Enhanced antioxidant effect of prenylated polyphenols as Fyn inhibitor

Polyphenols have antioxidant effects. In view of the diverse biological activities of prenylated natural products, this study investigated whether polyphenols with prenyl residues have improved antioxidant and cytoprotective activity against oxidative stress, and explored the underlying basis for this effect. A set of structurally related polyphenols exhibited varying degrees of antioxidant effect in HepG2 cells, as evidenced by increases in cell viability against oxidative injury; kazinol E and C with three prenyls had greater potency than other kazinols having fewer prenyl chains. Polyphenols without prenyl (tupichinol C and resveratrol) showed weaker potency. Treatment with kazinol E diminished H2O2 production and enabled cells to protect the mitochondria, as indicated by the inhibition of mitochondrial fragmentation, mitochondrial permeability transition, and cytochrome c release. Moreover, kazinol E activated LKB1 by its phosphorylation and cytoplasmic translocation, contributing to the protection of mitochondria via AMPK. In vitro or in a cell-based assay, tyrosine phosphorylation of Fyn was prohibited by kazinol E, which led to LKB1 activation, as shown by the experiments using Fyn over-expression construct or siRNA. SU6656, a known Fyn inhibitor, had a similar effect. Moreover, oxidative stress facilitated Fyn phosphorylation with repression of AMPKα and GSK3β phosphorylation, which was abolished by kazinol E treatment. The role of Fyn inhibition by kazinol E in AMPK-mediated protection of the cell viability and mitochondrial function was strengthened by ectopically expressed Fyn’s reversal of these effects. In conclusion, kazinols as multi-prenylated polyphenols possess increased antioxidant and cytoprotective activity, which depends on the activation of LKB1-AMPK pathway downstream of Fyn inhibition.

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► Polyphenols with more prenyls have greater antioxidant effects.
► Oxidative stress activates Fyn, which leads to AMPK inhibition.
► Fyn inhibition by prenylated polyphenols causes LKB1 and AMPK activation.
► Prenylated polyphenols protect mitochondria and cells from oxidative injury.