Zenoviy Tkachuk

Institute of Molecular Biology and Genetics

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Nataliia Melnichuk

Institute of Molecular Biology and Genetics

Tetiana Marchyshak

Institute of Molecular Biology and Genetics

ВИ

В. И. Кашуба

Karolinska Institutet

Tetiana Yakovenko

Research Institute of Obstetrics and Gynecology named after D.O. Ott

Volodymyr Shchodryi

Institute of Molecular Biology and Genetics

Natalia Melnichuk

Institute of Molecular Biology and Genetics

O.D. Kachkovsky

Institute of Bioorganic Chemistry and Petrochemistry V.P. Kukhar

Nataliya Obernikhina

Bogomolets National Medical University

L. I. Semernikova

Institute of Molecular Biology and Genetics

Igor O. Shmarakov

Rutgers, The State University of New Jersey

Cooperative Institutions

National Academy of Sciences of Ukraine

Institute of Molecular Biology and Genetics

Institute for Single Crystals

Taras Shevchenko National University of Kyiv

Institute of Organic Chemistry

Institute of Bioorganic Chemistry and Petrochemistry V.P. Kukhar

Danylo Zabolotny Institute of Microbiology and Virology

Kyiv City Clinical Oncology Center

Institutul de Chimie Macromoleculară Petru Poni

Romanian Academy

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Gene expression profile in peripheral blood cells of patients with COVID-19

Proceedings of 7th International Electronic Conference on Medicinal Chemistry (2020)

Nataliia Melnichuk Viktor Liashko В. И. Кашуба Zenoviy Tkachuk

The clinical course of coronavirus disease 2019 (COVID‐19) varies from mild symptoms to acute respiratory distress syndrome, hyperinflammation, and coagulation disorder. The hematopoietic system plays a critical role in the observed hyperinflammation, particularly in severely ill patients. Using peripheral blood cells (PBCs) for gene expression analysis is valuable to evaluate disease-associated and drug-response related genes. In this study, we aimed to explore the gene expression profile of PBCs in patients with COVID‐19. Material & methods. Whole blood samples were collected from 19 patients with acute COVID‐19 infection and 20 healthy volunteers. The gene expression of PBCs was determined by RT-qPCR. Results. We investigated the expression of cytokines, chemokines, interferon-stimulated pro-oxidation, and coagulation genes in PBCs of the infected and healthy samples. Up-regulated expression of some genes was found out in the blood of COVID‐19-infected patients compared to the healthy sample. Conclusions: We have identified some genes in whole blood that classifies COVID‐19-infected and healthy patients with good accuracy. These results suggested that the expression of cytokines, coagulation, and interferon-stimulated genes in PBCs can be used for early detection of hyperinflammation, coagulation disorders, and evaluation of efficiency treatment of this disease.

10.3390/ecmc2020-07298

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<strong>Antiviral Activity of a Substance from Yeast RNA</strong>

Anna Golovan Kristina Naumenko Natalia Melnichuk Г. В. Баранова Zenoviy Tkachuk

Inhibition of virus-cell interactions, which are required for virus replication, constitutes an exciting area of research for the discovery of novel antiviral agents. RNA based drugs are in clinical use for treatment of infectious diseases as immunomodulators, anti-inflammatory and antiviral agents. Nuclex, a low molecular weight exogenous yeast RNA, consists of a pure, homogeneous 25-membered oligonucleotide. The preventive and therapeutic effects of Nuclex were demonstrated against pandemic strains of influenza virus, parainfluenza virus, Hepatitis C, Herpes simplex virus types 1 and 2, cytomegalovirus, and HIV on experimental models in vitro and in vivo. The mechanism of the antiviral action of the drug relies on its ability to change conformations of cell regulatory proteins and viral coat proteins. An antiviral effect of Nuclex against Epstein-Barr virus (EBV) etiological agent of infectious mononucleosis associated with a number of lymphoproliferative and autoimmune diseases was studied in this work. The study was performed with EBV-positive human B-cells (Raji) – latently infected with EBV, and EBV-producing tamarin (Saguinus oedipus) B-cell line (B95-8). The drug cytotoxicity was assessed by MTT-method. As a result of investigations it was found that the drug has low toxicity relative to both lymphoblastoid cell cultures. The inhibitory concentrations suppressing 10% of cell viability (IC10) were 2000 µg/ml and IC50s (50% inhibited cell viability) were 5000 µg/ml for both cell lines. An antiviral activity of Nuclex was measured by PCR in EBV infected cells Raji, as a model of acute infection and in non-induced B95-8 cells as a model of chronic EBV infection after 48 hours incubation. The drug effectively inhibited viral replication in the studied concentration range from 10 to 500 µg/ml in EBV-infected Raji cells and B95-8 cells. Effective concentration of Nuclex that inhibited 90% level of the viral DNA accumulation (EC90) was 50 µg/ml for in both cell lines. A virucidal activity of the drug was investigated considering the ability of Nuclex to influence the conformation of the viral surface proteins. The levels of inhibition of the EBV DNA accumulation were 30% after incubation of the drug at the concentration 100 µg/ml with the EBV for the 30 and 60 min exposures and the subsequent infection of Raji cells incubated for 48 hours, while 50% inhibition of viral DNA accumulation was observed at the drug concentration 200 µg/ml under 30 min exposure and 30% at 60 min exposure. Thus Nuclex showed a strong antiviral effect against EBV. Considering an antiviral activity of the drug (EC90) at 50 µg/ml, and a virucidal action EC50 at 200 µg/ml, determination of its mechanism of action, which could be related to siRNA properties, will constitute the next stage of our research.

Raji cell

Antiviral drug

Viability assay

10.3390/ecmc-2-a025

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The influence of oligoribonucleotide complexes with D-mannitol on tumor formation in a murine model of B16 melanoma

Proceedings of 7th International Electronic Conference on Medicinal Chemistry (2019)

Ivanna Kraievska Zenoviy Tkachuk I. M. Vagina G. V. Gerashchenko Tetiana Yakovenko

Malignant melanoma is considered to be one of the most aggressive forms of skin cancer - about 80% of skin cancer deaths are associated with this disease. Because melanoma is an immunogenic tumor, effective treatment is based on strategies to enhance the body's immune response. Recent studies have shown that oligoribonucleotides-D-mannitol (ORNs-D-M) complexes possess exhibit in particular antiviral, anti-inflammatory and immunomodulatory actions due to the activation of immune responses. Given the wide range of biological effects, we aimed to investigate the effect of ORNs-D-M on the development of B16 melanoma in mice by controlling tumor growth and genetic analysis of marker genes. Methods. Adult female mice of a C57BL/6J line were used. Suspension of B16 mouse melanoma cell was subcutaneously introduced into the right posterior paw. For the experimental groups, the ORNs-D-M solution (in PBS) was injected once at concentrations of 1.4; 0.7; 0.35; 0.175 mg on animal. The control group received 100 μl of PBS. Tumor size was monitored during the experiment. Expression of T-cell markers (CD3, CD4, CD8, CD247), macrophage markers (CD68, CD163, NOS2), immunotherapy target genes (PDCD1, CD274, CTLA4, CTLA4 / del) and cytokine (IFNB1) were evaluated by real-time qPCR assay in peripheral blood of mice. Results. Our investigations show that different concentrations of ORNs-D-M have the opposite effect on the growth of melanoma B16 tumors. In the group where animals received 1.4 mg of ORNs-D-M, the formation of the solid tumors was not observed; however, in the group with 0.7 mg dose, the average tumor volume was 97% lower than the non-drug group. In the case of lower concentrations, the average tumor size was 2-3 times higher than in the non-drug group. Also, we observed the changes in the expression of major marker genes. The mRNA expression levels of markers of T-cell counts CD3, CD4, CD8, and CD247, in groups with high concentrations of ORNs-D-M approached those of healthy animals. However, in mice, bearing melanoma recorded a decrease in mRNA levels of these genes. As well ORNs-D-M increases in the immune response to cancer and generally decreases the level of immunosuppression, which reflect in the increased expression of CD274, PDCD1, and IFNB1.

10.3390/ecmc2019-06329

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Effect of oligoribonucleotides with D-mannitol complexes on oxidative stress indicators against thioacetamide-induced liver fibrosis

ScienceRise Biological Science (2020)

Tetiana Marchyshak Tetiana Yakovenko Zenoviy Tkachuk

The aim of the study. To determine the effect of oligoribonucleotides-D-mannitol complexes (ORN-D-M) on the indicators of oxidative destruction of biomolecules and the antioxidant system of cells in thioacetamide (TAA)-induced liver fibrosis.Materials and methods. Liver fibrosis was induced for 8 weeks by intraperitoneal administration of TAA (150 mg/kg body weight). ORN-D-M (200 mg/kg per os) was administered orally during intoxication. At the end of the experiment, the liver was excised and examined for the content of oxidative stress products and the activity of antioxidant enzymes. Data were analyzed using the ANOVA test followed by Tukey post hoc testing.Results. It is shown that the monotherapeutic treatment of ORN-D-M in TAA-induced liver fibrosis has a pronounced protective effect, which is manifested in the reduction of oxidative stress. ORN-D-M led to the attenuation of free radical damage of biopolymers, which was manifested in a decrease in the levels of peroxidation products of lipids and proteins with a simultaneous increase in the level of protein thiol groups and reduced glutathione. In addition, treatment with complexes increased the activity of the antioxidant defence system of cells.Conclusions. The obtained results indicate that ORN-D-M complexes have a potential hepatoprotective effect in TAA-induced liver fibrosis. The complexes are able to effectively reduce the indicators of oxidative damage of biomolecules with a simultaneous increase in the activity of enzymes of the antioxidant system in TAA-induced fibrosis

Thioacetamide

10.15587/2519-8025.2020.214418

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Hepatoprotective and antioxidant effects of oligoribonucleotides-D-mannitol complexes against thioacetamide-induced liver fibrosis

Proceedings of 7th International Electronic Conference on Medicinal Chemistry (2018)

Tetiana Marchyshak Zenoviy Tkachuk L. I. Semernikova Tetiana Yakovenko

Aim: Hepatic fibrosis is a common consequence of chronic liver injury caused by a variety of etiological factors. It is associated with inflammation, oxidative stress, necrosis and ends with cirrhosis, liver cancer, or liver failure. Oligoribonucleotides-D-mannitol complexes (ORNs-D-M) display a vast spectrum of biological effects, including cellular metabolism stimulation with activation of endogenous synthesis of regulatory proteins, stimulation of reparation processes. Therefore, the aim of this study was to investigate the protective effect of the ORNs-D-M on liver fibrosis. Materials and methods: Mice received thioacetamide (TAA) (200 mg/kg, intraperitoneal) thrice weekly, for 8 successive weeks to induce liver fibrosis. The ОRNs-D-M (200 mg/kg, per os) was administered orally during TAA intoxication. Body weights and mortality mice were assessed during the experiment. At the end of the experiment, oxidative stress, inflammatory and profibrogenic markers were evaluated. Results: The results of the research showed that treatment with the ORNs-D-M attenuated TAA-induced liver fibrosis in mice. The ORNs-D-M prevented TAA oxidative stress. The ORNs-D-M decreased TBA-reactive substances, carbonyl derivatives levels and myeloperoxidase activity by 60.6, 35 and 52% respectively in comparison to control thioacetamide in the liver cells. In addition, these complexes increased protein and non-protein thiol groups levels, and glutathione-S-transferase and glutathione peroxidase activities compared to the TAA-treated mice. During TAA-induced liver fibrosis, it was investigated that the ORNs-D-M reduced the expression mRNA level of pro-inflammatory (IL-6, TNF-α) genes by 40 and 56 % respectively, compared to the mice with TAA. Furthermore, the ORNs-D-M suppressed the HSCs/myofibroblasts activation by reduced expression of markers α-SMA, COL-1, and TGF-β1 in the liver. Conclusion: The ORNs-D-M could ameliorate the effects of TAA-induced liver fibrosis in mice by inhibiting oxidative stress, expressions of pro-inflammatory cytokines and profibrotic markers.

Thioacetamide

Centrilobular necrosis

10.3390/ecmc-4-05624

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Molecular docking study of oligonucleotides with D-mannitol

Visnik ukrains kogo tovaristva genetikiv i selekcioneriv (2017)

Volodymyr Shchodryi Д. М. Ложко Zenoviy Tkachuk

Aim. Complex of yeast RNA and D-mannitol has a specific antiviral activity. This complex inhibits the neuraminidase and hemagglutinin activity of viruses such as influenza, parainfluenza and thus it blocks virus entry into the cell and his replication. So, nowadays, study of the interaction of this compound is an important task. Study interaction of the oligoribonucleotides and oligodesoxynucleotides with D mannitol molecule. Methods. Molecular modeling structure of oligoribonucleotides and oligodesoxynucleotides were done by using «Hyperchem» software package. The AutoDock program was used to perform accuracy molecular docking. Results. Were obtained binding energies of D-mannitol molecule with oligoribonucleotides and oligodesoxynucleotides. We have shown the possible connections between atoms of oligonucleotides and D-mannitol molecule. Conclusions. The modeling results should give more detailed information about nature of the oligonucleotides binding with a shugar alcohol D-mannitol.Keywords: molecular docking, oligonucleotides, D-mannitol, binding energies.

Docking (animal)

AutoDock

10.7124/visnyk.utgis.15.1.714

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The Potential Protective Effect of Oligoribonucleotides-d-Mannitol Complexes against Thioacetamide-Induced Hepatotoxicity in Mice

Pharmaceuticals (2018)

Tetiana Marchyshak Tetiana Yakovenko Igor O. Shmarakov Zenoviy Tkachuk

This study investigated the potential hepatoprotective effect of oligoribonucleotides-d-mannitol complexes (ORNs-d-M) against thioacetamide (TAA)-induced hepatotoxicity in mice. The hepatoprotective activity of ORNs-d-M was evaluated in thioacetamide (TAA)-treated C57BL/6J. Results indicate that treatment with ORNs-d-M displayed a protective effect at the TAA-induced liver injury. Treatment with ORNs-d-M, starting at 0 h after the administration of TAA, decreased TAA-elevated serum alanine aminotransferase (ALT) and γ-glutamyl transpeptidase (GGT). Activities of glutathione S-transferase (GST) and glutathione peroxidase (GPx), and levels of glutathione (GSH), were enhanced with ORNs-d-M administration, while the hepatic oxidative biomarkers (TBA-reactive substances, protein carbonyl derivatives, protein-SH group) and myeloperoxidase (MPO) activity were reduced. Furthermore, genetic analysis has shown that the ORNs-d-M decreases the expression of mRNA pro-inflammatory cytokines, such as tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6), profibrogenic cytokine-transforming growth factor β1 (TGF-β1), as well as the principal protein of the extracellular matrix-collagen I. The present study demonstrates that ORNs-d-M exerts a protective effect against TAA-induced liver injury, which may be associated with its anti-inflammatory effects, inhibition of overexpression of mRNA cytokines, and direct effects on the metabolism of the toxin.

Thioacetamide

10.3390/ph11030077

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IDENTIFICATION OF CLINICALLY RELEVANT GENE VARIANTS IN COLON ADENOCARCINOMA SAMPLES OF UKRAINIAN PATIENTS USING A COMPREHENSIVE CANCER PANEL: A PILOT STUDY

Experimental Oncology (2024)

G. V. Gerashchenko R. V. Gulkovskyi Nataliia Melnichuk N. V. Hryshchenko Tetiana Marchyshak

The study aimed to identify the clinically relevant gene variants in colon adenocarcinoma samples of Ukrainian patients using the NGS Comprehensive Cancer Panel (CCP) to implement them conveniently in clinical practice. Methods. We have studied 20 samples of Ukrainian patients with colorectal adenocarcinomas of various differentiation grades. To identify the clinically relevant gene variants, the CCP data were filtered using the Franklin by Genoox database. Results. A total of 79 clinically relevant gene variant alterations (SNVs, INDELs) were found in 28 of 409 genes. The largest number of mutations was found in 3 genes, APC, TP53, and KRAS (16, 14, and 8, accordingly). We revealed 4 variants in PTEN and SMAD4, 3 variants in CHEK2, ERBB2, and PIK3CA genes, and 2 variants in AKT1, ATM, DST, IDH1, and TCF12. Mutations for 7 genes, KRAS, TP53, CHEK2, PTEN, AKT1, APC, and SMAD4, were found in more than 1 tumor tissue sample. Tier 1—2 gene variants rate was about 50% of all genetic variants. The therapeutic significance was found in more than 55% of mutations. Additionally, 11 novel genetic mutations in 9 genes have been identified, including G6PD, APC, DST, SINE1, SMAD2, and FLCN. Conclusions. These data suggest a high level of clinical relevance of the NGS CCP approach. Further confirmation on a larger number of samples and using a deeper analysis by other approaches is required.

CHEK2

Indel

10.15407/exp-oncology.2024.03.221

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Fluorescent Probe for Investigation of Influence of Ribonucleosides With D–Mannitol

Volodymyr Shchodryi Nataliya Obernikhina Ye. Shaydyk O.D. Kachkovsky Slominskiy Yu.

We have studied the interaction of ribonucleosides with D-mannitol and D-sorbitol using a fluorescent probe with fluorescent dye. Decreasing of intensity of fluorescence in solution during the titration of fluorescent dye with solutions of ribonucleosides (RN) and complexation of ribonucleosides with D-mannitol (RNM) were clearly observed. Fluorescence quenching in the RNM complex is less when compare with solution of ribonucleosides. We have shown these differences in spectral characteristics of ribonucleosides and complex RNM with a dye. The results may indicate the different interaction of D-mannitol with nucleosides. Such a different interaction is due to the structure of D-mannitol and D-sorbitol. Interaction is probably made with formation two hydrogen bonds between hydrogens of two parallel hydroxy (O-H) groups of D-mannitol and/or centers of hydrogen bonding in heterocyclic of nucleosides.

10.1109/elnano.2019.8783955

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336P Determination of the most common hereditary mutations associated with breast cancer and ovarian cancer in the population of Ukrainian women

Annals of Oncology (2024)

D. Nehrulia Dmytro Shapochka D. Dekar A. Fesenko N. Shtefan

Ukrainian

10.1016/j.annonc.2024.08.275

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