dimethyl-fumarate and Inflammation

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.

Topics: Alkylation; Animals; Anti-Inflammatory Agents; Antioxidants; Aquatic Organisms; Biological Products; Cell Line; Cell Line, Tumor; Cytoprotection; Female; Humans; Inflammation; Kelch-Like ECH-Associated Protein 1; MCF-7 Cells; Mice; NF-E2-Related Factor 2; RAW 264.7 Cells; Signal Transduction