Pharmacological Evidence on Augmented Antiallodynia Following Systemic Co-Treatment with GlyT-1 and GlyT-2 Inhibitors in Rat Neuropathic Pain Model

The limited effect of current medications on neuropathic pain (NP) has initiated large efforts to develop effective treatments. Animal studies showed that glycine transporter (GlyT) inhibitors are promising analgesics in NP, though concerns regarding adverse effects were raised. We aimed to study NFPS and Org-25543, GlyT-1 and GlyT-2 inhibitors, respectively and their combination in rat mononeuropathic pain evoked by partial sciatic nerve ligation. Cerebrospinal fluid (CSF) glycine content was also determined by capillary electrophoresis. Subcutaneous (s.c.) 4 mg/kg NFPS or Org-25543 showed analgesia following acute administration (30–60 min). Small doses of each compound failed to produce antiallodynia up to 180 min after the acute administration. However, NFPS (1 mg/kg) produced antiallodynia after four days of treatment. Co-treatment with subanalgesic doses of NFPS (1 mg/kg) and Org-25543 (2 mg/kg) produced analgesia at 60 min and thereafter meanwhile increased significantly the CSF glycine content. This combination alleviated NP without affecting motor function. Test compounds failed to activate G-proteins in spinal cord. To the best of our knowledge for the first time we demonstrated augmented analgesia by combining GlyT-1 and 2 inhibitors. Increased CSF glycine content supports involvement of glycinergic system. Combining selective GlyT inhibitors or developing non-selective GlyT inhibitors might have therapeutic value in NP.     

Stimulatory effect of ascorbate,the alternative electron donor of photosystem II,on the hydrogen production of sulphur-deprived Chlamydomonas reinhardtii

The green alga Chlamydomonas reinhardtii is capable of photoproducing molecular hydrogen following sulphur deprivation, which results in anaerobiosis and a suppression of oxygen evolution and thus an alleviation of the inhibitory effect of oxygen on the hydrogenase. At the same time it transiently maintains a limited supply of electrons arising from photosystem II (PSII) to the hydrogenase (Melis and Happe Plant Physiol 2001; 127:740–748). In this work, using fast chl a fluorescence and P700 measurements, we show that ascorbate (Asc), a naturally occurring PSII alternative electron donor, is capable of donating electrons to PSII in heat-treated and sulphur-deprived cells and this can be significantly accelerated by supplementing the culture with 10 mM Asc. It also enhances, about three-fold, the photoproduction of hydrogen in cells subjected to sulphur deprivation as shown by gas chromatography. Similar stimulation was obtained in the presence of diphenylcarbazide (DPC), an artificial PSII electron donor. Asc and DPC also facilitated the anaerobiosis of cells, probably via super reducing the oxygen evolving complex while feeding electrons to PSII reaction centres and the linear electron transport chain, and ultimately to the hydrogenase – as shown by the significant DCMU-sensitivity of the light-induced Asc- and DPC-dependent re-reduction of P700⁺ and hydrogen evolution.     

Synthesis and Cell Growth Inhibitory Activity of Six Non-glycosaminoglycan-Type Heparin-Analogue Trisaccharides

The design and synthesis of heparin mimetics with high anticancer activity but no anticoagulant activity is an important task in medicinal chemistry. Herein, we present the efficient synthesis of five Glc-GlcA-Glc-sequenced and one Glc-IdoA-Glc-sequenced non-glycosaminoglycan, heparin-related trisaccharides with various sulfation/sulfonylation and methylation patterns. The cell growth inhibitory effects of the compounds were tested against four cancerous human cell lines and two non-cancerous cell lines. Two d -glucuronate-containing tetra-O-sulfated, partially methylated trisaccharides displayed remarkable and selective inhibitory effects on the growth of ovary carcinoma (A2780) and melanoma (WM35) cells. Methyl substituents on the glucuronide unit proved to be detrimental, whereas acetyl substituents were beneficial to the cytostatic activity of the sulfated derivatives.     

The Irritant Effects of Pharmaceutically Applied Surfactants

Dermal or transdermal medication may lead to irritant contact dermatitis. However, little information is available on the irritant effect of surfactants which are applied in topical formulations. Our aim was to examine the irritant effect of the most frequent compounds in topical products. A murine model was applied. The following compounds were examined: sodium lauryl sulphate (SLS), polyethoxylated (40EO) hydrogenated castor oil and sucrose laurate. SLS led to severe erythema, increase in transepidermal water loss (TEWL) and induced necrosis and accumulation of neutrophylic granulocytes and lymphocytes. Exposure to sucrose laurate resulted in an elevation of TEWL, but histology did not reveal impairment of the skin structure. Application of polyethoxylated (40EO) hydrogenated castor oil was not accompanied by tissue damage. Special attention should be paid to the irritant effect of SLS. Polyethoxylated (40EO) hydrogenated castor oil seems to be a non-irritant agent and sucrose laurate is also a promising candidate for application in topical preparations.     

Modification of cellulose acetate with oligomeric polycaprolactone by reactive processing: Efficiency,compatibility, and properties

Oligomeric polycaprolactone (oPCL) was used for the modification of cellulose acetate by reactive processing in an internal mixer at 180°C, 50 rpm, 60 min reaction time, and 45 wt % caprolactone (CL) content. The product of the reaction was characterized by several analytical techniques and its mechanical properties were determined by dynamic mechanical thermal analysis and tensile testing. The synthesized oPCL contained small and large molecular weight components. The small molecular weight fraction plasticized cellulose acetate externally and helped fusion. Although composition and structure did not differ considerably from each other when CL monomer or polycaprolactone oligomer was used for modification, the grafting of a few long chains had considerable effect on some properties of the product. The large molecular weight chains attached to CA increased the viscosity of the melt considerably and resulted in larger deformability. oPCL homopolymer is not miscible with cellulose acetate and migrates to the surface of the polymer. Exuded polycaprolactone oligomers crystallize on the surface but can be removed very easily. More intense conditions may favor the grafting of long chains leading to polymers with advantageous properties. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

The Effect of Electroporation of a Lyotroic Liquid Crystal Genistein-Based Formulation in the Recovery of Murine Melanoma Lesions

A lamellar lyotropic liquid crystal genistein-based formulation (LLC-Gen) was prepared in order to increase the aqueous solubility of the lipophilic phytocompound genistein. The formulation was applied locally, in a murine model of melanoma, with or without electroporation. The results demonstrated that, when the formulation was applied by electroporation, the tumors appeared later. During the 21 days of the experiment, the LLC-Gen formulation decreased the tumor volume, the amount of melanin and the degree of erythema, but when electroporation was applied, all these parameters indicated a better prognosis even (lower tumor volume, amount of melanin and degree of erythema). Although hematoxylin–eosin (HE) staining confirmed the above events, application of the LLC-Gen formulation by electroporation did not lead to a significant effect in terms of the serum concentrations of the protein S100B and serum neuron specific enolase (NSE), or the tissue expression of the platelet-derived growth factor receptor β (PDGFRβ) antibody.     

Effects of Sulforaphane-Induced Cell Death upon Repeated Passage of Either P-Glycoprotein-Negative or P-Glycoprotein-Positive L1210 Cell Variants

The expression of the membrane ABCB1 transporter in neoplastic cells is one of the most common causes of reduced sensitivity to chemotherapy. In our previous study, we investigated the effect of a single culture of ABCB1-negative (S) and ABCB1-positive variants of L1210 cells (R and T) in the presence of sulforaphane (SFN). We demonstrated that SFN induces the onset of autophagy more markedly in S cells than in R or T cells. In the current study, we focused on the effect of the repeated culture of S, R and T cells in SFN-containing media. The repeated cultures increased the onset of autophagy compared to the simple culture, mainly in S cells and to a lesser extent in R and T cells, as indicated by changes in the cellular content of 16 and 18 kDa fragments of LC3B protein or changes in the specific staining of cells with monodansylcadaverine. We conclude that SFN affects ABCB1-negative S cells more than ABCB1-positive R and T cells during repeated culturing. Changes in cell sensitivity to SFN appear to be related to the expression of genes for cell-cycle checkpoints, such as cyclins and cyclin-dependent kinases.     

Effect of the solid precursors on the formation of nanosized TiBx powders in RF thermal plasma

Continuous synthesis of TiB_x (x≈0.5–2) nanoparticles from various low cost solid precursors such as titanium and titanium dioxide admixed with boron and/or carbon in radiofrequency thermal plasma was studied. Feasibility of TiB₂ formation was predicted by thermodynamic equilibrium calculations in the 500–5000 K temperature range. In all the investigated system high temperature reactions resulted in nanometer-sized TiB_x powders with a mean size varying between 13 and 83 nm. The yield of particular runs ranged from 38% to 97%. Among the synthesized products in addition to TiB_x, oxidized precursor residues were also found in smaller quantities. Although addition of carbon to the precursors could not completely prevent surface oxidation of boride particles, it contributed to the reduction of the mean particle size of the formed TiB₂.     

Fractal properties of AlGeNi layers on GaAs surfaces

The thermal interactions of thin AlGe and AlNiGe layers with a bulk GaAs monocrystal were investigated. The heat treatment of these systems was carried out in the working chamber of a scanning electron microscope. The SEM pictures were analysed using a fractal mathematical technique. It was found that the surface of the samples has fractal character. No temperature dependence of the fractal dimension was observed. The samples were also studied using the structural entropy versus filling factor maps of the samples in order to find their localization properties. The SEM pictures of AlGe perform mostly as a Gaussian functions, whereas the AlNiGe samples show usually a behaviour with exponential decay.