Uncovering strain- and age-dependent innate immune responses to SARS-CoV-2 infection in air-liquid-interface cultured nasal epithelia.

Continuous assessment of the impact of SARS-CoV-2 on the host at the cell-type level is crucial for understanding key mechanisms involved in host defense responses to viral infection. We investigated host response to ancestral-strain and Alpha-variant SARS-CoV-2 infections within air-liquid-interface human nasal epithelial cells from younger adults (26-32 Y) and older children (12-14 Y) using single-cell RNA-sequencing. Ciliated and secretory-ciliated cells formed the majority of highly infected cell-types, with the latter derived from ciliated lineages. Strong innate immune responses were observed across lowly infected and uninfected bystander cells and heightened in Alpha-infection. Alpha highly infected cells showed increased expression of protein-refolding genes compared with ancestral-strain-infected cells in children. Furthermore, oxidative phosphorylation-related genes were down-regulated in bystander cells versus infected and mock-control cells, underscoring the importance of these biological functions for viral replication. Overall, this study highlights the complexity of cell-type-, age- and viral strain-dependent host epithelial responses to SARS-CoV-2.

Evaluation of the mental health status of community frontline medical workers after the normalized management of COVID-19 in Sichuan, China.

Background: During the coronavirus disease 2019 (COVID-19) pandemic, community medical workers, as the primary enforcers of community control measures, undertook many tasks with high exposure risk, resulting in severe psychological pressure, anxiety, depression and other psychological problems. Gender, type of workers, education, marital status, working years and other demographic factors were affect the mental state of medical workers. Community frontline medical workers gradually returned to normal work and life after the normalized management of COVID-19, but heavy work and high psychological pressure may continue to affect them. Thus, our research team used the same psychological questionnaire to investigate the psychological status of community frontline medical workers after the normalized management of COVID-19 compared with the COVID-19 period. Methods: This was a cross-sectional study of community frontline medical workers in Sichuan, China, from February 6 to 17, 2023. Symptom Checklist-90 (SCL-90) and a self-designed questionnaire of demographic characteristics were provided to the participants point-to-point through a mobile network platform. Multiple logistic regression was used to analyze influencing factors related to community frontline medical workers' psychology. Results: A total of 440 valid questionnaires were statistically analyzed, including 192 (43.64%) from doctors and 248 (56.36%) from nurses. There were 222 (50.45%) participants who were SCL-90 positive. The median total SCL-90 score of medical workers was 105.0 (IQR 95.00-123.75), which was higher than that during the COVID-19 period. The doctor's median SCL-90 score was 108.5 (IQR 96.00-136.25), and the positive item score was 16.5; the nurse's median score was 104.0 (IQR 94.00-119.50), and the positive item score was 12.0. Bachelor's degree education, no fixed contract and working years (10-19 years, 20-29 years, 30-39 years) were independent influencing factors for community frontline medical workers' psychology. Conclusion: After the normalized management of COVID-19, community frontline medical workers still suffered from psychological problems that were even more serious than those during COVID-19. Doctors were more likely to have psychological problems than nurses. In addition, the mental health status of community frontline medical workers was affected by education, type of contract and working years. Managers should pay attention to the mental health of these people.

Visible Light-Mediated Organoboron-Catalyzed Metal-Free Synthesis of Silanols from Silanes.

Herein, a four-coordinated organoboron compound, aminoquinoline diarylboron (AQDAB), is utilized as the photocatalyst in the oxidation of silane to silanol. This strategy effectively oxidizes Si-H bonds, affording Si-O bonds. Generally, the corresponding silanols can be obtained in moderate to good yields at room temperature under oxygen atmospheres, representing a green protocol to complement the existing preparation methods for silanols.

Effect of statin use on risk and mortality of gastric cancer: a meta-analysis.

The effect of statins on gastric cancer risk is still controversial. And studies on the association between statins and gastric cancer mortality are very limited. Therefore, we conducted this systemic review and meta-analysis to evaluate the association between the use of statin and gastric cancer. Searched studies were published before November 2022. Odds ratios (ORs)/relative risks (RRs) or hazard ratios (HRs) and their 95% confidence intervals (CIs) were computed using STATA 12.0 software. The study showed that the statin use group showed a significantly lower risk of gastric cancer, compared to no statin use group (OR/RR, 0.74; 95% CI: 0.67-0.80, P  < 0.001). The study showed that the statin use group showed significantly lower all-cause mortality and cancer-specific mortality of gastric cancer, compared to no statin use group (all-cause mortality: HR, 0.70; 95% CI: 0.52-0.95, P  = 0.021; cancer-specific mortality: HR, 0.70; 95% CI: 0.58-0.84, P  < 0.001). Overall, results from this meta-analysis showed the protective effect of statins exposure on the risk and prognosis of gastric cancer; however, we still need more well designed, large-scale studies and randomized clinical trials to pinpoint the effect of statins on gastric cancer in future clinical practice.

Accuracy of Raman spectroscopy in the diagnosis of Alzheimer's disease.

Objective: To systematically evaluate the accuracy of Raman spectroscopy in the diagnosis of Alzheimer's disease. Methods: Databases including Web of Science, PubMed, The Cochrane Library, EMbase, CBM, CNKI, Wan Fang Data, and VIP were electronically searched for studies on Raman spectroscopy in diagnosis of Alzheimer's disease from inception to November 2022. Two reviewers independently screened the literature, extracted data, and assessed the risk of bias in the included studies. Then, meta-analysis was performed using Meta-Disc1.4 and Stata 16.0 software. Results: A total of eight studies were finally included. The pooled sensitivity of Raman spectroscopy was 0.86 [95% CI (0.80-0.91)], specificity was 0.87 [95% CI (0.79-0.92)], positive likelihood ratio was 5.50 [95% CI (3.55-8.51)], negative likelihood ratio was 0.17 [95% CI (0.09-0.34)], diagnosis odds ratio and area under the curve of SROC were 42.44 [95% CI (19.80-90.97)] and 0.931, respectively. Sensitivity analysis was carried out after each study was excluded one by one, and the results showed that pooled sensitivity and specificity had no significant change, indicating that the stability of the meta-analysis results was great. Conclusions: Our findings indicated that Raman spectroscopy had high accuracy in the diagnosis of AD, though it still did not rule out the possibility of misdiagnosis and missed diagnosis. Limited by the quantity and quality of the included studies, the above conclusions need to be verified by more high-quality studies.

Chlorination of trichlorosilane/chlorodimethylsilane using metal chlorides: experimental and mechanistic investigations.

Removal of carbonaceous impurities from trichlorosilane (SiHCl3) reduces the carbon content of solar grade polysilicon produced with the improved Siemens method. The separation of chlorodimethylsilane (CH3)2SiHCl from SiHCl3 by distillation remains challenging due to the small difference in their boiling points. Herein, the chlorination of (CH3)2SiHCl/SiHCl3 with metal chlorides (WCl6, MoCl5) were studied. The aim was to convert (CH3)2SiHCl into (CH3)2SiCl2, increase the relative volatility of (CH3)2SiHCl and SiHCl3 and facilitate the distillation. The optimum reaction conditions were 60 °C, 60 min and n(WCl6 or MoCl5): n(SiHCl3 or (CH3)2SiHCl) = 0.7 at 0.8 MPa. Under these conditions, and when WCl6 and MoCl5 were used as the chlorine sources, the extents of (CH3)2SiHCl conversion were 22.7 and 18.5 times higher than those of SiHCl3, respectively. In addition, a mechanistic study showed that the difference between the reactions of SiHCl3 and (CH3)2SiHCl resulted from the different energy barriers for the reactions of the and (CH3)2SiCl· radicals with WCl x or MoCl x , and the barrier for the reaction was higher than that for the (CH3)2SiCl· reaction.

Nonlinear motor-mechanism coupling tank gun control system based on adaptive radial basis function neural network optimised computed torque control.

This study investigates the spatial pointing control of a motor-mechanism coupling tank gun. The tank gun control system (TGCS) is driven and stabilised by the motor servo system. However, complicated nonlinearities in the TGCS are inevitable, such as friction, parameter uncertainty, and modelling errors. To solve this problem, the TGCS is regarded as a coupling system composed of mechanical, motor, and control systems. Accordingly, the mechanical and motor models of the marching tank gun are developed first in this paper. The motor-mechanism coupling dynamics model is established based on the principle of equivalent torque. On this basis, a computed torque controller, whose uncertainty was estimated using a radial basis function neural network (RBFNN), is constructed. A modified adaptive algorithm is used to estimate the weights of the RBFNN, and the estimation error of the uncertain observer is compensated by a compensation controller. Simulation results under different conditions validated the effectiveness of the proposed control system, revealing that the proposed control system has good tracking accuracy, strong adaptability, and robustness.

Evaluation of Carbon Nanoparticle Suspension and Methylene Blue Localization for Preoperative Localization of Nonpalpable Breast Lesions: A Comparative Study.

Background: The resection of nonpalpable breast lesions (NPBLs) largely depends on the preoperative localization technology. Although several techniques have been used for the guidance of NPBL resection, more comfortable and effective methods are needed. This aim of this study was to evaluate the use and feasibility of carbon nanoparticle suspension (CNS) and methylene blue (MB)-guided resection of NPBL, to introduce alternative techniques. Methods: A total of 105 patients with 172 NPBLs detected by breast ultrasound were randomized to CNS localization (CNSL) group and MB localization (MBL) group. The injection times of the two groups were divided into 2, 4, 6, 12, 16, and 20 h before surgery. In this study, localization time, stained area, operation time, total resection volume (TRV), calculated resection ratio (CRR), and pathological diagnosis were assessed. Results: All of the 172 lesions were finally confirmed benign. Dye persisted in all cases in the CNSL group (109/109, 100%), while that persisted in only 53 cases in the MBL group (53/63, 84.1%) (P < 0.001). There was a significant correlation between dyeing time and dyeing area in the MBL group (r = -0.767, P < 0.001); however, there was no significant correlation in the CNSL group (r = -0.154, P = 0.110). The operation time was 11.05 ± 3.40 min in the CNSL group and 13.48 ± 6.22 min in the MBL group (P < 0.001). The TRV was 2.51 ± 2.42 cm3 in the CNSL group and 3.69 ± 3.24 cm3 in the MBL group (P = 0.016). For CRR, the CNSL group was lower than the MBL group (7.62 ± 0.49 vs. 21.93 ± 78.00, P = 0.018). There is no dye remained on the skin in the MBL group; however, dye persisted in 12 patients (19.4%) in the CNSL group (P = 0.001). Conclusion: Carbon nanoparticle suspension localization and MBL are technically applicable and clinically acceptable procedures for intraoperatively localizing NPBL. Moreover, given the advantages of CNSL compared to MBL, including the ability to perform this technique 5 days before operation and smaller resection volume, it seems to be a more attractive alternative to be used in intraoperative localization of NPBL.

Evaluation of the mental health status of community healthcare workers during the COVID-19 outbreak.

ABSTRACT: Coronavirus disease 2019 (COVID-19) has rapidly spread across China and many countries worldwide, and community healthcare workers at the front lines of disease control are under high physical and mental pressure. This study investigated the mental health status of community healthcare workers during the COVID-19 outbreak in Sichuan Province, China. This cross-sectional study, which was conducted from February 8 to 18, 2020, involved 450 healthcare workers in 18 community hospitals who had worked for more than 1 year. A self-designed demographic data questionnaire and Symptom Checklist 90 (SCL-90) were provided to the participants through links and quick response codes. The respondents completed and submitted the questionnaires online. Binary logistic regression was used to analyze multiple factors related to the SCL-90 scores of these community healthcare workers in China. For the 450 community healthcare workers who completed the study, the median scores in each SCL-90 factor were lower than the Chinese norms, and 119 (26.4%) participants were SCL-90 positive. Among them, 178 participants were doctors and had the highest scores on most SCL-90 factors except for obsessive compulsiveness, hostility, phobic anxiety, and psychoticism (P < 0.05). The top 3 positive items for doctors working in the community were obsessive compulsiveness, others, and somatization, and those among nurses were obsessive compulsiveness, others, and hostility. Sex, type of workers, and occupational exposure risk to COVID-19 were independent risk factors for the mental health status of the community healthcare workers. Overall, the community healthcare workers experienced psychological problems during the COVID-19 outbreak in Sichuan Province, China. More attention should be paid to the mental health of these workers, and their mental status should be regularly assessed. Psychological interventions should be provided to those with serious mental problems through networks or telephone visits.

DCA-TGR5 signaling activation alleviates inflammatory response and improves cardiac function in myocardial infarction.

AIMS: The progression of myocardial infarction (MI) involves multiple metabolic disorders. Bile acid metabolites have been increasingly recognized as pleiotropic signaling molecules that regulate multiple cardiovascular functions. G protein-coupled bile acid receptor (TGR5) is one of the receptors sensing bile acids to mediate their biological functions. In this study, we aimed to elucidate the effects of bile acids-TGR5 signaling pathways in myocardial infarction (MI). METHODS AND RESULTS: Blood samples of AMI patients or control subjects were collected and plasma was used for bile acid metabolism analysis. We discovered that bile acid levels were altered and deoxycholic acid (DCA) was substantially reduced in the plasma of AMI patients. Mice underwent either the LAD ligation model of MI or sham operation. Both MI and sham mice were gavaged with 10 mg/kg/d DCA or vehicle control since 3-day before the operation. Cardiac function was assessed by ultrasound echocardiography, infarct area was evaluated by TTC staining and Masson trichrome staining. Administration of DCA improved cardiac function and reduced ischemic injury at the 7th-day post-MI. The effects of DCA were dependent on binding to its receptor TGR5. Tgr5-/- mice underwent the same MI model. Cardiac function deteriorated and infarct size was increased at the 7th-day post-MI, which were not savaged by DCA administration. Moreover, DCA inhibited interleukin (IL)-1ß expression in the infarcted hearts, and ameliorated IL-1ß activation at 1-day post-MI. DCA inhibited NF-κB signaling and further IL-1ß expression in cultured neonatal mouse cardiomyocytes under hypoxia as well as cardio-fibroblasts with the treatment of LPS. CONCLUSIONS: DCA-TGR5 signaling pathway activation decreases inflammation and ameliorates heart function post-infarction. Strategies that control bile acid metabolism and TGR5 signaling to ameliorate the inflammatory responses may provide beneficial effects in patients with myocardial infarction.

Synthesis of nano-octahedral MgO via a solvothermal-solid-decomposition method for the removal of methyl orange from aqueous solutions.

Nano magnesium oxide has wide applications, and MgO with (111) facets has wider potential applications than MgO with (100) facets (e.g., in catalysis and adsorption). However, nano MgO with (111) polar faces has not been studied throughly, so the preparation of nano-octahedral MgO (N-O-MgO) with eight exposed (111) facets remains a great challenge. Herein, we successfully synthesised N-O-MgO via an effective solvothermal-solid-decomposition method and studied its adsorption performance. The obtained N-O-MgO showed excellent performance (229.36 mg g-1) for methyl orange (MO). The adsorption follows the pseudo-second-order kinetic equation and the Langmuir isotherm model. The dimensionless parameter R L (0.042) and Gibbs free energy ΔG (-6.538 kJ mol-1) revealed that the adsorption of MO on N-O-MgO was a spontaneous and feasible process. The adsorption of MO and methyl blue (MB) on N-O-MgO were studied to determine the adsorption sites. Based on these experiments and analysis, it was determined that the adsorption sites were magnesium ions and the adsorption mechanism was proposed to describe the adsorption process.

Constructing Unique Cross-Sectional Structured Mixed Matrix Membranes by Incorporating Ultrathin Microporous Nanosheets for Efficient CO2 Separation.

Ultrathin microporous nanosheets denoted as Zn-tetra-(4-carboxyphenyl)porphyrin (Zn-TCPP) were synthesized and incorporated into a Pebax MH 1657 (Pebax) polymer to fabricate mixed matrix membranes (MMMs) for efficient CO2 separation. The Zn-TCPP nanosheets with a microporous structure provide high-speed channels for fast CO2 transport and shorten the diffusion pathways, both contributing toward high CO2 permeability. Furthermore, scanning electron microscopy results indicate that the ultrathin Zn-TCPP nanosheets with an ultrahigh aspect ratio (>200) tend to arrange horizontally in the Pebax matrix. The obtained unique cross-sectional structure of the MMMs functions as a selective barrier, allowing repeated discrimination of gases due to the tortuous interlayer of horizontal nanosheets, thus improving the selectivity of the MMMs. In addition, the horizontally arranged microporous nanosheets were found to strongly interact with the membrane matrix and endowed the MMMs with excellent interfacial compatibility, which improved the CO2 permeability and eliminated unselective permeation pathways. Significantly, the optimized CO2 separation performance of the MMMs surpassed the 2008 Robeson's limit.

Public mobilisation in implementation of smoke-free Beijing: a social media complaint platform.

In November 2014, Beijing People's Congress adopted the Beijing Smoking Control Ordinance and a key provision bans smoking in all indoor public places, workplaces and on public transport. To ensure effective implementation of the ordinance, the government calls on the whole society to take part. In response, Beijing Tobacco Control Association, with the support of a local technology company, developed the Beijing Tobacco Control Map, a digital system that enables comprehensive tobacco control information collection, data visualisation and mapping. A key component of the Beijing Tobacco Control Map is the Complaint Map which is generated by the data of reported violations of the smoke-free provisions by the general public through a social media platform. The Complaint Map visually displays the reported violations on a map of Beijing in real time. The general public can access the Complaint Map at any time to see which venues and locations have been reported. It is used by tobacco control volunteers, who are recruited and trained to address complaints and promote compliance. It is also used by the government's enforcement team for targeted inspections. The Complaint Map has effectively engaged the public and promoted a smoke-free Beijing. Beijing's innovative and systematic approach that involves the Complaint Map, volunteer management, coordination with the enforcement team, and media exposure can be replicated or adapted in other cities in China and abroad that are implementing smoke-free laws or tobacco control laws in general.

Multivisceral IgG4-related disease presenting as recurrent massive gastrointestinal bleeding: a case report and literature review.

BACKGROUND: IgG4-related disease (IgG4-RD) is a newly recognized autoimmune systemic disorder characterized by elevated levels of serum IgG4 and abundant infiltration of IgG4-positive plasmacytes in the affected organs. The liver, biliary system and pancreas are the most commonly affected organs. However, involvement of the digestive tract is very rare. To date, only a few cases of isolated gastric IgG4-RD have been reported. CASE PRESENTATION: We present a case of IgG4-RD of the liver, gallbladder, pancreas and duodenum, which was clinically misinterpreted and thereafter over-treated. A 52-year-old male presented with obstructive jaundice for 3 years, melena for 5 months and hematemesis for 10 days. Three years prior, the patient had undergone biopsies of pancreatic lesions, liver lesions, cholecystectomy and choledochojejunostomy. Histopathology showed chronic inflammatory changes. Endoscopy at admission revealed a duodenal ulcer with active bleeding. Despite medical management, the patient presented with repeated gastrointestinal bleeding. Upon evaluation, serum IgG4 levels were found to be elevated. Histopathology of the duodenal ulcer biopsy and repeated examination of the gallbladder and pancreatic and liver biopsies confirmed IgG4 positive plasma cell infiltration. A definitive diagnosis of IgG4-RD was made and steroid administration was initiated. At last follow up, 11 months to-the-day after initiating steroid treatment, the patient was asymptomatic. CONCLUSIONS: Notably, IgG4-RD of multiple digestive organs is still very rare. As a systemic disease, it is characterized by the infiltration of IgG4-bearing plasma cells and raised IgG4 levels. Histopathology findings remain the diagnostic gold standard for this disorder.

Cardiac Hypertrophy is Positively Regulated by MicroRNA­24 in Rats

Background: MicroRNA-24 (miR-24) plays an important role in heart failure by reducing the efficiency of myocardial excitation-contraction coupling. Prolonged cardiac hypertrophy may lead to heart failure, but little is known about the role of miR-24 in cardiac hypertrophy. This study aimed to preliminarily investigate the function of miR-24 and its mechanisms in cardiac hypertrophy. Methods: Twelve Sprague-Dawley rats with a body weight of 50 ± 5 g were recruited and randomly divided into two groups: a transverse aortic constriction (TAC) group and a sham surgery group. Hypertrophy index was measured and calculated by echocardiography and hematoxylin and eosin staining. TargetScans algorithm-based prediction was used to search for the targets of miR-24, which was subsequently confirmed by a real-time polymerase chain reaction and luciferase assay. Immunofluorescence labeling was used to measure the cell surface area, and 3H-leucine incorporation was used to detect the synthesis of total protein in neonatal rat cardiac myocytes (NRCMs) with the overexpression of miR-24. In addition, flow cytometry was performed to observe the alteration in the cell cycle. Statistical analysis was carried out with GraphPad Prism v5.0 and SPSS 19.0. A two-sided P < 0.05 was considered as the threshold for significance. Results: The expression of miR-24 was abnormally increased in TAC rat cardiac tissue (t = -2.938, P < 0.05). TargetScans algorithm-based prediction demonstrated that CDKN1B (p27, Kip1), a cell cycle regulator, was a putative target of miR-24, and was confirmed by luciferase assay. The expression of p27 was decreased in TAC rat cardiac tissue (t = 2.896, P < 0.05). The overexpression of miR-24 in NRCMs led to the decreased expression of p27 (t = 4.400, P < 0.01), and decreased G0/G1 arrest in cell cycle and cardiomyocyte hypertrophy. Conclusion: MiR-24 promotes cardiac hypertrophy partly by affecting the cell cycle through down-regulation of p27 expression.

Mixed matrix membranes with fast and selective transport pathways for efficient CO2 separation.

To improve CO2 separation performance, porous carbon nanosheets (PCNs) were used as a filler into a Pebax MH 1657 (Pebax) matrix, fabricating mixed matrix membranes (MMMs). The PCNs exhibited a preferential horizontal orientation within the Pebax matrix because of the extremely large 2D plane and nanoscale thickness of the matrix. Therefore, the micropores of the PCNs provided fast CO2 transport pathways, which led to increased CO2 permeability. The reduced pore size of the PCNs was a consequence of the overlapping of PCNs and the polymer chains penetrating into the pores of the PCNs. The reduction in the pore size of the PCNs improved the CO2/gas selectivity. As a result, the CO2 permeability and CO2/CH4 selectivity of the Pebax membrane with 10 wt% PCNs-loading (Pebax-PCNs-10) were 520 barrer and 51, respectively, for CO2/CH4 mixed-gas. The CO2 permeability and CO2/N2 selectivity of the Pebax-PCNs-10 membrane were 614 barrer and 61, respectively, for CO2/N2 mixed-gas.

Metformin attenuates angiotensin II-induced TGFß1 expression by targeting hepatocyte nuclear factor-4-α.

BACKGROUND AND PURPOSE: Metformin, a small molecule, antihyperglycaemic agent, is a well-known activator of AMP-activated protein kinase (AMPK) and protects against cardiac fibrosis. However, the underlying mechanisms remain elusive. TGFß1 is a key cytokine mediating cardiac fibrosis. Here, we investigated the effects of metformin on TGFß1 production induced by angiotensin II (AngII) and the underlying mechanisms. EXPERIMENTAL APPROACH: Wild-type and AMPKα2-/- C57BL/6 mice were injected s.c. with metformin or saline and infused with AngII (3 mg·kg-1 ·day-1 ) for 7 days. Adult mouse cardiac fibroblasts (CFs) were isolated for in vitro experiments. KEY RESULTS: In CFs, metformin inhibited AngII-induced TGFß1 expression via AMPK activation. Analysis using bioinformatics predicted a potential hepatocyte nuclear factor 4α (HNF4α)-binding site in the promoter region of the Tgfb1 gene. Overexpressing HNF4α increased TGFß1 expression in CFs. HNF4α siRNA attenuated AngII-induced TGFß1 production and cardiac fibrosis in vitro and in vivo. Metformin inhibited the AngII-induced increases in HNF4α protein expression and binding to the Tgfb1 promoter in CFs. In vivo, metformin blocked the AngII-induced increase in cardiac HNF4α protein levels in wild-type mice but not in AMPKα2-/- mice. Consequently, metformin inhibited AngII-induced TGFß1 production and cardiac fibrosis in wild-type mice but not in AMPKα2-/- mice. CONCLUSIONS AND IMPLICATIONS: HNF4α mediates AngII-induced TGFß1 transcription and cardiac fibrosis. Metformin inhibits AngII-induced HNF4α expression via AMPK activation, thus decreasing TGFß1 transcription and cardiac fibrosis. These findings reveal a novel antifibrotic mechanism of action of metformin and identify HNF4α as a new potential therapeutic target for cardiac fibrosis. LINKED ARTICLES: This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc.

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.

AMPK-KLF2 signaling pathway mediates the proangiogenic effect of erythropoietin in endothelial colony-forming cells.

Endothelial colony-forming cells (ECFCs) were proved to take part in postnatal vasculogenesis and injury repair. The angiogenic properties of ECFCs could be influenced by various cytokines, chemokines, and growth factors. Erythropoietin (EPO) is a promising cytokine participating in angiogenesis. However, the mechanisms for EPO's proangiogenic effect still remain largely elusive. Here, we investigated the role of the AMP-activated protein kinase (AMPK)-Krüppel-like factor 2 (KLF2) signaling pathway in the proangiogenic effect of EPO in ECFCs. Human ECFCs were isolated from cord blood and cultured. EPO significantly enhanced the migration and tube formation capacities of ECFCs and markedly increased the expression of endothelial markers and vascular endothelial growth factor (VEGF). Further, EPO caused the phosphorylation of AMPK and endothelial nitric oxide synthase, a process in which KLF2 was also upregulated on both mRNA and protein levels. The upregulation of KLF2 was blocked by inhibiting AMPK with Compound C or Ad-AMPK-DN, a recombinant adenovirus that encoded a dominant-negative mutant of AMPK. Furthermore, knockdown of KLF2 showed no effect on AMPK but abolished the EPO-enhanced migration and tube formation capacities of ECFCs. Of note, knockdown of KLF2 also diminished the EPO-induced expression of endothelial markers and VEGF; overexpression of KLF2 promoted the expression of endothelial markers and VEGF and enhanced the migration and tube formation capacities of ECFCs. These data suggest that upregulation of KLF2 by AMPK plays an essential role in EPO-induced angiogenesis.

Different roles of ß-arrestin and the PKA pathway in mitochondrial ROS production induced by acute ß-adrenergic receptor stimulation in neonatal mouse cardiomyocytes.

Reactive oxygen species (ROS) play a crucial role in various physiological and pathological processes mediated by ß-adrenergic receptors (ß-ARs) in cardiomyocytes. However, the sources and signaling pathways involved in ROS production induced by acute ß-AR activation have not yet been fully defined. In primary neonatal mouse cardiomyocytes (NMCMs), the ß-AR agonist isoproterenol (ISO) induced a rapid increase in mitochondrial ROS and total ROS production. Both the expression and activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2/4 (NOX 2/4) remained unchanged after 2 h of ISO treatment, suggesting that acute ISO stimulation mainly induces mitochondrial ROS production in NMCMs. Knockdown of ß-arrestin1, but not ß-arrestin2, inhibited ISO-induced mitochondrial ROS production within 1-2 h after ISO treatment. Moreover, forskolin, an adenylyl cyclase (AC) activator, rapidly increased mitochondrial ROS as early as 15 min after ISO treatment. Inhibition of the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway abolished the mitochondrial ROS production within 15-60 min after ISO treatment. In conclusion, mitochondria are the major source of ROS production upon acute ISO stimulation. ß-arrestin1, but not ß-arrestin2, is involved in ISO-induced mitochondrial ROS production. Upon acute ß-AR stimulation in NMCMs, the classical cAMP/PKA pathway is responsible for faster mitochondrial ROS production, whereas ß-arrestin1 signaling is responsible for slower mitochondrial ROS production.