Background. Evidence shows that microRNAs (miRNAs) could play a key role in the homeostasis and development of major depressive disorder and bipolar disorder. The present study is aimed at investigating the changes in circulating miRNA expression profiles in a plasma of patients suffering from major depressive disorder (MDD) and bipolar disorder (BD) to distinguish and evaluate these molecules as biomarkers for mood disorders. Methods. A study enrolled a total of 184 subjects: 74 controls, 84 MDD patients, and 26 BD patients. Small RNA sequencing revealed 11 deregulated circulating miRNAs in MDD and BD plasma, of which expression of 5, hsa-miR-139-3p, miRNAs hsa-let-7e-5p, hsa-let-7f-5p, hsa-miR-125a-5p, and hsa-miR-483-5p, were further verified using qPCR. miRNA gene expression data was evaluated alongside the data from clinical assessment questionnaires. Results. hsa-let-7e-5p and hsa-miR-125a-5p were both confirmed upregulated: 0.75-fold and 0.25-fold, respectively, in the MDD group as well as 1.36-fold and 0.68-fold in the BD group. Receiver operating curve (ROC) analysis showed mediocre diagnostic sensitivity and specificity of both hsa-let-7e-5p and hsa-miR-125a-5p with approximate area under the curve (AOC) of 0.66. ROC analysis of combined miRNA and clinical assessment data showed that hsa-let-7e-5p and hsa-miR-125a-5p testing could improve MDD and BD diagnostic accuracy by approximately 10. Conclusions. Circulating hsa-let-7e-5 and hsa-miR-125a-5p could serve as additional peripheral biomarkers for mood disorders; however, suicidal ideation remains the major diagnostic factor for MDD and BD.

Extracellular vesicles (EVs) are attractive anticancer drug delivery candidates as they confer several fundamental properties, such as low immunogenicity and the ability to cross biological barriers. Mesenchymal stem cells (MSCs) are convenient producers for high EV yields, and patient-derived adipose tissue MSC-EVs could serve as personalised carriers. However, MSC-EV applications raise critical concerns as their natural cargo can affect tumour progression in both inducing and suppressing ways. In this study, we investigated the effect of adipose tissue-derived mesenchymal stem cell EVs (ASC-EVs) on several glioblastoma (GBM) cell lines to define their applicability for anticancer therapies. ASC-EVs were isolated from a cell-conditioned medium and characterised by size and specific markers. The internalisation of fluorescently labelled ASC-EVs by human GBM cells HROG36, U87 MG, and T98G was evaluated by fluorescent microscopy. Changes in GBM cell proliferation after ASC-EV application were determined by the metabolic PrestoBlue assay. Expression alterations in genes responsible for cell adhesion, proliferation, migration, and angiogenesis were evaluated by quantitative real-time PCR. ASC-EV effects on tumour invasiveness and neoangiogenesis in ovo were analysed on the chicken embryo chorioallantoic membrane model (CAM). ASC-EV treatment reduced GBM proliferation in vitro and significantly downregulated invasiveness-related genes ITGα5 (in T98G and HROG63) and ITGβ3 (in HROG36) and the vascularisation-inducing gene KDR (in all GBM lines). Additionally, an approximate 65% reduction in the GBM invasion rate was observed in CAM after ASC-EV treatment. Our study indicates that ASC-EVs possess antitumour properties, reducing GBM cell proliferation and invasiveness, and can be applied as anticancer therapeutics and medicine carriers.

Glioblastoma multiforme (GBM) is the most aggressive CNS tumour with no efficient treatment, partly due to the retention of anticancer drugs by the blood–brain barrier (BBB) and their insufficient concentration in tumour cells. Extracellular vesicles (EVs) are attractive drug carriers because of their biocompatibility and ability to cross the BBB. Additional efficiency can be achieved by adding GBM-cell-specific ligands. GBM cells overexpress integrins; thus, one of the most straightforward targeting strategies is to modify EVs with integrin-recognising molecules. This study investigated the therapeutic potential of genetically engineered EVs with elevated membrane levels of the integrin-binding peptide RGD (RGD-EVs) against GBM cells in vitro. For RGD-EV production, stable RGD-HEK 293FT cells were generated by using a pcDNA4/TO-Lamp2b-iRGD-HA expression vector and performing antibiotic-based selection. RGD-EVs were isolated from RGD-HEK 293FT-cell-conditioned medium and characterised by size (Zetasizer), specific markers (ELISA) and RGD expression (Western Blot). Internalisation by human GBM cells HROG36 and U87 MG and BJ-5ta human fibroblasts was assessed by fluorescent EV RNA labelling. The effect of doxorubicin-loaded RGD-EVs on GBM cells was evaluated by the metabolic PrestoBlue viability assay; functional GAPDH gene knockdown by RGD-EV-encapsulated siRNA was determined by RT-qPCR. RGD-EVs had 40% higher accumulation in GBM cells (but not in fibroblasts) and induced significantly stronger toxicity by loaded doxorubicin and GAPDH silencing by loaded siRNA compared to unmodified EVs. Thus, RGD modification substantially increases the specific delivery capacity of HEK 293FT-derived EVs to GBM cells.

Background and Objectives. Thoracic aortic aneurysm (TAA) is a silent disease characterised by aortic wall expansion and vascular smooth muscle cell (VSMC) dedifferentiation from contractile to synthetic phenotype. Long noncoding RNAs (lncRNAs) involved in VSMC phenotypic regulation could be considered as potential diagnostic indicators and therapeutic targets of TAA. In vitro studies show that lncRNAs CARMN, LUCAT1, MALAT1, and SMILR are associated with the VSMC phenotypic state. Our aim was to test if these lncRNAs are dysregulated during TAA formation in clinical patient samples. Materials and Methods. Relative expression of lncRNAs CARMN, LUCAT1, SMILR, and MALAT1 was tested in clinical aortic tissue and blood plasma samples from TAA and non-TAA patients using the qRT-PCR method. The Mann–Whitney U test was used to compare ΔCt values between the study groups. ROC curve analysis was performed to evaluate the diagnostic value of plasma lncRNAs. Results. We found significantly reduced CARMN (p=0.033) and LUCAT1 (p=0.009) expression in aortic tissue samples from TAA patients. Relative expression of MALAT1 (p=0.117) and SMILR (p=0.610) did not differ in aortic tissue between the TAA and non-TAA groups. Expression of both LUCAT1 and SMILR was significantly decreased in TAA patients’ blood plasma compared to controls (p=0.018 and p=0.032, respectively). However, only LUCAT1 showed the ability to discriminate aneurysmal disease in patients’ blood plasma (AUC=0.654, 95%CI=0.534‐0.775, p=0.018). Conclusions. We have shown that the expression of lncRNAs CARMN and LUCAT1 is reduced in dilated aortic tissue and that the LUCAT1 and SMILR expression is lower in the blood plasma of TAA patients. Decreased LUCAT1 expression in TAA patients’ blood plasma may have diagnostic potential in discriminating patients with TAA.

Many high-income countries have met the SARS-CoV-2 pandemic with overwhelming sequencing resources and have identified numerous distinct lineages, including some with notably altered biology. Over a year into the pandemic following unprecedented reductions in worldwide human mobility, distinct introduced lineages of SARS-CoV-2 without sequenced antecedents are increasingly discovered in high-income countries as a result of ongoing SARS-CoV-2 genomic surveillance initiatives. We here describe one such SARS-CoV-2 lineage, carrying many mutations and deletions in the spike protein shared with widespread variants of concern (VOCs), including E484K, S477N and deletions HV69Δ, Y144Δ, and LLA241/243Δ. This lineage – designated B.1.620 – is known to circulate in Lithuania and has now been found in several European states, but also in increasing numbers in central Africa owing to important recent increases in genome sequencing efforts on the continent. We provide evidence of likely ongoing local transmission of B.1.620 in Lithuania, France, Germany, Spain, Belgium and the Central African Republic. We describe the suite of mutations this lineage carries, its potential to be resistant to neutralising antibodies, travel histories for a subset of the European cases, and evidence of local B.1.620 transmission in Europe. We make a case for the likely Central African origin of this lineage by providing travel records as well as the outcomes of carefully crafted phylogenetic and phylogeographic inference methodologies, the latter of which is able to exploit individual travel histories recorded for infected travellers having entered different European countries.

Sex differences identified in the COVID-19 pandemic are necessary to study. It is essential to investigate the efficacy of the drugs in clinical trials for the treatment of COVID-19, and to analyse the sex-related beneficial and adverse effects. The histone deacetylase inhibitor valproic acid (VPA) is a potential drug that could be adapted to prevent the progression and complications of SARS-CoV-2 infection. VPA has a history of research in the treatment of various viral infections. This article reviews the preclinical data, showing that the pharmacological impact of VPA may apply to COVID-19 pathogenetic mechanisms. VPA inhibits SARS-CoV-2 virus entry, suppresses the pro-inflammatory immune cell and cytokine response to infection, and reduces inflammatory tissue and organ damage by mechanisms that may appear to be sex-related. The antithrombotic, antiplatelet, anti-inflammatory, immunomodulatory, glucose- and testosterone-lowering in blood serum effects of VPA suggest that the drug could be promising for therapy of COVID-19. Sex-related differences in the efficacy of VPA treatment may be significant in developing a personalised treatment strategy for COVID-19.