Assuntos
Carcinoma Neuroendócrino/genética , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/metabolismo , Neoplasias do Colo do Útero/genética , Carcinoma Neuroendócrino/metabolismo , Carcinoma Neuroendócrino/patologia , Análise Mutacional de DNA , Feminino , Expressão Gênica , Humanos , Gradação de Tumores , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/patologiaRESUMO
Autophagy serves a role in preserving cellular homeostasis. Diabetes mellitus (DM) impairs cardiac autophagy and is associated with an accumulation of cytotoxic proteins that may provoke apoptosis and damage cardiomyocytes. Histone deacetylase (HDAC) inhibitors attenuate cardiac fibrosis and inflammation, and improve cardiomyopathy resulting from DM. However, the effect of HDAC inhibition on autophagy in DM cardiomyopathy has not been investigated. The purpose of the present study was to evaluate whether HDAC inhibition modulates cardiac autophagy and to investigate the potential mechanisms in type 2 DM (T2DM) hearts. Electrocardiography was used to evaluate cardiac function and western blotting was used to evaluate protein expression in autophagy, the serine/threonine protein kinase mTOR (mTOR) signaling pathway, poly adenosine diphosphate ribose polymerase 1 (PARP1), insulin signaling, advanced glycosylation end productspecific receptor (RAGE), and proinflammatory cytokines in control rats and in rats treated with a highfat diet (60% fat) and lowdose streptozotocin (35 mg/kg) in order to induce T2DM, with or without an HDAC inhibitor (MPT0E014; 50 mg/kg/rat daily for 7 days). Compared with the control rats, T2DM and T2DM rats treated with MPT0E014 exhibited elevated blood glucose levels and similar body weights. However, T2DM rats treated with MPT0E014 and control rats had a smaller left ventricular enddiastolic diameter compared with the T2DM rats. The control and T2DM rats treated with MPT0E014 had greater protein expression of cardiac phosphorylated (p)5' adenosine monophosphateactivated protein kinase α 2, light chain 3II, Beclin1, glucose transporter 4, pprotein kinase B, and insulin receptor substrate1 (Ser 307) compared with T2DM rats. In addition, control and T2DM rats treated with MPT0E014 had decreased cardiac protein expression of cleaved PARP1, pmTORS2448, pP70S6KThr389, RAGE, tumor necrosis factorα, and interleukin6 compared with T2DM rats. The present study demonstrated that MPT0E014 may improve cardiac function in T2DM rats by modulating myocardial autophagy, inflammation and insulin signaling.
Assuntos
Autofagia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/metabolismo , Dieta Hiperlipídica , Inibidores de Histona Desacetilases/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Animais , Biomarcadores , Citocinas/metabolismo , Diabetes Mellitus Experimental , Coração/efeitos dos fármacos , Coração/fisiopatologia , Testes de Função Cardíaca , Ácidos Hidroxâmicos/farmacologia , Indóis/farmacologia , Mediadores da Inflamação/metabolismo , Insulina/metabolismo , Masculino , Miocárdio/metabolismo , Ratos , Estreptozocina/efeitos adversosRESUMO
BACKGROUND: HER2 gene amplification and HER2 protein overexpression are important factors in predicting clinical sensitivity to anti-HER2 monoclonal antibody therapy in breast cancer patients. The purpose of this study is to evaluate the correlation between HER2 protein expressions and the HER2 gene copies per tumor cell either before or after chromosome-17 correction in epithelial ovarian cancer (EOC). METHODS: Adopting 2007 ASCO/CAP guideline recommendations for HER2 testing, 27 tissue microarray (TMA) samples from EOC patients were analyzed by immunohistochemistry (IHC) using Dako, c-erb-B2 antibody and subsequently examined by fluorescence in situ hybridization (FISH) using Abbott/Vysis, PathVysion HER2 DNA Probe Kit. RESULTS: The overall concordance revealed 81.5% between HER2 IHC and HER2 FISH results. Additionally, HER2 gene copies prior to chromosome-17 correction increased significantly in a stepwise order through the negative, equivocal, and positive IHC result categories (P = 0.026), as did the HER2 gene copies after chromosome-17 correction (P = 0.028). On the other hand, HER2 IHC results correlated significantly with both chromosome-17 uncorrected HER2 gene copy numbers (ρ = 0.430, P = 0.025) and chromosome-17 corrected HER2 gene copy numbers (ρ = 0.524, P = 0.027). CONCLUSION: We demonstrated that both chromosome-17 corrected and uncorrected HER2 gene copies correlated significantly with HER2 IHC result categories; and tests for the HER2 gene copies per tumor cell either before or after correction for chromosome-17 can be applied as a potentially valuable tool in analyzing the HER2 status in EOC.