Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 3 de 3
Filtrar
Mais filtros











Base de dados
Intervalo de ano de publicação
1.
Cell Death Discov ; 9(1): 311, 2023 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-37626043

RESUMO

Alcohol abuse is a significant cause of global morbidity and mortality, with alcoholic liver disease (ALD) being a common consequence. The pathogenesis of ALD involves various cellular processes, including oxidative stress, inflammation, and hepatic cell death. Recently, ferroptosis, an iron-dependent form of programmed cell death, has emerged as a potential mechanism in many diseases. However, the specific involvement and regulatory mechanisms of ferroptosis in ALD remain poorly understood. Here we aimed to investigate the presence and mechanism of alcohol-induced ferroptosis and the involvement of miRNAs in regulating ferroptosis sensitivity. Our findings revealed that long-term ethanol feeding induced ferroptosis in male mice, as evidenced by increased expression of ferroptosis-related genes, lipid peroxidation, and labile iron accumulation in the liver. Furthermore, we identified dysregulation of the methionine cycle and transsulfuration pathway, leading to severe glutathione (GSH) exhaustion and indirect deactivation of glutathione peroxidase 4 (GPx4), a critical enzyme in preventing ferroptosis. Additionally, we identified miR-214 as a ferroptosis regulator in ALD, enhancing hepatocyte ferroptosis by transcriptionally activating the expression of ferroptosis-driver genes. Our study provides novel insights into the involvement and regulatory mechanisms of ferroptosis in ALD, highlighting the potential therapeutic implications of targeting ferroptosis and miRNAs in ALD management.

2.
Biochem Pharmacol ; 188: 114582, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33895159

RESUMO

Cytochrome P450 (CYP) enzymes play critical roles in drug transformation, and the total CYPs are markedly decreased in alcoholic hepatitis (AH), a fatal alcoholic liver disease. miRNAs are endogenous small noncoding RNAs that regulate many essential biological processes. Knowledge concerning miRNA regulation of CYPs in AH disease is limited. Here we presented the changes of key CYPs in liver samples of AH patients retrieved from GEO database, performed in silico prediction of miRNAs potentially targeting the dysregulated CYP transcripts, and deciphered a novel mechanism underlying miRNA mediated CYPs expression in liver cells. Nine miRNAs were predicted to regulate CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2J2, and CYP3A4, among which hsa-miR-148a-3p was selected as a case study. Biochemical and molecular evidences demonstrated that miR-148a promoted CYP2B6 expression by increasing mRNA stability via directly binding to the 3'UTR sequence, and that this positive posttranscriptional regulation was AGO1/2-dependent. Further, luciferase reporter gene assay and RNA secondary structure analysis illustrated that the seedless target site, not the seed target site, controlled miR-148a-mediated CYP2B6 upregulation. Moreover, we identified HNF4A as a liver-specific transcription factor of MIR-148A through EMSA and chromatin immunoprecipitation experiments. In conclusion, ethanol downregulated miR-148a in hepatocytes through HNF4A regulation, which eventually decreased CYP2B6 expression. Our finding will benefit the understanding of dysregulated drug metabolism in AH patients and highlight an unconventional mechanism for epigenetic regulation of CYP gene expression.


Assuntos
Citocromo P-450 CYP2B6/metabolismo , Regulação para Baixo/fisiologia , Epigênese Genética/fisiologia , Hepatite Alcoólica/metabolismo , MicroRNAs/metabolismo , Citocromo P-450 CYP2B6/genética , Regulação para Baixo/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Etanol/toxicidade , Células HEK293 , Células Hep G2 , Hepatite Alcoólica/genética , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , MicroRNAs/genética
3.
Biochem Pharmacol ; 189: 114458, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33556337

RESUMO

The alcohol dehydrogenases (ADHs) and aldehyde dehydrogenases (ALDHs) play critical roles in alcoholism development and alcohol toxicology; however, few studies have focused on the miRNA-mediated mechanisms underlying the expressions of alcohol-metabolizing enzymes. In the present study, we showed the expression changes of each alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) in the liver samples of alcoholic hepatitis (AH) patients, and predicted the miRNAs targeting the dysregulated alcohol-metabolizing genes by a systematic in silico analysis. 13 miRNAs were predicted to regulate the expressions of ADH1A, ADH4, and ALDH2, respectively, with hsa-miR-148a-3p (miR-148a) showing the most significant down-regulation in AH patients. Following experimental evidence using HepG2 cells proved that miR-148a promoted ADH4 expression by directly binding to the coding sequence of ADH4 and increasing the mRNA stability via an AGO1-dependent manner. Additional assays showed that secondary structure of ADH4 transcript affected the target accessibility and binding of miR-148a-3p. In sum, our results suggest that the expressions of key alcohol-metabolizing enzymes are repressed in AH patients, and the non-canonical positive regulation of miR-148a on ADH4 reveals a new regulationary mechanism for ADH genes.


Assuntos
Álcool Desidrogenase/biossíntese , Proteínas Argonautas/metabolismo , Etanol/toxicidade , Fatores de Iniciação em Eucariotos/metabolismo , Regulação Enzimológica da Expressão Gênica , Hepatócitos/metabolismo , MicroRNAs/metabolismo , Álcool Desidrogenase/genética , Animais , Proteínas Argonautas/genética , Bases de Dados Genéticas , Fatores de Iniciação em Eucariotos/genética , Células HEK293 , Células Hep G2 , Hepatite Alcoólica/genética , Hepatite Alcoólica/metabolismo , Hepatócitos/efeitos dos fármacos , Humanos , Camundongos , MicroRNAs/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA