Jindrich

Monensin Inhibits Canonical Wnt Signaling in Human Colorectal Cancer Cells and Suppresses Tumor Growth in Multiple Intestinal Neoplasia Mice

The Wnt signaling pathway is required during embryonic development and for the maintenance of homeostasis in adult tissues. However, aberrant activation of the pathway is implicated in a number of human disorders, including cancer of the gastrointestinal tract, breast, liver, melanoma, and hematologic malignancies. In this study, we identified monensin, a polyether ionophore antibiotic, as a potent inhibitor of Wnt signaling. The inhibitory effect of monensin on the Wnt/β-catenin signaling cascade was observed in mammalian cells stimulated with Wnt ligands, glycogen synthase kinase-3 inhibitors, and in cells transfected with β-catenin expression constructs. Furthermore, monensin suppressed the Wnt-dependent tail fin regeneration in zebrafish and Wnt- or β-catenin–induced formation of secondary body axis in Xenopus embryos. In Wnt3a-activated HEK293 cells, monensin blocked the phoshorylation of Wnt coreceptor low-density lipoprotein receptor related protein 6 and promoted its degradation. In human colorectal carcinoma cells displaying deregulated Wnt signaling, monensin reduced the intracellular levels of β-catenin. The reduction attenuated the expression of Wnt signaling target genes such as cyclin D1 and SP5 and decreased the cell proliferation rate. In multiple intestinal neoplasia (Min) mice, daily administration of monensin suppressed progression of the intestinal tumors without any sign of toxicity on normal mucosa. Our data suggest monensin as a prospective anticancer drug for therapy of neoplasia with deregulated Wnt signaling. Mol Cancer Ther; 13(4); 812–22. ©2014 AACR.

Nanostructured porous silicon : Optical properties, surface modification and sensor applications

Porous silicon is a very attractive material due to its intense visible photoluminescence at room temperature. Its unique physical and chemical properties are determined by the porous structure where a nanosized silicon layer is formed during the electrochemical etching of crystalline silicon. So far, the high chemical reactivity of the porous silicon surface has prevented its extensive application in optoelectronics. Considerable effort has been put into the development of suitable techniques of stabilization. On the other hand, high chemical reactivity and sorption capacity of porous silicon represent the principal advantage for the construction of sensitive sensors of chemical species. This article provides a brief overview of the ongoing activities in the development of porous-silicon-based chemical sensors at the Charles University and at the Institute of Chemical Technology. So far, the detection of chemical species is based on the measurement of the changes in photoluminescence intensity and photoluminescence decay time, other complementary electrochemical and optical detection methods will follow in order to increase the selectivity of the detection. Another approach resulting in increased selectivity of sensor response utilizes the modification of porous silicon surface - either by physical adsorption or chemical derivatization - by various molecules with recognition properties. Due to the interdisciplinary nature of the research the involved scientists have built a network of collaborating laboratories specialized in various fields - material research, surface chemistry, design and synthesis of the molecules with recognition properties and sensor development.

Probes & Drugs portal: an interactive, open data resource for chemical biology

porated in commercial screening libraries and continue to be used by the community5,6. We developed the P&D portal (Fig. 1 and Supplementary Notes 1–3) to alleviate some of these problems. It is intended to serve as a central hub in chemical biology research, enabling users to easily answer questions both simple (e.g., “How many compounds are shared between these libraries?”) and complicated (e.g., “Which high-potent nuclear hormone receptor ligands, with molecular weight lower than 450, are similar to a given compound but have a different chemotype?”). The P&D portal offers an intuitive yet powerful filtering system (Fig. 1a and Supplementary Note 4), various visualization tools (Fig. 1b, Supplementary Note 5 and Supplementary Table 1) and an advanced chemical intelligence (structure-related queries and structural alerts; i.e., PAINS, aggregators and obsolete compounds) (Fig. 1c and Supplementary Note 6) supported by the implementation of several chemical and biological ontologies (Fig. 1d and Supplementary Note 7). The P&D portal is designed to reflect the current state of bioactive compound space. Its set of almost 30,000 compounds is assembled from 29 established public and commercial libraries, with high Probes & Drugs portal: an interactive, open data resource for chemical biology

Supramolecular structures based on regioisomers of cinnamyl-α-cyclodextrins – new media for capillary separation techniques

Summary This work focuses on the preparation and application of supramolecular structures based on mono-cinnamyl-α-cyclodextrins (Cin-α-CD). Pure regioisomers of Cin-α-CD having the cinnamyl moiety at the 2-O- or at the 3-O-position, respectively, were prepared, characterized and applied in capillary electrophoresis as additives to the background electrolyte. These new monomer units with a potential to self-organize into supramolecular structures were synthesized via a straightforward one-step synthetic procedure and purified using preparative reversed-phase chromatography allowing a large scale separation of the regioisomers. The ability of the monomers to self-assemble was proved by various methods including NMR spectroscopy and dynamic light scattering (DLS). The light scattering experiments showed that the monomer units have distinguishable ability to form supramolecular structures in different solvents and the size distribution of the aggregates in water can be easily modulated using different external stimuli, such as temperature or competitive guest molecules. The obtained results indicated that the two regioisomers of Cin-α-CD formed different supramolecular assemblies highlighting the fact that the position of the cinnamyl group plays an important role in the intermolecular complex formation.

Use of 6-O-mono-substituted derivatives of β-cyclodextrin-bearing substituent with two permanent positive charges in capillary electrophoresis

This study details the use of two permanently positively charged mono-substituted β-cyclodextrin derivatives, 6I -deoxy-6I-(N,N N′,N′,Nt’-pentamethyl-ethylene-1,2-diammonio)-cyclomaltoheptose dichloride (PEMEDA-β-CD) and the newly synthesised 6I-deoxy-6I-(N,N,N′,N′,N′-pentamethyl-propylene-1,3-diammonio)-cyclomaltoheptose (PEMPDA-β-CD) as chiral selectors in capillary electrophoresis. Cyclodextrin (CD) derivatives were tested as additives in various buffers at various pH values with the optional addition of an organic modifier. Fourteen anionogenic analytes were tested, including native amino acids, N-blocked amino acids and profens, which were detected using a UV-VIS detector at optimal wavelengths of 214 nm, 254 nm or 280 nm. A borate buffer (15 mmol L−1) at pH 9.5 without the addition of an organic modifier was chosen as a suitable background electrolyte. In addition, the effect of the concentration of the chiral selector on the separation and enantioseparation of selected analytes was monitored. The additions of cyclodextrin derivatives varied within the concentration range of 0.0–5.0 mmol L−1. Both chiral selectors were suitable for the enantioseparation of N-Boc-d,l-tryptophan, which was already separated on the baseline at 0.5 mmol L−1 concentration of the chiral selector.

Zebrabase: An Intuitive Tracking Solution for Aquatic Model Organisms

Abstract Small fish species, such as zebrafish and medaka, are increasingly gaining popularity in basic research and disease modeling as a useful alternative to rodent model organisms. However, the tracking options for fish within a facility are rather limited. In this study, we present an aquatic species tracking database, Zebrabase, developed in our zebrafish research and breeding facility that represents a practical and scalable solution and an intuitive platform for scientists, fish managers, and caretakers, in both small and large facilities. Zebrabase is a scalable, cross-platform fish tracking database developed especially for fish research facilities. Nevertheless, this platform can be easily adapted for a wide variety of aquatic model organisms housed in tanks. It provides sophisticated tracking, reporting, and management functions that help keep animal-related records well organized, including a QR code functionality for tank labeling. The implementation of various user roles ensures a functional hierarchy and customized access to specific functions and data. In addition, Zebrabase makes it easy to personalize rooms and racks, and its advanced statistics and reporting options make it an excellent tool for creating periodic reports of animal usage and productivity. Communication between the facility and the researchers can be streamlined by the database functions. Finally, Zebrabase also features an interactive breeding history and a smart interface with advanced visualizations and intuitive color coding that accelerate the processes.

Optical porous-silicon-based sensors with chemically modified surface for detection of organic vapors

Photoluminescence quenching response of as prepared and surface modified porous silicon sensors in presence of organic analytes in gas phase was studied. Surface modification aimed at increasing of operational stability and modification of sensoric response was performed by a hydrosilylation reaction with various organic compounds - methyl 10-undecenoate, haemin, cinchonine and quinine. These sensors were tested for a homological set of aliphatic alcohols from methanol to hexanol. We have systematically measured changes in porous silicon photoluminescence intensity as a function of concentration of detected analytes and evaluated sensitivity, detection limit and linear dynamic range of our sensors. Speed of the sensoric response was of the order of seconds. The obtained sensoric parameters were correlated with chemical and physical properties of both the compounds used for derivatization and the detected analytes.

SYNTHESIS OF 21,31-O-(PROPANE-1,2-DIYL)- AND 21,31-O-(3-HYDROXYPROPANE-1,2-DIYL)-CYCLOMALTOHEPTAOSE

Abstract 2 1 ,3 1 - O -(Propane-1,2-diyl)cyclomaltoheptaose has been prepared from 2- O -allylcyclomaltoheptaose by mercuration in trifluoroacetic acid, followed by reduction with sodium borohydride. 2- O -(2,3-Epoxypropyl)cyclomaltoheptaose, prepared from 2- O -allylcyclomaltoheptaose by oxidation with dimethyldioxirane, was converted into 2 1 ,3 1 - O -(3-hydroxypropane-1,2-diyl)cyclomaltoheptaose by treatment with trifluoroacetic acid. Both derivatives containing fused 1,4-dioxane rings are mixtures of stereoisomers, in which the methyl and hydroxymethyl group, respectively, that is linked to this ring, occupies an axial or an equatorial position.