Marine Natural Product Honaucin A Attenuates Inflammation by Activating the Nrf2-ARE Pathway

Samantha J. Mascuch, Paul D. Boudreau, Tristan M. Carland, N Tessa Pierce, Joshua Olson, Mary E. Hensler, Hyukjae Choi, Joseph Campanale, Amro Hamdoun, Victor Nizet, William H. Gerwick, Teresa. Gaasterland, Lena. Gerwick

Journal of Natural Products

March 23, 2018

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 Keap1. Honaucin A presents a potential therapeutic lead for diseases with an inflammatory component modulated by Nrf2-ARE.

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