Modulation of FoxO1 phosphorylation/acetylation by baicalin during aging

Abstract

Baicalin is a flavonoid known to modify various redox-related biological activities. Included is its ability to suppress reactive species (RS) producing activity and modulate nuclear factor-κB through cellular redox regulation with enhanced thiol ability. FoxO regulates various genes that are known to be involved in cellular metabolism related to cell death and the oxidative stress response. One such case is the prevention of FoxO1 expression by activated insulin-induced phosphatidylinositol 3-kinase (PI3K)/Akt, which leads to increased oxidative stress and aging processes. In the present study, we attempted to elucidate the molecular modulation of antioxidant baicalin on the insulin-induced FoxO1 inactivation. We used HEK293T cultured cells and kidney tissue isolated from 24-month-old rats treated with baicalin at a dose of 10 or 20 mg/kg/day for 10 days. We found that baicalin enhanced catalase and suppressed RS production in cell system and in isolated kidney tissue in contrast to the nontreated aged rats. Results also showed activation of insulin signaling (PI3K/Akt), FoxO1 phosphorylation/acetylation and the down-regulation of catalase and manganese superoxide dismutase, both of which are FoxO1-targeting genes. Furthermore, baicalin-treated rats showed a decreased FoxO1 phosphorylation via PI3K/Akt cascade and FoxO1 acetylation by the cAMP-response element-binding protein binding protein (CBP). These results strongly suggest that treatment with baicalin influenced phosphorylation/acetylation of FoxO1 by up-regulating PI3K/Akt signaling through insulin in aged rats. Our results further reveal that baicalin regulated FoxO1 phosphorylation via PI3K/Akt by insulin and FoxO1 acetylation by the interaction of CBP and SIRT1, leading to changes in catalase gene expression during aging.