Endoplasmic reticulum stress response in the roadway for the effects of non-steroidal anti-inflammatory drugs

Mügge, Fernanda L. B.; Silva, Aristóbolo M.

doi:10.1515/ersc-2015-0001

Cited by 8 publications

(11 citation statements)

References 88 publications

(112 reference statements)

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“…[ 1,24,25 ] Activation of ER stress signalling PERK/eIF‐2α/ATF‐4/CHOP and/or IRE‐1α/JNK1/2 pathways by indomethacin and diclofenac results in apoptosis in several culture models including primary pig gastric epithelial cells, Huh‐7, H‐4 and U‐87 cells. [ 4,5 ] In this study, we demonstrated that indomethacin and diclofenac caused ER stress‐mediated apoptosis in Caco‐2 cells by activating different arms of ER sensors. These two NSAIDs and the other two known ER stressors tunicamycin and thapsigargin shared a similar apoptosis‐inducing mechanism by activation of PERK/eIF‐2α/ATF‐4/CHOP pathway.…”

Section: Discussionmentioning

confidence: 78%

“…[ 3 ] Indomethacin and diclofenac have been linked to increased phosphorylation of ER sensors, particularly pancreatic‐like ER kinase (PERK) and inositol‐requiring enzymes‐1α (IRE‐1α), in various cell models such as human glioma cells. [ 4,5 ] Activation of PERK upregulates the C/EBP homologous transcription factor expression (CHOP), resulting in alteration of apoptotic proteins, mitochondrial dysfunction and apoptosis. [ 6,7 ]…”

Section: Introductionmentioning

confidence: 99%

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Modulation of non-steroidal anti-inflammatory drug-induced, ER stress-mediated apoptosis in Caco-2 cells by different polyphenolic antioxidants: a mechanistic study

Boonyong

Vardhanabhuti

Jianmongkol

2020

Journal of Pharmacy and Pharmacology

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Objectives Direct scavenging of reactive oxygen species could not prevent ER stress-associated cytotoxicity of indomethacin or diclofenac in Caco-2 cells. This study investigated the effects of three polyphenolic antioxidants epigallocatechin gallate (EGCG), phyllanthin and hypophyllathin in non-steroidal anti-inflammatory drug-induced Caco-2 apoptosis. Methods Cells were treated with ER stressors (indomethacin, diclofenac, tunicamycin or thapsigargin) and the polyphenols for up to 72 h. Cell viability, apoptosis and mitochondrial function were monitored by MTT, Hoechst 33342 and TMRE assays, respectively. Protein expression was measured by Western blot analysis. Key findings Epigallocatechin gallate suppressed increases in p-PERK/p-eIF-2a/ ATF-4/CHOP and p-IRE-1a/p-JNK1/2 expression levels in the cells treated with any of the ER stressors, leading to inhibition of apoptosis. In contrast, phyllanthin increased apoptosis in the cells subsequently exposed to either diclofenac, tunicamycin or thapsigargin, but not in the indomethacin-treated cells. The potentiation effect of phyllanthin seen with the three ER stressors was related to suppression of survival p-Nrf-2/HO-1 expression, resulting in increased activation of the eIF-2a/ATF-4/CHOP pathway. On the other hand, hypophyllanthin had no significant effect on the ER stressor-induced apoptosis. Conclusion Epigallocatechin gallate, phyllanthin and hypophyllanthin displayed different effects in the ER stress-mediated apoptosis, depending upon their interaction with the specific unfolded protein response signalling.

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Section: Discussionmentioning

confidence: 78%

Section: Introductionmentioning

confidence: 99%

Modulation of non-steroidal anti-inflammatory drug-induced, ER stress-mediated apoptosis in Caco-2 cells by different polyphenolic antioxidants: a mechanistic study

Boonyong

Vardhanabhuti

Jianmongkol

2020

Journal of Pharmacy and Pharmacology

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“…Therefore, we hypothesized that endoplasmic reticulum stress responses might be associated with SNX10 expression. The ER stress response is involved in NSAID-induced cell death and toxicity 26 , 27 where Ca 2+ -dependent CHOP induction plays an important role 28 . To assess whether NSAIDs elevate intracellular Ca 2+ level in liver cells, we treated NSAIDs on HepG2 cells loaded with fluo-3 AM, the calcium-binding fluorescent dye.…”

Section: Resultsmentioning

confidence: 99%

SNX10-mediated degradation of LAMP2A by NSAIDs inhibits chaperone-mediated autophagy and induces hepatic lipid accumulation

Lee¹,

Kim²,

Choi³

et al. 2022

Theranostics

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Rationale: While some non-steroidal anti-inflammatory drugs (NSAIDs) are reported to induce hepatic steatosis, the molecular mechanisms are poorly understood. This study presented the mechanism by which NSAIDs induce hepatic lipid accumulation. Methods: Mouse primary hepatocytes and HepG2 cells were used to examine the underlying mechanism of NSAID-induced hepatic steatosis. Lipid accumulation was measured using Nile-red assay and BODIPY 493/503. The activity of chaperone-mediated autophagy (CMA) was determined by western blotting, qRT-PCR, and confocal imaging. The effect of NSAID on CMA inhibition was evaluated in vivo using diclofenac and CMA activator (AR7) administered mice. Results: All tested NSAIDs in this study accumulated neutral lipids in hepatocytes, diclofenac having demonstrated the most potency in that regard. Diclofenac-induced lipid accumulation was confirmed in both mouse primary hepatocytes and the liver of mice. NSAIDs inhibited CMA, as reflected by the decreased expression of lysosome-associated membrane glycoprotein 2 isoform A (LAMP2A) protein, the increased expression of CMA substrate proteins such as PLIN2, and the decreased activity of photoactivatable KFERQ-PAmCherry reporter. Reactivation of CMA by treatment with AR7 or overexpression of LAMP2A inhibited diclofenac-induced lipid accumulation and hepatotoxicity. Upregulation of sorting nexin 10 (SNX10) via the CHOP-dependent endoplasmic reticulum stress response and thus maturation of cathepsin A (CTSA) was shown to be responsible for the lysosomal degradation of LAMP2A by diclofenac. Conclusion: We demonstrated that NSAIDs induced SNX10- and CTSA-dependent degradation of LAMP2A, thereby leading to the suppression of CMA. In turn, impaired CMA failed to degrade PLIN2 and disrupted cellular lipid homeostasis, thus leading to NSAID-induced steatosis and hepatotoxicity.

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“…Diclofenac belongs to the class of most frequently prescribed analgesic and anti-inflammatory drugs (NSAIDs) worldwide. Limited literature data indicate the involvement of NSAIDs in ER stress in different cellular systems [ 15 ], but it remains unknown how NSAIDs may affect ER stress in the endothelial cells. The main questions which we intended to answer in the present work were: (1) whether diclofenac can affect the tunicamycin-induced ER stress in endothelial cells and (2) how the drug can modulate the UPR signaling pathways activated under ER stress.…”

Section: Introductionmentioning

confidence: 99%

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

Sokołowska

Siatkowska²,

Jóźwiak-Bębenista

et al. 2022

Molecules

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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.

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Endoplasmic reticulum stress response in the roadway for the effects of non-steroidal anti-inflammatory drugs

Cited by 8 publications

References 88 publications

Modulation of non-steroidal anti-inflammatory drug-induced, ER stress-mediated apoptosis in Caco-2 cells by different polyphenolic antioxidants: a mechanistic study

Modulation of non-steroidal anti-inflammatory drug-induced, ER stress-mediated apoptosis in Caco-2 cells by different polyphenolic antioxidants: a mechanistic study

SNX10-mediated degradation of LAMP2A by NSAIDs inhibits chaperone-mediated autophagy and induces hepatic lipid accumulation

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

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