Department of Pharmacology and Toxicology, Medical University of Lodz, 7/9 Zeligowskiego, 90-752 Lodz, Poland.
Laboratory of Molecular and Nanostructural Biophysics, Bionanopark, 114/116 Dubois, 93-465 Lodz, Poland.
Molecules. 2022 May 26;27(11):3449. doi: 10.3390/molecules27113449.
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.
双氯芬酸属于非甾体抗炎药（NSAIDs）类，是最常被用于治疗发热、疼痛和炎症的处方药物之一。尽管 NSAIDs 已经在药物市场上存在了几十年，但流行病学研究显示了 NSAIDs 的新的临床应用，并且发现了它们作用的新机制。内质网（ER）应激下激活的未折叠蛋白反应（UPR）参与许多疾病的病理生理学，并且可能成为药物靶点，因此，本研究评估了双氯芬酸对内皮细胞中衣霉素诱导的 UPR 途径的影响。RT-PCR 分析表明，双氯芬酸显著抑制 ER 应激反应基因（即 CHOP/DITT3、GRP78/HSPA5 和 DNAJB9）的激活。此外，该药物通过 ELISA 测定显著减少了 GRP78 蛋白的显著上调和释放，这可能与导致内皮细胞凋亡诱导的 UPR 激活机制有关。这些结果表明双氯芬酸具有通过减少 UPR 来恢复内皮细胞 ER 平衡的作用，具有一定价值。
