A dual RNA-seq analyses revealed dynamic arms race during the invasion of walnut by Colletotrichum gloeosporioides.

BACKGROUND: Walnut anthracnose caused by Colletotrichum gloeosporioides seriously endangers the yield and quality of walnut, and has now become a catastrophic disease in the walnut industry. Therefore, understanding both pathogen invasion mechanisms and host response processes is crucial to defense against C. gloeosporioides infection. RESULTS: Here, we investigated the mechanisms of interaction between walnut fruits (anthracnose-resistant F26 fruit bracts and anthracnose-susceptible F423 fruit bracts) and C. gloeosporioides at three infection time points (24hpi, 48hpi, and 72hpi) using a high-resolution time series dual transcriptomic analysis, characterizing the arms race between walnut and C. gloeosporioides. A total of 20,780 and 6670 differentially expressed genes (DEGs) were identified in walnut and C. gloeosporioides against 24hpi, respectively. Generous DEGs in walnut exhibited opposite expression patterns between F26 and F423, which indicated that different resistant materials exhibited different transcriptional responses to C. gloeosporioides during the infection process. KEGG functional enrichment analysis indicated that F26 displayed a broader response to C. gloeosporioides than F423. Meanwhile, the functional analysis of the C. gloeosporioides transcriptome was conducted and found that PHI, SignalP, CAZy, TCDB genes, the Fungal Zn (2)-Cys (6) binuclear cluster domain (PF00172.19) and the Cytochrome P450 (PF00067.23) were largely prominent in F26 fruit. These results suggested that C. gloeosporioides secreted some type of effector proteins in walnut fruit and appeared a different behavior based on the developmental stage of the walnut. CONCLUSIONS: Our present results shed light on the arms race process by which C. gloeosporioides attacked host and walnut against pathogen infection, laying the foundation for the green prevention of walnut anthracnose.

SARS-CoV-2 spike protein acts as a ß-adrenergic receptor agonist: A potential mechanism for cardiac sequelae of long COVID.

BACKGROUND: Currently, pathophysiological mechanisms of post-acute sequelae of coronavirus disease-19-cardiovascular syndrome (PASC-CVS) remain unknown. METHODS AND RESULTS: Patients with PASC-CVS exhibited significantly higher circulating levels of severe acute respiratory syndrome-coronavirus-2 spike protein S1 than the non-PASC-CVS patients and healthy controls. Moreover, individuals with high plasma spike protein S1 concentrations exhibited elevated heart rates and normalized low frequency, suggesting cardiac ß-adrenergic receptor (ß-AR) hyperactivity. Microscale thermophoresis (MST) assay revealed that the spike protein bound to ß1- and ß2-AR, but not to D1-dopamine receptor. These interactions were blocked by ß1- and ß2-AR blockers. Molecular docking and MST assay of ß-AR mutants revealed that the spike protein interacted with the extracellular loop 2 of both ß-ARs. In cardiomyocytes, spike protein dose-dependently increased the cyclic adenosine monophosphate production with or without epinephrine, indicating its allosteric effects on ß-ARs. CONCLUSION: Severe acute respiratory syndrome-coronavirus-2 spike proteins act as an allosteric ß-AR agonist, leading to cardiac ß-AR hyperactivity, thus contributing to PASC-CVS.

Airborne magnetite nanoparticles induced early vascular pathologies by disrupting lipid metabolism under high-fat dietary patterns.

Magnetite nanoparticles (MNPs) have been extensively detected in the atmospheric environment and implicated as a prominent threat to atherosclerosis, a chronic vascular inflammatory disease. Due to globalization and economic development, the dramatic shift in diet from traditional to high-fat dietary patterns aggravated atherosclerosis progression induced by environmental factors. However, limited knowledge is available regarding vascular risks and underlying mechanisms of airborne MNPs in high-risk populations with high-fat dietary habits. Herein, we demonstrated that MNPs exerted a proatherogenic effect under high-fat dietary patterns, leading to aortic wall thickening, elastic fiber disorganization, macrophage infiltration, and local inflammation. Based on the correlation analysis between MNPs and PM group, we identified that MNPs might be a key PM component in atherogenic toxicity. MNPs exposure disturbed the dynamic process of lipid metabolism, manifested as aortic lipid accumulation, dyslipidemia, and hepatic lipid metabolism disorder, which was modulated by the JAK-STAT pathway. Overall, these findings provide new insight into understanding the cardiovascular risks and mechanisms of MNPs among high-risk populations.

[Different levels and clinical significance of growth differentiation factor-15 in patients with atrial fibrillation].

OBJECTIVE: To measure the concentration of growth differentiation factor-15 (GDF-15) in the serum of patients with atrial fibrillation (AF), to study the correlations between the levels of GDF-15 and different factors including basic clinical information, biochemical examinations, and atrial structure, and further to explore the association between GDF-15 and AF types and structural remodeling. METHODS: AF patients who were admitted to the ward of the Department of Cardiology at Peking University Third Hospital between October 2017 and October 2019 were prospectively enrolled. Patients admitted to the ward at the same time with sinus rhythm and no prior AF history were enrolled in the control group. Clinical information and blood samples of the patients were collected. Enzyme-linked immunosorbent assay was used to measure the concentration of GDF-15. SPSS 23.0 was used for statistical analysis. RESULTS: In the study, 156 AF patients (64 persistent AF and 92 paroxysmal AF) and 38 patients of the control group were included. Serum GDF-15 levels in the AF group were significantly higher than in the control group [1 112 (723, 1 525) ng/L vs. 697 (499, 825) ng/L, P < 0.001]. Serum GDF-15 levels in the persistent AF group were significantly higher than in the paroxysmal AF group [1 140 (858, 1 708) ng/L vs. 1 090 (662, 1 374) ng/L, P=0.047]. The area under the curve (AUC) of serum GDF-15 levels for prediction of AF was 0.736 (95%CI: 0.651-0.822, P < 0.001). The cut-off value was 843.2 ng/L with a sensitivity of 68.2% and a specificity of 78.9%. The AUC of serum GDF-15 levels for prediction of persistent AF was 0.594 (95%CI: 0.504-0.684, P=0.047). The cut-off va-lue was 771.5 ng/L with a sensitivity of 82.8% and a specificity of 35.9%. Spearman rank correlation analysis showed that the serum GDF-15 levels were positively correlated with age (r=0.480, P < 0.001), left atrial pressure (LAP, r=0.300, P < 0.001), and also negatively correlated with left atrial appendage flow velocity (LAAV, r=-0.252, P=0.002). Multiple linear regression analysis showed that age and LAP affected the GDF-15 levels significantly (P < 0.05). Logistic regression analysis suggested GDF-15 (OR=1.002, 95%CI: 1.001-1.003, P=0.004) and left atrial diameter (LAD, OR=1.400, 95%CI: 1.214-1.616, P < 0.001) were independent predictors of AF. CONCLUSIONS: Serum GDF-15 levels are higher in AF patients. Meanwhile, serum GDF-15 levels are higher in persistent AF patients than paroxysmal AF patients. GDF-15 is associated with AF and atrial structural remodeling.

An Asian-specific MPL genetic variant alters JAK-STAT signaling and influences platelet count in the population.

Genomic discovery efforts for hematological traits have been successfully conducted through genome-wide association study on samples of predominantly European ancestry. We sought to conduct unbiased genetic discovery for coding variants that influence hematological traits in a Han Chinese population. A total of 5257 Han Chinese subjects from Beijing, China were included in the discovery cohort and analyzed by an Illumina ExomeChip array. Replication analyses were conducted in 3827 independent Chinese subjects. We analyzed 12 hematological traits and identified 22 exome-wide significant single-nucleotide polymorphisms (SNP)-trait associations with 15 independent SNPs. Our study provides replication for two associations previously reported but not replicated. Further, one association was identified and replicated in the current study, of a coding variant in the myeloproliferative leukemia (MPL) gene, c.793C > T, p.Leu265Phe (L265F) with increased platelet count (ß = 20.6 109 cells/l, Pmeta-analysis = 2.6 × 10-13). This variant is observed at ~2% population frequency in East Asians, whereas it has not been reported in gnomAD European or African populations. Functional analysis demonstrated that expression of MPL L265F in Ba/F3 cells resulted in enhanced phosphorylation of Stat3 and ERK1/2 as compared with the reference MPL allele, supporting altered activation of the JAK-STAT signal transduction pathway as the mechanism underlying the novel association between MPL L265F and platelet count.

Exercise Training Attenuates Acute ß-Adrenergic Receptor Activation-Induced Cardiac Inflammation via the Activation of AMP-Activated Protein Kinase.

Exercise has proven cardiac benefits, but the underlying mechanisms of exercise that protect the heart from acute sympathetic stress injuries remain unknown. In this study, adult C57BL/6J mice and their AMP-activated protein kinase α2 knockout (AMPKα2-/-) littermates were either subjected to 6 weeks of exercise training or housed under sedentary conditions and then treated with or without a single subcutaneous injection of the ß-adrenergic receptor (ß-AR) agonist isoprenaline (ISO). We investigated the differences in the protective effects of exercise training on ISO-induced cardiac inflammation in wild-type (WT) and AMPKα2-/- mice using histology, enzyme-linked immunosorbent assay (ELISA) and Western blotting analyses. The results indicated that exercise training alleviated ISO-induced cardiac macrophage infiltration, chemokines and the expression of proinflammatory cytokines in wild-type mice. A mechanism study showed that exercise training attenuated the ISO-induced production of reactive oxygen species (ROS) and the activation of NLR Family, pyrin domain-containing 3 (NLRP3) inflammasomes. In cardiomyocytes, the ISO-induced effects on these processes were inhibited by AMP-activated protein kinase (AMPK) activator (metformin) pretreatment and reversed by the AMPK inhibitor (compound C). AMPKα2-/- mice showed more extensive cardiac inflammation following ISO exposure than their wild-type littermates. These results indicated that exercise training could attenuate ISO-induced cardiac inflammation by inhibiting the ROS-NLRP3 inflammasome pathway in an AMPK-dependent manner. Our findings suggested the identification of a novel mechanism for the cardioprotective effects of exercise.

Neuregulin-1 alleviate oxidative stress and mitigate inflammation by suppressing NOX4 and NLRP3/caspase-1 in myocardial ischaemia-reperfusion injury.

Neuregulin-1 (NRG-1) is reported to be cardioprotective through the extracellular-regulated protein kinase (ERK) 1/2 pathway in myocardial ischaemia-reperfusion injury (MIRI). NOX4-induced ROS activated NLRP3 inflammasome and exacerbates MIRI. This study aims to investigate whether NRG-1 can suppress NOX4 by ERK1/2 and consequently inhibit the NLRP3/caspase-1 signal in MIRI. The myocardial infarct size (IS) was measured by TTC-Evans blue staining. Immunohistochemical staining, real-time quantitative PCR (RT-qPCR) and Western blotting were used for detection of the factors, such as NOX4, ERK1/2, NLRP3, caspase-1 and IL-1ß .The IS in the NRG-1 (3 µg/kg, intravenous) group was lower than that in the IR group. Immunohistochemical analysis revealed NRG-1 decreased 4HNE and NOX4. The RT-qPCR and Western blot analyses revealed that NRG-1 mitigated the IR-induced up-regulation of NOX4 and ROS production. Compared with the IR group, the NRG-1 group exhibited a higher level of P-ERK1/2 and a lower level of NLRP3. In the Langendorff model, PD98059 inhibited ERK1/2 and up-regulated the expression of NOX4, NLRP3, caspase-1 and IL-1ß, which exacerbated oxidative stress and inflammation. In conclusion, NRG-1 can reduce ROS production by inhibiting NOX4 through ERK1/2 and inhibit the NLRP3/caspase-1 pathway to attenuate myocardial oxidative damage and inflammation in MIRI.

Ring finger protein 152-dependent degradation of TSPAN12 suppresses hepatocellular carcinoma progression.

BACKGROUND: Hepatocellular carcinoma (HCC) is the third cause of cancer death in the world, and few molecularly targeted anticancer therapies have been developed to treat it. The E3 ubiquitin ligase RNF152 has been reported to regulate the activity of the mechanistic target of rapamycin complex 1 (mTORC1), induce autophagy and apoptosis. However, the relationship between RNF152 and HCC is unclear. METHODS: Transcriptome RNA-sequencing data of HCC samples and normal tissues were used to detect the mRNA expression of RNF152. Luciferase reporter and chromatin immunoprecipitation (ChIP) assays were used to determine the transcriptional regulation of RNF152 in HCC by FoxO1. RNAi, cell proliferation, colony formation and transwell assays were used to determine the in vitro functions of RNF152. Mouse xenograft models were used to study the in vivo effects of RNF152. The immunoprecipitation assay was used to determine the interaction between RNF152 and TSPAN12. The in vivo ubiquitination assay was performed to determine the regulation of TSPAN12 by RNF152. RESULTS: We found that RNF152 is significantly down-regulated in clinic HCC samples, and its down-regulation is associated with pool overall survival (OS), progression-free survival (PFS) and disease-specific survival (DSS) in HCC patients. The transcription factor FoxO1 was significantly positively correlated RNF152 expression in HCC tissues. FoxO1 recognizes a classic insulin response element (IRE) on the RNF152 promoter to regulate its expression in HCC. RNF152 suppressed HCC cell proliferation, clonogenic survival, invasion in vitro, and tumorigenesis in vivo. Mechanistically, RNF152 interacted with TSPAN12 and targeted it for ubiquitination and proteasomal degradation, thereby inhibiting TSPAN12-dependent CXCL6 expression and HCC progression. CONCLUSION: Collectively, our data revealed a tumor suppressor role of RNF152 and a connection between RNF152 and FoxO1 in HCC. Our results support an important role of the FoxO1-RNF152-TSPAN12 axis in the development of HCC. Therapeutic targeting this axis may be an effective means of treating HCC.

Increased hemoglobin A1c level associates with low left atrial appendage flow velocity in patients of atrial fibrillation.

BACKGROUND AND AIMS: High hemoglobin A1c (HbAlc) level is associated with increased cardiovascular disease risk and thromboembolic events [1]. The study sought to explored the association between HbAlc and left atrial appendage flow velocity (LAAV) among non-valvular atrial fibrillation (AF) patients. METHODS AND RESULTS: A total of 249 consecutive non-valvular AF patients who underwent transesophageal echocardiography (TEE) were divided into two subgroups according to the median of LAAV level (<45 cm/s, ≥45 cm/s). Blood samples and other baseline clinical data of all patients were collected and analyzed. The low LAAV group included 126 patients and the high LAAV group included 123 patients. Patients in the low LAAV group were older and had a higher percentage of persistent AF, chronic heart failure, and higher CHA2DS2-VASc score (P < 0.05). HbAlc level in the low LAAV group was significantly higher than the high LAAV group [6.1 (5.7-6.5)% vs 5.9 (5.6-6.2)%, P = 0.010]. The low LAAV group had larger left atrial diameter (LAD), left atrial area (LAA), higher left atrial pressure (LAP), and lower left ventricular ejection fraction (LVEF) (P < 0.05). Spearman rank correlation analysis showed that the HbAlc level was negatively correlated with LAAV (r = -0.211, P = 0.001). Multivariate analysis indicated that female gender (OR = 2.233, 95% CI 1.110-4.492, P = 0.024), persistent AF (OR = 6.610, 95% CI 3.109-14.052, P < 0.001), and HbAlc (OR = 1.903, 95% CI 1.092-3.317, P = 0.023) were independent factors that associated with low LAAV in AF patients. CONCLUSION: Increased HbAlc level is associated with decreased LAAV and may reflect a low contractile function of the left atrial appendage.

Surface charge-dependent mitochondrial response to similar intracellular nanoparticle contents at sublethal dosages.

BACKGROUND: Considering the inevitability for humans to be frequently exposed to nanoparticles (NPs), understanding the biosafety of NPs is important for rational usage. As an important part of the innate immune system, macrophages are widely distributed in vital tissues and are also a dominant cell type that engulfs particles. Mitochondria are one of the most sensitive organelles when macrophages are exposed to NPs. However, previous studies have mainly reported the mitochondrial response upon high-dose NP treatment. Herein, with gold nanoparticles (AuNPs) as a model, we investigated the mitochondrial alterations induced by NPs at a sublethal concentration. RESULTS: At a similar internal exposure dose, different AuNPs showed distinct degrees of effects on mitochondrial alterations, including reduced tubular mitochondria, damaged mitochondria, increased reactive oxygen species, and decreased adenosine triphosphate. Cluster analysis, two-way ANOVA, and multiple linear regression suggested that the surface properties of AuNPs were the dominant determinants of the mitochondrial response. Based on the correlation analysis, the mitochondrial response was increased with the change in zeta potential from negative to positive. The alterations in mitochondrial respiratory chain proteins indicated that complex V was an indicator of the mitochondrial response to low-dose NPs. CONCLUSION: Our current study suggests potential hazards of modified AuNPs on mitochondria even under sublethal dose, indicates the possibility of surface modification in biocompatibility improvement, and provides a new way to better evaluation of nanomaterials biosafety.

Comparison of temporal changes in established cardiovascular biomarkers after acute coronary syndrome between Caucasian and Chinese patients with diabetes mellitus.

Background: Population means of conventional cardiovascular biomarkers are known to differ between ethnic groups. In this study we performed detailed comparisons in the temporal pattern of these biomarkers between Caucasian and Chinese diabetic patients with acute coronary syndrome (ACS).Methods: We studied differences in temporal changes of established cardiovascular biomarkers, including high-density lipoprotein (HDL), low-density lipoprotein (LDL), total cholesterol, cardiac Troponin T (TnT), NT-proBNP and C-reactive protein (CRP), in 48 Chinese and 48 clinically matched Caucasian patients with type 2 diabetes mellitus who were admitted for ACS. Blood samples were collected at regular time intervals during 30 days to 1 year after the index ACS.Results: In the >30 day post ACS period, mean serum levels of LDL (2.16 vs. 1.47 mmol/L; p-value <0.001), total cholesterol (4.08 vs. 3.11 mmol/L; p-value <0.001), TnT (11.0 vs. 7.76 ng/L; p-value 0.010) and CRP (2.0 vs. 0.78 mg/L; p-value <0.001) were systematically higher in Caucasian than in Chinese patients. HDL and NT-proBNP levels were similar.Conclusions: Our study showed clinically relevant differences in levels of established cardiovascular biomarkers between Caucasian and Chinese post ACS patients. Further cross-ethnic studies are warranted to determine secondary prevention treatment biomarker targets in specific populations.

The Predictive Value of Growth Differentiation Factor-15 in Recurrence of Atrial Fibrillation after Catheter Ablation.

The mechanisms underlying the recurrence of atrial fibrillation (AF) after radiofrequency catheter ablation (RFCA) are not well concerned. The study sought to explore the association between growth differentiation factor-15 (GDF-15) and the incidence of recurrent events among AF patients after the ablation procedure. We prospectively included 150 consecutive AF patients who underwent RFCA. Clinical information about the patients was collected. Blood samples on the second morning of hospital admission and three months after RFCA were collected, and enzyme-linked immunosorbent assay (ELISA) was used to measure the concentration of GDF-15. All participants were followed up at specific times (1st/3rd/6th/12th/18th/24th months) after RFCA to record recurrences events. During a median follow-up of 14.0 months, AF recurrence occurred in 37(24.7%) patients. Baseline serum GDF-15 level in the persistent AF group was significantly higher than the paroxysmal AF group [1140(854~1701)ng/L vs. 1062(651~1374)ng/L, P = 0.039]. Baseline serum GDF-15 level in the recurrence group was significantly higher than the nonrecurrence group [1287(889~1768) ng/L vs. 1062(694~1373)ng/L, P = 0.022]. Serum GDF-15 level at three months after RFCA was significantly lower than the baseline [870 (579~1270) ng/L vs. 1155 (735~1632)ng/L, P < 0.001]. The baseline GDF-15 correlated significantly with LAP (r = 0.296, P < 0.001) and LAAV(r = -0.235, P = 0.003). Kaplan-Meier analysis showed a significantly lower event-free survival time in the high baseline GDF-15 (≥1287.3 ng/L) group than the low baseline GDF-15 (<1287.3 ng/L) group (17.1 months vs. 20.4 months, Log Rank P = 0.017). In the multivariate Cox regression, baseline GDF-15(HR 1.053, 95% CI 1.007-1.100, P = 0.022) and LAD (HR 1.124, 95% CI 1.011-1.250, P = 0.030) were independent predictors of AF recurrence after RFCA. Our study indicated increased preprocedural GDF-15 is associated with left atrial remodeling and acts as a predictor of AF recurrence after ablation.

Correlation between Plasma Macrophage Migration Inhibitory Factor Levels and Long-Term Prognosis in Patients with Acute Myocardial Infarction Complicated with Diabetes.

Macrophage migration inhibitory factor (MIF), a widely expressed pleiotropic cytokine, is reportedly involved in several cardiovascular diseases, in addition to inflammatory diseases. Plasma MIF levels are elevated in the early phase of acute cardiac infarction. This study is aimed at investigating the correlation between plasma MIF levels and cardiac function and prognosis in patients with acute ST-segment elevation myocardial infarction (STEMI) with or without diabetes mellitus. Overall, 204 patients with STEMI who underwent emergency percutaneous coronary intervention were enrolled: 57 and 147 patients in the diabetes and nondiabetes STEMI groups, respectively. Sixty-five healthy people were selected as controls. Plasma MIF levels were measured at the time of diagnosis. Basic clinical data and echocardiographic findings within 72 h of admission were collected. Patients were followed up, and echocardiograms were reviewed at the 12-month follow-up. Plasma MIF levels were significantly higher in the diabetes and nondiabetes STEMI groups than in the control group and in patients with Killip grade ≥ II STEMI than in those with Killip grade I. Plasma MIF levels were negatively correlated with the left ventricular ejection fraction (LVEF) of myocardial infarction in patients with or without diabetes in the acute phase of infarction, whereas the left ventricular diastolic dysfunction (LVDD) was positively correlated. MIF levels in the nondiabetes STEMI group were positively correlated with N-terminal pro-b-type natriuretic peptide levels and were associated with LVEF and LVDD at the 12-month follow-up. The risk of adverse cardiovascular and cerebrovascular events was significantly higher in the MIF high-level group (≥52.7 ng/mL) than in the nondiabetes STEMI group 36 months after presentation. Thus, MIF levels in STEMI patients with or without diabetes can reflect acute cardiac function. In STEMI patients without diabetes, MIF levels can also indicate cardiac function and long-term prognosis at the 12-month follow-up.

IL-18 cleavage triggers cardiac inflammation and fibrosis upon ß-adrenergic insult.

Aims: Rapid over-activation of ß-adrenergic receptor (ß-AR) upon stress leads to cardiac inflammation, a prevailing factor that underlies heart injury. However, mechanisms by which acute ß-AR stimulation induce cardiac inflammation still remain unknown. Here, we set out to identify the crucial role of inflammasome/interleukin (IL)-18 in initiating and maintaining cardiac inflammatory cascades upon ß-AR insult. Methods and results: Male C57BL/6 mice were injected with a single dose of ß-AR agonist, isoproterenol (ISO, 5 mg/kg body weight) or saline subcutaneously. Cytokine array profiling demonstrated that chemokines dominated the initial cytokines upregulation specifically within the heart upon ß-AR insult, which promoted early macrophage infiltration. Further investigation revealed that the rapid inflammasome-dependent activation of IL-18, but not IL-1ß, was the critical up-stream regulator for elevated chemokine expression in the myocardium upon ISO induced ß1-AR-ROS signalling. Indeed, a positive correlation was observed between the serum levels of norepinephrine and IL-18 in patients with chest pain. Genetic deletion of IL-18 or the up-stream inflammasome component NLRP3 significantly attenuated ISO-induced chemokine expression and macrophage infiltration. In addition, IL-18 neutralizing antibodies selectively abated ISO-induced chemokines, proinflammatory cytokines and adhesion molecules but not growth factors. Moreover, blocking IL-18 early after ISO treatment effectively attenuated cardiac inflammation and fibrosis. Conclusion: Inflammasome-dependent activation of IL-18 within the myocardium upon acute ß-AR over-activation triggers cytokine cascades, macrophage infiltration and pathological cardiac remodelling. Blocking IL-18 at the early stage of ß-AR insult can successfully prevent inflammatory responses and cardiac injuries.

Enhanced MiR-711 transcription by PPARγ induces endoplasmic reticulum stress-mediated apoptosis targeting calnexin in rat cardiomyocytes after myocardial infarction.

MicroRNA 711 (miR-711) levels in the heart change dynamically after myocardial infarction (MI). As peroxisome proliferator-activated receptor gamma (PPARγ) can upregulate miR-711 in adipocytes and cardiac fibroblasts, this study examined the precise mechanism of PPARγ-mediated miR-711 upregulation and its role in the heart in the early stages after MI. In a rat model of MI induced by left anterior descending coronary artery ligation, immunohistochemical and western blot analyses revealed increased PPARγ expression in cardiomyocyte nuclei after MI. PPARγ modulated miR-711 levels in neonatal rat cardiomyocytes, and chromatin immunoprecipitation and luciferase assays revealed that it bound the premiR-711 promoter to upregulate miR-711. Bioinformatics analysis identified calnexin as a putative miR-711 target; this was confirmed by luciferase, western blot, and real-time polymerase chain reaction analyses. Additionally, the transfection of a miR-711 mimic into cardiomyocytes induced the endoplasmic reticulum (ER) stress-induced apoptosis response by upregulating glucose-regulated protein 78 (GRP78), activating transcription factor (ATF6), spliced X-box binding protein 1 (XBP1), apoptotic signal-regulating kinase 1 (ASK1), CCAAT-enhancer binding protein homologous protein (CHOP), caspase-12, and endoplasmic reticulum oxidoreductase 1 alpha (ERO1a). Similarly, on day 2 after MI, increased miR-711 levels in the heart were accompanied by increased cardiomyocyte apoptosis, decreased calnexin levels, and increased levels of GRP78, ATF6, spliced XBP1, ASK1, CHOP, and caspase-12, as well as cardiomyocytes apoptosis. The mechanism underlying these effects may involve the direct binding of PPARγ to the pre-miR-711 promoter for the upregulation of miR-711, which may induce ER stress-mediated cardiomyocyte apoptosis via calnexin. These findings augment the general knowledge of the post-MI pathological process and suggest a therapeutic strategy for cardiac remodelling in the early stages after MI.

Pharmacological postconditioning with Neuregulin-1 mimics the cardioprotective effects of ischaemic postconditioning via ErbB4-dependent activation of reperfusion injury salvage kinase pathway.

BACKGROUND: The protective effect of Neuregulin-1 (NRG-1) on heart failure is well established. In this study, we assessed whether NRG-1 could protect the heart by mimicking the cardioprotective effects of ischaemic postconditioning (IP). METHODS: We used a myocardial reperfusion injury rat model in vivo to compare the cardioprotective effects of NRG-1(3 µg/kg, iv. at the onset of reperfusion) and IP. In Langendorff isolated heart perfusion experiments, we used the erythroblastic leukaemia viral oncogene homolog 4 (ErbB4) inhibitor AG1478, a phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 and a mitogen-activated protein/extracellular signal regulated kinase (MEK) inhibitor PD98059 to clarify whether the protective effects of NRG-1and IP depend on the NRG-1/ErbB4 signals and the reperfusion injury salvage kinase (RISK) pathway. Infarct size was detected by Evans blue and TTC. Apoptosis was detected by TUNEL assays. The expression of NRG-1/ErbB4 and downstream ERK1/2, AKT, AMPK and p70s6K were detected by western blotting. Hematoxylin/eosin (H&E) staining was used for histological analysis. RESULTS: We found that NRG-1 and IP had similar effects on reducing myocardial infarct size and apoptosis in vivo. NRG-1 heart protein levels were upregulated in the IP group. Phosphorylation of AKT, ERK1/2 and ErbB4 were also increased in both the IP and NRG-1 groups. Furthermore, in Langendorff analyses, the ErbB4 inhibitor AG1478 suppressed the phosphorylation of ErbB4 and the RISK pathway and aggravated myocardial edema and fiber fracture, thereby inhibited the cardioprotective effects in both the IP and NRG-1 groups. For assessment of downstream signals, the PI3K inhibitor LY294002 and the MEK inhibitor PD98059 suppressed the phosphorylation of AKT and ERK1/2 respectively and abolished the cardioprotective effects induced by IP and NRG-1. CONCLUSION: In conclusion, both IP and NRG-1 could reduce infarct size and apoptosis through ErbB4-dependent activation of the RISK pathway in the same model; these results indicated the therapeutic potential of NRG-1 as a pharmacological postconditioning agent against myocardial reperfusion injury.

Plasma Catestatin in Patients with Acute Coronary Syndrome.

OBJECTIVES: To measure plasma catestatin levels in patients with acute coronary syndrome and investigate whether there is an association between catestatin levels and long-term outcome. METHODS: Patients (n = 170) with suspected acute coronary syndrome who underwent emergency coronary angiography were enrolled, including 46 with acute ST-segment elevation myocardial infarction (STEMI), 89 with unstable angina pectoris (UAP), and 35 without coronary artery disease (CAD). All patients were followed for 2 years to measure the occurrence of major adverse cardiovascular events (MACEs), including death from a cardiovascular cause, recurrent acute myocardial infarction, or hospital admission for heart failure or revascularization. RESULTS: On average, the plasma catestatin levels in patients with STEMI (0.80 ± 0.62 ng/ml) and UAP (0.99 ± 0.63 ng/ml) were significantly lower than the levels seen in the control group with no evidence of CAD (1.38 ± 0.98 ng/ml; p = 0.001). In multivariable linear regression, body mass index, presence of hypertension, and type of CAD were independently related to the plasma catestatin level. However, there were no significant differences in MACEs between patients with high and low levels of catestatin. CONCLUSIONS: The plasma catestatin levels in patients with STEMI and UAP were lower than the levels seen in patients without CAD.

Effect of high temperature on immune response of grass carp (Ctenopharyngodon idellus) by transcriptome analysis.

Exposure to high temperature is an inherent feature of grass carp culture in southern China and juvenile grass carps are predisposed to infectious disease in this condition. To understand how high temperature impacts the immune response to pathogens in grass carp, the transcriptomic profiles of the spleens from immune injected grass carp groups undergoing heat stress and normal temperature were investigated. An average of 72 million clean reads per library was obtained, and approximate 80% of these genes were successfully mapped to the reference genome. A total of 2287 up-regulated and 1068 down-regulated genes were identified. 10 immune-related categories involving 90 differently expressed genes were scrutinized. Expression patterns of 18 differentially expressed genes involving in immune response were validated by quantitative real-time RT-PCR. These results provide further significant insights into the influence mechanism of high temperature to immune response in grass carp.

Long-term outcome following thulium vaporesection of the prostate.

BACKGROUND: The continuous wave 2-µm Thulium Laser has been introduced as potential technology with both high efficiency and safe practice; although little data have been shown regarding the long-term outcomes. OBJECTIVE: To analyze the long-term outcomes after thulium vaporesection of the prostate (ThuVaRP). METHODS: ThuVaRP was performed using the continuous wave, 2-µm Thulium: YAG laser at 70 W. The perioperative and post-operative follow-up data were analyzed. RESULTS: The average age at surgery was 71.5 (range 55-94 years). The median prostate size was 60.1 g (range 36.3-109.8 g). A median operation time was noted at 44.8 ± 6.5 minutes, while the median catheterization time was 3.5 ± 0.5 days. In regards to hospital stay, most patients had an average duration of 5.5 ± 1.5 days. Minor complications requiring non-interventional treatment happened in 237 (36.24%) of 654 patients, while major complications requiring re-interventions occurred in one patient (0.15%). During a 60-month follow-up, bladder neck fibrosis occurred in 1.22% of the patients. A BPH recurrence happened in 17 (2.60%) patients, of which 14 patients (2.14%) received a second surgery. In comparison to the pre-operative baseline, the patients Qmax, PVR volume, IPSS, and Qol scores all improved significantly (P < 0.01) at time of discharge. This continued into the post-operative follow-up visits (3-6-12-18-14-26-48-60 months). CONCLUSIONS: ThuVaRP is both an effective and safe treatment procedure for symptomatic BPO (with a low occurrence of complications). Lasers Surg. Med. 48:505-510, 2016. © 2016 Wiley Periodicals, Inc.