Glycosylation enables aesculin to activate Nrf2

• Authors: Kyun Ha Kim, Pusan National University; Hyunsu Park, Pusan National University; Hee Jin Park, Pusan National University; Kyoung-Hwa Choi, Pusan National University; Ruxana Sadikot, Emory University; Jaeho Cha, Pusan National University; Myungsoo Joo, Pusan National University
• Journal Title: Scientific Reports
• Volume: Volume 6
• Publisher: Nature Publishing Group: Open Access Journals - Option C | 2016-07-15, Pages 29956-29956
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1038/srep29956
• Subjects: Health Sciences, Pathology; Biology, Microbiology
• Keywords: Science & Technology; Multidisciplinary Sciences; Science & Technology - Other Topics; ENHANCES SUSCEPTIBILITY; MEDICAL PROGRESS; LUNG INJURY; PATHWAY; MICE; PROTECTION; DEXTRANSUCRASE; DEGRADATION; ANTIOXIDANT; DERIVATIVES

Abstract

Since aesculin, 6,7-dihydroxycoumarin-6-O-β-glucopyranoside, suppresses inflammation, we asked whether its anti-inflammatory activity is associated with the activation of nuclear factor-E2-related factor 2 (Nrf2), a key anti-inflammatory factor. Our results, however, show that aesculin marginally activated Nrf2. Since glycosylation can enhance the function of a compound, we then asked whether adding a glucose makes aesculin activate Nrf2. Our results show that the glycosylated aesculin, 3-O-β-d-glycosyl aesculin, robustly activated Nrf2, inducing the expression of Nrf2-dependent genes, such as heme oxygenase-1, glutamate-cysteine ligase catalytic subunit, and NAD(P)H quinone oxidoreductase 1 in macrophages. Mechanistically, 3-O-β-d-glycosyl aesculin suppressed ubiquitination of Nrf2, retarding degradation of Nrf2. Unlike aesculin, 3-O-β-d-glycosyl aesculin significantly suppressed neutrophilic lung inflammation, a hallmark of acute lung injury (ALI), in mice, which was not recapitulated in Nrf2 knockout mice, suggesting that the anti-inflammatory function of the compound largely acts through Nrf2. In a mouse model of sepsis, a major cause of ALI, 3-O-β-d-glycosyl aesculin significantly enhanced the survival of mice, compared with aesculin. Together, these results show that glycosylation could confer the ability to activate Nrf2 on aesculin, enhancing the anti-inflammatory function of aesculin. These results suggest that glycosylation can be a way to improve or alter the function of aesculin.