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Vol 42, No 5 (2025)
ОБЗОРЫ
Posttranslational modifications of proteins with disordered structure in the regulation of regeneration and neurodegeneration of brain cells
Abstract
This review focuses on the role of intrinsically disordered proteins and their post-translational modifications in the regulation of neuronal regeneration and neurodegeneration processes. Intrinsically disordered proteins, with their high conformational flexibility and lack of stable tertiary structure, can participate in a variety of cellular processes through dynamic and specific interactions with various partners. They are involved in the regulation of transcription, apoptosis, cell cycle, and stress responses. Key examples of such proteins are the transcription factors p53, c-Myc, FOXO3a, and E2F1, which, depending on the set of post-translational modifications, can switch between the functions of protecting neurons and activating their death. Particular attention is paid to the mechanisms by which post-translational modifications – such as acetylation, phosphorylation, and ubiquitination – alter the localization, stability, and activity of intrinsically disordered proteins, affecting the outcome of cell fate. The contribution of misfolded proteins with structurally disordered domains, such as Tau and α-synuclein, to the pathogenesis of neurodegenerative diseases is also discussed. The article highlights the challenges associated with therapeutic targeting of such proteins due to their structural plasticity and diversity of post-translational modifications. Promising approaches to modulating the overall activity and functional state of target proteins are discussed, including modulation of the activity of post-translational modification enzymes and proteostasis mechanisms. The review illustrates the critical need for a comprehensive study of post-translational modifications as mechanisms of disordered protein regulation for the development of new strategies for the treatment of acute nerve cell damage and neurodegenerative diseases.
347-355
The role of nitric oxide and hydrogen sulfide in the regulation of pro- and antiapoptotic gene expression in central and peripheral nervous system injuries
Abstract
Injuries to the central and peripheral nervous systems are accompanied by complex cellular and molecular processes, including neuroinflammation, oxidative stress, and programmed cell death. Nitric oxide (NO) and hydrogen sulfide (H₂S) play pivotal roles in these processes, exhibiting dual effects. Apoptosis is a key mechanism involved in the death of neurons and glial cells following neurotrauma. NO and H₂S can regulate the expression of anti- and pro-apoptotic genes either through direct modification of DNA and RNA or via more complex epigenetic mechanisms involving activation or inhibition of transcription factors. This review provides a detailed overview of NO- and H₂S-dependent signaling pathways regulating the expression of anti- and pro-apoptotic genes in various types of neurotrauma and discusses the dual effects of these gasotransmitters in pharmacological modulation.
356-381
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Resistance to anthracyclines of CD33+ acute myeloid leukemia cells grown in three-dimensional culture
Abstract
Identification of the mechanisms of drug resistance of acute myeloid leukemia (AML) cells remains an important task for biomedicine and oncohematology. In our earlier work, using permanent cell lines, we showed that AML cells in 3D multicellular cultures had higher drug resistance. In this study, using flow cytometry and spectrofluometry, we found an increase in the resistance of primary CD33+ AML cells, grown in three-dimensional multicellular aggregates, to the cytotoxic effects of anthracyclines, which was accompanied by suppression of the pro-apoptotic signaling pathway, partial accumulation of cells in the G0/G1 phase of the cell cycle, and an increase in the content of the anti-apoptotic protein Bcl-2.
382-394
Activation of FLT3-associated signaling pathways in quizartinib-resistant macrophage-like cells of acute myeloid leukemia
Abstract
Investigating the mechanisms of resistance of acute myeloid leukemia (AML) cells to anticancer therapy, including targeted drugs such as the FLT3 inhibitor quizartinib, remains highly relevant in modern molecular oncology. In this work, we explored the mechanisms underlying quizartinib resistance in macrophage-like THP-1ad cells. We demonstrated that resistance is associated with downregulation of the expression of the FLT3 receptor due to suppressed FLT3 gene transcriptional activity, while key downstream signaling pathways (STAT5, PI3K/AKT, ERK) remain functionally active. The findings indicate that FLT3 inhibitor resistance in AML cells can develop independently of classical mutational mechanisms, instead relying on alternative activation of signaling cascades. These results expand current understanding of resistance mechanisms in AML and support the rationale for targeting signaling pathways downstream of FLT3 as a promising strategy to overcome resistance in tumor cells refractory to FLT3 inhibitors.
395-405
Astaxanthin prevents hydrogen peroxide-induced decrease in the viability of AC16 cardiomyocytes
Abstract
The effect of astaxanthin (5 and 10 μM), a xanthophyll carotenoid, on the viability of human cardiomyocytes AC16 under the cytotoxic action of 100 μM hydrogen peroxide was investigated. It was shown that the combined effect of these substances leads to an increase in the number of living cells and the mitotic activity index. It was found that under hydrogen peroxide-induced cytotoxicity astaxanthin promotes a decrease in the content of protein kinase R-like endoplasmic reticulum kinase (PERK), stimulator of endoplasmic reticulum stress and pro-apoptotic transcription factor C/BEP homologous protein (CHOP). Besides, in the conditions of hydrogen peroxide-induced cytotoxicity astaxanthin restored the expression of anti- and pro-apoptotic proteins of the Bcl-2 family. A protective effect of astaxanthin was revealed despite the toxic effect of hydrogen peroxide.
406-413
The Effect of Na+, K+-ATPase and Dihydropyridine Receptor Activity on Ca2+ Content and Contractile Properties of M. Soleus in Rats under Three-Day Functional Unloading
Abstract
Hypokinesia is characterized by muscle atrophy and decreased strength, which can occur at the earliest stages of unloading. To study the relationship between calcium-dependent processes in the fiber and changes in the contractile properties of m. soleus, a 3-day period of unloading was used in male Wistar rats, which were administered nifedipine, a dihydropyridine receptor (DHPR) blocker, or ouabain, a cardiac glycoside that binds to the α-subunit of Na+,K+-ATPase. In two series of experiments, three groups of rats were used (16 individuals in each group): control (C), suspension (3HS), suspension + nifedipine (3HS + N), or (for the second series) suspension + ouabain (3HS + Ou). A decrease in m. soleus weight was found in all suspension groups (HS, 3HS + N, 3HS + Ou) (p < 0.05). The three-day inhibition of DHPR during functional unloading prevented the decrease in force and the increase in the Ca2+ level in the myoplasm of m. soleus. Administration of nifedipine at early stages of unloading prevents the decrease in the maximum force of single and tetanic contraction of the soleus (in contrast to the group of suspension without the drug, where the decrease occurs by 24 and 29% relative to the control, respectively, p < 0.05). Administration of ouabain led to a decrease (by 22 and 18%, respectively, p < 0.05) in the specific maximum force of single and tetanic contraction of the soleus in animals subjected to suspension (without and with the drug), relative to the intact control. However, the drug significantly affected the passive mechanical properties of m. soleus: the maximum peak force and the maximum force at the end of the stretch test in muscles with ouabain administration did not differ from the intact control group, whereas in the suspended group (3HS) it decreased (by 33 and 34%, respectively, p < 0.05). In summary, the administration of ouabain and nifedipine leads to the prevention of myoplasmic calcium accumulation against the background of hindlimb unloading, which is accompanied by the preservation of specific muscle stiffness and strength, a slowdown in the decrease in the cross-sectional area of muscle fibers, and the prevention of a change in the percentage of fibers towards fast-type fibers.
414-420
The effect of pregnancy-specific β1-glycoprotein on PD-L1 and CD73 expression by myeloid-derived suppressor cells and their cytokine profile
Abstract
Myeloid-derived suppressor cells (MDSC) play a crucial role in establishing immune tolerance, including during pregnancy, due to their ability to suppress immune responses through various mechanisms. One of the key regulators of the immune system during gestation is pregnancy-specific β1-glycoprotein (PSG), which possesses pronounced immunosuppressive properties. The aim of this study was to investigate the effects of native and recombinant PSG on the functional activity of MDSC derived from the peripheral blood of healthy donors. For this purpose, CD11b+ cells were isolated by immunomagnetic separation and differentiated into MDSC using GM-CSF, IL-1β, and LPS. Various concentrations of native (1, 10, and 100 μg/mL) and recombinant (1 and 10 μg/mL) PSG were applied in the experiments. Cell phenotyping was performed by flow cytometry to assess the expression of PD-L1 and CD73, while inducible nitric oxide synthase (iNOS) levels were measured, and a cytokine profile comprising 17 markers was analyzed using multiplex assays. It was found that recombinant PSG at 1 μg/mL significantly increased PD-L1 expression on MDSC, and at 10 μg/mL elevated CD73 levels, whereas native PSG had no significant effect on these markers. Neither form of PSG influenced iNOS production; however, recombinant PSG (10 μg/mL) reduced the level of the chemokine MIP-1β without altering the production of other cytokines studied. These results suggest that recombinant PSG may enhance the immunosuppressive potential of MDSCs by increasing PD-L1 and CD73 expression and suppressing MIP-1β production, which may be important for the development of new biopharmaceutical strategies for modulating immune responses in autoimmune diseases and transplantation. The selective effects of recombinant PSG on MDSC functions are likely related to its structural features, including post-translational modifications.
421-428
Signaling effects of alpha-ketoglutarate precursor administration in rat soleus muscle during 7-day mechanical unloading
Abstract
In conditions of insufficient muscle activity (during functional unloading), a number of pathological processes are observed that lead to a deterioration in muscle function. Some of these processes are based on changes in gene expression, leading to the transformation of muscle fibers from the "slow" type, which is fatigue-resistant and has predominantly oxidative type of metabolism, to the "fast" type, which has glycolytic metabolism and is quickly fatigued. The mechanisms of changes in gene expression in muscle fibers under conditions of functional unloading have not been sufficiently studied. In particular, the role of methylation of CpG sequences in promoter regions of genes in the regulation of gene expression that mediate the “slow” or “fast” phenotype of muscle fibers has been virtually unexplored. We assume that a decrease in the expression of several genes regulating mitochondrial biogenesis and the phenotype of muscle fibers under conditions of muscle unloading can be determined by a deficiency of alpha-ketoglutarate (a coenzyme of TET translocases that demethylate CpG islands). To test this assumption, male Wistar rats were divided into three groups of 8 animals in each: (1) group C, vivarium control with daily intraperitoneal administration of placebo (saline); (2) group 7HS, 7-day hind limb suspension with daily intraperitoneal administration of placebo; (3) group 7HSD, 7-day hind limb suspension with daily intraperitoneal administration of 200 mg/kg dimethyl-2-ketoglutarate (alpha-ketoglutarate precursor). The analysis of the experimental data obtained has shown that administration of dimethyl-2-ketoglutarate to the hind limb suspended animals partially prevents the decline expression of mRNA regulators of mitochondrial biogenesis and mitochondrial DNA content. This effect may be mediated by the drug's effect on еру CpG methylation. However, in the 7HSD group there was also an upregulation of AMP-activated protein kinase phosphorylation levels compared to the 7HS and C groups, which may explain the effect of dimethyl-2-ketoglutarate on the expression of regulators of mitochondrial mRNA biogenesis and mitochondrial DNA content during rat hindlimb suspension.
429-438