A novel SIRT6 activator ameliorates neuroinflammation and ischemic brain injury via EZH2/FOXC1 axis

查看全文 作　　者：Tailin [1]He;Jialin [2]Shang;Chenglong [1]Gao;Xin [1]Guan;Yingyi [2]Chen;Liwen [3]Zhu;Luyong [1]Zhang;Cunjin [3]Zhang;Jian [2]Zhang;Tao [1]Pang

机构地区：[1]State Key Laboratory of Natural Medicines,Jiangsu Key Laboratory of Drug Screening,Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases,China Pharmaceutical University,Nanjing 210009,China;[2]Medicinal Bioinformatics Center,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China;[3]Department of Neurology of Drum Tower Hospital,Medical School and the State Key Laboratory of Pharmaceutical Biotechnology,Nanjing University,Nanjing 210008,China

出　　处：《Acta Pharmaceutica Sinica B》索引2021年第11卷第3期,共19页

基　　金：supported by the National Natural Science Foundation of China (81973512, 81925034, 81701235, and 81991514);Double First-Class Project of China Pharmaceutical University(CPU2018GY06 and CPU2018GY20, China);the Fundamental Research Funds for the Central Universities(021414380446, China);supported by the Six Talent Peaks Project of Jiangsu Province (China) to Tao Pang。 摘　　要：Ischemic stroke is the second leading cause of death worldwide with limited medications and neuroinflammation was recognized as a critical player in the progression of stroke,but how to control the overactive neuroinflammation is still a long-standing challenge.Here,we designed a novel SIRT6 activator MDL-811 which remarkably inhibited inflammatory response in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and primary mouse microglia,which were abolished by silencing SIRT6.RNA-seq screening identified the forkhead box C1 (Foxc1) is a key gene evoked by MDL-811stimulation and is required for the anti-inflammatory effects of MDL-811.We found MDL-811-activated SIRT6 directly interacted with enhancer of zeste homolog 2 (EZH2) and promoted deacetylation of EZH2 which could bind to the promoter of Foxc1 and upregulate its expression to modulate inflammation.Moreover,our data demonstrated that MDL-811 not only ameliorated sickness behaviors in neuroinflammatory mice induced by LPS,but also markedly reduced the brain injury in ischemic stroke mice in addition to promoting long-term functional recovery.Importantly,MDL-811 also exhibited strong anti-inflammatory effects in human monocytes isolated from ischemic stroke patients,underlying an interesting translational perspective.Taken together,MDL-811 could be an alternative therapeutic candidate for ischemic stroke and other brain disorders associated with neuroinflammation. 关键词：SIRT6 activator NEUROINFLAMMATION Ischemic stroke DEACETYLATION MICROGLIA Macrophage FOXC1 EZH2

相关文献

参考文献（64）
引证文献（11）
耦合文献（98）

参考文献(64)

引证文献(11)

耦合文献(98)

互联网出版许可证新出网证(渝)字10号全国400电话 - 免长途话费

A novel SIRT6 activator ameliorates neuroinflammation and ischemic brain injury via EZH2/FOXC1 axis

参考文献(64)

引证文献(11)

耦合文献(98)

用户提示