Biohimiâ
ISSN (print): 0320-9725
Media registration certificate: ПИ № ФС77–71478 от 23.11.2017
Founder: Russian Academy of Sciences
Editor-in-Chief: Dontsova Olga Anatolyevna, academician of the Russian Academy of Sciences, Professor, Doctor of Chemical Sciences
Number of issues per year: 12
Indexation:
- RISC,
- Higher Attestation Commission list,
- RISC core,
- RSCI,
- White List (2nd level)
Ағымдағы шығарылым
Ашық рұқсат
Рұқсат берілді
Тек жазылушылар үшін
Том 90, № 1 (2025)
Articles
4-Methylumbelliferone, an hyaluronan synthase inhibitor, prevents the development of oncological, inflammatory, degenerative and autoimmune disorders
Аннотация
In present review we consider numerous experiments on tissue cultures, animal models of diseases and the first clinical studies providing the prospects of creating new drugs based on 4-MU. We believe that along with many receptors and transcription factors, the main pharmacological target of 4-MU is the hyaluronan synthase, which produces the main component of the extracellular matrix, glycosaminoglycan, hyaluronic acid (HA). The pharmacological effects of 4-MU in oncological, autoimmune, degenerative and hypercompensated regenerative processes (fibrosis, scarring) are associated with inhibition of HA synthesis. Clinical drugs based on 4-MU will be the first in the class for the treatment of a wide range of diseases.
3-21
Rethinking the evolutionary origin, function, and treatment of cancer
Аннотация
Despite remarkable progress in basic oncology, practical results remain unsatisfactory. This discrepancy is partly due to the exclusive focus on processes within the cancer cell, which results in a lack of recognition of cancer as a systemic disease. It is evident that a wise balance is needed between two alternative methodological approaches: reductionism, which would break down complex phenomena into smaller units to be studied separately, and holism, which emphasizes the study of complex systems as integrated wholes. A consistent holistic approach has so far led to the notion of cancer as a special organ, stimulating debate about its function and evolutionary significance. This article discusses the role of cancer as a mechanism of purifying selection of the gene pool, the correlation between hereditary and sporadic cancer, the cancer interactome, and the role of metastasis in a lethal outcome. It is also proposed that neutralizing the cancer interactome may be a novel treatment strategy.
22-34
A portrait of three mammalian bicistronic mRNA transcripts, derived from the genes ASNSD1, SLC35A4, and MIEF1
Аннотация
Recent advances in functional genomics have allowed identification of thousands of translated short open reading frames (sORFs) in the 5′ leaders of mammalian mRNA transcripts. While most sORFs are unlikely to encode functional proteins, a small number have been shown to have evolved as protein-coding genes. As a result, dozens of these sORFs have already been annotated as protein-coding ORFs. mRNAs that contain both a protein-coding sORF and an annotated coding sequence (CDS) are referred to as bicistronic transcripts. In this study, we focus on three genes – ASNSD1, SLC35A4, and MIEF1 – which give rise to bicistronic mRNAs. We discuss recent findings regarding functional investigation of the corresponding polypeptide products, as well as how their translation is regulated, and how this unusual genetic arrangement may have evolved.
35-47
Energy dependent non-photoshemical quenching: PsbS, LhcSR and other players
Аннотация
The photosynthetic apparatus of plants is capable of capturing even weak fluxes of light energy. Hence, strong and rapid increase in irradiance should be dangerous for plants. To solve the problems caused by fluctuations of incident radiation (up to excessive), plants have developed a number of protective mechanisms, including non-photochemical quenching (NPQ) of excited chlorophyll states. NPQ is a set of mechanisms that shorten the lifetime of excited chlorophyll states in the photosynthetic antenna, thereby reducing dangerous effects of light. The most rapid mechanism of NPQ is energy-dependent quenching (qE) triggered by the proton potential formation on the thylakoid transmembrane. The main molecular players of qE are xanthophylls (oxygen-containing carotenoids) and proteins of the thylakoid membrane: antenna component LhcSR in algae and mosses and photosystem II component PsbS in higher plants and some groups of “green lineage” alga. This review discusses molecular mechanisms of qE, with a special focus on the PsbS-dependent quenching. The discovery that PsbS does not bind pigments has led to the hypothesis of PsbS-dependent indirect activation of quenching, in which PsbS acts as a relay switching on the quenching sites in the major (LHCII) and/or minor photosynthetic antennae. The suggested mechanisms include the effect of PsbS on carotenoid conformation and/or pKa values of amino acid residues in PSII antennae. PsbS can also act as a membrane “lubricant” that ensures migration of the major antenna LHCII in the thylakoid membrane and its aggregation followed by transition to the quenched state.
48-67
Colocalization of neurotransmitters in the hippocampus and afferent systems: possible functional role
Аннотация
In neurophysiology, the transmitter phenotype is considered a sign of neuronal identity. Since the end of the last century, it has become known that a nerve cell can produce and use several different molecules to communicate with other neurons. These can be “classical” transmitters: glutamate or gamma-aminobutyric acid (or acetylcholine, serotonin, norepinephrine), as well as second messengers, mainly neuropeptides released from the same neurons. If classical neurotransmitters are released together from the same nerve cell, this is called cotransmission or coreleasing (release from the same vesicles). In this review article, the term “cotransmission” is used in a broad sense, denoting neurons that can release more than one classical mediator. Since transmitters are often intermediate products of metabolism and are found in many cells, the classification of neurons is currently based on carrier proteins (transporters) that “pack” neurotransmitters synthesized in the cytoplasm into vesicles. Here, we limit the question of colocalization of the main neurotransmitters in mammals to neurons of the hippocampus and those structures that send their pathways to it. The review considers problems affecting the mechanisms of multitransmitter signaling, as well as the probable functional role of mediator colocalization in the work of the hippocampus, which has not yet been clarified. It is suggested that co-expression of different mediator phenotypes is involved in maintaining the balance of excitation and inhibition in different regions of the hippocampus; facilitates rapid selection of information processing methods, induction of long-term potentiation, maintenance of spatial coding by place cells, as well as ensuring flexibility of learning and formation of working memory. However, the functional role of mediator colocalization, as well as the mechanisms of release of “dual” transmitters, have not been fully clarified. The solution of these problems will advance some areas of fundamental neuroscience and help in the treatment of those diseases where a violation of the balance of excitation and inhibition is detected, for example, epilepsy, Alzheimer’s disease and many others.
68-86
Role of membrane proteins β- and α-structures in plasmalemm structure change
Аннотация
Changes in the structure of plasma membranes affect the functions of membranes and cells. Some of these changes can lead to the development of pathologies of the body, which makes it actually to study the effect of changes in the structure of membranes on their functions. It has now been established that when stress hormones and androgens interact with plasma membranes, their structure changes. At the same time, interactions between proteins and lipids change in plasmalemmas, and a fixed quasi-periodic network of protein-lipid domains associated with the cytoskeleton is formed. The initiators of the formation of protein-lipid domains are membrane proteins, which have changed their secondary structure during the interaction of the membrane with hormones. However, it is still unclear exactly what changes in the secondary structure of membrane proteins contribute to the formation of protein-lipid domains around them. The aim of this work was to establish these secondary structures of membrane proteins. To achieve this goal, changes in the structure of membranes during their interaction with dehydroepiandrosterone, cortisol, androsterone, testosterone, and adrenaline were studied. In this work, a fluorescent method for measuring the relative microviscosity of membranes using a pyrene probe was used to study changes in the membrane structure. The change in the secondary structure of membrane proteins during structural transitions in membranes was studied by measuring the IR absorption spectra of membranes. It has been established that the initiators of the appearance of protein-lipid domains in plasma membranes are membrane proteins, in which, after interaction with hormones, the proportion of β-structures increases. At the same time, the appearance of new α-helices in membrane proteins does not enhance the attraction between membrane proteins and protein-lipid domains are not formed. On the contrary, the appearance of a large number of α-helices in membrane proteins can lead to a decrease in the microviscosity of the lipid bilayer.
87-106
Evaluation of the effect of inhibition of LRRK2 kinase activity on glucocerebrosidase activity on patient-specific cells from patients with Gaucher disease
Аннотация
Biallelic mutations in the GBA1 gene, encoding the lysosomal enzyme glucocerebrosidase (GCase), lead to the development of a lysosomal storage disease, Gaucher disease (GD), and are also a high risk factor for a common neurodegenerative disease, Parkinson’s disease (PD). In most cases, mutations in the GBA1 gene are localized outside the active site and lead to a decrease in GCase activity due to a decrease in the efficiency of transport of the enzyme with an altered conformation into the lysosome. Drugs that are used to treat GD (enzyme replacement therapy) are not able to cross the blood-brain barrier and are not effective for the treatment of neuronal forms of GD or PD associated with mutations in the GBA1 gene (GBA1-PD). For the treatment of PD, drugs that inhibit the kinase activity of leucine-rich repeat kinase 2 (LRRK2) are currently undergoing clinical trials. It was previously shown that inhibition of LRRK2 kinase activity leads to an increase in GCase activity in patient-specific GBA1-PD cells. We first assessed the effect of the kinase activity inhibitor LRRK2 (MLi-2) on GCase activity in a primary culture of peripheral blood macrophages obtained from patients with type 1 GD. Assessment of GCase activity and its substrate levels in cells cultured with and without MLi-2 was performed using high-performance liquid chromatography coupled with tandem mass spectrometry. There was no effect of inhibition of LRRK2 activity on GCase activity in the group of patients with GD.
107-116
Mechanisms of antioxidant protection of low-density lipoprotein particles against free radical oxidation
Аннотация
It was found that when patients with atherosclerosis are orally administered ubiquinon Q10 (CoQ10), the oxidation (lipohydroperoxide content) of low-density lipoprotein (LDL) particles sharply decreases, which confirms the important role of this natural antioxidant in protecting LDL particles from free radical oxidation in vivo. The influence of lipophilic natural antioxidants ubiquinol Q10 (CoQ10H2) and α-tocopherol (α-TOH) on the kinetic parameters of Cu2+-initiated free radical oxidation of LDL particles was investigated. In this model system, the possible synergism of the antioxidant action of CoQ10H2 and α-TOH is shown. The probable mechanisms of bioregeneration of the lipophilic antioxidants in LDL particles, including regeneration of α-TOH from the tocopheroxyl radical (α-TO•) with the participation of CoQ10H2 and/or ascorbate, are discussed.
117-130
Determination of SARS-CoV-2 main protease (Mpro) activity based on electrooxidation of the tyrosine residue of a model peptide
Аннотация
The proposed approach for determining the catalytic activity of SARS-CoV-2 main protease (Mpro) is based on the registration of the peak area of the electrochemical oxidation of the tyrosine residue of the model peptide substrate CGGGAVLQSGY immobilized on the surface of a graphite screen-printed electrode (SPE) modified with gold nanoparticles (AuNP). The AuNP were obtained by electrosynthesis. The steady state kinetic parameters of Mpro towards the model peptide were determined: catalytic constant (kcat) was (3.1 ± 0.1)·10–3 s–1; Michaelis constant (KM) was (358 ± 32)·10–9 M; catalytic efficiency (kcat/KM) was 8659 s–1/M. The limit of detection (LOD) determined for Mpro using the proposed electrochemical system was 44 nM. The proposed approach is a promising tool to search for new Mpro inhibitors as drugs for the treatment of coronavirus infections.
131-143
Physiological concentrations of calciprotein particles trigger activation and pro-inflammatory response in endothelial cells and monocytes
Аннотация
Supraphysiological concentrations of calciprotein particles (CPPs), which are indispensable scavengers of excessive Ca2+ and PO43– ions in blood, induce pro-inflammatory activation of endothelial cells (ECs) and monocytes. Here, we determined physiological levels of CPPs (10 μg/mL calcium, corresponding to 10% increase in Ca2+ in the serum or medium) and investigated whether the pathological effects of calcium stress depend on the calcium delivery form, such as Ca2+ ions, albumin- or fetuin-centric calciprotein monomers (CPM-A/CPM-F), and albumin- or fetuin-centric CPPs (CPP-A/CPP-F). The treatment with CPP-A or CPP-F upregulated transcription of pro-inflammatory genes (VCAM1, ICAM1, SELE, IL6, CXCL8, CCL2, CXCL1, MIF) and promoted release of pro-inflammatory cytokines (IL-6, IL-8, MCP-1/CCL2, and MIP-3α/CCL20) and pro- and anti-thrombotic molecules (PAI-1 and uPAR) in human arterial ECs and monocytes, although these results depended on the type of cell and calcium-containing particles. Free Ca2+ ions and CPM-A/CPM-F induced less consistent detrimental effects. Intravenous administration of CaCl2, CPM-A, or CPP-A to Wistar rats increased production of chemokines (CX3CL1, MCP-1/CCL2, CXCL7, CCL11, CCL17), hepatokines (hepassocin, fetuin-A, FGF-21, GDF-15), proteases (MMP-2, MMP-3) and protease inhibitors (PAI-1) into the circulation. We concluded that molecular consequences of calcium overload are largely determined by the form of its delivery and CPPs are efficient inducers of mineral stress at physiological levels.
144-172