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Costunolide covalently targets NACHT domain of NLRP3 to inhibit inflammasome activation and alleviate NLRP3-driven inflammatory diseases

The NLRP3 inflammasome’s core and most specific protein, NLRP3, has a variety of functions in inflammation-driven diseases. Costunolide (COS) is the major active ingredient of the traditional Chinese medicinal herb Saussurea lappa and has anti-inflammatory activity, but the principal mechanism and m...

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Autores principales: Xu, Haowen, Chen, Jiahao, Chen, Pan, Li, Weifeng, Shao, Jingjing, Hong, Shanshan, Wang, Yi, Chen, Lingfeng, Luo, Wu, Liang, Guang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9978959/
https://www.ncbi.nlm.nih.gov/pubmed/36873170
http://dx.doi.org/10.1016/j.apsb.2022.09.014
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author Xu, Haowen
Chen, Jiahao
Chen, Pan
Li, Weifeng
Shao, Jingjing
Hong, Shanshan
Wang, Yi
Chen, Lingfeng
Luo, Wu
Liang, Guang
author_facet Xu, Haowen
Chen, Jiahao
Chen, Pan
Li, Weifeng
Shao, Jingjing
Hong, Shanshan
Wang, Yi
Chen, Lingfeng
Luo, Wu
Liang, Guang
author_sort Xu, Haowen
collection PubMed
description The NLRP3 inflammasome’s core and most specific protein, NLRP3, has a variety of functions in inflammation-driven diseases. Costunolide (COS) is the major active ingredient of the traditional Chinese medicinal herb Saussurea lappa and has anti-inflammatory activity, but the principal mechanism and molecular target of COS remain unclear. Here, we show that COS covalently binds to cysteine 598 in NACHT domain of NLRP3, altering the ATPase activity and assembly of NLRP3 inflammasome. We declare COS’s great anti-inflammasome efficacy in macrophages and disease models of gouty arthritis and ulcerative colitis via inhibiting NLRP3 inflammasome activation. We also reveal that the α-methylene-γ-butyrolactone motif in sesquiterpene lactone is the certain active group in inhibiting NLRP3 activation. Taken together, NLRP3 is identified as a direct target of COS for its anti-inflammasome activity. COS, especially the α-methylene-γ-butyrolactone motif in COS structure, might be used to design and produce novel NLRP3 inhibitors as a lead compound.
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spelling pubmed-99789592023-03-03 Costunolide covalently targets NACHT domain of NLRP3 to inhibit inflammasome activation and alleviate NLRP3-driven inflammatory diseases Xu, Haowen Chen, Jiahao Chen, Pan Li, Weifeng Shao, Jingjing Hong, Shanshan Wang, Yi Chen, Lingfeng Luo, Wu Liang, Guang Acta Pharm Sin B Original Article The NLRP3 inflammasome’s core and most specific protein, NLRP3, has a variety of functions in inflammation-driven diseases. Costunolide (COS) is the major active ingredient of the traditional Chinese medicinal herb Saussurea lappa and has anti-inflammatory activity, but the principal mechanism and molecular target of COS remain unclear. Here, we show that COS covalently binds to cysteine 598 in NACHT domain of NLRP3, altering the ATPase activity and assembly of NLRP3 inflammasome. We declare COS’s great anti-inflammasome efficacy in macrophages and disease models of gouty arthritis and ulcerative colitis via inhibiting NLRP3 inflammasome activation. We also reveal that the α-methylene-γ-butyrolactone motif in sesquiterpene lactone is the certain active group in inhibiting NLRP3 activation. Taken together, NLRP3 is identified as a direct target of COS for its anti-inflammasome activity. COS, especially the α-methylene-γ-butyrolactone motif in COS structure, might be used to design and produce novel NLRP3 inhibitors as a lead compound. Elsevier 2023-02 2022-09-25 /pmc/articles/PMC9978959/ /pubmed/36873170 http://dx.doi.org/10.1016/j.apsb.2022.09.014 Text en © 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Article
Xu, Haowen
Chen, Jiahao
Chen, Pan
Li, Weifeng
Shao, Jingjing
Hong, Shanshan
Wang, Yi
Chen, Lingfeng
Luo, Wu
Liang, Guang
Costunolide covalently targets NACHT domain of NLRP3 to inhibit inflammasome activation and alleviate NLRP3-driven inflammatory diseases
title Costunolide covalently targets NACHT domain of NLRP3 to inhibit inflammasome activation and alleviate NLRP3-driven inflammatory diseases
title_full Costunolide covalently targets NACHT domain of NLRP3 to inhibit inflammasome activation and alleviate NLRP3-driven inflammatory diseases
title_fullStr Costunolide covalently targets NACHT domain of NLRP3 to inhibit inflammasome activation and alleviate NLRP3-driven inflammatory diseases
title_full_unstemmed Costunolide covalently targets NACHT domain of NLRP3 to inhibit inflammasome activation and alleviate NLRP3-driven inflammatory diseases
title_short Costunolide covalently targets NACHT domain of NLRP3 to inhibit inflammasome activation and alleviate NLRP3-driven inflammatory diseases
title_sort costunolide covalently targets nacht domain of nlrp3 to inhibit inflammasome activation and alleviate nlrp3-driven inflammatory diseases
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9978959/
https://www.ncbi.nlm.nih.gov/pubmed/36873170
http://dx.doi.org/10.1016/j.apsb.2022.09.014
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