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Exosomes and microvesicles are two major categories of extracellular vesicles (EVs) released by almost all cell types and are highly abundant in biological fluids. Both the molecular composition of EVs and their release are thought to be strictly regulated by external stimuli. Multiple studies have consistently demonstrated that EVs transfer proteins, lipids and RNA between various cell types, thus mediating intercellular communication, and signaling. Importantly, small non-coding RNAs within EVs are thought to be major contributors to the molecular events occurring in the recipient cell. Furthermore, RNA cargo in exosomes and microvesicles could hold tremendous potential as non-invasive biomarkers for multiple disorders, including pathologies of the immune system. This mini-review is aimed to provide the state-of-the-art in the EVs-associated RNA transcriptome field, as well as the comprehensive analysis of previous studies characterizing RNA content within EVs released by various cells using next-generation sequencing. Finally, we highlight the technical challenges associated with obtaining pure EVs and deep sequencing of the EV-associated RNAs.

β-glucan, one of the homopolysaccharides composed of D-glucose, exists widely in cereals and microorganisms and possesses various biological activities, including anti-inflammatory, antioxidant, and anti-tumor properties. More recently, there has been mounting proof that β-glucan functions as a physiologically active “biological response modulator (BRM)”, promoting dendritic cell maturation, cytokine secretion, and regulating adaptive immune responses—all of which are directly connected with β-glucan-regulated glucan receptors. This review focuses on the sources, structures, immune regulation, and receptor recognition mechanisms of β-glucan.

Development of novel approaches for regulating the expression of angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) is becoming increasingly important within the context of the ongoing COVID-19 pandemic since these enzymes play a crucial role in cell infection. In this work we searched for putative ACE2 and TMPRSS2 expression regulation networks mediated by various miRNA isoforms (isomiR) across different human organs using publicly available paired miRNA/mRNA-sequencing data from The Cancer Genome Atlas (TCGA) project. As a result, we identified several miRNA families targeting ACE2 and TMPRSS2 genes in multiple tissues. In particular, we found that lysine-specific demethylase 5B (JARID1B), encoded by the KDM5B gene, can indirectly affect ACE2 / TMPRSS2 expression by repressing transcription of hsa-let-7e / hsa-mir-125a and hsa-mir-141 / hsa-miR-200 miRNA families which are targeting these genes.

Human leukocyte antigen (HLA) class I molecules play a crucial role in the development of a specific immune response to viral infections by presenting viral peptides at the cell surface where they will be further recognized by T cells. In the present manuscript, we explored whether HLA class I genotypes can be associated with the critical course of Coronavirus Disease-19 by searching possible connections between genotypes of deceased patients and their age at death. HLA-A, HLA-B, and HLA-C genotypes of n = 111 deceased patients with COVID-19 (Moscow, Russia) and n = 428 volunteers were identified with next-generation sequencing. Deceased patients were split into two groups according to age at the time of death: n = 26 adult patients aged below 60 and n = 85 elderly patients over 60. With the use of HLA class I genotypes, we developed a risk score (RS) which was associated with the ability to present severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) peptides by the HLA class I molecule set of an individual. The resulting RS was significantly higher in the group of deceased adults compared to elderly adults [ p = 0.00348, area under the receiver operating characteristic curve ( AUC ROC = 0.68)]. In particular, presence of HLA-A * 01:01 allele was associated with high risk, while HLA-A * 02:01 and HLA-A * 03:01 mainly contributed to low risk. The analysis of patients with homozygosity strongly highlighted these results: homozygosity by HLA-A * 01:01 accompanied early deaths, while only one HLA-A * 02:01 homozygote died before 60 years of age. Application of the constructed RS model to an independent Spanish patients cohort ( n = 45) revealed that the score was also associated with the severity of the disease. The obtained results suggest the important role of HLA class I peptide presentation in the development of a specific immune response to COVID-19.

Since 2003, the world has been confronted with three new betacoronaviruses that cause human respiratory infections: SARS-CoV, which causes severe acute respiratory syndrome (SARS), MERS-CoV, which causes Middle East respiratory syndrome (MERS), and SARS-CoV-2, which causes Coronavirus Disease 2019 (COVID-19). The mechanisms of coronavirus transmission and dissemination in the human body determine the diagnostic and therapeutic strategies. An important problem is the possibility that viral particles overcome tissue barriers such as the intestine, respiratory tract, blood-brain barrier, and placenta. In this work, we will 1) consider the issue of endocytosis and the possibility of transcytosis and paracellular trafficking of coronaviruses across tissue barriers with an emphasis on the intestinal epithelium; 2) discuss the possibility of antibody-mediated transcytosis of opsonized viruses due to complexes of immunoglobulins with their receptors; 3) assess the possibility of the virus transfer into extracellular vesicles during intracellular transport; and 4) describe the clinical significance of these processes. Models of the intestinal epithelium and other barrier tissues for in vitro transcytosis studies will also be briefly characterized.

Epithelial-mesenchymal transition (EMT) is a key process in embryonic development and metastases formation during malignant progression. This review focuses on transcriptional regulation, non-coding RNAs, alternative splicing events and cell adhesion molecules regulation during EMT. Additionally, we summarize the knowledge with regard to the small potentially druggable molecules capable of modulating EMT for cancer therapy.

Metastasis formation poses a significant challenge to oncologists, as it severely limits the survival of colorectal cancer (CRC) patients. Recently, we demonstrated that CD44 promotes spontaneous distant metastasis in a CRC xenograft model. The depletion of CD44 was associated with reduction in hypoxia, EMT, as well as improved mitochondrial metabolism in primary tumor. Collectively, these effects decreased the metastatic potential of the CRC xenograft tumors under investigation. In this study we explore the molecular mechanisms by which CD44 knockdown (kd) leads to such substantial changes of tumor properties. Using miRNA-Seq data combined with bioinformatic analysis, we investigated the role of miRNA expression changes in the metastasis prevention observed with CD44 kd. Among the differentially expressed miRNAs, three members of Let-7 family (let-7a-5p, let-7b-5p, and let-7c-5p), two isoforms of miR-203a (canonical miR-203a-3p and its +1 5'-isoform), miR-101-3p, miR-200b-3p|+1 5'-isoform, miR-125a-5p, and miR-185-5p were identified as potentially involved in regulating CD44-mediated metastasis. Gene set analysis of differentially expressed mRNA targets of these miRNAs, along with an examination of key regulators driving the observed changes in both mRNA and miRNA expression profiles, suggests that the CD44-STAT3-Let-7 miRNA axis as one of the most relevant in regulation of colon cancer metastasis via the CD44 receptor. Our findings suggest a regulatory relationship between CD44, Let-7 miRNAs, and STAT3 in HT-29 tumors. Additionally, we propose the potential involvement of both isoforms of miR-203a (canonical and its +1 5'-isoform) in this regulatory network and suggest a role for miR-101-3p and miR-125a-5p in metastasis regulation through CD44 kd.

Metastasis is a hallmark of malignancy and poses a formidable challenge for oncologists. This complex process begins when the primary malignant cells start to proliferate unlimitedly. Once the tumor reaches a certain size, cancer cells detach from the primary tumor mass and the basal lamina to which they are anchored, eventually invading nearby blood vessels. Within the bloodstream, these tumor cells have to survive and attach to the endothelium at distant sites. Cell‐to‐cell and cell‐to‐matrix interactions play an important role during these stages, in which integrins—a family of cell adhesion molecules (CAMs)—stand out as functionally centrally involved. Their expression on the tumor cell surface needs to be dynamically regulated throughout the process of metastasis. During the attachment phase to the endothelium, another group of CAMs, such as E‐/P‐selectins—primarily expressed on endothelial cells—may also play a critical role in certain malignancies. Additionally, the interplay between integrins and selectins may influence the tumor microenvironment. This review focuses on the role of integrins and their interplay with selectins in metastasis, emphasizing findings from in vivo studies. Here we review the role of integrins and their interplay with selectins in metastasis. The efficacy of integrin‐targeted therapies may be reduced in tumors where metastasis relies heavily on selectins. In certain tumors, integrins and selectins exhibit a synergistic interaction during intraperitoneal dissemination. Additionally, we highlight the interplay between integrins and selectins in shaping the tumor immune microenvironment.

Analysis of regulatory networks is a powerful framework for identification and quantification of intracellular interactions. We introduce miRGTF-net, a novel tool for construction of miRNA-gene-TF networks. We consider multiple transcriptional and post-transcriptional interaction types, including regulation of gene and miRNA expression by transcription factors, gene silencing by miRNAs, and co-expression of host genes with their intronic miRNAs. The underlying algorithm uses information on experimentally validated interactions as well as integrative miRNA/mRNA expression profiles in a given set of samples. The latter ensures simultaneous tissue-specificity and biological validity of interactions. We applied miRGTF-net to paired miRNA/mRNA-sequencing data of breast cancer samples from The Cancer Genome Atlas (TCGA). Together with topological analysis of the constructed network we showed that considered players can form reliable prognostic gene signatures for ER-positive breast cancer. A number of signatures demonstrated remarkably high accuracy on transcriptomic data obtained by both microarrays and RNA sequencing from several independent patient cohorts. Furthermore, an essential part of prognostic genes were identified as direct targets of transcription factor E2F1. The putative interplay between estrogen receptor alpha and E2F1 was suggested as a potential recurrence factor in patients treated with tamoxifen. Source codes of miRGTF-net are available at GitHub ( https://github.com/s-a-nersisyan/miRGTF-net ).

Host miRNAs are known as important regulators of virus replication and pathogenesis. They can interact with various viruses through several possible mechanisms including direct binding of viral RNA. Identification of human miRNAs involved in coronavirus-host interplay becomes important due to the ongoing COVID-19 pandemic. In this article we performed computational prediction of high-confidence direct interactions between miRNAs and seven human coronavirus RNAs. As a result, we identified six miRNAs (miR-21-3p, miR-195-5p, miR-16-5p, miR-3065-5p, miR-424-5p and miR-421) with high binding probability across all analyzed viruses. Further bioinformatic analysis of binding sites revealed high conservativity of miRNA binding regions within RNAs of human coronaviruses and their strains. In order to discover the entire miRNA-virus interplay we further analyzed lungs miRNome of SARS-CoV infected mice using publicly available miRNA sequencing data. We found that miRNA miR-21-3p has the largest probability of binding the human coronavirus RNAs and being dramatically up-regulated in mouse lungs during infection induced by SARS-CoV.