RESUMO
Brain iron levels are significantly increased in Parkinson's disease (PD) and iron deposition is observed in the substantia nigra (SN) of PD patients. It is unclear whether iron overload is an initial cause of dopaminergic neuronal death or merely a byproduct that occurs in the SN of PD patients. In this study, ceruloplasmin knockout (CP-/-) mice and mice receiving an intracerebroventricular injection of ferric ammonium citrate (FAC) were selected as mouse models with high levels of brain iron. These mice were administered with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) by intraperitoneal injection. Their behavior and the dopaminergic neuron damage to their substantia nigra pars compacta (SNpc) were assessed. These findings suggest that the injection of FAC or the absence of the CP gene may exacerbate both the observed apoptosis of TH-positive neurons and the behavioral symptoms of the MPTP-treated mice. The intracerebroventricular injection of deferoxamine (DFO) significantly alleviated the neuronal damage caused by MPTP in CP-/- mice. Furthermore, our findings suggest that the increased nigral iron content exacerbates the oxidative stress levels, promoting apoptosis through the Bcl-2/Bax pathway and the activated caspase-3 pathway in the brain. Therefore, iron overload in the brain exacerbates dopaminergic neuronal death in SNpc and leads to the onset of PD.
Assuntos
Encéfalo/fisiopatologia , Ferro/metabolismo , Intoxicação por MPTP/fisiopatologia , Animais , Antiparkinsonianos/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Encéfalo/efeitos dos fármacos , Caspase 3/metabolismo , Ceruloplasmina/deficiência , Ceruloplasmina/genética , Desferroxamina/farmacologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/fisiologia , Compostos Férricos , Intoxicação por MPTP/tratamento farmacológico , Masculino , Camundongos Endogâmicos BALB C , Camundongos Knockout , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Compostos de Amônio Quaternário , Tirosina 3-Mono-Oxigenase/metabolismo , Proteína X Associada a bcl-2/metabolismoRESUMO
Recently, a novel class of transcripts, long non-coding RNAs (lncRNAs), is being identified at a rapid pace. These RNAs have critical roles in diverse biological processes, including tumorigenesis. Here we report that taurine-upregulated gene 1 (TUG1), a 7.1-kb lncRNA, recruiting and binding to polycomb repressive complex 2 (PRC2), is generally downregulated in non-small cell lung carcinoma (NSCLC) tissues. In a cohort of 192 NSCLC patients, the lower expression of TUG1 was associated with a higher TNM stage and tumor size, as well as poorer overall survival (P<0.001). Univariate and multivariate analyses revealed that TUG1 expression serves as an independent predictor for overall survival (P<0.001). Further experiments revealed that TUG1 expression was induced by p53, and luciferase and chromatin immunoprecipitation (ChIP) assays confirmed that TUG1 was a direct transcriptional target of p53. TUG1 knockdown significantly promoted the proliferation in vitro and in vivo. Moreover, the lncRNA-mediated regulation of the expression of HOX genes in tumorigenesis and development has been recently receiving increased attention. Interestingly, inhibition of TUG1 could upregulate homeobox B7 (HOXB7) expression; ChIP assays demonstrated that the promoter of HOXB7 locus was bound by EZH2 (enhancer of zeste homolog 2), a key component of PRC2, and was H3K27 trimethylated. This TUG1-mediated growth regulation is in part due to specific modulation of HOXB7, thus participating in AKT and MAPK pathways. Together, these results suggest that p53-regulated TUG1 is a growth regulator, which acts in part through control of HOXB7. The p53/TUG1/PRC2/HOXB7 interaction might serve as targets for NSCLC diagnosis and therapy.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Proliferação de Células , Epigênese Genética , Proteínas de Homeodomínio/metabolismo , Neoplasias Pulmonares/metabolismo , RNA Longo não Codificante/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Sítios de Ligação , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Imunoprecipitação da Cromatina , Proteína Potenciadora do Homólogo 2 de Zeste , Feminino , Regulação Neoplásica da Expressão Gênica , Histonas/metabolismo , Proteínas de Homeodomínio/genética , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Metilação , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Análise Multivariada , Estadiamento de Neoplasias , Complexo Repressor Polycomb 2/metabolismo , RNA Longo não Codificante/genética , Elementos de Resposta , Fatores de Risco , Transdução de Sinais , Fatores de Tempo , Transcrição Gênica , Transfecção , Carga Tumoral , Proteína Supressora de Tumor p53/genéticaRESUMO
The results of an experimental study in rats fed with Equisetum hyemale and hyperlipid food have proved that inhibiting effects on the elevation of triglyceride and cholesterol can be obviously observed in both high and low doses of Equisetum. The study also shows that Equisetum hyemale can antagonize the hyperlipemia in rats. The acute toxic test has proved its low toxicity.
