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  1. AU="Jensen, Jan-Nygaard"
  2. AU="Abdusalam, Ashraf Ahmed Ali"
  3. AU="Wang, Xiaozhong"
  4. AU="Suner, Asli"
  5. AU="Charles Thickstun"
  6. AU="Tatar, Emel Cadalli"
  7. AU="Shcherbakova Tatyana"
  8. AU="Coats, Brittany"
  9. AU="Monte, Natasha"
  10. AU="Sarma, D.K."
  11. AU=Deng Lisi AU=Deng Lisi
  12. AU=Deshmukh V
  13. AU="Gutiérrez-García, Carmen"
  14. AU="Johnson, Sally"
  15. AU="Sousa, Amanda Freire Tamburini"
  16. AU="Cronin, Chunxia"
  17. AU=Weder W
  18. AU="Nirja Thakur"
  19. AU="Jiang, Shimin"
  20. AU="Wu, Xue-Ying"
  21. AU="Carlos Augusto de Mattos"
  22. AU="Procopio, Francesco A"
  23. AU="Nagata, Kosei"
  24. AU="Kevin Pottie"
  25. AU=Das Tandrila AU=Das Tandrila
  26. AU="Couto Souza, Paulo Henrique"
  27. AU="Morris, Zachary"

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  1. Artikel ; Online: Semantic text mining in early drug discovery for type 2 diabetes.

    Hansson, Lena K / Hansen, Rasmus Borup / Pletscher-Frankild, Sune / Berzins, Rudolfs / Hansen, Daniel Hvidberg / Madsen, Dennis / Christensen, Sten B / Christiansen, Malene Revsbech / Boulund, Ulrika / Wolf, Xenia Asbæk / Kjærulff, Sonny Kim / van de Bunt, Martijn / Tulin, Søren / Jensen, Thomas Skøt / Wernersson, Rasmus / Jensen, Jan Nygaard

    PloS one

    2020  Band 15, Heft 6, Seite(n) e0233956

    Abstract: Background: Surveying the scientific literature is an important part of early drug discovery; and with the ever-increasing amount of biomedical publications it is imperative to focus on the most interesting articles. Here we present a project that ... ...

    Abstract Background: Surveying the scientific literature is an important part of early drug discovery; and with the ever-increasing amount of biomedical publications it is imperative to focus on the most interesting articles. Here we present a project that highlights new understanding (e.g. recently discovered modes of action) and identifies potential drug targets, via a novel, data-driven text mining approach to score type 2 diabetes (T2D) relevance. We focused on monitoring trends and jumps in T2D relevance to help us be timely informed of important breakthroughs.
    Methods: We extracted over 7 million n-grams from PubMed abstracts and then clustered around 240,000 linked to T2D into almost 50,000 T2D relevant 'semantic concepts'. To score papers, we weighted the concepts based on co-mentioning with core T2D proteins. A protein's T2D relevance was determined by combining the scores of the papers mentioning it in the five preceding years. Each week all proteins were ranked according to their T2D relevance. Furthermore, the historical distribution of changes in rank from one week to the next was used to calculate the significance of a change in rank by T2D relevance for each protein.
    Results: We show that T2D relevant papers, even those not mentioning T2D explicitly, were prioritised by relevant semantic concepts. Well known T2D proteins were therefore enriched among the top scoring proteins. Our 'high jumpers' identified important past developments in the apprehension of how certain key proteins relate to T2D, indicating that our method will make us aware of future breakthroughs. In summary, this project facilitated keeping up with current T2D research by repeatedly providing short lists of potential novel targets into our early drug discovery pipeline.
    Mesh-Begriff(e) Algorithms ; Data Mining/methods ; Diabetes Mellitus, Type 2/drug therapy ; Drug Discovery/methods ; Humans ; Proteins/metabolism ; Semantics
    Chemische Substanzen Proteins
    Sprache Englisch
    Erscheinungsdatum 2020-06-15
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0233956
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  2. Artikel ; Online: Analysis artefacts of the INS-IGF2 fusion transcript.

    Wernersson, Rasmus / Frogne, Thomas / Rescan, Claude / Hansson, Lena / Bruun, Christine / Grønborg, Mads / Jensen, Jan Nygaard / Madsen, Ole Dragsbæk

    BMC molecular biology

    2015  Band 16, Seite(n) 13

    Abstract: Background: In gene expression analysis, overlapping genes, splice variants, and fusion transcripts are potential sources of data analysis artefacts, depending on how the observed intensity is assigned to one, or more genes. We here exemplify this by an ...

    Abstract Background: In gene expression analysis, overlapping genes, splice variants, and fusion transcripts are potential sources of data analysis artefacts, depending on how the observed intensity is assigned to one, or more genes. We here exemplify this by an in-depth analysis of the INS-IGF2 fusion transcript, which has recently been reported to be among the highest expressed transcripts in human pancreatic beta cells and its protein indicated as a novel autoantigen in Type 1 Diabetes.
    Results: Through RNA sequencing and variant specific qPCR analyses we demonstrate that the true abundance of INS-IGF2 is >20,000 fold lower than INS in human beta cells, and we suggest an explanation to the nature of the artefacts which have previously led to overestimation of the gene expression level in selected studies. We reinvestigated the previous reported findings of detection of INS-IGF2 using antibodies both in Western blotting and immunohistochemistry. We found that the one available commercial antibody (BO1P) raised against recombinant INS-IGF2 show strong cross-reaction to native proinsulin, and we did not detect INS-IGF2 protein in the human beta cell line EndoC-βH1. Furthermore, using highly sensitive proteomics analysis we could not demonstrate INS-IGF2 protein in samples of human islets nor in EndoC-βH1.
    Conclusions: Sequence features, such as fusion transcripts spanning multiple genes can lead to unexpected results in gene expression analysis, and care must be taken in generating and interpreting the results. For the specific case of INS-IGF2 we conclude that the abundance of the fusion transcript/protein is exceedingly lower than previously reported, and that current immuno-reagents available for detecting INS-IGF2 protein have a strong cross-reaction to native human proinsulin. Finally, we were unable to detect INS-IGF2 protein by proteomics analysis.
    Mesh-Begriff(e) Artifacts ; Cell Line ; Diabetes Mellitus, Type 1/genetics ; Diabetes Mellitus, Type 1/metabolism ; Humans ; Insulin-Secreting Cells/metabolism ; Mutant Chimeric Proteins/analysis ; Mutant Chimeric Proteins/genetics ; Mutant Chimeric Proteins/metabolism ; Proteomics/methods ; Sensitivity and Specificity ; Sequence Analysis, RNA/methods
    Chemische Substanzen INS-IGF2 protein, human ; Mutant Chimeric Proteins
    Sprache Englisch
    Erscheinungsdatum 2015-07-29
    Erscheinungsland England
    Dokumenttyp Journal Article
    ISSN 1471-2199
    ISSN (online) 1471-2199
    DOI 10.1186/s12867-015-0042-8
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  3. Artikel: A BAC transgenic Hes1-EGFP reporter reveals novel expression domains in mouse embryos

    Klinck, Rasmus / Füchtbauer, Ernst-Martin / Ahnfelt-Rønne, Jonas / Serup, Palle / Jensen, Jan Nygaard / Jørgensen, Mette Christine

    Gene expression patterns. 2011 Oct., v. 11, no. 7

    2011  

    Abstract: Expression of the basic helix-loop-helix factor Hairy and Enhancer of Split-1 (Hes1) is required for normal development of a number of tissues during embryonic development. Depending on context, Hes1 may act as a Notch signalling effector which promotes ... ...

    Abstract Expression of the basic helix-loop-helix factor Hairy and Enhancer of Split-1 (Hes1) is required for normal development of a number of tissues during embryonic development. Depending on context, Hes1 may act as a Notch signalling effector which promotes the undifferentiated and proliferative state of progenitor cells, but increasing evidence also points to Notch independent regulation of Hes1 expression. Here we use high resolution confocal scanning of EGFP in a novel BAC transgenic mouse reporter line, Tg(Hes1-EGFP)¹ᴴʳⁱ, to analyse Hes1 expression from embryonic day 7.0 (e7.0). Our data recapitulates some previous observations on Hes1 expression and suggests new, hitherto unrecognised expression domains including expression in the definitive endoderm at early somite stages before gut tube closure and thus preceding organogenesis. This mouse line will be a valuable tool for studies addressing the role of Hes1 in a number of different research areas including organ specification, development and regeneration.
    Schlagwörter bacterial artificial chromosomes ; digestive system ; embryo (animal) ; embryogenesis ; mice ; organogenesis ; reporter genes ; stem cells ; tissues ; transgenic animals
    Sprache Englisch
    Erscheinungsverlauf 2011-10
    Umfang p. 415-426.
    Erscheinungsort Elsevier B.V.
    Dokumenttyp Artikel
    ZDB-ID 2058346-1
    ISSN 1872-7298 ; 1567-133X
    ISSN (online) 1872-7298
    ISSN 1567-133X
    DOI 10.1016/j.gep.2011.06.004
    Datenquelle NAL Katalog (AGRICOLA)

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  4. Artikel: FGF10 signaling maintains the pancreatic progenitor cell state revealing a novel role of Notch in organ development.

    Norgaard, Gitte Anker / Jensen, Jan Nygaard / Jensen, Jan

    Developmental biology

    2003  Band 264, Heft 2, Seite(n) 323–338

    Abstract: FGF10 plays an important role in the morphogenesis of several tissues by control of mesenchymal-to-epithelial signaling. In the pancreas, mesenchymal FGF10 is required to maintain the Pdx1-expressing epithelial progenitor cell population, and in the ... ...

    Abstract FGF10 plays an important role in the morphogenesis of several tissues by control of mesenchymal-to-epithelial signaling. In the pancreas, mesenchymal FGF10 is required to maintain the Pdx1-expressing epithelial progenitor cell population, and in the absence of FGF10 signaling, these cells fail to proliferate. Ectopic expression of FGF10 in the pancreatic epithelium caused increased proliferation of pancreatic progenitor cells and abrogation of pancreatic cell differentiation of all cell types. A hyperplastic pancreas consisting of undifferentiated cells expressing Pdx1, Nkx6.1, and cell adhesion markers normally characterizing early pancreatic progenitor cells resulted. Differentiation was attenuated even as proliferation of the pancreatic cells slowed during late gestation, suggesting that the trophic effect of FGF10 was independent of its effects upon cell differentiation. The FGF10-positive pancreatic cells expressed Notch1 and Notch2, the Notch-ligand genes Jagged1 and Jagged2, as well as the Notch target gene Hes1. This activation of Notch is distinct from the previously recognized mechanism of lateral inhibition. These data suggest that FGF10 signaling serves to integrate cell growth and terminal differentiation at the level of Notch activation, revealing a novel second role of this key signaling system during pancreatic development.
    Mesh-Begriff(e) Animals ; Basic Helix-Loop-Helix Transcription Factors ; Cell Differentiation ; Fibroblast Growth Factor 10 ; Fibroblast Growth Factors/physiology ; Homeodomain Proteins ; Mice ; Mice, Transgenic ; Nerve Tissue Proteins/genetics ; Pancreas/embryology ; Receptor, Notch1 ; Receptor, Notch2 ; Receptors, Cell Surface/physiology ; Signal Transduction ; Stem Cells/cytology ; Trans-Activators/genetics ; Transcription Factors
    Chemische Substanzen Basic Helix-Loop-Helix Transcription Factors ; Fgf10 protein, mouse ; Fibroblast Growth Factor 10 ; Homeodomain Proteins ; Nerve Tissue Proteins ; Neurog3 protein, mouse ; Notch1 protein, mouse ; Notch2 protein, mouse ; Receptor, Notch1 ; Receptor, Notch2 ; Receptors, Cell Surface ; Trans-Activators ; Transcription Factors ; pancreatic and duodenal homeobox 1 protein ; Fibroblast Growth Factors (62031-54-3)
    Sprache Englisch
    Erscheinungsdatum 2003-12-15
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 1114-9
    ISSN 1095-564X ; 0012-1606
    ISSN (online) 1095-564X
    ISSN 0012-1606
    DOI 10.1016/j.ydbio.2003.08.013
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  5. Artikel ; Online: A BAC transgenic Hes1-EGFP reporter reveals novel expression domains in mouse embryos.

    Klinck, Rasmus / Füchtbauer, Ernst-Martin / Ahnfelt-Rønne, Jonas / Serup, Palle / Jensen, Jan Nygaard / Jørgensen, Mette Christine

    Gene expression patterns : GEP

    2011  Band 11, Heft 7, Seite(n) 415–426

    Abstract: Expression of the basic helix-loop-helix factor Hairy and Enhancer of Split-1 (Hes1) is required for normal development of a number of tissues during embryonic development. Depending on context, Hes1 may act as a Notch signalling effector which promotes ... ...

    Abstract Expression of the basic helix-loop-helix factor Hairy and Enhancer of Split-1 (Hes1) is required for normal development of a number of tissues during embryonic development. Depending on context, Hes1 may act as a Notch signalling effector which promotes the undifferentiated and proliferative state of progenitor cells, but increasing evidence also points to Notch independent regulation of Hes1 expression. Here we use high resolution confocal scanning of EGFP in a novel BAC transgenic mouse reporter line, Tg(Hes1-EGFP)(1Hri), to analyse Hes1 expression from embryonic day 7.0 (e7.0). Our data recapitulates some previous observations on Hes1 expression and suggests new, hitherto unrecognised expression domains including expression in the definitive endoderm at early somite stages before gut tube closure and thus preceding organogenesis. This mouse line will be a valuable tool for studies addressing the role of Hes1 in a number of different research areas including organ specification, development and regeneration.
    Mesh-Begriff(e) Animals ; Basic Helix-Loop-Helix Transcription Factors/genetics ; Basic Helix-Loop-Helix Transcription Factors/metabolism ; Chromosomes, Artificial, Bacterial/genetics ; Endoderm/cytology ; Endoderm/embryology ; Endoderm/metabolism ; Gene Expression Regulation, Developmental ; Green Fluorescent Proteins/genetics ; Green Fluorescent Proteins/metabolism ; Homeodomain Proteins/genetics ; Homeodomain Proteins/metabolism ; Mice ; Mice, Transgenic ; Organogenesis/genetics ; Somites/cytology ; Somites/embryology ; Somites/metabolism ; Transcription Factor HES-1
    Chemische Substanzen Basic Helix-Loop-Helix Transcription Factors ; Hes1 protein, mouse ; Homeodomain Proteins ; Transcription Factor HES-1 ; enhanced green fluorescent protein ; Green Fluorescent Proteins (147336-22-9)
    Sprache Englisch
    Erscheinungsdatum 2011-07-02
    Erscheinungsland Netherlands
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2058346-1
    ISSN 1872-7298 ; 1567-133X
    ISSN (online) 1872-7298
    ISSN 1567-133X
    DOI 10.1016/j.gep.2011.06.004
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  6. Artikel ; Online: The transcriptional activity of Neurog3 affects migration and differentiation of ectopic endocrine cells in chicken endoderm.

    Rosenberg, Louise C / Lafon, Merete L / Pedersen, Jesper Karup / Yassin, Hani / Jensen, Jan Nygaard / Serup, Palle / Hecksher-Sørensen, Jacob

    Developmental dynamics : an official publication of the American Association of Anatomists

    2010  Band 239, Heft 7, Seite(n) 1950–1966

    Abstract: Neurog3 is expressed transiently in pancreatic endocrine progenitors where it is responsible for activating a transcription factor cascade which eventually defines the mature endocrine cells. However, the mechanism by which Neurog3 regulates different ... ...

    Abstract Neurog3 is expressed transiently in pancreatic endocrine progenitors where it is responsible for activating a transcription factor cascade which eventually defines the mature endocrine cells. However, the mechanism by which Neurog3 regulates different aspects of the endocrine differentiation program is less clear. In this report we used in ovo electroporation to investigate how manipulation of Neurog3 protein activity affected migration, differentiation and fate determination. We found that changes in the onset of Neurog3 expression only had minor effect on differentiation. However increasing the transcriptional activity of Neurog3 by fusing it to VP16 or co-electroporating with Ep300 caused the electroporated cells to migrate rather than differentiate. In contrast, reducing the transcriptional activity of Neurog3 by deleting parts of the activation domain, by fusing Neurog3 to the engrailed repressor domain, or co-electroporating with Hdac1 greatly increased the proportion of glucagon expressing cells.
    Mesh-Begriff(e) Animals ; Cell Differentiation/genetics ; Cell Differentiation/physiology ; Cell Movement/genetics ; Cell Movement/physiology ; Chickens ; Electroporation ; Endocrine Cells/cytology ; Endocrine Cells/metabolism ; Endoderm/cytology ; Endoderm/metabolism ; In Situ Hybridization ; Microscopy, Confocal ; Nerve Tissue Proteins/chemistry ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/metabolism ; Transcription, Genetic/genetics ; Transcription, Genetic/physiology
    Chemische Substanzen Nerve Tissue Proteins
    Sprache Englisch
    Erscheinungsdatum 2010-05-20
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1102541-4
    ISSN 1097-0177 ; 1058-8388
    ISSN (online) 1097-0177
    ISSN 1058-8388
    DOI 10.1002/dvdy.22329
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  7. Artikel: Recapitulation of elements of embryonic development in adult mouse pancreatic regeneration.

    Jensen, Jan Nygaard / Cameron, Erin / Garay, Maria Veronica R / Starkey, Thomas W / Gianani, Roberto / Jensen, Jan

    Gastroenterology

    2005  Band 128, Heft 3, Seite(n) 728–741

    Abstract: Background & aims: The mammalian pancreas has a strong regenerative potential, but the origin of organ restoration is not clear, and it is not known to what degree such a process reflects pancreatic development. To define cell differentiation changes ... ...

    Abstract Background & aims: The mammalian pancreas has a strong regenerative potential, but the origin of organ restoration is not clear, and it is not known to what degree such a process reflects pancreatic development. To define cell differentiation changes associated with pancreatic regeneration in adult mice, we compared regeneration following caerulein-induced pancreatitis to that of normal pancreatic development.
    Methods: By performing comparative histology for adult and embryonic pancreatic markers in caerulein-treated and control pancreas, we addressed cellular proliferation and differentiation (amylase, DBA-agglutinin, insulin, glucagon, beta-catenin, E-cadherin, Pdx1, Nkx6.1, Notch1, Notch2, Jagged1, Jagged2, Hes1), hereby describing the kinetics of tissue restoration.
    Results: We demonstrate that surviving pancreatic exocrine cells repress the terminal exocrine gene program and induce genes normally associated with undifferentiated pancreatic progenitor cells such as Pdx1, E-cadherin, beta-catenin, and Notch components, including Notch1 , Notch2 , and Jagged2 . Expression of the Notch target gene Hes1 provides evidence that Notch signaling is reactivated in dedifferentiated pancreatic cells. Although previous studies have suggested a process of acino-to-ductal transdifferentiation in pancreatic regeneration, we find no evidence to suggest that dedifferentiated cells acquire a ductal fate during this process.
    Conclusions: Pancreatic regeneration following chemically induced pancreatitis in the mouse occurs predominantly through acinar cell dedifferentiation, whereby a genetic program resembling embryonic pancreatic precursors is reinstated.
    Mesh-Begriff(e) Animals ; Ceruletide ; Embryo, Mammalian/metabolism ; Female ; Gene Expression Regulation ; Homeodomain Proteins/metabolism ; Male ; Membrane Proteins/metabolism ; Mice ; Mice, Inbred Strains ; Mitosis ; Pancreas/embryology ; Pancreas/physiopathology ; Pancreas, Exocrine/metabolism ; Pancreas, Exocrine/physiopathology ; Pancreatitis/chemically induced ; Pancreatitis/genetics ; Pancreatitis/metabolism ; Pancreatitis/physiopathology ; Receptors, Notch ; Regeneration ; Signal Transduction ; Trans-Activators/metabolism
    Chemische Substanzen Homeodomain Proteins ; Membrane Proteins ; Nkx6-1 protein, mouse ; Receptors, Notch ; Trans-Activators ; pancreatic and duodenal homeobox 1 protein ; Ceruletide (888Y08971B)
    Sprache Englisch
    Erscheinungsdatum 2005-03
    Erscheinungsland United States
    Dokumenttyp Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 80112-4
    ISSN 1528-0012 ; 0016-5085
    ISSN (online) 1528-0012
    ISSN 0016-5085
    DOI 10.1053/j.gastro.2004.12.008
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  8. Artikel ; Online: Notch-mediated post-translational control of Ngn3 protein stability regulates pancreatic patterning and cell fate commitment.

    Qu, Xiaoling / Afelik, Solomon / Jensen, Jan Nygaard / Bukys, Michael A / Kobberup, Sune / Schmerr, Martin / Xiao, Fan / Nyeng, Pia / Veronica Albertoni, Maria / Grapin-Botton, Anne / Jensen, Jan

    Developmental biology

    2013  Band 376, Heft 1, Seite(n) 1–12

    Abstract: Ngn3 is recognized as a regulator of pancreatic endocrine formation, and Notch signaling as an important negative regulator Ngn3 gene expression. By conditionally controlling expression of Ngn3 in the pancreas, we find that these two signaling components ...

    Abstract Ngn3 is recognized as a regulator of pancreatic endocrine formation, and Notch signaling as an important negative regulator Ngn3 gene expression. By conditionally controlling expression of Ngn3 in the pancreas, we find that these two signaling components are dynamically linked. This connection involves transcriptional repression as previously shown, but also incorporates a novel post-translational mechanism. In addition to its ability to promote endocrine fate, we provide evidence of a competing ability of Ngn3 in the patterning of multipotent progenitor cells in turn controlling the formation of ducts. On one hand, Ngn3 cell-intrinsically activates endocrine target genes; on the other, Ngn3 cell-extrinsically promotes lateral signaling via the Dll1>Notch>Hes1 pathway which substantially limits its ability to sustain endocrine formation. Prior to endocrine commitment, the Ngn3-mediated activation of the Notch>Hes1 pathway impacts formation of the trunk domain in the pancreas causing multipotent progenitors to lose acinar, while gaining endocrine and ductal, competence. The subsequent selection of fate from such bipotential progenitors is then governed by lateral inhibition, where Notch>Hes1-mediated Ngn3 protein destabilization serves to limit endocrine differentiation by reducing cellular levels of Ngn3. This system thus allows for rapid dynamic changes between opposing bHLH proteins in cells approaching a terminal differentiation event. Inhibition of Notch signaling leads to Ngn3 protein stabilization in the normal mouse pancreas explants. We conclude that the mutually exclusive expression pattern of Ngn3/Hes1 proteins in the mammalian pancreas is partially controlled through Notch-mediated post-translational regulation and we demonstrate that the formation of insulin-producing beta-cells can be significantly enhanced upon induction of a pro-endocrine drive combined with the inhibition of Notch processing.
    Mesh-Begriff(e) Animals ; Basic Helix-Loop-Helix Transcription Factors/metabolism ; Cell Differentiation/physiology ; Dipeptides ; Gene Expression Regulation, Developmental/physiology ; Histological Techniques ; Immunohistochemistry ; Mice ; Morphogenesis/physiology ; Nerve Tissue Proteins/metabolism ; Pancreas/embryology ; Pancreas/metabolism ; Protein Stability ; Real-Time Polymerase Chain Reaction ; Receptors, Notch/metabolism ; Signal Transduction/physiology
    Chemische Substanzen Basic Helix-Loop-Helix Transcription Factors ; Dipeptides ; N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester ; Nerve Tissue Proteins ; Neurog3 protein, mouse ; Receptors, Notch
    Sprache Englisch
    Erscheinungsdatum 2013-01-29
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1114-9
    ISSN 1095-564X ; 0012-1606
    ISSN (online) 1095-564X
    ISSN 0012-1606
    DOI 10.1016/j.ydbio.2013.01.021
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  9. Artikel ; Online: Hedgehog signaling is required for effective regeneration of exocrine pancreas.

    Fendrich, Volker / Esni, Farzad / Garay, Maria Veronica R / Feldmann, Georg / Habbe, Nils / Jensen, Jan Nygaard / Dor, Yuval / Stoffers, Doris / Jensen, Jan / Leach, Steven D / Maitra, Anirban

    Gastroenterology

    2008  Band 135, Heft 2, Seite(n) 621–631

    Abstract: Although both endocrine and the exocrine pancreas display a significant capacity for tissue regeneration and renewal, the existence of progenitor cells in the adult pancreas remains uncertain. Using a model of cerulein-mediated injury and repair, we ... ...

    Abstract Although both endocrine and the exocrine pancreas display a significant capacity for tissue regeneration and renewal, the existence of progenitor cells in the adult pancreas remains uncertain. Using a model of cerulein-mediated injury and repair, we demonstrate that mature exocrine cells, defined by expression of an Elastase1 promoter, actively contribute to regenerating pancreatic epithelium through formation of metaplastic ductal intermediates. Acinar cell regeneration is associated with activation of Hedgehog (Hh) signaling, as assessed by up-regulated expression of multiple pathway components, as well as activation of a Ptch-lacZ reporter allele. Using both pharmacologic and genetic techniques, we also show that the ability of mature exocrine cells to accomplish pancreatic regeneration is impaired by blockade of Hh signaling. Specifically, attenuated regeneration in the absence of an intact Hh pathway is characterized by persistence of metaplastic epithelium expressing markers of pancreatic progenitor cells, suggesting an inhibition of redifferentiation into mature exocrine cells. Given the known role of Hh signaling in exocrine pancreatic cancer, these findings may provide a mechanistic link between injury-induced activation of pancreatic progenitors and subsequent pancreatic neoplasia.
    Mesh-Begriff(e) Animals ; Cell Differentiation ; Cell Proliferation ; Cell Transformation, Neoplastic/metabolism ; Ceruletide ; Disease Models, Animal ; Epithelial Cells/drug effects ; Epithelial Cells/metabolism ; Epithelial Cells/pathology ; Genes, Reporter ; Hedgehog Proteins/metabolism ; Intermediate Filament Proteins/metabolism ; Metaplasia ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Nerve Tissue Proteins/metabolism ; Nestin ; Pancreas, Exocrine/drug effects ; Pancreas, Exocrine/metabolism ; Pancreas, Exocrine/pathology ; Pancreatic Ducts/drug effects ; Pancreatic Ducts/metabolism ; Pancreatic Ducts/pathology ; Pancreatic Elastase/metabolism ; Pancreatitis/chemically induced ; Pancreatitis/metabolism ; Pancreatitis/pathology ; Receptors, G-Protein-Coupled/genetics ; Receptors, G-Protein-Coupled/metabolism ; Regeneration/drug effects ; Signal Transduction/drug effects ; Smoothened Receptor ; Stem Cells/drug effects ; Stem Cells/metabolism ; Stem Cells/pathology ; Time Factors ; Veratrum Alkaloids/pharmacology
    Chemische Substanzen Hedgehog Proteins ; Intermediate Filament Proteins ; Nerve Tissue Proteins ; Nes protein, mouse ; Nestin ; Receptors, G-Protein-Coupled ; Smo protein, mouse ; Smoothened Receptor ; Veratrum Alkaloids ; Ceruletide (888Y08971B) ; Pancreatic Elastase (EC 3.4.21.36) ; cyclopamine (ZH658AJ192)
    Sprache Englisch
    Erscheinungsdatum 2008-04-16
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 80112-4
    ISSN 1528-0012 ; 0016-5085
    ISSN (online) 1528-0012
    ISSN 0016-5085
    DOI 10.1053/j.gastro.2008.04.011
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  10. Artikel ; Online: The EndoC-βH1 cell line is a valid model of human beta cells and applicable for screenings to identify novel drug target candidates.

    Tsonkova, Violeta Georgieva / Sand, Fredrik Wolfhagen / Wolf, Xenia Asbæk / Grunnet, Lars Groth / Kirstine Ringgaard, Anna / Ingvorsen, Camilla / Winkel, Louise / Kalisz, Mark / Dalgaard, Kevin / Bruun, Christine / Fels, Johannes Josef / Helgstrand, Charlotte / Hastrup, Sven / Öberg, Fredrik Kryh / Vernet, Erik / Sandrini, Michael Paolo Bastner / Shaw, Allan Christian / Jessen, Carsten / Grønborg, Mads /
    Hald, Jacob / Willenbrock, Hanni / Madsen, Dennis / Wernersson, Rasmus / Hansson, Lena / Jensen, Jan Nygaard / Plesner, Annette / Alanentalo, Tomas / Petersen, Maja Borup Kjær / Grapin-Botton, Anne / Honoré, Christian / Ahnfelt-Rønne, Jonas / Hecksher-Sørensen, Jacob / Ravassard, Philippe / Madsen, Ole D / Rescan, Claude / Frogne, Thomas

    Molecular metabolism

    2017  Band 8, Seite(n) 144–157

    Abstract: Objective: To characterize the EndoC-βH1 cell line as a model for human beta cells and evaluate its beta cell functionality, focusing on insulin secretion, proliferation, apoptosis and ER stress, with the objective to assess its potential as a screening ...

    Abstract Objective: To characterize the EndoC-βH1 cell line as a model for human beta cells and evaluate its beta cell functionality, focusing on insulin secretion, proliferation, apoptosis and ER stress, with the objective to assess its potential as a screening platform for identification of novel anti-diabetic drug candidates.
    Methods: EndoC-βH1 was transplanted into mice for validation of in vivo functionality. Insulin secretion was evaluated in cells cultured as monolayer and as pseudoislets, as well as in diabetic mice. Cytokine induced apoptosis, glucolipotoxicity, and ER stress responses were assessed. Beta cell relevant mRNA and protein expression were investigated by qPCR and antibody staining. Hundreds of proteins or peptides were tested for their effect on insulin secretion and proliferation.
    Results: Transplantation of EndoC-βH1 cells restored normoglycemia in streptozotocin induced diabetic mice. Both in vitro and in vivo, we observed a clear insulin response to glucose, and, in vitro, we found a significant increase in insulin secretion from EndoC-βH1 pseudoislets compared to monolayer cultures for both glucose and incretins. Apoptosis and ER stress were inducible in the cells and caspase 3/7 activity was elevated in response to cytokines, but not affected by the saturated fatty acid palmitate. By screening of various proteins and peptides, we found Bombesin (BB) receptor agonists and Pituitary Adenylate Cyclase-Activating Polypeptides (PACAP) to significantly induce insulin secretion and the proteins SerpinA6, STC1, and APOH to significantly stimulate proliferation. ER stress was readily induced by Tunicamycin and resulted in a reduction of insulin mRNA. Somatostatin (SST) was found to be expressed by 1% of the cells and manipulation of the SST receptors was found to significantly affect insulin secretion.
    Conclusions: Overall, the EndoC-βH1 cells strongly resemble human islet beta cells in terms of glucose and incretin stimulated insulin secretion capabilities. The cell line has an active cytokine induced caspase 3/7 apoptotic pathway and is responsive to ER stress initiation factors. The cells' ability to proliferate can be further increased by already known compounds as well as by novel peptides and proteins. Based on its robust performance during the functionality assessment assays, the EndoC-βH1 cell line was successfully used as a screening platform for identification of novel anti-diabetic drug candidates.
    Mesh-Begriff(e) Animals ; Cell Culture Techniques/methods ; Cell Line ; Cells, Cultured ; Diabetes Mellitus, Experimental/therapy ; Drug Evaluation, Preclinical/methods ; Humans ; Hypoglycemic Agents/pharmacology ; Insulin Secretion ; Insulin-Secreting Cells/cytology ; Insulin-Secreting Cells/drug effects ; Insulin-Secreting Cells/metabolism ; Mice ; Mice, SCID
    Chemische Substanzen Hypoglycemic Agents
    Sprache Englisch
    Erscheinungsdatum 2017-12-19
    Erscheinungsland Germany
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't ; Validation Study
    ZDB-ID 2708735-9
    ISSN 2212-8778 ; 2212-8778
    ISSN (online) 2212-8778
    ISSN 2212-8778
    DOI 10.1016/j.molmet.2017.12.007
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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