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  • 1.
    Aboulaich, Nabila
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Expanding role of caveolae in control of adipocyte metabolism: proteomics of caveolae2006Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The primary function of adipose tissue is to store energy in the form of triacylglycerol, which is hydrolyzed to fatty acids to supply other tissues with energy. While insulin promotes the storage of triacylglycerol, catecholamines stimulate its hydrolysis. The development of type II diabetes is strongly associated with obesity, indicating a role of triacylglycerol metabolism in the pathogenesis of diabetes. Caveolae are plasma membrane invaginations found in most cells but are highly abundant in adipocytes. Insulin receptors are localized in caveolae and their function depends on intact caveolae structures. In the present thesis work, mass spectrometry-based methodology allowed identification of a number of new proteins and their posttranslational modifications in caveolae of human adipocytes. Variable N-terminal acetylation and phosphorylation of caveolin-1α and caveolin-1β were identified, which might regulate the function of caveolae. The transcription regulator protein PTRF was identified as the major caveolae associated protein. Specific proteolytic modifications of PTRF at the cytosolic surface of caveolae and phosphorylation on nine serine and one threonine residues were identified. Moreover, insulin induced translocation of PTRF from the plasma membrane to the nucleus. PTRF was previously shown to regulate the activity of both RNA polymerase I and polymerase II, thus a role of PTRF in mediating the anabolic action of insulin on protein synthesis and gene transcription is proposed.

    PTRF was also involved in an extranuclear function in the hormonal regulation of triacylglycerol metabolism in caveolae. PTRF was colocalized with the triacylglycerol regulator proteins perilipin and hormone-sensitive lipase (HSL) in the triacylglycerol-synthesizing caveolae subclass. We showed that, while perilipin was translocated to the plasma membrane, both PTRF and HSL were translocated from the plasma membrane to the cytosol as a complex in response to insulin. The perilipin recruited to the plasma membrane was highly threonine phosphorylated. By mass spectrometry, three phosphorylated threonine residues were identified and were located in an acidic domain in the lipid droplet targeting domain of perilipin. The insulin-induced recruitment of perilipin to the plasma membrane might, therefore be phosphorylation-dependent. Isoproterenol, which stimulates hydrolysis of triacylglycerol, induced a complete depletion of perilipin B from the plasma membrane, suggesting a function of perilipin B to protect newly synthesized triacylglycerol in caveolae from being hydrolyzed by HSL. The location of PTRF and HSL was not affected by isoproterenol, indicating that insulin is acting against a default presence of PTRF and HSL in caveolae.

    Taken together, this thesis expands our knowledge about caveolae and provided valuable information about their involvement in novel roles, particularly in the hormonal regulation of triacylglycerol metabolism.

    List of papers
    1. Vectorial proteomics reveal targeting, phosphorylation and specific fragmentation of polymerase I and transcript release factor (PTRF) at the surface of caveolae in human adipocytes
    Open this publication in new window or tab >>Vectorial proteomics reveal targeting, phosphorylation and specific fragmentation of polymerase I and transcript release factor (PTRF) at the surface of caveolae in human adipocytes
    2004 (English)In: The Biochemical journal, ISSN 1470-8728, Vol. 383, no Pt 2, 237-248 p.Article in journal (Refereed) Published
    Abstract [en]

    Caveolae, the specialized invaginations of plasma membranes, formed sealed vesicles with outwards-orientated cytosolic surface after isolation from primary human adipocytes. This morphology allowed differential, vectorial identification of proteins at the opposite membrane surfaces by proteolysis and MS. Extracellular-exposed caveolae-specific proteins CD36 and copper-containing amine oxidase were concealed inside the vesicles and resisted trypsin treatment. The cytosol-orientated caveolins were efficiently digested by trypsin, producing peptides amenable to direct MS sequencing. Isolation of peripheral proteins associated with the cytosolic surface of caveolae revealed a set of proteins that contained nuclear localization signals, leucine-zipper domains and PEST (amino acid sequence enriched in proline, glutamic acid, serine and threonine) domains implicated in regulation by proteolysis. In particular, PTRF (polymerase I and transcript release factor) was found as a major caveolae-associated protein and its co-localization with caveolin was confirmed by immunofluorescence confocal microscopy. PTRF was present at the surface of caveolae in the intact form and in five different truncated forms. Peptides (44 and 45 amino acids long) comprising both the PEST domains were sequenced by nanospray-quadrupole-time-of-flight MS from the full-length PTRF, but were not found in the truncated forms of the protein. Two endogenous cleavage sites corresponding to calpain specificity were identified in PTRF; one of them was in a PEST domain. Both cleavage sites were flanked by mono- or diphosphorylated sequences. The phosphorylation sites were localized to Ser-36, Ser-40, Ser-365 and Ser-366 in PTRF. Caveolae of human adipocytes are proposed to function in targeting, relocation and proteolytic control of PTRF and other PEST-domain-containing signalling proteins.

    Keyword
    Caveolae, human adipocyte, MS, PEST sequence, polymerase I and transcript release factor (PTRF), proteolysis
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-19145 (URN)10.1042/BJ20040647 (DOI)15242332 (PubMedID)
    Available from: 2009-06-12 Created: 2009-06-12 Last updated: 2009-06-12Bibliographically approved
    2. N-terminal processing and modifications of caveolin-1 in caveolae from human adipocytes
    Open this publication in new window or tab >>N-terminal processing and modifications of caveolin-1 in caveolae from human adipocytes
    Show others...
    2004 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 320, no 2, 480-486 p.Article in journal (Refereed) Published
    Abstract [en]

    Caveolin, the principal structural protein of caveolae membrane domains, has a cytosol-exposed N-terminal part that was cleaved off by trypsin treatment of caveolae vesicles isolated from primary human adipocytes. Sequencing of the released tryptic peptides by nanospray quadrupole time-of-flight mass spectrometry revealed that both caveolin-1alpha and caveolin-1beta were processed by excision of the starting methionines. The N-terminus of the mature caveolin-1alpha was acetylated, while caveolin-1beta was found in acetylated as well as in non-acetylated forms. Fractional phosphorylation of serine-36 in the mature caveolin-1alpha and of the homologous serine-5 in caveolin-1beta was identified. This is the first experimental evidence for in vivo phosphorylation of caveolin-1 at the consensus site for phosphorylation by protein kinase C. The phosphorylation was found in both the acetylated and non-acetylated variants of caveolin-1beta. This variability in modifications is consistent with critical involvement of the N-terminal domain of caveolin in the regulation of caveolae.

    Keyword
    Human adipocyte, Caveolin-1; Caveolae, Protein phosphorylation, N-terminal acetylation, Mass spectrometry
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-19146 (URN)10.1016/j.bbrc.2004.05.196 (DOI)15219854 (PubMedID)
    Available from: 2009-06-12 Created: 2009-06-12 Last updated: 2017-12-13Bibliographically approved
    3. Hormonal control of reversible translocation of perilipin B to the plasma membrane in primary human adipocytes
    Open this publication in new window or tab >>Hormonal control of reversible translocation of perilipin B to the plasma membrane in primary human adipocytes
    2006 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 281, no 17, 11446-11449 p.Article in journal (Refereed) Published
    Abstract [en]

    In adipocytes, perilipin coats and protects the central lipid droplet, which stores triacylglycerol. Alternative mRNA splicing gives rise to perilipin A and B. Hormones such as catecholamines and insulin regulate triacylglycerol metabolism through reversible serine phosphorylation of perilipin A. It was recently shown that perilipin was also located in triacylglycerol-synthesizing caveolae of the plasma membrane. We now report that perilipin at the plasma membrane of primary human adipocytes was phosphorylated on a cluster of threonine residues (299, 301, and 306) within an acidic domain that forms part of the lipid targeting domain. Perilipin B comprised <10% of total perilipin but was the major isoform associated with the plasma membrane of human adipocytes. This association was controlled by insulin and catecholamine: perilipin B was specifically depleted from the plasma membrane in response to the catecholamine isoproterenol, while insulin increased the amount of threonine phosphorylated perilipin at the plasma membrane. The reversible translocation of perilipin B to and from the plasma membrane in response to insulin and isoproterenol, respectively, suggests a specific function for perilipin B to protect newly synthesized triacylglycerol in the plasma membrane.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-19147 (URN)10.1074/jbc.C500461200 (DOI)16527823 (PubMedID)
    Available from: 2009-06-12 Created: 2009-06-12 Last updated: 2017-12-13Bibliographically approved
    4. Association and insulin regulated translocation of hormone-sensitive lipase with PTRF
    Open this publication in new window or tab >>Association and insulin regulated translocation of hormone-sensitive lipase with PTRF
    2006 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 350, no 3, 657-661 p.Article in journal (Refereed) Published
    Abstract [en]

    Polymerase I and transcript release factor (PTRF) is in human adipocytes mainly localized at the plasma membrane. This localization was under control of insulin, which translocated PTRF to the cytosol and nucleus, indicating a novel role for PTRF in insulin transcriptional control. In the plasma membrane PTRF was specifically bound to a triacylglycerol-metabolizing subclass of caveolae containing hormone-sensitive lipase (HSL). In response to insulin PTRF was translocated to the cytosol in parallel with HSL. PTRF and HSL were quantitatively immunoprecipitated from the cytosol by antibodies against either PTRF or HSL. The findings indicate also a novel extranuclear function for PTRF in the control of lipolysis.

    Keyword
    Hormone-sensitive lipase, Polymerase I and transcript release factor, Adipocyte, Human, Insulin, Translocation, Protein complex, Caveolae, Lipid metabolism, Transcriptional control
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-19148 (URN)10.1016/j.bbrc.2006.09.094 (DOI)17026959 (PubMedID)
    Available from: 2009-06-12 Created: 2009-06-12 Last updated: 2017-12-13Bibliographically approved
  • 2.
    Aboulaich, Nabila
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Ortegren, Unn
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Vener, Alexander V
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Strålfors, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Association and insulin regulated translocation of hormone-sensitive lipase with PTRF2006In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 350, no 3, 657-661 p.Article in journal (Refereed)
    Abstract [en]

    Polymerase I and transcript release factor (PTRF) is in human adipocytes mainly localized at the plasma membrane. This localization was under control of insulin, which translocated PTRF to the cytosol and nucleus, indicating a novel role for PTRF in insulin transcriptional control. In the plasma membrane PTRF was specifically bound to a triacylglycerol-metabolizing subclass of caveolae containing hormone-sensitive lipase (HSL). In response to insulin PTRF was translocated to the cytosol in parallel with HSL. PTRF and HSL were quantitatively immunoprecipitated from the cytosol by antibodies against either PTRF or HSL. The findings indicate also a novel extranuclear function for PTRF in the control of lipolysis.

  • 3.
    Aboulaich, Nabila
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Vainonen, Julia P
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Strålfors, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Vener, Alexander V
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Vectorial proteomics reveal targeting, phosphorylation and specific fragmentation of polymerase I and transcript release factor (PTRF) at the surface of caveolae in human adipocytes2004In: The Biochemical journal, ISSN 1470-8728, Vol. 383, no Pt 2, 237-248 p.Article in journal (Refereed)
    Abstract [en]

    Caveolae, the specialized invaginations of plasma membranes, formed sealed vesicles with outwards-orientated cytosolic surface after isolation from primary human adipocytes. This morphology allowed differential, vectorial identification of proteins at the opposite membrane surfaces by proteolysis and MS. Extracellular-exposed caveolae-specific proteins CD36 and copper-containing amine oxidase were concealed inside the vesicles and resisted trypsin treatment. The cytosol-orientated caveolins were efficiently digested by trypsin, producing peptides amenable to direct MS sequencing. Isolation of peripheral proteins associated with the cytosolic surface of caveolae revealed a set of proteins that contained nuclear localization signals, leucine-zipper domains and PEST (amino acid sequence enriched in proline, glutamic acid, serine and threonine) domains implicated in regulation by proteolysis. In particular, PTRF (polymerase I and transcript release factor) was found as a major caveolae-associated protein and its co-localization with caveolin was confirmed by immunofluorescence confocal microscopy. PTRF was present at the surface of caveolae in the intact form and in five different truncated forms. Peptides (44 and 45 amino acids long) comprising both the PEST domains were sequenced by nanospray-quadrupole-time-of-flight MS from the full-length PTRF, but were not found in the truncated forms of the protein. Two endogenous cleavage sites corresponding to calpain specificity were identified in PTRF; one of them was in a PEST domain. Both cleavage sites were flanked by mono- or diphosphorylated sequences. The phosphorylation sites were localized to Ser-36, Ser-40, Ser-365 and Ser-366 in PTRF. Caveolae of human adipocytes are proposed to function in targeting, relocation and proteolytic control of PTRF and other PEST-domain-containing signalling proteins.

  • 4.
    Aboulaich, Nabila
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Vener, Alexander V
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Strålfors, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Hormonal control of reversible translocation of perilipin B to the plasma membrane in primary human adipocytes2006In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 281, no 17, 11446-11449 p.Article in journal (Refereed)
    Abstract [en]

    In adipocytes, perilipin coats and protects the central lipid droplet, which stores triacylglycerol. Alternative mRNA splicing gives rise to perilipin A and B. Hormones such as catecholamines and insulin regulate triacylglycerol metabolism through reversible serine phosphorylation of perilipin A. It was recently shown that perilipin was also located in triacylglycerol-synthesizing caveolae of the plasma membrane. We now report that perilipin at the plasma membrane of primary human adipocytes was phosphorylated on a cluster of threonine residues (299, 301, and 306) within an acidic domain that forms part of the lipid targeting domain. Perilipin B comprised <10% of total perilipin but was the major isoform associated with the plasma membrane of human adipocytes. This association was controlled by insulin and catecholamine: perilipin B was specifically depleted from the plasma membrane in response to the catecholamine isoproterenol, while insulin increased the amount of threonine phosphorylated perilipin at the plasma membrane. The reversible translocation of perilipin B to and from the plasma membrane in response to insulin and isoproterenol, respectively, suggests a specific function for perilipin B to protect newly synthesized triacylglycerol in the plasma membrane.

  • 5.
    Ahl, Ing-Marie
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Protein Engineering of Extracellular Superoxide Dismutase: Characterization of Binding to Heparin and Cellular Surfaces2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Accumulating evidence indicates that oxygen free radicals are involved in many diseases and pathological conditions, such as aging, inflammation, reperfusion damage of ischemic tissue and various cardiovascular diseases. Extracellular superoxide dismutase (ECSOD) thus plays a major role in the maintenance of cells by providing protection against these toxic substances in the extracellular space. Various animal studies have shown that ECSOD has the ability to protect against many of these disorders, and interest has therefore evolved in the potential therapeutic use of the enzyme.

    However, despite strenuous efforts, large-scale production of the enzyme has not been achieved. To overcome this problem, a mimic of the enzyme, PseudoECSOD, has previously

    been constructed. This chimera is easy to produce in large amounts and has all the structural, enzymatic and heparin-binding characteristics of ECSOD, making it a potential substitute for ECSOD in therapeutic situations. However, the copper content of PseudoECSOD has been shown to be rather low, and since the copper ion is very important for the catalytic function of the enzyme, a production system that utilizes a copper chaperone for proper insertion of copper into the active site of the enzyme was constructed. The results show that the copper content of PseudoECSOD produced by this system is close to 100 %.

    In order to use PseudoECSOD therapeutically, further investigations of its binding capability and protective properties are needed. Therefore, the binding of ECSOD and PseudoECSOD to heparin was investigated using isothermal titration calorimetry. The results show that although some purely ionic interactions are important for the binding between ECSOD and heparin, there is also a substantial contribution from non-ionic interactions. The investigation also showed that the C-terminal domain is the only part of ECSOD that contributes to productive binding, and that the binding of PseudoECSOD and ECSOD to heparin is similar.

    In addition, analysis of mutant proteins strongly indicated that the amino acids R210, K211 and R214 are important for optimal binding of ECSOD to heparin, accounting for about 30 % of the total binding energy. The structural placement of these amino acids in an α-helix also confirms the hypothesis postulated by Margalit et al., that a common structural motif for heparin-binding proteins may be two positively charged amino acids at a distance of approximately 20 Å in the 3D-structure, facing opposite directions of a α-helix. The importance of these residues was also confirmed by analysis of a phage display library of the C-terminal domain of ECSOD.

    The binding of PseudoECSOD to heparan sulfate on cell surfaces of two different cell types, HepG2 and endothelial cells, was also investigated. The results clearly show that PseudoECSOD binds to these cells in a very similar manner to ECSOD. To investigate the protective properties of PseudoECSOD against ischemia-reperfusion injuries, an isolated rabbit heart model was used. The results indicate that the enzyme has a protective effect. However, more experiments using the rabbit heart and other animal models are needed to identify the optimal dose for protective purposes. The protective properties of PseudoECSOD in human tissue should also be thoroughly investigated.

    In summary, the findings in these studies, together with earlier results showing the close resemblance of PseudoECSOD to ECSOD in structural, enzymatic and heparin-binding properties, further support the proposition that PseudoECSOD may be a good substitute for ECSOD to use in therapeutic interventions.

    List of papers
    1. Thermodynamic Characterization of the Interaction between the C-Terminal Domain of Extracellular Superoxide Dismutase and Heparin by Isothermal Titration Calorimetry
    Open this publication in new window or tab >>Thermodynamic Characterization of the Interaction between the C-Terminal Domain of Extracellular Superoxide Dismutase and Heparin by Isothermal Titration Calorimetry
    2009 (English)In: BIOCHEMISTRY, ISSN 0006-2960, Vol. 48, no 41, 9932-9940 p.Article in journal (Refereed) Published
    Abstract [en]

    Extracellular superoxide dismutase (ECSOD) interacts with heparin through its C-terminal domain. In this study we used isothermal titration calorimetry (ITC) to get detailed thermodynamic information about the interaction. We have shown that the interaction between ECSOD and intestinal mucosal heparin (M-w 6000-30000 Da) is exothermic and driven by enthalpy at physiological salt concentration. However, the contribution from entropy is favorable for binding or small isolated heparin fragments. By studying different size-defined heparin fragments, we also concluded that it hexasaccharide moiety is sufficient for strong binding to ECSOD. The binding involves proton transfer from the buffer to the ECSOD-heparin complex, and the results indicate that the number of ionic interactions made between ECSOD and heparin upon binding varies from three to five for heparin and an octasaccharide fragment, respectively. Surprisingly and despite the many charges found oil both the protein and the polysaccharide, our results indicate that the nonionic contribution to the binding is large. From the temperature dependence we have calculated the constant pressure heat capacity change (Delta C-p) of the interaction to -644 J K-1 mol(-1) and -306 J K-1 mol(-1) for heparin and all octasaccharide, respectively

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-51398 (URN)10.1021/bi900981k (DOI)
    Available from: 2009-10-30 Created: 2009-10-30 Last updated: 2016-05-04
    2. Analysis of Effects of Mutations in the C-Terminal Domain of Extracellular Superoxide Dismutase by Isothermal Titration Calorimetry and Phage Display
    Open this publication in new window or tab >>Analysis of Effects of Mutations in the C-Terminal Domain of Extracellular Superoxide Dismutase by Isothermal Titration Calorimetry and Phage Display
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    n/a

    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:liu:diva-52450 (URN)
    Available from: 2009-12-21 Created: 2009-12-21 Last updated: 2016-05-04
    3. Coexpression of yeast copper chaperone (yCCS) and CuZn-superoxide dismutases in Escherichia coli yields protein with high copper contents
    Open this publication in new window or tab >>Coexpression of yeast copper chaperone (yCCS) and CuZn-superoxide dismutases in Escherichia coli yields protein with high copper contents
    2004 (English)In: Protein Expression and Purification, ISSN 1046-5928, E-ISSN 1096-0279, Vol. 37, no 2, 311-319 p.Article in journal (Refereed) Published
    Abstract [en]

    To fully understand the function of the Cu- and Zn-containing superoxide dismutases in normal and disordered cells, it is essential to study protein variants with full metal contents. We describe the use of an Escherichia coli-based expression system for the overproduction of human intracellular wild type CuZn-superoxide dismutase (SOD), the CuZnSOD variant F50E/G51E (monomeric), two amyotrophic lateral sclerosis-related mutant CuZnSOD variants (D90A and G93A), and PseudoEC-SOD, all with high Cu contents. This system is based on coexpression of the SOD variants with the yeast copper chaperone yCCS during growth in a medium supplemented with Cu2+ and Zn2+. The recombinant SOD enzymes were all found in the cytosol and represented 30-50% of the total bacterial protein. The enzymes were purified to homogeneity and active enzymes were obtained in high yield. The resulting proteins were characterized through immunochemical reactivity and specific activity analyses, in conjunction with mass-, photo-, and atomic absorption-spectroscopy. © 2004 Elsevier Inc. All rights reserved.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-22221 (URN)10.1016/j.pep.2004.06.006 (DOI)1379 (Local ID)1379 (Archive number)1379 (OAI)
    Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13
    4. Cell Association and Protective Effects of PseudoECSOD: a progress report
    Open this publication in new window or tab >>Cell Association and Protective Effects of PseudoECSOD: a progress report
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    n/a

    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:liu:diva-52451 (URN)
    Available from: 2009-12-21 Created: 2009-12-21 Last updated: 2016-05-04
  • 6.
    Ahl, Ing-Marie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Jonsson, Bengt-Harald
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology . Linköping University, The Institute of Technology.
    Tibell, Lena
    Linköping University, Department of Science and Technology, Visual Information Technology and Applications (VITA). Linköping University, The Institute of Technology.
    Thermodynamic Characterization of the Interaction between the C-Terminal Domain of Extracellular Superoxide Dismutase and Heparin by Isothermal Titration Calorimetry2009In: BIOCHEMISTRY, ISSN 0006-2960, Vol. 48, no 41, 9932-9940 p.Article in journal (Refereed)
    Abstract [en]

    Extracellular superoxide dismutase (ECSOD) interacts with heparin through its C-terminal domain. In this study we used isothermal titration calorimetry (ITC) to get detailed thermodynamic information about the interaction. We have shown that the interaction between ECSOD and intestinal mucosal heparin (M-w 6000-30000 Da) is exothermic and driven by enthalpy at physiological salt concentration. However, the contribution from entropy is favorable for binding or small isolated heparin fragments. By studying different size-defined heparin fragments, we also concluded that it hexasaccharide moiety is sufficient for strong binding to ECSOD. The binding involves proton transfer from the buffer to the ECSOD-heparin complex, and the results indicate that the number of ionic interactions made between ECSOD and heparin upon binding varies from three to five for heparin and an octasaccharide fragment, respectively. Surprisingly and despite the many charges found oil both the protein and the polysaccharide, our results indicate that the nonionic contribution to the binding is large. From the temperature dependence we have calculated the constant pressure heat capacity change (Delta C-p) of the interaction to -644 J K-1 mol(-1) and -306 J K-1 mol(-1) for heparin and all octasaccharide, respectively

  • 7.
    Ahl, Ing-Marie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Jonsson, Bengt-Harald
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology . Linköping University, The Institute of Technology.
    Tibell, Lena A. E.
    Linköping University, Department of Science and Technology, Visual Information Technology and Applications (VITA). Linköping University, The Institute of Technology.
    Analysis of Effects of Mutations in the C-Terminal Domain of Extracellular Superoxide Dismutase by Isothermal Titration Calorimetry and Phage DisplayManuscript (preprint) (Other academic)
    Abstract [en]

    n/a

  • 8.
    Ahl, Ing-Marie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Nelson, Sally K
    Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Denver, CO-800 45, Aurora, USA.
    Enström, Camilla
    Department of Medical Sciences, Uppsala University, SE-751 85, Uppsala, Sweden.
    Ericson, Ann-Charlotte
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Tibell, Lena A. E.
    Linköping University, Department of Science and Technology, Visual Information Technology and Applications (VITA). Linköping University, The Institute of Technology.
    Cell Association and Protective Effects of PseudoECSOD: a progress reportManuscript (preprint) (Other academic)
    Abstract [en]

    n/a

  • 9.
    Ahmad, Faiyaz
    et al.
    NHLBI, Translat Med Branch, NIH, Bethesda, MD 20892 USA .
    Lindh, Rebecka
    Lund University, Department Expt Med Science, S-22184 Lund, Sweden .
    Tang, Yan
    NHLBI, Translat Med Branch, NIH, Bethesda, MD 20892 USA .
    Ruishalme, Iida
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Öst, Anita
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Sahachartsiri, Bobby
    NHLBI, Translat Med Branch, NIH, Bethesda, MD 20892 USA .
    Strålfors, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Degerman, Eva
    Lund University, Department Expt Med Science, S-22184 Lund, Sweden .
    C Manganiello, Vincent
    NHLBI, Translat Med Branch, NIH, Bethesda, MD 20892 USA .
    Differential regulation of adipocyte PDE3B in distinct membrane compartments by insulin and the beta(3)-adrenergic receptor agonist CL316243: effects of caveolin-1 knockdown on formation/maintenance of macromolecular signalling complexes2009In: BIOCHEMICAL JOURNAL, ISSN 0264-6021, Vol. 424, no 3, 399-410 p.Article in journal (Refereed)
    Abstract [en]

    In adipocytes, PDE3B (phosphodiesterase 3B) is an important regulatory effector in signalling pathways controlled by insulin and cAMP-increasing hormones. Stimulation of 3T3-L1 adipocytes with insulin or the beta(3)-adrenergic receptor agonist CL316243 (termed CL) indicated that insulin preferentially phosphorylated/activated PDE3B associated with internal membranes (endoplasmic reticulum/Golgi), whereas CL preferentially phosphorylated/activated PDE3B associated with caveolae. siRNA (small interfering RNA)-mediated KD (knockdown) of CAV-1 (caveolin-1) in 3T3-L1 adipocytes resulted in down-regulation of expression of membrane-associated PDE3B. Insulin-induced activation of PDE3B was reduced, whereas CL-mediated activation was almost totally abolished. Similar results were obtained in adipocytes from Cav-1-deficient mice. siRNA-mediated KID of CAV-1 in 3T3-L1 adipocytes also resulted in inhibition of CL-stimulated phosphorylation of HSL (hormone-sensitive lipase) and perilipin A, and of lipolysis. Superose 6 gel-filtration chromatography of solubilized membrane proteins from adipocytes stimulated with insulin or CL demonstrated the reversible assembly of distinct macromolecular complexes that contained P-32-phosphorylated PDE3B and signalling molecules thought to be involved in its activation. Insulin- and CL-induced macromolecular complexes were enriched in cholesterol, and contained certain common signalling proteins [14-3-3, PP2A (protein phosphatase 2A) and cav-1]. The complexes present in insulin-stimulated cells contained tyrosine-phosphorylated IRS-1 (insulin receptor substrate 1) and its downstream signalling proteins, whereas CL-activated complexes contained beta(3)-adrenergic receptor, PKA-RII [PKA (cAMP-dependent protein kinase)-regulatory subunit] and HSL. Insulin- and CL-mediated macromolecular complex formation was significantly inhibited by CAV-1 KID. These results suggest that cav-1 acts as a molecular chaperone or scaffolding molecule in cholesterol-rich lipid rafts that may be necessary for the proper stabilization and activation of PDE3B in response to CL and insulin.

  • 10.
    Ahmadi, Ahmad
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Jonsson, Pia
    Linköping University, Department of Molecular and Clinical Medicine, Occupational and Environmental Medicine. Linköping University, Faculty of Health Sciences.
    Flodin, Ulf
    Linköping University, Department of Clinical and Experimental Medicine, Occupational and Environmental Medicine. Linköping University, Faculty of Health Sciences.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Interaction between smoking and glutathione S-transferase polymorphisms in solvent-induced chronic toxic encephalopathy2002In: Toxicology and industrial health, ISSN 0748-2337, E-ISSN 1477-0393, Vol. 18, no 6, 289-296 p.Article in journal (Refereed)
    Abstract [en]

    Exposure to organic solvents is still common in industrial and other work environments, and increases the risk of chronic toxic encephalopathy (CTE). Genetic variation in metabolic enzymes for solvents and other xenobiotics may modify the risk of developing toxic effects. Therefore, we investigated the presence of null genotypes for glutathione S-transferases M1 and T1 (GSTM1, GSTT1) and two genetic polymorphisms of microsomal epoxide hydrolase (mEPHX) in relation to the risk for chronic toxic encephalopathy (CTE) when exposed to solvents and smoking. We genotyped 115 patients who were classified into three categories: CTE (n = 56), incipient CTE (n = 27) and non-CTE (n = 32) patients. DNA was isolated from leucocytes and the GSTM 1 and GSTT1 null genotypes were determined by multiplex-polymerase chain reaction. The two polymorphisms of mEPHX were analysed by PCR-RFLP (restriction fragment length polymorphism) based assays. All analyses were performed blindly with regard to both exposure and disease status. An increased binomial regression risk ratio = 2.5, 95% confidence interval (CI) 1.5-4.2, of the GSTM1 null genotype for CTE was found in smokers and for the GSTT1 null genotype (binomial regression risk ratio 1.5, 95% CI 1.0-2.0). In nonsmokers, the GSTM1 null genotype did not confer any risk for CTE. None of the studied mEPHX polymorphisms were associated with an increased risk for CTE. We suggest that the GSTM1 null genotype in smokers is a possible risk for solvent-induced CTE.

  • 11.
    Ahrén, Maria
    et al.
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics .
    Olsson, Petter
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology.
    Söderlind, Fredrik
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology.
    Klasson, Anna
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Radiology . Linköping University, Center for Medical Image Science and Visualization, CMIV.
    Petoral, Rodrigo Jr
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics .
    Engström, Maria
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Center for Medical Image Science and Visualization, CMIV.
    Käll, Per-Olov
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Physical Chemistry .
    Uvdal, Kajsa
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics .
    Rare earth nanoparticles as contrast agent in MRI: Nanomaterial design and biofunctionalization2007In: IVC-17/ICSS-13 ICNT,2007, 2007Conference paper (Other academic)
  • 12.
    Akanda, Nesar
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Voltage-dependent anion channels (VDAC) in the plasma membrane induce apoptosis2006Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Apoptosis, or programmed cell death, is essential for proper development and functioning of the body systems. During development, apoptosis plays a central role to sculpt the embryo, and in adults, to maintain tissue homeostasis by eliminating redundant, damaged or effete cells. Therefore, a tight regulation of this process is essential. Cell shrinkage associated efflux of K+ and Cl through plasma membrane ion channels is an early event of apoptosis. However, little is known about these fluxes. The aim of this thesis was to investigate ion channels in the plasma membrane of neurons undergoing apoptosis. We studied differentiated (the mouse hippocampal cell line HT22, the human neuroblastoma cell line SK-N-MC, and rat primary hippocampal neurons) and undifferentiated (rat primary cortical neural stem cells cNSCs) cells with the patch-clamp technique. All cell types displayed a low electrical activity under control conditions. However, during apoptosis in differentiated neurons, we found an activation of a voltage-dependent anion channel. The conductance of the channel is 400 pS, the voltage dependence of the opening is bell shaped with respect to membrane voltage with a maximum open probability at 0 mV, and the Cl to cation selectivity is >5:1. These biophysical properties remind about the voltage-dependent anion channel normally found in the outer mitochondrial membrane (VDACmt). Hence, we call our apoptosis-inducing plasma membrane channel VDACpl. The molecular identity of the channel was corroborated with the specific labelling of different anti-VDAC antibodies. Block of this channel either with antibodies or with sucrose prevented apoptosis, suggesting a critical role for VDACpl in the apoptotic process. VDACpl is a NADH (-ferricyanide) reductase in control cells. We found that the enzymatic activity is altered while the VDACpl channel is activated during apoptosis. Surprisingly, in cNSCs we did not find any activation of VDACpl, no VDACpl-specific labelling, no enzymatic activity, and no prevention of apoptosis with VDACpl-blocking strategies. Instead, we found an activation of a voltage-independent 37 pS ion channel, and that the Cl channel blocker DIDS prevented apoptosis in cNSCs. Our finding that activation of VDACpl is critical for apoptosis in differentiated neurons hopefully can lead to new strategies in the treatment of several diseases related to apoptosis.

    List of papers
    1. Opening of plasma membrane voltage-dependent anion channels (VDAC) precedes caspase activation in neuronal apoptosis induced by toxic stimuli
    Open this publication in new window or tab >>Opening of plasma membrane voltage-dependent anion channels (VDAC) precedes caspase activation in neuronal apoptosis induced by toxic stimuli
    Show others...
    2005 (English)In: Cell Death and Differentiation, ISSN 1350-9047, E-ISSN 1476-5403, Vol. 12, no 8, 1134-1140 p.Article in journal (Refereed) Published
    Abstract [en]

    Apoptotic cell death is an essential process in the development of the central nervous system and in the pathogenesis of its degenerative diseases. Efflux of K+ and Cl- ions leads to the shrinkage of the apoptotic cell and facilitates the activation of caspases. Here, we present electrophysiological and immunocytochemical evidences for the activation of a voltage-dependent anion channel (VDAC) in the plasma membrane of neurons undergoing apoptosis. Anti-VDAC antibodies blocked the channel and inhibited the apoptotic process. In nonapoptotic cells, plasma membrane VDAC1 protein can function as a NADH (-ferricyanide) reductase. Opening of VDAC channels in apoptotic cells was associated with an increase in this activity, which was partly blocked by VDAC antibodies. Hence, it appears that there might be a dual role for this protein in the plasma membrane: (1) maintenance of redox homeostasis in normal cells and (2) promotion of anion efflux in apoptotic cells.

    Keyword
    VDAC, voltage-dependent anion channel; STS, staurosporine; PS, phosphatidylserine
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-14278 (URN)10.1038/sj.cdd.4401646 (DOI)
    Available from: 2007-02-01 Created: 2007-02-01 Last updated: 2017-12-13
    2. Voltage-dependent anion channels (VDAC) in the plasma membrane play a critical role in apoptosis in differentiated hippocampal neurons but not in neural stem cells
    Open this publication in new window or tab >>Voltage-dependent anion channels (VDAC) in the plasma membrane play a critical role in apoptosis in differentiated hippocampal neurons but not in neural stem cells
    Show others...
    2008 (English)In: Cell Cycle, ISSN 1538-4101, E-ISSN 1551-4005, Vol. 7, no 20, 3225-3234 p.Article in journal (Refereed) Published
    Abstract [en]

    microRNAs (miRNAs) are small non-coding RNAs that regulate a large variety of cellular processes including differentiation, apoptosis and proliferation. Several miRNAs display defective expression patterns in human tumors with the consequent alteration of target oncogene or tumor suppressor genes. Many of these miRNAs modulate the major proliferation pathways through direct interaction with critical regulators such as RAS, PI3K/PTEN or ABL, as well as members of the retinoblastoma pathway, Cyclin-CDK complexes or cell cycle inhibitors of the INK4 or Cip/Kip families. A complex interplay between miRNAs and MYC or E2F family members also exists to modulate cell cycle-dependent transcription during normal or tumoral proliferation. The ability of miRNAs to modulate these proliferation pathways may have relevant implications not only in physiological or developmental processes but also in tumor progression or cancer therapy.

    Keyword
    patch clamp, single-channel recordings, apoptosis, VDAC, hippocampal neurons, neural stem cells, sodium channels
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-47952 (URN)10.4161/cc.7.20.6831 (DOI)
    Available from: 2009-10-11 Created: 2009-10-11 Last updated: 2017-12-13
    3. Biophysical properties of the apoptosis-inducing plasma membrane voltage-dependent anion channel
    Open this publication in new window or tab >>Biophysical properties of the apoptosis-inducing plasma membrane voltage-dependent anion channel
    2006 (English)In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 90, no 12, 4405-4417 p.Article in journal (Refereed) Published
    Abstract [en]

    Ion channels in the plasma membrane play critical roles in apoptosis. In a recent study we found that a voltage-dependent anion channel in the plasma membrane (VDACpl) of neuronal hippocampal cell line (HT22) cells was activated during apoptosis and that channel block prevented apoptosis. Whether or not VDACpl is identical to the mitochondrial VDACmt has been debated. Here, we biophysically characterize the apoptosis-inducing VDACpl and compare it with other reports of VDACpls and VDACmt. Excised membrane patches of apoptotic HT22 cells were studied with the patch-clamp technique. VDACpl has a large main-conductance state (400 pS) and occasionally subconductance states of µ28 pS and 220 pS. The small subconductance state is associated with long-lived inactivated states, and the large subconductance state is associated with excision of the membrane patch and subsequent activation of the channel. The open-probability curve is bell shaped with its peak around 0mV and is blocked by 30µM Gd3+. The gating can be described by a symmetrical seven-state model with one open state and six closed or inactivated states. These channel properties are similar to those of VDACmt and other VDACpls and are discussed in relation to apoptosis.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-14280 (URN)10.1529/biophysj.105.080028 (DOI)
    Available from: 2007-02-01 Created: 2007-02-01 Last updated: 2017-12-13
    4. Sucrose reduces the current through plasma membrane voltage-dependent anion channels (VDACpl) mainly by reducing the open probability
    Open this publication in new window or tab >>Sucrose reduces the current through plasma membrane voltage-dependent anion channels (VDACpl) mainly by reducing the open probability
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:liu:diva-14281 (URN)
    Available from: 2007-02-01 Created: 2007-02-01 Last updated: 2010-01-13
  • 13.
    Akanda, Nesar
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cellbiology. Linköping University, Faculty of Health Sciences.
    Elinder, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Cellbiology. Linköping University, Faculty of Health Sciences.
    Biophysical properties of the apoptosis-inducing plasma membrane voltage-dependent anion channel2006In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 90, no 12, 4405-4417 p.Article in journal (Refereed)
    Abstract [en]

    Ion channels in the plasma membrane play critical roles in apoptosis. In a recent study we found that a voltage-dependent anion channel in the plasma membrane (VDACpl) of neuronal hippocampal cell line (HT22) cells was activated during apoptosis and that channel block prevented apoptosis. Whether or not VDACpl is identical to the mitochondrial VDACmt has been debated. Here, we biophysically characterize the apoptosis-inducing VDACpl and compare it with other reports of VDACpls and VDACmt. Excised membrane patches of apoptotic HT22 cells were studied with the patch-clamp technique. VDACpl has a large main-conductance state (400 pS) and occasionally subconductance states of µ28 pS and 220 pS. The small subconductance state is associated with long-lived inactivated states, and the large subconductance state is associated with excision of the membrane patch and subsequent activation of the channel. The open-probability curve is bell shaped with its peak around 0mV and is blocked by 30µM Gd3+. The gating can be described by a symmetrical seven-state model with one open state and six closed or inactivated states. These channel properties are similar to those of VDACmt and other VDACpls and are discussed in relation to apoptosis.

  • 14.
    Akanda, Nesar
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology.
    Tofighi, Roshan
    Karolinska Inst, Dept Neurosci, SE-17177 Stockholm, Sweden .
    Brask, Johan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Tamm, Christoffer
    Karolinska Inst, Dept Neurosci, SE-17177 Stockholm, Sweden .
    Elinder, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Ceccatelli, Sandra
    Karolinska Inst, Dept Neurosci, SE-17177 Stockholm, Sweden .
    Voltage-dependent anion channels (VDAC) in the plasma membrane play a critical role in apoptosis in differentiated hippocampal neurons but not in neural stem cells2008In: Cell Cycle, ISSN 1538-4101, E-ISSN 1551-4005, Vol. 7, no 20, 3225-3234 p.Article in journal (Refereed)
    Abstract [en]

    microRNAs (miRNAs) are small non-coding RNAs that regulate a large variety of cellular processes including differentiation, apoptosis and proliferation. Several miRNAs display defective expression patterns in human tumors with the consequent alteration of target oncogene or tumor suppressor genes. Many of these miRNAs modulate the major proliferation pathways through direct interaction with critical regulators such as RAS, PI3K/PTEN or ABL, as well as members of the retinoblastoma pathway, Cyclin-CDK complexes or cell cycle inhibitors of the INK4 or Cip/Kip families. A complex interplay between miRNAs and MYC or E2F family members also exists to modulate cell cycle-dependent transcription during normal or tumoral proliferation. The ability of miRNAs to modulate these proliferation pathways may have relevant implications not only in physiological or developmental processes but also in tumor progression or cancer therapy.

  • 15.
    Alarcon, Emilio I
    et al.
    University of Ottawa.
    Udekwu, Klas
    Karolinska Institute.
    Skog, Mårten
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Pacioni, NataliL
    University of Ottawa.
    Stamplecoskie, Kevin G
    University of Ottawa.
    Gonzalez-Bejar, Maria
    University of Ottawa.
    Polisetti, Naresh
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Wickham, Abeni
    Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics. Linköping University, The Institute of Technology.
    Richter-Dahlfors, Agneta
    Karolinska Institute.
    Griffith, May
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences.
    Scaiano, Juan C
    University of Ottawa.
    The biocompatibility and antibacterial properties of collagen-stabilized, photochemically prepared silver nanoparticles2012In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 33, no 19, 4947-4956 p.Article in journal (Refereed)
    Abstract [en]

    Spherical 3.5 nm diameter silver nanoparticles (AgNP) stabilized in type I collagen (AgNP@collagen) were prepared in minutes (5-15 min) at room temperature by a photochemical method initiated by UVA irradiation of a water-soluble non-toxic benzoin. This biocomposite was examined to evaluate its biocompatibility and its anti-bacterial properties and showed remarkable properties. Thus, while keratinocytes and fibroblasts were not affected by AgNP@collagen, it was bactericidal against Bacillus megaterium and E. coli but only bacteriostatic against S. epidermidis. In particular, the bactericidal properties displayed by AgNP@collagen were proven to be due to AgNP in AgNP@collagen, rather than to released silver ions, since equimolar concentrations of Ag are about four times less active than AgNP@collagen based on total Ag content. This new biocomposite was stable over a remarkable range of NaCl, phosphate, and 2-(N-morpholino)ethanesulfonic acid concentrations and for over one month at 4 degrees C. Circular dichroism studies show that the conformation of collagen in AgNP@collagen remains intact. Finally, we have compared the properties of AgNP@collagen with a similar biocomposite prepared using alpha-poly-L-Lysine and also with citrate stabilized AgNP; neither of these materials showed comparable biocompatibility, stability, or anti-bacterial activity.

  • 16.
    Alavian, S.M.
    et al.
    Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Tehran.
    Ande, S.R.
    University of Manitoba.
    Coombs, K.M.
    University of Manitoba.
    Yeganeh, B.
    University of Manitoba.
    Davoodpour, Padideh
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences.
    Hashemi, M.
    Zahedan University of Medical Sceince, Iran.
    Los, Marek Jan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Ghavami, S.
    University of Manitoba.
    Virus-triggered autophagy in viral hepatitis - possible novel strategies for drug development2011In: Journal of Viral Hepatitis, ISSN 1352-0504, E-ISSN 1365-2893, Vol. 18, no 12, 821-830 p.Article, review/survey (Refereed)
    Abstract [en]

    . Autophagy is a very tightly regulated process that is important in many cellular processes including development, differentiation, survival and homoeostasis. The importance of this process has already been proven in numerous common diseases such as cancer and neurodegenerative disorders. Emerging data indicate that autophagy plays an important role in some liver diseases including liver injury induced by ischaemia reperfusion and alpha-1 antitrypsin Z allele-dependent liver disease. Autophagy may also occur in viral infection, and it may play a crucial role in antimicrobial host defence against pathogens, while supporting cellular homoeostasis processes. Here, the latest findings on the role of autophagy in viral hepatitis B and C infection, which are both serious health threats, will be reviewed.

  • 17.
    Alehagen, Urban
    et al.
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Cardiology in Linköping.
    Johansson, Peter
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Cardiology in Linköping.
    Björnstedt, Mikael
    Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Rosén, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Dahlström, Ulf
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Cardiology in Linköping.
    Cardiovascular mortality and N-terminal-proBNP reduced after combined selenium and coenzyme Q10 supplementation: a 5-year prospective randomized double-blind placebo-controlled trial among elderly Swedish citizens2013In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 167, no 5, 1860-1866 p.Article in journal (Refereed)
    Abstract [en]

    Background

    Selenium and coenzyme Q10 are essential for the cell. Low cardiac contents of selenium and coenzyme Q10 have been shown in patients with cardiomyopathy, but inconsistent results are published on the effect of supplementation of the two components separately. A vital relationship exists between the two substances to obtain optimal function of the cell. However, reports on combined supplements are lacking.

    Methods

    A 5-year prospective randomized double-blind placebo-controlled trial among Swedish citizens aged 70 to 88 was performed in 443 participants given combined supplementation of selenium and coenzyme Q10 or a placebo. Clinical examinations, echocardiography and biomarker measurements were performed. Participants were monitored every 6th month throughout the intervention.

    The cardiac biomarker N-terminal proBNP (NT-proBNP) and echocardiographic changes were monitored and mortalities were registered. End-points of mortality were evaluated by Kaplan–Meier plots and Cox proportional hazard ratios were adjusted for potential confounding factors. Intention-to-treat and per-protocol analyses were applied.

    Results

    During a follow up time of 5.2 years a significant reduction of cardiovascular mortality was found in the active treatment group vs. the placebo group (5.9% vs. 12.6%; P = 0.015). NT-proBNP levels were significantly lower in the active group compared with the placebo group (mean values: 214 ng/L vs. 302 ng/L at 48 months; P = 0.014). In echocardiography a significant better cardiac function score was found in the active supplementation compared to the placebo group (P = 0.03).

    Conclusion

    Long-term supplementation of selenium/coenzyme Q10 reduces cardiovascular mortality. The positive effects could also be seen in NT-proBNP levels and on echocardiography.

  • 18.
    Alim, Abdul
    et al.
    Uppsala University, Sweden; Karolinska Institute, Sweden; Uppsala University, Sweden.
    Ackermann, Paul W.
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Eliasson, Pernilla M.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Blomgran, Parmis
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Kristiansson, Per
    Uppsala University, Sweden.
    Pejler, Gunnar
    Uppsala University, Sweden; Swedish University of Agriculture Science, Sweden.
    Peterson, Magnus
    Uppsala University, Sweden.
    Increased mast cell degranulation and co-localization of mast cells with the NMDA receptor-1 during healing after Achilles tendon rupture2017In: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 370, no 3, 451-460 p.Article in journal (Refereed)
    Abstract [en]

    The role of inflammation and the mechanism of tendon healing after rupture has historically been a matter of controversy. The purpose of the present study is to investigate the role of mast cells and their relation to the NMDA receptor-1 (a glutamate receptor) during healing after Achilles tendon rupture. Eight female Sprague Dawley rats had their right Achilles tendon transected. Three weeks after rupture, histological quantification of mast cell numbers and their state of degranulation was assessed by histochemistry. Co-localization of mast cell tryptase (a mast cell marker) and NMDA receptor-1 was determined by immunofluorescence. The intact left Achilles tendon was used as control. An increased number of mast cells and a higher proportion of degranulated mast cells were found in the healing Achilles tendon compared to the intact. In addition, increased co-localization of mast cell tryptase and NMDA receptor-1 was seen in the areas of myotendinous junction, mid-tendon proper and bone tendon junction of the healing versus the intact tendon. These findings introduce a possible role for mast cells in the healing phase after Achilles tendon rupture.

  • 19.
    Allahverdiyeva, Yagut
    et al.
    University of Turku.
    Mamedov, Fikret
    Uppsala University.
    Holmstrom, Maija
    University of Turku.
    Nurmi, Markus
    University of Turku.
    Lundin, Björn
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Styring, Stenbjorn
    Uppsala University.
    Spetea Wiklund, Cornelia
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Aro, Eva-Mari
    University of Turku.
    Comparison of the electron transport properties of the psbo1 and psbo2 mutants of Arabidopsis thaliana2009In: BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS, ISSN 0005-2728, Vol. 1787, no 10, 1230-1237 p.Article in journal (Refereed)
    Abstract [en]

    Genome sequence of Arabidopsis thaliana (Arabidopsis) revealed two psbO genes (At5g66570 and At3g50820) which encode two distinct PsbO isoforms: PsbO1 and PsbO2, respectively. To get insights into the function of the PsbO1 and PsbO2 isoforms in Arabidopsis we have performed systematic and comprehensive investigations of the whole photosynthetic electron transfer chain in the T-DNA insertion mutant lines, psbO1 and psbo2. The absence of the PsbO1 isoform and presence of only the PsbO2 isoform in the psbo1 mutant results in (i) malfunction of both the donor and acceptor sides of Photosystem (PS) 11 and (ii) high sensitivity of PSII centers to photodamage, thus implying the importance of the PsbO1 isoform for proper structure and function of PSII. The presence of only the PsbO2 isoform in the PSII centers has consequences not only to the function of PSII but also to the PSI/PSII ratio in thylakoids. These results in modification of the whole electron transfer chain with higher rate of cyclic electron transfer around PSI, faster induction of NPQ and a larger size of the PQ-pool compared to WT, being in line with apparently increased chlororespiration in the psbo1 mutant plants. The presence of only the PsbO1 isoform in the psbo2 mutant did not induce any significant differences in the performance of PSII under standard growth conditions as compared to WT. Nevertheless, under high light illumination, it seems that the presence of also the PsbO2 isoform becomes favourable for efficient repair of the PSII complex.

  • 20. Alvarsson, M
    et al.
    Sundkvist, G
    Lager, I
    Henricsson, M
    Berntorp, K
    Forbes, E
    Steen, L
    Westermark, Gunilla
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Orn, T
    Grill, V
    Different effects of withdrawal of insulin or glibenclamide treatment on beta cell function in recently diagnosed Type 2 diabetic patients.2003In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 46, 798- p.Conference paper (Other academic)
  • 21.
    Amandusson, Åsa
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Estrogen Receptor Expression in Relation to Pain Modulation and Transmission: Experimental Studies in Rats2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Estrogens have a remarkably wide range of actions in the mammalian brain. They not only play a pivotal role in reproductive behavior and sexual differentiation, but also contribute to e.g. thermoregulation, feeding, memory, neuronal survival and the perception of somatosensory stimuli. A multitude of studies on both animals and human subjects has demonstrated potential effects of gonadal hormones, such as estrogens, on pain transmission. These effects most likely involve multiple neuroanatomical circuits as well as diverse neurochemical systems and therefore need to be evaluated specifically in relation to the localization and intrinsic characteristics of the neurons engaged. The overall aim of this thesis is to gain specific knowledge of the possible cellular mechanisms by which estrogens may influence the transmission of nociceptive stimuli at the level of the spinal cord.

    The estrogen receptors, by which estrogens regulate non-genomic as well as genomic mechanisms, are crucial to estrogen signaling in general and essential to the estrogen-induced effects in the brain. In Paper I, we use immunohistochemistry to label neurons containing estrogen receptor-! (ERα) in the medullary and spinal dorsal horn of female rats. Large numbers of ER!-expressing neurons were found in lamina I and lamina II, i.e. in the areas involved in the processing of primary afferent nociceptive information. This distribution in part overlaps that of enkephalin, a potent pain-inhibiting endogenous opioid. The effects of gonadal hormones on pain modulation may, to a great extent, be blocked by the opioid antagonist naloxone, suggesting an involvement of the endogenous opioid system in the prosecution of hormonal pain regulation. By combining immunohistochemical labeling of ERα with in situ hybridization of preproenkephalin mRNA (Paper II), we demonstrate that the majority of enkephalinergic neurons in the superficial laminae of the spinal and medullary dorsal horn express ER!. This co-localization and the fact that the preproenkephalin gene contains a sequence that binds ERs, suggest that estrogens may potentially regulate enkephalin expression in these cells. This is further supported by the findings in Paper III in which we show that a single subcutaneous injection of estradiol induces a significant increase (on average 68%) in preproenkephalin mRNA content in the spinal cord after 4 hours. The expression of the enkephalin gene in the spinal cord is thus sensitive to fluctuating estradiol levels. In Paper IV, a noxious injection of formalin is used to induce activation of a neuronal population involved in nociceptive transmission from the face. By using a dual-labeling immunohistochemistry protocol, we were able to identify ER!-expressing cells within this neuronal population suggesting that nociceptive-responsive neurons in the medullary dorsal horn express ER!. In all, our findings provide morphological as well as biochemical evidence in support for an estrogen-dependent modulation of nociceptive processing at the level of the dorsal horn.

    List of papers
    1. Estrogen receptor-like immunoreactivity in the medullary and spinal dorsal horn of the female rat
    Open this publication in new window or tab >>Estrogen receptor-like immunoreactivity in the medullary and spinal dorsal horn of the female rat
    1995 (English)In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 196, no 1-2, 25-28 p.Article in journal (Refereed) Published
    Abstract [en]

    Using an immunohistochemical technique, we demonstrate that large numbers of neurons in the laminar spinal trigeminal nucleus and spinal gray matter of the female rat express estrogen receptors (ER). Densely packed ER-immunoreactive neurons were present in lamina II, but labeled neurons were also present in lamina I, the neck of the dorsal horn, and in lamina X. Labeling was present throughout the length of the spinal cord, with the exception of segments caudal to S1, which were unlabeled. The distribution of ER-containing neurons to areas that are involved in processing of primary afferent nociceptive information suggests that the pain modulatory effects of estrogen may be exerted at the spinal level.

    Keyword
    Gonadal hormones, Spinal trigeminal nucleus, Spinal cord, Substantia gelatinosa, Pain, Immunohistochemistry
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-17972 (URN)10.1016/0304-3940(95)11828-K (DOI)7501248 (PubMedID)
    Available from: 2009-04-29 Created: 2009-04-29 Last updated: 2017-12-13Bibliographically approved
    2. Colocalization of oestrogen receptor immunoreactivity and preproenkephalin mRNA expression to neurons in the superficial laminae of the spinal and medullary dorsal horn of rats
    Open this publication in new window or tab >>Colocalization of oestrogen receptor immunoreactivity and preproenkephalin mRNA expression to neurons in the superficial laminae of the spinal and medullary dorsal horn of rats
    1996 (English)In: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 8, no 11, 2440-2445 p.Article in journal (Refereed) Published
    Abstract [en]

    A double-labelling procedure combining immunohistochemical staining with in situ hybridization using a radiolabelled cRNA probe was employed to demonstrate oestrogen receptor-like immunoreactivity and preproenkephalin-A mRNA in the medullary and spinal dorsal horn of female rats. Both markers labelled large numbers of neurons in the substantia gelatinosa and its trigeminal homologue. Many of these neurons were double-labelled, displaying both oestrogen receptor-like-immunoreactivity and preproenkephalin-A mRNA; cell counts showed that 40-60% of the of the oestrogen receptor-like-immunoreactive cells in the superficial laminae also were labelled for preproenkephalin-A mRNA, and that 60-70% of the preproenkephalin-A mRNA-labelled neurons in the same laminae displayed oestrogen receptor-like immunoreactivity. Previous studies have shown that oestrogen receptors can bind to the promoter region of the preproenkephalin-A gene, and studies on the hypothalamus have demonstrated that oestrogen regulates enkephalin expression in select neuronal populations. The present results demonstrate that enkephalinergic neurons in the superficial dorsal horn contain oestrogen receptors and suggest that oestrogen may play an important role in the modulation of sensory and nociceptive processing in the lower medulla and spinal cord.

    Place, publisher, year, edition, pages
    Wiley InterScience, 1996
    Keyword
    Gonadal hormone enkephalin spinal cord, pain in situ hybridization
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-17973 (URN)10.1111/j.1460-9568.1996.tb01207.x (DOI)8950107 (PubMedID)
    Available from: 2009-04-29 Created: 2009-04-29 Last updated: 2017-12-13Bibliographically approved
    3. Estrogen-induced alterations of spinal cord enkephalin gene expression
    Open this publication in new window or tab >>Estrogen-induced alterations of spinal cord enkephalin gene expression
    1999 (English)In: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 83, no 2, 243-248 p.Article in journal (Refereed) Published
    Abstract [en]

    Enkephalin-synthesizing neurons in the super®cial laminae of the spinal and trigeminal dorsal horn are critical components of the endogenous pain-modulatory system. We have previously demonstrated that these neurons display intracellular estrogen receptors, suggesting that estrogen can potentially influence their enkephalin expression. By using Northern blot, we now show that a bolus injection of estrogen results in a rapid increase in spinal cord enkephalin mRNA levels in ovariectomized female rats. Thus, 4 h after estrogen administration the enkephalin mRNA-expression in the lumbar spinal cord was on average 68% higher (P , 0:05) than in control animals injected with vehicle only. A small increase in the amount of enkephalin mRNA was also seen after 8 h (P , 0:05), whereas no difference between estrogen-injected and control animals was found after 24 h or at time periods shorter than 4 h. Taken together with the previous anatomical data, the present findings imply that estrogen has an acute effect on spinal opioid levels in areas involved in the transmission of nociceptive information.

    Place, publisher, year, edition, pages
    Elsevier, 1999
    Keyword
    Preproenkephalin mRNA, Gonadal hormone, Pain, Spinal cord
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-17974 (URN)
    Available from: 2009-04-29 Created: 2009-04-29 Last updated: 2017-12-13Bibliographically approved
    4. Estrogen receptor-α expression in nociceptive-responsive neurons in the medullary dorsal horn of the female rat
    Open this publication in new window or tab >>Estrogen receptor-α expression in nociceptive-responsive neurons in the medullary dorsal horn of the female rat
    2010 (English)In: European Journal of Pain, ISSN 1090-3801, E-ISSN 1532-2149, Vol. 14, no 3, 245-248 p.Article in journal (Refereed) Published
    Abstract [en]

    Estrogens exert a substantial influence on the transmission of nociceptive stimuli and the susceptibility to pain disorders as made evident by studies in both animals and human subjects. The estrogen receptor (ER) seems to be of crucial importance to the cellular mechanisms underlying such an influence. However, it has not been clarified whether nociceptive neurons activated by pain express ERs. In this study, a noxious injection of formalin was given into the lower lip of female rats, thereby activating nociceptive neurons in the trigeminal subnucleus caudalis as demonstrated by immunohistochemical labeling of Fos. Using a dual-label immunohistochemistry protocol ERα-containing cells were visualized in the same sections. In the superficial layers of the medullary dorsal horn, 12 % of ERα-labeled cells, mainly located in lamina II, also expressed noxious-induced Fos. These findings show that nociceptive-responsive neurons in the medullary dorsal horn express ERα, thus providing a possible morphological basis for the hypothesis that estrogens directly regulate pain transmission at this level.

    Keyword
    Estrogen receptor, spinal trigeminal nucleus, gonadal hormone, pain, Fos
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-17975 (URN)10.1016/j.ejpain.2009.05.008 (DOI)000275117700003 ()
    Note
    On the day of the defence date the status of this article was Submitted.Available from: 2009-04-29 Created: 2009-04-29 Last updated: 2017-12-13Bibliographically approved
  • 22.
    Amandusson, Åsa
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Blomqvist, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Estrogen receptor-α expression in nociceptive-responsive neurons in the medullary dorsal horn of the female rat2010In: European Journal of Pain, ISSN 1090-3801, E-ISSN 1532-2149, Vol. 14, no 3, 245-248 p.Article in journal (Refereed)
    Abstract [en]

    Estrogens exert a substantial influence on the transmission of nociceptive stimuli and the susceptibility to pain disorders as made evident by studies in both animals and human subjects. The estrogen receptor (ER) seems to be of crucial importance to the cellular mechanisms underlying such an influence. However, it has not been clarified whether nociceptive neurons activated by pain express ERs. In this study, a noxious injection of formalin was given into the lower lip of female rats, thereby activating nociceptive neurons in the trigeminal subnucleus caudalis as demonstrated by immunohistochemical labeling of Fos. Using a dual-label immunohistochemistry protocol ERα-containing cells were visualized in the same sections. In the superficial layers of the medullary dorsal horn, 12 % of ERα-labeled cells, mainly located in lamina II, also expressed noxious-induced Fos. These findings show that nociceptive-responsive neurons in the medullary dorsal horn express ERα, thus providing a possible morphological basis for the hypothesis that estrogens directly regulate pain transmission at this level.

  • 23.
    Amandusson, Åsa
    et al.
    Linköping University, Department of Biomedicine and Surgery. Linköping University, Faculty of Health Sciences.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Hermanson, Ola
    Linköping University, Department of Biomedicine and Surgery. Linköping University, Faculty of Health Sciences.
    Blomqvist, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Estrogen-induced alterations of spinal cord enkephalin gene expression1999In: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 83, no 2, 243-248 p.Article in journal (Refereed)
    Abstract [en]

    Enkephalin-synthesizing neurons in the super®cial laminae of the spinal and trigeminal dorsal horn are critical components of the endogenous pain-modulatory system. We have previously demonstrated that these neurons display intracellular estrogen receptors, suggesting that estrogen can potentially influence their enkephalin expression. By using Northern blot, we now show that a bolus injection of estrogen results in a rapid increase in spinal cord enkephalin mRNA levels in ovariectomized female rats. Thus, 4 h after estrogen administration the enkephalin mRNA-expression in the lumbar spinal cord was on average 68% higher (P , 0:05) than in control animals injected with vehicle only. A small increase in the amount of enkephalin mRNA was also seen after 8 h (P , 0:05), whereas no difference between estrogen-injected and control animals was found after 24 h or at time periods shorter than 4 h. Taken together with the previous anatomical data, the present findings imply that estrogen has an acute effect on spinal opioid levels in areas involved in the transmission of nociceptive information.

  • 24.
    Anderson, Emma S.
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Bjartmar, Carl
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Hildebrand, Claes
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Myelination of prospective large fibres in chicken ventral funiculus2000In: Journal of Neurocytology, ISSN 0300-4864, E-ISSN 1573-7381, Vol. 29, no 10, 755-764 p.Article in journal (Refereed)
    Abstract [en]

    In mammals, the oligodendrocyte population includes morphological and molecular varieties. We reported previously that an antiserum against the T4-O molecule labels a subgroup of oligodendrocytes related to large myelinated axons in adult chicken white matter. We also reported that T4-O immunoreactive cells first appear in the developing ventral funiculus (VF) at embryonic day (E)15, subsequently increasing rapidly in number. Relevant fine structural data for comparison are not available in the literature. This prompted the present morphological analysis of developing and mature VF white matter in the chicken. The first axon-oligodendrocyte connections were seen at E10 and formation of compact myelin had started at E12. Between E12 and E15 the first myelinating oligodendrocytes attained a Schwann cell-like morphology. At hatching (E21) 60% of all VF axons were myelinated and in the adult this proportion had increased to 85%. The semilunar or polygonal oligodendrocytes associated with adult myelinated axons contained many organelles indicating a vivid metabolic activity. Domeshaped outbulgings with gap junction-like connections to astrocytic profiles were frequent. Oligodendrocytes surrounded by large myelinated axons and those surrounded by small myelinated axons were cytologically similar. But, thick and thin myelin sheaths had dissimilar periodicities and Marchi-positive myelinoid bodies occurred preferentially in relation to large myelinated axons. We conclude that early oligodendrocytes contact axons and form myelin well before the first expression of T4-O and that emergence of a T4-O immunoreactivity coincides in time with development of a Type IV phenotype. Our data also show that oligodendrocytes associated with thick axons are cytologically similar to cells related to thin axons. In addition, the development of chicken VF white matter was found to be similar to the development of mammalian white matter, except for the rapid time course.

  • 25.
    Anderson, K S
    et al.
    Harvard University.
    Petersson, Stina
    Sahlgrens University Hospital.
    Wong, J
    Sahlgrens University Hospital.
    Lokko, N N
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Enerbäck, Charlotta
    Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Dermatology and Venerology in Östergötland. Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Elevation of serum epidermal growth factor and interleukin 1 receptor antagonist in active psoriasis vulgaris2010In: BRITISH JOURNAL OF DERMATOLOGY, ISSN 0007-0963, Vol. 163, no 5, 1085-1089 p.Article in journal (Refereed)
    Abstract [en]

    Background Psoriatic plaques present a complex expression profile, including high levels of cytokines, chemokines and growth factors. Circulating cytokines have been suggested to reflect the activation status of the inflammatory process. Objectives To analyse 20 cytokines, chemokines and growth factors in 14 patients with psoriasis vulgaris at the start and during the course of ultraviolet B treatment. Methods A multiplex cytokine assay was used. Results We identified increased serum levels of epidermal growth factor (EGF) (mean 323 vs. 36 6 pg mL(-1), P = 0 0001), interleukin (IL)-1 receptor antagonist (mean 39 1 vs. 14 6 pg mL(-1), P = 0 02) and tumour necrosis factor-alpha (mean 7 5 vs. 4 5 pg mL(-1), P = 0 04) at baseline in patients with psoriasis compared with matched controls. None of these cytokines was correlated to the severity of the disease (Psoriasis Area and Severity Index) or decreased with phototherapy, suggesting that sources other than lesional skin contribute to the production of these cytokines. Using cluster analysis, we observed coordinate upregulation of EGF, IL-6, macrophage inflammatory protein-1 beta and vascular endothelial growth factor. Conclusions The sustained high expression of inflammatory circulating cytokines is a potential mechanism linking psoriasis with its extracutaneous comorbidities.

  • 26.
    Andersson, Arne
    et al.
    Uppsala University.
    Bohman, Sara
    Uppsala University.
    Borg, L A Hakan
    Uppsala University.
    Paulsson, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Schultz, Sebastian
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Westermark, Gunilla
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Westermark, Per
    Uppsala University.
    Amyloid Deposition in Transplanted Human Pancreatic Islets: A Conceivable Cause of Their Long-Term Failure2008In: EXPERIMENTAL DIABETES RESEARCH, ISSN 1687-5214, Vol. 2008, no 562985Article in journal (Refereed)
    Abstract [en]

    Following the encouraging report of the Edmonton group, there was a rejuvenation of the islet transplantation field. After that, more pessimistic views spread when long-term results of the clinical outcome were published. A progressive loss of the beta-cell function meant that almost all patients were back on insulin therapy after 5 years. More than 10 years ago, we demonstrated that amyloid deposits rapidly formed in human islets and in mouse islets transgenic for human IAPP when grafted into nude mice. It is, therefore, conceivable to consider amyloid formation as one potential candidate for the long-term failure. The present paper reviews attempts in our laboratories to elucidate the dynamics of and mechanisms behind the formation of amyloid in transplanted islets with special emphasis on the impact of long-term hyperglycemia.

  • 27.
    Andersson, Patiyan
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Molecular Genetic Studies on Prostate and Penile Cancer2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis is comprised of two parts. In the first part we study the influence of four frequently disputed genes on the susceptibility for developing prostate cancer, and in the second part we attempt to establish a basic understanding of the molecular genetic events in penile cancer.

    In a prostate cancer cohort we have investigated the relation of prostate cancer risk and single nucleotide polymorphisms (SNPs) in four different genes coding for the androgen receptor (AR), the vitamin D receptor (VDR), insulin (INS) and insulin receptor substrate 1 (IRS1). Despite strong biological indications of an involvement of these genes in prostate carcinogenesis, the results from different studies are contradictory and inconclusive.

    The action of the AR varies between individuals in part owing to a repetitive CAG sequence (polyglutamine) in the first exon of the AR gene. The results presented in this thesis show that in our cohort of prostate cancer patients the average number of repeats is 20.1, which is significantly (p<0.001) fewer repeats compared to healthy control individuals, where the average is 22.5 repeats. We find a 4.94 fold (p=0.00003) increased risk of developing prostate cancer associated with having short repeat lengths (≤19 repeats), compared with long repeats (≥23 repeats). In paper I we also study the TaqI polymorphism in the VDR gene, and find that it does not modify the risk of prostate cancer.

    In the INS gene we study the +1127 PstI polymorphism and find no overall effect on the risk of prostate cancer. However, we do find that the CC genotype is associated with low grade disease defined as having a Gleason score ≤6 (OR=1.46; p=0.018). In the IRS1 gene we study the G972R polymorphism and observe that the R allele is significantly associated with a 2.44 fold increased prostate cancer risk (p=0.010).

    The knowledge of molecular genetic events in penile cancer is very scarce and to date very few genes have been identified to be involved in penile carcinogenesis. We chose therefore to analyse the penile cancer samples using genome-wide high-density SNP arrays. We find major regions of frequent copy number gain in chromosome arms 3q, 5p and 8q, and slightly less frequent in 1p, 16q and 20q. The chromosomal regions of most frequent copy number losses are 3p, 4q, 11p and 13q. We suggest four candidate genes residing in these areas, the PIK3CA gene (3q26.32), the hTERT gene (5p15.33), the MYC gene (8q24.21) and the FHIT gene (3p14.2).

    The mutational status of the PIK3CA and PTEN genes in the PI3K/AKT pathway and the HRAS, KRAS, NRAS and BRAF genes in the RAS/MAPK pathway was assessed in the penile cancer samples. We find the PIK3CA, HRAS and KRAS genes to be mutated in 29%, 7% and 3% of the cases, respectively. All mutations are mutually exclusive. In total the PI3K/AKT and RAS/MAPK pathways were found to be activated through mutation or amplification in 64% of the cases, indicating the significance of these pathways in the aetiology of penile cancer.

    List of papers
    1. Androgen receptor and vitamin D receptor gene polymorphisms and prostate cancer risk
    Open this publication in new window or tab >>Androgen receptor and vitamin D receptor gene polymorphisms and prostate cancer risk
    2006 (English)In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 42, no 16, 2833-2837 p.Article in journal (Refereed) Published
    Abstract [en]

    We study the CAG repeat region in exon 1 of the androgen receptor (AR) and the TaqI polymorphism in exon 9 of the vitamin D receptor (VDR) and the association with prostate cancer. 137 incidentally discovered, histologically verified prostate cancers were analysed for CAG repeat length in AR and genotype at the TaqI site of the VDR. 124 control subjects were analysed to determine the CAG repeat length and TaqI genotype determined for 176 control subjects. An unpaired t-test shows that the mean CAG repeat length was significantly (p < 0.001) shorter among cases (20.1 repeats) compared with controls (22.5 repeats). Dividing the prostate cohort and controls into tertiles (19, 20–22, 23 repeats) shows that short repeats are significantly more common among cases (odds ratio (OR) 4.45, p = 0.00003). Genotype frequencies for the TaqI polymorphism reveals no significant differences between cases and controls. We conclude that men with a short CAG repeat in the androgen receptor gene have an increased risk of developing prostate cancer.

    Place, publisher, year, edition, pages
    Elsevier, 2006
    Keyword
    Androgen receptor; Vitamin D receptor; Prostate cancer; CAG repeat
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:liu:diva-15097 (URN)10.1016/j.ejca.2006.06.030 (DOI)
    Available from: 2008-10-15 Created: 2008-10-15 Last updated: 2017-12-11Bibliographically approved
    2. Association studies on INS and IRS1polymorphisms: IRS1 G972R is associated with increased prostate cancer risk
    Open this publication in new window or tab >>Association studies on INS and IRS1polymorphisms: IRS1 G972R is associated with increased prostate cancer risk
    2008 (English)In: Prostate Cancer and Prostatic Diseases, ISSN 1365-7852, E-ISSN 1476-5608Article in journal (Refereed) Submitted
    Abstract [en]

    We study the G972R polymorphism in the Insulin receptor substrate 1 gene (IRS1) and the +1127 PstI polymorphism of the Insulin gene (INS), in 120 and 151, respectively, incidentally discovered, histologically verified prostate cancers, and in 185 healthy control subjects. The number of IRS1 R allele was found to be significantly associated with increased risk of prostate cancer. Analysis of the INS +1127 PstI polymorphism shows no significant differences between cases and controls. We conclude that subjects carrying one or two R-alleles at the IRS1 G972R polymorphic site are at an elevated risk of developing prostate cancer.

    Keyword
    IRS1, G972R, INS, Insulin, prostate cancer
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:liu:diva-15098 (URN)
    Available from: 2008-10-15 Created: 2008-10-15 Last updated: 2017-12-11
    3. PIK3CA, HRAS and KRAS gene mutations in human penile cancer
    Open this publication in new window or tab >>PIK3CA, HRAS and KRAS gene mutations in human penile cancer
    Show others...
    2008 (English)In: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 179, no 5, 2030-2034 p.Article in journal (Refereed) Published
    Abstract [en]

    Purpose: The knowledge of somatic mutations that arise in penile cancer is limited. We examined the dysregulation of components in the phosphatidylinositol 3-kinase and Ras pathways.

    Materials and Methods: Using single stranded conformational analysis and direct sequencing we performed mutational analysis of the PIK3CA, PTEN, HRAS, KRAS, NRAS and BRAF genes in 28 penile tumors.

    Results: We identified somatic missense mutations in 11 of the 28 penile cancer samples (39%). In the PIK3CA gene 8 mutations (29%) were identified that were E542K or E545K. In the HRAS gene a G12S and a Q61L mutation were found (7%). The KRAS gene contained 1 mutation (3%), that is a G12S change. PIK3CA mutations were found in all grades and stages, whereas HRAS and KRAS mutations were found in larger and more advanced tumors. The mutations were mutually exclusive, suggesting that dysregulation of either pathway is sufficient for the development and progression of penile carcinoma.

    Conclusions: The high frequency of mutations in the PIK3CA, HRAS and KRAS genes leads us to believe that dysregulation of the phosphatidylinositol 3-kinase or Ras pathway is significant for the development and progression of penile carcinoma.

    Keyword
    Penis, penile neoplasms, mutation, 1-phosphatidylinositol 3-kinase, carcinoma, squamous cell
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:liu:diva-15099 (URN)10.1016/j.juro.2007.12.040 (DOI)
    Note
    On the day of the defence date the status of article III was: In Press.Available from: 2008-10-15 Created: 2008-10-15 Last updated: 2017-12-11Bibliographically approved
    4. Genome-wide analysis of penile cancer using high-density single nucleotide polymorphism arrays
    Open this publication in new window or tab >>Genome-wide analysis of penile cancer using high-density single nucleotide polymorphism arrays
    Show others...
    (English)Manuscript (Other academic)
    Abstract [en]

    The availability of genome-wide high-density single nucleotide polymorphism (SNP) arrays makes it possible to in a structured manner study chromosome aberrations in penile cancer where little is known of disruptive genetic events. In this study 19 penile squamous cell carcinomas were analyzed using the 250k NspI SNP array from Affymetrix. We find major regions of frequent copy number gain in chromosome arms 3q, 5p and 8q, and slightly less frequent in 1p, 16q and 20q. The chromosomal regions of most frequent copy number losses were 3p, 4q, 11p and 13q. We identified four candidate genes residing in the major chromosomal regions of aberration. Eight tumours showed copy number gain of the PIK3CA gene located to 3q26.3. Five of the remaining tumours carried an activating mutation of the PIK3CA gene and these tumours showed very few chromosomal aberrations. Collectively, disruption of the PIK3CA gene was found in 13/19 samples, and presence of active phosphorylated AKT was confirmed immunohistochemically in these tumours indicating an active signalling pathway. We found copy number gain of the hTERT gene (5p15.33) in 7 samples and of the Myc gene (8q24.21) in 7 samples. Copy number loss of the tumoursuppressor gene FHIT (3p14.2) was observed in 8 samples, the same 8 samples that showed copy number gain of the PIK3CA gene. In total the PI3K/AKT and RAS/MAPK pathways were found to be activated through mutation or amplification in 64% of the cases, indicating the significance of these pathways in the aetiology of penile cancer.

    Keyword
    SNP array, penile cancer, PIK3CA, Myc, TERT, FHIT
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:liu:diva-15100 (URN)
    Available from: 2008-10-15 Created: 2008-10-15 Last updated: 2010-01-14Bibliographically approved
  • 28.
    Andersson, Patiyan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Kolaric, Aleksandra
    Departments of Pathology, Örebro University Hospital, Örebro, Sweden.
    Windahl, Torgny
    Departments of Urology, Örebro University Hospital, Örebro, Sweden.
    Kirrander, Peter
    Departments of Urology, Örebro University Hospital, Örebro, Sweden.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Karlsson, Mats G.
    Departments of b Pathology, Örebro University Hospital, Örebro, Sweden.
    PIK3CA, HRAS and KRAS gene mutations in human penile cancer2008In: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 179, no 5, 2030-2034 p.Article in journal (Refereed)
    Abstract [en]

    Purpose: The knowledge of somatic mutations that arise in penile cancer is limited. We examined the dysregulation of components in the phosphatidylinositol 3-kinase and Ras pathways.

    Materials and Methods: Using single stranded conformational analysis and direct sequencing we performed mutational analysis of the PIK3CA, PTEN, HRAS, KRAS, NRAS and BRAF genes in 28 penile tumors.

    Results: We identified somatic missense mutations in 11 of the 28 penile cancer samples (39%). In the PIK3CA gene 8 mutations (29%) were identified that were E542K or E545K. In the HRAS gene a G12S and a Q61L mutation were found (7%). The KRAS gene contained 1 mutation (3%), that is a G12S change. PIK3CA mutations were found in all grades and stages, whereas HRAS and KRAS mutations were found in larger and more advanced tumors. The mutations were mutually exclusive, suggesting that dysregulation of either pathway is sufficient for the development and progression of penile carcinoma.

    Conclusions: The high frequency of mutations in the PIK3CA, HRAS and KRAS genes leads us to believe that dysregulation of the phosphatidylinositol 3-kinase or Ras pathway is significant for the development and progression of penile carcinoma.

  • 29.
    Andersson, Patiyan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Kolaric, Aleksandra
    Departments of Pathology, Örebro University Hospital, Örebro, Sweden.
    Windahl, Torgny
    Departments of Urology, Örebro University Hospital, Örebro, Sweden.
    Kirrander, Peter
    Departments of Urology, Örebro University Hospital, Örebro, Sweden..
    Andrén, Ove
    Departments of Urology, Örebro University Hospital, Örebro, Sweden..
    Jonasson, Jon
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology . Linköping University, Faculty of Health Sciences.
    Karlsson, Mats G
    Departments of Pathology, Örebro University Hospital, Örebro, Sweden.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Genome-wide analysis of penile cancer using high-density single nucleotide polymorphism arraysManuscript (Other academic)
    Abstract [en]

    The availability of genome-wide high-density single nucleotide polymorphism (SNP) arrays makes it possible to in a structured manner study chromosome aberrations in penile cancer where little is known of disruptive genetic events. In this study 19 penile squamous cell carcinomas were analyzed using the 250k NspI SNP array from Affymetrix. We find major regions of frequent copy number gain in chromosome arms 3q, 5p and 8q, and slightly less frequent in 1p, 16q and 20q. The chromosomal regions of most frequent copy number losses were 3p, 4q, 11p and 13q. We identified four candidate genes residing in the major chromosomal regions of aberration. Eight tumours showed copy number gain of the PIK3CA gene located to 3q26.3. Five of the remaining tumours carried an activating mutation of the PIK3CA gene and these tumours showed very few chromosomal aberrations. Collectively, disruption of the PIK3CA gene was found in 13/19 samples, and presence of active phosphorylated AKT was confirmed immunohistochemically in these tumours indicating an active signalling pathway. We found copy number gain of the hTERT gene (5p15.33) in 7 samples and of the Myc gene (8q24.21) in 7 samples. Copy number loss of the tumoursuppressor gene FHIT (3p14.2) was observed in 8 samples, the same 8 samples that showed copy number gain of the PIK3CA gene. In total the PI3K/AKT and RAS/MAPK pathways were found to be activated through mutation or amplification in 64% of the cases, indicating the significance of these pathways in the aetiology of penile cancer.

  • 30.
    Andersson, Patiyan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Varenhorst, Eberhard
    Linköping University, Department of Clinical and Experimental Medicine, Urology . Linköping University, Faculty of Health Sciences.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Association studies on INS and IRS1polymorphisms: IRS1 G972R is associated with increased prostate cancer risk2008In: Prostate Cancer and Prostatic Diseases, ISSN 1365-7852, E-ISSN 1476-5608Article in journal (Refereed)
    Abstract [en]

    We study the G972R polymorphism in the Insulin receptor substrate 1 gene (IRS1) and the +1127 PstI polymorphism of the Insulin gene (INS), in 120 and 151, respectively, incidentally discovered, histologically verified prostate cancers, and in 185 healthy control subjects. The number of IRS1 R allele was found to be significantly associated with increased risk of prostate cancer. Analysis of the INS +1127 PstI polymorphism shows no significant differences between cases and controls. We conclude that subjects carrying one or two R-alleles at the IRS1 G972R polymorphic site are at an elevated risk of developing prostate cancer.

  • 31.
    Andersson, Patiyan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cellbiology. Linköping University, Faculty of Health Sciences.
    Varenhorst, Eberhard
    Linköping University, Department of Clinical and Experimental Medicine, Urology . Linköping University, Faculty of Health Sciences.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cellbiology. Linköping University, Faculty of Health Sciences.
    Androgen receptor and vitamin D receptor gene polymorphisms and prostate cancer risk2006In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 42, no 16, 2833-2837 p.Article in journal (Refereed)
    Abstract [en]

    We study the CAG repeat region in exon 1 of the androgen receptor (AR) and the TaqI polymorphism in exon 9 of the vitamin D receptor (VDR) and the association with prostate cancer. 137 incidentally discovered, histologically verified prostate cancers were analysed for CAG repeat length in AR and genotype at the TaqI site of the VDR. 124 control subjects were analysed to determine the CAG repeat length and TaqI genotype determined for 176 control subjects. An unpaired t-test shows that the mean CAG repeat length was significantly (p < 0.001) shorter among cases (20.1 repeats) compared with controls (22.5 repeats). Dividing the prostate cohort and controls into tertiles (19, 20–22, 23 repeats) shows that short repeats are significantly more common among cases (odds ratio (OR) 4.45, p = 0.00003). Genotype frequencies for the TaqI polymorphism reveals no significant differences between cases and controls. We conclude that men with a short CAG repeat in the androgen receptor gene have an increased risk of developing prostate cancer.

  • 32.
    Aneq Åström, Meriam
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Physiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Clinical Physiology UHL.
    Fluur, Christina
    Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Cardiology UHL.
    Rehnberg, Malin
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Engvall, Jan
    Linköping University, Department of Medical and Health Sciences, Clinical Physiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Clinical Physiology UHL.
    Nylander, Eva
    Linköping University, Department of Medical and Health Sciences, Clinical Physiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Clinical Physiology UHL.
    Gunnarsson, Cecilia
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Novel plakophilin2 mutation. Three generation family with arrhythmogenic right ventricular cardiomyopathy2012In: Scandinavian Cardiovascular Journal, ISSN 1401-7431, E-ISSN 1651-2006, Vol. 46, no 2, 72-75 p.Article in journal (Refereed)
    Abstract [en]

    Objectives: The autosomal dominant form of arrhythmogenic right ventricular cardiomyopathy (ARVC)has been linked to mutations in desmosomal proteins. Different studies have shown that amutation in plakophilin-2 (PKP 2) is a frequent genetic cause for ARVC. We describe a newmutation in the PKP2 gene, the genotype-phenotype variation in this mutation and its clinicalconsequences.

    Design: Individuals in a three generation family were investigated after the sudden cardiac death of a young male. Clinical evaluation, electrocardiography, echocardiography, magnetic resonance imaging, endomyocardial biopsy and genetic testing were performed.

    Results: A novel heterozygote mutation, a c.368G>A transition, located in exon 3 of the PKP2 gene was found (p.Trp123X). The phenotype was characterized by arrhythmia at an early age in some individuals, with mild abnormalities on imaging. However a relative carrying this mutation, with positive findings on endomyocardial biopsy had an otherwise normal phenotype, for 16 years, whereas a relative fulfilling the modified Task Force Criteria for ARVC turned out to be a non-carrier.

    Conclusions: This shows the variable penetrance and phenotypic expression in ARVC and highlights the need of genetic testing as well as a thorough phenotype examination as a part of the investigations in ARVC pedigrees.

  • 33.
    Anguelova, M.
    et al.
    Chalmers University of Technology.
    Cedersund, Gunnar
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Johansson, M.
    Chalmers University of Technology.
    Franzen, C J
    Chalmers University of Technology.
    Wennberg, B.
    Chalmers University of Technology.
    Conservation laws and unidentifiability of rate expressions in biochemical models2007In: IET SYSTEMS BIOLOGY, ISSN 1751-8849, Vol. 1, no 4, 230-237 p.Article in journal (Refereed)
    Abstract [en]

    New experimental techniques in bioscience provide us with high-quality data allowing quantitative mathematical modelling. Parameter estimation is often necessary and, in connection with this, it is important to know whether all parameters can be uniquely estimated from available data, (i.e. whether the model is identifiable). Dealing essentially with models for metabolism, we show how the assumption of an algebraic relation between concentrations may cause parameters to be unidentifiable. If a sufficient data set is available, the problem with unidentifiability arises locally in individual rate expressions. A general method for reparameterisation to identifiable rate expressions is provided, together with a Mathematica code to help with the calculations. The general results are exemplified by four well-cited models for glycolysis.

  • 34.
    Ansell, Anna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oto-Rhiono-Laryngology and Head & Neck Surgery. Linköping University, Faculty of Health Sciences.
    Farnebo, Lovisa
    Linköping University, Department of Clinical and Experimental Medicine, Oto-Rhiono-Laryngology and Head & Neck Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Reconstruction Centre, Department of ENT - Head and Neck Surgery UHL.
    Grénman, Reidar
    Department of Otorhinolaryngology, Head & Neck Surgery, and Medical Biochemistry, University of Turku, Finland.
    Roberg, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Oto-Rhiono-Laryngology and Head & Neck Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Reconstruction Centre, Department of ENT - Head and Neck Surgery UHL.
    Thunell, Lena
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Polymorphism of FGFR4 in cancer development and sensitivity to cisplatin and radiation in head and neck cancer2009In: Oral Oncology, ISSN 1368-8375, E-ISSN 1879-0593, Vol. 45, no 1, 23-29 p.Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to investigate the predisposition of the FGFR4 Gly/Arg polymorphism for development of head and neck squamous cell carcinoma (HNSCC) and, furthermore, to examine if the FGFR4 Arg(388) allele can be associated with resistance to chemo-and radiotherapy.

    When analysing 110 tumour biopsies a significant 1.7-fold increased risk to develop HNSCC in individuals carrying the Gly(388) allele (p = 0.026) was found. Moreover a 2-fold increased risk for mates harbouring the Gly(388) allele (p = 0.031) to develop HNSCC was detected. In 39 HNSCC cell lines the role of the Arg(388) allele for radiation and cisplatin sensitivity was investigated. Our results show no rote of the Arg(388) allele for the radiosensitivity (p = 0.996) but indicate a tendency to increased cisplatin sensitivity (p = 0.141). When screening the transmembrane and kinase domains in the FGFR4 gene a novel mutation, probably generating a truncated protein lacking exons 14-18, was found in six of eight selected cell lines.

    Taken together, we have here identified a marker that predicts the risk to develop HNSCC and possibly the sensitivity to cisplatin as well as a novel. mutation in the FGFR4 gene.

  • 35.
    Appelqvist, Hanna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Sandin, Linnea
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Björnström, Karin
    Linköping University, Department of Medical and Health Sciences, Anesthesiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Intensive Care.
    Saftig, Paul
    Biochemical Institute, Christian-Albrechts-University Kiel, Kiel, Germany.
    Garner, Brett
    Illawarra Health and Medical Research Institute, University of Wollongong, Australia.
    Öllinger, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Kågedal, Katarina
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Sensitivity to Lysosome-Dependent Cell Death is Directly Regulated by Lysosomal Cholesterol Content2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 11Article in journal (Refereed)
    Abstract [en]

    Alterations in lipid homeostasis are implicated in several neurodegenerative diseases, although the mechanisms responsible are poorly understood. We evaluated the impact of cholesterol accumulation, induced by U18666A, quinacrine or mutations in the cholesterol transporting Niemann-Pick disease type C1 (NPC1) protein, on lysosomal stability and sensitivity to lysosome-mediated cell death. We found that neurons with lysosomal cholesterol accumulation were protected from oxidative stress-induced apoptosis. In addition, human fibroblasts with cholesterol-loaded lysosomes showed higher lysosomal membrane stability than controls. Previous studies have shown that cholesterol accumulation is accompanied by the storage of lipids such as sphingomyelin, glycosphingolipids and sphingosine and an up regulation of lysosomal associated membrane protein-2 (LAMP-2), which may also influence lysosomal stability. However, in this study the use of myriocin and LAMP deficient fibroblasts excluded these factors as responsible for the rescuing effect and instead suggested that primarily lysosomal cholesterol content determined the cellular sensitivity to toxic insults. Further strengthening this concept, depletion of cholesterol using methyl-β-cyclodextrin or 25-hydroxycholesterol decreased the stability of lysosomes and cells became more prone to undergo apoptosis. In conclusion, cholesterol content regulated lysosomal membrane permeabilization and thereby influenced cell death sensitivity. Our data suggests that lysosomal cholesterol modulation might be used as a therapeutic strategy for conditions associated with accelerated or repressed apoptosis.

  • 36.
    Arnqvist, Hans
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    The role of IGF-system in vascular insulin resistance2008In: Hormone and Metabolic Research, ISSN 0018-5043, E-ISSN 1439-4286, Vol. 40, no 9, 588-592 p.Article, review/survey (Refereed)
    Abstract [en]

    Insulin and IGF-I are closely related peptides, which interact by several mechanisms. In high supraphysiological concentrations (=10-8M), they cross-react with each other's receptors with 100- to 1000-fold lower affinity than with their cognate receptors. This can cause confusion, since in many in vitro studies, insulin has been used in high unphysiological concentrations, which activate IGF-I receptors. Due to the differences in affinity, insulin and IGF-I probably do not activate each other's receptors in vivo. IGF-I receptors are several-fold more abundant than insulin receptors in human micro- and macrovascular endothelial cells and in human vascular smooth muscle cells. Both insulin and IGF-I receptor protein can be demonstrated and they are activated by their cognate ligand at physiological concentrations of 10-9-10-10M. In vascular smooth muscle cells, IGF-I but not insulin stimulates metabolism and growth. IGF-I stimulates DNA-synthesis and growth in microvascular endothelial cells, but neither insulin nor IGF-I have any effect on macrovascular endothelial cells. Both insulin and IGF-I have been shown to stimulate nitric oxide production in endothelial cells, but only the effect of IGF-I was obtained at a physiological concentration. In both endothelial and vascular smooth muscle cells, insulin and IGF-I receptors occur as insulin/ICF-I hybrid receptors with high affinity to IGF-I and low for insulin. Due to the low number of insulin receptors and the presence of hybrid receptors the insulin receptor signal is probably too attenuated to elicit biological effects, explaining the insulin resistance of vascular cells in vitro. In vivo both insulin and IGF-I have been reported to increase muscle blood flow in physiological concentrations. Whether this is due to direct effects on endothelial cells or indirectly induced is not clear. The effect of insulin is attenuated by insulin resistance. In conclusion, the in vitro data suggest that endothelial cells and vascular smooth muscle cells are sensitive to IGF-I, but insensitive to insulin, and this is due to a preponderance of IGF-I receptors and the presence of insulin/IGF-l hybrid receptors. © Georg Thieme Verlag KG Stuttgart · New York.

  • 37.
    Asif, Muhammad H
    et al.
    Linköping University, Department of Science and Technology. Linköping University, The Institute of Technology.
    Fulati, Alimujiang
    Linköping University, Department of Science and Technology. Linköping University, The Institute of Technology.
    Nor, Omer
    Linköping University, Department of Science and Technology. Linköping University, The Institute of Technology.
    Willander, Magnus
    Linköping University, Department of Science and Technology. Linköping University, The Institute of Technology.
    Johansson, Cecilia
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Strålfors, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Börjesson, Sara I.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Elinder, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Functionalized zinc oxide nanorod with ionophore-membrane coatingas an intracellular Ca2+ selective sensor2009In: Applied Physics Letters, ISSN 0003-6951, E-ISSN 1077-3118, Vol. 95, no 2, 23703- p.Article in journal (Refereed)
    Abstract [en]

    The tip of a borosilicate glass capillary with functionalized hexagonal ZnO nanorods was used to make a sensitive electrochemical intracellular Ca2+ sensor. To adjust the sensor for Ca2+ measurements with sufficient selectivity and stability, polyvinyl chloride (PVC) membrane containing Ca2+ ionophores were coated on the surface. The membrane covered ZnO nanorods exhibited a Ca2+-dependent electrochemical potential difference versus an Ag/AgCl reference electrode. The potential difference was linear over a large concentration range (100 nM to 10 mM). The measurements of Ca2+ concentrations using our ZnO nanorods sensor in human fat cells or in frog egg cells were consistent with values of Ca2+ concentrations reported in the literature. This nanoelectrode device paves the way to measurements of intracellular biochemical species in specific locations within single living cells.

  • 38.
    Asif, Muhammad H.
    et al.
    Linköping University, Department of Science and Technology. Linköping University, The Institute of Technology.
    Nur, Omer
    Linköping University, Department of Science and Technology. Linköping University, The Institute of Technology.
    Willander, Magnus
    Linköping University, Department of Science and Technology. Linköping University, The Institute of Technology.
    Strålfors, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Brännmark, Cecilia
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Elinder, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Englund, Ulrika H
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Lu, Jun
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Hultman, Lars
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Growth and Structure of ZnO Nanorods on a Sub-Micrometer Glass Pipette and Their Application as Intracellular Potentiometric Selective Ion Sensors2010In: Materials, ISSN 1996-1944, Vol. 3, 4657-4667 p.Article in journal (Refereed)
    Abstract [en]

    This paper presents the growth and structure of ZnO nanorods on a sub-micrometer glass pipette and their application as an intracellular selective ion sensor. Highly oriented, vertical and aligned ZnO nanorods were grown on the tip of a borosilicate glass capillary (0.7 μm in diameter) by the low temperature aqueous chemical growth (ACG) technique. The relatively large surface-to-volume ratio of ZnO nanorods makes them attractive for electrochemical sensing. Transmission electron microscopy studies show that ZnO nanorods are single crystals and grow along the crystal’s c-axis. The ZnO nanorods were functionalized with a polymeric membrane for selective intracellular measurements of Na

     

    +. The membrane-coated ZnO nanorods exhibited a Na+-dependent electrochemical potential difference versus

    an Ag/AgCl reference micro-electrode within a wide concentration range from 0.5 mM to 100 mM. The fabrication of functionalized ZnO nanorods paves the way to sense a wide range of biochemical species at the intracellular level.

  • 39.
    Asif, Muhammad H
    et al.
    Linköping University, Department of Science and Technology. Linköping University, The Institute of Technology.
    Usman Ali, Syed M
    Linköping University, Department of Science and Technology. Linköping University, The Institute of Technology.
    Nur, Omer
    Linköping University, Department of Science and Technology. Linköping University, The Institute of Technology.
    Willander, Magnus
    Linköping University, Department of Science and Technology. Linköping University, The Institute of Technology.
    Brännmark, Cecilia
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Strålfors, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Englund H, Ulrika
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Elinder, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Danielsson, Bengt
    Pure and Applied Biochemistry, Lund University, Box 124, SE-221 00 Lund, Sweden.
    Functionalised ZnO-nanorod-based selective electrochemical sensor for intracellular glucose2010In: Biosensors & bioelectronics, ISSN 0956-5663, E-ISSN 1873-4235, Vol. 25, no 10, 2205-2211 p.Article in journal (Refereed)
    Abstract [en]

    In this article, we report a functionalised ZnO-nanorod-based selective electrochemical sensor for intracellular glucose. To adjust the sensor for intracellular glucose measurements, we grew hexagonal ZnO nanorods on the tip of a silver-covered borosilicate glass capillary (0.7 mu m diameter) and coated them with the enzyme glucose oxidase. The enzyme-coated ZnO nanorods exhibited a glucose-dependent electrochemical potential difference versus an Ag/AgCl reference microelectrode. The potential difference was linear over the concentration range of interest (0.5-1000 mu M). The measured glucose concentration in human adipocytes or frog oocytes using our ZnO-nanorod sensor was consistent with values of glucose concentration reported in the literature; furthermore, the sensor was able to show that insulin increased the intracellular glucose concentration. This nanoelectrode device demonstrates a simple technique to measure intracellular glucose concentration.

  • 40.
    Asif, Muhammad H.
    et al.
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, The Institute of Technology.
    Willander, Magnus
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, The Institute of Technology.
    Strålfors, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Danielsson, Bengt
    Lund University, Sweden.
    Zinc Oxide Nanorods and their Application to Intracellular Glucose Measurements2012In: Nanotechnology and Nanomedicine in Diabetes / [ed] Lan-Anh Le, Ross J. Hunter, Victor R. Preedy, CRC Press, 2012, 126-146 p.Chapter in book (Other academic)
  • 41.
    Asif, Muhammad
    et al.
    Linköping University, Department of Science and Technology. Linköping University, The Institute of Technology.
    Usman Ali, Syed
    Linköping University, Department of Science and Technology. Linköping University, The Institute of Technology.
    Nour, Omer
    Linköping University, Department of Science and Technology. Linköping University, The Institute of Technology.
    Willander, Magnus
    Linköping University, Department of Science and Technology. Linköping University, The Institute of Technology.
    Englund, Ulrika
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Elinder, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Functionalized ZnO nanorod-based selective magnesium ion sensor for intracellular measurements2010In: Biosensors & bioelectronics, ISSN 0956-5663, E-ISSN 1873-4235, Vol. 26, no 3, 1118-1123 p.Article in journal (Refereed)
    Abstract [en]

    ZnO nanorods were grown on a silver-coated tip of a borosilicate glass capillary (0.7 mu m in tip diameter) and used as selective potentiometric sensor of intracellular free Mg2+. To functionalize the ZnO nanorods for selectivity of Mg2+, a polymeric membrane with Mg2+-selective ionophores were coated on the surface of the ZnO nanorods. These functionalized ZnO nanorods exhibited a Mg2+-dependent electrochemical potential difference versus an Ag/AgCl reference microelectrode within the concentration range from 500 nM to 100 mM. Two types of cells, human adipocytes and frog oocytes, were used for the intracellular Mg2+ measurements. The intracellular concentration of free Mg2+ in human adipocytes and frog oocytes were 0.4-0.5 and 0.8-0.9 mM, respectively. Such type of nanoelectrode device paves the way to enable analytical measurements in single living cells and to sense other bio-chemical species at the intracellular level.

  • 42.
    Asklund, Thomas
    et al.
    Cancercentrum, Norrlands universitetssjukhus, Umeå.
    Björ, Ove
    Umeå universitet.
    Malmström, Annika
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, LAH Linköping.
    Blomquist, Erik
    Akademiska sjukhuset, Uppsala .
    Henriksson, Roger
    Regionalt cancercentrum Stockholm–Gotland, Karolinska universitetssjukhuset, Stockholm.
    Överlevnaden vid maligna gliom har ökat senaste tio åren - Analys av kvalitetsregisterdata: [Survival in malignant gliomas has increased the last decade. Analysis of quality data]2012In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 109, no 17-18, 875-878 p.Article in journal (Refereed)
    Abstract [en]

    The annual incidence rate of high grade malignant glioma (WHO grade III-IV) in Sweden is approximately 400 patients. The objective for the Swedish National CNS-tumor Group is to lay a foundation for research efforts and facilitate implementation and assessment of therapeutic strategies and health care for this patient group. In the analyses the diagnoses of high grade malignant gliomas are compared for the years 1999-2003, 2004-2006 and 2007-2009 for the Northern Region, the Uppsala Region and the South-east Region of Sweden, a population of 1844 patients. Survival was estimated from Kaplan-Meier survival curves, and a log-rank test was performed to assess whether the survival curves differed. The crude hazard ratio between years of diagnosis was estimated from a Cox regression model. Median survival for all patients 2004-2006 was 10.0 months (95 % confidence interval (CI) 8.9-10.9) compared to 8.1 months 1999-2003 (95 % CI 7.3-8.8). For patients 60-69 years of age almost a doubling of the survival rate has occurred during the last decade. Medan survival has increased from 5.8 months (95 % CI 5.1-7.5) 1999-2003 to 8.5 months (95 % CI 7.0-10.3) for 2004-2006 and to 10.5 months (95 % CI 9.0-12.6) for 2007-2009. Concomitant radiochemotherapy, but also the development of neurosurgical and radiotheraputic techniques and a more active therapeutic attitude, including the older patient groups, have probably contributed to the improved survival rate. A national population based registry, with a close to 100% registration compliance for important diagnostic and outcome parameters is probably an efficient instrument for evaluation of quality measures and implementation of new therapeutic strategies.

  • 43.
    Asklund, Thomas
    et al.
    Department of Radiation Sciences and Oncology, University Hospital, Umeå.
    Malmström, Annika
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Advanced Home Care in Linköping.
    Björ, Ove
    Department of Radiation Sciences and Oncology, University Hospital, Umeå.
    Blomquist, Erik
    Department of Oncology, Uppsala University Hospital.
    Henriksson, Roger
    Department of Radiation Sciences and Oncology, University Hospital, Umeå.
    Considerable improvement in survival for patients aged 60-84 years with high grade malignant gliomas - Data from the Swedish Brain Tumour Population-based Registry2013In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 52, no 5, 1043-1046 p.Article in journal (Refereed)
  • 44.
    Bachmann, Julie
    et al.
    German Cancer Research Centre.
    Raue, Andreas
    University of Freiburg.
    Schilling, Marcel
    German Cancer Research Centre.
    Boehm, Martin E
    University of Freiburg.
    Kaschek, Daniel
    University of Freiburg.
    Busch, Hauke
    University of Freiburg.
    Gretz, Norbert
    University of Heidelberg.
    Lehmann, Wolf D
    University of Freiburg.
    Timmer, Jens
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Klingmueller, Ursula
    German Canc Research Centre, Div Syst Biol Signal Transduct, DKFZ ZMBH Alliance, D-69120 Heidelberg, Germany .
    Division of labor by dual feedback regulators controls JAK2/STAT5 signaling over broad ligand range2011In: Molecular Systems Biology, ISSN 1744-4292, E-ISSN 1744-4292, Vol. 7, no 516Article in journal (Refereed)
    Abstract [en]

    Cellular signal transduction is governed by multiple feedback mechanisms to elicit robust cellular decisions. The specific contributions of individual feedback regulators, however, remain unclear. Based on extensive time-resolved data sets in primary erythroid progenitor cells, we established a dynamic pathway model to dissect the roles of the two transcriptional negative feedback regulators of the suppressor of cytokine signaling (SOCS) family, CIS and SOCS3, in JAK2/STAT5 signaling. Facilitated by the model, we calculated the STAT5 response for experimentally unobservable Epo concentrations and provide a quantitative link between cell survival and the integrated response of STAT5 in the nucleus. Model predictions show that the two feedbacks CIS and SOCS3 are most effective at different ligand concentration ranges due to their distinct inhibitory mechanisms. This divided function of dual feedback regulation enables control of STAT5 responses for Epo concentrations that can vary 1000-fold in vivo. Our modeling approach reveals dose-dependent feedback control as key property to regulate STAT5-mediated survival decisions over a broad range of ligand concentrations.

  • 45.
    Bagheri, Maryam
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Joghataei, Mohammad-Taghi
    University of Tehran Medical Science.
    Mohseni, Simin
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Roghani, Mehrdad
    Shahed University.
    Genistein ameliorates learning and memory deficits in amyloid beta((1-40)) rat model of Alzheimers disease2011In: Neurobiology of Learning and Memory, ISSN 1074-7427, E-ISSN 1095-9564, Vol. 95, no 3, 270-276 p.Article in journal (Refereed)
    Abstract [en]

    Alzheimers disease (AD) is a debilitating neurodegenerative disorder characterized by increased beta-amyloid (A beta) deposition and neuronal dysfunction leading to impaired learning and recall. Ageing, heredity, and induced oxidative stress are among proposed risk factors. The increased frequency of the disease in women also suggests a role for estrogen in development of AD. In the present study, effects of the phytoestrogen genistein (10 mg/kg) on learning and memory impairments was assessed in intrahippocampal A beta((1-40))-injected rats. The estrogen receptor antagonist fulvestrant was injected intracerebroventricularly in a group of A beta-lesioned rats. The A beta-injected animals exhibited the following: lower spontaneous alternation score in Y-maze tasks, impaired retention and recall capability in the passive avoidance test, and fewer correct choices and more errors in the RAM task. Genistein, but not genistein and fulvestrant, significantly improved most of these parameters. Measurements of oxidative stress markers in hippocampal tissue of A beta-injected rats showed an elevation of malondialdehyde (MDA) and nitrite content, and a reduction of superoxide dismutase (SOD) activity. Genistein significantly attenuated the increased MDA content but did not affect the nitrite content or SOD activity. These results indicate that genistein pretreatment ameliorates A beta-induced impairment of short-term spatial memory in rats through an estrogenic pathway and by inducing attenuation of oxidative stress.

  • 46.
    Bagheri, Maryam
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Rezakhani, Arjang
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Roghani, Mehrdad
    Department of Physiology, Neurophysiology Research Group, Shahed University, Tehran, Iran.
    Joghataei, Mohammad-Taghi
    Cellular and Molecular Research Center & Department of Anatomy and Neuroscience, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
    Mohseni, Simin
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Genistein inhibits Aβ1-40-induced astrogliosis: A three-dimensional confocal morphometric analysisManuscript (preprint) (Other academic)
    Abstract [en]

    Astrocytes are highly involved in regulation and homeostasis of the extracellular environment in the healthy brain. In pathological conditions, these cells play a major role in the inflammatory response seen in CNS tissues, which is called reactive astrogliosis and includes hypertrophy, proliferation, and remodeling. Here, we performed 3D confocal microscopy to evaluate the morphology of reactive glial fibrillary acidic protein (GFAP-positive) astrocytes in an animal model of Alzheimer’s disease, and we also assessed the effect of the antiinflammatory agent genistein on amyloid-beta-induced astrogliosis. In 50 astrocytes/animal, we measured the area and volume of the nucleus, cell body, astrocyte (soma and branches) and territory (tissue covered by each astrocyte), and total length of the branches. Moreover, we quantified the intensity of GFAP immunoreactivity in the hippocampus. Injecting amyloid beta (Aβ)1–40 into the brain caused astrogliosis, observed as significantly higher GFAP intensity in the hippocampus, and also led to significant enlargement of astrocytes in this area, indicated by increased values for all the above-mentioned parameters. In Aβ1–40-injected rats pretreated with genistein, GFAP intensity was decreased to the level seen in the shamoperated group, and Aβ1–40-induced enlargement of astrocytes was significantly inhibited. Interestingly, genistein also ameliorated the astrogliosis that was initiated by mechanical injury caused by insertion of the injection needle into the brain tissue. This  was indicated by the observation that the mean cell body volume and area of astrocytes were significantly smaller in the genistein-treated rats, even in comparison with the sham-operated animals.

  • 47.
    Bagheri, Maryam
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Roghani, Mehrdad
    Shahed University.
    Joghataei, Mohammad-Taghi
    Tehran University of Medical Sciences.
    Mohseni, Simin
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Genistein inhibits aggregation of exogenous amyloid-beta(1-40) and alleviates astrogliosis in the hippocampus of rats2012In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1429, 145-154 p.Article in journal (Refereed)
    Abstract [en]

    We addressed the question of whether injection of Amyloid beta (Aβ)(1-40) in the rat brain is associated with pathology in the hippocampus, and if genistein has any protective effect against the neuronal damage caused by Aβ(1-40). Genistein is a plant-derived compound with a structure similar to that of the female sex hormone estrogen and it was recently shown that pretreatment with a single dose of genistein ameliorated learning and memory deficits in an (Aβ)(1-40) rat model of Alzheimer's disease. Here, we report that injection of the amyloid peptide into the hippocampus of rats led to formation of Aβ(1-40) positive aggregates close to the lateral blade of the dentate gyrus (DGlb). We also observed the following in the hippocampus: extensive cell death in the DGlb (P<0.0001), CA1 (P=0.03), and CA3 (P=0.002); an increased number of iNOS-expressing cells (P=0.01) and gliosis. Genistein given to rats by gavage 1h before injection of Aβ(1-40) inhibited the formation of Aβ(1-40) positive aggregates in the brain tissue and led to increased number of nNOS(+) (P=0.0001) cells in the hippocampus compared to sham-operated genistein-treated controls. Treatment with genistein also alleviated the extensive astrogliosis that occurred in Aβ(1-40)-injected hippocampus to a level similar to that observed in sham-operated rats. We conclude that the neurons in the DGlb are most sensitive to Aβ(1-40), and a single dose of genistein can ameliorate Aβ(1-40) induced pathology.

  • 48.
    Bakhtadze, E
    et al.
    Lund University.
    Cervin, C
    Lund University.
    Lindholm, E
    Lund University.
    Borg, H
    Lund University.
    Nilsson, P
    Lund University.
    Arnqvist, Hans
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Bolinder, J
    Karolinska University.
    Eriksson, J W
    Umeå University Hospital.
    Gudbjornsdottir, S
    Sahlgrens University Hospital.
    Nystrom, L
    Umeå University Hospital.
    Agardh, C D
    Lund University.
    Landin-Olsson, M
    Lund University Hospital.
    Sundkvist, G
    Lund University Hospital.
    C Groop , L C
    Lund University Hospital.
    Common variants in the TCF7L2 gene help to differentiate autoimmune from non-autoimmune diabetes in young (15-34 years) but not in middle-aged (40-59 years) diabetic patients2008In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 51, no 12, 2224-2232 p.Article in journal (Refereed)
    Abstract [en]

    Type 1 diabetes in children is characterised by autoimmune destruction of pancreatic beta cells and the presence of certain risk genotypes. In adults the same situation is often referred to as latent autoimmune diabetes in adults (LADA). We tested whether genetic markers associated with type 1 or type 2 diabetes could help to discriminate between autoimmune and non-autoimmune diabetes in young (15-34 years) and middle-aged (40-59 years) diabetic patients.

    In 1,642 young and 1,619 middle-aged patients we determined: (1) HLA-DQB1 genotypes; (2) PTPN22 and INS variable-number tandem repeat (VNTR) polymorphisms; (3) two single nucleotide polymorphisms (rs7903146 and rs10885406) in the TCF7L2 gene; (4) glutamic acid decarboxylase (GAD) and IA-2-protein tyrosine phosphatase-like protein (IA-2) antibodies; and (5) fasting plasma C-peptide.

    Frequency of risk genotypes HLA-DQB1 (60% vs 25%, p =9.4x10(-34); 45% vs 18%, p= 1.4x10(-16)), PTPN22 CT/TT (34% vs 26%, p=0.0023; 31% vs 23%, p=0.034), INS VNTR class I/I (69% vs 53%, p=1.3x10(-8); 69% vs 51%, p=8.5x10(-5)) and INS VNTR class IIIA/IIIA (75% vs 63%, p=4.3x10(-6); 73% vs 60%, p=0.008) was increased in young and middle-aged GAD antibodies (GADA)-positive compared with GADA-negative patients. The type 2 diabetes-associated genotypes of TCF7L2 CT/TT of rs7903146 were significantly more common in young GADA-negative than in GADA-positive patients (53% vs 43%; p=0.0004). No such difference was seen in middle-aged patients, in whom the frequency of the CT/TT genotypes of TCF7L2 was similarly increased in GADA-negative and GADA-positive groups (55% vs 56%).

    Common variants in the TCF7L2 gene help to differentiate young but not middle-aged GADA-positive and GADA-negative diabetic patients, suggesting that young GADA-negative patients have type 2 diabetes and that middle-aged GADA-positive patients are different from their young GADA-positive counterparts and share genetic features with type 2 diabetes.

  • 49.
    Barral, Anna-Maria
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Immunological Studies in Malignant Melanoma: Importance of TNF and the Thioredoxin System2001Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Malignant melanoma is a tumor whose incidence is dramatically increasing in persons with light-coloured skin in all parts of the world. Due to its resistance against traditional chemo- and radiotherapy, melanoma has been a favourite target of alternative therapies, in particular those involving immunological mechanisms. Cytokines and particularly tumor necrosis factor (TNF) have been studied as possible antitumoral agents, but also as endogenous growth or differentiation factors. Previous studies showed that melanomas could express TNF in situ and that this expression correlated to decreased lymphocyte infiltration. On the other hand, redox reagents can modulate expression of cytokines, and the thioredoxin (Trx) system is particularly known to influence expression and secretion of TNF in vitro.

    The overall aim of this research was to explore immunological aspects of melanoma, particularly the role of TNF both in vitro and in vivo, as well as its possible modulation by Trx.

    In the in vitro studies first we developed a novel method for obtention of monoclonal antibodies against melanoma antigens, and generated and characterized specific monoclonal antibodies against both full-length and truncated Trx. We studied the cytokine expression of a panel of normal and transformed melanocytic cells by immunofluorescence, all of which presented TNF and Trx at levels comparable to monocytic cells, and TNF-receptors (TNFR) at low but detectable levels. Melanoma cells did not secrete TNF upon stimulation in spite of its presence in the Golgi apparatus. However, melanoma cells expressed the TNF-processing enzyme TACE and were capable of cleaving transfected GFP-tagged TNF. Imaging studies point to a possible cell-cell tranfer of endogenous TNF in melanoma cells.

    On the other hand, TNF and Trx expression in melanoma cell lines correlated to resistance against exogenous TNF. We studied then the in situ expression of TNF and Trx by immunohistochemistry in a group of 44 cutaneous melanoma patients. Trx expression did not correlated to survival or other clinicalpathological parameters. TNF expression significantly correlated to better survival in tumors thicker than 0,8 mm, and constituted an independent prognostic factor.

    These results point to a biological role of endogenous TNF in malignant melanoma, either by constituting an autocrine/paracrine differentiation factor or by modulating communication with other cell types, particularly of the host’s immune system.

    List of papers
    1. Cell–cell adherence as a selection method for the generation of anti-melanoma monoclonal antibodies
    Open this publication in new window or tab >>Cell–cell adherence as a selection method for the generation of anti-melanoma monoclonal antibodies
    Show others...
    1997 (English)In: Journal of Immunological Methods, ISSN 0022-1759, Vol. 203, no 1, 103-109 p.Article in journal (Refereed) Published
    Abstract [en]

    The aim of the present study was to obtain monoclonal antibodies (mAbs) recognising human melanoma-associated antigens after immunisation of BALB/c mice with a 70–150 kDa membrane fraction from melanoma tumour tissues. Screening of specific antibody- producing hybridomas was performed using a novel cell–cell adherence method with the melanoma cell line M-14. Three mAbs of IgG1 isotype were selected: Mel-1, Mel-2 and Mel-3 which recognised the immunogen by ELISA and stained several melanoma cell lines positive in immunofluorescence. The molecular weight of the antigen was studied by different methods; a 170-kDa band was identified following immunoblotting of tumour lysate and a 72-kDa band was observed following immunoaffinity purification. Cell–cell adherence appears to be a reliable procedure for the generation of mAbs against native cellular antigens.

    Keyword
    Malignant melanoma; Hybridoma selection; Monoclonal antibody
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-13713 (URN)10.1016/S0022-1759(97)00025-2 (DOI)
    Available from: 2002-01-11 Created: 2002-01-11 Last updated: 2017-09-22
    2. Thioredoxin Expression and Localization in Human Cell Lines: Detection of Full-Length and Truncated Species
    Open this publication in new window or tab >>Thioredoxin Expression and Localization in Human Cell Lines: Detection of Full-Length and Truncated Species
    Show others...
    1997 (English)In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 236, no 1, 181-192 p.Article in journal (Refereed) Published
    Abstract [en]

    Thioredoxin (Trx) is an intracellular multifunctional 12-kDa protein with a reduction/oxidation (redox) active disulfide constitutively expressed by most cells of the human body. Trx can also be released by cells such as lymphocytes upon activation or oxidative stress exposure and exert a cocytokine and cytoprotective activity. In addition, a truncated 10-kDa form of Trx has been reported. In order to better understand the function of full-length and truncated Trx, we have produced, for the first time, specific monoclonal antibodies, which can discriminate between the two forms. Using these novel antibodies, designated αTrx1 to αTrx4, a panel of cell lines derived from human B and T lymphocytes, monocytes, granulocytes, and melanomas was analyzed by immunochemical techniques. The cellular distribution differed between the two forms. All lines contained full-length Trx, also located to a minor extent on the cell surface. One exception was the melanoma cell line FM28.4, which did not show any Trx expression. Truncated Trx was present in most cells in minimal amounts only, whereas the monocytic cell lines THP-1 and U-937 expressed high amounts on the cell surface, as shown by flow cytometric analysis of living cells and confocal laser-scanning microscopy. The biological importance and function of the short versus long forms of Trx as detected by the antibodies are discussed.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-13714 (URN)10.1006/excr.1997.3699 (DOI)
    Available from: 2002-01-11 Created: 2002-01-11 Last updated: 2017-12-13Bibliographically approved
    3. Thioredoxin, thioredoxin reductase and tumour necrosis factor-alpha expression in melanoma cells: correlation to resistance against cytotoxic attack
    Open this publication in new window or tab >>Thioredoxin, thioredoxin reductase and tumour necrosis factor-alpha expression in melanoma cells: correlation to resistance against cytotoxic attack
    2000 (English)In: Melanoma research, ISSN 0960-8931, Vol. 10, no 4, 331-343 p.Article in journal (Refereed) Published
    Abstract [en]

    Although malignant melanomas are often associated with cytotoxic lymphocyte infiltration, these cells are largely ineffective in inducing tumour cell kill, indicating that the melanoma cells have protective mechanisms. These mechanisms are not fully understood, but cytokines and redox-active antioxidant proteins such as catalase, superoxide dismutase, thioredoxin (Trx) and Trx reductase (TrxR) present in the tumour cells constitute part of this protection. In this study firstly we investigated the constitutive intracellular expression of Trx, TrxR, the cytokines interleukin (IL)-1alpha, IL1beta, IL2, IL4, IL6, IL8, IL10, tumour necrosis factor-alpha (TNFalpha) and interferon-gamma (IFNgamma) in normal melanocytes and ten primary and metastatic malignant melanoma cell lines. Secondly, we analysed whether redox stimulation by Trx alone or in combination with the phorbol ester PMA affected the expression and release of TNFalpha. Thirdly, we explored the possible correlation between Trx/TrxR expression and resistance to exogenous TNFalpha. All the cultured cells showed intracellular overexpression of Trx and TrxR, which was not always the case for melanoma cells in vivo (tissue sections). The predominant intracellular cytokines found were TNFalpha, IL1alpha and IL1beta. In spite of its presence in the Golgi apparatus, none of the cell lines secreted TNFalpha constitutively, and only one melanoma, FM3, released detectable amounts after stimulation. In contrast, U-937 monocyte control cells released high amounts of TNFalpha on identical stimulation. All the melanoma cell lines were relatively resistant against exogenous TNFalpha, and there was a significant correlation (P < 0.01) between intracellular Trx/TrxR expression and TNFalpha resistance (IC50). In conclusion, Trx and TrxR, as well as TNFalpha, IL1alpha and IL1beta, were highly expressed in cultured normal skin melanocytes and malignant melanoma cell lines. In contrast to U-937 monocytic cells, TNFalpha showed a secretory block in these cells, suggesting a cytoprotective and possible autocrine role for TNFalpha. The intracellular expression of Trx and TrxR together with endogenous TNFalpha was correlated with the resistance to TNFalpha-induced cytotoxicity.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-13715 (URN)10.1097/00008390-200008000-00004 (DOI)
    Available from: 2002-01-11 Created: 2002-01-11 Last updated: 2017-09-22
    4. Redox-signaling transmitted in trans to neighboring cells by melanoma-derived TNF-containing exosomes
    Open this publication in new window or tab >>Redox-signaling transmitted in trans to neighboring cells by melanoma-derived TNF-containing exosomes
    Show others...
    2007 (English)In: Free Radical Biology and Medicine, ISSN 0891-5849, Vol. 43, no 1, 90-99 p.Article in journal (Refereed) Published
    Abstract [en]

    Hydrogen peroxide is known to be involved in redox signaling pathways that regulate normal processes and disease progression, including cytokine signaling, oxidative stress, and cancer. In studies on immune surveillance against cancer, hydrogen peroxide was found to disrupt cytotoxic T-cell function, thus contributing to tumor escape. In this study, secretion of TNF-containing vesicles of rab9+ endosomal origin, termed exosomes, was investigated using GFP-TNF constructs. We observed a polarized intracellular trafficking and apical secretion of TNF-positive nanovesicles. Cell-to-cell transfer of TNF was observed in exosomes in real-time microscopy, occurring separate from the melanin/melanosome compartment. Exosomes were prepared by ultracentrifugation or immunoisolation on anti-β2-microglobulin magnetic beads. TNF as well as TNF receptors 1 and 2 were present in the exosomes as determined by Western blot, flow cytometry, and deconvolution microscopy. The functional significance of melanoma-derived exosomes was established by their signaling competence with ability to generate significantly higher ROS levels in T cells compared with sham exosomes (P = 0.0006). In conclusion, we report here, for the first time, that TNF is found in tumor cell-derived exosomes and that these exosomes transmit redox signaling in trans to neighboring cells. The results are of importance for a better understanding of tumor escape mechanisms.

    Keyword
    TNF, Exosomes, Melanoma, Hydrogen peroxide, Redox signaling, Tumor escape mechanisms
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-13716 (URN)10.1016/j.freeradbiomed.2007.03.026 (DOI)000247395000011 ()
    Available from: 2002-01-11 Created: 2002-01-11 Last updated: 2017-09-22
    5. TNFα expression predicts a better outcome in thick malignant melanoma
    Open this publication in new window or tab >>TNFα expression predicts a better outcome in thick malignant melanoma
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:liu:diva-13717 (URN)
    Available from: 2002-01-11 Created: 2002-01-11 Last updated: 2010-01-13
  • 50.
    Barral, Anna-Maria
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cellbiology. Linköping University, Faculty of Health Sciences.
    Fernández, Alicia
    Molecular Immunology Center (CIMAB), Havana, Cuba.
    Faxas, María Elena
    National Institute of Oncology and Radiobiology, Havana, Cuba.
    Pérez, Xiomara
    National Institute of Oncology and Radiobiology, Havana, Cuba.
    García, Carlos A.
    National Institute of Oncology and Radiobiology, Havana, Cuba.
    Rosén, A.
    Linköping University, Department of Clinical and Experimental Medicine, Cellbiology. Linköping University, Faculty of Health Sciences.
    Cell–cell adherence as a selection method for the generation of anti-melanoma monoclonal antibodies1997In: Journal of Immunological Methods, ISSN 0022-1759, Vol. 203, no 1, 103-109 p.Article in journal (Refereed)
    Abstract [en]

    The aim of the present study was to obtain monoclonal antibodies (mAbs) recognising human melanoma-associated antigens after immunisation of BALB/c mice with a 70–150 kDa membrane fraction from melanoma tumour tissues. Screening of specific antibody- producing hybridomas was performed using a novel cell–cell adherence method with the melanoma cell line M-14. Three mAbs of IgG1 isotype were selected: Mel-1, Mel-2 and Mel-3 which recognised the immunogen by ELISA and stained several melanoma cell lines positive in immunofluorescence. The molecular weight of the antigen was studied by different methods; a 170-kDa band was identified following immunoblotting of tumour lysate and a 72-kDa band was observed following immunoaffinity purification. Cell–cell adherence appears to be a reliable procedure for the generation of mAbs against native cellular antigens.

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