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Sesquiterpene dimmer (DSF-27) inhibits the release of neuroinflammatory mediators from microglia by targeting spleen tyrosine kinase (Syk) and Janus kinase 2 (Jak2): Two major non-receptor tyrosine signaling proteins involved in inflammatory events
Zeng, Ke-Wu1; Wang, Shu1,2; Dong, Xin1; Jiang, Yong1; Jin, Hong-Wei1; Tu, Peng-Fei1
关键词Neuroinflammation Microglia Sesquiterpene Dimmer Non-receptor Tyrosine Kinase
刊名TOXICOLOGY AND APPLIED PHARMACOLOGY
2014-03-15
DOI10.1016/j.taap.2014.01.014
275期:3页:244-256
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Pharmacology & Pharmacy ; Toxicology
资助者National Key Technology R&amp ; D Program "New Drug Innovation" of China ; National Key Technology R&amp ; D Program "New Drug Innovation" of China
研究领域[WOS]Pharmacology & Pharmacy ; Toxicology
关键词[WOS]NF-KAPPA-B ; ALZHEIMERS-DISEASE ; DIMERIC SESQUITERPENE ; PARKINSONS-DISEASE ; NEURONAL DAMAGE ; IN-VIVO ; ACTIVATION ; PATHWAYS ; CELLS ; BRAIN
英文摘要

Non-receptor protein tyrosine kinases (NRPTKs)-dependent inflammatory signal transduction cascades play key roles in immunoregulation. However, drug intervention through NRPTKs-involved immunoregulation mechanism in microglia (the major immtine cells of the central nervous system) has not been widely investigated. A main aim of the present study is to elucidate the contribution of two major NRPTKs (Syk and Jak2) in neuroinflammation suppression by a bioactive sesquiterpene dimmer (DSF-27). We found that LPS-stimulated BV-2 cells activated Syk and further initiated Akt/NF-kappa B inflammatory pathway. This Syk-dependent Akt/NF-kappa B inflammatory pathway can be effectively ameliorated by DSF-27. Moreover, Jak2 was activated by LPS, which was followed by transcriptional factor Stat3 activation. The Jak2/Stat3 signal was suppressed by DSF-27 through inhibition of Jak2 and Stat3 phosphorylation, promotion of Jak/Stat3 inhibitory factors PIAS3 expression, and down-regulation of ERK and p38 MAPK phosphorylation. Furthermore, DSF-27 protected cortical and mesencephalic dopaminergic neurons against neuroinflammatory injury. Taken together, our findings indicate NRPTK signaling pathways including Syk/NF-kappa B and Jak2/Stat3 cascades are potential anti-neuroinflammatory targets in microglia, and may also set the basis for the use of sesquiterpene dimmer as a therapeutic approach for neuroinflammation via interruption of these pathways. (C) 2014 Elsevier Inc. All rights reserved.

语种英语
所属项目编号2012ZX09301002-002-002
资助者National Key Technology R&amp ; D Program "New Drug Innovation" of China ; National Key Technology R&amp ; D Program "New Drug Innovation" of China
WOS记录号WOS:000333320700006
Citation statistics
Cited Times:7[WOS]   [WOS Record]     [Related Records in WOS]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/52743
Collection北京大学药学院
作者单位1.Peking Univ, Sch Pharmaceut Sci, State Key Lab Nat & Biomimet Drugs, Hlth Sci Ctr, Beijing 100191, Peoples R China
2.Chinese Peoples Armed Police Forces, Dept Med Chem & Pharmaceut Anal, Logist Coll, Tianjin 300162, Peoples R China
Recommended Citation
GB/T 7714
Zeng, Ke-Wu,Wang, Shu,Dong, Xin,et al. Sesquiterpene dimmer (DSF-27) inhibits the release of neuroinflammatory mediators from microglia by targeting spleen tyrosine kinase (Syk) and Janus kinase 2 (Jak2): Two major non-receptor tyrosine signaling proteins involved in inflammatory events[J]. TOXICOLOGY AND APPLIED PHARMACOLOGY,2014,275(3):244-256.
APA Zeng, Ke-Wu,Wang, Shu,Dong, Xin,Jiang, Yong,Jin, Hong-Wei,&Tu, Peng-Fei.(2014).Sesquiterpene dimmer (DSF-27) inhibits the release of neuroinflammatory mediators from microglia by targeting spleen tyrosine kinase (Syk) and Janus kinase 2 (Jak2): Two major non-receptor tyrosine signaling proteins involved in inflammatory events.TOXICOLOGY AND APPLIED PHARMACOLOGY,275(3),244-256.
MLA Zeng, Ke-Wu,et al."Sesquiterpene dimmer (DSF-27) inhibits the release of neuroinflammatory mediators from microglia by targeting spleen tyrosine kinase (Syk) and Janus kinase 2 (Jak2): Two major non-receptor tyrosine signaling proteins involved in inflammatory events".TOXICOLOGY AND APPLIED PHARMACOLOGY 275.3(2014):244-256.
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