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  1. Article ; Online: Downregulation of transposable elements extends lifespan in Caenorhabditis elegans.

    Sturm, Ádám / Saskői, Éva / Hotzi, Bernadette / Tarnóci, Anna / Barna, János / Bodnár, Ferenc / Sharma, Himani / Kovács, Tibor / Ari, Eszter / Weinhardt, Nóra / Kerepesi, Csaba / Perczel, András / Ivics, Zoltán / Vellai, Tibor

    Nature communications

    2023  Volume 14, Issue 1, Page(s) 5278

    Abstract: Mobility of transposable elements (TEs) frequently leads to insertional mutations in functional DNA regions. In the potentially immortal germline, TEs are effectively suppressed by the Piwi-piRNA pathway. However, in the genomes of ageing somatic cells ... ...

    Abstract Mobility of transposable elements (TEs) frequently leads to insertional mutations in functional DNA regions. In the potentially immortal germline, TEs are effectively suppressed by the Piwi-piRNA pathway. However, in the genomes of ageing somatic cells lacking the effects of the pathway, TEs become increasingly mobile during the adult lifespan, and their activity is associated with genomic instability. Whether the progressively increasing mobilization of TEs is a cause or a consequence of ageing remains a fundamental problem in biology. Here we show that in the nematode Caenorhabditis elegans, the downregulation of active TE families extends lifespan. Ectopic activation of Piwi proteins in the soma also promotes longevity. Furthermore, DNA N
    MeSH term(s) Animals ; Longevity/genetics ; DNA Transposable Elements/genetics ; Caenorhabditis elegans/genetics ; Down-Regulation/genetics ; Adenine
    Chemical Substances DNA Transposable Elements ; Adenine (JAC85A2161)
    Language English
    Publishing date 2023-08-29
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-023-40957-9
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: AUTEN-67 (Autophagy Enhancer-67) Hampers the Progression of Neurodegenerative Symptoms in a Drosophila model of Huntington's Disease.

    Billes, Viktor / Kovács, Tibor / Hotzi, Bernadette / Manzéger, Anna / Tagscherer, Kinga / Komlós, Marcell / Tarnóci, Anna / Pádár, Zsolt / Erdős, Attila / Bjelik, Annamaria / Legradi, Adam / Gulya, Károly / Gulyás, Balázs / Vellai, Tibor

    Journal of Huntington's disease

    2016  Volume 5, Issue 2, Page(s) 133–147

    Abstract: Background: Autophagy, a lysosome-mediated self-degradation process of eukaryotic cells, serves as a main route for the elimination of cellular damage [1-3]. Such damages include aggregated, oxidized or misfolded proteins whose accumulation can cause ... ...

    Abstract Background: Autophagy, a lysosome-mediated self-degradation process of eukaryotic cells, serves as a main route for the elimination of cellular damage [1-3]. Such damages include aggregated, oxidized or misfolded proteins whose accumulation can cause various neurodegenerative pathologies, including Huntington's disease (HD).
    Objective: Here we examined whether enhanced autophagic activity can alleviate neurophatological features in a Drosophila model of HD (the transgenic animals express a human mutant Huntingtin protein with a long polyglutamine repeat, 128Q).
    Methods: We have recently identified an autophagy-enhancing small molecule, AUTEN-67 (autophagy enhancer 67), with potent neuroprotective effects [4]. AUTEN-67 was applied to induce autophagic activity in the HD model used in this study.
    Results: We showed that AUTEN-67 treatment interferes with the progressive accumulation of ubiquitinated proteins in the brain of Drosophila transgenic for the pathological 128Q form of human Huntingtin protein. The compound significantly improved the climbing ability and moderately extended the mean life span of these flies. Furthermore, brain tissue samples from human patients diagnosed for HD displayed increased levels of the autophagy substrate SQSTM1/p62 protein, as compared with controls.
    Conclusions: These results imply that AUTEN-67 impedes the progression of neurodegenerative symptoms characterizing HD, and that autophagy is a promising therapeutic target for treating this pathology. In humans, AUTEN-67 may have the potential to delay the onset and decrease the severity of HD.
    MeSH term(s) Animals ; Animals, Genetically Modified ; Autophagy/drug effects ; Brain/drug effects ; Brain/metabolism ; Disease Models, Animal ; Disease Progression ; Drosophila ; Drosophila Proteins/genetics ; Humans ; Huntingtin Protein/genetics ; Huntington Disease/complications ; Huntington Disease/genetics ; Huntington Disease/pathology ; Naphthoquinones/metabolism ; Naphthoquinones/therapeutic use ; Neurodegenerative Diseases/drug therapy ; Neurodegenerative Diseases/etiology ; Neurodegenerative Diseases/genetics ; Neuroprotective Agents/therapeutic use ; Peptides/genetics ; Statistics, Nonparametric ; Sulfonamides/metabolism ; Sulfonamides/therapeutic use
    Chemical Substances Drosophila Proteins ; HTT protein, human ; Huntingtin Protein ; N-(3-(benzimidazol-1-yl)-1,4-dioxonaphthalen-2-yl)-4-nitrobenzenesulfonamide ; Naphthoquinones ; Neuroprotective Agents ; Peptides ; Sulfonamides ; polyglutamine (26700-71-0)
    Language English
    Publishing date 2016-05-09
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1879-6400
    ISSN (online) 1879-6400
    DOI 10.3233/JHD-150180
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: AUTEN-67, an autophagy-enhancing drug candidate with potent antiaging and neuroprotective effects.

    Papp, Diána / Kovács, Tibor / Billes, Viktor / Varga, Máté / Tarnóci, Anna / Hackler, László / Puskás, László G / Liliom, Hanna / Tárnok, Krisztián / Schlett, Katalin / Borsy, Adrienn / Pádár, Zsolt / Kovács, Attila L / Hegedűs, Krisztina / Juhász, Gábor / Komlós, Marcell / Erdős, Attila / Gulyás, Balázs / Vellai, Tibor

    Autophagy

    2016  Volume 12, Issue 2, Page(s) 273–286

    Abstract: Autophagy is a major molecular mechanism that eliminates cellular damage in eukaryotic organisms. Basal levels of autophagy are required for maintaining cellular homeostasis and functioning. Defects in the autophagic process are implicated in the ... ...

    Abstract Autophagy is a major molecular mechanism that eliminates cellular damage in eukaryotic organisms. Basal levels of autophagy are required for maintaining cellular homeostasis and functioning. Defects in the autophagic process are implicated in the development of various age-dependent pathologies including cancer and neurodegenerative diseases, as well as in accelerated aging. Genetic activation of autophagy has been shown to retard the accumulation of damaged cytoplasmic constituents, delay the incidence of age-dependent diseases, and extend life span in genetic models. This implies that autophagy serves as a therapeutic target in treating such pathologies. Although several autophagy-inducing chemical agents have been identified, the majority of them operate upstream of the core autophagic process, thereby exerting undesired side effects. Here, we screened a small-molecule library for specific inhibitors of MTMR14, a myotubularin-related phosphatase antagonizing the formation of autophagic membrane structures, and isolated AUTEN-67 (autophagy enhancer-67) that significantly increases autophagic flux in cell lines and in vivo models. AUTEN-67 promotes longevity and protects neurons from undergoing stress-induced cell death. It also restores nesting behavior in a murine model of Alzheimer disease, without apparent side effects. Thus, AUTEN-67 is a potent drug candidate for treating autophagy-related diseases.
    MeSH term(s) Aging/drug effects ; Amyloid beta-Protein Precursor/metabolism ; Animals ; Autophagy/drug effects ; Drosophila melanogaster/drug effects ; Drosophila melanogaster/metabolism ; Fat Body/drug effects ; Fat Body/metabolism ; Female ; HeLa Cells ; Humans ; Longevity/drug effects ; Male ; Mice ; Naphthoquinones/chemistry ; Naphthoquinones/pharmacology ; Nesting Behavior/drug effects ; Neuroprotection/drug effects ; Neuroprotective Agents/chemistry ; Neuroprotective Agents/pharmacology ; Oxidative Stress/drug effects ; Phosphoric Monoester Hydrolases/metabolism ; Sulfonamides/chemistry ; Sulfonamides/pharmacology ; Zebrafish
    Chemical Substances Amyloid beta-Protein Precursor ; N-(3-(benzimidazol-1-yl)-1,4-dioxonaphthalen-2-yl)-4-nitrobenzenesulfonamide ; Naphthoquinones ; Neuroprotective Agents ; Sulfonamides ; MTMR14 protein, human (EC 3.1.3.-) ; Phosphoric Monoester Hydrolases (EC 3.1.3.2)
    Language English
    Publishing date 2016
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2454135-7
    ISSN 1554-8635 ; 1554-8627
    ISSN (online) 1554-8635
    ISSN 1554-8627
    DOI 10.1080/15548627.2015.1082023
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: The small molecule AUTEN-99 (autophagy enhancer-99) prevents the progression of neurodegenerative symptoms.

    Kovács, Tibor / Billes, Viktor / Komlós, Marcell / Hotzi, Bernadette / Manzéger, Anna / Tarnóci, Anna / Papp, Diána / Szikszai, Fanni / Szinyákovics, Janka / Rácz, Ákos / Noszál, Béla / Veszelka, Szilvia / Walter, Fruzsina R / Deli, Mária A / Hackler, Laszlo / Alfoldi, Robert / Huzian, Orsolya / Puskas, Laszlo G / Liliom, Hanna /
    Tárnok, Krisztián / Schlett, Katalin / Borsy, Adrienn / Welker, Ervin / Kovács, Attila L / Pádár, Zsolt / Erdős, Attila / Legradi, Adam / Bjelik, Annamaria / Gulya, Károly / Gulyás, Balázs / Vellai, Tibor

    Scientific reports

    2017  Volume 7, Page(s) 42014

    Abstract: Autophagy functions as a main route for the degradation of superfluous and damaged constituents of the cytoplasm. Defects in autophagy are implicated in the development of various age-dependent degenerative disorders such as cancer, neurodegeneration and ...

    Abstract Autophagy functions as a main route for the degradation of superfluous and damaged constituents of the cytoplasm. Defects in autophagy are implicated in the development of various age-dependent degenerative disorders such as cancer, neurodegeneration and tissue atrophy, and in accelerated aging. To promote basal levels of the process in pathological settings, we previously screened a small molecule library for novel autophagy-enhancing factors that inhibit the myotubularin-related phosphatase MTMR14/Jumpy, a negative regulator of autophagic membrane formation. Here we identify AUTEN-99 (autophagy enhancer-99), which activates autophagy in cell cultures and animal models. AUTEN-99 appears to effectively penetrate through the blood-brain barrier, and impedes the progression of neurodegenerative symptoms in Drosophila models of Parkinson's and Huntington's diseases. Furthermore, the molecule increases the survival of isolated neurons under normal and oxidative stress-induced conditions. Thus, AUTEN-99 serves as a potent neuroprotective drug candidate for preventing and treating diverse neurodegenerative pathologies, and may promote healthy aging.
    MeSH term(s) Animals ; Autophagy/drug effects ; Cell Survival/drug effects ; Cells, Cultured ; Disease Models, Animal ; Drosophila ; Neurodegenerative Diseases/prevention & control ; Neurons/drug effects ; Neurons/physiology ; Neuroprotective Agents/administration & dosage ; Neuroprotective Agents/pharmacology
    Chemical Substances Neuroprotective Agents
    Language English
    Publishing date 2017-02-16
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/srep42014
    Database MEDical Literature Analysis and Retrieval System OnLINE

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