Downregulation of apoptotic repressor AVEN exacerbates cardiac injury after myocardial infarction.

Myocardial infarction (MI) is a leading cause of heart failure (HF), associated with morbidity and mortality worldwide. As an essential part of gene expression regulation, the role of alternative polyadenylation (APA) in post-MI HF remains elusive. Here, we revealed a global, APA-mediated, 3' untranslated region (3' UTR)-lengthening pattern in both human and murine post-MI HF samples. Furthermore, the 3' UTR of apoptotic repressor gene, AVEN, is lengthened after MI, contributing to its downregulation. AVEN knockdown increased cardiomyocyte apoptosis, whereas restoration of AVEN expression substantially improved cardiac function. Mechanistically, AVEN 3' UTR lengthening provides additional binding sites for miR-30b-5p and miR-30c-5p, thus reducing AVEN expression. Additionally, PABPN1 (poly(A)-binding protein 1) was identified as a potential regulator of AVEN 3' UTR lengthening after MI. Altogether, our findings revealed APA as a unique mechanism regulating cardiac injury in response to MI and also indicated that the APA-regulated gene, AVEN, holds great potential as a critical therapeutic target for treating post-MI HF.

Critical Role of the cGAS-STING Pathway in Doxorubicin-Induced Cardiotoxicity.

BACKGROUND: Doxorubicin is an effective chemotherapy drug for treating various types of cancer. However, lethal cardiotoxicity severely limits its clinical use. Recent evidence has indicated that aberrant activation of the cytosolic DNA-sensing cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-STING (stimulator of interferon genes) pathway plays a critical role in cardiovascular destruction. Here, we investigate the involvement of this mechanism in doxorubicin-induced cardiotoxicity (DIC). METHODS: Mice were treated with low-dose doxorubicin to induce chronic DIC. The role of the cGAS-STING pathway in DIC was evaluated in cGAS-deficiency (cGAS-/-), Sting-deficiency (Sting-/-), and interferon regulatory factor 3 (Irf3)-deficiency (Irf3-/-) mice. Endothelial cell (EC)-specific conditional Sting deficiency (Stingflox/flox/Cdh5-CreERT) mice were used to assess the importance of this pathway in ECs during DIC. We also examined the direct effects of the cGAS-STING pathway on nicotinamide adenine dinucleotide (NAD) homeostasis in vitro and in vivo. RESULTS: In the chronic DIC model, we observed significant activation of the cGAS-STING pathway in cardiac ECs. Global cGAS, Sting, and Irf3 deficiency all markedly ameliorated DIC. EC-specific Sting deficiency significantly prevented DIC and endothelial dysfunction. Mechanistically, doxorubicin activated the cardiac EC cGAS-STING pathway and its target, IRF3, which directly induced CD38 expression. In cardiac ECs, the cGAS-STING pathway caused a reduction in NAD levels and subsequent mitochondrial dysfunction via the intracellular NAD glycohydrolase (NADase) activity of CD38. Furthermore, the cardiac EC cGAS-STING pathway also regulates NAD homeostasis and mitochondrial bioenergetics in cardiomyocytes through the ecto-NADase activity of CD38. We also demonstrated that pharmacological inhibition of TANK-binding kinase 1 or CD38 effectively ameliorated DIC without compromising the anticancer effects of doxorubicin. CONCLUSIONS: Our findings indicate a critical role of the cardiac EC cGAS-STING pathway in DIC. The cGAS-STING pathway may represent a novel therapeutic target for preventing DIC.

Brachytherapy in craniopharyngiomas: a systematic review and meta-analysis of long-term follow-up.

OBJECTIVE: Brachytherapy has been indicated as an alternative option for treating cystic craniopharyngiomas (CPs). The potential benefits of brachytherapy for CPs have not yet been clarified. The purpose of this work was to conduct a meta-analysis to analyze the long-term efficacy and adverse reactions profile of brachytherapy for CPs. MATERIALS AND METHODS: The relevant databases were searched to collect the clinical trials on brachytherapy in patients with CPs. Included studies were limited to publications in full manuscript form with at least 5-year median follow-up, and adequate reporting of treatment outcomes and adverse reactions data. Stata 12.0 was used for data analysis. RESULTS: According to the inclusion and exclusion criteria, a total of 6 clinical trials involving 266 patients with CPs were included in this meta-analysis. The minimum average follow-up was 5 years. The results of the meta-analysis showed that 1-year, 2-3 years and 5 years progression free survival rates (PFS) are 75% (95%CI: 66-84%), 62% (95%CI: 52-72%) and 57% (95%CI: 22-92%), respectively. At the last follow-up, less than 16% of patients with visual outcomes worser than baseline in all included studies. While, for endocrine outcomes, less than 32% of patients worser than baseline level. CONCLUSION: In general, based on the above results, brachytherapy should be considered as a good choice for the treatment of CP.

Interface-constrained catalytic hairpin assembly permits highly sensitive SERS signaling of miRNA.

The rapid and precise monitoring of peripheral blood miRNA levels holds paramount importance for disease diagnosis and treatment monitoring. In this study, we propose an innovative research strategy that combines the catalytic hairpin assembly reaction with SERS signal congregation and enhancement. This combination can significantly enhance the stability of SERS detection, enabling stable and efficient detection of miRNA. Specifically, our paper-based SERS detection platform incorporates a streptavidin-modified substrate, biotin-labeled catalytic hairpin assembly reaction probes, 4-ATP, and primer-co-modified gold nanoparticles. In the presence of miRNA, the 4-ATP and primer-co-modified gold nanoparticles can specifically recognize the miRNA and interact with the biotin-labeled CHA probes to initiate an interfacial catalytic hairpin assembly reaction. This enzyme-free high-efficiency catalytic process can accumulate a large amount of biotin on the gold nanoparticles, which then bind to the streptavidin on the substrate with the assistance of the driving liquid, forming red gold nanoparticle stripes. These provide a multitude of hotspots for SERS, enabling enhanced signal detection. This innovative design achieves a low detection limit of 3.47 fM while maintaining excellent stability and repeatability. This conceptually innovative detection platform offers new technological possibilities and solutions for clinical miRNA detection.

HA15 inhibits binding immunoglobulin protein and enhances the efficacy of radiation therapy in esophageal squamous cell carcinoma.

Proteomic profiling is a promising approach to identify novel predictors of radiation response. The present study aimed to identify potential biomarkers of radiation response by serum proteomics in esophageal squamous cell carcinoma (ESCC) patients and find efficacious therapeutic drugs to enhance the efficacy of radiation therapy (RT). Serum binding immunoglobulin protein (BIP) was identified and validated as a treatment response predictor in ESCC patients treated with RT. Novel BIP inhibitor HA15 showed antitumor activity in ESCC cells by viability assay. Tumor cell colony formation and apoptosis assay revealed targeting BIP was associated with significant improvements of radiation sensitivity. Further analyses revealed that HA15 enhanced radiation-induced endoplasmic reticulum (ER) stress and immunogenic cell death (ICD) in ESCC. Clinical data indicated that high expression of BIP was associated with poor survival in patients of ESCC. In conclusion, proteomics analysis suggested BIP was a promising predictor of radiation response in locally advanced ESCC. The BIP inhibitor HA15 acted as an ER stress inducer and ICD stimulator; RT combined with HA15 was effective in suppressing the growth of ESCC in vitro and in vivo. Pretreatment BIP was an essential prognostic biomarker in locally advanced ESCC patients treated with RT.

Evaluation of humoral and cellular immune responses induced by a cocktail of recombinant African swine fever virus antigens fused with OprI in domestic pigs.

BACKGROUND: African swine fever (ASF) is a highly fatal disease in domestic pigs caused by ASF virus (ASFV), for which there is currently no commercial vaccine available. The genome of ASFV encodes more than 150 proteins, some of which have been included in subunit vaccines but only induce limited protection against ASFV challenge. METHODS: To enhance immune responses induced by ASFV proteins, we expressed and purified three fusion proteins with each consisting of bacterial lipoprotein OprI, 2 different ASFV proteins/epitopes and a universal CD4+ T cell epitope, namely OprI-p30-modified p54-TT, OprI-p72 epitopes-truncated pE248R-TT, and OprI-truncated CD2v-truncated pEP153R-TT. The immunostimulatory activity of these recombinant proteins was first assessed on dendritic cells. Then, humoral and cellular immunity induced by these three OprI-fused proteins cocktail formulated with ISA206 adjuvant (O-Ags-T formulation) were assessed in pigs. RESULTS: The OprI-fused proteins activated dendritic cells with elevated secretion of proinflammatory cytokines. Furthermore, the O-Ags-T formulation elicited a high level of antigen-specific IgG responses and interferon-γ-secreting CD4+ and CD8+ T cells after stimulation in vitro. Importantly, the sera and peripheral blood mononuclear cells from pigs vaccinated with the O-Ags-T formulation respectively reduced ASFV infection in vitro by 82.8% and 92.6%. CONCLUSIONS: Our results suggest that the OprI-fused proteins cocktail formulated with ISA206 adjuvant induces robust ASFV-specific humoral and cellular immune responses in pigs. Our study provides valuable information for the further development of subunit vaccines against ASF.

Cadherin-11-Interleukin-6 Signaling between Cardiac Fibroblast and Cardiomyocyte Promotes Ventricular Remodeling in a Mouse Pressure Overload-Induced Heart Failure Model.

Heart failure is a serious and life-threatening disease worldwide. Cadherin-11 (Cad-11) is highly expressed in the heart and closely associated with inflammation. There is currently limited understanding on how Cad-11 contributes to cardiac remodeling and its underline molecular mechanism. We found an increased expression of Cad-11 in biopsy heart samples from heart failure patients, suggesting a link between Cad-11 and heart failure. To determine the role of Cad-11 in cardiac remodeling, Cad-11-deficient mice were used in a well-established mouse transverse aortic constriction (TAC) model. Loss of Cad11 greatly improved pressure overload-induced LV structural and electrical remodeling. IL (interleukin)-6 production was increased following TAC in WT mice and this increase was inhibited in cadherin-11-/- mice. We further tested the effect of IL-6 on myocyte hypertrophy and fibrosis in a primary culture system. The addition of hCad-11-Fc to cultured cardiac fibroblasts increased IL-6 production and fibroblast cell activation, whereas neutralizing IL-6 with an IL-6 antibody resulted in alleviating the fibroblast activation induced by hCad-11-Fc. On the other hand, cardiomyocytes were promoted to cardiomyocyte hypertrophy when cultured in condition media collected from cardiac fibroblasts stimulated by hCad-11-Fc.Similarly, neutralizing IL-6 prevented cardiomyocyte hypertrophy. Finally, we found that MAPKs and CaMKII-STAT3 pathways were activated in both hCad-11-Fc stimulated fibroblasts and cardiomyocytes treated with hCad-11-Fc stimulated fibroblast condition medium. IL-6 neutralization inhibited such MAPK and CaMKII-STAT3 signaling activation. These data demonstrate that Cad-11 functions in pressure overload-induced ventricular remodeling through inducing IL-6 secretion from cardiac fibroblasts to modulate the pathophysiology of neighboring cardiomyocytes.

A climate-water quality assessment framework for quantifying the contributions of climate change and human activities to water quality variations.

Water quality safety has attracted global attention and is closely related to the development of the social economy and human health. It is widely recognized that climate change and human activities significantly affect water quality changes. Therefore, quantifying the contributions of factors that drive long-term water quality changes is crucial for effective water quality management. Here, we built a climate-water quality assessment framework (CWQAF) based on climate-water quality response coefficients and trend analysis methods, to achieve this goal. Our results showed that the water quality improved significantly by 4.45%-20.54% from 2011 to 2020 in the Minjiang River basin (MRB). Human activities (including the construction of ecological projects, stricter discharge measures, etc.) were the main driving factors contributing 65%-77% of the improvement effect. Notably, there were differences in the contributions of human activities to water quality parameter changes, such as DO (increase (I): 0.12 mg/L, human contribution (HC): 66.8%), CODMn (decrease (D): 0.71 mg/L, HC: 67.2%), BOD5 (D: 1.10 mg/L, HC: 77.7%), CODCr (D: 4.20 mg/L, HC: 81.2%), TP (D: 0.13 mg/L,HC: 72.8%) and NH3-N (D: 0.40 mg/L, HC: 63.0%). Climate change explained 23%-35% of the variation in water quality. The water quality response to climate change was relatively significant with precipitation. For example, the downstream region was more susceptible to climate change than was the upstream region, as the downstream movement of precipitation centers strengthened the process of climatic factors affecting water quality changes in the MRB. Generally, although human activities were the main driving factor of water quality changes at the basin scale, the contribution of climate change could not be ignored. This study provided a manageable framework for the quantitative analysis of the influence of human activities and climate change on water quality to enable more precise and effective water quality management.

Source apportionment and risk assessment of soil heavy metals around a key drinking water source area in northern China: multivariate statistical analysis approach.

With the intensive urbanization and industrialization in recent years, lots of products containing heavy metals (HMs) have brought in severe environment problems. Yuqiao Reservoir (YQR) is an important drinking water source area in Tianjin of China, and the soil environmental quality of YQR is vital for human health. The goal of this study was to identify the priority control pollutants and hotspots of HMs contamination of YQR catchment. Thus, an integrated field investigation was conducted to analyze the major elements such as As, Cd, Cr, Cu, Hg, Ni, Pb and Zn in soils around YQR. Geoaccumulation index (Igeo), enrichment factor (EF) and potential ecological risk index (PERI) were employed to assess the contamination status of HMs. The average contents of these elements were given as follows: As 7.97 mg/kg, Cd 0.31 mg/kg, Cr 86.1 mg/kg, Cu 24.7 mg/kg, Hg 0.044 mg/kg, Ni 30.7 mg/kg, Pb 27.3 mg/kg and Zn 76.7 mg/kg. According to geoaccumulation index (Igeo) and enrichment factor (EF) values, Cd, Cr, Pb and As showed a prominent enrichment. The result of multivariate statistics showed that Cd, Cr, Cu, As, Ni, Pb and Zn concentrations were mainly affected by human activities, whereas Hg was mainly from natural release. The anthropogenic activities were the major sources with a contribution of 91.46%, while natural origins only contributed 8.54%. And agricultural fertilization, mining and traffic activities are the most probable sources of these heavy metals in the soil. The PERI values indicated that 65.7% of total HMs were at low risk, 22.5% in moderate risk and 11.8% in considerable risk. To ensure soil environmental quality and human health, cadmium should be listed as a priority control pollutant. Spatial maps of HMs and their integrated PERI provided clear hotspots that indicated lower risk in the region close to YQR but higher risk in the region far from YQR.

Ultrasensitive Antibiotic Perceiving Based on Aptamer-Functionalized Ultraclean Graphene Field-Effect Transistor Biosensor.

Antibiotics are powerful tools to treat bacterial infections, but antibiotic pollution is becoming a severe threat to the effective treatment of human bacterial infections. The detection of antibiotics in water has been a crucial research area for bioassays in recent years. There is still an urgent need for a simple ultrasensitive detection approach to achieve accurate antibiotic detection at low concentrations. Herein, a field-effect transistor (FET)-based biosensor was developed using ultraclean graphene and an aptamer for ultrasensitive tetracycline detection. Using a newly designed camphor-rosin clean transfer (CRCT) scheme to prepare ultraclean graphene, the carrier mobility of the FET is found to be improved by more than 10 times compared with the FET prepared by the conventional PMMA transfer (CPT) method. Based on the FET, aptamer-functionalized transistor antibiotic biosensors were constructed and characterized. A dynamic detection range of 5 orders of magnitude, a sensitivity of 21.7 mV/decade, and a low detection limit of 100 fM are achieved for the CRCT-FET biosensors with good stability, which are much improved compared with the biosensor prepared by the CPT method. The antibiotic sensing and sensing performance enhancement mechanisms for the CRCT-FET biosensor were studied and analyzed based on experimental results and a biosensing model. Finally, the CRCT-FET biosensor was verified by detecting antibiotics in actual samples obtained from the entrances of Bohai Bay.

Cadherin-11 deficiency mitigates high-fat diet-induced inflammatory atrial remodeling and vulnerability to atrial fibrillation.

Atrial fibrillation (AF) is the most common cardiac arrhythmia nowadays. The occurrence of AF is closely associated with obesity. Cadherin-11 (Cad-11), as a member of the cadherin family, can make a contribution to diet-induced obesity and it will be informative to know whether Cad-11 exerts its effects on atrial remodeling and AF vulnerability in a diet-induced obesity model. In this study, we demonstrated that the expression of Cad-11 was significantly upregulated in the left atrium of AF patients with obesity and mice following 16 weeks of high-fat diet (HFD) feeding. Further confirmed that Cad-11 could regulate the activity of atrial fibroblasts by participating in inducing proinflammatory cytokines production. At animal levels, we found that although there was a lack of statistical difference in body weight, Cad-11-/- mice could markedly improve impaired glucose tolerance and hyperlipidemia. Adverse atrial structural remodeling, including atrial enlargement, inflammation, and fibrosis provoked by HFD feeding were mitigated in Cad-11-/- mice. Mechanistically, Cad-11 activated mitogen-activated protein kinases and nuclear factor-κB for interleukin-6 production in atrial fibroblasts that may contribute to the atrial fibrosis process in obesity-related AF, suggesting Cad-11 might be a new therapeutic target for obesity-related AF.

EZH2 as an Epigenetic Regulator of Cardiovascular Development and Diseases.

ABSTRACT: Enhancer of zeste homolog 2(EZH2) is an enzymatic subunit of polycomb repressive complex 2 (PRC2) and is responsible for catalyzing mono-, di-, and trimethylation of histone H3 at lysine-27(H3K27me1/2/3). Many noncoding RNAs or signaling pathways are involved in EZH2 functional alterations. This new epigenetic regulation of target genes is able to silence downstream gene expression and modify physiological and pathological processes in heart development, cardiomyocyte regeneration, and cardiovascular diseases, such as hypertrophy, ischemic heart diseases, atherosclerosis, and cardiac fibrosis. Targeting the function of EZH2 could be a potential therapeutic approach for cardiovascular diseases.

Amphiregulin promotes cardiac fibrosis post myocardial infarction by inducing the endothelial-mesenchymal transition via the EGFR pathway in endothelial cells.

The endothelial-mesenchymal transition (EndMT) plays a key role in the development of cardiac fibrosis (CF) after acute myocardial infarction (AMI). The results of our previous study showed that amphiregulin (AR) expression was enhanced after MI. However, the role of AR on EndMT post MI remains unknown. This study aimed to elucidate the impact of AR on EndMT post MI and the associated molecular mechanisms. AR expression was markedly enhanced in infarct border area post MI, and endothelial cells were one of the primary cell sources of AR secretion. Stimulation with AR promoted endothelial cell proliferation, invasion, migration, collagen synthesis and EndMT. In addition, EGFR and downstream gene expression was significantly enhanced. In vivo, EndMT was significantly inhibited after lentivirus-AR-shRNA was delivered to the myocardium post MI. In addition, silencing AR ameliorated cardiac function by decreasing the extent of CF. Furthermore, the levels of EGFR pathway components in endothelial cells extracted from infarct border myocardium were all significantly decreased in lentivirus-AR-shRNA-treated MI mice. Our results demonstrate that AR induces CF post MI by enhancing EndMT in endothelial cells. Thus, targeting the regulation of AR may provide a potentially novel therapeutic option for CF after MI.

Evaluation of MTBH, a novel hesperetin derivative, on the activity of hepatic cytochrome P450 isoform in vitro and in vivo using a cocktail method by HPLC-MS/MS.

1. 8-methylene-tert-butylamine-3',5,7-trihydroxy-4'-methoxyflavanone (MTBH), a novel hesperidin derivative, has potential in the prevention of hepatic disease, however, its effects on cytochrome P450 isoforms (CYP450s) remains unexplored. The purpose was to investigate the effects of MTBH on the mRNA, protein levels, and activities of six CYP450s (1A2, 2C11/9, 2D2/6, 3A1/4, 2C13/19, and 2E1) in vitro and in vivo.2. In vitro study, rat and human liver microsomes were adopted to elucidate the inhibitory effect of MTBH on six CYP450s using probe drugs. In vivo study, Sprague-Dawley male rats were treated with MTBH (25, 50, or 100 mg/kg for 28 consecutive days), phenobarbital (80 mg/kg for 12 consecutive days), or 0.5% CMC-Na solution (control group) by intragastric administration, then, the mRNA, protein levels and activities of liver CYP450s were analysed by real-time PCR, western blotting and probe-drug incubation systems, respectively.3. The in vitro study indicated that MTBH inhibits the activities of CYP3A1/4 and CYP2E1 in rat and human liver microsomes. In vivo data showed that MTBH inhibits mRNA, protein levels, and activities of CYP3A1 and CYP2E1 in medium- and high-dose MTBH groups.4. MTBH has the potential to cause drug-drug interactions when co-administered with drugs that are metabolised by CYP3A1/4 and CYP2E1.

Source emissions and climate change impacts on the multimedia transport and fate of persistent organic pollutants, Chaohu watershed, eastern China.

Emission intensity and climate change control the transport flux and fate of persistent organic pollutants (POPs) in multiple environmental compartments. This study applied a multimedia model (BETR model) to explore alternations in the spatio-temporal trends of concentrations and transport flux of benzopyrene (BaP), phenanthrene (Phe), perfluorooctane sulfonates (PFOS) and polychlorinated biphenyls (PCBs) in the Chaohu watershed, located in the lower reaches of the Yangtze River, China in response to changes in source emissions and climate. The potential historic and future risks of these pollutants also were assessed. The results suggest that current trends in concentrations and transport were similar to that of their emissions between 2005 and 2018. During the next 100 years, temporal trends and spatial patterns were not predicted to change significantly, which is consistent with climate change. Based on sensitivity and correlation analyses, climate change had significant effects on multi-media concentrations and transport fluxes of BaP, Phe, PFOS and PCBs, and rainfall intensity was the predominant controlling factor. Risk quotients (RQs) of BaP and Phe-in soil increased from 0.42 to 0.95 and 0.06 to 0.35, respectively, from 2005 to 2090, indicating potential risks. The RQs of the other examined contaminants exhibited little potential risk in soil, water, or sediment. Based on spatial patterns, it was inferred that the ecosystem around Lake Chaohu is the most at risk. The study provides insights needed for local pollution control of POPs in the Chaohu watershed. In addition, the developed approach can be applied to other watersheds world-wide.

Role of linezolid combination therapy for serious infections: review of the current evidence.

As long-standing clinical problems, a series of complicated infections are more difficult to treat due to the development of antibiotic resistance, especially caused by methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecium (VRE), and multidrug-resistant Mycobacterium tuberculosis (M. tuberculosis). Moreover, the treatment options available to against these infections are also becoming increasingly limited. Linezolid is the first synthetic oxazolidinone antibiotic with a unique mechanism of action, and its efficacy against Gram-positive bacteria has been clearly demonstrated. However, the limitations of linezolid alone for the treatment of these complicated infections have been reported in the recent years. Combination therapy may be a good approach to enhance efficacy and prevent the development of resistance. In this review, the results of multiple linezolid combination therapies from in vitro, animal studies, and clinical cases for the treatment of MRSA, VRE, and multidrug-resistant M. tuberculosis strains will be discussed, and thus provide more relevant information for clinician in clinical practice.

Efficacy of fully covered self-expandable metal stents for the management of pancreatic duct strictures in chronic pancreatitis: A systematic review and meta-analysis.

BACKGROUND AND AIM: Recently, there has been burgeoning interest in the utilization of fully covered self-expandable metal stents (FCSEMSs) for managing main pancreatic duct strictures (MPDS) in chronic pancreatitis (CP). The primary aim was to investigate stricture resolution and recurrence rates of FCSEMS placement in patients with symptomatic CP complicated with MPDS. METHODS: MEDLINE, EMBASE, and ISI Web of Science and Cochrane Library (up to December 2019) were searched to identify eligible studies. A meta-analysis of stricture resolution and recurrence rates was carried out using R. The crude rate of adverse events related to stent therapy was also calculated. RESULTS: Ten studies involving 163 patients were included. The weighted pooled rate of MPDS resolution was 93% (95% confidence interval [95%CI] 84-99%) with substantial heterogeneity (I2  = 63%). Duration of stent placement more than 3 months did not result in a significantly higher resolution rate than that of 3 months or less (93% vs 93%, P = 0.91). The weighted pooled rate of stricture recurrence was 5% (95%CI: 0-12%). The stricture recurrence rate for patients with duration of stent placement more than 3 months (3%; 95%CI: 0-10%) was lower than that in patients with 3 months or less of stent placement (7%; 95%CI: 0-23%), but not significantly (P = 0.45). The overall rate of adverse events related to stent therapy was 34.9%, and spontaneous stent migration occurred in 14.1% of patients. CONCLUSIONS: The use of FCSEMSs appears to be effective and safe in the management of MPDS caused by symptomatic CP.

MeCP2 promotes endothelial-to-mesenchymal transition in human endothelial cells by downregulating BMP7 expression.

Endothelial-to-mesenchymal transition (EndMT) plays a pivotal role in the development of organ fibrosis and can be induced by TGF-ß. It is characterized by the loss of endothelial cell markers and the acquisition of mesenchymal markers. In this study, we found that methyl-CpG binding protein 2 (MeCP2) was increased in TGF-ß-induced EndMT, and silencing of MeCP2 inhibited EndMT induction. Viral overexpression of MeCP2 in vitro promoted EndMT and suppressed the expression of bone morphogenic protein-7 (BMP7). The methylation of CpG islands in BMP7 promoter was increased in MeCP2-overexpressing endothelial cells and Chromatin immunoprecipitation assay showed the direct binding of MeCP2 at the BMP7 promoter. In summary, our results suggest that MeCP2 promotes EndMT by epigenetically silencing BMP7 in endothelial cells and MeCP2 may be a target for diseases driven by EndMT.

A sensitive LC-MS/MS method to determine ginkgolide B in human plasma and urine: application in a pharmacokinetics and excretion study of healthy Chinese subjects.

1. Ginkgolide B (GB), the most active of the ginkgolides, has been developed as a new drug for the treatment of vascular insufficiency; however, the pharmacokinetics of GB remain unclear. Here, we investigated the pharmacokinetics and urine excretion properties of GB in healthy Chinese subjects administered single- and multiple-dose injectable GB based on a new LC-MS/MS method.2. GB pharmacokinetics were found to be dose-dependent from 20 to 60 mg. GB reached a steady state by day 6 with once-daily dosing at 40 mg. Systemic exposure to GB, as characterised by AUC0-∞, indicated accumulation following repeated once-daily dosing for seven consecutive days. The mean urinary cumulative excretion rate of GB in response to 20, 40, and 60 mg GB was 41.9 ± 18.5%, 32.9 ± 12.2%, and 43.9 ± 8.5%, respectively.3. Dose-proportional pharmacokinetics of GB were observed after intravenous administration in healthy subjects. A gradual reduction in the volume of distribution and slight change in mean resistance time led us to conjecture the limited accumulation of GB based on distribution equilibrium in vivo.4. This comprehensive study of the clinical pharmacokinetics of GB will provide useful information for its application and further development.

EZH2 as a novel therapeutic target for atrial fibrosis and atrial fibrillation.

Angiotensin II (Ang-II)-induced fibroblast differentiation plays an important role in the development of atrial fibrosis and atrial fibrillation (AF). Here, we show that the expression of the histone methyltransferase enhancer of zeste homolog 2 (EZH2) is increased in atrial muscle and atrial fibroblasts in patients with AF, accompanied by significant atrial fibrosis and atrial fibroblast differentiation. In addition, EZH2 is induced in murine models of atrial fibrosis. Furthermore, either pharmacological GSK126 inhibition or molecular silencing of EZH2 can inhibit the differentiation of atrial fibroblasts and the ability to produce ECM induced by Ang-II. Simultaneously, inhibition of EZH2 can block the Ang-II-induced migration of atrial fibroblasts. We found that EZH2 promotes fibroblast differentiation mainly through the Smad signaling pathway and can form a transcription complex with Smad2 to bind to the promoter region of the ACTA2 gene. Finally, our in vivo experiments demonstrated that the EZH2 inhibitor GSK126 significantly inhibited Ang-II-induced atrial enlargement and fibrosis and reduced AF vulnerability. Our results demonstrate that targeting EZH2 or EZH2-regulated genes might present therapeutic potential in AF.