Inhibition of PERK-eIF2α-ATF4 signaling enhances the antiviral effects of resveratrol-loaded nanoparticles against enterovirus 71 in hand, foot, and mouth disease.

Resveratrol-loaded nanoparticles (RES-NPs) have been found to reduce enterovirus 71 (EV71) replication in EV71-infected-rhabdosarcoma (RD) cells. However, the specific mechanism by which RES-NPs prevent EV71 infection in RD cells remains largely unclear. The cell viability, inflammatory response, and oxidative stress in EV71-infected RD cells were assessed. Inhibition of protein kinase RNA-like endoplasmic reticulum kinase (PERK) significantly increased the viability of infected RD cells, reduced inflammation and oxidative stress, and led to a significant decrease in EV71 mRNA levels. Furthermore, treatment of infected RD cells with RES-NPs significantly increased cell viability and alleviated inflammation and oxidative stress, and these effects were further enhanced by inhibition of PERK. RES-NP treatment also resulted in a decrease in phosphorylated PERK, phosphorylated eukaryotic translation initiation factor 2α (eIF2α), and activating transcription factor 4 (ATF4) levels in infected RD cells, and the levels of these protein were further reduced by treatment with the PERK inhibitor. RES-NPs were found to inhibit EV71 infection by reducing virus-induced inflammatory responses and oxidative stress in RD cells, possibly through inactivation of the PERK-eIF2α-ATF4 signaling pathway.