Superior neurometabolic protection by 8-hydroxy-dihydromyricetin over dihydromyricetin in diabetic zebrafish: insights from integrated metabolomics and transcriptomics

Abstract

Herein, the effects of C-8 hydroxylation on the protective properties of dihydromyricetin (DHM) in a zebrafish larval model of diabetes and neurometabolic dysfunction were investigated. Diabetes was induced using alloxan and glucose, followed by treatment with DHM and its hydroxylated form, 8-hydroxy-dihydromyricetin (H-DHM), obtained through Beauveria bassiana fermentation. Biochemical, metabolomic, and transcriptomic analyses were conducted to evaluate their differences in efficacy. The results demonstrated that hydroxylation enhanced DHM's ability to improve locomotor activity, regulate Na⁺/K⁺-ATPase, Ca²⁺-ATPase, acetylcholinesterase, glutamate, and ATP levels, and modulate oxidative stress, as well as glucose and lipid homeostasis in diabetic zebrafish. Metabolomic analysis revealed that both DHM and H-DHM influenced key metabolic pathways, including amino acid metabolism, purine metabolism, and glycerophospholipid metabolism, while H-DHM specifically regulated sphingolipid metabolism. Transcriptomic analysis and weighted gene co-expression network analysis (WGCNA) further indicated that hydroxylation enhanced DHM's ability to target genes associated with pancreatic β-cell function, oxidative stress, and energy metabolism, such as DUSP26, ITLN1, gdf11, insl5a, pik3r5, gck, kcnj1a.6, tfr2, ebi3, KYAT3, and hdac12. The enhancement of DHM's regulatory effects on diabetes-associated neurometabolic dysfunction highlights the potential of fermentation-derived natural product derivatives for chronic disease management.