Anti-inflammatory effects and improved metabolic derangements in ob/ob mice by a newly synthesized prenylated benzopyran with pan-PPAR activity. (January 2023)

• Record Type: Journal Article
• Authors: Marques, Patrice; Villarroel-Vicente, Carlos; Collado, Aida; García, Ainhoa; Vila, Laura; Duplan, Isabelle; Hennuyer, Nathalie; Garibotto, Francisco; Enriz, Ricardo D.; Dacquet, Catherine; Staels, Bart; Piqueras, Laura; Cortes, Diego; Sanz, María-Jesús; Cabedo, Nuria
• Is Part Of: Pharmacological research. Volume 187(2023)
• Publication Date: 2023-01
• Subjects: WY-14, 643 or Pirinixic acid (PubChem CID: 5694) -- GW501516 or Endurobol (PubChem CID: 9803963) -- Rosiglitazone (PubChem CID: 77999); ALT alanine aminotransferase -- AST aspartate transaminase -- BP-2 benzopyran––2-(ethyl 4'-methylheptenoate)-6-(p-fluorobenzyloxy)-2-(methyl)-benzodihydropyran -- BSA bovine serum albumin -- CAM cell adhesion molecule -- CVD cardiovascular disease -- DMSO dimethylsulfoxide -- FFAs free fatty acids -- HDL-c HDL-cholesterol -- HUVEC human umbilical venous endothelial cells -- ICAM-1 intercellular adhesion molecule-1 -- MCP-1/CCL2 monocyte chemoattractant protein-1 -- MD molecular dynamics -- MetS Metabolic syndrome -- PPAR peroxisome proliferator-activated receptor -- RXR 9-cis-retinoic acid receptor -- SEM standard error of the mean -- siRNA small interfering RNA -- T2D type 2 diabetes -- TNFα tumor necrosis factor-α -- TZDs thiazolidinediones/glitazones -- VCAM-1 vascular cell adhesion molecule-1 -- WAT white adipose tissue; Prenylated benzopyran -- PPAR -- Molecular modeling -- Metabolic disorders -- Anti-inflammatory effects -- ob/ob mice; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2022.106638
• Languages: English
• ISSNs: 1043-6618

Abstract

Abstract: 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/CX3 CL1 expression, suppressed mononuclear cell arrest via PPARβ/δ-RXRα interactions and decreased p38-MAPK/NF-κB activation. In vivo, BP-2 improved the circulating levels of glucose and triglycerides in ob/ob mice, suppressed T-lymphocyte/macrophage infiltration and proinflammatory markers in the liver and white adipose tissue, but increased the expression of the M2-like macrophage marker CD206. 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. Graphical Abstract: ga1 Highlights: Limited/side effects of selective PPAR agonists raise interest in pan-PPAR agonists. Therefore, a new prenylated benzopyran pan-PPAR agonist (BP-2 ) was synthetized. BP-2 reduces endothelial dysfunction in vitro through RXRα/PPARβ/δ interaction. In vivo BP-2 improves metabolic abnormalities and inflammatory status in ob/ob mice. BP-2 may prevent the development of cardiovascular disease in metabolic disorders.