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Marine Drugs
Special Issues
Marine Molecules for the Treatment of Thrombosis
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Marine Molecules for the Treatment of Thrombosis

A special issue of Marine Drugs (ISSN 1660-3397).

Deadline for manuscript submissions: closed (31 August 2020) | Viewed by 24227

Special Issue Editor

Dr. Ramon Novoa Carballal

E-Mail Website
Guest Editor
3B´s Research Group – Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, 4805-017, Barco, Guimarães, Portugal
Interests: drug delivery; tissue engineering; polysaccharide; chitosan; hybrid; pegylation; oxime click; proteoglycan; glycosaminoglycan; gel permeation chromatography; NMR relaxation

Special Issue Information

Dear Colleagues,

According to the World Health Organization, the formation of thrombi is one of the leading causes of death in modern life. Current antithrombotic treatments suffer from potential secondary effects or increase the health care costs because of a necessary control of the coagulation levels for vitamin k antagonists or of the high production costs for recent synthetic thrombin and factor Xa inhibitors.  For this reasons, marine molecules are being thoughtfully screened for anticoagulants. The best known marine anticoagulants are sulphated polysaccharides: fucoidans and carrageenans from algae; fucosylated chondroitin sulphates, sulfated fucans, and galactans from algae, ascidians, sea cucumbers, and urchins; heparins and heparan sulfate hybrids found in molluscs, crustacean, ascidians, and sea urchins. However, other less renowned marine molecules present interesting prospects: anticoagulant peptides (from blood-sucking worms and bacteria and sponges), fibrinolytic enzymes (from algae and bacteria), anticoagulant terpenes and sphingosines (from algae and sponges). The aim of this Special Issue is to recapitulate the current knowledge and publish novel articles on marine antithrombotic molecules.

Dr. Ramon Novoa Carballal
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Marine Drugs is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Thrombosis
  • Coagulation
  • Anticoagulant
  • Thrombin inhibitor
  • Factor Xa inhibitors
  • Vitamin k antagonists
  • Sulphated polysaccharides
  • Sulphated Glycosaminoglycans
  • GAG-like
  • Fucoidan
  • fucosylated chondroitin
  • sulphates and galactans
  • Sulfated fucans and galactans
  • Anticoagulant peptides
  • Fibrinolytic

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Published Papers (5 papers)

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Research

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13 pages, 1845 KiB  
Article
The Marine-Derived Triterpenoid Frondoside A Inhibits Thrombus Formation
by Emmanuel Ampofo, Thomas Später, Lisa Nalbach, Michael D. Menger and Matthias W. Laschke
Mar. Drugs 2020, 18(2), 111; https://doi.org/10.3390/md18020111 - 14 Feb 2020
Cited by 7 | Viewed by 2578
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Marine Molecules for the Treatment of Thrombosis)
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15 pages, 4684 KiB  
Article
Isolation and Characterization of a Heparin-Like Compound with Potent Anticoagulant and Fibrinolytic Activity from the Clam Coelomactra antiquata
by ZhenXing Du, XueJing Jia, Jing Chen, SiYi Zhou, JianPing Chen, XiaoFei Liu, XiaoHuang Cao, SaiYi Zhong and PengZhi Hong
Mar. Drugs 2020, 18(1), 6; https://doi.org/10.3390/md18010006 - 19 Dec 2019
Cited by 13 | Viewed by 3819
Abstract
Heparin from mollusks with unique sulfated glycosaminoglycan exhibits strong anti-thrombotic activities. This study reports on a purified heparinoid from Coelomactra antiquata, which shows potent anticoagulant and fibrinolytic abilities. Its structure was characterized by infrared spectroscopy, high-performance liquid chromatography, and one-dimensional and two-dimensional [...] Read more.
Heparin from mollusks with unique sulfated glycosaminoglycan exhibits strong anti-thrombotic activities. This study reports on a purified heparinoid from Coelomactra antiquata, which shows potent anticoagulant and fibrinolytic abilities. Its structure was characterized by infrared spectroscopy, high-performance liquid chromatography, and one-dimensional and two-dimensional nuclear magnetic resonance spectroscopy. Its fibrinolytic activity was determined in vitro and in vivo. Its anticoagulant activity was determined by activated partial thromboplastin time (APTT), prothrombin time (PT), and thrombin time (TT). The results indicated that clam heparinoid was a homogeneous glycosaminoglycan with a molecular weight of 30.99 kDa, mainly composed of →4)-α-IdoA2S-(1→4)-α-GlcNS3S6S (or GlcNS6S)-(1→4)-β-GlcA-(1→4)-α-GlcNS6S (or GlcNAC)-(1→. Furthermore, this heparinoid showed a highly anticoagulant titer and fibrinolytic value of 149.63 IU/mg and 1.96 IU/mg, respectively. In summary, clam heparinoid shows great potential for application in the clinic and antithrombotic drugs industry. Full article
(This article belongs to the Special Issue Marine Molecules for the Treatment of Thrombosis)
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13 pages, 2313 KiB  
Article
Precise Structure and Anticoagulant Activity of Fucosylated Glycosaminoglycan from Apostichopus japonicus: Analysis of Its Depolymerized Fragments
by Ruowei Guan, Yuan Peng, Lutan Zhou, Wenqi Zheng, Xixi Liu, Pin Wang, Qingxia Yuan, Na Gao, Longyan Zhao and Jinhua Zhao
Mar. Drugs 2019, 17(4), 195; https://doi.org/10.3390/md17040195 - 27 Mar 2019
Cited by 42 | Viewed by 6523
Abstract
Apostichopus japonicus is one of the most economically important species in sea cucumber aquaculture in China. Fucosylated glycosaminoglycan from A. japonicus (AjFG) has shown multiple pharmacological activities. However, results from studies on the structure of AjFG are still controversial. In this study, the [...] Read more.
Apostichopus japonicus is one of the most economically important species in sea cucumber aquaculture in China. Fucosylated glycosaminoglycan from A. japonicus (AjFG) has shown multiple pharmacological activities. However, results from studies on the structure of AjFG are still controversial. In this study, the deaminative depolymerization method that is glycosidic bond-selective was used to prepare the depolymerized products from AjFG (dAjFG), and then a series of purified oligosaccharide fragments such as tri-, hexa-, nona-, and dodecasaccharides were obtained from dAjFG by gel permeation chromatography. The 1D/2D NMR and ESI-MS spectrometry analyses showed that these oligosaccharides had the structural formula of l-FucS-α1,3-d-GlcA-β1,3-{d-GalNAc4S6S-β1,4-[l-FucS-α1,3-]d-GlcA-β1,3-}n-d-anTal-diol4S6S (n = 0, 1, 2, 3; FucS represents Fuc2S4S, Fuc3S4S, or Fuc4S). Thus, the unambiguous structure of native AjFG can be rationally deduced: it had the backbone of {-4-d-GlcA-β1,3-d-GalNAc4S6S-β1-}n, which is similar to chondroitin sulfate E, and each d-GlcA residue in the backbone was branched with a l-FucS monosaccharide at O-3. Bioactivity assays confirmed that dAjFG and nonasaccharides and dodecasaccharides from AjFG had potent anticoagulant activity by intrinsic FXase inhibition while avoiding side effects such as FXII activation and platelet aggregation. Full article
(This article belongs to the Special Issue Marine Molecules for the Treatment of Thrombosis)
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14 pages, 4957 KiB  
Article
Novel Fibrinolytic Protease Producing Streptomyces radiopugnans VITSD8 from Marine Sponges
by Dhamodharan D, Jemimah Naine S, Merlyn Keziah S and Subathra Devi C
Mar. Drugs 2019, 17(3), 164; https://doi.org/10.3390/md17030164 - 13 Mar 2019
Cited by 38 | Viewed by 5118
Abstract
Fibrinolytic enzymes have received more attention due to their medicinal potential for thrombolytic diseases. The aim of this study is to characterize the in vitro fibrinolytic nature of purified protease producing Streptomyces radiopugnans VITSD8 from marine brown tube sponges Agelas conifera. Three [...] Read more.
Fibrinolytic enzymes have received more attention due to their medicinal potential for thrombolytic diseases. The aim of this study is to characterize the in vitro fibrinolytic nature of purified protease producing Streptomyces radiopugnans VITSD8 from marine brown tube sponges Agelas conifera. Three varieties of sponge were collected from the Rameshwaram Sea coast, Tamil Nadu, India. The fibrinolytic activity of Streptomyces sp. was screened and determined by casein plasminogen plate and fibrin plate methods respectively. The crude caseinolytic protease was purified using ammonium sulfate fractionation, affinity and ion-exchange chromatography. Based on the morphological, biochemical, and molecular characterization, the isolate VITSD8 was confirmed as Streptomyces radiopugnans. Maltose and peptone were found to be the best carbon and nitrogen sources for the production of fibrinolytic protease. The carbon and nitrogen source peptone showed (781 U/mL) enzyme activity. The optimum pH and temperature for fibrinolytic protease production was found to be 7.0 and 33 °C respectively. The purified enzyme showed a maximum specific activity of 3891 U. The blood clot lysis activity was compared with the standard, and it was concluded that a minimum of 0.18 U (10 µL) of purified protease was required to dissolve the blood clot. This is the first report which exploits the fibrinolytic protease activity of Streptomyces radiopugnans VITSD8 extracted from a marine sponge. Hence the investigation suggests a potential benefit of purified fibrinolytic protease which will serve as an excellent clot buster alternative. Full article
(This article belongs to the Special Issue Marine Molecules for the Treatment of Thrombosis)
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Review

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26 pages, 3602 KiB  
Review
Marine Antithrombotics
by Rohini Dwivedi and Vitor H. Pomin
Mar. Drugs 2020, 18(10), 514; https://doi.org/10.3390/md18100514 - 13 Oct 2020
Cited by 20 | Viewed by 5552
Abstract
Thrombosis remains a prime reason of mortality worldwide. With the available antithrombotic drugs, bleeding remains the major downside of current treatments. This raises a clinical concern for all patients undergoing antithrombotic therapy. Novel antithrombotics from marine sources offer a promising therapeutic alternative to [...] Read more.
Thrombosis remains a prime reason of mortality worldwide. With the available antithrombotic drugs, bleeding remains the major downside of current treatments. This raises a clinical concern for all patients undergoing antithrombotic therapy. Novel antithrombotics from marine sources offer a promising therapeutic alternative to this pathology. However, for any potential new molecule to be introduced as a real alternative to existing drugs, the exhibition of comparable anticoagulant potential with minimal off-target effects must be achieved. The relevance of marine antithrombotics, particularly sulfated polysaccharides, is largely due to their unique mechanisms of action and lack of bleeding. There have been many investigations in the field and, in recent years, results have confirmed the role of potential marine molecules as alternative antithrombotics. Nonetheless, further clinical studies are required. This review covers the core of the data available so far regarding the science of marine molecules with potential medical applications to treat thrombosis. After a general discussion about the major biochemical steps involved in this pathology, we discuss the key structural and biomedical aspects of marine molecules of both low and high molecular weight endowed with antithrombotic/anticoagulant properties. Full article
(This article belongs to the Special Issue Marine Molecules for the Treatment of Thrombosis)
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