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  1. Article: Diabetes and suppressors of cytokine signaling proteins.

    Rønn, Sif G / Billestrup, Nils / Mandrup-Poulsen, Thomas

    Diabetes

    2007  Volume 56, Issue 2, Page(s) 541–548

    MeSH term(s) Cytokines/metabolism ; Diabetes Mellitus/etiology ; Humans ; Inflammation/metabolism ; Insulin/physiology ; Insulin Resistance/physiology ; Leptin/metabolism ; Obesity/metabolism ; Signal Transduction/physiology ; Suppressor of Cytokine Signaling Proteins/metabolism
    Chemical Substances Cytokines ; Insulin ; Leptin ; Suppressor of Cytokine Signaling Proteins
    Language English
    Publishing date 2007-02
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 80085-5
    ISSN 1939-327X ; 0012-1797
    ISSN (online) 1939-327X
    ISSN 0012-1797
    DOI 10.2337/db06-1068
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Uh III Zs.175: Show issues Location:
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  2. Article ; Online: Structural insight into antibody-mediated antagonism of the Glucagon-like peptide-1 Receptor.

    Hennen, Stephanie / Kodra, János T / Soroka, Vladyslav / Krogh, Berit O / Wu, Xiaoai / Kaastrup, Peter / Ørskov, Cathrine / Rønn, Sif G / Schluckebier, Gerd / Barbateskovic, Silvia / Gandhi, Prafull S / Reedtz-Runge, Steffen

    Scientific reports

    2016  Volume 6, Page(s) 26236

    Abstract: The Glucagon-like peptide-1 receptor (GLP-1R) is a member of the class B G protein-coupled receptor ...

    Abstract The Glucagon-like peptide-1 receptor (GLP-1R) is a member of the class B G protein-coupled receptor (GPCR) family and a well-established target for the treatment of type 2 diabetes. The N-terminal extracellular domain (ECD) of GLP-1R is important for GLP-1 binding and the crystal structure of the GLP-1/ECD complex was reported previously. The first structure of a class B GPCR transmembrane (TM) domain was solved recently, but the full length receptor structure is still not well understood. Here we describe the molecular details of antibody-mediated antagonism of the GLP-1R using both in vitro pharmacology and x-ray crystallography. We showed that the antibody Fab fragment (Fab 3F52) blocked the GLP-1 binding site of the ECD directly and thereby acts as a competitive antagonist of native GLP-1. Interestingly, Fab 3F52 also blocked a short peptide agonist believed to engage primarily the transmembrane and extracellular loop region of GLP-1R, whereas functionality of an allosteric small-molecule agonist was not inhibited. This study has implications for the structural understanding of the GLP-1R and related class B GPCRs, which is important for the development of new and improved therapeutics targeting these receptors.
    MeSH term(s) Antibodies/chemistry ; Antibodies/immunology ; Binding Sites ; Crystallography, X-Ray ; Glucagon-Like Peptide-1 Receptor/antagonists & inhibitors ; Glucagon-Like Peptide-1 Receptor/chemistry ; Humans ; Protein Binding ; Protein Conformation
    Chemical Substances Antibodies ; Glucagon-Like Peptide-1 Receptor
    Language English
    Publishing date 2016-05-19
    Publishing country England
    Document type Journal Article
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/srep26236
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Suppressor of cytokine signalling-3 inhibits Tumor necrosis factor-alpha induced apoptosis and signalling in beta cells.

    Bruun, Christine / Heding, Peter E / Rønn, Sif G / Frobøse, Helle / Rhodes, Christopher J / Mandrup-Poulsen, Thomas / Billestrup, Nils

    Molecular and cellular endocrinology

    2009  Volume 311, Issue 1-2, Page(s) 32–38

    Abstract: Tumor necrosis factor-alpha (TNFalpha) is a pro-inflammatory cytokine involved in the pathogenesis of several diseases including type 1 diabetes mellitus (T1DM). TNFalpha in combination with interleukin-1-beta (IL-1beta) and/or interferon-gamma (IFNgamma) ...

    Abstract Tumor necrosis factor-alpha (TNFalpha) is a pro-inflammatory cytokine involved in the pathogenesis of several diseases including type 1 diabetes mellitus (T1DM). TNFalpha in combination with interleukin-1-beta (IL-1beta) and/or interferon-gamma (IFNgamma) induces specific destruction of the pancreatic insulin-producing beta cells. Suppressor of cytokine signalling-3 (SOCS-3) proteins regulate signalling induced by a number of cytokines including growth hormone, IFNgamma and IL-1beta which signals via very distinctive pathways. The objective of this study was to investigate the effect of SOCS-3 on TNFalpha-induced signalling in beta cells. We found that apoptosis induced by TNFalpha alone or in combination with IL-1beta was suppressed by expression of SOCS-3 in the beta cell line INSr3#2. SOCS-3 inhibited TNFalpha-induced phosphorylation of the mitogen activated protein kinases ERK1/2, p38 and JNK in INSr3#2 cells and in primary rat islets. Furthermore, SOCS-3 repressed TNFalpha-induced degradation of IkappaB, NFkappaB DNA binding and transcription of the NFkappaB-dependent MnSOD promoter. Finally, expression of Socs-3 mRNA was induced by TNFalpha in rat islets in a transient manner with maximum expression after 1-2h. The ability of SOCS-3 to regulate signalling induced by the three major pro-inflammatory cytokines involved in the pathogenesis of T1DM makes SOCS-3 an interesting therapeutic candidate for protection of the beta cell mass.
    MeSH term(s) Animals ; Apoptosis/drug effects ; DNA/metabolism ; Enzyme Activation/drug effects ; Female ; Gene Expression Regulation/drug effects ; Humans ; I-kappa B Proteins/metabolism ; Insulin-Secreting Cells/drug effects ; Insulin-Secreting Cells/enzymology ; Interleukin-1beta/pharmacology ; Mice ; Middle Aged ; Mitogen-Activated Protein Kinases/metabolism ; NF-kappa B/metabolism ; Phosphorylation/drug effects ; Promoter Regions, Genetic/genetics ; Protein Binding/drug effects ; Protein Processing, Post-Translational/drug effects ; Rats ; Signal Transduction/drug effects ; Superoxide Dismutase/genetics ; Suppressor of Cytokine Signaling 3 Protein ; Suppressor of Cytokine Signaling Proteins/genetics ; Suppressor of Cytokine Signaling Proteins/metabolism ; Tumor Necrosis Factor-alpha/pharmacology
    Chemical Substances I-kappa B Proteins ; Interleukin-1beta ; NF-kappa B ; SOCS3 protein, human ; Socs3 protein, rat ; Suppressor of Cytokine Signaling 3 Protein ; Suppressor of Cytokine Signaling Proteins ; Tumor Necrosis Factor-alpha ; DNA (9007-49-2) ; Superoxide Dismutase (EC 1.15.1.1) ; Mitogen-Activated Protein Kinases (EC 2.7.11.24)
    Language English
    Publishing date 2009-07-28
    Publishing country Ireland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 187438-x
    ISSN 1872-8057 ; 0303-7207
    ISSN (online) 1872-8057
    ISSN 0303-7207
    DOI 10.1016/j.mce.2009.07.019
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1127: Show issues Location:
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    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  4. Article ; Online: The oral histone deacetylase inhibitor ITF2357 reduces cytokines and protects islet β cells in vivo and in vitro.

    Lewis, Eli C / Blaabjerg, Lykke / Størling, Joachim / Ronn, Sif G / Mascagni, Paolo / Dinarello, Charles A / Mandrup-Poulsen, Thomas

    Molecular medicine (Cambridge, Mass.)

    2010  Volume 17, Issue 5-6, Page(s) 369–377

    Abstract: In type 1 diabetes, inflammatory and immunocompetent cells enter the islet and produce proinflammatory cytokines such as interleukin-1β (IL-1β), IL-12, tumor necrosis factor-α (TNFα) and interferon-γ (IFNγ); each contribute to β-cell destruction, ... ...

    Abstract In type 1 diabetes, inflammatory and immunocompetent cells enter the islet and produce proinflammatory cytokines such as interleukin-1β (IL-1β), IL-12, tumor necrosis factor-α (TNFα) and interferon-γ (IFNγ); each contribute to β-cell destruction, mediated in part by nitric oxide. Inhibitors of histone deacetylases (HDAC) are used commonly in humans but also possess antiinflammatory and cytokine-suppressing properties. Here we show that oral administration of the HDAC inhibitor ITF2357 to mice normalized streptozotocin (STZ)-induced hyperglycemia at the clinically relevant doses of 1.25-2.5 mg/kg. Serum nitrite levels returned to nondiabetic values, islet function improved and glucose clearance increased from 14% (STZ) to 50% (STZ + ITF2357). In vitro, at 25 and 250 nmol/L, ITF2357 increased islet cell viability, enhanced insulin secretion, inhibited MIP-1α and MIP-2 release, reduced nitric oxide production and decreased apoptosis rates from 14.3% (vehicle) to 2.6% (ITF2357). Inducible nitric oxide synthase (iNOS) levels decreased in association with reduced islet-derived nitrite levels. In peritoneal macrophages and splenocytes, ITF2357 inhibited the production of nitrite, as well as that of TNFα and IFNγ at an IC(50) of 25-50 nmol/L. In the insulin-producing INS cells challenged with the combination of IL-1β plus IFNγ, apoptosis was reduced by 50% (P < 0.01). Thus at clinically relevant doses, the orally active HDAC inhibitor ITF2357 favors β-cell survival during inflammatory conditions.
    MeSH term(s) Animals ; Cell Line ; Cells, Cultured ; Cytokines/metabolism ; Female ; Glucose Tolerance Test ; Hydroxamic Acids/pharmacology ; Hydroxamic Acids/therapeutic use ; Hyperglycemia/blood ; Hyperglycemia/chemically induced ; Hyperglycemia/prevention & control ; Immunoblotting ; In Situ Nick-End Labeling ; In Vitro Techniques ; Insulin-Secreting Cells/drug effects ; Interferon-gamma/pharmacology ; Interleukin-1beta/pharmacology ; Islets of Langerhans/drug effects ; Islets of Langerhans/metabolism ; Macrophages, Peritoneal/drug effects ; Macrophages, Peritoneal/metabolism ; Mice ; Mice, Inbred C57BL ; Nitric Oxide/metabolism ; Nitric Oxide Synthase Type II/metabolism ; Nitrites/blood ; Rats ; Spleen/cytology ; Streptozocin/toxicity
    Chemical Substances Cytokines ; Hydroxamic Acids ; Interleukin-1beta ; Nitrites ; Nitric Oxide (31C4KY9ESH) ; Streptozocin (5W494URQ81) ; Interferon-gamma (82115-62-6) ; Nitric Oxide Synthase Type II (EC 1.14.13.39) ; givinostat hydrochloride (Z02132R2QQ)
    Language English
    Publishing date 2010-12-22
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1283676-x
    ISSN 1528-3658 ; 1076-1551
    ISSN (online) 1528-3658
    ISSN 1076-1551
    DOI 10.2119/molmed.2010.00152
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 4456: Show issues Location:
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  5. Article: The effect of suppressor of cytokine signaling 3 on GH signaling in beta-cells.

    Rønn, Sif G / Hansen, Johnny A / Lindberg, Karen / Karlsen, Allan E / Billestrup, Nils

    Molecular endocrinology (Baltimore, Md.)

    2002  Volume 16, Issue 9, Page(s) 2124–2134

    Abstract: GH is an important regulator of cell growth and metabolism. In the pancreas, GH stimulates mitogenesis as well as insulin production in beta-cells. The cellular effects of GH are exerted mainly through activation of the Janus kinase-signal transducer and ...

    Abstract GH is an important regulator of cell growth and metabolism. In the pancreas, GH stimulates mitogenesis as well as insulin production in beta-cells. The cellular effects of GH are exerted mainly through activation of the Janus kinase-signal transducer and activator of transcription (STAT) pathway. Recently it has been found that suppressors of cytokine signaling (SOCS) proteins are able to inhibit GH-induced signal transduction. In the present study, the role of SOCS-3 in GH signaling was investigated in the pancreatic beta-cell lines RIN-5AH and INS-1 by means of inducible expression systems. Via stable transfection of the beta-cell lines with plasmids expressing SOCS-3 under the control of an inducible promoter, a time- and dose-dependent expression of SOCS-3 in the cells was obtained. EMSA showed that SOCS-3 is able to inhibit GH-induced DNA binding of both STAT3 and STAT5 in RIN-5AH cells. Furthermore, using Northern blot analysis it was shown that SOCS-3 can completely inhibit GH-induced insulin production in these cells. Finally, 5-bromodeoxyuridine incorporation followed by fluorescence-activated cell sorting analysis showed that SOCS-3 inhibits GH-induced proliferation of INS-1 cells. These findings support the hypothesis that SOCS-3 is a major regulator of GH signaling in insulin-producing cells.
    MeSH term(s) Cell Division/drug effects ; Cells, Cultured ; DNA-Binding Proteins/metabolism ; Electrophoretic Mobility Shift Assay ; Flow Cytometry ; Growth Hormone/antagonists & inhibitors ; Growth Hormone/pharmacology ; Humans ; Insulin/genetics ; Insulin/metabolism ; Islets of Langerhans/cytology ; Islets of Langerhans/drug effects ; Islets of Langerhans/metabolism ; Milk Proteins ; Proteins/genetics ; Proteins/metabolism ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Repressor Proteins ; STAT3 Transcription Factor ; STAT5 Transcription Factor ; Signal Transduction/drug effects ; Suppressor of Cytokine Signaling 3 Protein ; Suppressor of Cytokine Signaling Proteins ; Trans-Activators/metabolism ; Transcription Factors
    Chemical Substances DNA-Binding Proteins ; Insulin ; Milk Proteins ; Proteins ; RNA, Messenger ; Repressor Proteins ; SOCS3 protein, human ; STAT3 Transcription Factor ; STAT3 protein, human ; STAT5 Transcription Factor ; Suppressor of Cytokine Signaling 3 Protein ; Suppressor of Cytokine Signaling Proteins ; Trans-Activators ; Transcription Factors ; Growth Hormone (9002-72-6)
    Language English
    Publishing date 2002-09
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 639167-9
    ISSN 1944-9917 ; 0888-8809
    ISSN (online) 1944-9917
    ISSN 0888-8809
    DOI 10.1210/me.2002-0082
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 2261: Show issues Location:
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