國家衛生研究院 NHRI:Item 3990099045/8767
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    題名: Pharmacological induction of human fetal globin gene in hydroxyurea-resistant primary adult erythroid cells
    作者: Chou, YC;Chen, RL;Lai, ZS;Song, JS;Chao, YS;Shen, CK
    貢獻者: Institute of Biotechnology and Pharmaceutical Research
    摘要: Pharmacological induction of the fetal gamma globin gene and the consequent formation of HbF (alpha2/gamma2) in adult erythroid cells is one feasible therapeutic strategy for sickle cell disease (SCD) and severe beta-thalassemias. Hydroxyurea (HU) is the current drug of choice for SCD, but the serious side effects limit its clinical use. Moreover, 30-50% of patients are irresponsive to HU treatment. We have used high-throughput screening to identify benzo[de]benzo[4,5]imidazo[2,1-a]isoquinolin-7-one and its derivatives (compounds I-VI) as potent gamma globin-inducers. Of the compounds, I-V exert superior gamma globin-induction and better therapeutic potential than HU, likely because of their activation of the p38 MAPK signaling pathway, modulation of the expression levels and/or chromosome-binding of gamma globin gene regulators including BCL11A, as well as chromatin structure over the gamma globin promoter. Unlike sodium butyrate (NaB), the global levels of acetylated histones H3 and H4 are not changed by compound II treatment. Remarkably, compound II induces the gamma globin gene in HU-resistant primary human adult erythroid cells, the p38 signaling pathway of which appears to be irresponsive to HU, NaB, as well as compound II. This study provides a new framework for the development of new and superior compounds for treating SCD and the severe beta-thalassemias.
    日期: 2015-07
    關聯: Molecular and Cellular Biology. 2015 Jul;35(14):2541-2553.
    Link to: http://dx.doi.org/10.1128/mcb.00035-15
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0270-7306&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000357457900014
    Cited Times(Scopus): http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=84932621889
    顯示於類別:[趙宇生(2002-2013)] 期刊論文

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