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  • 301.
    Hägglund, AC
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Dahl, Lina
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Carlsson, Leif
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Lhx2 is required for expansion of progenitor cells committed to eye developmentManuscript (preprint) (Other academic)
  • 302.
    Hägglund, Anna-Carin
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Berghard, Anna
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Carlsson, Leif
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Canonical Wnt/beta-Catenin Signalling Is Essential for Optic Cup Formation2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 12, p. e81158-Article in journal (Refereed)
    Abstract [en]

    A multitude of signalling pathways are involved in the process of forming an eye. Here we demonstrate that beta-catenin is essential for eye development as inactivation of beta-catenin prior to cellular specification in the optic vesicle caused anophthalmia in mice. By achieving this early and tissue-specific beta-catenin inactivation we find that retinal pigment epithelium (RPE) commitment was blocked and eye development was arrested prior to optic cup formation due to a loss of canonical Wnt signalling in the dorsal optic vesicle. Thus, these results show that Wnt/beta-catenin signalling is required earlier and play a more central role in eye development than previous studies have indicated. In our genetic model system a few RPE cells could escape beta-catenin inactivation leading to the formation of a small optic rudiment. The optic rudiment contained several neural retinal cell classes surrounded by an RPE. Unlike the RPE cells, the neural retinal cells could be beta-catenin- negative revealing that differentiation of the neural retinal cell classes is beta-catenin-independent. Moreover, although dorsoventral patterning is initiated in the mutant optic vesicle, the neural retinal cells in the optic rudiment displayed almost exclusively ventral identity. Thus, beta-catenin is required for optic cup formation, commitment to RPE cells and maintenance of dorsal identity of the retina.

  • 303.
    Håberg, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Membrane-remodeling by SNX18 in endosomal transport and autophagy2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The intracellular space of eukaryotic cells is subdivided into functionally distinct membrane-enclosed organelles. Regulation of these intracellular membranes requires an intricate network of specialized lipids and proteins that maintain organellar integrity and mediate transport between organelles. Proteins of the sorting nexin (SNX) family are membrane-binding regulators of transport events within the endomembrane system. The endomembrane system includes organelles associated with endocytic, secretory and degradative processes in the cell. The aims of this thesis were to functionally characterize SNX18 and SNX33, members of the SNX9-subfamily of sorting nexins, and to elucidate the role of SNX18 in autophagy.

    We demonstrated that all three proteins in the SNX9-family are capable of both membrane binding and remodeling, and interact with the membrane scission enzyme dynamin. We found that SNX18 localizes to endosomal structures in the endomembrane system, together with several identified factors previously described as regulators of endosomal transport. These results indicate that SNX18 mediates budding of membrane carriers in endosomal trafficking. In addition to this, knockdown of SNX18 in cultured cells was found to inhibit autophagy. Autophagy is a catabolic process by which cells degrade and recycle cellular components. It is a cellular response to various stress conditions such as oxidative stress, nutrient deprivation and infections. The components destined for degradation by autophagy are sequestered into a double-membrane structure called the autophagosome in which they are delivered to the lysosome. SNX18 interacts directly with proteins connected to autophagosome formation. Moreover, we demonstrated that the membrane-remodeling capability of SNX18 is a prerequisite for autophagosome formation.

    Taken together, our results lead to the conclusions that SNX18 remodels cellular membranes during formation of carriers for endosomal transport and that it is a positive regulator of autophagy and autophagosome formation.

  • 304.
    Håkansson, Pelle
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Ribonucleotide reductase and DNA damage2006Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    A prerequisite for a multicellular organism to survive is the ability to correctly replicate and repair DNA while minimizing the number of heritable mutations. To achieve this, cells need a balanced supply of deoxyribonucleoside triphosphates (dNTPs), the precursors for DNA synthesis. The rate-limiting step in de novo biosynthesis of dNTPs is catalyzed by the enzyme ribonucleotide reductase (RNR).

    The classic eukaryotic RNR enzyme consists of a large and a small subunit. Together, these subunits form a heterotetrameric RNR complex. The larger subunit harbours active sites whereas the smaller subunit contains a stable tyrosyl free radical. Both subunits are required for RNR activity.

    Since failure to correctly regulate de novo dNTP biosynthesis can lead to misincorporation of nucleotides into DNA, genetic abnormalities and cell death, RNR activity is tightly regulated. The regulation of RNR activity involves cell cycle-specific expression and degradation of the RNR proteins, as well as binding of allosteric effectors to the large RNR subunit.

    In this thesis, in vitro assays based on purified recombinant RNR proteins, in combination with in vivo assays, have been used successfully to study the regulation of RNR activity in response to DNA damage. I present new findings regarding the function of an alternative mammalian RNR small subunit, and on the role of a small RNR inhibitor protein of fission yeast, during normal growth and after DNA damage. I also show conclusively that there are fundamental differences in the regulation of dNTP biosynthesis between the cells of higher and lower eukaryotes after DNA damage.

  • 305.
    Höglund, Andreas
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Nilsson, Lisa M.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Plym Forshell, Linus
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Maclean, Kirsteen H.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Nilsson, Jonas A.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Myc sensitizes p53-deficient cancer cells to the DNA-damaging effects of the DNA methyltransferase inhibitor decitabine2009In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 113, no 18, p. 4281-4288Article in journal (Refereed)
    Abstract [en]

    Decitabine (also referred to as 5-aza-2'-deoxycytidine) is a drug that has recently been approved by the Food and Drug Administration (FDA) for the treatment of myelodysplastic syndrome (MDS). The mechanism of action is believed to be the blocking of DNA methylation and thereby reactivating silenced genes involved in harnessing MDS. When analyzing reactivation of genes involved in Burkitt lymphoma (BL), we discovered that decitabine also sensitizes tumor cells by inducing DNA damage. This sensitization is grossly augmented by the MYC oncogene, which is overexpressed in BL, and occurs in cells lacking a functional p53 tumor suppressor pathway. In p53-deficient BL cells and p53(-/-) mouse embryo fibroblasts, Myc overrides a transient G2-block exerted by decitabine via activation of Chk1. This triggers aneuploidy and cell death that correlates with, but can occur in the absence of, Epstein-Barr virus (EBV) reactivation, caspase activation, and/or expression of the BH3-only protein Puma. In vivo modeling of Myc-induced lymphoma suggests that decitabine constitutes a potential new drug against lymphoma that would selectively sensitize tumor cells but spare normal tissue.

  • 306.
    Hörnberg, Maria
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Gussing, Fredrik
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Berghard, Anna
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Bohm, Staffan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Retinoic acid selectively inhibits death of basal vomeronasal neurons during late stage of neural circuit formation2009In: Journal of Neurochemistry, ISSN 0022-3042, E-ISSN 1471-4159, Vol. 110, no 4, p. 1263-1275Article in journal (Refereed)
    Abstract [en]

    In mouse, sexual, aggressive, and social behaviors are influenced by G protein-coupled vomeronasal receptor signaling in two distinct subsets of vomeronasal sensory neurons (VSNs): apical and basal VSNs. In addition, G protein-signaling by these receptors inhibits developmental death of VSNs. We show that cells of the vomeronasal nerve express the retinoic acid (RA) synthesizing enzyme retinal dehydrogenase 2. Analyses of transgenic mice with VSNs expressing a dominant-negative RA receptor indicate that basal VSNs differ from apical VSNs with regard to a transient wave of RA-regulated and caspase 3-mediated cell death during the first postnatal week. Analyses of G-protein subunit deficient mice indicate that RA and vomeronasal receptor signaling combine to regulate postnatal expression of Kirrel-2 (Kin of IRRE-like), a cell adhesion molecule regulating neural activity-dependent formation of precise axonal projections in the main olfactory system. Collectively, the results indicate a novel connection between pre-synaptic RA receptor signaling and neural activity-dependent events that together regulate neuronal survival and maintenance of synaptic contacts.

  • 307.
    Hörnblad, Andreas
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Nord, Christoffer
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Parween, Saba
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Ahnfelt-Rønne, J
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    The pancreas2015In: Kaufman's atlas of mouse development supplement: with coronal sections / [ed] Richard Baldock, Jonathan Bard, Duncan R. Davidson and Gillian Morriss-Kay, Elsevier, 2015, 1, p. 85-94Chapter in book (Refereed)
    Abstract [en]

    This chapter aims to provide a three-dimensional description of the key morphological events, through which a discrete region of the early gut epithelium, as well as its associated mesenchyme, gives rise to the adult pancreas. Facilitated by recent advances in optical imaging techniques, including light sheet fluorescence microscopy and optical projection tomography, we present image series illustrating the growth of the organ and the formation of key morphological and anatomical features. Given the close developmental relationship between the pancreas-associated mesenchyme and the spleen anlage, and thus the potential for the developing spleen to influence pancreas morphogenesis, we include a brief section which covers the early development of this organ. Finally, we describe the spatial and quantitative distribution of the pancreatic endocrine (β-cell) component in adult mice and highlight lobular heterogeneities that may affect phenotypical evaluations of the gland.

  • 308.
    Hörnsten, Rolf
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
    Suhr, Ole B.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Olofsson, Bert-Ove
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Wiklund, Urban
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Arrhythmia - a pitfall in tests of cardiac autonomic function after liver transplantation for familial amyloidotic polyneuropathy: a long-term follow-up of Swedish patients2012In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 19, no 2, p. 81-86Article in journal (Refereed)
    Abstract [en]

    Liver transplantation (LT) is a potentially curative treatment for hereditary transthyretin amyloidosis, of which familial amyloid polyneuropathy (FAP) is the most common form in Sweden. This study investigated the long-term development in heart rate variability (HRV) after LT in Swedish FAP patients. HRV was analyzed before LT, and during a first (<40 months) and a second (>40 months) follow-up recording after transplantation, respectively. Power spectrum analysis was performed on 2-min sequences in the supine position and after passive tilt, after careful identification of patients with arrhythmia. Data were obtained from 33 patients, but 18 patients had developed cardiac arrhythmia or were pacemaker-treated (4 before LT and 14 after LT) and three patients had not performed the first follow-up recording. In the remaining 12 patients, HRV decreased between the pretransplant evaluation and the first follow-up, thereafter no significant changes were found. In conclusion, our study showed that the progressive development of cardiac arrhythmias after LT is a major pitfall when assessing cardiac autonomic function in FAP patients, especially in patients older than 40 years. In the minority of patients with sinus rhythm in all recordings, cardiac autonomic modulation remained stable after transplantation and no improvement was noted.

  • 309.
    Iakovleva, Irina
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Begum, Afshan
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Pokrzywa, Malgorzata
    Walfridsson, Malin
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Sauer-Eriksson, A Elisabeth
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Olofsson, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    The flavonoid luteolin, but not luteolin-7-o-glucoside, prevents a transthyretin mediated toxic response2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 5, article id e0128222Article in journal (Refereed)
    Abstract [en]

    Transthyretin (TTR) is a homotetrameric plasma protein with amyloidogenic properties that has been linked to the development of familial amyloidotic polyneuropathy (FAP), familial amyloidotic cardiomyopathy, and senile systemic amyloidosis. The in vivo role of TTR is associated with transport of thyroxine hormone T4 and retinol-binding protein. Loss of the tetrameric integrity of TTR is a rate-limiting step in the process of TTR amyloid formation, and ligands with the ability to bind within the thyroxin binding site (TBS) can stabilize the tetramer, a feature that is currently used as a therapeutic approach for FAP. Several different flavonoids have recently been identified that impair amyloid formation. The flavonoid luteolin shows therapeutic potential with low incidence of unwanted side effects. In this work, we show that luteolin effectively attenuates the cytotoxic response to TTR in cultured neuronal cells and rescues the phenotype of a Drosophila melanogaster model of FAP. The plant-derived luteolin analogue cynaroside has a glucoside group in position 7 of the flavone A-ring and as opposed to luteolin is unable to stabilize TTR tetramers and thus prevents a cytotoxic effect. We generated high-resolution crystal-structures of both TTR wild type and the amyloidogenic mutant V30M in complex with luteolin. The results show that the A-ring of luteolin, in contrast to what was previously suggested, is buried within the TBS, consequently explaining the lack of activity from cynaroside. The flavonoids represent an interesting group of drug candidates for TTR amyloidosis. The present investigation shows the potential of luteolin as a stabilizer of TTR in vivo. We also show an alternative orientation of luteolin within the TBS which could represent a general mode of binding of flavonoids to TTR and is of importance concerning the future design of tetramer stabilizing drugs.

  • 310. Igwe, Emeka I
    et al.
    Essler, Silke
    Al-Furoukh, Natalie
    1Institute of Biochemistry I/ZAFES, Faculty of Medicine, Goethe-University Frankfurt.
    Dehne, Nathalie
    Brüne, Bernhard
    Hypoxic transcription gene profiles under the modulation of nitric oxide in nuclear run on-microarray and proteomics.2009In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 10Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Microarray analysis still is a powerful tool to identify new components of the transcriptosome. It helps to increase the knowledge of targets triggered by stress conditions such as hypoxia and nitric oxide. However, analysis of transcriptional regulatory events remain elusive due to the contribution of altered mRNA stability to gene expression patterns as well as changes in the half-life of mRNAs, which influence mRNA expression levels and their turn over rates. To circumvent these problems, we have focused on the analysis of newly transcribed (nascent) mRNAs by nuclear run on (NRO), followed by microarray analysis.

    RESULTS: We identified 196 genes that were significantly regulated by hypoxia, 85 genes affected by nitric oxide and 292 genes induced by the cotreatment of macrophages with both NO and hypoxia. Fourteen genes (Bnip3, Ddit4, Vegfa, Trib3, Atf3, Cdkn1a, Scd1, D4Ertd765e, Sesn2, Son, Nnt, Lst1, Hps6 and Fxyd5) were common to all treatments but with different levels of expression in each group. We observed that 162 transcripts were regulated only when cells were co-treated with hypoxia and NO but not with either treatment alone, pointing to the importance of a crosstalk between hypoxia and NO. In addition, both array and proteomics data supported a consistent repression of hypoxia-regulated targets by NO.

    CONCLUSION: By eliminating the interference of steady state mRNA in gene expression profiling, we obtained a smaller number of significantly regulated transcripts in our study compared to published microarray data and identified previously unknown hypoxia-induced targets. Gene analysis profiling corroborated the interplay between NO- and hypoxia-induced signaling.

  • 311.
    Ikeda, Fumiyo
    et al.
    Frankfurt Institute for Molecular Life Sciences and Institute of Biochemistry II, Goethe University School of Medicine, Theodor-Stern-Kai 7, D-60590 Frankfurt (Main), Germany.
    Deribe, Yonathan Lissanu
    Frankfurt Institute for Molecular Life Sciences and Institute of Biochemistry II, Goethe University School of Medicine, Theodor-Stern-Kai 7, D-60590 Frankfurt (Main), Germany.
    Skånland, Sigrid S
    Frankfurt Institute for Molecular Life Sciences and Institute of Biochemistry II, Goethe University School of Medicine, Theodor-Stern-Kai 7, D-60590 Frankfurt (Main), Germany.
    Stieglitz, Benjamin
    MRC-National Institute for Medical Research, The Ridgeway, London NW7 1AA, UK.
    Grabbe, Caroline
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Franz-Wachtel, Mirita
    Proteome Center Tübingen, Interfaculty Institute for Cell Biology, University of Tübingen, Auf der Morgenstelle 15, 72076 Tübingen, Germany.
    van Wijk, Sjoerd J L
    Frankfurt Institute for Molecular Life Sciences and Institute of Biochemistry II, Goethe University School of Medicine, Theodor-Stern-Kai 7, D-60590 Frankfurt (Main), Germany.
    Goswami, Panchali
    Frankfurt Institute for Molecular Life Sciences and Institute of Biochemistry II, Goethe University School of Medicine, Theodor-Stern-Kai 7, D-60590 Frankfurt (Main), Germany.
    Nagy, Vanja
    IMBA-Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Dr. Bohrgasse 3, 1030 Vienna, Austria.
    Terzic, Janos
    School of Medicine, University of Split, Soltanska 2, Split, HR-21000, Croatia.
    Tokunaga, Fuminori
    Department of Biophysics and Biochemistry, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
    Androulidaki, Ariadne
    Institute for Genetics, Centre for Molecular Medicine (CMMC), and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Zülpicher Str. 47a, 50674 Cologne, Germany.
    Nakagawa, Tomoko
    Department of Biophysics and Biochemistry, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
    Pasparakis, Manolis
    Institute for Genetics, Centre for Molecular Medicine (CMMC), and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Zülpicher Str. 47a, 50674 Cologne, Germany.
    Iwai, Kazuhiro
    Department of Biophysics and Biochemistry, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
    Sundberg, John P
    The Jackson Laboratory, Bar Harbor, Maine 04609, USA.
    Schaefer, Liliana
    Allgemeine Pharmakologie und Toxikologie, Division Nephropharmakologie, Klinikum der Goethe Universität, Theodor-Stern Kai 7, 60590 Frankfurt, Germany.
    Rittinger, Katrin
    MRC-National Institute for Medical Research, The Ridgeway, London NW7 1AA, UK.
    Macek, Boris
    Proteome Center Tübingen, Interfaculty Institute for Cell Biology, University of Tübingen, Auf der Morgenstelle 15, 72076 Tübingen, Germany.
    Dikic, Ivan
    Frankfurt Institute for Molecular Life Sciences and Institute of Biochemistry II, Goethe University School of Medicine, Theodor-Stern-Kai 7, D-60590 Frankfurt (Main), Germany.
    SHARPIN forms a linear ubiquitin ligase complex regulating NF-κB activity and apoptosis.2011In: Nature, ISSN 1476-4687 EISSN, Vol. 471, no 7340, p. 637-641Article in journal (Refereed)
    Abstract [en]

    SHARPIN is a ubiquitin-binding and ubiquitin-like-domain-containing protein which, when mutated in mice, results in immune system disorders and multi-organ inflammation. Here we report that SHARPIN functions as a novel component of the linear ubiquitin chain assembly complex (LUBAC) and that the absence of SHARPIN causes dysregulation of NF-κB and apoptotic signalling pathways, explaining the severe phenotypes displayed by chronic proliferative dermatitis (cpdm) in SHARPIN-deficient mice. Upon binding to the LUBAC subunit HOIP (also known as RNF31), SHARPIN stimulates the formation of linear ubiquitin chains in vitro and in vivo. Coexpression of SHARPIN and HOIP promotes linear ubiquitination of NEMO (also known as IKBKG), an adaptor of the IκB kinases (IKKs) and subsequent activation of NF-κB signalling, whereas SHARPIN deficiency in mice causes an impaired activation of the IKK complex and NF-κB in B cells, macrophages and mouse embryonic fibroblasts (MEFs). This effect is further enhanced upon concurrent downregulation of HOIL-1L (also known as RBCK1), another HOIP-binding component of LUBAC. In addition, SHARPIN deficiency leads to rapid cell death upon tumour-necrosis factor α (TNF-α) stimulation via FADD- and caspase-8-dependent pathways. SHARPIN thus activates NF-κB and inhibits apoptosis via distinct pathways in vivo.

  • 312.
    Inkinen, Ritva
    et al.
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Lammi, Mikko
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Agren, Ulla
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Tammi, Raija
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Puustjärvi, Kaija
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Tammi, Markku
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Hyaluronan distribution in the human and canine intervertebral disc and cartilage endplate.1999In: The Histochemical Journal, ISSN 0018-2214, E-ISSN 1573-6865, Vol. 31, no 9, p. 579-587, article id 10579627Article in journal (Refereed)
    Abstract [en]

    A biotinylated complex of aggrecan G1-domain and link protein was used to characterize the distribution of hyaluronan in paraffin-embedded sections of adult human and canine intervertebral disc and cartilage endplate. Limited chondroitinase ABC and trypsin digestions of the sections before staining was utilized to expose hyaluronan potentially masked by aggrecan. Hyaluronan concentration and hyaluronan to uronic acid ratio in different parts of the discs were measured as a background for the histological analysis. Hyaluronan staining was strong in the nucleus pulposus and inner parts of annulus fibrosus of both species, corroborated by biochemical assays of the same compartments. Particularly in human samples, hyaluronan in the interterritorial matrix of nucleus pulposus and annulus fibrosus was readily accessible to the probe without enzyme treatments. In contrast, the cell-associated hyaluronan signal was enhanced after trypsin or limited chondroitinase ABC-treatment of the sections, suggesting that pericellular hyaluronan was more masked by aggrecan than in the distant matrix. A puzzling feature of canine cartilage endplate cells was their intensive cell-associated hyaluronan signal, part of which appeared intracellular. Hyaluronan was abundant between the collagenous lamellae in annulus fibrosus, perhaps important in the plasticity of this tissue.

  • 313. Ishijima, Nozomi
    et al.
    Suzuki, Masato
    Ashida, Hiroshi
    Ichikawa, Yusuke
    Kanegae, Yumi
    Saito, Izumu
    Borén, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Haas, Rainer
    Sasakawa, Chihiro
    Mimuro, Hitomi
    BabA-mediated adherence is a potentiator of the Helicobacter pylori type IV secretion system activity2011In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 286, no 28, p. 25256-25264Article in journal (Refereed)
    Abstract [en]

    Chronic infection of Helicobacter pylori in the stomach mucosa with translocation of the bacterial cytotoxin-associated gene A (CagA) effector protein via the cag-Type IV secretion system (TFSS) into host epithelial cells are major risk factors for gastritis, gastric ulcers, and cancer. The blood group antigen-binding adhesin BabA mediates the adherence of H. pylori to ABO/Lewis b (Le(b)) blood group antigens in the gastric pit region of the human stomach mucosa. Here, we show both in vitro and in vivo that BabA-mediated binding of H. pylori to Le(b) on the epithelial surface augments TFSS-dependent H. pylori pathogenicity by triggering the production of proinflammatory cytokines and precancer-related factors. We successfully generated Le(b)-positive cell lineages by transfecting Le(b)-negative cells with several glycosyltransferase genes. Using these established cell lines, we found increased mRNA levels of proinflammatory cytokines (CCL5 and IL-8) as well as precancer-related factors (CDX2 and MUC2) after the infection of Le(b)-positive cells with WT H. pylori but not with babA or TFSS deletion mutants. This increased mRNA expression was abrogated when Le(b)-negative cells were infected with WT H. pylori. Thus, H. pylori can exploit BabA-Le(b) binding to trigger TFSS-dependent host cell signaling to induce the transcription of genes that enhance inflammation, development of intestinal metaplasia, and associated precancerous transformations.

  • 314.
    Ishikawa, Takahiko
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Sabharwal, Dharmesh
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Bröms, Jeanette
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Milton, Debra L
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Sjöstedt, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Uhlin, Bernt Eric
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Wai, Sun Nyunt
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Pathoadaptive conditional regulation of the type VI secretion system in Vibrio cholerae O1 strains2012In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 80, no 2, p. 575-584Article in journal (Refereed)
    Abstract [en]

    The most recently discovered secretion pathway in gram-negative bacteria, the type VI secretion system (T6SS), is present in many species and is considered important for the survival of non-O1 non-O139 Vibrio cholerae in aquatic environments. Until now, it was not known whether there is a functionally active T6SS in wild-type V. cholerae O1 strains, the cause of cholera disease in humans. Here, we demonstrate the presence of a functionally active T6SS in wild-type V. cholerae O1 strains, as evidenced by the secretion of the T6SS substrate Hcp, which required several gene products encoded within the putative vas gene cluster. Our analyses showed that the T6SS of wild-type V. cholerae O1 strain A1552 was functionally activated when the bacteria were grown under high-osmolarity conditions. The T6SS was also active when the bacteria were grown under low temperature (23°C), suggesting that the system may be important for the survival of the bacterium in the environment. A test of the interbacterial virulence of V. cholerae strain A1552 against an Escherichia coli K-12 strain showed that it was strongly enhanced under high osmolarity and that it depended on the hcp genes. Interestingly, we found that the newly recognized osmoregulatory protein OscR plays a role in the regulation of T6SS gene expression and secretion of Hcp from V. cholerae O1 strains.

  • 315. Jacquet, S.
    et al.
    Garros, C.
    Lombaert, E.
    Walton, C.
    Restrepo, J.
    Allene, X.
    Baldet, T.
    Cetre-Sossah, C.
    Chaskopoulou, A.
    Delecolle, J. -C
    Desvars, Amélie
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Djerbal, M.
    Fall, M.
    Gardes, L.
    De Garine-Wichatitsky, M.
    Goffredo, M.
    Gottlieb, Y.
    Fall, A. Gueye
    Kasina, M.
    Labuschagne, K.
    Lhor, Y.
    Lucientes, J.
    Martin, T.
    Mathieu, B.
    Miranda, M.
    Pages, N.
    Pereira Da Fonseca, I.
    Ramilo, D. W.
    Segard, A.
    Setier-Rio, M. -L
    Stachurski, F.
    Tabbabi, A.
    Seck, M. Talla
    Venter, G.
    Zimba, M.
    Balenghien, T.
    Guis, H.
    Chevillon, C.
    Bouyer, J.
    Huber, K.
    Colonization of the Mediterranean basin by the vector biting midge species Culicoides imicola: an old story2015In: Molecular Ecology, ISSN 0962-1083, E-ISSN 1365-294X, Vol. 24, no 22, p. 5707-5725Article in journal (Refereed)
    Abstract [en]

    Understanding the demographic history and genetic make-up of colonizing species is critical for inferring population sources and colonization routes. This is of main interest for designing accurate control measures in areas newly colonized by vector species of economically important pathogens. The biting midge Culicoides imicola is a major vector of orbiviruses to livestock. Historically, the distribution of this species was limited to the Afrotropical region. Entomological surveys first revealed the presence of C. imicola in the south of the Mediterranean basin by the 1970s. Following recurrent reports of massive bluetongue outbreaks since the 1990s, the presence of the species was confirmed in northern areas. In this study, we addressed the chronology and processes of C. imicola colonization in the Mediterranean basin. We characterized the genetic structure of its populations across Mediterranean and African regions using both mitochondrial and nuclear markers, and combined phylogeographical analyses with population genetics and approximate Bayesian computation. We found a west/east genetic differentiation between populations, occurring both within Africa and within the Mediterranean basin. We demonstrated that three of these groups had experienced demographic expansions in the Pleistocene, probably because of climate changes during this period. Finally, we showed that C. imicola could have colonized the Mediterranean basin in the Late Pleistocene or Early Holocene through a single event of introduction; however, we cannot exclude the hypothesis involving two routes of colonization. Thus, the recent bluetongue outbreaks are not linked to C. imicola colonization event, but rather to biological changes in the vector or the virus.

  • 316.
    Jafari, Shadi
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin.
    Alkhori, Liza
    Linköpings universitet, Institutionen för klinisk och experimentell medicin.
    Schleiffer, Alexander
    Research Institute Molecular Pathol IMP, Vienna.
    Brochtrup, Anna
    University of Vienna.
    Hummel, Thomas
    University of Vienna.
    Alenius, Mattias
    Linköpings universitet, Utvecklingsbiologi.
    Combinatorial Activation and Repression by Seven Transcription Factors Specify Drosophila Odorant Receptor Expression2012In: PLoS biology, ISSN 1544-9173, E-ISSN 1545-7885, Vol. 10, no 3, article id e1001280Article in journal (Refereed)
    Abstract [en]

    The mechanism that specifies olfactory sensory neurons to express only one odorant receptor (OR) from a large repertoire is critical for odor discrimination but poorly understood. Here, we describe the first comprehensive analysis of OR expression regulation in Drosophila. A systematic, RNAi-mediated knock down of most of the predicted transcription factors identified an essential function of acj6, E93, Fer1, onecut, sim, xbp1, and zf30c in the regulation of more than 30 ORs. These regulatory factors are differentially expressed in antennal sensory neuron classes and specifically required for the adult expression of ORs. A systematic analysis reveals not only that combinations of these seven factors are necessary for receptor gene expression but also a prominent role for transcriptional repression in preventing ectopic receptor expression. Such regulation is supported by bioinformatics and OR promoter analyses, which uncovered a common promoter structure with distal repressive and proximal activating regions. Thus, our data provide insight into how combinatorial activation and repression can allow a small number of transcription factors to specify a large repertoire of neuron classes in the olfactory system.

  • 317.
    Janson, Veronica
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Behnam-Motlagh, Parviz
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hörstedt, Per
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Engström, Karl Gunnar
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Phase-contrast microscopy studies of early Cisplatin-induced morphological changes of malignant mesothelioma cells and the correspondence to induced apoptosis2008In: Experimental Lung Research, ISSN 0190-2148, E-ISSN 1521-0499, Vol. 34, no 2, p. 49-67Article in journal (Refereed)
    Abstract [en]

    Cisplatin treatment efficacy of malignant pleural mesothelioma (MPM) is aggravated by resistance and adverse effects. In P31 MPM cells, cisplatin induces morphological changes and apoptosis. To determine if very early (10 minutes) morphological responses corresponded to apoptosis-induction, cisplatin effects on P31 morphology were examined with phase-contrast microscopy (PCM), scanning electron microscopy (SEM), and flow cytometry (fluorescence-activated cell sorting [FACS]), and compared to apoptosis-induction over time. Increased membrane protrusions were identified with PCM and SEM, but these were not consistent with the induction of apoptosis. The authors concluded that very early morphological changes can be determined with PCM in MPM, but they did not convincingly correspond to apoptosis induction.

  • 318.
    Janson, Veronica
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Odontology.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Resistance to caspase-8 and -9 fragments in a malignant pleural mesothelioma cell line with acquired cisplatin-resistance.2010In: Cell death & disease, ISSN 2041-4889, Vol. 1, no 9, p. e78-Article in journal (Refereed)
    Abstract [en]

    Apoptotic cysteine-aspartate proteases (caspases) are essential for the progression and execution of apoptosis, and detection of caspase fragmentation or activity is often used as markers of apoptosis. Cisplatin (cis-diamminedichloroplatinum (II)) is a chemotherapeutic drug that is clinically used for the treatment of solid tumours. We compared a cisplatin-resistant pleural malignant mesothelioma cell line (P31res1.2) with its parental cell line (P31) regarding the consequences of in vitro acquired cisplatin-resistance on basal and cisplatin-induced (equitoxic and equiapoptotic cisplatin concentrations) caspase-3, -8 and -9 fragmentation and proteolytic activity. Acquisition of cisplatin-resistance resulted in basal fragmentation of caspase-8 and -9 without a concomitant increase in proteolytic activity, and there was an increased basal caspase-3/7 activity. Similarly, cisplatin-resistant non-small-cell lung cancer cells, H1299res, had increased caspase-3 and -9 content compared with the parental H1299 cells. In P31 cells, cisplatin exposure resulted in caspase-9-mediated caspase-3/7 activation, but in P31res1.2 cells the cisplatin-induced caspase-3/7 activation occurred before caspase-8 or -9 activation. We therefore concluded that in vitro acquisition of cisplatin-resistance rendered P31res1.2 cells resistant to caspase-8 and caspase-9 fragments and that cisplatin-induced, initiator-caspase independent caspase-3/7 activation was necessary to overcome this resistance. Finally, the results demonstrated that detection of cleaved caspase fragments alone might be insufficient as a marker of caspase activity and ensuing apoptosis induction.

  • 319. Jarrin, Miguel
    et al.
    Mansergh, Fiona C
    Boulton, Michael E
    Gunhaga, Lena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Wride, Michael A
    Survivin expression is associated with lens epithelial cell proliferation and fiber cell differentiation2012In: Molecular Vision, ISSN 1090-0535, E-ISSN 1090-0535, Vol. 18, no 283-86, p. 2758-2769Article in journal (Refereed)
    Abstract [en]

    Purpose: Survivin (Birc5) is the smallest member of the inhibitor of apoptosis (IAP) protein family, which regulates the cell cycle/apoptosis balance. The purpose of this study was to examine Survivin expression in the embryonic chick lens, in chick lens epithelial cell cultures, and in the postnatal mouse lens.

    Methods: Survivin expression was examined using a combination of quantitative real-time polymerase chain reaction, western blotting, and immunocytochemistry. To correlate Survivin expression with the timing of proliferation, we determined the profile of cell proliferation in the developing lens using the cell cycle marker proliferating cell nuclear antigen (PCNA) in quantitative western blotting and immunocytochemistry studies. We also examined the expression of PCNA and the extent of denucleation using terminal deoxynucleotidyl transferase (TdT)-mediated biotin-dUTP nick-end labeling (TUNEL) of lentoids (lens fiber-like cells) during chick lens epithelial cell differentiation in vitro.

    Results: At embryonic day (ED) 4, Survivin immunostaining was present in two pools in lens epithelial cells and fiber cells: cytoplasmic and nuclear. The nuclear staining became more pronounced as the lens epithelial cells differentiated into lens fiber cells. At ED12, Survivin staining was observed in lens fiber cell nuclei containing marginalized chromatin, indicative of early denucleation events. Using western blotting, Survivin expression peaked at ED6, diminishing thereafter. This profile of expression correlated with the events in chick lens epithelial cell cultures: i) increased Survivin expression was associated with an increase in PCNA staining up to day 6 of culture and ii) downregulation of Survivin expression at day 8 of culture was coincident with a dramatic decrease in PCNA staining and an increase in TdT-mediated biotin-dUTP nick-end labeling in lentoids. In early postnatal mouse lenses, Survivin and PCNA were highly expressed and decreased thereafter during postnatal lens maturation.

    Conclusions: Survivin is expressed during chick and mouse lens development and in chick lens epithelial cell cultures. High levels of Survivin expression correlated with high rates of proliferation of lens epithelial cells at early stages of development. Downregulation of Survivin expression with development and its progressive localization to the nuclei of lens fiber cells was coincident with a decrease in cell proliferation and increased denucleation in differentiating lens fiber cells. These studies suggest an important role for Survivin as a dual regulator of lens epithelial cell proliferation and lens fiber cell differentiation.

  • 320.
    Jarrin, Miguel
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Pandit, Tanushree
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Gunhaga, Lena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    A balance of FGF and BMP signals regulates cell cycle exit and Equarin expression in lens cells2012In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 23, no 16, p. 3266-3274Article in journal (Refereed)
    Abstract [en]

    In embryonic and adult lenses, a balance of cell proliferation, cell cycle exit, and differentiation is necessary to maintain physical function. The molecular mechanisms regulating the transition of proliferating lens epithelial cells to differentiated primary lens fiber cells are poorly characterized. To investigate this question, we used gain- and loss-of-function analyses to modulate fibroblast growth factor (FGF) and/or bone morphogenetic protein (BMP) signals in chick lens/retina explants. Here we show that FGF activity plays a key role for proliferation independent of BMP signals. Moreover, a balance of FGF and BMP signals regulates cell cycle exit and the expression of Ccdc80 (also called Equarin), which is expressed at sites where differentiation of lens fiber cells occurs. BMP activity promotes cell cycle exit and induces Equarin expression in an FGF-dependent manner. In contrast, FGF activity is required but not sufficient to induce cell cycle exit or Equarin expression. Furthermore, our results show that in the absence of BMP activity, lens cells have increased cell cycle length or are arrested in the cell cycle, which leads to decreased cell cycle exit. Taken together, these findings suggest that proliferation, cell cycle exit, and early differentiation of primary lens fiber cells are regulated by counterbalancing BMP and FGF signals.

  • 321.
    Jensen, Ninnie
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience. Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Biomedicinprogrammet.
    Effects of interleukin-1B upon anandamide metabolism in a human neuroblastoma cell line2014Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
  • 322.
    Jeon, Jongmin
    et al.
    Diabetes Research Institute, University of Miami Leonard M. Miller School of Medicine.
    Correa-Medina, Mayrin
    Diabetes Research Institute, University of Miami Leonard M. Miller School of Medicine.
    Ricordi, Camillo
    Diabetes Research Institute, University of Miami Leonard M. Miller School of Medicine.
    Edlund, Helena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Diez, Juan A
    Diabetes Research Institute, University of Miami Leonard M. Miller School of Medicine.
    Endocrine cell clustering during human pancreas development2009In: Journal of Histochemistry and Cytochemistry, ISSN 0022-1554, E-ISSN 1551-5044, Vol. 57, no 9, p. 811-824Article in journal (Refereed)
    Abstract [en]

    The development of efficient, reproducible protocols for directed in vitro differentiation of hES cells into insulin producing beta cells will benefit greatly from increased knowledge regarding the spatiotemporal expression profile of key instructive factors involved in human endocrine cell generation. Human fetal pancreases, from 7 to 21 weeks of gestational age, were collected following consent immediately after pregnancy termination and processed for immunostaining, in situ hybridization and real-time RT-PCR expression analyses. Islet-like structures appear from approximately week 12 and unlike the mixed architecture observed in the adult islets, fetal islets are initially formed predominantly by aggregated insulin or glucagon-expressing cells. The period studied (7-22 weeks) coincides with a decrease in the proliferation and an increase in the differentiation of the progenitor cells, the initiation of NGN3 expression and the appearance of differentiated endocrine cells. The present study provides a detailed characterization of islet formation and expression profiles of key intrinsic and extrinsic factors during human pancreas development. This information is beneficial for the development of efficient protocols that will allow guided in vitro differentiation of hES cells into insulin-producing cells.

  • 323.
    Jidigam, Vijay
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Gunhaga, Lena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Role of BMP signaling on cytoskeleton elements in the sensory placode invagination2014In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 25, article id P1653Article in journal (Other academic)
  • 324.
    Jidigam, Vijay K.
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Gunhaga, Lena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Development of cranial placodes: insights from studies in chick2013In: Development, Growth and Differentiation, ISSN 0012-1592, E-ISSN 1440-169X, Vol. 55, no 1, p. 79-95Article, review/survey (Refereed)
    Abstract [en]

    This review focuses on how research, using chick as a model system, has contributed to our knowledge regarding the development of cranial placodes. This review highlights when and how molecular signaling events regulate early specification of placodal progenitor cells, as well as the development of individual placodes including morphological movements. In addition, we briefly describe various techniques used in chick that are important for studies in cell and developmental biology.

  • 325.
    Jin, Taiyi
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Environmental Medicine. Fudan University, School of Public Health, Department of Occupational Health, Shanghai 200032, Peoples Republic of China.
    Chen, Liang
    Lei, Lijian
    Nordberg, Monica
    Nordberg, Gunnar F
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Environmental Medicine.
    An invited paper presented in the symposium "Health effects of low dose exposure to toxic metals"2008In: Cell Biology and Toxicology, ISSN 0742-2091, E-ISSN 1573-6822, Vol. 24, no 5, p. 451-455Article in journal (Refereed)
  • 326.
    Johannson, Carolina
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Regulatory mechanism of a potential riboswitch in Vibrio cholerae2016Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
  • 327.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Odontology.
    Aggregatibacter actinomycetemcomitans Leukotoxin: a Powerful Tool with Capacity to Cause Imbalance in the Host Inflammatory Response2011In: Toxins, ISSN 2072-6651, Vol. 2, no 3, p. 242-259Article in journal (Refereed)
    Abstract [en]

    Aggregatibacter actinomycetemcomitans has been described as a member of the indigenous oral microbiota of humans, and is involved in the pathology of periodontitis and various non-oral infections. This bacterium selectively kills human leukocytes through expression of leukotoxin, a large pore-forming protein that belongs to the Repeat in Toxin (RTX) family. The specificity of the toxin is related to its prerequisite for a specific target cell receptor, LFA-1, which is solely expressed on leukocytes. The leukotoxin causes death of different leukocyte populations in a variety of ways. It activates a rapid release of lysosomal enzymes and MMPs from neutrophils and causes apoptosis in lymphocytes. In the monocytes/macrophages, the toxin activates caspase-1, a cysteine proteinase, which causes a proinflammatory response by the activation and secretion of IL-1β and IL-18. A specific clone (JP2) of A. actinomycetemcomitans with enhanced leukotoxin expression significantly correlates to disease onset in infected individuals. Taken together, the mechanisms by which this toxin kills leukocytes are closely related to the pathogenic mechanisms of inflammatory disorders, such as periodontitis. Therapeutic strategies targeting the cellular and molecular inflammatory host response in periodontal diseases might be a future treatment alternative

  • 328.
    Johansson, Anna
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Examining the prostate stroma and vasculature: importance and potential as targets for therapy2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background. Recent studies in cancer research have focused on the reciprocal interaction between cancer cells and their microenvironment. Tumour growth is angiogenesis dependent and the rate of angiogenesis correlates with a poor prognosis in many different cancers. We have shown that the rate of angiogenesis correlates with prognosis in Prostate Cancer (PC). We have also observed that the vasculature is involved during the involution of the prostate in rodents subsequent to hormonal ablation. Patients with metastatic PC are subjected to hormonal ablation therapy – a therapy unfortunately not curative. Our ambition is therefore to find means to enhance the effects of castration therapy of prostate tumours, possibly by a simultaneous inhibition of angiogenesis and of growth factors populating the tumour stroma. The angiopoietins are a family of growth factors that regulate angiogenesis by direct effects on endothelial cells in a context dependent manner. The purpose of this thesis was therefore to examine the role of the angiopoietins and the stroma in general in PC and to explore their potential as novel targets.

    Materials and Methods. We have had at our disposal access to clinical materials in the form of paraffin embedded samples from untreated PC patients with a long follow up. We have also used animal tumour models and in vitro cell culture systems followed by immunohistochemistry, in situ hybridization, western blotting, laser micro dissection, and quantitative real-time PCR for evaluation of the experiments.

    Results. In paper I, we found a significant correlation between high levels of angiopoietin 2 (Ang 2) and high vascular density, histological grade, metastases and poor prognosis in PC patients. In the second paper we found that the receptor for the angiopoietins, Tie 2, and the ligand Ang 1 mediated the decrease in vascular stability observed after castration treatment. This was not observed in prostate tumours subsequent to hormonal ablation (paper III), nor was there a decrease of other growth factor receptors. In summary (paper III), we found that a combined inhibition of the tumour stroma in terms of an inhibition of the PDGF-Rs by the use of Imatinib, and the vasculature in terms of a perturbed Tie 2 signalling, inhibited tumour growth. Finally, in paper IV, we found that Imatinib inhibited the castration induced influx of mast cells after castration therapy. The mast cells expressed high levels of FGF 2 and epiregulin, and inhibition of mast cell function inhibited tumour growth, by inhibiting angiogenesis.

    Conclusions. We have observed that the tumour stroma is of particular importance for tumour growth in PC. Targeting the tumour microenvironment, and in particular by a simultaneous inhibition of the vasculature and stroma, could prove beneficial for patients with advanced PC.

  • 329.
    Johansson, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Rudolfsson, Stina Häggström
    Kilter, Sigrid
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Targeting castration-induced tumour hypoxia enhances the acute effects of castration therapy in a rat prostate cancer model2011In: BJU International, ISSN 1464-4096, E-ISSN 1464-410X, Vol. 107, no 11, p. 1818-1824Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: •  To explore the effects of castration therapy, the standard treatment for advanced prostate cancer, in relation to tumour hypoxia and to elicit its importance for the short- and long-term therapeutic response.

    MATERIAL AND METHODS: •  We used the androgen-sensitive rat Dunning H prostate tumour model that transiently responds to castration treatment followed by a subsequent relapse, much like the scenario in human patients. •  Tumour tissues were analysed using stereological methods in intact, 1 and 7 days after castration therapy.

    RESULTS: •  Hypoxia was transiently up-regulated after castration therapy and correlated with the induction of tumour cell apoptosis. •  When castration therapy was combined with tirapazamine (TPZ), a drug that targets hypoxic cells and the vasculature, the effects on tumour cell apoptosis and tumour volume were enhanced in comparison to either castration or TPZ alone.

    CONCLUSION: •  The present study suggests that castration-induced tumour hypoxia is a novel target for therapy.

  • 330.
    Johansson, B
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Eriksson, A
    Ramaekers, F
    Thornell, L
    Smoothelin in adult and developing human arteries and myocardium.1999In: Histochemistry and Cell Biology, ISSN 0948-6143, E-ISSN 1432-119X, Vol. 112, no 4, p. 291-9Article in journal (Refereed)
    Abstract [en]

    The aim of this investigation was to study, with immunohistochemical methods, the distribution of the novel cytoskeletal protein smoothelin in human cardiovascular tissues, the possible changes during the development of the cardiovascular system and its correlation to the intermediate filament proteins desmin and vimentin. Smoothelin was detected in smooth muscle cells of the fetal coronary arteries. In very young subjects (up to 3 months of age), only a few cells in the media of the elastic arteries contained smoothelin, whereas it was present in most smooth muscle cells in the muscular arteries. In individuals older than 1 year, most smooth muscle cells in the media of all blood vessels contained smoothelin. In vessels with a developed intima, smoothelin was present in a variable proportion of the smooth muscle cells. With few exceptions, smoothelin was more frequently detected than desmin in medial smooth muscle cells. Smoothelin and vimentin were codistributed in the smooth muscle cells of the media in most vessels. In the cardiomyocytes (fetal to adult age), the smoothelin antibody detected epitopes located at the Z-disc level but not in the intercalated discs. In conclusion, smoothelin is more widely distributed in the muscular arteries than in the elastic arteries early in life, and thus exhibits a variable distribution during postnatal development of vascular tissues. In the adult, smoothelin is detected in the media of most vascular smooth muscle cells, both in muscular and elastic arteries, and is not necessarily codistributed with either desmin or vimentin. Evidence that smoothelin is present in human striated cardiomyocytes is also presented.

  • 331. Johansson, B
    et al.
    Eriksson, A
    Ramaekers, F
    Thornell, L E
    Smoothelin and intermediate filament proteins in human aortocoronary saphenous vein by-pass grafts.1999In: The Histochemical Journal, ISSN 0018-2214, E-ISSN 1573-6865, Vol. 31, no 11, p. 723-7Article in journal (Refereed)
    Abstract [en]

    The aim of this immunohistochemical investigation was to study the distribution of the novel cytoskeletal protein smoothelin and the intermediate filament proteins vimentin and desmin in normal human great saphenous vein and in human aortocoronary by-pass vein grafts. Smoothelin was present in most smooth muscle cells in the media of the native vein. In the neointima of the vein grafts that had been in situ for three months or more, smoothelin was, in general, present only in few smooth muscle cells. Desmin was distributed in the same pattern as smoothelin in the native great saphenous vein. When desmin and smoothelin were present in the neointima, smoothelin was detected in more cells than desmin. Vimentin was present in most cells in all wall layers of both the native saphenous vein and the vein grafts. Vascular smooth muscle cells containing vimentin but not desmin or smoothelin are the principal cells in the neointima of human aortocoronary vein grafts. In some grafts, however, all three cytoskeletal proteins were detected in the neointima. The distribution of smoothelin and desmin in aortocoronary vein grafts support the postulate that these proteins are expressed mainly in the contractile smooth muscle cell phenotype.

  • 332. Johansson, B
    et al.
    Eriksson, A
    Thornell, L E
    Intermediate filament proteins in developing human arteries.1999In: Anatomy and Embryology, ISSN 0340-2061, E-ISSN 1432-0568, Vol. 199, no 3, p. 225-31Article in journal (Refereed)
    Abstract [en]

    The distribution of intermediate filament proteins in adult human blood vessels and in human fetal elastic arteries is relatively well-known. However, the distribution of these proteins in the course from neonate to adult has not been established. In this investigation, human postnatal arteries were studied with immunohistochemistry, using antibodies targeted on the intermediate filament proteins desmin, vimentin and cytokeratins 8, 18 and 19. Vimentin was present in most smooth muscle cells in all vessels and at all ages. The proportions of desmin-expressing cells increased in the elastic arteries during the first year of life and was higher in the pulmonary trunk than in the aorta. In the muscular arteries, the proportion of desmin-labelled cells increased in the coronary and the deep femoral arteries, but remained constant in the renal and the cerebral arteries. Cytokeratins were detected in the pulmonary trunk earlier than in the aorta. Cytokeratins were present throughout the wall of the ductus arteriosus, but desmin was present only in some cells. Thus, there are postnatal changes in the distribution of intermediate filament proteins in the elastic arteries and in some muscular arteries, whereas the intermediate filament pattern remains unchanged in other muscular arteries.

  • 333.
    Johansson, B
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Eriksson, A
    Virtanen, I
    Thornell, L E
    Intermediate filament proteins in adult human arteries.1997In: Anatomical Record, ISSN 0003-276X, E-ISSN 1097-0185, Vol. 247, no 4, p. 439-48Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The cytoskeleton of cells in blood vessel walls contains desmin, vimentin, and cytokeratins. The distribution of these proteins in human vessels is not fully known. We have mapped the distribution of intermediate filament proteins in human arterial walls.

    METHODS: Monoclonal antibodies targeted at the intermediate filament proteins desmin, vimentin, and cytokeratins were used, and the distribution of these proteins was studied by immunohistochemistry.

    RESULTS: In the muscular arteries, most smooth muscle cells in the media expressed both desmin and vimentin; in the elastic arteries, the proportion of desmin-labelled cells was lower and preferentially located to the periphery of the media. In general, the desmin immunoreactivity within the intima was weak, but some smooth muscle cells and smooth muscle cells in the musculoelastic layer showed strong immunoreactivity. The vasa vasorum exhibited a heterogeneous desmin-labelling pattern. The vimentin antibodies labelled the endothelium and showed a heterogeneous staining pattern in the other layers of the arterial wall. Cytokeratin was detected in occasional cells in the media of muscular arteries, in many adluminal cells and cell clusters in the coronary intima, and in smooth muscle cells in the media of the elastic arteries.

    CONCLUSIONS: Vimentin is widely distributed in vascular smooth muscle cells, whereas the distribution of desmin and cytokeratin varies. Each artery studied had an intermediate filament pattern typical for the anatomical location. There were no interindividual variations in the distribution of intermediate filament proteins.

  • 334.
    Johansson, Erik
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Speck, Christian
    Chabes, Andrei
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    A top-down view on DNA replication and recombination from 9,000 feet above sea level2011In: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 12, no 4, article id 304Article in journal (Refereed)
    Abstract [en]

    A report of the Keystone Symposium 'DNA Replication and Recombination' held in Keystone, USA, 27 February to 4 March 2011.

  • 335. Johansson, J.
    et al.
    Berg, T.
    Kurzejamska, E.
    Pang, M-F
    Tabor, V.
    Jansson, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Roswall, P.
    Pietras, K.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Religa, P.
    Fuxe, J.
    MiR-155-mediated loss of C/EBP beta shifts the TGF-beta response from growth inhibition to epithelial-mesenchymal transition, invasion and metastasis in breast cancer2013In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 32, no 50, p. 5614-5624Article in journal (Refereed)
    Abstract [en]

    During breast cancer progression, transforming growth factor-beta (TGF-beta) switches from acting as a growth inhibitor to become a major promoter of epithelial-mesenchymal transition (EMT), invasion and metastasis. However, the mechanisms involved in this switch are not clear. We found that loss of CCAAT-enhancer binding protein beta (C/EBP beta), a differentiation factor for the mammary epithelium, was associated with signs of EMT in triple-negative human breast cancer, and in invasive areas of mammary tumors in MMTV-PyMT mice. Using an established model of TGF-beta-induced EMT in mouse mammary gland epithelial cells, we discovered that C/EBP beta was repressed during EMT by miR-155, an oncomiR in breast cancer. Depletion of C/EBP beta potentiated the TGF-beta response towards EMT, and contributed to evasion of the growth inhibitory response to TGF-beta. Furthermore, loss of C/EBP beta enhanced invasion and metastatic dissemination of the mouse mammary tumor cells to the lungs after subcutaneous injection into mice. The mechanism by which loss of C/EBP beta promoted the TGF-beta response towards EMT, invasion and metastasis, was traced to a previously uncharacterized role of C/EBP beta as a transcriptional activator of genes encoding the epithelial junction proteins E-cadherin and coxsackie virus and adenovirus receptor. The results identify miR-155-mediated loss of C/EBP beta as a mechanism, which promotes breast cancer progression by shifting the TGF-beta response from growth inhibition to EMT, invasion and metastasis.

  • 336.
    Johansson Jänkänpää, Hanna
    et al.
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Mishra, Yogesh
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology.
    Schröder, Wolfgang P
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Jansson, Stefan
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Metabolic profiling reveals metabolic shifts in Arabidopsis plants grown under different light conditions2012In: Plant, Cell and Environment, ISSN 0140-7791, E-ISSN 1365-3040, Vol. 35, no 10, p. 1824-1836Article in journal (Refereed)
    Abstract [en]

    Plants have tremendous capacity to adjust their morphology, physiology and metabolism in response to changes in growing conditions. Thus, analysis solely of plants grown under constant conditions may give partial or misleading indications of their responses to the fluctuating natural conditions in which they evolved. To obtain data on growth-condition dependent differences in metabolite levels we compared leaf metabolite profiles of Arabidopsis thaliana growing under three constant laboratory light conditions: 30 (LL), 300 (NL) and 600 (HL) µmol photons m(-2) s(-1) . We also shifted plants to the field and followed their metabolite composition for three days. Numerous compounds showed light-intensity dependent accumulation, including: many sugars and sugar derivatives (fructose, sucrose, glucose, galactose and raffinose); tricarboxylic acid (TCA) cycle intermediates and amino acids (ca. 30% of which were more abundant under HL and 60% under LL). However, the patterns differed after shifting NL plants to field conditions. Levels of most identified metabolites (mainly amino acids, sugars and TCA cycle intermediates) rose after 2 h and peaked after 73 h, indicative of a "biphasic response" and "circadian" effects. The results provide new insight into metabolomic level mechanisms of plant acclimation, and highlight the role of known protectants under natural conditions.

  • 337.
    Johansson, Jörgen
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    RNA thermosensors in bacterial pathogens.2009In: Bacterial Sensing and Signaling / [ed] Collin M, Schuch R, S. Karger, 2009, Vol. 16, p. 150-160Chapter in book (Refereed)
    Abstract [en]

    During the course of an infection, a pathogenic bacterium has to sense the environment and adjust its gene expression appropriately. One such environmental cue is the difference in temperature inside and outside the host. RNA thermosensors are structures that can respond to differences in temperature by altering their conformation and thereby allowing/preventing binding of the ribosome to the translational start site. This chapter discusses different types of RNA thermosensors in general and RNA thermosensors known to control virulence gene expression in particular.

  • 338.
    Johansson, Marcus JO
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Jacobson, Allan
    University Massachusetts, School of Medicine, Dept Mol Genet & Microbiol, Worcester, MA .
    Nonsense-mediated mRNA decay maintains translational fidelity by limiting magnesium uptake2010In: Genes & Development, ISSN 0890-9369, E-ISSN 1549-5477, Vol. 24, no 14, p. 1491-1495Article in journal (Refereed)
    Abstract [en]

    Inactivation of the yeast nonsense-mediated mRNA decay (NMD) pathway stabilizes nonsense mRNAs and promotes readthrough of premature translation termination codons. Although the latter phenotype is thought to reflect a direct role of NMD factors in translation termination, its mechanism is unknown. Here we show that the reduced termination efficiency of NMD-deficient cells is attributable to increased expression of the magnesium transporter Alr1p and the resulting effects of elevated Mg2+ levels on termination fidelity. Alr1p levels increase because an upstream ORF in ALR1 mRNA targets the transcript for NMD. Our results demonstrate that NMD, at least in yeast, controls Mg2+ homeostasis and, consequently, translational fidelity.

  • 339. Johansson, Renzo
    et al.
    Jonna, Venkateswara Rao
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Kumar, Rohit
    Nayeri, Niloofar
    Lundin, Daniel
    Sjöberg, Britt-Marie
    Hofer, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Logan, Derek T
    Structural Mechanism of Allosteric Activity Regulation in a Ribonucleotide Reductase with Double ATP Cones2016In: Structure, ISSN 0969-2126, E-ISSN 1878-4186, Vol. 24, no 6, p. 906-917Article in journal (Refereed)
    Abstract [en]

    Ribonucleotide reductases (RNRs) reduce ribonucleotides to deoxyribonucleotides. Their overall activity is stimulated by ATP and downregulated by dATP via a genetically mobile ATP cone domain mediating the formation of oligomeric complexes with varying quaternary structures. The crystal structure and solution X-ray scattering data of a novel dATP-induced homotetramer of the Pseudomonas aeruginosa class I RNR reveal the structural bases for its unique properties, namely one ATP cone that binds two dATP molecules and a second one that is non-functional, binding no nucleotides. Mutations in the observed tetramer interface ablate oligomerization and dATP-induced inhibition but not the ability to bind dATP. Sequence analysis shows that the novel type of ATP cone may be widespread in RNRs. The present study supports a scenario in which diverse mechanisms for allosteric activity regulation are gained and lost through acquisition and evolutionary erosion of different types of ATP cone.

  • 340.
    Jonsson, Frida
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Burstedt, Marie S
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Sandgren, Ola
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Norberg, Anna
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Golovleva, Irina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Genetic heterogeneity and clinical outcome in a Swedish family with retinal degeneration caused by mutations in CRB1 and ABCA4 genes2014In: Retinal Degenerative Diseases: Mechanisms and Experimental Therapy, Springer Berlin/Heidelberg, 2014, Vol. 801, p. 177-183Conference paper (Refereed)
    Abstract [en]

    Genetic mechanisms underlying severe retinal dystrophy in a large Swedish family presenting two distinct phenotypes, Leber congenital amaurosis and Stargardt disease were investigated. In the family, four patients with Leber congenital amaurosis were homozygous for a novel c.2557C>T (p.Q853X) mutation in the CRB1 gene, while of two cases with Stargardt disease, one was homozygous for c.5461-10T>C in the ABCA4 gene and another was a compound heterozygous for c.5461-10T>C and a novel ABCA4 mutation c.4773+3 A>G. Sequence analysis of the entire ABCA4 gene in patients with Stargardt disease revealed complex alleles with additional sequence variants.Our results provide evidence of genetic complexity causative of different clinical features present in the same family, which is an obvious challenge for ophthalmologists, molecular geneticists and genetic counsellors.

  • 341.
    Jortikka, Matti
    et al.
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Parkkinen, Jyrki
    Department of Pathology, University of Kuopio, Kuopio, Finland.
    Inkinen, Rtiva
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Kärner, Jüri
    Department of Zoology, University of Tartu, Tartu, Estonia.
    Järveläinen, Hannu
    Department of Medicine, University of Turku, Finland; Medical Biochemistry, University of Turku, Finland.
    Nelimarkka, Lassi
    Medical Biochemistry, University of Turku, Finland.
    Tammi, Markku
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Lammi, Mikko
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    The role of microtubules in the regulation of proteoglycan synthesis in chondrocytes under hydrostatic pressure.2000In: Archives of Biochemistry and Biophysics, ISSN 0003-9861, E-ISSN 1096-0384, Vol. 374, no 2, p. 172-180, article id 10666295Article in journal (Refereed)
    Abstract [en]

    Chondrocytes of the articular cartilage sense mechanical factors associated with joint loading, such as hydrostatic pressure, and maintain the homeostasis of the extracellular matrix by regulating the metabolism of proteoglycans (PGs) and collagens. Intermittent hydrostatic pressure stimulates, while continuous high hydrostatic pressure inhibits, the biosynthesis of PGs. High continuous hydrostatic pressure also changes the structure of cytoskeleton and Golgi complex in cultured chondrocytes. Using microtubule (MT)-affecting drugs nocodazole and taxol as tools we examined whether MTs are involved in the regulation of PG synthesis in pressurized primary chondrocyte monolayer cultures. Disruption of the microtubular array by nocodazole inhibited [(35)S]sulfate incorporation by 39-48%, while MT stabilization by taxol caused maximally a 17% inhibition. Continuous hydrostatic pressure further decreased the synthesis by 34-42% in nocodazole-treated cultures. This suggests that high pressure exerts its inhibitory effect through mechanisms independent of MTs. On the other hand, nocodazole and taxol both prevented the stimulation of PG synthesis by cyclic 0. 5 Hz, 5 MPa hydrostatic pressure. The drugs did not affect the structural and functional properties of the PGs, and none of the treatments significantly affected cell viability, as indicated by the high level of PG synthesis 24-48 h after the release of drugs and/or high hydrostatic pressure. Our data on two-dimensional chondrocyte cultures indicate that inhibition of PG synthesis by continuous high hydrostatic pressure does not interfere with the MT-dependent vesicle traffic, while the stimulation of synthesis by cyclic pressure does not occur if the dynamic nature of MTs is disturbed by nocodazole. Similar phenomena may operate in cartilage matrix embedded chondrocytes.

  • 342.
    Jönsson, Maria
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    The neuronal and non-neuronal substance P, VIP and cholinergic systems in the colon in ulcerative colitis2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Ulcerative colitis (UC) is a chronic relapsing inflammatory bowel disease. Neuropeptides, especially vasoactive intestinal peptide (VIP) and substance P (SP), have long been considered to play key roles in UC. Among other effects, these neuropeptides have trophic and growth-modulating as well as wound-healing effects. Furthermore, whilst VIP has anti-inflammatory properties, SP has pro-inflammatory effects. It is generally assumed that the main source of SP and VIP in the intestine is the tissue innervation. It is not known whether or not they are produced in the epithelial layer. The details concerning the expressions of their receptors in UC are also, to a great extent, unclear. Apart from the occurrence of peptidergic systems in the intestine, there are also neuronal as well as non-neuronal cholinergic systems. The pattern concerning the latter is unknown with respect to UC.

    The studies in this thesis aimed to investigate the expression of SP and VIP and their major receptors (NK-1R and VPAC1) in UC colon, compared to non-UC colon. The main emphasis was devoted to the epithelium. A second aim was to examine for levels of these neuropeptides in blood plasma in UC. Another aim was to examine for the non-neuronal cholinergic system in UC, thus, to investigate whether there is acetylcholine production outside nerves in the UC colon. Methods used in the thesis were immunohistochemistry, in situ hybridization, enzyme immunosorbent assay, and in vitro receptor autoradiography.

    For the first time, mRNA for VIP and SP has here been found in the colonic epithelium. That was especially noted in UC mucosa showing a rather normal morphology, and in non-UC mucosa. Marked derangement of the mucosa was found to lead to a distinct decrease in VIP binding, and also a decrease in the expression level of VIP receptor VPAC1 in the epithelium. In general, there was an upregulation of the SP receptor NK-1R in the epithelium when the mucosa was deranged. The plasma levels of SP and VIP were higher for UC patients compared to healthy controls. There were marked correlations between the levels of the peptides in plasma, their levels in the mucosa and the degree of mucosal derangement/inflammation. A pronounced nonneuronal cholinergic system was found in both UC and non-UC colon. Certain changes occurred in this system in response to inflammation/derangement in UC. The present study shows unexpectedly that expressions for VIP and SP are not only related to the nerve structures and the inflammatory cells. The downregulation of VPAC1 expression, and the tendencies of upregulation of NK-1R expression levels when there is marked tissue derangement, may be a drawback for the intestinal function. The study also shows that there is a marked release of neuropeptides to the bloodstream in parallel with a marked derangement of the mucosa in UC. The cholinergic effects in the UC colon appear not only to be associated with nerverelated effects, but also effects of acetylcholine produced in local non-neuronal cells. The thesis shows that local productions for not only acetylcholine, but also SP and VIP, occur to a larger extent than previously considered.

  • 343.
    Jönsson, Maria
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Norrgård, Örjan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Presence of mRNA for VIP and Substance P and presence of VPAC1 and NK-1 receptor expressions in the colonic epithelium of man: changed pattern in ulcerative colitisManuscript (Other academic)
    Abstract [en]

     

    The neuropeptides vasoactive intestinal peptide (VIP) and substance P (SP) are considered to be important in ulcerative colitis (UC). It is generally assumed that the main source of VIP and SP in the intestine is the innervation. There is no information concerning whether or not they are produced by cells in the epithelial layer. Concerning UC, there is also a lack of information concerning the VIP-receptor VPAC1 in the epithelium. In the present study, UC and non-UC colon was examined concerning expressions of VIP, SP, VPAC1 and the SP-preferred receptor, neurokinin-1 (NK-1R). Both immunohistochemistry and in situ hybridization were applied. mRNA expression for both VIP and SP were observed in the epithelium. The mRNA reactions were seen in normal and little/moderately affected mucosa. There were very marked VPAC1 immunoreactions in the epithelium, in non-UC mucosa and in little affected UC mucosa. A decrease in VPAC1 immunoreactions was noted in the epithelium in markedly affected UC mucosa. Existence of VIP immunoreaction, VIP mRNA, VPAC1 immunoreaction, SP mRNA, NK-1R immunoreaction and Substance P receptor (TACR1) mRNA was shown for cells in lamina propria and submucosa. The present study shows unexpectedly that mRNA for both VIP and SP are not only expressed in neuronal perikarya and lamina propria and submucosal cells but also in the colonic epithelium, and that marked changes in VPAC1 receptor expressions occur for this layer in severe UC. It is tentative to speculate that autocrine/paracrine VIP and SP effects may occur within the epithelium. The decrease in VPAC1 receptor reactions seen in severely UC affected mucosa may be a drawback for the intestinal function.

     

  • 344.
    Kaarniranta, Kai
    et al.
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Elo, Mika
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Sironen, Reijo
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Karjalainen, Hannu
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Helminen, Heikki
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Lammi, Mikko
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Stress responses of mammalian cells to high hydrostatic pressure.2003In: Biorheology, ISSN 0006-355X, E-ISSN 1878-5034, Vol. 40, no 1-3, p. 87-92, article id 12454391Article in journal (Refereed)
    Abstract [en]

    High hydrostatic pressure causes stress response in many types of mammalian cells. We have previously shown that an accumulation of heat shock protein 70 (Hsp70) in a chondrocytic cell line occurred without an activation of the gene itself. Stabilization of the hsp70 mRNA was shown to be the reason for the Hsp70 stress response in the pressurized cells. Since accumulation of Hsp70 in pressurized cells indicated that high hydrostatic pressure induces a stress response without heat shock transcription factor activation, we decided to investigate the activation of two other stress-associated transcription factors, activator protein-1 (AP-1) and nuclear factor-kappaB (NF-kappaB). Induction of Hsp70 in immortalized and primary chondrocytes, murine Neuro-2a neuroblastoma and HeLa cervical carcinoma cell lines was investigated at both mRNA and protein levels. In immortalized chondrocytes and HeLa cells, hsp70 mRNA levels were clearly elevated after 6 hours of the onset of 30 MPa continuous hydrostatic pressure, while in primary chondrocytes and Neuro-2a cells (the cells known to be stress-sensitive) no induction was observed. Surprisingly, neither heat shock nor high hydrostatic pressure could induce the hsp70 mRNA in Neuro-2a cells, although an activation of heat shock transcription factor could be observed in heat-shocked cells. No activation of the AP-1 and NF-kappaB binding to their target DNA sequences could be shown in the immortalized chondrocytes.

  • 345.
    Kaarniranta, Kai
    et al.
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Elo, Mika
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Sironen, Reijo
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Lammi, Mikko
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Goldring, Mary
    Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
    Eriksson, John
    †Turku Centre for Biotechnology, University of Turku, Åbo Akademi University, Turku, Finland.
    Sistonen, Lea
    †Turku Centre for Biotechnology, University of Turku, Åbo Akademi University, Turku, Finland.
    Helminen, Heikki
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Hsp70 accumulation in chondrocytic cells exposed to high continuous hydrostatic pressure coincides with mRNA stabilization rather than transcriptional activation.1998In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 95, no 5, p. 2319-2324, article id 9482883Article in journal (Refereed)
    Abstract [en]

    In response to various stress stimuli, heat shock genes are induced to express heat shock proteins (Hsps). Previous studies have revealed that expression of heat shock genes is regulated both at transcriptional and posttranscriptional level, and the rapid transcriptional induction of heat shock genes involves activation of the specific transcription factor, heat shock factor 1 (HSF1). Furthermore, the transcriptional induction can vary in intensity and kinetics in a signal- and cell-type-dependent manner. In this study, we demonstrate that mechanical loading in the form of hydrostatic pressure increases heat shock gene expression in human chondrocyte-like cells. The response to continuous high hydrostatic pressure was characterized by elevated mRNA and protein levels of Hsp70, without activation of HSF1 and transcriptional induction of hsp70 gene. The increased expression of Hsp70 was mediated through stabilization of hsp70 mRNA molecules. Interestingly, in contrast to static pressurization, cyclic hydrostatic loading did not result in the induction of heat shock genes. Our findings show that hsp70 gene expression is regulated posttranscriptionally without transcriptional induction in chondrocyte-like cells upon exposure to high continuous hydrostatic pressure. We suggest that the posttranscriptional regulation in the form of hsp70 mRNA stabilization provides an additional mode of heat shock gene regulation that is likely to be of significant importance in certain forms of stress.

  • 346.
    Kaarniranta, Kai
    et al.
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Holmberg, Carina
    Turku Centre for Biotechnology, University of Turku, Åbo Akademi University, Turku, Finland; Department of Biochemistry and Pharmacy, Åbo Akademi University, Turku, Finland.
    Helminen, Heikki
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Eriksson, John
    Turku Centre for Biotechnology, University of Turku, Åbo Akademi University, Turku, Finland; Department of Biology, University of Turku, Turku, Finland.
    Sistonen, Lea
    Turku Centre for Biotechnology, University of Turku, Åbo Akademi University, Turku, Finland.
    Lammi, Mikko
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Protein synthesis is required for stabilization of hsp70 mRNA upon exposure to both hydrostatic pressurization and elevated temperature.2000In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 475, no 3, p. 283-286, article id 10869572Article in journal (Refereed)
    Abstract [en]

    We have recently described that in chondrocytic cells high hydrostatic pressure (HP) causes a heat shock response via mRNA stabilization without a transcriptional activation of the hsp70 gene. In this study, we investigated whether this exceptional regulatory mechanism occurs more generally in different types of cells. Indeed, hsp70 mRNA and protein accumulated in HeLa, HaCat and MG-63 cells under 30 MPa HP, without DNA-binding of heat shock transcription factor 1 (HSF1) to the heat shock element of the hsp70 gene or formation of nuclear HSF1 granules, revealing a lack of transcriptional activation. Moreover, we observed that protein synthesis is needed for mRNA stabilization. Thus, high HP offers a model to study the mechanisms of hsp70 mRNA stabilization without HSF1-mediated induction of the heat shock gene response.

  • 347.
    Kaarniranta, Kai
    et al.
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Holmberg, Carina
    Turku Centre for Biotechnology, University of Turku, Åbo Akademi University, Turku, Finland; Department of Biochemistry and Pharmacy, Åbo Akademi University, Turku, Finland.
    Lammi, Mikko
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Eriksson, John
    Turku Centre for Biotechnology, University of Turku, Åbo Akademi University, Turku, Finland.
    Sistonen, Lea
    Turku Centre for Biotechnology, University of Turku, Åbo Akademi University, Turku, Finland; Department of Biology, Åbo Akademi University, Turku, Finland.
    Helminen, Heikki
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Primary chondrocytes resist hydrostatic pressure-induced stress while primary synovial cells and fibroblasts show modified Hsp70 response.2001In: Osteoarthritis and Cartilage, ISSN 1063-4584, E-ISSN 1522-9653, Vol. 9, no 1, p. 7-13, article id 11178942Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: During joint loading, chondrocytes in the articular cartilage are subjected to gradients of high compressive hydrostatic pressure (HP). In response to diverse chemical or physical stresses, heat shock genes are induced to express heat shock proteins (Hsps). This study sought to examine the role of Hsps in baroresistance in primary bovine chondrocytes and synovial cells, as well as in primary human fibroblasts.

    METHODS: Northern blotting was used to analyze the steady-state levels of hsp70 mRNA in the primary cells exposed to HP or heat stress. Hsp70 protein accumulation was analyzed by Western blotting, and the DNA-binding activity was examined by gel mobility shift assay.

    RESULTS: Primary bovine chondrocytes which have been adapted to live under pressurized conditions showed negligible Hsp70 response upon HP loading, whereas primary bovine synovial cells and human fibroblasts accumulated hsp70 mRNA and protein when subjected to HP. The response was initiated without activation of the heat shock transcription factor 1. Interestingly, pre-conditioning of the barosensitive fibroblasts with HP or heat shock reduced the Hsp70 response, indicating induction of baroresistance.

    CONCLUSION: This study suggests that Hsp70 can play an important role in the early stages of adaptation of cells to HP. Thus, the Hsp70 gene expression upon HP loading may serve as one indicator of the chondrocytic phenotype of the cells. This can be of use in the treatment of cartilage lesions.

  • 348.
    Kaarniranta, Kai
    et al.
    Department of Ophthalmology, Kuopio University Hospital, Kuopio, Finland.
    Ihanamäki, Tapio
    Department of Ophthalmology, Helsinki University Hospital, Helsinki, Finland.
    Sahlman, Janne
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Pulkkinen, Hertta
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Uusitalo, Hannu
    Department of Ophthalmology, Kuopio University Hospital, Kuopio, Finland.
    Arita, Machiko
    Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA, USA.
    Tammi, Raija
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Lammi, Mikko
    Chondrogenic and Osteogenic Differentiation Group.
    Helminen, Heikki
    Chondrogenic and Osteogenic Differentiation Group.
    A mouse model for Stickler's syndrome; ocular phenotype of mice carrying a targeted heterozygous inactivation of type II (pro)collagen gene (Col2a1).2006In: Experimental Eye Research, ISSN 0014-4835, E-ISSN 1096-0007, Vol. 83, no 2, p. 297-303, article id 16546167Article in journal (Refereed)
    Abstract [en]

    The influences of targeted heterozygous inactivation of type II (pro)collagen gene (Col2a1) on eye structures in the 15-month-old C57BL/6JOlaHsd mouse was studied. The eyes were collected from C57BL mice heterozygous for a targeted inactivation of one allele of the Col2a1 gene (Col2a1(+/-) mice). The eyes of C57BL mice with normal gene alleles were used as controls (Col2a1(+/+) mice). Ocular histology was analyzed from tissue sections, stained with hematoxylin and eosin, toluidine blue and alcian blue. Type II collagen was localized by immunohistochemistry. Hyaluronan (HA) was stained utilizing the biotinylated complex of the hyaluronan-binding region of aggrecan and link protein (bHABC). The anterior segment of the eye was well-formed in both genotypes, but typical folding of ciliary processes was decreased, while increased stromal extracellular matrix vacuolization was seen in the Col2a1(+/-) mice. In the lens of these mice, subcapsular extracellular matrix changes were observed. Differences in retinal structures or the number of the eyes with retinal detachment were not detected between the genotypes. In Col2a1(+/-) mice, staining for type II collagen was weaker in cornea, ciliary body, iris, lens, vitreous, retina, choroid and sclera than in the control mice. HA staining was detected in the extraocular tissues, ciliary body, iris and the choroid of both genotypes. HA staining was observed only in the vitreous body of the control animals. Heterozygous inactivation of Col2a1 gene causes structural defects in the murine eye. The observed structural changes in the ciliary body, lens and vitreous of the Col2a1(+/-) mice may represent ocular features found in the human Stickler syndrome, where the abnormalities result from COL2A1 gene mutations which lead to functional haploinsufficiency.

  • 349.
    Kaarniranta, Kai
    et al.
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Oksala, Niku
    Department of Surgery, Kuopio University Hospital, Kuopio, Finland.
    Karjalainen, Hannu
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Suuronen, Tiina
    Department of Neuroscience and Neurology, University of Kuopio, Kuopio, Finland.
    Sistonen, Lea
    Turku Centre for Biotechnology, University of Turku, Åbo Akademi University, Turku, Finland.
    Helminen, Heikki
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Salminen, Antero
    Department of Neurology, Kuopio University Hospital, Kuopio, Finland; Department of Neuroscience and Neurology, University of Kuopio, Kuopio, Finland.
    Lammi, Mikko
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Neuronal cells show regulatory differences in the hsp70 gene response.2002In: Brain Research. Molecular Brain Research, ISSN 0169-328X, E-ISSN 1872-6941, Vol. 101, no 1-2, p. 136-140, article id 12007842Article in journal (Refereed)
    Abstract [en]

    The synthesis of heat shock proteins (Hsps), encoded by heat shock genes, is increased in response to various stress stimuli. Hsps function as molecular chaperones, they dissociate cytotoxic stress-induced protein aggregates within cells and ensure improved survival. Induction of heat shock genes is mainly regulated at the transcriptional level. The stress responsive transcription factor, heat shock factor 1 (HSF1), is involved in the transcriptional induction of the heat shock genes. Our objective was to examine how hsp70 genes are regulated in different transformed and primary neurons upon exposure to elevated temperature. Our findings reveal that the Hsp70 response is regulated at the translational level in Neuro-2a neuroblastoma cells, while the IMR-32 neuroblastoma cells respond to stress by the classical HSF1-driven transcriptional regulatory mechanism. Primary rat hippocampal neurons show a lack of HSF1 and induction of the hsp70 gene. These observations suggest that neuronal cells display different hsp70 gene expression patterns which range from undetected response to transcriptional and posttranscriptional regulation during heat stress.

  • 350.
    Kaarniranta, Kai
    et al.
    Department of Anatomy, University of Kuopio, Kuopio,Finland; Department of Neurosciences and Neurology, University of Kuopio, Kuopio, Finland.
    Oksala, Niku
    Department of Surgery, Kuopio University Hospital, Kuopio, Finland.
    Lammi, Mikko
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Helminen, Heikki
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Sistonen, Lea
    Department of Cell Biology, Åbo Academi, Turku, Finland; Center of Biotechnology, University of Turku, Turku, Finland.
    Solustressin tutkimuksesta kliinisiin läpimurtoihin? [From research of cellular stress to various clinical break through innovations?]2001In: Duodecim, ISSN 0012-7183, E-ISSN 2242-3281, Vol. 117, no 22, p. 2266-2272, article id 12183959Article, review/survey (Refereed)
    Abstract [fi]

    Fysikaalisen tai kemiallisen stressin seurauksena useiden geenien aktiivisuus vähenee,kun taas lämpösokki- eli stressigeenien induktio lisääntyy. Stressigeenit koodaavat lämpösokkiproteiineja(Hsp), jotka toimivat soluissa kaperoneina, »avustajina», auttaensolujen proteiineja laskostumaan oikein translaatiossa, kalvon läpi kuljetuksessa tai esimerkiksikorkean lämpötilan aiheuttaman vaurion jälkeen. Viime vuosina lämpösokkiproteiinienkliininen merkitys useiden sairauksien patogeneesissä, diagnostiikassa ja ennusteenmäärittämisessä on alkanut selvitä. Merkittävimmät kliiniset löydökset liittyvätiskeemisiin prosesseihin, kuten sydän- ja aivoinfarkteihin, useisiin neoplasioihin ja ikääntymiseen.Tässä katsauksessa käsittelemme stressigeenien säätelyä, Hsp70-stressiproteiinienkliinisiä yhteyksiä ja niiden mahdollisia hoitosovelluksia iskeemisissä, neoplastisissaja degeneratiivisissa prosesseissa.

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