Aorto-ventricular tunnel with three orifices: a unique case report diagnosed by transthoracic echocardiography.

BACKGROUND: Aorto-ventricular tunnel (AVT) is an abnormal communication channel between the ascending aorta and the ventricle. It commonly has two orifices, i.e., one aortic opening and one ventricular opening. In this study, we present a unique case of AVT with three orifices: one aortic opening, one LV opening, and one RV opening. CASE PRESENTATION: A 64-year-old male presented with chest discomfort and dyspnea on exertion lasting the past six months. Physical examination revealed a grade 4/6 continuous biphasic murmur along the left sternal edge and a grade 3/6 systolic murmur at the apex. Transthoracic echocardiography (TTE) demonstrated: (1) an AVT with three orifices, i.e., one aortic opening, one LV opening, and one RV opening. The LV and RV openings were located in the left and right ventricular outflow tracts, respectively. (2) The aortic valve (AV) was calcified with a small aneurysm at the non-coronary cusp. (3)The mitral valve (MV) chordal rupture of the P2 and P3 segments was observed in the posterior leaflet with severe eccentric regurgitation. Subsequent coronary computed tomography angiography (CTA) further confirmed the diagnosis of AVT with three openings, and clarified the coronary arteries normally arose from the aortic sinuses. The patient was then referred for surgical treatment, consisting of closure of three AVT orifices, AV replacement, and MV replacement. Six months following surgery, the patient was asymptomatic. TTE demonstrated normal mechanic AV and MV function, and there was no residual shunt among the ascending aorta, LV and RV. CONCLUSIONS: It is the first case to report an AVT with three orifices. This paper described the entire process from diagnosis to treatment of this unique case, thus providing some novel insights into AVT.

Citrate pretreatment attenuates hypoxia/reoxygenation-induced cardiomyocyte injury via regulating microRNA-142-3p/Rac1 aix.

Purpose: Citrate has a positive effect on improving the pathophysiological changes of cardiomyocytes such as cardiac failure and auricular fibrillation. However, the underlying mechanism remains still unclear.Methods: Rat cardiomyocytes were used to establish hypoxia/reoxygenation (H/R) cell model. Citrate was conduct to pretreat with cardiomyocytes, and microRNA-142-3p (miR-142-3p) knockdown and overexpression were used to determine the underlying mechanism of their functions in cardiomyocytes. Cell viability and apoptosis were respectively detected by CCK-8 and flow cytometry. Protein and mRNA levels were determined by Western blot and qRT-PCR. Luciferase reporter assay and Targetscan were performed to study the regulation of miR-142-3p and Rac1.Results: The level of miR-142-3p was down-regulated in H/R model, but up-regulated in cardiomyocytes following citrate treatment. Citrates attenuated H/R injury induced miR-142-3p level and cell viability, and also inhibited H/R injury induced apoptosis, LDH, MDA and autophagy. Cell viability was improved, and autophagy was suppressed by miR-142-3p mimic, while inhibitor had opposite results. Compared with H/R + miR-142-3p inhibitor group, cell viability was higher, and apoptosis and autophagy were lower in Cit + H/R + miR-142-3p inhibitor group. Furthermore, Rac1 was target gene of miR-142-3p, and decreased by citrate, in comparison with H/R + miR-142-3p inhibitor group.Conclusion: Taken together, our findings indicated that citrate ameliorates H/R injury-induced cardiomyocytes autophagy by regulating miR-142-3p/Rac1 aix.

A Hybrid Procedure Combining Mini-Thoracotomy with Interventional Endocardial Lead Implantation for Cardiac Resynchronization Therapy in Patients with Chronic Congestive Heart Failure: A Report of Four Cases.

BACKGROUND: We describe the application and effectiveness of transthoracic electrode implantation for epicardial left ventricular pacing in cardiac resynchronization therapy (CRT) for patients with chronic congestive heart failure. METHODS: We assessed four patients with chronic congestive heart failure for whom implantation of endocardial electrodes was contraindicated. The epicardial electrodes were implanted via a mini-thoracotomy in the fourth or fifth left intercostal space. We analyzed the surgical implantation technique and the short-term effectiveness of the procedure. RESULTS: The epicardial electrodes successfully were implanted in all four patients. The patients' hemodynamic status, cardiac function, and symptoms significantly improved. Patients I, II, III, and IV were discharged from the hospital on the 8, 11, 4, and 7 days, respectively, after the operation. Follow up lasted for 12 months. None of the patients presented with electrode fractures or surgical wound infections, and the pacing threshold and electrode impedance were normal. In one case, phrenic nerve stimulation occurred due to the low placement position of the electrode. When the electrode was moved slightly inward and upward, the sacral nerve stimulation sign disappeared, and no other complications were noted. One patient developed capsule infection, and the presence of an ectopic pacemaker was noted; therefore, a pacemaker replacement procedure was required. CONCLUSION: In CRT, the implantation of a left ventricular epicardial electrode through a left-sided small incision is safe, feasible, and effective. This hybrid surgery combining interventional and cardiac techniques can maximize the curative effect of CRT.

Knockdown of PSMC3IP suppresses the proliferation and xenografted tumorigenesis of hepatocellular carcinoma cell.

Hepatocellular carcinoma (HCC) is the fifth most frequent malignancy and the second leading cause of cancer-related death worldwide. Proteasome 26S subunit ATPase 3 interacting protein (PSMC3IP) is an oncogene in breast cancer, while its role in HCC remains unclear. Here, we found that PSMC3IP was critical for the cell proliferation and tumorigenic capacity of HCC cells. Upregulation of PSMC3IP was observed in HCC specimens, and high PSMC3IP expression predicted poor overall survival of HCC patients. In vitro, knockdown of PSMC3IP blunted the proliferation and colony formation of BEL-7404 and SMMC-7721 cells. Likewise, PSMC3IP silencing suppressed the xenografted tumor development of BEL-7404 cells. Mechanistically, apoptosis was enhanced after PSMC3IP knockdown in both BEL-7404 and SMMC-7721 cells. At the molecular level, TP53 and GNG4 were upregulated and eukaryotic translation initiation factor 4E (EIF4E) and insulin like growth factor 1 receptor (IGF1R) were downregulated in shPSMC3IP compared with shCtrl BEL-7404 cells. Therefore, targeting PSMC3IP maybe a promising strategy for HCC.

Associations of candidate gene polymorphisms with poor responsiveness to aspirin: a meta-analysis.

Recently, the roles of gene polymorphisms in poor responsiveness to aspirin were extensively investigated, with conflicting results. Therefore, we performed this meta-analysis to better assess the relationship between candidate genetic variants and poor responsiveness to aspirin. Eligible articles were searched in PubMed, Medline, Embase and CNKI. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to detect possible associations of gene polymorphisms with poor responsiveness to aspirin. Among 53 eligible articles, a total of 22 candidate gene polymorphisms were analyzed. A significant association with poor responsiveness to aspirin was observed for GP1BA rs2243093, PTGS1 rs1330344, PTGS2 rs689466 and TBXA2R rs1131882 polymorphisms in overall analyses. Further subgroup analyses demonstrated that ITGA2 rs1126643, PTGS1 rs1330344, PTGS2 rs20417, PTGS2 rs689466 and TBXA2R rs1131882 polymorphisms were significantly associated with poor responsiveness to aspirin in Asians, whereas only GP1BA rs2243093 polymorphism was significantly correlated with this phenomenon in Caucasians. In conclusion, our findings indicate that GP1BA rs2243093, ITGA2 rs1126643, PTGS1 rs1330344, PTGS2 rs20417, PTGS2 rs689466 and TBXA2R rs1131882 polymorphisms may serve as genetic biomarkers of poor responsiveness to aspirin in certain ethnic groups. This article is protected by copyright. All rights reserved.

Nicotinamide ribose ameliorates myocardial ischemia/reperfusion injury by regulating autophagy and regulating oxidative stress.

Nicotinamide riboside (NR) has been reported to play a protective role in myocardial ischemia-reperfusion (I/R) injury when used in association with other drugs; however, the individual effect of NR is unknown. In the present study Evan's blue/triphenyl tetrazolium chloride staining, hematoxylin and eosin staining, echocardiography, western blotting, reverse transcription-quantitative PCR, and the detection of myocardial injury-associated markers and oxidative stress metabolites were used to explore the ability of NR to alleviate cardiac I/R injury and the relevant mechanisms of action. In a mouse model of I/R injury, dietary supplementation with NR reduced the area of myocardial ischemic infarction, alleviated pathological myocardial changes, decreased inflammatory cell infiltration and attenuated the levels of mitochondrial reactive oxygen species (ROS) and creatine kinase myocardial band (CK-MB). In addition, echocardiography suggested that NR alleviated the functional damage of the myocardium caused by I/R injury. In H9c2 cells, NR pretreatment reduced the levels of lactate dehydrogenase, CK-MB, malondialdehyde, superoxide dismutase and ROS, and reduced cell mortality after the induction of hypoxia/reoxygenation (H/R) injury. In addition, the results indicated NR activated sirt 1 via the upregulation of nicotinamide adenine dinucleotide (NAD+) and protected the cells against autophagy. The sirt 1 inhibitor EX527 significantly attenuated the ability of NR to inhibit autophagy, but had no significant effect on the ROS content of the H9c2 cells. In summary, the present study suggests that NR protects against autophagy by increasing the NAD+ content in the body via the sirt 1 pathway, although the sirt 1 pathway does not affect oxidative stress.

Investigation of autophagy­related genes and immune infiltration in calcific aortic valve disease: A bioinformatics analysis and experimental validation.

The present study aimed to elucidate the role of autophagy-related genes (ARGs) in calcific aortic valve disease (CAVD) and their potential interactions with immune infiltration via experimental verification and bioinformatics analysis. A total of three microarray datasets (GSE12644, GSE51472 and GSE77287) were obtained from the Gene Expression Omnibus database, and gene set enrichment analysis was performed to identify the relationship between autophagy and CAVD. After differentially expressed genes and differentially expressed ARGs (DEARGs) were identified using CAVD samples and normal aortic valve samples, a functional analysis was performed, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses, protein-protein interaction network construction, hub gene identification and validation, immune infiltration and drug prediction. The results of the present study indicated a significant relationship between autophagy and CAVD. A total of 46 DEARGs were identified. GO and pathway enrichment analyses revealed the complex roles of DEARGs in regulating CAVD, including multiple gene functions and pathways. A total of 10 hub genes were identified, with three (SPP1, CXCL12 and CXCR4) consistently upregulated in CAVD samples compared with normal aortic valve samples in multiple datasets and experimental validation. Immune infiltration analyses demonstrated significant differences in immune cell proportions between CAVD samples and normal aortic valve samples, thus showing the crucial role of immune infiltration in CAVD development. Furthermore, therapeutic drugs were predicted that could target the identified hub genes, including bisphenol A, resveratrol, progesterone and estradiol. In summary, the present study illuminated the crucial role of autophagy in CAVD development and identified key ARGs as potential therapeutic targets. In addition, the observed immune cell infiltration and predicted autophagy-related drugs suggest promising avenues for future research and novel CAVD treatments.

Lactobacillus plantarum 24-7 improves postoperative bloating and hard stools by modulating intestinal microbiota in patients with congenital heart disease: a randomized controlled trial.

Gastrointestinal symptoms are a common postoperative complication in patients with congenital heart disease (CHD), affecting their postoperative recovery. Probiotic intervention may be a promising therapeutic approach to alleviate postoperative gastrointestinal symptoms. This study aimed to evaluate the potential of Lactobacillus plantarum 24-7 (L. plantarum 24-7) in mitigating postoperative gastrointestinal symptoms and promoting patient recovery. Adult CHD patients scheduled for surgical intervention were recruited. One hundred and twenty patients were randomized and received L. plantarum or placebo intervention twice daily for ten days. Gastrointestinal symptoms were assessed utilizing the Gastrointestinal Symptom Rating Scale (GSRS). Various postoperative variables were analyzed across both groups. Alterations in gut microbiota were evaluated through 16S rRNA sequencing. 112 patients completed the study, with 55 in the probiotic group and 57 in the placebo group. While the disparity in overall postoperative GSRS scores between the two groups did not reach statistical significance (P = 0.067), marked differences were observed in bloating (P = 0.004) and hard stool (P = 0.030) scores. Furthermore, individuals within the probiotic group exhibited lower postoperative neutrophil counts (P = 0.007) and concurrently higher lymphocyte counts (P = 0.001). Variations in the diversity and composition of postoperative gut microbiota were discerned between the probiotic and placebo groups. Remarkably, no probiotic-related adverse events were documented. Supplementation with L. plantarum was well-tolerated and demonstrated partial efficacy in ameliorating gastrointestinal symptoms in postoperative CHD patients. Modulating the gut microbiota may be a potential mechanism by which L. plantarum exerts clinical benefits.

Bifidobacterium animalis subsp. lactis LPL-RH improves postoperative gastrointestinal symptoms and nutrition indexes by regulating the gut microbiota in patients with valvular heart disease: a randomized controlled trial.

Gastrointestinal symptoms constitute a frequent complication in postoperative patients with valvular heart disease (VHD), impacting their postoperative recovery. Probiotics contribute to regulating human gut microbiota balance and alleviating postoperative gastrointestinal symptoms. Our objective involved assessing the potential of Bifidobacterium animalis subsp. lactis LPL-RH to alleviate postoperative gastrointestinal symptoms and expedite patient recovery. Adult patients diagnosed with VHD scheduled for valve surgery were enrolled. 110 patients were randomly divided into two groups and received LPL-RH or a placebo for 14 days. Gastrointestinal symptoms were evaluated using the Gastrointestinal Symptoms Questionnaire. An analysis of the time to recovery of bowel function and various postoperative variables was conducted in both study groups. Variations in the intestinal microbiota were detected via 16S rRNA sequencing. The study was completed by 105 participants, with 53 in the probiotic group and 52 in the placebo group. Compared to the placebo group, LPL-RH significantly reduced the total gastrointestinal symptom score after surgery (p = 0.004). Additionally, LPL-RH was found to significantly reduce abdominal pain (p = 0.001), bloating (p = 0.018), and constipation (p = 0.022) symptom scores. Furthermore, LPL-RH dramatically shortened the time to recovery of bowel function (p = 0.017). Moreover, LPL-RH administration significantly enhanced patients' postoperative nutrition indexes (red blood cell counts, hemoglobin level, p < 0.05). Microbiome analysis showed that the composition and diversity of the postoperative intestinal microbiota differed between the probiotic and placebo groups. No adverse incidents associated with probiotics were documented, emphasizing their safety. This study initially discovered that oral B. animalis subsp. lactis LPL-RH can assist in regulating intestinal microbiota balance, alleviating gastrointestinal symptoms, promoting intestinal function recovery, and enhancing nutrition indexes in patients with VHD after surgery. Regulating the intestinal microbiota may represent a potential mechanism for LPL-RH to exert clinical benefits.

Synergetic protective effect of remote ischemic preconditioning and prolyl 4­hydroxylase inhibition in ischemic cardiac injury.

It has been reported that hypoxia­inducible factor 1α (HIF­1α) serves a key role in the protective effect of remote ischemic preconditioning (RIP) in ischemia/reperfusion (I/R)­induced cardiac injury. Moreover, inhibition of prolyl 4­hydroxylase (PHD), an enzyme responsible for HIF­1α degradation, prevents I/R­induced cardiac injury. However, whether their protective effects are synergetic remains to be elucidated. The present study aimed to investigate the protective effect of RIP, PHD inhibition using dimethyloxalylglycine (DMOG) and their combination on I/R­induced cardiac injury. Rabbits were randomly divided into seven groups: i) Sham; ii) I/R; iii) lung RIP + I/R; iv) thigh RIP + I/R; v) DMOG + I/R; vi) DMOG + lung RIP + I/R; and vii) DMOG + thigh RIP + I/R. I/R models were established via 30 min left coronary artery occlusion and 3 h reperfusion. For lung/thigh RIP, rabbits received left pulmonary artery (or left limb) ischemia for 25 min and followed by release for 5 min. Some rabbits were administered 20 mg/kg DMOG. The results demonstrated that both lung/thigh RIP and DMOG significantly decreased myocardial infarct size, creatine kinase activity and myocardial apoptosis in I/R rabbits. Furthermore, the combination of RIP and PHD inhibition exerted synergetic protective effects on these aforementioned changes. The mechanistic study indicated that both treatments increased mRNA and protein expression levels of HIF­1α and its downstream regulators, including vascular endothelial growth factor (VEGF), AKT and endothelial nitric oxide synthase (eNOS). In conclusion, the present study demonstrated that RIP and PHD inhibition exerted synergetic protective effects on cardiac injury via activation of HIF­1α and the downstream VEGF/AKT­eNOS signaling pathway.

A novel predictive model for new-onset atrial fibrillation in patients after isolated cardiac valve surgery.

Background: Postoperative atrial fibrillation (POAF) is a severe complication after cardiac surgery and is associated with an increased risk of ischemic stroke and mortality. The main aim of this study was to identify the independent predictors associated with POAF after isolated valve operation and to develop a risk prediction model. Methods: This retrospective observational study involved patients without previous AF who underwent isolated valve surgery from November 2018 to October 2021. Patients were stratified into two groups according to the development of new-onset POAF. Baseline characteristics and perioperative data were collected from the two groups of patients. Univariate and multivariate logistic regression analyses were applied to identify independent risk factors for the occurrence of POAF, and the results of the multivariate analysis were used to create a predictive nomogram. Results: A total of 422 patients were included in the study, of which 163 (38.6%) developed POAF. The Multivariate logistic regression analysis indicated that cardiac function (odds ratio [OR] = 2.881, 95% confidence interval [CI] = 1.595-5.206; P < 0.001), Left atrial diameter index (OR = 1.071, 95%CI = 1.028-1.117; P = 0.001), Operative time (OR = 1.532, 95%CI = 1.095-2.141; P = 0.013), Neutrophil count (OR = 1.042, 95%CI = 1.006-1.08; P = 0.021) and the magnitude of fever (OR = 3.414, 95%CI = 2.454-4.751; P < 0.001) were independent predictors of POAF. The above Variables were incorporated, and a nomogram was successfully constructed with a C-index of 0.810. The area under the receiver operating characteristic curve was 0.817. Conclusion: Cardiac function, left atrial diameter index, operative time, neutrophil count, and fever were independent predictors of POAF in patients with isolated valve surgery. Establishing a nomogram model based on the above predictors helps predict the risk of POAF and may have potential clinical utility in preventive interventions.

Protective effect of inhibiting TRPM7 expression on hypoxia post-treatment H9C2 cardiomyocytes.

BACKGROUND: Transient receptor potential channel 7 (TRPM7) plays an important role in maintaining intracellular ion concentration and osmotic pressure. OBJECTIVE: The purpose of this study was to investigate the role and mechanism of inhibiting the expression of TRPM7 in the treatment of distal myocardial ischemia. METHODS: H9C2 cells were treated with hypoxia post-treatment and reperfusion, respectively, detect the expression of HIF-1α and TRPM7, the concentration of Ca2+ and the degree of apoptosis in the H9C2 cells. The relevant miRNAs targeting TRPM7 were searched, the TRPM7 interference vectors were constructed, and the interference of different interference vectors on TRPM7 in H9C2 cells was detected. RESULTS: The results showed that hypoxia post-treatment treatment would lead to increased expression of miR-22-3p which directly targeting TRPM7, decreased expression of TRPM7, increased expression of HIF-α and increased intracellular Ca2+ concentration. While reperfusion can increase the expression of HIF-1α and TRPM7 in H9C2 cells and increase the degree of apoptosis. CONCLUSION: Knockdown of TRPM7 can significantly reduce reperfusion injury in H9C2 cells, reduce the degree of apoptosis, and the TRPM7 interference vector can inhibit the expression of TRPM7 and have a certain protective effect on the reperfusion injury of H9C2 cells.

The covalent NLRP3-inflammasome inhibitor Oridonin relieves myocardial infarction induced myocardial fibrosis and cardiac remodeling in mice.

BACKGROUND: Myocardial infarction (MI) triggers a strong inflammatory response that is associated with myocardial fibrosis and cardiac remodeling. Interleukin (IL)-1ß and IL-18 are key players in this response and are controlled by NLRP3-inflammatory bodies. Oridonin is a newly reported NLRP3 inhibitor with strong anti-inflammatory activity. We hypothesized that the covalent NLRP3 inhibitor Oridonin could reduce IL-1ß and IL-18 expression and ameliorate myocardial fibrosis after myocardial infarction in mice, improve poor heart remodeling, and preserve heart function. METHODS: Male C57BL/6 mice were subjected to left coronary artery ligation to induce MI and then treated with Oridonin (1, 3, or 6 mg/kg), MCC950 (10 mg/kg), CY-09 (5 mg/kg) or saline three times a week for two weeks. Four weeks after MI, cardiac function and myocardial fibrosis were assessed. In addition, myocardial expressions of inflammatory factors and fibrotic markers were analyzed by western blot, immunofluorescence, enzyme-linked immunosorbent assay, and quantitative real-time polymerase chain reaction. RESULTS: Oridonin treatment preserved left ventricular ejection fraction and fractional shortening, and markedly limited the myocardial infarct size in treated mice. The myocardial fibrosis was lower in the 1 mg/kg group (15.98 ± 1.64)%, 3 mg/kg group (17.39 ± 2.45)%, and 6 mg/kg group (16.76 ± 3.06)% compared to the control group (23.38 ± 1.65)%. Moreover, similar with the results of Oridonin, MCC950 and CY-09 also preserved cardiac function and reduced myocardial fibrosis. The expression levels of NLRP3, IL-1ß and IL-18 were decreased in the Oridonin treatment group compared to non-treated group. In addition, myocardial macrophage and neutrophil influxes were attenuated in the Oridonin treated group. CONCLUSIONS: The covalent NLRP3-inflammasome inhibitor Oridonin reduces myocardial fibrosis and preserves cardiac function in a mouse MI model, which indicates potential therapeutic effect of Oridonin on acute MI patients.

Surface biofunctionalization of the decellularized porcine aortic valve with VEGF-loaded nanoparticles for accelerating endothelialization.

The original intention for building a tissue-engineered heart valve (TEHV) was to simulate a normal heart valve and overcome the insufficiency of the commonly used heart valve replacement in the clinic. The endothelialization of the TEHV is very important as the endothelialized TEHV can decrease platelet adhesion and delay the valvular calcification decline process. In this work, we encapsulated vascular endothelial growth factor (VEGF) into polycaprolactone (PCL) nanoparticles. Then, through the Michael addition reaction, PCL nanoparticles were introduced onto the decellularized aortic valve to prepare a hybrid valve. The encapsulation efficiency of the PCL nanoparticles for VEGF was up to 82%, and the in vitro accumulated release rate was slow without an evident initial burst release. In addition, the hybrid valve had a decreased hemolysis ratio and possessed antiplatelet adhesion capacity, and it was able to promote the adhesion and proliferation of endothelial cells, covering the surface with a dense cell layer to accelerate endothelialization. An experiment involving the subcutaneous implant in SD rats showed that at week 8, lots of blood capillaries were formed in the hybrid valve. Mechanics performance testing indicated that the mechanical property of the hybrid valve was partly improved. Taken together, we applied a nano-drug controlled release system to fabricate TEHV, and provide an approach for the biofunctionalization of the TEHV scaffold for accelerating endothelialization.

The selective NLRP3-inflammasome inhibitor MCC950 reduces myocardial fibrosis and improves cardiac remodeling in a mouse model of myocardial infarction.

BACKGROUND/AIMS: Early inflammatory responses after myocardial infarction (MI) are likely to increase myocardial fibrosis and subsequent cardiac remodeling. MCC950, a specific NLRP3 inhibitor, was previously found to effectively inhibit the release of inflammatory factors IL-18 and IL-1ß. In this study, we evaluated the effect of MCC950, as a potential new treatment strategy for MI, on myocardial fibrosis and cardiac remodeling using an experimental mouse model. METHODS: Male C57BL/6 mice were subjected to left coronary artery ligation to induce MI and then treated with MCC950 (10 mg/kg) or PBS for 14 days. After 30 days, echocardiography was performed to assess cardiac function and myocardial fibrosis was evaluated using H&E- and Masson's Trichrome-stained sections. Myocardial expression of inflammatory factors and fibrosis markers was analyzed by western blotting, immunofluorescence, ELISA, and real-time quantitative PCR. RESULTS: The ejection fraction in the 10 mg/kg group (40.7 ±â€¯4.2%; N = 6, p = 0.0029) was statistically preserved compared to that in the control group (14.0 ±â€¯4.4%). Myocardial fibrosis was also reduced in MCC950-treated animals (MCC950, 23.2 ±â€¯3.0 vs PBS, 36.2 ±â€¯3.7; p < 0.05). Moreover, myocardial NLRP3, cleaved IL-1ß, and IL-18 levels were reduced in MCC950-treated animals. H&E and molecular examination revealed decreases in inflammatory cell infiltration and inflammatory factor expression in the heart. In vitro, MCC950 inhibited NLRP3, reduced caspase-1 activity, and further downregulated IL-1ß and IL-18. CONCLUSION: MCC950, as a specific NLRP3 inhibitor, can alleviate fibrosis and improve cardiac function in a mouse model by suppressing early inflammatory responses post-MI.

Nanotubular TiO2 regulates macrophage M2 polarization and increases macrophage secretion of VEGF to accelerate endothelialization via the ERK1/2 and PI3K/AKT pathways.

Background: Macrophages play important roles in the immune response to, and successful implantation of, biomaterials. Titanium nanotubes are considered promising heart valve stent materials owing to their effects on modulation of macrophage behavior. However, the effects of nanotube-regulated macrophages on endothelial cells, which are essential for stent endothelialization, are unknown. Therefore, in this study we evaluated the inflammatory responses of endothelial cells to titanium nanotubes prepared at different voltages. Methods and results: In this study we used three different voltages (20, 40, and 60 V) to produce titania nanotubes with three different diameters by anodic oxidation. The state of macrophages on the samples was assessed, and the supernatants were collected as conditioned media (CM) to stimulate human umbilical vein endothelial cells (HUVECs), with pure titanium as a control group. The results indicated that titanium dioxide (TiO2) nanotubes induced macrophage polarization toward the anti-inflammatory M2 state and increased the expression of arginase-1, mannose receptor, and interleukin 10. Further mechanistic analysis revealed that M2 macrophage polarization controlled by the TiO2 nanotube surface activated the phosphatidylinositol 3-kinase/AKT and extracellular signal-regulated kinase 1/2 pathways through release of vascular endothelial growth factor to influence endothelialization. Conclusion: Our findings expanded our understanding of the complex influence of nanotubes in implants and the macrophage inflammatory response. Furthermore, CM generated from culture on the TiO2 nanotube surface may represent an integrated research model for studying the interactions of two different cell types and may be a promising approach for accelerating stent endothelialization through immunoregulation.

Biofunctionalization of decellularized porcine aortic valve with OPG-loaded PCL nanoparticles for anti-calcification.

Decellularized valve stents are widely used in tissue-engineered heart valves because they maintain the morphological structure of natural valves, have good histocompatibility and low immunogenicity. However, the surface of the cell valve loses the original endothelial cell coverage, exposing collagen and causing calcification and decay of the valve in advance. In this study, poly ε-caprolactone (PCL) nanoparticles loaded with osteoprotegerin (OPG) were bridged to a decellularized valve using a nanoparticle drug delivery system and tissue engineering technology to construct a new anti-calcification composite valve with sustained release function. The PCL nanoparticles loaded with OPG were prepared via an emulsion solvent evaporation method, which had a particle size of 133 nm and zeta potential of -27.8 mV. Transmission electron microscopy demonstrated that the prepared nanoparticles were round in shape, regular in size, and uniformly distributed, with an encapsulation efficiency of 75%, slow release in vitro, no burst release, no cytotoxicity to BMSCs, and contained OPG nanoparticles in vitro. There was a delay in the differentiation of BMSCs into osteoblasts. The decellularized valve modified by nanoparticles remained intact and its collagen fibers were continuous. After 8 weeks of subcutaneous implantation in rats, the morphological structure of the valve was almost complete, and the composite valve showed anti-calcification ability to a certain extent.

O-GlcNAc-modified SNAP29 inhibits autophagy-mediated degradation via the disturbed SNAP29-STX17-VAMP8 complex and exacerbates myocardial injury in type I diabetic rats.

The O­linked ß­N­acetylglucosamine (O­GlcNAc) modification and autophagy are associated with diabetic myocardial injury, however, the molecular mechanisms between the two processes remain to be fully elucidated. The purpose of the present study was to elucidate the molecular regulation of autophagy by O­GlcNAc­modified synaptosomal­associated protein 29 (SNAP29) in diabetic myocardial injury. A rat model of type I diabetes was established via intraperitoneal injection of streptozotocin (STZ; 55 mg/kg). Significant increases in the O­GlcNAc modification and accumulation of the autophagy markers microtubule­associated protein 1 light chain 3α II/I and P62, which suggest that autophagic flux is inhibited, were observed in rats 8 weeks following STZ induction. Subsequently, the selective O­GlcNAcase inhibitor, thiamet G, increased the level of O­GlcNAc modification, which further disrupted autophagic flux; deteriorated cardiac diastolic function, as indicated by an increased left ventricular filling peak velocity/atrial contraction flow peak velocity ratio shown by echocardiography; and exacerbated myocardial abnormalities, as characterized by cardiomyocyte disorganization and fat and interstitial fibrosis accumulation. By contrast, 6­diazo­5­oxo­L­norleucine, an inhibitor of glucosamine fructose­6­phosphate aminotransferase isomerizing 1, acted as an O­GlcNAc antagonist and reduced the level of O­GlcNAc modification, which maintained autophagic flux and improved cardiac diastolic function. In vitro, high glucose (25 mM) was used to stimulate primary neonatal rat cardiomyocytes (NRCMs). Consistent with the myocardium of diabetic rats, it was also shown in the NRCMs that O­GlcNAc modification of SNAP29 negatively regulated autophagic flux. The application of the short hairpin RNA interference lysosome­associated membrane protein (LAMP2) and the autophagy inhibitor 3­methyladenine demonstrated that high glucose inhibited autophagy­mediated degradation rather than affected the initial stage of autophagy. Finally, co­immunoprecipitation was used to determine the role of the O­GlcNAc­modified substrate protein SNAP29, which acted as an SNAP29­syntaxin­17 (STX17)­vesicle­associated membrane protein 8 (VAMP8) complex during disease progression. The present study is the first, to the best of our knowledge, to demonstrate that SNAP29 is an O­GlcNAc substrate and that an increase in O­GlcNAc­modified SNAP29 inhibits SNAP29­STX17­VAMP8 complex formation, thereby inhibiting the degradation of autophagy and exacerbating myocardial injury in type I diabetic rats.

Case-matched analysis of combined thoracoscopic-laparoscopic versus open esophagectomy for esophageal squamous cell carcinoma.

The aim of this study is to evaluate surgical results and long-term survival of combined thoracoscopic-laparoscopic esophagectomy (TLE) performed for esophageal squamous cell carcinoma. Data of 59 patients with esophageal squamous cell carcinoma, undergoing TLE from January 2007 to January 2015, were compared to a control group of 59 patients who underwent open esophagectomy (OE) during the same period. The two groups were matched in terms of age, sex, American Society of Anesthesiology (ASA) score and clinical TNM stage. Laparoscopic approach resulted in longer operating time (P=0.003) and lower blood loss (P=0.000). There was no difference in perioperative morbidity and mortality rate; TLE approach was associated with a shorter hospital stay (P=0.000). After a mean follow up of 38 months, 5-year disease free survival and 5-year overall survival were 38% and 50% for TLE group, and 36% and 45% for OE group (P>0.05). TLE for esophageal squamous cell carcinoma is feasible and safe in selected patients and can result in good surgical results, with similar outcomes in terms of long-term outcomes.