Novel glucocorticoid receptor agonists in the treatment of asthma

Introduction: Inhaled corticosteroids are the only drugs that effectively suppress the airway inflammation, but they can induce considerable systemic and adverse effects when they are administered chronically at high doses. Consequently, the pharmaceutical industry is still searching for newer entities with an improved therapeutic index.

Areas covered: Herein, the authors review the research in the glucocorticoid field to identify ligands of the glucocorticoid receptor (GR). These ligands preferentially induce transrepression with little or no transactivating activity, in order to have a potent anti-inflammatory action and a low side-effects profile.

Expert opinion: Several agents have been synthesized, but few have been tested in experimental models of asthma. Furthermore, only three (BI-54903, GW870086X and AZD5423) have entered clinical development, although the development of at least one of them (BI-54903) was discontinued. The reason for the limited success so far obtained is that the model of transactivation versus transrepression is a too simplistic representation of GR activity. It is difficult to uncouple the therapeutic and harmful effects mediated by GR, but some useful information that might change the current perspective is appearing in the literature. The generation of gene expression ‘fingerprints’ produced by different GR agonists in target and off-target human tissues could be useful in identifying drug candidates with an improved therapeutic ratio.     

A meta-analysis on the relationship of exosomes and the prognosis of lung cancer

Background:A lot of research evidence shows that exosomes play an indelible role in the prognosis of lung cancer, but there are many disputes. Therefore, we conduct a meta-analysis to further demonstrate.Methods:A literature retrieval was performed through a search of PubMed, Embase, Web of Science, Cochrane, CKNI, Wanfang, and other databases to locate documents from the literature that satisfied the inclusion criteria. There were four outcome indicators: overall survival (OS), disease-free survival (DFS), disease-specific survival (DSS), and progression-free survival (PFS). Subgroup analysis was conducted according to sample size, country, detection method, analysis method, and pathological type. Stata 14.0 software was used to evaluate the prognostic value of exosomes in lung cancer.Results:A total of 2456 patients with lung cancer from 29 studies in 16 articles were included. The expression level of exosomes was closely associated with the OS and DFS of patients, although no statistical difference was observed between exosomes and DSS or PFS. Eighteen studies with 2,110 patients were evaluated to examine the prognostic value of exosomes in lung cancer by exploring the association between exosomes and OS. The results showed that exosomes were strongly associated with worse OS, and the combined hazard ratio (HR) was 2.01 (95% confidence interval [CI]: 1.70–2.39, P = .000). Six studies investigated the association between exosomes and DFS, and showed a pooled HR of 2.48 (95% CI: 1.75–3.53, P = .000).Conclusion:Our analysis indicated that the expression level of exosomes was closely associated with the OS and DFS of patients with lung cancer, suggesting that exosomes are associated with poor prognosis of lung cancer. Exosomes may be a new biomarker for the prognosis of lung cancer, although a large number of prospective studies are still needed to support this.     

Naturally occurring bactericidal antibodies specific for Haemophilus influenzae Lipooligosaccharide are present in healthy adult individuals

Nontypeable Haemophilus influenzae (NTHi), a typical mucosal pathogen largely responsible for respiratory infections and pediatric otitis media, has been increasingly recognized as a significant cause of invasive disease, especially in immunocompromised individuals. Lipooligosaccharide (LOS) is a conserved molecule with an important role in H. influenzae virulence and immune evasion, and it may be considered as a vaccine candidate. However, abilities of H. influenzae LOS to induce protective immune response are poorly understood. The goal of this study was to determine whether antibodies against LOS isolated from H. influenzae strains Eagan, Rd and NTHi 375 are present in the sera of normal individuals. Antigen specific IgG and IgM were studied in sera of 71 and 30 healthy adults, respectively. IgG specific for LOS of all three strains was ubiquitously present in our sample population while IgM specific for Eagan, Rd and NTHi 375 LOS compounds was detected in 37%, 63%, and 40% of samples, respectively. All tested serum samples exhibited bactericidal activity against all three H. influenzae strains; the removal of anti-LOS antibodies from the sera resulted in significant increases in bacterial survival of the corresponding strain. NTHi 375 exhibited the highest serum resistance, whereas the Rd strain was the least resistant. Serum bactericidal activity of anti-LOS antibody was mediated via the classical complement pathway. These findings suggest that in healthy adults, naturally acquired complement-activating anti-LOS antibodies significantly contribute to the overall serum bactericidal activity against both encapsulated and non-encapsulated strains of H. influenzae.     

过表达NK4对人肺腺癌A549细胞增殖和凋亡的影响

目的:构建含有NK4基因的重组慢病毒载体(LV-NK4),感染人肺腺癌A549细胞后观察NK4基因的表达,并研究NK4对肺癌A549细胞增殖和凋亡的影响?方法:采用DNA重组技术,将NK4基因克隆至带增强型绿色荧光蛋白(EGFP)的慢病毒载体GV358,脂质体介导法将其与慢病毒包装系统共转染293T细胞,包装为慢病毒,感染A549细胞,观察感染效率?采用逆转录聚合酶链反应(RT-PCR)及免疫印迹法(Western blot)检测NK4基因和蛋白的表达?建立A549(空白对照组)?A549/NK4(实验组)?A549/LV(空病毒对照组)3组细胞;RT-PCR 法测定各组细胞c-met基因水平;噻唑蓝(MTT)比色法测定各组细胞第1~7天增殖情况,绘制生长曲线;流式细胞术检测各组细胞凋亡率?结果:经基因测序证实LV-NK4构建成功;感染后A549细胞中可见明显的NK4蛋白表达,Western blot显示50 000处有蛋白条带;RT-PCR结果显示实验组NK4 mRNA水平较空白对照组和空病毒对照组明显升高(P < 0.01),c-met mRNA水平较其他两组下降(P < 0.05);MTT结果显示实验组细胞从第4天起生长比正常对照组和空病毒对照组均缓慢(P < 0.05);流式细胞术结果显示实验组细胞凋亡率高于正常对照组和空病毒对照组(P < 0.05)?结论:成功构建NK4慢病毒载体且有效转染A549细胞;NK4具有抑制A549细胞增殖并促进其凋亡的作用,可能与下调c-met基因水平有关?     

联合检测血清SP-D、hs-CRP及血浆Fbg水平在慢性阻塞性肺疾病患者病情监测中的价值

[摘要]　目的　探讨联合检测血清肺泡表面活性蛋白-D（SP-D）、超敏-C反应蛋白（hs-CRP）及血浆纤维蛋白原（Fbg）水平在慢性阻塞性肺疾病患者病情监测中的价值。　方法　选取慢性阻塞性肺疾病急性加重（AECOPD）患者30例（AECOPD组）,COPD稳定期患者10例（COPD稳定期组）,健康对照30例（健康对照组）。分别检测3组研究对象的血清SP-D、hs-CRP水平,比较其差异,同时检测AECOPD组及COPD稳定期组患者血浆Fbg水平,并比较其差异。分析血清SP-D、hs-CRP及血浆Fbg水平与FEV1%pred、FEV1/FVC的相关性。　结果　（1）血清SP-D水平AECOPD组（21.90±7.89）ng/mL高于健康对照组（8.07±4.03）ng/mL与COPD稳定期组（12.49±3.52）ng/mL（P<0.05）,COPD稳定期组高于健康对照组（P<0.05）。（2）血清hs-CRP水平AECOPD组（14.23±7.00）mg/L高于健康对照组（1.06±1.09）mg/L与COPD稳定期组（3.19±3.04）mg/L（P<0.05）,COPD稳定期组与健康对照组比较,差异无显著性意义（P>0.05）。（3）血浆Fbg水平AECOPD组（4.27±1.15）g/L高于COPD稳定期组（3.38±1.26）g/L（P<0.05）。(4) COPD患者血清SP-D、hs-CRP及血浆Fbg水平与FEV1%pred、FEV1/FVC无关。　结论　血清SP-D、hs-CRP及血浆Fbg水平可作为COPD诊断及病情监测的良好指标;联合检测上述指标可增加敏感性及特异性。     

凝血和纤溶功能检测对判断慢性阻塞性肺疾病患者病情和并发症的价值

目的探讨凝血和纤溶功能检测对判断慢性阻塞性肺疾病(COPD)患者病情和并发症的价值。方法随机选取我院COPD患者135例,其中稳定期85例(其中24例合并肺栓塞),急性加重期50例,另选取同期门诊体检的健康者50例为对照组,比较各组凝血酶原时间(PT)、部分活化的凝血活酶时间(aPTT)、组织型纤溶酶原激活物(t PA)、纤维蛋白原(Fbg)、D二聚体(D-D)的变化。结果急性发作期COPD组患者PT和aPTT明显延长,tPA、Fbg和D-D水平均明显高于稳定期COPD组和健康对照组(P0.05);COPD患者中上述各项指标均明显高于对照组(P0.05),其中24例COPD合并合并肺栓塞患者,血清Fbg和D-D水平明显高于单纯COPD稳定期组患者,而PT和a PTT延长,差异呈显著性(P0.05)。结论 COPD患者凝血和纤溶功能异常,急性发作期患者常处于高凝低纤溶状态,而合并肺栓塞患者高凝状态更为明显。因此,检测凝血和纤溶指标有助于判断COPD病情和合并症有重要价值。     

β肾上腺素能受体激动剂对离体大鼠肺泡液体清除率的作用

目的探讨β1肾上腺素能受体激动剂地诺帕明、β2肾上腺素能受体激动剂特布他林、β3肾上腺素能受体激动剂BRL37344对离体大鼠肺泡液体清除率(AFC)的作用及机制。方法5%白蛋白等渗生理盐水溶液和不同药物混合后灌注到离体大鼠的肺泡腔内,根据灌注前及其孵育1h后白蛋白浓度的变化来计算大鼠AFC。结果基础AFC为6.9%±2.2%,地诺帕明、特布他林、BRL37344可显著提高AFC(分别为17.1%±2.4%、19.5%±1.2%、19.9%±2.5%)。β1肾上腺素能受体阻滞剂Atenolol可完全抑制地诺帕明提高AFC(6.1%±0.9%)的作用,但不能阻滞特布他林和BRL37344的作用。β2肾上腺素能受体阻滞剂ICI118551完全抑制了特布他林和BRL37344提高AFC(分别为5.7%±0.6%和7.8%±2.6%)的作用,部分抑制了地诺帕明的作用(AFC为12.7%±1.8%)。β3肾上腺素能受体阻滞剂SR59230A部分抑制了BRL37344和特布他林的作用(AFC分别为13.8%±3.1%和14.5%±3.4%),但不能阻滞地诺帕明的作用。结论地诺帕明、特布他林、BRL37344可以显著提高大鼠的AFC。但地诺帕明和特布他林是分别通过β1、β2肾上腺素能受体起作用;而BRL37344可能是通过β2肾上腺素能受体调节的。ICI118551和SR59230A可能分别具有抑制β1或β2肾上腺素能受体的作用。