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1.
Environ Toxicol Pharmacol ; 85: 103624, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33617954

RESUMO

Cardiotoxicity is one of the primary limitations in the clinical use of the anticancer drug doxorubicin (DOX). However, the role of microRNAs (miRNAs) in DOX-induced cardiomyocyte death has not yet been covered. To investigate this, we observed a significant increase in miR-98 expression in neonatal rat ventricular myocytes after DOX treatment, and MTT, LIVE/Dead and Viability/Cytotoxicity staining showed that miR-98 mimic inhibited DOX-induced cell death. This was also confirmed by Flow cytometry and Annexin V-FITC/PI staining. Interestingly, the protein expression of caspase-8 was upregulated by miR-98 mimics during this process, whereas Fas and RIP3 were downregulated. In addition, the effect of miR-98 against the expression of Fas and RIP3 were restored by the specific caspase-8 inhibitor Z-IETD-FMK. Thus, we demonstrate that miR-98 protects cardiomyocytes from DOX-induced injury by regulating the caspase-8-dependent Fas/RIP3 pathway. Our findings enhance understanding of the therapeutic role of miRNAs in the treatment of DOX-induced cardiotoxicity.


Assuntos
Antibióticos Antineoplásicos , Cardiotoxicidade/genética , Caspase 8/metabolismo , Doxorrubicina , MicroRNAs , Miócitos Cardíacos/metabolismo , Animais , Cardiotoxicidade/metabolismo , Sobrevivência Celular , Células Cultivadas , Potencial da Membrana Mitocondrial , Miócitos Cardíacos/fisiologia , Ratos Sprague-Dawley , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Transdução de Sinais , Receptor fas/metabolismo
2.
FASEB J ; 34(8): 10168-10181, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32562311

RESUMO

Enhancer of zeste homolog 2 (EZH2), a well-known methyltransferase, mediates histone H3 lysine 27 trimethylation (H3K27me3) and plays a vital role in ophthalmological disease. However, its role in corneal neovascularization (CoNV) remains unclear. In vitro and in vivo models were assessed in hypoxia-stimulated angiogenesis and in a mouse model of alkali burn-induced CoNV. Human umbilical vein endothelial cells (HUVECs) were cultured under hypoxic conditions and different reoxygenation times to identify the molecular mechanisms involved in this process. In this study, we found that EZH2 was positively related to corneal alkali burn-induced injury. Inhibition of EZH2 with 3-Deazaneplanocin A (DZNeP) alleviated corneal injury, including oxidative stress and neovascularization in vivo. Similarly, inhibition of EZH2 with either DZNeP or small interfering RNA (siRNA) exerted an inhibitory effect on hypoxia/reoxygenation (H/R)-induced oxidative stress and angiogenesis in HUVECs. Moreover, our study revealed that ablation of reactive oxygen species (ROS) with N-acetyl-cysteine suppressed angiogenesis in HUVECs exposed to H/R stimulation. Furthermore, Forkhead-box protein O3a (FoxO3a), which was positively associated with ROS production and angiogenesis, was elevated during H/R. This effect could be reversed through the suppression of the transcription activity of EZH2 with DZNeP or siRNA. In addition, the PI3K/Akt pathway, which is the upstream of FoxO3a, was activated in both DZNeP-treated mice and EZH2-inhibited HUVECs. Collectively, our results demonstrated that the inhibition of EZH2 alleviated corneal angiogenesis by inhibiting FoxO3a-dependent ROS production through the PI3K/Akt signaling pathway. These findings indicate that EZH2 may be a valuable therapeutic target for CoNV.


Assuntos
Adenosina/análogos & derivados , Neovascularização da Córnea/tratamento farmacológico , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Proteína Forkhead Box O3/metabolismo , Neovascularização Patológica/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Adenosina/farmacologia , Animais , Células Cultivadas , Neovascularização da Córnea/metabolismo , Modelos Animais de Doenças , Células Endoteliais da Veia Umbilical Humana , Humanos , Hipóxia/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neovascularização Patológica/metabolismo , Estresse Oxidativo/fisiologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Interferente Pequeno/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Transcrição Gênica/efeitos dos fármacos , Transcrição Gênica/fisiologia
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