ST2825, a Small Molecule Inhibitor of MyD88, Suppresses NF-κB Activation and the ROS/NLRP3/Cleaved Caspase-1 Signaling Pathway to Attenuate Lipopolysaccharide-Stimulated Neuroinflammation

被引:12
作者
Zhang, Shan-Shan [1 ,2 ]
Liu, Man [1 ,2 ]
Liu, Dong-Ni [1 ,2 ]
Shang, Yu-Fu [1 ,2 ]
Wang, Yue-Hua [1 ,2 ]
Du, Guan-Hua [1 ,2 ]
机构
[1] Chinese Acad Med Sci & Peking Union Med Coll, Inst Mat Med, State Key Lab Bioact Subst & Funct Nat Med, Beijing 100050, Peoples R China
[2] Chinese Acad Med Sci & Peking Union Med Coll, Inst Mat Med, Beijing Key Lab Drug Target Identificat & New Dru, Beijing 100050, Peoples R China
来源
MOLECULES | 2022年 / 27卷 / 09期
基金
中国国家自然科学基金;
关键词
neuroinflammation; ST2825; BV2 microglia cells; lipopolysaccharide (LPS); BRAIN; CELLS; MICROGLIA; MICE; RESPONSES; EXPRESSION; CHEMOKINES; INJURY; TLR4; MAPK;
D O I
10.3390/molecules27092990
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Neuroinflammation characterized by microglia activation is the mechanism of the occurrence and development of various central nervous system diseases. ST2825, as a peptide-mimetic MyD88 homodimerization inhibitor, has been identified as crucial molecule with an anti-inflammatory role in several immune cells, especially microglia. The purpose of the study was to investigate the anti-neuroinflammatory effects and the possible mechanism of ST2825. Methods: Lipopolysaccharide (LPS) was used to stimulate neuroinflammation in male BALB/c mice and BV2 microglia cells. The NO level was determined by Griess Reagents. The levels of pro-inflammatory cytokines and chemokines were determined by ELISA. The expressions of inflammatory proteins were determined by real-time PCR and Western blotting analysis. The level of ROS was detected by DCFH-DA staining. Results: In vivo, the improved levels of LPS-induced pro-inflammatory factors, including TNF-alpha, IL-6, IL-1 beta, MCP-1 and ICAM-1 in the cortex and hippocampus, were reduced after ST2825 treatment. In vitro, the levels of LPS-induced pro-inflammatory factors, including NO, TNF-alpha, IL-6, IL-1 beta, MCP-1, iNOS, COX2 and ROS, were remarkably decreased after ST2825 treatment. Further research found that the mechanism of its anti-neuroinflammatory effects appeared to be associated with inhibition of NF-kappa B activation and down-regulation of the NLRP3/cleaved caspase-1 signaling pathway. Conclusions: The current findings provide new insights into the activity and molecular mechanism of ST2825 for the treatment of neuroinflammation.
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页数:13
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