Obesity affects mitochondrial metabolism and proliferative potential of endometrial progenitor cells

The study aimed to investigate the influence of obesity on cellular features of equine endometrial progenitor cells (Eca EPCs), including viability, proliferation capacity, mitochondrial metabolism, and oxidative homeostasis. Eca EPCs derived from non-obese (Non-OB) and obese (OB) mares were characterised by cellular phenotype and multipotency.Obesity-induced changes in the activity of Eca EPCs include the decline of their proliferative activity, clonogenic potential, mitochondrial metabolism and enhanced oxidative stress. Eca EPCs isolated from obese mares were characterised by an increased occurrence of early apoptosis, loss of mitochondrial dynamics, and senescence-associated phenotype. Attenuated metabolism of Eca EPCs OB was related to increased expression of pro-apoptotic markers (CASP9, BAX, P53, P21), enhanced expression of OPN, PI3K and AKT, simultaneously with decreased signalling stabilising cellular homeostasis (including mitofusin, SIRT1, FOXP3).Obesity alters functional features and self-renewal potential of endometrial progenitor cells. The impaired cytophysiology of progenitor cells from obese endometrium predict lower regenerative capacity if used as autologous transplants.

G protein-coupled receptors that influence lifespan of human and animal models

Humanity has always sought to live longer and for this, multiple strategies have been tried with varying results. In this sense, G protein-coupled receptors (GPCRs) may be a good option to try to prolong our life while maintaining good health since they have a substantial participation in a wide variety of processes of human pathophysiology and are one of the main therapeutic targets. In this way, we present the analysis of a series of GPCRs whose activity has been shown to affect the lifespan of animal and human models, and in which we put a special interest in describing the molecular mechanisms involved. Our compilation of data revealed that the mechanisms most involved in the role of GPCRs in lifespan are those that mimic dietary restriction, those related to insulin signaling and the AMPK and TOR pathways, and those that alter oxidative homeostasis and severe and/or chronic inflammation. We also discuss the possibility of using agonist or antagonist drugs, depending on the beneficial or harmful effects of each GPCR, in order to prolong people's lifespan and healthspan.

Combining Human Genetics of Multiple Sclerosis with Oxidative Stress Phenotype for Drug Repositioning

In multiple sclerosis (MS), oxidative stress (OS) is implicated in the neurodegenerative processes that occur from the beginning of the disease. Unchecked OS initiates a vicious circle caused by its crosstalk with inflammation, leading to demyelination, axonal damage and neuronal loss. The failure of MS antioxidant therapies relying on the use of endogenous and natural compounds drives the application of novel approaches to assess target relevance to the disease prior to preclinical testing of new drug candidates. To identify drugs that can act as regulators of intracellular oxidative homeostasis, we applied an in silico approach that links genome-wide MS associations and molecular quantitative trait loci (QTLs) to proteins of the OS pathway. We found 10 drugs with both central nervous system and oral bioavailability, targeting five out of the 21 top-scoring hits, including arginine methyltransferase (CARM1), which was first linked to MS. In particular, the direction of brain expression QTLs for CARM1 and protein kinase MAPK1 enabled us to select BIIB021 and PEITC drugs with the required target modulation. Our study highlights OS-related molecules regulated by functional MS variants that could be targeted by existing drugs as a supplement to the approved disease-modifying treatments.

Mechanisms of glycolysis and bioenergy state of cells at the stages of cardiosurgical interventions in patients with hypoxic — ischemic impairments of the brain

Objective — to study the features of bioenergetic provision of oxidative homeostasis (OH) in patients with hypoxic‑ischemic brain lesions (HIBL) before and after cardiac surgery (CS) using artificial circulation (AC). Methods and subjects. Clinical and biochemical studies were performed in 38 patients, including 14 with ischemic stroke, 15 with encephalopathy, and 9 with severe cognitive dysfunction. Results. Analysis of metabolic indicators of glycolysis activity and energy homeostasis of cells before and after CS revealed the patterns of changes in the disorganization of glycolysis mechanisms, intensification of anaerobic mechanisms while limiting the energy supply of cells. The obtained data confirm the formation of specific postoperative metabolic provision of bioenergy in patients with CS, which should be considered as one of the triggers of HIBL and individualization of antioxidant cerebroprotection in the preoperative period, taking into account the state of bioenergetic metabolism of cells and the dominant mechanisms of glycolysis. Conclusions. Preoperative antioxidant cerebroprotection as a means of prevention of hypoxic‑ischemic brain lesions during cardiac surgery using artificial circulation should be based on the determination of bioenergetic and metabolic reserves, the depletion of which by antioxidant drugs suppression should not be considered, as activation of anaerobic glycolysis at simultaneous metabolic suppression of mitochondrial bioenergetics is a factor of formation or aggravation of ischemic lesions of brain.

Enzymatic-metabolic support of oxidative homeostasis in patients with hypoxic-ischemic brain lesions in the stages of cardiosurgical interventions

To study the features of enzymatic and metabolic support of oxidative homeostasis in patients with hypoxic-ischemic brain lesions before and after cardiac surgery using artificial circulation we examined 38 patients, in particular: ischemic stroke — 14 people, encephalopathy — 15 people, severe cognitive dysfunction — 9 people ; diagnosis of neurological status was performed according to clinical protocols. Clinical and biochemical study was performed at the preoperative (3—5 days) and postoperative (5—7 days) stages: determined the content of superoxide dismutase, glutathione peroxidase, catalase in erythrocytes and α-tocopherol acetate in the serum of the blood, as well as the product cells: diene conjugates, metabolites of nitritanion in plasma. Variation statistics, probabilistic distribution of data with the subsequent estimation of reliability of results are applied; relative biochemical parameters were used: metabolic index, metabolic coefficient and metabolic effect for each. Standard methods using the program adapted to the “Excel” environment were used for calculations. The obtained data support the formation of patients with specific postoperative enzymatic-metabolic support of oxidative homeostasis, which should be considered as one of the triggers of hypoxic-ischemic brain lesions. In particular, at the level of the enzymatic chain of pro-, antioxidant protection and at the level of metabolic processes associated with peroxidation of phospholipids of cell membranes, a number of significant metabolic effects were revealed, which are generalized due to secondary oxidation products and NO‑dependent metabolites.

Programmed suppression of oxidative phosphorylation and mitochondrial function by gestational alcohol exposure correlate with widespread increases in H3K9me2 that do not suppress transcription

Background A critical question emerging in the field of developmental toxicology is whether alterations in chromatin structure induced by toxicant exposure control patterns of gene expression or, instead, are structural changes that are part of a nuclear stress response. Previously, we used a mouse model to conduct a three-way comparison between control offspring, alcohol-exposed but phenotypically normal animals, and alcohol-exposed offspring exhibiting craniofacial and central nervous system structural defects. In the cerebral cortex of animals exhibiting alcohol-induced dysgenesis, we identified a dramatic increase in the enrichment of dimethylated histone H3, lysine 9 (H3K9me2) within the regulatory regions of key developmental factors driving histogenesis in the brain. However, whether this change in chromatin structure is causally involved in the development of structural defects remains unknown. Results Deep-sequencing analysis of the cortex transcriptome reveals that the emergence of alcohol-induced structural defects correlates with disruptions in the genetic pathways controlling oxidative phosphorylation and mitochondrial function. The majority of the affected pathways are downstream targets of the mammalian target of rapamycin complex 2 (mTORC2), indicating that this stress-responsive complex plays a role in propagating the epigenetic memory of alcohol exposure through gestation. Importantly, transcriptional disruptions of the pathways regulating oxidative homeostasis correlate with the emergence of increased H3K9me2 across genic, repetitive, and non-transcribed regions of the genome. However, although associated with gene silencing, none of the candidate genes displaying increased H3K9me2 become transcriptionally repressed, nor do they exhibit increased markers of canonical heterochromatin. Similar to studies in C. elegans, disruptions in oxidative homeostasis induce the chromatin looping factor SATB2, but in mammals, this protein does not appear to drive increased H3K9me2 or altered patterns of gene expression. Conclusions Our studies demonstrate that changes in H3K9me2 associate with alcohol-induced congenital defects, but that this epigenetic change does not correlate with transcriptional suppression. We speculate that the mobilization of SATB2 and increased enrichment of H3K9me2 may be components of a nuclear stress response that preserve chromatin integrity and interactions under prolonged oxidative stress. Further, we postulate that while this response may stabilize chromatin structure, it compromises the nuclear plasticity required for normal differentiation.

Mineral Waters of the Eastern Ukraine

This article considers the distribution, formation, and chemical composition of mineral waters of the Eastern region of Ukraine, and, in particular, Donetsk, Luhansk, and Kharkiv regions. The main types of mineral waters, most characteristic of the Eastern region of Ukraine, are determined. Their formation and distribution are considered. Manifestations of ferrous, bromine, boron and iodine waters have been studied in this region, which significantly expands hydromineral and balneological resources. The application of ferrous mineral waters to organisms exposed to radiation has been studied. Since one of the consequences of radiation damage is a violation of oxidative homeostasis, the effect of ferrous mineral waters on the course of free radical processes in the body was studied. The peculiarities of the organic composition and biological properties of Berezivsky mineral waters have been studied to identify them as Naftusya-type waters. It is established that Berezivsky mineral waters do not have a pronounced radiomodifier effect. They are inhibitors of the enzymatic activity of catalase — a key regulator of oxidative metabolism, which leads to a deterioration in the vital functions of the body after irradiation. According to the obtained data of mass spectra, active organic substances of different classes, which are part of mineral waters of the Naftusya type, differ from organic substances of Berezivsky mineral waters, both qualitatively and quantitatively. Therefore, Berezivsky mineral waters cannot be referred to as the class of mineral waters of the Naftusya type. Some studies were also conducted and an array of statistics was obtained, which showed that the mineral waters of the Podilsk region, Naftusya and Berezivsky waters have pesticide concentrations less than 0.01 ng/dm3, i.e. 10 000 times lower than their permissible concentrations according to international standards. This confirms the possibility of widespread use and export of Ukrainian mineral waters, which is of national importance. Prospects for the development and use of mineral waters in the Eastern region are shown.