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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. [ABSTRACT FROM AUTHOR]

This study aimed to assess the relationship between malnutrition and anemia in patients with ulcerative colitis (UC). The cross-sectional retrospective study included 80 patients with UC. Body mass index and total body fat mass were derived retrospectively from bioimpedance measurements. Anemia was diagnosed retrospectively according to WHO criteria. A binary logistic regression was performed to study the relationship between nutritional status parameters and anemia, and adjusted for demographic and disease-associated characteristics. The prevalence of anemia in the study population was 40.0%. Among all included patients, 86.3% had acute disease corresponding to S1–S3 disease behavior. In the adjusted binary logistic model, total serum protein level below 64 g/L and low body fat percentage were associated with high odds for the of development of anemia, with odds ratios of 5.1 (95% CI 1.5; 17.8; p = 0.01) and 8.5 (95% CI 1.1; 63.6; p = 0.037), respectively. The adjusted model included sex, age, disease activity, extent of gut involvement, quantity of relapses from disease onset, and treatment with immunosuppressive drugs as confounders. Hypoproteinemia and low body fat percentage were associated with anemia in patients with UC. These results suggested that undernutrition may be involved as one of the causative factors of anemia in UC. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 × 108 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. [ABSTRACT FROM AUTHOR]

The aim of the present study was to develop magnetic liposomes (MLPSs) incorporating an agent with the ability to act both as a photosensitizer and as a fluorophore for optical imaging. We therefore aimed to develop a preparation method for indocyanine green (ICG)-containing MLPS, followed by a detailed characterization of their physicochemical and magnetic properties. The ability of intravenously administered ICG-containing MLPSs to accumulate in tissue exposed to a constant magnetic field was tested in vivo. Using the thin film hydration method, 170-nm aqueous liposomes containing magnetic nanoparticles and indocyanine green were synthesized, followed by a detailed characterization of their physicochemical properties. It was shown that ICG-containing MLPSs possess the properties of T2 contrast for MRI. Apart from this, ICG-containing MLPSs were clearly visualized using near infrared fluorescent imaging, which was demonstrated in in vivo experiments showing an accumulation of ICG-containing MLPSs in the zone of magnetic field distribution produced by a previously implanted constant magnet in the tissue. Although not directly tested in the present study, therapeutic applications of ICG-containing MLPSs include magnetic hyperthermia, as well as the photodynamic, photothermal, and photoacoustic effects of ICG. Taking into account the fact that liposomes, iron oxide nanoparticles, and ICG are all FDA-approved agents, it is highly likely that ICG-containing MLPSs could be successfully translated to clinical practice. [ABSTRACT FROM AUTHOR]

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 IC50 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. [ABSTRACT FROM AUTHOR]

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 (GdFeO3) and trigadolinium pentairon(III) oxide (Gd3Fe5O12) nanoparticles was equal to 42 and 66 m2/g, respectively. The X-ray diffraction analysis confirmed that the synthesized substances were GdFeO3 and Gd3Fe5O12. 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 Fe2+/Fe3+ 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Summary: 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Silicon-containing nanoparticles (NPs) are considered promising drug carriers for targeted drug delivery. In this study, we investigated the physical and chemical properties of silicon-containing NPs, including silica and organomodified silica NPs (SiO2NPs and OrSiO2NPs, respectively), with different surface modifications, with the aim of increasing drug-loading efficiency. In addition, we described the original synthesis methods of different sizes of OrSiO2NPs, as well as new hybrid OrSiO2NPs with a silica core (SiO2 + OrSiO2NPs). Animal experiments revealed that the silicon-containing NPs investigated were non-toxic, as evidenced by a lack of hemodynamic response after intravenous administration. Bioelimination studies showed rapid renal excretion of OrSiO2NPs. In drug release kinetics studies, adenosine was immobilized on SiO2NPs using three different approaches: physical adsorption, ionic, and covalent bonding. We observed that the rate of adenosine desorption critically depended on the type of immobilization; therefore, adenosine release kinetics can be adjusted by SiO2NP surface modification technique. Adsorption of adenosine on SiO2 + OrSiO2NPs resulted in a significant attenuation of adenosine-induced hypotension and bradycardia. [ABSTRACT FROM PUBLISHER]

Background Several studies have demonstrated that local ischemic preconditioning can reduce myocardial ischemia-reperfusion injury in cardiac surgery patients; however, preconditioning has not become a standard cardioprotective intervention, primarily because of the increased risk of atheroembolism during repetitive aortic cross-clamping. In the present study, we aimed to describe and validate a novel technique of preconditioning induction. Methods Patients undergoing coronary artery bypass grafting (12 women and 78 men; mean age, 56 ± 11 years) were randomized into 3 groups: (1) Controls (n = 30), (2) Perfusion (n = 30), and (3) Preconditioning (n = 30). All patients were operated under cardiopulmonary bypass using normothermic blood cardioplegia. Preconditioning was induced by subjecting the hemodynamically unloaded heart to 2 cycles of 3 min of ischemia and 3 min of reperfusion with normokalemic blood prior to cardioplegia. In the Perfusion group, the heart perfusion remained unaffected for 12 min. Troponin I (TnI) levels were analyzed before surgery, and 12, 24, 48 h, and 7 days after surgery. The secondary endpoints included the cardiac index, plasma natriuretic peptide level, and postoperative use of inotropes. Results Preconditioning resulted in a significant reduction in the TnI level on the 7th postoperative day only (0.10 ± 0.05 and 0.33 ± 0.88 ng/ml in Preconditioning and Perfusion groups, respectively, P < 0.05). In addition, cardiac index was significantly higher in the Preconditioning group than in the Control and Perfusion groups just after weaning from cardiopulmonary bypass. The number of patients requiring inotropic support with ≥ 2 agents after surgery was significantly lower in the Preconditioning and Perfusion group than in the Control group (P < 0.05). No complications of the procedure were recorded in the Preconditioning group. Conclusions The preconditioning procedure described can be performed safely in cardiac surgery patients. The application of this technique of preconditioning was associated with certain benefits, including improved left ventricular function after weaning from cardiopulmonary bypass and a reduced need for inotropic support. However, the infarct-limiting effect of preconditioning in the early postoperative period was not evident. The procedure does not involve repetitive aortic cross-clamping, thus avoiding possible embolic complications. [ABSTRACT FROM AUTHOR]

Cerebral venous drainage is generally believed to be regulated primarily by hydrodynamic forces. To gain further insight into the regulation of this process, we investigated the response of blood flow velocity and cross-sectional area (CSA) of the internal jugular veins (IJVs) to local hemodynamic shifts. All procedures and assessments were performed on patients (n = 30) undergoing embolization of brain arteriovenous malformations (AVMs). The procedure efficiency was verified by the postembolization reduction in time-averaged maximum blood flow velocities, as well as the elevation of pulsatility index and resistance index in the arterial feeders. In cerebral veins, the dominant IJV pressure remained unchanged during the procedure. At the same time, AVM embolization caused a significant reduction in maximal CSA (84 ± 7.6 to 68 ± 7.7 mm², P < 0.05) and minimal CSA (68 ± 7.0 to 51 ± 7.0 mm², P < 0.01) of the IJV located ipsilateral to the AVM, while the maximal linear blood flow velocity in the IJV remained unchanged (71 ± 4.9 and 85 ± 8.4 cm/s, P = 0.098). Consistent with previously published studies, the data obtained provide further evidence of active regulation of the venous outflow, probably mediated by certain neurogenic and/or endothelium-dependent mechanisms. [ABSTRACT FROM AUTHOR]

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 AgInS2/ZnS (CQDs), which serve as secondary radiation sources. The potential theranostic platform was studied in laboratory animals. [ABSTRACT FROM AUTHOR]

Background: The Krebs-Henseleit buffer is the best perfusion solution for isolated mammalian hearts. We hypothesized that a Krebs-Henseleit buffer-based cardioplegic solution might provide better myocardial protection than well-known crystalloid cardioplegic solutions because of its optimal electrolyte and glucose levels, presence of buffer systems, and mild hyperosmolarity. Methods: Isolated Langendorff-perfused rat hearts were subjected to either global ischemia without cardioplegia (controls) or cardioplegic arrest for either 60 or 180 min, followed by 120 min of reperfusion. The modified Krebs- Henseleit buffer-based cardioplegic solution (mKHB) and St. Thomas' Hospital solution No. 2 (STH2) were studied. During global ischemia, the temperatures of the heart and the cardioplegic solutions were maintained at either 37°C (60 min of ischemia) or 22°C (moderate hypothermia, 180 min of ischemia). Hemodynamic parameters were registered throughout the experiments. The infarct size was determined through histochemical examination. Results: Cardioplegia with the mKHB solution at moderate hypothermia resulted in a minimal infarct size (5 ± 3%) compared to that in the controls and STH2 solution (35 ± 7% and 19 ± 9%, respectively; P < 0.001, for both groups vs. the mKHB group). In contrast to the control and STH2-treated hearts, no ischemic contracture was registered in the mKHB group during the 180-min global ischemia. At normothermia, the infarct sizes were 4 ± 3%, 72 ± 6%, and 70 ± 12% in the mKHB, controls, and STH2 groups, respectively (P < 0.0001). In addition, cardioplegia with mKHB at normothermia prevented ischemic contracture and improved the postischemic functional recovery of the left ventricle (P < 0.001, vs. STH2). Conclusions: The data suggest that the Krebs-Henseleit buffer-based cardioplegic might be superior to the standard crystalloid solution (STH2). [ABSTRACT FROM AUTHOR]

Introduction: The present study tested the hypothesis that long-term effects of baroreceptor activation might contribute to the prevention of persistent arterial blood pressure (BP) increase in the rat model of renovascular hypertension (HTN). Methods: Repetitive arterial baroreflex (BR) testing was performed in normo- and hypertensive rats. The relationship between initial arterial BR sensitivity and severity of subsequently induced two-kidney one-clip (2K1C) renovascular HTN was studied in Wistar rats. Additionally, the time course of changes in systolic BP (SBP) and cardiac beat-to-beat (RR) interval was studied for 8 weeks after the induction of 2K1C renovascular HTN in the rats with and without sinoaortic denervation (SAD). In a separate experimental series, cervical sympathetic nerve activity (cSNA) was assessed in controls, 2K1C rats, WKY rats, and SHR. Results: The inverse correlation between arterial BR sensitivity and BP was observed in the hypertensive rats during repetitive arterial BR testing. The animals with greater initial arterial BR sensitivity developed lower BP values after renal artery clipping than those with lower initial arterial BR sensitivity. BP elevation during the first 8 weeks of renal artery clipping in 2K1C rats was associated with decreased sensitivity of arterial BR. Although SAD itself resulted only in greater BP variability but not in persistent BP rise, the subsequent renal artery clipping invariably resulted in the development of sustained HTN. The time to onset of HTN was found to be shorter in the rats with SAD than in those with intact baroreceptors. cSNA was significantly greater in the 2K1C rats than in controls. Conclusions: Arterial BR appears to be an important mechanism of long-term regulation of BP, and is believed to be involved in the prevention of BP rise in the rat model of renovascular HTN. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. Image 1 [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. [ABSTRACT FROM AUTHOR]

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).

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.