RESUMO
Metformin is a widelyused antidiabetic drug with hypoglycemic activity and previously described antiinflammatory properties. Previous studies have demonstrated that metformin attenuates endotoxic hepatitis, however the mechanisms remain unclear. Inflammation and coagulation are closely associated pathological processes, therefore the potential effects of metformin on key steps in activation of the coagulation system were further investigated in endotoxic hepatitis induced by lipopolysaccharide/Dgalactosamine (LPS/DGal). The current study demonstrated that treatment with metformin significantly suppressed the upregulation of tissue factor and plasminogen activator inhibitor1 in LPS/DGalexposed mice. In addition, a reduction in the expression of interleukin 6 and inhibition of nuclear translocation of nuclear factorκB were observed. These data indicate that the LPS/DGalinduced elevation of the stable protein level of hypoxia inducible factor 1α, the mRNA level of erythropoietin, vascular endothelial growth factor and matrix metalloproteinase3, and the hepatic level of lactic acid were also suppressed by metformin. The current study indicates that the suppressive effects of metformin on inflammationinduced coagulation may be an additional mechanism underlying the hepatoprotective effects of metformin in mice with LPS/DGalinduced fulminant hepatitis.
Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Galactosamina/efeitos adversos , Hepatite/tratamento farmacológico , Lipopolissacarídeos/efeitos adversos , Metformina/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Modelos Animais de Doenças , Eritropoetina/genética , Eritropoetina/metabolismo , Hepatite/etiologia , Hipoglicemiantes/farmacologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Inflamação/tratamento farmacológico , Interleucina-6/genética , Interleucina-6/metabolismo , Ácido Láctico/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Metaloproteinase 3 da Matriz/genética , Metaloproteinase 3 da Matriz/metabolismo , Camundongos , NF-kappa B/genética , NF-kappa B/metabolismo , Inibidor 1 de Ativador de Plasminogênio/genética , Inibidor 1 de Ativador de Plasminogênio/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Tromboplastina/genética , Tromboplastina/metabolismo , Regulação para Cima , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Apoptosis repressor with caspase recruitment domain (ARC), an anti-apoptotic protein, plays an important role in the regulation of apoptosis by blocking both the extrinsic and intrinsic death pathways. However, its regulatory mechanism remains largely undefined. Here, we reported that hypoxia up-regulated the expression of ARC in p53 deficient human colon cancer cells. Moreover, ARC is a direct target of the hypoxia-inducible factor 1 (HIF-1), a key transcriptional factor for the cellular response to hypoxia. Silencing the expression of HIF-1α in SW480 colon cancer cells by RNA interference abolished hypoxia induced ARC expression. Using luciferase reporter and ChIP assay, we showed that HIF-1α directly bound to hypoxia-responsive element located at -419 to -414 of ARC gene, which is essential for HIF-1-induced expression. As a result of the increased ARC expression, TRAIL-induced apoptosis was reduced by hypoxia. These discoveries would shed novel insights on the mechanisms for ARC expression regulation and hypoxia induced inactivation of the intrinsic death pathway.
Assuntos
Proteínas Reguladoras de Apoptose/genética , Neoplasias do Colo/genética , Regulação Neoplásica da Expressão Gênica , Fator 1 Induzível por Hipóxia/metabolismo , Proteínas Musculares/genética , Apoptose/genética , Hipóxia Celular/genética , Células HT29 , Humanos , Proteína Supressora de Tumor p53/genéticaRESUMO
BACKGROUND: The purpose of this study was to use an enzyme-linked immunosorbent assay (ELISA) to detect cyclin-dependent kinase inhibitor 2A (CDKN2A; also known as p16(INK4a)) in exfoliative cervical cells. CDKN2A is upregulated and considered as a surrogate marker for cervical intraepithelial neoplasia and cancer. METHODS: Liquid-based ThinPrep((R)) cytologic test (TCT) and ELISA were performed on 1356 specimens collected prior to biopsy. A cotton swab was used to gather exfoliative cells. A sandwich ELISA was performed to measure the amount of solublized CDKN2A protein. RESULTS: The sensitivity and specificity of the TCT for screening of cervical dysplasia and cancer were 82.93% and 88.11%, respectively. The sensitivity and specificity for measuring CDKN2A with ELISA to detect significant cervical disease were 87.80% and 92.43%, respectively. CDKN2A expression was correlated with the severity of cervical damage (r = 0.774; p < 0.001). CONCLUSION: The sensitivity and specificity of detecting CDKN2A expression with ELISA in exfoliative cervical cells was superior to TCT (p = 0.023 and p < 0.001, respectively). These results suggest that detecting CDKN2A with ELISA has the potential to become a new screening method for cervical cancer.
