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JE-133 Suppresses LPS-Induced Neuroinflammation Associated with the Regulation of JAK/STAT and Nrf2 Signaling Pathways

文献类型：期刊论文

作者Tao, Lingxue3,4; Yu, Weichen2,4,6; Liu, Ziyi1,4; Zhao, Danfeng4; Lin, Sijin2,4,6; Szaloki, Dora5; Kicsak, Mate5; Kurtan, Tibor5; Zhang, Haiyan2,4,6
刊名ACS CHEMICAL NEUROSCIENCE
出版日期2024-01-05
卷号15期号:2页码:258-267
ISSN号1948-7193
关键词neuroinflammation microglia LPS JAK/STAT Nrf2
DOI10.1021/acschemneuro.3c00454
通讯作者Kurtan, Tibor() ; Zhang, Haiyan(hzhang@simm.ac.cn)
英文摘要Neuroinflammation plays an important role in the pathogenesis of neurodegenerative diseases, and interrupting the microglial-mediated neuroinflammation has been suggested as a promising strategy to delay or prevent the progression of neurodegeneration. In this study, we investigated the effects of JE-133, an optically active isochroman-2H-chromene conjugate containing a 1,3-disubstituted isochroman unit, on lipopolysaccharide (LPS)-induced microglial neuroinflammation and underlying mechanisms both in vitro and in vivo. First, JE-133 treatment decreased LPS-induced overproduction of interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), nitrite, and nitric oxide synthase (iNOS) in BV2 microglial cells. Further study revealed that JE-133 downregulated the phosphorylation level of JAK/STAT and upregulated the protein level of Nrf2/HO-1 in LPS-stimulated BV2 microglial cells and verified that JE-133 directly bound to Keap1 by a pull-down assay. Next, JE-133 administration also inhibited neuroinflammation in vivo, as indicated by a reduced CD11b protein level and an overexpressed mRNA level of the pro-inflammatory cytokine TNF-alpha in the hippocampus of LPS-injected mice. Moreover, the regulative effects of JE-133 on the JAK/STAT and Nrf2/HO-1 pathways were also verified in the hippocampus of LPS-injected mice. Taken together, our study for the first time reports that JE-133 exhibits inhibitory effects against LPS-stimulated neuroinflammation both in vitro and in vivo, which might be associated with the simultaneous regulation of the JAK/STAT and Nrf2 pathways. Our findings may provide important clues for the discovery of effective drug leads/candidates against neuroinflammation-associated neurodegeneration.
WOS关键词MICROGLIA ; ACTIVATION ; TARGET
资助项目Ministry of Science and Technology of the People's Republic of China[2021ZD0200900] ; STI2030-Major Projects[81872859] ; National Natural Science Foundation[K138672] ; National Research, Development and Innovation Office
WOS研究方向Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Neurosciences & Neurology
语种英语
出版者AMER CHEMICAL SOC
WOS记录号WOS:001144603900001
源URL[http://119.78.100.183/handle/2S10ELR8/308796]  
专题中国科学院上海药物研究所
通讯作者Kurtan, Tibor; Zhang, Haiyan
作者单位1.Nanchang Univ, Nanchang 330031, Peoples R China
2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
3.Lingang Lab, Shanghai 200031, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
5.Univ Debrecen, Dept Organ Chem, H-4002 Debrecen, Hungary
6.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
推荐引用方式
GB/T 7714		 Tao, Lingxue,Yu, Weichen,Liu, Ziyi,et al. JE-133 Suppresses LPS-Induced Neuroinflammation Associated with the Regulation of JAK/STAT and Nrf2 Signaling Pathways[J]. ACS CHEMICAL NEUROSCIENCE,2024,15(2):258-267.
APA Tao, Lingxue.,Yu, Weichen.,Liu, Ziyi.,Zhao, Danfeng.,Lin, Sijin.,...&Zhang, Haiyan.(2024).JE-133 Suppresses LPS-Induced Neuroinflammation Associated with the Regulation of JAK/STAT and Nrf2 Signaling Pathways.ACS CHEMICAL NEUROSCIENCE,15(2),258-267.
MLA Tao, Lingxue,et al."JE-133 Suppresses LPS-Induced Neuroinflammation Associated with the Regulation of JAK/STAT and Nrf2 Signaling Pathways".ACS CHEMICAL NEUROSCIENCE 15.2(2024):258-267.

入库方式： OAI收割

来源：上海药物研究所

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