Stereochemistry of phase-1 metabolites of mephedrone determines their effectiveness as releasers at the serotonin transporter

Mephedrone (4-methyl-N-methylcathinone) is a psychostimulant that promotes release of monoamines via the high affinity transporters for dopamine (DAT), norepinephrine (NET) and serotonin (SERT). Metabolic breakdown of mephedrone results in bioactive metabolites that act as substrate-type releasers at monoamine transporters and stereospecific metabolism of mephedrone has been reported. This study compared the effects of the enantiomers of the phase-1 metabolites nor-mephedrone, 4-hydroxytolyl-mephedrone (4-OH-mephedrone) and dihydro-mephedrone on (i) DAT, NET and SERT mediated substrate fluxes, (ii) determined their binding affinities towards a battery of monoamine receptors and (iii) examined the relative abundance of the enantiomers in human urine. Each of the enantiomers tested inhibited uptake mediated by DAT, NET and SERT. No marked differences were detected at DAT and NET. However, at SERT, the S-enantiomers of nor-mephedrone and 4-OH-mephedrone were several times more potent than the corresponding R-enantiomers. Moreover, the R-enantiomers were markedly less effective as releasers at SERT. S-nor-mephedrone displayed moderate affinities towards human alpha; 1A; , human 5-HT; 2A; and rat and mouse trace amine-associated receptor 1. These results demonstrate that stereochemistry dictates the pharmacodynamics of the phase-1 metabolites of mephedrone at SERT, but not at DAT and NET, which manifests in marked differences in their relative potencies, i.e. DAT/SERT ratios. Chiral analysis of urine samples demonstrated that nor-mephedrone predominantly exists as the S-enantiomer. Given the asymmetric abundance of the enantiomers in biological samples, these findings may add to our understanding of the subjective effects of administered mephedrone, which indicate pronounced effects on the serotonergic system

Aptasensor platform based on carbon nanofibers enriched screen printed electrodes for impedimetric detection of thrombin

WOS: 000367278400003Herein, impedimetric detection of THR could be achieved using an aptasensing platform based on carbon nano-fibers enriched screen-printed electrodes (CNF-SPE). The resistance to charge transfer (R-ct) was recorded using electrochemical impedance spectroscopy (EIS) technique before/after the immobilization of amino-modified DNA aptamer (APT) selective to thrombin (THR) onto the surface of CNF-SPEs and the specific interaction between APT and THR. The selectivity of the aptasensor was also tested in the presence of a random DNA oligonucleotide and a DNA aptamer that were different from THR specific APT. The impedimetric aptasensing of target protein was also explored in the fetal bovine serum (FBS) medium at different concentration levels of THR. Additionally, the selectivity of the aptasensor was tested against bovine serum albumin (BSA) and protein C (PC) in FBS medium. This CNF-SPE based aptasensor platform allows a reliable, sensitive and selective impedimetric monitoring of THR. (C) 2015 Elsevier B.V. All rights reserved

Fixed Future and Uncertain Past: Theorems Explain Why It Is Often More Difficult to Reconstruct the Past Than to Predict the Future

At first glance. it may seem that reconstructing the past is, in general, easier than predicting the future, because the past has already occurred and it has already left its traces, while the future is still yet to come, and so no traces of the future are available. However, in many real life situations, including problems from geophysics and celestial mechanics, reconstructing the past is much more computationally difficult than predicting the future. In this paper, we give an explanation of this difficulty. This explanation is given both on a formal level (as a theorem) and on the informal level (as a more intuitive explanation)

Fachbereich Mathematik

In many practical applications, we are interested in computing the product of given matrices and/or a power of a given matrix. In some cases, the initial matrices are only known with interval uncertainty. It turns out that under this uncertainty, there is a principal difference between the product of two matrices and the product of three (or more) matrices: • on the one hand, it is more or less known that the problems of computing the exact range for the product of two matrices – and for the square of a matrix – are computationally feasible; • on the other hand, we prove that the problems of computing the exact ranges for the product of three matrices – and for the third power of a matrix – are NP-hard

Towards a General Description of Interval Multiplications: Algebraic Analysis and Its Relation to t-Norms

Abstract—It is well known that interval computations are very important, both by themselves (as a method for processing data known with interval uncertainty) and as a way to process fuzzy data. In general, the problem of computing the range of a given function under interval uncertainty is computationally dif cult (NP-hard). As a result, there exist different methods for estimating such a range: some methods require a longer computation time and lead to more accurate results, other methods lead to somewhat less accurate results but are much faster than the more accurate techniques. In particular, different methods exist for interval multiplication, i.e., for computing the range of a product of two numbers known with interval uncertainty. To select a method which is the best in a given situation, it is desired to be able to describe all possible methods. In this paper, we provide a description of all possible operations for interval multiplication; this description is based on the same ideas as a known description of t-norms in fuzzy logic. I. NEED FOR DATA PROCESSING In many real-life situations, we are interested in the value of a physical quantity y that is dif cult or impossible to measure directly. Examples of such quantities are the distance to a star and the amount of oil in a given well. Since we cannot measure y directly, a natural idea is to measure y indirectly. Speci-cally, we nd some easier-to-measure quantities x1,..., xn which are related to y by a known relation y = f(x1,..., xn); this relation may be a simple functional transformation, or complex algorithm (e.g., for the amount of oil, numerical solution to an inverse problem). Then, to estimate y, we rst measure the values of the quantities x1,..., xn, and then of these measurements to to we use the results ˜x1,..., ˜xn compute an estimate ˜y for y as ˜y = f(˜x1,..., ˜xn)

Characterization of the Inducible and Slow-Releasing Hydrogen Sulfide and Persulfide Donor P*: Insights into Hydrogen Sulfide Signaling

Hydrogen sulfide (H2S) is an important mediator of inflammatory processes. However, controversial findings also exist, and its underlying molecular mechanisms are largely unknown. Recently, the byproducts of H2S, per-/polysulfides, emerged as biological mediators themselves, highlighting the complex chemistry of H2S. In this study, we characterized the biological effects of P*, a slow-releasing H2S and persulfide donor. To differentiate between H2S and polysulfide-derived effects, we decomposed P* into polysulfides. P* was further compared to the commonly used fast-releasing H2S donor sodium hydrogen sulfide (NaHS). The effects on oxidative stress and interleukin-6 (IL-6) expression were assessed in ATDC5 cells using superoxide measurement, qPCR, ELISA, and Western blotting. The findings on IL-6 expression were corroborated in primary chondrocytes from osteoarthritis patients. In ATDC5 cells, P* not only induced the expression of the antioxidant enzyme heme oxygenase-1 via per-/polysulfides, but also induced activation of Akt and p38 MAPK. NaHS and P* significantly impaired menadione-induced superoxide production. P* reduced IL-6 levels in both ATDC5 cells and primary chondrocytes dependent on H2S release. Taken together, P* provides a valuable research tool for the investigation of H2S and per-/polysulfide signaling. These data demonstrate the importance of not only H2S, but also per-/polysulfides as bioactive signaling molecules with potent anti-inflammatory and, in particular, antioxidant properties