188 results on '"Sailer, Andreas W."'
Search Results
2. Gut-inhabiting Clostridia build human GPCR ligands by conjugating neurotransmitters with diet- and human-derived fatty acids
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Chang, Fang-Yuan, Siuti, Piro, Laurent, Stephane, Williams, Thomas, Glassey, Emerson, Sailer, Andreas W., Gordon, David Benjamin, Hemmerle, Horst, and Voigt, Christopher A.
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- 2021
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3. Publisher Correction: Gut-inhabiting Clostridia build human GPCR ligands by conjugating neurotransmitters with diet- and human-derived fatty acids
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Chang, Fang-Yuan, Siuti, Piro, Laurent, Stephane, Williams, Thomas, Glassey, Emerson, Sailer, Andreas W., Gordon, David Benjamin, Hemmerle, Horst, and Voigt, Christopher A.
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- 2021
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4. Genome-wide CRISPR screen for PARKIN regulators reveals transcriptional repression as a determinant of mitophagy
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Potting, Christoph, Crochemore, Christophe, Moretti, Francesca, Nigsch, Florian, Schmidt, Isabel, Manneville, Carole, Carbone, Walter, Knehr, Judith, DeJesus, Rowena, Lindeman, Alicia, Maher, Rob, Russ, Carsten, McAllister, Gregory, Reece-Hoyes, John S., Hoffman, Gregory R., Roma, Guglielmo, Müller, Matthias, Sailer, Andreas W., and Helliwell, Stephen B.
- Published
- 2018
5. The EBI2-oxysterol axis promotes the development of intestinal lymphoid structures and colitis
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Wyss, Annika, Raselli, Tina, Perkins, Nathan, Ruiz, Florian, Schmelczer, Gérard, Klinke, Glynis, Moncsek, Anja, Roth, René, Spalinger, Marianne R., Hering, Larissa, Atrott, Kirstin, Lang, Silvia, Frey-Wagner, Isabelle, Mertens, Joachim C., Scharl, Michael, Sailer, Andreas W., Pabst, Oliver, Hersberger, Martin, Pot, Caroline, Rogler, Gerhard, and Misselwitz, Benjamin
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- 2019
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6. A Role for the Melanocortin 4 Receptor in Sexual Function
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Martin, William J., Howard, Andrew D., Nargund, Ravi P., Austin, Christopher P., Guan, Xiaoming, Drisko, Jennifer, Cashen, Doreen, Sebhat, Iyassu, Patchett, Arthur A., Figueroa, David J., DiLella, Anthony G., Connolly, Brett M., Weinberg, David H., Tan, Carina P., Palyha, Oksana C., Pong, Sheng-Shung, MacNeil, Tanya, Rosenblum, Charles, Vongs, Aurawan, Tang, Rui, Yu, Hong, Sailer, Andreas W., Fong, Tung Ming, Huang, Cathy, Tota, Michael R., Chang, Ray S., Stearns, Ralph, Tamvakopoulos, Constantin, Christ, George, Drazen, Deborah L., Spar, Brian D., Nelson, Randy J., and MacIntyre, D. Euan
- Published
- 2002
7. Identification and Characterization of a Second Melanin-Concentrating Hormone Receptor, MCH-2R
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Sailer, Andreas W., Sano, Hideki, Zeng, Zhizhen, McDonald, Terrence P., Pan, Jie, Pong, Sheng-Shung, Feighner, Scott D., Tan, Carina P., Fukami, Takehiro, Iwaasa, Hisashi, Hreniuk, Donna L., Morin, Nancy R., Sadowski, Sharon J., Ito, Makoto, Ito, Masahiko, Bansal, Alka, Ky, Betty, Figueroa, David J., Jiang, Qingping, Austin, Christopher P., MacNeil, Douglas J., Ishihara, Akane, Ihara, Masaki, Kanatani, Akio, Howard, Andrew D., and Liu, Qingyun
- Published
- 2001
8. Reduced Plasma Levels of 25-Hydroxycholesterol and Increased Cerebrospinal Fluid Levels of Bile Acid Precursors in Multiple Sclerosis Patients
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Crick, Peter J., Griffiths, William J., Zhang, Juan, Beibel, Martin, Abdel-Khalik, Jonas, Kuhle, Jens, Sailer, Andreas W., and Wang, Yuqin
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- 2016
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9. Naive B-cell trafficking is shaped by local chemokine availability and LFA-1–independent stromal interactions
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Coelho, Fernanda M., Natale, Daniela, Soriano, Silvia F., Hons, Miroslav, Swoger, Jim, Mayer, Jürgen, Danuser, Renzo, Scandella, Elke, Pieczyk, Markus, Zerwes, Hans-Günter, Junt, Tobias, Sailer, Andreas W., Ludewig, Burkhard, Sharpe, James, Figge, Marc Thilo, and Stein, Jens V.
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- 2013
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10. Detection of dihydroxycholesterols in human plasma using HPLC–ESI-MS/MS
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Karuna, Ratna, Christen, Isabelle, Sailer, Andreas W., Bitsch, Francis, and Zhang, Juan
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- 2015
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11. EBI2 regulates intracellular signaling and migration in human astrocyte
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Rutkowska, Aleksandra, Preuss, Inga, Gessier, Francois, Sailer, Andreas W., and Dev, Kumlesh K.
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- 2015
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12. EBI2 Is Temporarily Upregulated in MO3.13 Oligodendrocytes during Maturation and Regulates Remyelination in the Organotypic Cerebellar Slice Model
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Velasco-Estevez, Maria, Koch, Nina, Klejbor, Ilona, Laurent, Stephane, Dev, Kumlesh K., Sailer, Andreas W., and Rutkowska, Aleksandra
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remyelination ,organotypic slice model ,nervous system ,cell migration ,MO3.13 oligodendrocytes ,EBI2 receptor ,receptor trafficking ,chemotaxis - Abstract
Research journal article in the field of Neuroscience. The paper reports research data on EBI2 receptor expression in the cells of the CNS (oligodendrocyte progenitor cells, oligodendrocytes, microglia, neurons and astrocytes) and the effects of EBI2 receptor on remyelination in organotypic cerebellar slices.
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- 2021
13. Cholestenoic acids regulate motor neuron survival via liver X receptors
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Theofilopoulos, Spyridon, Griffiths, William J., Crick, Peter J., Yang, Shanzheng, Meljon, Anna, Ogundare, Michael, Kitambi, Satish Srinivas, Lockhart, Andrew, Tuschl, Karin, Clayton, Peter T., Morris, Andrew A., Martinez, Adelaida, Reddy, Ashwin M., Martinuzzi, Andrea, Bassi, Maria T., Honda, Akira, Mizuochi, Tatsuki, Kimura, Akihiko, Nittono, Hiroshi, De Michele, Giuseppe, Carbone, Rosa, Criscuolo, Chiara, Yau, Joyce L., Seckl, Jonathan R., Schüle, Rebecca, Schöls, Ludger, Sailer, Andreas W., Kuhle, Jens, Fraidakis, Matthew J., Gustafsson, Jan-Åke, Steffensen, Knut R., Björkhem, Ingemar, Ernfors, Patrik, Sjövall, Jan, Arenas, Ernest, and Wang, Yuqin
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- 2014
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14. The protein interacting with C-kinase (PICK1) interacts with and attenuates parkin-associated endothelial-like (PAEL) receptor-mediated cell death
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Dutta, Priyanka, OʼConnell, Kara E., Ozkan, Sefika B., Sailer, Andreas W., and Dev, Kumlesh K.
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- 2014
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15. Preferential amplification of a human mitochondrial DNA deletion in vitro and in vivo
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Russell, Oliver M., Fruh, Isabelle, Rai, Pavandeep K., Marcellin, David, Doll, Thierry, Reeve, Amy, Germain, Mitchel, Bastien, Julie, Rygiel, Karolina A., Cerino, Raffaele, Sailer, Andreas W., Lako, Majlinda, Taylor, Robert W., Mueller, Matthias, Lightowlers, Robert N., Turnbull, Doug M., and Helliwell, Stephen B.
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Induced Pluripotent Stem Cells ,lcsh:R ,lcsh:Medicine ,Cell Differentiation ,Fibroblasts ,DNA, Mitochondrial ,Article ,Cell Line ,Clone Cells ,Mitochondria ,Humans ,Point Mutation ,lcsh:Q ,lcsh:Science ,Sequence Deletion - Abstract
We generated induced pluripotent stem cells (iPSCs) from patient fibroblasts to yield cell lines containing varying degrees of heteroplasmy for a m.13514 A > G mtDNA point mutation (2 lines) and for a ~6 kb single, large scale mtDNA deletion (3 lines). Long term culture of the iPSCs containing a single, large-scale mtDNA deletion showed consistent increase in mtDNA deletion levels with time. Higher levels of mtDNA heteroplasmy correlated with increased respiratory deficiency. To determine what changes occurred in deletion level during differentiation, teratomas comprising all three embryonic germ layers were generated from low (20%) and intermediate heteroplasmy (55%) mtDNA deletion clones. Regardless of whether iPSCs harbouring low or intermediate mtDNA heteroplasmy were used, the final levels of heteroplasmy in all teratoma germ layers increased to a similar high level (>60%). Thus, during human stem cell division, cells not only tolerate high mtDNA deletion loads but seem to preferentially replicate deleted mtDNA genomes. This has implications for the involvement of mtDNA deletions in both disease and ageing.
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- 2018
16. A role for the melanocortin 4 receptor in sexual function
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Van der Ploeg, Lex H.T., Martin, William J., Howard, Andrew D., Nargund, Ravi P., Austin, Christopher P., Guan, Xiaoming, Drisko, Jennifer, Cashen, Doreen, Sebhat, Iyassu, Patchett, Arthur A., Figueroa, David J., DiLella, Anthony G., Connolly, Brett M., Weinberg, David H., Tan, Carina P., Palyha, Oksana C., Pong, Sheng-Shung, MacNeil, Tanya, Rosenblum, Charles, Vongs, Aurawan, Tang, Rui, Yu, Hong, Sailer, Andreas W., Fong, Tung Ming, Huang, Cathy, Tota, Michael R., Chang, Ray S., Stearns, Ralph, Tamvakopoulos, Constantin, Christ, George, Drazen, Deborah L., Spar, Brian D., Nelson, Randy J., and MacIntyre, Euan D.
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Energy metabolism -- Physiological aspects ,Ingestion -- Physiological aspects ,Penis -- Physiological aspects ,Sex (Biology) -- Physiological aspects ,Science and technology - Abstract
By using a combination of genetic, pharmacological, and anatomical approaches, we show that the melanocortin 4 receptor (MC4R), implicated in the control of food intake and energy expenditure, also modulates erectile function and sexual behavior. Evidence supporting this notion is based on several findings: (i) a highly selective non-peptide MC4R agonist augments erectile activity initiated by electrical stimulation of the cavernous nerve in wild-type but not Mc4r-null mice; (ii) copulatory behavior is enhanced by administration of a selective MC4R agonist and is diminished in mice lacking Mc4r; (iii) reverse transcription (RT)-PCR and non-PCR based methods demonstrate MC4R expression in rat and human penis, and rat spinal cord, hypothalamus, brainstem, pelvic ganglion (major autonomic relay center to the penis), but not in rat primary corpus smooth muscle cavernosum cells; and (iv) in situ hybridization of glans tissue from the human and rat penis reveal MC4R expression in nerve fibers and mechanoreceptors in the glans of the penis. Collectively, these data implicate the MC4R in the modulation of penile erectile function and provide evidence that MC4R-mediated proerectile responses may be activated through neuronal circuitry in spinal cord erectile centers and somatosensory afferent nerve terminals of the penis. Our results provide a basis for the existence of MC4R-controlled neuronal pathways that control sexual function.
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- 2002
17. Oxysterol Gradient Generation by Lymphoid Stromal Cells Guides Activated B Cell Movement during Humoral Responses
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Yi, Tangsheng, Wang, Xiaoming, Kelly, Lisa M., An, Jinping, Xu, Ying, Sailer, Andreas W., Gustafsson, Jan-Ake, Russell, David W., and Cyster, Jason G.
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- 2012
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18. Oxysterols direct immune cell migration via EBI2
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Hannedouche, Sébastien, Zhang, Juan, Yi, Tangsheng, Shen, Weijun, Nguyen, Deborah, Pereira, João P., Guerini, Danilo, Baumgarten, Birgit U., Roggo, Silvio, Wen, Ben, Knochenmuss, Richard, Noël, Sophie, Gessier, Francois, Kelly, Lisa M., Vanek, Mirka, Laurent, Stephane, Preuss, Inga, Miault, Charlotte, Christen, Isabelle, Karuna, Ratna, Li, Wei, Koo, Dong-In, Suply, Thomas, Schmedt, Christian, Peters, Eric C., Falchetto, Rocco, Katopodis, Andreas, Spanka, Carsten, Roy, Marie-Odile, Detheux, Michel, Chen, Yu Alice, Schultz, Peter G., Cho, Charles Y., Seuwen, Klaus, Cyster, Jason G., and Sailer, Andreas W.
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- 2011
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19. Neuropeptide S receptor deficiency modulates spontaneous locomotor activity and the acoustic startle response
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Fendt, Markus, Buchi, Mélanie, Bürki, Hugo, Imobersteg, Stefan, Ricoux, Bérangère, Suply, Thomas, and Sailer, Andreas W.
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- 2011
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20. The oxysterol receptor GPR183 in inflammatory bowel diseases.
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Misselwitz, Benjamin, Wyss, Annika, Raselli, Tina, Cerovic, Vuk, Sailer, Andreas W., Krupka, Niklas, Ruiz, Florian, Pot, Caroline, and Pabst, Oliver
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INFLAMMATORY bowel diseases ,BEHCET'S disease ,INNATE lymphoid cells ,LYMPHOID tissue ,SODIUM sulfate ,COLITIS - Abstract
Immune cell trafficking is an important mechanism for the pathogenesis of inflammatory bowel disease (IBD). The oxysterol receptor GPR183 and its ligands, dihydroxylated oxysterols, can mediate positioning of immune cells including innate lymphoid cells. GPR183 has been mapped to an IBD risk locus, however another gene, Ubac2 is encoded on the reverse strand and associated with Behçet's disease, therefore the role of GPR183 as a genetic risk factor requires validation. GPR183 and production of its oxysterol ligands are up-regulated in human IBD and murine colitis. Gpr183 inactivation reduced severity of colitis in group 3 innate lymphoid cells-dependent colitis and in IL-10 colitis but not in dextran sodium sulphate colitis. Irrespectively, Gpr183 knockout strongly reduced accumulation of intestinal lymphoid tissue in health and all colitis models. In conclusion, genetic, translational and experimental studies implicate GPR183 in IBD pathogenesis and GPR183-dependent cell migration might be a therapeutic drug target for IBD. LINKED ARTICLES: This article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc. [ABSTRACT FROM AUTHOR]
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- 2021
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21. NIBR-LTSi is a selective LATS kinase inhibitor activating YAP signaling and expanding tissue stem cells in vitroand in vivo
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Namoto, Kenji, Baader, Clara, Orsini, Vanessa, Landshammer, Alexandro, Breuer, Eva, Dinh, Kieu Trinh, Ungricht, Rosemarie, Pikiolek, Monika, Laurent, Stephane, Lu, Bo, Aebi, Alexandra, Schönberger, Katharina, Vangrevelinghe, Eric, Evrova, Olivera, Sun, Tianliang, Annunziato, Stefano, Lachal, Julie, Redmond, Emily, Wang, Louis, Wetzel, Kristie, Capodieci, Paola, Turner, Jonathan, Schutzius, Gabi, Unterreiner, Vincent, Trunzer, Markus, Buschmann, Nicole, Behnke, Dirk, Machauer, Rainer, Scheufler, Clemens, Parker, Christian N., Ferro, Magali, Grevot, Armelle, Beyerbach, Armin, Lu, Wei-Yu, Forbes, Stuart J., Wagner, Jürgen, Bouwmeester, Tewis, Liu, Jun, Sohal, Bindi, Sahambi, Sukhdeep, Greenbaum, Linda E., Lohmann, Felix, Hoppe, Philipp, Cong, Feng, Sailer, Andreas W., Ruffner, Heinz, Glatthar, Ralf, Humar, Bostjan, Clavien, Pierre-Alain, Dill, Michael T., George, Elizabeth, Maibaum, Jürgen, Liberali, Prisca, and Tchorz, Jan S.
- Abstract
The YAP/Hippo pathway is an organ growth and size regulation rheostat safeguarding multiple tissue stem cell compartments. LATS kinases phosphorylate and thereby inactivate YAP, thus representing a potential direct drug target for promoting tissue regeneration. Here, we report the identification and characterization of the selective small-molecule LATS kinase inhibitor NIBR-LTSi. NIBR-LTSi activates YAP signaling, shows good oral bioavailability, and expands organoids derived from several mouse and human tissues. In tissue stem cells, NIBR-LTSi promotes proliferation, maintains stemness, and blocks differentiation in vitroand in vivo. NIBR-LTSi accelerates liver regeneration following extended hepatectomy in mice. However, increased proliferation and cell dedifferentiation in multiple organs prevent prolonged systemic LATS inhibition, thus limiting potential therapeutic benefit. Together, we report a selective LATS kinase inhibitor agonizing YAP signaling and promoting tissue regeneration in vitroand in vivo, enabling future research on the regenerative potential of the YAP/Hippo pathway.
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- 2024
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22. Cholestenoic acids regulate motor neuron survival via liver X receptors
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Theofilopoulos, Spyridon Griffiths, William J. Crick, Peter J. and Yang, Shanzheng Meljon, Anna Ogundare, Michael Kitambi, Satish Srinivas Lockhart, Andrew Tuschl, Karin Clayton, Peter T. Morris, Andrew A. Martinez, Adelaide Reddy, M. Ashwin Martinuzzi, Andrea Bassi, Maria T. Honda, Akira and Mizuochi, Tatsuki Kimura, Akihiko Nittono, Hiroshi De Michele, Giuseppe Carbone, Rosa Criscuolo, Chiara Yau, Joyce L. Seckl, Jonathan R. Schuele, Rebecca Schoels, Ludger and Sailer, Andreas W. Kuhle, Jens Fraidakis, Matthew J. and Gustafsson, Jan-Ake Steffensen, Knut R. Bjorkhem, Ingemar and Ernfors, Patrik Sjovall, Jan Arenas, Ernest Wang, Yuqin
- Abstract
Cholestenoic acids are formed as intermediates in metabolism of cholesterol to bile acids, and the biosynthetic enzymes that generate cholestenoic acids are expressed in the mammalian CNS. Here, we evaluated the cholestenoic acid profile of mammalian cerebrospinal fluid (CSF) and determined that specific cholestenoic acids activate the liver X receptors (LXRs), enhance islet-1 expression in zebrafish, and increase the number of oculomotor neurons in the developing mouse in vitro and in vivo. While 3 beta,7 alpha-dihydroxycholest-5-en-26-oic acid (3 beta,7 alpha-diHCA) promoted motor neuron survival in an LXR-dependent manner, 3 beta-hydroxy-7-oxocholest-5-en-26-oic acid (3 beta H,70-CA) promoted maturation of precursors into islet-1(+) cells. Unlike 3 beta,7 alpha-diHCA and 3 beta H,70-CA, 3 beta-hydroxycholest-5-en-26-oic acid (3 beta-HCA) caused motor neuron cell loss in mice. Mutations in CYP7B1 or CYP27A7, which encode enzymes involved in cholestenoic acid metabolism, result in different neurological diseases, hereditary spastic paresis type 5 (SPG5) and cerebrotendinous xanthomatosis (CTX), respectively. SPG5 is characterized by spastic paresis, and similar symptoms may occur in CTX. Analysis of CSF and plasma from patients with SPG5 revealed an excess of the toxic LXR ligand, 3 beta-HCA, while patients with CTX and SPG5 exhibited low levels of the survival-promoting LXR ligand 3 beta,7 alpha-diHCA. Moreover, 3 beta,7 alpha-diHCA prevented the loss of motor neurons induced by 3 beta-HCA in the developing mouse midbrain in vivo.Our results indicate that specific cholestenoic acids selectively work on motor neurons, via LXR, to regulate the balance between survival and death.
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- 2014
23. EBI2 receptor regulates myelin development and inhibits LPC-induced demyelination.
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Rutkowska, Aleksandra, Sailer, Andreas W., and Dev, Kumlesh K.
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EPSTEIN-Barr virus , *G protein coupled receptors , *LYSOLECITHIN , *DEMYELINATION , *CELL migration , *ANIMALS , *CELL receptors , *CEREBELLUM , *RESEARCH methodology , *MICE , *NERVE tissue , *NERVE tissue proteins , *PHOSPHOLIPIDS , *TISSUE culture - Abstract
Background: The G protein-coupled receptor EBI2 (Epstein-Barr virus-induced gene 2) is activated by 7α, 25-dihydroxycholesterol (7α25HC) and plays a role in T cell-dependant antibody response and B cell migration. Abnormal EBI2 signaling is implicated in a range of autoimmune disorders; however, its role in the CNS remains poorly understood.Methods: Here we characterize the role of EBI2 in myelination under normal and pathophysiological conditions using organotypic cerebellar slice cultures and EBI2 knock-out (KO) animals.Results: We find that MBP expression in brains taken from EBI2 KO mice is delayed compared to those taken from wild type (WT) mice. In agreement with these in vivo findings, we show that antagonism of EBI2 reduces MBP expression in vitro. Importantly, we demonstrate that EBI2 activation attenuates lysolecithin (LPC)-induced demyelination in mouse organotypic slice cultures. Moreover, EBI2 activation also inhibits LPC-mediated release of pro-inflammatory cytokines such as IL6 and IL1β in cerebellar slices.Conclusions: These results, for the first time, display a role for EBI2 in myelin development and protection from demyelination under pathophysiological conditions and suggest that modulation of this receptor may be beneficial in neuroinflammatory and demyelinating disorders such as multiple sclerosis. [ABSTRACT FROM AUTHOR]- Published
- 2017
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24. An Activating Janus Kinase-3 Mutation is Associated with Cytotoxic T Lymphocyte Antigen-4-Dependent Immune Dysregulation Syndrome.
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Sic, Heiko, Speletas, Matthaios, Cornacchione, Vanessa, Seidl, Maximillian, Beibel, Martin, Linghu, Bolan, Fan Yang, Sevdali, Eirini, Germenis, Anastasios E., Oakeley, Edward J., Vangrevelinghe, Eric, Sailer, Andreas W., Traggiai, Elisabetta, Gram, Hermann, and Eibel, Hermann
- Subjects
CYTOTOXIC T lymphocyte-associated molecule-4 ,JANUS kinases ,IMMUNOLOGIC diseases - Abstract
Heterozygous mutations in the cytotoxic T lymphocyte antigen-4 (CTLA-4) are associated with lymphadenopathy, autoimmunity, immune dysregulation, and hypogammaglob- ulinemia in about 70% of the carriers. So far, the incomplete penetrance of CTLA-4 haploinsufficiency has been attributed to unknown genetic modifiers, epigenetic changes, or environmental effects. We sought to identify potential genetic modifiers in a family with differential clinical penetrance of CTLA-4 haploinsufficiency. Here, we report on a rare heterozygous gain-of-function mutation in Janus kinase-3 (JAK3) (p.R840C), which is associated with the clinical manifestation of CTLA-4 haploinsufficiency in a patient carrying a novel loss-of-function mutation in CTLA-4 (p.Y139C). While the asymptomatic parents carry either the CTLA-4 mutation or the JAK3 variant, their son has inherited both heterozygous mutations and suffers from hypogammaglobulinemia combined with autoimmunity and lymphoid hyperplasia. Although the patient's lymph node and spleen contained many hyperplastic germinal centers with follicular helper T (TFH) cells and immunoglobulin (Ig) G-positive B cells, plasma cell, and memory B cell development was impaired. CXCR5+PD-1+TIGIT+ TFH cells contributed to a large part of circulating T cells, but they produced only very low amounts of interleukin (IL)-4, IL-10, and IL-21 required for the development of memory B cells and plasma cells. We, therefore, suggest that the combination of the loss-of-function mutation in CTLA-4 with the gain-of-function mutation in JAK3 directs the differentiation of CD4 T cells into dysfunctional TFH cells supporting the development of lymphadenopathy, hypogammaglobulinemia, and immu- nodeficiency. Thus, the combination of rare genetic heterozygous variants that remain clinically unnoticed individually may lead to T cell hyperactivity, impaired memory B cell, and plasma cell development resulting finally in combined immunodeficiency. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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25. Elevated oxysterol levels in human and mouse livers reflect nonalcoholic steatohepatitis[S]
- Author
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Raselli, Tina, Hearn, Tom, Wyss, Annika, Atrott, Kirstin, Peter, Alain, Frey-Wagner, Isabelle, Spalinger, Marianne R., Maggio, Ewerton M., Sailer, Andreas W., Schmitt, Johannes, Schreiner, Philipp, Moncsek, Anja, Mertens, Joachim, Scharl, Michael, Griffiths, William J., Bueter, Marco, Geier, Andreas, Rogler, Gerhard, Wang, Yuqin, and Misselwitz, Benjamin
- Abstract
Nonalcoholic steatohepatitis (NASH), a primary cause of liver disease, leads to complications such as fibrosis, cirrhosis, and carcinoma, but the pathophysiology of NASH is incompletely understood. Epstein-Barr virus-induced G protein-coupled receptor 2 (EBI2) and its oxysterol ligand 7α,25-dihydroxycholesterol (7α,25-diHC) are recently discovered immune regulators. Several lines of evidence suggest a role of oxysterols in NASH pathogenesis, but rigorous testing has not been performed. We measured oxysterol levels in the livers of NASH patients by LC-MS and tested the role of the EBI2-7α,25-diHC system in a murine feeding model of NASH. Free oxysterol profiling in livers from NASH patients revealed a pronounced increase in 24- and 7-hydroxylated oxysterols in NASH compared with controls. Levels of 24- and 7-hydroxylated oxysterols correlated with histological NASH activity. Histological analysis of murine liver samples demonstrated ballooning and liver inflammation. No significant genotype-related differences were observed in Ebi2−/−mice and mice with defects in the 7α,25-diHC synthesizing enzymes CH25H and CYP7B1 compared with wild-type littermate controls, arguing against an essential role of these genes in NASH pathogenesis. Elevated 24- and 7-hydroxylated oxysterol levels were confirmed in murine NASH liver samples. Our results suggest increased bile acid synthesis in NASH samples, as judged by the enhanced level of 7α-hydroxycholest-4-en-3-one and impaired 24S-hydroxycholesterol metabolism as characteristic biochemical changes in livers affected by NASH.
- Published
- 2019
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26. Oxysterols direct immune cell migration through EBI2
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Hannedouche, Sébastien, Zhang, Juan, Yi, Tangsheng, Shen, Weijun, Nguyen, Deborah, Pereira, João P., Guerini, Danilo, Baumgarten, Birgit U., Roggo, Silvio, Wen, Ben, Knochenmuss, Richard, Noël, Sophie, Gessier, Francois, Kelly, Lisa M., Vanek, Mirka, Laurent, Stephane, Preuss, Inga, Miault, Charlotte, Christen, Isabelle, Karuna, Ratna, Li, Wei, Koo, Dong-In, Suply, Thomas, Schmedt, Christian, Peters, Eric C., Falchetto, Rocco, Katopodis, Andreas, Spanka, Carsten, Roy, Marie-Odile, Detheux, Michel, Chen, Yu Alice, Schultz, Peter G., Cho, Charles Y., Seuwen, Klaus, Cyster, Jason G., and Sailer, Andreas W.
- Subjects
Mice, Knockout ,B-Lymphocytes ,Sheep ,Gene Expression Profiling ,T-Lymphocytes ,Receptors, Cell Surface ,Article ,Hydroxycholesterols ,Cell Line ,Receptors, G-Protein-Coupled ,Mice ,Gene Expression Regulation ,Liver ,Cell Movement ,Antibody Formation ,Animals ,Humans - Abstract
Epstein-Barr virus-induced gene 2 (EBI2, also known as GPR183) is a G-protein-coupled receptor that is required for humoral immune responses; polymorphisms in the receptor have been associated with inflammatory autoimmune diseases. The natural ligand for EBI2 has been unknown. Here we describe the identification of 7α,25-dihydroxycholesterol (also called 7α,25-OHC or 5-cholesten-3β,7α,25-triol) as a potent and selective agonist of EBI2. Functional activation of human EBI2 by 7α,25-OHC and closely related oxysterols was verified by monitoring second messenger readouts and saturable, high-affinity radioligand binding. Furthermore, we find that 7α,25-OHC and closely related oxysterols act as chemoattractants for immune cells expressing EBI2 by directing cell migration in vitro and in vivo. A critical enzyme required for the generation of 7α,25-OHC is cholesterol 25-hydroxylase (CH25H). Similar to EBI2 receptor knockout mice, mice deficient in CH25H fail to position activated B cells within the spleen to the outer follicle and mount a reduced plasma cell response after an immune challenge. This demonstrates that CH25H generates EBI2 biological activity in vivo and indicates that the EBI2-oxysterol signalling pathway has an important role in the adaptive immune response.
- Published
- 2011
27. Oxysterol-EBI2 signaling in immune regulation and viral infection
- Author
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Daugvilaite, Viktorija, Arfelt, Kristine Niss, Benned-Jensen, Tau, Sailer, Andreas W, Rosenkilde, Mette M, Daugvilaite, Viktorija, Arfelt, Kristine Niss, Benned-Jensen, Tau, Sailer, Andreas W, and Rosenkilde, Mette M
- Abstract
The seven transmembrane G protein-coupled receptor Epstein-Barr virus (EBV) induced gene 2 (EBI2; also known as GPR183) was identified in 1993 on the basis of its substantial upregulation in EBV-infected cells. It is primarily expressed in lymphoid cells; most abundantly in B cells. EBI2 is central for the positioning of B cells within the lymphoid organs, a process that is regulated in part by a chemotactic gradient formed by the endogenous lipid agonists, and in part by a fine-tuned regulation of EBI2 cell surface expression. The most potent endogenous EBI2 agonist is 7α, 25-dihydroxyxcholesterol (7α,25-OHC), yet many structurally related oxysterols can bind to an EBI2 pocket that is defined by the upper parts of the transmembrane helices and extracellular receptor regions. EBI2 signals via Gαi, as well as via G protein-independent pathways like β-arrestin recruitment. The concerted action of these pathways leads to cell migration. By genetically interfering with its up- and downregulation, EBI2 was also recently shown to induce cell proliferation, an action that could be inhibited by small molecule antagonists. Here, we focus on the oxysterol-EBI2 axis in immune control, including its role in the EBV life cycle. We also summarize the structural and functional properties of EBI2 interaction with oxysterol agonists and small molecule antagonists and discuss EBI2 as therapeutic target for diseases of the immune system.
- Published
- 2014
28. Identification and characterization of small molecule modulators of the Epstein-Barr virus-induced gene 2 (EBI2) receptor
- Author
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Gessier, Francois, Preuss, Inga, Yin, Hong, Rosenkilde, Mette Marie, Laurent, Stephane, Endres, Ralf, Chen, Yu A, Marsilje, Thomas H, Seuwen, Klaus, Nguyen, Deborah G, Sailer, Andreas W, Gessier, Francois, Preuss, Inga, Yin, Hong, Rosenkilde, Mette Marie, Laurent, Stephane, Endres, Ralf, Chen, Yu A, Marsilje, Thomas H, Seuwen, Klaus, Nguyen, Deborah G, and Sailer, Andreas W
- Abstract
Oxysterols have recently been identified as natural ligands for a G protein-coupled receptor called EBI2 (aka GPR183) ( Nature 2011 , 475 , 524 ; 519 ). EBI2 is highly expressed in immune cells ( J. Biol. Chem. 2006 , 281 , 13199 ), and its activation has been shown to be critical for the adaptive immune response and has been genetically linked to autoimmune diseases such as type I diabetes ( Nature 2010 , 467 , 460 ). Here we describe the isolation of a potent small molecule antagonist for the EBI2 receptor. First, we identified a small molecule agonist NIBR51 (1), which enabled identification of inhibitors of receptor activation. One antagonist called NIBR127 (2) was used as a starting point for a medicinal chemistry campaign, which yielded NIBR189 (4m). This compound was extensively characterized in binding and various functional signaling assays. Furthermore, we have used 4m to block migration of a monocyte cell line called U937, suggesting a functional role of the oxysterol/EBI2 pathway in these immune cells.
- Published
- 2014
29. EBI2 Expression and Function: Robust in Memory Lymphocytes and Increased by Natalizumab in Multiple Sclerosis.
- Author
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Clottu, Aurélie S., Mathias, Amandine, Sailer, Andreas W., Schluep, Myriam, Seebach, Jörg D., Du Pasquier, Renaud, and Pot, Caroline
- Abstract
Summary The interaction between oxysterols and the G protein-coupled receptor Epstein-Barr virus-induced gene 2 (EBI2) fine-tunes immune cell migration, a mechanism efficiently targeted by several disease-modifying treatments developed to treat multiple sclerosis (MS), such as natalizumab. We previously showed that memory CD4 + T lymphocytes migrate specifically in response to 7α,25-dihydroxycholesterol (7α,25-OHC) via EBI2 in the MS murine model experimental autoimmune encephalomyelitis. However, the EBI2 expression profile in human lymphocytes in both healthy and MS donors is unknown. Here, we characterize EBI2 biology in human lymphocytes. We observed that EBI2 is functionally expressed on memory CD4 + T cells and is enhanced under natalizumab treatment. These data suggest a significant role for EBI2 in human CD4 + T cell migration, notably in patients with MS. Better knowledge of EBI2 involvement in autoimmunity may therefore lead to an improved understanding of the physiopathology of MS. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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30. Molecular characterization of oxysterol binding to the Epstein-Barr virus-induced gene 2 (GPR183)
- Author
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Benned-Jensen, Tau, Norn, Christoffer, Laurent, Stephane, Madsen, Christian M, Larsen, Hjalte Martin, Arfelt, Kristine N, Wolf, Romain M, Frimurer, Thomas, Sailer, Andreas W, Rosenkilde, Mette M, Benned-Jensen, Tau, Norn, Christoffer, Laurent, Stephane, Madsen, Christian M, Larsen, Hjalte Martin, Arfelt, Kristine N, Wolf, Romain M, Frimurer, Thomas, Sailer, Andreas W, and Rosenkilde, Mette M
- Abstract
Oxysterols are oxygenated cholesterol derivates that are emerging as a physiologically important group of molecules. Although they regulate a range of cellular processes, only few oxysterol-binding effector proteins have been identified, and the knowledge of their binding mode is limited. Recently, the family of G protein-coupled seven transmembrane-spanning receptors (7TM receptors) was added to this group. Specifically, the Epstein-Barr virus-induced gene 2 (EBI2 or GPR183) was shown to be activated by several oxysterols, most potently by 7α,25-dihydroxycholesterol (7α,25-OHC). Nothing is known about the binding mode, however. Using mutational analysis, we identify here four key residues for 7α,25-OHC binding: Arg-87 in TM-II (position II:20/2.60), Tyr-112 and Tyr-116 (positions III:09/3.33 and III:13/3.37) in TM-III, and Tyr-260 in TM-VI (position VI:16/6.51). Substituting these residues with Ala and/or Phe results in a severe decrease in agonist binding and receptor activation. Docking simulations suggest that Tyr-116 interacts with the 3β-OH group in the agonist, Tyr-260 with the 7α-OH group, and Arg-87, either directly or indirectly, with the 25-OH group, although nearby residues likely also contribute. In addition, Tyr-112 is involved in 7α,25-OHC binding but via hydrophobic interactions. Finally, we show that II:20/2.60 constitutes an important residue for ligand binding in receptors carrying a positively charged residue at this position. This group is dominated by lipid- and nucleotide-activated receptors, here exemplified by the CysLTs, P2Y12, and P2Y14. In conclusion, we present the first molecular characterization of oxysterol binding to a 7TM receptor and identify position II:20/2.60 as a generally important residue for ligand binding in certain 7TM receptors.
- Published
- 2012
31. Sa1872 EBI2 Plays a Role in the Development of Intestinal Lymphoid Structures
- Author
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Wyss, Annika, Raselli, Tina, Schmidt, Sebastian, Atrott, Kirstin, Frey-Wagner, Isabelle, von Mering, Christian, Sailer, Andreas W., Rogler, Gerhard, and Misselwitz, Benjamin
- Published
- 2016
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32. EBI2 Is Highly Expressed in Multiple Sclerosis Lesions and Promotes Early CNS Migration of Encephalitogenic CD4 T Cells
- Author
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Wanke, Florian, Moos, Sonja, Croxford, Andrew L., Heinen, André P., Gräf, Stephanie, Kalt, Bettina, Tischner, Denise, Zhang, Juan, Christen, Isabelle, Bruttger, Julia, Yogev, Nir, Tang, Yilang, Zayoud, Morad, Israel, Nicole, Karram, Khalad, Reißig, Sonja, Lacher, Sonja M., Reichhold, Christian, Mufazalov, Ilgiz A., Ben-Nun, Avraham, Kuhlmann, Tanja, Wettschureck, Nina, Sailer, Andreas W., Rajewsky, Klaus, Casola, Stefano, Waisman, Ari, and Kurschus, Florian C.
- Abstract
Arrival of encephalitogenic T cells at inflammatory foci represents a critical step in development of experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis. EBI2 and its ligand, 7α,25-OHC, direct immune cell localization in secondary lymphoid organs. CH25H and CYP7B1 hydroxylate cholesterol to 7α,25-OHC. During EAE, we found increased expression of CH25H by microglia and CYP7B1 by CNS-infiltrating immune cells elevating the ligand concentration in the CNS. Two critical pro-inflammatory cytokines, interleukin-23 (IL-23) and interleukin-1 beta (IL-1β), maintained expression of EBI2 in differentiating Th17 cells. In line with this, EBI2 enhanced early migration of encephalitogenic T cells into the CNS in a transfer EAE model. Nonetheless, EBI2 was dispensable in active EAE. Human Th17 cells do also express EBI2, and EBI2 expressing cells are abundant within multiple sclerosis (MS) white matter lesions. These findings implicate EBI2 as a mediator of CNS autoimmunity and describe mechanistically its contribution to the migration of autoreactive T cells into inflamed organs.
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- 2017
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33. 4-Aminoquinoline melanin-concentrating hormone 1-receptor (MCH1R) antagonists
- Author
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Jiang, Jinlong, Lin, Peter, Hoang, Myle, Chang, Lehua, Tan, Carina, Feighner, Scott, Palyha, Oksana C., Hreniuk, Donna L., Pan, Jie, Sailer, Andreas W., Morin, Nancy R., MacNeil, Douglas J., Howard, Andrew D., Van der Ploeg, Lex H.T., Goulet, Mark T., and DeVita, Robert J.
- Published
- 2006
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34. 2-Aminoquinoline melanin-concentrating hormone (MCH)1R antagonists
- Author
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Jiang, Jinlong, Hoang, Myle, Young, Jonathan R., Chaung, Danny, Eid, Ronsar, Turner, Cherilyn, Lin, Peter, Tong, Xinchun, Wang, Junying, Tan, Carina, Feighner, Scott, Palyha, Oksana, Hreniuk, Donna L., Pan, Jie, Sailer, Andreas W., MacNeil, Douglas J., Howard, Andrew, Shearman, Lauren, Stribling, Sloan, Camacho, Ramon, Strack, Alison, Van der Ploeg, Lex H.T., Goulet, Mark T., and DeVita, Robert J.
- Published
- 2006
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35. Identification and Characterizationof Small MoleculeModulators of the Epstein–Barr Virus-Induced Gene 2 (EBI2) Receptor.
- Author
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Gessier, Francois, Preuss, Inga, Yin, Hong, Rosenkilde, Mette M., Laurent, Stephane, Endres, Ralf, Chen, Yu A., Marsilje, Thomas H., Seuwen, Klaus, Nguyen, Deborah G., and Sailer, Andreas W.
- Published
- 2014
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- View/download PDF
36. Monoclonal Antibodies against the Human Somatostatin Receptor Subtypes 1-5: Development and Immunohistochemical Application in Neuroendocrine Tumors.
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Schmid, Herbert A., Lambertini, Chiara, van Vugt, Harmke H., Barzaghi-Rinaudo, Patrizia, Schäfer, Judith, Hillenbrand, Rainer, Sailer, Andreas W., Kaufmann, Martina, and Nuciforo, Paolo
- Subjects
SOMATOSTATIN receptors ,CUSHING'S syndrome ,MONOCLONAL antibodies ,IMMUNOHISTOCHEMISTRY ,NEUROENDOCRINE tumors - Abstract
Background: Activation of somatostatin receptors (sstr1-5) by somatostatin and its analogues exerts an inhibitory effect on hormone secretion and provides the basis for the treatment of a range of endocrine diseases such as acromegaly, Cushing's disease and neuroendocrine tumors (NET). The lack of well-characterized commercially available sstr subtype-specific antibodies prevents routine identification of the sstr expression profile in patients. Methods: We generated and characterized new mouse monoclonal antibodies (mAbs) targeting the five human sstr subtypes using ELISA and immunohistochemistry, and tested their suitability in formalin-fixed and paraffin-embedded (FFPE) human tissues and archival samples of normal pancreatic tissue and NET. Results: All mAbs were highly specific with no cross-reactivity. The sstr1-5 immunoreactivity in gastrointestinal NET (n = 67) was correlated with clinicopathologic data. With the exception of sstr3, NET were highly positive for all receptor subtypes (42, 63, 6, 32 and 65% of tumors were positive for sstr1, sstr2a, sstr3, sstr4 and sstr5, respectively). sstr1, sstr2a and sstr5 were present at the plasma membrane and in the cytoplasm of tumor cells, whereas sstr3 and sstr4 were almost exclusively cytoplasmic. Immunoreactivity of sstr1, sstr2a and sstr4 tended to decrease as tumor aggressiveness increased. sstr5 showed an opposite pattern, with higher staining in well-differentiated carcinomas compared with well-differentiated tumors. sstr5 immunoreactivity was correlated with the presence of metastases and angioinvasion, suggesting a possible association with more aggressive behavior. Conclusion: Determination of the sstr1-5 by immunohistochemistry using subtype-specific mAbs is feasible in FFPE tissue and may provide a tool for routine clinical practice. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]
- Published
- 2012
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37. Gαi2 Signaling Promotes Skeletal Muscle Hypertrophy, Myoblast Differentiation, and Muscle Regeneration.
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Minetti, Giulia C., Feige, Jerome N., Rosenstiel, Antonia, Bombard, Florian, Meier, Viktor, Werner, Annick, Bassilana, Frederic, Sailer, Andreas W., Kahle, Peter, Lambert, Christian, Glass, David J., and Fornaro, Mara
- Published
- 2011
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- View/download PDF
38. A Conditional Deletion of the NR1 Subunit of the NMDA Receptor in Adult Spinal Cord Dorsal Horn Reduces NMDA Currents and Injury-Induced Pain.
- Author
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South, Samantha M., Kohno, Tatsuro, Kaspar, Brian K., Hegarty, Deborah, Vissel, Bryce, Drake, Carrie T., Ohata, Megumi, Jenab, Shirzad, Sailer, Andreas W., Malkmus, Shelle, Masuyama, Takashi, Horner, Philip, Bogulavsky, Johanna, Gage, Fred H., Yaksh, Tony L., Woolf, Clifford J., Heinemann, Stephen F., and Inturrisi, Charles E.
- Subjects
METHYL aspartate ,SPINAL cord ,MESSENGER RNA ,ALLERGIES ,PAIN management - Abstract
To determine the importance of the NMDA receptor (NMDAR) in pain hypersensitivity after injury, the NMDAR1 (NR1) subunit was selectively deleted in the lumbar spinal cord of adult mice by the localized injection of an adeno-associated virus expressing Cre recombinase into floxed NR1 mice. NR1 subunit mRNA and dendritic protein are reduced by 80% in the area of the virus injection, and NMDA currents, but not AMPA currents, are reduced 86-88% in lamina II neurons. The spatial NR1 knock-out does not alter heat or cold paw-withdrawal latencies, mechanical threshold, or motor function. However, injury-induced pain produced by intraplantar formalin is reduced by 70%. Our results demonstrate conclusively that the postsynaptic NR1 receptor subunit in the lumbar dorsal horn of the spinal cord is required for central sensitization, the central facilitation of pain transmission produced by peripheral injury. [ABSTRACT FROM AUTHOR]
- Published
- 2003
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39. Loss of Kainate Receptor-Mediated Heterosynaptic Facilitation of Mossy-Fiber Synapses in KA2[sup-I-] Mice.
- Author
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Contractor, Anis, Sailer, Andreas W., Darstein, Melanie, Maron, Cornelia, Jian Xu, Swanson, Geoffrey T., and Heinemann, Stephen F.
- Subjects
- *
NEURAL receptors , *SYNAPSES , *NEURAL transmission , *NEUROSCIENCES , *NERVOUS system - Abstract
Presents a study which examined the effect of genetic ablation of kainate (KA) receptors on synaptic transmission at mossy-fiber pyramidal cell synapse. Heteromeric combinations which form KA receptors; Generation and molecular characterization of KA2[sup-I-] mutant mice; Mossy-fiber long-term plasticity in KA2[sup-I-] mice.
- Published
- 2003
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40. Mutations in TRAF3IP1/IFT54 reveal a new role for IFT proteins in microtubule stabilization
- Author
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Bizet, Albane A., Becker-Heck, Anita, Ryan, Rebecca, Weber, Kristina, Filhol, Emilie, Krug, Pauline, Halbritter, Jan, Delous, Marion, Lasbennes, Marie-Christine, Linghu, Bolan, Oakeley, Edward J., Zarhrate, Mohammed, Nitschké, Patrick, Garfa-Traore, Meriem, Serluca, Fabrizio, Yang, Fan, Bouwmeester, Tewis, Pinson, Lucile, Cassuto, Elisabeth, Dubot, Philippe, Elshakhs, Neveen A. Soliman, Sahel, José A., Salomon, Rémi, Drummond, Iain A., Gubler, Marie-Claire, Antignac, Corinne, Chibout, Salahdine, Szustakowski, Joseph D., Hildebrandt, Friedhelm, Lorentzen, Esben, Sailer, Andreas W., Benmerah, Alexandre, Saint-Mezard, Pierre, and Saunier, Sophie
- Abstract
Ciliopathies are a large group of clinically and genetically heterogeneous disorders caused by defects in primary cilia. Here we identified mutations in TRAF3IP1 (TNF Receptor-Associated Factor Interacting Protein 1) in eight patients from five families with nephronophthisis (NPH) and retinal degeneration, two of the most common manifestations of ciliopathies. TRAF3IP1 encodes IFT54, a subunit of the IFT-B complex required for ciliogenesis. The identified mutations result in mild ciliary defects in patients but also reveal an unexpected role of IFT54 as a negative regulator of microtubule stability via MAP4 (microtubule-associated protein 4). Microtubule defects are associated with altered epithelialization/polarity in renal cells and with pronephric cysts and microphthalmia in zebrafish embryos. Our findings highlight the regulation of cytoplasmic microtubule dynamics as a role of the IFT54 protein beyond the cilium, contributing to the development of NPH-related ciliopathies.
- Published
- 2015
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41. ZNRF3 and RNF43 cooperate to safeguard metabolic liver zonation and hepatocyte proliferation
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Sun, Tianliang, Annunziato, Stefano, Bergling, Sebastian, Sheng, Caibin, Orsini, Vanessa, Forcella, Pascal, Pikiolek, Monika, Kancherla, Venkatesh, Holwerda, Sjoerd, Imanci, Dilek, Wu, Fabian, Meylan, Ludivine Challet, Puehringer, Lea F., Waldt, Annick, Oertli, Mevion, Schuierer, Sven, Terracciano, Luigi M., Reinker, Stefan, Ruffner, Heinz, Bouwmeester, Tewis, Sailer, Andreas W., George, Elizabeth, Roma, Guglielmo, de Weck, Antoine, Piscuoglio, Salvatore, Lohmann, Felix, Naumann, Ulrike, Liberali, Prisca, Cong, Feng, and Tchorz, Jan S.
- Abstract
AXIN2 and LGR5 mark intestinal stem cells (ISCs) that require WNT/β-Catenin signaling for constant homeostatic proliferation. In contrast, AXIN2/LGR5+ pericentral hepatocytes show low proliferation rates despite a WNT/β-Catenin activity gradient required for metabolic liver zonation. The mechanisms restricting proliferation in AXIN2+ hepatocytes and metabolic gene expression in AXIN2+ ISCs remained elusive. We now show that restricted chromatin accessibility in ISCs prevents the expression of β-Catenin-regulated metabolic enzymes, whereas fine-tuning of WNT/β-Catenin activity by ZNRF3 and RNF43 restricts proliferation in chromatin-permissive AXIN2+ hepatocytes, while preserving metabolic function. ZNRF3 deletion promotes hepatocyte proliferation, which in turn becomes limited by RNF43 upregulation. Concomitant deletion of RNF43 in ZNRF3 mutant mice results in metabolic reprogramming of periportal hepatocytes and induces clonal expansion in a subset of hepatocytes, ultimately promoting liver tumors. Together, ZNRF3 and RNF43 cooperate to safeguard liver homeostasis by spatially and temporally restricting WNT/β-Catenin activity, balancing metabolic function and hepatocyte proliferation.
- Published
- 2021
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42. Elevated oxysterol levels in human and mouse livers reflect nonalcoholic steatohepatitis
- Author
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Raselli, Tina, Hearn, Tom, Wyss, Annika, Atrott, Kirstin, Peter, Alain, Frey-Wagner, Isabelle, Spalinger, Marianne R, Maggio, Ewerton M, Sailer, Andreas W, Schmitt, Johannes, Schreiner, Philipp, Moncsek, Anja, Mertens, Joachim, Scharl, Michael, Griffiths, William J, Bueter, Marco, Geier, Andreas, Rogler, Gerhard, Wang, Yuqin, and Misselwitz, Benjamin
- Subjects
polycyclic compounds ,nutritional and metabolic diseases ,lipids (amino acids, peptides, and proteins) ,610 Medicine & health ,digestive system ,digestive system diseases ,3. Good health - Abstract
Nonalcoholic steatohepatitis (NASH), a primary cause of liver disease, leads to complications such as fibrosis, cirrhosis, and carcinoma, but the pathophysiology of NASH is incompletely understood. Epstein-Barr virus-induced G protein-coupled receptor 2 (EBI2) and its oxysterol ligand 7α,25-dihydroxycholesterol (7α,25-diHC) are recently discovered immune regulators. Several lines of evidence suggest a role of oxysterols in NASH pathogenesis, but rigorous testing has not been performed. We measured oxysterol levels in the livers of NASH patients by LC-MS and tested the role of the EBI2-7α,25-diHC system in a murine feeding model of NASH. Free oxysterol profiling in livers from NASH patients revealed a pronounced increase in 24- and 7-hydroxylated oxysterols in NASH compared with controls. Levels of 24- and 7-hydroxylated oxysterols correlated with histological NASH activity. Histological analysis of murine liver samples demonstrated ballooning and liver inflammation. No significant genotype-related differences were observed in Ebi2-/- mice and mice with defects in the 7α,25-diHC synthesizing enzymes CH25H and CYP7B1 compared with wild-type littermate controls, arguing against an essential role of these genes in NASH pathogenesis. Elevated 24- and 7-hydroxylated oxysterol levels were confirmed in murine NASH liver samples. Our results suggest increased bile acid synthesis in NASH samples, as judged by the enhanced level of 7α-hydroxycholest-4-en-3-one and impaired 24S-hydroxycholesterol metabolism as characteristic biochemical changes in livers affected by NASH.
43. The oxysterol receptor GPR183 in inflammatory bowel diseases
- Author
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Misselwitz, Benjamin, Wyss, Annika, Raselli, Tina, Cerovic, Vuc, Sailer, Andreas W, Krupka, Niklas, Ruiz, Florian, Pot, Caroline, and Pabst, Oliver
- Subjects
610 Medicine & health ,3. Good health - Abstract
Immune cell trafficking is an important mechanism for the pathogenesis of inflammatory bowel disease (IBD). The G-protein-coupled receptor 183 (GPR183, also called EBI2) and its ligands, dihydroxylated oxysterols can mediate positioning of immune cells including innate lymphoid cells (ILCs). GPR183 has been mapped to an IBD risk locus; however, another gene, UBAC2, is encoded on the reverse strand and associated with Behçet's disease and the role of GPR183 as a genetic risk factor requires validation. GPR183 and production of its oxysterol ligands are upregulated in human IBD and murine colitis. Gpr183 inactivation reduced severity of colitis in ILC3-dependent colitis and in IL-10 colitis but not in dextran sodium sulphate colitis. Irrespectively, Gpr183 knockout strongly reduced accumulation of intestinal lymphoid tissue in health and all colitis models. In conclusion, genetic, translational and experimental studies implicate GPR183 in IBD pathogenesis and GPR183-dependent cell migration might be a therapeutic drug target for IBD.
44. YAP, but Not RSPO-LGR4/5, Signaling in Biliary Epithelial Cells Promotes a Ductular Reaction in Response to Liver Injury
- Author
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Planas-Paz, Lara, Sun, Tianliang, Pikiolek, Monika, Cochran, Nadire R., Bergling, Sebastian, Orsini, Vanessa, Yang, Zinger, Sigoillot, Frederic, Jetzer, Jasna, Syed, Maryam, Neri, Marilisa, Schuierer, Sven, Morelli, Lapo, Hoppe, Philipp S., Schwarzer, Wibke, Cobos, Carlos M., Alford, John L., Zhang, Le, Cuttat, Rachel, Waldt, Annick, Carballido-Perrig, Nicole, Nigsch, Florian, Kinzel, Bernd, Nicholson, Thomas B., Yang, Yi, Mao, Xiaohong, Terracciano, Luigi M., Russ, Carsten, Reece-Hoyes, John S., Gubser Keller, Caroline, Sailer, Andreas W., Bouwmeester, Tewis, Greenbaum, Linda E., Lugus, Jesse J., Cong, Feng, McAllister, Gregory, Hoffman, Gregory R., Roma, Guglielmo, and Tchorz, Jan S.
- Abstract
Biliary epithelial cells (BECs) form bile ducts in the liver and are facultative liver stem cells that establish a ductular reaction (DR) to support liver regeneration following injury. Liver damage induces periportal LGR5+ putative liver stem cells that can form BEC-like organoids, suggesting that RSPO-LGR4/5-mediated WNT/β-catenin activity is important for a DR. We addressed the roles of this and other signaling pathways in a DR by performing a focused CRISPR-based loss-of-function screen in BEC-like organoids, followed by in vivovalidation and single-cell RNA sequencing. We found that BECs lack and do not require LGR4/5-mediated WNT/β-catenin signaling during a DR, whereas YAP and mTORC1 signaling are required for this process. Upregulation of AXIN2 and LGR5 is required in hepatocytes to enable their regenerative capacity in response to injury. Together, these data highlight heterogeneity within the BEC pool, delineate signaling pathways involved in a DR, and clarify the identity and roles of injury-induced periportal LGR5+ cells.
- Published
- 2019
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45. The EBI2 signalling pathway plays a role in cellular crosstalk between astrocytes and macrophages.
- Author
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Rutkowska, Aleksandra, O'Sullivan, Sinead A., Christen, Isabelle, Zhang, Juan, Sailer, Andreas W., and Dev, Kumlesh K.
- Published
- 2016
- Full Text
- View/download PDF
46. Gαi2Signaling Promotes Skeletal Muscle Hypertrophy, Myoblast Differentiation, and Muscle Regeneration
- Author
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Minetti, Giulia C., Feige, Jerome N., Rosenstiel, Antonia, Bombard, Florian, Meier, Viktor, Werner, Annick, Bassilana, Frederic, Sailer, Andreas W., Kahle, Peter, Lambert, Christian, Glass, David J., and Fornaro, Mara
- Abstract
Signaling through Gαi2induces hypertrophy and can counterbalance pathways that promote muscle wasting.
- Published
- 2011
- Full Text
- View/download PDF
47. Enzymatic interconversion of the oxysterols 7β,25-dihydroxycholesterol and 7-keto,25-hydroxycholesterol by 11β-hydroxysteroid dehydrogenase type 1 and 2.
- Author
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Beck, Katharina R., Kanagaratnam, Sharavan, Kratschmar, Denise V., Birk, Julia, Yamaguchi, Hideaki, Sailer, Andreas W., Seuwen, Klaus, and Odermatt, Alex
- Subjects
- *
HYDROXYCHOLESTEROLS , *OXYSTEROLS , *METABOLITES , *CHOLESTEROL , *OXIDATION , *MOLECULAR models - Abstract
• hydroxylation of 7-ketocholesterol to 7-keto,25-hydroxycholesterol (7k25OHC) by CH25H. • stereospecific reduction of 7k25OHC to 7β,25-dihydroxycholesterol (7β25OHC) by 11β-HSD1. • oxidation of 7β25OHC to 7k25OHC catalyzed by 11β-HSD2. • 7k25OHC may not be a physiological relevant ligand for EBI2. • novel glucocorticoid-independent pre-receptor regulation mediated by 11β-HSDs. Oxysterols are cholesterol metabolites derived through either autoxidation or enzymatic processes. They consist of a large family of bioactive lipids that have been associated with the progression of multiple pathologies. In order to unravel (patho-)physiological mechanisms involving oxysterols, it is crucial to elucidate the underlying formation and degradation of oxysterols. A role of 11β-hydroxysteroid dehydrogenases (11β-HSDs) in oxysterol metabolism by catalyzing the interconversion of 7-ketocholesterol (7kC) and 7β-hydroxycholesterol (7βOHC) has already been reported. The present study addresses a function of 11β-HSD1 in the enzymatic generation of 7β,25-dihydroxycholesterol (7β25OHC) from 7-keto,25-hydroxycholesterol (7k25OHC) and tested whether 11β-HSD2 is able to catalyze the reverse reaction. For the first time, using recombinant enzymes, the formation of 7k25OHC from 7kC by cholesterol 25-hydroxylase (CH25H) and further stereospecific oxoreduction to 7β25OHC by human and mouse 11β-HSD1 could be demonstrated. Additionally, experiments using human 11β-HSD2 showed the oxidation of 7β25OHC to 7k25OHC. Molecular modeling provided an explanation for the stereospecific interconversion of 7β25OHC and 7k25OHC. Production of the Epstein-Barr virus-induced gene 2 (EBI2) ligand 7β25OHC from 7k25OHC in challenged tissue by 11β-HSD1 may be important in inflammation. In conclusion, these results demonstrate a novel glucocorticoid-independent pre-receptor regulation mediated by 11β-HSDs. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
48. EBI2 regulates pro-inflammatory signalling and cytokine release in astrocytes.
- Author
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Dev, Kumlesh K., Rutkowska, Aleksandra, Shimshek, Derya R., and Sailer, Andreas W.
- Subjects
- *
EPSTEIN-Barr virus , *OXYSTEROLS , *CYTOKINES , *ASTROCYTES , *HYDROXYLASES - Abstract
The endogenous oxysterol 7α, 25-dihydroxycholesterol (7α25HC) ligand activates the G protein-coupled receptor EBI2 to regulate T cell-dependant antibody response and B cell migration. We have demonstrated that EBI2 is expressed in human and mouse astrocytes, that 7α25HC induces intracellular signalling and astrocyte migration, and that EBI2 plays a role in the crosstalk between astrocytes and macrophages. Recently, we demonstrate that EBI2 regulates myelin development and inhibits LPC-induced demyelination. Here, we show that 7α25HC inhibits LPS- and IL17/TNF-induced pro-inflammatory cytokine release in astrocytes. We observe the following: 1. Human astrocytes treated with IL17/TNF increases the nuclear translocation of NFκB, which is attenuated by pre-treatment with 7α25HC; 2. IL17/TNF increases cell impedance in human astrocytes, which is also attenuated by pre-treatment with 7α25HC; 3. The EBI2 antagonist NIBR189 inhibits these effects of 7α25HC, supporting the role of EBI2; 4. in vivo data corroborate these in vitro findings, showing that EBI2 knock-out (KO) animals display enhanced pro-inflammatory cytokine in response to LPS challenge, in the brain. These results demonstrate a role for oxysterol/EBI2 signalling in attenuating the response of astrocytes to pro-inflammatory signals as well as limiting the levels of pro-inflammatory cytokines in the brain. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
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49. A novel modelling mechanism of PAEL receptor and GABARAPL2 interaction involved in Parkinson’s disease.
- Author
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Dutta, Priyanka, Dargahi, Leila, O'Connell, Kara E., Dev, Kumlesh K., Bolia, Ashini, Ozkan, Banu, and Sailer, Andreas W.
- Subjects
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PARKINSON'S disease , *ENDOPLASMIC reticulum , *NEUROTOXICOLOGY , *AUTOPHAGY , *AFFINITY chromatography , *PARKIN (Protein) - Abstract
Parkin associated endothelin like receptor (PAELR) is G-protein coupled and ubiquitinated by parkin, promoting its degradation. In autosomal recessive Parkinson’s disease, mutations in parkin lead to PAELR aggregation in the endoplasmic reticulum (ER), ER stress, neurotoxicity and cell death. We have identified previously that the protein kinase C interacting protein (PICK1) interacts with and regulates the expression and cell toxicity of PAELR. Here, we experimentally identify and provide in-silico modelling of a novel interaction between PAELR and GABARAPL2 (γ-aminobutyrate type A receptor associated protein like 2), which is an autophagosome-specific Ub-like protein implicated in vesicle trafficking and autophagy. We show that the family of GABARAPs interact with the carboxy terminal (ct) of PAELR and find the cysteine rich region (-CCCCCC-EEC) of ct-PAELR interacts with the GABA A binding site of GABARAPL2. This interaction is modelled by in-slico analysis and confirmed using affinity chromatography, showing Myc-tagged GABARAPL2 is retained by a GST fusion of the ct-PAELR. We also demonstrate that transient transfection of GABARAPL2 in HEK293 cells reduces PAELR expression. This study supports the idea that protein levels of PAELR are likely regulated by a multitude of proteins including parkin, PICK1 and GABARAPL2 via mechanisms that include ubiquitination, proteasomal degradagtion and autophagy. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
50. Transcriptional regulation and functional characterization of the oxysterol/EBI2 system in primary human macrophages.
- Author
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Preuss, Inga, Ludwig, Marie-Gabrielle, Baumgarten, Birgit, Bassilana, Frederic, Gessier, Francois, Seuwen, Klaus, and Sailer, Andreas W.
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GENETIC transcription regulation , *OXYSTEROLS , *MACROPHAGES , *GENE expression , *ENZYME metabolism - Abstract
Highlights: [•] Oxysterol metabolizing enzymes are dynamically regulated in macrophages upon LPS challenge. [•] LPS-induced up-regulation of CH25H and CYP7B1 leads to enhanced release of oxysterols. [•] LPS induces a transient increase of EBI2 expression in primary human macrophages. [•] Oxysterols can activate EBI2 endogenously expressed on macrophages and direct their migration. [Copyright &y& Elsevier]
- Published
- 2014
- Full Text
- View/download PDF
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