Relevance of the deletion polymorphisms of the glutathione S-transferases GSTT1 and GSTM1 in pharmacology and toxicology

Although cytosolic glutathione S-transferase (GST) enzymes occupy a key position in biological detoxification processes, two of the most relevant human isoenzymes, GSTT1-1 and GSTM1-1, are genetically deleted (non-functional alleles GSTT1*0 and GSTM1*0) in a high percentage of the human population, with major ethnic differences. The structures of the GSTT and GSTM gene areas explain the underlying genetic processes. GSTT1-1 is highly conserved during evolution and plays a major role in phase-II biotransformation of a number of drugs and industrial chemicals, e.g. cytostatic drugs, hydrocarbons and halogenated hydrocarbons. GSTM1-1 is particularly relevant in the deactivation of carcinogenic intermediates of polycyclic aromatic hydrocarbons. Several lines of evidence suggest that hGSTT1-1 and/or hGSTM1-1 play a role in the deactivation of reactive oxygen species that are likely to be involved in cellular processes of inflammation, ageing and degenerative diseases. There is cumulating evidence that combinations of the GSTM1*0 state with other genetic traits affecting the metabolism of carcinogens (CYP1A1, GSTP1) may predispose the aero-digestive tract and lung, especially in smokers, to a higher risk of cancer. The GSTM1*0 status appears also associated with a modest increase in the risk of bladder cancer, consistent with a GSTM1 interaction with carcinogenic tobacco smoke constituents. Both human GST deletions, although largely counterbalanced by overlapping substrate affinities within the GST superfamily, have consequences when the organism comes into contact with distinct man-made chemicals. This appears relevant in industrial toxicology and in drug metabolism.

Rapid analysis of GSTM1, GSTT1 and GSTP1 polymorphisms using real-time polymerase chain reaction

Polymorphisms of glutathione transferases (GST) are important genetic determinants of susceptibility to environmental carcinogens (Rebbeck, 1997). The GSTs are a multigene family of dimeric enzymes involved in detoxification, and, in a few cases, the bioactivation of a variety of xenobiotics (Hayes et al., 1995). The cytosolic GST enzyme family consists of four major classes of enzymes, referred to as alpha, mu, pi and theta. Several members of this family (for example, GSTM1, GSTT1 and GSTP1) are polymorphic in human populations (Wormhoudt et al., 1999). Molecular epidemiology studies have examined the role of GST polymorphisms as susceptibility factors for environmentally and/or occupationally induced cancers (Wormhoudt et al., 1999). In particular, case-control studies showed a relationship between the GSTM1 null genotype and the development of cancer in association with smoking habits, which has been shown for cancers of the respiratory and gastrointestinal tracts as well as other cancer types (Miller et al., 1997). Only a few molecular epidemiological studies addressed the role of GSTT1 and GSTP1 polymorphisms in cancer susceptibility. Since GSTP1 is a key player in biotransformation/bioactivation of benzo(a)pyrene, GSTP1 may be even more important than GSTM1 in the prevention of tobacco-induced cancers (Harries et al., 1997; Harris et al., 1998). To date, this relationship has not been sufficiently addressed in humans. Comprehensive molecular epidemiological studies may add to the current knowledge of the role of GST polymorphisms in cancer susceptibility and extent of the knowledge gained from approaches that used phenotyping, such as GSTM1 activity as it relates to trans-stilbene oxide, or polymerase chain reaction (PCR) based genotyping of polymorphic isoenzymes (Bell et al., 1993; Pemble et al., 1994; Harries et al., 1997).

聚氧化苯乙烯的合成与性能研究

环氧化合物的聚合物被广泛地应用于表面活性剂，增塑剂，涂料和膜等领域。到目前为止，二乙基锌作为络合催化剂的一种，在合成高分子量，高规整度的环氧化合物的均聚产物方面发挥着重要的作用。由于氧化苯乙烯中苯环的存在，使得氧化苯乙烯的开环聚合行为不同于其它的环氧化合物。在迄今为止的催化体系中，聚氧化苯乙烯的数均分子量只能达到800～4000，分子量分布大于100，玻璃化转变为32-40 ℃，且反应通常需要进行10-60天才能得到较高的聚合产率。本工作采用二乙基锌／α-氧化蒎烯为主要催化体系，对氧化苯乙烯的聚合行为、聚合物结构与性能进行了研究，并研究了不同的旋光性催化配体对氧化苯乙烯不对称聚合结果的影响。实验结果表明：一．二乙基锌／α-氧化蒎烯催化体系可以有效地催化氧化苯乙烯的均聚。聚合反应进行72小时即可以有很高的产率（90％），较高的粘度以及分子量（数均分子量大于2.0 * 10~4）。其催化效率远远大于以往的催化体系。二．所得的聚氧化苯乙烯产物为无色透明的塑料状固体，当其对数比浓粘度为1.38dL/g时，玻璃化转变温度为50 ℃，数均分子量可以达到4.07 * 10~4，重均分子量为2.3 * 10~5，分子量分布为5.7。该聚合物的热分解温度为240～250 ℃（5％weight loss，under N_2）。聚合物在空气中长期放置会发生缓慢氧化降解反应而导致聚合物分子量下降。聚氧化苯乙烯在80 ℃下压膜，可以得到无色透明的薄膜，但较脆。该聚氧化苯乙烯溶于氯仿、二氯甲烷、甲苯、苯、四氢呋喃、二氧六环等溶剂，不溶于己烷、甲醇、丙酮等。聚氧化苯乙烯膜耐碱不耐浓硫酸，通常不溶于水，但在沸水中煮过后膜呈不透明状，显示出一定的水溶性。三．催化体系中二乙基锌同α-氧化蒎烯的比例变化对聚合反应的结果有较大的影响。当二乙基锌／α-氧化蒎烯为2:1时，聚氧化苯乙烯的产率、粘度、玻璃化转变温度和分子量都达到最高值，相反当比例为1:3和1:4时，只能得到低分子量的聚合物。二乙基锌与α-氧化蒎烯的预反应时间对于聚合反应的结果没有明显的影响。四．聚合反应的产率随反应时间的增长而增长，表明该体系具有阴离子活性聚合的特点。同时，在相同的单体与催化剂比例中，聚氧化苯乙烯的分子量和产率随着氧化苯乙烯单体的浓度降低而增加。五．聚合反应在80 ℃达到最高值，在室温下产率极低而分子量仍然较高，在100 ℃下却导致分子量下降。聚合物的高温处理结果表明，在聚合体系中同时存在着增长与分解反应，两种反应对于温度的依赖程度不同。六．采用二乙基锌／α-氧化蒎烯、Stilbene oxide、环氧肉桂醇等大位阻的环氧化合物作为催化剂配体同样可以催化氧化苯乙烯得到高分子量的聚合物。催化体系同样适用于环氧丙烷、环氧化环己烯的开环聚合。七．采用旋光α-氧化蒎烯、二苯基乙二醇、环氧肉桂醇等手性化合物为配体可以引发氧化苯乙烯的不对称聚合，其中手性环氧肉桂醇的不对称选择能力最强，所得聚合物的旋光值可达-17.2°。八．通过旋光纯的氧化苯乙烯单体的聚合证实了氧化苯乙烯聚合反应的开环方向为β位，所得的旋光性聚氧化苯乙烯同对应的外消旋体相比，其基本性能并无明显差异，两种聚合物同为无定型结构，其中旋光性聚氧化苯乙烯具有较高的立体规整度和热分解温度，同时在添加了防老剂和紫外线吸收剂的两种聚合物中，旋光性聚氧化苯乙烯具有十分优异的耐老化性能。

Separation of enantiomers by nanoliquid chromatography and capillary electrochromatography using a bonded cellulose trisphenylcarbamate stationary phase

A cellulose trisphenylcarbamate-bonded chiral stationary phase was applied to nano-liquid chromatography (nano-LC) and capillary electrochromatography (CEC) with nonaqueous and aqueous solutions as the mobile phases. Several chiral compounds were successfully resolved on the prepared phase by nano-LC. The applicability of nonaqueous CEC on a cellulose derivative stationary phase was investigated with the organic solvents methanol, hexane, 2-propanol, and tetrahydrofuran (THF) containing acetic acid, as well as triethylamine as the mobile phases. Enantiomers of warfarin and praziquantel were baseline-resolved with plate numbers of 82 300 and 38 800 plates/m, respectively, for the first eluting enantiomer. The influence of applied voltage, concentration of nonpolar solvent, apparent pH, and buffer concentration in the mobile phase on the electroosmotic flow (EOF) and the mobility of the enantiomers was evaluated. Enantioseparations of traps-stilbene oxide and praziquantel were also achieved in aqueous CEC with plate numbers of 111 100 and 107 400 plates/m, respectively, for the first eluting enantiomer. A comparison between nonaqueous CEC and aqueous CEC based on a cellulose trisphenylcarbamate stationary phase was discussed. Pressure-assisted CEC was examined for the chiral separation of praziquantel and faster analysis with high enantioselectivity was acquired with the proper pressurization of the inlet vial.

Relevance of the deletion polymorphisms of the glutathione S-transferases GSTT1 and GSTM1 in pharmacology and toxicology

Although cytosolic glutathione S-transterase (GST) enzymes occupy a key position in biological detoxification processes, two of the most relevant human isoenzymes. GST1-1 and GSTM1-1, are genetically deleted (non-functional alleles GSTT1*0 and GsTM1*0) in a high percentage of the human population, with major ethnic differences. The structures of the GSTT and GSTM gene areas explain the underlying genetic processes. GSTT1-1 is highly conserved during evolution and plays a major role in phase-II biotransformation of a number of drugs and industrial chemicals. e.g. cytostatic drugs, hydrocarbons and halogenated hydrocarbons. GSTM1-1 is particularly relevant in the deactivation of carcinogenic intermediates of polycyclic aromatic hydrocarbons. Several lines of evidence Suggest that hGSTT1-1 and/or hGSTM1-1 play a role in the deactivation of reactive oxygen species that are likely to be involved in cellular processes of inflammation, ageing and degenerative diseases. There is cumulating evidence that combinations of the GSTM1*0 state with other genetic traits affecting the metabolism of carcinogens (CYP1A1, GSTP1) may predispose the aero-digestivc tract and lung, especially in smokers, to a higher risk of cancer. The GSTM1*0 status appears also associated with a modest increase in the risk of bladder cancer, consistent with a GSTM1 interaction with carcinogenic tobacco smoke constituents. Both human GST deletions, although largely counterbalanced by overlapping substrate affinities within the GST superfamily, have consequences when the organism comes into contact with distinct man-made chemicals. This appears relevant in industrial toxicology and in drug metabolism.

Infrared and infrared emission spectroscopy of gallium oxide α-GaO(OH) nanostructures

Infrared spectroscopy has been used to study nano to micro sized gallium oxyhydroxide α-GaO(OH), prepared using a low temperature hydrothermal route. Rod-like α-GaO(OH) crystals with average length of ~2.5 μm and width of 1.5 μm were prepared when the initial molar ratio of Ga to OH was 1:3. β-Ga2O3 nano and micro-rods were prepared through the calcination of α-GaO(OH) The initial morphology of α-GaO(OH) is retained in the β-Ga2O3 nanorods. The combination of infrared and infrared emission spectroscopy complimented with dynamic thermal analysis were used to characterise the α-GaO(OH) nanotubes and the formation of β-Ga2O3 nanorods. Bands at around 2903 and 2836 cm-1 are assigned to the -OH stretching vibration of α-GaO(OH) nanorods. Infrared bands at around 952 and 1026 cm-1 are assigned to the Ga-OH deformation modes of α-GaO(OH). A significant number of bands are observed in the 620 to 725 cm-1 region and are assigned to GaO stretching vibrations.

High-performance ceramic membranes with a separation layer of metal oxide nanofibers

In conventional fabrication of ceramic separation membranes, the particulate sols are applied onto porous supports. Major structural deficiencies under this approach are pin-holes and cracks, and the dramatic losses of flux when pore sizes are reduced to enhance selectivity. We have overcome these structural deficiencies by constructing hierarchically structured separation layer on a porous substrate using lager titanate nanofibers and smaller boehmite nanofibers. This yields a radical change in membrane texture. The resulting membranes effectively filter out species larger than 60 nm at flow rates orders of magnitude greater than conventional membranes. This reveals a new direction in membrane fabrication.

Ceramic membranes for separation of proteins and DNA by in situ growth of alumina nanofibres with a nanomesh of metal oxide nanofibres

Ceramic membranes were fabricated by in situ synthesis of alumina nanofibres in the pores of an alumina support as a separation layer, and exhibited a high permeation selectivity for bovine serum albumin relative to bovine hemoglobin (over 60 times) and can effectively retain DNA molecules at high fluxes.

High-flux ceramic membranes with a nanomesh of metal oxide nanofibers

Traditional ceramic separation membranes, which are fabricated by applying colloidal suspensions of metal hydroxides to porous supports, tend to suffer from pinholes and cracks that seriously affect their quality. Other intrinsic problems for these membranes include dramatic losses of flux when the pore sizes are reduced to enhance selectivity and dead-end pores that make no contribution to filtration. In this work, we propose a new strategy for addressing these problems by constructing a hierarchically structured separation layer on a porous substrate using large titanate nanofibers and smaller boehmite nanofibers. The nanofibers are able to divide large voids into smaller ones without forming dead-end pores and with the minimum reduction of the total void volume. The separation layer of nanofibers has a porosity of over 70% of its volume, whereas the separation layer in conventional ceramic membranes has a porosity below 36% and inevitably includes dead-end pores that make no contribution to the flux. This radical change in membrane texture greatly enhances membrane performance. The resulting membranes were able to filter out 95.3% of 60-nm particles from a 0.01 wt % latex while maintaining a relatively high flux of between 800 and 1000 L/m2·h, under a low driving pressure (20 kPa). Such flow rates are orders of magnitude greater than those of conventional membranes with equal selectivity. Moreover, the flux was stable at approximately 800 L/m2·h with a selectivity of more than 95%, even after six repeated runs of filtration and calcination. Use of different supports, either porous glass or porous alumina, had no substantial effect on the performance of the membranes; thus, it is possible to construct the membranes from a variety of supports without compromising functionality. The Darcy equation satisfactorily describes the correlation between the filtration flux and the structural parameters of the new membranes. The assembly of nanofiber meshes to combine high flux with excellent selectivity is an exciting new direction in membrane fabrication.

Synthesis and characterisation of cobalt hydroxide, cobalt oxyhydroxide and cobalt oxide nanodiscs

Cobalt hydroxide, cobalt oxyhydroxide and cobalt oxide nanomaterials were synthesized through simple soft chemistry. The cobalt hydroxide displays hexagonal morphology with clear edges 20 nm long. This morphology and nanosize is retained through to cobalt oxide Co3O4 through a topotactical relationship. Cobalt oxyhydroxide and cobalt oxide nanomaterials were synthesized through oxidation and low temperature calcination from the as-prepared cobalt hydroxide. Characterisation of these cobalt-based nanomaterials were fully developed, including X-ray diffraction, transmission electron microscopy combined with selected area electron diffraction, scanning electron microscopy, X-ray photoelectron spectroscopy, Raman spectroscopy, and thermal gravimetric analysis. Bonding of the divalent cobalt hydroxide from the oxyhydroxide and oxides by studying their high resolution XPS spectra for Co 2p3/2 and O 1s. Raman spectroscopy of the as-prepared Co(OH)2, CoO(OH) and Co3O4 nanomaterials characterised each material. The thermal stability of the materials Co(OH)2 and CoO(OH) were established. This research has developed methodology for the synthesis of cobalt oxide and cobalt oxyhydroxide nanodiscs at low temperatures.