Репозиторий Университета

Over the last decade, a dual character of cell response to oxidative stress, eustress versus distress, has become increasingly recognized. A growing body of evidence indicates that under physiological conditions, low concentrations of reactive oxygen and nitrogen species (RONS) maintained by the activity of endogenous antioxidant system (AOS) allow reversible oxidative/nitrosative modifications of key redox-sensitive residues in regulatory proteins. The reversibility of redox modifications such as Cys S-sulphenylation/S-glutathionylation/S-nitrosylation/S-persulphidation and disulphide bond formation, or Tyr nitration, which occur through electrophilic attack of RONS to nucleophilic groups in amino acid residues provides redox switches in the activities of signalling proteins. Key requirement for the involvement of the redox modifications in RONS signalling including ROS-MAPK, ROS-PI3K/Akt, and RNS-TNF-α/NF-kB signalling is their specificity provided by a residue microenvironment and reaction kinetics. Glutathione, glutathione peroxidases, peroxiredoxins, thioredoxin, glutathione reductases, and glutaredoxins modulate RONS level and cell signalling, while some of the modulators (glutathione, glutathione peroxidases and peroxiredoxins) are themselves targets for redox modifications. Additionally, gene expression, activities of transcription factors, and epigenetic pathways are also under redox regulation. The present review focuses on RONS sources (NADPH-oxidases, mitochondrial electron-transportation chain (ETC), nitric oxide synthase (NOS), etc.), and their cross-talks, which influence reversible redox modifications of proteins as physiological phenomenon attained by living cells during the evolution to control cell signalling in the oxygen-enriched environment. We discussed recent advances in investigation of mechanisms of protein redox modifications and adaptive redox switches such as MAPK/PI3K/PTEN, Nrf2/Keap1, and NF-κB/IκB, powerful regulators of numerous physiological processes, also implicated in various diseases.

Blue biotechnologies implement marine bio-resources for addressing practical concerns. The isolation of biologically active molecules from marine animals is one of the main ways this field develops. Strikingly, cnidaria are considered as sustainable resources for this purpose, as they possess unique cells for attack and protection, producing an articulated cocktail of bioactive substances. The Mediterranean sea anemone Anemonia viridis has been studied extensively for years. In this short review, we summarize advances in bioprospecting of the A. viridis toxin arsenal. A. viridis RNA datasets and toxin data mining approaches are briefly described. Analysis reveals the major pool of neurotoxins of A. viridis, which are particularly active on sodium and potassium channels. This review therefore integrates progress in both RNA-Seq based and biochemical-based bioprospecting of A. viridis toxins for biotechnological exploitation. View Full-Text

Sequential courses of anticancer target therapy lead to selection of drug-resistant cells, which results in continuous decrease of clinical response. Here we present a new approach for predicting effective combinations of target drugs, which act in a synergistic manner. Synergistic combinations of drugs may prevent or postpone acquired resistance, thus increasing treatment efficiency. We cultured human ovarian carcinoma SKOV-3 and neuroblastoma NGP-127 cancer cell lines in the presence of Tyrosine Kinase Inhibitors (Pazopanib, Sorafenib, and Sunitinib) and Rapalogues (Temsirolimus and Everolimus) for four months and obtained cell lines demonstrating increased drug resistance. We investigated gene expression profiles of intact and resistant cells by microarrays and analyzed alterations in 378 cancer-related signaling pathways using the bioinformatical platform Oncobox. This revealed numerous pathways linked with development of drug resistant phenotypes. Our approach is based on targeting proteins involved in as many as possible signaling pathways upregulated in resistant cells. We tested 13 combinations of drugs and/or selective inhibitors predicted by Oncobox and 10 random combinations. Synergy scores for Oncobox predictions were significantly higher than for randomly selected drug combinations. Thus, the proposed approach significantly outperforms random selection of drugs and can be adopted to enhance discovery of new synergistic combinations of anticancer target drugs. View Full-Text

Over the last decade, a dual character of cell response to oxidative stress, eustress versus distress, has become increasingly recognized. A growing body of evidence indicates that under physiological conditions, low concentrations of reactive oxygen and nitrogen species (RONS) maintained by the activity of endogenous antioxidant system (AOS) allow reversible oxidative/nitrosative modifications of key redox-sensitive residues in regulatory proteins. The reversibility of redox modifications such as Cys S-sulphenylation/S-glutathionylation/S-nitrosylation/S-persulphidation and disulphide bond formation, or Tyr nitration, which occur through electrophilic attack of RONS to nucleophilic groups in amino acid residues provides redox switches in the activities of signalling proteins. Key requirement for the involvement of the redox modifications in RONS signalling including ROS-MAPK, ROS-PI3K/Akt, and RNS-TNF-α/NF-kB signalling is their specificity provided by a residue microenvironment and reaction kinetics. Glutathione, glutathione peroxidases, peroxiredoxins, thioredoxin, glutathione reductases, and glutaredoxins modulate RONS level and cell signalling, while some of the modulators (glutathione, glutathione peroxidases and peroxiredoxins) are themselves targets for redox modifications. Additionally, gene expression, activities of transcription factors, and epigenetic pathways are also under redox regulation. The present review focuses on RONS sources (NADPH-oxidases, mitochondrial electron-transportation chain (ETC), nitric oxide synthase (NOS), etc.), and their cross-talks, which influence reversible redox modifications of proteins as physiological phenomenon attained by living cells during the evolution to control cell signalling in the oxygen-enriched environment. We discussed recent advances in investigation of mechanisms of protein redox modifications and adaptive redox switches such as MAPK/PI3K/PTEN, Nrf2/Keap1, and NF-κB/IκB, powerful regulators of numerous physiological processes, also implicated in various diseases.

Blue biotechnologies implement marine bio-resources for addressing practical concerns. The isolation of biologically active molecules from marine animals is one of the main ways this field develops. Strikingly, cnidaria are considered as sustainable resources for this purpose, as they possess unique cells for attack and protection, producing an articulated cocktail of bioactive substances. The Mediterranean sea anemone Anemonia viridis has been studied extensively for years. In this short review, we summarize advances in bioprospecting of the A. viridis toxin arsenal. A. viridis RNA datasets and toxin data mining approaches are briefly described. Analysis reveals the major pool of neurotoxins of A. viridis, which are particularly active on sodium and potassium channels. This review therefore integrates progress in both RNA-Seq based and biochemical-based bioprospecting of A. viridis toxins for biotechnological exploitation. View Full-Text

Sequential courses of anticancer target therapy lead to selection of drug-resistant cells, which results in continuous decrease of clinical response. Here we present a new approach for predicting effective combinations of target drugs, which act in a synergistic manner. Synergistic combinations of drugs may prevent or postpone acquired resistance, thus increasing treatment efficiency. We cultured human ovarian carcinoma SKOV-3 and neuroblastoma NGP-127 cancer cell lines in the presence of Tyrosine Kinase Inhibitors (Pazopanib, Sorafenib, and Sunitinib) and Rapalogues (Temsirolimus and Everolimus) for four months and obtained cell lines demonstrating increased drug resistance. We investigated gene expression profiles of intact and resistant cells by microarrays and analyzed alterations in 378 cancer-related signaling pathways using the bioinformatical platform Oncobox. This revealed numerous pathways linked with development of drug resistant phenotypes. Our approach is based on targeting proteins involved in as many as possible signaling pathways upregulated in resistant cells. We tested 13 combinations of drugs and/or selective inhibitors predicted by Oncobox and 10 random combinations. Synergy scores for Oncobox predictions were significantly higher than for randomly selected drug combinations. Thus, the proposed approach significantly outperforms random selection of drugs and can be adopted to enhance discovery of new synergistic combinations of anticancer target drugs. View Full-Text

The goal of this study was to find genes that encode cytoskeletal proteins that are potential candidates for the role of triggers in cell mechanosensitivity in the fruit fly. Centrifugation was used to simulate the hypergravity effects (2g group); the constantly changing orientation of the larvae in the gravity field was performed in order to simulate the effects of microgravity (0g group) for 1.5, 6, 12 and 24 h. mRNA levels of different genes that encode the components of both tubulin and actin cytoskeleton were assessed by qRT-PCR. In the 0g group the mRNA levels of beta-tubulin and Msps were reduced after 1.5 h of the exposure and remained unchanged until 12 h, while they exceeded the control level after 24 h. The mRNA level of chaperonin containing T-complex 1 polypeptide subunits recovered earlier: after 6 and 12 h of the microgravity exposure. At the same time, the hypergravity effect led to more significant changes in the mRNA level of TCP1 complex components compared with those of tubulin and Msps. The mRNA level of beta-actin isoforms under micro- and hypergravity was decreased up to 12 h of the exposure, however, it remained reduced under microgravity conditions, while it recovered (Act87E) and even exceeded (Act57B) the reference level under hypergravity conditions. The mRNA level of supervillin was almost unchanged. Under microgravity conditions the mRNA level of fimbrin was decreased (it recovered by the 24 h time point), while the mRNA level of alpha-actinin was significantly increased by the 12 h time point of the exposure and after 24 h it was reduced to the control level. In contrast, under hypergravity conditions the mRNA level of fimbrin initially increased, and after 24 h it dropped below the control, while the mRNA level of alpha-actinin was significantly reduced, and after 24 h it was higher than the reference level. Similar results were obtained earlier in the experiments in rodents, but similar dynamics were observed for alpha-actinin isoforms 1 and 4, although no changes were observed for fimbrin. Since Drosophila melanogaster has no alpha-actinin isoform 4, it is hypothesized that its role in the cell is played by fimbrin.

Background: The vascular endothelial growth factor (VEGF) is a neuroprotective cytokine that promotes neurogenesis and angiogenesis in the brain. In animal models, it has been shown that environmental enrichment and exercise, two non-pharmacological interventions that are beneficial decreasing the progression of Alzheimer disease (AD) and depressive-like behavior, enhance hippocampal VEGF expression and neurogenesis. Furthermore, the stimulation of VEGF expression promotes neurotransmission and synaptic plasticity processes such as neurogenesis. It is thought that these VEGF actions in the brain, may underly its beneficial therapeutic effects against psychiatric and other neurological conditions.

Conclusion: In this review, evidence linking VEGF deficit with the development of AD as well as the potential role of VEGF signaling as a therapeutic target for cotinine and other interventions in neurodegenerative conditions are discussed.

Цель работы — совершенствование диагностики и лечения односторонних параличей возвратных гортанных нервов с преходящим рефлекторным спазмом функционирующей голосовой складки. Проведено обследование и лечение 49 больных (46 женщин и 3 мужчин) в возрасте от 21 года до 75 лет с односторонним параличом возвратного гортанного нерва и преходящим рефлекторным спазмом функционирующей голосовой складки, возникшим вследствие операции на щитовидной железе. Для диагностики и объективизации результатов лечения проводились электромиографический тест на скрытую тетанию, исследование уровня ионизированного кальция крови и видеоларингостробоскопия. Лечение включало дыхательную гимнастику, рефлексотерапию (новокаиновые блокады зон Захарьина—Геда для гортани, аурикулотерапию), медикаментозную терапию (витаминно-кальциевая терапия, миорелаксанты и седативные препараты), фонопедию. У всех 49 больных был восстановлен достаточно громкий и звучный голос, а также нормализовано дыхание и прекращены или минимизированы приступы рефлекторного кашля и ларингоспазмы. Ни одному больному в дальнейшем не потребовалось проведение трахеотомии.