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

作     者：Tailin He Jialin Shang Chenglong Gao Xin Guan Yingyi Chen Liwen Zhu Luyong Zhang Cunjin Zhang Jian Zhang Tao Pang Tailin He;Jialin Shang;Chenglong Gao;Xin Guan;Yingyi Chen;Liwen Zhu;Luyong Zhang;Cunjin Zhang;Jian Zhang;Tao Pang

作者机构：State Key Laboratory of Natural MedicinesJiangsu Key Laboratory of Drug ScreeningJiangsu Key Laboratory of Drug Discovery for Metabolic DiseasesChina Pharmaceutical UniversityNanjing 210009China Medicinal Bioinformatics CenterShanghai Jiao Tong University School of MedicineShanghai 200025China Department of Neurology of Drum Tower HospitalMedical School and the State Key Laboratory of Pharmaceutical BiotechnologyNanjing UniversityNanjing 210008China 

出 版 物：《Acta Pharmaceutica Sinica B》 (药学学报（英文版）)

年 卷 期：2021年第11卷第3期

页      面：708-726页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 1006[医学-中西医结合] 1004[医学-公共卫生与预防医学(可授医学、理学学位)] 1001[医学-基础医学(可授医学、理学学位)] 10[医学] 100602[医学-中西医结合临床] 

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。 

主　　题：SIRT6 activator Neuroinflammation Ischemic stroke Deacetylation Microglia Macrophage FOXC1 EZH2 

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.