RESUMO
Adipogenesis is closely related to various metabolic diseases, such as obesity, type 2 diabetes, cardiovascular diseases and cancer. This cellular process is highly dependent on the expression and sequential activation of a diverse group of transcription factors. Here, we report that ADAR1 (also known as ADAR) could inhibit adipogenesis through binding with Dicer (also known as DICER1), resulting in enhanced production of miR-155-5p, which downregulates the adipogenic early transcription factor C/EBPß. Consequently, the expression levels of late-stage adipogenic transcription factors (C/EBPα and PPARγ) are reduced and adipogenesis is inhibited. More importantly, in vivo studies reveal that overexpression of ADAR1 suppresses white adipose tissue expansion in high fat diet-induced obese mice, leading to improved metabolic phenotypes, such as insulin sensitivity and glucose tolerance.
Assuntos
Adenosina Desaminase , Adipogenia , RNA Helicases DEAD-box , MicroRNAs , Obesidade , Ribonuclease III , Células 3T3-L1 , Adenosina Desaminase/genética , Adenosina Desaminase/metabolismo , Adipogenia/genética , Tecido Adiposo , Animais , Proteína alfa Estimuladora de Ligação a CCAAT/genética , Proteína alfa Estimuladora de Ligação a CCAAT/metabolismo , Diferenciação Celular , RNA Helicases DEAD-box/genética , RNA Helicases DEAD-box/metabolismo , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Obesidade/genética , Obesidade/metabolismo , PPAR gama/metabolismo , Ribonuclease III/genética , Ribonuclease III/metabolismoRESUMO
Endotoxin-induced acute liver injury (ALI) is a severe disease associated with a poor prognosis. Therefore, it is urgent to discover new effective therapies to prevent ALI. Daidzein, extracted from leguminous plants, possess anti-inflammatory and antioxidative bioactivities. However, little is known about whether daidzein could attenuate lipopolysaccharide (LPS)-induced ALI. We investigated the effects of daidzein on hepatocyte injury and its underlying mechanisms. In LPS-induced hepatocyte supernatant, 100 µM daidzein decreased ALT and AST expression levels by 49.3% ± 5.6% and 39.3% ± 3.5%, respectively, with no cytotoxicity. In addition, the expression of inflammatory factors, including interleukin-1ß (IL-lß), interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α) were decreased by 100 µM daidzein (73.8% ± 5.3%, 58.8 ± 9.0% and 55.5% ± 7.2%, respectively) in LPS-treated hepatocytes. Western blot analysis showed that daidzein inhibited LPS-induced p-ERK1/2, p-IκBα and p-p65 expression levels. Moreover, 100 µM daidzein reduced the LPS-induced production of Reactive oxygen species by 23.9 ± 7.8% and increased SOD activity by 88.4% ± 18.9% by downregulating Keap-1 and upregulating Nrf2 expression. In conclusion, these data indicate that daidzein ameliorates LPS-induced hepatocyte injury by inhibiting inflammation and oxidative stress.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Estrogênios não Esteroides/farmacologia , Estrogênios não Esteroides/uso terapêutico , Hepatócitos/patologia , Isoflavonas/uso terapêutico , Lipopolissacarídeos , Estresse Oxidativo/efeitos dos fármacos , Alanina Transaminase/sangue , Animais , Antioxidantes/farmacologia , Aspartato Aminotransferases/sangue , Doença Hepática Induzida por Substâncias e Drogas/patologia , Citocinas/biossíntese , Citocinas/efeitos dos fármacos , Isoflavonas/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Cultura Primária de Células , Fator de Transcrição RelA/efeitos dos fármacosRESUMO
The aim of this study was to investigate the effect of WR2721(amifostine) against bone marrow hematopoietic damage of mice exposed to 6.5 Gy of (60)Co-γ ray. A total of 60 C57/BL6J mice was divided into 3 groups:normal group (mice were injected with physiological salt solution), irradiation group (mice were injected with physiologic salt solution before irradiation) and WR2721 group (mice were injected with WR2721 before irradiation). The WBC, neutrophil (Neut), Plt and RBC levels in peripheral blood of 3 group mice were counted within 60 days after irradiation; the bone marrow nuclear cells (BMNC) were counted at 2 and 24 hours after irradiation; the hematopoietic stem/progenitor cell (LK/LSK) level and colony formation capability were detected by flow cytometry at 2 and 24 hours after irradiation. The results indicated that the counts of WBC and neut at 4 and 18 days, Plt at 7-18 days and RBC at 10-30 day after irradiation in WR2721 group were higher than those in irradiation group (P < 0.05); the BMNC, LSK and LK levels obviously increased at 24 hours after irradiation (P < 0.05), the CFU-GEMM, CFU-GM, CFU-MK BFU-E and CFU-E all significantly increased at 2 and 24 hours after irradiation (P < 0.01), as compared with irradiation group. It is concluded that WR2721 can effectively alleviate early hematopoietic damage and promote the fast recovery of peripheral blood cells in mice exposed to γ-ray, suggesting that the WR2721 has significant radioprotective effect on hematopoietic system.