RESUMO
Up-regulation of utrophin in muscles represents a promising therapeutic strategy for the treatment of Duchenne Muscular Dystrophy. We previously demonstrated that eEF1A2 associates with the 5'UTR of utrophin A to promote IRES-dependent translation. Here, we examine whether eEF1A2 directly regulates utrophin A expression and identify via an ELISA-based high-throughput screen, FDA-approved drugs that upregulate both eEF1A2 and utrophin A. Our results show that transient overexpression of eEF1A2 in mouse muscles causes an increase in IRES-mediated translation of utrophin A. Through the assessment of our screen, we reveal 7 classes of FDA-approved drugs that increase eEF1A2 and utrophin A protein levels. Treatment of mdx mice with the 2 top leads results in multiple improvements of the dystrophic phenotype. Here, we report that IRES-mediated translation of utrophin A via eEF1A2 is a critical mechanism of regulating utrophin A expression and reveal the potential of repurposed drugs for treating DMD via this pathway.
Assuntos
Distrofia Muscular de Duchenne/tratamento farmacológico , Fator 1 de Elongação de Peptídeos/antagonistas & inibidores , Biossíntese de Proteínas/efeitos dos fármacos , Utrofina/genética , Regiões 5' não Traduzidas/genética , Animais , Betaxolol/farmacologia , Betaxolol/uso terapêutico , Linhagem Celular , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Reposicionamento de Medicamentos , Humanos , Sítios Internos de Entrada Ribossomal/genética , Camundongos , Camundongos Endogâmicos mdx , Camundongos Knockout , Distrofia Muscular de Duchenne/genética , Mioblastos , Fator 1 de Elongação de Peptídeos/genética , Fator 1 de Elongação de Peptídeos/metabolismo , Pravastatina/farmacologia , Pravastatina/uso terapêutico , Biossíntese de Proteínas/genética , Regulação para Cima/efeitos dos fármacos , Utrofina/metabolismoRESUMO
Administration of vitamin E in children with immunoglobulin A (IgA) nephropathy, focal segmental glomerulosclerosis (FSGS) and type I diabetes demonstrated potential towards ameliorating progression. Oral vitamin E therapy reduced endothelial dysfunction, lipid peroxidation and oxidative stress in patients with chronic kidney failure (CKF). Moreover, the use of vitamin E-bonded hemodialyzers reduced atherosclerotic changes, erythropoietin dosage and muscular cramps in patients on hemodialysis (HD). However, several controlled clinical trials failed to document beneficial effects on the study subjects' cardiovascular and renal outcomes. A recent report of increased all-cause mortality in adult patients receiving high dose vitamin E therapy has caused considerable concern and debate. These issues regarding the efficacy and safety of vitamin E in renal therapeutic regimens will be reviewed in this article.
Assuntos
Nefropatias/tratamento farmacológico , Vitamina E/uso terapêutico , Animais , HumanosRESUMO
Wyeth Research was developing apratastat (TMI-005), one in a series of dual TNFalpha-converting enzyme and matrix metalloprotease-13 inhibitors, for the potential treatment of inflammation, especially rheumatoid arthritis. By January 2005, apratastat had entered a phase II clinical trial; however, in October 2006, Wyeth reported that it had terminated development of the drug because of lack of efficacy in this trial.