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The Marine-Derived Triterpenoid Frondoside A Inhibits Thrombus Formation.

ABSTRACT: BACKGROUND:The marine-derived triterpenoid frondoside A inhibits the phosphatidylinositol-3-kinase (PI3K) pathway in cancer cells. Because this pathway is also crucially involved in platelet activation, we studied the effect of frondoside A on thrombus formation. METHODS:Frondoside A effects on platelet viability, surface adhesion molecule expression, and intracellular signaling were analyzed by flow cytometry and Western blot. The effect of frondoside A was analyzed by photochemically induced thrombus formation in the mouse dorsal skinfold chamber model and by tail vein bleeding. RESULTS:Concentrations of up to 15 µM frondoside A did not affect the viability of platelets, but reduced their surface expression of P-selectin (CD62P) and the activation of glycoprotein (GP)IIb/IIIa after agonist stimulation. Additional mechanistic analyses revealed that this was mediated by downregulation of PI3K-dependent Akt and extracellular-stimuli-responsive kinase (ERK) phosphorylation. Frondoside A significantly prolonged the complete vessel occlusion time in the mouse dorsal skinfold chamber model of photochemically induced thrombus formation and also the tail vein bleeding time when compared to vehicle-treated controls. CONCLUSION:Our findings demonstrated that frondoside A inhibits agonist-induced CD62P expression and activation of GPIIb/IIIa. Moreover, frondoside A suppresses thrombus formation. Therefore, this marine-derived triterpenoid may serve as a lead compound for the development of novel antithrombotic drugs.

SUBMITTER: Ampofo E

PROVIDER: S-EPMC7074411 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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The Marine-Derived Triterpenoid Frondoside A Inhibits Thrombus Formation.

Ampofo Emmanuel E Später Thomas T Nalbach Lisa L Menger Michael D MD Laschke Matthias W MW

Marine drugs 20200214 2

<h4>Background</h4>The marine-derived triterpenoid frondoside A inhibits the phosphatidylinositol-3-kinase (PI3K) pathway in cancer cells. Because this pathway is also crucially involved in platelet activation, we studied the effect of frondoside A on thrombus formation.<h4>Methods</h4>Frondoside A effects on platelet viability, surface adhesion molecule expression, and intracellular signaling were analyzed by flow cytometry and Western blot. The effect of frondoside A was analyzed by photochemi ...[more]

PMID: 32074969

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Project description:Staphylococcus epidermidis, the common inhabitant of human skin and mucosal surfaces has emerged as an important pathogen in patients receiving surgical implants and medical devices. Entering the body via surgical sites and colonizing the medical devices through formation of multi-layered biofilms it leads to refractory and persistent device-related infections (DRIs). Staphylococcal proportions within biofilms are more tolerant to antibiotics and immune responses, and thus are hard-to-treat. The consequent morbidity and mortality, and economic losses in health care systems has strongly necessitated the need for development of new anti-bacterial and anti-biofilm based therapeutics. In this study, we describe the biological activity of a marine sponge-derived Streptomyces sp. SBT348 extract in restraining staphylococcal growth and biofilm formation on polystyrene, glass, medically relevant titan metal and silicone surfaces. A bio-assay guided fractionation was performed to isolate the active compound (C3) from the crude SBT348 extract. Our results demonstrated that C3 effectively inhibits the growth (MIC: 31.25 µg/ml) and biofilm formation (sub-MIC range: 1.95-<31.25 µg/ml) of S. epidermidis RP62A in vitro. Chemical characterization of C3 by heat and enzyme treatments, and High-Resolution Fourier Transform Mass Spectrometry (HRMS) revealed its heat-stable and non-proteinaceous nature, and high molecular weight (1258. 3257 Da). Cytotoxicity profiling of C3 in vitro on mouse fibroblast (NIH/3T3) and macrophage (J774.1) cell lines, and in vivo on the greater wax moth larvae Galleria melonella revealed its non-toxic nature at the effective dose. Transcriptome analysis of C3 treated-S. epidermidis RP62A has further unmasked the negative effect of C3 on central metabolism (carbon, amino acid and protein, lipids, nucleotide and energy) suggesting its mode of action. Taken together, these findings suggest that C3 could be possibly used as antibacterial and antibiofilm coatings on medically-relevant surfaces and prevent the relapsing staphylococcal DRIs.

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The Marine-Derived Triterpenoid Frondoside A Inhibits Thrombus Formation.

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The Marine-Derived Triterpenoid Frondoside A Inhibits Thrombus Formation.

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