title: Resveratrol encapsulated in novel fusogenic liposomes activates Nrf2 and attenuates oxidative stress in cerebromicrovascular endothelial cells from aged rats.
abstract: Resveratrol (3,4',5-trihydroxystilbene) is a plant-derived polyphenolic trans-stilbenoid, which exerts multifaceted antiaging effects. Here, we propose a novel delivery system for resveratrol, which significantly increases its cellular uptake into aged cells. Combination of resveratrol with a positively charged lipid component to "conventional" liposomes converts these lipid vesicles to a robust fusogenic system. To study their cellular uptake and cellular effects, we treated primary cerebromicrovascular endothelial cells isolated from aged F344xBN rats with resveratrol encapsulated in fusogenic liposomes (FL-RSV). To demonstrate effective cellular uptake of FL-RSV, accumulation of the lipophilic tracer dye, DiR, and resveratrol in cerebromicrovascular endothelial cells was confirmed using flow cytometry and confocal microscopy and high-performance liquid chromatography electrochemical detection. Treatment of aged cerebromicrovascular endothelial cells with FL-RSV activated Nrf2 (assessed with a reporter gene assay), significantly decreased cellular production of reactive oxygen species (assessed by a flow cytometry-based H2DCFDA fluorescence method), and inhibited apoptosis. Taken together, encapsulation of resveratrol into novel fusogenic liposomes significantly enhances the delivery of resveratrol into aged cells, which subsequently results in rapid activation of cellular Nrf2-driven antioxidant defense mechanisms. Our studies provide proof-of-concept for the development of a novel, translationally relevant interventional strategy for prevention and/or control of oxidative stress-related pathophysiological conditions in aging.
authors.affiliation: Institute of Complex Systems, ICS-7: Biomechanics, Forschungszentrum Jülich GmbH, Germany.
authors.forename: Agnes
authors.initials: A
authors.lastname: Csiszár
authors.forename: Anna
authors.initials: A
authors.lastname: Csiszar
authors.affiliation: Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla.
authors.forename: John T
authors.initials: JT
authors.lastname: Pinto
authors.affiliation: Reynolds Oklahoma Center on Aging, Donald W. Reynolds Department of Geriatric Medicine.
authors.forename: Tripti
authors.initials: T
authors.lastname: Gautam
authors.affiliation: Institute of Complex Systems, ICS-7: Biomechanics, Forschungszentrum Jülich GmbH, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Kleusch
authors.affiliation: Institute of Complex Systems, ICS-7: Biomechanics, Forschungszentrum Jülich GmbH, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Hoffmann
authors.affiliation: Reynolds Oklahoma Center on Aging, Donald W. Reynolds Department of Geriatric Medicine.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Tucsek
authors.affiliation: Reynolds Oklahoma Center on Aging, Donald W. Reynolds Department of Geriatric Medicine.
authors.forename: Peter
authors.initials: P
authors.lastname: Toth
authors.forename: William E
authors.initials: WE
authors.lastname: Sonntag
authors.affiliation: zoltan-ungvari@ouhsc.edu.
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Ungvari
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001921:Brain / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D018929:Cell Culture Techniques; D016922:Cellular Senescence / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D008081:Liposomes; D008297:Male; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D014677:Pharmaceutical Vehicles; D051381:Rats; D011914:Rats, Inbred BN; D011916:Rats, Inbred F344; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D008081:Liposomes; D051267:NF-E2-Related Factor 2; D014677:Pharmaceutical Vehicles; D017382:Reactive Oxygen Species; D013267:Stilbenes; D000077185:Resveratrol
keywords: Endothelial; Fusogenic liposomes; Oxidative stress; Polyphenol.