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Yana G Toropova,1 Alexey S Golovkin,2 Anna B Malashicheva,3,4 Dmitry V Korolev,5,6 Andrey N Gorshkov,7 Kamil G Gareev,8 Michael V Afonin,9 Michael M Galagudza10,11 1Laboratory of Cardioprotection, Institute of Experimental Medicine, Federal Almazov North-West Medical Research Centre, Saint Petersburg, Russian Federation; 2Gene and Cell Engineering Group, Institute of Molecular Biology and Genetics, Federal Almazov North-West Medical Research Centre, Saint Petersburg, Russian Federation; 3Laboratory of Molecular Cardiology, Institute of Molecular Biology and Genetics, Federal Almazov North-West Medical Research Centre, Saint Petersburg, Russian Federation; 4Department of Embryology, Faculty of Biology, Saint Petersburg State University, Saint Petersburg, Russian Federation; 5Laboratory of Nanotechnology, Institute of Experimental Medicine, Federal Almazov North-West Medical Research Centre, Saint Petersburg, Russian Federation; 6Department of Photonics and Optical Information Technology ITMO University, Saint Petersburg, Russian Federation; 7Laboratory of Intracellular Signaling and Transport Research Institute of Influenza, Saint Petersburg, Russian Federation; 8Department of Micro and Nanoelectronics, Faculty of Electronics, Saint Petersburg Electrotechnical University LETI, Saint Petersburg, Russian Federation; 9Department of Inorganic Chemistry Saint Petersburg State Technological Institute (Technical University), Saint Petersburg, Russian Federation; 10Institute of Experimental Medicine, Federal Almazov North-West Medical Research Centre, Saint Petersburg, Russian Federation; 11Departament of Pathophysiology, First Pavlov State Medical University of Saint Petersburg, Saint Petersburg, Russian Federation Abstract: Over the last decade, magnetic iron oxide nanoparticles (IONPs) have drawn much attention for their potential biomedical applications. However, serious in vitro and in vivo safety concerns continue to exist. In this study, the effects of uncoated, FemOn-SiO2 composite flake-like, and SiO2-FemOn core-shell IONPs on cell viability, function, and morphology were tested 48 h postincubation in human umbilical vein endothelial cell culture. Cell viability and apoptosis/necrosis rate were determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and annexin V-phycoerythrin kit, respectively. Cell morphology was evaluated using bright-field microscopy and forward and lateral light scattering profiles obtained with flow cytometry analysis. All tested IONP types were used at three different doses, that is, 0.7, 7.0, and 70.0 µg. Dose-dependent changes in cell morphology, viability, and apoptosis rate were shown. At higher doses, all types of IONPs caused formation of binucleated cells suggesting impaired cytokinesis. FemOn-SiO2 composite flake-like and SiO2-FemOn core-shell IONPs were characterized by similar profile of cytotoxicity, whereas bare IONPs were shown to be less toxic. The presence of either silica core or silica nanoflakes in composite IONPs can promote cytotoxic effects. Keywords: iron oxide nanoparticles, composite nanoparticles, silica coating, silica nanoflakes, cytotoxicity

Background: Cardiovascular events occur more often in winter than in summer; however, the dependence of strokes on various meteorological factors remains unclear. Aims: The purpose of this meta-analysis was to determine the dependence of the circannual dynamics of hospitalizations for hemorrhagic stroke and ischemic stroke on seasonal fluctuations in meteorological factors. Summary of review and conclusions: For our meta-analysis, we selected 20 and 26 publications examining the seasonal dynamics of hemorrhagic stroke and ischemic stroke, respectively. The meta-analysis showed that hemorrhagic stroke is less likely to occur in summer than in other seasons and does not depend on a region's climate. The seasonal dynamics of ischemic stroke are not clearly expressed and are determined by the characteristics of a region's climate. In a climate without pronounced seasonal dynamics of atmospheric pressure and in wet winters, the vector of ischemic stroke incidents will not be expressed or slightly shifted toward winter. Low atmospheric pressure in summer is associated with an increased likelihood of ischemic stroke during this season compared to winter. There was also a relation between ischemic stroke risk with high relative humidity and a significant decrease in ρO2 in summer, but there is not enough evidence regarding this association. We did not reveal dependence of the seasonal dynamics of strokes on the amplitude of annual fluctuations in air temperature. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the cardioprotective effect of quinacrine in an in vivo model of myocardial ischemia/reperfusion injury. A 30-min regional myocardial ischemia followed by a 2-h reperfusion was modeled in anesthetized Wistar rats. Starting at the last minute of ischemia and during the first 9 min of reperfusion the rats in the control (n=8) and experimental (n=9) groups were injected with 0.9% NaCl and quinacrine solution (5 mg/kg), respectively. The area at risk and infarct size were evaluated by "double staining" with Evans blue and triphenyltetrazolium chloride. To assess vascular permeability in the area at risk zone, indocyanine green (ICG) and thioflavin S (ThS) were injected intravenously at the 90th and 120th minutes of reperfusion, respectively, to assess the no-reflow zone. The images of ICG and ThS fluorescence in transverse sections of rat hearts were obtained using a FLUM multispectral fluorescence organoscope. HR tended to decrease by 13% after intravenous administration of quinacrine and then recovered within 50 min. Quinacrine reduced the size of the necrotic zone (p=0.01), vascular permeability in the necrosis region, and the no-reflow area (p=0.027); at the same time, the area at risk did not significantly differ between the groups. Intravenous administration of quinacrine at the beginning of reperfusion of the rat myocardium reduces no-reflow phenomenon and infarct size., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature.)

We studied the dynamics of the main hemodynamic parameters in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats with visceral obesity and chemically induced colitis (CIC) against the background of probiotic therapy. Systolic BP, HR, and body temperature were recorded over 36 days using a wireless telemetry system. During 8 days (3 days before CIC induction and until the end of the experiment) the animals were intragastrically administered a probiotic based on Lactobacillus delbrueckii D5 strain. At baseline, systolic BP was significantly higher in the SHR group, while HR and body temperature did not differ in SHR and WKY rats. On day 8 after CIC induction, systolic BP, HR, and body temperature in SHR were significantly increased in comparison with the initial values. In the group of WKY rats, all indices at the end of the experiment remained at the initial levels. Probiotic therapy in SHR, in contrast to WKY rats, did not lead to normalization of body temperature and hemodynamic disorders resulting from CIC., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The method of photodynamic therapy for skin rejuvenation (PDT-SR) provides an improvement in appearance with a safe and painless effect. The quality of treatment is most often assessed subjectively. The most informative morphological control methods are rarely used due to the invasiveness of the sampling procedure., Aim: This study aimed to find out the possibility of using skin autofluorescence spectroscopy (SAF) for an objective assessment of changes occurring in the skin during PDT-SR., Methods: This study included 12 volunteers (10 women, 2 men) aged 32 to 79 years. Two (n = 6) or three (n = 6) PDT sessions were performed at intervals of 13-30 days. Photosensitizer chlorin e6, exposure 20 min, energy density 18-24 J/cm 2 were used. SAF spectra were recorded using a two-wavelength fiber optic spectrometer under excitation at wavelengths (λ ex ) of 365 nm and 440 nm. Measurements were made both before and after each PDT session and up to 25-238 days from the start of treatment. For the evaluation, we used the spectra AF365(λ) and AF440(λ) averaged over 40 points corrected for diffuse reflection at λ ex =440 nm in the range λ em = 460-700 nm, as well as the spectra of the ratios AFN365(λ) and AFN440(λ), which were obtained by dividing the intensities of the current spectra by the intensities collected before PDT-SR., Results: PDT-SR led to changes in both the intensity and shape of the spectra. Analysis of the spectra using numerical fitting of the spectra showed that the main changes can be explained by changes in the content of advanced glycation end products (AGEs), as well as lipofuscin-like lipopigments (LPs) and porphyrins (PPs). The spectra of AGEs upon excitation at wavelengths of 365 and 440 nm differ, which may be due to the formation of two types of bonds, with collagen and elastin. By the end of the study, the vast majority of the examined volunteers showed a significant decrease of the parameters characterizing both of these types of AGEs, AGE365 (0.56-1.2) and AGE440 (0.58-1.01), relative to the beginning of the study. In most cases, a decrease was also noted for LPs and PPs. AGE365 and AGE440 were positively correlated with the age of the volunteers (r 2  = 0.26-0.46 %). A steady decrease in the content of AGEs occurred approximately on the 40th day., Conclusion: SAF spectroscopy makes it possible to assess changes in the content of AGEs, LPs, and PPs in the skin during PDT-SR. The method has great potential for non-invasive monitoring of the treatment process, as well as its improvement, including through its personalization. In addition, the method can be used to study the mechanisms of age-related skin changes at the molecular level and to study the processes of rejuvenation., Competing Interests: Declaration of Competing Interest The authors have declared that no conflict interest exists., (Copyright © 2024. Published by Elsevier B.V.)

A morphological analysis of the liver of Wistar rats was performed 2 months after a single intravenous injection of porous silicon particles of different sizes (60-80, 250-300, and 500-600 nm; 2 mg/ml, 1 ml). Histological, immunohistochemical, and electron microscopic methods showed the development of CD68 + granulomas in all experimental groups. Injection of 60-80-nm porous silicon particles led to the formation of single large granulomas (>2000 μm 2 ), while 500-600-nm nanoparticles caused the formation of numerous smaller granulomas. The mechanism of involution of granulomas by apoptosis of Kupffer cells and the absence of subsequent connective tissue remodeling of the organ tissue is shown., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature.)

Seasonal changes in external conditions (photoperiod, meteorological conditions, diet) cause adaptive changes in both energy and substrate metabolism in the animals of mammalian species. In summer, long days and a rich diet contribute to relative elevation in the levels of thyroid hormones (TH), but warmer weather lowers their levels. In winter, short days and a poor diet inhibit TH synthesis, but low temperatures increase their secretion. In addition, the results of our meta-analyses revealed a significant role of atmospheric pressure in circannual fluctuations of metabolic parameters in humans. The changes in photoperiod are generally viewed as a major factor contributing to seasonal rhythm regulation However, numerous data show that season-dependent metabolic changes in mammals could be also accounted for by meteorological factors and diet., (Copyright © 2024. Published by Elsevier Inc.)

Here we developed a model of chronic thromboembolic pulmonary hypertension (CTEPH) using repeated intravenous administration of microencapsulated thrombi with a controlled rate of biodegradation. Autologous thrombi encapsulated in alginate microspheres with a diameter of 190±48 μm were intravenously injected to rats 8 times every 4 days. In the comparison group, nonmodified thrombi were injected. After 6 weeks, a significant increase in systolic pressure in the right ventricle, a decrease in exercise tolerance, and an increase in the index of vascular wall hypertrophy were revealed in the group receiving injections of microencapsulated thrombi in comparison with the group receiving nonmodified thrombi and healthy animals. Thus, the developed representative CTEPH model can be used to test promising pharmacological substances., (© 2023. Springer Science+Business Media, LLC, part of Springer Nature.)

The sensitivity of exercise ECG is marginally sufficient for the detection of mild reduction of coronary blood flow in patients with early coronary atherosclerosis. Here, we describe the application of a new technique of ECG registration/analysis-ultra-high-resolution ECG (UHR ECG)-for early detection of myocardial ischemia (MIS). The utility of UHR ECG vs. conventional ECG (C ECG) was tested in anesthetized rats and pigs. Transmural MIS was induced in rats by the ligation of the left coronary artery (CA). In pigs, subendocardial ischemia of a variable extent was produced by stepwise inflation of a balloon within the right CA, causing a 25-100% reduction of its lumen. In rats, a reduction in power spectral density (PSD) in the high-frequency (HF) channel of UHR ECG was registered at 60 s after ischemia (power 0.81 ± 0.14 vs. 1.25 ± 0.12 mW at baseline, p < 0.01). This was not accompanied by any ST segment elevation on C ECG. In pigs, PSD in the HF channel of UHR ECG was significantly decreased at a 25% reduction of CA lumen, while the ST segment on C ECG remained unchanged. In conclusion, UHR ECG enabled earlier detection of transmural MIS compared to C ECG. PSD in the HF channel of UHR ECG demonstrated greater sensitivity in the settings of subendocardial ischemia.

We studied the influence of recombinant IL-2 and brain-derived neurotrophic factor (BDNF) on the size of the myocardial necrosis zone of rats with systemic inflammatory response syndrome (SIRS). A significant increase in the necrosis zone and the levels of proinflammatory cytokines was revealed in animals with SIRS in comparison with the control. The administration of IL-2 to animals with SIRS significantly reduced the size of the necrosis zone, which was paralleled by a pronounced increase in IL-2 and BDNF in comparison with the corresponding parameters in rats with SIRS that did not receive IL-2. Administration of BDNF to animals with SIRS was followed by normalization of TNFα and IL-1α levels, but did not lead to a decrease in the size of the necrosis zone., (© 2023. Springer Science+Business Media, LLC, part of Springer Nature.)

Chronic thromboembolic pulmonary hypertension (CTEPH) develops in 1.5-2.0% of patients experiencing pulmonary embolism (PE) and is characterized by stable pulmonary artery obstruction, heart failure, and poor prognosis. Little is known about involvement of autonomic nervous system (ANS) in the mechanisms of CTEPH. This study was aimed at evaluation of the effect of vagal and sympathetic denervation, as well as stimulation of the parasympathetic nervous system, on the outcomes of CTEPH in rats. CTEPH was induced by multiple intravenous injections of alginate microspheres. Sympathetic and vagal denervation was performed using unilateral surgical ablation of the stellate ganglion and vagotomy, respectively. Stimulation of the parasympathetic nervous system was carried out by administering pyridostigmine. The effect of neuromodulatory effects was assessed in terms of hemodynamics, histology, and gene expression. The results demonstrated the key role of ANS in the development of CTEPH. Sympathetic denervation as well as parasympathetic stimulation resulted in attenuated pulmonary vascular remodeling. These salutary changes were associated with altered MMP2 and TIMP1 expression in the lung and decreased FGFb level in the blood. Unilateral vagotomy had no effect on physiological and morphological outcomes of the study. The data obtained contribute to the identification of new therapeutic targets for CTEPH treatment., Competing Interests: The authors declare no conflicts of interest.

Background: It is known that cardiovascular events (CVE) occur more often in winter than in summer. However, dependence of myocardial infarction (MI) risk of on various meteorological factors is still not fully understood. Also, the dependence of the seasonal dynamics of MI on gender and age has not yet been studied. The purpose of our meta-analysis is to reveal dependence of the circannual dynamics of MI hospitalizations on gender, age, and characteristics of a region's climate., Main Body: Using Review Manager 5.3, we performed a meta-analysis of 26 publications on the seasonal dynamics of MI. In our meta-analysis, the relative MI risk was higher in colder compared to warmer seasons. Old age insignificantly increased the seasonal MI risk; gender did not affect the seasonal dynamics of MI, but MI was more common in men than in women. The severity of the seasonal dynamics of MI risk depended on the climate of the region. In a climate with a small amplitude of circannual fluctuations in air temperature, atmospheric pressure, and partial oxygen density in the air, as well as in regions where air humidity is higher in winter than in summer, an increase in MI risk in winter compared to summer was significant. It was not significant in regions with opposite climatic tendencies., Conclusions: Based on the results of our studies, it can be concluded that a decrease in air temperature increases in MI risk; in addition, hypoxia in the hot season can provoke CVE associated with ischemia., (© 2022. The Author(s).)

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare complication of acute pulmonary embolism with poor clinical outcomes. Therapeutic approaches to prevention of fibrotic remodeling of the pulmonary vascular bed in CTEPH are limited. In this work, we tested the hypothesis that Janus kinase 1/2 (JAK1/2) inhibition with ruxolitinib might prevent and attenuate CTEPH in a rat model. CTEPH was induced by repeated embolization of the pulmonary artery with partially biodegradable 180 ± 30 μm alginate microspheres. Two weeks after the last injection of microspheres, ruxolitinib was administered orally at doses of 0.86, 2.58, and 4.28 mg/kg per day for 4 weeks. Prednisolone (1.475 mg/kg, i.m.) was used as a reference drug. Ruxolitinib in all doses as well as prednisolone reduced pulmonary vascular wall hypertrophy. Ruxolitinib at a dose of 2.58 mg/kg and prednisolone reduced vascular wall fibrosis. Prednisolone treatment resulted in decreased right ventricular systolic pressure. Pulmonary vascular resistance was lower in the prednisolone and ruxolitinib (4.28 mg/kg) groups in comparison with the placebo group. The plasma level of brain natriuretic peptide was lower in groups receiving ruxolitinib at doses of 2.58 and 4.28 mg/kg versus placebo. This study demonstrated that JAK1/2 inhibitor ruxolitinib dose-dependently reduced pulmonary vascular remodeling, thereby preventing CTEPH formation in rats.

As a result of bright complexation properties, easy functionalization and the ability to self-organize in an aqueous solution, amphiphilic supramolecular macrocycles are being actively studied for their application in nanomedicine (drug delivery systems, therapeutic and theranostic agents, and others). In this regard, it is important to study their potential toxic effects. Here, the synthesis of amphiphilic calix[4]resorcinarene carboxybetaines and their esters and the study of a number of their microbiological properties are presented: cytotoxic effect on normal and tumor cells and effect on cellular and non-cellular components of blood (hemotoxicity, anti-platelet effect, and anticoagulant activity). Additionally, the interaction of macrocycles with bovine serum albumin as a model plasma protein is estimated by various methods (fluorescence spectroscopy, synchronous fluorescence spectroscopy, circular dichroic spectroscopy, and dynamic light scattering). The results demonstrate the low toxicity of the macrocycles, their anti-platelet effects at the level of acetylsalicylic acid, and weak anticoagulant activity. The study of BSA-macrocycle interactions demonstrates the dependence on macrocycle hydrophilic/hydrophobic group structure; in the case of carboxybetaines, the formation of complexes prevents self-aggregation of BSA molecules in solution. The present study demonstrates new data on potential drug delivery nanosystems based on amphiphilic calix[4]resorcinarenes for their cytotoxicity and effects on blood components.

We studied the role of both parts of the autonomic intracardiac nervous system in the pathogenesis of atrial fibrillation (AF). In 12 pigs weighing 39±3 kg, AF was induced by burst stimulation. Chemical inactivation of intrinsic cardiac neurons within the right atria was performed by transendocardial injections of liposomal neuromodulators into the dorsal part of the right atrial wall. Sympathetic and parasympathetic terminals were inactivated with 6-hydroxydopamine (6-OHDA, n=6) and ethylcholine aziridinium ion (AF64A, n=6), respectively. Neuromodulators were encapsulated in liposomes (LS) with diameters of 310±50 nm for OHDA and 290±50 nm for AF64A. LS-6-OHDA and LS-AF64A were injected into the ganglionated plexuses after measuring the baseline effective refractory period and assessing myocardial resistance to AF. These measurements were repeated 90 min after the injections. The optimal doses were 0.2 mg/kg for LS-6-OHDA and 0.4 mg/kg for LS-AF64A (in 4 ml of suspension). Immediately after injections of liposomal neuromodulators, almost all pigs showed an increase in HR, and a short-term BP elevation was observed in the LS-AF64A group. At the end of the experiment, similar decrease in the effective refractory period and similar increase in the resistance to AF were observed in all animals. Thus, selective chemical inactivation of cholinergic and adrenergic terminals of the intracardiac nervous system with liposomal neuromodulators increased the resistance to AF in an acute experiment. However, the short observation period does not allow making a definite conclusion about the role of the autonomic nervous system in the pathogenesis of AF, which requires verification of the obtained data in a chronic experiment., (© 2023. Springer Science+Business Media, LLC, part of Springer Nature.)

In this study, we investigated the effect of three different probiotics, namely, a combination of Lactobacillus acidophilus (LA-5) and Bifidobacterium animalis subsp. lactis (BB-12) , Saccharomyces boulardii , and Enterococcus faecium L3 on myocardial infarct size in rats with diet-induced obesity (DIO) and chemically-induced colitis (CIC). Potential associations between the effects of probiotics on myocardial ischemia-reperfusion injury and gut microbiome patterns as well as the serum levels of pro- and anti-inflammatory cytokines, lipopolysaccharide, and short chain fatty acids were also studied. Intragastric administration of lyophilized Lactobacillus acidophilus and Bifidobacterium animalis subsp. lactis at a dose of 1.2 × 10 8 CFU/mL for 15 days resulted in myocardial infarct size reduction in rats with DIO, CIC, and antibiotic-induced dysbiosis. This cardioprotective effect was associated with specific changes in cytokine concentrations, namely reduced levels of IL-1β, TNF-α, IL-2, and IL-8. At the same time, the use of Lactobacillus acidophilus and Bifidobacterium animalis subsp. lactis was accompanied by a significant reduction in lipopolysaccharide level, suggesting normalization of intestinal epithelial barrier permeability. However, the cardioprotective effect of Lactobacillus acidophilus and Bifidobacterium animalis subsp. lactis is not secondary to improved healing of the intestinal mucosa in CIC, as evidenced by the lack of difference in histopathological scores.

Cardiac denervation is a serious problem in a number of patients, including patients after heart transplantation. The status of the parasympathetic ganglia after crossing the preganglionic fibers of the vagus nerve has not been enough studied. The aim of our study was to assess the effect of physical training on the morphological parameters of the parasympathetic atrial ganglia and autonomic regulation of heart rate after right- and left-sided vagotomy in rats. Morphometric characteristics of the right atrial ganglia were evaluated using an immunohistochemical method after a study that included a three-time assessment of heart rate variability. It was found that right-sided vagotomy leads to both an increase in the volume of ganglion and autonomic dysfunction. No significant change in the number of nerve cells was found in animals with false and left-sided vagotomy while maintaining preganglionic innervation after the physical training, whereas exercises led to a decrease in the volume of nerve tissue of rats with right-sided denervation. It was also found that in animals with preserved vagal innervation, the volume of atrial ganglion tissue correlates with overall heart rate variability and a normalized parasympathetic component. Therefore, a positive effect from regular physical activity on parasympathetic regulation can be expected only if preganglionic vagal influence is preserved.

A series of heterocyclic compounds containing spirofused barbiturate and 3-azabicyclo[3.1.0]hexane frameworks have been studied as potential antitumor agents. Antiproliferative activity of products was screened in human erythroleukemia (K562), T lymphocyte (Jurkat), and cervical carcinoma (HeLa) as well as mouse colon carcinoma (CT26) and African green monkey kidney epithelial (Vero) cell lines. The most effective among the screened compounds show IC 50 in the range from 4.2 to 24.1 μM for all tested cell lines. The screened compounds have demonstrated a significant effect of the distribution of HeLa and CT26 cells across the cell cycle stage, with accumulation of cells in SubG1 phase and induced apoptosis. It was found, using a confocal microscopy, that actin filaments disappeared and granular actin was distributed diffusely in the cytoplasm of up to 90% of HeLa cells and up to 64% of CT26 cells after treatment with tested 3-azaspiro[bicyclo [3.1.0]hexane-2,5'-pyrimidines]. We discovered that the number of HeLa cells with filopodium-like membrane protrusions was reduced significantly (from 91% in control cells to 35%) after treatment with the most active compounds. A decrease in cell motility was also noticed. Preliminary in vivo experiments on the impact of the studied compounds on the dynamics of CT26 tumor growth in Balb/C mice were also performed.

Various gadolinium compounds have been proposed as contrasting agents for magnetic resonance imaging (MRI). In this study, we suggested a new synthesis method of gadolinium ferrate/trigadolinium pentairon(III) oxide nanoparticles (GF/TPO NPs). The specific surface area of gadolinium ferrate (GdFeO 3 ) and trigadolinium pentairon(III) oxide (Gd 3 Fe 5 O 12 ) nanoparticles was equal to 42 and 66 m 2 /g, respectively. The X-ray diffraction analysis confirmed that the synthesized substances were GdFeO 3 and Gd 3 Fe 5 O 12 . The gadolinium content in the samples was close to the theoretically calculated value. The free gadolinium content was negligible. Biodistribution of the GF/TPO NPs was studied in rats by fluorescent imaging and Fe 2+ /Fe 3+ quantification demonstrating predominant accumulation in such organs as lung, kidney, and liver. We showed in the in vivo rat model of myocardial ischemia-reperfusion injury that GF/TPO NPs are able to target the area of myocardial infarction as evidenced by the significantly greater level of fluorescence. In perspective, the use of fluorescently labeled GF/TPO NPs in multimodal imaging may provide basis for high-resolution 3D reconstruction of the infarcted heart, thereby serving as unique theranostic platform.

The effect of probiotic therapy on the main hemodynamic parameters was studied in Wistar rats with modeled syndrome of systemic inflammatory response resulting from chemically induced colitis complicated by antibiotic-induced dysbiosis. Using a wireless telemetry monitoring system in round-the-clock mode, the mean systolic and diastolic BP, HR, and body temperature were measured over 27 days. In the group of animals receiving no probiotics, a significant decrease in feed consumption and body weight loss were observed. By the end of the experiment, BP in this group was lower by 12% and HR was higher by 10% than in the control. In animals treated with a mixture of probiotic strains Lactobacillus acidophilus and Bifidobacterium animalis subsp. lactis, all the studied parameters returned to the initial values. Thus, we demonstrated the possibility of using probiotic drugs for the treatment of acute systemic inflammatory process, which should be considered in the development of new treatment protocols in veterinary and medicine., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature.)

Pulmonary embolism (PE) is the third most prevalent cardiovascular disease. It is associated with high in-hospital mortality and the development of acute and chronic complications. New approaches aimed at improving the prognosis of patients with PE are largely dependent on reliable animal models. Mice, rats, hamsters, and rabbits, are currently most commonly used for PE modeling because of their ethical acceptability and economic feasibility. This article provides an overview of the main approaches to PE modeling, and the advantages and disadvantages of each method. Special attention is paid to experimental endpoints, including morphological, functional, and molecular endpoints. All approaches to PE modeling can be broadly divided into three main groups: 1) induction of thromboembolism, either by thrombus formation in vivo or by injection of in vitro prepared blood clots; 2) introduction of particles of non-thrombotic origin; and 3) surgical procedures. The choice of a specific model and animal species is determined based on the objectives of the study. Rodent models of chronic thromboembolic pulmonary hypertension (CTEPH), which is the most devastating complication of PE, are also described. CTEPH models are especially challenging because of insufficient knowledge about the pathogenesis and high fibrinolytic activity of rodent plasma. The CTEPH model should demonstrate a persistent increase in pulmonary artery pressure and stable reduction of the vascular bed due to recurrent embolism. Based on the analysis of available evidence, one might conclude that currently, there is no single optimal method for modeling PE and CTEPH., Competing Interests: The authors declare no conflict of interest., (© 2022 The Authors.)

In this paper, we describe the synthesis of multilayer nanoparticles as a platform for the diagnosis and treatment of ischemic injuries. The platform is based on magnetite (MNP) and silica (SNP) nanoparticles, while quinacrine is used as an anti-ischemic agent. The synthesis includes the surface modification of nanoparticles with (3-glycidyloxypropyl)trimethoxysilane (GPMS), the immobilization of quinacrine, and the formation of a chitosan coating, which is used to fix the fluorophore indocyanine green (ICG) and colloidal quantum dots AgInS 2 /ZnS (CQDs), which serve as secondary radiation sources. The potential theranostic platform was studied in laboratory animals.

Numerous experimental and clinical studies have shown the effectiveness of various probiotic strains in metabolic disorders, gastrointestinal and liver diseases, immune system pathology. The effects of probiotics on cardiovascular dysfunction are less well known. The development and validation of a new experimental model in rats, including obesity, acute colon inflammation and antibiotic-induced dysbiosis, with common characteristics of systemic inflammatory response syndrome (SIRS), became the basis for investigating the effects of probiotic drugs on myocardial resistance to ischemic-reperfusion injury (IRI) using an in vivo model of infarction after coronary occlusion. A 24% increase in myocardial infarction compared to intact animals ( p < 0.05) and significant changes in leukogram, biochemical and immunological parameters were found in Wistar rats with SIRS modelling. Introduction of a mixture of strains of Lactobacillus acidophilus (LA-5) and Bifidobacterium animalis subsp. lactis (BB-12) to animals with SIRS reduced infarct size to a value close to the control. Rats treated with LA-5 and BB-12 also showed normalization of the leukocyte count, bile acids, transforming growth factor-β, interleukins: IL-1α, IL-2, IL-6, IL-8, tumor necrosis factor-α, lipopolysaccharide and monocyte chemoattractant protein-1 in blood in comparison with the SIRS group and with the groups treated with other probiotic strains. The obtained data convincingly show the prospects for further study of the cardiotropic potential of probiotic microorganisms in translational studies., Competing Interests: CONFLICT OF INTERESTThe authors declare that they have no conflicts of interest., (© Pleiades Publishing, Ltd. 2022.)

Aim: Hyperleptinemia potentiates the effects of many atherogenic factors, such as inflammation, platelet aggregation, migration, hypertrophy, proliferation of vascular smooth muscle cells, and endothelial cell dysfunction. The present study analysed the effects of long-term hyperleptinemia in an in vivo myocardial ischemia-reperfusion model to demonstrate whether the in vivo deleterious effect also affects cardiac structure and function., Main Methods: Rats were subcutaneously administered leptin for 8 days to estimate the involvement of the JAK/STAT pathway. Data from 58 male Wistar rats were included in the final analysis. Myocardial infarction (MI) was modelled by the 30-minute ligation of the main left coronary artery followed by 120-minute reperfusion. Hemodynamic measurements, electrocardiography monitoring, echocardiography, myocardial infarct size and area at risk, blood biochemical parameters, leptin, IL-6, TNF-alpha, FGF-21, and cardiomyocyte morphology were measured. The expression of JAK2, p-JAK2, STAT3, p-STAT3 was assessed by Western Blot analysis. Statistical analyses were performed using IBM SPSS Statistics v.26., Key Findings: Eight-day hyperleptinemia in rats leads to an increase in blood pressure and heart rate, myocardial hypertrophy, impaired LV function, the frequency of ischemic arrhythmias, dyslipidemia, systemic inflammation, and the size of induced myocardial infarction. Significance: The blockade of the JAK/STAT signalling pathway effectively reverses the negative effects of leptin, including increased blood pressure and total cholesterol., Competing Interests: The authors declare no conflict of interest., (© 2021 The Authors. Published by Elsevier Ltd.)

Aims: The effects of three types of bariatric interventions on myocardial infarct size were tested in the rat model of type 2 diabetes mellitus (T2DM). We also evaluated the effects of bariatric surgery on no-reflow phenomenon and vascular dysfunction caused by T2DM., Main Methods: Rats with T2DM were assigned into groups: without surgery, sham-operated, ileal transposition, Roux-en-Y gastric bypass, and sleeve gastrectomy. Oral glucose tolerance, glucagon-like peptide-1, and insulin levels were measured. Six weeks after surgery, the animals were subjected to myocardial ischemia-reperfusion followed by histochemical determination of infarct size (IS), no-reflow zone, and blood stasis area size. Vascular dysfunction was characterized using wire myography., Key Findings: All bariatric surgery types caused significant reductions in animal body weight and resulted in T2DM compensation. All bariatric interventions partially normalized glucagon-like peptide-1 responses attenuated by T2DM. IS was significantly smaller in animals with T2DM. Bariatric surgery provided no additional IS limitation compared with T2DM alone. Bariatric surgeries reversed T2DM-induced enhanced contractile responses of the mesenteric artery to 5-hydroxytryptamine. Sleeve gastrectomy normalized decreased nitric oxide synthase contribution to the endothelium-dependent vasodilatation in T2DM., Significance: T2DM resulted in a reduction of infarct size and no-reflow zone size. Bariatric surgery provided no additional infarct-limiting effect, but it normalized T2DM-induced augmented vascular contractility and reversed decreased contribution of nitric oxide to endothelium-dependent vasodilatation typical of T2DM. All taken together, we suggest that this type of surgery may have a beneficial effect on T2DM-induced cardiovascular diseases., (Copyright © 2021. Published by Elsevier Inc.)

U46619, a synthetic analogue of thromboxane A2 was used for modeling acute stable and reversible pulmonary arterial hypertension. Administration of U46619 in high doses led to vascular collapse and inhibition of cardiac function. The doses of U46619 were empirically selected that allow attaining the target level of pulmonary hypertension without systemic hemodynamic disturbances. The possibility of attaining the target level of pulmonary hypertension and reversibility of changes after termination of U46619 infusion make this model attractive for evaluation of the efficiency of different therapeutic methods of treatment of pulmonary hypertension in large animals.

The study focuses on the effects of azithromycin on severity of ischemia/reperfusion myocardial injury during simulated systemic inflammatory response syndrome (SIRS) in primary visceral obesity (PVO). Total ischemia/reperfusion was modeled by Langendorff perfusion of isolated heart with following estimation of the size of myocardial infarction. SIRS was accompanied by an increase in blood levels of proinflammatory cytokines and LPS. Combination of PVO and SIRS produced no significant changes in the infarct size compared to the control. Administration of azithromycin to rats with PVO and SIRS resulted in pronounced alterations of biochemical and immunological parameters, although it did not affect the infarct size. In contrast, the use of tetracycline increased the size of myocardial infarction. This phenomenon should be taken into consideration in antimicrobial therapy.

Seasonal dynamics in biological functions of mammals is regulated by melatonin-mediated circannual fluctuations in the secretion of thyroid-stimulating hormone (TSH) and thyroid hormones. Most anatomical and molecular structures responsive to photoperiod and melatonin secretion changes and the associated receptors are preserved in modern humans. This work aimed to determine the seasonal dynamics of TSH and thyroid hormone levels (total triiodothyronine (T3), free triiodothyronine (FT3), thyroxine (T4), free thyroxine (FT4) and to investigate the dependence of these variations on gender, age and amplitude of meteorological fluctuations. A meta-analysis of 13 panel and 7 cross-sectional studies was performed using Review Manager 5.3 (Cochrane Library). We found that circulating TSH levels were higher in winter than in other seasons, and FT4 levels were higher in autumn than in winter. T4 level had no pronounced seasonal dynamics. The level of circulating T3 was significantly higher in winter than in summer and FT3 levels were lower in summer than in autumn and spring. In addition, analysis of TSH seasonal dynamics (winter vs summer) accounting for gender differences showed pronounced increases in TSH levels during winter in women, but not in men; and also significant increases in FT4 levels during summer in men, but not in women. Seasonal dynamics of FT3 and T4 did not depend on gender. Seasonal dynamics of TSH did not change with respect to age. We also found that the extent of the seasonal dynamics of TSH is influenced by the extent of the annual dynamics of the partial density of oxygen in the air, as well as the magnitude of the annual dynamic of meteorological factors that determine it (atmospheric pressure and relative humidity).

Heart failure is common in adult population, accounting for substantial morbidity and mortality worldwide. The main risk factors for heart failure are coronary artery disease, hypertension, obesity, diabetes mellitus, chronic pulmonary diseases, family history of cardiovascular diseases, cardiotoxic therapy. The main factor associated with poor outcome of these patients is constant progression of heart failure. In the current review we present evidence on the role of established and candidate neurohumoral biomarkers for heart failure progression management and diagnostics. A growing number of biomarkers have been proposed as potentially useful in heart failure patients, but not one of them still resembles the characteristics of the "ideal biomarker." A single marker will hardly perform well for screening, diagnostic, prognostic, and therapeutic management purposes. Moreover, the pathophysiological and clinical significance of biomarkers may depend on the presentation, stage, and severity of the disease. The authors cover main classification of heart failure phenotypes, based on the measurement of left ventricular ejection fraction, including heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, and the recently proposed category heart failure with mid-range ejection fraction. One could envisage specific sets of biomarker with different performances in heart failure progression with different left ventricular ejection fraction especially as concerns prediction of the future course of the disease and of left ventricular adverse/reverse remodeling. This article is intended to provide an overview of basic and additional mechanisms of heart failure progression will contribute to a more comprehensive knowledge of the disease pathogenesis., (Copyright and License information: Journal of Geriatric Cardiology 2021.)

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare and life-threatening complication of pulmonary embolism. As existing animal models of CTEPH do not fully recapitulate complex disease pathophysiology, we report a new rat model for CTEPH evoked by repetitive embolization of the distal pulmonary artery branches with partially biodegradable alginate microspheres (MSs). MSs (180 ± 28 μm) were intravenously administered eight times at 4-day intervals; control animals received saline. The validity of the model was confirmed using transthoracic echocardiography, exercise testing, catheterization of the right ventricle, and histological examination of the lung and heart. The animals in the CTEPH group demonstrated a stable increase in right ventricular systolic pressure (RVSP) and decreased exercise tolerance. Histopathological examination revealed advanced medial hypertrophy in the small pulmonary arteries associated with fibrosis. The diameter of the main pulmonary artery was significantly larger in the CTEPH group than in the control group. Marinobufagenin and endothelin-1 serum levels were significantly elevated in rats with CTEPH. In conclusion, repetitive administration of alginate MSs in rats resulted in CTEPH development characterized by specific lung vasculature remodeling, reduced exercise tolerance, and a persistent rise in RVSP. The developed model can be used for pre-clinical testing of promising drug candidates.

Background: MicroRNA (miRNAs) participate in the pathogenesis of coronary artery disease (CAD)., Objective: To evaluate the expressions of myocardial and serum miRNA-27а, miRNA-133а, and miRNA-203 in CAD patients., Method: This cross-sectional observational study comprised 100 subjects (60.9 ± 1.0 years; 67% men). The right atrial and serum expressions of miRNA-27a, miRNA -133a, and miRNA-203 in 80 patients referred for elective coronary artery bypass graft surgery (CABG) and 20 control patients scheduled for heart valve surgery were analyzed using real-time polymerase chain reaction., Results: There was a positive correlation between the SYNTAX score I index and serum miRNA-203 expression level (r = 0.693; p < .001). Patients with ≥3 coronary artery lesions had significantly higher myocardial expressions of miRNA-27a, miRNA-133а, and miRNA-203 than patients with 1-2 vessel disease in the atrial myocardium (miRNA-27a: 234.62 ± 29.51 vs. 182.39 ± 19.62 relative expression unit (REU); miRNA-133а: 127.53 ± 13.41 vs. 111.35 ± 12.31 REU; and miRNA-203: 5.25 ± 0.96 vs. 4.71 ± 0.67 REU; р < 0.05); the same association was found for serum miRNA expressions (miRNA-27a: 11.41 ± 3.85 vs. 4.82 ± 1.82 REU; miRNA-133а: 8.42 ± 2.43 vs. 4.35 ± 1.23 REU; and miRNA-203: 145.71 ± 15.73 vs. 43.70 ± 9.67 REU; р < 0.05). The decision tree method established that the risk of multivessel lesions was increased five-fold if the miRNA-203 serum expression was >101.00 REU (OR, 5.90; 95% CI, 2.34-9.46; p < .001)., Conclusions: Both myocardial and serum miRNA-27а, miRNA-133а, and miRNA-203 expressions are higher in CABG patients than in non-CAD subjects. The serum miRNA-203 expression level corresponds to myocardial expression and is strongly correlated with the extent of coronary atherosclerosis., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2020. Published by Elsevier B.V.)

For studying the possibility of using catheter denervation of the pulmonary artery for the treatment of pulmonary hypertension, large animals, such as pigs, are more suitable, because the diameter of the pulmonary artery in this case allows manipulation of the ablation catheter. The study of the perivascular adipose tissue of the trunk and bifurcation of the pulmonary artery in humans and pigs revealed differences in the density and diameter of nerve fibers, but their depth did not differ. Immunohistochemical analysis with different markers of the autonomic nervous system receptors revealed similar receptor profile in human and pigs, though the expression of all studied markers in pigs was less pronounced than in humans. These findings attest to similarity of the innervation of the pulmonary arteries in humans and pigs under normal conditions.

Morphological analysis of the respiratory tract of Wistar rats was performed after a single parenteral administration of 12-nm silicon dioxide nanoparticles (1 ml, 2 mg/ml, intravenously) was performed. On day 21 and in 2, 4, and 6 months after the administration of nanoparticles, the development of macrophage infiltration in the interstitium of the respiratory tract was demonstrated by histological and immunohistochemical methods. The pool of alveolar macrophages increased in 4 months after administration (p=0.004) and returned to the control values in 6 months. The number of mast cells did not significantly change at all stages of the experiment. Connective tissue remodeling in the interstitium of the respiratory tract was not observed throughout the observation period.

Background: Previous studies implicated cardiotonic steroids, including Na/K-ATPase inhibitor marinobufagenin (MBG), in the pathogenesis of preeclampsia (PE). We demonstrated that MBG induces fibrosis via mechanism involving inhibition of Fli1, a nuclear transcription factor and a negative regulator of collagen-1 synthesis. We hypothesized that PE blockade of increased MBG with antibody would lessen the fibrosis of umbilical arteries and lower the blood pressure in rats with PE., Methods: We tested 36 pregnant Sprague-Dawley rats in which 12 were made hypertensive by 1.8% Na supplementation (days 6-19 of gestation), 12 pregnant rats served controls. At day 19, PE rats received one intraperitoneal injection of polyclonal anti-MBG-4 antibody (0.5 ug/ml) for 4 hours., Results: PE was associated with higher blood pressure (117 ± 2 vs. 107 ± 2 mm Hg; P < 0.01), plasma MBG levels (1.54 ± 0.34 vs. 0.49 ± 0.11 nmol/L; P < 0.01), protein excretion (26 vs. 12 mg/24 hours), sFlt-1 (3-fold), decrease in Fli1 (7-fold) and increase in collagen-1 in aorta (4-fold) vs. control rats (all P < 0.01). In 12 rats treated with polyclonal anti-MBG-4 antibody blood pressure dropped (93 ± 3 mm Hg) and Fli1 was decreased much less (2-fold; P < 0.01 vs. nontreated rats)., Conclusions: These results demonstrate that in experimental PE elevated MBG level is implicated in umbilical fibrosis via suppression of Fli1., (© American Journal of Hypertension, Ltd 2019. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

We studied the effect of metformin (100 and 200 mg/kg/day, 4 weeks) on the adenylyl cyclasestimulating effects of β-agonists and relaxin in the myocardial membranes and on activities of Akt-kinase, an effector component of insulin signaling, and AMP-activated protein kinase (AMPK), a cellular energy sensor, in the myocardium of rats with type 2 diabetes mellitus induced by high-fat diet and streptozotocin. Metformin normalized the ratio of adenylyl cyclase effects of β 1/2 - and β 3 -agonists in the myocardial membranes, that is reduced in DM2, and restored phosphorylation of Akt-kinase by Ser473 and AMPK by Thr172 in the myocardium of diabetic rats. The effect of metformin in a dose of 200 mg/kg/day was more pronounced. Thus, the cardioprotective effect of metformin is due to its ability to restore the adrenergic and insulin regulation in cardiomyocytes and their energy status.

Tumor resistance to chemotherapy represents an important challenge in modern oncology. Although platinum (Pt)-based drugs have demonstrated excellent therapeutic potential, their effectiveness in a wide range of tumors is limited by the development of resistance mechanisms. One of these mechanisms includes increased cisplatin sequestration/efflux by the copper-transporting ATPase, ATP7B. However, targeting ATP7B to reduce Pt tolerance in tumors could represent a serious risk because suppression of ATP7B might compromise copper homeostasis, as happens in Wilson disease. To circumvent ATP7B-mediated Pt tolerance we employed a high-throughput screen (HTS) of an FDA/EMA-approved drug library to detect safe therapeutic molecules that promote cisplatin toxicity in the IGROV-CP20 ovarian carcinoma cells, whose resistance significantly relies on ATP7B. Using a synthetic lethality approach, we identified and validated three hits (Tranilast, Telmisartan, and Amphotericin B) that reduced cisplatin resistance. All three drugs induced Pt-mediated DNA damage and inhibited either expression or trafficking of ATP7B in a tumor-specific manner. Global transcriptome analyses showed that Tranilast and Amphotericin B affect expression of genes operating in several pathways that confer tolerance to cisplatin. In the case of Tranilast, these comprised key Pt-transporting proteins, including ATOX1, whose suppression affected ability of ATP7B to traffic in response to cisplatin. In summary, our findings reveal Tranilast, Telmisartan, and Amphotericin B as effective drugs that selectively promote cisplatin toxicity in Pt-resistant ovarian cancer cells and underscore the efficiency of HTS strategy for identification of biosafe compounds, which might be rapidly repurposed to overcome resistance of tumors to Pt-based chemotherapy.

We studied the effect of combined antimicrobial therapy with amoxicillin, metronidazole, and clarithromycin on the severity of ischemia/reperfusion myocardial injury in Wistar rats with alimentary obesity and acute inflammation of the large intestine. General ischemia/reperfusion was reproduced on Langendorff-perfused isolated hearts and infarct size was estimated. Acute inflammation of the large intestine was accompanied by an increase in the blood levels of proinflammatory cytokines. The presence of obesity and acute inflammation of the large intestine did not significantly affect the infarct size in comparison with the control. Administration of antimicrobial drugs to animals with obesity and acute inflammation of the large intestine led to a significant increase in the infarct size, which should be considered when prescribing antimicrobial therapy to patients with comorbidity.

The effects of bariatric surgeries (sleeve gastrectomy and ileal transposition) on the dynamics of changes in ghrelin level were studied in rats with severe decompensated type 2 diabetes mellitus under conditions of glucose challenge as well as on the size of myocardial infarction in these animals. Diabetes was modelled by high fat diet and a single administration of streptozotocin (25 mg/kg, intraperitoneally). Both bariatric surgeries significantly decreased glucose-induced ghrelin level in the blood of rats with type 2 diabetes mellitus, which attested to an increase in the tissue sensitivity to ghrelin. Sleeve gastrectomy resulted in a decrease in the size of myocardial infarction in diabetic rats, which was calculated as the ratio of the necrosis zone to the zone of the risk of myocardial infarction. Ileal transposition had no effect on this parameter. Our data can be used as the basis for optimization of treatment approaches when using bariatric surgery in the treatment of patients with severe forms of type 2 diabetes mellitus with a high risk of cardiovascular diseases.

The prevalence of dementia worldwide is growing at an alarming rate. A number of studies and meta-analyses have provided evidence for increased risk of dementia in patients with metabolic syndrome (MS) as compared to persons without MS. However, there are some reports demonstrating a lack of association between MS and increased dementia risk. In this review, taking into account the potential role of individual MS components in the pathogenesis of MS-related cognitive dysfunction, we considered the underlying mechanisms in arterial hypertension, diabetes mellitus, dyslipidemia, and obesity. The pathogenesis of dementia in MS is multifactorial, involving both vascular injury and non-ischemic neuronal death due to neurodegeneration. Neurodegenerative and ischemic lesions do not simply coexist in the brain due to independent evolution, but rather exacerbate each other, leading to more severe consequences for cognition than would either pathology alone. In addition to universal mechanisms of cognitive dysfunction shared by all MS components, other pathogenetic pathways leading to cognitive deficits and dementia, which are specific for each component, also play a role. Examples of such component-specific pathogenetic pathways include central insulin resistance and hypoglycemia in diabetes, neuroinflammation and adipokine imbalance in obesity, as well as arteriolosclerosis and lipohyalinosis in arterial hypertension. A more detailed understanding of cognitive disorders based on the recognition of underlying molecular mechanisms will aid in the development of new methods for prevention and treatment of devastating cognitive problems in MS., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Recent evidence suggests that antibiotic-induced changes in the composition of intestinal microflora, as well as the systemic immunoendocrine effects that result from them, can modulate myocardial tolerance to ischemia-reperfusion injury. The aim of this study was to investigate the effects of tetracycline (TTC) on myocardial infarct size in the isolated hearts obtained from obese rats with chemically-induced colitis (CIC). The association between TTC-induced changes in infarct size and intestinal microbiome composition as well as plasma levels of cytokines and short-chain fatty acids (SCFAs) was also studied., Methods: Obesity was induced in Wistar rats by feeding them a high-fat, high-carbohydrate diet for five weeks. A single rectal administration of 3% acetic acid (2 mL) to the rats resulted in CIC. Healthy rats as well as obese rats with CIC received TTC (15 mg daily for 3 days) via gavage. The rats were euthanized, after which isolated heart perfusion with simulated global ischemia and reperfusion was performed. Infarct size was determined histochemically. Lipopolysaccharide (LPS) and cytokine levels in plasma were measured by enzyme-linked immunosorbent assay, whereas SCFA levels in plasma were measured by gas chromatography/mass spectrometry. The intestinal microbiome was analyzed using reverse transcription polymerase chain reaction., Results: The treatment with TTC resulted in significant infarct size limitation (50 ± 7 vs. 62 ± 4% for the control mice, p < 0.05) in the hearts from intact animals. However, infarct size was not different between the control rats and the obese rats with CIC. Furthermore, infarct size was significantly larger in TTC-treated obese rats with CIC than it was in the control animals (77 ± 5%, p < 0.05). The concentrations of proinflammatory cytokines and LPS in serum were elevated in the obese rats with CIC. Compared to the control rats, the rats with both obesity and CIC had lower counts of Lactobacillus and Bifidobacterium spp. but higher counts of Escherichia coli. The effects of TTC on infarct size were not associated with specific changes in SCFA levels., Conclusions: TTC reduced infarct size in the healthy rats. However, this effect was reversed in the obese animals with CIC. Additionally, it was associated with specific changes in gut microbiota and significantly elevated levels of cytokines and LPS., Competing Interests: The authors have declared that no competing interests exist.

A major translational barrier to the use of stem cell (SC)-based therapy in patients with myocardial infarction (MI) is the lack of a clear understanding of the mechanism(s) underlying the cardioprotective effect of SCs. Numerous paracrine factors from SCs may account for reduction in infarct size, but myocardial salvage associated with transdifferentiation of SCs into vascular cells as well as cardiomyocyte-like cells may be involved too. In this study, bone marrow-derived rat mesenchymal SC (MSCs) were microencapsulated in alginate preventing viable cell release while supporting their secretory phenotype. The hypothesis on the key role of paracrine factors from MSCs in their cardioprotective activity was tested by comparison of the effect of encapsulated vs free MSCs in the rat model of MI. Intramyocardial administration of both free and encapsulated MSCs after MI caused reduction in scar size (12.1 ± 6.83 and 14.7 ± 4.26%, respectively, vs 21.7 ± 6.88% in controls, P = 0.015 and P = 0.03 respectively). Scar size was not different in animals treated with free and encapsulated MSC (P = 0.637). These data provide evidence that MSC-derived growth factors and cytokines are crucial for cardioprotection elicited by MSC. Administration of either free or encapsulated MSCs was not arrhythmogenic in non-infarcted rats. The consistency of our data with the results of other studies on the major role of MSC secretome components in cardiac protection further support the theory that the use of live, though encapsulated, cells for MI therapy may be replaced with heart-targeted-sustained delivery of growth factors/cytokines., (© 2019 The Authors. International Journal of Experimental Pathology © 2019 International Journal of Experimental Pathology.)

Changes in morphofunctional parameters of the isolated heart subjected to global ischemia-reperfusion were studied in SPF Wistar rats with antibiotic-induced dysbiosis (AID) treated with lyophilized yeast Saccharomyces boulardii and inactivated probiotic bacteria Lactobacillus reuteri KR2017. In contrast to S. boulardii, correction of dysbiosis with L. reuteri KR2017 against the background of gastric hypersecretion and standard antimicrobial therapy led to an increase in fat content and a decrease in free and bound water in tissues and to a significant reduction in myocardial infarct size caused by ischemia/ reperfusion injury.

Age-related changes in thermoregulation occur due to the deterioration of the adaptive capacity of the cardiovascular system caused by remodeling of the vascular wall and myocardium, capillary density reduction, changes in the synthesis and clearance of neurotransmitters and vasoactive substances, as well as the inhibition of the vegetative mechanisms of hemodynamic parameters regulation. A common way to simulate hyper- and hypothermal conditions is to use a suit with tubes to fill with water at different temperatures. The purpose of this work is to conduct a meta-analysis of the hemodynamic parameters shifts when modeling hyper- and hypothermia using such a suit in people of different age groups. As a result of the meta-analysis, it was found that heating the whole body is accompanied by a decrease in blood pressure (BP) and an increase in heart rate (HR). The reaction of hemodynamic parameters to hyperthermia does not significantly change with aging. Cooling of the whole body is accompanied by an increase in BP without changing the HR. In hypothermia, the amplitude of the elevation of the systolic BP is greater in older people.

Currently, one of the approaches to correct metabolic disorders in the type 2 diabetes mellitus (DM2) with obesity are bariatric surgery (BS), including sleeve gastrectomy (SG), gastric bypass (GB) and ileal transposition (IT). However, their effectiveness and impact on the hypothalamic signaling and hormonal status in severe forms of DM2 without obesity remain little studied. The aim of the work was to study the effect of IT, SG and GB on the insulin, leptin, ghrelin and glucagon-like peptide-1 (GLP-1) levels in the blood and on the expression of the genes encoding the main components of the hypothalamic signaling systems in rats with decompensated form of DM2, which was induced by a high-fat diet (3 months) and a single low dose of streptozotocin (25 mg/kg, 2 months after the start of the diet). In diabetic rats, a significantly expressed hyperglycemia, an impaired glucose tolerance, a decrease in glucose-stimulated GLP-1 level, a slight decrease in the insulin and leptin levels and an slight increase in ghrelin level were detected. In the hypothalamus, the expression of the genes encoding GLP-1 receptor, orexigenic agouti-related peptide (AgRP), as well as phosphotyrosine phosphatase 1B and SOCS3, the negative regulators of the leptin and insulin pathways was increased. In diabetic rats, the IT reduced the glucose levels 120 minutes after glucose load, increased the basal and glucose-stimulated GLP-1 levels, normalized the gene expression for phosphotyrosine phosphatase 1B, SOCS3, AgRP and GLP-1 receptor, which indicates the restoration of the hypothalamic signaling responsible for the control of energy metabolism and insulin sensitivity. In the case of SG and GB, an improvement in the glucose tolerance was found, and in the case of SG, an increase in the basal and glucose-stimulated GLP-1 levels was shown. However, no significant effect on the expression of the hypothalamic genes in SG and GB was found. Thus, IT is the most effective of all studied BS in the treatment of severe forms of DM2 without obesity.

Aims: Because the mechanism of mature cardiomyocyte (CM) development from cardiac stem cells (CSCs) is not fully understood, we explored the involvement of CSCs into two pathways of cardiomyogenesis in adult mammalian heart: (1) via colony formation and (2) by means of intracellular development of CSCs inside CMs followed by the formation of "cell-in-cell structures" (CICSs)., Methods and Results: Using immunostaining and confocal microscopy, we studied the presence of CSC-derived colonies, CICSs and transitory amplifying cells (TACs), released from ruptured CICSs, in a suspension of ex vivo freshly isolated myocardial cells of mammals of different age and species, human including. All subsets of CSCs (c-kit+, Sca-1+ and Isl-1+) were found in mammals of different age. It was shown that c-kit+ and Sca-1+ CSCs produce both colonies and CICSs. However, Isl-1+ CSCs seem to be involved in cardiac growth during first month of age only both through colony formation and CICS generation. In turn, the studies on myocardial cell suspensions of adult C57/bl6N mice, one-year-old bull and 45-year-old woman not only confirmed the involvement of c-kit+ and Sca-1+ CSCs in both mechanisms of cardiomyogenesis, but also showed that Isl-1+ colonies are present in the myocardium of adult mice and rarely in human., Conclusions: The presence of CSC-derived colonies, CICSs and TACs in all experimental specimens of myocardium proved our previous hypothesis about two pathways that generate new CMs in adult heart. Moreover, we suggest that TACs play a central role in self-renewal of myocardium throughout the lifetime of mammals., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

Aim: To evaluate the effects of glucagon-like peptide-1 analogs (GLP-1a) combined with insulin on myocardial ischemia-reperfusion injury in diabetic rats., Methods: Type 2 diabetes mellitus (T2DM) was induced in male Wistar rats with streptozotocin (65 mg/kg) and verified using an oral glucose tolerance test. After anesthesia, the left coronary artery was occluded for 40 min followed by 80 min reperfusion. Blood glucose level was measured during surgery. Rats were randomized into six groups as follows: (1) control rats; (2) insulin (0.1 U/kg) treated rats prior to ischemia; (3) insulin (0.1 U/kg) treated rats at reperfusion; (4) GLP-1a (140 mg/kg) treated rats prior to ischemia; (5) GLP-1a (140 mg/kg) treated rats at reperfusion; and (6) rats treated with GLP-1a (140 mg/kg) prior to ischemia plus insulin (0.1 U/kg) at reperfusion. Myocardial area at risk and infarct size was measured planimetrically using Evans blue and triphenyltetrazolium chloride staining, respectively., Results: There was no significant difference in the myocardial area at risk among groups. Insulin treatment before ischemia resulted in a significant increase in infarct size (34.7% ± 3.4% vs 18.6% ± 3.1% in the control rats, P < 0.05). Post-ischemic administration of insulin or GLP-1a had no effect on infarct size. However, pre-ischemic administration of GLP-1a reduced infarct size to 12% ± 2.2% ( P < 0.05). The maximal infarct size reduction was observed in the group treated with GLP-1a prior to ischemia and insulin at reperfusion (8% ± 1.6%, P < 0.05 vs the control and GLP-1a alone treated groups)., Conclusion: GLP-1a pre-administration results in myocardial infarct size reduction in rats with T2DM. These effects are maximal in rats treated with GLP-1a pre-ischemia plus insulin at reperfusion., Competing Interests: Institutional animal care and use committee statement: All animal experiments were performed according to the Guide for the Care and Use of Laboratory Animals in Almazov National Medical Research Centre, which strictly conforms to the Guide for the Care and Use of Laboratory Animals, published by the US National Institutes of Health (NIH, Bethesda, MD). The protocol was approved by the Institutional Animal Care and Use Committee of Almazov National Medical Research Centre (protocol #2016-3).

Use of mesenchymal stem cell (MSC) transplantation after myocardial infarction (MI) has been found to have infarct-limiting effects in numerous experimental and clinical studies. However, recent meta-analyses of randomized clinical trials on MSC-based MI therapy have highlighted the need for improving its efficacy. There are two principal approaches for increasing therapeutic effect of MSCs: (i) preventing massive MSC death in ischaemic tissue and (ii) increasing production of cardioreparative growth factors and cytokines with transplanted MSCs. In this review, we aim to integrate our current understanding of genetic approaches that are used for modification of MSCs to enable their improved survival, engraftment, integration, proliferation and differentiation in the ischaemic heart. Genetic modification of MSCs resulting in increased secretion of paracrine factors has also been discussed. In addition, data on MSC preconditioning with physical, chemical and pharmacological factors prior to transplantation are summarized. MSC seeding on three-dimensional polymeric scaffolds facilitates formation of both intercellular connections and contacts between cells and the extracellular matrix, thereby enhancing cell viability and function. Use of genetic and non-genetic approaches to modify MSC function holds great promise for regenerative therapy of myocardial ischaemic injury., (© 2016 John Wiley & Sons Ltd.)

Over the last decade, magnetic iron oxide nanoparticles (IONPs) have drawn much attention for their potential biomedical applications. However, serious in vitro and in vivo safety concerns continue to exist. In this study, the effects of uncoated, Fe m O n -SiO 2 composite flake-like, and SiO 2 -Fe m O n core-shell IONPs on cell viability, function, and morphology were tested 48 h postincubation in human umbilical vein endothelial cell culture. Cell viability and apoptosis/necrosis rate were determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and annexin V-phycoerythrin kit, respectively. Cell morphology was evaluated using bright-field microscopy and forward and lateral light scattering profiles obtained with flow cytometry analysis. All tested IONP types were used at three different doses, that is, 0.7, 7.0, and 70.0 μg. Dose-dependent changes in cell morphology, viability, and apoptosis rate were shown. At higher doses, all types of IONPs caused formation of binucleated cells suggesting impaired cytokinesis. Fe m O n -SiO 2 composite flake-like and SiO 2 -Fe m O n core-shell IONPs were characterized by similar profile of cytotoxicity, whereas bare IONPs were shown to be less toxic. The presence of either silica core or silica nanoflakes in composite IONPs can promote cytotoxic effects., Competing Interests: The authors report no conflicts of interest in this work.