Tumor Necrosis Factor-α-Induced Protein-8-like 2 Transfected Adipose-Derived Stem Cells Regulated the Dysfunction of Monocrotaline Pyrrole-Induced Pulmonary Arterial Smooth Muscle Cells and Pulmonary Arterial Endothelial Cells.

ABSTRACT: Pulmonary arterial hypertension (PAH) is characterized by pulmonary arterial endothelial cell (PAEC) dysfunction and pulmonary arterial smooth muscle cell (PASMC) activation. For decades, the therapies for PAH based on stem cells have been shown to be effective. Meanwhile, tumor necrosis factor-α-induced protein-8-like 2 (TIPE2) promote the viability of human amniotic mesenchymal stem cells. Therefore, we aimed to explore the role of TIPE2 in adipose-derived stem cells (ADSCs) and the function of TIPE2-transfected ADSCs in the regulation of PAH. We first explored the role and underlying molecular mechanism of TIPE2 in viability and migration of ADSCs. Moreover, the ADSCs transfected with TIPE2 were cocultured with monocrotaline pyrrole (MCTP)-stimulated PASMCs or PAECs. The effects and mechanisms of TIPE2-transfected ADSCs on MCTP-induced PASMCs and PAECs were further investigated. The results showed that TIPE2 overexpression promoted viability and migration of ADSCs by activating the TLR4-ERK1/2 pathway. In addition, TIPE2-transfected ADSCs inhibited the abnormal proliferation and the impaired apoptosis of PASMCs via NF-κB signaling and promoted the conversion of PASMCs from synthetic to contractile. Meanwhile, TIPE2-transfected ADSCs reduced the apoptosis, endothelial-to-mesenchymal transition, and migration of PAECs via PI3K/AKT signaling after MCTP treatment. MCTP-induced oxidative stress and inflammation of PAECs were significantly decreased by TIPE2-transfected ADSCs. In rat model, TIPE2-ADSCs administration further decreased the monocrotaline-induced increase in the right ventricular systolic pressure and ratio of right ventricle weight/left ventricle and septa weight (L + S) and right ventricle weight/body weight compared with the ADSCs group. In conclusion, TIPE2-transfected ADSCs dramatically attenuated the PAH via inhibiting the dysfunction of PASMCs and PAECs.

Aortic Root Reinforcement Combined with Vascular Grafts Eversion and Built-in Procedure (XJ-Procedure) for Acute Type A Aortic Dissection Surgery.

INTRODUCTION: Current root reinforcement methods for acute type A aortic dissection (ATAAD) risk the tearing of endothelial tissue by sutures. This study proposed a novel technique for aortic root reinforcement and evaluated its effectiveness. METHODS: Patients who diagnosed with ATAAD and had mild to moderate aortic root involvement, combined with aortic arch involvement undergoing Sun's procedure in the First Affiliated Hospital of Xi'an Jiaotong University from January 2020 to December 2021, were retrospectively enrolled. They were divided into two groups according to their surgical procedures of aortic root: continuous aortic root suture group (CARS group) and aortic root reinforcement combined with vascular grafts eversion and built-in procedure (XJ-procedure) group. The 30-day mortality rates and incidence of operation-related complications were evaluated. RESULTS: The study cohort comprised 183 patients, including 114 in the XJ-procedure group. The 30-day mortality rates were 7.2% in the CARS group and 6.9% in the XJ-procedure group (P = 1.000). The incidence of residual aortic root dissection in the XJ-procedure group was lower than that in the CARS group before discharge (1.8% vs. 10.1%, P = 0.028), at 3-month (0% vs. 8.7%, P = 0.002) and 6-month (0% vs. 7.2%, P = 0.007) follow-up. In the CARS group, the incidence of anastomotic pseudoaneurysm was 2.9%, 2.9%, and 2.9% compared with none in the XJ-procedure group before discharge, at 3 and 6 months. The XJ-procedure group also showed less chest tube drainage in the first 24-h after the surgery, with lower incidence of hemodialysis and sepsis during hospitalization. No differences were observed in the incidence of bleeding necessitating reoperation and severe aortic regurgitation between the two groups. CONCLUSIONS: The XJ-procedure did not increase 30-day mortality and effectively reduced the incidence of residual aortic root dissection during the 6-month follow-up. Subsequent studies with larger samples and prolonged follow-up are needed to evaluate it. TRIAL REGISTRATION: NCT05751200. The video showed the partial process of the XJ-procedure in managing the aortic root in the ATAAD surgery. The vascular graft was folded outward about 15 mm, and the eversion was intermittently sutured to the full layers aortic wall using 2-0 pad polyester sutures. Then, the eversion of the graft and aortic wall were continuously sutured in one more turn using 3-0 polypropylene sutures. (XJ-procedure, aortic root reinforcement combined with vascular grafts eversion and built-in procedure; ATAAD, acute type A aortic dissection.). (MP4 297097 kb).

Activity-guided isolation and identification of antiherpesvirus and antineuroinflammatory active terpenoids from Artemisia vulgaris L. based on the LC-MS/MS molecular network.

Seven undescribed terpenoids, comprising two guaiane-type sesquiterpene lactones (1-2), one eucalyptol-type sesquiterpene (3), one monolactone (4), and three triterpenoids (5-7), along with 35 known analogues, were isolated from the leaves of Artemisia vulgaris L. Their structures and configurations were analysed by extensive spectroscopy. Compounds 1, 2, 8-10, 13, 17, 19, and 28 showed antineuroinflammatory activity, and compounds 1 and 2 revealed remarkable antineuroinflammatory effects, with an IC50 value of 2.2 ± 0.1 and 1.6 ± 0.1 µM, more potent than the positive control drug dexamethasone. Furthermore, compounds 1 and 2 could inhibit the expression of BV-2 inflammatory genes (IL-6, TNF-α, IL-1ß) induced by LPS, downregulate the critical inflammatory protein production of iNOS and COX-2. The anti-HSV-1 activity screening revealed that compounds 28, 29 and 38 exhibited inhibitory activity against HSV-1 proliferation. Particularly, compound 28 exhibited a significant anti-HSV-1 effect, inhibiting the proliferation of HSV-1 and acyclovir-resistant strains of HSV-1/153 and HSV-1/Blue. Our research identified compounds 1, 2, and 28 from A. vulgaris., which could potentially serve as lead compounds for antineuroinflammatory and anti-HSV-1 activities.

Exosomal miR-127-5p from BMSCs alleviated sepsis-related acute lung injury by inhibiting neutrophil extracellular trap formation.

Neutrophil extracellular traps (NETs) play an important role in sepsis-related acute lung injury (ALI). Bone marrow mesenchymal stem cells (BMSCs)-derived exosomes and miRNA are becoming promising agents for the treatment of ALI. The current study aimed to elucidate the mechanism by BMSCs-derived exosomes carrying miR-127-5p inhibiting to the formation of NETs in sepsis-related ALI. We successfully isolated exosomes from BMSCs and confirmed that miR-127-5p was enriched in the exosomes. ALI mice treated with BMSCs-derived exosomes histologically improved, and the release of NETs and inflammatory factors in lung tissue and peripheral blood of mice also decreased compared with LPS group, while the protective effect of exosomes was attenuated after the knockdown of miR-127-5p. Using dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay, we identified CD64 as a direct target of miR-127-5p. Meanwhile, BMSCs-derived exosomes can synergize with anti-CD64 mab in ALI mice to reduce tissue damage, inhibit the release of inflammatory factors and NETs formation. The synergistic effect of exosomes was attenuated when miR-127-5p was down-regulated. These findings suggest that exosomal miR-127-5p derived from BMSCs is a potential therapeutic agent for treatment of sepsis-induced ALI through reducing NETs formation by targeting CD64.

Commercial and novel anticoagulant ECMO coatings: a review.

Extracorporeal membrane oxygenation (ECMO) is an invasive and last-resort treatment for circulatory and respiratory failure. Prolonged ECMO support can disrupt the coagulation and anticoagulation systems in a patient, leading to adverse consequences, such as bleeding and thrombosis. To address this problem, anticoagulation coatings have been developed for use in ECMO circuits. This article reviews commonly used commercial and novel anticoagulant coatings developed in recent years and proposes a new classification of coatings based on the current state. While commercial coatings have been used clinically for decades, this review focuses on comparing the effectiveness and stability of coatings to support clinical selections. Furthermore, novel anticoagulation coatings often involve complex mechanisms and elaborate design strategies, and this review summarises representative studies on mainstream anticoagulation coatings to provide a point of reference for future studies.

TFAM-Mediated mitochondrial transfer of MSCs improved the permeability barrier in sepsis-associated acute lung injury.

Vascular endothelial cell barrier disruption is a hallmark of sepsis-induced acute lung injury (ALI). Mesenchymal stem cells (MSCs)-based therapy has been regarded as a promising treatment for repairing injured lungs, and mitochondrial transfer was shown to be important for the therapeutic effects of MSCs. Here we investigated the ability of MSCs to modulate endothelial barrier integrity through mitochondrial transfer in sepsis-induced ALI. We found that mitochondrial transfer from MSCs to LPS-induced PMVECs through forming tunneling nanotubes (TNTs). Due to the inhibition of TNTs (using LAT-A), MSCs-mediated reparation on PMVECs functions, including cell apoptosis, MMP, ATP generation, TEER level and monolayer permeability of FITC-dextran were greatly inhibited. In addition, silencing of mitochondrial transcription factor A (TFAM) in MSCs could also partly inhibit the TNTs formation and aggravate the LPS-induced mitochondrial dysfunction and permeability barrier in PMVECs. Furthermore, the LPS-induced pulmonary edema and higher pulmonary vascular permeability were alleviated by MSCs while that of lung tissue bounced back after MSCs were pre-incubated by LAT-A and or down-regulation of TFAM. Therefore, we firstly revealed that regulation of TFAM expression in MSCs played a critical role to improve the permeability barrier of PMVECs by TNTs mediating mitochondrial transfer in sepsis-associated ALI. This study provided a new therapeutic strategy for the treatment of sepsis-induced ALI.

Serum CIRP increases the risk of acute kidney injury after cardiac surgery.

Introduction: Acute kidney injury (AKI) is a frequent perioperative complication. The underlying mechanisms of cardiac surgery-associated AKI are still not completely elucidated. Cold-induced RNA-binding protein (CIRP) has been subsequently found to be regulated by various stress conditions. During cardiac surgery and cardiopulmonary bypass (CPB), the host is subjected to hypothermia and inadequate organ perfusion, resulting in an upregulation of CIRP secretion. The aim of this study is to evaluate the role of elevated extracellular CIRP level as a contributing factor in the development of AKI. Methods: A total of 292 patients who underwent cardiac surgery were retrospectively enrolled and their serum samples were collected preoperative and postoperative. Demographic data, intraoperative data, in-hospital outcomes, and the occurrence of AKI were also collected for the patients. The correlation between CIRP and intraoperative procedures, as well as its association with postoperative outcomes were analyzed. Results: In multivariable analysis, higher ΔCIRP (p = 0.036) and body mass index (p = 0.015) were independent risk factors for postoperative AKI. Meanwhile, patients with postoperative AKI exhibited lower survival rate in 2-year follow-up (p = 0.008). Compared to off-pump coronary artery bypass grafting surgery, patients who underwent on-pump coronary artery bypass grafting, valve surgery, aortic dissection and other surgery showed higher ΔCIRP, measuring 1,093, 666, 914 and 258 pg/mL, respectively (p < 0.001). The levels of ΔCIRP were significantly higher in patients who underwent CPB compared to those who did not (793.0 ± 648.7 vs. 149.5 ± 289.1 pg/mL, p < 0.001). Correlation analysis revealed a positive correlation between ΔCIRP levels and the duration of CPB (r = 0.502, p < 0.001). Patients with higher CIRP levels are at greater risk of postoperative AKI (OR: 1.67, p = 0.032), especially the stage 2-3 AKI (OR: 2.11, p = 0.037). Conclusion: CIRP secretion increases with prolonged CPB time after cardiac surgery, and CIRP secretion is positively correlated with the duration of CPB. Cardiac surgeries with CPB exhibited significantly higher levels of CIRP compared to non-CPB surgeries. Elevation of CIRP level is an independent risk factor for the incidence of AKI, especially the severe AKI, and were associated with adverse in-hospital outcomes.

Immunological risk factors for sepsis-associated delirium and mortality in ICU patients.

Background: A major challenge in intervention of critical patients, especially sepsis-associated delirium (SAD) intervention, is the lack of predictive risk factors. As sepsis and SAD are heavily entangled with inflammatory and immunological processes, to identify the risk factors of SAD and mortality in the intensive care unit (ICU) and determine the underlying molecular mechanisms, the peripheral immune profiles of patients in the ICU were characterized. Methods: This study contains a cohort of 52 critical patients who were admitted to the ICU of the First Affiliated Hospital of Jinan University. Comorbidity, including sepsis and SAD, of this cohort was diagnosed and recorded. Furthermore, peripheral blood samples were collected on days 1, 3, and 5 of admission for peripheral immune profiling with blood routine examination, flow cytometry, ELISA, RNA-seq, and qPCR. Results: The patients with SAD had higher mortality during ICU admission and within 28 days of discharge. Compared with survivors, nonsurvivors had higher neutrophilic granulocyte percentage, higher CRP concentration, lower monocyte count, lower monocyte percentage, lower C3 complement level, higher CD14loCD16+ monocytes percentage, and higher levels of IL-6 and TNFα. The CD14hiCD16- monocyte percentage manifested favorable prediction values for the occurrence of SAD. Differentially expressed genes between the nonsurvival and survival groups were mainly associated with immune response and metabolism process. The longitudinal expression pattern of SLC2A1 and STIMATE were different between nonsurvivors and survivors, which were validated by qPCR. Conclusions: Nonsurvival critical patients have a distinct immune profile when compared with survival patients. CD14hiCD16- monocyte prevalence and expression levels of SLC2A1 and STIMATE may be predictors of SAD and 28-day mortality in ICU patients.

Coronary Angiography Within 48 Hours Before Cardiac Surgery Increases the Risk of Postoperative Acute Kidney Injury.

BACKGROUND: Cardiac surgery and coronary examination, such as invasive coronary angiography (CAG), are both possibly associated with acute kidney injury (AKI). Preoperative CAG examination and cardiac surgery within a short interval may increase the incidence of AKI. METHODS: We retrospectively reviewed 1112 patients who underwent CAG examination within 30 days prior to the cardiac operation in this study. Postoperative AKI was defined, according to Kidney Disease Improving Global Outcomes Definition and Staging (KDIGO) criteria. RESULTS: The total incidence of AKI was 40.8% and cystatin C level was 1.260 (1.028, 1.672) mg/L. For patients who received CAG, age, body mass index, cardiopulmonary time, and the time interval between preoperative CAG examination and cardiac operation within 48h was shown to be independent predictors of postoperative AKI. The incidence of AKI in patients undergoing preoperative CAG within 48h was 11.2% higher than in those more than 48h (P < 0.001). Patients undergoing valve surgery with or without coronary artery bypass grafting (CABG) exhibited a higher AKI risk than those only accepting CABG. The in-hospital stay of patients who developed AKI was 2 days longer than those without AKI. However, undergoing CAG within 48h prior to cardiac operation did not prolong ICU length of stay or hospital length of stay, nor did it increase the risk of death or renal failure after an operation. CONCLUSION: Undergoing CAG within 48 hours before cardiac surgery increases the risk of postoperative AKI.

Change in Oxidative Stress and Mitochondrial Dynamics in Response to Elevated Cold-Inducible RNA-Binding Protein in Cardiac Surgery-Associated Acute Kidney Injury.

Cardiac surgery-associated acute kidney injury (CSA-AKI) is a common yet serious complication that is closely related to cardiopulmonary bypass (CPB). Extracellular cold-inducible RNA-binding protein (eCIRP) can mediate aseptic inflammation and trigger intracellular oxidative stress. In the present study, expression of serum CIRP was significantly elevated post-CPB (785.0 ± 640.5 pg/mL vs. 149.5 ± 289.1 pg/mL, P < 0.001) and was positively correlated with CPB duration (r = 0.502, P < 0.001). Patients with high expression of CIRP had higher risks of postoperative AKI than patients with low CIRP expression (OR: 1.67, 95% CI 1.04-2.68). In a rat CPB model, the serum CIRP concentration increased significantly after CPB. Similarly, the levels of Scr and BUN significantly increased 4 hours after CPB. KIM-1 and NGAL mRNA levels in the CPB group were 8.2 and 4.3 times higher than the sham group, respectively. In addition, the levels of inflammatory cell infiltration, oxidative stress, and apoptosis in the renal tissue of the CPB group were significantly higher compared to the sham group. The expression levels of serum inflammatory factors at 4 hours post-CPB were also increased. Administration of recombinant human CIRP protein promoted the expression of NADPH oxidase via the TLR-4/MyD88 pathway, aggravated intracellular oxidative stress, mediated mitochondrial dynamics disorder, and eventually increased apoptosis in HK-2 cells. However, the CIRP inhibitor C23 improved the CIRP-mediated oxidative stress and mitochondrial dysfunction in both rat and cell models. In summary, elevated CIRP could mediate oxidative stress and mitochondrial dynamics in the kidney to promote CSA-AKI.

Normothermic machine perfusion attenuates hepatic ischaemia-reperfusion injury by inhibiting CIRP-mediated oxidative stress and mitochondrial fission.

Extracellular cold-inducible RNA-binding protein (CIRP) is a proinflammatory mediator that aggravates ischaemia-reperfusion injury (IRI). Normothermic machine perfusion (NMP) could effectively alleviate the IRI of the liver, but the underlying mechanism remains to be explored. We show that human DCD livers secreted a large amount of CIRP during static cold storage (CS), which is released into the circulation after reperfusion. The expression of CIRP was related to postoperative IL-6 levels and liver function. In a rat model, the CIRP expression was upregulated during warm ischaemia and cold storage. Then, rat DCD livers were preserved using CS, hypothermic oxygenated machine perfusion (HOPE) and NMP. C23, a CIRP inhibitor, was administrated in the HOPE group. Compared with CS, NMP significantly inhibited CIRP expression and decreased oxidative stress by downregulating NADPH oxidase and upregulating UCP2. NMP markedly inhibited the mitochondrial fission-related proteins Drp-1 and Fis-1. Further, NMP increased the mitochondrial biogenesis-related protein, TFAM. NMP significantly reduced inflammatory reactions and apoptosis after reperfusion, and NMP-preserved liver tissue had higher bile secretion and ICG metabolism compared to the CS group. Moreover, C23 administration attenuated IRI in the HOPE group. Additionally, HL-7702 cells were stimulated with rhCIRP and C23. High rhCIRP levels increased oxidative stress and apoptosis. In summary, NMP attenuates the IRI of DCD liver by inhibiting CIRP-mediated oxidative stress and mitochondrial fission.

Association of biomarkers related to preoperative inflammatory and coagulation with postoperative in-hospital deaths in patients with type A acute aortic dissection.

The aim of this study was to analyze the role of blood biomarkers regarding preoperative inflammation and coagulation in predicting the postoperative in-hospital mortality of patients with type A acute aortic dissection (AAD). A total of 206 patients with type A AAD who had received surgical treatment were enrolled in this study. Patients were divided into two groups: the death group (28 patients who died during hospitalization) and the survival group (178 patients). Peripheral blood samples were collected before anesthesia induction. Preoperative levels of D-dimer, fibrinogen (FIB), platelet (PLT), white blood cells (WBC) and neutrophil (NEU) were compared between the two groups. Univariable and multivariable logistic regression analysis were utilized to identify the independent risk factors for postoperative in-hospital deaths of patients with type A AAD. Receiver operating characteristic (ROC) curve were used to analyze the predictive value of these indices in the postoperative in-hospital mortality of the patients. Univariable logistic regression analysis showed that the P values of the five parameters including D-dimer, FIB, PLT, WBC and NEU were all less than 0.1, which may be risk factors for postoperative in-hospital deaths of patients with type A AAD. Further multivariable logistic regression analysis indicated that higher preoperative D-dimer and WBC levels were independent risk factors for postoperative in-hospital mortality of patients with type A AAD. ROC curve analysis indicated that application of combining FIB and PLT could improve accuracy in prediction of postoperative in-hospital mortality in patients with type A AAD. Both preoperative D-dimer and WBC in patients with type A AAD may be used as independent risk factors for the postoperative in-hospital mortality of such patients. The combination of FIB and PLT may improve the accuracy of clinical prognostic assessment.

CIRP Secretion during Cardiopulmonary Bypass Is Associated with Increased Risk of Postoperative Acute Kidney Injury.

BACKGROUND: Systemic inflammation contributes to cardiac surgery-associated acute kidney injury (AKI). Cardiomyocytes and other organs experience hypothermia and hypoxia during cardiopulmonary bypass (CPB), which induces the secretion of cold-inducible RNA-binding protein (CIRP). Extracellular CIRP may induce a proinflammatory response. MATERIALS AND METHODS: The serum CIRP levels in 76 patients before and after cardiac surgery were determined to analyze the correlation between CIRP levels and CPB time. The risk factors for AKI after cardiac surgery and the in-hospital outcomes were also analyzed. RESULTS: The difference in the levels of CIRP (ΔCIRP) after and before surgery in patients who experienced cardioplegic arrest (CA) was 26-fold higher than those who did not, and 2.7-fold of those who experienced CPB without CA. The ΔCIRP levels were positively correlated with CPB time (r = 0.574, p < 0.001) and cross-clamp time (r = 0.54, p < 0.001). Multivariable analysis indicated that ΔCIRP (odds ratio: 1.003; 95% confidence interval: 1.000-1.006; p = 0.027) was an independent risk factor for postoperative AKI. Patients who underwent aortic dissection surgery had higher levels of CIRP and higher incidence of AKI than other patients. The incidence of AKI and duration of mechanical ventilation in patients whose serum CIRP levels more than 405 pg/mL were significantly higher than those less than 405 pg/mL (65.8 vs. 42.1%, p = 0.038; 23.1 ± 18.2 vs. 13.8 ± 9.2 hours, p = 0.007). CONCLUSION: A large amount of CIRP was released during cardiac surgery. The secreted CIRP was associated with the increased risk of AKI after cardiac surgery.

Coronary computed tomography angiography before on-pump cardiac surgery does not reduce the risk of postoperative acute kidney injury compared to coronary angiography.

OBJECTIVES: Cardiac surgery and contrast media are both related to acute kidney injury. We investigated whether undergoing coronary computed tomography angiography, which uses less contrast medium, before on-pump cardiac surgery could reduce the risk of postoperative acute kidney injury compared to coronary angiography. METHODS: In this retrospective study, 745 and 171 patients underwent coronary angiography and coronary computed tomography angiography, respectively, within 30 days before on-pump cardiac surgery. Postoperative acute kidney injury was defined according to Kidney Disease Improving Global Outcomes Definition and Staging criteria. RESULTS: Age, hypertension, cardiopulmonary bypass time, and performing cardiac surgery within 24 h of preoperative angiography (odds ratio: 1.507, 95% confidence interval: 1.111‒2.045, P = 0.008) independently predicted postoperative acute kidney injury on multivariable analysis. After propensity score matching, the acute kidney injury incidence in coronary angiography and computed tomography angiography groups was 43% and 46%, respectively (P = 0.65), and the groups had similar intensive care unit stay (2 days vs. 2 days, P = 0.209), postoperative hospital stay (11 days vs. 12 days, P = 0.084), postoperative continuous renal replacement therapy use (0.6% vs 1.9%, P = 0.314), and in-hospital mortality (0 vs. 1.3%, P = 0.156). In-hospital outcomes were similar among patients who underwent preoperative coronary angiography or computed tomography angiography within 24 h before cardiac surgery. CONCLUSION: Although coronary computed tomography angiography uses less contrast medium, it does not reduce the risk of postoperative acute kidney injury or improve in-hospital outcomes compared to coronary angiography.

Pharmacological corrections of the mutant hERG channels by posaconazole.

Properties of mutant human ether-à-go-go-related gene (hERG) channels can be modified by some antibiotics. However, the pharmacological effects of posaconazole on cardiomyocyte hERG channels remain unclear. Whole-cell patch clamping, western blotting and laser confocal scanning microscopy were used to evaluate the effects of posaconazole on wild-type (WT)-, A561V- and L539 fs/47-hERG channels expressed in human embryonic kidney (HEK) 293 cells. In electrophysiological experiments, HEK 293 cells were transiently co-transfected with equal amounts of WT-hERG, WT+A561 V-hERG and WT+L539 fs/47-hERG plasmids to mimic a heterozygous genotype. Posaconazole (30 µM) increased tail currents in cells expressing WT-hERG, WT+A561 V-hERG and WT+L539 fs/47-hERG by 82.65%, 147.72% and 134.73%, respectively, compared to controls. Posaconazole increased hERG protein expression in cells expressing WT-hERG, WT+A561 V-hERG and WT+L539 fs/47-hERG compared to controls condition as well as their trafficking to the cell membrane. To our knowledge, this is the first study to show that antifungal agent posaconazole rescues the mutant A561 V-hERG and L539 fs/47-hERG channels by altering the gating kinetics, enhancing the expression and trafficking of hERG channels. The results demonstrate that posaconazole could be a promising candidate for the prevention and treatment of long QT syndrome and other arrhythmia-related diseases.

[Development of Liver Normothermic Machine Perfusion Repair and Assessment System].

This paper introduced a liver normothermic machine perfusion repair and assessment system. This system consists of a liver normothermic machine perfusion device, a fluorescence imaging system and a tissue oxygen detector. The normothermic machine perfusion device can continuously perfuse the donor liver and monitor and control the perfusion parameters in real time. The fluorescence imaging system can detect the indocyanine green metabolized by the liver to evaluate the microcirculation and the metabolism function of hepatocytes. The tissue oxygen detector can monitor the change of oxygen partial pressure of liver tissue in real time to evaluate the state of cell oxygen consumption.

The effect of aging on VEGF/VEGFR2 signal pathway genes expression in rat liver sinusoidal endothelial cell.

Liver sinusoidal endothelial cells (LSECs) play a key role in the initiation and neoangiogenesis of liver regeneration. We presume that the abnormity of the VEGF/VEGFR2 and its pathway gene Id1, Wnt2 and HGF expression in aged LSECs may be an important mechanism to affect liver regeneration of the elderly. LSECs from two different groups (adult and old) were isolated in a rodent model, and observed by SEM and TEM. The adult and old rats were underwent 70% partial hepatectomy. The proliferation of hepatocytes and LSECs were analyzed by Immunofluorescence staining. The expression of VEGF/VEGFR2 and its pathway gene in isolated LSECs and liver tissue after hepatectomy were detected by qRT-PCR and Western blot. There is a decreased number of endothelial fenestrae in the LSECs of the old group, compared to the adult group. The old group had a lower expression of VEGF/VEGFR2 and its pathway gene than the adult groups (p < 0.01). The results of western blot were consistent with those of qRT-PCR. The hepatocytes had a high proliferation rate at first 4 days after hepatectomy, and a significantly higher proliferation rate in the adult group. The LSECs began to proliferate after 4 days of hepatectomy, and showed a quantity advantage in the adult group. The adult group had a significantly higher expression of VEGF/VEGFR2 and its pathway gene after hepatectomy than the old group (p < 0.01). LSCEs turn to be defenestration in structure and have a low expression of VEGF/VEGFR2 and its pathway gene with aging.

Bioinformatics Analysis to Reveal Potential Differentially Expressed Long Non-Coding RNAs and Genes Associated with Tumour Metastasis in Lung Adenocarcinoma.

BACKGROUND: Due to the onset of metastases, the survival rate of lung adenocarcinoma (LUAD) is still low. In view of this, we performed this study to screen metastasis-associated genes and lncRNAs in LUAD. METHODS: The mRNA and lncRNA expression profiles of 185 metastatic LUAD and 217 non-metastatic LAUD samples were retrieved from the TCGA database and included in this study. The differentially expressed mRNAs (DEmRNAs) and lncRNAs (DElncRNAs) between metastatic samples and non-metastatic samples of LAUD, as well as the cis nearby-targeted DEmRNAs of DElncRNAs and the DElncRNA-DEmRNA co-expression network, were obtained. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression levels of selected DEmRNAs. Survival analysis of selected DElncRNAs and DEmRNAs was performed. RESULTS: In total, 1351 DEmRNAs and 627 DElncRNAs were screened between the LUAD primary tissue samples and metastatic samples. Then, 194 DElncRNA-nearby-targeted DEmRNA pairs and 191 DElncRNA-DEmRNA co-expression pairs were detected. Except for RHCG and KRT81, the expression of the other six DEmRNAs in the qRT-PCR results generally exhibited the same pattern as that in our integrated analysis. The expression of CRHR2, FAM83A-AS1, FAM83A and Z83843.1 was significantly correlated with the overall survival time of patients with metastatic LUAD. CONCLUSION: We speculate that two interaction pairs (FAM83A-AS1-FAM83A and Z83843.1-MATR3) and four genes (CRHR2, UGT2B15, CHGB and NEFL) are closely associated with the metastasis of LUAD.

Cost-effectiveness analysis of aspirin for primary prevention of cardiovascular events among patients with type 2 diabetes in China.

The use of aspirin for primary prevention of cardiovascular disease (CVD) in patients with diabetes mellitus (DM) is associated with lower rates of cardiovascular events but increased risks of bleeding complications. We aimed to examine the cost-effectiveness of aspirin therapy for primary prevention of CVD in Chinese DM patients. A life-long Markov model was developed to compare aspirin therapy (100mg daily) versus no use of aspirin in DM patients with no history of CVD. Model validation was conducted by comparing the simulated event rates with data reported in a clinical trial. Direct medical costs and quality-adjusted life-years gained (QALYs) were the primary outcomes from the perspective of healthcare system in China. Sensitivity analyses were performed to examine the uncertainty of model inputs. Base-case analysis showed aspirin therapy was more costly (USD1,086 versus USD819) with higher QALYs gained (11.94 versus 11.86 QALYs) compared to no use of aspirin. The base-case results were sensitive to the odds ratio of all-cause death in aspirin therapy versus no use of aspirin. Probabilistic sensitivity analysis found that aspirin therapy gained an additional 0.066 QALYs (95% CI: -0.167 QALYs-0.286 QALYs) at higher cost by USD352 (95% CI: USD130-644)). Using 30,000 USD/QALY as willingness-to-pay threshold, aspirin therapy and no use of aspirin were the preferred option in 68.71% and 31.29% of 10,000 Monte Carlo simulations, respectively. In conclusion, aspirin therapy appears to be cost-effective compared with no use of aspirin in primary prevention of CVD in Chinese DM patients.