Medical academic journal

The journal “Meditsinskiy Akademicheskiy Zhurnal” published since 2001 is an official journal of the Northwest Branch of the Russian Academy Sciences. Its initiator and Editor-in-Chief in 2001-2009 was Academician of the Russian Academy of Medical Sciences Boris Ivanovich Tkachenko whose contribution to the development of the journal is invaluable. The first Deputy Editor-in-Chief of the journal was Academician of RAMS V.A. Nagornev, and its Executive Secretary was Corresponding Member of RAMS N.S. Sapronov.

In September 2009, the position of Editor-in-Chief was taken by Corresponding Member of RAMS I.P. Dudanov, of Deputy Editor-in Chief, by Corresponding Member of RAMS N.S. Sapronov, and of Executive Secretary, by Prof. P.D. Shabanov.

The high publication level and wide appreciation by specialists in the course of formation and development of the journal were ensured by outstanding contributors, including Academicians E.K. Ailamazyan, N.A. Belyakov, Yu.D. Ignatov, Yu.V. Lobzin, V.I. Mazurov, N.A. Maystrenko, and A.A. Totolyan, and Corresponding Members of RAS I.A. Yeriukhin, S.A. Ketlinskiy, M.M. Odinak, Ye.A. Selivanov, and S.A. Simbirtsev.

Since 2010 up to the present time, Editor-in-Chief of the journal is Academician G.A. Sofronov. Since 2012, its Deputy Editor-in-Chief is Academician N.A. Belyakov, and its Executive Secretary is A.B. Dmitriyev PhD. The Editorial and Advisory Boards of the journal include prominent scientists representing the Northwest of Russia and distinguished scientific schools of Saint Petersburg.



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Vol 23, No 2 (2023)

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Analytical reviews

Nonimmune binding of human immunoglobulins G and A by Streptococcus pyogenes: the role of this phenomenon in pathology
Burova L.A., Suvorov A.N., Pigarevsky P.V., Totolian A.A.

M and M-like proteins are key pathogenicity factors of Streptococcus pyogenes, a widely prevalent and potentially lethal bacterium. These proteins confer resistance to the host’s innate and adaptive immune response by attracting specific human proteins to the streptococcal surface. The nonimmune binding of host immunoglobulins G (IgG) and A (IgA) to M and M-like proteins via their Fc domains was first described over 50 years ago, but its role in the pathogenicity of S. pyogenes remains unclear. This discovery has had a significant impact on the development of innovative diagnostic approaches, technologies, and tools in microbiology, immunology, and molecular biology. The nonimmune binding of immunoglobulins has been suggested to play a role in immune conditions on mucosal surfaces and their secretions, but not in blood plasma, while other studies suggest it protects microbes from phagocytosis in the host’s nonimmune blood. The Fc-binding effect has been shown to increase the pathogenicity of streptococci, contributing to the development of autoimmune diseases and tissue damage in experimental animals. The experimental autoimmune process can be prevented by administering purified Fc fragments of immunoglobulins to animals. Streptococcal diseases play a significant role in the pathogenesis of IgA-nephropathy (IgAN), a mesangial proliferative process caused by initial IgA-Fcα deposition in renal mesangium cells. Literature suggests a relevance of recent ideas about the important role of nonimmune Ig binding in streptococcal diseases, and further efforts are required to study the binding of Fc fragments of IgG and IgA to M and M-like proteins of S. pyogenes, with the aim of developing preventive and potentially therapeutic applications. The paper speculates on the role of nonimmune Ig binding in streptococcal diseases, including cases with various mechanisms of development. These studies also focuses on preventive and potentially therapeutic applications of Fc fragments of IgG to M or M-like proteins of S. pyogenes.

Medical academic journal. 2023;23(2):9-29
pages 9-29 views
Antimicrobial activity of the complement system
Egorova E.V., Krenev I.A., Oborin N.N., Berlov M.N.

The complement system plays a key role in homeostasis and defense against pathogens. The antimicrobial activity of serum against Gram-negative bacteria is usually attributed to the action of the membrane attack complex. However, there is increasing evidence that some other components of the complement system and the products of its activation are also capable of direct killing of both Gram-negative and Gram-positive bacteria. In the course of complement activation, anaphylatoxins C3a, C4a, C5a are produced, which, in addition to their main function, can exhibit a bactericidal effect and disrupt the bacterial membrane. Recent studies have shown that in fish, complement factors D, I, as well as a Ba fragment of factor B, are able to neutralize pathogens. The triggering and amplification of complement usually occurs on the surface of pathogen cells, so the local production of antimicrobial components can potentially make a significant contribution to their elimination. The aim of this review is to outline the role of individual complement members in the elimination of pathogens through direct antibiotic action. The problem of antimicrobial protection in the context of therapeutic complement inhibition is considered.

Medical academic journal. 2023;23(2):31-45
pages 31-45 views
The molecular mechanisms of drug resistance of glioblastoma. Part 3. Differentiation and apoptosis of glioblastoma cells
Chernov A.N., Galimova E.S., Shamova O.V.

Glioblastomas are one of the most malignant and frequent human tumors, characterized by rapid growth, metastasis, resistance to therapy and the formation of relapses. The formation of multidrug resistance mechanisms in glioblastomas cells is often combined with inhibition of cell death and differentiation pathways and prevents an increase in the effectiveness of therapy in this group of patients. The review examines the relationship of molecular mechanisms of multidrug resistance with differentiation and apoptosis of glioblastomas with an emphasis on identifying new targets among proteins, microRNAs, suppressor genes, and oncogenes.

Medical academic journal. 2023;23(2):47-62
pages 47-62 views

Original research

Influence of constant lighting on the morphofunctional state and rhythmostasis of the liver of rats
Grabeklis S.A., Mikhaleva L.M., Kozlova M.A., Areshidze D.A., Dygai A.M.

BACKGROUND: There are evidences that light pollution, which causes melatonin deficiency and disruption of circadian rhythm, is associated with the development of malignant neoplasms of the liver, non-alcoholic fatty liver disease, biliary cirrhosis, and a number of other pathologies of this organ.

AIM: The aim of research was to study the features of chronic influence of constant lighting on lability of morphofunctional state of liver of mature Wistar rats and the structure of circadian rhythms of its parameters.

MATERIALS AND METHODS: The study was conducted on 80 rats divided into 2 groups: a control group kept under a fixed light regime (light/dark 12/12 h, lights on at 8:00 and off at 20:00), and an experimental group kept under constant lighting 24 h a day. The duration of the experiment was 3 weeks.

RESULTS: It’s established that influence of constant light led to an increase in the size of hepatocytes and a decrease in nuclear-cytoplasmic ratio, average ploidy and proportion of binuclear hepatocytes, and also to development of fatty degeneration, a decrease in the expression of Bmal1 and Clock, and an increase in the expression of per2 and p53 in hepatocytes. At the same time, there was a decrease in glycogen content in hepatocytes. Dark deprivation also caused an increase in glucose levels, AST activity, and a decrease in blood levels of total protein and albumin. Constant lighting caused a rearrangement of the circadian rhythms of the area of nuclei, the area of the hepatocyte and nuclear-cytoplasmic ratio, Bmal1, per2, Clock expression, and led to destruction of Ki67 and p53 circadian rhythms in hepatocytes. Under conditions of constant lighting, the circadian rhythms of the content of lipids and glycogen in hepatocytes, ALT activity in the blood, and the content of total and direct bilirubin were also destroyed.

CONCLUSIONS: It has been established that constant illumination causes a restructuring of the circadian rhythms of a number of studied parameters against the background of morphological and functional changes, indicating a decrease in the adaptive capacity of the liver.

Medical academic journal. 2023;23(2):63-74
pages 63-74 views
The features of neuronal loss in the hippocampus during acute generalized seizure (experimental study)
Demyashkin G.A., Grigoryan M.S., Vetrov I.V., Vetrov F.V., Rauzheva V.P., Zorin I.A., Shapovalova E.Y.

BACKGROUND: Today, epilepsy is one of the most frequently diagnosed neurological diseases. Despite more than several centuries of research on epileptogenesis and the development of treatment protocols, the neurobiological basis of the disease remains poorly understood. It is reliably known that patients with epilepsy are found to have a reduced number of hippocampal neurons and gliosis: mesial temporal sclerosis (hippocampal sclerosis), but the causal relationship with seizures has not yet been established. It is of particular interest to evaluate the survival of hippocampal neurons against the background of acute epileptic seizures, which will allow to determine the mechanisms of degenerative changes in nervous tissue.

AIM: The aim of the study was to immunohistochemically assess the levels of NeuN and caspase-8 in the hippocampus during acute epileptic seizures.

MATERIALS AND METHODS: Male mice of the CBA population were used as models. The animals were divided into groups: 1st (n = 28) — simulated acute epileptic seizure by intraperitoneal injection of pentyltetrazole, 2nd (n = 20) — control. Histological and immunohistochemical studies were performed on hippocampal fragments, regions: CA1, CA3 and dentate gyrus.

RESULTS: Generalized epileptic seizures were noted in all animals of Group I. The weakest labeling of hippocampal pyramidal neurons with NeuN (light nuclei) was observed in CA3 region, which was observed 24 hours after pentyltetrazole injection. The same immunophenotypic pattern was observed in the CA3 region during reaction with caspase-8, which demonstrated an increase in the number of immunopositive hippocampal pyramidal neurons 24 hours after pentyltetrazole injection.

CONCLUSIONS: After a single injection of pentyltetrazole at a dose of 45 µg/kg, immunohistochemical evaluation of the distribution of NeuN- and caspase-8-positive pyramidal neurons of the hippocampus revealed: a decrease in the NeuN-positive neurons and an increase in caspase-8-positive neurons one day after the seizure with subsequent recovery of the studied markers by day 5.

Medical academic journal. 2023;23(2):75-85
pages 75-85 views
The study of the spectrum of pharmacological activity of the new original NT-3 mimetic dipeptide GTS-302
Nikiforov D.M., Povarnina P.Y., Gudasheva T.A., Nadorova A.V., Kolik L.G., Valdman E.A., Vakhitova J.V., Seredenin S.B.

BACKGROUND: The association of the pathogenesis of neurodegenerative diseases, depression, anxiety, and cognitive disorders with the deficit of neurotrophin-3 determines the prospect of creating drugs with a similar mechanism of action. Since the use of full-size neurotrophin-3 is limited by unsatisfactory pharmacokinetic properties, it is relevant to create low-molecular-weight mimetics of neurotrophin-3 that are active when administered systemically. A dimeric dipeptide mimetic of the 4th loop of neurotrophin-3, hexamethylenediamide bis(N-γ-oxibutyryl-L-glutamyl-L-asparagine) GTS-302, which activates TrkC and TrkB receptors, has been developed at the V.V. Zakusov Research Institute of Pharmacology.

AIM: The aim of this study was to investigate the spectrum of pharmacological activity of GTS-302.

MATERIALS AND МETHODS: The pharmacological effects of GTS-302 were investigated following its intraperitoneal administration. The antidepressant-like activity of GTS-302 was studied in the forced swim test in mice after acute and 7-day administration. The anxiolytic and cognitive activity of the dipeptide were studied in the elevated plus maze test in mice and the novel object recognition test in rats after acute administration, respectively. The effect of GTS-302 on pain sensitivity was studied in the hot plate test in mice after acute administration.

RESULTS: It was found that GTS-302 exhibits antidepressant-like activity after acute administration at doses of 0.5, 1.0, 5.0 and 10 mg/kg. After 7-day administration, the antidepressant-like activity of GTS-302 was more pronounced in terms of effect size and statistical significance. The dipeptide GTS-302 at doses of 1.0, 5.0 and 10.0 mg/kg showed anxiolytic and cognitive activity and did not affect pain sensitivity.

CONCLUSIONS: The pharmacological spectrum of the low-molecular-weight mimetic of neurotrophin-3, dipeptide GTS-302, revealed upon systemic administration includes a number of neuropsychotropic effects characteristic of the full-sized neurotrophin. This allows us to consider GTS-302 as a potential neuropsychotropic drug.

Medical academic journal. 2023;23(2):87-99
pages 87-99 views
NeuN-immunopositive cells in subfornical organ of spontaneously hypertensive rats
Razenkova V.A.

BACKGROUND: Hypertension is one of the predominant risk factors for the development of several cardiovascular and central nervous system diseases. It is important to investigate the hypertensive effects on the tissue of brain areas, lacking blood-brain barrier, such as the subfornical organ, as they provide the CNS response to stress and damage.

AIM: The aim of the research was to study the localization and functional status of the neuronal cell population within the subfornical organ of Spontaneously Hypertensive Rats.

MATERIALS AND METHODS: The study was carried out on paraffin sections of the brain of Spontaneously Hypertensive Rats and Wistar rats (n = 12). Mouse monoclonal antibodies against NeuN were used for the light microscopy. Images were analyzed by the Fiji software.

RESULTS: It was demonstrated that the spatial neuron distribution of the subfornical organ of Wistar and SHR rats is different. NeuN-positive cells of the subfornical organ of Wistar rats demonstrated dense distribution. On the contrary, subfornical organ neurons of SHRs tended to form separate groups. That observation was additionally confirmed by cluster analysis. Between the groups of NeuN-positive cells. Histochemical counterstain revealed that the “gaps” between neuronal groups are composed of glial cells.

CONCLUSIONS: The study showed neurons in the subfornical organ of spontaneously hypertensive rats may undergo reorganization, which is, apparently, caused by the neuronal cell death and gliosis.

Medical academic journal. 2023;23(2):101-108
pages 101-108 views
Immunohistochemical study of human pineal vessels
Sufieva D.A., Fedorova E.A., Yakovlev V.S., Grigorev I.P.

BACKGROUND: The pineal gland is a neuroendocrine organ located in the epithalamic area of the brain. By using the melatonin, a pineal hormone, the pineal gland synchronizes the work of the internal physiological systems of the body with the circadian light-darkness cycle. Melatonin is synthesized in pinealocytes, the endocrine cells of the pineal gland, and secreted into the bloodstream. However, the structural features of the blood vessels in the pineal gland are still not well understood.

AIM: The purpose of this study was to elucidate the intraorgan localization and immunohistochemical pattern of the blood vessels of the pineal gland of human, which had not been previously studied.

MATERIALS AND METHODS: In the research, immunohistochemistry methods were applied using two selective markers of blood vessels, the antibodies to von Willebrand factor and type IV collagen. Von Willebrand factor is expressed selectively in endothelial cells that form blood vessels, including small capillaries, while type IV collagen is inherent to the basement membrane that separates the vascular endothelium from the underlying tissue.

RESULTS: The immunohistochemical reaction to both markers clearly visualize the blood vessels of the human pineal gland, which in both cases were observed mainly in the connective tissue septa (trabeculae), or, in the absence of a regular lobular structure, in the connective tissue layers. In lobules surrounded by connective tissue trabeculae and containing a large number of densely packed pinealocytes, von Willebrand factor- and type IV collagen-immunoreactive structures were very rare, and in many cases were not observed. The found phenomenon of distribution of blood vessels in the human pineal gland is described for the first time.

CONCLUSIONS: Since blood vessel markers with well-proven selectivity were used, the results obtained with their usage can be considered reliable; this gives grounds with a high degree of probability to assert that the majority of pinealocytes in the human pineal gland do not have direct contact with blood vessels and, accordingly, cannot secrete melatonin directly into the bloodstream. On the basis of the results obtained, a hypothesis is proposed that the hormone secretion from pinealocytes into blood vessels is mediated by astroglial cells.

Medical academic journal. 2023;23(2):109-118
pages 109-118 views

Clinical research

BDNF content and catalase activity in the blood of children with autism spectrum disorders
Belokoskova S.G., Malsagova E.M., Ivleva I.S., Karpenko M.N., Tsikunov S.G.

BACKGROUND: With the increasing prevalence of autism spectrum disorders worldwide, it is relevant to study the mechanisms contributing to their development and progression. The participation of brain-derived neurotrophic factor and oxidative stress in the pathogenesis of the disease is considered, however, their role in this process remains unclear. The relationship between BDNF levels and oxidative stress in the blood of patients with autism spectrum disorders has not been studied.

AIM: The aim was to evaluate the content of brain neurotrophic factor, BDNF, and catalase, an antioxidant defense enzyme, in children with various clinical forms of autism spectrum disorders.

MATERIALS AND METHODS: BDNF content and catalase activity were assessed in the blood plasma of 78 children with autism spectrum disorders, including 41 patients with childhood autism, 19 children with atypical autism, 6 patients with Asperger’s syndrome, and 12 patients with other general developmental disorders (with elements of autism). The control group consisted of 20 conditionally healthy children. The diagnosis was established in accordance with the ICD-10. The severity of disorders was determined using the Childhood Autism Rating Scale. The content of BDNF was evaluated using the method of enzyme immunoassay, catalase activity was determined by colorimetric method.

RESULTS: The content of BDNF in blood plasma was reduced in children with autism spectrum disorders compared to its levels in control group subjects. BDNF levels depended on the clinical form of the disease: the content of BDNF was reduced in patients with childhood autism, atypical autism, Asperger’s syndrome compared to control group subjects; in patients with atypical autism it is lower than in patients with childhood autism; BDNF levels in the group of patients with other general developmental disorders and in control group did not differ. The content of BDNF did not depend on gender, age and severity of autism spectrum disorders. A negative correlation was found between BDNF levels and the age of control group children. There were no differences in the activity of catalase in the blood of children with autism spectrum disorders and in control group. A positive correlation was found between BDNF levels and catalase activity in children with autism spectrum disorders and control group subjects.

CONCLUSIONS: A decrease in the content of BDNF in the blood of children with autism spectrum disorders was revealed. Neurotrophin content differed in children with separate clinical forms of the disease. To varying degrees the decrease in BDNF levels in patients with childhood autism, atypical autism, Asperger’s syndrome and the absence of changes in patients with other general developmental disorders compared with controls could be associated with a different contribution of neurotrophin to the pathogenesis of clinical forms of autism spectrum disorders. In children with autism spectrum disorders, there were no age-related changes in neurotrophin levels, while in healthy children a negative correlation was found between the content of BDNF and age. The absence of changes in the activity of catalase in the blood of children with autism spectrum disorders indicated the safety of the antioxidant defense system in terms of this indicator. The positive correlation between BDNF levels and catalase activity in the blood of patients with autism spectrum disorders and control group subjects reflected the protective role of neurotrophin from the damaging effects of oxidative stress.

Medical academic journal. 2023;23(2):119-128
pages 119-128 views

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