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.

Endothelia-Targeting Protection by Escin in Decompression Sickness Rats

“…Although much recent attention focuses on its anti-cancer properties, escin is well known for its remarkable efficacy in treating chronic venous insufficiency (CVI), hemorrhoids and post-operative edema11. Therapeutic benefit is supported by a number of investigations using various models and clinically, indicative of clear endothelia-protective effects, most of which appear due to selective endothelial permeabilization to ions and other molecules9.…”

“…Escin may inhibit the activation of endothelial cells and the subsequent secretion of proinflammatory mediators like E-selectin and adhesion molecules in thrombotic events or gas embolism131621. Other mechanisms, including protection of the reorganization of endothelial cytoskeleton, and inhibition of the enzymes elastase and hyaluronidase, further underline the wide ranging mechanisms of the endothelia-protective activity of escin911.…”

“…It exists in two forms, α and β and the latter is the active component of the mixture10. Escin has been traditionally used as a carminative, stomachic, and endothelia-protective agent in treating peripheral vascular disorders, in particular varicosis11. It is recognized as having vasoconstrictor activity by increasing sensitivity to molecular ions, resulting in increased venous tension1112.…”

“…Escin has been traditionally used as a carminative, stomachic, and endothelia-protective agent in treating peripheral vascular disorders, in particular varicosis11. It is recognized as having vasoconstrictor activity by increasing sensitivity to molecular ions, resulting in increased venous tension1112. Accumulating evidence suggests that escin exerts anti-edematous and anti-inflammatory properties mainly due to its endothelia-protective ability11.…”

“…It is recognized as having vasoconstrictor activity by increasing sensitivity to molecular ions, resulting in increased venous tension1112. Accumulating evidence suggests that escin exerts anti-edematous and anti-inflammatory properties mainly due to its endothelia-protective ability11. Escin reduces endothelia activation and sensitization to ions resulting in decreased neutrophil adherence and permeability to water13, and exerts anti-inflammatory and synergistic anti-inflammatory effects without immunosuppression1014.…”