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  • 1
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    Aryl hydrocarbon receptor control of a disease tolerance defence pathway (2014)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2014-06-17
    Description: Disease tolerance is the ability of the host to reduce the effect of infection on host fitness. Analysis of disease tolerance pathways could provide new approaches for treating infections and other inflammatory diseases. Typically, an initial exposure to bacterial lipopolysaccharide (LPS) induces a state of refractoriness to further LPS challenge (endotoxin tolerance). We found that a first exposure of mice to LPS activated the ligand-operated transcription factor aryl hydrocarbon receptor (AhR) and the hepatic enzyme tryptophan 2,3-dioxygenase, which provided an activating ligand to the former, to downregulate early inflammatory gene expression. However, on LPS rechallenge, AhR engaged in long-term regulation of systemic inflammation only in the presence of indoleamine 2,3-dioxygenase 1 (IDO1). AhR-complex-associated Src kinase activity promoted IDO1 phosphorylation and signalling ability. The resulting endotoxin-tolerant state was found to protect mice against immunopathology in Gram-negative and Gram-positive infections, pointing to a role for AhR in contributing to host fitness.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4098076/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4098076/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bessede, Alban -- Gargaro, Marco -- Pallotta, Maria T -- Matino, Davide -- Servillo, Giuseppe -- Brunacci, Cinzia -- Bicciato, Silvio -- Mazza, Emilia M C -- Macchiarulo, Antonio -- Vacca, Carmine -- Iannitti, Rossana -- Tissi, Luciana -- Volpi, Claudia -- Belladonna, Maria L -- Orabona, Ciriana -- Bianchi, Roberta -- Lanz, Tobias V -- Platten, Michael -- Della Fazia, Maria A -- Piobbico, Danilo -- Zelante, Teresa -- Funakoshi, Hiroshi -- Nakamura, Toshikazu -- Gilot, David -- Denison, Michael S -- Guillemin, Gilles J -- DuHadaway, James B -- Prendergast, George C -- Metz, Richard -- Geffard, Michel -- Boon, Louis -- Pirro, Matteo -- Iorio, Alfonso -- Veyret, Bernard -- Romani, Luigina -- Grohmann, Ursula -- Fallarino, Francesca -- Puccetti, Paolo -- P30 CA056036/CA/NCI NIH HHS/ -- R01 CA109542/CA/NCI NIH HHS/ -- R01 ES007685/ES/NIEHS NIH HHS/ -- R01ES007685/ES/NIEHS NIH HHS/ -- England -- Nature. 2014 Jul 10;511(7508):184-90. doi: 10.1038/nature13323.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy [2] IMS Laboratory, University of Bordeaux, 33607 Pessac, France [3]. ; 1] Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy [2]. ; Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy. ; Center for Genome Research, University of Modena and Reggio Emilia, 41125 Modena, Italy. ; Department of Chemistry and Technology of Drugs, University of Perugia, 06123 Perugia, Italy. ; 1] Experimental Neuroimmunology Unit, German Cancer Research Center, 69120 Heidelberg, Germany [2] Department of Neurooncology, University Hospital, 69120 Heidelberg, Germany. ; Center for Advanced Research and Education, Asahikawa Medical University, 078-8510 Asahikawa, Japan. ; Kringle Pharma Joint Research Division for Regenerative Drug Discovery, Center for Advanced Science and Innovation, Osaka University, 565-0871 Osaka, Japan. ; CNRS UMR6290, Institut de Genetique et Developpement de Rennes, Universite de Rennes 1, 35043 Rennes, France. ; Department of Environmental Toxicology, University of California, Davis, 95616 California, USA. ; Australian School of Advanced Medicine (ASAM), Macquarie University, 2109 New South Wales, Australia. ; Lankenau Institute for Medical Research, Wynnewood, 19096 Pennsylvania, USA. ; New Link Genetics Corporation, Ames, 50010 Iowa, USA. ; IMS Laboratory, University of Bordeaux, 33607 Pessac, France. ; Bioceros, 3584 Utrecht, The Netherlands. ; Department of Medicine, University of Perugia, 06132 Perugia, Italy. ; Department of Clinical Epidemiology & Biostatistics, McMaster University, Ontario L8S 4K1, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24930766" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bacterial Infections/immunology/metabolism ; Disease Resistance/drug effects/*genetics/*immunology ; Endotoxemia/genetics/immunology/metabolism ; Enzyme Activation/drug effects ; Gene Expression Regulation/drug effects ; Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism ; Inflammation/enzymology/genetics/metabolism ; Kynurenine/metabolism ; Lipopolysaccharides/pharmacology ; Mice ; Phosphorylation ; Receptors, Aryl Hydrocarbon/genetics/*metabolism ; Signal Transduction ; Tryptophan Oxygenase/metabolism ; src-Family Kinases/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor (2011)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2011-10-07
    Description: Activation of the aryl hydrocarbon receptor (AHR) by environmental xenobiotic toxic chemicals, for instance 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin), has been implicated in a variety of cellular processes such as embryogenesis, transformation, tumorigenesis and inflammation. But the identity of an endogenous ligand activating the AHR under physiological conditions in the absence of environmental toxic chemicals is still unknown. Here we identify the tryptophan (Trp) catabolite kynurenine (Kyn) as an endogenous ligand of the human AHR that is constitutively generated by human tumour cells via tryptophan-2,3-dioxygenase (TDO), a liver- and neuron-derived Trp-degrading enzyme not yet implicated in cancer biology. TDO-derived Kyn suppresses antitumour immune responses and promotes tumour-cell survival and motility through the AHR in an autocrine/paracrine fashion. The TDO-AHR pathway is active in human brain tumours and is associated with malignant progression and poor survival. Because Kyn is produced during cancer progression and inflammation in the local microenvironment in amounts sufficient for activating the human AHR, these results provide evidence for a previously unidentified pathophysiological function of the AHR with profound implications for cancer and immune biology.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Opitz, Christiane A -- Litzenburger, Ulrike M -- Sahm, Felix -- Ott, Martina -- Tritschler, Isabel -- Trump, Saskia -- Schumacher, Theresa -- Jestaedt, Leonie -- Schrenk, Dieter -- Weller, Michael -- Jugold, Manfred -- Guillemin, Gilles J -- Miller, Christine L -- Lutz, Christian -- Radlwimmer, Bernhard -- Lehmann, Irina -- von Deimling, Andreas -- Wick, Wolfgang -- Platten, Michael -- England -- Nature. 2011 Oct 5;478(7368):197-203. doi: 10.1038/nature10491.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurooncology, Neurology Clinic and National Center for Tumor Diseases, University Hospital of Heidelberg, 69120 Heidelberg, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21976023" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Autocrine Communication ; Brain Neoplasms/genetics/immunology/*metabolism/*pathology ; Cell Line, Tumor ; Cell Survival ; Disease Progression ; Gene Expression Regulation, Neoplastic ; Glioma/genetics/immunology/*metabolism/*pathology ; Humans ; Kynurenine/immunology/*metabolism/pharmacology/secretion ; Ligands ; Mice ; Mice, Inbred C57BL ; Mice, Nude ; Neoplasm Transplantation ; Paracrine Communication ; Receptors, Aryl Hydrocarbon/immunology/*metabolism ; Tryptophan/metabolism ; Tryptophan Oxygenase/deficiency/genetics/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 3
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    Defects in optineurin- and myosin VI-mediated cellular trafficking in amyotrophic lateral sclerosis (2015)
    Oxford University Press
    Details
    Publication Date: 2015-06-09
    Description: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder primarily affecting motor neurons. Mutations in optineurin cause a small proportion of familial ALS cases, and wild-type (WT) optineurin is misfolded and forms inclusions in sporadic ALS patient motor neurons. However, it is unknown how optineurin mutation or misfolding leads to ALS. Optineurin acts an adaptor protein connecting the molecular motor myosin VI to secretory vesicles and autophagosomes. Here, we demonstrate that ALS-linked mutations p.Q398X and p.E478G disrupt the association of optineurin with myosin VI, leading to an abnormal diffuse cytoplasmic distribution, inhibition of secretory protein trafficking, endoplasmic reticulum (ER) stress and Golgi fragmentation in motor neuron-like NSC-34 cells. We also provide further insight into the role of optineurin as an autophagy receptor. WT optineurin associated with lysosomes and promoted autophagosome fusion to lysosomes in neuronal cells, implying that it mediates trafficking of lysosomes during autophagy in association with myosin VI. However, either expression of ALS mutant optineurin or small interfering RNA-mediated knockdown of endogenous optineurin blocked lysosome fusion to autophagosomes, resulting in autophagosome accumulation. Together these results indicate that ALS-linked mutations in optineurin disrupt myosin VI-mediated intracellular trafficking processes. In addition, in control human patient tissues, optineurin displayed its normal vesicular localization, but in sporadic ALS patient tissues, vesicles were present in a significantly decreased proportion of motor neurons. Optineurin binding to myosin VI was also decreased in tissue lysates from sporadic ALS spinal cords. This study therefore links several previously described pathological mechanisms in ALS, including defects in autophagy, fragmentation of the Golgi and induction of ER stress, to disruption of optineurin function. These findings also indicate that optineurin–myosin VI dysfunction is a common feature of both sporadic and familial ALS.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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