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  • 1.
    Alavian, S.M.
    et al.
    Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Tehran.
    Ande, S.R.
    University of Manitoba.
    Coombs, K.M.
    University of Manitoba.
    Yeganeh, B.
    University of Manitoba.
    Davoodpour, Padideh
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences.
    Hashemi, M.
    Zahedan University of Medical Sceince, Iran.
    Los, Marek Jan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Ghavami, S.
    University of Manitoba.
    Virus-triggered autophagy in viral hepatitis - possible novel strategies for drug development2011In: Journal of Viral Hepatitis, ISSN 1352-0504, E-ISSN 1365-2893, Vol. 18, no 12, p. 821-830Article, review/survey (Refereed)
    Abstract [en]

    . Autophagy is a very tightly regulated process that is important in many cellular processes including development, differentiation, survival and homoeostasis. The importance of this process has already been proven in numerous common diseases such as cancer and neurodegenerative disorders. Emerging data indicate that autophagy plays an important role in some liver diseases including liver injury induced by ischaemia reperfusion and alpha-1 antitrypsin Z allele-dependent liver disease. Autophagy may also occur in viral infection, and it may play a crucial role in antimicrobial host defence against pathogens, while supporting cellular homoeostasis processes. Here, the latest findings on the role of autophagy in viral hepatitis B and C infection, which are both serious health threats, will be reviewed.

  • 2.
    Alberti, Esteban
    et al.
    Department of Neurobiology, International Center of Neurological Restoration, CIREN, Havana, Cuba..
    Los, Marek Jan
    Interfaculty Institute for Biochemistry, University of Tübingen, Germany; BioApplications Enterprises, Winnipeg, MB, Canada.
    Garcia, Rocio
    Department of Neurobiology, International Center of Neurological Restoration, CIREN, Havana, Cuba..
    Fraga, JL
    Department of Neurobiology, International Center of Neurological Restoration, CIREN, Havana, Cuba..
    Serrano, T.
    Department of Neurobiology, International Center of Neurological Restoration, CIREN, Havana, Cuba..
    Hernandez, E.
    Department of Neurobiology, International Center of Neurological Restoration, CIREN, Havana, Cuba..
    Klonisch, Thomas
    Department of Human Anatomy and Cell Sciences, and Manitoba Institute of Child Health, Winnipeg, Canada.
    Macías, R.
    Department of Neurobiology, International Center of Neurological Restoration, CIREN, Havana, Cuba..
    Martinez, L.
    Department of Neurobiology, International Center of Neurological Restoration, CIREN, Havana, Cuba..
    Castillo, L.
    Department of Neurobiology, International Center of Neurological Restoration, CIREN, Havana, Cuba..
    de la Cuétara, K.
    Department of Neurobiology, International Center of Neurological Restoration, CIREN, Havana, Cuba.
    Prolonged Survival and expression of neural markers by bone marrow-derived stem cells transplanted into brain lesions2009In: Medical Science Monitor, ISSN 1234-1010, E-ISSN 1643-3750, Vol. 15, no 2, p. BR47-BR54Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Bone marrow-derived stem cell transplantation is a potentially viable therapeutic option for the treatment of neurodegenerative disease. MATERIAL/METHODS: We have isolated bone marrow stem cells by standard method. We then evaluated the survival of rats' bone marrow mononuclear cells implanted in rats' brain. The cells were extracted from rats' femurs, and marked for monitoring purposes by adenoviral transduction with Green Fluorescent Protein (GFP). Labeled cells were implanted within the area of rats' striatum lesions that were induced a month earlier employing quinolinic acid-based method. The implants were phenotyped by monitoring CD34; CD38; CD45 and CD90 expression. Bone marrow stromal cells were extracted from rats' femurs and cultivated until monolayer bone marrow stromal cells were obtained. The ability of bone marrow stromal cells to express NGF and GDNF was evaluated by RT-PCR. RESULTS: Implanted cells survived for at least one month after transplantation and dispersed from the area of injection towards corpus callosum and brain cortex. Interestingly, passaged rat bone marrow stromal cells expressed NGF and GDNF mRNA. CONCLUSIONS: The bone marrow cells could be successfully transplanted to the brain either for the purpose of trans-differentiation, or for the expression of desired growth factors.

  • 3.
    Alexander, Helen K.
    et al.
    Manitoba Institute of Cell Biology, and Department of Biochemistry and Medical Genetics, Univ. Manitoba, Winnipeg, Canada.
    Booy, Evan P.
    Manitoba Institute of Cell Biology, and Department of Biochemistry and Medical Genetics, Univ. Manitoba, Winnipeg, Canada.
    Xiao, Wenyan
    Cancer Care Manitoba, Manitoba Institute of Cell Biology, University of Manitoba,.
    Ezzati, Peyman
    Cancer Care Manitoba, Manitoba Institute of Cell Biology, University of Manitoba,.
    Baust, Heinrich
    Cancer Care Manitoba, Manitoba Institute of Cell Biology, University of Manitoba,.
    Los, Marek Jan
    Department of Human Anatomy and Cell Science, University of Manitoba, Winnipeg, Canada.
    Selected technologies to control genes and their products for experimental and clinical purposes2007In: Archivum Immunologiae et Therapiae Experimentalis, ISSN 0004-069X, Vol. 55, no 3, p. 139-149Article, review/survey (Refereed)
    Abstract [en]

    "On-demand" regulation of gene expression is a powerful tool to elucidate the functions of proteins and biologically-active RNAs. We describe here three different approaches to the regulation of expression or activity of genes or proteins. Promoter-based regulation of gene expression was among the most rapidly developing techniques in the 1980s and 1990s. Here we provide basic information and also some characteristics of the metallothionein-promoter-based system, the tet-off system, Muristerone-A-regulated expression through the ecdysone response element, RheoSwitch (R), coumermycin/novobiocin-regulated gene expression, chemical dimerizer-based promoter activation systems, the "Dual Drug Control" system, "constitutive androstane receptor"-based regulation of gene expression, and RU486/mifepristone-driven regulation of promoter activity. A large part of the review concentrates on the principles and usage of various RNA interference techniques (RNAi: siRNA, shRNA, and miRNA-based methods). Finally, the last part of the review deals with historically the oldest, but still widely used, methods of temperature-dependent regulation of enzymatic activity or protein stability (temperature-sensitive mutants). Due to space limitations we do not describe in detail but just mention the tet-regulated systems and also fusion-protein-based regulation of protein activity, such as estrogen-receptor fusion proteins. The information provided below is aimed to assist researchers in choosing the most appropriate method for the planned development of experimental systems with regulated expression or activity of studied proteins.

  • 4.
    Alexander, Helen K.
    et al.
    Cancer Care Manitoba, Manitoba Institute of Cell Biology, University of Manitoba.
    Booy, Evan P.
    Cancer Care Manitoba, Manitoba Institute of Cell Biology, University of Manitoba; Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Canada .
    Xiao, Wenyan
    Cancer Care Manitoba, Manitoba Institute of Cell Biology, University of Manitoba.
    Ezzati, Peyman
    Cancer Care Manitoba, Manitoba Institute of Cell Biology, University of Manitoba.
    Baust, Heinrich
    Department of Radiooncology, University of Erlangen, Erlangen, Germany .
    Los, Marek Jan
    Manitoba Institute of Cell Biology, Cancer Care Manitoba; Manitoba Institute of Child Health; Department of Biochemistry and Medical Genetics; Department of Human Anatomy and Cell Science, University Manitoba, Winnipeg, Canada, .
    Selected technologies to control genes and their products for experimental and clinical purposes2007In: Archivum Immunologiae et Therapiae Experimentalis, ISSN 0004-069X, E-ISSN 1661-4917, Vol. 55, no 3, p. 139-149Article in journal (Refereed)
    Abstract [en]

    "On-demand" regulation of gene expression is a powerful tool to elucidate the functions of proteins and biologically-active RNAs. We describe here three different approaches to the regulation of expression or activity of genes or proteins. Promoter-based regulation of gene expression was among the most rapidly developing techniques in the 1980s and 1990s. Here we provide basic information and also some characteristics of the metallothionein-promoter-based system, the tet-off system, Muristerone-A-regulated expression through the ecdysone response element, RheoSwitch (R), coumermycin/novobiocin-regulated gene expression, chemical dimerizer-based promoter activation systems, the "Dual Drug Control" system, "constitutive androstane receptor"-based regulation of gene expression, and RU486/mifepristone-driven regulation of promoter activity. A large part of the review concentrates on the principles and usage of various RNA interference techniques (RNAi: siRNA, shRNA, and miRNA-based methods). Finally, the last part of the review deals with historically the oldest, but still widely used, methods of temperature-dependent regulation of enzymatic activity or protein stability (temperature-sensitive mutants). Due to space limitations we do not describe in detail but just mention the tet-regulated systems and also fusion-protein-based regulation of protein activity, such as estrogen-receptor fusion proteins. The information provided below is aimed to assist researchers in choosing the most appropriate method for the planned development of experimental systems with regulated expression or activity of studied proteins.

  • 5.
    Anderson, Judy E.
    et al.
    Department of Human Anatomy and Cell Science, University of Manitoba, Winnipeg, Canada; Manitoba Institute of Child's Health (MICH), University of Manitoba, Winnipeg, Canada.
    Hansen, Lise Lotte
    Institute of Human Genetics, University of Aarhus, Denmark.
    Mooren, Frank C.
    Department of Sports Medicine, Institute of Sport Sciences, University Giessen, Germany.
    Post, Markus
    Department of Sports Medicine, Institute of Sport Sciences, University Giessen, Germany.
    Hug, Hubert
    DSM Nutritional Products Ltd, Research & Development, Kaiseraugst, Switzerland.
    Zuse, Anne
    Manitoba Institute of Cell Biology (MICB), CancerCare Manitoba, 675 McDermot Ave. Rm. ON6010, Winnipeg, Man. R3E 0V9, Canada.
    Los, Marek Jan
    Manitoba Institute of Cell Biology, Cancer Care Manitoba; Manitoba Institute of Child Health; Department of Biochemistry and Medical Genetics; Department of Human Anatomy and Cell Science, University Manitoba, Winnipeg, Canada, .
    Methods and biomarkers for the diagnosis and prognosis of cancer and other diseases: Towards personalized medicine2006In: Drug resistance updates, ISSN 1368-7646, E-ISSN 1532-2084, Vol. 9, no 4-5, p. 198-210Article in journal (Refereed)
    Abstract [en]

    The rapid development of new diagnostic procedures, the mapping of the human genome, progress in mapping genetic polymorphisms, and recent advances in nucleic acid- and protein chip technologies are driving the development of personalized therapies. This breakthrough in medicine is expected to be achieved largely due to the implementation of "lab-on-the-chip" technology capable of performing hundreds, even thousands of biochemical, cellular and genetic tests on a single sample of blood or other body fluid. Focusing on a few disease-specific examples, this review discusses selected technologies and their combinations likely to be incorporated in the "lab-on-the-chip" and to provide rapid and versatile information about specific diseases entities. Focusing on breast cancer and after an overview of single-nucleofide polymorphism (SNP)-screening methodologies, we discuss the diagnostic and prognostic importance of SNPs. Next, using Duchenne muscular dystrophy (DMD) as an example, we provide a brief overview of powerful and innovative integration of traditional immuno-histochemistry techniques with advanced biophysical methods such as NMR-spectroscopy or Fourier-transformed infrared (FT-IR) spectroscopy. A brief overview of the challenges and opportunities provided by protein and aptamer microarrays follows. We conclude by highlighting novel and promising biochemical markers for the development of personalized treatment of cancer and other diseases: serum cytochrome c, cytokeratin-18 and -19 and their proteolytic fragments for the detection and quantitation of malignant tumor mass, tumor cell turn-over, inflammatory processes during hepatitis and Epstein-Barr virus (EBV)-induced hemophagocytic lymphohistiocytosis and apoptotic/necrotic cancer cell death. (c) 2006 Elsevier Ltd. All rights reserved.

  • 6.
    Banerji, Shantanu
    et al.
    Manitoba Institute of Cell Biology, Winnipeg, Manitoba, Canada .
    Los, Marek Jan
    Manitoba Institute of Cell Biology, Cancer Care Manitoba; Manitoba Institute of Child Health; Department of Biochemistry and Medical Genetics; Department of Human Anatomy and Cell Science, University Manitoba, Winnipeg, Canada.
    Important differences between topoisomerase-I and -II targeting agents2006In: Cancer Biology & Therapy, ISSN 1538-4047, E-ISSN 1555-8576, Vol. 5, no 8, p. 965-966Article in journal (Other academic)
    Abstract [en]

    Commentary to: Activation of ATM and Histone H2AX Phosphorylation Induced by Mitoxantrone But Not by Topotecan is Prevented by the Antioxidant N-acetyl-L-Cysteine Xuan Huang, Akira Kurose, Toshiki Tanaka, Frank Traganos, Wei Dai and Zbigniew Darzynkiewicz

     

  • 7. Bantel, H.
    et al.
    Berg, C.
    Vieth, M. W.
    Stolte, M.
    Kruis, W.
    Luegering, N.
    Domschke, W.
    Los, Marek Jan
    Department of Immunology and Cell Biology, University of Münster, Münster, Germany.
    Schulze-Osthoff, Klaus
    Department of Immunology and Cell Biology, University of Münster, Münster, Germany .
    Mesalazine inhibits activation of transcription factor NF-KB in inflamed mucosa of patients with ulcerative colitis.2000In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 118, no 4, p. A1116-A1116Article in journal (Refereed)
  • 8.
    Barczyk, K.
    et al.
    Department of Immunology, Faculty of Biotechnology, Jagiellonian University, Krakow, Poland; Institute of Experimental Dermatology, University of Münster, Münster, Germany.
    Kreuter, M.
    Department of Medicine/Hematology and Oncology, University of Münster, Münster, Germany.
    Pryjma, J.
    Department of Immunology, Faculty of Biotechnology, Jagiellonian University, Krakow, Poland.
    Booy, Evan P.
    Manitoba Institute of Cell Biology, and Department of Biochemistry and Medical Genetics, Univ. Manitoba, Winnipeg, Canada.
    Maddika, Subbareddy
    Manitoba Institute of Cell Biology, Cancer Care Manitoba; Department of Biochemistry and Medical Genetics,University of Manitoba, Winnipeg, Canada .
    Ghavami, Saeid
    Department of Biochemistry and Medical Genetics, Manitoba Institute of Cell Biology, Cancer Care Manitoba, Winnipeg, Manitoba, Canada.
    Berdel, W. E.
    Department of Medicine/Hematology and Oncology, University of Münster, Münster, Germany.
    Roth, J.
    Institute of Experimental Dermatology, University of Münster, Münster, Germany.
    Los, Marek Jan
    Institute of Experimental Dermatology, University of Münster, Münster, Germany Manitoba Institute of Cell Biology, Cancer Care Manitoba; Manitoba Institute of Child Health; Department of Biochemistry and Medical Genetics; Department of Human Anatomy and Cell Science, University Manitoba, Winnipeg, Canada, .
    Serum cytochrome c indicates in vivo apoptosis and can serve as a prognostic marker during cancer therapy2005In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 116, no 2, p. 167-173Article in journal (Refereed)
    Abstract [en]

    Despite significant progress in cancer therapy, the outcome of the treatment is often unfavorable. Better treatment monitoring would not only allow an individual more effective, patient-adjusted therapy, but also it would eliminate some of the side effects. Using a cytochrome c ELISA that was modified to increase sensitivity, we demonstrate that serum cytochrome c is a sensitive apoptotic marker in vivo reflecting therapy-induced cell death burden. Furthermore, increased serum cytochrome c level is a negative prognostic marker. Cancer patients whose serum cytochrome c level was normal 3 years ago have a twice as high probability to be still alive, as judged from sera samples collected for years, analyzed recently and matched with survival data. Moreover, we show that serum cytochrome c and serum LDH-activity reflect different stages and different forms of cell death. Cellular cytochrome c release is specific for apoptosis, whereas increased LDH activity is an indicator of (secondary) necrosis. Whereas serum LDH activity reflects the "global" degree of cell death over a period of time, the sensitive cytochrome c-based method allows confirmation of the individual cancer therapy-induced and spontaneous cell death events. The combination of cytochrome c with tissue-specific markers may provide the foundation for precise monitoring of apoptosis in vivo, by "lab-on-the-chip" technology. (c) 2005 Wiley-Liss, Inc.

  • 9.
    Bauer, M. K. A.
    et al.
    Department of Internal Medicine I, Medical Clinics, Eberhard-Karls-University, Tübingen.
    Vogt, M.
    Department of Internal Medicine I, Medical Clinics, Eberhard-Karls-University, Tübingen.
    Los, Marek Jan
    Department of Internal Medicine I, Medical Clinics, Eberhard-Karls-University, Tübingen, Germany.
    Siegel, J.
    Department of Virology, Albrecht-Ludwigs-University, Freiburg, Germany.
    Wesselborg, Sebastian
    Department of Internal Medicine I, Medical Clinics, Eberhard-Karls-University, Tübingen, Germany.
    Schulze-Osthoff, Klaus
    Department of Internal Medicine I, Medical Clinics, Eberhard-Karls-University, Tübingen.
    Role of reactive oxygen intermediates in activation-induced CD95 (APO-1/Fas) ligand expression1998In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 273, no 14, p. 8048-8055Article in journal (Refereed)
    Abstract [en]

    Activation-induced cell death of T lymphocytes requires the inducible expression of CD95 (APO-1/Fas) ligand, which triggers apoptosis in CD95-bearing target cells by an autocrine or paracrine mechanism. Although execution of the CD95 death pathway is largely independent of reactive oxygen intermediates, activation-induced cell death is blocked by a variety of antioxidants. In the present study, we investigated the involvement of redox processes in the regulation of CD95 ligand (CD95L) expression in Jurkat T cells. We show that various antioxidants potently inhibited the transcriptional activation of CD95L following T cell receptor litigation or stimulation of cells with phorbol ester and ionomycin. Conversely, a prooxidant such as hydrogen peroxide alone was able to increase CD95L expression. As detected by Western blot and cytotoxicity assays, functional expression of CD95L protein was likewise diminished by antioxidants. Inhibition of CD95L expression was associated with a decreased DNA binding activity of nuclear factor (NF)-kappa B, an important redox-controlled transcription factor. Moreover, inhibition of NF-kappa B activity by a transdominant I kappa B mutant attenuated CD95L expression. Our data suggest that, although reactive oxygen intermediates do not act as mediators in the execution phase of CD95-mediated apoptosis, they are involved in the transcriptional regulation of CD95L expression.

  • 10. Baust, H.
    et al.
    Schiessl, I.
    Mueller, B.
    Roedel, F.
    Distel, L.
    Los, Marek Jan
    Manitoba Institute of Cell Biology, Cancer Care Manitoba; Manitoba Institute of Child Health; Department of Biochemistry and Medical Genetics; Department of Human Anatomy and Cell Science, University Manitoba, Winnipeg, Canada, .
    Thomas, S.
    Rolf, S.
    Implications for the role of PKD2 in the radiotherapy of tumours2006In: Strahlentherapie und Onkologie (Print), ISSN 0179-7158, E-ISSN 1439-099X, Vol. 182, p. 81-81Article in journal (Refereed)
  • 11.
    Baust, H.
    et al.
    Department of Radiation Oncology, University of Ulm, D-89081 Ulm, Germany.
    Schoke, A.
    Department of Internal Medicine, University of Ulm, D-89081 Ulm, Germany.
    Brey, A.
    Department of Internal Medicine, University of Ulm, D-89081 Ulm, Germany.
    Gern, U.
    Department of Internal Medicine, University of Ulm, D-89081 Ulm, Germany.
    Los, Marek Jan
    Institute of Experimental Dermatology, University of Muenster, D-48149 Muenster, Germany.
    Schmid, R. M.
    2nd Department of Internal Medicine, University of Munich, D-81675 Munich, Germany.
    Röttinger, E. M.
    Department of Radiation Oncology, University of Ulm, D-89081 Ulm, Germany.
    Seufferlein, T.
    Department of Internal Medicine, University of Ulm, D-89081 Ulm, Germany.
    Evidence for radiosensitizing by gliotoxin in HL-60 cells: implications for a role of NF-kappa B independent mechanisms2003In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 22, no 54, p. 8786-8796Article in journal (Refereed)
    Abstract [en]

    Radioresistance markedly impairs the efficacy of tumor radiotherapy and may involve antiapoptotic signal transduction pathways that prevent radiation-induced cell death. A common cellular response to genotoxic stress induced by radiation is the activation of the nuclear factor kappa B (NF-kappaB). NF-kappaB activation in turn can lead to an inhibition of radiation-induced apoptotic cell death. Thus, inhibition of NF-kappaB activation is commonly regarded as an important strategy to abolish radioresistance. Among other compounds, the fungal metabolite gliotoxin (GT) has been reported to be a highly selective inhibitor of NF-kappaB activation. Indeed, low doses of GT were sufficient to significantly enhance radiation-induced apoptosis in HL-60 cells. However, this effect turned out to be largely independent of NF-kappaB activation since radiation of HL-60 cells with clinically relevant doses of radiation induced only a marginal increase in NF-kappaB activity, and selective inhibition of NF-kappaB by SN50 did not result in a marked enhancement of GT-induced apoptosis. GT induced activation of JNKs, cytochrome c release from the mitochondria and potently stimulated the caspase cascade inducing cleavage of caspases -9, -8, -7 and -3. Furthermore, cleavage of the antiapoptotic protein X-linked IAP and downregulation of the G2/M-specific IAP-family member survivin were observed during GT-induced apoptosis. Finally, the radiation-induced G2/M arrest was markedly reduced in GT-treated cells most likely due to the rapid induction of apoptosis. Our data demonstrate that various other pathways apart from the NF-kappaB signaling complex can sensitize tumor cells to radiation and propose a novel mechanism for radio-sensitization by GT, the interference with the G2/M checkpoint that is important for repair of radiation-induced DNA damage in p53-deficient tumor cells.

  • 12.
    Belka, C.
    et al.
    Department of Radiation Oncology, University of Tuebingen (Germany), Hoppe Seyler Str. 3, 72076 Tuebingen, Germany.
    Marini, P.
    Department of Radiation Oncology, University of Tuebingen (Germany), Hoppe Seyler Str. 3, 72076 Tuebingen, Germany.
    Lepple-Wienhues, A.
    Department of Physiology, University of Tuebingen (Germany), Gmelinstrasse 5, 72076 Tuebingen, Germany.
    Budach, W.
    Department of Radiation Oncology, University of Tuebingen (Germany), Hoppe Seyler Str. 3, 72076 Tuebingen, Germany.
    Jekle, A.
    Department of Physiology, University of Tuebingen (Germany), Gmelinstrasse 5, 72076 Tuebingen, Germany.
    Los, Marek Jan
    Department of Internal Medicine I, University of Tuebingen (Germany), Otfried Müller Str. 10, 72076 Tuebingen, Germany.
    Lang, F.
    Department of Physiology, University of Tuebingen (Germany), Gmelinstrasse 5, 72076 Tuebingen, Germany.
    Schulze-Osthoff, K.
    Department of Internal Medicine I, University of Tuebingen (Germany), Otfried Müller Str. 10, 72076 Tuebingen, Germany.
    Gulbins, E.
    Department of Physiology, University of Tuebingen (Germany), Gmelinstrasse 5, 72076 Tuebingen, Germany.
    Bamberg, M.
    Department of Radiation Oncology, University of Tuebingen (Germany), Hoppe Seyler Str. 3, 72076 Tuebingen, Germany.
    The tyrosine kinase Lck is required for CD95-independent caspase-8 activation and apoptosis in response to ionizing radiation1999In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 18, no 35, p. 4983-4992Article in journal (Refereed)
    Abstract [en]

    Induction of apoptosis is a hallmark of cytostatic drug and radiation-induced cell death in human lymphocytes and lymphoma cells. However, the mechanisms leading to apoptosis are not well understood. We provide evidence that ionizing radiation induces a rapid activation of caspase-8 (FLICE) followed by apoptosis independently of CD95 ligand/receptor interaction. The radiation induced cleavage pattern of procaspase-8 into mature caspase-8 resembled that following CD95 crosslinking and resulted in cleavage of the proapoptotic substrate BID. Overexpression of dominant-negative caspase-8 interfered with radiation-induced apoptosis, Caspase-8 activation by ionizing radiation was not observed in cells genetically defective for the Src-like tyrosine kinase Lck, Cells lacking Lck also displayed a marked resistance towards apoptosis induction upon ionizing radiation. After retransfection of Lck, caspase-8 activation and the capability to undergo apoptosis in response to ionizing radiation was restored. We conclude that radiation activates caspase-8 via an Lck-controlled pathway independently of CD95 ligand expression, This is a novel signaling event required for radiation induced apoptosis in T lymphoma cells.

  • 13.
    Booy, Evan P.
    et al.
    Manitoba Institute of Cell Biology, and Department of Biochemistry and Medical Genetics, Univ. Manitoba, Winnipeg, Canada.
    Johar, Dina
    Manitoba Institute of Cell Biology,CancerCare Manitoba, University of Manitoba, ON6010-675 McDermot Ave., Winnipeg, MB, R3E 0V9, Canada; Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Canada .
    Maddika, Srilekha
    Manitoba Institute of Cell Biology,CancerCare Manitoba, University of Manitoba, ON6010-675 McDermot Ave., Winnipeg, MB, R3E 0V9, Canada; Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Canada .
    Pirzada, Hasan
    Manitoba Institute of Cell Biology,CancerCare Manitoba, University of Manitoba, ON6010-675 McDermot Ave., Winnipeg, MB, R3E 0V9, Canada.
    Sahib, Mickey M.
    Department of Oral Biology, University of Manitoba, Winnipeg, Canada .
    Gehrke, Iris
    Manitoba Institute of Cell Biology,CancerCare Manitoba, University of Manitoba, ON6010-675 McDermot Ave., Winnipeg, MB, R3E 0V9, Canada.
    Loewen, Shauna
    Manitoba Institute of Cell Biology,CancerCare Manitoba, University of Manitoba, ON6010-675 McDermot Ave., Winnipeg, MB, R3E 0V9, Canada; Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Canada .
    Louis, Sherif F.
    Manitoba Institute of Cell Biology,CancerCare Manitoba, University of Manitoba, ON6010-675 McDermot Ave., Winnipeg, MB, R3E 0V9, Canada.
    Kadkhoda, Kamran
    Manitoba Institute of Cell Biology,CancerCare Manitoba, University of Manitoba, ON6010-675 McDermot Ave., Winnipeg, MB, R3E 0V9, Canada; Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Canada .
    Mowat, Michael
    Manitoba Institute of Cell Biology,CancerCare Manitoba, University of Manitoba, ON6010-675 McDermot Ave., Winnipeg, MB, R3E 0V9, Canada; Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Canada .
    Los, Marek Jan
    Manitoba Institute of Cell Biology, Cancer Care Manitoba; Manitoba Institute of Child Health; Department of Biochemistry and Medical Genetics; Department of Human Anatomy and Cell Science, University Manitoba, Winnipeg, Canada, .
    Monoclonal and bispecific antibodies as novel therapeutics2006In: Archivum Immunologiae et Therapiae Experimentalis, ISSN 0004-069X, E-ISSN 1661-4917, Vol. 54, no 2, p. 85-101Article in journal (Refereed)
    Abstract [en]

    Gene amplification, over-expression, and mutation of growth factors, or the receptors themselves, causes increased signaling through receptor kinases, which has been implicated in many human cancers and is associated with poor prognosis. Tumor growth has been shown to be decreased by interrupting this process of extensive growth factor-mediated signaling by directly targeting either the surface receptor or the ligand and thereby preventing cell survival and promoting apoptosis. Monoclonal antibodies have long been eyed as a potential new class of therapeutics targeting cancer and other diseases. Antibody-based therapy initially entered clinical practice when trastuzumab/Herceptin became the first clinically approved drug against an oncogene product as a well-established blocking reagent for tumors with hyperactivity of epidermal growth factor signaling pathways. In the first part of this review we explain basic terms related to the development of antibody-based drugs, give a brief historic perspective of the field, and also touch on topics such as the "humanization of antibodies" or creation of hybrid antibodies. The second part of the review gives an overview of the clinical usage of bispecific antibodies and antibodies "armed" with cytotoxic agents or enzymes. Further within this section, cancer-specific, site-specific, or signaling pathway-specific therapies are discussed in detail. Among other antibody-based therapeutic products, we discuss: Avastin (bevacizumab), CG76030, Theragyn (pemtumomab), daclizumab (Zenapax), TriAb, MDX-210, Herceptin (trastuzumab), panitumumab (ABX-EGF), mastuzimab (EMD-72000), Erbitux (certuximab, IMC225), Panorex (edrecolomab), STI571, CeaVac, Campath (alemtuizumab), Mylotarg (gemtuzumab, ozogamicin), and many others. The end of the review deliberates upon potential problems associated with cancer immunotherapy.

  • 14.
    Burek, C. J.
    et al.
    University of Münster, Germany.
    Roth, J.
    University of Münster, Germany.
    Koch, H. G.
    University of Münster, Germany.
    Harzer, K.
    University of Tübingen, Germany.
    Los, Marek Jan
    Department of Immunology and Cell Biology, University of Münster, Germany.
    Schulze-Osthoff, Klaus
    University of Münster, Germany .
    The role of ceramide in receptor- and stress-induced apoptosis studied in acidic ceramidase-deficient Farber disease cells2001In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 20, no 45, p. 6493-6502Article in journal (Refereed)
    Abstract [en]

    The activation of sphingomyelinases leading to the generation of ceramide has been implicated in various apoptotic pathways. However, the role of ceramide as an essential death mediator remains highly controversial. In the present study, we investigated the functional relevance of ceramide in a genetic model by using primary cells from a Farber disease patient. These cells accumulate ceramide as the result of an inherited deficiency of acidic ceramidase. We demonstrate that Farber disease lymphocytes and fibroblasts underwent apoptosis induced by various stress stimuli, including staurosporine, anticancer drugs and gamma -irradiation, equally as normal control cells. In addition, caspase activation by these proapoptotic agents occurred rather similarly in Farber disease and control fibroblasts. Interestingly, Farber disease lymphoid cells underwent apoptosis induced by the CD95 death receptor more rapidly than control cells. Our data therefore suggest that ceramide does not play an essential role as a second messenger in stress-induced apoptosis. However, in accordance with a role in lipid-rich microdomains, ceramide by altering membrane composition may function as an amplifier in CD95-mediated apoptosis.

  • 15.
    Burek, M.
    et al.
    Department of Immunology and Cell Biology, University of Münster, Münster, Germany.
    Maddika, Subbareddy
    Manitoba Institute of Cell Biology, Cancer Care Manitoba; Department of Biochemistry and Medical Genetics,University of Manitoba, Winnipeg, Canada .
    Burek, C. J.
    Department of Immunology and Cell Biology, University of Münster, Münster, Germany.
    Daniel, P. T.
    Department of Hematology, Oncology and Tumor Immunology, Charité, Berlin, Germany.
    Schulze-Osthoff, Klaus
    nstitute of Molecular Medicine, University of Düsseldorf, Düsseldorf, Germany .
    Los, Marek Jan
    Manitoba Institute of Cell Biology, Cancer Care Manitoba; Manitoba Institute of Child Health; Department of Biochemistry and Medical Genetics; Department of Human Anatomy and Cell Science, University Manitoba, Winnipeg, Canada, .
    Apoptin-induced cell death is modulated by Bcl-2 family members and is Apaf-1dependent2006In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 25, no 15, p. 2213-2222Article in journal (Refereed)
    Abstract [en]

    Apoptin, a chicken anemia virus-derived protein, selectively induces apoptosis in transformed but not in normal cells, thus making it a promising candidate as a novel anticancer therapeutic. The mechanism of apoptin-induced apoptosis is largely unknown. Here, we report that contrary to previous assumptions, Bcl-2 and Bcl-x(L) inhibit apoptin-induced cell death in several tumor cell lines. In contrast, deficiency of Bax conferred resistance, whereas Bax expression sensitized cells to apoptin-induced death. Cell death induction by apoptin was associated with cytochrome c release from mitochondria as well as with caspase-3 and -7 activation. Benzyloxy-carbonyl-Val-Ala-Asp-fluoromethyl ketone, a broad spectrum caspase inhibitor, was highly protective against apoptin-induced cell death. Apoptosis induced by apoptin required Apaf-1, as immortalized Apaf-1-deficient fibroblasts as well as tumor cells devoid of Apaf-1 were strongly protected. Thus, our data indicate that apoptin-induced apoptosis is not only Bcl-2- and caspase dependent, but also engages an Apaf-1 apoptosome-mediated mitochondrial death pathway.

  • 16.
    Cassens, U.
    et al.
    Institute of Transfusion Medicine, University of Münster, D-48149 Münster, Germany.
    Lewinski, G.
    Unit of Surgery, Municipal Hospital, 38-300 Gorlice, Poland.
    Samraj, A. K.
    Institute of Molecular Medicine, University of Düsseldorf, D-40225 Düsseldorf, Germany.
    von Bernuth, H.
    Children´s University Clinic, Laboratory for Clinical Research, D-01307 Dresden, Germany.
    Baust, H.
    Department of Radiotherapy, University of Ulm, D-89070 Ulm, Germany.
    Khazaie, K.
    Department of Cancer Immunology and Aids, Dana Farber Cancer Institute/Harvard Medical School, Boston, Massachusetts, MA 02115, USA.
    Los, Marek Jan
    Institute of Experimental Dermatology, University of Muenster, Germany.
    Viral modulation of cell death by inhibition of caspases2003In: Archivum Immunologiae et Therapiae Experimentalis, ISSN 0004-069X, E-ISSN 1661-4917, Vol. 51, no 1, p. 19-27Article, review/survey (Refereed)
    Abstract [en]

    Caspases are key effectors of the apoptotic process. Some of them play important roles in the immune system, being involved in the proteolytic maturation of the key cytokines, including interleukin 1beta (IL-1beta) and IL-18. The latter directs the production of interferon gamma (IFN-gamma). Among pathogens, particularly viruses express various modulators of caspases that inhibit their activity by direct binding. By evading the apoptotic process, viruses can better control their production in the infected cell and avoid the attack of the immune system. Targeting the maturation of the key cytokines involved in the initiation of (antiviral) immune response helps to avoid recognition and eradication by the immune system. The three main classes of caspase inhibitors frequently found among viruses include serine proteinase inhibitors (serpins: CrmA/SPI-2), viral IAPs (vIAPs) and p35. Their molecular mechanisms of action, structures and overall influence on cellular physiology are discussed in the review below.

  • 17.
    Chaabane, Wiem
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Tunis University, Tunisia.
    Cieślar-Pobuda, Artur
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Silesian University of Technology, Gliwice, Poland.
    El-Gazzah, Mohamed
    Tunis University, Tunisia.
    Jain, Mayur V.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Rzeszowska-Wolny, Joanna
    Silesian University of Technology, Gliwice, Poland.
    Rafat, Mehrdad
    Linköping University, Department of Biomedical Engineering, Biomedical Instrumentation. Linköping University, Faculty of Health Sciences.
    Stetefeld, Joerg
    University of Manitoba, Winnipeg, Canada.
    Ghavami, Saeid
    University of Manitoba, Winnipeg, Canada.
    Los, Marek
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Pomeranian Medical University, Szczecin, Poland.
    Human-Gyrovirus-Apoptin Triggers Mitochondrial Death Pathway—Nur77 is Required for Apoptosis Triggering: 2014In: Neoplasia, ISSN 1522-8002, E-ISSN 1476-5586, Vol. 16, no 9, p. 679-693Article in journal (Refereed)
    Abstract [en]

    The human gyrovirus derived protein Apoptin (HGV-Apoptin) a homologue of the chicken anemia virus Apoptin (CAV-Apoptin), a protein with high cancer cells selective toxicity, trigger apoptosis selectively in cancer cells. In this paper, we show that HGV-Apoptin acts independently from the death receptor pathway as it induces apoptosis in similar rates in Jurkat cells deficient in either FADD-function or caspase-8 (key players of the extrinsic pathway) and their parental clones. HGV-Apoptin induces apoptosis via the activation of the mitochondrial intrinsic pathway. It induces both mitochondrial inner and outer membrane permebilization, characterized by the loss of the mitochondrial potential and the release into cytoplasm of the pro-apoptotic molecules including apoptosis inducing factor (AIF) and cytochrome c. HGV-Apoptin acts via the apoptosome, as lack of expression of APAF1 in murine embryonic fibroblast strongly protected the cells from HGV-Apoptin-induced apoptosis. Moreover, QVD-oph a broad-spectrum caspase inhibitor delayed HGV-Apoptin-induced death. On the other hand, overexpression of the anti-apoptotic BCL-XL confers resistance to HGV-Apoptin induced cell death. In contrast, cells that lack the expression of the pro-apoptotic BAX and BAK are protected from HGV-Apoptin induced apoptosis. Furthermore, HGV-Apoptin acts independently from p53 signal but triggers the cytoplasmic translocation of Nur77. Taking together this data indicate that HGV-Apoptin acts through the mitochondrial pathway, in a caspase-dependent manner but independently from the death receptor pathway.

  • 18.
    Chaabane, Wiem
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    User, Sirma D.
    Middle East Technical University, Ankara, Turkey .
    El-Gazzah, Mohamed
    Tunis University, Tunisia .
    Jaksik, Roman
    Silesian University of Technology, Gliwice, Poland.
    Sajjadi, Elaheh
    Tehran University of Medical Sciences, Iran .
    Rzeszowska-Wolny, Joanna
    Silesian University of Technology, Gliwice, Poland.
    Łos, Marek J.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Autophagy, Apoptosis, Mitoptosis and Necrosis: Interdependence Between Those Pathways and Effects on Cancer2013In: Archivum Immunologiae et Therapiae Experimentalis, ISSN 0004-069X, E-ISSN 1661-4917, Vol. 61, no 1, p. 43-58Article, review/survey (Refereed)
    Abstract [en]

    Cell death is a fundamental ingredient of life. Thus, not surprisingly more than one form of cell death exists. Several excellent reviews on various forms of cell death have already been published but manuscripts describing interconnection and interdependence between such processes are uncommon. Here, what follows is a brief introduction on all three classical forms of cell death, followed by a more detailed insight into the role of p53, the master regulator of apoptosis, and other forms of cell death. While discussing p53 and also the role of caspases in cell death forms, we offer insight into the interplay between autophagy and apoptosis, or necrosis, where autophagy may initially serve pro-survival functions. The review moves further to present some details about less researched forms of programmed cell death, namely necroptosis, necrosis and mitoptosis. These “mixed” forms of cell death allow us to highlight the interconnected nature of cell death forms, particularly apoptosis and necrosis. The interdependence between apoptosis, autophagy and necrosis, and their significance for cancer development and treatment are also analyzed in further parts of the review. In the concluding parts, the afore-mentioned issues will be put in perspective for the development of novel anti-cancer therapies.

  • 19. 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.

  • 20.
    Cieslar-Pobuda, Artur
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Bäck, Marcus
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Magnusson, Karin
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Vilas Jain, Mayur
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Rafat, Mehrdad
    Linköping University, Department of Biomedical Engineering. Linköping University, Faculty of Health Sciences.
    Ghavami, Saeid
    Manitoba Institute Child Heatlh, Canada; University of Manitoba, Canada .
    Nilsson, Peter R.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Los, Marek Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Cell Type Related Differences in Staining with Pentameric Thiophene Derivatives2014In: Cytometry Part A, ISSN 1552-4922, E-ISSN 1552-4930, Vol. 85A, no 7, p. 628-635Article in journal (Refereed)
    Abstract [en]

    Fluorescent compounds capable of staining cells selectively without affecting their viability are gaining importance in biology and medicine. Recently, a new family of optical dyes, denoted luminescent conjugated oligothiophenes (LCOs), has emerged as an interesting class of highly emissive molecules for studying various biological phenomena. Properly functionalized LCOs have been utilized for selective identification of disease-associated protein aggregates and for selective detection of distinct cells. Herein, we present data on differential staining of various cell types, including cancer cells. The differential staining observed with newly developed pentameric LCOs is attributed to distinct side chain functionalities along the thiophene backbone. Employing flow cytometry and fluorescence microscopy we examined a library of LCOs for stainability of a variety of cell lines. Among tested dyes we found promising candidates that showed strong or moderate capability to stain cells to different extent, depending on target cells. Hence, LCOs with diverse imidazole motifs along the thiophene backbone were identified as an interesting class of agents for staining of cancer cells, whereas LCOs with other amino acid side chains along the backbone showed a complete lack of staining for the cells included in the study. Furthermore, for p-HTMI,a LCO functionalized with methylated imidazole moieties, the staining was dependent on the p53 status of the cells, indicating that the molecular target for the dye is a cellular component regulated by p53. We foresee that functionalized LCOs will serve as a new class of optical ligands for fluorescent classification of cells and expand the toolbox of reagents for fluorescent live imaging of different cells.

  • 21.
    Cieślar-Pobuda, Artur
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Biosystems Group, Institute of Automatic Control, Silesian University of Technology, Gliwice, Poland.
    Los, Marek Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Department of Pathology, Pomeranian Medical University, Szczecin, Poland.
    Comments: Prospects and Limitations of“Click-Chemistry”-Based DNA LabelingTechnique Employing 5-Ethynyl-20deoxyuridine(EdU)2013In: Cytometry Part A, ISSN 1552-4922, E-ISSN 1552-4930, Vol. 83, p. 977-978Article in journal (Other academic)
    Abstract [en]

    n/a

  • 22.
    Debatin, K. M.
    et al.
    GERMAN CANC RES CTR,DIV MOL ONCOL,D-69120 HEIDELBERG,GERMANY.
    Beltinger, C.
    GERMAN CANC RES CTR,DIV MOL ONCOL,D-69120 HEIDELBERG,GERMANY.
    Bohler, T.
    GERMAN CANC RES CTR,DIV MOL ONCOL,D-69120 HEIDELBERG,GERMANY.
    Fellenberg, J.
    GERMAN CANC RES CTR,DIV MOL ONCOL,D-69120 HEIDELBERG,GERMANY.
    Friesen, C.
    GERMAN CANC RES CTR,DIV MOL ONCOL,D-69120 HEIDELBERG,GERMANY.
    Fulda, S.
    GERMAN CANC RES CTR,DIV MOL ONCOL,D-69120 HEIDELBERG,GERMANY.
    Herr, I.
    GERMAN CANC RES CTR,DIV MOL ONCOL,D-69120 HEIDELBERG,GERMANY.
    Los, Marek Jan
    GERMAN CANC RES CTR,DIV MOL ONCOL,D-69120 HEIDELBERG,GERMANY.
    Scheuerpflug, C.
    GERMAN CANC RES CTR,DIV MOL ONCOL,D-69120 HEIDELBERG,GERMANY.
    Sieverts, H.
    GERMAN CANC RES CTR,DIV MOL ONCOL,D-69120 HEIDELBERG,GERMANY.
    Stahnke, K.
    GERMAN CANC RES CTR,DIV MOL ONCOL,D-69120 HEIDELBERG,GERMANY.
    Regulation of apoptosis through CD95 (APO-I/Fas) receptor-ligand interaction1997In: Biochemical Society Transactions, ISSN 0300-5127, E-ISSN 1470-8752, Vol. 25, no 2, p. 405-410Article in journal (Refereed)
  • 23.
    Debatin, K. M.
    et al.
    UNIV HEIDELBERG,CHILDRENS HOSP,D-6900 HEIDELBERG,GERMANY.
    Friesen, C.
    UNIV HEIDELBERG,CHILDRENS HOSP,D-6900 HEIDELBERG,GERMANY.
    Herr, I.
    UNIV HEIDELBERG,CHILDRENS HOSP,D-6900 HEIDELBERG,GERMANY.
    Los, Marek Jan
    UNIV HEIDELBERG,CHILDRENS HOSP,D-6900 HEIDELBERG,GERMANY.
    Activation of the CD95 pathway by anticancer drugs.1996In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 88, no 10, p. 2641-2641Article in journal (Refereed)
  • 24.
    Ferrari, D.
    et al.
    Department of Internal Medicine I, Medical Clinics, Eberhard-Karls-University, Otfried-Müller-Str. 10, D-72076 Tübingen, Germany.
    Los, Marek Jan
    Department of Internal Medicine I, Medical Clinics, Eberhard-Karls-University, Otfried-Müller-Str. 10, D-72076 Tübingen, Germany.
    Bauer, M. K. A.
    Department of Internal Medicine I, Medical Clinics, Eberhard-Karls-University, Otfried-Müller-Str. 10, D-72076 Tübingen, Germany.
    Vandenabeele, P.
    Department of Molecular Biology, Flanders Interuniversity Institute for Biotechnology, Ghent, Belgium.
    Wesselborg, Sebastian
    Department of Internal Medicine I, Medical Clinics, Eberhard-Karls-University, Otfried-Müller-Str. 10, D-72076 Tübingen, Germany.
    Schulze-Osthoff, K.
    Department of Internal Medicine I, Medical Clinics, Eberhard-Karls-University, Otfried-Müller-Str. 10, D-72076 Tübingen, Germany.
    P2Z purinoreceptor ligation induces activation of caspases with distinct roles in apoptotic and necrotic alterations of cell death1999In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 447, no 1, p. 71-75Article in journal (Refereed)
    Abstract [en]

    Myeloic cells express a peculiar surface receptor for extracellular ATP, called the P2Z/P2X(7) purinoreceptor, which is involved in cell death signalling. Here, we investigated the role of caspases, a family of proteases implicated in apoptosis and the cytokine secretion. We observed that extracellular ATP induced the activation of multiple caspases including caspase-1, -3 and -8, and subsequent cleavage of the caspase substrates PARP and Iamin B. Using caspase inhibitors, it was found that caspases were specifically involved in ATP-induced apoptotic damage such as chromatin condensation and DNA fragmentation, In contrast, inhibition of caspases only marginally affected necrotic alterations and cell death proceeded normally whether or not nuclear damage was blocked. Our results therefore suggest that the activation of caspases by the P2Z receptor is required for apoptotic but not necrotic alterations of ATP-induced cell death. (C) 1999 Federation of European Biochemical Societies.

  • 25.
    Ferrari, D.
    et al.
    Department of Internal Medicine I, Eberhard-Karls University, D-72076 Tübingen, Germany.
    Stepczynska, A.
    Department of Internal Medicine I, Eberhard-Karls University, D-72076 Tübingen, Germany.
    Los, Marek Jan
    Department of Internal Medicine I, Eberhard-Karls University, D-72076 Tübingen, Germany.
    Wesselborg, Sebastian
    Department of Internal Medicine I, Eberhard-Karls University, D-72076 Tübingen, Germany.
    Schulze-Osthoff, Klaus
    Department of Internal Medicine I, Eberhard-Karls University, D-72076 Tübingen, Germany.
    Differential regulation and ATP requirement for caspase-8 and caspase-3 activation during CD95- and anticancer drug-induced apoptosis1998In: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 188, no 5, p. 979-984Article in journal (Refereed)
    Abstract [en]

    Apoptosis is induced by different stimuli, among them triggering of the death receptor CD95, staurosporine, and chemotherapeutic drugs. In all cases, apoptosis is mediated by caspases, although it is unclear how these diverse apoptotic stimuli cause protease activation. Two regulatory pathways have been recently identified, but it remains unknown whether they are functionally independent or linked to each other. One is mediated by recruitment of the proximal regulator caspase-8 to the death receptor complex. The other pathway is controlled by the release of cytochrome c from mitochondria and the subsequent ATP-dependent activation of the death regulator apoptotic protease-activating factor 1 (Apaf-1). Here, we report that both pathways can be dissected by depletion of intracellular ATP. Prevention of ATP production completely inhibited caspase activation and apoptosis in response to chemotherapeutic drugs and staurosporine. Interestingly, caspase-8, whose function appeared to be restricted to death receptors, was also activated by these drugs under normal conditions, but not after ATP depletion. In contrast, inhibition of ATP production did not affect caspase activation after triggering of CD95. These results suggest that chemotherapeutic drug-induced caspase activation is entirely controlled by a receptor-independent mitochondrial pathway, whereas CD95-induced apoptosis can be regulated by a separate pathway not requiring Apaf-1 function.

  • 26.
    Friesen, C.
    et al.
    UNIV HEIDELBERG,CHILDRENS HOSP,W-6900 HEIDELBERG,GERMANY .
    Herr, I.
    UNIV HEIDELBERG,CHILDRENS HOSP,W-6900 HEIDELBERG,GERMANY .
    Los, Marek Jan
    GERMAN CANC RES CTR,DIV MOLEC ONCOL,D-69120 HEIDELBERG,GERMANY.
    Debatin, K. M.
    GERMAN CANC RES CTR,DIV MOLEC ONCOL,D-69120 HEIDELBERG,GERMANY.
    Drug induced cytotoxicity in leukemia cells involves the CD95 (APO-1/FAS) pathway of apoptosis1996In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 93, p. 367-367Article in journal (Refereed)
  • 27.
    Fulda, S.
    et al.
    GERMAN CANC RES CTR,D-6900 HEIDELBERG,GERMANY.
    Friesen, C.
    GERMAN CANC RES CTR,D-6900 HEIDELBERG,GERMANY.
    Los, Marek Jan
    Department of Immunology and Cell Biology, University of Münster, Münster, Germany.
    Benedict, M.
    UNIV MICHIGAN,SCH MED,DEPT PATHOL,ANN ARBOR,MI.
    Nunez, G.
    UNIV MICHIGAN,SCH MED,DEPT PATHOL,ANN ARBOR,MI.
    Peter, M. E.
    UNIV ULM, CHILDRENS HOSP, ULM, GERMANY .
    Debatin, K. M.
    GERMAN CANC RES CTR,D-6900 HEIDELBERG,GERMANY.
    CD95 (APO-1/Fas)- and p53-independent apoptosis by betulinic acid involves mitochondrial alterations and activation of caspases.1997In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 90, no 10, p. 2207-2207Article in journal (Refereed)
  • 28.
    Fulda, S.
    et al.
    Division of Hematology/Oncology, University Children's Hospital and Division of Molecular Oncology, German Cancer Research Center, Heidelberg, Germany; Divisions of Immunogenetics and Molecular Toxicology, German Cancer Research Center, Heidelberg, Germany; and Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.
    Friesen, C.
    Division of Hematology/Oncology, University Children's Hospital and Division of Molecular Oncology, German Cancer Research Center, Heidelberg, Germany; Divisions of Immunogenetics and Molecular Toxicology, German Cancer Research Center, Heidelberg, Germany; and Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.
    Los, Marek Jan
    Division of Hematology/Oncology, University Children's Hospital and Division of Molecular Oncology, German Cancer Research Center, Heidelberg, Germany; Divisions of Immunogenetics and Molecular Toxicology, German Cancer Research Center, Heidelberg, Germany; and Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.
    Scaffidi, C.
    Division of Hematology/Oncology, University Children's Hospital and Division of Molecular Oncology, German Cancer Research Center, Heidelberg, Germany; Divisions of Immunogenetics and Molecular Toxicology, German Cancer Research Center, Heidelberg, Germany; and Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.
    Mier, W.
    Division of Hematology/Oncology, University Children's Hospital and Division of Molecular Oncology, German Cancer Research Center, Heidelberg, Germany; Divisions of Immunogenetics and Molecular Toxicology, German Cancer Research Center, Heidelberg, Germany; and Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.
    Benedict, M.
    Division of Hematology/Oncology, University Children's Hospital and Division of Molecular Oncology, German Cancer Research Center, Heidelberg, Germany; Divisions of Immunogenetics and Molecular Toxicology, German Cancer Research Center, Heidelberg, Germany; and Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.
    Nunez, G.
    Division of Hematology/Oncology, University Children's Hospital and Division of Molecular Oncology, German Cancer Research Center, Heidelberg, Germany; Divisions of Immunogenetics and Molecular Toxicology, German Cancer Research Center, Heidelberg, Germany; and Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.
    Krammer, P. H.
    Division of Hematology/Oncology, University Children's Hospital and Division of Molecular Oncology, German Cancer Research Center, Heidelberg, Germany; Divisions of Immunogenetics and Molecular Toxicology, German Cancer Research Center, Heidelberg, Germany; and Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.
    Peter, M. E.
    Division of Hematology/Oncology, University Children's Hospital and Division of Molecular Oncology, German Cancer Research Center, Heidelberg, Germany; Divisions of Immunogenetics and Molecular Toxicology, German Cancer Research Center, Heidelberg, Germany; and Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.
    Debatin, K. M.
    Division of Hematology/Oncology, University Children's Hospital and Division of Molecular Oncology, German Cancer Research Center, Heidelberg, Germany; Divisions of Immunogenetics and Molecular Toxicology, German Cancer Research Center, Heidelberg, Germany; and Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.
    Betulinic acid triggers CD95 (APO-1/Fas)- and p53-independent apoptosis via activation of caspases in neuroectodermal tumors1997In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 57, no 21, p. 4956-4964Article in journal (Refereed)
    Abstract [en]

    Betulinic acid CBA), a melanoma-specific cytotoxic agent, induced apoptosis in neuroectodermal tumors, such as neuroblastoma, medulloblastoma, and Ewing's sarcoma, representing the most common solid tumors of childhood. BA triggered an apoptosis pathway different from the one previously identified for standard chemotherapeutic drugs. BA-induced apoptosis was independent of CD95-ligand/receptor interaction and accumulation of wild-type p53 protein, but it critically depended on activation of caspases (interleukin 1 beta-converting enzyme/Ced-3-like proteases), FLICE/MACH (caspase-8), considered to be an upstream protease in the caspase cascade, and the downstream caspase CPP32/YAMA/Apopain (caspase-3) were activated, resulting in cleavage of the prototype substrate of caspases PARP. The broad-spectrum peptide inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone, which blocked cleavage of FLICE and PARP, also completely abrogated BA-triggered apoptosis. Cleavage of caspases was preceded by disturbance of mitochondrial membrane potential and by generation of reactive oxygen species. Overexpression of Bcl-2 and Bcl-x(L) conferred resistance to BA at the level of mitochondrial dysfunction, protease activation, and nuclear fragmentation. This suggested that mitochondrial alterations were involved in BA-induced activation of caspases. Furthermore, pax and Bcl-x(s), two death-promoting proteins of the Bcl-2 family, were up-regulated following BA treatment. Most importantly, neuroblastoma cells resistant to CD95- and doxorubicin-mediated apoptosis were sensitive to treatment with BA, suggesting that BA may bypass some forms of drug resistance. Because BA exhibited significant antitumor activity on patients' derived neuroblastoma cells ex vivo, BA may be a promising new agent for the treatment of neuroectodermal tumors in vivo.

  • 29.
    Fulda, S.
    et al.
    Hematology/Oncology, University Children's Hospital and Division of Molecular Oncology, German Cancer Research Center, Heidelberg, Germany.
    Los, Marek Jan
    Hematology/Oncology, University Children's Hospital and Division of Molecular Oncology, German Cancer Research Center, Heidelberg, Germany.
    Friesen, C.
    Hematology/Oncology, University Children's Hospital and Division of Molecular Oncology, German Cancer Research Center, Heidelberg, Germany.
    Debatin, K. M.
    Hematology/Oncology, University Children's Hospital and Division of Molecular University Children's Hospital, Prittwitzstr. 43, D-89075 Ulm, Germany.
    Chemosensitivity of solid tumor cells in vitro is related to activation of the CD95 system1998In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 76, no 1, p. 105-114Article in journal (Refereed)
    Abstract [en]

    We have identified the CD95 system as a key mediator of chemotherapy-induced apoptosis in leukemia and neuroblastoma cells. Here, we report that sensitivity of various solid tumor cell lines for drug-induced cell death corresponds to activation of the CD95 system, Upon drug treatment, strong induction of CD95 ligand (CD95-L) and caspase activity were found in chemosensitive tumor cells (Hodgkin, Ewing's sarcoma, colon carcinoma and small cell lung carcinoma) but not in tumor cells which responded poorly to drug treatment (breast carcinoma and renal cell carcinoma). Blockade of CD95 using F(ab')(2) anti-CD95 antibody fragments markedly reduced drug-induced apoptosis, suggesting that drug-triggered apoptosis depended on CD95-L/receptor interaction. Moreover, drug treatment induced CD95 expression, thereby increasing sensitivity for CD95-induced apoptosis, Drug-induced apoptosis critically depended on activation of caspases (ICE/Ced-3-like proteases) since the broad-spectrum inhibitor of caspases zVAD-fmk strongly reduced drug-mediated apoptosis, The prototype substrate of caspases, poly(ADP-ribose) polymerase, was cleaved upon drug treatment, suggesting that CD95-L triggered autocrine/paracrine death via activation of caspases, Our data suggest that chemosensitivity of solid tumor cells depends on intact apoptosis pathways involving activation of the CD95 system and processing of caspases. Our findings may have important implications for new treatment approaches to increase sensitivity and to overcome resistance of solid tumors. (C) 1998 Wiley-Liss, Inc.

  • 30.
    Gelmi, Amy
    et al.
    Linköping University, Faculty of Science & Engineering. Linköping University, Department of Physics, Chemistry and Biology, Biosensors and Bioelectronics. Imperial Coll London, England.
    Cieslar-Pobuda, Artur
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Silesian Technical University, Poland.
    de Muinck, Ebo
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Los, Marek Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Pomeranian Medical University, Poland.
    Rafat, Mehrdad
    Linköping University, Department of Biomedical Engineering, Biomedical Instrumentation. Linköping University, Faculty of Science & Engineering.
    Jager, Edwin
    Linköping University, Department of Physics, Chemistry and Biology, Biosensors and Bioelectronics. Linköping University, Faculty of Science & Engineering.
    Direct Mechanical Stimulation of Stem Cells: A Beating Electromechanically Active Scaffold for Cardiac Tissue Engineering2016In: Advanced Healthcare Materials, ISSN 2192-2640, E-ISSN 2192-2659, Vol. 5, no 12, p. 1471-1480Article in journal (Refereed)
    Abstract [en]

    The combination of stem cell therapy with a supportive scaffold is a promising approach to improving cardiac tissue engineering. Stem cell therapy can be used to repair nonfunctioning heart tissue and achieve myocardial regeneration, and scaffold materials can be utilized in order to successfully deliver and support stem cells in vivo. Current research describes passive scaffold materials; here an electroactive scaffold that provides electrical, mechanical, and topographical cues to induced human pluripotent stem cells (iPS) is presented. The poly(lactic-co-glycolic acid) fiber scaffold coated with conductive polymer polypyrrole (PPy) is capable of delivering direct electrical and mechanical stimulation to the iPS. The electroactive scaffolds demonstrate no cytotoxic effects on the iPS as well as an increased expression of cardiac markers for both stimulated and unstimulated protocols. This study demonstrates the first application of PPy as a supportive electroactive material for iPS and the first development of a fiber scaffold capable of dynamic mechanical actuation.

  • 31.
    Gelmi, Amy
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biosensors and Bioelectronics. Linköping University, Faculty of Science & Engineering.
    Zhang, Jiabin
    Linköping University, Department of Physics, Chemistry and Biology, Biosensors and Bioelectronics. Linköping University, Faculty of Science & Engineering.
    Cieslar-Pobuda, Artur
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Ljunggren, Monika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Los, Marek
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Rafat, Mehrdad
    Linköping University, Department of Biomedical Engineering, Biomedical Instrumentation. Linköping University, Faculty of Medicine and Health Sciences.
    Jager, Edwin
    Linköping University, Department of Physics, Chemistry and Biology, Biosensors and Bioelectronics. Linköping University, Faculty of Science & Engineering.
    Electroactive polymer scaffolds for cardiac tissue engineering2015In: Proc. SPIE 9430, Electroactive Polymer Actuators and Devices (EAPAD) 2015 / [ed] Bar-Cohen, SPIE - International Society for Optical Engineering, 2015, Vol. 9430, p. 94301T-1-94301T-7Conference paper (Refereed)
    Abstract [en]

    By-pass surgery and heart transplantation are traditionally used to restore the heart’s functionality after a myocardial Infarction (MI or heart attack) that results in scar tissue formation and impaired cardiac function. However, both procedures are associated with serious post-surgical complications. Therefore, new strategies to help re-establish heart functionality are necessary. Tissue engineering and stem cell therapy are the promising approaches that are being explored for the treatment of MI. The stem cell niche is extremely important for the proliferation and differentiation of stem cells and tissue regeneration. For the introduction of stem cells into the host tissue an artificial carrier such as a scaffold is preferred as direct injection of stem cells has resulted in fast stem cell death. Such scaffold will provide the proper microenvironment that can be altered electronically to provide temporal stimulation to the cells. We have developed an electroactive polymer (EAP) scaffold for cardiac tissue engineering. The EAP scaffold mimics the extracellular matrix and provides a 3D microenvironment that can be easily tuned during fabrication, such as controllable fibre dimensions, alignment, and coating. In addition, the scaffold can provide electrical and electromechanical stimulation to the stem cells which are important external stimuli to stem cell differentiation. We tested the initial biocompatibility of these scaffolds using cardiac progenitor cells (CPCs), and continued onto more sensitive induced pluripotent stem cells (iPS). We present the fabrication and characterisation of these electroactive fibres as well as the response of increasingly sensitive cell types to the scaffolds.

  • 32.
    Ghavami, S.
    et al.
    University of Manitoba, Winnipeg, Canada.
    Hashemi, M.
    Zahedan University of Medical Sciences, Iran .
    Ande, S. R.
    MICB, CancerCare Manitoba, Winnipeg, Canada.
    Yeganeh, B.
    St Boniface General Hospital Research Centre and University of Manitoba, Winnipeg, Canada.
    Xiao, W.
    MICB, CancerCare Manitoba, Winnipeg, Canada.
    Eshraghi, M.
    MICB, CancerCare Manitoba, Winnipeg, Canada.
    Bus, C. J.
    University of Tübingen, Germany.
    Kadkhoda, K.
    University of Manitoba and Diagnostic Services of Manitoba, Winnipeg, Canada .
    Wiechec, Emilia
    University of Aarhus, Denmark.
    Halayko, A. J.
    University of Manitoba, Winnipeg, Canada.
    Los, Marek
    University of Tübingen, Germany.
    Apoptosis and cancer: mutations within caspase genes2009In: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 46, no 8, p. 497-510Article, review/survey (Refereed)
    Abstract [en]

    The inactivation of programmed cell death has profound effects not only on the development but also on the overall integrity of multicellular organisms. Beside developmental abnormalities, it may lead to tumorigenesis, autoimmunity, and other serious health problems. Deregulated apoptosis may also be the leading cause of cancer therapy chemoresistance. Caspase family of cysteinyl-proteases plays the key role in the initiation and execution of programmed cell death. This review gives an overview of the role of caspases, their natural modulators like IAPs, FLIPs, and Smac/Diablo in apoptosis and upon inactivation, and also in cancer development. Besides describing the basic mechanisms governing programmed cell death, a large part of this review is dedicated to previous studies that were focused on screening tumours for mutations within caspase genes as well as their regulators. The last part of this review discusses several emerging treatments that involve modulation of caspases and their regulators. Thus, we also highlight caspase cascade modulating experimental anticancer drugs like cFLIP-antagonist CDDO-Me; cIAP1 antagonists OSU-03012 and ME-BS; and XIAP small molecule antagonists 1396-11, 1396-12, 1396-28, triptolide, AEG35156, survivin/Hsp90 antagonist shephedrin, and some of the direct activators of procaspase-3.

  • 33.
    Ghavami, Saeid
    et al.
    Department of Biochemistry and Medical Genetics, Manitoba Institute of Cell Biology, Cancer Care Manitoba, Winnipeg, Manitoba, Canada.
    Asoodeh, Ahmad
    Department of Biophysics and Biochemistry, Faculty of Basic Sciences, Tarbiat Modares University, Tehran, Iran; Department of Chemistry Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran .
    Klonisch, Thomas
    Department of Human Anatomy and Cell Sciences, and Manitoba Institute of Child Health, Winnipeg, Canada.
    Halayko, Andrew J.
    Department of Physiology, University of Manitoba, Winnipeg, MB, Canada; Manitoba Institute of Child Health, Winnipeg, MB, Canada.
    Kadkhoda, Kamran
    Department of Biochemistry and Medical Genetics, Manitoba Institute of Cell Biology, Cancer Care Manitoba, Winnipeg, Manitoba, Canada.
    Kroczak, Tadeusz J.
    Department of Biochemistry and Medical Genetics, Manitoba Institute of Cell Biology, Cancer Care Manitoba, Winnipeg, Manitoba, Canada.
    Gibson, Spencer B.
    Department of Biochemistry and Medical Genetics, Manitoba Institute of Cell Biology, Cancer Care Manitoba, Winnipeg, Manitoba, Canada; BioApplications Enterprises, Winnipeg, Canada.
    Booy, Evan P.
    Department of Biochemistry and Medical Genetics, Manitoba Institute of Cell Biology, Cancer Care Manitoba, Winnipeg, Manitoba, Canada.
    Naderi-Manesh, Hossein
    Department of Biophysics and Biochemistry, Faculty of Basic Sciences, Tarbiat Modares University, Tehran, Iran.
    Los, Marek Jan
    BioApplications Enterprises, Winnipeg, MB, Canada.
    Brevinin-2R semi-selectively kills cancer cells by a distinct mechanism, which involves the lysosomal-mitochondrial death pathway2008In: Journal of Cellular and Molecular Medicine (Print), ISSN 1582-1838, E-ISSN 1582-4934, Vol. 12, no 3, p. 1005-1022Article in journal (Refereed)
    Abstract [en]

    Brevinin-2R is a novel non-hemolytic defensin that was isolated from the skin of the frog Rana ridibunda. It exhibits preferential cytotoxicity towards malignant cells, including Jurkat (T-cell leukemia), BJAB (B-cell lymphoma), HT29/219, SW742 (colon carcinomas), L929 (fibrosarcoma), MCF-7 (breast adenocarcinoma), A549 (lung carcinoma), as compared to primary cells including peripheral blood mononuclear cells (PBMC), T cells and human lung fibroblasts. Jurkat and MCF-7 cells overexpressing Bcl2, and L929 and MCF-7 over-expressing a dominant-negative mutant of a pro-apoptotic BNIP3 (ΔTM-BNIP3) were largely resistant towards Brevinin-2R treatment. The decrease in mitochondrial membrane potential (ΔΨm), or total cellular ATP levels, and increased reactive oxygen species (ROS) production, but not caspase activation or the release of apoptosis-inducing factor (AIF) or endonuclease G (Endo G), were early indicators of Brevinin-2R-triggered death. Brevinin-2R interacts with both early and late endosomes. Lysosomal membrane permeabilization inhibitors and inhibitors of cathepsin-B and cathepsin-L prevented Brevinin-2R-induced cell death. Autophagosomes have been detected upon Brevinin-2R treatment. Our results show that Brevinin-2R activates the lysosomalmitochondrial death pathway, and involves autophagy-like cell death.

  • 34.
    Ghavami, Saeid
    et al.
    Department of Physiology, University of Manitoba, Canada.
    Cunnington, Ryan H
    Institute of Cardiovascular Sciences, University of Manitoba, Canada.
    Yeganeh, Behzad
    Department of Physiology, University of Manitoba, Canada.
    Davies, Jared J L
    Institute of Cardiovascular Sciences, University of Manitoba, Canada.
    Rattan, Sunil G
    Institute of Cardiovascular Sciences, University of Manitoba, Canada.
    Bathe, Krista
    Institute of Cardiovascular Sciences, University of Manitoba, Canada.
    Kavosh, Morvarid
    Institute of Cardiovascular Sciences, University of Manitoba, Canada.
    Los, Marek J
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Freed, Darren H
    Department of Physiology, University of Manitoba, Canada.
    Klonisch, Thomas
    Department of Human Anatomy and Cell Science, University of Manitoba, Canada.
    Pierce, Grant N
    Department of Physiology, University of Manitoba, Canada.
    Halayko, Andrew J
    Department of Physiology, University of Manitoba, Canada.
    Dixon, Ian M C
    Department of Physiology, University of Manitoba, Canada.
    Autophagy regulates trans fatty acid-mediated apoptosis in primary cardiac myofibroblasts.2012In: Biochimica et Biophysica Acta. Molecular Cell Research, ISSN 0167-4889, E-ISSN 1879-2596, Vol. 1823, no 12, p. 2274-2286Article in journal (Refereed)
    Abstract [en]

    Trans fats are not a homogeneous group of molecules and less is known about the cellular effects of individual members of the group. Vaccenic acid (VA) and elaidic acid (EA) are the predominant trans monoenes in ruminant fats and vegetable oil, respectively. Here, we investigated the mechanism of cell death induced by VA and EA on primary rat ventricular myofibroblasts (rVF). The MTT assay demonstrated that both VA and EA (200μM, 0-72h) reduced cell viability in rVF (P<0.001). The FACS assay confirmed that both VA and EA induced apoptosis in rVF, and this was concomitant with elevation in cleaved caspase-9, -3 and -7, but not caspase-8. VA and EA decreased the expression ratio of Bcl2:Bax, induced Bax translocation to mitochondria and decrease in mitochondrial membrane potential (Δψ). BAX and BAX/BAK silencing in mouse embryonic fibroblasts (MEF) inhibited VA and EA-induced cell death compared to the corresponding wild type cells. Transmission electron microscopy revealed that VA and EA also induced macroautophagosome formation in rVF, and immunoblot analysis confirmed the induction of several autophagy markers: LC3-β lipidation, Atg5-12 accumulation, and increased beclin-1. Finally, deletion of autophagy genes, ATG3 and ATG5 significantly inhibited VA and EA-induced cell death (P<0.001). Our findings show for the first time that trans fat acid (TFA) induces simultaneous apoptosis and autophagy in rVF. Furthermore, TFA-induced autophagy is required for this pro-apoptotic effect. Further studies to address the effect of TFA on the heart may reveal significant translational value for prevention of TFA-linked heart disease.

  • 35.
    Ghavami, Saeid
    et al.
    Manitoba Institute of Cell Biology, and Department of Biochemistry and Medical Genetics, University of Manitoba, Canada.
    Eshraghi, Mehdi
    Manitoba Institute of Cell Biology, and Department of Biochemistry and Medical Genetics, University of Manitoba, Canada.
    Kadkhoda, Kamran
    Manitoba Institute of Cell Biology, and Department of Biochemistry and Medical Genetics, University of Manitoba, Canada.
    Mutawe, Mark M.
    Department of Physiology, University of Manitoba, Canada; Manitoba Institute of Child's Health, University of Manitoba, Canada.
    Maddika, Subbareddy
    Manitoba Institute of Cell Biology, and Department of Biochemistry and Medical Genetics, University of Manitoba, Canada.
    Bay, Graham H.
    Manitoba Institute of Cell Biology, and Department of Biochemistry and Medical Genetics, University of Manitoba, Canada.
    Wesselborg, Sebastian
    Department of Internal Medicine I, University of Tübingen, Tübingen, Germany.
    Halayko, Andrew J.
    Department of Physiology, University of Manitoba, Winnipeg, MB, Canada; Manitoba Institute of Child Health, Winnipeg, MB, Canada; Department of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada .
    Klonisch, Thomas
    Department of Human Anatomy and Cell Sciences, and Manitoba Institute of Child Health, Winnipeg, Canada.
    Los, Marek Jan
    Interfaculty Institute for Biochemistry, University of Tübingen, Germany; BioApplications Enterprises, Winnipeg, MB, Canada.
    Role of BNIP3 in TNF-induced cell death - TNF upregulates BNIP3 expression2009In: Biochimica et Biophysica Acta. Molecular Cell Research, ISSN 0167-4889, E-ISSN 1879-2596, Vol. 1793, no 3, p. 546-560Article in journal (Refereed)
    Abstract [en]

    Tumor necrosis factor alpha (TNF) is a cytokine that induces caspase-dependent (apoptotic) and caspase-independent (necrosis-like) cell death in different cells. We used the murine fibrosarcoma cell line model L929 and a stable L929 transfectant over-expressing a mutated dominant-negative form of BNIP3 lacking the C-terminal transmembrane (TM) domain (L929-ΔTM-BNIP3) to test if TNF-induced cell death involved pro-apoptotic Bcl2 protein BNIP3. Treatment of cells with TNF in the absence of actinomycin D caused a rapid fall in the mitochondrial membrane potential (ΔΨm) and a prompt increase in reactive oxygen species (ROS) production, which was significantly less pronounced in L929-ΔTM-BNIP3. TNF did not cause the mitochondrial release of apoptosis inducing factor (AIF) and Endonuclease G (Endo-G) but provoked the release of cytochrome c, Smac/Diablo, and Omi/HtrA2 at similar levels in both L929 and in L929-ΔTM-BNIP3 cells. We observed TNF-associated increase in the expression of BNIP3 in L929 that was mediated by nitric oxide and significantly inhibited by nitric oxide synthase inhibitor N5-(methylamidino)-l-ornithine acetate. In L929, lysosomal swelling and activation were markedly increased as compared to L929-ΔTM-BNIP3 and could be inhibited by treatment with inhibitors to vacuolar H+-ATPase and cathepsins −B/−L. Together, these data indicate that TNF-induced cell death involves BNIP3, ROS production, and activation of the lysosomal death pathway.

  • 36.
    Ghavami, Saeid
    et al.
    Department of Physiology, University of Manitoba, Winnipeg, MB, Canada; National Training Program in Allergy and Asthma, University of Manitoba, Winnipeg, MB, Canada; Biology of Breathing Group, Manitoba Institute of Child Health, Winnipeg, MB, Canada.
    Eshragi, Mehdi
    Department of Biochemistry and Medical Genetics, Manitoba Institute of Cell Biology, CancerCare Manitoba, Winnipeg, Canada.
    Ande, Sudharsana R
    Department of Biochemistry and Medical Genetics, Manitoba Institute of Cell Biology, CancerCare Manitoba, Winnipeg, Canada.
    Chazin, Walter J
    Department of Biochemistry and Chemistry, Center for Structural Biology, Vanderbilt University, Nashville, USA.
    Klonisch, Thomas
    Department of Human Anatomy and Cell Science, University of Manitoba, Winnipeg, Canada.
    Halayko, Andrew J.
    Department of Physiology, University of Manitoba, Winnipeg, MB, Canada; Manitoba Institute of Child Health, Winnipeg, MB, Canada; Department of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada .
    Mcneill, Karol D
    Manitoba Institute of Child Health, University of Manitoba, Winnipeg, Canada.
    Hashemi, Mohammad
    Department of Clinical Biochemistry, Zahedan University of Medical Sciences, Zahedan, Iran.
    Kerkhoff, Claus
    Institute of Immunology, University of Muenster, Roentgenstr. 21, Muenster, Germany.
    Los, Marek Jan
    Interfaculty Institute for Biochemistry, University of Tübingen, Germany.
    S100A8/A9 induces autophagy and apoptosis via ROS-mediated cross-talk between mitochondria and lysosomes that involves BNIP32010In: Cell Research, ISSN 1001-0602, E-ISSN 1748-7838, Vol. 20, no 3, p. 314-331Article in journal (Refereed)
    Abstract [en]

    The complex formed by two members of the S100 calcium-binding protein family, S100A8/A9, exerts apoptosis-inducing activity in various cells of different origins. Here, we present evidence that the underlying molecular mechanisms involve both programmed cell death I (PCD I, apoptosis) and PCD II (autophagy)-like death. Treatment of cells with S100A8/A9 caused the increase of Beclin-1 expression as well as Atg12-Atg5 formation. S100A8/A9-induced cell death was partially inhibited by the specific PI3-kinase class III inhibitor, 3-methyladenine (3-MA), and by the vacuole H+-ATPase inhibitor, bafilomycin-A1 (Baf-A1). S100A8/A9 provoked the translocation of BNIP3, a BH3 only pro-apoptotic Bcl2 family member, to mitochondria. Consistent with this finding, ΔTM-BNIP3 overexpression partially inhibited S100A8/A9-induced cell death, decreased reactive oxygen species (ROS) generation, and partially protected against the decrease in mitochondrial transmembrane potential in S100A8/A9-treated cells. In addition, either ΔTM-BNIP3 overexpression or N-acetyl-L-cysteine co-treatment decreased lysosomal activation in cells treated with S100A8/A9. Our data indicate that S100A8/A9-promoted cell death occurs through the cross-talk of mitochondria and lysosomes via ROS and the process involves BNIP3.

  • 37.
    Ghavami, Saeid
    et al.
    Department of Biochemistry and Medical Genetics, Manitoba Institute of Cell Biology, Cancer Care Manitoba, Winnipeg, Manitoba, Canada.
    Hashemi, M.
    Manitoba Institute of Cell Biology, CancerCare Manitoba, Winnipeg, Canada.
    Kadkhoda, K.
    Manitoba Institute of Cell Biology, CancerCare Manitoba, Winnipeg, Canada.
    Alavian, S. M.
    Manitoba Institute of Cell Biology, CancerCare Manitoba, Winnipeg, Canada.
    Bay, G. H.
    Manitoba Institute of Cell Biology, CancerCare Manitoba, Winnipeg, Canada.
    Los, Marek Jan
    Manitoba Institute of Cell Biology, Cancer Care Manitoba; Manitoba Institute of Child Health; Department of Biochemistry and Medical Genetics; Department of Human Anatomy and Cell Science, University Manitoba, Winnipeg, Canada, .
    Apoptosis in liver diseases - detection and therapeutic applications2005In: Medical Science Monitor, ISSN 1234-1010, E-ISSN 1643-3750, Vol. 11, no 11, p. RA337-RA345Article, review/survey (Refereed)
    Abstract [en]

    The liver is continuously exposed to a large antigenic load that includes pathogens, toxins, tumor cells and dietary antigens. Amongst the hepatitis viruses, only hepatitis B virus (HBV) and hepatitis C virus (HCV) cause chronic hepatitis, which can progress to cirrhosis and hepatocellular carcinoma. Of the different antiviral defense systems employed by the tissue, apoptosis significantly contributes to the prevention of viral replication, dissemination, and persistence. Loss of tolerance to the liver autoantigens may result in autoimmune hepatitis (AIH). This review outlines the recent findings that highlight the role and mechanisms of apoptotic processes in the course of liver diseases. Among factors that contribute to liver pathology, we discuss the role of tumor necrosis factor (TNF)-alpha, HBx, ds-PKR, TRAIL, FasL, and IL-1 alpha. Since TNF and FasL-induced hepatocyte apoptosis is implicated in a wide range of liver diseases, including viral hepatitis, alcoholic hepatitis, ischemia/reperfusion liver injury, and fulminant hepatic failure, these items will be discussed in greater detail in this review. We also highlight some recent discoveries that pave the way for the development of new therapeutic strategies by protecting hepatocytes (for example by employing Bcl-2, Bcl-X-L or A1/Bfl-1, IAPs, or synthetic caspase inhibitors), or by the induction of apoptosis in stellate cells. The assessment of the severity of liver disease, as well as monitoring of patients with chronic liver disease, remains a major challenge in clinical hepatology practice. Therefore, a separate chapter is devoted to a novel cytochrome c - based method useful for the diagnosis and monitoring of fulminant hepatitis.

  • 38.
    Ghavami, Saeid
    et al.
    Tarbiat Modarres University, Tehran, Iran.
    Kerkhoff, C.
    Institute of Experimental Dermatology, Münster, Germany .
    Los, Marek Jan
    Institute of Experimental Dermatology, Münster, Germany .
    Hashemi, M.
    Tarbiat Modarres University, Tehran, Iran.
    Sorg, C.
    Institute of Experimental Dermatology, Münster, Germany .
    Karami-Tehrani, F.
    Tarbiat Modarres University, Tehran, Iran.
    Mechanism of apoptosis induced by S100A8/A9 in colon cancer cell lines: the role of ROS and the effect of metal ions2004In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 76, no 1, p. 169-175Article in journal (Refereed)
    Abstract [en]

    The protein complex S100A8/A9, abundant in the cytosol of neutrophils, is secreted from the cells upon cellular activation and induces apoptosis in tumor cell lines and normal fibroblasts in a zinc-reversible manner. In the present study, we present evidence that the S100A8/A9 also exerts its apoptotic effect by a zinc-independent mechanism. Treatment of the colon carcinoma cells with different concentrations of human SI00A8/A9 or the metal ion chelator diethylenetriaminepentacetic acid (DTPA) resulted in a significant increase of cell death. Annexin V/phosphatidylinositol and Hoechst 33258 staining revealed that cell death was mainly of the apoptotic type. A significant increase in the activity of caspase-3 and -9 was observed in both cell lines after treatment. Caspase-8 activation was negligible in both cell lines. The cytotoxicity/apoptotic effect of human SI00A8/A9 and DTPA was inhibited significantly 2 2 (P<0.05) by Zn+2 and Cu+2, more effectively than by Ca2+ and Mg2+. The antioxidant N-acetyl-L-cysteine inhibited the cytotoxicity/apoptotic effect of SI00A8/A9 and DTPA. However, as a result of the different time-courses of both agents and that the S100A8/A9-induced apoptosis was not completely reversed, we conclude that S100A8/A9 exerts its apoptotic effect on two colon carcinoma cell lines through a dual mechanism: one via zinc exclusion from the target cells and the other through a yet-undefined mechanism, probably relaying on the cell-surface receptor(s).

  • 39.
    Ghavami, Saeid
    et al.
    Department of Biochemistry and Medical Genetics, Manitoba Institute of Cell Biology, Cancer Care Manitoba, Winnipeg, Manitoba, Canada.
    Kerkhoff, Claus
    Institute of Experimental Dermatology, Münster, Germany.
    Chazin, Walter J.
    Department of Biochemistry Vanderbilt University, Nashville, USA; Department of Chemistry, Vanderbilt University, Nashville, USA; Center for Structural Biology, Vanderbilt University, Nashville, TN 37232-8725, USA.
    Kadhoka, Kamran
    Manitoba Institute of Cell Biology, Canada; Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Canada.
    Xiao, Wenyan
    Manitoba Institute of Cell Biology, Canada.
    Zusea, Anne
    Manitoba Institute of Cell Biology, Canada; Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Canada.
    Hashemi, Mohammad
    Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Science, Zahedan, Iran.
    Eshraghi, Mehdi
    Manitoba Institute of Cell Biology, Canada b Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Canada.
    Schulze-Osthoff, Klaus
    Institute of Molecular Medicine, University of Düsseldorf, Düsseldorf, Germany .
    Klonisch, Thomas
    Department of Human Anatomy and Cell Sciences, and Manitoba Institute of Child Health, Winnipeg, Canada.
    Los, Marek Jan
    Manitoba Institute of Cell Biology, Canada; Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Canada; BioApplications Enterprises, Winnipeg, MB, Canada.
    S100A8/9 induces cell death via a novel, RAGE-independent pathway that involves selective release of Smac/DIABLO and Omi/HtrA22008In: Biochimica et Biophysica Acta. Molecular Cell Research, ISSN 0167-4889, E-ISSN 1879-2596, Vol. 1783, no 2, p. 297-311Article in journal (Refereed)
    Abstract [en]

    A complex of two S100 EF-hand calcium-binding proteins S100A8/A9 induces apoptosis in various cells, especially tumor cells. Using several cell lines, we have shown that S100A8/A9-induced cell death is not mediated by the receptor for advanced glycation endproducts (RAGE), a receptor previously demonstrated to engage S100 proteins. Investigation of cell lines either deficient in, or over-expressing components of the death signaling machinery provided insight into the S100A8/A9-mediated cell death pathway. Treatment of cells with S100A8/A9 caused a rapid decrease in the mitochondrial membrane potential (ΔΨm) and activated Bak, but did not cause release of apoptosis-inducing factor (AIF), endonuclease G (Endo G) or cytochrome c. However, both Smac/DIABLO and Omi/HtrA2 were selectively released into the cytoplasm concomitantly with a decrease in Drp1 expression, which inhibits mitochondrial fission machinery. S100A8/A9 treatment also resulted in decreased expression of the anti-apoptotic proteins Bcl2 and Bcl-XL, whereas expression of the pro-apoptotic proteins Bax, Bad and BNIP3 was not altered. Over-expression of Bcl2 partially reversed the cytotoxicity of S100A8/A9. Together, these data indicate that S100A8/A9-induced cell death involves Bak, selective release of Smac/DIABLO and Omi/HtrA2 from mitochondria, and modulation of the balance between pro- and anti-apoptotic proteins.

  • 40.
    Ghavami, Saeid
    et al.
    Department of Physiology, University of Manitoba, Winnipeg, MB, Canada; National Training Program in Allergy and Asthma, University of Manitoba, Winnipeg, MB, Canada; Biology of Breathing Group, Manitoba Institute of Child Health, Winnipeg, MB, Canada.
    Mutawe, Mark M.
    Department of Physiology, University of Manitoba, Winnipeg, MB, Canada; Biology of Breathing Group, Manitoba Institute of Child Health, Winnipeg, MB, Canada.
    Hauff, Kristin
    Department of Pharmacology, University of Manitoba, Winnipeg, MB, Canada.
    Stelmack, Gerald L.
    Department of Physiology, University of Manitoba, Winnipeg, MB, Canada; Biology of Breathing Group, Manitoba Institute of Child Health, Winnipeg, MB, Canada.
    Schaafsma, Dedmer
    Department of Physiology, University of Manitoba, Winnipeg, MB, Canada; Biology of Breathing Group, Manitoba Institute of Child Health, Winnipeg, MB, Canada.
    Sharma, Pawan
    Department of Physiology, University of Manitoba, Winnipeg, MB, Canada; National Training Program in Allergy and Asthma, University of Manitoba, Winnipeg, MB, Canada; Biology of Breathing Group, Manitoba Institute of Child Health, Winnipeg, MB, Canada.
    McNeill, Karol D.
    Department of Physiology, University of Manitoba, Winnipeg, MB, Canada; Biology of Breathing Group, Manitoba Institute of Child Health, Winnipeg, MB, Canada.
    Hynes, Tyler S.
    Department of Physiology, University of Manitoba, Winnipeg, MB, Canada; National Training Program in Allergy and Asthma, University of Manitoba, Winnipeg, MB, Canada; Biology of Breathing Group, Manitoba Institute of Child Health, Winnipeg, MB, Canada.
    Kung, Sam K.
    Department of Immunology, University of Manitoba, Winnipeg, MB, Canada.
    Unruh, Helmut
    Department of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada.
    Klonisch, Thomas
    Department of Human Anatomy and Cell Science, University of Manitoba, Winnipeg, MB, Canada.
    Hatch, Grant M.
    Department of Pharmacology, University of Manitoba, Winnipeg, MB, Canada.
    Los, Marek Jan
    Interfaculty Institute for Biochemistry, University of Tübingen, Germany.
    Halayko, Andrew J.
    Department of Physiology, University of Manitoba, Winnipeg, MB, Canada; National Training Program in Allergy and Asthma, University of Manitoba, Winnipeg, MB, Canada; Biology of Breathing Group, Manitoba Institute of Child Health, Winnipeg, MB, Canada; Department of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada .
    Statin-triggered cell death in primary human lung mesenchyrnal cells involves p53-PUMA and release of Smac and Omi but not cytochrome c2010In: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 1803, no 4, p. 452-467Article in journal (Refereed)
    Abstract [en]

    Statins inhibit 3-hydroxy-3-methyl-glutarylcoenzyme CoA (HMG-CoA) reductase, the proximal enzyme forcholesterol biosynthesis. They exhibit pleiotropic effects and are linked to health benefits for diseasesincluding cancer and lung disease. Understanding their mechanism of action could point to new therapies,thus we investigated the response of primary cultured human airway mesenchymal cells, which play aneffector role in asthma and chronic obstructive lung disease (COPD), to simvastatin exposure. Simvastatininduced apoptosis involving caspase-9, -3 and -7, but not caspase-8 in airway smooth muscle cells andfibroblasts. HMG-CoA inhibition did not alter cellular cholesterol content but did abrogate de novocholesterol synthesis. Pro-apoptotic effects were prevented by exogenous mevalonate, geranylgeranylpyrophosphate and farnesyl pyrophosphate, downstream products of HMG-CoA. Simvastatin increasedexpression of Bax, oligomerization of Bax and Bak, and expression of BH3-only p53-dependent genes, PUMAand NOXA. Inhibition of p53 and silencing of p53 unregulated modulator of apoptosis (PUMA) expressionpartly counteracted simvastatin-induced cell death, suggesting a role for p53-independent mechanisms.Simvastatin did not induce mitochondrial release of cytochrome c, but did promote release of inhibitor ofapoptosis (IAP) proteins, Smac and Omi. Simvastatin also inhibited mitochondrial fission with the loss ofmitochondrial Drp1, an essential component of mitochondrial fission machinery. Thus, simvastatin activatesnovel apoptosis pathways in lung mesenchymal cells involving p53, IAP inhibitor release, and disruption ofmitochondrial fission.

  • 41.
    Ghavami, Saeid
    et al.
    University of Manitoba.
    Mutawe, Mark M
    University of Manitoba.
    Sharma, Pawan
    University of Manitoba.
    Yeganeh, Behzad
    University of Manitoba.
    McNeill, Karol D
    University of Manitoba.
    Klonisch, Thomas
    University of Manitoba.
    Unruh, Helmut
    University of Manitoba.
    Kashani, Hessam H
    University of Manitoba.
    Schaafsma, Dedmer
    University of Manitoba.
    Jan Los, Marek
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Halayko, Andrew J
    University of Manitoba.
    Mevalonate Cascade Regulation of Airway Mesenchymal Cell Autophagy and Apoptosis: A Dual Role for p532011In: PLOS ONE, ISSN 1932-6203, Vol. 6, no 1, p. 0016523-Article in journal (Refereed)
    Abstract [en]

    Statins inhibit the proximal steps of cholesterol biosynthesis, and are linked to health benefits in various conditions, including cancer and lung disease. We have previously investigated apoptotic pathways triggered by statins in airway mesenchymal cells, and identified reduced prenylation of small GTPases as a primary effector mechanism leading to p53-mediated cell death. Here, we extend our studies of statin-induced cell death by assessing endpoints of both apoptosis and autophagy, and investigating their interplay and coincident regulation. Using primary cultured human airway smooth muscle (HASM) and human airway fibroblasts (HAF), autophagy, and autophagosome formation and flux were assessed by transmission electron microscopy, cytochemistry (lysosome number and co-localization with LC3) and immunoblotting (LC3 lipidation and Atg 12-5 complex formation). Chemical inhibition of autophagy increased simvastatin-induced caspase activation and cell death. Similarly, Atg5 silencing with shRNA, thus preventing Atg5-12 complex formation, increased proapoptotic effects of simvastatin. Simvastatin concomitantly increased p53-dependent expression of p53 up-regulated modulator of apoptosis (PUMA), NOXA, and damage-regulated autophagy modulator (DRAM). Notably both mevalonate cascade inhibition-induced autophagy and apoptosis were p53 dependent: simvastatin increased nuclear p53 accumulation, and both cyclic pifithrin-alpha and p53 shRNAi partially inhibited NOXA, PUMA expression and caspase-3/7 cleavage (apoptosis) and DRAM expression, Atg5-12 complex formation, LC3 lipidation, and autophagosome formation (autophagy). Furthermore, the autophagy response is induced rapidly, significantly delaying apoptosis, suggesting the existence of a temporally coordinated p53 regulation network. These findings are relevant for the development of statin-based therapeutic approaches in obstructive airway disease.

  • 42.
    Ghavami, Saeid
    et al.
    Department of Biochemistry and Medical Genetics, Manitoba Institute of Cell Biology, Cancer Care Manitoba, Winnipeg, Manitoba, Canada.
    Rashedi, Iran
    Manitoba Institute of Cell Biology and Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada.
    Dattilo, Brian M.
    Departments of Biochemistry, Physics and Chemistry, Center for Structural Biology, Vanderbilt University, Nashville, Tennessee, USA;.
    Eshraghi, Mehdi
    Manitoba Institute of Cell Biology and Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada.
    Chazin, Walter J.
    Departments of Biochemistry, Physics and Chemistry, Center for Structural Biology, Vanderbilt University, Nashville, Tennessee, USA;.
    HashemI, Mohammad
    Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Science, Zahedan, Iran.
    Wesselborg, Sebastian
    Department of Internal Medicine I, University of Tübingen, Tübingen, Germany; and BioApplications Enterprises, Winnipeg, Manitoba, Canada.
    Kerkhoff, Claus
    Institute of Experimental Dermatology, Münster, Germany.
    Los, Marek Jan
    BioApplications Enterprises, Winnipeg, MB, Canada.
    S100A8/A9 at low concentration promotes tumor cell growth via RAGE ligation and MAP kinase-dependent pathway2008In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 83, no 6, p. 1484-1492Article in journal (Refereed)
    Abstract [en]

    The complex formed by two members of the S100 calcium-binding protein family, S100A8/A9, exerts apoptosis-inducing activity against various cells, especially tumor cells. Here, we present evidence that S100A8/A9 also has cell growth-promoting activity at low concentrations. Receptor of advanced glycation end product (RAGE) gene silencing and cotreatment with a RAGE-specific blocking antibody revealed that this activity was mediated via RAGE ligation. To investigate the signaling pathways, MAPK phosphorylation and NF-κB activation were characterized in S100A8/A9-treated cells. S100A8/A9 caused a significant increase in p38 MAPK and p44/42 kinase phosphorylation, and the status of stress-activated protein kinase/JNK phosphorylation remained unchanged. Treatment of cells with S100A8/A9 also enhanced NF-κB activation. RAGE small interfering RNA pretreatment abrogated the S100A8/A9-induced NF-κB activation. Our data indicate that S100A8/A9-promoted cell growth occurs through RAGE signaling and activation of NF-κB.

  • 43.
    Ghavami, Saeid
    et al.
    University of Manitoba, Canada.
    Sharma, Pawan
    University of Manitoba, Canada.
    Yeganeh, Behzad
    University of Manitoba, Canada.
    Ojo, Oluwaseun O.
    University of Manitoba, Canada.
    Jha, Aruni
    University of Manitoba, Canada.
    Mutawe, Mark M.
    University of Manitoba, Canada.
    Kashani, Hessam H.
    University of Manitoba, Canada.
    Los, Marek Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Klonisch, Thomas
    University of Manitoba, Canada .
    Unruh, Helmut
    University of Manitoba, Canada .
    Halayko, Andrew J.
    University of Manitoba, Canada.
    Airway mesenchymal cell death by mevalonate cascade inhibition: integration of autophagy, unfolded protein response and apoptosis focusing on Bcl2 family proteins2014In: Biochimica et Biophysica Acta. Molecular Cell Research, ISSN 0167-4889, E-ISSN 1879-2596, Vol. 1843, no 7, p. 1259-1271Article in journal (Refereed)
    Abstract [en]

    HMG-CoA reductase, the proximal rate-limiting enzyme in the mevalonate pathway, is inhibited by statins. Beyond their cholesterol lowering impact, statins have pleiotropic effects and their use is linked to improved lung health. We have shown that mevalonate cascade inhibition induces apoptosis and autophagy in cultured human airway mesenchymal cells. Here, we show that simvastatin also induces endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in these cells. We tested whether coordination of ER stress, autophagy and apoptosis determines survival or demise of human lung mesenchymal cells exposed to statin. We observed that simvastatin exposure activates UPR (activated transcription factor 4, activated transcription factor 6 and IRE1 alpha) and caspase-4 in primary human airway fibroblasts and smooth muscle cells. Exogenous mevalonate inhibited apoptosis, autophagy and UPR, but exogenous cholesterol was without impact, indicating that sterol intermediates are involved with mechanisms mediating statin effects. Caspase-4 inhibition decreased simvastatin-induced apoptosis, whereas inhibition of autophagy by ATG7 or ATG3 knockdown significantly increased cell death. In BAX(-/-)/BAIC(-/) murine embryonic fibroblasts, simvastatin-triggered apoptotic and UPR events were abrogated, but autophagy flux was increased leading to cell death via necrosis. Our data indicate that mevalonate cascade inhibition, likely associated with depletion of sterol intermediates, can lead to cell death via coordinated apoptosis, autophagy, and ER stress. The interplay between these pathways appears to be principally regulated by autophagy and Bcl-2-family pro-apoptotic proteins. These findings uncover multiple mechanisms of action of statins that could contribute to refining the use of such agent in treatment of lung disease.

  • 44.
    Ghavami, Saeid
    et al.
    University of Manitoba.
    Shojaei, Shahla
    Shiraz University of Medical Sciences.
    Yeganeh, Behzad
    University of Manitoba.
    Ande, Sudharsana R.
    University of Manitoba.
    Jangamreddy, Jaganmohan R.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Mehrpour, Maryam
    Paris Descartes University Medical School.
    Christoffersson, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Chaabane, Wiem
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Moghadam, Adel Rezaei
    Islamic Azad University.
    Kashani, Hessam H.
    University of Manitoba.
    Hashemi, Mohammad
    Zahedan University of Medical Sciences.
    Owji, Ali A.
    Shiraz University of Medical Sciences.
    Łos, Marek J
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Autophagy and Apoptosis Dysfunction in Neurodegenerative Disorders2014In: Progress in Neurobiology, ISSN 0301-0082, E-ISSN 1873-5118, Vol. 112, p. 24-49Article, review/survey (Refereed)
    Abstract [en]

    Autophagy and apoptosis are basic physiologic processes contributing to the maintenance of cellular homeostasis. Autophagy encompasses pathways that target long-lived cytosolic proteins and damaged organelles. It involves a sequential set of events including double membrane formation, elongation, vesicle maturation and finally delivery of the targeted materials to the lysosome. Apoptotic cell death is best described through its morphology. It is characterized by cell rounding, membrane blebbing, cytoskeletal collapse, cytoplasmic condensation, and fragmentation, nuclear pyknosis, chromatin condensation/fragmentation, and formation of membrane-enveloped apoptotic bodies, that are rapidly phagocytosed by macrophages or neighboring cells. Neurodegenerative disorders are becoming increasingly prevalent, especially in the Western societies, with larger percentage of members living to an older age. They have to be seen not only as a health problem, but since they are care-intensive, they also carry a significant economic burden. Deregulation of autophagy plays a pivotal role in the etiology and/or progress of many of these diseases. Herein, we briefly review the latest findings that indicate the involvement of autophagy in neurodegenerative diseases. We provide a brief introduction to autophagy and apoptosis pathways focusing on the role of mitochondria and lysosomes. We then briefly highlight pathophysiology of common neurodegenerative disorders like Alzheimer's diseases, Parkinson's disease, Huntington's disease and Amyotrophic lateral sclerosis. Then, we describe functions of autophagy and apoptosis in brain homeostasis, especially in the context of the aforementioned disorders. Finally, we discuss different ways that autophagy and apoptosis modulation may be employed for therapeutic intervention during the maintenance of neurodegenerative disorders.

  • 45.
    Glogowska, Aleksandra
    et al.
    Department of Human Anatomy and Cell Science, Winnipeg, Manitoba, Canada.
    Pyka, Janette
    Clinics of Surgery, Medical Faculty, Martin Luther University Halle-Wittenberg, Halle, Germany.
    Kehlen, Astrid
    Probiodrug AG, Weinbergweg, Halle, Germany.
    Los, Marek Jan
    BioApplications Enterprises, Winnipeg, MB, Canada.
    Perumal, Paul
    Department of Human Anatomy and Cell Science, Winnipeg, Manitoba, Canada.
    Weber, Ekkehard
    Cheng, Sheue-yann
    Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, USA.
    Hoang-Vu, Cuong
    Clinics of Surgery, Medical Faculty, Martin Luther University Halle-Wittenberg, Halle, Germany.
    Klonisch, Thomas
    Department of Human Anatomy and Cell Science; Department of Medical Microbiology and Infectious Diseases, Faculty of Medicine, University of Manitoba, Winnipeg, Canada.
    The cytoplasmic domain of proEGF negatively regulates motility and elastinolytic activity in thyroid carcinoma cells2008In: Neoplasia, ISSN 1522-8002, E-ISSN 1476-5586, Vol. 10, no 10, p. 1120-1130Article in journal (Refereed)
    Abstract [en]

    The intracellular domains of the membrane-anchoring regions of some precursors of epidermal growth factor (EGF) family members have intrinsic biologic activities. We have determined the role of the human proEGF cytoplasmic domain (proEGFcyt) as part of the proEGF transmembrane-anchored region (proEGFctF) in the regulation of motility and elastinolytic invasion in human thyroid cancer cells. We found proEGFctF to act as a negative regulator of motility and elastin matrix penetration and the presence of proEGFcyt or proEGF22.23 resulted in a similar reduction in motility and elastinolytic migration. This activity was counteracted by EGF-induced activation of EGF receptor signaling. Decreased elastinolytic migratory activity in the presence of proEGFctF and proEGFcyt/proEGF22.23 coincided with decreased secretion of elastinolytic procathepsin L. The presence of proEGFctF and proEGFcyt/proEGF22.23 coincided with the specific transcriptional up-regulation of t-SNARE member SNAP25. Treatment with siRNA-SNAP25 resulted in motility and elastin migration being restored to normal levels. Epidermal growth factor treatment down-regulated SNAP25 protein by activating EGF receptor-mediated proteasomal degradation of SNAP25. These data provide first evidence for an important function of the cytoplasmic domain of the human proEGF transmembrane region as a novel suppressor of motility and cathepsin L-mediated elastinolytic invasion in human thyroid carcinoma cells and suggest important clinical implications for EGF-expressing tumors.

  • 46.
    Grage-Griebenow, E.
    et al.
    Forschungszentrum Borstel, Department of Immunology and Cell Biology, Borstel, Germany.
    Baran, J.
    Jagiellonian University, Institute of Molecular Biology, Cracow, Poland.
    Loppnow, H.
    Forschungszentrum Borstel, Department of Immunology and Cell Biology, Borstel, Germany.
    Los, Marek Jan
    Deutsches Krebsforschungs-zentrum, Heidelberg, Germany.
    Ernst, M.
    Forschungszentrum Borstel, Department of Immunology and Cell Biology, Borstel, Germany.
    Flad, H. D.
    Forschungszentrum Borstel, Department of Immunology and Cell Biology, Borstel, Germany.
    Pryjma, J.
    Jagiellonian University, Institute of Molecular Biology, Cracow, Poland.
    An Fcγ receptor I (CD64)-negative subpopulation of human peripheral blood monocytes is resistant to killing by antigen-activated CD4-positive cytotoxic T cells1997In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 27, no 9, p. 2358-2365Article in journal (Refereed)
    Abstract [en]

    It has been demonstrated that in monocyte/T cell co-cultures activated with recall antigens, cytotoxic T cells were generated which are able to reduce the number of antigen-presenting monocytes. In previous studies we could show that a minor subset of monocytes, the Fc gamma receptor I-negative (CD64(-)) monocytes, exhibits significantly higher antigen-presenting capacity than the main population of monocytes (> 90%) which are Fc gamma receptor I-positive (CD64(+)). Therefore, we addressed the question whether they are also differentially susceptible to T cell-mediated killing. In the present study we demonstrate that the CD64(-) monocyte subset is more resistant to killing by antigen-activated T cells than CD64(+) monocytes, as indicated by a higher viability and recovery of CD64(-) monocytes. This mechanism involves CD95 (Fas) antigen, since monocyte death in co-cultures with antigen-activated T cells could be partially reduced by blocking anti-Fas monoclonal antibodies (mAb). In agreement with this finding, although CD95 antigen was expressed on CD64(+) and CD64(-) monocytes at comparable levels, killing of CD64(-) monocytes by activating anti-Fas mAb was lower than of CD64(+) monocytes.

  • 47.
    Grote, Jens
    et al.
    Institute of Experimental Dermatology, University of Muenster, Germany; Interdisciplinary Center for Clinical Research, Core Group Integrated Functional Genomics, Medical Faculty, University of Muenster, Muenster, Germany .
    Koenig, Simone
    Interdisciplinary Center for Clinical Research, Core Group Integrated Functional Genomics, Medical Faculty, University of Muenster, Muenster, Germany .
    Ackermann, Doreen
    Interdisciplinary Center for Clinical Research, Core Group Integrated Functional Genomics, Medical Faculty, University of Muenster, Muenster, Germany .
    Sopalla, Claudia
    Institute of Experimental Dermatology, University of Muenster, Germany; Interdisciplinary Center for Clinical Research (IZKF) Münster, Germany .
    Benedyk, Malgorzata
    Institute of Experimental Dermatology, University of Muenster, Germany .
    Los, Marek Jan
    Manitoba Institute of Cell Biology, Cancer Care Manitoba; Manitoba Institute of Child Health; Department of Biochemistry and Medical Genetics; Department of Human Anatomy and Cell Science, University Manitoba, Winnipeg, Canada, .
    Kerkhoff, Claus
    Interdisciplinary Center for Clinical Research (IZKF) Münster, Germany; Institute of Experimental Dermatology, University of Muenster, Germany .
    Identification of poly(ADP-ribose) polymerase-1 and Ku70/Ku80 as transcriptional regulators of S100A9 gene expression2006In: BMC Molecular Biology, ISSN 1471-2199, E-ISSN 1471-2199, Vol. 7Article in journal (Refereed)
    Abstract [en]

    Background: S100 proteins, a multigenic family of non-ubiquitous cytoplasmic Ca2+-binding proteins, have been linked to human pathologies in recent years. Dysregulated expression of S100 proteins, including S100A9, has been reported in the epidermis as a response to stress and in association with neoplastic disorders. Recently, we characterized a regulatory element within the S100A9 promotor, referred to as MRE that drives the S100A9 gene expression in a cell type-specific, activation- and differentiation-dependent manner (Kerkhoff et al. ( 2002) J. Biol. Chem. 277, 41879-41887). Results: In the present study, we investigated transcription factors that bind to MRE. Using the MRE motif for a pull-down assay, poly(ADP-ribose) polymerase-I (PARP-I) and the heterodimeric complex Ku70/Ku80 were identified by mass spectrometry and confirmed by chromatin immunoprecipitation. Furthermore, TPA-induced S100A9 gene expression in HaCaT keratinocytes was blocked after the pharmacologic inhibition of PARP-l with 1,5- isoquinolinediol (DiQ). Conclusion: The candidates, poly(ADP-ribose) polymerase-l (PARP-l) and the heterodimeric complex Ku70/ Ku80, are known to participate in inflammatory disorders as well as tumorgenesis. The latter may indicate a possible link between S100 and inflammation-associated cancer.

  • 48.
    Gurevich-Panigrahi, Tatiana
    et al.
    BioApplication Enterprises, Winnipeg, Canada.
    Wiechec, Emilia
    Manitoba Institute of Cell Biology, CancerCare Manitoba; Department of Human Genetics, University of Aarhus, Aarhus, Denmark.
    Panigrahi, Soumya
    Department of Immunology, Lerner Research Institute, Cleveland, USA.
    Los, Marek Jan
    Interfaculty Institute for Biochemistry, University of Tübingen, Germany; BioApplications Enterprises, Winnipeg, MB, Canada.
    Obesity: Pathophysiology and Clinical2009In: Current Medicinal Chemistry, ISSN 0929-8673, E-ISSN 1875-533X, Vol. 16, no 4, p. 506-521Article in journal (Refereed)
    Abstract [en]

    Obesity is an increasingly serious socioeconomic and clinical problem. Between 1/4 - 1/3 of population in the developed countries can be classified as obese. Four major etiological factors for development of obesity are genetic determinants, environmental factors, food intake and exercise. Obesity increases the risk of the development of various pathologic conditions including: insulin-resistant diabetes mellitus, cardiovascular disease, non-alcoholic fatty liver disease, endocrine problems, and certain forms of cancer. Thus, obesity is a negative determinant for longevity. In this review we provide broad overview of pathophysiology of obesity. We also discuss various available, and experimental therapeutic methods. We highlight functions of adipocytes including fat storing capacity and secretory activity resulting in numerous endocrine effects like leptin, IL-6, adiponectin, and resistin. The anti-obesity drugs are classified according to their primary action on energy balance. Major classes of these drugs are: appetite suppressants, inhibitors of fat absorption (i.e. orlistat), stimulators of thermogenesis and stimulators of fat mobilization. The appetite suppressants are further divided into noradrenergic agents, (i.e. phentermine, phendimetrazine, benzphetamine, diethylpropion), serotoninergic agents (i.e. dexfenfluramine), and mixed noradrenergic-serotoninergic agents (i.e. sibutramine). Thus, we highlight recent advances in the understanding of the central neural control of energy balance, current treatment strategies for obesity and the most promising targets for the development of novel anti-obesity drugs.

  • 49.
    Gökay, O.
    et al.
    Institute of Organic Chemistry, University of Tübingen, Germany.
    Kühner, D.
    Institute of Microbiology and Infectious Diseases, University of Tübingen, Germany.
    Los, Marek Jan
    Interfaculty Institute for Biochemistry, University of Tübingen, Germany.
    Götz, F.
    Institute of Microbiology and Infectious Diseases, University of Tübingen, Germany.
    Bertsche, U.
    Institute of Microbiology and Infectious Diseases, University of Tübingen, Gemany.
    Albert, K.
    Institute of Organic Chemistry, University of Tübingen, Germany.
    An efficient approach for the isolation, identification and evaluation of antimicrobial plant components on an analytical scale, demonstrated by the example of Radix imperatoriae2010In: Analytical and Bioanalytical Chemistry, ISSN 1618-2642, E-ISSN 1618-2650, Vol. 398, no 5, p. 2039-2047Article in journal (Refereed)
    Abstract [en]

    Using Radix imperatoriae (the root of masterwort) as an example, we describe an efficient approach for the isolation, identification and evaluation of bioactive plant components on an analytical scale. The extraction of Radix imperatoriae with ethyl acetate was enhanced by the application of ultrasound oscillations. This rhizome extract was applied to three pathogenic bacteria ( Bacillus cereus, Escherichia coli, and Staphylococcus aureus) to determine its antimicrobial activity. Disk diffusion was utilized to determine susceptibility. The extract components were separated using a series of chromatography approaches (semi-preparative RP-HPLC, or RP-HPLC on an analytical scale), followed by testing. All fractions were analyzed by LC-UV-ESI-MS and 600 MHz microcoil H NMR spectroscopy. Among other findings, in the fraction with the highest antibacterial activity we were able to identify oxypeucedanin and oxypeucedanin hydrate. Subsequent analysis revealed that only oxypeucedanin hydrate had antibacterial activity, whereas oxypeucedanin itself was inactive at the concentrations applied. Furthermore, oxypeucedanin hydrate appears to be largely, or exclusively, a by-product of sample preparation, since it is either not synthesized by the plant as a second metabolite or is produced by it in only very small quantities.

  • 50.
    Hashemi, M.
    et al.
    Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran.
    Karami-Tehrani, F.
    Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modarres University, Tehran, Iran.
    Ghavami, Saeid
    Department of Biochemistry and Medical Genetics, Manitoba Institute of Cell Biology, Cancer Care Manitoba, Winnipeg, Manitoba, Canada; Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran.
    Maddika, Subbareddy
    Manitoba Institute of Cell Biology, Cancer Care Manitoba; Department of Biochemistry and Medical Genetics,University of Manitoba, Winnipeg, Canada .
    Los, Marek Jan
    Manitoba Institute of Cell Biology, Cancer Care Manitoba; Manitoba Institute of Child Health; Department of Biochemistry and Medical Genetics; Department of Human Anatomy and Cell Science, University Manitoba, Winnipeg, Canada, .
    Adenosine and deoxyadenosine induces apoptosis in oestrogen receptor-positive and -negative human breast cancer cells via the intrinsic pathway2005In: Cell Proliferation, ISSN 0960-7722, E-ISSN 1365-2184, Vol. 38, no 5, p. 269-285Article in journal (Refereed)
    Abstract [en]

    In this study we have examined the cytotoxic effects of different concentrations of adenosine (Ado) and deoxyadenosine (dAdo) on human breast cancer cell lines. Ado and dAdo alone had little effect on cell cytotoxicity. However, in the presence of adenosine deaminase (ADA) inhibitor, EHNA, adenosine and deoxyadenosine led to significant growth inhibition of cells of the lines tested. Ado/EHNA and dAdo/EHNA-induced cell death was significantly inhibited by NBTI, an inhibitor of nucleoside transport, and 5'-amino-5'-deoxyadenosine, an inhibitor of adenosine kinase, but the effects were not affected by 8-phenyltheophylline, a broad inhibitor of adenosine receptors. The Ado/EHNA combination brought about morphological changes consistent with apoptosis. Caspase-9 activation was observed in MCF-7 and MDA-MB468 human breast cancer cell lines on treatment with Ado/EHNA or dAdo/EHNA, but, as expected, caspase-3 activation was only observed in MDA-MB468 cells. The results of the study, thus, suggest that extracellular adenosine and deoxyadenosine induce apoptosis in both oestrogen receptor-positive (MCF-7) and also oestrogen receptor-negative (MDA-MB468) human breast cancer cells by its uptake into the cells and conversion to AMP (dAMP) followed by activation of nucleoside kinase, and finally by the activation of the mitochondrial/intrinsic apoptotic pathway.

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