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  • 1.
    Bergemalm, Daniel
    et al.
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Medicine.
    Ramström, Sofia
    Örebro University, School of Medical Sciences. Department of Clinical Chemistry, and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    Kardeby, Caroline
    Örebro University, School of Medical Sciences.
    Hultenby, Kjell
    Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm.
    Göthlin Eremo, Anna
    Örebro University, School of Medical Sciences. Department of Clinical Research Laboratory.
    Sihlbom, Carina
    Proteomics Core Facility, University of Gothenburg, Gothenburg.
    Bergström, Jörgen
    Proteomics Core Facility, University of Gothenburg, Gothenburg.
    Palmblad, Jan
    Åström, Maria
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Medicine.
    Platelet proteome and function in X-linked thrombocytopenia with thalassemia and in silico comparisons with gray platelet syndrome2021In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 106, no 11, p. 2947-2959Article in journal (Refereed)
    Abstract [en]

    In X-linked thrombocytopenia with thalassemia (XLTT; OMIM 314050), caused by the mutation p.R216Q in exon 4 of the GATA1 gene, male hemizygous patients display macrothrombocytopenia, bleeding diathesis and a β-thalassemia trait. Herein, we describe findings in two unrelated Swedish XLTT families with a bleeding tendency exceeding what is expected from the thrombocytopenia. Blood tests revealed low P-PAI-1 and P-factor 5, and elevated S-thrombopoietin levels. Transmission electron microscopy showed diminished numbers of platelet α- and dense granules. The proteomes of isolated blood platelets from 5 male XLTT patients, compared to 5 gender- and age matched controls, were explored. Quantitative mass spectrometry showed alterations of 83 proteins (fold change ≥±1.2, q< .05). Of 46 downregulated proteins, 39 were previously reported to be associated with platelet granules. Reduced protein levels of PTGS1 and SLC35D3 were validated in megakaryocytes of XLTT bone marrow biopsies by immunohistochemistry. Platelet function testing by flow cytometry revealed low dense- and α-granule release and fibrinogen binding in response to ligation of receptors for ADP, the thrombin receptor PAR4 and the collagen receptor GPVI. Significant reductions of a number of α-granule proteins overlapped with a previous platelet proteomics investigation in the inherited macrothrombocytopenia gray platelet syndrome (GPS). In contrast, Ca2+ transporter proteins that facilitate dense granule release were downregulated in XLTT but upregulated in GPS. Ingenuity Pathway Analysis showed altered Coagulation System and Protein Ubiquitination pathways in the XLTT platelets. Collectively, the results revealed protein and functional alterations affecting platelet α- and dense granules in XLTT, probably contributing to bleeding.

  • 2.
    Fälker, Knut
    et al.
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Ljungberg, Liza
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Kardeby, Caroline
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Lindkvist, Madelene
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Sirsjö, Allan
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Grenegård, Magnus
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Adrenoceptor α2A signalling countervails the taming effects of synchronous cyclic nucleotide-elevation on thrombin-induced human platelet activation and aggregation2019In: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 59, p. 96-109Article in journal (Refereed)
    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.

  • 3.
    Kardeby, Caroline
    Örebro University, School of Medical Sciences.
    Studies of platelet signalling and endothelial cell responses using unique synthetic drugs2019Doctoral thesis, comprehensive summary (Other academic)
    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.

    List of papers
    1. Fucoidan-Mimetic Glycopolymers as Tools for Studying Molecular and Cellular Responses in Human Blood Platelets
    Open this publication in new window or tab >>Fucoidan-Mimetic Glycopolymers as Tools for Studying Molecular and Cellular Responses in Human Blood Platelets
    Show others...
    2017 (English)In: Macromolecular Bioscience, ISSN 1616-5187, E-ISSN 1616-5195, Vol. 17, no 2, article id UNSP 1600257Article in journal (Refereed) Published
    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.

    Place, publisher, year, edition, pages
    Weinheim, Germany: Wiley-VCH Verlagsgesellschaft, 2017
    Keywords
    biological applications of polymers; biomimetic; radical polymerization; reversible addition fragmentation chain transfer; structure-property relations
    National Category
    Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
    Identifiers
    urn:nbn:se:oru:diva-52179 (URN)10.1002/mabi.201600257 (DOI)000394592600012 ()27616165 (PubMedID)2-s2.0-84987653303 (Scopus ID)
    Note

    Funding Agency:

    AFA Insurance, VR Treatments of the Future grant

    Available from: 2016-09-21 Created: 2016-09-14 Last updated: 2019-05-06Bibliographically approved
    2. Synthetic glycopolymers and natural fucoidans cause human platelet aggregation via PEAR1 and GPIbα
    Open this publication in new window or tab >>Synthetic glycopolymers and natural fucoidans cause human platelet aggregation via PEAR1 and GPIbα
    Show others...
    2019 (English)In: Blood Advances, ISSN 2473-9529 , E-ISSN 2473-9537, Vol. 3, no 3, p. 275-287Article in journal (Refereed) Published
    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.

    Place, publisher, year, edition, pages
    American Society of Hematology, 2019
    National Category
    Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Hematology
    Identifiers
    urn:nbn:se:oru:diva-72478 (URN)10.1182/bloodadvances.2018024950 (DOI)000458442500007 ()30700416 (PubMedID)2-s2.0-85060943358 (Scopus ID)
    Funder
    Knowledge Foundation
    Note

    Funding Agencies:

    BHF  PG/16/53/32242  RG/13/18/30563 

    Deutsche Forschungsgemeinschaft  DFG: Eb 177/14-1 

    Fonds voor Wetenschappelijk Onderzoek Vlaanderen grant  G0A6514N 

    Available from: 2019-02-14 Created: 2019-02-14 Last updated: 2022-12-19Bibliographically approved
    3. Sulfated glycopolymers and polysaccharides regulate inflammation-related proteins in human vascular endothelial cells
    Open this publication in new window or tab >>Sulfated glycopolymers and polysaccharides regulate inflammation-related proteins in human vascular endothelial cells
    (English)Manuscript (preprint) (Other academic)
    National Category
    Other Basic Medicine
    Identifiers
    urn:nbn:se:oru:diva-74033 (URN)
    Available from: 2019-05-06 Created: 2019-05-06 Last updated: 2019-05-06Bibliographically approved
    4. A novel purine analogue bearing nitrate ester prevents platelet activation by ROCK activity inhibition
    Open this publication in new window or tab >>A novel purine analogue bearing nitrate ester prevents platelet activation by ROCK activity inhibition
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Other Basic Medicine
    Identifiers
    urn:nbn:se:oru:diva-74034 (URN)
    Available from: 2019-05-06 Created: 2019-05-06 Last updated: 2019-05-06Bibliographically approved
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  • 4.
    Kardeby, Caroline
    et al.
    Örebro University, School of Medical Sciences.
    Fälker, Knut
    Örebro University, School of Medical Sciences.
    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 University, School of Medical Sciences.
    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 University, School of Medical Sciences.
    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 University, School of Medical Sciences.
    Synthetic glycopolymers and natural fucoidans cause human platelet aggregation via PEAR1 and GPIbα2019In: Blood Advances, ISSN 2473-9529 , E-ISSN 2473-9537, Vol. 3, no 3, p. 275-287Article in journal (Refereed)
    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.

  • 5.
    Kardeby, Caroline
    et al.
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Paramel Varghese, Geena
    Örebro University, School of Medical Sciences. 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 University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Koufaki, Maria
    National Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry and Biotechnology, Athens, Greece.
    Fransén, Karin
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Grenegård, Magnus
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    A novel purine analogue bearing nitrate ester prevents platelet activation by ROCK activity inhibitionManuscript (preprint) (Other academic)
  • 6.
    Kardeby, Caroline
    et al.
    Örebro University, School of Medical Sciences.
    Paramel Varghese, Geena
    Örebro University, School of Medical Sciences.
    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 University, School of Medical Sciences.
    Koufaki, Maria
    National Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry and Biotechnology, Athens, Greece.
    Fransén, Karin
    Örebro University, School of Medical Sciences.
    Grenegård, Magnus
    Örebro University, School of Medical Sciences.
    A novel purine analogue bearing nitrate ester prevents platelet activation by ROCK activity inhibition2019In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 857, article id 172428Article in journal (Refereed)
    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.

  • 7.
    Kardeby, Caroline
    et al.
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Sirsjö, Allan
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Ljungberg, Liza
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Grenegård, Magnus
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Sulfated glycopolymers and polysaccharides regulate inflammation-related proteins in human vascular endothelial cellsManuscript (preprint) (Other academic)
  • 8.
    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 University, School of Medical Sciences.
    Repsilber, Dirk
    Örebro University, School of Medical Sciences.
    Ivarsson, Mikael
    Örebro University, School of Health Sciences.
    IL-1α Counteract TGF-β Regulated Genes and Pathways in Human Fibroblasts2016In: Journal of Cellular Biochemistry, ISSN 0730-2312, E-ISSN 1097-4644, Vol. 117, no 7, p. 1622-1632Article in journal (Refereed)
    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.

  • 9.
    Lindkvist, Madelene
    et al.
    Örebro University, School of Medical Sciences.
    Ljungberg, Liza U
    Örebro University, School of Medical Sciences.
    Fälker, Knut
    Örebro University, School of Medical Sciences.
    Ramström, Sofia
    Örebro University, School of Medical Sciences.
    Kardeby, Caroline
    Örebro University, School of Medical Sciences.
    Sirsjö, Allan
    Örebro University, School of Medical Sciences.
    Grenegård, Magnus
    Örebro University, School of Medical Sciences.
    IL-6 trans-signalling inhibits micro- and macro-aggregation induced by epinephrine in human plateletsManuscript (preprint) (Other academic)
  • 10.
    Ljungberg, Liza
    et al.
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre.
    Zegeye, Mulugeta M
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre.
    Kardeby, Caroline
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre.
    Fälker, Knut
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre.
    Repsilber, Dirk
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre.
    Sirsjö, Allan
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre.
    Global Transcriptional Profiling Reveals Novel Autocrine Functions of Interleukin 6 in Human Vascular Endothelial Cells2020In: Mediators of Inflammation, ISSN 0962-9351, E-ISSN 1466-1861, Vol. 2020, article id 4623107Article in journal (Refereed)
    Abstract [en]

    Background: Interleukin 6 (IL6) is a multifunctional cytokine produced by various cells, including vascular endothelial cells. IL6 has both pro- and non-/anti-inflammatory functions, and the response to IL6 is dependent on whether it acts via the membrane-bound IL6 receptor alpha (IL6R alpha) (classic signaling) or the soluble form of the receptor (transsignaling). As human endothelial cells produce IL6 and at the same time express IL6R alpha, we hypothesized that IL6 may have autocrine functions.

    Methods: Knockdown of IL6 in cultured human endothelial cells was performed using siRNA. Knockdown efficiency was evaluated using ELISA. RNA sequencing was employed to characterize the transcriptional consequence of IL6 knockdown, and Ingenuity Pathway Analysis was used to further explore the functional roles of IL6.

    Results: Knockdown of IL6 in cultured endothelial cells resulted in a 84-92% reduction in the release of IL6. Knockdown of IL6 resulted in dramatic changes in transcriptional pattern; knockdown of IL6 in the absence of soluble IL6R alpha (sIL6R alpha) led to differential regulation of 1915 genes, and knockdown of IL6 in the presence of sIL6R alpha led to differential regulation of 1967 genes (fold change 1.5, false discovery rate<0.05). Pathway analysis revealed that the autocrine functions of IL6 in human endothelial cells are mainly related to basal cellular functions such as regulation of cell cycle, signaling, and cellular movement. Furthermore, we found that knockdown of IL6 activates functions related to adhesion, binding, and interaction of endothelial cells, which seem to be mediated mainly via STAT3.

    Conclusion: In this study, a large number of novel genes that are under autocrine regulation by IL6 in human endothelial cells were identified. Overall, our data indicate that IL6 acts in an autocrine manner to regulate basal cellular functions, such as cell cycle regulation, signaling, and cellular movement, and suggests that the autocrine functions of IL6 in human endothelial cells are mediated via IL6 classic signaling.

  • 11.
    Paramel Varghese, Geena
    et al.
    Örebro University, School of Medical Sciences.
    Lindkvist, Madelene
    Örebro University, School of Medical Sciences.
    Idosa, Berhane A.
    School of Medical Sciences, Örebro University, Örebro, Sweden.
    Sebina, Laila Sharon
    School of Medical Sciences, Örebro University, Örebro, Sweden.
    Kardeby, Caroline
    School of Medical Sciences, Örebro University, Örebro, Sweden; Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, West Midlands, United Kingdom.
    Fotopoulou, Theano
    Institute of Chemical Biology, National Hellenic Research Foundation, Athens, Greece.
    Pournara, Dimitra
    Institute of Chemical Biology, National Hellenic Resear.
    Kritsi, Eftichia
    Institute of Chemical Biology, National Hellenic Resear.
    Ifanti, Eleni
    Institute of Chemical Biology, National Hellenic Resear.
    Zervou, Maria
    Institute of Chemical Biology, National Hellenic Resear.
    Koufaki, Maria
    Institute of Chemical Biology, National Hellenic Resear.
    Grenegård, Magnus
    Örebro University, School of Medical Sciences.
    Fransén, Karin
    Örebro University, School of Medical Sciences.
    Novel purine analogues regulate IL-1β release via inhibition of JAK activity in human aortic smooth muscle cells2022In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 929, article id 175128Article in journal (Refereed)
    Abstract [en]

    Purine analogues bearing a nitrate ester motif were previously discovered as cardioprotective and anti-inflammatory agents, but the anti-inflammatory mechanism remains to be established. We therefore investigated the anti-inflammatory effect of two purine analogues, MK118 bearing a nitrate ester moiety and the methyl-substituted analogue MK196 in Aortic Smooth Muscle Cells (AoSMCs), with emphasis on IL-1β release. The AoSMCs were stimulated with LPS with or without purine analogue, followed by ELISA, Olink proteomics, Western blot and real time PCR of NLRP3 inflammasome components. Both purine analogues inhibited the release of proteins involved in inflammation, such as TRAIL, CCL4, CSF1 and IL-1β in AoSMCs, as well as intracellular gene and protein expression of IL-1β and NLRP3 inflammasome components. MK196, but not MK118, also inhibited the LPS-induced release of IL-7, CXCL10, PD-L1, FLT3L and CCL20. We also showed that MK118 and possibly MK196 act via inhibition of JAKs. In silico studies showed that the purine moiety is a competent hinge binding motif and that the purine-piperazine scaffold is well accommodated in the lipophilic groove of JAK1-3. Both compounds establish interactions with catalytic amino acids in the active site of JAK1-3 and the terminal nitrate ester of MK118 was revealed as a promising pharmacophore. Our data suggest that MK118 and MK196 inhibit the release of proinflammatory proteins in AoSMCs, and targets JAK1-3 activation. Purine analogues also inhibit the expression of NLRP3 inflammasome genes and proteins and may in the future be evaluated for anti-inflammatory aspects on inflammatory diseases.

  • 12.
    Tengdelius, Mattias
    et al.
    Division of Organic Chemistry, Department of Physics, Biology and Chemistry (IFM), Linköping University, Linköping , Sweden.
    Kardeby, Caroline
    Örebro University, School of Medical Sciences.
    Fälker, Knut
    Örebro University, School of Medical Sciences.
    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 University, School of Medical Sciences.
    Fucoidan-Mimetic Glycopolymers as Tools for Studying Molecular and Cellular Responses in Human Blood Platelets2017In: Macromolecular Bioscience, ISSN 1616-5187, E-ISSN 1616-5195, Vol. 17, no 2, article id UNSP 1600257Article in journal (Refereed)
    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.

  • 13. Welander, Edward
    et al.
    Åström, Maria
    Örebro University, School of Medical Sciences. Örebro University Hospital.
    Enonge Fotabe, Leslie
    Kardeby, Caroline
    Örebro University, School of Medical Sciences.
    Tina, Elisabet
    Örebro University, School of Medical Sciences.
    Elgbratt, Kristina
    Örebro University, School of Health Sciences.
    Pourlotfi, Arvid
    Abawi, Akram
    Romild, Alma
    Kruse, Robert
    Örebro University, School of Medical Sciences.
    Repsilber, Dirk
    Örebro University, School of Medical Sciences.
    Crafoord, Jakob
    Ahlstrand, Erik
    Örebro University Hospital. Örebro University, School of Medical Sciences.
    Ivarsson, Mikael
    Örebro University, School of Health Sciences.
    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 myelofibrosis2018Conference paper (Refereed)
1 - 13 of 13
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