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  • 1.
    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, p. 657-661Article 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.

  • 2.
    Ahlen, K.
    et al.
    Åhlén, K., Dept. Med. Biochem. and Microbiol., University of Uppsala, Biomedical Center, SE-751 23 Uppsala, Sweden.
    Ring, P.
    Dept. Med. Biochem. and Microbiol., University of Uppsala, Biomedical Center, SE-751 23 Uppsala, Sweden.
    Tomasini-Johansson, B.
    Dept. Med. Biochem. and Microbiol., University of Uppsala, Biomedical Center, SE-751 23 Uppsala, Sweden, Department of Medicine, University of Wisconsin-Madison, 4285 MSC, 1300 University Ave, Madison, WI 53706, United States.
    Holmqvist, K.
    Dept. Med. Biochem. and Microbiol., University of Uppsala, Biomedical Center, SE-751 23 Uppsala, Sweden, Department of Medical Cell Biology, University of Uppsala, Biomedical Center, SE-751 23 Uppsala, Sweden.
    Magnusson, Karl-Eric
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology .
    Rubin, K.
    Dept. Med. Biochem. and Microbiol., University of Uppsala, Biomedical Center, SE-751 23 Uppsala, Sweden.
    Platelet-derived growth factor-BB modulates membrane mobility of ß1 integrins2004In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 314, no 1, p. 89-96Article in journal (Refereed)
    Abstract [en]

    Platelet-derived growth factor (PDGF)-BB elicits a migratory response including reorganization of the actin cytoskeleton in different cell types. Here we have investigated the effects of PDGF-BB stimulation on ß 1 integrin containing focal adhesions in human diploid fibroblasts adhered to collagen type I. Stimulation with PDGF-BB dissociated focal adhesions and relocated ß1 integrins from focal adhesions to the periphery of the cells. These changes were rapid and transient in character. Relocation of ß1 integrins was prevented by inhibitors of phosphoinositide-3-kinase and protein kinase C. PDGF-BB stimulated fibroblasts exhibited an increased diffusion coefficient of cell surface ß1 integrins as determined by fluorescence recovery of photobleaching. The cell surface expression of ß1 integrins was not changed after stimulation with PDGF-BB. Our data suggest that PDGF-BB increases the dynamic properties of cell-surface ß1 integrins, which most likely are important for the migratory response elicited by PDGF-BB. © 2003 Elsevier Inc. All rights reserved.

  • 3.
    Ahmadi, Ahmad
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Fredriksson, Mats
    Linköping University, Department of Molecular and Clinical Medicine, Occupational and Environmental Medicine. Linköping University, Faculty of Health Sciences.
    Jerregård, H.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Åkerbäck, Anita
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Fall, Per-Arne
    Linköping University, Department of Neuroscience and Locomotion, Geriatrics. Linköping University, Faculty of Health Sciences.
    Rannug, A.
    National Institute for Working Life, Solna and Inst. of Environ. Medicine, Karolinska Institutet, Stockholm, Sweden.
    Axelson, Olav
    Linköping University, Department of Molecular and Clinical Medicine, Occupational and Environmental Medicine. Linköping University, Faculty of Health Sciences.
    Söderkvist, Peter
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    GSTM1 and mEPHX polymorphisms in Parkinson's disease and age of onset2000In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 269, no 3, p. 676-680Article in journal (Refereed)
    Abstract [en]

    Both environmental and genetic factors are involved in the development of PD and biotransformation of exogenous and endogenous compounds and may play a role in inter-individual susceptibility. Therefore, we investigated the presence of null genotypes of GSTM1, GSTT1, and two polymorphisms of mEPHX in subjects with Parkinson's disease and in a reference population. The study included 35 male PD patients and a male control group including 283 subjects. Homozygosity of the histidine (H) 113 isoform of mEPHX was significantly increased in PD patients (odds ratio = 3.8 CI 95% 1.2–11.8) and analysis of allele frequencies displayed an increased frequency of the H-allele among PD patients (odds ratio = 1.9 CI 95% 1.1–3.3). However, a significantly elevated median age for the onset of PD was found among GSTM1 gene carriers (median age = 68 years) compared to PD patients being GSTM1 null genotypes (median age = 57 years). Our observations suggest that (H) 113 isoform of mEPHX, which has been suggested as a low activity isoform, is overrepresented in PD patients and that inherited carriers of the GSTM1 gene postpone the onset of PD. These detoxification pathways may represent important protective mechanisms against reactive intermediates modifying the susceptibility and onset of PD.

  • 4. Aifa, Sami
    et al.
    Frikha, Fakher
    Miled, Nabil
    Johansen, Knut
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Applied Physics .
    Lundström, Ingemar
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Applied Physics .
    Svensson, Samuel P.S.
    Astra Zeneca.
    Phosphorylation of Thr654 but not Thr669 within the juxtamembrane domain of the EGF receptor inhibits calmodulin binding2006In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 347, no 2, p. 381-387Article in journal (Refereed)
    Abstract [en]

    Calcium-calmodulin (CaM) binding to the epidermal growth factor receptor (EGFR) has been shown to both inhibit and stimulate receptor activity. CaM binds to the intracellular juxtamembrane (JM) domain (Met645-Phe688) of EGFR. Protein kinase C (PKC) mediated phosphorylation of Thr654 occurs within this domain. CaM binding to the JM domain inhibits PKC phosphorylation and conversely PKC mediated phosphorylation of Thr654 or Glu substitution of Thr654 inhibits CaM binding. A second threonine residue (Thr669) within the JM domain is phosphorylated by the mitogen-activated protein kinase (MAPK). Previous results have shown that CaM interferes with EGFR-induced MAPK activation. If and how phosphorylation of Thr669 affects CaM-EGFR interaction is however not known.In the present study we have used surface plasmon resonance (BIAcore) to study the influence of Thr669 phosphorylation on real time interactions between the intracellular juxtamembrane (JM) domain of EGFR and CaM. The EGFR-JM was expressed as GST fusion proteins in Escherichia coli and phosphorylation was mimicked by generating Glu substitutions of either Thr654 or Thr669. Purified proteins were coupled to immobilized anti-GST antibodies at the sensor surface and increasing concentration of CaM was applied. When mutating Thr654 to Glu654 no specific CaM binding could be detected. However, neither single substitutions of Thr669 (Gly669 or Glu669) nor double mutants Gly654/Gly669 or Gly654/Glu669 influenced the binding of CaM to the EGFR-JM. This clearly shows that PKC may regulate EGF-mediated CaM signalling through phosphorylation of Thr654 whereas phosphorylation of Thr669 seems to play a CaM independent regulatory role. The role of both residues in the EGFR-calmodulin interaction was also studied in silico. Our modelling work supports a scenario where Thr654 from the JM domain interacts with Glu120 in the calmodulin molecule. Phosphorylation of Thr654 or Glu654 substitution creates a repulsive electrostatic force that would diminish CaM binding to the JM domain. These results are in line with the Biacore experiments showing a weak binding of the CaM to the JM domain with Thr654 mutated to Glu. Furthermore, these results provide a hypothesis to how CaM binding to EGFR might both positively and negatively interfere with EGFR-activity. © 2006 Elsevier Inc. All rights reserved.

  • 5.
    Alila-Fersi, Olfa
    et al.
    Molecular and Functional Genetics Laboratory, Faculty of Science of Sfax, University of Sfax, Tunisia.
    Tabebi, Mouna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Maalej, Marwa
    Molecular and Functional Genetics Laboratory, Faculty of Science of Sfax, University of Sfax, Tunisia.
    Belguith, Neila
    Department of Medical Genetics, Hédi Chaker Hospital, Sfax, Tunisia.
    Keskes, Leila
    Human Molecular Genetics Laboratory, Faculty of Medecine of Sfax, University of Sfax, Tunisia.
    Mkaouar-Rebai, Emna
    Molecular and Functional Genetics Laboratory, Faculty of Science of Sfax, University of Sfax, Tunisia.
    Fakhfakh, Faiza
    Molecular and Functional Genetics Laboratory, Faculty of Science of Sfax, University of Sfax, Tunisia.
    First description of a novel mitochondrial mutation in the MT-TI gene associated with multiple mitochondrial DNA deletion and depletion in family with severe dilated mitochondrial cardiomyopathy2018In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 497, no 4, p. 1049-1054Article in journal (Refereed)
    Abstract [en]

    Mitochondria are essential for early cardiac development and impaired mitochondria] function was described associated with heart diseases such as hypertrophic or dilated mitochondrial cardiomyopathy. In this study, we report a family including two individuals with severe dilated mitochondrial cardiomyopathy. The whole mitochondrial genome screening showed the presence of several variations and a novel homoplasmic mutation m.4318-4322deIC in the MT-TI gene shared by the two patients and their mother and leading to a disruption of the tRNA(IIe) secondary structure. In addition, a mitochondrial depletion was present in blood leucocyte of the two affected brother whereas a de novo heteroplasmic multiple deletion in the major arc of mtDNA was present in blood leucocyte and mucosa of only one of them. These deletions in the major arc of the mtDNA resulted to the loss of several protein-encoding genes and also some tRNA genes. The mtDNA deletion and depletion could result to an impairment of the oxidative phosphorylation and energy metabolism in the respiratory chain in the studied patients. Our report is the first description of a family with severe lethal dilated mitochondrial cardiomyopathy and presenting several mtDNA abnormalities including punctual mutation, deletion and depletion.

  • 6.
    Amarzguioui, Mohammed
    et al.
    The Biotechnology Centre of Oslo, University of Oslo, Gaustadalleen 21, Oslo, Norway.
    Mucchiano, Gerd
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Häggqvist, Bo
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Westermark, Bo
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Kavlie, Anita
    The Biotechnology Centre of Oslo, University of Oslo, Gaustadalleen 21, Oslo, Norway.
    Sletten, Knut
    The Biotechnology Centre of Oslo, University of Oslo, Gaustadalleen 21, Oslo, Norway.
    Prydz, Hans
    The Biotechnology Centre of Oslo, University of Oslo, Gaustadalleen 21, Oslo, Norway.
    Extensive Intimal Apolipoprotein A1-Derived Amyloid Deposits in a Patient with an Apolipoprotein A1 Mutation1998In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 242, no 3, p. 534-539Article in journal (Refereed)
    Abstract [en]

    In the aortic intima amyloid deposits are often associated with atherosclerotic plaques. In a recent study of one patient with aortic intimal amyloid the major fibril protein was an N-terminal fragment of apolipoprotein A1 (apoA1) consisting of 69 amino acid residues. In the present study, we have screened the apoA1 gene for mutations in autopsy cases with aortic intimal amyloid immunohistochemically positive for apoA1, using single stranded conformational polymorphism (SSCP) analysis and DNA sequencing. All cases except one had a normal apoA1 gene sequence. One case of exceptionally severe atherosclerosis combined with extensive intimal amyloid deposits showed an apoA1 deletion corresponding to Lys 107. Thus, wild type apoA1 is amyloidogenic but our findings suggest that the expression of a mutant apoA1-form may be associated with enhanced amyloidogenicity.

  • 7.
    Andersson, Viktor
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics. Linköping University, The Institute of Technology.
    Skoglund, Caroline
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, The Institute of Technology.
    Uvdal, Kajsa
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, Faculty of Science & Engineering.
    Solin, Niclas
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics. Linköping University, Faculty of Science & Engineering.
    Preparation of amyloidlike fibrils containing magnetic iron oxide nanoparticles: Effect of protein aggregation on proton relaxivity2012In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 419, no 4, p. 682-686Article in journal (Refereed)
    Abstract [en]

    A method to prepare amyloid-like fibrils functionalized with magnetic nanoparticles has been developed. The amyloid-like fibrils are prepared in a two step procedure, where insulin and magnetic nanoparticles are mixed simply by grinding in the solid state, resulting in a water soluble hybrid material. When the hybrid material is heated in aqueous acid, the insulin/nanoparticle hybrid material self assembles to form amyloid-like fibrils incorporating the magnetic nanoparticles. This results in magnetically labeled amyloid-like fibrils which has been characterized by Transmission Electron Microscopy (TEM) and electron tomography. The influence of the aggregation process on proton relaxivity is investigated. The prepared materials have potential uses in a range of bio-imaging applications.

  • 8.
    Appelkvist, Eewa-Liisa
    et al.
    Karolinska Institutet, Huddinge Hospital, Sweden.
    Söderström, Mats
    Arrhenius Laboratory for the Natural Sciences, Stockholm University, Sweden.
    Nässberger, Lennart
    Stockholm University, Sweden.
    Damberg, Charlotta
    Stockholm University, Sweden.
    Dallner, Gustav
    Karolinska Institutet, Huddinge Hospital, Sweden / Stockholm University, Sweden.
    DePierre, Joseph W
    Stockholm University, Sweden.
    Characterization of the lipid and protein contents of myelin bodies isolated from the renal cortex of gentamicin-treated rats1991In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 181, no 2, p. 894-901Article in journal (Refereed)
    Abstract [en]

    Myelin bodies were isolated from the renal cortex of gentamicin-treated rats (100 mg/kg body weight, twice daily for 3 days, i.p.) employing an initial pelleting by differential centrifugation and subsequent flotation on a discontinuous sucrose gradient. These structures were found to contain almost twice as much protein as phospholipid and SDS-polyacrylamide gel electrophoresis revealed the presence of many different polypeptides. All the major phospholipids are present, although myelin bodies contain a considerably higher proportion of phosphatidylinositol, somewhat more phosphatidylcholine and considerably lower percentages of phosphatidylserine and sphingomyelin than do normal renal phospholipids. The fatty acids of myelin body phospholipids are highly saturated (67.3-87.9%) and a striking feature is the occurrence of relatively large amounts of 22:1, presumably erucic acid, especially in sphingomyelin. Myelin bodies contain small amounts of unesterified cholesterol, unesterified dolichol and coenzymes Q9 and Q10.

  • 9. Bergström, Joakim
    et al.
    Murphy, Charles
    Eulitz, Manfred
    Weiss, Deborah
    Westermark, Gunilla
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Solomon, Alan
    Westermark, Per
    Codeposition of apolipoprotein A-IV and transthyretin in senile systemic (ATTR) amyloidosis2001In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 285, no 4, p. 903-908Article in journal (Refereed)
    Abstract [en]

    Protein material was extracted from amyloid-rich sections of formalin-fixed and paraffin-embedded heart tissue from an individual with senile systemic amyloidosis, known to contain wild-type transthyretin as major amyloid fibril protein. Amino acid sequence analysis of tryptic peptides of this material revealed in addition to transthyretin sequences, also amino acid sequence corresponding to an N-terminal fragment of apolipoprotein A-IV. In immunohistochemistry, an antiserum to a synthetic apolipoprotein A-IV peptide labeled amyloid specifically. This peptide formed spontaneously amyloid-like fibrils in vitro and enhanced fibril formation from wild-type transthyretin. We conclude that several apolipoproteins, including apolipoprotein A-IV, may be important minor amyloid constituents, promoting fibril formation.

  • 10.
    Bronnikov, Gennady
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Aboulaich, Nabila
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Vener, Alexander
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Strålfors, Peter
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Acute effects of insulin on the activity of mitochondrial GPAT1 in primary adipocytes2008In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 367, no 1, p. 201-207Article in journal (Refereed)
    Abstract [en]

    The mitochondrial enzyme 1-acyl-sn-glycerol-3-phosphate acyltransferase (mtGPAT1) catalyzes a rate-limiting step in triacylglycerol and glycerophospholipid biosynthesis, which can be modulated by protein kinases in cell free analyses. We report that treatment of primary rat adipocytes with insulin acutely affects the activity of mtGPAT1 by increasing VMAX and KM for the substrates glycerol-3-phosphate and palmitoyl-CoA. Proteolytic cleavage of isolated mitochondrial membranes and mass spectrometric peptide sequencing identify in vivo phosphorylation of serine 632 and serine 639 in mtGPAT1. These phosphorylation sites correspond to casein kinase-2 consensus sequences and are highly conserved in chordate animal, but not fly, fungal or plant, mtGPAT1. © 2007 Elsevier Inc. All rights reserved.

  • 11. Brurok, H
    et al.
    Ardenkjaer-Larsen, J-H
    Hansson, G
    Skarra,
    Berg, K
    Karlsson, I
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Manganese Dipyridoxyl Diphosphate: MRI Contrast Agent with antioxidative and cardioprotective properties.1999In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 254, p. 768-772Article in journal (Refereed)
  • 12.
    Carlsson, Karin
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Persson, Egon
    Haemostasis Biochemistry, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark.
    Carlsson, Uno
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Svensson, Magdalena
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Inhibitors of factor VIIa affect the interface between the protease domain and tissue factor2006In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 349, no 3, p. 1111-1116Article in journal (Refereed)
    Abstract [en]

    Blood coagulation is triggered by the formation of a complex between factor VIIa (FVIIa) and its cofactor, tissue factor (TF). The γ-carboxyglutamic acid-rich domain of FVIIa docks with the C-terminal domain of TF, the EGF1 domain of FVIIa contacts both domains of TF, and the EGF2 domain and protease domain (PD) form a continuous surface that sits on the N-terminal domain of TF. Our aim was to investigate the conformational changes that occur in the sTF·PD binding region when different types of inhibitors, i.e., one active-site inhibitor (FFR-chloromethyl ketone (FFR)), two different peptide exosite inhibitors (E-76 and A-183), and the natural inhibitor tissue factor pathway inhibitor (TFPI), were allowed to bind to FVIIa. For this purpose, we constructed two sTF mutants (Q37C and E91C). By the aid of site-directed labeling technique, a fluorescent label was attached to the free cysteine. The sTF·PD interface was affected in position 37 by the binding of FFR, TFPI, and E-76, i.e., a more compact structure was sensed by the probe, while for position 91 located in the same region no change in the surrounding structure was observed. Thus, the active site inhibitors FFR and TFPI, and the exosite inhibitor E-76 have similar effects on the probe in position 37 of sTF, despite their differences in size and inhibition mechanism. The allosteric changes at the active site caused by binding of the exosite inhibitor E-76 in turn induce similar conformational changes in the sTF·PD interface as does the binding of the active site inhibitors. A-183, on the other hand, did not affect position 37 in sTF, indicating that the A-183 inhibition mechanism is different from that of E-76.

  • 13.
    Carlsson, Karin
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Persson, Egon
    Haemostasis Biochemistry, Novo Nordisk A/S, DK-2760 Måløv, Denmark.
    Østergaard, Henrik
    Department of Physics, Norwegian University of Science and Technology, Trondheim, Norway.
    Lindgren, Mikael
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Carlsson, Uno
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Svensson, Magdalena
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Effects on the conformation of FVIIa by sTF and Ca(2+) binding: Studies of fluorescence resonance energy transfer and quenching2011In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 413, no 4, p. 545-549Article in journal (Refereed)
    Abstract [en]

    The apparent length of FVIIa in buffer solution was estimated by a FRET analysis. Two fluorescent probes, fluorescein linked to an inhibitor (FPR-chloromethyl ketone) and a rhodamine derivative (tetramethylrhodamine-5-maleimide), were covalently attached to FVIIa. The binding site of fluorescein was in the PD whereas rhodamine was positioned in the Gla domain, thus allowing a length measure over approximately the whole extension of the protein. From the FRET measurements the distances between the two probes were determined to 61.4 for free FVIIa and 65.5 Å for FVIIa bound to the soluble TF (sTF). Thus, the apparent distance from the FRET analysis was shown to increase with 4 Å upon formation of a complex with sTF in solution. However, by considering how protein dynamics, based on recently published molecular dynamics simulations of FVIIa and sTF:FVIIa (Ohkubo et al., 2010 J. Thromb. Haemost. 8, 1044-1053), can influence the apparent  fluorescence signal our calculations indicated that the global average conformation of active-site inhibited FVIIa is nearly unaltered upon ligation to sTF.

    Moreover, it is known that Ca2+ binding leads to activation of FVIIa, and we have for the first time demonstrated conformational changes in the environment of the active site upon Ca2+ binding by direct measurements, previously suggested based on indirect measurements (Persson & Petersen, 1995 Eur. J. Biochem. 234, 293-300). Interestingly, this Ca2+-induced conformational change can be noted even in the presence of an inhibitor. By forming the sTF:FVIIa complex the conformational change of the active site is further developed, leading to a more inaccessible active-site located probe.

  • 14.
    Chantzoura, Eleni
    et al.
    Center of Basic Research I, Biochemistry Division, Biomedical Research Foundation, Academy of Athens, Greece.
    Prinarakis, Efthimios
    Center of Basic Research I, Biochemistry Division, Biomedical Research Foundation, Academy of Athens, Greece.
    Panagopoulos, Dimitris
    School of Biology, Aristotle University of Thessaloniki, Greece.
    Mosialos, George
    School of Biology, Aristotle University of Thessaloniki, Greece.
    Spyrou, Giannis
    Center of Basic Research I, Biochemistry Division, Biomedical Research Foundation, Academy of Athens, Greece.
    Glutaredoxin-1 regulates TRAF6 activation and the IL-1 receptor/TLR4 signalling2010In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 403, no 3-4, p. 335-339Article in journal (Refereed)
    Abstract [en]

    Glutaredoxin-1 (GRX-1) is a cytoplasmic enzyme that highly contributes to the antioxidant defense system. It catalyzes the reversible reduction of glutathione-protein mixed disulfides, a process called deglutathionylation. Here, we investigated the role of GRX-1 in the pathway triggered by interleukin-1/Toll-like receptor 4 (IL-1R/TLR4) by using RNA interference (RNAi) in HEK293 and HeLa cells. TNF receptor-associated factor 6 (TRAF6) is an intermediate signalling molecule involved in the signal transduction by members of the interleukin-1/Toll-like receptor (IL-1R/TLR) family. TRAF6 has an E3 ubiquitin ligase activity which depends on the integrity of an amino-terminal really interesting new gene (RING) finger motif. Upon receptor activation, TRAF6 undergoes K63-linked auto-polyubiquitination which mediates protein-protein interactions and signal propagation. Our data showed that IL-1R and TLR4-mediated NF-κB induction was severely reduced in GRX-1 knockdown cells. We found that the RING-finger motif of TRAF6 is S-glutathionylated under normal conditions. Moreover, upon IL-1 stimulation TRAF6 undergoes deglutathionylation catalyzed by GRX-1. The deglutathionylation of TRAF6 is essential for its auto-polyubiquitination and subsequent activation. Taken together, our findings reveal another signalling molecule affected by S-glutathionylation and uncover a crucial role for GRX-1 in the TRAF6-dependent activation of NF-κB by IL-1R/TLRs.

  • 15.
    Djerf, Emelie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Trinks, Cecilia
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Green, Henrik
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Abdiu, Avni
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Sinnescentrum, Department of Plastic Surgery, Hand surgery UHL.
    Hallbeck, Anna-Lotta
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology UHL.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology UHL.
    Walz, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology UHL.
    The pan-ErbB receptor tyrosine kinase inhibitor canertinib promotes apoptosis of malignant melanoma in vitro and displays anti-tumor activity in vivo2011In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 414, no 3, p. 563-568Article in journal (Refereed)
    Abstract [en]

    The ErbB receptor family has been suggested to constitute a therapeutic target for tumor-specific treatment of malignant melanoma. Here we investigate the effect of the pan-ErbB tyrosine kinase inhibitor canertinib on cell growth and survival in human melanoma cells in vitro and in vivo. Canertinib significantly inhibited growth of cultured melanoma cells, RaH3 and RaH5, in a dose-dependent manner as determined by cell counting. Half-maximum growth inhibitory dose (IC(50)) was approximately 0.8 mu M and by 5 mu M both cell lines were completely growth-arrested within 72 h of treatment. Incubation of exponentially growing RaH3 and RaH5 with 1 mu M canertinib accumulated the cells in the G(1)-phase of the cell cycle within 24 h of treatment without induction of apoptosis as determined by flow cytometry. Immunoblot analysis showed that 1 mu M canertinib inhibited ErbB1-3 receptor phosphorylation with a concomitant decrease of Akt-, Erk1/2- and Stat3 activity in both cell lines. In contrast to the cytostatic effect observed at doses less than= 5 mu M canertinib, higher concentrations induced apoptosis as demonstrated by the Annexin V method and Western blot analysis of PARP cleavage. Furthermore, canertinib significantly inhibited growth of RaH3 and RaH5 melanoma xenografts in nude mice. Pharmacological targeting of the ErbB receptors may prove successful in the treatment of patients with metastatic melanoma.

  • 16.
    Elander, Nils
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Ungerbäck, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Olsson, Hans
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Uematsu, Satoshi
    Department of Host Defense, Research Institute for Microbial Diseases Osaka University, Osaka, Japan.
    Akira, Shizuo
    Department of Host Defense, Research Institute for Microbial Diseases Osaka University, Osaka, Japan.
    Söderkvist, Peter
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Genetic deletion of mPGES-1 accelerates intestinal tumorigenesis in APCMin/+ mice2008In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 372, no 1, p. 249-253Article in journal (Refereed)
    Abstract [en]

    The induced synthesis of bioactive prostanoids downstream of cyclooxygenase-2 (COX-2) and prostaglandin H2 (PGH2) exerts a critical event in colorectal carcinogenesis. Here we demonstrate that APCMin/+ mice with genetic deletion of microsomal prostaglandin E synthase-1 (mPGES-1), which catalyses the terminal conversion of PGH2 into PGE2, surprisingly develop more and generally larger intestinal tumors than do mPGES-1 wild type littermates (mean number of tumors/intestine 80 vs. 38, p < 0.0005, mean tumor diameter 1.64 vs. 1.12 mm, p < 0.0005). No deviation regarding the expression of other PGE2 related enzymes (COX-1, COX-2, mPGES-2, cPGES, and 15-PGDH) or receptors (EP1-4) was obvious among the mPGES-1 deficient mice. PGE2 levels were suppressed in tumors of mPGES-1 deficient animals, but the concentrations of other PGH2 derived prostanoids were generally enhanced, being most prominent for TxA2 and PGD2. Thus, we hypothesise that a redirected synthesis towards other lipid mediators might (over)compensate for loss of mPGES-1/PGE2 during intestinal tumorigenesis. Nevertheless, our results question the suitability for mPGES-1 targeting therapy in the treatment or prevention of colorectal cancer. © 2008 Elsevier Inc. All rights reserved.

  • 17.
    Forslund, Tony
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Nilsson, Harriet
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Sundqvist, Tommy
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Nitric Oxide Regulates the Aggregation of Stimulated Human Neutrophils2000In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 274, no 2, p. 482-487Article in journal (Refereed)
    Abstract [en]

    Neutrophil aggregation is mediated by both CD18 integrin and L-selectin. Nitric oxide attenuates the integrin-mediated adhesion of neutrophils to collagen and to endothelium and may therefore affect aggregation as well. FMLP-stimulated neutrophils exposed to -arginine showed increased and prolonged aggregation, whereas cells pretreated with L-NAME did not differ from FMLP-stimulated controls. Nitric oxide is known to induce ADP ribosylation of G-actin, which inhibits polymerization. We detected equivalent levels of total F-actin in cells pretreated with -arginine or L-NAME and non-pretreated controls. However, neutrophils pretreated with -arginine and stimulated by CD18 integrin cross-linking exhibited a more limited increase in total F-actin, compared to control and L-NAME-pretreated cells. Thus at least two signaling pathways may be involved FMLP-stimulated aggregation, mediated by CD18 integrins. More specifically, it is plausible that FMLP-receptor signaling upregulates CD18 integrins and endogenous NO subsequently modulates CD18-mediated signaling to prolong aggregation, possibly through ADP-ribosylation of actin.

  • 18.
    Fotoohi, Alan Kambiz
    et al.
    KI, Stockholm.
    Lindqvist Appell, Malin
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology.
    Peterson, Curt
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Albertioni, Freidoun
    KI, Stockholm.
    Involvement of the concentrative nucleoside transporter 3 and equilibrative nucleoside transporter 2 in the resistance of T-lymphoblastic cell lines to thiopurines2006In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 343, no 1, p. 208-215Article in journal (Refereed)
    Abstract [en]

    Mechanisms of resistance to thiopurines, 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) were investigated in human leukemia cell lines. We developed two 6-MP- and 6-TG-resistant cell lines from the human T-lymphoblastic cell line (MOLT-4) by prolonged exposure to these drugs. The resistant cells were highly cross resistant to 6-MP and 6-TG, and exhibited marked reduction in cellular uptake of 6-MP (70% and 80%, respectively). No significant modification of the activities of hypoxanthine-guanine phosphoribosyl transferase, thiopurine methyltransferase or inosine monophosphate dehydrogenase was observed. Real-time PCR of concentrative nucleoside transporter 3 (CNT3) and equilibrative nucleoside transporter 2 (ENT2) of resistant cells showed substantial reductions in expression of messenger RNAs. Small interfering RNA designed to silence the CNT3 and ENT2 genes down-regulated the expression of these genes in leukemia cells. These decreases were accompanied by reduction of transport of 6-MP (47% and 21%, respectively) as well as its cytocidal effect (30% and 21%, respectively). Taken together these results show that CNT3 and ENT2 play a key role in the transport of 6-MP and 6-TG by leukemia cells. From a clinical point of view determination of CNT3 and ENT2 levels in leukemia cells may be useful in predicting the efficacy of thiopurine treatment. © 2006 Elsevier Inc. All rights reserved.

  • 19.
    Fyrberg, Anna
    et al.
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Faculty of Health Sciences.
    Albertioni, Freidoun
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology.
    Lotfi, Kourosh
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Cell cycle effect on the activity of deoxynucleoside analogue metabolising enzymes2007In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 357, no 4, p. 847-853Article in journal (Refereed)
    Abstract [en]

    Deoxynucleoside analogues (dNAs) are cytotoxic towards both replicating and indolent malignancies. The impact of fluctuations in the metabolism of dNAs in relation to cell cycle could have strong implications regarding the activity of dNAs. Deoxycytidine kinase (dCK) and deoxyguanosine kinase (dGK) are important enzymes for phosphorylation/activation of dNAs. These drugs can be dephosphorylated/deactivated by 5′-nucleotidases (5′-NTs) and elevated activities of 5′-NTs and decreased dCK and/or dGK activities represent resistance mechanisms towards dNAs. The activities of dCK, dGK, and three 5′-NTs were investigated in four human leukemic cell lines in relationship to cell cycle progression and cytotoxicity of dNAs. Synchronization of cell cultures to arrest in G0/G1 by serum-deprivation was performed followed by serum-supplementation for cell cycle progression. The activities of dCK and dGK increased up to 3-fold in CEM, HL60, and MOLT-4 cells as they started to proliferate, while the activity of cytosolic nucleotidase I was reduced in proliferating cells. CEM, HL60, and MOLT-4 cells were also more sensitive to cladribine, cytarabine, 9-β-d-arabinofuranosylguanine and clofarabine than K562 cells which demonstrated lower levels and less alteration of these enzymes and were least susceptible to the cytotoxic effects of most dNAs. The results suggest that, in the cell lines studied, the proliferation process is associated with a general shift in the direction of activation of dNAs by inducing activities of dCK/dGK and reducing the activity of cN-I which is favourable for the cytotoxic effects of cladribine, cytarabine and, 9-β-d-arabinofuranosylguanine. These results emphasize the importance of cellular proliferation and dNA metabolism by both phosphorylation and dephosphorylation for susceptibility to dNAs. It underscores the need to understand the mechanisms of action and resistance to dNAs in order to increase efficacy of dNAs treatment by new rational. © 2007 Elsevier Inc. All rights reserved.

  • 20.
    Fyrberg, Anna
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Skoglund, Karin
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Wolk, M
    Israel Minist Health Central Labs, Israel .
    Lotfi, Kourosh
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pharmacology.
    A potential role of fetal hemoglobin in the development of multidrug resistance2012In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 427, no 3, p. 456-460Article in journal (Refereed)
    Abstract [en]

    Our previous data from a human leukemic cell line made resistant to the nucleoside analog (NA) 9-beta-D-arabinofuranosylguanine (AraG) revealed a massive upregulation of fetal hemoglobin (HbF) genes and the ABCB1 gene coding for the multidrug resistance P-glycoprotein (P-gp). The expression of these genes is regulated through the same mechanisms, with activation of the p38-MAPK pathway and inhibition of methylation making transcription factors more accessible to activate these genes. We could show that AraG, as well as other NAs, and P-gp substrates could induce global DNA demethylation and induction of Hb gamma and P-gp both at the mRNA and protein expression level. We speculate that the expression of HbF prior to drug exposure or in drug-resistant cell lines is a strategy of the cancer to gain more oxygen, and thereby survival benefits. We also believe that P-gp may be induced in order to excrete Hb degradation products from the cells that would otherwise be toxic. By using Hb gamma siRNA and pharmacological inhibitors of HbF production we here present a possible relationship between HbF induction and multi-drug resistance in a human leukemia cell line model.

  • 21.
    Gabrielson, Marike
    et al.
    University of Örebro, Sweden; Karolinska Institute, Sweden.
    Reizer, Edwin
    University of Örebro, Sweden.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Tina, Elisabet
    University of Örebro, Sweden.
    Mitochondrial regulation of cell cycle progression through SLC25A432016In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 469, no 4, p. 1090-1096Article in journal (Refereed)
    Abstract [en]

    An increasing body of evidence is pointing towards mitochondrial regulation of the cell cycle. In a previous study of HER2-positive tumours we could demonstrate a common loss in the gene encoding for the mitochondrial transporter SLC25A43 and also a significant relation between SLC25A43 protein expression and S-phase fraction. Here, we investigated the consequence of suppressed SLC25A43 expression on cell cycle progression and proliferation in breast epithelial cells. In the present study, we suppressed SLC25A43 using siRNA in immortalised non-cancerous breast epithelial MCF10A cells and HER2-positive breast cancer cells BT-474. Viability, apoptosis, cell proliferation rate, cell cycle phase distribution, and nuclear Ki-67 and p21, were assessed by flow cytometry. Cell cycle related gene expressions were analysed using real-time PCR. We found that SLC25A43 knockdown in MCF10A cells significantly inhibited cell cycle progression during G(1)-to-S transition, thus significantly reducing the proliferation rate and fraction of Ki-67 positive MCF10A cells. In contrast, suppressed SLC25A43 expression in BT-474 cells resulted in a significantly increased proliferation rate together with an enhanced G(1)-to-S transition. This was reflected by an increased fraction of Ki-67 positive cells and reduced level of nuclear p21. In line with our previous results, we show a role for SLC25A43 as a regulator of cell cycle progression and proliferation through a putative mitochondrial checkpoint. These novel data further strengthen the connection between mitochondrial function and the cell cycle, both in non-malignant and in cancer cells. (C) 2015 Elsevier Inc. All rights reserved.

  • 22.
    Ganowiak, Katarzyna
    et al.
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Hultman, Per
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Engström, Ulla
    Ludwig Institute of Cancer Research, Uppsala Branch, Uppsala, Sweden.
    Gustavsson, Åsa
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Westermark, Per
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Fibrils from Synthetic Amyloid-Related Peptides Enhance Development of Experimental AA-Amyloidosis in Mice1994In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 199, no 1, p. 306-312Article in journal (Refereed)
    Abstract [en]

    Amyloid enhancing factor is an incompletely characterized activity of extracts from many amyloid-containing tissues and which greatly shortens the preamyloidotic phase during experimental induction of AA-amyloidosis. In this communication we show that amyloid-like fibrils made in vitro from synthetic peptides, corresponding to segments of amyloid fibril proteins, have amyloid enhancing factor-like activity. Thus, there is a possibility that amyloid enhancing factor activity depends on small fibrils serving as nucleation centers for fibril elongation.

  • 23.
    Göransson, Anna-Lena
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology.
    Kanmert, Daniel
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology.
    Nilsson, K. Peter R.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Kågedal, Katarina
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology.
    Brorsson, Ann-Christin
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology.
    Identification of distinct physiochemical properties of the toxic prefibrillar species formed by Aβ peptide variants2012In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 420, no 4, p. 895-900Article in journal (Refereed)
    Abstract [en]

    The formation of amyloid-β peptide (Aβ) aggregates at an early stage during the self-assembly process is an important factor in the development of Alzheimer’s disease. The toxic effect is believed to be exerted by prefibrillar species of Aβ. It is therefore important to identify which prefibrillar species are toxic and characterize their distinct properties. In the present study, we investigated the in vitro aggregation behavior of Aβ-derived peptides possessing different levels of neurotoxic activity, using fluorescence spectroscopy in combination with transmission electron microscopy. The toxicity of various Aβ aggregates was assessed by using cultures of human neuroblastoma cells. Through combined use of the fluorescence probe 8-anilino-1-napthalenesulfonate (ANS) and the novel luminescent probe pentamer formyl thiophene acetic acid (p-FTAA), we were able to identify those Aβ peptide-derived prefibrillar species which exhibited cellular toxicity. In particular, species, which formed early during the aggregation process and showed strong p-FTAA and ANS fluorescence, were the species that possessed toxic activities. Moreover, by manipulating the aggregation conditions, it was possible to change the capacity of the Aβ peptide to form nontoxic versus toxic species.

  • 24.
    Hammarström, Per
    et al.
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biochemistry.
    Carlsson, Uno
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biochemistry.
    Is the unfolded state the Rosetta Stone of the protein folding problem?2000In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 276, no 2, p. 393-398Article in journal (Refereed)
    Abstract [en]

    Solving the protein folding problem is one of the most challenging tasks in the post genomic era. Identification of folding-initiation sites is very important in order to understand the protein folding mechanism. Detection of residual structure in unfolded proteins can yield important clues to the initiation sites in protein folding. A substantial number of studied proteins possess residual structure in hydrophobic regions clustered together in the protein core. These stable structures can work as seeds in the folding process. In addition, local preferences for secondary structure in the form of turns for ▀-sheet initiation and helical turns for a-helix formation can guide the folding reaction. In this respect the unfolded states, studied at increasing structural resolution, can be the Rosetta Stone of the protein folding problem. (C) 2000 Academic Press.

  • 25. Hansson, Anders
    et al.
    Zetterblad, Jenny
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology.
    van Duren, Cathelijne
    Axelson, Håkan
    Jönsson, Jan-Ingvar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology.
    The Lim-only protein LMO2 acts as a positive regulator of erythroid differentiation2007In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 364, no 3, p. 675-681Article in journal (Refereed)
    Abstract [en]

    LMO2, a member of the LIM-only protein family, is essential for the regulation of hematopoietic stem cells and formation of erythroid cells. It is found in a transcriptional complex comprising LMO2, TAL1, E47, GATA-1, and LDB1 which regulates erythroid genes. While TAL1 has been shown to induce erythroid differentiation, LMO2 appears to suppress fetal erythropoiesis. In addition to LMO2, the closely related LMO4 gene is expressed in hematopoietic cells, but has unknown functions. Here we demonstrate that LMO2 and LMO4 are expressed at the same level in erythroid colonies from mouse bone marrow, implying a function in erythroid differentiation. However, while LMO2 induced erythroid differentiation, LMO4 had no such effect. Interestingly, both LMO2 and TAL1 were able to partially suppress myeloid differentiation, implying that they activate erythroid differentiation in uncommitted bone marrow progenitors. Both LMO2 and LMO4 interacted strongly to LDB1, which was required for their localization to the nucleus. © 2007 Elsevier Inc. All rights reserved.

  • 26.
    Hasmats, Johanna
    et al.
    Science for Life Laboratory, School of Biotechnology, Division of Gene Technology, Royal Institute of Technology, Stockholm, Sweden.
    Green, Henrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Science for Life Laboratory, School of Biotechnology, Division of Gene Technology, Royal Institute of Technology, Stockholm, Sweden.
    Solnestam, Beata Werne
    Science for Life Laboratory, School of Biotechnology, Division of Gene Technology, Royal Institute of Technology, Stockholm, Sweden.
    Zajac, Pawel
    Laboratory for Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
    Huss, Mikael
    Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
    Orear, Cedric
    Genomics Unit, Institut Gustave Roussy, Villejuif, France.
    Validire, Pierre
    Department of Pathology, Institut Mutualiste Montsouris, Paris, France.
    Bjursell, Magnus
    AstraZeneca R&D, Mölndal, Sweden.
    Lundeberg, Joakim
    Science for Life Laboratory, School of Biotechnology, Division of Gene Technology, Royal Institute of Technology, Stockholm, Sweden.
    Validation of whole genome amplification for analysis of the p53 tumor suppressor gene in limited amounts of tumor samples.2012In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 425, no 2, p. 379-83Article in journal (Refereed)
    Abstract [en]

    Personalized cancer treatment requires molecular characterization of individual tumor biopsies. These samples are frequently only available in limited quantities hampering genomic analysis. Several whole genome amplification (WGA) protocols have been developed with reported varying representation of genomic regions post amplification. In this study we investigate region dropout using a φ29 polymerase based WGA approach. DNA from 123 lung cancers specimens and corresponding normal tissue were used and evaluated by Sanger sequencing of the p53 exons 5-8. To enable comparative analysis of this scarce material, WGA samples were compared with unamplified material using a pooling strategy of the 123 samples. In addition, a more detailed analysis of exon 7 amplicons were performed followed by extensive cloning and Sanger sequencing. Interestingly, by comparing data from the pooled samples to the individually sequenced exon 7, we demonstrate that mutations are more easily recovered from WGA pools and this was also supported by simulations of different sequencing coverage. Overall this data indicate a limited random loss of genomic regions supporting the use of whole genome amplification for genomic analysis.

  • 27.
    Helander, Sara
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Montecchio, Meri
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Lemak, Alexander
    Princess Margaret Cancer Centre and Department of Medical Biophysics, University of Toronto, Canada.
    Farès, Christophe
    Princess Margaret Cancer Centre and Department of Medical Biophysics, University of Toronto, Canada.
    Almlöf, Jonas
    Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Sweden.
    Li, Yanjun
    Structural Genomics Consortium, University of Toronto, Canada.
    Yee, Adelinda
    Princess Margaret Cancer Centre and Department of Medical Biophysics, University of Toronto, Canada.
    Arrowsmith, Cheryl H
    Princess Margaret Cancer Centre and Department of Medical Biophysics, University of Toronto, Canada.
    Dhe-Paganon, Sirano
    Structural Genomics Consortium, University of Toronto, Canada.
    Sunnerhagen, Maria
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Basic Tilted Helix Bundle - A new protein fold in human FKBP25/FKBP3 and HectD12014In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 447, no 1, p. 26-31Article in journal (Refereed)
    Abstract [en]

    In this paper, we describe the structure of a N-terminal domain motif in nuclear-localized FKBP251-73, a member of the FKBP family, together with the structure of a sequence-related subdomain of the E3 ubiquitin ligase HectD1 that we show belongs to the same fold. This motif adopts a compact 5-helix bundle which we name the Basic Tilted Helix Bundle (BTHB) domain. A positively charged surface patch, structurally centered around the tilted helix H4, is present in both FKBP25 and HectD1 and is conserved in both proteins, suggesting a conserved functional role. We provide detailed comparative analysis of the structures of the two proteins and their sequence similarities, and analysis of the interaction of the proposed FKBP25 binding protein YY1. We suggest that the basic motif in BTHB is involved in the observed DNA binding of FKBP25, and that the function of this domain can be affected by regulatory YY1 binding and/or interactions with adjacent domains.

  • 28.
    Holm, Åsa
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Tejle, Katarina
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Gunnarsson, T.
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Magnusson, Karl-Eric
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Descoteaux, A.
    INRS—Institut Armand-Frappier, Université du Québec, Laval, Qué., Canada.
    Rasmusson, Birgitta
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Role of protein kinase C α for uptake of unopsonized prey and phagosomal maturation in macrophages2003In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 302, no 4, p. 653-658Article in journal (Refereed)
    Abstract [en]

    Protein kinase C α (PKCα) participates in F-actin remodeling during phagocytosis and phagosomal maturation in macrophages. Leishmania donovani promastigotes, which inhibit phagosomal maturation, cause accumulation of periphagosomal F-actin instead of the dissassembly observed around other prey [Cell. Microbiol. 7 (2001) 439]. This accumulation is induced by promastigote lipophosphoglycan (LPG), which has several effects on macrophages including inhibition of PKCα. To investigate a possible connection between PKCα and LPG’s effects on actin dynamics, we utilized RAW264.7 macrophages overexpressing dominant-negative PKCα (DN PKCα). We found increased cortical F-actin and decreased phagocytic capacity, as well as defective periphagosomal F-actin breakdown and inhibited phagosomal maturation in the DN PKCα-overexpressing cells, effects similar to those seen in controls subjected to LPG-coated prey. The results indicate that PKCα is involved in F-actin turnover in macrophages and that PKCα-dependent breakdown of periphagosomal F-actin is required for phagosomal maturation, and endorse the hypothesis that intracellular survival of L. donovani involves inhibition of PKCα by LPG.

  • 29.
    Jiang, Kai
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Spyrou, Giannis
    Karolinska Institutet, Stockholm, Sweden.
    Rökaeus, Åke
    Karolinska Institutet, Stockholm, Sweden.
    Characterization of phorbolester-inducible human neuronal factors involved in trans-activation of the galanin gene1998In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 246, no 1, p. 192-198Article in journal (Refereed)
    Abstract [en]

    The expression of the neuropeptide galanin (GAL) is elevated in vivo upon nerve stimulation, injury, and in vitro by phorbol 12-myristate-13-acetate (PMA), suggesting that a signal pathway involving protein kinase C activation may be involved in GAL-gene activation. When plasmids containing a different length of the bovine GAL-promoter fused to luciferase were transfected into the human neuroblastoma cell line (SK-N-SH subclone SH-SY5Y), a PMA-responsive element was identified in the promoter-region -68 to -46 base pairs (bp). Co-transfection experiments with plasmids expressing cJun and cFos revealed that they could act alone, as well as synergistically with PMA to induce luciferase activity. Electrical mobility shift assays revealed that a cAMP response element (CRE)-like sequence (TGACGCGG; -59 to -52 bp) bound PMA-inducible nuclear proteins present in SH-SY5Y cells. These proteins appear to bind mainly as CRE-binding protein/activating-transcription-factor (CREB/ATF) and Jun/ATF heterodimers. In addition, an apparent PMA-inducible protein(s) not recognized by CREB/ATF and Jun antibodies bound to the CRE-like containing probe.

  • 30. Jostarndt, K
    et al.
    Gellert, N
    Rubic, T
    Weber, C
    Kuhn, H
    Johansen, B
    Hrboticky, N
    Neuzil, Jiri
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology .
    Dissociation of apoptosis induction and CD36 upregulation by enzymatically modified low-density lipoprotein in monocytic cells2002In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 290, no 3, p. 988-993Article in journal (Refereed)
    Abstract [en]

    Modified low-density lipoprotein (LDL) has been implicated as an initiating or amplifying factor in atherogenesis. Some of its biological activities, such as apoptosis induction and upregulation of the scavenger receptor CD36, appear to share common signaling pathways in cells of the cardiovascular system. Exposure of low-differentiated monocytic cells to LDL modified with 15-lipoxygenase and secretory phospholipase A(2) induced apoptosis and upregulated CD36. Cell treatment with constituents of modified LDL, such as 13-hydroxyoctadecadienoic acid (13-HODE), 25-hydroxycholesterol, and lysophosphatidyl choline, and with an unrelated apoptogen (TNF-related apoptosis-inducing ligand) induced apoptosis. In contrast, only 13-HODE caused upregulation of CD36 expression. Cotreatment with the pan-caspase inhibitor z.VAD-fmk resulted in suppression of apoptosis, but was without any effect on CD36 expression. These data indicate that in monocytic cells enzymatically modified LDL is capable of inducing both apoptosis and upregulation of CD36 expression. However, in our cellular model, the two induction processes appear to be causally unrelated. (C) 2002 Elsevier Science (USA).

  • 31.
    Jönsson, Maria
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology.
    Engström, Maria
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology.
    Jönsson, Jan-Ingvar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology.
    FLT3 ligand regulates apoptosis through AKT-dependent inactivation of transcription factor FoxO32004In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 318, no 4, p. 899-903Article in journal (Refereed)
    Abstract [en]

    Proliferation, differentiation, and survival of hematopoietic cells are regulated by cytokines, acting through specific receptors. FLT3 ligand (FL) is one of the most important cytokines for regulation of the hematopoietic system, and its receptor FLT3 is expressed on both stem cells and progenitors. Regulation of Forkhead transcription factors has been described as an important mechanism to control apoptosis and cell cycle progression in hematopoietic progenitors. Here we report that FL induces AKT/PKB activation, which in turn phosphorylates and thereby inactivates the Forkhead protein FoxO3 in the progenitor cell line FDC-P1 stably expressing murine FLT3 receptor. Phosphorylation of AKT and FoxO3 was blocked by the PI-3 kinase inhibitor LY294002 but not by the MAP kinase inhibitor PD98059. Expression of a mutated FoxO3, in which all three inhibitory phosphorylation sites were mutated to alanine, led to rapid increase of apoptotic cells in the presence of FL. These results suggest that FL-induced regulation of apoptosis is executed by FoxO3.

  • 32.
    Kalén, Anders
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Orthopaedics and Sports Medicine . Östergötlands Läns Landsting, Orthopaedic Centre, Department of Orthopaedics Linköping.
    Wahlström, Ola
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Orthopaedics and Sports Medicine . Östergötlands Läns Landsting, Orthopaedic Centre, Department of Orthopaedics Linköping.
    Linder, Cecilia
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    Magnusson, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    The content of bone morphogenetic proteins in platelets varies greatly between different platelet donors2008In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 375, no 2, p. 261-264Article in journal (Refereed)
    Abstract [en]

    Platelet derivates and platelet rich plasma have been used to stimulate bone formation and wound healing because of the rich content of potent growth factors. However, not all reports have been conclusive since some have not been able to demonstrate a positive effect. We investigated the interindividual variation of bone morphogenetic proteins (BMPs) in platelets from healthy donors, and the pH-dependent effect on the release of BMPs in preparations of lysed platelets in buffer (LPB). Platelet concentrates from 31 healthy donors were prepared in pH 4.3 and pH 7.4 buffers and investigated with respect to BMP-2, -4, -6, and -7. BMP-2 and BMP-4 were significantly more common in acidic LPBs in comparison with neutral preparations. We also observed a considerable variation among platelet donors with respect to the release of BMPs at pH 4.3 and 7.4. In conclusion, a considerable variation was found among platelet donors, which may be of importance considering the ambiguous results previously reported on osteoblast proliferation and differentiation. © 2008 Elsevier Inc. All rights reserved.

  • 33.
    Karlsson, Thommie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Lagerholm, Christoffer B.
    University of So Denmark, Denmark .
    Vikström, Elena
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Loitto, Vesa
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Magnusson, Karl-Eric
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Water fluxes through aquaporin-9 prime epithelial cells for rapid wound healing2013In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 430, no 3, p. 993-998Article in journal (Refereed)
    Abstract [en]

    Cells move along surfaces both as single cells and multi-cellular units. Recent research points toward pivotal roles for water flux through aquaporins (AQPs) in single cell migration. Their expression is known to facilitate this process by promoting rapid shape changes. However, little is known about the impact on migrating epithelial sheets during wound healing and epithelial renewal. Here, we investigate and compare the effects of AQP9 on single cell and epithelial sheet migration. To achieve this, MDCK-1 cells stably expressing AQP9 were subjected to migration assessment. We found that AQP9 facilitated cell locomotion at both the single and multi-cellular level. Furthermore, we identified major differences in the monolayer integrity and cell size upon expression of AQP9 during epithelial sheet migration, indicating a rapid volume-regulatory mechanism. We suggest a novel mechanism for epithelial wound healing based on AQP-induced swelling and expansion of the monolayer.

  • 34.
    Khotin, Mikhail
    et al.
    Russian Acadamy of Science.
    Turoverova, Lidia
    Russian Acadamy of Science.
    Aksenova, Vasilisa
    Russian Acadamy of Science.
    Barlev, Nikolai
    Russian Acadamy of Science.
    Borutinskaité, Veronika
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Microbiology . Linköping University, Faculty of Health Sciences.
    Vener, Alexander
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Bajenova, Olga
    St Petersburg State University.
    Magnusson, Karl-Eric
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Pinaev, George P.
    Russian Acadamy of Science.
    Tentler, Dmitri
    Russian Acadamy of Science.
    Proteomic analysis of ACTN4-interacting proteins reveals its a putative involvement in mRNA metabolism2010In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 397, no 2, p. 192-196Article in journal (Refereed)
    Abstract [en]

    Alpha-actinin 4 (ACTN4) is an actin-binding protein. In the cytoplasm, ACTN4 participates in structural organisation of the cytoskeleton via cross-linking of actin filaments. Nuclear localisation of ACTN4 has also been reported, but no clear role in the nucleus has been established. In this report, we describe the identification of proteins associated with ACTN4 in the nucleus. A combination of two-dimensional gel electrophoresis (2D-GE) and MALDI-TOF mass-spectrometry revealed a large number of ACTN4-bound proteins that are involved in various aspects of mRNA processing and transport. The association of ACTN4 with different ribonucleoproteins suggests that a major function of nuclear ACTN4 may be regulation of mRNA metabolism and signaling.

  • 35. Larsson, Annika
    et al.
    Söderberg, Linda
    Westermark, Gunilla
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology.
    Sletten, Knut
    Engström, Ulla
    Tjernberg, Lars O
    Näslund, Jan
    Westermark, Per
    Unwinding fibril formation of medin, the peptide of the most common form of human amyloid2007In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 361, no 4, p. 822-828Article in journal (Refereed)
    Abstract [en]

    Medin amyloid affects the medial layer of the thoracic aorta of most people above 50 years of age. The consequences of this amyloid are not completely known but the deposits may contribute to diseases such as thoracic aortic aneurysm and dissection or to the general diminished elasticity of blood vessels seen in elderly people. We show that the 50-amino acid residue peptide medin forms amyloid-like fibrils in vitro. With the use of Congo red staining, Thioflavin T fluorescence, electron microscopy, and a solid-phase binding assay on different synthetic peptides, we identified the last 18-19 amino acid residues to constitute the amyloid-promoting region of medin. We also demonstrate that the two C-terminal phenylalanines, previously suggested to be of importance for amyloid formation, are not required for medin amyloid formation.

  • 36.
    Laskar, Amit
    et al.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Eilertsen, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Li, Wei
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Yuan, Xi-Ming
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Occupational and Environmental Medicine Center.
    SPION primes THP1 derived M2 macrophages towards M1-like macrophages2013In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 441, no 4, p. 737-742Article in journal (Refereed)
    Abstract [en]

    Potentially, cellular iron regulates functional plasticity in macrophages yet; interaction of functionally polarized macrophages with iron-oxide nanoparticles has never been studied. We found that monocyte differentiation alters cellular ferritin and cathepsin L levels and induces functional polarization in macrophages. Iron in super paramagnetic iron-oxide nanoparticle (SPION) induces a phenotypic shift in THP1 derived M2 macrophages towards a high CD86+ macrophage subtype. This phenotypic shift was accompanied by up-regulated intracellular levels of ferritin and cathepsin L in M2 macrophages, which we found as a characteristic hallmark of M1 macrophages. Atherogenic oxysterols reduce phagocytic activity in both macrophage subtypes and thus these cells may escape detection by ironoxide nanoparticles (INPs) in-vivo.

  • 37.
    Li, Wei
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Ghosh, Moumita
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Eftekhari, Sina
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Yuan, Ximing
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Lipid accumulation and lysosomal pathways contribute to dysfunction and apoptosis of human endothelial cells caused by 7-oxysterols2011In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 409, no 4, p. 711-716Article in journal (Refereed)
    Abstract [en]

    Endothelial dysfunction and cell death play an important role in pathogenesis of atherosclerosis. 7-Oxysterols, the major cytotoxic component found in oxidized low-density lipoprotein, are toxic to endothelial cells. However, the pathways and molecular mechanism involved in the process remain incompletely understood. In this study, we first investigate whether 7 beta-hydroxycholesterol (7 beta OH) or 7-ketocholesterol (7keto) induces apoptosis of human endothelial cell line (HUVEC-CS). We then examine possible involved pathways by focusing on cellular lipid, lysosomal pathways, cellular oxidative stress and mitochondrial pathways. Our results for the first time showed that 7-oxysterols induced apoptotic cell death of HUVEC-CS after 24 h, which was preceded by early lipid accumulation (6 h) and lysosomal membrane permeabilization (6-12 h). Afterward, levels of reactive oxygen species, mitochondrial membrane permeabilization, and lysosomal cathepsin were increased assayed by immuno-cytochemistry and blotting. Notably, the exposure to 7 beta OH or 7keto induced expressions and secretion of isoforms of von Willebrand factor (VWF). We conclude that apoptosis of HUVEC-CS induced by 7 beta OH or 7keto mediates by early lysosomal lipid accumulation and oxidative lysosomal pathways, which results in induction and release of VWF. The results suggest the cell death induced by 7-oxysterols may contribute to endothelial dysfunction and atherothrombosis.

  • 38.
    Lofti, Kourosh
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology.
    Månsson, Emma
    Stockholm.
    Peterson, Curt
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology.
    Eriksson, Staffan
    Uppsala.
    Low level of mitochondrical deoxyguanosine kinase is the dominant factor in acquired resistance to 9- -D-arabinofuranosylguanine cytotoxicity2002In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 293, p. 1489-1496Article in journal (Refereed)
  • 39.
    Loitto, Vesa
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology.
    Magnusson, Karl-Eric
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology.
    Hg2+ and small-sized polyethylene glycols have inverse effects on membrane permeability, while both impair neutrophil cell motility2004In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 316, no 2, p. 370-378Article in journal (Refereed)
    Abstract [en]

    Toxic effects after exposure to mercury are well documented in human. Little is, however, known about how Hg2+ affect host defense in general and neutrophil functions in particular. We show here that exposure of human neutrophils to HgCl2 dose-dependently impairs chemoattractant-stimulated motility. Long-term exposure (5-10min) to Hg 2+ yields a rapid influx of extracellular Ca2+ followed by leakage of cytosolic fluorophores, as assessed using fura-2 and ratio imaging microscopy. The inhibition on motility was partly reversible, since pre-treated neutrophils placed in an Hg2+-free environment displayed higher migration rates. The Hg2+-induced fluxes were prevented by addition of small-sized polyethylene glycols (PEG 200-400), which also dose-dependently inhibited neutrophil transmigration. Localized, minute micropipette additions of Hg2+ or PEG caused retraction of the leading edge and redirection of cell migration. Since Hg2+ increases and PEGs decrease membrane permeability in a partially competitive manner, we suggest that the known aquaporin-inhibitor Hg2+ alters membrane permeability by affecting the bidirectional flux through the leukocyte aquaporin-9 (AQP9) while small-sized PEGs yield decreased membrane permeability by becoming trapped in the promiscuous channel. The local additions of Hg 2+ or PEG probably force other cell regions to take over from those with blocked AQPs. Hence, the cells turn direction of motility away from the micromanipulator needle.

  • 40.
    Luo, Liman
    et al.
    Peking University, Peoples R China .
    Liu, Die
    Peking University, Peoples R China .
    Tang, Chaoshu
    Peking University, Peoples R China .
    Du, Junbao
    Peking University, Peoples R China .
    Dong Liu, Angie
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Health Sciences.
    Holmberg, Lukas
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Health Sciences.
    Jin, Hongfang
    Peking University, Peoples R China .
    Sulfur dioxide upregulates the inhibited endogenous hydrogen sulfide pathway in rats with pulmonary hypertension induced by high pulmonary blood flow2013In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 433, no 4, p. 519-525Article in journal (Refereed)
    Abstract [en]

    Pulmonary hypertension (PH) is an important pathophysiological process in the development of many diseases. However, the mechanism responsible for the development of PH remains unknown. The objective of the study was to explore the possible impact of sulfur dioxide (SO2) on the endogenous hydrogen sulfide (H2S) pathway in rats with PH induced by high pulmonary blood flow. Compared with sham group, the systolic pulmonary artery pressure (SPAP) in the shunt group was significantly increased, along with the increased percentage of muscularized arteries and partially muscularized arteries of small pulmonary arteries. Compared with the shunt group, SPAP in the shunt + SO2 group was significantly decreased, and the percentage of muscularized pulmonary arteries was also decreased. Additionally, rats that developed PH had significantly lower levels of SO2 concentration, aspartate aminotransferase (AAT) activity, protein and mRNA expressions of AAT2 in pulmonary tissues. Administration of an SO2 donor could alleviate the elevated pulmonary arterial pressure and decrease the muscularization of pulmonary arteries. At the same time, it increased the H2S production, protein expression of cystathionine-gamma-lyase (CSE), mRNA expression of CSE, mercaptopyruvate transsulphurase (MPST) and cystathionine-beta-synthase (CBS) in the pulmonary tissue of the rats. The results suggested that endogenous SO2/AAT2 pathway and the endognous H2S production were downregulated in rats with PH induced by high pulmonary blood flow. However, SO2 could reduce pulmonary arterial pressure and improve the pulmonary vascular pathological changes in association with upregulating endogenous H2S pathway.

  • 41. Löfgren, C
    et al.
    Hjortsberg, L
    Blennow, M
    Lotfi, Kourosh
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology.
    Paul, C
    Eriksson, S
    Albertioni, F
    Mechanisms of cross-resistance between nucleoside analogues and vincristine or daunorubicin in leukemic cells2004In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 320, no 3, p. 825-832Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to clarify the biochemical and molecular mechanisms behind the cross-resistance to nucleoside analogues (Nas) in four erythroleukemic cell lines with acquired resistance to the anthracycline daunorubicin and to the vinca alkaloid vincristine, expressing high levels of p-glycoprotein (P-gp, MDR1). All resistant strains exhibited cross-resistance to NA (cladribine and cytosine arabinoside) -induced apoptosis, assessed by caspase-3-like activation and were less sensitive to NA cytotoxicity in MTT assay. Real-time PCR and enzyme activity analysis showed reduced amounts of deoxycytidine kinase (35-80%) and elevated levels of 5′- nucleotidases (50-100%). The ratio 5′-nucleotidase to deoxycytidine kinase increased between 2.5- and 7.5-folds in resistant cells. This is in agreement with the observation that 5′-nucleotidase/ deoxycytidine kinase ratio might be an important factor in predicting resistance to Nas. Implications of this finding for combining anthracyclines or vinca alkaloids with Nas toward leukemic cells are discussed.

  • 42.
    Mi, Yushuai
    et al.
    Shanghai Jiao Tong University, Peoples R China.
    Zhao, Senlin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Shanghai Jiao Tong University, Peoples R China.
    Zhang, Weihao
    Shanghai Jiao Tong University, Peoples R China.
    Zhang, Dongyuan
    Shanghai Jiao Tong University, Peoples R China.
    Weng, Junyong
    Shanghai Jiao Tong University, Peoples R China.
    Huang, Kejian
    Shanghai Jiao Tong University, Peoples R China.
    Sun, Huimin
    Shanghai Jiao Tong University, Peoples R China.
    Tang, Huamei
    Shanghai Jiao Tong University, Peoples R China.
    Zhang, Xin
    Zhejiang Prov Peoples Hospital, Peoples R China.
    Sun, Xiao-Feng
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Peng, Zhihai
    Shanghai Jiao Tong University, Peoples R China.
    Wen, Yugang
    Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Shanghai Jiao Tong University, Peoples R China.
    Down-regulation of Barx2 predicts poor survival in colorectal cancer2016In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 478, no 1, p. 67-73Article in journal (Refereed)
    Abstract [en]

    Human BarH-like homeobox 2 (Barx2), a homeodomain factor of the Bar family, has an important role in controlling the expression of cell adhesion molecules and has been reported in an increasing array of tumor types except colorectal cancer (CRC). The purpose of the current study was to characterize the expression of Barx2 and assess the clinical significance of Barx2 in CRC. First, we analyzed the expression of Barx2 in two independent public datasets from Oncomine. Subsequently, we evaluated Barx2 mRNA and protein expression by quantitative real-time PCR and western blotting, respectively. It was determined that Barx2 expression was lower in tumor tissues than in adjacent non-tumorous colorectal tissues of CRC patients, consistent with results from the public datasets. Subsequently, a tissue microarray containing 196 CRC specimens was evaluated for Barx2 expression by immunohistochemical staining. It was found that low expression of Barx2 significantly correlated with TNM stage, AJCC stage, differentiation, and relapse in patients with CRC. Patients with lower levels of Barx2 expression showed reduced disease-free survival and overall survival. Furthermore, a trend toward shorter overall survival in the patient group with Barx2-negative tumors independent of advanced AJCC stage and poor differentiation was determined by Kaplan-Meier survival analysis. Based on univariate and multivariate analyses, Barx2 expression was an independent prognostic factor for determining CRC prognosis. Taken together, low Barx2 expression was associated with the progression of CRC and could serve as a potential independent prognostic biomarker for patients with CRC. (C) 2016 The Authors. Published by Elsevier Inc.

  • 43.
    Miranda-Vizuete, A
    et al.
    Karolinska Institute, Huddinge, Sweden.
    Gustafsson, Jan-.Åke
    Karolinska Institute, Huddinge, Sweden.
    Spyrou, Giannis
    Karolinska Institute, Huddinge, Sweden.
    Molecular cloning and expression of a cDNA encoding a human thioredoxin-like protein1998In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 243, no 1, p. 284-288Article in journal (Refereed)
    Abstract [en]

    This report describes the cloning of a human cDNA that encodes a new protein (Txl, Thioredoxin-like) that belongs to the expanding family of thioredoxins based on sequence comparison of the deduced amino acid sequence. This cDNA, with a total length of 1,278 bp, consists of 205 bp of 5'-untranslated sequence (including an in frame stop codon), an open reading frame of 870 bp and a 203 bp fragment of 3'-untranslated sequence. The coding sequence predicts a protein of 289 amino acids with two distinct domains: an N-terminal domain of 105 residues homologous to the rest of mammalian thioredoxins containing the conserved active site (CGPC) and a C-terminal domain of 184 residues with no homology with any other protein in the database. Northern blot analysis indicates that the txl probe hybridizes to a 1.3 Kb mRNA and is ubiquitously expressed in human tissues with the highest expression in stomach, testis and bone marrow.

  • 44.
    Monstein, Hans-Jurg
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of health and environment.
    Jonasson, Jon
    Linköping University, Faculty of Health Sciences. Linköping University, Department of health and environment. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Microbiology.
    Differential virulence-gene mRNA expression in coccoid forms of Helicobacter pylori2001In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 285, no 2, p. 530-536Article in journal (Refereed)
    Abstract [en]

    Controversy exists whether coccoid forms of Helicobacter pylori maintain transcriptional and translational processes. The aim of the present study was to investigate mRNA levels in coccoid H. pylori and, if possible, to establish a correlation with the state of nonrandom fragmentation of rRNA in those cells. For that purpose, UreA, UreI, CagA, VacA, SodB, and Hsp60 mRNA levels in bacillary and coccoid forms of H. pylori CCUG 17874T, H. pylori 26695, and H. pylori J99, respectively, were studied by means of a multiplex reverse-transcription PCR assay and Southern blot analysis of the RT-PCR-amplified products. Nonrandom fragmentation of 23S rRNA was assessed by a recently described assay. Virulence-gene-derived mRNA transcripts were visualized in DNase I-treated RNA preparations. All three strains revealed the presence of different mRNA patterns in bacillary and coccoid forms. Putative promoter sequences similar to the consensus Escherichia coli -10 hexamer TATAAA box were present in all six virulence genes analyzed. Moreover, the decrease seen in mRNA levels during conversion into the coccoid form appeared to correlate with the 23S rRNA nonrandom fragmentation pattern. The present data indicate that modulation of virulence-gene expression is differently regulated in bacillary and coccoid H. pylori.

  • 45.
    Neuzil, Jiri
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    a-tocopheryl succinate epitomizes a compound with a shift in biological activity due to pro-vitamin-to-vitamin conversion2002In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 293, no 5, p. 1309-1313Article in journal (Refereed)
    Abstract [en]

    With the advent of the third millennium, a number of pathologies have been eradicated or taken under control. However, the incidences of cancer and atherosclerosis, the two most common causes of death in developed countries, have increased or, in some instances, only stagnated. Therefore there has been an intensive search for agents effective against such life-threatening conditions. Accordingly, the potential anti-atherogenic activity of vitamin E analogs has been studied extensively. Interestingly, recent reports strongly suggest that certain vitamin E analogs, represented in particular by a-tocopheryl succinate (a-TOS), also possess anti-neoplastic activity. In this communication, we review our current understanding of the molecular basis for these double effects of a-TOS and propose a testable hypothesis, according to which this semi-synthetic analog exerts both anti-atherogenic and anti-neoplastic activities. We propose that the prevalence of each activity depends on the actual form of the vitamin E analog. That is, the conversion of the pro-vitamin E form, a-TOS, to the corresponding vitamin form, a-tocopherol, makes this anti-neoplastic agent active against inflammatory diseases like atherosclerosis. ⌐ 2002 Elsevier Science (USA). All rights reserved.

  • 46.
    Nikitovic, D.
    et al.
    Department of Medical Biochemistry and Biophysics, Karolinska Institute, Sweden.
    Holmgren, A.
    Department of Medical Biochemistry and Biophysics, Karolinska Institute, Sweden.
    Spyrou, Giannis
    Department of Biosciences at Novum, Karolinska Institute, Huddinge, Sweden.
    Inhibition of AP-1 DNA binding by nitric oxide involving conserved cysteine residues in Jun and Fos1998In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 242, no 1, p. 109-112Article in journal (Refereed)
    Abstract [en]

    Nitric oxide (NO), which has diverse biological effects, can modulate AP-1 activity. Since DNA binding of Jun-Jun and Jun-Fos dimers is regulated in vitro by redox control involving conserved cysteines, we hypothesized that the action of NO is mediated via these residues. We performed electrophoretic mobility-shift analyses using Jun and Fos recombinant proteins and NO solutions. Cysteine-to-serine mutants showed that the inhibition of AP-1 activity following NO treatment was dependent on the presence of Cys7272 and Cys154 in the DNA binding domain of Jun and Fos, respectively. The inhibitory effect of NO was reversed by DTT and the thioredoxin system. Our results demonstrate that NO mediates its inhibitory effect by reacting specifically with the conserved cysteine residues in Jun and Fos.

  • 47.
    Patlaka, Christina
    et al.
    Karolinska University, Sweden.
    Anh Mai, Hong
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Lang, Pernilla
    Karolinska University, Sweden.
    Andersson, Goeran
    Karolinska University, Sweden.
    The growth factor-like adipokine tartrate-resistant acid phosphatase 5a interacts with the rod G3 domain of adipocyte-produced nidogen-22014In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 454, no 3, p. 446-452Article in journal (Refereed)
    Abstract [en]

    The adipoldne tartrate resistant acid phosphatase (TRAP) 5a isoform exerts a growth factor-effect on pre-adipocytes. This study aimed to identify potential TRAP 5a interacting proteins in pre-adipocytes using pull down assays in combination with mass spectrometry. Nidogen-2, a protein shown to be expressed intracellularly and for secretion by pre-adipocytes, was shown to interact, through its globular G3 domain, with TRAP 5a in vitro. In vivo, TRAP 5a interacted with nidogen-2 in cultured 3T3-L1 mouse pre-adipocytes, as well as with transforming growth factor-beta (TGF-beta) interacting protein (TRIP-1), which is a protein that has previously been suggested to interact with TRAP in bone. In addition, TRAP 5a and nidogen-2 co-localized in adipose tissue cells in situ. These results indicate that TRAP 5a interacts with nidogen-2 and TRIP-1 in pre-adipocytic cells.

  • 48.
    Pursglove, SE
    et al.
    Karolinska Institutet.
    Fladvad, M
    Karolinska Institutet.
    Bellanda, M
    University of Padova.
    Moshref, A
    Karolinska Institutet.
    Henriksson, M
    Karolinska Institutet.
    Carey, J
    Princeton University.
    Sunnerhagen, Maria
    Karolinska Institutet.
    Biophysical properties of regions flanking the bHLH-Zip motif in the p22 Max protein2004In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 323, no 3, p. 750-759Article in journal (Refereed)
    Abstract [en]

    The Max protein is the central dimerization partner in the Myc-Max-Mad network of transcriptional regulators, and a founding structural member of the family of basic-helix-loop-helix (bHLH)-leucine zipper (Zip) proteins. Biologically important regions flanking its bHLH-Zip motif have been disordered or absent in crystal structures. The present study shows that these regions are resistant to proteolysis in both the presence and absence of DNA, and that Max dimers containing both flanking regions have significantly higher helix content as measured by circular dichroism than that predicted from the crystal structures. Nuclear magnetic resonance measurements in the absence of DNA also support the inferred structural order. Deletion of both flanking regions is required to achieve maximal DNA affinity as measured by EMSA. Thus, the previously observed functionalities of these Max regions in DNA binding, phosphorylation, and apoptosis are suggested to be linked to structural properties.

  • 49.
    Samarin, Stanislav N.
    et al.
    Epithelial Pathobiology Research Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA.
    Koch, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Epithelial Pathobiology Research Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA.
    Ivanov, Andrei I.
    Department of Medicine, University of Rochester, Rochester, NY, USA.
    Parkos, Charles A.
    Epithelial Pathobiology Research Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA.
    Nusrat, Asma
    Epithelial Pathobiology Research Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA.
    Coronin 1C negatively regulates cell-matrix adhesion and motility of intestinal epithelial cells2010In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 391, no 1, p. 394-400Article in journal (Refereed)
    Abstract [en]

    Coronins, WD-repeat actin-binding proteins, are known to regulate cell motility by coordinating actin filament turnover in lamellipodia of migrating cell. Here we report a novel mechanism of Coronin 1C-mediated cell motility that involves regulation of cell-matrix adhesion. RNAi silencing of Coronin 1C in intestinal epithelial cells enhanced cell migration and modulated lamellipodia dynamics by increasing the persistence of lamellipodial protrusion. Coronin 1C-depleted cells showed increased cell-matrix adhesions and enhanced cell spreading compared to control cells, while over-expression of Coronin 1C antagonized cell adhesion and spreading. Enhanced cell-matrix adhesion of coronin-deficient cells correlated with hyperphosphorylation of focal adhesion kinase (FAK) and paxillin, and an increase in number of focal adhesions and their redistribution at the cell periphery. siRNA depletion of FAK in coronin-deficient cells rescued the effects of Coronin 1C depletion on motility, cell-matrix adhesion, and spreading. Thus, our findings provide the first evidence that Coronin 1C negatively regulates epithelial cell migration via FAK-mediated inhibition of cell-matrix adhesion.

  • 50.
    Sheikine, Yuri
    et al.
    Karolinska University Hospital Solna.
    Deodato, Barbara
    Karolinska University Hospital Solna.
    Olofsson, Peder S.
    Karolinska University Hospital Solna.
    Soderstrom, Leif A.
    Karolinska University Hospital Solna.
    Lundberg, Anna M.
    Karolinska University Hospital Solna.
    Bodin, Inger
    Karolinska University Hospital Solna.
    Rudling, Mats
    Karolinska University Hospital.
    Theodorsson, Elvar
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    Hansson, Goran K.
    Karolinska University Hospital Solna.
    Activation of VPAC(1) receptors aggravates early atherosclerosis in hypercholesterolemic apolipoprotein E-deficient mice2010In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 402, no 3, p. 471-476Article in journal (Refereed)
    Abstract [en]

    Objective Vasoactive intestinal peptide (VIP) is a 28-amino acid peptide widely expressed in the body and binding three types of receptors VPAC(1)-R, VPAC(2)-R and PAC(1)-R Based on beneficial effects of VIP and VPAC(1)-R agonists in mouse models of several chronic inflammatory disorders, we hypothesized that activation of VIP receptors would prevent atherosclerosis development in apolipoprotein E-deficient mice Methods and results Contrary to our hypothesis, administration of a VPAC(1)-R agonist. (Ala(11 22,28))-VIP aggravated atherosclerotic lesion development in the aortic root of these mice compared to control mice This was accompanied by a significant Increase in the expression of MHC class II protein I-A(b), and suggests enhanced inflammatory activity in the vessel wall The amount of macrophage-specific CD68 staining as well as serum cholesterol and triglyceride levels did not change as a result of the (Ala(11 22,28))-VIP treatment, i e the treatment resulted in significant changes in lipid accumulation in the lesions without changing the number of macrophages or systemic lipid levels Interestingly, administration of VIP did not alter the course of the disease. Conclusion: Despite beneficial effects in murine models of several inflammatory disorders, VPAC(1)-R activation aggravates atherosclerotic lesion formation in apolipoprotein E-deficient mice through enhanced inflammatory activity in the vessel wall

12 1 - 50 of 74
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