Nonsteroidal Anti-Inflammatory Drugs Induced Endothelial Apoptosis by Perturbing Peroxisome Proliferator-Activated Receptor-δ Transcriptional Pathway

2008 ◽  
Vol 74 (5) ◽  
pp. 1399-1406 ◽  
Author(s):  
Jun-Yang Liou ◽  
Chia-Ching Wu ◽  
Bo-Rui Chen ◽  
Linju B. Yen ◽  
Kenneth K. Wu
Keyword(s):  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Endothelial Apoptosis ◽  
Inflammatory Drugs ◽  
Anti Inflammatory ◽  
Transcriptional Pathway

scholarly journals Pharmacological (or Synthetic) and Nutritional Agonists of PPAR-γ as Candidates for Cytokine Storm Modulation in COVID-19 Disease

Molecules ◽  
2020 ◽  
Vol 25 (9) ◽  
pp. 2076 ◽  
Author(s):  
Carmen Ciavarella ◽  
Ilenia Motta ◽  
Sabrina Valente ◽  
Gianandrea Pasquinelli
Keyword(s):  
Peroxisome Proliferator ◽  
Cytokine Storm ◽  
Disease Treatment ◽  
Peroxisome Proliferator Activated Receptor ◽  
Dual Approach ◽  
Ppar Γ ◽  
Inflammatory Drugs ◽  
Coronavirus Infection ◽  
Anti Inflammatory ◽  
Dietary Strategies

The cytokine storm is an abnormal production of inflammatory cytokines, due to the over-activation of the innate immune response. This mechanism has been recognized as a critical mediator of influenza-induced lung disease, and it could be pivotal for COVID-19 infections. Thus, an immunomodulatory approach targeting the over-production of cytokines could be proposed for viral aggressive pulmonary disease treatment. In this regard, the peroxisome proliferator-activated receptor (PPAR)-γ, a member of the PPAR transcription factor family, could represent a potential target. Beside the well-known regulatory role on lipid and glucose metabolism, PPAR-γ also represses the inflammatory process. Similarly, the PPAR-γ agonist thiazolidinediones (TZDs), like pioglitazone, are anti-inflammatory drugs with ameliorating effects on severe viral pneumonia. In addition to the pharmacological agonists, also nutritional ligands of PPAR-γ, like curcuma, lemongrass, and pomegranate, possess anti-inflammatory properties through PPAR-γ activation. Here, we review the main synthetic and nutritional PPAR-γ ligands, proposing a dual approach based on the strengthening of the immune system using pharmacological and dietary strategies as an attempt to prevent/treat cytokine storm in the case of coronavirus infection.

scholarly journals Mechanisms of Peroxisome Proliferator Activated Receptor γ Regulation by Non-steroidal Anti-inflammatory Drugs

2015 ◽  
Vol 13 (1) ◽  
pp. nrs.13004 ◽  
Author(s):  
Ana C. Puhl ◽  
Flora A. Milton ◽  
Aleksandra Cvoro ◽  
Douglas H. Sieglaff ◽  
Jéssica C.L. Campos ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Target Genes ◽  
Partial Agonist ◽  
High Dose ◽  
Peroxisome Proliferator ◽  
Binding Modes ◽  
Peroxisome Proliferator Activated Receptor ◽  
Sulindac Sulfide ◽  
Inflammatory Drugs ◽  
Anti Inflammatory

Non-steroidal anti-inflammatory drugs (NSAIDs) display anti-inflammatory, antipyretic and analgesic properties by inhibiting cyclooxygenases and blocking prostaglandin production. Previous studies, however, suggested that some NSAIDs also modulate peroxisome proliferator activated receptors (PPARs), raising the possibility that such off target effects contribute to the spectrum of clinically relevant NSAID actions. In this study, we set out to understand how peroxisome proliferator activated receptor-γ (PPARγ/PPARG) interacts with NSAIDs using X-ray crystallography and to relate ligand binding modes to effects on receptor activity. We find that several NSAIDs (sulindac sulfide, diclofenac, indomethacin and ibuprofen) bind PPARγ and modulate PPARγ activity at pharmacologically relevant concentrations. Diclofenac acts as a partial agonist and binds to the PPARγ ligand binding pocket (LBP) in typical partial agonist mode, near the β-sheets and helix 3. By contrast, two copies of indomethacin and sulindac sulfide bind the LBP and, in aggregate, these ligands engage in LBP contacts that resemble agonists. Accordingly, both compounds, and ibuprofen, act as strong partial agonists. Assessment of NSAID activities in PPARγ-dependent 3T3-L1 cells reveals that NSAIDs display adipogenic activities and exclusively regulate PPARγ-dependent target genes in a manner that is consistent with their observed binding modes. Further, PPARγ knockdown eliminates indomethacin activities at selected endogenous genes, confirming receptor-dependence of observed effects. We propose that it is important to consider how individual NSAIDs interact with PPARγ to understand their activities, and that it will be interesting to determine whether high dose NSAID therapies result in PPAR activation.

Nonsteroidal anti-inflammatory drugs inhibit a Fyn-dependent pathway coupled to Rac and stress kinase activation in TCR signaling

Blood ◽  
2005 ◽  
Vol 105 (5) ◽  
pp. 2042-2048 ◽  
Author(s):  
Silvia Rossi Paccani ◽  
Laura Patrussi ◽  
Cristina Ulivieri ◽  
Jaime L. Masferrer ◽  
Mario Milco D'Elios ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Protein Tyrosine Kinase ◽  
Peroxisome Proliferator ◽  
Tcr Signaling ◽  
Peroxisome Proliferator Activated Receptor ◽  
Kinase Activation ◽  
Stress Kinase ◽  
Inflammatory Drugs ◽  
Anti Inflammatory ◽  
Cox 1

AbstractIn addition to their anti-inflammatory properties, nonsteroidal anti-inflammatory drugs (NSAIDs) harbor immunosuppressive activities related to their capacity both to inhibit cyclooxygenases (COXs) and to act as peroxisome proliferator-activated receptor (PPAR) ligands. We have previously shown that the stress-activated kinase p38 is a selective target of NSAIDs in T cells. Here we have investigated the effect of NSAIDs on the signaling pathway triggered by the T-cell antigen receptor (TCR) and leading to stress kinase activation. The results show that nonselective and COX-1–selective NSAIDs also block activation of the stress kinase c-Jun N-terminal kinase (JNK) and that prostaglandin-E2 (PGE2) reverses this block and enhances TCR-dependent JNK activation. Analysis of the activation state of the components upstream of p38 and JNK showed that NSAIDs inhibit the serine-threonine kinase p21-activated protein kinase 1 (Pak1) and the small guanosine 5′-triphosphatase (GTPase) Rac, as well as the Rac-specific guanine nucleotide exchanger, Vav. Furthermore, activation of Fyn, which controls Vav phosphorylation, is inhibited by NSAIDs, whereas activation of lymphocyte-specific protein tyrosine kinase (Lck) and of the Lck-dependent tyrosine kinase cascade is unaffected. Accordingly, constitutively active Fyn reverses the NSAID-dependent stress kinase inhibition. The data identify COX-1 as an important early modulator of TCR signaling and highlight a TCR proximal pathway selectively coupling the TCR to stress kinase activation.

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