Anti-inflammatory effects and improved metabolic derangements in ob/ob mice by a newly synthesized prenylated benzopyran with pan-PPAR activity.
| Autor: | Marques P; Department of Pharmacology, University of Valencia, Valencia, Spain; Institute of Health Research-INCLIVA, University Clinic Hospital of Valencia, Valencia, Spain., Villarroel-Vicente C; Department of Pharmacology, University of Valencia, Valencia, Spain; Institute of Health Research-INCLIVA, University Clinic Hospital of Valencia, Valencia, Spain., Collado A; Department of Pharmacology, University of Valencia, Valencia, Spain; Institute of Health Research-INCLIVA, University Clinic Hospital of Valencia, Valencia, Spain., García A; Department of Pharmacology, University of Valencia, Valencia, Spain; Institute of Health Research-INCLIVA, University Clinic Hospital of Valencia, Valencia, Spain., Vila L; Institute of Health Research-INCLIVA, University Clinic Hospital of Valencia, Valencia, Spain., Duplan I; University of Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U-1011-EGID, F-59000 Lille, France., Hennuyer N; University of Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U-1011-EGID, F-59000 Lille, France., Garibotto F; Faculty of Chemistry, Biochemistry and Pharmacy, National University of San Luis-IMIBIO-SL-CONICET, Chacabuco 917-5700, San Luis, Argentina., Enriz RD; Faculty of Chemistry, Biochemistry and Pharmacy, National University of San Luis-IMIBIO-SL-CONICET, Chacabuco 917-5700, San Luis, Argentina., Dacquet C; Institut de Recherches Servier, Suresnes 92150, France., Staels B; University of Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U-1011-EGID, F-59000 Lille, France., Piqueras L; Department of Pharmacology, University of Valencia, Valencia, Spain; Institute of Health Research-INCLIVA, University Clinic Hospital of Valencia, Valencia, Spain; CIBERDEM-Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders, Carlos III Health Institute, Madrid, Spain., Cortes D; Department of Pharmacology, University of Valencia, Valencia, Spain. Electronic address: dcortes@uv.es., Sanz MJ; Department of Pharmacology, University of Valencia, Valencia, Spain; Institute of Health Research-INCLIVA, University Clinic Hospital of Valencia, Valencia, Spain; CIBERDEM-Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders, Carlos III Health Institute, Madrid, Spain. Electronic address: maria.j.sanz@uv.es., Cabedo N; Department of Pharmacology, University of Valencia, Valencia, Spain; Institute of Health Research-INCLIVA, University Clinic Hospital of Valencia, Valencia, Spain. Electronic address: ncabedo@uv.es. |
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| Jazyk: | angličtina |
| Zdroj: | Pharmacological research [Pharmacol Res] 2023 Jan; Vol. 187, pp. 106638. Date of Electronic Publication: 2022 Dec 28. |
| DOI: | 10.1016/j.phrs.2022.106638 |
| Abstrakt: | Background and Purpose: Selective peroxisome proliferator-activated receptors (PPARs) are widely used to treat metabolic complications; however, the limited effect of PPARα agonists on glucose metabolism and the adverse effects associated with selective PPARγ activators have stimulated the development of novel pan-PPAR agonists to treat metabolic disorders. Here, we synthesized a new prenylated benzopyran (BP-2) and evaluated its PPAR-activating properties, anti-inflammatory effects and impact on metabolic derangements. Experimental Approach: BP-2 was used in transactivation assays to evaluate its agonism to PPARα, PPARβ/δ and PPARγ. A parallel-plate flow chamber was employed to investigate its effect on TNFα-induced leukocyte-endothelium interactions. Flow cytometry and immunofluorescence were used to determine its effects on the expression of endothelial cell adhesion molecules (CAMs) and chemokines and p38-MAPK/NF-κB activation. PPARs/RXRα interactions were determined using a gene silencing approach. Analysis of its impact on metabolic abnormalities and inflammation was performed in ob/ob mice. Key Results: BP-2 displayed strong PPARα activity, with moderate and weak activity against PPARβ/δ and PPARγ, respectively. In vitro, BP-2 reduced TNFα-induced endothelial ICAM-1, VCAM-1 and fractalkine/CX Conclusion and Implications: BP-2 emerges as a novel pan-PPAR lead candidate to normalize glycemia/triglyceridemia and minimize inflammation in metabolic disorders, likely preventing the development of further cardiovascular complications. Competing Interests: Declaration of Competing Interest No potential conflicts of interest relevant to this article were reported. (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.) |
| Databáze: | MEDLINE |
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