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  1. Article ; Online: Mitochondria-targeted Uncouplers Decrease Inflammatory Reactions in Endothelial Cells by Enhancing Methylation of the ICAM1 Gene Promoter.

    Zinovkina, Liudmila A / Makievskaya, Ciara I / Galkin, Ivan I / Zinovkin, Roman A

    Current molecular pharmacology

    2023  Volume 17, Issue 1, Page(s) e150823219723

    Abstract: Introduction: The study aimed to investigate the effects of low concentrations of mitochondrial uncouplers in endothelial cells on the CpG dinucleotide methylation of the ICAM1 gene promoter. The excessive inflammatory response in the endothelium is ... ...

    Abstract Introduction: The study aimed to investigate the effects of low concentrations of mitochondrial uncouplers in endothelial cells on the CpG dinucleotide methylation of the ICAM1 gene promoter. The excessive inflammatory response in the endothelium is responsible for the development of many cardiovascular diseases. Mitochondria are important regulators of endothelial cell functions. Mild uncoupling of oxidative phosphorylation and respiration in endothelial mitochondria exerts a long lasting anti-inflammatory effect. However, the detailed mechanism of the anti-inflammatory activity of mitochondrial uncouplers remains unclear.We hypothesized that mild mitochondrial uncoupling leads to epigenetic changes in genomic DNA contributing to the anti-inflammatory response.
    Methods: We studied the long-term effects of mitochondria-targeted compounds with the uncoupler's activities: the antioxidant plastoquinonyl-decyltriphenylphosphonium (SkQ1), dodecyl-triphenylphosphonium (C12TPP), and 2,4-dinitrophenol (DNP). The mRNA expression of the intercellular adhesion molecule 1 (ICAM1), a marker of inflammatory activation of endothelial cells, was measured by RT-qPCR. Cytosine methylation in the CpG sites of the ICAM1 gene promoter was estimated by bisulfite sequencing of individual clones.
    Results: It was found that downregulation of ICAM1 expression caused by DNP and C12TPP was accompanied by an increase in the methylation of CpG sites in the ICAM1 gene promoter. None of the compounds affected intracellular or intramitochondrial ATP levels.
    Conclusion: Low concentrations of mitochondrial oxidative phosphorylation uncouplers are able to increase methylation of ICAM1 gene promoter, which corresponds to the observed decrease in the levels of mRNA of this gene. Thus, the change in methylation of the ICAM1 gene promoter may underlie the mechanism of decreased ICAM1 expression caused by mild mitochondrial depolarization. Mitochondrial uncouplers may be exploited as possible therapeutic candidates to treat excessive inflammation in endothelium, by changing the methylation status of genomic DNA.
    MeSH term(s) Humans ; Endothelial Cells/metabolism ; Mitochondria/metabolism ; Inflammation/metabolism ; DNA Methylation ; Anti-Inflammatory Agents/pharmacology ; DNA/metabolism ; DNA/pharmacology ; RNA, Messenger/metabolism ; Intercellular Adhesion Molecule-1/genetics ; Intercellular Adhesion Molecule-1/metabolism ; Intercellular Adhesion Molecule-1/pharmacology
    Chemical Substances Anti-Inflammatory Agents ; DNA (9007-49-2) ; RNA, Messenger ; ICAM1 protein, human ; Intercellular Adhesion Molecule-1 (126547-89-5)
    Language English
    Publishing date 2023-08-17
    Publishing country United Arab Emirates
    Document type Journal Article
    ISSN 1874-4702
    ISSN (online) 1874-4702
    DOI 10.2174/1874467217666230815142556
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Ketogenic Diet and Ketone Bodies against Ischemic Injury: Targets, Mechanisms, and Therapeutic Potential.

    Makievskaya, Ciara I / Popkov, Vasily A / Andrianova, Nadezda V / Liao, Xinyu / Zorov, Dmitry B / Plotnikov, Egor Y

    International journal of molecular sciences

    2023  Volume 24, Issue 3

    Abstract: The ketogenic diet (KD) has been used as a treatment for epilepsy since the 1920s, and its role in the prevention of many other diseases is now being considered. In recent years, there has been an intensive investigation on using the KD as a therapeutic ... ...

    Abstract The ketogenic diet (KD) has been used as a treatment for epilepsy since the 1920s, and its role in the prevention of many other diseases is now being considered. In recent years, there has been an intensive investigation on using the KD as a therapeutic approach to treat acute pathologies, including ischemic ones. However, contradictory data are observed for the effects of the KD on various organs after ischemic injury. In this review, we provide the first systematic analysis of studies conducted from 1980 to 2022 investigating the effects and main mechanisms of the KD and its mimetics on ischemia-reperfusion injury of the brain, heart, kidneys, liver, gut, and eyes. Our analysis demonstrated a high diversity of both the composition of the used KD and the protocols for the treatment of animals, which could be the reason for contradictory effects in different studies. It can be concluded that a true KD or its mimetics, such as β-hydroxybutyrate, can be considered as positive exposure, protecting the organ from ischemia and its negative consequences, whereas the shift to a rather similar high-calorie or high-fat diet leads to the opposite effect.
    MeSH term(s) Animals ; Ketone Bodies/therapeutic use ; Diet, Ketogenic/methods ; Epilepsy/drug therapy ; Brain ; Ischemia/drug therapy
    Chemical Substances Ketone Bodies
    Language English
    Publishing date 2023-01-30
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms24032576
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Sex-Specific Effects of Estradiol and Progesterone in Ischemic Kidney Injury.

    Andrianova, Nadezda V / Brezgunova, Anna A / Buyan, Marina I / Makievskaya, Ciara I / Buyan, Andrey I / Cherkesova, Kseniia S / Pevzner, Irina B / Zorova, Ljubava D / Zorov, Dmitry B / Plotnikov, Egor Y / Popkov, Vasily A

    International journal of molecular sciences

    2024  Volume 25, Issue 6

    Abstract: The positive effects of female sex hormones, particularly estradiol and progesterone, have been observed in treatment of various pathologies. Acute kidney injury (AKI) is a common condition in hospitalized patients in which the molecular mechanisms of ... ...

    Abstract The positive effects of female sex hormones, particularly estradiol and progesterone, have been observed in treatment of various pathologies. Acute kidney injury (AKI) is a common condition in hospitalized patients in which the molecular mechanisms of hormone action are poorly characterized. In this study, we investigated the influence of estradiol and progesterone on renal cells during ischemic injury. We performed both in vivo experiments on female and male rats and in vitro experiments on renal tubular cells (RTCs) obtained from the kidneys of intact animals of different sexes. Since mitochondria play an important role in the pathogenesis of AKI, we analyzed the properties of individual mitochondria in renal cells, including the area, roundness, mitochondrial membrane potential, and mitochondrial permeability transition pore (mPTP) opening time. We found that pre-treatment with progesterone or estradiol attenuated the severity of ischemia/reperfusion (I/R)-induced AKI in female rats, whereas in male rats, these hormones exacerbated renal dysfunction. We demonstrated that the mPTP opening time was higher in RTCs from female rats than that in those from male rats, which may be one of the reasons for the higher tolerance of females to ischemic injury. In RTCs from the kidneys of male rats, progesterone caused mitochondrial fragmentation, which can be associated with reduced cell viability. Thus, therapy with progesterone or estradiol displays quite different effects depending on sex, and could be only effective against ischemic AKI in females.
    MeSH term(s) Humans ; Rats ; Male ; Female ; Animals ; Progesterone/adverse effects ; Estradiol/adverse effects ; Kidney/pathology ; Ischemia/complications ; Reperfusion Injury/pathology ; Acute Kidney Injury/etiology
    Chemical Substances Progesterone (4G7DS2Q64Y) ; Estradiol (4TI98Z838E)
    Language English
    Publishing date 2024-03-09
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms25063155
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: Mitochondria-targeted triphenylphosphonium-based compounds inhibit FcεRI-dependent degranulation of mast cells by preventing mitochondrial dysfunction through Erk1/2

    Pavlyuchenkova, Anastasia N. / Zinovkin, Roman A. / Makievskaya, Ciara I. / Galkin, Ivan I. / Chelombitko, Maria A.

    Life sciences. 2022 Jan. 01, v. 288

    2022  

    Abstract: FcεRI-dependent activation and degranulation of mast cells (MC) play an important role in allergic diseases. We have previously demonstrated that triphenylphosphonium (TPP)-based antioxidant SkQ1 inhibits mast cell degranulation, but the exact mechanism ... ...

    Abstract FcεRI-dependent activation and degranulation of mast cells (MC) play an important role in allergic diseases. We have previously demonstrated that triphenylphosphonium (TPP)-based antioxidant SkQ1 inhibits mast cell degranulation, but the exact mechanism of this inhibition is still unknown. This study focused on investigating the influence of TPP-based compounds SkQ1 and C₁₂TPP on FcεRI-dependent mitochondrial dysfunction and signaling during MC degranulation.MC were sensitized by anti-dinitrophenyl IgE and stimulated by BSA-conjugated dinitrophenyl. The degranulation of MC was estimated by β-hexosaminidase release. The effect of TPP-based compounds on FcεRI-dependent signaling was determined by Western blot analysis for adapter molecule LAT, kinases Syk, PI3K, Erk1/2, and p38. Fluorescent microscopy was used to evaluate mitochondrial parameters such as morphology, membrane potential, reactive oxygen species and ATP level.Pretreatment with TPP-based compounds significantly decreased FcεRI-dependent degranulation of MC. TPP-based compounds also prevented mitochondrial dysfunction (drop in mitochondrial ATP level and mitochondrial fission), and decreased Erk1/2 kinase phosphorylation. Selective Erk1/2 inhibition by U0126 also reduced β-hexosaminidase release and prevented mitochondrial fragmentation during FcεRI-dependent degranulation of MC.These findings expand the fundamental understanding of the role of mitochondria in the activation of MC. It also contributes to the rationale for the development of mitochondrial-targeted drugs for the treatment of allergic diseases.
    Keywords Western blotting ; fluorescence microscopy ; mast cells ; membrane potential ; mitochondria ; phosphatidylinositol 3-kinase ; phosphorylation ; reactive oxygen species
    Language English
    Dates of publication 2022-0101
    Publishing place Elsevier Inc.
    Document type Article
    ZDB-ID 3378-9
    ISSN 1879-0631 ; 0024-3205
    ISSN (online) 1879-0631
    ISSN 0024-3205
    DOI 10.1016/j.lfs.2021.120174
    Database NAL-Catalogue (AGRICOLA)

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    In stock of ZB MED Bonn / Germany

    Z 73/732: Show issues

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  5. Article ; Online: Mitochondria-targeted triphenylphosphonium-based compounds inhibit FcεRI-dependent degranulation of mast cells by preventing mitochondrial dysfunction through Erk1/2.

    Pavlyuchenkova, Anastasia N / Zinovkin, Roman A / Makievskaya, Ciara I / Galkin, Ivan I / Chelombitko, Maria A

    Life sciences

    2021  Volume 288, Page(s) 120174

    Abstract: Aims: FcεRI-dependent activation and degranulation of mast cells (MC) play an important role in allergic diseases. We have previously demonstrated that triphenylphosphonium (TPP)-based antioxidant SkQ1 inhibits mast cell degranulation, but the exact ... ...

    Abstract Aims: FcεRI-dependent activation and degranulation of mast cells (MC) play an important role in allergic diseases. We have previously demonstrated that triphenylphosphonium (TPP)-based antioxidant SkQ1 inhibits mast cell degranulation, but the exact mechanism of this inhibition is still unknown. This study focused on investigating the influence of TPP-based compounds SkQ1 and C
    Main methods: MC were sensitized by anti-dinitrophenyl IgE and stimulated by BSA-conjugated dinitrophenyl. The degranulation of MC was estimated by β-hexosaminidase release. The effect of TPP-based compounds on FcεRI-dependent signaling was determined by Western blot analysis for adapter molecule LAT, kinases Syk, PI3K, Erk1/2, and p38. Fluorescent microscopy was used to evaluate mitochondrial parameters such as morphology, membrane potential, reactive oxygen species and ATP level.
    Key findings: Pretreatment with TPP-based compounds significantly decreased FcεRI-dependent degranulation of MC. TPP-based compounds also prevented mitochondrial dysfunction (drop in mitochondrial ATP level and mitochondrial fission), and decreased Erk1/2 kinase phosphorylation. Selective Erk1/2 inhibition by U0126 also reduced β-hexosaminidase release and prevented mitochondrial fragmentation during FcεRI-dependent degranulation of MC.
    Significance: These findings expand the fundamental understanding of the role of mitochondria in the activation of MC. It also contributes to the rationale for the development of mitochondrial-targeted drugs for the treatment of allergic diseases.
    MeSH term(s) Animals ; Cell Degranulation ; Gene Expression Regulation ; Mast Cells/drug effects ; Mast Cells/immunology ; Mast Cells/metabolism ; Mast Cells/pathology ; Mitochondria/drug effects ; Mitochondria/immunology ; Mitochondria/metabolism ; Mitochondria/pathology ; Mitogen-Activated Protein Kinase 1/genetics ; Mitogen-Activated Protein Kinase 1/metabolism ; Mitogen-Activated Protein Kinase 3/genetics ; Mitogen-Activated Protein Kinase 3/metabolism ; Plastoquinone/analogs & derivatives ; Plastoquinone/pharmacology ; Rats ; Receptors, IgE/genetics ; Receptors, IgE/metabolism
    Chemical Substances 10-(6'-plastoquinonyl)decyltriphenylphosphonium ; Receptors, IgE ; Mapk1 protein, rat (EC 2.7.11.24) ; Mitogen-Activated Protein Kinase 1 (EC 2.7.11.24) ; Mitogen-Activated Protein Kinase 3 (EC 2.7.11.24) ; Plastoquinone (OAC30J69CN)
    Language English
    Publishing date 2021-11-23
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 3378-9
    ISSN 1879-0631 ; 0024-3205
    ISSN (online) 1879-0631
    ISSN 0024-3205
    DOI 10.1016/j.lfs.2021.120174
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Uc I Zs.368: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)

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