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

Citation:
Mascuch, SJ, Boudreau PD, Carland TM, Pierce NT, Olson J, Hensler ME, Choi H, Campanale J, Hamdoun A, Nizet V, Gerwick WH, Gaasterland T, Gerwick L.  2018.  Marine natural product honaucin A attenuates inflammation by activating the Nrf2-ARE pathway. Journal of Natural Products. 81:506-514.

Date Published:

2018/03

Keywords:

antioxidant, 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.

Notes:

n/a

Website

DOI:

10.1021/acs.jnatprod.7b00734