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A novel sirt6 activator ameliorates neuroinflammation and ischemic brain injury via EZH2/FOXC1 axis

Acta Pharmaceutica Sinica B 2021年第3期11卷 708-726页

作者： Tailin He Jialin Shang Chenglong Gao Xin Guan Yingyi Chen Liwen Zhu Luyong Zhang Cunjin Zhang Jian Zhang Tao Pang State Key Laboratory of Natural Medicines Jiangsu Key Laboratory of Drug ScreeningJiangsu Key Laboratory of Drug Discovery for Metabolic DiseasesChina Pharmaceutical UniversityNanjing 210009China Medicinal Bioinformatics Center Shanghai Jiao Tong University School of MedicineShanghai 200025China Department of Neurology of Drum Tower Hospital Medical School and the State Key Laboratory of Pharmaceutical BiotechnologyNanjing UniversityNanjing 210008China

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 ***,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 ***-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 *** 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 ***,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 ***,MDL-811 also exhibited strong anti-inflammatory effects in human monocytes isolated from ischemic stroke patients,underlying an interesting translational *** 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

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Modulation of sirt6 activity acts as an emerging therapeutic implication for pathological disorders in the skeletal system

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Genes & Diseases 2023年第3期10卷 864-876页

作者： Zicai Dong Chuan Yang Jiulin Tan Ce Dou Yueqi Chen Department of Biomedical Materials Science Army Medical UniversityChongqing 400038China Department of Orthopedics Southwest HospitalArmy Medical UniversityChongqing 400038China

The skeletal system is a dynamically balanced system, which undergoes continuous bone resorption and formation to maintain bone matrix homeostasis. As an important ADP-ribosylase and NAD+-dependent deacylase, sirt6 (SIR2-like protein 6) is widely expressed on various kinds of bone cells, such as chondrocytes, osteoblasts, osteoclasts. The aberration of sirt6 impairs gene expression (e.g., NF-κB and Wnt target genes) and cellular functions (e.g., DNA repair, glucose and lipid metabolism, telomeric maintenance), which disturbs the dynamic balance and ultimately leads to several bone-related diseases. In this review, we summarize the critical roles of sirt6 in the onset and progression of bone-related diseases including osteoporosis, osteoarthritis, rheumatoid arthritis, and intervertebral disc degeneration, as well as the relevant signaling pathways. In addition, we discuss the advances in the development of sirt6 activators and elucidate their pharmacological profiles, which may provide novel treatment strategies for these skeletal diseases.

关键词： Intervertebral disc degeneration(IDD) Osteoarthritis(OA) Osteoporosis(OP) Rheumatoid arthritis(RA) sirt6(SIR2-Like protein 6) sirt6 activator

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