Biohimiâ

Neutrophils are phagocytic, myeloid-type leukocytes that are the most common myeloid cells in human blood, normally comprising 65 to 80% of all circulating leukocytes. Over the years of research into these cells, more and more evidence has emerged demonstrating the functional plasticity of neutrophils and their ambiguous role in tumor development. Similar to the M1/M2 classification of macrophages, the N1/N2 paradigm can be applied to neutrophils, where N1 neutrophils exhibit tumor-suppressive properties, while N2 neutrophils promote tumor development and suppression of immunity. An important natural feature of neutrophils is their mobility and ability to overcome physical barriers, which is why these cells, as well as their vesicles and membranes, can be used to deliver therapeutic drugs to tumor cells. Moreover, neutrophils themselves can be activated and mobilized to fight tumors. This review describes the current state of research into the role of neutrophils in carcinogenesis, as well as possible approaches to the use of these cells and their derivatives as delivery systems for therapeutic drugs for the treatment of malignant neoplasms.

To date, Alzheimer's disease (AD) is an incurable disease with enormous socioeconomic consequences. One of the known mechanisms of Alzheimer's disease pathogenesis is the deposition of amyloid plaques as a result of beta-amyloid (Aβ) accumulation. Receptor for glycation end products (RAGE) plays an important role in the transport of Aβ across the GEB. Also, ligand interaction with RAGE regulates the expression of amyloid precursor protein (APP), which plays a key role in Aβ accumulation. In this analytical review, we dissect the biochemical mechanism of toxic effects of exogenous formaldehyde in the hippocampus leading to the development of insulin resistance and further molecular mechanisms of neuroinflammation contributing to increased RAGE expression. Accumulation of endogenous formaldehyde in the body may occur as a result of impaired utilization. However, the accumulation associated with the ingestion of exogenous formaldehyde has much more acute and dangerous consequences. Formaldehyde is one of the main toxins, MAC of which is stably exceeded in many cities of Russia, as well as in countries of East, South and South-East Asia, Central Africa, North and South America. Formaldehyde plays a major role in the pathogenesis of neurodegenerative diseases, as its biochemical mechanism of action is closely related to increased Aβ accumulation. In individuals more susceptible to beta-amyloid accumulation (due to age or genetic predisposition), exposure to exogenous formaldehyde may have an additional effect on beta-amyloid accumulation. Experiments have previously been conducted investigating the role of formaldehyde in neurodegenerative diseases. A correlation was found between the degree of air pollution and hyperglycaemia. However, the detailed mechanism for the further development of neurodegeneration remains unclear. This review emphasizes the importance of studying the interaction between environmental toxins and neurodegenerative diseases, which may lead to the development of a therapeutic approach based on the protection of neurons from the effects of toxic substances in individuals susceptible to this pathology.

According to modern concepts, neuroinflammation and peripheral immune dysfunction play a key role in the onset and progression of Parkinson's disease (PD), one of the most common and severe neurodegenerative diseases. However, changes of cellular and molecular immune parameters under development of PD are still little defined. The work is devoted to the analysis of immune cell populations (monocytes, T and B cells and their subtypes), expression of Toll-like receptors (TLR) and spontaneous and mitogen-induced production of pro- and anti-inflammatory cytokines in the peripheral blood of patients at different stages of idiopathic PD and healthy individuals. It is shown that the stage II of PD is characterized by a decrease in the amount of CD3⁺ T cells, an increase in TLR2 expression on CD4⁺CD25⁺ Tregs, as well as an increase in the spontaneous production of proinflammatory cytokines IFNγ and IL-17A. Stage III of PD is associated with a decrease in the production of mitogen-induced IFNγ. The relative number of CD19⁺CD25⁺ Breg cells in patients with PD increased regardless of the disease stage. Thus, the obtained results indicate differences in cellular and molecular immune parameters existing in patients with PD and in healthy individuals, which are dependent on the stage of the disease. These data are important for understanding the molecular basis of PD development and prognosis of its course, and may be useful in identifying biomarkers of disease severity and developing new treatment approaches depending on the stage of the disease.

Mutations in sarcomeric proteins associated with hypertrophic cardiomyopathy (HCM) lead to disruption of actin-myosin interaction, its calcium regulation, and myocardial hypercontractility. About half of such mutations are found in the MYBPC3 gene encoding cardiac myosin binding protein C (cMyBP-C). A new approach to normalize cardiac contractile function in HCM is the use of inhibitors of β-cardiac myosin function, one of which is mavacamten. We studied the effect of mavacamten on calcium regulation of actin-myosin interaction using isolated cardiac contractile proteins in an in vitro motility assay. The L352P mutation did not affect the maximum sliding velocity of regulated thin filaments on myosin in an in vitro motility assay and the calcium sensitivity of the velocity and led to underinhibition of actin-myosin interaction at low calcium concentrations. Mavacamten decreased the maximum sliding velocity of thin filaments with WT and L352P C0-C2 fragments, and in the presence of L352P C0-C2 fragment stopped their movement at low calcium concentrations. Slowing down the kinetics of cross-bridge and inhibition of actin-myosin interaction at low calcium concentrations in the presence of mavacamten may reduce hypercontractility in HCM and the degree of myocardial hypertrophy.

The viral capsids of the potexvirus family are characterized by the presence on the surface of virions of partially disordered N-terminal fragments of proteins of various lengths. The present study is devoted to studying the effect of in situ removal of the N-terminal domain of the coat protein (CP) on the structural organization and physicochemical properties of potato virus X (PVX) virions. The work considers PVX virions containing an intact Ps-form CP, as well as virions including an in situ degraded Pf-form devoid of 19/21 amino acid residues from the N-end (PVXΔN). Synchrotron small-angle X-ray scattering (SAXS), transmission electron microscopy (TEM), tritium bombardment, and several other physicochemical methods were used for the study. Analysis of images obtained using TEM revealed similarities in the architecture of filamentous PVX and PVXΔN virions. SAXS results demonstrated differences in the organization of the capsid of PVX and PVXΔN virions: the latter was characterized by a reduction in the size of ordered regions, indicating partial disruption of the structure of the viral protein framework. In addition, based on the SAXS scattering curves, parameters of the spiral packing of virions in solution were calculated, and structural modeling of particles was performed. Modeling results also indicate changes in the structure of the capsid due to the removal of the ΔN-peptide. Using information about the secondary structure of the PVX model (PDB ID: 6R7G) and data from our previous studies on tritium labeling of surface sites of PVX and PVXΔN virions, a comparative analysis of label incorporation profiles into elements of the protein's secondary structure was conducted. This approach made it possible to predict the localization of the ΔN-peptide above the amino acid residues of neighboring helical subunits (122-129 and 143-153) and demonstrate the stabilizing role of this peptide on the overall structure of the virion. An increase in the level of the label in the C-terminal region after removing the ΔN-peptide also indicates a decrease in the compactness of the virion. Overall, the knowledge gained will be useful when using virus-like nanoparticles in biotechnology.