胸腺肽β4研究进展

β胸腺肽是一个多肽家族,由高度保守的极性氨基酸组成,相对分子质量约5000.研究表明,在绝大多数哺乳动物组织中,胸腺肽β4都是该家族丰度最高的成员。1991年发现胸腺肽β4是人血小板中主要的肌动蛋白隐蔽肽,随后发现它在创伤愈合和血管生成、角膜修复、抑制炎症及肿瘤转移等方面具有重要作用。我们简要综述胸腺肽β4的上述作用及临床应用的研究进展。     

胸腺肽Tβ4

胸腺肽Tβ4是具有多重生物功能的小肽,是肌动蛋白的结合蛋白之一,该多肽的基因差异性表达与肿瘤恶变和转移、胚胎发育等关系密切,本综述了胸腺肽Tβ4的研究进展。     

整合素β4研究进展

整合素又名整联蛋白,是一种介导细胞与其外环境如细胞外基质之间连接的跨膜受体。整合素β4因其特殊的结构,发挥着诸多功能:与整合素α6亚单位组成α6β4,参与构成半桥粒;介导细胞与细胞外基质相互作用、细胞与细胞间相互作用;介导细胞的增殖与存活,迁移和侵袭;通过激活多条信号通路参与各种疾病进程。本文将对整合素β4的结构组成、生理功能及其在呼吸系统、肿瘤、神经系统等相关疾病中的作用进行综述。     

4-Hydroxy-β-damascone and 4-Hydroxy-dihydro-β-damascone from Cigar Tobacco

The cDNA encoding a putative xylose reductase (xyrA) from Aspergillus oryzae was cloned and coexpressed in the yeast Saccharomyces cerevisiae with A. oryzae xylitol dehydrogenase cDNA (xdhA). XyrA exhibited NADPH-dependent xylose reductase activity. The S. cerevisiae strain, overexpressing the xyrA, xdhA, endogenous XKS1, and TAL1 genes, grew on xylose as sole carbon source, and produced ethanol.     

α4β7研究进展

α４β７是一种整合素分子，主要介导淋巴细胞向粘膜部位的迁移和归巢，同时参与一些炎症反应，并对肠相关淋巴组织（ＧＡＬＴ）的发育，粘膜部位的免疫应答等有重要作用。     

Action of rat liver Galβ1-4GlcNAc α(2-6)-sialyltransferase on Manβ1-4GlcNAcβ-OMe,GalNAcβ1-4GlcNAcβ-OMe,Glcβ1-4GlcNAcβ-OMe and GlcNAcβ1-4GlcNAcβ-OMe as synthetic substrates

Incubation of synthetic Man\1-4GlcNAc-OMe, GalNAc1-4GlcNAc-OMe, Glc1-4GlcNAc-OMe, and GlcNAc1-4GlcNac-OMe with CMP-Neu5Ac and rat liver Gal1-4GlcNAc (2-6)-sialyltransferase resulted in the formation of Neu5Ac2-6Man1-4GlcNAc-OMe, Neu5Ac2-6GalNAc1-4GlcNAc-OMe, Neu5Ac2-6Glc1-4GlcNAc-OMe and Neu5Ac2-6GlcNAc1-4GlcNAc-OMe, respectively. Under conditions which led to quantitative conversion of Gal1-4GlcNAc-OEt into Neu5Ac2-6Gal1-4GlcNAc-OEt, the aforementioned products were obtained in yields of 4%, 48%, 16% and 8%, respectively. HPLC on Partisil 10 SAX was used to isolate the various sialyltrisaccharides, and identification was carried out using 1- and 2-dimensional 500-MHz¹H-NMR spectroscopy.Abbreviations 2D 2-dimensional - CMP cytidine 5-monophosphate - CMP-Neu5Ac cytidine 5-monophospho--N-acetylneuraminic acid - COSY correlation spectroscopy - DQF double quantum filtered - HOHAHA homonuclear Hartmann-Hahn - MLEV composite pulse devised by M. Levitt - Neu5Ac N-acetylneuraminic acid - Neu5Ac2en 2-deoxy-2,3-didehydro-N-acetylneuraminic acid     

整合素α4β7研究进展

α4β7是一种整合素分子 ,主要介导淋巴细胞向粘膜部位的迁移和归巢 ,同时参与一些炎症反应 ,并对肠相关淋巴组织 (GAL T)的发育、粘膜部位的免疫应答等有重要作用     

6β-Hydroxy-4-stigmasten-3-one and 6β-hydroxy-4-campesten-3-one

The first naturally occurring 6-hydroxylated Δ⁴-3-oxo steroids with intact sterol side chains have been isolated as a molecular complex from the bark extracts of Melia azedarach L. The complex has been characterized by UV, IR, NMR and MS analyses to consist of 6β-hydroxy-4-stigmasten-3-one and 6β-hydroxy-4-campesten-3-one, and these structures confirmed by partial synthesis.     

Synthesis,structure and anti-acetylcholinesterase activity of 4β-methoxymethyl-4β-demethyl territrem B

4β-Methoxymethyl-4β-demethyl territrem B [5] was synthesized from 4β-hydroxymethyl-β-demethyl territrem B [4] by treatment with dimethyl sulfate in methanolic NaOH. The structure of 5 was elucidated by uv, nmr and mass spectra. The IC50 of 5 on acetylcholinesterase (AChE) was 6.30 × 10-5 M, which indicated 0.4% of the anti-AChE activity of territrem B [2]. This revised version was published online in August 2006 with corrections to the Cover Date.     

胸腺素β4与药物开发

胸腺素β4是广泛分布于脊椎动物体内的一种蛋白质,能够调节肌动蛋白聚合、解聚,具有多项生物学功能。胸腺素β4尤其具有促进组织再生、修复的重要功能,在创伤修复、角膜修复和心肌修复方面极具药物开发潜力。近年来,研究者们对胸腺素β4进行了大量生理机制研究,本文对其目前的研究状况和药物开发情况进行了综述。     

A short synthesis of 4-deoxy-4-fluoroglucosaminides: Methylumbelliferyl N-acetyl-4-deoxy-4-fluoro-β-D-glucosaminide

A convenient method of synthesis of 1,6-anhydro-4-deoxy-2-O-tosyl-4-fluoro-β-D-glucopyranose by fusion of 1,6;3,4-dianhydro-2-O-tosyl-β-D-galactopyranose with 2,4,6-trimethylpyridinium fluoride was found. By a successive action of ammonia, methyl trifluoroacetate, and acetic anhydride, the resulting compound was transformed into 1,6-anhydro-3-O-acetyl-2,4-dideoxy-2-trifluoroacetamido-4-fluoro-β-D-glucopyranose, which was converted into 3,6-di-O-acetyl-2,4-dideoxy-2-trifluoroacetamido-4-fluoro-αD-glucopyranosyl fluoride by the reaction with HF/Py. The resulting fluoride was further used as a glycosyl donor in the synthesis of methylumbelliferyl N-acetyl-4-deoxy-4-fluoro-β-D-glucosaminide.     

SMAD4/DPC4基因与TGF-β超家族信号传导

SMAD4基因是一个肿瘤抑制基因。本介绍了SMAD4基因和SMADs家族在TGF-β超家族信号传导中的作用,并讨论了其抑制肿瘤的机制及其与肿瘤发生与发展的关系。     

Effect of vitamin A deficiency on thymosin-β4 and CD4 concentrations

Vitamins are evaluated for their role in immunity. Recently, vitamin A received a particular attention as a critical micronutrient for regulating immune system. Therefore, the present study aimed to search for new about vitamin A. Forty-eight Egyptian adults aged from 18 to 42?years old from both sexes were subjected to clinical examination and nutrition questionnaire and were screened for vitamin A by using ELISA method. Forty subjects were selected and subdivided into two groups. Group 1 with vitamin A at level >200?µg/dl consists of 10 healthy subjects. Group 2 with vitamin A deficiency at level <50?µg/dl consists of 30 subjects. Tβ4 and CD4 levels were also determined by a commercial ELISA kit. Results showed a significant decrease in serum levels of Tβ4 and CD4 in group 2 than group 1 at P < .003 and P < .019 respectively. Both of Tβ4 and CD4 had positive correlation with vitamin A level at P < .000 and P < .003 respectively as well as with each other at p < .000. We concluded that vitamin A deficiency may be influence the levels of Tβ4 and CD4.     

A novel series of [3.2.1] azabicyclic biaryl ethers as α3β4 and α6/4β4 nicotinic receptor agonists

We report the synthesis of a series of [3.2.1]azabicyclic biaryl ethers as selective agonists of α3- and α6-containing nicotinic receptors. In particular, compound 17a from this series is a potent α3β4 and α6/4β4 receptor agonist in terms of both binding and functional activity. Compound 17a also shows potent in vivo activity in CNS-mediated animal models that are sensitive to antipsychotic drugs. Compound 17a may thus be a useful tool for studying the role of α3β4 and α6/4β4 nicotinic receptors in CNS pharmacology.     

Nachweis von Zearalenon-4-β-D-Glucopyranosid in Weizen

Maize (Zea mays) cell cultures were used for the production of zearalenone-4-β-D-glucopyranoside as standard compound. Wheat samples were extracted with acetonitrile: water, applied to a florisil column and eluted with methanol:ethyl acetate. For determination and quantification of zearalenone-4-β-D-glucopyranoside and zearalenone a LC-MS method was developed. A concentration of 10 μg/kg zearalenone-4-β-D-glucopyranoside and zearalenone was detectable. The recovery rates were calculated to be 69% and 89% at a concentration level of 100 μg/kg for zearalenone-4-β-D-glucopyranoside and zearalenone, respectively.24 Bavarian wheat samples from harvest 1999 were analyzed. Zearalenone was present in 22 out of 24 field samples, the levels ranged from 11–860 μg/kg. Zearalenone-4-β-D-glucopyranoside was found in 10 out of the zearalenone positive samples (42%) at levels ranging from 17 to 104 μg/kg. The amounts of zearalenone-4-β-D-glucopyranoside were correlated to those of zearalenone (r2=0,86; b=0,10).     

Identification of a negative allosteric site on human α4β2 and α3β4 neuronal nicotinic acetylcholine receptors

Acetylcholine-based neurotransmission is regulated by cationic, ligand-gated ion channels called nicotinic acetylcholine receptors (nAChRs). These receptors have been linked to numerous neurological diseases and disorders such as Alzheimer's disease, Parkinson's disease, and nicotine addiction. Recently, a class of compounds has been discovered that antagonize nAChR function in an allosteric fashion. Models of human α4β2 and α3β4 nicotinic acetylcholine receptor (nAChR) extracellular domains have been developed to computationally explore the binding of these compounds, including the dynamics and free energy changes associated with ligand binding. Through a blind docking study to multiple receptor conformations, the models were used to determine a putative binding mode for the negative allosteric modulators. This mode, in close proximity to the agonist binding site, is presented in addition to a hypothetical mode of antagonism that involves obstruction of C loop closure. Molecular dynamics simulations and MM-PBSA free energy of binding calculations were used as computational validation of the predicted binding mode, while functional assays on wild-type and mutated receptors provided experimental support. Based on the proposed binding mode, two residues on the β2 subunit were independently mutated to the corresponding residues found on the β4 subunit. The T58K mutation resulted in an eight-fold decrease in the potency of KAB-18, a compound that exhibits preferential antagonism for human α4β2 over α3β4 nAChRs, while the F118L mutation resulted in a loss of inhibitory activity for KAB-18 at concentrations up to 100 μM. These results demonstrate the selectivity of KAB-18 for human α4β2 nAChRs and validate the methods used for identifying the nAChR modulator binding site. Exploitation of this site may lead to the development of more potent and subtype-selective nAChR antagonists which may be used in the treatment of a number of neurological diseases and disorders.     

电压门控钠离子通道β4亚基的研究进展

电压门控钠离子通道由一个功能性的α亚基孔道蛋白和几个起辅助作用的β亚基组成。已知的4种β亚基共同调节钠离子通道的功能,并且在控制神经兴奋性、细胞黏附、迁移等方面发挥重要作用。其中β4亚基是钠离子通道的阻遏蛋白,可以诱导产生复苏电流。当β4亚基在基因或蛋白质水平表达异常时,会导致多种疾病的发生,如神经退行性疾病、长QT综合征等。我们简要综述了β亚基的结构与功能、各β亚基之间的关系、β亚基异常表达与相关疾病,以及β亚基与钠通道抑制剂的相互作用,并对β4亚基的研究发展方向予以评述。     

钠离子通道β4亚基糖基化的初步研究

异常表达的糖蛋白与PD等多种神经退行性疾病有关。糖蛋白组学研究发现,电压门控钠离子通道β4亚基在PD病人脑组织中表达明显增加。为了深入探索β4亚基及其糖链在帕金森发生发展中的作用,采用PD转基因鼠对其表达进行验证,对其潜在的糖基化位点进行定点突变,构建重组表达质粒。结果发现,在新生PD转基因鼠和野生成鼠脑组织中有~38kDa蛋白条带表达,而在新生野生鼠脑组织中不表达;用PNGase F酶处理去除糖链后,~38kDa蛋白条带变成迁移速递更快的较小分子量条带,说明β4亚基是高度糖基化的蛋白,并且其糖基化与生长发育有关。将突变重组质粒转入HEK-293细胞和小鼠神经瘤细胞Neuro2A中表达,结果发现突变型质粒分子量明显低于野生型。为研究β4亚基及其糖链的功能提供了一定的实验数据并打下了基础。     

胸腺素β4及胸腺素β10与非小细胞肺癌转移和预后关系

目的研究胸腺素β4(thymosinβ4,Tβ4)和胸腺素β10(thymosinβ10 ,Tβ10)在人非小细胞肺癌(NSCLC)组织中表达的临床意义及其与肺癌转移和预后的关系.方法应用免疫组织化学SP法检测Tβ4、和Tβ10在NSCLC中的表达,并结合临床资料分析Tβ4和Tβ10表达意义.结果 NSCLC中,Tβ4和Tβ10主要表达在癌细胞质中,癌组织的表达率分别为76.3%和72.4%.统计分析显示:Tβ4表达水平与肺癌的分化程度呈明显负相关;Tβ10的表达水平与与淋巴结转移呈明显正相关,二者单独表达均与患者的年龄、性别、肺癌的分型无关.Tβ4与Tβ10具有明显相关性,二者共表达时与肺癌的分化程度、淋巴结转移具有更显著相关性.Tβ4、Tβ10、、Tβ4/Tβ10的高表达组5年生存率明显低于低表达组(P<0.05).同时Tβ4可作为肺癌患者预后评估的独立指标.结论 Tβ4和Tβ10的高表达明显增强肺癌的恶性度,促进肺癌转移,使患者预后更差.通过研制降低两者表达的药物将为肺癌的治疗提供新的靶点.     

Synthesis and biological evaluation of 4β-sulphonamido and 4β-[(4'-sulphonamido)benzamide]podophyllotoxins as DNA topoisomerase-IIα and apoptosis inducing agents

A series of new 4β-sulphonamido and 4β-[(4'-sulphonamido)benzamide] conjugates of podophyllotoxin (11a-j and 15a-g) were synthesized and evaluated for anticancer activity against six human cancer cell lines and found to be more potent than etoposide. Some of the compounds 11b, 11d and 11e that showed significant antiproliferative activity in Colo-205 cells, were superior to etoposide. The flow cytometric analysis indicates that these compounds (11b, 11d and 11e) showed G2/M cell cycle arrest and among them 11e is the most effective. It is observed that this compound (11e) caused both single-strand DNA breaks as observed by comet assay as well as double-strand DNA breaks as indicated by γ-H2AX. Further 11e showed inhibition of topo-IIα as observed from Western blot analysis and related studies. Compounds caused activation of ATM as well as Chk1 protein indicating that the compound caused effective DNA damage. Moreover activation of caspase-3, p21, p16, NF-kB and down regulation of Bcl-2 protein suggests that this compound (11e) has apoptotic cell death inducing ability, apart from acting as a topo-IIα inhibitor.