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Vol 88, No 12 (2023)

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Articles

Editorial

Zinovkin R.A.

Abstract

Академик Владимир Петрович Скулачёв - один из наиболее известных и уважаемых российских учёных, он внёс огромный вклад в современную биоэнергетику и биохимию. Одним из его последних научных достижений стала концепция феноптоза, предложенная им в 1999 году. В данном выпуске опубликованы экспериментальные и теоретические работы, которые с разных сторон рассматривают проблемы феноптоза, старения, а также иных феноменов, связанных с этими процессами.
Biohimiâ. 2023;88(12):2357-2357
pages 2357-2357 views

Changes in the glutamate/gaba system in the hippocampus of rats with age and during the Alzheimer’s disease signs development

Burnyasheva A.O., Stefanova N.A., Kolosova N.G., Telegina D.V.

Abstract

GABA and glutamate are the most abundant neurotransmitters in the CNS and play a pivotal part in synaptic stability/plasticity. Glutamate and GABA homeostasis is important for healthy aging and reducing the risk of various neurological diseases, while long-term imbalance can contribute to the development of neurodegenerative disorders, including Alzheimer’s disease (AD). Its normalization discussed as a promising strategy for the prevention and/or treatment of AD, however, data on changes in the GABAergic and glutamatergic systems in with age, as well as in the dynamics of AD development, are limited. It is not clear whether the imbalance of the excitatory/inhibitory systems is a cause or a consequence of the development of the disease. Here we analyzed age-related alterations of the expression of glutamate, GABA, and enzymes that synthesize them (glutaminase, glutamine synthetase, GABA-T, and GAD67), transporters (GLAST, GLT-1, and GAT1), and relevant receptors (GluA1, NMDAR1, NMDA2B, and GABAAr1) in the whole hippocampus of Wistar rats and of senescence-accelerated OXYS rats, a model of the most common (> 95%) sporadic AD. Our results suggest that there is a decline of glutamate and GABA signaling with aging in the hippocampus of the both rat strains. However, we have not identified significant changes or compensatory enhancements in this system in the hippocampus of OXYS rats during development of neurodegenerative processes that are characteristic of AD.
Biohimiâ. 2023;88(12):2358-2374
pages 2358-2374 views

A new mouse strain with mutation in the NFE2L2 (NRF2 gene

Egorov E.S., Kondratenko N.D., Averina O.A., Permyakov O.A., Emelyanova M.A., Prikhodko A.S., Zinovkina L.A., Sergiev P.V., Zinovkin R.A.

Abstract

The transcription factor NRF2 is involved in inflammatory reactions, maintenance of redox balance, metabolism of xenobiotics, and is of particular interest for aging studies. In the present work, CRISPR/Cas9 genome editing technology was used to generate NRF2ΔNeh2 mice containing a substitution of eight amino acid residues at the N-terminus of the NRF2 protein, upstream of the functional Neh2 domain, which ensures binding of NRF2 to its inhibitor KEAP1. Heterozygote NRF2wt/ΔNeh2 mice gave birth to homozygous mice with lower than expected frequency, accompanied by their increased embryonic lethality and visual signs of anemia. Mouse embryonic fibroblasts (MEFs) from NRF2ΔNeh2/ΔNeh2 homozygotes showed impaired resistance to oxidative stress compared to wild-type MEFs. The tissues of homozygous NRF2ΔNeh2/ΔNeh2 animals had a decreased expression of NRF2 target genes: NAD(P)H: Quinone oxidoreductase-1 (Nqo1); aldehyde oxidase-1 (Aox1); glutathione-S-transferase A4 (Gsta4); while the relative mRNA level of monocyte chemoattractant protein 1 (Ccl2), vascular cell adhesion molecule 1 (Vcam1) and chemokine Cxcl8 was increased. Thus, the resulting mutation in the Nfe2l2 gene partially impaired the function of this transcription factor, expanding the insights into the functional role of the unstructured N-terminus of NRF2. The obtained NRF2ΔNeh2 mouse line can be used as a model object for studying various pathologies associated with oxidative stress and inflammation.
Biohimiâ. 2023;88(12):2375-2386
pages 2375-2386 views

Role of mitochondrial DNA in yeast replicative aging

Azbarova A.V., Knorre D.A.

Abstract

Despite the variety of manifestations of aging, there are some common features and underlying mechanisms. In particular, mitochondria appears to be one of the most vulnerable systems in both metazoa and fungi. In this review, we discuss how mitochondrial dysfunction is related to replicative aging in the simplest eukaryotic model, the baker’s yeast Saccharomyces cerevisiae. We discuss a chain of events that starts from asymmetric inheritance of mitochondria by mother and daughter cells. With age, yeast mother cells start to experience a decrease in mitochondrial transmembrane potential and, consequently, a decrease in mitochondrial protein import efficiency. This induces mitochondrial protein precursors accumulation in the cytoplasm, the loss of mitochondrial DNA, and at the later stages - cell death. Interestingly, yeast strains without mitochondrial DNA can have both increased and increased lifespan compared to their counterparts with mtDNA. The direction of the effect depends on their ability to activate compensatory mechanisms preventing or mitigating negative consequences of mitochondrial dysfunction. The central role of mitochondria in yeast aging and death indicates that it is one of the most complex and, therefore, deregulation-prone systems in eukaryotic cells.
Biohimiâ. 2023;88(12):2387-2398
pages 2387-2398 views

Serotonin receptors - a potential target for the treatment of Alzheimer’s disease

Eremin D.V., Kondaurova E.M., Rodny A.Y., Molobekova K.A., Kudlay D.A., Naumenko V.S.

Abstract

Alzheimer’s disease (AD) is the most common cause of dementia worldwide, having an increasing impact on aging societies. It is known that the serotonin (5-HT) system of the brain, in addition to its critical role in the control of various physiological functions and behaviors, is involved in the regulation of migration, proliferation, differentiation, maturation and programmed death of neurons. At the same time, increasing evidence indicates the involvement of 5-HT neurotransmission in the mechanisms underlying the formation of insoluble aggregates of β-amyloid and tau protein, which are the main histopathological signs of AD. In this review, we focused our attention on the available data on the participation of various 5-HT receptors and the intracellular signaling cascades induced by them in pathological processes leading to the development of AD. First of all, this concerns information about the involvement of 5-HT receptors in the mechanisms of protein aggregation in AD, which indicate that specific changes in the function of certain 5-HT receptors or associated intracellular signal transduction mediators prevent the accumulation of β-amyloid plaques and neurofibrillary tau protein tangles. Based on the accumulated experimental data, it can be assumed that the use of 5-HT receptors as new drug targets may not only be useful for improving cognitive performance in AD, but will also play an important role in treating the causes of AD-related dementia.
Biohimiâ. 2023;88(12):2399-2421
pages 2399-2421 views

Role of ubiquitin-proteasome system in stem cell biology

Burov A.V., Rodin A.A., Karpov V.L., Morozov A.V.

Abstract

Selective degradation of cellular proteins by the ubiquitin -proteasome system is one of the key regulatory mechanisms in eukaryotic cells. Accumulating data indicate that the ubiquitin - proteasome system is involved in the regulation of fundamental processes in mammalian stem cells, including proliferation, differentiation, cell migration, aging and programmed cell death. Regulation can be carried out either by proteolytic degradation of key transcription factors and signaling pathway proteins, or by posttranslational modifications of target proteins with ubiquitin or other ubiquitin-like modifiers. Studies of the molecular mechanisms of proteostasis maintenance in stem cells are of great importance for the development of new therapeutic approaches aimed at the treatment of autoimmune and neurodegenerative diseases, cancer and other socially significant pathologies. This review covers current data on the function of the ubiquitin-proteasome system in stem cells.
Biohimiâ. 2023;88(12):2422-2434
pages 2422-2434 views

The role of Aurora B kinase in normal and cancer cells

Titova E.V., Shagieva G.S., Dugina V.B., Kopnin P.B.

Abstract

Aurora kinases are essential players in the process of mammalian cell division. Intracellular events in which Aurora kinases are involved include the regulation of spindle dynamics, microtubule-kinetochore interactions, chromosome condensation and orientation during mitosis. At least three members of the Aurora family - A, B and C - have been identified in mammals. Aurora B has been shown to be essential for maintaining genomic stability and normal cell division. Mutations and dysregulation of this kinase have been implicated in tumour initiation and progression. In this review, we discuss the functions of Aurora B, the relationship between increased Aurora B activity and carcinogenesis, and the prospects for the use of Aurora B kinase inhibitors in antitumour therapy.
Biohimiâ. 2023;88(12):2435-2445
pages 2435-2445 views

Topology of ubiquitin chains in the e3 ubiquitin ligase rnf168 chromatosome entourage

Kudriaeva A.A., Yakubova L.A., Saratov G.A., Vladimirov V.I., Lipkin V.M., Belogurov A.A.

Abstract

Genome stability is critical for normal functioning of cells and depends on accuracy of DNA replication, chromosome segregation, and DNA repair. Cellular defense mechanisms against DNA damage are important for preventing the development of cancer and aging. The E3 ubiquitin ligase RNF168 of the RING superfamily is an essential component of the complex responsible for the ubiquitination of H2A/H2A.X histones near DNA double-strand breaks, which is a key step in attracting repair factors to the injury site. In this study, we unequivocally showed that RNF168 does not have ability to directly distinguish the architecture of polyubiquitin chains, except for tropism of its two ubiquitin-binding domains UDM1/2 to K63 ubiquitin chains. Analysis of the intracellular chromatosomal environment of full-length RNF168 and its domains by ligand-induced bioluminescence resonance energy transfer (BRET) revealed that the C-terminal part of UDM1 is associated with K63 ubiquitin chains; RING and the N-terminal part of UDM2 are sterically close to K63- and K48- ubiquitin chains, while the C-terminal part of UDM1 is colocalized with all possible ubiquitin variants. Our observations together with the available structural data suggest that the C-terminal part of UDM1 binds K63 polyubiquitin chains on linker histone H1; RING and the N-terminal part of UDM2 are located in the central part of the nucleosome and sterically close to H1 and K48-ubiquitinated alternative substrates of RNF168, such as JMJD2A/B demethylases, while the C-terminal part of UDM1 is in the region of an activated ubiquitin residue associated with E2 ubiquitin ligase, engaged by RNF168.
Biohimiâ. 2023;88(12):2446-2456
pages 2446-2456 views

Impact of lipid matrix composition on the activity of membranotropic enzymes galactonolactone oxidase from Trypanosoma cruzi and L-galactono-1,4-lactone dehydrogenase from Arabidopsis thaliana in the system of reverse micelles

Chudin A.A., Kudryashova E.V.

Abstract

The study of many membrane enzymes in an aqueous medium is difficult due to the loss of their catalytic activity, which makes it necessary to use membrane-like systems, such as reverse micelles of surfactants in nonpolar organic solvents. However, it should be taken into account that micelles are a simplified model of natural membranes, since membranes contain many different components, a significant part of which are phospholipids. In this work, we studied the impact of the main phospholipids, phosphatidylcholine (PC) and phosphatidylethanolamine (PE), on the activity of membrane enzymes using galactonolactone oxidase from Trypanosoma cruzi (TcGAL) and L-galactono-1,4-lactone dehydrogenase from Arabidopsis thaliana (AtGALDH) as an examples. Effect of the structure (and charge) of the micelle-forming surfactant itself on the activity of both enzymes has been studied using an anionic surfactant (AOT), a neutral surfactant (Bridge-96), and a mixture of cationic and anionic surfactants (CTAB and AOT) as an examples. The pronounced effect of addition of PC and PE lipids on the activity of AtGALDH and TcGAL has been detected, which manifests as increase in catalytic activity and significant change in the activity profile. This can be explained by formation of the tetrameric form of enzymes and/or protein-lipid complexes. By varying composition and structure of the micelle-forming surfactants (AOT, CTAB, and Brijdge-96 and their combinations) it has been possible to change catalytic properties of the enzyme due to effect of the surfactant on the micelle size, lipid mobility, charge, and rigidity of the matrix itself.
Biohimiâ. 2023;88(12):2457-2468
pages 2457-2468 views

Low-frequency vibrations of bacteriochlorophyll oligomers in chlorosomes of photosynthetic green bacteria

Yakovlev A.G., Taisova A.S., Fetisova Z.G.

Abstract

In green photosynthetic bacteria, light absorption occurs in bacteriochlorophyll (BChl) c/d/e oligomers, which are located in chlorosomes - unique structures created by nature to collect the energy of very weak light fluxes. Using coherent femtosecond spectroscopy at cryogenic temperature, we detected and studied low-frequency vibrational motions of BChl c oligomers in the chlorosomes of the green bacteria Chloroflexus (Cfx.) aurantiacus. The objects of the study were chlorosomes isolated from bacterial cultures grown under different light intensity. It was found that the Fourier spectrum of low-frequency coherent oscillations in the Qy band of BChl c oligomers depends on the light intensity used for the growth of bacteria. It turned out that the number of low-frequency vibrational modes of chlorosomes increases as the illumination under which they were cultivated decreases. Also, the frequency range within which these modes are observed expands, and the frequencies of most modes change. Theoretical modeling of the obtained data and analysis of the literature led to the conclusion that the structural basis of Cfx. aurantiacus chlorosomes are short linear chains of BChl c combined into more complex structures. An increase in the length of these chains in chlorosomes grown under weaker light leads to the observed changes in the spectrum of vibrations of BChl c oligomers. This increase is an effective mechanism for the adaptation of bacteria to changing external conditions.
Biohimiâ. 2023;88(12):2469-2480
pages 2469-2480 views

Effect of dexamethasone on human neutrophil adhesion and concomitant secretion

Galkina S.I., Golenkina E.A., Fedorova N.V., Ksenofontov A.L., Serebryakova M.V., Stadnichuk V.I., Baratova L.A., Sud'ina G.F.

Abstract

Neutrophils play a dual role in protecting the body. They are able to penetrate infected tissues and destroy pathogens there, releasing aggressive bactericidal substances. Getting into the surrounding tissues, aggressive secretion products of neutrophils initiate the development of inflammatory processes. Invasion of neutrophils into tissues is observed during the development of pneumonia in patients with lung diseases of various etiologies, including acute respiratory distress syndrome caused by coronavirus disease. The synthetic corticosteroid hormone dexamethasone has a therapeutic effect in the treatment of lung diseases, including reducing mortality in patients with severe Covid-19. The acute (short-term) effect of dexamethasone on neutrophil adhesion to fibrinogen and concomitant secretion was studied. Dexamethasone did not affect either the attachment of neutrophils to the substrate or their morphology. The production of reactive oxygen species (ROS) and nitric oxide (NO) by neutrophils during adhesion also did not change in the presence of dexamethasone. Dexamethasone stimulated the release of metalloproteinases in addition to proteins secreted by neutrophil adhesion under control conditions, and selectively stimulated the release of the free amino acid hydroxylysine, a product of lysyl hydroxylase. Metalloproteinases play a key role and closely interact with lysyl hydroxylase in the processes of rearrangement of the extracellular matrix. The therapeutic effect of dexamethasone may be associated with its ability, by changing the composition of neutrophil secretions, to reorganize the extracellular matrix in tissues, which can lead to improved gas exchange in patients with severe lung diseases.
Biohimiâ. 2023;88(12):2481-2495
pages 2481-2495 views

Opposing effects of CRABP1 and CRABP2 homologs on the proliferation of breast cancer cells and their sensitivity to retinoic acid

Enikeev A.D., Abramov P.M., Elkin D.S., Komelkov A.V., Belyaeva A.A., Sylantieva D.M., Tchevkina E.M.

Abstract

Resistance of tumor cells to retinoic acid (RA), a promising therapeutic agent, is the major factor limiting the use of RA in clinical practice. The mechanisms of RA resistance are still poorly understood. Cellular Retinoic Acid Binding Proteins, CRABP1 and CRABP2, are essential mediators of RA signaling, but the role of the two CRABP homologs in regulating cellular sensitivity to RA has not been well studied. In addition, the effects of CRABP1 and CRABP2 on cell proliferation have not been compared. Here, using a broad panel of breast cancer cell lines with different levels of RA sensitivity/resistance, we show for the first time that in RA-sensitive cells, CRABP1 expression is restricted by methylation and protein levels are highly variable. In moderately RA-resistant lines, a high level of CRABP1 is observed both at the mRNA and protein levels, unchanged by inhibition of DNA methylation. The maximally resistant cell lines are characterized by complete repression of CRABP1 implemented at transcriptional and posttranscriptional levels, and exogenous expression of each of CRABP homologs has no effect on the studied characteristics. CRABP1 and CRABP2 proteins have opposing effects on proliferation and sensitivity to RA. Specifically, in initially RA-sensitive cells CRABP1 stimulates and CRABP2 reduces proliferation and resistance to RA, while in more resistant cells the role of each homolog in both of these indications is reversed. Overall, we have shown for the first time that CRABP proteins exert different effects on the growth and sensitivity to RA of breast cancer cells (stimulation, suppression, or no effect) depending on the baseline level of RA-sensitivity, with the effects of CRABP1 and CRABP2 homologs on the studied properties always being opposite.
Biohimiâ. 2023;88(12):2496-2516
pages 2496-2516 views

Dicarbonyl-modified low-density lipoproteins are key inducers of LOX-1 and NOX1 gene expression in cultured human umbilical vein endotheliocytes

Lankin V.Z., Sharapov M.G., Tihaze A.K., Goncharov R.G., Antonova O.A., Konovalova G.G., Novoselov V.I.

Abstract

The expression of LOX-1 and NOX1 genes in human umbilical vein endotheliocytes (HUVECs) when cultured in the presence of low-density lipoproteins (LDL) modified with various natural dicarbonyls was investigated for the first time. It was found that of the investigated dicarbonyl-modified LDLs (malondialdehyde (MDA)-modified LDLs, glyoxal-modified LDLs, and methylglyoxal-modified LDLs), namely MDA-modified LDLs caused the greatest induction of LOX-1 and NOX1 genes, as well as genes of antioxidant enzymes and genes of signaling molecules in HUVECs. MDA-modified LDLs also induce the highest peroxiredoxins expression of the studied antioxidant enzyme genes. The key role of dicarbonyl-modified LDLs in the molecular mechanisms of vascular wall damage and endothelial dysfunction is discussed.
Biohimiâ. 2023;88(12):2517-2530
pages 2517-2530 views

Nocistatin and products of its proteolysis as dual modulators of type 3 acid-sensing ion channels (ASIC3) with an algesic and analgesic effect

Osmakov D.I., Tarasova N.V., Nedorubov A.A., Palikov V.A., Palikova Y.A., Dyachenko I.A., Andreev Y.A., Kozlov S.A.

Abstract

The neuropeptide nocistatin (NS) is expressed by cells of the nervous system and neutrophils as part of a precursor protein and can undergo limited proteolysis through stepwise degradation. Previously, it was shown that rat NS (rNS) is able to activate acid-sensing ion channels (ASIC), but this effect correlated with the acidic nature of NS. In this work, we investigated the change in the properties of rNS during its degradation by a comparison of rNS and its two synthesized fragments. We estimated their activity on rat ASIC3 channels expressed in X. laevis oocytes, and the effects in pain tests on mice. We have shown that rNS combines the properties of both positive and negative modulators of ASIC3, which is expressed in the ability to lower the channel’s steady-state desensitization in the pH range 6.8-7.0 and the reduction of the channel’s response to stimuli in the 6.0-6.9 pH range. A shortened analogue (rNSΔ21) (21 amino acid residues (aa) from the N-terminus) retained the effect of the ASIC3 positive modulator only, while the C-terminal pentapeptide (rNSΔ30) retained the ability of the ASIC3 negative modulator only. This tendency was confirmed in animal tests, where rNS and rNSΔ21 induced pain related behavior, but rNSΔ30 showed an analgesic effect. Thus, we have shown the change of the rNS action mode during stepwise degradation, from an algesic molecule through a pain-enhancer to a pain-relief wherefore the final pentapeptide can even be considered as a promising starting point for further drug development.
Biohimiâ. 2023;88(12):2531-2540
pages 2531-2540 views

Changes in the structure of potato virus A virions during limited proteolysis in situ according to tritium labeling data and computer simulation

Ksenofontov A.L., Baratova L.A., Semenyuk P.I., Fedorova N.V., Badun G.A.

Abstract

The coat proteins (CP) of potato virus A virions (PVA) contain partially disordered N-terminal domains, which are necessary for performing vital functions of the virus. A comparative analysis of the structures of coat proteins (CPs) in intact PVA virions and in virus particles lacking the N-terminal 32 amino acids (PVAΔ32) was carried out in this work based on the tritium planigraphy data. Using the atomic resolution structure of the potato virus Y potyvirus (PVY) protein, which is a homolog of CP PVA, the available CP surfaces in the PVY virion were calculated and the areas of intersubunit/ interhelix contacts were determined. For this purpose, the approach of Lee and Richards (Lee, B., and Richards, F. M. (1971) J. Mol. Biol., 55, 379-400) was used. Comparison of the incorporation profiles of the tritium label in intact and trypsin-degraded PVA∆32 revealed the position of the ΔN-peptide shielding the surface domain (a.a. 66-73, 141-146) and the interhelix zone (a.a. 161-175) of the PVA CP. The presence of channels/cavities was found in the virion, which turned out to be partially permeable to tritium atoms. Upon removal of the ∆N-peptide, a decrease in the label within the virion (a.a. 184-200) was also observed, indicating a possible structural transition leading to virion compactization. Based on the data obtained, we can conclude that part of the surface ∆N-peptide is located between the coils of the virion helix, which increases the helix pitch and provides greater flexibility of the virion, which is important for the intercellular transport of the viruses in the plants.

Biohimiâ. 2023;88(12):2541-2552
pages 2541-2552 views

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