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81.
Hypericin phototoxicity induces different modes of cell death in melanoma and human skin cells 总被引:1,自引:0,他引:1
Davids LM Kleemann B Kacerovská D Pizinger K Kidson SH 《Journal of photochemistry and photobiology. B, Biology》2008,91(2-3):67-76
Hypericin, the major component of St. John's Wort, absorbs light in the UV and visible ranges whereupon it becomes phototoxic through the production of reactive oxygen species. Although photodynamic mechanisms (i.e. through endogenous photosensitizers) play a role in UVA phototherapy for the treatment of skin disorders such as eczema and psoriasis, photodynamic therapy employing exogenous photosensitizers are currently being used only for the treatment of certain forms of non-melanoma skin cancers and actinic keratoses. There are few reports however on its use in treating melanomas. This in vitro study analyses the phototoxic effect of UVA (400-315 nm) - activated hypericin in human pigmented and unpigmented melanomas and immortalised keratinocytes and melanocytes. We show that neither hypericin exposure nor UV irradiation alone reduces cell viability. We show that an exposure to 1 microM UVA-activated hypericin does not bring about cell death, while 3 microM activated hypericin induces a necrotic mode of cell death in pigmented melanoma cells and melanocytes and an apoptotic mode of cell death in non-pigmented melanoma cells and keratinocytes. We hypothesis that the necrotic mode of cell death in the pigmented cells is possibly related to the presence of melanin-containing melanosomes in these cells and that the hypericin-induced increase in reactive oxygen species leads to an increase in permeability of melanosomes. This would result in toxic melanin precursors (of an indolic and phenolic nature) leaking into the cytoplasm which in turn leads to cell death. Hypericin localisation in the endoplasmic reticulum in these cells shown by fluorescent microscopy, further support a disruption in cellular processing and induction of cell death. In contrast, this study shows that cells that do not contain melanosomes (non-pigmented melanoma cells and keratinocytes) die by apoptosis. Further, using a mitochondrial-specific fluorescent dye, we show that intracellular accumulation of hypericin induces a mitochondrial-associated caspase-dependent apoptotic mode of cell death. This work suggests that UVA is effective in activating hypericin and that this phototoxicity may be considered as treatment option in some cases of lentigo maligna or lentigo maligna melanoma that are too large for surgical resection. 相似文献
82.
83.
Weichold O Tigges B Bertmer M Möller M 《Journal of colloid and interface science》2008,324(1-2):105-109
A method to prevent the irreversible agglomeration of silica nanoparticles prepared from sodium silicate, which occurs upon treatment with trialkoxy silanes, is presented. Electrostatic stabilisation is maintained by using mixtures of 3-aminopropyltrimethoxysilane and the cationic derivative N-trimethoxysilylpropyl-N,N,N-trimethylammoniumchloride (TMAPS), which gives rise to stable dispersions of aminofunctionalised particles with unusually high amine content. The particles can be isolated and redispersed without significant increase in particle size. However, an increase in the dispersed particle-size was observed on increasing the APS content in the reaction mixture. This was least pronounced for the 9 nm particles prepared from sodium silicate and more pronounced for the 30 nm particles, for which gel and/or precipitate formation occurred at high APS contents. 相似文献
84.
Expanding the Landscape of Diterpene Structural Diversity through Stereochemically Controlled Combinatorial Biosynthesis 下载免费PDF全文
Dr. Johan Andersen‐Ranberg Dr. Kenneth Thermann Kongstad Dr. Morten Thrane Nielsen Dr. Niels Bjerg Jensen Dr. Irini Pateraki Dr. Søren Spanner Bach Britta Hamberger Prof. Dr. Philipp Zerbe Prof. Dr. Dan Staerk Prof. Dr. Jörg Bohlmann Prof. Dr. Birger Lindberg Møller Prof. Dr. Björn Hamberger 《Angewandte Chemie (International ed. in English)》2016,55(6):2142-2146
Plant‐derived diterpenoids serve as important pharmaceuticals, food additives, and fragrances, yet their low natural abundance and high structural complexity limits their broader industrial utilization. By mimicking the modularity of diterpene biosynthesis in plants, we constructed 51 functional combinations of class I and II diterpene synthases, 41 of which are “new‐to‐nature”. Stereoselective biosynthesis of over 50 diterpene skeletons was demonstrated, including natural variants and novel enantiomeric or diastereomeric counterparts. Scalable biotechnological production for four industrially relevant targets was accomplished in engineered strains of Saccharomyces cerevisiae. 相似文献
85.
Electrical impedance gives multivariate complex number data as results. Two examples of multivariate electrical impedance data measured on lipid monolayers in different solutions give rise to matrices (16x50 and 38x50) of complex numbers. Multivariate data analysis by principal component analysis (PCA) or singular value decomposition (SVD) can be used for complex data and the necessary equations are given. The scores and loadings obtained are vectors of complex numbers. It is shown that the complex number PCA and SVD are better at concentrating information in a few components than the na?ve juxtaposition method and that Argand diagrams can replace score and loading plots. Different concentrations of Magainin and Gramicidin A give different responses and also the role of the electrolyte medium can be studied. An interaction of Gramicidin A in the solution with the monolayer over time can be observed. 相似文献
86.
Kjellander B Masimirembwa CM Zamora I 《Journal of chemical information and modeling》2007,47(3):1234-1247
New crystal structures of human CYP2D6 and CYP3A4 have recently been reported, and in this study, we wanted to compare them with previously used homology models with respect to predictions of site of metabolism and ligand-enzyme interactions. The data set consisted of a family of synthetic opioid analgesics with the aim to cover both CYP2D6 and CYP3A4, as most of these compounds are metabolized by both isoforms. The program MetaSite was used for the site of metabolism predictions, and the results were validated by experimental assessment of the major metabolites formed with recombinant CYP450s. This was made on a selection of 14 compounds in the data set. The prediction rates for MetaSite were 79-100% except for the CYP3A4 homology model, which picked the correct site in half of the cases. Despite differences in orientation of some important amino acids in the active sites, the MetaSite-predicted sites were the same for the different structures, with the exception of the CYP3A4 homology model. Further exploration of interactions with ligands was done by docking substrates/inhibitors in the different structures with the docking program GLUE. To address the challenge in interpreting patterns of enzyme-ligand interactions for the large number of different docking poses, a new computational tool to handle the results from the dockings was developed, in which the output highlights the relative importance of amino acids in CYP450-substrate/inhibitor interactions. The method is based on calculations of the interaction energies for each pose with the surrounding amino acids. For the CYP3A4 structures, this method was compared with consensus principal component analysis (CPCA), a commonly used method for structural comparison to evaluate the usefulness of the new method. The results from the two methods were comparable with each other, and the highlighted amino acids resemble those that were identified to have a different orientation in the compared structures. The new method has clear advantages over CPCA in that it is far simpler to interpret and there is no need for protein alignment. The methodology enables structural comparison but also gives insights on important amino acid substrate/inhibitor interactions and can therefore be very useful when suggesting modifications of new chemical entities to improve their metabolic profiles. 相似文献
87.
Britta Hartard C. Máguas M. Lakatos 《Isotopes in environmental and health studies》2013,49(1):111-128
The study presents first data on the δ18O performance of poikilohydrous lichen ground cover, and its potential impact on the isotopic composition of water fluxes arising from subjacent soil layers. As a model organism, the globally distributed lichen Cladina arbuscula was studied under laboratory conditions as well as in the field. During a desiccation experiment, δ18O of the lichen's thallus water and of its respired CO2 became enriched by ~7‰ and followed a similar enrichment pattern to that expected from homoiohydrous, vascular plants. However, the observed degree of enrichment was lower in comparison to vascular plants due to (i) the lichen's inherent lower evaporative resistances; and (ii) a stronger effect of the more depleted surrounding water vapour. In lichens growing in their natural habitat, this specific pattern may show substantial variations depending on prevailing microclimatic conditions. Within a field study, thallus water δ18O of lichens principally proved to become more depleted when close to equilibration with the surroundings. It thereby strongly depended on the absorption of surrounding water vapour. Moreover, the results indicate that lichen mats substantially reduce evaporation rates arising from subjacent soil layers, and may alter the isotopic signal of vapour diffusing away from these layers into more depleted values. 相似文献
88.
Ripphausen P Nisius B Wawer M Bajorath J 《Journal of chemical information and modeling》2011,51(4):837-842
It is well appreciated that the results of ligand-based virtual screening (LBVS) are much influenced by methodological details, given the generally strong compound class dependence of LBVS methods. It is less well understood to what extent structure-activity relationship (SAR) characteristics might influence the outcome of LBVS. We have assessed the hypothesis that the success of prospective LBVS depends on the SAR tolerance of screening targets, in addition to methodological aspects. In this context, SAR tolerance is rationalized as the ability of a target protein to specifically interact with series of structurally diverse active compounds. In compound data sets, SAR tolerance articulates itself as SAR continuity, i.e., the presence of structurally diverse compounds having similar potency. In order to analyze the role of SAR tolerance for LBVS, activity landscape representations of compounds active against 16 different target proteins were generated for which successful LBVS applications were reported. In all instances, the activity landscapes of known active compounds contained multiple regions of local SAR continuity. When analyzing the location of newly identified LBVS hits and their SAR environments, we found that these hits almost exclusively mapped to regions of distinct local SAR continuity. Taken together, these findings indicate the presence of a close link between SAR tolerance at the target level, SAR continuity at the ligand level, and the probability of LBVS success. 相似文献
89.
Free-flow electrophoresis techniques have been applied for separations in various areas of chemistry and biochemistry. Here
we focus on the generation of a free-flow electrophoresis chip and direct monitoring of the separation of different molecules
in the separation bed of the miniaturized chip. We demonstrate a fast and efficient way to generate a low-cost micro-free-flow
electrophoresis (μFFE) chip with a filling capacity of 9.5 μL based on a multi-lamination technique. Separating webs realized
by two transfer-adhesive tapes avoid the problem of gas bubbles entering the separation area. The chip is characterized by
isoelectric focusing markers (IEF markers). The functionality of the chip is demonstrated by free-flow isoelectric focusing
(FFIEF) of the proteins BSA (bovine serum albumin) and avidin and a single-stranded DNA (ssDNA) fragment in the pH range 3
to 10. The separation voltage ranges between 167 V cm−1 and 422 V cm−1, depending on the application. 相似文献
90.