Modelling the metabolic action of human and rat CYP1A2 and its relationship with the carcinogenicity of heterocyclic amines

Cytochrome P450 (CYP) is a family of enzymes responsible for organism detoxification. However, some of the members of the CYP1A subfamily also catalyse the activation of heterocyclic amines (HAs), present in cooked meat, to carcinogenic compounds which have been shown to increase the risk of breast, colorectal and lung cancer. In humans, CYP1A2 is the enzyme with the most significant action in HA metabolism but in rodents CYP1A1 is also important in this biotransformation. Understanding the metabolic action of these enzymes is essential to predict the factors that enable the formation of the carcinogenic products. We have built two models of CYP1A2, one for the human enzyme and one for the rat homologue. The templates chosen include the only X-ray structure published to date for a mammal CYP, a quimeric C2A5 from rabbit, as well as CYPs belonging to Bacillus megaterium (CYPBm-3), Pseudomonas putida (CYPcam), Pseudomonas sp. (CYPterp), and Saccharopolyspora erythraea (CYPeryf). Two HAs, MeIQ (2-amino-3,4-dimethylimidazo[4,5-?]quinoline) and MeIQx (2-amino-3,8-dimethylimidazo[4,5-?]quinoxaline), known substrates of human and rat CYPIA2, were docked in the active site of the models, providing information regarding the different catalytic rates associated with the metabolisms in both enzymes. This is important for analysing the behaviour of animal models concerning the testing of anticancer drugs.     

Theoretical Study on Destruction Mechanism of 2,3,7,8-TCDD by O3 and NO3

采用B3LYP/6-31G(d)方法优化获得O₃及NO₃降解2,3,7,8-TCDD反应通道上驻点的几何构型, 得到微观反应进程,并采用MP2/6-311G(d,p)//B3LYP/6-31G(d)方法计算得到相关反应的活化能. 研究表明,O₃和NO₃采用不同的方式对2,3,7,8-TCDD进行降解. O₃通过臭氧加成及碳碳双键断裂使2,3,7,8-TCDD降解,而NO₃通过氯取代反应使得2,3,7,8-TCDD上2,3,7,8取代位置上的氯原子被取代为氧原子,从而达到有效降解的目的. O₃降解2,3,7,8-TCDD的反应能垒显著小于NO₃降解2,3,7,8-TCDD的反应能垒,表明O₃降解2,3,7,8-TCDD的能力显著高于NO₃.     

Chemical safety of aquatic ecosystems: Biological methods of control

A comparative analysis of biological methods for monitoring the toxic properties of water in the context of ensuring the chemical safety of aquatic ecosystems is carried out. The analysis is based on the time scale of response to the toxic impact, possibility of identifying sources of chemical pollution, quantitative assessment of toxicity effects, and sensitivity. The method of bioassaying the genotoxic properties of native (without preliminary treatment) samples of natural and waste water by recording changes in the number of chromosomal aberrations in transplantable mammalian cell cultures is described in detail as the most informative. The sensitivity of the method makes it possible to detect the genotoxic effects of hydrophobic toxicants at a concentration of less than 1 μg/dm³. Analysis of ecotoxicological situations in surface water bodies indicates that water-soluble compounds not controlled by hydrochemical monitoring can play a key role in the formation of toxic properties of aquatic media.     

本征及掺杂磷烯对2,3,7,8-TCDD吸附机理的计算模拟研究

2,3,7,8-四氯二苯并对二噁英(2,3,7,8-TCDD)是二噁英家族中危害人类和环境最显著的一种.设计一种高效，灵敏的吸附剂来检测和去除2,3,7,8-TCDD对人类和环境的影响是亟需解决的问题.本研究利用基于密度泛函理论(DFT)的计算模拟方法探索了本征磷烯对2,3,7,8-TCDD的吸附机理，并详细考察了掺杂Ti, Fe, Ca, Al金属原子后磷烯对2,3,7,8-TCDD吸附的影响.研究结果表明2,3,7,8-TCDD初始构型会影响磷烯对其吸附，当平躺于磷烯表面时有较大的吸附.而且掺杂金属原子的磷烯对2,3,7,8-TCDD的吸附也存在较大的影响，掺杂金属原子均增大了磷烯对2,3,7,8-TCDD的吸附，其中Ca掺杂磷烯>Fe掺杂磷烯>Ti掺杂磷烯>Al掺杂磷烯.研究结论对于2,3,7,8-TCDD的处理带来了新的思考方向，有望为二噁英的检测和去除提供有用的理论指导.     

磷烧伤的31P NMR研究

为了明确磷烧伤创面及吸收毒性物质的化学形式及分布.作者采用³¹P PNMR波谱,研究皮下注射黄磷、磷酸及磷烧伤后创面残留、肝脏及脑组织吸收的元素磷及其化合物含量.其结果皮下注射非致死与致死剂量的黄磷后,肝脏可测到元素磷的吸收,磷燃烧后创面磷绝大部分转化为磷酸及其结合物,极少部分以元素磷形式存在.致死面积的磷酸烫伤与磷烧伤后肝脏区域磷酸增加4~5倍,未检测到元素磷的波谱,各组脑组织均未检测到元素磷峰,而磷酸峰只有微小的增加.结论为磷烧烧后吸收的主要中毒物质与创面残留的主要化学物质一致,磷烧伤中毒的致死性主要是创面磷酸吸收所致.     

反射式无孔径近场Raman研究(英文)

近场扫描光学显微技术与Raman光谱技术的结合能够在纳米尺度下提供化学 /结构信息 ,这对很多应用都是至关重要的 ,比如硅器件 ,纳米器件 ,量子点及生物样品单分子研究。本文报导了采用无孔径探针的近场Raman研究。我们的系统有两大特征 :1 近场Raman的增强是通过金属探针上的银镀层实现的 ,无需样品准备 ;2 系统在反射模式下工作 ,适用于任何样品。这两点对实际应用是至关重要的。我们首次在实际硅器件上用 1秒积分时间获得了 1维近场Raman映射和 2维近场Raman图象。我们首次展示了由于积分时间短 ,该技术可用于成象用途。因此 ,这是近场扫描Raman研究中的一次巨大进步。此外 ,我们系统中采用的金属探针可同时用于AFM及电学特性成象 ,比如电阻 ,电容 ,这些是器件应用中的重要参数。     

A fluorescence based assay for DNA damage induced by radiation,chemical mutagens and enzymes

A simple and rapid assay to detect DNA damage is reported. This novel assay is based on changes in melting/annealing behavior and facilitated using certain dyes that increase their fluorescence upon association with double stranded (ds)DNA. Damage caused by ultraviolet (UV) radiation, chemical mutagens or restriction enzymes produced an assay response. UV radiation at 254 nm (approximating UV-C) and 360 nm (approximating UV-A) were used to induce the damage in dsDNA. Chemical damage was induced using several compounds with known effects on nucleic acids. Restriction enzymes Hind III, Msp1, Sau 3A1 were used to cut the plasmid (pUC19) at specific sequences in addition to the non-specific endonuclease DNase I. The effects of these types of damage on repeated melting and annealing of dsDNA were observed in real time using several fluorescence indicator dyes. Low concentrations of dsDNA (between 10 and 100 ng/ml) and small volumes (20 μl) were required for this assay. Repeated measures yielded a coefficient of variation of 2% (CV%). In addition to measuring various DNA damaging agents, the potential application of this assay to study the efficiency of various sun blocking agents against UV-induced DNA damage is discussed.     

Integration of Hybrid Dendrimers and Their Generations for Modulated Spatio-Temporal Action

Hybrid dendrimers constitute a unique class of well-defined complex architecture featured with a central domain and bifurcated branches with two different dendritic sequences for their atomic configuration and functional groups at the periphery. This review article pioneers the field of new hybrid dendrimers using different generations by nanoconjugation with metals, carbohydrates, nucleotides, proteins/peptides, carbosilane, urea, silica, stem cells, guanidine, etc. The smart dendrimers contain desirable electrical, magnetic, optical, and biological attributes to increase surface area, monodisperse behavior, dose reduction, dissolution, permeability, long-term stability, and significant decrement in nanotoxicity studies. The higher encapsulation of lipid soluble and insoluble moieties explores an excellent platform for the delivery of drugs (ibuprofen, indomethacin, etc.), nucleic acids (oligonucleotide, siRNA, and aptamer), genetic materials , and chemical diagnostic agents (gadolinium chelates and superparamagnetic iron oxide particles) for imaging. Owing to their flexibility in structural adaptability, different health conditions like glaucoma, inflammation, microbial infection, neurodegenerative problems (Alzheimer's disease and Parkinsonism), and cancer are benefited using such long-lasting drug delivery. Advancements in molecular engineering techniques, 3D printing, artificial intelligence, robotic, green synthesis, and microwave-assisted methods aid in the development of economically reliable and personalized pharmaceutical hybrid dendritic systems resembling antibodies, globular proteins, stem cells, enzymes, and genetic materials.     

核磁共振波谱在肿瘤诊疗中的应用研究进展

在介绍肿瘤样品代谢物的核磁共振波谱技术的研究方法的基础上,从离体组织和活体组织两个方面综述核磁共振波谱(NMR)在诊断肿瘤方面的应用进展,分析了它在肿瘤诊疗中的应用前景。在离体组织方面,人们通过1H和31P-NMR谱观测病人的体液样品、培养的细胞、切除的组织等来研究脂质、磷脂等代谢物的分布,观测肿瘤与对照组织之间的差别。其中利用组织提取物的方法能够得到分辨率较高的图谱,非常适合应用于肿瘤诊断和治疗方法的研究。高分辨魔角旋转(HR-MAS)的方法在肿瘤诊断研究方面展现出新的生命力,利用高分辨魔角旋转技术可以直接得到组织细胞中很多分子水平的代谢物结构和组成信息,因此它在癌症的早期诊断中具有很好的前景。在活体核磁共振波谱诊断肿瘤方面,主要应用1H和31P核磁共振波谱,结合MRI为非侵入性肿瘤分析提供了一种临床可用的方法。MRI与MRS技术的结合将使核磁共振波谱在医学领域有更大的应用空间。     

Fluorine-19 Solid-State NMR Magic-Angle-Turning Experiments Using Multiple-Pulse Homonuclear Decoupling

For compounds giving “crowded” 1-dimensional magic-angle-spinning spectra, information about the local atomic environment in the form of the chemical shift anisotropy (CSA) is sacrificed for high resolution of the less informative isotropic chemical shift. Magic-angle-turning (MAT) NMR pulse sequences preserve the CSA information by correlating it to the isotropic chemical shift in a 2-dimensional experiment. For low natural abundance nuclei such as ¹³C and ¹⁵N and under ¹H heteronuclear dipolar decoupling conditions, the dominant NMR interaction is the chemical shift. For abundant nuclei such as ¹H, ¹⁹F, and ³¹P, the homonuclear dipolar interaction becomes a significant contribution to the observed linewidth in both F₁ and F₂ dimensions. We incorporate MREV8 homonuclear multiple-pulse decoupling sequences into the MAT experiment to give a multiple-pulse MAT (MP-MAT) experiment in which the homonuclear dipolar interaction is suppressed while maintaining the chemical shift information. Extensive use of computer simulation using GAMMA has guided the pulse sequence development. In particular, we show how the MREV8 pulses can be incorporated into a quadrature-detected sequence such as MAT. The MP-MAT technique is demonstrated for a model two-site system containing a mixture of silver trifluoroacetate and calcium difluoride. The resolution in the isotropic evolution dimension is improved by faster sample spinning, shorter MREV8 cycle times in the evolution dimension, and modifications of the MAT component of the pulse sequence.     

Cancer targeting potential of bioinspired chain like magnetite (Fe3O4) nanostructures

Iron is significant, earth abundant and inexpensive materials in everyday use. Non toxicity and clean manufacturing process is still a challenging role in scientific world. The chain like Fe₃O₄ nanostructures were synthesized using the mixtures such as iron nitrate and Rambutan. Magnetite Fe₃O₄ was verified using X-ray powder diffraction (XRD). Metal oxide (Fe–O) and A_1g and E_g phonon modes are substantiated employing Fourier-transform infrared spectroscopy (FTIR) and Raman spectra. A product chemical state was investigated by high resolution X-ray photoelectron spectroscopy (XPS) spectra. Chain like morphology and polycrystalline nature is attributed by transmission electron microscopy (TEM) analysis. Weight loss activity was revealed through thermogravimetric analysis (TGA) analysis. In application studies, higher concentration of Fe₃O₄ nanostructures was more effective than the low concentration. Moreover, cytotoxicity effects and cell viability on human cancer cell lines were observed and tested for cancer treatment.     

The time-dependence of exchange-induced relaxation during modulated radio frequency pulses

The problem of the relaxation of identical spins 1/2 induced by chemical exchange between spins with different chemical shifts in the presence of time-dependent RF irradiation (in the first rotating frame) is considered for the fast exchange regime. The solution for the time evolution under the chemical exchange Hamiltonian in the tilted doubly rotating frame (TDRF) is presented. Detailed derivation is specified to the case of a two-site chemical exchange system with complete randomization between jumps of the exchanging spins. The derived theory can be applied to describe the modulation of the chemical exchange relaxation rate constants when using a train of adiabatic pulses, such as the hyperbolic secant pulse. Theory presented is valid for quantification of the exchange-induced time-dependent rotating frame longitudinal T1rho,ex and transverse T2rho,ex relaxations in the fast chemical exchange regime.     

Micelle-Enhanced Spectrofluorimetric Method for Determination of Cyproheptadine Hydrochloride in Tablets: Application to In-Vitro Drug Release and Content Uniformity Test

A highly sensitive and simple spectrofluorimetric method was developed for the determination of cyproheptadine hydrochloride (CYP) in its pharmaceutical formulations. The proposed method is based on the investigation of the fluorescence spectral behaviour of CYP in a sodium dodecyl sulphate (SDS) micellar system. In aqueous solution, the fluorescence intensity of CYP was greatly enhanced (150 %) in the presence of SDS. The fluorescence intensity was measured at 410 nm after excitation at 280 nm. The fluorescence–concentration plot was rectilinear over the range 0.2–2.0 μg/mL, with lower detection limit of 0.06 μg/mL. The proposed method was successfully applied to the assay of commercial tablets as well as content uniformity testing. The application of the proposed method was extended to test the in-vitro drug release of CYP tablets, according to USP guidelines. The results were statistically compared with those obtained by official USP method and were found to be in good agreement.     

2,3,7,8-TCDD分子结构及振动光谱的理论研究

本文用B3LYP方法,在6-31G＊基组水平上对2,3,7,8-TCDD分子的构型进行了优化,得到它的稳定构型为平面型,具有D2h对称性。在优化构型的基础上计算了红外光谱和Raman光谱,并进行了振动分析。     

Design of multiplexed fiber optic chemical sensing system using clad-removable optical fibers

To prevent possible threats to public safety and economic loss from chemical leakage accidents, novel chemical sensing techniques for regular monitoring and leakage detection have been developed for various fields. We propose a fiber optic liquid chemical sensor (FOCS) system using specialty optical fibers and an optical time domain reflectometer (OTDR), and is based on the leaky wave mode sensing principle. OTDR enables simple multiplexing where individual sensor nodes along the fiber length could be interrogated by a common OTDR. The sensor node in the optical fiber is prepared by removing the desired length of a protective layer using mechanical stripping and chemical etching techniques. A novel laser stripping technique with superior capability to fabricate quasi-distributed dense sensor nodes is devised as well. The FOCS system is further analyzed to characterize the sensor response behavior in relation to the sensor node length and possible environmental and chemical temperature effect. Under the condition satisfying the leaky wave mode principle and within the minimum acceptable refractive index (RI) range by the system, this FOCS system could monitor numerous liquid chemicals with variable refractive indices and has been tested with positive results. In addition, the system shows the possibility for multi-point detection and is further expanded into a hybrid technique capable of estimating the refractive index range of the detected chemical.     

Facile production of multivalent enzyme-nanoparticle conjugates

Nanoparticles (NPs) enable the development of new, biologically relevant, multifunctional agents. Multifunctional NPs can mimic the invasive biological processes involved in cancer metastasis. We have demonstrated a facile and controllable method of conjugating multiple enzyme species to superparamagnetic (SPM) NPs. Horseradish peroxidase, α-glucosidase, and collagenase were conjugated to SPM NPs with a functional enzyme:NP ratio of 15:127:103:1. N-succinimidyl-S-acetylthiopropionate (SATP)-mediated addition of sulfhydryls to enzymes was achieved without significant activity loss. Conjugation of all enzymes was simultaneously accomplished using maleimide reactive groups generated from activation of amines associated with polyethylene glycol molecules on the NP surface. Cross reactivity between enzyme activity assay systems was negligible.     

CHAOS AND OTHER TEMPORAL SELF-ORGANIZATION PATTERNS IN COUPLED ENZYME-CATALYZED SYSTEMS

This paper is a study of the dynamic behaviors of the coupled biochemical model systems containing two instability generating mechanisms. The system, as studied in detail, consists of two allosteric enzymes coupled in series, the first inhibited by its substrates and the second activated by its products. It can exhibit all known patterns of temporal selforganization: periodic oscillation, bistability, hard excitation,birhythmicity, period-doubling leading to chaos, etc. The relationship between these modes of dynamic behavior is analyzed as a function of the control parameter. A plausible reason is given to how the two instability mechanisms cooperate to induce these behaviors. All the four possible combinations of the two instability generators are discussed. At least three out of the four systems are able to exhibit such phenomena. This shows that they can generally be expected to occur in such coupled enzyme-catalyzed systems. Similarities between behaviors of our model system and experimental observations. in a similar chemical system are discussed.     

Geometry and ground-state electronic structure of neutral ruthenium metal complexes of potential relevance to metal-based drugs for cancer control

There is considerable current interest in some Ru metal complexes in relation to the general area of metal-based drugs for cancer control. Therefore, we stress here the potential role of quantum chemical modelling as an aid to cancer technology in the above area. Prompted by earlier experience on the role of a Ru metal surface in influencing the geometry of small adsorbed molecules (e.g. H₂O outside metallic Ru) we here consider models of specific neutral metal complexes with a single Ru atom which are relevant in this area of cancer control using metal-based drugs. In particular, geometries plus some ground-state electronic structure properties are presented using quantum chemical methods.