title: Glycosylation enables aesculin to activate Nrf2.
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.
authors.affiliation: School of Korean Medicine, Pusan National University, Yangsan 626-870, Korea.
authors.forename: Kyun Ha
authors.initials: KH
authors.lastname: Kim
authors.affiliation: Department of Microbiology, Pusan National University, Busan 609-735, Korea.
authors.forename: Hyunsu
authors.initials: H
authors.lastname: Park
authors.affiliation: Department of Microbiology, Pusan National University, Busan 609-735, Korea.
authors.forename: Hee Jin
authors.initials: HJ
authors.lastname: Park
authors.affiliation: Department of Microbiology, Pusan National University, Busan 609-735, Korea.
authors.forename: Kyoung-Hwa
authors.initials: KH
authors.lastname: Choi
authors.affiliation: Section of Pulmonary and Critical Care Medicine, Atlanta Veterans Affairs Medical Center, Emory University, Decatur, GA30033, USA.
authors.forename: Ruxana T
authors.initials: RT
authors.lastname: Sadikot
authors.affiliation: Department of Microbiology, Pusan National University, Busan 609-735, Korea.
authors.forename: Jaeho
authors.initials: J
authors.lastname: Cha
authors.affiliation: School of Korean Medicine, Pusan National University, Yangsan 626-870, Korea.
authors.forename: Myungsoo
authors.initials: M
authors.lastname: Joo
mesh_terms: D055371:Acute Lung Injury / Q000150:complications / Q000378:metabolism / Q000473:pathology; D000818:Animals; D066241:Carbon-13 Magnetic Resonance Spectroscopy; D004929:Esculin / Q000737:chemistry / Q000494:pharmacology*; D006031:Glycosylation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011014:Pneumonia / Q000378:metabolism / Q000473:pathology; D066244:Proton Magnetic Resonance Spectroscopy; D000067996:RAW 264.7 Cells; D018805:Sepsis / Q000150:complications / Q000378:metabolism / Q000473:pathology; D016019:Survival Analysis; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D051267:NF-E2-Related Factor 2; D004929:Esculin