DNA interactions of new cytotoxic tetrafunctional dinuclear platinum complex trans,trans-[{PtCl2(NH3)}2(piperazine)

A new tetrafunctional dinuclear platinum complex trans,trans-[{PtCl2(NH3)}2(piperazine)] with sterically rigid linking group was designed, synthesized and characterized. In this novel molecule, the DNA-binding features of two classes of the platinum compounds with proven antitumor activity are combined, namely trans oriented bifunctional mononuclear platinum complexes with a heterocyclic ligand and polynuclear platinum complexes. DNA-binding mode of this new complex was analyzed by various methods of molecular biology and biophysics. The complex coordinates DNA in a unique way and interstrand and intrastrand cross-links are the predominant lesions formed in DNA in cell-free media and in absence of proteins. An intriguing aspect of trans,trans-[{PtCl2(NH3)}2(piperazine)] is that, using a semi-rigid linker, interstrand cross-linking is diminished relative to other dinuclear platinum complexes with flexible linking groups and lesions that span several base pairs, such as tri- and tetrafunctional adducts, become unlikely. In addition, in contrast to the inability of trans,trans-[{PtCl2(NH3)}2(piperazine)] to cross-link two DNA duplexes, the results of the present work convincingly demonstrate that this dinuclear platinum complex forms specific DNA lesions which can efficiently cross-link proteins to DNA. The results substantiate the view that trans,trans-[{PtCl2(NH3)}2(piperazine)] or its analogues could be used as a tool for studies of DNA properties and their interactions or as a potential antitumor agent. The latter view is also corroborated by the observation that trans,trans-[{PtCl2(NH3)}2(piperazine)] is a more effective cytotoxic agent than cisplatin against human tumor ovarian cell lines.     

New insights into human prostacyclin receptor structure and function through natural and synthetic mutations of transmembrane charged residues

BACKGROUND AND PURPOSE: The human prostacyclin receptor (hIP), a G-protein coupled receptor (GPCR) expressed mainly on platelets and vascular smooth muscle cells, plays important protective roles in the cardiovascular system. We hypothesized that significant insights could be gained into the structure and function of the hIP through mutagenesis of its energetically unfavourably located transmembrane charged residues. EXPERIMENTAL APPROACH: Within its putative transmembrane helices fourteen hydrophilic residues, both unique and conserved across GPCRs, were systematically mutated to assess for effects on receptor structure and function. KEY RESULTS: Mutations of ten of the fourteen charged residues to alanine exhibited defective binding and/or activation. Key potential interactions were identified between 6 core residues; E116(3.49)-R117(3.50) (salt bridge TMIII), D274(7.35)-R279(7.40) (salt bridge TMVII), and D60(2.50)-D288(7.49) (H-bond network TMII-TMVII). Further detailed investigation of E116(3.49) (TMIII) with mutation to a glutamine showed a 2.6-fold increase in agonist-independent basal activity. This increase in activity accounts for a proportion ( approximately 13%) of full agonist induced activation. We further characterized two novel naturally occurring human mutations, R77(2.33)C and R279(7.40)C recently identified in a 1455 human genomic DNA sample screen. The R77(2.33)C variant appeared to exclusively affect expression, while the R279(7.40)C variant, exhibited considerable deficiencies in both agonist binding and activation. CONCLUSIONS AND IMPLICATIONS: Transmembrane charged residues play important roles in maintaining the hIP binding pocket and ensuring normal activation. The critical nature of these charged residues and the presence of naturally occurring mutations have important implications in the rational design of prostacyclin agonists for treating cardiovascular disease.     

烟酸肌醇酯中残留吡啶的考察与探讨

本文介绍了用气相色谱法考核八个药厂共28批烟酸肌醇酯中溶剂吡啶的残留量,并发现不同的生产工艺其产品残留量有显著差异。     

毛发有机氯农药残留量与皮下脂肪有机氯蓄积量相关性研究

用湿法消化、气相色谱法测定人发中有机氯农药残留量。结果表明人发有机氯残留与环境负荷水平有密切关系,即农药使用量越高、接触量越多的地区,人群发样中有机氯残留量亦越高。动物模型进一步证实了毛发六六六残留与体脂六六六蓄积,存在着极其密切的相关性(γ=0.685;P<0.001)。因而毛发可作为有机氯农药人体负荷的一种新的代表性材料。     

Characteristic sequential residue environment of amino acids in proteins

The occurrence of all di- and tripeptide segments of proteins was counted in a large data base containing about 119 000 residues. It was found that the abundance of the amino acids does not determine the frequency of the various di- and tripeptide segments. In addition, the frequency of the various tripeptides cannot be predicted from the observed pair-frequency values. The pair-frequency distribution of amino acids is highly asymmetrical, pairs formed from identical residues are generally preferred and amino acids cannot be clustered on the basis of their first neighbour preferences. These data indicate the existence of general short range regularities in the primary structure of proteins. The consequences of these short range regularities were studied by comparing Chou-Fasman parameters with analogous parameters determined from the results of conformational energy calculations of single amino acids. This comparison shows that Chou-Fasman parameters carry significant information about the environment of each amino acid. The success of the Chou-Fasman's prediction and the properties of the pair and triplet distribution of the amino acid residues suggest that every amino acid has a characteristic sequential residue environment in proteins. The observed preferences could be invoked, for example, in protein design or in the study of the evolutionary relationship of proteins.     

甘草废渣中1个新的香豆素类化合物

目的研究甘草Glycyrrhiza uralensis废渣的化学成分。方法采用硅胶吸附柱色谱、Sephadex LH-20柱色谱、高效液相色谱等分离手段进行分离纯化,根据化合物的理化性质和波谱数据鉴定化合物的结构。结果从新疆产甘草废渣75%乙醇提取物中分离得到了5个化合物,分别鉴定为槐香豆素C(1)、3β-O-对羟基-反-肉桂酰-齐墩果酸(2)、3-羰基甘草次酸(3)、3β,18-O-异丙叉-8(14),15-异右松脂烷二烯(4)、3β,18-O-异丙叉-7,15-异右松脂烷二烯(5)。结论化合物1为新的香豆素类化合物,命名为槐香豆素C;化合物2、4、5为首次从该属植物中分离得到。     

毒死蜱在韭菜和土壤中最终残留的研究

为了全面准确地评价毒死蜱及其制剂在韭菜园中使用后的生态环境安全性,指导毒死蜱及其制剂的科学合理使用,有效地保护农业生态环境,确保农产品质量安全;本文借助气相色谱检测技术,通过田间试验研究毒死蜱在韭菜和土壤中的最终残留。实验结果表明,在韭菜生长期按常规用药剂量和高剂量喷施毒死蜱,毒死蜱最终残留表现为：韭菜〈土壤,施药后3d、7d、14d后韭菜中的毒死蜱最终残留量均小于0.1mg/kg,符合GB18406.1-2001《农产品安全质量无公害蔬菜安全要求》（Safety qualification for agricultural product-Safety requirements for non-environmental pollution vegetable）规定的最大残留量1.0mg/kg和GB2763-2005《食品中农药最大残留限量》规定的0.1mg/kg。     

经阴道超声结合彩色多普勒诊断宫内残留物的临床价值

目的探讨阴道超声结合彩色多普勒诊断宫内残留物的临床价值。方法采用腹部超声与阴道超声结合彩色多普勒对116例宫内残留物患者进行超声检查,对比阴道超声结合彩色多普勒检查及腹部超声的灵敏度和漏诊率。结果阴道超声结合彩色多普勒检查的灵敏度为98.28%,腹部超声灵敏度90.52%,差异有统计学意义(P<0.05)。结论阴道超声结合彩色多普勒较腹部超声能更准确地诊断宫内残留物的位置、大小。     

经阴道彩色多普勒超声(TVS)对宫内残留物的诊断价值

目的探讨经阴道彩色多普勒超声(TVS)检查在诊断宫腔内残留组织的临床应用价值。方法将136例临床怀疑宫内组织残留者行经阴道彩色多普勒超声(TVS)检查,观察子宫的大小形态、宫内残留物残留范围及血流情况。结果经阴道彩色多普勒超声(TVS)诊断结果与清宫术后病理检查结果相对照,诊断符合率为97.8%(133/136),误诊率为2.2%(3/136)。结论经阴道彩色多普勒(TVS)超声检查可以准确诊断子宫腔内组织的残留,还可以为临床医师的正确处理提供明确的部位。     

谈医疗器械环氧乙烷残留限量的确定原则

阐述了如何根据ISO10993－7：1997和风险分析确定环氧乙烷灭菌医疗器械的环氧乙烷残留限量,以及确定环氧乙烷限量时需考虑的有关因素。