20 results on '"Schneditz, Georg"'
Search Results
2. Cholangiocytes modulate CD100 expression in the liver and facilitate pathogenic Th17 differentiation
- Author
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Jiang, Xiaojun, primary, Otterdal, Kari, additional, Chung, Brian K., additional, Maucourant, Christopher, additional, Rønneberg, Jørgen D., additional, Zimmer, Christine L., additional, Øgaard, Jonas, additional, Boichuk, Yuliia, additional, Holm, Sverre, additional, Geanon, Daniel, additional, Schneditz, Georg, additional, Bergquist, Annika, additional, Björkström, Niklas K., additional, and Melum, Espen, additional
- Published
- 2023
- Full Text
- View/download PDF
3. Klebsiella oxytoca enterotoxins tilimycin and tilivalline have distinct host DNA-damaging and microtubule-stabilizing activities
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Unterhauser, Katrin, Pöltl, Lisa, Schneditz, Georg, Kienesberger, Sabine, Glabonjat, Ronald A., Kitsera, Maksym, Pletz, Jakob, Josa-Prado, Fernando, Dornisch, Elisabeth, Lembacher-Fadum, Christian, Roier, Sandro, Gorkiewicz, Gregor, Lucena, Daniel, Barasoain, Isabel, Kroutil, Wolfgang, Wiedner, Marc, Loizou, Joanna I., Breinbauer, Rolf, Díaz, José Fernando, Schild, Stefan, Högenauer, Christoph, and Zechner, Ellen L.
- Published
- 2019
4. Impact of human gut microbiota from PSC patients on a mouse model of biliary disease
- Author
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Hradicka, Petra, primary, Rasmussen, Henrik, additional, Schneditz, Georg, additional, Holm, Kristian, additional, Bjørnholt, Jørgen, additional, Melum, Espen, additional, and Hov, Johannes R., additional
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- 2023
- Full Text
- View/download PDF
5. Enterotoxicity of a nonribosomal peptide causes antibiotic-associated colitis
- Author
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Schneditz, Georg, Rentner, Jana, Roier, Sandro, Pletz, Jakob, Herzog, Kathrin A. T., Bücker, Roland, Troeger, Hanno, Schild, Stefan, Weber, Hansjörg, Breinbauer, Rolf, Gorkiewicz, Gregor, Högenauer, Christoph, and Zechner, Ellen L.
- Published
- 2014
6. The Toxin-Producing Pathobiont Klebsiella oxytoca Is Not Associated with Flares of Inflammatory Bowel Diseases
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Zollner-Schwetz, Ines, Herzog, Kathrin A. T., Feierl, Gebhard, Leitner, Eva, Schneditz, Georg, Sprenger, Hanna, Prattes, Jürgen, Petritsch, Wolfgang, Wenzl, Heimo, Kump, Patrizia, Gorkiewicz, Gregor, Zechner, Ellen, and Högenauer, Christoph
- Published
- 2015
- Full Text
- View/download PDF
7. Klebsiella oxytoca enterotoxins tilimycin and tilivalline have distinct host DNA-damaging and microtubulestabilizing activities
- Author
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European Commission, Ministerio de Economía y Competitividad (España), Schneditz, Georg [0000-0001-6734-5861], Kienesberger, Sabine [0000-0003-3190-3678], Kitsera, Maksym [0000-0003-1214-1313], Josa-Prado, Fernando [0000-0002-6162-3231], Roier, Sandro [0000-0003-2429-9839], Lucena-Agell, Daniel [0000-0001-7198-2900], Barasoain, Isabel [0000-0003-2013-085X], Kroutil, Wolfgang [0000-0002-2151-6394], Loizou, Joanna I. [0000-0003-1853-0424], Breinbauer, Rolf [0000-0001-6009-7359], Díaz, José Fernando [0000-0003-2743-3319], Schild, Stefan [0000-0001-7842-0177], Zechner, Ellen L. [0000-0003-2035-1898], Unterhauser, Katrin, Poltl, Lisa, Schneditz, Georg, Kienesberger, Sabine, Glabonjat, Ronald A., Kitsera, Maksym, Pletz, Jakob, Josa-Prado, Fernando, Dornisch, Elisabeth, Lembacher-Fadum, Christian, Roier, Sandro, Gorkiewicz, Gregor, Lucena-Agell, Daniel, Barasoain, Isabel, Kroutil, Wolfgang, Wiedner, Marc, Loizou, Joanna I., Breinbauer, Rolf, Díaz, José Fernando, Schild, Stefan, Hog̈enauer, Christoph, Zechner, Ellen L., European Commission, Ministerio de Economía y Competitividad (España), Schneditz, Georg [0000-0001-6734-5861], Kienesberger, Sabine [0000-0003-3190-3678], Kitsera, Maksym [0000-0003-1214-1313], Josa-Prado, Fernando [0000-0002-6162-3231], Roier, Sandro [0000-0003-2429-9839], Lucena-Agell, Daniel [0000-0001-7198-2900], Barasoain, Isabel [0000-0003-2013-085X], Kroutil, Wolfgang [0000-0002-2151-6394], Loizou, Joanna I. [0000-0003-1853-0424], Breinbauer, Rolf [0000-0001-6009-7359], Díaz, José Fernando [0000-0003-2743-3319], Schild, Stefan [0000-0001-7842-0177], Zechner, Ellen L. [0000-0003-2035-1898], Unterhauser, Katrin, Poltl, Lisa, Schneditz, Georg, Kienesberger, Sabine, Glabonjat, Ronald A., Kitsera, Maksym, Pletz, Jakob, Josa-Prado, Fernando, Dornisch, Elisabeth, Lembacher-Fadum, Christian, Roier, Sandro, Gorkiewicz, Gregor, Lucena-Agell, Daniel, Barasoain, Isabel, Kroutil, Wolfgang, Wiedner, Marc, Loizou, Joanna I., Breinbauer, Rolf, Díaz, José Fernando, Schild, Stefan, Hog̈enauer, Christoph, and Zechner, Ellen L.
- Abstract
Establishing causal links between bacterial metabolites and human intestinal disease is a significant challenge. This study reveals the molecular basis of antibiotic-associated hemorrhagic colitis (AAHC) caused by intestinal resident Klebsiella oxytoca Colitogenic strains produce the nonribosomal peptides tilivalline and tilimycin. Here, we verify that these enterotoxins are present in the human intestine during active colitis and determine their concentrations in a murine disease model. Although both toxins share a pyrrolobenzodiazepine structure, they have distinct molecular targets. Tilimycin acts as a genotoxin. Its interaction with DNA activates damage repair mechanisms in cultured cells and causes DNA strand breakage and an increased lesion burden in cecal enterocytes of colonized mice. In contrast, tilivalline binds tubulin and stabilizes microtubules leading to mitotic arrest. To our knowledge, this activity is unique for microbiota-derived metabolites of the human intestine. The capacity of both toxins to induce apoptosis in intestinal epithelial cells-a hallmark feature of AAHC-by independent modes of action, strengthens our proposal that these metabolites act collectively in the pathogenicity of colitis.
- Published
- 2019
8. Activation of the GPR35 pathway drives angiogenesis in the tumour microenvironment
- Author
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Pagano, Ester, primary, Elias, Joshua E, additional, Schneditz, Georg, additional, Saveljeva, Svetlana, additional, Holland, Lorraine M, additional, Borrelli, Francesca, additional, Karlsen, Tom H, additional, Kaser, Arthur, additional, and Kaneider, Nicole C, additional
- Published
- 2021
- Full Text
- View/download PDF
9. THU-225 - Impact of human gut microbiota from PSC patients on a mouse model of biliary disease
- Author
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Hradicka, Petra, Rasmussen, Henrik, Schneditz, Georg, Holm, Kristian, Bjørnholt, Jørgen, Melum, Espen, and Hov, Johannes R.
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- 2023
- Full Text
- View/download PDF
10. Activation of the GPR35 pathway drives angiogenesis in the tumour microenvironment.
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Pagano, Ester, Elias, Joshua E., Schneditz, Georg, Saveljeva, Svetlana, Holland, Lorraine M., Borrelli, Francesca, Karlsen, Tom H., Kaser, Arthur, and Kaneider, Nicole C.
- Subjects
CHOLANGITIS ,INTESTINAL tumors ,TUMOR microenvironment ,NEOVASCULARIZATION - Published
- 2022
- Full Text
- View/download PDF
11. GPR35 promotes glycolysis, proliferation, and oncogenic signaling by engaging with the sodium potassium pump
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Schneditz, Georg, primary, Elias, Joshua E., additional, Pagano, Ester, additional, Zaeem Cader, M., additional, Saveljeva, Svetlana, additional, Long, Kathleen, additional, Mukhopadhyay, Subhankar, additional, Arasteh, Maryam, additional, Lawley, Trevor D., additional, Dougan, Gordon, additional, Bassett, Andrew, additional, Karlsen, Tom H., additional, Kaser, Arthur, additional, and Kaneider, Nicole C., additional
- Published
- 2019
- Full Text
- View/download PDF
12. Causes of hematochezia and hemorrhagic antibiotic-associated colitis in children and adolescents
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Stampfer, Laura, primary, Deutschmann, Andrea, additional, Dür, Elisabeth, additional, Eitelberger, Franz G., additional, Fürpass, Theresia, additional, Gorkiewicz, Gregor, additional, Heinz-Erian, Peter, additional, Heller, Ingrid, additional, Herzog, Kathrin, additional, Hopfer, Barbara, additional, Kerbl, Reinhold, additional, Klug, Evelyn, additional, Krause, Robert, additional, Leitner, Eva, additional, Mache, Christoph, additional, Müller, Thomas, additional, Pansy, Jasmin, additional, Pocivalnik, Mirjam, additional, Scheuba, Eva, additional, Schneditz, Georg, additional, Schweintzger, Gerolf, additional, Sterniczky, Edith, additional, Zechner, Ellen, additional, Hauer, Almuthe C., additional, Högenauer, Christoph, additional, and Hoffmann, Karl Martin, additional
- Published
- 2017
- Full Text
- View/download PDF
13. Genetic analysis of klebsiella oxytoca cytotoxin production
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Schneditz, Georg
- Subjects
Cytotoxin ,Klebsiella oxytoca - Abstract
Georg Schneditz Zsfassung in dt. Sprache Graz, Univ., Masterarb., 2010
- Published
- 2010
14. Genotypes of Klebsiella oxytoca Isolates from Patients with Nosocomial Pneumonia Are Distinct from Those of Isolates from Patients with Antibiotic-Associated Hemorrhagic Colitis
- Author
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Herzog, Kathrin A. T., primary, Schneditz, Georg, additional, Leitner, Eva, additional, Feierl, Gebhard, additional, Hoffmann, Karl Martin, additional, Zollner-Schwetz, Ines, additional, Krause, Robert, additional, Gorkiewicz, Gregor, additional, Zechner, Ellen L., additional, and Högenauer, Christoph, additional
- Published
- 2014
- Full Text
- View/download PDF
15. Genotypes of Klebsiella oxytocaIsolates from Patients with Nosocomial Pneumonia Are Distinct from Those of Isolates from Patients with Antibiotic-Associated Hemorrhagic Colitis
- Author
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Herzog, Kathrin A. T., Schneditz, Georg, Leitner, Eva, Feierl, Gebhard, Hoffmann, Karl Martin, Zollner-Schwetz, Ines, Krause, Robert, Gorkiewicz, Gregor, Zechner, Ellen L., and Högenauer, Christoph
- Abstract
ABSTRACTKlebsiella oxytocaacts as a pathobiont in the dysbiotic human intestinal microbiota, causing antibiotic-associated hemorrhagic colitis (AAHC), but it also infects other organs, resulting in pneumonia and urinary tract and skin infections. The virulence of K. oxytocais still poorly understood. The production of a specific cytotoxin has been linked to AAHC pathogenesis. To investigate the clonal relationships of K. oxytocawith regard to clinical origin and virulence attributes, we established a multilocus sequence typing (MLST) method and analyzed 74 clinical K. oxytocaisolates from asymptomatic carriers and patients with AAHC, respiratory infections, and other infections. The isolates were phenotypically characterized, typed, and compared phylogenetically based on the sequences of seven housekeeping genes. MLST analysis yielded 60 sequence types, 12 of which were represented by more than one isolate. The phylogenetic tree distinguished clusters of K. oxytocaisolates between patients with AAHC and those with respiratory infections. Toxin-positive and -negative strains were observed within one sequence type. Our findings indicate that AAHC isolates share a genetic background. Interestingly, K. oxytocaisolates from nosocomial pneumonia showed a different genetic clustering, suggesting that these strains do not originate from the intestines or that they are specialized for respiratory tract colonization. Our results further indicate a polyphyletic origin and possible horizontal transfer of the genes involved in K. oxytocacytotoxin production. This work provides evidence that K. oxytocaisolates colonizing the two main clinically relevant habitats (lower gastrointestinal [GI] tract and respiratory tract) of the human host are genetically distinct. Applications of this MLST analysis should help clarify the sources of nosocomial infections.
- Published
- 2014
- Full Text
- View/download PDF
16. Activation of the GPR35 pathway drives angiogenesis in the tumour microenvironment
- Author
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Pagano, Ester, Elias, Joshua E, Schneditz, Georg, Saveljeva, Svetlana, Holland, Lorraine M, Borrelli, Francesca, Karlsen, Tom H, Kaser, Arthur, and Kaneider, Nicole
- Subjects
GI cancer ,angiogenesis ,receptor characterisation ,primary sclerosing cholangitis ,colorectal cancer ,ComputingMilieux_MISCELLANEOUS ,3. Good health ,ulcerative colitis - Abstract
Funder: NIHR Cambridge BRC, Objective: Primary sclerosing cholangitis (PSC) is in 70% of cases associated with inflammatory bowel disease. The hypermorphic T108M variant of the orphan G protein-coupled receptor GPR35 increases risk for PSC and ulcerative colitis (UC), conditions strongly predisposing for inflammation-associated liver and colon cancer. Lack of GPR35 reduces tumour numbers in mouse models of spontaneous and colitis associated cancer. The tumour microenvironment substantially determines tumour growth, and tumour-associated macrophages are crucial for neovascularisation. We aim to understand the role of the GPR35 pathway in the tumour microenvironment of spontaneous and colitis-associated colon cancers. Design: Mice lacking GPR35 on their macrophages underwent models of spontaneous colon cancer or colitis-associated cancer. The role of tumour-associated macrophages was then assessed in biochemical and functional assays. Results: Here, we show that GPR35 on macrophages is a potent amplifier of tumour growth by stimulating neoangiogenesis and tumour tissue remodelling. Deletion of Gpr35 in macrophages profoundly reduces tumour growth in inflammation-associated and spontaneous tumour models caused by mutant tumour suppressor adenomatous polyposis coli. Neoangiogenesis and matrix metalloproteinase activity is promoted by GPR35 via Na/K-ATPase-dependent ion pumping and Src activation, and is selectively inhibited by a GPR35-specific pepducin. Supernatants from human inducible-pluripotent-stem-cell derived macrophages carrying the UC and PSC risk variant stimulate tube formation by enhancing the release of angiogenic factors. Conclusions: Activation of the GPR35 pathway promotes tumour growth via two separate routes, by directly augmenting proliferation in epithelial cells that express the receptor, and by coordinating macrophages’ ability to create a tumour-permissive environment.
17. Activation of the GPR35 pathway drives angiogenesis in the tumour microenvironment
- Author
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Pagano, Ester, Elias, Joshua E, Schneditz, Georg, Saveljeva, Svetlana, Holland, Lorraine M, Borrelli, Francesca, Karlsen, Tom H, Kaser, Arthur, and Kaneider, Nicole C
- Subjects
GI cancer ,angiogenesis ,receptor characterisation ,primary sclerosing cholangitis ,colorectal cancer ,ComputingMilieux_MISCELLANEOUS ,3. Good health ,ulcerative colitis - Abstract
Funder: NIHR Cambridge BRC, Objective: Primary sclerosing cholangitis (PSC) is in 70% of cases associated with inflammatory bowel disease. The hypermorphic T108M variant of the orphan G protein-coupled receptor GPR35 increases risk for PSC and ulcerative colitis (UC), conditions strongly predisposing for inflammation-associated liver and colon cancer. Lack of GPR35 reduces tumour numbers in mouse models of spontaneous and colitis associated cancer. The tumour microenvironment substantially determines tumour growth, and tumour-associated macrophages are crucial for neovascularisation. We aim to understand the role of the GPR35 pathway in the tumour microenvironment of spontaneous and colitis-associated colon cancers. Design: Mice lacking GPR35 on their macrophages underwent models of spontaneous colon cancer or colitis-associated cancer. The role of tumour-associated macrophages was then assessed in biochemical and functional assays. Results: Here, we show that GPR35 on macrophages is a potent amplifier of tumour growth by stimulating neoangiogenesis and tumour tissue remodelling. Deletion of Gpr35 in macrophages profoundly reduces tumour growth in inflammation-associated and spontaneous tumour models caused by mutant tumour suppressor adenomatous polyposis coli. Neoangiogenesis and matrix metalloproteinase activity is promoted by GPR35 via Na/K-ATPase-dependent ion pumping and Src activation, and is selectively inhibited by a GPR35-specific pepducin. Supernatants from human inducible-pluripotent-stem-cell derived macrophages carrying the UC and PSC risk variant stimulate tube formation by enhancing the release of angiogenic factors. Conclusions: Activation of the GPR35 pathway promotes tumour growth via two separate routes, by directly augmenting proliferation in epithelial cells that express the receptor, and by coordinating macrophages’ ability to create a tumour-permissive environment.
18. Activation of the GPR35 pathway drives angiogenesis in the tumour microenvironment
- Author
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Pagano, Ester, Elias, Joshua E, Schneditz, Georg, Saveljeva, Svetlana, Holland, Lorraine M, Borrelli, Francesca, Karlsen, Tom H, Kaser, Arthur, and Kaneider, Nicole C
- Subjects
Neovascularization, Pathologic ,Macrophages ,receptor characterisation ,Cholangitis, Sclerosing ,primary sclerosing cholangitis ,colorectal cancer ,3. Good health ,Receptors, G-Protein-Coupled ,angiogenesis ,Disease Models, Animal ,Mice ,Colonic Neoplasms ,Tumor Microenvironment ,Animals ,Colitis, Ulcerative ,ulcerative colitis - Abstract
OBJECTIVE: Primary sclerosing cholangitis (PSC) is in 70% of cases associated with inflammatory bowel disease. The hypermorphic T108M variant of the orphan G protein-coupled receptor GPR35 increases risk for PSC and ulcerative colitis (UC), conditions strongly predisposing for inflammation-associated liver and colon cancer. Lack of GPR35 reduces tumour numbers in mouse models of spontaneous and colitis associated cancer. The tumour microenvironment substantially determines tumour growth, and tumour-associated macrophages are crucial for neovascularisation. We aim to understand the role of the GPR35 pathway in the tumour microenvironment of spontaneous and colitis-associated colon cancers. DESIGN: Mice lacking GPR35 on their macrophages underwent models of spontaneous colon cancer or colitis-associated cancer. The role of tumour-associated macrophages was then assessed in biochemical and functional assays. RESULTS: Here, we show that GPR35 on macrophages is a potent amplifier of tumour growth by stimulating neoangiogenesis and tumour tissue remodelling. Deletion of Gpr35 in macrophages profoundly reduces tumour growth in inflammation-associated and spontaneous tumour models caused by mutant tumour suppressor adenomatous polyposis coli. Neoangiogenesis and matrix metalloproteinase activity is promoted by GPR35 via Na/K-ATPase-dependent ion pumping and Src activation, and is selectively inhibited by a GPR35-specific pepducin. Supernatants from human inducible-pluripotent-stem-cell derived macrophages carrying the UC and PSC risk variant stimulate tube formation by enhancing the release of angiogenic factors. CONCLUSIONS: Activation of the GPR35 pathway promotes tumour growth via two separate routes, by directly augmenting proliferation in epithelial cells that express the receptor, and by coordinating macrophages' ability to create a tumour-permissive environment.
19. Klebsiella oxytoca enterotoxins tilimycin and tilivalline have distinct host DNA-damaging and microtubule-stabilizing activities
- Author
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Sabine Kienesberger, Maksym Kitsera, Ronald A. Glabonjat, Jakob Pletz, Stefan Schild, José Fernando Díaz, Isabel Barasoain, Daniel Lucena, Joanna I. Loizou, Georg Schneditz, Rolf Breinbauer, Ellen L. Zechner, Lisa Pöltl, Katrin Unterhauser, Christian Lembacher-Fadum, Fernando Josa-Prado, Elisabeth Dornisch, Marc Wiedner, Wolfgang Kroutil, Gregor Gorkiewicz, Sandro Roier, Christoph Högenauer, European Commission, Ministerio de Economía y Competitividad (España), Schneditz, Georg [0000-0001-6734-5861], Kienesberger, Sabine [0000-0003-3190-3678], Kitsera, Maksym [0000-0003-1214-1313], Josa-Prado, Fernando [0000-0002-6162-3231], Roier, Sandro [0000-0003-2429-9839], Lucena-Agell, Daniel [0000-0001-7198-2900], Barasoain, Isabel [0000-0003-2013-085X], Kroutil, Wolfgang [0000-0002-2151-6394], Loizou, Joanna I. [0000-0003-1853-0424], Breinbauer, Rolf [0000-0001-6009-7359], Díaz, José Fernando [0000-0003-2743-3319], Schild, Stefan [0000-0001-7842-0177], Zechner, Ellen L. [0000-0003-2035-1898], Schneditz, Georg, Kienesberger, Sabine, Kitsera, Maksym, Josa-Prado, Fernando, Roier, Sandro, Lucena-Agell, Daniel, Barasoain, Isabel, Kroutil, Wolfgang, Loizou, Joanna I., Breinbauer, Rolf, Díaz, José Fernando, Schild, Stefan, and Zechner, Ellen L.
- Subjects
intestinal microbiota ,0301 basic medicine ,Intestinal microbiota ,DNA damage ,Enterotoxin ,Microbiology ,01 natural sciences ,03 medical and health sciences ,chemistry.chemical_compound ,Microtubule ,medicine ,Colitis ,tubulin inhibitor ,antibiotic-induced diarrhea ,Multidisciplinary ,biology ,010405 organic chemistry ,Klebsiella oxytoca ,dysbiosis ,Biological Sciences ,medicine.disease ,biology.organism_classification ,Antibiotic-induced diarrhea ,0104 chemical sciences ,030104 developmental biology ,Tubulin ,PNAS Plus ,chemistry ,biology.protein ,Dysbiosis ,Tubulin inhibitor ,DNA - Abstract
10 p.-6 fig., Establishing causal links between bacterial metabolites and human intestinal disease is a significant challenge. This study reveals the molecular basis of antibiotic-associated hemorrhagic colitis (AAHC) caused by intestinal resident Klebsiella oxytoca Colitogenic strains produce the nonribosomal peptides tilivalline and tilimycin. Here, we verify that these enterotoxins are present in the human intestine during active colitis and determine their concentrations in a murine disease model. Although both toxins share a pyrrolobenzodiazepine structure, they have distinct molecular targets. Tilimycin acts as a genotoxin. Its interaction with DNA activates damage repair mechanisms in cultured cells and causes DNA strand breakage and an increased lesion burden in cecal enterocytes of colonized mice. In contrast, tilivalline binds tubulin and stabilizes microtubules leading to mitotic arrest. To our knowledge, this activity is unique for microbiota-derived metabolites of the human intestine. The capacity of both toxins to induce apoptosis in intestinal epithelial cells-a hallmark feature of AAHC-by independent modes of action, strengthens our proposal that these metabolites act collectively in the pathogenicity of colitis., We acknowledge networking contributions from European Cooperation in Science and Technology Action CM1407, “Challenging Organic Syntheses Inspired by Nature—From Natural Products Chemistry to Drug Discovery.” Research was funded by the Austrian Science Fund W901 Doktoratskolleg Molecular Enzymology (to E.L.Z., S.S., W.K., and R.B.), BioTechMed-Graz Secretome Flagship (to S.S., E.L.Z., G.G., C.H., and R.B.), and Grant BFU2016-75319-R (Agencia Española de Investigacion/Fondo Europeo de desarrollo regional, Unión Europea) (to J.F.D.) from Ministerio de Economica y Competitividad.
- Published
- 2019
20. GPR35 promotes glycolysis, proliferation, and oncogenic signaling by engaging with the sodium potassium pump
- Author
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Kathleen Long, Maryam Arasteh, Andrew R. Bassett, M. Zaeem Cader, Arthur Kaser, Trevor D. Lawley, Ester Pagano, Svetlana Saveljeva, Gordon Dougan, Joshua E. Elias, Subhankar Mukhopadhyay, Tom H. Karlsen, Nicole C. Kaneider, Georg Schneditz, Schneditz, G., Elias, J. E., Pagano, E., Zaeem Cader, M., Saveljeva, S., Long, K., Mukhopadhyay, S., Arasteh, M., Lawley, T. D., Dougan, G., Bassett, A., Karlsen, T. H., Kaser, A., Kaneider, N. C., Schneditz, Georg [0000-0001-6734-5861], Elias, Joshua E [0000-0003-2137-117X], Zaeem Cader, M [0000-0002-4121-748X], Saveljeva, Svetlana [0000-0002-0644-9752], Bassett, Andrew [0000-0003-1632-9137], Kaser, Arthur [0000-0003-1419-3344], Kaneider, Nicole C [0000-0002-6079-4389], and Apollo - University of Cambridge Repository
- Subjects
Carcinogenesis ,THP-1 Cells ,Biochemistry ,Polymorphism, Single Nucleotide ,Article ,Receptors, G-Protein-Coupled ,03 medical and health sciences ,0302 clinical medicine ,Intestinal mucosa ,Animals ,Humans ,Na+/K+-ATPase ,Pepducin ,Intestinal Mucosa ,Molecular Biology ,Ion transporter ,030304 developmental biology ,Cell Proliferation ,Mice, Knockout ,0303 health sciences ,Chemistry ,Macrophages ,Epithelial Cells ,Cell Biology ,Cell biology ,HEK293 Cells ,src-Family Kinases ,Colitis, Ulcerative ,Signal transduction ,Sodium-Potassium-Exchanging ATPase ,GPR35 ,Glycolysis ,030217 neurology & neurosurgery ,Homeostasis ,Proto-oncogene tyrosine-protein kinase Src ,Signal Transduction - Abstract
The sodium potassium pump (Na/K-ATPase) ensures the electrochemical gradient of a cell through an energy-dependent process that consumes approximately one third of regenerated ATP. We report that the G protein-coupled receptor GPR35 interacted with the α chain of Na/K-ATPase and promotes its ion transport and Src signaling activity in a ligand-independent manner. Deletion of Gpr35 increased baseline Ca(2+) to maximal levels and reduced Src activation and overall metabolic activity in macrophages and intestinal epithelial cells (IECs). In contrast, a common T108M polymorphism in GPR35 was hypermorphic and had the opposite effects to Gpr35 deletion on Src activation and metabolic activity. The T108M polymorphism is associated with ulcerative colitis and primary sclerosing cholangitis, inflammatory diseases with a high cancer risk. GPR35 promoted homeostatic IEC turnover, whereas Gpr35 deletion or inhibition by a selective pepducin prevented inflammation-associated and spontaneous intestinal tumorigenesis in mice. Thus, GPR35 acts as a central signaling and metabolic pacesetter, which reveals an unexpected role of Na/K-ATPase in macrophage and IEC biology.
- Published
- 2019
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