期刊
JOURNAL OF NATURAL PRODUCTS
卷 81, 期 3, 页码 506-514出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jnatprod.7b00734
关键词
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资金
- NIEHS/NIH [R21ES024105]
- NEI/NIH [R01EY022306]
- NIH [CA100851, ES024105]
- NIH Marine Biotechnology Training Fellowship [NIH GM067550]
- P.E.O. Scholar Award
- Claude E. Zobell Fellowship
- Robert Scripps Fellowship
- SIO Cheng An Lun Fellowship
- SIO Haymet First Year Fellowship
- Wyer Family Fellowship
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.
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