桥本甲状腺炎甲状腺组织TRAIL、Caspase-3的表达

目的 研究桥本甲状腺炎(HT)患者甲状腺组织中肿瘤坏死因子相关凋亡诱导配体(TRAIL)、天冬氨酸特异性半胱氨酸蛋白酶-3(caspase-3)的表达及其在HT发病和病理改变中的意义. 方法 采用S-P免疫组织化学方法检测26例HT(HT组)和12例正常甲状腺组织(对照组)中TRAIL、caspase-3的表达情况. 结果 (1)TRAIL、caspase-3在HT组呈高表达,多见于浸润淋巴细胞旁的甲状腺滤泡上皮细胞;而浸润的淋巴细胞TRAIL染色阴性,caspase-3染色呈弱阳性.(2)TRAIL的表达阳性率在HT组明显高于对照组(72.92%vs 41.67%,P＜0.05),前者滤泡上皮细胞的表达强度明显高于后者[(0.051±0.016)vs (0.016±0.010),P＜0.05].(3)caspase-3的表达阳性率在HT组明显高于对照组(92.31%vs 33.33%,P＜0.01),滤泡上皮细胞的表达强度明显高于对照组[(0.065±0.025)vs(0.022±0.008),P＜0.05].(4)TRAIL与caspase-3的表达程度呈正相关 (rs=0.631,P=0.001). 结论 TRAIL与caspase-3可能共同参与HT的病理演变过程,通过表达TRAIL激活caspase-3而诱导甲状腺滤泡细胞凋亡,损伤甲状腺组织.     

Eph家族蛋白研究进展

Eph家族蛋白包括Eph受体和Ephrin配体,是蛋白酪氨酸激酶家族中的最大成员。由于其具有独特的受体-配体复合物的结构特点及其受体与配体间特有的相互作用模式,所以它们极有可能成为疾病治疗的药物靶标,故该蛋白家族的相关领域研究日益受到重视。该文首先从Eph家族蛋白的分类、表达特点、结构和受体-配体相互作用特点以及其在神经系统中的功能等几个方面简要综述了其相关领域的最新研究进展,进而从结构、作用模式、功能几方面对Eph家族蛋白在神经系统疾患防治中的潜在价值和未来的研究方向进行了探讨和展望。     

PPAR-α激动剂对大鼠内皮功能不全的作用及机制探讨

目的:观察PPAR-α激动剂对高脂血症模型大鼠内皮功能不全的作用,并初步探讨其作用机制。方法:称重后,32只SD雄性大鼠随机分成4组,每组8只:正常对照组(A组);正常+非诺贝特治疗组(B组);高脂组(C组);高脂+非诺贝特治疗组(D组)。每周称体重,按体重调整饲料及药物量。12周后,分别检测血脂4项(TC、TG、LDL-c、HDL-c)及血清中NO含量。分离胸主动脉,检测组织匀浆中总NOS活性及离体血管环的舒缩功能。结果:在调脂方面,PPAR-α激动剂非诺贝特能显著降低TG,并能在一定程度上降低LDL,同时显著升高HDL的作用。此外,PPAR-α激动剂非诺贝特具有显著增加总NOS活性及升高NO含量的作用,能显著改善内皮依赖性舒张功能,其作用并不完全依赖于血脂的降低。结论:PPAR-α激动剂非诺贝特能显著增加总NOS活性从而升高NO含量及改善血管内皮依赖性舒张功能,对内皮功能不全起到预防及治疗的作用,这可能是来自于调脂以外的作用。     

Effector modelling of the action of GABA-receptor-complex ligands. Functional interaction between subunits of the complex

Department of Physicochemical Pharmacology, A. V. Bogatskii Physicochemical Institute, Academy of Sciences of the Ukrainian SSR, Odessa. (Presented by Academician of the Academy of Medical Sciences of the USSR A. V. Val'dman.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 105, No. 5, pp. 529–531, May, 1988.     

Relationship between benzodiazepine receptors and experimental anxiety in rats.

The in vitro and in vivo ability of benzodiazepines to inhibit specific 3H-diazepam binding correlated with their ability to increase punished responding in a conflict situation. Conflict and foot shock, the punishing stimulus used in most conflict procedures, also altered 3H-diazepam binding. These data implicate 3H-diazepam binding sites in mediating at least some of the anxiolytic properties of benzodiazepines and suggest the existence of some endogenous substance which might be involved in the etiology of anxiety.     

Structure-activity relationships in kynurenine,diazepam and some putative endogenous ligands of the benzodiazepine receptors

Kynurenine, an endogenous cerebral and peripheral neuroactive metabolite of l-tryptophan, exerts stimulant and convulsant effects in mice, rats and frogs. In mice it (intracerebroventricularly, ICV) antagonized the anticaffeine effect of diazepam and in smaller doses potentiated its sedative action. In rats l-kynurenine (ICV) potentiated the convulsant action of caffeine. The effect of pentylenetetrazol was not altered in either species. The convulsant effect of l-kynurenine is the most resistant among various convulsants towards the protective action of diazepam. The structure of l-kynurenine is similar to benzophenones, metabolites of diazepam, and has four structural fragments common with diazepam. Putative endogenous and non-endogenous ligands of the benzodiazepine receptors have from one to three of these common fragments. Among the antagonists of diazepam exhibiting stimulant and convulsant action ethyl-β-carbonline-3-carboxylate has the same four fragments, Ro 5–3663 and Ro 15–1788 have three and caffeine two. The most striking dissimilarity is a diazo-moiety (NCCN or NCCC N) absent in the structure of l-kynurenine. This moiety seems to be the most important for the binding to the benzodiazepine receptors. A role of each fragment and their combinations as well as the stereoconfiguration for the pharmacological activity is considered. It is suggested that l-kynurenine is a putative endogenous modulator or, less probably, ligand of the benzodiazepine receptor of either type (most probably that which mediates anxiolytic action of benzodiazepines) or a part of this receptor. The benzodiazepine receptor might be a phylogenetically transformed kynurenine receptor. Highly selective antagonism of purines to l-kynurenine suggests that it can modulate the function of the benzodiazepine receptors via purinergic mechanisms. Stimulant and convulsant action of l-kynurenine can be related to a moiety of succinic acid (OCCCCO) which is typical of quinolinic acid, the strongest endogenous convulsant among kynurenines, and aspartic acid, an excitatory amino acid. l-Kynurenine is suggested to be an anxiogenic and convulsigenic endogenous factor.     

Prostasomes as zinc ligands in human seminal plasma

Prostasomes are small vesicles, containing zinc, secreted by prostate in human seminal plasma and showing a physiological role on sperm properties. In this study, the possible correspondence between prostasomes and a prostatic high molecular weight protein complex, recently indicated as zinc ligand, has been investigated. Isolated prostasomes, examined by scanning electron microscopy, were dialysed to evaluate their zinc binding capacity. Furthermore, seminal plasma Sephadex G-75 elution was carried out before and after prostasome removal. Prostasome preparations, containing typical vesicles of 50-500 nm, showed a positive correlation between their zinc and protein levels. They were able to take up zinc against gradient. Furthermore, the seminal zinc amount, bound to the high molecular weight proteins, was strongly reduced in the free-prostasome sample with respect to the total seminal plasma. This study suggested the correspondence between the prostasomes and a high-sized zinc ligand complex of prostatic origin. Therefore, it demonstrated, for the first time, the zinc binding capacity of prostasomes, a new property which could be related to their biological functions.     

Advances in modeling of biomolecular interactions

Modeling of molecular interactions is increasingly used in life science research and biotechnology development. Examples are computer aided drug design, prediction of protein interactions with other molecules, and simulation of networks of biomolecules in a particular process in human body. This article reviews recent progress in the related fields and provides a brief overview on the methods used in molecular modeling of biological systems.     

In Vivo Phage Display to Identify M Cell-Targeting Ligands

PURPOSE: The purpose of this study was to use in vivo phage display screening technology to identify novel lead peptides that target delivery to M cells and to follicle-associated epithelium (FAE) of the intestine. METHODS: Phage display libraries were screened in vivo within the gastrointestinal tract of a rat model by successive screenings across four cycles of selection. RESULTS: Following four cycles of in vivo screening, we identified 30 unique peptide sequences that bound to Peyer's patch tissue, human Caco-2, and rat IEC-6 epithelial cells. Two of the lead targeting peptides, peptides P8 (LETTCASLCYPS) and P25 (VPPHPMTYSCQY), were shown to bind to receptors on the surface of human intestinal tissue. The L-form, D-form, retro-inverted D-form, and selective Cys-to-Ala site-directed mutants of peptides P8 and P25 were also shown to retain binding to Caco-2 cell membranes when immobilized on the surface of a model particulate. Finally, the D-peptide analog of peptide P8 (yqcsytmphppv) enhanced the delivery of polystyrene particles to M cells in vivo in a mouse model, and these particles were delivered into Peyer's patch tissue, as determined by confocal microscopy. CONCLUSIONS: In summary, we have identified novel ligands that target M cells and Peyer's patch tissue, and thus may have utility in the targeted oral delivery of vaccines and vaccine carrier systems to the mucosal immune system within the gastrointestinal tract.     

Population of the HLA ligand database

We have established an HLA ligand database to provide scientists and clinicians with access to Major Histocompatibility Complex (MHC) class I and II motif and ligand data. The HLA Ligand Database is available on the world wide web at http://hlaligand.ouhsc.edu and contains ligands that have been published in peer-reviewed journals. HLA peptide datasets prove useful in several areas: ligands are important as targets for various immune responses while algorithms built upon ligand datasets allow identification of new peptides without time-consuming experimental procedures. A review of the HLA class I ligands in the database identifies strengths and deficiencies in the database and, therefore, the utility of the dataset for identifying new peptides. For instance, 212 HLA-A phenotypes exist of which 23 have a motif determined and 43 have peptides characterized. In terms of number of ligands, HLA-A*0201 has 258 characterized ligands, A*1101 has 25 peptides, while the remaining two-thirds of the HLA-A phenotypes have less than 10 associated peptide sequences. Characterization of ligands and motifs remains roughly the same at the HLA-B locus while the peptides of the HLA-C locus tend to be less characterized. These data show that 74% of HLA class I molecules do not have ligands represented in the database and thus algorithms based on the dataset could not predict ligands for a majority of the US population. Building upon this dataset and knowledge of HLA allelic frequencies, it is possible to plan a systematic expansion of the HLA class I ligand database to better identify ligands useful throughout the population.