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- Kardeby, Caroline, 1989-, et al.
(författare)
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Synthetic glycopolymers and natural fucoidans cause human platelet aggregation via PEAR1 and GPIbα
- 2019
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Ingår i: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 3:3, s. 275-287
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Tidskriftsartikel (refereegranskat)abstract
- Fucoidans are sulfated fucose-based polysaccharides that activate platelets and have pro- and anticoagulant effects; thus, they may have therapeutic value. In the present study, we show that 2 synthetic sulfated α-l-fucoside-pendant glycopolymers (with average monomeric units of 13 and 329) and natural fucoidans activate human platelets through a Src- and phosphatidylinositol 3-kinase (PI3K)-dependent and Syk-independent signaling cascade downstream of the platelet endothelial aggregation receptor 1 (PEAR1). Synthetic glycopolymers and natural fucoidan stimulate marked phosphorylation of PEAR1 and Akt, but not Syk. Platelet aggregation and Akt phosphorylation induced by natural fucoidan and synthetic glycopolymers are blocked by a monoclonal antibody to PEAR1. Direct binding of sulfated glycopolymers to epidermal like growth factor (EGF)-like repeat 13 of PEAR1 was shown by avidity-based extracellular protein interaction screen technology. In contrast, synthetic glycopolymers and natural fucoidans activate mouse platelets through a Src- and Syk-dependent pathway regulated by C-type lectin-like receptor 2 (CLEC-2) with only a minor role for PEAR1. Mouse platelets lacking the extracellular domain of GPIbα and human platelets treated with GPIbα-blocking antibodies display a reduced aggregation response to synthetic glycopolymers. We found that synthetic sulfated glycopolymers bind directly to GPIbα, substantiating that GPIbα facilitates the interaction of synthetic glycopolymers with CLEC-2 or PEAR1. Our results establish PEAR1 as the major signaling receptor for natural fucose-based polysaccharides and synthetic glycopolymers in human, but not in mouse, platelets. Sulfated α-l-fucoside-pendant glycopolymers are unique tools for further investigation of the physiological role of PEAR1 in platelets and beyond.
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| 2. |
- Tengdelius, Mattias, 1984-
(författare)
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Fucoidan-Mimetic Glycopolymers : Synthesis and Biomedical Applications
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The marine polysaccharide fucoidan has demonstrated several interesting biological properties, for instance being antiviral, anticoagulant, anti-inflammatory, anticancer, and platelet activating. Many of these properties are desirable for various biomedical applications. Yet, there are few reports on fucoidan being used in such applications. The reasons for this are primarily the heterogeneity and low structural reproducibility of fucoidan.This thesis describes the synthesis of polymers with pendant saccharides bearing the key structural features of fucoidan. These glycopolymers were synthesized via different radical polymerization techniques yielding polymers of different chain lengths and dispersity. These glycopolymers showed antiviral and platelet activating properties similar to those of natural fucoidan, thus making them fucoidan-mimetic glycopolymers. However, compared to fucoidan from natural sources, the fucoidan-mimetic glycopolymers had homogeneous and reproducible structures making them suitable for biomedical applications.Further studies demonstrated that platelet activation, caused by these glycopolymers, showed dose-response curves almost identical to fucoidan. The platelet activation was induced via intracellular signaling and caused platelet surface changes similar to those of fucoidan. Fucoidan-mimetic glycopolymers can therefore be used as unique biomolecular tools for studying the molecular and cellular responses of human platelets.Fucoidan-mimetic glycopolymers generally assert their antiviral activity by blocking viral entry to host cells, thus inhibiting spreading of the viral infection but not acting virucidal, i.e. not killing the viruses. Introduction of hydrophobic groups to the polymer’s chain ends improved the antiviral properties significantly and is an important step towards yielding glycopolymers with virucidal properties.The fucoidan-mimetic glycopolymers were also applied as capping agents when synthesizing gold nanoparticles. These fucoidan-mimetic glycopolymer coated gold nanoparticles showed improved colloidal stability compared to uncapped gold nanoparticles. Furthermore, the nanoparticles also demonstrated selective cytotoxicity against a human colon cancer cell line over fibroblast cells.
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