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  • 1.
    Alleva, R.
    et al.
    Rizzoli Orthopaedic Institute, Bologna, Italy.
    Tomasetti, M.
    Institute of Experimental Pathology, University of Ancona, Ancona, Italy.
    Andera, L.
    Institute of Molecular Genetics, Czech Academy of Sciences, Prague, Czech Republic.
    Gellert, N.
    Institute for Prevention of Cardiovascular Diseases, Ludwig Maximilians University, Pettenkoferstrasse 9, 80336 Munich, Germany.
    Borghi, B.
    Rizzoli Orthopaedic Institute, Bologna, Italy.
    Weber, C.
    Institute for Prevention of Cardiovascular Diseases, Ludwig Maximilians University, Pettenkoferstrasse 9, 80336 Munich, Germany.
    Murphy, M.P.
    Mitochondrial Dysfunction Group, MRC Dunn Human Nutrition Unit, Cambridge, United Kingdom.
    Neuzil, Jiri
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology .
    Coenzyme Q blocks biochemical but not receptor-mediated apoptosis by increasing mitochondrial antioxidant protection2001In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 503, no 1, p. 46-50Article in journal (Refereed)
    Abstract [en]

    Generation of free radicals is often associated with the induction and progression of apoptosis. Therefore, antioxidants can prove anti-apoptotic, and can help to elucidate specific apoptotic pathways. Here we studied whether coenzyme Q, present in membranes in reduced (ubiquinol) or oxidised (ubiquinone) forms, can affect apoptosis induced by various stimuli. Exposure of Jurkat cells to a-tocopheryl succinate (a-TOS), hydrogen peroxide, anti-Fas IgM or TRAIL led to induction of apoptosis. Cell death due to the chemical agents was suppressed in cells enriched with the reduced form of coenzyme Q. However, coenzyme Q did not block cell death induced by the immunological agents. Ubiquinol-10 inhibited reactive oxygen species (ROS) generation in cells exposed to a-TOS, and a mitochondrially targeted coenzyme Q analogue also blocked apoptosis triggered by a-TOS or hydrogen peroxide. Therefore, it is plausible that ubiquinol-10 protects cells from chemically-induced apoptosis by acting as an antioxidant in mitochondria. Our results also indicate that generation of free radicals may not be a critical step in induction of apoptosis by immunological agents. © 2001 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved.

  • 2. Birringer, M
    et al.
    EyTina, J H
    Salvatore, B A
    Neuzil, Jiri
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Vitamin E analogues as inducers of apoptosis: Structure-function relation2003In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 88, no 12, p. 1948-1955Article in journal (Refereed)
    Abstract [en]

    Recent results show that a-tocopheryl succinate (a-TOS) is a proapoptotic agent with antineoplastic activity. As modifications of the vitamin E (VE) molecule may affect its apoptogenic activity, we tested a number of newly synthesised VE analogues using malignant cell lines. Analogues of a-TOS with lower number of methyl substitutions on the aromatic ring were less active than a-TOS. Replacement of the succinyl group with a maleyl group greatly enhanced the activity, while it was lower for the glutaryl esters. Methylation of the free succinyl carboxyl group on a-TOS and d-TOS completely prevented the apoptogenic activity of the parent compounds. Both Trolox and its succinylated derivative were inactive. a-tocotrienol (a-T3 H) failed to induce apoptosis, while ?-T3 H was apoptogenic, and more so when succinylated. Shortening the aliphatic side chain of ?-T3 by one isoprenyl unit increased its activity. Neither phytyl nor oleyl succinate caused apoptosis. These findings show that modifications of different functional moieties of the VE molecule can enhance apoptogenic activity. It is hoped that these observations will lead to the synthesis of analogues with even higher apoptogenic and, consequently, antineoplastic efficacy.

  • 3. Brigelius-Flohé, R
    et al.
    Kelly, FJ
    Salonen, JT
    Neuzil, Jiri
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Zing, JM
    Azzi, A
    The European perspective on vitamin E: Current knowledge and future research2002In: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 76, no 4, p. 703-716Article in journal (Refereed)
    Abstract [en]

    Vitamin E is indispensible for reproduction in female rats. In humans, vitamin E deficiency primarily causes neurologic dysfunctions, but the underlying molecular mechanisms are unclear. Because of its antioxidative properties, vitamin E is believed to help prevent diseases associated with oxidative stress, such as cardiovascular disease, cancer, chronic inflammation, and neurologic disorders. However, recent clinical trials undertaken to prove this hypothesis failed to verify a consistent benefit. Given these findings, a group of European scientists met to analyze the most recent knowledge of vitamin E function and metabolism. An overview of their discussions is presented in this article, which includes considerations of the mechanisms of absorption, distribution, and metabolism of different forms of vitamin E, including the a-tocopherol transfer protein and a-tocopherol-associated proteins, the mechanism of tocopherol side-chain degradation and its putative interaction with drug metabolism, the usefulness of tocopherol metabolites as biomarkers, and the novel mechanisms of the antiatherosclerotic and anticarcinogenic properties of vitamin E, which involve modulation of cellular signaling, transcriptional regulation, and induction of apoptosis. Clinical trials were analyzed on the basis of the selection of subjects, the stage of disease, and the mode of intake, dosage, and chemical form of vitamin E. In addition, the scarce knowledge on the role of vitamin E in reproduction was summarized. In conclusion, the scientists agreed that the functions of vitamin E were underestimated if one considered only its antioxidative properties. Future research on this essential vitamin should focus on what makes it essential for humans, why the body apparently utilizes a-tocopherol preferentially, and what functions other forms of vitamin E have.

  • 4. Buss, Joan L
    et al.
    Neuzil, Jiri
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Gellert, Nina
    Weber, Christian
    Ponka, Prem
    Pyridoxal isonicotinoyl hydrazone analogs induce apoptosis in hematopoietic cells due to their iron-chelating properties2003In: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 65, no 2, p. 161-172Article in journal (Refereed)
    Abstract [en]

    Analogs of pyridoxal isonicotinoyl hydrazone (PIH) are of interest as iron chelators for the treatment of secondary iron overload and cancer. PIH, salicylaldehyde isonicotinoyl hydrazone (SIH), and 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone (NIH), the toxicity of which vary over two orders of magnitude, were selected for a study of their mechanisms of toxicity. PIH analogs and their iron complexes caused concentration- and time-dependent apoptosis in Jurkat T lymphocytes and K562 cells. Bcl-2 overexpression was partially anti-apoptotic, suggesting mitochondrial mediation of apoptosis. Since the pan-caspase inhibitor zVAD-fmk did not reduce lysosomal and mitochondrial destabilization, these events occur upstream of caspase activation. In contrast, phosphatidylserine externalization and the development of apoptotic morphology were inhibited significantly, indicating the role of caspases in mediating these later events. Since overexpression of CrmA had no effect on apoptosis, caspase-8 is not likely involved. Fe3+ complexes of SIH and NIH, which accumulated in 59Fe-labeled mouse reticulocytes during incubation with the chelators, also caused apoptosis. BSA, which promotes release of the complexes from cells, reduced the toxicity of SIH and NIH, suggesting that the induction of apoptosis by PIH analogs involves toxic effects mediated by their Fe3+ complexes. Moreover, analogs of these agents lacking the iron-chelating moiety were non-toxic. ⌐ 2002 Published by Elsevier Science Inc.

  • 5. Buss, Joan L
    et al.
    Neuzil, Jiri
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Ponka, Prem
    Oxidative stress mediates toxicity of pyridoxal isonicotinoyl hydrazone analogs2004In: Archives of Biochemistry and Biophysics, ISSN 0003-9861, E-ISSN 1096-0384, Vol. 421, no 1Article in journal (Refereed)
    Abstract [en]

    Pyridoxal isonicotinoyl hydrazone (PIH) and many of its analogs are effective iron chelators in vivo and in vitro, and are of interest for the treatment of secondary iron overload. Because previous work has implicated the Fe3+-chelator complexes as a determinant of toxicity, the role of iron-based oxidative stress in the toxicity of PIH analogs was assessed. The Fe3+ complexes of PIH analogs were reduced by K562 cells and the physiological reductant, ascorbate. Depletion of the antioxidant, glutathione, sensitized Jurkat T lymphocytes to the toxicity of PIH analogs and their Fe 3+ complexes, and toxicity of the chelators increased with oxygen tension. Fe3+ complexes of pyridoxal benzoyl hydrazone (PBH) and salicyloyl isonicotinoyl hydrazone (SIH) caused lipid peroxidation and toxicity in K562 cells loaded with eicosapentenoic acid (EPA), a readily oxidized fatty acid, whereas Fe(PIH)2 did not. The lipophilic antioxidant, vitamin E, completely prevented both the toxicity and lipid peroxidation caused by Fe(PBH)2 in EPA-loaded cells, indicating a causal relationship between oxidative stress and toxicity. PBH also caused concomitant lipid peroxidation and toxicity in EPA-loaded cells, both of which were reversed as its concentration increased. In contrast, PIH was inactive, while SIH was equally toxic toward control and EPA-loaded cells, without causing lipid peroxidation, indicating a much smaller contribution of oxidative stress to the mechanism of toxicity of these analogs. In summary, PIH analogs and their Fe3+ complexes are redox active in the intracellular environment. The contribution of oxidative stress to the overall mechanism of toxicity varies across the series. © 2003 Elsevier Inc. All rights reserved.

  • 6.
    Dalen, Helge
    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.
    Neuzil, Jiri
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    a-tocopheryl succinate sensitises a T lymphoma cell line to TRAIL-induced apoptosis by suppressing NF-?B activation2003In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 88, no 1, p. 153-158Article in journal (Refereed)
    Abstract [en]

    Activation of nuclear factor-?B (NF-?B) can interfere with induction of apoptosis triggered by the tumour necrosis factor-related apoptosis-inducing ligand (TRAIL, Apo2L). Therefore, agents that suppress NF-?B activation may sensitise cells to TRAIL-dependent apoptosis. Exposure of Jurkat cells to TRAIL resulted in massive and saturable apoptosis induction, following an initial lag time. This lag was abolished by pretreatment of the cells with subapoptotic doses of a-tocopheryl succinate (a-TOS) or the proteasome inhibitor MGI32. Exposure of the cells to TRAIL led to a rapid, transient activation of NF-?B, a process that was suppressed by cell pretreatment with a-TOS or MGI32. Activation of NF-?B by TNF-a prior to TRAIL exposure increased resistance of the cells to TRAIL-mediated apoptosis. We conclude that a-TOS sensitises cells to TRAIL killing, at least in some cases, through inhibition of NF-?B activation. This further supports the possibility that this semisynthetic analogue of vitamin E is a potential adjuvant in cancer treatment, such as in the case of TRAIL-mediated inhibition of cancer.

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

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

  • 8. Jostarndt, K
    et al.
    Rubic, T
    Kuhn, H
    Anthosen, M W
    Andera, L
    Gellert, N
    Trottman, M
    Weber, Christian
    Johansen, B
    Hrboticky, N
    Neuzil, Jiri
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Enzymatically modified low-density lipoprotein upregulates CD36 in low-differentiated monocytic cells in a peroxisome proliferator-activated receptor-γ-dependent way2004In: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 67, no 5, p. 841-854Article in journal (Refereed)
    Abstract [en]

    Peroxisome proliferator-activated receptor-γ (PPARγ) has been suggested to upregulate CD36. Since free oxidized polyunsaturated fatty acids are PPARγ ligands, we studied the effects of LDL modified by the simultaneous action of sPLA2 and 15-lipoxygenase (15LO) on CD36 expression and PPARγ activation in monocytic cells. Exposure of MM6 cells, which do not express CD36 or other scavenger receptors, to such enzymatically modified LDL (enzLDL) resulted in upregulation of CD36 surface protein and mRNA expression. Similar effects were observed with free 13-hydroperoxyoctadecadienoic acid but not its esterified counterpart. Less pronounced effects were observed with LDL modified by 15LO alone. Upregulation of CD36 was inversely correlated to the state of cell differentiation, as showed by lower response to enzLDL of the scavenger receptor-expressing MM6-sr and THP1 cells. Importantly, LDL modified by sPLA2 and 15LO did not efficiently induce upregulation CD36 in PPARγ-deficient macrophage-differentiated embryonic stem cells confirming a role of PPARγ in CD36 expression in cells stimulated with enzLDL. Our data show that LDL modified with physiologically relevant enzymes stimulates CD36 expression in non-differentiated monocytes and that this process involves PPARγ activation. These effects of enzLDL can be considered pro-atherogenic in the context of early atherosclerosis.

  • 9.
    Neuzil, Jiri
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    a-tocopheryl succinate epitomizes a compound with a shift in biological activity due to pro-vitamin-to-vitamin conversion2002In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 293, no 5, p. 1309-1313Article in journal (Refereed)
    Abstract [en]

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

  • 10.
    Neuzil, Jiri
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Vitamin E succinate and cancer treatment: A vitamin E prototype for selective antitumour activity2003In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 89, no 10, p. 1822-1826Article in journal (Refereed)
    Abstract [en]

    Great hope has been given to micronutrients as anticancer agents, since they present natural compounds with beneficial effects for normal cells and tissues. One of these is vitamin E (VE), an antioxidant and an essential component of biological membranes and circulating lipoproteins. In spite of a number of epidemiological and intervention studies, little or no correlation between VE intake and incidence of cancer has been found. Recent reports have identified a redox-silent analogue of VE, a-tocopheryl succinate (a-TOS), as a potent anticancer agent with a unique structure and pharmacokinetics in vivo. a-TOS is highly selective for malignant cells, inducing them into apoptotic death largely via the mitochondrial route. The molecule of a-TOS may be modified so that analogues with higher activity are generated. Finally, a-TOS and similar agents are metabolised to VE, thereby yielding a compound with a secondary beneficial activity. Thus, a-TOS epitomises a group of novel compounds that hold substantial promise as future anticancer drugs. The reasons for this optimistic notion are discussed in the following paragraphs. ⌐ 2003 Cancer Research UK.

  • 11.
    Neuzil, Jiri
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Kågedal, Katarina
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Andrea, L
    Weber, Christian
    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.
    Vitamin E analogs: A new class of multiple action agents with anti-neoplastic and anti-atherogenic activity2002In: Apoptosis (London), ISSN 1360-8185, E-ISSN 1573-675X, Vol. 7, no 2, p. 179-187Article in journal (Refereed)
    Abstract [en]

    The incidence of cancer and atherosclerosis, two most common causes of death in developed countries, has been stagnating or, even, increasing. Drugs effective against such conditions are needed and, in this regard, the potential anti-atherosclerotic activity of vitamin E analogs has been studied extensively. Surprisingly, recent results indicate that these agents may also exert anti-neoplastic effects. Here we review the evidence that particular analogs of vitamin E may act as both anti-atherogenic and anti-cancer agents, and discuss the possible molecular bases for these actions.

  • 12.
    Neuzil, Jiri
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Tomasetti, Marco
    Mellick, Albert S
    Alleva, Renata
    Salvatore, Brian A
    Birringer, Marc
    Fariss, Marc W
    Vitamin E analogues: A new class of inducers of apoptosis with selective anti-cancer effects2004In: Current Cancer Drug Targets, ISSN 1568-0096, E-ISSN 1873-5576, Vol. 4, no 4, p. 355-372Article in journal (Refereed)
    Abstract [en]

    In spite of unrelenting effort, the net incidence of neoplastic diseases appears not to have been curbed. While some types of cancer have been suppressed significantly, others are either stagnating or on the increase. Therefore, the need for a cure is imperative, in particularly a drug or combination of drugs that would be selective for malignant cells, i.e. with as low secondary toxicity as possible. Recent data strongly suggest that analogues of vitamin E, epitomised by the most studied α-tocopheryl succinate (α-TOS), may meet the need for the coveted drugs with a selective anti-neoplastic effect. The reasons for this optimism are reviewed in this article.

  • 13.
    Neuzil, Jiri
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Weber, Tobias
    Terman, Alexei
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Weber, Christian
    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.
    Vitamin E analogues as inducers of apoptosis: implications for their potential anti-neoplastic role2001In: Redox report, ISSN 1351-0002, E-ISSN 1743-2928, Vol. 6, p. 143-151Article in journal (Refereed)
  • 14.
    Neuzil, Jiri
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Zhao, Ming
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Ostermann, Georg
    Sticha, Martin
    Gellert, Nina
    Weber, Christian
    Eaton, John Wallace
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    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.
    Alfa-Tocopheryl succinate, an agent with in vivo anti-tumour activity, induces apoptosis by causing lysosomal instability2002In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 362, p. 709-715Article in journal (Refereed)
  • 15.
    Terman, Alexei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Dalen, Helge
    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.
    Eaton, John Wallace
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Neuzil, Jiri
    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 Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Mitochondrial recycling and aging of cardiac myocytes: The role of autophagocytosis2003In: Experimental Gerontology, ISSN 0531-5565, E-ISSN 1873-6815, Vol. 38, no 8, p. 863-876Article in journal (Refereed)
    Abstract [en]

    The mechanisms of mitochondrial alterations in aged post-mitotic cells, including formation of so-called 'giant' mitochondria, are poorly understood. To test whether these large mitochondria might appear due to imperfect autophagic mitochondrial turnover, we inhibited autophagocytosis in cultured neonatal rat cardiac myocytes with 3-methyladenine. This resulted in abnormal accumulation of mitochondria within myocytes, loss of contractility, and reduced survival time in culture. Unlike normal aging, which is associated with slow accumulation of predominantly large defective mitochondria, pharmacological inhibition of autophagy caused only moderate accumulation of large (senescent-like) mitochondria but dramatically enhanced the numbers of small mitochondria, probably reflecting their normally more rapid turnover. Furthermore, the 3-methyladenine-induced accumulation of large mitochondria was irreversible, while small mitochondria gradually decreased in number after withdrawal of the drug. We, therefore, tentatively conclude that large mitochondria selectively accumulate in aging post-mitotic cells because they are poorly autophagocytosed. Mitochondrial enlargement may result from impaired fission, a possibility supported by depressed DNA synthesis in large mitochondria. Nevertheless, enlarged mitochondria retained immunoreactivity for cytochrome c oxidase subunit 1, implying that mitochondrial genes remain active in defective mitochondria. Our findings suggest that imperfect autophagic recycling of these critical organelles may underlie the progressive mitochondrial damage, which characterizes aging post-mitotic cells.

  • 16.
    Terman, Alexei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Geriatric .
    Dalen, Helge
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology .
    Eaton, John Wallace
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Neuzil, Jiri
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology .
    Brunka, UT
    Aging of cardiac myocytes in culture - Oxidative stress, lipofuscin accumulation, and mitochondrial turnover2004In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1019, p. 70-77Article in journal (Refereed)
    Abstract [en]

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

  • 17.
    Terman, Alexei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Neuzil, Jiri
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Kågedal, Katarina
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    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.
    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.
    Decreased apoptotic response of inclusion-cell disease fibroblasts: A consequence of lysosomal enzyme missorting?2002In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 274, no 1Article in journal (Refereed)
    Abstract [en]

    To better understand the role of lysosomes in apoptosis, we compared the responses to apoptotic stimuli of normal fibroblasts with those of inclusion cells (I-cells), i.e., fibroblasts with impaired function of lysosomal enzymes due to their missorting and ensuing nonlysosomal localization. Although both cell types did undergo apoptosis when exposed to the lysosomotropic detergent MSDH, the redox-cycling quinone naphthazarin, or the protein kinase inhibitor staurosporine, I-cells exerted a markedly decreased response to these agonists than did normal fibroblasts. Furthermore, leupeptin and pepstatin A (inhibitors of cysteine and aspartic proteases, respectively) suppressed staurosporine-induced apoptosis of normal fibroblasts, whereas survival of I-cells was unaffected. These findings give further support for the involvement of lysosomal enzymes in apoptosis and suggest I-cells as a suitable model for studying the role of lysosomes in programmed cell death.

  • 18. Tomasetti, M
    et al.
    Rippo, MR
    Alleva, R
    Moretti, S
    Andera, L
    Neuzil, Jiri
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Procopio, A
    α-tocopheryl succinate and TRAIL selectively synergise in induction of apoptosis in human malignant mesothelioma cells2004In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 90, no 8, p. 1644-1653Article in journal (Refereed)
    Abstract [en]

    Malignant mesothelioma (MM) is a fatal type of neoplasia with poor therapeutic prognosis, largely due to resistance to apoptosis. We investigated the apoptotic effect of α-tocopheryl succinate (α-TOS), a strong proapoptotic agent, in combination with the immunological apoptogen TNF-related apoptosis-inducing ligand (TRAIL) on both MM and nonmalignant mesothelial cells, since MM cells show low susceptibility to the clinically intriguing TRAIL. All MM cell lines tested were sensitive to α-TOS-induced apoptosis, and exerted high sensitivity to TRAIL in the presence of subapoptotic doses of the vitamin E analogue. Neither TRAIL or α-TOS alone or in combination caused apoptosis in nonmalignant mesothelial cells. Isobologram analysis of the cytotoxicity assays revealed a synergistic interaction between the two agents in MM cells and their antagonistic effect in nonmalignant mesothelial cells. TRAIL-induced apoptosis and its augmentation by α-TOS were inhibited by the caspase-8 inhibitor Z-IETD-FMK and the pan-caspase inhibitor Z-VAD-FMK. Activation of caspase-8 was required to induce apoptosis, which was amplified by α-TOS via cytochrome c release following Bid cleavage, with ensuing activation of caspase-9. Enhancement of TRAIL-induced apoptosis in MM cells by α-TOS was also associated with upregulation of the TRAIL cognate death receptors DR4 and DR5. Our results show that α-TOS and TRAIL act in synergism to kill MM cells via mitochondrial pathway, and are nontoxic to nonmalignant mesothelial cells. These findings are indicative of a novel strategy for treatment of thus far fatal MM.

  • 19. Weber, A
    et al.
    Dalen, Helge
    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.
    Andera, L
    Nègre-Salvayre, A
    Augé, N
    Sticha, M
    Loret, A
    Terman, Alexei
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Witting, PK
    Higuchi, M
    Plasilova, M
    Zivny, J
    Gellert, N
    Weber, C
    Neuzil, Jiri
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Mitochondria play a central role in apoptosis induced by a-tocopheryl succinate, an agent with antineoplastic activity: Comparison with receptor-mediated pro-apoptotic signaling2003In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 42, no 14, p. 4277-4291Article in journal (Refereed)
    Abstract [en]

    a-Tocopheryl succinate (a-TOS) is a semisynthetic vitamin E analogue with high pro-apoptotic and anti-neoplastic activity [Weber, T et al. (2002) Clin. Cancer Res. 8, 863-869]. Previous studies suggested that it acts through destabilization of subcellular organelles, including mitochondria, but compelling evidence is missing. Cells treated with a-TOS showed altered mitochondrial structure, generation of free radicals, activation of the sphingomyelin cycle, relocalization of cytochrome c and Smac/Diablo, and activation of multiple caspases. A pan-caspase inhibitor suppressed caspase-3 and -6 activation and phosphatidyl serine externalization, but not decrease of mitochondrial membrane potential or generation of radicals. For a-TOS, but not Fas or TRAIL, apoptosis was suppressed by caspase-9 inhibition, while TRAIL- and Fas-resistant cells overexpressing cFLIP or CrmA were susceptible to a-TOS. The central role of mitochondria was confirmed by resistance of mtDNA-deficient cells to a-TOS, by regulation of a-TOS apoptosis by Bcl-2 family members, and by anti-apoptotic activity of mitochondrially targeted radical scavengers. Co-treatment with a-TOS and anti-Fas IgM showed their cooperative effect, probably by signaling via different, convergent pathways. These data provide an insight into the molecular mechanism, by which a-TOS kills malignant cells, and advocate its testing as a potential anticancer agent or adjuvant.

  • 20. Weber, Tobias
    et al.
    Lu, Min
    Andera, Ladislav
    Lahm, Harald
    Gellert, Nina
    Fariss, Marc W
    Korinek, Vladimir
    Sattler, Wolfgang
    Ucker, David S
    Terman, Alexei
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Schröder, Andreas
    Erl, Wolfgang
    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.
    Coffey, Robert
    Weber, Christian
    Neuzil, Jiri
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Vitamin E succinate is a potent novel anti-neoplastic agent with high selectivity and cooperativity with tumor necrosis factor-related apoptosis-inducing ligand (Apo2 ligand) in vivo2002In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 8, p. 863-869Article in journal (Refereed)
1 - 20 of 20
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