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1.
Psychoneuroendocrinology ; 115: 104629, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32171900

RESUMO

OBJECTIVE: Prenatal stress (PS) contributes to depression-like behavior in the offspring. PDLIM5 is involved in the onset of mental disorders. This study is to investigate the role and mechanism of PDLIM5 in depression-like behavior of PS offspring rats. METHODS: PS model was used to analyze the effects of different treatments to PS offspring rats with different sex, including PDLIM5, PDLIM5 shRNA and 5-aza-2' -deoxycytidine (5-azaD). The depression-like behavior was assessed by the sucrose preference test (SPT) and forced swimming test (FST). The mRNA and protein expression levels of PDLIM5 in the hippocampus of PS offspring rats were detected by qRT-PCR and western blot, respectively. The methylation of PDLIM5 promoter were analyzed by bisulfite sequencing. RESULTS: Our data revealed that PS offspring rats showed a significant decrease in sucrose preference and a prolonged immobility time. Injection of PDLIM5 significantly improved the depression-like behavior in PS offspring rats, whereas administration of PDLIM5 shRNA aggravated it. In addition, PDLIM5 expression was decreased at the mRNA and protein levels, and the methylation level of PDLIM5 promoter was increased in hippocampus of PS male but not female offspring rats. Furthermore, microinjection of 5-azaD improved the PS induced depression-like behavior in offspring rats. Moreover, in male PS offspring rats, microinjection of 5-azaD reversed the effect of PS on PDLIM5 expression and promoter methylation. CONCLUSION: PDLIM5 can significantly improve the depression-like behavior of both male and female PS offspring rats, while the PDLIM5 promoter methylation is only observed in male PS offspring rats. Our study may provide new mechanism for the pathogenesis of depression and experimental evidence for sex-based precise treatment.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/farmacologia , Comportamento Animal/efeitos dos fármacos , Depressão/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Proteínas com Domínio LIM/farmacologia , Complicações na Gravidez , Efeitos Tardios da Exposição Pré-Natal/tratamento farmacológico , Caracteres Sexuais , Estresse Psicológico , Proteínas Adaptadoras de Transdução de Sinal/administração & dosagem , Animais , Metilação de DNA/genética , Modelos Animais de Doenças , Epigênese Genética/genética , Feminino , Proteínas com Domínio LIM/administração & dosagem , Masculino , Gravidez , Regiões Promotoras Genéticas/genética , RNA Interferente Pequeno , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes
2.
J Exp Clin Cancer Res ; 37(1): 228, 2018 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-30219064

RESUMO

BACKGROUND: In this research, we aimed to investigate the biological functions of LIM domain only 3 (LMO3) in hepatocellular carcinoma (HCC) and uncover the underlying molecular mechanism in it. METHODS: HCC tissue microarray (n = 180) was used to analyze the correlation between LMO3 expression and clinicopathological findings. In vitro transwell matrigel invasion assay and annexin V anoikis assay in HCC cells were conducted to investigate LMO3 related biological functions. In vivo intrahepatic and lung metastasis models were used to determine the role of LMO3 in HCC metastasis. Quantitative real-time PCR, western blotting and immunohistochemical staining were performed to investigate the expression and mechanism of LMO3 in HCC. RESULTS: We found that the expression of LMO3 was significantly upregulated in HCC tissues, and it was closely related to clinicopathological findings and patient prognoses. Knockdown of LMO3 suppressed the invasion and anoikis inhibition of HCC cells in vitro. Meanwhile, the metastasis of SMMC-7721 cells was also suppressed by LMO3 knockdown in vivo. Furthermore, we found that LMO3 knockdown increased the phosphorylation of YAP and LATS1, and decrease Rho GTPases activities. LMO3 directly interacted with LATS1, and thus suppressed Hippo signaling. Recombinant LMO3 (rLMO3) protein administration decreased the phosphorylation of YAP and LATS1, and increased Rho GTPases activities. The inhibitors of the Hippo pathway abrogated rLMO3 protein-induced HCC cell invasion and anoikis inhibition. CONCLUSIONS: These results suggest that LMO3 promotes HCC cell invasion and anoikis inhibition by interacting with LATS1 and suppressing Hippo signaling. LMO3 may serve as a potential therapeutic target for HCC in future.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Carcinoma Hepatocelular/genética , Proteínas com Domínio LIM/genética , Neoplasias Hepáticas/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Adaptadoras de Transdução de Sinal/administração & dosagem , Anoikis/efeitos dos fármacos , Anoikis/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Via de Sinalização Hippo , Humanos , Proteínas com Domínio LIM/administração & dosagem , Neoplasias Hepáticas/patologia , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Metástase Neoplásica , Fosfoproteínas/genética , Fosforilação , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Fatores de Transcrição , Proteínas de Sinalização YAP
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