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42 Publications visible to you, out of a total of 42
Transcriptome alterations in long-term mining region residents: Insights into immune response and molecular pathways.

Abstract (Expand)

Pollution with metals and metalloids is a global problem that adversely affects human health and environment. Although several studies have reported gene expression changes in response to human exposures … to metals, there are a limited number of studies exploring the effect of long-term residence in mining areas. The evidence of increased levels of several essential and non-essential metals in soil, water, and plants in Kapan mining area (Armenia) has been previously demonstrated in several environmental studies. Our study investigated the impact of long-term residence in this mining area on the transcriptome state of human peripheral blood mononuclear cells and the possible association of transcriptome changes with the blood metallome. In total, 58 participants including 27 mining region residents (MRR) and 31 non-mining region residents (NMR) were selected for our study. Transcriptomic analysis of peripheral blood mononuclear cells was performed by mRNA sequencing. Differential expression analyses were conducted using generalized linear modeling, optimized for participant demographics, cell types, and sequencing technical factors, followed by pathway analysis. The study revealed that long-term residence in a mining area is correlated with alterations in the blood transcriptome, with responses varying by sex. The identified transcriptome changes were enriched for pathways related to immune response and RNA translation. These changes correlated with higher blood levels of a mixture of non-essential metals, including arsenic, antimony, nickel, thallium, and beryllium. Additionally, the study identified differences in the transcriptome response between male and female MRR. While females exhibited a stronger immune response, males show dysregulation in ion transport and epigenetic modifications. Our findings contribute to understanding the effects of long-term residence in mining regions and can aid in developing more effective risk assessment and mitigation approaches in target populations.

Authors: A. Stepanyan, A. Arakelyan, J. Schug

Date Published: 24th Mar 2025

Publication Type: Journal

Molecular Epidemiology and In-Depth Characterization of Klebsiella pneumoniae Clinical Isolates from Armenia

Abstract (Expand)

The global dissemination of Klebsiella pneumoniae pathotypes with multidrug-resistant (MDR) and hypervirulent traits poses a threat to public health. The situation in Armenia is unclear, and we performed … a comprehensive characterisation of 48 clinical isolates of K. pneumoniae, collected from 2018 to 2024. The majority of the isolates (64.58%) were extensively drug-resistant (XDR) and MDR. Genomic analysis of 21 isolates revealed the presence of international high-risk MDR clones (ST395, ST15, and ST307). The ST395 strains were isolated from children and resisted the first-line drugs such as beta-lactams. These isolates harboured a range of virulence determinants, from capsule polysaccharides to siderophores to regulators of the mucoid phenotype. The ST395 strains are enriched by ICEs, plasmids, and prophages, on which antimicrobial resistance (AMR) and virulence genes are located and which may lead to the convergence of MDR and hypervirulent traits. There is a widespread non-specific AMR mechanism among our K. pneumoniae strains. These are mutations in the porin genes, which reduce permeability to antimicrobials, and mutations in the regulators of efflux pumps, which lead to overexpression of drug efflux pumps such as AcrAB. These mechanisms may contribute to the elevated MICs and confer AMR to strains with no specific AMR genes.

Authors: Anahit Sedrakyan, Zaruhi Gevorgyan, Magdalina Zakharyan, Karine Arakelova, Shoghik Hakobyan, Alvard Hovhannisyan, Rustam Aminov

Date Published: 9th Jan 2025

Publication Type: Journal

Targeting SARS-CoV-2 main protease: a comprehensive approach using advanced virtual screening, molecular dynamics, and in vitro validation.

Abstract (Expand)

The COVID-19 pandemic, driven by the SARS-CoV-2 virus, necessitates the development of effective therapeutics. The main protease of the virus, Mpro, is a key target due to its crucial role in viral … replication. Our study presents a novel approach combining ligand-based pharmacophore modeling with structure-based advanced virtual screening to identify potential inhibitors of Mpro. We screened around 200 million compounds using this integrated methodology, resulting in a shortlist of promising compounds. These were further scrutinized through molecular dynamics simulations, revealing their interaction dynamics with Mpro. Subsequent in vitro assays using the Mpro enzyme identified two compounds exhibiting significant micromolar inhibitory activity. These findings provide valuable scaffolds for the development of advanced therapeutics targeting Mpro. The comprehensive nature of our approach, spanning computational predictions to experimental validations, offers a robust pathway for rapid and efficient identification of potential drug candidates against COVID-19.

Authors: Smbat Gevorgyan, Hamlet Khachatryan, Anastasiya Shavina, Sajjad Gharaghani, Hovakim Zakaryan

Date Published: 21st Dec 2024

Publication Type: Journal

Computational evaluation and benchmark study of 342 crystallographic holo-structures of SARS-CoV-2 Mpro enzyme.

Abstract (Expand)

The coronavirus disease 19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to a global health crisis with millions of confirmed cases and related deaths. The … main protease (Mpro) of SARS-CoV-2 is crucial for viral replication and presents an attractive target for drug development. Despite the approval of some drugs, the search for effective treatments continues. In this study, we systematically evaluated 342 holo-crystal structures of Mpro to identify optimal conformations for structure-based virtual screening (SBVS). Our analysis revealed limited structural flexibility among the structures. Three docking programs, AutoDock Vina, rDock, and Glide were employed to assess the efficiency of virtual screening, revealing diverse performances across selected Mpro structures. We found that the structures 5RHE, 7DDC, and 7DPU (PDB Ids) consistently displayed the lowest EF, AUC, and BEDROCK scores. Furthermore, these structures demonstrated the worst pose prediction results in all docking programs. Two structural differences contribute to variations in docking performance: the absence of the S1 subsite in 7DDC and 7DPU, and the presence of a subpocket in the S2 subsite of 7DDC, 7DPU, and 5RHE. These findings underscore the importance of selecting appropriate Mpro conformations for SBVS, providing valuable insights for advancing drug discovery efforts.

Authors: Hamlet Khachatryan, Mher Matevosyan, Vardan Harutyunyan, Smbat Gevorgyan, Anastasiya Shavina, Irina Tirosyan, Yeva Gabrielyan, Marusya Ayvazyan, Marine Bozdaganyan, Zeynab Fakhar, Sajjad Gharaghani, Hovakim Zakaryan

Date Published: 20th Jun 2024

Publication Type: Journal

Temporal changes of gene expression in health, schizophrenia, bipolar disorder, and major depressive disorder.

Abstract (Expand)

The molecular events underlying the development, manifestation, and course of schizophrenia, bipolar disorder, and major depressive disorder span from embryonic life to advanced age. However, little … is known about the early dynamics of gene expression in these disorders due to their relatively late manifestation. To address this, we conducted a secondary analysis of post-mortem prefrontal cortex datasets using bioinformatics and machine learning techniques to identify differentially expressed gene modules associated with aging and the diseases, determine their time-perturbation points, and assess enrichment with expression quantitative trait loci (eQTL) genes. Our findings revealed early, mid, and late deregulation of expression of functional gene modules involved in neurodevelopment, plasticity, homeostasis, and immune response. This supports the hypothesis that multiple hits throughout life contribute to disease manifestation rather than a single early-life event. Moreover, the time-perturbed functional gene modules were associated with genetic loci affecting gene expression, highlighting the role of genetic factors in gene expression dynamics and the development of disease phenotypes. Our findings emphasize the importance of investigating time-dependent perturbations in gene expression before the age of onset in elucidating the molecular mechanisms of psychiatric disorders.

Authors: A. Arakelyan, S. Avagyan, A. Kurnosov, T. Mkrtchyan, G. Mkrtchyan, R. Zakharyan, K. R. Mayilyan, H. Binder

Date Published: 17th Feb 2024

Publication Type: Journal

Temporal changes of gene expression in health, schizophrenia, bipolar disorder, and major depressive disorder

Abstract (Expand)

The molecular events underlying the development, manifestation, and course of schizophrenia, bipolar disorder, and major depressive disorder span from embryonic life to advanced age. However, little … is known about the early dynamics of gene expression in these disorders due to their relatively late manifestation. To address this, we conducted a secondary analysis of post-mortem prefrontal cortex datasets using bioinformatics and machine learning techniques to identify differentially expressed gene modules associated with aging and the diseases, determine their time-perturbation points, and assess enrichment with expression quantitative trait loci (eQTL) genes. Our findings revealed early, mid, and late deregulation of expression of functional gene modules involved in neurodevelopment, plasticity, homeostasis, and immune response. This supports the hypothesis that multiple hits throughout life contribute to disease manifestation rather than a single early-life event. Moreover, the time-perturbed functional gene modules were associated with genetic loci affecting gene expression, highlighting the role of genetic factors in gene expression dynamics and the development of disease phenotypes. Our findings emphasize the importance of investigating time-dependent perturbations in gene expression before the age of onset in elucidating the molecular mechanisms of psychiatric disorders.

Authors: Arsen Arakelyan, Susanna Avagyan, Aleksey Kurnosov, Tigran Mkrtchyan, Gohar Mkrtchyan, Roksana Zakharyan, Karine R. Mayilyan, Hans Binder

Date Published: 17th Feb 2024

Publication Type: Journal

Development of an optimized, non‐stem cell line for intranasal delivery of therapeutic cargo to the central nervous system

Abstract (Expand)

Neural stem cells (NSCs) are considered to be valuable candidates for delivering a variety of anti-cancer agents, including oncolytic viruses, to brain tumors. However, owing to the previously reported … tumorigenic potential of NSC cell lines after intranasal administration (INA), here we identified the human hepatic stellate cell line LX-2 as a cell type capable of longer resistance to replication of oncolytic adenoviruses (OAVs) as a therapeutic cargo, and that is non-tumorigenic after INA. Our data show that LX-2 cells can longer withstand the OAV XVir-N-31 replication and oncolysis than NSCs. By selecting the highly migratory cell population out of LX-2, an offspring cell line with a higher and more stable capability to migrate was generated. Additionally, as a safety backup, we applied genomic herpes simplex virus thymidine kinase (HSV-TK) integration into LX-2, leading to high vulnerability to ganciclovir (GCV). Histopathological analyses confirmed the absence of neoplasia in the respiratory tracts and brains of immuno-compromised mice 3 months after INA of LX-2 cells. Our data suggest that LX-2 is a novel, robust, and safe cell line for delivering anti-cancer and other therapeutic agents to the brain.

Authors: Ali El‐Ayoubi, Arsen Arakelyan, Moritz Klawitter, Luisa Merk, Siras Hakobyan, Irene Gonzalez‐Menendez, Leticia Quintanilla Fend, Per Sonne Holm, Wolfgang Mikulits, Matthias Schwab, Lusine Danielyan, Ulrike Naumann

Date Published: 26th Dec 2023

Publication Type: Journal

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