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  • 301.
    Söderström, Mats
    et al.
    Stockholm University, Sweden.
    Bolling, Anders
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Hammarström, Sven
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Induction of leukotriene C4 synthase activity in differentiating human erythroleukemia cells1992In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 189, no 2, p. 1043-1049Article in journal (Refereed)
    Abstract [en]

    Leukotriene (LT)C4 synthase is a membrane-bound, specific glutathione transferase which catalyzes the transformation of LTA4 to LTC4. It was originally shown to be present in rodent mastocytoma and basophilic leukemia cells as well as in macrophages. Recently, expression of human LTC4 synthase was demonstrated in platelets (Söderström, M., et al. (1992) Arch. Biochem. Biophys. 294, 70-74). The present report describes the induction of LTC4 synthase activity during differentiation of human erythroleukemia (HEL) cells by the protein kinase C stimulator 12-O-tetradecanoyl phorbol 13-acetate (TPA), ligands of the steroid-thyroid hormone receptor superfamily: all-trans-retinoic acid (RA) and 1 alpha, 25-dihydroxy-vitamin D3 and in addition dimethylsulfoxide (DMSO). TPA was the most powerful inducer of enzyme activity followed by 1 alpha, 25-dihydroxy-vitamin D3 and DMSO. RA did not induce LTC4 synthase activity.

  • 302.
    Söderström, Mats
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Engblom, David
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Blomqvist, Anders
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Hammarström, Sven
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Expression of leukotriene C4 synthase mRNA by the choroid plexus in mouse brain suggests novel neurohormone functions of cysteinyl leukotrienes2003In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 307, no 4, p. 987-990Article in journal (Refereed)
    Abstract [en]

    Leukotriene C4 is a potent mediator of allergic and inflammatory reactions, and is formed from arachidonic acid and glutathione through the sequential action of 5-lipoxygenase and leukotriene C4 synthase (LTCS). These enzymes are predominantly expressed in cells of myeloid lineage. In this report, we have investigated LTCS mRNA expression in mouse brain. Expression was demonstrated using RT-PCR and RNase protection assays. In situ hybridization experiments showed exclusive staining of the choroid plexus of all brain ventricles. This expression pattern may provide a mechanism for the generation of LTC4 on the cerebral side of the blood-brain barrier and suggests a possible novel regulator function of LTC4 in the formation of cerebrospinal fluid.

  • 303.
    Söderström, Mats
    et al.
    Department of Biochemistry, Arrhenius Laboratory, University of Stockholm, Sweden.
    Hammarström, Sven
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Mannervik, Bengt
    Department of Biochemistry, Arrhenius Laboratory, University of Stockholm, Sweden.
    Leukotriene C synthase in mouse mastocytoma cells. An enzyme distinct from cytosolic and microsomal glutathione transferases1988In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 250, no 3, p. 713-718Article in journal (Refereed)
    Abstract [en]

    Leukotriene C4 synthesis was studied in preparations from mouse mastocytoma cells. Enzymic conjugation of leukotriene A4 with glutathione was catalysed by both the cytosol and the microsomal fraction. The specific activity of the microsomal fraction (7.8 nmol/min per mg of protein) was 17 times that of the cytosol fraction. The cytosol fraction of the mastocytoma cells contained two glutathione transferases, which were purified to homogeneity and characterized. A microsomal glutathione transferase was purified from mouse liver; this enzyme was shown by immunoblot analysis to be present in the mastocytoma microsomal fraction at a concentration one-tenth or less of that in the liver microsomal fraction. Both the cytosolic and the microsomal glutathione transferases in the mastocytoma cells were identified with enzymes previously characterized, by determining specific activities with various substrates, sensitivities to inhibitors, reactions with antibodies, and physical properties. The purified microsomal glutathione transferase from liver was inactive with leukotriene A4 or its methyl ester as substrate. The cytosolic enzymes displayed activity with leukotriene A4, but their specific activities and intracellular concentrations were too low to account for the leukotriene C4 formation in the mastocytoma cells. The microsomal fraction of the cells contained an enzyme distinguishable by various criteria from the previously studied glutathione transferases. This membrane-bound enzyme, leukotriene C synthase (leukotriene A4:glutathione S-leukotrienyltransferase), appears to carry the main responsibility for the biosynthesis of leukotriene C4.

  • 304.
    Söderström, Mats
    et al.
    Wallenberg Laboratory, Stockholm University, Sweden.
    Mannervik, Bengt
    Uppsala University, Sweden.
    Garkov, Vladimir
    Pennsylvania State University, USA.
    Hammarström, Sven
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    On the nature of leukotriene C4 synthase in human platelets1992In: Archives of Biochemistry and Biophysics, ISSN 0003-9861, E-ISSN 1096-0384, Vol. 294, no 1, p. 70-74Article in journal (Refereed)
    Abstract [en]

    Leukotriene C4 is considered to play a major role in several important pathophysiological conditions, e.g., allergy, asthma, and shock. The present investigation demonstrates the presence in human platelets of a membrane-associated enzyme catalyzing the final step in the biosynthesis of leukotriene C4. This leukotriene C4 synthase was shown to be distinct from previously characterized "microsomal" and soluble glutathione transferases. The latter enzymes did not contribute significantly to the leukotriene A4 conjugating activity in platelets. As determined with leukotriene C4 synthase of a crude membrane fraction from human platelets, the Km value was 7 microM and the V value was 0.56 nmol x min-1 x mg-1 with leukotriene A4 as substrate. The enzyme was 20-fold more efficient with leukotriene A4 than with leukotriene A5 and 30-fold more efficient than with the unphysiological derivative leukotriene A4 methyl ester, as measured by the corresponding V/Km values; 14,15-leukotriene A4 was not a substrate. Platelets should be a useful source for the purification and further characterization of human leukotriene C4 synthase.

  • 305.
    Söderström, Mats
    et al.
    Stockholm University, Sweden.
    Mannervik, Bengt
    Uppsala University, Sweden.
    Hammarström, Sven
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Leukotriene C4 synthase: characterization in mouse mastocytoma cells1990In: Methods in Enzymology, ISSN 0076-6879, E-ISSN 1557-7988, Vol. 187, p. 306-312Article in journal (Refereed)
    Abstract [en]

    The chapter presents a study on leukotriene C4 (LTC4) synthase, discussing the characterization in mouse mastocytoma cells. LTC4 is formed by conjugation of leukotriene A4 (LTA4) with glutathione (GSH). In biological systems, the reaction is catalyzed by a membrane-bound enzyme, leukotriene C4 synthase (EC 2.5.1.37). Cytosolic glutathione transferases, in particular, members of the class Mu, have been shown to catalyze formation of LTC4.The most efficient isoenzymes are transferase 6-6 isolated from rat brain, transferase 4-4 from rat liver, and transferase μ from human liver. The name leukotriene C4 synthase, used for the enzyme described in this chapter, has been adopted to distinguish the enzyme from the above glutathione transferases, which display broad substrate specificity. Reports from three groups of investigators have shown that LTC4 formation in rat basophilic leukemia cells is catalyzed by a membrane-bound enzyme. Leukotriene C4 synthase activity has been described and an enzyme partially purified from the microsomal fraction of guinea pig lung. The formation of LTC4 is especially high in mouse mastocytoma cells, the source from which LTC4 was first isolated. The partial purification of leukotriene C4 synthase from this source is described in the chapter.

  • 306.
    Söderström, Mats
    et al.
    Wallenberg Laboratory, Stockholm University, Sweden.
    Morgenstern, Ralf
    Karolinska Institute, Stockholm, Sweden.
    Hammarström, Sven
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Protein-protein interaction affinity chromatography of leukotriene C4 synthase1995In: Protein Expression and Purification, ISSN 1046-5928, E-ISSN 1096-0279, Vol. 6, no 3, p. 352-356Article in journal (Refereed)
    Abstract [en]

    A novel affinity chromatography purification for human leukotriene C4 synthase is described. It is based on a specific interaction between leukotriene C4 synthase and microsomal glutathione S-transferase which occurs in the presence of magnesium ion. Microsomal glutathione S-transferase was immobilized on NHS-activated Sepharose 4B and used as an affinity matrix. Microsomes from 12-O-tetradecanoyl phorbol 13-acetate-treated human erythroleukemia cells were solubilized with taurocholic acid and applied on the affinity matrix at 0.1 M Mg2+ concentration. After washing with a buffer containing Mg2+, the enzyme was eluted with a glutathione-containing buffer lacking Mg2+. This facile one-step procedure gave a 166-fold purification of leukotriene C4 synthase with a yield of 44%. Analyses of proteins specifically adsorbed to the affinity matrix revealed components with apparent molecular weights of 18, 37, 48, and 60 kDa.

  • 307.
    Söderström, Mats
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Wigren, Jane
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Surapureddi, Sailesh
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Glass, Christopher K
    University of California, San Diego, La Jolla, CA , USA.
    Hammarström, Sven
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Novel prostaglandin D2-derived activators of peroxisome proliferator-activated receptor-γ are formed in macrophage cell cultures2003In: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 1631, no 1, p. 35-41Article in journal (Refereed)
    Abstract [en]

    Incubation of RAW 264.7 murine macrophages with 9,15-dihydroxy-11-oxo-, (5Z,9alpha,13E,15(S))-Prosta-5,13-dien-1-oic acid [prostaglandin D(2) (PGD(2))] induced formation of considerable peroxisome proliferator-activated receptor-gamma (PPARgamma) activity [Nature 391 (1998) 79]. Because PGD(2) itself is a poor PPARgamma ligand, we incubated RAW 264.7 macrophage cultures with prostaglandin D(2) for 24 h and studied the ability of the metabolites formed to activate PPARgamma. PGD(2) products were extracted and fractionated by reverse phase high-performance liquid chromatography. Chemical identification was achieved by UV spectroscopy, gas-liquid chromatography/mass spectrometry and chemical syntheses of reference compounds. PGD(2) was converted to eight products, six of which were identified. Ligand-induced interaction of PPARgamma with steroid receptor coactivator-1 was determined by glutathione-S-transferase pull-down assays and PPARgamma activation was investigated by transient transfection of RAW 264.7 macrophages. In addition to the previously known ligand 11-oxo-(5Z,9,12E,14Z)-Prosta-5,9,12,14-tetraen-1-oic acid (15-deoxy-delta(12,14)-PGJ(2)), a novel PPARgamma ligand and activator viz. 9-hydroxy-11-oxo-, (5Z,9alpha,12E,14Z)-Prosta-5,12,14-trien-1-oic acid (15-deoxy-delta(12,14)-PGD(2)) was identified. The biological significance of these results is currently under investigation.

  • 308. Taniguchi, Kazuya
    et al.
    Kaya, Shunji
    Abe, Kazuhiro
    Mårdh, Sven
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    The oligomeric nature of Na/K-transport ATPase2001In: Journal of Biochemistry (Tokyo), ISSN 0021-924X, E-ISSN 1756-2651, Vol. 129, no 3, p. 335-342Article in journal (Refereed)
    Abstract [en]

    Since the discovery of Na/K-ATPase, evidence has accumulated to suggest that 1 mol of ATP hydrolysis occurs via the Na+-occluded ADP-sensitive phosphoenzyme, the K+-sensitive phosphoenzyme and the K+-occluded enzyme accompanying active transport of 3Na+ and 2K+ according the Post-Albers scheme. However, some controversial issues have arisen concerning whether the functional unit of the enzyme is an a▀-protomer or a much higher oligomer, which would be related to the mechanism of transport, either sequential or simultaneous. Detailed studies of oligomer interaction and the reactivity of the enzyme and a comparison of the extent of phosphorylation with ligand-binding capacities in the presence or absence of ATP hydrolysis and others strongly suggest that the functional unit of the enzyme in the membrane is a tetraprotomer, (a▀)4. They also suggest that each reaction intermediate of the Post-Albers scheme, respectively, reflects half of the site property of the intermediate and that another half binds ATP. These data may be useful not only to answer the long-standing question of whether the mechanism functions in the presence of both Na+ and K+ but also contribute to a better understanding of the mechanism of P-type pump ATPase in general.

  • 309.
    Thorn, Hans
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Caveolae structure and importance in insulin action2004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Type II diabetes is a disease characterized by chronic hyperglycaemia and abnormalities in lipid metabolism that affects approximately 5% of the population in the Western World. Caveolae are invaginations of the plasma membrane, described as 25-150 nm omega shaped structures, which are enriched in cholesterol, sphingolipids and the constituent protein caveolin. Caveolae have been shown to be involved in signal transduction, uptake over the plasma membrane and intracellular transport. By electron microscopy studies of cell membranes and biochemical analyses of isolated caveolae, we report that in rat adipocytes glucose transporter GLUT4 was translocated to caveolae in response to insulin. Insulin stimulation increased the amount of GLUT4 in the plasma membrane, but the ratio between GLUT4 in the planar and caveolae membrane remained constant. These findings indicate that caveolae are the locales for glucose uptake in the cell. We also report that the insulin receptor, independently of insulin stimulation, was localised in caveolae in human adipocytes. In these cells depletion of cholesterol destroyed the caveolae structure and the adipocytes became insulin resistant. Cholesterol depletion did not affect the insulinstimulated autophosphorylation of the insulin receptor nor the phosphorylation of the downstream IRS1. Further signalling to metabolic control or mitogenic control was inhibited, however. With transmission electron-, scanning electron- and fluorescence-microscopic techniques, we studied the ultrastructure and distribution of caveolae in the rat adipocyte. We found that caveolae can be divided into two subpopulations, small (<50 nm) and large (50-150 nm). The large caveolae are connected to the extracellular space via narrow necks and the orifices of caveolae were herein shown in primary adipocytes for the first time. Caveolin is located in the membrane proximal part of the small caveolae and to the neck in the large caveolae. The insulin receptor substrate IRS 1 was shown to be localized to caveolae in human adipocytes and to colocalize with the insulin receptor. In rat adipocytes, however, IRS1 was not localized to the plasma membrane in the absence of insulin stimulation. By transfection of rat adipocytes with human IRS1 we found that human IRS1 bound to the plasma membrane in the rat adipocyte, whereas the endogenous rat IRS1 did not. Taken together, caveolae seem to be closely involved in regulation of insulin action in the adipocyte.

  • 310.
    Trulsson, Lena
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery.
    Velin, Åsa
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery.
    Herder, Anders
    Söderkvist, Peter
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Rüter, Anders
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Smeds, Staffan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Telomerase activity in surgical specimens and fine-needle aspiration biopsies from hyperplastic and neoplastic human thyroid tissues2003In: American Journal of Surgery, ISSN 0002-9610, E-ISSN 1879-1883, Vol. 186, no 1, p. 83-88Article in journal (Refereed)
    Abstract [en]

    Background: Telomerase activity (TA) indicates malignancy, but activated lymphocytes also express TA. Correlation between TA in thyroid tissues and fine-needle aspiration (FNA) samples and knowledge about TA in adjacent tissue are of importance. Methods: The telomeric repeat amplification protocol assay followed by enzyme-linked immunosorbent assay detection was performed on 78 thyroid cases including 53 suspected malignancies, preoperative and perioperative FNA specimens, and adjacent tissue. Results: Benign lesions in cancer-suspected cases were TA negative. Eight of 13 papillary (62%) and 4 of 5 follicular (80%) tumors were TA positive (TA+). Lower TA was observed in conventional papillary cancer than in follicular, tall cell variant of papillary and anaplastic cancers. Adjacent tissues with lymphocyte infiltration were TA+ in 9 of 17 cases (53%). Nine of 65 adjacent tissues (14%) were TA+. Three of 6 preoperative and 9 of 11 perioperative FNA samples from malignant tumors corresponded to the tissue TA. Conclusions: High TA may reflect more severe thyroid cancer. Telomerase activity in FNA biopsies does not add reliable diagnostic information, and presence of lymphocytes can give false-positive results.

  • 311.
    Tuisku, Fredrik
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Nerve fibres in relation to gingiva, tooth germs and teeth in the polyphyodont cichlid Tilapia mariae1995Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In the late 19th century Retzius observed the presence of nerve fibres in goldfish tooth pulps. However, later studies on the relationship between the dentition and its innervation in non-mammalian vertebrates and its use in experimental research are rare. This thesis presents data on how nerve fibres are related to gingiva, tooth germsand teeth in the lower jaw of a polyphyodont teleost- the cichlid Tilapia mariae. It provides some new aspects on the structure and function of gingival and dental axons. Paper I shows that the complexity of the nodal-paranodal organization in trigeminal alveolar branch (TAB) nerve fibres decreases with decreasing fibre size, like in mammalian nerve fibres. The exceptionally thin myelinated TAB fibres of T. mariae (axonal diameters down to 0. 3 µm) exhibit nodes of Ranvier. The internodal lengths of these fibres varies between 35-50 µm. Theoretical calculations suggest that these extremely thin fibres may be capable of saltatory conduction. Paper II shows that the normal turnover time of an individual tooth (i.e. from eruption to shedding)is about 100 days. Following unilateral neurectomy of the TAB, tooth turnover stops on the denervated side of the jaw. The arrest in tooth turnover is due to a cessation of tooth germ formation. Papers III and IV show that gingival and dental domains are extensively innervated by nerve fibres exhibiting neurofllarnent-, calcitonin generelatedpeptide-, substance P-, tyrosine hydroxylase-, neuropeptide Y -,choline acteyl transferase- or vasoactive intestinal polypeptide-like itnmunoreactivity in a pattern similar to the mammalian counterpart. The rich innervation of odontogenic tissue components in T. mariae by sensory as well as autonomic axons is compatible with the results obtttined in paper II that axons may be involved in odontogenesis. Paper V shows that gingiva and tooth pulps in T. mariae are innervated by trigeminal ganglion (TG) neurons. Like in the rat, TG neurons in T. mariae differ in size and neuropeptide content depending on whether they project to gingiva or tooth pulps.While gingival neurons are exclusively small (perikaryal diameter [Pd]< 20 µm), pulpal neurons may be small or large (Pd;o: 20 µm). Hence, this seems to be an evolutionary old pattern. Taken together, the present results show that the lower jaw dentition and its trigeminal branch in T. mariae is a useful experimental system that may be used for future studies on e. g. the functional properties of the exceptionally thin TAB fibres or the molecular mechanisms behind the neuronal influence on tooth germ formation.

  • 312. Törn, C
    et al.
    Landin-Olsson, M
    Lernmark, Å
    Palmer, JP
    Arnqvist, Hans
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology. Östergötlands Läns Landsting, MKC-2, GE: endomed.
    Blohmé, G
    Lithner, F
    Littorin, B
    Nyström, L
    Scherstén, B
    Sundkvist, G
    Wibell, L
    Östman, J
    Prognostic factors for the course of beta cell function in autoimmune diabetes2000In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 85, no 12, p. 4619-4623Article in journal (Refereed)
    Abstract [en]

    This study presents a 2-yr follow-up of 281 patients, aged 15-34 yr, diagnosed with diabetes between 1992 and 1993. At diagnosis, 224 (80%) patients were positive for at least one of the following autoantibodies: islet cell antibodies (ICAs), glutamic acid decarboxylase antibodies (GADAs), or tyrosine phosphatase antibodies (IA-2As), the remaining 57 (20%) patients were negative for all three autoantibodies. At diagnosis, C-peptide levels were lower (0.27, 0.16-0.40 nmol/L) in autoantibody-positive patients compared with autoantibody-negative patients (0.51, 0.28-0.78 nmol/L, P < 0.001). After 2 yr, C-peptide levels had decreased significantly in patients with autoimmune diabetes (0.20, 0.10-0.37 nmol/L, P = 0.0018), but not in autoantibody-negative patients. In patients with autoimmune diabetes, a low initial level of C-peptide (odds ratio, 2.6, 95% confidence interval, 1.7-4.0) and a high level of GADAs (odds ratio, 2.5, 95% confidence interval, 1.1-5.7) were risk factors for a C-peptide level below the reference level of 0.25 nmol/L 2 yr after diagnosis. Body mass index had a significant effect in the multivariate analysis only when initial C-peptide was not considered. Factors such as age, gender, levels of ICA or IA-2A or insulin autoantibodies (analyzed in a subset of 180 patients) had no effect on the decrease in ▀-cell function. It is concluded that the absence of pancreatic islet autoantibodies at diagnosis were highly predictive for a maintained ▀-cell function during the 2 yr after diagnosis, whereas high levels of GADA indicated a course of decreased ▀-cell function with low levels of C-peptide. In autoimmune diabetes, an initial low level of C-peptide was a strong risk factor for a decrease in ▀-cell function and conversely high C-peptide levels were protective. Other factors such as age, gender, body mass index, levels of ICA, IA-2A or IAA had no prognostic importance.

  • 313. Törn, C
    et al.
    Landin-Olsson, M
    Lernmark, Å
    Scherstén, B
    Östman, J
    Arnqvist, Hans
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology. Östergötlands Läns Landsting, MKC-2, GE: endomed.
    Björk, E
    Blohmé, G
    Bolinder, J
    Eriksson, J
    Littorin, B
    Nyström, L
    Sundkvist, G
    Combinations of beta cell specific autoantibodies at diagnosis of diabetes in young adults reflects different courses of beta cell damage.2001In: Autoimmunity, ISSN 0891-6934, E-ISSN 1607-842X, Vol. 33, p. 115-120Article in journal (Refereed)
  • 314. Törn, Carina
    et al.
    Landin-Olsson, Mona
    Östman, Jan
    Scherstén, Bengt
    Arnqvist, Hans
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology. Östergötlands Läns Landsting, MKC-2, GE: endomed.
    Blohmé, Göran
    Björk, Elisabeth
    Bolinder, Jan
    Eriksson, Jan
    Littorin, Bengt
    Nyström, Lennarth
    Sundkvist, Göran
    Lernmark, Åke
    Glutamic acid decarboxylase antibodies (GADA) is the most important factor for prediction of insulin therapy within 3 years in young adult diabetic patients not classified as Type 1 diabetes on clinical grounds2000In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 16, no 6, p. 442-447Article in journal (Refereed)
    Abstract [en]

    Background Differentiation between Type 1 and Type 2 diabetes in adults is difficult at diagnosis. In this study we tested the hypothesis that autoantibodies at diagnosis are predictive for insulin treatment within 3 years in patients initially not classified as Type 1 diabetes. Methods In a nationwide population-based study, blood samples were obtained from 764 patients, all diagnosed with diabetes during a 2-year period. At diagnosis, 583 (76%) were classified as Type 1, 110 (14%) as Type 2 and 71 (9.3%) could not be classified. Results Among patients not classified as Type 1 diabetes, 52 (47%) of Type 2 and 42 (59%) of unclassified patients were positive for islet cell antibodies CICA), glutamic acid decarboxylase antibodies (GADA) or tyrosine phosphatase antibodies (IA-2A). These patients (n=94) had lower body mass index (BMI) (p<0.001) and lower C-peptide (p<0.001) compared to the autoantibody negative patients (n=87). Compared to clinically classified Type 1 diabetes patients positive for autoantibodies (n=477), they have higher BMI (p<0.001), higher C-peptide (p<0.001) and the same levels of ICA, GADA and IA-2A. After 3 years, 93% of autoantibody positive patients initially not classified as Type 1 were on insulin. When ICA, GADA, IA-2A, BMI and C-peptide were tested in a multiple logistic regression, only GADA was signiificant for insulin treatment within 3 years (OR = 18.8, 95% CI 1.8-191) in patients treated with diet or oral drugs at diagnosis. Conclusions A correct classification is difficult in adult diabetic patients. The presence of pancreatic autoantibodies, especially GADA, at diagnosis of diabetes are highly predictive for insulin therapy within 3 years from diagnosis. Copyright ⌐ 2000 John Wiley & Sons, Ltd.

  • 315.
    Törnkvist, Åsa
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Parpal, Santiago
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Gustavsson, Johanna
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Strålfors, Peter
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Inhibition of Raf-1 kinase expression abolishes insulin stimulation of DNA synthesis in H4IIE hepatoma cells1994In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 269, no 19, p. 13919-13921Article in journal (Refereed)
    Abstract [en]

    The involvement of Raf-1 kinase in the insulin signal transduction chain leading to control of cell proliferation was studied in the H4IIE rat hepatoma cell line by inhibiting expression of the kinase with antisense oligodeoxyribonucleotide directed against Raf-1 mRNA. Antisense oligonucleotide was found to reduce (at 2 microM) or completely block (at 15 microM) the stimulation by insulin of DNA synthesis, measured as thymidine incorporation. The residual DNA synthesis seen in the absence of insulin stimulation was also inhibited by the Raf-1 kinase antisense oligonucleotide.

  • 316.
    Tømmerås, Karin
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    The role of gastrin and extracellular matrix proteins in proliferation and differentiation of gastric epithelial cells2000Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The mechanisms regulating the proliferation and differentiation processes that give rise to and maintain the gastric epithelium have not yet been completely elucidated.

    In the present studies, in vitro models were established and the influence of growth factors and extracellular matrix proteins on these processes were investigated. Pentagastrin and hydrocortisone were found to accelerate the development of H,KTPase-positive parietal cells and other epithelial cells from undifferentiated gastric epithelial cells of foetal rats. These undifferentiated cells and also presumably immature epithelial cells in the progenitor zone of adult gastric glands were shown to express cholecystokinin-2 (CCK2) receptors and are therefore targets for the trophic action of gastrin.

    H,K-ATPase-positive parietal cells in the progenitor zone of adult glands were also found to express CCK2 receptors, indicating that gastrin may stimulate maturation of the parietal cell lineage even during adult life. Parietal cells located in the upper region of the glandular unit are probably responsible for most of the acid secretion, because these cells were found to express the membrane-cytoskeletallinker ezrin, reported to be present in the canaliculi of stimulated parietal cells.

    Pulse-labelling with 5-bromo-2'-deoxyuridine showed that during the gestational period, when the main motphological conformations and maturation of the gastric epithelium occur, proliferating cells appear at the basal epithelial cell layer and migrate towards the gastric lumen. This indicates that epithelial-mesenchymal cell and cell-matrix interactions may be involved in regulation of the cell proliferation and differentiation. Investigation of the expression of extracellular matrix proteins in foetal rat stomachs revealed a marked increase in collagen type I, suggesting that collagen, which is known to stimulate epithelial cell proliferation, is involved in the initial folding of the embryonic epithelium and formation of glandular structures.

    In experiments in vitro, development of mucus-producing cells from undifferentiated gastric epithelial cells was stimulated by collagens but inhibited by fibronectin and laminin. In adult gastric epithelium, collagen type I was present only in the pit region of the glandular unit, where surface mucous cells are located. Thus, collagen type I, which is overexpressed in gastric ulcers and gastric cancers, likely stimulates proliferation of mucus-producing cells.

    In conclusion, expression of CCK2 receptors was detected in foetal gastric epithelium and in the progenitor zone of adult gastric epithelium, implying that gastrin exerts trophic effects on immature gastric epithelial cells, during both stomach organogenesis and adult life. The spatial and temporal expression of extracellular matrix proteins and the effects of these proteins on development of mucus-producing cells in vitro indicate that extracellular matrix proteins may play an important role in regulation of epithelial cell proliferation and differentiation, and thus in the maintenance of normal cellular composition and function ofthe gastric epithelium.

  • 317.
    Tømmerås, Karin
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Ay, Juliyana
    Discovery, Research Area CV & GI, AstraZeneca R&D Mölndal, Mölndal, Sweden.
    Cabero, José Luis
    Discovery, Research Area CV & GI, AstraZeneca R&D Mölndal, Mölndal, Sweden.
    Sundler, Frank
    Department of Physiological Sciences, Section for Neuroendocrine Cell Biology, Lund University, Lund, Sweden.
    Mårdh, Sven
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Effects of Extracellular Matrix Proteins on Development of Fetal Rat Gastric Epithelial Cells in CultureManuscript (preprint) (Other academic)
    Abstract [en]

    Undifferentiated fetal gastric epithelial cells and stem cells of adult gastric glands give rise to surface mucous, parietal, mucous neck, zymogenic, caveolated, and endocrine cells by yet-unknown mechanisms. Our aim was to establish an in vitro model for investigating the effects of extracellular matrix proteins on development of gastric epithelial cells, and to determine whether collagen type I affects growth and maturation of undifferentiated epithelial cells. Fetal rat gastric cells were isolated and then cultured for 15 days on uncoated glass coverslips or on collagen types I or IV, fibronectin, or laminin. The appearance of epithelial cells was investigated by means of Alcian blue-periodic acid Schiff (AB-PAS) staining, inununostaining for cytokeratin, H,K-ATPase and chromogranin A, acridine orange accumulation, and by transmission and scamting electron microscopy. AB-PAS-positive cells containing mucous-type granules were detected. These mucoid cells were abundant on uncoated coverslips and collagen, but scarce on fibronectin and laminin. No cytokeratin, H,K-ATPase or chromogranin A, or increased acridine orange accumulation in response to secretagogues were observed. Rarely, endocrine cells were observed by electron microscopy. In conclusion, undifferentiated epithelial cells did proliferate and differentiate, and mucoid and endocrine cells matured in the established in vitro system. Moreover, development of mucoid cells from undifferentiated gastric epithelial cells was stimulated by collagen matrices but inhibited by fibronectin and laminin.

  • 318.
    Tømmerås, Karin
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Cabero, José Luis
    Department of Cell Biology and Biochemistry, AstraZeneca R&D, Mölndal, Sweden.
    Mårdh, Sven
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Expression of extracellular matrix proteins in the fetal rat gastric mucosa2000In: Anatomy and Embryology, ISSN 0340-2061, E-ISSN 1432-0568, Vol. 201, no 3, p. 149-156Article in journal (Refereed)
    Abstract [en]

    At gestational day 16 the epithelium of the rat stomach consists of a stratified layer of undifferentiated cells, and two days later glandular structures appear. The present study was carried out to identify extracellular matrix proteins that could be involved in the epithelial cell proliferation and differentiation processes that occur in the fetal rat stomach during this period. For comparative purposes the expression of the same components in the adult gastric mucosa was examined. Pregnant Sprague-Dawley rats received an intraperitoneal injection of 5-bromo-2’-deoxyuridine to label proliferating cells. One, 3.5, or 6 h post-injection the stomachs were excised and immediately frozen. The specimens were sectioned and stained with hematoxylin and eosin or for 5-bromo-2’-deoxyuridine, cytokeratin no. 8, H,K-ATPase, and the extracellular matrix proteins fibronectin, laminin, and collagens type I and IV. A stratified layer of proliferating cells was observed in the epithelium of the fetal stomachs, while in adult stomachs proliferating cells were detected in the isthmus/neck region of the glands. Cytokeratin, an epithelial cell marker, was sparse at gestational day 16 but abundant both at gestational day 18 and in the isthmus/neck region of gastric glands of the adult stomach. The parietal cell marker H,K-ATPase could not be detected in the fetal stomachs during this period. Fibronectin was observed in the stroma of both fetal and adult stomachs. Collagen type I could only be detected in the stroma close to the oesophagus at gestational day 16. Two days later, collagen type I was abundant in the lamina propria, the submucosa and in the serosa of the fetal stomachs. In adult tissue collagen type I was detected in the surface epithelium, the submucosa and in the serosa of the stomach. Collagen type IV and laminin were expressed in the lamina propria, the basement membranes around blood vessels, muscle cells, and nerve bundles, as well as in the serosa of both 16- and 18-day-old fetal and adult rat stomachs. In conclusion, a high cell proliferation rate was observed in the epithelium at both gestational days 16 and 18. The increased expression of cytokeratin observed during this period indicates that the epithelial character of the embryonic cells becomes more distinct, while the remarkable change in the expression of collagen type I might reflect an important role of collagen type I in the development of the gastric epithelium.

  • 319.
    Tømmerås, Karin
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Chen, Y.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Rhedin, M.
    Department of Cell Biology, Astra Hässle AB, Mölndal, Sweden.
    Cabero, J. L.
    Department of Cell Biology, Astra Hässle AB, Mölndal, Sweden.
    Mårdh, Sven
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Proliferation and differentiation of cells from explants of fetal rat stomach1997In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 159, no 2, p. 155-161Article in journal (Refereed)
    Abstract [en]

    The current understanding of the mechanisms controlling the proliferation and differentiation of the stem cells of the gastric oxyntic glands is limited. The aim of the present study was to develop a method for investigating proliferation and differentiation of undifferentiated cells from fetal rat stomach. Outgrowth of cells was initiated from explants of 16-day-old fetal rat stomachs. At this stage of the fetal development the gastric epithelial cells are undifferentiated. The explants were cultured in DMEM/F-12 medium supplemented with fetal calf serum only, or fetal calf serum combined with either hydrocortisone or pentagastrin. Morphological characterization by means of light microscopy, dye staining and immunostaining was used to identify the growing cells. Both hydrocortisone and pentagastrin accelerated the differentiation towards H,K-ATPase-positive cells, mucus-producing cells and other epithelial cells. H,K-ATPase-positive cells, which were identified by immunostaining with a monoclonal antibody reacting with the α-subunit of the H,K-ATPase, grew on top of the confluent layer of epithelioid and fibroblastoid cells. With this method in vitro investigations of the mechanisms of proliferation and differentiation of gastric mucosal cells are possible. Although by different mechanisms, both hydrocortisone and pentagastrin appear to play a regulatory role in these processes.

  • 320.
    Tømmerås, Karin
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Hammer, Pål
    Linköping University, Department of Biomedicine and Surgery. Linköping University, Faculty of Health Sciences.
    Sundler, Frank
    Department of Physiological Sciences, Section of Neuroendocrine Cell Biology, Lund University, Lund, Sweden.
    Borch, Kurt
    Linköping University, Department of Biomedicine and Surgery. Linköping University, Faculty of Health Sciences.
    Mårdh, Sven
    Linköping University, Department of Biomedicine and Surgery. Linköping University, Faculty of Health Sciences.
    Cabero, José Lius
    Discovery, Research Area CV & GI, AstraZeneca R&D Mölndal, Mölndal, Sweden.
    Immunolocalization of Cholecystokinin-2 Receptors in Rat Gastric Mucosa2002In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 37, no 9, p. 1017-1024Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Gastrin exerts trophic effects on the gastric mucosa by mechanisms not yet completely elucidated. Our aim was to localize the cholecystokinin-2 (CCK2) receptor in epithelial cells of foetal and adult rat stomachs in order to determine the cell types that are directly affected by gastrin.

    METHODS: Gastric tissue was subjected to indirect double immunofluorescence staining with antiserum against the C-terminal decapeptide of the CCK2 receptor and antibodies against 5' bromo-2-deoxyuridine, which had been injected into the rats I h before they were killed, the acid pump H,K-ATPase, the membrane-cytoskeletal linker ezrin, pepsin/pepsinogen or histidine decarboxylase.

    RESULTS: Undifferentiated foetal gastric epithelial cells expressed CCK2 receptors, whereas stem cells of adult gastric glands did not exhibit immunoreactivity. However, other epithelial cells in the progenitor zone of adult gastric glands did express CCK2 receptors. Some of these cells were faintly stained for H,K-ATPase; pepsin/pepsinogen was also detected in this region. Parietal cells in the isthmus/pit region of the glands contained ezrin, and some showed weak immunoreactivity for the CCK2 receptor. As expected, enterochromaffin-like cells also expressed CCK2 receptors.

    CONCLUSION: Our findings are consistent with the hypothesis that a CCK2 receptor mediates direct effects of gastrin on gastric epithelial cells during both stomach organogenesis and adult life.

  • 321.
    Valdimarsson, Trausti
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Gastroenterology and Hepatology. Östergötlands Läns Landsting, MKC - Medicin och kirurgicentrum, GE: gastromed.
    Arnqvist, Hans
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Toss, Göran
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Internal Medicine. Östergötlands Läns Landsting, MKC-2, GE: endomed.
    Järnerot, G
    IHM Gastroenterologi och hepatologi.
    Nyström, Fredrik
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Internal Medicine. Östergötlands Läns Landsting, MKC-2, GE: endomed.
    Ström, Magnus
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Gastroenterology and Hepatology. Östergötlands Läns Landsting, MKC - Medicin och kirurgicentrum, GE: gastromed.
    Low circulating insulin-like growth factor I in coeliac disease and its relation to bone mineral density.1999In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 34, no 9, p. 904-908Article in journal (Refereed)
  • 322.
    Vener, Alexander
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Peptidyl-prolyl isomerases and regulation of photosynthetic functions.2001In: Regulation of photosynthesis / [ed] Eva-Mari Aro and Bertil Andersson, Linköping: Linköpings universitet , 2001, p. 177-193Chapter in book (Other academic)
    Abstract [en]

    The book covers the expression of photosynthesis related genes including regulation both at transcriptional and translational levels. Biogenesis, turnover and senescence of thylakoid pigment protein complexes are reviewed and some crucial regulatory steps in carbon metabolism are highlighted. The stress and acclimation responses in chloroplasts are examined at molecular level. The book also provides examples of novel methods for studies of photosynthetic regulation.

  • 323.
    Vener, Alexander
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Harms, Amy
    Sussmann, Michael R
    Vierstra, Richard
    Mass spectrometric resolution of reversible protein phosphorylation in photosynthetic membranes of arabidopsis thaliana.2001In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 276, p. 6959-6966Article in journal (Refereed)
  • 324.
    Vrethem, Magnus
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Neurology.
    Boivie, Jörgen
    Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Neurology.
    Arnqvist, Hans
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Holmgren, Helen
    Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Neurology.
    Lindström, Torbjörn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Internal Medicine. Östergötlands Läns Landsting, MKC - Medicin och kirurgicentrum, EMK-endokrin.
    Painful polyneuropathy in patients with and without diabetes: Clinical, neurophysiologic, and quantitative sensory characteristics2002In: The Clinical Journal of Pain, ISSN 0749-8047, E-ISSN 1536-5409, Vol. 18, no 2, p. 122-127Article in journal (Refereed)
    Abstract [en]

    Objectives: To study pain characteristics and peripheral nerve involvement in patients with painful diabetic and nondiabetic polyneuropathy in comparison with patients with nonpainful polyneuropathy. Patients and Methods: Fifty-five patients with polyneuropathy (37 with painful polyneuropathy, of whom 19 had diabetes and 18 had no diabetes, and 18 with painless polyneuropathy of different etiologies) were examined clinically using quantitative sensory tests and neurophysiology. Pain intensity and characteristics were analyzed by daily ratings on a 10-step verbal scale and by a questionnaire. Results: Most patients experienced pain of more than one character. There was no clear difference in character or duration of pain between patients with and without diabetes. The mean value of the daily rating of pain intensity showed that pain was more severe in the evenings than in the mornings and that diabetic patients reported worse pain than nondiabetic patients. Thirty-two of the 37 patients with pain had paresthesias and/or dysesthesias, whereas only 7 of 18 patients without pain had paresthesias. Pain was always located in the feet, and, in most patients, also in the lower part of the legs. Some patients also experienced pain in the hands. Tactile sensibility, measured by quantitative tests, was more affected in both diabetic and nondiabetic patients with painful polyneuropathy compared with patients without pain (p = 0.02). Temperature, pain, and vibratory sensibility were equally affected in all patient groups. Nerve conduction velocity, amplitudes, and distal latency were equally affected in the pain group as compared with the control group, indicating that both thin and thick nerve afferents are affected in patients with painful as well as nonpainful polyneuropathy and that etiology has no clear impact on nerve involvement. Conclusions: Neuropathy pain was always located in the feet and more severe in diabetic patients compared with patients with neuropathy pain of other etiologies. The authors also found evidence for a greater tactile sensibility involvement in patients with neuropathy pain, irrespective of etiology, whereas other quantitative sensibility and neurography parameters were equally affected in all patient groups.

  • 325.
    Walz, Thomas M.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Transforming growth factor a in human hematopoietic cells1994Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    TGF-a, transforming growth factor a, is a potent growth factor belonging to the family of EGF (epidermal growth factor) -related proteins. Binding to the same receptor as EGF it has a ubiquitous repertoire of target cells, including, mesenchymal, epithelial and neuronal cells. The occurrence and role of TGF-a in hematopoietic cells has not been elucidated. Therefore the present work was initiated to (I) examine the expression of TGF-a and the EGF receptor in nmmal circulating human blood cells; (2) study the effects of specific cytokines on TGFa mRNA levels and protein release in mature blood cells; (3) examine the occurrence of TGF-a and the EGF receptor in normal human bone marrow cells; (4) determine TGF-a gene expression and protein production during granulocyte and monocyte/macrophage differentiation in vitro.

    TGF-a mRNA was consistently found in white blood cells from normalhealthy donors as shown by Northern blot analysis. In situ hybridizationexperiments assigned the TGF-a gene expression to the eosinophils; no other cell types were recognized by the complementary TGF-a RNA probe. Incubation of white blood cells led to liberation of TGF-a to the culture medium, as determined by ELISA.

    White blood cells exposed in vitro to the cytokines GM-CSF (granulocytemacrophage colony stimulating factor) or interleukin (IL)-3 showed increased levels of TGF-a mRNA. The effect of GM-CSF was different from that of IL-3, since only GM-CSF augmented the release of TGF-a protein from the cells.

    Immunohistochemical examination of human normal bone marrow cells, using a monoclonal TGF-a antibody, revealed TGF-a-reactive material on erythroid cells, at all stages of differentiation. The nature of the stain, in conjunction with the fact that the cells could be pulled out by immunomagnetic cell sorting would seem to indicate a membrane-bound, extracellular configuration of TGF-a, rather than an intracellular one. Using a different antibody a different staining pattern was obtained, indicating the presence of TGF-a in eosinophilic precursor cells and in promyelocytes and neutrophilic myelocytes.

    Attempts were made to identify target cells for TGF-a, i.e. EGF receptorcarrying cells. Intron-differential reverse transcriptase PCR was used to detect the EGF receptor signal. Immunohistochemistry revealed the EGF receptor protein in a small but distinct population of immature, blast-like cells of myelomonocytic appearance.

    The expression of TGF-a was monitored, at the mRNA and protein level, in human leukemic cells induced to differentiate in culture. Differentiation of the promyelocytic cell line, HL-60, along the granulocytic pathway was accompanied by increased TGF-a mRNA levels and TGF-a protein release.

    When tbe HL-60 cells were brought towards monocytes/macrophages tbe effect on TGF-a expression depended on the inducing agent used, irrespective of a number of differentiation criteria.

    Differentiation of tbe monocytoid cell line, U-937, witb different inducers had different effects on TGF-a mRNA levels as well as TGF-a release. This supports tbe idea of phenotypic heterogeneity in tbe differentiated cells.

  • 326. Wang, Feng
    et al.
    Adrian, TE
    Westermark, Gunilla
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Gasslanderq, Thomas
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, MKC-2, GE: Gastrokir.
    Permert, Johan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, MKC-2, GE: Gastrokir.
    Dissociated insulin and islet amyloid polypeptide secretion from isolated rat pancreatic islets cocultured with human pancreatic adenocarcinoma cells.1999In: Pancreas, ISSN 0885-3177, E-ISSN 1536-4828, Vol. 18, p. 403-409Article in journal (Refereed)
  • 327. Wang, Xiao-Ling
    et al.
    Wu, Guo-Xiang
    Zhang, Ming-Dao
    Guo, Ming
    Zhang, Hong
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Sun, Xiao-Feng
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology.
    A favourable impact of preoperative FPLC chemotherapy on patients with gastric cardia cancer.2000In: Oncology Reports, ISSN 1021-335X, E-ISSN 1791-2431, Vol. 7, p. 241-244Article in journal (Refereed)
  • 328.
    Westermark, Gunilla
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Falkmer, Sture
    Steiner, Donald
    Chan, Shu Jin
    Engström, Ulla
    Westermark, Per
    Islet amyloid polypeptide is expressed in the pancreatic islet parenchyma of the teleostean fish, Myoxocephalus (cottus) scorpius2002In: Comparative Biochemistry and Physiology - Part B: Biochemistry & Molecular Biology, ISSN 1096-4959, E-ISSN 1879-1107, Vol. 133, no 1, p. 119-125Article in journal (Refereed)
    Abstract [en]

    The comparative endocrinology of the 37-amino-acid-residue islet amyloid polypeptide (IAPP) is poorly known, possibly due to the fact that available antisera, raised against mammalian IAPP, fail to give immunoreactivity with islet parenchymal cells of non-mammalian vertebrates. Using reverse transcriptase-linked polymerase chain reaction with degenerate primers, IAPP was identified, and its deduced amino-acid sequence partially characterized, in three species of teleostean fish, i.e. Danio rerio (zebrafish), Salmo salar (Atlantic salmon), and Myoxocephalus (cottus) scorpius (daddy sculpin). The daddy sculpin is a species where the histophysiology of the pancreatic islet parenchyma has previously been comprehensively studied. From the deduced amino-acid sequence, a synthetic peptide, corresponding to positions 20-29 of Salmo IAPP, was synthesized. A mouse antiserum to this peptide gave a distinct immunoreactivity with the insulin-producing beta cells of the sculpin Brockmann bodies and salmon endocrine pancreas. Thus, IAPP belongs to the group of peptide hormones expressed by the islet parenchymal cells in both mammals and non-mammalian vertebrates. Salmo salar IAPP(20-29) was found to give rise to amyloid-like fibrils in vitro.

  • 329.
    Westermark, Gunilla
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Johnson, KH
    Westermark, P
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Staining methods for identification of amyloid in tissue.  1999In: Methods in Enzymology, ISSN 0076-6879, E-ISSN 1557-7988, Vol. 309Article in journal (Refereed)
  • 330.
    Westermark, Gunilla
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Steiner, Donald
    Gebre-Medhin, Samuel
    Engström, Ulla
    Westermark, Per
    Pro islet amyloid polypeptide (ProIAPP) immunoreactivity in the islets of langerhans2000In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 105, no 2, p. 97-106Article in journal (Refereed)
    Abstract [en]

    Islet amyloid is typically found in type 2 diabetes mellitus and is believed to participate in the beta cell deterioration. The islet amyloid fibril consists of the 37-amino-acid islet amyloid polypeptide (IAPP) but its pathogenesis is only partly understood. We developed several different rabbit antisera against the flanking peptides of the IAPP precursor (proIAPP) and the proIAPP processing sites in order to study the possible occurrence of unprocessed proIAPP or parts thereof in islet amyloid. We applied these antisera in an immunohistochemical study on islet amyloid deposits present in a newly generated mouse strain that over-expresses human IAPP but is devoid of mouse IAPP. Male mice of this strain develop severe islet amyloidosis when given a high fat diet. Generally, the antisera showed no immunoreactivity with the amyloid. However, in scattered single beta cells, where amyloid could be seen intracellularly, immunoreactivity with one or more of the antisera colocalized with the amyloid. Although virtually all amyloid in human islets of Langerhans is found extracellularly, we propose that the initial amyloid formation occurs intracellularly, perhaps by not fully processed or folded (pro)IAPP. This amyloid, which may develop rapidly under certain circumstances, probably leads to cell death. If not degraded these amyloid spots may then act as nidus for further amyloid formation from fully processed IAPP, secreted from surrounding beta cells.

  • 331.
    Westermark, Gunilla
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Westermark, P
    Nordin, A
    Tornelius, E
    Andersson, A
    Formation of amyloid in human pancreatic islets transplanted to the liver and spleen of nude mice2003In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 108, no 3, p. 193-203Article in journal (Refereed)
    Abstract [en]

    In previous studies we have shown that apparently normal human islets, transplanted under the renal capsule of nude mice, frequently and rapidly develop amyloid deposits derived from the ▀-cell hormone islet amyloid polypeptide (IAPP). In the present study, we show for the first time that human islets, transplanted into the liver or spleen of nude mice, also develop islet amyloid rapidly. Ultrastructural studies of such islets showed that the first aggregation of IAPP takes place within the ▀-cells and that extracellular deposits show up later in the amyloid formation process. We also found that the amount of amyloid formed in human islet grafts placed under the kidney capsule increased with extended (26 weeks) observation time. Moreover, prolonged in vitro culture (14 days) prior to the implantation under the renal capsule seemed to enhance the formation of amyloid in the grafted islets. Since aggregated IAPP has been shown to be toxic to ▀-cells, the finding of amyloid deposits in transplanted islets offers a possible explanation to the frequent loss of function of islets transplanted into diabetic patients.

  • 332.
    Westermark, Gunilla
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Westermark, P
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Pipeleers, D
    Eizirik, D
    Hellerström, C
    Fox, N
    Steiner, DF
    Andersson, A
    Differences in amyloid deposition in islets of transgenic mice expressing human islet amyloid polypeptide versus human islets implanted into nude mice. 1999In: Metabolism: Clinical and Experimental, ISSN 0026-0495, E-ISSN 1532-8600, Vol. 48, p. 448-454Article in journal (Refereed)
  • 333.
    Westermark, Gunilla
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Westermark, Per
    Endocrine amyloid - A subject of increasing interest for the next century2000In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 7, no 1, p. 19-22Article in journal (Refereed)
  • 334. Wibell, L
    et al.
    Nyström, L
    Östman, J
    Arnqvist, Hans
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology. Östergötlands Läns Landsting, MKC-2, GE: endomed.
    Blohmé, G
    Lithner, F
    Littorin, B
    Sundkvist, G
    Increased mortality in diabetes during the first 10 years of the disease. A population-based study (DISS) in Swedish adults 15-34 years old at diagnosis2001In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 249, no 3, p. 263-270Article in journal (Refereed)
    Abstract [en]

    Objectives. To study, prospectively, in young adult patients, the mortality during the first years after the diagnosis of diabetes. Design. The Diabetes Incidence Study in Sweden (DISS) aims to register all incident cases aged 15-34 years. During a 10-year period all deaths were identified by record linkage to the national Cause of Death Registry. Subjects. During the period, 4097 new cases were registered and classified as type 1 diabetes (73%), type 2 (16%), secondary (2%) and unclassified (9%). The median follow-up was 5 years (21 001 person-years). Main outcome measures. Calculation of the standardized mortality ratio (SMR) and 95% confidence interval (CI). Evaluation of all deceased by scrutiny of clinical records, death certificates and autopsy protocols. Results. Fifty-eight patients died, corresponding to an SMR of 3.5 (CI = 2.7-4.5), which increased from 1.5 at 15-19 years to 4.1 at 30-34 years. SMR was 2.7 in primary diabetes: 2.3 (1.6-3.3) in type 1 and 4.1 (2.6-6.7) in type 2. In secondary diabetes, alcohol-associated pancreatitis a common cause, SMR was 32 (CI = 24-45). Evidence of alcohol or drug misuse, mental dysfunction or suicide was found in 40 of all 58 deceased cases. Less often, hypoglycaemia (n = 7) or hyperglycaemia-ketoacidosis (n = 11) was present at death. Unexplained 'dead in bed' was found once. Conclusions. In the investigated population-based cohort the early mortality was about threefold increased. Hypoglycaemia and ketoacidosis per se played a relatively small role compared with a heavy impact from social and mental dysfunction, and from careless use of alcohol or drugs.

  • 335.
    Wigren, Jane
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Identification of natural activators of the nuclear receptor peroxisome proliferator-activated receptor: relevance to the pathogenesis of atherosclerosis1999Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Polyunsaturated fatty acids induce peroxisome proliferation. This phenomenon is mediated by the ligand-dependent transcription factor peroxisome proliferator-activated receptor (PPAR). This thesis is an investigation on the role of eicosanoids and oxidized products of linoleic acid for the activation of PPARs. Special emphasis was given to the subtype PPAR/gamma/ in the context of atherosclerosis.

    It had earlier been shown that arachidonic acid induces peroxisome proliferation in Morris Hepatoma 7800C1 cells. We investigated whether this effect could be attributed to a cytochrome P-450IVA product of arachidonic acid, 20-hydroxy-arachidonic acid. Arachidonic acid, but not 20-hydroxy-arachidonic acid induced lauryl-CoA oxidase activity. The effect of arachidonic acid was potentiated by all-trans retinoic acid, consistent with the notion that PPAR/RXR heterodimers mediate the effect.

    Several reports in the litterature were suggestive of an important role of peroxisomes in eicosanoid metabolism. However, nobody had isolated pure peroxisomes and investigated their eicosanoid metabolizing ability. We therefore investigated the ability of peroxisomes to metabolize the eicosanoid 12(S)-hydroxy-5,8,10,14-eicosatetraenoic acid (12(S)-HETE). Incubation of tritium-labeled 12(S)-HETE with isolated peroxisomes from rat liver or kidney peroxisomes demonstrated that more than 90 % of the diethyl ether extractable radioactivity was due to a single metabolite, identified as 8-hydroxy-6, 8, 12-octadecatrienoic acid (8-OH-16:3). This compound was apparently formed by two rounds of ß-oxidation. The data for the first time provided conclusive evidence for a role of peroxisomes in HETE metabolism.

    The second half of the thesis deals with the identification of natural PPAR/gamma/ ligands in LDL from atherosclerotic patients and in activated macrophages. Analyses of the endogenous content of selected monohydroxy fatty acids in LDL isolated from a group of patients diagnosed with intermittent claudication, showed the presence of 9- and 13-HODE, 5-, 12-, and 15-HETE. These compounds activated PPAR/gamma/ in macrophages and preferentially recruited the coactivator protein CBP to PPAR/gamma/RXR/alpha/ heterodimers. 15-deoxy-/DELTA/12,14-Prostaglandin J2 (15-deoxy-/DELTA/12,14-PGJ2) was identified as a PGD2 metabolite in macrophage cultures (see below). It induced the interaction of PPAR/gamma/RXR/alpha/ heterodimers with both CBP and SRC-1. This observation suggests that different PPAR/gamma/ ligands may induce different effects through a single kind of receptor by differential recruitment of coactivators.

    Although PGD2, is not a PPAR/gamma/ ligand, it induces PPAR/gamma/-mediated effects in IFN-/gamma/-stimulated RAW 264.7 macrophages, suggesting that the effects required metabolism. We therefore investigated PGD2 metabolism in macrophage cultures, and determined the capacity of these metabolites to activate PPAR/gamma/. Two novel (/DELTA/12-PGD2, 15-deoxy-/DELTA/12,14-PGD2) and two previously known PPAR/gamma/ activators (/DELTA/12-PGJ2 and 15-deoxy-/DELTA/12,14-PGJ2) were identified by mass spectrometry. The structural difference between the novel products and the previously recognized PPAR/gamma/ agonists , /DELTA/12-PGJ2 and 15-deoxy-/DELTA/12,14-PGJ2, is that they contain a 9/alpha/-hydroxy group and lack a /DELTA/9,10 double bond. Two novel PPAR/gamma/ activators were formed in equal or greater amounts and were more potent activators of PPAR/gamma/ in macrophages.

  • 336.
    Wigren, Jane
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Surapureddi, Sailesh
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Olsson, Anders
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, MC - Medicincentrum, EMT-endo.
    Glass, C. K.
    University of California, San Diego, La Jolla, CA, USA.
    Hammarström, Sven
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Söderström, Mats
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Differential recruitment of the coactivator proteins CREB-binding protein and steroid receptor coactivator-1 to peroxisome proliferator-activated receptor gamma/9-cis-retinoic acid receptor heterodimers by ligands present in oxidized low-density lipoprotein2003In: Journal of Endocrinology, ISSN 0022-0795, E-ISSN 1479-6805, Vol. 177, no 2, p. 207-214Article in journal (Refereed)
    Abstract [en]

    Peroxisome proliferator-activated receptor gamma (PPAR?) colocalizes with oxidized low-density lipoprotein (LDL) in foam cells in atherosclerotic lesions. We have explored a potential role of oxidized fatty acids in LDL as PPAR? activators. LDL from patients suffering from intermittent claudication due to atherosclerosis was analyzed using HPLC and gas chromatography/mass spectrophotometry and found to contain 9-hydroxy-and 13-hydroxyoctadecadienoic acid (9- and 13-HODE), as well as 5-hydroxy-, 12-hydroxy- and 15-hydroxyeicosatetraenoic acid (5-, 12- and 15-HETE respectively). PPAR? was potently activated by 13(S)-HODE and 15(S)-HETE, as judged by transient transfection assays in macrophages or CV-1 cells. 5(S)- and 12(S)-HETE as well as 15-deoxy-?12,14 -prostaglandin J2 also activated PPAR? but were less potent. Interestingly, the effect of the lipoxygenase products 13(S -HODE and 15(S)-HETE as well as of the drug rosiglitazone were preferentially enhanced by the coactivator CREB-binding protein, whereas the effect of the cyclooxygenase product 15-deoxy-?12,14-prostaglandin J2 was preferentially enhanced by steroid receptor coactivator-1. We interpret these results, which may have relevance to the pathogenesis of atherosclerosis, to indicate that the lipoxygenase products on the one hand and the cyclooxygenase product on the other exert specific effects on the transcription of target genes through differential coactivator recruitment by PPAR?/9-cis retinoic acid receptor heterodimer complexes.

  • 337. Williams, Cecilia
    et al.
    Pontén, Fredrik
    Moberg, Catherine
    Söderkvist, Peter
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Uhlén, Mathias
    Pontén, Jan
    Sitbon, Gisela
    Lundeberg, Joakim
    A high frequency of sequence alterations is due to formalin fixation of Archival specimens2000In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 155, p. 1467-1471Article in journal (Refereed)
  • 338. Yang, Dan-Hui
    et al.
    Andersson, Bertil
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Aro, Eva-Mari
    Ohad, Itzhak
    The redox state of the plastoquinone pool controls the level of the light-harvesting chlorophyll a/b binding protein complex II (LHC II) during photoacclimation.2001In: Photosynthesis Research, ISSN 0166-8595, E-ISSN 1573-5079, Vol. 68, p. 163-174Article in journal (Refereed)
  • 339. Yang, Dan-Hui
    et al.
    Paulsen, Harald
    Andersson, Bertil
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    The N-terminal domain of the light-harvesting chlorophyll a/b-binding protein complex (LHCII) is essential for its acclimative proteolysis2000In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 466, no 2-3, p. 385-388Article in journal (Refereed)
    Abstract [en]

    Variations in the amount of the light-harvesting chlorophyll a/b-binding protein complex (LHCII) is essential for regulation of the uptake of light into photosystem II. An endogenous proteolytic system was found to be involved in the degradation of LHCII in response to elevated light intensities and the proteolysis was shown to be under tight regulation [Yang, D.-H. et al. (1998) Plant Physiol. 118, 827-834]. In this study, the substrate specificity and recognition site towards the protease were examined using reconstituted wild-type and mutant recombinant LHCII. The results show that the LHCII apoprotein and the monomeric form of the holoprotein are targeted for proteolysis while the trimeric form is not. The N-terminal domain of LHCII was found to be essential for recognition by the regulatory protease and the involvement of the N-end rule pathway is discussed. (C) 2000 Federation of European Biochemical Societies.

  • 340.
    Ydrenius, Liselotte
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Majeed, Meytham
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology.
    J Rasmusson, Birgitta
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology.
    Stendahl, Olle
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology.
    Särndahl, Eva
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Activation of cAMP-dependent protein kinase is necessary for actin rearrangements in human neutrophils during phagocytosis2000In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 67, no 4, p. 520-528Article in journal (Refereed)
    Abstract [en]

    We have investigated the role of cAMP and cAMP-dependent protein kinase (cAPK) in neutrophil phagocytosis. Inhibition of cAPK with H-89 reduced complement- and IgG-dependent phagocytosis to 83 and 46%, respectively. Fluorescence intensity measurements of phalloidin-stained actin in neutrophils showed a reduced amount of filamentous actin (F-actin) in pseudopods and around the phagosome in cells treated with H-89 or cAMP-elevating agents (forskolin and rolipram). The amount of phosphotyrosine-containing proteins was also reduced in pseudopods and around the phagosome. Taken together, the data show that cAMP/cAPK regulates F-actin reorganization during receptor-mediated phagocytosis, particularly triggered by IgG-FcR interaction. Our results support the hypothesis that active subcortical reorganization of F-actin is a prerequisite for FcR-mediated phagocytosis, but is less important during CR3-mediated ingestion.

  • 341. Yngveson, Anna
    et al.
    Williams, C
    Hjerpe, A
    Lundeberg, J
    Söderkvist, Peter
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Pershagen, G
    p53 mutations in lung cancer associated with residential radon exposure.1999In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 8, p. 433-438Article in journal (Refereed)
  • 342. Yokohama, T
    et al.
    Kaya, S
    Abe, K
    Taniguchi, K
    Katoh, T
    Yazawa, M
    Hayashi, Y
    Mårdh, Sven
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Acid-labile ATP and/or ADP/Pi binding to the tetraprotomeric form ofNa/K-ATPase accompanying catalytic phosphorylation-dephosphorylation cycle.1999In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 274, p. 31792-31794Article in journal (Refereed)
  • 343. Zak, Elena
    et al.
    Norling, Birgitta
    Maitra, Radhashree
    Huang, Fang
    Andersson, Bertil
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Pakrasi, Himadri
    The initial steps of biogenesis of cyanobacterial photosystems occur in plasma membranes2001In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 98, no 23, p. 13443-13448Article in journal (Refereed)
    Abstract [en]

    During oxygenic photosynthesis in cyanobacteria and chloroplasts of plants and eukaryotic algae, conversion of light energy to biologically useful chemical energy occurs in the specialized thylakoid membranes. Light-induced charge separation at the reaction centers of photosystems I and II, two multisubunit pigment-protein complexes in the thylakoid membranes, energetically drive sequential photosynthetic electron transfer reactions in this membrane system. In general, in the prokaryotic cyanobacterial cells, the thylakoid membrane is distinctly different from the plasma membrane. We have recently developed a two-dimensional separation procedure to purify thylakoid and plasma membranes from the genetically widely studied cyanobacterium Synechocystis sp. PCC 6803. Immunoblotting analysis demonstrated that the purified plasma membrane contained a number of protein components closely associated with the reaction centers of both photosystems. Moreover, these proteins were assembled in the plasma membrane as chlorophyll-containing multiprotein complexes, as evidenced from nondenaturing green gel and low-temperature fluorescence spectroscopy data. Furthermore, electron paramagnetic resonance spectroscopic analysis showed that in the partially assembled photosystem I core complex in the plasma membrane, the P700 reaction center was capable of undergoing light-induced charge separation. Based on these data, we propose that the plasma membrane, and not the thylakoid membrane, is the site for a number of the early steps of biogenesis of the photosynthetic reaction center complexes in these cyanobacterial cells.

  • 344.
    Zhang, Hong
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Ahmadi, Ahmad
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Arbman, G
    Zdolsek, J
    Carstensen, J
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Nordenskjöld, Bo
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Söderkvist, Peter
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Sun, Xiao-Feng
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology.
    Glutathione S-transferase T1 and M1 genotypes in normal mucosa, transitional mucosa and colorectal adenocarcinom.1999In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 84, p. 135-138Article in journal (Refereed)
  • 345.
    Zhang, Hong
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Evertsson, Sofia
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology.
    Sun, Xiao-Feng
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology.
    Clinicopathological and genetic characteristics of mucinous carcinomas in the colorectal.1999In: International Journal of Oncology, ISSN 1019-6439, Vol. 14, p. 1057-1061Article in journal (Refereed)
  • 346.
    Zhang, Hong
    et al.
    Linköping University, Department of Biomedicine and Surgery, Division of dermatology and venereology. Linköping University, Faculty of Health Sciences.
    Nordenskjöld, Bo
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Dufmats, Monika
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Söderkvist, Peter
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Sun, Xiao-Feng
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    K-ras mutations in colorectal adenocarcinomas and neighbouring transitional mucosa.1998In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 34, no 13, p. 2053-2057Article in journal (Refereed)
    Abstract [en]

    The K-ras gene in codons 12 and 13 was investigated using allele-specific polymerase chain reaction in matched normal mucosa (n = 106), transitional mucosa (n = 69) and tumours (n = 149) from 149 patients with colorectal adenocarcinomas. K-ras mutations in codon 12 were detected in 41/149 (28%) of tumours and 4/69 (6%) of transitional mucosa samples, but not in the normal mucosa. Further, mutation rates were increased in younger patients (P = 0.001) and in mucinous carcinomas (50%) compared with well differentiated (17%), moderately differentiated (26%) or poorly differentiated (24%) tumours. Our findings indicate that mucinous carcinoma may represent a distinct genetic entity.

  • 347.
    Zhao, Ming
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Liu, Yawei
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Bao, Mingmin
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Kato, Yutaka
    Han, Jiahuai
    Eaton, John Wallace
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Vascular smooth muscle cell proliferation requires both p38 and BMK1 MAP kinases2002In: Archives of Biochemistry and Biophysics, ISSN 0003-9861, E-ISSN 1096-0384, Vol. 400, no 2, p. 199-207Article in journal (Refereed)
    Abstract [en]

    Vascular smooth muscle cell (VSMC) proliferation is a key event in the progression of atherosclerosis. Induction of both c-fos (through the transcription factor Elk-1) and c-jun, both immediate early genes, is important for the stimulation of VSMC proliferation and migration. It was earlier found that p38 mitogen-activated protein (MAP) kinase upregulates c-jun gene transcription through phosphorylation of two myocyte enhancer factor 2 (MEF2) family transcription factors, MEF2A and MEF2C, while big MAP kinase 1 (BMK1) may upregulate c-jun gene transcription through MEF2A, MEF2C, and also MEF2D. Here, we report that inhibition of BMK1 by a dominant negative form of MEK5 or pharmacologic inhibition of p38 by SB 203580 additively suppress serum-induced VSMC proliferation. This additive effect of p38 and BMK1 inhibition implies that these two kinases coordinately regulate MEF2 transcription factors. The exclusive activation of MEF2D by BMK1 appears required for this cooperative upregulation of c-jun in VSMC, and coactivation of p38 and BMK1 also has additive effects on the activation of a reporter gene linked to the c-jun promoter in our experimental system. Thus, coordinate activity of both the p38 and BMK1 pathways appears necessary for optimal transcription of c-jun and, pari pasu, VSMC proliferation. These results may have implications for the future design of pharmacologic agents for inhibition of VSMC growth.

  • 348.
    Zhuang, Shi-Mei
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Molecular genetic alterations in chemically-induced lymphomas1999Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Lymphoma is one of the most common malignancies in humans. Its incidence has increased rapidly in the past 30 years. However, the molecular mechanisms underlying the development of lymphomas are largely unknown.

    Environmental carcinogens play an important role in tumorigenesis. 1,3-butadiene (BD) and 2~,3-dideoxycytidine (ddC) are two carcinogens to which humans are exposed. Cancer bioassays in mice have revealed that both BD and ddC induce high frequencies of lymphomas. The present study provides a genetic dissection of these chemically-induced lymphomas, with a focus on identification of potential turner suppressor loci and genetic alterations in genes involved in the pRb, p53 and Ras/Raf pathways. These pathways are important in the control of cell proliferation.

    Approximately 87% of BD-induced and 75% of ddC-induced lymphomas show allelic losses or mutations in genes examined. Similar frequencies for inactivation of the p53 pathway were observed in BD- and ddC-induced tumors, whereas disruption of the pRb pathway is more common in ddC-induced lymphomas. On the other hand, BD-induced tumors display more frequent activation of the Ras/Raf pathway. These data indicate the genotoxicity of both ddC and BD, and also confirm the carcinogenicity of these chemicals at a molecular level.

    This study also reveals that different genetic alterations occur in distinct stages of the development of BD-induced lymphomas. Ras mutations were detected in tumors derived from mice exposed to BD for only 26 weeks or at a rather low concentration (20 ppm), suggesting that ras mutations may occur early in tumor formation. In contrast, all six tumors with aberrations of p53 occurred in the high dose (625 ppm), continuous long-term exposure group, and these tumors appear to have a more aggressive phenotype, indicating that inactivation of p53 may be a late event, associated with progression of BD-induced lymphomas. Furthermore, two or more genetic alterations were found in 67% of tumors from the 625 ppm dose group and in only 46% of lymphomas derived from mice exposed to s312 ppm of BD. In addition, more than five genetic aberrations occurred only in the 625 ppm dose group. These results support the contention that there is a dose-dependent increase of genetic alterations in BD-induced tumors.

    The mutational pattern resulting from carcinogen-exposure has been observed in both human and animal turners. In the present study, the specific K-ras codon 13 CGC mutation and allelic loss of the Rafl locus on chromosome 6 were detected only in BD-induced lymphomas, while frequent allelic loss of the telomeric region of chromosome 2 was observed only in ddC-induced tumors, suggesting an agent-specific effect.

    The genome-wide screen of allelic losses revealed that multiple potential tumor suppressor genes contribute to the development of BD- and ddC-induced lymphomas. Moreover, most of the identified regions with frequent allelic losses carry unknown tumor suppressor genes, whose isolation and identification are of great interest for further investigation.

  • 349.
    Zhuang, Shi-Mei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Wiseman, Roger W
    Söderkvist, Peter
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Frequent mutations of the Trp53,Hras1 and beta-catenin (Catnb) genes in 1,3-butadiene-induced mammary adenocarcinomas in B6C3F1 mice2002In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 21, no 36, p. 5643-5648Article in journal (Refereed)
    Abstract [en]

    DNAs from 1,3-butadiene-induced mammary adenocarcinomas of B6C3F1 mice were examined for mutations in the Trp53 gene, the ras gene family and several components of the Wnt signaling pathway, including ▀-catenin (Catnb), Apc and Axin. Trp53 mutations were detected in 41% (7 out of 17) of tumors. Each tumor with a Trp53 mutation also exhibited loss of the wildtype Trp53 allele, supporting the importance of Trp53 inactivation during development of these tumors. Analyses of the Hras1, Kras2 and Aras proto-oncogenes revealed Hras1 mutations in 53% (9 out of 17) of tumors. Seven of these mutations were a G?C transversion in Hras1 codon 13, consistent with a 1,3-butadiene-specific Kras2 mutation previously reported in several other tumor types. Mutation screens in Catnb exon 2, the Apc mutation cluster region and the Catnb-binding domain of the Axin gene identified Catnb missense mutations in 3 out of 17 (18%) tumors. In total, mutations of the Trp53, Hras1 and/or Catnb genes were identified in 15 out of 17 1,3-butadiene-induced mammary adenocarcinomas. These results indicate that multiple genetic pathways are disrupted in chemically induced mammary tumors, and that studies in mouse models may help to understand the etiology of human breast cancers.

  • 350.
    Zhuang, Shi-Mei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Wiseman, Roger W
    Söderkvist, Peter
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Mutation analysis of the pRb pathway in 2',3'-dideoxycytidine- and 1,3-butadiene-induced mouse lymphomas2000In: Cancer Letters, ISSN 0304-3835, E-ISSN 1872-7980, Vol. 152, no 2, p. 129-134Article in journal (Refereed)
    Abstract [en]

    The pRb pathway plays a key role in controlling the G1/S transition in cell cycle progression. Aberrations of various components of the pRb pathway, such as retinoblastoma protein and its upstream actors including cyclin D1, cyclin dependence kinase-4 and p16/p15 cyclin dependent kinase inhibitors, have been reported in a variety of human tumors. Furthermore, the alterations of retinoblastoma protein and its upstream components often occur in a reciprocal manner. Previously, we have reported frequent inactivation of the Cdkn2a/Cdkn2b loci encoding p16/p15 cyclin dependent kinase inhibitors in a subset of 2',3'-dideoxycytidine- and 1,3-butadiene-induced mouse lymphomas (S.-M. Zhuang, A. Schippert, A. Haugen-Strano, R.W. Wiseman, P. Soderkvist, Inactivation of p16(INK4a)-a, p16(INK4a)-▀ and p15(INK4b) genes in 2',3'-dideoxycytidine- and 1,3-butadiene-induced lymphomas, Oncogene 16 (1998) 803-808), indicating the involvement of pRb pathway in lymphomagenesis. To investigate whether alteration of other components in pRb pathway is an alternative mechanism underlying the development of these chemically induced lymphomas, we have examined the genetic status of Rb1, Ccnd1 and Cdk4 genes that encode retinoblastoma protein, cyclin D1 and cyclin dependence kinase-4, respectively. Gross alterations of the Rb1, Ccnd1, and Cdk4 genes were not detected by Southern analysis in any of the tumors examined. In addition, single-strand conformation analysis failed to reveal point mutations in the Cdk4 amino terminal domain that is important for its association with Cdkn2a gene products. These results indicate that the mechanisms underlying the development of 2',3'-dideoxycytidine- and 1,3-butadiene-induced lymphomas involve inactivation of p16/p15 cyclin-dependent kinase inhibitors but not genomic alterations of the Rb1, Ccnd1 and Cdk4 genes. Copyright (C) 2000 Elsevier Science Ireland Ltd.

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