Rimma A. Poltavtseva

Angiotensin-converting enzyme 2 (ACE2) is a key component of the renin–angiotensin system’s counter-regulatory pathway. ACE2 is a multifunctional protein whose location and form determine its catalytic and non-catalytic functions, including amino acid transport, the creation of structural complexes, adhesion, and involvement in signaling pathways. In addition, ACE2 influences neurotransmitter systems in the brain. As the main receptor for SARS-CoV-2, ACE2 has been the subject of increasing research interest. Although ACE2 levels in the brain are low, brain damage from SARS-CoV-2 increases the risk of neurodegenerative diseases. This review aims to clarify an important issue: does the temporary inactivation of ACE2 by the SARS-CoV-2 spike protein play a role in Alzheimer-like neurodegeneration, meaning that the protein may serve as a biomarker or therapeutic target?

Alzheimer’s disease (AD) is one of the most common progressive neurodegenerative diseases leading to impairments in memory, orientation, and behavior. However, significant work is still needed to fully understand the progression of such disease and develop novel therapeutic agents for AD prevention and treatment. Small extracellular vesicles (sEVs) have received attention in recent years due to their potential therapeutic effects on AD. The aim of this study was to determine the potential effect of sEVs in an in vitro model of AD. sEVs were isolated from human Wharton’s jelly mesenchymal stem cells (MSCs) by asymmetric depth filtration, a method developed recently by us. AD was modeled in vitro using cells obtained from the hippocampi of newborn 5xFAD transgenic mice carrying mutations involved in familial AD. After isolation, sEVs underwent detailed characterization that included scanning electron microscopy, nanoparticle tracking analysis, confocal microscopy, Western blotting, and Luminex assay. When added to 5xFAD hippocampal cells, sEVs were nontoxic, colocalized with neurons and astrocytes, decreased the level of Aβ peptide, and increased the synaptic density. These results support the possibility that sEVs can improve brain cell function during aging, decrease the risk of AD, and potentially be used for AD therapeutics.

The pandemic caused by a new strain of SARS-CоV-2 coronavirus has swept the whole world, however, despite the developed strategic directions for the treatment of coronavirus infection and intensive research in all countries, effective methods for treating this severe pathology have not yet been created. The list of drugs against COVID-19 practically does not use compounds that affect the renin-angiotensin system, in the functioning of which the ACE2 coronavirus binding receptor plays a central role. It is assumed that the virus, causing a decrease in the density of ACE2 receptors, leads to disruption of RAS activity. This review presents current research on the response of the immune system to infection with the SARS-CoV-2 virus, describes adaptive and innate cellular mechanisms, and describes a number of predictors of severe COVID-19. To write this review, a search was made in the PubMed database and the scientific electronic library eLibrary.ru. The selection of articles was carried out manually with the main goal of synthesizing data and describing the mechanisms of influence of SARS-CoV-2 on the renin-angiotensin system, and, as a result, on the activation of the adaptive and innate immune response. This review includes 53 publications, including methodological recommendations of the Ministry of Health of the Russian Federation, data from ongoing clinical trials and patents. Data from selected scientific sources were structured and visualized.

The pandemic caused by a new strain of SARS-CоV-2 coronavirus has swept the whole world, however, despite the developed strategic directions for the treatment of coronavirus infection and intensive research in all countries, effective methods for treating this severe pathology have not yet been created. The list of drugs against COVID-19 practically does not use compounds that affect the renin-angiotensin system, in the functioning of which the ACE2 coronavirus binding receptor plays a central role. It is assumed that the virus, causing a decrease in the density of ACE2 receptors, leads to disruption of RAS activity. This review presents current research on the response of the immune system to infection with the SARS-CoV-2 virus, describes adaptive and innate cellular mechanisms, and describes a number of predictors of severe COVID-19. To write this review, a search was made in the PubMed database and the scientific electronic library eLibrary.ru. The selection of articles was carried out manually with the main goal of synthesizing data and describing the mechanisms of influence of SARS-CoV-2 on the renin-angiotensin system, and, as a result, on the activation of the adaptive and innate immune response. This review includes 53 publications, including methodological recommendations of the Ministry of Health of the Russian Federation, data from ongoing clinical trials and patents. Data from selected scientific sources were structured and visualized.

Alzheimer’s disease (AD) is an incurable neurodegenerative disease that is the main cause of dementia in the elderly. When looking for new treatments for AD, attention was drawn to the multifunctional Y-box-binding protein 1 (YB-1). Previously, we revealed a positive effect of intranasal administration of YB-1 on learning and spatial memory, along with a decrease in the content of cerebral β-amyloid and the intensity of plaque initiation, with an improvement in the survival of neurons in the cortex and hippocampus of male AD mice. However, AD affects women twice as often as men, so it is of great interest to study the effects of YB-1 on aging females. Estrogens and androgens are necessary for the maintenance of cognitive function during aging and, apparently, may prevent the development of AD. In this work, peripheral levels of estradiol (E2) and cytokines were studied after intranasal administration of YB-1 to aging female 5xFAD transgenic mice and control non-transgenic animals. In intact aging animals of both groups, a violation of the estrous cycle and a decrease in the level of E2 in blood plasma were revealed. Mice treated with YB-1 did not show a characteristic age-related decrease in plasma E2 levels. The introduction of YB-1 did not affect the peripheral level of cytokines. Thus, a novel, previously undescribed effect of YB-1 on plasma E2 levels in aging female mice is shown. These data indicate that YB-1 may be a promising compound in the prevention and treatment of neurodegenerative diseases. However, further experiments are needed to gain insight into the detailed mechanisms of YB-1 action.

Alzheimer’s disease (AD) is an incurable neurodegenerative disease that is the main cause of dementia in the elderly. When looking for new treatments for AD, attention was drawn to the multifunctional Y-box-binding protein 1 (YB-1). Previously, we revealed a positive effect of intranasal YB-1 administration on learning and spatial memory, along with a decrease in the content of cerebral β-amyloid and intensity of plaque initiation, with improved survival of cortical and hippocampal neurons in a male mouse model of AD. However, AD affects women twice as often as men, so it is of great interest to study the effects of YB-1 on aging females. Estrogens and androgens are required for the maintenance of cognitive function during aging and, apparently, may prevent the development of AD. In this work, peripheral levels of estradiol (E2) and cytokines were studied after intranasal YB-1 administration to aging female 5xFAD transgenic mice and control nontransgenic animals. In intact aging animals of both groups, a disruption of the estrous cycle and a decrease in plasma E2 levels were revealed. YB-1-treated mice exhibited no characteristic age-related decline in plasma E2 levels. YB-1 administration did not affect the peripheral level of cytokines. Thus, a novel, previously undescribed effect of YB-1 on plasma E2 levels in aging female mice is demonstrated, suggesting that YB-1 may be a promising drug in the prevention and treatment of neurodegenerative diseases. Further experiments are needed to gain a deeper insight into the mechanisms of YB-1 action.

Chemokines are involved in the humoral regulation of body homeostasis. Changes in the blood level of chemokines were found in cancer, atherosclerosis, diabetes, and other systemic diseases. It is essential to distinguish the effects of co-morbid pathologies and cancer on the level of chemokines in the blood. We aimed to analyze, by multiplex cytometry, the levels of chemokines in the blood of healthy young volunteers as well as of intact mice and mice with CT26 colon and Pan02 pancreatic tumors. Two types of chemokines were identified both in human and murine plasmas: homeostatic ones, which were found in high concentrations (>100 pg/mL), and inducible ones, which can be undetectable or determined at very low levels (0–100 pg/mL). There was a high variability in the chemokine levels, both in healthy humans and mice. To analyze chemokine levels during tumor growth, C57BL/6 and BALB/c were inoculated with Pan02 or CT26 tumor cells, accordingly. The tumors significantly differed in the growth and the mortality of mice. However, the blood chemokine levels did not change in tumor-bearing mice until the very late stages. Taken collectively, blood chemokine level is highly variable and reflects in situ homeostasis. Care should be taken when considering chemokines as prognostic parameters or therapeutic targets in cancer.

Multiple studies have demonstrated that various nanoparticles (NPs) stimulate osteogenic differentiation of mesenchymal stem cells (MSCs) and inhibit adipogenic ones. The mechanisms of these effects are not determined. The aim of this paper was to estimate Wharton’s Jelly MSCs phenotype and humoral factor production during tri-lineage differentiation per se and in the presence of silicon–gold NPs. Silicon (SiNPs), gold (AuNPs), and 10% Au-doped Si nanoparticles (SiAuNPs) were synthesized by laser ablation, characterized, and studied in MSC cultures before and during differentiation. Humoral factor production (n = 41) was analyzed by Luminex technology. NPs were nontoxic, did not induce ROS production, and stimulated G-CSF, GM-CSF, VEGF, CXCL1 (GRO) production in four day MSC cultures. During MSC differentiation, all NPs stimulated CD13 and CD90 expression in osteogenic cultures. MSC differentiation resulted in a decrease in multiple humoral factor production to day 14 of incubation. NPs did not significantly affect the production in chondrogenic cultures and stimulated it in both osteogenic and adipogenic ones. The major difference in the protein production between osteogenic and adipogenic MSC cultures in the presence of NPs was VEGF level, which was unaffected in osteogenic cells and 4–9 times increased in adipogenic ones. The effects of NPs decreased in a row AuNPs > SiAuNPs > SiNPs. Taken collectively, high expression of CD13 and CD90 by MSCs and critical level of VEGF production can, at least, partially explain the stimulatory effect of NPs on MSC osteogenic differentiation.