Diclofenac Diminished the Unfolded Protein Response (UPR) Induced by Tunicamycin in Human Endothelial Cells

Abstract

Diclofenac belongs to the class of nonsteroidal anti-inflammatory drugs (NSAIDs), which are amongst the most frequently prescribed drugs to treat fever, pain and inflammation. Despite the presence of NSAIDs on the pharmaceutical market for several decades, epidemiological studies have shown new clinical applications of NSAIDs, and new mechanisms of their action were discovered. The unfolded protein response (UPR) activated under endoplasmic reticulum (ER) stress is involved in the pathophysiology of many diseases and may become a drug target, therefore, the study evaluated the effects of diclofenac on the tunicamycin-induced UPR pathways in endothelial cells. RT PCR analysis showed that diclofenac significantly inhibited activation of ER stress-responsive genes, i.e., CHOP/DITT3, GRP78/HSPA5 and DNAJB9. Additionally, the drug diminished the significant upregulation and release of the GRP78 protein, as evaluated using the ELISA assay, which was likely to be involved in the mechanism of the UPR activation resulting in apoptosis induction in endothelial cells. These results suggest the value of diclofenac as a factor capable of restoring the ER homeostasis in endothelial cells by diminishing the UPR.

Lycopene Alleviates Chronic Stress-Induced Liver Injury by Inhibiting Oxidative Stress-Mediated Endoplasmic Reticulum Stress Pathway Apoptosis in Rats

“…However, when ER homeostasis is disrupted, these proteins are released. 36 In this study, we found that the liver ER of CRS rats was significantly swollen, and the expression of GRP78 was substantially increased, suggesting the occurrence of ERS. ERS is a vital self-defense mechanism of cells, which can improve the adaptability of cells to environmental changes, but too intense and prolonged ERS can lead to cell apoptosis.…”

“…These transmembrane proteins bind to the ER chaperone GRP78 under normal physiological conditions. However, when ER homeostasis is disrupted, these proteins are released . In this study, we found that the liver ER of CRS rats was significantly swollen, and the expression of GRP78 was substantially increased, suggesting the occurrence of ERS.…”

PPARγ, NF-κB and the UPR pathway as new molecular targets in the anti-inflammatory actions of NSAIDs: Novel applications in cancers and central nervous system diseases?

“…Additionally, the drug diminished the significant upregulation and release of the GRP78 protein in endothelial cells. 24 Similar effects in endothelial cells (e.g., HCAEC, HPAEC and HUVECs) were obtained after the application of meloxicam, ibuprofen and acetylsalicylic acid, although notably not for celecoxib. Celecoxib downregulated ATF6 and GRP78 expression, as well as IRE1α and PERK phosphorylation stimulated by ER-stress inducer tunicamycin.…”

Endoplasmic reticulum-quality control pathway and endoplasmic reticulum-associated degradation mechanism regulate the N-glycoproteins and N-glycan structures in the diatom Phaeodactylum tricornutum

“…The cell density of P. tricornutum was significantly reduced by tunicamycin in a dose-dependent manner. Similarly, the mortality rate of plants and the cell viability of human endothelial cells were also dependent on the concentration of tunicamycin [25,27]. The efficiency of photosynthesis (Fv/Fm) and the rate of photosynthetic electron transport (ETR) were significantly inhibited by tunicamycin stress, indicating that tunicamycin might result in the differentially expression of genes related to photosynthesis.…”