Transcriptome-Guided Drug Repositioning

Arakelyan, Arsen; Nersisyan, Lilit; Nikoghosyan, Maria; Hakobyan, Siras; Simonyan, Arman; Hopp, Lydia; Loeffler‐Wirth, Henry; Binder, Hans

doi:10.3390/pharmaceutics11120677

Cited by 17 publications

(18 citation statements)

References 83 publications

(119 reference statements)

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“…Transcriptome analysis was performed using a multi-layer self-organizing maps (SOM) machine learning approach described in detail previously [ 74 , 75 , 78 , 79 ]. In the present study, we performed two-layer training, each containing the transcriptomic dataset from one TCGA project.…”

Section: Methodsmentioning

confidence: 99%

“…The metagene expression values of each sample are visualized (expression portrayal) by arranging them into a two-dimensional 45 × 45 grid and by using maroon to blue colors for maximum to minimum expression values in each of the portraits. Multi-layer SOM ensures that each of the layers is projected into identical SOM-space formed of metagenes that contain the same single genes at the same position of the metagene-grid in each of the layers, which made them directly comparable across the layers [ 79 ].…”

Section: Methodsmentioning

confidence: 99%

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Transcriptome Patterns of BRCA1- and BRCA2- Mutated Breast and Ovarian Cancers

Arakelyan

Melkonyan

Hakobyan

et al. 2021

IJMS

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Mutations in the BRCA1 and BRCA2 genes are known risk factors and drivers of breast and ovarian cancers. So far, few studies have been focused on understanding the differences in transcriptome and functional landscapes associated with the disease (breast vs. ovarian cancers), gene (BRCA1 vs. BRCA2), and mutation type (germline vs. somatic). In this study, we were aimed at systemic evaluation of the association of BRCA1 and BRCA2 germline and somatic mutations with gene expression, disease clinical features, outcome, and treatment. We performed BRCA1/2 mutation centered RNA-seq data analysis of breast and ovarian cancers from the TCGA repository using transcriptome and phenotype “portrayal” with multi-layer self-organizing maps and functional annotation. The results revealed considerable differences in BRCA1- and BRCA2-dependent transcriptome landscapes in the studied cancers. Furthermore, our data indicated that somatic and germline mutations for both genes are characterized by deregulation of different biological functions and differential associations with phenotype characteristics and poly(ADP-ribose) polymerase (PARP)-inhibitor gene signatures. Overall, this study demonstrates considerable variation in transcriptomic landscapes of breast and ovarian cancers associated with the affected gene (BRCA1 vs. BRCA2), as well as the mutation type (somatic vs. germline). These results warrant further investigations with larger groups of mutation carriers aimed at refining the understanding of molecular mechanisms of breast and ovarian cancers.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Transcriptome Patterns of BRCA1- and BRCA2- Mutated Breast and Ovarian Cancers

Arakelyan

Melkonyan

Hakobyan

et al. 2021

IJMS

Self Cite

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“…Repurposed drugs are generally safe and have no associated adverse side effects. Drug repurposing research is a big data-driven task that highly relies on bioinformatics and chemical informatics [15,16]. Researchers use computer programs to analyze gene profiles, and then match the small compounds in the database.…”

Section: Ivyspring International Publishermentioning

confidence: 99%

Glucocorticoids improve severe or critical COVID-19 by activating ACE2 and reducing IL-6 levels

Xiang¹,

Liu²,

Shi³

et al. 2020

Int. J. Biol. Sci.

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COVID-19 is a public health emergency that has rapidly spread to over 200 countries and regions, and no effective treatment has been established to date. Severe and critical cases have been associated with higher mortality due to acute respiratory distress syndrome (ARDS) and cytokine storm. Based on the novelty and recent emergence of COVID-19, no effective treatment regimen has been identified, thus prompting clinicians to engage in drug repurposing to address the immediate therapeutic need. This study focused on the molecular target angiotensin-converting enzyme 2 (ACE2) of SARS-CoV-2 and screened a group of ACE2 agonists by bioinformatics. Glucocorticoids are a type of ACE2 activator. We verified the efficacy of nine chemicals on regulating ACE2 expression in human GES-1, an upper digestive tract epithelial cell line, and THP-1, a human monocyte cell line, and found that several glucocorticoids imparted activating effects on ACE2 in both cell lines. The drugs triciribine and kinetin riboside activate ACE2 expression or inhibit IL-6 production in macrophages to some extent. In addition, we compared the efficacies of several glucocorticoids. Hydrocortisone showed the strongest effect on ACE2 activation, followed by prednisolone, dexamethasone, and methylprednisolone. We retrospectively analyzed the therapeutic efficacy of nine severe or critical patients from a cohort of 90 COVID-19 cases, who received medium to small doses of glucocorticoids from our integrated medical team in Wuhan. Seven out of nine patients revealed significant improvement in clinical parameters and chest CT images. This study provides experimental and clinical evidence that medium-to-low-dose glucocorticoids may play a protective role in the respiratory and digestive systems by activating ACE2 and suppressing cytokine storm.

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“… 2013 ; Wu, Wang and Chen 2013 ; Arakelyan et al . 2019 ) and can be considered as a orthogonal and complementary method. We used bronchoalveolar lavage fluid (BALF) transcriptomics data from 8 COVID-19 patients and 20 healthy controls to explore the gene expression signature of the disease and applied a coexpression-based drug repositioning pipeline, which we previously developed, to search for candidate drugs for COVID-19.…”

Section: Introductionmentioning

confidence: 99%

Transcriptome-based drug repositioning for coronavirus disease 2019 (COVID-19)

Jia

Song

Shi

et al. 2020

Pathogens and Disease

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The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) around the world has led to a pandemic with high morbidity and mortality. However, there are no effective drugs to prevent and treat the disease. Transcriptome-based drug repositioning, identifying new indications for old drugs, is a powerful tool for drug development. Using bronchoalveolar lavage fluid transcriptome data of COVID-19 patients, we found that the endocytosis and lysosome pathways are highly involved in the disease and that the regulation of genes involved in neutrophil degranulation was disrupted, suggesting an intense battle between SARS-CoV-2 and humans. Furthermore, we implemented a coexpression drug repositioning analysis, cogena, and identified two antiviral drugs (saquinavir and ribavirin) and several other candidate drugs (such as dinoprost, dipivefrine, dexamethasone and (-)-isoprenaline). Notably, the two antiviral drugs have also previously been identified using molecular docking methods, and ribavirin is a recommended drug in the diagnosis and treatment protocol for COVID pneumonia (trial version 5–7) published by the National Health Commission of the P.R. of China. Our study demonstrates the value of the cogena-based drug repositioning method for emerging infectious diseases, improves our understanding of SARS-CoV-2-induced disease, and provides potential drugs for the prevention and treatment of COVID-19 pneumonia.

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Transcriptome-Guided Drug Repositioning

Cited by 17 publications

References 83 publications

Transcriptome Patterns of BRCA1- and BRCA2- Mutated Breast and Ovarian Cancers

Transcriptome Patterns of BRCA1- and BRCA2- Mutated Breast and Ovarian Cancers

Glucocorticoids improve severe or critical COVID-19 by activating ACE2 and reducing IL-6 levels

Transcriptome-based drug repositioning for coronavirus disease 2019 (COVID-19)

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