Change search
Refine search result
1 - 36 of 36
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Rows per page
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sort
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
Select
The maximal number of hits you can export is 250. When you want to export more records please use the Create feeds function.
  • 1.
    Abdiu, Avni
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Plastic Surgery, Hand Surgery and Burns. Östergötlands Läns Landsting, Reconstruction Centre, Department of Plastic Surgery, Hand surgery UHL.
    Nakamura, Hajime
    Sahaf, Bita
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Yodoi, Junji
    Holmgren, Arne
    Rosén, Anders
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Thioredoxin blood level increases after severe burn injury2000In: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 2, no 4, p. 707-716Article in journal (Refereed)
    Abstract [en]

    We have investigated the thioredoxin (TRX) levels in severely burned patients and the possible origin of TRX, based on the recent understanding that TRX is a potent antioxidant with cytoprotective functions. Serum and plasma samples from burns patients and healthy blood donors were collected during the first 10 post-bum days and analyzed in a sandwich TRX enzyme-linked immunosorbent assay (ELISA). The TRX levels found were correlated to a panel of blood tests. The presence of TRX in platelets was investigated by immunoelectron microscopy and Western blotting. TRX serum levels of the severely burned patients showed a significant increase, with a mean serum TRX concentration on the day of injury of 76.5 ▒ 19.5 ng/ml (mean ▒ SD) and on post-burn day one 122.6 ▒ 66.9 ng/ml, compared to control blood donor levels of 22.7 ▒ 12.2 ng/ml (p = 0.0041 and 0.0117, respectively). A second peak of increase was found on post-burn days 7 to 9 with a four- to five-fold rise in concentration compared to controls. TRX elevation correlated well with increased platelet (p = 0.007) and leukocyte counts (p = 0.002). We also demonstrated by immunoelectron microscopy and Western blotting the presence of TRX in platelets. In conclusion, our demonstration of TRX release in burn injuries indicates that the TRX system is involved in a rapid antioxidant defense, coagulation processes, cell growth, and control of the extracellular peroxide tone intimately linked to cytoprotection and wound healing in burns. One of the cell types that delivers TRX promptly and efficiently into the blood may be the platelet.

  • 2.
    Aboye, Teshome Leta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Clark, Richard J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Burman, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Roig, Marta Bajona
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Craik, David J.
    University of Queensland, Institute for Molecular Bioscience.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Interlocking disulfides in circular proteins: toward efficient oxidative folding of cyclotides.2011In: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 14, no 1, p. 77-86Article in journal (Refereed)
    Abstract [en]

    Cyclotides are ultrastable plant proteins characterized by the presence of a cyclic amide backbone and three disulfide bonds that form a cystine knot. Because of their extreme stability, there has been significant interest in developing these molecules as a drug design scaffold. For this potential to be realized, efficient methods for the synthesis and oxidative folding of cyclotides need to be developed, yet we currently have only a basic understanding of the folding mechanism and the factors influencing this process. In this study, we determine the major factors influencing oxidative folding of the different subfamilies of cyclotides. The folding of all the cyclotides examined was heavily influenced by the concentration of redox reagents, with the folding rate and final yield of the native isomer greatly enhanced by high concentrations of oxidized glutathione. Addition of hydrophobic solvents to the buffer also enhanced the folding rates and appeared to alter the folding pathway. Significant deamidation and isoaspartate formation were seen when oxidation conditions were conducive to slow folding. The identification of factors that influence the folding and degradation pathways of cyclotides will facilitate the development of folding screens and optimized conditions for producing cyclotides and grafted analogs as stable peptide-based therapeutics.

  • 3. Barregard, Lars
    et al.
    Haghdoost, Siamak
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Cooke, Marcus S.
    Human and Methodological Sources of Variability in the Measurement of Urinary 8-Oxo-7,8-dihydro-2 '-deoxyguanosine2013In: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 18, no 18, p. 2377-2391Article in journal (Refereed)
    Abstract [en]

    Aims: Urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) is a widely used biomarker of oxidative stress. However, variability between chromatographic and ELISA methods hampers interpretation of data, and this variability may increase should urine composition differ between individuals, leading to assay interference. Furthermore, optimal urine sampling conditions are not well defined. We performed inter-laboratory comparisons of 8-oxodG measurement between mass spectrometric-, electrochemical- and ELISA-based methods, using common within-technique calibrants to analyze 8-oxodG-spiked phosphate-buffered saline and urine samples. We also investigated human subject- and sample collection-related variables, as potential sources of variability. Results: Chromatographic assays showed high agreement across urines from different subjects, whereas ELISAs showed far more inter-laboratory variation and generally overestimated levels, compared to the chromatographic assays. Excretion rates in timed 'spot' samples showed strong correlations with 24 h excretion (the 'gold' standard) of urinary 8-oxodG (r(p) 0.67-0.90), although the associations were weaker for 8-oxodG adjusted for creatinine or specific gravity (SG). The within-individual excretion of 8-oxodG varied only moderately between days (CV 17% for 24 h excretion and 20% for first void, creatinine-corrected samples). Innovation: This is the first comprehensive study of both human and methodological factors influencing 8-oxodG measurement, providing key information for future studies with this important biomarker. Conclusion: ELISA variability is greater than chromatographic assay variability, and cannot determine absolute levels of 8-oxodG. Use of standardized calibrants greatly improves intra-technique agreement and, for the chromatographic assays, importantly allows integration of results for pooled analyses. If 24 h samples are not feasible, creatinine- or SG-adjusted first morning samples are recommended.

  • 4.
    Basu, Samar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    F2-isoprostanes in human health and diseases: from molecular mechanisms to clinical implications2008In: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 10, no 8, p. 1405-1434Article, review/survey (Refereed)
    Abstract [en]

    Oxidative stress is implicated as one of the major underlying mechanisms behind many acute and chronic diseases, and involved in normal aging. However, the measurement of free radicals or their end products is complicated. Thus, proof of association of free radicals in pathologic conditions has been absent. Isoprostanes are prostaglandin-like bioactive compounds that are biosynthesized in vivo independent of cyclooxygenases, principally through free-radical catalyzation of arachidonic acid. Isoprostanes are now considered to be reliable biomarkers of oxidative stress, as evidenced by an autonomous study organized recently by the National Institutes of Health (NIH) in the United States. A number of these compounds have potent biologic activities such as vasoconstrictive and certain inflammatory properties. Isoprostanes are involved in many human diseases. Additionally, elevated levels of F2-isoprostanes have been seen in normal human pregnancy and after intake of some fatty acids, but their physiologic assignments have not yet been distinctive. This evidence indicates that measurement of bioactive F2-isoprostanes in body fluids offers a unique noninvasive analytic utensil to study the role of free radicals in physiology, oxidative stress–related diseases, experimental acute or chronic inflammatory conditions, and also in the assessment of various antioxidants, radical scavengers, and drugs.

  • 5.
    Basu, Samar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Oxidative Stress and Inflammation.
    Harris, Holly
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Vasson, Marie-Paule
    Wolk, Alicja
    Is There any Role for Serum Cathepsin S, CRP levels on Prognostic Information in Breast Cancer?: The Swedish Mammography Cohort2015In: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 23, no 16, p. 1298-1302Article in journal (Refereed)
    Abstract [en]

    Breast cancer is the most common cancer among women, and both low-grade inflammation and cathepsins might have important roles in breast cancer. We questioned whether prediagnostic circulating levels of C-reactive protein (CRP), cathepsin B and cathepsin S were associated with breast cancer risk. Sixty-nine incident breast cancer cases diagnosed after blood collection and 719 controls from the Swedish Mammography Cohort were analysed for systemic CRP, cathepsin B and cathepsin S. Cathepsin S and inflammation (hsCRP) adjusted cathepsin S were inversely associated with breast cancer risk (cathepsin S: OR for top vs. bottom tertile = 0.46; 95% CI = 0.23-0.92; Ptrend = 0.02; hsCRP adjusted cathepsin S: OR of 0.44; 95% CI = 0.22-0.87; Ptrend = 0.02). hsCRP was significantly associated with increased breast cancer risk (OR for top vs. bottom tertile= 2.01; 95% CI = 1.02-3.95; Ptrend = 0.04). No significant association was observed between cathepsin B and breast cancer risk (OR for top vs. bottom tertile= 0.67; 95% CI = 0.32-1.40; Ptrend = 0.30). These observations lead to hypothesis that levels of cathepsin S and hsCRP observed in women who later developed breast cancer may provide prognostic information regarding tumor development and need to be evaluated in prospective studies.

  • 6.
    Basu, Samar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Oxidative Stress and Inflammation.
    Nachat-Kappes, Rachida
    Caldefie-Chezet, Florence
    Vasson, Marie-Paule
    Eicosanoids and Adipokines in Breast Cancer: From Molecular Mechanisms to Clinical Considerations2013In: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 18, no 3, p. 323-360Article, review/survey (Refereed)
    Abstract [en]

    Chronic inflammation is one of the foremost risk factors for different types of malignancies, including breast cancer. Additional risk factors of this pathology in postmenopausal women are weight gain, obesity, estrogen secretion, and an imbalance in the production of adipokines, such as leptin and adiponectin. Various signaling products of transcription factor, nuclear factor-kappaB, in particular inflammatory eicosanoids, reactive oxygen species (ROS), and cytokines, are thought to be involved in chronic inflammation-induced cancer. Together, these key components have an influence on inflammatory reactions in malignant tissue damage when their levels are deregulated endogenously. Prostaglandins (PGs) are well recognized in inflammation and cancer, and they are solely biosynthesized through cyclooxygenases (COXs) from arachidonic acid. Concurrently, ROS give rise to bioactive isoprostanes from arachidonic acid precursors that are also involved in acute and chronic inflammation, but their specific characteristics in breast cancer are less demonstrated. Higher aromatase activity, a cytochrome P-450 enzyme, is intimately connected to tumor growth in the breast through estrogen synthesis, and is interrelated to COXs that catalyze the formation of both inflammatory and anti-inflammatory PGs such as PGE(2), PGF(2 alpha), PGD(2), and PGJ(2) synchronously under the influence of specific mediators and downstream enzymes. Some of the latter compounds upsurge the intracellular cyclic adenosine monophosphate concentration and appear to be associated with estrogen synthesis. This review discusses the role of COX- and ROS-catalyzed eicosanoids and adipokines in breast cancer, and therefore ranges from their molecular mechanisms to clinical aspects to understand the impact of inflammation.

  • 7. Brnjic, Slavica
    et al.
    Mazurkiewicz, Magdalena
    Fryknäs, Mårten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Sun, Chao
    Zhang, Xiaonan
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    D'Arcy, Padraig
    Linder, Stig
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Induction of Tumor Cell Apoptosis by a Proteasome Deubiquitinase Inhibitor Is Associated with Oxidative Stress2014In: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 21, no 17, p. 2271-2285Article in journal (Refereed)
    Abstract [en]

    Aims: b-AP15 is a recently described inhibitor of the USP14/UCHL5 deubiquitinases (DUBs) of the 19S proteasome. Exposure to b-AP15 results in blocking of proteasome function and accumulation of polyubiquitinated protein substrates in cells. This novel mechanism of proteasome inhibition may potentially be exploited for cancer therapy, in particular for treatment of malignancies resistant to currently used proteasome inhibitors. The aim of the present study was to characterize the cellular response to b-AP15-mediated proteasome DUB inhibition. Results: We report that b-AP15 elicits a similar, but yet distinct, cellular response as the clinically used proteasome inhibitor bortezomib. b-AP15 induces a rapid apoptotic response, associated with enhanced induction of oxidative stress and rapid activation of Jun-N-terminal kinase 1/2 (JNK)/activating protein-1 signaling. Scavenging of reactive oxygen species and pharmacological inhibition of JNK reduced b-AP15-induced apoptosis. We further report that endoplasmic reticulum (ER) stress is induced by b-AP15 and is involved in apoptosis induction. In contrast to bortezomib, ER stress is associated with induction of alpha-subunit of eukaryotic initiation factor 2 phosphorylation. Innovation: The findings establish that different modes of proteasome inhibition result in distinct cellular responses, a finding of potential therapeutic importance. Conclusion: Our data show that enhanced oxidative stress and ER stress are major determinants of the strong apoptotic response elicited by the 19S DUB inhibitor b-AP15. Antioxid. Redox Signal. 21, 2271-2285.

  • 8.
    Carlström, Mattias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Karolinska Inst, Dept Physiol & Pharmacol, S-17177 Stockholm, Sweden..
    Liu, Ming
    Karolinska Inst, Dept Physiol & Pharmacol, S-17177 Stockholm, Sweden..
    Yang, Ting
    Karolinska Inst, Dept Physiol & Pharmacol, S-17177 Stockholm, Sweden..
    Zollbrecht, Christa
    Karolinska Inst, Dept Physiol & Pharmacol, S-17177 Stockholm, Sweden..
    Huang, Liyue
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Karolinska Inst, Dept Physiol & Pharmacol, S-17177 Stockholm, Sweden..
    Peleli, Maria
    Karolinska Inst, Dept Physiol & Pharmacol, S-17177 Stockholm, Sweden..
    Borniquel, Sara
    Karolinska Inst, Dept Physiol & Pharmacol, S-17177 Stockholm, Sweden..
    Kishikawa, Hiroaki
    Karolinska Inst, Dept Physiol & Pharmacol, S-17177 Stockholm, Sweden..
    Hezel, Michael
    Karolinska Inst, Dept Physiol & Pharmacol, S-17177 Stockholm, Sweden..
    Persson, A. Erik G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Weitzberg, Eddie
    Karolinska Inst, Div Anesthesiol & Intens Care, Dept Physiol & Pharmacol, Stockholm, Sweden..
    Lundberg, Jon O.
    Karolinska Inst, Dept Physiol & Pharmacol, S-17177 Stockholm, Sweden..
    Cross-talk Between Nitrate-Nitrite-NO and NO Synthase Pathways in Control of Vascular NO Homeostasis2015In: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 23, no 4, p. 295-306Article in journal (Refereed)
    Abstract [en]

    Aims: Inorganic nitrate and nitrite from endogenous and dietary sources have emerged as alternative substrates for nitric oxide (NO) formation in addition to the classic L-arginine NO synthase (NOS)-dependent pathway. Here, we investigated a potential cross-talk between these two pathways in the regulation of vascular function. Results: Long-term dietary supplementation with sodium nitrate (0.1 and 1mmol kg(-1) day(-1)) in rats caused a reversible dose-dependent reduction in phosphorylated endothelial NOS (eNOS) (Ser1177) in aorta and a concomitant increase in phosphorylation at Thr495. Moreover, eNOS-dependent vascular responses were attenuated in vessels harvested from nitrate-treated mice or when nitrite was acutely added to control vessels. The citrulline-to-arginine ratio in plasma, as a measure of eNOS activity, was reduced in nitrate-treated rodents. Telemetry measurements revealed that a low dietary nitrate dose reduced blood pressure, whereas a higher dose was associated with a paradoxical elevation. Finally, plasma cyclic guanosine monophosphate increased in mice that were treated with a low dietary nitrate dose and decreased with a higher dose. Innovation and Conclusions: These results demonstrate the existence of a cross-talk between the nitrate-nitrite-NO pathway and the NOS-dependent pathway in control of vascular NO homeostasis. Antioxid. Redox Signal. 23, 295-306.

  • 9. Chlichlia, K.
    et al.
    Los, Marek Jan
    Department of Immunology and Cell Biology, University of Muenster, Roentgenstr. 21, D-48149 Muenster, Germany.
    Schulze-Osthoff, Klaus
    Department of Immunology and Cell Biology, University of Muenster, Roentgenstr. 21, D-48149 Muenster, Germany.
    Gazzolo, L.
    INSERM U412, Ecole Normale S périeure de Lyon, 69367 Lyon, Cedex 07, France.
    Schirrmacher, V.
    Division of Cellular Immunology (G0100), Tumor Immunology Program, German Cancer Research Center, Im Neuenheimer Feld 280, D69120 Heidelberg, Germany.
    Khazaie, K.
    Division of Cellular Immunology (G0100), Tumor Immunology Program, German Cancer Research Center, Im Neuenheimer Feld 280, D69120 Heidelberg, Germany; 4Department of Cancer Immunology and AIDS, Dana Farber Cancer Institute, Boston, MA 02115, U.S.A..
    Redox events in HTLV-1 tax-induced apoptotic T-cell death2002In: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 4, no 3, p. 471-477Article in journal (Refereed)
    Abstract [en]

    A number of studies implicate reactive oxygen intermediates in the induction of DNA damage and apoptosis. Recent studies suggest that the human T-cell leukemia virus type I (HTLV-1) Tax protein induces oxidative stress and apoptotic T-cell death. Activation of the T-cell receptor/CD3 pathway enhances the Tax-mediated oxidative and apoptotic effects. Tax-mediated apoptosis and oxidative stress as well as activation of nuclear factor-kappaB can be potently suppressed by antioxidants. This review focuses on Tax-dependent changes in the intracellular redox status and their role in Tax-mediated DNA damage and apoptosis. The relevance of these observations to HTLV-1 virus-mediated T-cell transformation and leukemogenesis are discussed.

  • 10.
    de Muinck, Ebo
    Dartmouth Medical School.
    Gene and Cell Therapy for Heart Failure2009In: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 11, p. 2025-2042Article in journal (Refereed)
    Abstract [en]

    Cardiac gene and cell therapy have both entered clinical trials aimed at ameliorating ventricular dysfunction in patients with chronic congestive heart failure. The transduction of myocardial cells with viral constructs encoding a specific cardiomyocyte Ca2+ pump in the sarcoplasmic reticulum (SR), SRCa2+-ATPase has been shown to correct deficient Ca2+ handling in cardiomyocytes and improvements in contractility in preclinical studies, thus leading to the first clinical trial of gene therapy for heart failure. In cell therapy, it is not clear whether beneficial effects are cell-type specific and how improvements in contractility are brought about. Despite these uncertainties, a number of clinical trials are under way, supported by safety and efficacy data from trials of cell therapy in the setting of myocardial infarction. Safety concerns for gene therapy center on inflammatory and immune responses triggered by viral constructs, and for cell therapy with myoblast cells, the major concern is increased incidence of ventricular arrhythmia after cell transplantation. Principles and mechanisms of action of gene and cell therapy for heart failure are discussed, together with the potential influence of reactive oxygen species on the efficacy of these treatments and the status of myocardial-delivery techniques for viral constructs and cells.

  • 11.
    De Muinck, Ebo D.
    et al.
    Dartmouth Medical School, Hanover, New Hampshire, USA.
    Nagy, Norbert
    Tirziu, Daniela
    Murakami, Masahiro
    Dartmouth Medical School, Hanover, New Hampshire, USA.
    Gurusamy, Narasimman
    Goswami, Shyamal K.
    Ghatpande, Satish
    Engelman, Richard M.
    Simons, Michael
    Dartmouth Medical School, Hanover, New Hampshire, USA.
    Das, Dipak K.
    University of Connecticut, USA.
    Protection against myocardial ischemia-reperfusion injury by the angiogenic masterswitch protein PR 39 gene therapy: the roles of HIF1 alpha stabilization and FGFR1 signaling2007In: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 9, no 4, p. 437-445Article in journal (Refereed)
    Abstract [en]

    PR-39, a proline-arginine-rich angiogenic response peptide, has been implicated in myocardial ischemic reperfusion injury. The present study examined the cardioprotective abilities of PR39 gene therapy. Male C5713146 mice were randomized to intramyocardial injecton of 10(9) p.f.u. adenovirus encoding PR39 (PR39), FGFR1 dominant negative signaling construct (FGFR1-dn), empty vector (EV), or PR39 adenovirus plus 4 mu g of plasmid endcoding a HIF1 alpha dominant negative construct (PR39 + HIF1 alpha-dn). Seven days later, hearts were subjected to 20 min of ischemia (1) and 2 h. reperfusion (R) ex vivo and aortic and coronary flow, left ventricular developed pressure (LVDP), and LVdp/dt were measured. Myocardial infarct (MI) size and cardiomyocyte apoptosis were measured by TTC staining and TUNEL, respectively. PR39 expression was robust up to 14 days after gene transfer and was absent after EV and FGFR1-dn. Hemodynamics showed no differences at baseline, and heart rate remained unchanged in all groups throughout the experiment. After I-R, hemodynamics remained unchanged in PR39 hearts, but deteriorated significantly in the other groups, except for aortic flow, which remained significantly higher in FGFR1-dn than in EV and PR39 + HIF1 alpha-dn (p less than 0.05), although it was lower than in PR39 (p less than 0.05). MI was 8.7 +/- 0.9 % in PR39, 23.8 +/- 1.1 % in FGFR1-dn, 29.9 +/- 2.2% in EV, and 30.8 +/- 2.7 % in PR39 + HIF1 alpha-dn (PR39 vs. other groups: p less than 0.05; FGFR1-dn vs. EV and PR39 + HIF1 alpha-dn: p less than 0.05). In PR39, HIF-1 alpha protein was higher than in FGFR1-dn and EV. Importantly, cotransfection of HlF1 alpha-dn with PR39 completely abolished cardioprotection by PR39. Cardioprotection by PR39 is likely conveyed by protective metabolic and survival responses through HIF1-alpha stabilization and not by angiogenesis, because baseline coronary How was the same in all groups. Abrogation of FGFR1 signaling conveyed an intermediate degree of cardioprotection.

  • 12. Garcia-Rodriguez, Cruz E.
    et al.
    Helmersson-Karlqvist, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Oxidative Stress and Inflammation. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Dolores Mesa, Maria
    Miles, Elizabeth A.
    Noakes, Paul S.
    Vlachava, Maria
    Kremmyda, Lefkothea-Stella
    Diaper, Norma D.
    Godfrey, Keith M.
    Calder, Philip C.
    Gil, Angel
    Basu, Samar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Oxidative Stress and Inflammation.
    Does Increased Intake of Salmon Increase Markers of Oxidative Stress in Pregnant Women?: The Salmon in Pregnancy Study2011In: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 15, no 11, p. 2819-2823Article in journal (Refereed)
    Abstract [en]

    The Salmon in Pregnancy Study provided two meals of salmon per week to pregnant women from week 20 of gestation; the control group maintained their habitual diet low in oily fish. Salmon is a rich source of marine n-3 fatty acids. Since marine n-3 fatty acids may increase oxidative stress, we investigated whether increased salmon consumption could affect markers of oxidative stress in mid and late pregnancy. Urinary 8-iso-prostaglandin F(2 alpha), urinary 8-hydroxy-2'-deoxyguanosine, and plasma lipid peroxide concentrations did not change from week 20 to 38 of pregnancy and were not altered by increased consumption of salmon. Thus, increased intake of salmon during pregnancy does not increase oxidative stress, as judged by the markers of oxidative damage to lipids and DNA measured herein.

  • 13. Garcia-Rodriguez, Cruz E.
    et al.
    Mesa, Maria D.
    Olza, Josune
    Vlachava, Maria
    Kremmyda, Lefkothea-Stella
    Diaper, Norma D.
    Noakes, Paul S.
    Miles, Elizabeth A.
    Ramirez-Tortosa, Maria Carmen
    Liaset, Bjorn
    Froyland, Livar
    Rossary, Adrien
    Farges, Marie-Chantal
    Vasson, Marie-Paule
    Aguilera, Concepcion M.
    Helmersson-Karlqvist, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Oxidative Stress and Inflammation. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Godfrey, Keith M.
    Calder, Philip C.
    Basu, Samar
    Gil, Angel
    Does Consumption of Two Portions of Salmon Per Week Enhance the Antioxidant Defense System in Pregnant Women?2012In: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 16, no 12, p. 1401-1406Article in journal (Refereed)
    Abstract [en]

    Salmon is a rich source of marine n-3 fatty acids, which may increase oxidative stress and, in turn, could affect the antioxidant defense system in blood plasma and erythrocytes of pregnant women. The Salmon in Pregnancy Study provided two meals of salmon per week to pregnant women from week 20 of gestation; the control group maintained their habitual diet low in oily fish. Higher selenium and retinol plasma concentrations were observed after dietary salmon supplementation. Besides, a concomitant increase in selenium and glutathione concentration as well as glutathione peroxidase and reductase activities were detected as pregnancy progressed. However, tocopherols, retinol, beta-carotene, and coenzyme Q(10) decreased in late pregnancy. Collectively, our findings lead to the hypothesis that increased farmed salmon intake may increase antioxidant defenses during pregnancy.

  • 14. Gruber, Jan
    et al.
    Tang, Soon Yew
    Jenner, Andrew M
    Mudway, Ian
    Blomberg, Anders
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine, Pulmonary Medicine.
    Behndig, Annelie
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine, Pulmonary Medicine.
    Kasiman, Katherine
    Lee, Chung-Yung J
    Seet, Raymond C S
    Zhang, Wenxia
    Chen, Christopher
    Kelly, Frank J
    Halliwell, Barry
    Allantoin in human plasma, serum, and nasal-lining fluids as a biomarker of oxidative stress: avoiding artifacts and establishing real in vivo concentrations.2009In: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 11, no 8, p. 1767-1776Article in journal (Refereed)
    Abstract [en]

    Urate is the terminal product of purine metabolism in primates, including humans. Urate is also an efficient scavenger of oxidizing species and is thought to be an important antioxidant in human body fluids. Allantoin, the major oxidation product of urate, has been suggested as a candidate biomarker of oxidative stress because it is not produced metabolically. Although urate is converted to allantoin under strongly alkaline pH, such conditions have been used in the past to facilitate extraction of allantoin. We evolved a method for the determination of allantoin concentrations in human plasma and serum by gas chromatography-mass spectrometry without such artifact. With this method, we show that alkaline conditions do indeed cause breakdown of urate, leading to significant overestimation of allantoin concentration in human samples. By using our alternative method, serum samples from 98 volunteers were analyzed, and allantoin levels were found to be significantly lower than was previously reported. The in vivo utility and sensitivity of our method was further evaluated in human nasal-lining fluids. We were able to demonstrate an ozone-induced increase in allantoin, in the absence of increases in either ascorbate or glutathione oxidation products.

  • 15.
    Halvarsson, Camilla
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Rörby, Emma
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Eliasson, Pernilla
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Lang, Stefan
    Lund Stem Cell Center, Lund University, Lund, Sweden.
    Soneji, Shamit
    Lund Stem Cell Center, Lund University, Lund, Sweden.
    Jönsson, Jan-Ingvar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Putative Role of Nuclear Factor-Kappa B But Not Hypoxia-Inducible Factor-1α in Hypoxia-Dependent Regulation of Oxidative Stress in Hematopoietic Stem and Progenitor Cells2019In: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 31, no 3, p. 211-226Article in journal (Refereed)
    Abstract [en]

    Aims: Adaptation to low oxygen of hematopoietic stem cells (HSCs) in the bone marrow has been demonstrated to depend on the activation of hypoxia-inducible factor (HIF)-1α as well as the limited production of reactive oxygen species (ROS). In this study, we aimed at determining whether HIF-1α is involved in protecting HSCs from ROS.

    Results: Oxidative stress was induced by DL-buthionine-(S,R)-sulfoximine (BSO)-treatment, which increases the mitochondrial ROS level. Hypoxia rescued Lineage-Sca-1+c-kit+ (LSK) cells from BSO-induced apoptosis, whereas cells succumbed to apoptosis in normoxia. Apoptosis in normoxia was inhibited with the antioxidant N-acetyl-L-cysteine or by overexpression of anti-apoptotic BCL-2. Moreover, stabilized expression of oxygen-insensitive HIFs could not protect LSK cells from oxidative stress-induced apoptosis at normoxia, neither could short hairpin RNA to Hif-1α inhibit the protective effects by hypoxia in LSK cells. Likewise, BSO treatment of LSK cells from Hif-1α knockout mice did not suppress the effects seen in hypoxia. Microarray analysis identified the nuclear factor-kappa B (NF-κB) pathway as a pathway induced by hypoxia. By using NF-κB lentiviral construct and DNA-binding assay, we found increased NF-κB activity in cells cultured in hypoxia compared with normoxia. Using an inhibitor against NF-κB activation, we could confirm the involvement of NF-κB signaling as BSO-mediated cell death was significantly increased in hypoxia after adding the inhibitor.

    Innovation: HIF-1α is not involved in protecting HSCs and progenitors to elevated levels of ROS on glutathione depletion during hypoxic conditions.

    Conclusion: The study proposes a putative role of NF-κB signaling as a hypoxia-induced regulator in early hematopoietic cells.

  • 16.
    Hultqvist, Malin
    et al.
    Redoxis AB, Lund Life Science Incubator, Lund, Sweden.
    Sareila, Outi
    Medical Inflammation Research, Medicity, University of Turku, Turku, Finland..
    Vilhardt, Frederik
    Institute for cellular and molecular medicine, The Panum Institute, Copenhagen University, Copenhagen, Denmark.
    Norin, Ulrika
    Medical Inflammation Research, MBB, Karolinska Institutet, Stockholm, Sweden.
    Olsson, Lina M.
    Medical Inflammation Research, C12 BMC, Lund University, Lund, Sweden.
    Olofsson, Peter
    Redoxis AB, Sahlgrenska Science Park, Go¨ teborg, Sweden.
    Hellman, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Holmdahl, Rikard
    Medical Inflammation Research, C12 BMC, Lund University, Lund, Sweden.
    Positioning of a Polymorphic Quantitative Trait Nucleotide in the Ncf1 Gene Controlling Oxidative Burst Response and Arthritis Severity in Rats2011In: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 14, no 12, p. 2373-2383Article in journal (Refereed)
    Abstract [en]

    The Ncf1 gene, encoding the P47(PHOX) protein that regulates production of reactive oxygen species (ROS) by the phagocyte NADPH oxidase (NOX2) complex, is associated with autoimmunity and arthritis severity in rats. We have now identified that the single-nucleotide polymorphism (SNP) resulting in an M153T amino acid substitution mediates arthritis resistance and thus explains the molecular polymorphism underlying the earlier identified Ncf1 gene effect. We identified the SNP in position 153 to regulate ROS production using COSPHOX cells transfected with mutated Ncf1. To determine the role of this SNP for control of arthritis, we used the Wistar strain, identified to carry only the postulated arthritis resistant SNP in position 153. When this Ncf1 allele was backcrossed to the arthritis susceptible DA strain, both granulocyte ROS production and arthritis resistance were restored. Position 153 is located in the hinge region between the PX and SH3 domains of P47(PHOX). Mutational analysis of this position revealed a need for an -OH group in the side chain but we found no evidence for phosphorylation. The polymorphism did not affect assembly of the P47(PHOX)/P67(PHOX) complex in the cytosol or membrane localization, but is likely to operate downstream of assembly, affecting activity of the membrane NOX2 complex.

  • 17.
    Kaluza, Joanna
    et al.
    Karolinska Inst, Inst Environm Med, Unit Nutr Epidemiol, Stockholm, Sweden.; Warsaw Univ Life Sci SGGW, Dept Human Nutr, Nutr Res Lab, 159C Nowoursynowska St, PL-02776 Warsaw, Poland..
    Harris, Holly
    Fred Hutchinson Canc Res Ctr, Program Epidemiol, Div Publ Hlth Sci, Seattle, WA 98104 USA.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Wolk, Alicja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics. Karolinska Inst, Inst Environm Med, Unit Nutr Epidemiol, Stockholm, Sweden.
    Questionnaire-Based Anti-Inflammatory Diet Index as a Predictor of Low-Grade Systemic Inflammation.2018In: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 28, no 1, p. 78-84Article in journal (Refereed)
    Abstract [en]

    There is accumulating evidence that diet may be associated with markers of inflammation. We have evaluated if an empirically developed questionnaire-based Anti-Inflammatory Diet Index (AIDI) may predict low-grade systemic chronic inflammation in a Nordic population. The AIDI was developed using a 123-item food frequency questionnaire among 3503 women (56-74 years old) with high-sensitivity C-reactive protein (hsCRP) plasma concentration <20 mg/L. Using Spearman correlations, we identified 20 foods (AIDI-20) statistically significantly related to hsCRP. The median (range) of AIDI-20 was 8 (0-17) scores, and the median concentration of hsCRP in the lowest versus the highest quintile of AIDI-20 (≤6 vs. ≥11 scores) varied by 80% (1.8 vs. 1.0 mg/L, respectively). In a multivariable-adjusted linear regression model, women in the highest quintile of AIDI-20 compared with those in the lowest had a 26% (95% confidence interval [CI] 18-33%; p-trend <0.001) lower hsCRP concentration; each 1-score increment in the AIDI-20 was associated with a 0.06 (95% CI 0.04-0.08) mg/L lower hsCRP. The observed association between the AIDI-20 and hsCRP was robust by all hsCRP levels and in subgroups defined by inflammatory-related factors. Our results lead to the hypothesis that the empirically developed questionnaire-based dietary anti-inflammatory index may predict low-grade systemic inflammation. Antioxid. Redox Signal. 28, 78-84.

  • 18.
    Kehrein, Kirsten
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Bonnefoy, Nathalie
    Ott, Martin
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Mitochondrial Protein Synthesis: Efficiency and Accuracy2013In: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 19, no 16, p. 1928-1939Article, review/survey (Refereed)
    Abstract [en]

    Significance: The mitochondrial genetic system is responsible for the production of a few core-subunits of the respiratory chain and ATP synthase, the membrane protein complexes driving oxidative phosphorylation (OXPHOS). Efficiency and accuracy of mitochondrial protein synthesis determines how efficiently new OXPHOS complexes can be made. Recent Advances: The system responsible for expression of the mitochondrial-encoded subunits developed from that of the bacterial ancestor of mitochondria. Importantly, many aspects of genome organization, transcription, and translation have diverged during evolution. Recent research has provided new insights into the architecture, regulation, and organelle-specific features of mitochondrial translation. Mitochondrial ribosomes contain a number of proteins absent from prokaryotic ribosomes, implying that in mitochondria, ribosomes were tailored to fit the requirements of the organelle. In addition, mitochondrial gene expression is regulated post-transcriptionally by a number of mRNA-specific translational activators. At least in yeast, these factors can regulate translation in respect to OXPHOS complex assembly to adjust the level of newly synthesized proteins to amounts that can be successfully assembled into respiratory chain complexes. Critical Issues: Mitochondrial gene expression is determining aging in eukaryotes, and a number of recent reports indicate that efficiency of translation directly influences this process. Future Directions: Here we will summarize recent advances in our understanding of mitochondrial protein synthesis by comparing the knowledge acquired in the systems most commonly used to study mitochondrial biogenesis. However, many steps have not been understood mechanistically. Innovative biochemical and genetic approaches have to be elaborated to shed light on these important processes. Antioxid. Redox Signal. 19, 1928-1939.

  • 19.
    Kieselbach, Thomas
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Oxidative folding in chloroplasts2013In: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 19, no 1, p. 72-82Article in journal (Refereed)
    Abstract [en]

    Significance: Disulfide-bonded proteins in chloroplasts from green plants exist in the envelope and the thylakoid membrane, and in the stroma and the lumen. The formation of disulfide bonds in proteins is referred to as oxidative folding and is linked to the import and folding of chloroplast proteins as well as the assembly and repair of thylakoid complexes. It is also important in the redox regulation of enzymes and signal transfer.

    Recent Advances: Green-plant chloroplasts contain enzymes that can form and isomerize disulfide bonds in proteins. In Arabidopsis thaliana, four proteins are identified that are relevant for the catalysis of disulfide bond formation in chloroplast proteins. The proteins' low quantum yield of Photosystem II 1 (LQY1, At1g75690) and snowy cotyledon 2 (SCO2, At3g19220) exhibits protein disulfide isomerase activity and is suggested to function in the assembly and repair of Photosystem II (PSII), and the biogenesis of thylakoids in cotyledons, respectively. The thylakoid-located Lumen thiol oxidoreductase 1 (LTO1, At4g35760) can catalyze the formation of the disulfide bond of the extrinsic PsbO protein of PSII. In addition, the stroma-located protein disulfide isomerase PDIL1-3 (At3g54960) may have a role in oxidative folding.

    Critical Issues: Research on oxidative folding in chloroplasts plants is in an early stage and little is known about the mechanisms of disulfide bond formation in chloroplast proteins.

    Future Directions: The close link between the import and folding of chloroplast proteins suggests that Hsp93, a component of the inner envelope's import apparatus, may have co-chaperones that can catalyze disulfide bond formation in newly imported proteins.

  • 20. Kummu, Outi
    et al.
    Turunen, S Pauliina
    Wang, Chunguang
    Lehtimäki, Jaakko
    Veneskoski, Marja
    Kastarinen, Helena
    Koivula, Marja-Kaisa
    Risteli, Juha
    Kesäniemi, Y Antero
    Hörkkö, Sohvi
    Carbamyl adducts on low-density lipoprotein induce IgG response in LDLR-/- mice and bind plasma autoantibodies in humans under enhanced carbamylation.2013In: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 19, no 10, p. 1047-62Article in journal (Refereed)
    Abstract [en]

    AIMS: Post-translational modification of proteins via carbamylation predicts increased risk for coronary artery disease. Uremia and smoke exposure are known to increase carbamylation. The aim was to investigate the role of carbamylated low-density lipoprotein (LDL) immunization on antibody formation and atherogenesis in LDL receptor-deficient (LDLR-/-) mice, and to study autoantibodies to carbamylated proteins in humans with carbamylative load.

    RESULTS: LDLR-/- mice immunized with carbamylated mouse LDL (msLDL; n=10) without adjuvant showed specific immunoglobulin G (IgG) antibody levels to carbamyl-LDL and malondialdehyde-modified LDL (MDA-LDL) but not to oxidized LDL or native LDL. Immunization did not influence the atherosclerotic plaque area compared with control LDLR-/- mice immunized with native msLDL (n=10) or phosphate-buffered saline (n=11). Humans with high plasma urea levels, as well as smokers, had increased IgG autoantibody levels to carbamyl-modified proteins compared to the subjects with normal plasma urea levels, or to nonsmokers.

    INNOVATION: Carbamyl-LDL induced specific IgG antibody response cross-reactive with MDA-LDL in mice. IgG antibodies to carbamyl-LDL were also found in human plasma and related to conditions known to have increased carbamylation, such as uremia and smoking. Plasma antibodies to carbamylated proteins may serve as new indicator of in vivo carbamylation.

    CONCLUSION: These data give insight into mechanisms of in vivo humoral recognition of post-translationally modified structures. Humoral IgG immune response to carbamylated proteins is suggested to play a role in conditions leading to enhanced carbamylation, such as uremia and smoking.

  • 21.
    Kurz, Tino
    et al.
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Eaton, John W.
    University of Louisville.
    Brunk, Ulf
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Redox Activity Within the Lysosomal Compartment: Implications for Aging and Apoptosis2010In: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 13, no 4, p. 511-523Article, review/survey (Refereed)
    Abstract [en]

    The lysosome is a redox-active compartment containing low-mass iron and copper liberated by autophagic degradation of metalloproteins. The acidic milieu and high concentration of thiols within lysosomes will keep iron in a reduced ( ferrous) state, which can react with endogenous or exogenous hydrogen peroxide. Consequent intralysosomal Fenton reactions may give rise to the formation of lipofuscin or "age pigment that accumulates in long-lived postmitotic cells that cannot dilute it by division. Extensive accumulation of lipofuscin seems to hinder normal autophagy and may be an important factor behind aging and age-related pathologies. Enhanced oxidative stress causes lysosomal membrane permeabilization, with ensuing relocation to the cytosol of iron and lysosomal hydrolytic enzymes, with resulting apoptosis or necrosis. Lysosomal copper is normally not redox active because it will form non-redox-active complexes with various thiols. However, if cells are exposed to lysosomotropic chelators that do not bind all the copper coordinates, highly redox-active complexes may form, with ensuing extensive lysosomal Fenton-type reactions and loss of lysosomal stability. Because many malignancies seem to have increased amounts of copper-containing macromolecules that are turned over by autophagy, it is conceivable that lysosomotropic copper chelators may be used in the future in ROS-based anticancer therapies.

  • 22. Lindahl, Marika
    et al.
    Mata-Cabana, Alejandro
    Kieselbach, Thomas
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    The disulfide proteome and other reactive cysteine proteomes: analysis and functional significance2011In: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 14, no 12, p. 1-63Article in journal (Refereed)
    Abstract [en]

    Abstract Ten years ago, proteomics techniques designed for large-scale investigations of redox-sensitive proteins started to emerge. The proteomes, defined as sets of proteins containing reactive cysteines that undergo oxidative post-translational modifications, have had a particular impact on research concerning the redox regulation of cellular processes. These proteomes, which are hereafter termed "disulfide proteomes," have been studied in nearly all kingdoms of life, including animals, plants, fungi, and bacteria. Disulfide proteomics has been applied to the identification of proteins modified by reactive oxygen and nitrogen species under stress conditions. Other studies involving disulfide proteomics have addressed the functions of thioredoxins and glutaredoxins. Hence, there is a steadily growing number of proteins containing reactive cysteines, which are probable targets for redox regulation. The disulfide proteomes have provided evidence that entire pathways, such as glycolysis, the tricarboxylic acid cycle, and the Calvin-Benson cycle, are controlled by mechanisms involving changes in the cysteine redox state of each enzyme implicated. Synthesis and degradation of proteins are processes highly represented in disulfide proteomes and additional biochemical data have established some mechanisms for their redox regulation. Thus, combined with biochemistry and genetics, disulfide proteomics has a significant potential to contribute to new discoveries on redox regulation and signaling. Antioxid. Redox Signal. 14, 000-000.

  • 23.
    Lomoth, Reiner
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Physical Chemistry.
    Redox-Stimulated Motion and Bistability in Metal Complexes and Organometallic Compounds2013In: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 19, no 15, p. 1803-1814Article, review/survey (Refereed)
    Abstract [en]

    Significance: Control over reversible changes to molecular structure forms the basis for artificial molecular machines that could eventually lead to the development of molecule-based nanotechnology. Recent Advances: Particular applications in information storage and processing could emerge where the structural rearrangements give rise to bistability and molecular hysteresis effects. Critical Issues: Oxidation-state-dependent coordination and bonding preferences in transition metal complexes and organometallic compounds provide a versatile approach to the control of molecular motions by redox input, but so far, few structural motifs have been applied in redox-actuated molecular machines. Future Directions: Further progress toward molecule-based nanoscale devices might be accomplished with molecular components derived from a wider range of structural themes and forms of molecular motion. Examples of redox-stimulated rearrangements in metal complexes and organometallic compounds are described that have been employed in molecular machines or could be considered for the design of new functional molecules.

  • 24.
    Miranda-Vizuete, Antonio
    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.
    The mitochondrial thioredoxin system2000In: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 2, no 4, p. 801-810Article in journal (Refereed)
    Abstract [en]

    Eukaryotic organisms from yeast to human possess a mitochondrial thioredoxin system composed of thioredoxin and thioredoxin reductase, similar to the cytosolic thioredoxin system that exists in the same cells. Yeast and mammalian mitochondrial thioredoxins are monomers of approximately 12 kDa and contain the typical conserved active site WCGPC. However, there are important differences between yeast and mammalian mitochondrial thioredoxin reductases that resemble the differences between their cytosolic counterparts. Mammalian mitochondrial thioredoxin reductase is a selenoprotein that forms a homodimer of 55 kDa/subunit; while yeast mitochondrial thioredoxin reductase is a homodimer of 37 kDa/subunit and does not contain selenocysteine. A function of the mitochondrial thioredoxin system is as electron donor for a mitochondrial peroxiredoxin, an enzyme that detoxifies the hydrogen peroxide generated by the mitochondrial metabolism. Experiments with yeast mutants lacking both the mitochondrial thioredoxin system as well as the mitochondrial peroxiredoxin system suggest an important role for mitochondrial thioredoxin, thioredoxin reductase, and peroxiredoxin in the protection against oxidative stress.

  • 25.
    Olejnicka, Beata
    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.
    Andersson, A.
    Tyrberg, B.
    Dalen, H.
    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.
    Beta cells, oxidative stress, lysosomal stability and apoptotic/neurotic cell death.1999In: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 1, p. 305-315Article in journal (Refereed)
  • 26.
    Papaevgeniou, Nikoletta
    et al.
    Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece; Faculty of Biology and Pharmacy, Institute of Nutrition, Friedrich Schiller University of Jena, Jena, Germany.
    Sakellari, Marianthi
    Örebro University, School of Medical Sciences. Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece.
    Jha, Sweta
    Translational Cancer Biology Program, Research Programs Unit, University of Helsinki, Helsinki, Finland.
    Tavernarakis, Nektarios
    Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Heraklion, Greece; Faculty of Medicine, Department of Basic Sciences, University of Crete, Heraklion, Greece.
    Holmberg, Carina I
    Programs Unit, University of Helsinki, Helsinki, Finland.
    Gonos, Efstathios S.
    Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece; Medical School, Örebro University, Örebro, Sweden.
    Chondrogianni, Niki
    Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece.
    18α-Glycyrrhetinic Acid Proteasome Activator Decelerates Aging and Alzheimer's Disease Progression in Caenorhabditis elegans and Neuronal Cultures2016In: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 25, no 16, p. 855-869Article in journal (Refereed)
    Abstract [en]

    Aims: Proteasomes are constituents of the cellular proteolytic networks that maintain protein homeostasis through regulated proteolysis of normal and abnormal (in any way) proteins. Genetically mediated proteasome activation in multicellular organisms has been shown to promote longevity and to exert protein antiaggregation activity. In this study, we investigate whether compound-mediated proteasome activation is feasible in a multicellular organism and we dissect the effects of such approach in aging and Alzheimer's disease (AD) progression.

    Results: Feeding of wild-type Caenorhabditis elegans with 18α-glycyrrhetinic acid (18α-GA; a previously shown proteasome activator in cell culture) results in enhanced levels of proteasome activities that lead to a skinhead-1- and proteasome activation-dependent life span extension. The elevated proteasome function confers lower paralysis rates in various AD nematode models accompanied by decreased Aβ deposits, thus ultimately decelerating the progression of AD phenotype. More importantly, similar positive results are also delivered when human and murine cells of nervous origin are subjected to 18α-GA treatment.

    Innovation: This is the first report of the use of 18α-GA, a diet-derived compound as prolongevity and antiaggregation factor in the context of a multicellular organism.

    Conclusion: Our results suggest that proteasome activation with downstream positive outcomes on aging and AD, an aggregation-related disease, is feasible in a nongenetic manipulation manner in a multicellular organism. Moreover, they unveil the need for identification of antiaging and antiamyloidogenic compounds among the nutrients found in our normal diet.

  • 27. Rouhier, Nicolas
    et al.
    Gelhaye, Eric
    Dietz, Karl Josef
    Jacquot, Jean-Pierre
    Wingsle, Gunnar
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Villarejo, Arsenio
    Srivastava, Manoj
    Keech, Olivier
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Droux, Michel
    Finkemeier, Iris
    Samuelsson, Göran
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Identification of plant glutaredoxin targets2005In: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 7, no 7-8, p. 919-929Article in journal (Refereed)
    Abstract [en]

    Glutaredoxins (Grxs) are small ubiquitous proteins of the thioredoxin (Trx) family, which catalyze dithiol–disulfide exchange reactions or reduce protein-mixed glutathione disulfides. In plants, several Trx-interacting proteins have been isolated from different compartments, whereas very few Grx-interacting proteins are known. We describe here the determination of Grx target proteins using a mutated poplar Grx, various tissular and subcellular plant extracts, and liquid chromatography coupled to tandem mass spectrometry detection. We have identified 94 putative targets, involved in many processes, including oxidative stress response [peroxiredoxins (Prxs), ascorbate peroxidase, catalase], nitrogen, sulfur, and carbon metabolisms (methionine synthase, alanine aminotransferase, phosphoglycerate kinase), translation (elongation factors E and Tu), or protein folding (heat shock protein 70). Some of these proteins were previously found to interact with Trx or to be glutathiolated in other organisms, but others could be more specific partners of Grx. To substantiate further these data, Grx was shown to support catalysis of the stroma β-type carbonic anhydrase and Prx IIF of Arabidopsis thaliana, but not of poplar 2-Cys Prx. Overall, these data suggest that the interaction could occur randomly either with exposed cysteinyl disulfide bonds formed within or between target proteins or with mixed disulfides between a protein thiol and glutathione.

  • 28.
    Sahaf, Bita
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Rosén, Anders
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Secretion of 10-kDa and 12-kDa Thioredoxin Species from Blood Monocytes and Transformed Leukocytes2000In: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 2, no 4, p. 717-726Article in journal (Refereed)
    Abstract [en]

    Thioredoxins (TRX) are ubiquitous, small redox-active proteins with multiple functions, including antioxidant, cytoprotective, and chemoattractant activities. In addition to a 12-kDa intracellular form, extracellular 10-kDa and 12-kDa TRX have been defined. The biological activities of the 10-kDa TRX were previously measured as eosinophil cytotoxicity enhancing activity or B-cell stimulatory activity. Cytotrophoblastic cell lines also release a 10-kDa TRX form. To study the biological role of 10-kDa TRX, we established two highly sensitive enzyme-linked immuno-spot assays (ELISPOT), which detect secreted truncated 10-kDa and full-length 12-kDa TRX at the single cell level. TRX secretion was investigated in several cell lines including the T-helper cell hybridoma MP6, the Jurkat T-cell leukemia, the U-937 myelomonocytic leukemia, and the 3B6, EBV-transformed, lymphoblastoid B-cell line. The highest number of secreting cells was found in 3B6 cultures, median = 34 (quartiles, 27–39) per well (105 cells). Peripheral blood monocytes isolated from healthy donors secreted significantly more TRX after stimulation with ionomycin, phorbol myristate acetate (PMA), fMLP, and lipopolysaccharide (LPS), compared to unstimulated cells. Oxidative stress induced by thioloxidant diamide also induced the secretion of both truncated and full-length TRX measured in ELISPOT (p = 0.047 and p = 0.031, respectively). The biological activity of the truncated and full-length forms was tested in a cell migration assay. Truncated TRX was devoid of protein disulfide reductase activity, but retained strong chemoattractant activity for human monocytes, in the same range as full-length TRX, as previously reported.

  • 29.
    Sareila, Outi
    et al.
    Univ Turku, Med Res Lab, Turku, Finland..
    Hagert, Cecilia
    Univ Turku, Med Res Lab, Turku, Finland.;Natl Doctoral Programme Informat & Struct Biol, Turku, Finland..
    Kelkka, Tiina
    Univ Turku, Med Res Lab, Turku, Finland.;Turku Doctoral Programme Biomed Sci, Turku, Finland.;Univ Helsinki, Hematol Res Unit Helsinki, Helsinki, Finland..
    Linja, Marjo
    Univ Turku, Med Res Lab, Turku, Finland..
    Xu, Bingze
    Karolinska Inst, Dept Med Biochem & Biophys, Div Med Inflammat Res, SE-7177 Stockholm, Sweden..
    Kihlberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Holmdahl, Rikard
    Univ Turku, Med Res Lab, Turku, Finland.;Karolinska Inst, Dept Med Biochem & Biophys, Div Med Inflammat Res, SE-7177 Stockholm, Sweden..
    Reactive Oxygen Species Regulate Both Priming and Established Arthritis, but with Different Mechanisms2017In: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 27, no 18, p. 1473-1490Article in journal (Refereed)
    Abstract [en]

    Aims: Neutrophil cytosolic factor 1 (NCF1) is a key regulatory component of the phagocytic NOX2 complex, which produces reactive oxygen species (ROS). Polymorphism of the Ncf1 gene is associated with increased arthritis severity. In this study, we generated targeted Ncf1 knock-in mice with inducible Ncf1 expression and determined the critical time window during which the NOX2-derived ROS protect the mice from arthritis.

    Results: Targeted Ncf1 knock-in mice lacked NOX2-derived ROS, and in vivo allelic conversion of Ncf1 by the CreER(T2) recombinase led to full protein expression and ROS production within 10 days. Mice in which Ncf1 had been activated before immunization with type II collagen (CII) developed only mild clinical symptoms of collagen-induced arthritis (CIA), whereas the ROS-deficient littermates had severe arthritis. The functional Ncf1 restricted the expansion of IL-17A-producing T cells specific for the immunodominant CII peptide. When the Ncf1 gene was activated after the priming phase, Ncf1-dependent protection from autoimmune arthritis was still observed, together with a reduced number of splenic monocytes but it was not associated with alterations in peptide-specific T cell response. The Ncf1-deficient mice expressed pronounced interferon signature, which could be normalized by conditional expression of Ncf1 and was also present in the Ncf1-mutated mouse during arthritis.

    Innovation and Conclusion: Ncf1 deficiency has been known to predispose to autoimmunity in both humans and rodents. Our in vivo results point to a regulatory role of NOX2-derived ROS not only during priming but also during the effector phase of CIA, most likely via different mechanisms.

  • 30.
    Selin, Jinjin Zheng
    et al.
    Inst Environm Med, Div Nutr Epidemiol, Karolinska Inst, Stockholm, Sweden.
    Lindblad, Birgitta Ejdervik
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital. Division of Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Ophthalmology, Örebro University Hospital, Örebro, Sweden.
    Rautiainen, Susanne
    Inst Environm Med, Div Nutr Epidemiol, Karolinska Inst, Stockholm, Sweden.
    Michaelsson, Karl
    Dept Surg Sci, Sect Orthopaed, Uppsala Univ, Uppsala, Sweden.
    Morgenstern, Ralf
    Inst Environm Med, Div Biochem Toxicol, Karolinska Inst, Stockholm, Sweden.
    Bottai, Matteo
    Inst Environm Med, Div Biostat, Karolinska Inst, Stockholm, Sweden.
    Basu, Samar
    Fac Med, Dept Publ Hlth & Caring Sci, Uppsala Univ, Uppsala, Sweden; Ctr Excellence Inflammat, Univ Uppsala Hosp, Uppsala, Sweden; Lab Biochem Mol Biol & Nutr, Univ Auvergne, Clermont Ferrand, France.
    Wolk, Alicja
    Inst Environm Med, Div Nutr Epidemiol, Karolinska Inst, Stockholm, Sweden.
    Are increased levels of systemic oxidative stress and inflammation associated with age-related cataract?2014In: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 21, no 5, p. 700-704Article in journal (Refereed)
    Abstract [en]

    Oxidative stress and inflammation may be involved in the etiology of age-related cataract. This study is the first to investigate the association between urinary levels of 8-iso-prostaglandin F-2 alpha (PGF(2 alpha); as a biomarker for systemic oxidative stress in vivo) and 15-keto-dihydro-PGF(2 alpha) (as a biomarker for systemic inflammation in vivo) and risk of age-related cataract. We observed in a nested case-control study, including 258 women with incident cataract diagnosis and/or cataract extraction and 258 women without cataract, matched on age and date of urine sample collection that, women with higher levels of urinary 8-iso-PGF(2 alpha) as compared with lower levels had an increased risk of age-related cataract. There was no difference in 15-keto-dihydro-PGF(2 alpha) levels between cases and controls. Our observations lead to the hypothesis that higher systemic oxidative stress increases the risk of developing age-related cataract.

  • 31. Selin, Jinjin Zheng
    et al.
    Lindblad, Birgitta Ejdervik
    Rautiainen, Susanne
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Morgenstern, Ralf
    Bottai, Matteo
    Basu, Samar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Oxidative Stress and Inflammation.
    Wolk, Alicja
    Are Increased Levels of Systemic Oxidative Stress and Inflammation Associated with Age-Related Cataract?2014In: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 21, no 5, p. 700-704Article in journal (Refereed)
    Abstract [en]

    Oxidative stress and inflammation may be involved in the etiology of age-related cataract. This study is the first to investigate the association between urinary levels of 8-iso-prostaglandin F-2 alpha (PGF(2 alpha); as a biomarker for systemic oxidative stress in vivo) and 15-keto-dihydro-PGF(2 alpha) (as a biomarker for systemic inflammation in vivo) and risk of age-related cataract. We observed in a nested case-control study, including 258 women with incident cataract diagnosis and/or cataract extraction and 258 women without cataract, matched on age and date of urine sample collection that, women with higher levels of urinary 8-iso-PGF(2 alpha) as compared with lower levels had an increased risk of age-related cataract. There was no difference in 15-keto-dihydro-PGF(2 alpha) levels between cases and controls. Our observations lead to the hypothesis that higher systemic oxidative stress increases the risk of developing age-related cataract.

  • 32.
    Söderberg, Anita
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Akter, Hossain
    Department of Emergency Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden..
    Rosén, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    A protein disulfide isomerase/thioredoxin-1 complex is physically attached to exofacial membrane TNF-receptors: overexpression in chronic lymphocytic leukemia2012In: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 18, no 4, p. 363-375Article in journal (Refereed)
    Abstract [en]

    Aims: The 3D structures and functions of cysteine-rich receptors such as tumor necrosis factor receptors (TNFRs) are redox-modulated by dithiol–disulfide exchange. TNFR superfamily members participate in growth regulation in B-cell chronic lymphocytic leukemia (CLL), and tissue stromal cells interact with leukemia cells, profoundly affecting their viability via release of redox-active components, including cysteine, thioredoxin-1 (Trx1), and Trx reductase. Trx1 was previously shown to enhance release of TNF, which acts as an autocrine/paracrine growth factor in CLL. The nature of the mechanism is not known, however. Here, we investigated whether Trx1 and protein disulfide isomerase (PDI), a chaperone and Trx-family member, may interact with TNFRs. Results: We found direct physical association between PDI and TNFR1 or TNFR2 by coclustering and affinity isolation. PDI (57 kDa) formed covalent/reduction-sensitive 69-kDa complexes with Trx1 (12 kDa) in a majority of CLL cell samples, detected at low levels only in control B-cells. Functionally, the TNF/TNFR signaling via the nuclear factor kappa B-driven autocrine loop was disrupted in a dose-dependent fashion by PDI-inhibitors bacitracin, anti-PDI, or anti-Trx1 antibodies, resulting in reduced viability. PDI was significantly overexpressed in immunoglobulin heavy-chain variable (IGHV) unmutated versus mutated CLL (p=0.0102), and amplified TNF release was observed in the former group. Innovation: This study points out a previously unrecognized physical and functional association of TNFRs with the redox-active proteins PDI and Trx1. Conclusion: We describe here a new level of TNF regulation, in which membrane TNFRs are redox controlled at the exofacial surface by PDI/Trx1. These findings shed new light on the observed survival benefit in CLL B-cells exerted by TNFR-superfamily ligands and point at potential therapeutic strategies

  • 33.
    Terman, Alexei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Oxidative stress, accumulation of biological 'garbage', and aging2006In: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 8, no 1-2, p. 197-204Article in journal (Refereed)
    Abstract [en]

    Normal metabolism is associated with unavoidable mild oxidative stress resulting in biomolecular damage that cannot be totally repaired or removed by cellular degradative systems, including lysosomes, proteasomes, and cytosolic and mitochondrial proteases. Consequently, irreversibly damaged and functionally defective structures (biological 'garbage') accumulate within long-lived postmitotic cells, such as cardiac myocytes and neurons, leading to progressive loss of adaptability and increased probability of death and characterizing a process called aging, or senescence. Intralysosomal 'garbage' is represented by lipofuscin (age pigment), an undegradable autophagocytosed material, while extralysosomal 'garbage' involves oxidatively modified cytosolic proteins, altered biomembranes, defective mitochondria and other organelles. In aged postmitotic cells, heavily lipofuscin-loaded lysosomes perform poorly, resulting in the enhanced accumulation of defective mitochondria, which in turn produce more reactive oxygen species causing additional damage (the mitochondrial- lysosomal axis theory). Potential anti-aging strategies may involve not only overall reduction of oxidative stress, but also the use of intralysosomal iron chelators hampering Fenton-type chemistry as well as the stimulation of cellular degradative systems. © Mary Ann Liebert, Inc.

  • 34.
    Terman, Alexei
    et al.
    Department of Clinical Pathology and Cytology, Karolinska University Hospital in Huddinge, Stockholm, Sweden .
    Kurz, Tino
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Lysosomal iron, iron chelation, and cell death2013In: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 18, no 8, p. 888-898Article, review/survey (Refereed)
    Abstract [en]

    Significance: Lysosomes are acidic organelles containing more than fifty hydrolases that provide for the degradation of intracellular and endocytosed materials by autophagy and heterophagy, respectively. They digest a variety of macromolecules, as well as all organelles, and their integrity is crucial. As a result of the degradation of iron-containing macromolecules (e.g., ferritin and mitochondrial components) or endocytosed erythrocytes (by macrophages), lysosomes can accumulate large amounts of iron. This iron occurs often as Fe(II) due to the acidic and reducing lysosomal environment. Fe(II) is known to catalyze Fenton reactions, yielding extremely reactive hydroxyl radicals that may jeopardize lysosomal membrane integrity during oxidative stress. This results in the release of hydrolases and redox-active iron into the cytosol with ensuing damage or cell death. Lysosomes play key roles not only in apoptosis and necrosis but also in neurodegeneration, aging, and atherosclerosis. Recent Advances: The damaging effect of intralysosomal iron can be hampered by endogenous or exogenous iron chelators that enter the lysosomal compartment by membrane permeation, endocytosis, or autophagy. Critical Issues: Cellular sensitivity to oxidative stress is enhanced by lysosomal redox-active iron or by lysosomal-targeted copper chelators binding copper (from degradation of copper-containing macromolecules) in redox-active complexes. Probably due to higher copper levels, lysosomes of malignant cells may be specifically sensitized by such chelators. Future Directions: By increasing lysosomal redox-active iron or exposing cells to lysosomal-targeted copper chelators, it should be possible to enhance the sensitivity of cancer cells to radiation-induced oxidative stress or treatment with cytostatics that induce such stress.

  • 35.
    Terman, Alexei
    et al.
    Karolinska University Hospital.
    Kurz, Tino
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Navratil, Marian
    University of Minnesota.
    Arriaga, Edgar A
    University of Minnesota.
    Brunk, Ulf
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Mitochondrial Turnover and Aging of Long-Lived Postmitotic Cells: The Mitochondrial-Lysosomal Axis Theory of Aging2010In: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 12, no 4, p. 503-535Article, review/survey (Refereed)
    Abstract [en]

    It is now generally accepted that aging and eventual death of multicellular organisms is to a large extent related to macromolecular damage by mitochondrially produced reactive oxygen species, mostly affecting long-lived postmitotic cells, such as neurons and cardiac myocytes. These cells are rarely or not at all replaced during life and can be as old as the whole organism. The inherent inability of autophagy and other cellular-degradation mechanisms to remove damaged structures completely results in the progressive accumulation of garbage, including cytosolic protein aggregates, defective mitochondria, and lipofuscin, an intralysosomal indigestible material. In this review, we stress the importance of crosstalk between mitochondria and lysosomes in aging. The slow accumulation of lipofuscin within lysosomes seems to depress autophagy, resulting in reduced turnover of effective mitochondria. The latter not only are functionally deficient but also produce increased amounts of reactive oxygen species, prompting lipofuscinogenesis. Moreover, defective and enlarged mitochondria are poorly autophagocytosed and constitute a growing population of badly functioning organelles that do not fuse and exchange their contents with normal mitochondria. The progress of these changes seems to result in enhanced oxidative stress, decreased ATP production, and collapse of the cellular catabolic machinery, which eventually is incompatible with survival.

  • 36. Wicher, Krzysztof B.
    et al.
    Fries, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Evolutionary aspects of hemoglobin scavengers2010In: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 12, no 2, p. 249-259Article, review/survey (Refereed)
    Abstract [en]

    With the evolution of fish, systems appeared for the disposal of the hemoglobin (Hb) that was inevitably released from erythrocytes. Thus, a plasma protein that bound free Hb with great affinity, haptoglobin (Hp), evolved from a protease of the innate immune system. In parallel, other proteins appeared (for example, hemopexin and alpha(1)-microglobulin), which bound and mediated the removal of free heme groups. Remarkably, Hp later disappeared in some vertebrate lineages, suggesting that it could also be disadvantageous. In the avian lineage, a soluble protein evolved, possibly from a scavenger receptor, which in some birds seems to have replaced Hp. Among mammals, multimeric forms of Hp appeared independently at two discrete times, suggesting that this form of the protein confers an advantage on the bearer, possibly by improving resistance to infection.

1 - 36 of 36
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf