Enhanced Inhibition of Tumorigenesis Using Combinations of miRNA-Targeted Therapeutics

The search for effective strategies to inhibit tumorigenesis remains one of the most relevant scientific challenges. Among the most promising approaches is the direct modulation of the function of short non-coding RNAs, particularly miRNAs. These molecules are propitious targets for anticancer therapy, since they perform key regulatory roles in a variety of signaling cascades related to cell proliferation, apoptosis, migration, and invasion. The development of pathological states is often associated with deregulation of miRNA expression. The present review describes in detail the strategies aimed at modulating miRNA activity that invoke antisense oligonucleotide construction, such as small RNA zippers, miRNases (miRNA-targeted artificial ribonucleases), miRNA sponges, miRNA masks, anti-miRNA oligonucleotides, and synthetic miRNA mimics. The broad impact of developed miRNA-based therapeutics on the various events of tumorigenesis is also discussed. Above all, the focus of this review is to evaluate the results of the combined application of different miRNA-based agents and chemotherapeutic drugs for the inhibition of tumor development. Many studies indicate a considerable increase in the efficacy of anticancer therapy as a result of additive or synergistic effects of simultaneously applied therapies. Different drug combinations, such as a cocktail of antisense oligonucleotides or multipotent miRNA sponges directed at several oncogenic microRNAs belonging to the same/different miRNA families, a mixture of anti-miRNA oligonucleotides and cytostatic drugs, and a combination of synthetic miRNA mimics, have a more complex and profound effect on the various events of tumorigenesis as compared with treatment with a single miRNA-based agent or chemotherapeutic drug. These data provide strong evidence that the simultaneous application of several distinct strategies aimed at suppressing different cellular processes linked to tumorigenesis is a promising approach for cancer therapy

Translation arrest of potato virus X RNA in Krebs-2 cell-free system: RNase H cleavage promoted by complementary oligodeoxynucleotides

AbstractTranslation arrest of genomic potato virus X (PVX) RNA promoted by complementary oligodeoxynucleotides in Krebs-2 cell-free system is described. 14–15 mer oligodeoxynucleotides complementary to the 5′-proximal cistron of PVX RNA were shown to induce specific truncation of the major non-structural polypeptide coded by PVX RNA. Evidence is presented that effective translational arrest of PVX RNA in the presence of complementary oligonucleotides restults from the site-specific cleavage of RNA by endogenous RNase H intrinsic to the Krebs-2 extract. No similar translational arrest was found in the rabbit reticulocyte lysate cell-free system

Trends and lessons of anti-crisis legal regulationin in the period of the COVID-19 pandemic

The article attempts to structure the impact of the coronavirus pandemic on the sociopolitical organization of society and legal regulation. The authors offer their own vision of the most significant changes that have occurred in various spheres of society in this specific period. The pandemic has demonstrated the diverse effects of digitalization (both highly positive in terms of social progress and sustainable development, and extremely negative). In addition, during the period of antiviral regulation, certain trends and patterns of legal regulation were spontaneously laid down; they can lead to fundamental and critical changes in the legal system. The article features the trends outlined by the pandemic and formulates proposals, allowing to take into account the extreme experience of survival in the conditions of the viral threat and to enter the post-pandemic world with minimal losses

Engineering supramolecular dynamics of self-assembly and turnover of oncogenic microRNAs to drive their synergistic destruction in tumor models

Rationally-engineered functional biomaterials offer the opportunity to interface with complex biology in a predictive, precise, yet dynamic way to reprogram their behaviour and correct shortcomings. Success here may lead to a desired therapeutic effect against life-threatening diseases, such as cancer. Here, we engineered “Crab”-like artificial ribonucleases through coupling of peptide and nucleic acid building blocks, capable of operating alongside and synergistically with intracellular enzymes (RNase H and Ago 2) for potent destruction of oncogenic microRNAs. “Crab”-like configuration of two catalytic peptides (“pincers”) flanking the recognition oligonucleotide was instrumental here in providing increased catalytic turnover, leading to ≈30-fold decrease in miRNA half-life as compared with that for “single-pincer” conjugates. Dynamic modelling of miRNA cleavage illustrated how such design enabled “Crabs” to drive catalytic turnover through simultaneous attacks at different locations of the RNA-DNA heteroduplex, presumably by producing smaller cleavage products and by providing toeholds for competitive displacement by intact miRNA strands. miRNA cleavage at the 5’-site, spreading further into double-stranded region, likely provided a synergy for RNase H1 through demolition of its loading region, thus facilitating enzyme turnover. Such synergy was critical for sustaining persistent disposal of continually-emerging oncogenic miRNAs. A single exposure to the best structural variant (Crab-p-21) prior to transplantation into mice suppressed their malignant properties and reduced primary tumor volume (by 85%) in MCF-7 murine xenograft models

Doctrinal comprehension of cyber terrorism in the context of intensive development of information and communication technologies in the modern world

The paper examines the doctrinal aspects of understanding cyber terrorism as an atypical manifestation (form) of traditional terrorism updated in light of the intensive development and widespread dissemination of information and communication technologies (ICT) in the modern world. The conclusion is substantiated that cyber terrorism is a conceptually relevant concept, which is perceived either as a method of committing a terrorist act (reduced understanding), or as any crimes of a terrorist nature that are committed using information and communication technologies (broad understanding).У статті розглядаються доктринальні аспекти розуміння кібертероризму як нетипового прояву (форми) традиційного тероризму, оновленого у світлі інтенсивного розвитку та широкого розповсюдження інформаційно-комунікаційних технологій (ІКТ) у сучасному світі. Обґрунтовано висновок, що кібертероризм - це концептуально відповідне поняття, яке сприймається або як метод вчинення терористичного акту (знижене розуміння), або як будь-які злочини терористичного характеру, що вчиняються з використанням інформаційно-комунікаційних технологій (широке розуміння).В статье рассматриваются доктринальные аспекты понимания кибертерроризма как нетипичного проявления (формы) традиционного терроризма, обновленного в свете интенсивного развития и широкого распространения информационно-коммуникационных технологий (ИКТ) в современном мире. Обоснован вывод, что кибертерроризм — это концептуально соответствующее понятие, воспринимается либо как метод совершения террористического акта (пониженное понимание), или как любые преступления террористического характера, совершаемых с использованием информационно-коммуникационных технологий (широкое понимание)

CRISPR/Cas9-induced modification of the conservative promoter region of VRN-A1 alters the heading time of hexaploid bread wheat

In cereals, the vernalization-related gene network plays an important role in regulating the transition from the vegetative to the reproductive phase to ensure optimal reproduction in a temperate climate. In hexaploid bread wheat (Triticum aestivum L.), the spring growth habit is associated with the presence of at least one dominant locus of VERNALIZATION 1 gene (VRN-1), which usually differs from recessive alleles due to mutations in the regulatory sequences of the promoter or/and the first intron. VRN-1 gene is a key regulator of floral initiation; various combinations of dominant and recessive alleles, especially VRN-A1 homeologs, determine the differences in the timing of wheat heading/flowering. In the present study, we attempt to expand the types of VRN-A1 alleles using CRISPR/Cas9 targeted modification of the promoter sequence. Several mono- and biallelic changes were achieved within the 125-117 bp upstream sequence of the start codon of the recessive vrn-A1 gene in plants of semi-winter cv. ‘Chinese Spring’. New mutations stably inherited in subsequent progenies and transgene-free homozygous plants carrying novel VRN-A1 variants were generated. Minor changes in the promoter sequence, such as 1–4 nucleotide insertions/deletions, had no effect on the heading time of plants, whereas the CRISPR/Cas9-mediated 8 bp deletion between −125 and −117 bp of the vrn-A1 promoter shortened the time of head emergence by up to 2-3 days. Such a growth habit was consistently observed in homozygous mutant plants under nonvernalized cultivation using different long day regimes (16, 18, or 22 h), whereas the cold treatment (from two weeks and more) completely leveled the effect of the 8 bp deletion. Importantly, comparison with wild-type plants showed that the implemented alteration has no negative effects on main yield characteristics. Our results demonstrate the potential to manipulate the heading time of wheat through targeted editing of the VRN-A1 gene promoter sequence on an otherwise unchanged genetic background

Luminescent silica mesoparticles for protein transduction

Unlike silica nanoparticles, the potential of silica mesoparticles (SMPs) (i.e. particles of submicron size) for biological applications in particular the in vitro (let alone in vivo) cellular delivery of biological cargo has so far not been sufficiently studied. Here we examine the potential of luminescent (namely, octahedral molybdenum cluster doped) SMPs synthesised by a simple one-pot reaction for the labelling of cells and for protein transduction into larynx carcinoma (Hep-2) cells using GFP as a model protein. Our data demonstrates that the SMPs internalise into the cells within half an hour. This results in cells that detectably luminesce via conventional methods. In addition, the particles are non-toxic both in darkness and upon photo-irradiation. The SMPs were modified to allow their functionalisation by a protein, which then delivered the protein (GFP) efficiently into the cells. Thus, the luminescent SMPs offer a cheap and trackable alternative to existing materials for cellular internalisation of proteins, such as the HIV TAT protein and commercial protein delivery agents (e.g. Pierce™)

Evolution of the Reagent for Iodination and Iodonitration. Optimization of the Synthesis Conditions in the Framework of Green Chemistry

Показана эволюция реагента Тронова-Новикова, проанализированы результаты работы нашей группы под руководством профессора М. С. Юсубова за последние двадцать лет в области йодирования и йоднитрования. Показаны новые возможности твердофазного реагента на основе йода (йодида калия) и (или) нитратов. Изучены химические свойства твердофазных реагентов и оптимизированы условия проведения реакций, которые позволяют проводить целенаправленный синтез продуктов моно- или дийодирования, йоднитрования, нитрования и гетероциклизации. Показано, что при йодировании активированных и умеренно активированных ароматических субстратов и фенилацетилена в условиях «solvent-free » с более высокими выходами получены продукты, аналогичные продуктам в синтезе с использованием растворителя. Предложены возможные окислительно-восстановительные схемы образования промежуточных частиц дийодосеребра (I) нитрата и нитрилйодида в реакциях без растворителя. Полученные теоретические и экспериментальные данные подтверждают возможность распада нитрилйодида по гомо- и гетеролитическому пути в зависимости от природы субстрата не только в синтезе с участием растворителя, но и в условиях «solvent-free »The evolution of the Tronov-Novikov reagent is shown. Scientific investigations of our research group under the leading of professor M. S. Usubov in the field of iodination and iodonitration have been analyzed. New possibilities of a solid-phase reagent based on iodine (potassium iodide) and (or) nitrates are represented. We have studied chemical properties of the solid-phase reagents and optimized conditions of reactions, which allow prediction the synthesis of products of mono- or diiodination, iodonitration, nitration, and heterocyclization. It has been found that iodination of activated and mild activated aromatic substrates and phenylacetylene under solvent-free conditions results with products similar to those obtained in the presence of solvent. However, the solvent-free procedure offers significant advantages such as higher yields, short reaction times with mild reaction conditions. Possible redox schemes were proposed for the formation of potential intermediate particles diiodosilver(I) nitrate and nitrile iodide in solvent-free reactions. Obtained theoretical and experimental data confirm the possibility of the homo- and heterolytic pathways decomposition of nitrile iodide, depending on the nature of the substrate, in the synthesis with a solvent, as well as under “solvent-free” condition