Hemodynamic Parameters in Spontaneously Hypertensive Rats with Obesity and Chemically Induced Colitis during Probiotic Therapy.

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.

The Pattern of Granuloma Formation in the Liver of Rats as a Reflection of the Mechanism of Internalization of Submicron Silicon Particles.

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 µm2), 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.

The Use of Microencapsulated Autologous Thrombi for Modelling Chronic Thromboembolic Pulmonary Hypertension in Rats.

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.

Influence of Interleukin-2 and Brain-Derived Neurotrophic Factor (BDNF) on the Size of Myocardial Infarction in Rats with Systemic Inflammatory Response.

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.

The Effect of Probiotic Strains on Myocardial Infarction Size, Biochemical and Immunological Parameters in Rats with Systemic Inflammatory Response Syndrome and Polymorbidity.

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-ß, 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.

Effect of Probiotic Therapy on Hemodynamic Response Associated with Systemic Inflammatory Reaction and Antibiotic-Induced Dysbiosis in Chronic Experiments in Rats.

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.

Acute Effect of Selective Chemical Inactivation of Sympathetic or Parasympathetic Atrial Ganglionated Plexus Structures on Atrial Fibrillation Inducibility in Pigs.

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.

Dependence of seasonal dynamics of hemorrhagic and ischemic strokes on the climate of a region: A meta-analysis.

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.

Modeling of Acute Pulmonary Arterial Hypertension in Pigs Using a Stable Thromboxane A2 Analogue (U46619): Dose Adjustment and Assessment of Hemodynamic Reactions.

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.

Effect of Azithromycin on Myocardial Resistance to Ischemia/Reperfusion in Systemic Inflammatory Response Syndrome and Alimentary Obesity.

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 variations in levels of human thyroid-stimulating hormone and thyroid hormones: a meta-analysis.

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).

Association of myocardial and serum miRNA expression patterns with the presence and extent of coronary artery disease: A cross-sectional study.

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.

Perivascular Innervation of the Pulmonary Artery in Human and Swine: A Comparative Study for the Development of an Experimental Model of Denervation.

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 Rats after Parenteral Administration of Silicon Dioxide Nanoparticles.

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.

Restoration of ß-Adrenergic Signaling and Activity of Akt-Kinase and AMP-Activated Protein Kinase with Metformin in the Myocardium of Diabetic Rats.

We studied the effect of metformin (100 and 200 mg/kg/day, 4 weeks) on the adenylyl cyclasestimulating effects of ß-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 ß1/2- and ß3-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.

Effect of Combined Antimicrobial Therapy on Ischemia/Reperfusion Myocardial Injury in Rats with Acute Inflammation of the Large Intestine against the Background of Alimentary Obesity.

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.

Effects of Bariatric Surgeries on the Size of Myocardial Infarction and Ghrelin Level in Rats with Experimental Decompensated Type 2 Diabetes Mellitus.

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 effect of different types of bariatric surgery on the metabolic and hormonal parameters in rats with decompensed form of type 2 diabetes mellitus.]

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.

Effect of Antiobiotic-Induced Disbiosis and Its Correction with Probiotics on Myocardial Tolerance to Ischemia-Reperfusion Injury in SPF Rats.

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.

[Effects of hyper- and hypothermia on hemodynamic parameters in people of different age groups. Meta-analysis.]

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.