miR-124 delivered by BM-MSCs-derived exosomes targets MCT1 of tumor-infiltrating Treg cells and improves ovarian cancer immunotherapy.

Metabolic rewiring of tumor cells leads to an enrichment of lactate in the tumor microenvironment (TME). This lactate-rich environment of solid tumors has been reported to support tumor-infiltrating regulatory T (Treg) cells. Therefore, agents that modify the lactate metabolism of Treg cells have therapeutic potential. Monocarboxylate transporter 1 (MCT1), which Treg cells predominantly express, plays an essential role in the metabolism of tumor-infiltrating Treg cells. In this study, we show that miR-124 directly targets MCT1 and reduces lactate uptake, eventually impairing the immune-suppressive capacity of Treg cells. Particularly, exosomal miR-124 derived from bone marrow mesenchymal stromal cells (BM-MSCs) slows tumor growth and increases response to PD-1 blockade therapy. These data indicate a potential treatment strategy for improving immune checkpoint blockade therapy using miR-124-carried BM-MSCs-derived exosomes.

Effect of pocket irrigation with antimicrobial on prevention of pacemaker pocket infection: a meta-analysis.

BACKGROUND: The presence of cardiac implantable electronic devices (CIEDs) pocket infection is difficult to treat, causing serious clinical outcomes, but little is known for prevention. Results from some studies suggested that pocket irrigation could reduce infection while others showed conflicting results. We pooled the effects of pocket irrigations on the prevention of pocket infection by meta-analysis methods. METHOD: Relevant studies published before June, 2017 were retrieved mainly by the computer-based search of PubMed, Cochrane, EMBASE, Web of Science, Chinese BioMedical, Global Health and BIOSIS Previews databases. Estimations of relative ratios (RRs) and 95% confidence intervals (95% CIs) were pooled. Subgroup analyses according to potential key factors affecting the effects were conducted, which was confirmed by meta-regression. Sensitivity analysis and test for publication bias were also performed. RESULTS: We identified 10 studies providing data of 5467 patients receiving CIEDs implantations. Pooled infection rates were 1.48 and 3.49% respectively for medication and saline irrigation groups. Meta-analysis showed that medication irrigation conferred protection to pocket infection (RR = 0.44, 95% CI: 0.31-0.63). Subgroup analysis showed that antibiotics, rather than non-antibiotics (antiseptics) exerting the protection. The first and second lines antibiotics against staphylococcus aureus, which is the main pathogen for pocket infection, were both effective (RR = 0.42, 95% CI: 0.24-0.75 and RR = 0.34, 95% CI: 0.20-0.58 respectively for first line and second line therapies). Meta-regression revealed that region and class of irrigation medication completely explained the variance among studies and implied that effects of region were masked by medication types. Sensitivity analysis did not showed any significant change of the result and publication bias were not statistical significance. CONCLUSION: Pocket irrigation with antibiotics were effective for reducing pocket infection and should be encouraged in CIEDs implantation.

Atorvastatin Attenuates TNF-alpha Production via Heme Oxygenase-1 Pathway in LPS-stimulated RAW264.7 Macrophages.

OBJECTIVE: To assess the effect of atorvastatin on lipopolysaccharide (LPS)-induced TNF-α production in RAW264.7 macrophages. METHODS: RAW264.7 macrophages were treated in different LPS concentrations or at different time points with or without atorvastatin. TNF-α level in supernatant was measured. Expressions of TNF-α mRNA and protein and heme oxygenase-1 (HO-1) were detected by ELISA, PCR, and Western blot, respectively. HO activity was assayed. RESULTS: LPS significantly increased the TNF-α expression and secretion in a dose- and time-dependent manner. The HO-1 activity and HO-1 expression level were significantly higher after atorvastatin treatment than before atorvastatin treatment and attenuated by SB203580 and PD98059 but not by SP600125, suggesting that the ERK and p38 mitogen-activated protein kinase (MAPK) pathways participate in regulating the above-mentioned effects of atorvastatin. Moreover, the HO-1 activity suppressed by SnPP or the HO-1 expression inhibited by siRNA significantly attenuated the effect of atorvastatin on TNF-α expression and production in LPS-stimulated macrophages. CONCLUSION: Atorvastatin can attenuate LPS-induced TNF-α expression and production by activating HO-1 via the ERK and p38 MAPK pathways, suggesting that atorvastatin can be used in treatment of inflammatory diseases such as sepsis, especially in those with atherosclerotic diseases.

Plant diversity increases diversity and network complexity rather than alters community assembly processes of leaf-associated fungi in a subtropical forest.

Plant diversity significantly impacts ecosystem processes and functions, yet its influence on the community assembly of leaf fungi remains poorly understood. In this study, we investigated leaf epiphytic and endophytic fungal communities in a Chinese subtropical tree species richness experiment, ranging from 1 to 16 species, using amplicon sequencing to target the internal transcribed spacer 1 region of the rDNA. We found that the community assembly of epiphytic and endophytic fungi was predominantly governed by stochastic processes, with a higher contribution of dispersal limitation on epiphytic than on endophytic fungal communities but a higher contribution of selection on endophytic than on epiphytic fungal communities. The plant-epiphytic fungus interaction network was more complex (e.g., more highly connected and strongly nested but less specialized and modularized) than the plant-endophytic fungus interaction network. Additionally, tree species richness was positively correlated with the network complexity and diversity of epiphytic (α-, ß- and γ-diversity) and endophytic (ß- and γ-diversity) fungi, but was not associated with the contribution of the stochastic and deterministic processes on the community assembly of epiphytic and endophytic fungi. This study highlights that tree species diversity enhances the diversity and network complexity, rather than alters the ecological processes in community assembly of leaf-associated fungi.

Enrichment of cardiac differentiation of mouse embryonic stem cells by optimizing the hanging drop method.

Hanging drop (HD) culture is used to induce differentiation of embryonic stem cells (ESCs) into other cell types including cardiomyocytes. However, the factors affecting cardiac differentiation of ESCs with this method remain incompletely understood. We have investigated the effects of the starting number of ESCs in embryoid bodies (EBs) and the time of EB adherence to gelatin-coated plates on cardiac differentiation: cardiac differentiation was increased in the EBs by a larger number of ESCs and was decreased by plating EBs at day 4 or earlier. These two factors can thus be optimized to enrich the cardiac differentiation in ESCs using the HD method.

Effect of C reactive protein on the sodium-calcium exchanger 1 in cardiomyocytes.

Numerous previous studies have found that C-reactive protein (CRP) is associated with cardiac arrhythmia and cardiac remodeling. However, the underlying mechanisms of this association remain unclear. Sodium-calcium exchanger 1 (NCX1) serves an important role in the regulation of intracellular calcium concentration, which is closely related with cardiac arrhythmia and cardiac remodeling. The present study aimed to evaluate the effects of CRP on NCX1 and intracellular calcium concentration in cardiomyocytes. Primary neonatal mouse ventricular cardiomyocytes were cultured and treated with varying concentrations of CRP (0, 5, 10, 20 and 40 µg/ml). The cardiomyocytes were also treated with NF-κB-specific inhibitor PTDC and a specific inhibitor of the reverse NCX1 KB-R7943 before their intracellular calcium concentrations were measured. mRNA and protein expression levels of NCX1 were detected by reverse transcription-quantitative PCR and western blotting, respectively and intracellular calcium concentration was evaluated by flow cytometry. CRP treatment significantly increased mRNA and protein expression levels of NCX1 in myocytes (P=0.024), as well as intracellular calcium concentration (P=0.01). These results were significantly attenuated by the NF-κB-specific inhibitor PDTC and a specific inhibitor of the reverse NCX1, KB-R7943. CRP significantly upregulated NCX1 expression and increased intracellular calcium concentration in cardiomyocytes via the NF-κB pathway, suggesting that CRP may serve a pro-arrhythmia role via direct influence on the calcium homeostasis of cardiomyocytes.

Mitogen-activated protein kinase in endothelin-1-induced cardiac differentiation of mouse embryonic stem cells.

Endothelin-1(ET-1) is a potent vasoconstrictor involved in the development of cardiovascular diseases and is an important regulator of heart development. However, the role of ET-1 in cardiac differentiation of mouse embryonic stem cells (mESCs) and the underlying molecular mechanisms remain poorly understood. In the present study, we showed that ET-1 significantly up-regulated gene expression of the cardiac specific transcriptional factors Nkx2.5, GATA4, and conduction system specific marker CX40, with no affect on the gene expression of α-MHC and ß-MHC in cardiac differentiation of mESCs. The percentage of beating embryoid bodies (EB) and the Troponin T (TnT) positive area in total EBs was unchanged following ET-1 treatment, while the percentage of spindle cells that stained positively with TnT was increased in the presence of ET-1. Further investigation indicated that the percentage of beating EBs and the TnT positive area were decreased by the extracellular signal-related kinases (ERK)-1/2 inhibitor U0126 and the p38 inhibitor SB203580, but not by the Jun amino-terminal kinases (JNK) inhibitor SP600125. Inhibition of ERK1/2, p38, and JNK pathways also blocked the up-regulation of Nkx2.5 and GATA4 by ET-1, however only inhibition of the ERK1/2 pathway had negatively effects on the increase in CX40 expression in response to ET-1. ET-1 induced an increase in the percentage of spindle cells was also inhibited by U0126. Our results suggest that ET-1 plays a significant role in the cardiac differentiation of mESCs, especially in those cells committed to the conduction system, with the ERK1/2 pathway playing a critical role in this process.

[Alcohol intake and stroke in Eastern Asian men:a systemic review and meta-analysis of 17 prospective cohort studies].

OBJECTIVE: To assess the dose-response relationship between alcohol intake and relative risk of stroke and all-cause mortality among Eastern Asian men. METHODS: Potential prospective cohort studies were retrieved by searching Pubmed (1966 - 2000), OVID (1980 - 2009), Embase (1980 - 2009) and ISI Web of Knowledge (1986 - 2009) using Medical Subject Headings: alcohol drinking, ethanol, stroke, cerebrovascular disease, mortality, etc; and Koreans or Japanese or Chinese. From the relevant retrieved reports, 17 prospective cohort studies fulfilling the criteria were included into the study. Information on study design, participant characteristics, amount of alcohol intake, stroke and/or all-cause mortality outcomes, control for potential confounding factors and risk estimates was abstracted by a standardized protocol. For each study, relative risk (RR) and 95% confidence interval (CI) were extracted and pooled with either a fixed or random effect model according to the results of the test of heterogeneity. RESULTS: As data available for women were too limited to be included into our meta-analysis, this study focused on male subjects, ranging from 1322 to 108 461 subjects among these 17 cohort studies. Compared with nondrinkers, the RRs of ischemic stroke for those drinking alcohol ≤ 20, 21 - 40, 41 - 60, > 60 g/d, were 0.85 (0.78 - 0.93, P = 0.0002), 0.94 (0.79 - 1.11, P = 0.46), 1.08 (0.86 - 1.37, P = 0.50) and 1.24 (0.96 - 1.59, P = 0.10) respectively. Similarly, RRs of hemorrhagic stroke were 0.92 (0.75 - 1.12, P = 0.46), 1.11 (0.96 - 1.28, P = 0.17), 1.20 (0.92 - 1.56, P = 0.18) and 1.74 (1.32 - 2.28, P < 0.01); and those of all-cause mortality were 0.83 (0.75 - 0.91, P = 0.01), 0.93 (0.87 - 0.99, P = 0.03), 1.01 (0.95 - 1.07, P = 0.86) and 1.32 (1.29 - 1.36, P < 0.01) respectively. CONCLUSION: In Eastern Asian men, light alcohol intake (≤ 20 g/d) is associated with a lowered risk of ischemic stroke whereas heavy alcohol intake is associated with an elevated risk of stroke, particularly hemorrhagic stroke and all-cause mortality.

[Alcohol consumption and coronary heart disease in Eastern Asian men: a meta-analysis of prospective cohort studies].

OBJECTIVE: To assess the dose-response relationship between alcohol consumption and relative risk of coronary heart disease (CHD) morbidity, mortality and all-cause mortality among Eastern Asian men. METHODS: Potential prospective cohort studies were retrieved by searching Pubmed (1966 - 2000), Biosis Previews (1980 - 2009), Embase (1980 - 2009) and ISI Web of Knowledge (1986 - 2009) using Medical Subject Headings alcohol drinking, ethanol, coronary heart (or artery) disease, myocardial infarction, mortality, etc; and Koreans, or Japanese or Chinese. From the 28 relevant retrieved reports, 15 prospective cohort studies met the criteria were included. Information on study design, participant characteristics, level of alcohol consumption, CHD outcome, control for potential confounding factors, and risk estimates were abstracted using a standardized protocol. For each study, relative risks (RR) and 95% confidence intervals (CI) were extracted and pooled with either a fixed effect model or random effect model according to the result of the test of heterogeneity. RESULTS: Due to the limited available data for women, this study only comprised of 2406 cases of CHD among 177 723 male subjects. Findings were also pooled from 216 233 male subjects and 15 462 deaths from any cause. Compared with nondrinkers, the RRs on CHD morbidity for those who drank alcohol ≤ 20, 21 - 40, 41 - 60, > 60 g/d were 0.65 (0.34 - 1.23, P = 0.18), 0.48 (0.26 - 0.87, P = 0.02), 0.46 (0.32 - 0.67, P < 0.01), and 0.48 (0.29 - 0.78, P < 0.01) respectively; the RRs on CHD mortality were 0.98 (0.73 - 1.31, P = 0.87), 0.68 (0.58 - 0.79, P < 0.01), 0.64 (0.43 - 0.96, P = 0.03), 0.75 (0.54 - 1.03, P = 0.08); and on all-cause mortality were 0.83 (0.79 - 0.91, P < 0.01), 0.93 (0.87 - 0.99, P = 0.03), 1.01 (0.95 - 1.07, P = 0.86), 1.32 (1.29 - 1.36, P < 0.01). CONCLUSION: Light-to-moderate alcohol intake was associated with decreased risk of CHD morbidity and mortality, while heavy alcohol intake was associated with increased all-cause mortality among Eastern Asian men.

The improvement of spatial-temporal resolution of PM2.5 estimation based on micro-air quality sensors by using data fusion technique.

With the rapid development of the Internet of things (IoTs) and modern industrial society, forecasting air pollution concentration, e.g., the concentration of PM2.5, is of great significance to protect human health and the environment. Accurate prediction of PM2.5 concentrations is limited by the number and the data quality of air quality monitoring stations. In Taiwan, the spatial and temporal data of PM2.5 concentrations are measured by 77 national air quality monitoring stations (built by Taiwan EPA). However, the national stations are costly and scarce because of the highly precise instrument and their size. Therefore, many places are still out of coverage of the monitoring network. Recently, under the framework of IoTs, there are hundreds of portable air quality sensors called "AirBox" developed jointly by the Taiwan local government and a private company. By virtue of its low price and portability, the AirBox can provide a higher resolution of space-time PM2.5 measurement. However, the spatiotemporal distribution is different between AirBox and EPA stations, and data quality and accuracy of AirBox is poorer than national air quality monitoring stations. Thus, to integrate the heterogeneous PM2.5 data, the data fusion technique should be used before further analysis. In this study, we propose a new data fusion method called multi-sensor space-time data fusion framework. It is based on the Optimum Linear Data Fusion theory and integrating with a multi-time step Kriging method for spatial-temporal estimation. The method is used to do heterogeneous data fusion from different sources and data qualities. It is able to improve the estimation of PM2.5 concentration in space and time. Results have shown that by combining PM2.5 concentration data from 1176 low-cost AirBoxes as additional information in our model, the estimation of spatial-temporal PM2.5 concentration becomes better and more reasonable. The r2 of the validation regression model is 0.89. Under the approach proposed in this study, we made the information of the micro-sensors more reliable and improved the higher spatial-temporal resolution of air quality monitoring. It could provide very useful information for better spatial-temporal data analysis and further environmental management, such as air pollution source localization, health risk assessment, and micro-scale air pollution analysis.

Plasma D-dimer as a predictor of intraluminal thrombus burden and progression of abdominal aortic aneurysm.

AIM: Intraluminal thrombus (ILT) is presented in most abdominal aortic aneurysms (AAAs) and is suggested to promote AAA expansion. D-dimer, a breakdown product in the thrombus remodeling, may have prognostic value for AAA. This study investigated the interrelation between plasma D-dimer level, ILT volume, AAA size and progression. MAIN METHODS: This was a retrospective observational study that involved 181 patients with infra-renal AAA. They were divided into small and large AAA groups according to AAA diameter. 24 of them had repeated abdominal computed tomography angiography (CTA) scan and were divided into slow-growing and fast-growing AAA groups according to the median value of AAA growth rate. Baseline and follow-up plasma D-dimer level, maximum diameter of AAA, total infra-renal aortic volume and ILT volume were analyzed. KEY FINDINGS: Plasma D-dimer level was positively correlated with ILT volume (R = 0.382, P < 0.001) and maximum diameter of AAA (R = 0.442, P < 0.001). Increasing value of plasma D-dimer was positively associated with the accelerated growth rate of AAA (R = 0.720, P < 0.01). ILT volume showed positive correlation with maximum diameter (R = 0.859, P < 0.001) and growth rate of AAA (R = 0.490, P < 0.05). After adjusting the baseline ILT volume, the positive correlations remained to be statistically significant between plasma D-dimer level and AAA size (R = 0.200, P < 0.05), as well as increasing value of plasma D-dimer and growth rate of AAA (R = 0.642, P < 0.05). SIGNIFICANCE: Plasma D-dimer level reflected ILT burden in AAAs. Plasma D-dimer level and ILT volume were positively correlated with AAA size. Increasing value of plasma D-dimer and baseline ILT volume could be predictors of AAA progression.

[The expression and significance of activator protein-1 and matrix metalloproteinases in the human heart post acute myocardial infarction].

OBJECTIVE: To investigate the expression and significance of activator protein-1 (AP-1) and matrix metalloproteinases (MMPs) in acute myocardial infarction (AMI) subjects. METHODS: Immunohistochemical techniques were used to detect the subunit of AP-1 (c-Jun), MMP-2 and MMP-9 in human AMI and normal heart tissue and the expressions of c-Jun and MMPs were measured with computer image analysis system. RESULTS: (1) There were expressions of c-Jun, MMP-2 and MMP-9 in normal heart tissue, mainly in myocardial cells and cardiac fibroblasts, and their expressions in AMI myocardial tissues were all significantly higher than those in normal myocardial tissues (P < 0.05). (2) The level of MMP-9 expression was significantly and positively correlated with c-Jun in AMI heart tissue (r = 0.773, P < 0.01). CONCLUSIONS: The expressions of AP-1 and MMPs increase in human myocardial infarction. These findings suggest that AP-1 transcription activation pathway and MMPs may play an important role in ventricular remodeling of myocardial infarction.

Pharmacodynamic changes of platelet reactivity status in patients with chronic kidney disease after coronary artery stenting.

OBJECTIVES: This study was to evaluate platelet reactivity over time among patients with chronic kidney disease (CKD) receiving standard dose of clopidogrel after percutaneous coronary intervention (PCI). The effect of CYP2C19 loss-of-function genotypes on platelet reactivity was also determined. METHODS: Patients with CKD (n = 138) on maintenance dose of clopidogrel after PCI were enrolled. Platelet reactivity was assessed by measuring P2Y12 reaction units (PRU) with VerifyNow P2Y12 assay, and platelet reactivity index (PRI) with flow cytometric using vasodilator-stimulated phosphoprotein (VASP) at baseline and 2 weeks later, respectively. The genotypes of CYP2C19 were also measured concurrently. RESULTS: The proportion of patients with high platelet reactivity (HPR) ranged from 23.2% to 59.4%, and almost 1 in 5 patients had a dual conversion between HPR and non-HPR status. Patients carrying CYP2C19 loss-of-function genotypes showed a higher platelet reactivity than non-carriers, but with an undetermined HPR status between the first and second visits. The individual switch of HPR to non-HPR status existed in both loss-of-function genotype carriers and non-carriers. CONCLUSIONS: HPR conversions occur in a significant proportion of CKD patients with maintenance doses of clopidogrel treatment post-PCI, and this conversion was not confined to CYP2C19 loss-of-function genotype carriers. Risk stratification for treatment adjustment in personalized antiplatelet therapy should be investigated in future research.

A monoclonal antibody targeting amyloid ß (Aß) restores complement factor I bioactivity: Potential implications in age-related macular degeneration and Alzheimer's disease.

Activation of the alternative complement cascade has been implicated in the pathogenesis of age related macular degeneration (AMD) and Alzheimer's disease (AD). Amyloid ß (Aß), a component of drusen, may promote complement activation by inhibiting CFI bioactivity. We determined whether Aß reduced CFI bioactivity and whether antibodies against Aß including a monoclonal antibody, GSK933776 could restore CFI bioactivity. We also measured CFI bioactivity in plasma of subjects with AMD and AD. In support of the GSK933776 development program in AMD (geographic atrophy), we developed a quantitative assay to measure CFI bioactivity based on its ability to cleave C3b to iC3b, and repeated it in presence or absence of Aß and anti-Aß antibodies. Using this assay, we measured CFI bioactivity in plasma of 194 subjects with AMD, and in samples from subjects with AD that had been treated with GSK933776 as part of the GSK933776 development program in AD. Aß reduced the CFI bioactivity by 5-fold and pre-incubation with GSK933776 restored CFI bioactivity. In subjects with AMD, plasma CFI levels and bioactivity were not significantly different from non-AMD controls. However, we detected a positive linear trend, suggesting increasing activity with disease severity. In subjects with AD, we observed a 10% and 27% increase in overall CFI bioactivity after treatment with GSK933776 during the second and third dose. Our studies indicate that CFI enzymatic activity can be inhibited by Aß and be altered in proinflammatory diseases such as AMD and AD, in which deposition of Aß and activation of the alternative complement cascade are believed to play a key role in the disease process.

IL-33 promotes IL-10 production in macrophages: a role for IL-33 in macrophage foam cell formation.

We evaluated the role of IL-10- in IL-33-mediated cholesterol reduction in macrophage-derived foam cells (MFCs) and the mechanism by which IL-33 upregulates IL-10. Serum IL-33 and IL-10 levels in coronary artery disease patients were measured. The effects of IL-33 on intra-MFC cholesterol level, IL-10, ABCA1 and CD36 expression, ERK 1/2, Sp1, STAT3 and STAT4 activation, and IL-10 promoter activity were determined. Core sequences were identified using bioinformatic analysis and site-specific mutagenesis. The serum IL-33 levels positively correlated with those of IL-10. IL-33 decreased cellular cholesterol level and upregulated IL-10 and ABCA1 but had no effect on CD36 expression. siRNA-IL-10 partially abolished cellular cholesterol reduction and ABCA1 elevation by IL-33 but did not reverse the decreased CD36 levels. IL-33 increased IL-10 mRNA production but had little effect on its stability. IL-33 induced ERK 1/2 phosphorylation and increased the luciferase expression driven by the IL-10 promoter, with the highest extent within the -2000 to -1752 bp segment of the 5'-flank of the transcription start site; these effects were counteracted by U0126. IL-33 activated Sp1, STAT3 and STAT4, but only the STAT3 binding site was predicted in the above segment. Site-directed mutagenesis of the predicted STAT3-binding sites (CTGCTTCCTGGCAGCAGAA→︀CTGCCTGGCAGCAGAA) reduced luciferase activity, and a STAT3 inhibitor blocked the regulatory effects of IL-33 on IL-10 expression. Chromatin immunoprecipitation (CHIP) confirmed the STAT3-binding sequences within the -1997 to -1700 and -1091 to -811 bp locus regions. IL-33 increased IL-10 expression in MFCs via activating ERK 1/2 and STAT3, which subsequently promoted IL-10 transcription and thus contributed to the beneficial effects of IL-33 on MFCs.

Effects of C-reactive protein on K(+) channel interaction protein 2 in cardiomyocytes.

Several studies have found that C-reactive protein (CRP) was associated with QTc interval prolongation and ventricular arrhythmia. However, little is known about the mechanisms involved. K(+) channel interaction protein 2 (KChIP2) is a necessary subunit for the formation of transient outward potassium current (Ito.f) which plays a critical role in early repolarization and QTc interval of heart. In this study, we aimed to evaluate the effects of CRP on KChIP2 and Ito.f in cardiomyocytes and to explore the potential mechanism. The neonatal mice ventricular cardiomyocytes were cultured and treated with CRP at different concentrations. The expression of KChIP2 was detected by real time quantitative PCR and Western blot. In addition, Ito.f current density was evaluated by whole cell patch clamp techniques. Our results showed that CRP significantly decreased the mRNA and protein expression of KChIP2 in time and doses dependent manners (P < 0.05), and also reduced the current density of Ito.f (P < 0.05). In addition, CRP increased the expression of NF-κB and decreased IκBα expression without significant influence on the expression of ERK1/2 and JNK. Meanwhile, the NF-κB inhibitor PDTC significantly attenuated the effects of CRP on KChIP2 and Ito.f current density. In conclusion, CRP could significantly down-regulate KChIP2 expression and reduce current density of Ito.f partly through NF-κB pathway, suggesting that CRP may directly or indirectly influence QTc interval and arrhythmia via influencing KChIP2 expression and Ito.f current density of cardiomyocytes.

Interleukin 18 and extracellular matrix metalloproteinase inducer cross-regulation: implications in acute myocardial infarction.

Circulating interleukin-18 (IL-18) is thought to promote atherosclerosis and cardiovascular complications such as plaque rupture. Atherosclerosis is also characterized by smooth muscle cell migration, a consequence of extracellular matrix (ECM) degradation regulated by metalloproteinases (MMPs). Because extracellular matrix metalloproteinase inducer (EMMPRIN) has been shown to promote plaque instability by inducing ECM degradation and MMP synthesis, we investigated whether a cross-regulatory interaction exists between IL-18 and EMMPRIN in human monocytes. EMMPRIN levels in monocytes were markedly greater in 20 patients with acute myocardial infarction (AMI) compared with 20 patients with stable angina pectoris or 20 healthy volunteers (control group). The levels of IL-18 and MMP-9 in serum were also significantly greater in the AMI group in comparison with the other 2 groups. IL-18 levels positively correlated with increased levels of EMMPRIN in monocytes. In vitro, the expression of EMMPRIN was increased in monocytes cultured with IL-18, and IL-18 secretion was augmented in monocytes cultured with EMMPRIN. Gene silencing of EMMPRIN by small interfering RNA reduced monocyte secretion of both IL-18 and MMP-9. In the present study, cross-regulation between IL-18 and EMMPRIN in monocytes was demonstrated. This interaction may amplify the inflammatory cascade and be responsible for increased monocytic MMP-9 serum levels in atherosclerosis, contributing to atherosclerotic plaque destabilization and subsequent AMI.

Angiotensin II-derived reactive oxygen species promote angiogenesis in human late endothelial progenitor cells through heme oxygenase-1 via ERK1/2 and AKT/PI3K pathways.

Angiotensin II (Ang II), the main component of renin-angiotensin system, could mediate pathogenic angiogenesis in cardiovascular disorders. Late endothelial progenitor cells (EPCs) possess potent self-renewal and angiogenic potency superior to early EPCs, but few study focused on the cross-talk between Ang II and late EPCs. We observed that Ang II could increase reactive oxygen species (ROS) and promote capillary formation in late EPCs. Ang II-derived ROS could also upregulate heme oxygenase-1 (HO-1) expression, and treating late EPCs with HO-1 small interfering RNA or heme oxygenase inhibitor (HO inhibitor) could inhibit Ang II-induced tube formation and increase ROS level and apoptosis rate. In addition, PD98059 and LY294002 pretreatment attenuated Ang II-induced HO-1 expression. Accordingly, Ang II-derived ROS could promote angiogenesis in late EPCs by inducing HO-1 expression via ERK1/2 and AKT/PI3K pathways, and we believe HO-1 might be a promising intervention target in EPCs due to its potent proangiogenic, antioxidant, and antiapoptosis potentials.

[The responses of moxibustion and the countermeasures].

To make a distinction among the local response of body, the moxibustion sensation, its influence on the disease, adverse reaction and others during and after the moxibustion treatment, and explore the countermeasures to these reactions in order to guide the clinical practice. Of them, the responses of the body surface and local acupoints are usual one of the bases to assess the moxibustion effect, while the occurs of moxibustion sensation and its influence on the disease are normal, which is not necessary to deal with, and the adverse reaction and others could be handled according to the different situations.