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991.
Yu-Chi Chou Ruei-Lin Chen Zheng-Sheng Lai Jen-Shin Song Yu-Sheng Chao Che-Kun James Shen 《Molecular and cellular biology》2015,35(14):2541-2553
Pharmacological induction of the fetal γ globin gene and the consequent formation of HbF (α2/γ2) in adult erythroid cells are one feasible therapeutic strategy for sickle cell disease (SCD) and severe β-thalassemias. Hydroxyurea (HU) is the current drug of choice for SCD, but serious side effects limit its clinical use. Moreover, 30 to 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 to VI) as potent γ globin inducers. Of the compounds, I to V exert superior γ globin induction and have better therapeutic potential than HU, likely because of their activation of the p38 mitogen-activated protein kinase (MAPK) signaling pathway and modulation of expression levels and/or chromosome binding of γ globin gene regulators, including BCL11A, and chromatin structure over the γ 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 γ globin gene in HU-resistant primary human adult erythroid cells, the p38 signaling pathway of which appears to be irresponsive to HU and NaB as well as compound II. This study provides a new framework for the development of new and superior compounds for treating SCD and severe β-thalassemias. 相似文献
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Okazaki fragment maturation involves α-segment error editing by the mammalian FEN1/MutSα functional complex 下载免费PDF全文
Songbai Liu Guojun Lu Shafat Ali Wenpeng Liu Li Zheng Huifang Dai Hongzhi Li Hong Xu Yuejin Hua Yajing Zhou Janice Ortega Guo-Min Li Thomas A Kunkel Binghui Shen 《The EMBO journal》2015,34(13):1829-1843
During nuclear DNA replication, proofreading-deficient DNA polymerase α (Pol α) initiates Okazaki fragment synthesis with lower fidelity than bulk replication by proofreading-proficient Pol δ or Pol ε. Here, we provide evidence that the exonuclease activity of mammalian flap endonuclease (FEN1) excises Pol α replication errors in a MutSα-dependent, MutLα-independent mismatch repair process we call Pol α-segment error editing (AEE). We show that MSH2 interacts with FEN1 and facilitates its nuclease activity to remove mismatches near the 5′ ends of DNA substrates. Mouse cells and mice encoding FEN1 mutations display AEE deficiency, a strong mutator phenotype, enhanced cellular transformation, and increased cancer susceptibility. The results identify a novel role for FEN1 in a specialized mismatch repair pathway and a new cancer etiological mechanism. 相似文献
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A novel chiral sensing platform, employing silver nanoparticles capped with N‐acetyl‐L‐cysteine (NALC‐Ag NPs), was utilized for the discrimination of L‐tyrosine and D‐tyrosine. This nanosensor, which could be used as an optical sensing unit and chiral probe, was characterized by transmission electron microscopy (TEM) and resonance Rayleigh scattering (RRS) spectroscopy. After the proposed sensing platform interacted with L‐tyrosine and D‐tyrosine, a decreased resonance scattering signal was only obtained from L‐tyrosine. This phenomenon offered a useful assay for the selectivity and determination of L‐tyrosine with the RRS method. The linear range and detection limit of L‐tyrosine were 0.2838–20.0 µg⋅mL‐1 and 0.0860 µg⋅mL‐1, respectively. In addition, experimental factors such as acidity, interaction time, and the concentration of enantiomers were investigated with regard to the effect on enantioselective interaction. Chirality 27:194–198, 2015. © 2014 Wiley Periodicals, Inc. 相似文献
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