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Cyclic acetals of ethylene glycol, cis-but-2-ene-1,4-diol and their dichlorocyclopropyl derivatives were synthesized. Compounds simultaneously containing the gem-dichlorocyclopropane and 1,3-dioxacycloalkane cycles are shown to exhibit cytotoxic activity against the HEK293, SH-SY5Y, HepG2, MCF-7, A549, and Jurkat cell lines. The obtained results open up prospects for further studies of antitumor activity of 2-(2,2-dichlorocyclopropyl)-2-ethyl-1,3-dioxolane.

The biological activity of cyclic acetals (penta- and dipentaerythritol, ethriol, and diglycerol) and 5-ethyl-5-hydroxymethyl-1,3-dioxane esters was studied in vitro. The cytotoxic properties of 5-ethyl-5-hydroxymethyl-1,3-dioxane esters were established on HEK293 and SH-SY5Y cell lines. Potential antioxidant properties of 7,11,18,21-tetraoxaspiro-5,2,2,5-heneicosane, 2-[(5-ethyl-5-hydroxymethyl)-1,3-dioxan-2-yl]phenol, 4.4-[oxydi(methylene)]-bis-2-diisopropyl-1,3-dioxolane, 4,4_-[oxydi(methylene)]-bis-1,3-dioxolane, (5-ethyl-1,3-dioxan-5-yl)methyl-2-methyl acrylate, and bis(5-ethyl-1,3-dioxan-5-yl)methyl maleate were established in vitro using an oxidative stress model.

The results of recent studies indicate that the hyperactivation of the glutamatergic system plays an important role in the pathophysiology of multiple sclerosis (MS). In addition to the well-known direct toxic effect of the excessive extracellular level of the glutamate neurotransmitter on neurons, additional mechanisms of glutamate-induced cell damage have been described in the literature, including effects on oligodendrocytes, astrocytes, endothelial cells and immune cells. The study of these toxic effects will reveal the possible link between various pathological hallmarks of MS, such as axonal damage, oligodendrocyte death, demyelination, neurodegeneration, autoimmune reactions and dysfunction of blood-brain barrier. Understanding the mechanisms underlying the glutamate toxicity will contribute to the development of new therapeutic approaches for the diagnosis and treatment of patients with MS. This review focuses on the mechanisms that lead to an increase in the concentration of neurotransmitter glutamate and excitotoxicity in the context of the pathogenesis of this disease. Also the authors present the data on existing and currently developed medicines and therapeutic approaches to regulate the activity of the glutamatergic system.Результаты исследований последних лет свидетельствуют о том, что гиперактивация глутаматергической системы играет важную роль в патофизиологии рассеянного склероза (РС). Помимо хорошо известных непосредственных токсических эффектов нейромедиатора глутамата на нейроны описаны дополнительные механизмы глутамат-индуцированного клеточного повреждения, включая воздействие на олигодендроциты, астроциты, эндотелиальные и иммунные клетки. Эти токсические эффекты могут раскрыть связь между различными патологическими звеньями РС, такими как аксональное повреждение, гибель олигодендроцитов, демиелинизация, аутоиммунные реакции, дисфункция гематоэнцефалического барьера. Понимание механизмов, лежащих в основе глутаматной токсичности при РС, может способствовать разработке новых подходов для диагностики, лечения и ведения пациентов с РС. В обзоре приводятся сведения о механизмах, приводящих к повышению концентрации нейромедиатора глутамата и эксайтотоксичности, в контексте патогенеза заболевания. Также приводятся данные о существующих и разрабатываемых в настоящее время лекарственных препаратах и терапевтических подходах, способных регулировать работу глутаматергической системы.

Multiple sclerosis is a chronic autoimmune inflammatory and neurodegenerative disease leading to demyelination of nerve cells in the brain and the spinal cord. Despite extensive research, the pathogenesis of this disease is not fully understood. A review of most recent experimental studies shows that epigenetic mechanisms regulating gene expression, such as DNA methylation, histone acetylation, and microRNAs, play the crucial role in the pathogenesis of multiple sclerosis. Analysis of the published data suggests that multiple sclerosis develops as a result of abnormal regulation of gene expression in the nervous and immune systems.

A series of new functionalized allenoates has been synthesized, and their cytotoxic effect has been studied against the tumor cell line (HepG2 and Jurkat) and the normal origin cells (HEK293). The highest cytotoxic effect has been shown for diterpene-containing allenic compounds, which can be attributed to promising substances with potential antitumor activity.

Selective anxiolytic fabomotisol (Afobazol®) has affinity for the Sigma-1 chaperone receptor site, quinone reductase 2 (NQO2) and MAO-A regulatory sites, and melatonin receptor type 1 (MT1 receptor). The analysis of the effect of fabomotisol on the gene expression profile in the brain of MR (Maudsley Reactive) rats was carried out when modeling emotional stress in the open field test. A change in the expression of 14 genes was found, the results of the functional annotation of which show that the mechanisms of action of fabomotisol may be associated with the regulation of translation of proteins (Rpl5, Rpl15, Ncl, Ybx1), synaptic functions (Cplx2, Dlg4, Syngap1, Add1, Rab8b, Klc1, Chn1) and cellular metabolism (Akr1d1, Bcat1, Pkm).

Using flow cytometry and real-time RT-PCR, we studied the effect of the blockade of glutamate NMDA receptors on the quantitative distribution of IFNγ- and IL-4-producing CD4+ and CD8+ T-lymphocytes and the expression of transcription factor of genes T-bet and GATA-3 in immune cells derived from healthy individuals and multiple sclerosis patients (MS). From the results of the study, it follows that blockade of NMDA receptors leads to a decrease in the proportion of studied effector subpopulations of T-lymphocytes, as well as differential modulation of gene expression of transcription factors (TBX21, GATA3). The severity of the negative effect of receptor blockade differs in different subpopulations of CD4+ and CD8+ T cells, which leads to a shift in the cytokine balance towards “proinflammatory” type 1 T-cells, to a greater extent in patients with MS. Thus, glutamate can regulate the Th1/Th2 and Tc1/Tc2 сytokine balance by modulating the activity of NMDA receptors of T lymphocytes in MS.

Aim of study. To study chemotactic properties of glutamate and glutamate receptor agonists on T cells migration from healthy donors and patients with multiple sclerosis (MS) in vitro. Materials and methods. T cell migration of 15 patients with MS and 15 healthy donors was studied in vitro using transwells. Lymphocytes were activated with PMA (10 ng/mL). T cells were added to transwells with fibronectin (10 μg/mL) pretreated membrane. The lower chamber contained glutamate or AMPA or NMDA (100 μM for each) in complete RPMI medium. Migrated cells were collected and stained with antibodies to CD3-marker for subsequent analysis by cytofluorimetry. Results and conclusion. In presence of glutamate, there is a tendency to a decrease in migration activity in both groups of donors. T-cell chemotaxis of healthy donors, but not MS patients, decreased in concentration gradient of NMDA. The activation of lymphocytes with PMA leads to a decrease in the number of migrated cells by an average of 17% (p < 0.01). In MS patients there is a tendency to an increase in chemotaxis of activated cells in concentration gradient of glutamate, and a decrease with AMPA. Thus, glutamate and glutamate receptors agonists do not possess pronounced chemotactic properties, but rather enhance T-cell migration through synthesis of adhesion molecules on the surface of lymphocytes and endothelium.