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.     

Theoretical model for calculation of breakdown voltage of implanted p-n junctions

Avalanche breakdown voltage (ABV) of an implanted planar p-n junction was calculated taking the junction curvature into consideration. Curvature was determined from the two-dimensional form of LSS-profiles incorporating lateral spread of implanted ions. Supposing a one-sided abrupt junction, theoretical ABVs are compared with experimental values. The junctions were produced by 20–80 keV boron implantation into 〈111〉 oriented, 1·5 ohmcm silicon. The structure was gate-controlled to set the surface into flat-band condition. The model satisfactorily describes the ABVs of fully annealed implanted planar junctions. For partially annealed diodes, the increase in ABV was attributed to effective curvature due to the depth-dependence of the electrically active portion.     

Methionine metabolism. 2. Biochemical and histological studies in rats]

Male rats weighing 100 g were used in a 19-day trial. The rats received diets containing varying proportions of methionine. Their absolute liver weight was lower, due to the high methionine levels, than that of the animals fed optimum rations, whereas the relative liver weight was found to be lower only in the pair-fed group. No essential differences were observed between the levels of dry matter, protein, and fat. Glycogen levels were found to be lowered only in cases when high methionine doses were administered. Pathologically low levels of glycogen were found in animals of the pair-fed group. High methionine consumption reduced the percentages of 12 glucogenetic amino acids in the liver. This, in turn, suggests an increased rate of glucose formation from amino acids, a process which was not observed in animals of the pair-fed group. High methionine doses produced a condition of hyperglycaemia, while in the pair-fed group hypoglycaemia was observed. The highest rate of secretion of thyroid hormones was found in animals receiving the optimum ration; a lower rate of secretion was observed in the animals consuming less or more methionine. In animals receiving high methionine levels the rate of hormone secretion decreased in a stepwise manner with increasing methionine supplementation. Only the highest methionine doses (5,3%) were found to have a negative effect on the maximum rate of iodine incorporation into the thyroid gland. These findings were also substantiated by histological investigations because a true pathological picture was only found in histological sections of thyroid tissue from animals fed the highest methionine doses (5,3%) The thyroid tissue of these animals consisted predominantly of small glandular alveoli whose colloid was slightly coloured. The epithelial cells of these alveoli were degenerated; some cases of liver cell disintegration and, more rarely, cellular necrosis were noted.     

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.     

Global Approach of Tribomechanical Development of Hybrid Aluminium Matrix Syntactic Foams

Hybrid syntactic foams with AlSi12 aluminium matrix were produced by pressure infiltration. The volume ratio of iron to ceramic hollow sphere reinforcement (in the same size range) was varied, and hybrid syntactic foams were also produced with bimodal size ceramic reinforcement. Previously, a very detailed analysis of the mechanical properties of the composites was made with quasi-static compression tests, and their tribological properties were investigated by pin-on-disc method in dry and lubricated conditions. The present article establishes and clarifies the correlations between mechanical and tribological properties. The coefficient of friction, height loss of the specimens and specific wear showed good correlation with different mechanical parameters, e.g. density, structural stiffness and yield strength. The established trends and correlations between mechanical and tribological behaviour enable a better understanding of materials design and selection for further applications of mechanically loaded sliding machine parts.