Glycosylation enables aesculin to activate Nrf2

Area of Science:

• Pharmacology
• Molecular Biology
• Immunology

Background:

• Aesculin exhibits anti-inflammatory properties.
• The role of nuclear factor-E2-related factor 2 (Nrf2) in aesculin's anti-inflammatory activity was investigated.
• Glycosylation is known to potentially enhance compound function.

Purpose of the Study:

• To determine if aesculin's anti-inflammatory activity is linked to Nrf2 activation.
• To investigate the effect of glycosylation on aesculin's ability to activate Nrf2.
• To evaluate the therapeutic potential of glycosylated aesculin in inflammatory conditions.

Main Methods:

• Aesculin and its glycosylated derivative, 3-O-β-d-glycosyl aesculin, were tested for Nrf2 activation in macrophages.
• Nrf2-dependent gene expression (HO-1, GCLC, NQO1) was measured.
• Ubiquitination and degradation of Nrf2 were analyzed.
• Efficacy was assessed in mouse models of neutrophilic lung inflammation and sepsis.

Main Results:

• Aesculin showed marginal Nrf2 activation, while 3-O-β-d-glycosyl aesculin robustly activated Nrf2 and induced downstream genes.
• 3-O-β-d-glycosyl aesculin suppressed Nrf2 ubiquitination and degradation.
• 3-O-β-d-glycosyl aesculin significantly reduced lung inflammation and improved survival in sepsis models, effects dependent on Nrf2.
• The anti-inflammatory effects of 3-O-β-d-glycosyl aesculin were superior to aesculin.

Conclusions:

• Glycosylation confers Nrf2-activating ability to aesculin, enhancing its anti-inflammatory function.
• 3-O-β-d-glycosyl aesculin demonstrates significant therapeutic potential for acute lung injury and sepsis.
• Glycosylation represents a viable strategy for improving or modifying aesculin's pharmacological properties.