Ultrasound Trigger Ce-Based MOF Nanoenzyme For Efficient Thrombolytic Therapy.

The inflammatory damage caused by thrombus formation and dissolution can increase the risk of thrombotic complications on top of cell death and organ dysfunction caused by thrombus itself. Therefore, a rapid and precise thrombolytic therapy strategy is in urgent need to effectively dissolve thrombus and resist oxidation simultaneously. In this study, Ce-UiO-66, a cerium-based metal-organic framework (Ce-MOF) with reactive oxygen species (ROS) scavenging properties, encapsulated by low-immunogenic mesenchymal stem cell membrane with inflammation-targeting properties, is used to construct a targeted nanomedicine Ce-UiO-CM. Ce-UiO-CM is applied in combination with external ultrasound stimulation for thrombolytic therapy in rat femoral artery. Ce-UiO-66 has abundant Ce (III)/Ce (IV) coupling sites that react with hydrogen peroxide (H2O2) to produce oxygen, exhibiting catalase (CAT) activity. The multi-cavity structure of Ce-UiO-66 can generate electron holes, and its pore channels can act as micro-reactors to further enhance its ROS scavenging capacity. Additionally, the porous structure of Ce-UiO-66 and the oxygen produced by its reaction with H2O2 may enhance the cavitation effects of ultrasound, thereby improving thrombolysis efficacy.

Mechanical injury accentuates lipid deposition in ApoE-/- mice and advance aortic valve stenosis: A novel modified aortic valve stenosis model.

Background: Current mouse models still have limitations in studying aortic valve stenosis (AVS). A suitable animal model bearing a close resemblance to the pathophysiological processes of humans needs to be developed. Here, we combined two risk factors to create a mouse model that mimics the pathological features of human AVS. Methods and results: We combined WI and hyperlipidemia in ApoE-/- mice to explore the synergistic effect on the stenosis of the aortic valve. Transthoracic echocardiography revealed progressively increased peak velocity with age in ApoE-/- mice to velocities above C57 mice when fed a high-fat diet after wire injury. Moreover, ApoE-/- mice demonstrated lower cusp separation and lower aortic valve area after 8 weeks vs. C57 mice. Gross morphology and MRI showed advanced thickening, sclerosis aortic valve, narrowing of the orifice area, and micro-CT showed obvious calcification in the aortic valves in the hyperlipidemia group after wire injury. Histopathology studies showed thickening and fibrosis of aortic valve leaflets in the hyperlipidemia group after wire injury. Notably, lipid deposition was observed in ApoE-/- mice 8 weeks after wire injury, accompanied by overexpressed apoB and apoA proteins. After wire injury, the hyperlipidemia group exhibited augmented inflammation, ROS production, and apoptosis in the leaflets. Moreover, the combination group exhibited advanced fibro-calcific aortic valves after wire injury. Conclusion: Overall, we present the synergistic effect of wire injury and hyperlipidemia on lipoproteins deposition in the development of AVS in ApoE-/- mice, this model bear close resemblance to human AVS pathology.

MiRNA-21 promotes differentiation of bone marrow mesenchymal stem cells into cardiomyocyte-like cells by regulating the Ajuba/Isl1 axis pathway.

Introduction: In this study, we aimed to investigate the role of miRNA-21 and the regulating pathway that promotes the differentiation of bone marrow mesenchymal stem cells (BMSCs). Methods: We used miR-21-OE, miR-21-KD, ajuba-OE and ajuba-KD plasmids to infect BMSCs. The expression of miRNA-21, ajuba, Isl1 and cTnI was detected by RT-qPCR, WB and immunofluorescence staining in groups. Results: MiRNA-21 over-expression increased the expression of Isl1, and vice versa. Ajuba over-expression decreased the expression of Isl1, and vice versa. Ajuba negatively regulated the differentiation of BMSCs into cardiomyocyte-like cells. Conclusions: MiRNA-21 could regulate differentiation of bone marrow mesenchymal stem cells (BMSCs) to cardiomyocyte-like cells through the ajuba/Isl1 axis pathway.

Oestrogen Receptor ß Activation Protects Against Myocardial Infarction via Notch1 Signalling.

PURPOSE: Oestrogen receptor ß is believed to exert a cardioprotective effect against ischaemic injury. Nonetheless, the mechanism underlying its protective action remains to be fully elucidated. Recently, increased attention has been focused on Notch1 signalling for ameliorating cardiac ischaemic injury. Here, we hypothesised that oestrogen receptor ß activation attenuates myocardial infarction (MI)-induced cardiac damage by modulating the Notch1 signalling pathway. METHODS: Male C57BL/6 mice were used to establish an MI model through the ligation of the anterior descending branch of the left coronary artery. Two chemical drugs, 2,3-Bis(4-hydroxyphenyl)-propionitrile (DPN) and N-[N-(3,5-difluorophenacetyl)-l-alanyl]-s-phenylglycine t-butyl ester (DAPT), a specific inhibitor of Notch1 signalling) were administered via intraperitoneal injection to change oestrogen receptor ß and Notch1 activities. Immunohistochemistry, western blot analysis, enzyme-linked immunosorbent assay (Elisa) assessment and echocardiography were used in this study to analyse cardiac oxidative stress, apoptosis, infraction volume, fibrosis and cardiac function. RESULTS: DPN-mediated oestrogen receptor ß activation effectively protected cardiomyocytes from MI-induced oxidative damage and apoptosis. Furthermore, oestrogen receptor ß activation reduced the infarct size and lowered the levels of myocardial enzymes in the serum, thereby leading to greater overall cardiac function improvement. Ischaemic injury-induced myocardial fibrosis was attenuated by oestrogen receptor ß activation. Nevertheless, all of these cardioprotective effects of oestrogen receptor ß activation were almost abrogated by DAPT administration, i.e. DAPT attenuated the anti-oxidative and anti-apoptotic effects and the decrease in infarct and fibrotic areas and reversed cardiac functional recovery. The levels of phospho-phosphatidylinositol-3-kinase (PI3K) and phospho-protein kinase B (Akt) were increased after DPN administration, and this change was reversed after DAPT was administered. CONCLUSIONS: All of these new findings indicate that oestrogen receptor ß activation is effective in ameliorating MI-induced cardiac dysfunction by enhancing Notch1 signalling and that PI3K/Akt signalling is the downstream mediator.

Ascending Aortic Constriction Promotes Cardiomyocyte Proliferation in Neonatal Rats.

Adult heart suffering from increased workload will undergo myocardial hypertrophy, subsequent cardiomyocyte (CM) death, and eventually heart failure. However, the effect of increasing afterload on the neonatal heart remains unknown. We performed ascending aortic constriction (AAC) in neonatal rats 8-12 hours after birth (P0, P indicates postpartum). Seven days after surgery, in vivo heart function was evaluated using cardiac ultrasonography. Haematoxylineosin and Masson staining were used to assess CM diameter and collagen deposition. Moreover, expression of both EdU and Ki67 were evaluated to determine DNA synthesis levels, and pH3 and aurora B as markers for mitosis in CMs. CM isolation was performed by heart perfusion at P0, P3, P5, and P7, respectively. CM number on P0 was 1.01 ± 0.29 × 106. We found that CM cell cycle activation was significantly increased among constricted hearts, as demonstrated by increased Ki67, EdU, pH3, and aurora B positive cells/1000 CMs. At day 7 (P7), constriction group hearts manifested increased wall thickness (0.55 ± 0.05 mm versus 0.85 ± 0.10 mm, P < 0.01, n = 6), and improved hemodynamics as well as left ventricular ejection fraction (65.5 ± 3.7% versus 77.7 ± 4.8%, P < 0.01, n = 6). Of note, the population of CMs was also markedly increased in the constriction group (2.92 ± 0.27 × 106 versus 3.41 ± 0.40 × 106, P < 0.05, n = 6). In summary, we found that during the first week after birth significant numbers of neonatal CMs can reenter the cell cycle. Ascending aortic constriction promotes neonatal rat CM proliferation resulting in 16.7% more CMs in the heart.

Inhibition of PKR protects against H2O2-induced injury on neonatal cardiac myocytes by attenuating apoptosis and inflammation.

Reactive oxygenation species (ROS) generated from reperfusion results in cardiac injury through apoptosis and inflammation, while PKR has the ability to promote apoptosis and inflammation. The aim of the study was to investigate whether PKR is involved in hydrogen peroxide (H2O2) induced neonatal cardiac myocytes (NCM) injury. In our study, NCM, when exposed to H2O2, resulted in persistent activation of PKR due to NCM endogenous RNA. Inhibition of PKR by 2-aminopurine (2-AP) or siRNA protected against H2O2 induced apoptosis and injury. To elucidate the mechanism, we revealed that inhibition of PKR alleviated H2O2 induced apoptosis companied by decreased caspase3/7 activity, BAX and caspase-3 expression. We also revealed that inhibition of PKR suppressed H2O2 induced NFκB pathway and NLRP3 activation. Finally, we found ADAR1 mRNA and protein expression were both induced after H2O2 treatment through STAT-2 dependent pathway. By gain and loss of ADAR1 expression, we confirmed ADAR1 modulated PKR activity. Therefore, we concluded inhibition of PKR protected against H2O2-induced injury by attenuating apoptosis and inflammation. A self-preservation mechanism existed in NCM that ADAR1 expression is induced by H2O2 to limit PKR activation simultaneously. These findings identify a novel role for PKR/ADAR1 in myocardial reperfusion injury.

Thoracic Endovascular Aortic Repair for Traumatic Thoracic Aortic Injury: A Single-Center Initial Experience.

BACKGROUND: Several publications have documented the technical feasibility and efficacy of stent grafting for aortic injuries. We report short- and mid-term results of thoracic endovascular repair with covered stent grafts for type B blunt thoracic aortic injury. METHODS: We performed a retrospective review of patients who had sustained blunt thoracic aortic injuries. From January 2010 to March 2014, 13 patients (12 men and 1 woman) were admitted and treated in our department for type B thoracic aortic injury. The patients' ages ranged from 19 to 62 years. Traffic accidents were responsible for 10 of the 13 blunt thoracic aortic injuries, and the remainder was caused by blunt trauma from falls. Medical records were examined to identify the clinical outcomes of the procedures, and follow-up computed tomography scans were reviewed to document the efficacy of thoracic endovascular aortic repair. RESULTS: Endovascular stent grafting was technically successful in all cases, and no paraplegia or stroke-like events were reported. No major cardiac, neurologic, or peripheral vascular complications were observed during early or late follow-up. None of the patients died from procedure-related complications. CONCLUSIONS: Our single-center experience demonstrates the feasibility of performing endovascular repair for type B blunt aortic injury. As experience with endovascular surgery accumulates, this method of treatment promises to become the first-choice option for repairing this type of aortic injury, with less associated morbidity and mortality relative to conventional surgical repair.

The use of statins to prevent postoperative atrial fibrillation after coronary artery bypass grafting: a meta-analysis of 12 studies.

There is no agreement on whether statins influence the incidence of atrial fibrillation after coronary artery bypass grafting. We performed a meta-analysis of 12 studies that compared statins with controls. Statin therapy significantly reduced the incidence of postoperative atrial fibrillation (POAF) (odds ratio, 0.50; 95% confidence interval, 0.35-0.73) and length of hospital stay (weighted mean difference, -0.72; 95% confidence interval, -0.99 to -0.45), an effect that survived detailed subgroup analysis. Meta-regression analysis revealed that patient characteristics did not influence the extent of improvement in the incidence of POAF attributable to statins. In conclusion, patients undergoing coronary artery bypass grafting benefit from perioperative treatment with statins, which significantly reduce the incidence of POAF and length of hospital stay.

High mobility group box 1 (HMGB1) mediates high-glucose-induced calcification in vascular smooth muscle cells of saphenous veins.

Diabetes accelerates saphenous vein grafts calcification after years of coronary artery bypass grafting (CABG) surgery. Vascular smooth muscle cells (VSMC) undergoing a phenotypic switch to osteoblast-like cells play a key role in this process. The receptor for advanced glycation and products (RAGE) and toll-like receptors (TLRs) are all involved in various cardiovascular calcification processes. Therefore, the role of their common ligand, high mobility group box 1 (HMGB1), in high-glucose-induced calcification in VSMC of saphenous vein was investigated. In this study, VSMC were cultured from saphenous vein of patients arranged for CABG. We first demonstrated high-glucose-induced HMGB1 translocation from nucleus to cytosol, and this translocation was induced through a NADPH oxidase and PKC-dependent pathway. We next found high glucose also increased TLR2, TLR4, and RAGE expression. Then, we revealed downregulating HMGB1 expression abolished high-glucose-induced calcification accompanied by NFκB inactivation and low expression of bone morphogenetic protein-2 (BMP-2). We further demonstrated NFκB activation was necessary in high-glucose-induced BMP-2 expression and calcification. Finally, by using a chromatin immunoprecipitation assay, we demonstrated NFκB transcriptional regulation of BMP-2 promoter was induced by NFκB binding to its κB element on the BMP-2 promoter. Our findings thus suggest HMGB1 plays an important role in mediating the calcification process induced by high glucose through NFκB activation and BMP-2 expression in VSMC of saphenous vein.

[Effects of acupuncture-drug compound anesthesia on perioperative inflammatory factors in patients undergoing cardiac surgery].

OBJECTIVE: To explore the effect of acupuncture-drug compound anesthesia on immune function in patients with extracorporeal circulation undergoing cardiac surgery. METHODS: Thirty cases undergoing cardiac surgery which included atrial septal defect neoplasty, ventricular septal defect neoplasty, mitral valve replacement and pulmonary valve coarctotomy were randomly divided into group A and group B, 15 cases in each group. Group A was given general anesthesia plus acupuncture at Neiguan (PC 6), Lieque (LU 7) and Yunmen (LU 2), and group B was given simple general anesthesia. Tumor necrosis factor-alpha (TNF-alpha), interleukin-2 (IL-2) and interleukin-10 (IL-10) levels before and after surgery were compared. RESULTS: The level of TNF-alpha was increased and the levels of IL-2 and IL-10 in the serum were decreased in both groups after extracorporeal circulation for 2 h and 24 h, and the ranges of all changes were more less in group A (all P < 0.05). CONCLUSION: Compared with simple general anesthesia, acupuncture-drug compound anesthesia can improve immune suppression partially in the perioperative periods under the same conditions of controlling anesthesia degree.