RESUMO
Hepatic stellate cells (HSCs) are critical regulator contributing to the onset and progression of liver fibrosis. Chronic liver injury triggers HSCs to undergo vast changes and trans-differentiation into a myofibroblast HSCs, the mechanism remains to be elucidated. This study investigated that the involvement of hydroxymethylase TET1 (ten-eleven translocation 1) in HSC activation and liver fibrosis. It is revealed that TET1 levels were downregulated in the livers in mouse models of liver fibrosis and patients with cirrhosis, as well as activated HSCs in comparison to quiescent HSCs. In vitro data showed that the inhibition of TET1 promoted the activation HSC, whereas TET1 overexpression inhibited HSC activation. Moreover, TET1 could regulate KLF2 (Kruppel-like transcription factors) transcription by promoting hydroxymethylation of its promoter, which in turn suppressed the activation of HSCs. In vivo, it is confirmed that liver fibrosis was aggravated in Tet1 knockout mice after CCl4 injection, accompanied by excessive activation of primary stellate cells, in contrast to wild-type mice. In conclusion, we suggested that TET1 plays a significant role in HSC activation and liver fibrosis, which provides a promising target for anti-fibrotic therapies.
Assuntos
Proteínas de Ligação a DNA , Modelos Animais de Doenças , Células Estreladas do Fígado , Cirrose Hepática , Proteínas Proto-Oncogênicas , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Animais , Cirrose Hepática/patologia , Cirrose Hepática/genética , Cirrose Hepática/metabolismo , Cirrose Hepática/etiologia , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas/genética , Humanos , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Camundongos Knockout , Camundongos , Masculino , Fatores de Transcrição Kruppel-Like/metabolismo , Fatores de Transcrição Kruppel-Like/genética , Camundongos Endogâmicos C57BL , Regulação para Baixo , Oxigenases de Função Mista/genética , Oxigenases de Função Mista/metabolismo , Células Cultivadas , Tetracloreto de CarbonoAssuntos
Dispepsia , Infecções por Helicobacter , Helicobacter pylori , Humanos , Dispepsia/tratamento farmacológico , Dispepsia/etiologia , Dispepsia/patologia , Metaloproteinase 9 da Matriz/uso terapêutico , Infecções por Helicobacter/complicações , Infecções por Helicobacter/tratamento farmacológico , Infecções por Helicobacter/patologiaRESUMO
Regulated cell death (RCD) is a ubiquitous process in living organisms that is essential for tissue homeostasis or to restore biological balance under stress. Over the decades, various forms of RCD have been reported and are increasingly being found to involve in human pathologies and clinical outcomes. We focus on five high-profile forms of RCD, including apoptosis, pyroptosis, autophagy-dependent cell death, necroptosis and ferroptosis. Cumulative evidence supports that not only they have different features and various pathways, but also there are extensive cross-talks between modes of cell death. As the understanding of RCD pathway in evolution, development, physiology and disease continues to improve. Here we review an updated classification of RCD on the discovery and features of processes. The prominent focus will be placed on key mechanisms of RCD and its critical role in neurodegenerative disease. Video abstract.
