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Mol Cell Endocrinol ; 392(1-2): 14-22, 2014 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-24859603


Poly(ADP-ribose) polymerase-1 (PARP-1) enzyme, as a sensor of DNA damage, could convert nicotinamide adenine dinucleotide (NAD) into long poly(ADP-ribose) chains and regulate many cellular processes, including DNA repair, gene transcription, cell survival and chromatin remodeling. However, excessive activation of PARP-1 depletes its substrate NAD and leads to cell death. Mounting evidences have shown that PARP-1 overactivation plays a pivotal role in the pathogenesis of cardiac hypertrophy and heart failure. In present study, a novel PARP-1 inhibitor AG-690/11026014 (6014) was identified based on virtual screening and validated by bioassay. Our results further showed that 6014 prevented the cardiomyocytes from AngII-induced hypertrophy, accompanying attenuation of the mRNA and protein expressions of atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP), and reduce in the cell surface area. Additionally, 6014 reversed the depletion ofcellular NAD and SIRT6 deacetylase activity induced by AngII in cardiomyocytes. These observations suggest that anti-hypertrophic effect of 6014 might be partially attributed to the rescue of NAD depletion and subsequent restoring of SIRT6 activity by inhibition of PARP-1. Moreover, 6014 attenuated the generation of oxidative stress via suppression of NADPH oxidase 2 and 4, which might probably contribute to the inhibition of PARP-1.

Cardiomegalia/enzimologia , Cardiomegalia/prevenção & controle , Cardiotônicos/uso terapêutico , Citoproteção/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Miócitos Cardíacos/patologia , Inibidores de Poli(ADP-Ribose) Polimerases , Tioglicolatos/farmacologia , Xantinas/farmacologia , Angiotensina II , Animais , Cardiotônicos/farmacologia , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/análise , Inibidores Enzimáticos/química , Humanos , Concentração Inibidora 50 , Glicoproteínas de Membrana/metabolismo , Simulação de Acoplamento Molecular , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/enzimologia , NAD/metabolismo , NADPH Oxidase 2 , NADPH Oxidase 4 , NADPH Oxidases/metabolismo , Poli(ADP-Ribose) Polimerases/metabolismo , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Proteínas Recombinantes/metabolismo , Sirtuínas/metabolismo , Tioglicolatos/análise , Tioglicolatos/química , Regulação para Cima/efeitos dos fármacos , Xantinas/análise , Xantinas/química
J Colloid Interface Sci ; 329(1): 48-53, 2009 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-18922543


High molecular weight powdery polyacrylonitrile (PAN) polymers were prepared by aqueous suspension polymerization employing itaconic acid (IA) as comonomer and alpha,alpha(')-azobisisobutyronitrile (AIBN) as initiator at 60 degrees C. PAN polymers obtained with different monomer ratios were characterized by EA, DSC, FTIR and XRD. It is investigated that the oxygen element content in PAN polymers increased with the increase of required IA amounts in the feed and heat-treatment temperatures. DSC curves of PAN copolymers exhibited the triplet character, owing to the exothermic cyclization and oxidative reactions during heat-treatment process. Introduction of IA in the feed relaxed exothermic reactions of PAN polymers under air atmosphere. Structure and crystallinity changes were affected by required IA amounts in the feed and enhancement of heat-treatment temperatures. The characteristic functional groups (including C[triple bond]N, C=O, CH(2)) presented in FTIR spectra of PAN polymers indicated copolymerization reaction of AN and IA. Existence of some organic groups (C-O, C=C and/or C=N) indicated formation of ladderlike structure during heat-treatment process. PAN homopolymer had the better crystallinity (mainly peak intensity and peak area around 2theta = 17 degrees) than most RT-PAN copolymers. When heat-treatment temperature is around 210 degrees C, peak intensity, peak area, L(c) and CI of HT-PAN polymers corresponding to samples 1# and 2# got maxima, while crystallinity became weak at higher heat-treatment temperatures.