Use of p38 MAPK Inhibitors for the Treatment of Werner Syndrome.
Use of p38 MAPK Inhibitors for the Treatment of Werner Syndrome.
复制标题
使用 p38 MAPK 抑制剂治疗维尔纳综合征。
DOI：
10.3390/ph3061842
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发表时间：
2010-06-04
期刊：
影响因子：
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通讯作者：
Kipling D
中科院分区：
文献类型：
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作者：
Bagley MC;Davis T;Murziani PG;Widdowson CS;Kipling D
维尔纳综合征为正常衰老表型的各个方面提供了令人信服的模型，并可能为旨在对抗衰老过程的治疗干预提供合适的模型。体外培养的Werner综合征患者原代成纤维细胞为研究体外复制性衰老与体内病理生理之间的联系提供了一个强大的模型系统。基因组不稳定，加上促氧化状态的增加，以及频繁的复制叉停滞，都为Werner综合征细胞内应激提供了可能的触发因素，并暗示p38 MAPK信号在其复制寿命缩短中起作用。利用微波加热技术快速高效地制备了多种不同的p38 MAPK抑制剂化学型，用于Werner综合征细胞的生物学研究，包括SB203580、VX-745、RO3201195、UR-13756和BIRB 796，并在细胞环境下评估了它们的选择性和效价。用p38 MAPK抑制剂治疗的维尔纳综合征成纤维细胞显示出意想不到的加速衰老表型逆转。因此，p38抑制及其对Werner病理生理的影响的研究可能为未来细胞衰老和人类衰老的生物学机制提供新的启示。
Werner syndrome provides a convincing model for aspects of the normal ageing phenotype and may provide a suitable model for therapeutic interventions designed to combat the ageing process. Cultured primary fibroblast cells from Werner syndrome patients provide a powerful model system to study the link between replicative senescence in vitro and in vivo pathophysiology. Genome instability, together with an increased pro-oxidant state, and frequent replication fork stalling, all provide plausible triggers for intracellular stress in Werner syndrome cells, and implicates p38 MAPK signaling in their shortened replicative lifespan. A number of different p38 MAPK inhibitor chemotypes have been prepared rapidly and efficiently using microwave heating techniques for biological study in Werner syndrome cells, including SB203580, VX-745, RO3201195, UR-13756 and BIRB 796, and their selectivity and potency evaluated in this cellular context. Werner syndrome fibroblasts treated with a p38 MAPK inhibitor reveal an unexpected reversal of the accelerated ageing phenotype. Thus the study of p38 inhibition and its effect upon Werner pathophysiology is likely to provide new revelations into the biological mechanisms operating in cellular senescence and human ageing in the future.