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Article: Costunolide Plays an Anti-Neuroinflammation Role in Lipopolysaccharide-Induced BV2 Microglial Activation by Targeting Cyclin-Dependent Kinase 2

TitleCostunolide Plays an Anti-Neuroinflammation Role in Lipopolysaccharide-Induced BV2 Microglial Activation by Targeting Cyclin-Dependent Kinase 2
Authors
Keywordscostunolide
natural product
anti-neuroinflammation
target identification
CDK2
Issue Date2020
PublisherMolecular Diversity Preservation International. The Journal's web site is located at http://www.mdpi.org/molecules
Citation
Molecules, 2020, v. 25 n. 12, p. article no. 2840 How to Cite?
AbstractHyperactivation of microglia in the brain is closely related to neuroinflammation and leads to neuronal dysfunction. Costunolide (CTL) is a natural sesquiterpene lactone with wide pharmacological activities including anti-inflammation and antioxidation. In this study, we found that CTL significantly inhibited the production of inflammatory mediators including nitric oxide, IL-6, TNF-α, and PGE2 in lipopolysaccharide (LPS)-stimulated BV2 microglia. Moreover, CTL effectively attenuated IKKβ/NF-κB signaling pathway activation. To identify direct cellular target of CTL, we performed high-throughput reverse virtual screening assay using scPDB protein structure library, and found cyclin-dependent kinase 2 (CDK2) was the most specific binding protein for CTL. We further confirmed the binding ability of CTL with CDK2 using cellular thermal shift assay (CETSA) and drug affinity responsive target stability (DARTS) assays. Surface plasmon resonance analysis also supported that CTL specifically bound to CDK2 with a dissociation constant at micromole level. Furthermore, knocking down CDK2 obviously reversed the anti-inflammation effect of CTL via AKT/IKKβ/NF-κB signaling pathway on BV-2 cells. Collectively, these results indicate that CTL inhibits microglia-mediated neuroinflammation through directly targeting CDK2, and provide insights into the role of CDK2 as a promising anti-neuroinflammation therapeutic target.
Descriptioneid_2-s2.0-85086966578
Persistent Identifierhttp://hdl.handle.net/10722/287212
ISSN
2018 Impact Factor: 3.06
2020 SCImago Journal Rankings: 0.782
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorLIU, YC-
dc.contributor.authorFeng, N-
dc.contributor.authorLi, WW-
dc.contributor.authorTu, PF-
dc.contributor.authorChen, JP-
dc.contributor.authorHan, JY-
dc.contributor.authorzeng, KW-
dc.date.accessioned2020-09-22T02:57:32Z-
dc.date.available2020-09-22T02:57:32Z-
dc.date.issued2020-
dc.identifier.citationMolecules, 2020, v. 25 n. 12, p. article no. 2840-
dc.identifier.issn1420-3049-
dc.identifier.urihttp://hdl.handle.net/10722/287212-
dc.descriptioneid_2-s2.0-85086966578-
dc.description.abstractHyperactivation of microglia in the brain is closely related to neuroinflammation and leads to neuronal dysfunction. Costunolide (CTL) is a natural sesquiterpene lactone with wide pharmacological activities including anti-inflammation and antioxidation. In this study, we found that CTL significantly inhibited the production of inflammatory mediators including nitric oxide, IL-6, TNF-α, and PGE2 in lipopolysaccharide (LPS)-stimulated BV2 microglia. Moreover, CTL effectively attenuated IKKβ/NF-κB signaling pathway activation. To identify direct cellular target of CTL, we performed high-throughput reverse virtual screening assay using scPDB protein structure library, and found cyclin-dependent kinase 2 (CDK2) was the most specific binding protein for CTL. We further confirmed the binding ability of CTL with CDK2 using cellular thermal shift assay (CETSA) and drug affinity responsive target stability (DARTS) assays. Surface plasmon resonance analysis also supported that CTL specifically bound to CDK2 with a dissociation constant at micromole level. Furthermore, knocking down CDK2 obviously reversed the anti-inflammation effect of CTL via AKT/IKKβ/NF-κB signaling pathway on BV-2 cells. Collectively, these results indicate that CTL inhibits microglia-mediated neuroinflammation through directly targeting CDK2, and provide insights into the role of CDK2 as a promising anti-neuroinflammation therapeutic target.-
dc.languageeng-
dc.publisherMolecular Diversity Preservation International. The Journal's web site is located at http://www.mdpi.org/molecules-
dc.relation.ispartofMolecules-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectcostunolide-
dc.subjectnatural product-
dc.subjectanti-neuroinflammation-
dc.subjecttarget identification-
dc.subjectCDK2-
dc.titleCostunolide Plays an Anti-Neuroinflammation Role in Lipopolysaccharide-Induced BV2 Microglial Activation by Targeting Cyclin-Dependent Kinase 2-
dc.typeArticle-
dc.identifier.emailChen, JP: abchen@hkucc.hku.hk-
dc.identifier.authorityChen, JP=rp01316-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.3390/molecules25122840-
dc.identifier.pmid32575562-
dc.identifier.pmcidPMC7355650-
dc.identifier.scopuseid_2-s2.0-85086966578-
dc.identifier.hkuros314502-
dc.identifier.volume25-
dc.identifier.issue12-
dc.identifier.spagearticle no. 2840-
dc.identifier.epagearticle no. 2840-
dc.identifier.isiWOS:000550243800001-
dc.publisher.placeSwitzerland-
dc.identifier.issnl1420-3049-

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