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  1. Artikel ; Online: Astrocytic Slc4a4 regulates blood-brain barrier integrity in healthy and stroke brains via a CCL2-CCR2 pathway and NO dysregulation.

    Ye, Qi / Jo, Juyeon / Wang, Chih-Yen / Oh, Heavin / Zhan, Jiangshan / Choy, Tiffany J / Kim, Kyoung In / D'Alessandro, Angelo / Reshetnyak, Yana K / Jung, Sung Yun / Chen, Zheng / Marrelli, Sean P / Lee, Hyun Kyoung

    Cell reports

    2024  Band 43, Heft 5, Seite(n) 114193

    Abstract: Astrocytes play vital roles in blood-brain barrier (BBB) maintenance, yet how they support BBB integrity under normal or pathological conditions remains poorly defined. Recent evidence suggests that ion homeostasis is a cellular mechanism important for ... ...

    Abstract Astrocytes play vital roles in blood-brain barrier (BBB) maintenance, yet how they support BBB integrity under normal or pathological conditions remains poorly defined. Recent evidence suggests that ion homeostasis is a cellular mechanism important for BBB integrity. In the current study, we investigated the function of an astrocyte-specific pH regulator, Slc4a4, in BBB maintenance and repair. We show that astrocytic Slc4a4 is required for normal astrocyte morphological complexity and BBB function. Multi-omics analyses identified increased astrocytic secretion of CCL2 coupled with dysregulated arginine-NO metabolism after Slc4a4 deletion. Using a model of ischemic stroke, we found that loss of Slc4a4 exacerbates BBB disruption, which was rescued by pharmacological or genetic inhibition of the CCL2-CCR2 pathway in vivo. Together, our study identifies the astrocytic Slc4a4-CCL2 and endothelial CCR2 axis as a mechanism controlling BBB integrity and repair, while providing insights for a therapeutic approach against BBB-related CNS disorders.
    Mesh-Begriff(e) Blood-Brain Barrier/metabolism ; Blood-Brain Barrier/pathology ; Astrocytes/metabolism ; Astrocytes/pathology ; Receptors, CCR2/metabolism ; Animals ; Chemokine CCL2/metabolism ; Stroke/metabolism ; Stroke/pathology ; Mice ; Signal Transduction ; Male ; Humans ; Mice, Inbred C57BL ; Brain/metabolism ; Brain/pathology
    Chemische Substanzen Receptors, CCR2 ; Chemokine CCL2 ; Ccr2 protein, mouse
    Sprache Englisch
    Erscheinungsdatum 2024-05-05
    Erscheinungsland United States
    Dokumenttyp Journal Article
    ZDB-ID 2649101-1
    ISSN 2211-1247 ; 2211-1247
    ISSN (online) 2211-1247
    ISSN 2211-1247
    DOI 10.1016/j.celrep.2024.114193
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  2. Artikel: Astrocytic Slc4a4 regulates blood-brain barrier integrity in healthy and stroke brains via a NO-CCL2-CCR2 pathway.

    Ye, Qi / Jo, Juyeon / Wang, Chih-Yen / Oh, Heavin / Choy, Tiffany J / Kim, Kyoungin / D'Alessandro, Angelo / Reshetnyak, Yana K / Jung, Sung Yun / Chen, Zheng / Marrelli, Sean P / Lee, Hyun Kyoung

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Astrocytes play vital roles in blood-brain barrier (BBB) maintenance, yet how they support BBB integrity under normal or pathological conditions remains poorly defined. Recent evidence suggests pH homeostasis is a new cellular mechanism important for BBB ...

    Abstract Astrocytes play vital roles in blood-brain barrier (BBB) maintenance, yet how they support BBB integrity under normal or pathological conditions remains poorly defined. Recent evidence suggests pH homeostasis is a new cellular mechanism important for BBB integrity. In the current study, we investigated the function of an astrocyte-specific pH regulator, Slc4a4, in BBB maintenance and repair. We show that astrocytic Slc4a4 is required for normal astrocyte morphological complexity and BBB function. Multi-omics analyses identified increased astrocytic secretion of CCL2 coupled with dysregulated arginine-NO metabolism after Slc4a4 deletion. Using a model of ischemic stroke, we found that loss of Slc4a4 exacerbates BBB disruption and reactive gliosis, which were both rescued by pharmacological or genetic inhibition of the NO-CCL2 pathway
    Sprache Englisch
    Erscheinungsdatum 2023-04-03
    Erscheinungsland United States
    Dokumenttyp Preprint
    DOI 10.1101/2023.04.03.535167
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  3. Artikel ; Online: Chemical remodeling of a cellular chaperone to target the active state of mutant KRAS.

    Schulze, Christopher J / Seamon, Kyle J / Zhao, Yulei / Yang, Yu C / Cregg, Jim / Kim, Dongsung / Tomlinson, Aidan / Choy, Tiffany J / Wang, Zhican / Sang, Ben / Pourfarjam, Yasin / Lucas, Jessica / Cuevas-Navarro, Antonio / Ayala-Santos, Carlos / Vides, Alberto / Li, Chuanchuan / Marquez, Abby / Zhong, Mengqi / Vemulapalli, Vidyasiri /
    Weller, Caroline / Gould, Andrea / Whalen, Daniel M / Salvador, Anthony / Milin, Anthony / Saldajeno-Concar, Mae / Dinglasan, Nuntana / Chen, Anqi / Evans, Jim / Knox, John E / Koltun, Elena S / Singh, Mallika / Nichols, Robert / Wildes, David / Gill, Adrian L / Smith, Jacqueline A M / Lito, Piro

    Science (New York, N.Y.)

    2023  Band 381, Heft 6659, Seite(n) 794–799

    Abstract: The discovery of small-molecule inhibitors requires suitable binding pockets on protein surfaces. Proteins that lack this feature are considered undruggable and require innovative strategies for therapeutic targeting. ...

    Abstract The discovery of small-molecule inhibitors requires suitable binding pockets on protein surfaces. Proteins that lack this feature are considered undruggable and require innovative strategies for therapeutic targeting.
    Mesh-Begriff(e) Humans ; Biological Products/chemistry ; Biological Products/pharmacology ; Biological Products/therapeutic use ; Cysteine/chemistry ; Cysteine/genetics ; Molecular Chaperones/chemistry ; Molecular Chaperones/metabolism ; Proto-Oncogene Proteins p21(ras)/antagonists & inhibitors ; Proto-Oncogene Proteins p21(ras)/chemistry ; Proto-Oncogene Proteins p21(ras)/genetics ; Signal Transduction ; Cyclophilin A/chemistry ; Cyclophilin A/metabolism ; Immunophilins/chemistry ; Immunophilins/metabolism ; Neoplasms/drug therapy ; Neoplasms/genetics
    Chemische Substanzen Biological Products ; Cysteine (K848JZ4886) ; KRAS protein, human ; Molecular Chaperones ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2) ; Cyclophilin A (EC 5.2.1.-) ; Immunophilins (EC 5.2.1.8)
    Sprache Englisch
    Erscheinungsdatum 2023-08-17
    Erscheinungsland United States
    Dokumenttyp Journal Article
    ZDB-ID 128410-1
    ISSN 1095-9203 ; 0036-8075
    ISSN (online) 1095-9203
    ISSN 0036-8075
    DOI 10.1126/science.adg9652
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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    Verfügbar in ZB MED Köln/Königswinter

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  4. Artikel ; Online: Allosteric Inhibition of SHP2 Stimulates Antitumor Immunity by Transforming the Immunosuppressive Environment.

    Quintana, Elsa / Schulze, Christopher J / Myers, Darienne R / Choy, Tiffany J / Mordec, Kasia / Wildes, David / Shifrin, Nataliya Tobvis / Belwafa, Amira / Koltun, Elena S / Gill, Adrian L / Singh, Mallika / Kelsey, Stephen / Goldsmith, Mark A / Nichols, Robert / Smith, Jacqueline A M

    Cancer research

    2020  Band 80, Heft 13, Seite(n) 2889–2902

    Abstract: The protein tyrosine phosphatase SHP2 binds to phosphorylated signaling motifs on regulatory immunoreceptors including PD-1, but its functional role in tumor immunity is unclear. Using preclinical models, we show that RMC-4550, an allosteric inhibitor of ...

    Abstract The protein tyrosine phosphatase SHP2 binds to phosphorylated signaling motifs on regulatory immunoreceptors including PD-1, but its functional role in tumor immunity is unclear. Using preclinical models, we show that RMC-4550, an allosteric inhibitor of SHP2, induces antitumor immunity, with effects equivalent to or greater than those resulting from checkpoint blockade. In the tumor microenvironment, inhibition of SHP2 modulated T-cell infiltrates similar to checkpoint blockade. In addition, RMC-4550 drove direct, selective depletion of protumorigenic M2 macrophages via attenuation of CSF1 receptor signaling and increased M1 macrophages via a mechanism independent of CD8
    Mesh-Begriff(e) Allosteric Regulation ; Animals ; Apoptosis ; Breast Neoplasms/immunology ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Breast Neoplasms/prevention & control ; Cell Proliferation ; Female ; Humans ; Immunosuppressive Agents/pharmacology ; Macrophages/immunology ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Protein Tyrosine Phosphatase, Non-Receptor Type 11/antagonists & inhibitors ; Protein Tyrosine Phosphatase, Non-Receptor Type 11/genetics ; Protein Tyrosine Phosphatase, Non-Receptor Type 11/metabolism ; Signal Transduction ; Tumor Cells, Cultured ; Tumor Microenvironment/immunology ; Xenograft Model Antitumor Assays
    Chemische Substanzen Immunosuppressive Agents ; PTPN11 protein, human (EC 3.1.3.48) ; Protein Tyrosine Phosphatase, Non-Receptor Type 11 (EC 3.1.3.48)
    Sprache Englisch
    Erscheinungsdatum 2020-04-29
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1432-1
    ISSN 1538-7445 ; 0008-5472
    ISSN (online) 1538-7445
    ISSN 0008-5472
    DOI 10.1158/0008-5472.CAN-19-3038
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  5. Artikel ; Online: Shp1 Loss Enhances Macrophage Effector Function and Promotes Anti-Tumor Immunity.

    Myers, Darienne R / Abram, Clare L / Wildes, David / Belwafa, Amira / Welsh, Alia M N / Schulze, Christopher J / Choy, Tiffany J / Nguyen, Tram / Omaque, Neil / Hu, Yongmei / Singh, Mallika / Hansen, Rich / Goldsmith, Mark A / Quintana, Elsa / Smith, Jacqueline A M / Lowell, Clifford A

    Frontiers in immunology

    2020  Band 11, Seite(n) 576310

    Abstract: Shp1, encoded by the ... ...

    Abstract Shp1, encoded by the gene
    Mesh-Begriff(e) Adaptive Immunity ; Adenocarcinoma/enzymology ; Adenocarcinoma/immunology ; Adenocarcinoma/pathology ; Adenocarcinoma/therapy ; Animals ; Antigens, Differentiation/metabolism ; Breast Neoplasms/enzymology ; Breast Neoplasms/immunology ; Breast Neoplasms/pathology ; Breast Neoplasms/therapy ; Colonic Neoplasms/enzymology ; Colonic Neoplasms/immunology ; Colonic Neoplasms/pathology ; Colonic Neoplasms/therapy ; Female ; Humans ; Immunity, Innate ; Lymphocytes, Tumor-Infiltrating/immunology ; Lymphocytes, Tumor-Infiltrating/metabolism ; Melanoma, Experimental/enzymology ; Melanoma, Experimental/immunology ; Melanoma, Experimental/pathology ; Melanoma, Experimental/therapy ; Mice, Inbred C57BL ; Mice, Knockout ; Phagocytosis ; Protein Tyrosine Phosphatase, Non-Receptor Type 6/deficiency ; Protein Tyrosine Phosphatase, Non-Receptor Type 6/genetics ; Receptors, Immunologic/metabolism ; Signal Transduction ; Skin Neoplasms/enzymology ; Skin Neoplasms/immunology ; Skin Neoplasms/pathology ; Skin Neoplasms/therapy ; THP-1 Cells ; Tumor Burden ; Tumor Microenvironment ; Tumor-Associated Macrophages/enzymology ; Tumor-Associated Macrophages/immunology
    Chemische Substanzen Antigens, Differentiation ; Ptpns1 protein, mouse ; Receptors, Immunologic ; SIRPA protein, human ; PTPN6 protein, human (EC 3.1.3.48) ; Protein Tyrosine Phosphatase, Non-Receptor Type 6 (EC 3.1.3.48) ; Ptpn6 protein, mouse (EC 3.1.3.48)
    Sprache Englisch
    Erscheinungsdatum 2020-09-29
    Erscheinungsland Switzerland
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2606827-8
    ISSN 1664-3224 ; 1664-3224
    ISSN (online) 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2020.576310
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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