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Abstract Radiofrequency ablation (RFA) comparative efficacy of treatments using video-assisted thoracoscopic sympathectomy (VATS) in the long term remains uncertain in patients with palmar hyperhidrosis (PHH). This study aimed to compare the efficacy and safety of RFA and VATS in patients with PHH. We recruited patients aged ≥ 14 years with diagnosed PHH from 14 centres in China. The treatment options of RFA or VATS were assigned to two cohort in patients with PHH. The primary outcome was the efficacy at 1-year. A total of 807 patients were enrolled. After propensity score matching, the rate of complete remission was lower in RFA group than VATS group (95% CI 0.21–0.57; p

In order to address the disposal challenge of waste glass fiber composite materials and provide a feasible reference for the utilization of recycled glass fiber (RGF), contributing to the sustainable development of concrete engineering. This study focuses on the reuse of RGF to reinforce the impermeability of concrete. The effects of thermal treatment temperature on the properties of RGF are studied and the microstructural morphology of RGF and its reinforcement effect to concrete are evaluated. Additionally, the permeability resistance of recycled glass fiber reinforced concrete (RGFRC) is investigated, and the mechanism of elevated permeability resistance in RGFRC is revealed. Results indicate that with increasing thermal treatment temperature, the diameter of the thermal treated RGF is notably reduced and the surface of the fiber is covered with a significant amount of impurity. When thermal treated under 600 °C, the RGF presents the optimal structure with appropriate surface roughness, higher crystallinity, stable molecular structure, good compactness. Thus the concrete with RGF calcinated under 600 °C demonstrates the highest compressive strength, demonstrating that the optimal thermal treatment temperature is around 600 °C. Furthermore, the concrete exhibits a continuous reduction in internal water penetration height and sustained improvement in permeability resistance as the fiber content increases. The mechanism behind the improved impermeability of RGF to RGFRC lies in the interweaving of RGF within the concrete matrix, forming a three-dimensional network structure. This structure partially inhibits crack formation and pore expansion, effectively reducing the continuity of interconnected pores, decreasing the size of voids and cracks, and slowing down water permeation, thereby enhancing the impermeability of concrete.

Abstract Myocardial infarction that causes damage to heart muscle can lead to heart failure. The identification of molecular mechanisms promoting myocardial regeneration represents a promising strategy to improve cardiac function. Here we show that IGF2BP3 plays an important role in regulating adult cardiomyocyte proliferation and regeneration in a mouse model of myocardial infarction. IGF2BP3 expression progressively decreases during postnatal development and becomes undetectable in the adult heart. However, it becomes upregulated after cardiac injury. Both gain- and loss-of-function analyses indicate that IGF2BP3 regulates cardiomyocyte proliferation in vitro and in vivo. In particular, IGF2BP3 promotes cardiac regeneration and improves cardiac function after myocardial infarction. Mechanistically, we demonstrate that IGF2BP3 binds to and stabilizes MMP3 mRNA through interaction with N6-methyladenosine modification. The expression of MMP3 protein is also progressively downregulated during postnatal development. Functional analyses indicate that MMP3 acts downstream of IGF2BP3 to regulate cardiomyocyte proliferation. These results suggest that IGF2BP3-mediated post-transcriptional regulation of extracellular matrix and tissue remodeling contributes to cardiomyocyte regeneration. They should help to define therapeutic strategy for ameliorating myocardial infarction by inducing cell proliferation and heart repair.

Abstract Background Ischemia-reperfusion (IR) induces increased release of extracellular vesicles in the heart and exacerbates myocardial IR injury. We have previously shown that propofol attenuates hypoxia/reoxygenation (HR)-induced injury in human umbilical vein endothelial cells (HUVECs) and that microvesicles derived from propofol-treated HUVECs inhibit oxidative stress in endothelial cells. However, the role of microvesicles derived from propofol post-treated HUVECs ((HR + P)-EMVs) in IR-injured cardiomyocytes is unclear. In this study, we aimed to investigate the role of (HR + P)-EMVs in cardiac IR injury compared to microvesicles derived from hypoxic/reoxygenated HUVECs (HR-EMVs) and to elucidate the underlying mechanisms. Methods Hypoxia/reoxygenation (HR) models of HUVECs and AC16 cells and a mouse cardiac IR model were established. Microvesicles from HR-injured HUVECs, DMSO post-treated HUVECs and propofol post-treated HUVECs were extracted by ultra-high speed centrifugation, respectively. The above EMVs were co-cultured with HR-injured AC16 cells or injected intracardially into IR mice. Flow cytometry and immunofluorescence were used to determine the levels of oxidative stress and apoptosis in cardiomyocytes. Apoptosis related proteins were detected by Western blot. Echocardiography for cardiac function and Evans blue-TTC staining for myocardial infarct size. Expression of lncCCT4-2 in EMVs and AC16 cells was analysed by whole transcriptome sequencing of EMVs and RT-qPCR. The molecular mechanism of inhibition of myocardial injury by (HR + P)-EMVs was elucidated by lentiviral knockdown of lncCCT4-2, plasmid overexpression or knockdown of CCT4, and actinomycin D assay. Results In vitro and in vivo experiments confirmed that HR-EMVs exacerbated oxidative stress and apoptosis in IR-injured cardiomyocytes, leading to increased infarct size and worsened cardiac function. Notably, (HR + P)-EMVs induced significantly less oxidative stress and apoptosis in IR-injured cardiomyocytes compared to HR-EMVs. Mechanistically, RNA sequencing of EMVs and RT-qPCR showed that lncCCT4-2 was significantly upregulated in (HR + P)-EMVs and cardiomyocytes co-cultured with (HR + P)-EMVs. Reduction of lncCCT4-2 in (HR + P)-EMVs enhanced oxidative stress and apoptosis in IR-injured cardiomyocytes. Furthermore, the anti-apoptotic activity of lncCCT4-2 from (HR + P)-EMVs was achieved by increasing the stability of CCT4 mRNA and promoting the expression of CCT4 protein in cardiomyocytes. Conclusions Our study showed that (HR + P)-EMVs uptake by IR-injured cardiomyocytes upregulated lncCCT4-2 in cardiomyocytes and promoted CCT4 expression, thereby inhibiting HR-EMVs induced oxidative stress and apoptosis.

Introduction: Sepsis-induced apoptosis leads to lymphopenia including the decrease of CD4+ T cells thus favoring immunosuppression. Objectives: Although epidermal growth factor receptor (EGFR) inhibitors significantly improve the survival rate of septic mice, the effect of EGFR on the function and metabolism of CD4+ T cells in sepsis remained unknown. Methods: CD4+ T cells from septic mice and patients were assessed for apoptosis, activation, Warburg metabolism and glucose transporter 1 (Glut1) expression with or without the interference of EGFR activation. Results: EGFR facilitates CD4+ T cell activation and apoptosis through Glut1, which is a key enzyme that controls glycolysis in T cells. EGFR, TANK binding kinase 1 (TBK1) and Glut1 form a complex to facilitate Glut1 transportation from cytoplasm to cell surface. Both the levels of membrane expression of EGFR and Glut1 and the activation levels of CD4+ T cells were significantly higher in patients with sepsis as compared with healthy subjects. Conclusion: Our data demonstrated that through its downstream TBK1/Exo84/RalA protein system, EGFR regulates Glut1 transporting to the cell surface, which is a key step for inducing the Warburg effect and the subsequent cellular activation and apoptosis of CD4+ T lymphocytes and may eventually affect the immune functional status, causing immune cell exhaustion in sepsis.

The graphical abstract of the potential mechanism of m6A modulates long non-coding RNA in the developing mouse heart.

Summary: N6-methyladenosine (m6A) modification accounts for the most prevalent mRNA internal modification and has emerged as a widespread regulatory mechanism in multiple physiological processes. We address a role of methyltransferase-like protein 3 (METTL3) in neutrophil activation. METTL3 controls neutrophil release from bone marrow to circulation through surface expression of CXC chemokine receptor 2 (CXCR2) in a Toll-like receptor 4 (TLR4) signaling-dependent manner in lipopolysaccharide (LPS)-induced endotoxemia. We show that the mRNA of TLR4 is modified by m6A, exhibiting increased translation and slowed degradation simultaneously, leading to elevated protein levels of TLR4, which eventually promotes the TLR4 signaling activation of neutrophil. The reduced expression of TLR4 lowers cytokine secretion in METTL3-deleted neutrophils upon LPS stimulation through TLR4/Myd88/nuclear factor κB (NF-κB) signaling. Collectively, these data demonstrate that METTL3 modulation of TLR4 expression is a critical determinant of neutrophil activation in endotoxemia.

Abstract Background Central venous catheter (CVC) insertion complications are a prevalent and important problem in the intensive care unit (ICU), and source control by immediate catheter removal is considered urgent in patients with septic shock suspected to be caused by catheter-related bloodstream infection (CRBSI). We sought to determine the impact of immediate reinsertion of a new catheter (IRINC) on mortality among patients after CVC removal for suspected CRBSI. Methods A propensity score-matched cohort of patients with suspected CRBSI who underwent IRINC or no IRINC in a 32-bed ICU in a university hospital in China from January 2009 through April 2021. Catheter tip culture and clinical symptoms were used to identify patients with suspected CRBSI. The Kaplan–Meier method was used to analyse 30-day mortality before and after propensity score matching, and adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for mortality in the matched cohort were estimated with Cox proportional hazards models. Results In total, 1,238 patients who had a CVC removed due to suspected CRBSI were identified. Among these patients, 877 (70.8%) underwent IRINC, and 361 (29.2%) did not. Among 682 propensity score-matched patients, IRINC was associated with an increased risk of 30-day mortality (HR, 1.481; 95% CI, 1.028 to 2.134) after multivariable, multilevel adjustment. Kaplan–Meier analysis found that IRINC was associated with the risk of mortality both before matching (P = 0.00096) and after matching (P = 0.018). A competing risk analysis confirmed the results of the propensity score-matched analysis. The attributable risk associated with bloodstream infection was not significantly different (HR, 1.081; 95% CI 0.964 to 1.213) among patients with suspected CRBSI in terms of 30-day mortality compared with that associated with other infections. Conclusions In this cohort study, IRINC was associated with higher 30-day mortality compared to delayed CVC or no CVC among patients with suspected CRBSI. A large-sample randomized controlled trial is needed to define the best management for CVC in cases of suspected CRBSI because IRINC may also be associated with noninfectious complications. Trial registration This study was registered with the China Clinical Trials Registry (URL: http://www.chictr.org.cn/index.aspx ) under the following registration number: ChiCTR1900022175.

The diabetic population has been increasing in the past decades and diabetic cardiomyopathy (DCM), a pathology that is defined by the presence of cardiac remodeling and dysfunction without conventional cardiac risk factors such as hypertension and coronary heart diseases, would eventually lead to fatal heart failure in the absence of effective treatment. Impaired insulin signaling, commonly known as insulin resistance, plays an important role in the development of DCM. A family of integral membrane proteins named caveolins (mainly caveolin-1 and caveolin-3 in the myocardium) and a protein hormone adiponectin (APN) have all been shown to be important for maintaining normal insulin signaling. Abnormalities in caveolins and APN have respectively been demonstrated to cause DCM. This review aims to summarize recent research findings of the roles and mechanisms of caveolins and APN in the development of DCM, and also explore the possible interplay between caveolins and APN.

Abstract Intracellular ion channel inositol 1,4,5-triphosphate receptor (IP3R1) releases Ca2+ from endoplasmic reticulum. The disturbance of IP3R1 is related to several neurodegenerative diseases. This study investigated the mechanism of IP3R1 in myocardial ischemia/reperfusion (MI/R). After MI/R modeling, IP3R1 expression was silenced in myocardium of MI/R rats to explore its role in the concentration of myocardial enzymes, infarct area, Ca2+ level, NLRP3/Caspase-1, and pyroptosis markers and inflammatory factors. The adult rat cardiomyocytes were isolated and cultured to establish hypoxia/reperfusion (H/R) cell model. The expression of IP3R1 was downregulated or ERP44 was overexpressed in H/R-induced cells. Nifedipine D6 was added to H/R-induced cells to block Ca2+ channel or Nigericin was added to activate NLRP3. IP3R1 was highly expressed in myocardium of MI/R rats, and silencing IP3R1 alleviated MI/R injury, reduced Ca2+ overload, inflammation and pyroptosis in MI/R rats, and H/R-induced cells. The binding of ERP44 to IP3R1 inhibited Ca2+ overload, alleviated cardiomyocyte inflammation, and pyroptosis. The increase of intracellular Ca2+ level caused H/R-induced cardiomyocyte pyroptosis through the NLRP3/Caspase-1 pathway. Activation of NLRP3 pathway reversed the protection of IP3R1 inhibition/ERP44 overexpression/Nifedipine D6 on H/R-induced cells. Overall, ERP44 binding to IP3R1 inhibits Ca2+ overload, thus alleviating pyroptosis and MI/R injury.

Abstract The prevalence of cardiomyopathy is higher in diabetic patients than those without diabetes. Diabetic cardiomyopathy (DCM) is defined as a clinical condition of abnormal myocardial structure and performance in diabetic patients without other cardiac risk factors, such as coronary artery disease, hypertension, and significant valvular disease. Multiple molecular events contribute to the development of DCM, which include the alterations in energy metabolism (fatty acid, glucose, ketone and branched chain amino acids) and the abnormalities of subcellular components in the heart, such as impaired insulin signaling, increased oxidative stress, calcium mishandling and inflammation. There are no specific drugs in treating DCM despite of decades of basic and clinical investigations. This is, in part, due to the lack of our understanding as to how heart failure initiates and develops, especially in diabetic patients without an underlying ischemic cause. Some of the traditional anti-diabetic or lipid-lowering agents aimed at shifting the balance of cardiac metabolism from utilizing fat to glucose have been shown inadequately targeting multiple aspects of the conditions. Peroxisome proliferator-activated receptor α (PPARα), a transcription factor, plays an important role in mediating DCM-related molecular events. Pharmacological targeting of PPARα activation has been demonstrated to be one of the important strategies for patients with diabetes, metabolic syndrome, and atherosclerotic cardiovascular diseases. The aim of this review is to provide a contemporary view of PPARα in association with the underlying pathophysiological changes in DCM. We discuss the PPARα-related drugs in clinical applications and facts related to the drugs that may be considered as risky (such as fenofibrate, bezafibrate, clofibrate) or safe (pemafibrate, metformin and glucagon-like peptide 1-receptor agonists) or having the potential (sodium–glucose co-transporter 2 inhibitor) in treating DCM.

Abstract Aims/Introduction Diabetic hearts are more vulnerable to ischemia‐reperfusion injury (I/RI). The activation of nucleotide‐binding oligomerization domain‐like receptor protein 3 (NLRP3) inflammasome can mediate the inflammatory process, and hence might contribute to myocardial I/RI. Activation of autophagy can eliminate excess reactive oxygen species and alleviate myocardial I/RI in diabetes. The present study aimed to investigate whether the activation of autophagy can alleviate diabetic myocardial I/RI through inhibition of NLRP3 inflammasome activation. Materials and Methods A dose of 65 mg/kg streptozotocin was given by tail vein injection to establish a type 1 diabetes model in the rats. The left anterior descending coronary artery was ligated for 30 min followed by reperfusion for 2 h to establish a myocardial I/RI model. H9C2 cardiomyocytes were exposed to high glucose (33 mmol/L) and subjected to hypoxia–reoxygenation (6 h hypoxia followed by 4 h reoxygenation). Results The diabetic rats showed significant inhibition of cardiac autophagy (decreased LC3‐II/I and increased p62) that was concomitant with increased activation of NLRP3 inflammasome (increased NLRP3, apoptosis‐related spots protein cleaved caspase‐1, interleukin‐18, interleukin‐1β) and more severe myocardial I/RI (elevated creatine kinase myocardial band, lactate dehydrogenase and larger infarct size). However, administration of rapamycin, an inhibitor of the autophagy, to activate autophagy resulted in the inhibition of NLRP3 inflammasome, and finally alleviated myocardial I/RI. In vitro, high glucose inhibited autophagy, while activating NLRP3 inflammasome in H9C2 cardiomyocytes and aggravating hypoxia–reoxygenation injury, but rapamycin reversed these adverse effects of high glucose. Conclusion Activation of autophagy can suppress the formation of NLRP3 inflammasome, which in turn attenuates myocardial ischemia‐reperfusion injury in diabetic rats.

Abstract Background To investigate the effect of intravenous injection of dexmedetomidine combined with parecoxib sodium on sedation and anxiety and stress response of tracheal intubation in patients undergoing functional endoscopic sinus surgery. Methods One hundred twenty patients undergoing endoscopic sinus surgery were randomly divided into four groups: group DP, group D, group P and group N. The blood pressure (BP), heart rate (HR), blood oxygen saturation (SPO2), EEG, bispectral index (BIS), Ramsay sedation score and state anxiety questionnaire (SAI) were recorded before administration (T0), 10 min (T1), 20 min (T2) and 30 min (T3) after administration. After 30 min, endotracheal intubation was performed after anesthesia induction. The BP, HR, SPO2 were recorded 1 min before intubation (T4), intubation (T5), 3 min (T6) after intubation, 5 min (T7) after intubation, and blood samples were collected from patients before administration and after intubation 2 min to detect serum cortisol (Cor), adrenalin (E) norepinephrine (NE) and blood glucose (BS). Results There was no significant difference in Ramsay sedation score before anesthesia, but the Ramsay sedation score in group D、DP was significantly higher than that in group P and group N, the BIS, BP, HR and anxiety scores were significantly lower than those in the group P and group N (p 0.05). Compared with T4, there was no significant difference in BIS and BP, HR in group D, group DP and group P (p > 0.05), but the BIS, BP and HR in group N were significantly higher than T4, (p 0.05), but the changes of Cor, E, NE and BS values were significantly lower than that in group N (p

Remimazolam is a new benzodiazepine of sedative drugs with an ultra-short-acting anesthetic effect, commonly used for critically ill patients (especially septic patients) in intensive care units (ICUs). Although some anesthetics have been reported to show certain anti-inflammatory effects, the role of remimazolam in inflammation is still remained unknown. Here, we studied the effects of remimazolam on macrophage in response to LPS both in vivo and in vitro. Interestingly, compared with LPS treatment group, remimazolam remarkably improved survival rate of endotoxemia mice and decreased the release of LPS-induced inflammatory mediators (such as TNF-α, IL-6, and IL-1β). We further found that remimazolam not only inhibited the activation of MAPK signal pathway at 15 min after LPS treatment but also disturbed Rab5a related TLR4 expression at cell surface in response to LPS at a later time. Such evidence suggests that remimazolam might be beneficial to septic patients who are suffering from uncontrolled inflammatory responses.

The practical application of polymer composites in the electronic and communications industries often requires multi-properties, such as high thermal conductivity (TC), efficient electromagnetic interference (EMI) shielding ability with low electrical conductivity, superior tribological performance, reliable thermal stability and excellent mechanical properties. However, the integration of these mutually exclusive properties is still a challenge, ascribed to their different requirement on the incorporated nanofillers, composite microstructure as well as processing process. Herein, a well-designed boron nitride nanosheet (BN)/graphene nanosheet (GNP)/polyphenylene sulfide (PPS) composite with a dual-segregated structure is fabricated via high-pressure molding. Rather than homogenous mixing of the hybrid fillers, GNP is first coated on PPS particles and followed by encapsulating the conductive GNP layers with insulating BN, forming a BN shell-GNP layer-PPS core composite particles. After hot-pressing, a dual segregated structure is constructed, in which GNP and BN are distinctly separated and arranged in the interfaces of PPS, which on the one hand gives rise to high thermal conductivity, and on the other hand, the aggregated BN layer can act as an “isolation belt” to effectively reduce the electronic transmission. Impressively, high-pressure is loaded and it has a more profound effect on the EMI shielding and thermal conductive properties of PPS composites with a segregated structure than that with homogenous mixed-structure composites. Intriguingly, the synergetic enhancement effect of BN and GNP on both thermal conductive performance and EMI shielding is stimulated by high pressure. Consequently, PPS composites with 30 wt% GNP and 10 wt% BN hot-pressed under 600 MPa present the most superior comprehensive properties with a high TC of 6.4 W/m/K, outstanding EMI SE as high as 70 dB, marvelous tribological performance, reliable thermal stability and satisfactory mechanical properties, which make it promising for application in miniaturized electronic devices in complex environments.

Background: The outbreak of 2019 novel coronavirus disease (COVID-19) in Wuhan, China, has spread rapidly worldwide. In the early stage, we encountered a small but meaningful number of patients who were unintentionally scheduled for elective surgeries during the incubation period of COVID-19. We intended to describe their clinical characteristics and outcomes. Methods: We retrospectively analyzed the clinical data of 34 patients underwent elective surgeries during the incubation period of COVID-19 at Renmin Hospital, Zhongnan Hospital, Tongji Hospital and Central Hospital in Wuhan, from January 1 to February 5, 2020. Findings: Of the 34 operative patients, the median age was 55 years (IQR, 43–63), and 20 (58·8%) patients were women. All patients developed COVID-19 pneumonia shortly after surgery with abnormal findings on chest computed tomographic scans. Common symptoms included fever (31 [91·2%]), fatigue (25 [73·5%]) and dry cough (18 [52·9%]). 15 (44·1%) patients required admission to intensive care unit (ICU) during disease progression, and 7 patients (20·5%) died after admission to ICU. Compared with non-ICU patients, ICU patients were older, were more likely to have underlying comorbidities, underwent more difficult surgeries, as well as more severe laboratory abnormalities (eg, hyperleukocytemia, lymphopenia). The most common complications in non-survivors included ARDS, shock, arrhythmia and acute cardiac injury. Interpretation: In this retrospective cohort study of 34 operative patients with confirmed COVID-19, 15 (44·1%) patients needed ICU care, and the mortality rate was 20·5%. Funding: National Natural Science Foundation of China. Keywords: COVID-19, SARS-cov-2, Surgery, Incubation period

Background/Aims: Hearts from diabetic subjects are susceptible to myocardial ischemia reperfusion (I/R) injury. Propofol has been shown to protect against myocardial I/R injury due to its antioxidant properties while the underlying mechanism remained incompletely understood. Thus, this study aimed to determine whether or not propofol could attenuate myocardial I/R injury by attenuating mitochondrial dysfunction/damage through upregulating Caveolin (Cav)-3 under hyperglycemia. Methods: Cultured rat cardiomyocyte H9C2 cells were subjected to hypoxia/reoxygenation (H/R) in the absence or presence of propofol under high glucose (HG), and cell viability, lactate dehydrogenase (LDH) and mitochondrial viability as well as creatine kinase-MB (CK-MB), cardiac troponin I (cTnI) and intracellular adenosine triphosphate (ATP) content were measured with colorimetric Enzyme-Linked Immunosorbent Assays. Intracellular levels of oxidative stress was assessed using 2,7-dichlorodihydrofluorescein diacetate (DCF-DA) fluorescent staining and mitochondrial-dependent apoptosis was assessed by detecting mitochondrial membrane potential and the activation of apoptotic caspases 3 and 9. Results: Exposure of cells to HG without or with H/R both significantly increased cell injury, cell apoptosis and enhanced oxidative stress that were associated with mitochondrial dysfunction and decreased Cav-3 protein expression. All these changes were further exacerbated following H/R under HG. Administration of propofol at concentrations from 12.5 to 50 µM but not 100 µM significantly attenuated H/R injury that was associated with increased Cav-3 expression and activation of the prosurvival proteins Akt and STAT3 with the optimal protective effects seen at 50 µM of propofol (P25). The beneficial effects of propofol(P25) were abrogated by Cav-3 disruption with β-methyl-cyclodextrin. Conclusion: Propofol counteracts cardiomyocyte H/R injury by attenuating mitochondrial damage and improving mitochondrial biogenesis through upregulating Cav-3 during hyperglycemia.

Angiotensin II (AngII), a vasoactive peptide that elevates arterial blood pressure and results in hypertension, has been reported to directly induce vascular endothelial cell apoptosis. Recent work has demonstrated that propofol pre-treatment attenuates angiotensin II-induced apoptosis in human coronary artery endothelial cells. However, the underlying mechanism remains largely unknown. Here, we investigated human umbilical vein endothelial cells (HUVECs) subjected to angiotensin II-induced apoptosis in the presence or absence of propofol treatment and found that angiotensin II-induced apoptosis was attenuated by propofol in a dose-dependent manner. Furthermore, ELISA assays demonstrated that the ratio of angiotensin (1-7) (Ang (1-7)) to Ang II was increased after propofol treatment. We examined the expression of ACE2, Ang (1-7) and Mas and found that the ACE2-Ang (1-7)-Mas axis was up-regulated by propofol, while ACE2 overexpression increased phosphorylated endothelial nitric oxide synthase (phosphorylated eNOS) expression and siACE2 resulted in the repression of endothelial nitric oxide synthase (eNOS) phosphorylation. In conclusion, our study revealed that propofol can inhibit endothelial cell apoptosis induced by Ang II by activating the ACE2-Ang (1-7)-Mas axis and further up-regulating the expression and phosphorylation of eNOS.

Inhalation anesthetic isoflurane inhibits hypoxia pulmonary vasoconstriction (HPV), while dexmedetomidine (Dex) could reduce the dose of isoflurane inhalation and potentiate HPV, but the mechanism is unclear. Inhibition of reactive oxygen species (ROS) production can favor HPV during one-lung ventilation (OLV). Similarly, nitric oxide (NO), an important endothelium-derived vasodilator in lung circulation, can decrease the regional pulmonary vascular resistance of ventilated lung and reduce intrapulmonary shunting. We hypothesized that Dex may augment HPV and improve oxygenation during OLV through inhibiting oxidative stress and increasing NO release. Patients undergoing OLV during elective thoracic surgery were randomly allocated to either isoflurane + saline (NISO, n=24) or isoflurane + dexmedetomidine (DISO, n=25) group. Anesthesia was maintained with intravenous remifentanil and inhalational isoflurane (1.0–2.0%), with concomitant infusion of dexmedetomidine 0.7 μgkg−1h−1 in DISO and saline 0.25 mL kg−1h−1 in NISO group. Hemodynamic variables or depth of anesthesia did not significantly differ between groups. Administration of Dex significantly reduced Qs/Qt and increased PaO2 after OLV, accompanied with reduced lipid peroxidation product malondialdehyde and higher levels of SOD activity as well as serum NO (all P

The anesthetic propofol confers cardioprotection against myocardial ischemia-reperfusion injury (IRI) by reducing reactive oxygen species (ROS). However, its cardioprotection on patients is inconsistent. Similarly, the beneficial effect of tight glycemic control during cardiac surgery in patients has recently been questioned. We postulated that low glucose (LG) may promote ROS formation through enhancing fatty acid (FA) oxidation and unmask propofol cardioprotection during IRI. Rat hearts were isolated and randomly assigned to be perfused with Krebs-Henseleit solution with glucose at 5.5 mM (LG) or 8 mM (G) in the absence or presence of propofol (5 μg/mL) or propofol plus trimetazidine (TMZ). Hearts were subjected to 35 minutes of ischemia followed by 60 minutes of reperfusion. Myocardial infarct size (IS) and cardiac CK-MB were significantly higher in LG than in G group (P

Objective. To investigate the correlation between TREM-1 and LPS-induced left ventricular systolic dysfunction in BALB/c mice. Methods. Male BALB/c mice were randomly divided into 3 groups: LPS, LPS/TREM-1, and control groups which were injected intraperitoneally with 25 mg/kg LPS, 5 μg TREM-1mAb 1 h after LPS challenge, and sterilized normal saline, respectively. Left ventricular systolic function was monitored by echocardiography at 6 h, 12 h, and 24 h. Meanwhile, TNF-α, IL-1β, and sTREM-1 in serum and myocardium were determined by ELISA or real-time PCR; at last left ventricles were taken for light microscopy examination. Results. FS and EF in LPS/mAbTREM-1 group, significantly declined compared with LPS and control group at 12 h, were accompanied with a markedly increase in serum IL-1β (at 6 h) and sTREM-1 (at 12 h and 24 h) expression. Myocardium TNF-α (at 6 h and 24 h) and sTREM-1 (at 6 h) were significantly higher in LPS/mAbTrem-1-treated mice than in time-matched LPS-treated mice; meanwhile myocardium TNF-α mRNA were markedly increased in comparison with LPS-treated or saline-treated mice at 24 h. Besides, mAbTREM-1 aggravated LPS-induced myocardial damage was observed. Conclusions. Our results suggest that TREM-1 is significantly associated with LPS-induced left ventricular systolic dysfunction in BALB/c mice.

Peroxisome proliferator-activated receptor-γ (PPAR-γ) is a ligand-binding nuclear receptor, and its activation plays a prominent role in regulating the inflammatory response. Therefore, PPAR-γ has been suggested as a candidate gene for sepsis. In the present study, we investigated the association between the Pro12Ala polymorphism of PPAR-γ and sepsis in a Han Chinese population. A total of 308 patients with sepsis and 345 healthy controls were enrolled in this study. Genotyping was performed using the polymerase chain reaction-ligation detection reaction (PCR-LDR) method. No significant differences were detected in the allele and genotype distributions of the PPAR-γ Pro12Ala SNP between septic patients and controls (P=0.622 for genotype; P=0.629 for allele). However, stratification by subtypes (sepsis, septic shock, and severe sepsis) revealed a statistically significant difference in the frequency of the Ala allele and Ala-carrier genotype between the patients with the sepsis subtype and the healthy controls (P=0.014 for allele and P=0.012, for genotype). Moreover, significant differences were found in the frequency of the Ala allele and genotype between the sepsis survivors and nonsurvivors (all P=0.002). In the survivors, the PPAR-γ Pro12Ala genotype was significantly associated with decreased disease severity and recovery time (all P

Cisatracurium besylate is an ideal non-depolarizing muscle relaxant which is widely used in clinical application. However, some studies have suggested that cisatracurium besylate can affect cell proliferation. Moreover, its specific mechanism of action remains unclear. Here, we found that the number of GFP-LC3 (green fluoresent protein-light chain 3) positive autophagosomes and the rate of mitochondria fracture both increased significantly in drug-treated GFP-LC3 and MitoDsRed stable HeLa cells. Moreover, cisatracurium promoted the co-localization of LC3 and mitochondria and induced formation of autolysosomes. Levels of mitochondrial proteins decreased, which were reversed by the lysosome inhibitor Bafinomycin A1. Similar results with evidence of dose-dependent effects were found in both HeLa and Human Umbilical Vein Endothelial Cells (HUVECs). Cisatracurium lowered HUVEC viability to 0.16 (OD490) at 100 µM and to 0.05 (OD490) after 48 h in vitro; it increased the cell death rate to 56% at 100 µM and to 60% after 24 h in a concentration- and time-dependent manner (p < 0.01). Cell proliferation decreased significantly by four fold in Atg5 WT (wildtype) MEF (mouse embryonic fibroblast) (p < 0.01) but was unaffected in Atg5 KO (Knockout) MEF, even upon treatment with a high dose of cisatracurium. Cisatracurium induced significant increase in cell death of wild-type MEFs even in the presence of the apoptosis inhibitor zVAD. Thus, we conclude that activation of both the autophagic cell death and cell apoptosis pathways contributes to cisatracurium-mediated cell injury.

This study investigated the role of stromal cell-derived factor-1α (SDF-1α)/CXC chemokine receptor 4 (CXCR4) axis in brain and endothelial progenitor cells (EPCs), and explored the efficacy of CXCR4 primed EPCs in treating ischemic stroke in diabetes. The db/db diabetic and db/+ mice were used in this study. Levels of plasma SDF-1α and circulating CD34+CXCR4+ cells were measured. Brain SDF-1α and CXCR4 expression were quantified at basal and after middle cerebral artery occlusion (MCAO). In in vitro study, EPCs were transfected with adenovirus carrying null (Ad-null) or CXCR4 (Ad-CXCR4) followed with high glucose (HG) treatment for 4 days. For pathway block experiments, cells were pre-incubated with PI3K inhibitor or nitric oxide synthase (NOS) inhibitor for two hours. The CXCR4 expression, function and apoptosis of EPCs were determined. The p-Akt/Akt and p-eNOS/eNOS expression in EPCs were also measured. In in vivo study, EPCs transfected with Ad-null or Ad-CXCR4 were infused into mice via tail vein. On day 2 and 7, the cerebral blood flow, neurologic deficit score, infarct volume, cerebral microvascular density, angiogenesis and neurogenesis were determined. We found: 1) The levels of plasma SDF-1α and circulating CD34+CXCR4+ cells were decreased in db/db mice; 2) The basal level of SDF-1α and MCAO-induced up-regulation of SDF-1α/CXCR4 axis were reduced in the brain of db/db mice; 3) Ad-CXCR4 transfection increased CXCR4 expression in EPCs and enhanced EPC colonic forming capacity; 4) Ad-CXCR4 transfection prevented EPCs from HG-induced dysfunction (migration and tube formation) and apoptosis via activation of PI3K/Akt/eNOS signal pathway; 4) Ad-CXCR4 transfection enhanced the efficacy of EPC infusion in attenuating infarct volume and promoting angiogenesis and neurogenesis. Our data suggest that Ad-CXCR4 primed EPCs have better therapeutic effects for ischemia stroke in diabetes than unmodified EPCs do.

BACKGROUND: The STEP (Strategy of Blood Pressure Intervention in the Elderly Hypertensive Patients) trial demonstrated that intensive systolic blood pressure (SBP) lowering has cardiovascular benefits. However, the influence of baseline diastolic blood pressure (DBP) on the effects of intensive blood pressure lowering on cardiovascular outcomes has not been fully elucidated. METHODS: We performed a post hoc analysis of the STEP trial. Participants were randomly allocated to intensive (110 to <130 mmHg) or standard (130 to <150 mmHg) treatment groups. The effects of intensive SBP lowering on the primary composite outcome (stroke, acute coronary syndrome, acute decompensated heart failure, coronary revascularization, atrial fibrillation, and cardiovascular death), major adverse cardiac event (a composite of the individual components of the primary outcome except for stroke), and all-cause mortality were analyzed according to baseline DBP as both a categorical and a continuous variable. RESULTS: The 8259 participants had a mean age of 66.2±4.8 years, and 46.5% were men. Participants with lower DBP were slightly older and had greater histories of cardiovascular disease, diabetes, and hyperlipidemia. Within each baseline DBP quartile, the mean achieved DBP was lower in the intensive versus standard group. The effects of intensive SBP lowering were not modified by baseline DBP as a continuous variable or as a categorical variable (quartiles, or <70, 70 to <80, and =80 mmHg; all P value for interaction >0.05). CONCLUSIONS: The beneficial effects of intensive SBP lowering on cardiovascular outcomes were unaffected by baseline DBP. Lower DBP should not be an obstacle to intensive SBP control. [ABSTRACT FROM AUTHOR]