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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: Genome Replication Is Associated With Release of Immunogenic DNA Waste.

    Schubert, Nadja / Schumann, Tina / Daum, Elena / Flade, Karolin / Ge, Yan / Hagedorn, Lara / Edelmann, Winfried / Müller, Luise / Schmitz, Marc / Kuut, Gunnar / Hornung, Veit / Behrendt, Rayk / Roers, Axel

    Frontiers in immunology

    2022  Volume 13, Page(s) 880413

    Abstract: Innate DNA sensors detect foreign and endogenous DNA to induce responses to infection and cellular stress or damage. Inappropriate activation by self-DNA triggers severe autoinflammatory conditions, including Aicardi-Goutières syndrome (AGS) that can be ... ...

    Abstract Innate DNA sensors detect foreign and endogenous DNA to induce responses to infection and cellular stress or damage. Inappropriate activation by self-DNA triggers severe autoinflammatory conditions, including Aicardi-Goutières syndrome (AGS) that can be caused by defects of the cytosolic DNase 3'repair exonuclease 1 (TREX1).
    MeSH term(s) Animals ; Autoimmune Diseases of the Nervous System ; Mice ; Nervous System Malformations/pathology ; Nucleotidyltransferases/metabolism ; Retroelements ; Virus Replication
    Chemical Substances Retroelements ; Nucleotidyltransferases (EC 2.7.7.-)
    Language English
    Publishing date 2022-05-11
    Publishing country Switzerland
    Document type Journal Article ; 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.2022.880413
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: vPIF-1 is an insulin-like antiferroptotic viral peptide.

    Belavgeni, Alexia / Maremonti, Francesca / Tonnus, Wulf / Stadtmüller, Marlena / Gavali, Shubhangi / Mallais, Melodie / Flade, Karolin / Brucker, Anne / Becker, Jorunn Naila / Beer, Kristina / Tmava, Mirela / Stumpf, Julian / Gembardt, Florian / Hugo, Christian / Giacca, Mauro / Hale, Benjamin G / Perakakis, Nikolaos / Sha, Wei / Pratt, Derek A /
    Schally, Andrew V / Bornstein, Stefan R / Linkermann, Andreas

    Proceedings of the National Academy of Sciences of the United States of America

    2023  Volume 120, Issue 21, Page(s) e2300320120

    Abstract: Iridoviridae, such as the lymphocystis disease virus-1 (LCDV-1) and other viruses, encode viral insulin-like peptides (VILPs) which are capable of triggering insulin receptors (IRs) and insulin-like growth factor receptors. The homology of VILPs includes ...

    Abstract Iridoviridae, such as the lymphocystis disease virus-1 (LCDV-1) and other viruses, encode viral insulin-like peptides (VILPs) which are capable of triggering insulin receptors (IRs) and insulin-like growth factor receptors. The homology of VILPs includes highly conserved disulfide bridges. However, the binding affinities to IRs were reported to be 200- to 500-fold less effective compared to the endogenous ligands. We therefore speculated that these peptides also have noninsulin functions. Here, we report that the LCDV-1 VILP can function as a potent and highly specific inhibitor of ferroptosis. Induction of cell death by the ferroptosis inducers erastin, RSL3, FIN56, and FINO2 and nonferroptotic necrosis produced by the thioredoxin-reductase inhibitor ferroptocide were potently prevented by LCDV-1, while human insulin had no effect. Fas-induced apoptosis, necroptosis, mitotane-induced cell death and growth hormone-releasing hormone antagonist-induced necrosis were unaffected, suggesting the specificity to ferroptosis inhibition by the LCDV-1 VILP. Mechanistically, we identified the viral C-peptide to be required for inhibition of lipid peroxidation and ferroptosis inhibition, while the human C-peptide exhibited no antiferroptotic properties. In addition, the deletion of the viral C-peptide abolishes radical trapping activity in cell-free systems. We conclude that iridoviridae, through the expression of insulin-like viral peptides, are capable of preventing ferroptosis. In analogy to the viral mitochondrial inhibitor of apoptosis and the viral inhibitor of RIP activation (vIRA) that prevents necroptosis, we rename the LCDV-1 VILP a viral peptide inhibitor of ferroptosis-1. Finally, our findings indicate that ferroptosis may function as a viral defense mechanism in lower organisms.
    MeSH term(s) Humans ; Insulin ; C-Peptide ; Apoptosis ; Necrosis ; Cell Death
    Chemical Substances Insulin ; C-Peptide
    Language English
    Publishing date 2023-05-15
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.2300320120
    Database MEDical Literature Analysis and Retrieval System OnLINE

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