting PSTPIP2 as a promising therapeutic target for ALI.


Assuntos
Apoptose , Camundongos Endogâmicos C57BL , Fator de Transcrição STAT3 , Animais , Apoptose/fisiologia , Apoptose/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT3/genética , Camundongos , Masculino , Hepatopatias Alcoólicas/metabolismo , Hepatopatias Alcoólicas/patologia , Hepatopatias Alcoólicas/prevenção & controle , Etanol/toxicidade , Etanol/administração & dosagem , Hepatócitos/metabolismo , Hepatócitos/patologia , Linhagem Celular , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética
10.
G Ital Nefrol ; 41(3)2024 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-38943330

RESUMO

IgA nephropathy (IgAN) is a fairly common association with alcoholic liver disease. However, IgA vasculitis (IgAV) is quite an uncommon association with alcoholic liver cirrhosis and only a handful of cases have been reported in literature. Secondary IgAN usually presents in a docile manner, progressing slowly in about 5-25 years. It is usually responsive to steroid therapy, very rarely progressing to End-Stage Renal Disease. Here, we present a man in his late 50s, a known hypertensive and alcohol related liver-cirrhotic, who presented to our hospital with rash and rapidly progressive renal failure (RPRF). He was diagnosed with IgA nephritis with IgA vasculitis (IgAVN). His diagnosis was confirmed with skin and renal biopsy. He was started on renal replacement therapy for his renal failure and began oral steroid therapy. After administration of steroid therapy for 6 months, the patient recovered and was dialysis independent with stable renal parameters.


Assuntos
Glomerulonefrite por IGA , Humanos , Masculino , Glomerulonefrite por IGA/complicações , Glomerulonefrite por IGA/diagnóstico , Pessoa de Meia-Idade , Progressão da Doença , Hepatopatias Alcoólicas/complicações , Vasculite por IgA/complicações , Vasculite por IgA/diagnóstico , Vasculite por IgA/tratamento farmacológico , Vasculite/complicações , Vasculite/etiologia , Vasculite/diagnóstico , Vasculite/tratamento farmacológico
11.
Mol Nutr Food Res ; 68(12): e2300833, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38850176

RESUMO

SCOPE: Alcoholic liver disease (ALD) is a global public health concern. Nobiletin, a polymethoxyflavone abundant in citrus fruits, enhances circadian rhythms and ameliorates diet-induced hepatic steatosis, but its influences on ALD are unknown. This study investigates the role of brain and muscle Arnt-like protein-1 (Bmal1), a key regulator of the circadian clock, in nobiletin-alleviated ALD. METHODS AND RESULTS: This study uses chronic ethanol feeding plus an ethanol binge to establish ALD models in Bmal1flox/flox and Bmal1 liver-specific knockout (Bmal1LKO) mice. Nobiletin mitigates ethanol-induced liver injury (alanine aminotransferase [ALT]), glucose intolerance, hepatic apoptosis, and lipid deposition (triglyceride [TG], total cholesterol [TC]) in Bmal1flox/flox mice. Nobiletin fails to modulated liver injury (ALT, aspartate aminotransferase [AST]), apoptosis, and TG accumulation in Bmal1LKO mice. The expression of lipogenic genes (acetyl-CoA carboxylase alpha [Acaca], fatty acid synthase [Fasn]) and fatty acid oxidative genes (carnitine pamitoyltransferase [Cpt1a], cytochrome P450, family 4, subfamily a, polypeptide 10 [Cyp4a10], and cytochrome P450, family4, subfamily a, polypeptide 14 [Cyp4a14]) is inhibited, and the expression of proapoptotic genes (Bcl2 inteacting mediator of cell death [Bim]) is enhanced by ethanol in Bmal1flox/flox mice. Nobiletin antagonizes the expression of these genes in Bmal1flox/flox mice and not in Bmal1LKO mice. Nobiletin activates protein kinase B (PKB, also known as AKT) phosphorylation, increases the levels of the carbohydrate response element binding protein (ChREBP), ACC1, and FASN, and reduces the level of sterol-regulatory element binding protein 1 (SREBP1) and phosphorylation of ACC1 in a Bmal1-dependent manner. CONCLUSION: Nobiletin alleviates ALD by increasing the expression of genes involved in fatty acid oxidation by increasing AKT phosphorylation and lipogenesis in a Bmal1-dependent manner.


Assuntos
Fatores de Transcrição ARNTL , Flavonas , Lipogênese , Hepatopatias Alcoólicas , Camundongos Knockout , Proteínas Proto-Oncogênicas c-akt , Animais , Flavonas/farmacologia , Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Hepatopatias Alcoólicas/prevenção & controle , Hepatopatias Alcoólicas/metabolismo , Hepatopatias Alcoólicas/tratamento farmacológico , Lipogênese/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Masculino , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos Endogâmicos C57BL , Camundongos , Substâncias Protetoras/farmacologia , Etanol , Transdução de Sinais/efeitos dos fármacos , Apoptose/efeitos dos fármacos
12.
Aliment Pharmacol Ther ; 60(3): 378-388, 2024 08.
Artigo em Inglês | MEDLINE | ID: mdl-38828940

RESUMO

BACKGROUND AND AIMS: The objective of the study was to analyse the prevalence, incidence, and death of alcohol-associated liver disease (ALD) among adolescents and young adults globally, continentally, and nationally, focusing on trends over time. METHODS: The study analysed data from the Global Burden of Disease (GBD) study between 2000 and 2019. It examined ALD's prevalence, incidence, and death in adolescents and young adults aged 15-29, segmented by region, nation, and sociodemographic index. The analysis utilised Joinpoint regression modelling to calculate the annual per cent change (APC) in the rate of these parameters over time. RESULTS: In 2019, there were 281,450 ALD prevalences, 18,930 incidences, and 3190 deaths among adolescents and young adults globally. From 2000 to 2019, the age-adjusted prevalence rate per 100,000 increased in the 25-29 age group (APC: +0.6%, p = 0.003), remained stable among ages 20-24 (p = 0.302) and ages 15-19 (p = 0.160). Prevalence increased significantly from age 15-19 to 20-24 (19-fold increase) and from age 20-24 to 25-29 (2.5-fold increase). ALD prevalence rates increased in all age groups in adolescents and young adults in Africa and the Eastern Mediterranean region. Around three-quarters of countries and territories experienced an increase in ALD incidence rates in young adults. CONCLUSION: Over two decades, the burden of ALD among adolescents and young adults has increased globally. The study emphasises the importance of public health policies aimed at reducing alcohol consumption and preventing ALD among younger populations.


Assuntos
Saúde Global , Hepatopatias Alcoólicas , Humanos , Adolescente , Adulto Jovem , Masculino , Feminino , Adulto , Prevalência , Incidência , Hepatopatias Alcoólicas/epidemiologia , Carga Global da Doença , Consumo de Bebidas Alcoólicas/epidemiologia , Consumo de Bebidas Alcoólicas/efeitos adversos
13.
Commun Biol ; 7(1): 756, 2024 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-38907105

RESUMO

Tuberous sclerosis complex 2 (TSC2) crucially suppresses Rheb activity to prevent mTORC1 activation. However, mutations in TSC genes lead to mTORC1 overactivation, thereby causing various developmental disorders and cancer. Therefore, the discovery of novel Rheb inhibitors is vital to prevent mTOR overactivation. Here, we reveals that the anti-inflammatory cytokine IL-37d can bind to lysosomal Rheb and suppress its activity independent of TSC2, thereby preventing mTORC1 activation. The binding of IL-37d to Rheb switch-II subregion destabilizes the Rheb-mTOR and mTOR-S6K interactions, further halting mTORC1 signaling. Unlike TSC2, IL-37d is reduced under ethanol stimulation, which results in mitigating the suppression of lysosomal Rheb-mTORC1 activity. Consequently, the recombinant human IL-37d protein (rh-IL-37d) with a TAT peptide greatly improves alcohol-induced liver disorders by hindering Rheb-mTORC1 axis overactivation in a TSC2- independent manner. Together, IL-37d emerges as a novel Rheb suppressor independent of TSC2 to terminate mTORC1 activation and improve abnormal lipid metabolism in the liver.


Assuntos
Hepatopatias Alcoólicas , Alvo Mecanístico do Complexo 1 de Rapamicina , Proteína Enriquecida em Homólogo de Ras do Encéfalo , Transdução de Sinais , Proteína 2 do Complexo Esclerose Tuberosa , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Proteína Enriquecida em Homólogo de Ras do Encéfalo/metabolismo , Proteína Enriquecida em Homólogo de Ras do Encéfalo/genética , Humanos , Animais , Camundongos , Proteína 2 do Complexo Esclerose Tuberosa/metabolismo , Proteína 2 do Complexo Esclerose Tuberosa/genética , Hepatopatias Alcoólicas/metabolismo , Hepatopatias Alcoólicas/genética , Interleucina-1/metabolismo , Interleucina-1/genética , Camundongos Endogâmicos C57BL , Masculino , Células HEK293
14.
J Agric Food Chem ; 72(27): 15265-15275, 2024 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-38918075

RESUMO

Probiotics can regulate gut microbiota and protect against acute alcohol-induced liver injury through the gut-liver axis. However, efficacy is strain-dependent, and their mechanism remains unclear. This study investigated the effect of lactic acid bacteria (LAB), including Lacticaseibacillus paracasei E10 (E10), Lactiplantibacillus plantarum M (M), Lacticaseibacillus rhamnosus LGG (LGG), Lacticaseibacillus paracasei JN-1 (JN-1), and Lacticaseibacillus paracasei JN-8 (JN-8), on the prevention of acute alcoholic liver injury in mice. We found that LAB pretreatment reduced serum alanine transaminase (ALT) and aspartate transaminase (AST) and reduced hepatic total cholesterol (TC) and triglyceride (TG). JN-8 pretreatment exhibited superior efficacy in improving hepatic antioxidation. LGG and JN-8 pretreatment significantly attenuated hepatic and colonic inflammation by decreasing the expression of interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) and increasing the expression of interleukin 10 (IL-10). JN-1 and JN-8 pretreatments have better preventive effects than other LAB pretreatment on intestinal barrier dysfunction. In addition, the LAB pretreatment improved gut microbial dysbiosis and bile acid (BA) metabolic abnormality. All of the strains were confirmed to have bile salt deconjugation capacities in vitro, where M and JN-8 displayed higher activities. This study provides new insights into the prevention and mechanism of LAB strains in preventing acute alcoholic liver injury.


Assuntos
Ácidos e Sais Biliares , Microbioma Gastrointestinal , Lactobacillales , Fígado , Camundongos Endogâmicos C57BL , Probióticos , Animais , Camundongos , Probióticos/administração & dosagem , Fígado/metabolismo , Masculino , Humanos , Ácidos e Sais Biliares/metabolismo , Lactobacillales/metabolismo , Hepatopatias Alcoólicas/prevenção & controle , Hepatopatias Alcoólicas/metabolismo , Hepatopatias Alcoólicas/microbiologia , Aspartato Aminotransferases/metabolismo , Aspartato Aminotransferases/sangue , Alanina Transaminase/metabolismo , Alanina Transaminase/sangue , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/genética , Interleucina-6/metabolismo , Interleucina-6/genética , Interleucina-10/genética , Interleucina-10/metabolismo , Etanol/efeitos adversos
15.
Biochim Biophys Acta Mol Basis Dis ; 1870(6): 167259, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38796918

RESUMO

BACKGROUND: Alcohol-associated liver disease (ALD) is a leading cause of liver disease-related deaths worldwide. Unfortunately, approved medications for the treatment of this condition are quite limited. One promising candidate is the anthocyanin, Cyanidin-3-O-glucoside (C3G), which has been reported to protect mice against hepatic lipid accumulation, as well as fibrosis in different animal models. However, the specific effects and mechanisms of C3G on ALD remain to be investigated. EXPERIMENTAL APPROACH: In this report, a Gao-binge mouse model of ALD was used to investigate the effects of C3G on ethanol-induced liver injury. The mechanisms of these C3G effects were assessed using AML12 hepatocytes. RESULTS: C3G administration ameliorated ethanol-induced liver injury by suppressing hepatic oxidative stress, as well as through reducing hepatic lipid accumulation and inflammation. Mechanistically, C3G activated the AMPK pathway and enhanced mitophagy to eliminate damaged mitochondria, thus reducing mitochondria-derived reactive oxidative species in ethanol-challenged hepatocytes. CONCLUSIONS: The results of this study indicate that mitophagy plays a potentially important role underlying the hepatoprotective action of C3G, as demonstrated in a Gao-binge mouse model of ALD. Accordingly, C3G may serve as a promising, new therapeutic drug candidate for use in ALD.


Assuntos
Antocianinas , Modelos Animais de Doenças , Etanol , Glucosídeos , Hepatopatias Alcoólicas , Mitofagia , Estresse Oxidativo , Animais , Antocianinas/farmacologia , Mitofagia/efeitos dos fármacos , Camundongos , Glucosídeos/farmacologia , Hepatopatias Alcoólicas/metabolismo , Hepatopatias Alcoólicas/patologia , Hepatopatias Alcoólicas/tratamento farmacológico , Hepatopatias Alcoólicas/prevenção & controle , Etanol/toxicidade , Etanol/efeitos adversos , Estresse Oxidativo/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/patologia , Masculino , Camundongos Endogâmicos C57BL , Fígado/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Espécies Reativas de Oxigênio/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos
16.
Minerva Med ; 115(3): 354-363, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38727709

RESUMO

Alcoholic liver disease (ALD) is currently, worldwide, the second most common cause of human fatalities every year. Alcohol use disorders (AUDs) lead to 80% of hepatotoxic deaths, and about 40% of cases of cirrhosis are alcohol-related. An acceptable daily intake (ADI) of ethanol is hard to establish and studies somewhat controversially recommend a variety of dosages of ADI, whilst others regard any intake as dangerous. Steatohepatitis should be viewed as "the rate limiting step": generally, it can be overcome by abstinence, although in some patients, abstinence has little effect, with the risk of fibrosis, leading in some cases to hepatocellular carcinoma (HCC). Chronic alcoholism can also cause hypercortisolism, specifically pseudo-Cushing Syndrome, whose diagnosis is challenging. If fibrosis is spotted early, patients may be enrolled in detoxification programs to achieve abstinence. Treatment drugs include silybin, metadoxine and adenosyl methionine. Nutrition and the proper use of micronutrients are important, albeit often overlooked in ALD treatment. Other drugs, with promising antifibrotic effects, are now being studied. This review deals with the clinical and pathogenetic aspects of alcohol-related liver fibrosis and suggests possible future strategies to prevent cirrhosis.


Assuntos
Alcoolismo , Humanos , Alcoolismo/complicações , Cirrose Hepática/etiologia , Cirrose Hepática Alcoólica/complicações , Cirrose Hepática Alcoólica/etiologia , Hepatopatias Alcoólicas/etiologia , Hepatopatias Alcoólicas/complicações
17.
Phytomedicine ; 130: 155693, 2024 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-38763006

RESUMO

BACKGROUND: Alcoholic liver disease (ALD), a public health challenge worldwide caused by long-term persistent drinking, is life-threatening with minimal approved therapies. Hepatic steatosis accompanied by inflammation is an initial and inevitable stage in the complex progression of simple alcoholic liver injury to more severe liver diseases such as hepatitis, liver fibrosis, cirrhosis and liver cancer. PURPOSE: We aimed to identify the therapeutic role of Bruceine A (BA) in ALD whilst attempting to explore whether its protective effects depend specifically on the farnesoid X receptor (FXR). METHODS: Autodock was applied to detect the affinity between BA and FXR. Lieber-DeCarli liquid diet with 5 % ethanol (v/v) was adopted to establish the mouse ALD model. The lentivirus mediating FXR (LV-FXR) was injected into mice via the tail vein to establish FXR-overexpressed mice. FXR silencing or overexpression plasmids were transfected into AML-12 cells prior to ethanol stimulation. Quantitative real-time PCR, Western blotting and immunofluorescence assays were employed to determine the expression of related genes. We subjected liver sections to H&E and Oil Red O staining to evaluate the liver histological injury and the deposition of lipid droplets. RESULTS: BA significantly reduced body weight and liver-to-body weight ratios as well as biochemical indexes in mice. Ethanol-induced liver damage and lipid accumulation could be alleviated by BA treatment. BA bound to FXR by two hydrogen bonds. There was a positive correlation between BA administration and FXR expression. BA inhibited the expression of lipid synthesis genes and enhanced the expression of lipid metabolism genes by activating FXR, thus alleviating steatosis in ALD. Moreover, BA exerted an ameliorative effect against inflammation by inhibiting the activation of absent in melanoma 2 (AIM2) inflammasome by activating FXR. FXR overexpression possessed the ability to counter the accumulation of lipid and the activation of AIM2 inflammasome caused by ethanol. FXR deficiency exacerbated ethanol-induced liver steatosis and inflammation. The hepatoprotective effect of BA could be disrupted by FXR antagonist guggulsterone (GS) in vivo and FXR siRNA in vitro. CONCLUSION: BA alleviated alcoholic liver disease by inhibiting AIM2 inflammasome activation through an FXR-dependent mechanism. This study may potentially represent a new therapeutic approach for ALD.


Assuntos
Inflamassomos , Hepatopatias Alcoólicas , Camundongos Endogâmicos C57BL , Receptores Citoplasmáticos e Nucleares , Animais , Receptores Citoplasmáticos e Nucleares/metabolismo , Hepatopatias Alcoólicas/tratamento farmacológico , Inflamassomos/metabolismo , Inflamassomos/efeitos dos fármacos , Masculino , Camundongos , Modelos Animais de Doenças , Fígado/efeitos dos fármacos , Fígado/patologia , Fígado/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Etanol
18.
J Biomed Sci ; 31(1): 54, 2024 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-38790021

RESUMO

BACKGROUND: Alcohol-related liver disease (ALD) is a major health concern worldwide, but effective therapeutics for ALD are still lacking. Tumor necrosis factor-inducible gene 6 protein (TSG-6), a cytokine released from mesenchymal stem cells, was shown to reduce liver fibrosis and promote successful liver repair in mice with chronically damaged livers. However, the effect of TSG-6 and the mechanism underlying its activity in ALD remain poorly understood. METHODS: To investigate its function in ALD mice with fibrosis, male mice chronically fed an ethanol (EtOH)-containing diet for 9 weeks were treated with TSG-6 (EtOH + TSG-6) or PBS (EtOH + Veh) for an additional 3 weeks. RESULTS: Severe hepatic injury in EtOH-treated mice was markedly decreased in TSG-6-treated mice fed EtOH. The EtOH + TSG-6 group had less fibrosis than the EtOH + Veh group. Activation of cluster of differentiation 44 (CD44) was reported to promote HSC activation. CD44 and nuclear CD44 intracellular domain (ICD), a CD44 activator which were upregulated in activated HSCs and ALD mice were significantly downregulated in TSG-6-exposed mice fed EtOH. TSG-6 interacted directly with the catalytic site of MMP14, a proteolytic enzyme that cleaves CD44, inhibited CD44 cleavage to CD44ICD, and reduced HSC activation and liver fibrosis in ALD mice. In addition, a novel peptide designed to include a region that binds to the catalytic site of MMP14 suppressed CD44 activation and attenuated alcohol-induced liver injury, including fibrosis, in mice. CONCLUSIONS: These results demonstrate that TSG-6 attenuates alcohol-induced liver damage and fibrosis by blocking CD44 cleavage to CD44ICD and suggest that TSG-6 and TSG-6-mimicking peptide could be used as therapeutics for ALD with fibrosis.


Assuntos
Moléculas de Adesão Celular , Receptores de Hialuronatos , Cirrose Hepática , Hepatopatias Alcoólicas , Animais , Masculino , Camundongos , Moléculas de Adesão Celular/administração & dosagem , Etanol , Receptores de Hialuronatos/metabolismo , Receptores de Hialuronatos/genética , Cirrose Hepática/metabolismo , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/induzido quimicamente , Hepatopatias Alcoólicas/metabolismo , Hepatopatias Alcoólicas/tratamento farmacológico , Camundongos Endogâmicos C57BL , Peptídeos/farmacologia , Peptídeos/metabolismo
19.
Int J Biol Macromol ; 270(Pt 1): 132093, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38710247

RESUMO

Long-term and excessive alcohol consumption can lead to the development of alcoholic liver disease (ALD), characterized by oxidative damage, intestinal barrier injury, and disruption of intestinal microbiota. In this study, we extracted fucoidan (Aj-FUC) from Apostichopus japonicus using enzymatic methods and characterized its structure. The ALD model was established in male Balb/c mice using 56° Baijiu, with silymarin as a positive control. Mice were orally administered 100 mg/kg·bw and 300 mg/kg·bw of Aj-FUC for 28 days to evaluate its effects on liver injury in ALD mice and explore its potential role in modulating the gut-liver axis. The results showed significant improvements in histopathological changes and liver disease in the Aj-FUC group. Aj-FUC treatment significantly increased the levels of glutathione (GSH) and glutathione peroxidase (GSH-Px) while weakly reduced the elevation of malondialdehyde (MDA) induced by ALD. It also regulated the Nrf2/HO-1 signaling pathway, collectively alleviating hepatic oxidative stress. Aj-FUC intervention upregulated the expression of ZO-1 and Occludin, thus contributing to repair the intestinal barrier. Additionally, Aj-FUC increased the content of short-chain fatty acids (SCFAs) and regulated the imbalance in gut microbiota. These results suggested that Aj-FUC alleviates ALD by modulating the gut-liver axis homeostasis. It may prove to be a useful dietary supplement in the treatment of alcoholic liver damage.


Assuntos
Homeostase , Hepatopatias Alcoólicas , Fígado , Estresse Oxidativo , Polissacarídeos , Stichopus , Animais , Hepatopatias Alcoólicas/tratamento farmacológico , Hepatopatias Alcoólicas/metabolismo , Hepatopatias Alcoólicas/patologia , Polissacarídeos/farmacologia , Polissacarídeos/química , Camundongos , Masculino , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Homeostase/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Stichopus/química , Camundongos Endogâmicos BALB C , Malondialdeído/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Glutationa/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Modelos Animais de Doenças , Glutationa Peroxidase/metabolismo
20.
Phytomedicine ; 130: 155774, 2024 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-38820659

RESUMO

BACKGROUND: Metabolic and alcohol-associated liver disease (MetALD) shows a high prevalence rate in liver patients, but there is currently no effective treatment for MetALD. As a typical edible traditional Chinese medicinal herb, the anti-inflammatory, antioxidant, and hepatoprotective properties of water extract of Chrysanthemum morifolium Ramat. (WECM) has been demonstrated. However, its therapeutic effect on MetALD and the associated mechanisms remain unclear. PURPOSE: To investigate the underlying mechanisms of WECM against MetALD. METHODS: We constructed a MetALD rat model following a high-fat & high-sucrose plus alcohol diet (HFHSAD). MetALD rats were treated with WECM at 2.1, 4.2, and 8.4 g/kg/d for six weeks. Efficacy was determined, and pathways associated with WECM against MetALD were predicted through serum and hepatic biochemical marker measurement, histopathological section analysis, 16S rDNA sequencing of the gut microbiota and untargeted serum metabolomics analyses. Changes in genes and proteins in the peroxisome proliferator-activated receptor alpha (PPARα) and gamma (PPARγ) signaling pathways were detected by RT‒PCR and Western blotting. RESULTS: WECM treatment significantly attenuated hepatic steatosis, hyperlipidemia and markers of liver injury in MetALD rats. Moreover, WECM improved vascular endothelial function, hypertension, and systematic oxidative stress. Mechanistically, WECM treatment altered the overall structure of the gut microbiota through maintaining Firmicutes/Bacteroidota ratio and reducing harmful bacterial abundances such as Clostridium, Faecalibaculum, and Herminiimonas. Notably, WECM promoted 15-deoxy-△12, 14-prostaglandin J2 (15d-PGJ2) release and further activated the PPARγ to reduce serum TNF-α, IL-1ß, and IL-6 levels. Additionally, WECM upregulated PPARα and downregulated the levels of CD36 and FABP4 to improve lipid metabolism. CONCLUSION: Our findings provide the first evidence that WECM treatment significantly improved hepatic steatosis, oxidative stress and inflammation in MetALD rats by regulating the gut microbiota and activating the 15d-PGJ2/PPARγ and PPARα signaling pathway.


Assuntos
Chrysanthemum , Microbioma Gastrointestinal , Hepatopatias Alcoólicas , PPAR alfa , PPAR gama , Ratos Sprague-Dawley , Chrysanthemum/química , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , PPAR gama/metabolismo , PPAR alfa/metabolismo , Masculino , Hepatopatias Alcoólicas/tratamento farmacológico , Dieta Hiperlipídica/efeitos adversos , Ratos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Extratos Vegetais/farmacologia , Modelos Animais de Doenças , Transdução de Sinais/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Estresse Oxidativo/efeitos dos fármacos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...