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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: COVID-19 and Diabetic Nephropathy.

    Maremonti, Francesca / Locke, Sophie / Tonnus, Wulf / Beer, Kristina / Brucker, Anne / Gonzalez, Nadia Zamora / Latk, Marcus / Belavgeni, Alexia / Hoppenz, Paul / Hugo, Christian / Linkermann, Andreas

    Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme

    2022  Volume 54, Issue 8, Page(s) 510–513

    Abstract: Diabetic nephropathy is the most common condition that requires a chronic renal replacement therapy, such as hemodialysis, peritoneal dialysis, kidney transplantation, or simultaneous kidney-pancreas transplantation. Chronic kidney disease progression, ... ...

    Abstract Diabetic nephropathy is the most common condition that requires a chronic renal replacement therapy, such as hemodialysis, peritoneal dialysis, kidney transplantation, or simultaneous kidney-pancreas transplantation. Chronic kidney disease progression, that is the loss of nephrons, which causes the continuous decline of the eGFR, underlies the pathogenesis of diabetic nephropathy. During the COVID-19 pandemic, it became clear that diabetic nephropathy is amongst the independent risk factors that predicts unfavourable outcome upon SARS-CoV2 infection. While we still lack conclusive mechanistic insights into how nephrons are rapidly lost upon SARS-CoV2 infection and why patients with diabetic nephropathy are more susceptible to severe outcomes upon SARS-CoV2 infection, here, we discuss several aspects of the interface of COVID-19 with diabetic nephropathy. We identify the shortage of reliable rodent models of diabetic nephropathy, limited treatment options for human diabetic nephropathy and the lack of knowledge about virus-induced signalling pathways of regulated necrosis, such as necroptosis, as key factors that explain our failure to understand this system. Finally, we focus on immunosuppressed patients and discuss vaccination efficacy in these and diabetic patients. We conclude that more basic science and mechanistic understanding will be required both in diabetic nephropathy as well as in host immune responses to the SARS-CoV2 virus if novel therapeutic strategies are desired.
    MeSH term(s) COVID-19 ; Diabetes Mellitus ; Diabetic Nephropathies/pathology ; Humans ; Kidney Failure, Chronic ; Pandemics ; RNA, Viral ; SARS-CoV-2
    Chemical Substances RNA, Viral
    Language English
    Publishing date 2022-04-06
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 80125-2
    ISSN 1439-4286 ; 0018-5043
    ISSN (online) 1439-4286
    ISSN 0018-5043
    DOI 10.1055/a-1819-4822
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 681: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  3. Article ; Online: Induction of ferroptosis selectively eliminates senescent tubular cells.

    Liao, Chieh M / Wulfmeyer, Vera C / Chen, Rongjun / Erlangga, Zulrahman / Sinning, Julius / von Mässenhausen, Anne / Sörensen-Zender, Inga / Beer, Kristina / von Vietinghoff, Sibylle / Haller, Hermann / Linkermann, Andreas / Melk, Anette / Schmitt, Roland

    American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons

    2022  Volume 22, Issue 9, Page(s) 2158–2168

    Abstract: The accumulation of senescent cells is an important contributor to kidney aging, chronic renal disease, and poor outcome after kidney transplantation. Approaches to eliminate senescent cells with senolytic compounds have been proposed as novel strategies ...

    Abstract The accumulation of senescent cells is an important contributor to kidney aging, chronic renal disease, and poor outcome after kidney transplantation. Approaches to eliminate senescent cells with senolytic compounds have been proposed as novel strategies to improve marginal organs. While most existing senolytics induce senescent cell clearance by apoptosis, we observed that ferroptosis, an iron-catalyzed subtype of regulated necrosis, might serve as an alternative way to ablate senescent cells. We found that murine kidney tubular epithelial cells became sensitized to ferroptosis when turning senescent. This was linked to increased expression of pro-ferroptotic lipoxygenase-5 and reduced expression of anti-ferroptotic glutathione peroxidase 4 (GPX4). In tissue slice cultures from aged kidneys low dose application of the ferroptosis-inducer RSL3 selectively eliminated senescent cells while leaving healthy tubular cells unaffected. Similar results were seen in a transplantation model, in which RSL3 reduced the senescent cell burden of aged donor kidneys and caused a reduction of damage and inflammatory cell infiltration during the early post-transplantation period. In summary, these data reveal an increased susceptibility of senescent tubular cells to ferroptosis with the potential to be exploited for selective reduction of renal senescence in aged kidney transplants.
    MeSH term(s) Aging ; Animals ; Apoptosis ; Epithelial Cells ; Ferroptosis ; Mice
    Language English
    Publishing date 2022-06-08
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2060594-8
    ISSN 1600-6143 ; 1600-6135
    ISSN (online) 1600-6143
    ISSN 1600-6135
    DOI 10.1111/ajt.17102
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5542: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  4. 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

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  5. Article ; Online: Gasdermin D-deficient mice are hypersensitive to acute kidney injury.

    Tonnus, Wulf / Maremonti, Francesca / Belavgeni, Alexia / Latk, Markus / Kusunoki, Yoshihiro / Brucker, Anne / von Mässenhausen, Anne / Meyer, Claudia / Locke, Sophie / Gembardt, Florian / Beer, Kristina / Hoppenz, Paul / Becker, Jan U / Hugo, Christian / Anders, Hans-Joachim / Bornstein, Stefan R / Shao, Feng / Linkermann, Andreas

    Cell death & disease

    2022  Volume 13, Issue 9, Page(s) 792

    Abstract: Signaling pathways of regulated necrosis, such as necroptosis and ferroptosis, contribute to acute kidney injury (AKI), but the role of pyroptosis is unclear. Pyroptosis is mediated by the pore-forming protein gasdermin D (GSDMD). Here, we report a ... ...

    Abstract Signaling pathways of regulated necrosis, such as necroptosis and ferroptosis, contribute to acute kidney injury (AKI), but the role of pyroptosis is unclear. Pyroptosis is mediated by the pore-forming protein gasdermin D (GSDMD). Here, we report a specific pattern of GSDMD-protein expression in the peritubular compartment of mice that underwent bilateral ischemia and reperfusion injury (IRI). Along similar lines, the GSDMD-protein expression in whole kidney lysates increased during the first 84 h following cisplatin-induced AKI. Importantly, unlike whole kidney lysates, no GSDMD-protein expression was detectable in isolated kidney tubules. In IRI and cisplatin-induced AKI, GSDMD-deficient mice exhibited hypersensitivity to injury as assessed by tubular damage, elevated markers of serum urea, and serum creatinine. This hypersensitivity was reversed by a combined deficiency of GSDMD and the necroptosis mediator mixed lineage kinase domain-like (MLKL). In conclusion, we demonstrate a non-cell autonomous role for GSDMD in protecting the tubular compartment from necroptosis-mediated damage in IRI.
    MeSH term(s) Acute Kidney Injury/metabolism ; Animals ; Cisplatin/adverse effects ; Creatinine ; Hypersensitivity ; Intracellular Signaling Peptides and Proteins/genetics ; Intracellular Signaling Peptides and Proteins/metabolism ; Mice ; Phosphate-Binding Proteins/genetics ; Phosphate-Binding Proteins/metabolism ; Urea
    Chemical Substances Intracellular Signaling Peptides and Proteins ; Phosphate-Binding Proteins ; Urea (8W8T17847W) ; Creatinine (AYI8EX34EU) ; Cisplatin (Q20Q21Q62J)
    Language English
    Publishing date 2022-09-15
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2541626-1
    ISSN 2041-4889 ; 2041-4889
    ISSN (online) 2041-4889
    ISSN 2041-4889
    DOI 10.1038/s41419-022-05230-9
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. 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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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1148: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  7. Article: COVID-19 and Diabetic Nephropathy

    Maremonti, Francesca / Locke, Sophie / Tonnus, Wulf / Beer, Kristina / Brucker, Anne / Gonzalez, Nadia Zamora / Latk, Marcus / Belavgeni, Alexia / Hoppenz, Paul / Hugo, Christian / Linkermann, Andreas

    Hormone and Metabolic Research

    (Transcampus Long Covid)

    2022  Volume 54, Issue 08, Page(s) 510–513

    Abstract: Diabetic nephropathy is the most common condition that requires a chronic renal replacement therapy, such as hemodialysis, peritoneal dialysis, kidney transplantation, or simultaneous kidney-pancreas ... ...

    Series title Transcampus Long Covid
    Abstract Diabetic nephropathy is the most common condition that requires a chronic renal replacement therapy, such as hemodialysis, peritoneal dialysis, kidney transplantation, or simultaneous kidney-pancreas transplantation. Chronic kidney disease progression, that is the loss of nephrons, which causes the continuous decline of the eGFR, underlies the pathogenesis of diabetic nephropathy. During the COVID-19 pandemic, it became clear that diabetic nephropathy is amongst the independent risk factors that predicts unfavourable outcome upon SARS-CoV2 infection. While we still lack conclusive mechanistic insights into how nephrons are rapidly lost upon SARS-CoV2 infection and why patients with diabetic nephropathy are more susceptible to severe outcomes upon SARS-CoV2 infection, here, we discuss several aspects of the interface of COVID-19 with diabetic nephropathy. We identify the shortage of reliable rodent models of diabetic nephropathy, limited treatment options for human diabetic nephropathy and the lack of knowledge about virus-induced signalling pathways of regulated necrosis, such as necroptosis, as key factors that explain our failure to understand this system. Finally, we focus on immunosuppressed patients and discuss vaccination efficacy in these and diabetic patients. We conclude that more basic science and mechanistic understanding will be required both in diabetic nephropathy as well as in host immune responses to the SARS-CoV2 virus if novel therapeutic strategies are desired.
    Keywords diabetic nephropathy ; diabetes ; chronic kidney disease ; COVID19 ; necroptosis
    Language English
    Publishing date 2022-04-06
    Publisher Georg Thieme Verlag KG
    Publishing place Stuttgart ; New York
    Document type Article
    ZDB-ID 80125-2
    ISSN 1439-4286 ; 0018-5043
    ISSN (online) 1439-4286
    ISSN 0018-5043
    DOI 10.1055/a-1819-4822
    Database Thieme publisher's database

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 681: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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