Anti-Inflammatory, Antioxidant, and WAT/BAT-Conversion Stimulation Induced by Novel PPAR Ligands: Results from Ex Vivo and In Vitro Studies
-
Published:2023-02-24
Issue:3
Volume:16
Page:346
-
ISSN:1424-8247
-
Container-title:Pharmaceuticals
-
language:en
-
Short-container-title:Pharmaceuticals
Author:
Recinella Lucia1, De Filippis Barbara1ORCID, Libero Maria Loreta1ORCID, Ammazzalorso Alessandra1ORCID, Chiavaroli Annalisa1ORCID, Orlando Giustino1, Ferrante Claudio1ORCID, Giampietro Letizia1ORCID, Veschi Serena1ORCID, Cama Alessandro1ORCID, Mannino Federica2, Gasparo Irene2, Bitto Alessandra2, Amoroso Rosa1ORCID, Brunetti Luigi1, Leone Sheila1ORCID
Affiliation:
1. Department of Pharmacy, G. d’Annunzio University, 66100 Chieti, Italy 2. Department of Clinical and Experimental Medicine, University of Messina, 98122 Messina, Italy
Abstract
Activation of peroxisome proliferator-activated receptors (PPARs) not only regulates multiple metabolic pathways, but mediates various biological effects related to inflammation and oxidative stress. We investigated the effects of four new PPAR ligands containing a fibrate scaffold—the PPAR agonists (1a (αEC50 1.0 μM) and 1b (γEC50 0.012 μM)) and antagonists (2a (αIC50 6.5 μM) and 2b (αIC50 0.98 μM, with a weak antagonist activity on γ isoform))—on proinflammatory and oxidative stress biomarkers. The PPAR ligands 1a-b and 2a-b (0.1–10 μM) were tested on isolated liver specimens treated with lipopolysaccharide (LPS), and the levels of lactate dehydrogenase (LDH), prostaglandin (PG) E2, and 8-iso-PGF2α were measured. The effects of these compounds on the gene expression of the adipose tissue markers of browning, PPARα, and PPARγ, in white adipocytes, were evaluated as well. We found a significant reduction in LPS-induced LDH, PGE2, and 8-iso-PGF2α levels after 1a treatment. On the other hand, 1b decreased LPS-induced LDH activity. Compared to the control, 1a stimulated uncoupling protein 1 (UCP1), PR-(PRD1-BF1-RIZ1 homologous) domain containing 16 (PRDM16), deiodinase type II (DIO2), and PPARα and PPARγ gene expression, in 3T3-L1 cells. Similarly, 1b increased UCP1, DIO2, and PPARγ gene expression. 2a-b caused a reduction in the gene expression of UCP1, PRDM16, and DIO2 when tested at 10 μM. In addition, 2a-b significantly decreased PPARα gene expression. A significant reduction in PPARγ gene expression was also found after 2b treatment. The novel PPARα agonist 1a might be a promising lead compound and represents a valuable pharmacological tool for further assessment. The PPARγ agonist 1b could play a minor role in the regulation of inflammatory pathways.
Funder
Italian Ministry of University University “G. D’Annunzio” of Chieti-Pescara, Italy
Subject
Drug Discovery,Pharmaceutical Science,Molecular Medicine
Reference68 articles.
1. Peroxisome proliferator-activated receptors in inflammation control;Delerive;J. Endocrinol.,2001 2. Peroxisome proliferator-activated receptors and inflammation;Moraes;Pharmacol. Ther.,2006 3. Peroxisome-proliferator-activated receptors regulate redox signaling in the cardiovascular system;Kim;World J. Cardiol.,2013 4. Laganà, A.S., Vitale, S.G., Nigro, A., Sofo, V., Salmeri, F.M., Rossetti, P., Rapisarda, A.M.C., La Vignera, S., Condorelli, R.A., and Rizzo, G. (2016). Pleiotropic actions of peroxisome proliferator-activated receptors (PPARs) in dysregulated metabolic homeostasis, inflammation and cancer: Current evidence and future perspectives. Int. J. Mol. Sci., 17. 5. Changes in peroxisome proliferatoractivated receptor alpha target gene expression in peripheral blood mononuclear cells associated with non-alcoholic fatty liver disease;Li;Lipids Health Dis.,2018
Cited by
1 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献
|
|