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  • 1.
    Fälker, Knut
    et al.
    Örebro universitet, Institutionen för medicinska vetenskaper. Cardiovascular Research Centre (CVRC).
    Ljungberg, Liza
    Örebro universitet, Institutionen för medicinska vetenskaper. Cardiovascular Research Centre (CVRC).
    Kardeby, Caroline
    Örebro universitet, Institutionen för medicinska vetenskaper. Cardiovascular Research Centre (CVRC).
    Lindkvist, Madelene
    Örebro universitet, Institutionen för medicinska vetenskaper. Cardiovascular Research Centre (CVRC).
    Sirsjö, Allan
    Örebro universitet, Institutionen för medicinska vetenskaper. Cardiovascular Research Centre (CVRC).
    Grenegård, Magnus
    Örebro universitet, Institutionen för medicinska vetenskaper. Cardiovascular Research Centre (CVRC).
    Adrenoceptor α2A signalling countervails the taming effects of synchronous cyclic nucleotide-elevation on thrombin-induced human platelet activation and aggregation2019Ingår i: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 59, s. 96-109Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The healthy vascular endothelium constantly releases autacoids which cause an increase of intracellular cyclic nucleotides to tame platelets from inappropriate activation. Elevating cGMP and cAMP, in line with previous reports, cooperated in the inhibition of isolated human platelet intracellular calcium-mobilization, dense granules secretion, and aggregation provoked by thrombin. Further, platelet alpha granules secretion and, most relevant, integrin αIIaβ3 activation in response to thrombin are shown to be prominently affected by the combined elevation of cGMP and cAMP. Since stress-related sympathetic nervous activity is associated with an increase in thrombotic events, we investigated the impact of epinephrine in this setting. We found that the assessed signalling events and functional consequences were to various extents restored by epinephrine, resulting in full and sustained aggregation of isolated platelets. The restoring effects of epinephrine were abolished by either interfering with intracellular calcium-elevation or with PI3-K signalling. Finally, we show that in our experimental setting epinephrine likewise reconstitutes platelet aggregation in heparinized whole blood, which may indicate that this mechanism could also apply in vivo.

  • 2.
    Kardeby, Caroline
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Studies of platelet signalling and endothelial cell responses using unique synthetic drugs2019Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Haemostasis is a complex and tightly regulated process which protects us from bleeding. Platelets are essential for maintained haemostasis. Under normal conditions platelets are calmed by antithrombotic substances release by the endothelium. During vascular injury, the platelets will activate and form a haemostatic plug to prevent bleeding. Inflammatory processes like atherosclerosis can disturb the haemostatic balance and lead to severe consequences like myocardial infarction and stroke. Inhibition of platelets and coagulation are common treatments to prevent unwanted blood clot formation. There is a great need for increased knowledge on the mechanisms of thrombosis and characterisation of new substances with possible therapeutic potential. This thesis used unique synthetic drugs to study platelet signalling and endothelial responses. Paper I showed that both sulfated polysaccharides from seaweed and synthetic glycopolymers which mimic their chemical properties caused platelet activation.

    Paper II elucidated the molecular mechanism underlying platelet activation by sulfated glycopolymers and polysaccharides. We found that human platelet activation took place via the Platelet endothelial aggregation receptor 1 (PEAR1), while mouse platelet activation was mainly via C-type lectin-like receptor 2. Aggregation was supported by Glycoprotein Ibα in both species.

    Paper III showed the effect of synthetic glycopolymers and natural polysaccharides on cultured human endothelial cells. We found that both the glycopolymers and polysaccharides caused a proinflammatory response after 24h.

    In Paper IV, the effect of a synthetic purine analogue with a nitrate ester motif was studied. We found that the purine analogue reduced platelet functions by inhibiting Rho-associated protein kinase (ROCK).

    This thesis describes unique synthetic drugs that can be used for further studies of the mechanisms underlying the biological processes of thrombosis and inflammation. The synthetic glycopolymers can be used to further elucidate the physiological role of PEAR1, a potential future therapeutic target.

  • 3.
    Kardeby, Caroline
    et al.
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Fälker, Knut
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Haining, Elizabeth J.
    Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
    Criel, Maarten
    Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium.
    Lindkvist, Madelene
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Barroso, Ruben
    Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom; Centre of Membrane Proteins and Receptors, Universities of Birmingham and Nottingham, The Midlands, United Kingdom.
    Påhlsson, Peter
    Division of Cell Biology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Ljungberg, Liza
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Tengdelius, Mattias
    Division of Organic Chemistry, Linköping University, Linköping, Sweden.
    Rainger, G. Ed.
    Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
    Watson, Stephanie
    Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
    Eble, Johannes A.
    Institute of Physiological Chemistry and Pathobiochemistry, University of Münster, Münster, Germany.
    Hoylaerts, Marc F.
    Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium.
    Emsley, Jonas
    Centre of Membrane Proteins and Receptors, Universities of Birmingham and Nottingham, The Midlands, United Kingdom; Division of Biomolecular Science and Medicinal Chemistry, Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham, United Kingdom.
    Konradsson, Peter
    Division of Organic Chemistry, Linköping University, Linköping, Sweden.
    Watson, Steve P.
    Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom; Centre of Membrane Proteins and Receptors, Universities of Birmingham and Nottingham, The Midlands, United Kingdom.
    Sun, Yi
    Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom; Centre of Membrane Proteins and Receptors, Universities of Birmingham and Nottingham, The Midlands, United Kingdom.
    Grenegård, Magnus
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Synthetic glycopolymers and natural fucoidans cause human platelet aggregation via PEAR1 and GPIbα2019Ingår i: Blood advances, ISSN 2473-9529, Vol. 3, nr 3, s. 275-287Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    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.

  • 4.
    Kardeby, Caroline
    et al.
    Örebro universitet, Institutionen för medicinska vetenskaper. Cardiovascular Research Centre (CVRC).
    Paramel Varghese, Geena
    Örebro universitet, Institutionen för medicinska vetenskaper. Cardiovascular Research Centre (CVRC).
    Pournara, Dimitra
    National Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry and Biotechnology, Athens, Greece.
    Fotopoulou, Theano
    National Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry and Biotechnology, Athens, Greece.
    Sirsjö, Allan
    Örebro universitet, Institutionen för medicinska vetenskaper. Cardiovascular Research Centre (CVRC).
    Koufaki, Maria
    National Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry and Biotechnology, Athens, Greece.
    Fransén, Karin
    Örebro universitet, Institutionen för medicinska vetenskaper. Cardiovascular Research Centre (CVRC).
    Grenegård, Magnus
    Örebro universitet, Institutionen för medicinska vetenskaper. Cardiovascular Research Centre (CVRC).
    A novel purine analogue bearing nitrate ester prevents platelet activation by ROCK activity inhibitionManuskript (preprint) (Övrigt vetenskapligt)
  • 5.
    Kardeby, Caroline
    et al.
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Paramel Varghese, Geena
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Pournara, Dimitra
    National Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry and Biotechnology, Athens, Greece.
    Fotopoulou, Theano
    National Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry and Biotechnology, Athens, Greece.
    Sirsjö, Allan
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Koufaki, Maria
    National Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry and Biotechnology, Athens, Greece.
    Fransén, Karin
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Grenegård, Magnus
    Örebro universitet, Institutionen för medicinska vetenskaper.
    A novel purine analogue bearing nitrate ester prevents platelet activation by ROCK activity inhibition2019Ingår i: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 857, artikel-id 172428Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Natural purines like ATP, ADP and adenosine have crucial roles in platelet physiology. This knowledge has been significant in drug development and today ADP receptor antagonists are widely used for prevention of thrombotic events following myocardial infarction and ischaemic stroke.

    Recent studies have shown that a purine analogue bearing nitrate ester group (denoted MK128) has anti-inflammatory effects probably due to its ability to donate nitric oxide (NO). However, other pharmacological mechanisms may contribute to the observed effect. The aim of the present study was to establish the anti-platelet activity and elucidate the underlying molecular mechanism(s) of the purine analogue MK128.

    We found that MK128 reduced aggregation and secretion induced by the thrombin receptor agonist SFLLRN and nearly abolished aggregation and secretion induced by thromboxane A2 (TxA2) and collagen receptor agonists. The inhibition took place despite blockage of the NO/cGMP signalling system. Furthermore, interaction between MK128 and platelet purinergic receptors did not explain the observed inhibition. Instead, we found that MK128 concentration-dependently inhibited Rho-associated kinase (ROCK), which led to decreased ROCK-dependent myosin phosphatase target subunit (MYPT)-1 phosphorylation and suppression of platelet functional responses.

  • 6.
    Kardeby, Caroline
    et al.
    Örebro universitet, Institutionen för medicinska vetenskaper. Cardiovascular Research Centre (CVRC).
    Sirsjö, Allan
    Örebro universitet, Institutionen för medicinska vetenskaper. Cardiovascular Research Centre (CVRC).
    Ljungberg, Liza
    Örebro universitet, Institutionen för medicinska vetenskaper. Cardiovascular Research Centre (CVRC).
    Grenegård, Magnus
    Örebro universitet, Institutionen för medicinska vetenskaper. Cardiovascular Research Centre (CVRC).
    Sulfated glycopolymers and polysaccharides regulate inflammation-related proteins in human vascular endothelial cellsManuskript (preprint) (Övrigt vetenskapligt)
  • 7.
    Koskela von Sydow, Anita
    et al.
    Department of Clinical Research Laboratory, Örebro University Hospital, Örebro, Sweden.
    Janbaz, Chris
    Faculty of Medicine and Health, Örebro University, Örebro, Sweden; Department of Plastic and Reconstructive Surgery, Örebro University Hospital, Örebro, Sweden .
    Kardeby, Caroline
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Repsilber, Dirk
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Ivarsson, Mikael
    Örebro universitet, Institutionen för hälsovetenskaper.
    IL-1α Counteract TGF-β Regulated Genes and Pathways in Human Fibroblasts2016Ingår i: Journal of Cellular Biochemistry, ISSN 0730-2312, E-ISSN 1097-4644, Vol. 117, nr 7, s. 1622-1632Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Dysregulated wound healing is commonly associated with excessive fibrosis. Connective tissue growth factor (CTGF/CCN2) is characteristically overexpressed in fibrotic diseases and stimulated by transforming growth factor-β (TGF-β) in dermal fibroblasts. We previously showed that interleukin-1 (IL-1α) counteracts TGF-β-stimulated CTGF mRNA and protein expression in these cells. The aim of this study was to explore the effects of IL-1α on further genes and pathways in TGF-β regulated fibroblasts. Transcriptional microarray and multiple comparison analysis showed that the antagonizing effects of IL-1α was much more prominent than the synergistic effects, both with respect to number of genes and extent of changes in gene expression. Moreover, comparing canonical pathways by gene set enrichment analysis and the Ingenuity Pathway Analysis tool revealed that IL-1α counteracted TGF-β in the top six most confident pathways regulated by both cytokines. Interferon and IL-1 signaling, as well as two pathways involved in apoptosis signaling were suppressed by TGF-β and activated by IL-1α. Pathways involving actin remodeling and focal adhesion dynamics were activated by TGF-β and suppressed by IL-1α. Analyzing upstream regulators in part corroborate the comparison of canonical pathways and added cell cycle regulators as another functional group regulated by IL-1α. Finally, gene set enrichment analysis of fibrosis-related genes indicated that IL-1 moderately counteracts the collective effect of TGF-β on these genes. Microarray results were validated by qPCR. Taken together, the results indicate prominent antagonistic effects of IL-1α on TGF-β regulated interferon signaling, as well as on a wide variety of other genes and pathways in fibroblasts. This article is protected by copyright. All rights reserved.

  • 8.
    Tengdelius, Mattias
    et al.
    Division of Organic Chemistry, Department of Physics, Biology and Chemistry (IFM), Linköping University, Linköping , Sweden.
    Kardeby, Caroline
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Fälker, Knut
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Griffith, May
    Division of Cell Biology, Department of Clinical and Experimental Medicine (IKE), Linköping University, Linköping, Sweden.
    Påhlsson, Peter
    Division of Cell Biology, Department of Clinical and Experimental Medicine (IKE), Linköping University, Linköping, Sweden.
    Konradsson, Peter
    Division of Organic Chemistry, Department of Physics, Biology and Chemistry (IFM), Linköping University, Linköping , Sweden.
    Grenegård, Magnus
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Fucoidan-Mimetic Glycopolymers as Tools for Studying Molecular and Cellular Responses in Human Blood Platelets2017Ingår i: Macromolecular Bioscience, ISSN 1616-5187, E-ISSN 1616-5195, Vol. 17, nr 2, artikel-id UNSP 1600257Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The marine sulfated polysaccharide fucoidan displays superior ability to induce platelet aggregation compared to other sulfated polysaccharides. As such, it is an attractive tool for studying molecular and cellular responses in activated platelets. The heterogeneous structure, however, poses a problem in such applications. This study describes the synthesis of sulfated α-l-fucoside-pendant poly(methacryl amides) with homogeneous structures. By using both thiol-mediated chain transfer and reversible addition-fragmentation chain transfer polymerization techniques, glycopolymers with different chain lengths are obtained. These glycopolymers show platelet aggregation response and surface changes similar to those of fucoidan, and cause platelet activation through intracellular signaling as shown by extensive protein tyrosine phosphorylation. As the platelet activating properties of the glycopolymers strongly mimic those of fucoidan, this study concludes these fucoidan-mimetic glycopolymers are unique tools for studying molecular and cellular responses in human blood platelets.

  • 9. Welander, Edward
    et al.
    Åström, Maria
    Örebro universitet, Institutionen för medicinska vetenskaper. Örebro universitet, Institutionen för hälsovetenskaper.
    Enonge Fotabe, Leslie
    Kardeby, Caroline
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Tina, Elisabet
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Elgbratt, Kristina
    Örebro universitet, Institutionen för hälsovetenskaper.
    Pourlofti, Arvid
    Abawi, Akram
    Romild, Alma
    Kruse, Robert
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Repsilber, Dirk
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Crafoord, Jakob
    Ahlstrand, Erik
    Ivarsson, Mikael
    Örebro universitet, Institutionen för hälsovetenskaper.
    Integrated analysis indicates reciprocal immune response dysregulations between bone marrow multipotent stromal cells and granulocytes at the mRNA but not at the protein level in myelofibrosis2018Konferensbidrag (Refereegranskat)
1 - 9 av 9
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Permanent länk
Referera
Referensformat
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  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Annat format
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Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf