Studying Signaling Pathway Activation in TRAIL-Resistant Macrophage-Like Acute Myeloid Leukemia Cells.

Acute myeloid leukemia (AML) is a malignant neoplasm characterized by extremely low curability and survival. The inflammatory microenvironment and maturation (differentiation) of AML cells induced by it contribute to the evasion of these cells from effectors of antitumor immunity. One of the key molecular effectors of immune surveillance, the cytokine TRAIL, is considered a promising platform for developing selective anticancer drugs. Previously, under in vitro conditions of the inflammatory microenvironment (a three-dimensional high-density culture of THP-1 AML cells), we demonstrated the emergence of differentiated macrophage-like THP-1ad clones resistant to TRAIL-induced death. In the present study, constitutive activation of proinflammatory signaling pathways, associated transcription factors, and increased expression of the anti-apoptotic BIRC3 gene were observed in TRAIL-resistant macrophage-like THP-1ad AML cells. For the first time, a bioinformatic analysis of the transcriptome revealed the main regulator, the IL1B gene, which triggers proinflammatory activation and induces resistance to TRAIL in THP-1ad macrophage-like cells.

Coronavirus Infections in Animals: Risks of Direct and Reverse Zoonoses.

The publications on animal coronavirus infections that have the greatest emerging potential, as well as official data from the World Organization for Animal Health (OIE) on cases of animal infection with COVID-19, are analyzed. Like most infectious diseases common to humans, coronavirus infections were first discovered in animals. Due to the increased rate of replication and recombination activity compared to other viruses, mutations occur more often in the genome of coronaviruses, which contribute to the acquisition of new qualities in order to consolidate in the host organism. Examples of cross-species transmission are not only SARS-CoV, MERS-CoV, and SARS-CoV-2, which are dangerous to humans, but also coronaviruses of agricultural and domestic animals, between which there is a genetic relationship. There are several known cases of zoo, wild, domestic, and farm animals displaying symptoms characteristic of COVID-19 and identification of the genome of the SARS-CoV-2 virus in them. The issue of cross-species transmission of coronavirus infections, in particular the reverse zoonosis of SARS-CoV-2 from animals to humans, is widely discussed. According to the conclusions of many researchers, including OIE experts, there is no direct evidence base for infection of humans with COVID-19 from animals. However, people with suspected COVID-19 and with a confirmed diagnosis are still advised to isolate not only from people but also from animals. A number of methods for specific prevention, diagnosis, and immunization against a wide range of coronavirus infections are being developed at the All-Russia Research Institute for Animal Protection.

Structure and Functions of Gap Junctions and Their Constituent Connexins in the Mammalian CNS.

Numerous data obtained in the last 20 years indicate that all parts of the mature central nervous system, from the retina and olfactory bulb to the spinal cord and brain, contain cells connected by gap junctions (GJs). The morphological basis of the GJs is a group of joined membrane hemichannels called connexons, the subunit of each connexon is the protein connexin. In the central nervous system, connexins show specificity and certain types of them are expressed either in neurons or in glial cells. Connexins and GJs of neurons, combining certain types of inhibitory hippocampal and neocortical neuronal ensembles, provide synchronization of local impulse and rhythmic activity, thalamocortical conduction, control of excitatory connections, which reflects their important role in the processes of perception, concentration of attention and consolidation of memory, both on the cellular and at the system level. Connexins of glial cells are ubiquitously expressed in the brain, and the GJs formed by them provide molecular signaling and metabolic cooperation and play a certain role in the processes of neuronal migration during brain development, myelination, tissue homeostasis, and apoptosis. At the same time, mutations in the genes of glial connexins, as well as a deficiency of these proteins, are associated with such diseases as congenital neuropathies, hearing loss, skin diseases, and brain tumors. This review summarizes the existing data of numerous molecular, electrophysiological, pharmacological, and morphological studies aimed at progress in the study of the physiological and pathophysiological significance of glial and neuronal connexins and GJs for the central nervous system.

Biocompatible dextran-coated gadolinium-doped cerium oxide nanoparticles as MRI contrast agents with high T1 relaxivity and selective cytotoxicity to cancer cells.

Gd-based complexes are widely used as magnetic resonance imaging (MRI) contrast agents. The safety of previously approved contrast agents is questionable and is being re-assessed. The main causes of concern are possible gadolinium deposition in the brain and the development of systemic nephrogenic fibrosis after repeated use of MRI contrasts. Thus, there is an urgent need to develop a new generation of MRI contrasts that are safe and that have high selectivity in tissue accumulation with improved local contrast. Here, we report on a new type of theranostic MRI contrast, namely dextran stabilised, gadolinium doped cerium dioxide nanoparticles. These ultra-small (4-6 nm) Ce0.9Gd0.1O1.95 nanoparticles have been shown to possess excellent colloidal stability and high r1-relaxivity (3.6 mM-1 s-1). They are effectively internalised by human normal and cancer cells and demonstrate dose-dependent selective cytotoxicity to cancer cells.

Coronavirus Infections of Animals: Future Risks to Humans.

Coronaviruses have tremendous evolutionary potential, and three major outbreaks of new human coronavirus infections have occurred in the recent history of humankind. In this paper, the patterns of occurrence of new zoonotic coronavirus infections and the role of bioveterinary control in preventing their potential outbreaks in the future are determined. The possibility of SARS-CoV-2 infection in companion animals is considered. Diverse human activities may trigger various interactions between animal species and their viruses, sometimes causing the emergence of new viral pathogens. In addition, the possibility of using probiotics for the control of viral infections in animals is discussed.

Ceria-Containing Hybrid Multilayered Microcapsules for Enhanced Cellular Internalisation with High Radioprotection Efficiency.

Cerium oxide nanoparticles (nanoceria) are believed to be the most versatile nanozyme, showing great promise for biomedical applications. At the same time, the controlled intracellular delivery of nanoceria remains an unresolved problem. Here, we have demonstrated the radioprotective effect of polyelectrolyte microcapsules modified with cerium oxide nanoparticles, which provide controlled loading and intracellular release. The optimal (both safe and uptake efficient) concentrations of ceria-containing microcapsules for human mesenchymal stem cells range from 1:10 to 1:20 cell-to-capsules ratio. We have revealed the molecular mechanisms of nanoceria radioprotective action on mesenchymal stem cells by assessing the level of intracellular reactive oxygen species (ROS), as well as by a detailed 96-genes expression analysis, featuring genes responsible for oxidative stress, mitochondrial metabolism, apoptosis, inflammation etc. Hybrid ceria-containing microcapsules have been shown to provide an indirect genoprotective effect, reducing the number of cytogenetic damages in irradiated cells. These findings give new insight into cerium oxide nanoparticles' protective action for living beings against ionising radiation.

Opposite effects of low intensity light of different wavelengths on the planarian regeneration rate.

Planarian freshwater flatworms have the unique ability to regenerate due to stem cell activity. The process of regeneration is extremely sensitive to various factors, including light radiation. Here, the effect of low-intensity LED light of different wavelengths on regeneration, stem cell proliferation and gene expression associated with these processes was studied. LED matrices with different wavelengths (red (λmax = 635 nm), green (λmax = 520 nm) and blue (λmax = 463 nm), as well as LED laser diodes (red (λmax = 638.5 nm), green (λmax = 533 nm) and blue (λmax = 420 nm), were used in the experiments. Computer-assisted morphometry, whole-mount immunocytochemical study and RT-PCR were used to analyze the biological effects of LED light exposure on the planarian regeneration in vivo. It was found that a one-time exposure of regenerating planarians with low-intensity red light diodes stimulated head blastema growth in a dose-dependent manner (up to 40%). The green light exposure of planarians resulted in the opposite effect, showing a reduced head blastema growth rate by up to 21%. The blue light exposure did not lead to any changes in the rate of head blastema growth. The maximum effects of light exposure were observed at a dose of 175.2 mJ/cm2. No significant differences were revealed in the dynamics of neoblasts' (planarian stem cells) proliferation under red and green light exposure. However, the RT-PCR gene expression analysis of 46 wound-induced genes revealed their up-regulation upon red LED light exposure, and down-regulation upon green light exposure. Thus, we have demonstrated that the planarian regeneration process is rather sensitive to the effects of low-intensity light radiation of certain wavelengths, the biological activity of red and green light being dictated by the different expression of the genes regulating transcriptional activity.

Influence of electromagnetic waves, with maxima in the green or red range, on the morphofunctional properties of multipotent stem cells.

This paper examines the effect of electromagnetic waves, with maxima in the green or red regions of the spectrum, on the morphofunctional state of multipotent mesenchymal stromal cells. The illumination regimes used in our experiments did not lead to any substantial heating of the samples; the physical parameters of the lighting were carefully monitored. When the samples were illuminated with a green light, no significant photostimulatory effect was observed. Red light, on the other hand, had an evident photostimulatory effect. It is shown that photostimulation with a red light decreases the enzymatic activities of mitochondrial dehydrogenases and enhances the viability of cells, their proliferative activity, and their ability to form bone tissue. It is also established that red light stimulates cell proliferation, while not activating the genes that increase the risk of the subsequent malignant transformation of cells or their death. This paper discusses the possible role of hydrogen peroxide in the processes examined.

[Study of possible involvement of MEK mitogen-activated protein kinase and TGF-ß receptor in planarian regeneration processes using pharmacological inhibition analysis].

Possible involvement of MEK mitogen-activated protein kinase and TGF-ß receptor in the processes of regeneration and morphogenesis in freshwater planarian flatworms Schmidtea mediterranea was studied using a pharmacological inhibitor analysis. It was found that pharmacological inhibitors of these kinases significantly inhibit the regeneration of the head end of the animals and that this effect is realized due to inhibition of proliferative activity of neoblasts, planarian stem cells. It is shown that that the inhibition of the studied protein kinases in regenerating planarians markedly disturbs stem cell differentiation and morphogenesis.

[A role of some intracellular signaling cascades in planarian regeneration activated under irradiation with low-temperature argon plasma].

Using inhibitory analysis the role of some intracellular signaling pathways in activation of planarian regeneration under the influence of low-temperature argon plasma (LTAP) has been investigated. Inactivation of specific inhibitors of intracellular signaling enzymes such as the receptor tyrosine kinase (EGFR), TGF ß receptor, calmodulin, adenylate cyclase, phospholipase A2, phospholipase C, cyclin-dependent protein kinase, JAK2-protein kinase, JNK-protein kinase MEK-protein kinase led to inhibition of the head growth during its regeneration in planarians. Pretreatment with LTAP irradiation provided no inhibitory action of some cascades regulating proliferation. However, the inhibitors of the key regulators of regeneration: TGF ß receptor, calmodulin and MEK-protein kinase completely suppressed the activating effect of plasma. Thus, by the example of regenerating planarians it is shown, that biological activity of low-temperature argon plasma LTAP is caused by modulation of a plurality of cellular signaling systems.

[Functional effects of transcranial electromagnetic stimulation (60 and 70 Hz) of the brain of intact rats and rats with acute brainstem damage].

Behavior and brain electrical activity of 79 male Wistar rats (intact and with acute experimental brainstem injury) were studied during the course of therapeutic transcranial electromagnetic stimulation (TEMS) with frequencies 60 and 70 Hz. In intact animals this effect was accompanied by a decrease in voluntary motor activity and increase in synchronization of the brain electrical activity, in particular, in the delta and beta1 frequency ranges. This inhibitory effect was similar to that of sleep. In the early period of acute experimental stem pathology, the TEMS course was accompanied by suppression of EEG signs of adaptive post-operative stress response and could lead to increased severity of the condition of an animal, along with the slowing of postoperative recovery. Cytomorphological evidence was obtained to the importance of vascular factor in the formation of cerebral reactions to TEMS.

[Effect of the extremely weak alternating magnetic fields on the regeneration of planarians and the gravitropic response of plants].

The influence of extremely weak alternating magnetic fields (EW AMF) directed colinearly to the static Earth magnetic field on the rate of regeneration of planarians and the rate of gravitropic response in the stem segments of flax has been studied. The value of bioeffects of EW AMF is determined by the parameter gamma B(AC)/f, where y is the gyromagnetic ratio of the magnetic moments induced by the orbital movements of electrons in atoms, and B(AC) and f correspond to magnetic induction and frequency of the alternating magnetic component. It was shown that the magnitude of bioeffects depends on the amplitude (at fixed 1000 Hz - frequency) and frequency (at fixed 192 nT - amplitude) of the alternating component. Maxima of bioeffects are observed at gamma B(AC)/f = 0.9; 2.75, and minor maxima gamma B(AC)/f = 4.5; 6.1. The bioeffects are absent at gamma B(AC)/f = 1.8, 3.8, 5.3, 6.7. The positions of the maxima and minima of bioeffects correspond to the theoretical prediction (at gamma = 14000 Hz/microT). Primary targets for the EW AMF of this type are the magnetic moments induced by the orbital movements of electrons in atoms.

[Effect of weak combined magnetic fields on the metamorphosis of the meal-worm beetle Tenebrio molitor].

The effects of weak combined magnetic fields adjusted to the parametric resonance for Ca2+ and K+ and extremely weak alternating magnetic field on the metamorphosis of the meal-worm beetle Tenebrio molitor have been studied. It was shown that the exposure of pupas of insects to all above-indicated types of fields stimulates the metamorphosis. However, after the exposure to weak combined magnetic fields adjusted to the parametric resonance for Ca2+ and K+, the number of insects with anomalies increases, which is not observed by the action of the weak alternating magnetic field.

[Retinoic acid as a regulator of planarian morphogenesis].

The effect of retinoic acid on regeneration of two species of asexual planarian races, Girardia tigrina and Schmidtea mediterranea, was studied. It was established that retinoic acids at physiological concentrations (10(-7)-10(-10) M) inhibit the regeneration of the head part of planarians but have no effect on tail blastema growth. It is shown that regeneration of the head part is inhibited as a result of arrest of the cell cycle of neoblasts, proliferating stem cells, during the transition from the G1/G0 to the S phase. Thus, the morphogenetic role of retinoic acids in planarians, primitive bilaterally symmetrical animals, has been demonstrated.

[Melatonin effect on the regeneration of the flatworm Girardia tigrina].

The melatonin effect on the anterior and posterior ends of a free-living flatworm Girardia tigrina was studied, as well as the variability of the mitotic activity of the stem cells (neoblasts) in the anterior and posterior postblasteme. This hormone may inhibit the regeneration of the anterior end of the animal in the physiologic-friendly concentrations of 10(-10)-10(-15) M by suppressing the mitotic activity of the neoblasts. This hormone does not affect the posterior end's regeneration; thus, its regeneration effect is significantly elective.

[Modulation of cardiac rhythms in humans exposed to extremely weak alternating magnetic fields].

The influence of extremely weak alternating magnetic fields (EW AMF) with amplitudes of < or = 2 microT on the heart rate variability in humans has been studied. The volunteers were placed in a large- volume square coils system (2x2x2 m), which provided the exposure of the whole body to extremely weak alternating magnetic fields homogeneous in amplitude. It was shown that the exposure of volunteers to different types of extremely weak alternating magnetic fields can both increase and decrease the magnitude of stress. In particular, the field tuned to the nuclear spins of hydrogen atoms (amplitude 1.6 microT, frequency 76 Hz) induces a decrease in the Baevsky's stress index, while the field tuned to the magnetic moments formed by the orbiting electrons in some atoms (amplitude 0.192 microT, frequency 3000 Hz) increases the stress index. The results obtained provide a possible explanation for the mechanism of adverse effects of some particular types of technogenic and natural extremely weak alternating magnetic fields on the human cardiovascular system.

[The system of evaluation of the severity of injuries (status and prospects of the problem)]. / Sistema otsenki tiazhesti travm (sostoianie i perspektivy problemy).

The authors have substantiated the necessity of elaboration and introduction of a single all-state++ system of objective quantitative evaluation of the severity of the injuries. A brief comparative characteristic of the most popular Soviet and foreign systems of the severity of the injuries is presented. The synthesized scales (elaborated at the prognosis laboratory of the Central Institute of Traumatology and Orthopedics ) for a quantitative evaluation of the character and the localization of the fractures are presented.