AMPK调控内质网应激抵抗COPD大鼠肺泡上皮细胞凋亡的实验研究

目的:初步探讨AMPK在内质网应激所致COPD大鼠肺泡上皮细胞凋亡中所起的作用及机制。方法:实验分三组:对照组,COPD模型组,AICAR干预组,以香烟烟雾烟熏加气管内滴注脂多糖方法构建COPD大鼠模型,取大鼠肺组织行HE染色病理观察,免疫组化,western blot检测p-AMPK/AMPK,ORP150,caspase-3及CHOP表达,TUNEL法检测各组凋亡情况。结果:病理HE染色提示模型组大量炎症细胞浸润,肺大疱形成,支气管壁发生狭窄;AICAR干预组炎症细胞较模型组减少。与正常对照组相比,免疫组化及western blot均提示模型组中p-AMPK和ORP150蛋白表达含量增强,差异有统计学意义(P0.05)。而AICAR干预组中p-AMPK/AMPK及ORP150蛋白表达较模型组明显上升,差异有统计学意义(P0.05)。内质网应激相关凋亡指标CHOP及caspase-3的表达在模型组明显增强,较正常组比较差异有显著性(P0.05),而AICAR组中凋亡指标较模型组明显下调。结论:AMPK可以保护肺泡上皮细胞免于香烟烟雾所致内质网应激凋亡,且有可能通过增加ORP150来实现其保护作用。     

Fears,attitudes and opinions of suburban residents with regards to their urban foxes

Throughout Central Europe, foxes have taken over urban areas as their habitat. In Southern Germany, these foxes are also carriers of the small fox tapeworm, which causes a serious zoonotic infection in humans. Therefore, a survey was carried out in a suburb of the city of Munich. A postal questionnaire was used to analyse the attitudes, opinions and fears of these participants towards their urban foxes and the background to these attitudes. Questionnaires were sent to all households with gardens and collected in again via the community council. Seven hundred and seventy-nine or 31% of questionnaires were returned. Only a few people are afraid of the fox itself; however, 55% are afraid of the fox tapeworm. Worming the animals is the preferred counter-measure, with 81% in favour. The majority of inhabitants are pleased to see a fox in the community and feel the animals have a right to live. People are afraid of the tapeworm either because they have children in the household or because of increased knowledge of the subject or because it has increasingly become an issue. On the basis of the results of this study, it is to be expected that radical solutions such as killing the foxes are unlikely to be accepted among the population. Worming of the foxes does, however, meet with general approval.     

Decision analysis approach to risk/benefit evaluation in the ethical review of controlled human infection studies

Risks and benefit evaluation for controlled human infection studies, where healthy volunteers are deliberately exposed to infectious agents to evaluate vaccine efficacy, should be explicit, systematic, thorough, and non-arbitrary. Decision analysis promotes these qualities using four steps: (1) determining explicit criteria and measures for evaluation, (2) identifying alternatives to the study, (3) defining the models used to estimate the measures for each alternative, and (4) running the models to produce the estimates and compare the alternatives. In this paper, we describe how decision analysis might be applied by funders and regulators, as well as by others contemplating the use of novel controlled human infection studies for vaccine development and evaluation.     

Discovery of 4-hydroxy-2-oxo-1,2-dihydroquinolines as potential inhibitors of Streptococcus pneumoniae,including drug-resistant strains

New therapies for treating drug-resistant pneumococcal infections are urgently needed. The novel scaffold 6-hydroxy-4-oxo-1,2-dihydro-4H-quinoline was shown to have similar efficacies against all three different serotypes of S. pneumoniae, ATCC 49617™ (19F), ATCC BAA-1663™ (15B), and ATCC 700904™ (19A), in a resazurin-based high-throughput screen using the Korea Chemical Bank library. Further studies to identify a new lead with this scaffold, including tricyclic pyrrolo[3,2,1-ij]quinolone and pyrido[3,2,1-ij]quinolone derivatives, led to the identification of 6d, 7d and 12a. Compound 6d (IC₅₀ = 0.92, 0.75, and 0.77 µM), 7d (IC₅₀ = 0.57, 0.66, and 0.38 µM) and 12a (IC₅₀ = 0.27, 1.03, and 0.62 µM) showed submicromolar IC₅₀ values against 19F, 15B, and 19A, respectively, and thus serve as a starting point for further optimization. While some of compounds in this series exhibited acceptable pharmacokinetic profiles in preliminary in vivo rat experiments, the most active compound 12a showed poor solubility and high plasma protein binding. Our current research efforts are focused on optimizing compounds to improve physicochemical properties as well as potency.     

Synthesis and biological evaluation of 4-oxoquinoline-3-carboxamides derivatives as potent anti-fibrosis agents

Thirty-one 4-oxoquinoline-3-carboxamides derivatives were synthesized and evaluated for their anti-fibrotic activities by the inhibition of TGF-β1-induced total collagen accumulation and anti-inflammatory activities by the inhibition of LPS-stimulated TNF-α production. Among them, three compounds (10a, 10l and 11g) exhibited potent inhibitory effects on both TGF-β1-induced total collagen accumulation and LPS-stimulated TNF-α production. Furthermore, oral administrations of 10l at a dose of 20 mg/kg/day for 4 weeks effectively alleviated lung inflammation and injury, and decreased lung collagen accumulation in bleomycin-induced pulmonary fibrosis model. Histopathological evaluation of lung tissue confirmed 10l as a potential, orally active agent for the treatment of pulmonary fibrosis.     

Effects of Peanut Genotypes on Meloidogyne Species Interactions

A 3-year microplot study was conducted to characterize the interaction between Meloidogyne arenaria race 1 (MA1) and M. hapla (MH), as affected by the five peanut genotypes: Florigiant, NC 7, NC 6, NC Ac 18416, and NC Ac 18016. The interactive effects on infection (total parasitic forms per root unit) and reproduction potentials of each nematode species and crop damage were determined. As a single population, MA1 had greater infection capacity and caused more crop damage than did MH, but both species had similar reproduction potentials. In mixed infestations, MA1 was more competitive than MH, as reflected by incidence of infection. Infection and reproduction potentials, and crop-damage capabilities of the mixed populations were similar to those of MA1 alone. All peanut genotypes were susceptible to infection by both nematodes. NC 6 was less susceptible to damage by MA1 and the mixed populations than other genotypes. A nematode treatment x genotype interaction was detected for root infection and crop damage, but not for population density or reproduction. With high preplant nematode levels (Pi), the populations reached their peak by midseason, whereas those with low Pi peaked after midseason. Crop damage in the second and third years was correlated with Pi level.     

African trypanosomes and brain infection – the unsolved question

African trypanosomes induce sleeping sickness. The parasites are transmitted during the blood meal of a tsetse fly and appear primarily in blood and lymph vessels, before they enter the central nervous system. During the latter stage, trypanosomes induce a deregulation of sleep–wake cycles and some additional neurological disorders. Historically, it was assumed that trypanosomes cross the blood–brain barrier and settle somewhere between the brain cells. The brain, however, is a strictly controlled and immune‐privileged area that is completely surrounded by a dense barrier that covers the blood vessels: this is the blood–brain barrier. It is known that some immune cells are able to cross this barrier, but this requires a sophisticated mechanism and highly specific cell–cell interactions that have not been observed for trypanosomes within the mammalian host. Interestingly, trypanosomes injected directly into the brain parenchyma did not induce an infection. Likewise, after an intraperitoneal infection of rats, Trypanosoma brucei brucei was not observed within the brain, but appeared readily within the cerebrospinal fluid (CSF) and the meninges. Therefore, the parasite did not cross the blood–brain barrier, but the blood–CSF barrier, which is formed by the choroid plexus, i.e. the part of the ventricles where CSF is produced from blood. While there is no question that trypanosomes are able to invade the brain to induce a deadly encephalopathy, controversy exists about the pathway involved. This review lists experimental results that support crossing of the blood–brain barrier and of the blood–CSF barrier and discuss the implications that either pathway would have on infection progress and on the survival strategy of the parasite. For reasons discussed below, we prefer the latter pathway and suggest the existence of an additional distinct meningeal stage, from which trypanosomes could invade the brain via the Virchow–Robin space thereby bypassing the blood–brain barrier. We also consider healthy carriers, i.e. people living symptomless with the disease for up to several decades, and discuss implications the proposed meningeal stage would have for new anti‐trypanosomal drug development. Considering the re‐infection of blood, a process called relapse, we discuss the likely involvement of the newly described glymphatic connection between the meningeal space and the lymphatic system, that seems also be important for other infectious diseases.     

肺癌合并肺部感染患者病原菌分布、耐药性分析及血清炎性因子检测的临床意义

摘要 目的：探讨肺癌合并肺部感染患者病原菌分布、耐药性分析及血清炎性因子检测的临床意义。方法：选取我院于2018年6月~2020年3月期间收治的肺癌合并肺部感染患者90例为感染组，选取同期我院收治的肺癌未合并肺部感染患者100例为肺癌组，选取同期于我院进行体检的健康志愿者60例为对照组，对肺癌合并肺部感染患者的感染病原菌类型进行总结分析，分析常见病原菌药敏试验结果，统计病原菌耐药率。对比三组受试者的炎性因子水平。结果：90例肺癌合并肺部感染患者的送检痰液标本共检出100株病原菌，100株病原菌中以革兰阴性菌为主，其次为革兰阳性菌、真菌，分别占比63.00%、22.00%、15.00%。肺炎克雷伯菌、鲍氏不动杆菌、铜绿假单胞菌对亚胺培南的耐药率较低，对氨苄西林、甲氨苄啶的耐药率均较高。凝固酶阴性葡萄球菌、金黄色葡萄球菌对万古霉素的耐药率较高，对左氧氟沙星的耐药率较低。白色念珠菌、热带念珠菌对两性霉素B、氟康唑、酮康唑、伊曲康唑的耐药率均较低。感染组、肺癌组的血清白介素-6（IL-6）、降钙素原（PCT）、肿瘤坏死因子-α（TNF-α）水平均高于对照组，且感染组以上指标水平高于肺癌组（P<0.05）。结论：肺癌合并肺部感染患者体内病原菌种类繁多，对常见抗菌药物的耐药性存在差异，且患者体内存在较强的炎性反应，临床应根据药敏结果合理应用抗菌药物 。