Evaluating the Role of p38 MAPK in the Accelerated Cell Senescence of Werner Syndrome Fibroblasts.
Evaluating the Role of p38 MAPK in the Accelerated Cell Senescence of Werner Syndrome Fibroblasts.
复制标题
DOI：
10.3390/ph9020023
复制
发表时间：
2016-04-28
期刊：
影响因子：
--
通讯作者：
Kipling D
中科院分区：
文献类型：
--
作者：
Davis T;Brook AJ;Rokicki MJ;Bagley MC;Kipling D
类早衰综合征表现出加速衰老的特征，并被用作人类衰老的模型，其中Werner综合征（WS）是研究最广泛的一种。WS成纤维细胞显示加速衰老，这可能是由p38 MAP激酶激活引起的，因为它被p38抑制剂SB 203580阻止。因此，小分子抑制p38信号可能是WS的治疗策略。为了开发这种方法，如现有p38抑制剂的体内毒性和激酶选择性问题需要解决，以加强证据表明，p38本身在介导SB 203580的作用中起着至关重要的作用，并找到适合于体内使用的抑制剂。在这项工作中，我们使用了一组不同的p38抑制剂：（1）在动物模型或人体临床试验中已成功地在体内使用;（2）与p38结合的不同模式;（3）不同的脱靶激酶特异性谱，以关键地解决p38在WS细胞中观察到的过早衰老中的作用。我们的研究结果证实了p38参与加速细胞衰老，并确定了适用于WS体内使用的p38抑制剂，其中BIRB 796最有效。
Progeroid syndromes show features of accelerated ageing and are used as models for human ageing, of which Werner syndrome (WS) is one of the most widely studied. WS fibroblasts show accelerated senescence that may result from p38 MAP kinase activation since it is prevented by the p38 inhibitor SB203580. Thus, small molecule inhibition of p38-signalling may be a therapeutic strategy for WS. To develop this approach issues such as the in vivo toxicity and kinase selectivity of existing p38 inhibitors need to be addressed, so as to strengthen the evidence that p38 itself plays a critical role in mediating the effect of SB203580, and to find an inhibitor suitable for in vivo use. In this work we used a panel of different p38 inhibitors selected for: (1) having been used successfully in vivo in either animal models or human clinical trials; (2) different modes of binding to p38; and (3) different off-target kinase specificity profiles, in order to critically address the role of p38 in the premature senescence seen in WS cells. Our findings confirmed the involvement of p38 in accelerated cell senescence and identified p38 inhibitors suitable for in vivo use in WS, with BIRB 796 the most effective.