Marine natural product honaucin A attenuates inflammation by activating the Nrf2-ARE pathway

TitleMarine natural product honaucin A attenuates inflammation by activating the Nrf2-ARE pathway
Publication TypeJournal Article
Year of Publication2018
AuthorsMascuch S.J, Boudreau P.D, Carland T.M, Pierce N.T, Olson J., Hensler M.E, Choi H., Campanale J., Hamdoun A., Nizet V., Gerwick WH, Gaasterland T., Gerwick L
JournalJournal of Natural Products
Volume81
Pagination506-514
Date Published2018/03
Type of ArticleArticle
ISBN Number0163-3864
Accession NumberWOS:000428608300008
Keywordsantioxidant; chemical biology; degradation; drug discovery; keap1; mechanism; nrf2/are pathway; oxidative stress; Pharmacology & Pharmacy; Plant Sciences; provides neuroprotection; response; target
Abstract

The cyanobacterial marine natural product honaucin A inhibits mammalian innate inflammation in vitro and in vivo. To decipher its mechanism of action, RNA sequencing was used to evaluate differences in gene expression of cultured macrophages following honaucin A treatment. This analysis led to the hypothesis that honaucin A exerts its anti-inflammatory activity through activation of the cytoprotective nuclear erythroid 2-related factor 2 (Nrf2)-antioxidant response element/electrophile response element (ARE/EpRE) signaling pathway. Activation of this pathway by honaucin A in cultured human MCF7 cells was confirmed using an Nrf2 luciferase reporter assay. In vitro alkylation experiments with the natural product and N-acetyl-L-cysteine suggest that honaucin A activates this pathway through covalent interaction with the sulfhydryl residues of the cytosolic repressor protein Keapl. Honaucin A presents a potential therapeutic lead for diseases with an inflammatory component modulated by Nrf2-ARE.

DOI10.1021/acs.jnatprod.7b00734
Short TitleJ. Nat. Prod.
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