Aging of Vascular System Is a Complex Process: The Cornerstone Mechanisms

Aging is one of the most intriguing processes of human ontogenesis. It is associated with the development of a wide variety of diseases affecting all organs and their systems. The victory over aging is the most desired goal of scientists; however, it is hardly achievable in the foreseeable future due to the complexity and ambiguity of the process itself. All body systems age, lose their performance, and structural disorders accumulate. The cardiovascular system is no exception. And it is cardiovascular diseases that occupy a leading position as a cause of death, especially among the elderly. The aging of the cardiovascular system is well described from a mechanical point of view. Moreover, it is known that at the cellular level, a huge number of mechanisms are involved in this process, from mitochondrial dysfunction to inflammation. It is on these mechanisms, as well as the potential for taking control of the aging of the cardiovascular system, that we focused on in this review.     

Novel Epoxides of Soloxolone Methyl: An Effect of the Formation of Oxirane Ring and Stereoisomerism on Cytotoxic Profile,Anti-Metastatic and Anti-Inflammatory Activities In Vitro and In Vivo

It is known that epoxide-bearing compounds display pronounced pharmacological activities, and the epoxidation of natural metabolites can be a promising strategy to improve their bioactivity. Here, we report the design, synthesis and evaluation of biological properties of αO-SM and βO-SM, novel epoxides of soloxolone methyl (SM), a cyanoenone-bearing derivative of 18βH-glycyrrhetinic acid. We demonstrated that the replacement of a double-bound within the cyanoenone pharmacophore group of SM with α- and β-epoxide moieties did not abrogate the high antitumor and anti-inflammatory potentials of the triterpenoid. It was found that novel SM epoxides induced the death of tumor cells at low micromolar concentrations (IC₅₀^(24h) = 0.7–4.1 µM) via the induction of mitochondrial-mediated apoptosis, reinforced intracellular accumulation of doxorubicin in B16 melanoma cells, probably by direct interaction with key drug efflux pumps (P-glycoprotein, MRP1, MXR1), and the suppressed pro-metastatic phenotype of B16 cells, effectively inhibiting their metastasis in a murine model. Moreover, αO-SM and βO-SM hampered macrophage functionality in vitro (motility, NO production) and significantly suppressed carrageenan-induced peritonitis in vivo. Furthermore, the effect of the stereoisomerism of SM epoxides on the mentioned bioactivities and toxic profiles of these compounds in vivo were evaluated. Considering the comparable antitumor and anti-inflammatory effects of SM epoxides with SM and reference drugs (dacarbazine, dexamethasone), αO-SM and βO-SM can be considered novel promising antitumor and anti-inflammatory drug candidates.     

Structural Insights into Iron Ions Accumulation in Dps Nanocage

Dps (DNA-binding protein from starved cells) is well known for the structural protection of bacterial DNA by the formation of highly ordered intracellular assemblies under stress conditions. Moreover, this ferritin-like protein can perform fast oxidation of ferrous ions and subsequently accumulate clusters of ferric ions in its nanocages, thus providing the bacterium with physical and chemical protection. Here, cryo-electron microscopy was used to study the accumulation of iron ions in the nanocage of a Dps protein from Escherichia coli. We demonstrate that Fe²⁺ concentration in the solution and incubation time have an insignificant effect on the volume and the morphology of iron minerals formed in Dps nanocages. However, an increase in the Fe²⁺ level leads to an increase in the proportion of larger clusters and the clusters themselves are composed of discrete ~1–1.5 nm subunits.     

Exogenous dsRNA Induces RNA Interference of a Chalcone Synthase Gene in Arabidopsis thaliana

Recent investigations have shown the possibility of artificial induction of RNA interference (RNAi) via plant foliar treatments with naked double-stranded RNA (dsRNA) to silence essential genes in plant fungal pathogens or to target viral RNAs. Furthermore, several studies have documented the downregulation of plant endogenous genes via external application of naked gene-specific dsRNAs and siRNAs to the plant surfaces. However, there are limited studies on the dsRNA processing and gene silencing mechanisms after external dsRNA application. Such studies would assist in the development of innovative tools for crop improvement and plant functional studies. In this study, we used exogenous gene-specific dsRNA to downregulate the gene of chalcone synthase (CHS), the key enzyme in the flavonoid/anthocyanin biosynthesis pathway, in Arabidopsis. The nonspecific NPTII-dsRNA encoding the nonrelated neomycin phosphotransferase II bacterial gene was used to treat plants in order to verify that any observed effects and processing of AtCHS mRNA were sequence specific. Using high-throughput small RNA (sRNA) sequencing, we obtained six sRNA-seq libraries for plants treated with water, AtCHS-dsRNA, or NPTII-dsRNA. After plant foliar treatments, we detected the emergence of a large number of AtCHS- and NPTII-encoding sRNAs, while there were no such sRNAs after control water treatment. Thus, the exogenous AtCHS-dsRNAs were processed into siRNAs and induced RNAi-mediated AtCHS gene silencing. The analysis showed that gene-specific sRNAs mapped to the AtCHS and NPTII genes unevenly with peak read counts at particular positions, involving primarily the sense strand, and documented a gradual decrease in read counts from 17-nt to 30-nt sRNAs. Results of the present study highlight a significant potential of exogenous dsRNAs as a promising strategy to induce RNAi-based downregulation of plant gene targets for plant management and gene functional studies.     

The Cytoskeletal Protein Zyxin Inhibits Retinoic Acid Signaling by Destabilizing the Maternal mRNA of the RXRγ Nuclear Receptor

Zyxin is an LIM-domain-containing protein that regulates the assembly of F-actin filaments in cell contacts. Additionally, as a result of mechanical stress, Zyxin can enter nuclei and regulate gene expression. Previously, we found that Zyxin could affect mRNA stability of the maternally derived stemness factors of Pou5f3 family in Xenopus laevis embryos through binding to Y-box factor1. In the present work, we demonstrate that Zyxin can also affect mRNA stability of the maternally derived retinoid receptor Rxrγ through the same mechanism. Moreover, we confirmed the functional link between Zyxin and Rxrγ-dependent gene expression. As a result, Zyxin appears to play an essential role in the regulation of the retinoic acid signal pathway during early embryonic development. Besides, our research indicates that the mechanism based on the mRNA destabilization by Zyxin may take part in the control of the expression of a fairly wide range of maternal genes.     

Relative Frequencies of PAX6 Mutational Events in a Russian Cohort of Aniridia Patients in Comparison with the World’s Population and the Human Genome

Genome-wide sequencing metadata allows researchers to infer bias in the relative frequencies of mutational events and to predict putative mutagenic models. In addition, much less data could be useful in the evaluation of the mutational frequency spectrum and the prevalent local mutagenic process. Here we analyzed the PAX6 gene locus for mutational spectra obtained in our own and previous studies and compared them with data on other genes as well as the whole human genome. MLPA and Sanger sequencing were used for mutation searching in a cohort of 199 index patients from Russia with aniridia and aniridia-related phenotypes. The relative frequencies of different categories of PAX6 mutations were consistent with those previously reported by other researchers. The ratio between substitutions, small indels, and chromosome deletions in the 11p13 locus was within the interval previously published for 20 disease associated genomic loci, but corresponded to a higher end due to very high frequencies of small indels and chromosome deletions. The ratio between substitutions, small indels, and chromosome deletions for disease associated genes, including the PAX6 gene as well as the share of PAX6 missense mutations, differed considerably from those typical for the whole genome.     

Behavior of Tl(2212)-Normal Metal Point Contacts under Microwave Irradiation

Current-voltage characteristics and their derivatives of S-c-N point contacts formed by Tl₂Ba₂CaCu₂O_8–x anvil - niobium needle have been studied in the temperature range from 4.2 to T_c under microwave irradiation of wide frequency range. At frequencies of order 10¹⁰ Hz two types of excess current (I_exc) dependence on irradiation power level P was observed. In one case at temperatures near T/T_c 0.5 an excess current oscillates with increasing of P as the square of zero order Bessel function. In another case closer to the critical temperature (mainly at T/T_c 0.9) the enhancement of I_exc by the microwave power was revealed. Observed effects demonstrate complicated dynamics of quasiparticles in Tl-based HTS.     

Numerical characterization of a piezoelectric composite with hollow metal fillers including new figures of merit,pore shape effects,and distinct piezoceramic types

International Journal of Mechanics and Materials in Design - This paper focuses on the numerical analysis of the properties of porous piezoelectric composites with metal-doped pore surfaces and...