Cyclolab Ltd.

Budapest, Hungary

Cyclolab Ltd.

Budapest, Hungary
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Horvath G.,University of Pécs | Szoke E.,University of Pécs | Kemeny A.,University of Pécs | Bagoly T.,University of Pécs | And 7 more authors.
Journal of Molecular Neuroscience | Year: 2012

Transient receptor potential (TRP) ion channels, such as TRP vanilloid 1 and ankyrin repeat domain 1 (TRPV1 and TRPA1), are expressed on primary sensory neurons. Lutein, a natural tetraterpene carotenoid, can be incorporated into membranes and might modulate TRP channels. Therefore, the effects of the water-soluble randomly methylated-β-cyclodextrin (RAMEB) complex of lutein were investigated on TRPV1 and TRPA1 activation. RAMEB-lutein (100 μM) significantly diminished Ca2+influx to cultured rat trigeminal neurons induced by TRPA1 activation with mustard oil, but not by TRPV1 stimulation with capsaicin, as determined with microfluorimetry. Calcitonin gene-related peptide release from afferents of isolated tracheae evoked by mustard oil, but not by capsaicin, was inhibited by RAMEB-lutein. Mustard oilinduced neurogenic mouse ear swelling was also significantly decreased by 100 μg/ml s.c. RAMEB-lutein pretreatment, while capsaicin-evoked edema was not altered. Myeloperoxidase activity indicating non-neurogenic granulocyte accumulation in the ear was not influenced by RAMEB-lutein in either case. It is concluded that lutein inhibits TRPA1, but not TRPV1 stimulation-induced responses on cell bodies and peripheral terminals of sensory neurons in vitro and in vivo. Based on these distinct actions and the carotenoid structure, the ability of lutein to modulate lipid rafts in the membrane around TRP channels can be suggested. © Springer Science+Business Media, LLC 2011.


PubMed | Cyclolab Ltd., University Claude Bernard Lyon 1, Hungarian Academy of Sciences and Debrecen University
Type: Journal Article | Journal: Molecules (Basel, Switzerland) | Year: 2015

Cyclodextrins, even the 6-membered -cyclodextrin, are approved in the various pharmacopoeias as pharmaceutical excipients for solubilizing and stabilizing drugs as well as for controlling drug release. Recently -cyclodextrin has also been marketed as health food with beneficial effects on blood lipid profiles. However, the concentration of -cyclodextrin used may be very high in these cases, and its toxic attributes have to be seriously considered. The objective of this study was to investigate the cytotoxicity of various, differently substituted -cyclodextrin derivatives and determine relationship between the structures and cytotoxicity. Three different methods were used, viability tests (MTT assay and Real Time Cell Electronic Sensing on Caco-2 cells) as well as hemolysis test on human red blood cells. The effect of -cyclodextrin derivatives resulted in concentration-dependent cytotoxicity, so the IC50 values have been determined. Based on our evaluation, the Real Time Cell Electronic Sensing method is the most accurate for describing the time and concentration dependency of the observed toxic effects. Regarding the cytotoxicity on Caco-2 cells, phosphatidylcholine extraction may play a main role in the mechanism. Our results should provide help in selecting those -cyclodextrin derivatives which have the potential of being used safely in medical formulations.


Sohajda T.,Semmelweis University | Sohajda T.,Cyclolab Ltd. | Szakacs Z.,Gedeon Richter Plc Spectroscopic Research | Szente L.,Cyclolab Ltd. | And 2 more authors.
Electrophoresis | Year: 2012

The enantiomers of imperanene, a novel polyphenolic compound of Imperata cylindrica (L.), were separated via cyclodextrin-modified capillary electrophoresis. The anionic form of the analyte at pH 9.0 was subject to complexation and enantioseparation CE studies with neutral and charged cyclodextrins. As chiral selectors 27 CDs were applied differing in cavity size, sidechain, degree of substitution (DS) and charge. Three hydroxypropylated and three sulfoalkylated CD preparations provided enantioseparation and the migration order was successfully interpreted in each case in terms of complex mobilities and stability constants. The best enantioresolution (R S = 1.26) was achieved using sulfobutyl-ether-γ-CD (DS ∼4), but it could be enhanced by extensive investigations on dual selector systems. After optimization (CD concentrations and pH) R S = 4.47 was achieved using a 12.5 mM sulfobutyl-ether-γ-CD and 10 mM 6-monodeoxy-6-mono-(3-hydroxy)-propylamino-β-cyclodextrin dual system. The average stoichiometry of the complex was determined with Job's method using NMR-titration and resulted in a 1:1 complex for both (2-hydroxy)propyl-β- and sulfobutyl-ether-γ-CD. Further NMR experiments suggest that the coniferyl moiety of imperanene is involved in the host-guest interaction. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Milles S.,Humboldt University of Berlin | Meyer T.,University of Leipzig | Scheidt H.A.,University of Leipzig | Schwarzer R.,Humboldt University of Berlin | And 8 more authors.
Biochimica et Biophysica Acta - Biomembranes | Year: 2013

To characterize the structure and dynamics of cholesterol in membranes, fluorescent analogs of the native molecule have widely been employed. The cholesterol content in membranes is in general manipulated by using water-soluble cyclodextrins. Since the interactions between cyclodextrins and fluorescent-labeled cholesterol have not been investigated in detail so far, we have compared the cyclodextrin-mediated membrane extraction of three different fluorescent cholesterol analogs (one bearing a NBD and two bearing BODIPY moieties). Extraction of these analogs was followed by measuring the Förster resonance energy transfer between a rhodamine moiety linked to phosphatidylethanolamine and the labeled cholesterol. The extraction kinetics revealed that the analogs are differently extracted from membranes. We examined the orientation of the analogs within the membrane and their influence on lipid condensation using NMR and EPR spectroscopies. Our data indicate that the extraction of fluorescent sterols from membranes is determined by several parameters, including their impact on lipid order, their hydrophobicity, their intermolecular interactions with surrounding lipids, their orientation within the bilayer, and their affinity with the exogenous acceptor. © 2013 Elsevier B.V.


PubMed | Cyclolab Ltd., University of Leipzig and Humboldt University of Berlin
Type: | Journal: Chemistry and physics of lipids | Year: 2016

Fluorescent analogs of phospholipids are often employed to investigate the structure and dynamics of lipids in membranes. Some of those studies have used cyclodextrins e.g., to modulate the lipid phase. However, the role of the fluorescence moiety of analogs for the interaction between cyclodextrins and fluorescent lipids has not been investigated so far in detail. Therefore, in the present study the interaction of various fluorescent phospholipid analogs with methylated -, - and - cyclodextrins was investigated. The analogs differed in their structure, in the length of the fatty acyl chain, in the position of the fluorescence group, and in the attached fluorescence moiety (7-nitrobenz-2-oxa-1,3-diazol-4-yl (NBD) or dipyrrometheneboron difluoride (BODIPY)). In aqueous buffer, cyclodextrins bind fluorescent lipids disturbing the organization of the analogs. When incorporated into lipid vesicles, analogs are selectively extracted from the membrane upon addition of cyclodextrins. The results show that the interaction of cyclodextrins with fluorescent phospholipids depends on the cyclodextrin species, the fluorescence moiety and the phospholipid structure. The presented data should be of interest for studies using fluorescent phospholipids and cyclodextrins, since the interaction between the fluorescence group and the cyclodextrin may interfere with the process(es) under study.


Krumkacheva O.A.,Novosibirsk State University | Fedin M.V.,Russian Academy of Sciences | Polovyanenko D.N.,RAS Institute of Organic Chemistry | Jicsinszky L.,Cyclolab Ltd. | And 2 more authors.
Journal of Physical Chemistry B | Year: 2013

Design of the new spin-labeled cyclodextrins can significantly extend the functionality of nitroxides. A series of new complexes based on fully methylated cyclodextrin (TRIMEB) covalently bound to the piperidine, pyrroline, pyrrolidine, and pH-sensitive imidazoline type nitroxides has been synthesized and studied using pulse and continuous wave electron paramagnetic resonance (EPR). The influence of the radical and linker properties on the structure of complexes formed has been investigated. Using the electron spin echo envelope modulation technique, we have analyzed quantitatively the accessibility of radicals to solvent molecules in studied complexes depending on the structure and length of the linkers. In all studied systems we observed different types of equilibria between conformations with radical fragment being outside the TRIMEB cavity and radical fragment capping the cavity of TRIMEB. The observed guest-induced shift of equilibrium toward the complex with radical capping TRIMEB cavity was explained by a change of macrocyclic configuration of TRIMEB. Complex with the -NH-CO- linker has been found most perspective for the applications requiring close location of nitroxide to the inclusion complex of TRIMEB. Using continuous wave EPR, we have shown that the pH-sensitive radical covalently bound to TRIMEB maintains its pH-sensitivity, but this complexation does not reduce radical reduction rate in the reaction with ascorbic acid. © 2013 American Chemical Society.


Daruhazi A.E.,Semmelweis University | Kiss T.,Debrecen University | Vecsernyes M.,Debrecen University | Szente L.,CycloLab Ltd. | And 2 more authors.
Journal of Pharmaceutical and Biomedical Analysis | Year: 2013

Isoflavonoids are widespread constituents in medical plants especially in legumes (Fabaceae), but occur in other different plant families as well (Rosaceae, Iridaceae, Amaranthaceae). Their antioxidant, estrogen-like, anti-inflammatory and analgesic effects make them promising compounds in therapy of important disorders especially in estrogen related diseases. Poor solubility in aqueous system of genistein and daidzein needs a solubility enhancement for pharmaceutical use. These compounds are suitable guest molecules for inclusion complex formation with cyclodextrins (CDs) considering matching their size and polarity.The molecular encapsulation with beta-cyclodextrin (β-CD), gamma-cyclodextrin (γ-CD), hydroxypropyl-beta-cyclodextrin (HP-β-CD) and random methyl-beta cyclodextrin (RAMEB-CD) results in a solid, molecularly dispersed form and in a significantly improved aqueous solubility of genistein and daidzein. Determining enhancement in solubility and bioavailability we investigated the transport of these inclusion complexes across Caco-2 cell line comparing that of the pure compounds and found significant improving effect of the different CD derivatives on membrane permeation of the two isoflavone aglycons. © 2013 Elsevier B.V.


Horvath G.,University of Pécs | Kemeny A.,University of Pécs | Bartho L.,University of Pécs | Molnar P.,University of Pécs | And 8 more authors.
Journal of Molecular Neuroscience | Year: 2015

Mechanisms of the potent anti-inflammatory actions of carotenoids are unknown. Since carotenoids are incorporated into membranes, they might modulate transient receptor potential ankyrin 1 and vanilloid 1 (TRPA1 and TRPV1) activation predominantly on peptidergic sensory nerves. We therefore investigated the effects of three carotenoids (β-carotene, lutein and lycopene) on cutaneous neurogenic inflammation. Acute neurogenic edema and inflammatory cell recruitment were induced by smearing the TRPA1 agonist mustard oil (5 %) or the TRPV1 activator capsaicin (2.5 %) on the mouse ear. Ear thickness was then determined by micrometry, microcirculation by laser Doppler imaging and neutrophil accumulation by histopathology and spectrophotometric determination of myeloperoxidase activity. The effects of lutein on the stimulatory action of the TRPA1 agonist mustard oil were also tested on the guinea-pig small intestine, in isolated organ experiments. Mustard oil evoked 50–55 % ear edema and granulocyte influx, as shown by histology and myeloperoxidase activity. Swelling was significantly reduced between 2 and 4 h after administration of lutein or β-carotene (100 mg/kg subcutane three times during 24 h). Lutein also decreased neutrophil accumulation induced by TRPA1 activation, but did not affect mustard oil-evoked intestinal contraction. Lycopene had no effect on any of these parameters. None of the three carotenoids altered capsaicin-evoked inflammation. It is proposed that the dihydroxycarotenoid lutein selectively inhibits TRPA1 activation and consequent neurogenic inflammation, possibly by modulating lipid rafts. © 2015, Springer Science+Business Media New York.


Sohajda T.,Semmelweis University | Hu W.H.,Chinese Academy of Sciences | Zeng L.L.,Chinese Academy of Sciences | Li H.,Chinese Academy of Sciences | And 3 more authors.
Electrophoresis | Year: 2011

An aqueous capillary electrophoretic method was developed for chiral analysis of the novel anti-diabetic drug, sitagliptin. The acid-base profiling of the analyte was carried out using both capillary electrophoresis and nuclear magnetic resonance pH titrations. The apparent complex stability and chiral separation properties were investigated with 30 different cyclodextrins under acidic conditions. The effect of concentration and pH of the BGE, temperature of the capillary, and the type and concentration of the chiral selector on the enantiomer resolution were thoroughly investigated. The effects of dual cyclodextrin systems on separation were also extensively studied. Complete separation of racemic sitagliptin with good resolution (R S=2.24) was achieved within a short time (15min) with optimized parameters (10°C, pH=4.4, 40mM phosphate buffer) of a sulfobutylether-β-cyclodextrin (averaged degree of substitution ~4) and native β-cyclodextrin dual system. The averaged stoichiometry of the inclusion complex was determined using the Job plot method with both 1H and 19F NMR experiments and resulted in a 1:1 complex. The structure of the inclusion complex was elucidated using 2-D ROESY NMR experiments. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Beni S.,Semmelweis University | Sohajda T.,Semmelweis University | Neumajer G.,Semmelweis University | Ivanyi R.,Cyclolab Ltd. | And 2 more authors.
Journal of Pharmaceutical and Biomedical Analysis | Year: 2010

The (S)-(+)-isomer of 3-isobutyl-GABA (pregabalin), the blockbuster drug in the treatment of neuropathic pain has been separated from its R isomer by cyclodextrin modified capillary zone electrophoresis (CZE) using uncoated fused-silica capillary. Derivatization of the single isomer and the racemate with tosyl- and dansyl-chloride was carried out to introduce strong UV chromophores of different size. CE-pH titrations were performed to determine the dissociation constants for both derivatives. 30 cyclodextrin (CD) derivatives as chiral agents were used at four different pH values to study the enantioseparation of the differently protonated guest molecules. The separation was optimized as a function of CD concentration, buffer type and concentration, pH and applied voltage. For the tosylated derivate the best resolution (Rs = 2.76) was found with 6-monodeoxy-6-mono-(3-hydroxy)-propylamino-beta-cyclodextrin hydrochloride (PA-β-CD) at pH 6.8, while with the same selector at pH 7.2 enantioseparation with an Rs value of 4.32 could be achieved for the dansylated pregabalin. At pH 2.5 for the dansylated derivative trimethylated alpha- and beta-CD systems resulted the most significant separation (Rs = 7.38 and Rs = 7.74, respectively). Experiments with dual CD systems were carried out as well. The stoichiometry of the complexes was determined using the Job plot method and resulted in a 1:1 complex in both cases. The structures of the inclusion complexes were elucidated using 2D ROESY NMR experiments. © 2009 Elsevier B.V. All rights reserved.

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