Journal
JOURNAL OF PINEAL RESEARCH
Volume 74, Issue 1, Pages -Publisher
WILEY
DOI: 10.1111/jpi.12835
Keywords
anti-inflammation; colitis; electrophile; melatonin; N-Acetylserotonin; nuclear factor erythroid 2-related factor 2 (Nrf2)-heme oxygenase (HO)-1 pathway; oxidation
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The study demonstrates that N-acetylserotonin (NAS) can activate the anti-inflammatory pathway and mitigate colonic inflammation through its oxidized form, Oxi-NAS.
N-Acetylserotonin (NAS) is an intermediate in the melatonin biosynthetic pathway. We investigated the anti-inflammatory activity of NAS by focusing on its chemical feature oxidizable to an electrophile. NAS was readily oxidized by reaction with HOCl, an oxidant produced in the inflammatory state. HOCl-reacted NAS (Oxi-NAS), but not NAS, activated the anti-inflammatory nuclear factor erythroid 2-related factor 2 (Nrf2)-heme oxygenase (HO)-1 pathway in cells. Chromatographic and mass analyses demonstrated that Oxi-NAS was the iminoquinone form of NAS and could react with N-acetylcysteine possessing a nucleophilic thiol to form a covalent adduct. Oxi-NAS bound to Kelch-like ECH-associated protein 1, resulting in Nrf2 dissociation. Moreover, rectally administered NAS increased the levels of nuclear Nrf2 and HO-1 proteins in the inflamed colon of rats. Simultaneously, NAS was converted to Oxi-NAS in the inflamed colon. Rectal NAS mitigated colonic damage and inflammation. The anticolitic effects were significantly compromised by the coadministration of an HO-1 inhibitor.
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