新型阿片受体配基特异性结合μ受体并抑制cAMP生成

本文研究新合成阿片受体配基对稳定表达 μ阿片受体的CHO细胞的受体结合特性和对胞内cAMP的抑制作用。采用放射性配基结合的方法研究了阿片受体配基 [3H] diprenorphine(3H dip)在稳定表达 μ阿片受体的CHO细胞模型上 ,对 μ阿片受体的饱和性结合特征及和一系列新合成阿片配基A、B、C、D、E、F、G、及DAMGO([D Ala ,N Me Phe4 ,Gly ol5] enkephalin)和吗啡的竞争性结合特征。利用竞争性结合蛋白法测定阿片受体配基对胞内cAMP的抑制作用。 [3H] diprenorphine结合 μ阿片受体的Kd值为 1 0 6nmol L ;Bmax为 930fmol mg蛋白。结果表明新配基、DAMGO和吗啡竞争性结合 μ受体的IC50 值分别为 13 33± 3 73、14 36± 1 5 8、0 6 2± 0 0 3、5 6 38± 2 33、6 5 72±2 6 4 4、33 10± 11 33、0 5 5± 0 0 6、3 6 9± 1 5 9和 1 83± 0 5 0。其中C和G配基对 μ阿片受体的亲和力高于DAMGO和吗啡。B、D、E和F配基对μ受体的亲和力低于DAMGO和吗啡。新配基、DAMGO和吗啡抑制cAMP生成的IC50 值分别为 6 4 9± 1 5 9、1390± 6 1 10、0 84± 0 11、2 33± 1 2 4、2 5 0 0± 17 2 0、1 4 2± 1 2 1、0 0 1± 0 0 1、0 10± 0 0 5和0 0 4± 0 0 1。其中G配基的抑制胞内cAMP作用最强 ,强于吗啡 ,类     

葛根素对肺缺血-再灌注损伤时Fas/FasL表达的影响

目的：探讨葛根素对肺缺血-再灌注损伤（PIRI）时Fas/FasL表达的影响。方法：采用在体兔单肺原位缺血-再灌注模型。实验兔70只，随机分为假手术对照组（sham，10只）、肺缺血-再灌注组（I-R，30只）和肺缺血-再灌注加葛根素组（Pur，30只）。每组又分为再灌注1 h、3 h、5 h 3个亚组，每个亚 组10只，分别于再灌注 1 h、3 h、5 h 3个时点取左肺组织，观察Fas/Fas配体（Fas/FasL）mRNA定位表达、凋亡指数（AI）、肺组织湿干重比（W/D）、肺损伤组织学定量评价指标（IQA）及光镜、电镜下的组织形态学改变。结果：肺再灌注1 h、3 h、5 h，Pur组Fas/FasL mRNA在肺小动脉内（外）膜、肺小静脉内膜、肺泡上皮及肺支气管上皮呈弱阳性表达，明显低于同一时点I-R组（P<0.05）；AI、W/D和IQA值显著低于I-R组（P<0.01和P<0.05）；肺组织形态学异常改变不同程度减轻。结论：葛根素可下调肺组织Fas/FasL mRNA的表达而减轻细胞凋亡，对PIRI发挥积极的防治作用。     

Production and detection of monoclonal anti-idiotype antibodies directed against a monoclonal anti-beta-adrenergic ligand antibody

A new method has been developed to raise monoclonal anti-idiotypic antibodies. Monoclonal anti-idiotypic antibodies were obtained by fusion of NS-1 myeloma cells with splenocytes of mice immunised by intravenous injections of fixed hybridoma cells bearing a monoclonal antibody specific for beta-adrenergic ligands. New screening tests were developed to analyse the resulting hybridoma supernatants for different anti-idiotypic properties. Among 23 hybridoma supernatants recognising the idiotype, 6 were found to inhibit hapten binding and 3 of these recognised beta-adrenergic receptors.     

Investigation of activating and inhibitory killer cell immunoglobulin-like receptors and their putative ligands in type 1 diabetes (T1D)

Genetic and environmental factors play important roles in predisposing an individual to the development of type 1 diabetes (T1D). Several studies have investigated the role of killer cell immunoglobulin-like receptors (KIRs) and their HLA-class I ligands in susceptibility to T1D development, but only some of these studies have demonstrated an association. KIRs and their corresponding HLA class I ligands were investigated in Saudi patients with T1D compared with healthy controls. No significant differences in KIR gene distribution were observed between T1D patients and healthy controls. However, the homozygous C1/C1 ligand was considered a risk factor in predisposing individuals to T1D, whereas C2/C2 and HLA-Bw4 were considered protective factors against T1D. KIR2DL2/2DS2-C1C1 and KIR2DL3-C1C1 were significantly associated with T1D, and KIR2DS1-C2C2 and KIR2DL1-C2C2 were significantly less frequent in T1D patients. Stratification of KIR-HLA class I ligands in terms of the absence/presence of specific genotypes has different indications for susceptibility to T1D.     

Antileukemic action of novel diamine Pt(II) halogenido complexes: Comparison of the representative novel Pt(II) with corresponding Pt(IV) complex

This study presents the synthesis, characterization, and antitumor action of five new Pt(II ) halogenido, chlorido, and iodido complexes with edda type of ligands. (S,S)‐ Ethylenediamine‐N,N′‐di‐2‐(3‐cyclohexyl)propanoic acid dihydrochloride and its methyl, ethyl, and n‐propyl esters were prepared according to the previously reported procedure. All investigated complexes were characterized by IR , ESI ‐MS (¹H, ¹³C, and HMBC ) NMR spectroscopy, and elemental analysis. Their cytotoxic action was investigated in four human tumor cell lines: promyelocytic (HL ‐60) and lymphocytic (REH ) leukemia, glioma (U251), and lung carcinoma (H460). Cell viability was assessed by acid phosphatase and LDH assay, while oxidative stress and cell death parameters were analyzed by flow cytometry. The results showed that novel Pt(II ) complexes exhibited antitumor action superior to precursor ligands, with iodido complexes being more efficient than corresponding chlorido complexes. Human promyelocytic cell line (HL ‐60) was the most sensitive to antitumor action of all investigated substances and was used for investigation of the underlying mode of antileukemic action. The investigated Pt(II ) complexes showed more potent antileukemic action than corresponding Pt(IV ) complex, through induction of oxidative stress and apoptosis, evidenced by caspase (8, 9, and 3) activation and phosphatidylserine externalization.     

Targeted nanotechnologies for cancer intervention: a patent review (2010-2016)

Introduction: In recent years, several active targeting nanostrategies have been patented for application in cancer theranostics. The versatility of nanostructures in terms of composition, manufacturability, functionalization, and matrix formation make them ideal for carrying large dose of bioactive contents, high density of targeting ligands on their surface, efficient delivery to the site of interest, and capable of forming multicomponent platforms.

Areas covered: The patents were classified into polymeric and non-polymeric nanostructures and their applicability in addressing the targeting paradigm related to cancer intervention was explored. Specialized platforms such as nanoparticles, nanomicelles, nanocomposites, nanotubes, quantum dots, metal/silica particles, and dendrimers were cited as targeted nanostructures along with ligands such as antibody fragments, synthetic peptides, aptamers, small molecules, and folates. Here, we focused on patented targeted nanotechnological advances in recent years (2010–2016).

Expert opinion: The formulation and performance prerequisites, available nanomaterial options, fabrication feasibility, and challenges and issues related with regulatory approval and patenting of cancer targeted nanocarriers are reviewed. Future research in this area should focus on clinically relevant bioactive combinations, better metastasis control, integration of imaging and theranostic techniques, predictive animal/pre-clinical models, maximal utilisation of extra- and intracellular tumor microenvironment for drug delivery, and exploring the metabolomic-, proteomic-, and genomic-based personalization of cancer nanomedicine.     

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.     

Molecular modeling of μ opioid receptor and receptor-ligand interaction

目的：构建μ阿片受体（μＯＲ）的三维结构模型并研究它与芬太尼衍生物的相互作用．方法：以细菌视紫红质为模板，模拟μＯＲ的三维结构；然后，将芬太尼衍生物对接到μＯＲ的七个α螺旋束之内，并计算结合能．结果：（１）得到受体－配基作用模型．（２）模型中，基本结合位点可能是Ａｓｐ１４７和Ｈｉｓ２９７．Ａｓｐ１４７与配基的正电性铵基形成强的静电和氢键相互作用，这种作用在Ｈｉｓ２９７和配基的羰基Ｏ原子之间较弱．受体、配基间还存在某些π－π相互作用．（３）受体配基结合能与芬太尼衍生物的镇痛活性间有良好的相关性．结论：模型有助于理解受体配基的相互作用和设计新的阿片μ选择性配基．     

Reduction of guinea pig pup isolation calls by anxiolytic and antidepressant drugs

 Guinea pigs possess central 5-HT_1D receptors similar to humans but different from rats and mice. In order to study the role of this receptor on animal behaviour, it may be of interest to develop a paradigm measuring affective states in the guinea pig. Therefore we assessed the effects of a variety of psychotropic drugs on guinea pig pup isolation calls. Anxiolytic compounds such as the benzodiazepine receptor agonists diazepam and alprazolam, the full 5-HT_1A receptor agonists 8-OH-DPAT and flesinoxan, and alcohol reduced isolation calling by the guinea pig pup. Moreover, mixed antidepressant/anxiolytic compounds like the 5-HT uptake inhibitors fluvoxamine and clomipramine or the MAO-inhibitor clorgyline as well as the antidepressant NA uptake inhibitors desipramine and maprotiline suppressed vocalizations. The 5-HT_1D/1A receptor agonist 5-CT was also very effective in reducing separation calls. Remarkably, the partial 5-HT_1A receptor agonists buspirone and BMY 7378 did not affect calling. The neuroleptic haloperidol, the psychostimulant d-amphetamine, the putative anxiogenics DMCM and m-CPP and the putative anxiolytics ondansetron and CI-988 had no effect on isolation calls of guinea pig pups. We propose this paradigm could be helpful to assess behavioural effects of anxiolytic and antidepressant drugs in a species different from rat or mouse, and in which the effects of 5-HT_1D receptor ligands may possibly be established. Received: 18 May 1995 / Final version: 20 June 1996