Protective effects of intratracheally administered quercetin on lipopolysaccharide-induced acute lung injury

Background

Acute respiratory distress syndrome (ARDS) can result in a life-threatening form of respiratory failure, and established, effective pharmacotherapies are therefore urgently required. Quercetin is one of the most common flavonoids found in fruits and vegetables, and has potent anti-inflammatory and anti-oxidant activities. Quercetin has been demonstrated to exhibit cytoprotective effects through the induction of heme oxygenase (HO)-1. Here, we investigated whether the intratracheal administration of quercetin could suppress lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice as well as the involvement of HO-1 in quercetin’s suppressive effects.

Methods

Mouse model of ALI were established by challenging intratracheally LPS. The wet lung-to-body weight ratio, matrix metalloproteinase (MMP)-9 activities, and pro-inflammatory cytokine productions, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 in bronchoalveolar lavage fluid (BALF) were examined in ALI mice with or without quercetin pretreatment. We also examined the effects of quercetin on LPS stimulation in the mouse alveolar macrophage cell line, AMJ2-C11 cells.

Results

Intratracheal administration of quercetin decreased the wet lung-to-body weight ratio. Moreover, quercetin decreased MMP-9 activity and the production of pro-inflammatory cytokines in BALF cells activated by LPS in advance. We determined the expression of quercetin-induced HO-1 in mouse lung, e.g., alveolar macrophages (AMs), alveolar and bronchial epithelial cells. When AMJ2-C11 cells were cultured with quercetin, a marked suppression of LPS-induced pro-inflammatory cytokine production was observed. The cytoprotective effects were attenuated by the addition of the HO-1 inhibitor SnPP. These results indicated that quercetin suppressed LPS-induced lung inflammation, and that an HO-1-dependent pathway mediated these cytoprotective effects.

Conclusions

Our findings indicated that quercetin suppressed LPS-induced lung inflammation, and that an HO-1-dependent pathway mediated these cytoprotective effects. Intratracheal administration of quercetin will lead to new supportive strategies for cytoprotection in these serious lung conditions.     

我院2010年度药物不良反应分析

目的分析药物不良反应(ADR)发生的特点与规律,促进临床合理用药。方法回顾性分析2010年1~12月我院上报的401份ADR报告,按患者年龄、性别、给药途径、引起ADR的药品种类、涉及器官或系统以及临床表现等进行统计、分析。结果静脉给药较其他给药途径更易发生ADR(336例,占83.89%);抗感染药物引发ADR的比例最高(159例,占39.65%),其次为营养药、消化系统药物及抗肿瘤药物;头孢菌素类药物是引发ADR的主要抗菌药物(15种,28.85%),其次为青霉素类(10种,19.23%)。ADR主要累及皮肤及附件损害为主,其次涉及到消化系统以及神经系统损害。结论临床科室应重视ADR监测,减少ADR的发生,提高合理用药水平。     

我国农业转基因生物安全管理现状

转基因技术可以打破物种界限,实现作物性状的定向改造,在解决粮食增产、环境污染、节水增效,以及改进农产品质量等方面显示出巨大潜力。同时,转基因技术具有潜在的风险,转基因生物的安全性受到人们的广泛关注。本文介绍了我国农业转基因生物安全管理状况,包括法规制度体系、安全评价体系和安全监管体系,旨在让人们更好地了解我国农业转基因生物安全管理知识。     

减毒沙门氏菌介导的血小板第四因子活性片段的放射保护作用研究

目的:观察减毒沙门氏菌携带的血小板第四因子活性片段PF417 70 的放射保护作用。方法:通过口服途经喂饲小鼠携带PF4活性片段的减毒沙门氏菌,在第 2次喂饲后小鼠接受 70 0cGy全身照射,然后观察PIRES2 EGFP PF417 70 在小鼠体内的表达,并观察小鼠的造血恢复情况。结果:在小鼠的肝脏、脾脏、肾脏、小肠、外周血及骨髓均能检测到GFP的表达和转基因的整合。与对照组比较,实验组小鼠的生存期明显延长,照射后第 7d和 1 4d骨髓有核细胞数、骨髓培养的CFU GM和HPP CFC数量明显增加 (P <0 0 5 )。结论:首次应用减毒沙门氏菌SL32 61为载体来介导PF4活性片段的生物学作用,并证实通过口服途径可以保护小鼠免受放射损伤,并促进放射损伤后小鼠的造血恢复。     

鱼类消化道具有吸收外源生长激素的能力

采用草鱼生长激素夹心式酶联免疫吸附测定法（ＥＬＩＳＡ）,研究了重组鲤生长激素（ｒｃＧＨ）经胃或肠灌注后,胡子鲶、大口鲶和银鲫血清ＧＨ水平的变化规律。胡子鲶、大口鲶直肠分别灌注ｒｃＧＨ（１μｇ／ｇ和５μｇ／ｇ）后,血清ＧＨ水平迅速升高,而在对照组胡子鲶和大口鲶血清中未检测到内源性的ＧＨ,预示处理组血清ＧＨ水平的迅速升高是由ｒｃＧＨ从小肠内转移进血液引起的。胡子鲶胃内灌注ｒｃＧＨ（２５μｇ／ｇ）后,在     

Savanna Fires in East-Central Senegal: Distribution Patterns, Resource Management and Perceptions

The temporal and spatial distribution of fires for an area in east-central Senegal was determined on the basis of multi-temporal NOAA AVHRR satellite images. Three years of data (1990–1992) were analyzed defining the boundary between two different fire regimes: very few and scattered fires to the north with the majority of fires south of the boundary. This boundary was stable for the three dry seasons examined and was identical to the northernmost extension of fires as determined by visual inspection of a hard copy Landsat image mosaic. Fire frequencies were analyzed in relation to dominant vegetation types and yearly precipitation, and the findings compared to results of a field survey of the local population's perceptions of the causes and implications of fires. Survey results clearly showed that the use of fire in the study area is closely linked to the utilization of the environment for livestock grazing and crop production. We conclude that the local population has a high degree of awareness about the application of fire, that different fire use practices concerning can be identified respectively in the grasslands of the northern and the savanna of the southern parts of the study area, and that these practices reflect a well adapted production strategy. Finally, we recommend policy decisions be more flexible in the light of local understanding of fire use.     

A mathematical model to investigate the effects of intravenous fluid administration and fluid loss

The optimal fluid administration protocol for critically ill perioperative patients is hard to estimate due to the lack of tools to directly measure the patient fluid status. This results in the suboptimal clinical outcome of interventions. Previously developed predictive mathematical models focus on describing the fluid exchange over time but they lack clinical applicability, since they do not allow prediction of clinically measurable indices. The aim of this study is to make a first step towards a model predictive clinical decision support system for fluid administration, by extending the current fluid exchange models with a regulated cardiovascular circulation, to allow prediction of these indices. The parameters of the model were tuned to correctly reproduce experimentally measured changes in arterial pressure and heart rate, observed during infusion of normal saline in healthy volunteers. With the resulting tuned model, a different experiment including blood loss and infusion could be reproduced as well. These results show the potential of using this model as a basis for a decision support tool in a clinical setting.     

Bicuculline Up-Regulation of GABAA Receptors in Rat Brain

Effects of acute and subacute administration of bicuculline on [3H]muscimol, [3H]flunitrazepam, and t-[35S]butylbicyclophosphorothionate ([35S]TBPS) binding to various brain regions were studied in Sprague-Dawley rats. Acute administration of bicuculline affected neither the KD nor the Bmax of the three receptor sites. In rats treated subacutely with bicuculline (2 mg/kg, i.p., daily for 10 days), [3H]muscimol binding was increased in the frontal cortex, cerebellum, striatum, and substantia nigra. Scatchard analysis revealed that subacute treatment of rats with bicuculline resulted in a significantly lower KD of high-affinity sites in the striatum and in a significantly lower KD of high- and low-affinity sites in the frontal cortex. In the cerebellum, two binding sites were apparent in controls and acutely treated animals; however, only the high-affinity site was defined in subacutely treated animals, with an increase in the Bmax value. Triton X-100 treatment of frontal cortical membranes eliminated the difference in [3H]muscimol binding between control and subacute bicuculline treatments. On the other hand, [3H]muscimol binding was significantly increased in the cerebellum from bicuculline-treated animals even after Triton X-100 treatment. The apparent Ki of bicuculline for the GABAA receptor was also decreased in the frontal cortex and the striatum following the treatment. However, subacute administration of bicuculline affected neither the KD nor the Bmax of [3H]flunitrazepam and [35S]TBPS binding in the frontal cortex and the cerebellum. These results suggest that GABAA receptors are up-regulated after subacute administration of bicuculline, with no change in benzodiazepine and picrotoxin binding sites.     

MicroRNAs and extracellular vesicles in cholangiopathies

Cholangiopathies encompass a heterogeneous group of disorders affecting biliary epithelial cells (i.e. cholangiocytes). Early diagnosis, prognosis and treatment still remain clinically challenging for most of these diseases and are critical for adequate patient care. In the past decade, extensive research has emphasized microRNAs (miRs) as potential non-invasive biomarkers and tools to accurately identify, predict and treat cholangiopathies. MiRs can be released extracellularly conjugated with lipoproteins or encapsulated in extracellular vesicles (EVs). Research on EVs is also gaining attention since they are present in multiple biological fluids and may represent a relevant source of novel non-invasive biomarkers and be vehicles for new therapeutic approaches. This review highlights the most promising candidate miRs and EV-related biomarkers in cholangiopathies, as well as their relevant roles in biliary pathophysiology. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.

Discovery of a novel 2-(1H-pyrazolo[3,4-b]pyridin-1-yl)thiazole derivative as an EP1 receptor antagonist and in vivo studies in a bone fracture model

We describe a medicinal chemistry approach to the discovery of a novel EP₁ antagonist exhibiting high potency and good pharmacokinetics. Our starting point is 1, an EP₁ receptor antagonist that exhibits pharmacological efficacy in cystometry models following intravenous administration. Despite its good potency in vitro, the high lipophilicity of 1 is a concern in long-term in vivo studies. Further medicinal chemistry efforts identified 4 as an improved lead compound with good in vitro ADME profile applicable to long term in vivo studies. A rat fracture study was conducted with 4 for 4?weeks to validate its utility in bone fracture healing. The results suggest that this EP₁ receptor antagonist stimulates callus formation and thus 4 has potential for enhancing fracture healing.