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  1. Article ; Online: Pharmacological targeting of host chaperones protects from pertussis toxin in vitro and in vivo

    Katharina Ernst / Ann-Katrin Mittler / Veronika Winkelmann / Carolin Kling / Nina Eberhardt / Anna Anastasia / Michael Sonnabend / Robin Lochbaum / Jan Wirsching / Moona Sakari / Arto T. Pulliainen / Ciaran Skerry / Nicholas H. Carbonetti / Manfred Frick / Holger Barth

    Scientific Reports, Vol 11, Iss 1, Pp 1-

    2021  Volume 17

    Abstract: Abstract Whooping cough is caused by Bordetella pertussis that releases pertussis toxin (PT) which comprises enzyme A-subunit PTS1 and binding/transport B-subunit. After receptor-mediated endocytosis, PT reaches the endoplasmic reticulum from where ... ...

    Abstract Abstract Whooping cough is caused by Bordetella pertussis that releases pertussis toxin (PT) which comprises enzyme A-subunit PTS1 and binding/transport B-subunit. After receptor-mediated endocytosis, PT reaches the endoplasmic reticulum from where unfolded PTS1 is transported to the cytosol. PTS1 ADP-ribosylates G-protein α-subunits resulting in increased cAMP signaling. Here, a role of target cell chaperones Hsp90, Hsp70, cyclophilins and FK506-binding proteins for cytosolic PTS1-uptake is demonstrated. PTS1 specifically and directly interacts with chaperones in vitro and in cells. Specific pharmacological chaperone inhibition protects CHO-K1, human primary airway basal cells and a fully differentiated airway epithelium from PT-intoxication by reducing intracellular PTS1-amounts without affecting cell binding or enzyme activity. PT is internalized by human airway epithelium secretory but not ciliated cells and leads to increase of apical surface liquid. Cyclophilin-inhibitors reduced leukocytosis in infant mouse model of pertussis, indicating their promising potential for developing novel therapeutic strategies against whooping cough.
    Keywords Medicine ; R ; Science ; Q
    Language English
    Publishing date 2021-03-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: IL-13 Impairs Tight Junctions in Airway Epithelia

    Hanna Schmidt / Peter Braubach / Carolin Schilpp / Robin Lochbaum / Kathrin Neuland / Kristin Thompson / Danny Jonigk / Manfred Frick / Paul Dietl / Oliver H. Wittekindt

    International Journal of Molecular Sciences, Vol 20, Iss 13, p

    2019  Volume 3222

    Abstract: Interleukin-13 (IL-13) drives symptoms in asthma with high levels of T-helper type 2 cells (T h 2-cells). Since tight junctions (TJ) constitute the epithelial diffusion barrier, we investigated the effect of IL-13 on TJ in human tracheal epithelial cells. ...

    Abstract Interleukin-13 (IL-13) drives symptoms in asthma with high levels of T-helper type 2 cells (T h 2-cells). Since tight junctions (TJ) constitute the epithelial diffusion barrier, we investigated the effect of IL-13 on TJ in human tracheal epithelial cells. We observed that IL-13 increases paracellular permeability, changes claudin expression pattern and induces intracellular aggregation of the TJ proteins zonlua occludens protein 1, as well as claudins. Furthermore, IL-13 treatment increases expression of ubiquitin conjugating E2 enzyme UBE2Z. Co-localization and proximity ligation assays further showed that ubiquitin and the proteasomal marker PSMA5 co-localize with TJ proteins in IL-13 treated cells, showing that TJ proteins are ubiquitinated following IL-13 exposure. UBE2Z upregulation occurs within the first day after IL-13 exposure. Proteasomal aggregation of ubiquitinated TJ proteins starts three days after IL-13 exposure and transepithelial electrical resistance (TEER) decrease follows the time course of TJ-protein aggregation. Inhibition of JAK/STAT signaling abolishes IL-13 induced effects. Our data suggest that that IL-13 induces ubiquitination and proteasomal aggregation of TJ proteins via JAK/STAT dependent expression of UBE2Z, resulting in opening of TJs. This may contribute to barrier disturbances in pulmonary epithelia and lung damage of patients with inflammatory lung diseases.
    Keywords lung ; epithelia ; interleukin 13 ; tight junction ; UBE2Z ; ubiquitin ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Language English
    Publishing date 2019-06-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Alpha-1 antitrypsin inhibits TMPRSS2 protease activity and SARS-CoV-2 infection

    Lukas Wettstein / Tatjana Weil / Carina Conzelmann / Janis A. Müller / Rüdiger Groß / Maximilian Hirschenberger / Alina Seidel / Susanne Klute / Fabian Zech / Caterina Prelli Bozzo / Nico Preising / Giorgio Fois / Robin Lochbaum / Philip Maximilian Knaff / Volker Mailänder / Ludger Ständker / Dietmar Rudolf Thal / Christian Schumann / Steffen Stenger /
    Alexander Kleger / Günter Lochnit / Benjamin Mayer / Yasser B. Ruiz-Blanco / Markus Hoffmann / Konstantin M. J. Sparrer / Stefan Pöhlmann / Elsa Sanchez-Garcia / Frank Kirchhoff / Manfred Frick / Jan Münch

    Nature Communications, Vol 12, Iss 1, Pp 1-

    2021  Volume 10

    Abstract: Here, via screening of a polypeptide library from bronchoalveolar lavage, the authors identify and characterize α1-antitrypsin (α1AT) as SARS-CoV-2 inhibitor and show that α1AT binds and inactivates the serine protease TMPRSS2, which enzymatically primes ...

    Abstract Here, via screening of a polypeptide library from bronchoalveolar lavage, the authors identify and characterize α1-antitrypsin (α1AT) as SARS-CoV-2 inhibitor and show that α1AT binds and inactivates the serine protease TMPRSS2, which enzymatically primes the SARS-CoV-2 spike protein for membrane fusion.
    Keywords Science ; Q
    Language English
    Publishing date 2021-03-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

    Full text online

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    Inter-library loan at ZB MED

    Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

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