title: Molecular Mechanism for Cellular Response to β-Escin and Its Therapeutic Implications.
abstract: β-escin is a mixture of triterpene saponins isolated from the horse chestnut seeds (Aesculus hippocastanum L.). The anti-edematous, anti-inflammatory and venotonic properties of β-escin have been the most extensively clinically investigated effects of this plant-based drug and randomized controlled trials have proved the efficacy of β-escin for the treatment of chronic venous insufficiency. However, despite the clinical recognition of the drug its pharmacological mechanism of action still remains largely elusive. To determine the cellular and molecular basis for the therapeutic effectiveness of β-escin we performed discovery and targeted proteomic analyses and in vitro evaluation of cellular and molecular responses in human endothelial cells under inflammatory conditions. Our results demonstrate that in endothelial cells β-escin potently induces cholesterol synthesis which is rapidly followed with marked fall in actin cytoskeleton integrity. The concomitant changes in cell functioning result in a significantly diminished responses to TNF-α stimulation. These include reduced migration, alleviated endothelial monolayer permeability, and inhibition of NFκB signal transduction leading to down-expression of TNF-α-induced effector proteins. Moreover, the study provides evidence for novel therapeutic potential of β-escin beyond the current vascular indications.
authors.affiliation: Laboratory of Mass Spectrometry, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland.
authors.forename: Dominik
authors.initials: D
authors.lastname: Domanski
authors.affiliation: Centre for Preclinical Research and Technology, Department of Immunology, Biochemistry and Nutrition, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Oliwia
authors.initials: O
authors.lastname: Zegrocka-Stendel
authors.affiliation: Laboratory of Mass Spectrometry, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Perzanowska
authors.affiliation: Centre for Preclinical Research and Technology, Department of Immunology, Biochemistry and Nutrition, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Dutkiewicz
authors.affiliation: Department of Molecular and Translational Oncology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Kowalewska
authors.affiliation: Department of Cytology, Faculty of Biology, University of Warsaw, Warsaw, Miecznikowa 1, 02-096 Warsaw, Poland.
authors.forename: Iwona
authors.initials: I
authors.lastname: Grabowska
authors.affiliation: Centre for Preclinical Research and Technology, Department of Immunology, Biochemistry and Nutrition, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Dorota
authors.initials: D
authors.lastname: Maciejko
authors.affiliation: Laboratory for Microarray Analysis CORELAB, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Fogtman
authors.affiliation: Laboratory of Mass Spectrometry, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland.
authors.forename: Michal
authors.initials: M
authors.lastname: Dadlez
authors.affiliation: Centre for Preclinical Research and Technology, Department of Immunology, Biochemistry and Nutrition, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Koziak
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D031319:Aesculus / Q000737:chemistry* / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002784:Cholesterol / Q000096:biosynthesis; D004928:Escin / Q000737:chemistry / Q000494:pharmacology*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D010539:Permeability / Q000187:drug effects; D020543:Proteome / Q000032:analysis / Q000187:drug effects; D040901:Proteomics; D012639:Seeds / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D016328:NF-kappa B; D020543:Proteome; D014409:Tumor Necrosis Factor-alpha; D004928:Escin; D002784:Cholesterol