β受体阻滞在心血管疾病中的临床应用研究进展

依据国内外的临床研究和循证医学分析,对β受体阻滞剂在心血管疾病方面的合理应用以及适应证,给药方法进行循证性举证,提示β受体阻滞剂可明显改善心血管疾病的临床预后,除非有禁忌证及不能酎受者,β受体阻滞剂应作为心血管疾病的常规治疗病物广泛应用于心血管疾病。     

刺梨酸的分离与结构研究

从刺梨中分离出一种新的五环三萜酸,命名为刺梨酸。通过光谱分析和衍生物的制备,确定其化学结构为2β,3α,7β,19α-四羟基乌苏-12-烯-28-羧酸。     

Gating modifier peptides as probes of pancreatic beta-cell physiology.

Pancreatic beta-cells depolarize in response to glucose and fire calcium-dependent actions potentials that trigger insulin secretion. The major current responsible for action potential repolarization in these cells is a delayed rectifier and Kv2.1 subunits are thought be a major contributor of the delayed rectifier channels. Hence, blockers of Kv2.1 channels might prolong action potentials and enhance calcium influx and insulin secretion. However, the lack of specific small molecule Kv2.1 inhibitors has hindered the testing of this mechanism. Importantly, several gating modifier peptides inhibit Kv2.1 channels in a relatively specific fashion. Hanatoxin (HaTX) and guangxitoxin-1 (GxTX-1) are examples that have been used to probe the role of Kv2.1 channels in beta-cell physiology. Both HaTX and GxTX-1 strongly inhibit the Kv current of beta-cells from various species, arguing that Kv2.1 subunits contribute significantly to the beta-cell delayed rectifier. GxTX-1 prolongs glucose-triggered action potentials, enhances glucose-dependent intracellular calcium elevations and augments glucose-dependent insulin secretion. Taken together, these data suggest that blockers of Kv2.1 channels may be a useful approach to the design of novel therapeutic agents for the treatment of type 2 diabetes. These studies highlight the utility of gating modifier peptides in the study of physiological systems.     

超抗原TSST-1之靶TCRVβHV4序列的特征分析

首先对人和小鼠的TCRVβ的氨基酸序列进行多序列对准,就Vβ之HV4片段进行比较,分析与超抗原TSST-1结合的四种Vβ（小鼠Vβ3、Vβ15、Vβ17和人Vβ2）之HV4序列内是否存在特定的氨基酸残基排列主型。结果发现:小鼠Vβ3和Vβ17的HV4具有特异的RFSAXCXSNS主型,而小鼠Vβ15和人β2的HV4则含独特的KFXIXH主型。提示:与TSST-1结合的四种Vβ所对应的T细胞识别表位可能不止一个。     

邻苯二甲酸二乙基己酯对新生小鼠睾丸及Leydig细胞影响的实验研究

目的:探讨邻苯二甲酸二乙基己酯(DEHP)对新生小鼠睾丸及Leyd ig细胞形态结构及功能的影响。方法:DEHP分别以低、中、高3组剂量[100、200、500 mg/(kg.d)]灌胃作用于怀孕12 d到产后3 d(GD12~PND3)的KM母鼠,观察DEHP对新生雄性仔鼠体重、睾丸重量、Leyd ig细胞形态结构和3β-羟基类固醇脱氢酶(3-βHSD)活性、酶反应面积的影响。结果:DEHP作用于母鼠后,其雄性子代幼鼠体重和睾丸重量减轻,睾丸Leyd ig细胞形态、超微结构发生改变;高剂量组Leyd ig细胞数量明显增多;低、中剂量组睾酮合成关键酶3β-HSD酶活性下降,酶反应面积减小,但高剂量组在仔鼠出生后15 d时酶活性降低[(吸光度值(0.154±0.011)vs空白对照组(0.222±0.013),P<0.01],而酶反应面积增大[(6 303.0±745.6)μm2vs空白对照组(5 091.4±214.4)μm2,P<0.01)]。结论:DEHP能影响新生雄性小鼠体重、睾丸重量、Leyd ig细胞的形态结构和3β-HSD活性,具有抗雄激素效应。     

Biochemical and ultrastructural alterations produced by miconazole and econazole in Trypanosoma cruzi

Miconazole and econazole, two fungicide imidazole derivatives, completely inhibited growth of Trypanosoma cruzi (Tulahuen strain) at concentrations of about 20 muM. Culturing of T. cruzi in the presence of lower doses of imidazole derivatives produced: decrease of 5,7-diene sterol content in epimastigotes (including ergosterol); disappearance of the nuclear chromatin, vacuolization and decrease in the electron density of the cytoplasm; selective surface alterations as revealed by an increased response to wheat-germ- and phytohemagglutinin. At variance with the effect of miconazole on Candida (De Nollin et al. (1977) Antimicrobial. Agents Chemother. 11, 500-513), miconazole and econazole, under the experimental conditions used, did not increase the rate of hydrogen peroxide generation by T. cruzi.     

新抗喘药物的研究——茶碱衍生物及卤代苯乙醇胺化合物的合成

本文根据β_2-受体兴奋剂和茶碱类药物的作用机制,结合两类药物的基本结构和构效关系,运用新药设计中的拼合原理及生物电子等排原理,设计扦合成了两类共十六个尚未见于文献报导的化合物。经初步药理实验证明均具有抗哮喘作用,其中I_(5-8)活性较高,且对心脏副作用轻微,可望成为治疗哮喘的新药。     

Heterologous Expression of Rat Testis GABAA Receptor β3t Splicing Variant in CHO Cells

Objective To characterize a possible retention function of unique sequence in the 5'end of rat testis GABAA receptor β3t splicing variantMethods Rat testis GABAA receptor β3t splicing variant cDNA was cloned and two eukaryotic expression recombinant plasmids of pEGFP-N1 and pEGFP-C1 were constructed respectively by fusing green fluorescent protein to the N or C-terminus of β3t isoform. The recombinant plasmids were transfected into CHO cells by calcium phosphate co-precipitation method. Fluorescence microscope and laser confocal microscope were used to analyze localization of β3t in the transfected cells. ConA-Texas-Red was used to label cell ER and the localization of rat testis β3t splicing variant in CHO cells was determined.Results When rat testis β3t splicing variant was expressed in CHO cells, two expression patterns were delineated, the distributions of uniform and mainly discrete intracellular compartments respectively. The chimera product failed to be translocated into the cell surface when expressed in CHO cells; whereas the β3 subunit of rat brain was incorporated into the plasma membrane.Conclusion The inability of β3t to target into the ER may be a consequence of the unique 25 specific amino acid segments in the N terminus.     

Neurosteroid modulation of allopregnanolone and GABA effect on the GABA-A receptor

The neurosteroid allopregnanolone (ALLO) or 3α-OH-5α-pregnane-20-one interacts with the GABA type A receptor chloride ion channel complex and enhances the effect of GABA. Animal and human studies suggest that ALLO plays an important role in several disorders including premenstrual syndrome, anxiety, and memory impairment. In contrast to ALLO, steroids with a hydroxy group in the 3β position usually exert a reducing effect and have recently attracted interest due to their suggested role in counteracting the negative action of ALLO. In this study, five different 3β-steroids were tested for their ability to modulate GABA-mediated chloride ion uptake in the absence and presence of ALLO in rat brain microsacs preparations. In addition, the effects of the 3β-steroids and their interaction with ALLO were investigated by patch-clamp recordings of spontaneous inhibitory postsynaptic currents (sIPSCs) in rat hypothalamic neurons from the medial preoptic nucleus (MPN). All tested 3β-steroids reduced the ALLO-enhanced GABA response in cerebral cortex, in hippocampus and in MPN. In cerebellum, only one had this effect. However, in the absence of ALLO, two of the 3β-steroids potentiated GABA-evoked chloride ion uptake and prolonged the sIPSCs decay time, whereas the others had little or no effect. Therefore, it is possible that at least some 3β-steroids can act as positive GABA_A receptor modulators as well as negative modulators depending on whether or not ALLO is present. Finally, these results suggest that the 3β-steroids could be of interest as pharmacological agents that could counteract the negative effects of ALLO.     

实验性糖尿病大鼠肾脏损害和脂质过氧化物水平的动态研究

动态观察实验性糖尿病大鼠于发病后２、４、６、１２、和１６周肾脏损害指标和肾脏脂质过氧化物（ＬＰＯ）水平的变化。结果表明，发病后各观察时间．或糖尿病大鼠２４ｈ尿Ａｌｂ、β２──ＭＧ排泄量和尿ＮＡＧ活性均明显增高，而２４ｈ尿ＴＨＰ排泄量显著降低，肾脏ＬＰＯ水平明显升高。其中尿ＮＡＧ活性、ＴＨＰ排泄量和肾脏ＬＰＯ水平均随病程延长而更趋明显。这些结果提示，在糖尿病早期除有肾小球功能损害外，肾小管也明显受损，过氧化损伤在糖尿病肾病发病中可能是重要因素之一。尿Ａｌｂ、β２──ＭＧ、ＴＨＰ含量和ＮＡＧ活性可作为糖尿病肾病早期肾损害的敏感指标。