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1.

Background

Increased endothelial permeability is central to shock and organ dysfunction in sepsis but therapeutics targeted to known mediators of increased endothelial permeability have been unsuccessful in patient studies. We previously reported that cell-free hemoglobin (CFH) is elevated in the majority of patients with sepsis and is associated with organ dysfunction, poor clinical outcomes and elevated markers of oxidant injury. Others have shown that Vitamin C (ascorbate) may have endothelial protective effects in sepsis. In this study, we tested the hypothesis that high levels of CFH, as seen in the circulation of patients with sepsis, disrupt endothelial barrier integrity.

Methods

Human umbilical vein endothelial cells (HUVEC) were grown to confluence and treated with CFH with or without ascorbate. Monolayer permeability was measured by Electric Cell-substrate Impedance Sensing (ECIS) or transfer of 14C-inulin. Viability was measured by trypan blue exclusion. Intracellular ascorbate was measured by HPLC.

Results

CFH increased permeability in a dose- and time-dependent manner with 1 mg/ml of CFH increasing inulin transfer by 50% without affecting cell viability. CFH (1 mg/ml) also caused a dramatic reduction in intracellular ascorbate in the same time frame (1.4 mM without CFH, 0.23 mM 18 h after 1 mg/ml CFH, p < 0.05). Pre-treatment of HUVECs with ascorbate attenuated CFH induced permeability.

Conclusions

CFH increases endothelial permeability in part through depletion of intracellular ascorbate. Supplementation of ascorbate can attenuate increases in permeability mediated by CFH suggesting a possible therapeutic approach in sepsis.  相似文献   

2.

Problem

Recurrent spontaneous abortion (RSA) is associated with immune imbalance at the maternal–fetal interface. Decidual immune cells and cytokines expressed at this interface regulate the response of the maternal immune system to the fetus. However, the populations and cytokine expression levels of these lymphocytes in miscarriage with normal and abnormal chromosome karyotypes remain unclear.

Methods

We assessed the populations and cytokine expression levels of Natural Killer (NK), Natural Killer T (NKT), Helper T (Th) and Cytotoxic T (Tc) cells in the decidua of RSA by flow cytometry and simultaneously analyzed the fetal chromosome karyotypes of these miscarriages.

Results

Flow cytometry showed no significant difference between RSA and normal pregnancy in the percentages of Th, Tc, NK, and NKT cells. Type-1 cells decreased significantly in the decidua of normal pregnancy, and NK2 and NKT2 cells increased significantly in the normal pregnancy group. We also found no difference in the lymphocyte composition and the proportion of types 1 and 2 subsets of the four lymphocytes in the decidua between RSA with abnormal chromosome karyotypes of villous trophoblasts (RSA-A) and RSA with normal chromosome karyotypes of villous trophoblasts (RSA-N), but the proportion of type-1 cells in both groups was significantly higher than that in normal pregnancy.

Conclusion

No difference existed between the type-1 immune response of RSA in normal and abnormal chromosome karyotypes of villous trophoblasts.  相似文献   

3.
4.

Background

Current algorithms and device morphology templates have been proposed in current Implantable Cardioverter-Defibrillators (ICDs) to minimize inappropriate therapies (ITS), but this has not been completely successful.

Aim

Assess the impact of a deliberate strategy of using an atrial lead implant with standardized parameters; based on all current ICD discriminators and technologies, on the burden of ITS.

Method

A retrospective single-centre analysis of 250 patients with either dual chamber (DR) ICDs or biventricular ICDs (CRTDs) over a (41.9 ± 27.3) month period was performed. The incidence of ITS on all ICD and CRTD patients was chronicled after the implementation of standardized programming.

Results

39 events of anti-tachycardial pacing (ATP) and/or shocks were identified in 20 patients (8% incidence rate among patients). The total number of individual therapies was 120, of which 34% were inappropriate ATP, and 36% were inappropriate shocks. 11 patients of the 250 patients received ITS (4.4%). Of the 20 patients, four had ICDs for primary prevention and 16 for a secondary prevention. All the episodes in the primary indication group were inappropriate, while seven patients (43%) of the secondary indication group experienced inappropriate therapies.

Conclusions

The burden of ITS in the population of patients receiving ICDs was 4.4% in the presence of atrial leads. The proposed rationalized programming criteria seems an effective strategy to minimize the burden of inappropriate therapies and will require further validation.  相似文献   

5.

Purpose

Three-dimensional retinal organoids can be differentiated from embryonic stem cells/induced pluripotent stem cells (ES/iPS cells) under defined medium conditions. We modified the serum-free floating culture of embryoid body-like aggregates with quick reaggregation (SFEBq) culture procedure to obtain retinal organoids expressing more rod photoreceptors and S- and M-cone opsins.

Methods

Retinal organoids differentiated from mouse Nrl-eGFP iPS cells were cultured in various mediums during photoreceptor development. To promote rod photoreceptor development, organoids were maintained in media containing 9-cis retinoic acids (9cRA). To obtain retinal organoids with M-opsin expression, we cultured in medium with 1% fetal bovine serum (FBS) supplemented with T3, BMP4, and DAPT. Section immunohistochemistry was performed to visualize the expression of photoreceptor markers.

Results

In three-dimensional (3D) retinas exposed to 9cRA, rhodopsin was expressed earlier and S-cone opsins were suppressed. We could maintain 3D retinas up to DD 35 in culture media with 1% FBS. The 3D retinas expressed rhodopsin, S- and M-opsins, but most cone photoreceptors expressed either S- or M-opsins.

Conclusion

By modifying culture conditions in the SFEBq protocol, we obtained rod-dominated 3D retinas and S- and M-opsin expressing 3D retinas.  相似文献   

6.

Objective

The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor atorvastatin has been reported to exert vasculo-protective action in diabetes. We investigated the vasculo-protective mechanism of atorvastatin by evaluating its effect on two major pathogenic molecules, FOXO1 and ICAM1, mediated by S-phase kinase-associated protein 2 (Skp2) in diabetic endothelial dysfunction.

Approach and results

[1] FOXO1: Hyperglycemic condition increased FOXO1 protein level in endothelial cells, which was reversed by atorvastatin. This atorvastatin effect was obliterated by treatment of protease inhibitor, suggesting that atorvastatin induces degradation of FOXO1. Immunoprecipitation showed that atorvastatin facilitated the binding of Skp2 to FOXO1, leading to ubiquitination and degradation of FOXO1.[2] ICAM-1: Increased ICAM1 in high glucose condition was reduced by atorvastatin. But this effect of atorvastatin was obliterated when Skp2 was inhibited, suggesting that atorvastatin enhances binding of Skp2 to ICAM1 leading to degradation. Actually, ubiquitination and degradation of ICAM-1 were reduced when Skp2 was inhibited. In vitro monocyte adhesion assay revealed that atorvastatin reduced monocyte adhesion on endothelial cells in high glucose condition, which was reversed by Skp2 knock-down.

Conclusion

Atorvastatin strengthens Skp2 binding to FOXO1 or ICAM1, leading to ubiquitination and degradation. Skp2-dependent ubiquitination of major pathogenic molecules is the key mechanism for statin's protective effect on endothelial function in diabetes.  相似文献   

7.

Background

Cryoballoon-based pulmonary vein isolation (PVI) is a treatment option for atrial fibrillation (AF). Left atrial volume (LAV) and left atrial volume index (LAVi) are important parameters for long term success of PVI. Galectin-3 (Gal-3) and neutrophil to lymphocyte ratio (N/L ratio) are biomarkers to demonstrate the cardiac fibrosis and remodelling.

Methods

50 patients with symptomatic PAF despite ≥1 antiarrhythmic drug(s), who underwent PVI were enrolled. LAV, LAVi, Gal-3 and N/L ratio were calculated before ablation and after ablation at 6 and 12 months. According to AF recurrence patients were divided into two groups, recurrent AF (n?=?14) and non-recurrent AF (n?=?36).

Results

In both groups (recurrent and non-recurrent), initial and 12 months follow-up LAV values were 41.39?±?18.13?ml and 53.24?±?22.11?ml vs 48.85?±?12.89?ml and 42.08?±?13.85 (p?=?0.037). LAVi were 20.9?±?8.91 ml/m2 and 26.85?±?11.28 ml/m2 vs 25.36?±?6.21 and 21.87?±?6.66 (p?=?0.05) for recurrent and non-recurrent AF groups, respectively. In both groups PVI had no significant effect on serum Gal-3 levels and N/L ratio during 12 months follow-up. The comparison between two groups at the end of 12th month showed Gal-3 values of 6.66?±?4.09?ng/ml and 6.02?±?2.95?ng/ml (p?=?0.516), N/L ratio values of 2.28?±?1.07 103/μl and 1.98?±?0.66?103/μl (p?=?0.674).

Conclusion

LAV and LAVi are useful to predict the remodelling of the left atrium and AF recurrence after cryoballoon-based PVI. However, biomarkers such as Gal-3 and N/L ratio are not associated with AF recurrence.  相似文献   

8.

Background

Cardiomyocyte autophagy and apoptosis are crucial events underlying the development of cardiac abnormalities and dysfunction after myocardial infarction (MI). A better understanding of the cell signaling pathways involved in cardiac remodeling may support the development of new therapeutic strategies for the treatment of heart failure (HF) after MI.

Methods

A cardiac MI injury model was constructed by ligating the left anterior descending (LAD) coronary artery. Neonatal cardiomyocytes were isolated and cultured to investigate the mechanisms underlying the protective effects of nicorandil on MI-induced injury.

Results

Nicorandil reduced cardiac enzyme release, mitigated left ventricular enlargement and cardiac dysfunction after MI, as evaluated by echocardiography and hemodynamic measurements. According to the results of the western blot analysis and immunofluorescence staining, nicorandil enhanced autophagic flux and reduced apoptosis in cardiomyocytes subjected to hypoxic injury. Interestingly, nicorandil increased Mst1 and p-Mst1 levels in cardiomyocytes subjected to MI injury. Mst1 knockout abolished the protective effects of nicorandil on cardiac remodeling and dysfunction after MI. Mst1 knockout also abolished the beneficial effects of nicorandil on cardiac enzyme release and cardiomyocyte autophagy and apoptosis.

Conclusions

Nicorandil alleviates post-MI cardiac dysfunction and remodeling. The mechanisms were associated with enhancing autophagy and inhibiting apoptosis through Mst1 inhibition.  相似文献   

9.

Background

Nano-particles have been widely used in target-specific drug delivery system and showed advantages in cancers treatment. This study aims to evaluate the effect of chitosan coated doxorubicin nano-particles drug delivery system in liver cancer.

Methods

The chitosan nano-particles were prepared by using the ionic gelation method. The characterizations of the nano-particles were determined by transmission electron microscopy. The cytotoxicity was detected by MTT assay, and the endocytosis, cell apoptosis and cell cycle were examined by flow cytometry. The protein level was analyzed with western blot. The dual luciferase reporter assay was performed to assess the interaction between p53 and the promoter of PRC1, and chromatin immune-precipitation was used to verify the binding between them.

Results

The FA-CS-DOX nano-particles were irregular and spherical particles around 30–40 nm, with uniform size and no adhesion. No significant difference was noted in doxorubicin release rate between CS-DOX and FA-CS-DOX. FA-CS-DOX nano-particles showed stronger cytotoxicity than CS-DOX. FA-CS-DOX nano-particles promoted the apoptosis and arrested cell cycle at G2/M phase, and they up-regulated p53. FA-CS-DOX nano-particles inhibited cell survival through p53/PRC1 pathway.

Conclusion

Chitosan-coated doxorubicin nano-particles drug delivery system inhibits cell growth of liver cancer by promoting apoptosis and arresting cell cycle at G2/M phase through p53/PRC1 pathway.  相似文献   

10.

Background

Expert opinion recommends performing exercise testing with initiation of Class Ic antiarrhythmic medication.

Objective

To evaluate the rate and reason for discontinuation of Ic agent within the first year of follow up, with particular attention to rate of proarrhythmia and the value of routine treadmill testing.

Methods

This is a single center retrospective cohort study including consecutive patients with atrial arrhythmias who were initiated on a Class Ic agent from 2011 to 2016. Data was collated from chart review and pharmacy database.

Results

The study population included 300 patients (55% male, mean age 61; mean ejection fraction, 56%) started on flecainide (n = 153; 51%) and propafenone (n = 147; 49%). Drug initiation was completed while hospitalized on telemetry and the staff electrophysiologists directed dosing. There was one proarrhythmic event during initiation (0.3%). The primary reason for not being discharged on Ic agent was due to detection of proarrhythmia (n = 15) or ischemia (n = 1) with treadmill testing (5.3%). Exercise testing was the single significant variable to affect the decision to discontinue Ic drug, p < 0.0001 (95% CI: 1.89–6.08%). During follow up, the primary reason for discontinuation of Ic agent was lack of efficacy, 32%.

Conclusions

With proper screening, initiation of Class Ic agent is associated with very low rate of proarrhythmia. Treadmill testing is of incremental value and should be completed in all patients after loading Class Ic antiarrhythmic.  相似文献   

11.

Background

Intestinal ischemia-reperfusion (I-R) injury is a serious abdominal condition leading to multiple organ failure with high mortality. However, no reliable treatment is available. A redox nanoparticle (RNPO) was recently developed, and its efficacy for several intestinal inflammatory conditions has been reported. To this end, the aim of this study was to investigate the therapeutic effects of RNPO on intestinal I-R injury in mice.

Methods

Ischemia was induced in the small intestine of C57BL/6 mice by occluding the superior mesenteric artery for 45 min under anesthesia followed by reperfusion for 4 h. Mice were orally administered the vehicle or RNPO 1 h before ischemia. Inflammatory markers such as histological findings, thiobarbituric acid (TBA)-reactive substances as an index of lipid peroxidation, myeloperoxidase (MPO) activity as an index of neutrophil infiltration, and expression of pro-inflammatory cytokine mRNA in the intestinal mucosa were assessed.

Results

Induction of I-R caused a significant increase in inflammatory markers (histological scores, TBA-reactive substances, MPO activity, and expression of keratinocyte chemoattractant mRNA). These changes were significantly attenuated in RNPO-treated mice as compared to vehicle-treated mice.

Conclusion

Orally administered RNPO attenuated intestinal I-R injury in mice in association with reductions in neutrophil infiltration and lipid peroxidation, suggesting the possibly potential of RNPO as a therapeutic agent for intestinal I-R injury.  相似文献   

12.

Background

Pacing from RV mid septum and outflow tract septum has been proposed as a more physiological site of pacing and narrower paced QRS complex duration. The paced QRS morphology and duration in different RV pacing sites is under continued discussion. Hence, this study was designed to address the correlation of pacing sites in right ventricle with paced QRS complex duration.

Methods

Two hundred fifty-two consecutive patients who underwent pacemaker implantation were enrolled. Baseline clinical characteristics were recorded for each patient. All patient underwent fluoroscopy, electrocardiogram and echocardiography post pacemaker implantation. Paced QRS duration was calculated from the leads with maximum QRS duration.

Results

Mean paced QRS (pQRS) duration was significantly higher in apical septum group with a mean of 148.9?±?14.8?m?s compared to mid septum (139.6?±?19.9?m?s; p-value 0.003) and RVOT septum (139.6?±?14.8?m?s; p-value 0.002) groups, respectively. There was no significant difference between mid-septal and RVOT septal pQRS duration. On multivariate analysis, female gender, baseline QRS duration and RVOT septal pacing were the only predictors for narrow pQRS duration (<150?msec).

Conclusion

RV mid-septal and RVOT septal pacing were associated with significantly lower pQRS duration as compared with apical pacing. Based on multivariate analysis RVOT septal pacing appears to be preferred and more physiological pacing site.  相似文献   

13.

Background

Long noncoding RNAs (lncRNAs) have been revealed to participate in cellular biological processes in multiple diseases, including asthma. Nevertheless, the role of lncRNA TCF7 (lncTCF7) in airway smooth muscle cells (ASMCs) is still covered.

Methods

The expression of lncTCF7 and TIMMDC1 in ASMCs from 12 asthma patients and 12 healthy controls were detected using qRT-PCR. Then MTT assay, EdU assay and transwell assay were conducted respectively to assess the impact of lncTCF7 on ASMCs viability, proliferation and migration. Besides, western blotting was performed to determine the protein levels of TIMMDC1 and AKT/p-AKT.

Results

We discovered that lncTCF7 and TIMMDC1 were upregulated in asthma groups and lncTCF7 improved ASMCs viability/proliferation and migration. In addition, lncTCF7 regulated TIMMDC1 expression indeed and PDGF-BB treated ASMCs exhibited elevated levels of lncTCF7 and TIMMDC1. Moreover, lncTCF7 suppression diminished both the mRNA and protein levels of TIMMDC1 and markedly reduced p-AKT level which could be enhanced under TIMMDC1 overexpression. Finally, both TIMMDC1 overexpression and AKT activator could restored the inhibitory impacts of lncTCF7 silence on PDGF-BB treated ASMCs.

Conclusion

Our study uncovered that lncTCF7 facilitated human ASMCs growth and migration via targeting TIMMDC1 thus activating AKT signaling, providing a novel possible target for asthma therapy.  相似文献   

14.

Background

Cyclosporine-A (CsA) is an immunosuppressant indicated for various immunological diseases; however, it can induce chronic kidney injury. Oxidative stress and apoptosis play a crucial role in CsA-induced nephrotoxicity. The present study evaluated the protective effect of combining 5-aminolaevulinic acid with iron (5-ALA/SFC), a precursor of heme synthesis, to enhance HO-1 activity against CsA-induced chronic nephrotoxicity.

Methods

Mice were divided into three groups: the control group (using olive oil as a vehicle), CsA-only group, and CsA+5-ALA/SFC group. After 28 days, the mice were sacrificed, and blood and kidney samples were collected. In addition to histological and biochemical examination, the mRNA expression of proinflammatory and profibrotic cytokines was assessed.

Results

Renal function in the 5-ALA/SFC treatment group as assessed by the serum creatinine and serum urea nitrogen levels was superior to that of the CsA-only treatment group, demonstrating that 5-ALA/SFC significantly attenuated CsA-induced kidney tissue inflammation, fibrosis, apoptosis, and tubular atrophy, as well as reducing the mRNA level of TNF-α, IL-6, TGF-β1, and iNOS while increasing HO-1.

Conclusion

The activity of 5-ALA/SFC has important implications for clarifying the mechanism of HO-1 activity in CsA-induced nephrotoxicity and may provide a favorable basis for clinical therapy.  相似文献   

15.

Objective

The decreased expression of muscle-specific microRNA-1 (miR-1) has been found in many cardiovascular diseases and is considered to contribute to heart failure (HF). Here we investigated the role of miR-1 in myocardium protection by infusion of miR-1 in a cardiac global miRNA-deficient mouse.

Methods

We generated a cardiac-selective miRNA-deficient mouse by crossing Dicerflox/flox mice with mice expressing tamoxifen-inducible Cre recombinase under the control of a mouse αMHC promoter. When Dicer gene was removed following tamoxifen injection, the mice were treated with micrONTM mmu-miR-1a-3p agomir (agomir-1). The mice were subjected to echocardiography measurement, and the heart tissue specimens were stained with hematoxylin and eosin (H&E) and Sirius red. Terminal deoxynucleotidyl transferase-mediated dUTP nickend labeling assay and Ki67 immunofluorescence were used to determine apoptosis and proliferation.

Results

Dicer deletion resulted in extensive decrease in cardiac miRNAs in the mice. In echocardiography, the mice developed rapid and dramatic left ventricular enlargement. In histology, apparent cardiomyocyte hypertrophy, myofiber disarray, ventricular fibrosis, inflammatory infiltration, and severe ventricular remodeling were exhibited. When the mice were treated with agomir-1, they did not show any significant abnormalities in heart structure and histology in response to Dicer ablation.

Conclusion

The proper expression of miRNAs plays vital roles in the maintenance of heart histology and function. Among these miRNAs, miR-1 is critical to inhibit myocyte hypertrophy and extracellular matrix deposition, thereby preventing cardiac remodeling in cardiac-selective Dicer deficient mice.  相似文献   

16.

Background

Neutrophils are known to be key players in innate immunity. Activated neutrophils induce local inflammation, which results in pathophysiologic changes during intestinal ischemia-reperfusion injury (IRI). However, most studies have been based on static assessments, and few have examined real-time intravital neutrophil recruitment. We herein report a method for imaging and evaluating dynamic changes in the neutrophil recruitment in intestinal IRI using two-photon laser scanning microscopy (TPLSM).

Methods

LysM-eGFP mice were subjected to 45?min of warm intestinal ischemia followed by reperfusion. Mice received an intravenous injection of tetramethylrhodamine isothiocyanate-labeled albumin to visualize the microvasculature. Using a time-lapse TPLSM technique, we directly observed the behavior of neutrophils in intestinal IRI.

Results

We were able to image all layers of the intestine without invasive surgical stress. At low-magnification, the number of neutrophils per field of view continued to increase for 4?h after reperfusion. High-magnification images revealed the presence or absence of blood circulation. At 0–2?h after reperfusion, rolling and adhesive neutrophils increased along the vasculature. At 2–4?h after reperfusion, the irregularity of crypt architecture and transmigration of neutrophils were observed in the lamina propria. Furthermore, TPLSM imaging revealed the villus height, the diameters of the crypt, and the number of infiltrating neutrophils in the crypt. In the IRI group, the villus height 4?h after reperfusion was significantly shorter than in the control group.

Conclusions

TPLSM imaging revealed the real-time neutrophil recruitment in intestinal IRI. Z-stack imaging was useful for evaluating pathophysiological changes in the intestinal wall.  相似文献   

17.

Introduction

With the recent publication of the negative DANISH trial, the mortality benefit of the implantable cardioverter-defibrillator (ICD) has been put in question in patients with non-ischemic cardiomyopathy (NICM). Because a majority of patients in DANISH receive cardiac resynchronization therapy (CRT) devices, we investigated in the present study the survival of recipients of CRT pacemakers (CRT-P) versus CRT ICDs (CRT-D) in a cohort of older (≥75 years) NICM patients at our institution.

Methods

A total of 135 NICM patients with CRT device were identified (42 with CRT-P and 93 with CRT-D) and were followed to the endpoint of all-cause mortality. Overall survival was compared between the CRT-P and CRT-D groups with adjustment for differences in baseline characteristics.

Results

Over a median follow-up of 46 months from the time of CRT device implantation, there were 54 total deaths (40%): 14 in the CRT-P (33%) and 40 in the CRT-D (43%) groups. Overall, CRT-P recipients had similar unadjusted mortality compared to CRT-D recipients (hazard ratio [HR] 1.04, 95% confidence interval [CI] 0.56–1.93), and this remained unchanged after adjusting for unbalanced covariates (HR 0.95, 95% CI 0.47–1.89) including left ventricular ejection fraction, used of angiotensin converting enzyme inhibitors/angiotensin receptor blockers, and the Charlson comorbidity index.

Conclusion

Our data support that in older NICM patients with CRT devices, the addition of ICD therapy does not improve survival.  相似文献   

18.

Background

With increasing use of cardiac resynchronization therapy (CRT), treating physicians should be familiar with different electrocardiographic (ECG) patterns of left ventricular (LV) lead and biventricular (BiV) pacing. However, there are a few publications on ECG patterns during BiV pacing.

Purpose

This study was sought to determine different ECG patterns in patients with BiV pacing.

Methods

Twelve-lead ECGs during BiV pacing (right ventricular leads at apex and LV leads in one of the lateral coronary veins) were analyzed in 181 consecutive patients (121 male; mean age, 62.0 ± 13.5 years) with advanced heart failure and baseline left bundle branch block pattern after at least 6-month of uncomplicated CRT.

Results

During BiV pacing, 65% of the patients showed a dominant R wave in V1. There was a right axis deviation in 57% in frontal plane. However, a left superior axis emerged in 34% and normal frontal plane axis in 9%. Sequential BiV pacing (73% vs. 58%, P = 0.04) and pacing from posterolateral coronary vein (80% vs. 60%, p = 0.045) were more likely to present with a dominant R wave in V1. In sequential pacing, AV interval was significantly longer in patients with negative complex in V1 than in those with positive complex (124 ± 21 vs. 116 ± 8.0, p = 0.005). A Q/q wave was detected in 85% of patients in lead I and 78% in lead aVL.

Conclusions

BiV pacing from lateral coronary venous branches and right ventricular apex characteristically presented with dominant R wave in V1, Q/q wave in leads I and aVL, and right or left superior axis. However, a negative complex in V1, QRS axis in other quadrants, and lack of Q/q wave in leads I and aVL did not necessarily indicate a problem.  相似文献   

19.

Object

The wall thickness of intracranial aneurysms (IAs) is heterogeneous. Although thinning of the IA wall is thought to contribute to IA rupture, the underlying mechanism remains poorly understood. Recently, imaging mass spectroscopy (IMS) has been used to reveal the distribution of phospholipids in vascular diseases. To investigate the feature of phospholipid composition of IA walls, we conducted IMS in a rat model of experimentally induced IA.

Material and methods

IAs were surgically induced in 7-week-old male rats and analyzed by IMS in negative-ion mode.

Results

A molecule at m/z 885.5 was more abundant in the thickened wall than in the thinned wall (P = 0.03). Multiple-stage mass spectroscopy revealed the molecule to be phosphatidylinositol containing stearic acid and arachidonic acid (PI 18:0/20:4). Immunohistochemistry indicated that vascular smooth muscle cells (SMCs) in the thickened wall had dedifferentiated phenotypes. To investigate the relationship between accumulation of PI (18:0/20:4) and phenotypic changes in SMCs, we subjected primary mouse aortic SMCs to liquid chromatography–tandem mass spectrometry. Notably, dedifferentiated SMCs had 1.3-fold more PI (18:0/20:4) than partly differentiated SMCs.

Conclusions

Our study demonstrated the heterogeneity in phospholipid composition of the aneurysmal walls using experimentally induced IAs. PI (18:0/20:4) accumulated at high levels in the thickened aneurysmal wall where synthetic dedifferentiated SMCs exist, suggesting that this phospholipid may be involved in the phenotypic switching of medial SMCs in the IA wall.  相似文献   

20.

Objective

The purpose of this study is to provide a further theoretical basis for the role of Suberoyllanilide hyroxamic acid (SAHA) affect on Dendritic cells (DCs).

Methods

We first downloaded the GSE74306 microarray data, which was about the effect of SAHA act on DCs, from the Gene Expression Omnibus database. Then we analyzed the differential expression genes (DEGs) between SAHA-treated DCs and SAHA-untreated DCs by limma package of R software; The Database for Annotation, Visualization and Integrated Discovery was used to analyze the Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways for these DEGs. The protein protein interaction (PPI) network was constructed by using STRING database, Cytoscape 3.6.1 software was used to dispose the PPI network for visualization. Finally, we determine the Hub genes in the PPI network according by the degree centrality and betweenness centrality, which were calculated by the CentScaPe 2.2 plug-in of Cytoscape 3.6.1 software.

Result

There were 551 DEGs between SAHA-treated DC cells and SAHA-untreated DC cells, including 357 upregulated genes and 194 downregulated genes. These DEGs genes were enriched in 115 Go terms (Biological Process, 51; Cellular Component, 35 and Molecular Function, 29) and a total of 16 pathways. Glutathione metabolic process, Glutathione metabolism pathway, Rheumatoid arthritis pathway and Systemic lupus erythematosus pathway were most significant function clusters. In the PPI network, Rad51, Src, and Eno2 were Hub genes.

Conclusion

The biological function and KEGG pathway enriched by DEGs may reveal the molecular mechanism of SAHA acting on DC cells. Its Hub genes, Src, Rad51 and Eno2, were expected to be new targets for SAHA therapeutic effects. However, it still need to be confirmed by the next more rigorous molecular biological experiments research.  相似文献   

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