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Abstract House dust mites (HDM) are common aeroallergens linked to airway inflammation and remodeling in asthma. Protease-activated receptor 2 (PAR2) and thymic stromal lymphopoietin (TSLP) may mediate these immune responses. However, how the epithelium influences fibroblasts toward airway remodeling remains unclear. We hypothesize that HDM stimulates human bronchial epithelial cells (HBECs) to produce TSLP via PAR2 activation, driving fibroblasts toward remodeling processes. HBECs were treated with HDM, with or without the PAR2 antagonist FSLLRY-NH2 (FSL), and TSLP expression was measured by qPCR and ELISA. Phosphorylation of MAPKs was assessed by western blotting. Human lung fibroblasts (HLFs) were exposed to recombinant TSLP or conditioned medium (CM) from HDM-stimulated HBECs, with or without anti-TSLP antibodies. Fibroblast proliferation and collagen production were assessed as remodeling markers. HDM increased ERK phosphorylation (not p38 or JNK) and TSLP expression at mRNA and protein levels. FSL preincubation significantly reduced ERK phosphorylation and TSLP production: HDM-stimulated CM induced fibroblast proliferation and collagen production, effects suppressed by anti-TSLP or FSL. Direct treatment with recombinant TSLP also promoted fibroblast proliferation and collagen synthesis. These findings suggest that HDM promotes HBEC-to-HLF paracrine interactions via PAR2-ERK-TSLP axis, participating in airway remodeling. PAR2 antagonists may represent potential therapeutic targets for HDM-induced remodeling processes.

Rationale: Surgical interventions have been recognized as the main method to repair of valvular disorders. Percutaneous transcatheter intervention with a clipping system is being actively introduced into the treatment of chronic heart failure (CHF) patients and mitral valve insufficiency (MVI) for correction of mitral regurgitation (MR), along with drug therapy. Aim: To establish the effect of the mitral valve leaflet clipping in the combination treatment of CHF patients on the clinical course of heart failure and the remodeling process. Methods: This single center prospective comparative study included 80 patients with CHF NYHA class II–IV and secondary MR grade 3–4. The patients were on optimal medical treatment (OMT) for CHF for at least 3 months before inclusion into the study. The main group included 55 patients who underwent transcatheter mitral valve repair with the use of MitraClip system, and the control group consisted of 25 patients in whom the surgery for MR was waived for various reasons (refusal of the surgery by the patient, some valve characteristics), and only OMT for CHF was used. At baseline, main clinical and demographic characteristics of the patients in the both groups were comparable. The duration of the follow-up was 6 months. Echocardiography (echoCG), a 6-minute walk test, and measurements of the brain natriuretic propeptide level were performed in all patients at baseline and at 6 months of the follow-up. Results: At 6 months, there was a significant reduction in CHF NYHA class and an increase in the 6-minute walk test distance and a decrease in diuretic requirements (converted to furosemide, from 58.4 ± 17.2 to 38.1 ± 20.7 mg daily, р = 0.02) in the group with the MitraClip implant, but not in the control group. In the OMT only group, there were no changes over 6 months in the diuretic requirements (48.1 ± 6.68 and 43.8 ± 27.15 mg daily, respectively, р = 0.8). The number of hospital readmissions due to CHF decompensation was 7 (12.7%) in the implanted MitraClip group and 4 (16%) in the OMT group (р = 0.69). EchoCG performed at 6 months after the surgical intervention identified no cases of MR grade 2. In the MitraClip implant group, there was a decrease in the size and volumes of the left atrium (р = 0.02 and р = 0.05, respectively), left ventricle (for end-diastolic diameter p = 0.002, end-diastolic volume p = 0.03), mean pulmonary artery pressure (p = 0.03), as well as an increase in cardiac output (р = 0.04). In the patients receiving OMT only, there were no significant changes in EchoCG parameters over time. Conclusion: Our study has shown benefits of the implantation of the mitral valve leaflet clipping system, compared to OMT only, in CHF. The clipping procedure promotes a significant improvement in clinical course of CHF, reverse myocardial remodeling, and reduction in diuretic requirements.

Background: Aortico right atrial tunnel (ARAT) is a rare extracardiac communication between the aorta and the right atrium with two anatomical types. A recent global review identified 59 patients. Methods: Patients with ARAT from two centers were analyzed for their demographics, symptoms, morphology, management, and follow-up thromboprophylaxis. Results: Among 21 patients including 8 males with a median age of 3 years (18 days–72 years) diagnosed as ARAT, 12 (57%) had posterior tunnels and 9 had anterior tunnels. Four patients had multiple exits. Eighteen tunnels were closed after arteriovenous circuit formation. Six patients (29%) weighing

Aim. To determine the effect of dapagliflozin therapy on myocardial remodeling and fibrosis according to magnetic resonance imaging (MRI) with contrast in patients with chronic heart failure (CHF) and atrial fibrillation (AF). Materials and methods. In the group of 22 patients with a combination of CHF and AF we analyzed the dynamics of remodeling parameters and assessed myocardial fibrosis during 6-month therapy with dapagliflozin according to cardiac MRI with contrast. Results. After 6 months of dapagliflozin therapy there was a statistically significant increase in LVEF (27 [23-32]-32 [26.5-36.5] p-0.04) and a tendency to decrease volume and linear dimensions of LV, LP. There was no progression of myocardial fibrosis according to the results of cardiac MRI with contrast in patients with HFrFV and AF. Conclusions. Dapagliflozin therapy in patients with HFrEF and AF led to favorable myocardial remodeling changes.

Aim: to provide a literature review of the current conсepts on phenotypic heterogeneity of left ventricular (LV) remodeling in heart failure (HF), and highlight the significance of such a diversity for an implementation of personalized patients` management. This paper is a second part of the review, devoted to the current state of pathophysiology of LV remodeling in HF. Material and methods. The thematic scientific papers, published predominantly during the last decade, constituted the study material. The research methodology involved bibliosemantic method and structural and logical analysis. Results and discussion. HF is a heterogeneous, multifactorial and rising epidemic syndrome. To date, the LV ejection fraction (EF) is used as a substantial criterion for HF classification and management. However, the existing research data has revealed the significant overlapping between different LV EF-based HF patterns in terms of the risk factors, comorbidities and disease modifiers; bidirectional transitions of LV EF due to disease treatment and progression; myocardial fibrosis and dysfunction; effectiveness of neurohumoral inhibitors etc. Moreover, the «spectrum» paradigm has been recently proposed, positioning HF as a spectrum across different phenotypes. Particularly, each HF phenotype is the result of a patient-specific trajectory, being an exceptional and unique «track» for the heart transition towards different remodeling patterns. The HF phenotyping may be an innovative approach to the study of myocardial remodeling and HF, which is potentially an important prerequisite for the development of individualized patients` treatment. Personalized medicine can offer the particular options for managing HF patients, that, in turn, will better identify responders, non-responders, and those at high risk of adverse events, and ultimately improve of the treatment efficacy and safety. Conclusions. The baseline heterogeneity of the structural and functional patients` characteristics, including those describing the LV remodeling, and their dynamic change over time, creates a spectrum across overlapping HF phenotypes, challenging a categorical HF classification based solely on LV EF. Such an approach to treat the HF phenotypic heterogeneity may provide further insights into the pathomechanisms, related to LV remodeling in HF, and has the potential to improve the personalized patients` management.

Abstract Background Exosomes (EXOs), tiny extracellular vesicles that facilitate cell–cell communication, are being explored as a heart failure treatment, although the features of the cell source restrict their efficacy. Fibroblasts the most prevalent non-myocyte heart cells, release poor cardioprotective EXOs. A noninvasive method for manufacturing fibroblast-derived exosomes (F-EXOs) that target cardiomyocytes and slow cardiac remodeling is expected. As a cardioprotective isothiocyanate, sulforaphane (SFN)-induced F-EXOs (SFN-F-EXOs) should recapitulate its anti-remodeling properties. Methods Exosomes from low-dose SFN (3 μM/7 days)-treated NIH/3T3 murine cells were examined for number, size, and protein composition. Fluorescence microscopy, RT-qPCR, and western blot assessed cell size, oxidative stress, AcH4 levels, hypertrophic gene expression, and caspase-3 activation in angiotensin II (AngII)-stressed HL-1 murine cardiomyocytes 12 h-treated with various EXOs. The uptake of fluorescently-labeled EXOs was also measured in cardiomyocytes. The cardiac function of infarcted male Wistar rats intramyocardially injected with different EXOs (1·1012) was examined by echocardiography. Left ventricular infarct size, hypertrophy, and capillary density were measured. Results Sustained treatment of NIH/3T3 with non-toxic SFN concentration significantly enhances the release of CD81 + EXOs rich in TSG101 (Tumor susceptibility gene 101) and Hsp70 (Heat Shock Protein 70), and containing maspin, an endogenous histone deacetylase 1 inhibitor. SFN-F-EXOs counteract angiotensin II (AngII)-induced hypertrophy and apoptosis in murine HL-1 cardiomyocytes enhancing SERCA2a (sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a) levels more effectively than F-EXOs. In stressed cardiomyocytes, SFN-F-EXOs boost AcH4 levels by 30% (p

Abstract Background Fine particulate matter (PM2.5) is associated with increased incidence and severity of asthma. PM2.5 exposure disrupts airway epithelial cells, which elicits and sustains PM2.5-induced airway inflammation and remodeling. However, the mechanisms underlying development and exacerbation of PM2.5-induced asthma were still poorly understood. The aryl hydrocarbon receptor nuclear translocator-like protein 1 (BMAL1) is a major circadian clock transcriptional activator that is also extensively expressed in peripheral tissues and plays a crucial role in organ and tissue metabolism. Results In this study, we found PM2.5 aggravated airway remodeling in mouse chronic asthma, and exacerbated asthma manifestation in mouse acute asthma. Next, low BMAL1 expression was found to be crucial for airway remodeling in PM2.5-challenged asthmatic mice. Subsequently, we confirmed that BMAL1 could bind and promote ubiquitination of p53, which can regulate p53 degradation and block its increase under normal conditions. However, PM2.5-induced BMAL1 inhibition resulted in up-regulation of p53 protein in bronchial epithelial cells, then increased-p53 promoted autophagy. Autophagy in bronchial epithelial cells mediated collagen-I synthesis as well as airway remodeling in asthma. Conclusions Taken together, our results suggest that BMAL1/p53-mediated bronchial epithelial cell autophagy contributes to PM2.5-aggravated asthma. This study highlights the functional importance of BMAL1-dependent p53 regulation during asthma, and provides a novel mechanistic insight into the therapeutic mechanisms of BMAL1. Graphic abstract Video Abstract

The mechanism underlying atrial fibrillation （AF） is not completely understood due to its complexity. In addition to anatomical structure of the heart， structural remodeling， electrical remodeling， autonomic nervous system regulation， and calcium ion （Ca2+） malfunctioning can also cause focal ectopic discharges and trigger AF. Moreover， triggering the incidence and persistence of reentrant AF through a reentry maintenance mechanism is also an important mechanism leading to AF. Further studies have found that the synthesis and degradation of related pathways， ion channel proteins and transporters can be changed through the role of microRNA （miR） inregulating messenger RNA. It not only affects the ionic current， leading to abnormal Ca2+ transport and cardiac electrical remodeling，but also influences fibroblasts， resulting in tissue fibrosis andstructural remodeling， and eventually inducing the incidence and maintenance of AF. Cardiac development， cardiomyocyte proliferation and substrate formation due to reentry mechanism causing AF were correlated with miR. MiR would become a novel biomarker for diagnosis of AF and a novel target for upstream treatment.

Aim: to provide a literature review of the current data on various pathomechanisms of left ventricular (LV) remodeling in heart failure (HF) patients and their role in the development and progression of myocardial dysfunction. This paper is a first part of the review, devoted to the current state of pathophysiology of LV remodeling in HF. Material and methods. The thematic scientific papers, published during the last decade, constituted the study material. The research methodology involved bibliosemantic method and structural and logical analysis. Results and discussion. LV remodeling is the result of complex changes at the molecular, cellular and tissue levels, affecting the myocardial mass, geometry and performance, and ultimately leading to HF development and progression. LV systolic dysfunction occurs through the numerous mechanisms, including the defects in sarcomere function, abnormal excitation-contraction coupling and calcium homeostasis, ion channel dysfunction, mitochondrial and metabolic abnormalities, depressed cardiomyocytes survival signaling, redox pathobiology, inflammation and inadequate vasculogenesis. The term «LV diastolic dysfunction» covers the alterations in diastolic distensibility, filling or relaxation of the LV, regardless of whether LV (global) systolic function is normal or abnormal, and regardless of whether the patient has clinical manifestations of HF. The up-to-date pathophysiological paradigm of the development and progression of HF with LV diastolic dysfunction and preserved LV (global) systolic function considers systemic inflammation as a key pathomechanism of structural and functional changes of the myocardium, promoted by various cardiovascular and extracardiac conditions. In its turn, the systemic inflammation promotes endothelial dysfunction, contributing to multiple end-organ damage. Conclusion. The deepening one`s knowledge of various pathomechanisms of LV remodeling and related myocardial dysfunction in HF patients is an important prerequisite for identifying new perspectives on further fundamental research аnd more rational designing of future clinical trials.

Highlights 1. Female patients with HCM showed worse LV remodeling with a higher indexed LV mass and a smaller indexed LV end-diastolic volume (measured by CMR) at the time of ASA. 2. Both men and women exhibited the LV reverse remodeling, however, men experienced more favorable LV reverse remodeling than women after ASA. The overall percentage of the LVM index regression was greater among men than women. 3. Women with HCM had worse relative composite endpoint than men. Sex and LV mass preablation were independent predictors of cardiovascular outcomes. 4. Sex appears to be a significant modifier in HCM patients receiving ASA treatment and highlighted the need for a different approach to women with HCM, such as improving women’s awareness of diagnosis and follow-up management as well as earlier referral for advanced therapies (e.g., septal reduction therapy and ICD implantation).

Abstract Cancer progression involves several biological steps where angiogenesis is a key tumorigenic phenomenon. Extracellular vesicles (EVs) derived from tumor cells and other cells in the tumor microenvironment (TME) help modulate and maintain favorable microenvironments for tumors. Endothelial cells (ECs) activated by cancer-derived EVs have important roles in tumor angiogenesis. Interestingly, EVs from ECs activate tumor cells, i.e. extracellular matrix (ECM) remodeling and provide more supplements for tumor cells. Thus, EV communications between cancer cells and ECs may be effective therapeutic targets for controlling cancer progression. In this review, we describe the current knowledge on EVs derived from ECs and we examine how these EVs affect TME remodeling. Video abstract

During COVID-19 pandemic and due to the need for its prevention and control, the training of interns and graduates in nuclear medicine are facing challenges. This paper analyzed these challenges and reported a series of reformation implemented by the Department of Nuclear Medicine of Peking Union Medical College Hospital. During the pandemic, students face various difficulties in the process of clinical practice, which also leads to some psychological problems such as fear, anxiety and depression. Therefore, the department of nuclear medicine remodels the teaching and training plan based on the needs of trainees and constantly modify the training procedures to protect trainees and meet the needs of training as well as pandemic prevention and control.

Vaping has been reported to cause acute epiglottitis, a life-threatening airway obstruction induced by direct epithelial injury and subsequent inflammatory reaction. Here, we show that we were able to recapitulate this phenomenon in vitro. Exposure of human engineered vocal fold (VF) mucosae to 0.5% and 5% electronic cigarette (e-cigarette) vapor extract (ECVE) for 1 week induced cellular damage of luminal cells, disrupting homeostasis and innate immune responses. Epithelial erosion was likely caused by accumulation of solvents and lipid particles in the cytosol and intercellular spaces, which altered lipid metabolism and plasma membrane properties. Next, we investigated how the mucosal cells responded to the epithelial damage. We withdrew the ECVE from the experimental system and allowed VF mucosae to regenerate for 1, 3 and 7 days, which triggered intense epithelial remodeling. The epithelial changes included expansion of P63 (TP63)-positive basal cells and cytokeratin 14 (KRT14) and laminin subunit α-5 (LAMA5) deposition, which might lead to local basal cell hyperplasia, hyperkeratinization and basement membrane thickening. In summary, vaping presents a threat to VF mucosal health and airway protection, thereby raising further concerns over the safety of e-cigarette use. This article has an associated First Person interview with the first author of the paper.

Aim. To analyze and demonstrate various phenotypes in patients with familial left ventricular noncompaction (LVNC). Materials and methods. In 2013 was created a multicenter registry of LVNC patients. On its basis 30 families with a familial LVNC were selected. Results. 30 LVNC families were selected from the register. From a total of 115 people (probands and relatives) in 71 (61.7%) LVNC was diagnosed (30 probands and 41 relatives with non-compact myocardial criteria). The most common type of remodeling in patients was the dilated type (DT) (n=30), the isolated LVNC with preserved ejection fraction (EF) was slightly less common (n=23), and the hypertrophic type (GT) was detected in 8 patients. 4 patients were diagnosed with the isolated LVNC with a reduced EF. 3 patients were with a combination of non-compact myocardium with congenital heart disease and with a combination of DT and GT (DT+GT). During the analysis of cases a combination of different phenotypes in the same family was observed. The largest number of families was diagnosed with a combination of DT and the isolated LVNC with preserved EF. The development of cardiovascular complications was associated with DT. Conclusion. Family cases of LVNC had different types of myocardial remodeling and variants of clinical course. In one family a combination of different types of left ventricular remodeling is possible. DT is associated with the most severe clinical manifestations. The clinical picture of the isolated LVNC with preserved EF, is the most favorable, but in rare cases, serious clinical manifestations were observed.

Aim.Study of the remodeling of the carotid arteries with violation of intracardiac hemodynamics in patients with MFA, and the estimation of the main parameters of dyslipidemia, apoptosis, and oxidative stress in patients with high vascular risk older age group (6175 years) in a Regional vascular center of Ufa. Materials and methods.Depending on the predominant lesion of the vascular pool, patients were divided into 3 clusters by the method of hierarchical analysis of categorical variables according to the clinical manifestation of atherosclerotic lesions of the heart, brain and lower limb arteries confirmed by coronary angiography, ultrasound Doppler of the main arteries of the head and lower extremities. 96 of them were IPA with a primary lesion of the heart (1st cluster), the 96 IPA with a predominance of lesions of the carotid arteries (2nd cluster), 96 patients with ischemia of lower extremities (3rd cluster). At the hospital stage, electrocardiography, echocardiography, magnetic resonance imaging of the chest and abdomen, ultrasound of the OBP and kidneys, if necessary, ultrasound of the pelvis were performed. Determination of 8-ON-deoxyguanosine, annexin-5 (An-5) and Aan-5 in blood by ELISA was performed in all patients with MFA, as well as standard biochemical screening for lipidogram examination. Results.We have found that most often in different combinations and with different degrees of severity according to our data are observed: Clinical manifestation of atherosclerotic heart disease (cluster 1) mainly due to its history in combination with stage III hypertension with increasing thickness of intima-media complex and stenosis of the right WASP, left ventricular dilatation, as well as a higher concentration of Aan-5IgMand LP-A as a risk factor for coronary heart disease, atherosclerosis, atherothrombosis. 2. Hemodynamically significant violations of the main arteries of the head in patients of the 2nd cluster mainly with acute ischemic cerebral circulation, in which there was a development of left ventricular hypertrophy with an increase in the size of the left atrium and the presence of atherosclerotic plaque of the right and left WASP. The higher prevalence of stroke was combined with a marked cognitive deficit among patients of cluster 2 with the lowest level of An-5, an increase in total cholesterol and low-density lipoprotein cholesterol. 3. The total severity of the condition in patients with hemodynamic ischemia with clinical manifestation of vascular lesions of the lower extremities was accompanied by a predominant increase in stable angina with FC2, lerish syndrome with occlusion of the iliac, superficial femoral arteries, the presence of insulin-independent type 2 diabetes, which in this group was established in 59.4% of cases, combined with a higher concentration of the marker of oxidative stress 8-ON-deoxyguanosine and hypertriglyceridemia. Conclusion.The construction of a three-cluster model in patients at high vascular risk of the elderly age category showed the interaction of cardio-carotid comorbid background on the clinical diversity of systemic vascular lesions in MFA with the development of remodeling of the main arteries and disorders of intracardiac hemodynamics associated with laboratory changes in the assessment of the main parameters of dyslipidemia, apoptosis markers, oxidative stress.

Abstract Sacubitril/valsartan has been shown to reduce cardiovascular mortality and hospitalizations in patients with HFrEF when compared to enalapril. There are also some evidences of its potential antiarrhythmic effects. We present a report where we found a relation between reverse ventricular remodeling and arrhythmic reduction in a patient treated with sacubitril/valsartan.

Resume. Ischemic-repefusion injury is a complex multifactorial tissue damage as the result of restoration of blood circulation, after the period of ischemia or lack of the oxygen, accompanied by the local and systemic disorders. Recently, more and more attention in treatment and prevention of postischemic disorders is paid to nootropic medicine, which smooths the phenomena of hypo- and hyperperfusion, and also improves tissue microcirculation.The aim of the study was to establish the manifestations of morpho-functional remodeling of the vascular bed of the hind limbs of the rats during ischemia-reperfusion and under conditions of carbacetam correction using histological and morphometric іnvestigations methods.Materials and methods. There was histological and morphometric examination of the arterial bed of the hind limbs of 30 rats under conditions of ischemia-reperfusion injury (group I) and 30 rats in the simulation of ischemia-reperfusion injury, which in the post-ischemic period was administered carbacetam once a day (5 mg / kg) for 14 days (group II) was performed. There were 6 intact animals in the control group.Simulation of ischemia was performed by applying SWAT rubber tourniquets on the hind limbs for 2 hours, and reperfusion - by removing the tourniquet. The animals were divided into 5 subgroups with reperfusion terms after 1, 2 hours and 1 day, as well as after 7 and 14 days. Histological examination was performed according to generally accepted methods. The vascular bed in the middle third of the thigh and shin, below the level of the application of the tourniquet was examined by Bresser Trino Researcher 40x – 1000x microscope. The morphometric parameters were calculated using SEO Image Lab software from Sumy Electron Optics.Research results and their discussion. Analyzing of the obtained results, it was founded that after 1 hour of the repefusion the structural changes became systemic, and after 1 day they were the most significant. Histologically, the elastic membranes were thinned and torned up, the swelling became a total character. In the late reperfusion period, a gradual return of morphological changes to the initial state and the increased in the proliferative activity of the fibroblasts were revealed. Under the conditions of correction after 1 day, the positive dynamics became more pronounced and reached its maximum after 7 days of the study. Morphometrically, the differences between the groups are especially pronounced 7 days after the removal of the tourniquet. At the level of the femoral artery revealed a lower value of external (D1) by 1.9% (p2) diameters by 3,0% (pIn small-caliber arteries, on the contrary, there was a less pronounced vasoconstriction level, when applying the correction, because the value of T decreased by 5,4% (p1 by 1,89 % (p2 by 11.55% (pConclusions. Ischemia and repfusion cause vascular remodeling after 1 hour with a peak of manifestations after 1 day of reperfusion. Under the conditions of the correction, the acceleration of the remodeling with stabilization of the process and the most possible structural restoration after 7 days of the study was noted. Morphometric data indicate less pronounced vasodilation at the level of large caliber arteries and spasm of arteries of muscular branches during that experimental period in the group with correction.

Introduction. Recently, the attention of researchers has again attracted the problem of pregnancy in the presence of scar on the uterus.The aim of the study is to evaluate the processes of myometrium remodeling in women with uterine scar using non-invasive ultrasonic monitoring. It is shown that the frequency of relative failure of yellowing in the uterus does not exceed 2.7% of the total number of women examined. The ratio of the thickness of the residual in the plane of the yellow and normal endometrium indicates complete remodeling and is in women after KP, this index was 0.96 ± 0.08, and after KME - 0.94 ± 0.06 (p> 0.05). The difference in maximum systolic velocity of arterial blood flow in patients after CR (38.8 ±1.2 cm/ s) and after CME (34.2 ±1.4 cm/ sec, p

BmooMPα-I has kininogenase activity, cleaving kininogen releasing bradykinin and can hydrolyze angiotensin I at post-proline and aspartic acid positions, generating an inactive peptide. We evaluated the antihypertensive activity of BmooMPα-I in a model of two-kidney, one-clip (2K1C). Wistar rats were divided into groups: Sham, who underwent sham surgery, and 2K1C, who suffered stenosis of the right renal artery. In the second week of hypertension, we started treatment (Vehicle, BmooMPα-I and Losartan) for two weeks. We performed an electrocardiogram and blood and heart collection in the fourth week of hypertension. The 2K1C BmooMPα-I showed a reduction in blood pressure (systolic pressure: 131 ± 2 mmHg; diastolic pressure: 84 ± 2 mmHg versus 174 ± 3 mmHg; 97 ± 4 mmHg, 2K1C Vehicle, p < 0.05), improvement in electrocardiographic parameters (Heart Rate: 297 ± 4 bpm; QRS: 42 ± 0.1 ms; QT: 92 ± 1 ms versus 332 ± 6 bpm; 48 ± 0.2 ms; 122 ± 1 ms, 2K1C Vehicle, p < 0.05), without changing the hematological profile (platelets: 758 ± 67; leukocytes: 3980 ± 326 versus 758 ± 75; 4400 ± 800, 2K1C Vehicle, p > 0.05), with reversal of hypertrophy (left ventricular area: 12.1 ± 0.3; left ventricle wall thickness: 2.5 ± 0.2; septum wall thickness: 2.3 ± 0.06 versus 10.5 ± 0.3; 2.7 ± 0.2; 2.5 ± 0.04, 2K1C Vehicle, p < 0.05) and fibrosis (3.9 ± 0.2 versus 7.4 ± 0.7, 2K1C Vehicle, p < 0.05). We concluded that BmooMPα-I improved blood pressure levels and cardiac remodeling, having a cardioprotective effect.

The chromatin remodeler ALC1 is recruited to and activated by DNA damage-induced poly(ADP-ribose) (PAR) chains deposited by PARP1/PARP2/HPF1 upon detection of DNA lesions. ALC1 has emerged as a candidate drug target for cancer therapy as its loss confers synthetic lethality in homologous recombination-deficient cells. However, structure-based drug design and molecular analysis of ALC1 have been hindered by the requirement for PARylation and the highly heterogeneous nature of this post-translational modification. Here, we reconstituted an ALC1 and PARylated nucleosome complex modified in vitro using PARP2 and HPF1. This complex was amenable to cryo-EM structure determination without cross-linking, which enabled visualization of several intermediate states of ALC1 from the recognition of the PARylated nucleosome to the tight binding and activation of the remodeler. Functional biochemical assays with PARylated nucleosomes highlight the importance of nucleosomal epitopes for productive remodeling and suggest that ALC1 preferentially slides nucleosomes away from DNA breaks.

Abstract Background Over a third of reproductive-age women in the USA are obese, and the prevalence of cardiovascular disease (CVD) is rising in premenopausal women. Cardiac hypertrophy is an independent predictor of CVD. In contrast to pregnancy, where transiently increased left ventricular (LV) mass is not associated with cardiac damage, obesity-mediated cardiac hypertrophy is pathological. There is a paucity of data describing the effect of obesity during pregnancy on maternal cardiovascular health. The purpose of this study was to determine the long-term effect of obesity during pregnancy on cardiac function and structure in mice. Methods Female C57BL/6 J mice were fed a high-fat (HF) or a low-fat (LF) diet for 20 weeks. After 4 weeks, LF- and HF-fed female mice were either crossed with males to become pregnant or remained non-pregnant controls. Following delivery, pups were euthanized, and females maintained on respective diets. After 20 weeks of diet feeding, cardiac function was quantified by echocardiography, and plasma leptin and adiponectin concentrations quantified in LF- and HF-fed postpartum and nulliparous females. mRNA abundance of genes regulating cardiac hypertrophy and remodeling was quantified from left ventricles using the NanoString nCounter Analysis System. Cardiac fibrosis was assessed from picrosirius red staining of left ventricles. Results HF-fed postpartum mice had markedly greater weight gain and fat mass expansion with obesity, associated with significantly increased LV mass, cardiac output, and stroke volume compared with HF-fed nulliparous mice. Plasma leptin, but not adiponectin, concentrations were correlated with LV mass in HF-fed females. HF feeding increased LV posterior wall thickness; however, LV chamber diameter was only increased in HF-fed postpartum females. Despite the marked increase in LV mass in HF-fed postpartum mice, mRNA abundance of genes regulating fibrosis and interstitial collagen content was similar between HF-fed nulliparous and postpartum mice. In contrast, only HF-fed postpartum mice exhibited altered expression of genes regulating the extracellular matrix. Conclusions These results suggest that the combined effects of pregnancy and obesity augment cardiac hypertrophy and promote remodeling. The rising prevalence of CVD in premenopausal women may be attributed to an increased prevalence of women entering pregnancy with an overweight or obese BMI.

Abstract Background Skeletal muscle wasting is a hallmark of Huntington’s disease (HD). However, data on myocellular characteristics and myofiber remodeling in HD patients are scarce. We aimed at gaining insights into myocellular characteristics of HD patients as compared to healthy controls at rest and after a period of increased skeletal muscle turnover. Methods Myosin heavy chain (MyHC)-specific cross-sectional area, satellite cell content, myonuclear number, myonuclear domain, and muscle fiber type distribution were determined from vastus lateralis muscle biopsies at rest and after 26 weeks of endurance training in HD patients and healthy controls. Results At the beginning of the study, there were no differences in myocellular characteristics between HD patients and healthy controls. Satellite cell content per MyHC-1 fiber (P = 0.014) and per MyHC-1 myonucleus (P = 0.006) increased significantly in healthy controls during the endurance training intervention, whereas it remained constant in HD patients (P = 0.804 and P = 0.975 for satellite cell content per MyHC-1 fiber and myonucleus, respectively). All further variables were not altered during the training intervention in HD patients and healthy controls. Conclusions Similar skeletal muscle characteristics between HD patients and healthy controls at baseline suggested similar potential for myofiber remodeling in response to exercise. However, the missing satellite cell response in MyHC-1 myofibers following endurance training in HD patients points to a potential dysregulation in the exercise-induced activation and/or proliferation of satellite cells. In the longer-term, impaired myonuclear turnover might be associated with the clinical observation of skeletal muscle wasting.

Abstract Background Excess dietary sodium is not only excreted by the kidneys, but can also be stored by non-osmotic binding with glycosaminoglycans in dermal connective tissue. Such storage has been associated with dermal inflammation and lymphangiogenesis. We aim to investigate if skin storage of sodium is increased in kidney patients and if this storage is associated with clinical parameters of sodium homeostasis and dermal tissue remodeling. Methods Abdominal skin tissue of 12 kidney patients (5 on hemodialysis) and 12 healthy kidney donors was obtained during surgery. Skin biopsies were processed for dermal sodium measurement by atomic absorption spectroscopy, and evaluated for CD68+ macrophages, CD3+ T-cells, collagen I, podoplanin + lymph vessels, and glycosaminoglycans by qRT-PCR and immunohistochemistry. Results Dermal sodium content of kidney patients did not differ from healthy individuals, but was inversely associated with plasma sodium values (p

Abstract Background Vascular grafts are widely used as a treatment in coronary artery bypass surgery, hemodialysis, peripheral arterial bypass and congenital heart disease. Various types of synthetic and natural materials were experimented to produce tissue engineering vascular grafts. In this study, we investigated in vivo tissue engineering technology in miniature pigs to prepare decellularized autologous extracellular matrix-based grafts that could be used as vascular grafts for small-diameter vascular bypass surgery. Methods Autologous tissue conduits (3.9 mm in diameter) were fabricated by embedding Teflon tubings in the subcutaneous pocket of female miniature pigs (n = 8, body weight 25–30 kg) for 4 weeks. They were then decellularized by CHAPS decellularization solution. Heparin was covalently-linked to decellularized tissue conduits by Sulfo-NHS/EDC. We implanted these decellularized, completely autologous extracellular matrix-based grafts into the carotid arteries of miniature pigs, then sacrificed the pigs at 1 or 2 months after implantation and evaluated the patency rate and explants histologically. Results After 1 month, the patency rate was 100% (5/5) while the inner diameter of the grafts was 3.43 ± 0.05 mm (n = 5). After 2 months, the patency rate was 67% (2/3) while the inner diameter of the grafts was 2.32 ± 0.14 mm (n = 3). Histological staining confirmed successful cell infiltration, and collagen and elastin deposition in 2-month samples. A monolayer of endothelial cells was observed along the inner lumen while smooth muscle cells were dominant in the graft wall. Conclusion A completely autologous acellular conduit with excellent performance in mechanical properties can be remodeled into a neoartery in a minipig model. This proof-of-concept study in the large animal model is very encouraging and indicates that this is a highly feasible idea worthy of further study in non-human primates before clinical translation.

Besides skeletal muscle abnormalities, Duchenne muscular dystrophy (DMD) patients present with dilated cardiomyopathy development, which considerably contributes to morbidity and mortality. Because the mechanisms responsible for the cardiac complications in the context of DMD are largely unknown, evidence-based therapy approaches are still lacking. This has increased the need for basic research efforts into animal models for DMD. Here, we characterized in detail the cardiovascular abnormalities of Dmdmdx rats, with the aim of determining the suitability of this recently established dystrophin-deficient small animal as a model for DMD. Various methods were applied to compare cardiovascular properties between wild-type and Dmdmdx rats, and to characterize the Dmdmdx cardiomyopathy. These methods comprised echocardiography, invasive assessment of left ventricular hemodynamics, examination of adverse remodeling and endothelial cell inflammation, and evaluation of vascular function, employing wire myography. Finally, intracellular Ca2+ transient measurements, and recordings of currents through L-type Ca2+ channels were performed in isolated single ventricular cardiomyocytes. We found that, similar to respective observations in DMD patients, the hearts of Dmdmdx rats show significantly impaired cardiac function, fibrosis and inflammation, consistent with the development of a dilated cardiomyopathy. Moreover, in Dmdmdx rats, vascular endothelial function is impaired, which may relate to inflammation and oxidative stress, and Ca2+ handling in Dmdmdx cardiomyocytes is abnormal. These findings indicate that Dmdmdx rats represent a promising small-animal model to elucidate mechanisms of cardiomyopathy development in the dystrophic heart, and to test mechanism-based therapies aiming to combat cardiovascular complications in DMD.

Irisin, a skeletal-muscle secreted myokine, facilitates muscle-bone crosstalk and skeletal remodeling in part by its action on osteoblasts and osteocytes. In this study, we investigated whether irisin directly regulates osteoclasts. In vitro, irisin (2–10 ng/mL) increased osteoclast differentiation in C57BL/6J mouse bone marrow progenitors; however, this increase was blocked by a neutralizing antibody to integrin αVβ5. Irisin also increased bone resorption on several substrates in situ. RNAseq revealed differential gene expression induced by irisin including upregulation of markers for osteoclast differentiation and resorption, as well as osteoblast-stimulating ‘clastokines’. Forced expression of the irisin precursor Fndc5 in transgenic C57BL/6J mice resulted in lower bone mass at three ages and greater in vitro osteoclastogenesis from Fndc5-transgenic bone marrow progenitors. This study demonstrates that irisin acts directly on osteoclast progenitors to increase differentiation and promote bone resorption, supporting the tenet that irisin not only stimulates bone remodeling but may also be an important counter-regulatory hormone.

In allergic asthma IgE plays a fundamental role in the development and maintenance of chronic inflammation, leading to remodelling of the airways, reduced lung function, development of fixed bronchial obstruction and resistance to therapy. Authors present literature data and clinical observation of the effectiveness of omalizumab-drug anti-IgE therapy in severe therapyresistant allergic asthma with fixed airflow obstruction.

Abstract Background Transcatheter mitral valve repair (TMVR) has been shown to have acute effects on mitral valve geometry in patients with functional mitral regurgitation (FMR). This study investigates the impact of MitraClip® therapy-induced annular remodeling on clinical outcome and mitral regurgitation in heart failure patients. Methods TMVR was performed successfully in 45 patients with FMR. In this study, mitral valve datasets were obtained before and directly after MitraClip® implantation using three-dimensional (3D) transesophageal echocardiography, and were analyzed offline retrospectively using dedicated 3D reconstruction software. Patients underwent clinical and echocardiographic evaluation at baseline and after 6 months. At follow-up, the patients were allocated into two groups according to their improvement in New York Heart Association (NYHA) functional class: a Low Responder group with ΔNYHA

The purpose of this study was to characterize the short-term effects of Achilles tendon ruptures on medial gastrocnemius. We hypothesized that the fascicles of the medial gastrocnemius muscle of the injured Achilles tendon would be shorter and more pennate immediately following the injury and would persist throughout 4 weeks post-injury. B-mode longitudinal ultrasound images of the medial gastrocnemius were acquired in 10 adults who suffered acute Achilles tendon ruptures and were treated non-operatively. Ultrasound images were acquired during the initial clinical visit following injury as well as 2 and 4 weeks following this initial clinical visit. Resting muscle structure was characterized by measuring fascicle length, pennation angle, muscle thickness, and muscle echo intensity in both the injured and contralateral (control) limbs. Fascicle length was 15% shorter (P < 0.001) and pennation angle was 21% greater (P < 0.001) in the injured muscle compared to the uninjured (control) muscle at the presentation of injury (week 0). These differences in fascicle length persisted through 4 weeks after injury (P < 0.002) and pennation angle returned to pre-injury levels. Muscle thickness changes were not detected at any of the post-injury visits (difference < 4%, P > 0.026). Echo intensity of the injured limb was 8% lower at the presentation of the injury but was not different compared to the contralateral muscle at 2 and 4 weeks post-injury. Our results suggest that Achilles tendon ruptures elicit rapid changes in the configuration of the medial gastrocnemius, which may explain long-term functional deficits.

The use of bioresorbable materials in the anterior cruciate ligament reconstruction is a promising direction. Thus today there is no single point of view on the long-term results of using absorbable interference screws. The article presents an analysis of the results of surgical treatment of 30 patients with use of bioresorbable materials, operated on for rupture of the anterior cruciate ligament (ACL) in the department of traumatology and orthopedics from 2010 to 2016 in the Federal Scientific Clinical Center FMBA of Russia. The aim of our study was to evaluate in vivo transformation of bioresorbable screws and bone assimilation into the tibial canal in long-term period after surgery, as well as the effect of the polymeric material and bone on these processes.

Osteoclasts are bone-resorbing cells derived from the monocyte/macrophage lineage. Excess osteoclast activity leads to reduced bone mineral density, a hallmark of diseases such as osteoporosis. Processes that regulate osteoclast activity are therefore targeted in current osteoporosis therapies. To identify and characterize drugs for treatment of bone diseases, suitable in vivo models are needed to complement cell-culture assays. We have previously reported transgenic medaka lines expressing the osteoclast-inducing factor receptor activator of nuclear factor κB ligand (Rankl) under control of a heat shock-inducible promoter. Forced Rankl expression resulted in ectopic osteoclast formation, as visualized by live imaging in fluorescent reporter lines. This led to increased bone resorption and a dramatic reduction of mineralized matrix similar to the situation in humans with osteoporosis. In an attempt to establish the medaka as an in vivo model for osteoporosis drug screening, we treated Rankl-expressing larvae with etidronate and alendronate, two bisphosphonates commonly used in human osteoporosis therapy. Using live imaging, we observed an efficient, dose-dependent inhibition of osteoclast activity, which resulted in the maintenance of bone integrity despite an excess of osteoclast formation. Strikingly, we also found that bone recovery was efficiently promoted after inhibition of osteoclast activity and that osteoblast distribution was altered, suggesting effects on osteoblast-osteoclast coupling. Our data show that transgenic medaka lines are suitable in vivo models for the characterization of antiresorptive or bone-anabolic compounds by live imaging and for screening of novel osteoporosis drugs.

Under chronic or severe liver injury, liver progenitor cells (LPCs) of biliary origin are known to expand and contribute to the regeneration of hepatocytes and cholangiocytes. This regeneration process is called ductular reaction (DR), which is accompanied by dynamic remodeling of biliary tissue. Although the DR shows apparently distinct mode of biliary extension depending on the type of liver injury, the key regulatory mechanism remains poorly understood. Here, we show that Lutheran (Lu)/Basal cell adhesion molecule (BCAM) regulates the morphogenesis of DR depending on liver disease models. Lu+ and Lu- biliary cells isolated from injured liver exhibit opposite phenotypes in cell motility and duct formation capacities in vitro. By overexpression of Lu, Lu- biliary cells acquire the phenotype of Lu+ biliary cells. Lu-deficient mice showed severe defects in DR. Our findings reveal a critical role of Lu in the control of phenotypic heterogeneity of DR in distinct liver disease models.

The feature of chronic heart failure (CHF) in elderly people is increasing incidence of heart failure with preserved left ventricular ejection fraction (LVEF) which is associated with age. Such patients account for almost half of the total number of patients with heart failure. Cardiorenal syndrome (CRS) is associated with an increased risk of mortality in patients with CHF. The impact of CRS on the structural and functional condition of the heart in these patients is studied insufficiently. The study involved 103 patients with CHF II-IV NYHA with preserved LVEF (>45%) and CRS (hemoglobin

The feature of chronic heart failure (CHF) in elderly people is increasing incidence of heart failure with preserved left ventricular ejection fraction (LVEF) which is associated with age. Such patients account for almost half of the total number of patients with heart failure. Cardiorenal syndrome (CRS) is associated with an increased risk of mortality in patients with CHF. The impact of CRS on the structural and functional condition of the heart in these patients is studied insufficiently. The study involved 103 patients with CHF II-IV NYHA with preserved LVEF (>45%) and CRS (hemoglobin

Transcription factors (TFs) are proteins that control the transcription of genetic information from DNA to mRNA by binding to specific DNA sequences either on their own or with other proteins as a complex. TFs thus support or suppress the recruitment of the corresponding RNA polymerase. In general, TFs are classified by structure or function. The TF, Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), is expressed in all cell types and tissues. NF-κB signaling and crosstalk are involved in several steps of carcinogenesis including in sequences involving pathogenic stimulus, chronic inflammation, fibrosis, establishment of its remodeling to the precancerous niche (PCN) and transition of a normal cell to a cancer cell. Triggered by various inflammatory cytokines, NF-κB is activated along with other TFs with subsequent stimulation of cell proliferation and inhibition of apoptosis. The involvement of NF-κB in carcinogenesis provides an opportunity to develop anti-NF-κB therapies. The complexity of these interactions requires that we elucidate those aspects of NF-κB interactions that play a role in carcinogenesis, the sequence of events leading to cancer.