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  • 1.
    Arnér, Elias S. J.
    et al.
    Karolinska Institute, Stockholm, Sweden.
    Nakamura, H.
    Kyoto University, Japan.
    Sasada, Tetsuro
    Karolinska Institute, Huddinge, Sweden.
    Yodoi, Junji
    Karolinska Institute, Huddinge, Sweden.
    Holmgren, Arne
    Karolinska Institute, Stockholm, Sweden.
    Spyrou, Giannis
    Department of Biosciences at Novum, Center for Biotechnology, Karolinska Institute, Huddinge, Sweden.
    Analysis of the inhibition of mammalian thioredoxin, thioredoxin reductase, and glutaredoxin by cis-diamminedichloroplatinum (II) and its major metabolite, the glutathione-platinum complex2001In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 31, no 10, p. 1170-1178Article in journal (Refereed)
    Abstract [en]

    Several studies have demonstrated a correlation between cellular toxicity of cis-diamminedichloroplatinum (II) (cisplatin, CDDP) and inhibited intracellular activity of the thioredoxin system, i.e., thioredoxin (Trx), thioredoxin reductase (TrxR), and NADPH. Conversely, increased cellular activity of the Trx system confers resistance to CDDP. In this study, we have analyzed the interaction of CDDP with Trx and TrxR in order to clarify the mechanism. The inhibition with time-dependent kinetics by CDDP of NADPH-reduced (but not oxidized) TrxR was irreversible, strongly suggesting covalent modification of the reduced selenocysteine-containing active site. Assuming second order kinetics, the rate constant of TrxR inhibition by CDDP was 21 +/- 3 M(-1) x s(-1). Transplatin was found to be an even more efficient inhibitor, with a second order rate constant of 84 +/- 22 M(-1) x s(-1), whereas carboplatin (up to 1 mM) gave no inhibition of the enzyme under the same conditions. Escherichia coli Trx or human or bacterial glutaredoxin (Grx) activities were in comparison only slightly or not at all inhibited by either CDDP, transplatin, or carboplatin. However, glutaredoxins were found to be inhibited by the purified glutathione adduct of cisplatin, bis-(glutathionato)platinum(II) (GS-Platinum complex, GS-Pt), with an IC50 = 350 microM in the standard beta-hydroxyethyl disulfide-coupled assay for human Grx. Also the mammalian Trx system was inhibited by GS-Pt with similar efficiency (IC(50) = 325 microM), whereas neither the E. coli Trx system nor glutathione reductase were inhibited. Formation of GS-Pt is a major route for cellular elimination of CDDP. The fact that GS-Pt inhibits the mammalian Trx as well as Grx systems shows that CDDP may exert effects at several stages of its metabolism, including after conjugation with GSH, which are intimately linked with the cellular disulfide/dithiol redox regulatory systems.

  • 2. Bergman, Vivi
    et al.
    Leanderson, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Occupational and Environmental Medicine. Östergötlands Läns Landsting, Pain and Occupational Centre, Occupational and Environmental Medicine Centre.
    Starkhammar, Hans
    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.
    Tagesson, Christer
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Occupational and Environmental Medicine. Östergötlands Läns Landsting, Pain and Occupational Centre, Occupational and Environmental Medicine Centre.
    Urinary excretion of 8-hydroxydeoxyguanosine and malondialdehyde after high dose radiochemotherapy preceding stem cell transplantation2004In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 36, no 3, p. 300-306Article in journal (Refereed)
    Abstract [en]

    The urinary excretion of the hydroxylated DNA base 8-hydroxydeoxyguanosine (8-OHdG) and the lipid peroxidation product malondialdehyde (MDA) was monitored in 11 patients with hematological malignancies undergoing total body irradiation and high-dose chemotherapy preceding bone marrow transplantation. Nine patients showed a prompt increase in urinary 8-OHdG (8-25 times the initial baseline level) on days 0-7 after irradiation onset, the excretion then decreased during the aplastic period and increased again when engraftment took place (in 7 patients). A significant positive correlation was found between urinary 8-OHdG and whole blood leukocyte count, both on day 5 (p = .04, r = .72) and on day 22 (p = .009, r = .80) after irradiation onset. One patient who lacked the first peak of 8-OHdG excretion showed low blood leukocyte counts (less than 2×109/l) before therapy onset, this patient, however, later had a successful engraftment and then also showed considerable increases in both 8-OHdG excretion and leukocyte count. These observations suggest leukocytes play a part in the excretion of 8-OHdG after conditioning therapy preceding bone marrow transplantation. As opposed to the biphasic 8-OHdG excretion, the excretion of MDA showed a single peak appearing on days 11-19 after radiochemotherapy onset, i.e., during the period in which the patients suffered from cytopenia, mucositis, and other side effects of the treatment. It is suggested, therefore, that these clinical manifestations are associated with increased lipid peroxidation. Altogether, these findings illustrate the utility of serial urinary samples for monitoring oxidative stress due to conditioning therapy in clinical practice. They also demonstrate that different oxidative stress markers may behave quite differently regarding their appearance in the urine after whole-body oxidative stress.

  • 3.
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
    Lysosomal involvement in apoptosis2002In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 33, p. 195-Conference paper (Other academic)
  • 4.
    Brunk, Ulf
    et al.
    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.
    Terman, Alexei
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Lipofuscin: Mechanisms of age-related accumulation and influence on cell function2002In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 33, no 5, p. 611-619Article in journal (Refereed)
    Abstract [en]

    The accumulation of lipofuscin within postmitotic cells is a recognized hallmark of aging occuring with a rate inversely related to longevity. Lipofuscin is an intralysosomal, polymeric substance, primarily composed of cross-linked protein residues, formed due to iron-catalyzed oxidative processes. Because it is undegradable and cannot be removed via exocytosis, lipofuscin accumulation in postmitotic cells is inevitable, whereas proliferative cells efficiently dilute it during division. The rate of lipofuscin formation can be experimentally manipulated. In cell culture models, oxidative stress (e.g., exposure to 40% ambient oxygen or low molecular weight iron) promotes lipofuscin accumulation, whereas growth at 8% oxygen and treatment with antioxidants or iron-chelators diminish it. Lipofuscin is a fluorochrome and may sensitize lysosomes to visible light, a process potentially important for the pathogenesis of age-related macular degeneration. Lipofuscin-associated iron sensitizes lysosomes to oxidative stress, jeopardizing lysosomal stability and causing apoptosis due to release of lysosomal contents. Lipofuscin accumulation may also diminish autophagocytotic capacity by acting as a sink for newly produced lysosomal enzymes and, therefore, interfere with recycling of cellular components. Lipofuscin, thus, may be much more directly related to cellular degeneration at old age than was hitherto believed.

  • 5.
    Brurok, H
    et al.
    Norwegian Univ Sci & Technol, Dept Physiol & Biomed Engn, N-7034 Trondheim, Norway Nycomed Innovat AB, Malmo, Sweden Linkoping Univ, Dept Pharmacol, S-58185 Linkoping, Sweden Denmark Univ Technol, Dept Automat, Lyngby, Denmark.
    Ardenkjaer-Larsen, JH
    Norwegian Univ Sci & Technol, Dept Physiol & Biomed Engn, N-7034 Trondheim, Norway Nycomed Innovat AB, Malmo, Sweden Linkoping Univ, Dept Pharmacol, S-58185 Linkoping, Sweden Denmark Univ Technol, Dept Automat, Lyngby, Denmark.
    Skarra, S
    Norwegian Univ Sci & Technol, Dept Physiol & Biomed Engn, N-7034 Trondheim, Norway Nycomed Innovat AB, Malmo, Sweden Linkoping Univ, Dept Pharmacol, S-58185 Linkoping, Sweden Denmark Univ Technol, Dept Automat, Lyngby, Denmark.
    Karlsson, JOG
    Laursen, I
    Norwegian Univ Sci & Technol, Dept Physiol & Biomed Engn, N-7034 Trondheim, Norway Nycomed Innovat AB, Malmo, Sweden Linkoping Univ, Dept Pharmacol, S-58185 Linkoping, Sweden Denmark Univ Technol, Dept Automat, Lyngby, Denmark.
    Jynge, P
    Norwegian Univ Sci & Technol, Dept Physiol & Biomed Engn, N-7034 Trondheim, Norway Nycomed Innovat AB, Malmo, Sweden Linkoping Univ, Dept Pharmacol, S-58185 Linkoping, Sweden Denmark Univ Technol, Dept Automat, Lyngby, Denmark.
    Manganese dipyridoxyl diphosphate: MRI contrast agent with antioxidative and cardioprotective properties?2001In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 31, p. 59-Conference paper (Other academic)
  • 6.
    Chasapis, Christos T.
    et al.
    Hellas Forth, Greece.
    Makridakis, Manousos
    Acad Athens BRFAA, Greece.
    Damdimopoulos, Anastassios E.
    Karolinska Inst, Sweden.
    Zoidakis, Jerome
    Acad Athens BRFAA, Greece.
    Lygirou, Vasiliki
    Acad Athens BRFAA, Greece.
    Mavroidis, Manolis
    Acad Athens BRFAA, Greece.
    Vlahou, Antonia
    Acad Athens BRFAA, Greece.
    Miranda-Vizuete, Antonio
    Univ Seville, Spain.
    Spyrou, Giannis
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Chemistry. Linköping University, Faculty of Medicine and Health Sciences.
    Vlamis-Gardikas, Alexios
    Univ Patras, Greece.
    Implications of the mitochondrial interactome of mammalian thioredoxin 2 for normal cellular function and disease2019In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 137, p. 59-73Article in journal (Refereed)
    Abstract [en]

    Multiple thioredoxin isoforms exist in all living cells. To explore the possible functions of mammalian mitochondrial thioredoxin 2 (Trx2), an interactome of mouse Trx2 was initially created using (i) a monothiol mouse Trx2 species for capturing protein partners from different organs and (ii) yeast two hybrid screens on human liver and rat brain cDNA libraries. The resulting interactome consisted of 195 proteins (Trx2 included) plus the mitochondrial 16S RNA. 48 of these proteins were classified as mitochondrial (MitoCarta2.0 human inventory). In a second step, the mouse interactome was combined with the current four-membered mitochondrial sub-network of human Trx2 (BioGRID) to give a 53-membered human Trx2 mitochondrial interactome (52 interactor proteins plus the mitochondrial 16S RNA). Although thioredoxins are thiol-employing disulfide oxidoreductases, approximately half of the detected interactions were not due to covalent disulfide bonds. This finding reinstates the extended role of thioredoxins as moderators of protein function by specific non-covalent, protein-protein interactions. Analysis of the mitochondrial interactome suggested that human Trx2 was involved potentially in mitochondrial integrity, formation of iron sulfur clusters, detoxification of aldehydes, mitoribosome assembly and protein synthesis, protein folding, ADP ribosylation, amino acid and lipid metabolism, glycolysis, the TCA cycle and the electron transport chain. The oxidoreductase functions of Trx2 were verified by its detected interactions with mitochondrial peroxiredoxins and methionine sulfoxide reductase. Parkinsons disease, triosephosphate isomerase deficiency, combined oxidative phosphorylation deficiency, and lactate dehydrogenase b deficiency are some of the diseases where the proposed mitochondrial network of Trx2 may be implicated.

  • 7.
    Dabrosin, Charlotta
    et al.
    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.
    Öllinger, Karin
    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.
    Variability of glutathione during the menstrual cycle - Due to estrogen effects on hepatocytes?2004In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 36, no 2, p. 145-151Article in journal (Refereed)
    Abstract [en]

    Oxidative stress and alterations in the antioxidative defense system may be involved in carcinogenesis. We have previously shown that the levels of glutathione (GSH) in vivo in both breast tissue and subcutaneous fat were higher in the luteal phase compared with the follicular phase, suggesting an overall increase in GSH. This result was confirmed in the present study. Moreover, we exposed normal breast tissue in vivo, breast epithelial cells in vitro, and hepatocytes in culture to ovarian hormones. We found that local perfusion with estradiol, using microdialysis, in normal human breast tissue did not alter the local GSH levels in vivo. In vitro, treatment with estradiol and progesterone of normal human breast epithelial cells did not alter GSH levels. However, levels of GSH in hepatocytes were after 8 h estradiol exposure initially decreased, 76.6 ± 5% of control cells, p < .05, whereas 20 h exposure more than doubled GSH, 209 ± 26% compared with control cells, p < .01. Progesterone had no additional effect. Exposure of hepatocytes to estradiol increased the cellular content of γ-glutamylcysteine synthetase, the rate-limiting enzyme in GSH synthesis. In conclusion we suggest that estradiol affects the GSH homeostasis mainly by effects on hepatocytes, whereas local production in the breast is unaffected by estradiol.

  • 8. Dare, E
    et al.
    Li, Wei
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Zhivotovsky, B
    Yuan, Xi Ming
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Ceccatelli, S
    Methylmercury and H2O2 provoke lysosomal damage in human astrocytoma D384 cells followed by apoptosis2001In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 30, no 12, p. 1347-1356Article in journal (Refereed)
    Abstract [en]

    Methylmercury (MeHg) is a neurotoxic agent acting via diverse mechanisms, including oxidative stress. MeHg also induces astrocytic dysfunction, which can contribute to neuronal damage. The cellular effects of MeHg were investigated in human astrocytoma D384 cells, with special reference to the induction of oxidative-stress-related events. Lysosomal rupture was detected after short MeHg-exposure (1 ╡M, 1 h) in cells maintaining plasma membrane integrity. Disruption of lysosomes was also observed after hydrogen peroxide (H2O2) exposure (100 ╡M, 1 h), supporting the hypothesis that lysosomal membranes represent a possible target of agents causing oxidative stress. The lysosomal alterations induced by MeHg and H2O2 preceded a decrease of the mitochondrial potential. At later time points, both toxic agents caused the appearance of cells with apoptotic morphology, chromatin condensation, and regular DNA fragmentation. However, MeHg and H2O2 stimulated divergent pathways, with caspases being activated only by H2O2. The caspase inhibitor z-VAD-fmk did not prevent DNA fragmentation induced by H2O2, suggesting that the formation of high-molecular-weight DNA fragments was caspase independent with both MeHg and H2O2. The data point to the possibility that lysosomal hydrolytic enzymes act as executor factors in D384 cell death induced by oxidative stress. ⌐ 2001 Elsevier Science Inc.

  • 9.
    Daré, Elisabetta
    et al.
    The National Institute of Environmental Medicine, Division of Toxicology and Neurotoxicology, Karolinska Institutet, Stockholm, Sweden.
    Li, Wei
    Linköping University, Department of Neuroscience and Locomotion. Linköping University, Faculty of Health Sciences.
    Zhivotovsky, Boris
    The National Institute of Environmental Medicine, Division of Toxicology and Neurotoxicology, Karolinska Institutet, Stockholm, Sweden.
    Yuan, Ximing
    Linköping University, Department of Neuroscience and Locomotion. Linköping University, Faculty of Health Sciences.
    Ceccatelli, Sandra
    The National Institute of Environmental Medicine, Division of Toxicology and Neurotoxicology, Karolinska Institutet, Stockholm, Sweden.
    Methylmercury and H2O2 provoke lysosomal damage in human astrocytoma D384 cells followed by apoptosis2001In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 30, no 12, p. 1347-1356Article in journal (Refereed)
    Abstract [en]

    Methylmercury (MeHg) is a neurotoxic agent acting via diverse mechanisms, including oxidative stress. MeHg also induces astrocytic dysfunction, which can contribute to neuronal damage. The cellular effects of MeHg were investigated in human astrocytoma D384 cells, with special reference to the induction of oxidative-stress-related events. Lysosomal rupture was detected after short MeHg-exposure (1 μM, 1 h) in cells maintaining plasma membrane integrity. Disruption of lysosomes was also observed after hydrogen peroxide (H2O2) exposure (100 μM, 1 h), supporting the hypothesis that lysosomal membranes represent a possible target of agents causing oxidative stress. The lysosomal alterations induced by MeHg and H2O2 preceded a decrease of the mitochondrial potential. At later time points, both toxic agents caused the appearance of cells with apoptotic morphology, chromatin condensation, and regular DNA fragmentation. However, MeHg and H2O2 stimulated divergent pathways, with caspases being activated only by H2O2. The caspase inhibitor z-VAD-fmk did not prevent DNA fragmentation induced by H2O2, suggesting that the formation of high-molecular-weight DNA fragments was caspase independent with both MeHg and H2O2. The data point to the possibility that lysosomal hydrolytic enzymes act as executor factors in D384 cell death induced by oxidative stress.

  • 10. Doulias, Paschalis-Thomas
    et al.
    Christoforidis, Savas
    Brunk, Ulf
    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.
    Galaris, Dimitrios
    Endosomal and lysosomal effects of desferrioxamine: Protection of HeLa cells from hydrogen peroxide-induced DNA damage and induction of cell-cycle arrest2003In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 35, no 7, p. 719-728Article in journal (Refereed)
    Abstract [en]

    The role of endosomal/lysosomal redox-active iron in H2O 2-induced nuclear DNA damage as well as in cell proliferation was examined using the iron chelator desferrioxamine (DFO). Transient transfections of HeLa cells with vectors encoding dominant proteins involved in the regulation of various routes of endocytosis (dynamin and Rab5) were used to show that DFO (a potent and rather specific iron chelator) enters cells by fluid-phase endocytosis and exerts its effects by chelating redox-active iron present in the endosomal/lysosomal compartment. Endocytosed DFO effectively protected cells against H2O2-induced DNA damage, indicating the importance of endosomal/lysosomal redox-active iron in these processes. Moreover, exposure of cells to DFO in a range of concentrations (0.1 to 100 ╡M) inhibited cell proliferation in a fluid-phase endocytosis- dependent manner. Flow cytometric analysis of cells exposed to 100 ╡M DFO for 24 h showed that the cell cycle was transiently interrupted at the G 2/M phase, while treatment for 48 h led to permanent cell arrest. Collectively, the above results clearly indicate that DFO has to be endocytosed by the fluid-phase pathway to protect cells against H2O 2-induced DNA damage. Moreover, chelation of iron in the endosomal/lysosomal cell compartment leads to cell cycle interruption, indicating that all cellular labile iron is propagated through this compartment before its anabolic use is possible.

  • 11.
    Douoalis, Paschalis-Thomas
    et al.
    Ioannina Greece.
    Kotoglou, Plychronis
    Ioannina Greece.
    Tenopoulou, Margarita
    Ioannina Greece.
    Keramisanou, Dimitra
    Ioannina Greece.
    Tzavaras, Theodore
    Ioannina Greece.
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Galaris, Dimitrios
    Ioannina Greece.
    Angelidis, Charalampos
    Ioannina Greece.
    Involvement of heat shock protein-70 in the mechanism of hydrogen peroxide-induced DNA damage: The role of lysosomes and iron2007In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 42, no 4, p. 567-577Article in journal (Refereed)
    Abstract [en]

    Heat shock protein-70 (Hsp70) is the main heat-inducible member of the 70-kDa family of chaperones that assist cells in maintaining proteins functional under stressful conditions. In the present investigation, the role of Hsp70 in the molecular mechanism of hydrogen peroxide-induced DNA damage to HeLa cells in culture was examined. Stably transfected HeLa cell lines, overexpressing or lacking Hsp70, were created by utilizing constitutive expression of plasmids containing the functional hsp70 gene or hsp70-siRNA, respectively. Compared to control cells, the Hsp70-overexpressing ones were significantly resistant to hydrogen peroxide-induced DNA damage, while Hsp70-depleted cells showed an enhanced sensitivity. In addition, the "intracellular calcein-chelatable iron pool" was determined in the presence or absence of Hsp70 and found to be related to the sensitivity of nuclear DNA to H2O2. It seems likely that the main action of Hsp70, at least in this system, is exerted at the lysosomal level, by protecting the membranes of these organelles against oxidative stress-induced destabilization. Apart from shedding additional light on the mechanistic details behind the action of Hsp70 during oxidative stress, our results indicate that modulation of cellular Hsp70 may represent a way to make cancer cells more sensitive to normal host defense mechanisms or chemotherapeutic drug treatment. © 2006 Elsevier Inc. All rights reserved.

  • 12.
    Gao, X.
    et al.
    Molecular Targets Group, J. G. Brown Cancer Center, University of Louisville, Louisville, KY 40202, United States, Department of Oncology, Institute of Biomedicine and Surgery, University of Linköping, Linköping, 58185, Sweden.
    Qian, M.
    Molecular Targets Group, J. G. Brown Cancer Center, University of Louisville, Louisville, KY 40202, United States.
    Campian, J.L.
    Molecular Targets Group, J. G. Brown Cancer Center, University of Louisville, Louisville, KY 40202, United States.
    Clark, D.R.
    Molecular Targets Group, J. G. Brown Cancer Center, University of Louisville, Louisville, KY 40202, United States, Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, United States.
    Burke, T.J.
    Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, United States.
    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.
    McGregor, W.G.
    Molecular Targets Group, J. G. Brown Cancer Center, University of Louisville, Louisville, KY 40202, United States, Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, United States, Center for Genetics and Molecular Medicine, University of Louisville, Louisville, KY 40202, United States.
    Cytotoxic and mutagenic effects of tobacco-borne free fatty acids2006In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 40, no 1, p. 165-172Article in journal (Refereed)
    Abstract [en]

    Tobacco smoke contains substances capable of binding iron in an aqueous medium and transferring the metal into both organic solvents and intact mammalian red cells. This iron-binding activity is due to free fatty acids which are abundant in tobacco smoke and form 2:1 (free fatty acid:iron) chelates with ferrous iron. These earlier observations suggested that smoke-borne free fatty acids and the associated delocalization of iron within the lung might contribute to both the chronic pulmonary inflammation and the carcinogenesis associated with smoking. We now report that micromolar concentrations of iron or free fatty acid are not toxic to cultured human lung fibroblasts. However, when combined, the same low concentrations of iron and free fatty acid exert synergistic toxicity. Furthermore, the combination of free fatty acid and iron is highly mutagenic, inducing almost as many selectable mutations in the gene for hypoxanthine/guanine phosphoribosyl transferase as does benzo[a] pyrenediolepoxide, a class I carcinogen generated from benzo[a]pyrene present in cigarette smoke. The combination of free fatty acid and iron also promotes transformation of NIH 3T3 cells into an anchorage-independent phenotype. We conclude that free fatty acids in tobacco smoke may be important contributors to both the pulmonary damage and the carcinogenesis associated with smoking. © 2005 Elsevier Inc. All rights reserved.

  • 13.
    Gao, Xueshan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences.
    Qian, Mingwei
    James Graham Brown Cancer Centre.
    Li Campian, Jian
    James Graham Brown Cancer Centre.
    Marshall, James
    University of Louisville.
    Zhou, Zhanxiang
    University of Louisville.
    Roberts, Andrew M.
    University of Louisville.
    Kang, Y. James
    University of Louisville.
    Prabhu, Sumanth D.
    University of Louisville.
    Sun, Xiao-Feng
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Eaton, John W.
    University of Louisville.
    Mitochondrial dysfunction may explain the cardiomyopathy of chronic iron overload2010In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 49, no 3, p. 401-407Article in journal (Refereed)
    Abstract [en]

    In patients with hemochromatosis, cardiac dysfunction may appear years after they have reached a state of iron overload. We hypothesized that cumulative iron-catalyzed oxidant damage to mitochondrial DNA (mtDNA) might explain the cardiomyopathy of chronic iron overload. Mice were given repetitive injections of iron dextran for a total of 4 weeks after which the iron-loaded mice had elevated cardiac iron, modest cardiac hypertrophy, and cardiac dysfunction. OCR amplification of near-full-length (similar to 16 kb) mtDNA revealed greater than50% loss of full-length product, whereas amounts of a OCR product of a nuclear gene (13 kb region of beta globin) were unaffected. Quantitative rtPCR analyses revealed 60-70% loss of mRNA for proteins encoded by mtDNA with no change in mRNA abundance for nuclear-encoded respiratory subunits. These changes coincided with proportionate reductions in complex I and IV activities and decreased respiration of isolated cardiac mitochondria. We conclude that chronic iron overload leads to cumulative iron-mediated damage to mtDNA and impaired synthesis of mitochondrial respiratory chain subunits. The resulting respiratory dysfunction may explain the slow development of cardiomyopathy in chronic iron overload and similar accumulation of damage to mtDNA may also explain the mitochondrial dysfunction observed in slowly progressing diseases such as neurodegenerative disorders.

  • 14.
    Gustafsson, Håkan
    et al.
    Linköping University, Department of Medical and Health Sciences, Radiology. Linköping University, Faculty of Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Berg, Kirsti
    Norwegian University of Science and Technology.
    Lindgren, Mikael
    Norwegian University of Science and Technology.
    Engström, Maria
    Linköping University, Department of Medical and Health Sciences, Radiology. Linköping University, Faculty of Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    De Muinck, Ebo
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Zachrisson, Helene
    Linköping University, Department of Medical and Health Sciences, Clinical Physiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Clinical Physiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Fe(3+) Heterogeneity in Ex Vivo Carotid Atherosclerotic Plaques2011In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 51, no Suppl. 1, p. S40-S40Article in journal (Other academic)
    Abstract [en]

    n/a

  • 15. Larsson, David A
    et al.
    Baird, Sarah
    Nyhalah, Jerome Diinga
    Yuan, Xi Ming
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Li, Wei
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Oxysterol mixtures, in atheroma-relevant proportions, display synergistic and proapoptotic effects2006In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 41, no 6, p. 902-910Article in journal (Refereed)
    Abstract [en]

    Apoptotic cells in atheroma lesions may contribute to plaque development and instability. Oxysterols constitute the major toxic component in oxLDL and are present in mixed forms in human atheroma lesions. However, the cellular effects of oxysterols have been mostly studied individually. In the present study, we investigated the cytotoxic effects of 7β-hydroxycholesterol (7βOH), 7-ketocholesterol (7keto), 25-hydroxycholesterol (25OH), and 27-hydroxycholesterol (27OH) on U937 monocytic cells, both individually and in atheroma-relevant mixtures mimicking the oxysterol composition reported in human atheroma lesions. Apoptosis and necrosis were studied by examining cell morphology, phosphatidylserine exposure, caspase activation, and the terminal dUTP nick end-labeling technique. Cellular reactive oxygen species and total amount of reduced thiols were measured by using fluorescence probes and 5,5′-dithiobis-(2-nitrobenzoic acid), respectively. We found that 7βOH and 7keto induced caspase activation, ROS production, cellular thiol depletion, permeabilization of lysosomal and mitochondrial membranes, and cell death. 25OH and 27OH did not cause any of the above alterations, whereas 7βOH and 7keto exerted synergistic toxic effects. Although single 25OH or 27OH exhibited quenching effects on both 7βOH- and 7keto-induced cell death, the combination of all four oxysterols in atheroma-relevant proportions was proapoptotic. Our findings indicate that the major oxysterols accumulated in human atheroma are proapoptotic and may contribute to atherosclerotic lesion development. © 2006 Elsevier Inc. All rights reserved.

  • 16.
    Li, Wei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Hellsten, Anna
    Linköping University, Department of Neuroscience and Locomotion. Linköping University, Faculty of Health Sciences.
    Xu, Lihua
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Zhuang, D-M
    Jansson, Katarina
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Yuan, Xi Ming
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Foam cell death induced by 7β-hydroxycholesterol is mediated by labile iron-driven oxidative injury: Mechanisms underlying induction of ferritin in human atheroma2005In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 39, no 7, p. 864-875Article in journal (Refereed)
    Abstract [en]

    Human atherosclerotic lesions typically contain large amounts of ferritin associated with apoptotic macrophages and foam cells, although the reasons are unknown. In the present investigation, we studied the relationship between ferritin induction and occurrence of apoptosis in 7β-hydroxycholesterol (7β-OH)-treated monocytic cells and macrophages. We found that 7β-OH enlarges the intracellular labile iron pool, increases formation of reactive oxygen species (ROS), and induces ferritin and cytosolic accumulation of lipid droplets, lysosomal destabilization, and apoptototic macrophage death. Since ferritin is a phase II-type protective protein, our findings suggest that ferritin upregulation here worked as an inefficient defense mechanism. Addition to the culture medium of both a membrane-permeable iron chelator 10-phenanthroline and the non-membrane-permeable iron chelators apoferritin and desferrioxamine afforded significant protection against the 7β-OH-induced effects. Consequently, endocytosed iron compounds dramatically augmented 7β-OH-induced cytotoxicity. We conclude that oxidized lipid 7β-OH causes not only foam cell formation but also oxidative damage with abnormal metabolism of cellular iron. The findings suggest that modulation of iron metabolism in human atheroma may be a potential therapeutic strategy against atherosclerosis. © 2005 Elsevier Inc. All rights reserved.

  • 17.
    Li, Wei
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Laskar, Amit
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Sultana, Nargis
    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.
    Ghosh, Moumita
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Li, Qianqian
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Yuan, Ximing
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Occupational and Environmental Medicine Center.
    Cell death induced by 7-oxysterols via lysosomal and mitochondrial pathways is p53-dependent2012In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 53, no 11, p. 2054-2061Article in journal (Refereed)
    Abstract [en]

    Oxysterol accumulation and p53 expression mainly in macrophages have been associated with cell death and necrotic core formation in human atheroma progression. Oxidative stress and lysosomal membrane permeabilization (LMP) in macrophages are important causes of macrophage apoptosis. However, it is not understood how p53 and oxysterols interact in the process. We show here that 7-oxysterols induce endogenous full-length p53 and phospho-p53 (p53-Ser15) in both nucleus and cytoplasm of THP1 and J774 cells, which is followed by cellular oxidative stress and apoptotic cell death. The role of p53 in 7-oxysterol-mediated cell death is further investigated in temperature sensitive p53-transfected (M1-t-p53) and in p53-deficient (M1) cells. These results reveal that 7-oxysterols induce induction and nuclear translocation of p53 in M1-t-p53 cells, which in turn enhances LMP, mitochondrial translocation of Bax, mitochondrial membrane permeabilization, cytosolic release of cytochrome c, and cell death. Most importantly, the above effects of 7-oxysterols were not observed in p53-deficient M1 cells. The findings reveal that 7-oxysterol-induced cell death occurs via p53-dependent pathways. Subsequent p53 nuclear translocation and induction of wild-type and phosphorylated p53 are early steps in oxysterol-induced lysosomal-mitochondrial pathways involved in cell death.

  • 18.
    Nalvarte, Ivan
    et al.
    Department of Biosciences at Novum, Center for Biotechnology, Karolinska Institutet, Huddinge, Sweden.
    Damdimopoulos, Anastasios E
    Department of Biosciences at Novum, Center for Biotechnology, Karolinska Institutet, Huddinge, Sweden.
    Spyrou, Giannis
    Department of Biosciences at Novum, Center for Biotechnology, Karolinska Institutet, Huddinge, Sweden.
    Human mitochondrial thioredoxin reductase reduces cytochrome c and confers resistance to complex III inhibition2004In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 36, no 10, p. 1270-1278Article in journal (Refereed)
    Abstract [en]

    The ubiquitously expressed mammalian thioredoxin reductases are selenoproteins that together with NADPH regenerate active reduced thioredoxins and are involved in diverse actions mediated by redox control. Two main forms of mammalian thioredoxin reductases have been isolated, one cytosolic (TrxR1) and one present in mitochondria (TrxR2). Although the principal target for TrxRs is thioredoxin, the cytosolic form can regenerate several important antioxidants such as ascorbic acid, lipoic acid, and ubiquinone. In this study we demonstrate that cytochrome c is a substrate for both TrxR1 and TrxR2. In addition, cells overexpressing TrxR2 are more resistant to impairment of complex III in the mitochondrial respiratory chain upon both antimycin A and myxothiazol treatments, suggesting a complex III bypassing function of TrxR2. Furthermore, we show that cytochrome c is reduced by TrxR2 in vitro, not only by using NADPH as an electron donor but also by using NADH, pointing at TrxR2 as an important redox protein on complex III impairment. These findings may be valuable in understanding respiratory disorders in mitochondrial diseases.

  • 19.
    Persson, Lennart
    et al.
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Department of Medicine and Care, Pulmonary Medicine. Linköping University, Faculty of Health Sciences.
    Yu, Zhengquan
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Department of Neuroscience and Locomotion, Neurosurgery. Linköping University, Faculty of Health Sciences.
    Tirosh, Oren
    Institute of Biochemistry, Food Science and Nutrition, Faculty of Agricultural, Food and Environmental Quality Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.
    Eaton, John Wallace
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Brunk, Ulf
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Prevention of oxidant-induced cell death by lysosomotropic iron chelators2003In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 34, no 10, p. 1295-1305Article in journal (Refereed)
    Abstract [en]

    Intralysosomal iron powerfully synergizes oxidant-induced cellular damage. The iron chelator, desferrioxamine (DFO), protects cultured cells against oxidant challenge but pharmacologically effective concentrations of this drug cannot readily be achieved in vivo. DFO localizes almost exclusively within the lysosomes following endocytic uptake, suggesting that truly lysosomotropic chelators might be even more effective. We hypothesized that an amine derivative of α-lipoamide (LM), 5-[1,2] dithiolan-3-yl-pentanoic acid (2-dimethylamino-ethyl)-amide (α-lipoic acid-plus [LAP]; pKa = 8.0), would concentrate via proton trapping within lysosomes, and that the vicinal thiols of the reduced form of this agent would interact with intralysosomal iron, preventing oxidant-mediated cell damage. Using a thiol-reactive fluorochrome, we find that reduced LAP does accumulate within the lysosomes of cultured J774 cells. Furthermore, LAP is approximately 1,000 and 5,000 times more effective than LM and DFO, respectively, in protecting lysosomes against oxidant-induced rupture and in preventing ensuing apoptotic cell death. Suppression of lysosomal accumulation of LAP (by ammonium-mediated lysosomal alkalinization) blocks these protective effects. Electron paramagnetic resonance reveals that the intracellular generation of hydroxyl radical following addition of hydrogen peroxide to J774 cells is totally eliminated by pretreatment with either DFO (1 mM) or LAP (0.2 μM) whereas LM (200 μM) is much less effective.

  • 20.
    Roberg, Karin
    et al.
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Johansson, Uno
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Öllinger, Karin
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Lysosomal release of Cathepsin D precedes relocation of Cytochrome C and loss of mitochondrial transmembrane potential during apoptosis induced by oxidative stress1999In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 27, no 11-12, p. 1228-1237Article in journal (Refereed)
    Abstract [en]

    Apoptosis was induced in human foreskin fibroblasts by the redox-cycling quinone naphthazarin (5,8-dihydroxy-1,4-naphthoquinone). Most of the cells displayed ultrastructure typical of apoptosis after 8 h of exposure to naphthazarin. Apoptosis was inhibited in fibroblasts pretreated with the cathepsin D inhibitor pepstatin A. Immunofluorescence analysis of the intracellular distribution of cathepsin D revealed a distinct granular pattern in control cells, whereas cells treated with naphthazarin for 30 min exhibited more diffuse staining that corresponded to release of the enzyme from lysosomes to the cytosol. After 2 h, release of cytochrome c from mitochondria to the cytosol was indicated by immunofluorescence. The membrane-potential–sensitive probe JC-1 and flow cytometry did not detect a permanent decrease in mitochondrial transmembrane potential (ΔΨm) until after 5 h of naphthazarin treatment. Our findings show that, during naphthazarin-induced apoptosis, lysosomal destabilization (measured as release of cathepsin D) precedes release of cytochrome c, loss of ΔΨm, and morphologic alterations. Moreover, apoptosis could be inhibited by pretreatment with pepstatin A.

  • 21.
    Sasada, T.
    et al.
    Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto, Japan.
    Nakamura, H.
    Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto, Japan.
    Ueda, S.
    Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto, Japan.
    Sato, N.
    Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto, Japan.
    Kitaoka, Y.
    Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto, Japan.
    Gon, Y.
    Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto, Japan.
    Takabayashi, A.
    Department of Surgery, Tazuke Kofukai Kitano Hospital Medical Institute, Osaka, Japan.
    Spyrou, Giannis
    Medical Nobel Institute for Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
    Holmgren, Arne
    Medical Nobel Institute for Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
    Yodoi, J.
    Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto, Japan.
    Possible involvement of thioredoxin reductase as well as thioredoxin in cellular sensitivity to cis-diamminedichloroplatinum (II)1999In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 27, no 5-6, p. 504-514Article in journal (Refereed)
    Abstract [en]

    The thioredoxin (TRX) system, composed of nicotinamide adenine dinucleotide phosphate (reduced form), TRX, and TRX reductase (TRXR), has multiple biologic functions via thiol-mediated redox control. In this study, we investigated the relationship between intracellular TRXR levels and cellular sensitivity to cis-diamminedichloroplatinum (II) (CDDP). HeLa, a human cervical carcinoma cell line, cultured with CDDP showed a time- and dose-dependent reduction of intracellular TRXR activity, which was well correlated with the decrease in cell viability after exposure to CDDP. In a cell-free system, CDDP was found to directly inactivate the reduced form of purified human TRXR. The CDDP-resistant variants of HeLa cells, established by continuous exposure to CDDP, exhibited an increased expression and activity of TRXR as well as TRX compared with the parental cells. In addition, sodium selenate, an inhibitor of TRXR, was found to increase the susceptibility to CDDP in the CDDP-resistant cells. Moreover, the HeLa cells transfected with an antisense TRXR RNA expression vector to reduce the intracellular enzyme activity displayed an enhanced sensitivity to CDDP. Taken together with previous reports on TRX, these results indicate the possible involvement of TRXR as well as TRX in the cellular sensitivity and resistance to CDDP.

  • 22.
    Sundelin, Staffan P.
    et al.
    Linköping University, Department of Neuroscience and Locomotion, Ophthalmology. Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Nilsson, Sven Erik
    Linköping University, Department of Neuroscience and Locomotion, Ophthalmology. Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Lipofuscin-formation in retinal pigment epithelial cells is reduced by antioxidants2001In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 31, no 2, p. 217-225Article in journal (Refereed)
    Abstract [en]

    The accumulation of lipofuscin by retinal pigment epithelium may be an important feature in the pathogenesis of age-related macular degeneration, suggesting the possibility that this common cause of blindness might be prevented or delayed by antioxidants. In support of this idea, we now report significantly reduced formation of lipofuscin when the antioxidant substances lutein, zeaxanthin, lycopene (carotenoids), or α-tocopherol were added to rabbit and bovine (calf) retinal pigment epithelial (RPE) cells exposed to normobaric hyperoxia (40%) and photoreceptor outer segments. Rabbit and calf RPE cells were grown for 2 weeks with addition of one of the test substances every 48 h. The cellular uptake of carotenoids and α-tocopherol was assayed by HPLC after 2 weeks. The lipofuscin-content was measured by static fluorometry (rabbit cells) or by image analysis (calf cells). Both rabbit and calf RPE showed similar results with significantly lower amounts of lipofuscin in antioxidant-treated cells. The effect of carotenoids is especially interesting, since the result is not dependent on their protective effect against photo-oxidative reactions. The chain-breaking abilities of these antioxidants in peroxidative reactions of lipid membranes and quenching of free radicals seem to be of importance for inhibition of lipofuscin formation.

  • 23.
    Sundelin, Staffan P.
    et al.
    Linköping University, Department of Neuroscience and Locomotion, Ophthalmology. Linköping University, Faculty of Health Sciences.
    Nilsson, Sven Erik G.
    Linköping University, Department of Neuroscience and Locomotion, Ophthalmology. Linköping University, Faculty of Health Sciences.
    Brunk, Ulf
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Lipofuscin-formation in cultured retinal pigment epithelial cells is related to their melanin content2001In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 30, no 1, p. 74-81Article in journal (Refereed)
    Abstract [en]

    Age-related macular degeneration (AMD), the leading cause of blindness in the developed world, is accompanied by degeneration of the retinal pigment epithelial (RPE) cells. There is an inverse correlation between the melanin content of the eye and the incidence of AMD. Lipofuscin (LF)-accumulation in RPE cells accompanies the process of aging, and may also be related to AMD. This study was designed to evaluate the effect of melanin/melanosomes on the rate of LF formation in cultured rabbit and bovine RPE cells subjected to oxidative stress (40% normobaric O2) and daily supplementation with photoreceptor outer segments for 4 weeks. The LF content was measured at 0, 2, and 4 weeks in RPE cells from pigmented and albino rabbits, as well as in pigment-rich and pigment-poor bovine cells. Albino rabbit and pigment-poor bovine cells accumulated significantly higher amounts of LF than pigmented rabbit cells and pigment-rich bovine RPE cells after both 2 and 4 weeks of exposure. Autometallography of melanin-containing cells, without previous exposure to ammonium sulfide, showed a positive outcome, indicating either the occurrence of pre-existing iron-sulphur clusters or an extremely high intrinsic reducing capacity. These results suggest that melanin acts as an efficient antioxidant, perhaps by interacting with transition metals.

  • 24.
    Yu, Zhengquan
    et al.
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Department of Neuroscience and Locomotion, Neurosurgery. Linköping University, Faculty of Health Sciences.
    Persson, Lennart
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Department of Medicine and Care, Pulmonary Medicine. Linköping University, Faculty of Health Sciences.
    Eaton, John Wallace
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Brunk, Ulf
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Intralysosomal iron: a major determinant of oxidant-induced cell death2003In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 34, no 10, p. 1243-1252Article in journal (Refereed)
    Abstract [en]

    As a result of continuous digestion of iron-containing metalloproteins, the lysosomes within normal cells contain a pool of labile, redox-active, low-molecular-weight iron, which may make these organelles particularly susceptible to oxidative damage. Oxidant-mediated destabilization of lysosomal membranes with release of hydrolytic enzymes into the cell cytoplasm can lead to a cascade of events eventuating in cell death (either apoptotic or necrotic depending on the magnitude of the insult). To assess the importance of the intralysosomal pool of redox-active iron, we have temporarily blocked lysosomal digestion by exposing cells to the lysosomotropic alkalinizing agent, ammonium chloride (NH4Cl). The consequent increase in lysosomal pH (from ca. 4.5 to > 6) inhibits intralysosomal proteolysis and, hence, the continuous flow of reactive iron into this pool. Preincubation of J774 cells with 10 mM NH4Cl for 4 h dramatically decreased apoptotic death caused by subsequent exposure to H2O2, and the protection was as great as that afforded by the powerful iron chelator, desferrioxamine (which probably localizes predominantly in the lysosomal compartment). Sulfide-silver cytochemical detection of iron revealed a pronounced decrease in lysosomal content of redox-active iron after NH4Cl exposure, probably due to diminished intralysosomal digestion of iron-containing material coupled with continuing iron export from this organelle. Electron paramagnetic resonance experiments revealed that hydroxyl radical formation, readily detectable in control cells following H2O2 addition, was absent in cells preexposed to 10 mM NH4Cl. Thus, the major pool of redox-active, low-molecular-weight iron may be located within the lysosomes. In a number of clinical situations, pharmacologic strategies that minimize the amount or reactivity of intralysosomal iron should be effective in preventing oxidant-induced cell death.

  • 25.
    Yuan, Xi Ming
    et al.
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Li, Wei
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Brunk, Ulf
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Dalen, Helge
    Department of Pathology, The Gade Institute, University of Bergen, Bergen, Norway.
    Chang, Yi Hsin
    Department of Molecular Pharmacology and Toxicology, School of Pharmacy, University of Southern California, Los Angeles, CA, USA.
    Sevanian, Alex
    Department of Molecular Pharmacology and Toxicology, School of Pharmacy, University of Southern California, Los Angeles, CA, USA.
    Lysosomal destabilization during macrophage damage induced by cholesterol oxidation products2000In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 28, no 2, p. 208-218Article in journal (Refereed)
    Abstract [en]

    We have previously shown that oxidized low-density lipoprotein (LDL) induces damage to the macrophage lysosomal membranes, with ensuing leakage of lysosomal contents and macrophage cell death. Cholesterol oxidation products (ChOx) have been reported to be the major cytotoxic components of oxidized LDL/LDL and also to stimulate cholesterol accumulation in vascular cells. In the present study, we characterized the initial events during macrophage damage induced by cholesterol oxidation products (ChOx). Within 24 h of exposure, ChOx caused lysosomal destabilization, release to the cytosol of the lysosomal marker-enzyme cathepsin D, apoptosis, and postapoptotic necrosis. Enhanced autophagocytosis and chromatin margination was found 12 h after the exposure to ChOx, whereas apoptosis and postapoptotic necrosis was pronounced 24 and 48 h after the exposure. Some lysosomal vacuoles were then filled with degraded cellular organelles, indicating phagocytosis of apoptotic bodies by surviving cells. Because caspase-3 activation was detected in the ChOx-exposed cells, lysosomal destabilization may associate with the leakage of lysosomal enzymes, and activation of the caspase cascade. MnSOD mRNA levels were markedly increased after 24 h of exposure to ChOx, suggesting associated induction of mitochondrial protection repair or turnover. We conclude that ChOx-induced damage to lysosomes and mitochondria are sequelae to the cascade of oxysterol cytotoxic events. The early disruption of lysosomes induced by ChOx, with resultant autophagocytosis may be a critical event in apoptosis and/or necrosis of macrophages/foam cells during the development of atherosclerotic lesions.

  • 26.
    Zheng, Lin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Geriatric. Linköping University, Faculty of Health Sciences.
    Kågedal, Katarina
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Dehvari, Nodi
    Karolinska Institutet, Stockholm.
    Benedikz, Eirikur
    Karolinska Institutet, Stockholm.
    Cowburn, Richard
    AstraZeneca R&D.
    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.
    Terman, Alexei
    Linköping University, Department of Clinical and Experimental Medicine, Geriatric. Linköping University, Faculty of Health Sciences.
    Oxidative stress induces macroautophagy of amyloid beta-protein and ensuing apoptosis2009In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 46, no 3, p. 422-429Article in journal (Refereed)
    Abstract [en]

    There is increasing evidence for the toxicity of intracellular amyloid beta-protein (A beta) to neurons and the involvement of lysosomes in this process in Alzheimer disease (AD). We have recently shown that oxidative stress, a recognized determinant of AD. enhances macroautophagy and leads to intralysosomal accumulation of A beta in Cultured neuroblastoma cells. We hypothesized that oxidative stress promotes AD by stimulating macroautophagy of A that further may induce cell death by destabilizing lysosomal membranes. To investigate such possibility, we compared the effects of hyperoxia (40% ambient oxygen) in cultured HEK293 cells that were transfected with an empty vector (Vector), wild-type APP (APPwt), or Swedish mutant APP (APPswe). Exposure to hyperoxia for 5 days increased the number of cells with A beta-containing lysosomes, as well as the number of apoptotic cells, compared to normoxic conditions. The rate of apoptosis in all three cell lines demonstrated dependence on intralysosomal A beta content (Vector<APPwt<APPswe). Furthermore, the degree of apoptosis was positively correlated with lysosomal membrane permeabilization, whereas inhibitors Of macroautophagy and lysosomal function decreased oxidant-induced apoptosis and diminished the differences in apoptotic response between different cell lines. These results suggest that oxidative stress can induce neuronal death through macroautophagy of A beta and consequent lysosomal membrane permeabilization, which may help explain the mechanisms behind neuronal loss in AD.

  • 27.
    Zhou, Jie
    et al.
    Institute of Biochemistry I, Faculty of Medicine, Johann Wolfgang Goethe-University Frankfurt, Germany.
    Eleni, Chantzoura
    Biochemical Research Foundation, Academy of Athens, Greece.
    Spyrou, Giannis
    Biochemical Research Foundation, Academy of Athens, Greece.
    Brüne, Bernhard
    Institute of Biochemistry I, Faculty of Medicine, Johann Wolfgang Goethe-University Frankfurt, Germany.
    The mitochondrial thioredoxin system regulates nitric oxide-induced HIF-1a protein2008In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 44, no 1, p. 91-98Article in journal (Refereed)
    Abstract [en]

    Hypoxia-inducible factor-1 (HIF-1), consisting of two subunits, HIF-1alpha and HIF-1beta, is a key regulator for adaptation to low oxygen availability, i.e., hypoxia. Compared to the constitutively expressed HIF-1beta, HIF-1alpha is regulated by hypoxia but also under normoxia (21% O(2)) by several stimuli, including nitric oxide (NO). In this study, we present evidence that overexpression of mitochondrial-located thioredoxin 2 (Trx2) or thioredoxin reductase 2 (TrxR2) attenuated NO-evoked HIF-1alpha accumulation and transactivation of HIF-1 in HEK293 cells. In contrast, cytosolic-located thioredoxin 1 (Trx1) enhanced HIF-1alpha protein amount and activity under NO treatments. Taking into consideration that thioredoxins affect the synthesis of HIF-1alpha by altering Akt/mTOR signaling, we herein show that p42/44 mitogen-activated protein kinase and p70S6 kinase are involved. Moreover, intracellular ATP was increased in Trx1-overexpressing cells but reduced in cells overexpressing Trx2 or TrxR2, providing thus an understanding of how protein synthesis is regulated by thioredoxins.

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