Pre-clinical evidences of the antileishmanial effects of diselenides and selenocyanates.

A series of thirty-one selenocompounds covering a wide chemical space was assessed for in vitro leishmanicidal activities against Leishmania infantum amastigotes. The cytotoxicity of those compounds was also evaluated on human THP-1 cells. Interestingly most tested derivatives were active in the low micromolar range and seven of them (A.I.3, A.I.7, B.I.1, B.I.2, C.I.7 C.I.8 and C.II.8) stood out for selectivity indexes higher than the ones exhibited by reference compounds mitelfosine and edelfosine. These leader compounds were evaluated against infected macrophages and their trypanothione reductase (TryR) inhibition potency was measured to further approach the mechanism by which they caused their action. Among them diselenide tested structures were pointed out for their ability to reduce infection rates. Three of the leader compounds inhibited TryR effectively, therefore this enzyme may be implicated in the mechanism of action by which these compounds cause their leishmanicidal effect.

Ex vivo nail infection as an effective preclinical method for screening of new topical antifungals.

Onychomycosis are fungal nail infections comprising of about 50% of onychopathies and are commonly caused by dermatophytes. The treatment of this dermatomycosis requires a long period of time and is associated with high rates of recurrence. In view of the need to evaluate the antifungal performance of promising preclinical compounds, we developed, in this study, a practical and accessibleex vivo model for establishing a Trichophyton rubrum onychomycosis framework using porcine hooves. This model has as its main advantage the similar structural and three-dimensional characteristics that the porcine hooves have with the human nail. The proposed model allowed to evaluate the antifungal activity of a new antifungal compound and a reference drug (terbinafine), both already incorporated into a nail lacquer for topical use. Treatments with compound 3-selenocyanate-indole (Se4a) and with terbinafine incorporated into this nail lacquer completely inhibited fungal growth, corresponding to the profile of in vitro activity observed against T. rubrum. This study concludes that the ex vivo porcine hoof model is an effective alternative method for preclinical screening of drugs or new topical compounds developed to combat onychomycosis. Further studies are needed to compare the permeability of porcine hooves with human nails permeability.

Intervention in cyclophosphamide induced oxidative stress and DNA damage by a flavonyl-thiazolidinedione based organoselenocyanate and evaluation of its efficacy during adjuvant therapy in tumor bearing mice.

A novel flavonyl-thiazolidinedione based organoselenocyanate compound was synthesized and established as nontoxic at the doses of 2.5 and 5 mg/kg b.w. in mice. Oral administration of the compound in combination with cyclophosphamide (CP) resulted in an improved therapeutic efficacy which was mostly evidenced in terms of tumor burden and protection of normal cells. The adjuvant therapy was proved to be immensely significant in increasing the mean survivability of the tumor bearing hosts. Reduction in the tumor volume was manifested through the induction of apoptosis and generation of ROS in transformed cells. Moreover, the organoselenium compound could efficiently suppress CP-induced DNA damage, chromosomal aberration, hepatic damage and enhanced the activities of various antioxidant enzymes in normal cells.

Effect of castor oil enrichment layer produced by reaction on the properties of PLA/HDI-g-starch blends.

Blends of entirely bio-sourced polymers, namely polylactide (PLA) and starch, have been melt-compounded by lab-scale co-extruder with castor oil (CO) as a plasticizer. The enrichment of castor oil on starch had great effect on the properties of the blends. If the castor oil was mainly dispersed in PLA matrix, the properties of the blends were poor, but when the hexamethylenediisocyanate (HDI) was grafted on starch granules the ready reactions between the hydroxyl on CO and the isocyante on the HDI-grafted starch (HGSTs) brought CO molecules enriched on starch particles. DSC analysis shows that the CO layer on starch has a positive effect on the crystallization of PLA in the ternary blend. The accumulation of CO on starch greatly improves the toughness and impact strength of PLA/starch blends. The grafting content of HDI on the starch granules primarily determined the compatibility and properties of the resulted blends.

Molecular simulation of fibronectin adsorption onto polyurethane surfaces.

Poly(ethylene glycol)-based polyurethanes have been widely used in biomedical applications; however, they are prone to swelling. A natural polyol, castor oil, can be incorporated into these polyurethanes to control the degree of the swelling, which alters mechanical properties and protein adsorption characteristic of the polymers. In this work, we modeled poly(ethylene glycol) and castor oil copolymers of hexamethylene diisocyanate-based polyurethanes (PEG-HDI and CO-HDI, respectively) and compared their mechanisms for fibronectin adsorption using molecular mechanics and molecular dynamics simulations. Results showed that the interplay between the hydrophobic residues concentrated at the N-terminal end of the protein, the surface roughness, and the hydrophilicity of the polymer surface determine the overall protein adsorption affinity. Incorporating explicit water molecules in the simulations results in higher affinity for fibronectin adsorption to more hydrophobic surface of CO-HDI surfaces, emphasizing the role that water molecules play during adsorption. We also observed that the strain energies that are indicative of flexibility and consequently entropy are significantly affected by the changes in the patterns of ß-sheet formation/breaking. Our study lends supports to the view that while castor oil controls the degree of swelling, it increases the adsorption of fibronectin to a limited extent due to the interplay between its hydrophobicity and its surface roughness, which needs to be taken into account during the design of polyurethane-based biomaterials.

Supercritical fluid chromatography of myrosinase reaction products in ground yellow mustard seed oil.

UNLABELLED: Escherichia coli O157:H7 can survive the dry fermented sausage manufacturing process. Compounds generated by enzymatic hydrolysis of glucosinolates present in ground mustard have shown potential antibacterial properties against E. coli O157:H7. In the present study, supercritical fluid chromatography (SFC) was used to investigate degradation products of 4-hydroxybenzyl glucosinolate (sinalbin), the major glucosinolate present in yellow mustard seed. Using SFC the concentration of the reactive component, 4-hydroxybenzyl isothiocyanate (PHBITC) was measured during the hydrolysis of sinalbin with myrosinase while imposing the temperature and pH regimen used for the fermentation phase of dry fermented sausage production. The PHBITC concentration grew to a maximum after 7 h and decreased rapidly. The concentration of 4-hydroxybenzyl alcohol increased rapidly to reach a maximum at 31 h and stayed at that level. The concentration of 4-hydroxybenzyl cyanate increased up to 24 h, then decreased to 65% of its maximum, and stayed constant. The stability of 4-hydroxybenzyl isothiocyanate in the presence of maltodextrin in this system was investigated. It was concluded that the major PHBITC loss in the mixture of the oil with maltodextrin occurred within the first 4 d of its storage. PRACTICAL APPLICATION: During the work 4-hydroxybenzyl isothiocyanate (PHBITC) was measured during the hydrolysis of sinalbin with myrosinase while imposing the temperature and pH regimen used for the fermentation phase of dry fermented sausage production. The results on PHBITC stability in maltodextrin presented provide precautionary information on the limited ability of this material to afford stability of PHBITC expected.

Fatty acid-derived diisocyanate and biobased polyurethane produced from vegetable oil: synthesis, polymerization, and characterization.

A new linear saturated terminal diisocyanate was synthesized from oleic acid via Curtius rearrangement, and its chemical structure was identified by FTIR, (1)H and (13)C NMR, and MS. The feasibility of utilizing this new diisocyanate for the production of polyurethanes (PUs) was demonstrated by reacting it with commercial petroleum-derived polyols and canola oil-derived polyols, respectively. The physical properties of the PUs prepared from fatty acid-derived diisocyanate were compared to those prepared from the same polyols with a similar but petroleum-derived commercially available diisocyanate: 1,6-hexamethylene diisocyanate. It was found that the fatty acid-derived diisocyanate was capable of producing PUs with comparable properties within acceptable tolerances. This work is the first that establishes the production of linear saturated terminal diisocyanate derived from fatty acids and corresponding PUs mostly from lipid feedstock.

Immobilization of oligonucleotides on poly(ethylene glycol) brush-coated Si surfaces.

High-density poly(ethylene glycol) (PEG) molecules are grafted onto Si surfaces in a brush-like configuration. We demonstrate that this surface is an excellent substrate for oligonucleotide immobilization. p-Maleimidophenyl isocyanate is used as a heterobifunctional cross-linker to tether thiol-modified oligonucleotides to terminal OH groups on the PEG brush. This approach gives excellent immobilization specificity and low background. The immobilized oligonucleotides show high sensitivity for the detection of complementary targets.

Evaluation of benzyl selenocyanate glutathione conjugate for potential chemopreventive properties in colon carcinogenesis.

Observational, clinical and experimental studies have suggested that dietary supplementation with selenium can inhibit the development of colon cancer. Since toxicity and chemopreventive efficacy of selenium compounds depend to a large extent, on the form of selenium the development of efficacious organoselenium compounds with low toxicity is being pursued in our laboratory. We have assessed the chemopreventive properties of a newly synthesized organoselenium compound, benzyl selenocyanate glutathione conjugate (BSeSG), and of benzyl selenocyanate (BSC), as a positive control, using azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) as a measure of efficacy. Five-week-old male F344 rats were fed the control diet (modified AIN-76A) or experimental diets containing 10 or 20 ppm BSeSG (1.7 and 3.4 ppm as Se, respectively), or 10 ppm BSC (4.1 ppm as Se). One week later, all animals except those in vehicle (normal saline)-treated groups were s.c. injected with AOM (15 mg/kg of body weight, once weekly for 2 weeks). All animals were sacrificed 7 weeks after the last AOM injection, and the ACF, levels of prostaglandin E2 (PGE2), cyclooxygenase protein expression (COX-1 and -2), and glutathione S-transferase type mu (GST-mu) were determined in the colon. As expected, dietary administration of BSC suppressed ACF development by about 37%. In rats administered 10 or 20 ppm BSeSG, the frequencies of AOM-induced colonic ACF were significantly decreased compared to those of rats given AOM and control diet by about 41% (P<0.01) and 61% (P<0.001), respectively. Administration of BSeSG inhibited PGE2 production (81-88% inhibition) via COX-2 synthesis in the colonic mucosa (18-60% inhibition). Also, BSeSG increased GST-mu protein activity in colonic mucosa (30-32% increase). These data suggest that a newly synthesized organoselenium compound, BSeSG might be a promising chemopreventive agent against colon carcinogenesis.

Viscoelastic stress analysis of thermally compatible and incompatible metal-ceramic systems.

OBJECTIVE: The purpose of this study was to analyze transient and residual midpoint deflections and stresses in metal-opaque porcelain-body porcelain systems with matched and mismatched thermal contraction coefficients. METHODS: Calculations and measurements were made for seven trimaterial strips that covered a wide range of thermal contraction mismatches among constituent materials. Midpoint deflections were measured in a beam-bending viscometer during slow cooling from an initial temperature of 700 degrees C. Linear regression analysis with a correlation coefficient of 0.950 was used to compare measured and calculated residual midpoint deflections. Stress relaxation data were fit to a three-term exponential series by nonlinear regression analyses with correlation ratios ranging from 0.9972 to 0.9999. RESULTS: While finite element analyses correctly predicted the general shape of the deflection behavior as a function of temperature for all combinations, the best agreement between measured mean residual midpoint deflections and calculated values (+250 microns vs. +268 microns) was obtained for strips composed of a Au-Pd alloy (alpha m = 13.5 ppm/ degree C) with a medium expansion opaque porcelain (alpha o = 13.3 ppm/degree C) and a high expansion body porcelain (alpha B = 14.4 ppm/degree C). The highest calculated residual tensile stress of +26 MPa at the surface of body porcelain was associated with the 0.5-mm-thick Ni-Cr-Be alloy strip (alpha m = 15.1 ppm/degree C) with medium expansion porcelains (alpha o = 13.5 ppm/degree C and alpha B = 13.9 ppm/degree C). The smallest measured residual deflection (+10 microns) was also associated with this combination. The results of this study indicated that metal-ceramic strips are sensitive indicators of stress development caused by a thermal contraction mismatch; however, the magnitudes of the residual deflections do not necessarily correlate with the stress magnitudes in the ceramic. SIGNIFICANCE: Currently there are no U.S. or international standards that define the maximum difference in thermal contraction coefficients that can exist between a metal and its ceramic veneer without causing transient failures of ceramic during cooling or delayed failures in ceramic because of high residual tensile stresses. The present research represents a major step in understanding the various factors that influence the development of transient and residual stresses. A knowledge of the effects of process variables on stress development is necessary for selection of potentially successful metal-ceramic systems and for optimizing the design of dental prostheses.