title: Effects on Nitric Oxide Production of Urolithins, Gut-Derived Ellagitannin Metabolites, in Human Aortic Endothelial Cells.
abstract: The consumption of foodstuffs yielding circulating compounds able to maintain endothelial function by improving nitric oxide (NO) bioavailability can be considered as an effective strategy for cardiovascular disease prevention. This work assessed the in vitro effects of urolithin A, urolithin B, and urolithin B-glucuronide, ellagitannin-derived metabolites of colonic origin, on NO release and endothelial NO synthase (eNOS) activation in primary human aortic endothelial cells (HAECs). Urolithins were tested both individually at 15 μM and as a mixture of 5 μM each, at different time points. The biotransformation of these molecules in cell media due to cell metabolism was also evaluated by UHPLC-MS(n). The mix of urolithins at 5 μM significantly increased nitrite/nitrate levels following 24 h of incubation, while single urolithins at 15 μM did not modify NO bioavailability. Both the mix of urolithins at 5 μM and urolithin B-glucuronide at 15 μM activated eNOS expression. All urolithins underwent metabolic reactions, but these were limited to conjugation with sulfate moieties. This study represents a step forward in the understanding of cardiovascular health benefits of ellagitannin-rich foodstuffs and backs the idea that peripheral cells may contribute to urolithin metabolism.
authors.affiliation: Endocrinology and Metabolism, Department of Clinical and Experimental Medicine, University of Parma, Parma 43126, Italy. valentina.spigoni@unipr.it.
authors.forename: Valentina
authors.initials: V
authors.lastname: Spigoni
authors.affiliation: The Laboratory of Phytochemicals in Physiology, Department of Food Science, University of Parma, Parma 43125, Italy. pedromiguel.menaparreno@unipr.it.
authors.forename: Pedro
authors.initials: P
authors.lastname: Mena
authors.affiliation: Endocrinology and Metabolism, Department of Clinical and Experimental Medicine, University of Parma, Parma 43126, Italy. monia.cito@hotmail.it.
authors.forename: Monia
authors.initials: M
authors.lastname: Cito
authors.affiliation: Endocrinology and Metabolism, Department of Clinical and Experimental Medicine, University of Parma, Parma 43126, Italy. federica.fantuzzi1@gmail.com.|Division of Endocrinology, Azienda Ospedaliero-Universitaria of Parma, Parma 43126, Italy. federica.fantuzzi1@gmail.com.
authors.forename: Federica
authors.initials: F
authors.lastname: Fantuzzi
authors.affiliation: Endocrinology and Metabolism, Department of Clinical and Experimental Medicine, University of Parma, Parma 43126, Italy. riccardo.bonadonna@unipr.it.|Division of Endocrinology, Azienda Ospedaliero-Universitaria of Parma, Parma 43126, Italy. riccardo.bonadonna@unipr.it.
authors.forename: Riccardo C
authors.initials: RC
authors.lastname: Bonadonna
authors.affiliation: The Laboratory of Phytochemicals in Physiology, Department of Food Science, University of Parma, Parma 43125, Italy. furio.brighenti@unipr.it.
authors.forename: Furio
authors.initials: F
authors.lastname: Brighenti
authors.affiliation: Endocrinology and Metabolism, Department of Clinical and Experimental Medicine, University of Parma, Parma 43126, Italy. alessandra.deicas@unipr.it.|Division of Endocrinology, Azienda Ospedaliero-Universitaria of Parma, Parma 43126, Italy. alessandra.deicas@unipr.it.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Dei Cas
authors.affiliation: The Laboratory of Phytochemicals in Physiology, Department of Food Science, University of Parma, Parma 43125, Italy. daniele.delrio@unipr.it.
authors.forename: Daniele
authors.initials: D
authors.lastname: Del Rio
mesh_terms: D001011:Aorta / Q000166:cytology*; D002478:Cells, Cultured; D003374:Coumarins / Q000494:pharmacology*; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects*; D041981:Gastrointestinal Tract / Q000378:metabolism; D020719:Glucuronides / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D047348:Hydrolyzable Tannins / Q000737:chemistry; D009569:Nitric Oxide / Q000378:metabolism*
chemical_list: D003374:Coumarins; D020719:Glucuronides; D047348:Hydrolyzable Tannins; C013515:ellagitannin; C000595064:urolithin B; C026423:3,8-dihydroxy-6H-dibenzo(b,d)pyran-6-one; D009569:Nitric Oxide
keywords: atherosclerosis; ellagic acid; endothelial cells; endothelial function; endothelial nitric oxide synthase; microbiota metabolites; peripheral metabolism; urolithin