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  1. Article: New Perspectives on the Role of Nuclear Proteases in Cell Death Pathways.

    Frolova, Anastasia S / Chepikova, Olga E / Deviataikina, Anna S / Solonkina, Alena D / Zamyatnin, Andrey A

    Biology

    2023  Volume 12, Issue 6

    Abstract: Multiple factors can trigger cell death via various pathways, and nuclear proteases have emerged as essential regulators of these processes. While certain nuclear proteases have been extensively studied and their mechanisms of action are well understood, ...

    Abstract Multiple factors can trigger cell death via various pathways, and nuclear proteases have emerged as essential regulators of these processes. While certain nuclear proteases have been extensively studied and their mechanisms of action are well understood, others remain poorly characterized. Regulation of nuclear protease activity is a promising therapeutic strategy that could selectively induce favorable cell death pathways in specific tissues or organs. Thus, by understanding the roles of newly discovered or predicted nuclear proteases in cell death processes, we can identify new pharmacological targets for improving therapeutic outcomes. In this article, we delved into the role of nuclear proteases in several types of cell death and explore potential avenues for future research and therapeutic development.
    Language English
    Publishing date 2023-05-31
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2661517-4
    ISSN 2079-7737
    ISSN 2079-7737
    DOI 10.3390/biology12060797
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: New Perspectives on the Role of Nuclear Proteases in Cell Death Pathways

    Frolova, Anastasia S. / Chepikova, Olga E. / Deviataikina, Anna S. / Solonkina, Alena D. / Zamyatnin, Andrey A.

    Biology (Basel). 2023 May 31, v. 12, no. 6

    2023  

    Abstract: Multiple factors can trigger cell death via various pathways, and nuclear proteases have emerged as essential regulators of these processes. While certain nuclear proteases have been extensively studied and their mechanisms of action are well understood, ...

    Abstract Multiple factors can trigger cell death via various pathways, and nuclear proteases have emerged as essential regulators of these processes. While certain nuclear proteases have been extensively studied and their mechanisms of action are well understood, others remain poorly characterized. Regulation of nuclear protease activity is a promising therapeutic strategy that could selectively induce favorable cell death pathways in specific tissues or organs. Thus, by understanding the roles of newly discovered or predicted nuclear proteases in cell death processes, we can identify new pharmacological targets for improving therapeutic outcomes. In this article, we delved into the role of nuclear proteases in several types of cell death and explore potential avenues for future research and therapeutic development.
    Keywords cell death ; enzyme activity ; proteinases ; therapeutics
    Language English
    Dates of publication 2023-0531
    Publishing place Multidisciplinary Digital Publishing Institute
    Document type Article ; Online
    ZDB-ID 2661517-4
    ISSN 2079-7737
    ISSN 2079-7737
    DOI 10.3390/biology12060797
    Database NAL-Catalogue (AGRICOLA)

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  3. Article ; Online: Evaluation of molecular mechanisms of riboflavin anti-COVID-19 action reveals anti-inflammatory efficacy rather than antiviral activity.

    Akasov, Roman A / Chepikova, Olga E / Pallaeva, Tatiana N / Gorokhovets, Neonila V / Siniavin, Andrei E / Gushchin, Vladimir A / Savvateeva, Lyudmila V / Vinokurov, Ivan A / Khochenkov, Dmitry A / Zamyatnin, Andrey A / Khaydukov, Evgeny V

    Biochimica et biophysica acta. General subjects

    2024  Volume 1868, Issue 5, Page(s) 130582

    Abstract: Background: Riboflavin (vitamin B2) is one of the most important water-soluble vitamins and a coenzyme involved in many biochemical processes. It has previously been shown that adjuvant therapy with flavin mononucleotide (a water-soluble form of ... ...

    Abstract Background: Riboflavin (vitamin B2) is one of the most important water-soluble vitamins and a coenzyme involved in many biochemical processes. It has previously been shown that adjuvant therapy with flavin mononucleotide (a water-soluble form of riboflavin) correlates with normalization of clinically relevant immune markers in patients with COVID-19, but the mechanism of this effect remains unclear. Here, the antiviral and anti-inflammatory effects of riboflavin were investigated to elucidate the molecular mechanisms underlying the riboflavin-induced effects.
    Methods: Riboflavin was evaluated for recombinant SARS-CoV-2 PLpro inhibition in an enzyme kinetic assay and for direct inhibition of SARS-CoV-2 replication in Vero E6 cells, as well as for anti-inflammatory activity in polysaccharide-induced inflammation models, including endothelial cells in vitro and acute lung inflammation in vivo.
    Results: For the first time, the ability of riboflavin at high concentrations (above 50 μM) to inhibit SARS-CoV-2 PLpro protease in vitro was demonstrated; however, no inhibition of viral replication in Vero E6 cells in vitro was found. At the same time, riboflavin exerted a pronounced anti-inflammatory effect in the polysaccharide-induced inflammation model, both in vitro, preventing polysaccharide-induced cell death, and in vivo, reducing inflammatory markers (IL-1β, IL-6, and TNF-α) and normalizing lung histology.
    Conclusions: It is concluded that riboflavin reveals anti-inflammatory rather than antiviral activity for SARS-CoV-2 infection.
    General significance: Riboflavin could be suggested as a promising compound for the therapy of inflammatory diseases of broad origin.
    MeSH term(s) Humans ; Endothelial Cells ; COVID-19 ; Anti-Inflammatory Agents/pharmacology ; Inflammation/drug therapy ; Antiviral Agents/pharmacology ; Riboflavin/pharmacology ; Polysaccharides ; Water
    Chemical Substances Anti-Inflammatory Agents ; Antiviral Agents ; Riboflavin (TLM2976OFR) ; Polysaccharides ; Water (059QF0KO0R)
    Language English
    Publishing date 2024-02-08
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 60-7
    ISSN 1872-8006 ; 1879-2596 ; 1879-260X ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
    ISSN (online) 1872-8006 ; 1879-2596 ; 1879-260X ; 1879-2642 ; 1879-2618 ; 1879-2650
    ISSN 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
    DOI 10.1016/j.bbagen.2024.130582
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: Cellular Aging Characteristics and Their Association with Age-Related Disorders.

    Rudzińska, Magdalena / Parodi, Alessandro / Balakireva, Anastasia V / Chepikova, Olga E / Venanzi, Franco M / Zamyatnin, Andrey A

    Antioxidants (Basel, Switzerland)

    2020  Volume 9, Issue 2

    Abstract: Different molecular signaling pathways, biological processes, and intercellular communication mechanisms control longevity and are affected during cellular senescence. Recent data have suggested that organelle communication, as well as genomic and ... ...

    Abstract Different molecular signaling pathways, biological processes, and intercellular communication mechanisms control longevity and are affected during cellular senescence. Recent data have suggested that organelle communication, as well as genomic and metabolic dysfunctions, contribute to this phenomenon. Oxidative stress plays a critical role by inducing structural modifications to biological molecules while affecting their function and catabolism and eventually contributing to the onset of age-related dysfunctions. In this scenario, proteins are not adequately degraded and accumulate in the cell cytoplasm as toxic aggregates, increasing cell senescence progression. In particular, carbonylation, defined as a chemical reaction that covalently and irreversibly modifies proteins with carbonyl groups, is considered to be a significant indicator of protein oxidative stress and aging. Here, we emphasize the role and dysregulation of the molecular pathways controlling cell metabolism and proteostasis, the complexity of the mechanisms that occur during aging, and their association with various age-related disorders. The last segment of the review details current knowledge on protein carbonylation as a biomarker of cellular senescence in the development of diagnostics and therapeutics for age-related dysfunctions.
    Language English
    Publishing date 2020-01-22
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2704216-9
    ISSN 2076-3921
    ISSN 2076-3921
    DOI 10.3390/antiox9020094
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Lysine oxidase exposes a dependency on the thioredoxin antioxidant pathway in triple-negative breast cancer cells.

    Chepikova, Olga E / Malin, Dmitry / Strekalova, Elena / Lukasheva, Elena V / Zamyatnin, Andrey A / Cryns, Vincent L

    Breast cancer research and treatment

    2020  Volume 183, Issue 3, Page(s) 549–564

    Abstract: Purpose: Transformed cells are vulnerable to depletion of certain amino acids. Lysine oxidase (LO) catalyzes the oxidative deamination of lysine, resulting in lysine depletion and hydrogen peroxide production. Although LO has broad antitumor activity in ...

    Abstract Purpose: Transformed cells are vulnerable to depletion of certain amino acids. Lysine oxidase (LO) catalyzes the oxidative deamination of lysine, resulting in lysine depletion and hydrogen peroxide production. Although LO has broad antitumor activity in preclinical models, the cytotoxic mechanisms of LO are poorly understood.
    Methods: Triple (ER/PR/HER2)-negative breast cancer (TNBC) cells were treated with control media, lysine-free media or control media supplemented with LO and examined for cell viability, caspase activation, induction of reactive oxygen species (ROS) and antioxidant signaling. To determine the role of nuclear factor erythroid 2-related factor 2 (NRF2) and thioredoxin reductase-1 (TXNRD1) in LO-induced cell death, NRF2 and TXNRD1 were individually silenced by RNAi. Additionally, the pan-TXNRD inhibitor auranofin was used in combination with LO.
    Results: LO activates caspase-independent cell death that is suppressed by necroptosis and ferroptosis inhibitors, which are inactive against lysine depletion, pointing to fundamental differences between LO and lysine depletion. LO rapidly induces ROS with a return to baseline levels within 24 h that coincides temporally with induction of TXNRD activity, the rate-limiting enzyme in the thioredoxin antioxidant pathway. ROS induction is required for LO-mediated cell death and NRF2-dependent induction of TXNRD1. Silencing NRF2 or TXNRD1 enhances the cytotoxicity of LO. The pan-TXNRD inhibitor auranofin is synergistic with LO against transformed breast epithelial cells, but not untransformed cells, underscoring the tumor-selectivity of this strategy.
    Conclusions: LO exposes a redox vulnerability of TNBC cells to TXNRD inhibition by rendering tumor cells dependent on the thioredoxin antioxidant pathway for survival.
    MeSH term(s) Antioxidants/pharmacology ; Humans ; Lysine ; Oxidative Stress ; Oxidoreductases ; Reactive Oxygen Species ; Thioredoxins/genetics ; Thioredoxins/metabolism ; Triple Negative Breast Neoplasms/drug therapy ; Triple Negative Breast Neoplasms/genetics
    Chemical Substances Antioxidants ; Reactive Oxygen Species ; Thioredoxins (52500-60-4) ; Oxidoreductases (EC 1.-) ; Lysine (K3Z4F929H6)
    Language English
    Publishing date 2020-07-21
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 604563-7
    ISSN 1573-7217 ; 0167-6806
    ISSN (online) 1573-7217
    ISSN 0167-6806
    DOI 10.1007/s10549-020-05801-4
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1655: Show issues Location:
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  6. Article ; Online: Design and synthesis of atorvastatin derivatives with enhanced water solubility, hepatoselectivity and stability.

    Maklakova, Svetlana Yu / Lopukhov, Anton V / Khudyakov, Alexandr D / Kovalev, Sergey V / Mazhuga, Maria P / Chepikova, Olga E / Zamyatnin, Andrey A / Majouga, Alexander G / Klyachko, Natalia L / Beloglazkina, Elena K

    RSC medicinal chemistry

    2022  Volume 14, Issue 1, Page(s) 56–64

    Abstract: Statins are effective 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-R) inhibitors, which are successfully used for cardiovascular disease treatment. Statins' side effects are generally attributed to poor bioavailability and hepatoselectivity, ... ...

    Abstract Statins are effective 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-R) inhibitors, which are successfully used for cardiovascular disease treatment. Statins' side effects are generally attributed to poor bioavailability and hepatoselectivity, which are closely related to their high lipophilicity. Targeted delivery of statins to the liver is considered as a way to reduce unwanted side effects. Herein we report on synthesis and evaluation of atorvastatin conjugates targeting the galactose-specific hepatic asialoglycoprotein receptor (ASGPR). The prepared conjugates showed greater water solubility compared to unmodified atorvastatin. The synthesised compounds demonstrated potent binding to the ASGPR with submicromolar
    Language English
    Publishing date 2022-10-11
    Publishing country England
    Document type Journal Article
    ISSN 2632-8682
    ISSN (online) 2632-8682
    DOI 10.1039/d2md00119e
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Amino Acid Degrading Enzymes and their Application in Cancer Therapy.

    Pokrovsky, Vadim S / Chepikova, Olga E / Davydov, Denis Zh / Zamyatnin, Andrey A / Lukashev, Alexander N / Lukasheva, Elena V

    Current medicinal chemistry

    2017  Volume 26, Issue 3, Page(s) 446–464

    Abstract: Background: Amino acids are essential components in various biochemical pathways. The deprivation of certain amino acids is an antimetabolite strategy for the treatment of amino acid-dependent cancers which exploits the compromised metabolism of ... ...

    Abstract Background: Amino acids are essential components in various biochemical pathways. The deprivation of certain amino acids is an antimetabolite strategy for the treatment of amino acid-dependent cancers which exploits the compromised metabolism of malignant cells. Several studies have focused on the development and preclinical and clinical evaluation of amino acid degrading enzymes, namely L-asparaginase, L-methionine γ-lyase, L-arginine deiminase, L-lysine α-oxidase. Further research into cancer cell metabolism may therefore define possible targets for controlling tumor growth.
    Objective: The purpose of this review was to summarize recent progress in the relationship between amino acids metabolism and cancer therapy, with a particular focus on Lasparagine, L-methionine, L-arginine and L-lysine degrading enzymes and their formulations, which have been successfully used in the treatment of several types of cancer.
    Methods: We carried out a structured search among literature regarding to amino acid degrading enzymes. The main aspects of search were in vitro and in vivo studies, clinical trials concerning application of these enzymes in oncology.
    Results: Most published research are on the subject of L-asparaginase properties and it's use for cancer treatment. L-arginine deiminase has shown promising results in a phase II trial in advanced melanoma and hepatocellular carcinoma. Other enzymes, in particular Lmethionine γ-lyase and L-lysine α-oxidase, were effective in vitro and in vivo.
    Conclusion: The findings of this review revealed that therapy based on amino acid depletion may have the potential application for cancer treatment but further clinical investigations are required to provide the efficacy and safety of these agents.
    MeSH term(s) Amino Acids/metabolism ; Antineoplastic Agents/therapeutic use ; Enzymes/metabolism ; Humans ; Hydrolysis ; Neoplasms/drug therapy
    Chemical Substances Amino Acids ; Antineoplastic Agents ; Enzymes
    Language English
    Publishing date 2017-10-05
    Publishing country United Arab Emirates
    Document type Journal Article ; Review
    ZDB-ID 1319315-6
    ISSN 1875-533X ; 0929-8673
    ISSN (online) 1875-533X
    ISSN 0929-8673
    DOI 10.2174/0929867324666171006132729
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 4432: Show issues Location:
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  8. Article ; Online: Synthesis, Characterization, and Preclinical Evaluation of a Small-Molecule Prostate-Specific Membrane Antigen-Targeted Monomethyl Auristatin E Conjugate.

    Machulkin, Aleksei E / Uspenskaya, Anastasia A / Zyk, Nikolay U / Nimenko, Ekaterina A / Ber, Anton P / Petrov, Stanislav A / Polshakov, Vladimir I / Shafikov, Radik R / Skvortsov, Dmitry A / Plotnikova, Ekaterina A / Pankratov, Andrei A / Smirnova, Galina B / Borisova, Yulia A / Pokrovsky, Vadim S / Kolmogorov, Vasilii S / Vaneev, Alexander N / Khudyakov, Alexander D / Chepikova, Olga E / Kovalev, Sergey /
    Zamyatnin, Andrey A / Erofeev, Alexander / Gorelkin, Petr / Beloglazkina, Elena K / Zyk, Nikolay V / Khazanova, Elena S / Majouga, Alexander G

    Journal of medicinal chemistry

    2021  Volume 64, Issue 23, Page(s) 17123–17145

    Abstract: Prostate cancer is the second most common type of cancer among men. Its main method of treatment is chemotherapy, which has a wide range of side effects. One of the solutions to this challenge is targeted delivery to prostate cancer cells. Here we ... ...

    Abstract Prostate cancer is the second most common type of cancer among men. Its main method of treatment is chemotherapy, which has a wide range of side effects. One of the solutions to this challenge is targeted delivery to prostate cancer cells. Here we synthesized a novel small-molecule PSMA-targeted conjugate based on the monomethyl auristatin E. Its structure and conformational properties were investigated by NMR spectroscopy. Cytotoxicity, intracellular reactive oxygen species induction, and stability under liver microsomes and P450-cytochrome species were investigated for this conjugate. The conjugate demonstrated 77-85% tumor growth inhibition levels on 22Rv1 (PSMA (+)) xenografts, compared with a 37% inhibition level on PC-3 (PSMA (-)) xenografts, in a single dose of 0.3 mg/kg and a sufficiently high therapeutic index of 21. Acute, chronic, and subchronic toxicities and pharmacokinetics have shown that the synthesized conjugate is a promising potential agent for the chemotherapy of prostate cancer.
    MeSH term(s) Antigens, Surface/chemistry ; Cell Line, Tumor ; Coordination Complexes/chemical synthesis ; Coordination Complexes/chemistry ; Coordination Complexes/pharmacology ; Glutamate Carboxypeptidase II/chemistry ; Humans ; Male ; Microsomes, Liver/enzymology ; Microsomes, Liver/metabolism ; Oligopeptides/chemistry ; Prostatic Neoplasms/pathology ; Reactive Oxygen Species/metabolism ; Xenograft Model Antitumor Assays
    Chemical Substances Antigens, Surface ; Coordination Complexes ; Oligopeptides ; Reactive Oxygen Species ; FOLH1 protein, human (EC 3.4.17.21) ; Glutamate Carboxypeptidase II (EC 3.4.17.21) ; monomethyl auristatin E (V7I58RC5EJ)
    Language English
    Publishing date 2021-11-19
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 218133-2
    ISSN 1520-4804 ; 0022-2623
    ISSN (online) 1520-4804
    ISSN 0022-2623
    DOI 10.1021/acs.jmedchem.1c01157
    Database MEDical Literature Analysis and Retrieval System OnLINE

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