MiR-223 Enhances the Neuroprotection of Estradiol Against Oxidative Stress Injury by Inhibiting the FOXO3/TXNIP Axis.

Abstract

Alzheimer's disease (AD) is an irreversible neurodegenerative disorder characterized by complex pathogenesis, of which oxidative stress has long been regarded as a major mechanism. Previously, the protective effects of estradiol on SH-SY5Y cells against Aβ42-induced injuries were demonstrated. In this study, the protection of SH-SY5Y cells by estradiol from H2O2-caused oxidative stress injury and Alzheimer's mice was further confirmed. H2O2 downregulated, whereas estradiol upregulated miR-223 expression. miR-223 overexpression promoted cell viability, inhibited cell apoptosis, reduced ROS levels, enhanced Superoxide Dismutase (SOD) activity, and decreased malondialdehyde (MDA) content. However, miR-223 inhibition exerted opposite effects. miR-223 directly targeted forkhead box O3 (FOXO3) and inhibited FOXO3 expression. H2O2 increased, whereas estradiol decreased thioredoxin interacting protein (TXNIP) levels; FOXO3 positively regulated TXNIP protein levels. In SH-SY5Y cells, FOXO3 overexpression increased, whereas FOXO3 knockdown reduced the cell apoptosis and ROS levels. FOXO3 bound to TXNIP promoter region and activated TXNIP transcription, whereas the activation could be partially inhibited by estradiol. Collectively, the FOXO3/TXNIP axis is downstream of miR-223. miR-223 enhances the neuroprotection of estradiol against oxidative stress injury through the FOXO3/TXNIP axis.