Research progress on the mechanism of action of endoplasmic reticulum stress inhibitors / 中国药理学与毒理学杂志

ABSTRACT

Endoplasmic reticulum stress(ERS)is closely related to the mechanisms of multiple diseases,and regulation of ERS has become a therapeutic target for several diseases.Previous studies by our group have demonstrated that ERS can be alleviated and neuronal cells can be protected by downregulating ERS-related proteins such as GRP78,caspase12 and caspase3.The research on ERS inhibitors has progressed rapidly in recent years,and they can be classified into various types such as molecular chaperones,small molecule compounds and natural products,such as 4-phenylbutyric acid(4-PBA),tauroursodeoxycholic acid(TUDCA)and tumor necrosis factor α-stimulating factor 6(TSG-6),etc.These inhibitors can regulate the ERS signaling pathway through different pathways,such assilent information regulator 1(SIRT1)promotes the expression of anti-apop-totic proteins by inhibiting the PERK-eIF2α-ATF4-CHOP pathway,thus reducing apoptosis.In addition,SIRT1 deacetylates XBP-1,regulates the IRE1α-XBP1 signaling pathway,and inhibits the expressions of GRP78 and CHOP,thereby reducing the protein load of endoplasmic reticulum(ER)and alleviating ERS;PDE4 inhibitor regu-lates c-Jun-mediated apoptotic pathway,reduces the interaction between IRE1 and TRAF2,and attenuates the level of c-Jun phosphorylation,thereby restoring ER homeostasis.In addition,PDE4 inhibitor activates the antioxidant-acting Nrf-2 pathway,decreases the concen-tration of intracellular calcium ion and reduces the pro-duction of ROS;TSG-6 exerts anti-inflammatory effects by regulating the secretion of inflammatory factors through PERK-eIF-2α-NF-κB p65 and IRE1α-TRAF2-NF-κB p65 signaling pathways.In-depth exploration of the potential mechanism of action of ERS inhibitors is of great signifi-cance for finding ways to treat related diseases by regu-lating ERS.