Search

This study demonstrates a novel method to improve the density, interface bonding strength and mechanical properties of the B4Cp/Al composites by directly adding TiB2 to the material. Specifically, the (TiB2p+B4Cp)/Al composites with different TiB2 contents were successfully fabricated by ball milling (BM) and microwave sintering (MS). The results indicate that the developed (TiB2p+B4Cp)/Al possess a clean interface, with the absence of any reaction, thus, confirming microwave sintering as one of the preferred ways to prepare the (TiB2p+B4Cp)/Al composites. On adding TiB2, the densification in the microstructure is noted to initially increase, followed by a decrease. Overall, the TiB2 and B4C particles are noted to synergistically improve the densification as well as ameliorate the interfaces and microstructure. As a result, the optimized composites exhibit the compactness and Vickers hardness as high as 94.6% and 153.42HV0.3 respectively. The highest value of the compressive strength is determined to be 578.71 MPa at 50.0%. Further, no macroscopic fracture is noted to occur after 50% compression strain.

Cardiac senescence is associated with cardiomyopathy which is a degenerative disease in the aging process of the elderly. The present study investigates using multiple experimental approaches whether the natural flavone acacetin could attenuate myocardial senescence in C57/BL6 mice and H9C2 rat cardiac cells induced by D-galactose. We found that the impaired heart function in D-galactose-induced accelerated aging mice was improved by oral acacetin treatment in a dose-dependent manner. Acacetin significantly countered the increased serum advanced glycation end products, the myocardial telomere length shortening, the increased cellular senescence marker proteins p21 and p53, and the reduced mitophagy signaling proteins PINK1/Parkin and Sirt6 expression in aging mice. In H9C2 rat cardiac cells, acacetin alleviated cell senescence induced by D-galactose in a concentration-dependent manner. Acacetin decreased p21 and p53 expression, up-regulated PINK1/Parkin, LC3II/LC3I ratio, pLKB1, pAMPK and Sirt6, and reversed the depolarized mitochondrial membrane potential in aging cardiac cells. Mitophagy inhibition with 3-methyladenine or silencing Sirt6 abolished the protective effects of acacetin against cardiac senescence. Further analysis revealed that acacetin effect on Sirt6 was mediated by Sirt1 activation and increase of NAD+/NADH ratio. These results demonstrate that acacetin significantly inhibits in vivo and in vitro cardiac senescence induced by D-galactose via Sirt1-mediated activation of Sirt6/AMPK signaling pathway, thereby enhancing mitophagy and preserving mitochondrial function, which suggests that acacetin may be a drug candidate for treating cardiovascular disorders related to aging.

Doxorubicin cardiotoxicity is frequently reported in patients undergoing chemotherapy. The present study investigates whether cardiomyopathy induced by doxorubicin can be improved by the natural flavone acacetin in a mouse model and uncovers the potential molecular mechanism using cultured rat cardiomyoblasts. It was found that the cardiac dysfunction and myocardial fibrosis induced by doxorubicin were significantly improved by acacetin in mice with impaired Nrf2/HO‐1 and Sirt1/pAMPK molecules, which is reversed by acacetin treatment. Doxorubicin decreased cell viability and increased ROS production in rat cardiomyoblasts; these effects are significantly countered by acacetin (0.3‐3 μM) in a concentration‐dependent manner via activating Sirt1/pAMPK signals and enhancing antioxidation (Nrf2/HO‐1 and SOD1/SOD2) and anti‐apoptosis. These protective effects were abolished in cells with silencing Sirt1. The results demonstrate for the first time that doxorubicin cardiotoxicity is antagonized by acacetin via Sirt1‐mediated activation of AMPK/Nrf2 signal molecules, indicating that acacetin may be a drug candidate used clinically for protecting against doxorubicin cardiomyopathy.

The effects of rare earth yttrium with 0.1, 0.2 and 0.5 atomic ratios on the microstructure and properties of FeCoNi1.5CuB high-entropy alloy were investigated. The results show that the lattice distortion of the matrix alloy is increased after yttrium addition. There are three characteristic zones: the bulk trivalent boride phase zone, basement zone and yttrium-rich precipitate zone. When the yttrium atom ratio is > 0.2, the nanoscale YB6 particles disperse uniformly in the yttrium-rich zone, which can improve the strength of the alloy. As for the mechanical properties, the FeCoNi1.5CuBY0.2 alloy has the highest strength. The corresponding compressive strength, yield strength and maximum compression ratio have been increased by 19.9%, 75.4% and 37%, respectively, compared with those of FeCoNi1.5CuB alloy. This is attributed to the solid solution, grain refinement and dispersion strengthening in the presence of yttrium addition.

Cardiac hypertrophy is a major risk factor for developing heart failure. This study investigates the effects of the natural flavone acacetin on myocardial hypertrophy in cellular level and whole animals. In cardiomyocytes from neonatal rat with hypertrophy induced by angiotensin II (Ang II), acacetin at 0.3, 1, and 3 μM reduced the increased myocyte surface area, brain natriuretic peptide (BNP), and ROS production by upregulating anti-oxidative molecules (i.e. Nrf2, SOD1, SOD2, HO-1), anti-apoptotic protein Bcl-2, and downregulating the pro-apoptotic protein Bax and the inflammatory cytokine IL-6 in a concentration-dependent manner. In addition, acacetin rescued Ang II-induced impairment of PGC-1α, PPARα and pAMPK. These beneficial effects of acacetin were mediated by activation of Sirt1, which was confirmed in cardiac hypertrophy induced by abdominal aorta constriction (AAC) in SD rats. Acacetin prodrug (10 mg/kg, s.c., b.i.d.) treatment reduced the elevated artery blood pressure, improved the increased heart size and thickness of left ventricular wall and the ventricular fibrosis associated with inhibiting myocardial fibrosis and BNP, and reversed the impaired protective signal molecules including PGC-1α, Nrf2, PPARα, pAMPK and Sirt1 of left ventricular tissue. Our results demonstrate the novel pharmacological effect that acacetin ameliorates cardiac hypertrophy via Sirt1-mediated activation of AMPK/PGC-1α signal molecules followed by reducing oxidation, inflammation and apoptosis.

The social factors that moderate stroke caregiver burden have been found to be culture- and gender-specific. We examined the factors that influence the social support and self-efficacy of caregivers of stroke survivors and the burden of caregiving in China. To determine the caregiver burden of stroke survivors, their social support, and their self-efficacy. A total of 328 stroke survivors and their caregivers were recruited from 4 tertiary medical centers to participate in this cross-sectional study. The sociodemographic and stroke-related characteristics of the participants were obtained. Perceived social support and self-efficacy were assessed using the Social Support Rating Scale and General Self-efficacy Scale, respectively. Caregiver burden was assessed using the Zarit Burden Interview Scale. Relationships between the variables were assessed using Pearson's correlation, the chi-square test, and a paired t test. A total of 27.4% of the caregivers reported receiving adequate social support, while 20.7% reported high levels of self-efficacy. A total of 67.1% of the caregivers experienced varying degrees of care burden, while the remaining 32.9% felt no burden. Participants' sociodemographic characteristics (age, daily care time, self-rated health, and financial situation) were significantly related to caregiver burden, social support, and self-efficacy (P .001). The findings indicate an inverse relationship between caregiver burden, social support and self-efficacy. Adequate social support and self-efficacy can reduce stroke caregivers' burden. Hospital departments should provide assistance to stroke caregivers through educational programs and group training to increase their social support and self-efficacy, thereby alleviating their burden.

Diabetic cardiomyopathy seriously affects the life quality of diabetic patients and can lead to heart failure and death in severe cases. Acacetin was reported to be an anti-oxidant and anti-inflammatory agent in several cardiovascular diseases. However, the effect of acacetin on diabetic cardiomyopathy was not understood. This study was designed to explore the therapeutic effect of acacetin on diabetic cardiomyopathy and the potential mechanism with in vitro and in vivo experimental techniques. In cultured neonatal rat cardiomyocytes and H9C2 cardiac cells, acacetin (0.3, 1, 3 μM) showed effective protection against high glucose-induced injury in a concentration-dependent manner. Acacetin countered high glucose-induced increase of Bax and decrease of Bcl-2, SOD1, and SOD2. In streptozotocin-induced rat diabetic cardiomyopathy model, treatment with acacetin prodrug (10 mg/kg, s.c., b.i.d.) significantly improved the cardiac function and reduced myocardial injury, and reversed the increase of serum MDA, Ang Ⅱ, and IL-6 levels and myocardial Bax and IL-6, and the decrease of serum SOD, indicating that acacetin plays a cardioprotective effect by inhibiting oxidative stress, inflammation, and apoptosis. In addition, both in vitro and in vivo experimental results showed that acacetin increased the expression of PPAR-α and pAMPK, indicating that PPAR-α and pAMPK are potential targets of acacetin for the protection against diabetic cardiomyopathy. This study demonstrates the new application of acacetin for treating diabetic cardiomyopathy.

The nanometer and uniform distributed in-situ γ-Al2O3 particles reinforced aluminum matrix composites have been successfully fabricated in the Al-Co3O4 components at 850 °C by means of direct melt reaction method. The microstructure and properties of composites were investigated. The nanometer γ-Al2O3 distributes uniformly in the matrix and is assumed as γ-Al2O3 that is a stable phase of Al2O3 when the temperature is lower than 1000 °C. The Al/γ-Al2O3 interface is clean with certain matching degree. High density dislocation has been found around the nano γ-Al2O3 particles. At the grain boundary the submicron Al9Co2 particles exist, which can restrict the grain boundary moving. The tensile properties of 0.6 vol% γ-Al2O3 sample arrives at utmost while the 0.8 vol% sample decrease a lot due to the particle agglomeration.

In this study, the ZrB2/Al nanocomposites were fabricated via in-situ reaction of the Al-K2ZrF6-KBF4 system, assisted with ultrasonic vibration and spiral electromagnetic stirring. Microstructure, tensile property and creep behavior of the fabricated nanocomposites were further investigated. Microstructure observation showed that the ultrasonic vibration could prevent the fast growth as well as break the clusters of in-situ synthesized nanoparticles in melt, resulted in smaller size (10–50 nm) and relatively more uniform distribution of the in-situ nanoparticles located on the boundary of and/or inside the aluminum matrix grains in the final composites. The fabricated nanocomposites exhibited an enhancement in both strength and ductility, due to the elevated work hardening ability, i.e., improved dislocation propagating ability and decreased dynamic recovery of the existing dislocations induced by the in-situ nanoparticles. Meanwhile, the nanocomposites exhibited excellent creep resistance ability, which was about 2–18 times higher than those of the corresponding aluminum matrix. The stress exponent of 5 was identified for the fabricated nanocomposites, which suggested that their creep behavior was related to dislocation climb mechanism. The enhanced creep resistance of the nanocomposites was attributed to the Orowan strengthening and grain boundary strengthening induced by the ZrB2 nanoparticles. Thus, the ultrasonic-chemical in-situ reaction promises a low cost but effective way to fabricate aluminum nanocomposites with high strength and high creep resistance.

In this study, the nanometer in-situ γ-Al2O3 particles reinforced aluminum matrix composites was successfully fabricated by the A356 aluminum alloy and Co3O4 powder at 850 °C by means of in-situ reaction in the high temperature melt. The effects of γ-Al2O3 particle and cobalt element on the microstructure and properties of the composites were investigated in detail. The endogenous γ-Al2O3 and cobalt could modify the coarse plate like eutectic Si into fine fibrous like and refine the second dendrite arm spacing (SDAS) of the grains simultaneously. When the content of cobalt was lower than 0.57% and content of γ-Al2O3particles was lower than 0.6 vol%, the particles distributed uniformly in the grain, however, when the particulate amount was up to 0.8 vol%, the particles would distribute at the grains boundaries or form as a rodlike phase. The grain size was sharply refined to 200 μm when the particulate content was 0.8 vol%. It was found that the ultimate tensile strength (UTS), elongation of the 0.6 vol% γ-Al2O3/A356 composites had arrived at the maximum that had enhanced by 43.6% and 85.7% in comparison to the matrix respectively, which were attributed to the homogeneous distribution of the nanoparticles, the refinement of the SDAS of the α-Al grains and the modification of the eutectic Si phases.

Background Since December 2019, coronavirus disease (COVID-19) has been rapidly spreading worldwide. Nurses play a key role in fighting this disease and are at risk of COVID-19 infection. Therefore, there is an urgent need to assess the mental health condition of nurses and establish appropriate interventions to reduce the negative psychiatric outcomes of the pandemic. Objective The objectives of this study were to evaluate the knowledge and psychological stress related to COVID-19 among nursing staff and to provide evidence of the need for targeted training and psychological intervention. Methods This cross-sectional web-based survey study was performed in a class 3 grade A general hospital in a southwest province of China from March 1 to March 15, 2020. A self-designed questionnaire with questions about COVID-19–related prevention and control knowledge and the Triage Assessment Form (TAF) were used to assess nursing staff’s knowledge of COVID-19 and their degree of psychological stress, respectively. SPSS 23.0 was applied for statistical analysis of the collected data. Results A total of 979 nurses completed the questionnaire. The results showed that the nursing staff provided the fewest correct answers to questions about continuous viral nucleic acid testing specifications (379/979 correct answers, 38.7%), isolation/discharge criteria (539/979 correct answers, 55.1%), and management measures for patients with suspected symptoms (713/979 correct answers, 72.8%). The median total score of the TAF was 7.0 (IQR 5.0-12.0), and there were statistically significant differences in scores between different nursing roles, years of work experience, and hospital departments (P Conclusions This study indicated that nursing staff have insufficient knowledge about COVID-19. Meanwhile, although the psychological damage to nurses during the pandemic was found to be low, nurse managers must continue to monitor the mental health of nursing staff and perform timely interventions.

BackgroundThe strategy of decreasing atherosclerotic cardiovascular disorder is imperative to reduce premature death and improve quality of life in patients with diabetes mellitus. The present study was designed to investigate whether the natural flavone acacetin could improve diabetes- accelerated atherosclerotic lesions.MethodsDiabetic model was established in 7-week-old ApoE−/− mice by intraperitoneal injection of STZ (daily 50 mg/kg) for 5 days. Animals of control, control with acacetin treatment, STZ-diabetes, STZ-diabetes with acacetin treatment received acacetin prodrug subcutaneously (20 mg/kg, b.i.d.) or equivolume saline for 12 weeks, and the elasticity of carotid artery and the ability of vascular wall movement were determined with ultrasound and magnetic resonance imaging. Human umbilical vein endothelial cells (HUVECs) were cultured with medium containing 5.5 mM or 33 mM glucose and treated with acacetin or vehicle. Changes of related aortic lesions and signaling molecules were determined by biochemical and molecular approaches in animals and cultured HUVECs.ResultsIt was found that acacetin significantly suppressed atherosclerotic lesions and neointima hyperplasia, improved the elasticity of carotid artery and the ability of vascular wall movement without reducing blood glucose level and reversed the impaired signaling molecules (i.e. SOD, Bcl2, PGC-1α, pAMPK, Sirt3 and Sirt1) in artery tissues in diabetic mice. In cultured HUVECs, high glucose-induced cell viability reduction, ROS over-production, decrease of anti-oxidation, increase of apoptosis, and impairment of mitochondrial function were countered by acacetin (0.3-3 µM) in a concentration-dependent manner. Moreover, acacetin relies on Sirt1 activation by increasing NAMPT and NAD+ followed by Sirt3, pAMPK and PGC-1α activation. Silencing Sirt1 abolished acacetin-induced activation of Sirt3, pAMPK, and PGC-1α.ConclusionsThese results indicate that Sirt1-mediated activation of pAMPK/Sirt3 signals is involved in protective effects of acacetin against atherosclerosis in diabetes by preserving mitochondrial function via reducing mitochondrial apoptosis and ROS production and enhancing its biogenesis, which suggests that acacetin may be a drug candidate for reducing atherosclerotic cardiovascular disorder in patients with diabetes.

Our recent study showed that bradykinin increases cell cycling progression and migration of human cardiac c-Kit+ progenitor cells by activating pAkt and pERK1/2 signals. This study investigated whether bradykinin-mediated Ca2+ signalling participates in regulating cellular functions in cultured human cardiac c-Kit+ progenitor cells using laser scanning confocal microscopy and biochemical approaches. It was found that bradykinin increased cytosolic free Ca2+ ( Cai2+ ) by triggering a transient Ca2+ release from ER IP3Rs followed by sustained Ca2+ influx through store-operated Ca2+ entry (SOCE) channel. Blockade of B2 receptor with HOE140 or IP3Rs with araguspongin B or silencing IP3R3 with siRNA abolished both Ca2+ release and Ca2+ influx. It is interesting to note that the bradykinin-induced cell cycle progression and migration were not observed in cells with siRNA-silenced IP3R3 or the SOCE component TRPC1, Orai1 or STIM1. Also the bradykinin-induced increase in pAkt and pERK1/2 as well as cyclin D1 was reduced in these cells. These results demonstrate for the first time that bradykinin-mediated increase in free Cai2+ via ER-IP3R3 Ca2+ release followed by Ca2+ influx through SOCE channel plays a crucial role in regulating cell growth and migration via activating pAkt, pERK1/2 and cyclin D1 in human cardiac c-Kit+ progenitor cells.

Background and purpose Adrenergic regulation of cell volume-regulated chloride current (ICl.vol ) is species-dependent. The present study investigates the mechanism underlying adrenergic regulation of ICl.vol in human atrial myocytes. Experimental approach Conventional whole-cell patch voltage-clamp techniques were used to record membrane current in human atrial myocytes. ICl.vol was evoked by hyposmotic bath solution (0.6 times isosmotic, 0.6 T). Key results ICl.vol was augmented by noradrenaline (1 μM) during cell swelling in 0.6 T but not under isosmotic (1 T) conditions. Up-regulation of ICl.vol in 0.6 T was blocked by the β-adrenoceptor antagonist propranolol (2 μM), but not by the α1 -adrenoceptor antagonist prazosin (2 μM). This β-adrenergic response involved cAMP but was independent of PKA; the protein kinase inhibitor H-89 (2 μM) or PKI (10 μM in pipette solution) failed to prevent ICl.vol up-regulation by noradrenaline. Moreover, the PI3K/PKB inhibitor LY294002 (50 μM) and the PKG inhibitor KT5823 (10 μM) did not affect noradrenaline-induced increases in ICl.vol . Interestingly, the exchange protein directly activated by cAMP (Epac) agonist 8-pCPT-2'-O-Me-cAMP (50 μM) also up-regulated ICl.vol , and the noradrenaline-induced increase of ICl.vol in 0.6 T was reversed or prevented by the Epac inhibitor ESI-09 (10 μM). Conclusion and implications These data show that ICl.vol evoked by cell swelling of human atrial myocytes is up-regulated by noradrenaline via a PKA-independent cAMP/Epac pathway in human atrial myocytes. cAMP/Epac-induced ICl.vol is expected to shorten action potential duration during human atrial myocytes swelling and may be involved in abnormal cardiac electrical activity during cardiac pathologies that evoke β-adrenoceptor signalling.

At T6 state, Al–Zn–Mg–Cu aluminum matrix composites reinforced with Al2O3 particles generated in situ were subjected to high pulsed magnetic fields at different magnetic induction intensities (B = 2, 3 and 4 T). The results show that the dislocation densities in the treated samples increased with increasing B, and the magnetoplastic effect was determined to be the primary cause. The effect of the magnetic field is believed to alter the spin state of free electrons between dislocations and obstacles from the singlet state (associated with high bonding energy) to the triplet state (low bonding energy). The maximum ultimate tensile strength of 532 MPa was obtained at B = 4 T with 30 pulses, which was 20.7% higher than that of the initial sample, primarily because of dislocation strengthening. At B = 2 T, the elongation was at its maximum of 9.3%, representing an increase of 12% compared with the initial sample, while the associated ultimate tensile strength (447 MPa) was still higher than that of the untreated sample (440 MPa). The relationship between mechanical properties and microstructure was analyzed, and the improved properties observed in this work are explained by the transition of the electron spin state and the piling up of dislocations.

Polymer modifiers have been used to improve the performances of asphalt binders in pavement engineering. The modifying effect of polymers on asphalt is largely dependent on the morphological characteristics of polymer-modified asphalt. The morphologies of polymer-modified asphalt are composed of a polymer-rich phase, a asphaltene-rich phase, and the interphase between the two phases. Interfacial interactions importantly contribute to the morphology but are commonly overlooked. In this study, carbon nanotubes (CNTs) were selected to improve the interfacial interactions of polymer-modified asphalt. Fluorescence microscopy (FM), scanning electron microscopy (SEM), micro-Raman spectroscopy (MRS), and molecular dynamics (MD) simulation were used to capture the characteristics of the interphase and polymer-rich phase. CNTs-polymer-modified asphalt involves stronger intermolecular forces than those in asphalt-modified by only styrene–butadiene–styrene (SBS) or CNTs. This discrepancy highlights the intensified in...

In this study, the addition of Zr element (K2ZrF6) was employed to improve the wettability, inhibit the serious chemical reaction of B4C to Al, and uniformly disperse the B4C particles in the Al melt, during the fabrication of B4C/Al composites via melt stirring method. And the particle distribution, interface microstructure and mechanical properties of the fabricated composites were further investigated. The metallography observation shows that the B4C particles could be effectively introduced to the Al melt with the addition of Zr element, while there were few B4C particles observed in the composites without Zr addition. The XRD analysis indicates that the ZrB2 and ZrC peaks arise with the addition of Zr, where the ZrB2 and ZrC have better chemical stabilization and wettability than the B4C ceramic particles. The SEM, EDS, TEM and SAED analysis shows that the ZrB2 and ZrC interface layer with a thickness of about 200–350 nm on the B4C surface was formed, which could avoid the serious chemical reaction and improve the wettability of B4C to Al, simultaneously. In addition, the easy introduction of B4C particles to the Al melt with K2ZrF6, the formation mechanism of ZrB2 and ZrC layer, and mechanical properties of the composites were also discussed.

The aim of the present study was to investigate key genes in fibroids based on the multiple affinity propogation-Krzanowski and Lai (mAP-KL) method, which included the maxT multiple hypothesis, Krzanowski and Lai (KL) cluster quality index, affinity propagation (AP) clustering algorithm and mutual information network (MIN) constructed by the context likelihood of relatedness (CLR) algorithm. In order to achieve this goal, mAP-KL was initially implemented to investigate exemplars in fibroid, and the maxT function was employed to rank the genes of training and test sets, and the top 200 genes were obtained for further study. In addition, the KL cluster index was applied to determine the quantity of clusters and the AP clustering algorithm was conducted to identify the clusters and their exemplars. Subsequently, the support vector machine (SVM) model was selected to evaluate the classification performance of mAP-KL. Finally, topological properties (degree, closeness, betweenness and transitivity) of exemplars in MIN constructed according to the CLR algorithm were assessed to investigate key genes in fibroid. The SVM model validated that the classification between normal controls and fibroid patients by mAP-KL had a good performance. A total of 9 clusters and exemplars were identified based on mAP-KL, which were comprised of CALCOCO2, COL4A2, COPS8, SNCG, PA2G4, C17orf70, MARK3, BTNL3 and TBC1D13. By accessing the topological analysis for exemplars in MIN, SNCG and COL4A2 were identified as the two most significant genes of four types of methods, and they were denoted as key genes in the progress of fibroid. In conclusion, two key genes (SNCG and COL4A2) and 9 exemplars were successfully investigated, and these may be potential biomarkers for the detection and treatment of fibroid.

The present study was designed to investigate whether large conductance Ca2+‐activated K+ (BK) channels were regulated by epidermal growth factor (EGF) receptor (EGFR) tyrosine kinase. BK current and channel tyrosine phosphorylation level were measured in BK‐HEK 293 cells expressing both functional α‐subunits and the auxiliary β1‐subunits using electrophysiology, immunoprecipitation and Western blotting approaches, respectively, and the function of rat cerebral basilar arteries was determined with a wire myography system. We found that BK current in BK‐HEK 293 cells was increased by the broad spectrum protein tyrosine kinase (PTK) inhibitor genistein and the selective EGFR tyrosine kinase inhibitor AG556, one of the known tyrphostin. The effect of genistein or AG556 was antagonized by the protein tyrosine phosphatase (PTP) inhibitor orthovanadate. On the other hand, orthovanadate or EGF decreased BK current, and the effect was counteracted by AG556. The tyrosine phosphorylation level of BK channels (α‐ and β1‐subunits) was increased by EGF and orthovanadate, while decreased by genistein and AG556, and the reduced tyrosine phosphorylation of BK channels by genistein or AG556 was reversed by orthovanadate. Interestingly, AG556 induced a remarkable enhancement of BK current in rat cerebral artery smooth muscle cells and relaxation of pre‐contracted rat cerebral basilar arteries with denuded endothelium, and these effects were antagonized by the BK channel blocker paxilline or orthovanadate. These results demonstrate that tyrosine phosphorylation of BK channels by EGFR kinase decreases the channel activity, and inhibition of EGFR kinase by AG556 enhances the channel activity and dilates rat cerebral basilar arteries.

Background and purpose The ultra-rapidly activating delayed rectifier K+ current IKur (encoded by Kv 1.5 or KCNA5) plays an important role in human atrial repolarization. The present study investigates the regulation of this current by protein tyrosine kinases (PTKs). Experimental approach Whole-cell patch voltage clamp technique and immunoprecipitation and Western blotting analysis were used to investigate whether the PTK inhibitors genistein, tyrphostin AG556 (AG556) and PP2 regulate human atrial IKur and hKv1.5 channels stably expressed in HEK 293 cells. Key results Human atrial IKur was decreased by genistein (a broad-spectrum PTK inhibitor) and AG556 (a highly selective EGFR TK inhibitor) in a concentration-dependent manner. Inhibition of IKur induced by 30 μM genistein or 10 μM AG556 was significantly reversed by 1 mM orthovanadate (a protein tyrosine phosphatase inhibitor). Similar results were observed in HEK 293 cells stably expressing hKv 1.5 channels. On the other hand, the Src family kinase inhibitor PP2 (1 μM) slightly enhanced IKur and hKv 1.5 current, and the current increase was also reversed by orthovanadate. Immunoprecipitation and Western blotting analysis showed that genistein, AG556, and PP2 decreased tyrosine phosphorylation of hKv 1.5 channels and that the decrease was countered by orthovanadate. Conclusion and implications The PTK inhibitors genistein and AG556 decrease human atrial IKur and cloned hKv 1.5 channels by inhibiting EGFR TK, whereas the Src kinase inhibitor PP2 increases IKur and hKv 1.5 current. These results imply that EGFR TK and the soluble Src kinases may have opposite effects on human atrial IKur .

BACKGROUND AND PURPOSE Recent studies showed that clemizole has a potential therapeutic effect for hepatitis C infection and also potently inhibits TRPC5 channels. The aim of the present study was to investigate whether clemizole blocks cardiac K+ currents and affects cardiac repolarization. EXPERIMENTAL APPROACH Whole-cell patch technique was employed to examine the effects of clemizole on hERG channel current, IKs and Kv1.5 current in HEK 293 cell expression systems as well as on ventricular action potentials of guinea pig hearts. The ex vivo guinea pig hearts were used to determine the effect on electrocardiogram. KEY RESULTS Clemizole decreased hERG current by blocking both open and closed states of the channel in a concentration-dependent manner (IC50: 0.07 μM). The S631A, S636A, Y652A and F656V hERG mutant channels reduced the inhibitory effect of clemizole (IC50: 0.82, 0.89, 1.49 and 2.98 μM, respectively), suggesting that clemizole is a pore blocker of hERG channels. Clemizole also moderately decreased IKs and hKv1.5 current. Moreover, clemizole increased ventricular action potential duration of guinea pig hearts and the QTc interval in perfused ex vivo guinea pig hearts in a concentration dependent manner (0.1-1.0 μM). CONCLUSION AND IMPLICATIONS Our results demonstrate the first evidence that clemizole potently blocks hERG channels, moderately inhibits cardiac IKs, delays cardiac repolarization, and thereby prolongs QT intervals. Thus, caution should be taken when clemizole is used as a TRPC5 channel blocker or for treating hepatitis C infection.

// Gang Li 1,2 , Yan Wang 1 and Gui-Rong Li 1,2 1 Xiamen Cardiovascular Hospital, Xiamen University, Xiamen, Fujian, China 2 Department of Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pokfulam, Hong Kong, China Correspondence to: Yan Wang, email: // Gui-Rong Li, email: // Keywords : Bradykinin; bradykinin receptor 2; human cardiac c-Kit+ progenitor cells; proliferation; migration; Pathology Section Received : June 27, 2016 Accepted : January 06, 2017 Published : January 12, 2017 Abstract Bradykinin is a well-known endogenous vasoactive peptide. The present study investigated the bradykinin receptor expression in human cardiac c-Kit + progenitor cells and the potential role of bradykinin in regulating cell cycling progression and mobility. It was found that mRNA and protein of bradykinin type 2 receptors, but not bradykinin type 1 receptors, were abundant in cultured human cardiac c-Kit + progenitor cells. Bradykinin (1-10 nM) stimulated cell growth and migration in a concentration-dependent manner. The increase of cell proliferation was related to promoting G0/G1 transition into G2/M and S phase. Western blots revealed that bradykinin significantly increased pAkt and pERK1/2 as well as cyclin D1, which were countered by HOE140 (an antagonist of bradykinin type 2 receptors) or by silencing bradykinin type 2 receptors. The increase of pAkt, pERK1/2 and cyclin D1 by bradykinin was prevented by the PI3K inhibitor Ly294002, the PLC inhibitors U73122 and neomycin, and/or the PKC inhibitor chelerythrine and the MAPK inhibitor PD98059. Our results demonstrate the novel information that bradykinin promotes cell cycling progression and migration in human cardiac c-Kit + progenitor cells via activating PI3K, PLC, PKC, cyclin D1, pERK1/2, and pAkt.

Background Our recent study demonstrated that the nonselective cation current mediated by the transient receptor potential canonical 1 (TRPC1) channel is activated by endothelin-1 (ET-1) in human atrial myocytes; however, the related signal molecules involved are unknown. Objective The purpose of this study was to investigate how the TRPC1 channel is regulated by ET-1 and whether it is upregulated in human atria from patients with atrial fibrillation (AF). Methods Whole-cell patch technique and molecular biology techniques were used in the study. Results The ET-1–evoked TRPC1 current was inhibited by the ET-1 type A (ETA) receptor antagonist BQ123 and the ET-1 type B (ETB) receptor antagonist BQ788 as well as the protein kinase C inhibitor chelerythrine. ETA receptor–mediated TRPC1 channel activity was selectively inhibited by the phosphoinositide-3-kinase inhibitor wortmannin, while ETB receptor–mediated TRPC1 activity was inhibited by the phospholipase C inhibitor U73122. The messenger RNAs and proteins of the TRPC1 channel and ETA receptor, but not the ETB receptor, were significantly upregulated in atria from patients with AF. The basal TRPC1 current increased in AF myocytes, and the response to ET-1 was greater in AF myocytes than in sinus rhythm myocytes. ET-1 induced a delayed repolarization in 20% of AF myocytes. Conclusion These results demonstrate for the first time that TRPC1 activation by ET-1 is mediated by protein kinase C through the distinct phospholipids pathways phosphoinositide-3-kinase and phospholipase C and that the TRPC1 channel and ETA receptor are upregulated in AF atria, which are likely involved in atrial electrical remodeling in patients with AF.

The aim of this study is to describe our clinical outcomes in isolated superior mesenteric artery dissection (SMAD) patients that underwent uncovered stent insertion.Between January 2016 and August 2019, consecutive isolated SMAD patients at our center were treated via uncovered stent insertion. Both short- and long-term outcomes in these patients were analyzed.Over the course of the study period, 11 total isolated SMAD patients meeting the criteria for stent insertion at our hospital were treated via uncovered stent insertion. Stent placement across the SMAD site was successful in all patients, with 1 stent being used per patient. There were no instances of procedure-related complications, and the median operative duration was 60 minutes. Patency of the distal superior mesenteric artery and branches thereof was achieved in all cases. Patients experienced progressive SMAD-related symptom relief and were followed for 6 to 49 months (median: 22 months). Over this follow-up period, the obliteration of the dissection was observed within 3 months in all patients. We did not detect any instances of stent occlusion, bowel ischemia, or anti-platelet-related bleeding during the follow-up period.Uncovered stent insertion can achieve favorable short- and long-term outcomes in isolated SMAD patients.

In this study, A356 matrix and 0.2 vol.%∼0.8 vol.% in-situ Al2O3p/A356 composite were hot rolled to 75% reduction ratio and 0.6 vol.% composite was hot rolled to 75% and 83% reduction ratios. Scanning electron microscope (SEM), electron back scattering diffraction (EBSD) and transmission electron microscopy (TEM) were used to characterize the microstructure and texture evolution so as to investigate the effect of the particle content and reduction ratios. In the 75% rolling reduction, the Si phase in the A356 matrix and Al2O3p/A356 composites was fragmented and distributed along the rolling direction (RD), obvious Al2O3 agglomeration diminished. On the state of 75% reduction, when the content of Al2O3 was 0.2 vol.%, the composite had the finest grain size, however the 0.6 vol.% composite had a better Si phase and Al2O3 distribution. The Al2O3 particle in 0.2 vol.% sample can enhance the dislocation density and accelerate the sub-grain boundary formation. For the 75% reduction materials, the tensile properties increased with the increase of particulate content to 0.6 vol.% then decreased. The mechanical properties of 83% rolling reduction sample was better than the 75% reduction. Tensile tests showed that the ultimate tensile strength (UTS), yield strength (YS) and elongation (El) of 0.6 vol.% Al2O3p/A356 composite increased to 282 MPa, 221 MPa and 17.5%, respectively, due to the uniform distribution of the particles and refined Si phase upon increasing the rolling reduction to 83%, in combination with T4 heat treatment. In addition, the mechanisms of particle dispersion, recrystallization grain refinement and strengthening are also discussed.

In this investigation, FeCoNi1.5CrCu high-entropy alloy (HEA) was prepared by mechanical alloying, following which HEA particles reinforced 2024 aluminum matrix composites were obtained using a microwave with low-temperature sintering. The microstructural characterization and mechanical properties of the composites under different sintering time at isothermal temperature were investigated systematically. The results showed that HEA particles at first diffuse uniformly and then agglomerate with an increase in the sintering time. An interdiffusion (ID) layer exists between the HEA particle and the matrix, and high-density dislocations surround the interface of the HEA/2024Al composite, with a width of 80–120 nm. The hardness and elastic modulus of the interface was tested using nanoindentation technique, which presents excellent interface micro-domains with the mechanical strength reaching about 1331.1 MPa and 47.544 GPa. At 40 min of sintering time, the compressive strength, yield strength and microhardness of the composites were reaching the maximum of 248.7 MPa, 227.4 MPa and 93.1 HV, respectively.

BackgroundJ wave syndromes (JWS), including Brugada (BrS) and early repolarization syndromes (ERS), are associated with increased risk for life-threatening ventricular arrhythmias. Pharmacologic approaches to therapy are currently very limited. Here, we evaluate the effects of the natural flavone acacetin.MethodsThe effects of acacetin on action potential (AP) morphology and transient outward current (Ito) were first studied in isolated canine RV epicardial myocytes using whole-cell patch clamp techniques. Acacetin’s effects on transmembrane APs, unipolar electrograms and transmural ECGs were then studied in isolated coronary-perfused canine RV and LV wedge preparations as well as in whole-heart, Langendorff-perfused preparations from which we recorded a 12 lead ECG and unipolar electrograms. Using floating glass microelectrodes we also recorded transmembrane APs from the RVOT of the whole-heart model. The Itoagonist NS5806, sodium channel blocker ajmaline, calcium channel blocker verapamil or hypothermia (32°C) were used to pharmacologically mimic the genetic defects and conditions associated with JWS, thus eliciting prominent J waves and provoking VT/VF.ResultsAcacetin (5–10 μM) reduced Itodensity, AP notch and J wave area and totally suppressed the electrocardiographic and arrhythmic manifestation of both BrS and ERS, regardless of the experimental model used. In wedge and whole-heart models of JWS, increasing Itowith NS5806, decreasing INaor ICa(with ajmaline or verapamil) or hypothermia all resulted in accentuation of epicardial AP notch and ECG J waves, resulting in characteristic BrS and ERS phenotypes. Phase 2-reentrant extrasystoles originating from the RVOT triggered VT/VF. The J waves in leads V1 and V2 were never associated with a delay of RVOT activation and always coincided with the appearance of the AP notch recorded from RVOT epicardium. All repolarization defects giving rise to VT/VF in the BrS and ERS models were reversed by acacetin, resulting in total suppression of VT/VF.ConclusionsWe present experimental models of BrS and ERS capable of recapitulating all of the ECG and arrhythmic manifestations of the JWS. Our findings provide definitive support for the repolarization but not the depolarization hypothesis proposed to underlie BrS and point to acacetin as a promising new pharmacologic treatment for JWS.

Face-centered-cubic (FCC) type high-entropy alloys (HEAs) exhibit outstanding ductility, but their performance is still inferior to body-centered-cubic (BCC) type HEAs, limiting its structural applications. The addition of boron (B) has effectively improved the strength, but it induces severe embrittlement because of the formation of M3B (M = Fe, Co, Ni) borides. In this paper, FeCoNi1·5CuB0·5Y0.2 HEA was obtained by high-energy ball milling and microwave vacuum sintering process. Besides, the effects of annealing temperature on microstructural and mechanical properties were investigated. The specimen annealed at 950 °C exhibited moderate grain growth, and copper (Cu) precipitated in the FCC solid solution at 900 °C. The hexagonal close-packed (HCP) phase was piled up in blocks, and particles of YB6-type precipitated. Overall performance improvement of the material was the greatest by annealing at 1050 °C.

// Yuan Wang 1,2 , Yan Wang 1 and Gui-Rong Li 1,2 1 Xiamen Cardiovascular Hospital, Medical School of Xiamen University, Xiamen, Fujian, China 2 Department of Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pokfulam, Hong Kong, China Correspondence to: Yan Wang, email: // Gui-Rong Li, email: // Keywords : lysophosphatidylcholine; cell viability; apoptosis; transient receptor potential channels; Pathology Section Received : March 01, 2016 Accepted : July 09, 2016 Published : July 26, 2016 Abstract The earlier study showed that lysophosphatidylcholine (lysoPC) induced apoptosis in human coronary artery smooth muscle cells (SMCs); however, the related molecular mechanisms are not fully understood. The present study investigated how lysoPC induces apoptosis in cultured human coronary artery SMCs using cell viability assay, flow cytometry, confocal microscopy, and molecular biological approaches. We found that lysoPC reduced cell viability in human coronary artery SMCs by eliciting a remarkable Ca 2+ influx. The effect was antagonized by La 3+ , SKF-96365, or Pyr3 as well as by silencing TRPC1 or TRPC3. Co-immunoprecipitation revealed that TRPC1 and TRPC3 had protein-protein interaction. Silencing TRPC1 or TRPC3 countered the lysoPC-induced increase of Ca 2+ influx and apoptosis, and the pro-apoptotic proteins Bax and cleaved caspase-3 and decrease of the anti-apoptotic protein Bcl-2 and the survival kinase pAkt. These results demonstrate the novel information that TRPC1/TRPC3 channels mediate lysoPC-induced Ca 2+ influx and apoptosis via activating the pro-apoptotic proteins Bax and cleaved caspase-3 and inhibiting the anti-apoptotic protein Bcl-2 and the survival kinase pAkt in human coronary artery SMCs, which implies that TRPC1/TRC3 channels may be the therapeutic target of lysoPC-induced disorders such as atherosclerosis.

Background Several mammalian species display distinct biophysical properties between atrial and ventricular voltage-gated sodium current (I Na ); however, the potential mechanism behind this phenomenon is unknown. Objective The purpose of this study was to investigate the potential molecular identities of the different I Na in atrial and ventricular myocytes of rat hearts. Methods Whole-cell patch voltage-clamp and molecular biology techniques were used in the study. Results Ventricular I Na exhibited a slower inactivation, more positive potential of inactivation, and quicker recovery from inactivation compared to atrial I Na . Real-time polymerase chain reaction and western blot analysis revealed that mRNA and protein levels of Na V β2 and Na V β4 subunits, but not Na V 1.5, were greater in ventricular myocytes than in atrial myocytes. I Na in heterologous HEK 293 cell expression system with coexpressing hNa V 1.5 and hNa V β2/hNa V β4 showed similar biophysical properties to ventricular I Na . Greater protein expression of Na V β2 and Na V β4 subunits was also observed in human ventricles. Interestingly, pharmacologic study revealed that the antiarrhythmic drug dronedarone (10 μM) inhibited atrial I Na more (by 73%) than ventricular I Na (by 42%), and shifted its inactivation to more negative voltages (–4.6 mV) compared to ventricular I Na . Conclusion The results of this study demonstrate the novel information that the distinctive biophysical properties of I Na in atrial and ventricular myocytes can be attributed to inhomogeneous expression of Na V β2 and Na V β4 subunits, and that atrial I Na is more sensitive to inhibition by dronedarone.

The cellular physiology and biology of human cardiac c-kit(+) progenitor cells has not been extensively characterized and remains an area of active research. This study investigates the functional expression of transient receptor potential vanilloid (TRPV) and possible roles for this ion channel in regulating proliferation and migration of human cardiac c-kit(+) progenitor cells. We found that genes coding for TRPV2 and TRPV4 channels and their proteins are significantly expressed in human c-kit(+) cardiac stem cells. Probenecid, an activator of TRPV2, induced an increase in intracellular Ca(2+) (Ca(2+) i ), an effect that may be attenuated or abolished by the TRPV2 blocker ruthenium red. The TRPV4 channel activator 4α-phorbol 12-13-dicaprinate induced Ca(2+) i oscillations, which can be inhibited by the TRPV4 blocker RN-1734. The alteration of Ca(2+) i by probenecid or 4α-phorbol 12-13-dicprinate was dramatically inhibited in cells infected with TRPV2 short hairpin RNA (shRNA) or TRPV4 shRNA. Silencing TRPV2, but not TRPV4, significantly reduced cell proliferation by arresting cells at the G0/G1 boundary of the cell cycle. Cell migration was reduced by silencing TRPV2 or TRPV4. Western blot revealed that silencing TRPV2 decreased expression of cyclin D1, cyclin E, pERK1/2 and pAkt, whereas silencing TRPV4 only reduced pAkt expression. Our results demonstrate for the first time that functional TRPV2 and TRPV4 channels are abundantly expressed in human cardiac c-kit(+) progenitor cells. TRPV2 channels, but not TRPV4 channels, participate in regulating cell cycle progression; moreover, both TRPV2 and TRPV4 are involved in migration of human cardiac c-kit(+) progenitor cells.

SKF-96365 is a TRPC channel antagonist commonly used to characterize the potential functions of TRPC channels in different systems, which was recently reported to induce QTc prolongation on ECG by inhibiting TRPC channels. The present study investigates whether the blockade of cardiac repolarization currents would be involved in the increase of QTc interval. Cardiac repolarization currents were recorded in HEK 293 cells stably expressing human ether-à-go-go-related gene potassium (hERG or hKv11.1) channels, hKCNQ1/hKCNE1 channels (IKs) or hKir2.1 channels and cardiac action potentials were recorded in guinea pig ventricular myocytes using a whole-cell patch technique. The potential effect of SKF-96365 on QT interval was evaluated in ex vivo guinea pig hearts. It was found that SKF-96365 inhibited hERG current in a concentration-dependent manner (IC50, 3.4μM). The hERG mutants S631A in the pore helix and F656V of the S6 region reduced the inhibitory sensitivity with IC50s of 27.4μM and 11.0μM, suggesting a channel pore blocker. In addition, this compound inhibited IKs and hKir2.1currents with IC50s of 10.8 and 8.7μM. SKF-96365 (10μM) significantly prolonged ventricular APD90 in guinea pig ventricular myocytes and QTc interval in ex vivo guinea pig hearts. These results indicate that the TRPC channel antagonist SKF-96365 exerts blocking effects on hERG, IKs, and hKir2.1 channels. Prolongation of ventricular APD and QT interval is related to the inhibition of multiple repolarization potassium currents, especially hERG channels.

Cardiac c-kit+progenitor cells are important for maintaining cardiac homeostasis and can potentially contribute to myocardial repair. However, cellular physiology of human cardiac c-kit+progenitor cells is not well understood. The present study investigates the functional store-operated Ca2+entry (SOCE) channels and the potential role in regulating cell cycling and migration using confocal microscopy, RT-PCR, Western blot, coimmunoprecipitation, cell proliferation, and migration assays. We found that SOCE channels mediated Ca2+influx, and TRPC1, STIM1, and Orai1 were involved in the formation of SOCE channels in human cardiac c-kit+progenitor cells. Silencing TRPC1, STIM1, or Orai1 with the corresponding siRNA significantly reduced the Ca2+signaling through SOCE channels, decreased cell proliferation and migration, and reduced expression of cyclin D1, cyclin E, and/or p-Akt. Our results demonstrate the novel information that Ca2+signaling through SOCE channels regulates cell cycling and migration via activating cyclin D1, cyclin E, and/or p-Akt in human cardiac c-kit+cells.