Effects of a novel marine natural product: pyrano indolone alkaloid fibrinolytic compound on thrombolysis and hemorrhagic activities in vitro and in vivo

Abstract

Fungi fibrinolytic compound 1 (FGFC1) is a novel marine natural product as a low-weight fibrinolytic pyranoindole molecule, whose thrombolytic effects were evaluated on FITC-fibrin (Fluorescein isothiocyanate, FITC) degradation methods in vitro and on acute pulmonary thromboembolism animal model in vivo. We determined the FGFC1 induced thrombolysis that stems from its fibrin(ogen)olytic activities as measured by fibrin(ogen) degradation products (FDPs) experiment, acute pulmonary thromboembolism animal model experiment, and euglobulin lysis assay. In vitro, measurement of FITC-fibrin degradation revealed that fibrin hydrolysis occurred in a concentration-dependent manner of FGFC1 from 5 to 25 μ mol/L. In vivo test of a classical acute pulmonary thromboembolism model in rat showed that when the injected dose was 5 mg/kg or above, FGFC1 was effective in dissolution of extrinsic FITC-fibrin induced blood clots. Euglobulin lysis time (ELT) in FGFC1-treated rats was shortened 30 s compared with rats in the positive control group, which were injected with clopidogrel sulfate and single-chain urokinase-type plasminogen activator. As compared to the control, FGFC1 (5-25 mg/kg) did not significantly alter the formation of fibrinogen and FDPs in vivo. Our research indicates that FGFC1 presents pharmacodynamic action in both the thrombolysis and the hemolytic procedure, which can be characterized by fibrinogenolysis in blood and FDPs in plasma. In vivo, increasing fibrinolytic doses of FGFC1 from 5 to 25 mg/kg did not induce fibrinogenolysis when compared with control group, this result corresponds to that FGFC1 did not induce the increasing of FDPs (compared with the saline-treated control). It indicates that the FGFC1 may act as a novel thrombolytic agent and represent an effective approach to the treatment of thrombus without significant risk of hemorrhagic activity.

Marine natural products

“…356 FGFC1 (fungi brinolytic compound 1), 357 a metabolite of Stachyhotrys longispora 358 has potential as a thrombolytic agent since it induces thrombolysis in a rat model of acute pulmonary thromboembolism without associated bleeding. 359 Several studies have explored production of the lipopeptides scopularides A and B 360 produced by Scopulariopsis brevicaulis (also known as Microascus brevicaulis). One study, the rst proteome study of a marine fungus, determined that production levels of scopularides were not caused by changes in secondary metabolism, but by complex changes in primary metabolism.…”

Producing Novel Fibrinolytic Isoindolinone Derivatives in Marine Fungus Stachybotrys longispora FG216 by the Rational Supply of Amino Compounds According to Its Biosynthesis Pathway

“…It has been shown to produce FGFC1 on a 10 g/L level under an optimized glucose/ornithine replenishment strategy [ 12 ]. FGFC1 has also shown positive effects on thrombolysis and hemorrhagic activities, both in vitro and in vivo [ 13 ]. Thus, FG216 has the potential for manufacturing cardiovascular drugs.…”

In Vitro Study of the Fibrinolytic Activity via Single Chain Urokinase-Type Plasminogen Activator and Molecular Docking of FGFC1

“…FGFC1 (10 mg/mL) could dissolve most of the pulmonary thrombi when used to treat Wistar rats. FGFC1 is a potential drug for the treatment of thrombosis [19][20][21]. Furthermore, FGFC1 possesses fibrinolytic activity mainly through influencing the secondary and tertiary structure of plasminogen, enabling its activation [22].…”