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  1. Article ; Online: Treatment with siRNAs is commonly associated with GPX4 up-regulation and target knockdown-independent sensitization to ferroptosis.

    von Mässenhausen, Anne / Schlecht, Marlena Nastassja / Beer, Kristina / Maremonti, Francesca / Tonnus, Wulf / Belavgeni, Alexia / Gavali, Shubhangi / Flade, Karolin / Riley, Joel S / Zamora Gonzalez, Nadia / Brucker, Anne / Becker, Jorunn Naila / Tmava, Mirela / Meyer, Claudia / Peitzsch, Mirko / Hugo, Christian / Gembardt, Florian / Angeli, Jose Pedro Friedmann / Bornstein, Stefan R /
    Tait, Stephen W G / Linkermann, Andreas

    Science advances

    2024  Volume 10, Issue 11, Page(s) eadk7329

    Abstract: Small interfering RNAs (siRNAs) are widely used in biomedical research and in clinical trials. Here, we demonstrate that siRNA treatment is commonly associated with significant sensitization to ferroptosis, independently of the target protein knockdown. ... ...

    Abstract Small interfering RNAs (siRNAs) are widely used in biomedical research and in clinical trials. Here, we demonstrate that siRNA treatment is commonly associated with significant sensitization to ferroptosis, independently of the target protein knockdown. Genetically targeting mitochondrial antiviral-signaling protein (MAVS) reversed the siRNA-mediated sensitizing effect, but no activation of canonical MAVS signaling, which involves phosphorylation of IkBα and interferon regulatory transcription factor 3 (IRF3), was observed. In contrast, MAVS mediated a noncanonical signal resulting in a prominent increase in mitochondrial ROS levels, and increase in the BACH1/pNRF2 transcription factor ratio and GPX4 up-regulation, which was associated with a 50% decrease in intracellular glutathione levels. We conclude that siRNAs commonly sensitize to ferroptosis and may severely compromise the conclusions drawn from silencing approaches in biomedical research. Finally, as ferroptosis contributes to a variety of pathophysiological processes, we cannot exclude side effects in human siRNA-based therapeutical concepts that should be clinically tested.
    MeSH term(s) Humans ; Signal Transduction ; RNA, Small Interfering/genetics ; Ferroptosis/genetics ; Up-Regulation ; Transcription Factors/metabolism
    Chemical Substances RNA, Small Interfering ; Transcription Factors
    Language English
    Publishing date 2024-03-15
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2810933-8
    ISSN 2375-2548 ; 2375-2548
    ISSN (online) 2375-2548
    ISSN 2375-2548
    DOI 10.1126/sciadv.adk7329
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Dexamethasone sensitizes to ferroptosis by glucocorticoid receptor-induced dipeptidase-1 expression and glutathione depletion.

    von Mässenhausen, Anne / Zamora Gonzalez, Nadia / Maremonti, Francesca / Belavgeni, Alexia / Tonnus, Wulf / Meyer, Claudia / Beer, Kristina / Hannani, Monica T / Lau, Arthur / Peitzsch, Mirko / Hoppenz, Paul / Locke, Sophie / Chavakis, Triantafyllos / Kramann, Rafael / Muruve, Daniel A / Hugo, Christian / Bornstein, Stefan R / Linkermann, Andreas

    Science advances

    2022  Volume 8, Issue 5, Page(s) eabl8920

    Abstract: Dexamethasone is widely used as an immunosuppressive therapy and recently as COVID-19 treatment. Here, we demonstrate that dexamethasone sensitizes to ferroptosis, a form of iron-catalyzed necrosis, previously suggested to contribute to diseases such as ... ...

    Abstract Dexamethasone is widely used as an immunosuppressive therapy and recently as COVID-19 treatment. Here, we demonstrate that dexamethasone sensitizes to ferroptosis, a form of iron-catalyzed necrosis, previously suggested to contribute to diseases such as acute kidney injury, myocardial infarction, and stroke, all of which are triggered by glutathione (GSH) depletion. GSH levels were significantly decreased by dexamethasone. Mechanistically, we identified that dexamethasone up-regulated the GSH metabolism regulating protein dipeptidase-1 (DPEP1) in a glucocorticoid receptor (GR)-dependent manner. DPEP1 knockdown reversed the phenotype of dexamethasone-induced ferroptosis sensitization. Ferroptosis inhibitors, the DPEP1 inhibitor cilastatin, or genetic
    MeSH term(s) Carbolines/adverse effects ; Carbolines/pharmacology ; Cell Line ; Dexamethasone/pharmacology ; Dipeptidases/genetics ; Dipeptidases/metabolism ; Ferroptosis/drug effects ; Ferroptosis/genetics ; Fluorescent Antibody Technique ; GPI-Linked Proteins/genetics ; GPI-Linked Proteins/metabolism ; Gene Expression Regulation/drug effects ; Gene Knockdown Techniques ; Glutathione/metabolism ; Humans ; Immunophenotyping ; Oxidation-Reduction/drug effects ; Piperazines/adverse effects ; Piperazines/pharmacology ; Receptors, Glucocorticoid/metabolism
    Chemical Substances Carbolines ; GPI-Linked Proteins ; Piperazines ; RSL3 compound ; Receptors, Glucocorticoid ; erastin ; Dexamethasone (7S5I7G3JQL) ; Dipeptidases (EC 3.4.13.-) ; dipeptidase 1 (EC 3.4.13.19) ; Glutathione (GAN16C9B8O)
    Language English
    Publishing date 2022-02-02
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2810933-8
    ISSN 2375-2548 ; 2375-2548
    ISSN (online) 2375-2548
    ISSN 2375-2548
    DOI 10.1126/sciadv.abl8920
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

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