High-throughput small molecule screening reveals Nrf2-dependent and -independent pathways of cellular stress resistance.
High-throughput small molecule screening reveals Nrf2-dependent and -independent pathways of cellular stress resistance.
复制标题
DOI：
10.1126/sciadv.aaz7628
复制
发表时间：
2020-10
期刊：
影响因子：
13.6
通讯作者：
Miller RA
中科院分区：
文献类型：
--
作者：
Lombard DB;Kohler WJ;Guo AH;Gendron C;Han M;Ding W;Lyu Y;Ching TT;Wang FY;Chakraborty TS;Nikolovska-Coleska Z;Duan Y;Girke T;Hsu AL;Pletcher SD;Miller RA
高通量筛选可识别促进细胞应激抵抗的小分子。衰老是大多数慢性疾病的主要危险因素。抗衰老干预措施的发展有望同时预防许多此类疾病。细胞的抗应激能力是长寿的进化保守特征。在此，我们鉴定了可诱导对超氧化物生成剂百草枯 (PQ)、重金属镉 (Cd) 和 DNA 烷化剂甲磺酸甲酯 (MMS) 产生抗性的化合物。一些救援化合物赋予对单一应激源的抵抗力，而另一些则引发多重抵抗。在一项已发表的对秀丽隐杆线虫的大规模长寿筛选中，成纤维细胞的应激抵抗力的诱导可以预测寿命的延长，尽管在使用一组更严格的化合物对蠕虫和苍蝇进行的测试中并未发现这一点。转录组分析和遗传学研究表明 Nrf2/SKN-1 信号传导与两种保护性化合物小豆蔻苷和 AEG 3482 提供的应激抵抗有关。这项工作中鉴定的小分子可能是阐明哺乳动物细胞应激抵抗机制的有吸引力的工具。
High-throughput screening identifies small molecules that promote cellular stress resistance. Aging is the dominant risk factor for most chronic diseases. Development of antiaging interventions offers the promise of preventing many such illnesses simultaneously. Cellular stress resistance is an evolutionarily conserved feature of longevity. Here, we identify compounds that induced resistance to the superoxide generator paraquat (PQ), the heavy metal cadmium (Cd), and the DNA alkylator methyl methanesulfonate (MMS). Some rescue compounds conferred resistance to a single stressor, while others provoked multiplex resistance. Induction of stress resistance in fibroblasts was predictive of longevity extension in a published large-scale longevity screen in Caenorhabditis elegans, although not in testing performed in worms and flies with a more restricted set of compounds. Transcriptomic analysis and genetic studies implicated Nrf2/SKN-1 signaling in stress resistance provided by two protective compounds, cardamonin and AEG 3482. Small molecules identified in this work may represent attractive tools to elucidate mechanisms of stress resistance in mammalian cells.
登录
查看更多内容
bioassayR：小分子生物活性的跨目标分析。
影响因子：
5.6
作者：
Backman TW;Girke T
通讯作者：
Girke T
影响因子：
29
作者：
Bjedov I;Toivonen JM;Kerr F;Slack C;Jacobson J;Foley A;Partridge L
通讯作者：
Partridge L
影响因子：
1.2
作者：
Linford, Nancy J.;Bilgir, Ceyda;Pletcher, Scott D.
通讯作者：
Pletcher, Scott D.
影响因子：
3.7
作者：
Backman TW;Evans DS;Girke T
通讯作者：
Girke T
影响因子：
7.8
作者：
Kim, Yongsoon;Sun, Hong
通讯作者：
Sun, Hong