Original articles
Tailin He, Jialin Shang, Chenglong Gao, Xin Guan, Yingyi Chen, Liwen Zhu, Luyong Zhang, Cunjin Zhang, Jian Zhang, Tao Pang. A novel SIRT6 activator ameliorates neuroinflammation and ischemic brain injury via EZH2/FOXC1 axis[J]. Acta Pharmaceutica Sinica B, 2021, 11(3): 708-726

A novel SIRT6 activator ameliorates neuroinflammation and ischemic brain injury via EZH2/FOXC1 axis
Tailin Hea, Jialin Shangb, Chenglong Gaoa, Xin Guana, Yingyi Chenb, Liwen Zhuc, Luyong Zhanga, Cunjin Zhangc, Jian Zhangb, Tao Panga
a 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;
b Medicinal Bioinformatics Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China;
c Department of Neurology of Drum Tower Hospital, Medical School and the State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210008, China
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-811 stimulation 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.
Key words:    SIRT6 activator    Neuroinflammation    Ischemic stroke    Deacetylation    Microglia    Macrophage    FOXC1    EZH2   
Received: 2020-06-16     Revised: 2020-08-26
DOI: 10.1016/j.apsb.2020.11.002
Funds: This work was 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), and the Fundamental Research Funds for the Central Universities (021414380446, China). This work was also supported by the Six Talent Peaks Project of Jiangsu Province (China) to Tao Pang.
Corresponding author: Cunjin Zhang, Jian Zhang, Tao Pang     Email:tpang@cpu.edu.cn;jian.zhang@sjtu.edu.cn;zhangcj@nju.edu.cn
Author description:
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Tailin He
Jialin Shang
Chenglong Gao
Xin Guan
Yingyi Chen
Liwen Zhu
Luyong Zhang
Cunjin Zhang
Jian Zhang
Tao Pang

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