Aspirin is an efficient inhibitor of quorum sensing,virulence and toxins in Pseudomonas aeruginosa

Quorum sensing (QS) plays a vital role in regulation of virulence factors and toxins in Pseudomonas aeruginosa, which can cause serious human infections. Therefore, the QS system in P. aeruginosa may be an important target for pharmacological intervention. Activity of aspirin on the QS system was assessed using a reporter strain assay and confirmed using RT-PCR to test expression of virulence factors and toxins. In addition, molecular modeling techniques including docking, flexible alignment and surface mapping were also applied to further understand aspirin's potential QS inhibition activity. Aspirin (6 mg/ml) showed significant reduction (p < 0.01) of quorum sensing signals in P. aeruginosa, including expression of elastase, total proteases, and pyocyanin (p < 0.01) without affecting bacterial viability. Aspirin also significantly reduced organism motility and biofilm production (p < 0.01) and decreased expression of lasI, lasR, rhlI, rhlR, pqsA and pqsR genes by 38, 72, 69, 72, 74 and 43% respectively. Moreover, the expression of Pseudomonas toxins exoS and exoY was reduced by 47 and 55% respectively. The molecular modeling analysis suggests the QS inhibitory action of aspirin occurs through interaction of aspirin's aryl group and Tyr-88 of the LasR receptor, by strong π–π stacking interactions, which associated with a conformational change of the receptor–aspirin complex. The inhibitory effect of aspirin on virulence factors was specific to P. aeruginosa as aspirin at sub-MIC did not affect the biofilm or motility of Escherichia coli.To summarize, the collective data demonstrate that low concentrations of aspirin inhibit quorum sensing of P. aeruginosa.     

阿司匹林对Poly-IC诱导小胶质细胞激活的影响及其机制

目的研究阿司匹林对Poly-IC诱导小胶质细胞激活的影响及其机制。方法通过体外培养小鼠小胶质细胞BV2细胞株,建立Poly-IC刺激诱导小胶质细胞免疫激活模型。本研究分为对照组(不做处理)、模型组(Poly-IC 10μg/ml)、高剂量阿司匹林组(1 mmol/L阿司匹林)、低剂量阿司匹林组(0.1 mmol/L阿司匹林)、高剂量阿司匹林预处理组(Poly-IC 10μg/ml+1 mmol/L阿司匹林)、低剂量阿司匹林预处理组(Poly-IC 10μg/ml+0.1 mmol/L阿司匹林)。应用细胞免疫荧光法检测小胶质细胞吞噬能力﹑活性氧﹑Iba1蛋白表达,RT-qPCR法检测各组小胶质细胞炎症因子IL-1β﹑IL-6﹑IL-10﹑TNF-α﹑COX-2的mRNA表达。结果与对照组相比较,模型组中小胶质细胞形态发生改变,吞噬能力增强,活性氧产生增加,Iba1蛋白表达下降。且模型组中IL-1β(20.55±1.92)﹑IL-6(63.98±7.83)﹑TNF-α(16.84±3.19)﹑COX-2(6.78±0.42)的mRNA表达较对照组IL-1β(1.01±0.14)﹑IL-6(0.95±0.17)﹑TNF-α(1.22±0.38)﹑COX-2(0.87±0.11)显著增加(t=26.14,10.22,17.06,37.07;均P<0.01)。经阿司匹林预处理的小胶质细胞吞噬能力较模型组减弱,活性氧产生较模型组降低,且Iba1蛋白表达较模型组有一定恢复。高剂量阿司匹林预处理组促炎因子IL-1β(9.95±0.52)﹑IL-6(39.64±6.89)﹑TNF-α(1.57±0.42)﹑COX-2(2.47±0.14)的mRNA表达较模型组明显降低(t=14.18,3.69,16.68,27.03;均P<0.01)。结论阿司匹林对Poly-IC诱导小胶质细胞激活有抑制作用,其机制可能与阿司匹林抑制胶质细胞炎性因子的表达有关。     

Additive effect of dabigatran and high-dose aspirin in the development of haemorrhagic pleural effusion in a patient with tuberculous pleuritis

Tuberculous pleuritis can rarely cause haemorrhagic pleural effusion. Dabigatran etexilate can have an additive effect on increasing the risk of haemorrhage. Aspirin cannot cause major haemorrhage, but in the elderly it can cause gastrointestinal bleeding via ulceration of the gastrointestinal mucosa. We report here the case of a 77-year-old male who presented to the hospital with a 2-month history of progressive dyspnoea. He had been taking dabigatran etexilate (220 mg) and high-dose acetylsalicylic acid (aspirin; 300 mg) daily for chronic atrial fibrillation. A chest X-ray revealed a moderately sized right pleural effusion confirmed by a computed tomography scan, which also showed bronchiectasis of both lungs. Dabigatran was discontinued and aspirin was decreased to the minimal therapeutic dose of 100 mg before thoracentesis was performed. Lymphocyte-predominant (50%) haemorrhagic fluid of 500 ml was drained, positive for acid-fast bacilli smear and polymerase chain reaction of Mycobacterium tuberculosis. A chest tube was placed and an additional 1250 ml of haemorrhagic exudate drained out. We treated the patient with a routine regimen of antituberculous medication and the infection resolved without complications other than the bronchiectasis present before treatment. We think that the combination of dabigatran etexilate and high doses of aspirin increased the risk of pleural haemorrhage in this patient with tuberculous pleuritis.     

Combining Antiplatelet and Antithrombotic Therapy (Triple Therapy): What Are the Risks and Benefits?

Most patients with mechanical heart valves and many patients with atrial fibrillation will require long-term anticoagulation therapy. For patients with mechanical prosthetic valves, only warfarin is indicated. However, for patients with nonvalvular atrial fibrillation who are at increased risk for embolic stroke, one of the newer antithrombotic medications, such as rivaroxaban, dabigatran, and apixaban, also can be used. Patients with indications for antithrombotic therapy often will have coexisting vascular disease, such as coronary artery disease, requiring concomitant antiplatelet therapy with aspirin alone or more commonly with a dual antiplatelet regimen, aspirin and clopidogrel, or prasugrel or ticagrelor. The risks and benefits of this approach are still not well defined, and current guidelines have included recommendations based primarily on expert opinion.     

缺血性卒中或短暂性脑缺血发作的双重抗血小板治疗

2013年美国心脏协会/美国卒中协会颁布的缺血性卒中早期处理指南推荐单用阿司匹林进行抗血小板治疗,并未推荐其他抗血小板药,更未推荐联合应用多种抗血小板药.然而,2013年之后发表的大量文献显示,双重抗血小板药在防治缺血性卒中和短暂性脑缺血发作方面优于单个抗血小板药,并评估了双重抗血小板药治疗的安全性.     

Low-molecular –weight heparin in pregnancies after ART -A retrospective study-

Introduction

The utility of an antithrombotic prophylaxis in Assisted Reproductive Technologies (ART) is highly debated. It has been hypothesised that specific effects of heparin on the coagulation system during implantation can improve the number of clinical pregnancies and live births.

Materials and Methods

We studied a cohort of 327 women undergone at least 1 ART cycle before thrombophilia testing. Overall, a number of 751 cycles was analysed. Low-Molecular-Weight Heparin (LMWH) and/or low-dose aspirin (ASA) were prescribed in 132 (17.6%) cycles. Furthermore, all the women underwent thrombophilia screening.

Results

The univariate analysis showed that LMWH with/without ASA was significantly associated with both the outcomes clinical pregnancy and live birth, while the use of ASA was not associated with live birth. The logistic regression showed that the use of LMWH was significantly associated with both the outcomes, clinical pregnancy (OR: 6.0, 95%CI: 2.8-15.6) and live birth (OR: 10.7, 95%CI: 3.2-36.1). The type of ART procedure significantly influenced the likelihood of achieving clinical pregnancy.

Conclusions

Present findings suggest that LMWH alone or combined with ASA could have a role in fostering the implantation of embryos and improving the number of live births after ART.     

华法林与阿司匹林和氯吡格雷三重抗栓治疗的安全性

目的观察有华法林抗栓指征的患者,冠状动脉(简称冠脉)支架植入术后,联合华法林、阿司匹林和氯吡格雷三重抗栓治疗的安全性。方法选择23例心房颤动(有1项以上危险因素)、机械瓣置换术后和左室血栓的患者,冠脉植入药物洗脱支架后,联合华法林、阿司匹林和氯吡格雷(三重抗栓组)治疗,严格控制国际标准化比值(INR)1.6～2.5,观察1年总的和严重出血事件的发生率。分别选择同期86例冠心病患者,植入冠脉支架后应用阿司匹林和氯吡格雷(双重抗血小板组)治疗,64例有华法林抗凝指征的患者,应用华法林抗凝(抗凝组)治疗(INR2.0～3.0)进行比较。结果三重抗栓组1年总的出血发生率为17.4%,与双重抗血小板组(4.7%)比较有显著性差异(P<0.05),而与抗凝组(10.9%)比较差异无显著性。严重出血事件三重抗栓组显著高于其他两者(13.3%vs 1.2%,4.7%,P<0.01或0.05)。结论三重抗栓治疗明显增加患者出血的发生率。     

莫沙必利对阿司匹林致大鼠急性胃黏膜损伤的保护作用

研究显示促胃肠动力药物莫沙必利对胃黏膜损伤具有一定的保护作用。目的：研究不同剂量莫沙必利对阿司匹林致大鼠急性胃黏膜损伤的保护作用及其机制。方法：将50只大鼠随机分为阴性对照组、单纯损伤组以及不同剂量莫沙必利干预组（0．25mg／kg、0．50mg／kg、0．75mg／kg）。干预组大鼠以不同剂量莫沙必利灌胃行预处理,以150mg／kg阿司匹林灌胃制备急性胃黏膜损伤模型。实验第4d,处死大鼠。评估大鼠胃黏膜损伤指数和组织学变化,以免疫组化法检测Occludin蛋白分布,蛋白质印迹法检测Occludin、ZO．1以及磷酸化ERK（p-ERK）、磷酸化JNK（p-JNK）和磷酸化p38（p-p38）蛋白表达。结果：与单纯损伤组相比,各莫沙必利干预组胃黏膜损伤指数均明显降低（P〈0．05）;胃黏膜组织学明显改善;胃黏膜Occludin、ZO-1蛋白表达呈剂量依赖性升高（P〈0．05）;胃黏膜p-ERK、p-p38蛋白表达呈剂量依赖性降低（P〈0．05）;而胃黏膜p-JNK蛋白表达无明显差异。结论：莫沙必利对阿司匹林致大鼠急性胃黏膜损伤具有明显保护作用,其机制可能为降低MAPKs信号通路中ERK和p38蛋白磷酸化程度,并上调胃黏膜紧密连接蛋白Occludin和ZO-1表达,从而改善胃黏膜屏障的功能。