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  1. Article ; Online: Modulating Copper Reactivity: A New Approach to Reprogram Mitochondrial Retrograde Signaling.

    Zacharioudakis, Emmanouil

    ACS chemical biology

    2023  Volume 18, Issue 6, Page(s) 1256–1258

    Abstract: The crosstalk between mitochondria and the nucleus regulates cell plasticity and innate immune response. A new study shows that copper(II) accumulates in mitochondria of activated macrophages in response to pathogen infection and induces metabolic and ... ...

    Abstract The crosstalk between mitochondria and the nucleus regulates cell plasticity and innate immune response. A new study shows that copper(II) accumulates in mitochondria of activated macrophages in response to pathogen infection and induces metabolic and epigenetic reprogramming that promotes inflammation. Pharmacologic targeting of mitochondrial copper(II) uncovers a new therapeutic strategy to combat aberrant inflammation and regulate cell plasticity.
    MeSH term(s) Humans ; Copper/metabolism ; Mitochondria/metabolism ; Immunity, Innate ; Macrophages/metabolism ; Inflammation/metabolism
    Chemical Substances Copper (789U1901C5)
    Language English
    Publishing date 2023-06-08
    Publishing country United States
    Document type News
    ISSN 1554-8937
    ISSN (online) 1554-8937
    DOI 10.1021/acschembio.3c00298
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Repurposing Platinum(IV) Prodrugs to Modulate Mitochondrial Metabolism.

    Zacharioudakis, Emmanouil / Rodriguez, Raphaël

    ACS central science

    2023  Volume 9, Issue 7, Page(s) 1257–1259

    Language English
    Publishing date 2023-07-12
    Publishing country United States
    Document type News
    ISSN 2374-7943
    ISSN 2374-7943
    DOI 10.1021/acscentsci.3c00654
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Repurposing Platinum(IV) Prodrugs to Modulate Mitochondrial Metabolism

    Emmanouil Zacharioudakis / Raphaël Rodriguez

    ACS Central Science, Vol 9, Iss 7, Pp 1257-

    2023  Volume 1259

    Keywords Chemistry ; QD1-999
    Language English
    Publishing date 2023-07-01T00:00:00Z
    Publisher American Chemical Society
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article: Targeting protein conformations with small molecules to control protein complexes.

    Zacharioudakis, Emmanouil / Gavathiotis, Evripidis

    Trends in biochemical sciences

    2022  Volume 47, Issue 12, Page(s) 1023–1037

    Abstract: Dynamic protein complexes function in all cellular processes, from signaling to transcription, using distinct conformations that regulate their activity. Conformational switching of proteins can turn on or off their activity through protein-protein ... ...

    Abstract Dynamic protein complexes function in all cellular processes, from signaling to transcription, using distinct conformations that regulate their activity. Conformational switching of proteins can turn on or off their activity through protein-protein interactions, catalytic function, cellular localization, or membrane interaction. Recent advances in structural, computational, and chemical methodologies have enabled the discovery of small-molecule activators and inhibitors of conformationally dynamic proteins by using a more rational design than a serendipitous screening approach. Here, we discuss such recent examples, focusing on the mechanism of protein conformational switching and its regulation by small molecules. We emphasize the rational approaches to control protein oligomerization with small molecules that offer exciting opportunities for investigation of novel biological mechanisms and drug discovery.
    MeSH term(s) Protein Conformation ; Proteins/chemistry ; Drug Discovery
    Chemical Substances Proteins
    Language English
    Publishing date 2022-08-16
    Publishing country England
    Document type Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 194216-5
    ISSN 1362-4326 ; 0968-0004 ; 0376-5067
    ISSN (online) 1362-4326
    ISSN 0968-0004 ; 0376-5067
    DOI 10.1016/j.tibs.2022.07.002
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1207: Show issues Location:
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    Jg. 1995 - 2021: Lesesall (1.OG)
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  5. Article ; Online: Mitochondrial dynamics proteins as emerging drug targets.

    Zacharioudakis, Emmanouil / Gavathiotis, Evripidis

    Trends in pharmacological sciences

    2022  Volume 44, Issue 2, Page(s) 112–127

    Abstract: The importance of mitochondrial dynamics, the physiological process of mitochondrial fusion and fission, in regulating diverse cellular functions and cellular fitness has been well established. Several pathologies are associated with aberrant ... ...

    Abstract The importance of mitochondrial dynamics, the physiological process of mitochondrial fusion and fission, in regulating diverse cellular functions and cellular fitness has been well established. Several pathologies are associated with aberrant mitochondrial fusion or fission that is often a consequence of deregulated mitochondrial dynamics proteins; however, pharmacological targeting of these proteins has been lacking and is challenged by complex molecular mechanisms. Recent studies have advanced our understanding in this area and have enabled rational drug design and chemical screening strategies. We provide an updated overview of the regulatory mechanisms of fusion and fission proteins, their structure-function relationships, and the discovery of pharmacological modulators demonstrating their therapeutic potential. These advances provide exciting opportunities for the development of prototype therapeutics for various diseases.
    MeSH term(s) Humans ; Drug Design ; Mitochondria/metabolism ; Mitochondrial Dynamics/drug effects ; Mitochondrial Proteins/metabolism
    Chemical Substances Mitochondrial Proteins
    Language English
    Publishing date 2022-12-07
    Publishing country England
    Document type Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 282846-7
    ISSN 1873-3735 ; 0165-6147
    ISSN (online) 1873-3735
    ISSN 0165-6147
    DOI 10.1016/j.tips.2022.11.004
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 1513: Show issues Location:
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    Zs.MG 6: Show issues

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  6. Article: Targeting protein conformations with small molecules to control protein complexes

    Zacharioudakis, Emmanouil / Gavathiotis, Evripidis

    Trends in biochemical sciences. 2022,

    2022  

    Abstract: Dynamic protein complexes function in all cellular processes, from signaling to transcription, using distinct conformations that regulate their activity. Conformational switching of proteins can turn on or off their activity through protein–protein ... ...

    Abstract Dynamic protein complexes function in all cellular processes, from signaling to transcription, using distinct conformations that regulate their activity. Conformational switching of proteins can turn on or off their activity through protein–protein interactions, catalytic function, cellular localization, or membrane interaction. Recent advances in structural, computational, and chemical methodologies have enabled the discovery of small-molecule activators and inhibitors of conformationally dynamic proteins by using a more rational design than a serendipitous screening approach. Here, we discuss such recent examples, focusing on the mechanism of protein conformational switching and its regulation by small molecules. We emphasize the rational approaches to control protein oligomerization with small molecules that offer exciting opportunities for investigation of novel biological mechanisms and drug discovery.
    Keywords drugs ; oligomerization ; protein conformation ; protein-protein interactions ; proteins ; screening
    Language English
    Publishing place Elsevier Ltd
    Document type Article
    Note Pre-press version
    ZDB-ID 194220-7
    ISSN 0968-0004 ; 0376-5067
    ISSN 0968-0004 ; 0376-5067
    DOI 10.1016/j.tibs.2022.07.002
    Database NAL-Catalogue (AGRICOLA)

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    In stock of ZB MED Bonn / Germany

    Z 78/716: Show issues

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  7. Article ; Online: Eltrombopag directly inhibits BAX and prevents cell death.

    Spitz, Adam Z / Zacharioudakis, Emmanouil / Reyna, Denis E / Garner, Thomas P / Gavathiotis, Evripidis

    Nature communications

    2021  Volume 12, Issue 1, Page(s) 1134

    Abstract: The BCL-2 family protein BAX has essential activity in mitochondrial regulation of cell death. While BAX activity ensures tissue homeostasis, when dysregulated it contributes to aberrant cell death in several diseases. During cellular stress BAX is ... ...

    Abstract The BCL-2 family protein BAX has essential activity in mitochondrial regulation of cell death. While BAX activity ensures tissue homeostasis, when dysregulated it contributes to aberrant cell death in several diseases. During cellular stress BAX is transformed from an inactive cytosolic conformation to a toxic mitochondrial oligomer. Although the BAX transformation process is not well understood, drugs that interfere with this process are useful research tools and potential therapeutics. Here, we show that Eltrombopag,  an FDA-approved drug,  is a direct inhibitor of BAX. Eltrombopag binds the BAX trigger site distinctly from BAX activators, preventing them from triggering BAX conformational transformation and simultaneously promoting stabilization of the inactive BAX structure. Accordingly, Eltrombopag is capable of inhibiting BAX-mediated apoptosis induced by cytotoxic stimuli. Our data demonstrate structure-function insights into a mechanism of BAX inhibition and reveal a mechanism for Eltrombopag that may expand its use in diseases of uncontrolled cell death.
    MeSH term(s) 3T3 Cells ; Animals ; Apoptosis/drug effects ; Benzoates/chemistry ; Benzoates/pharmacology ; Cell Death/drug effects ; Humans ; Hydrazines/chemistry ; Hydrazines/pharmacology ; Magnetic Resonance Spectroscopy ; Mice ; Models, Biological ; Models, Molecular ; Protein Stability/drug effects ; Pyrazoles/chemistry ; Pyrazoles/pharmacology ; bcl-2-Associated X Protein/antagonists & inhibitors ; bcl-2-Associated X Protein/chemistry ; bcl-2-Associated X Protein/metabolism
    Chemical Substances Benzoates ; Hydrazines ; Pyrazoles ; bcl-2-Associated X Protein ; eltrombopag (S56D65XJ9G)
    Language English
    Publishing date 2021-02-18
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-021-21224-1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article: Alzheimer's disease-linked risk alleles elevate microglial cGAS-associated senescence and neurodegeneration in a tauopathy model.

    Carling, Gillian K / Fan, Li / Foxe, Nessa R / Norman, Kendra / Ye, Pearly / Wong, Man Ying / Zhu, Daphne / Yu, Fangmin / Xu, Jielin / Yarahmady, Allan / Chen, Hao / Huang, Yige / Amin, Sadaf / Zacharioudakis, Emmanouil / Chen, Xiaoying / Holtzman, David M / Mok, Sue-Ann / Gavathiotis, Evripidis / Sinha, Subhash C /
    Cheng, Feixiong / Luo, Wenjie / Gong, Shiaoching / Gan, Li

    bioRxiv : the preprint server for biology

    2024  

    Abstract: The strongest risk factors for Alzheimer's disease (AD) include the χ4 allele of apolipoprotein E (APOE), ... ...

    Abstract The strongest risk factors for Alzheimer's disease (AD) include the χ4 allele of apolipoprotein E (APOE), the
    Language English
    Publishing date 2024-01-25
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2024.01.24.577107
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Eltrombopag directly inhibits BAX and prevents cell death

    Adam Z. Spitz / Emmanouil Zacharioudakis / Denis E. Reyna / Thomas P. Garner / Evripidis Gavathiotis

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

    2021  Volume 15

    Abstract: The BCL-2 family protein BAX functions to regulate mitochondria-driven cell death. Here the authors show that the drug Eltrombopag inhibits BAX and prevents apoptosis induced by cytotoxic stimuli. ...

    Abstract The BCL-2 family protein BAX functions to regulate mitochondria-driven cell death. Here the authors show that the drug Eltrombopag inhibits BAX and prevents apoptosis induced by cytotoxic stimuli.
    Keywords Science ; Q
    Language English
    Publishing date 2021-02-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  10. Article ; Online: Mitophagy Promotes Resistance to BH3 Mimetics in Acute Myeloid Leukemia.

    Glytsou, Christina / Chen, Xufeng / Zacharioudakis, Emmanouil / Al-Santli, Wafa / Zhou, Hua / Nadorp, Bettina / Lee, Soobeom / Lasry, Audrey / Sun, Zhengxi / Papaioannou, Dimitrios / Cammer, Michael / Wang, Kun / Zal, Tomasz / Zal, Malgorzata Anna / Carter, Bing Z / Ishizawa, Jo / Tibes, Raoul / Tsirigos, Aristotelis / Andreeff, Michael /
    Gavathiotis, Evripidis / Aifantis, Iannis

    Cancer discovery

    2023  Volume 13, Issue 7, Page(s) 1656–1677

    Abstract: BH3 mimetics are used as an efficient strategy to induce cell death in several blood malignancies, including acute myeloid leukemia (AML). Venetoclax, a potent BCL-2 antagonist, is used clinically in combination with hypomethylating agents for the ... ...

    Abstract BH3 mimetics are used as an efficient strategy to induce cell death in several blood malignancies, including acute myeloid leukemia (AML). Venetoclax, a potent BCL-2 antagonist, is used clinically in combination with hypomethylating agents for the treatment of AML. Moreover, MCL1 or dual BCL-2/BCL-xL antagonists are under investigation. Yet, resistance to single or combinatorial BH3-mimetic therapies eventually ensues. Integration of multiple genome-wide CRISPR/Cas9 screens revealed that loss of mitophagy modulators sensitizes AML cells to various BH3 mimetics targeting different BCL-2 family members. One such regulator is MFN2, whose protein levels positively correlate with drug resistance in patients with AML. MFN2 overexpression is sufficient to drive resistance to BH3 mimetics in AML. Insensitivity to BH3 mimetics is accompanied by enhanced mitochondria-endoplasmic reticulum interactions and augmented mitophagy flux, which acts as a prosurvival mechanism to eliminate mitochondrial damage. Genetic or pharmacologic MFN2 targeting synergizes with BH3 mimetics by impairing mitochondrial clearance and enhancing apoptosis in AML.
    Significance: AML remains one of the most difficult-to-treat blood cancers. BH3 mimetics represent a promising therapeutic approach to eliminate AML blasts by activating the apoptotic pathway. Enhanced mitochondrial clearance drives resistance to BH3 mimetics and predicts poor prognosis. Reverting excessive mitophagy can halt BH3-mimetic resistance in AML. This article is highlighted in the In This Issue feature, p. 1501.
    MeSH term(s) Humans ; Myeloid Cell Leukemia Sequence 1 Protein ; Mitophagy ; Leukemia, Myeloid, Acute/drug therapy ; Leukemia, Myeloid, Acute/genetics ; Leukemia, Myeloid, Acute/metabolism ; Apoptosis ; Cell Death ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Cell Line, Tumor ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use
    Chemical Substances Myeloid Cell Leukemia Sequence 1 Protein ; Proto-Oncogene Proteins c-bcl-2 ; Antineoplastic Agents
    Language English
    Publishing date 2023-04-22
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2625242-9
    ISSN 2159-8290 ; 2159-8274
    ISSN (online) 2159-8290
    ISSN 2159-8274
    DOI 10.1158/2159-8290.CD-22-0601
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 6916: Show issues Location:
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