title: Resveratrol improves TNF-α-induced endothelial dysfunction in a coculture model of a Caco-2 with an endothelial cell line.
abstract: The bioactivity of trans-resveratrol (RSV), an important wine polyphenol, and of its metabolites was investigated in a more relevant setup comprising an in vitro coculture cell model that combines intestinal absorption and conjugation with changes in endothelial function, which is primarily affected in cardiovascular diseases. Caco-2 and endothelial EA.hy926 cells were grown in a coculture, and Caco-2 cells were treated with RSV in the coculture and in two different sequential setups for 4 h and 24 h. Transported metabolites were investigated by UPLC-MS/MSE, and the effects on NO production, ROS inhibition and secretion of vascular endothelial growth factor (VEGF), interleukin-8 (IL-8) and intercellular adhesion molecule-1 (ICAM-1) were evaluated in TNF-α-activated and nonactivated endothelial cells. RSV and four conjugated metabolites, two sulfates and two glucuronides, were identified after intestinal transport. In both coculture and sequential systems, RSV at 20 μM strongly induced NO production. Changes in ROS and NO levels demonstrated a clear effect of crosstalk between cells in the coculture. The secretion of proinflammatory cytokines and VEGF was largely increased by treatment with TNF-α (inflammatory condition). The polyphenol intervention significantly reduced the levels of VEGF, ROS, IL-8 and ICAM-1, with a more pronounced effect in TNF-α-activated endothelial cells. In conclusion, RSV and its metabolites showed accentuated bioactivity on TNF-α-induced inflammation, and the metabolism of endothelial cells as a biological target was not only influenced by these phenolics but also by the communication between distinct cell lines, showing a new perspective for investigations on polyphenol intervention and its biological outcomes.
authors: Department of Food Science and Technology, Federal University of Santa Catarina, Admar Gonzaga 1346, 88034001 Florianópolis, Brazil; Department of Food Safety and Food Quality, Ghent University, Coupure Links 653, 9000 Gent, Belgium.
authors: Isabela Maia
authors: IM
authors: Toaldo
authors: Department of Food Safety and Food Quality, Ghent University, Coupure Links 653, 9000 Gent, Belgium.
authors: John
authors: J
authors: Van Camp
authors: Department of Food Safety and Food Quality, Ghent University, Coupure Links 653, 9000 Gent, Belgium.
authors: Gerard Bryan
authors: GB
authors: Gonzales
authors: Department of Food Safety and Food Quality, Ghent University, Coupure Links 653, 9000 Gent, Belgium; Department of Food Engineering, Faculty of Chemical and Metallurgical Engineering, Istanbul Technical University, 34469 Maslak, Istanbul, Turkey.
authors: Senem
authors: S
authors: Kamiloglu
authors: Department of Food Science and Technology, Federal University of Santa Catarina, Admar Gonzaga 1346, 88034001 Florianópolis, Brazil.
authors: Marilde T
authors: MT
authors: Bordignon-Luiz
authors: Department of Crop Protection, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000 Gent, Belgium.
authors: Guy
authors: G
authors: Smagghe
authors: Department of Industrial Biological Sciences, Faculty of Bioscience Engineering, Ghent University, Graaf Karel de Goedelaan 5, 8500 Kortrijk, Belgium.
authors: Katleen
authors: K
authors: Raes
authors: Department of Food Engineering, Faculty of Chemical and Metallurgical Engineering, Istanbul Technical University, 34469 Maslak, Istanbul, Turkey.
authors: Esra
authors: E
authors: Capanoglu
authors: Department of Food Safety and Food Quality, Ghent University, Coupure Links 653, 9000 Gent, Belgium. Electronic address: charlotte.grootaert@ugent.be.
authors: Charlotte
authors: C
authors: Grootaert
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000378:metabolism*; D000975:Antioxidants / Q000737:chemistry / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D018938:Caco-2 Cells; D002450:Cell Communication; D002460:Cell Line; D018920:Coculture Techniques; D004730:Endothelium, Vascular / Q000276:immunology / Q000378:metabolism*; D020895:Enterocytes / Q000276:immunology / Q000378:metabolism*; D020719:Glucuronides / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000737:chemistry / Q000378:metabolism; D016209:Interleukin-8 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D007408:Intestinal Absorption; D009569:Nitric Oxide / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077185:Resveratrol; D013267:Stilbenes / Q000737:chemistry / Q000378:metabolism*; D013431:Sulfates / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism; D042442:Vascular Endothelial Growth Factors / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000975:Antioxidants; D015415:Biomarkers; C508606:CXCL8 protein, human; D020719:Glucuronides; C573420:ICAM1 protein, human; D018836:Inflammation Mediators; D016209:Interleukin-8; D017382:Reactive Oxygen Species; D013267:Stilbenes; D013431:Sulfates; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha; D042442:Vascular Endothelial Growth Factors; D018799:Intercellular Adhesion Molecule-1; D009569:Nitric Oxide; D000077185:Resveratrol
keywords: Cardiovascular disease; Coculture; ICAM-1; Intestine; Nitric oxide; Resveratrol