Portal de investigación
Anti-inflammatory effects and improved metabolic derangements in ob/ob mice by a newly synthesized prenylated benzopyran with pan-PPAR activity
Fecha de publicación:
Fecha Ahead of Print:
Autores de INCLIVA
Participantes ajenos a INCLIVA
- Collado, Aida
- Duplan, Isabelle
- Hennuyer, Nathalie
- Garibotto, Francisco
- Enriz, Ricardo D
- Dacquet, Catherine
- Staels, Bart
Grupos y Plataformas de I+D+i
Abstract
Background and purpose: Selective peroxisome proliferator-activated receptors (PPARs) are widely used to treat metabolic complications; however, the limited effect of PPAR alpha agonists on glucose metabolism and the adverse effects associated with selective PPAR gamma 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 PPAR alpha, PPAR beta/delta and PPAR gamma. A parallel-plate flow chamber was employed to investigate its effect on TNF alpha-induced leukocyteendothelium 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-kappa B activation. PPARs/RXR alpha 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 PPAR alpha activity, with moderate and weak activity against PPAR beta/delta and PPAR gamma, respectively. In vitro, BP-2 reduced TNF alpha-induced endothelial ICAM-1, VCAM-1 and fractalkine/CX3CL1 expression, suppressed mononuclear cell arrest via PPAR beta/delta-RXR alpha interactions and decreased p38-MAPK/NF-kappa B activation. In vivo, BP-2 improved the circulating levels of glucose and triglycerides in ob/ob mice, suppressed Tlymphocyte/macrophage infiltration and proinflammatory markers in the liver and white adipose tissue, but increased the expression of the M2-like macrophage marker CD206.
Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.
Datos de la publicación
- ISSN/ISSNe:
- 1043-6618, 1096-1186
- Tipo:
- Article
- Páginas:
- 106638-106638
- PubMed:
- 36586645
PHARMACOLOGICAL RESEARCH Elsevier Inc.
Citas Recibidas en Web of Science: 13
Documentos
Filiaciones
Keywords
- Prenylated benzopyran; PPAR; Molecular modeling; Metabolic disorders; Anti-inflammatory effects; ob/ob mice
Financiación
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Cita
Anti-inflammatory effects and improved metabolic derangements in <i>ob</i>/<i>ob</i> mice by a newly synthesized prenylated benzopyran with pan-PPAR activity. Marques P, Villarroel C, Collado A, Garcia A, Vila L, Duplan I, Hennuyer N et al. PHARMACOLOGICAL RESEARCH. 2023 enero 01. 187106638-106638. DOI:10.1016/j.phrs.2022.106638. PMID:36586645.
