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  • 101.
    Stroikin, Yuri
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Linköping University, Faculty of Health Sciences.
    Dalen, Helge
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Linköping University, Faculty of Health Sciences.
    Lööf, Sara
    Terman, Alexei
    Linköping University, Department of Clinical and Experimental Medicine, Geriatric . Linköping University, Faculty of Health Sciences.
    Inhibition of autophagy with 3-methyladenine results in impaired turnover of lysosomes and accumulation of lipofuscin-like material2004In: European journal of cell biology, ISSN 0171-9335, Vol. 83, no 10, p. 583-590Article in journal (Refereed)
    Abstract [en]

    Autophagy (which includes macro-, micro-, and chaperone-mediated autophagy) is an important biological mechanism for degradation of damaged/obsolete macromolecules and organelles. Ageing non-dividing cells, however, progressively accumulate oxidised proteins, defective organelles and intralysosomal lipofuscin inclusions, suggesting inherent insufficiency of autophagy. To learn more about the role of macroautophagy in the turnover of organelles and lipofuscin formation, we inhibited autophagic sequestration with 3-methyladenine (3 MA) in growth-arrested human fibroblasts, a classical model of cellular ageing. Such treatment resulted in a dramatic accumulation of altered lysosomes, displaying lipofuscin-like autofluorescence, as well as in a moderate increase of mitochondria with lowered membrane potential. The size of the late endosomal compartment appeared not to be significantly altered following 3 MA exposure. The accumulation of lipofuscin-like material was enhanced when 3 MA administration was combined with hyperoxia. The findings suggest that macroautophagy is essential for normal turnover of lysosomes. This notion is supported by reports in the literature of lysosomal membrane proteins inside lysosomes and/or late endosomes, as well as lysosomes with active hydrolases within autophagosomes following vinblastine-induced block of fusion between lysosomes and autophagosomes. The data also suggest that specific components of lysosomes, such as membranes and proteins, may be direct sources of lipofuscin.

  • 102.
    Stroikin, Yuri
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Linköping University, Faculty of Health Sciences.
    Johansson, Uno
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Linköping University, Faculty of Health Sciences.
    Asplund, Sofia
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Linköping University, Faculty of Health Sciences.
    Öllinger, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Linköping University, Faculty of Health Sciences.
    Increased resistance of lipofuscin-loaded prematurely senescent fibroblasts to starvation-induced programmed cell death2007In: Biogerontology (Dordrecht), ISSN 1389-5729, E-ISSN 1573-6768, Vol. 8, no 1, p. 43-53Article in journal (Refereed)
    Abstract [en]

    Alterations of cellular structures often found in ageing cells is mainly the result of production of reactive oxygen species and a consequence of aerobic life. Both oxidative stress and decreased degradative capacity of lysosomal system cause accumulation of intralysosomal age-related pigment called lipofuscin. To investigate the influence of lipofuscin on cell function, we compared survival of lipofuscin-loaded and control human fibroblasts following complete starvation induced by exposure to phosphate-buffered saline (PBS). Starving of control fibroblasts resulted in lysosomal alkalinisation, relocation of cathepsin D to the cytosol, caspase-3 activation and, finally, cell death, which became evident 72 h after the start of exposure to PBS. Increase of lysosomal pH was significantly less prominent in lipofuscin-loaded cells than in controls and was accompanied neither by leakage of cathepsin D nor by caspase-3 activation even 96 h after the initiation of starvation. Suppression of autophagy by 3-methyladenine (3-MA) accelerated cell death, while inhibition of cathepsin D delayed it, implying an important role of autophagy in cell survival during starvation and showing the involvement of lysosomes in starvation-induced cell death. Disturbed apoptotic response found in lipofuscin-loaded cells can be interpreted as an example of hormesis—an adaptation to low doses of otherwise harmful agents, in this case of lipofuscin, which has a protective effect at moderate amounts but becomes toxic at large quantities.

  • 103.
    Stroikin, Yuri
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Mild, Hanna
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Johansson, Uno
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Roberg, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Oto-Rhiono-Laryngology and Head & Neck Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Reconstruction Centre, Department of ENT - Head and Neck Surgery UHL.
    Öllinger, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Lysosome-targeted stress reveals increased stability of lipofuscin-containing lysosomes2008In: Age (Omaha), ISSN 0161-9152, E-ISSN 1574-4647, Vol. 30, no 1, p. 31-42Article in journal (Refereed)
    Abstract [en]

    Cellular ageing is associated with accumulation of undegradable intralysosomal material, called lipofuscin. In order to accelerate the lipofuscin-accumulation, confluent, growth arrested human fibroblasts were cultured under hyperoxic conditions. To provide a better insight into the effects of lipofuscin on cellular functions, we compared lysosomal stability in control and lipofuscin-loaded human fibroblasts under conditions of lysosome-targeted stress induced by exposure to either the lysosomotropic detergent MSDH or the redox-cycling quinone naphthazarin. We show that lysosomal damage, assessed by acridine-orange relocation, translocation of cathepsin D to the cytosol, and alkalinization of lysosomes is more pronounced in control than in lipofuscin-loaded fibroblasts. Finding that lysosomal integrity was less affected or even preserved in case of lipofuscin-loaded cells enables us to suggest that lipofuscin exerts lysosome-stabilizing properties.

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  • 104.
    Svensson Holm, Ann-Charlotte
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Bengtsson, Torbjörn
    Örebro University.
    Grenegård, Magnus
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Lindström, Eva G
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Hyaluronic acid influence on platelet-induced airway smooth muscle cell proliferation2012In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 318, no 5, p. 632-640Article in journal (Refereed)
    Abstract [en]

    Hyaluronic acid (HA) is one of the main components of the extracellular matrix (ECM) and is expressed throughout the body including the lung and mostly in areas surrounding proliferating and migrating cells. Furthermore, platelets have been implicated as important players in the airway remodelling process, e.g. due to their ability to induce airway smooth muscle cell (ASMC) proliferation. The aim of the present study was to investigate the role of HA, the HA-binding surface receptor CD44 and focal adhesion kinase (FAK) in platelet-induced ASMC proliferation. Proliferation of ASMC was measured using the MTS-assay, and we found that the CD44 blocking antibody and the HA synthase inhibitor 4-Methylumbelliferone (4-MU) significantly inhibited platelet-induced ASMC proliferation. The interaction between ASMC and platelets was studied by fluorescent staining of F-actin. In addition, the ability of ASMC to synthesise HA was investigated by fluorescent staining using biotinylated HA-binding protein and a streptavidin conjugate. We observed that ASMC produced HA and that a CD44 blocking antibody and 4-MU significantly inhibited platelet binding to the area surrounding the ASMC. Furthermore, the FAK-inhibitor PF 573228 inhibited platelet-induced ASMC proliferation. Co-culture of ASMC and platelets also resulted in increased phosphorylation of FAK as detected by Western blot analysis. In addition, 4-MU significantly inhibited the increased FAK-phosphorylation. In conclusion, our findings demonstrate that ECM has the ability to influence platelet-induced ASMC proliferation. Specifically, we propose that HA produced by ASMC is recognised by platelet CD44. The platelet/HA interaction is followed by FAK activation and increased proliferation of co-cultured ASMC. We also suggest that the mitogenic effect of platelets represents a potential important and novel mechanism that may contribute to airway remodelling.

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  • 105.
    Söderholm, Johan D
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Surgery . Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Wiren, M
    Linkoping Univ, Linkoping, Sweden McMaster Univ, Hamilton, ON, Canada.
    Franzén, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Perdue, MH
    Linkoping Univ, Linkoping, Sweden McMaster Univ, Hamilton, ON, Canada.
    Olaison, Gunnar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Surgery . Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    "Topical" phase effects of acetysalicylic acid on human small bowel epithelium: Inhibition of oxidative phosphorylation and increased tight junction permeability.2000In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 118, no 4, p. 4298-Conference paper (Other academic)
  • 106.
    Sörgjerd, Karin
    et al.
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biochemistry.
    Klingstedt, Therése
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Lindgren, Mikael
    Norwegian University of Science & Technology.
    Kågedal, Katarina
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Linköping University, Faculty of Health Sciences.
    Hammarström , Per
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Prefibrillar transthyretin oligomers and cold stored native tetrameric transthyretin are cytotoxic in cell culture2008In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 377, no 4, p. 1072-1078Article in journal (Refereed)
    Abstract [en]

    Recent studies Suggest that Soluble, oligomeric species, which are intermediates in the fibril formation process in amyloid disease, might be the key species in amyloid pathogenesis. Soluble oligomers of human wild type transthyretin (TTR) were produced to elucidate oligomer properties. Employing ThT fluorescence, time-resolved fluorescence anisotropy of pyrene-labeled TTR, chemical cross-linking, and electron microscopy we demonstrated that early formed soluble oligomers (within minutes) from A-state TTR comprised on the average 20-30 TTR monomers. When administered to neuroblastoma cells these early oligomers proved highly cytotoxic and induced apoptosis after 48 h of incubation. More Mature fibrils (> 24 h of fibrillation) were non-toxic. Surprisingly, we also found that native tetrameric TTR, when purified and stored under cold conditions (4 degrees C) was highly cytotoxic. The effect Could be partially restored by increasing the temperature of the protein. The cytotoxic effects of native tetrameric TTR likely stems from a hitherto unexplored low temperature induced rearrangement of the tetramer conformation that possibly is related to the conformation of misfolded TTR in amyloigogenic oligomers.

  • 107.
    Sörgjerd, Karin
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Klingstedt, Therése
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Lindgren, Mikael
    Department of Physics, Norwegian University of Science and Technology, 7491 Trondheim, Norway.
    Kågedal, Katarina
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Linköping University, Faculty of Health Sciences.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Prefibrillar Amyloid Aggregates and Cold Shocked Tetrameric Wild Type Transthyretin are CytotoxicManuscript (Other academic)
    Abstract [en]

    Recent studies suggest that soluble, oligomeric species, which are intermediates in the fibril formation process in amyloid disease, might be the key species in amyloid pathogenesis. Soluble oligomers of TTR were produced by kinetic sampling from a TTR fibrillation reaction (A-state TTR, pH 2, 100 mM NaCl). The reaction was terminated at different time points, and different states in the aggregation process were captured and analyzed to elucidate the oligomer properties followed by sampling for cytotoxicity using exposure towards human SH-SYY5 neuroblastoma cells. Employing ThT fluorescence, time-resolved fluorescence anisotropy of pyrenelabeled TTR, chemical cross-linking and electron microscopy we demonstrated that early formed oligomers from A-state TTR were soluble and comprised on the average 20-30 TTR monomers. Early oligomers were highly cytotoxic and induced apoptosis as indicated by the MTT assay and caspase-3 activation, whereas mature fibrils were non-toxic. We also indicate an activated unfolded protein response in cells exposed to oligomers as evidenced by an increased expression of the endoplasmic reticulum located molecular chaperone BiP. Following exposure, BiP appeared relocalized to the cytoplasm. Surprisingly, we also found that native tetrameric TTR purified and stored under cold conditions (4 °C) was highly cytotoxic. The effect could be partially restored by increasing the temperature of the protein. The molecular basis for this pathogenicity is rather unclear but likely stems from previously reported increased sensitivity towards dissociation and denaturation of TTR at low temperatures and opens the possibility that rearranged tetrameric TTR is cytotoxic towards neuroblastoma cells.

  • 108.
    Sörgjerd, Karin
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Wiseman, R. Luke
    Skirball Institute, New York University School of Medicine, 540 First Avenue, New York, NY, USA.
    Kågedal, Katarina
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Berg, Ina
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Klingstedt, Therése
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Budka, Herbert
    Institute of Neurology, Medical University of Vienna, Vienna, Austria.
    Nilsson, K. Peter R.
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry .
    Ron, David
    Skirball Institute, New York University School of Medicine, 540 First Avenue, New York, NY, USA.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    BiP can function as a molecular shepherd that alleviates oligomer toxicity and amass amyloidManuscript (Other academic)
    Abstract [en]

    A wide range of diseases are linked to protein misfolding and aggregation inside and outside the cell. It is of utmost interest to understand how the molecular chaperone machinery of the endoplasmic reticulum (ER) handles the expression of highly amyloidogenic proteins. We explored the hypothesis that the ER located Hsp70 molecular chaperone BiP plays a crucial role in amyloid diseases and influence the misfolding process and disease progression. We used the transthyretin mutant TTR D18G associated with an unusual central nervous system amyloid disease as the model substrate because it represents the most destabilized and degraded TTR variant known. Over-expression of TTR D18G in concert with BiP showed that BiP selectively recognize the amyloidogenic mutant protein as compared to wild type in human cells and collects the mutant in stable intermediate size oligomers within the ER. Furthermore, whereas TTR D18G was found to be highly cytotoxic to neuroblastoma cells, TTR D18G preincubated with BiP was non-toxic indicating that BiP protects the cell from cytotoxicity. BiP was also found present in cerebellar amyloid deposits and co-localized with TTR in a TTR D18G patient suggesting that the complex can be found in the extracellular space. We promote a fundamental role of BiP in misfolding diseases and describe a molecular shepharding function of BiP in sequestrating amyloidogenic protein molecules in benign oligomeric states.

  • 109.
    Telang, S
    et al.
    Baylor Coll Med, Dept Ped, Houston, TX 77030 USA Calif State Univ Los Angeles, Dept Biol, Chico, CA 95929 USA Linkoping Univ, Div Path, Linkoping, Sweden.
    Mahoney, J
    Baylor Coll Med, Dept Ped, Houston, TX 77030 USA Calif State Univ Los Angeles, Dept Biol, Chico, CA 95929 USA Linkoping Univ, Div Path, Linkoping, Sweden.
    Law, I
    Baylor Coll Med, Dept Ped, Houston, TX 77030 USA Calif State Univ Los Angeles, Dept Biol, Chico, CA 95929 USA Linkoping Univ, Div Path, Linkoping, Sweden.
    Lundqvist-Gustafsson, H
    Baylor Coll Med, Dept Ped, Houston, TX 77030 USA Calif State Univ Los Angeles, Dept Biol, Chico, CA 95929 USA Linkoping Univ, Div Path, Linkoping, Sweden.
    Qian, M
    Baylor Coll Med, Dept Ped, Houston, TX 77030 USA Calif State Univ Los Angeles, Dept Biol, Chico, CA 95929 USA Linkoping Univ, Div Path, Linkoping, Sweden.
    Eaton, John Wallace
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Iron dependent virulence in E. coli - A strain specific phenomenon2000In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 14, no 4, p. A280-A280Conference paper (Other academic)
  • 110.
    Telang, S
    et al.
    Univ Louisville, James Graham Brown Canc Ctr, Louisville, KY 40202 USA Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA Univ Illinois, Dept Pathobiol, Urbana, IL 61801 USA Calif State Univ Chico, Dept Biol, Chico, CA USA Linkoping Univ, Fac Hlth Sci, Div Pathol 2, Linkoping, Sweden.
    Vimr, E
    Univ Louisville, James Graham Brown Canc Ctr, Louisville, KY 40202 USA Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA Univ Illinois, Dept Pathobiol, Urbana, IL 61801 USA Calif State Univ Chico, Dept Biol, Chico, CA USA Linkoping Univ, Fac Hlth Sci, Div Pathol 2, Linkoping, Sweden.
    Mahoney, JR
    Univ Louisville, James Graham Brown Canc Ctr, Louisville, KY 40202 USA Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA Univ Illinois, Dept Pathobiol, Urbana, IL 61801 USA Calif State Univ Chico, Dept Biol, Chico, CA USA Linkoping Univ, Fac Hlth Sci, Div Pathol 2, Linkoping, Sweden.
    Law, I
    Univ Louisville, James Graham Brown Canc Ctr, Louisville, KY 40202 USA Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA Univ Illinois, Dept Pathobiol, Urbana, IL 61801 USA Calif State Univ Chico, Dept Biol, Chico, CA USA Linkoping Univ, Fac Hlth Sci, Div Pathol 2, Linkoping, Sweden.
    Lundqvist-Gustafsson, H
    Univ Louisville, James Graham Brown Canc Ctr, Louisville, KY 40202 USA Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA Univ Illinois, Dept Pathobiol, Urbana, IL 61801 USA Calif State Univ Chico, Dept Biol, Chico, CA USA Linkoping Univ, Fac Hlth Sci, Div Pathol 2, Linkoping, Sweden.
    Qian, MW
    Univ Louisville, James Graham Brown Canc Ctr, Louisville, KY 40202 USA Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA Univ Illinois, Dept Pathobiol, Urbana, IL 61801 USA Calif State Univ Chico, Dept Biol, Chico, CA USA Linkoping Univ, Fac Hlth Sci, Div Pathol 2, Linkoping, Sweden.
    Eaton, John Wallace
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Strain-specific iron-dependent virulence in Escherichia coli2001In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 184, no 2, p. 159-165Article in journal (Refereed)
    Abstract [en]

    For reasons unknown, certain Escherichia coli strains become highly virulent when injected with hemoglobin or other soluble iron sources. Two clinical isolates (virulent and nonvirulent) showed equivalent hemoglobin-mediated growth acceleration in vitro. However, when injected intraperitoneally into mice without hemoglobin, the virulent strain was cleared more slowly (t(1/2), >4 h vs. <30 min). The virulent E. coli strain had a polysialic acid-containing capsule, whereas the nonvirulent strain did not. Virulent E. coli grown at 20C (which blocks polysialylation) were cleared as rapidly as nonvirulent organisms. In another virulent E. coli strain having abundant outer membrane polysialic acid, targeted deletion of the polysialyltransferase accelerated host clearance and blocked iron-dependent virulence. The iron-dependent virulence of certain E. coli strains may represent the combined effect of slow in vivo clearance-associated, in this case, with outer membrane polysialylation coupled with accelerated growth permitted by iron compounds.

  • 111.
    Terman, Alexei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Geriatric .
    Dalen, Helge
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology .
    Eaton, John Wallace
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Neuzil, Jiri
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology .
    Brunka, UT
    Aging of cardiac myocytes in culture - Oxidative stress, lipofuscin accumulation, and mitochondrial turnover2004In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1019, p. 70-77Article in journal (Refereed)
    Abstract [en]

    Oxidative stress is believed to be an important contributor to aging, mainly affecting long-lived postmitotic cells such as cardiac myocytes and neurons. Aging cells accumulate functionally effete, often mutant and enlarged mitochondria, as well as an intralysosomal undegradable pigment, lipofuscin. To provide better insight into the role of oxidative stress, mitochondrial damage, and lipofuscinogenesis in postmitotic aging, we studied the relationship between these parameters in cultured neonatal rat cardiac myocytes. It was found that the content of lipofuscin, which varied drastically between cells, positively correlated with mitochondrial damage (evaluated by decreased innermembrane potential), as well as with the production of reactive oxygen species. These results suggest that both lipofuscin accumulation and mitochondrial damage have common underlying mechanisms, likely including imperfect autophagy and ensuing lysosomal degradation of oxidatively damaged mitochondria and other organelles. Increased size of mitochondria (possibly resulting from impaired fission due to oxidative damage to mitochondrial DNA, membranes, and proteins) also may interfere with mitochondrial turnover, leading to the appearance of so-called "giant" mitochondria. This assumption is based on our observation that pharmacological inhibition of autophagy with 3-methyladenine induced only moderate accumulation of large (senescent-like) mitochondria but drastically increased numbers of small, apparently normal mitochondria, reflecting their rapid turnover and suggesting that enlarged mitochondria are poorly autophagocytosed. Overall, our findings emphasize the importance of mitochondrial turnover in postmitotic aging and provide further support for the mitochondrial-lysosomal axis theory of aging.

  • 112. Veress, B
    et al.
    Franzén, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Bodin, L
    Borch, Kurt
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Surgery . Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Duodenal intraepithelial lymphocyte-count revisited2004In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 39, no 2, p. 138-144Article in journal (Refereed)
    Abstract [en]

    Background: The number of intraepithelial lymphocytes in the duodenum was determined 30 years ago, the suggested normal upper limit being 40 lymphocytes per 100 epithelial cells. Methods: Duodenal mucosa was analysed from 18 healthy individuals and 56 consecutive patients biopsied because of epigastralgia (17 cases), diarrhoea (10 cases), oesophagitis (10 cases), iron-deficiency (9 cases) and B12-deficiency (10 cases) showing normal histology, along with 10 cases of active coeliac disease. The biopsies were fixed in 4% formalin overnight and embedded in paraffin. Three micrometre thick sections were stained with haematoxylin and eosin and CD3. At least 300 epithelial cells were counted, the number of intraepithelial lymphocytes was given as the mean/100 epithelial cells. Extensive statistical analyses were performed. Results: In the healthy individuals the mean number (s) of intraepithelial lymphocytes/100 epithelial cells was 10.8 (2.6) and 13.2 (3.8) in H&E and CD3 stained sections, respectively. The upper limit of the confidence interval for CD3 staining was 29. There was no significant difference between normal individuals and the clinical groups, with the exception of coeliac disease. Conclusion: Two-step analysis of intraepithelial lymphocyte-determination is suggested: (a) semi-quantitative estimate on H&E-stained sections (normal ratio of 1:5 between lymphocytes and enterocytes, upper normal limit 20 lymphocytes) and (b) CD3-staining and counting if intraepithelial lymphocytosis is suspected. The upper normal range of intraepithelial lymphocytes is set at 25 CD3+ lymphocytes/100 epithelial cells. Values between 25 and 29 are regarded as 'borderline' and 30 or more represent pathologic intraepithelial lymphocytosis in the duodenum.

  • 113.
    Wallon, Conny
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Braaf, Ylva
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Wolving, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Linköping University, Faculty of Health Sciences.
    Olaison, Gunnar
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Söderholm, Johan D.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Endoscopic biopsies in Ussing chambers evaluated for studies of macromolecular permeability in the human colon2005In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, Vol. 40, no 5, p. 586-595Article in journal (Refereed)
    Abstract [en]

    Objective Studies of mucosal permeability to protein antigens in humans are limited to in vitro techniques. The use of surgical specimens for such studies has major shortcomings. Endoscopic biopsies in Ussing chambers have been introduced as a means of studying secretion and transepithelial permeability, but have not been evaluated for studies of protein antigen uptake in human intestine.

    Material and methods Standard forceps biopsies from the sigmoid colon of 24 healthy volunteers were mounted in Ussing chambers with an exposed tissue area of 1.76 mm2. 51Cr-EDTA (paracellular probe) and horseradish peroxidase (HRP; 45 kDa protein antigen) were used as permeability markers. Mucosal permeability, electrophysiology, histology and energy contents of the biopsies were studied over time. To evaluate the ability of the technique to detect permeability changes, the mucosa was modulated with capric acid, a medium-chain fatty acid, known to affect tight junctions.

    Results In the Ussing chamber the mucosal biopsies were viable for 160 min with stable levels of ATP and lactate, and only minor changes in morphology. Steady-state permeability with low variability was seen for both markers during the 30-90 min period. Exposure to capric acid induced a rapid decrease in short-circuit current (Isc) and a slower reversible decrease in transepithelial resistance (TER), as well as an increased permeability to 51Cr-EDTA and HRP.

    Conclusions Endoscopic biopsies of human colon are viable in Ussing chambers and are reliable tools for studies of mucosal permeability to protein antigens. The technique offers a broad potential for studies of mucosal function in the pathophysiology of human gastrointestinal diseases.

  • 114.
    Wearden, ME
    et al.
    Baylor Coll Med, Houston, TX 77030 USA Linkoping Univ Hosp, S-58185 Linkoping, Sweden.
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
    Terman, Alexei
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Geriatric .
    Eaton, John Wallace
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Mitochondria: Potential importance in hyperoxic lung injury2000In: Pediatric Research, ISSN 0031-3998, E-ISSN 1530-0447, Vol. 47, no 4, p. 2244-Conference paper (Other academic)
  • 115.
    Wäster, Petra
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Dermatology and Venerology . Linköping University, Faculty of Health Sciences.
    Öllinger, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Redox-Dependent Translocation of p53 to Mitochondria or Nucleus in Human Melanocytes after UVA- and UVB-Induced Apoptosis2009In: JOURNAL OF INVESTIGATIVE DERMATOLOGY, ISSN 0022-202X, Vol. 129, no 7, p. 1769-1781Article in journal (Refereed)
    Abstract [en]

    The p53 protein is an important transcription factor and tumor suppressor that is induced in response to many forms of cellular stress. UVA irradiation of human melanocytes caused generation of reactive oxygen species, which altered the intracellular redox balance and was accompanied by translocation of p53 to mitochondria. In contrast, UVB did not affect the redox status and p53 was translocated to the nucleus. Although different intracellular location of p53, UVA/B induced apoptosis through the intrinsic pathway detected as translocation of Bax to mitochondria, release of cytochrome c, and activation of caspases. These events were all prevented by inhibition of p53 with pifithrin-alpha. Furthermore, inhibition of p53 prevented lysosomal membrane permeabilization, detected as translocation of cathepsins to the cytosol, after UVB exposure, whereas UVA-induced lysosomal release was unaffected by inhibition of p53. In control cells, p53 coimmunoprecipitated with the antiapoptotic proteins Bcl-2 and Bcl-x(L) and upon UVA exposure the interaction was replaced by binding to the proapoptotic proteins Bax, Noxa, and Puma. Our findings suggest that UVA-induced apoptosis is caused by extensive oxidative damage leading to p53-regulated mitochondrial release, whereas UVB induces DNA damage and apoptosis signaling upstream of lysosomal membrane permeabilization.

  • 116. Xu, HT
    et al.
    Wang, L
    Lin, D
    Liu, Yawei
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology .
    Liu, N
    Yuan, Ximing
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine.
    Wang, EH
    Abnormal beta-catenin and reduced axin expression are associated with poor differentiation and progression in non-small cell lung cancer2006In: American Journal of Clinical Pathology, ISSN 0002-9173, E-ISSN 1943-7722, Vol. 125, no 4, p. 534-541Article in journal (Refereed)
    Abstract [en]

    We studied the expression of axin and beta-catenin and their relation to clinicopathologic factors in 100 non-small cell lung cancers (NSCLCs) by immunohistochemical analysis. The mutation in exon 3 of the beta-catenin gene was examined by polymerase chain reaction and direct sequencing. Preserved axin expression was significantly higher in well- and moderately differentiated NSCLC samples than in poorly differentiated ones. Reduced membranous expression of beta-catenin was shown in 80 cases, whereas 26 cases had aberrant nuclear expression. Poor differentiation and lymph node metastasis were associated significantly with reduced beta-catenin expression. Lower axin expression was related significantly to higher nuclear beta-catenin expression. However, this study failed to detect any exon 3 mutation in the beta-catenin gene in the 100 NSCLC samples. We conclude that reduced beta-catenin and axin expression might predict poor differentiation in NSCLC. Reduced axin expression, but not mutation in exon 3, might be an important explanation for the abnormal beta-catenin expression in NSCLC.

  • 117. Yang, H.
    et al.
    Larsson, Jenny
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology .
    Permert, J.
    Wiren, M.
    Bolus ornithine and arginine-ketoglutarate supplementation in distal intestine after 65% resection in rats2000In: Nutrition Research, ISSN 0271-5317, E-ISSN 1879-0739, Vol. 20, no 12, p. 1807-1816Article in journal (Refereed)
    Abstract [en]

    Introduction: Enteral feeding has been reported to increase intestinal mucosa proliferation after resection. Dietary components influence the intestinal adaptive response. The purpose of this study was to evaluate the effect of ornithine- (OKG) or arginine-ketoglutarate (AKG) bolus supplementation on intestinal postresectional adaptation in the rat. Methods: Male Wistar rats underwent 65% small-bowel resection and received either OKG 3 g/kg/day, isonitrogenous AKG or saline by gavage once daily. The animals had free access to rat chow. Sampling was done 10 days after resection. Fed animals without surgery or specific treatment served as controls. Results: Mucosal wet weight, DNA, RNA, protein content and sucrose activity of the mucosa, as well as villus height were significantly increased in all resected animals compared to controls. No significant differences in body weight or intestinal adaptation could be found between the three dietary groups. Conclusion: Postoperative enteral bolus feeding supplemented with OKG or AKG did not significantly enhance the adaptation of the remnant small bowel 10 days after massive intestinal resection when rats had free access to rat chow. © 2000 Elsevier Science Inc.

  • 118.
    Yuan, XiMing
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Brunk, Ulf
    Linköping University, Department of Medicine and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Iron and LDL-oxidation in atherogenesis1998In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 106, no 9, p. 825-842Article in journal (Refereed)
    Abstract [en]

    It has been proposed that the development of atherosclerosis may be linked to the size of the body iron stores. The exact role of iron in the initiation and progression of atherogenesis is, however, still unknown. As a result of increasing support for the LDL-oxidation hypothesis, much additional knowledge about the relation between iron and atherosclerosis has recently been gained. This review presents the current evidence on the role of iron--being a potent catalyst of oxidative reactions--and macrophage-mediated LDL-oxidation in atherogenesis. The authors hypothesize that iron, as a possible central intermediary, may play an important role in cell-mediated LDL-oxidation.

  • 119.
    Yuan, XiMing
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Brunk, Ulf
    Linköping University, Department of Medicine and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Olsson, Anders
    Linköping University, Department of Medicine and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Endocrinology and Gastroenterology UHL.
    Effects of iron- and hemoglobin-loaded human monocyte-derived macrophages on oxidation and uptake of LDL1995In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 15, no 9, p. 1345-51Article in journal (Refereed)
    Abstract [en]

    It is generally accepted that transition metals are required for cellular LDL oxidation. LDL may also be oxidized by iron and reducing agents in cell-free systems. We hypothesized that lysosomal iron may be exocytosed from macrophages that have been iron loaded by phagocytosis and degradation of iron-rich structures, eg, erythrocytes, and that such released iron may promote LDL oxidation and uptake by macrophages. Human monocyte-derived macrophages (HMDMs) were isolated and cultured for 7 days and then exposed to FeCl3, Fe-ADP, or Fe-EDTA (100 mumol/L) or hemoglobin (25 or 50 micrograms/mL) for 24 hours. After rinsing, LDL (50 to 150 micrograms/mL) was added in fresh culture medium without serum. After another 24 hours the media concentrations of iron and thiobarbituric acid-reacting substances as well as the electrophoretic mobility of LDL were increased, while the cells showed only minimal signs of decreased viability. Lipofuscin, neutral lipids, and phospholipids accumulated in a granular, lysosome-like pattern, and the cells acquired a foam cell-like morphology. There was a strong correlation (r = .87, P = .005) between the amount of iron added during the pre-exposure period and lipofuscin accumulation during the ensuing exposure to LDL in fresh, serum-free medium. Our results support our hypothesis and indicate that lysosomal iron may be exocytosed from HMDMs and promote oxidation and uptake of LDL and thus induce foam cell formation.

  • 120.
    Yuan, XiMing
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Li, Wei
    Linköping University, Department of Medicine and Health Sciences. Linköping University, Faculty of Health Sciences.
    Olsson, Anders
    Linköping University, Department of Medicine and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Endocrinology and Gastroenterology UHL.
    Brunk, Ulf
    Linköping University, Department of Medicine and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    The toxicity to macrophages of oxidized low-density lipoprotein is mediated through lysosomal damage1997In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 133, no 2, p. 153-61Article in journal (Refereed)
    Abstract [en]

    Oxidized low-density lipoprotein (ox-LDL) has been shown to degrade poorly within the secondary lysosomes of macrophages but its possible effect on lysosomal integrity has received less attention. The effect of ultraviolet-C oxidized LDL (UVox-LDL) on cellular viability, and lysosomal membrane stability, was examined on cultured murine J-774 cells and human monocyte-derived macrophages (HMDMs). The acridine orange (AO) relocalization test was applied to study the lysosomal integrity of living cells. UVox-LDL dramatically reduced J-774 cell proliferation at a concentration of 25 microg/ml. Incubation with 5 microM copper alone, normally used to induce LDL oxidation, was also toxic. In contrast to the effects of ox-LDL, in concentrations up to 75 microg/ml, native LDL (nLDL) rather stimulated J-774 cell replication. Incubation with UVox-LDL (25-75 microg/ml) also altered cellular AO uptake, depending on time and dose: its lysosomal accumulation decreased and its cytosolic accumulation increased. This shift indicates damaged lysosomal membranes with decreased intralysosomal, and increased cytosolic, H+ concentration. Many J-774 cells exposed to UVox-LDL initially transformed into foam cells and then assumed an apoptotic-type morphology with TUNEL-positive nuclei. We conclude that ox-LDL is cytotoxic to macrophages due to oxidative damage of lysosomal membranes, with ensuing destabilization and leakage to the cytosol of lysosomal contents, such as hydrolytic enzymes, causing degeneration of apoptotic type.

  • 121.
    Yuan, XiMing
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Olsson, Anders
    Linköping University, Department of Medicine and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Brunk, Ulf
    Linköping University, Department of Medicine and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Iron in human atheroma and LDL oxidation by macrophages following erythrophagocytosis1996In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 124, no 1, p. 61-73Article in journal (Refereed)
    Abstract [en]

    The oxidative modification of low density lipoprotein (LDL) has been implicated as an early step in the formation of atheromatous lesions. In vitro studies suggest it to be accelerated, or even initiated, by transition metals such as iron or copper in combination with a reducing agent. Even if such metals have been demonstrated in atheroma gruels, their origin and precise localisation within human atheroma are presently unknown. In the initial part of this study we applied Pearl's method, energy dispersive X-ray microanalysis, and a modified Timm sulphide silver method (SSM) to demonstrate the occurrence of iron in early atherosclerotic lesions from a number of consecutive autopsy cases with evident, general atheromatosis. With the very sensitive SSM, but not with the other techniques, we found foam cells to contain heavy metals with a mainly lysosomal localization. On the basis of the hypothesis that such a lysosomal accumulation of iron might be due to erythrophagocytosis by migrating tissue-bound macrophages that later develop into foam cells, we designed an in vitro model system where human monocyte-derived macrophages were exposed to artificially aged, UV-exposed erythrocytes. The macrophages were then exposed to LDL in serum-and iron-free RPMI medium, occasionally in the presence of the potent iron-chelator desferrioxamine. The capacity of macrophages to oxidise LDL was much enhanced following erythrophagocytosis, and the process was shown to involve secretion of iron. Consequently, LDL oxidation was greatly inhibited by desferrioxamine. We conclude that iron may be exocytosed by macrophages that previously had their lysosomal apparatus enriched with iron, e.g. due to erythrophagocytosis. Oxidation of LDL may result in ensuing foam cell-formation secondary to scavenger-receptor mediated endocytosis by macrophages.

  • 122.
    Yuan, Xi-Ming
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Osman, Ehab
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Miah, Sayem
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Zadeh, Shahram Nour Mohammad
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Xu, Lihua
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Forssell, Claes
    Linköping University, Department of Medical and Health Sciences, Vascular surgery. Linköping University, Faculty of Health Sciences.
    Li, Wei
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    p53 expression in human carotid atheroma is significantly related to plaque instability and clinical manifestations2010In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 210, no 2, p. 392-399Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The expression of p53 has been associated with DNA damage, cell senescence, proliferation and apoptosis in human atherosclerotic plaques. However, it is largely unknown whether p53 expression is related to the stability and clinical manifestations of atherosclerotic plaques in humans. In the present study, we examined whether p53 expression is related to clinical symptoms and plaque integrity in patients with carotid atherosclerosis (n=62). We also investigated p53 expression and its relation to apoptosis and apoptosis-related cathepsin L and ferritin in the carotid lesions. METHODS AND RESULTS: We found that smooth muscle cells often had nuclear p53 in the shoulder region of carotid lesions while CD68-positive macrophages, which had both nuclear and cytoplasmic p53, frequently appeared in the surrounding areas of necrotic cores or plaque cap regions. Quantitative image analysis of immunohistochemistry showed that p53 expression was significantly increased in plaques with necrotic core formation or cap rupture and lesions from patients with transient ischemic attacks (TIAs). The levels of p53 expression was significantly increased in more severe stenosed lesions but decreased with prolonged time between symptom onset and carotid endarterectomy. Furthermore, p53 expression was significantly correlated with the expression of ferritin, lysosomal cathepsin L, and apoptosis. CONCLUSION: The increased p53 expression, particularly macrophage p53 levels, is associated with the enlargement of necrotic cores, plaque rupture and clinical manifestations of carotid plaques. Concomitant increases of lysosomal cathepsin, ferritin, and p53 levels may promote the apoptosis and atheroma progression in patients with carotid atherosclerosis.

  • 123.
    Yuan, XiMing
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Xie, F P
    Dalian Medical University, China.
    Lu, Z B
    Dalian Medical University, China.
    Wen, T X
    Dalian Medical University, China.
    Zhuang, Y J
    Dalian Medical University, China.
    Jones, A C
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Zhang, Z
    Dalian Medical University, Chin.
    The establishment of two cell lines from a mouse uterine cervical carcinoma (U14) and their metastatic phenotype changes1995In: Clinical and Experimental Metastasis, ISSN 0262-0898, E-ISSN 1573-7276, Vol. 13, no 6, p. 463-73Article in journal (Refereed)
    Abstract [en]

    This paper studies the heterogeneity of metastatic potential of murine cervical carcinoma (U14). Two cell lines, P11-90 and L10-90, were established from a pulmonary metastatic substrain (U14AP11) and a lymphatic metastatic substrain (U14AL10), which were selected from U14 in vivo after 11 and 10 passages, respectively. The biologic differences between the two cell lines are as follows. (1) The cells of the P11-90 line grow more rapidly compared with the L10-90 line. From the 40th passage the medium pH was different. (2) The median number of chromosomes in P11-90 and L10-90 was 72 and 64, respectively; the rates of gap aberration were 88% and 78%, respectively. (3) The number of T lymphocytes and T helper lymphocytes in the peripheral blood from hosts with P11-90 were higher than that of hosts transplanted with L10-90, but the number of B lymphocytes in the latter was larger than that in the former. (4) The metastatic potential of each cell line partially decreased compared to the relative tumor substrain, but their organ preference still remained and the transplant locations, axillary or footpad, had a prominent influence on their metastatic behavior. To observe the effects of metastatic target organs on the metastatic phenotypes of tumor cells, as well as to explore a method for the establishment and maintenance of the metastatic organ preference of tumor cells, conditioned medium (CM) from pulmonary or lymphatic node diploid cells was added to the culture medium of P11-90 and L10-90. Two sublines, P + P11-90 and Ln + L10-90, were thus established. Using stereological methods we found that the majority of P + P11-90 cells became larger and their nuclei also increased in size compared with their parental lines, but the majority of Ln + L10-90 cells became smaller in size, though the nuclei were enlarged. The pulmonary metastatic rate and lymphatic metastatic rate of P + P11-90, as well as the lymphatic metastatic rate of Ln + L10-90, were restored dramatically. The results suggest that by taking advantage of the interaction between tumor cells and the CM of host cells the metastatic potential of tumor cell lines can be maintained in vitro. Our work may offer an experimental model for the manipulation of metastasis of cell lines coming from the same parent strain but with different metastatic potentials.(ABSTRACT TRUNCATED AT 400 WORDS)

  • 124.
    Zhao, Ming
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine.
    Liu, Yawei
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology .
    Wang, X.
    Department of Immunology, Scripps Research Institute, 10550 North Torrey Pines Road, San Diego, CA, United States.
    New, L.
    Department of Immunology, Scripps Research Institute, 10550 North Torrey Pines Road, San Diego, CA, United States.
    Han, J.
    Department of Immunology, Scripps Research Institute, 10550 North Torrey Pines Road, San Diego, CA, United States.
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
    Activation of the p38 MAP kinase pathway is required for foam cell formation from macrophages exposed to oxidized LDL2002In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 110, no 6, p. 458-468Article in journal (Refereed)
    Abstract [en]

    Endocytosis of oxidized low density lipoproteins (oxLDL) by macrophages, mediated by scavenger receptors, is thought to play a central role in foam cell formation and, thus, in the pathogenesis of atherosclerosis. OxLDL activates several MAP kinases, including the ERK, JNK and p38 MAP kinases, but the role of these activations in oxLDL uptake has not been studied. In the present investigation, we find that SB203580, a specific inhibitor of p38, blocks oxLDL-exposed J774 cells from becoming foam cells. Inhibition of foam cell formation by blockade of the p38 pathway is, at least in part, due to inhibition of oxLDL-induced up-regulation of the scavenger receptor CD36. Using pharmaceutical inhibitors and dominant active MAP kinase kinases, we demonstrated that activation of the p38 pathway, but not the ERK or JNK pathways, is necessary and sufficient to transactivate PPAR?, a nuclear receptor that has recently been shown to play a pivotal role in oxLDL-induced CD36 expression. Our results for the first time demonstrate a regulation of CD36 by p38, and the importance of the p38 pathway in regulation of foam cell formation.

  • 125.
    Zheng, Lin
    et al.
    Karolinska Inst, NVS, KI Alzheimers Dis Res Ctr, S-14186 Stockholm, Sweden.
    Cedazo-Minguez, Angel
    KI-AlzheimerDisease Research Center, NVS, Novum, Karolinska Institutet, SE-141 57, Stockholm,Sweden.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Jerhammar, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Oto-Rhiono-Laryngology and Head & Neck Surgery. Linköping University, Faculty of Health Sciences.
    Hultenby, Kjell
    Clinical Research Center, Department of Laboratory Medicine, Karolinska Institutet, SE-141 86 Stockholm, Sweden.
    Marcusson, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Geriatric. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Geriatric Medicine in Linköping.
    Terman, Alexi
    Department of Clinical Pathology and Cytology, Karolinska University Hospital, Huddinge, SE-141 86 Stockholm, Sweden.
    Intracellular localization of amyloid beta peptide in SH-SY5Y neuroblastoma cells2013In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 37, no 4, p. 713-733Article in journal (Refereed)
    Abstract [en]

    Amyloid-beta peptide (A beta), the main component of Alzheimer's disease (AD) senile plaques, has been found to accumulate within the lysosomal compartment of AD neurons. We have previously shown that in differentiated SH-SY5Y neuroblastoma cells cultured under normal conditions, the majority of A beta is localized extralysosomally, while oxidative stress significantly increases intralysosomal A beta content through activation of macroautophagy. It is, however, not clear which cellular compartments contain extralysosomal A beta in intact SH-SY5Y cells, and how oxidative stress influences the distribution of extralysosomal A beta. Using confocal laser scanning microscopy and immunoelectron microscopy, we showed that in differentiated neuroblastoma cells cultured under normal conditions A beta (A beta(40), A beta(42), and A beta oligomers) is colocalized with both membrane-bound organelles (endoplasmic reticulum, Golgi complexes, multivesicular bodies/late endosomes, lysosomes, exocytotic vesicles and mitochondria) and non-membrane-bound cytosolic structures. Neuroblastoma cells stably transfected with A beta PP Swedish KM670/671NL double mutation showed enlarged amount of A beta colocalized with membrane compartments. Suppression of exocytosis by 5 nM tetanus toxin resulted in a significant increase of the amount of cytosolic A beta as well as A beta colocalized with exocytotic vesicles, endoplasmic reticulum, Golgi complexes, and lysosomes. Hyperoxia increased A beta localization in the endoplasmic reticulum, Golgi apparatus, mitochondria, and lysosomes, but not in the secretory vesicles. These results indicate that in SH-SY5Y neuroblastoma cells intracellular A beta is not preferentially localized to any particular organelle and, to a large extent, is secreted from the cells. Challenging cells to hyperoxia, exocytosis inhibition, or A beta overproduction increased intracellular A beta levels but did not dramatically changed its localization pattern.

  • 126.
    Zheng, Lin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Geriatric.
    Cedazo-Minguez, Angel
    KI-AlzheimerDisease Research Center, NVS, Novum, Karolinska Institutet, Stockholm, Sweden.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Jerhammar, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Marcusson, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Geriatric. Linköping University, Faculty of Health Sciences.
    Terman, Alexei
    Department of Clinical Pathology and Cytology, Karolinska University Hospital, Stockholm, Sweden.
    Intracellular distribution of amyloid beta peptide and its relationship to the lysosomal system.2012In: Translational Neurodegeneration, ISSN 2047-9158, Vol. 1, no 1, p. 19-Article in journal (Refereed)
    Abstract [en]

    Background

    Amyloid beta peptide (Aβ) is the main component of extraneuronal senile plaques typical of Alzheimer’s disease (AD) brains. Although Aβ is produced by normal neurons, it is shown to accumulate in large amounts within neuronal lysosomes in AD. We have recently shown that under normal conditions the majority of Aβ is localized extralysosomally, while oxidative stress significantly increases intralysosomal Aβ content through activation of macroautophagy. It is also suggested that impaired Aβ secretion and resulting intraneuronal increase of Aβ can contribute to AD pathology. However, it is not clear how Aβ is distributed inside normal neurons, and how this distribution is effected when Aβ secretion is inhibited.

    Methods

    Using retinoic acid differentiated neuroblastoma cells and neonatal rat cortical neurons, we studied intracellular distribution of Aβ by double immunofluorescence microscopy for Aβ40 or Aβ42 and different organelle markers. In addition, we analysed the effect of tetanus toxin-induced exocytosis inhibition on the intracellular distribution of Aβ.

    Results

    Under normal conditions, Aβ was found in the small cytoplasmic granules in both neurites and perikarya. Only minor portion of Aβ was colocalized with trans-Golgi network, Golgi-derived vesicles, early and late endosomes, lysosomes, and synaptic vesicles, while the majority of Aβ granules were not colocalized with any of these structures. Furthermore, treatment of cells with tetanus toxin significantly increased the amount of intracellular Aβ in both perikarya and neurites. Finally, we found that tetanus toxin increased the levels of intralysosomal Aβ although the majority of Aβ still remained extralysosomally.

    Conclusion

    Our results indicate that most Aβ is not localized to Golgi-related structures, endosomes, lysosomes secretory vesicles or other organelles, while the suppression of Aβ secretion increases intracellular intra- and extralysosomal Aβ.

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  • 127.
    Zheng, Lin
    et al.
    Linköping University, Department of Neuroscience and Locomotion, Geriatrics. Linköping University, Faculty of Health Sciences.
    Roberg, Karin
    Linköping University, Department of Neuroscience and Locomotion, Oto-Rhiono-Laryngology and Head & Neck Surgery. Linköping University, Faculty of Health Sciences.
    Jerhammar, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Marcusson, Jan
    Linköping University, Department of Neuroscience and Locomotion, Geriatrics. Linköping University, Faculty of Health Sciences.
    Terman, Alexei
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Oxidative Stress Induces Intralysosomal Accumulation of Alzheimer Amyloid β-Protein in Cultured Neuroblastoma Cells2006In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1067, p. 248-251Article in journal (Refereed)
    Abstract [en]

    Oxidative stress is considered important for the pathogenesis of Alzheimer's disease (AD), which is characterized by the formation of extracellular senile plaques, mainly composed of amyloid β-protein (Aβ). Aβ also accumulates within AD neurons and is believed to exert cellular toxicity through lysosomal labilization. We report that the exposure of human neuroblastoma cells to hyperoxia (40% vs. 8% ambient oxygen) induced the accumulation of large (over 1 μM) Aβ-containing lysosomes, which were not typical of control cells, showing a distinct localization of Aβ and lysosomal markers. An inhibitor of autophagy, 3-methyladenine, suppressed the effect of hyperoxia. The results suggest a link between the involvement of oxidative stress and lysosomes in AD.

  • 128.
    Zheng, Lin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Geriatric. Linköping University, Faculty of Health Sciences.
    Terman, Alexi
    Karolinska University Hospital, Stockholm.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Dehvari, Nodi
    Karolinska Institutet, Stockholm.
    Cowburn, Richard F.
    AstraZeneca, Södertälje.
    Benedikz, Eirikur
    Karolinska Institutet.
    Kågedal, Katarina
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Cedazo-Minguez, Angel
    Karolinska Institutet.
    Marcusson, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Geriatric. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Geriatric Medicine.
    Macroautophagy-generated increase of lysosomal amyloid β-protein mediates oxidant-induced apoptosis of cultured neuroblastoma cells2011In: Autophagy, ISSN 1554-8627, E-ISSN 1554-8635, Vol. 7, no 12, p. 1528-1545Article in journal (Refereed)
    Abstract [en]

    Increasing evidence suggests the toxicity of intracellular amyloid β-protein (Aβ) to neurons, as well as the involvement of oxidative stress in Alzheimer disease (AD). Here we show that normobaric hyperoxia (exposure of cells to 40% oxygen for five days, and consequent activation of macroautophagy and accumulation of Aβ within lysosomes, induced apoptosis in differentiated SH-SY5Y neuroblastoma cells. Cells under hyperoxia showed: (1) increased numbers of autophagic vacuoles that contained amyloid precursor protein (APP) as well as Aβ monomers and oligomers, (2) increased reactive oxygen species production, and (3) enhanced apoptosis. Oxidant-induced apoptosis positively correlated with cellular Aβ production, being the highest in cells that were stably transfected with APP Swedish KM670/671NL double mutation. Inhibition of γ-secretase, prior and/or in parallel to hyperoxia, suggested that the increase of lysosomal Aβ resulted mainly from its autophagic uptake, but also from APP processing within autophagic vacuoles. The oxidative stress-mediated effects were prevented by macroautophagy inhibition using 3-methyladenine or ATG5 downregulation. Our results suggest that upregulation of macroautophagy and resulting lysosomal Aβ accumulation are essential for oxidant-induced apoptosis in cultured neuroblastoma cells and provide aditional support for the interactive role of oxidative stress and the lysosomal system in AD-related neurodegeneration.

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