Saida Karshieva
@misis.ru
Center for Biomedical Engineering
The National University of Science and Technology MISIS
Scopus Publications
Scopus Publications
Mikhail V. Kiselevskiy, H. M. Treshalina, I. N. Mikhailova, D. V. Martirosyan, I. V. Manina, V. V. Reshetnikova, and I. G. Kozlov
SPb RAACI
Here, we review thematic publications in available literature sources of the databases PubMed, Scopus, Web of Science, eLibrary, 49 of which were dated of the years 19972022. Analysis of such reports is aimed at assessing features of cytokine storm-induced hyperinflammatory reaction with signs of immunosuppression accompanied by pronounced lymphopenia and lowered count of CD4+T helpers during severe COVID-19. The prognostic factor for unfavorable prognosis was based on the marker of systemic inflammatory reaction correlating with the disease severity the soluble IL-2 receptor as well as the neutrophil-to-lymphocyte ratio and the lymphocyte subset imbalance. An immunosuppressive therapy of severe forms of COVID-19, aimed at weakening the inflammatory response, exacerbates immune dysfunction by suppressing the T cell function, mainly due to Th1 lymphocytes involved in recognizing and eliminating intracellular pathogens particularly viruses. Upon that, cell-mediated immunity becomes compromised that relies on cytotoxic T-lymphocytes, natural killer cells and macrophages. Timely and targeted immunocorrection is required to prevent or reduce the immunosuppression that accompanies a severe disease course and leads to serious and prolonged complications, as well as to association of secondary infections. In fight against the cytokine storm, it is important not to miss a time point of developing immunosuppressive condition that transitions into immunoparalysis as follows from recent publications covering the tactics of treating immune-mediated complications of coronavirus infection. The review discusses opportunities for immunosuppressive therapy along with glucocorticosteroids and monoclonal antibodies blocking IL-6 or cognate receptors. Studies using mesenchymal stem cells (MSCs) to reduce systemic inflammatory response at COVID-19 are outlined in the review. The use of antigen-specific Treg and their combinations with antagonists of tumor necrosis factor- (TNF), interferon- (IFN) as well as low-dose IL-2 in patients with SARS-CoV-2 infection were analyzed. The prognostic perspectives for CAR-T cells and CAR-NK cells technology have been considered as novel therapeutic approaches aimed at training effector cells to recognize the surface SARS-CoV-2 virus spike-like (S) protein. The feasibility of a therapeutic approach is also emphasized by comparatively analyzed of efficacy of using IL-7 or IL-15 during lymphopenia in patients with COVID-19. Here, side effects complicating immunocorrection come to the fore. Critical evaluation of corrected immunosuppressive conditions in patients with COVID-19 in the post-COVID-19 period by using low-dose IL-2 therapy revealed its ability to repair cellular immune response. As a result, a low-dose IL-2 therapy is recommended as a cytokine replacement therapy in such patients with COVID-19 during hyper-to-hypo-inflammatory phase transition in immune response.
Michael I. Treshchalin, Vasilisa A. Polozkova, Elena I. Moiseenko, Helen M. Treshalina, Andrey E. Shchekotikhin, and Eleonora R. Pereverzeva
MDPI AG
Glycopeptide antibiotics have side effects that limit their clinical use. In view of this, the development of glycopeptides with improved chemotherapeutic properties remains the main direction in the search for new antibacterial drugs. The objective of this study was to evaluate the toxicological characteristics of new semi-synthetic glycopeptide flavancin. Acute and chronic toxicity of antibiotic was evaluated in Wistar rats. The medium lethal dose (LD50) and the maximum tolerated doses (MTD) were calculated by the method of Litchfield and Wilcoxon. In the chronic toxicity study, the treatment regimen consisted of 15 daily intraperitoneal injections using two dosage levels: 6 and 10 mg/kg/day. Total doses were equivalent to MTD or LD50 of flavancin, respectively. The study included assessment of the body weight, hematological parameters, blood biochemical parameters, urinalysis, and pathomorphological evaluation of the internal organs. The results of the study demonstrated that no clinical-laboratory signs of toxicity were found after 15 daily injections of flavancin at a total dose close to the MTD or LD50. The pathomorphological study did not reveal any lesions on the organ structure of animals after low-dose administration of flavancin. Thus, flavancin favorably differs in terms of toxicological properties from the glycopeptides currently used in the clinic.
H. M. Treshalina, M. A. Baryshnikova, E. V. Neborak, and V. S. Kosorukov
Publishing House ABV Press
Antitumor vaccines are aimed at correcting cellular immunity by overcoming immunological tolerance with eluding surveillance due to the specific presentation of tumor-associated or tumor-specific antigens to immunocompetent cells.The purpose of this review was to study modern strategies for the development of antitumor vaccines containing epitopes of HER2/neu receptors acting as tumor-associated antigens. Approaches to the creation of such vaccines are classified by targeting the T-cell link or B-cells by the choice and length of the epitopes used or by the use of specific adjuvants.The review provides information on this topic, obtained from more than 50 publications of the last 20 years, found in the most significant sources of citation. The text is categorized for the convenience of perception by scientists of different specialties and is completed with a brief conclusion with an emphasis on development prospects. The results of clinical studies of vaccines with an analysis of the immunological features of the results of immunotherapy, mainly breast cancer with HER2/neu expression, are considered. Vaccines targeting different histocompatibility complexes are compared. The review traces the evolution of vaccine preparations from the simplest containing short peptide sequences to complex combined systems, including viral vectors. Attention is paid to various methodological approaches used in the development of such drugs: from computer design and phage display in experiments in vitro/in vivo. The emphasis is placed on the problem of a personalized approach to vaccination of an oncological patient associated with a mutation process occurring inside tumors and leading to the appearance of unique tumor-associated antigens. The participation of complement system components in antibody-mediated lysis of tumor cells induced by the presented vaccines is discussed.Thus, the review introduces readers to the existing directions of creating immune drugs designed to suppress the development of the tumor process by activating the body’s own immune forces and the prospect of their development.
Michael I. Treshchalin, Helen M. Treshalina, Vasilisa A. Golibrodo, Andrey E. Shchekotikhin, and Eleonora R. Pereverzeva
MDPI AG
A new antitumor multi-target drug anthrafuran, with cellular targets such as topoisomerase I/II and some protein kinases, was obtained in Gause Institute of New Antibiotics and was demonstrated to have a reliable specific effect on different murine and human tumor models by oral administration. In this study, we focused on the evaluation of subchronic toxicity of oral anthrafuran drug formulation (AF) on Chinchilla rabbits. The absence of any changes in the condition or behavior of animals was shown for oral anthrafuran. Changes with reversible and dose-dependent hepato- and nephrotoxicity at low doses, as well as hemato- and gastrointestinal toxicity at high doses, were confirmed pathomorphologically. The identified toxic properties are extremely valuable, since oral anthrafuran does not have the limiting cardio- and myelotoxicity. Anthrafuran with 2 mg/kg/day or 6 mg/kg/day doses was administrated orally over 15 days. Investigations include assessment of the body weight, hematological and serum biochemical parameters and urinalysis, electrocardiography and pathomorphological evaluation of the internal organs. Quantitative data were processed statistically with Student’s t-Test, p < 0.05. Revealed during the subchronic study were the favorable toxicological properties of oral anthrafuran as opposed to clinical anthracyclines, oral idarubicin, or parenteral doxorubicin, which allows it to be considered promising for further research.
I. N. Mikhaylova, H. M. Treshalina, I. A. Utyashev, M. V. Kiselevsky, A. A. Lushnikova, and I. Zh. Shubina
Tomsk Cancer Research Institute
Purpose of the study: to analyze characteristics of cancer-testis antigens (Ctas) as potential biomarkers for dissemination of primary human skin melanoma (sm).Material and Methods. Recent publications from Pubmed, scopus and elibrary databases were analyzed for the available appropriate literature review. In total, 176 papers reported the description of Ctas and encoding genes and their potential for prognosis of primary sm dissemination. The authors included 52 of them in the given review.Results. Two sections of the paper comprise clinically significant characteristics of Ctas and their genes, including overexpression, which is selective for the heterogeneous tumor cell populations and mediated by humoral and/or cellular immune reactions; the association of tumor process and activation of Cta genes by demethylation of promotor sites, which is correlated with tumor progression; and the conditions required for effective immunotherapy involving Ctas and/or their genes.Conclusion. At present, there are no standards or clinical recommendations for the Cta-based prognosis of the early dissemination of primary skin melanoma. Therefore, it is important to study and analyze the Cta and encoding gene characteristics that reveal the connection between primary sm progression and tumor genesis including the role of circulating tumor cells (ctc), similar to stem cells, which have epithelial-mesenchymal transition (emt) phenotype, for clinical diagnostics of early sm dissemination. As a result of the study, the following Ctas could be considered as significant biomarkers of the early sm dissemination: mage-a1, mage-a4 and ny-eso-1, which expression correlates with the clinical pathological description of the disease progression, as well as with the relapse-free period and overall survival of the patients; magea3, which expression correlates with spag5 activation and Cd8+ t-cell abundance; ssx, a marker for stem cell migration including identification of the cells with emt and/or ctcs; and prame, signaling marker for dissemination of the uveal melanoma.
Andrey E. Shchekotikhin, Helen M. Treshalina, Michael I. Treshchalin, Eleonora R. Pereverzeva, Helen B. Isakova, and Alexander S. Tikhomirov
MDPI AG
The new antitumor agent anthrafuran has demonstrated a consistent effect in murine tumor models when administered parenterally due to the simultaneous inhibition of multiple cellular targets such as topoisomerases I/II and protein kinases. In this study, we assessed the anticancer efficiency and acute toxicity of anthrafuran administered orally. The action of anthrafuran was studied on transplanted tumor models which included P388 leukemia, Ca755 mammary adenocarcinoma, LLC lung carcinoma, and T47D human breast cancer xenografts on Balb/c nude mice. A significant antitumor efficacy of oral anthrafuran was revealed for all tested tumor models as follows: T/Cmax = 219% for P388, TGImax = 91% for Ca755, TGImax = 84% with CRmax = 54% for LLC, and T/C = 38% for T47D. The optimal treatment schedule of orally administered anthrafuran was 70–100 mg/kg given daily for five days. The LD50 value of orally administered anthrafuran (306.7 mg/kg) in mice was six times higher than that for i.p. administration (52.5 mg/kg). The rates of antitumor efficacy and acute toxicity indicate the high potential for further research on anthrafuran as a new original oral anticancer multitarget agent with an expected satisfactory tolerability and bioavailability.
I. N. Mikhaylova, N. M. Treshalina, I. Zh. Shubina, I. V. Manina, M. V. Kiselevsky, and A. N. Lukashev
Publishing House ABV Press
Imatinib mesilate (Glivec) is a well-known antitumor target inhibitor of protein tyrosine kinase, which is effective in different cancer types expressing Bcr / Abl and, in particular, in hemoblastosis. A higher interest to imatinib during the COVID-19 epidemic is explained by the fact that cancer patients are one of the COVID-19 risk groups. Moreover, imatinib target mechanism of action, which is effective in cancer, can have a high potential against the most severe COVID-19 complication such as the disease associated pulmonary fibrosis. COVID-19 associated interstitial pulmonary fibrosis develops as an autoimmune process caused by systemic inflammation with atypical (idiopathic) pneumonia resulting from acute respiratory distress syndrome with the tyrosine kinase mechanism of signaling pathway activation and cellular response. Experimental and clinical results showing antifibrotic and dose-related antithrombotic imatinib effect demonstrate perspective use of this antitumor agent to correct COVID-19 associated pneumonia causing a high death rate of patients with COVID-19.The review presents literature data of 2001–2020 discussing pathologic genetic and clinical characteristics of the fibrosis which exacerbates COVID-19 pneumonia in adults. The sequence of the disease processes demonstrates that disease progression with the decreasing oxygen saturation in the peripheral blood intensifies local thrombosis in the lungs. As a result, hypoxia is developing, which is difficult to control and can cause lethal outcome in severe cases. Yet, the conventional antifibrotic and thrombolytic agents can only partially control the process of pneumofibrosis including that of cancer patients. The approximate antifibrotic dose of imatinib 400 mg / day is therapeutic for oncopathology. The antitumor drug registered in many countries and well described side effects and contraindications needs no long-term registration studies for a new indication, therefore, it may be easily prepared for clinical testing.
Yelena Treshchalina, M. Lkunina, K. Makovetskaya, and A. Stanzhevskiy
Autonomous non-profit scientific and medical organization - Questions of Oncology
Introduction. For the treatment of primary inoperable and metastatic solid human tumors with local regional arterial blood flow, a minimally invasive embolization method is used, which causes a decrease in the growth rate and size of the malignancy (cytoreduction), local side effects of which depend on the viscosity of the embolizing agent. Nanostructured ferro- and ferrimagnetics (ferrites) allow selectively achieving not only cytoreduction, but also full effect by following the embolization of magnetic hyperthermia (MHT). Material and methods. The study of a new original embolizing nano-ferrimagnetic nanoembosil with low viscosity was performed with intra-arterial (i.a.) administration to anesthetized animals with intramuscular (i.m.) developed tumors (PC1 and VX2). This allowed us to evaluate its effectiveness using adequate criteria and the method of variation statistics (Fisher-Student’s criterion «t» in the environment of the IBM SPSS 21 package) and statistically significant differences at p≤0.05. Results and discussion. It is shown that nanoembosil in doses of 0.1 and 0.2 ml for rats and 1.5 ml for rabbits is dose-dependent, and in the case of VX2 it is statistically significant (p=0.001) for a long time in 2-6 times inhibits the rate of tumor growth without side effects with long-term stabilization and cytoreduction by 50-65%. Structural analogs of nanoembosil in the practice of medicine there. Conclusion. Thus, nanoembosil can be considered an original effective agent for selective arterial embolization and it is recommended to continue its preclinical study in therapeutic and preoperative modes. Good tolerance of i.a. administration of nanoembosil in the studied doses with no local side effects opens the possibility of studying the possibility of studying it as a thermo-sensitive nanomaterial for low-frequency MHT.
M. I. Treshchalin, E. V. Neborak, and H. M. Treshchalina
Tomsk Cancer Research Institute
Purpose of research: to identify the prospects of search for new antitumor non-camptothecin inhibitors of topoisomerase I/II among the various chemical compounds based on the analysis of side effects.Material and Methods. The analysis included 65 relevant literature sources for 2002–2018 years, found in Systems such as Scopus, Web of Science, Pubmed, and eLIBRARY.Results. The antitumor and side effect characteristics of the agents, associated with the selective suppression of the activity of type I and/or II topoisomerase (Top1, Top2) in tumor cells were emphasized. Examples of the relationship between side effects of inhibitors and their structure and catalytic mechanisms were given. The following factors were highlighted as significant: 1) blocking of cells in G2 and S phases with a delay of entry into mitosis; 2) inhibition of the reaction of re-ligation with DNA breaks without re-linking; 3) launching of cytotoxic events with the inhibition of DNA replication and generation of double-strand breaks. Incurable cancers, such as gastric cancer, colorectal cancer, non-small cell lung cancer, hepatocellular carcinoma, glioblastoma, etc. were determined as more sensitive to inhibitors. Side effects of treatment and their connection with the mechanism of activity were described.Conclusion. Based on the comparative analysis of prognostically valuable data regarding the efficacy and safety of topoisomerase I/II inhibitors, multitargeted heterocyclic condensed nitrogen-containing compounds, in particular, anthrafurans, can be considered as new promising clinical candidates with higher selectivity of action.
H. M. Treshalina, N. V. Andronova, J. R. Tcherkassova, E. Yu. Klinski, G. Babayeva, E. V. Lukasheva, M. I. Treshchalin, and S. A. Tsurkan
Tomsk Cancer Research Institute
Helen M. Treshalina, Vladimir I. Romanenko, Dmitry N. Kaluzhny, Michael I. Treshalin, Aleksey A. Nikitin, Alexander S. Tikhomirov, and Andrey E. Shchekotikhin
Elsevier BV
Janneta Tcherkassova, Sergei Tsurkan, Galina Smirnova, Julia Borisova, Ricardo Moro, and Helen Treshalina
IOS Press
The main objective of this study was the characterization of preclinical tumor models based on their expression of alpha-fetoprotein receptor (RECAF) for targeting cancer cells with a new non-covalent complex (AIMPILA) containing alpha-fetoprotein as the carrier and Atractyloside as an apoptosis-inducing agent. For that purpose, we measured the amount of RECAF in the homogenates of the grafted tumors T47D and SW620 and in HepG2 cell extracts. We also determined the alpha-fetoprotein binding specificity of the targeting drug AIMPILA using a solid-phase chemiluminescent assay with AIMPILA-Acrdidinium. We found that RECAF is practically absent from healthy mice tissues (100 Units/mg) where in malignant cells, the amount of alpha-fetoprotein receptors follows this order: T47D (9152 Units/mg) > HepG2 (4865 Units/mg) > SW620 (2839 Units/mg). This agrees with our findings regarding AIMPILA-induced tumor growth inhibition (T47D (T/C = 22%) > HepG2 (T/C = 51%) > SW620 (T/C = 70%), where T/C is the ratio of tumor volume in treated vs control animals). Our results demonstrate that the therapeutic response to the targeting drug AIMPILA strongly depends on the RECAF expression by human tumors and confirms the choice of the tumor models used for an AIMPILA preclinical study.
Anton Bonartsev, Anton Zernov, Sergey Yakovlev, Irina Zharkova, Vera Myshkina, Tatiana Mahina, Garina Bonartseva, Natalia Andronova, Galina Smirnova, Juliya Borisova,et al.
Bentham Science Publishers Ltd.
BACKGROUND
Poly(hydroxyalkanoates) (PHA) have recently attracted increasing attention due to their biodegradability and high biocompatibility, which makes them suitable for the development of new prolong drug formulations.
OBJECTIVE
This study was conducted to develop new prolong paclitaxel (PTX) formulation based on poly(3- hydroxybutyrate) (PHB) microparticles.
METHOD
PHB microparticles loaded with antitumor cytostatic drug PTX were obtained by spray-drying method using Nano Spray Dryer B-90. The PTX release kinetics in vitro from PHB microparticles and their cytotoxity on murine hepatoma cell line MH-22a were studied. Microparticles antitumor activity in vivo was studied using intraperitoneally (i.p.) transplanted tumor models: murine Lewis lung carcinoma and xenografts of human breast cancer RMG1.
RESULTS
Uniform PTX release from PHB-microparticles during 2 months was observed. PTX-loaded PHB microparticles have demonstrated a significant antitumor activity versus pure drug both in vitro in murine hepatoma cells and in vivo when administered i.p. to mice with murine Lewis lung carcinoma and xenografts of human breast cancer RMG1.
CONCLUSION
The developed technique of PTX sustained delivery from PHB-microparticles has therapeutic potential as prolong anticancer drug formulation.
Andrey E. Shchekotikhin, Lyubov G. Dezhenkova, Vladimir B. Tsvetkov, Yuri N. Luzikov, Yulia L. Volodina, Victor V. Tatarskiy, Anastasia A. Kalinina, Michael I. Treshalin, Helen M. Treshalina, Vladimir I. Romanenko,et al.
Elsevier BV
Kseniya Rubina, Ekaterina Surkova, Ekaterina Semina, Veronika Sysoeva, Natalia Kalinina, Alexei Poliakov, Helena Treshalina, and Vsevolod Tkachuk
MDPI AG
T-cadherin is a glycosyl-phosphatidylinositol (GPI) anchored member of the cadherin superfamily involved in the guidance of migrating cells. We have previously shown that in vivo T-cadherin overexpression leads to increased melanoma primary tumor growth due to the recruitment of mesenchymal stromal cells as well as the enhanced metastasis. Since tumor progression is highly dependent upon cell migration and invasion, the aim of the present study was to elucidate the mechanisms of T-cadherin participation in these processes. Herein we show that T-cadherin expression results in the increased invasive potential due to the upregulated expression of pro-oncogenic integrins, chemokines, adhesion molecules and extracellular matrix components. The detected increase in chemokine expression could be responsible for the stromal cell recruitment. At the same time our previous data demonstrated that T-cadherin expression inhibited neoangiogenesis in the primary tumors. We demonstrate that T-cadherin overexpression leads to the increase in the expression of anti-angiogenic molecules and reduction in pro-angiogenic factors. Thus, T-cadherin plays a dual role in melanoma growth and progression: T-cadherin expression results in anti-angiogenic effects in melanoma, however, this also stimulates transcription of genes responsible for migration and invasion of melanoma cells.
L.A. Osminkina, A.L. Nikolaev, A.P. Sviridov, N.V. Andronova, K.P. Tamarov, M.B. Gongalsky, A.A. Kudryavtsev, H.M. Treshalina, and V.Yu. Timoshenko
Elsevier BV
A. L. Nikolaev, A. V. Gopin, V. E. Bozhevol’nov, H. M. Treshalina, N. V. Andronova, I. V. Melikhov, D. V. Filonenko, S. E. Mazina, G. K. Gerasimova, E. V. Khorosheva,et al.
Pleiades Publishing Ltd
Andrey E. Shchekotikhin, Valeria A. Glazunova, Lyubov G. Dezhenkova, Yuri N. Luzikov, Vladimir N. Buyanov, Helena M. Treshalina, Nina A. Lesnaya, Vladimir I. Romanenko, Dmitry N. Kaluzhny, Jan Balzarini,et al.
Elsevier BV
Vadim S. Pokrovsky, Helen M. Treshalina, Elena V. Lukasheva, Ludmila A. Sedakova, Alexander G. Medentzev, Anna Yu. Arinbasarova, and Temirbolat T. Berezov
Ovid Technologies (Wolters Kluwer Health)
L-Lysine &agr;-oxidase (LO) from a novel Trichoderma strain: Trichoderma cf. aureoviride Rifai shows favorable biochemical and kinetic properties (Km for L-lysine of 17.9 µmol/l, optimum pH 8.0, high stability) and significant antiproliferative activity both in vitro and in vivo. The molecular weight of LO was determined to be 115–116 kDa; the active dimer consists of two identical 57–58 kDa subunits. LO shows considerable cytotoxicity against the following tumor cell lines: K562, LS174T, HT29, SCOV3, PC3, and MCF7, with the inhibition concentration (IC50) ranging from 3.0×10–6 to 7.8×10–2 U/ml (3.2×10–8 to 8.2×10–4 mg/ml). Two human colon cancer xenografts HCT116 and LS174T and breast adenocarcinoma T47D implanted subcutaneously into Balb/c nude mice showed high sensitivity to LO with a T/C of 12, 37, and 36%, respectively (P<0.05). The antitumor efficacy of LO was observed in the absence of pronounced morbidity or toxicity in vivo. Taken together, these data suggest that LO may be considered as an effective anticancer agent for the treatment of solid tumors in vivo. This study presents promising data on the possible application of LO in clinical oncology for patients with colorectal cancer.
E.V. Lukasheva, A.A. Efremova, E.M. Treshalina, A.Ju. Arinbasarova, A.G. Medentzev, and T.T. Berezov
Institute of Biochemistry
During previous decade L-amino acid oxidases (LAAO) attracted the steady interest of researchers due to their poly functional effects on different biological systems. The review summarizes information concerning the sources, structure, phisico-chemical and catalytical properties of LAAO which exhibit antibacterial, antifungal, antiprotozoal, antiviral effects as well as the ambiguous action on platelet aggregation. Special attention is devoted to the elucidation of molecular mechanisms of LAAO action. It is proposed that the unique properties of LAAO are based on their catalytic reaction, which causes the decrease of L-amino acid levels, including the essential amino acids and formation of hydrogen peroxide. The action of liberated H2O2 on cells involves the synthesis of oxygen reactive species and the development of necrotic and apoptotic pathways of cell death. The presence of carbohydrate moieties in LAAO molecules promotes their attachment to cell's surface and creation of high H2O2 local concentrations. The wide range of LAAO biological effects is undoubtedly connected with their important functional roles in the organism. In particular, it was shown that in the mice brain the LAAO-catalyzed reaction is the single pathway of L-lysine degradation, while in the mice milk LAAO carry out the antibacterial effect and in human leucocytes LAAO take part in fulfilling their defending role. Protector action may be also attributed to the oxidases from the other numerous sources: microscopic fungi, snake venoms and sea inhabitants.
E. V. Lukasheva, A. A. Efremova, E. M. Treshalina, A. Yu. Arinbasarova, A. G. Medentzev, and T. T. Berezov
Pleiades Publishing Ltd
M. N. Yakunina and E. M. Treshalina
Springer Science and Business Media LLC