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  • 51. 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 death2002Ingår i: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 4, nr 3, s. 471-477Artikel i tidskrift (Refereegranskat)
    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.

  • 52.
    Cristobal, Susana
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Tedesco, Sara
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Bayat, Narges
    Stockholm University.
    Danielsson, Gabriela
    Stockholm University.
    Buque, Xavier
    Basque country University, Spain.
    Aspichueta, Patricia
    Basque Country University, Spain.
    Fresnedo, Olatz
    Basque Country University, Spain.
    Proteomic and lipidomic analysis of primary mouse hepatocytes exposed to metal and metal oxide nanoparticles2015Ingår i: Journal of Integrated OMICS, ISSN 2182-0287, Vol. 5, nr 1, s. 44-57Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The global analysis of the cellular lipid and protein content upon exposure to metal and metal oxide nanoparticles (NPs) can provide an overviewof the possible impact of exposure. Proteomic analysis has been applied to understand the nanoimpact however the relevance of the alterationon the lipidic proOle has been underestimated. In our study, primary mouse hepatocytes were treated with ultra-small (US) TiO2-USNPsas well as ZnO-NPs, CuO-NPs and Ag-NPs. e protein extracts were analysed by 2D-DIGE and quantiOed by imaging soPware and the selecteddi9erentially expressed proteins were identiOed by nLC-ESI-MS/MS. In parallel, lipidomic analysis of the samples was performed usingthin layer chromatography (TLC) and analyzed by imaging soPware. Our Ondings show an overall ranking of the nanoimpact at the cellularand molecular level: TiO2-USNPs<ZnO-NPs<Ag-NPs<CuO-NPs. CuO-NPs and Ag-NPs were cytotoxic while ZnO-NPs and CuO-NPs hadoxidative capacity. TiO2-USNPs did not have oxidative capacity and were not cytotoxic. e most common cellular impact of the exposurewas the down-regulation of proteins. e proteins identiOed were involved in urea cycle, lipid metabolism, electron transport chain, metabolismsignaling, cellular structure and we could also identify nuclear proteins. CuO-NPs exposure decreased phosphatidylethanolamine andphosphatidylinositol and caused down-regulation of electron transferring protein subunit beta. Ag-NPs exposure caused increased of totallipids and triacylglycerol and decrease of sphingomyelin. TiO2-USNPs also caused decrease of sphingomyelin as well as up-regulation of ATPsynthase and electron transferring protein alfa. ZnO-NPs a9ected the proteome in a concentration-independent manner with down-regulationof RNA helicase. ZnO-NPs exposure did not a9ect the cellular lipids. To our knowledge this work represents the Orst integrated proteomic andlipidomic approach to study the e9ect of NPs exposure to primary mouse hepatocytes in vitro.

  • 53.
    Csizmok, Veronika
    et al.
    Hospital Sick Children, Canada; University of British Columbia, Canada.
    Montecchio, Meri
    Linköpings universitet, Institutionen för fysik, kemi och biologi. Linköpings universitet, Tekniska fakulteten.
    Lin, Hong
    Hospital Sick Children, Canada.
    Tyers, Mike
    University of Montreal, Canada.
    Sunnerhagen, Maria
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Forman-Kay, Julie D.
    Hospital Sick Children, Canada; University of Toronto, Canada.
    Multivalent Interactions with Fbw7 and Pin1 Facilitate Recognition of c-Jun by the SCFFbw7 Ubiquitin Ligase2018Ingår i: Structure, ISSN 0969-2126, E-ISSN 1878-4186, Vol. 26, nr 1, s. 28-+Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Many regulatory proteins, including the transcription factor c-Jun, are highly enriched in disordered protein regions that govern growth, division, survival, differentiation, and response to signals. The stability of c-Jun is controlled by poorly understood regulatory interactions of its disordered region with both the E3 ubiquitin ligase SCFFbw7 and prolyl cis-trans isomerase Pin1. We use nuclear magnetic resonance and fluorescence studies of c-Jun to demonstrate that multisite c-Jun phosphorylation is required for high-affinity interaction with Fbw7. We show that the Pin1 WW and PPIase domains interact in a dynamic complex with multiply phosphorylated c-Jun. Importantly, Pin1 isomerizes a pSer-Pro peptide bond at the c-Jun N terminus that affects binding to Fbw7 and thus modulates the ubiquitin-mediated degradation of c-Jun. Our findings support the general principle that multiple weak binding motifs within disordered regions can synergize to yield high-affinity interactions and provide rapidly evolvable means to build and fine-tune regulatory events.

  • 54.
    de Souza Marinho, Thatiany
    et al.
    University of Estado Rio De Janeiro, Brazil.
    Kawasaki, Adriana
    University of Estado Rio De Janeiro, Brazil.
    Bryntesson, Marcus
    Linköpings universitet, Medicinska fakulteten.
    Souza-Mello, Vanessa
    University of Estado Rio De Janeiro, Brazil.
    Barbosa-da-Silva, Sandra
    University of Estado Rio De Janeiro, Brazil.
    Aguila, Marcia B.
    University of Estado Rio De Janeiro, Brazil.
    Mandarim-de-Lacerda, Carlos A.
    University of Estado Rio De Janeiro, Brazil.
    Rosuvastatin limits the activation of hepatic stellate cells in diet-induced obese mice2017Ingår i: Hepatology Research, ISSN 1386-6346, E-ISSN 1872-034X, Vol. 47, nr 9, s. 928-940Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aim The aim of this study was to investigate the effects of rosuvastatin in a model of diet-induced obesity and non-alcoholic fatty liver disease, with attention to the activation of hepatic stellate cells (HSCs). Method Male C57BL/6 mice received a control diet (C; 10% energy as lipids) or a high-fat diet (HF; 50% energy as lipids) for 12 weeks, followed by 7 weeks of treatment. Group CR received control diet + rosuvastatin; group HFR received high-fat diet + rosuvastatin. Results The HF group showed higher insulin, total cholesterol, triacylglycerol, and leptin levels than the C group, all of which were significantly diminished by rosuvastatin in the HFR group. The HF group had greater steatosis and activated HSCs than the C group, whereas rosuvastatin diminished the steatosis (less 21%, P amp;lt; 0.001) and significantly inhibited the activation of the HSCs in the HFR group compared to the HF group. The sterol regulatory element-binding protein-1 and the peroxisome proliferator-activated receptor (PPAR)-gamma protein expressions were increased in HF animals and reduced after treatment in the HFR group. By contrast, low PPAR-alpha and carnitine palmitoyltransferase-1 expressions were found in the HF group, and were restored by rosuvastatin treatment in the HFR group. Conclusion Rosuvastatin mitigated hepatic steatosis by modulating PPAR balance, favoring PPAR-alpha over PPAR-gamma downstream effects. The effects were accompanied by a diminishing of insulin resistance, the anti-inflammatory adipokine profile, and HSC activation, avoiding non-alcoholic fatty liver disease progression and non-alcoholic steatohepatitis onset in this model.

  • 55.
    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 interaction1997Ingår i: Biochemical Society Transactions, ISSN 0300-5127, E-ISSN 1470-8752, Vol. 25, nr 2, s. 405-410Artikel i tidskrift (Refereegranskat)
  • 56.
    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.1996Ingår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 88, nr 10, s. 2641-2641Artikel i tidskrift (Refereegranskat)
  • 57.
    Dominguez-Perez, Dany
    et al.
    Univ Porto, Portugal.
    Campos, Alexandre
    Univ Porto, Portugal.
    Rodriguez, Armando Alexei
    Hanover Med Sch MHH, Germany.
    Turkina, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Ribeiro, Tiago
    Univ Porto, Portugal.
    Osorio, Hugo
    Univ Porto, Portugal.
    Vasconcelos, Vitor
    Univ Porto, Portugal; Univ Porto, Portugal.
    Antunes, Agostinho
    Univ Porto, Portugal.
    Proteomic Analyses of the Unexplored Sea Anemone Bunodactis verrucosa2018Ingår i: Marine Drugs, ISSN 1660-3397, E-ISSN 1660-3397, Vol. 16, nr 2, artikel-id 42Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cnidarian toxic products, particularly peptide toxins, constitute a promising target for biomedicine research. Indeed, cnidarians are considered as the largest phylum of generally toxic animals. However, research on peptides and toxins of sea anemones is still limited. Moreover, most of the toxins from sea anemones have been discovered by classical purification approaches. Recently, high-throughput methodologies have been used for this purpose but in other Phyla. Hence, the present work was focused on the proteomic analyses of whole-body extract from the unexplored sea anemone Bunodactis verrucosa. The proteomic analyses applied were based on two methods: two-dimensional gel electrophoresis combined with MALDI-TOF/TOF and shotgun proteomic approach. In total, 413 proteins were identified, but only eight proteins were identified from gel-based analyses. Such proteins are mainly involved in basal metabolism and biosynthesis of antibiotics as the most relevant pathways. In addition, some putative toxins including metalloproteinases and neurotoxins were also identified. These findings reinforce the significance of the production of antimicrobial compounds and toxins by sea anemones, which play a significant role in defense and feeding. In general, the present study provides the first proteome map of the sea anemone B. verrucosa stablishing a reference for future studies in the discovery of new compounds.

  • 58.
    Dunbring, Daniel
    Linköpings universitet, Institutionen för fysik, kemi och biologi.
    Biophysical characterization of tryptophan mutants in carbonic anhydrase from Neisseria Gonorrhoeae2007Självständigt arbete på avancerad nivå (magisterexamen), 20 poäng / 30 hpStudentuppsats
    Abstract [en]

    In this project the aim has been to study the model protein carbonic anhydrase in Neisseria gonorrhoeae, a bacterium whose carbonic anhydrase has great similarities both structurally and functionally with the human form. By measuring and comparing the wild type of NGCA with mutants lacking one of the four tryptophan residues it can be seen what effect these tryptophans has on stability and activity and then compare with the known data of HCA II to learn more about their differences and similarities. The results from the stability and activity measurements are that the wild type is by far the most stable protein with W141L mutant coming thereafter.

    From Trp-fluorescence and CO2-hydration measurement a clear two-transition steps (N→ I→ U) can be seen. This differs from earlier data where it instead only was a one-transition step for the wild type (N→U). The data is also very reliable and gives in most cases a perfect fit to the line. We also see this two-transition step for the other mutants stable enough, strengthening the theory further.

    One fact that could be drawn from all the measurements is that when an intermediate is formed the ability for the enzyme NGCA to perform it’s catalytically ability is disabled.

    Another thing is that the purification scheme of HCA II is not optimal to be directly applied to NGCA, despite the similarity in secondary and tertiary structure.

  • 59.
    Edqvist, Johan
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    Blomqvist, Kristina
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska högskolan.
    Nieuwland, Jeroen
    Univ South Wales, Wales.
    Salminen, Tiina A.
    Abo Akad Univ, Finland.
    Plant lipid transfer proteins: are we finally closing in on the roles of these enigmatic proteins?2018Ingår i: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 59, nr 8, s. 1374-1382Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    The nonspecific lipid transfer proteins (LTPs) are small compact proteins folded around a tunnel-like hydrophobic cavity, making them suitable for lipid binding and transport. LTPs are encoded by large gene families in all land plants, but they have not been identified in algae or any other organisms. Thus, LTPs are considered key proteins for plant survival on and colonization of land. LTPs are abundantly expressed in most plant tissues, both above and below ground. They are usually localized to extracellular spaces outside the plasma membrane. Although the in vivo functions of LTPs remain unclear, accumulating evidence suggests a role for LTPs in the transfer and deposition of monomers required for assembly of the waterproof lipid barriers, such as cutin and cuticular wax, suberin, and sporopollenin, formed on many plant surfaces. Some LTPs may be involved in other processes, such as signaling during pathogen attacks. Here, we present the current status of LTP research with a focus on the role of these proteins in lipid barrier deposition and cell expansion. We suggest that LTPs facilitate extracellular transfer of barrier materials and adhesion between barriers and extracellular materials. A growing body of research may uncover the true role of LTPs in plants.

  • 60.
    Eliasson, Pernilla
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell hematologi. Linköpings universitet, Hälsouniversitetet.
    Live and Let Die: Critical regulation of survival in normal and malignant hematopoietic stem and progenitor cells2009Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    The hematopoietic stem cell (HSC) is characterized by its ability to self-renew and produce all mature blood cells throughout the life of an organism. This is tightly regulated to maintain a balance between survival, proliferation, and differentiation. The HSCs are located in specialized niches in the bone marrow thought to be low in oxygen, which is suggested to be involved in the regulation of HSC maintenance, proliferation, and migration. However, the importance of hypoxia in the stem cell niche and the molecular mechanisms involved remain fairly undefined. Another important regulator of human HSCs maintenance is the tyrosine kinase receptor FLT3, which triggers survival of HSCs and progenitor cells. Mutations in FLT3 cause constitutively active signaling. This leads to uncontrolled survival and proliferation, which can result in development of acute myeloid leukemia (AML). One of the purposes with this thesis is to investigate how survival, proliferation and self-renewal in normal HSCs are affected by hypoxia. To study this, we used both in vitro and in vivo models with isolated Lineage-Sca-1+Kit+ (LSK) and CD34-Flt3-LSK cells from mouse bone marrow. We found that hypoxia maintained an immature phenotype. In addition, hypoxia decreased proliferation and induced cell cycle arrest, which is the signature of HSCs with long term multipotential capacity. A dormant state of HSCs is suggested to be critical for protecting and preventing depletion of the stem cell pool. Furthermore, we observed that hypoxia rescues HSCs from oxidative stress-induced cell death, implicating that hypoxia is important in the bone marrow niche to limit reactive oxidative species (ROS) production and give life-long protection of HSCs. Another focus in this thesis is to investigate downstream pathways involved in tyrosine kinase inhibitor-induced cell death of primary AML cells and cell lines expressing mutated FLT3. Our results demonstrate an important role of the PI3K/AKT pathway to mediate survival signals from FLT3. We found FoxO3a and its target gene Bim to be key players of apoptosis in cells carrying oncogenic FLT3 after treatment with tyrosine kinase inhibitors. In conclusion, this thesis highlights hypoxic-mediated regulation of normal HSCs maintenance and critical effectors of apoptosis in leukemic cells expressing mutated FLT3.

    Delarbeten
    1. Hypoxia Expands Primitive Hematopoietic Progenitor Cells from Mouse Bone Marrow During In Vitro Culture and Preserves the Colony-Forming Ability
    Öppna denna publikation i ny flik eller fönster >>Hypoxia Expands Primitive Hematopoietic Progenitor Cells from Mouse Bone Marrow During In Vitro Culture and Preserves the Colony-Forming Ability
    2006 (Engelska)Ingår i: Journal of Stem Cells, ISSN 1556-8539, Vol. 1, nr 4, s. 247-257Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Self-renewal is a prerequisite for the maintenance of hematopoietic stem cells (HSCs) in the bone marrow throughout adult life. Cytokines are mainly providing pro-survival signals of HSC, whereas low oxygen levels (hypoxia) were recently shown to influence self-renewal. In contrast, the effects on other progenitor cell types is not clear. In the present work, we have analyzed whether hypoxia has any effects on mouse multipotent progenitors. When bone marrow-derived Lin-Sca1+c-kit+ (LSK) cells were kept in hypoxic cultures (1% O2 ) for 4 days together with cytokines, the numbers of colony forming high-proliferative progenitors (HPP-CFC) and precursors for cobble-stone forming cells (CAFC) were increased compared to normoxic conditions. A similar effect was seen with pre-CFCmulti from unfractionated bone marrow, whereas more committed progenitors (CFU-GM) were expanded better in normoxia compared to hypoxia. The observed increase in numbers of primitive colony-forming progenitor cells was associated with maintenance of the c-kit/Sca-1 phenotype and a preferential expansion of immature  blast-like appearing cells. The results suggest that a major function of hypoxia is to regulate differentiation by increased self-renewal. Furthermore, in cultures of limited cytokine supply, survival of the stem cell-like cell line FDCP-mix was increased during hypoxia. Thus, hypoxia allows for better survival and self-renewal of multipotent progenitors and HSCs from adult bone marrow. Such culture conditions may have beneficial clinical implications for ex vivo purposes and may improve the yields of stem cells and early progenitors.

    Ort, förlag, år, upplaga, sidor
    Nova Science Publishers, Inc., 2006
    Nyckelord
    Hematopoiesis, Stem cells, Progenitor, Hypoxia, Survival, Self-renewal
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-17713 (URN)
    Anmärkning

    Original Publication: Pernilla Eliasson, Richard Karlsson and Jan-Ingvar Jönsson, Hypoxia Expands Primitive Hematopoietic Progenitor Cellsfrom Mouse Bone Marrow During In Vitro Culture and Preserves the Colony-Forming Ability, 2006, Journal of Stem Cells, (1), 4, 247-257. https://www.novapublishers.com/catalog/editorial.php?products_id=3730 Copyright: Nova Science Publishers https://www.novapublishers.com/

    Tillgänglig från: 2009-04-16 Skapad: 2009-04-16 Senast uppdaterad: 2018-05-29Bibliografiskt granskad
    2. Hypoxia mediates low cell-cycle activity and increases the proportion of long-term reconstituting hematopoietic stem cells during in vitro culture
    Öppna denna publikation i ny flik eller fönster >>Hypoxia mediates low cell-cycle activity and increases the proportion of long-term reconstituting hematopoietic stem cells during in vitro culture
    Visa övriga...
    2010 (Engelska)Ingår i: Experimental Hematology, ISSN 0301-472X, E-ISSN 1873-2399, Vol. 38, nr 4, s. 301-310Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Objective. Recent evidence suggests that hematopoietic stem cells (HSCs) in the bone marrow (BM) are located in areas where the environment is hypoxic. Although previous studies have demonstrated positive effects by hypoxia, its role in HSC maintenance has not been fully elucidated, neither has the molecular mechanisms been delineated. Here, we have investigated the consequence of in vitro incubation of HSCs in hypoxia prior to transplantation and analyzed the role of hypoxia-inducible factor (HIF)-1 alpha. Materials and Methods. HSC and progenitor populations isolated from mouse BM were cultured in 20% or 1% O-2, and analyzed for effects on cell cycle, expression of cyclin-dependent kinase inhibitors genes, and reconstituting ability to lethally irradiated mice. The involvement of HIF-1 alpha was studied using methods of protein stabilization and gene silencing. Results. When long-term FLT3(-)CD34(-)Lin(-)Sca-1(+)c-Kit(+) (LSK) cells were cultured in hypoxia, cell numbers were significantly reduced in comparison to normoxia. This was due to a decrease in proliferation and more cells accumulating in G(0). Moreover, the proportion of HSCs with long-term engraftment potential was increased. Whereas expression of the cyclin-dependent kinase inhibitor genes p21(cip1), p27(Kip1), and p57(Kip2) increased in LSK cells by hypoxia, only p21(cip1) was upregulated in FLT3(-)CD34(-)LSK cells. We could demonstrate that expression of p27(KiP1) and p57(Kip2) was dependent of HIF-1 alpha. Surprisingly, overexpression of constitutively active HIF-1 alpha or treatment with the HIF stabilizer agent FG-4497 led to a reduction in HSC reconstituting ability. Conclusions. Our results imply that hypoxia, in part via HIF-1 alpha, maintains HSCs by decreasing proliferation and favoring quiescence.

    Ort, förlag, år, upplaga, sidor
    Elsevier, 2010
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-54780 (URN)10.1016/j.exphem.2010.01.005 (DOI)000276054300005 ()
    Anmärkning

    Original Publication: Pernilla Eliasson, Matilda Rehn, Petter Hammar, Peter Larsson, Oksana Sirenko, Lee A Flippin, Jorg Cammenga and Jan-Ingvar Jönsson, Hypoxia mediates low cell-cycle activity and increases the proportion of long-term reconstituting hematopoietic stem cells during in vitro culture, 2010, EXPERIMENTAL HEMATOLOGY, (38), 4, 301-310. http://dx.doi.org/10.1016/j.exphem.2010.01.005 Copyright: Elsevier Science B.V., Amsterdam. http://www.elsevier.com/

    On the day of the defence date the title of this article was "Hypoxia, via hypoxia-inducible factor (HIF)-1, mediates low cell cycle activity and preserves the engraftment potential of mouse hematopoietic stem cells" and one of the authors is no longer included in the article.

    When finally published online the title of this article changed name to Hypoxia mediates low cell-cycle activity and increases the proportion of long-term-reconstituting hematopoietic stem cells during in vitro culture.

    Tillgänglig från: 2010-04-09 Skapad: 2010-04-09 Senast uppdaterad: 2017-12-12Bibliografiskt granskad
    3. Hypoxia rescues hematopoietic stem cells from oxidative stress-induced cell death and preserves the long-term repopulation ability
    Öppna denna publikation i ny flik eller fönster >>Hypoxia rescues hematopoietic stem cells from oxidative stress-induced cell death and preserves the long-term repopulation ability
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    A balanced regulation of the ability of hematopoietic stem cells (HSCs) to undergo self-renewal and give rise to new blood cells is crucial for blood homeostasis. Recent studies utilizing genetically modified mice have demonstrated that reactive oxygen species (ROS) damage cellular functions and decrease the lifespan of long-term (LT) HSCs. These LT-HSCs are predominately located in a low-oxygen, or hypoxic, niche, essential for maintaining stem cell capacities. Here, we show that hypoxic culturing rescues HSCs from oxidative stress-induced cell death. Hypoxia inducible factor (HIF)-1 and its target gene pyruvate dehydrogenase kinase 1 (PDK1) were both crucial for survival and long term repopulating ability of HSCs, but less important for hypoxic resistance towards oxidative stress. Moreover, hypoxia increased the expression of Foxo3a, a transcription factor important in adaption to stress stimuli. In conclusion, hypoxia protects LT-HSCs from oxidative stress, possibly by multiple mechanisms, where Foxo3a is likely to play a central role.

    Nyckelord
    Hematopoiesis, Stem cells, Progenitor, Hypoxia, Hypoxia-inducible factor 1 alpha, oxidative stress, Puruvate dehydrogenase kinase 1
    Nationell ämneskategori
    Biokemi och molekylärbiologi
    Identifikatorer
    urn:nbn:se:liu:diva-52941 (URN)
    Tillgänglig från: 2010-01-13 Skapad: 2010-01-13 Senast uppdaterad: 2018-10-08
    4. BH3-only protein Bim more critical than Puma in tyrosine kinase inhibitor-induced apoptosis of human leukemic cells and transduced hematopoietic progenitors carrying oncogenic FLT3.
    Öppna denna publikation i ny flik eller fönster >>BH3-only protein Bim more critical than Puma in tyrosine kinase inhibitor-induced apoptosis of human leukemic cells and transduced hematopoietic progenitors carrying oncogenic FLT3.
    Visa övriga...
    2009 (Engelska)Ingår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 113, nr 10, s. 2302-2311Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Constitutively activating internal tandem duplications (ITD) of FLT3 (FMS-like tyrosine kinase 3) are the most common mutations in acute myeloid leukemia (AML) and correlate with poor prognosis. Receptor tyrosine kinase inhibitors targeting FLT3 have developed as attractive treatment options. Because relapses occur after initial responses, identification of FLT3-ITD–mediated signaling events are important to facilitate novel therapeutic interventions. Here, we have determined the growth-inhibitory and proapototic mechanisms of 2 small molecule inhibitors of FLT3, AG1295 or PKC412, in hematopoietic progenitor cells, human leukemic cell lines, and primary AML cells expressing FLT3-ITD. Inactivation of the PI3-kinase pathway, but not of Ras–mitogen-activated protein (MAP) kinase signaling, was essential to elicit cytotoxic responses. Both compounds induced up-regulation of proapoptotic BH3-only proteins Bim and Puma, and subsequent cell death. However, only silencing of Bim, or its direct transcriptional activator FOXO3a, abrogated apoptosis efficiently. Similar findings were made in bone marrow cells from gene-targeted mice lacking Bim and/or Puma infected with FLT3-ITD and treated with inhibitor, where loss of Puma only provided transient protection from apoptosis, but loss of Bim preserved clonal survival upon FLT3-ITD inhibition.

     

    Ort, förlag, år, upplaga, sidor
    Washington, D.C: The American Society of Hematology, 2009
    Nationell ämneskategori
    Cell- och molekylärbiologi
    Identifikatorer
    urn:nbn:se:liu:diva-52728 (URN)10.1182/blood-2008-07-167023 (DOI)
    Tillgänglig från: 2010-01-11 Skapad: 2010-01-11 Senast uppdaterad: 2018-01-12
  • 61.
    Eliasson, Pernilla
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell hematologi. Linköpings universitet, Hälsouniversitetet.
    Widegren, Emma
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell hematologi. Linköpings universitet, Hälsouniversitetet.
    Jönsson, Jan-Ingvar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell hematologi. Linköpings universitet, Hälsouniversitetet.
    Hypoxia rescues hematopoietic stem cells from oxidative stress-induced cell death and preserves the long-term repopulation abilityManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    A balanced regulation of the ability of hematopoietic stem cells (HSCs) to undergo self-renewal and give rise to new blood cells is crucial for blood homeostasis. Recent studies utilizing genetically modified mice have demonstrated that reactive oxygen species (ROS) damage cellular functions and decrease the lifespan of long-term (LT) HSCs. These LT-HSCs are predominately located in a low-oxygen, or hypoxic, niche, essential for maintaining stem cell capacities. Here, we show that hypoxic culturing rescues HSCs from oxidative stress-induced cell death. Hypoxia inducible factor (HIF)-1 and its target gene pyruvate dehydrogenase kinase 1 (PDK1) were both crucial for survival and long term repopulating ability of HSCs, but less important for hypoxic resistance towards oxidative stress. Moreover, hypoxia increased the expression of Foxo3a, a transcription factor important in adaption to stress stimuli. In conclusion, hypoxia protects LT-HSCs from oxidative stress, possibly by multiple mechanisms, where Foxo3a is likely to play a central role.

  • 62.
    Elinder, Fredrik
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Börjesson, Sara I.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Actions and Mechanisms of Polyunsaturated Fatty Acids on Voltage-Gated Ion Channels2017Ingår i: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 8, artikel-id 43Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Polyunsaturated fatty acids (PUFAs) act on most ion channels, thereby having significant physiological and pharmacological effects. In this review we summarize data from numerous PUFAs on voltage-gated ion channels containing one or several voltage-sensor domains, such as voltage-gated sodium (NaV), potassium (KV), calcium (CaV), and proton (HV) channels, as well as calcium-activated potassium (KCa), and transient receptor potential (TRP) channels. Some effects of fatty acids appear to be channel specific, whereas others seem to be more general. Common features for the fatty acids to act on the ion channels are at least two double bonds in cis geometry and a charged carboxyl group. In total we identify and label five different sites for the PUFAs. PUFA site 1: The intracellular cavity. Binding of PUFA reduces the current, sometimes as a time-dependent block, inducing an apparent inactivation. PUFA site 2: The extracellular entrance to the pore. Binding leads to a block of the channel. PUFA site 3: The intracellular gate. Binding to this site can bend the gate open and increase the current. PUFA site 4: The interface between the extracellular leaflet of the lipid bilayer and the voltage-sensor domain. Binding to this site leads to an opening of the channel via an electrostatic attraction between the negatively charged PUFA and the positively charged voltage sensor. PUFA site 5: The interface between the extracellular leaflet of the lipid bilayer and the pore domain. Binding to this site affects slow inactivation. This mapping of functional PUFA sites can form the basis for physiological and pharmacological modifications of voltage-gated ion channels.

  • 63.
    Elnerud, Maja
    Linköpings universitet, Institutionen för fysik, kemi och biologi.
    Method development for studying the interactions between antithrombin and heparin2008Självständigt arbete på avancerad nivå (magisterexamen), 20 poäng / 30 hpStudentuppsats
    Abstract [en]

    Antithrombin (AT) is one of the most important anticoagulant factors in the blood, and its effects are increased by the interaction with glycosaminoglycans, especially heparin. AT appears in two additional variants, other than the native form, and those variants have antiangiogenic properties and also bind to heparin. AT is found in two distinct isoforms (alfa, beta) where the difference lie in the degree of glycosylation. This project has shown interesting results regarding the dependence of calcium ions on the binding between heparin and antithrombin. The results show that the beta-isoform increases its affinity for heparin in the presence of calcium in contrast to the alfa-isoform, which shows a decrease in the heparin affinity under the same conditions. This project has also given results that after further investigation and development could be used for an improved set-up of the immobilisation of AT variants in a surface plasmon resonance system. The results show that immobilisation of a protein in the reference channel gives a better shielding effect between the negatively charged heparin molecules and the negatively charged dextran matrix. Furthermore a more significant difference was seen between the two heparin moieties used during binding affinity studies, especially for native AT.

  • 64.
    Engstrand, Annika
    Linköpings universitet, Institutionen för fysik, kemi och biologi.
    Dendritic cell response after exposure to Salmonella enterica with different LPS structure.2009Självständigt arbete på avancerad nivå (magisterexamen), 20 poäng / 30 hpStudentuppsats
    Abstract [en]

    Lipopolysaccharide (LPS) is a structure of the gram-negative bacteria that protect from chemicals and works as a stabilization component for the membrane. Studies show that LPS also may have a function to avoid immune defense. In this project we investigate two Salmonella enterica variants with different LPS conformation. The wild-type Salmonella got an originally LPS structure and the mutant form had a defect one. The bacteria were transfected with a green fluorescent protein (GFP) to allow measuring of phagocytosis. Monocytes were isolated from human blood and were incubated for several days with cytokines to give dendritic cells. The cells were exposed to each type of Salmonella and incubated for different times. After labeling with phalloidin and studies with fluorescent microscopy, phagocytosis and F-actin were measured. The results show that it is a difference in phagocytosis and F-actin depending on LPS conformation. That means that LPS may have a decisive role for the pathogenicity of Salmonella.

  • 65.
    Eriksson, Sabina
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Molekylär genetik.
    Studies of peripheral tolerance in AIRE deficient mice2011Självständigt arbete på grundnivå (kandidatexamen), 10,5 poäng / 16 hpStudentuppsats (Examensarbete)
    Abstract [en]

    Autoimmune Polyendocrine Syndrome Type 1(APS I) is a monogenic autosomal recessive autoimmune disorder which is the result of mutations in the autoimmune regulator (AIRE) gene. Symptoms of the disease include circulation of multiple organ specific autoantibodies, which leads to the breakdown of several tissues, including the adrenal cortex and the parathyroid glands. The patients also develop a number of non-endocrine disorders. This study has investigated the peripheral tolerance mechanisms controlled by the AIRE gene in Aire deficient mice, an animal model of the disease. The B cell Activating Factor (BAFF), which is a cytokine involved in B cell survival and growth, is elevated in Aire-/- mice, resulting in an increased release of autoantibodies and B cell proliferation. Therefore the BAFF level differences between TCR-/- and B6 mice was studied, and the results showed significantly higher levels of BAFF in TCR-/- mice. This is not in accordance with earlier studies. ICOS and ICOSL are involved in the activation of follicular T helper cells. The expression of ICOSL on different subpopulations of DC from mice was studied to evaluate the possible influence of AIRE expression on the T cells in the spleen. The results showed that ICOSL is significantly higher expressed in peripheral 33D1+ DCs in Aire-/- mice, showing that AIRE has a role in the over-activation of the follicular T helper cells, which can lead to autoantibody production and inflammation. These results show that AIRE is involved in peripheral tolerance.

  • 66.
    Erlandsson, Per
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Ytors Fysik och Kemi. Linköpings universitet, Tekniska fakulteten.
    Åström, Eva
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Påhlsson, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Robinson, Nathaniel D
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Sensor- och aktuatorsystem. Linköpings universitet, Tekniska fakulteten.
    Determination of Fucose Concentration in a Lectin-Based Displacement Microfluidic Assay2019Ingår i: Applied Biochemistry and Biotechnology, ISSN 0273-2289, E-ISSN 1559-0291, Vol. 188, nr 3, s. 868-877Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We compare three different methods to quantify the monosaccharide fucose in solutions using the displacement of a large glycoprotein, lactoferrin. Two microfluidic analysis methods, namely fluorescence detection of (labeled) lactoferrin as it is displaced by unlabeled fucose and the displacement of (unlabeled) lactoferrin in SPR, provide fast responses and continuous data during the experiment, theoretically providing significant information regarding the interaction kinetics between the saccharide groups and binding sites. For comparison, we also performed a static displacement ELISA. The stationary binding site in all cases was immobilized S2-AAL, a monovalent polypeptide based on Aleuria aurantia lectin. Although all three assays showed a similar dynamic range, the microfluidic assays with fluorescent or SPR detection show an advantage in short analysis times. Furthermore, the microfluidic displacement assays provide a possibility to develop a one-step analytical platform.

  • 67.
    Falkeborn, Tina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet.
    Nasal vaccination using novel mucosal adjuvants: with main focus on influenza A virus2015Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Influenza viruses have sporadically caused pandemics during the last century, with the most severe occurring in 1918 when the “Spanish flu”, an A/H1N1 influenza virus, passed around the globe killing about 20-100 million people. Today 250 000-500 000 deaths occur annually due to influenza virus or secondary infection after influenza, e.g. pneumonia. Influenza viruses cause severe infections in susceptible age groups like children and elderly and in individuals with impaired immune response due to other medical conditions. The best way to prevent an influenza epidemic is by vaccination. Since the 1950´s we have vaccines against seasonal flu, but vaccine efficacy is not 100 % and there is a need to develop better and more effective vaccines, especially for the risk groups. Since the virus enters the host through the nasal cavity, nasal vaccination is a good approach. By stimulating a mucosal immune response already in the nasal cavity, the goal with nasal vaccination is to stop the virus before it enters the host. Nasal vaccination also reduces the risk of transmission of blood-borne diseases, and is less painful and easier to administer, compared to injectable vaccines.

    In order to be able to use less immunogenic antigens, like split and subunit antigens, as nasal vaccine components, an adjuvant is needed to enhance the immune response. At the moment there is no licensed mucosal adjuvant for human use. Several studies are ongoing, but it is a complicated and long way to reach the market. In this thesis nasal vaccination with influenza antigen together with the mucosal adjuvant Endocine™ and other mucosal adjuvants has been evaluated. The Endocine™ adjuvant has been shown to be safe and well tolerated in clinical trials. Depending on the pathogen of interest, different approaches are necessary. For HIV, DNA-vaccination has been evaluated together with a plasmid encoding Salmonella typhimurium flagellin C and the mucosal adjuvant N3. The results found in paper I-IV show that by adding adjuvant to the antigen enhances the protective immune response towards the antigen. Enhanced systemic, mucosal and cell-mediated immunity were observed. Hopefully in the future these adjuvants evaluated in this thesis, will be used in vaccines for humans.

    Delarbeten
    1. Endocine™, N3OA and N3OASq; Three Mucosal Adjuvants That Enhance the Immune Response to Nasal Influenza Vaccination
    Öppna denna publikation i ny flik eller fönster >>Endocine™, N3OA and N3OASq; Three Mucosal Adjuvants That Enhance the Immune Response to Nasal Influenza Vaccination
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    2013 (Engelska)Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 8Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Annual outbreaks of seasonal influenza are controlled or prevented through vaccination in many countries. The seasonal vaccines used are either inactivated, currently administered parenterally, or live-attenuated given intranasally. In this study three mucosal adjuvants were examined for the influence on the humoral (mucosal and systemic) and cellular influenza A-specific immune responses induced by a nasally administered vaccine. We investigated in detail how the anionic Endocine™ and the cationic adjuvants N3OA and N3OASq mixed with a split inactivated influenza vaccine induced influenza A-specific immune responses as compared to the vaccine alone after intranasal immunization. The study showed that nasal administration of a split virus vaccine together with Endocine™ or N3OA induced significantly higher humoral and cell-mediated immune responses than the non-adjuvanted vaccine. N3OASq only significantly increased the cell-mediated immune response. Furthermore, nasal administration of the influenza vaccine in combination with any of the adjuvants; Endocine™, N3OA or N3OASq, significantly enhanced the mucosal immunity against influenza HA protein. Thus the addition of these mucosal adjuvants leads to enhanced immunity in the most relevant tissues, the upper respiratory tract and the systemic circulation. Nasal influenza vaccination with an inactivated split vaccine can therefore provide an important mucosal immune response, which is often low or absent after traditional parenteral vaccination.

    Ort, förlag, år, upplaga, sidor
    Public Library of Science, 2013
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-97667 (URN)10.1371/journal.pone.0070527 (DOI)000323124000019 ()
    Anmärkning

    Funding Agencies|Eurocine Vaccines||Vinnova Research funds||Halsofonden||

    Tillgänglig från: 2013-09-19 Skapad: 2013-09-19 Senast uppdaterad: 2017-12-06
    2. DNA-Encoded Flagellin Activates Toll-Like Receptor 5 (TLR5), Nod-like Receptor Family CARD Domain-Containing Protein 4 (NRLC4), and Acts as an Epidermal, Systemic, and Mucosal-Adjuvant
    Öppna denna publikation i ny flik eller fönster >>DNA-Encoded Flagellin Activates Toll-Like Receptor 5 (TLR5), Nod-like Receptor Family CARD Domain-Containing Protein 4 (NRLC4), and Acts as an Epidermal, Systemic, and Mucosal-Adjuvant
    Visa övriga...
    2013 (Engelska)Ingår i: Vaccines, ISSN 2076-393X, Vol. 1, nr 4, s. 415-443Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Eliciting effective immune responses using non-living/replicating DNA vaccines is a significant challenge. We have previously shown that ballistic dermal plasmid DNA-encoded flagellin (FliC) promotes humoral as well as cellular immunity to co-delivered antigens. Here, we observe that a plasmid encoding secreted FliC (pFliC(-gly)) produces flagellin capable of activating two innate immune receptors known to detect flagellin; Toll-like Receptor 5 (TLR5) and Nod-like Receptor family CARD domain-containing protein 4 (NRLC4). To test the ability of pFliC(-gly) to act as an adjuvant we immunized mice with plasmid encoding secreted FliC (pFliC(-gly)) and plasmid encoding a model antigen (ovalbumin) by three different immunization routes representative of dermal, systemic, and mucosal tissues. By all three routes we observed increases in antigen-specific antibodies in serum as well as MHC Class I-dependent cellular immune responses when pFliC(-gly) adjuvant was added. Additionally, we were able to induce mucosal antibody responses and Class II-dependent cellular immune responses after mucosal vaccination with pFliC(-gly). Humoral immune responses elicited by heterologus prime-boost immunization with a plasmid encoding HIV-1 from gp160 followed by protein boosting could be enhanced by use of pFliC(-gly). We also observed enhancement of cross-clade reactive IgA as well as a broadening of B cell epitope reactivity. These observations indicate that plasmid-encoded secreted flagellin can activate multiple innate immune responses and function as an adjuvant to non-living/replicating DNA immunizations. Moreover, the capacity to elicit mucosal immune responses, in addition to dermal and systemic properties, demonstrates the potential of flagellin to be used with vaccines designed to be delivered by various routes.

    Ort, förlag, år, upplaga, sidor
    Basel, Switzerland: MDPI AG, 2013
    Nyckelord
    adaptive immunity; DNA adjuvant; flagellin; NLRC4; TLR5
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-99352 (URN)10.3390/vaccines1040415 (DOI)
    Tillgänglig från: 2013-10-16 Skapad: 2013-10-16 Senast uppdaterad: 2015-05-19Bibliografiskt granskad
    3. Comparison of the mucosal adjuvant Endocine™ with two well-known adjuvants: cholera toxin and alum
    Öppna denna publikation i ny flik eller fönster >>Comparison of the mucosal adjuvant Endocine™ with two well-known adjuvants: cholera toxin and alum
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    2015 (Engelska)Ingår i: Jacobs Journal of Vaccine and Vaccination, ISSN 2381-2664, Vol. 1, nr 1, artikel-id 006Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    To enable efficient mucosal vaccination with split or subunit antigens, an adjuvant is often needed. To date, no mucosal adjuvants are approved for human use, however, there are a variety of mucosal adjuvants in development, including the liposome-based adjuvant Endocine™. The aim of this study was to evaluate split influenza antigens together with Endocine™ and in order to assess the potency of Endocine™, the induction of humoral immune responses were compared to those following influenza vaccination with cholera toxin (CT) or aluminum salt (alum). We show that Endocine™ significantly enhances influenza-specific immune responses in intranasally immunized mice compared to nonadjuvanted vaccine. Furthermore, vaccines adjuvanted with Endocine™ evoked comparable serum IgG and virus neutralizing (VN) antibody titers as nasal vaccines adjuvanted with CT. Compared to parenteral vaccination with alum, Endocine™ triggered significantly higher mucosal and serum IgA titers, and similar VN titers. Taken together, these results support further development of Endocine™ as a mucosal adjuvant and as part of a nasal influenza vaccine candidate.

    Ort, förlag, år, upplaga, sidor
    Jacobs Publishers, 2015
    Nyckelord
    Mucosal adjuvant; nasal immunization; vaccine; Endocine; influenza; neutralizing antibodies
    Nationell ämneskategori
    Klinisk laboratoriemedicin Cell- och molekylärbiologi
    Identifikatorer
    urn:nbn:se:liu:diva-117979 (URN)
    Tillgänglig från: 2015-05-19 Skapad: 2015-05-19 Senast uppdaterad: 2018-01-11Bibliografiskt granskad
    4. The mucosal adjuvant 1 Endocine™ increases immune responses to influenza antigen in aged mice
    Öppna denna publikation i ny flik eller fönster >>The mucosal adjuvant 1 Endocine™ increases immune responses to influenza antigen in aged mice
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    More effective influenza vaccines for the elderly population is needed. The vaccines used today are less effective in elderly compared to in adults. It is more difficult to stimulate a protective immune response in elderly due to immunosenescence. Elderly people have a decline in both humoral and cell mediated immunity, which make them more susceptible to viral infections. The aim of this study was to evaluate the mucosal adjuvant Endocine™ together with split influenza antigen in different ages of BALB/c mice (15, 20 and 25 months old). The results from this study show that a nasal influenza vaccine  formulated with Endocine™ enhanced both systemic and mucosal immune responses compared to an unadjuvanted vaccine delivered subcutaneously or intra nasal in aged mice. However, in the 25 months old mice only a very modest immune response was detected. Although the influenza-specific immune responses in aged mice were not induced to the same levels as achieved in young mice, the results show that nasal vaccine formulated with Endocine™ could provide benefits for the elderly.

    Nationell ämneskategori
    Klinisk laboratoriemedicin Cell- och molekylärbiologi
    Identifikatorer
    urn:nbn:se:liu:diva-117980 (URN)
    Tillgänglig från: 2015-05-19 Skapad: 2015-05-19 Senast uppdaterad: 2018-01-11Bibliografiskt granskad
  • 68.
    Feng, Xinmei
    et al.
    Linköpings universitet, Institutionen för tema. Linköpings universitet, Filosofiska fakulteten.
    Karlsson, Anna
    Linköpings universitet, Institutionen för tema, Tema vatten i natur och samhälle. Linköpings universitet, Filosofiska fakulteten.
    Svensson, Bo
    Linköpings universitet, Institutionen för tema, Tema vatten i natur och samhälle. Linköpings universitet, Filosofiska fakulteten.
    Bertilsson, Stefan
    Uppsala University.
    Impact of trace element addition on biogas production from food industrial waste - linking process to microbial communities2010Ingår i: FEMS MICROBIOLOGY ECOLOGY, ISSN 0168-6496, Vol. 74, nr 1, s. 226-240Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Laboratory-scale reactors treating food industry waste were used to investigate the effects of additions of cobalt (Co), nickel/molybdenum/boron (Ni/Mo/B) and selenium/tungsten (Se/W) on the biogas process and the associated microbial community. The highest methane production (predicted value: 860 mL g-1 VS) was linked to high Se/W concentrations in combination with a low level of Co. A combination of quantitative real-time PCR of 16S rRNA genes, terminal restriction fragment length polymorphism (T-RFLP) and clone library sequencing was used for the community analysis. The T-RFLP data show a higher diversity for bacteria than for archaea in all the treatments. The most abundant bacterial population (31-55% of the total T-RFLP fragments intensity) was most closely related to Actinomyces europaeus (94% homology). Two dominant archaeal populations shared 98-99% sequence homology with Methanosarcina siciliae and Methanoculleus bourgensis, respectively. Only limited influence of the trace metal additions was found on the bacterial community composition, with two bacterial populations responding to the addition of a combination of Ni/Mo/B, while the dominant archaeal populations were influenced by the addition of Ni/Mo/B and/or Se/W. The maintenance of methanogenic activity was largely independent of archaeal community composition, suggesting a high degree of functional redundancy in the methanogens of the biogas reactors.

  • 69.
    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 death1999Ingår i: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 447, nr 1, s. 71-75Artikel i tidskrift (Refereegranskat)
    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.

  • 70.
    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 apoptosis1998Ingår i: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 188, nr 5, s. 979-984Artikel i tidskrift (Refereegranskat)
    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.

  • 71.
    Fornander, Louise
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Upper Airway Mucosal Inflammation: Proteomic Studies after Exposure to Irritants and Microbial Agents2015Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    People are, in their daily lives, exposed to a number of airborne foreign compounds that do not normally affect the body. However, depending on the nature of these compounds, dose and duration of exposure, various airway symptoms may arise. Early symptoms are often manifested as upper airway mucosal inflammation which generates changes in protein composition in the airway lining fluid.

    This thesis aims at identifying, understanding mechanisms and characterizing protein alterations in the upper airway mucosa that can be used as potential new biomarkers for inflammation in the mucosa. The protein composition in the mucosa was studied by sampling of nasal lavage fluid that was further analyzed with a proteomic approach using twodimensional gel electrophoresis and mass spectrometry. Additionally, by studying factors on site through environmental examination, health questionnaires and biological analyses, we have tried to understand the background to these protein alterations and their impact on health.

    Respiratory symptoms from the upper airways are common among people who are exposed to irritative and microbial agents. This thesis have focused on personnel in swimming pool facilities exposed to trichloramine, metal industry workers exposed to metalworking fluids, employees working in damp and moldy buildings and infants diagnosed with respiratory syncytial virus infection. The common denominator in these four studies is that the subjects experience upper airway mucosal inflammation, which is manifested as cough, rhinitis, phlegm etc. In the three occupational studies, the symptoms were work related. Notably, a high prevalence of perceived mucosal symptoms was shown despite the relatively low levels of airborne irritants revealed by the environmental examination. Protein profiling verified an ongoing inflammatory response by identification of several proteins that displayed altered levels. Interestingly, innate immune proteins dominated and four protein alterations occurred in most of the studies; SPLUNC1, protein S100A8 and S100A9 and alpha-1-antitrypsin. Similarly, these proteins were also found in nasal fluid from children with virus infection and in addition a truncated form of SPLUNC1 and two other S100 proteins (S100A7-like 2 and S100A16), not previously found in nasal secretion, were identified.

    Altogether, the results indicate the potential use of a proteomic approach for identifying new biomarkers for the upper respiratory tract at an early stage in the disease process after exposure to irritant and microbial agents. The results indicate an effect on the innate immunity system and the proteins; SPLUNC1, protein S100A8 and S100A9 and alpha-1-antitrypsin are especially promising new biomarkers. Moreover, further studies of these proteins may help us to understand the molecular mechanisms involved in irritant-induced airway inflammation.

    Delarbeten
    1. Innate immunity proteins and a new truncated form of SPLUNC1 in nasopharyngeal aspirates from infants with respiratory syncytial virus infection
    Öppna denna publikation i ny flik eller fönster >>Innate immunity proteins and a new truncated form of SPLUNC1 in nasopharyngeal aspirates from infants with respiratory syncytial virus infection
    Visa övriga...
    2011 (Engelska)Ingår i: PROTEOMICS CLINICAL APPLICATIONS, ISSN 1862-8346, Vol. 5, nr 9-10, s. 513-522Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Purpose: Respiratory syncytial virus (RSV) is the most common cause of severe respiratory tract infection in infants. The aim was to identify host defence components in nasopharyngeal aspirate (NPA) from infants with RSV infection and to study the expression of the novel 25 kDa innate immunity protein SPLUNC1. less thanbrgreater than less thanbrgreater thanExperimental design: NPAs from infants were analyzed with 2-DE and MS in a pilot study. The levels of SPLUNC1 were analyzed with immunoblotting in 47 NPAs, admitted for RSV diagnosis. less thanbrgreater than less thanbrgreater thanResults: Totally, 35 proteins were identified in NPA, including several innate immunity proteins such as group X phospholipase A(2), different S100 proteins and SPLUNC1. In addition, a new truncated 15 kDa form of SPLUNC1 was identified that was detected in about 50% of the aspirates admitted for RSV diagnosis. RSV-positive boys had significantly less 25 kDa SPLUNC1 than RSV-negative boys while there were no significant differences among girls. less thanbrgreater than less thanbrgreater thanConclusions and clinical relevance: Several important innate immunity proteins were identified in NPA. Notably, a new truncated form of the newly suggested anti-bacterial protein SPLUNC1 was found. It is possible that a decrease in SPLUNC1 in the upper airways may increase the risk for severe pneumonia in boys.

    Ort, förlag, år, upplaga, sidor
    Wiley-VCH Verlag Berlin, 2011
    Nyckelord
    MS, Nasopharynx, PLUNC, Respiratory syncytial virus, Two-dimensional gel electrophoresis
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-72142 (URN)10.1002/prca.201100016 (DOI)000296418400005 ()
    Anmärkning
    Funding Agencies|The Research Council of South East Sweden|FORSS-36761- 8505|Tillgänglig från: 2011-11-18 Skapad: 2011-11-18 Senast uppdaterad: 2015-04-23
    2. Airway irritation among indoor swimming pool personnel: trichloramine exposure, exhaled NO and protein profiling of nasal lavage fluids
    Öppna denna publikation i ny flik eller fönster >>Airway irritation among indoor swimming pool personnel: trichloramine exposure, exhaled NO and protein profiling of nasal lavage fluids
    2013 (Engelska)Ingår i: International Archives of Occupational and Environmental Health, ISSN 0340-0131, E-ISSN 1432-1246, Vol. 86, nr 5, s. 571-580Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Purpose

    Occurrence of airway irritation among indoor swimming pool personnel was investigated. The aims of this study were to assess trichloramine exposure levels and exhaled nitric oxide in relation to the prevalence of airway symptoms in swimming pool facilities and to determine protein effects in the upper respiratory tract.

    Methods

    The presence of airway symptoms related to work was examined in 146 individuals working at 46 indoor swimming pool facilities. Levels of trichloramine, as well as exhaled nitric oxide, were measured in five facilities with high prevalence of airway irritation and four facilities with no airway irritation among the personnel. Nasal lavage fluid was collected, and protein profiles were determined by a proteomic approach.

    Results

    17 % of the swimming pool personnel reported airway symptoms related to work. The levels of trichloramine in the swimming pool facilities ranged from 0.04 to 0.36 mg/m3. There was no covariance between trichloramine levels, exhaled nitric oxide and prevalence of airway symptoms. Protein profiling of the nasal lavage fluid showed that the levels alpha-1-antitrypsin and lactoferrin were significantly higher, and S100-A8 was significantly lower in swimming pool personnel.

    Conclusions

    This study confirms the occurrence of airway irritation among indoor swimming pool personnel. Our results indicate altered levels of innate immunity proteins in the upper airways that may pose as potential biomarkers. However, swimming pool facilities with high prevalence of airway irritation could not be explained by higher trichloramine exposure levels. Further studies are needed to clarify the environmental factors in indoor swimming pools that cause airway problems and affect the immune system.

    Ort, förlag, år, upplaga, sidor
    Springer, 2013
    Nyckelord
    Innate immunity, Occupational medicine, roteomics, Upper respiratory tract
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-86713 (URN)10.1007/s00420-012-0790-4 (DOI)000320394300008 ()22729567 (PubMedID)
    Tillgänglig från: 2012-12-25 Skapad: 2012-12-25 Senast uppdaterad: 2017-12-06Bibliografiskt granskad
    3. Airway symptoms and biological markers in nasal lavage fluid in subjects exposed to metalworking fluids
    Öppna denna publikation i ny flik eller fönster >>Airway symptoms and biological markers in nasal lavage fluid in subjects exposed to metalworking fluids
    Visa övriga...
    2013 (Engelska)Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 12, s. e83089-Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    BACKGROUNDS: Occurrence of airway irritation among industrial metal workers was investigated. The aims were to study the association between exposures from water-based metal working fluids (MWF) and the health outcome among the personnel, to assess potential effects on the proteome in nasal mucous membranes, and evaluate preventive actions.

    METHODS: The prevalence of airway symptoms related to work were examined among 271 metalworkers exposed to MWF and 24 metal workers not exposed to MWF at the same factory. At the same time, air levels of potentially harmful substances (oil mist, morpholine, monoethanolamine, formaldehyde) generated from MWF was measured. Nasal lavage fluid was collected from 13 workers and 15 controls and protein profiles were determined by a proteomic approach.

    RESULTS: Airway symptoms were reported in 39% of the workers exposed to MWF although the measured levels of MWF substances in the work place air were low. Highest prevalence was found among workers handling the MWF machines but also those working in the same hall were affected. Improvement of the ventilation to reduce MWF exposure lowered the prevalence of airway problems. Protein profiling showed significantly higher levels of S100-A9 and lower levels of SPLUNC1, cystatin SN, Ig J and β2-microglobulin among workers with airway symptoms.

    CONCLUSIONS: This study confirms that upper airway symptoms among metal workers are a common problem and despite low levels of MWF-generated substances, effects on airway immune proteins are found. Further studies to clarify the role of specific MWF components in connection to airway inflammation and the identified biological markers are warranted.

    Ort, förlag, år, upplaga, sidor
    Public Library of Science, 2013
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-103739 (URN)10.1371/journal.pone.0083089 (DOI)000329325200035 ()24391738 (PubMedID)
    Tillgänglig från: 2014-01-24 Skapad: 2014-01-24 Senast uppdaterad: 2019-02-11Bibliografiskt granskad
    4. Protein profiles of nasal lavage fluid from individuals with work-related upper airway symptoms associated to moldy and damp buildings
    Öppna denna publikation i ny flik eller fönster >>Protein profiles of nasal lavage fluid from individuals with work-related upper airway symptoms associated to moldy and damp buildings
    Visa övriga...
    2016 (Engelska)Ingår i: Indoor Air, ISSN 0905-6947, E-ISSN 1600-0668, Vol. 26, nr 5, s. 743-754Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Upper airway irritation is common among individuals working in moldy and damp buildings. The aim was to investigate effects on the protein composition of the nasal lining fluid. The prevalence of symptoms in relation to work was examined in 37 individuals working in two damp buildings. Microbial growth was confirmed in one of the buildings. Nasal lavage fluid was collected from 29 exposed subjects and 13 controls. Protein profiles were investigated with a proteomic approach and evaluated by multivariate statistical models. Subjects from both workplaces reported upper airway and ocular symptoms. Based on protein profiles, symptomatic subjects in the two workplaces were discriminated from each other and separated from healthy controls. The groups differed in proteins involved in inflammation and host defense. Measurements of innate immunity proteins showed a significant increa e of protein S100-A8 and decrease of SPLUNC1 in subjects from one workplace while alpha-1-antitrypsin was elevated in subjects from the other workplace, compared to healthy controls. The results show that protein profiles in nasal lavage fluid can be used to monitor airway mucosal effects in personnel working in damp buildings and indicate that the profile may be separate when the dampness is associated with the presence of molds.

    Ort, förlag, år, upplaga, sidor
    Wiley-Blackwell, 2016
    Nyckelord
    Sick building syndrome, proteomics, nasal mucosa, SPLUNC1, alpha-1-antitrypsin, protein S100-A8
    Nationell ämneskategori
    Arbetsmedicin och miljömedicin Infektionsmedicin
    Identifikatorer
    urn:nbn:se:liu:diva-117339 (URN)10.1111/ina.12257 (DOI)000387348500009 ()
    Anmärkning

    Funding agencies: Research Council of South East Sweden [FORSS-222751, FORSS-389061]; Cancer and Allergy Foundation [150441]

    Tillgänglig från: 2015-04-23 Skapad: 2015-04-23 Senast uppdaterad: 2018-01-11Bibliografiskt granskad
  • 72.
    Fredén, Linnéa
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi.
    The Impact of Abiotic Stress on Alternative Splicing in Lipid Transfer Protein in Marchantia polymorpha2018Självständigt arbete på grundnivå (kandidatexamen), 10,5 poäng / 16 hpStudentuppsats (Examensarbete)
    Abstract [en]

    All plants have a protection against the surrounding environment called a cuticle coating. When this cuticle coating is constructed it is believed that the family of protein called lipid transfer proteins (LTPs) is involved. The LTPs are small and cysteine rich. In Marchantia polymorpha the groups of LTPs called LTPd and LTPg can be found. 8 and 4 in each group respectively. In the genes of LTPd there is an intron placed downstream of the start codon. Firstly, a sequence database search was performed and LTPd2 and LTPd3 were chosen for further experiments in this study. Secondly, a control that the intron was present in the samples were done by preforming a PCR reaction of cDNA from isolated RNA taken from untreated Marchantia polymorpha. A gel electrophoresis of the product was also performed. Lastly, the amount of alternative splicing in LTPd2 and LTPd3 from Marchantia polymorpha after treated with cold and dehydration were studied using quantitative PCR. For the qPCR MpACT and the exon of respective gene were used as references. The ΔCt values and the expression fold (2ΔΔCt) calculated from the qPCR results showed that most of the transcript with introns preserved were upregulated after subjected to stress. Only the intron in MpLTPd2 and MpLTPd3 with MpACT as reference showed a small downregulation after the cold treatment. The intron in MpLTPd3 with MpLTPd3s exon as reference didn’t show any difference. None of the intron transcript in any of the genes on the other hand showed any significant difference in the alternative splicing. This could be because of small sample groups when the test was performed. In conclusion, there were no significant difference in intron expression between treated and control samples. Therefore, nothing can be said about the change in alternative splicing in MpLTPds after cold and dehydration treatments.

  • 73.
    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 apoptosis1996Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 93, s. 367-367Artikel i tidskrift (Refereegranskat)
  • 74.
    Fröberg, Henric
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska högskolan.
    A metaproteomics-based method for environmental assessment: A pilot study2013Självständigt arbete på avancerad nivå (masterexamen), 20 poäng / 30 hpStudentuppsats (Examensarbete)
    Abstract [en]

    Metaproteomics, as a proteomic approach to analyse environmental samples, is a new and expanding field of research. The field promises new ways of determining the status of the organisms present in a sample, and could provide additional information compared to metagenomics. Being a novel field of research, robust methods and protocols have not yet been established. In this thesis, we examine several methods for a reliable extraction of protein from soil and periphyton samples. The extraction should preferably be fast, compatible with downstream analysis by mass spectrometry and extract proteins in proportion to their presence in the original sample. A variety of methods and buffers were used to extract proteins from soil and periphyton samples. Concentration determinations showed that all of these methods extracted enough protein for further analysis. For purification and digestion of the samples, several methods were used. The purified samples were analysed on three different mass spectrometers, with the Orbitrap Velos Pro delivering the best results. The results were matched against four genomic and metagenomic databases for identification of proteins, of which the UniProt/SwissProt database gave the best result. A maximum of 52 proteins were identified from periphyton samples when searching against UniProt/SwissProt with strict settings, of which the majority were highly conserved proteins. The main limitation for this type of work is currently the lack of proper metagenomic databases.

  • 75.
    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 tumors1997Ingår i: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 57, nr 21, s. 4956-4964Artikel i tidskrift (Refereegranskat)
    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.

  • 76.
    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 system1998Ingår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 76, nr 1, s. 105-114Artikel i tidskrift (Refereegranskat)
    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.

  • 77.
    Gabrielsson, Erik O.
    et al.
    Linköpings universitet, Institutionen för teknik och naturvetenskap, Fysik och elektroteknik. Linköpings universitet, Tekniska högskolan.
    Armgarth, Astrid
    Linköpings universitet, Institutionen för teknik och naturvetenskap, Fysik och elektroteknik. Linköpings universitet, Tekniska högskolan.
    Hammarström, Per
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska högskolan.
    Nilsson, K. Peter N.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska högskolan.
    Berggren, Magnus
    Linköpings universitet, Institutionen för teknik och naturvetenskap, Fysik och elektroteknik. Linköpings universitet, Tekniska högskolan.
    Controlled Microscopic Formation of Amyloid-Like Aβ Aggregates Using an Organic Electronic DeviceManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Alzheimer’s disease (AD), primarily associated with formation of fibrillar amyloid-beta peptide (Aβ) aggregates in the brain, is one of the most common old-age diseases. It is therefore crucial with an elevated scientific interest in Aβ, and its fundamental properties in a wide sense, to develop efficient methods for early detection and to combat AD. For the development of new techniques, both for AD detection and prevention, researchers are dependent on either tissue samples from deceased patients, animal models or in vitro systems. In vitro systems, such as producing protein aggregates of the Aβ-peptide in a test tube by incubation under denaturing conditions, offers us a simple but rather blunt tool for evaluating aggregation inhibition caused by compounds or to investigate new detection methods. We recently introduced the organic electronic ion pump (OEIP) as a method for creating amyloid-like aggregates at high spatiotemporal control as compared to the resulting aggregates manufactured using regular test tube-conditions. Combined with a fluorescent probe that is specific for the fibrillar aggregated form of misfolded peptides commonly seen in AD, this allowed us to control and to monitor the aggregation of a model peptide system in a highly confined space.

    To further elaborate the functionality of the OEIP together with amyloid-specific probes, we here present experiments demonstrating electronically controlled micron sized formation of Aβ-aggregates with morphologies ranging from fine fibers, to bundles of fibers, and thick mesh-like fiber structures. We foresee that the methodology can be implemented in multi array systems that can be utilized for studies of protein aggregation in confined spaces or together with cultured cells, as well as for the development of screening platforms for assessment of molecules influencing the Aβ-aggregation process.

  • 78.
    Gacic, Jelena
    et al.
    Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi.
    Vorkapic, Emina
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Slind Olsen, Renate
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. County Hospital Ryhov, Sweden.
    Söderberg, Daniel
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Gustafsson, Therese
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Geffers, Robert
    Helmholtz Centre Infect Research, Germany.
    Skoglund, Karin
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Matussek, Andreas
    County Hospital Ryhov, Sweden.
    Wågsäter, Dick
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Imatinib reduces cholesterol uptake and matrix metalloproteinase activity in human THP-1 macrophages2016Ingår i: Pharmacological Reports, ISSN 1734-1140, E-ISSN 2299-5684, Vol. 68, nr 1, s. 1-6Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Imatinib mesylate (Glivec, formerly STI-571) is a selective tyrosine kinase inhibitor used for the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors. However, there are reports suggesting that imatinib could be atheroprotective by lowering plasma low-density lipoprotein (LDL). Aim: To investigate the potential inhibitory effect of imatinib on cholesterol uptake in human macrophages as well as its effect on matrix metalloproteinase (MMP) activity. Methods and results: Uptake of fluorescence-labeled LDL was analyzed using flow cytometry. Macrophages treated with imatinib showed a 23.5%, 27%, and 15% decrease in uptake of native LDL (p &lt; 0.05), acetylated LDL (p &lt; 0.01), and copper-modified oxidized LDL (p &lt; 0.01), respectively. Gel based zymography showed that secretion and activity of MMP-2 and MMP-9 were inhibited by imatinib. Using GeneChip Whole Transcript Expression array analysis, no obvious gene candidates involved in the mechanisms of cholesterol metabolism or MMP regulation were found to be affected by imatinib. Instead, we found that imatinib up-regulated microRNA 155 (miR155) by 43.8% and down-regulated ADAM metallopeptidase domain 28 (ADAM28) by 41.4%. Both genes could potentially play an atheroprotective role and would be interesting targets in future studies. Conclusion: Our results indicate that imatinib causes post-translational inhibition with respect to cholesterol uptake and regulation of MMP-2 and MMP-9. More research is needed to further evaluate the role of imatinib in the regulation of other genes and processes. (c) 2015 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Sp. z o.o. All rights reserved.

  • 79.
    Gao, Feng
    et al.
    Cavendish Laboratory, University of Cambridge, Cambridge, United Kingdom.
    Li, Zhe
    University of Cambridge, England.
    Wang, Jianpu
    University of Cambridge, England.
    Rao, Akshay
    University of Cambridge, England.
    Howard, Ian A.
    University of Cambridge, England.
    Abrusci, Agnese
    University of Cambridge, England.
    Massip, Sylvain
    University of Cambridge, England.
    McNeill, Christopher R.
    University of Cambridge, England.
    Greenham, Neil C.
    University of Cambridge, England.
    Trap-Induced Losses in Hybrid Photovoltaics2014Ingår i: ACS Nano, ISSN 1936-0851, E-ISSN 1936-086X, Vol. 8, nr 4, s. 3213-3221Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We investigate the loss mechanisms in hybrid photovoltaics based on blends of poly(3-hexylthiophene) with CdSe nanocrystals of various sizes. By combining the spectroscopic and electrical measurements on working devices as well as films, we identify that high trap-mediated recombination is responsible for the loss of photogenerated charge carriers in devices with small nanocrystals. In addition, we demonstrate that the reduced open-circuit voltage for devices with small nanocrystals is also caused by the traps.

  • 80.
    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 pathway2008Ingår i: Journal of Cellular and Molecular Medicine (Print), ISSN 1582-1838, E-ISSN 1582-4934, Vol. 12, nr 3, s. 1005-1022Artikel i tidskrift (Refereegranskat)
    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.

  • 81.
    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 expression2009Ingår i: Biochimica et Biophysica Acta. Molecular Cell Research, ISSN 0167-4889, E-ISSN 1879-2596, Vol. 1793, nr 3, s. 546-560Artikel i tidskrift (Refereegranskat)
    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.

  • 82.
    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 BNIP32010Ingår i: Cell Research, ISSN 1001-0602, E-ISSN 1748-7838, Vol. 20, nr 3, s. 314-331Artikel i tidskrift (Refereegranskat)
    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.

  • 83.
    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 applications2005Ingår i: Medical Science Monitor, ISSN 1234-1010, E-ISSN 1643-3750, Vol. 11, nr 11, s. RA337-RA345Artikel, forskningsöversikt (Refereegranskat)
    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.

  • 84.
    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 ions2004Ingår i: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 76, nr 1, s. 169-175Artikel i tidskrift (Refereegranskat)
    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).

  • 85.
    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/HtrA22008Ingår i: Biochimica et Biophysica Acta. Molecular Cell Research, ISSN 0167-4889, E-ISSN 1879-2596, Vol. 1783, nr 2, s. 297-311Artikel i tidskrift (Refereegranskat)
    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.

  • 86.
    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 c2010Ingår i: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 1803, nr 4, s. 452-467Artikel i tidskrift (Refereegranskat)
    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.

  • 87.
    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 pathway2008Ingår i: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 83, nr 6, s. 1484-1492Artikel i tidskrift (Refereegranskat)
    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.

  • 88.
    Gjesing Welinder, Karen
    et al.
    Aalborg University, Denmark.
    Hansen, Rasmus
    Aalborg University, Denmark; .
    Toft Overgaard, Michael
    Aalborg University, Denmark.
    Brohus, Malene
    Aalborg University, Denmark.
    Sonderkaer, Mads
    Aalborg University, Denmark.
    von Bergen, Martin
    Aalborg University, Denmark; UFZ Helmholtz Centre Environm Research, Germany; UFZ Helmholtz Centre Environm Research, Germany.
    Rolle-Kampczyk, Ulrike
    UFZ Helmholtz Centre Environm Research, Germany.
    Otto, Wolfgang
    UFZ Helmholtz Centre Environm Research, Germany.
    Lindahl, Tomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Arinell, Karin
    University of Örebro, Sweden.
    Evans, Alina L.
    Hedmark University of Coll, Norway.
    Swenson, Jon E.
    Norwegian University of Life Science, Norway; Norwegian Institute Nat Research, Norway.
    Revsbech, Inge G.
    Aarhus University, Denmark.
    Frobert, Ole
    University of Örebro, Sweden.
    Biochemical Foundations of Health and Energy Conservation in Hibernating Free-ranging Subadult Brown Bear Ursus arctos2016Ingår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 291, nr 43, s. 22509-22523Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Brown bears (Ursus arctos) hibernate for 5-7 months without eating, drinking, urinating, and defecating at a metabolic rate of only 25% of the summer activity rate. Nonetheless, they emerge healthy and alert in spring. We quantified the biochemical adaptations for hibernation by comparing the proteome, metabolome, and hematological features of blood from hibernating and active free-ranging subadult brown bears with a focus on conservation of health and energy. We found that total plasma protein concentration increased during hibernation, even though the concentrations of most individual plasma proteins decreased, as did the white blood cell types. Strikingly, antimicrobial defense proteins increased in concentration. Central functions in hibernation involving the coagulation response and protease inhibition, as well as lipid transport and metabolism, were upheld by increased levels of very few key or broad specificity proteins. The changes in coagulation factor levels matched the changes in activity measurements. A dramatic 45-fold increase in sex hormone-binding globulin levels during hibernation draws, for the first time, attention to its significant but unknown role in maintaining hibernation physiology. We propose that energy for the costly protein synthesis is reduced by three mechanisms as follows: (i) dehydration, which increases protein concentration without de novo synthesis; (ii) reduced protein degradation rates due to a 6 degrees C reduction in body temperature and decreased protease activity; and (iii) a marked redistribution of energy resources only increasing de novo synthesis of a few key proteins. The comprehensive global data identified novel biochemical strategies for bear adaptations to the extreme condition of hibernation and have implications for our understanding of physiology in general.

  • 89.
    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 cells2008Ingår i: Neoplasia, ISSN 1522-8002, E-ISSN 1476-5586, Vol. 10, nr 10, s. 1120-1130Artikel i tidskrift (Refereegranskat)
    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.

  • 90.
    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 cells1997Ingår i: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 27, nr 9, s. 2358-2365Artikel i tidskrift (Refereegranskat)
    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.

  • 91.
    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 expression2006Ingår i: BMC Molecular Biology, ISSN 1471-2199, E-ISSN 1471-2199, Vol. 7Artikel i tidskrift (Refereegranskat)
    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.

  • 92.
    Gullberg, Erik
    Linköpings universitet, Institutionen för fysik, kemi och biologi.
    Construction of a system for heterologous production of carbonic anhydrase from Plasmodium falciparum in Pichia pastoris2008Självständigt arbete på avancerad nivå (masterexamen), 20 poäng / 30 hpStudentuppsats
    Abstract [en]

    Malaria is one of the biggest current global health problems, and with the increasing occurance of drug resistant Plasmodium falciparum strains, there is an urgent need for new antimalarial drugs. Given the important role of carbonic anhydrase in Plasmodium falciparum (PfCA), it is a potential novel drug target. Heterologous expression of malaria proteins is problematic due to the unusual codon usage of the Plasmodium genome, so to overcome this problem a synthetic PfCA gene was designed, optimized for expression in Pichia pastoris. This gene was also modified to avoid glycosylation, and cloned into the vector pPICZαA under the control of the methanol inducible promoter AOX1. To facilitate export of the protein into the growth medium, the gene was fused in-frame with the α-factor secretion signal from Saccharomyces cerevisiae. The construct was successfully integrated in the genome of P. pastoris GS115, and attempts were made to express the protein and purify it using immobilized metal ion affinity chromatography.In this work, no expression of the PfCA protein could be detected, so further research should focus on optimization of expression conditions, or redesign of the expression vector.

  • 93.
    Gunnar, Erika
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten.
    Bivik Stadler, Caroline
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten.
    Starkenberg, Annika
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten.
    Thor, Stefan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten.
    sequoia controls the type I>0 daughter proliferation switch in the developing Drosophila nervous system2016Ingår i: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 143, nr 20, s. 3774-3784Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Neural progenitors typically divide asymmetrically to renew themselves, while producing daughters with more limited potential. In the Drosophila embryonic ventral nerve cord, neuroblasts initially produce daughters that divide once to generate two neurons/glia (type I proliferation mode). Subsequently, many neuroblasts switch to generating daughters that differentiate directly (type 0). This programmed type I&gt;0 switch is controlled by Notch signaling, triggered at a distinct point of lineage progression in each neuroblast. However, how Notch signaling onset is gated was unclear. We recently identified Sequoia (Seq), a C2H2 zinc-finger transcription factor with homology to Drosophila Tramtrack (Ttk) and the positive regulatory domain (PRDM) family, as important for lineage progression. Here, we find that seq mutants fail to execute the type I&gt;0 daughter proliferation switch and also display increased neuroblast proliferation. Genetic interaction studies reveal that seq interacts with the Notch pathway, and seq furthermore affects expression of a Notch pathway reporter. These findings suggest that seq may act as a context-dependent regulator of Notch signaling, and underscore the growing connection between Seq, Ttk, the PRDM family and Notch signaling.

  • 94.
    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 Clinical2009Ingår i: Current Medicinal Chemistry, ISSN 0929-8673, E-ISSN 1875-533X, Vol. 16, nr 4, s. 506-521Artikel i tidskrift (Refereegranskat)
    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.

  • 95.
    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 imperatoriae2010Ingår i: Analytical and Bioanalytical Chemistry, ISSN 1618-2642, E-ISSN 1618-2650, Vol. 398, nr 5, s. 2039-2047Artikel i tidskrift (Refereegranskat)
    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.

  • 96.
    Hadrévi, Jenny
    et al.
    Umeå University, Sweden.
    Turkina, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Carlsson, Anders
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för samhällsmedicin. Östergötlands Läns Landsting, Sinnescentrum, Smärt och rehabiliteringscentrum. Linköpings universitet, Medicinska fakulteten.
    Gerdle, Björn
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för samhällsmedicin. Linköpings universitet, Medicinska fakulteten. Östergötlands Läns Landsting, Sinnescentrum, Smärt och rehabiliteringscentrum.
    Larsson, Britt
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för samhällsmedicin. Linköpings universitet, Medicinska fakulteten. Östergötlands Läns Landsting, Sinnescentrum, Smärt och rehabiliteringscentrum.
    Hellström, Fredrik
    University of Gävle, Sweden.
    Ghafouri, Bijar
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för samhällsmedicin. Linköpings universitet, Medicinska fakulteten. Östergötlands Läns Landsting, Sinnescentrum, Smärt och rehabiliteringscentrum.
    Myosin light chain and calcium regulating protein differences in chronic musculoskeletal neck and shoulder pain2016Ingår i: Journal of Integrated OMICS, ISSN 2182-0287, Vol. 6, nr 1, s. 1-8Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Proteomic screening analysis has detected myosin light chain (MLC) as a protein implied to be involved in chronic musculoskeletal neck and shoulder pain. Several analyses of MLC proteins have stated a difference in phosphorylation being the determining factor for protein activation hence altered contrability of the muscle in i.e. senescence. In continuation of a previous publication, this study is an attempt to analyze the different MLC isoforms by mass spectrometry and immune-analyses in myalgic and healthy trapezius muscle. In the present study no differences in phosphorylation level between the corresponding individual proteins were detected using LC-MSMS and immunoblotting; instead we assigned different isoforms of regulatory MLCs. To further elucidate the contrability: calcium (Ca2+) regulatory proteins, sarco(endo)plasmic reticulum Ca2+ ATPase 1 (SERCA-1) and calsequestrine (CSQ) were analyzed by western blot. The analysis revealed a significantly increased abundance of SERCA-1 protein in the myalgic muscle and a significantly increased abundance of CSQ in healthy muscle. Myalgic muscle contraction patterns have in previous studies shown to differ from healthy muscle which may be connected to the Ca2+ availability in the muscle. Here we present the proteomic characterization of differences in Ca2+ regulating proteins and particularly regulatory MLCs in trapezius muscle of women with chronic musculoskeletal neck and shoulder pain.

  • 97.
    Hakizimana, Pierre
    Université Libre de Bruxelles, Belgium.
    Interactions between membrane transporters and phospholipids: Phosphatidylethanolamine regulates the function and the structure of LmrP, a bacterial ... associated to antibiotic resistance2009Bok (Övrigt vetenskapligt)
    Abstract [en]

    Highly solved crystal structures and a wealth of biochemical data are now available for an increasing number of membrane proteins. However, the question of how lipid molecules interact with integral membrane proteins and regulate their structure and function in biological membranes remains unsatisfactorily addressed. This book discusses the functional mechanisms of membrane proteins in general and the effect of the surrounding lipidic environment, in the context of recent developments in the field. Recent experimental investigations on the proton gradient-driven multidrug transporter LmrP are also discussed. Using this membrane protein as a model, we demonstrated that the protein structure and function was depending on the phosphatidylethanolamine (PE) headgroup. We then showed that a negatively charged residue, Asp68, could participate in the interaction with PE and that such interaction is required for proper activity and structure of the protein. Because Asp-68 belongs to a highly conserved motif of the Major Facilitator Superfamily (MFS) , this interaction might be a general feature of these transporters that is involved in proton gradient sensing and lipid dependence.

  • 98.
    Hammerman, Malin
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Proteinkemi. Linköpings universitet, Tekniska högskolan.
    Oxidative Stress and Protein Acetylation in Adipocytes2011Självständigt arbete på avancerad nivå (masterexamen), 20 poäng / 30 hpStudentuppsats (Examensarbete)
    Abstract [en]

    Obesity is an increasing health problem which is causally associated with insulin resistance and type 2 diabetes. Oxidative stress, i.e. overproduction of reactive oxygen species, is associated with insulin resistance and obesity and may be a major risk factor in the onset and progression of diabetes. Bernlohr Lab at University of Minnesota have study oxidative stress in adipocytes by silencing the enzyme glutathione S-transferase A-4 (GSTA4), an enzyme detoxifying 4-hydroxynonenal formed during oxidative stress. Their results indicate that lysine acetylation, an important post-translational modification, may be involved during oxidative stress. In this study lysine acetylation has been investigated in condition of oxidative stress in 3T3-L1 adipocytes and subcutaneous adipose tissue from mice using SDS-PAGE gel electrophoresis and western blot. Lysine acetylation was analyzed in different compartments of the cell such as in cytoplasm, mitochondria as well as in whole cell extracts. Silencing of GSTA4 and stimulation by TNF-α in 3T3-L1 adipocytes resulted in an increase of lysine acetylation in cytoplasm. Furthermore, stimulation by IL-6 did not have any effect on lysine acetylation. Surprisingly, subcutaneous adipose tissue from mice fed on a high-fat diet showed a decrease of lysine acetylation in cytoplasm compare to mice fed on a chow diet. In conclusion, lysine acetylation seems to change during oxidative stress and may be an important factor during insulin resistance, type 2 diabetes and obesity. Therefore, studying lysine acetylation and enzymes modulating acetylation may potentially increase our understanding of insulin resistance, type 2 diabetes and obesity and could lead to new therapies.

  • 99.
    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 pathway2005Ingår i: Cell Proliferation, ISSN 0960-7722, E-ISSN 1365-2184, Vol. 38, nr 5, s. 269-285Artikel i tidskrift (Refereegranskat)
    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.

  • 100.
    Hauff, K.
    et al.
    Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Canada; Manitoba Institute of Cell Biology, CancerCare Manitoba, Winnipeg, Canada.
    Zamzow, C.
    Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Canada.
    Law, W. J.
    Manitoba Institute of Cell Biology, CancerCare Manitoba, Winnipeg, Canada.
    De Melo, J.
    Department of Anatomy, University of Manitoba, Winnipeg, Canada; Manitoba Institute of Cell Biology, CancerCare Manitoba, Winnipeg, Canada.
    Kennedy, K.
    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, .
    Peptide-based approaches to treat asthma, arthritis, other autoimmune diseases and pathologies of the central nervous system2005Ingår i: Archivum Immunologiae et Therapiae Experimentalis, ISSN 0004-069X, E-ISSN 1661-4917, Vol. 53, nr 4, s. 308-320Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In this review we focus on peptide- and peptidomimetic-based approaches that target autoimmune diseases and some pathologies of the central nervous system. Special attention is given to asthma, allergic rhinitis, osteoarthritis, and Alzheimer's disease, but other related pathologies are also reviewed, although to a lesser degree. Among others, drugs like Diacerhein and its active form Rhein, Pralnacasan, Anakinra (Kineret), Omalizumab, an antibody "BION-1", directed against the common beta-chain of cytokine receptors, are described below as well as attempts to target beta-amyloid peptide aggregation. Parts of the review are also dedicated to targeting of pathologic conditions in the brain and in other tissues with peptides as well as methods to deliver larger molecules through the "blood-brain barrier" by exploring receptor-mediated transport, or elsewhere in the body by using peptides as carriers through cellular membranes. In addition to highlighting current developments in the field, we also propose, for future drug targets, the components of the inflammasome protein complex, which is believed to initiate the activation of caspase-1 dependent signaling events, as well as other pathways that signal inflammation. Thus we discuss the possibility of targeting inflammasome components for negative or positive modulation of an inflammatory response.

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