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Vol 20, No 6 (2022)
Reviews
Mitochondrial transport molecules as the potential objects for targeted therapy
Abstract
Mitochondria are the active cell organelles whose structures (the membrane in particular) express a large number of signaling molecules, proteins mainly, that play an important regulatory role in cell active functioning. The biological activity of mitochondrial proteins suggests their key role as the objects in targeted therapy of mitochondrial functioning processes impaired as the result of the development of infectious, neurodegenerative, stress or pathological process of various etiologies and pathogenesis. Mitochondrial regulatory proteins have recently been of even greater interest and relevance for research, due to their established participation in the pathogenesis of viral infection, oncogenesis and metabolic dysfunctions.
Material and methods. The analysis of the properties of the key signaling molecules of mitochondrial membranes that regulate the transport function of protein compounds in normal and under various pathological conditions was carried out.
Conclusion. The biological properties of the key mitochondrial membrane proteins and their role in the pathogenesis make it relevant to study their verification as possible objects for targeted pharmacotherapy of socially significant diseases based on mitochondrial dysfunction.
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Signaling molecules of tumor transformation in tuberculosis
Abstract
The review is devoted to the analysis of modern ideas about the molecular mechanisms of tumor transformation in tuberculosis; signal molecules are described, which may be biomarkers and targets for optimizing personalized diagnosis and targeted therapy of the disease.
The aim of the study was to determine the current state of the issue and characterize the molecular markers of tumor transformation in tuberculosis.
Material and methods: analysis and systematization of scientific literature over the past 10 years was performed in the PubMed, Scopus and Google Scholar databases.
Results: particular attention in the review is given to the factors contributing to tumor transformation in tuberculosis. Both direct effects of Mycobacterium tuberculosis on proliferation and immune response, and indirect mechanisms of action on cells involved in inflammation processes are considered. The choice of signaling molecules to optimize the personalized diagnosis of tumor transformation in tuberculosis is substantiated.
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Application of mesenchymal stem cells and extracellular vesicles in infectious treatment
Abstract
Mesenchymal stem cells (MSCs) are attractive in various fields of regenerative medicine due to their therapeutic potential and complex unique properties. Basic stem cell research and the global COVID-19 pandemic have given impetus to the development of cell therapy for infectious diseases.
The aim of this review is to systematize scientific data on the use of MSCs and their extracellular vesicles (MSC-EVs) in the complex treatment of infectious diseases.
Material and methods: an analysis of the main foreign sources in the databases of NCBI, Elsevier, PubMed/Medline for 2004–2022 was carried out.
Results. Application of MSCs and MSC-EVs in the treatment of infectious diseases has an immunomodulatory, anti-inflammatory and antibacterial effect, and also promotes the restoration of the epithelium and stimulates tissue regeneration. The use of MSC-EVs is a promising cell-free treatment strategy that allows solving the problems associated with the safety of cell therapy and increasing its effectiveness.
Conclusion. In this review, experimental data and clinical trials based on MSCs and MSC-EVs for the treatment of infectious diseases are presented. MSCs and MSC-EVs can be a promising tool for the treatment of various infectious diseases in combination with antiviral drugs. Using of MSC-EVs instead of cells is a more promising strategy for cell-free treatment, since it allows solving various problems of cell therapy.
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Original research
Comparative study of the soluble forms of immune checkpoint proteins VISTA, PD-1, PD-l1, and bone homeostasis regulator RANKL in bone tumor patients
Abstract
Background. Low sensitivity of bone tumors to various schemes of standard chemotherapy stimulated the search of new targets for their medicamentous treatment. Among such targets are the so-called “immune checkpoints” promoting the escape of the tumor from the immune response of the organism, and some proteins directly affecting the remodeling and homeostasis of bone tissue.
The aim of this study was the comparative evaluation of the content of the soluble forms of VISTA, PD-1, PD-L1, and RANKL in blood serum of patients with malignant and borderline bone tumors, and practically healthy persons; analysis of the associations between these markers and the key clinical and pathological features of bone tumors.
Material and methods. The study enclosed 82 patients with malignant bone tumors (osteosarcoma – 50, chondrosarcoma – 16, chordoma – 12, Ewing sarcoma – 4), 18 patients with borderline giant-cell bone tumor (GCBT), and 29 practically healthy persons. Proteins’ content was measured in blood serum with standard ELISA kits: «Human VISTA/B7-H5/PD-1H ELISA Кit» (RayBiotech,), «Human PD-L1 Platinum ELISA», «Human PD-1 ELISA kit» (Affimetrix, eBioscience), «ampli-sRANKL» (Biomedica Medizinprodukte).
Results. In patients with bone sarcomas, a statistically significant increase in the level of sPD-L1 was revealed, as well as a pronounced trend towards a decrease in the levels of sVISTA and an increase in sRANKL compared with the control, while the level of sPD-1 practically did not differ from the control. A weak positive correlation between sVISTA and sPD-1 serum levels most prominent in chordoma patients (rs=0.63) was observed. Significant positive correlation was also found between sPD-1 and sRANKL concentrations. sVISTA and sRANKL levels did not differ significantly between histological types of bone sarcomas. More than 20-fold increase of sVISTA level in Ewing sarcoma patients as compared to other malignant bone neoplasms did not reach the statistical significance level. The highest sPD-1 level was also observed in Ewing sarcoma, the difference with chordoma and chondrosarcoma being statistically significant. In GCBT patients both sPD-L1 and sPD-1 levels were significantly increased as compared to control, sVISTA level did not differ from control, while sRANKL was significantly higher than both in control, and in bone sarcoma patients. Negative correlation between sVISTA and sRANKL (rs=-0.67) was also observed in this patients group.
Conclusion. Multidirectional changes in the levels of soluble forms of the proteins affected by targeted immunotherapy in peripheral blood of malignant and borderline bone tumor patients were demonstrated. The most prominent changes were found in the neoplasms with specific origin – GCBT and Ewing sarcoma that has a neuroectodermal derivation. Presumably, these diseases are the most plausible candidates for immune modulatory therapies.
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Relationships of hemostasis indexes and microcirculatory hemodynamics indicators in knee and hip joint transplantation
Abstract
Aim of investigation. The development of a non-invasive express method for assessing the state of the hemostasis system during transplantation of large joints is an urgent task, since it allows you to adjust the appointment of anticoagulant therapy and prevent the development of thromboembolic complications. Target. To assess the informative value of the non-invasive express method, which makes it possible to judge the state of the hemostasis system during transplantation of the knee and hip joints.
Methods. The studies were carried out on 136 patients, divided into 2 groups. The first group included 46 patients with arthrosis of the hip or knee joints of I–II stages, the second group consisted of 90 patients with similar arthrosis of III–IV degrees, in whom the studies were carried out in the preoperative period and on the 6th day after arthroplasty. The state of blood flow was studied using an mDLS sensor (Dynamic Light Scattering, Rehovot, Israel). At the same time, the main indicators of the coagulogram were studied according to generally accepted methods and the spatial growth of the fibrin clot, carried out on the apparatus "Trombodynamics Registrar T-2". To assess the relationship between the parameters of hemodynamics and the hemostasis system, the Spearman rank correlation method was used.
Results. Correlation relationships were established between individual hemodynamic parameters and the state of the blood coagulation system and fibroinolysis cascade. It is important to note that these relationships are found between all shear flows (HI1, HI2, and HI3) and the APTT, INR, and D-dimer indices, which allows not only to roughly judge the state of the hemostasis and fibrinolysis system, but also the intensity of the intravascular blood coagulation process.
Conclusion. Based on the data obtained, by measuring hemodynamic parameters, the dose of direct and indirect anticoagulants used can be adjusted during transplantation of large joints.
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Cycline dependent kinase 4 decreased level in the population of Ki-67-negative melanoma cells
Abstract
Introduction. A transition of proliferating cancer cells to a G0 phase of a cell cycle considered to be implicated in cancer cell drug resistance.
The aim of the study. A separation of G0-positive melanoma B16 cells fraction that correspond to resting followed by cyclin dependent kinase 4 and cyclin dependent kinase inhibitor B1 expression estimation in these cells was the aim of the study.
Methods. Melanoma B16 cells were subjected to incubation with alkylating agent dacarbazine to induce a transition of cancer cells in a G0 phase of a cell cycle. Immunocytochemical assay was applied to visualize Ki-67-negative, Go-positive melanoma cells. Fluorescent sorting was used to separate an isolated population resting cells with subsequent cyclin dependent kinase 4 and cyclin dependent kinase inhibitor B1 expression evaluation.
Results. Dacarbazine induced the percentage of Ki-67-negative melanoma B16 cells that correspond to G0-positive cells. Fluorescent sorting application revealed 26% of resting cells among all melanoma cells population. Resting melanoma cells exhibited diminished levels of cyclin dependent kinase 4.
Conclusion. Alkylating agent dacarbazine induces the percentage of resting cancer cells that may be an additional mechanism of cancer cell drug resistance. Cell sorting allowas to separate of resting cancer cells population. Further study for these cell phenotype characterization is important for developing new strategies of targeting quiescent, G0-positive cancer cells.
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Possibilities of application of allogenic tissue engineering products in the experimental urinary bladder reconstruction
Abstract
The article describes the results of an experimental study of tissue-engineering constructions based on lactic acid – poly-L,L-lactide, containing allogeneic cells of various tissue origin. Aim: to show experimentally the possibility of using an allogeneic tissue-engineered graft to replace a defect in the bladder wall.
Material and methods: the study was performed on male Chinchilla rabbits (n=15), which, after resection of the bladder, underwent augmentation cystoplasty with tissue-engineered constructions (TECs) consisting of a polylactide matrix reinforced with silk fibroin and populated with smooth muscle cells with urothelium, fibroblasts, and mesenchymal stem cells.
Results: in 100% of cases of partial bladder replacement with a cell-free matrix or scaffolds containing smooth myocytes with urothelium and fibroblasts, an implant was rejected with a different severity of the inflammatory reaction and a decrease in the capacity of the bladder. Only in the group with mesenchymal stem cells TEC, on the contrary, in 5 cases out of 6 lysis of the matrix occurred, the capacity of the bladders 2,5 months post-surgery was comparable to the preoperative one. At the implantation site, an area of the modified mucous membrane with signs of vascularization was determined. Histologically, the initial stages of reparation and angiogenesis were revealed. With confocal microscopy of cryosections at the implantation site, labeled cells are identified that are involved in the formation of a structure similar to the urothelium.
Conclusion: the effectiveness of mesenchymal stem cells applying as part of a tissue-engineering product for partial replacement of the bladder wall has been shown. There are a number of pathological conditions in urology that require bladder replacement, primarily of a tumor and infectious nature, in which autologous material cannot be used to create a tissue-engineered construction. Such situations dictate necessity for further development of implants using allogeneic cells.
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Outcomes of tuberculosis combined with HIV infection
Abstract
Introduction. The epidemiological process in tuberculosis is negatively affected by the HIV epidemic, the identification of vulnerable groups in relation to the unfavorable course of tuberculosis in combination with HIV infection will improve approaches to treatment and prevention.
The aim of the study was to determine the outcomes of tuberculosis in HIV-infected patients under dispensary supervision with active tuberculosis, and the results of dispensary observation of clinically cured patients with co-infection.
Method. 187 patients aged 18–60 years with tuberculosis and HIV infection underwent clinical and laboratory, microbiological and radiation studies, statistical processing was carried out using the Microsoft Excel application software package.
Results. HIV-infected patients with clinical treatment of tuberculosis have low rates of CD4+ lymphocytes – (0,315•109±0,02)•109 and a high viral load compared to patients with active tuberculosis. After a year, 16.7% of patients with clinical treatment are removed from the register, 36.0% of patients with active tuberculosis are cured, 28.8% of patients have an exacerbation of the process or interruption of treatment, 11.3% die.
Conclusion. In HIV-infected patients with clinical treatment of tuberculosis, the indicators of CD4+ lymphocytes are lower and the viral load is higher than in patients with active tuberculosis, which indicates insufficient adherence to treatment at the outpatient stage and a high risk of recurrence of tuberculosis. The involvement of patients in working with the Call Center contributes to the formation of adherence to both anti-tuberculosis treatment and antiretroviral therapy and favorable outcomes of the disease.
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Correction of alcohol-induced disorders of working memory with noopept
Abstract
Introduction. Nootropic drugs are used at all stages in treatment of behavioral disorders associated with alcohol consumption, when the correction of the functions of operational (working) memory and attention contributes to a more adequate processing and assimilation of information.
The aim of this work is a comparative study of the effect of piracetam and its peptide analogue noopept on ethanol-induced non-spatial memory impairment in in vivo and ex vivo experiments.
Material and methods. To reproduce alcohol-induced cognitive disturbances, a method of chronic alcohol exposure of outbred rats was used, based on providing animals with a 10% ethanol solution as the only source of fluid for 30 weeks, followed by behavioral and neurochemical studies of the pharmacological effects of noopept (1.5 mg/kg) and piracetam (100 mg/kg) after 7 daily intraperitoneal administration during ethanol withdrawal.
Results. According to morphological studies, chronic ethanol consumption induced a neurotoxic effect on the cerebral cortex, as well as pronounced damage in the pyramidal neurons of the CA1 and CA3 zones of the hippocampus in rats. In the "Novel object recognition" test, noopept, like piracetam, prevented the impairment of working memory induced by ethanol withdrawal. Unlike piracetam, noopept restored the content of glutamate and gamma aminobutyric acid in the hippocampus of rats exposed to ethanol to the level of values of non-ethanol exposed rats.
Thus, in experimental studies, the positive mnemotropic properties of noopept have been proven in relation to alcohol-induced disorders of non-spatial long-term working memory, which are comparable to piracetam.
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