MCT Group Research Articles

Colchicine as a therapeutic option for the treatment of pulmonary arterial hypertension (PAH) in a rat model

Abstract Introduction Pulmonary arterial hypertension (PAH) is a cardiovascular disease that is characterized by severe structural and functional damages, resulting from the obstructive remodeling of the pulmonary vasculature and consequent right ventricular pressure overload. The current therapy mainly focuses on the pulmonary vascular system, with uncertain efficacy. Therefore, it is crucial to explore new therapeutic approaches. The mechanism of colchicine is complex and not-fully understood, but it has been proven to exert cardiopulmonary protective effects. Methods PAH induction was carried out in 8-week-old male WKY rats with a single subcutaneous injection of 60 mg/kg monocrotaline. Monocrotaline, a pyrrolizidine alkaloid, is metabolized in liver and induces inflammatory processes, which can cause PAH in rats. Starting from day 14 after MCT injection, the animals received three times a week intraperitoneal colchicine treatment at a dose of 0.5 mg/kg for two weeks. Echocardiographic examinations were performed during the study. At the end of the study, besides histological examination of the right ventricles and lungs [arterial wall thickness (WT%) and area (WA%)], the expression and phosphorylation levels of the proteins involved in cardiac remodeling were evaluated using Western blot. We assessed the pyruvate dehydrogenase (PDH) enzyme activity in the heart, which plays an important role in energy metabolism. We also examined the production of cytokines and chemokines in the right ventricle. Results The VW/BW ratio in the colchicine-treated group was significantly reduced compared to the MCT group (p<0.01). Echocardiographic parameters, EF% and E/e' ratio – characterizing the left ventricular function – did not differ considerably between the groups during the treatment. The TAPSE and PAT values characterizing right ventricular function improved in the MCT+C group (p<0.05). Collagen deposition and TGFβ level were significantly reduced by colchicine (p<0.05) in PAH animals. In the MCT+C group, the vascular remodeling (WT% and WA%) significantly decreased compared to the MCT group (p<0.01). The expression of α-SMA in vessel walls was most pronounced in the MCT group (p<0.01), which was significantly reduced by colchicine treatment. The phosphorylation of prosurvival signaling factors (ERK1/2, Akt1, GSK3β) was significantly increased in the MCT+C group (p<0.01) compared to the MCT group. In the right ventricle, PDH enzyme activity increased in the MCT+C group compared to the MCT group (p<0.01). According to cytokine array, cytokines involved in mediating fibrosis and inflammatory processes (TIMP-1, VEGF, L-selectin, CXCL7) showed increased secretion in the MCT group, which was moderately attenuated by colchicine treatment. Conclusion Colchicine treatment reduced the extent of fibrosis and inflammation, improved the structure of the pulmonary vasculature, and enhanced right ventricular function and energy supply.

Comparative Analysis of Tailored Minicraniotomy versus Standard Pterional Craniotomy in the Treatment of Anterior Circulation Aneurysms: A Single-Center Case–Control Observational Study

Abstract Introduction Multiple minicraniotomies (Mct) have been proposed as alternatives to standard pterional craniotomy (Pct) for intracranial aneurysm treatment. These approaches offer limited surgical corridors and distinct working angles, posing challenges in addressing all aneurysm types with one method. We suggest a tailored Mct technique, comprising three minimally invasive approaches targeting anterior circulation aneurysm sites (middle cerebral artery, internal carotid artery, anterior communicating artery). Methods We conducted a retrospective, case–control study at a single center comparing Pct and Mct outcomes for ruptured and unruptured aneurysms. Parameters evaluated included conversion rates to Pct or decompressive hemicraniectomy (DHC), intraoperative rupture (IOR), surgical complications, complete aneurysm exclusion, 6-month modified Rankin Scale (mRS) scores, and aesthetic outcomes using a visual analog scale. A total of 146 patients were included, with 103 in the Mct group and 43 in the Pct group, comparable in mean age, sex, and aneurysm topography. Hunt–Hess scores and Fisher grades were lower in the Mct group initially. Results No cases required conversion from Mct to Pct or DHC. No significant differences were observed in IOR, surgical complications, and aneurysm exclusion rates between groups. The Mct group demonstrated better 6-month mRS scores and aesthetic outcomes. Conclusion Our study indicates that tailored Mct is as safe and effective as standard Pct for intracranial aneurysms, with significant cosmetic benefits. Thus, tailored Mct can be considered a valuable alternative not only to Pct but also to other minimally invasive surgical methods for these aneurysms.

Low Thyroid Hormones Level Attenuates Mitochondrial Dysfunction and Right Ventricular Failure in Pulmonary Hypertensive Rats.

This study is to investigate the repercussions of hypothyroidism in the pathophysiological progression of pulmonary arterial hypertension (PAH). While the control (CTL, n = 5) male Wistar rats received vehicle, PAH was induced with monocrotaline (MCT group, n = 15). Hypothyroidism was induced in a subset of rats by methimazole 3weeks prior to the MCT injection (MMZ + MCT group, n = 15). Plasma thyroid hormones were measured by radioimmunoassay. Electrocardiographic, echocardiographic, and hemodynamic analyses were performed to evaluate the progression of PAH. Gene expression of antioxidant enzymes and cardiac hypertrophy markers were assessed by qPCR. Mitochondrial respiration, ATP levels, and ROS production were measured in right ventricular (RV) samples. Plasma T3 and T4 decreased in both MCT and MMZ + MCT groups (p < 0.05). Right ventricular systolic pressure (RVSP) increased, and RV - dP/dt, + dP/dt, and contractility index decreased in the MCT versus the CTL group and remained within control levels in the MMZ + MCT group (p < 0.05). Relative RV weight, RV wall thickness, RV diastolic area, and relative lung weight were augmented in the MCT versus the CTL group, whereas all parameters were improved to the CTL levels in the MMZ + MCT group (p < 0.05). Only the MCT group exhibited an increased duration of QTc interval compared to the baseline period (p < 0.05). ADP-induced mitochondrial respiration and ATP levels were decreased, and ROS production was increased in MCT versus the CTL group (p < 0.05), while the MMZ + MCT group exhibited increased mitochondrial respiration versus the MCT group (p < 0.05). Hypothyroidism attenuated the RV mitochondrial dysfunction and the pathophysiological progression of MCT-induced PAH.

MiR-210-5p Promotes Pulmonary Hypertension by Blocking ATP2A2.

Aberrant expression of ATPase sarcoplasmic/endoplasmic retic Ca2+ transporting 2 (ATP2A2) has attracted attention for its pathophysiologic role in pulmonary hypertension (PH). Several miRNAs, including miR-210-5p, have also been reported to be pathogenic factors in PH, but their exact mechanisms remain unknown. This study aimed to elucidate the potential mechanisms of miR-210-5p and ATP2A2 in MCT-induced PH. Eighteen Sprague-Dawley rats were randomly divided into two groups-monoclonal (MCT) group and control group-and then administered MCT (60mg/kg) and saline, respectively. mPAP, PVR, RVHI, WT%, and WA% were significantly increased in PH rats after 3weeks, confirming that the modeling of PH rats was successful. Subsequently, we determined the expression of ATP2A2 and miR-210-5p in lung tissues using WB and qRT-PCR methods. We established an in vitro model using BMP4 and TGF-β1 treatment of pulmonary artery smooth muscle cells (PASMCs) and examined the expression of ATP2A2 and miR-210-5p using the same method. To further elucidate the regulatory relationship between ATP2A2 and miR-210-5p, we altered the expression level of miR-210-5p and detected the corresponding changes in ATP2A2 levels. In addition, we demonstrated the relationship by dual luciferase experiments. Finally, the effect of silencing ATP2A2 could be confirmed by the level of cell membrane Ca2+ in PAMSCs. Up-regulation of miR-210-5p and down-regulation of ATP2A2 were observed in the MCT group compared with the control group, which was confirmed in the in vitro model. In addition, elevated miR-210-5p expression decreased the level of ATP2A2 while increasing the proliferation of PASMCs, and the results of the dual luciferase assay further confirmed that ATP2A2 is a downstream target of miR-210-5p. Additionally, silencing ATP2A2 resulted in increased cytoplasmic Ca2+ levels in PAMSCs. In MCT-induced PH, miR-210-5p promotes pulmonary vascular remodeling by inhibiting ATP2A2.

Pinocembrin attenuates susceptibility to atrial fibrillation in rats with pulmonary arterial hypertension

BackgroundPulmonary arterial hypertension (PAH) is a disease characterized by pulmonary vascular remodeling that triggers fibrosis and excessive myocardium apoptosis, ultimately facilitating atrial fibrillation (AF). In various rat models, Pinocembrin has anti-fibrotic and anti-apoptotic effects, reducing arrhythmia vulnerability. However, whether pinocembrin alleviates to AF in a PAH model remains unclear. The experiment aims to investigate how pinocembrin affects AF susceptibility in PAH rats and the possible mechanisms involved. MethodsThe PAH model was induced by monocrotaline (MCT; i. p. 60 mg/kg). Concurrently, rats received pinocembrin (i.p.50 mg/kg) or saline. Hemodynamics parameters, electrocardiogram parameters, lung H.E. staining, atrial electrophysiological parameters, histology, Western blot, and TUNEL assay were detected. ResultsCompared to the control rats, MCT-induced PAH rats possessed prominently enhancive mPAP (mean pulmonary artery pressure), pulmonary vascular remodeling, AF inducibility, HRV, right atrial myocardial fibrosis, apoptosis, atrial ERP, APD, and P-wave duration. Additionally, there were lowered protein levels of Cav1.2, Kv4.2, Kv4.3, and connexin 40 (CX40) in the MCT group in right atrial tissue. However, pinocembrin reversed the above pathologies and alleviated the activity of the Rho A/ROCKs signaling pathway, including the expression of Rho A, ROCK1, ROCK2, and its downstream MYPT-1, LIMK2, BCL-2, BAX, cleaved-caspase3 in right atrial and HL-1 cells. ConclusionPresent data exhibited pinocembrin attenuated atrial electrical, ion-channel, and autonomic remodeling, diminished myocardial fibrosis and apoptosis levels, thereby reducing susceptibility to AF in the MCT-induced PAH rats. Furthermore, we found that pinocembrin exerted inhibitory action on the Rho A/ROCK signaling pathway, which may be potentially associated with its anti-AF effects.

Prenatal diagnosis and perinatal outcomes of twin pregnancies disharmonious for one fetus with nuchal translucency above the 95th percentile

ObjectiveTo assess prenatal diagnosis and pregnancy outcomes in twin pregnancies where one fetus has nuchal translucency (NT) above the 95th percentile.MethodIn this retrospective analysis, 130 twin pregnancies (260 fetuses) in which one twin had an NT measurement above the 95th percentile while that of the other twin was normal were analyzed. Prenatal diagnostic results such as G bands, chromosomal microarray analysis, ultrasound findings, and pregnancy outcomes were reviewed.ResultsKaryotype analysis and CMA results revealed that 15 (15.6 percent, 15/96) fetuses exhibited chromosomal abnormalities and that 13 fetuses were Variant of Uncertain Significance. Chromosome abnormalities were detected at a rate of 8.9% (5/56) in the DCT group and 25.0% (10/40) in the MCT group (p = 0.033, X2 = 4.571). 2 fetuses in DCT (3.9 percent, 2/51) and 4 fetuses in MCT (13.3 percent, 4/30) (p = 0.187) revealed structural abnormalities among the cases with normal prenatal diagnosis. Fetuses in the DCT group had an overall survival rate of 75.4 percent (95/126), whereas those in the MCT group had a survival rate of 60.4 percent (81/134) (p = 0.01, X2 = 6.636). According to the findings of Logistics regression analysis, NT thickening, maternal age and method of conception were all significant risk factors for chromosome abnormalities.ConclusionIn twin pregnancies with one fetus with NT above the 95th percentile, the prevalence of fetal structural abnormalities of the MCT group and the DCT group were comparable. Pregnant women’s age and mode of pregnancy are risk factors for chromosomal abnormalities.

Effectiveness of group metacognitive therapy on recovery indicators in Muslim female drug abusers: Evidence from Afghanistan

Objective: Substance abuse is associated with a plethora of issues and harmful outcomes. It contributes to antisocial behavior and psychological disorders. The present study evaluated the effectiveness of metacognitive group therapy (MCGT) on recovery indicators in Muslim female drug abusers in the Herat Province of Afghanistan.Methods: In this study, Muslim female drug abusers (N=30, mean age 38.15 years, 100% female, 100% Afghan) were randomized to group metacognitive therapy (MCGT) or treatment as usual (TAU). The MCT group received six sessions of MCT in addition to conventional treatment. The TAU group received only conventional treatment. All participants completed a demographic questionnaire and Metacognition Questionnaire, Beck Anxiety Inventory, Beck Depression Inventory-II, Drug Use Evaluation Questionnaire, Personal Concerns Inventory, Motivational Structure Questionnaire, and Situational Confidence Questionnaire (SCQ). Data were collected at baseline and at the 3-month follow-up sessions. Results: Compared with TAU, MCT reduced anxiety, depression, drug use evaluation, and personal concerns, as well as improved motivational structure, situational confidence, and metacognitive beliefs. Conclusions: It seems that MCT may be an essential addition to methadone maintenance therapy.This study strongly suggests that MCT is an effective treatment for improving Muslim drug abusers’ recovery indicators, but only in cases of mild to moderate severity. For persons with severe substance abuse, additional treatment may be necessary.

Jagged/Notch proteins promote endothelial-mesenchymal transition-mediated pulmonary arterial hypertension via upregulation of the expression of GATAs.

This study tested the hypothesis that Jagged2/Notches promoted the endothelial-mesenchymal transition (endMT)-mediated pulmonary arterial hypertension (PAH) (i.e. induction by monocrotaline [MCT]/63 mg/kg/subcutaneous injection) through increasing the expression of GATA-binding factors which were inhibited by propylthiouracil (PTU) (i.e. 0.1% in water for daily drinking since Day 5 after PAH induction) in rodent. As compared with the control (i.e. HUVECs), the protein expressions of GATAs (3/4/6) and endMT markers (Snail/Zeb1/N-cadherin/vimentin/fibronectin/α-SMA/p-Smad2) were significantly reduced, whereas the endothelial-phenotype markers (CD31/E-cadherin) were significantly increased in silenced JAG2 gene or in silenced GATA3 gene of HUVECs (all p < 0.001). As compared with the control, the protein expressions of intercellular signallings (GATAs [3/4/6], Jagged1/2, notch1/2 and Snail/Zeb1/N-cadherin/vimentin/fibronectin/α-SMA/p-Smad2) were significantly upregulated in TGF-ß/monocrotaline-treated HUVECs that were significantly reversed by PTU treatment (all p < 0.001). By Day 42, the results of animal study demonstrated that the right-ventricular systolic-blood-pressure (RVSBP), RV weight (RVW) and lung injury/fibrotic scores were significantly increased in MCT group than sham-control (SC) that were reversed in MCT + PTU groups, whereas arterial oxygen saturation (%) and vasorelaxation/nitric oxide production of PA exhibited an opposite pattern of RVW among the groups (all p < 0.0001). The protein expressions of hypertrophic (ß-MHC)/pressure-overload (BNP)/oxidative-stress (NOX-1/NOX-2) biomarkers in RV and the protein expressions of intercellular signalling (GATAs3/4/6, Jagged1/2, notch1/2) and endMT markers (Snail/Zeb1/N-cadherin/vimentin/fibronectin/TGF-ß/α-SMA/p-Smad2) in lung parenchyma displayed an identical pattern of RVW among the groups (all p < 0.0001). Jagged-Notch-GATAs signalling, endMT markers and RVSBP that were increased in PAH were suppressed by PTU.

Glucose loading for heart failure protects the myocardium and improves physical function.

[Purpose] The purpose of this study was to investigate the effects of glucose intake on physical function in a heart failure rat model. [Materials and Methods] Five-week-old male Wistar rats were used for this study. Monocrotalin (40 mg/kg) was administered intraperitoneally to rats to induce heart failure. The rats were divided into two groups, control and MCT; the MCT group was further classified according to glucose concentration (0%, 10%, and 50%). [Results] Glucose intake during heart failure prevented the loss of body weight, skeletal muscle, and fat mass. Myocardial metabolism in heart failure was enhanced by hypoxia, which in turn, enhanced the glycolytic system. [Conclusion] Glucose loading suppressed cardiac hypertrophy and improved physical function in the heart failure rat model.

New method to decrease the air recirculation of mechanical draft wet cooling tower group by increasing height of fan duct

The air recirculation will increase the temperature and moisture content of air entering the mechanical draft wet cooling tower group (MCT group) and seriously reduce the cooling capacity. This study proposes to increase the height of the fan duct to reduce air recirculation. The aerodynamic field outside the MCT group is reconstructed to improve the cooling capacity of MCT group. A 3D model is established to explain the influence mechanism of air recirculation and the change of the thermal performance of MCT group. The main research variables are crosswind speed and direction. The numerical results show that, after the retrofit, the air recirculation rate of leeward MCT is reduced by 10.9 % on average and 16.0 % at most under the crosswind angle of 0°, 16.8 % mean and 25.0 % maximum under 45°, 1.0 % average and 2.0 % at most under 90°. The water temperature drop is increased by 0.5 °C on average and 0.8 °C at most under 0°, 0.7 °C mean and 1.1 °C maximum under 45°, 0.1 °C on average and 0.2 °C at most under 90°, compared to original MCT group.

Dapagliflozin reduces pulmonary vascular damage and susceptibility to atrial fibrillation in right heart disease.

Sodium-glucose cotransporter 2 inhibitors (SGLT2is) have made considerable progress in the field of heart failure, but their application in arrhythmia remains to be in-depth. Right heart disease (RHD) often leads to right heart dysfunction and is associated with atrial fibrillation (AF). Here, we explored the possible electrophysiologic effect of dapagliflozin (a type of SGLT2is) in the development of AF in rats with RHD. Rats in the experimental group were intraperitoneally injected with a single dose of 60mg/kg monocrotaline (MCT group, n=32) on the first day of the experiment, whereas rats in the control group were injected with vehicle (CTL group, n=32). Rats in the treatment subgroup were treated with dapagliflozin solution orally (MCT+DAPA and CTL+DAPA groups) for a total of 4weeks, whereas rats in the rest of subgroups were given sterile drinking water. After 4weeks, echocardiography demonstrated that MCT group rats developed obvious pulmonary arterial hypertension and right heart dysfunction. In addition, there were also obvious inflammatory infiltration, fibrosis, and muscularization in right atrial and pulmonary arteries. The P-wave duration (17.00±0.53ms, vs. 14.43±0.57ms in CTL; 14.00±0.65ms in CTL+DAPA; 14.57±0.65ms in MCT+DAPA; P<0.05), RR interval (171.60±1.48ms, vs. 163.10±1.10ms in CTL; 163.30±1.19ms in CTL+DAPA; 163.10±1.50ms in MCT+DAPA; P<0.05), Tpeak-Tend interval (65.93±2.55ms, vs. 49.55±1.71ms in CTL; 48.27±3.08ms in CTL+DAPA; P<0.05), and corrected QT interval (200.90±2.40ms, vs. 160.00±0.82ms in CTL; 160.40±1.36ms in CTL+DAPA; 176.6±1.57ms in MCT+DAPA; P<0.01) were significantly prolonged in the MCT group after 4weeks, whereas P-wave amplitude (0.07±0.0011mV, vs. 0.14±0.0009mV in CTL; 0.14±0.0011mV in CTL+DAPA; 0.08±0.0047mV in MCT+DAPA; P<0.05) and T-wave amplitude (0.04±0.002mV, vs. 0.13±0.003mV in CTL; 0.13±0.003mV in CTL+DAPA; P<0.01) were decreased, and atrial 90% action potential duration (47.50±0.93ms, vs. 59.13±2.1ms in CTL; 59.75±1.13ms in CTL+DAPA; 60.63±1.07ms in MCT+DAPA; P<0.01) and effective refractory periods (41.14±0.88ms, vs. 62.86±0.99ms in CTL; 63.14±0.67ms in CTL+DAPA; 54.86±0.70ms in MCT+DAPA; P<0.01) were shortened. Importantly, the inducibility rate (80%, vs. 0% in CTL; 10% in CTL+DAPA; 40% in MCT+DAPA; P<0.05) and duration of AF (30.85±22.90s, vs. 0±0s in CTL; 0.24±0.76s in CTL+DAPA; 5.08±7.92s in MCT+DAPA; P<0.05) were significantly increased, whereas the expression levels of cardiac ion channels and calcium-handling proteins such as potassium/calcium channels and calmodulin were decreased. Mechanistically, 'NACHT, LRR, and PYD domain-containing protein 3' inflammasome-related pathway was significantly activated in the MCT group. Nevertheless, in the MCT+DAPA group, the above abnormalities were significantly improved. Dapagliflozin reduces pulmonary vascular damage and right heart dysfunction, as well as the susceptibility to AF in RHD rats.

Increased Plasma L-Arginine Levels and L-Arginine/ADMA Ratios after Twelve Weeks of Omega-3 Fatty Acid Supplementation in Amateur Male Endurance Runners.

It is not fully understood how supplementation with omega-3 fatty acids affects the metabolism of amino acids required for the bioavailability/synthesis of NO, i.e., L-arginine (L-arg), asymmetric dimethylarginine (ADMA), their metabolites, and the L-arg/ADMA ratio and their impact on running economy (RE) in runners. Thus, 26 male amateur endurance runners completed a twelve-week study in which they were divided into two supplemented groups: the OMEGA group (n = 14; 2234 mg and 916 mg of eicosapentaenoic and docosahexaenoic acid daily) or the MCT group (n = 12; 4000 mg of medium-chain triglycerides daily). At the same time, all participants followed an endurance training program. Before and after the 12-week intervention, blood was collected from participants at two time points (at rest and immediately post-exercise) to determine EPA and DHA in red blood cells (RBCs) and plasma levels of L-arg, ADMA, and their metabolites. RBC EPA and DHA significantly increased in the OMEGA group (p &lt; 0.001), which was related to the resting increase in L-arg (p = 0.001) and in the L-arg/ADMA ratio (p = 0.005) with no changes in the MCT group. No differences were found in post-exercise amino acid levels. A total of 12 weeks of omega-3 fatty acid supplementation at a dose of 2234 mg of EPA and 916 mg of DHA daily increased levels of L-arg and the L-arg/ADMA ratio, which indirectly indicates increased bioavailability/NO synthesis. However, these changes were not associated with improved RE in male amateur endurance runners.

Influence of layout pattern on thermal performance of mechanical draft wet cooling tower group

Mechanical draft wet cooling tower group is often arranged the back-to-back (back-to-back MCT group). However, the thermal performance of back-to-back MCT group will be weakened under crosswind. To resist the adverse effects of crosswind, an annular MCT group is proposed. A 3D model is established to compare the two types of MCT groups. The main research variables are ambient wind speed and direction. The results show that the outlet water temperature of the annular MCT group is lower than that of the back-to-back MCT group under windless or crosswind. The annular MCT group mainly improves the thermal performance of the leeward MCT, and the fluctuation range of outlet water temperature of each MCT in the annular MCT group is reduced. The water temperature drop of the annular MCT group is about 0.3 °C higher than that of the back-to-back MCT group under windless. Under crosswind, the improvement effect is most obvious under the crosswind angle of 45° with the increase of circulating water temperature drop of 0.8 °C on average. That is least under the crosswind angle of 90° with the increase of circulating water temperature drop of 0.3 °C on average.

Effects of panax notoginseng saponins on pulmonary vascular remodeling in rats with pulmonary hypertension and its mechanisms

Objective: To investigate the effects of panax notoginseng saponins (PNS) on pulmonary vascular remodeling and SIRT1/FOXO3a/p27 pathway in pulmonary arterial hypertension (PAH) rats. Methods: Male SD rats weighing 200~250g were randomly divided into control group, monocrotaline group (MCT) and monocrotaline + panax notoginseng saponins group (MCT+PNS), with 10 rats in each group. The rats in control group were injected intraperitoneally with normal saline 3 ml/kg on the first day, then injected intraperitoneally with normal saline 2.5 ml/kg every day. The rats in MCT group were injected intraperitoneally with MCT 60 mg/kg on the first day, followed by daily injection of normal saline 2.5 ml/kg. In MCT+PNS group, 60 mg/kg MCT was injected intraperitoneally on the first day, and 50 mg/kg PNS was injected intraperitoneally every day. The above models were fed conventionally for 4 weeks. After the modeling was completed, the mean pulmonary artery pressure (mPAP) and right ventricular systolic pressure (RVSP) of rats in each group were detected by right heart catheter method, weighed and calculated right ventricular hypertrophy index (RVHI), and the pulmonary vascular structure and morphological changes were observed by HE and Masson staining. The protein and gene expressions of SIRT1, FOXO3a, p27, PCNA and Caspase-3 were detected by qPCR and Western blot. Results: Compared with control group, mPAP, RVSP and RVHI in MCT group were increased significantly (P＜0.01), pulmonary vessels were thickened significantly and collagen fibers were increased, protein and gene expressions of SIRT1, FOXO3a, p27 and Caspase-3 were decreased (P＜0.05 or P＜0.01). The protein and gene expressions of PCNA were increased (P＜0.05). Compared with MCT group, the levels of mPAP, RVSP and RVHI in MCT+PNS group were decreased significantly (P＜0.05 or P＜0.01), pulmonary vascular thickening was alleviated and collagen fibers were reduced. The protein and gene expressions of SIRT1, FOXO3a, p27 and Caspase-3 were increased (P＜0.05 or P＜0.01), while the protein and gene expressions of PCNA were decreased (P＜0.05 or P＜0.01). Conclusion: Panax notoginseng saponins can relieve pulmonary vascular remodeling in rats with pulmonary hypertension by activating SIRT1/FOXO3a/p27 pathway.

Therapeutic effects of nebulization-based delivery of anti-miR-146a in experimental pulmonary arterial hypertension

Abstract Pulmonary arterial hypertension (PAH), is a chronic disorder characterized by excessive pulmonary vascular remodelling, resulting in elevated pulmonary vascular resistance and right ventricle (RV) overload and failure. PAH remains incurable, and new therapeutic approaches are required. The microRNA-146a (miR-146a) promotes vascular smooth muscle cell proliferation and vascular neointimal hyperplasia, both important hallmarks of PAH. This study aimed to investigate the role of miR-146a in the pathophysiology of PAH and in the progression to RV hypertrophy and failure. Sprague Dawley rats received a subcutaneous injection of monocrotaline (MCT group) or vehicle (CTRL group) and, after fourteen days they were treated, by intratracheal nebulization, with an anti-miR-146a, forming four distinct groups: CTRL-treated; CTRL-untreated, MCT-treated, and MCT-untreated. Twenty-seven days after MCT injection, echocardiographic and invasive hemodynamic evaluations were performed in all animal groups. Also, wild-type (WT) and miR-146a knock-out (KO) (miR-146a−/−) mice were submitted to either 3 weeks of chronic hypoxia-induced PAH with weekly Sugen 5416 administration (SuHx). Compared to MCT-untreated rats, the MCT-treated rats showed decreased RV hypertrophy, (as measured by the Fulton index),decreased RV end-diastolic diameter/left ventricle end-diastolic diameter (RVEDD/LVEDD) ratio, and decreased in RV diastolic pressures. KO-SuHx group, when compared to WT-SuHx group, showed decreased RV hypertrophy (as measured by the Fulton index), and decreased RV systolic pressures and dilation, as well as lower RV end end-diastolic diameter (RVEDDi) and right atria area (RAAi). Our findings show that miR-146a pharmacological or genetic inhibition reduces RV remodelling and improves cardiac function. Thus, miR-146a represents a promising therapeutic target in PAH. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): This research was supported by the Portuguese Foundation for Science and Technology (FCT).

Effects of 12 Wk of Omega-3 Fatty Acid Supplementation in Long-Distance Runners.

This study aimed to investigate the effects of 12 wk of omega-3 fatty acid supplementation during endurance training on omega-3 index (O3I) and indicators of running performance in amateur long-distance runners. Twenty-six amateur male long-distance runners ≥29 yr old supplemented omega-3 fatty acid capsules (OMEGA group, n = 14; 2234 mg of eicosapentaenoic acid and 916 mg of docosahexaenoic acid daily) or medium-chain triglycerides capsules as placebo (medium-chain triglyceride [MCT] group, n = 12; 4000 mg of MCT daily) during 12 wk of endurance training. Before and after intervention, blood samples were collected for O3I assessment, and an incremental test to exhaustion and a 1500-m run trial were performed. O3I was significantly increased in the OMEGA group (from 5.8% to 11.6%, P < 0.0001). A significant increase in V̇O 2peak was observed in the OMEGA group (from 53.6 ± 4.4 to 56.0 ± 3.7 mL·kg -1 ⋅min -1 , P = 0.0219) without such change in MCT group (from 54.7 ± 6.8 to 56.4 ± 5.9 mL·kg -1 ⋅min -1 , P = 0.1308). A positive correlation between the change in O3I and the change in running economy was observed when data of participants from both groups were combined (-0.1808 ± 1.917, P = 0.0020), without such an effect in OMEGA group alone ( P = 0.1741). No effect of omega-3 supplementation on 1500-m run results was observed. Twelve weeks of omega-3 fatty acid supplementation at a dose of 2234 mg of eicosapentaenoic acid and 916 mg of docosahexaenoic acid daily during endurance training resulted in the improvement of O3I and running economy and increased V̇O 2peak without improvement in the 1500-m run trial time in amateur runners.

THERAPEUTIC EFFECTS OF NEBULIZATION- BASED DELIVERY OF ANTI-MIR-146A IN EXPERIMENTAL PULMONARY ARTERIAL HYPERTENSION

Objective: Pulmonary arterial hypertension (PAH), is a chronic disorder characterized by excessive pulmonary vascular remodelling, resulting in elevated pulmonary vascular resistance and right ventricle (RV) overload and failure. PAH remains incurable, and new therapeutic approaches are required. The microRNA-146a (miR-146a) promotes vascular smooth muscle cell proliferation and vascular neointimal hyperplasia, both important hallmarks of PAH. This study aimed to investigate the role of miR-146a in the pathophysiology of PAH and in the progression to RV hypertrophy and failure. Design and method: Sprague Dawley rats received a subcutaneous injection of monocrotaline (MCT group) or vehicle (CTRL group) and, after fourteen days they were treated, by intratracheal nebulization, with an anti-miR-146a, forming four distinct groups: CTRL-treated; CTRL-untreated, MCT-treated, and MCT-untreated. Twenty-seven days after MCT injection, echocardiographic and invasive hemodynamic evaluations were performed in all animal groups. Also, wild-type (WT) and miR-146a knock-out (KO) (miR-146a-/-) mice were submitted to either 3 weeks of chronic hypoxia-induced PAH with weekly Sugen 5416 administration (SuHx). Results: Compared to MCT-untreated rats, the MCT-treated rats showed decreased RV hypertrophy, (as measured by the Fulton index), decreased RV end-diastolic diameter/left ventricle end-diastolic diameter (RVEDD/LVEDD) ratio, and decreased in RV diastolic pressures. KO-SuHx group, when compared to WT-SuHx group, showed decreased RV hypertrophy (as measured by the Fulton index), and decreased RV systolic pressures and dilation, as well as lower RV end end-diastolic diameter (RVEDDi) and right atria area (RAAi). Conclusions: Our findings show that miR-146a pharmacological or genetic inhibition reduces RV remodelling and improves cardiac function. Thus, miR-146a represents a promising therapeutic target in PAH.

Efficacy of Metacognitive Training for Patients With Schizophrenia in Psychiatric Emergency Wards: A Pilot Randomized Controlled Trial.

IntroductionMetacognitive training (MCT) is a group program for improving cognitive bias in patients with schizophrenia. MCT has a reported positive effect on psychiatric symptoms and cognitive bias in patients with schizophrenia, but the effect of the intervention on patients with schizophrenia in the early recovery stage during hospitalization is not comprehensible. Therefore, this study aimed to investigate the efficacy of MCT in the early recovery stage of patients with schizophrenia in a Japanese emergency psychiatric ward.MethodThis unblinded, pilot randomized controlled trial recruited 24 patients with schizophrenia aged 20–65 years. Patients were randomly divided into two groups: occupational therapy (OT) + MCT group and OT-only group. Using the two-way repeated-measures analysis of variance (ANOVA), changes in cognitive function, psychiatric symptoms, cognitive insight, and intrinsic motivation were compared between those at baseline and post-intervention and between the two groups. Furthermore, patient readmission during the year after discharge was compared between the groups.ResultsThe final analysis included eight patients in each group, owing to the withdrawal of some patients from the study. The two-way repeated-measures analysis of variance revealed significant differences in cognitive function in several domains within subjects. However, no significant differences between subjects were observed. Psychiatric symptoms showed significant within-subject improvement, and interaction was found for general psychopathology (p = 0.03). The variable of cognitive insight and self-reflectiveness was significantly different between subjects (p = 0.03). There was no significant difference in intrinsic motivation. Readmission within a year was significantly lower in the OT + MCT group than in the OT-only group (2 [25%] vs. 6 [75%]; p = 0.046).ConclusionIn a Japanese emergency psychiatric ward, this pilot randomized controlled study was the first attempt to investigate the efficacy of MCT in patients with schizophrenia suggesting that MCT may be effective in preventing psychiatric symptoms, poor self-reflectiveness, and readmissions.The study was registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR; UMIN000034106).

Reduced LVEDD following a 12 week exercise training program in patients with symptomatic chronic heart failure is associated with reduction in serum levels of Troponin I

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Norwegian University of Science and Technology Danish Research Council Background Exercise training (ET) exerts many beneficial effects on the cardiovascular system, and longitudinal observational data from epidemiological studies suggest that higher physical activity is associated with lower concentrations of cardiac troponins. We have previously shown that ET can reduce Left Ventricle End-diastolic diameter (LVEDD), and improve exercise capacity. Purpose Our aim was to explore the relationship between changes in LVEDD and changes in high-sensitive plasma troponin I (hs-TnI) levels in patients with symptomatic heart failure undergoing a 12 week structured exercise training program in the randomized multicenter SMARTEX trial. Methods This was a post hoc analysis in 199 patients with symptomatic HF with LVEF &amp;lt;35% and NYHA II-III that were randomly assigned to High Intensity Interval Training (HIIT, n = 73), Moderate Continuous Training (MCT, n = 59) or Recommendation of Regular Exercise, (RRT, n = 67) for 12 weeks. Log-transformed Hs-TnI measurements and clinical data acquired before (BL) and after a 12 week exercise training intervention (12 weeks) and at 1 year follow-up (1 year) were analysed using a linear mixed model. For Troponin analysis the STAT Troponin-I from Abbott Diagnostics was used. Nakagawa’s marginal R2 and conditional R2 were used to evaluate variance explained by fixed effects only and by fixed and random effects together, respectively. Changes of LVEDD between baseline and 12 weeks and baseline and 52 weeks were evaluated using linear mixed model. The outcome variable were measures of LVEDD, while age, sex, visit and training group and their interaction [visit × training group] were included as fixed effects. Patient id and training center were random effects. Covariance structure was compound symmetry. Linear association between log-transformed TnI and LVEDD baseline was evaluated using Pearson correlation coefficient (R). Results Serum was available for hs-TnI analyses in 199 patients. In the HIIT group there was a sustained significant reduction in LVEDD at both 12 and 52 weeks. In the MCT group this reduction was statistically significant at 52 weeks only. Mixed model analysis predicts that each 1 mm decrease in LVEDD is associated with 1.2% decrease in TnI levels (95% CI: 0.6 – 1.9%, p &amp;lt;0.001). Neither time nor training group were associated with changes of TnI (overall test p = 0.739 and p = 0.987, respectively). Dynamics of TnI is highly patient-specific with Intraclass correlation coefficient (ICC) = 0.86. Mixed model explains 87% variation of the data (conditional R2), however, only 7% is attributed to the fixed effects (marginal R2). At baseline, TnI and LVEDD have modest but statistically significant correlation (R = 0.2, p= 0.004). Conclusions A reduction of LVEDD following a 12-week exercise-training program is associated with a reduction in plasma troponin levels, in patients with mild to moderate chronic heart failure. Abstract Figure.

Effects of Intensity Modulated Total-Body Circuit Training Combined with Soccer Training on Physical Fitness in Prepubertal Boys after a 6-Month Intervention.

The purpose of this study was to examine the effects of a 6-month high- or moderate-intensity total-body circuit training (CT) program on physical fitness in prepubertal soccer players. Sixty-seven prepubertal boys with a mean age of 11.2 ± 0.7 years completed the study. Participants from a soccer academy were randomly assigned either to a high-intensity CT group (HCT, n = 22) or a moderate-intensity CT group (MCT, n = 24). A control group (CON, n = 21) comprised age-matched individuals who were not involved in any regular training regime. CT protocols were included in the experimental group’s training sessions 3 times per week over 24 weeks as part of their usual weekly training regime. Based on the HR zone method, CT protocols included high- or moderate-intensity (85–95% HRmax or 75–85% HRmax) series of 3 different sets of upper- and lower-body strength exercises with articular and muscular mobilization, all culminated with 40-m sprints. Physical fitness was evaluated by the Eurofit test which included the flamingo balance (FLB), plate tapping (PLT), sit-and-reach (SAR), standing broad jump (SBJ), handgrip (HG), sit-ups (SUP), bent arm hang (BAH), 10×5 m shuttle run (SHR), and the Physical Working Capacity test (PWC170). The two-way ANOVA indicated group×time interaction effects for 5 components: the largest was for the SBJ (F2,63 = 42.895, p < 0.001, η2 = 0.577), and the lowest for the SHR (F2,63 = 5.006, p < 0.01, η2 = 0.137) indicating better improvements in the HCT compared to the MCT group. Furthermore, for HCT and MCT groups the highest pre- to post-intervention percentage changes were for the FLB and the SAR, while in the CON group the changes of all physical fitness components were not significant (p < 0.05). In conclusion, the intensity-controlled total-body CT protocol incorporated into a standard soccer training program is effective for enhancement in physical fitness performance in prepubertal soccer players.